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Stereoselective nucleophilic fluoromethylations: from methodology to mechanistic studies

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Stereoselective nucleophilic fluoromethylations: from methodology to mechanistic studies

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STEREOSELECTIVE NUCLEOPHILIC FLUOROMETHYLATIONS:
FROM METHODOLOGY TO MECHANISTIC STUDIES

By

Fang Wang

A Dissertation Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(Chemistry)

December 2012

Copyright 2012 Fang Wang
ii

Dedication

To Professor George A. Olah and Professor G. K. Surya Prakash

iii

Acknowledgments
First and foremost, I would like to thank Professor G. K. Surya Prakash, who has
been a wonderful and forever-supportive mentor to me. Since the inception of my
graduate education, Professor Prakash has always given much invaluable guidance over
the course of my research projects, making them possible and successful. His exceptional
knowledge, innovative ideas, and intellectual insight into chemistry have always been
tremendously helpful. Professor Prakash also cultivates an absolutely free and stimulating
research environment, which has allowed me to explore many of my own ideas with his
strong support and encouragement. His excellent mentorship has offered me great
opportunities to train myself as a qualified scientist, and I believe there is no better
mentor for me to pursue my doctoral research with. I have learnt so much from you,
Professor Prakash!
I am grateful to Professor George A. Olah for his helpful advice during my Ph.D.
study and critical comments on some of my doctoral work. It has been a privilege to
attend our weekly group meeting and listen to Professor Olah’s thoughtful comments on
chemistry, society, history, and philosophy. His broad perspective on chemistry and keen
chemical sense have led me to tackle more fundamental problems in chemistry, instead of
just pursuing decent publications or footnote-of-footnote-type scientific research.
Certainly, his direct and indirect guidance has led me to rethink my scientific career and
has made me a better chemist.
iv

Professor Karl O. Christe is probably one of the most unique professors I have ever
met by far. During my last few years in Ph.D. study, I happened to get a spot in one of
Karl’s offices and thus have been lucky to interact with him (and his crew). His
invaluable suggestions and encouragements over many things have had tremendous
positive influence on both my chemical and non-chemical life. His great sense of humor
has always helped me release day-to-day stresses. Finally, I also would like to thank him
for being my fencing coach and my Mandarin tutor.
Professor Thieo E. Hogen-Esch and Professor Katherine Shing have served on my
thesis committee since my second year at USC. I am grateful for their time and advice for
my study in graduate school. I would like to thank Professor Travis J. Williams, who is a
brilliant and extremely helpful chemist, for his comments on Chapter 6 of the thesis and
many discussions on reaction kinetics and NMR spectroscopy. Professor Ralf Haiges is
gratefully thanked for solving all the crystal structures in the thesis. Without these data,
much of my work would not be accomplished.
Dr. Thomas Mathew is to be thanked for his mentorship, tremendous support and
friendship. Among all things I learned from him over the years, I would like to thank him
particularly for his collaboration on many projects, teaching me how to write properly
and scientifically, and, most importantly, showing me how to become a nice person.
Professor Golam Rasul has taught me many fundamentals in computational
chemistry, which benefited me enormously during my Ph.D. study. I also wish to thank
him for his constant support.
v

According to Confucianism, “Once being my Mentor, being my Mentor Forever”. I
thus would like to heartily thank two of my undergrad mentors, Professor Ping Lu at the
Zhejiang University and Professor Jinbo Hu at the Shanghai Institute of Organic
Chemistry (SIOC), for fostering my scientific development and reshaping my life.
Professor Lu enlightened me on organic chemistry, basic laboratory training (particularly
column chromatography) and even English. Without her encouragement, I would not
have had the confidence to apply to USC and to join LHI. Professor Hu introduced me
into the field of organofluorine chemistry in his lab at SIOC and is also largely
responsible for me joining the research group led by Professors Olah and Prakash. I
would like to thank both of them again for their tremendous help over years.
I also would like to thank Professor Chuanfa Ni at SIOC for his guidance and
friendship since my undergrad study at SIOC in Nov 2005. When I was a visiting
undergrad student at SIOC, he was a senior graduate student providing me hands-on
training on both basic laboratory techniques and fundamental organofluorine chemistry.
When I was a third-year graduate student in 2009, he joined the Olah-Prakash group as a
postdoctoral fellow, helping me again with almost every aspect in my graduate study.
Undoubtedly, his vast knowledge of chemistry and our very frequent discussions have
contributed significantly to this thesis. I cannot be luckier to have a mentor and friend
like him.
I am also very grateful to Dr. Martin (Lars Gustaf) Rahm, who has been an incredible
friend, mentor and collaborator. He has tirelessly taught me on both computational
chemistry and English writing skills. Without him, much of the work in this thesis would
vi

not be possible or would have had many flaws. In particular, he always induced me to
write, talk, and think more logically and critically. Although we have not agreed with
each other on everything, which has brought up frequent discussions or even debates,
these have always been very beneficial to me (I am not very sure how beneficial to him
though). I deeply appreciate his suggestions (both in chemistry and in other aspects),
patience and time. I also thank him for his immense effort to teach me basic Swedish;
however, I have still been stuck in trying to pronounce the number seven properly for
more than a year, due to my poor language learning capability. Thank you anyway,
Martin!
Dr. Jingguo Shen is an intelligent chemist and a remarkable and helpful friend. He
prompted me to learn DFT calculations starting from scratch. He provided PES
calculations in Chapters 6 and 8, which significantly contributed to these two chapters
and facilitated my understanding of the relevant chemistry. I thank him for his support
over the years.
I have been very lucky to have many peers and younger friends in the group. Arjun
Narayanan has been a good friend and talented labmate, who has always attempted to
remind me there are many facets in life other than chemistry and there are many different
types of food other than orange chicken. Zhe (Gigi) Zhang has been a remarkably
intelligent and energetic young collaborator and friend, who has contributed considerably
to some of the work in this thesis. Nan Shao has also been a collaborator and friend for
years. Without his remarkable hands, miracles of some crystallization would not have
happened. Dr. Charlie Krause has been a wonderful classmate and friend since 2006, who
vii

has proofread and corrected several chapters in this thesis. I am also grateful to Dr.
Clement Do for our collaboration. His very distinct sense of humor released many of my
day-to-day stresses. Socrates Munoz has been an extraordinary young chemist in the
group, whom I have been delighted to collaborate with. Dr. Akihisa Saitoh is a true
gentleman, and I gratefully thank him for his exceptionally generous help over the years.
Philipp Schmid from the University of Munich has been a very good friend, who taught
me many things about Germany. I also would like to express my appreciation to Dr. Ying
Wang for her tremendous help in the beginning of my life in the US and with many
things afterwards. It has been my pleasure to share an office with Dr. William W. Wilson
and to have daily discussions about many interesting topics.
I have to acknowledge many other friends and labmates in the group, who have
maintained a highly productive and professional environment for work. Among these
people are Dr. Robert A. Aniszfield, Dr. Alain Goeppert, Dr. Bo Yang (particularly for
his tutoring on my driving skills), Dr. Rehana Ismail, Dr. Chiradeep Panja, Dr. Sujith
Chacko, Dr. Miklos Czaun, Dr. Atila Papp, Dr. Somesh Kumar, Dr. Aditya Kulkarni, Dr.
Inessa Bychinskaya, Dr. Habiba Vaghoo, Dr. Mikhail Zibinsky, Dr. Farzaneh Paknia,
Dr. Patrice Batamack, Dr. Parag Jog, Xu Liu, Marc Iuliucci, Hang Zhang, Laxman
Gurung, John-Paul Jones (for his efforts in building up computational source in the
group), Anton Shakhmin, Hema Krishnan, Hyun Woo Kim, Tisa Thomas, Tito Thomas,
and Robert May.
I also would like to thank so many friends in the Loker building and the department
for their support, including Dr. Wei Huang, Dr. Dongqing Zhuang (for collaboration on
viii

the Merck project and many others), Dr. Siyi Wang, Mr. Guilaume Chabot and Mrs.
Kathleen Chabot (for allowing me to be a good target during fencing), Jia Liu, Bing Xu,
Anne-Marie Finaldi, Janet Olsen, Dr. Rong Yang, Fengtian Shi, Min Zhu, Dr. Jianmei
Wang, Dr. Spyridon Vicatos, Dr. Wei Wei, Dr. Jie Cao, Dr. Wenbo Hou, Shuting Sun,
Yue Wu, Dr. Qi Cai, and Dr. Ross Wagner (whose remarkable enthusiasm for chemistry
has always motivated me).
I must thank those of you who were occasionally hanging out with me for nice food
and chatting, I do not think I have to mention your names!!
Mr. Allan Kershaw and Mr. Ralph Pan are thanked for their technical help with NMR
instruments. I would like to thank Jessy May, whose exceptional energetic character,
hospitality, and even her resounding laugh have given me tremendous positive influence
in my life. I especially thank Carole Phillips, David Hunter, Michele Dea, Heather
Connor, and Katie McKissick for their kind support.
Finally, I have to express my deepest appreciation to my parents, who not only gave
me my life but also the freedom to choose my life style. They have been constantly
considerate and selflessly supportive of me over the years. I do feel that I am extremely
lucky to be their child.

ix

Table of Contents
Dedication ........................................................................................................................... ii
Acknowledgments.............................................................................................................. iii
List of Tables .....................................................................................................................xv
List of Figures ....................................................................................................................xx
List of Schemes .............................................................................................................. xxvi
Abstract .......................................................................................................................... xxix
Chapter 1. Introduction - Flourishing Organofluorine Chemistry: Brief History and State
of the Art ...........................................................................................................1
1.1. Introduction .....................................................................................................2
1.2. Synthetic Approaches for the Introduction of Fluorine-Containing
Functionalities and Related Chemistry ..........................................................7
1.2.1. Novel Fluorinating Reagents and C-F Bond Formation Reactions ..11
1.2.1.1. Nucleophilic Fluorinations.......................................................12
1.2.1.2. Electrophilic Fluorinations.......................................................23
1.2.2. Efficient Trifluoroalkylation Reactions ............................................33
1.2.2.1. Nucleophilic Trifluoromethylating Reagents, Trifluoromethyl-
Metal Reagents and Related Chemical Transformations .........35
1.2.2.2. Electrophilic Trifluoromethylating Reagents and Reactions ...43
1.2.2.3. Recent Developments in the Construction of CF
3
-C Bonds ....50
1.2.3. Novel Methods for the Introduction of Difluoromethyl Motifs........64
1.2.3.1. Nucleophilic Difluoromethyl Building Blocks and Approaches
..................................................................................................66
1.2.3.2. Electrophilic Difluoromethyl Reagents and Approaches ........76
1.2.4. Catalytic Asymmetric Synthesis of Chiral Monofluoromethylated
Organic Molecules via Nucleophilic Fluoromethylating Reactions .77
1.3. Conclusion and Perspectives...........................................................................91
1.4. References .......................................................................................................94
Chapter 2. Efficient Michael Addition of α-Substituted Fluoro(phenylsulfonyl)methane
Derivatives to α,β-Unsaturated Carbonyl Compounds .................................122
2.1. Introduction ...................................................................................................123
2.2. Results and Discussion .................................................................................124
x

2.3. Experimental .................................................................................................129
2.3.1. General Procedure for the Oxidation of Sulfides ............................130
2.3.2. Improved Procedure for Monofluorination Using Selectfluor® ....131
2.3.3. General Procedure For Phosphine-Catalyzed 1,4-Addition of α-
Substituted Fluoro(Phenylsulfonyl)methane Derivatives ...............133
2.4. References .....................................................................................................138
Chapter 3. Highly Efficient Synthesis of α-Fluoro, Chloro and Methoxy-
Disulfonylmethane Derivatives as Tunable α-Substituted-Methyl Synthons
via C-S Bond Forming Strategy ...................................................................141
3.1. Introduction ...................................................................................................142
3.2. Results and Discussion .................................................................................144
3.3. Conclusion ....................................................................................................151
3.4. Experimental .................................................................................................151
3.4.1. General Procedure for the Preparation of α-
Fluoro(disulfonyl)methanes ............................................................152
3.4.2. General Procedure for the Preparation of α-
Chloro(disulfonyl)methanes ...........................................................153
3.4.3. General Procedure for the Preparation of α-
Methoxy(disulfonyl)methanes ........................................................153
3.4.4. Compound Characterization ...........................................................154
3.5. References .....................................................................................................161
Chapter 4. α-Fluoro-α-nitro(phenylsulfonyl)methane as a Fluoromethyl Pronucleophile:
Efficient Stereoselective Michael Addition to Chalcone Derivatives ..........164
4.1. Introduction ...................................................................................................165
4.2. Results and Discussion .................................................................................167
4.3. Conclusion ....................................................................................................177
4.4. Experimental .................................................................................................178
4.4.1. Catalyst Preparation and Characterization ......................................178
4.4.2. Typical Procedure for Catalytic 1,4-Addition of α-Fluoro-α-
Nitro(phenylsulfonyl)methane to α,β-Unsaturated Ketones ...........181
4.4.3. Typical Procedure for Catalytic Enantioselective 1,4-Addition of α-
Fluoro-α-nitro(phenylsulfonyl)methane to Chalcones ....................182
4.4.4. Product Characterization .................................................................182
xi

4.4.5. Typical Procedure for Catalytic Monofluoromethylation of Methyl
Vinyl Ketone ...................................................................................192
4.4.6. Crystal Structure of (3R, 4R)-4-Fluoro-4-nitro-1,3-diphenyl-4-
(phenylsulfonyl)-butan-1-one (3a) ..................................................193
4.4.7. Procedure for Preparation of α-Fluorocarbanion Crystal ...............194
4.4.8. Typical Procedure for Preparation of α-Fluorocarbanion DMSO
Solution ...........................................................................................195
4.4.9. Crystal Structure of FBSM Anion-tetra(n-Butylammonium) Salt .197
4.4.10. Crystal Structure of HBSM Anion-tetra(n-Butylammonium) Salt 199
4.4.11. Crystal Structure of NSM Anion-tetra(n-Butylammonium) Salt ...201
4.5.Reference .......................................................................................................203
Chapter 5. Facile Enantioselective Synthesis of α-Stereogenic γ-Keto Esters via Formal
Umpolung: Utilization of Nitro(phenylsulfonyl)methane as an Acyl Anion
Equivalent .....................................................................................................206
5.1. Introduction ...................................................................................................207
5.2. Results and Discussion .................................................................................208
5.3. Conclusion ....................................................................................................217
5.4. Experimental .................................................................................................218
5.4.1. Large-Scale Preparation of Nitro(phenylsulfonyl)methane ............219
5.4.2. Typical Procedure for One-Pot Enantioselective Synthesis of α-
Stereogenic γ-Keto Esters ...............................................................220
5.4.3. Complete Tables of Reaction Condition Screening ........................221
5.4.4. Product Characterization .................................................................224
5.4.5. Crystal Structures ............................................................................230
5.5. References .....................................................................................................240
Chapter 6. Conformational Study of 9-Dehydro-9-Trifluoromethyl Cinchona Alkaloids
via
19
F NMR Spectroscopy: Emergence of Trifluoromethyl Moiety as a
Conformational Stabilizer and a Probe. ........................................................246
6.1. Introduction ...................................................................................................247
6.2. Probe Design and Synthetic Method .............................................................249
6.3. Results and Discussion .................................................................................252
6.4. Conclusion ....................................................................................................257
6.5. Experimental .................................................................................................258
xii

6.5.1. General Information ........................................................................258
6.5.2. Preparation of epiCF
3
QD (1) ..........................................................259
6.5.3. Characterization of Cinchona Alkaloid Derivatives and epiCF
3
QD
.........................................................................................................259
6.6. References .....................................................................................................293
Chapter 7. On the Nature of C-H
…
F-C Interactions in Hindered CF
3
-C(sp
3
) Bond
Rotations .......................................................................................................297
7.1. Introduction ...................................................................................................298
7.2. Results and Discussion .................................................................................298
7.3. Conclusion ....................................................................................................306
7.4. Experimental .................................................................................................307
7.4.1. General Information ........................................................................307
7.4.2. Typical Procedure for the Preparation of O-Alkyl-9-dehydro-9-
trifluoromethyl-9-epiquinine (2) and their Characterization ..........308
7.4.3. Computational Studies ....................................................................315
7.4.4. Selected NMR Spectra ....................................................................323
7.4.5. Crystal Structure of 2c ....................................................................373
7.5. References .....................................................................................................375
Chapter 8. Exploiting the Trifluoromethyl Group as a Conformational Stabilizer and
Probe: Conformations of Cinchona Alkaloid Scaffolds and their Catalytic
Activity .........................................................................................................379
8.1. Introduction ...................................................................................................380
8.2. Methods.........................................................................................................387
8.2.1. Identification of Conformers via DFT Calculations ........................387
8.2.2. Energy Calculation and Population Distribution .............................388
8.2.3. NMR Experiments ............................................................................389
8.3. Results and Discussion .................................................................................390
8.3.1. Investigation of the Conformations of Quinidine Derivatives via
Quantum Chemical Calculation ......................................................390
8.3.2. Conformational Behavior of epiCF
3
QD .........................................394
8.3.2.1. Conformational Study of epiCF
3
QD via
19
F NMR ................394
8.3.2.2. Elucidation of Solvent Effects via Linear Free Energy
Relationship (LEFR) ..............................................................398
xiii

8.3.2.3. Comparison of Theoretical Calculations with Experimental
Data ........................................................................................406
8.3.3. Conformational Behavior of epiQD in Various Solvents ...............408
8.3.4. Conformational Behavior of QD in Various Solvents ....................411
8.3.5. Elucidation of Catalytically Active Conformations Using the
Trifluoromethyl Group as a Conformational Stabilizer: A Case
Study. ..............................................................................................419
8.4. Conclusions ...................................................................................................430
8.5. Experimental .................................................................................................431
8.5.1. General Information ........................................................................431
8.5.2. Conformational analysis of epiCF
3
QD based on high level DFT
calculations .....................................................................................432
8.5.3. Conformational Analysis of epiCF
3
QD Conformers using LFER .456
8.5.4. Conformational analysis of QD based on DFT calculations ..........461
8.5.5. Conformational Analysis of QD Conformers using LFER.............480
8.5.6. Conformational Analysis of epiQD based on DFT Calculations....482
8.5.7. Conformational Analysis of QD Conformers using LFER.............490
8.5.8. Calculated Conformational Distribution of epiMeOCF
3
QD ..........492
8.5.9. Calculated Conformational Distribution of MeOMeQD ................493
8.5.10. Calculated Conformational Distribution of MeOQD .....................494
8.5.11. Calculated Conformational Distribution of epiMeOQD.................495
8.5.12. Calculated Conformational Distribution of βiQD ..........................496
8.5.13. Comparison of Nucleophilicity of 6-Methoxyquinoline and Different
Quinuclidine Derivatives. ...............................................................497
8.5.14. Comparison of H-Bond Accepting Ability of H
2
O and Alcohols ..498
8.5.15. Crystal Structures ............................................................................499
8.5.16. Characterization of Various Cinchona Alkaloids Derivatives ........503
8.5.17. NMR Data of N-(2-(t-Butoxy)-2-oxoethyl)-6-methoxyquinolinium
Bromide in CD
3
CN .........................................................................527
8.5.18. Comparison of Catalytic Activity of Different Cinchona Alkaloid
Derivatives. .....................................................................................530
8.5.19. Kinetic Studies ................................................................................535
8.6. Reference ......................................................................................................536
xiv

Bibliography ....................................................................................................................544

xv

List of Tables
Table 2.1. Oxidation of sulfides and monofluorination of sulfones................................125
Table 2.2. PMe
3
-catalyzed reaction of fluoro(phenylsulfonyl) substituted methane
derivatives with methyl vinyl ketone and ethyl acrylate. ................................................127
Table 3.1. Formation of fluorophenylsulfonylmethide anion under different bases and its
reaction with phenyl sulfonyl halides. ............................................................................145
Table 3.2. Synthesis of α-fluorobis(phenylsulfonyl)methane (FBSM) and its analogues
by the new C-S bond forming strategy ............................................................................147
Table 3.3. Synthesis of 1-methoxybis(phenylsulfonyl)methane and its analogues by the
new C-S bond forming strategy. ..................................................................................... 149
Table 3.4. Synthesis of 1-chlorobis(phenylsulfonyl)methane and its analogues by the new
C-S bond forming strategy. ..............................................................................................150
Table 4.1. Screening of catalysts CN/CD I, QN/QD I and QN I-IV for enantioselective
addition of FNSM to chalcone. .......................................................................................163
Table 4.2. Enantioselective 1,4-addition of FNSM to chalcone catalyzed by QN I in
various solvents. ...............................................................................................................164
Table 4.3. Enantioselective 1,4-addition of FNSM to chalcone under different catalyst
loading of QN I at different temperatures. .......................................................................165
Table 4.4. Enantioselective 1,4-addition of FNSM to chalcone. ....................................166
Table 5.1. Thiourea-catalyzed synthesis of α-stereogenic γ-keto esters. ........................211
Table 5.2. One-pot synthesis of α-stereogenic γ-keto esters using primary amine
catalysts. ...........................................................................................................................213
Table 5.3. Investigation of Brønsted acid additives and solvent effects on primary amine-
catalyzed Michael reaction. .............................................................................................215
Table 5.4. Investigation of substrate scope. ....................................................................216
Table 5.5. Thiourea-catalyzed synthesis of α-stereogenic γ-keto esters. ........................221
Table 5.6. One-pot synthesis of α-stereogenic γ-keto esters using primary amine
catalysts. ...........................................................................................................................222
Table 5.7. Employment of phenols as Brønsted acid additives. .....................................223
Table 7.1. Synthesis of O-alkyl 9-dehydro-9-trifluoromethyl-9-epiquinidine compounds,
their
19
F NMR spectra and activation parameters derived from Eyring plots. ................299
Table 7.2. Canonical MOs showing C3’-H1…F1-C interactions in 3. ...........................305
Table 7.3. Optimized structures of the syn- and the anti-Closed conformations of 2a. ..316
xvi

Table 7.4. CF
3
Rotation profile in syn-Closed 2a at the B3LYP/6-311+G(2d,p) level of
theory. ..............................................................................................................................317
Table 7.5. CF
3
Rotation profile in anti-Closed 2a at the B3LYP/6-311+G(2d,p) level of
theory ...............................................................................................................................318
Table 7.6. Optimized ground state and transition state structures of anti-Closed 2a at the
B3LYP/6-31+G(d,p)+ZPE level of theory.. ....................................................................319
Table 7.7. NBO Analysis of the ground state of syn-closed 2a at the B3LYP/6-31+G(d,p)
level of theory ..................................................................................................................320
Table 7.8. NBO Analysis of the transition state of syn-closed 2a at the B3LYP/6-
31+G(d,p) level of theory ................................................................................................320
Table 7.9. Canonical molecular orbitals showing C3’-H1…F1-C interactions in 3. ......322
Table 8.1. Computational and experimental population distributions of epiCF
3
QD at 298
K and the corresponding relative Gibbs free energy (ΔG
syn
) of syn conformations of
epiCF
3
QD in various solvents. .........................................................................................397
Table 8.2. LFER Analysis of solvent effects on the conformational behavior of quinidine
and its derivatives ............................................................................................................399
Table 8.3. Calculated properties of different conformers of epiQD in the gas phase. ....409
Table 8.4. PCM-Based calculated conformational distribution of epiQD in various
solvents. ...........................................................................................................................411
Table 8.5. Calculated properties of different conformers of QD in the gas phase. .........412
Table 8.6. Conformational distribution of QD and ΔG
open,exp
in various solvents. .........413
Table 8.7. Nucleophilicity of different N-nucleophiles toward CH
3
Cl. ..........................428
Table 8.8. Gas phase structures of epiCF
3
QD optimized at the B3LYP-6-311+G(d,p)
level of theory. .................................................................................................................435
Table 8.9. Gas Phase Energy of epiCF
3
QD at the B3LYP-6-311+G(d,p) level. (Geometry
optimization was performed at the same level.) ..............................................................436
Table 8.10. SPE of epiCF
3
QD at the M06-2X-6-311+G(d,p) level of theory in the gas
phase. ...............................................................................................................................437
Table 8.11. SPE of epiCF
3
QD at the M06-2X-6-311+G(d,p) level of theory in CHCl
3

(PCM). .............................................................................................................................438
Table 8.12. SPE of epiCF
3
QD at the M06-2X-6-311+G(d,p) level of theory in benzene
(PCM). .............................................................................................................................439
Table 8.13. SPE of epiCF
3
QD at the M06-2X-6-311+G(d,p) level of theory in THF
(PCM). .............................................................................................................................440
Table 8.14. SPE of epiCF
3
QD at the M06-2X-6-311+G(d,p) level of theory in DMSO
(PCM). .............................................................................................................................441
xvii

Table 8.15. SPE of epiCF
3
QD at the M06-2X-6-311+G(d,p) level of theory in MeOH
(PCM). .............................................................................................................................442
Table 8.16. SPE of epiCF
3
QD at the M06-2X-6-311+G(d,p) level of theory in H
2
O
(PCM). .............................................................................................................................443
Table 8.17. SPE of epiCF
3
QD at the M06-2X-6-311+G(d,p) level of theory in MeCN
(PCM) ..............................................................................................................................444
Table 8.18. SPE of epiCF
3
QD at the M06-2X-6-311+G(d,p) level of theory in acetone
(PCM). .............................................................................................................................445
Table 8.19. SPE of epiCF
3
QD at the M06-2X-6-311+G(d,p) level of theory in CH
2
Cl
2

(PCM) ..............................................................................................................................446
Table 8.20. SPE of epiCF
3
QD at the M06-2X-6-311+G(d,p) level of theory in DMF
(PCM) ..............................................................................................................................447
Table 8.21. SPE of epiCF
3
QD at the M06-2X-6-311+G(d,p) level of theory in ethyl
acetate (PCM) ..................................................................................................................448
Table 8.22. SPE of epiCF
3
QD at the M06-2X-6-311+G(d,p) level of theory in EtOH
(PCM) ..............................................................................................................................449
Table 8.23. SPE of epiCF
3
QD at the M06-2X-6-311+G(d,p) level of theory in i-PrOH
(PCM) ..............................................................................................................................450
Table 8.24. SPE of epiCF
3
QD at the M06-2X-6-311+G(d,p) level of theory in MeNO
2

(PCM) ..............................................................................................................................451
Table 8.25. SPE of epiCF
3
QD at the M06-2X-6-311+G(d,p) level of theory in pentane
(PCM) ..............................................................................................................................452
Table 8.26. SPE of epiCF
3
QD at the M06-2X-6-311+G(d,p) level of theory in PhNO
2

(PCM) ..............................................................................................................................453
Table 8.27. SPE of epiCF
3
QD at the M06-2X-6-311+G(d,p) level of theory in pyridine
(PCM). ............................................................................................................................ 454
Table 8.28. SPE of epiCF
3
QD at the M06-2X-6-311+G(d,p) level of theory in toluene
(PCM) ..............................................................................................................................455
Table 8.29. Experimental population distributions of epiCF
3
QD at 298K and the
corresponding relative Gibbs free energy (ΔG
syn
) of syn conformations of epiCF
3
QD in
various solvents. ...............................................................................................................456
Table 8.30. Gas phase structures of QD conformers optimized at the B3LYP-6-
311+G(d,p) level of theory. .............................................................................................464
Table 8.31. Gas phase energy of QD conformers at the B3LYP-6-311+G(d,p) level of
theory. ..............................................................................................................................465
xviii

Table 8.32. SPE of QD conformers at the M06-2X-6-311+G(d,p) level of theory in gas
phase. ...............................................................................................................................466
Table 8.33. SPE of QD conformers at the M06-2X-6-311+G(d,p) level of theory in
CHCl
3
(PCM) ...................................................................................................................467
Table 8.34. SPE of QD conformers at the M06-2X-6-311+G(d,p) level of theory in
Benzene (PCM) ................................................................................................................468
Table 8.35. SPE of QD conformers at the M06-2X-6-311+G(d,p) level of theory in THF
(PCM) ..............................................................................................................................469
Table 8.36. SPE of QD conformers at the M06-2X-6-311+G(d,p) level of theory in
DMSO (PCM) ..................................................................................................................470
Table 8.37. SPE of QD conformers at the M06-2X-6-311+G(d,p) level of theory in
MeOH (PCM) ..................................................................................................................471
Table 8.38. SPE of QD conformers at the M06-2X-6-311+G(d,p) level of theory in EtOH
(PCM) ..............................................................................................................................472
Table 8.39. SPE of QD conformers at the M06-2X-6-311+G(d,p) level of theory in i-
PrOH (PCM) ....................................................................................................................473
Table 8.40. SPE of QD conformers at the M06-2X-6-311+G(d,p) level of theory in
pyridine (PCM) ................................................................................................................474
Table 8.41. SPE of QD conformers at the M06-2X-6-311+G(d,p) level of theory in
PhNO
2
(PCM) ..................................................................................................................475
Table 8.42. SPE of QD conformers at the M06-2X-6-311+G(d,p) level of theory in
MeNO
2
(PCM) .................................................................................................................476
Table 8.43. SPE of QD conformers at the M06-2X-6-311+G(d,p) level of theory in DMF
(PCM) ..............................................................................................................................477
Table 8.44. SPE of QD conformers at the M06-2X-6-311+G(d,p) level of theory in
acetone (PCM) .................................................................................................................478
Table 8.45. SPE of QD conformers at the M06-2X-6-311+G(d,p) level of theory in H
2
O
(PCM) ..............................................................................................................................479
Table 8.46. Gas phase structures of epiQD optimized at the B3LYP-6-311+G(d,p) level
of theory ...........................................................................................................................484
Table 8.47. SPE of epiQD at the M06-2X-6-311+G(d,p) level in the gas phase. ...........484
Table 8.48. SPE of epiQD at the M06-2X-6-311+G(d,p) level in CHCl
3
(PCM). .........485
Table 8.49. SPE of epiQD at the M06-2X-6-311+G(d,p) level in benzene (PCM). .......485
Table 8.50. SPE of epiQD at the M06-2X-6-311+G(d,p) level in THF (PCM). ............486
Table 8.51. SPE of epiQD at the M06-2X-6-311+G(d,p) level in DMSO (PCM) .........486
xix

Table 8.52. SPE of epiQD at the M06-2X-6-311+G(d,p) level in MeOH (PCM) ..........487
Table 8.53. SPE of epiQD at the M06-2X-6-311+G(d,p) level in MeCN (PCM) ..........487
Table 8.54. SPE of epiQD at the M06-2X-6-311+G(d,p) level in H
2
O (PCM) ..............488
Table 8.55. Calculated conformational distribution of epiQD in the gas phase. ............488
Table 8.56. Conformational distribution of QD and ΔG
open,exp
in various solvents. .......490
Table 8.57. Calculated transition state of the reaction of N-nucleophiles with methyl
chloride (MeCl). ...............................................................................................................497

xx

List of Figures
Figure 1.1. A. Properties involving fluorine, trifluoromethyl group and others; B.
fluorine effects on acidity and basicity; C. fluorine effects on lipophilicity; D. selected
fluorine stereoelectronic effects; E. resonance effects of fluorine .......................................3
Figure 1.2. A. Fluorinated drugs among 10 best-selling drugs in 2011; B. Selected
fluorine-containing drugs and drug candidates. ...................................................................5
Figure 1.3. A. Publications relevant to organofluorine chemistry and fluorine-containing
drugs (based on a SciFinder search in April 2012); B. Milestones in synthetic
organofluorine chemistry prior to 1960s; C. Chemical bonds of interest to organofluorine
chemists................................................................................................................................9
Figure 1.4. Four synthetic pathways for C-F bond formations. ........................................12
Figure 1.5. Pd-catalyzed nucleophilic fluorination of aryl halides and aryl triflate. ........20
Figure 4.1. Calculated structures and X-ray structures of key reaction intermediates. ..167
Figure 4.2. Formation of α-fluoro-α-nitro(phenylsulfonyl)methide anion and suggested
transition state involving chalcone-QN I assembly during Michael addition..................169
Figure 4.3. Crystal structure of (3R, 4R)-4-fluoro-4-nitro-1,3-diphenyl-4-(phenylsulfo-
nyl)-butan-1-one (3a). ......................................................................................................170
Figure 5.1. Crystal Structure of 4h derived from Mo data ..............................................230
Figure 5.2. Crystal Structure of 4h derived from Cu data. ..............................................230
Figure 5.3. Crystal Structure of 4e derived from Mo data. .............................................235
Figure 5.4. Crystal Structure of 4e derived from Cu data. .............................................235
Figure 6.1. Four energetically preferred conformations of cinchona alkaloids and their
interconversions. ..............................................................................................................248
Figure 6.2. Substitution of H8 with the trifluoromethyl moiety. ....................................249
Figure 6.3. Relative Populations of syn-Conformations in Various Solvents. ...............247
Figure 7.1. A. Conformational analysis of 2a based on NMR spectroscopic studies; B.
optimized conformation of 2a at the B3LYP/6-31+G(d,p) level in the gas phase (the OMe
group on the quinoline ring is omitted for clarity.); C. Calculated
19
F NMR chemical
shifts of 3 and experimental 19F NMR chemical shifts of 2. ..........................................301
Figure 7.2. A. X-ray crystal structure of 2c; B. Short proton-fluorine contacts as
indicated by the crystal structure of 2c (as the average values measured in both molecules
in the unit cell). ................................................................................................................302
Figure 7.3.
1
H NMR chemical shifts of H1 in 2a-2e in CDCl
3
. The chemical shift of H1
in 2d was estimated through HSQC spectroscopy. .........................................................303
xxi

Figure 7.4. CF
3
Rotation profile in syn-Closed 2a at the B3LYP/6-311+G(2d,p) level of
theory. ..............................................................................................................................317
Figure 7.5. CF
3
Rotation profile in anti-Closed 2a at the B3LYP/6-311+G(2d,p) level of
theory. ..............................................................................................................................318
Figure 8.1. A. Critical rotations considered in the conformational analysis; B-D. PES of
epiCF
3
QD, epiQD, and cinchonidine in the gas phase, respectively (Figure 8.1-D. was
reproduced from Ref. 8d with permission); E-G. representative conformers of epiCF
3
QD,
epiQD, and QD in the gas phase, respectively; relative Gibbs free energies in the gas
phase are shown in parentheses. ......................................................................................393
Figure 8.2. A. Observed conformational distribution of epiCF
3
QD in CDCl
3
; B.
Observed conformational distribution of epiCF
3
QD in DMSO-d
6
; C.-D.
19
F NMR
spectrum of epiCF
3
QD in various solvents. .....................................................................395
Figure 8.3. A. Correlation of ΔG
syn,exp
of epiCF
3
QD with multiparameter polarity scale
XYZ1; B. Correlation of ΔG
syn,exp
of epiCF
3
QD with H-bond accepting ability (β) of
various solvents; C. Plot of ΔG
syn,exp
of epiCF
3
QD versus (ε-1)/(ε+2) of various solvents
(dielectric interaction). .....................................................................................................401
Figure 8.4. A. Plausible role of H-bonding interaction in the syn-anti conformational
equilibrium; B. Determination of H-bond accepting ability (β) using solvatochromic
probe, in which the H-bond acceptor possesses less steric encumbrance than the hydroxyl
group in epiCF
3
QD; C. Steric effect of solvents on the conformational distribution.
ΔG
syn,exp
varies significantly with relatively unchanged β values, revealing the steric
effect on solvents influencing the conformational distribution of epiCF
3
QD. ................403
Figure 8.5. A. Correlation of ΔG
syn,exp
of epiCF
3
QD with ΔG
syn,cal
; five uncircled
calculated ΔG
syn,cal
values significantly diverge from the experimental data; B.
Correlation of ΔG
syn,cal
of epiCF
3
QD with (ε-1)/(ε+2) of various solvents (dipolar
interaction); C. Correlation of (ε-1)/(ε+2) with β, which shows a scattered pattern similar
to Figure 8.5-A. ...............................................................................................................407
Figure 8.6. A. Correlation of ΔG
open,exp
with multiparameter XYZ2; B. Correlation of
ΔG
open,cal
of QD with (ε-1)/(ε+2) of various solvents (dielectric interaction); C.
Correlation of multiparameter XYZ2 with (ε-1)/(ε+2). ...................................................416
Figure 8.7. A. Contribution from individual solvent properties to the multiparameter
XYZ2; B. rationalization of stabilization/destabilization from different solvent-solute
interactions. ......................................................................................................................418
Figure 8.8. A.-C. Calculated energy minimum conformations of epiMeOCF
3
QD,
MeOMeQD, and MeOQD in the gas phase and in CH
3
CN, respectively. ......................421
Figure 8.9. Conformational distribution of active conformation probes and their catalytic
activity..............................................................................................................................424
Figure 8.10. A. Time-dependent concentration of t-butyl α-bromoacetate under different
reaction conditions; B-(a)
1
H NMR spectrum of MeOQD in CD
3
CN at 343 K; B-(b)
1
H
xxii

NMR spectrum of MeOQD and quinuclidine-N alkylated MeOQD (5a) in CD
3
CN at 343
K; B-(c)
1
H NMR spectrum of MeOQD-catalyzed cyclopropanation reaction in CD
3
CN
at 343 K (taken 30 min after the reaction started). ..........................................................425
Figure 8.11. A. Reactivity of βiQD toward t-butyl α-bromoester in CD
3
CN (Eq. 12) and
catalytic activity of βiQD in cyclopropanation reaction (Eq. 13); B. conformation of t-
butyl α-bromoester-epiMeOQD quaternary ammonium salt in the solid state and in
CD
3
CN. ............................................................................................................................429
Figure 8.12. Optimized Conformations of epiCF
3
QD in the gas phase at the B3LYP/6-
311+(d,p) level of theory (Part-A). ..................................................................................432
Figure 8.13. Optimized Conformations of epiCF
3
QD in the gas phase at the B3LYP/6-
311+(d,p) level of theory (Part-B). ..................................................................................433
Figure 8.14. Optimized Conformations of epiCF
3
QD in the gas phase at the B3LYP/6-
311+(d,p) level of theory (Part-C). .................................................................................434
Figure 8.15. Calculated population of epiCF
3
QD conformers in different solvents. The
population of Open-3a was found to decrease with the increase in dielectric constants of
solvents. ...........................................................................................................................455
Figure 8.16. Correlation of ΔG
syn,exp
and ΔG
syn,cal
of epiCF
3
QD with various solvent
polarity parameters and related correlations. ...................................................................460
Figure 8.17. Optimized conformations of QD in the gas phase at the B3LYP/6-311+(d,p)
level of theory (Part-A). ..................................................................................................461
Figure 8.18. Optimized conformations of QD in the gas phase at the B3LYP/6-311+(d,p)
level of theory (Part-B). ...................................................................................................462
Figure 8.19. Optimized conformations of QD in the gas phase at the B3LYP/6-311+(d,p)
level of theory (Part-C). ..................................................................................................463
Figure 8.20. Calculated population of QD conformers in different solvents. .................479
Figure 8.21. Correlation of ΔG
syn,exp
and ΔG
syn,cal
of QD with various solvent polarity
parameters and related correlations (Part A). ..................................................................480
Figure 8.22. Correlation of ΔG
syn,exp
and ΔG
syn,cal
of QD with various solvent polarity
parameters and related correlations (Part B). ...................................................................481
Figure 8.23. Optimized Conformations of epiQD in the gas phase at the B3LYP/6-
311+(d,p) level of theory (Part-A). ..................................................................................482
Figure 8.24. Optimized Conformations of epiQD in the gas phase at the B3LYP/6-
311+(d,p) level of theory (Part-B). ..................................................................................483
Figure 8.25. Calculated population of epiQD conformers in different solvents, showing
the predominance of Open-3a and Open-4a conformations. ...........................................488
Figure 8.26. Correlation of Calculated ΔG
Open-3
with (ε-1)(ε+2). ΔGOpen-3 = -RT ln
(∑PopOpen-3). .................................................................................................................491
xxiii

Figure 8.27. Optimized Conformations of epiMeOCF
3
QD in the gas phase at the
B3LYP/6-311+(d,p) level of theory. ................................................................................492
Figure 8.28. Optimized Conformations of MeOMeQD in the gas phase at the B3LYP/6-
311+(d,p) level of theory. ................................................................................................493
Figure 8.29. Optimized Conformations of MeOQD in the gas phase at the B3LYP/6-
311+(d,p) level of theory. ................................................................................................494
Figure 8.30. Optimized Conformations of epiMeOQD in the gas phase at the B3LYP/6-
311+(d,p) level of theory. ................................................................................................495
Figure 8.31. Optimized Conformations of βiQD in the gas phase at the B3LYP/6-
311+(d,p) level of theory.. ...............................................................................................496
Figure 8.32. Calculated aniline-ROH binding energies in the gas phase. ......................498
Figure 8.33. Crystal structure of t-butyl α-bromoester-epiMeOQD quaternary ammonium
salt. ...................................................................................................................................499
Figure 8.34. Crystal structure of MeOMeQD.. ...............................................................501
Figure 8.35.
1
H NMR Spectrum of epiMeOQD in CD
3
CN. ...........................................504
Figure 8.36.
13
C NMR Spectrum of epiMeOQD in CD
3
CN. ..........................................504
Figure 8.37. COSY Spectrum of epiMeOQD in CD
3
CN. ..............................................505
Figure 8.38. NOESY Spectrum of epiMeOQD in CD
3
CN. ............................................505
Figure 8.39. HSQC Spectrum of epiMeOQD in CD
3
CN. ..............................................506
Figure 8.40. Strong nOe in epiMeOQD in CD
3
CN. .......................................................506
Figure 8.41.
1
H NMR Spectrum of MeOMeQD in CD
3
CN. ..........................................508
Figure 8.42.
13
C NMR Spectrum of MeOMeQD in CD
3
CN. .........................................508
Figure 8.43. COSY Spectrum of MeOMeQD in CD
3
CN. ..............................................509
Figure 8.44. NOESY Spectrum of MeOMeQD in CD
3
CN. ...........................................509
Figure 8.45. HSQC Spectrum of MeOMeQD in CD
3
CN. ..............................................510
Figure 8.46. Strong nOe in MeOMeQD in CD
3
CN. .......................................................510
Figure 8.47.
1
H NMR Spectrum of MeOQD in CD
3
CN. ................................................512
Figure 8.48.
13
C NMR Spectrum of MeOQD in CD
3
CN. ...............................................512
Figure 8.49. HSQC Spectrum of MeOQD in CD
3
CN. ...................................................513
Figure 8.50. NOESY Spectrum of MeOQD in CD
3
CN. .................................................513
Figure 8.51. Strong nOe in MeOQD in CD
3
CN. ............................................................514
Figure 8.52.
1
H NMR Spectrum of epiMeOCF
3
QD in CD
3
CN......................................515
Figure 8.53.
19
F NMR Spectrum of epiMeOCF
3
QD in CD
3
CN. ....................................516
xxiv

Figure 8.54. COSY Spectrum of epiMeOCF
3
QD in CD
3
CN. ........................................516
Figure 8.55. NOESY Spectrum of epiMeOCF
3
QD in CD
3
CN.......................................517
Figure 8.56. HSQC Spectrum of epiMeOCF
3
QD in CD
3
CN. ........................................517
Figure 8.57. Strong nOe in epiMeOCF
3
QD in CD
3
CN. .................................................518
Figure 8.58. NOESY spectra of epiMeOQD in CD
2
Cl
2
and DMSO-d
6
. ........................519
Figure 8.59.
1
H NMR Spectrum of 7 in CD
3
CN. ............................................................520
Figure 8.60. COSY Spectrum of 7 in CD
3
CN. ...............................................................521
Figure 8.61. HSQC Spectrum of 7 in CD
3
CN. ...............................................................521
Figure 8.62. NOESY Spectrum of 7 in CD
3
CN. .............................................................522
Figure 8.63. Strong nOe in 7 in CD
3
CN. ........................................................................522
Figure 8.64.
1
H NMR Spectrum of BnOMeQD in CD
3
CN. ...........................................524
Figure 8.65.
13
C NMR Spectrum of BnOMeQD in CD
3
CN. ..........................................524
Figure 8.66. COSY Spectrum of BnOMeQD in CD
3
CN. ...............................................525
Figure 8.67. HSQC Spectrum of BnOMeQD in CD
3
CN. ...............................................525
Figure 8.68. NOESY Spectrum of BnOMeQD in CD
3
CN. ............................................526
Figure 8.69. Strong nOe in BnOMeQD in CD
3
CN.........................................................526
Figure 8.70.
1
H NMR Spectrum of N-(2-(tert-butoxy)-2-oxoethyl)-6-methoxy-
quinolinium bromide in CD
3
CN. .....................................................................................527
Figure 8.71.
1
H NMR of the mixture of 6-methoxyquinoline and its N-alkylated
derivative..........................................................................................................................528
Figure 8.72.
1
H NMR of the mixture of MeOMeQD and its quinoline-N-alkylated
derivative..........................................................................................................................528
Figure 8.73.
1
H NMR of the mixture of epiMeOCF
3
QD and its quinoline-N-alkylated
derivative..........................................................................................................................529
Figure 8.74.
1
H NMR of the mixture of MeOQD and its quinuclidine-N-alkylated
derivative..........................................................................................................................529
Figure 8.75. epiMeOCF
3
QD-catalyzed cyclopropanation reaction. ...............................531
Figure 8.76. BnOMeQD-catalyzed cyclopropanation reaction. .....................................531
Figure 8.77. MeOMeQD-catalyzed cyclopropanation reaction. .....................................532
Figure 8.78. epiMeOQD-catalyzed cyclopropanation reaction. .....................................532
Figure 8.79. βiQD-catalyzed cyclopropanation reaction (10% catalyst loading). ..........533
Figure 8.80. βiQD-catalyzed cyclopropanation reaction (20% catalyst loading). ..........533
xxv

Figure 8.81. MeOQD-catalyzed cyclopropanation reaction (10% catalyst loading). .....534
Figure 8.82. Racemic trans tert-butyl 2-benzoylcyclopropanecarboxylate. ...................534

xxvi

List of Schemes
Scheme 1.1. Nucleophilic fluorination reactions and the related reagents. .......................14
Scheme 1.2. Development of S-F bond based deoxofluorinating reagents. ......................16
Scheme 1.3. Ring-opening reactions of aziridines and epoxides using BF
3
-OEt
2
as the
fluorine source. ..................................................................................................................17
Scheme 1.4. Development of asymmetric nucleophilic fluorinations. ..............................19
Scheme 1.5. Development of palladium-mediated nucleophilic fluorination of arenes. ..22
Scheme 1.6. Cu-mediated nucleophilic fluorination of arenes. .........................................23
Scheme 1.7. Electrophilic fluorinations and the related reagents. ....................................25
Scheme 1.8. Development of asymmetric electrophilic fluorinations. .............................29
Scheme 1.9. Electrophilic fluorinations of aryl magnesium reagents. ..............................31
Scheme 1.10. Recent developments in transition-metal mediated electrophilic
fluorinations of arenes........................................................................................................33
Scheme 1.11. Various key reaction intermediates involved in fluoroalkylations. ............35
Scheme 1.12. Typical nucleophilic trifluoromethylation reactions...................................36
Scheme 1.13. Historical development of trifluoromethyl sources for nucleophilic
trifluoromethylations..........................................................................................................37
Scheme 1.14. Landmark applications of trifluoromethyl organometallic reagents and
intermediates. .....................................................................................................................38
Scheme 1.15. Development of nonmetal-based trifluoromethylating agents....................41
Scheme 1.16. Nucleophilic trifluoromethylation using fluoroform as trifluoromethyl
source. ................................................................................................................................42
Scheme 1.17. Typical electrophilic trifluoromethylation reactions. .................................43
Scheme 1.18. Difficulties in electrophilic trifluoromethylations. .....................................45
Scheme 1.19. S-(Trifluoromethyl)chalcogen salts as electrophilic trifluoromethylating
reagents. .............................................................................................................................47
Scheme 1.20. Sulfoximine-based electrophilic trifluoromethylating reagents. ................48
Scheme 1.21. Preparation of (trifluoromethyl)iodonium compounds. ..............................49
Scheme 1.22. Electrophilic trifluoromethylation using (trifluoromethyl)iodonium
compounds. ........................................................................................................................50
Scheme 1.23. Diastereoselective nucleophilic trifluoromethylation of carbonyl
compounds. ........................................................................................................................51
Scheme 1.24. Enantioselective trifluoromethylation of carbonyl compounds. .................54
xxvii

Scheme 1.25. Stereoselective trifluoromethylation of imines. ..........................................57
Scheme 1.26. α-Trifluoromethylation of enolate derivatives and their analogs. ..............60
Scheme 1.27. Cu-Mediated aromatic trifluoromethylations. ............................................62
Scheme 1.28. Pd-Mediated aromatic trifluoromethylations. .............................................64
Scheme 1.29. Difluoromethylations and difluoromethylenations via synthon strategies. 66
Scheme 1.30. Typical nucleophilic difluoromethylations and their reaction
intermediates. .....................................................................................................................67
Scheme 1.31. Conventional nucleophilic difluoromethylating reagents. ..........................69
Scheme 1.32. Development of “S-CF
2
” bond-based nucleophilic difluoromethylating
reagents. .............................................................................................................................71
Scheme 1.33. Difluoromethylation using the Ruppert-Prakash reagent and its analogs...74
Scheme 1.34. Novel electrophilic difluoromethylating reagents. .....................................77
Scheme 1.35. Typical transformations and reaction intermediates of nucleophilic
monofluoromethylation......................................................................................................80
Scheme 1.36. Selected nucleophilic monofluoromethylating reagents. ............................83
Scheme 1.37. Asymmetric monofluoromethylations using α-fluorinated carbonyl
compounds as pronucleophiles. .........................................................................................86
Scheme 1.38. Asymmetric monofluoromethylations via decarboxylative allylation and
allylic alkylation.................................................................................................................88
Scheme 1.39. Developments in the synthesis of fluorobis(phenylsulfonyl)methane. .......89
Scheme 1.40. Catalytic enantioselective monofluoromethylations using sulfone-based
reagents. .............................................................................................................................90
Scheme 2.1. Reaction mechanism for phosphine catalyzed 1, 4-addition to ,-
unsaturated compounds ....................................................................................................129
Scheme 3.1. Synthesis of fluorobis(phenylsulfonyl)methane (FBSM) by (a) C-F bond
forming routes and (b) C-S bond forming route. .............................................................143
Scheme 3.2. Reaction of fluorophenylsulfonyl methide anion with phenyl sulfonyl
chloride. ...........................................................................................................................145
Scheme 3.3. The novel C-S bond forming route for the preparation of
fluorobis(phenylsulfonyl)methane (FBSM) and its and derivatives. ...............................146
Scheme 4.1. Synthetic Applications of FBSM. ...............................................................160
Scheme 4.2. Michael addition of FSM derivatives to ,-unsaturated compounds. ......161
Scheme 4.3. Catalytic enantioselective conjugate addition of FNSM to chalcone. ........162
xxviii

Scheme 4.4 1,4-Addition of α-fluoro-α-nitro(phenylsulfonyl)methane (FNSM) to methyl
vinyl ketone with the bifunctional catalyst QN I. ............................................................170
Scheme 5.1. Enantioselective selective synthesis of α-stereogenic γ-keto esters. ..........208
Scheme 5.2. Improved preparation of NSM. ...................................................................209
Scheme 5.3. Stereoselective synthesis of tetrahydropyridine. ........................................217
Scheme 6.1. (A) Stereoselective synthesis of trifluoromethylated quinidine; (B)
19
F NMR
Spectra of the trifluoromethylated products under different reaction conditions; (C)
19
F
NMR Spectra of 1 in mixed solvents of DMSO-d
6
and CDCl
3
; (D)
1
H NMR Spectra of 1
in mixed solvents of DMSO-d
6
and CDCl
3
(aromatic region). .......................................250
Scheme 6.2. Interconversion of different conformers of 1 in CDCl
3
and in DMSO-d
6
. .253
Scheme 8.1. Six possible conformations of cinchona alkaloids generated via rotations
around τ
1
and τ
2
. ...............................................................................................................381
Scheme 8.2. Flowcharts for cinchona alkaloid conformational analyses. Box A.
Conventional analyzing protocol; B. conformational analysis via trifluoromethyl-
conformational stabilizing/probing strategy. ...................................................................383
Scheme 8.3. Cinchona alkaloid derivative-catalyzed enantioselective cyclopropanation
reaction. ............................................................................................................................420
Scheme 8.4. Comparison of the nucleophilicity of 6-methoxyquinoline and quinuclidine
toward t-butyl α-bromoacetate in CD
3
CN. ......................................................................426

xxix

Abstract
This dissertation is primarily focused on two topics, namely asymmetric nucleophilic
fluoromethylation reactions and the relevant mechanistic studies. The asymmetric
nucleophilic fluoromethylation reactions were achieved using robust nucleophilic
fluoromethylating reagents and a series of cinchona alkaloid-derived catalysts. The
employment of the trifluoromethyl group as a conformational stabilizer and a probe
advanced the knowledge of conformational behavior of cinchona alkaloids and their
derivatives.
Chapter One briefly reviews the history and state of the art of organofluorine
chemistry. The major achievements in synthetic organofluorine chemistry are discussed
in a chronological order, which illustrates a clear overview of the developments in this
field in recent years.
Chapter Two describes the 1,4-addition of α-fluoro(phenylsulfonyl)methane
derivatives to a variety of α,β-unsaturated carbonyl compounds using phosphine-based
catalysts.
Chapter Three conveys a novel synthetic strategy for the preparation of α-
fluoro(disulfonyl)methane and its chloro and methoxy analogues. On the basis of this
method, fluoro(bisphenylsulfonyl)methane (FBSM), a versatile monofluoromethylating
reagent, is easily synthesized on large scale with high yield and selectivity.
Chapter Four demonstrates the catalytic asymmetric 1,4-addition of α-fluoro-α-
nitro(phenylsulfonyl)methane (FNSM) to α,β-unsaturated ketones using cinchona
alkaloid-based thiourea catalysts. As implied by theoretical calculations and X-ray crystal
xxx

structures, α-fluoro-α-nitro(phenylsulfonyl)methide anion adopts pyramidal geometry at
the anionic carbon center, while its non-fluorinated counterpart assumes a planar
structure. Such structural difference leads to fundamentally different origins in
stereoselectivities.
Chapter Five involves the enantioselective synthesis of α-stereogenic γ-keto esters.
By employing nitro(phenylsulfonyl)methane (NSM) as a surrogate for an acyl anion, the
integrated Michael addition reaction-oxidative methanolysis protocol allows the
preparation of various γ-keto esters with high optical purities.
Chapter Six demonstrates the introduction of a trifluoromethyl group into cinchona
alkaloid scaffold as conformational stabilizer and probe, revealing a wealth of
conformational information, which otherwise difficult to achieve.
Chapter Seven discusses hindered CF
3
rotations observed in cinchona alkaloid-based
scaffolds, which allows the exploration of the nature of noncovalent C-H···F-C
interactions.
Chapter Eight is focused on quantitative investigation of conformational behavior of
cinchona alkaloids. By utilizing the CF
3
conformational tool described in Chapter Six, the
conformational behavior of a trifluoromethylated quinidine derivative in various solvents
was analyzed via Linear Free Energy Relationship. These results enables the
quantitatively assessment of the accuracy of theoretical calculations in cinchona alkaloid
conformational analysis.

1

Chapter 1

Introduction - Flourishing Organofluorine
Chemistry: Brief History and State of the Art

2
1.1. Introduction
Organofluorine chemistry concerns molecules with C-F bonds. As an element of
extremes, fluorine has been continuously attracting chemists for more than a century.
1

Over the past two decades, fluoroorganics have been receiving increasing attention
because of their unique chemical properties and promising applications in biology and
materials science (Figure 1.1-A and B). Concomitant with the structural enrichment of
fluoroorganics, the applicability of these compounds has been extending significantly,
which in turn triggers the impetus for synthesizing molecules with higher degrees of
sophistication. Promoted by this intriguing demand-driven mechanism, organofluorine
chemistry has been booming and offering fruitful results to chemists across many
disciplines.
Possessing exceptional electronegativity, fluorine can drastically alter the chemical
nature of organic molecules via various mechanisms, including electron-withdrawing
effects, negative hyperconjugation, field effects, and charge-charge repulsion (Figure
1.1-C and D).
2
On the other hand, due to the presence of non-bonding electron lone-pairs,
fluorine may also behave as an electron-donating substituent through resonance (Figure
1.1-E).
3
Although carbon-fluorine bonds are of great thermodynamic stability, the
extraordinarily high metal-fluoride lattice energies, compared with those of other metal
halides, can lead to facile cleavage of C-F bonds under specific chemical régimes. For

3
these reasons, fluorinating reagents, fluorine-containing building blocks, and the related
reaction intermediates always demonstrate unusual inertness and/or unexpected instability,
considerably limiting their chemical applicability. The theme of contemporary synthetic
organofluorine chemistry is therefore focused on the development of efficient
fluorinating reagents, novel fluorinated building blocks, as well as highly selective
synthetic methodologies for the preparation of useful fluoroorganics.

Figure 1.1. A. Properties involving fluorine, trifluoromethyl group and others; B. fluorine
effects on acidity and basicity; C. fluorine effects on lipophilicity; D. selected fluorine
stereoelectronic effects; E. resonance effects of fluorine.

4
In particular, there have been an increasing number of chemical transformations
necessitating fluorinated organic compounds as privileged catalysts to achieve
extraordinary selectivity and productivity. Owing to the substantial weakness of
intermolecular interactions with non-fluoroorganics, perfluorinated organic compounds
always exhibit low surface tension and unusual miscibility, which have been extensively
exploited as lubricants and fluorous reaction media in a plethora of synthetic processes.
4

Aside from the above mentioned synthetic aspects, fluoroorganics have also been
extensively utilized as valuable materials owing to their unique biological activities
(Figure 1.2).
5
In brief, the remarkable “fluorine effects” are primarily attributed to the
combination of fluorine’s extreme electronegativity and its steric resemblance to a proton.
Biologically, fluorine substitution can lead to fundamental changes in lipophilicity
(controlling the absorption and transportation of molecules in vivo), acidity, basicity, and
protein bonding affinity of organic molecules. Though often believed to be a consequence
of the thermodynamic stability of C-F bonds, the outstanding metabolic stability of
fluorinated organic molecules (bioavailability) can be de facto attributed to the energetic
unfavorableness of breaking a C-F bond to form a C-O bond.
6
Due to the
stereoelectronic effect, fluorine shows a profound tendency to adopt a gauche position to
adjacent heteroatomic substituents. This anomeric/gauche effect always causes
unexpected variations in bioactivity through stabilization of unusual conformations, and

5
has been utilized as conformational tool in organic and biological chemistry.
2
The
applications of
19
F nuclear magnetic resonance (NMR) spectroscopy,
19
F NMR-magnetic
resonance imaging (MRI),
7
and
18
F radiolabeling have become the most promising
strategies in in vivo and ex vivo biological studies.

Figure 1.2. A. Fluorinated drugs among 10 best-selling drugs in 2011; B. Selected
fluorine-containing drugs and drug candidates.

6
More importantly, introduction of fluorinated moieties into catalysts or ligands for
chemical transformations can lead to unusual variation in their catalytic activity by
manipulating the electronic profiles of these molecules. In fact, a plethora of structurally
simple fluorinated small molecules has been developed and thoroughly investigated as
strong/superacids since the late 19
th
century.
8
On the other hand, structurally complicated
fluorine-containing molecules have been extensively employed in metal-based catalytic
and organocatalytic processes as ligands or catalysts over the past two decades.
9

Moreover, owing to the considerable increase in the van der Waals radii of fluoroalkyl
groups compared with the corresponding non-fluorinated counterparts, fluoroalkylated
catalysts can exhibit their stereoselections.
10
Over the past several years, “antagonistic
pairs” (from German term antagonistiches paar)
11
or “frustrated Lewis pairs”,
12

usually composed of fluorinated Lewis acids, have received growing attention. Capable
of activating a series of small molecules such as H
2
, CO
2
, THF, and alkenes,
“antagonistic pairs”/“frustrated Lewis pairs” have shown immense potential in
metal-free catalytic reactions.
13

Organofluorine chemistry has become a rather comprehensive subject impacting a
broad scope of scientific fields. For the sake of brevity, we will refrain from compiling
every detail of the development in organofluorine chemistry. Instead, from the viewpoint
of synthetic chemists, we will focus the majority of our attention on the innovative

7
achievements in the syntheses of useful fluorinated organic molecules over the past
twenty years. We expect this brief review to provide some conceptual insight into the
achievements and primary challenges in this field since the end of the last century.
1.2. Synthetic Approaches for the Introduction of Fluorine-Containing
Functionalities and Related Chemistry
Fluoroorganics are extremely scarce in nature. Hence the primary challenge
encountered in the early stages of organofluorine chemistry was to efficiently construct
carbon-fluorine bonds (Figure 1.3-C, Bond α-β). Historically, attempts to obtain
fluorinated organic compounds via synthetic approaches date back to the 18
th
century
(Figure 1.3-B).
14
The first construction of a C-F bond was achieved by Dumas and
Péligot who successfully prepared methyl fluoride by treating dimethyl sulfate with KF,
which marked the beginning of the organofluorine chemistry.
15
Half a century later,
elemental fluorine was successfully isolated by Moissan in 1886, who was awarded the
Nobel Prize in chemistry for this achievement in 1906 (Figure 1.3-B).
16
As such, in
addition to hydrofluoric acid and metallic fluorides, elemental fluorine was added into the
toolbox of fluorinating reagents to achieve new fluorination methods. More efficient
preparative methods for fluoroorganics of practical interests were then pioneered by
Swarts, who first exploited halogen exchange processes under Lewis acid conditions in
1892 (Figure 1.3-B).
17
In the early part of the last century, various important

8
fluorine-containing chemicals and materials became accessible at the industrial scale by
means of various practical protocols, such as the Balz-Schiemann reaction (Figure
1.3-B),
18
the cobalt trifluoride process (by Fowler et al.),
19
electrochemical fluorination
(by Simons and co-workers),
20
and the Halex process.
21
Since the availability of
fluorinated organic molecules has dramatically increased, the investigations of chemical
transformations of these compounds eventually evolved as building block strategies in
the mid twentieth century.

9

Figure 1.3. A. Publications relevant to organofluorine chemistry and fluorine-containing
drugs (based on a SciFinder search in April 2012); B. Milestones in synthetic
organofluorine chemistry prior to 1960s; C. Chemical bonds of interest to organofluorine
chemists.

10
A series of synthetic approaches was then adopted as powerful tools for the
introduction of fluorinated functionalities (primarily fluoroalkyl moieties) in the 1980s
(Figure 1.3-C, formation of β-γ, γ-δ bonds, and so on). Since the substrates are
“preinstalled” with C-F bonds, the harsh conditions usually involved in C-F bond
formations can be avoided, which allows the construction of more complex molecular
structures with enhanced selectivity.
Utilizing a variety of fluorination/fluoroalkylation reagents and protocols,
organofluorine chemists have been able to prepare fluoroorganics based on nucleophilic,
electrophilic, carbene, ylide, electrochemical, and radical pathways.
22
To date, the
majority of effort is devoted toward the development of versatile reagents and novel
synthetic methods being applicable under milder conditions with higher efficiency.
Aiming at syntheses of stereogenic molecules of potential bioactivity, the asymmetric
introduction of fluorinated moieties has become an attractive field. In addition to C-F
bond formation reactions, C-F bond activations have also been revisited for their
promising utility in the preparation of partially fluorinated molecules.
23
Moreover,
transition-metal-mediated and catalyzed fluorinations and fluoroalkylations have
burgeoned recently, and have demonstrated prominent synthetic advantages making them
valuable synthetic tools in organofluorine chemistry.
Very importantly, the discovery of fluorinase enzyme capable of catalyzing C-F

11
formation by O’Hagan and coworkers also paves the way for the biosyntheses of
fluorinated organic compounds.
24

1.2.1. Novel Fluorinating Reagents and C-F Bond Formation Reactions
Conceptually, the formation of C-F bonds can be achieved by four mechanistic
pathways: radical fluorinations (direct fluorination), electrochemical fluorination (ECF),
nucleophilic fluorination, and electrophilic fluorination (Figure 1.4). Direct fluorination
and ECF have been successfully utilized in the preparation of perfluorinated organic
compounds in many of industrial processes. In the early 1970s, Margrave, Lagow and
Adcock demonstrated the controllable direct fluorination reaction of hydrocarbons (the
Aerosol Direct Fluorination Process) under a radical pathway to afford various useful
perfluorochemicals such as perfluorinated alkanes and perfluorinated ethers.
25

Nevertheless, the applicability of these methods is always limited when it comes to
fluorine-containing moieties bearing reactive functionalities due to their unsatisfactory
selectivity and harsh operating conditions. In contrast, the nucleophilic and electrophilic
fluorinations have prevailed in terms of selectivity and functional group compatibility.

12

Figure 1.4. Four synthetic pathways for C-F bond formations.

1.2.1.1. Nucleophilic Fluorinations
As the first utilized fluorination method, nucleophilic fluorinations are still among the
most important routes to fine fluorochemicals in industry.
26
Apart from the large-scale
syntheses, its importance has also been reflected in the extensive applications in
preparing [
18
F]-radiolabeled compounds for positron emission tomography (PET).
27

Since nucleophilic fluorinations of halides and pseudohalides undergo S
N
2 or S
N
Ar
mechanisms in many cases, the displacement generally enables the introduction of C-F
bonds with good regio- and/or stereospecificity. Nevertheless, the low nucleophilicity of
the fluoride ion, arising from its poor polarizability, considerably limits the applications
of the methodology. In order to tackle this problem, two strategies have been frequently
employed, namely (a) the enhancement of the nucleophilicity of the fluoride ion by
weakening its solvation, hydrogen bonding, and interactions with counterions (metallic
cations and so on); and (b) the activation of the electrophiles with Brønsted or Lewis
acids.

13
For the first strategy, a great portion of the efforts has been concentrated on seeking
uncoordinating cationic species (such as tetraalkylammonium, and tetraphenylphosphium
ions) to render the so-called “naked” fluoride ion as termed by Liotta.
28
However, owing
to their extreme hygroscopic nature, these reagents are always associated with practical
problems, such as storage and handling. Moreover, other than tetramethylammonium
fluoride,
29
anhydrous tetraalkylammonium fluorides are usually unavailable as solids
because of the significantly increased basicity of the fluoride ion, which can lead to the
severe decomposition of the cations. The preparation of anhydrous TBAF (TBAF
anh
) was
achieved by treating tetrabutylammonium cyanide with hexafluorobenze in DMSO by
Dimagno.
30
The same group further demonstrated the nucleophilic fluorination of
electron-deficient aromatic compounds using this reagent under ambient conditions.
31

Since the late 1970s, instead of modifying the cations, chemists have shifted their
attention to stabilizing the fluoride ion by using difluorinated hypervalent silicates and
stannates, which have demonstrated superior chemical and physical properties compared
with alkali metal and tetraalkylammonium fluorides (Scheme 1.1).
32,33,34
Alternatively,
probably one of the most impressive findings was achieved in 2006 by Chi et al, who
discovered that nonpolar protonic tertiary alcohols can significantly promote nucleophilic
fluorination with alkali metal fluorides.
35
Contrary to conventional theory, the beneficial
effects of tertiary alcohols were further elucidated as (a) the solvation of the fluoride ion

14
by weakening ionic metal-fluoride bonding; (b) formation of more nucleophilic “flexible”
fluoride by hydrogen bonding with suitable strength; (c) increasing nucleofugality of
leaving groups by stabilization of them in the reaction media; (d) inhibiting side reactions
such as elimination and intramolecular alkylation by decreasing basicity of fluoride ion.
36

More recently Kim et al. reported the preparation of tetrabutylammonium tetra(tert-butyl
alcohol)-coordinated fluoride as a low hygroscopic fluoride source.
37
As indicated by
X-ray crystal structure, the fluoride ion was confirmed to coordinate with four tert-butyl
alcohol molecules through hydrogen bonding (Scheme 1.1). Synthetically, the
fluorinating power of TBAF-(tBuOH)
4
was shown to be substantially stronger in
comparison with other F
-
sources.

Scheme 1.1. Nucleophilic fluorination reactions and the related reagents.

15
Facile nucleophilic fluorination can also be accomplished through the activation of
electrophiles using Brønsted and/or Lewis acids. Such a strategy dates back to the late
19
th
century. Over the past century, a series of important fluorination systems have been
developed based on this mechanism, including SbF
3
-HF, SbF
5
-HF, AlF
3
-HF, hypervalent
halogen fluorides,
38
as well as amine-hydrogen fluoride (such as 70% HF-pyridine,
Olah’s reagent
39
). In addition to these systems, gaseous sulfur tetrafluoride (SF
4
),
40

PhSF
3
,
41
and its derivatives are among the most versatile nucleophilic fluorinating
reagents with significant synthetic usefulness.
42
The treatment of alcohols, carbonyl
compounds, and carboxylic acids with these reagents results in the replacement of the
C-O bonds with C-F bonds to generate corresponding mono-, di-, and
tri-fluoromethylated products (termed the deoxofluorination process) (Scheme 1.2).
Noticeably, undergoing an S
N
2 pathway, deoxofluorination of chiral secondary alcohols
may afford products with inverted configurations with high stereoselectivity, which has
been shown as a critical synthetic protocol toward the formation of stereogenic
fluorinated carbon centers.
43
Due to the toxicity and high volatility of SF
4
,
N,N-diethylaminosulfur trifluoride (DAST) was developed by Middleton as a superior
deoxofluorinating agent that has been used for over 30 years.
44
However, the storage and
handling of DAST are rather tedious because of its violently explosive nature and
insufficient thermal stability. In order to overcome these deficiencies, intense efforts have

16
been made on the development of user-benign alternatives to DAST. Over the past
several years, a variety of deoxofluorinating reagents have been introduced with both
satisfactory reactivity and enhanced stability, such as dialkylaminodifluorosulfinium salts
(XtalFluor-E and -M),
45
bis(methoxyethyl)aminosulfur trifluoride (Deoxo-Fluor),
46
and
4-tert-butyl-2,6 -dimethyl-phenylsulfur trifluoride (Fluolead).
47

Scheme 1.2. Development of S-F bond based deoxofluorinating reagents.
In addition to the above-mentioned fluorinations, a series of fluorine-containing
Lewis acids has been used as fluoride sources in ring opening reactions. BF
3
-Et
2
O was
employed by House in the ring opening of epoxides in 1956 to afford the corresponding
hydrofluorinated products.
48
Nakayama, Hu, and Hou have expanded this chemistry into

17
the stereoselective ring opening reaction of aziridines (Scheme 1.3) in recent years.
49

Lately, Davies reported the efficient ring-opening hydrofluorination of a range of
substituted aryl epoxides to syn-fluorohydrins.
50
The stereochemical outcomes explicitly
indicated substantially different mechanistic pathways during the course of these
transformations. As illustrated in Scheme 1.3, in contrast to the ring-opening reactions
undergoing an S
N
2-type pathway to afford configurationally inverted products,
carbocation intermediates are involved in the ring opening of epoxides resulting in
conservation in stereochemical profiles.

Scheme 1.3. Ring-opening reactions of aziridines and epoxides using BF
3
-OEt
2
as the
fluorine source.

18
While a large number of reactant-controlled stereospecific nucleophilic fluorinations
have been demonstrated, only a handful of reagent-controlled stereoselective nucleophilic
fluorinations are known. Since the S
N
2 mechanistic pathway presents a strong tendency
to afford configurationally inverted products, kinetic resolution has been frequently
involved in asymmetric nucleophilic fluorinations of racemic substrates. Hann and
Sampson first described enantioselective deoxofluorination using a stoichiometric
amount of an optically enriched DAST analog (1) (Scheme 1.4).
51
However, no
appreciable stereoselectivity was observed. Instead of using homochiral fluorinating
reagents, Bruns and Haufe exploited stoichiometric Jacobsen’s (salen) complexes (2) and
hydrofluorides to achieve the asymmetric ring opening of epoxides with elevated
enantiomeric excesses (ee) (Scheme 1.4).
52
Very recently, a more encouraging process
toward this goal was developed by Doyle et al.
53
Realizing that conventional reaction
conditions suffer from competitive background reactions and catalyst inhibition, they
adopted specially designed cocatalytic systems to achieve catalytic asymmetric ring
opening of epoxides by the fluoride anion.

19

Scheme 1.4. Development of asymmetric nucleophilic fluorinations.

As previously mentioned, synthesis of various aryl fluorides was achieved over a
century ago, and has been successfully commercialized. In particular, the nucleophilic
replacement of electron-deficient aryl halides or psuedohalides (activated) with fluoride

20
can be readily achieved to render regiospecific products. Due to the difficulty in forming
Meisenheimer complexes, nonactivated substrates are always inert under regular
non-catalytic nucleophilic fluorinating conditions. To overcome this problem,
organometallic fluorine chemistry was introduced and has been vibrant over the last
several years.
54
Unlike other aromatic halogenations (Cl, Br, I) mediated by transition
metals, the analogous fluorination reactions were a long-standing challenge. Conceptually,
the catalytic cycle is composed of three steps as (a) the oxidative addition of aryl halides
or triflate with Pd(0) complexes; (b) the halogen exchange with fluoride; (c) the reductive
elimination of the fluorinated Pd(II) complexes to release the corresponding aryl
fluorides (Figure 1.5).

Figure 1.5. Pd-catalyzed nucleophilic fluorination of aryl halides and aryl triflate.

21
Although the oxidative addition of Ar-X had been well established over the past
several decades, the other two steps were in question (Figure 13.3). The formation of
low-valent transition-metal fluoro compounds turns out to be the first obstacle in this
catalytic process primarily due to the incompatibility in the hardness of fluoride and
transition metal centers.
55
Dixon et al. reported the detection of [(Et
3
P)
3
Pd
II
F]
+
via
19
F
NMR spectroscopy, however, the attempted isolation of the complex resulted in severe
decomposition to yield Et
3
PF
2
and Pd(0) complexes (Scheme 1.5).
56
Grushin et al. made
pioneering attempts at catalytic fluorination of arenes using a series of transition metals
(including Pd, Rh, Ni, Pt, and so on) in the late 1980s to early 1990s.
57
The unproductive
results led to further examining the mechanistic validity of the proposal by the synthesis
of the key reaction intermediates. The synthesis and the isolation of aryl palladium(II)
fluoride ([(Ph
3
P)
2
Pd
II
(Ph)F]) was eventually accomplished by ultrasound-promoted I-F
exchange or neutralization of M-OH species using Et
3
N-(HF)
3
, which demonstrated the
theoretical possibility of halogen exchange.
57,58,59
On the other hand, the reductive
elimination of aryl palladium(II) fluorides to generate aryl fluorides seems to be more
difficult because of the facile intramolecular nucleophilic attack of the fluoride on the
phosphine ligands (Scheme 1.5).
60
The decomposition of aryl palladium(II) fluoride was
recently observed to yield a small quantity of aryl fluoride;
61
however, whether this
outcome is a consequence of reductive elimination is still questionable (Scheme 1.5).
62

22
Although these elegant mechanistic studies have not completely ascertained the catalytic
cycle, a palladium-catalyzed nucleophilic fluorination of aryl triflates was achieved by
Buchwald, who finally put the last piece into this puzzle (Scheme 1.5).
63
In addition to
good yields and selectivity, the synthetic protocol has also demonstrated satisfactory
functional group compatibility and broad substrate scope, which permits the facile
syntheses of various fluorinated arenes. More recently, Ritter and co-workers have
recently shown that phenols can also participate in deoxofluorination in the presence of
an imidazole-based reagent.
64

Scheme 1.5. Development of palladium-mediated nucleophilic fluorination of arenes.

23
Noticeably, in 2002, Subramanian and Manzer described the Cu-mediated
oxidative fluorination of benzene in gas phase to form fluorobenzene as the exclusive
product (Scheme 1.6).
65
In spite of a “greener” protocol, the reaction suffered from
unsatisfactory yield and poor recyclability of the metal reagent. Dolbier et al. further
improved the process by using nominal CuAl
2
F
8
as an effective fluorinating agent
capable of multiple regeneration.
66
In comparison with the Pd(II)-catalyzed nucleophilic
aromatic fluorinations, these synthetic approaches are exclusively restricted to simple
aromatics due to severe reaction conditions.

Scheme 1.6. Cu-mediated nucleophilic fluorination of arenes.

1.2.1.2. Electrophilic Fluorinations
Unlike the fluoride ion, free “F
+
” remains unknown in the condensed phase. As a
consequence, compared with nucleophilic fluorinations, the electrophilic construction of
C-F bonds was established much later due to the dearth of appropriate “F
+
” sources. The
first electrophilic fluorination was de facto achieved by Inman et al. in the reaction of
active methylene groups with perchloryl fluoride (FClO
3
)
67
to afford the corresponding
fluorinated compounds.
68
In 1968, Barton and Hesse introduced the concept of

24
electrophilic fluorination for the first time by demonstrating fluoroxytrifluoromethane
(CF
3
OF)
69
as a versatile reagent for the electrophilic olefinic and aromatic
fluorinations.
70
Their elegant work further led to the development of a family of
electrophilic fluorinating reagents based on the O-F moiety,
71
including CF
3
CO
2
F,
72

HOF,
73
and CsSO
4
F.
74
Furthermore, the application of xenon difluoride (XeF
2
)
75
was
reported by Yang et al. for the fluorination of alkenes and aromatics.
76
In addition to
utilizing the labile O-F and Xe-F bonds, the weakness of the F-F bond also allows
electrophilic fluorination using elemental fluorine. Wolf et al. have demonstrated the
selective electrophilic aromatic fluorination with highly diluted molecular fluorine.
77

Rozen and Gal later reported the electrophilic fluorination of saturated hydrocarbons
using F
2
-CHCl
3
/CFCl
3
system through a C-H bond insertion pathway, which led to
monofluorinated products.
78
Despite their frequent utilization as electrophilic fluorine
sources prior to the 1990s, applicability of these reagents was still restricted by their
drawbacks such as low stability, unsatisfactory selectivity, and limited commercial
availability.

25

Scheme 1.7. Electrophilic fluorinations and the related reagents.

26
While extensive studies were focused the O-F based electrophilic fluorinating
reagents from the late 1960s to the early 1980s, the difficulties in their commercialization
significantly impeded the applications of these reagents.
71
Instead, the N-F based systems
emerged as versatile reagents.
79
Interestingly, the utility of labile N-F linkage as a
fluorinating agent was discovered prior to the O-F reagents.
80
However, because of the
poor yields and harsh conditions, these reagents were for years not drawing sufficient
attention. Since the 1980s and particularly from the late 1980s to the early 1990s,
realizing the potential synthetic usefulness of the N-F class of agents, organofluorine
chemists have devoted tremendous efforts to this field. During this NF reagent era, a
spectrum of compounds (neutral R
2
NF and R
3
N
+
F salts) with different fluorinating
capabilities
81
were explored, including 1-fluoro-2-pyridone (Tee in 1983),
82

N-fluoropyridinium triflate (Umemoto in 1986),
83
N-fluoroperfluoroalkylsulfonimides
(DesMarteau in 1987),
84
as well as N
2
F
+
and NF
4
+
salts (Scheme 1.7).
85
Eventually two
compounds that evolved from this class of reagents were commercialized in the early
1990s, they are N-fluorobenzenesulfonimide (NFSI) (Differding in 1991)
86
and
1-chloromethyl-4-fluoro-1,4-diazoniabicyclo [2.2.2]octane bis(tetrafluoroborate)
(Selectfluor
®
, Banks in 1992).
87
To date, NFSI and Selectfluor
®
are among the most
commonly employed electrophilic fluorinating agents enabling a variety of C-F bond
forming reactions.
79,88 ,89
Theoretically, there has been much controversy about the

27
mechanistic details of electrophilic fluorinations since the early 1990s.
79,89,90
Based on a
series of mechanistic studies, two pathways are usually proposed: single-electron transfer
(SET) and nucleophilic substitution (S
N
2) depending on reagents, substrates, as well as
reaction conditions (Scheme 1.7 bottom). It is also important to point out that the
electrophilic fluorination of saturated hydrocarbons using F
2
, N
2
F
+
and N
4
F
+
salts always
proceed through a C-H bond insertion pathway instead of the two mechanisms mentioned
above.
78,91

As previously discussed, although a few enantioselective protocols have been
reported, nucleophilic fluorinations usually provide configurationally inverted products
stereospecifically via an S
N
2 reaction pathway. In comparison, asymmetric electrophilic
fluorinations are quite spectacular. Without the mechanistic restriction (the S
N
2
configurational inversion requirement), electrophilic fluorinating reactions are capable of
stereoselective construction of nonracemic stereogenic fluorinated carbon centers under
various chemical regimens.
89,92

Enantiocontrolled electrophilic fluorination dates back to the late 1980s.
α-Fluorination of carbonyl compounds is of particular interest and has been one of the
major synthetic goals in asymmetric fluorination. Differding and Lang first documented
camphor-based N-fluorosultam (6) as the homochiral fluorinating reagent in the
asymmetric fluorination of metal enolates (Scheme 1.8).
93
Thereafter, a series of

28
N-fluorosultams were synthesized and explored by Davis (7)
94
and Takeuchi et al. (8,
95

9
96
). Although appreciable increase in enantiomeric excesses was achieved by attentive
structural modifications, the synthetic usefulness of these approaches was still
questionable to a large extent because of their low efficacy. Allowed by the
fluorine-transferring reaction of the quinuclidine moieties in cinchona alkaloids,
97

Cahard (10)
98
and Takeuchi (11)
99
independently discovered the efficient asymmetric
fluorinations of enolates by delivering the stereo-information from in situ prepared
N-fluoro-cinchona alkaloid scaffolds. More importantly, a breakthrough was achieved by
Togni et al. who developed the first efficient catalytic asymmetric fluorination method.
100

Instead of using stoichiometric chiral fluorinating agents, taddol-titanium complexes (12)
were exploited as Lewis acid catalysts in combination with Selectfluor in the
enantioselective α-fluorination of β-keto esters. Likewise, a large number of chiral Lewis
acid complexes, including late-transition metal-based Lewis acids (13), have been found
to be efficient catalysts in asymmetric fluorination.
92d,101
In recent years, organocatalysis
has emerged as a valuable synthetic tool in asymmetric chemical transformations.
102
In
2002, Kim et al. documented the catalytic enantioselective fluorination of β-keto esters

using a cinchonidine-based phase transfer catalyst (PTC, 14) to afford the products in
moderate enantiomeric excesses.
103
Shortly afterwards, in 2005, three research
laboratories independently developed asymmetric α-fluorinations of aldehydes via

29
enamine catalysis using different catalysts. MacMillan et al. utilized imidazolidinone (15)
as the asymmetric catalyst in the transformation to achieve excellent enantioselectivity.
104

Jørgensen et al. accomplished the α-fluorination of aldehydes employing the remarkably
efficient proline derivative (16) as the catalyst to afford the products with good
enantiomeric discrimination.
105
Barbas III et al., on the other hand, have examined a
variety of proline analogs and imidazolidinone (15), which revealed the latter as the
optimal catalyst.
106

Scheme 1.8. Development of asymmetric electrophilic fluorinations.

30
Electrophilic aromatic fluorination has been known for several decades since Hesse
et al.
70b
and Shaw et al.
107
reported the reactions between electrophilic fluorinating
reagents with arenes in the late 1960s.
108
In general, direct electrophilic fluorination of
electron-rich aromatic compounds is feasible to achieve, but the fluorination of the
electron-deficient arenes which exhibit substantially lower reactivity was achieved under
superacid conditions.
109
However, these methods always proceed with unsatisfactory
regioselectivity. An alternative synthetic approach treats organometallic reagents with
“F
+
” to afford the corresponding fluoroarenes; however, it is limited to simple
substrates.
110
Very recently, Knochel et al. have disclosed a convenient electrophilic
fluorinating protocol for the functionalization of aryl magnesium compounds in the
presence of LiCl and NFSI.
111
The methodology has shown remarkable applicability to a
broad scope of aromatic compounds including highly functionalized arenes,
electron-deficient aromatic, and heterocyclic compounds (Scheme 1.9, Top).
Independently, Beller et al. reported a similar procedure using
N-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate as the fluorine source to afford
various fluoroarenes (Scheme 1.9, Bottom).
112

31

Scheme 1.9. Electrophilic fluorinations of aryl magnesium reagents.

Apart from those employing a stoichiometric amount of aryl organometallic reagents,
transition metal-catalyzed electrophilic aromatic fluorinations have also emerged in
recent years.
54,113,114
Although the conventional arene fluorination methods will still
govern the synthesis of fluorinated aromatics on an industrial scale in the foreseeable
future, these novel approaches are believed to be superior in sophisticated syntheses due
to their milder reaction conditions. In 2006, Sanford et al. demonstrated the first
palladium-catalyzed electrophilic aromatic fluorination by means of C-H activation
(Scheme 1.10, eq 1).
115
In the presence of directing groups, the method permits the
formation of ortho-fluorinated arenes in moderate to good yields. However, the harsh
reaction conditions and unsatisfactory regioselectivity are the major obstacles to its
practical synthetic utility. Yu reported the conceptually similar electrophilic fluorination
of N-benzyltriflamides adopting palladium (II) triflate as the catalyst (Scheme 1.10, eq

32
2).
116
Although the directing group can be readily converted into other functionalities,
the above-mentioned drawbacks remain. In comparison, Ritter et al. have attempted to
achieve facile electrophilic fluorinations undergoing a transmetallation mechanism,
which are expected to render enhanced selectivities and synthetic utility. As depicted in
Scheme 1.10, aryl-fluorine bonds can be formed by treating aryl stannanes (eq. 3)
117
or
boronic acids (eq. 4)
118
with “F
+
” reagents in the presence of stoichiometric amounts of
silver triflate.
119
Most recently, a catalytic variant of these methodologies has been
established by the same research laboratory, which allows regiospecific transformation of
a C-Sn bond into the corresponding C-F bond.
120
Interestingly, although further
experiments remain necessary for ascertaining the mechanism, a silver redox catalytic
pathway involving aggregated silver complexes and high-valent silver species was
proposed for this cross-coupling reaction. Ritter’s group also established an aromatic
fluorination protocol utilizing Pd(IV) fluoride generated from the corresponding Pd(IV)
complex and KF (Scheme 1.10, eq. 6).
121
The protocol was also found to be applicable to
the synthesis of aromatic
18
F-labeled molecules via late-stage fluorination.

33

Scheme 1.10. Recent developments in transition-metal mediated electrophilic
fluorinations of arenes.

34
1.2.2. Efficient Trifluoroalkylation Reactions
Despite the fact that fluoroalkyl moieties can be obtained by direct fluorinations with
SF
4
derivatives, fluorides, and/or electrophilic fluorinating agents, utilization of
fluoroalkyl synthons prevails unequivocally because of higher efficiency and functional
group compatibility. Due to the lack of versatile fluoroalkylating precursors (particularly
fluoromethylating reagents), the introduction of fluorinated motifs by direct construction
of C-F bonds monopolized synthetic organofluorine chemistry until the 1950s.
Concomitant with the increased number of functionalized fluoroorganics, building block
methodologies have become viable synthetic tools in organofluorine chemistry.
Mechanistically, a number of key reaction intermediates are involved in fluoroalkylations,
including α-fluorocarbanions, α-fluorocarbocations, α-fluorocarbenes, α-fluorinated
radicals, β-fluorocarbanions, and others (Scheme 1.11). Because of the steric demand and
the extremely strong electronegativity of fluorine, these fluorinated species always
demonstrate fundamentally different chemical behavior in comparison with their
nonfluorinated counterparts. In this section, the majority of our attention is focused on the
most extensively employed nucleophilic and electrophilic α-fluoroalkylation methods for
the CF
X
-C bond formations. Therefore, nucleophilic β-fluoroalkylations, recently
reviewed by Uneyama,
122
as well as fluoroalkylating protocols based on radicals,
123

ylides,
124
and carbenes
125
intermediates, well established in the last century, will not be

35
covered in this section. Moreover, the Julia-Kocienski fluoroolefination, which has also
been reviewed thoughtfully, will not be included in this chapter either.
126

Scheme 1.11. Various key reaction intermediates involved in fluoroalkylations.

1.2.2.1. Nucleophilic Trifluoromethylating Reagents, Trifluoromethyl-Metal
Reagents and Related Chemical Transformations
Defined by the key reaction intermediate, the trifluoromethyl carbanion, nucleophilic
trifluoromethylation has been extensively exploited in the syntheses of numerous
trifluoromethyl-containing organic molecules of scientific and practical interest. A variety
of electrophilic species have been found to be reactive toward the trifluoromethyl anion,
including aldehydes, ketones, esters, imines, nitriles, nitrones, alkyl halides, and so on
(Scheme 1.12).
127 , 128 , 129 , 130 , 131
Apart from these transformations, trifluoromethyl
organometallic reagents are also applicable in cross coupling reactions with aromatic
halides (the Ullmann reaction), alkenyl halides, and alkynes.

36

Scheme 1.12. Typical nucleophilic trifluoromethylation reactions.
Mechanistically, the repulsive force of the vicinal “anion-lone pair” (derived from the
adjacent anionic carbon center and non-bonded sp
3
lone pairs on the α-fluorine atom)
significantly impairs the stability of the anion, and leads to -fluoride elimination under
many reaction conditions (Scheme 1.12).
132
Even though C-F bonds are among the
strongest chemical bonds in organic compounds, stabilization of the CF
3
carbanion
proved to be difficult in the presence of metal cations owing to the energy compensation
arising from the extraordinary stability of metal-fluoride lattices. The breakthrough was
achieved in 1948, when Haszeldine first prepared trifluoromethyl iodide (CF
3
I), which
was employed as the exclusive CF
3
anion precursor through the 1950s to the 1980s.
133

37
Since the 1980s, several fluoromethyl-containing species have entered the nucleophilic
trifluoromethyl arena, such as CF
2
Br
2
, trifluoro acetates,
134
and CF
3
Br.
135
Importantly,
Burton et al. disclosed the preparation of trifluoromethyl organometallics using CF
2
Br
2
via a difluorocarbene intermediate.
136
Chen and co-worker have utilized methyl
fluorosulfonyldifluoroacetate as a trifluoromethylating reagent toward a variety of aryl
and alkyl halides in the presence of a catalytic amount of CuI.
137
Noticeably, although
CF
3
H is a seemingly obvious trifluoromethyl anion source which was even available
prior to the 20
th
century,
138
its synthetic utility was not achieved until two decades ago.
139

Scheme 1.13. Historical development of trifluoromethyl sources for nucleophilic
trifluoromethylations.
Despite having achieved various nucleophilic perfluoroalkylations based on
organometallic reagents having been achieved in the early 1950s,
140
facile incorporation

38
of the trifluoromethyl motif using similar trifluoromethyl organometallics was a
longstanding synthetic challenge.
141
Indeed, extensive attempts to prepare a series of
trifluoromethyl metal species with CF
3
I were made in the mid-20
th
century, including
bis(trifluoromethyl) mercury (the first trifluoromethyl organometallic compounds),
142

trifluoromethyl lithium,
140b,142
and trifluoromethyl magnesium iodide.
143
Unfortunately,
these species are either extremely labile or unexpectedly unreactive, considerably
limiting their application in terms of synthetic chemistry. Instead, trifluoromethyl
copper
144
and zinc derivatives
135b,145
were found to furnish superior reactivity and
stability. Particularly, CF
3
Cu, generated in situ by treating Cu metal with CF
3
I or CF
2
Br
2
,
was developed for a variety of cross-coupling reactions with aryl halides and these are
still widely employed for CF
3
incorporation today (Scheme 1.14).

Scheme 1.14. Landmark applications of trifluoromethyl organometallic reagents and
intermediates.

On the other hand, the emergence of a variety of nonmetal-based trifluoromethylating
reagents has ushered a new era since the late 1980s. Meijere first reported nucleophilic

39
trifluoromethylation of ketones with in situ generated
trialkylsilyl(trifluoromethyl)diazenes to afford the corresponding carbinols in 30-34%
yield under harsh conditions.
146
Afterward, while the preparative approach toward
trifluoromethyltrimethylsilane (TMSCF
3
, the Ruppert-Prakash reagent) was established
by Ruppert in 1984,
147
the synthetic usefulness of this compound as a nucleophilic
trifluoromethylating agent was not realized until Prakash et al. made the breakthrough in
1989.127a In comparison with the organometallic reagents and
trialkylsilyl(trifluoromethyl)diazenes, the lability of the Si-CF
3
bond enables the
transformation of the CF
3
anion under mild conditions with remarkably high efficacy.
Moreover, the reagent has also shown excellent reactivity to a wide scope of functional
groups, including aldehydes, ketones, esters, imines, nitriles, nitrones, alkyl halides, as
well as metallic substrates for in situ generation of corresponding organometallic
species.
148
Noticeably, TMSCF
3
has demonstrated superior applicability in the
asymmetric construction of C-CF
3
bonds, thereby significantly facilitating the efficient
syntheses of various bioactive chiral fluoroorganics.92e In contrast, the synthetic
applicability of other trifluoromethytrialkylsilanes has been quite limited presumably due
to the relatively low reactivity of these reagents.
149
Similar to the synthesis of TMSCF
3
by Ruppert, Pawelke exploited CF
3
-tetrakis(dimethylamino)ethylene complex as a
trifluoromethylating reagent for the formation of CF
3
-B and CF
3
-Si bonds.
150
The

40
chemistry was later extended by Dolbier for synthesizing various trifluoromethylated
organic molecules.
151
On the other hand, Prakash et al. have also disclosed the utility of
trifluoromethyl phenyl sulfone (PhSO
2
CF
3
), prepared from non-ozone depleting CF
3
H, as
a versatile trifluoromethylating reagent toward carbonyl compounds and imines (Scheme
1.15).
152,153

41

Scheme 1.15. Development of nonmetal-based trifluoromethylating agents.
Compared with other precursors (CF
3
I, CF
3
Br, CF
2
Br
2
, and so on), fluoroform (CF
3
H)
is conceptually the most efficient trifluoromethyl precursor in terms of atom economy; its
synthetic utility, however, was unknown for a long while.
154
Pioneered by Shono et al.,

42
the incorporation of the CF
3
moiety was achieved through deprotonation of CF
3
H in
DMF with electrogenerated bases.139,
155
Roques improved the methodologies using
readily available bases, and first inferred the formation of the trifluoromethylated
hemiaminal intermediate,18, responsible for the stabilization of the labile CF
3
anion.
156

Several trifluoromethyl hemiaminals have been prepared thus far by means of the
addition of the CF
3
anion to formamides (19b and 19c) or the reaction of fluoral
methylhemiacetal with amines (19a and 19b) as trifluoromethylating reagents for a
variety of organic substrates.
157

Scheme 1.16. Nucleophilic trifluoromethylation using fluoroform as trifluoromethyl
source.

43
1.2.2.2. Electrophilic Trifluoromethylating Reagents and Reactions
158

In comparison with the trifluoromethylations using an anionic trifluoromethyl
equivalent, which date back to the early 1950s, electrophilic trifluoromethylations were
achieved only recently. Thanks to the efforts devoted to this field, a variety of efficient
reagents have been developed over the past three decades. Electrophilic introduction of
the trifluoromethyl moiety has therefore become one of the most promising
trifluoromethylating strategies. In addition to construction of CF
3
-C (sp
3
, sp
2
or sp) bonds,
electrophilic trifluoromethylations have also enabled a large number of heteroatom-CF
3

bond forming reactions, which are of significance in syntheses of compounds possessing
unique biological and chemical properties (Scheme 1.17).

Scheme 1.17. Typical electrophilic trifluoromethylation reactions.

44
Historically, Haszeldine first investigated the capability of CF
3
I as an electrophilic
trifluoromethylating reagent. Treated with potassium hydroxide, CF
3
I was converted into
fluoroform (CF
3
H) as the product implying the reverse polarization of the C-I bond
compared with the non-fluorinated analogs.
159
In 1976, Olah first described the
preparation of trifluoromethyl triflate (CF
3
OTf) by reaction of triflic acid with
fluorosulfuric acid, which evidentially suggested an electrophilic trifluoromethylation
mechanism.
160

On the other hand, attempts to trifluoromethylate nucleophilic species using
trifluoromethyl triflate in which the leaving group (CF
3
SO
3
-
) demonstrates tremendous
nucleofugality resulted in nucleophilic attack on the sulfur atom. One may argue that the
sluggishness of the electrophilic trifluoromethylations was primarily caused by the
extraordinarily strong electronegativity the CF
3

moiety and the difficulties in generation
of the cation thereby. However, mass spectrometry confirms the existence of the
trifluoromethyl cation as an abundant species.
161
Surprisingly enough, a gas-phase ion
study has suggested that the order of the stability of various methyl cations decreases as
CHF
2
+
> CH
2
F
+
> CF
3
+
> CH
3
+
,
162
which can be attributed to a balance between the high
electronegativity of fluorine and the back donation of its lone-pair of electrons to the
vacant p-orbital (Scheme 1.18). In fact, the inertness of the CF
3
moiety toward
nucleophiles was realized to be a consequence of (a) the reverse polarization of the

45
CF
3
-halogen and CF
3
-O bonds in nature; (b) the steric inaccessibility of the CF
3
group for
nucleophilic attack (Scheme 1.18).

Scheme 1.18. Difficulties in electrophilic trifluoromethylations.
Although trifluoromethyl sulfonium salts were known as early as 1973,
163
the first
electrophilic trifluoromethylation was indeed described by Yagupolskii et al. using
diaryl(trifluoromethyl)sulfonium salts in 1984 (Scheme 1.19).
164
Prepared by treating
p-chlorophenyl trifluoromethyl sulfoxide with SF
3
+
SbF
6
-
followed by anisole or m-xylene,
the reagents were capable of transferring CF
3
electrophilically onto p-nitrothiophenolate
rendering the corresponding trifluoromethyl sulfide in moderate yield (Scheme 1.19).
165

However, the inertness of these reagents toward N,N-dimethylaniline at elevated
temperature clearly indicates their rather low reactivity. Seeking agents with higher
generality and reactivity, Umemoto and co-workers synthesized a series of
(trifluoromethyl)dibenzo chalcogenium salts. With variable trifluoromethylating
capability (in a general order of S > Se > Te), these reagents demonstrated superior
applicability, compared with Yagupolskii’s agents, for trifluoromethylation of various
nucleophiles, including carbanions, thiophenolates, phosphines, as well as iodide. Despite

46
of this achievement, the tedious and costly preparative routes significantly limited their
synthetic usefulness. Shreeve et al. revisited the synthesis and the reactivity of
diaryl(trifluoromethyl)sulfonium salts, and have exploited them as alternatives to
Umemoto’s reagents.
166
Further improvements were made by Magnier and Blazejewski,
who achieved straightforward one-pot syntheses of diaryl(trifluoromethyl)sulfonium salts
by the treatment of aromatic compounds with potassium trifluoromethanesulfinate and
triflic acid.
167
Recently, Umemoto et al. have reported O-(trifluoromethyl)oxonium salts
prepared by photochemical decomposition of corresponding diazonium salts, which
permitted direct trifluoromethylation of N- or O-nucleophiles.
168
Importantly, while the
chalcogenium salts enable reactions between the CF
3
moiety and nucleophilic species, a
standard S
N
2 mechanism is adopted only when O-(trifluoromethyl)dibenzofuranium salts
are employed.
168,169
Very recently, Shibata and co-workers demonstrated the use of
S-(trifluoromethyl)thiophenium salts for electrophilic trifluoromethylations of carbon
nucleophiles to give the products in low to high yields.
170
However, attempts to achieve
asymmetric incorporation of the CF
3
moiety into a β-ketoester using camphor-based
S-(trifluoromethyl)benzothiophenium salt only afforded a racemate.

47

Scheme 1.19. S-(Trifluoromethyl)chalcogen salts as electrophilic trifluoromethylating
reagents.

In addition to the previously mentioned chalcogenium salts,
S-(trifluoromethyl)sulfoximines have also emerged as efficient electrophilic
trifluoromethylating reagents over the last decade (Scheme 1.20). Yagupolskii first
prepared S-trifluoromethylated sulfoximine in 1984 by treating trifluoromethyl phenyl
sulfoxide and sodium azide in the presence of oleum, but its trifluoromethylating
capability was not explored.
171
Adachi and Ishihara patented the cyclic and acyclic
trifluoromethyl sulfoximines as viable electrophilic trifluoromethylating reagents toward
carbon nucleophiles and thiolates to generate the corresponding products in low to
moderate yields.
172
Noticeably, Shibata et al. have recently disclosed the utilization of a
trifluoromethylated counterpart of Johnson’s reagent.
173
Similar to the agents mentioned
above, the compound enables the trifluoromethylation of various carbon nucleophiles in
the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or phosphazene base.

48

Scheme 1.20. Sulfoximine-based electrophilic trifluoromethylating reagents.

Apart from the electrophilic trifluoromethylating agents based on the CF
3
-S bond
functionalities, hypervalent iodonium compounds have also been adopted recently for the
introduction of the trifluoromethyl moiety. In comparison with
(perfluoroalkyl)aryliodonium triflates, corresponding (trifluoromethyl)iodonium species
were not known for many years due to their thermal instability.
158,174
In 2006, Togni and
co-workers demonstrated, for the first time, a series of stable trifluoromethyl(iodonium)
compounds that can be utilized as efficient electrophilic trifluoromethylating reagents
under mild conditions (Scheme 1.21).
175
Intriguingly, the synthetic route was achieved
by a formal umpolung of the CF
3
functionality using the Ruppert-Prakash reagent. For
the sake of both operative simplicity and expense, an improved synthetic protocol was
established by the same research group exploiting anhydrous KOAc in a one-pot
procedure (Scheme 1.21).
176

49

Scheme 1.21. Preparation of (trifluoromethyl)iodonium compounds.
Synthetically, the trifluoromethylating capability of these agents was initially
explored by treating 21 with a β-keto ester, which afforded trifluoromethylated product in
67% yield under basic conditions (Scheme 1.22).
175
This chemistry was later extended to
other β-keto esters and α-nitro esters.
176
The agents were also found to be reactive toward
sulfur
176
and phosphine
177
nucleophiles. Remarkably, reagent 20 has been successfully
applied in the trifluoromethylation of alcohols and sulfonic acids to form the
corresponding trifluoromethyl ethers
178
and sulfonates,
179
respectively. It is worth
mentioning that electrophilic trifluoromethylation of aliphatic alcohols is still rather
challenging. Since a large excess of alcohols (75 equiv.) was necessary for the completion
of the reaction, the practicability of the protocol can be argued. Moreover, attempts to
treat phenols with reagent 20 lead to trifluoromethylation of aromatic rings instead of
forming O-CF
3
bonds (Scheme 1.22).
180

50

Scheme 1.22. Electrophilic trifluoromethylation using (trifluoromethyl)iodonium
compounds.
1.2.2.3. Recent Developments in the Construction of CF
3
-C Bonds
1.2.2.3.1. Asymmetric CF
3
-C Bond Forming Reactions
Trifluoromethylated organic molecules have received increasing attention in recent
years due to their superior biological and physical properties.
181
Although constructions
of a stereogenic center bearing the CF
3
group from the corresponding prochiral
trifluoromethylated carbonyl compounds have been known for decades,
182
direct
asymmetric introductions of the CF
3
moiety into organic compounds, namely
stereoselective CF
3
-C bond formations, remains challenging.
In fact, the first diastereoselective nucleophilic trifluoromethylation of carbonyl
compounds was achieved in 1989 when Prakash et al. showed the synthetic usefulness of

51
TMSCF
3
(Scheme 1.23).
127a
Taguchi et al. later reported trifluoromethylation of chiral
aldehydes using CF
3
I and zinc under the irradiation of ultrasound to afford two
diastereomers in a ratio of 2.6:1 with moderate yields.
183
Intriguingly, Portella and
co-workers have reinvestigated the synthesis employing TMSCF
3
-fluoride system giving
the two isomers in 4:1 ratio with excellent yields, which clearly demonstrated the
advantages of TMSCF
3
.
184
Noticeably, although nucleophilic trifluoromethylation of
chiral carbonyl compounds may render the corresponding products with satisfactory
facial discrimination, low stereoselectivities have also been observed under some
circumstances.
185

Scheme 1.23. Diastereoselective nucleophilic trifluoromethylation of carbonyl
compounds.

52
On the other hand, the first catalytic enantioselective trifluoromethylation of carbonyl
compounds was reported by Prakash and coworker, who employed the quinidinium
fluoride 22 as the initiator in the trifluoromethylation of 9-anthraldehyde affording the
corresponding product with excellent enantiomeric purity (Scheme 1.24).
186
Shortly
afterwards, Iseki, Kobayashi and Nagai used cinchonium fluorides (23 and 24) as
initiators and catalysts, which facilitated the synthesis of α-trifluoromethyl alcohols with
low to moderate enantiomeric excesses.
187
Instead of using fluoride initiators, Fuchikami
et al. have shown the trifluoromethylation of benzaldehyde with
trifluoromethyltriethylsilane in the presence of quinine as a Lewis base catalyst, but only
low stereoselectivity was achieved.
188
Iseki and co-workers further attempted to obtain
enhanced enantioselection by employing chiral tris(dialkylamino)sulfonium
difluorotrimethylsilicate (26) which, however, did not demonstrate appreciable
superiority.
189
Although suffering from lack of generality, a highly efficient asymmetric
nucleophilic trifluoromethylation using catalyst 25 was developed by Caron et al., which
afforded 31 with 92% enantiomeric excess.
190
Promising synthetic approaches utilizing
different catalytic systems were established in 2007 by several research laboratories.
Feng reported the use of a new combinatorial catalytic system (29) containing disodium
(R)-binaphtholate and quinidinium salt for enantioselective trifluoromethylation of
aromatic aldehydes giving products in moderate enantiomeric excess.
191
Meanwhile

53
Mukaiyama and co-workers also discovered cinchonidium phenoxide 27 (an
alkoxide-based initiator) as an efficient catalyst furnishing trifluoromethylated alcohols in
the trifluoromethylation of ketones.
192
Shortly afterwards, Shibata and Toru devised a
synthetic method based on a combination of cinchonium bromide and
tetramethylammonium fluoride (28).
193
In comparison with the previous catalytic
systems, significantly enhanced stereochemical control and generality were achieved as
most of the products were obtained with good enantiomeric excesses (>70%). In spite of
the great effort devoted, it is still of significant challenge to develop generally applicable
synthetic approaches toward enantiomeric enriched α-trilfuoromethyl alcohols from the
corresponding carbonyl compounds.

54

Scheme 1.24. Enantioselective trifluoromethylation of carbonyl compounds.

55
Compared with the asymmetric nucleophilic trifluoromethylation of carbonyl
compounds, stereoselective syntheses of α-trilfuoromethyl amines from imines have been
achieved mainly due to the contributions from Prakash and co-workers over the last
decade (Scheme 1.25). In 2001, Prakash, Olah and Mandal first disclosed a novel
stereoselective synthetic approach toward chiral trifluoromethylated amines.
194
Utilizing
(S)-tert-butanesulfinyl as a chiral auxiliary and activating functionality for imines, the
protocol enabled an efficient synthesis of a variety of chiral trifluoromethylated amines in
good yields with excellent diastereoselectivities. It is worth noting that the removal of the
sulfinyl auxiliary can be achieved by treating the products with HCl and MeOH without
loss of optical activity (Scheme 1.25). The strategy was further extended by the same
research laboratory to α,β-unsaturated N-tert-butanesulfinyl aldimines, which afforded
1,2-adducts with excellent stereoselectivity.
195
Prakash et al. have also developed the
asymmetric synthesis of trifluoromethylated vicinal ethylenediamines using TMSCF
3
and
α-L-amino N-tert-butanesulfinimines.
196
Intriguingly, when an imine derived from
D-amino aldehyde was subjected to the reaction, only a slightly decreased
diastereoselectivity was observed, which provides an applicable and general synthetic
route to both syn and anti vicinal ethylenediamines. Dolbier and co-workers have also
described a similar methodology employing the CF
3
I/TDAE system instead of
TMSCF
3
-fluoride, while the products were obtained in lower yields and

56
diastereoselectivities.
151c
To date, these robust synthetic methods have been extensively
utilized in the synthesis of an arsenal of trifluoromethylated amine derivatives.
197

Recently, Shibata et al. disclosed the catalytic enantioselective trifluoromethylation of
azomethine imines with TMSCF
3
as an alternative approach toward α-trifluoromethylated
amines.
198
Employing cinchonium salts in the presence of potassium hydroxide, the
trifluoromethyl anion equivalent can be transferred to a variety of azomethine imines
rendering (S)-amines in good enantiomeric control. Further treatment of the products with
Raney-Ni and subsequent decomposition under acid conditions led to the formation of
chiral amines without loss of optical activity.

57

Scheme 1.25. Stereoselective trifluoromethylation of imines.
In addition to the above-mentioned stereoselective nucleophilic trifluoromethylating
reactions, asymmetric construction of CF
3
-C bonds via different mechanistic profiles
have also been initiated in recent years. By far, all of these synthetic methodologies have
been involved in trifluoromethylation of enolate derivatives and analogs under radical or
electrophilic mechanistic pathways (Scheme 1.26). The first α-trifluoromethylation of
carbonyl compounds was described by Kitazume et al. in 1985 using the optically pure
enamine to react with CF
3
Br or CF
3
I in the presence of Cp
2
TiCl
2
and ultrasonically
dispersed zinc power.
145b
Elliott later disclosed a photochemical intramolecular

58
rearrangement of dienol triflate 36 yielding β-trifluoromethyl enone 37 as a single
stereoisomer.
199
Early work by Umemoto has shown a diastereoselective synthesis of
γ-trifluoromethyl enones under different conditions.
165b, 200
Accordingly, direct
trifluoromethylation of trimethylsilyl enol ether 38 generated products 40 and 41 in a
ratio of 1:3.6 (Scheme 1.26). In contrast, the ratio of 40:41 was found to be 4:1 when
potassium enolate 39 was sequentially treated with borole 44 and electrophilic
trifluoromethylating agent 42, indicating different transition states under these reaction
conditions. Moreover, Umemoto reported, for the first time, an enantioselective
α-trifluoromethylation of ketone mediated by chiral borepin 32, although only low yield
with 45% enantiomeric excess was achieved.
200
Noticeably, Iseki and Kobayashi have
established triethylborane-mediated diastereoselective trifluoromethylation of chiral
imide enolates 45 with CF
3
I via a radical mechanism.
201
Under these reaction conditions,
moderate to good diastereomeric discriminations were observed. Strikingly, thereafter
chemists have paid little attention to this field until very recently. In 2006, Mikami further
extended Iseki and Kobayashi’s methodology as the first enantioselective radical
trifluoromethylation of ketone enolates with a stoichiometric amount of chiral
additives.
202
According to Ma and Cahard, an enantioselective trifluoromethylation of
β-keto esters was achieved exploiting the Umemoto’s reagent 43 with dihydroquinine as
chiral base.92e Encouragingly, MacMillan and co-workers have successfully developed a

59
highly productive organocatalyzed α-trifluoromethylation of aldehydes via a photoredox
pathway.
203
Co-catalyzed by acidified chiral amine catalyst 33 and photocatalyst 34,
aldehydes reacted with CF
3
I under radiation from household light to generate the
corresponding products with high stereoselectivities. The same reseach laboratory further
disclosed a similar transformation by means of electrophilic trifluoromethylation using
(trifluoromethyl)iodonium compound in the presence of imidazolidinone 35 and 5 mol%
CuCl.
204
It is worth noting that these two synthetic methods have shown excellent
generality as well as stereochemistry and functional group compatibility, making them
viable synthetic approaches.

60

Scheme 1.26. α-Trifluoromethylation of enolate derivatives and their analogs.

61
1.2.2.3.2. Aromatic Trifluoromethylations Mediated by Transition-Metal
Due to the immense potential for the preparation of trifluoromethyl-containing
aromatic pharmaceuticals, the formation of aryl-CF
3
bonds has received increasing
attention. Generally speaking, Cu and Pd metals have been frequently involved in
aromatic trifluoromethylations. In fact, the first Cu-mediated aromatic
trifluoromethylation was pioneered by Kobayashi in 1969, who treated aryl halides with
copper powder and a large amount of CF
3
I (15 equivalents) at elevated temperatures
(Scheme 1.27).
144b
The proposed mechanism of this transformation was established
experimentally by the X-ray crystal structures of NHC stabilized Cu-CF
3
complexes, 46,
which demonstrated effective trifluoromethylating ability.
205
Addressing the demand of
Cu-catalyzed aromatic trifluoromethylations, Amii and co-workers have developed a
remarkable catalytic protocol permitting the recycling of active copper species during the
course of the reaction.
206
In the previous methods, the slow regeneration of CuI
significantly limited the formation rate of Cu-CF
3
complexes, resulting in severe
decomposition of the CF
3
-
anion. Using a combination of CuI and 1,10-phenanthroline
(phen) as the catalytic system which substantially accelerated the cross-coupling step, the
reaction proceeded smoothly to give the products in moderate to good yields. It is worth
mentioning that Qing has also utilized a stoichiometric amount of CuI/phen system in the
oxidative cross coupling reaction between the Ruppert-Prakash reagent and terminal

62
alkynes to yield the corresponding trifluoromethylated products.
207
Hartwig’s group
recently reported the preparation of copper-based bench-stable perfluoroalkylating
reagents, which enabled the trifluoromethylation and n-perfluoropropanation of various
aryl iodides (Scheme 1.27).
208
Grushin et al. prepared CF
3
Cu in DMF solution from
CF
3
H, which readily reacted with various aryl halides.
209
In addition, the oxidative
trifluoromethylation of aryl boronic acids was also demonstrated by Qing and
coworkers.
210

Scheme 1.27. Cu-Mediated aromatic trifluoromethylations.
In comparison, palladium-mediated aryl-CF
3
bond-forming reactions are
mechanistically more challenging. While a handful of trifluoromethyl palladium

63
compounds had been known prior the 1980s,
141b
the reductive elimination in the catalytic
cycle was energetically prohibitive due to the extraordinary stability of Pd-CF
3
bonds.
57

Ishikawa demonstrated the first palladium-catalyzed trifluoromethylation of aryl iodides
employing in situ generated trifluoromethyl zinc compounds to afford the corresponding
products in moderate to high yields (Scheme 1.28).
211
Grushin and Marshall first
reported a facile trifluoromethyl-aryl reductive elimination from a xantphos-coordinated
Pd(II) center revealing the mechanistic possibility of Pd-mediated aromatic
trifluoromethylations.
212
Sanford et al. additionally disclosed the aryl-CF
3
bond
formation via reductive elimination from high valent Pd(IV) complexes.
213
With more
practical synthetic utility, Pd(II)-catalyzed ortho-trifluoromethylation of arenes bearing
pyridine directing groups has been accomplished by Yu et al. in the presence of triflic
acid and Umemoto’s electrophilic trifluoromethylating reagent.
214
Accordingly, the
reaction underwent either direct nucleophilic attack of the “CF
3
+
” by the Pd-aryl
complexes or an oxidative addition-reductive elimination process. Very recently a
breakthrough in this field has been demonstrated by Buckwald, which allows
trifluoromethylation of aryl chlorides with a substoichiometric amount of Pd complexes
under a regular Pd(0)-Pd(II) catalytic cycle.
215
This process has shown satisfactory
efficacy as well as remarkable substrate compatibility, making it a valuable and facile
route toward trifluoromethylated arenes.

64

Scheme 1.28. Pd-Mediated aromatic trifluoromethylation.

1.2.3. Novel Methods for the Introduction of Difluoromethyl Motifs
Compared with the continuing enthusiasm for the syntheses of trifluoromethylated
organic compounds over a century, difluoromethylations have received much less
attention until very recently. To date, difluoromethyl (CF
2
H)- and difluoromethylene

65
(CF
2
)-containing organic molecules are of particular interest due to their diverse
applications in materials science, agrochemistry, and the pharmaceutical industry.
216
The
CF
2
moiety is known to be isosteric and isopolar to ethereal oxygen in nature, which has
shown vast potential in the development of bioactive fluorinated analogs of oxygenated
molecules such as sugars. The difluoromethyl group, on the other hand, has been found to
be a steric and electronic mimic of a hydroxyl group, particularly in terms of its function
as a hydrogen bonding donor without developing a negative charge. Due to these
promising applications, organic chemists have devoted their efforts in the investigation of
synthetic methods toward partially fluorinated molecules bearing CF
2
and CF
2
H groups.
Synthetically, a variety of methods for the introduction of gem-difluoromethylene
moieties into organic compounds were established prior the early 1990s.
217
Broadly
speaking, current synthetic protocols are primarily based on three strategies (a)
nucleophilic difluorination of carbonyl compounds and their derivatives; (b) direct
electrophilic gem-difluorination of carbanions; and (c) methodologies using fluorinated
synthons by means of nucleophilic, electrophilic, radical and single electron transfer
processes,
123
as well as carbene-based reaction intermediates (Scheme 1.29).
125218
In
addition to these methods, reductive defluorination from readily available
trifluoromethyl-containing precursors has also been described for the synthesis of
corresponding difluorinated compounds.
23
In this section, we will emphasize building

66
block approaches utilizing difluorinated carbanion and carbocation equivalents, which are
the major achievements of the past 20 years. Those interested in the difluoromethylations
and difluoromethylenations by using radicals, carbene, as well as organometallic reagents
are referred to the excellent review articles indicated above.

Scheme 1.29. Difluoromethylations and difluoromethylenations via synthon strategies.

1.2.3.1. Nucleophilic Difluoromethyl Building Blocks and Approaches
Nucleophilic difluoromethylations are extensively employed in the synthesis of CF
2
-
and CF
2
H-containing organic molecules. As key reaction intermediates, difluoromethyl
carbanions are found to react with a series of electrophilic substrates, such as alkyl
halides (to form the corresponding substituted alkanes), carbonyl compounds, and their
analogs (to generate the corresponding difluoromethyl alcohols, amines, ketones, as well

67
as gem-difluorinated alkenes) (Scheme 1.30). Mechanistically, due to the strong
electronegative nature of fluorine, difluoromethyl carbanions usually exhibit a substantial
preference for adopting pyramidal geometries over planar structures. Despite the planar
conformation being usually assumed by the carbanions in conjugation with nitro or
carbonyl groups, an sp
3
-hybridization is still energetically favored by the difluorinated
counterparts because of increased p-orbital character on the fluorine atoms.
219
Similar to
the CF
3
anion, RCF
2
-
species also tend to decompose by α-elimination of fluoride and
auxiliary groups to form more thermodynamically stable carbenes, which can lead to be
significant competitive reactions diminishing the synthetic applicability of RCF
2
-
anions.

Scheme 1.30. Typical nucleophilic difluoromethylations and their reaction intermediates.

68
Hence, these anionic species are usually functionalized with auxiliary groups
possessing electron-withdrawing and charge-delocalizing properties to modulate their
stability and reactivity. Many of the auxiliaries also permit further chemical
transformations toward useful fluoroorganics. To date, an arsenal of functional groups has
been developed as auxiliaries in nucleophilic difluoromethylation reactions for various
synthetic purposes. Historically, nucleophilic introduction of the CF
2
moieties was
achieved by the use of “P-CF
2
” derivatives (Scheme 1.31). Pioneered by Burton,
difluorinated phosphonium salts were first found to be suitable for the synthesis of
gem-difluorinated olefins via the Wittig reaction.
220
To increase the nucleophilicity of the
ylides, Burton et al. further utilized the analogous phosphonate ylide. Mediated by
cadmium or zinc metal, diethyl bromodifluoromethylphosphonate was able to react with
a large number of electrophiles, such as aldehydes, ketones, acyl chlorides, and allyl
bromides.
221
Kondo later demonstrated the use of diethyl
difluoromethylphosphontate-lithium diisopropylamide and diethyl
difluoro(trimethylsilyl)methylphosphonate-cesium fluoride systems as the precursors of
(diethoxyphosphoryl)difluoromethide anion.
222
In fact, due to the immense importance
of bi- and triphosphate functionalities in cellular chemistry, difluoromethylene-containing
phosphates and phosphoric acids have been prepared as their analogs, which
demonstrated significantly increased biostability, through the above-mentioned

69
methodologies.
223
Fokin et al. reported the Michael addition and the Henry reaction of
difluoronitromethane in moderate yields.
224
However, the synthon was not explored
further due to its limited synthetic accessibility.
225

Scheme 1.31. Conventional nucleophilic difluoromethylating reagents.
Aside from these “heteroatom-CF
2
” based synthons, α,α-difluorinated carbonyl
compounds and their derivatives have also been employed as viable building blocks since
the early 1980s (Scheme 1.31). Ishihara initially demonstrated the synthetic applicability
of enol silyl ethers, prepared from chlorodifluoromethyl ketones and
chlorotrimethylsilane in the presence of Zn, as efficient difluoromethyl building blocks in
the aldol reaction.
226
Under similar conditions, Kobayashi et al. prepared
2,2-difluoroketene silyl acetals, which reacted with imines, aldehydes, as well as ketones

70
rendering products with remarkable stereoselectivities.
227
Iseki and Kobayashi further
developed a catalytic asymmetric aldol reaction of difluoroketene silyl acetal with
aldehydes to yield α,α-difluoro-β-hydroxy esters in excellent enantiomeric excesses.
228

Huang et al. reported the preparation of (2,2-difluorovinyloxy)triphenylsilane, however,
its synthetic applications remain unexplored.
229
More recently, Uneyama has
documented the electrochemical preparation of N-TMS-β,β-difluoroenamines and the
related chemical transformations in an aldol reaction and nucleophilic substitution with
alkyl iodide.
230
Intriguingly, the same research laboratory has also developed a series of
preparative methods toward α,α-difluoro carbonyl compound derivatives from the readily
available trifluoromethylated precursors.
231
Using similar methodology, Prakash et al.
have prepared a series of 2,2-difluoro silyl enol ethers as versatile precursors for
radiochemical synthesis of [
18
F]-labeled trifluoromethyl ketones.
232
In addition to the
above mentioned difluoromethide precursors, commercially available
halodifluoroacetates have become one of the most important functionalized difluorinated
synthons. First employed in the Reformatskii-type reaction for the synthesis of
2,2-difluoro-3-hydroxyesters,
233
the halodifluoroacetates-Zn systems have allowed both
diastereoselective
234
and enantioselective
235
addition of α,α-difluorinated esters to
aldehydes, ketones, and imines.
236
Similar to trifluoromethyl organometallic reagents, a
handful of difluoromethyl variants have been available since the late 1980s. Primarily

71
contributed by Burton and co-workers, these reagents have been successfully applied in
the preparation of difluoromethyl-substituted allenes and in allylation reactions.
237

Scheme 1.32. Development of “S-CF
2
” bond-based nucleophilic difluoromethylating
reagents.

72
Over the past decade, a series of novel difluoromethylating reagents derived from
“S-CF
2
” motifs have been well developed (Scheme 1.32).
238
Remarkably, thanks to the
facile reductive S-CF
2
bond cleavage (to form CF
2
H moiety) and their diverse chemical
transformations into other difluoromethyl functionalities, utilization of “S-CF
2
” building
blocks gives superior synthetic advantages. Although difluoromethyl phenyl sulfone
(PhSO
2
CF
2
H) was known as early as 1960,
239
a detailed description of PhSO
2
CF
2
H as a
nucleophilic (phenylsulfonyl)dilfuoromethylation reagent did not appear until much later.
Stahly utilized PhSO
2
CF
2
H in nucleophilic additions to aldehydes to produce the
corresponding carbinols in good yield.
240
Shortly afterward, McCarthy reported a
multiple-step gem-difluoromethylenation of ketones using PhSO
2
CF
2
H as a
difluoromethyl ylide equivalent.
241
However, the related chemistry did not receive
particular attention for over a decade until Prakash and Hu et al. revisited its potential. In
2003, Prakash and co-workers described an efficient one-pot stereoselective synthesis of
anti-2,2-difluoropropane-1,3-diols.
242
In the presence of an excess amount of tBuOK,
PhSO
2
CF
2
H was able to act as a difluoromethylene dianion equivalent. Intriguingly, due
to the charge-charge repulsion during the course of the second addition, the reaction
exhibited a substantial preference for generating products with the anti-configuration.
Additionally, PhSO
2
CF
2
H was found to react with primary alkyl iodides through an S
N
2
mechanistic pathway.
243
Further treatments of the substituted products under basic and

73
reductive conditions yielded 1,1-difluoro-1-alkenes and 1,1-difluoromethylalkanes,
respectively. It is worth noting that the reagent was also able to incorporate the
(phenylsulfonyl)difluoromethyl moiety into chiral N-(tert-butylsulfinyl)aldimines with
excellent diastereomeric discrimination.
244
Despite these valuable methodologies,
PhSO
2
CF
2
H was found to be inert toward epoxides and aziridines.
245
To achieve the
synthesis of β-difluoromethylated or β-difluoromethylenated alcohols and amines,
1,2-cyclic sulfates and sulfamidates exhibiting enhanced electrophilicity in comparison
with epoxides and aziridines were utilized by Hu et al. to afford the products in good
yields.
246
In addition to the reactions mentioned above, PhSO
2
CF
2
H has been employed
in the enantioselective nucleophilic addition of aldehydes catalyzed by cinchona
alkaloid-derived ammonium salts, which gave chiral carbinols with 4-64% ee.
247
Very
recently, the same research laboratory has developed novel difluoromethylating reagents
by altering the phenyl group with a series of heterocyclic aromatic motifs.
248
Using
shelf-stable difluoromethyl 2-pyridyl sulfone, the methodology allowed the facile one-pot
gem-difluoroolefination of aldehydes and ketones. Noticeably, while PhSO
2
CF
2
H can
react with enolizable ketones and aldehydes, the synthetic route still suffered from low
efficiency and harsh reaction conditions.
249
To overcome this problem, Prakash and Hu
further developed fluoride-induced nucleophilic (phenylthio)difluoromethylation and
(phenylsulfonyl)difluoromethylation of carbonyl compounds using

74
[difluoro(phenylthio)methyl]trimethylsilane (PhSCF
2
TMS) and
[(phenylsulfonyl)difluoromethyl]trimethylsilane (PhSO
2
CF
2
TMS), respectively (Scheme
1.32).
250
Under milder conditions, difluoromethylated carbinols can be obtained in good
yields from both enolizable and non-enolizable carbonyl compounds. It should be
mentioned that the preparation of TMSCF
2
H from TMSCF
3
was recently reported by
Igoumnov.
251
Such a facile preparative method facilitated the utilization of TMSCF
2
H in
nucleophilic difluoromethylation of various carbonyl compounds and sulfinyl imines
(Scheme 1.33).
252
Interestingly, Qing et al. have adopted
[difluoro(phenylseleno)methyl]trimethylsilane (PhSeCF
2
TMS) as an efficient
difluoromethylating agent for enolizable ketones and aldehydes.
253

Scheme 1.33. Difluoromethylation using the Ruppert-Prakash reagent and its analogs.

75
In addition to the previously described reagents, several other
difluoromethyl-containing species have also been utilized in nucleophilic
difluoromethylation reaction of carbonyl compounds. In 1995, Fuchikami first reported a
direct fluoride-induced difluoromethylation of ketones and aldehydes using
(difluoromethyl)dimethylphenylsilane (Scheme 1.33).
254
Additionally, a series of
(1,1-difluoroalkyl)silane derivatives were investigated under similar conditions affording
1,1-difluoroalkylated products. Prakash et al. later employed
difluorobis(trimethylsilyl)methane (TMSCF
2
TMS) as a difluoromethylene dianion
equivalent, which readily reacted with aldehydes in the presence of TBAF. It is worth
noting that the CF
2
H moiety can be also introduced through the partial defluorination of
the trifluoromethyl group. By using the Ruppert-Prakash reagent, Portella et al. were able
to realize the Brook rearrangement to afford 2,2-difluoroenol silyl ethers, which can be
converted into various difluoromethylated compounds (Scheme 1.33).
255
On the other
hand, Prakash and coworkers have shown that difluoromethylated imines can be achieved
through the treatment of aldimines with TMSCF
3
in the presence of TMAF.
256
The
corresponding amines were obtained feasibly by in situ reduction using NaBH
4
with
moderate yields.

76
1.2.3.2. Electrophilic Difluoromethyl Reagents and Approaches
Because difluorocarbene can readily react with a variety of nucleophilic species to
afford the corresponding difluoromethylated organics, difluorocarbene is de facto a
“
+
CF
2
-
” equivalent. The design and development of other electrophilic
difluoromethyl-containing species (“RCF
2
+
”) were therefore not ardently sought and
remained unexplored. In 2007, Prakash and co-workers first demonstrated
S-(difluoromethyl)diarylsulfonium salt as an electrophilic difluoromethylating agent
(Scheme 1.34).
257
It was found that the reagent enabled effective difluoromethylation of
varied substrates including oxygen, nitrogen, and phosphorus nucleophiles. The same
research group further investigated difluoromethylation of sulfonic acid salts and
imidazoles using polystyrene-bound S-difluoromethyl sulfonium reagent which rendered
products without need of purifications.
258
Hu et al. disclosed electrophilic
(phenylsulfonyl)difluoromethylation with a hypervalent iodine(III)-CF
2
SO
2
Ph
compound.
259
Under mild conditions, the reagent has exhibited excellent
difluoromethylating capability toward various thiols to provide phenylsulfonyl
difluoromethyl sulfides in good yields (Scheme 1.34). More recently, Prakash and
coworkers reported the synthetic application of a difluoromethyl-containing Johnson-type
reagent, which was proven to be a genuine electrophilic difluoromethylating reagent
instead of a difluorocarbene precusor (Scheme 1.34).
260

77

Scheme 1.34. Novel electrophilic difluoromethylating reagents.

1.2.4. Catalytic Asymmetric Synthesis of Chiral Monofluoromethylated
Organic Molecules via Nucleophilic Fluoromethylating Reactions
As previously mentioned, synthon strategies have represented substantial synthetic
advantages over direct fluorinations for the introduction of the trifluoromethyl and the
difluoromethyl motifs. In contrast, both monofluorinated synthons and direct
fluorinations are applicable for the selective incorporation of functionalities bearing a
single C-F bond depending on the synthetic purpose. In contrary to the extensive
utilization of difluorocarbene and difluoromethyl radicals for the introduction of the CF
2

moieties, the synthetic utility of monofluorinated radicals and carbenes has received
relatively less attention, and the related studies can be referred to the excellent review
articles indicated above. As alternative protocols toward monofluoromethyl-containing

78
compounds, monofluoromethylations are achieved primarily in nucleophilic and
electrophilic manners (Scheme 1.35).
261
In fact, Olah and co-workers developed the first
electrophilic monofluoromethylation of arenes with fluoromethanol to yield benzyl
fluorides in 1953.
262
Since then several reagents have been utilized in the electrophilic
monofluoromethylation of a variety of nucleophiles.
263
In addition to these studies,
Prakash et al. recently demonstrated the synthetic utility of
S-(monofluoromethyl)diarylsulfonium salts as a novel electrophilic
monofluoromethylating reagent.
264
In contrast with the limited acknowledgement of
electrophilic monofluoromethylation, a large number of studies have emphasized the
introduction of monofluoromethyl moieties by means of monofluoromethide species. It is
found that monofluoromethides are able to react with a broad range of electron-deficient
substrates in many types of transformations including nucleophilic substitutions, aldol
reactions, 1,4-addition reactions, the Wittig-type reactions, as well as ring opening
reactions (Scheme 1.35). Recently reported novel agents allow chemists to further
investigate the monofluoromethylation of other substrates, such as allylic acetates,
265

benzynes,
266
alcohols,
267
and nitrones.
268

Mechanistically, while the trifluoromethyl and difluoromethyl carbanions exhibit
extreme lability, many α-monofluorocarbanions possess reasonable thermostability if
their anionic centers are adjacent to electron-withdrawing groups. Hence fluoromethide

79
intermediates can usually be generated in situ and readily undergo reactions with
electrophilic substrates. However, these carbanions can be rather labile per se for
isolation due to the rapid release of fluoride as depicted in Scheme 1.35. A recent study
by Prakash, Olah, and colleagues on the other hand, has for the first time demonstrated
the isolation and structural characterization by X-ray diffraction of an α-fluorinated
methide.
269
As predicted by computational studies, α-fluoro(bisphenylsulfonyl)methide
was subject to Bent’s rule and preferentially assumed a pyramidal geometry.
219
It is
important to point out that the pyramidalization of α-fluorocarbanions can play a critical
role in construction of fluorinated stereogenic carbon centers because additional dynamic
kinetic resolution of chiral methide intermediates is involved (Scheme 1.35). Moreover,
due to the α-fluorine effect, fluoromethides can exhibit distinct nucleophilicity and
reactivity in comparison with their non-fluorinated counterparts.
270

80

Scheme 1.35. Typical transformations and reaction intermediates of nucleophilic
monofluoromethylation.

The first nucleophilic fluoromethylation was achieved by Blank and Mager using
ethyl fluoroacetate for the preparation of diethyl oxalofluoroacetate (Scheme 1.36).
271

Bergmann and coworkers further systematically studied the reactions between various
electrophiles and α-fluoroenolates generated from fluoroacetate, fluoroacetone, and
α-fluoro-β-keto esters.
272
Buchanan also described the Michael addition of diethyl
fluoromalonate to α,β-unsaturated carbonyl compounds and nitroolefins to yield
functionalized α-fluorinated carboxylic acids.
273
In addition to these nucleophilic
monofluoromethides obtained by deprotonation, Ishikawa has reported an

81
ultrasound-promoted Reformatskii-type reaction between trifluoroacetaldehyde and ethyl
bromofluoroacetate in the presence of zinc.
274
Since the 1980s, enol silyl ethers
275
and
silyl ketene acetals
276
have facilitated a number of chemical transformations for the
introduction of monofluoromethyl moieties, such as aldol reactions. In particular, Chen
et al. have also demonstrated the stereoselective synthesis of ethyl α-fluoro silyl enol
ether and its synthetic utility in the Mukayama aldol reaction.
277

Even though the carbonyl-stabilized fluoromethides have been extensively exploited
as valuable fluoromethyl synthons, these reagents are still not applicable in many
chemical scenarios owing to the difficult removal of the carbonyl groups by C-C bond
cleavage and the limited further conversions into other functionalities.
261
To meet this
demand, a series of reagents have been designed and employed for incorporating diverse
fluoromethyl moieties. Kaplan and Pickard utilized fluorodinitromethane (HCF(NO
2
)
2
as
a pronucleophile in the Michael addition to methyl acrylate for the demonstration of the
α-fluorine effect (Scheme 1.36).
270
The synthetic utility of HCF(NO
2
)
2
was described by
Gilligan for the synthesis of N,N-Bis(2-fluoro-2,2-dinitroethyl)-N-alkylamines.
278

Nevertheless, the tremendous explosive potential of HCF
2
NO
2
undermines its synthetic
availability and usefulness.
279
In contrast, several sulfur-based reagents have been
developed over the past decade. Due to the facile conversion of the sulfur-containing
auxiliaries into other valuable functionalities as well as their capability of altering the

82
reactivity of fluoromethides, these reagents have been employed in a large number of
fluoromethylating processes. Makosza first described the nucleophilic substitution of
hydrogen in nitroarenes with fluoromethyl phenyl sulfone (PhSO
2
CH
2
F).
280
Shortly
thereafter, Peet and McCarthy discovered that β-fluoro-alcohols could be obtained by
reacting lithiofluoromethyl phenyl sulfone with carbonyl compounds. Further treatment
of the alcohols with MeSO
2
Cl/NEt
3
or orthophosphoric acid followed by reductive
elimination of the sulfone group provided an entry to a series of terminal vinyl
fluorides.
281
Hu et al. also demonstrated the use of PhSO
2
CH
2
F in stereoselective
syntheses of β-fluoroamines.
282
In recent years, a series of robust reagents have been
derived from PhSO
2
CH
2
F by the incorporation of additional functional groups on the
fluorinated carbon (Scheme 1.36). In 2006, Shibata and Toru reported an asymmetric
palladium-catalyzed allylic monofluoromethylation reaction using
fluorobis(phenylsulfonyl)methane (FBSM) to yield the corresponding fluoromethylated
adducts with high enantiomeric excesses.
265
Simultaneously, Hu et al. independently
described the ring opening reaction of epoxides with FBSM as a pronucleophile.
245

Thanks to its strong electron-withdrawing nature arising from the two sulfonyl groups,
the acidity of FBSM and stability of its anion are significantly enhanced, thereby
permitting its application toward various synthetic targets. In addition to FBSM, several
functionalized fluoromethyl phenyl sulfone derivatives have been developed by Prakash

83
and coworkers as versatile monofluoromethyl synthons.
283
Recently, Hu et al. further
disclosed the remarkable reaction between α-fluorosulfoximines and nitrones to afford
Z-monofluoroolefins with high stereoselectivity.
268

Scheme 1.36. Selected nucleophilic monofluoromethylating reagents.

Most importantly, catalytic asymmetric syntheses of fluorine-containing organic
molecules based on various α-fluorinated pronucleophilies have been marked as one of
the major achievements in synthetic organofluorine chemistry of the last two decades
(Scheme 1.37). Generally speaking, these synthetic protocols have emphasized (a) the
stereoselective introduction of achiral fluorinated functionalities and (b) the formation of

84
nonracemic stereogenic fluorocarbon centers.
92c,92f,284
Due to their remarkable reactivity
and facile conversions into structurally sophisticated molecules, α-fluorocarbonyl units
are among the most extensively utilized synthons in catalytic asymmetric
monofluorinating reactions (Scheme 1.37). Lerner and Barbas III first described the
reaction between fluoroacetone and an aldehyde catalyzed by aldolase catalytic antibody
38C2 via the enamine mechanism.
285
Iseki exploited bromofluoroketene ethyl
trimethylsilyl acetal as a fluoromethyl synthon to react with various aldehydes in the
presence of a catalytic amount of chiral Lewis acid, which afforded aldol adducts in good
stereoselectivities.
286
Another example was demonstrated by Kim, who utilized diethyl
fluoromalonate as a pronucleophile in the Michael addition to chalcone derivatives.
287

Promoted by cinchonium-based PTC, moderate enantiomeric purities could be achieved
under mild conditions. In 2004, Barbas and co-workers reported an organocatalyzed
asymmetric aldol reaction for the synthesis of anti-α-fluoro-β-hydroxy ketones.
288
Using
L-prolinol as the catalyst, the protocol enabled direct C-C bond forming reaction between
fluoroacetone and aldehydes to give the products in satisfactory enantio- and
diastereoselectivities. Toward pyrrolidine-based PDE4 inhibitors, Nichols et al. have
shown an enantioselective conjugation addition of diethyl fluoromalonate to
trans-nitroolefins in the presence of Lewis acid and chiral bis(oxazoline).
289
Moreover,
the first asymmetric amination of α-fluoro-β-keto esters with diazodicarboxylates have

85
been shown by Togni using Cu/Ph-Box catalyst.
290
Likewise, Maruoka and Kim later
achieved the transformation by utilization of chiral quaternary phosphonium salts and
chiral nickel complexes as catalysts, respectively.
291
In fact, phase transfer catalysis was
also found to be an effective strategy for the construction of stereogenic fluorinated
carbon centers through alkylation of a racemate of α-fluoro-β-keto esters.
292
Thanks to
the rapid development of organocatalysis, Rios et al. and Córdova have independently
investigated the conjugate addition of fluoromalonates and α-fluoro-β-keto esters to
α,β-unsaturated aldehydes undergoing the imine catalytic pathway.
293
Apart from these
catalytic systems, chiral hydrogen bonding donors have been used as efficient catalysts
for many Michael-type reactions with monofluoromethyl pronucleophiles.
294
In
particular, Lu and Huang explored the asymmetric Mannich reaction of fluorinated
ketoesters with a tryptophan-derived bifunctional thiourea catalyst, which rendered the
products with excellent enantioselectivities and low to good diastereomeric ratios.
295

Meanwhile, Jiang, Tan and co-workers demonstrated a similar synthetic protocol
catalyzed by a bicyclic guanidine derivative toward the synthesis α-fluorinated β-amino
acids.
296

86

Scheme 1.37. Asymmetric monofluoromethylations using α-fluorinated carbonyl
compounds as pronucleophiles.

87
Intriguingly, several research laboratories have been involved in the investigations of
Pd-mediated asymmetric monofluoromethylaton reactions with α-fluorinated carbonyl
compounds (Scheme 1.38). In 2005, Stoltz et al. demonstrated a Pd-catalyzed
enantioconvergent decarboxylative allylation of α-fluoro-β-ketoester.
297
Almost
simultaneously, Nakamura and co-workers systematically studied the construction of
fluorinated quaternary stereocenters by enantioselective decarboxylation in the presence
of an identical catalytic system.
298
It is worth noting that this synthetic route is the first
example enabling the asymmetric synthesis of chiral fluorinated carbons via the
deracemization of quaternary carbon stereocenters. Paquin and co-workers, on the other
hand, showed enantioselective allylation reaction of fluorinated silyl enol ethers with
allyl carbonates in the presence of a catalytic amount of (S)-tBu-PHOX and Pd.
299

Shortly afterwards, a variant intramolecular route was disclosed by the same research
group for the synthesis of allylated tertiary α-fluoroketones.
300
Jiang also uncovered the
application of fluoromalonate to a Pd-catalyzed asymmetric allylic alkylation with
N-phenyl-(S)-prolinol-derived P,N-ligand, which gave the product in excellent
enantioselectivity and yield.
301

88

Scheme 1.38. Asymmetric monofluoromethylations via decarboxylative allylation and
allylic alkylation.

While α-fluorinated carbonyl compounds have successfully provided access to the
syntheses of monofluoromethyl-containing molecules, the difficult removal of the
carbonyl moieties to form unfunctionalized CH
2
F motif impedes their synthetic
applicability. In order to overcome this challenge, FBSM, featuring facile reductive
removal of the sulfonyl groups, has been ubiquitously used as a monofluoromethyl
equivalent. First developed by Shibata and Hu in 2006, electrophilic fluorination
245,265

and/or electrochemical fluorination
302
processes were employed in the conventional
preparation of the agent (Scheme 1.39). Hu and co-workers described a superior synthetic
route based on the sulfoxidation of fluoromethyl phenyl sulfone followed by oxidation,
which avoids the tedious purification necessary in the conventional synthesis.
303
Very

89
recently, Prakash et al. designed a practical one-step synthesis of FBSM with
fluoromethyl phenyl sulfone and less costly phenylsulfonyl fluoride rendering FBSM
with high efficiency and purity.
304

Scheme 1.39. Developments in the synthesis of fluorobis(phenylsulfonyl)methane.
Mechanistically, FBSM undergoes deprotonation under mild conditions, thereby
permitting many chemical transformations that cannot be achieved otherwise. Since its
emergence in 2006, FBSM has been explored by Shibata, Hu, Prakash, and many others
as a robust synthon in various chemical reactions, including the ring opening of
epoxides;245 the Michael addition;283,266 the Mitsunobu reaction;267 and the
fluoromethylation of alkanes,
305
arenes,266 and alkynes.
306
In particular, FBSM and its
analogs have been deployed as versatile reagents in asymmetric catalysis (Scheme 1.40).
Shibata and Toru first demonstrated FBSM as a pronucleophile in the Tsuji-Trost allylic
alkylation.265 Mediated by [(S)-iPr-PHOX]-ligated Pd complex, FBSM was shown to be
capable of reacting with allyl acetates to afford enantiomerically enriched products with

90
moderate to excellent yields. In 2007, the same research laboratory extended the
application of FBSM to an enantioselective Mannich-type reaction.
307
Using the
quinidinium salt 22 as a phase transfer catalyst, the protocol yielded fluorinated N-Boc
α-fluoro(bisphenylsulfonyl) amines with high enantiomeric excesses, which could
undergo reductive desulfonation to form monofluorinated amines without loss of
enantiomeric purity. Under similar conditions, an efficient enantioselective Michael
addition of FBSM to α,β-unsaturated carbonyl compounds was achieved by Shibata and
co-workers.
308
Almost simultaneously, Prakash and Olah developed the stereoselective
Michael addition of α-fluoro-α-nitro(phenylsulfonyl)methane to chalcone derivatives via
a hydrogen-bonding activating mechanism using cinchona alkaloid-derived thiourea
catalyst 56.
309
Intriguingly, due to the pyramidalization of the fluorinated carbanion
intermediate, the observed stereoselectivity was rationalized as a consequence of a
dynamic kinetic resolution process. In addition to these two methods, Kim et al. later
reported the primary amine-catalyzed Michael addition of FBSM to α,β-unsaturated
ketones to generate the adducts with excellent enantiomeric enrichment.
310
It is also
noteworthy that Rios and Wang independently explored the conjugate addition of FBSM
to enals in the presence of chiral diphenylprolinol trimethylsilyl ether 51.
311
Under
almost identical conditions, these protocols enabled the formation of 1,4-adducts with
high enantioselectivities.

91

Scheme 1.40. Catalytic enantioselective monofluoromethylations using sulfone-based
reagents.

1.3. Conclusion and Perspectives
Organofluorine chemistry is a flourishing field. In contrast to the abundant
naturally-occurring hydrocarbons and their derivatives, fluoroorganics are extremely
scarce in nature and are almost exclusively man-made molecules. Thanks to the efforts of
numerous dedicated chemists over the past 175 years, a multitude of fluorinated organic
compounds, ranging from rather simple to highly sophisticated, have become a reality
with many practical applications. Possessing unique properties, fluoroorganics offer

92
advantages as privileged materials for chemical, physical, and biological sciences. Over
the past fifty years, and particularly over the last two decades, organofluorine chemistry
has experienced exponential growth, reflecting the development of various new protocols
and robust reagents toward the efficient syntheses of useful organofluorine compounds.
As a fruitful paradise for chemists, the field has intrigued not only the “specialists” within
this community, but also received attention from many “outsiders” to bring their concepts,
leading to remarkable advance in organofluorine chemistry. As previously mentioned,
thanks to the rapid development in asymmetric synthesis, the stereoselective
incorporation of fluorine or fluorinated functionalities has come of age in recent years.
Notably, much effort has also been directed toward transition-metal promoted
fluorinations and fluoroalkylations that were previously considered arduous
transformations.
Even though making predictions is, of course, always risky, we still believe that
organofluorine chemistry will remain fascinating and dynamic, just as it has been over
the past two decades. Still, the proliferation of efficient synthetic protocols and robust
fluorinated synthons will be instrumental to the contribution of fluorinated molecules
with immense structural diversity and extraordinary functions. To introduce fluorinated
motifs in an asymmetric fashion and/or organometallic pathways should be the central
theme in the foreseeable future. Apparently, longstanding challenges, such as the

93
enhancement of nucleophilicity of fluorides and the stabilization of α- and
β-fluorocarbanions, will continue to be the impetus for organofluorine chemists to seek
intellectual solutions.

94
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106

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122

Chapter 2

Efficient Michael Addition of  -Substituted
Fluoro(phenylsulfonyl)methane Derivatives to , -
Unsaturated Carbonyl Compounds

123

2.1. Introduction
Compounds bearing a monofluoromethyl moiety are of immense importance with
regards to isostere-based drug design.
1,2,3
The synthesis of functionalized -fluorine-
substitued active methylene derivatives has thus attracted considerable attention in the
field of medicinal chemistry.
4,5
One of the major interests in our group has been focused
on developing new fluorination reagents and fluorinated building blocks for the
preparation of fluorine-substituted compounds.
6
As part of our ongoing effort to exploit
α-fluoro(phenylsulfonyl)methane derivatives as nucleophilic fluoromethylating reagents,
we envisaged that 1-fluoro-(phenylsulfonyl)methane derivatives could facilitate the
synthesis of functionalized monofluoromethylated compounds.
Based on HSAB principle, -fluorocarbanions are “harder” nucleophiles than their
non-fluorinated counterparts, thereby perferring 1,2-addition towards Michael acceptors
instead of 1,4-addition.
7
To achieve 1,4-addition, various strategies have been employed.
Yamamoto
8
and Röshenthaler
9
have utilized bulky aluminum-based Lewis acids to mask
the carbonyl group of Michael acceptors, which allowed the introduction of the
trifluoromethyl anion to the β-position of Michael acceptors. Portella et al. have shown
that the difluoroenoxysilanes can be used to introduce difluoromethylene moiety into
enones.
10
Kumadaki and coworkers have achieved a similar transformation using
bromodifuoroacetate in the presence of a copper catalyst.
11
Moreover, Takeuchi and
coworkers have shown that -fluoronitroalkanes can undergo 1,4- addition to methyl
vinly ketone and acrylonitirile to afford the corresponding dialkylated products.
12

124

2.2. Results and Discussion
Herein, we disclose the reaction of α-fluoro(phenylsulfonyl)methane derivatives and
various Michael acceptors. Our investigation was initially focused on the preparation of
nitro, cyano, ester, and acetyl-substituted phenylsulfonylmethanes from the
corresponding phenylthiomethane derivatives, which are precursors of -substituted
fluoro(phenylsulfonyl)methane derivatives. The oxidation of (nitromethyl)(phenyl)sulfide
with aqueous hydrogen peroxide (H
2
O
2
, 30% wt) was attempted in acetic acid at room
temperature. Tuning the conditions by using 4-fold excess of H
2
O
2
afforded
(nitromethylsulfonyl)benzene in 90% yield (Table 2.1, entry 1).
13
Compound 2d was
synthesized according to a known procedure.
14
The oxidation of 1d gave a mixture of 2d
along with methylsulfonylbenzene in a ratio of 2:1. Other sulfones were prepared in 70-
91% yields under optimized conditions and used without further purification (Table 2.1,
entries 2-4).
15

The α-fluorination of 2 was achieved using Selectfluor
 16
as the electrophilic
fluorination reagent. With an slightly modified precedure,
6e,17
the monofluorination of
(nitromethylsulfonyl)benzene gave (fluoro(nitro)methylsulfonyl)benzene 3a (FNSM) in
62% isolated yield (Table 2.1, entry 1). A doublet was observed at  -142.16 ppm in the
19
F NMR spectrum of 3a, which was consistent with the previously reported result.
6e

Other fluoro(phenylsulfonyl)methane derivatives were synthesized in 56-61% yields
under similar conditions (Table 2.1, entries 2-5). α-Fluorobis(phenylsulfonyl)methane 3f
(FBSM) was prepared following a known procedure.
6e,17

125

Table 2.1. Oxidation of sulfides and monofluorination of sulfones.

With these reagents in hand, we intially attempted to utilize phosphines as Lewis base
catalysts.
18
A reaction of (fluoro(nitro)methylsulfonyl)benzene with methyl vinyl ketone
was performed in the presence of PPh
3
(50 mol%) in THF at room temperature under
126

argon (Table 2.2). 5-Fluoro-5-nitro-5-(phenylsulfonyl)pentan-2-one (5a) was obtained as
the product in 93% yield, which was confirmed by
1
H,
13
C,
19
F NMR, and HRMS.
Although it is known that the H-C(sp
3
)-C(sp
3
)-F moiety can undergo dehydrofluorination
under basic conditions, the product was found to be intact in the present reaction.
A series of phosphine-based catalysts (PPh
3
, n-Bu
3
P, i-Pr
3
P and PMe
3
) possessing
various electronic and steric properties were further screened. Initial experiments
revealed that the catalytic activity of phosphines and phosphine loading (varying from
20% to 50%) could significantly influence the efficacy of the reaction. With 50 mol%
PPh
3
, the reaction rates were approximately 2- to 3-fold faster than the reaction catalyzed
using 20 mol% PPh
3
. A dramatic increase in the reaction rate was found by using
sterically less hindered PMe
3
(20 mol %) (Table 2.2, entry 1).
Having established optimal conditions, we further investigated the scope of substrates
in the reaction (Table 2.2). Methyl vinyl ketone was found to readily react with 3a, 3b,
3c, and 3f to furnish the corresponding products in good to excellent yields, respectively
The reaction using 1-fluoro-1-(phenylsulfonyl)propane-2-one (3d) as a pronucleophile
afforded a complex mixture, presumably due to the presence of acidic protons on the α-
position of the carbonyl group.

127

Table 2.2. PMe
3
-catalyzed reaction of fluoro(phenylsulfonyl) substituted methane
derivatives with methyl vinyl ketone and ethyl acrylate.

128

When ethyl acrylate was subjected to similar reaction conditions, the corresponding
products were obtained with 60-88% yields after prolonged reaction time. Such lower
reaction rates reflected the lower reactivity of ethyl acrylate compared with methyl vinyl
ketone (Table 2, entries 5-8). All products obtained were characterised by
19
F,
1
H,
13
C
NMR spectra, as well as HRMS. In addition, base-sensitive functional groups such as
cyano, nitro, and ester were well tolerated during the course of the reaction. The failure of
(E)-pent-3-en-2-one to undergo the Michael reaction under these conditions implied that
the reaction was significantly affected by the steric emcumbrance of the terminal carbon
on the double bond.
On the basis of the experimental results, a plausible mechanism is proposed for the
formation of 5a-h (Scheme 1). Addition of PMe
3
to alkene 4 generates the zwitterion
intermediate. Intermediate 4 abstracts a proton from the α-fluorine-substituted methylene
derivative 3, followed by an intermolecular disproportionation reaction to furnish the
desired product 5 before releasing PMe
3
(Scheme 2.1).

129

Scheme 2.1. Reaction mechanism for phosphine catalyzed 1, 4-addition to ,  -
unsaturated compounds

In summary, a convenient protocol for the preparation of α-substituted
fluoro(phenylsulfonyl)methane derivatives has been described and its subsequent use in
1,4-addition to a variety of Michael acceptors has also been demonstrated.

2.3. Experimental
Unless otherwise mentioned, all other reagents were purchased from commercial
sources. Diethyl ether and THF were all distilled under nitrogen over
sodium/benzophenone ketyl prior to use. Toluene was distilled over sodium. Column
chromatography was carried out using silca gel (60-200 mesh).
130

1
H,
13
C and
19
F NMR spectra were recorded on Varian Mercury 400 NMR
spectrometers.
1
H NMR chemical shifts were determined relative to internal (CH
3
)
4
Si
(TMS) at δ 0.0 or to the signal of a residual protonated solvent: CDCl
3
δ 7.26.
13
C NMR
chemical shifts were determined relative to internal TMS at δ 0.0 or to the
13
C signal of
solvent: CDCl
3
δ 77.16.
19
F NMR chemical shifts were determined relative to internal
CFCl
3
at δ 0.0.
2.3.1. General Procedure for the Oxidation of Sulfides
Aqueous hydrogen peroxide (13.5mL, 160 mmol, 30%wt) was added into a solution
of the sulfide (40 mmol) in CH
3
CO
2
H (60 mL) at 0 C and the reaction mixture was
stirred about 2h. The reaction mixture was allowed warming to room temperature and
stirred overnight. The mixture was poured into ice water (200 mL) and extracted with
dichloromethane (200 mL). The organic phase was washed with ice water (200 mL × 3),
dried over MgSO
4
, and evaporated. The residual was purified by chromatography column
to afford the title product (2a-2e).

(Nitromethylsulfonyl)benzene (2a):

White solid, 90% yield.
1
H NMR (CDCl
3
)  5.60 (s, 2H), 7.64-7.68 (m, 2H), 7.78-7.82
(m, 1H), 7.96-7.99 (m, 2H).

131

2-(Phenylsulfonyl)acetonitrile (2b):

Colorless oil, 76% yield.
1
H NMR (CDCl
3
)  4.07 (s, 2H), 7.65-7.70 (m, 2H), 7.77-
7.82 (m, 1H), 8.04-8.06 (m, 2H).
Ethyl 2-(phenylsulfonyl)acetate (2c):

Colorless oil, in 83% yield.
1
H NMR (CDCl
3
)  1.29 (t, J = 7.2 Hz, 3H), 4.26-4.42
(m, 2H), 7.59-7.64 (m, 2H), 7.73-7.78 (m, 1H), 7.93-7.95 (m, 2H).
1-(Phenylsulfonyl)propan-2-one (2d):

Colorless oil, in 70% yield.
1
H NMR (CDCl
3
)  2.42 (s, 3H), 4.16 (s, 2H), 7.57-7.61
(m, 2H), 7.68-7.72 (m, 1H), 7.88-7.91 (m, 2H).

2.3.2. Improved Procedure For The Monofluorination With Selectfluor
®

To a slurry of NaH (6.75 mmol) in THF (15 mL) was added a solution of 1-
substituted phenylsulfonylmathane (6.75 mmol) in THF (10 mL) at 0 C under argon.
After stirred for 2h, a solution of Selectfluor (6.75 mmol) in dried DMF (15 mL) was
dropping into above-mentioned mixture at 0 C and the reaction mixture was stirring
132

overnight, monitoring with TLC. After the completion of the reaction, CH
2
Cl
2
(20 mL) is
added and the mixture was washed with water, brine, then dried with MgSO
4
and filtered.
The filtrate was evaporated, and the residue was purified with a chromatography column
to give a title product in good yield.
(Fluoro(nitro)methylsulfonyl)benzene (3a):

As white solid in 62 % yield isolated.
1
H NMR (CDCl
3
)  6.44 (d, J = 48.4 Hz, 1H),
7.66-7.70 (m, 2H), 7.83-7.87 (m, 1H), 7.94-7.96 (m, 2H).
13
C NMR (CDCl
3
)  111.81 (d,
J = 283.0 Hz), 130.06, 130.72, 131.43, 136.84.
19
F NMR (CDCl
3
)  -142.16 (d, J = 48.4
Hz, 1F).
2-Fluoro-2-(phenylsulfonyl)acetonitrile (3b):

As colorless oil in 45 % yield isolated.
1
H NMR (CDCl
3
)  5.69 (d, J = 46.8 Hz, 1H),
7.68-7.73 (m, 2H), 7.84-7.88 (m, 1H), 8.04-8.07 (m, 2H).
13
C NMR (CDCl
3
)  88.11 (d, J
= 232.3 Hz), 109.87 (d, J = 29.5 Hz), 130.00, 130.69, 132.25, 136.59.
19
F NMR (CDCl
3
)
 -179.23 (d, J = 47.8 Hz, 1F). HRMS Calcd for C
8
H
6
FNO
2
S: 199.0103; Found:
199.0107.
133

Ethyl-2-fluoro-2-(phenylsulfonyl)acetate (3c):

As colorless oil in 56 % yield isolated.
1
H NMR (CDCl
3
)  1.29 (t, J = 7.2 Hz, 3H),
4.29 (q, 2H), 5.57 (d, J = 48.0 Hz, 1H), 7.59-7.64 (m, 2H), 7.73-7.78 (m, 1H), 7.93-7.96
(m, 2H).
13
C NMR (CDCl
3
)  14.03, 63.64, 97.39 (d, J = 232.5 Hz), 129.54, 129.93,
134.65, 135.46, 161.11 (d, J = 22.9 Hz).
19
F NMR (CDCl
3
)  -180.91 (d, J = 48.0 Hz,
1F).
1-Fluoro-1-(phenylsulfonyl)propane-2-one (3d):

As white solid in 61 % yield isolated.
1
H NMR (CDCl
3
)  2.37 (d, J = 3.6 Hz, 3H),
5.46 (d, J = 49.2 Hz, 1H), 7.61-7.65 (m, 2H), 7.75-7.77 (m, 1H), 7.92-7.95 (m, 2H).
13
C
NMR (CDCl
3
)  27.65, 101.51 (d, J = 874.8 Hz), 129.68, 129.74, 134.95, 135.51, 195.71
(d, J = 81.7 Hz).
19
F NMR (CDCl
3
)  -113.56 (tq, J = 49.2 Hz, 3.6 Hz, 1F).
2.3.3. General Procedure For Phosphine-Catalyzed 1,4-Addition Of -
Substituted Fluoro(Phenylsulfonyl)methane Derivatives
To a solution of fluorine-substituted active methylene (0.2 mmol, 1 equivalent) and
vinyl methyl acetone (0.6 mmol, 3 equivalent ) in THF (0.5 mL) was added
trimethylphospine (0.04 mmol, 1.0 M in THF) dropwise by a syringe at room temperature
under argon, monitoring by TLC. After completed the reaction, the solvents were
134

removed under reduce vacuum. The crude products were purified by a chromatography
column (hexane/ ethyl acetate = 3/1) to produce the title product in good to excellent
yield.
5-Fluoro-5-nitro-5-(phenylsulfonyl)pentan-2-one (5a):

As white solid in 93 % yield isolated.
1
H NMR (CDCl
3
)  2.18 (s, 3H), 2.50-2.56 (m,
1H), 2.70-2.78 (m, 1H), 2.88-2.92 (m, 1H), 2.98-3.09 (m, 1H), 7.62-7.66 (m, 2H), 7.79-
7.83 (m, 1H), 7.91-7.94 (m, 2H).
13
C NMR (CDCl
3
)  25.56 (d, J = 17.9 Hz), 27.19,
30.01, 35.53 (d, J = 2.2 Hz), 123.63 (d, J=282.4), 125.04, 129.91, 131.09, 131.33,
136.55, 203.79.
19
F NMR (CDCl
3
)  -125.90, -125.96 (dd, J
1
= 28.6 Hz, 10.5 Hz, 1F).
HRMS: (FAB) calcd for C
11
H
13
FNO
5
S 290.0499 (M+1) found: m/z 290.0500.
2-Fluoro-5-oxo-2-(phenylsulfonyl)hexanenitrile (5b):

As white solid in 90 % yield isolated.
1
H NMR (CDCl
3
)  2.23 (s, 3H), 2.66-2.75 (m,
1H), 2.85-2.92 (m, 1H), 7.65-7.69 (m, 2H), 7.81-7.85 (m, 1H), 8.02-8.04 (m, 2H).
13
C
NMR (CDCl
3
)  25.84 (d, J = 21.4 Hz), 30.00, 36.82 (d, J = 2.4 Hz), 99.20 (d, J = 228.8
Hz), 112.24 (d, J = 33.1 Hz), 129.75, 131.14, 132.04, 136.32, 204.03.
19
F NMR (CDCl
3
)
 -148.50 (dd, J= 27.1 Hz, 16.9 Hz, 1F). HRMS: (FAB) calcd for C
12
H
13
FNO
3
S
270.0600 (M+1) found: m/z 270.0612.
135

Ethyl 2-fluoro-5-oxo-2-(phenylsulfonyl)hexanoate (5c):

As white solid in 75 % yield isolated.
1
H NMR (CDCl
3
)  1.20 (t, J = 7.2 Hz, 3H),
2.14 (s, 3H), 2.49-2.56 (m, 2H), 2.67-2.78 (m, 2H), 4.15-4.23 (m, 2H), 7.56-7.60 (m,
2H), 7.70-7.74 (m, 1H), 7.89-7.92 (m, 2H).
13
C NMR (CDCl
3
)  13.93, 25.28 (d, J = 19.9
Hz), 29.92, 36.48 (d, J = 3.2 Hz), 63.58, 106.26 (d, J = 233.3 Hz), 129.30, 130.45,
134.13, 135.24, 163.63 (d, J = 24.8 Hz), 205.27.
19
F NMR (CDCl
3
)  -158.34 (m, 1F).
HRMS: (FAB) calcd for C
14
H
18
FNO
5
S 317.0859 (M+1) found: m/z 317.0861.

5-Fluoro-5,5-bis(phenylsulfonyl)pentan-2-one (5d):

As white solid in 91 % yield isolated.
1
H NMR (CDCl
3
)  2.17 (s, 3H), 2.56-2.64 (m,
2H), 3.05-3.09 (m, 2H), 7.55-7.59 (m, 4H), 7.72-7.76 (m, 2H), 7.91-7.93 (m, 4H).
13
C
NMR (CDCl
3
)  24.81 (d, J = 18.9 Hz), 29.95, 36.51 (d, J = 6.2 Hz), 115.07 (d, J = 264.4
Hz), 129.20, 130.99, 134.89, 135.52.
19
F NMR (CDCl
3
)  -140.70 (t, J = 15.4 Hz, 1F).
HRMS: (FAB) calcd for C
17
H
18
FO
5
S
2
385.0580

(M+1) found: m/z 385.0565.
136

Ethyl 4-fluoro-4-nitro-4-(phenylsulfonyl)butanoate (5e):

As white solid in 64 % yield isolated.
1
H NMR (CDCl
3
)  1.26 (t, J = 7.2 Hz, 3H),
2.31-2.39 (m, 1H), 2.50-2.58 (m, 1H), 2.87-2.95 (m, 1H), 3.04-3.20 (m, 1H), 4.11 (q, J =
7.2 Hz, 2H), 7.58-7.62 (m, 2H), 7.76-7.80 (m, 1H), 7.88-7.90 (m, 2H).
13
C NMR (CDCl
3
)
 14.37, 26.70 (d, J = 18.2 Hz), 27.04 (d, J = 3.8 Hz), 61.73, 123.43 (d, J = 282.8 Hz),
130.04, 131.22, 131.27, 136.73, 170.35.
19
F NMR (CDCl
3
)  -126.70 (dd, J= 30.1 Hz, 9.8
Hz, 1F). HRMS: (FAB) calcd for C
12
H
15
FNO
6
S 320.0604 (M+1) found: m/z 320.0612.
Ethyl 4-cyano-4-fluoro-4-(phenylsulfonyl)butanoate (5f)

As white solid in 60 % yield isolated.
1
H NMR (CDCl
3
)  1.30 (t, J = 7.2 Hz, 3H),
2.70-2.83 (m, 4H), 4.17-4.22 (m, J = 7.2 Hz, 2H), 7.66-7.70 (m, 2H), 7.81-7.86 (m, 1H),
8.03-8.06 (m, 2H).
13
C NMR (CDCl
3
)  14.32, 27.59 (d, J = 18.9 Hz), 28.33 (d, J = 3.0
Hz), 61.59, 99.04 (d, J = 228.8 Hz), 112.15 (d, J = 33.2 Hz), 129.86, 131.28, 132.08,
136.44, 170.49.
19
F NMR (CDCl
3
)  -149.63 (m, 1F). HRMS: (FAB) calcd for
C
13
H
15
FNO
4
S 300.0706 (M+1) found: m/z 300.0719.
137

Diethyl 2-fluoro-2-(phenylsulfonyl)pentanedioate (5g):

A white solid in 71 % yield isolated.
1
H NMR (CDCl
3
)  1.18-1.25 (m, 6H), 2.32-
2.38 (m, 1H), 2.55-2.59 (m, 2H), 2.76-2.84 (m, 1H), 4.06-4.21 (m, 4H), 7.54-7.58 (m,
2H), 7.68-7.72 (m, 1H), 7.87-7.90 (m, 2H).
13
C NMR (CDCl
3
)  14.15, 14.41, 26.63 (d, J
= 20.2 Hz), 28.05 (d, J = 3.4 Hz), 61.31, 63.82, 106.38 (d, J = 234.5 Hz), 129.51, 130.67,
134.23, 135.47, 163.61 (d, J = 25.5 Hz), 171.40.
19
F NMR (CDCl
3
)  -159.13 (dd, J=
31.2 Hz, 10.5 Hz, 1F). HRMS: (FAB) calcd for C
15
H
20
FNO
6
S 347.0965 (M+1) found:
m/z 347.0962.
Ethyl 5-fluoro-2-oxo-5,5-bis(phenylsulfonyl)pentanoate (5h):

A white solid in 71 % yield isolated.
1
H NMR (CDCl
3
)  1.20 (t, J = 7.2 Hz, 3H),
2.62-2.71 (m, 2H), 2.78-2.83 (m, 2H), 4.04-4.09 (m, 2H), 7.51-7.56 (m, 2H), 7.68-7.72
(m, 1H), 7.88-7.90 (m, 2H).
13
C NMR (CDCl
3
)  14.22, 26.01 (d, J = 19.4 Hz), 27.69 (d,
J = 7.7 Hz), 61.06, 114.75 (d, J = 266.1 Hz), 129.21, 130.96, 134.85, 135.52, 171.43.
19
F
NMR (CDCl
3
)  -142.91 (t, J = 15.8 Hz, 1F). HRMS: (FAB) calcd for C
18
H
20
FO
6
S
2

415.0685 (M+1) found: m/z 415.0673.

138

2.4. References

[1] Banks, R. E.; Smart, B. E.; Tatlow, J. C. Eds.: Organofluorine Chemistry:
Principles and Commercial Applications, Plenum, New York, 1994, chap. 3.
[2] Smart, B. E. J. Fluorine Chem. 2001, 109, 3-11.
[3] Kirsch, P. Modern Fluoroorganic Chemistry; Wiley-VCH Verlag GMBH & Co
KGaA: Weinheim, Germany, 2004. d) K. L. Kirk, J. Fluorine Chem. 2006, 127,
1013 – 1029.
[4] Ojima, I.; McCarthy, J. R.; Welch, J. T. Eds. Biomedical Frontiers Chemistry: ACS
Symp. Ser., V. 639, 1996.
[5] Filler, R.; Kobayashi, Y.; Yagupolsk, L. M. Eds. Organofluorine Compounds in
Medicinal Chemistry and Biomedical Applications, Elsevier, Amsterdam, 1993.
[6] (a) Prakash, G. K. S.; Hu, J.; Olah, G. A. J. Org. Chem. 2003, 68, 4457-4463; (b)
Prakash, G. K. S.; Mandal, M. J. Am. Chem. Soc. 2002, 124, 6538-6539; (c)
Prakash, G. K. S.; Hu, J.; Mathew, T.; Olah, G. A. Angew. Chem. Int. Ed. 2003, 42,
5216-5219; (d) Prakash, G. K. S.; Mandal, M.; Olah, G. A. Angew. Chem. Int. Ed.
2001, 40, 589-590; (e) Prakash, G. K. S.; Chacko, S.; Alconcel S.; Stewart, S.;
Mathew, T.; Olah, G. A. Angew. Chem. Int. Ed. 2007, 46, 4933-4936; (f) Prakash,
G. K. S.; Weber, C.; Chacko, S.; Olah, G. A. J. Comb. Chem. 2007, 9, 920-923;
(g) Prakash, G. K. S.; Weber, C.; Chacko, S.; Olah, G. A. Org. Lett. 2007, 9, 1863-
1866.
[7] (a) Prakash, G. K. S.; Hu, J. New Nucleophilic Fluoroalkylation Chemistry.
Fluorine-Containing Synthons; Soloshonok, V. A., Ed.; American Chemical
139

Society, DC, 2005; (b) Prakash, G. K. S.; Yudin, A. K. Chem. Rev. 1997, 97, 757-
786; (c) Prakash, G. K. S.; Mandal, M. J. Fluorine Chem. 2001, 112, 123-131; (d)
Ni, C.; Zhang, L.; Hu, J. J. Org. Chem. 2008, 73, 5699-5713.
[8] Maruoka, K.; Shimada, I.; Akakura, M.; Yamamoto, H. Synlett, 1994, 847-848.
[9] (a) Sevenard, D. V.; Sosnovskikh, V. Y.; Kolomeitsev, A. A.; Königsmann, M.H.;
Röschenthaler, G-V. Tetrahedron Lett. 2003, 44, 7623-7627; (b) Sosnovskikh, V.
Y.; Usachev, B. I.; Sevenard, D. V.; Röschenthaler, G-V. J. Org. Chem. 2003, 68,
7747-7754.
[10] Lefebvre, O.; Brigaud, T.; Portella, C. Tetrahedron, 1998, 54, 5939-5948.
[11] (a) Sato, K.; Nakazato, S.; Enko, H.; Tsujota, H.; Fujita, K.; Yamamoto, T.; Omote,
M.; Ando, A.; Kumadaki, I. J. Fluorine Chem. 2003, 121, 105-107; (b) Sato, K.;
Omote, M.; Ando, A.; Kumadaki, I. J. Fluorine Chem. 2004, 125, 509-515.
[12] Takeuchi, Y.; Nagata, K.; Koizumi, T. J. Org. Chem. 1989, 54, 5453-5459.
[13] (a) Wade, P. A.; Hinney, H. R.; Amin, N. V.; Mail, P. D.; Morrow, S. D.;
Hardinger, S. A.; Saft, M.S. J. Org. Chem. 1981, 46, 765-770; (b) Truce, W. E.;
Klingler, T. C.; Paar, J. E.; Feuer, H.; Wu, D. K. J. Org. Chem. 1969, 34, 3104-
3107; (c) Peng, W.; Shreeve, J. M. Tetrahedron Lett. 2005, 46, 4905-4909.
[14] Fargeas, V.; Baalouch, M.; Metay, E.; Baffreau, J.; Menard, D.; Gosselin, P.;
Berge, J. P.; Barthomeuf, C.; Lebreton, J. Tetrahedron, 2004, 60, 10359-10364.
[15] (a) Walker, D. J. Org. Chem. 1966, 31, 835-837; (b) Doyle, K. J.; Moody, C. J.;
Tetrahedron, 1994, 50, 3761-3772; (c) Takeuchi, Y.; Asahina, M.; Hori, K.;
Koizumi, T. J. Chem. Soc. (Perkin Trans. 1) 1988, 5, 1149-1153; (d) Ohta, H.;
140

Kato, Y.; Tsuchihashi, G. J. Org. Chem. 1987, 52, 2735-2739; (e) Takeuchi, Y.;
Ogura, H.; Kanada, A.; Koizumi, T.; J. Org. Chem. 1992, 57, 2196-2199.
[16] For a recent review, see: Nyffeler, P. T.; Duron, S. C.; Burkart, M. D.; Vincent, S.
P.; Wong, C. H. Angew. Chem. Int. Ed. 2005, 44, 192-212.
[17] Fukuzumi, T.; Shibata, N.; Sugiura, M.; Yasui, H.; Nakamura, S.; Toru, T. Angew.
Chem. Int. Ed. 2006, 45, 4973-4977.
[18] For a recent review on Lewis base catalysis, Denmark, S. E.; Beutner, G. L. Angew.
Chem. Int. Ed. 2008, 47, 1560-1638.
141

Chapter 3

Highly Efficient Synthesis of α-Fluoro, Chloro and
Methoxy-Disulfonylmethane Derivatives as Tunable α-
Substituted-Methyl Synthons via C-S Bond Forming
Strategy

142

3.1. Introduction
Sulfone-based organic compounds are widely used for introduction of synthetically
useful building blocks as well as bioactive functionalities.
1
In particular, arylsulfonyl
methane derivatives have been extensively utilized in modern organic chemistry as
methyl synthons.
2
Sulfonyl, a strong electron-withdrawing group, is capable of activating
sp
3
-hybridized C-H bonds by significantly increasing their acidities. Successive
substitution of protons with methylsulfonyl groups in a methane molecule reduces the
pK
a
values of the corresponding derivatives in H
2
O to 29, 12 and 0, respectively.
3
The
resulting carbon-acids can be readily used as tunable pronucleophiles in many reactions.
2

On the other hand, further transformations of sulfonyl group can be achieved via a variety
of methods compatible with different functional groups.
4

Incorporation of fluoromethyl groups into organic molecules has attracted increasing
attention in pharmaceutical arena since it can dramatically change their physical and
biological properties.
5
In recent years, phenylsulfonyl-functionalized fluoromethylation
reagents and related methodologies have been developed by Prakash, Hu, Shibata, and
many others as highly selective and efficient fluoromethylation protocols in
organofluorine chemistry.
6
The presence of phenylsulfonyl group in these
fluoromethylation reagents can suppress α-elimination of fluoride and increase the
thermodynamic stability of these species by delocalizing the negative charge.
7
Among
these elegant reagents, -fluorobis(phenylsulfonyl)methane (FBSM) and its analogues
have been used as an efficient monofluoromethyl equivalent in various
transformations.
6d-6j
Although FBSM has been successfully applied in numerous
143

reactions which cannot be achieved by other fluoromethylation reagents, such as
fluoromethyl phenyl sulfone (PhSO
2
CH
2
F), it is still not considered a practical reagent
due to the difficulties in its preparation. During our continued efforts on the facile
synthesis of FBSM and its derivatives, a highly efficient method was developed for the
convenient synthesis of fluoro(disulfonyl)methanes as well as chloro- and
methoxy(disulfonyl)methanes.

Scheme 3.1. Synthesis of fluorobis(phenylsulfonyl)methane (FBSM) by (a) C-F bond
forming routes and (b) C-S bond forming route.

Fluoro(disulfonyl)methanes were first synthesized in 1998 by Wickiser et al. as
anthelmintic and insecticidal active compounds via C-F bond forming reaction between
disulfonylmethide anions and Selectfluor
®
.
8
Realizing the potential applications of
fluoro(disulfonyl)methanes in synthetic chemistry, FBSM was independently developed
by Shibata and Hu as a nucleophilic fluoromethylation reagent in the same route
mentioned above.
6d-6j
Recently, Hirokatsu and Toshio described the electrochemical
144

reaction between NEt
4
F-4HF and phenyl(phenylsulfonylmethyl)sulfane (PhSO
2
CH
2
SPh)
to afford FBSM in 52% yield.
9
However, the major problems of these synthetic routes
involving C-F bond formation are a) the fluorine sources are costly or hazardous; b) the
reactions can only afford the products in moderate yield (50%-70%); c) the selectivity of
the reactions is unsatisfactory leading to a mixture containing the desired compounds,
difluorinated products and the unreacted starting materials; d) the separation, including
chromatographic process, limits the application of these reactions.

3.2. Results and Discussion
Lately, Hu et al. disclosed the synthesis of FBSM by the treatment of PhSO
2
CH
2
F
with methyl benzenesulfinate followed by the oxidation using m-chloroperoxybenzoic
acid (mCPBA) (Scheme 3.1).
10
The method first demonstrated the preparation of α-
fluoro(disulfonyl)methane derivatives via a C-S bond forming strategy instead of the
construction of C-F bond. By this methodology the problems mentioned above were
successfully eliminated, and the product can be selectively afforded in excellent yield.
However, the utilization of sulfinates as arylsulfonyl precursors increases the cost of the
method considerably, which may limit the practicability thereof. On the other hand,
methoxy(disulfonyl)methanes were synthesized via the C-S bond forming strategy using
methoxymethyl phenyl sulfone and phenylsulfonyl chloride (PhSO
2
Cl), which
significantly reduces the expense and shortens the synthetic route.
11

145

Scheme 3.2. Reaction of fluorophenylsulfonyl methide anion with phenyl sulfonyl
chloride.
Inspired by the C-S bond forming strategy, we performed the reaction between
fluoro(phenylsulfonyl)methide anion (PhSO
2
CHF
-
) and PhSO
2
Cl expecting the formation
of FBSM. To our dismay, instead of sulfonylation, chlorination occurred at the -carbon
leading to chlorofluoromethyl phenyl sulfone (PhSO
2
CHClF) as the only product
(Scheme 3.2).
Table 3.1. Formation of fluorophenylsulfonylmethide anion under different bases and its
reaction with phenyl sulfonyl halides.

146

Moreover, PhSO
2
CHClF was predominately generated as the product even when
different bases or addition sequences of starting materials are applied (Table 3.1, Entries
1-6). Higher yields were observed when KHMDS was used as the base which can
diminish the defluorination of PhSO
2
CHF
-
possibly due to the weaker coordination
between fluorine and potassium compared with sodium and lithium.
The result indicates that the sulfur atom in PhSO
2
Cl is less electrophilic towards the
PhSO
2
CHF
-
anion than the Cl atom. Therefore, we decided to utilize PhSO
2
F, which can
act as a superior precursor due to the strong electronegativity of F resulting in maximum
positive charge on the sulfur atom and the negative charge on itself. Consequently, the
possible halogenation process would be suppressed. After a few trials (Table 3.1, entries
7 and 8), we delighted to that FBSM can be obtained in almost quantitative yield with
high NMR purity (>95%) by the treatment of PhSO
2
CHF
-
with PhSO
2
F (Scheme 3.3).

Scheme 3.3. The novel C-S bond forming route for the preparation of
fluorobis(phenylsulfonyl)methane (FBSM) and its and derivatives.

The novel synthetic route successfully avoids tedious separation processes such as
chromatography or utilization of any expensive or low efficient reagents. In particular,
PhSO
2
CH
2
F can be readily synthesized in large scale from fairly inexpensive substrate
147

chloromethyl phenyl sulfide and KF followed by oxidation with Oxone.
12
Phenylsulfonyl
fluoride can also be simply prepared from the corresponding chlorine-containing
counterpart (phenylsulfonyl chloride) by chlorine-fluorine exchange using KF.
Noticeably, KF is used as the only fluorine source in the new protocol which
tremendously increases the atom efficiency and remarkably reduces the cost of the
reaction. Compared with the utilization of Selectfluor
®
(the “F
+
” reagent) which is
contrary to the nucleophilic and electronegative nature of fluorine, KF as an “F
+
” reagent
takes advantages of these properties.
Table 3.2. Synthesis of α-fluorobis(phenylsulfonyl)methane (FBSM) and its analogues
by the new C-S bond forming strategy
a

148

It has been demonstrated that alkoxymethyl sulfonyl methanes can be readily applied
as a carbonyl 1,1-dipole synthon
13
and methoxymethyl synthon
14
. Nevertheless, the facile
and efficient synthesis of methoxy(disulfonyl)methanes is still challenging. Diekmann, in
1965, reported the synthesis of alkoxybis(phenylsulfonyl)methanes by photolysis of
bis(phenylsulfonyl)diazomethane in alcohols.
15
The drawbacks of this method appear to
be a) the availability of bis(phenylsulfonyl)diazomethane is limited; b) the alcoholysis
has to be performed under UV radiation which is difficult to perform in many organic
chemistry laboratories. The 2-alkoxybenzo-1,3-disulfone was prepared by the oxidation
of the corresponding sulfide with MoO
5
HMPA H
2
O.
13
However, attempt to oxidize
methoxybis(phenylthio)methane under the same condition resulted in the decomposition
of the starting material. As mentioned above, alkoxydisulfonylmethanes can also be
obtained by the treatment of methoxyphenyl sulfonylmethide (PhSO
2
CH
-
OCH
3
) with the
corresponding sulfonyl chlorides in moderate yield (50-70%).
11
Encouraged by the
successful preparation of fluorodisulfonylmethanes, we attempted the synthesis of
alkoxydisulfonylmethanes using the approach we developed for higher efficiency. As
expected, we were pleased to find that the desired products were generally afforded in
higher yields by the replacement of sulfonyl chlorides with sulfonyl fluorides (Table 3.3).

149

Table 3.3. Synthesis of 1-methoxybis(phenylsulfonyl)methane and its analogues by
the new C-S bond forming strategy.

Chlorodisulfonylmethanes were accidentally prepared by Gibson in 1931 from the
reaction between disulfonylmethide salts with PhSO
2
Cl.
16
However, the details of the
reaction were not described. On the other hand, symmetric chlorodisulfonylmethanes can
be achieved by the careful treatment of disulfonylmethanes and NaOH aqueous solution
with NaOCl.
17
Our attempts to obtain chlorodisulfonylmethanes via the oxidation of the
corresponding disulfides failed due to the high instability of the
chlorodisulfonylmethanes. On the other hand, since the disulfonylmethanes are much less
150

acidic than the monochlorinated intermediates which are rapidly chlorinated, the reaction
between disulfonylmethide carbanions with N-chlorosuccinimide (NCS) always afforded
a mixture of dichlorinated products and the starting materials. Based on the success of the
C-S bond forming strategy in the preparation of fluoro- and methoxy-disulfonylmethane
derivatives, we carried out the reaction between PhSO
2
CH
2
Cl and RSO
2
F under the same
condition mentioned previously. To our delight, our methodology appeared an efficient
synthetic route which can also afford highly pure diarylsulfonylmethanes, both
symmetric and asymmetric, in excellent yield, and chloromethyl perfluoroalkylsulfonyl
phenyl sulfone in moderate yield (Table 3.4).
Table 3.4. Synthesis of 1-chlorobis(phenylsulfonyl)methane and its analogues by the new
C-S bond forming strategy.

151

3.3. Conclusion
In conclusion, a universal and highly efficient C-S bond forming protocol for the
synthesis of the α-substituted disulfonylmethane derivatives was developed. The novel
methodology realizes the one-step synthesis of the compounds as useful methyl synthons
for various reactions. Particularly, the synthetic route of FBSM and its analogues based
on the nature of fluorine successfully diminishes the problems occurring in the
conventional methods, which enables the large-scale preparation of these compounds.

3.4. Experimental
Unless otherwise mentioned, all chemicals were purchased from commercial sources.
1
H,
13
C and
19
F NMR spectra were recorded on Mercury NMR spectrometers at 400 MHz.
Structures of all known products were confirmed by comparison with those of the
authentic samples.
1
H NMR chemical shifts were determined relative to internal
tetramethylsilane at δ 0.0 ppm or to the signal of a residual solvent in CDCl
3
(δ 7.26
ppm).
13
C NMR chemical shifts were determined relative to internal tetramethylsilane at
δ 0.0 ppm or to the
13
C signal of CDCl
3
at δ 77.16 ppm.

152

3.4.1. General Procedure for the Preparation of α-
Fluoro(disulfonyl)methanes

PhSO
2
CH
2
F (348 mg, 2 mmol) and phenyl sulfonyl fluoride (320 mg, 2 mmol) were
dissolved in anhydrous THF (10 mL) in a 50 mL Schlenk flask under Ar. The solution
was cooled to -78
o
C. KHMDS (499 mg, 5 mmol) was dissolved in anhydrous THF (5 mL)
and added to the Schlenk flask dropwise. The reaction mixture was stirred for 30 min at
the same temperature before poured into 4M HCl aqueous solution (20 mL). The
resultant mixture was washed with water and was extracted with CH
2
Cl
2
(15 mL  3).
The combined organic layer was dried over MgSO
4
, and the solvent was evaporate to
afford an oil which crystallized after standing for a while as the product (598 mg, 95%).
1
H NMR and
19
F NMR spectroscopy showed the high purity of the product (>95%).

153

3.4.2. General Procedure for the Preparation of α-
Chloro(disulfonyl)methanes

Chloro(disulfonyl)methanes were obtained according to the same procedure for
fluoro(disulfonyl)methane synthesis. The reactions afforded the products in high purity
(>95%) by simple extraction technique.

3.4.3. General Procedure for the Preparation of
Methoxy(disulfonyl)methanes

Methoxy(disulfonyl)methanes were synthesized by the same procedure for
fluoro(disulfonyl)methane synthesis. The products were obtained with a small amount of
PhSCH
2
OCH
3
which can be removed by chromatography with hexanes-CH
2
Cl
2
as the
eluent.
154

3.4.4. Compound Characterization
-Fluorobis(phenylsulfonyl)methane
S S
F
O OO O

As white solid.
1
H NMR (CDCl
3
)  5.70 (d, J = 45.8 Hz, 1H), 7.60-7.66 (t, J = 7.6
Hz, 4H), 7.74-7.83 (t, J = 7.6 Hz, 2H), 7.95-8.03 (m, 4H).
19
F NMR (CDCl
3
)  -168.2 (d,
J = 45.6 Hz, 1F). The data are consistent with the reference.
6d

1-(Fluoro(phenylsulfonyl)methylsulfonyl)-4-methylbenzene
S S
F
O OO O
CH
3
As white solid in 93 % yield isolated.
1
H NMR (CDCl
3
)  2.48 (s, 3H), 5.70 (d, J =
45.6 Hz, 1H), 7.39-7.41 (m, 2H), 7.59-7.63 (m, 2H), 7.74-7.78 (m, 1H), 7.85 (d, J = 8.4
Hz, 2H), 7.97-8.00 (m, 2H).
19
F NMR (CDCl
3
)  -168.87 (d, J = 45.5 Hz, 1F). The data
are consistent with the reference.
Error! Bookmark not defined.

1-(Fluoro(phenylsulfonyl)methylsulfonyl)-4-nitrobenzene
S S
F
O OO O
NO
2
As white solid in 90 % yield isolated.
1
H NMR (CDCl
3
)  5.83 (d, J = 45.6 Hz, 1H),
7.61-7.65 (m, 2H), 7.77-7.81 (m, 1H), 7.94-7.96 (m, 2H), 8.22-8.24 (m, 2H), 8.43-8.46
(m, 2H).
13
C NMR (CDCl
3
)  105.8 (d, J = 265.4 Hz), 124.7, 130.0, 130.2, 132.2, 135.2,
155

136.3, 140.7, 152.1.
19
F NMR (CDCl
3
)  -168.47 (d, J = 45.8 Hz, 1F). MS (ESI, m/z):
357.9 (M-H
-
), 202.1, 157.0, 137.9. HRMS: calcd for C
13
H
9
FNO
6
S
2
357.9861 (M-H
-
)
found: m/z 357.9859.
1-Chloro-4-(fluoro(phenylsulfonyl)methylsulfonyl)benzene
S S
F
O OO O
Cl
As white solid in 97 % yield isolated.
1
H NMR (CDCl
3
)  5.72 (d, J = 46.0 Hz, 1H),
7.58-7.64 (m, 4H), 7.76-7.80 (m, 1H), 7.92-7.98 (m, 4H).
13
C NMR (CDCl
3
)  105.8 (d, J
= 265.0 Hz), 129.7, 130.0, 130.2, 131.9, 133.6, 135.4, 136.0, 143.1.
19
F NMR (CDCl
3
)  -
168.61 (d, J = 45.8 Hz, 1F). MS (ESI, m/z): 371.0 (M+Na
+
). HRMS: calcd for
C
13
H
10
ClFO
4
S
2
Na 370.9591 (M+Na
+
) found: m/z 370.9590.
2-(Fluoro(phenylsulfonyl)methylsulfonyl)-1,3,5-trimethylbenzene
S S
F
O OO O

As pale powder in 73 % yield isolated.
1
H NMR (CDCl
3
)  2.32 (s, 3H), 2.61 (s, 6H),
5.68 (d, J = 46.4 Hz, 1H), 6.99 (s, 2H), 7.62 (t, J = 7.8 Hz, 2H), 7.77 (t, J = 7.7 Hz, 1H),
8.04 (d, J = 7.8 Hz, 2H).
13
C NMR (CDCl
3
)  21.4, 23.2, 106.4 (d, J = 265.9 Hz), 129.4,
130.4, 130.5,132.8, 135.4, 135.7, 142.4, 145.9.
19
F NMR (CDCl
3
)  -168.02 (d, J = 46.4
Hz, 1F). MS (ESI, m/z): 379.1 (M+Na
+
), 338.3. HRMS: calcd for C
16
H
18
FO
4
S
2
357.0631
(M+H
+
) found: m/z 357.0625.
156

(Fluoro(perfluorobutylsulfonyl)methylsulfonyl)benzene
S S
F
C
4
F
9
O OO O

As white waxy solid in 86 % yield isolated.
1
H NMR (CDCl
3
)  6.15 (d, J = 46.5 Hz,
1H), 7.67-7.71 (m, 2H), 7.85 (tq,
1
J = 7.7 Hz,
2
J = 1.2 Hz, 1H), 8.05-8.08 (m, 2H).
13
C
NMR (CDCl
3
)  103.4 (d, J = 274.5 Hz), 105.1-121.6 (m, 4C), 130.0, 130.7, 134.3,
136.9.
19
F NMR (CDCl
3
)  -81.2 (t, J = 9.7 Hz, 3F), -109.9 (m, 2F), -121.5 (m, 2F), -
126.3 (m, 2F), -166.5 (m, 1F). MS (ESI, m/z): 932.5 (2M+Na-2H
-
), 455.0 (M-H
-
), 282.8.
HRMS: calcd for C
11
H
5
F
10
O
4
S
2
454.9475 (M-H
-
) found: m/z 454.9469.
-Methoxybis(phenylsulfonyl)methane
S S
Cl
O OO O

As white solid in 78 % yield isolated.
1
H NMR (CDCl
3
)  3.61 (s, 3H), 5.03 (s, 1H),
7.55-7.59 (m, 4H), 7.68-7.73 (m, 2H), 7.94-8.96 (m, 4H),
13
C NMR (CDCl
3
)  64.6,
106.1, 129.2, 130.3, 135.1, 136.3. MS (ESI, m/z): 349.0 (M+Na
+
). HRMS: calcd for
C
14
H
14
NaO
5
S
2
349.0175 (M+Na
+
) found: m/z 349.0173.
1-Chloro-4-(methoxy(phenylsulfonyl)methylsulfonyl)benzene
S S
Cl
O OO O
CH
3
As white solid in 82 % yield isolated.
1
H NMR (CDCl
3
)  2.46 (s, 3H), 3.60 (s, 3H),
5.00 (s, 1H), 7.35 (d, J = 8.0 Hz, 2H), 7.55-7.58 (m, 2H), 7.67-7.73 (m, 1H), 7.82-7.84
157

(m, 2H), 7.94-7.96 (m, 2H).
13
C NMR (CDCl
3
)  21.9, 64.5, 106.1, 129.1, 129.9, 130.2,
133.3, 135.0, 136.4, 146.4. MS (ESI, m/z): 702.7 (2M+Na
+
), 363.0 (M+Na
+
). HRMS:
calcd for C
15
H
16
NaO
5
S
2
363.0331 (M+Na
+
) found: m/z 363.0334.
1-(Methoxy(phenylsulfonyl)methylsulfonyl)-4-nitrobenzene
S S
Cl
O OO O
NO
2
As white solid in 62% yield isolated.
1
H NMR (CDCl
3
)  3.66 (s, 3H), 5.08 (s, 1H),
7.59 (t, J = 7.6 Hz, 2H), 7.74 (m, 1H), 7.93 (m, 2H), 8.18 (d, J = 8.8 Hz, 2H), 8.40 (d, J =
8.8 Hz, 2H).
13
C NMR (CDCl
3
)  64.8, 106.2, 124.1, 129.5, 130.1, 132.2, 135.4, 136.2,
141.5, 151.6. MS (ESI, m/z): 370.0 (M-H
-
), 153.6, 145.8. HRMS: calcd for C
14
H
12
NO
7
S
2

370.0061 (M-H
-
) found: m/z 370.0066.
1-Chloro-4-(methoxy(phenylsulfonyl)methylsulfonyl)benzene
S S
Cl
O OO O
Cl
As white solid in 74% yield isolated.
1
H NMR (CDCl
3
)  3.62 (s, 3H), 5.07 (s, 1H),
7.51-7.59 (m, 4H), 7.72 (m, 1H), 7.86-7.94 (m, 4H)
13
C NMR (CDCl
3
)  64.6, 106.1,
129.3, 129.5, 130.2, 131.8, 134.5, 135.1, 136.3, 142.1. MS (ESI, m/z): 382.9 (M+Na
+
).
HRMS: calcd for C
14
H
13
ClNaO
5
S
2
382.9785 (M+Na
+
) found: m/z 382.9784.

158

(Methoxy(perfluorobutylsulfonyl)methylsulfonyl)benzene
S S
Cl
C
4
F
9
O OO O

As white waxy solid in 74% yield isolated.
1
H NMR (CDCl
3
)  3.91 (s, 3H), 5.55 (s,
1H), 7.63 (t, J = 7.6 Hz, 2H), 7.78 (t, J = 7.6 Hz, 1H), 8.03 (d, J = 8.0 Hz, 2H),
13
C NMR
(CDCl
3
)  64.4, 105.3-121.8 (m, 4C), 104.6, 129.5, 130.7, 135.1, 136.0.
19
F NMR
(CDCl
3
)  -81.2 (t, J = 9.0 Hz, 3F), -110.5-108.5 (m, 2F), -122.6-120.5 (m, 2F), -127.3-
125.4 (m, 2F). MS (ESI, m/z): 620.9 (2M+Na-2H
-
), 299.2 (C
4
F
9
SO
3
-
). HRMS: calcd for
C
12
H
8
F
9
O
5
S
2
466.9675 (M-H
-
) found: m/z 466.9670.
-Chlorobis(phenylsulfonyl)methane
S S
OMe
O OO O

As white solid in 78 % yield isolated.
1
H NMR (CDCl
3
)  5.56 (s, 1H), 7.61-7.65 (m,
4H), 7.75-7.80 (m, 2H), 8.03-8.05 (m, 4H).
13
C NMR (CDCl
3
)  84.0, 129.4, 130.7,
135.6, 135.7. The data are consistent with the reference.
18

1-(Chloro(phenylsulfonyl)methylsulfonyl)-4-methylbenzene
S S
OMe
O OO O
CH
3
As white solid in 82 % yield isolated.
1
H NMR (CDCl
3
)  2.48 (s, 3H), 5.56 (s, 1H),
7.40 (d, J = 8.0 Hz 2H), 7.59-7.63 (m, 2H), 7.73-7.78 (m, 1H), 7.90 (d, J = 8.0 Hz, 2H),
8.01-8.04 (m, 2H).
13
C NMR (CDCl
3
)  22.0, 84.0, 129.3, 130.0, 130.7, 130.8, 132.5,
159

135.6, 135.7, 147.2. MS (ESI, m/z): 710.5 (2M+Na
+
), 367.0 (m+Na
+
). HRMS: calcd for
C
14
H
13
ClO
4
S
2
Na 366.9836 (M+Na
+
) found: m/z 366.9831
1-(Chloro(phenylsulfonyl)methylsulfonyl)-4-nitrobenzene
S S
OMe
O OO O
NO
2
As white solid in 77 % yield isolated.
1
H NMR (CDCl
3
)  5.63 (s, 1H), 7.62-7.66 (m,
2H), 7.77-7.81 (m, 1H), 7.99-8.02 (m, 2H), 8.27-8.30 (m, 2H), 8.45-8.47 (m, 2H).
13
C
NMR (CDCl
3
)  83.9, 124.3, 129.6, 130.6, 132.6, 135.3, 136.0, 140.8, 151.9. MS (ESI,
m/z): 374.0 (M-H
-
). HRMS: calcd for C
13
H
9
ClNO
6
S
2
373.9565 (M-H) found: m/z
373.9561.
1-Chloro-4-(chloro(phenylsulfonyl)methylsulfonyl)benzene
S S
OMe
O OO O
Cl
As white solid in 74 % yield isolated.
1
H NMR (CDCl
3
)  5.58 (s, 1H), 7.58-7.64 (m,
4H), 7.75-7.79 (m, 1H), 7.96-8.03 (m, 4H),
13
C NMR (CDCl
3
)  83.9, 129.5, 129.7,
130.6, 132.3, 133.8, 135.5, 135.8, 142.8. MS (ESI, m/z): 386.9 (M+Na
+
). HRMS: calcd
for C
13
H
11
Cl
2
O
4
S
2
364.9470 (M+H
+
) found: m/z 364.9476.

160

(Chloro(perfluorobutylsulfonyl)methylsulfonyl)benzene
S S
OMe
C
4
F
9
O OO O

As white waxy solid in 52 % yield isolated.
1
H NMR (CDCl
3
)  5.93 (s, 1H), 7.66 (t,
J = 7.8 Hz, 2H), 7.83 (t, J = 7.7 Hz, 1H), 8.08 (d, J = 7.7 Hz, 2H).
13
C NMR (CDCl
3
) 
81.0, 106.6-119.8 (m, 4C), 129.7, 131.2, 134.5, 136.6.
19
F NMR (CDCl
3
)  -81.1 (m, 3F),
-106.1 (m, 2F), -122.2 (m, 2F), -126.2 (m, 2F). MS (ESI, m/z): 964.5 (2M+Na
+
-2H
-
),
471.1 (M-H
-
). HRMS: calcd for C
11
H
5
ClF
9
O
4
S
2
470.9180 (M-H
-
) found: m/z 470.9183.

161

3.4. References

[1] Simpkins, N. S. Sulphones in Organic Synthesis; Pergamon Press: Oxford,
England, 1993.
[2] El-Awa, A.; Noshi, M. N.; Jourdin, X. M.; Fuchs, P. L. Chem. Rev., 2009, 109,
2315–2349.
[3] Cram, D. J. Fundamentals of Carbanion Chemistry; Academic Press: New York,
1965.
[4] (a) Najera, C.; Jus, M. Tetrahedron 1999, 55, 10547; (b) Magnus, P. D.
Tetrahedron 1977, 33, 2019; (c)

Schoenebeck, F.; Murphy, J. A.; Zhou, S.;
Uenoyama, Y.; Miclo, Y.; Tuttle, T. J. Am. Chem. Soc. 2007, 129, 13368; (d) Ni,
C.; Hu, J. Tetrahedron Lett. 2005, 46, 8273; (e) Liu, J.; Ni, C.; Wang, F.; Hu, J.
Tetrahedron Lett. 2008, 49, 1605.
[5] (a) Banks, R. E.; Smart, B. E.; Tatlow J. C. Eds.; Organofluorine Chemistry:
Principles and Commercial Applications, Plenum, New York, 1994, Chapter. 3;
(b) Smart, B. E. J. Fluorine Chem. 2001, 109, 3–11.
[6] (a) Prakash, G. K. S.; Hu, J. J. Org. Chem. 2003, 68, 4457-4463; (b) Li, Y.; Hu, J.
Angew. Chem. Int. Ed. 2005, 44, 5882–5886; (c) Prakash, G. K. S.; Hu, J. Acc.
Chem. Res. 2007, 40, 921–930; (d) Ni, C.; Li, Y.; Hu, J. J. Org. Chem. 2006, 71,
6829-6833; (e) Fukuzumi, T.; Shibata, N.; Sugiura, M.; Yasui, H.; Nakamura, S.;
Toru, T. Angew. Chem. Int. Ed. 2006, 45, 4973-4977; (f) Prakash, G. K. S.;
Chacko, S. Alconcel, S.; Stewart, T.; Mathew, T.; Olah, G. A. Angew. Chem. Int.
Ed. 2007, 46, 4933-4936; (g) Furukawa, T.; Shibata, N.; Mizuta, S.; Nakamura,
162

S.; Toru, T.; Shiro, M. Angew. Chem. Int. Ed. 2008, 47, 8051-8054; (h) Prakash,
G. K. S.; Wang, F.; Stewart, T.; Mathew, T.; Olah, G. A. Proc. Natl. Acad. Sci.
USA. 2009, 106, 4090-4094; (i) Alba, A. N.; Companyó, X.; Moyano, A.; Rios,
R. Chem. Eur. J. 2009, 15, 7035-7038; (j) Ullah, F; Zhao, G. L.; Deiana, L.; Zhu,
M.; Dziedzic, P.; Ibrahem, I.; Hammar, P.; Sun, J.; Córdova, A. Chem. Eur. J.
2009, 15: 10013-10017.
[7] Prakash, G. K. S.; Wang, F.; Shao, N.; Mathew, T.; Rasul, G.; Haiges, R.;
Stewart, T.; Olah, G. A. Angew. Chem., Int. Ed. 2009, 48, 5358–5362.
[8] Wickiser, D. I.; Wilson, S. A.; Snyder, D. E.; Dahnke, K. R. Smith, C. K. II;
McDermott, P. J. J. Med. Chem., 1998, 41, 1092–1098.
[9] Hirokatsu, N.; Toshio, F. Synlett 2008, 11, 1714-1718.
[10] Ni, C.; Zhang, L.; Hu, J. J. Org. Chem. 2009 74, 3767-3771.
[11] Schank, K.; Schroeder, F.; Weber, A. Liebigs Ann. Chem. 1979, 547-553.
[12] McCarthy, J. R.; Matthews, D. P.; Paolini, J. P. Org. Synth. 1998, 72, 209.
[13] Trost, B. M.; Quayle, P. J. Am. Chem. Soc. 1984, 106, 2469-2471.
[14] (a) Finch, H.; Mjalli, A. M. M.; Montana, J. G.; Roberts, S. M.; Taylor, R. J. K.
Tetrahedron 1990, 46, 4925-4950; (b) Ley, S. V.; Tackett, M. N.; Maddess, M.
L.; Anderson, J. C.; Brennan, P. E.; Cappi, M. W.; Heer, J. P.; Helgen, C.; Kori,
M.; Kouklovsky, C.; Marsden, S. P.; Norman, J.; Osborn, D. P.; Palomero, M. A.;
Pavey, J. B. J.; Pinel, C. ; Robinson, L. A.; Schnaubelt, J.; Scott, J. S.; Spilling, C.
D.; Watanabe, H.; Wesson, K. E.; Willis, M. C. Chem. Eur. J. 2009, 15, 2874-
2914.
163

[15] Diekmann, J. J. Org. Chem. 1965 30, 2272-2275.
[16] Gibson, D. T. J. Chem. Soc., 1931, 2637-2644.
[17] Dubenko, R. G.; Neplyuev, V. M.; Pel'kis, P. S. Zh. Org. Khim. 1968, 4, 324-328.
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164

Chapter 4

α-Fluoro-α-nitro(phenylsulfonyl)methane as a
Fluoromethyl Pronucleophile: Efficient Stereoselective
Michael Addition to Chalcone Derivatives

165

4.1. Introduction
Enantioselective preparation of fluoromethylated organic molecules is of immense
interest today since fluoromethyl substituted compounds carry great importance in
pharmaceutical chemistry, materials science, and healthcare.
1,2,3,4,5
Transfer of the active
fluoro(phenylsulfonyl)methyl group into knoveneagel systems or systems carrying other
active groups can lead to very efficient synthons for the preparation of various
biologically active systems. For over a decade, our group has made significant
contribution towards efficient nucleophilic flouroalkylation.
6,7,8,9,10,11,12
For example, α-
Fluoro-bis(phenylsulfonyl)methane (FBSM) has been found to be an effective synthetic
equivalent of monofluoromethide in a series of nucleophilic fluoromethylation reactions,
including the ring-opening reaction of epoxides and aziridines,
13
the allylic
monofluoromethylation reaction,
14
the Mitsunobu reaction,
15
conjugate addition
reactions,
16
the Mannich reaction,
17
the aldol reaction,
18
as well as many others
19

(Scheme 4.1).
In particular, FBSM-based asymmetric monofluoromethylation was successfully
carried out by Shibata et al. for allylic monofluoromethylation
14
and Mannich type
monofluoromethylation
17
for the synthesis of chiral α–fluoromethylamines.

Very
recently, Shibata et al. achieved a catalytic enantioselective Michael addition of FBSM to
chalcone derivatives using cinchona-based phase transfer catalysts.
20
However, this
protocol did not only require the employment of large amounts of base (Cs
2
CO
3
, 3
equiv.)

but also fairly low reaction temperature (-40
o
C).

166

Scheme 4.1. Synthetic Applications of FBSM.

H-bonding donor-containing small molecules have been proven to be privileged
catalysts in asymmetric catalysis.
21
In particular,

Takemoto,
22
Soós,
23
Connon,
24
and
many others have utilized thiourea-based bifunctional catalysts in highly enantioselective
Michael addition of active methylene pronucleophiles to chalcone derivatives. Our recent
investigations showed that the acidity of α-proton in fluoro(phenylsulfonyl)methane can
be significantly enhanced by α-substitution with an electron-withdraw group, such as
167

nitro, cyano, ester and acetyl groups. These derivatives can thus be used as viable α-
fluoromethide equivalents in conjugate addition reaction (Scheme 4.2).
16b
On the basis of
these reports, we envisaged that α-fluoro-α-nitro(phenylsulfonyl)methane (FNSM) can be
used as an versatile fluoromethyl pronucleophile.

Scheme 4.2. Michael addition of FSM derivatives to ,-unsaturated compounds.

4.2. Results and Discussion
Parallel to our previous racemic conjugate addition reactions,
16b
we conducted a
series of reactions towards a highly efficient enantioselective 1,4-addition of FNSM to
α,β-unsaturated ketones. The reactions were performed using a wide range of thiourea-
based organocatalysts in the absence of an additional base (Scheme 4.3).
168

Scheme 4.3 Catalytic enantioselective conjugate addition of FNSM to chalcone.

In order to find the best catalyst and optimal conditions, reactions were carried out
with different combination of parameters such as catalyst, catalyst loading, solvent,
temperature and ratio of substrates. Preliminary screening of the catalysts was carried out
using dichloromethane or toluene as solvent. In both solvents, when FNSM (1) and trans-
169

chalcone (2a) were taken in a 1:1 stoichiometric ratio, the conversion was low
irrespective of the catalyst. However, when the ratio was changed to 1:2, a higher
conversion and stereoselectivity was observed in the presence of QN I in toluene as the
solvent (Table 4.1, entry 6).

Table 4.1. Screening of catalysts CN/CD I, QN/QD I and QN I-IV for
enantioselective addition of FNSM (1) to chalcone (2).

With optimal catalyst QN I in hand, our further reaction condition screening was
focused on solvents and reaction temperatures (Tables 4.2 and 4.3).
170

Table 4.2. Enantioselective 1,4-addition of FNSM (1) to chalcone (2) catalyzed by
QN I in various solvents.

171

Table 4.3. Enantioselective 1,4-addition of FNSM (1) to chalcone (2) under different
catalyst loading of QN I at different temperatures.

As mentioned, in the case of enantioselective additions using phenylsulfonylmethane
derivatives reported earlier strong bases such as CsOH·H
2
O, Cs
2
CO
3
and K
2
CO
3
were
required in excessive amounts for the formation of the corresponding
phenylsulfonylmethide nucleophile in the medium.
20
However, FNSM is found to be an
efficient Michael-type donor in the absence of a base in all reactions performed in our
study. The presence of the nitro group and proper catalyst selection not only eliminate the
use of a base, but also add the prospects of further derivatization and modification of the
FNSM-adduct. Using racemic starting material (FNSM, which acts as a good carbon
acid), we have discovered that 1,4-addition products with high diastereoselectivity as
well as enantioselectivity could be achieved under the reaction conditions using
172

cinchona-based bifunctional catalyst QN I (Table 4.3). Under the optimized conditions,
FNSM has been added to a series of chalcone derivatives to obtain the corresponding
adducts in high yields with high diastereomeric ratios and excellent enantiomeric
excesses (Table 4.4).
173

Table 4.4. Enantioselective 1,4-addition of FNSM (1) to chalcone (2).

174

DFT calculations at the B3LYP/6-311+G(2d,p) level of theory have shown that the
key reaction intermediate, FNSM carbanion, assumes a pyramidal geometry rather than a
planar on the anionic carbon (Figure 4.1). In contrast, its nonfluorinated counterpart
adopts a planar structure on the central carbon. This theoretical study has been further
supported by the crystal structure of FBSM anion, which also assumed a pyramidal
geometry.
25
According to the DFT calculation at the B3LYP/6-311+G(2d,p) level, the
trans-planar structure of FBSM anion is +2.1 kcal/mol higher in energy than the cis-
pyramidal structure in the gas phase.
Figure 4.1 Calculated structures and X-ray structures of key reaction intermediates.
175

On the basis of these calculations and crystal structures, a mechanism involving
dynamic-kinetic resolution of FNSM has been proposed to elucidate the outcome of the
present reaction. The remarkable and unprecedented efficacy of the bifunctional catalyst
QN I is manifested from the observed deracemization, enantioselectivity and
diastereoselectivity since four stereoisomers were obtained in almost equal amounts in
the absence of chiral catalysts. The bifunctional catalysts themselves are capable of
deprotonating the FNSM into the corresponding carbanion (enol-like intermediate),
26

which can attack the Michael acceptors in an appropriate configuration by undergoing an
inversion (Figure 4.2). The high facial selectivity of chalcones is due to the coordination
of chalcones and the catalyst QN I via di-hydrogen bonding and possibly aromatic - 
interactions. As a result, TS3, in which the carbonyl group in the chalcone and the nitro
group in the FNSM anion coordinate with the catalyst QN I, is lower in energy due to
minimum steric interaction.
176

Figure 4.2. Formation of α-fluoro-α-nitro(phenylsulfonyl)methide anion and suggested
transition state involving chalcone-QN I assembly during Michael addition.

To validate the suggested mechanism, we carried out a model reaction between
FNSM and methyl vinyl ketone (4) under similar conditions (Scheme 4.4). The substrate
4 is used as the analog of chalcones. It is able to coordinate with QN I in a similar way,
nevertheless, the steric interaction between FNSM and 4 has been minimized. As
expected, a racemic product was obtained. This demonstrates that the stereoselectivity on
the α-carbon does not originate from the “stereoselective deprotonation” of FNSM by the
bifunctional catalyst QN I. Rather, the stereoselectivity is derived from the interaction
between FNSM and the chalcone-QN I complex.

177

Scheme 4.4 1,4-Addition of α-fluoro-α-nitro(phenylsulfonyl)methane (FNSM) to
methyl vinyl ketone with the bifunctional catalyst QN I.

The absolute configuration of the product 3a was unequivocally established by X-ray
crystallographic analysis (Figure 4.3).
S
O
2
N
F
O
O
H
O
3a

Figure 4.3 Crystal structure of (3R, 4R)-4-fluoro-4-nitro-1,3-diphenyl-4-
(phenylsulfonyl)-butan-1-one (3a).

4.3 Conclusion
In conclusion, we have achieved the first enantioselective as well as
diastereoselective 1,4-conjugate addition of FNSM, an effective
fluoromethylpronucleophile to chalcones using cinchona alkaloid-based bifunctional
catalysts with highest efficacy observed for QN I. It is worthwhile to note that no
additional base was required for the 1,4-addition reactions, which were carried out in a
178

homogneous catalytic mode. Further explorations involving other α-substituted subtrates
such as α-cyano, α-ester or α-acetyl-α-fluoro(phenylsulfonyl)-methane for various
stereoselective addition reactions are now underway in our research group.
4.4 Experimental
Unless otherwise mentioned, all other reagents were purchased from commercial
sources. Column chromatography was performed using silica gel (60-200 mesh).
Analytical thin-layer chromatography (TLC) was performed on precoated, glass-backed
silica gel.
1
H,
13
C and
19
F NMR spectra were recorded on Oxford AS400 NMR
spectrometers.
1
H NMR chemical shifts were determined relative to (CH
3
)
4
Si (TMS) as
internal standard at δ 0.0 or to the signal of a residual protonated solvent CDCl
3
as
internal standard at δ 7.26 or CD
3
OD as internal standard at δ 3.31.
13
C NMR chemical
shifts were determined relative to TMS as internal standard at δ 0.0 or to the
13
C signal of
solvent CDCl
3
as internal standard at δ 77.16 or CD
3
OD as internal standard at δ 49.00.
19
F NMR chemical shifts were determined relative to CFCl
3
as internal standard at δ 0.0.
HPLC analysis was carried out on ChiralCel OD-H or ChiralPak AD-H columns.

4.4.1 Catalyst Preparation and Characterization
All the catalysts were prepared according to Soós’s procedure.
23
New catalysts QN
II-IV have been completely characterized by spectral and HRMS analysis.

179

N
NH
N
OMe
N
H
S
CF
3 QN II
As white amorphous solid, 80% yield.
1
H NMR (CD
3
OD)  0.92 (pseudo q, J = 6.4
Hz, 1H), 1.41 (m, 1H), 1.63-1.72 (m, 3H), 2.34 (br, 1H), 2.73-2.85 (m, 2H), 3.23-3.27
(m, 1H), 3.33 (br, partially overlapping with solvent peak, 1H), 3.51 (br, 1H), 4.04 (s,
3H), 4.96 (dd, J
1
= 10.4 Hz, J
2
= 0.8 Hz, 1H), 5.01 (dd, J
1
= 17.2 Hz, J
2
= 1.6 Hz, 1H),
5.82 (ddd, J
1
= 17.2, J
2
= 10.4 Hz, J
3
= 7.2 Hz, 1H), 6.16 (br, 1H), 7.39 (t, J = 7.6 Hz,
1H), 7.43 (dd, J
1
= 9.2 Hz, J
2
= 2.8 Hz, 1H), 7.52-7.58 (m, 2H), 7.65 (t, J = 8.0 Hz, 2H),
7.94 (d, J

= 9.2, 1H), 8.01 (br, 1H), 8.66 (d, J = 4.8 Hz, 1H).
13
C NMR (CD
3
OD) 
26.95, 28.70, 28.88, 40.83, 42.53, 56.45, 56.70, 61.53, 61.60, 104.15, 114.95, 121.29 (br),
123.66, 125.01 (q, partially overlapping with the peak at 123.66 ppm,
1
J
CF
= 272.2 Hz,
CF
3
), 125.96 (q,
3
J
CF
= 5.3 Hz), 127.29 (q,
2
J
CF
= 30.0 Hz), 127.95, 130.22, 131.13,
132.67, 133.46, 138.09, 142.61, 145.07, 148.16, 148.26 (br, partially overlapping with
the peak at 148.16 ppm), 159.54, 184.30.

HRMS (ESI) Calcd for C
28
H
30
F
3
N
4
OS (MH
+
): 527.2092; Found: 527.2090.

180

N
NH
N
OMe
N
H
S
F
F
QN III
As white amorphous solid in 82% yield.
1
H NMR (CD
3
OD)  0.84-1.09 (m, 2H),
1.23-1.33 (m, 1H), 1.63-1.65 (br m, 3H), 2.39 (br pseudo q, J = 7.2 Hz, 1H), 3.00-
3.08(m, 3H), 3.33-3.35 (m, 1H), 4.04 (s, 3H), 5.16 (d, J = 10.4 Hz, 1H), 5.24 (d, J = 17.6
Hz, 1H), 5.97 (ddd, J
1
= 17.6 Hz, J
2
= 10.4 Hz, J
3
= 6.0 Hz, 1H), 6.34 (d, J = 10.8 Hz,
1H), 6.64 (tt, J
1
= 8.8 Hz, J
2
= 2.4 Hz, 1H), 7.19-7.22 (m, 2H), 7.44 (dd, J
1
= 8.8 Hz, J
2
=
2.4 Hz ,1H), 7.56 (d, J = 4.8 Hz, 1H), 7.94 (d, J = 9.6 Hz, 1H), 8.03 (d, J = 2.4 Hz, 1H),
8.67 (d, J = 4.4 Hz, 1H)
13
C NMR (CD
3
OD)  26.39, 27.31, 28.69, 40.20, 49.21 (partially
overlapping with solvent peak), 50.10, 55.45 (br), 56.50, 61.56, 99.88 (t, J = 26.0 Hz),
103.95, 106.15 (dd, J
1
= -20.7 Hz, J
2
= 8.4 Hz), 115.30, 102.98, 123.95, 130.18, 131.13,
141.73, 146.32, 148.09, 148.24, 159.60, 164.32 (dd, J
1
= 244.6 Hz, J
2
= 15.4 Hz), 165.54
(d, J = 15.3 Hz), 182.19.
HRMS (ESI) Calcd for C
27
H
29
F
2
N
4
OS (MH
+
): 495.2030; Found: 495.2033.

N
NH
N
OMe
N
H
O CF
3
QN IV
As white amorphous solid, 83% yield.
1
H NMR (CD
3
OD)  0.88 (pseudo q, J = 6.0
Hz, 1H), 1.59 (t, J = 12.4 Hz, 1H), 1.66 (m, 3H), 2.38 (br, 1H), 2.80-2.83 (m, 2H), 3.28-
181

3.42 (m, partially overlapping with solvent peak, 2H), 3.49 (br, 1H), 4.00 (s, 3H), 5.00 (d,
J = 10.4 Hz, 1H), 5.05 (dd, J
1
= 17.2 Hz, J
2
= 1.2 Hz, 1H), 5.60 (br, 1H), 5.89 (ddd, J
1
=
17.2, J
2
= 10.4 Hz, J
3
= 7.2 Hz, 1H), 7.19 (d, J = 7.6 Hz, 1H), 7.36 (t, J= 7.6 Hz, 1H),
7.43-7.45 (m, 2H), 7.55 (d, J = 4.8 Hz, 1H), 7.78 (s, 1H), 7.84 (s, 1H), 7.94-7.97 (m, 1H),
8.67-8.69 (m, 1H).
13
C NMR (CD
3
OD)  27.47, 28.47, 28.88, 40.73, 42.16, 52.15 (br),
56.32, 56.85, 60.75, 103.11, 115.12, 116.00 (q,
3
J
CF
= 3.8 Hz), 123.66 (q,
3
J
CF
= 3.8 Hz),
120.80 (br), 120.79, 123.721, 125.59 (q,
1
J
CF
= 271.4 Hz, CF
3
), 130.06, 130.55, 131.37,
132.06 (q,
2
J
CF
= 31.4 Hz), 141.84, 142.53, 145.15, 147.93, 148.26, 157.05, 159.83,
176.40. HRMS (ESI) Calcd for C
28
H
30
F
3
N
4
O
2
(MH
+
): 521.2321; Found: 521.2318

4.4.2. Typical Procedure for Catalytic 1,4-Addition of α-Fluoro-α-
Nitro(phenylsulfonyl)methane to α,β-Unsaturated Ketones

To a solution of α-fluoro-α-nitro(phenylsulfonyl)methane (21.9 mg, 0.1 mmol, 1
equivalent) and ketone (0.2 mmol, 2 equivalent) in CH
2
Cl
2
, Et
3
N (10.0 μL 0.1 mmol, 0.7
equivalent) was added. The reaction mixture was stirred for 12 h at room temperature and
the conversion was monitored by
19
F NMR before purification (diastereomeric ratios
were about 1:1 in all the cases). The reaction mixture was loaded on to a preparative TLC
plate. In most cases, the diastereomers can be separated with hexane/ethyl acetate (4/1-
6/1) to produce the title product in good to excellent yield.
182

4.4.3. Typical Procedure for Catalytic Enantioselective 1,4-Addition of
α-Fluoro-α-nitro(phenylsulfonyl)methane to Chalcones

To a solution of α-fluoro-α-nitro(phenylsulfonyl)methane (21.9 mg, 0.1 mmol, 1
equivalent) and ketone (0.2 mmol, 2 equivalent) in precooled toluene (-20
o
C, 0.5 mL),
catalyst QN I was added (6.0 mg 0.01 mmol, 10 mol%) in one load. The reaction mixture
was stirred for 1 min and placed in freezer (-20
o
C) for 2 days without stirring. The
reaction mixture was monitored by
19
F NMR for conversion and diastereoselectivity, and
loaded on to preparative TLC plate. In most cases, the diastereomers can be separated
with hexane/ethyl acetate (4/1-6/1) to produce the title product in good to excellent yield.

4.4.4. Product Characterization
4-Fluoro-4-nitro-1,3-diphenyl-4-(phenylsulfonyl)butan-1-one
O
S
F
NO
2
Ph
O O

Diastereomer I (Minor)
4-Fluoro-4-nitro-1,3-diphenyl-4-(phenylsulfonyl)butan-1-one:
183

1
H NMR (CDCl
3
)  3.85 (dd, J
1
= 18.0 Hz, J
2
= 10.8 Hz, 1H), 4.22 (dd, J
1
= 18.0 Hz,
J
2
= 2.4 Hz, 1H), 5.13 (ddd, J
1
= 32.8 Hz, J
2
= 10.8 Hz, J
3
= 2.4 Hz, 1H), 7.31-7.23 (m,
3H), 7.28-7.31 (m, 2H), 7.46 (t, J = 7.6 Hz, 2H), 7.56 (d, J = 8.0 Hz, 1H), 7.61 (t, J = 7.2
Hz, 2H), 7.78 (tq, J
1
= 8.0 Hz, J
2
= 1.2 Hz, 1H). 7.92-7.95 (m, 4H).
13
C NMR (CDCl
3
) 
39.17, 43.40 (d, J = 16.09 Hz), 125.67 (d,
1
J
CF
= 290.0 Hz), 128.30, 128.90, 129.00,
129.05, 129.42, 129.52, 129.81, 130.93, 132.07, 133.74, 134.03, 136.37, 136.55, 194.65.
19
F NMR (CDCl
3
)  -121.63 (d, J = 25.2 Hz).
HRMS (ESI) Calcd for C
22
H
18
FNNaO
5
S (MNa
+
): 450.0787; Found: 450.0784.
Diastereomer II (Major)
(3R, 4R)-4-Fluoro-4-nitro-1,3-diphenyl-4-(phenylsulfonyl)butan-1-one:
1
H NMR (CDCl
3
)  3.37 (dd, J
1
= 17.6 Hz, J
2
= 2.8 Hz, 1H), 3.80 (dd, J
1
= 17.6 Hz,
J
2
= 10.4 Hz, 1H), 5.10 (ddd, J
1
= 26.4 Hz, J
2
= 10.4 Hz, J
3
= 2.8 Hz, 1H), 7.19-7.24 (m,
3H), 7.29-7.31 (m, 2H), 7.39-7.43 (m, 4H), 7.52-7.56 (m, 3H), 7.62-7.66 (m, 1H), 7.82-
7.84 (m, 2H).
13
C NMR (CDCl
3
)  39.53 (d, J = 1.5 Hz), 44.08 (d, J = 16.09 Hz), 125.50
(d,
1
J
CF
= 287.7 Hz), 128.17, 128.86, 128.90, 128.97, 129.32, 130.38, 130.74, 132.70,
132.85, 133.79, 135.66, 136.08, 194.12.
19
F NMR (CDCl
3
)  -121.63 (d, J = 25.2 Hz)
HRMS (ESI) Calcd for C
22
H
19
FNO
5
S (MH
+
): 428.0968; Found: 428.0967.
HPLC (DAICEL CHIRALCEL OD-H, hexane/2-propanol = 98/2, flow 0.5 mL/min,
detection at 254 nm) t
R-Diastereomer I
minor 34.0 min, t
R-Diastereomer I
major 38.1 min, t
R-
Diastereomer II
minor 42.2 min, t
R-Diastereomer II
major 49.2 min. The enantiomeric excess of the
four diastereomers were measured after purification by preparative TLC.

184

4-Fluoro-3-(4-methoxyphenyl)-4-nitro-1-phenyl-4-(phenylsulfonyl)butan-1-one
O
S
F
NO
2
Ph
O O
O
Diastereomer I (Minor)
4-Fluoro-3-(4-methoxyphenyl)-4-nitro-1-phenyl-4-(phenylsulfonyl)butan-1-one:
1
H NMR (CDCl
3
)  3.70 (s, 3H), 3.82 (dd, J
1
= 17.6 Hz, J
2
= 11.2 Hz, 1H), 4.18 (dd,
J
1
= 17.6Hz, J
2
= 2.4, 1H), 5.07 (ddd, J
1
= 32.4 Hz, J
2
= 11.2 Hz, J
3
= 2.4 Hz, 1H), 6.74
(m, 2H), 7.20 (dd, J
1
= 8.8 Hz, J
2
= 1.6 Hz, 2H), 7.46 (m, 2H), 7.55-7.62 (m, 3H), 7.76-
7.80 (m, 1H), 7.92-7.94 (m, 4H).
13
C NMR (CDCl
3
)  39.16, 42.81 (d, J = 16.1 Hz),
43.47 (d, J = 16.8 Hz), 55.26, 114.41, 125.65, 125.76 (d,
1
J
CF
= 289.1 Hz), 128.28,
128.86, 129.78, 130.55, 130.86, 132.13, 133.68, 136.38, 136.48, 159.85, 194.79.
19
F
NMR (CDCl
3
)  -129.98 (d, J = 32.0 Hz)
HRMS (ESI) Calcd for C
23
H
21
FNO
6
S (MH
+
): 458.1074; Found: 458.1076.
Diastereomer II (Major)
(3R,4R)-4-Fluoro-3-(4-methoxyphenyl)-4-nitro-1-phenyl-4-(phenylsulfonyl)butan-1-
one:
1
H NMR (CDCl
3
)  3.32 (dd, J
1
= 17.2 Hz, J2 = 2.8 Hz, 1H), 3.75 (s, 3H), 3.80 (dd,
partially overlapping with the peak at 3.75 ppm, J
1
= 17.2 Hz, J
2
= 10.8 Hz, 1H), 5.04
(ddd, J
1
= 27.2 Hz, J
2
= 10.8 Hz, J
3
= 2.8 Hz, 1H), 6.71 (d, J = 8.4 Hz, 2H), 7.19 (d, J =
7.6 Hz, 2H), 7.42 (dt, J
1
= 8.0 Hz, J
2
= 3.2 Hz, 4H), 7.53-7.58 (m, 3H), 7.65 (t, J = 8.0
Hz, 1H), 7.82-7.84 (m, 2H).
13
C NMR (CDCl
3
)  39.50 (d, J = 1.5 Hz), 43.47 (d, J = 16.8
185

Hz), 55.35, 114.30, 124.47, 125.64 (d,
1
J
CF
= 286.1 Hz), 128.19, 128.86, 129.25, 130.70,
131.48 (d, J = 1.5 Hz), 132.91, 133.77, 135.59, 136.15, 160.04, 194.27.
19
F NMR
(CDCl
3
)  -122.15 (d, J = 26.0 Hz)
HRMS (ESI) Calcd for C
23
H
20
FNO
6
SNa (MNa
+
): 480.0893; Found: 480.0888.
HPLC (DAICEL CHIRALPAK AD-H, hexane/2-propanol = 95/5, flow 1.0 mL/min,
detection at 254 nm) ) t
R-Diastereomer I
minor 55.9 min, t
R-Diastereomer I
major 73.4 min, t
R-
Diastereomer II
minor 48.2 min, t
R-Diastereomer II
major 64.3 min.. The enantiomeric excess of the
four diastereomers were measured after purification by preparative TLC.
1-(4-Chlorophenyl)-4-fluoro-4-nitro-3-phenyl-4-(phenylsulfonyl)butan-1-one
O
S
F
NO
2
Ph
O O
Cl
Isolated as a mixture of diastereomers.
1
H NMR (CDCl
3
)  3.39 (dd, J
1
= 17.6 Hz, J
2
= 2.4 Hz, 1H), 3.73-3.83 (m, 2H), 4.20
(dd, J
1
= 17.6 Hz, J
2
= 2.4, 1H), 5.01-5.18 (m, 2H), 7.19-7.29 (m, 8H), 7.38-7.45 (m,
4H), 7.56-7.68 (m, 4H), 7.76-7.80 (m, 2H), 7.85-7.88 (m, 2H), 7.89-7.94 (m, 2H).
13
C
NMR (CDCl
3
)  39.14, 39.47 (d,
3
J
CF
= 1.5 Hz), 43.30 (d,
2
J
CF
= 16.1 Hz), 44.04 (d,
2
J
CF

= 16.9 Hz), 125.24 (d,
1
J
CF
= 286.9 Hz), 125.48 (d,
1
J
CF
= 289.3 Hz), 128.98, 129.08,
129.21, 129.38, 129.61, 129.69, 129.82, 130.31, 130.77, 130.88, 131.92, 132.63, 132.73,
133.83, 134.43, 134.63, 135.75, 136.59, 140.25, 140.36, 193.07, 193.53.
19
F NMR
(CDCl
3
)  -121.31 (d, J = 26.0 Hz), -129.65 (d, J = 33.6 Hz)
186

In
13
C NMR, there are supposed to be 24 peaks in aromatic region, however, only 20
peaks were observed due to overlap.
HRMS (ESI) Calcd for C
22
H
18
ClFNO
5
S (MH
+
): 462.0578; Found: 462.0577.
HPLC (DAICEL CHIRALPAK AD-H, hexane/2-propanol = 85/15, flow 0.5
mL/min, detection at 254 nm) t
R-Diastereomer I
minor 62.5 min, t
R-Diastereomer I
major 67.5 min,
t
R-Diastereomer II
minor 42.8 min, t
R-Diastereomer II
major 55.1 min. The enantiomeric excess of
the four diastereomers were measured after purification by preparative TLC.
4-Fluoro-1,3-bis(4-fluorophenyl)-4-nitro-4-(phenylsulfonyl)butan-1-one
O
S
F
NO
2
Ph
O O
F F
Diastereomer I (Minor)
1
H NMR (CDCl
3
)  3.76 (dd, J
1
= 18.0 Hz, J
2
= 11.2 Hz, 1H), 4.20 (dd, J
1
= 18.0 Hz,
J
2
= 2.4 Hz, 1H), 5.12 (ddd, J
1
= 32.0 Hz, J
2
= 11.2 Hz, J
3
= 2.4 Hz, 1H), 6.93 (tt, J
1
=
8.8 Hz, J
2
= 2.4 Hz, 2H), 7.14 (tt, J
1
= 8.8 Hz, J
2
= 2.0 Hz, 2H), 7.28 (m, 2H), 7.61 (m,
2H), 7.79 (tt, J
1
= 7.6 Hz, J
2
= 1.2 Hz, 1H), 7.91-7.98 (m, 4H).
13
C NMR (CDCl
3
) 
39.11, 42.71 (d,
2
J
CF
= 16.2 Hz), 116.10 (d,
2
J
CF
= 22.2 Hz), 116.17 (d,
2
J
CF
= 22.2 Hz),
125.39 (d,
1
J
CF
= 289.3 Hz), 129.68 (d,
4
J
CF
= 3.0 Hz), 129.86, 130.87, 130.97 (d,
3
J
CF
=
9.2 Hz), 131.18 (d,
3
J
CF
= 7.6 Hz), 131.83, 132.67 (d,
4
J
CF
= 3.0 Hz), 136.66, 162.91 (d,
1
J
CF
= 249.4 Hz), 166.22 (d,
1
J
CF
= 256.3 Hz), 192.98.
19
F NMR (CDCl
3
)  -104.42 (m,
1F), -112.67 (m, 1F), -129.97 (d, J = 32.1 Hz, 1F).
HRMS (ESI) Calcd for C
22
H
17
F
3
NO
5
S (MH
+
): 464.0780; Found: 464.0778.
187

Diastereomer II (Major)
1
H NMR (CDCl
3
)  3.33 (dd, J
1
= 17.6 Hz, J
2
= 2.4 Hz, 1H), 3.72 (dd, J
1
= 17.6 Hz,
J
2
= 10.4 Hz, 1H), 5.08 (ddd, J
1
= 26.4 Hz, J
2
= 10.8 Hz, J
3
= 2.4 Hz, 1H), 6.91 (m, 2H),
7.10 (m, 2H), 7.28 (m, 2H), 7.47 (m, 2H), 7.60 (m, 2H), 7.69 (tt, J
1
= 6.4 Hz, J
2
= 1.2 Hz,
1H), 7.86 (m, 2H).
13
C NMR (CDCl
3
)  39.41 (d,
3
J
CF
= 2.6 Hz), 43.38 (d,
2
J
CF
= 17.6
Hz), 116.02 (d,
2
J
CF
= 21.7 Hz), 116.15 (d,
2
J
CF
= 21.8 Hz), 125.24 (d,
1
J
CF
= 286.7 Hz),
128.59 (d,
4
J
CF
= 4.2 Hz), 129.47, 130.73, 130.93 (d,
3
J
CF
= 10.6 Hz), 132.11 (pseudo-dd,
J
1
= 8.5 Hz, J
2
= 1.6 Hz), 132.48 (d,
4
J
CF
= 3.3 Hz), 132.61, 135.96, 163.08 (d,
1
J
CF
=
249.6 Hz), 166.26 (d,
1
J
CF
= 256.6 Hz), 192.46.
19
F NMR (CDCl
3
)  -104.12 (m, 1F), -
112.81 (m, 1F), -122.28 (d, J = 24.8 Hz, 1F)
HRMS (ESI) Calcd for C
22
H
17
F
3
NO
5
S (MH
+
): 464.0780; Found: 464.0778.
HPLC (DAICEL CHIRALCEL OD-H, hexane/2-propanol = 99/1, flow 0.5 mL/min,
detection at 254 nm) t
R-Diastereomer I
minor 42.3 min, t
R-Diastereomer I
major 47.5 min, t
R-
Diastereomer II
minor 58.3 min, t
R-Diastereomer II
major 72.6 min. The enantiomeric excess of the
four diastereomers were measured after purification by preparative TLC.
(3R,4R)-4-Fluoro-4-nitro-3-(4-nitrophenyl)-1-phenyl-4-(phenylsulfonyl)bu-tan-1-
one
O
S
F
NO
2
Ph
O O
O
2
N

Only one isomer was obtained as white solid in 93 % yield isolated.
1
H NMR
(CDCl
3
)  3.39 (dd, J
1
= 18.0 Hz, J
2
= 2.4 Hz, 1H), 3.85 (dd, J
1
= 18.0 Hz, J
2
= 11.2 Hz,
188

1H), 5.25 (ddd, J
1
= 26.4 Hz, J
2
= 11.2 Hz, J
3
= 2.4 Hz, 1H), 7.44 (t, J = 8.0 Hz, 2H),
7.50 (d, J = 8.4 Hz, 2H), 7.56-7.60 (m, 3H), 7.67-7.75 (m, 3H), 7.82-7.84 (m, 2H), 8.10-
8.13 (m, 2H).
13
C NMR (CDCl
3
)  39.16, 43.56 (d,
2
J
CF
= 16.8 Hz), 123.87, 124.66 (d,
1
J
CF
= 288.6 Hz), 128.18, 129.03, 129.64, 130.76, 131.43 (d,
3
J
CF
= 1.6 Hz), 132.05,
134.24, 135.63, 136.37, 140.31, 148.21, 193.48.
19
F NMR (CDCl
3
)  -123.13 (d, J = 26.0
Hz)
HRMS (ESI) Calcd for C
22
H
18
FN
2
O
7
S (MH
+
): 473.0819; Found: 473.0809.
HPLC (DAICEL CHIRALPAK AD-H, hexane/2-propanol = 90/10, flow 1.0 mL/min,
detection at 254 nm) t
R
minor 62.6 min, t
R
major 87.1 min. The enantiomeric excess of
the four diastereomers were measured after purification by preparative TLC. (The
diastereomers did not separate well on HPLC, although the enantiomers had good
separation.)
1,3-Bis(4-chlorophenyl)-4-fluoro-4-nitro-4-(phenylsulfonyl)butan-1-one
O
S
F
NO
2
Ph
O O
Cl Cl
Diastereomer I (Minor)
1
H NMR (CDCl
3
)  3.75 (dd, J
1
= 17.6 Hz, J
2
= 10.8 Hz, 1H), 4.21 (dd, J
1
= 17.6
Hz, J
2
= 2.4, 1H), 5.11 (ddd, J
1
= 32.0 Hz, J
2
= 10.8 Hz, J
2
= 2.4 Hz, 1H), 7.23 (m, 4H),
7.44 (m, 2H), 7.62 (m, 2H), 7.79 (m, 1H), 7.87 (m, 2H), 7.92 (m, 2H).
13
C NMR (CDCl
3
)
 39.07, 42.75 (d,
2
J
CF
= 16.1 Hz), 125.21 (d,
1
J
CF
= 290.1 Hz), 129.29, 129.36, 129.68,
189

129.88, 130.69, 130.87, 131.72, 132.37, 134.44, 135.21, 136.71, 140.45, 193.30.
19
F
NMR (CDCl
3
)  -129.84 (d, J = 32.0 Hz).
HRMS (ESI) Calcd for C
22
H
17
Cl
2
FNO
5
S (MH
+
): 496.0189; Found: 496.0185.
Diastereomer II (Major)
1
H NMR (CDCl
3
)  3.2 (dd, J
1
= 17.6 Hz, J
2
= 2.8 Hz, 1H), 3.71 (dd, J
1
= 17.6 Hz,
J
2
= 10.8 Hz, 1H), 5.06 (ddd, J
1
= 26.4 Hz, J
2
= 10.8 Hz, J
3
= 2.4 Hz, 1H), 7.15-7.25 (m,
4H), 7.40 (m, 2H), 7.47 (m, 2H), 7.59 (m, 2H), 7.70 (tt, J
1
= 7.2 Hz, J
2
= 1.2 Hz, 1H),
7.77 (m, 2H).
13
C NMR (CDCl
3
)  39.30 (d,
3
J
CF
= 1.5 Hz), 43.43 (d,
2
J
CF
= 16.8 Hz),
125.11 (d,
1
J
CF
= 286.9 Hz), 129.16, 129.28, 129.45, 129.58, 130.68, 131.32, 131.64,
132.50, 134.23, 135.29, 135.94, 140.55, 192.76.
19
F NMR (CDCl
3
)  -122.29 (d, J = 25.9
Hz)
HRMS (ESI) Calcd for C
22
H
17
Cl
2
FNO
5
S (MH
+
): 496.0189; Found: 496.0189.
HPLC (DAICEL CHIRALCEL OD-H, hexane/2-propanol = 99/1, flow 0.5 mL/min,
detection at 254 nm) t
R-Diastereomer I
minor 46.8 min, t
R-Diastereomer I
major 53.5 min, t
R-
Diastereomer II
minor 65.6 min, t
R-Diastereomer II
major 89.9 min. The enantiomeric excess of the
four diastereomers were measured after purification by preparative TLC.
3-(4-Chlorophenyl)-4-fluoro-4-nitro-1-phenyl-4-(phenylsulfonyl)butan-1-one
O
S
F
NO
2
Ph
O O
Cl
Diastereomer I (Minor)
3-(4-Chlorophenyl)-4-fluoro-4-nitro-1-phenyl-4-(phenylsulfonyl)butan-1-one
190

1
H NMR (CDCl
3
)  3.80 (dd, J
1
= 18.0 Hz, J
2
= 11.2 Hz, 1H), 4.22 (dd, J
1
= 18.0 Hz,
J
2
= 2.4, 1H), 5.12 (ddd, J
1
= 32.0 Hz, J
2
= 11.2 Hz, J
3
= 2.4 Hz, 1H), 7.16-7.25 (m, 4H),
7.47 (m, 2H), 7.55-7.65 (m, 3H), 7.76-7.82 (m, 1H), 7.92-7.94 (m, 4H).
13
C NMR
(CDCl
3
)  39.07, 42.65 (d,
2
J
CF
= 15.9 Hz), 55.26, 114.41, 125.65, 125.76 (d,
1
J
CF
=
289.1 Hz), 128.27, 128.94, 129.30, 129.86, 130.73, 130.89, 131.86, 132.54, 133.88,
135.11, 136.16, 136.65, 194.42.
19
F NMR (CDCl
3
)  -129.77 (d, J = 32.0 Hz).
HRMS (ESI) Calcd for C
22
H
18
ClFNO
5
S (MH
+
): 462.0578; Found: 462.0580.
Diastereomer II (Major)
(3R,4R)-3-(4-Chlorophenyl)-4-fluoro-4-nitro-1-phenyl-4-(phenylsulfonyl)butan-1-
one
1
H NMR (CDCl
3
)  3.31 (dd, J
1
= 17.6 Hz, J2 = 2.4 Hz, 1H), 3.75 (dd, J
1
= 17.6 Hz,
J
2
= 10.8 Hz, 1H), 5.09 (ddd, J
1
= 26.8 Hz, J
2
= 10.8 Hz, J
3
= 2.4 Hz, 1H), 7.16-7.26 (m,
4H), 7.41-7.49 (m, 4H), 7.54-7.59 (m, 3H), 7.69 (tq, J
1
= 7.2 Hz, J
2
= 0.8 Hz, 1H), 7.81-
7.83 (m, 2H).
13
C NMR (CDCl
3
)  39.34 (d,
3
J
CF
= 1.6 Hz), 43.50 (d,
2
J
CF
= 16.9 Hz),
125.32 (d,
1
J
CF
= 286.9 Hz), 128.17, 128.94, 129.10, 129.41, 130.67, 131.37, 131.72 (d,
3
J
CF
= 1.6 Hz), 132.60, 133.98, 135.19, 135.86, 135.92, 193.85.
19
F NMR (CDCl
3
)  -
122.57 (d, J = 26.0 Hz).
HRMS (ESI) Calcd for C
22
H
18
ClFNO
5
S (MH
+
): 462.0578; Found: 462.0570.
HPLC (DAICEL CHIRALCEL OD-H, hexane/2-propanol = 99.5/1, flow 1.0
mL/min, detection at 254 nm) t
R-Diastereomer I
minor 25.2 min, t
R-Diastereomer I
major 30.2 min,
t
R-Diastereomer II
minor 39.7 min, t
R-Diastereomer II
major 42.0 min. The enantiomeric excess of
the four diastereomers were measured after purification by preparative TLC.
191

4-Fluoro-1-(4-methoxyphenyl)-4-nitro-3-phenyl-4-(phenylsulfonyl)butan-1-one
O
S
F
NO
2
Ph
O O
OMe
Obtained as a mixture of diastereomers.
1
H NMR (CDCl
3
)  3.29 (dd, J
1
= 17.6 Hz, J
2
= 2.8 Hz, 1H), 3.74 (dd, J
1
= 17.2 Hz,
J
2
= 10.8 Hz, 1H), 3.80 (dd, J
1
= 17.6 Hz, J
2
= 6.4 Hz, 1H), 3.84 (s, 3H), 3.86 (s, 3H),
4.15 (dd, J
1
= 17.6 Hz, J
2
= 2.8 Hz, 1H), 5.03-5.17 (m, 2H), 6.87-6.94 (m, 4H), 7.17-7.25
(m, 6H), 7.27-7.30 (m, 4H), 7.38-7.43 (m, 2H), 7.55 (td, J
1
= 8.4 Hz, J
2
= 1.2 Hz, 2H),
7.58-7.66 (m, 3H), 7.75-7.95 (m, 7H).
13
C NMR (CDCl
3
)  38.66, 39.10 (d,
3
J
CF
= 2.3
Hz), 43.54 (d,
2
J
CF
= 16.2 Hz), 44.22 (d,
2
J
CF
= 16.9 Hz), 55.65, 113.99, 125.64 (d,
1
J
CF
=
286.9 Hz), 125.74 (d,
1
J
CF
= 290.1 Hz), 128.86, 128.94, 128.97, 129.19, 129.30, 129.39,
129.42, 129.77, 130.42 (d,
3
J
CF
= 1.5 Hz), 130.51, 130.58, 130.74 (d,
3
J
CF
= 1.6 Hz),
130.89, 132.09, 132.79, 132.96, 134.08, 135.62, 136.49, 163.97, 164.02, 192.52, 193.06.
19
F NMR (CDCl
3
)  -121.72 (d, J = 27.5 Hz), -129.56 (d, J = 32.0 Hz).
In
13
C NMR, there are supposed to be 24 peaks in aromatic region, however, only 22
peaks were observed due to overlap.
HRMS (ESI) Calcd for C
23
H
21
FNO
6
S (MH
+
): 458.1074; Found: 458.01073.
HPLC (DAICEL CHIRALPAK AD-H, hexane/2-propanol = 92/8, flow 1.0 mL/min,
detection at 254 nm) t
R-Diastereomer I
minor 84.9 min, t
R-Diastereomer I
major 135.0 min, t
R-
Diastereomer II
minor 62.2 min, t
R-Diastereomer II
major 97.0 min. The enantiomeric excess of the
four diastereomers were measured after purification by preparative TLC.
192

4.4.5. Typical Procedure for Catalytic Monofluoromethylation of
Methyl Vinyl Ketone

To a solution of α-fluoro-α-nitro phenylsulfonyl methane (21.9 mg, 0.1 mmol, 1
equivalent) and methyl vinyl ketone (0.2 mmol, 2 equivalent) in CH
2
Cl
2
(0.5 mL),
catalyst QN I was added (6.0 mg 0.01 mmol, 10 mol%). The reaction mixture was stirred
for 2 days with monitoring by
19
F NMR for conversion. It was then loaded on to a
preparative TLC plate for purification.
HPLC (DAICEL CHIRALCEL OD-H, hexane/2-propanol = 90/10, flow 1.0 mL/min,
detection at 254 nm) t
R1
26.4 min, t
R2
28.6 min.

193

4.4.6. Crystal Structure of (3R, 4R)-4-Fluoro-4-nitro-1,3-diphenyl-4-
(phenylsulfonyl)-butan-1-one (3a)
S
O
2
N
F
O
O
H
O
3a

Crystal data and structure refinement for C22H18NO5FS.
Empirical formula C44 H36 F2 N2 O10 S2
Formula weight 854.87
Temperature 135(2) K
Wavelength 0.71073 Å
Crystal system Monoclinic
Space group P2(1)
Unit cell dimensions a = 14.7652(8) Å
b = 5.8032(3) Å = 90.1530(10)°.
c = 22.6883(12) Å = 90°.
Volume 1944.05(18) Å
3

Z 2
Density (calculated) 1.460 Mg/m
3

Absorption coefficient 0.212 mm
-1

F(000) 888
194

Crystal size 0.31 x 0.28 x 0.12 mm
3

Theta range for data collection 1.38 to 27.52°.
Index ranges -19<=h<=19, -7<=k<=3, -29<=l<=28
Reflections collected 12109
Independent reflections 5947 [R(int) = 0.0365]
Completeness to theta = 27.52° 98.0 %
Absorption correction Semi-empirical
Max. and min. transmission 0.9760 and 0.9372
Refinement method Full-matrix least-squares on F
2

Data / restraints / parameters 5947 / 1 / 535
Goodness-of-fit on F
2
1.033
Final R indices [I>2sigma(I)] R1 = 0.0634, wR2 = 0.1676
R indices (all data) R1 = 0.0708, wR2 = 0.1749
Absolute structure parameter 0.01(11)
Largest diff. peak and hole 1.242 and -0.770 e.Å
-3

4.4.7. Procedure for Preparation of α-Fluorocarbanion Crystal
FBSM (157 mg, 0.5 mmol) was dissolved in anhydrous THF (1 mL) in a Schlenk
flask under argon atmosphere. Tetra-n-butylammonium (1 M in MeOH, 0.5 mL) was
added to the solution dropwise at room temperature. The reaction mixture was stirred for
20 min before evaporating the volatile solvents and water under vacuum in the same
195

flask. The resulting salt was redissolved in anhydrous THF and toluene (1:1, 2~3 mL)
which was quickly transferred into a vial through a syringe. Anhydrous hexanes (about
0.5 mL) was added to this solution thereafter. The vial was stored at room temperature
under argon atmosphere to allow evaporation of the solvents. Fine crystalline solid,
which was slightly yellowish, was formed after most of the solvents evaporated.
Tetra-n-butylammonium-HBSM anion was prepared using the same procedure.

4.4.8. Typical Procedure for Preparation of α-Fluorocarbanion DMSO
Solution
FBSM (157 mg, 0.5 mmol) was dissolved in anhydrous THF (1 mL) in a Schlenk
flask under argon atmosphere. The base (tetra-n-butylammonium hydroxide or sodium
methoxide in MeOH, 0.5 mmol) was added to the solution dropwise at room temperature.
(nBuLi was added at -40
o
C.) The reaction mixture was stirred for 20 min before
evaporating the volatile solvents and water under vacuum in the same flask. The resulting
salt was redissolved in DMSO-d
6
. The solution was carefully transferred into a pre-dried
NMR through a syringe.
Tetra-n-butylammonium-HBSM anion solution was prepared using the same
procedure.

196

Bis(phenylsulfonyl)methane (HBSM)

As white solid,
1
H NMR (DMSO-d
6
) δ 5.94 (s, 2H), 7.60-7.64 (m, 4H), 7.73-7.77 (m,
2H), 7.87-7.89 (m, 4H).
13
C NMR (DMSO-d
6
) δ 71.8, 128.4, 129.2, 134.4, 138.9.
Bis(phenylsulfonyl)methane tetra-n-butylammonium salt

As slightly yellowish crystalline solid,
1
H NMR (DMSO-d
6
) δ 0.93 (t, J = 7.3 Hz,
12H), 1.30 (h, J = 7.3 Hz, 8H), 1.52-1.60 (m, 8H), 3.13-3.18 (m, 8H), 3.65 (s, 1H), 7.31-
7.33 (m, 6H), 7.70-7.73 (m, 4H).
13
C NMR (DMSO-d
6
) 13.4, 19.1, 23.0, 57.4, 63.7,
125.1, 127.6, 128.8, 150.5. HRMS (ESI): m/z calcd for C
13
H
11
O
4
S
2
-
[(PhSO
2
)
2
CH
-
] (M
-
):
295.0099, Found: 295.0107, calcd for C
16
H
36
N
+
[nBu
4
N
+
] (M
+
): 242.2842, Found:
242.2840.
-Fluoro(bisphenylsulfonyl)methane

As white solid,
1
H NMR (DMSO-d
6
) δ 7.46 (d, J = 42.5 Hz, 1H), 7.71-7.75 (m, 4H),
7.86-7.90 (m, 2H), 7.93-7.95 (m, 4H).
13
C NMR (DMSO-d
6
) δ 104.4 (d, J
CF
= 255 Hz),
129.70, 129.80, 135.3, 136.0.
19
F NMR (DMSO-d
6
) δ -171.9 (d, J = 42.5 Hz, 1F).
-Fluorobis(phenylsulfonyl)methane tetra-n-butylammonium salt

197

As colorless crystal,
1
H NMR (DMSO-d
6
) δ 0.92 (t, J = 7.2 Hz, 12H), 1.30 (h, J =
7.2 Hz, 8H), 1.56 (m, 8H), 3.15-3.19 (m, 8H), 7.04-7.08 (m, 4H), 7.16-7.23 (m, 6H).
13
C
NMR (DMSO-d
6
) δ 13.5, 19.2, 23.1, 57.5, 125.3, 127.0 (d, J
CF
= 273 Hz), 127.7, 129.5,
142.1.
19
F NMR (DMSO-d
6
) δ -202.3 (s, 1F).

4.4.9. Crystal Structure of FBSM Anion-tetra(n-Butylammonium) Salt

Crystal data and structure refinement for C27H46NO4FS2.
Empirical formula C29 H46 F N O4 S2
Formula weight 555.79
Temperature 143(2) K
Wavelength 0.71073 Å
Crystal system Triclinic
Space group P-1
Unit cell dimensions a = 10.7312(15) Å = 82.923(2)°.
198

b = 11.3434(16) Å = 89.493(2)°.
c = 12.4291(18) Å  = 84.532(2)°.
Volume 1494.6(4) Å
3

Z 2
Density (calculated) 1.235 Mg/m
3

Absorption coefficient 0.218 mm
-1

F(000) 600
Crystal size 0.99 x 0.73 x 0.33 mm
3

Theta range for data collection 1.65 to 25.68°.
Index ranges -6<=h<=13, -13<=k<=13, -15<=l<=15
Reflections collected 4136
Independent reflections 2585 [R(int) = 0.0401]
Completeness to theta = 25.68° 45.6 %
Absorption correction Semi-empirical
Max. and min. transmission 0.9310 and 0.8126
Refinement method Full-matrix least-squares on F
2

Data / restraints / parameters 2585 / 0 / 338
Goodness-of-fit on F
2
0.990
Final R indices [I>2sigma(I)] R1 = 0.0432, wR2 = 0.1063
R indices (all data) R1 = 0.0490, wR2 = 0.1103
Largest diff. peak and hole 0.150 and -0.202 e.Å
-3
199

4.4.10. Crystal Structure of HBSM Anion-tetra(n-Butylammonium) Salt

Crystal data and structure refinement for C29H47NO4S2.
Empirical formula C29 H47 N O4 S2
Formula weight 537.80
Temperature 143(2) K
Wavelength 0.71073 Å
Crystal system Orthorhombic
Space group P2(1)2(1)2(1)
Unit cell dimensions a = 11.811(2) Å α= 90°.
b = 12.038(2) Å β= 90°.
c = 42.498(9) Å γ = 90°.
Volume 6042(2) Å
3

Z 8
200

Density (calculated) 1.182 Mg/m
3

Absorption coefficient 0.209 mm
-1

F(000) 2336
Crystal size 0.28 x 0.17 x 0.13 mm
3

Theta range for data collection 1.76 to 25.68°.
Index ranges -8<=h<=14, -14<=k<=13, -51<=l<=48
Reflections collected 34901
Independent reflections 11496 [R(int) = 0.0827]
Completeness to theta = 25.68° 100.0 %
Absorption correction Semi-empirical
Max. and min. transmission 0.9744 and 0.9448
Refinement method Full-matrix least-squares on F
2

Data / restraints / parameters 11496 / 0 / 667
Goodness-of-fit on F
2
0.777
Final R indices [I>2sigma(I)] R1 = 0.0589, wR2 = 0.1569
R indices (all data) R1 = 0.1013, wR2 = 0.1928
Absolute structure parameter 0.04(8)
Largest diff. peak and hole 0.329 and -0.211 e.Å
-3

201

4.4.11. Crystal Structure of NSM Anion-tetra(n-Butylammonium) Salt

Crystal data and structure refinement for C23H42N2O4S.
Empirical formula C23H42N2O4 S
Formula weight 442.65
Temperature 135(2) K
Wavelength 0.71073 Å
Crystal system Monoclinic
Space group P2(1)/n
Unit cell dimensions a = 12.2377(15) Å α= 90°.
b = 15.2819(19) Å β= 103.970(2)°.
c = 13.9978(17) Å γ = 90°.
Volume 2540.4(5) Å
3

Z 4
Density (calculated) 1.157 Mg/m
3

202

Absorption coefficient 0.156 mm
-1

F(000) 968
Crystal size 1.13 x 0.70 x 0.37 mm
3

Theta range for data collection 1.99 to 27.54°.
Index ranges -13<=h<=15, -19<=k<=15, -18<=l<=18
Reflections collected 15459
Independent reflections 5728 [R(int) = 0.0260]
Completeness to theta = 27.54° 97.8 %
Absorption correction Semi-empirical
Max. and min. transmission 0.9448 and 0.8429
Refinement method Full-matrix least-squares on F
2

Data / restraints / parameters 5728 / 0 / 275
Goodness-of-fit on F
2
1.015
Final R indices [I>2sigma(I)] R1 = 0.0429, wR2 = 0.1226
R indices (all data) R1 = 0.0492, wR2 = 0.1306
Largest diff. peak and hole 0.415 and -0.212 e.Å
-3

203

4.5. Reference

[1] Kirsh, P. Modern Flouroorganic Chemistry, Wiley-VCH, Weinheim, 2004.
[2] Smart, B.E. J. Fluorine Chem. 2001, 109, 3-11.
[3] Soloshonok, V. A. Enantiocontrolled synthesis of Fluoroorganic Compounds:
Stereochemical Challenges and Biomedical Targets, Wiley-VCH: Chichester,
UK, 1999.
[4] Banks, R. E.; Smart, B. E.; Tatlow, J. C. Organofluorine Chemistry: Principles
and commercial applications, Plenum, New York, 1994.
[5] Filler, R.; Kobayashim, Y.; Yagupolski, L. M. Organofluorine Compounds in
Medicinal Chemistry and Biomedical Applications, Elsevier, Amsterdam, 1993.
[6] Prakash, G. K. S.; Yudin, A. K. Chem. Rev. 1997, 97, 757-786.
[7] Prakash, G. K. S.; Hu, J. Acc. Chem. Res. 2007, 40, 921-930.
[8] Prakash, G. K. S.; Hu, J.; Olah, G. A. J. Org. Chem. 2003, 68, 4457-4463.
[9] Prakash, G. K. S.; Mandal, M. J. Am. Chem. Soc. 2002, 124, 6538-6539.
[10] Prakash, G. K. S.; Hu, J. ACS Symposium Series 2005, 911, 16-56.
[11] Prakash, G. K. S.; Mandal, M.; Olah, G. A. Angew. Chem. Int. Ed. 2001, 40, 589-
590.
[12] Prakash, G. K. S.; Hu, J.; Mathew, T.; Olah, G. A. Angew. Chem. Int. Ed. 2003,
42, 5216-5219.
[13] Ni, C.; Li, Y.; Hu, J. J. Org. Chem. 2006, 71, 6829-6833.
[14] Fukuzumi, T.; Shibata, N.; Sugiura, M.; Yasui, H.; Nakamura, S.; Toru, T.;
Angew. Chem. Int. Ed. 2006, 45, 4973-4977.
204

[15] Prakash, G. K. S.; Chacko, S.; Alconcel, S.; Stewart, T.; Mathew, T.; Olah, G. A.
Angew. Chem. Int. Ed. 2007, 46, 4933-4936.
[16] (a) Ni, C.; Zhang, L.; Hu, J. J. Org. Chem. 2008, 73, 5699-5713; (b) Prakash, G.
K. S.; Zhao, X. ; Chacko, S. ; Wang, F.; Vaghoo, H.; Olah, G. A. Beilstein J. Org.
Chem. 2008, 4, No. 17; (c) Moon, H. W.; Cho, M. J.; Kim, D. Y. Tetrahedron
Lett. 2009, 50, 4896-4898; (d) Alba, A.-N.; Companyó, X.; Moyano, A.; Rios, R.
Chem. Eur. J. 2009, 15, 7035-7038; (e) Zhang, S.; Zhang, Y.; Ji, Y.; Li, H.;
Wang, W. Chem. Commun. 2009, 4886-4888.
[17] Mizuta, S.; Shibata, N.; Goto, Y.; Furukawa, T.; Nakamura, S.; Toru, T. J. Am.
Chem. Soc. 2007, 129, 6394-6395.
[18] Shen, X.; Zhang, L.; Zhao, Y.; Zhu, L.; Li, G.; Hu, J. Angew. Chem. Int. Ed.
2011, 50, 2588-2592.
[19] Review articles on the synthetic applications of FBSM: (a) Prakash, G. K. S.;
Chacko, S. Curr. Opin. Drug Discov. Dev. 2008, 11, 793-802; (b) Hu, J.; Zhang,
W.; Wang, F. Chem. Commun. 2009, 7465-7478; (c) Ni, C.; Hu, J. Synlett 2011,
770-782; (d) Vallero, G.; Companyo, X.; Rios, R. Chem. Eur. J. 2011, 17, 2018-
2037.
[20] Furukawa, T.; Shibata, N.; Mizuta, S.; Nakamura, S.; Toru, T.; Motoo, S. Angew.
Chem. Int. Ed. 2008, 47, 8051-8054.
[21] (a) Yoon, T. P.; Jacobsen, E. N. Science 2003, 299, 1691–1693; (b) Taylor, M. S.;
Jacobsen, E. N. Angew. Chem. Int. Ed. 2006, 45, 1520–1543; (c) Knowles, R. R.;
Jacobsen, E. N. Proc. Natl. Acad. Sci. USA 2010, 107, 20678–20685.
205

[22] Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003, 125, 12672-12673.
[23] Vakulya, B.; Varga, S.; Csámpai, A; Soós, T. Org. Lett. 2005, 7, 1967-1969.
[24] McCooey, S. H.; Connon, S. J. Angew. Chem. Int. Ed. 2005, 44, 6367-6370.
[25] Prakash, G. K. S.; Wang, F.; Shao, N.; Mathew, T.; Rasul, G.; Haiges, R.;
Stewart, T.; Olah, G. A. Angew. Chem. Int. Ed. 2009, 48, 5358-5362.
[26] DFT calculations at B3LYP/6-311+G(2d,p) level have shown that FNSM can
form two enol-like intermediates, which are a pair of enantiomers. Therefore, if
the enol-like species are the key reaction intermediates, the reaction mechanism
still involves the dynamic-kinetic resolution of racemic FNSM.
206

Chapter 5

Facile Enantioselective Synthesis of α-Stereogenic γ-
Keto Esters via Formal Umpolung: Utilization of
Nitro(phenylsulfonyl)methane as an Acyl Anion
Equivalent

207

5.1. Introduction
γ-Keto esters are amongst the most important synthetic feedstock for constructing
complex molecules. Although various methods have been developed for the preparation
of ra c e mi c γ -keto esters,
1
majority of them use arduous synthetic procedures and/or
utilization of scarce reagents. Feasible protocols towards these compounds are thus
ardently sought. Enantioselective synthesis of α-stereogenic γ-keto esters are mainly
achieved through the conjugate addition of 4-oxo-4-butenoates with various nucleophiles
(Eq. 1, Scheme 5.1).
2
Although metal- c a t a l y z e d a s y m metric c y a n a ti on of α , β -unsaturated
c a rbon y l c ompounds a lso pa ve s a n a lt e rna ti ve route to γ -keto ester,
3
the method is
disadvantageous as it employs hazardous cyanides with possible undesirable 1,2-addition
pathway (Eq. 2, Scheme 1).
4

The above mentioned challenge is essentially due to the incompatible
dona ti ng /a c c e pti n g na tur e s of the β - a nd the γ - c a rbon a tom s in γ -keto ester backbones.
Therefore implementation of an organocatalyzed conjugate addition merging with the
umpolung strategy
5
can be a robust solution (Eq. 3, Scheme 5.1).
6,7
In principle, such a
proposal can be attained by integrating an enantioselective malononitrile-enones
conjugate addition
8
with the oxidative degradation of the adducts (Eq. 4, Scheme 5.1).
9

Nonetheless, the applicability of this approach is significantly diminished by the acute
toxicity of malononitrile (through its metabolization to cyanide in body).
10

208

Scheme 5.1. Enantioselective selective synthesis of α-stereogenic γ-keto esters.

5.2. Results and Discussion
Addressing such an inherent synthetic challenge, we envisaged
nitro(phenylsulfonyl)methane (NSM, 1) to be a versatile acyl anion precursor due to its
superior properties over other active methylene pronucleophiles. First, among strong
carbon acids, NSM (pK
a
≈ 7 in DMS O)
11
a nd it s α -substituted derivatives can undergo
feasible deprotonation to form the corresponding anions as nucleophiles in many organic
209

transformations.
12
Secondly, the oxidative degradation of primary nitroalkanes
(NO
2
CH
2
R)
13
and primary sulfones (RSO
2
CH
2
R ’)
14
usually requires harsh reaction
conditions, such as utilization of strong bases and/or oxidants. In comparison, the
oxidative methanolysis of nitro(phenylsulfonyl)methyl moiety (NO
2
CHSO
2
Ph) can be
achieved under considerably milder conditions.
15
I n pa rticula r, α -fluoro- α-
nitro(phenylsulfonyl)methane (FNSM) can participate in various asymmetric conjugate
addition reactions, which further validates the analogous NSM as a viable
pronucleophile.
16
To the best of our knowledge, NSM is also considerably user-benign,
therefore prevailing over other highly toxic acyl anion equivalents, such as malononitrile
and HCN. In spite of its vast potential as an acyl precursor, NSM

is disadvantaged by its
high cost and limited synthetic accessibility.
12b,16e,17
To overcome this obstacle, our initial
efforts were made on developing a facile preparative approach toward NSM. As shown in
Scheme 2, by modifying a known procedure,
18
NSM can be easily obtained on a 40 g-
scale without advanced purification techniques (Scheme 5.2).

Scheme 5.2. Improved Preparation of NSM.

With readily accessible NSM in hand, we performed its thiourea-catalyzed Michael
addition reaction
19
under the conditions previously employed for that of FNSM (Table
210

1).
16a
However, the reaction was found to be very sluggish with NSM as a pronucleophile
(Entries 1-4, Table 5.1). This is similar to the observation that dinitromethane is much
less reactive than fluorodinitromethane in Michael addition reaction
20
owing to th e α -
fluorine effects.
21
We thus increased the reaction concentration to 2 M, which led to
remarkable enhancements in reaction yields (Entries 5, 6, and 10-14, Table 5.1). Further
oxidative methanolysis of the adduct (3a) l e d to t he de sir e d γ -keto ester (4a) with good
enantiomeric ratios (er ), indi c a ti ng the e ss e nti a l ster e oc h e mi c a l stabil it y o f the α -carbon
in the adduct and the product. Nevertheless, attempts to improve er by lowering reaction
temperatures resulted in a drastic decrease in yields due to the insufficient solubility of
the substrates under the reaction conditions (Entries 7, 8, and 15, Table 5.1). It is also
worth noting that the solubilities of many enones can marginally reach the required high
concentration (2 M) even at room temperature, therefore diminishing the applicability of
the present reaction conditions.

211

Table 5.1. Thiourea-Catalyzed Synthesis of α-Stereogenic γ-Keto Esters.

212

Further optimization was emphasized on acceleration of the reaction by exploiting
cinchona alkaloid-derived primary amines, which have been widely used as amenable
catalysts in many asymmetric reactions.
22
As s hown in Ta ble 2, while γ -keto ester 4a was
obtained with inferior er by using primary amine catalysts, the Michael addition was
significantly accelerated and could be completed at a concentration of 0.5 M within 48 h.
Notably, it was found that the present Michael addition-oxidative methanolysis approach
could also be achieved in a one-pot fashion. After the removal of the solvent in the
Michael reaction, the direct oxidative methanolysis of 3a could furnish 4a in moderate
yield, therefore significantly streamlining the protocol. Despite the fact that excess
amount of 2a led to the formation of 1,3-diphenyl-2,3-epoxy-1-propanone under the
oxidative conditions, it could be easily separated from 4a via column chromatography. It
was found that different primary amines afforded the desired product 4a with similar
levels of stereoselectivity (Entries 1 and 3, Entries 2 and 4, Table 5.2). Screening of the
solvents revealed that both CH
2
Cl
2
and CHCl
3
were suitable solvents for the reaction
(Entries 2 and 5-11, Table 5.2). CN-2 and CH
2
Cl
2
were thus selected as the catalyst and
the solvent for further optimization, respectively.

213

Table 5.2. One-Pot Synthesis of α-Stereogenic γ-Keto Esters Catalyzed using Primary
Amine Catalysts.

It has been demonstrated that Brønsted acids can facilitate amine-catalyzed reactions
by means of iminium activation
23
or mediating H-bonding interactions.
24
On this basis,
we surmised that Brønsted acids could also be effective co-catalysts. Although initial
attempts to exploit phenols and fluorinated alcohols as additives were unsuccessful (See
Supporting Information for details), benzenesulfonic acid monohydrate brought a rather
promising result (Entry 1, Table 5.3), indicating the essentials of acid strengths.
214

However, the excessive acidity of CF
3
SO
3
H was found to have a detrimental impact on
the stereoselectivity (Entry 2, Table 5.3). A series of carboxylic acids, whose acidities
range between sulfonic acids and alcohols, was thus screened. The er of the reaction was
gradually increased along with the increase in the acid strength of the additive, as from
acetic acid to trichloroacetic acid (Entries 4-7, Table 5.3). Excellent stereoselectivity was
thus obtained via the employment of trichloroacetic acid. Presumably, such a trend could
be rationalized by certain strong acidity that could facilitate iminium catalysis pathway
more efficiently than the weak acids. Meanwhile, by decreasing the concentration of free
primary amines, enhanced acidity also suppressed the less stereoselective reaction
pathway mediated by neutral primary amines, i.e. the reactions in Table 2. Similar to
triflic acid, the overwhelming acidity of CF
3
CO
2
H also impaired the stereoselectivity of
the reaction (Entries 8, Table 5.3). Although increasing the amount of ClCH
2
CO
2
H could
slightly enhance the er, this led to dramatic decreases in reaction yields (Entries 5, 9, and
10, Table 3). Further screening of catalysts showed QD 2 to be a superior catalyst over
CN 2. Based on this result, the solvent effects on the stereoselectivity were also
investigated, which revealed THF to be the optimal solvent (Entry 26, Table 5.3). The
optimized reaction conditions were eventually attained using 10 mol% of QD-2 as the
catalyst along with 10 mol% of Cl
2
CHCO
2
H in THF (Entry 29, Table 5.3).
215

Table 5.3. Investigation of Brønsted acid additives and solvent effects on primary amine-
catalyzed Michael reaction.

As outlined in Table 5.4, a variety of enones was investigated in the one-pot Michael
addition-oxidative methanolysis protocol. In general, both electron-rich and electron-
deficient chalcone derivatives underwent the reaction smoothly, affording α-stereogenic
γ-keto esters in moderate yields with high enantiomeric selectivities (Entries 1 and 4-11,
Table 5.4). However, when furfural acetone was subjected to the reaction, only a
complex mixture was obtained, possibly due to the lability of the furan ring under the
oxidation conditions (Entry 3, Table 5.4).
25
Although methyl styryl ketone also
216

participated in the reaction, the stereoselectivity was found to be rather low (Entry 2,
Table 5.4).

Table 5.4. Investigation of substrate scope.

a
Isolated yields;
b
major:minor, measured by chiral HPLC;
c
performed in THF-
CH
2
Cl
2
(1:2, v:v) due to the low solubilities of enones in THF;
d
performed in CH
2
Cl
2

due to the low solubilities of the enone in THF;
e
the absolute configuration determined
by X-ray crystallography
217

To demonstrate the synthetic utility of the present protocol, 4i was subjected to a
tandem reduction-reductive amination reaction.
26
As depicted in Scheme 5.3,
synthetically useful tetrahydroquinoline-4-carboxylic ester 5 was obtained as a single
diastereomer in good yield without significant loss of optical purity.
27

Scheme 5.3. Stereoselective synthesis of tetrahydropyridine.

5.3. Conclusion
In summary, a feasible protocol has been achieved for the enantioselective
preparation of α-stereogenic γ-keto esters via an umpolung strategy. Exploiting
nitro(phenylsulfonyl)methane (NSM) as an acyl anion precursor, various γ-keto esters
can be obtained in moderate yields with good enantioselectivities. Large-scale
preparation of NSM has been achieved through the modification of a known synthetic
route, which enhances the practicality of the protocol. In particular, the protocol is also
significantly streamlined by merging the asymmetric organocatalyzed Michael addition
reaction and the subsequent oxidative methanolysis into a one-pot fashion. Further
investigation of NSM as an acyl anion equivalent in the Mannich reaction is currently
underway in our laboratory.
218

5.4. Experimental
Unless otherwise mentioned, all the chemicals were purchased from commercial
sources. Tetra-n-butylammonium Oxone (TBA-Oxone) was prepared according to a
known procedure.
15a
Silica gel chromatography was performed to isolate the products
using 60-200 mesh silica gel (from silicycle) and using suitable solvent systems as eluent.
1
H,
13
C, and
19
F spectra were recorded on 400 MHz or 500 MHz Varian NMR
spectrometers.
1
H NMR chemical shifts were determined relative to CDCl
3
as the internal
standa rd (δ 7.26 ).
13
C NMR shifts were determined relative to CDCl
3
δ 77.16 .
19
F NMR
chemical shifts were determined relative to internal standard CFCl
3
a t δ 0.00 . Mass
spectra were recorded on a high resolution mass spectrometer in the ESI mode. The high
resolution X-ray crystal structures were derived from the Mo data, while the absolute
configurations were determined with Cu data structures. Therefore, the high resolution
absolute configurations were obtained from a Cu data set to refine the Mo data structures.
The reliability of the absolute configurations thus obtained can be assessed by the Flack x
parameter, which is between 0 and 1. X = 0 means the absolute configuration is correct, x
= 1 means it is inverse, and x = 0.5 means the crystal is a racemic twin. The Hooft y
parameter is similar to Flack x but is more sensitive for light atom structures. The
Bayesian Statistics P2 value describes the likelihood that the absolute configuration is
correct. P2 = 1 means 100% confidence.
219

5.4.1 Large-Scale Preparation of Nitro(phenylsulfonyl)methane (NSM,
1)

At 0 °C, to a solution of nitromethane (30.5 g, 0.5 mol) in DMF (600 mL) was added
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 76.1 g, 0.5 mol). The reaction mixture was
stirred for 10 min. After the addition of sodium phenylsulfinate (68.9 g, 0.42 mol) and
iodine (96.4 g, 0.38 mmol), the solution was allowed to warm to room temperature and
stirred for another 1 h. Subsequently, saturated sodium sulfite aq. solution was added
until the mixture turned to bright yellow. The pH was adjusted to 1 with concentrated
HCl aq. solution. The aqueous layer was extracted three times with CH
2
Cl
2
. The
combined CH
2
Cl
2
solution was then extracted with NaOH aq. solution (2 M) four times
[sodium nitro(phenylsulfonyl)methide dissolves in NaOH aq. solution rather than in
CH
2
Cl
2
]. The combined aq. layers were further washed with CH
2
Cl
2
twice and acidified
to pH = 1 using HCl aq. solution with ice (ca. 2 M). A large amount of white precipitate
(NSM) was observed. This aqueous mixture was then extracted with CH
2
Cl
2
three times,
and the combined organic layers were dried over MgSO
4
before the removal of the
solvents under vacuum. The crude product was recrystallized in EtOH to afford white
crystalline solid as NSM (39.6 g, 47%, based on sodium phenylsulfinate).
1
H NMR (500
MHz, CDCl
3
)  7.99-7.96 (m, 2H), 7.78-7.82 (m, 1H), 7.68-7.64 (m, 2H), 5.60 (s, 2H).
220

5.4.2. Typical Procedure for One-pot Enantioselective Synthesis of α-
Stereogenic γ-Keto Esters

To a solution of enone (0.6 mmol, 1.5 equiv) in the indicated solvent (0.8 mL), QD-2
(12.9 mg, 0.04 mmol, 10 mol %) and CHCl
2
CO
2
H (5.2 mg, 0.04 mmol, 10 mol %) were
added sequentially. NSM (80 mg, 0.4 mmol, 1.0 equiv) was added to the above
mentioned solution. The reaction mixture was stirred for 48 h at room temperature before
the removal of the reaction solvent under vacuum.
The chunk of the crude Michael adduct was then broken by a spatula and suspended
in MeOH (4.4 mL) a t 0 C. To this suspension, 1,1,3,3- tetra meth y l g ua nidi ne (60 μ L , 0.48
mmol, 1.2 equiv) was added dropwise. Upon the completion of the addition, a clear
solution was formed, which was stirred at 0
o
C for 10 min. TBA-Oxone (1.92 g, ca. 2
mmol active oxidizing agent Bu
4
NHSO
5
, ca. 5.0 equiv) was added in one load, followed
by the addition of Na
2
CO
3
(204 mg, 1.92 mmol, 4.8 equiv) and CH
2
Cl
2
(6 mL). The
reaction mixture was stirred vigorously for 12 h and the solvent was then removed under
vacuum. The resulting mixture was passed through a short column (packed with ca. 50
mL silica gel) using CH
2
Cl
2
-Hexanes (1:1) as eluent to remove tetra-n-butyl ammonium
221

salts and other inorganic salts. The organic solution was evaporated on a rotavap and the
mixture was purified on column chromatography to afford the titled product.
5.4.3. Complete Tables of Reaction Condition Screening
Table 5.5. Thiourea-Catalyzed Synthesis of α-Stereogenic γ-Keto Esters.

222

Table 5.6. One-Pot Synthesis of α-Stereogenic γ-Keto Esters using Primary Amine
Catalysts.

223

Table 5.7. Employment of Phenols as Brønsted Acid Additives.

224

5.4.4. Product Characterization
Methyl 4-oxo-2,4-diphenylbutanoate (4a)

Prepared according to the typical procedure on a 0.4 mmol scale (based on NSM). A
colorless oil (55 mg, 51%) was obtained with 96:4 er.
1
H NMR (400 MHz, CDCl
3
)  3.28
(dd, J = 18.1, 4.1 Hz, 1H), 3.70 (s, 3H), 3.96 (dd, J = 18.1, 10.3 Hz, 1H), 4.30 (dd, J =
10.3, 4.0 Hz, 1H), 7.28-7.36 (m, 5H), 7.45-7.47 (m, 2H), 7.55-7.58 (m, 1H), 7.97-7.98
(m, 2H).
28
HPLC (DAICEL CHIRALCEL OD-H, hexane/2-propanol = 98/2, flow 1.0
mL/min, detection at 280 nm): t
R1
=14.3 min, t
R2
= 16.1 min.
Methyl 4-oxo-2-phenylpentanoate (4b)

Prepared according to the typical procedure on a 0.4 mmol scale (based on NSM). A
colorless oil (37 mg, 45%) was obtained with 73:27 er.
1
H NMR (400 MHz, CDCl
3
) δ
7.34-7.30 (m, 2H), 7.29-7.24 (m, 3H), 4.11 (dd, J = 10.4, 4.2 Hz, 1H), 3.66 (s, 3H), 3.40
(dd, J = 18.0, 10.4 Hz, 1H), 2.72 (dd, J = 18.0, 4.3 Hz, 1H), 2.18 (s, 3H).
29
HPLC
(DAICEL CHIRALCEL OD-H, hexane/2-propanol = 93/7, flow 0.5 mL/min, detection at
254 nm): t
R1
= 27.8 min, t
R2
= 30.5 min.
225

Methyl 2-(4-methoxyphenyl)-4-oxo-4-phenylbutanoate (4d)

Prepared according to the typical procedure on a 0.4 mmol scale (based on NSM). A
colorless oil (63 mg, 53%) was obtained with 94:6 er.
1
H NMR (500 MHz, CDCl
3
) δ 7.99-7.95 (m, 2H), 7.59-7.53 (m, 1H), 7.48-7.42 (m, 2H), 7.30-7.25 (m, 2H), 4.25 (dd, J
= 10.2, 4.2 Hz, 1H), 3.91 (dd, J = 18.0, 10.2 Hz, 1H), 3.80 (s, 3H), 3.69 (s, 2H), 3.26 (dd,
J = 18.0, 4.2 Hz, 1H).
13
C NMR (125 MHz, CDCl
3
) δ 197.9, 174.3, 159. 2, 136.6, 133.4,
130.5, 129.0, 128.7, 128.2, 114.4, 55.4, 52.5, 45.6, 43.0. MS (EI): 298, 238, 207, 161,
133, 105, 91, 77, 51. HRMS: Calcd for C
18
H
19
O
4
(MH
+
): 299.1278; Found: 299.1276.
HPLC (DAICEL CHIRALCEL OD-H, hexane/2-propanol = 98/2, flow 1.0 mL/min,
detection at 254 nm): t
R1
= 18.5 min, t
R2
= 25.6 min.
(R)-Methyl 4-(4-methoxyphenyl)-4-oxo-2-phenylbutanoate (4e)

Prepared according to the typical procedure on a 0.4 mmol scale (based on NSM). A
colorless oil (66 mg, 55%) was obtained with with 97:3 er. The single crystal of 4e was
obtained via crystallization from a methanol-water solution.
1
H NMR (500 MHz, CDCl
3
)
δ 7.97-7.92 (m, 2H), 7.38-7.32 (m, 4H), 7.31 –7.26 (m, 1H), 6.96 – 6.88 (m, 2H), 4.29
(dd, J = 10.3, 4.1 Hz, 1H), 3.90 (dd, J = 17.8, 10.3 Hz, 1H), 3.86 (s, 1H), 3.69 (s, 1H),
226

3.23 (dd, J = 10.3, 4.1 Hz, 1H).
28
HPLC (DAICEL CHIRALCEL OD-H, hexane/2-
propanol = 98/2, flow 1.0 mL/min, detection at 254 nm): t
R1
= 40.2 min, t
R2
= 48.4 min.
Methyl 2-(4-chlorophenyl)-4-oxo-4-phenylbutanoate (4f)

Prepared according to the typical procedure on a 0.4 mmol scale (based on NSM). A
colorless oil (67 mg, 55%) was obtained with 96:4 er.
1
H NMR (500 MHz, CDCl
3
) δ 7.99 – 7.93 (m, 2H), 7.57 (m, 1H), 7.49-7.43 (m, 2H), 7.33-7.28 (m, 4H), 4.28 (dd, J = 9.9, 4.5
Hz, 1H), 3.91 (dd, J = 18.0, 9.9 Hz, 1H), 3.70 (s, 3H), 3.27 (dd, J = 18.0, 4.5 Hz, 1H).
13
C
NMR (125 MHz, CDCl
3
) δ 197.4, 173.7, 137.0, 136.4, 133.7, 133.6, 129.4, 129.2, 128.8,
128.2, 52.6, 45.9, 42.7. MS (EI): 272, 270, 209, 207, 167, 165, 105, 77, 50. HRMS:
Calcd for C
17
H
15
ClNaO
3
(MNa
+
): 325.0605; Found: 325.0602. HPLC (DAICEL
CHIRALCEL OD-H, hexane/2-propanol = 98/2, flow 1.0 mL/min, detection at 220 nm):
t
R1
= 11.9 min, t
R2
= 15.7 min.
Methyl 4-(4-chlorophenyl)-4-oxo-2-phenylbutanoate (4g)

Prepared according to the typical procedure on a 0.4 mmol scale (based on NSM). A
colorless oil (80 mg, 66%) was obtained with 94:6 er.
1
H NMR (500 MHz, CDCl
3
) δ 7.95- 7.86 (m, 2H), 7.47- 7.39 (m, 2H), 7.38-7.27 (m, 5H), 4.29 (dd, J = 10.3, 4.0 Hz,
1H), 3.92 (dd, J = 18.0, 10.3 Hz, 1H), 3.70 (s, 3H), 3.22 (dd, J = 10.3, 4.0 Hz, 1H).
28
227

HPLC (DAICEL CHIRALCEL OD-H, hexane/2-propanol = 98/2, flow 1.0 mL/min,
detection at 254 nm): t
R1
= 20.1 min, t
R2
= 24.1 min.
(R)-Methyl 2-(4-nitrophenyl)-4-oxo-4-phenylbutanoate (4h)

Prepared according to the typical procedure on a 0.4 mmol scale (based on NSM). A
colorless oil (71 mg, 57%) was obtained with 94:6 er. The single crystal of 4h was
obtained via crystallization from a methanol-water solution.
1
H NMR (500 MHz, CDCl
3
)
δ 8.24-8.16 (m, 2H), 7.99-7.92 (m, 2H), 7.62-7.56 (m, 1H), 7.56-7.51 (m, 2H), 7.50-7.44
(m, 2H), 4.44 (dd, J = 9.3, 5.0 Hz, 1H), 3.95 (dd, J = 18.0, 9.3 Hz, 1H), 3.72 (s, 3H), 4.44
(dd, J = 18.0, 5.0 Hz, 1H).
13
C NMR (125 MHz, CDCl
3
) δ 196.8, 172. 8, 147.6, 145.8, 136.2, 133.8, 129.1, 128.9, 128.2, 124.2, 52.9, 46.4, 42.3. MS (EI): 313, 281, 207, 105,
77, 51. HRMS: Calcd for C
17
H
16
NO
5
(MH
+
): 314.1023; Found: 314.1021. HPLC
(DAICEL CHIRALCEL OD-H, hexane/2-propanol = 98/2, flow 1.0 mL/min, detection at
254 nm): t
R1
= 50.3 min, t
R2
= 58.7 min.
Methyl 2-(2-nitrophenyl)-4-oxo-4-phenylbutanoate (4i)

Prepared according to the typical procedure on a 0.4 mmol scale (based on NSM). A
colorless oil (81 mg, 65%) was obtained with 97:3 er.
1
H NMR (500 MHz, CDCl
3
) δ 8.02-7.94 (m, 3H), 7.62 -7.53 (m, 3H), 7.49- 7.42 (m, 3H), 4.91 (dd, J = 7.9, 5.1 Hz, 1H),
228

4.03 (dd, J = 18.1, 7.9 Hz, 1H), 3.69 (s, 3H), 3.47 (dd, J = 18.1, 5.1 Hz, 1H).
26
HPLC
(DAICEL CHIRALCEL OD-H, hexane/2-propanol = 92/8, flow 0.5 mL/min, detection at
254 nm): t
R1
= 38.8 min, t
R2
= 40.8 min.
Methyl 2,4-bis(4-fluorophenyl)-4-oxobutanoate (4j)

Prepared according to the typical procedure on a 0.4 mmol scale (based on NSM). A
colorless oil (73 mg, 60%) was obtained with 94:6 er.
1
H NMR (500 MHz, CDCl
3
)  3.23
(dd, J = 17.9, 4.4 Hz, 1H), 3.71 (s, 3H), 3.89 (dd, J = 17.9, 10.0 Hz, 1H), 4.39 (dd, J =
10.0, 4.3 Hz, 1H), 7.04 (m, 2H), 7.14 (m, 2H), 7.33 (m, 2H), 8.01 (m, 2H).
13
C NMR
(125 MHz, CDCl
3
)  42.8, 45.7, 52.6, 115.9 (d, J = 22.0 Hz, 1C), 116.0 (d, J = 21.4 Hz,
1C), 129.6 (d, J = 8.1 Hz, 1C), 130.9 (d, J = 9.4 Hz, 1C), 132.9 (d, J = 3.1 Hz, 1C), 134.1
(d, J = 3.4 Hz, 1C), 162.4 (d, J = 246.5 Hz, 1C), 166.1 (d, J = 225.3 Hz, 1C), 173.8,
196.0.
19
F NMR (470 MHz, CDCl
3
)  -105.1 (m, 1F), -115.3 (m, 1F). MS (EI): 304, 272,
149, 123, 95, 75. HRMS: Calcd for C
17
H
14
F2NaO
3
(MNa
+
): 327.0803; Found: 327.0799.
HPLC (DAICEL CHIRALCEL OD-H, hexane/2-propanol = 98/2, flow 1.0 mL/min,
detection at 254 nm): t
R1
= 14.4 min, t
R2
= 23.9 min.

229

Methyl 2,4-bis(4-chlorophenyl)-4-oxobutanoate (4k)

Prepared according to the typical procedure on a 0.4 mmol scale (based on NSM). A
colorless oil (65 mg, 48%) was obtained with 93:7 er.
1
H NMR (500 MHz, CDCl
3
) δ
7.92-7.88 (m, 2H), 7.45- 7.41 (m, 2H), 7.34- 7.26 (m, 4H), 4.27 (dd, J = 9.9, 4.4 Hz, 1H),
3.87 (dd, J = 18.0, 9.9 Hz, 1H), 3.69 (s, 3H), 3.21 (dd, J = 18.0, 4.4 Hz, 1H).
13
C NMR
(125 MHz, CDCl
3
) δ 200 .0, 196.2, 173.6, 140.1 , 136.8, 134.7, 133.8, 129.6, 129.4, 129.3,
129.2, 52.7, 45.8, 42.6. MS (EI): 306, 304, 241, 167, 165, 141, 139, 113, 111, 77, 51.
HRMS: Calcd for C
17
H
14
Cl
2
NaO
3
(MNa
+
): 359.0212; Found: 259.0213. HPLC (DAICEL
CHIRALCEL OD-H, hexane/2-propanol = 98/2, flow 1.0 mL/min, detection at 254 nm):
t
R1
= 17.2 min, t
R2
= 20.8 min.
cis-Methyl 2-phenyl-1,2,3,4-tetrahydroquinoline-4-carboxylate (5)

Prepared according to a known procedure
4
with 4i on a 0.25 mmol scale. To avoid
undesired demethylcarboxylation reaction, the reaction time was shortened to 1 h. A light
yellow oil (54 mg, 81%) was obtained with 97:3 er.
1
H NMR (500 MHz, CDCl
3
) δ 7.45-
7.43 (m, 2H), 7.42-7.35 (m, 2H), 7.32 (ddt, J = 8.0, 7.1, 3.5 Hz, 1H), 7.12-7.02 (m, 2H),
6.74-6.68 (m, 1H), 6.58 (d, J = 8.0 Hz, 1H), 4.43 (dd, J = 10.7, 3.1 Hz, 1H), 4.12 (dd, J =
11.4, 6.0 Hz, 1H), 4.00 (br, 1H), 3.72 (s, 3H), 2.45-2.27 (m, 2H). HPLC (DAICEL
230

CHIRALCEL OD-H, hexane/2-propanol = 90/10, flow 0.5 mL/min, detection at 254
nm): t
R1
= 32.0 min, t
R2
= 35.3 min.

5.4.5. Crystal Structures
Crystal Structure of 4h

Figure 5.1. Crystal Structure of 4h derived from Mo data.

Figure 5.2. Crystal Structure of 4h derived from Cu data.
Critical Parameters
C
17
H
15
NO
5
:
Flack x: 0.2(2)
Hooft y: 0.2 (0.1)
Bayesian Statistics: P2(true) 1.000
231

Crystal data and structure refinement for C17H15NO5. (Cu data)
Empirical formula C17 H15 N O5
Formula weight 313.30
Temperature 100(2) K
Wavelength 1.54178 Å
Crystal system Monoclinic
Space group P 21
Unit cell dimensions a = 7.41820(10) Å = 90°.
b = 12.6302(2) Å = 104.4550(10)°.
c = 7.90890(10) Å  = 90°.
Volume 717.554(17) Å
3

Z 2
Density (calculated) 1.450 Mg/m
3

Absorption coefficient 0.901 mm
-1

F(000) 328
Crystal size 0.46 x 0.16 x 0.14 mm
3

Theta range for data collection 5.78 to 50.42°.
Index ranges -7<=h<=6, -12<=k<=12, -7<=l<=7
Reflections collected 3689
Independent reflections 1443 [R(int) = 0.0256]
Completeness to theta = 50.42° 97.0 %
Absorption correction Semi-empirical from equivalents
232

Max. and min. transmission 0.99 and 0.85
Refinement method Full-matrix least-squares on F
2

Data / restraints / parameters 1443 / 1 / 210
Goodness-of-fit on F
2
1.098
Final R indices [I>2sigma(I)] R1 = 0.0260, wR2 = 0.0650
R indices (all data) R1 = 0.0263, wR2 = 0.0652
Absolute structure parameter 0.2(2)
Extinction coefficient 0.0069(9)
Largest diff. peak and hole 0.152 and -0.150 e.Å
-3

233

Crystal data and structure refinement for C17H15NO5 (Mo data).
Empirical formula C17 H15 N O5
Formula weight 313.30
Temperature 100(2) K
Wavelength 0.71073 Å
Crystal system Monoclinic
Space group P 21
Unit cell dimensions a = 7.4205(4) Å α= 90°.
b = 12.6395(7) Å β= 104.4190(10)°.
c = 7.9161(5) Å δ = 90°.
Volume 719.08(7) Å
3

Z 2
Density (calculated) 1.447 Mg/m
3

Absorption coefficient 0.108 mm
-1

F(000) 328
Crystal size 0.46 x 0.16 x 0.14 mm
3

Theta range for data collection 2.66 to 30.64°.
Index ranges -10<=h<=10, -18<=k<=17, -11<=l<=11
Reflections collected 17872
Independent reflections 4367 [R(int) = 0.0444]
Completeness to theta = 30.64° 99.0 %
Absorption correction Semi-empirical from equivalents
234

Max. and min. transmission 0.99 and 0.84
Refinement method Full-matrix least-squares on F
2

Data / restraints / parameters 4367 / 1 / 209
Goodness-of-fit on F
2
1.055
Final R indices [I>2sigma(I)] R1 = 0.0408, wR2 = 0.0910
R indices (all data) R1 = 0.0543, wR2 = 0.0969
Absolute structure parameter 0.6(8)
Largest diff. peak and hole 0.301 and -0.254 e.Å
-3

235

Crystal Structure of 4e

Figure 5.3. Crystal Structure of 4e derived from Mo data.

Figure 5.4. Crystal Structure of 4e derived from Cu data.
Critical Parameters
C
18
H
18
O
4

Flack x: 0.0(2)
Hooft y: -0.02(0.07)
Bayesian Statistics: P2(true) 1.000

236

Structure refinement for C18H18O4 (Cu data).
Empirical formula C18 H18 O4
Formula weight 298.32
Temperature 100(2) K
Wavelength 1.54178 Å
Crystal system Orthorhombic
Space group P2(1)2(1)2(1)
Unit cell dimensions a = 7.7671(2) Å = 90°.
b = 7.9627(2) Å = 90°.
c = 24.9339(5) Å  = 90°.
Volume 1542.09(6) Å
3

Z 4
Density (calculated) 1.285 Mg/m
3

Absorption coefficient 0.738 mm
-1

F(000) 632
Crystal size 0.44 x 0.44 x 0.16 mm
3

Theta range for data collection 3.55 to 44.38°.
Index ranges -7<=h<=7, -7<=k<=7, -21<=l<=22
Reflections collected 10685
Independent reflections 1194 [R(int) = 0.0374]
Completeness to theta = 44.38° 99.3 %
Absorption correction Semi-empirical from equivalents
237

Max. and min. transmission 0.89 and 0.72
Refinement method Full-matrix least-squares on F
2

Data / restraints / parameters 1194 / 0 / 202
Goodness-of-fit on F
2
1.073
Final R indices [I>2sigma(I)] R1 = 0.0245, wR2 = 0.0604
R indices (all data) R1 = 0.0245, wR2 = 0.0606
Absolute structure parameter 0.0(2)
Extinction coefficient 0.0114(7)
Largest diff. peak and hole 0.189 and -0.172 e.Å
-3

238

Crystal data and structure refinement for C18H18O4 (Mo data).
Empirical formula C18 H18 O4
Formula weight 298.32
Temperature 100(2) K
Wavelength 0.71073 Å
Crystal system Orthorhombic
Space group P2(1)2(1)2(1)
Unit cell dimensions a = 7.7714(4) Å α = 90°.
b = 7.9651(4) Å β = 90°.
c = 24.9654(14) Å γ = 90°.
Volume 1545.36(14) Å
3

Z 4
Density (calculated) 1.282 Mg/m
3

Absorption coefficient 0.090 mm
-1

F(000) 632
Crystal size 0.44 x 0.44 x 0.16 mm
3

Theta range for data collection 1.63 to 30.50°.
Index ranges -10<=h<=11, -11<=k<=11, -35<=l<=35
Reflections collected 38337
Independent reflections 4667 [R(int) = 0.0328]
Completeness to theta = 29.00° 100.0 %
Absorption correction Semi-empirical from equivalents
239

Max. and min. transmission 0.9855 and 0.9614
Refinement method Full-matrix least-squares on F
2

Data / restraints / parameters 4667 / 0 / 201
Goodness-of-fit on F
2
1.043
Final R indices [I>2sigma(I)] R1 = 0.0319, wR2 = 0.0816
R indices (all data) R1 = 0.0355, wR2 = 0.0838
Absolute structure parameter -0.5(6)
Largest diff. peak and hole 0.277 and -0.216 e.Å
-3

240

5.5. References

[1] F or se le c ted e x a mpl e s of the pr e pa r a ti on of ra c e mi c γ -keto esters, see: (a) Russell,
G. A.; Ochrymowycz, L. A. J. Org. Chem. 1969, 34, 3624-3626; (b) Miyashita,
M.; Yamaguchi, R.; Yoshikoshi, A. J. Org. Chem. 1984, 49, 2857-2863; (c)
Miyashita, M.; Yanami, T.; Kumazawa, T.; Yoshikoshi, A. J. Am. Chem. Soc.
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Yan, M.; Zhao, W.-J.; Huang, D.; Ji, S.-J. Tetrahedron Lett. 2004, 45, 6365-6367;
(f) Wang, W.; Xu, B.; Hammond, G. B. J. Org. Chem. 2009, 74, 1640-1643; (g)
Barluenga, J.; Lonzi, G.; Riesgo, L.; Tomás, M.; López, L. A. J. Am. Chem. Soc.
2011, 133, 18138-18141; (h) Gururaja, G. N.; Mobin, S. M.; Namboothiri, I. N.
N. Eur. J. Org. Chem. 2011, 2048-2052.
[2] The related Friedel-Crafts reaction, (a) Evans, D. A.; Fandrick, K. R. Org. Lett.
2006, 8, 2249-2252; (b) Evans, D. A.; Fandrick, K. R.; Song, H.-J.; Scheidt, K.
A.; Xu, R. J. Am. Chem. Soc. 2007, 129, 10029-10041; (c) Bartoli, G.; Bosco, M.;
Carlone, A.; Pesciaioli, F.; Sambri, L.; Melchiorre, P. Org. Lett. 2007, 9, 1403-
1405; the realated Michael addition, (d) Wang, Z.; Chen, D.; Yang, Z.; Bai, S.;
Liu, X.; Lin, L.; Feng, X. Chem. Eur. J. 2010, 16, 10130-10136; (e) Wang, Z.;
Yang, Z.; Chen, D.; Liu, X.; Lin, L.; Feng, X. Angew. Chem. Int. Ed. 2011, 50,
4928-4932.
241

[3] A typical method for methanolysis of cyanide-enone adducts, see: Davey, W.;
Tivey, D. J. J. Chem. Soc. 1958, 1230-1236.
[4] (a) Tanaka, Y.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2008, 130, 6072-
6073; (b) Tanaka, Y.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2010, 132,
8862-8863; (c) Kurono, N.; Nii, N.; Sakaguchi, Y.; Uemura, M.; Ohkuma, T.
Angew. Chem. Int. Ed. 2011, 50, 5541-5544.
[5] Seebach, D. Angew. Chem. Int. Ed. Engl. 1979, 18, 239-258.
[6] In spite of the extensive utilization of NHC-catalyzed Stetter reaction in the
asymmetric synthesis of 1,4-dicarbonyl compounds, to the best of our knowledge,
the Stetter reaction is unable to produce α-stereogenic γ-keto esters. For an early
review on the Stetter reaction, see: (a) Stetter, H. Angew. Chem. Int. Ed. Engl.
1976, 15, 639-647; (b) Christmann, M. Angew. Chem. Int. Ed. 2005, 44, 2632-
2634; (c) Marion, N.; Díez-González, S.; Nolan, S. P. Angew. Chem. Int. Ed.
2007, 46, 2988-3000; (d) Biju, A. T.; Kuhl, N.; Glorius, F. Acc. Chem. Res. 2011,
44, 1182-1195; (e) Bugaut, X.; Glorius, F. Chem. Soc. Rev. 2012, 41, 3511-3522.
[7] For recent examples of exploiting umpolung strategies in asymmetric
organocatalysis, see: (a) Shen, B.; Makley, D. M.; Johnston J. N. Nature 2010,
465, 1027-1032; (b) Zhang, S.-L.; Xie, H.-X.; Zhu, J.; Li, H.; Zhang, X.-S.; Li, J.;
Wang, W. Nat. Commun. 2011, 2, 211-218; (c) Hayashi, Y.; Itoh, T.; Ishikawa, H.
Angew. Chem. Int. Ed. 2011, 50, 3920-3924.
[8] For selected examples of non-transition metal-catalyzed asymmetric conjugate
addition of malononitrile, see: (a) Taylor, M. S.; Zalatan, D. N.; Lerchner, A. M.;
242

Jacobsen, E. N. J. Am. Chem. Soc. 2005, 127, 1313-1317; (b) Wang, J.; Li, H.;
Zu, L.; Jiang, W.; Xie, H.; Duan, W.; Wang, W. J. Am. Chem. Soc. 2006, 128,
12652-12653; (c) Li, X.; Cun, L.; Lian, C.; Zhong, L.; Chen, Y.; Liao, J.; Zhu, J.;
Deng, J. Org. Biomol. Chem. 2008, 6, 349-353; (d) Naka, H.; Kanase, N.; Ueno,
M.; Kondo, Y. Chem. Eur. J. 2008, 14, 5267-5274; (e) Shi, J.; Wang, M.; He, L.;
Zheng, K.; Liu, X.; Lin, L.; Feng, X. Chem. Commun. 2009, 4711-4713; (f)
Pansare, S. V.; Lingampally, R. Org. Biomol. Chem. 2009, 7, 319-324; (g) Yang,
W.; Jia, Y.; Du, D.-M. Org. Biomol. Chem. 2012, 10, 332-338.
[9] Förster, S.; Tverskoy, O.; Helmchen, G. Synlett 2008, 2803-2806.
[10] Material Safety Data Sheets (MSDS) from Sigma-Aldrich Inc.
[11] Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456-463.
[12] Other synthetic utilities of NSM, see: (a) Wade, P. A.; Morrow, S. D.; Hardinger,
S. A.; Saft, M. S.; Hinney, H. R. J. Chem. Soc., Chem. Commun. 1980, 287-288;
(b) Wade, P. A.; Hinney, H. R.; Amin, N. V.; Vail, P. D.; Morrow, S. D.;
Hardinger, S. A.; Saft, M. S. J. Org. Chem. 1981, 43, 765-770.
[13] The Nef reaction: Pinnick, H. W. Org. React. 1990, 38, 655-792.
[14] Bonaparte, A. C.; Betush, M. P.; Panseri, B. M.; Mastarone, D. J.; Murohy, R. K.;
Murphree, S. S. Org. Lett. 2011, 13, 1447-1449, and the references therein.
[15] (a) Trost, B. M.; Kuo, G.-H.; Benneche, T. J. Am. Chem. Soc. 1988, 110, 621-
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Brown, B. J. Am. Chem. Soc. 2000, 122, 5947-5956.
243

[16] For enantioselective conjugate addition of FNSM, see: (a) Prakash, G. K. S.;
Wang, F.; Stewart, T.; Mathew, T.; Olah, G. A. Proc. Natl. Acad. Sci. USA. 2009,
106, 4090-4094; (b) Ullah, F.; Zhao, G.-L.; Deiana, L.; Zhu, M.; Dziedzic, P.;
Ibrahem, I.; Hammar, P.; Sun, J.; Córdova, A. Chem. Eur. J. 2009, 15, 10013-
10017; (c) Kamlar, M.; Bravo, N.; Alba, A.- N. R .; H y b e lbaue rová , S .; C ísař ová ,
I.; Veselý, J.; Moyano, A.; Rios, R. Eur. J. Org. Chem. 2010, 5464-5470; for
other utilities of FNSM, see: (d) Prakash, G. K. S.; Chacko, S.; Alconcel, S.;
Stewart, T.; Mathew, T.; Olah, G. A. Angew. Chem. Int. Ed. 2007, 46, 4933-4936;
(e) Prakash, G. K. S.; Zhao, X.; Chacko, S.; Wang, F.; Vaghoo, H.; Olah, G. A.
Beilstein J. Org. Chem. 2008, 4, 17; (f) Pan, Y.; Zhao, Y.; Ma, T.; Yang, Y.; Liu,
H.; Jiang, Z.; Tan, C.-H. Chem. Eur. J. 2010, 16, 779-782.
[17] NSM can be obtained via the oxidation of PhSCH
2
NO
2
, which can be prepared
using PhSCl and NaCH
2
NO
2
, see: (a) Barrett, A. G. M.; Dhanak, D.; Graboski, G.
G.; Taylor, S. J. Org. Synth. 1990, 68, 8-13; or using PhSCH
2
N
3
and
F
2
/H
2
O/CH
3
CN system, see: (b) Carmeli, M.; Rozen, S. J. Org. Chem. 2006, 71,
4585 –4589.
[18] Based on a known procedure, Weigl, U.; Heimberger, M.; Pierik, A. J.; Rétey, J.
Chem. Eur. J. 2003, 9, 652-660.
[19] Pioneer work on thiourea catalysis, see: (a) Sigman, M. S.; Jacobsen, E. N. J. Am.
Chem. Soc. 1998, 120, 4901-4902; (b) Schreiner, P. R.; Wittkopp, A. Org. Lett.
2002, 4, 217-220; (c) Wittkopp, A.; Schreiner, P. R. Chem. Eur. J. 2003, 9, 407-
414; (d) Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003, 125,
244

12672-12673; (e) Wang, J.; Li, H.; Yu, X.; Zu, L.; Wang, W. Org. Lett. 2005, 7,
4293-4296; (f) Vakulya, B.; Varga, S.; Csámpai, A.; Soós, T. Org. Lett. 2005, 7,
1967-1969; (g) McCooey, S. H.; Connon, S. J. Angew. Chem. Int. Ed. 2005, 44,
6367-6370; (h) Cao, C.-L.; Ye, M.-C.; Sun, X.-L.; Tang, Y. Org. Lett. 2006, 8,
2901-2904; Recent review articles on thiourea catalysis, see: (i) Schreiner, P. R.
Chem. Soc. Rev. 2003, 32, 289-296; (j) Connon, S. J. Chem. Eur. J. 2006, 12,
5418 -5427; (k) Taylor, M. S.; Jacobsen, E. N. Angew. Chem. Int. Ed. 2006, 45,
1520-1543; (l) Kotke, M.; Schreiner, P. R. (Thio)urea Organocatalysts in Pihko,
P. M. ed. Hydrogen Bonding in Organic Synthesis, Wiley-VCH Verlag GmbH,
Weinheim, 2009, pp 141-345.
[20] Significantly enhanced nucleophilicity of fluorodinitromethide in conjugate
addition was previously reported, Kaplan, L. A.; Pickard, H. B. J. Chem. Soc.,
Chem. Commun. 1969, 1500-1501.
[21] R e c e nt discussi ons on fl uorine e ff e c ts on α -fluorocarbanions, see: (a) Qian, C.-P.;
Nakai, T.; Dixon, D. A.; Smart, B. E. J. Am. Chem. Soc. 1990, 112, 4602-4604;
(b) Castejon, H. J.; Wiberg, K. B. J. Org. Chem. 1998, 63, 3937-3942; (c) Ni, C.;
Zhang, L.; Hu, J. J. Org. Chem. 2008, 73, 5699-5713; (d) Prakash, G. K. S.;
Wang, F.; Shao, N.; Mathew, T.; Rasul, G.; Haiges, R.; Stewart, T.; Olah, G. A.
Angew. Chem. Int. Ed. 2009, 48, 5358-5362; (e) Ni, C.; Hu, J. Synlett 2011, 770-
782.
245

[22] Reviews on primary amine catalysis: (a) Bartoli, G.; Melchiorre, P. Synlett 2008,
1759-1771; (b) Chen, Y.-C. Synlett 2008, 1919-1930; (c) Xu, L.-W.; Luo, J.; Lu,
Y. Chem. Commun. 2009, 1807-1821.
[23] Erkkilä, A.; Majander, I.; Pihko, P. M. Chem. Rev. 2007, 107, 5416–5470.
[24] (a) Xu, H.; Zuend, S. J.; Woll, M. G.; Tao, Y.; Jacobsen, E. N. Science 2010, 327,
986-990; (b) Knowles, R. R.; Jacobsen, E. N. Proc. Natl. Acad. Sci. USA 2010,
107, 20678-20685.
[25] Badovskaya, L. A.; Povarova, L. V. Chem. Heterocycl. Compd. 2009, 45, 1023-
1034.
[26] Bunce, R. A.; Herron, D. M.; Johnson, L. B.; Kotturi, S. V. J. Org. Chem. 2001,
66, 2822-2827.
[27] Differing from the observation described in ref. 26, 5 underwent a
demethylcarboxylation reaction under the hydrogenation conditions. Such a side
reaction was essentially evitable by shortening the reaction time to 1 h.
[28] The
1
H NMR data are consistent with those reported in the literature, Zhao, W.-J.;
Yan, M.; Huang, D.; Ji, S.-J. Tetrahedron 2005, 61, 5585-5593.
[29] The
1
H NMR data are consistent with those reported in the literature, Kobayashi,
Y.; Taguchi, T.; Morikawa, T.; Takase, T.; Takanashi, H. J. Org. Chem. 1982, 47,
3232-3236.
246

Chapter 6

Conformational Study of 9-Dehydro-9-
Trifluoromethyl Cinchona Alkaloids via
19
F NMR
Spectroscopy: Emergence of Trifluoromethyl Moiety as
a Conformational Stabilizer and a Probe

247

6.1. Introduction
Cinchona alkaloids and their derivatives are widely applicable in asymmetric
synthesis as efficient catalysts.
1
The conformations of cinchona alkaloids have been
found to play a crucial role in their catalytic activities through the formation of
energetically favorable diastereomeric complexes with substrates as transition state
structures.
2,3,4,5
Pioneered by Dijkstra, Wynberg
6,7
and Sharpless,
7
a wealth of
conformational information on cinchona alkaloids has been achieved by means of NMR
spectroscopy and molecular modeling, which identified four species as the energetically
preferred conformations (Figure 6.1). Additionally, extensive investigations were
recently performed by Baiker
8
and Zeara
9
revealing the environmental dependence of the
conformational behavior of cinchona alkaloids. In fact, the interconversion between the
Open and the Closed conformations has been thoroughly investigated by conventional
NMR techniques, particularly based on vicinal coupling constant analysis and dynamic
NMR spectroscopy. In contrast, exchange processes between the syn and the anti
conformations were exclusively accomplished by nuclear Overhauser enhancement (nOe)
spectroscopy, which, however, may lead to considerable uncertainty in the determination
of the populations of these two conformations.
10
Particularly, Sugiura and co-workers
have utilized cross-relaxations and correlation times for molecular reorientation to
achieve a relatively accurate conformational analysis of quinidine.
11
Although
sporadically used, this relaxation method remains incapable of providing the detailed
conformational profile along 
2
. Hence, an efficient and reliable method is still ardently
248

sought for the accurate determination of the populations of the syn and the anti
conformations.
Apparently, the present difficulty in the investigation of the 
2
rotation is primarily
due to the rapid interchange between the syn and the anti conformations at room
temperature, which results in the complete coalescence of the corresponding NMR
signals. Although in theory spectral decoalescence can be achieved by lowering
temperatures, the extremely low temperatures (~183 K) required in these experiments are
not applicable under many scenarios.
8a
Alternatively, we envisioned that 
2
can be
considerably restricted if H
8
is substituted by an appropriate alkyl group possessing
sufficient steric demand. As such, the direct observation of the spectra of individual
conformers arising from the 
2
rotation can be achieved under relatively high temperature
ranges.

Figure 6.1. Four energetically preferred conformations of cinchona alkaloids and their
interconversions.
249

6.2. Probe Design and Synthetic Method
Among various alkyl groups, the trifluoromethyl group was ultimately chosen to
function as a conformational stabilizer and a probe. Simply, this twofold advantage of the
CF
3
moiety relies on the bulkiness of the CF
3
moiety
13
and the applicability of highly
sensitive
19
F NMR spectroscopy.
14
Sterically, a trifluoromethyl group is significantly
larger than a methyl group, and indeed isosteric with an isopropyl or a sec-butyl group
depending on the choice of steric scale (Figure 6.2).
15
In fact, Casarini et al. have
demonstrated that the rotational barrier around the sp
2
-sp
3
Ar-COH bond in α,α-
dialkylnaphthylcarbinols is elevated to 14.9 kcal/mol when two isopropyl groups are
present in the molecules.
12
The interconversion barriers around both 
1
and 
2
are
therefore anticipated to be considerably increased because of the substitution of H
8
with
the CF
3
, which allows the conformers to possess sufficient lifetime on the NMR
timescale. In contrast, the three-dimensional structures of the minimum energy
conformations and their population distribution presumably resemble the parent
molecules.

Figure 6.2. Substitution of H
8
with the trifluoromethyl moiety.

250

Scheme 6.1. (A) Stereoselective Synthesis of Trifluoromethylated Quinidine; (B)
19
F
NMR Spectra of the Trifluoromethylated Products under Different Reaction Conditions;
(C)
19
F NMR Spectra of 1 in Mixed Solvents of DMSO-d
6
and CDCl
3
; (D)
1
H NMR
Spectra of 1 in Mixed Solvents of DMSO-d
6
and CDCl
3
(Aromatic Region).

251

This proposal is validated by the fact that the steric interactions between the
quinuclidine and the quinoline moieties are still predominant due to their considerably
larger steric encumbrance compared to that of the CF
3
group. Moreover, with the
hydroxyl and amino functionalities intact, the strong inter- and intra-molecular
interactions involving hydrogen bonding are also expected to remain relatively
unperturbed, thereby conserving the related conformational dependence upon
environmental variations. In addition to the conformational stabilizing effect, the
presence of the CF
3
moiety further makes
19
F NMR spectroscopy applicable for the
detection of the subtle conformational changes of the molecule.
To explore the aforementioned proposal, we initially converted quinine into the
corresponding ketone through the oxidation reaction described by Woodward.
16

Crystallized from Et
2
O and further identified as quinidinone by X-ray crystallographic
studies, the ketone was treated with 2.5 eq. of trifluoromethyltrimethylsilane (TMSCF
3
,
the Ruppert-Prakash reagent) in the presence of a catalytic amount of
tetrabutylammonium difluorotriphenylsilicate (TBAT) to achieve the desired
trifluoromethylated compound (Scheme 6.1-A, eq 1).
17
The reaction afforded an
inseparable mixture of two isomers (1a and 1b) in a ratio of 83:17 as determined by
1
H
and
19
F NMR spectroscopy in CDCl
3
(Scheme 2B, top). Further experiments employing a
mixture of quinidinone and quininone resulted in four isomers (1a, 1b, 1’ a, and 1’ b),
unequivocally suggesting 1a and 1b were not generated due to the epimerization of C
8
in
quinidinone (Scheme 6.1-B, bottom).
18
Moreover, instead of in the ratio of 83:17, 1a and
1b were observed with equal intensity in DMSO-d
6
as measured via both
1
H and
19
F
NMR spectroscopy. In fact, the ratios of 1a and 1b turned out to decrease by increasing
252

the proportion of DMSO-d
6
in CDCl
3
, which eventually became 50:50 after the addition
of 100 molar equivalents of DMSO-d
6
(Scheme 6.1-C and D). These remarkable
interconversion phenomena evidently confirm that the generation of 1a and 1b de facto
originates from conformational isomerism instead of stereoisomerism.
Thermodynamically, the relative populations of 1a and 1b (83:17) in CDCl
3
show that 1a
is energetically preferred by 1 kcal/mol, while in DMSO-d
6
, the population equivalence
suggests the negligible energy difference between the two isomers. As established by X-
ray crystallographic analysis, 1 has been revealed as a 9-trifluoromethylated epimer of
quinidine (Scheme 6.1-A).
6.3. Results and Discussion
Exhaustive conformational analyses of 1 were conducted via various NMR
techniques (See Section 6.5). As depicted in Scheme 6.2, the observed conformation of
1a can be rationalized as a weighted average of two conformers (1a
1
and 1a
2
) generated
by a partially unrestricted rotation around 
2
. On the other hand, the overall restriction of

2
in CDCl
3
results in the formation of two NMR-distinguishable species presenting as
kinetically persistent atropisomers, 1a
1
-1a
2
and 1b
1
, which have been identified as the
syn-Open and anti-Open conformations, respectively. Similarly, two conformers have
been detected in DMSO-d
6
via the
19
F NMR spectroscopy with equal population as well.
Detailed 2D NMR studies suggested that 1c and 1d preferentially adopt the anti-Closed
and syn-Closed conformations, respectively. Intriguingly, a 1:1 complex between 1 and
DMSO-d
6
was detected by atmospheric pressure ionization (API) mass spectrometry,
which is formed presumably through hydrogen bonding interactions.
19
253

Scheme 6.2. Interconversion of Different Conformres of 1 in CDCl
3
and in DMSO-d
6
.

To further elucidate the relationship of the two isomers, DNMR studies of 1 in
CD
2
Cl
2
(at low temperatures) and in CDCl
3
(at high temperatures) have been carried out
to provide valuable conformational information (See Section 6.5 for details). Notably,
although only line broadenings occurred in the
19
F NMR spectra with the rise in
temperature, the complete coalescence of the aromatic protons of 1 was observed in the
1
H NMR spectra in CDCl
3
at 333 K due to considerably smaller chemical shift
differences of the two conformers in the latter. Similar to the observation described by
Baiker et al.,
8a
this result apparently implies a rather restricted rotation around 
2
and
confirms the previously proposed conformational stabilizing effect of the trifluoromethyl
group. Likewise, as demonstrated by the
19
F NMR spectra in DMSO-d
6
, the two signals
of 1 were found to coalesce at 327 K with a frequency difference of 5.7 Hz. In
accordance with the original and the modified Eyring equation,
20
the rotational barriers
254

around 
2
were estimated to be 18.0 and 17.5 kcal/mol at 327 K by the respective
methods (See Section 6.5). Aside from these experimental studies, preliminary theoretical
calculations have also revealed the conformational profile of 1 in the gas phase according
to a potential energy surface (PES) as the function of the two critical torsion angles CF
3
-
C
9
-C
8
-H
9
and O-C
9
-C
4’
-C
5’
. As indicated by the PES, the rotational barriers around 
1
are
4-5 kcal/mol suggesting that the C
8
-C
9
bond undergo a rather rapid rotation on the NMR
timescale. In contrast, the interconversion barriers between the syn and the anti
conformations were found to be considerably higher (> 11 kcal/mol), which is consistent
with the observation of the partially restricted rotation 
2
(See Section 6.5 for details).
With 1 on hand, we were able to study the interconversion between the anti and the
syn conformations in various solvents via
19
F NMR spectroscopy. Importantly, compared
with the conformational studies by means of conventional NMR techniques, the present
method has exhibited remarkably improved efficacy and accuracy in the measurement of
the P
syn
and the P
anti
because of the utilization of 1D NMR at room temperature. Thanks
to the availability of
19
F NMR spectroscopy, both deuterated and non-deuterated solvents
are applicable for the conformational studies. Moreover, the identification of the syn and
the anti conformations can be also feasibly achieved by comparing the
19
F NMR spectra
of a series of solutions of 1 with different CHCl
3
concentrations. As such, we were
allowed to expediently investigate the conformational behavior of 1 in 47 different
solvents, whose dielectric constants span a range of approximately 80 units, within a day!
(See Section 6.5 for the data)
255

Figure 6.3. Relative Populations of the syn Conformations in Various Solvents.

The analysis of the syn populations in several representative solvents has shown that
the anti conformations are generally stabilized in polar solvents such as ethanol, DMSO,
and acetone (red squares, Figure 6.3). This outcome resembles the previous conclusion
that the populations of the anti conformations (corresponds to the Closed(1) and Open(4)
conformations in the previous studies) are increased with the rise of the solvent polarity.
8a

In particular, despite the unexpected high population of the syn conformers in D
2
O, these
data points are generally aligned in a curve similar to the one associated with the P
Open(3)

of cinchonidine described by Baiker et al. (the grey curve, Figure 6.3), which indicates
the pivotal role of dipole-dipole interaction in the population distribution of different
256

conformations. However, the attempts to further correlate the P
syn
with the dielectric
constants of the 47 different solvents resulted in a rather scattered plot (Figure 6.3),
which can be attributed to the influence of other non-covalent interactions. Apparently,
these specific interactions can include π-π interactions, the protonation of the
quinuclidine and quinoline nitrogens, hydrogen bonding interactions, as well as the
backpolarization of the solute caused by solvent polarization.
To further manifest the effects of specific intermolecular interactions on the
conformational behavior of 1, the relative populations of the syn conformers in a series of
aromatic solvents have been plotted versus the dielectric constants of the solvents. In fact,
essentially identical syn populations (80%~85%) were observed in simple aromatic
hydrocarbons, aromatic halides, and aromatic ethers over a dielectric constant range of 10
units. In particular, despite the fact that nitrobenzene is known as a highly polar solvent
(ε
r
= 35.60), only a small decrease in the syn population (P
syn
= 78%) was shown
indicating that the π-π interactions can significantly stabilize the syn conformations and
overwhelm the dipole-dipole interaction to a large extent. Intriguingly, the relative
populations of the syn conformers in benzyl alcohol and pyridine have been found to be
dramatically decreased. Since the polarity of solvents is not a crucial factor affecting the
syn populations in the aromatic solvents, the current observation can be associated with
the hydrogen bonding interactions of 1 with the hydroxyl moiety in benzyl alcohol.
Particularly, in comparison with other primary alcohols possessing similar dielectric
constants, benzyl alcohol is capable of stabilizing the syn conformations more efficiently,
which further confirms the aforementioned stabilizing effect arising from the π-π
interactions.
257

6.4. Conclusion
In conclusion, we have developed a unique method for studying the conformational
behavior of cinchona alkaloids by the introduction of the CF
3
moiety as a conformational
stabilizer and a probe. As effectively stabilized by the restriction of 
2
, the corresponding
atropisomers can possess sufficient lifetime on the NMR timescale; thus allowing the
feasible observation of the conformers via 1D NMR at room temperature. Because of the
feasible application of
19
F NMR spectroscopy, we have been able to investigate the
conformations of 1 in a large number of solvents revealing that the conformations of
cinchona alkaloids are also closely associated with many intermolecular interactions
beyond the dipole-dipole mechanism. Importantly, differing from the well known
conformational tool exploiting the electronic effects of the C-F bond to alter the
population distributions of conformers,
21,22
the present strategy is featured with
increasing the interconversion barriers of critical rotations through the utilization of the
steric encumbrance of the trifluoromethyl moiety. The catalytic utilities of 1 in
asymmetric syntheses are currently under investigation.
23
Detailed discussions on the
environmental dependence of the conformational behavior of 1 and the related
computational studies will be published later.

258

6.5. Experimental
6.5.1. General Information
Unless otherwise mentioned, all the chemicals were purchased from commercial
sources. Anhydrous DMSO-d
6
was purchased from the Sigma-Aldrich Inc. without
further purification. Other deuterated solvents were purchased from the Cambridge
Isotope Laboratories, Inc. The non-deuterated solvents for the NMR experiments were
purchased from commercial sources and used as received. The DriSolv
®
solvents were
purchased from EMD
TM
and used without further purification. Silica gel chromatography
was performed to isolate the products using 60-200 mesh silica gel. One dimensional
1
H,
13
C,
19
F and Dynamic NMR spectra were recorded on Varian Mercury 400 MHz NMR
Spectrometer or Varian VNMRS-500 NMR Spectrometer. The temperature calibration
was carried by measuring the chemical-shift separation between the OH resonances and
CH resonances in methanol (at low temperature) and ethylene glycol (at high
temperature) to give an accuracy at ±0.1 K. COSY and NOESY spectra were performed
on Varian 400-MR NMR Spectrometer or Varian VNMRS-500 NMR Spectrometer.
1
H-
19
F HOESY spectra were recorded on Bruker AMX-500 NMR Spectrometer.
1
H NMR
chemical shifts were determined relative to CDCl
3
and DMSO-d
6
as the internal
standards at δ 7.26 ppm and 2.50 ppm, respectively.
13
C NMR shifts were determined
relative to CDCl
3
and DMSO-d
6
as the internal standards at δ 77.16 ppm and 39.52 ppm,
respectively.
19
F NMR chemical shifts were determined relative to internal standard
CFCl
3
at δ 0.00 ppm. Mass spectra were recorded on a high resolution mass spectrometer
in the ESI mode.
259

6.5.2. Preparation of epiCF
3
QD (1)

Quinidinone was prepared according to the known procedures described by
Woodward et al.
16
and Skarżewski et al.
24
Quinidinone (3.74 g, 11.6 mmol) and TMSCF
3

(4.14 g, 29.1 mmol, 2.5 eq.) were quickly dissolved in anhydrous THF (72 mL) in a
Schlenk flask under argon atmosphere. Tetrabutylammonium difluorotriphenylsilicate
(1.57 g, 2.9 mmol, 0.25 eq.) was added to above mentioned solution within 2 min at 0 ºC.
The ice bath was removed thereafter, and the reaction mixture was warmed to room
temperature and the mixture was stirred for 2h before evaporating the volatile matters.
The resulting crude product was purified by column chromatography with Et
2
O-
Et
2
O/MeOH (98:2) as the eluent affording the desired product as a yellowish amorphous
solid (3.24 g, 71%).

6.5.3. Characterization of Cinchona Alkaloid Derivatives and epiCF
3
QD
Atom numbering of cinchona alkaloids and epiCF
3
QD (1)

260

General procedure for NMR experiments
All the NMR spectroscopic studies were performed using the 0.1 M solutions of 1,
and the possible dimerization of the cinchona alkaloid can been substantially suppressed
at this concentration.
6,25, 26

Characterization of 1a

(in CDCl
3
)

1
H NMR (400 MHz, CDCl
3
, 293K) δ 1.65-1.71 (m, 2H), 1.77 (m, 1H), 1.94 (m,
pseudo s, 1H), 2.19-2.25 (m, 1H), 2.26-2.33 (m, 1H), 2.77-3.00 (m, 2H), 2.89-3.07 (m,
2H), 3.47 (m, pseudo t, J = 10.2 Hz, 1H), 5.07-5.13 (m, 2H), 5.92 (ddd, J = 17.3, 10.6, 7.1
Hz, 1H), 7.05 (br s, 1H), 7.33 (d, J = 4.8 Hz, 1H), 7.36 (dd, J = 9.2, 2.8 Hz, 1H), 8.00 (d,
J = 9.2 Hz, 1H), 8.54 (d, J = 2.8 Hz, 1H), 8.69 (d, J = 4.8 Hz, 1H).
13
C NMR (101 MHz,
CDCl
3
, 293 K) δ 24.0, 26.0, 29.3, 39.4, 48.9 (q, J = 3.3 Hz), 51.2, 55.5, 64.5, 79.8 (q, J =
27.5 Hz), 105.5, 115.6, 120.1, 122.0, 125.8 (q, J = 288.2 Hz), 128.1, 131.6, 139.0, 143.5,
146.0, 146.3, 157.4.
19
F NMR (376 MHz, CDCl
3
, 293K) δ -70.64 (s, 3F). HRMS (ESI)
Exact mass calculated for C
21
H
24
F
3
N
2
O
2
[M+H
+
] 393.1784; Found 393.1788.
261

Characterization of 1c and 1d (in DMSO-d
6
)
Due to the high complexity of the spectra of 1 in DMSO, several
1
H NMR resonances
are indicated by the individual chemical shifts of each multiplet in order to differentiate
resonances of different protons (H
1
, H
3
, H
4
in 1c; H
3
, H
4
in 1d). For the severely
overlapped signals such as H
10
, the chemical shift ranges of the signals are given based
on their COSY and HSQC spectra. The
13
C NMR signals of the critical carbon atoms are
assigned, and are indicated in the parentheses.
6.06-6.16 (141.23)
HO
CF
3
N
HO CF
3
N
N
H
3
CO
6.01-6.12 (140.75)
2.02 (39.33,partially
overlapwithDMSO)
2.10 (39.28, partially
overlapwith DMSO)
1.75 (28.30)
1.72 (28.30)
N
OCH3
7.29
7.26
H
H
3.13(49.38)
2.47-2.55(overlaps
with H10in1c)
8.63 (106.76)
7.379,7.386,7.402,
7.409 (120.63)
7.915,7.938 (131.03)
8.67(146.45)
7.44-7.48 (120.83,
overlapswith C8 in1c)
3.53 (59.42)
H
H
1.48-1.56(21.64)
2.23-2.32
1.60-1.70 (25.52)
H H
H H
2.67-2.76(49.82)
2.37-2.46
1.40-1.49
1d
H H
H H
H
H
H
H
7.392, 7.398,7.414,
7.421 (120.14)
7.949,7.972 (120.83,
overlapswithC3 in 1d)
7.428 br (105.36)
3.89 (55.52)
3.86 (55.09)
4.12 (56.86)
8.75-8.77(147.48)
7.952,7.964 (131.54)
1.56-1.64 (21.68)
2.19-2.26(48.45)
2.74-2.79
1.36-1.46 1.68-1.77 (25.97)
2.61-2.69(49.36)
2.27-2.37
1c
2.48-2.56 (overlaps
with H19in 1d)

1
H NMR (400 MHz, DMSO-d
6
, 293K) δ 1.36-1.46 (m, 1H), 1.40-1.49 (m, 1H), 1.48-
1.56 (m, 1H), 1.56-1.64 (m, 1H), 1.60-1.70 (m, 1H), 1.68-1.77 (m, 1H), 1.72 (m, 1H),
1.75 (m, 1H), 2.02 (pseudo q, J = 8.5 Hz, 1H), 2.10 (pseudo q, J = 8.4 Hz, 1H), 2.19-2.26
(m, 1H), 2.23-2.32 (m, 1H), 2.27-2.32 (m, 1H), 2.37-2.46 (m, 1H), 2.47-2.55 (m, 1H),
2.48-2.56 (m, 1H), 2.61-2.69 (m, 1H), 2.67-2.76(m, 1H), 2.74-2.79 (m, 1H), 3.13 (dd, J =
12.8, 8.6 Hz, 1H), 3.53 (pseudo t, J = 9.3 Hz, 1H), 3.86 (s, 3H), 3.89 (s, 3H), 4.12
(pseudo t, J = 8.8 Hz, 1H), 4.97-5.01 (m, 4H), 6.02-6.15 (m, 2H), 7.26 (s, 1H), 7.29 (s,
1H), 7.39 (dd, J = 9.2, 2.9 Hz, 1H), 7.39-7.42 (m, 1H), 7.43 (br, 1H), 7.46 (d, J = 4.9 Hz,
1H), 7.92-7.94 (d, J = 9.2 Hz, 1H), 7.95-7.96 (d, J =4.9 Hz, 1H), 7.95-7.97 (d, J = 8.9 Hz,
262

1H), 8.63 (d, J = 2.9 Hz, 1H), 8.67 (d, J = 4.9 Hz, 1H), 8.76 (d, J = 4.9 Hz, 1H).
13
C NMR
(101 MHz, DMSO-d
6
, 293 K) δ 21.64, 21.68, 25.55, 25.97, 28.30 (2C), 39.28, 39.33,
48.45, 49.36, 49.38, 49.82, 55.09, 55.52, 56.86, 59.42, 81.45 (q, J = 26.7 Hz, 1C), 83.82
(q, J = 24.6 Hz, 1C), 105.33(q, J = 4.7 Hz, 1C), 106.76, 114.32, 114.40, 120.14, 120.63,
120.83 (2C), 125.67 (q, J = 290.1 Hz, 1C), 125.77 (q, J = 291.2 Hz, 1C), 127.38, 129.08,
131.03, 131.54, 140.75, 141.23, 141.96, 144.40, 144.42, 145.29, 146.45, 147.48, 155.97,
156.49.
19
F NMR (376 MHz, DMSO-d
6
, 293K) δ -71.70 (s, 3F), -71.82 (s, 3F).
Characterization of quinidinone
1
H NMR (400 MHz, DMSO-d
6
, 293K) δ 1.71 – 1.43 (m, 4H), 2.36 – 2.12 (m, 4H),
1.77-1.81 (m, 1H), 2.80 – 2.62 (m, 3H), 3.05 – 2.95 (m, 1H), 4.42 (pseudo t, J = 8.8 Hz,
1H), 4.98-5.08 (m, 2H), 5.93 (ddd, J = 17.3, 10.4, 7.1 Hz, 1H), 7.47 – 7.44 (m, 2H), 7.84
(d, J = 4.5 Hz, 1H), 8.01 (dd, J = 8.8, 0.8 Hz, 1H), 8.85 (d, J = 4.4 Hz, 1H).
13
C NMR
(101 MHz, DMSO-d
6
, 293K) δ17.41, 21.07, 26.41, 27.13, 47.87, 49.38, 55.39, 62.37,
102.78, 114.69, 120.32, 121.92, 124.96, 131.27, 140.72, 141.81, 144.55, 147.39, 158.25,
204.29.
263

The NMR spectra of 1 in a series of CDCl
3
-DMSO-d
6
systems

264

Determination of the conformations of 1 in CDCl
3

The conformational analysis of 1 in CDCl
3
was investigated by various NMR
techniques. The signal assignments were assisted by correlation spectroscopy (COSY)
and heteronuclear single quantum coherence (HSQC). The conformation of 1a was
derived from the critical interproton and proton-fluorine interactions, which were
deciphered from
1
H-
1
H nuclear Overhauser effect spectroscopy (NOESY) and
1
H{
19
F}
heteronuclear Overhauser effect spectroscopy (HOESY), respectively. The HOESY
spectrum of 1a shows the strong interactions of H
1
-CF
3
and H
5
-CF
3
with essentially the
same intensity, indicating the CF
3
-C
9
bond is roughly perpendicular to the quinoline
system. H
18-
CF
3
and H
10
-CF
3
interactions have also been observed with similar strengths,
which can be interpreted as the CF
3
group pointing towards the H
18
and H
10
protons. The
cross-peaks corresponding to the H
9
-CF
3
and H
11
-CF
3
interactions were not found in the
265

HOESY spectrum; thus the approximate trans-orientation of the CF
3
-C
9
bond relative to
the C
8
-H
9
bond can be confirmed.
In the NOESY spectrum, the strong interactions of H
1
-H
11
and H
1
-H
9
have been
shown with approximately the same intensity representing a conformation in which H
9

and H
11
are spatially close to H
1
at similar distances. In comparison, slightly weaker
interaction between H
5
and H
9
was observed, which evidently indicates the syn-
conformation. Notably, although the H
5
-H
9
distance is estimated to be considerably
longer than the H
1
-H
9
distance in a typical syn-Open conformation, the cross-peaks of H
5
-
H
9
and H
1
-H
9
were found to display similar volumes. Hence, the observed conformation
of 1a can be rationalized as a weighted average of two or more conformers generated by
the partial free rotation around τ
2
. In particular, the negative nOe effects in the
1
H-
1
H
NOESY spectrum (the blue cross peaks in the aromatic region) appear to correlate with
the signals arising from the minor and the major conformations, which can be attributed
the exchange processes between these species. We therefore were able to conclude that
there are two NMR-distinguishable species that exist in CDCl
3
at room temperature as
kinetically persistent conformers, 1a
1
-1a
2
and 1b
1
.
Determination of the conformations of 1 in DMSO-d
6
Strong nOe Weak nOe
H10
H
1c
O CF3
N H9
N
OCH3
H5
H1
H
O CF3
N H9
N
OCH3
H5
H
10
1
H-
19
F nOe
1d
H
O
CF3
N H9
N
H1
H5
H3CO
H
O CF3
N H9
N
H1
H5
H3CO
H18
1
H-
1
H nOe
1
H-
1
H nOe
1
H-
19
F nOe

Similar to the aforementioned observations, two conformers have been found by
19
F
NMR spectroscopy in DMSO-d
6
with equal population. Detailed 2D NMR studies were
266

performed at room temperature to further characterize the two conformers. As depicted,
the strong H
1
-OH and H
5
-CF
3
interactions in 1c have been observed in the NOESY and
the HOESY spectra, respectively. In contrast, the interaction between H
5
and the OH
group was not detectable, which unequivocally confirms the anti orientation of the O-C
9
-
C
4’
-C
5’
system. Furthermore, consistent with the nOe correlation between OH and H
10
in
1c, an intensive cross-peak corresponding to the CF
3
-H
9
interaction has also been
detected in the HOESY spectrum, and this suggests the Closed conformation.
On the other hand, the syn conformation adopted by 1d was validated by the
observation of the cross peaks due to the H
5
-OH, H
5
-H
18
, H
1
-H
9
and CF
3
-H
1
interactions.
In comparison with the intensive CF
3
-H
1
interaction, the cross-peak corresponding to the
CF
3
-H
5
interaction was found to be rather weak, which further validates the proposed syn
structure. Similar to 1c, the strong nOe signal between OH and H
10
has been found to
indicate the Closed conformation.
267

268

API Mass spectrometry data of 1 in 0.1 M DMSO-d
6
solution

The atmospheric pressure ionization (API) mass spectrometry of the DMSO-d
6

solution of 1 has clearly shown a complex of 1 and DMSO-d
6
in a 1:1 ratio suggesting
remarkably strong intermolecular interactions between the two species. Under similar
conditions, the aggregation between 1 and solvent molecules in 0.1 M CD
3
OD solution
was not observed indicating a relatively weak hydrogen bonding interaction.

269

DNMR Spectra of 1 in CDCl
3
(293K-333K) and CD
2
Cl
2
(213K-297K)

270

DNMR Spectra of 1 in DMSO-d
6
(303K-343K)

271

Concentration dependence of the NMR spectra of 1
As illustrated, the relative populations of the two conformers have been found to be
independent of the concentrations of the solutions of 1, implying that the aggregation of 1
in different solvents is negligible even at a concentration of 0.1 M. Notably, the line
shapes of 1 in CDCl
3
appear to be rather concentration-dependent. The line broadening of
1a at low concentrations can be attributed to the presence of the trace amounts of
moisture and HCl in CDCl
3
, which protonate the bridge-head nitrogen of 1 and display a
profound influence thereof.

272

Validation of the equilibration of 1a and 1b in CDCl
3
at room temperature.

Since a complete coalescence of the CF
3
signals of 1a and 1b has not been observed
in CDCl
3
in temperature dependent
19
F NMR, a further experiment was performed to
confirm that in the chloroform solution, 1a and 1b exists as an equilibration mixture at
room temperature. As shown by NMR experiments, even at high concentrations (>0.1
M), 1a and 1b can still reach equilibrium rapidly with a ratio of 1:1 in DMSO-d
6
at room
temperature. Hence, a quick addition of a large amount of chloroform into the
aforementioned solution (0.25M) is anticipated to “freeze” the two conformations, 1a and
1b, so that no thermodynamic equilibrium is observed in the mixed solvents. As such 1a
and 1b are supposed to be detected in a ratio of approximately 50:50. To the contrary, the
experiment in fact led to the syn and the anti conformations in a ratio of 83:17, which
unequivocally confirms the equilibrium between 1a and 1b.

273

Preliminary computational studies of the potential energy surface 1.

The potential energy surface (PES) of 1 was computed at the B3LYP/6-31G(d) level
using the Gaussian 03 program package
27
as a function of the two characteristic rotations,
τ
1
and τ
2
. The dihedral angles of these two rotations were systematically varied from 0° to
360° by an increment of 10°. The formed conformations were allowed to calculate up to
five optimization steps for each constrained dihedral angles, and this computational
method was previously validated for the estimation of the energetic and geometric
properties of conformations with satisfactory accuracy.
28
As such, the conformational
profile of 1 in the gas phase was permitted to plot in a 36×36 PES with 1296 geometry
optimizations. The identified local minima have been further fully optimized at the HF 6-
311+G(dp)//B3LYP/6-311+G(2d,p) level, which have shown a good agreement with both
the PES and the experimental outcomes (will be published separately).
274

Relative populations of the syn-conformations in various solvents
The experiments were generally performed using solutions of 1 at concentrations of
ca. 0.05 M. Saturated solutions were used for the solvents in which the solubility of 1 is
essentially low.

Solvent ε
r
P
syn
(%) Solvent ε
r
P
syn
(%)
pentane 1.84 86 1-PrOH 20.80 52
C
6
D
6
2.27 80 EtOH-d
6
25.30 54
p-xylene 2.27 82 MeOH-d
4
33.00 58
toluene-d
8
2.28 82 HOC
2
H
4
OH 40.40 65
m-xylene 2.36 82 D
2
O 80.10 71
PhCH
2
OCH
2
Ph 3.82 84 CD
3
CN 36.64 55
PhOEt 4.22 83 DMF-d
7
38.25 55
anisole 4.30 81 DMSO-d
6
47.24 50
m-dimethoxylbenzene 5.36 81 acetone-d
6
21.01 55
PhCl 5.69 85 THF-d
8
7.52 65
o-ClC
6
H
4
Cl-d
4
10.12 84 CH
3
OC
2
H
4
OCH
3
7.30 62
PhCH
2
OH 11.92 59 Et
2
O 4.27 64
PhNO
2
-d
5
35.60 78 n-Bu
2
O 3.08 72
pyridine-d
5
13.26 53 1,4-dioxane 2.22 60
4-methyl-4-heptanol 2.92 63 t-BuOMe - 61
2-octanol 8.13 52 ClC
2
D
4
Cl 10.42 81
1-octanol 10.30 54 CD
2
Cl
2
8.93 83
1-heptanol 10.75 55 CDCl
3
4.80 83
t-BuOH 12.47 51 CCl
4
2.24 82
1-pentanol 15.13 54 ethyl acetate 6.08 61
sec-BuOH 17.26 51 CD
3
NO
2
37.27 82
n-BuOH 17.84 55 EtNO
2
29.11 78
Iso-BuOH 17.93 52 1-PrNO
2
24.70 79
i-PrOH-d
8
20.18 50

275

19
F NMR Spectra of 1 in ethers

276

NMR Spectra of 1 in CDCl
3
1
H NMR

13
C NMR

277

19
F NMR

1
H-
1
H COSY

278

1
H-
13
C HSQC

1
H-
1
H NOESY (Negative signals are omitted for clarity.)

279

6.5.3.18. NMR Spectra of 1 in DMSO-d
6
1
H NMR

13
C NMR

280

19
F NMR

1
H-
1
H COSY (1)

281

1
H-
1
H COSY (2)

1
H-
1
H COSY (3)

282

1
H-
1
H COSY (4)

1
H-
13
C HSQC (1)

283

1
H-
13
C HSQC (2)

1
H-
13
C HSQC (3)

284

1
H-
13
C HSQC (4)

1
H-
1
H NOESY (1) (Negative signals are omitted for clarity.)

285

1
H-
1
H NOESY (2) (Negative signals are omitted for clarity.)

1
H-
1
H NOESY (3) (Negative signals are omitted for clarity.)

286

1
H-
1
H NOESY (4) (Negative signals are omitted for clarity.)

6.5.3.19. NMR Spectra of quinidinone (DMSO-d
6
)
1
H NMR

287

13
C NMR

6.5.3.20.
1
H NMR Spectra of quinidinone and quininone (DMSO-d
6
)

288

6.5.3.21.
1
H NMR Spectra of epiCF
3
QD and epiCF
3
QN (CDCl
3
)

289

X-Ray crystal structure of quinidinone (crystallized from ether)

Crystal data and structure refinement for C
20
H
22
N
2
O
2
.
Empirical formula C
20
H
22
N
2
O
2

Formula weight 322.40
Temperature 143(2) K
Wavelength 0.71073 Å
Crystal system Monoclinic
Space group P2(1)
Unit cell dimensions a = 8.293(2) Å α = 90°.
b = 8.115(2) Å β = 95.021(4)°.
c = 12.531(3) Å γ = 90°.
Volume 840.1(4) Å
3

Z 2
Density (calculated) 1.274 Mg/m
3

Absorption coefficient 0.083 mm
-1

290

F(000) 344
Crystal size 0.26 x 0.15 x 0.06 mm
3

Theta range for data collection 2.47 to 27.44°.
Index ranges -10<=h<=10, -10<=k<=10, -15<=l<=14
Reflections collected 7135
Independent reflections 3621 [R(int) = 0.0408]
Completeness to theta = 27.44° 98.6 %
Absorption correction semi-empirical
Transmission factors min/max: 0.746
Refinement method Full-matrix least-squares on F
2

Data / restraints / parameters 3621 / 1 / 218
Goodness-of-fit on F
2
1.021
Final R indices [I>2sigma(I)] R1 = 0.0638, wR2 = 0.1257
R indices (all data) R1 = 0.1113, wR2 = 0.1470
Absolute structure parameter -1(2)
Largest diff. peak and hole 0.322 and -0.214 e.Å
-3

291

X-Ray crystal structure of epiCF
3
QD and epiCF
3
QN

Crystal data and structure refinement for C
21
H
23
F
3
N
2
O
2

Empirical formula C
21
H
23
F
3
N
2
O
2

Formula weight 392.41
Temperature 153(2) K
Wavelength 0.71073 Å
Crystal system Monoclinic
Space group P2(1)/c
Unit cell dimensions a = 12.440(10) Å α = 90°.
b = 12.594(10) Å β = 100.954(14)°.
c = 12.697(10) Å γ = 90°.
Volume 1953(3) Å
3

Z 4
Density (calculated) 1.334 Mg/m
3

Absorption coefficient 0.105 mm
-1

292

F(000) 824
Crystal size 0.19 x 0.14 x 0.08 mm
3

Theta range for data collection 1.62 to 28.09°.
Index ranges -16<=h<=16, -16<=k<=16, -15<=l<=16
Reflections collected 16803
Independent reflections 13747 [R(int) = 0.0563]
Completeness to theta = 28.09° 89.5 %
Absorption correction Multi-scan
Transmission factors min/max: 0.743
Refinement method Full-matrix least-squares on F
2

Data / restraints / parameters 13747 / 3 / 1017
Goodness-of-fit on F
2
0.705
Final R indices [I>2sigma(I)] R1 = 0.0513, wR2 = 0.0878
R indices (all data) R1 = 0.1818, wR2 = 0.1196
Absolute structure parameter -1.4(9)
Largest diff. peak and hole 0.218 and -0.143 e.Å
-3

293

6.6. References
[1] Song, C. E. Ed. Cinchona Alkaloids in Synthesis and Catalysis; Willey-VCH:
Weinheim, 2009.
[2] Vayner, G.; Houk, K. N.; Sun, Y.-K. J. Am. Chem. Soc. 2004, 126, 199-203, and
references therein.
[3] (a) Corey, E. J.; Noe, M. C. J. Am. Chem. Soc. 1993, 115, 12579-12580; (b)
Corey, E. J.; Noe, M. C.; Sarshar, S. Tetrahedron Lett. 1994, 35, 2861-2864; (c)
Corey, E. J.; Noe, M. C. J. Am. Chem. Soc. 1996, 118, 319-329.
[4] Li, H.; Liu, X.; Wu, F.; Tang, L.; Deng, L. Proc. Natl. Acad. Sci. USA 2010, 107,
20625-20629.
[5] For a pioneering discussion on conformations of cinchona alkaloids see, Prelog,
V.; Wilhelm, M. Helv. Chim. Acta 1954, 37, 1634-1660.
[6] (a) Hiemstra, H.; Wynberg, H. J. Am. Chem. Soc. 1981, 103, 417-430; (b)
Dijkstra, G. D. H.; Kellogg, R. M.; Wynburg, H. J. Org. Chem. 1990, 55, 6121-
6131.
[7] Dijkstra, G. D. H.; Kellogg, R. M.; Wynberg, H.; Svendsen, J. S.; Marko, I.;
Sharpless, K. B. J. Am. Chem. Soc. 1989, 111, 8069-8076.
[8] (a) Bürgi, T.; Baiker, A. J. Am. Chem. Soc. 1998, 120, 12920-12926; (b) Ferri, D.;
Bürgi, T.; Baiker, A. J. Chem. Soc., Perkin Trans. 2 1999, 1305-1311; (c)
Urakawa, A.; Meier, D. M.; Rüegger, H.; Baiker, A. J. Phys. Chem. A 2008, 112,
7250-7255.
294

[9] Olsen, R. A.; Borchardt, D.; Mink, L.; Agarwal, A.; Mueller, L. J.; Zaera, F., J.
Am. Chem. Soc. 2006, 128, 15594-15595.
[10] Neuhaus, D.; Williamson, M. P. The Nuclear Overhauser Effect in Structural and
Conformational Analysis, 2nd ed.; John Wiley & Sons, 2000, 321-322 and 391-
398.
[11] Sai, T.; Takao, N.; Sugiura, M. Magn. Reson. Chem. 1992, 30, 1041-1046.
[12] Casarini, D.; Lunazzi, L.; Mazzanti, A. J. Org. Chem. 1997, 62, 3315-3323.
[13] Schlosser, M.; Michel, D. Tetrahedron 1996, 52, 99-108.
[14] Dolbier, Jr. W. R. Guide to Fluorine NMR for Organic Chemists; John Wiley and
Sons, 2009, 4-5.
[15] (a) For comparison using the Taft’s steric substituent constants E
s
, Uneyama, K.
Organofluorine Chemistry; Blackwell Publish, 2006, 82-83. (b) For comparison
using the steric parameters  introduced by Charton, Charton, M. J. Am. Chem.
Soc. 1975, 97, 1552-1556.
[16] Woodward, R. B.; Wendler, N. L.; Brutschy, F. J. J. Am. Chem. Soc. 1945, 67,
1425-1429. Although the oxidized product of quinine was originally assigned as
quininone, X-ray diffraction has identified the compound as quinidinone.
[17] (a) Prakash, G. K. S.; Krishnamurti, R.; Olah, G. A. J. Am. Chem. Soc. 1989,
111, 393-395; (b) Krishnamurti, R.; Bellew, D. R.; Prakash, G. K. S. J. Org.
Chem. 1991, 56, 984-989; (c) Prakash, G. K. S.; Yudin, A. K. Chem. Rev. 1997,
97, 757-786; (d) Prakash, G. K. S.; Hu, J. Acc. Chem. Res. 2007, 40, 921-930.
295

[18]
1
H NMR spectroscopic studies have suggested that the epimerization of
quinidinone was substantially negligible in THF or DMSO at room temperature
(less than 5% of quinidinone converted into quininone within 2 hours).
[19] For selected references on hydrogen bonding interactions between DMSO and
alcohols: (a) Krueger, P. J.; Mettee, H. D. Can. J. Chem. 1964, 42, 288-293; (b)
Murakami, Y.; Sunamoto, J. Chem. Soc., Perkin Trans. 2 1973, 1231-1234.
[20] (a) Glasstone, S.; Laidler, K. J.; Eyring, H. The Theory of Rate Processes: The
Kinetics of Chemical Reactions, Viscosity, Diffusion and Electrochemical
Phenomena, McGraw-Hill, 1941, chap. 1. (b) Holík, M.; Mannschreck, A. Org.
Magn. Reson. 1979, 12, 28-33.
[21] (a) For a recently review article on the conformational studies utilizing the C-F
bond see, Hunter, L. Beilstein J. Org. Chem. 2010, 6, 38; (b) For an excellent
review on the steric and the electronic effects of the C-F bond see, O'Hagan, D.
Chem. Soc. Rev. 2008, 37, 308-319.
[22] For recent important achievements utilizing the C-F bond as a conformational
tool, (a) Briggs, C. R. S.; O’Hagan, D.; Howard, J. A. K.; Yufit, D. S.
J. Fluorine Chem. 2003, 119, 9-13; (b) Hunter, L.; Slawin, A. M. Z.; Kirsch, P.;
O’Hagan, D. Angew. Chem., Int. Ed. 2007, 46, 7887–7890; (c) Hunter, L.;
Kirsch, P.; Slawin, A. M. Z.; O’Hagan, D. Angew. Chem., Int. Ed. 2009, 48,
5457-5460; (d) Sparr, C.; Schweizer, W. B.; Senn, H. M.; Gilmour, R.
Angew. Chem., Int. Ed. 2009, 48, 3065-3068; (e) Sparr, C.; Gilmour, R.
Angew. Chem., Int. Ed. 2010, 49, 6520-6523; (f) Bucher, C.; Mondelli, C.; Baiker,
A. ; Gilmour, R. J. Mol. Catal. A: Chem. 2010, 327, 87-91.
296

[23] Preliminary results have shown that 1 can catalyze the methanolysis of meso exo-
3,6-epoxy-1,2,3,6-tetrahydrophthalic anhydride in methanol to afford the
corresponding product with 20% enantiomeric excess.
[24] Zielińska-Błajet, M.; Kucharska, M.; Skarżewski, J. Synthesis 2006, 1176.
[25] Williams, T.; Pitcher, R. G.; Bommer, P.; Gutzwiller, J.; Uskoković, M. J. Am.
Chem. Soc. 1969, 91, 1871.
[26] Uccello-Barretta, G.; Bari, L. D.; Salvadori, P. Magn. Reson. Chem. 1992, 30,
1054.
[27] Frisch, M. J.; et al., Gaussian 03, revision C.02; Gaussian, Inc.: Wallingford, CT,
2004.
[28] Hamza, A.; Schubert, G.; Soós, T.; Papai, I. J. Am. Chem. Soc. 2006, 128, 13151.

297

Chapter 7
On the Nature of C-H
…
F-C Interactions in
Hindered CF
3
-C(sp
3
) Bond Rotations

298

7.1 Introduction
Hindered rotations about single bonds
1
are of immense scientific significance due to
their applications in the investigation of intramolecular interactions,
2
in asymmetric
synthesis and catalysis,
3
as well as in many other fields.
4
Although slow rotations of
many bulky tetrahedral moieties are frequently reported,
5
restricted F
3
C-C(sp
3
) single
bond rotations have only been sporadically documented.
6,7,8
As they are generated via
strong non-covalent interactions between the CF
3
group and its surrounding atoms (X),
hindered CF
3
rotations offer ideal regimes for investigating various C-F
…
X interactions.
In particular, C-F
…
H-N/O hydrogen bondings have received much attention in the fields
of physical organic and biological chemistry, whereas prevalence and energetic
importance of C-F
…
H-C interactions are frequently debated.
9
To address these problems,
we have investigated CF
3
-C(sp
3
) rotations in O-alkyl-9-dehydro-9-trifluoromethyl-9-
epiquinidine scaffolds. Extremely short C-F
...
H-C distances have been observed both in
solution and in the solid state, and provide insight into the nature of C-H
…
F-C
interactions.
7.2 Results and Discussion
9-Dehydro-9-trifluoromethyl-9-epiquinidine (1) was recently synthesized in our
laboratory to enable the conformational study of cinchona alkaloids in various solvents.
10

The C
9
-C
4’
bond was found to possess unusual restriction leading to slow exchange
between the syn- and the anti-conformers, which clearly indicates a considerable steric
encumbrance around the C
9
atom. Interestingly, ether 2a, prepared through the
299

methylation of the hydroxyl group in 1, demonstrates an exceptionally broad signal in
19
F
NMR spectrum at 298 K (Entry 1, Table 7.1). Upon lowering the temperature, the signal
broadens further and then appears as three individual sharp pseudo triplets, indicating a
gradual decrease in rotational rates. At 223 K, a clear first order AEM-type spin system
exhibits
2
J
F-F
coupling constants of ca. 115 Hz and reveals the freezing of the rotation
about the CF
3
-C
9
bond on the NMR time scale. Furthermore, hindered CF
3
rotations were
also observed when a number of alkyl groups (R) possessing various steric demands were
incorporated into 1 (2b-2e), (Entries 2-5, Table 7.1). The
19
F NMR spectra of 2c-2e
display partially decoalesced resonances even at 298 K, showing high barrier restricted
rotations about the CF
3
-C
9
bonds.
Table 7.1. Synthesis of O-alkyl 9-dehydro-9-trifluoromethyl-9- epiquinidine compounds,
their
19
F NMR spectra and activation parameters derived from Eyring plots.

300

It has been shown that cinchona alkaloid derivatives can adopt various
conformations under different conditions.
11
To identify the conformations responsible for
the restricted CF
3
rotations, exhaustive experimental and computational studies were
performed. Based on nuclear Overhauser enhancement spectroscopic studies (NOESY),
2a was found to preferentially adopt a syn-closed conformation (Figure 7.1-A), (See
Section 7.4). In addition, through-space couplings were observed between the CF
3
group
and the OCH
3
group (
5
J
F-C(H3)
= 1.9 Hz;
4
J
F-(C)H3
= 1.6 Hz), indicating an interaction
between these two functionalities.
12
A close contact between the CF
3
group and the C
3’
-
H
1
substructure was also evident by the corresponding scalar couplings (
5
J
F-H1
= 1.6 Hz;
4
J
F-C3'
= 3.9 Hz), further validating the syn-closed structure.
Our DFT calculations indicate the syn-closed conformation of 2a to be 1.9 kcal/mol
lower in energy than the anti-closed conformation in chloroform,
13
corresponding to a
population distribution of 94:6 (syn-closed:anti-closed), consistent with the population
ratio observed in the
19
F NMR spectrum (ca. 95:5).
14
The accuracy of the B3LYP method
is expected to be ca. ±2 kcal/mol in this case. Therefore, the good agreement is in part
fortuitous. Several short H/C-F contacts in the syn-closed conformation are responsible
for the observed through-space H-F and C-F couplings (Figure 7.1-B). The computed
individual chemical shifts of the fluorine nuclei in 3 are in good agreement with the NMR
spectroscopic study (Figure 7.1-C). We also performed a potential energy surface (PES)
scan for the CF
3
rotations in the syn-closed-2a and the anti-closed-2a conformers with
implicit consideration of solvent CHCl
3
-solvation. The CF
3
rotational barriers in the syn-
closed and the anti-closed conformations were calculated to be 12.1 kcal/mol and 6.8
301

kcal/mol, respectively. These two conformations likely correspond to the broad and the
sharp peaks observed in the
19
F NMR spectrum (See Section 7.4).

Figure 7.1. A. Conformational analysis of 2a based on NMR spectroscopic studies; B.
Optimized conformation of 2a at the B3LYP/6-31+G(d,p) level in the gas phase (the
OMe group on the quinoline ring is omitted for clarity.); C. Calculated
19
F NMR
chemical shifts of 3 and experimental
19
F NMR chemical shifts of 2.

The preference for the syn-closed conformation was also confirmed by the X-ray
crystal structure of 2c (Figure 7.2-A). The interatomic distances between F atoms and
majority of the surrounding protons were within the sum of van der Waals radii (ca. 2.5
Å) (Figure 7.2-B).
9d
In particular, a short C-H
…
F-C distance of 2.26 Å was found
302

between F
1
and H
1
(corresponding to the computed distance of 2.19 Å in 2a), which is
among the shortest C-H
...
F-C contacts ever reported in the solid state.
9f,9i

Figure 7.2. A. X-ray crystal structure of 2c; B. Short proton-fluorine contacts as
indicated by the crystal structure of 2c (as the average values measured in both molecules
in the unit cell).

To make a quantitative assessment of the rotational barriers in 2a-2e, dynamic NMR
(DNMR) experiments were performed (See Section 7.4). Utilizing Eyring plots,
activation enthalpies and entropies of the rotations of 2a-2e were determined to show first
order relationships. The enthalpy barriers (ΔH
‡
) of the CF
3
rotations were found to
increase as the substituent was altered from a methyl group to an allyl group (ca. 9.0
kcal/mol versus ca. 10.1 kcal/mol). However, no significant impact on the activation
enthalpies was found by further increasing the bulkiness of the substituents (R)
(2a<2b≈2c≈2d≈2e, Table 7.1). Compared with other substituents possessing lower
symmetries, the CH
3
group in 2a can undergo a correlated rotation with the CF
3
rotation,
303

thereby releasing more steric strain (ΔH
‡
) in the transition state (TS) than other
substituents. On the other hand, as shown by conformational studies, CF
3
…
R-O
interactions in 2b-2e only occur between the CF
3
group and the intervening methylene
group in R. Therefore, the increase in the bulkiness of R does not significantly increase
the steric strain around the CF
3
groups in 2b-2e, neither in the TS nor in the ground state.
Noticeably, ΔS
‡
was found to increase in 2b to 2e, following their increase in size. 2a
stands out with a small R group but a large ΔS
‡
value, the latter comparable to those of
2b-2d. This might be attributed to the ground state of 2a, in which the CH
3
group has a
largely unhindered rotation, contrary to the bulkier R groups of 2b-2d. The entropic
effect of hindering the CH
3
rotation in the TS will thus be relatively large in 2a. Such
hindered CH
3
rotation is also indicated in our DFT calculations, which show a
contraction of the C-F
3
...
H
3
CO distance by 0.31 Å (12%) in 2a.

Figure 7.3.
1
H NMR chemical shifts of H
1
in 2a-2e in CDCl
3
. The chemical shift of H
1
in
2d was estimated through HSQC spectroscopy.
304

Having a wealth of valuable geometric and spectroscopic information in hand, we
were able to explore the nature of the C-F
1
…
H
1
-C
3
interactions and their effects on the
hindered CF
3
rotations. First of all, in addition to the short C-F
1
…
H
1
-C
3’
distance in 2c,
the C
3’
-H
1
…
F angle is 130.1°, which fulfills the directionality requirement for hydrogen
bonding (>110°).
15,16
Noticeable proton deshieldings for H
1
(δ > 7.42 ppm versus δ =
7.33 in 1) were also observed in 2, which could be indicative for the occurrence of C-
F
…
H
1
-C
3’
hydrogen bonding (Figure 7.3).
15,17
It is worth noting that
5
J
F-H1
constants in
2a-2e are essentially identical (1.6~1.7 Hz), which indicates very similar C-F
...
H
1
-C
3‘

distances.
12a
Thus, lower field chemical shifts observed in 2c-2e, compared with those of
2a and 2b, are probably due to increased ring current induced deshieldings from different
aromatic substructures, instead of stronger hydrogen bonding interactions or shorter H
...
F
distances.
In addition, several delocalized molecular orbitals can be envisioned between the CF
3

group and the surrounding hydrogen atoms (Table 7.2).
13
This is particularly obvious for
the C-F
…
H
1
-C
3’
interaction. To estimate the magnitude of the different interactions,
Wiberg bond indices
18
were calculated from natural atomic orbitals (NAO).
13
The bond
index for the strongest interaction (C-F
1
…
H
1
-C
3’
) was found to be 0.0055. This suggests a
relatively weak hydrogen bonding-like interaction as compared with the H
...
F hydrogen
bonding in the HF dimer (with bond index of 0.0296 and bonding energy of 4.6
kcal/mol)
19
and the C-H
...
F-C hydrogen bondings in the CH
2
F
2
dimer (with bond indices
of 0.0007-0.0018 and an average hydrogen bonding energy of 0.6 kcal/mol).
9h
The
remaining six C-F
…
H-C interactions were calculated to only 13-31% of this value.
305

Additionally, NBO second-order perturbation analysis
20
was used to estimate the
interaction energies of the fluorine lone pairs with the C
3’
-H
1
anti-bonding orbital. It is
well established that such hyperconjugative interactions, which are a measure of charge
transfer, are the major contributors to hydrogen bonding.
20a
The two relevant n
F
→σ*
H1-C3’
interaction energies were found to be only 0.6 and 1.3 kcal/mol, further suggesting a
rather limited contribution of the C-F
1
…
H
1
-C
3’
hydrogen bonding interaction to the
overall rotational barrier.
Table 7.2. Canonical MOs showing C
3’
-H
1
…
F
1
-C interactions in 3.

306

Investigation of the TS structure has revealed the importance of the steric strain to the
hindered rotation. The CF
3
group was found to undergo noticeable geometric distortions
in the TS, indicating an increased steric strain upon rotation.
21
Also worth noting is the
0.05 Å (ca. 2%) contraction of the F
1
…
H
1
distance in the TS corresponding to CF
3

rotation. Despite a shorter distance, which is typically taken as an indication of a stronger
H-bonding interaction, the single n
F
→σ*
H1-C3’
interaction energy is reduced to 0.5
kcal/mol. This again hints to a limited importance of the C-F
1
…
H
1
-C
3’
H-bonding
interaction to the actual ground state geometry or the hindered rotation. In other words,
the extraordinary short F
1
…
H
1
distance in 2a appears to be a consequence of steric
crowding (buttressing), rather than any meaningful measurable of hydrogen bonding
interaction.
7.3 Conclusion
In conclusion, we have investigated hindered CF
3
rotations in cinchona alkaloid-
based scaffolds. DNMR studies have shown the barriers to rotations in the range of 11.9
to 13.5 kcal/mol. The increase in the hindrance of the CF
3
rotations in 2b-2e is driven by
the difference in their entropic changes. Quantum mechanical and experimental studies
have shown that the non-covalent C
3’
-H
1
…
F-C interactions possess some hydrogen
bonding-like character. Nonetheless, their contributions to the restricted CF
3
rotations are
rather limited. Instead, the steric interactions between the C
3’
-H
1
moiety and the CF
3

group plays a pivotal role in the hindered rotations in the present systems.

307

7.4. Experimental
7.4.1. General Information
Unless otherwise mentioned, all the chemicals were purchased from commercial
sources. CDCl
3
was purchased from the Cambridge Isotope Laboratories, Inc. The
DriSolv
®
solvents were purchased from EMD
TM
and used without further purification.
Silica gel chromatography was performed to isolate the products using 60-200 mesh
silica gel. One dimensional
1
H,
13
C,
19
F and Dynamic NMR spectra were recorded on
Varian Mercury 400 MHz NMR Spectrometer. The temperature calibration was carried
by measuring the chemical-shift separation between the OH resonances and CH
resonances in methanol (at low temperature) and ethylene glycol (at high temperature) to
give an accuracy at ±0.1 K. COSY and NOESY spectra were performed on Varian 400-
MR NMR Spectrometer or Varian VNMRS-500 NMR Spectrometer.
1
H NMR chemical
shifts were determined relative to CDCl
3
as the internal standards at δ 7.26 ppm.
13
C
NMR shifts were determined relative to CDCl
3
the internal standards at δ 77.16 ppm.
19
F
NMR chemical shifts were determined relative to internal standard CFCl
3
at δ 0.00 ppm.
Mass spectra were recorded on a high resolution mass spectrometer in the ESI mode.

308

7.4.2. Typical Procedure for the Preparation of O-Alkyl-9-dehydro-9-
trifluoromethyl-9-epiquinine (2) and their Characterization

To a suspension of sodium hydride (30 mg, 12.5 mmol) in anhydrous DMF (8 mL)
was quickly added 9-dehydro-9-trifluoromethyl-9-epiquinine (1, 196 mg, 0.5 mmol, in 2
mL DMF) under argon at 0
°
C. The resulting mixture was stirred at the same temperature
for 30 min. Methyl iodide (78 mg, 0.55 mmol, 34 μL) was subsequently added dropwise.
The reaction was stirred overnight and then quenched with brine (10 mL). The reaction
mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were
washed with brine (3×5 mL) and dried over MgSO
4
before the removal of the solvent
under vacuum. The crude product was purified by column chromatography to afford 2a
as a brownish solid (164 mg, 81%).
O-Methyl-9-dehydro-9-trifluoromethyl-9-epiquinine (2a)

309

1
H NMR (400 MHz, CDCl
3
) δ 1.31~1.38 (m, 1H), 1.42~1.58 (m, 2H), 1.76 (pseudo
s, 1H), 2.09~2.15 (m, 1H), 2.11~2.19 (m, 1H), 2.46~2.56 (m, 2H), 2.77 (pseudo dd, J =
13.8, 9.6 Hz, 1H), 3.15 (ddd, J = 13.8, 8.5, 2.0 Hz, 1H), 3.32 (pseudo t, J = 9.9 Hz, 1H),
3.38 (q, J = 1.8 Hz, 3H), 3.91 (s, 3H), 4.94~5.03 (m, 2H), 5.90 (ddd, J = 17.3, 10.4, 7.4
Hz, 1H), 7.36 (dd, J = 9.2, 2.8 Hz, 1H), 7.43 (dq, J = 4.9, 1.6 Hz, 1H), 8.00 (d, J = 9.2
Hz, 1H), 8.12 (d, J = 2.8 Hz, 1H), 8.72 (d, J = 4.9 Hz, 1H).
13
C NMR (101 MHz, CDCl
3
)
δ 22.8, 25.9, 29.0, 40.1, 50.5, 51.6, 55.5 (the signals of the two OCH
3
group overlap with
each other), 63.8, 89.4 (q,
2
J
C-F
= 22.6 Hz), 104.9, 114.6, 120.6 (q,
4
J
C-F
= 3.9 Hz), 121.9,
125.5 (q,
1
J
C-F
= 295.5 Hz) 128.9, 131.7, 139.8, 140.2, 145.4, 146.9, 157.5.
19
F NMR
(376 MHz, CDCl
3
) δ -62.8 (br, 3F). HRMS (ESI) Exact mass calculated for
C
22
H
26
F
3
N
2
O
2
+
[M+H
+
] 407.1941; Found 407.1940.
O-Vinyl-9-dehydro-9-trifluoromethyl-9-epiquinine (2b)

310

According to the typical procedure, 2b was prepared via the reaction between 1 and
allyl bromide. The product was obtained as a grey solid (69%).
1
H NMR (400 MHz,
CDCl
3
) δ 1.39~1.59 (m, 2H, chemical shift determined according to HSQC), 1.47~1.57
(m, 1H, chemical shift determined according to HSQC), 1.81 (m, 1H), 2.13 (dd, J = 17.1,
8.6 Hz, 1H), 2.29 (pseudo t, J = 12.0 Hz, 1H), 2.40~2.52 (m, 2H), 2.77 (dd, J = 13.3, 9.6
Hz, 1H), 3.25 (t, J = 9.7 Hz, 1H), 3.30 (ddd, J = 13.5, 8.5, 1.8 Hz, 1H), 3.88 (s, 3H,
OMe), 3.88 (ddt, J = 12.3, 5.9, 1.4 Hz, 1H, H
b
), 4.13 (ddq, J = 12.3, 4.0, 2.0 Hz, 1H, H
a
),
4.98 (pseudo dt, J = 17.2, 1.6 Hz, 1H), 5.02 (ddd, J = 10.4, 1.7, 1.2 Hz, 1H), 5.24 (ddd, J
= 17.3, 3.4, 1.6 Hz, 1H, H
d
), 5.31 (ddd, J = 17.3, 3.4, 1.6 Hz, 1H, H
e
), 5.93 (ddd, J =
17.3, 10.4, 7.2 Hz, 1H), 5.99 (dddd, J = 18.0, 10.5, 5.9, 4.2 Hz, 1H, H
c
), 7.33 (dd, J = 9.2,
2.8 Hz, 1H), 7.42 (dq, J = 4.9, 1.7 Hz, 1H), 7.98 (d, J = 9.2 Hz, 1H), 8.03 (d, J = 2.8 Hz,
1H), 8.72 (d, J = 4.9 Hz, 1H).
13
C NMR (101 MHz, CDCl
3
) δ 22.9, 25.9, 28.9, 40.1, 50.9,
51.5, 55.7, 64.0, 67.6 (q,
4
J
C-F
= 1.9 Hz), 89.3 (q,
2
J
C-F
= 22.4 Hz), 105.1, 114.7, 117.2,
120.2 (q,
4
J
C-F
= 3.9 Hz), 122.1, 125.5 (q,
1
J
C-F
= 295.8 Hz), 129.2, 131.5, 134.0, 140.0,
140.2, 145.3, 146.8, 157.3.
19
F NMR (376 MHz, CDCl
3
) δ ca. -56.2~-72.3 (br, 3F).
HRMS (ESI) Exact mass calculated for C
24
H
28
F
3
N
2
O
2
+
[M+H
+
] 433.2097; Found
433.2103.

311

O-Benzyl-9-dehydro-9-trifluoromethyl-9-epiquinine (2c)

According to the typical procedure, 2c was prepared via the reaction between 1 and
benzyl bromide. The product was obtained as a grey solid (82%).
1
H NMR (400 MHz,
CDCl
3
) δ1.41-1.59 (m, 1H), 1.53-1.64 (m, 1H), 1.63-1.74 (m ,1H), 1.88 (pseudo t, J = 4.0
Hz, 1H), 2.12 (dd, J = 16.4, 8.4 Hz, 1H), 2.39-2.50 (m, 1H), 2.33-2.50 (m, 2H), 2.67 (dd,
J = 13.3, 9.5 Hz, 1H), 3.03 (s, 3H), 3.26 (pseudo t, J = 9.6 Hz, 1H), 3.31 (ddd, J = 13.7,
8.7, 2.1 Hz, 1H), 4.25 (d, J = 10.9 Hz, 1H), 4.77 (dq, J = 10.8, 1.4 Hz, 1H), 4.93 (dt, J =
17.3, 1.6 Hz, 1H), 5.07 (pseudo dt, J = 10.4, 1.6 Hz, 1H), 5.97 (ddd, J = 17.2, 10.4, 6.7
312

Hz, 1H), 7.27 (dd, J = 9.2, 2.8 Hz, 1H), 7.25-7.39 (m, 5H), 7.48 (dq, J = 4.9, 1.6 Hz, 1H)
7.81 (d, J = 2.8 Hz, 2H), 7.97 (d, J = 9.2 Hz, 1H), 8.75 (d, J = 4.9 Hz, 1H).
13
C NMR
(101 MHz, CDCl
3
) δ 23.1, 26.0, 28.9, 39.9, 50.9, 51.4, 54.5, 64.1, 68.8 (q,
4
J
C-F
= 2.2
Hz), 89.7 (q,
2
J
C-F
= 22.4 Hz), 105.1, 114.6, 120.1 (q,
4
J
C-F
= 4.4 Hz), 122.4, 125.6 (q,
1
J
C-
F
= 296.4 Hz), 127.6, 128.1, 128.6, 129.3, 131.4, 137.7, 140.2, 143.3, 145.3, 146.8, 157.1.
19
F NMR (376 MHz, CDCl
3
) δ ca. -60.0 (br, 2F), 67.5 (br, 1F). HRMS (ESI) Exact mass
calculated for C
28
H
30
F
3
N
2
O
2
+
[M+H
+
] 483.2254; Found 533.2255.
O-2-Naphthyl-9-dehydro-9-trifluoromethyl-9-epiquinine (2d)

According to the typical procedure, 2d was prepared via the reaction between 1 and
2-(bromomethyl)naphthalene. The product was obtained as a grey solid (65%).
1
H NMR
313

(400 MHz, CDCl
3
) δ 1.42-1.52 (m, 1H), 1.54-1.67 (m, 1H), 1.73 (quintet, J = 6.7 Hz,
1H), 1.91 (t, J = 3.6 Hz, 1H), 2.13 (dd, J = 16.5, 8.4 Hz, 1H), 2.33-2.50 (m, 2H), 2.52 (t,
J = 12.0 Hz, 1H), 2.68 (dd, J = 13.2, 9.6 Hz, 1H), 2.88 (s, 3H), 3.29 (t, J = 9.6 Hz, 1H),
3.38 (ddd, J = 13.2, 8.5, 1.7 Hz, 1H), 4.45 (d, J = 11.1 Hz, 1H), 4.92 (br d, J = 11.1 Hz,
1H), 4.96 (dt, J = 17.3, 1.5 Hz, 1H), 5.11 (dt, J = 10.4, 1.5 Hz, 1H), 6.04 (ddd, J = 17.3,
10.4, 6.9 Hz, 2H), 7.27 (dd, J = 9.2, 2.8 Hz, 1H), 7.41 (dd, J = 8.4, 1.5 Hz, 1H), 7.48-7.53
(m, 3H), 7.76 (br s, 1H), 7.80-7.86 (m, 3H), 7.88 (d, J = 2.8 Hz, 1H), 8.00 (d, J = 9.2 Hz,
1H), 8.77 (d, J = 4.9 Hz, 1H).
13
C NMR (101 MHz, CDCl
3
) δ 23.1, 25.9, 28.8, 39.9, 50.9,
51.4, 54.5, 64.2, 68.9 (q,
4
J
C-F
= 1.5 Hz), 89.8 (q,
2
J
C-F
= 22.2 Hz), 105.1, 114.7, 120.1 (q,
4
J
C-F
= 3.8 Hz), 122.4, 125.6, 125.6 (CF
3
, q,
1
J
C-F
= 296.2 Hz),126.2(5), 126.3(4), 126.5,
127.8, 127.9, 128.3, 129.3, 130.0, 131.4, 133.1, 133.3, 135.1, 140.2, 145.3, 146.8, 157.2.
19
F NMR (376 MHz, CDCl
3
) δ -58.3 (br, 1F), 60.0 (br, 1F), -68.1 (br, 1F). HRMS (ESI)
Exact mass calculated for C
32
H
32
F
3
N
2
O
2
+
[M+H
+
] 533.2410; Found 533.2418.

314

O- 9-Anthracenylmethyl-9-dehydro-9-trifluoromethyl-9-epiquinine (2e)

According to the typical procedure, 2e was prepared via the reaction between 1 and 9-
(chloromethyl)anthracene. The product was obtained as a slightly yellowish solid (74%).
1
H NMR (400 MHz, CDCl
3
) δ 1.38 (pseudo t, J = 11.7 Hz, 1H), 1.55 (pseudo t, J = 9.4
Hz, 1H), 1.73-1.80 (t, J = 6.5 Hz, 1H, partially overlaps with the signal at 1.79 ppm),
1.79 (pseudo d, J = 4.1 Hz, 1H), 1.90 (dd, J = 16.7, 8.1 Hz, 1H), 2.13 (s, 3H), 2.23-2.32
(m, 1H), 2.32-2.38 (m, 1H), 2.37-2.43 (m, 1H), 2.49 (t, J = 11.5 Hz, 1H), 2.82 (ddd, J =
12.0, 9.6, 1.9 Hz, 1H), 3.26-3.32 (m, 1H), 4.54 (pseudo dt, J = 17.1, 1.4 Hz, 1H), 4.61
(ddd, J = 10.3, 1.7, 1.1 Hz, 1H), 5.36 (d, J = 10.8 Hz, 1H), 5.51 (dq, J = 10.8, 1.6 Hz,
1H), 5.56 (ddd, J = 17.6, 10.3, 7.4 Hz, 1H), 7.01 (dd, J = 9.2, 2.8 Hz, 1H), 7.28 (ddd, J =
315

8.9, 6.6, 1.2 Hz, 2H), 7.44 (ddd, J = 8.3, 6.9, 0.6 Hz, 2H)7.57 (d, J = 2.8 Hz, 1H), 7.61
(dq, J = 4.8, 1.5 Hz, 1H), 7.76 (d, J = 8.8 Hz, 2H), 7.97 (d, J = 9.2 Hz, 1H), 8.00 (d, J =
8.4 Hz, 2H), 8.49 (s, 1H), 8.82 (d, J = 4.9 Hz, 1H).
13
C NMR (101 MHz, CDCl
3
) δ 23.4,
25.8, 29.3, 40.2, 51.1, 51.3, 53.6, 62.4 (q, J = 1.8 Hz), 64.1, 90.6 (q, J = 21.8 Hz), 106.0,
114.3, 120.4 (q, J = 3.8 Hz), 122.2, 124.8, 125.1, 125.6 (CF
3
, q,
1
J
C-F
= 296.2 Hz), 126.2,
128.1, 128.7(9), 128.8(2), 129.1, 130.6, 130.9, 131.5, 140.1, 140.6, 145.4, 146.6, 156.5.
19
F NMR (376 MHz, CDCl
3
) δ -59.0 (br, 1F), 60.5 (br, 1F), -66.6 (br, 1F). HRMS (ESI)
Exact mass calculated for C
36
H
34
F
3
N
2
O
2
+
[M+H
+
] 583.2567; Found 583.2571.

7.4.3. Computational Studies
13a

Geometry optimization of 2a was performed at the B3LYP 6-31G+(d,p) level.
Accordingly, the syn-closed conformation was found to be lowest in energy,
demonstrating several short H/C-F contacts, which is in good agreement with the NMR
spectroscopic study. In addition to this minimum energy structure, several other
conformations identified as local minima on the potential energy surface. The single
point energies of these structures were subsequently computed using B3LYP/6-
311+G(2d,p) method, and showed the syn-closed and the anti-closed conformations as
the two most abundant species in the gas phase. Taking solvation effects of CHCl
3
into
account (PCM), the relative energies of the syn-closed and the anti-closed species were
computed to be 0.0 and 1.9 kcal/mol, respectively, which indicates a corresponding
population distribution of 94:6 at 298 K.
316

Table 7.3. Optimized structures of the syn- and the anti-Closed conformations of 2a.

SCF energy scans for the CF
3
rotations in the syn-closed and the anti-closed
conformations were computed over the dihedral angle F
1
-C-C
9
-C
8
( φ
F1CC9C8
) by
increments of 10
o
. A series of conformers, due to the rotations of F
3
C-C
9
bonds, was
optimized with the HF/6-31+G(d,p) method. The single point energies of these
conformers were calculated with implicit consideration of CHCl
3
solution at the
B3LYP/6-311+G(2d,p) level, and were further plotted against the ϕ
F1CC9C8
. A Sine-like
behavior was observed. The CF
3
rotation in syn-closed 2a was found to be 12.1 kcal/mol
a value close to the value obtained via DNMR experiments (11.5-12.3 kcal/mol). In
comparison, the CF
3
rotation in the anti-closed conformation possesses a much lower
rotational barrier (6.8 kcal/mol), which explains the sharp signal detected in the
19
F NMR
spectroscopy.

317

Table 7.4. CF
3
Rotation profile in syn-Closed 2a at the B3LYP/6-311+G(2d,p) level.
φ
F1CC9C8
E(a.u.) E
SCF

0.0 1413.21586056 9.2
10.0 1413.22033770 6.4
20.0 1413.22523357 3.3
30.0 1413.22895784 1.0
40.0 1413.23036953 0.0
50.0 1413.22926994 3.0
60.0 1413.22579947 6.1
70.0 1413.22083252 9.0
80.0 1413.21616084 11.1
90.0 1413.21279117 12.1
100.0 1413.21129906 11.5
110.0 1413.21218039 9.6
120.0 1413.21522329 9.2

Figure 7.4. CF
3
Rotation profile in syn-Closed 2a at the B3LYP/6-311+G(2d,p) level.
318

Table 7.5. CF
3
Rotation Profile in anti-Closed 2a at the B3LYP/6-311+G(2d,p) level.
φ
F1CC9C8
E(a.u.) E
SCF

0.0 1413.22012580 4.6
10.0 1413.22314008 2.7
20.0 1413.22608709 0.9
30.0 1413.22679185 0.0
40.0 1413.22672707 0.3
50.0 1413.22624383 1.2
60.0 1413.22489410 2.8
70.0 1413.22240863 4.7
80.0 1413.21928055 6.2
90.0 1413.21698556 6.8
100.0 1413.21593794 6.1
110.0 1413.21712932 4.4
120.0 1413.21979879 4.6

Figure 7.5. CF
3
Rotation profile in anti-Closed 2a at the B3LYP/6-311+G(2d,p) level.
319

Further density functional theory calculation at the B3LYP/6-31+G(d,p) level has
shown that the transition state (TS) of the CF
3
rotation in the syn-closed conformer occurs
when dihedral angle F
1
-C-C
9
-C
8
( φ
F1CC9C8
)

is 101.9° with a barrier of 11.9 kcal/mol,
which is consistent with the DNMR study.

Table 7.6. Optimized ground state and transition state structures of anti-Closed 2a at the
B3LYP/6-31+G(d,p)+ZPE level.

320

Table 7.7. NBO Analysis of the Ground State of syn-closed 2a at the B3LYP/6-
31+G(d,p) level.

Wiberg
Index
Distance
(Å)
φ
F-H-C

% of strongest
bond
ΔE
nF-σ*C-H
(kcal/mol)
F
1
-H
1
0.0055 2.204 126.4 100% 0.59+1.27
F
1
-H
9
0.0011 2.413 97.4 20% -
F
1
-H
10
0.0007 2.730 103.7 13% -
F
1
-H
11
0.0007 2.529 99.9 13% -
F
2
-H
1
0.0014 2.804 85.2 25% -
F
2
-H
11
0.0017 2.526 106.7 31% -
F
3
-H
3
CO 0.0010 2.572 97.7 18% -

Table 7.8. NBO Analysis of the transition state of syn-closed 2a at the B3LYP/6-
31+G(d,p) level

Wiberg
Index
Distance
(Å)
φ
F-H-C

% of strongest
bond
ΔE
nF-σ*C-H
(kcal/mol)
F
1
-H
1
0.0030 2.156 103.3 55% 0.54
F
1
-H
9
0.0002 3.014 98.2 4% -
F
1
-H
10
0.0000 4.544 71.8 0% -
F
1
-H
11
0.0001 4.198 89.6 2% -
F
2
-H
1
0.0001 3.387 113.0 2% -
F
2
-H
11
0.0012 2.312 101.5 22% -
F
3
-H
3
CO 0.0015 2.260 93.7 27% -

321

NBO Analysis of HF dimer and CH
2
F
2
dimer at the B3LYP/6-31+G(d,p) level.
Geometry optimizations of HF- and CH
2
F
2
-dimer systems were performed at the
B3LYP/6-31+G(d,p) level. The dissociation energies were found to be substantially close
to reported experimental data.
22
The NBO analysis of the intermolecular interactions was
carried out at the same level.

322

Molecular orbitals of O- ethyl-9-dehydro-9-trifluoromethyl-9-epiquinine (3)
3 was optimized at the B3LYP/6-31+(d,p) level. Its nuclear magnetic shielding
tensors were calculated at the GIAO-PCM-B3LYP/6-31+(d,p) level of theory. The effect
of chloroform solvent was treated implicitly using the standard PCM method of
Gaussian03. Wiberg bond indices were calculated from natural atomic orbitals. Canonical
molecular orbitals were visualized as 0.02 isosurfaces using the Avogadro code.
23

Table 7.9. Canonical Molecular Orbitals showing C3’-H1
…
F1-C interactions in 3.

323

7.4.4. Selected NMR Spectra

1
H NMR spectrum of 2a

13
C NMR spectrum of 2a

324

19
F NMR spectrum of 2a

COSY spectrum of 2a

325

COSY spectrum of 2a

COSY spectrum of 2a

326

NOESY spectrum of 2a

NOESY spectrum of 2a

327

NOESY spectrum of 2a

HSQC spectrum of 2a

328

HSQC spectrum of 2a

1
H NMR spectrum of 2b

329

1
H NMR spectrum of 2b

13
C NMR spectrum of 2b

330

19
F NMR spectrum of 2b

COSY spectrum of 2b

331

COSY spectrum of 2b

COSY spectrum of 2b

332

COSY spectrum of 2b

NOESY spectrum of 2b

333

NOESY spectrum of 2b

NOESY spectrum of 2b

334

NOESY spectrum of 2b

HSQC spectrum of 2b

335

HSQC spectrum of 2b

HSQC spectrum of 2b

336

1
H NMR spectrum of 2c

1
H NMR spectrum of 2c

337

13
C NMR spectrum of 2c

19
F NMR spectrum of 2c

338

COSY spectrum of 2c

COSY spectrum of 2c

339

COSY spectrum of 2c

COSY spectrum of 2c

340

NOESY spectrum of 2c

NOESY spectrum of 2c

341

NOESY spectrum of 2c

HSQC spectrum of 2c

342

HSQC spectrum of 2c

HSQC spectrum of 2c

343

1
H NMR spectrum of 2d

1
H NMR spectrum of 2d

344

13
C NMR spectrum of 2d

19
F NMR spectrum of 2d

345

COSY spectrum of 2d

COSY spectrum of 2d

346

COSY spectrum of 2d

COSY spectrum of 2d

347

NOESY spectrum of 2d

NOESY spectrum of 2d

348

NOESY spectrum of 2d

HSQC spectrum of 2d

349

HSQC spectrum of 2d

HSQC spectrum of 2d

350

1
H NMR spectrum of 2e

1
H NMR spectrum of 2e

351

1
H NMR spectrum of 2e

13
C NMR spectrum of 2e

352

19
F NMR spectrum of 2e

COSY spectrum of 2e

353

COSY spectrum of 2e

COSY spectrum of 2e

354

COSY spectrum of 2e

NOESY spectrum of 2e

355

NOESY spectrum of 2e

NOESY spectrum of 2e

356

HSQC spectrum of 2e

HSQC spectrum of 2e

357

HSQC spectrum of 2e

358

Dynamic NMR spectra of 2a and the corresponding simulated spectra (program
TopSpin
®
)

The spectra in blue were obtained from DNMR experiments. The spectra in white and
orange were obtained from simulation.

359

T = 288K; k = 6855 Hz

T = 273 K; k = 2509 Hz

T = 263 K; k = 1269 Hz

360

T = 253 K; k = 693 Hz

T = 243 K; k = 296 Hz

T = 233 K; k = 130 Hz

361

Dynamic NMR spectra of 2b and the corresponding simulated spectra (program
TopSpin
®
)

The spectra in blue were obtained from DNMR experiments. The spectra in white and
orange were obtained from simulation.

362

T = 283 K; k = 3950 Hz

T = 273 K; k = 1785 Hz

T = 263 K; k = 996 Hz

363

T = 253 K; k = 391 Hz

T = 243 K; k = 163 Hz

T = 233 K; k = 68 Hz

364

Dynamic NMR spectra of 2c and the corresponding simulated spectra (program
TopSpin
®
)

The spectra in blue were obtained from DNMR experiments. The spectra in white and
orange were obtained from simulation.

365

T = 283 K; k = 1881 Hz

T = 273 K; k = 863 Hz

T = 263 K; k = 292 Hz

366

T = 253 K; k = 174 Hz

T = 243 K; k = 74 Hz

T = 233 K; k = 32 Hz

367

Dynamic NMR spectra of 2d and the corresponding simulated spectra (program
TopSpin
®
)

The spectra in blue were obtained from DNMR experiments. The spectra in white and
orange were obtained from simulation.

368

T = 283 K; k = 1726 Hz

T = 273 K; k = 770 Hz

T = 263 K; k = 417 Hz

369

T = 253 K; k = 164 Hz

T = 243 K; k = 70 Hz

T = 233 K; k = 31 Hz

370

Dynamic NMR spectra of 2e and the corresponding simulated spectra (program
TopSpin
®
)

The spectra in blue were obtained from DNMR experiments. The spectra in white and
orange were obtained from simulation.

371

T = 293 K; k = 625 Hz

T = 283 K; k = 301 Hz

T = 273 K; k = 138 Hz

372

T = 263 K; k = 64 Hz

T = 253 K; k = 34 Hz

373

7.4.5. Crystal Structure of 2c

Table 1. Crystal data and structure refinement for C
28
H
29
F
3
N
2
O
2
.
Empirical formula C
28
H
29
F
3
N
2
O
2

Formula weight 482.53
Temperature 143(2) K
Wavelength 0.71073 Å
Crystal system Monoclinic
Space group P 21
Unit cell dimensions a = 11.1759(15) Å = 90°.
b = 12.3706(17) Å = 99.385(2)°.
c = 17.622(2) Å  = 90°.
Volume 2403.6(6) Å
3

Z 4
Density (calculated) 1.333 Mg/m
3

Absorption coefficient 0.100 mm
-1

F(000) 1016
Crystal size 0.20 x 0.10 x 0.10 mm
3

374

Theta range for data collection 1.85 to 27.55°.
Index ranges -14<=h<=14, -15<=k<=15, -20<=l<=22
Reflections collected 21033
Independent reflections 5686 [R(int) = 0.0539]
Completeness to theta = 27.55° 98.0 %
Absorption correction Semi-empirical from equivalents
Max. and min. transmission 0.9901 and 0.9580
Refinement method Full-matrix least-squares on F
2

Data / restraints / parameters 5686 / 1 / 633
Goodness-of-fit on F
2
1.028
Final R indices [I>2sigma(I)] R1 = 0.0465, wR2 = 0.0886
R indices (all data) R1 = 0.0687, wR2 = 0.0978
Absolute structure parameter ?
Largest diff. peak and hole 0.251 and -0.180 e.Å
-3

375

7.5. References
[1] Orville-Thomas, W. J. Ed. Internal Rotations in Molecules, Wiley, London, New
York, 1974.
[2] (a) Ōki, M. Acc. Chem. Res. 1990, 23, 351; (b) Mati, I. K.; Cockroft, S. L. Chem.
Soc. Rev. 2010, 39, 4195.
[3] (a) Chen, Y.; Yekta, S.; Yudin, A. K. Chem. Rev. 2003, 103, 3155; (b) Brunel, J.
M. Chem. Rev. 2007, 107, PR1; (b) Clayden, J.; Moran, W. J.; Edwards, P. J.;
LaPlante, S. R. Angew. Chem. Int. Ed. 2009, 48, 6398; (c) Bringmann, G.; Gulder,
T.; Gulder, T. A. M.; Breuning, M. Chem. Rev. 2011, 111, 563.
[4] (a) Kelly, T. R. Acc. Chem. Res. 2001, 34, 514; (b) Kottas, G. S.; Clarke, L. I.;
Horinek, D.; Michl, J. Chem. Rev. 2005, 105, 1281; (c) Kay, E. R.; Leigh, D. A.;
Zerbetto, F. Angew. Chem. Int. Ed. 2007, 46, 72.
[5] Ōki, M. Applications of Dynamic NMR Spectroscopy to Organic Chemistry, VCH
Publishers, Deerfield Beach, Florida, 1985, chap. 6.
[6] The barriers to rotations about F
3
C-C(sp
3
) bonds are usually rather low. Lowe, J.
P. in Progress in Physical Organic Chemistry, Streitwieser, A. Jr; Taft, R. W.
Eds, John Wiley and Sons, 1968, p 36.
[7] Kareev et al. have summarized hindered rotations of CF
3
-C(sp
3
) bonds, Kareev, I.
E.; Santiso-Quinones, G.; Kuvychko, I. V.; Ioffe, I. N.; Goldt, I. V.; Lebedkin, S.
F.; Seppelt, K.; Strauss, S. H.; Boltalina, O. V. J. Am. Chem. Soc. 2005, 127,
11497.
376

[8] Only a single report has demonstrated that the rotational barrier of CF
3
-C(sp
3
)
bonds can be higher than 25 kcal/mol, Toyota, S.; Watanabe, Y.; Yoshida, H.;
Ōki, M. Bull. Chem. Soc. Jpn. 1995, 68, 2751.
[9] Selected examples and review articles on C-F
…
H-X: (a) West, R.; Powell, D. L.;
Whatley, L. S.; Lee, M. K. T.; Schleyer, P. R. J. Am. Chem. Soc. 1962, 84, 3221;
(b) Shimoni, L.; Glusker, J. P.; Bock, C. W. J. Phys. Chem. 1995, 99, 1194; (c)
Howard, J. A. K.; Hoy, V. J.; O’Hagan, D.; Smith, G. T. Tetrahedron 1996, 52,
12613; (d) Dunitz, J. D.; Taylor, R. Chem. Eur. J. 1997, 3, 89; (e) Wang, X.;
Houk, K. N. Chem. Commun. 1998, 2631; (f) Thalladi, V. R.; Weiss, H.-C.;
Bläser, D.; Boese, R.; Nangia, A.; Desiraju, G. R. J. Am. Chem. Soc. 1998, 120,
8702; (g) Barbarich, T. J.; Rithner, C. D.; Miller, S. M.; Anderson, O. P.; Strauss,
S. H. J. Am. Chem. Soc. 1999, 121, 4280; (h) Caminati, W.; Melandri, S.;
Moreschini, P.; Favero, P. G. Angew. Chem. Int. Ed. 1999, 38, 2924; (i) Parsch,
J.; Engels, J. W. J. Am. Chem. Soc. 2002, 124, 5664; (j) Kui, S. C. F.; Zhu, N.;
Chan, M. C. W. Angew. Chem. Int. Ed. 2003, 42, 1628; (k) Hof, F.; Diederich, F.
Chem. Commun. 2004, 484; (l) Samsonov, S. A.; Salwiczek, M.; Anders, G.;
Koksch, B.; Pisabarro, M. T. J. Phys. Chem. B 2009, 113, 16400; (m) Anzahaee,
M. Y.; Watts, J. K.; Alla, N. R.; Nicholson, A. W.; Damha, M. J. J. Am. Chem.
Soc. 2011, 133, 728.
[10] Prakash, G. K. S.; Wang, F.; Ni, C.; Shen, J.; Haiges, R.; Yudin, A. K.; Mathew,
T.; Olah, G. A. J. Am. Chem. Soc. 2011, 133, 9992.
377

[11] (a) Dijkstra, G. D. H.; Kellogg, R. M.; Wynberg, H.; Svendsen, J. S.; Marko, I.;
Sharpless, K. B. J. Am. Chem. Soc. 1989, 111, 8069; (b) Aune, M.; Gogoll, A.;
Matsson, O. J. Org. Chem. 1995, 60, 1356; (c) Bürgi, T.; Baiker, A. J. Am. Chem.
Soc. 1998, 120, 12920; (d) Urakawa, A.; Meier, D. M.; Rüegger, H.; Baiker, A. J.
Phys. Chem. A 2008, 112, 7250.
[12] (a) Myhre, P. C.; Edmonds, J. W.; Kruger, J. D. J. Am. Chem. Soc. 1966, 88,
2459; (b) Wasylishen, R. E.; Barfield, M. J. Am. Chem. Soc. 1974, 97, 4545; (c)
Dolbier, W. R. Guide to Fluorine NMR for Organic Chemists, John Wiley &
Sons, Hoboken, New Jersey, 2009, Chap. 1.
[13] (a) Computed using the Gaussian 03, Revision C.02, M. J. Frisch, Gaussian, Inc.,
Wallingford CT, 2004; (b) Details of the compuational studies are included in the
Supporting Information.
[14] In addition to the broad/decoalesced signal observed in each case, a sharp peak
(with a relative population of ca. 5% according to the
19
F NMR integrations) was
also observed that shows temperature dependence in its lineshape.
[15] Steiner, T.; Desiraju, G. R. Chem. Commun. 1998, 891.
[16] Desiraju, G. R. Angew. Chem. Int. Ed. 2011, 50, 52.
[17] Pimentel G. C.; McClellan, A. L. The Hydrogen Bond, Reinhold Publishing
Corporation, New York, 1960, pp. 142.
[18] Wiberg, K. B. Tetrahedron 1968, 24, 1083.
[19] Bohac, E. J.; Marshall, M. D.; Miller, R. E. J. Chem. Phys. 1992, 96, 6681.
378

[20] (a) Reed, A. E.; Curtiss, L. A.; Weinhold, F. Chem. Rev. 1988, 88, 899. Recent
examples utilizing second order perturbation analysis to estimate intramolecular
H-bond strengths, (b) Tian, S. X.; Li, H.-B. J. Phys. Chem. A 2007, 111, 4404; (c)
Shchavlev, A. E.; Pankratov, A. N.; Enchev, V. J. Phys. Chem. A 2007, 111,
7112; (d) Jesus, A. J. L.; Rosado, M. T. S.; Reva, I.; Fausto, R.; Eusébio, M. E. S.;
Redinha, J. S. J. Phys. Chem. A 2008, 112, 4669; (e) Lämmermann, A.; Szátmari,
I.; Fülöp, F.; Kleinpeter, E. J. Phys. Chem. A 2009, 113, 6197.
[21] Several obvious distortions in the transition state include the increase in the F
3
C-
C
9
bond distance (from 1.580Å to 1.621Å) and the increase in the F
1
-C-C
9
angle
(from 113.3° to 116.0°).
[22] (a) Bohac, E. J.; Marshall, M. D.; Miller, R. E. J. Chem. Phys. 1992, 96, 6681-
6695; (b) Caminati, W.; Melandri, S.; Moreschini, P.; Favero, P. G. Angew.
Chem. Int. Ed. 1999, 38, 2924-2925.
[23] Avogadro: an open-source molecular builder and visualization tool. Version
1.03. http://avogadro.openmolecules.net/
379

Chapter 8

Exploiting the Trifluoromethyl Group as a
Conformational Stabilizer and Probe: Conformations of
Cinchona Alkaloid Scaffolds and their Catalytic
Activity

380

8.1. Introduction
Cinchona alkaloid-based catalysts are privileged chiral scaffolds in asymmetric
catalysis.
1
In an effort to improve their catalytic efficacy, in-depth mechanistic insight has
been ardently sought. Among various factors, the conformations of cinchona alkaloid
catalysts have long been proposed to play a pivotal role in relevant catalysis. Although
this hypothesis has been invoked by both experiments
2 , 3 , 4 , 5 , 6
and theory,
7
the
conformational behavior of cinchona alkaloids is still not thoroughly understood due to
its capricious nature.
Pioneering studies by Dijkstra, Wynberg, and Sharpless have shown that the
substantial fluxionality of cinchona alkaloids arises from rotations around the C8-C9 and
C4’-C9 bonds (τ
1
and

τ
2
, respectively, Scheme 8.1). Through the τ
1
rotation, syn and anti
conformations are generated, as differentiated by the relative orientation of the -OH
group aligning along and apart from Ring B of the quinoline moiety, respectively. The τ
2

rotation leads to the formation of Closed and Open conformations, in which the
quinuclidine nitrogen points to and away from Ring A of quinoline, respectively.
Baiker,
4, 8
Zeara,
9
and others
6a, 10
have revealed that the conformational behavior of
cinchona alkaloids could be significantly influenced by various intermolecular forces,
such as dipole-dipole interactions, hydrogen bonding interactions, and protonation on the
quinuclidine nitrogen. Due to the complicated conformational scenario, several
techniques are required for conformational studies of cinchona alkaloids.

381

Scheme 8.1. Six Possible Conformations of Cinchona Alkaloids Generated via Rotations
around τ
1
and τ
2
.

Among various means, quantum chemical calculations have been extensively used to
provide precise descriptions of the conformers’ three -dimensional structures. Three major
minimum energy species have been identified in the gas phase, the Open-3, the Closed-1,
and the Closed-2 conformers (Scheme 8.1).
2, 11
Energy calculations of conformers in
solution are usually performed with an implicit consideration of solvent molecules. Since
the cinchona alkaloid scaffold contains both H-bond accepting and donating moieties, the
accuracy of such calculations can be limited.
12

382

In comparison, NMR spectroscopic techniques have been widely applied in liquid
phase conformational analyses. Since theoretical studies have found that conformers
Closed-1 and Closed-2 have very similar φ
H8C9H8H9
dihedral angles,
4
Closed-1 and
Closed-2 are expected to have practically the same
3
J
H8H9
coupling constant.
13
Hence, the
Open-Closed equilibrium can be quantified via the
3
J
H8-H9
coupling analysis using the
following two-variable-two-equation system,
4

where in J
H8H9
obs
is the observed J
H8H9
, and J
H8H9
Open-3
and J
H8H9
Closed
are J
H8H9
of Open-3
conformation and Closed conformations, respectively. Pop
Open-3
and Pop
Closed
are the
population of Open-3 conformation and Closed conformations. Since the conformational
equilibrium was indirectly determined based on the Karplus-type correlation
13
and the
exclusion of minor conformers, systematic errors are expected to be introduced (Scheme
8.2, Box A).
In contrast to the relatively well studied τ
2
rotation, detailed knowledge of the τ
1

rotation has been limited due to the absence of the corresponding vicinal protons. Even
though nuclear Overhauser enhancement (nOe) spectroscopy can deliver information on
τ
1
qualitatively, its accuracy in the quantification of conformational equilibria is under
debate.
14
In practice, systematic conformational studies on cinchona alkaloids have also
been obstructed by the availability of deuterated solvents, which are necessary in most of
383

the above mentioned NMR experiments. The conformational study of cinchona alkaloids
in liquid media has thus remained a challenge due to (a) difficulty in obtaining accurate
experimental conformational distribution data, (b) reliability of quantum chemical
calculations, and (c) lack of coherent studies of solvent effects on the conformational
behavior of cinchona alkaloids.
Scheme 8.2. Flowcharts for cinchona alkaloid conformational analyses. Box A.
Conventional analyzing protocol; B. Conformational analysis via trifluoromethyl-
conformational stabilizing/probing strategy.

384

The aforementioned difficulties are essentially due to (a) complicated conformational
profiles of cinchona alkaloid scaffolds; (b) low conformational interconversion barriers;
(c) complication of conformational behavior owing to solute-solvent interactions, and (d)
limitations of implicit solvation models. Addressing such inherent challenges, we
recently demonstrated that the sterically bulky CF
3
group
15
could be incorporated into the
C9 atom in quinidine as a conformational stabilizer and a probe (Scheme 8.2, Box B).
16

The protocol is based on the significant increased barrier to the τ
2
rotation, which leads to
the decoalescence of the signals of the syn and the anti conformations in both
1
H and
19
F
NMR spectra at room temperature. The determination of the corresponding
conformational equilibria is thus possible by
19
F NMR integration.
17
This direct analytic
protocol is not only more reliable than the vicinal coupling constant analysis or 2D nOe
spectroscopy, but also applicable in both deuterated and non-deuterated solvents. With
the protocol, a more diverse selection of solvents could be subjected to the systematic
elucidation of the solvent effects. Based on this accurate conformational information,
possible errors in energy calculations can be assessed. Since strongly interacting moieties
(the hydroxyl and the amino groups) remain intact, various specific solvent-solute
interactions are expected to be relatively unperturbed in the trifluoromethylated analogue
(epiCF
3
QD). More importantly, due to its weakly interacting nature, the CF
3
group,
although bulky, should only introduce negligible specific interactions. Thus, the
environmental dependence of the conformations of epiCF
3
QD is anticipated to largely
reflect that of naturally occurring cinchona alkaloids, and the conformational behavior of
the latter can be investigated using a similar analytical protocol (Scheme 8.2).
385

Based on the above mentioned method, reasonable cinchona alkaloid conformational
profiles in solution can be obtained, which are expected to be informative for related
studies. However, it should be noted that the assumption of ground-state observable
conformers as predominant species in the transition state can be misleading.
18
To explore
active conformations in catalysis, conformationally rigid cinchona alkaloid analogues are
required. Corey et al. have shown that conformational rigidity can be achieved by
introducing intramolecular covalent linkages into cinchona alkaloid backbones.
3a-c
This
strategy was also recently utilized by Deng in the mechanistic study of alcoholysis of
meso anhydrides.

Alternatively, elegant work by Gilmour et al.
5
has demonstrated that
the stereoelectronic effects of C-F bonds
19
can alter the relative thermodynamic stability
of different conformations of cinchona alkaloid derivatives, thereby enabling the
exploration of catalytically active species.
20
Other than these two approaches, we now
demonstrate that conformationally stable 9-trifluoromethylated cinchona alkaloid
scaffolds can be employed as robust probes, which facilitate the identification of active
conformations in an enantioselective cyclopropanation reaction previously reported by
Gaunt et al.
21
. Moreover, these probes were obtained via feasible synthetic routes from
quinidinone, making them viable probes.
In this chapter, we quantitatively analyze the solvent dependence of the
conformational behavior of cinchona alkaloids, which is primarily facilitated by a
combination of NMR studies and DFT calculations. In the first part, we describe the
quantitative assessment of the reliability of quantum chemical calculation based on the
accurate conformational information of epiCF
3
QD obtained from
19
F NMR spectroscopy.
386

The first section is organized as follows: (a) DFT calculations of the geometry of
conformers of cinchona alkaloids and their derivatives, such as epiCF
3
QD, QD and 9-
epiquindine (epiQD); (b) DFT calculations of the relative energy of these conformers in
the gas phase and in solution and the corresponding conformational distribution; (c)
determination of the syn-anti conformational distribution of epiCF
3
QD in various
solvents via
19
F NMR spectroscopy; (d) systematic analysis of solvent effects on
epiCF
3
QD conformational behavior based on linear free energy relationship; (e)
assessment of the accuracy of the quantum chemical calculation by comparing calculated
conformational distribution of epiCF
3
QD with experimental outcomes. This section leads
to the conclusion that the small solvation energy difference of conformers cannot be
adequately predicted by implicit solvation models, such as the Polarizable Continuum
Model (PCM) commonly used in cinchona alkaloid conformational studies, due to the
existence of specific interactions with solvent molecules.
In the second part of the chapter, we discuss the solvent-dependent conformational
behavior of epiQD. This section involves: (a) determination of the Open-Closed
conformational distribution of epiQD in various solvents via
1
H NMR spectroscopy and
Karplus-type analysis; (b) analysis of solvent effects on epiQD conformational behavior
based on linear free energy relationship; (c) assessment of the quantum chemical
calculation based on experimental data, which demonstrates that conformers with higher
than 3.5 kcal/mol relative energy in the gas phase are unlikely to be populated in solution.
The third section of the chapter is focused on (a) determination of the Open-Closed
conformational distribution of QD in solution via
1
H NMR spectroscopy and Karplus-
387

type analysis; (b) systematic analysis of solvent effects on QD conformational behavior
based on linear free energy relationship; (c) quantitative evaluation of the calculated
conformational behavior of QD in solution, showing that PCM may not be suitable for
conformational study of QD.
Finally, we demonstrate the utilization of the CF
3
group as a conformational stabilizer
and probe for the elucidation of active conformations in cinchona alkaloid derivative-
catalyzed cyclopropanation reaction.
8.2. Methods
8.2.1. Identification of Conformers via DFT Calculations
The conformational behavior of cinchona alkaloid scaffolds is primarily determined
by two critical rotations τ
1
and τ
2
(Figure 8.1-A). To identify the major conformations of
a given cinchona alkaloid derivative, a potential energy surface (PES) as a function of τ
1

and τ
2
was calculated at the B3LYP/6-31+G(d) level in the gas phase using Gaussian
09.
22
The dihedral angles of the two rotations were systematically varied from 0° to 360°
by an increment of 10°. The formed conformations were then allowed to calculate up to
five optimization steps for each constrained dihedral angles.
23
The conformational profile
was formed as a 36×36 PES with 1296 geometry optimizations, revealing a series of
conformations (numbered similarly to the previous report, Figure 8.1-B and -C).
8d
Based
on these structures, further refinement was performed at the B3LYP/6-311+G (d,p) level,
which led to very small geometric changes. In addition to the τ
1
and the τ
2
rotations, two
more rotations, τ
3
and τ
4
, were also taken into consideration as they could result in the
formation of intramolecular H-bonding and/or significant change in the dipole moment of
388

the conformers. Our theoretical calculations showed that 1’-like conformers are generally
1 kcal/mol higher in energy than 1 in the gas phase (Figure 8.1-A). Similar results were
also observed in the liquid phase by NOESY spectroscopy, in which only 1-like
conformations were detected. Because of this, 1’ was not considered for further
calculations. As τ
3
was found to have three minima around its rotational axis, the number
of possible conformations tripled as identified on the PES. The additional conformers due
to the τ
3
rotation were also optimized at the B3LYP/6-311+G (d,p) level in the gas phase.
Since τ
1
and τ
2
angles were essentially unchanged upon the τ
3
rotation, the conformers
generated due to the τ
3
rotation were differentiated by alphabetic appendices (such as
Closed-1a, Closed-1b, and Closed-1c, Figure 8.1-A). In other words, for a given
molecule, the conformers with the same numerical name have similar τ
1
and τ
2
values
(for different molecules, the same numerical name may not indicate similar τ
1
and τ
2

values).
For O-methylated cinchona alkaloid derivatives, six stable conformers were taken
into consideration, which resembles the geometry of Closed-1, Closed-2 and Open-3-6
conformations (Scheme 8.1).
8.2.2. Energy Calculation and Population Distribution
To obtain accurate estimates of each conformer's energy, single point energies were
calculated at the M06-2X/6-311+G(d,p)//B3LYP/6-311+G(d,p) level of theory. The
recent hybrid meta exchange-correlation density functional M06-2X empirically accounts
for dispersive interactions and has demonstrated high accuracy in main-group
thermochemistry.
24
Solvent effects were included implicitly through the self-consistent
389

reaction field approach, as implemented in the default Polarizable Continuum Model
(PCM) in Gaussian 09.
25,26
Thermal and entropic corrections for both gas-phase and
PCM-optimized structures were obtained by frequency analysis at the B3LYP/6-
311+G(d,p) level. The frequency analyses also confirmed that all considered structures
were true minima on the PES.
The relative populations of each conformer at 298K were derived using the
Boltzmann equation. Herein, ΔG
syn,cal
is defined as the free energy corresponding to the
difference between the calculated syn population relative to the calculated anti
population,
ΔG
syn,cal
= -RT ln(∑Pop
syn
/

∑Pop
anti
). Eq. 3
ΔG
open,cal
is similarly defined as,
ΔG
open,cal
= -RT ln(∑Pop
open
/

∑Pop
closed
). Eq. 4
Intramolecular H-bonding interactions were investigated by second order perturbation
analysis of NBO orbitals.
27
The NBO framework ascribes charge transfer as the major
contributor to H-bonding, and enables comparison between relevant n
quinuclidine-N
→σ
O-H
*
interaction energies.
8.2.3. NMR Experiments
The conformational analysis of epiCF
3
QD in CDCl
3
and DMSO-d
6
was achieved via
NOESY with a concentration of 15 mM at 298 K, and the corresponding conformational
distribution was determined by
1
H NMR and
19
F NMR peak integrations. To determine
the syn-anti conformational distribution of epiCF
3
QD in other solvents, we initially
focused on the assignment of
19
F NMR signals. In most non-alcoholic solvents, the
19
F
390

NMR signal corresponding to the syn conformations appeared in the downfield to the anti
conformations (Figure 8.2-C and -D). In alcohols and water, the
19
F NMR signal of the
syn conformations appeared upfield. The assignment could be verified by adding CHCl
3

or DMSO into a particular solvent, which led to increase or decrease of the syn
population, respectively. When deuterated solvents were used, the population distribution
could also be determined by comparing the intensities of H9 signals in the
1
H NMR,
whose relative chemical shifts did not vary with solvent. Using these methods, the syn-
anti conformational distribution of epiCF
3
QD in 47 solvents was determined via
19
F
NMR peak integrations.
16
The Open-Closed conformational equilibria of QD and epiQD
in various solvents were derived based on
3
J
H8H9
coupling constants, which were
measured in the corresponding solvents with a concentration of 15 mM at 298 K.
8.3. Results and Discussion
8.3.1. Investigation of the Conformations of Quinidine Derivatives via
Quantum Chemical Calculation
Figure 8.1-E illustrates the most stable conformers of epiCF
3
QD in each local
minimum on the PES (See Section 8.5 for all 21 conformers). The indicated relative
energies of stable conformers on the PES slightly differ from those obtained after the
complete geometry optimization. At the B3LYP/6-311+(d,p) level of theory, seven
conformers were identified on the PES of 9-epiquinidine (epiQD) (Figure 8.1-C). Taking
the τ
3
rotation into consideration, the number of conformers increased to 13, and the most
stable species of conformers 1-7 are shown in Figure 8.1-F (See Section 8.5 for the
details of all 13 conformers). Because of the structural resemblance of quinidine (QD) to
391

cinchonidine (CD), the conformers of QD could be identified with the help of the PES of
cinchonidine (Figure 8.1-D).
8d
By including the τ
3
rotation into the conformer
exploration, 19 conformers were found (Open-11 was not found), and the minimum-
energy species of conformers 1-10 are shown in Figure 8.1-G.
As depicted in Figure 8.1-B, C and D, epiCF
3
QD, epiQD, and QD were found to
share several similar patterns on their PESs. First, seven major conformers, Closed-1,
Closed-2, Open-3, Open-4 (Open-9 for epiCF
3
QD), Open-5, Open-6, and Closed-7, were
distributed at relatively similar locations on the PESs of the three molecules, clearly
indicating their analogous conformational behavior (Figure 8.1-B, C and D). Second,
high barriers to τ
1
rotation have been observed in all three cases, which lead to the natural
categorization of conformers into two groups, namely, the syn- and the anti-
conformations. This was particularly important for the conformational study of
epiCF
3
QD, as it led to two NMR distinguishable signals responsible for the syn- and the
anti-conformers at room temperature, respectively. The direct measurement of the syn-
anti conformational equilibrium could thus be achieved through NMR peak integration.
16

Third, barriers to the τ
2
rotations were generally found in the range of a few kcal/mol.
With such low rotational barriers, signals of all syn (or anti) conformers of epiCF
3
QD
coalesce into a single peak in the
19
F NMR spectrum, significantly streamlining the
conformational analysis.
Apart from these similarities, noticeable differences in conformational distributions
were also observed. On the PES of QD, only two minima, Open-3 and Open-4, were
found in the zone of τ
2
≈180°-260° (Scheme 8.1-D). In comparison, the PES of epiCF
3
QD
392

in the same region proved more intricate. Three additional conformers were identified as
Open-4, Open-8 and Open-10, corresponding to eclipsed geometry along the C8-C9
bond. Presumably, the energetic cost for forming these seemingly unfavorable
conformers is largely reduced due to intramolecular H-bonding and the avoidance of a
crowded situation around the C9 atom. Compared with the scattered conformational
distribution in the region of τ
2
≈ 90°-120° on the PES of QD, no conformers were
identified in the same region for epiCF
3
QD. This can be due to steric interactions
between the CF
3
group and the H18 atom. epiQD was found to be conformationally less
diverse than QD and epiCF
3
QD (Figure 8.1-C). This could be ascribed to (a) significant
stabilization of Open-3 and Open-4 via intramolecular H-bonding (compared with QD)
and (b) less steric congestion around the C8-C9 bond in Open-3 and Open-4 (compared
with epiCF
3
QD). Moreover, while the conformational distribution of epiQD is restricted
due to high thermodynamic stabilities of Open-3 and Open-4 conformers compared with
others, the shallow PES of epiQD leads to a faster conformational exchange than
epiCF
3
QD.

393

Figure 8.1. A. Critical rotations considered in the conformational analysis; B-D. PES of
epiCF
3
QD, epiQD, and cinchonidine
8d
in the gas phase, respectively (Figure 8.1-D was
reproduced from Ref. 8d with permission); E-G. Representative conformers of
epiCF
3
QD, epiQD, and QD in the gas phase, respectively; Relative Gibbs free energies in
the gas phase are shown in parentheses.
394

8.3.2. Conformational Behavior of epiCF
3
QD
8.3.2.1. Conformational Study of epiCF
3
QD via
19
F NMR
By introducing the CF
3
group into quinidine, the conformational equilibrium around
τ
1
, namely the syn-anti equilibrium could be investigated in various solvents. According
to NOESY spectroscopy, the major species of epiCF
3
QD in CDCl
3
were Open-3-like
(syn) conformations, while the minor species adopted Open-4-like (anti) geometry
(Figure 8.2-A).
16
This result is similar to the above-mentioned calculations in the gas
phase. The relative populations of these two species were determined to be 83:17 by
19
F
NMR signal integrations, respectively. In DMSO, the Closed-1 and the Closed-2
conformations were adopted by epiCF
3
QD with a ratio of 50:50 (Figure 8.2-B).
Representative results have been shown in Figure 8.2-C, 8.2-D and Table 8.1. In
general, high syn:anti ratios were seen in solvents possessing low dielectric constants (ε),
such as pentane (ε = 1.84), benzene (ε = 2.27), and CHCl
3
(ε = 4.89). In contrast,
significant stabilization of anti conformation was found in solvents with relatively high ε,
such as acetone (ε = 21.0), acetonitrile (ε = 36.6), and DMSO (ε = 47.2). This trend is
consistent with both our theoretical calculations (Table 8.1) and previous
observations,
2,4,6a
which showed inverse correlation between the population of Open-3-
like conformations with ε of solvents.
395

Figure 8.2. A. Observed conformational distribution of epiCF
3
QD in CDCl
3
; B.
Observed conformational distribution of epiCF
3
QD in DMSO-d
6
; C.-D.
19
F NMR
spectrum of epiCF
3
QD in various solvents.
Apart from the agreement of experimental results with calculations, noticeable
differences were also observed. Nitrobenzene and nitromethane are “highly polar”
396

solvents based on their dielectric constants (ε = 35.6 and ε = 37.7, respectively).
However, the population of syn conformations (P
syn,exp
) of epiCF
3
QD in these two
solvents was found to be fairly high (78% and 82%, respectively), which is essentially the
same as the P
syn
in “non-polar” solvent toluene (ε = 2.28, P
syn,exp
= 82%, Figure 8.2-C,
spectrum 3; Figure 8.2-D, spectra 3 and 4). Despite the fact that water is among the most
polar solvent on the dielectric constant polarity scale (ε = 80.8), a relatively high P
syn,exp

(71%) was observed. Moreover, according to dielectric constants, the conformational
behavior of epiCF
3
QD in THF (ε = 7.52) and pyridine (ε = 10.4) was expected to be
similar to that in CH
2
Cl
2
(ε = 8.93). Instead, dramatically different conformational
distributions were found, as P
syn,exp
= 65% in THF, P
syn,exp
= 83% in CH
2
Cl
2
, and P
syn,exp

= 53% in pyridine. These exceptional results clearly indicate certain deficiencies of
dielectric polarity in describing solvent-solute interactions involving epiCF
3
QD. In other
words, specific interactions, such as H-bonding, may influence the conformational
behavior of cinchona alkaloids. It is worth noting that the possible effects of specific
interactions were also noticed by Bürgi and Baiker;
4
however, a clear mechanistic
rationale was not achieved due to the scarcity of the related data.

397

Table 8.1. Computational and Experimental Population Distributions of epiCF
3
QD at
298K and the corresponding relative Gibbs Free Energy (ΔG
syn
) of syn conformations of
epiCF
3
QD in Various Solvents.

a
Calculated based on the relative ΔG of each conformer at the PCM-M06-2X/6-
311+G(d,p)//B3LYP/6-311+G(d,p) level of theory. Thermal corrections to ΔG were
obtained at the B3LYP/6-311+G(d,p) level of theory;
b
measured via
19
F NMR
spectroscopy at 298K;
c
dielectric constant of solvents (ε), refractive index of solvents
(n), and solvatochromatic polarity parameter (E
T
N
), taken from ref. 29b, page 550-552;
d

polarity/polarizability parameter (π*), H -bond donating ability (α), and H -bond accepting
ability (β), taken from ref. 33b;
f
derived from linear combination of (n
2
-1)/(n
2
+2), π*, α
and β using linear regression.
398

8.3.2.2. Elucidation of Solvent Effects via Linear Free Energy Relationship (LEFR)
Thanks to a wealth of conformational information of epiCF
3
QD, a systematic
exploration of solvent effects on the syn-anti equilibrium was possible by means of linear
free energy relationship (LFER).
28
By correlating solvation energy data with solvent
polarity scales, LFER has been successfully utilized in elucidating various complicated
solvent-solute interactions.
28b, 29
In principle, the establishment of a good linear
relationship with a solvent polarity scale indicates the predominance of the corresponding
solvent-solute interaction in a chemical process or equilibrium. To examine the
previously proposed accuracy of the Onsager function
30
in predicting the population of
the Open-3-like conformations,
4
we attempted to establish a linear correlation of ΔG
syn,exp

with (ε-1)/(ε+2).
31
However, only a moderate correlation (R
2
= 0.351) was obtained with
39 data points (Table 8.2, see Section 8.5 for details), excluding electrostatic interaction
as the dominant solvent effect in the syn-anti equilibrium. Similarly, plotting the
previously reported ΔG
open-3
of cinchonidine (CD)
4, 32
against (ε-1)/(ε+2) also led to
moderate correlation (R
2
= 0.361). Both of these results are in agreement with the notion
that specific interactions also significantly influence the conformational behavior of
cinchona alkaloids and their derivatives (See Section 8.5 for details).

399

Table 8.2. LFER Analysis of Solvent Effects on the Conformational Behavior of
Quinidine and Its Derivatives

To describe the complicated case of multiple solvent effects, a multiparameter
approach, incorporating both specific and nonspecific aspects of solvation by means of
linear combination, is necessary.
28b,29b,33
Given the fact that cinchona alkaloids are known
to form π -π complexes at high con centrations,
34
dispersive forces should be taken into
consideration as part of the solvent effect. H-bonding interactions are expected to be
predominant due to the presence of the quinoline/quinuclidine and the hydroxyl
functionalities. Based on this analysis, the multiparameter expression should be
composed of at least four independent parameters, namely, (a) the polarization term (ε -
1)/(ε+2) (reflects electrostatic interaction, denoted by Y),
28b
(b) the polarizability term (n
2
-
1)/(n
2
+2) (reflects London’s dispersion force, denoted by P),
28b
and (c) the H-bond
donating and accepting ability α and β.
35
Since overall nonspecific solvent-solute
400

interactions can be approximated by the empirical polarity scale π* (primarily a blend of
dipolarity Y and polarizability P) with a polarizability correction term p·(n
2
-1)/(n
2
+2),
36
a
multiparameter polarity scale was devised as
XYZ=XYZ
0
+a·α+b·β+s·π*+d·P,
37

where XYZ
0
, a, b, s, and d are solvent independent regression coefficients and
indicative of the sensitivity of the conformational equilibrium toward the corresponding
solvent property. This equation resembles the well known Kamlet-Taft expression.
35
To
compare the quality of the correlation with XYZ, XYZ’ (XYZ ’ =
XYZ
0
’+a·α+b·β+y·Y+p·P) and the empirical polarity scale E
T
N 38
were also investigated.
In the XYZ scale, the nonspecific polarity term s·π*+p· P accounts for effects induced by
solvent dipoles, quadruples, higher multipoles and dispersive force. On the other hand,
because the nonspecific polarity term y·Y+p·P can only describe dipolar and dispersive
interactions, the XYZ’ scale differs from the XYZ scale mainly as the former does not
include quadruplar and higher multipolar interactions.
36b

401

Figure 8.3. A. Correlation of ΔG
syn,exp
of epiCF
3
QD with multiparameter polarity scale
XYZ
1
; B. Correlation of ΔG
syn,exp
of epiCF
3
QD with H-bond accepting ability (β) of
various solvents; C. Plot of ΔG
syn,exp
of epiCF
3
QD versus (ε -1)/(ε+2) of various solvents
(dielectric interaction).

402

Table 8.1 and Figure 8.3-A show fairly good linearity between ΔG
syn,exp
and the
XYZ
1
polarity scale (R
2

= 0.868). A good correlation was also obtained with the XYZ
1
’
scale, presumably excluding effects induced by solvent quadrupoles and higher
multipoles.
36b
In contrast, ΔG
syn,exp
was found to weakly correlate with E
T
N
(See Section
8.5 for details). In spite of the weak dependence of ΔG
syn,exp
with the single parameters Y,
P, π*, and α, the H-bond accepting ability of solvents (β) was found to well correlate to
ΔG
syn,exp
. The coefficient of the ΔG
syn,exp
-β correlation was essentially the same as that of
the ΔG
syn,exp
-XYZ correlation, revealing the predominance of the H-bond accepting
ability of solvents in overall solvent effects (Figure 8.3-B).
The positive correlation of ΔG
syn,exp
with β in Figure 8.3-B indicates that the syn
conformations are stabilized in solvents with low β values. This observation can be
attributed to different steric environments around the hydroxyl group in the syn and the
anti conformations (Figure 8.4-A). In the syn conformations, the hydroxyl group is
sterically insulated by the quinoline ring and thus less involved in H-bonding interaction.
In contrast, Ring B of the quinoline moiety and the hydroxyl group orient apart from each
other in the anti conformations, thereby making the hydroxyl group an effective H-bond
donor. The H-bonding thus tends to stabilize anti conformations more than its syn
counterparts and such a preference is expected to increase with the increased β value. In
general, hydrocarbon-based solvents and their halogenated derivatives are poor H-bond
acceptors; this results in relatively large energy differences (ca. -1.0 kcal/mol) between
the syn and the anti conformations. Some ethers, such as diethyl ether (Et
2
O), di-n-butyl
ether (n-Bu
2
O), and THF, possess moderate H-bond acceptance, thus leading to moderate
403

ΔG
syn,exp
values (ca. -0.4 kcal/mol). Such ΔG
exp
-β correlation was particularly strong
within the alcoholic solvent set, which demonstrated almost perfect linearity in the series
H
2
O, ethylene glycol, MeOH, EtOH and i-PrOH (Figure 8.3-B).

Figure 8.4. A. Plausible role of H-bonding interaction in the syn-anti conformational
equilibrium; B. Determination of H-bond accepting ability (β) using solvatochromic
probe, in which the H-bond acceptor possesses less steric encumbrance than the hydroxyl
group in epiCF
3
QD; C. Steric effect of solvents on the conformational distribution.
ΔG
syn,exp
varies significantly with relatively unchanged β values, revealing the steric
effect on solvents influencing the conformational distribution of epiCF
3
QD.
404

Apart from these good linear relationships, noticeable deviations of ΔG
syn,exp
from the
β-scale were also observed. For example, according to β values, all ethers of interest
possess similar H-bond accepting abilities (0.30 < β < 0.54); nevertheless, significantly
higher ΔG
syn,exp
values were observed in aromatic ethers than in saturated ethers (Figure
8.4-C, Example 1). Since the β-scale was derived based on the H-bonding interaction of
sterically “non-hindered” p-nitroaniline (and other structurally similar probes), the steric
effects of H-bond acceptors on β values should be minimal (Figure 8.4-B). In comparison,
the hydroxyl group in epiCF
3
QD is located in a rather crowded environment. The H-
bonding interaction of epiCF
3
QD with ethers is expected to decrease as the steric
hindrance around the ethereal oxygen atom increases (aromatic ether > n-Bu
2
O > other
ethers). Likewise, although acetonitrile, acetone, ethyl acetate, and Et
2
O are similar in β
values, their stabilizing effects on the anti conformations were found to gradually
decrease with the steric encumbrance around the H-bond accepting site (Figure 8.4,
Example 2).
Regarding the ΔG
syn,exp
-(ε-1)/(ε+2) correlation, the most significant data scattering
was found in the moderate polarity region (0.3 < (ε -1)/(ε+2) < 0.7). We ascribe this
observation to the incapability of (ε -1)/(ε+2) in describing steric effects and H-bond
accepting ability. For example, although the presence of the NO
2
group and C-Cl bond
can largely increase the ε of solvents, these moieties per se are quite weak H-bond
acceptors. Significant deviation in ΔG
syn,exp
-(ε-1)/(ε+2) correlation was observ ed due to
such mismatching.
405

In contrast, a close association of ΔG
syn,exp
with dielectric constant polarity was found
in solvents possessing high or low ε values. Large ΔG
syn,exp
(ca. -1.0 ‒ -0.8 kcal/mol)
values were commonly observed in solvents with (ε -1)/(ε+2) values < 0.3, whereas
ΔG
syn,exp
became rather small (ca. 0.0 ‒ -0.3 kcal/mol) with high (ε -1)/(ε+2) values (>
0.7). Although this trend appears in good agreement with the previous conclusion by
Bürgi and Baiker, this consistency may just simply be due to the positive interrelation
between the β and the ε scales. Strong H -bond accepting ability generally necessitates
significant charge separation within solvent molecules (such as DMSO and DMF), which
in turn leads to high ε values. On the other han d, solvents containing no dipolar moieties,
such as hydrocarbons, have both low dielectric constants and weak H-bond accepting
ability.
Fairly good linearity (R
2
= 0.964) was established between ΔG
syn,exp
and (ε-1)/(ε+2)
in the family of simple alcohols (water, ethylene glycol, MeOH, EtOH, n-PrOH and i-
PrOH), as ΔG
syn,exp
decreased with the increase in dielectric constant. Moreover, a strong
negative correlation (R
2
= 0.969) was also found between β and (ε -1)/(ε+2) in simple
alcohols, implying the complicated interrelation of ΔG
syn,exp
, (ε-1)/(ε+2) and β . Gas phase
calculations have shown that binding energies of aniline (as a donor) with water, MeOH,
EtOH and n-PrOH (as acceptors) are essentially the same; namely, their “intrinsic” H -
bond accepting abilities are identical (See Section 8.5 for details). This reveals that the
different H-bond accepting abilities of these structurally similar alcohols mainly originate
from their dielectric constants. In other words, with increased dielectric constant, an
alcoholic solvent tends to solvate itself more strongly via dipolar interaction, therefore
406

leading to decreased H-bond accepting ability. Due to practically the same “intrinsic” H -
bond accepting abilities of simple alcohols, solvation energies of the syn and the anti
conformers in these solvents are anticipated to strongly correlate with (ε -1)/(ε+2).
Therefore, the difference in solvation energies of the syn and the anti conformers
(ΔG
syn,exp
) is also proportional to (ε -1)/(ε+2). This result evidently shows that the Onsager
function can be applicable in the cases wherein the influence of other interactions is
essentially similar or negligible. Similar good correlations were also found with other
solvent polarity scales, including α, π* and E
T
N
. It can be concluded that ε, α, β, π* and
E
T
N
values of simple alcohols are interrelated to a certain extent.
8.3.2.3. Comparison of Theoretical Calculations with Experimental Data
Based on the DFT calculations mentioned in 8.3.1, ΔG
syn,cal
of epiCF
3
QD obtained in
18 solvents was plotted against the corresponding ΔG
syn,exp
, which yielded a moderate
correlation with a R
2
value of 0.381 (Figure 8.5-A, red line). In contrast, ΔG
syn,cal
was
found to be strongly correlated to (ε -1)/(ε+2) (R
2
= 0.967), resembling the Onsager
model. Because of this, the moderate correlation between ΔG
syn,exp
and ΔG
syn,cal
can be
ascribed to the inconsistency of (ε -1)/(ε+2) with β, as conf irmed by the resemblance of
the β-(ε-1)/(ε+2) plot to the ΔG
syn,exp
-ΔG
syn,cal
plot (Figure 8.5-A and -C). As depicted,
ΔG
syn,exp
and ΔG
syn,cal
significantly diverged when β and (ε -1)/(ε+2) values were
“mismatched” (Figure 8.5-A and -C, red spots without circles).
407

Figure 8.5. A. Correlation of ΔG
syn,exp
of epiCF
3
QD with ΔG
syn,cal
; five uncircled
calculated ΔG
syn,cal
values significantly diverge from the experimental data; B.
Correlation of ΔG
syn,cal
of epiCF
3
QD with (ε -1)/(ε+2) of various solvents (dipolar
interaction); C. Correlation of (ε -1)/(ε+2) with β, which shows a scattered pattern similar
to Figure 8.5-A.
408

Even though ΔG
syn,exp
and (ε-1)/(ε+2) were found to be positively correlated in
alcohols (See Section 8.5 for details), theory predicted the opposite result (Figure 8.5-B).
In our PCM-based calculation, only epiCF
3
QD is considered in the reaction field. This
differs from the actual solvation, in which the reaction field interacts with the H-bonded
epiCF
3
QD-alcohol complexes (ROH-syn or ROH-anti) instead of the syn or anti
conformations of epiCF
3
QD. We attribute such contrasts to different signs of the
(μ
syn
2
/r
syn
3
- μ
anti
2
/r
anti
3
) and (μ
ROH-syn
2
/r
ROH-syn
3
- μ
ROH-anti
2
/r
ROH-anti
3
) terms in the
corresponding Onsager function, where μ
i
is the dipole moment of a conformer or its H-
bonded complex, and r
i
is the radius of the corresponding species (Eq. 3 and Eq. 4).
Δ

ε 1
ε+2

Δ

ε 1
ε+2

8.3.3. Conformational Behavior of epiQD in Various Solvents
As mentioned in Section 8.3.1, DFT calculations have provided ΔG
open,cal
of the 13
conformers of epiQD in the gas phase. Two major conformers were identified in the gas
phase, as Open-3a and Open-4a, with relative energies of 0.0 and 0.4 kcal/mol,
respectively (Table 8.3). Other than these two species, all other conformers are fairly
energetically unfavorable (ΔG > 3.5 kcal/mol). Similar to epiCF
3
QD, the intramolecular
quinuclidine-N
…
H-O H-bonding has been found in Open-3a and Open-4a as indicated by
the short N-H contacts. According to second order perturbation theory analysis,
39
the
donor (lone pair on N)-acceptor (σ
O-H
*) interaction energies were around 0.5 kcal/mol or
less. Compared with the internal H-bonding in Open-3a of epiCF
3
QD of 5.7 kcal/mol
409

bonding energy, the internal H-bonding in epiQD is substantially weak. Because the
N
…
H distances and N
…
H-O bond angles in epiQD conformers are close to the
corresponding values in Open-3a of epiCF
3
QD, the significantly smaller interaction
energy can be attributed to the weaker acidity of the OH group in the non-fluorinated
counterpart. Moreover, with calculated H8-C9-C8-H9 dihedral angles (φ
H8H9
) on hand,
the corresponding vicinal coupling constants (J
H8H9
) of different conformers were
obtained via a modified Karplus equation by Altona and co-workers,
40
in which both
substituent and stereochemistry effects are taken into consideration.

Table 8.3. Calculated Properties of Different Conformers of epiQD in the Gas Phase.
a

Conformer
ΔG
(kcal/mol)
b

Pop
(%)
c

φ
H8H9
d

J
H8H9
(Hz)
e

J
H8H9
×Pop (Hz)
f

Closed-1a 5.6 0.0 299.4 3.41 0.0
Closed-1b 3.8 0.1 299.0 3.36 0.0
Closed-2b 5.1 0.0 293.9 2.80 0.0
Closed-7c 4.6 0.0 290.1 2.41 0.0
Open-3a 0.0 67.8 185.3 8.81 6.0
Open-3b 4.7 0.0 169.5 8.40 0.0
Open-4a 0.4 31.9 184.8 8.84 2.8
Open-4b 4.9 0.0 165.6 8.02 0.0
Open-4c 8.6 0.0 165.6 8.02 0.0
Open-6a 4.9 0.0 60.1 3.47 0.0
Open-6b 3.5 0.2 60.3 3.45 0.0
Open-5a 7.5 0.0 62.8 3.71 0.0
Open-5b 5.6 0.0 60.0 3.48 0.0
a
Calculated at the M06-2X/6-311+G(d,p)//B3LYP/6-311+G(d,p) level of theory. See the
Method section for details of calculations;
b
relative Gibbs Free Energies (ΔG) to Open-
3a;
c
population (Pop);
d
dihedral angle of H
8
-C
9
-C
8
-H
9
(φ
H8H9
);
e
predicted J
H8-H9
based
on modified Karplus equation;

f
the coupling constant contribution of each conformer to
the overall J
H8H9
.
410

As shown in Table 8.3, the overall fraction of Open-3 and Open-4 was calculated to
be >99.6% in solvents under investigation, and the ΔG
open-3
was obtained based on the
corresponding Pop
open-3
/Pop
open-4
values. Plotting the ΔG
open-3
against (ε-1)/(ε+2) led to a
perfectly straight line (R
2
= 1.000), which resembles the Onsager function. To quantify
the population distribution of epiQD in different solvents, we adopted a method described
by Baiker et al,
4
which assumed the observed J
H8H9
as a weighted averaged coupling
constants of all conformers, namely ∑( Pop
(i)
×J
H8H9(i)
). Given the facts that the observed
J
H8-H9
was almost constant in all solvents and Open-3 and Open-4 had essentially the
same J
H8-H9
, these two conformers are assumed to be dominant in all solvents. This result
is in good agreement with our calculated coupling constant, in which J
H8H9
was shown to
be invariable upon changing solvents (Table 8.4). Hence, it could be concluded that
conformers with ΔG > 3.5 kcal/mol in the gas phase were unlikely to be significantly
populated in solution. Moreover, the NOESY of epiQD in CD
2
Cl
2
and DMSO-d
6
also
identified both Open-3 and Open-4 as major conformers with very similar correlation
patterns, revealing that the Pop
open-3
/Pop
open-4
ratio did not change significantly in
different solvents (See Section 8.5 for details). According to the gas phase calculation at
the B3LYP/6-311+G(d,p) level, Open-3 and Open-4 possessed very similar dipole
moments (5.20 and 5.42, respectively). Thus the dipolar interaction on the
conformational equilibrium should be quite insignificant.

411

Table 8.4. PCM-Based Calculated Conformational Distribution of epiQD in Various
Solvents.
a

solvent
Pop
open-3
/Pop
open-4
(%/%)
a,b

ΔG
open-3
(kcal/mol)
a

J
H8H9,cal
(Hz)
c

J
H8H9,exp
(Hz)
d

benzene 61.9/37.8 -0.29 8.8 9.8
toluene - - - 9.8
CHCl
3
57.5/42.3 -0.18 8.8 9.8
CH
2
Cl
2
- - - 9.9
THF 55.4/44.3 -0.13 8.8 9.7
i-PrOH - - - 9.8
acetone - - - 9.8
EtOH - - - 9.4
MeOH 51.4/48.3 -0.03 8.8 9.3
PhNO
2
- - - 9.8
MeCN 51.3/48.4 -0.03 8.8 9.5
MeNO
2
- - - 9.9
DMF - - - 9.8
DMSO 51.0/48.7 -0.02 8.8 9.0
H
2
O 50.5/49.1 -0.01 8.8 9.3
a
Calculated at the PCM-M06-2X/6-311+G(d,p)//B3LYP/6-311+G(d,p) level of theory.
See the Method section for details of calculations;
b
according to the calculation, Open-3
and Open-4 were found to be the major conformers, and the overall population of other
conformers ranges from 0.2-0.4% in various solvents;
c
predicted J
H8-H9
based on
modified Karplus equation;
d
measured by
1
H NMR (500 MHz) in deuterated solvents.
8.3.4. Conformational Behavior of QD in Various Solvents
The conformational distribution of QD in the gas phase was calculated as described in
the Method section. As shown in Table 8.5, QD is more conformationally flexible than
epiQD, which is not only reflected by its higher number of conformers (19 minimum
energy conformers were found for QD), but also by its shallower PES in the gas phase.
412

Table 8.5. Calculated Properties of Different Conformers of QD in the Gas Phase.
a

Conformer
ΔG
cal

(kcal/mol)
b

Pop
(%)
c

φ
H8H9
d

J
H8H9
(Hz)
e

J
H8H9
×Pop (Hz)
f

Closed-1a 3.1 0.4 175.4 9.15 0.0
Closed-1b 1.2 9.2 173.3 9.13 0.8
Closed-2a 3.3 0.3 175.6 9.15 0.0
Closed-2b 1.8 3.6 176.0 9.15 0.3
Closed-7a 4.1 0.1 179.8 9.11 0.0
Closed-7b 2.4 1.3 178.9 9.13 0.1
Closed-7c 2.0 2.6 179.6 9.11 0.2
Open-3b 0.0 74.4 78.3 0.95 0.7
Open-3c 2.3 1.7 82.5 0.92 0.0
Open-4a 4.0 0.1 60.2 1.89 0.0
Open-4b 3.1 0.4 80.7 0.92 0.0
Open-9b 3.3 0.3 80.4 0.92 0.0
Open-9c 3.2 0.3 81.3 0.92 0.0
Open-5b 4.3 0.1 281.4 1.38 0.0
Open-6a 4.7 0.0 293.8 2.27 0.0
Open-6b 2.9 0.5 287.2 1.73 0.0
Open-6c 3.5 0.2 315.3 4.58 0.0
Open-8c 9.0 0.0 316.6 4.72 0.0
Open-10c 1.4 6.5 317.1 4.78 0.3
a
Calculated at the M06-2X/6-311+G(d,p)//B3LYP/6-311+G(d,p) level of theory. See the
Method section for details of calculations;
b
relative Gibbs Free Energies (ΔG
cal
) to Open-
3b;
c
relative population (Pop);
d
dihedral angle of H
8
-C
9
-C
8
-H
9
(φ
H8H9
);
e
predicted J
H8H9
obtained via modified Karplus equation;

f
the coupling constant contribution of each
conformer to the overall J
H8H9
.

Compared with epiQD, which only had two conformers possessing ΔG < 3.0
kcal/mol, eight conformers were found for QD within that energy range. Similar to
cinchonidine,
4,8d
Open-3b, Closed-1b, Closed-2b, Closed-7c, and Open-10c were
identified to be important conformers with population higher than 2%. Differing from the
413

Open-3 conformation of epiCF
3
QD and epiQD, the stereochemistry of QD does not allow
the formation of internal H-bonding in its Open-3 conformation (Figure 8.1-G). Instead,
internal H-bonding was found in Open-10c, which provided an extra stabilization of 3.0
kcal/mol as indicated by the second order perturbation theory analysis.
39

Table 8.6. Conformational Distribution of QD and ΔG
open,exp
in Various Solvents.
solvent
J
H8H9,exp
(Hz)
a,b

Pop
open,exp
(%)
c

ΔG
open,exp
(kcal/mol)
d

ΔG
open,cal
(kcal/mol)
e

dioxane 4.3 59 -0.21 -
benzene 3.9 64 -0.34 -0.56
p-xylene 3.4 70 -0.49 -
PhCl 4.4 58 -0.18 -
THF 4.9 52 -0.04 -0.0
o-C
6
H
4
Cl
2
4.9 52 -0.04 -
ClC
2
H
4
Cl 5.4 46 0.10 -
pyridine 4.9 52 -0.04 0.183
i-PrOH 2.0 87 -1.12 0.28
acetone 5.4 46 0.10 0.29
EtOD 2.5 81 -0.88 0.36
MeOD 2.8 77 -0.71 0.35
PhNO
2
5.4 46 0.10 0.38
MeCN 7.8 16 0.97 0.38
MeNO
2
7.3 22 0.74 0.38
DMF 4.9 52 -0.04 0.38
DMSO 4.9 52 -0.04 0.40
H
2
O 7.3 22 0.74 0.45
a
Observed J
H8H9
, measured by
1
H NMR (500 MHz) in deuterated solvents as indicated;
b
significant line broadening of the H
8
signal (d) was found in many cases, which leads to
difficulty in determination of J
H8H9,exp
. Under such circumstance, J
H8H9,exp
was achieved
by measuring the coupling constant of the doublet of the H
9
signal (td);
c
population of
Open-conformations calculated based on J
H8H9,exp
and modified Karplus equation;
d

414

derived based on Pop
open,exp
using the Boltzmann equation;
e
free energy difference
between the calculated syn population relative to the calculated anti population (ΔG
open,cal

= -RT ln(∑Pop
open
/

∑Pop
closed
))

As described in the Section 8.2.1, ΔG
open,cal
in various solvents was calculated based
on the overall population of Open conformations, i.e. Open-3~8 and Open-8~10. The
ΔG
open,cal
was found to perfectly correlate with (ε-1)/(ε+2) of 13 solvents with R
2
of 0.998
(Figure 8.6-B). The population of Open-3b significantly decreases with the increase in
dielectric constant of solvents, while the population of Closed conformers generally
increases in solvents with high dielectric constant. This result could be ascribed to the
relatively lower dipole moment of Open-3b (μ = 2.65 in the gas phase) compare d with
other conformers (μ > 3.12 in the gas phase).

To quantify the population distribution of QD in solvents via J
H8-H9
analysis, we
adopted the two-equation-two-variable linear system described by Baiker et al.
4
As the
Closed conformations had essentially the same coupling constant, the linear system
involved two equations and at least three variables, Pop
Open-3
, Pop
Closed
, and Pop
Open-10

(Eq. 5 and 6).

5

6
415

where J
H8H9
obs
is the observed J
H8H9
; J
H8H9
Open-3
, J
H8H9
Closed
and J
H8H9
Open-10
are J
H8H9

of Open-3, Closed and Open-10 conformations, respectively. Pop
Open-3
, Pop
Closed
and
Pop
Open-10
are the population of Open-3, Closed, and Open-10 conformations,
respectively.
According to the NOESY spectrum, Open-10c was not a major conformer in solution,
which was consistent with both the present and the previous PCM calculations.
8d

Moreover, it was anticipated that the population of Open-10c could further decrease in H-
bond acceptor solvents because of diminishing internal H-bonding. Therefore, with
moderate J
H8H9
values, the contribution from J
H8H9,exp
of Open-10c to the observed vicinal
coupling constant was estimated to be even lower than the PCM-derived value of 0.5 Hz.
Apparently, the exclusion of the contribution from Open-10c only led systematic errors in
quantification, which did not significantly affect the trend of solvent dependence.
On this basis, a two-equation-two-variable linear system similar to the previous
expression
4
was formulated (Eq. 1 and Eq. 2), which allowed the determination of
(Pop
Open
/Pop
Closed
)
exp
via J
H8H9
analysis (Table 8.6). ΔG
open,exp
in 18 solvents was thus
obtained. Even though ΔG
open,exp
was almost independent on (ε-1)/(ε+2) (R
2
= 0.088,
Table 8.2), a good correlation was found within the family of alcoholic solvents. It
appears that the PCM calculations are in agreement with the experimental data, which
also demonstrate a positive correlation between ΔG
open,exp
and (ε-1)/(ε+2). Nevertheless,
as discussed in Section 8.2.2.3, such a convergence is more likely to be fortuitous and the
two positive correlations should have de facto different physical origins.

416

Figure 8.6. A. Correlation of ΔG
open,exp
with multiparameter XYZ
2
; B. Correlation of
ΔG
open,cal
of QD with (ε -1)/(ε+2) of various solvents (dielectric interaction); C.
Correlation of multiparameter XYZ
2
with (ε-1)/(ε+2).

On the other hand, a good linear relationship of ΔG
open,exp
was established with
multiparameter XYZ
2
, which is a linear combination of α, β, π*, and a polarizability
correction term p·P (R
2
= 0.872) (Figure 8.6-A and Table 8.2). In contrast, the
417

multiparameter XYZ
2
’, namely XYZ
0
’+yY+pP+aα+bβ, was a relatively less correlating
scale, presumably owing to the exclusion of quadrupole and higher multipole terms. To
assess the reliability of PCM-based calculations, XYZ
2
was plotted against (ε -1)/(ε+2) to
yield a very weak correlation (Figure 8.6-C). Evidently, the present PCM calculation,
essentially operating as the Onsager function, was unable to accurately describe the
solvation of QD, which involved interacting mechanisms other than dielectric interaction.
Figure 8.7-A demonstrates the contribution from individual polarity parameter to the
multiparameter XYZ
2
. According to the large values of s·π* terms, aromatic solvents
were as “polar” as other solvents , such as CH
3
CN and CH
3
NO
2
, thus leading to the
expectation of large ΔG
open
. However, the high π* polarity of aromatic solvents was
largely compensated for polarizability correction term p·P (Figure 8.7-A, notice the
significant blue bars (p·P) of aromatic solvents compared with the small p·P values of
CH
3
CN and CH
3
NO
2
). This may imply that the Open conformations (mainly Open-3)
were stabilized by solvent-solute π-π interaction (Figure 8.7-B). Such effects were
particularly obvious for the conformational equilibrium in CH
3
NO
2
and PhNO
2
, as
Pop
open
was found doubled in the latter (Table 8.6).
As shown in Figure 8.7-A, the overall H-bonding interaction was approximately the
same in H
2
O and alcohols (notice purple bars and green bars of alcohols in Figure 8.7-A).
Therefore, the significant destabilization of Open conformations in H
2
O, compared with
alcohols, is primarily due to dielectrics (notice red bars of alcohols in Figure 8.7-A).

418

Figure 8.7. A. Contribution from individual solvent properties to the multiparameter
XYZ
2
; B. rationalization of stabilization/destabilization from different solvent-solute
interactions.

Based on the multiparameter dissection, it is also obvious that the exceptionally high
Pop
open
in alcohols is due to both H-bond accepting and donating capacity of the solvents,
which dwarfs other nonspecific van der Waals interactions (s·π+ p·P). Intriguingly,
419

similar to the observation with epiCF
3
QD, the H-bond accepting ability of solvents was
also found to stabilize the anti conformations of QD (Open-3, Figure 8.3-B). The
relatively weak impact of β on the co nformational equilibrium of QD is in part due to the
lower acidity of the OH and the absence of intramolecular H-bonding in major
conformers. On the other hand, the stabilization of Open conformations by H-bond
donation from solvents can be rationalized by the higher accessibility of the quinuclidine
nitrogen in the respective conformations (Figure 8.3-B).

8.3.5. Elucidation of Catalytically Active Conformations Using the
Trifluoromethyl Group as a Conformational Stabilizer: A Case Study.
To demonstrate the utility of the trifluoromethylated cinchona alkaloid scaffolds as
active conformation probes, an enantioselective cyclopropanation reaction previously
reported by Gaunt et al. was chosen as a model reaction (Scheme 8.3, Eq. 7). The
proposed reaction mechanism involves an initial S
N
2 reaction between catalyst MeOQD
and α-bromoacetate 3.
21
Afterwards, the formed quaternary ammonium salt 5 undergoes
α-deprotonation in the presence of base to yield the ammonium ylide 5-H
+
, which further
reacts with α,β -unsaturated carbonyl compound 2 via Michael addition. Afterwards,
intermediate 6 undergoes a ring-closing reaction to form the cyclopropane 4 and releases
MeOQD. A handful of studies have looked into some of the mechanistic aspects of this
reaction, such as catalyst deactivation,
21d
and the effect of proton transfer.
41
However, the
role of conformations in the catalysis has remained unexplored.
420

Scheme 8.3. Cinchona Alkaloid Derivative-Catalyzed Enantioselective Cyclopropanation
Reaction.

To investigate the active conformers in this cyclopropanation reaction, a series of
cinchona alkaloids with different conformational preferences were synthesized. For
epiMeOCF
3
QD, Open-3, 4, and 6 were found to have relative energies > 3.5 kcal/mol in
the gas phase (Figure 8.8-A). These three species can be excluded as abundant
conformers in CH
3
CN due to their very high relative energies (See discussion in Section
8.3.3). The result was in good agreement with both X-ray crystal structure, NOESY and
19
F NMR spectroscopy, which revealed the Closed-2 conformation to be the major
species with a population of ca. 95% in CH
3
CN.
42

In addition to epiMeOCF
3
QD, BnOMeQD and MeOMeQD were also synthesized.
43

These two molecules possess conformational rigidity and steric encumbrance around the
quinuclidine-N higher than MeOQD but lower than epiMeOCF
3
QD. As shown by
421

NOESY spectroscopy, Open-3 and Open-4 conformers are the major conformations
adopted by MeOMeQD and BnOMeOQD in CH
3
CN.
44
This was consistent with DFT
calculations both in the gas phase and in CH
3
CN, which showed substantial energetic
preference of Open-3 and Open-4 (Figure 8.8-B).

Figure 8.8. A.-C. Calculated energy minimum conformations of epiMeOCF
3
QD,
MeOMeQD, and MeOQD in the gas phase and in CH
3
CN, respectively. For
epiMeOCF
3
QD and MeOMeQD, the Gibbs Free Energies are relevant to Closed-2. For
MeOQD, the Gibbs Free Energies are relevant to Open-3. See the Method section for
details of calculations.
422

To investigate effects of the stereochemistry of C9 carbon on the catalysis,
epiMeOQD was also prepared. According to the DFT calculation both in the gas phase
and in CH
3
CN (with the PCM model), all six conformers of epiMeOQD demonstrated
very similar relative energies, indicating its highly flexible backbone (see Section 8.5 for
details). Due to the existence of six conformers in CH
3
CN, quantitative conformational
analysis was not permitted by the above mentioned two-variable-two-equation linear
system. However, since the
3
J
H8-H9
decreased in an order of Open-3 and -4, Open-5 and -
6, Closed-1 and -2, it could be inferred that epiMeOQD mainly assumed Open-3 and -4
in CH
3
CN (Figure 8.9). Based on DFT calculation of MeOQD, Open-3, Closed-1, and
Closed-2 were possible species in CH
3
CN (Figure 8.8-C). Employing Baiker’s two -
variable-two-equation protocol, the Open population was computed to be 10%. As shown
by NOESY, the major conformer is Closed-2, which is consistent with DFT calculation.
To search catalytic active conformations, we initially performed a series of
cyclopropanation reaction using different probes. As depicted in Figure 8.9, both
MeOQD and epiMeOQD demonstrated high activity in terms of reaction yields, while
epiMeOCF
3
QD, MeOMeQD, and BnOMeQD were relatively catalytically inefficient.
This result was further verified by the time dependence in the concentration of α-
bromoacetate in the cyclopropanation reaction at 343 K (blue and green spots in Figure
8.10).
45
Because epiMeOCF
3
QD exclusively adopts Closed-2, Closed-1 and Open-5
conformations, it can be inferred that these three conformations (particularly the most
populated Closed-2) are of low catalytic activity, i.e. Open-3, 4, and 6 can be catalytically
active. Moreover, as shown by a control experiment, the cyclopropane product could also
423

be generated with 12%
1
H NMR yield in the absence of tertiary amine catalysts. This
observation implies that the reaction in the presence of epiMeOCF
3
QD is mainly a
background reaction.
46

Compared with epiMeOCF
3
QD, MeOMeQD and BnOMeQD are conformationally
less restricted, therefore demonstrating a considerable amount of Open-3 and 4
conformers in CH
3
CN, which allowed the formation of 5-type active intermediate
(Scheme 8.3). Due to the presence of the methyl group on the C9 atom, the quinuclidine-
N is more sterically hindered than MeOQD and epiMeOQD. The reactions with
MeOMeQD and BnOMeQD thus possibly involved 5-type active intermediate, which
rendered the product in high enantioselectivity but with low yield. Intriguingly, the
chirality around the C9 atom was found not to influence the stereochemical outcome of
the cyclopropanation reaction, implying that reactions promoted by different probes
involved a similar transition state structure.

424

Figure 8.9. Conformational distribution of active conformation probes and their catalytic
activity.

To further validate the hypothesis of Open-3 and -4 as active conformations, we
investigated the nucleophilic substitution reaction between the conformational probes and
α-bromoacetate (Figure 8.9). At 298 K, both MeOQD and epiMeOQD were found to
undergo the substitution reaction, whose rate was significantly accelerated at 343 K. As
such, the decay of ester in the reaction with MeOQD in CH
3
CN at 343 K was appreciably
faster than that in the corresponding cyclization reaction at 343 K, implying the
nucleophilic substitution was not the rate determining step (red and blue spots, Figure
8.10-A). This was further confirmed by the observation of the active quaternary
425

ammonium intermediate (5) as the predominant derivative of MeOQD under the standard
reaction conditions (Figure 8.10-B). Moreover, given the fact that 6 was not observed as
an abundant species, the Michael addition reaction was possibly the rate determining step.

Figure 8.10. A. Time-dependent concentration of t-butyl α-bromoacetate under different
reaction conditions. Time-dependent concentrations of α -bromoacetate in the presence of
10 mmol% MeOQD and epiMeOCF
3
QD were computed based on reaction rates of α -
bromoacetate with 1 equiv of the corresponding N-nucleophiles; B-(a)
1
H NMR spectrum
of MeOQD in CD
3
CN at 343 K; B-(b)
1
H NMR spectrum of MeOQD and quinuclidine-N
alkylated MeOQD (5a) in CD
3
CN at 343 K; B-(c)
1
H NMR spectrum of MeOQD-
catalyzed cyclopropanation reaction in CD
3
CN at 343 K (taken 30 min after the reaction
started).

426

On the other hand, epiMeOCF
3
QD, MeOMeQD, and BnOMeQD did not demonstrate
observable reactivity towards α-bromoacetate at room temperature. At 343 K, the
reaction rates of these inactive probes were determined to be ca. 5×10
-4
L·mol
-1
·s
-1
, which
was lower than that of MeOQD by approximately a factor of ca. 50-fold (purple spots,
Figure 8.10-A). Intriguingly, as indicated by NMR experiments, the substitution reaction
occurred primarily on the quinoline-N of epiMeOCF
3
QD, MeOMeQD and BnOMeQD,
instead of as on the quinuclidine-N of MeOQD and epiMeOQD (see Section 8.5 for
details). Since quinoline-N-substituted species were known to be catalytically
unproductive,
21d
the essentially slow cyclopropanation reaction with epiMeOCF
3
QD at
343 K was impeded at the first step of the catalytic cycle, i.e. the substitution reaction
was rate determining in the reaction involving epiMeOCF
3
QD, MeOMeQD and
BnOMeQD (purple spots v.s. blue spots, Figure 8.10-A).

Scheme 8.4. Comparison of the nucleophilicity of 6-methoxyquinoline and quinuclidine
toward t-butyl α-bromoacetate in CD
3
CN.

To explore the origin of the different catalytic activities of the Open and Closed
conformations, additional experiment and theoretical calculation were focused on the
nucleophilic nature of the probes. According to Mayr’s nucleophilicity scale,
47
the
427

nucleophilicity of the quinuclidine moiety was found to significantly decrease by
incorporating bulky α -substituent (Entries 1 and 4, Table 8.7).
48
Hence, the Closed
conformations were anticipated to be less reactive towards α -bromoacetate than the Open
conformations (3 and 4). Since the reaction of quinuclidine with t-butyl α-bromoacetate
(Eq. 10) is significantly faster than that of quinoline (Eq. 11),
48,49
the substantially low
reactivity of the quinuclidine-N on the inactive catalysts, compared with the quinoline-N,
can be ascribed to steric encumbrance around the former.
50
To assess the electronic
effects of the β -CF
3
group on the nucleophilicity of the quinuclidine moiety,
51
activation
barriers of the corresponding S
N
2 reaction in CH
3
CN was calculated, revealing a
transition state destabilization of 2.8 kcal/mol by the trifluoromethyl substitution (Entries
1 and 4, Table 8.7). In spite of the low activity of epiMeOCF
3
QD to electron-
withdrawing effects of the trifluoromethyl group, the considerably lower nucleophilicity
of 6-methoxyquinoline evidently demonstrated the pivotal role of steric effects in
diminishing the nucleophilicity of the quinuclidine-N.
Apart from the aforementioned investigations, the role of Open conformations in
catalysis was also evident by the high activity of β -isoquinidine (βiQD), in which only
Open-3, 4 or 7-like conformations are allowed (Eq. 12 and 13, Figure 8.11-A).
52

Compared with epiMeOQD, the reaction of βiQD with α -bromoacetate 3 was found to be
slightly slower. This was presumably attributed to the high population of sterically less
accessible Open-3 conformer than Open-4 in βiQD. Moreover, the crystal structure and
NOESY spectrum of quinuclidine-N substituted epiMeOQD (7) provided further insight
428

into active conformations. As illustrated in Scheme 8.11-B, the cinchona alkaloid
skeleton in 7 adopted an Open-4-like conformation.

Table 8.7. Nucleophilicity of different N-nucleophiles toward CH
3
Cl.

a
Calculated at the B3LYP/6-31+G(d,p) level with implicit consideration of solvent
CH
3
CN-solvation;
b
Mayr’s nucleophilicity parameter;
b
Mayr’s nucleophile-specific
slope parameter.

Overall, based on the different activities of the conformational probes mentioned
above, particularly epiMeOCF
3
QD, an explicit mechanistic scenario involving
catalytically active conformations has been depicted. Open-3 and Open-4 like
conformations are catalytically active in the current cyclopropanation reaction; while
Closed-1 and, in particular, Closed-2 conformers are of low catalytic activity due to the
429

steric inaccessibility around the quinuclidine-N. Essentially, the diverged activities of
different conformers are mainly due to the difference in the nucleophilicity of
quinuclidine-N, which alters rate determining step in catalysis. With the active catalysts,
the rate determining step was found to be the Michael addition reaction. In contrast, the
formation of active quaternary ammonium salt, the initial step of the catalytic cycle, was
substantially impeded with inactive catalysts. It is worth noting that the predominant
species of MeOQD in CD
3
CN is not the productive conformations, unequivocally
revealing that the assumption of populated species in ground state as active
conformations can be misleading under certain circumstance.
18

Figure 8.11. A. Reactivity of βiQD toward t-butyl α-bromoester in CD
3
CN (Eq. 12) and
catalytic activity of βiQD in cyclopropanation reaction (Eq. 13); B. conformation of t-
butyl α-bromoester-epiMeOQD quaternary ammonium salt in the solid state and in
CD
3
CN.
430

8.4. Conclusions
By incorporating a trifluoromethyl group in the C9 atom of quinidine, the
conformational exchange can be significantly decelerated to allow the direct
determination of the conformational distribution in various solvents. With these results,
the reliabitly of the PCM model-based theoretical calculation was assessed, which
demonstrated considerable divergence from the experimental data. These are apparently
due to the complicated solvent-cinchona alkaloids interaction mechanism that cannot be
fully described by the PCM model. In fact, only the conformers with calculated Gibbs
free energies higher that 3.5 kcal/mol in the gas phase can be excluded as populated
species in solution. Instead, the LFER analysis using multiparameter polarity scales has
been proven to be a powerful tool for quantitative elucidation of solvent effects on the
conformational behavior of cinchona alkaloids and their derivatives. Baiker’s seminal
two-equation-two-variable linear system is also critical for the current work, which
allows the determination of the Open-Closed conformational equilibrium. On this basis,
the conformational behavior of QD and epiQD in various solvents has been quantitatively
investigated by LEFR analysis. This reveals a fairly complicated solvation mechanism
involving various nonspecific and specific interactions. Moreover, by employing
epiMeOCF
3
QD and other modified cinchona alkaloids as probes, the active
conformations of an asymmetric cyclopropanation reaction were elucidated.

431

8.5. Experimental
8.5.1. General Information
Unless otherwise mentioned, all the chemicals were purchased from commercial
sources. Anhydrous DMSO-d
6
was purchased from the Sigma-Aldrich Inc. without
further purification. Other deuterated solvents were purchased from the Cambridge
Isotope Laboratories, Inc. The non-deuterated solvents for the NMR experiments were
purchased from commercial sources and used as received. The DriSolv
®
solvents were
purchased from EMD
TM
and used without further purification. Silica gel chromatography
was performed to isolate the products using 60-200 mesh silica gel. One dimensional
1
H,
13
C,
19
F and Dynamic NMR spectra were recorded on Varian VNMR-500S NMR
Spectrometer. The temperature calibration was carried by measuring the chemical-shift
separation between the OH resonances and CH resonances in methanol (at low
temperature) and ethylene glycol (at high temperature) to give an accuracy at ±0.1 K.
COSY and NOESY spectra were performed on Varian VNMR-500S NMR Spectrometer.
1
H NMR chemical shifts were determined relative to CDCl
3
, DMSO-d
6
and CD
3
CN as
the internal standards at δ 7.26 ppm, 2.50 ppm and 2.00 ppm, respectively.
13
C NMR
shifts were determined relative to CDCl
3
and DMSO-d
6
as the internal standards at δ
77.16 ppm, 39.52 ppm and 118.26 ppm, respectively.
19
F NMR chemical shifts were
determined relative to internal standard CFCl
3
at δ 0.00 ppm. Mass spectra were recorded
on a high resolution mass spectrometer in the ESI mode. The X-ray intensity data were
measured on a Bruker APEX II CCD system equipped with a TRIUMPH curved-crystal
monochromator and a Mo fine-focus tube (λ = 0.71073 Å).
432

8.5.2. Conformational analysis of epiCF
3
QD based on DFT calculations
Optimized Structures of epiCF
3
QD Conformers

Figure 8.12. Optimized Conformations of epiCF
3
QD in the gas phase at the B3LYP/6-
311+(d,p) level of theory (Part-A).
433

Figure 8.13. Optimized Conformations of epiCF
3
QD in the gas phase at the B3LYP/6-
311+(d,p) level of theory (Part-B).
434

Figure 8.14. Optimized Conformations of epiCF
3
QD in the gas phase at the B3LYP/6-
311+(d,p) level of theory (Part-C).

435

Table 8.8. Gas Phase Structures of epiCF
3
QD optimized at the B3LYP-6-311+G(d,p)
level.
Conformer
τ
1

(φ
C5'-C4'-C9-C8
)
τ
2

(φ
C4'-C9-C8-N
)
τ
3
(φ
C4'-C9-O-H
)
Electronic Energy (E, a.u.) ΔE (kcal/mol)
μ
(Debye)
Closed-1a 123.7 318.7 189.1 -1373.88760313 3.1 4.9880
Closed-1b 123.4 323.7 294.9 -1373.88804004 3.6 3.1463
Closed-1c 132.8 321.1 55.1 -1373.88372493 6.3 4.4292
Open-4a 126.1 243.1 104.4 -1373.89056963 2.0 5.8504
Open-4c 126.1 243.1 63.2 -1373.88045217 8.3 4.3991
Open-9a 102.9 206.7 148.3 -1373.88913744 2.9 5.6717
Open-9b 84.2 189.1 302.7 -1373.87550086 11.4 2.1223
Open-6a 105.1 53.0 186.5 -1373.88367861 6.3 5.1418
Open-6b 103.7 54.3 299.8 -1373.88368288 6.3 3.3729
Open-6c 112.7 51.1 81.7 -1373.87854267 9.5 5.5407
Closed-2a 302.0 311.4 186.7 -1373.88724593 4.1 5.1245
Closed-2b 285.9 308.6 305.6 -1373.88809295 3.5 3.3218
Closed-7a 323.5 314.0 183.5 -1373.88722143 4.1 5.2191
Closed-7c 335.4 311.1 21.8 -1373.88715434 4.1 2.9039
Open-10b 252.6 246.6 313.5 -1373.88257915 7.0 2.9870
Open-8a 322.6 226.2 122.0 -1373.89374672 0.0 5.7486
Open-3a 266.4 198.0 152.4 -1373.89260378 0.7 5.1893
Open-3b 256.4 183.1 307.5 -1373.88361417 6.4 2.5780
Open-5a 276.0 47.7 186.9 -1373.88454744 5.1 4.8967
Open-5b 273.1 52.1 304.6 -1373.88555078 4.4 3.3999
Open-5c 304.0 43.5 74.3 -1373.87797572 9.2 4.8774

436

Table 8.9. Gas Phase Energy of epiCF
3
QD at the B3LYP-6-311+G(d,p) level. (Geometry
optimization was performed at the same level.)
Conformer
Electronic
Energy (E, a.u.)
ΔE
(kcal/
mol)
Dipole
(Debye)
Thermal
Correction
to Gibbs
Free
Energies
(a.u.)
Gibbs Free
Energies (G,
a.u.)
ΔG
(kcal/
mol)
Pop.
Closed-1a -1373.88760313 3.1 4.9880 0.35734 -1373.53026113 1.9 3.0%
Anti
7.8%
Closed-1b -1373.88804004 3.6 3.1463 0.35735 -1373.53069304 2.5 1.1%
Closed-1c -1373.88372493 6.3 4.4292 0.35667 -1373.52705793 4.8 0.0%
Open-4a -1373.89056963 2.0 5.8504 0.35879 -1373.53177563 1.8 3.3%
Open-4c -1373.88045217 8.3 4.3991 0.35808 -1373.52236817 7.7 0.0%
Open-9a -1373.88913744 2.9 5.6717 0.35927 -1373.52986944 3.0 0.4%
Open-9b -1373.87550086 11.4 2.1223 0.35780 -1373.51769686 10.7 0.0%
Open-6a -1373.88367861 6.3 5.1418 0.35867 -1373.52500961 6.1 0.0%
Open-6b -1373.88368288 6.3 3.3729 0.35853 -1373.52515488 6.0 0.0%
Open-6c -1373.87854267 9.5 5.5407 0.35776 -1373.52077967 8.7 0.0%
Closed-2a -1373.88724593 4.1 5.1245 0.35689 -1373.53035693 2.7 0.7%
Syn
92.2
%
Closed-2b -1373.88809295 3.5 3.3218 0.35836 -1373.52972995 3.1 0.4%
Closed-7a -1373.88722143 4.1 5.2191 0.35632 -1373.53089743 2.4 1.3%
Closed-7c -1373.88715434 4.1 2.9039 0.35775 -1373.52940334 3.3 0.3%
Open-10b -1373.88257915 7.0 2.987 0.35936 -1373.52321815 7.2 0.0%
Open-8a -1373.89374672 0.0 5.7486 0.35905 -1373.53469872 0.0 73.0%
Open-3a -1373.89260378 0.7 5.1893 0.35931 -1373.53328978 0.9 16.4%
Open-3b -1373.88361417 6.4 2.5780 0.35937 -1373.52424617 6.6 0.0%
Open-5a -1373.88454744 5.1 4.8967 0.35842 -1373.52613044 5.4 0.0%
Open-5b -1373.88555078 4.4 3.3999 0.35798 -1373.52756778 4.5 0.0%
Open-5c -1373.87797572 9.2 4.8774 0.35730 -1373.52067172 8.8 0.0%

437

Table 8.10. SPE of epiCF
3
QD at the M06-2X-6-311+G(d,p) level in the gas phase.
Conformer
Electronic Energy
(E, a.u.)
Gibbs Free Energies
(G, a.u.)
ΔG
(kcal/
mol)
Pop.
Closed-1a -1373.37602939 -1373.01868739 1.7 1.8%
Anti
25.7
%
Closed-1b -1373.37710846 -1373.01976146 1.1 5.7%
Closed-1c -1373.37290283 -1373.01623583 3.3 0.1%
Open-4a -1373.37955284 -1373.02075884 0.4 16.4%
Open-4c -1373.37021680 -1373.01213280 5.8 0.0%
Open-9a -1373.37763700 -1373.01836850 1.9 1.3%
Open-9b -1373.36474300 -1373.00693869 9.1 0.0%
Open-6a -1373.37499293 -1373.01632393 3.2 0.2%
Open-6b -1373.37490836 -1373.01638036 3.2 0.2%
Open-6c -1373.36976280 -1373.01199980 5.9 0.0%
Closed-2a -1373.37405405 -1373.01716505 2.7 0.4%
Syn
74.3
%
Closed-2b -1373.37705182 -1373.01868882 1.7 1.8%
Closed-7a -1373.37439400 -1373.01806951 2.1 1.0%
Closed-7c -1373.37637471 -1373.01862371 1.8 1.7%
Open-10b -1373.37438000 -1373.01501905 4.0 0.0%
Open-8a -1373.38049500 -1373.02144737 0.0 34.0%
Open-3a -1373.38076849 -1373.02145449 0.0 34.2%
Open-3b -1373.37357208 -1373.01420408 4.5 0.0%
Open-5a -1373.37515065 -1373.01673365 3.0 0.2%
Open-5b -1373.37606566 -1373.01808266 2.1 1.0%
Open-5c -1373.36640337 -1373.00909937 7.8 0.0%

438

Table 8.11. SPE of epiCF
3
QD at the M06-2X-6-311+G(d,p) level in CHCl
3
(PCM).
Conformer
Electronic Energy
(E, a.u.)
Gibbs Free Energies
(G, a.u.)
ΔG
(kcal/
mol)
Pop.
Closed-1a -1373.38554254 -1373.02820054 1.6 2.8%
Anti
28.4%
Closed-1b -1373.38642215 -1373.02907515 1.0 7.1%
Closed-1c -1373.38308988 -1373.02642288 2.7 0.4%
Open-4a -1373.38868038 -1373.02988638 0.5 16.9%
Open-4c -1373.37910106 -1373.02101706 6.1 0.0%
Open-9a -1373.38642300 -1373.02715511 2.2 0.9%
Open-9b -1373.37506000 -1373.01725554 8.4 0.0%
Open-6a -1373.38382807 -1373.02515907 3.5 0.1%
Open-6b -1373.38350273 -1373.02497473 3.6 0.1%
Open-6c -1373.38019437 -1373.02243137 5.2 0.0%
Closed-2a -1373.38401450 -1373.02712550 2.2 0.9%
Syn
71.6%
Closed-2b -1373.38623569 -1373.02787269 1.8 2.0%
Closed-7a -1373.38442400 -1373.02810000 1.6 2.5%
Closed-7c -1373.38540754 -1373.02765654 1.9 1.6%
Open-10b -1373.38238900 -1373.02302836 4.8 0.0%
Open-8a -1373.38975900 -1373.03071107 0.0 40.4%
Open-3a -1373.38949783 -1373.03018383 0.3 23.1%
Open-3b -1373.38360621 -1373.02423821 4.1 0.0%
Open-5a -1373.38448468 -1373.02606768 2.9 0.3%
Open-5b -1373.38487613 -1373.02689313 2.4 0.7%
Open-5c -1373.37653281 -1373.01922881 7.2 0.0%

439

Table 8.12. SPE of epiCF
3
QD at the M06-2X-6-311+G(d,p) level in benzene (PCM).
Conformer
Electronic Energy
(E, a.u.)
Gibbs Free Energies
(G, a.u.)
ΔG
(kcal/
mol)
Pop.
Closed-1a -1373.38173760 -1373.02439560 1.8 2.0%
Anti
26.7%
Closed-1b -1373.38271496 -1373.02536796 1.1 5.7%
Closed-1c -1373.37907808 -1373.02241108 3.0 0.3%
Open-4a -1373.38520797 -1373.02641397 0.5 17.3%
Open-4c -1373.37567651 -1373.01759251 6.0 0.0%
Open-9a -1373.38307638 -1373.02380838 2.1 1.1%
Open-9b -1373.37098115 -1373.01317715 8.8 0.0%
Open-6a -1373.38038269 -1373.02171369 3.4 0.1%
Open-6b -1373.38020607 -1373.02167807 3.5 0.1%
Open-6c -1373.37615659 -1373.01839359 5.5 0.0%
Closed-2a -1373.38007018 -1373.02318118 2.5 0.6%
Syn
73.3%
Closed-2b -1373.38264974 -1373.02428674 1.8 1.8%
Closed-7a -1373.38047934 -1373.02415534 1.9 1.6%
Closed-7c -1373.38193419 -1373.02418319 1.9 1.6%
Open-10b -1373.37933355 -1373.01997255 4.5 0.0%
Open-8a -1373.38624298 -1373.02719498 0.0 39.6%
Open-3a -1373.38614888 -1373.02683488 0.2 27.0%
Open-3b -1373.37968320 -1373.02031520 4.3 0.0%
Open-5a -1373.38081857 -1373.02240157 3.0 0.2%
Open-5b -1373.38151425 -1373.02353125 2.3 0.8%
Open-5c -1373.37264339 -1373.01533939 7.4 0.0%

440

Table 8.13. SPE of epiCF
3
QD at the M06-2X-6-311+G(d,p) level in THF (PCM).
Conformer
Electronic
Energy (E, a.u.)
Gibbs Free Energies
(G, a.u.)
ΔG
(kcal/
mol)
Pop.
Closed-1a -1373.38722371 -1373.02988171 1.4 3.5%
Anti
29.8%
Closed-1b -1373.38804865 -1373.03070165 0.9 8.4%
Closed-1c -1373.38482841 -1373.02816141 2.5 0.6%
Open-4a -1373.39012684 -1373.03133284 0.5 16.3%
Open-4c -1373.38054589 -1373.02246189 6.1 0.0%
Open-9a -1373.38782100 -1373.02855290 2.3 0.9%
Open-9b -1373.37682800 -1373.01902449 8.2 0.0%
Open-6a -1373.38529811 -1373.02662911 3.5 0.1%
Open-6b -1373.38488496 -1373.02635696 3.6 0.1%
Open-6c -1373.38190531 -1373.02414231 5.0 0.0%
Closed-2a -1373.38572924 -1373.02884024 2.1 1.2%
Syn
70.2%
Closed-2b -1373.38777604 -1373.02941304 1.7 2.1%
Closed-7a -1373.38612500 -1373.02980051 1.5 3.2%
Closed-7c -1373.38686867 -1373.02911767 1.9 1.6%
Open-10b -1373.38366500 -1373.02430422 4.9 0.0%
Open-8a -1373.39122000 -1373.03217201 0.0 39.6%
Open-3a -1373.39090982 -1373.03159582 0.4 21.5%
Open-3b -1373.38528809 -1373.02592009 3.9 0.1%
Open-5a -1373.38606189 -1373.02764489 2.8 0.3%
Open-5b -1373.38628224 -1373.02829924 2.4 0.7%
Open-5c -1373.37817980 -1373.02087580 7.1 0.0%

441

Table 8.14. SPE of epiCF
3
QD at the M06-2X-6-311+G(d,p) level in DMSO (PCM).
Conformer
Electronic Energy
(E, a.u.)
Gibbs Free Energies
(G, a.u.)
ΔG
(kcal/
mol)
Pop.
Closed-1a -1373.39026578 -1373.03292378 1.1 5.7%
Anti
33.9%
Closed-1b -1373.39096441 -1373.03361741 0.6 11.9%
Closed-1c -1373.38790392 -1373.03123692 2.1 1.0%
Open-4a -1373.39258859 -1373.03379459 0.5 14.4%
Open-4c -1373.38303216 -1373.02494816 6.1 0.0%
Open-9a -1373.39021000 -1373.03094150 2.3 0.7%
Open-9b -1373.37995100 -1373.02214694 7.8 0.0%
Open-6a -1373.38784975 -1373.02918075 3.4 0.1%
Open-6b -1373.38724638 -1373.02871838 3.7 0.1%
Open-6c -1373.38485784 -1373.02709484 4.7 0.0%
Closed-2a -1373.38876650 -1373.03187750 1.7 1.9%
Syn
66.1%
Closed-2b -1373.39048018 -1373.03211718 1.6 2.4%
Closed-7a -1373.38910900 -1373.03278549 1.2 5.0%
Closed-7c -1373.38937243 -1373.03162143 1.9 1.4%
Open-10b -1373.38584100 -1373.02648011 5.1 0.0%
Open-8a -1373.39369900 -1373.03465110 0.0 35.7%
Open-3a -1373.39335057 -1373.03403657 0.4 18.6%
Open-3b -1373.38822743 -1373.02885943 3.6 0.1%
Open-5a -1373.38882123 -1373.03040423 2.7 0.4%
Open-5b -1373.38868421 -1373.03070121 2.5 0.5%
Open-5c -1373.38104385 -1373.02373985 6.8 0.0%

442

Table 8.15. SPE of epiCF
3
QD at the M06-2X-6-311+G(d,p) level in MeOH (PCM).
Conformer
Electronic
Energy (E, a.u.)
Gibbs Free Energies
(G, a.u.)
ΔG
(kcal/
mol)
Pop.
Closed-1a -1373.38998133 -1373.03263933 1.1 5.4%
Anti
33.4%
Closed-1b -1373.39069369 -1373.03334669 0.7 11.5%
Closed-1c -1373.38762090 -1373.03095390 2.2 0.9%
Open-4a -1373.39236753 -1373.03357353 0.5 14.6%
Open-4c -1373.38280742 -1373.02472342 6.1 0.0%
Open-9a -1373.38999400 -1373.03072633 2.3 0.7%
Open-9b -1373.37966400 -1373.02186030 7.9 0.0%
Open-6a -1373.38761804 -1373.02894904 3.4 0.1%
Open-6b -1373.38703400 -1373.02850600 3.7 0.1%
Open-6c -1373.38459065 -1373.02682765 4.8 0.0%
Closed-2a -1373.38848691 -1373.03159791 1.8 1.8%
Syn
66.6%
Closed-2b -1373.39023243 -1373.03186943 1.6 2.4%
Closed-7a -1373.38883600 -1373.03251235 1.2 4.8%
Closed-7c -1373.38914687 -1373.03139587 1.9 1.5%
Open-10b -1373.38564500 -1373.02628446 5.1 0.0%
Open-8a -1373.39347700 -1373.03442896 0.0 36.2%
Open-3a -1373.39312882 -1373.03381482 0.4 18.9%
Open-3b -1373.38795914 -1373.02859114 3.7 0.1%
Open-5a -1373.38856943 -1373.03015243 2.7 0.4%
Open-5b -1373.38846805 -1373.03048505 2.5 0.6%
Open-5c -1373.38078251 -1373.02347851 6.9 0.0%

443

Table 8.16. SPE of epiCF
3
QD at the M06-2X-6-311+G(d,p) level in H
2
O (PCM).
Conformer
Electronic Energy
(E, a.u.)
Gibbs Free Energies
(G, a.u.)
ΔG
(kcal/
mol)
Pop.
Closed-1a -1373.39053522 -1373.03319322 1.0 6.0%
Anti
34.5%
Closed-1b -1373.39122038 -1373.03387338 0.6 12.4%
Closed-1c -1373.38817101 -1373.03150401 2.1 1.0%
Open-4a -1373.39279613 -1373.03400213 0.5 14.2%
Open-4c -1373.38324344 -1373.02515944 6.1 0.0%
Open-9a -1373.39041200 -1373.03114368 2.3 0.7%
Open-9b -1373.38022100 -1373.02241726 7.8 0.0%
Open-6a -1373.38806777 -1373.02939877 3.4 0.1%
Open-6b -1373.38744583 -1373.02891783 3.7 0.1%
Open-6c -1373.38510908 -1373.02734608 4.7 0.0%
Closed-2a -1373.38903036 -1373.03214136 1.7 2.0%
Syn
65.5%
Closed-2b -1373.39071377 -1373.03235077 1.6 2.5%
Closed-7a -1373.38936700 -1373.03304292 1.1 5.1%
Closed-7c -1373.38958432 -1373.03183332 1.9 1.4%
Open-10b -1373.38602500 -1373.02666386 5.1 0.0%
Open-8a -1373.39390800 -1373.03485956 0.0 35.1%
Open-3a -1373.39355934 -1373.03424534 0.4 18.3%
Open-3b -1373.38848018 -1373.02911218 3.6 0.1%
Open-5a -1373.38905838 -1373.03064138 2.6 0.4%
Open-5b -1373.38888725 -1373.03090425 2.5 0.5%
Open-5c -1373.38129015 -1373.02398615 6.8 0.0%

444

Table 8.17. SPE of epiCF
3
QD at the M06-2X-6-311+G(d,p) level in MeCN (PCM)
Conformer
Electronic Energy
(E, a.u.)
Gibbs Free Energies
(G, a.u.)
ΔG
(kcal/
mol)
Pop.
Closed-1a -1373.39006132 -1373.03271932 1.1 5.5%
Anti
33.6%
Closed-1b -1373.39076987 -1373.03342287 0.7 11.6%
Closed-1c -1373.38770059 -1373.03103359 2.2 0.9%
Open-4a -1373.39242990 -1373.03363590 0.5 14.6%
Open-4c -1373.38287080 -1373.02478680 6.1 0.0%
Open-9a -1373.39005502 -1373.03078702 2.3 0.7%
Open-9b -1373.37974503 -1373.02194103 7.9 0.0%
Open-6a -1373.38768336 -1373.02901436 3.4 0.1%
Open-6b -1373.38709392 -1373.02856592 3.7 0.1%
Open-6c -1373.38466599 -1373.02690299 4.8 0.0%
Closed-2a -1373.38856564 -1373.03167664 1.8 1.8%
Syn
66.4%
Closed-2b -1373.39030222 -1373.03193922 1.6 2.4%
Closed-7a -1373.38891330 -1373.03258930 1.2 4.8%
Closed-7c -1373.38921049 -1373.03145949 1.9 1.5%
Open-10b -1373.38570066 -1373.02633966 5.1 0.0%
Open-8a -1373.39353964 -1373.03449164 0.0 36.0%
Open-3a -1373.39319132 -1373.03387732 0.4 18.8%
Open-3b -1373.38803474 -1373.02866674 3.7 0.1%
Open-5a -1373.38864039 -1373.03022339 2.7 0.4%
Open-5b -1373.38852903 -1373.03054603 2.5 0.6%
Open-5c -1373.38085614 -1373.02355214 6.9 0.0%

445

Table 8.18. SPE of epiCF
3
QD at the M06-2X-6-311+G(d,p) level in acetone (PCM).
Conformer
Electronic Energy
(E, a.u.)
Gibbs Free Energies
(G, a.u.)
ΔG
(kcal/
mol)
Pop.
Closed-1a -1373.38944759 -1373.03210559 1.2 5.0%
Anti
32.5%
Closed-1b -1373.39018451 -1373.03283751 0.7 10.8%
Closed-1c -1373.38708706 -1373.03042006 2.3 0.8%
Open-4a -1373.39194747 -1373.03315347 0.5 15.0%
Open-4c -1373.38238119 -1373.02429719 6.1 0.0%
Open-9a -1373.38958600 -1373.03031788 2.3 0.7%
Open-9b -1373.37912300 -1373.02131915 8.0 0.0%
Open-6a -1373.38717913 -1373.02851013 3.4 0.1%
Open-6b -1373.38663057 -1373.02810257 3.7 0.1%
Open-6c -1373.38408401 -1373.02632101 4.8 0.0%
Closed-2a -1373.38795956 -1373.03107056 1.8 1.7%
Syn
67.5%
Closed-2b -1373.38976454 -1373.03140154 1.6 2.4%
Closed-7a -1373.3883200 -1373.03199622 1.3 4.4%
Closed-7c -1373.38871859 -1373.03096759 1.9 1.5%
Open-10b -1373.38527400 -1373.02591284 5.1 0.0%
Open-8a -1373.39305500 -1373.03400654 0.0 37.1%
Open-3a -1373.39270907 -1373.03339507 0.4 19.4%
Open-3b -1373.38745179 -1373.02808379 3.7 0.1%
Open-5a -1373.38809317 -1373.02967617 2.7 0.4%
Open-5b -1373.38805755 -1373.03007455 2.5 0.6%
Open-5c -1373.38028850 -1373.02298450 6.9 0.0%

446

Table 8.19. SPE of epiCF
3
QD at the M06-2X-6-311+G(d,p) level in CH
2
Cl
2
(PCM)
Conformer
Electronic Energy
(E, a.u.)
Gibbs Free Energies
(G, a.u.)
ΔG
(kcal/
mol)
Pop.
Closed-1a -1373.38776866 -1373.03042666 1.4 3.8%
Anti
30.3%
Closed-1b -1373.38857390 -1373.03122690 0.9 8.8%
Closed-1c -1373.38538657 -1373.02871957 2.5 0.6%
Open-4a -1373.39058310 -1373.03178910 0.5 16.0%
Open-4c -1373.38100404 -1373.02292004 6.1 0.0%
Open-9a -1373.38826300 -1373.02899452 2.3 0.8%
Open-9b -1373.37739600 -1373.01959211 8.2 0.0%
Open-6a -1373.38576626 -1373.02709726 3.5 0.1%
Open-6b -1373.38532189 -1373.02679389 3.7 0.1%
Open-6c -1373.38244867 -1373.02468567 5.0 0.0%
Closed-2a -1373.38628020 -1373.02939120 2.0 1.3%
Syn
69.7%
Closed-2b -1373.38826878 -1373.02990578 1.7 2.2%
Closed-7a -1373.38666900 -1373.03034473 1.4 3.5%
Closed-7c -1373.38733121 -1373.02958021 1.9 1.5%
Open-10b -1373.38406800 -1373.02470705 5.0 0.0%
Open-8a -1373.39168000 -1373.03263226 0.0 39.1%
Open-3a -1373.39135809 -1373.03204409 0.4 21.0%
Open-3b -1373.38582520 -1373.02645720 3.9 0.1%
Open-5a -1373.38656601 -1373.02814901 2.8 0.3%
Open-5b -1373.38672656 -1373.02874356 2.4 0.6%
Open-5c -1373.37870399 -1373.02139999 7.0 0.0%

447

Table 8.20. SPE of epiCF
3
QD at the M06-2X-6-311+G(d,p) level in DMF (PCM)
Conformer
Electronic Energy
(E, a.u.)
Gibbs Free Energies
(G, a.u.)
ΔG
(kcal/
mol)
Pop.
Closed-1a -1373.39009641 -1373.03275441 1.1 5.6%
Anti
33.6%
Closed-1b -1373.39080327 -1373.03345627 0.7 11.7%
Closed-1c -1373.38773552 -1373.03106852 2.2 0.9%
Open-4a -1373.39245720 -1373.03366320 0.5 14.6%
Open-4c -1373.38289855 -1373.02481455 6.1 0.0%
Open-9a -1373.3900820 -1373.03081359 2.3 0.7%
Open-9b -1373.37978000 -1373.02197641 7.9 0.0%
Open-6a -1373.38771197 -1373.02904297 3.4 0.1%
Open-6b -1373.38712015 -1373.02859215 3.7 0.1%
Open-6c -1373.38469898 -1373.02693598 4.8 0.0%
Closed-2a -1373.38860015 -1373.03171115 1.8 1.8%
Syn
66.4%
Closed-2b -1373.39033280 -1373.03196980 1.6 2.4%
Closed-7a -1373.38894700 -1373.03262302 1.2 4.8%
Closed-7c -1373.38923835 -1373.03148735 1.9 1.5%
Open-10b -1373.38572500 -1373.02636382 5.1 0.0%
Open-8a -1373.39356700 -1373.03451908 0.0 36.0%
Open-3a -1373.39321869 -1373.03390469 0.4 18.8%
Open-3b -1373.38806786 -1373.02869986 3.7 0.1%
Open-5a -1373.38867147 -1373.03025447 2.7 0.4%
Open-5b -1373.38855573 -1373.03057273 2.5 0.6%
Open-5c -1373.38088839 -1373.02358439 6.9 0.0%

448

Table 8.21. SPE of epiCF
3
QD at the M06-2X-6-311+G(d,p) level in ethyl acetate (PCM)
Conformer
Electronic Energy
(E, a.u.)
Gibbs Free Energies
(G, a.u.)
ΔG
(kcal/
mol)
Pop.
Closed-1a -1373.38649044 -1373.02914844 1.5 3.2%
Anti
29.1%
Closed-1b -1373.38734029 -1373.02999329 1.0 7.8%
Closed-1c -1373.38407307 -1373.02740607 2.6 0.5%
Open-4a -1373.38950303 -1373.03070903 0.5 16.6%
Open-4c -1373.37992139 -1373.02183739 6.1 0.0%
Open-9a -1373.38721800 -1373.02794969 2.3 0.9%
Open-9b -1373.37606000 -1373.01825604 8.3 0.0%
Open-6a -1373.38466152 -1373.02599252 3.5 0.1%
Open-6b -1373.38428828 -1373.02576028 3.6 0.1%
Open-6c -1373.38116528 -1373.02340228 5.1 0.0%
Closed-2a -1373.38498395 -1373.02809495 2.2 1.0%
Syn
70.9%
Closed-2b -1373.38710784 -1373.02874484 1.8 2.1%
Closed-7a -1373.38538700 -1373.02906262 1.6 2.9%
Closed-7c -1373.38623754 -1373.02848654 1.9 1.6%
Open-10b -1373.38311500 -1373.02375376 4.9 0.0%
Open-8a -1373.39059000 -1373.03154228 0.0 40.0%
Open-3a -1373.39029930 -1373.03098530 0.3 22.2%
Open-3b -1373.38455896 -1373.02519096 4.0 0.0%
Open-5a -1373.38537784 -1373.02696084 2.9 0.3%
Open-5b -1373.38567537 -1373.02769237 2.4 0.7%
Open-5c -1373.37746696 -1373.02016296 7.1 0.0%

449

Table 8.22. SPE of epiCF
3
QD at the M06-2X-6-311+G(d,p) level in EtOH (PCM)
Conformer
Electronic
Energy (E, a.u.)
Gibbs Free Energies
(G, a.u.)
ΔG
(kcal/
mol)
Pop.
Closed-1a -1373.38969624 -1373.03235424 1.2 5.2%
Anti
33.0%
Closed-1b -1373.39042191 -1373.03307491 0.7 11.1%
Closed-1c -1373.38733620 -1373.03066920 2.2 0.9%
Open-4a -1373.39214401 -1373.03335001 0.5 14.9%
Open-4c -1373.38258048 -1373.02449648 6.1 0.0%
Open-9a -1373.38977700 -1373.03050892 2.3 0.7%
Open-9b -1373.37937600 -1373.02157177 7.9 0.0%
Open-6a -1373.38738426 -1373.02871526 3.4 0.1%
Open-6b -1373.38681930 -1373.02829130 3.7 0.1%
Open-6c -1373.38432087 -1373.02655787 4.8 0.0%
Closed-2a -1373.38820566 -1373.03131666 1.8 1.7%
Syn
67.0%
Closed-2b -1373.38998300 -1373.03162000 1.6 2.4%
Closed-7a -1373.38856100 -1373.03223724 1.2 4.6%
Closed-7c -1373.38891891 -1373.03116791 1.9 1.5%
Open-10b -1373.38544800 -1373.02608669 5.1 0.0%
Open-8a -1373.39325200 -1373.03420423 0.0 36.7%
Open-3a -1373.39290521 -1373.03359121 0.4 19.2%
Open-3b -1373.38768877 -1373.02832077 3.7 0.1%
Open-5a -1373.38831565 -1373.02989865 2.7 0.4%
Open-5b -1373.38824958 -1373.03026658 2.5 0.6%
Open-5c -1373.38051923 -1373.02321523 6.9 0.0%

450

Table 8.23. SPE of epiCF
3
QD at the M06-2X-6-311+G(d,p) level in i-PrOH (PCM)
Conformer
Electronic Energy
(E, a.u.)
Gibbs Free Energies
(G, a.u.)
ΔG
(kcal/
mol)
Pop.
Closed-1a -1373.38933887 -1373.03199687 1.2 4.9%
Anti
32.4%
Closed-1b -1373.39008061 -1373.03273361 0.7 10.6%
Closed-1c -1373.38697790 -1373.03031090 2.3 0.8%
Open-4a -1373.39186108 -1373.03306708 0.5 15.1%
Open-4c -1373.38229366 -1373.02420966 6.1 0.0%
Open-9a -1373.38950194 -1373.03023394 2.3 0.8%
Open-9b -1373.37901242 -1373.02120842 8.0 0.0%
Open-6a -1373.38708909 -1373.02842009 3.5 0.1%
Open-6b -1373.38654762 -1373.02801962 3.7 0.1%
Open-6c -1373.38397999 -1373.02621699 4.8 0.0%
Closed-2a -1373.38785173 -1373.03096273 1.9 1.6%
Syn
67.6%
Closed-2b -1373.38966876 -1373.03130576 1.6 2.3%
Closed-7a -1373.38821453 -1373.03189053 1.3 4.4%
Closed-7c -1373.38863056 -1373.03087956 1.9 1.5%
Open-10b -1373.38519743 -1373.02583643 5.1 0.0%
Open-8a -1373.39296762 -1373.03391962 0.0 37.3%
Open-3a -1373.39262299 -1373.03330899 0.4 19.5%
Open-3b -1373.38734784 -1373.02797984 3.7 0.1%
Open-5a -1373.38799558 -1373.02957858 2.7 0.4%
Open-5b -1373.38797317 -1373.02999017 2.5 0.6%
Open-5c -1373.38018730 -1373.02288330 6.9 0.0%

451

Table 8.24. SPE of epiCF
3
QD at the M06-2X-6-311+G(d,p) level in MeNO
2
(PCM)
Conformer
Electronic Energy
(E, a.u.)
Gibbs Free Energies
(G, a.u.)
ΔG
(kcal/
mol)
Pop.
Closed-1a -1373.39008170 -1373.03273970 1.1 5.5%
Anti
33.6%
Closed-1b -1373.39078927 -1373.03344227 0.7 11.7%
Closed-1c -1373.38772088 -1373.03105388 2.2 0.9%
Open-4a -1373.39244576 -1373.03365176 0.5 14.6%
Open-4c -1373.38288692 -1373.02480292 6.1 0.0%
Open-9a -1373.39007045 -1373.03080245 2.3 0.7%
Open-9b -1373.37976558 -1373.02196158 7.9 0.0%
Open-6a -1373.38769998 -1373.02903098 3.4 0.1%
Open-6b -1373.38710915 -1373.02858115 3.7 0.1%
Open-6c -1373.38468515 -1373.02692215 4.8 0.0%
Closed-2a -1373.38858568 -1373.03169668 1.8 1.8%
Syn
66.4%
Closed-2b -1373.39031998 -1373.03195698 1.6 2.4%
Closed-7a -1373.38893289 -1373.03260889 1.2 4.8%
Closed-7c -1373.38922667 -1373.03147567 1.9 1.5%
Open-10b -1373.38571469 -1373.02635369 5.1 0.0%
Open-8a -1373.39355558 -1373.03450758 0.0 36.0%
Open-3a -1373.39320722 -1373.03389322 0.4 18.8%
Open-3b -1373.38805397 -1373.02868597 3.7 0.1%
Open-5a -1373.38865844 -1373.03024144 2.7 0.4%
Open-5b -1373.38854454 -1373.03056154 2.5 0.6%
Open-5c -1373.38087487 -1373.02357087 6.9 0.0%

452

Table 8.25. SPE of epiCF
3
QD at the M06-2X-6-311+G(d,p) level in pentane (PCM)
Conformer
Electronic Energy
(E, a.u.)
Gibbs Free Energies
(G, a.u.)
ΔG
(kcal/
mol)
Pop.
Closed-1a -1373.38038327 -1373.02304127 1.8 1.9%
Anti
26.3%
Closed-1b -1373.38138883 -1373.02404183 1.2 5.5%
Closed-1c -1373.37762848 -1373.02096148 3.1 0.2%
Open-4a -1373.38391153 -1373.02511753 0.5 17.3%
Open-4c -1373.37441267 -1373.01632867 6.0 0.0%
Open-9a -1373.38182900 -1373.02256059 2.1 1.2%
Open-9b -1373.36951100 -1373.01170740 8.9 0.0%
Open-6a -1373.37912448 -1373.02045548 3.4 0.1%
Open-6b -1373.37898377 -1373.02045577 3.4 0.1%
Open-6c -1373.37467249 -1373.01690949 5.6 0.0%
Closed-2a -1373.37865097 -1373.02176197 2.6 0.5%
Syn
73.7%
Closed-2b -1373.38134372 -1373.02298072 1.8 1.8%
Closed-7a -1373.37905100 -1373.02272651 2.0 1.4%
Closed-7c -1373.38064967 -1373.02289867 1.9 1.6%
Open-10b -1373.36951100 -1373.01015040 9.9 0.0%
Open-8a -1373.38492800 -1373.02587957 0.0 38.6%
Open-3a -1373.38490897 -1373.02559497 0.2 28.6%
Open-3b -1373.37825468 -1373.01888668 4.4 0.0%
Open-5a -1373.37948897 -1373.02107197 3.0 0.2%
Open-5b -1373.38026303 -1373.02228003 2.3 0.9%
Open-5c -1373.37120639 -1373.01390239 7.5 0.0%

453

Table 8.26. SPE of epiCF
3
QD at the M06-2X-6-311+G(d,p) level in PhNO
2
(PCM)
Conformer
Electronic Energy
(E, a.u.)
Gibbs Free Energies
(G, a.u.)
ΔG
(kcal/
mol)
Pop.
Closed-1a -1373.39003984 -1373.03269784 1.1 5.5%
Anti
33.5%
Closed-1b -1373.39074942 -1373.03340242 0.7 11.6%
Closed-1c -1373.38767920 -1373.03101220 2.2 0.9%
Open-4a -1373.39241316 -1373.03361916 0.5 14.6%
Open-4c -1373.38285379 -1373.02476979 6.1 0.0%
Open-9a -1373.39003900 -1373.03077073 2.3 0.7%
Open-9b -1373.37972300 -1373.02191936 7.9 0.0%
Open-6a -1373.38766583 -1373.02899683 3.4 0.1%
Open-6b -1373.38707784 -1373.02854984 3.7 0.1%
Open-6c -1373.38464577 -1373.02688277 4.8 0.0%
Closed-2a -1373.38854451 -1373.03165551 1.8 1.8%
Syn
66.5%
Closed-2b -1373.39028349 -1373.03192049 1.6 2.4%
Closed-7a -1373.38889300 -1373.03256865 1.2 4.8%
Closed-7c -1373.38919342 -1373.03144242 1.9 1.5%
Open-10b -1373.38568600 -1373.02632485 5.1 0.0%
Open-8a -1373.39352300 -1373.03447482 0.0 36.1%
Open-3a -1373.39317455 -1373.03386055 0.4 18.8%
Open-3b -1373.38801444 -1373.02864644 3.7 0.1%
Open-5a -1373.38862134 -1373.03020434 2.7 0.4%
Open-5b -1373.38851267 -1373.03052967 2.5 0.6%
Open-5c -1373.38083637 -1373.02353237 6.9 0.0%

454

Table 8.27. SPE of epiCF
3
QD at the M06-2X-6-311+G(d,p) level in pyridine (PCM)
Conformer
Electronic Energy
(E, a.u.)
Gibbs Free Energies
(G, a.u.)
ΔG
(kcal/
mol)
Pop.
Closed-1a -1373.38866475 -1373.03132275 1.3 4.4%
Anti
31.4%
Closed-1b -1373.38943507 -1373.03208807 0.8 9.8%
Closed-1c -1373.38629797 -1373.02963097 2.3 0.7%
Open-4a -1373.39131925 -1373.03252525 0.5 15.5%
Open-4c -1373.38174572 -1373.02366172 6.1 0.0%
Open-9a -1373.38897600 -1373.02970797 2.3 0.8%
Open-9b -1373.37832200 -1373.02051825 8.1 0.0%
Open-6a -1373.38652616 -1373.02785716 3.5 0.1%
Open-6b -1373.38602763 -1373.02749963 3.7 0.1%
Open-6c -1373.38332907 -1373.02556607 4.9 0.0%
Closed-2a -1373.38718016 -1373.03029116 1.9 1.5%
Syn
68.6%
Closed-2b -1373.38907146 -1373.03070846 1.7 2.3%
Closed-7a -1373.38755500 -1373.03123118 1.3 4.0%
Closed-7c -1373.38807902 -1373.03032802 1.9 1.5%
Open-10b -1373.38471800 -1373.02535740 5.0 0.0%
Open-8a -1373.39242200 -1373.03337416 0.0 38.2%
Open-3a -1373.39208486 -1373.03277086 0.4 20.2%
Open-3b -1373.38669890 -1373.02733090 3.8 0.1%
Open-5a -1373.38738628 -1373.02896928 2.8 0.4%
Open-5b -1373.38744426 -1373.02946126 2.5 0.6%
Open-5c -1373.37955544 -1373.02225144 7.0 0.0%

455

Table 8.28. SPE of epiCF
3
QD at the M06-2X-6-311+G(d,p) level in toluene (PCM)
Conformer
Electronic Energy
(E, a.u.)
Gibbs Free Energies
(G, a.u.)
ΔG
(kcal/
mol)
Pop.
Closed-1a -1373.38200917 -1373.02466717 1.7 2.1%
Anti
26.7%
Closed-1b -1373.38298051 -1373.02563351 1.1 5.8%
Closed-1c -1373.37936749 -1373.02270049 3.0 0.3%
Open-4a -1373.38546429 -1373.02667029 0.5 17.3%
Open-4c -1373.37592729 -1373.01784329 6.0 0.0%
Open-9a -1373.38332300 -1373.02405515 2.1 1.1%
Open-9b -1373.37127500 -1373.01347090 8.8 0.0%
Open-6a -1373.38063318 -1373.02196418 3.4 0.1%
Open-6b -1373.38044828 -1373.02192028 3.5 0.1%
Open-6c -1373.37645144 -1373.01868844 5.5 0.0%
Closed-2a -1373.38035395 -1373.02346495 2.5 0.6%
Syn
73.3%
Closed-2b -1373.38290985 -1373.02454685 1.8 1.8%
Closed-7a -1373.38076400 -1373.02444048 1.9 1.6%
Closed-7c -1373.38218892 -1373.02443792 1.9 1.6%
Open-10b -1373.37955900 -1373.02019778 4.6 0.0%
Open-8a -1373.38650300 -1373.02745488 0.0 39.7%
Open-3a -1373.38639459 -1373.02708059 0.2 26.7%
Open-3b -1373.37996780 -1373.02059980 4.3 0.0%
Open-5a -1373.38108382 -1373.02266682 3.0 0.3%
Open-5b -1373.38176184 -1373.02377884 2.3 0.8%
Open-5c -1373.37292825 -1373.01562425 7.4 0.0%

Figure 8.15. Calculated population of epiCF
3
QD conformers in different solvents. The
population of Open-3a was found to decrease with the increase in dielectric constants.
456

8.5.3. Conformational Analysis of epiCF
3
QD Conformers using LFER

Table 8.29. Experimental Population Distributions of epiCF
3
QD at 298K and the
corresponding relative Gibbs Free Energy (ΔG
syn
) of syn conformations of epiCF
3
QD in
Various Solvents.

# solvent
Pop
syn
a

(%)
ΔG
syn,exp
(kcal/
mol)
(ε-1)/
(ε+2)
b

(n
2
-1)/
(n
2
+2)
b

E
T
N b
π*
c
α
c
β
c

XYZ
1
d

XYZ
1
’
e

1 pentane 86 -1.08 0.22 0.2193 0.009 -0.08 0.00 0.00 1.01 0.94
2 C
6
D
6
80 -0.82 0.30 0.2947 0.111 0.59 0.00 0.10 0.96 0.99
3 p-xylene-d
10
82 -0.90 0.30 0.2920 0.074 0.43 0.00 0.12 0.97 0.96
4 toluene-d
8
82 -0.90 0.30 0.2926 0.099 0.54 0.00 0.11 0.96 0.97
5 PhCl-d
5
85 -1.03 0.61 0.3064 0.188 0.71 0.00 0.07 1.01 0.98
6 Pyridine-d
5
53 -0.07 0.80 0.2992 0.302 0.87 0.00 0.64 0.25 0.26
7 n-Octanol 54 -0.10 0.76 0.2578 0.537 0.40 0.77 0.81 0.15 0.11
8 PhCH
2
OH 59 -0.22 0.78 0.3139 0.608 0.98 0.60 0.52 0.51 0.54
9 t-BuOH 51 -0.02 0.79 0.2358 0.389 0.41 0.42 0.93 -0.13 -0.15
10 n-Pentanol 54 -0.10 0.82 0.2478 0.568 0.40 0.84 0.86 0.07 0.03
11 sec-BuOH 51 -0.02 0.84 0.2409 0.506 0.40 0.69 0.80 0.09 0.05
12 n-BuOH 55 -0.12 0.85 0.2420 0.586 0.47 0.84 0.84 0.06 0.03
13 i-BuOH 52 -0.05 0.85 0.2402 0.552 0.40 0.79 0.84 0.06 0.02
14 i-PrOH-d
8
50 -0.00 0.86 0.2301 0.546 0.48 0.76 0.84 0.00 -0.02
15 n-PrOH 50 -0.00 0.87 0.2347 0.617 0.52 0.84 0.90 -0.05 -0.06
16 EtOH-d
6
54 -0.10 0.89 0.2215 0.654 0.54 0.86 0.75 0.08 0.08
17 MeOH-d
4
58 -0.19 0.91 0.2031 0.762 0.60 0.98 0.66 0.14 0.15
18 HOC
2
H
4
OH 65 -0.37 0.92 0.2593 0.790 0.92 0.90 0.52 0.40 0.43
19 D
2
O 71 -0.53 0.96 0.2057 1.000 1.09 1.17 0.47 0.29 0.39
20 CH
3
CN-d
3
55 -0.12 0.92 0.2119 0.460 0.75 0.19 0.40 0.32 0.33
21 DMF-d
7
55 -0.12 0.93 0.2586 0.386 0.88 0.00 0.69 0.05 0.08
22 DMSO-d
6
50 -0.00 0.94 0.2837 0.444 1.00 0.00 0.76 0.02 0.05
23 acetone-d
6
55 -0.12 0.87 0.2200 0.355 0.71 0.80 0.43 0.42 0.43
24 THF-d
8
65 -0.37 0.68 0.2463 0.207 0.58 0.00 0.54 0.27 0.28
25 anisole 81 -0.86 0.52 0.3025 0.198 0.73 0.00 0.32 0.69 0.70
26 Et
2
O 64 -0.34 0.52 0.2165 0.117 0.27 0.00 0.47 0.34 0.32
27 PhOEt 83 -0.94 0.52 0.2978 0.182 0.69 0.00 0.30 0.70 0.72
28 (PhCH
2
)
2
O 84 -0.98 0.48 0.3238 0.173 0.80 0.00 0.41 0.63 0.66
29 n-Bu
2
O 72 -0.56 0.41 0.2420 0.071 0.27 0.00 0.46 0.43 0.43
30 1,4-Dioxane-d
8
60 -0.24 0.29 0.2543 0.164 0.55 0.00 0.37 0.51 0.59
31 ClC
2
H
4
Cl-d
4
81 -0.86 0.76 0.2660 0.327 0.81 0.00 0.10 0.81 0.81
457

continued
32 o-C
6
H
4
Cl
2
-d
4
84 -0.98 0.75 0.3193 0.225 0.80 0.00 0.03 1.08 1.02
33 CH
2
Cl
2
-d
2
83 -0.94 0.73 0.2553 0.309 0.82 0.13 0.10 0.80 0.81
34 CDCl
3
83 -0.94 0.56 0.2666 0.259 0.58 0.20 0.10 0.91 0.89
35 CCl
4
82 -0.90 0.29 0.2740 0.052 0.28 0.00 0.10 0.97 0.94
36 ethyl acetate 61 -0.27 0.63 0.2275 0.228 0.55 0.00 0.45 0.33 0.35
37 CH
3
NO
2
-d
3
82 -0.90 0.92 0.2327 0.481 0.85 0.22 0.06 0.78 0.77
38 PhNO
2
-d
5
78 -0.75 0.92 0.3215 0.324 1.01 0.00 0.30 0.70 0.67
a
Measured via
19
F NMR spectroscopy at 298K; dielectric constant of solvents (ε),
refractive index of solvents (n), and solvatochromatic polarity parameter (E
T
N
), taken
from ref. 29b, page 550-552; polarity/polarizability parameter (π*), H -bond donating
ability (α), and H -bond accepting ability (β), taken from ref. 33b;
d
derived from linear
combination of (n
2
-1)/(n
2
+2), π*, α and β using linear regression;
e
derived from linear
combination of (ε -1)/(ε+2), (n
2
-1)/(n
2
+2), α and β using linear regression.

458

Conformational Analysis of epiCF
3
QD based on LFER

459

460

Figure 8.16. Correlation of ΔG
syn,exp
and ΔG
syn,cal
of epiCF
3
QD with various solvent
polarity parameters and related correlations.

461

8.5.4. Conformational analysis of QD based on DFT calculations
Optimized Structures of QD Conformers

Figure 8.17. Optimized conformations of QD in the gas phase at the B3LYP/6-311+(d,p)
level of theory (Part-A).
462

Figure 8.18. Optimized conformations of QD in the gas phase at the B3LYP/6-311+(d,p)
level of theory (Part-B).
463

Figure 8.19. Optimized conformations of QD in the gas phase at the B3LYP/6-311+(d,p)
level of theory (Part-C).

464

Table 8.30. Gas phase structures of QD conformers optimized at the B3LYP-6-
311+G(d,p) level.
Conformer
τ
1

(φ
C5'-C4'-C9-C8
)
τ
2
(φ
C4'-C9-C8-
N
)
τ
3
(φ
C4'-C9-O-H
)
τ
4
(φ
H8-C9-C8-H9
)
J
H8H9
(Hz)
Electronic
Energy (E, a.u.)
ΔE
(kcal/mol)
Closed-1a 104.8 301.4 167.0 175.44 9.15 -1373.88760313 3.1
Closed-1b 107.2 299.4 54.0 173.30 9.13 -1373.88804004 3.6
Open-4a 83.0 192.7 146.6 60.21 1.89 -1373.88372493 6.3
Open-4b 91.8 212.7 60.7 80.67 0.92 -1373.89056963 2.0
Open-6a 95.7 63.7 186.6 293.76 2.27 -1373.88045217 8.3
Open-6b 100.2 56.2 45.4 287.22 1.73 -1373.88913744 2.9
Open-6c 82.6 88.9 24.7 315.32 4.58 -1373.87550086 11.4
Closed-2a 285.3 297.8 178.5 175.62 9.15 -1373.88367861 6.3
Closed-2b 287.2 298.2 53.7 175.98 9.15 -1373.88368288 6.3
Closed-7a 348.3 302.0 174.0 179.8 9.11 -1373.87854267 9.5
Closed-7b 341.5 302.6 34.9 178.9 9.13 -1373.88724593 4.1
Closed-7c 348.7 301.9 313.4 179.6 9.11 -1373.88809295 3.5
Open-3b 260.4 206.2 63.5 78.30 0.95 -1373.88722143 4.1
Open-3c 255.0 211.2 296.1 82.54 0.92 -1373.88715434 4.1
Open-9b 338.2 209.0 33.6 80.4 0.92 -1373.88257915 7.0
Open-9c 341.8 210.1 325.9 81.29 0.92 -1373.89374672 0.0
Open-5b 277.3 46.0 46.5 281.42 1.38 -1373.89260378 0.7
Open-8c 354.9 88.4 256.0 316.55 4.72 -1373.88361417 6.4
Open-10c 260.91 86.27 256 317.06 4.78 -1373.88454744 5.1

465

Table 8.31. Gas Phase Energy of QD conformers at the B3LYP-6-311+G(d,p) level.
Conformer
Electronic
Energy (E, a.u.)
ΔE
(kcal/
mol)
Dipole
(Debye)
Thermal
Correction to
Gibbs Free
Energies (a.u.)
Gibbs Free
Energies (G, a.u.)
ΔG
(kcal
/mol
)
Pop.
(%)
Pop.×
J
H8-H9
(Hz)
Closed-1a -1036.75270568 3.4 5.6423 0.35634 -1036.39637068 2.6 0.9 0.1
Closed-1b -1036.75579795 1.4 3.4582 0.35657 -1036.39922895 0.8 18.7 1.7
Open-4a -1036.75109604 4.4 4.1762 0.35719 -1036.39390204 4.1 0.1 0.0
Open-4b -1036.75370904 2.8 2.5607 0.35783 -1036.39587704 2.9 0.5 0.0
Open-6a -1036.74824940 6.2 5.5052 0.3576 -1036.39065140 6.1 0.0 0.0
Open-6b -1036.75120172 4.3 3.3622 0.35797 -1036.39323472 4.5 0.0 0.0
Open-6c -1036.75239163 3.6 4.7483 0.35914 -1036.39324763 4.5 0.0 0.0
Closed-2a -1036.75210782 3.8 5.8128 0.35662 -1036.39549282 3.1 0.4 0.0
Closed-2b -1036.75497478 2.0 3.5062 0.35686 -1036.39811278 1.5 5.7 0.5
Closed-7a -1036.75125383 4.3 5.8925 0.35671 -1036.39454683 3.7 0.1 0.0
Closed-7b -1036.75355104 2.9 3.1202 0.3561 -1036.39745004 1.9 2.8 0.3
Closed-7c -1036.75465835 2.2 3.7641 0.3569 -1036.39776335 1.7 4.0 0.4
Open-3b -1036.75810348 0.0 2.6455 0.35766 -1036.40044048 0.0 67.4 0.6
Open-3c -1036.75347331 2.9 3.5535 0.35675 -1036.39672231 2.3 1.3 0.0
Open-9b -1036.75307119 3.2 1.8881 0.35752 -1036.39554819 3.1 0.4 0.0
Open-9c -1036.75333332 3.0 2.3812 0.35736 -1036.39597332 2.8 0.6 0.0
Open-5b -1036.74980746 5.2 3.5667 0.35774 -1036.39206746 5.3 0.0 0.0
Open-8c -1036.74587498 7.7 5.3651 0.35968 -1036.38619198 8.9 0.0 0.0
Open-10c -1036.75563993 1.5 5.0847 0.35924 -1036.39640293 2.5 0.9 0.0

466

Table 8.32. SPE of QD conformers at the M06-2X-6-311+G(d,p) level in the gas phase.
Conformer
Electronic
Energy (E, a.u.)
Gibbs Free
Energies
(G, a.u.)
ΔG
(kcal/
mol)
Pop.
(%)
Pop.×
J
H8-H9
(Hz)

Calc.
J
H8-H9
(Hz)

Closed-1a -1036.32942314 -1035.97308814 3.1 0.4 0.0
2.7
Closed-1b -1036.33259425 -1035.97602525 1.2 9.2 0.8
Open-4a -1036.32880025 -1035.97160625 4.0 0.1 0.0
Open-4b -1036.33086823 -1035.97303623 3.1 0.4 0.0
Open-6a -1036.32804724 -1035.97044924 4.7 0.0 0.0
Open-6b -1036.33130562 -1035.97333862 2.9 0.5 0.0
Open-6c -1036.33149555 -1035.97235155 3.5 0.2 0.0
Closed-2a -1036.32930496 -1035.97268996 3.3 0.3 0.0
Closed-2b -1036.33201199 -1035.97514999 1.8 3.6 0.3
Closed-7a -1036.32824270 -1035.97153570 4.1 0.1 0.0
Closed-7b -1036.33030834 -1035.97420734 2.4 1.3 0.1
Closed-7c -1036.33173930 -1035.97484430 2.0 2.6 0.2
Open-3b -1036.33566648 -1035.97800348 0.0 74.4 0.7
Open-3c -1036.33116847 -1035.97441747 2.3 1.7 0.0
Open-9b -1036.32996505 -1035.97244205 3.5 0.3 0.2
Open-9c -1036.33019687 -1035.97283687 3.2 0.3 0.0
Open-5b -1036.32889911 -1035.97115911 4.3 0.1 0.0
Open-8c -1036.32330310 -1035.96362010 9.0 0.0 0.0
Open-10c -1036.33493886 -1035.97570186 1.4 6.5 0.3

467

Table 8.33. SPE of QD conformers at the M06-2X-6-311+G(d,p) level in CHCl
3
(PCM)
Conformer
Electronic
Energy (E, a.u.)
Gibbs Free
Energies
(G, a.u.)
ΔG
(kcal/
mol)
Pop
(%)
Pop×
J
H8H9
(Hz)

Calc.
J
H8H9
(Hz)

Closed-1a -1036.34081581 -1035.98448081 1.5 3.2 0.3
4.8
Closed-1b -1036.34266588 -1035.98609688 0.5 17.6 1.6
Open-4a -1036.33855486 -1035.98136086 3.5 0.1 0.0
Open-4b -1036.33988812 -1035.98205612 3.1 0.2 0.0
Open-6a -1036.33864669 -1035.98104869 3.7 0.1 0.0
Open-6b -1036.34051045 -1035.98254345 2.8 0.4 0.0
Open-6c -1036.34096419 -1035.98182019 3.2 0.2 0.0
Closed-2a -1036.34103522 -1035.98442022 1.6 3.0 0.3
Closed-2b -1036.34244535 -1035.98558335 0.8 10.2 0.9
Closed-7a -1036.33996303 -1035.98325603 2.3 0.9 0.1
Closed-7b -1036.34020767 -1035.98410667 1.8 2.1 0.2
Closed-7c -1036.34167541 -1035.98478041 1.3 4.4 0.4
Open-3b -1036.34459097 -1035.98692797 0.0 42.5 0.4
Open-3c -1036.34110749 -1035.98435649 1.6 2.8 0.0
Open-9b -1036.33860788 -1035.98108488 3.7 0.1 0.0
Open-9c -1036.33934618 -1035.98198618 3.1 0.2 0.0
Open-5b -1036.34110749 -1035.98336749 2.2 1.0 0.0
Open-8c -1036.33281732 -1035.97313432 8.7 0.0 0.0
Open-10c -1036.34487717 -1035.98564017 0.8 10.9 0.5

468

Table 8.34. SPE of QD conformers at the M06-2X-6-311+G(d,p) level in Benzene (PCM)
Conformer
Electronic
Energy (E, a.u.)
Gibbs Free
Energies
(G, a.u.)
ΔG
(kcal/
mol)
Pop.
(%)
Pop.×
J
H8H9
(Hz)

Calc.
J
H8H9
(Hz)

Closed-1a -1036.33628916 -1035.97995416 2.3 1.3 0.1
3.6
Closed-1b -1036.33872031 -1035.98215131 0.9 13.4 1.2
Open-4a -1036.33480308 -1035.97760908 3.7 0.1 0.0
Open-4b -1036.33644904 -1035.97861704 3.1 0.3 0.0
Open-6a -1036.33446056 -1035.97686256 4.2 0.0 0.0
Open-6b -1036.33694520 -1035.97897820 2.9 0.5 0.0
Open-6c -1036.33731596 -1035.97817196 3.4 0.2 0.0
Closed-2a -1036.33637647 -1035.97976147 2.4 1.1 0.1
Closed-2b -1036.33832738 -1035.98146538 1.3 6.5 0.6
Closed-7a -1036.33532768 -1035.97862068 3.1 0.3 0.0
Closed-7b -1036.33634344 -1035.98024244 2.1 1.8 0.2
Closed-7c -1036.33781812 -1035.98092312 1.6 3.6 0.3
Open-3b -1036.34120311 -1035.98354011 0.0 58.1 0.6
Open-3c -1036.33725593 -1035.98050493 1.9 2.3 0.0
Open-9b -1036.33527844 -1035.97775544 3.6 0.1 0.0
Open-9c -1036.33581462 -1035.97845462 3.2 0.3 0.0
Open-5b -1036.33725593 -1035.97951593 2.5 0.8 0.0
Open-8c -1036.32918183 -1035.96949883 8.8 0.0 0.0
Open-10c -1036.34104761 -1035.98181061 1.1 9.3 0.4

469

Table 8.35. SPE of QD conformers at the M06-2X-6-311+G(d,p) level in THF (PCM)
Conformer
Electronic
Energy (E, a.u.)
Gibbs Free
Energies
(G, a.u.)
ΔG
(kcal/
mol)
Pop
(%)
Pop×
J
H8H9
(Hz)

Calc.
J
H8H9
(Hz)

Closed-1a -1036.34278477 -1035.98644977 1.2 4.7 0.4
5.4
Closed-1b -1036.34436009 -1035.98779109 0.3 19.4 1.8
Open-4a -1036.34012701 -1035.98293301 3.4 0.1 0.0
Open-4b -1036.34131690 -1035.98348490 3.0 0.2 0.0
Open-6a -1036.34044818 -1035.98285018 3.4 0.1 0.0
Open-6b -1036.34202435 -1035.98405735 2.7 0.4 0.0
Open-6c -1036.34250042 -1035.98335642 3.1 0.2 0.0
Closed-2a -1036.34306603 -1035.98645103 1.2 4.7 0.4
Closed-2b -1036.34423631 -1035.98737431 0.6 12.5 1.1
Closed-7a -1036.34196678 -1035.98525978 1.9 1.3 0.1
Closed-7b -1036.34185789 -1035.98575689 1.6 2.3 0.2
Closed-7c -1036.34331237 -1035.98641737 1.2 4.5 0.4
Open-3b -1036.34599236 -1035.98832936 0.0 34.4 0.3
Open-3c -1036.34273453 -1035.98598353 1.5 2.9 0.0
Open-9b -1036.34000459 -1035.98248159 3.7 0.1 0.0
Open-9c -1036.34083201 -1035.98347201 3.0 0.2 0.0
Open-5b -1036.34273453 -1035.98499453 2.1 1.0 0.0
Open-8c -1036.33433738 -1035.97465438 8.6 0.0 0.0
Open-10c -1036.34649239 -1035.98725539 0.7 11.0 0.5

470

Table 8.36. SPE of QD conformers at the M06-2X-6-311+G(d,p) level in DMSO (PCM)
Conformer
Electronic
Energy (E, a.u.)
Gibbs Free
Energies
(G, a.u.)
ΔG
(kcal/
mol)
Pop
(%)
Pop×
J
H8H9
(Hz)

Calc.
J
H8H9
(Hz)

Closed-1a -1036.34626502 -1035.98993002 0.5 8.8 0.8
6.7
Closed-1b -1036.34732558 -1035.99075658 0.0 21.1 1.9
Open-4a -1036.34280729 -1035.98561329 3.2 0.1 0.0
Open-4b -1036.34373426 -1035.98590226 3.0 0.1 0.0
Open-6a -1036.34359039 -1035.98599239 2.9 0.1 0.0
Open-6b -1036.34464804 -1035.98668104 2.5 0.3 0.0
Open-6c -1036.34513448 -1035.98599048 2.9 0.1 0.0
Closed-2a -1036.34667520 -1035.99006020 0.4 10.1 0.9
Closed-2b -1036.34742440 -1035.99056240 0.1 17.1 1.6
Closed-7a -1036.34548332 -1035.98877632 1.2 2.6 0.2
Closed-7b -1036.34472627 -1035.98862527 1.3 2.2 0.2
Closed-7c -1036.34613992 -1035.98924492 0.9 4.3 0.4
Open-3b -1036.34835405 -1035.99069105 0.0 19.6 0.2
Open-3c -1036.34552947 -1035.98877847 1.2 2.6 0.0
Open-9b -1036.34238579 -1035.98486279 3.7 0.0 0.0
Open-9c -1036.34337362 -1035.98601362 2.9 0.1 0.0
Open-5b -1036.34552947 -1035.98778947 1.8 0.9 0.0
Open-8c -1036.33693182 -1035.97724882 8.4 0.0 0.0
Open-10c -1036.34927094 -1035.99003394 0.4 9.8 0.5

471

Table 8.37. SPE of QD conformers at the M06-2X-6-311+G(d,p) level in MeOH (PCM)
Conformer
Electronic
Energy (E, a.u.)
Gibbs Free
Energies (G,
a.u.)
ΔG
(kcal/
mol)
Pop
(%)
Pop×
J
H8H9
(Hz)

Calc.
J
H8H9
(Hz)

Closed-1a -1036.34594538 -1035.98961038 0.5 8.3 0.8
6.6
Closed-1b -1036.34705462 -1035.99048562 0.0 21.0 1.9
Open-4a -1036.34256664 -1035.98537264 3.2 0.1 0.0
Open-4b -1036.34351823 -1035.98568623 3.0 0.1 0.0
Open-6a -1036.34330445 -1035.98570645 3.0 0.1 0.0
Open-6b -1036.34440975 -1035.98644275 2.5 0.3 0.0
Open-6c -1036.34489709 -1035.98575309 3.0 0.1 0.0
Closed-2a -1036.34634212 -1035.98972712 0.5 9.4 0.9
Closed-2b -1036.34712951 -1035.99026751 0.1 16.7 1.5
Closed-7a -1036.34516193 -1035.98845493 1.3 2.5 0.2
Closed-7b -1036.34446550 -1035.98836450 1.3 2.2 0.2
Closed-7c -1036.34588391 -1035.98898891 0.9 4.3 0.4
Open-3b -1036.34814351 -1035.99048051 0.0 20.9 0.2
Open-3c -1036.34527732 -1035.98852632 1.2 2.6 0.0
Open-9b -1036.34217209 -1035.98464909 3.7 0.0 0.0
Open-9c -1036.34314501 -1035.98578501 2.9 0.1 0.0
Open-5b -1036.34527732 -1035.98753732 1.8 0.9 0.0
Open-8c -1036.33669849 -1035.97701549 8.5 0.0 0.0
Open-10c -1036.34901985 -1035.98978285 0.4 10.0 0.5

472

Table 8.38. SPE of QD conformers at the M06-2X-6-311+G(d,p) level in EtOH (PCM)
Conformer
Electronic
Energy (E, a.u.)
Gibbs Free
Energies (G,
a.u.)
ΔG
(kcal/
mol)
Pop
(%)
Pop×
J
H8H9
(Hz)

Calc.
J
H8H9
(Hz)

Closed-1a -1036.34562365 -1035.98928865 0.6 8.0 0.7
6.5
Closed-1b -1036.34678163 -1035.99021263 0.0 21.2 1.9
Open-4a -1036.34232326 -1035.98512926 3.2 0.1 0.0
Open-4b -1036.34329954 -1035.98546754 3.0 0.1 0.0
Open-6a -1036.34301606 -1035.98541806 3.0 0.1 0.0
Open-6b -1036.34416938 -1035.98620238 2.6 0.3 0.0
Open-6c -1036.34465720 -1035.98551320 3.0 0.1 0.0
Closed-2a -1036.34600727 -1035.98939227 0.5 8.9 0.8
Closed-2b -1036.34683324 -1035.98997124 0.2 16.4 1.5
Closed-7a -1036.34483809 -1035.98813109 1.3 2.3 0.2
Closed-7b -1036.34420248 -1035.98810148 1.4 2.3 0.2
Closed-7c -1036.34562754 -1035.98873254 1.0 4.4 0.4
Open-3b -1036.34793027 -1035.99026727 0.0 22.4 0.2
Open-3c -1036.34502257 -1035.98827157 1.3 2.7 0.0
Open-9b -1036.34195594 -1035.98443294 3.7 0.0 0.0
Open-9c -1036.34291388 -1035.98555388 3.0 0.2 0.0
Open-5b -1036.34329413 -1035.98555413 3.0 0.2 0.0
Open-8c -1036.33646262 -1035.97677962 8.5 0.0 0.0

473

Table 8.39. SPE of QD conformers at the M06-2X-6-311+G(d,p) level in i-PrOH (PCM)
Conformer
Electronic
Energy (E, a.u.)
Gibbs Free
Energies (G,
a.u.)
ΔG
(kcal/
mol)
Pop
(%)
Pop×
J
H8H9
(Hz)

Calc.
J
H8H9
(Hz)

Closed-1a -1036.34521853 -1035.98888353 0.7 7.4 0.7
6.4
Closed-1b -1036.34643747 -1035.98986847 0.1 21.1 1.9
Open-4a -1036.34201516 -1035.98482116 3.2 0.1 0.0
Open-4b -1036.34302240 -1035.98519040 3.0 0.1 0.0
Open-6a -1036.34265208 -1035.98505408 3.1 0.1 0.0
Open-6b -1036.34386592 -1035.98589892 2.6 0.3 0.0
Open-6c -1036.34435379 -1035.98520979 3.0 0.2 0.0
Closed-2a -1036.34558616 -1035.98897116 0.6 8.1 0.7
Closed-2b -1036.34646088 -1035.98959888 0.2 15.8 1.4
Closed-7a -1036.34442981 -1035.98772281 1.4 2.2 0.2
Closed-7b -1036.34387048 -1035.98776948 1.4 2.3 0.2
Closed-7c -1036.34530097 -1035.98840597 1.0 4.5 0.4
Open-3b -1036.34765988 -1035.98999688 0.0 24.1 0.2
Open-3c -1036.34470043 -1035.98794943 1.3 2.8 0.0
Open-9b -1036.34168226 -1035.98415926 3.7 0.1 0.0
Open-9c -1036.34262140 -1035.98526140 3.0 0.2 0.0
Open-5b -1036.34293963 -1035.98519963 3.0 0.2 0.0
Open-8c -1036.33616416 -1035.97648116 8.5 0.0 0.0
Open-10c -1036.34844578 -1035.98920878 0.5 10.5 0.5

474

Table 8.40. SPE of QD conformers at the M06-2X-6-311+G(d,p) level in pyridine (PCM)
Conformer
Electronic
Energy (E, a.u.)
Gibbs Free
Energies
(G, a.u.)
ΔG
(kcal/
mol)
Pop.
(%)
Pop.×
J
H8-H9
(Hz)

Calc.
J
H8-H9
(Hz)

Closed-1a -1036.34444915 -1035.98811415 0.9 6.5 0.6
6.1
Closed-1b -1036.34578264 -1035.98921364 0.2 20.7 1.9
Open-4a -1036.34142509 -1035.98423109 3.3 0.1 0.0
Open-4b -1036.34249069 -1035.98465869 3.0 0.2 0.0
Open-6a -1036.34195846 -1035.98436046 3.2 0.1 0.0
Open-6b -1036.34328722 -1035.98532022 2.6 0.3 0.0
Open-6c -1036.34377350 -1035.98462950 3.0 0.2 0.0
Closed-2a -1036.34478786 -1035.98817286 0.8 6.9 0.6
Closed-2b -1036.34575562 -1035.98889362 0.4 14.8 1.4
Closed-7a -1036.34365302 -1035.98694602 1.6 1.9 0.2
Closed-7b -1036.34323758 -1035.98713658 1.5 2.3 0.2
Closed-7c -1036.34467747 -1035.98778247 1.1 4.6 0.4
Open-3b -1036.34714066 -1035.98947766 0.0 27.4 0.3
Open-3c -1036.34408458 -1035.98733358 1.3 2.8 0.0
Open-9b -1036.34115803 -1035.98363503 3.7 0.1 0.0
Open-9c -1036.34206164 -1035.98470164 3.0 0.2 0.0
Open-5b -1036.34226616 -1035.98452616 3.1 0.1 0.0
Open-8c -1036.33559293 -1035.97590993 8.5 0.0 0.0
Open-10c -1036.34783344 -1035.98859644 0.6 10.8 0.5

475

Table 8.41. SPE of QD conformers at the M06-2X-6-311+G(d,p) level in PhNO
2
(PCM)
Conformer
Electronic
Energy (E, a.u.)
Gibbs Free
Energies
(G, a.u.)
ΔG
(kcal/
mol)
Pop
(%)
Pop×
J
H8H9
(Hz)

Calc.
J
H8H9
(Hz)

Closed-1a -1036.34601124 -1035.98967624 0.5 8.5 0.8
6.7
Closed-1b -1036.34711048 -1035.99054148 0.0 21.2 1.9
Open-4a -1036.34261632 -1035.98542232 3.2 0.1 0.0
Open-4b -1036.34356285 -1035.98573085 3.0 0.1 0.0
Open-6a -1036.34336342 -1035.98576542 3.0 0.1 0.0
Open-6b -1036.34445889 -1035.98649189 2.5 0.3 0.0
Open-6c -1036.34494608 -1035.98580208 3.0 0.1 0.0
Closed-2a -1036.34641072 -1035.98979572 0.5 9.6 0.9
Closed-2b -1036.34719023 -1035.99032823 0.1 16.9 1.5
Closed-7a -1036.34522819 -1035.98852119 1.3 2.5 0.2
Closed-7b -1036.34451928 -1035.98841828 1.3 2.2 0.2
Closed-7c -1036.34593884 -1035.98904384 0.9 4.3 0.4
Open-3b -1036.34818700 -1035.99052400 0.0 20.8 0.2
Open-3c -1036.34532935 -1035.98857835 1.2 2.7 0.0
Open-9b -1036.34221621 -1035.98469321 3.7 0.0 0.0
Open-9c -1036.34319220 -1035.98583220 3.0 0.1 0.0
Open-5b -1036.34363323 -1035.98589323 2.9 0.2 0.0
Open-8c -1036.33674665 -1035.97706365 8.5 0.0 0.0
Open-10c -1036.34907165 -1035.98983465 0.4 10.0 0.5

476

Table 8.42. SPE of QD conformers at the M06-2X-6-311+G(d,p) level in MeNO
2
(PCM)
Conformer
Electronic
Energy (E, a.u.)
Gibbs Free
Energies (G,
a.u.)
ΔG
(kcal/
mol)
Pop
(%)
Pop×
J
H8H9
(Hz)

Calc.
J
H8H9
(Hz)

Closed-1a -1036.34605832 -1035.98972332 0.5 8.6 0.8
6.7
Closed-1b -1036.34715039 -1035.99058139 0.0 21.2 1.9
Open-4a -1036.34265180 -1035.98545780 3.2 0.1 0.0
Open-4b -1036.34359471 -1035.98576271 3.0 0.1 0.0
Open-6a -1036.34340555 -1035.98580755 3.0 0.1 0.0
Open-6b -1036.34449401 -1035.98652701 2.5 0.3 0.0
Open-6c -1036.34498108 -1035.98583708 3.0 0.1 0.0
Closed-2a -1036.34645976 -1035.98984476 0.5 9.7 0.9
Closed-2b -1036.34723364 -1035.99037164 0.1 17.0 1.6
Closed-7a -1036.34527554 -1035.98856854 1.3 2.5 0.2
Closed-7b -1036.34455770 -1035.98845670 1.3 2.2 0.2
Closed-7c -1036.34597657 -1035.98908157 0.9 4.3 0.4
Open-3b -1036.34821805 -1035.99055505 0.0 20.6 0.2
Open-3c -1036.34536652 -1035.98861552 1.2 2.6 0.0
Open-9b -1036.34224772 -1035.98472472 3.7 0.0 0.0
Open-9c -1036.34322590 -1035.98586590 2.9 0.1 0.0
Open-5b -1036.34367442 -1035.98593442 2.9 0.2 0.0
Open-8c -1036.33678105 -1035.97709805 8.5 0.0 0.0
Open-10c -1036.34910866 -1035.98987166 0.4 10.0 0.5

477

Table 8.43. SPE of QD conformers at the M06-2X-6-311+G(d,p) level in DMF (PCM)
Conformer
Electronic
Energy (E, a.u.)
Gibbs Free
Energies
(G, a.u.)
ΔG
(kcal/
mol)
Pop
(%)
Pop×
J
H8H9
(Hz)

Calc.
J
H8H9
(Hz)

Closed-1a -1036.34607486 -1035.98973986 0.5 8.6 0.8
6.7
Closed-1b -1036.34716442 -1035.99059542 0.0 21.2 1.9
Open-4a -1036.34266426 -1035.98547026 3.2 0.1 0.0
Open-4b -1036.34360589 -1035.98577389 3.0 0.1 0.0
Open-6a -1036.34342035 -1035.98582235 3.0 0.1 0.0
Open-6b -1036.34450634 -1035.98653934 2.5 0.3 0.0
Open-6c -1036.34499337 -1035.98584937 3.0 0.1 0.0
Closed-2a -1036.34647699 -1035.98986199 0.4 9.8 0.9
Closed-2b -1036.34724890 -1035.99038690 0.1 17.0 1.6
Closed-7a -1036.34529217 -1035.98858517 1.2 2.5 0.2
Closed-7b -1036.34457120 -1035.98847020 1.3 2.2 0.2
Closed-7c -1036.34598982 -1035.98909482 0.9 4.3 0.4
Open-3b -1036.34822895 -1035.99056595 0.0 20.6 0.2
Open-3c -1036.34537957 -1035.98862857 1.2 2.6 0.0
Open-9b -1036.34225879 -1035.98473579 3.7 0.0 0.0
Open-9c -1036.34323774 -1035.98587774 2.9 0.1 0.0
Open-5b -1036.34368889 -1035.98594889 2.9 0.2 0.0
Open-8c -1036.33679313 -1035.97711013 8.4 0.0 0.0
Open-10c -1036.34912166 -1035.98988466 0.4 10.0 0.5

478

Table 8.44. SPE of QD conformers at the M06-2X-6-311+G(d,p) level in acetone (PCM)
Conformer
Electronic
Energy (E, a.u.)
Gibbs Free
Energies (G,
a.u.)
ΔG
(kcal/
mol)
Pop
(%)
Pop×
J
H8H9
(Hz)

Calc.
J
H8H9
(Hz)

Closed-1a -1036.34534198 -1035.98900698 0.7 7.6 0.7
6.4
Closed-1b -1036.34654240 -1035.98997340 0.1 21.1 1.9
Open-4a -1036.34210924 -1035.98491524 3.2 0.1 0.0
Open-4b -1036.34310706 -1035.98527506 3.0 0.1 0.0
Open-6a -1036.34276309 -1035.98516509 3.1 0.1 0.0
Open-6b -1036.34395848 -1035.98599148 2.6 0.3 0.0
Open-6c -1036.34444640 -1035.98530240 3.0 0.2 0.0
Closed-2a -1036.34571442 -1035.98909942 0.6 8.4 0.8
Closed-2b -1036.34657427 -1035.98971227 0.2 16.0 1.5
Closed-7a -1036.34455429 -1035.98784729 1.4 2.2 0.2
Closed-7b -1036.34397174 -1035.98787074 1.4 2.3 0.2
Closed-7c -1036.34540061 -1035.98850561 1.0 4.5 0.4
Open-3b -1036.34774250 -1035.99007950 0.0 23.6 0.2
Open-3c -1036.34479876 -1035.98804776 1.3 2.7 0.0
Open-9b -1036.34176583 -1035.98424283 3.7 0.0 0.0
Open-9c -1036.34271070 -1035.98535070 3.0 0.2 0.0
Open-5b -1036.34304767 -1035.98530767 3.0 0.2 0.0
Open-8c -1036.33625528 -1035.97657228 8.5 0.0 0.0
Open-10c -1036.34854358 -1035.98930658 0.5 10.4 0.5

479

Table 8.45. SPE of QD conformers at the M06-2X-6-311+G(d,p) level in H
2
O (PCM)
Conformer
Electronic
Energy (E, a.u.)
Gibbs Free
Energies
(G, a.u.)
ΔG
(kcal/
mol)
Pop
(%)
Pop×
J
H8H9
(Hz)

Calc.
J
H8H9
(Hz)

Closed-1a -1036.34656648 -1035.99023148 0.5 9.3 0.8
6.9
Closed-1b -1036.34758090 -1035.99101190 0.0 21.2 1.9
Open-4a -1036.34303320 -1035.98583920 3.2 0.1 0.0
Open-4b -1036.34393686 -1035.98610486 3.1 0.1 0.0
Open-6a -1036.34385951 -1035.98626151 3.0 0.1 0.0
Open-6b -1036.34487229 -1035.98690529 2.6 0.3 0.0
Open-6c -1036.34535750 -1035.98621350 3.0 0.1 0.0
Closed-2a -1036.34698972 -1035.99037472 0.4 10.8 1.0
Closed-2b -1036.34770306 -1035.99084106 0.1 17.7 1.6
Closed-7a -1036.34578610 -1035.98907910 1.2 2.7 0.2
Closed-7b -1036.34497168 -1035.98887068 1.3 2.2 0.2
Closed-7c -1036.34638281 -1035.98948781 1.0 4.2 0.4
Open-3b -1036.34855139 -1035.99088839 0.1 18.6 0.2
Open-3c -1036.34576640 -1035.98901540 1.3 2.6 0.0
Open-9b -1036.34258636 -1035.98506336 3.7 0.0 0.0
Open-9c -1036.34358830 -1035.98622830 3.0 0.1 0.0
Open-5b -1036.34411900 -1035.98637900 2.9 0.2 0.0
Open-8c -1036.33715096 -1035.97746796 8.5 0.0 0.0
Open-10c -1036.34950699 -1035.99026999 0.5 9.7 0.5

Figure 8.20. Calculated population of QD conformers in different solvents. The
population of Open-3b was found to decrease with the increase in dielectric constants.
480

8.5.5. Conformational Analysis of QD Conformers using LFER

Figure 8.21. Correlation of ΔG
syn,exp
and ΔG
syn,cal
of QD with various solvent polarity
parameters and related correlations (Part A).
481

Figure 8.22. Correlation of ΔG
syn,exp
and ΔG
syn,cal
of QD with various solvent polarity
parameters and related correlations (Part B).

482

8.5.6. Conformational Analysis of epiQD based on DFT Calculations
Optimized Structures of epiQD Conformers

Figure 8.23. Optimized Conformations of epiQD in the gas phase at the B3LYP/6-
311+(d,p) level of theory (Part-A).
483

Figure 8.24. Optimized Conformations of epiQD in the gas phase at the B3LYP/6-
311+(d,p) level of theory (Part-B).

484

Calculated Data of epiQD Conformers
Table 8.46. Gas phase structures of epiQD optimized at the B3LYP-6-311+G(d,p) level
Conformer
τ
1

(φ
C5'-C4'-C9-C8
)
τ
2
(φ
C4'-C9-C8-N
)
τ
3
(φ
C4'-C9-O-H
)
τ
4
(φ
H8-C9-C8-H9
)
J
H8H9
(Hz)
Electronic Energy
(E, a.u.)
ΔE
(kcal/
mol)
Closed-1a 101.69 303.22 207.2 299.38 3.41 -1036.75155021 6.6
Closed-1b 96.24 303.18 301.71 298.97 3.36 -1036.75517329 4.4
Open-4a 77.67 193.32 153.24 184.84 8.84 -1036.76127775 0.5
Open-4b 71.73 173.41 301.39 165.55 8.02 -1036.75260785 6.0
Open-4c 71.73 173.4 59.05 165.55 8.02 -1036.74649118 9.8
Open-6a 91.26 69.87 185.93 60.12 3.47 -1036.75117413 6.9
Open-6b 89.67 69.37 306.34 60.3 3.45 -1036.75374351 5.3
Closed-2b 268.22 293.75 305.08 293.87 2.80 -1036.75245750 6.1
Closed-7c 337.42 291.92 39.18 290.12 2.41 -1036.75384193 5.2
Open-3a 255.63 189.13 157.41 185.26 8.81 -1036.76214594 0.0
Open-3b 251.07 173 302.86 169.47 8.40 -1036.75374746 5.3
Open-5a 265.53 68.76 195.46 62.76 3.71 -1036.74818071 8.8
Open-5b 264.31 65.34 305.06 60.03 3.48 -1036.75061297 7.2

Table 8.47. SPE of epiQD at the M06-2X-6-311+G(d,p) level in the gas phase.
Conformer
Electronic
Energy (E, a.u.)
Gibbs Free
Energies
(G, a.u.)
ΔG
(kcal/
mol)
Pop.
(%)
Pop.×
J
H8H9
(Hz)

Calc.
J
H8-H9
(Hz)

Closed-1a -1036.32846474 -1035.97199074 5.6 0.0 0.0
8.8
Closed-1b -1036.33212685 -1035.97478485 3.8 0.1 0.0
Open-4a -1036.33842622 -1035.98016822 0.4 31.9 2.8
Open-4b -1036.32995363 -1035.97314063 4.9 0.0 0.0
Open-4c -1036.32414029 -1035.96721329 8.6 0.0 0.0
Open-6a -1036.33117504 -1035.97300504 4.9 0.0 0.0
Open-6b -1036.33376299 -1035.97538199 3.5 0.2 0.0
Closed-2b -1036.33054562 -1035.97280662 5.1 0.0 0.0
Closed-7c -1036.33083747 -1035.97349047 4.6 0.0 0.0
Open-3a -1036.33913926 -1035.98088126 0.0 67.8 6.0
Open-3b -1036.33067679 -1035.97336879 4.7 0.0 0.0
Open-5a -1036.32735284 -1035.96897184 7.5 0.0 0.0
Open-5b -1036.33018579 -1035.97196279 5.6 0.0 0.0

485

Table 8.48. SPE of epiQD at the M06-2X-6-311+G(d,p) level in CHCl
3
(PCM).
Conformer
Electronic
Energy (E, a.u.)
Gibbs Free
Energies
(G, a.u.)
ΔG
(kcal/
mol)
Pop.
(%)
Pop.×
J
H8H9
(Hz)

Calc.
J
H8-H9
(Hz)

Closed-1a -1036.33982419 -1035.98335019 4.5 0.0 0.0
8.8
Closed-1b -1036.34202366 -1035.98468166 3.7 0.1 0.0
Open-4a -1036.34854476 -1035.99028676 0.2 42.2 3.7
Open-4b -1036.34131364 -1035.98450064 3.8 0.1 0.0
Open-4c -1036.33648543 -1035.97955843 6.9 0.0 0.0
Open-6a -1036.34118811 -1035.98301811 4.7 0.0 0.0
Open-6b -1036.34269163 -1035.98431063 3.9 0.1 0.0
Closed-2b -1036.34013630 -1035.98239730 5.1 0.0 0.0
Closed-7c -1036.33961528 -1035.98226828 5.2 0.0 0.0
Open-3a -1036.34883596 -1035.99057796 0.0 57.4 5.1
Open-3b -1036.34179242 -1035.98448442 3.8 0.1 0.0
Open-5a -1036.33752759 -1035.97914659 7.2 0.0 0.0
Open-5b -1036.33927669 -1035.98105369 6.0 0.0 0.0

Table 8.49. SPE of epiQD at the M06-2X-6-311+G(d,p) level in benzene (PCM).
Conformer
Electronic
Energy (E, a.u.)
Gibbs Free
Energies
(G, a.u.)
ΔG
(kcal/
mol)
Pop.
(%)
Pop.×
J
H8H9
(Hz)

Calc.
J
H8-H9
(Hz)

Closed-1a -1036.33524100 -1035.97876700 5.1 0.0 0.0
8.8
Closed-1b -1036.33809171 -1035.98074971 3.8 0.1 0.0
Open-4a -1036.34463621 -1035.98637821 0.3 37.8 3.3
Open-4b -1036.33682348 -1035.98001048 4.3 0.0 0.0
Open-4c -1036.33159490 -1035.97466790 7.6 0.0 0.0
Open-6a -1036.33727741 -1035.97910741 4.9 0.0 0.0
Open-6b -1036.33927782 -1035.98089682 3.7 0.1 0.0
Closed-2b -1036.33637188 -1035.97863288 5.2 0.0 0.0
Closed-7c -1036.33628403 -1035.97893703 5.0 0.0 0.0
Open-3a -1036.34510098 -1035.98684298 0.0 61.8 5.4
Open-3b -1036.33742258 -1035.98011458 4.2 0.0 0.0
Open-5a -1036.33354482 -1035.97516382 7.3 0.0 0.0
Open-5b -1036.33580879 -1035.97758579 5.8 0.0 0.0

486

Table 8.50. SPE of epiQD at the M06-2X-6-311+G(d,p) level in THF (PCM).
Conformer
Electronic
Energy (E, a.u.)
Gibbs Free
Energies
(G, a.u.)
ΔG
(kcal/
mol)
Pop.
(%)
Pop.×
J
H8H9
(Hz)

Calc.
J
H8-H9
(Hz)

Closed-1a -1036.34185224 -1035.98537824 4.3 0.0 0.0
8.8
Closed-1b -1036.34373969 -1035.98639769 3.6 0.1 0.0
Open-4a -1036.35020180 -1035.99194380 0.1 44.2 3.9
Open-4b -1036.34325984 -1035.98644684 3.6 0.1 0.0
Open-4c -1036.33860367 -1035.98167667 6.6 0.0 0.0
Open-6a -1036.34285195 -1035.98468195 4.7 0.0 0.0
Open-6b -1036.34411715 -1035.98573615 4.0 0.1 0.0
Closed-2b -1036.34175961 -1035.98402061 5.1 0.0 0.0
Closed-7c -1036.34099458 -1035.98364758 5.3 0.0 0.0
Open-3a -1036.35041162 -1035.99215362 0.0 55.2 4.9
Open-3b -1036.34366789 -1035.98635989 3.6 0.1 0.0
Open-5a -1036.33922425 -1035.98084325 7.1 0.0 0.0
Open-5b -1036.34072177 -1035.98249877 6.1 0.0 0.0

Table 8.51. SPE of epiQD at the M06-2X-6-311+G(d,p) level in DMSO (PCM)
Conformer
Electronic
Energy (E, a.u.)
Gibbs Free
Energies
(G, a.u.)
ΔG
(kcal/
mol)
Pop.
(%)
Pop.×
J
H8H9
(Hz)

Calc.
J
H8-H9
(Hz)

Closed-1a -1036.34549910 -1035.98902510 3.7 0.1 0.0
8.8
Closed-1b -1036.34679233 -1035.98945033 3.4 0.2 0.0
Open-4a -1036.35308037 -1035.99482237 0.0 48.4 4.3
Open-4b -1036.34670833 -1035.98989533 3.1 0.3 0.0
Open-4c -1036.34234302 -1035.98541602 5.9 0.0 0.0
Open-6a -1036.34572637 -1035.98755637 4.6 0.0 0.0
Open-6b -1036.34654565 -1035.98816465 4.2 0.0 0.0
Closed-2b -1036.34462015 -1035.98688115 5.0 0.0 0.0
Closed-7c -1036.34332299 -1035.98597599 5.6 0.0 0.0
Open-3a -1036.35312466 -1035.99486666 0.0 50.8 4.5
Open-3b -1036.34693761 -1035.98962961 3.3 0.2 0.0
Open-5a -1036.34215629 -1035.98377529 7.0 0.0 0.0
Open-5b -1036.34317756 -1035.98495456 6.2 0.0 0.0

487

Table 8.52. SPE of epiQD at the M06-2X-6-311+G(d,p) level in MeOH (PCM)
Conformer
Electronic
Energy (E, a.u.)
Gibbs Free
Energies
(G, a.u.)
ΔG
(kcal/
mol)
Pop.
(%)
Pop.×
J
H8H9
(Hz)

Calc.
J
H8-H9
(Hz)

Closed-1a -1036.34516045 -1035.98868645 3.7 0.1 0.0
8.8
Closed-1b -1036.34651053 -1035.98916853 3.4 0.2 0.0
Open-4a -1036.35281799 -1035.99455999 0.0 48.0 4.2
Open-4b -1036.34638982 -1035.98957682 3.2 0.2 0.0
Open-4c -1036.34199895 -1035.98507195 6.0 0.0 0.0
Open-6a -1036.34546623 -1035.98729623 4.6 0.0 0.0
Open-6b -1036.34632749 -1035.98794649 4.2 0.0 0.0
Closed-2b -1036.34435737 -1035.98661837 5.0 0.0 0.0
Closed-7c -1036.34311514 -1035.98576814 5.6 0.0 0.0
Open-3a -1036.35287928 -1035.99462128 0.0 51.2 4.5
Open-3b -1036.34663993 -1035.98933193 3.3 0.2 0.0
Open-5a -1036.34189096 -1035.98350996 7.0 0.0 0.0
Open-5b -1036.34295737 -1035.98473437 6.2 0.0 0.0

Table 8.53. SPE of epiQD at the M06-2X-6-311+G(d,p) level in MeCN (PCM)
Conformer
Electronic
Energy (E, a.u.)
Gibbs Free
Energies
(G, a.u.)
ΔG
(kcal/
mol)
Pop.
(%)
Pop.×
J
H8H9
(Hz)

Calc.
J
H8-H9
(Hz)

Closed-1a -1036.34525575 -1035.98878175 3.7 0.1 0.0
8.8
Closed-1b -1036.34658987 -1035.98924787 3.4 0.2 0.0
Open-4a -1036.35289192 -1035.99463392 0.0 0.0 4.3
Open-4b -1036.34647946 -1035.98966646 3.2 0.0 0.0
Open-4c -1036.34209583 -1035.98516883 6.0 51.1 0.0
Open-6a -1036.34553958 -1035.98736958 4.6 0.2 0.0
Open-6b -1036.34638904 -1035.98800804 4.2 48.1 0.0
Closed-2b -1036.34443138 -1035.98669238 5.0 0.3 0.0
Closed-7c -1036.34317381 -1035.98582681 5.6 0.0 0.0
Open-3a -1036.35294847 -1035.99469047 0.0 0.0 4.5
Open-3b -1036.34672383 -1035.98941583 3.3 0.0 0.0
Open-5a -1036.34196578 -1035.98358478 7.0 0.0 0.0
Open-5b -1036.34301950 -1035.98479650 6.2 0.0 0.0

488

Table 8.54. SPE of epiQD at the M06-2X-6-311+G(d,p) level in H
2
O (PCM)
Conformer
Electronic
Energy (E, a.u.)
Gibbs Free
Energies
(G, a.u.)
ΔG
(kcal/
mol)
Pop.
(%)
Pop.×
J
H8-H9
(Hz)

Calc.
J
H8-H9
(Hz)

Closed-1a -1036.34525575 -1035.98878175 3.7 0.2 0.0
8.8
Closed-1b -1036.34658987 -1035.98924787 3.4 0.3 0.0
Open-4a -1036.35289192 -1035.99463392 0.0 94.2 4.3
Open-4b -1036.34647946 -1035.98966646 3.2 0.5 0.0
Open-4c -1036.34209583 -1035.98516883 6.0 0.0 0.0
Open-6a -1036.34553958 -1035.98736958 4.6 0.0 0.0
Open-6b -1036.34638904 -1035.98800804 4.2 0.1 0.0
Closed-2b -1036.34443138 -1035.98669238 5.0 0.0 0.0
Closed-7c -1036.34317381 -1035.98582681 5.6 0.0 0.0
Open-3a -1036.35294847 -1035.99469047 0.0 100.0 4.5
Open-3b -1036.34672383 -1035.98941583 3.3 0.4 0.0
Open-5a -1036.34196578 -1035.98358478 7.0 0.0 0.0
Open-5b -1036.34301950 -1035.98479650 6.2 0.0 0.0
Table 8.55. Calculated Conformational Distribution of epiQD in the gas phase.
a

Conformer
ΔG
(kcal/mol)
b

Pop(%)
c

Dipole
(Debye)
g

φ
H8H9
d

J
H8H9
(Hz)
e

J
H8H9
×Pop (Hz)
f

Closed-1a 5.6 0.0 5.488 299.4 3.41 0.0
Closed-1b 3.8 0.1 3.742 299.0 3.36 0.0
Closed-2b 5.1 0.0 3.551 293.9 2.80 0.0
Closed-7c 4.6 0.0 3.479 290.1 2.41 0.0
Open-3a 0.0 67.8 5.203 185.3 8.81 6.0
Open-3b 4.7 0.0 2.358 169.5 8.40 0.0
Open-4a 0.4 31.9 5.424 184.8 8.84 2.8
Open-4b 4.9 0.0 2.692 165.6 8.02 0.0
Open-4c 8.6 0.0 3.115 165.6 8.02 0.0
Open-6a 4.9 0.0 5.342 60.1 3.47 0.0
Open-6b 3.5 0.2 3.245 60.3 3.45 0.0
Open-5a 7.5 0.0 5.047 62.8 3.71 0.0
Open-5b 5.6 0.0 3.141 60.0 3.48 0.0
a
Calculated at the M06-2X/6-311+G(d,p)//B3LYP/6-311+G(d,p) level of theory. See the
Method section for details of calculations;
b
relative Gibbs Free Energies (ΔG
cal
) to Open-
3b;
c
relative population (Pop);
d
dihedral angle of H
8
-C
9
-C
8
-H
9
(φ
H8H9
);
e
predicted J
H8H9
obtained via modified Karplus equation;

f
the coupling constant contribution of each
conformer to the overall J
H8H9
;
g
calculated at the B3LYP/6-311+G(d,p) level of theory.
489

Figure 8.25. Calculated population of epiQD conformers in different solvents, showing
the predominance of Open-3a and Open-4a conformations. The population of the Open-
3a was found to decrease with the increase in dielectric constants, while opposite solvent
dependence was found with the Open-4a conformation.

490

8.5.7. Conformational Analysis of QD Conformers using LFER
Table 8.56. Conformational distribution of QD and ΔG
open,exp
in various solvents.
solvent
J
H8H9,exp
(Hz)
a,b

Pop
open-3,cal
(%)
c

Pop
open-4,cal
(%)
d

Pop
open-3,cal
+
Pop
open-4,cal
(%)

Predicted
J
H8H9
(Hz)
e

benzene 9.8 61.8 37.8 99.6 8.8
CHCl
3
9.8 57.5 42.3 99.8 8.8
THF 9.7 55.3 44.3 99.6 8.8
toluene 9.8 - - - -
i-PrOH 9.8 - - - -
acetone 9.8 - - - -
EtOD 9.4 - - - -
MeOD 9.3 - - - -
PhNO
2
9.8 - - - -
MeCN 9.5 51.3 48.4 99.7 8.8
MeNO
2
9.9 - - - -
DMF 9.8 - - - -
DMSO 9.0 51.0 48.7 99.7 8.8
H
2
O 9.3 50.5 49.1 99.6 8.8
a
Observed J
H8H9
, measured by
1
H NMR (500 MHz) in deuterated solvents as indicated;
b,c
calculated

Open-3 and Open-4 populations at the M06-2X/6-311+G(d,p)//B3LYP/6-
311+G(d,p) level of theory. Solvent effects were included implicitly through the self-
consistent reaction field approach (PCM).
e
predicated coupling constant J
H8H9

(∑Pop
i
·J
H8H9,i
). Pop
i
was calculated based on the relative energy of the corresponding
conformer. J
H8H9,i
was estimated via modified Karplus equation.

491

Figure 8.26. Correlation of Calculated ΔG
Open-3
with (ε-1)(ε+2). ΔG
Open-3
= -RT ln
(∑Pop
Open-3
).

492

8.5.8. Calculated Conformational Distribution of epiMeOCF
3
QD

Figure 8.27. Optimized Conformations of epiMeOCF
3
QD in the gas phase at the
B3LYP/6-311+(d,p) level of theory. Gibbs free energies, relevant to Closed-2, were
calculated at the M06-2X/6-311+G(d,p)//B3LYP/6-311+G(d,p) level of theory. Thermal
and entropic corrections for both gas-phase and PCM-optimized structures were obtained
by frequency analysis at the B3LYP/6-311+G(d,p) level.

493

8.5.9. Calculated Conformational Distribution of MeOMeQD

Figure 8.28. Optimized Conformations of MeOMeQD in the gas phase at the B3LYP/6-
311+(d,p) level of theory. Gibbs free energies, relevant to Closed-2, were calculated at
the M06-2X/6-311+G(d,p)//B3LYP/6-311+G(d,p) level of theory. Thermal and entropic
corrections for both gas-phase and PCM-optimized structures were obtained by frequency
analysis at the B3LYP/6-311+G(d,p) level.

494

8.5.10. Calculated Conformational Distribution of MeOQD

Figure 8.29. Optimized Conformations of MeOQD in the gas phase at the B3LYP/6-
311+(d,p) level of theory. Gibbs free energies, relevant to Closed-2, were calculated at
the M06-2X/6-311+G(d,p)//B3LYP/6-311+G(d,p) level of theory. Thermal and entropic
corrections for both gas-phase and PCM-optimized structures were obtained by frequency
analysis at the B3LYP/6-311+G(d,p) level.

495

8.5.11. Calculated Conformational Distribution of epiMeOQD

Figure 8.30. Optimized Conformations of epiMeOQD in the gas phase at the B3LYP/6-
311+(d,p) level of theory. Gibbs free energies, relevant to Closed-2, were calculated at
the M06-2X/6-311+G(d,p)//B3LYP/6-311+G(d,p) level of theory. Thermal and entropic
corrections for both gas-phase and PCM-optimized structures were obtained by frequency
analysis at the B3LYP/6-311+G(d,p) level.

496

8.5.12. Calculated Conformational Distribution of βiQD

Figure 8.31. Optimized Conformations of βiQD in the gas phase at the B3LYP/6 -
311+(d,p) level of theory. Gibbs free energies, relevant to Closed-2, were calculated at
the M06-2X/6-311+G(d,p)//B3LYP/6-311+G(d,p) level of theory. Thermal and entropic
corrections for both gas-phase and PCM-optimized structures were obtained by frequency
analysis at the B3LYP/6-311+G(d,p) level.

497

8.5.13. Comparison of Nucleophilicity of 6-Methoxyquinoline and
Different Quinuclidine Derivatives.
Table 8.57. Calculated transition state of the reaction of N-nucleophiles with methyl
chloride (MeCl).
a

a
In kcal/mol. For structures in the gas phase, geometry optimization was performed at
the B3LYP/6-31+G(d,p) level of theory, and the corresponding Gibbs free energies were
calculated at the same level. For structures in CH
3
CN, optimized structures and the
corresponding Gibbs free energies were calulated at the B3LYP/6-31+G(d,p) level with
implicit consideration of solvent CH
3
CN-solvation.
498

8.5.14. Comparison of H-bond Accepting Ability of H
2
O and Alcohols

Figure 8.32. Calculated aniline-ROH binding energies in the gas phase. Geometry
optimization were performed at the M06-2X/6-31+G(d,p) level of theory. Binding
energies were calculated at the same level with thermal correction (G
binding energy
= G
ROH
+
G
aniline
‒ G
complex
).

499

8.5.15. Crystal Structures
Crystal structures of t-butyl α-bromoester-epiMeOQD quaternary ammonium salt

Figure 8.33. Crystal structure of t-butyl α-bromoester-epiMeOQD quaternary ammonium
salt. (Br
-
was omitted for clarity)
A clear colorless prism-like specimen of C
27
H
37
BrN
2
O
4
, approximate dimensions 0.13
mm × 0.29 mm × 0.52 mm, was used for the X-ray crystallographic analysis. The X-ray
intensity data were measured on a Bruker APEX II CCD system equipped with a
TRIUMPH curved-crystal monochromator and a Mo fine-focus tube (λ = 0.71073 Å)
Empirical formula C
28
H
37
BrNO
4

Formula weight 531.50
Temperature 100(2) K
Wavelength 0.71073 Å
Crystal system Monoclinic
Space group C2
Unit cell dimensions a = 21.0276(7) Å α= 90°.
b = 9.2282(3) Å β= 113.3350(10)°.
c = 15.0440(5) Å γ = 90°.
Volume 2680.46(15) Å
3

Z 4
500

Density (calculated) 1.317 Mg/m
3

Absorption coefficient 1.566 mm
-1

F(000) 1116
Crystal size 0.52 x 0.29 x 0.13 mm
3

Theta range for data collection 2.04 to 30.69°.
Index ranges -30<=h<=30, -13<=k<=13, -21<=l<=21
Reflections collected 37636
Independent reflections 8195 [R(int) = 0.0423]
Completeness to theta = 27.50° 100.0 %
Absorption correction Semi-empirical from equivalents
Max. and min. transmission 0.82 and 0.61
Refinement method Full-matrix least-squares on F
2

Data / restraints / parameters 8195 / 2 / 322
Goodness-of-fit on F
2
1.038
Final R indices [I>2sigma(I)] R1 = 0.0318, wR2 = 0.0756
R indices (all data) R1 = 0.0386, wR2 = 0.0778
Absolute structure parameter 0.007(5)
Largest diff. peak and hole 0.639 and -0.832 e.Å
-3

501

Crystal structure of MeOMeQD

Figure 8.34. Crystal structure of MeOMeQD. (Two H
2
O molecules were omitted for
clarity).
53

Crystal data and structure refinement for C
21
H
30
N
2
O
4
.
Identification code fang2m
Empirical formula C
21
H
30
N
2
O
4

Formula weight 374.47
Temperature 143(2) K
Wavelength 0.71073 Å
Crystal system Orthorhombic
Space group P2(1)2(1)2(1)
Unit cell dimensions a = 7.6012(16) Å α= 90°.
b = 14.074(3) Å β= 90°.
c = 18.373(4) Å γ = 90°.
Volume 1965.4(7) Å
3

Z 4
Density (calculated) 1.266 Mg/m
3

Absorption coefficient 0.087 mm
-1

F(000) 808
502

Crystal size 0.30 x 0.06 x 0.04 mm
3

Theta range for data collection 1.82 to 27.57°.
Index ranges -9<=h<=9, -17<=k<=18, -20<=l<=23
Reflections collected 13589
Independent reflections 4421 [R(int) = 0.1418]
Completeness to theta = 27.57° 99.0 %
Absorption correction semi-empirical
Transmission factor min/max: 0.697
Refinement method Full-matrix least-squares on F
2

Data / restraints / parameters 4421 / 0 / 263
Goodness-of-fit on F
2
0.942
Final R indices [I>2sigma(I)] R1 = 0.0624, wR2 = 0.0821
R indices (all data) R1 = 0.1958, wR2 = 0.1056
Absolute structure parameter 0.3(19)
Largest diff. peak and hole0.212 and -0.207 e.Å
-3

503

8.5.16. Characterization of Various Cinchona Alkaloids Derivatives
NMR and MS Data of epiMeOQD in CD
3
CN

1
H NMR (500 MHz, CD
3
CN, 298K) δ 8.78 (d, J = 4.4 Hz, 1H), 8.04 (d, J = 9.2 Hz, 1H),
7.67 (d, J = 2.7 Hz, 1H), 7.50 (d, J = 4.4 Hz, 1H), 7.45 (dd, J = 9.2, 2.8 Hz, 1H), 6.02
(ddd, J = 7.0, 10.4, 17.4 Hz, 1H), 5.09-5.16 (m, 2H), 4.95 (d, J = 8.3 Hz, 1H), 4.02 (s,
3H), 3.29 (psuedo q, J = 9.0 Hz, 1H), 3.25 (s, 3H), 3.12 (ddd, J = 2.0, 7.9, 14.0 Hz, 1H),
2.99 (dd, J = 9.9, 13.9 Hz, 1H), 2.83-2.94 (m, 2H), 2.33 (dd, J = 9.9, 13.9 Hz, 1H), 1.63
(s, 1H), 1.57 (m, 2H), 1.31 (dd, J = 9.4, 13.3 Hz, 1H), 0.93 (dddd, J = 1.4, 4.7, 9.5, 14.6
Hz, 1H).
13
C NMR (125 MHz, CD
3
CN, 298 K) δ 158.6, 148.5, 145.6, 145.1, 142.0,
132.5, 129.2, 122.4, 121.8, 114.7, 103.1, 81.7, 61.2, 57.3, 56.4, 49.9, 48.9, 40.6, 29.0,
27.1, 24.7. HRMS (ESI) Exact mass calculated for C
21
H
27
N
2
O
2
[M+H
+
] 339.2067; Found
339.2068.
504

Figure 8.35.
1
H NMR Spectrum of epiMeOQD in CD
3
CN.

Figure 8.36.
13
C NMR Spectrum of epiMeOQD in CD
3
CN.
505

Figure 8.37. COSY Spectrum of epiMeOQD in CD
3
CN.

Figure 8.38. NOESY Spectrum of epiMeOQD in CD
3
CN.
506

Figure 8.39. HSQC Spectrum of epiMeOQD in CD
3
CN.

Figure 8.40. Strong nOe in epiMeOQD in CD
3
CN.
507

NMR and MS Data of MeOMeQD in CD
3
CN

1
H NMR (500 MHz, CD
3
CN, 298 K) δ 8.72 (d, J = 4.7 Hz, 1H), 8.30 (br s, 1H), 8.00 (d,
J = 9.2 Hz, 1H), 7.46 (d, J = 4.7 Hz, 1H), 7.40 (dd, J = 9.2, 2.8 Hz, 1H), 6.02 (ddd, J =
17.5, 10.7, 7.1 Hz, 1H), 5.04-5.08 (m, 2H), 3.98 (s, 3H), 3.22-3.28 (m, 1H, overlaps with
CH
3
at δ = 3.25 ), 3.25 (s, 3H), 3.18 (m, 1H), 2.93 (s, 1H), 2.76-2.85 (m, 2H), 2.26
(pseudo q, J = 7.3 Hz, 1H), 2.18 (pseudo t, J = 12.7 Hz, 1H), 1.96 (s, 3H), 1.73 (s, 1H),
1.53-1.56 (m, 2H), 0.98-1.03 (m, 1H).
13
C NMR (500 MHz, CD
3
CN, 298 K) δ 158.1,
148.7, 148.4, 146.2, 141.7, 132.5, 129.0, 122.8, 121.9, 114.7, 106.1, 85.6, 66.2, 56.2,
51.6, 51.4, 50.3, 40.4, 29.7, 26.4, 24.3, 22.8. HRMS (ESI) Exact mass calculated for
C
22
H
29
N
2
O
2
[M+H
+
] 353.2224; Found 335.2222.

508

Figure 8.41.
1
H NMR Spectrum of MeOMeQD in CD
3
CN.

Figure 8.42.
13
C NMR Spectrum of MeOMeQD in CD
3
CN.
509

Figure 8.43. COSY Spectrum of MeOMeQD in CD
3
CN.

Figure 8.44. NOESY Spectrum of MeOMeQD in CD
3
CN.
510

Figure 8.45. HSQC Spectrum of MeOMeQD in CD
3
CN.

Figure 8.46. Strong nOe in MeOMeQD in CD
3
CN.
511

NMR Data of MeOQD in CD
3
CN

1
H NMR (500 MHz, CD
3
CN, 298 K) δ 8.75 (d, J = 4.4 Hz, 1H), 8.02 (d, J = 9.2 Hz, 1H),
7.61 (d, J = 2.6 Hz, 1H), 7.48 (d, J = 4.4 Hz, 1H), 7.43 (dd, J = 9.2, 2.8 Hz, 1H), 6.18
(ddd, J = 17.6, 10.4, 7.5 Hz, 1H), 5.20-5.13 (m, 2H), 5.08 (br s, 1H), 4.00 (s, 3H), 3.29 (s,
3H), 3.20 (pseudo q, J = 8.3 Hz, 1H), 3.09 (br s, 1H), 2.84 (pseudo t, J = 11.5 Hz, 1H),
2.70-2.60 (m, 2H), 2.33 (pseudo q, J = 8.3 Hz, 1H), 1.80 (s, 1H), 1.53-1.64 (m, 3H).

512

Figure 8.47.
1
H NMR Spectrum of MeOQD in CD
3
CN.

Figure 8.48.
13
C NMR Spectrum of MeOQD in CD
3
CN.
513

Figure 8.49. HSQC Spectrum of MeOQD in CD
3
CN.

Figure 8.50. NOESY Spectrum of MeOQD in CD
3
CN.
514

Figure 8.51. Strong nOe in MeOQD in CD
3
CN.

NMR Data of epiMeOMeQD in CD
3
CN

1
H NMR (500 MHz, CD
3
CN, 298 K) δ 8.76 (d, J = 4.9 Hz, 1H), 8.19 (d, J = 2.8 Hz, 1H),
8.00 (d, J = 9.2 Hz, 1H), 7.52 (dq, J = 4.7, 1.5 Hz, 1H), 7.42 (dd, J = 9.2, 2.8 Hz, 1H),
6.08-6.00 (m, 1H), 5.12 (d, J = 1.3 Hz, 1H), 5.10-5.08 (m, 1H), 3.97 (s, 3H), 3.44 (q, J =
515

1.9 Hz, 3H), 3.43-3.39 (m, 1H), 3.29 (pseudo t, J = 9.5 Hz, 1H), 2.79 (dd, J = 13.2, 10.3
Hz, 1H), 2.44-2.38 (m, 2H), 2.34- 2.27 (m, 1H), 2.26- 2.20 (m, 1H), 1.86 (m, 1H), 1.69-
1.60 (m, 2H), 1.52-1.45 (m, 1H).
19
F NMR (470 MHz, CD
3
CN, 298 K) δ -63.3 (br s, CF
3

in syn conformations, population = 96%), -61.3 (sharp s, CF
3
in anti conformations,
population = 4%).

Figure 8.52.
1
H NMR Spectrum of epiMeOCF
3
QD in CD
3
CN.

516

Figure 8.53.
19
F NMR Spectrum of epiMeOCF
3
QD in CD
3
CN.

Figure 8.54. COSY Spectrum of epiMeOCF
3
QD in CD
3
CN.
517

Figure 8.55. NOESY Spectrum of epiMeOCF
3
QD in CD
3
CN.

Figure 8.56. HSQC Spectrum of epiMeOCF
3
QD in CD
3
CN.
518

Figure 8.57. Strong nOe in epiMeOCF
3
QD in CD
3
CN.

519

NMR Data of epiMeOQD in CD
3
CN

Figure 8. 58. NOESY spectra of epiMeOQD in CD
2
Cl
2
and DMSO-d
6
. H5-H8 and H5-
H10 interactions were found to be stronger than H1-H8 and H1-H10 interactions in both
CD
2
Cl
2
and DMSO-d
6
. Such an observation can be ascribed to significantly shorter H5-
H8 and H5-H10 distances in the anti conformation. Thus, although H1-H8 and H1-H10
interactions are relatively weak, syn-Open conformation can be fairly populated in both
solvents.
520

NMR Data of 7 in CD
3
CN

1
H NMR (500 MHz, CD
3
CN, 298 K) δ 8.91 -8.74 (br m, 1H), 8.08 (d, J = 9.2 Hz, 1H),
7.82-7.64 (br m, 1H), 7.52 (d, J = 4.4 Hz, 1H), 7.50 (dd, J = 9.2, 2.7 Hz, 1H), 5.92 (br m,
1H), 5.47-5.25 (m, 2H), 5.15 (s, 1H), 4.72 (pseudo s, 1H), 4.45 (br m, 2H), 4.06 (m, C6’ -
OCH
3
overlaps with H9, 4H), 3.94 (s, 1H), 3.66 (s, 1H), 3.53 (dd, J = 21.9, 9.7 Hz, 1H),
3.25 (s, 3H), 2.93 (dd, J = 16.4, 8.9 Hz, 1H), 2.07- 2.02 (m, 2H), 1.90 (s, 1H), 1.61 (s,
9H), 1.39- 0.94 (br m, 2H).

Figure 8.59.
1
H NMR Spectrum of 7 in CD
3
CN.
521

Figure 8.60. COSY Spectrum of 7 in CD
3
CN.

Figure 8.61. HSQC Spectrum of 7 in CD
3
CN.
522

Figure 8.62. NOESY Spectrum of 7 in CD
3
CN.

Figure 8.63. Strong nOe in 7 in CD
3
CN.
523

NMR Data of BnOMeQD in CD
3
CN

1
H NMR (500 MHz, CD
3
CN, 298 K) δ 8.74 (d, J = 4.7 Hz, 1H), 8.20 (br s, 1H), 7.99 (d,
J = 9.2 Hz, 1H), 7.51 (d, J = 4.6 Hz, 1H), 7.44-7.37 (m, 5H, partially overlaps with H4),
7.35 (dd, J = 9.2, 2.6 Hz, 1H), 6.00 (ddd, J = 12.0, 9.8, 7.1 Hz, 1H), 5.06-4.96 (m, 2H),
4.70 (d, J = 11.4 Hz, 1H), 4.17 (d, J = 11.2 Hz, 1H), 3.53 (s, 3H), 3.35 (dd, J = 11.9, 8.8
Hz, 1H), 3.19 (pseudo t, J = 9.3 Hz, 1H), 2.94-2.83 (m, 2H), 2.83-2.71 (m, 1H), 2.32-2.19
(m, 2H), 2.08 (s, 3H), 1.73 (pseudo s, 1H), 1.58-1.46 (m, 2H), 1.05 (pseudo s, 1H).
13
C
NMR (126 MHz, cd
3
cn) δ 157.8, 148.4, 146.2, 141.9, 140.0, 132.8, 132.5, 129.2, 128.9,
128.6, 128.3, 124.6, 122.6, 122.1, 114.5, 106.2, 66.4, 66.0, 55.7, 51.6, 50.7, 40.7, 29.7,
26.6, 25.2, 23.1.
524

Figure 8.64.
1
H NMR Spectrum of BnOMeQD in CD
3
CN.

Figure 8.65.
13
C NMR Spectrum of BnOMeQD in CD
3
CN.
525

Figure 8.66. COSY Spectrum of BnOMeQD in CD
3
CN.

Figure 8.67. HSQC Spectrum of BnOMeQD in CD
3
CN.
526

Figure 8.68. NOESY Spectrum of BnOMeQD in CD
3
CN.

Figure 8.69. Strong nOe in BnOMeQD in CD
3
CN.
527

8.5.17. NMR Data of N-(2-(t-Butoxy)-2-oxoethyl)-6-methoxyquinolinium
Bromide in CD
3
CN

1
H NMR (500 MHz, CD
3
CN, 298 K) δ 9.23 (d, J = 5.8 Hz, 1H), 9.12 (d, J = 8.4 Hz, 1H),
8.17 (d, J = 9.7 Hz, 1H), 8.08 (dd, J = 8.5, 5.8 Hz, 1H), 7.89 (dd, J = 9.6, 2.9 Hz, 1H),
7.82 (d, J = 2.8 Hz, 1H), 5.84 (s, 2H), 4.08 (s, 3H), 1.51 (s, 9H).
13
C NMR (126 MHz,
CD
3
CN, 298 K) δ 165.3, 161.0, 148.4, 148.0, 135.4, 133.0, 129.74, 123.2, 120.8, 109.2,
85.7, 59.6, 57.3, 28.0. HRMS (ESI) Exact mass calculated for C
16
H
20
NO
3
[M
+
] 274.1438;
Found 335.1442.

Figure 8.70.
1
H NMR Spectrum of N-(2-(tert-butoxy)-2-oxoethyl)-6-methoxy-
quinolinium bromide in CD
3
CN.
528

Chemical shift variations of 6-methoxyquinoline protons upon N-alkylation

Figure 8.71.
1
H NMR of the mixture of 6-methoxyquinoline and its N-alkylated
derivative.

Figure 8.72.
1
H NMR of a mixture of MeOMeQD and its quinoline-N-alkylated
derivative.
529

Figure 8.73.
1
H NMR of a mixture of epiMeOCF
3
QD and its quinoline-N-alkylated
derivative.

Figure 8.74.
1
H NMR of a mixture of MeOQD and its quinuclidine-N-alkylated
derivative.
530

8.5.18. Comparison of Catalytic Activity of Different Cinchona Alkaloid
Derivatives.
Typical Procedure
54

The catalyst, tert-butyl α-bromoacetate (98 mg, 0.5 mmol, 1.0 equiv) and phenyl
vinyl ketone (80 mg, 0.6 mmol, 1.2 equiv) were sequentially added to a stirred solution of
Cs
2
CO
3
(196 mg, 0.6 1.2 equiv) in anhydrous MeCN (2 mL). The reaction mixture was
stirred at 80 °C for 24h. The reaction was quenched with aqueous HCl solution (1M) and
extracted three times with Et
2
O. The combined organic phase was washed with saturated
NaHCO
3
aq. and dried over MgSO
4
. The solvent was removed under vacuum and the
residue was purified by flash chromatography. The obtained product was confirmed via
1
H NMR spectroscopy. The enantiomeric excess was determined by chiral HPLC.
HPLC conditions: DAICEL CHIRALCEL AD-H, hexane/2-propanol = 95/5, flow 1.0
mL/min, detection at 254 nm) t
R1
=4.4 min, t
R2
= 4.9 min.

531

Figure 8.75. epiMeOCF
3
QD-catalyzed cyclopropanation reaction.

Figure 8.76. BnOMeQD-catalyzed cyclopropanation reaction.
532

Figure 8.77. MeOMeQD-catalyzed cyclopropanation reaction.

Figure 8.78. epiMeOQD-catalyzed cyclopropanation reaction.
533

Figure 8.79. βiQD-catalyzed cyclopropanation reaction (10% catalyst loading).

Figure 8.80. βiQD-catalyzed cyclopropanation reaction (20% catalyst loading).
534

Figure 8.81. MeOQD-catalyzed cyclopropanation reaction (10% catalyst loading).

Figure 8.82. Racemic trans tert-Butyl 2-Benzoylcyclopropanecarboxylate.

535

8.5.19. Kinetic Studies
Typical Procedure
Kinetics of N-Alkylation reactions was studied using tert-butyl α-bromoacetate
(0.025 mmol) and cinchona alkaloid derivatives and other N-nucleophiles (0.025 mmol)
in CD
3
CN (0.6 mL) at indicated temperature. The reactions were monitored with
1
H
NMR spectroscopy and the progress of the reactions was quantified with
1
H NMR peak
integration (in aromatic region).
Kinetics of cyclopropanation reactions was investigated using tert-butyl α-
bromoacetate (0.010 mmol), cinchona alkaloid derivatives (0.001 mmol) and phenyl
vinyl ketone (0.010 mmol) in CD
3
CN (0.6 mL) at 343 K. The reactions were monitored
with
1
H NMR spectroscopy and the progress of the reactions was quantified with
1
H
NMR peak integration (at δ = 3.15 ppm, a
1
H NMR signal of cyclopropane product). The
time-dependent concentration of tert-butyl α-bromoacetate was calculated based on the
generation of the product.

536

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19
F NMR spectroscopy, see: Dolbier, Jr. W. R.
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539

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540

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Abstract (if available)

Abstract This dissertation is primarily focused on two topics, namely asymmetric nucleophilic fluoromethylation reactions and the relevant mechanistic studies. The asymmetric nucleophilic fluoromethylation reactions were achieved using robust nucleophilic fluoromethylating reagents and a series of cinchona alkaloid-derived catalysts. The employment of the trifluoromethyl group as a conformational stabilizer and a probe advanced the knowledge of conformational behavior of cinchona alkaloids and their derivatives. ❧ Chapter One briefly reviews the history and state of the art of organofluorine chemistry. The major achievements in synthetic organofluorine chemistry are discussed in a chronological order, which illustrates a clear overview of the developments in this field in recent years. ❧ Chapter Two describes the 1,4-addition of α-fluoro(phenylsulfonyl)methane derivatives to a variety of α,β-unsaturated carbonyl compounds using phosphine-based catalysts. ❧ Chapter Three conveys a novel synthetic strategy for the preparation of α-fluoro(disulfonyl)methane and its chloro and methoxy analogues. On the basis of this method, fluoro(bisphenylsulfonyl)methane (FBSM), a versatile monofluoromethylating reagent, is easily synthesized on large scale with high yield and selectivity. ❧ Chapter Four demonstrates the catalytic asymmetric 1,4-addition of α-fluoro-α-nitro(phenylsulfonyl)methane (FNSM) to α,β-unsaturated ketones using cinchona alkaloid-based thiourea catalysts. As implied by theoretical calculations and X-ray crystal structures, α-fluoro-α-nitro(phenylsulfonyl)methide anion adopts pyramidal geometry at the anionic carbon center, while its non-fluorinated counterpart assumes a planar structure. Such structural difference leads to fundamentally different origins in stereoselectivities. ❧ Chapter Five involves the enantioselective synthesis of α-stereogenic γ-keto esters. By employing nitro(phenylsulfonyl)methane (NSM) as a surrogate for an acyl anion, the integrated Michael addition reaction-oxidative methanolysis protocol allows the preparation of various γ-keto esters with high optical purities. ❧ Chapter Six demonstrates the introduction of a trifluoromethyl group into cinchona alkaloid scaffold as conformational stabilizer and probe, revealing a wealth of conformational information, which otherwise difficult to achieve. ❧ Chapter Seven discusses hindered CF3 rotations observed in cinchona alkaloid-based scaffolds, which allows the exploration of the nature of noncovalent C-H•••F-C interactions. ❧ Chapter Eight is focused on quantitative investigation of conformational behavior of cinchona alkaloids. By utilizing the CF3 conformational tool described in Chapter Six, the conformational behavior of a trifluoromethylated quinidine derivative in various solvents was analyzed via Linear Free Energy Relationship. These results enables the quantitatively assessment of the accuracy of theoretical calculations in cinchona alkaloid conformational analysis.

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Asset Metadata

Creator Wang, Fang (author)

Core Title Stereoselective nucleophilic fluoromethylations: from methodology to mechanistic studies

School College of Letters, Arts and Sciences

Degree Doctor of Philosophy

Degree Program Chemistry

Publication Date 11/20/2012

Defense Date 10/10/2012

Publisher University of Southern California (original), University of Southern California. Libraries (digital)

Tag asymmetric catalysis,cinchona alkaloids,conformational analysis,DFT calculation,fluoromethylation,OAI-PMH Harvest

Language English

Contributor Electronically uploaded by the author (provenance)

Advisor Prakash, G. K. Surya (committee chair), Hogen-Esch, Thieo E. (committee member), Olah, George A. (committee member), Shing, Katherine (committee member)

Creator Email chemwangfang@yahoo.com,wangf@usc.edu

Permanent Link (DOI) https://doi.org/10.25549/usctheses-c3-116976

Unique identifier UC11290512

Identifier usctheses-c3-116976 (legacy record id)

Legacy Identifier etd-WangFang-1315.pdf

Dmrecord 116976

Document Type Dissertation

Rights Wang, Fang

Type texts

Source University of Southern California (contributing entity), University of Southern California Dissertations and Theses (collection)

Access Conditions The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the a...

Repository Name University of Southern California Digital Library

Repository Location USC Digital Library, University of Southern California, University Park Campus MC 2810, 3434 South Grand Avenue, 2nd Floor, Los Angeles, California 90089-2810, USA