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Towards selective fluoroalkylating reactions: synthesis and mechanistic studies

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Towards selective fluoroalkylating reactions: synthesis and mechanistic studies

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Content i

Towards Selective Fluoroalkylating Reactions:
Synthesis and Mechanistic Studies

By
Zhe Zhang

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)
August 2015
ii

Dedication

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

iii

Acknowledgements
First of all, I would like to express my sincere thanks to Professor G. K. Surya Prakash, who has always
been a very supportive mentor full of creative ideas. During my years as a graduate student, Professor
Prakash has provided to me with invaluable suggestions and guidance to enable the fruitfulness and success
of my projects. His comprehensive knowledge, innovative ideas, and in-depth insight into chemistry have
always been of great help to me. It is extremely joyful to work in such a free and inspiring research
environment cultivated by Professor Prakash. I am extremely grateful to him for the opportunities he
provided for me to collaborate with other research groups to conduct interdisciplinary research projects.
His excellent mentorship has not only allowed me to be trained as a qualified chemist, but also extended
my research interest to related fields, which pave the road to my future career.
I would like to thank Professor George A. Olah for the privilege to enjoy his knowledgeable and
profound thoughts on chemistry, science, society, history and philosophy. His inspiring perspectives have
always led me ponder on my research as well as future scientific career.
Professor Barry C. Thompson and Professor Katherine Shing have been my committee members since
my screening examinations. I am grateful for their presence and advice for my study in graduate school.
Professor Karl O. Christe is a brilliant scientist with great sense of humor. His valuable suggestions and
sharp comments have brought in much to Chapter 5 in this thesis. Professor Ralf Haiges is a creative and
skillful chemist, without whom the work in Chapter 5 would not have been easily achieved.
I would like to thank Professor Herbert Mayr at the Ludwig Maximilian University of Munich who
provided me the opportunity of collaboration which leads to the work presented in Chapter 6. Professor
Mayr is thanked not only for his guidance on our collaborative project, but also for his great personality.
During the two months in Munich, I enjoyed the experience of exhaustive kinetic studies, well organized
group meetings and sub-group meetings, weekend hang-outs, and Oktoberfest of course. Dr. Puente Angel
is thanked for his kind help during my stay in Munich. Also, I would like to thank him for teaching me
interesting culture of Spain and for tutoring my Spanish.
I would like to thank Professor Peter S. Conti, Professor Zibo Li, and Dr. Shaunglong Liu with whom
the collaboration research on
18
F PET imaging project was accomplished. Professor Zibo is a very smart,
extremely hard-working, and friendly colleague who introduced me to the field of radiochemistry. Dr.
Shuanglong Liu is thanked for our collaboration and his kind help during the training of radio- and bio-
chemistry.
iv

I am extremely thankful to Dr. Fang Wang for his continuous support during my PhD study. His
dedication and commitment to scientific research have always motivated me to make more effort and try
harder. I am exceedingly grateful to him for everything he taught me and the collaboration projects would
not be possible without him. Although a serious member in the lab, he is very easy-going and friendly as
well. Thanks to Fang for being such a great mentor, colleague, and friend. Dr. Thomas Mathew is thanked
for his tremendous helpful advice and mentorship. He has always been considerate and help me whenever
there is a problem in my research projects. Professor Chuanfa Ni is thanked for his insightful suggestion
and kind encouragements to me during his postdoctoral period in LHI. He has enormous knowledge of
chemistry and comprehensive grasp of literatures which have been constantly influencing me to not only
work harder in the lab but also spend time reading literature which should be fundamentally important and
sometimes could lead to insightful interpretations of complicated experimental results. I would like to thank
Dr. Martin Rahm for his help with theoretical and computational chemistry which contributes much to our
collaboration. He is a very intelligent person with great sense of humor and I think it is my luck to know
and work with him.
I am very grateful to spend my graduate student life in such a great research group and I have to
acknowledge my friends and labmates who have maintained a highly professional and friendly environment
for work. Among these people are Dr. Robert A. Aniszfield, Dr. Alain Goeppert, Dr. John-Paul Jones, Dr.
Bo Yang, Dr. Patrice Batamack, Dr. Hema Krishnan, Dr. Parag Jog, Dr. Bing Xu, Xu Liu, Hang Zhang, Dr.
Miklos Czaun, Dr. Attila Papp, Laxman Gurung, Socrates Munoz, Marc Iuliucci, Kavita Belligund,
Sankarganesh Krishnamoorthy, Jotheeswari Kothandaraman, Chenguang Yang, Dean, Dr. Nan Shao, Dr.
Xinping Wu, Dr. Min Zhu, Dr. Anne-Marie Finaldi, Dr. Arjun Narayan, Dr. Somesh Ganesh, Dr. Aditya
Kulkarni, Dr. Inessa Bychinskaya, Dr. Farzaneh Paknia, Dr. Anton Shakhmin, Yuncai Mei, Tito Thomas.
I would like to thank Dr. Saitoh who has set a role model of a fully devoted scientist for me. Also, he is
very gentle and kind to practice Japanese with me during lunch time.
I would like to thank Mr. Allan Kershaw and Mr. Ralph Pan for their technical help with NMR
instruments. I would like to thank Jessy May, Carole Phillips, David Hunter, Michele Dea, Magnolia
Benitez, Heather Connor, and Katie McKissick for their kind support.
Finally, I would like to express my whole-hearted gratefulness to my parents, who have always been
considerate and supportive. I would like to thank my husband, Dr. Jia Zhuo, who has accompanied me
through five years in USC and brought sunshine and happiness to my graduate student life.

v

Table of Contents
Dedication ........................................................................................................................................... ii
Acknowledgements ............................................................................................................................. iii
List of Tables ...................................................................................................................................... x
List of Figures ..................................................................................................................................... xvi
List of Schemes................................................................................................................................... xx
Abstract ............................................................................................................................................... xxii
Chapter 1. Introduction − Development of Organofluorine Chemistry .......................................... 1
1.1. Introduction .................................................................................................................... 2
1.2. Synthetic Approaches for the Introduction of Fluorine-Containing Functionalities...... 4
1.2.1. Novel Fluorination Reagents and Related Reactions ........................................ 5
1.2.1.1. Nucleophilic Fluorinations .................................................................. 6
1.2.1.2. Electrophilic Fluorinations ................................................................. 10
1.2.2. Monofluoroalkylating Reagents and Related Reactions .................................. 11
1.2.2.1. Electrophilic Monofluoroalkylating Reagents and Reactions ............ 13
1.2.2.2. Nucleophilic Monofluoromethylating Reagents and Reactions ......... 13
1.2.2.3. Monofluoroolefination ........................................................................ 15
1.2.3. Difluoromethylating Reagents and Related Reactions .................................... 16
1.2.3.1. Nucleophilic Difluoromethylating Reagents and Reactions ............... 17
1.2.3.2. Electrophilic Difluoromethylating Reagents and Reactions ............... 22
1.2.4. Trifluoroalkylating Reagents and Related Reactions....................................... 23
1.2.4.1. Nucleophilic Trifluoromethylating Reagents and Trifluoromethyl-
Metal Reagents ................................................................................... 23
1.2.4.2. Electrophilic Trifluoromethylating Reagents and Related Reactions
............................................................................................................ 26
1.2.4.3. Transition-Metal Mediated Aromatic Trifluoromethylating............... 29
1.3. Conclusion .................................................................................................................... 32
1.4. References ..................................................................................................................... 32
Chapter 2. Stereoselective Synthesis of Fluoroalkenoates and Fluorinated Isoxazolidinones:
N-Substituents Governing the Dual Reactivity of Nitrones ......................................... 44
2.1. Introduction ................................................................................................................... 45
vi

2.2. Results and Discussion ................................................................................................. 46
2.3. Conclusion .................................................................................................................... 59
2.4. Experimental ................................................................................................................. 60
2.4.1. General procedure for the preparation of N-phenyl nitrones (1) ..................... 60
2.4.2. Preparation of (Z)-N-benzylidenemethanamine oxide (i) ................................ 65
2.4.3. General procedure for preparation of (Z)-aryl-N-alkylnitrones (ii, iii, and
2a-j) ................................................................................................................. 66
2.4.4. General Procedure for Reaction between Ethyl monofluorobromoacetate
3a and (Z)-aryl-N-phenylnitrones 1 and (Z)-aryl-N-tert-butylnitrones 2 ......... 69
2.4.5. Elucidation of the Formation of Imine Side-products ..................................... 77
2.4.6. DFT Calculations on reaction mechanisms ..................................................... 80
2.4.7. Elucidation of N-substituent effects based on linear free energy
relationship analysis ......................................................................................... 87
2.4.8. NMR Spectra ................................................................................................... 97
2.5. References .................................................................................................................... 149
Chapter 3. N,N-Dimethyl-S-difluoromethyl-S-phenylsulfoximinium Tetrafluoroborate: A
Versatile Electrophilic Difluoromethylating Reagent .................................................. 153
3.1. Introduction .................................................................................................................. 154
3.2. Results and Discussion ................................................................................................ 155
3.3. Conclusion ................................................................................................................... 162
3.4. Experimental ................................................................................................................ 162
3.4.1. General procedure for the preparation of S-difluoromethyl-S-phenyl-
sulfoximine (2) ................................................................................................ 163
3.4.2. Preparation of N-methyl-S-difluoromethyl-S-phenyl sulfoximine (3) ............ 163
3.4.3. General procedure for the preparation of N,N-dimethyl-S-difluoromethyl-
S-phenyl sulfoximinium tetrafluoroborate (1) ................................................ 164
3.4.4. General Procedure for difluoromethylations of phosphorus nucleophiles ...... 164
3.4.5. General procedure for difluoromethylations of nitrogen nucleophiles ........... 166
3.4.6. General procedure for difluoromethylations of sulfur nucleophiles ............... 167
3.4.7. General procedure for difluoromethylations of oxygen nucleophiles............. 167
3.4.8. NMR Spectra .................................................................................................. 167
vii

3.5. References .................................................................................................................... 175
Chapter 4. Nucleophilic Trifluoromethylation of Carbonyl Compounds:
Trifluoroacetaldehyde Hydrate as a Trifluoromethyl Source ...................................... 176
4.1. Introduction .................................................................................................................. 177
4.2. Results and Discussion ................................................................................................ 178
4.3. Conclusion ................................................................................................................... 186
4.4. Experimental ................................................................................................................ 186
4.4.1. General procedure for Removal of Excess Water from
Commercial Trifluoroacetaldehyde Hydrate 1c .............................................. 186
4.4.2. General Procedure for Nucleophilic Trifluoromethylation of Carbonyl
Compounds ..................................................................................................... 187
4.4.3. Theoretical Calculations ................................................................................. 189
4.4.4 NMR Spectra .................................................................................................. 194
4.5. References .................................................................................................................... 211
Chapter 5. The Long-Lived Trifluoromethide Anion: A Key Intermediate in
Nucleophilic Trifluoromethylations ............................................................................. 213
5.1. Introduction .................................................................................................................. 214
5.2. Results and Discussion ................................................................................................ 215
5.3. Conclusion ................................................................................................................... 220
5.4. Experimental ................................................................................................................ 220
5.4.1. General procedure for the preparation of trifluoromethyl(triisopropyl)-
silane (TIPSCF 3) ............................................................................................. 221
5.4.2. General procedure for the preparation of the CF 3
-
anion from CF 3H in an
NMR tube ....................................................................................................... 221
5.4.3. General procedure for the preparation of the CF 3
-
anion from TMSCF 3 in
an NMR tube ................................................................................................... 221
5.4.4. General procedure for the preparation of the CF 3
-
anion from TIPSCF 3 in
an NMR tube ................................................................................................... 222
5.4.5. Trapping the CF 3
-
anion with various electrophiles ........................................ 223
5.4.5.1. General procedure for the reaction between the CF 3
-
anion and
diphenyl disulfide .............................................................................. 223
viii

5.4.5.2. General procedure for the reaction of the CF 3
-
anion with
benzaldehyde ..................................................................................... 223
5.4.5.3. General procedure for the reaction of the CF 3
-
anion with iodine ..... 223
5.4.5.4. General procedure for the reaction of the CF 3
-
anion with
acetophenone ..................................................................................... 223
5.4.5.5. General procedure for the reaction of the CF 3
-
anion with
iodomethane ....................................................................................... 224
5.4.5.6. General procedure for the reaction of the CF 3
-
anion with
o-fluoronitrobenzene .......................................................................... 224
5.4.5.7. General procedure for the reaction of the CF 3
-
anion with carbon
dioxide ............................................................................................... 224
5.4.5.8. General procedure for the reaction of the CF 3
-
anion with
N-fluorobenzenesulfonimide ............................................................. 224
5.4.5.9. General procedure for the reaction of the CF 3
-
anion with CuI ......... 224
5.4.6. Trapping of the CF 3
-
anion generated in situ with various electrophiles ........ 225
5.4.6.1. General procedure for reaction of the CF 3
-
anion generated in situ
and iodine ........................................................................................... 225
5.4.6.2. General procedure for reaction of the CF 3
-
anion generated in situ
and o-fluoronitrobenzene ................................................................... 225
5.4.6.3. General procedure for reaction of the CF 3
-
anion generated in situ
and carbon dioxide ............................................................................. 225
5.4.7. Computational Details and Results ................................................................. 233
5.4.8. Details on the Calculations of NMR Properties .............................................. 236
5.4.9. Lone Pair and Bonding Analysis .................................................................... 238
5.4.10. Standard Orientation of Calculated Species ................................................... 240
5.5. References .................................................................................................................... 246
Chapter 6. On the Nucleophilicity of Persistent α-Monofluoromethanide Derivatives ................ 250
6.1. Introduction .................................................................................................................. 251
6.2. Results and Discussion ................................................................................................ 251
6.3. Conclusion ................................................................................................................... 256
6.4. Experimental ................................................................................................................ 256
ix

6.4.1. Synthesis of Starting Materials ....................................................................... 256
6.4.2. Selective isolation of carbanions as potassium salts ....................................... 259
6.4.3. Investigation of persistency of carbanions ...................................................... 260
6.4.4 General procedure for the synthesis of nucleophilic addition products .......... 261
6.4.5. Kinetic Experiments ....................................................................................... 265
6.4.6. Structure-Reactivity Relationship ................................................................... 290
6.4.7. Conformational study ..................................................................................... 291
6.4.8. NMR Spectra .................................................................................................. 296
6.5. References .................................................................................................................... 316
x

List of Tables
Table 2.1. Effects of bases on reaction yield and stereoselectivity ................................................ 46
Table 2.2. Effects of temperatures, additives, and concentrations on reaction yield
and stereoselectivity ...................................................................................................... 47
Table 2.3. Reaction condition screening on solvent effects and substrate proportions ................. 48
Table 2.4. Preparation of E-monofluoroalkenoates using N-phenyl nitrones 1 and
α-bromo-α-fluoroacetate 3 ............................................................................................ 49
Table 2.5. Reaction condition optimization of isoxazolidinone forming reaction ........................ 51
Table 2.6. Preparation of isoxazolidinones using N-tert-butyl nitrones 2 and α-bromo-
α-fluoroacetate 3a ......................................................................................................... 52
Table 3.1. Optimization of the reaction conditions ....................................................................... 156
Table 3.2. Difluoromethylation of phosphines using 1 ................................................................. 157
Table 3.3. Difluoromethylation of nitrogen nucleophiles using 1 ................................................ 159
Table 3.4. Difluoromethylation of sulfur and oxygen nucleophiles using 1 ................................. 161
Table 4.1. Reaction condition optimization using 1c [CF 3CH(OH) 2-2H 2O] as a CF 3
-

precursor ...................................................................................................................... 179
Table 4.2. Reaction condition optimization using 1c [CF 3CH(OH) 2-½H 2O] as a CF 3
-

precursor ..................................................................................................................... 180
Table 4.3 Nucleophilic trifluoromethylation of carbonyl compounds 2 with trifluoro-
acetaldehyde hydrate 1c [CF 3CH(OH) 2-½H 2O] .......................................................... 181
Table 5.1. Capture of CF 3
-
with various electrophiles ................................................................. 219
Table 5.2. Summary of calculated and experimental NMR properties of the cf 3
-
anion and
reference compounds .......................................................................................................... 236
Table 5.3. Selected lone pair domain and bond characteristics of NF 3, CF 3
-
and KCF 3 ...................... 240
Table 6.1. Michael acceptors 5a~5h and benzhydrylium ions 5i~5m employed as
reference electrophiles ................................................................................................. 252
Table 6.2. Rate constants k 2 for the reactions of the carbanions 1~4 with the reference
electrophiles 5j or 5f in DMSO at 20
o
C ...................................................................... 254
Table 6.3. Kinetics of the reactions of 1a with 5i in DMSO (20 ° C, stopped-flow,
xi

  = 630 nm).................................................................................................................. 266
Table 6.4. Kinetics of the reactions of 1a with 5j in DMSO (20 ° C, stopped-flow,
  = 635 nm).................................................................................................................. 266
Table 6.5. Kinetics of the reactions of 1a with 5k in DMSO (20 ° C, stopped-flow,
  = 627 nm).................................................................................................................. 266
Table 6.6. Kinetics of the reactions of 1a with 5l in DMSO (20 ° C, stopped-flow,
  = 618 nm)................................................................................................................... 266
Table 6.7. Kinetics of the reactions of 1a with 5m in DMSO (20 ° C, stopped-flow,
  = 620 nm).................................................................................................................. 267
Table 6.8. Rate Constants of the reactions of 1a with different electrophiles .............................. 267
Table 6.9. Kinetics of the reactions of 1b with 5b in DMSO (20 ° C, stopped-flow,
  = 620 nm).................................................................................................................. 267
Table 6.10. Kinetics of the reactions of 1b with 5f in DMSO (20 ° C, stopped-flow,
  = 620 nm).................................................................................................................. 267
Table 6.11. Kinetics of the reactions of 1b with 5g in DMSO (20 ° C, stopped-flow,
  = 620 nm).................................................................................................................. 268
Table 6.12. Rate Constants of the reactions of 1b with different electrophiles .............................. 268
Table 6.13. Kinetics of the reactions of 1c with 5f in DMSO (20 ° C, stopped-flow,
  = 533 nm).................................................................................................................. 268
Table 6.14. Kinetics of the reactions of 1c with 5g in DMSO (20 ° C, stopped-flow,
  = 422 nm).................................................................................................................. 269
Table 6.15. Kinetics of the reactions of 1c with 5i in DMSO (20 ° C, stopped-flow,
  = 630 nm).................................................................................................................. 269
Table 6.16. Kinetics of the reactions of 1c with 5j in DMSO (20 ° C, stopped-flow,
  = 635 nm).................................................................................................................. 269
Table 6.17. Kinetics of the reactions of 1c with 5k in DMSO (20 ° C, stopped-flow,
  = 627 nm).................................................................................................................. 270
Table 6.18. Rate Constants of the reactions of 1c with different electrophiles............................... 270
Table 6.19. Kinetics of the reactions of 1d with 5i in DMSO (20 ° C, stopped-flow,
  = 630 nm).................................................................................................................. 270
Table 6.20. Kinetics of the reactions of 1d with 5j in DMSO (20 ° C, stopped-flow,
xii

  = 635 nm).................................................................................................................. 271
Table 6.21. Kinetics of the reactions of 1d with 5k in DMSO (20 ° C, stopped-flow,
  = 627 nm).................................................................................................................. 271
Table 6.22. Kinetics of the reactions of 1d with 5l in DMSO (20 ° C, stopped-flow,
  = 618 nm).................................................................................................................. 271
Table 6.23. Kinetics of the reactions of 1d with 5m in DMSO (20 ° C, stopped-flow,
  = 620 nm).................................................................................................................. 272
Table 6.24. Rate Constants of the reactions of 1d with different electrophiles .............................. 272
Table 6.25. Kinetics of the reactions of 2a with 5i in DMSO (20 ° C, stopped-flow,
  = 630 nm).................................................................................................................. 272
Table 6.26. Kinetics of the reactions of 2a with 5j in DMSO (20 ° C, stopped-flow,
  = 635 nm).................................................................................................................. 273
Table 6.27. Kinetics of the reactions of 2a with 5k in DMSO (20 ° C, stopped-flow,
  = 627 nm).................................................................................................................. 273
Table 6.28. Kinetics of the reactions of 2a with 5l in DMSO (20 ° C, stopped-flow,
  = 618 nm).................................................................................................................. 273
Table 6.29. Kinetics of the reactions of 2a with 5m in DMSO (20 ° C, stopped-flow,
  = 620nm)................................................................................................................... 274
Table 6.30. Rate Constants of the reactions of 2a with different electrophiles .............................. 274
Table 6.31. Kinetics of the reactions of 2b with 5f in DMSO (20 ° C, stopped-flow,
  = 533 nm).................................................................................................................. 274
Table 6.32. Kinetics of the reactions of 2b with 5g in DMSO (20 ° C, stopped-flow,
  = 422 nm).................................................................................................................. 274
Table 6.33. Kinetics of the reactions of 2b with 5i in DMSO (20 ° C, stopped-flow,
  = 630 nm).................................................................................................................. 275
Table 6.34. Kinetics of the reactions of 2b with 5j in DMSO (20 ° C, stopped-flow,
  = 635 nm).................................................................................................................. 275
Table 6.35. Kinetics of the reactions of 2b with 5k in DMSO (20 ° C, stopped-flow,
  = 627 nm).................................................................................................................. 275
Table 6.36. Rate Constants of the reactions of 2b with different electrophiles .............................. 276
Table 6.37. Kinetics of the reactions of 2f with 5a in DMSO (20 ° C, stopped-flow,
xiii

  = 486 nm).................................................................................................................. 276
Table 6.38. Kinetics of the reactions of 2f with 5b in DMSO (20 ° C, stopped-flow,
  = 393 nm).................................................................................................................. 276
Table 6.39. Kinetics of the reactions of 2f with 5e in DMSO (20 ° C, stopped-flow,
  = 374 nm).................................................................................................................. 277
Table 6.40. Kinetics of the reactions of 2f with 5f in DMSO (20 ° C, stopped-flow,
  = 533 nm).................................................................................................................. 277
Table 6.41. Kinetics of the reactions of 2f with 5g in DMSO (20 ° C, stopped-flow,
  = 422 nm).................................................................................................................. 277
Table 6.42. Rate Constants of the reactions of 2f with different electrophiles ............................... 278
Table 6.43. Kinetics of the reactions of 2d with 5i in DMSO (20 ° C, stopped-flow,
  = 630 nm).................................................................................................................. 278
Table 6.44. Kinetics of the reactions of 2d with 5j in DMSO (20 ° C, stopped-flow,
  = 635 nm).................................................................................................................. 278
Table 6.45. Kinetics of the reactions of 2d with 5k in DMSO (20 ° C, stopped-flow,
  = 627 nm).................................................................................................................. 278
Table 6.46. Kinetics of the reactions of 2d with 5l in DMSO (20 ° C, stopped-flow,
  = 618 nm).................................................................................................................. 279
Table 6.47. Kinetics of the reactions of 2d with 5m in DMSO (20 ° C, stopped-flow,
  = 620 nm).................................................................................................................. 279
Table 6.48. Rate Constants of the reactions of 2d with different electrophiles .............................. 279
Table 6.49. Kinetics of the reactions of 3a with 5f in DMSO (20 ° C, stopped-flow,
  = 533 nm).................................................................................................................. 280
Table 6.50. Kinetics of the reactions of 3a with 5g in DMSO (20 ° C, stopped-flow,
  = 422 nm).................................................................................................................. 280
Table 6.51. Kinetics of the reactions of 3a with 5i in DMSO (20 ° C, stopped-flow,
  = 630 nm).................................................................................................................. 280
Table 6.52. Kinetics of the reactions of 3a with 5j in DMSO (20 ° C, stopped-flow,
  = 635 nm).................................................................................................................. 281
Table 6.53. Kinetics of the reactions of 3a with 5k in DMSO (20 ° C, stopped-flow,
  = 627 nm).................................................................................................................. 281
xiv

Table 6.54. Rate Constants of the reactions of 3a with different electrophiles .............................. 281
Table 6.55. Kinetics of the reactions of 3b with 5c in DMSO (20 ° C, stopped-flow,
  = 371 nm).................................................................................................................. 282
Table 6.56. Kinetics of the reactions of 3b with 5e in DMSO (20 ° C, stopped-flow,
  = 374 nm).................................................................................................................. 282
Table 6.57. Kinetics of the reactions of 3b with 5f in DMSO (20 ° C, stopped-flow,
  = 533 nm).................................................................................................................. 282
Table 6.58. Kinetics of the reactions of 3b with 5g in DMSO (20 ° C, stopped-flow,
  = 422 nm).................................................................................................................. 283
Table 6.59. Kinetics of the reactions of 3b with 5i in DMSO (20 ° C, stopped-flow,
  = 630 nm).................................................................................................................. 283
Table 6.60. Rate Constants of the reactions of 3b with different electrophiles .............................. 283
Table 6.61. Kinetics of the reactions of 3c with 5f in DMSO (20 ° C, stopped-flow,
  = 533 nm).................................................................................................................. 284
Table 6.62. Kinetics of the reactions of 3c with 5i in DMSO (20 ° C, stopped-flow,
  = 533 nm).................................................................................................................. 284
Table 6.63. Kinetics of the reactions of 3c with 5j in DMSO (20 ° C, stopped-flow,
  = 533 nm).................................................................................................................. 284
Table 6.64. Rate Constants of the reactions of 3c with different electrophiles............................... 284
Table 6.65. Kinetics of the reactions of 4b with 5a in DMSO (20 ° C, stopped-flow,
  = 486 nm).................................................................................................................. 285
Table 6.66. Kinetics of the reactions of 4b with 5c in DMSO (20 ° C, stopped-flow,
  = 393 nm).................................................................................................................. 285
Table 6.67. Kinetics of the reactions of 4b with 5d in DMSO (20 ° C, stopped-flow,
  = 354 nm).................................................................................................................. 285
Table 6.68. Kinetics of the reactions of 4b with 5e in DMSO (20 ° C, stopped-flow,
  = 374 nm).................................................................................................................. 286
Table 6.69. Rate Constants of the reactions of 4b with different electrophiles .............................. 286
Table 6.70. Kinetics of the reactions of 4c with 5e in DMSO (20 ° C, stopped-flow,
  = 374 nm).................................................................................................................. 286
Table 6.71. Kinetics of the reactions of 4c with 5f in DMSO (20 ° C, stopped-flow,
xv

  = 533 nm).................................................................................................................. 287
Table 6.72. Kinetics of the reactions of 4c with 5g in DMSO (20 ° C, stopped-flow,
  = 422 nm).................................................................................................................. 287
Table 6.73. Kinetics of the reactions of 4c with 5i in DMSO (20 ° C, stopped-flow,
  = 630 nm).................................................................................................................. 287
Table 6.74. Rate Constants of the reactions of 4c with different electrophiles............................... 288
Table 6.75. Kinetics of the reactions of 4e with 5a in DMSO (20 ° C, stopped-flow,
  = 486 nm).................................................................................................................. 288
Table 6.76. Kinetics of the reactions of 4e with 5b in DMSO (20 ° C, stopped-flow,
  = 393 nm).................................................................................................................. 288
Table 6.77. Kinetics of the reactions of 4e with 5d in DMSO (20 ° C, stopped-flow,
  = 354 nm).................................................................................................................. 289
Table 6.78. Kinetics of the reactions of 4e with 5f in DMSO (20 ° C, stopped-flow,
  = 533 nm).................................................................................................................. 289
Table 6.79. Rate Constants of the reactions of 4e with different electrophiles............................... 289
Table 6.80. Correlation between population of trans-planar geometry and the NOE intensity ..... 294
Table 6.81. Population of trans-planar geometry of 7 .................................................................... 294
xvi

List of Figures
Figure 1.1. A. Comparison of properties of fluorine, trifluoromethyl group and their analogues;
B. fluorine effects on acidity and basicity; C. fluorine effects on lipophilicity
and hydrophobicity; D. fluorine effects on stereoelectronic configuration; E.
fluorine effects through resonance ................................................................................. 2
Figure 1.2. A. Fluorinated drugs among 10 best-selling drugs in 2011; B. Selected fluorine-
containing drugs and drug candidates ............................................................................ 4
Figure 1.3. Fluorinated motifs of interest ......................................................................................... 5
Figure 1.4. Typical pathways of constructions of the C−F bond ..................................................... 6
Figure 1.5. Proposed mechanism of Pd-catalyzed nucleophilic fluorination of aryl halides and
aryl triflates .................................................................................................................... 9
Figure 2.1. X-ray crystal structures of 5a, 6a and 7e ...................................................................... 54
Figure 2.2. Calculated thermodynamics and kinetics of the aldol and [3+2] reactions between
nitrones and α-bromo-α-fluoroacetate enolate .............................................................. 55
Figure 2.3. Calculated reaction pathways of N-phenyl-substituted nitrones (Top) and N-tert-
butyl-substituted nitrones (Bottom) .............................................................................. 56
Figure 2.4. Correlations of steric and electronic parameters with calculated Gibbs free energies
of reaction key intermediates and transition states. A. Calculated transition states
and reaction key intermediates; B. steric and electronic parameters of N-substituents;
C. calculated Gibbs Free Energies (kcal/mol); D. ΔG-steric/electronic
parameters correlation coefficients (R
2
) ...................................................................... 57
Figure 3.1. Investigation of the difluoromethylation and oxidation ability of 1 with Ph 3P. (A)
19
F
NMR spectrum of 3; (B)
19
F NMR spectrum of the reaction mixture of 3 and
Me 3O
+
BF 4
-
in 2:1 ratio; (C)
19
F NMR spectrum of the reaction mixture of 3 and
Me 3O
+
BF 4
-
in 1:1 ratio; (D)
31
P NMR spectrum of the reaction mixture B and Ph 3P.
All the spectra were taken in CD 3CN .......................................................................... 158
Figure 4.1. Calculated reaction coordinate from 1c to 3a-K .......................................................... 184
Figure 4.2. Calculated reaction coordinate of nucleophilic trifluoromethylation of aldehyde
using trifluoroacetaldehyde hemiacetal (1a) and hexafluoroacetone hydrate (5) ........ 185
Figure 5.1. A. Central role of trifluoromethide in fluoroalkylation chemistry. B. Proposed
mechanisms for the decomposition of trifluoromethide and ionic metal-CF 3
xvii

complexes. C. Calculated C-F bond dissociation enthalpies and free energies of CF 3
-

and the KCF 3 ion pair (1 M concentration) in THF at 298 K ....................................... 214
Figure 5.2. A.
19
F NMR spectrum of CF 3
-
, generated according to Eq. 5 in Scheme 1, in THF at
-78 ° C with PhCF 3 as an internal standard at -63.0 ppm relative to CFCl 3. The CF 3H
is due to protonation from the solvent or crown ether by CF 3
-
. B.
13
C NMR spectrum
of CF 3
-
, generated according to Eq. 3 in Scheme 1, in THF at -56 ° C ......................... 217
Figure 5.3.
19
F NMR spectrum of the CF 3
-
anion generated from CF 3H at -78 ° C. A large amount of
CF 3H remained (a broad strong signal at -79.6 ppm) ......................................................... 226
Figure 5.4.
19
F NMR spectrum of the CF 3
-
anion generated from TMSCF 3 at -78 ° C. The
1
J C-F
coupling constant of the CF 3
-
anion is in good agreement with the value obtained from

13
C NMR. The chemical shift (-65.6 ppm) and the coupling constant (377.1 Hz) of the
observed pentacoordinated silicon species are close to the values reported for
[Me 3Si(CF 3) 2]
-
(-62.6 ppm and 378 Hz) and [Me 3Si(CF 3)F]
-
(-63.9 ppm and 375 Hz).
We therefore tentatively assign the species to [Me 3Si(CF 3) 2]
-
........................................... 226
Figure 5.5.
13
C NMR spectrum of the CF 3
-
anion prepared from TMSCF 3 at -56 ° C ........................... 227
Figure 5.6.
19
F NMR spectrum of the CF 3
-
anion generated from TIPSCF 3 at -78 ° C ......................... 227
Figure 5.7.
19
F NMR spectrum of trapping the CF 3
-
anion with PhSSPh ............................................. 228
Figure 5.8.
19
F NMR spectrum of trapping the CF 3
-
anion with I 2 ....................................................... 228
Figure 5.9.
19
F NMR spectrum of trapping the CF 3
-
anion with benzaldehyde .................................... 228
Figure 5.10.
19
F NMR spectrum of trapping the CF 3
-
anion with acetophenone .................................... 229
Figure 5.11.
19
F NMR spectrum of trapping the CF 3
-
anion with CO 2 ................................................... 229
Figure 5.12.
19
F NMR spectrum of trapping the CF 3
-
anion with CH 3I .................................................. 229
Figure 5.13.
19
F NMR spectrum of trapping the CF 3
-
anion with o-fluoronitrobenzene......................... 230
Figure 5.14.
19
F NMR spectrum of trapping the CF 3
-
anion with CuI .................................................... 230
Figure 5.15.
19
F NMR experiments at -35 ° C with a sample obtained from the reaction between
TIPSCF 3 and tert-BuOK in the presence of 18-crown-6 in THF (performed in a flame
sealed NMR tube) ............................................................................................................... 231
Figure 5.16.
19
F NMR experiments at -50 ° C with a sample obtained from the reaction between
TIPSCF 3 and tert-BuOK in the presence of 18-crown-6 in THF (performed in a flame
sealed NMR tube) ............................................................................................................... 231
Figure 5.17. Variable temperature
19
F NMR experiments of a sample from the reaction between
TMSCF 3 and tert-BuOK in the presence of 18-crown-6 in THF at -78 ° C from 0 h to 24
xviii

h and at -56 ° C from 26 -70 h (performed in a flame sealed NMR tube) ........................... 232
Figure 5.18.
19
F NMR experiments at -50 ° C of a sample from the reaction between TMSCF 3 and
tert-BuOK in the presence of 18-crown-6 in THF at -78 ° C (performed in a flame sealed
NMR tube and the signal of the penta-coordinated silicon species is adjusted to be the
highest peak in each spectrum) .......................................................................................... 233
Figure 5.19. SCF energy of CF 3
-
as a function of the carbon–fluoride distance (kcal/mol). Energies
are obtained at the level of UM06-2X/Def2-TZVPPD. Maximum energy is obtained at
infinite separation of CF 2 and F
-
......................................................................................... 234
Figure 5.20. The four predicted conformers of KCF 3 in THF solution. Energies are given in kcal/mol
and bond distances in Å ...................................................................................................... 235
Figure 5.21. Top left. Correlation between calculated and experimental
19
F NMR chemical shifts.
Top right. Correlation between calculated and experimental
13
C NMR chemical shifts.
Bottom. Correlation between calculated and experimental
1
J C-F coupling constants.......... 238
Figure 5.22. The ionic KCF 3 bonding interaction visualized using ELF/HELP. η(r) = 1.0 (red)
denotes electrons which are alone with respect to their same spin counterparts (or
“localized”). η(r) = ½ (blue) denotes electrons which on average exhibit kinetic
energies due to Pauli repulsion equal to that of a homogeneous electron gas of identical
electron density (or “delocalized”) .................................................................................... 239
Figure 6.1. Carbanions 1~4 ............................................................................................................ 252
Figure 6.2. N/s N parameters of carbanions 1~4. The parameters were determined by applying
logk 2 = s N(N+E) with 3~5 proper reference electrophiles (see 6.4.6 for details) ......... 253
Figure 6.3. Conformational study of carbanion 7 via NOESY 1D experiments ............................ 255
Figure 6.4. Correlation of the second-order rate constants logk 2 for the reactions of the
nucleophiles 1 with the electrophiles 2 in DMSO with their electrophilicity
parameters E ................................................................................................................ 290
Figure 6.5. NOE measurement of 7a .............................................................................................. 292
Figure 6.6. NOE measurement of 7b ............................................................................................. 292
Figure 6.7. NOE measurement of 7c .............................................................................................. 293
Figure 6.8. NOE build up curve using 7c ....................................................................................... 293
Figure 6.9. Correlation between population of trans-planar geometry and the NOE
intensity (Crystal) ........................................................................................................ 295
Figure 6.10. Correlation between population of trans-planar geometry and the NOE
xix

intensity (DFT) ............................................................................................................ 295

xx

List of Schemes
Scheme 1.1. Nucleophilic fluorination prototypes and selected reagents .......................................... 7
Scheme 1.2. Deoxofluorination prototypes and selected reagents ..................................................... 8
Scheme 1.3. Ring-opening reactions prototypes using BF 3∙OEt 2 ....................................................... 8
Scheme 1.4. Development of palladium-catalyzed nucleophilic fluorination of arenes .................... 9
Scheme 1.5. Cu-mediated nucleophilic oxidative fluorination of arenes .......................................... 10
Scheme 1.6. Electrophilic fluorination prototypes, selected reagents, and possible mechanisms .... 11
Scheme 1.7. Various key reaction intermediates involved in fluoroalkylations ............................... 12
Scheme 1.8. Nucleophilic monofluoromethylation prototypes and intermediates ............................ 13
Scheme 1.9. Typical nucleophilic monofluoromethylating reagents and synthons .......................... 14
Scheme 1.10. Development of the synthesis of fluorobis(phenylsulfonyl)methane ........................... 15
Scheme 1.11. Development of the synthesis of monofluoroolefins .................................................... 16
Scheme 1.12. Difluoromethylations and difluoromethylenations protocols ....................................... 17
Scheme 1.13. Nucleophilic difluoromethylation prototypes and key reaction intermediates ............. 18
Scheme 1.14. Typical nucleophilic difluoromethylating reagents ...................................................... 19
Scheme 1.15. S- and Se-based nucleophilic difluoromethylating reagents and typical reactions ....... 20
Scheme 1.16. Difluoromethylation using Si-based reagents ............................................................... 21
Scheme 1.17. Novel electrophilic difluoromethylating reagents ......................................................... 22
Scheme 1.18. Nucleophilic trifluoromethylation prototypes ............................................................... 23
Scheme 1.19. Typical nucleophilic trifluoromethylating reagents ...................................................... 24
Scheme 1.20. Typical trifluoromethyl organometallic reagents and intermediates ............................ 24
Scheme 1.21. Typical nonmetal-based trifluoromethylating agents ................................................... 25
Scheme 1.22. Nucleophilic trifluoromethylation using CF 3H as trifluoromethyl source .................... 26
Scheme 1.23. Electrophilic trifluoromethylation prototypes ............................................................... 26
Scheme 1.24. Challenges of electrophilic trifluoromethylations......................................................... 27
Scheme 1.25. Electrophilic trifluoromethylating reagents based on chalcogen-CF 3 salts .................. 28
Scheme 1.26. Electrophilic trifluoromethylating reagents based on S-CF 3 sulfoximines ................... 28
Scheme 1.27. Electrophilic trifluoromethylation with I-CF 3 based reagents ...................................... 29
Scheme 1.28. Cu-Mediated aromatic trifluoromethylations ............................................................... 30
Scheme 1.29. Pd-Catalyzed aromatic trifluoromethylation and proposed mechanisms ...................... 31
Scheme 2.1. Synthesis of monofluorinated olefins using nitrones .................................................... 45
xxi

Scheme 2.2. Investigation of N-substituent effects in the reaction between nitrones and α-bromo-
α-fluoroacetate 3a. The indicated relative configuration of 5a was confirmed by
X-ray diffraction. Other diastereoisomers were not observed ...................................... 50
Scheme 2.3. Elucidation of possible reaction pathways based on the detection of by-products and
side products. A. Desired reaction and key reaction intermediates; B. observed and
isolated species; C. plausible reaction pathways; D. rationalization of imine
formation ....................................................................................................................... 53
Scheme 3.1. Preparation of N,N-dimethyl-S-difluoromethyl-S-phenylsulfoximinium tetrafluoro-
borate (1) ...................................................................................................................... 155
Scheme 3.2. Plausible mechanism of the oxidation of Ph 3P ............................................................ 158
Scheme 3.3. Mechanistic studies based on isotope-labeling experiments ........................................ 162
Scheme 4.1. Generation of "CF 3
-
" synthon through the release of neutral or stable species ............ 177
Scheme 4.2. Generation of CF 3
-
from different trifluoroacetaldehyde hemiacetal derivatives ........ 178
Scheme 4.3. Calculated thermodynamics of the nucleophilic trifluoromethylation reaction using
1c and the related reactions .......................................................................................... 182
Scheme 5.1. Equations 1-3: Attempted preparations of CF 3
-
under various reaction conditions.
Equation 4: Equilibrium between CF 3
-
and the pentacoordinated [(CH 3) 3Si(CF 3) 2]
-

anion at different temperatures in a THF solution. Equation 5: Optimal conditions
for the synthesis of CF 3
-
............................................................................................... 216

xxii

Abstract
This dissertation mainly explored two aspects in organofluorine chemistry, the development of novel
efficient fluoroalkylating protocols (CF−, CF 2−, CF 3−) and the related in-depth mechanistic studies.
In chapter one a brief review of the history of organofluorine chemistry is given. The major
achievements in organofluorine chemistry are discussed in a chronological order following the CF−, CF 2−,
CF 3− sequence.
Chapter two demonstrates the exploration of a versatile method of the stereoselective syntheses of
bioactive fluoroalkenoates and oxazolidinones via the monofluoroolefination of nitrones. By altering N-
substituents in nitrones, preparation of (E)- -fluoroalkenoates and 4-fluoro-5-isoxazolidinones,
respectively, can be achieved with high chemo- and stereoselectivities. Experimental and computational
studies have been conducted to elucidate the reaction mechanisms.
Chapter three reports the design and synthesis of novel electrophilic difluoromethylating reagent N,N-
dimethyl-S-difluoromethyl-S-phenylsulfoximinium salt which is the difluoromethylated analogue of
Johnson Reagent. The reagent provides excellent reactivity toward a broad spectrum of nucleophilic species
(N-, P-, S-, and O-nucleophiles) to yield the corresponding difluoromethylated products with high efficacy
under mild conditions.
Chapter four describes the investigation of atom-economical nucleophilic trifluoromethylating method
employing readily available reagent trifluoroacetaldehyde hydrate. A wide scope of carbonyl compounds
are applicable to this reaction with high yields under mild condition. DFT calculations have been performed
to provide mechanistic insight into the present and related reactions employing 2,2,2-trifluoro-1-
methoxyethanol and hexafluoroacetone hydrate.
Chapter five delivers the first bulk synthesis and characterization of CF 3
−
anion. Based on high level
theoretical calculations, the α-defluorination of the CF 3
−
anion was found to possess a barrier of 25.4
kcal/mol in THF allowing direct observations via spectroscopic methods. NMR spectra collected at -78
o
C
clearly demonstrated the existence of the CF 3
−
anion as a persistent species in the presence of potassium
cation and 18-crown-6 for the first time, which facilitates various nucleophilic trifluoromethylation
reactions.
Chapter six conveys the investigation of nucleophilicity of α-monofluoromethanide derivatives by
comparing to a series of α-substituted carbanion analogues. The nucleophilicity parameters N and
nucleophile specific parameter s N of a series of α-substituted nucleophiles have been determined. NOE
xxiii

experiments have been performed to understand the geometry configuration of carbanions. The effects of
α-substituents (−F, −Cl, −OMe) on carbanions have been explicitly demonstrated.
1

Chapter 1

Introduction − Development of
Organofluorine Chemistry

2

1.1 Introduction
Organofluorine chemistry pertains to the molecules that contains carbon-fluorine bonds. As a
“small atom with a big ego”, fluorine has been of great interest to chemists for more than a century.
1

Over the past twenty years, fluoroorganics have received increasing attention due to their unique
chemical properties and potential applications in biology, pharmaceutical and materials sciences
(Figure 1.1-A and B).

Figure 1.1. A. Comparison of properties of fluorine, trifluoromethyl group, and their analogues; B.
fluorine effects on acidity and basicity; C. fluorine effects on lipophilicity and hydrophobicity; D.
fluorine effects on stereoelectronic configuration; E. fluorine effects through resonance.
Being the most electronegative element, fluorine can drastically change the chemical properties
of organic compounds via various fashions, including electron-withdrawing effects, negative
hyperconjugation, field effects, and charge-charge repulsion (Figure 1.1-C and D).
2
On the other
hand, fluorine is also endowed with electron-donating ability through resonance due to the presence
of non-bonding electron lone-pairs on the 2p orbitals (Figure 1.1-E).
3
As a result, fluoroorganic
compounds can possess unparalleled physicochemical properties. For example, perfluorinated
organic compounds always exhibit low surface tension and unusual miscibility, which have been
widely applied in the development of lubricants and fluorous reaction media.
4
Aside from the
applications in materials science and synthetic chemsitry, fluoroorganics have also been
extensively exploited owing to their unique biological activities (Figure 1.2).
5
For examples,
3

fluorine substitution can change the lipophilicity, acidity, basicity, and protein binding affinity of
organic molecules. The prominent “fluorine effects” are principally a consequence of fluorine’s
strongest electronegativity and its steric resemblance to a proton atom. Furthermore,
18
F− a fluorine
radioisotope−plays an important role in radiopharmaceutical industry due to its short half-life
(109.7 min) and the emission of positrons while decaying. The applications of
19
F nuclear magnetic
resonance (NMR) spectroscope,
19
F NMR-magnetic resonance imaging (MRI),
6
and
18
F
radiolabeling in positron emission tomography (PET)
7
have become the promising strategies in in
vivo and ex vivo biological studies.
Although the C−F bond is one of the strongest carbon-heteroatom bond and has great
thermodynamic stability with an average bond dissociation energy around 114.6 kcal/mol,
8
the
exceptional high metal-fluoride lattice energies as compared with those of other metal-halide
species can result in facile cleavage of carbon-fluorine bonds under certain conditions. Therefore,
fluorinating reagents, fluorine-containing building blocks, and the related reaction intermediates
always demonstrate unusual inertness or unexpected instability, thus limiting their chemical
applicability.
9
As a result, the focus of contemporary synthetic organofluorine chemistry is
concentrated on the development of efficient fluorinating and fluoroalkylating reagents and novel
fluorinated building blocks.
Organofluorine chemistry has evolved to a very comprehensive subject impacting a broad scope
of scientific fields. From the standpoint of synthetic and physical organic chemists, the introduction
mainly focuses on the developments of innovative methodologies in the syntheses of useful
fluorinated organic compounds. More specifically, the introduction of trifluoromethyl,
difluoromethyl, and monofluoroalkyl motifs in electrophilic and nucleophilic pathways are of
particular interest, which reveals the importance and necessity of the work presented in this
dissertation.

4

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

1.2 Synthetic Approaches for the Introduction of Fluorine-Containing
Functionalities
In 1835, Dumas and Pé ligot made the first attempt to construct a C−F bond and successfully
synthesized methyl fluoride by treating dimethyl sulfate with KF.
10
Half a century later, the
successful isolation of elemental fluorine was achieved in 1886 by Moissan. He was awarded the
Nobel Prize in chemistry for this achievement in 1906, marking the discovery of a new fluorination
reagent.
11
Shortly afterwards, Swarts developed more efficient synthetic methods for
fluoroorganics by exploiting halogen exchange processes under Lewis acid conditions.
12
In the
early 20
th
century, various practical protocols have been developed to prepare useful fluorine-
containing chemicals and materials, including the Balz-Schiemann reaction,
13
the cobalt trifluoride
5

process,
14
electrochemical fluorination,
15
and the Halex process.
16
In the late 20
th
century, the focus
of such chemical transformations has been shifted from the formation of C−F bond under harsh
conditions to the introduction of fluorinated functionalities (primarily fluoroalkyl groups, Figure
1.3), which allows the construction of more complex compounds with enhanced selectivity.

Figure 1.3. Fluorinated motifs of interest.
In the past half century, a wide variety of fluorination/fluoroalkylations methodologies and
reagents have been developed for the preparation of fluorine-containing compounds via
nucleophilic, electrophilic, carbene, ylide, electrochemical, and radical pathways.
17
The majority
of efforts has been devoted toward the development of novel reagents and methodologies under
milder conditions with higher efficiencies, which is also the main focus of the synthetic part of the
research demonstrated in this thesis.

1.2.1 Novel Fluorination Reagents and Related Reactions
The formation of carbon-fluorine bonds can be accomplished through: radical fluorination,
nucleophilic fluorination, electrophilic fluorination, and electrochemical fluorination (Figure 1.4).
In the early 1970s, Margrave, Lagow, and Adcock developed the controllable radical fluorination
of hydrocarbons (which is called the Aerosol Direct Fluorination Process) to afford useful
perfluorochemicals such as perfluorinated alkanes and perfluorinated ethers.
18
However, the radical
and electrochemical fluorination methods have limited functional group tolerance due to their
insufficient selectivity and harsh conditions, whereas the nucleophilic and electrophilic fluorination
methods are superior in terms of selectivity and tolerance of reactive functionalities.

Figure 1.4. Typical pathways of constructions of the C−F bond.
6

1.2.1.1 Nucleophilic Fluorinations
Nucleophilic fluorination plays a very important role in large-scale syntheses as well as
applications in the preparation of [
18
F]-radiolabeled probes for positron emission tomography
(PET).
19
Although the applicability of nucleophilic fluorination is limited by the low
nucleophilicity of the fluoride ion due to its poor polarizability, its nucleophilicity can be enhanced
by two strategies: i) weakening the solvation, hydrogen bonding, and interactions with counterions
of the fluoride ion; ii) increasing the electrophilicity of the electrophiles by adding Brø nsted or
Lewis acids.
For strategy i), weakly coordinating cationic species such as tetraalkylammonium and
tetraphenylphosphonium ions are employed to decrease the interactions with the fluoride ion,
therefore forming the so-called “naked” fluoride ion.
20
However, there are practical problems with
the storage and handling of these reagents due to their extreme hygroscopic property. Besides,
anhydrous tetraalkylammonium fluorides (except tetramethylammonium fluoride) are usually
unavailable in solid forms because the increased basicity of the fluoride ion can lead to the severe
decomposition of the cations. As a result, chemists have been exploring other methods to stabilize
the fluoride ion by using defluorinated hypervalent silicates and stannates, which have superior
chemical and physical properties compared to the alkali metal and tetraalkylammonium fluorides
(Scheme 1.1).
21
In 2006, Chi and co-workers have discovered that nonpolar protonic tertiary
alcohols can significantly promote the nucleophilic fluorination with alkali metal fluorides.
22
The
key effects of tertiary alcohols were elucidated as i) the solvation of the fluoride ion by weakening
ionic metal-fluoride bonding; ii) formation of more nucleophilic “flexible” fluoride by hydrogen
bonding with suitable strength; iii) increasing nucleofugality of leaving groups by stabilization in
the reaction media; iv) inhibiting side reactions such as elimination and intramolecular alkylation
by decreasing basicity of the fluoride ion.
23
In 2008, Kim and co-workers successfully prepared
tetrabutylammonium tetra(tert-butylalcohol)-coordinated fluoride as a lower hygroscopic and
stronger fluorinating reagent.
24

For strategy ii), a series of fluorinating regimes have been developed employing Brø nsted and/or
Lewis acids to activate the electrophiles, such as SbF 3−HF, SbF 5−HF, AlF 3−HF, hypervalent
halogen fluorides, and amine-hydrogen fluoride (Olah’s reagent, 70% HF−pyridine).
25
In addition,
a series of deoxofluorinating reagents (conversion of C−O bonds to C−F bonds) have been
developed based on S-F bond, such as gaseous sulfur tetrafluoride (SF 4),
26
PhSF 3,
27
N,N-
diethylaminosulfur trifluoride (DAST),
28
dialkylaminodifluorosulfinium salts (XtalFluor−E and
7

XtalFluor−M),
29
bis(methoxyethyl)-aminosulfur trifluoride (Deoxo−Fluor),
30
and 4-tert-butyl-2,6-
dimethyl-phenylsulfur trifluoride (Fluolead)
31
(Scheme 1.2).
Scheme 1.1. Nucleophilic fluorination prototypes and selected reagents.

Scheme 1.2. Deoxofluorination prototypes and selected reagents.
Furthermore, a series of fluorine-containing Lewis acids such as BF 3∙Et 2O have been employed
as fluoride sources in ring opening reactions of epoxides and aziridines.
32
Interestingly, two
different mechanistic pathways have been observed: i) configurationally inverted products were
8

observed for S N2-type pathway; ii) stereochemistry conserved products were obtained for S N1-type
epoxide ring opening process was involved (Scheme 1.3).

Scheme 1.3. Ring-opening reactions prototypes using BF 3∙OEt 2.
Over the last several years, organometallic fluorine chemistry has been introduced and
developing very quickly to accomplish the fluorination of nonactivated substrates.
33
The catalytic
cycle is proposed to compose three steps i) the oxidative addition of aryl halides or triflates to Pd(0)
complexes; ii) the halogen exchange with fluoride; iii) the reductive elimination of the fluorinated
Pd(II) complexes to form the corresponding aryl fluorides (Figure 1.5). Although step i) had been
well established over the past decades, the other two steps remained a challenge. The formation of
low-valent transition-metal fluorine-containing compounds is the first obstacle due to the
incompatibility of the weak polarizability of fluoride and the transition metal centers.
34

Figure 1.5. Proposed mechanism of Pd-catalyzed nucleophilic fluorination of aryl halides and
aryl triflates.
9

Dixon and co-workers observed [(Et 3P) 3Pd
II
F]
+
with
19
F NMR spectroscopy, however, the
attempted isolation of the complex led to severe decomposition to form Et 3PF 2 and Pd(0)
complexes.
35
In the late 1980s, Grushin et al. made great initial attempts for the catalytic
fluorination of arenes with a series of transition metals (Pd, Rh, Ni, Pt etc.).
36
For a long time,
chemists have been trying to synthesize the key intermediates to examine the mechanistic feasibility
of the proposed catalytic cycle. Grushin and co-workers demonstrated the theoretical possibility of
halogen exchange by successfully synthesizing and isolating the aryl palladium(II) fluoride species
[(Ph 3P) 2Pd
II
(Ph)F]. Nevertheless, the reductive elimination of aryl palladium(II) fluorides to form
aryl fluorides is the second difficulty due to the facile intramolecular nucleophilic attack of the
fluoride ion to the phosphine ligands.
37
Although there is still no solid mechanistic evidence to
prove the feasibility of catalytic cycle,
38
Buchwald and co-workers have successfully achieved a
palladium-catalyzed nucleophilic fluorination of aryl triflates.
39
Later, Ritter et al. have
demonstrated that phenols can also participate in the deoxofluorination in the presence of an
imidazole-based reagent (Scheme 1.4).
40

Scheme 1.4. Development of palladium-catalyzed nucleophilic fluorination of arenes.
Copper has also been successfully employed in the oxidative fluorination of benzene in gas
phase (Scheme 1.5).
41
Due to the unsatisfactory yield and poor recyclability of copper reagent,
Dolbier and co-workers further improved the protocol by using nominal CuAl 2F 8 which can be
regenerated multiple times.
42
Different from the Pd(II)-catalyzed nucleophilic aromatic
10

fluorinations, the Cu-mediated oxidative aromatic fluorination only applies to simple aromatics due
to harsh reaction conditions.

Scheme 1.5. Cu-mediated nucleophilic oxidative fluorination of arenes.

1.2.1.2 Electrophilic Fluorinations
The construction of carbon-fluorine bonds via electrophilic fashion was developed much later
than nucleophilic pathway due to the limited “F
+
” sources. In 1958, Inman and co-workers reported
the first electrophilic fluorination of active methylene groups by using perchloryl fluoride
(FClO 3).
43
Later, Barton and Hesse firstly introduced the concept of electrophilic fluorination by
employing fluoroxytrifluoromethane (FOCF 3) as a versatile fluorination reagent for olefins and
aromatic compounds.
44
Subsequently, a series of electrophilic fluorinating reagents based on the
F−O moiety
45
was developed, including CF 3CO 2F,
46
HOF,
47
and CsSO 4F.
48
Besides the utilization
of labile F−O bond, the weakness of F−Xe and F−F bonds led to the application of xenon difluoride
(XeF 2)
49
and elemental fluorine
50
for the electrophilic fluorination of alkenes and aromatics. Later
electrophilic fluorination of saturated hydrocarbons were also achieved by using F 2-CHCl 3/CFCl 3
regimen via a C−H bond insertion pathway.
51
While the above-mentioned compounds have been
frequently utilized as fluorinating reagents, it is not until the prevalence of the F−N based
electrophilic fluorination systems that accelerated the commercialization of the reagents.
52

Although the utilization of labile F−N bond as a fluorinating reagent was introduced prior to the
F−O bond based reagents, they didn’t draw enough attention due to the poor yields and harsh
reaction conditions.
53
Since 1980s, a series of F−N bond based compounds (R 2NF and R 3N
+
F
salts)
54
with different fluorinating capabilities were developed, including 1-fluoro-2-pyridone,
55
N-
fluoropyridinium triflates,
56
N-fluoroperfluoroalkylsulfonimides,
57
and related N 2F
+
and NF 4
+
salts
(Scheme 1.6).
58
Specifically, N-fluorobenzenesulfonimide (NFSI)
59
and 1-chloromethyl-4-fluoro-
1,4-diazoniabicyclo-[2.2.2]-octane bis(tetrafluoroborate) (Selectfluor
®
)
60
were commercialized in
the early 1990s and are among the most significant and commonly used electrophilic fluorinating
reagents.
52, 61
Although there has been controversy regarding the mechanism of electrophilic
fluorinations, two pathways are generally proposed: i) single-electron transfer (SET) and ii)
11

nucleophilic substitution (S N2) (Scheme 1.6).
52,61b,62
It is worth mentioning that when F 2, N 2F
+
, and
N 4F
+
salts are used the reactions always proceed via a C−H bond insertion pathway instead of the
two mechanisms described below.
51,63

Scheme 1.6. Electrophilic fluorination prototypes, selected reagents, and possible mechanisms.

1.2.2 Monofluoroalkylating Reagents and Related Reactions
Fluoroalkyl synthons have been playing significant roles in constructing fluorine-containing
compounds due to their higher efficiency and tolerance of various functionalities. Mechanistically,
several intermediates are involved in fluoroalkylations, including α-fluorocarbanions, α-
fluorocarbocations, α-fluorocarbenes, α-fluorinated radicals, β-fluorocarbanions, and others
(Scheme 1.7). Interestingly, these fluorinated species often exhibit fundamentally different
chemical behavior in comparison with their nonfluorinated counterparts due to the steric
12

resemblance and the extremely strong electronegativity of fluorine. In this section, the introduction
will be focused on α-fluoroalkylation methods (in the order of monofluoroalkylation,
difluoromethylation, and trifluoromethylation) for the purpose of relevance to the dissertation and
brevity. Therefore, reviews on nucleophilic β-fluoroalkylations,
64
as well as fluoroalkylation
protocols based on radicals,
65
ylides,
66
and carbenes
67
intermediates will not be covered here.

Scheme 1.7. Key reaction intermediates involved in fluoroalkylations and potential difficulties.

1.2.2.1 Electrophilic Monofluoroalkylating Reagents and Reactions
The incorporation of C−F bond can be accomplished through either direct fluorinations or
introduction of monofluoroalkyl synthons depending on the specific situations. Unlike the
difluorocarbene and difluoromethyl radicals, the synthetic applications of monofluorinated radicals
and carbenes have drawn less attention. The monofluoromethylation are primarily via nucleophilic
and electrophilic pathways.
68

Introduction of monofluoromethyl motif via electrophilic pathway has been much relatively less
explored. In 1953, Olah et al. achieved the first electrophilic monofluoromethylation of arenes
using fluoromethanol to afford benzyl fluorides.
69
Afterwards, several other reagents have been
developed toward a wide scope of nucleophiles.
70
More recently, Prakash and co-workers reported
the syntheses of S-(monofluoromethyl)diarylsulfonium salts as a novel electrophilic
monofluoromethylating reagent.
71

1.2.2.2 Nucleophilic Monofluoromethylating Reagents and Reactions
In contrast to the limited studies on electrophilic monofluoromethylation, a variety of
nucleophilic-type reactions have been explored to introduce monofluoromethyl moieties, including
nucleophilic substitutions, aldol reactions, 1,4-addition reactions, the Wittig-type reactions, ring
opening reactions, and etc.
72
Although monofluorocarbanions are generally believed to be
13

reasonably stable with electron-withdrawing groups adjacent to the carbanion center, the isolation
and characterization of these carbanions can be quite difficult due to the rapid elimination of
fluoride. Intriguingly, Prakash and co-workers have for the first time successfully isolated and
characterized a monofluorinated methide species with single crystal X-ray diffraction.
73

Interestingly, the fluorocarbanions adopt a cis-pyramidal geometry over a trans-planar structure
which can play an important role in the distinct nucleophilic reactivity compared with their non-
fluorinated analogues (Scheme 1.8).
74

Scheme 1.8. Nucleophilic monofluoromethylation prototypes and intermediates.
In 1954, Blank and Mager reported the first nucleophilic monofluoromethylation with ethyl
fluoroacetate.
75
Subsequently, a systematic study has been conducted by Bergmann et al. with
reactions between various electrophiles and a series of monofluoroenolates generated from
fluoroacetate, fluoroacetone, and α-fluoro-β-keto esters.
76
Later, Buchanan reported the Michael
addition of diethyl fluoromalonate to α,β-unsaturated carbonyl compounds and nitroolefins to
afford various α-fluorinated carboxylic acids.
77
It is noteworthy that Ishikawa developed an
ultrasound-promoted Reformatsky-type reaction between trifluoroacetaldehyde and ethyl
bromofluoroacetate in the presence of Zn metal.
78
Afterwards, the development of enol silyl
ethers
79
and silyl ketene acetals
80
have led to the monofluoromethylation via a variety of reaction
pathways.
81

Despite that the carbonyl-stabilized monofluoromethides have been extensively employed in
the monofluoromethylations, their applications and further conversions are limited due to the
14

difficulty of removing the carbonyl groups.
68a
Great efforts have been made for exploration of a
variety of reagents to overcome this problem. Kaplan et al. exploited fluorodinitromethane
(HCF(NO 2) 2) as a pronucleophile for the Michael reaction with methyl acrylate.
74
The further
examination of HCF(NO 2) 2 was made by Gilligan, who prepared N,N-bis(2-fluoro-2,2-
dinitroethyl)-N-alkylamines.
82
However, the application of HCF(NO 2) 2 is limited due to its
potential instability.
83
On the other hand, S-based auxiliaries have been drawing great attention due
to their facile conversion into other functionalities and their capability of altering the nucleophilic
reactivity of monofluoromethides. In 1984, Makosza reported the first nucleophilic substitution
reaction between nitroarenes and monofluoromethyl phenyl sulfone (PhSO 2CFH 2).
84
Later, Peet
and McCarthy reported the reaction between carbonyl compounds and lithiofluoromethyl phenyl
sulfone to afford β-fluoroalcohols, which can be further converted to a series of terminal vinyl
fluorides.
85
More recently, Hu and co-workers utilized PhSO 2CFH 2 in stereoselective syntheses of
β-fluoroamines.
86
Apart from investigating various applications with PhSO 2CFH 2, great efforts
have been made to explore alternatives derived from PhSO 2CFH 2 by introducing additional
functional groups on the fluorinated carbon. In 2006, Shibata et al. successfully prepared
fluorobis(phenylsulfonyl)methane (FBSM) and used it for an asymmetric Pd-catalyzed allylic
monofluoromethylations with high enantiomeric excesses.
72
At the same time, Hu and co-workers
independently reported the utilization of FBSM as a pronucleophile in the ring opening reaction of
epoxides.
87
Additionally, Prakash et al. have developed several functionalized monofluoromethyl
phenyl sulfone derivatives as versatile monofluoromethylating reagents.
88
Furthermore, α-
fluorosulfoximines have also been applied in the reaction with nitrones to generate Z-
monofluoroolefins with high stereoselectivity (Scheme 1.9).
72d

15

Scheme 1.9. Typical nucleophilic monofluoromethylating reagents and synthons.
It is worth mentioning that a facile and efficient protocol to prepare FBSM has been keenly
pursued because FBSM can undergo protonation under mild conditions and allow many chemical
transformations that are difficult to achieve otherwise. Conventionally, Shibata and Hu prepared
FBSM for the first time via electrophilic fluorination. Subsequently, Fuchigami developed the
synthesis using electrochemical fluorination.
89
Shortly afterwards, Hu et al. reported a superior
synthetic protocol using fluoromethyl phenyl sulfone which avoids the tedious purification step.
90

More recently, Prakash and co-workers improved the protocol of Hu by using less costly
phenylsulfonyl fluoride with fewer steps, higher efficiency and purity (Scheme 1.10).
91

Scheme 1.10. Development of the synthesis of fluorobis(phenylsulfonyl)methane.

1.2.2.3 Monofluoroolefination
Construction of monofluoroolefin derivatives are most commonly accomplished through Wittg
and Wittig-type olefination reactions.
66
Monofluoromethylene ylide can be pregenerated from
phosphonium salt and alkyl lithium and readily react with aldehydes and ketones to afford
corresponding monofluoroolefins. On the other hand, the application of modified Julia-Kocienski
olefination to prepare fluorovinyl compounds are relatively less explored.
92
In 2003, Lequeux and
co-workers reported the first preparation of monofluoroalkylidenes via base-mediated
condensation reactions of benzothiazol-2-yl-1-fluoroethylsulfone with aldehydes and ketones.
93

Later, Zajc et al. developed a series of monofluorinated phenyltetrazole-based sulfones which
showed higher stability under basic conditions compared to benzothiazol-based reagents and the
reactions with aldehydes and ketones afforded monofluorovinyl compounds with moderate Z/E
selectivity.
94
Furthermore, a-fluoroacrylates have also been successfully prepared through Julia-
16

Kocienski olefination by Blakemore
95
and Zajc
96
independently. Efforts made by Prakash, Ná jera,
and Jørgensen have also made great contributions to highly efficient preparation of
monofluoroolefins (Scheme 1.11).
97

Scheme 1.11. Development of the synthesis of monofluoroolefins.

1.2.3 Difluoromethylating Reagents and Related Reactions
Difluoromethyl (CF 2H)- and difluoromethylene (CF 2)-containing compounds have been
drawing great attention recently due to their diverse applications in materials science,
17

agrochemistry and the pharmaceutical industry.
98
The CF 2 moiety has shown potential in the
development of bioactive fluorinated analogues of oxygenated molecules (such as sugars) due to
its isosteric and isopolar property compared with ethereal oxygen. On the other hand, the CF 2H
moiety is also found to be isosteric and isopolar to a hydroxyl group, specifically in respect of its
function as a hydrogen bonding donor without generating a negative charge.
Various methods have been developed around the early 1990s to introduce gem-
difluoromethylene moieties.
99
Generally speaking, current synthetic protocols are primarily based
on three strategies i) nucleophilic difluorination of carbonyl compounds and their derivatives; ii)
direct electrophilic gem-difluorination of carbanions; iii) fluorinated synthons via nucleophilic,
electrophilic, radical, single electron transfer,
65
and carbene-based reaction intermediates (Scheme
1.12).
67,100
Additionally, reductive defluorination from available CF 3-containing precursors has
also been often utilized.
101
Herein the attention will be focused on the utilization of difluorinated
carbanion and carbocation synthons developed in the past two decades.

Scheme 1.12. Difluoromethylations and difluoromethylenations protocols.

1.2.3.1 Nucleophilic Difluoromethylating Reagents and Reactions
The key intermediate in nucleophilic difluoromethylating reactions is difluoromethyl carbanion
which can react with a range of electrophilic substrates, including alkyl halides, carbonyl
compounds, and their analogues to afford the corresponding difluoromethylated alcohols, amines,
ketones, and gem-difluorinated alkenes (Scheme 1.13). Unlike the carbanions in conjugation with
nitro or carbonyl groups which usually adopt the planar conformation, the difluorinated
counterparts always adopt pyramidal geometries primarily because the increased p-orbital character
18

of the fluorine atoms favors an sp
3
-hybridization energetically.
102
Similar to the CF 3 anion, RCF 2
anions also have the tendency to undergo α-elimination of fluoride or auxiliary groups to form
thermodynamically more stable carbenes, resulting in competitive side-reactions and limiting the
applicability of RCF 2
−
synthons.
Scheme 1.13. Nucleophilic difluoromethylation prototypes and key reaction intermediates.
Therefore, RCF 2
−
species are usually functionalized with auxiliary groups with electron-
withdrawing ability and charge-delocalizing properties to increase their stability and reactivity.
Initially, nucleophilic incorporation of the CF 2 groups was accomplished by utilizing “P−CF 2”
derivatives. In 1971, Burton and co-workers demonstrated the first difluoromethylene olefination
with difluorinated phosphonium salts via Wittig reaction.
103
Later, phosphonate ylide was utilized
to improve the nucleophilicity of the ylides. A wide range of electrophiles can undergo the reaction
with diethyl bromodifluoromethylphosphonate mediated by cadmium or zinc, including aldehydes,
ketones, acyl chlorides, and allyl bromides.
104
Later, Kondo and co-workers employed diethyl
difluoromethylphosphonate-lithium diisopropylamide and diethyl difluoro(trimethylsilyl)methyl-
phosphonate−cesium fluoride regimens as the precursors of (diethoxyphosphoryl)difluoromethide
anion.
105
Furthermore, CF 2-containing phosphates and phosphoric acids have also been prepared
with these methods, demonstrating significantly increased biostability.
106
Fokin and co-workers
utilized difluoronitromethane as CF 2-synthon in Michael addition and the Henry reaction but this
was not further explored due to its limited synthetic applicability (Scheme 1.14).
107

19

Scheme 1.14. Typical nucleophilic difluoromethylating reagents.
In addition to the “CF 2-heteroatom” based synthons, α,α-difluorinated carbonyl compounds and
their derivatives have also been utilized as CF 2 synthons since the early 1980s. In 1983, Ishihara
and co-workers reported the preparation of enol silyl ethers from chlorodifluoromethyl ketones and
chlorotrimethylsilane and their application in the aldol reaction as efficient CF 2-synthons.
108
Later,
Kobayashi and co-workers reported the syntheses of 2,2-difluoroketene silyl acetals under similar
conditions and their reactions with imines, aldehydes, and ketones with great stereoselectivities.
109

Nearly a decade afterwards, a catalytic asymmetric aldol reaction of difluoroketene silyl acetal with
aldehydes has been developed in excellent enantiomeric excesses.
110
While Huang and co-workers
reported the preparation of (2,2-difluorovinyloxy)triphenylsilane, its synthetic applications still
remain unexplored.
111
In the late 20th century, Uneyama et al. reported the electrochemical
syntheses of N-TMS- β,β-difluoroenamines and their applications in aldol reaction and nucleophilic
substitution with alkyl iodides.
112
Subsequently, a series of synthetic protocols toward α ,α-difluoro
carbonyl compound derivatives have been developed by the same research laboratory.
113
Prakash
and co-workers have synthesized a series of 2,2-difluoro silyl enol ethers for radiochemical
syntheses of [
18
F]-labeled trifluoromethyl ketones using similar methodology.
114
Besides,
commercially available halodifluoroacetates are among the most important difluorinated synthons
as well. Initially utilized in the Reformatsky-type reaction to prepare 2,2-difluoro-3-
hydroxyesters,
115
the halodifluoroacetates-Zn systems are also applicable to both
diastereoselective
116
and enantioselective
117
addition of α ,α-difluorinated esters to aldehydes,
ketones, and imines.
118
Since late 1980s, a range of difluoromethyl analogues have been applied
for the preparation of difluoromethylated allenes and allylation reactions (Scheme 1.14).
119

20

Scheme 1.15. S- and Se-based nucleophilic difluoromethylating reagents and typical reactions.
Among the numerous novel difluoromethylating reagents based on S-CF 2 moieties,
120

difluoromethyl phenyl sulfone (PhSO 2CF 2H)
121
has been extensively explored in the past two
decades due to the facile reductive S-CF 2 bond cleavage and further transformations into other CF 2-
containing derivatives. In 1989, Stahly first applied PhSO 2CF 2H to the nucleophilic
difluoromethylation of aldehydes with good results.
122
Later, the gem-difluoromethylenation of
ketones with PhSO 2CF 2H was reported via difluoromethyl ylide intermediate.
123
In 2003, Prakash
and Hu et al. reported an efficient one-pot stereoselective preparation of anti-2,2-difluoropropane-
1,3-diols using PhSO 2CF 2H as a difluoromethylene dianion equivalent.
124
Further investigation has
21

been made by the same research laboratory to reveal the S N2 reaction between PhSO 2CF 2H and
primary alkyl iodides.
125
Additionally, PhSO 2CF 2H was able to introduce PhSO 2CF 2-moiety into
chiral N-(tert-butylsulfinyl)aldimines with excellent diastereoselectivity.
126
Although epoxides and
aziridines were found not reactive with PhSO 2CF 2H, Hu and co-workers achieved the preparation
of β-difluoromethylated and β-difluoromethylenated alcohols and amines using the more
electrophilic 1,2-cyclic sulfates and sulfamidates.
127
The enantioselective nucleophilic
difluoromethylation of aldehydes catalyzed by cinchona alkaloid-derived ammonium salts have
also been reported by the same group.
128
Furthermore, they also explored a series of alternatives to
PhSO 2CF 2H as novel difluoromethylating reagents toward aldehydes and ketones by substituting
the phenyl group with heterocyclic aromatic functionalities.
129
While PhSO 2CF 2H can only react
with enolizable ketones and aldehydes with low efficiency and under harsh conditions, a novel
protocol utilizing difluoro(phenylthio)methyltrimethylsilane (PhSCF 2TMS) and (phenylsulfonyl)-
difluoromethyltrimethylsilane (PhSO 2CF 2TMS) induced by fluoride has been developed with
milder condition and higher efficiency.
130
Similarly, difluoro(phenylseleno)methyltrimethylsilane
(PhSeCF 2TMS) has been developed by Qing and co-workers as a viable difluoromethylating
reagent toward enolizable ketones and aldehydes.
131
It is worth noting that a facile synthesis of
TMSCF 2H from TMSCF 3 has been reported by Igoumnov,
132
which enables the employment of
TMSCF 2H as a nucleophilic difluoromethylating reagent toward various carbonyl compounds and
sulfinyl imines (Scheme 1.15).
133

Scheme 1.16. Difluoromethylation using Si-based reagents.
A series of Si-CF 2H derivatives were explored as difluoromethylating reagents, including
(difluoromethyl)dimethylphenylsilane (Me 2PhSiCF 2H) which once induced by fluoride could react
22

with ketones and aldehydes.
134
Later, Prakash and co-workers utilized difluorobis(trimethylsilyl)-
methane (TMSCF 2TMS) as a difluoromethylene dianion equivalent. The same research laboratory
have also achieved the preparation of difluoromethylated imines from aldimines and TMSCF 3 in
the presence of TMAF.
135
Furthermore, TMSCF 3 was found to undergo partial defluorination to
afford 2,2-difluoroenol silyl ethers via Brook rearrangement which can be further transformed to
various difluoromethylated compounds (Scheme 1.16).
136

1.2.3.2 Electrophilic Difluoromethylating Reagents and Reactions
The exploration and development of electrophilic difluoromethylating reagents were not of
particular interest to chemists because difluorocarbene (a de facto “
+
CF 2
−
” equivalent) can readily
react with a wide scope of nucleophiles. Prakash et al. made the first achievement by successfully
synthesizing S-(difluoromethyl)diarylsulfonium salt as an electrophilic difluoromethylating
reagent toward O-, N-, and P-nucleophiles.
137
Later, they utilized polystyrene-bound S-
difluoromethyl sulfonium reagent for the difluoromethylation of sulfonic acid salts and imidazoles
affording the products with high purity.
138
Subsequently, Hu and co-workers reported a mild
protocol using a hypervalent iodine(III)-CF 2SO 2Ph reagent toward various thiols with high
efficiency (Scheme 1.17).
139

Scheme 1.17. Novel electrophilic difluoromethylating reagents.

23

1.2.4 Trifluoromethylating Reagents and Related Reactions
1.2.4.1 Nucleophilic Trifluoromethylating Reagents and Trifluoromethyl-Metal Reagents
Nucleophilic trifluoromethylation has been extensively explored in the transformation of a wide
range of electrophilic species to various trifluoromethyl-containing compounds, including
aldehydes, ketones, esters, imines, nitriles, nitrones, alkyl halides, and others (Scheme 1.18).
140

Furthermore, trifluoromethyl-metal reagents can also react with aromatic halides, alkenyl halides,
and alkynes via cross coupling pathway.
It is generally believed that the decrease of stability of the anion caused by the repulsive force
of the vicinal “anion-lone pair” outruns the electron withdrawing ability of fluorine atom, leading
to easy α-elimination of fluoride (Scheme 1.8).
141
On the other hand, the extraordinarily high lattice
energy of metal-fluoride results in difficulty to stabilize the CF 3
-
anion in the presence of metal
cations. Such notion has been widely accepted for more than half century. It is extremely gratifying
for me to include in chapter 5 of my dissertation the synthesis and characterization of CF 3
-
anion in
bulk for the first time − a long sought challenge for over 60 years.

Scheme 1.18. Nucleophilic trifluoromethylation prototypes.
In 1948, Haszeldine and co-workers successfully prepared trifluoromethyl iodide (CF 3I) for the
first time, which was exploited as the exclusive CF 3 anion precursor until 1980s.
142
In 1981, two
other compounds trifluoro acetates
143
and CF 3Br
144
have been utilized as CF 3 anion precursors
24

despite that they have been synthesized four decades earlier. Later in 1985, Burton and co-workers
reported the preparation of trifluoromethyl-metal complexes with CF 2Br 2 as a difluorocarbene
source.
145
Subsequently, Chen et al. employed methyl fluorosulfonyldifluoroacetate as a
trifluoromethylating reagent toward a range of aryl and alkyl halides catalyzed by CuI.
146

Interestingly, CF 3H was not exploited in the trifluoromethylation reactions until 100 years after its
first preparation (Scheme 1.19).
147

Scheme 1.19. Typical nucleophilic trifluoromethylating reagents.
The facile preparation of trifluoromethyl metal complexes has been a long-time interest to
chemists.
148
In the mid-20
th
century, several trifluoromethyl metal species have been prepared,
including bis(trifluoromethyl) mercury,
149
trifluoromethyl lithium,
148b,149
and trifluoromethyl
magnesium iodide.
150
However, these compounds are either not stable or not reactive enough. Later,
the successful preparation of trifluoromethyl copper
151
and zinc species
152
solved this problem with
their superior reactivity and stability (Scheme 1.20).

Scheme 1.20. Typical trifluoromethyl organometallic reagents and intermediates.
Since the late 1980s, the development of a series of nonmetal-based trifluoromethylating
reagents have been contributing to the trifluoromethylation field continuously. In 1982, De Meijere
successfully introduced the trifluoromethylation of ketones using in situ generated
trialkylsilyl(trifluoromethyl)diazenes under harsh conditions.
153
Later in 1989, the exploitation of
trifluoromethyltrimethylsilane (TMSCF 3, the Ruppert-Prakash reagent)
140a
as an efficient
nucleophilic trifluoromethylating reagent marked the breakthrough in the trifluoromethylation field
because of its mild conditions, high efficacy, and applicability toward a wide range of substrates
(aldehydes, ketones, esters, imines, nitriles, nitrones, alkyl halides, and metal species).
154
Similar
25

to the preparation of TMSCF 3 developed by Ruppert, Pawelke reported the synthesis of CF 3-
tetrakis(dimethylamino)ethylene complex and its utilization as a trifluoromethylating reagent to
construct CF 3-B and CF 3-Si bonds.
155
The chemistry was then employed by Dolbier toward various
ketones, aldehydes, cyclic sulfates, aldimines, and sulfinimines.
156
Meanwhile, Prakash and co-
workers have reported the preparation of trifluoromethyl phenyl sulfone (PhSO 2CF 3) from CF 3H
and its application as a nucleophilic trifluoromethylating reagent toward carbonyl compounds and
imines (Scheme 1.21).
157

Scheme 1.21. Typical nonmetal-based trifluoromethylating agents.
The direct utilization of fluoroform (CF 3H) is ideally a better trifluoromethylating reagent in
respect of atom economy and other advantages,
158
however, it is not until the end of 20
th
century
when CF 3H was exploited to introduce a CF 3 moiety via deprotonation in DMF with
electrogenerated bases by Shono and co-workers for the first time.
159
Later Roques et al. extended
this chemistry by using readily available bases and first proposed the formation of the
trifluoromethylated hemiaminal intermediate with DMF which stabilizes the labile CF 3 anion.
160

Afterwards, several trifluoromethyl hemiaminals generated from fluoral methylhemiacetal and
amines or CF 3H and formamides have been employed as trifluoromethylating reagents towards a
range of substrates (Scheme 1.22).
161
More recently, Prakash and co-workers have reported the
direct nucleophilic trifluoromethylations of silicon, boron, sulfur, and carbon-based electrophiles
using stoichiometric amounts of fluoroform in common solvents other than DMF.
162

26

Scheme 1.22. Nucleophilic trifluoromethylation using CF 3H as trifluoromethyl source.

1.2.4.2 Electrophilic Trifluoromethylating Reagents and Related Reactions
Unlike nucleophilic trifluoromethylation, electrophilic trifluoromethylations were introduced
and developed only in the past three decades. Electrophilic trifluoromethylation has enabled the
construction of various heteroatom-CF 3 bonds apart from C−CF 3 (sp
3
, sp
2
or sp) bonds, exhibiting
great significance in syntheses of compounds with unique biological and chemical properties
(Scheme 1.23).
163

Scheme 1.23. Electrophilic trifluoromethylation prototypes.
27

The first attempt of electrophilic trifluoromethylation was made by Haszeldine, who treated
CF 3I with potassium hydroxide, only affording CF 3H which indicates the reverse polarization of
the C−I bond.
164
Later in 1976, the successful preparation of trifluoromethyl triflates (CF 3OTf)
from triflic acid and fluorosulfuric acid by Olah evidentially suggested an electrophilic
trifluoromethylation mechanism.
165
However, attempts to use CF 3OTf as a trifluoromethyl source
only resulted in nucleophilic attack on the sulfur atom. Although it is believed that the
extraordinarily strong electronegativity of CF 3 moiety led to the difficulties in generation of the
cation, a gas-phase ion study has surprisingly showed that the order of the stability of various
methyl cations decreases in the order of CHF 2
+
> CH 2F
+
> CF 3
+
> CH 3
+
,
166
which is due to a balance
between the high electronegativity of fluorine and the back donation of its lone-pair of electrons to
the vacant p-orbital on carbon center (Scheme 1.24). It is generally accepted that the inertness of
the CF 3 cation toward nucleophiles is contributed to two factors: i) the reverse polarization of the
CF 3-X and CF 3-O bonds; ii) the steric hindrance of the CF 3 moiety.

Scheme 1.24. Challenges of electrophilic trifluoromethylations.
In 1984, Yagupolskii and co-workers reported the first electrophilic trifluoromethylation
utilizing trifluoromethyl sulfonium salts (diaryl(trifluoromethyl)sulfonium salts)
167
nearly a decade
after its first preparation in 1973.
168
Generated from the p-chlorophenyl trifluoromethyl sulfoxide,
SF 3
+
SbF 6
−
and anisole or m-xylene, the reagents could react with p-nitrothiophenolate to form the
corresponding trifluoromethyl sulfide in moderate to good yields (Scheme 1.25). To overcome the
rather low reactivity of these reagents, Umemoto and co-workers reported the preparation of a
series of (trifluoromethyl)dibenzo chalcogenium (S, Se, and Te) salts, which are applicable for
trifluoromethylation of a broader range of nucleophiles, including carbanion, thiophenolates,
phosphines, and iodide.
169
Later, Shreeve and co-workers revisited the synthesis and reactivity of
diaryl(trifluoromethyl)sulfonium salts to enrich the library of electrophilic trifluoromethylating
reagents.
170
Magnier and Blazejewski further improved the syntheses of these reagents with a more
straightforward method.
171
Recently, Umemoto and co-workers have achieved the preparation of
28

O-(trifluoromethyl)oxonium salts for direct trifluoromethylation of N- and O-nucleophiles.
172
In
2010, Shibata et al. reported the employment of S-(trifluoromethyl)thiophenium salts for
electrophilic trifluoromethylations of carbon nucleophiles.
173

Scheme 1.25. Electrophilic trifluoromethylating reagents based on chalcogen-CF 3 salts.
In addition to the reagents shown in Scheme 1.25, S-(trifluoromethyl)sulfoximines have also
been explored as efficient electrophilic trifluoromethylating reagents in the past decade (Scheme
1.26). In 1984, S-trifluoromethylated sulfoximine was first prepared by Yagupolskii by treating
trifluoromethyl phenyl sulfoxide with sodium azide in the presence of oleum.
174
However, it is not
until 2003 when the cyclic and acyclic trifluoromethyl sulfoximines have been patented as viable
electrophilic trifluoromethylating reagents towards carbon nucleophiles and thiolates.
175
Later,
Shibata and co-workers have reported the trifluoromethylated counterpart of Johnson’s reagent,
which could trifluoromethylate various carbon nucleophiles in the presence of 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) or phosphazene base.
176

Scheme 1.26. Electrophilic trifluoromethylating reagents based on S-CF 3 sulfoximines.
In addition to the two above-mentioned types of reagents, hypervalent iodonium compounds
have also demonstrated great reactivity and efficacy as potent electrophilic trifluoromethylating
reagents. In 2006, Togni et al. reported the preparation of a series of stable trifluoromethyl-
(iodonium) compounds from TMSCF 3 for the first time as efficient electrophilic
trifluoromethylating reagents.
177
Later the synthetic protocol was improved by the same group for
easier operation, higher yield and cheaper materials (Scheme 1.27).
178
The Togni reagent type I
was applicable to a range of substrates, including β-keto esters,
177
α-nitro esters,
178
sulfur
178
and
phosphine
179
nucleophiles. The Togni reagent type II has been applied in the trifluoromethylation
29

of alcohols
180
and sulfonic acids.
181
Despite the great achievement, the electrophilic
trifluoromethylation of alcohols still remains challenging because a large excess of alcohols was
required for aliphatic alcohols while attempts with phenols result in the trifluoromethylation of
aromatic rings instead of hydroxyl group (Scheme 1.27).
182
More recently, Shen et al. have reported
a new hypervalent iodine reagent for the transfer of an electrophilic trifluoromethylsulfur (SCF 3)
group.
183
The reagent was proposed to bear the cyclic iodine 
3
-benziodoxole structure, which was
later revisited by Buchwald et al. and demonstrated to be of acyclic thioperoxy structure.
184

Scheme 1.27. Electrophilic trifluoromethylation with I-CF 3 based reagents.

1.2.4.3 Transition-Metal Mediated Aromatic Trifluoromethylating
The employment of Cu in aromatic trifluoromethylations was first studied in late 1960s when
Kobayashi and co-workers reported the first Cu-mediated aromatic trifluoromethylation with
30

CF 3I.
151b
In 2008, the mechanism was established experimentally with the single crystal X-ray
structures of NHC stabilized Cu−CF 3 complexes.
185
However, the slow regeneration of CuI
significantly limited the formation of Cu−CF 3 species, leading to severe decomposition of the CF 3
anion. Therefore, Amii et al. have developed an efficient catalytic protocol using a combination of
CuI and 1,10-phenanthroline (phen), which significantly accelerated the cross-coupling process.
186

Despite using a stoichiometric amount of CuI/phen system, Qing and co-workers successfully
demonstrated the cross coupling reaction between TMSCF 3 and terminal alkynes.
187
Noticeably,
Hartwig et al. reported the syntheses of Cu-based bench-stable perfluoroalkylating
188
reagents
toward various aryl iodides. Grushin and co-workers reported the preparation of CuCF 3 directly
from CF 3H in DMF, which underwent reaction with various aryl halides smoothly.
189
Furthermore,
Qing et al. also achieved the oxidative trifluoromethylation of aryl boronic acids with TMSCF 3
(Scheme 1.28).
190

Scheme 1.28. Cu-Mediated aromatic trifluoromethylations.
31

Scheme 1.29. Pd-Catalyzed aromatic trifluoromethylation and proposed mechanisms.
On the other hand, Pd-catalyzed aromatic trifluoromethylations are mechanistically more
challenging because the reductive elimination step in the catalytic cycle was energetically
prohibitive due to the extraordinary stability of Pd−CF 3 bond.
36
The initial attempt was made by
Ishikawa who demonstrated the first Pd-catalyzed trifluoromethylation of aryl iodides utilizing in
situ generated Zn−CF 3 species.
191
More than two decades later, Grushin and Marshall proved the
mechanistic feasibility of Pd-catalyzed aromatic trifluoromethylations by achieving a facile
trifluoromethyl-aryl reductive elimination from a xantphos-coordinated Ph(II) center.
192

Subsequently, Sanford and co-workers reported the aromatic trifluoromethylation involving
32

reductive elimination from high valent Pd(IV) species.
193
In the same year, Yu and co-workers have
achieved a more practical synthetic protocol for Pd(II)-catalyzed ortho-trifluoromethylation of
arenes bearing pyridine as directing groups with Umemoto’s reagent.
194
A breakthrough has been
achieved recently by Buchwald et al. who demonstrated efficient trifluoromethylation of a wide
scope of aryl chlorides with Pd complexes via a regular Pd(0)-Pd(II) catalytic cycle (Scheme
1.29).
195

1.3 Conclusion
Fluoroorganics are extremely scarce in nature while they show great advantages in chemical,
physical, and biological sciences due to their unique properties. Therefore, great effort has been
made to construct a large number of fluorine-containing compounds. Over the past half century,
organofluorine chemistry has experienced a rapid growth, contributing to the development of
various new methods and novel efficient reagents for the incorporation of fluorine-containing
motifs. However, there are still challenges in this field such as the stabilization of α- and β-
fluorocarbanions, and introduction of fluorine-containing moieties asymmetrically, that are to be
solved. On the other hand, mechanistic investigations are very important to obtain better
understanding of the fundamental properties of fluorine-containing motifs, thus providing
instructive guidance to solve remaining obstacles, improve current protocols, and develop new
methodologies.

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44

Chapter 2

Stereoselective Synthesis of
Fluoroalkenoates and Fluorinated
Isoxazolidinones: N-Substituents Governing
the Dual Reactivity of Nitrones

45

2.1 Introduction
Fluorine substitution
1
has been a practical tool to adjust biological and physicochemical
properties of organic compounds.
2
Among various fluorinated functionalities,
monofluoroalkenoates have been of enormous interest due to their potential medicinal
applications.
3
While quite a few methods have been developed to prepare monofluoroalkenoates,
4,5
stereoselective syntheses of monofluoroalkenoates are limited to a handful of reactions, such as the
Horner-Wadsworth-Emmons (HWE) reaction
4,6
and the Julia-Kocienski olefination.
7
Recently, Hu
et al. demonstrated a one-step synthesis of (Z)-monofluoroolefin via the reaction between nitrones
and α-fluoro-α-sulfoximines aryl methides,
8,9
in which the sulfoximine moiety served as both an
activating group and a leaving group (Scheme 2.1). Considering the high nucleofugality of
bromide,
10
we proposed that monofluoroalkenoates can also be synthesized via a similar reaction
with α-fluoro-α-bromoacetate as a pronucleophile.

Scheme 2.1. Synthesis of monofluorinated olefins using nitrones.
Furthermore, isoxazolidinone derivatives have been recognized as key heterocyclic skeletons in
numerous bioactive compounds,
11
which can be constituted through the reaction of esters with
nitrones.
12,13
In principle, with a precise modulation of reaction pathways, the preparation of
monofluoroalkenoates and fluorinated isoxazolidinones can be achieved, respectively, via the
reactions between α-fluoro-α-bromoacetate and nitrones.

46

2.2 Results and Discussion
Herein, we report the stereoselective synthesis of α-fluoroalkenoates using ethyl α-fluoro-α-
bromoacetate (3) and nitrones. By altering the N-substituent in nitrones, (E)-α-fluoroalkenoates (4),
4-fluoro-5-isoxazolidinones (5),

and 4-fluoro-5-isoxazolones (6) can be obtained under respective
reaction conditions.
Table 2.1. Effects of bases on reaction yield and stereoselectivity.

Entry Solvent Base Additive Yield [%]
[d]
E/Z
1 THF
[a]
KHMDS N/A 36 94/6
2 THF
[a]
NaHMDS N/A 38 90/10
3 THF
[a]
LiHMDS N/A 11 94/6
4 THF
[a]

N/A 9 99/1
5 THF
[a]

N/A -
[e]
-
[e]

6 THF
[a]

N/A -
[e]
-
[e]

7 THF
[a],[c]
NaH N/A -
[f]
-
[e]

8 THF
[a]
KHMDS HMPA 22 97/3
9 THF
[a]
NaHMDS HMPA 30 97/3
10 DMF
[b]
KHMDS HMPA -
[e]
-
[e]

11 DMF
[b]
NaHMDS HMPA -
[e]
-
[e]

12 DMF
[b]
LiHMDS HMPA -
[e]
-
[e]

[a] The base in THF (0.1 M) was added dropwise to a mixture of 1a (0.05 M) and 3a ( 0.075 M) in
THF at -78
o
C within 5 min (ca. 1.2 M/h). [b] The reaction was carried out in DMF at -40
o
C with
a procedure similar to footnote a. [c] The reaction was performed with 1a, 3a and NaH in a molar
ratio of 1.0/3.0/3.0, respectively. [d]
19
F NMR yields were determined using PhCF 3 as an internal
standard. [e] Complete decomposition of 3a. [f] 3a was recovered.
Our studies were initiated by adding 1a to a mixture of 3a and KHMDS in THF at -78
°
C, which
resulted in the complete decomposition of 3a probably through α-fluoride
14
and/or α-bromide
eliminations. Further investigation was conducted by treating a mixture of 1a and 3a with KHMDS,
expecting the in situ capture of 3a-enolate. As desired, product 4a was obtained with satisfactory
E/Z selectivity (Table 2.1, Entry 1); however, the reaction yields did not significantly improve even
after an extensive screening of bases (Table 2.1, Entries 2-7). Hexamethylphosphoric triamide
(HMPA) was utilized as a cation-coordinating additive in the hope to enhance both the yields and
the stereoselectivities.
15
Whereas this led to slight increase in the E/Z ratio of the product,
detrimental effects on the reaction yield were observed (Table 2.1, Entries 1-2 and 8-9). Other
47

solvents, such as DMF, were found to be unsuitable for the present reaction (Table 2.1, Entries 10-
12).
Table 2.2. Effects of temperatures, additives, and concentrations on reaction yield and
stereoselectivity.

Entry
Temp.
(
o
C)
Additive 1a (equiv.) 3a (equiv.)
NaHMDS
(equiv.)
Yield
[%]
[a,b]

E/Z
1
[c]
-78 N/A 2.0 1.0 1.0 53 94/6
2
[c]
-78 HMPA (2 equiv.) 1.0 1.5 2.0 27 97/3
3
[c]
-78 HMPA (10 equiv) 1.0 1.5 2.0 20 95/5
4
[c]
-78 HMPA (20 equiv) 1.0 1.5 2.0 -
[e]
-
[e]

5
[d]
-78 N/A 2.0 1.0 1.0 63 93/7
6
[d]
-50 N/A 2.0 1.0 1.0 47 91/9
7
[d]
-30 N/A 2.0 1.0 1.0 46 90/10
8
[d]
0 N/A 2.0 1.0 1.0 15 85/15
9
[d]
-78 N/A 1.5 1.0 1.0 62 92/8
10
[d]
-78 N/A 1.2 1.0 1.0 47 93/7
11
[d]
-78 N/A 1.0 1.0 1.0 45 90/10
12
[d]
-78 N/A 1.0 2.0 1.0 28 96/4
13
[d]
-78 N/A 3.0 1.0 1.0 58 89/11
[a] A solution of BrFCHCO2Et (3a) in THF was added to a solution of 1a and NaHMDS in THF
within 5 min. [b]
19
F NMR yields were determined using PhCF 3 as the internal standard. [c] The
concentration of reaction solution is 0.05 M (0.2 mmol 1a in 4.0 mL THF). [d] The concentration
of reaction solution is 0.2 M (0.2 mmol 1a in 1.0 mL THF). [e] Complete decomposition of 3a.
Since 3a and the corresponding enolate co-existed under the above mentioned reaction
conditions, the observed low yields could be partially ascribed to the self-Claisen condensation of
3a. To eliminate this competing reaction, an alternative addition sequence was adopted by adding
3a to a solution of 1a and NaHMDS, which increased the yield to 53% with slightly improved
stereoselectivity (Table 2.2, Entry 1). Despite that the addition of HMPA did not show positive
effects, the reaction yield was enhanced by increasing the reaction concentration (Table 2.2,
compare Entries 1 with 2). This was presumably due to the higher reaction order of the aldol-like
addition as compared to the above mentioned enolate decomposition (possibly a second order
reaction versus a first order reaction, respectively). Further reaction condition screening was
focused on alternating reaction temperatures and the proportion of reagents; however, the yields
did not improve (Table 2.2, Entries 5-13).
48

Table 2.3. Reaction condition screening on solvent effects and substrate proportions.

Entry Solvent
1a
(equiv.)
3a (equiv.) Base (equiv.)
Yield
[%]
[a,b]

E/Z
1
[c]
THF 1.5 1.0 NaHMDS (1.0) 50 92/8
2
[c]
THF 1.0 1.0 NaHMDS (1.5) 62 97/3
3
[c]
THF 1.0 2.0 NaHMDS (2.0) 71 91/9
4
[c]
THF 1.0 3.0 NaHMDS (3.0) 33 87/13
5
[d]
toluene 1.0 2.0 NaHMDS (2.0) 10 49/51
6
d]
1,2-dimethoxyethane 1.0 2.0 NaHMDS (2.0) -
[c]
-
[c]

7
[d]
Et 2O 1.0 2.0 NaHMDS (2.0) -
[c]
-
[c]

8
[d]
THF 1.0 2.0 KHMDS (2.0) 30 94/6
9
[d]
THF 1.5 2.0 NaOtBu (2.0) 45 84/16
[a] A solution of BrFCHCO 2Et (3a, 0.4 mmol) in THF (1 mL) was added to a solution of 1a and
base in THF at - 78
o
C using syringe pump over 3 hrs. (ca. 0.13 M/h). [b]
19
F NMR yields were
determined using PhCF 3 as the internal standard. [c] Severe decomposition of 3a.
It was recognized that a quick addition of 3a (ca. 2.4 M/h) could lead to high local concentration
of 3a-enolate, thereby favoring the decomposition reaction over the desired addition reaction. A
syringe pump was therefore utilized to enable a significantly lower addition rate of 3a (ca. 0.13
M/h, Table 2.3, Entries 1-2). The product was obtained in 71% yield by employing 1a, 3a and
NaHMDS in a molar ratio of 1.0:2.0:2.0, respectively (Table 2.3, Entry 3). Further attempts to
enhance the efficacy of the reaction by varying solvents and bases were not successful (Table 2.3,
Entries 5-9).

49

Table 2.4. Preparation of E-monofluoroalkenoates using N-phenyl nitrones 1 and α-bromo-α-
fluoroacetate 3.

Entry
[a]
R
Yield
[%]
[b]

E/Z Entry
[a]
R
Yield
[%]
[b]

E/Z
1

71(56) 90/10 9

30 (24) 67/33
2

15(10) 90/10 10

81(80) 93/7
3

39(28) 94/6 11

68(61) 97/3
4

54(43) 92/8 12

72(63) 94/6
5

60(44) 99/1 13

60(52) 90/10
6

22(21) 90/10 14

-
[c]
-
[e]

7

-
[c]
-
[e]

15

-
[c]
-
[e]

8

-
[d]
-
[e]

[a] The reaction was carried out as follows: A solution of 3a (2.0 mmol ) was added into a solution
of 1 (1.0 mmol ) and NaHMDS (2.0 mmol ) in 5.0 mL THF at -78
o
C using syringe pump over 3hrs.
(ca. 0.13 M/h). [b] The yields are illustrated in the form of:
19
F NMR yield % (isolated yield %).
[c] No major product was observed in the
19
F NMR spectrum due to a severe decomposition. [d]
Complex mixture. [e] Not isolated.
50

Table 2.4 outlines the substrate scope of the present protocol. A variety of aromatic nitrones
readily reacted with 3a to afford α-fluoroalkenoates 4 with high E/Z selectivity. 4c was obtained in
poor yield probably because of the lability of the cyano group under basic conditions,
16
whereas
the low yield of 4f was likely due to the ipso substitution of the nitro group with strong
nucleophiles.
17
As indicated by Entries 1, 4, 5, and 10-13 in Table 2.4, the electron-withdrawing
ability of substituents was found to exert little influence on reaction yields. Nevertheless, the low
reactivity of nitrones bearing ortho-substituents and bulky aryl groups indeed revealed the pivotal
role of steric effects (Table 2.4, Entries 2, 7, 8, 14 and 15). Noticeably, nitrones 1i also participated
in the present transformation to render an E-isomer as the major product; however, with low yield
and reduced stereoselectivity (Table 2.4, Entry 9).
Scheme 2.2. Investigation of N-substituent effects in the reaction between nitrones and α-bromo-
α-fluoroacetate 3a. The indicated relative configuration of 5a was confirmed by X-ray diffraction.
Other diastereoisomers were not observed.
To modulate the reactivity of nitrones, we explored the N-substituent effects in the present
reaction. By using N-methyl, ethyl, and isopropyl nitrones under the above mentioned reaction
conditions, our initial investigation led to the complete decomposition of 3a (Scheme 2.2). These
unsuccessful reactions with i-iii could be probably ascribed to the acidity of α-protons on the N-
alkyl groups, which not only consumed the base but also diminished the reactivity of the nitrones
(Scheme 2.2).
18
N-tert-butyl nitrones (2a) was thus chosen to react with 3a. Instead of α-
fluoroalkenoate 4a, isoxazolidinone (5a) and the corresponding dehydrobrominated product
isoxazolone (6a) were isolated and their structures were confirmed by X-ray diffraction (Scheme
2.2 and Figure 2.1).
19

51

Table 2.5. Reaction condition optimization of isoxazolidinone forming reaction.

Entry Base (equiv.) 3a (equiv.) 5a yield (%)
[a,b]
6a yield (%)
[b]

1 NaHMDS (2.0) 2.0 45 22
2 NaHMDS (1.0) 2.0 10 0
3 NaHMDS (1.5) 2.0 20 0
4 NaHMDS (3.0) 2.0 0 37
5
[d]
NaHMDS (4.0) Br (2.0) 0 0
5
[c]
NaHMDS (4.0) 4.0 54 0
6
[d]
KHMDS (3.0) 2.0 0 0
7 LiHMDS (3.0) 2.0 0 39
9
[d]
tBuOK (3.0) Br (2.0) 0 0
10
[d]
tBuONa (3.0) Br (2.0) 0 0
11 NaHMDS (3.0) Cl (2.0) 0 37
12 NaHMDS (3.0) I (2.0) 0 17
[a] A solution of 2a and base in THF (0.5 mL) was added XFCHCO 2Et (3, 0.4 mmol) in THF (1
mL) at - 78
o
C using a syringe pump over 3 hrs. (ca. 0.13 M/h) [b]
19
F NMR yield were determined
using PhCF 3 as the internal standard. [c] A solution of base (0.8 M) and and another solution of 3
(0.4 M) were added simultaneously using syringe pump over 3 hrs. [d] Complete decomposition of
3.
After a careful screening, the optimal reaction conditions were achieved with 2a, NaHMDS,
and 3 in a molar ratio of 1.0:2.0:2.0, respectively (Table 2.5, Entry 1). Similar to the
fluoroalkenoates-forming reaction described above, the present reaction also required the slow
addition of 3 into reaction mixture using a syringe pump. It is worth mentioning that 5a could also
be formed exclusively in 54 % yield when NaHMDS and 3 were simultaneously added to 2a via a
syringe pump (Table 2.5, Entry 5).
With the optimal reaction conditions in hand, we examined the substrate scope of this reaction.
As shown in Table 2.6, a variety of N-tert-butyl substituted nitrones reacted with 3a to afford 5 and
6 with moderate overall yields (Table 2.6, Entry 1-5). Nevertheless, sterically hindered substrates
demonstrated rather low reactivity (Table 2.6, Entries 6 and 7). Differing from the
fluoroalkenoation reaction, naphthyl substituted nitrones (2i and 2j) were found to be inactive
(Table 2.6, Entries 9 and 10). Nitrone 2h was found to be incompatible with the present reaction
(Table 2.6, Entry 8), although its counterpart 1i could participate in the fluoroalkenoate-forming
reaction.
52

Table 2.6. Preparation of isoxazolidinones using N-tert-butyl nitrones 2 and α-bromo-α-
fluoroacetate 3a.

Entry
[a]
Ar
19
F NMR yield
(%)
[b]
5/6
isolated yield
(%) 5/6
Entry
[a]
Ar
19
F NMR yield
(%)
[b]
5/6
isolated yield
(%) 5/6
1

45/35 40/28 6

-
[c]
-
[d]

2

64/0 48/0 7

-
[c]
-
[d]

3

30/14 25/11 8

-
[c]
-
[d]

4

51/15 43/13 9

2/0 -
[d]

5

39/15 30/14 10

26/0 21/0
[a] The reaction was carried out by syringe pumping 3a (2.0 mmol in 5 mL THF) into a mixture of
2 (1.0 mmol) and NaHMDS (how much?) in 5 mL THF at -78
o
C over 3 hrs. (ca. 0.13 M/h). [b]
19
F
NMR yield were determined using PhCF 3 as the internal standard. [c] Complete decomposition of
3a. [d] Not isolated. [e] The indicated relative configuration of 5 was deduced by
19
F NMR
spectroscopy. Other diastereoisomers were not observed.
53

Scheme 2.3. Elucidation of possible reaction pathways based on the detection of by-products and
side products. A. Desired reaction and key reaction intermediates; B. observed and isolated species;
C. plausible reaction pathways; D. rationalization of imine formation.
54

To gain in-depth insight into these two reactions, we have performed detailed experimental and
computational mechanistic studies. As depicted in Scheme 2.2-A, these reactions have been
proposed to initially undergo an addition reaction to generate an aldol-type key reaction
intermediate, which leads to the formation of alkenoate product 4 and isoxazolidinone product 5.
The GC-MS analysis of the reaction mixture of 3-enolate with N-phenyl nitrone 1a revealed the
existence of imine 9a aside from nitrobenzene 8a
20
and fluoroalkenoate 4a (Scheme 2.2-B, left).
Although a four-membered ring intermediate 7 (R = Ph) can provide a rationale for this observation,
we found that the observed imine 9a can in fact be formed via the reaction between N-phenyl
nitrone 1 and NaHMDS (Scheme 2.2-D). In addition, 1,2-oxazetidine 7e was isolated as a side
product from the reaction of N-tert-butyl nitrone 2e with 3-enolate in 15% yield. Considering the
essential stability of 7e at 50 ° C and the inertness of many other 1,2-oxazetidines,
21,22
phenyl-
substituted 7 can be presumably ruled out as key reaction intermediates (Scheme 2.2-C, TS1).
Similarly, isoxazolidinone 5a was also shown to be fairly stable at elevated temperature (-50
o
C),
therefore excluding intermediacy of isoxazolidinone in the olefination reaction.

Figure 2.1. X-ray crystal structures of 5a, 6a and 7e.
27

To decipher the detailed mechanistic profiles of the present reactions, we have performed DFT
calculations at the M06-2X/6-311+G(d,p)//B3LYP/6-31+G(d,p) level of theory in Gaussian 09.
23,24

Solvent effects of THF were included implicitly through the self-consistent reaction field approach,
as implemented in the default PCM model.
25
Thermal and entropic corrections were obtained by
frequency analysis at the B3LYP/6-31+G(d,p) level in THF. The frequency analysis confirmed that
all considered ground structures were true minima on the PES. The transition state structures were
indicated by a single imaginary frequency.

55

Figure 2.2. Calculated thermodynamics and kinetics of the aldol and [3+2] reactions between
nitrones and α-bromo-α-fluoroacetate enolate.
As depicted in Figure 2.2, the barriers (ΔG
‡
TS1e and ΔG
‡
TS1f) to the nitrones-enolate [3+2]
cycloaddition
13(f),26
were calculated to be +13.5~+16.0 kcal/mol. In comparison, the aldol-type
addition of 3-enolate to N-phenyl nitrone 1a is kinetically more favorable with the corresponding
activation energies ranging from +2.3 to +4.7 kcal/mol (Figure 2.2). Among the four possible aldol-
type transition states, TS1b is the most preferential structure, which also leads to a
thermodynamically favorable aldol-type adduct with a corresponding ΔG IM1b of -19.0 kcal/mol.
Similarly, the reaction between 3-enolate and N- tert-butyl nitrone 2a also preferentially adopts the
aldol-type addition pathway via the TS2b transition state structure. However, this reaction is
kinetically and thermodynamically less feasible than the corresponding reaction with N-phenyl
nitrone 1a.
Following the above mentioned results, further calculations focused on elucidating different
reaction pathways toward the observed products. As shown in Figure 2.3, through the transition
state TS1b, an aldol-type adduct can be formed as IM1b, which can rearrange to IM1b’ with
similar thermostability. The former can undergo an elimination reaction with a barrier of +25.4
kcal/mol to generate the E-fluoroalkenoate 4a. Although the isoxazolidinone formation reaction
toward 5-Ph was also found to be kinetically feasible, such a reaction is thermodynamically
unfavorable. Similarly, the aldol-type addition of 2a also leads to the formation of IM2b and IM2b’.
Despite that E-fluoroalkenoate 4a and 1,2-oxazetidine 7-tert-Bu are thermodynamically preferred
products, the corresponding reactions are kinetically impeded by high activation barriers of +40.6
and +29.1 kcal/mol, respectively. In comparison, the formation of isoxazolidinone 5-tert-Bu,
56

although thermodynamically unfavorable, was calculated to be kinetically feasible with a barrier
of +22.4 kcal/mol.

Figure 2.3. Calculated reaction pathways of N-phenyl-substituted nitrones (Left) and N-tert-butyl-
substituted nitrones (Right).
In other words, the reaction between 2a and 3 leads to equilibrium between IM2b’ and
isoxazolidinone 5-tert-Bu, which can shift to the latter by acidic work-up of NaOMe side product.
Overall, with N-phenyl substituted 1a, the generation of fluoroalkenoates is favored by its low
kinetic barrier. However, due to the relatively high barrier to the olefination reaction, IM2b’ can
only undergo the 5-membered ring-forming reaction to generate isoxazolidinone 5-tert-Bu. It is
worth mentioning that the ring-opening reactions of 7-Ph and 7-tert-Bu were calculated to possess
barriers of ca. +40 kcal/mol (See 2.4.6 for details). This is in good agreement with our experimental
results, which excludes the 4-membered ring opening reaction as a plausible pathway toward
fluoroalkenoates.
Noticeably, the formation of 1,2-oxazetidine 7-Ph was calculated to be kinetically and
thermodynamically favorable, which is inconsistent with our experimental observation. Moreover,
the calculation of Z-olefination demonstrated a low barrier (ΔG TS
‡
= +1.9 kcal/mol) relative to the
observed E-olefination pathway (See 2.4.6 for details). It is likely that this is due to specific THF-
Na
+
interactions, which have not been considered in our implicit solvation calculations. More
detailed investigations of these reaction pathways are still needed in future work.
57

Figure 2.4. Correlations of steric and electronic parameters with calculated Gibbs free energies of
reaction key intermediates and transition states. A. Calculated transition states and reaction key
intermediates; B. steric and electronic parameters of N-substituents; C. calculated Gibbs Free
Energies (kcal/mol); D. ΔG-steric/electronic parameters correlation coefficients (R
2
).
We have further calculated the reaction of 3-enolate with N-methyl and N-vinyl (Figure 2.4-A
and C). Given the N-substituent’s electronegativities χ P,
28
Hammett’s σ para parameters,
29
Taft’s
steric parameters E s
30
and Charton’s steric parameters υ (Figure 2.4-B),
31
various correlations can
be established with our computational results. As shown in Figure 2.4-D, the substituent effects in
58

aldol reaction step can be primarily attributed to electronic effects, as reflected by the high
correlation coefficients of ΔG IM and ΔG TS
‡
with σ para. Despite that ΔG IM also correlates with E s and
υ to some extent (R
2
≈ 0.4), the relatively weaker dependence suggest the diminished role of steric
effects. On the other hand, the transition state energies of the olefination reaction correlate with
both electronic and steric parameters of the N-substituents with moderate correlation coefficients,
respectively. Although the electronic effects are predominant, the sterics of the N-substituents also
has noticeable contribution to the overall substituent effects. According to the strong σ para-ΔG IM
and σ para-ΔG TS
‡
correlations, the electronic effects also operate as the major contributor to the
overall substituent effects in the 5-membered ring forming reaction. On this basis, we can conclude
that the observed different reactivities of 1a and 2a are mainly due to the electronic effects of the
N-substituents. In other words, the phenyl ring in 1a can facilitate the formation of nitrosobenzene
as a by-product through π-conjugation, which can stabilize the transition state during the olefination
reaction. However, the tert-Bu group would increase the charge density and the nucleophilicity of
the N-O
-
moiety, therefore enabling the 5- membered ring-forming reaction. This hypothesis is
supported by the significant stabilization of IM2b’ and TS6b relative to IM2b’ and TS4b,
respectively (Figure 2.3).

59

2.3 Conclusion
In conclusion, we report a one-step reaction between ethyl fluorobromoacetate and nitrones. By
altering the N-substituents of nitrones, both fluorinated alkenoates and isoxazolidinones can be
obtained with high stereoselectivity. Experimental mechanistic studies have provided convincing
evidence for possible reaction pathways. The computational study has further revealed the
mechanistic aspects of the reactions. By correlating steric and electronic parameters with DFT
calculation results, the observed N-substituent effects have been found to be primarily of electronic
origin as reflected by the good correlation of ΔG and Hammett σ para parameters.

60

2.4 Experimental
Unless otherwise mentioned, all the chemicals were purchased from commercial sources.
Preparative thin layer chromatography was performed to isolate the products using 1500 microns
preparative thin layer chromatography plates 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 standard (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
CFCl 3 at δ 0.00, Mass spectra were recorded on a high resolution mass spectrometer, in the EI,
FAB or ESI modes.
2.4.1 General procedure for the preparation of N-phenyl nitrones (1)
32

To a stirred mixture of nitrobenzene (2.46 g, 20 mmol) and NH 4Cl (1.22 g, 23 mmol) in H 2O
(35 mL) was slowly added zinc dust (90%, 2.84 g, 40 mmol) while maintaining the temperature
below 60 ° C. After stirring for 15 min, the reaction mixture was filtered while still warm (~ 45
o
C)
and the solid was washed with hot water (10 mL) three times. The filtrate was saturated with NaCl
and cooled to 0 ° C. The crude N-phenylhydroxylamine, precipitated from the filtrate, was collected,
dried under vacuum, and recrystallized from hot hexanes.
A solution of phenylhydroxylamine (1.09 g, 10 mmol) and the corresponding aldehyde (10
mmol) in 15 mL ethanol was stirred overnight at room temperature in the absence of light. The
solvent was removed under reduced pressure and the crude product was recrystallized from hot
hexanes to afford the titled product.
(Z)-N-Benzylideneaniline-N-oxide (1a).

White crystal.
1
H NMR (400 MHz, CDCl 3) δ 8.42-8.39 (m, 2H), 7.93 (s, 1H), 7.81-7.76 (m,
2H), 7.52-7.45 (m, 5H).

61

(Z)-N-(2-Bromobenzylidene)aniline N-oxide (1b).

Yellow crystal.
1
H NMR (400 MHz, CDCl 3) δ 9.52-9.49 (m, 1H), 8.42 (s, 1H), 7.81-7.78 (m,
2H), 7.68-7.65 (m, 1H), 7.51-7.44 (m, 5H), 7.32-7.26 (m, 1H).
13
C NMR (100 MHz, CDCl 3) δ
149.6, 133.3, 133.1, 131.9, 130.4, 129.9, 129.6, 129.4, 127.9, 124.3, 122.0. Exact mass calcd for
C 13H 11BrNO [M+H]
+
: 276.0019. Found : 276.0014.
(Z)-N-(3-Cyanobenzylidene)aniline N-oxide (1c).

Yellow crystal.
1
H NMR (400 MHz, CDCl 3) δ 8.86-8.85 (m, 1H), 8.50-8.48 (m, 1H), 7.97 (s,
1H), 7.77-7.70 (m, 3H), 7.60-7.56 (m, 1H), 7.52-7.49 (m, 3H).
13
C NMR (100 MHz, CDCl 3) δ
148.9, 133.7, 132.7, 132.3, 132.0, 131.8, 130.7, 129.6, 129.5, 121.8, 118.4, 113.
(Z)-N-(3-Fluorobenzylidene)aniline N-oxide (1d).

Yellow crystal.
1
H NMR (400 MHz, CDCl 3) δ 8.46-8.43 (m, 1H), 7.94 (s, 1H), 7.90-7.87 (m,
1H), 7.77-7.74 (m, 2H), 7.50-7.40 (m, 4H), 7.19-7.15 (m, 1H).
13
C NMR (100 MHz, CDCl 3) δ
162.7 (d, J = 245.4 Hz), 149.1, 133.6, 132.6 (d, J = 8.9 Hz), 130.4, 130.1 (d, J = 8.2 Hz), 129.4,
125.1 (d, J = 3.0 Hz), 121.9, 118.0 (d, J = 21.7 Hz), 115.3 (d, J = 24.7 Hz).

62

(Z)-N-(4-Fluorobenzylidene)aniline N-oxide (1e).

White crystal.
1
H NMR (400 MHz, CDCl 3) δ 8.47-8.43 (m, 2H), 7.91 (s, 1H), 7.78-7.76 (m,
2H), 7.50-7.47 (m, 3H), 7.17-7.15 (m, 2H).
13
C NMR (100 MHz, CDCl 3) δ 163.81 (d, J = 252.47
Hz), 149.1, 133.6, 131.5 (d, J = 8.3 Hz), 130.2, 129.4, 127.3 (d, J = 3.5 Hz), 121.9, 116.0 (d, J =
21.8 Hz).
(Z)-N-(4-Nitrobenzylidene)aniline N-oxide (1f).

Yellow crystal.
1
H NMR (400 MHz, CDCl 3) δ 8.56-8.54 (m, 2H), 8.33-8.30 (m, 2H), 8.07 (s,
1H), 7.79-7.77 (m, 2H), 7.53-7.52 (m, 3H).
13
C NMR (100 MHz, CDCl 3) δ 149.0, 148.1, 136.3,
132.5, 130.9, 129.5, 129.4, 124.1, 121.9.
(Z)-N-(2, 6-Dimethylbenzylidene)aniline N-oxide (1g).

Yellow crystal.
1
H NMR (400 MHz, CDCl 3) δ 8.10 (s, 1H), 7.81-7.79 (m, 2H), 7.51-7.49 (m,
3H), 7.26-7.24 (m, 1H), 7.13-7.11 (m, 2H), 2.39 (s, 6H).
13
C NMR (126 MHz, CDCl 3) δ 148.79),
138.1, 135.2, 130.4, 129.8, 129.4, 128.6, 127.9, 122.2, 20.3.

63

(Z)-N-(2,4,6-Trimethoxybenzylidene)aniline N-oxide (1h).

White crystal.
1
H NMR (400 MHz, CDCl 3) δ 7.90 (s, 1H), 7.80-7.78 (m, 2H), 7.44-7.42 (m,
3H), 6.16 (s, 2H), 3.85 (s, 6H), 3.84 (2, 3H).
13
C NMR (101 MHz, CDCl 3) δ 163.4, 160.1, 148.9,
130.1, 129.7, 128.9, 122.4, 101.9, 90.9, 56.0, 55.6.
(Z)-N-(3-Phenylallylidene)aniline N-oxide (1i).

Yellow crystal.
1
H NMR (400 MHz, CDCl 3) δ 7.85 (dd, J = 9.7, 0.7 Hz, 1H), 7.77-7.75 (m, 2H),
7.71-7.68 (m, 1H), 7.59-7.57 (m, 2H), 7.48-7.40 (m, 3H), 7.38-7.34 (m, 3H), 7.17 (d, J = 16.2 Hz,
1H).
13
C NMR (100 MHz, CDCl 3)

δ 147.6, 140.2, 136.5, 136.2, 130.2, 129.7, 129.3, 129.1, 127.7,
121.6, 119.2.
(Z)-N-(2-Naphthalenylmethylene)aniline N-oxide (1j).

White crystal.
1
H NMR (400 MHz, CDCl 3) δ 9.45 (m, 1H), 8.08 (s, 1H), 8.02-7.97 (m, 2H),
7.90-7.82 (m, 4H), 7.56-7.48 (m, 5H).
13
C NMR (100 MHz, CDCl 3) δ 149.2, 134.8, 134.5, 133.3,
130.1, 129.6, 129.4, 129.3, 128.3, 128.0, 127.9, 127.7, 126.8, 126.3, 121.9.

64

(Z)-N-(1-Naphthalenylmethylene)aniline N-oxide (1k).

Yellow crystal.
1
H NMR (400 MHz, CDCl 3) δ 9.34 (s, 1H), 8.01-7.99 (m, 2H), 7.85-7.75 (m,
5H), 7.49-7.46 (m, 2H), 7.26-7.13 (m, 2H), 3.93 (s, 3H).
13
C NMR (100 MHz, CDCl 3) δ 150.1,
133.7, 131.7, 131.0, 130.7, 130.1, 129.6, 129.4, 127.2, 127.2, 126.1, 126.0, 125.9, 122.1, 121.8.
(Z)-N-(6-Methoxy-2-naphthalenylmethylene)aniline N-oxide (1l).

Yellow crystal.
1
H NMR (400 MHz, CDCl 3) δ 9.79-9.76 (m, 1H), 8.72 (s, 1H), 8.10-8.08 (m,
1H), 8.03-8.02 (m, 1H), 8.00-7.99 (m, 1H), 7.88-7.81 (m, 4H), 7.49-7.46 (m, 3H), 7.20-7.14 (m,
1H), 3.94 (s, 3H).
13
C NMR (100 MHz, CDCl 3) δ 192.1, 159.4, 149.2, 136.1, 134.8, 131.2, 129.9,
129.31, 129.27, 128.7, 127.0, 126.0, 121.8, 119.6, 106.0, 55.5. Exact mass calcd for C 18H 16NO 2
[M+H]
+
: 278.1176. Found: 278.1177.
(Z)-N-(4-Methoxy-1-naphthalenylmethylene)aniline N-oxide (1m).

Yellow crystal.
1
H NMR (400 MHz, CDCl 3) δ 9.91 (d, J = 8.5 Hz, 1H), 8.59 (s, 1H), 8.37 (dd,
J = 8.3, 1.2 Hz, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.89-7.79 (m, 2H), 7.60-7.42 (m, 5H), 6.94 (d, J =
8.6 Hz, 1H), 4.06 (s, 3H).
13
C NMR (100 MHz, CDCl 3) δ 157.79), 149.9, 132.3, 130.4, 129.6, 129.3,
128.9, 127.7, 125.7, 125.4, 123.2, 121.9, 121.4, 118.8, 103.8, 55.9.

65

(Z)-N-(9-Anthracenylmethylene)aniline N-oxide (1n).

Yellow crystal.
1
H NMR (400 MHz, CDCl 3) δ 8.91 (s, 1H), 8.60 (s, 1H), 8.05-7.98 (m, 6H),
7.60-7.50 (m, 7H).
13
C NMR (100 MHz, CDCl 3) δ 148.8, 133.0, 131.5, 130.6, 130.6, 129.9, 129.5,
129.3, 127.1, 125.7, 125.4, 122.7, 122.3.
(Z)-N-(1-Pyrenylmethylene)aniline N-oxide (1o).

Yellow Crystal.
1
H NMR (400 MHz, CDCl 3) δ 10.11 (d, J = 8.4 Hz, 1H), 8.94 (s, 1H), 8.30-
7.93 (m, 10 H), 7.58-7.55 (m, 3H).
13
C NMR (101 MHz, CDCl 3) δ 150.1, 133.3, 131.4, 131.4, 130.6,
130.2, 129.5, 129.0, 129.0, 127.8, 126.5, 126.4, 126.1, 125.7, 125.3, 124.8, 124.8, 124.7, 123.7,
122.2, 121.5. Exact mass calcd for C 23H 16NO [M+H]
+
: 322.1226. Found: 322.1232.
2.4.2 Preparation of (Z)-N-benzylidenemethanamine oxide (i).
33

A mixture of benzaldehyde (2.12 g, 20 mmol), the hydroxylamine hydrochloride (2.11 g, 25
mmol), MgSO 4 (5.80 g, 50 mmol) and NaHCO 3 (5.28 g, 63 mmol) in CH 2Cl 2 (40 mL) was refluxed
for 6 h. The solution was cooled to room temperature and the solvent was removed under vacuum.
The crude mixture was purified by column chromatography (2:1 hexanes/ethyl acetate) to give i.
(Z)-N-Benzylidenemethanamine oxide (i).

Colorless oil.
1
H NMR (400 MHz, CDCl 3) δ 8.23-8.20 (m, 2H), 7.43-7.37 (m, 3H), 7.26 (s, 1H),
3.88 (s, 3H).
66

2.4.3 General procedure for preparation of (Z)-aryl-N-alkylnitrones (ii, iii, and 2a-
j).
34

To a solution of the corresponding aldehyde (10 mmol) in EtOH (100 mL) was added
nitroalkane (20 mmol) in the case of 2 and zinc (40 mmol). The reaction mixture was cooled to 0
o
C, and glacial acetic acid (60 mmol) was added dropwise. The reaction mixture was stirred at room
temperature for 6 h, and then was kept at 0
o
C overnight. The precipitate was filtered off and washed
with EtOH (10×3 mL). The combined filtrate was evaporated and the resulting solid was purified
by column chromatography (hexanes/ethyl acetate = 20:1).
(Z)-N-Benzylideneethanamine oxide (ii).

Yellow oil.
1
H NMR (400 MHz, CDCl 3) δ 8.25-8.22 (m, 2H), 7.43-7.41 (m, 4H), 4.01 (q, J =
7.3 Hz, 2H), 1.58 (t, J = 7.3 Hz, 3H).
(Z)-N-Benzylidenepropan-2-amine oxide (iii).

Yellow oil.
1
H NMR (400 MHz, CDCl 3) δ 8.26-8.23 (m, 2H), 7.45 (s, 1H), 7.42-7.40 (m, 3H),
4.23 (h, J = 6.6 Hz, 1H), 1.51 (d, J = 6.6 Hz, 6H).
(Z)-N-Benzylidene-tert-butanamine oxide (2a).

White solid.
1
H NMR (400 MHz, CDCl 3) δ 8.30-8.27 (m, 2H), 7.55 (s, 1H), 7.42-7.40 (m, 3H),
1.62 (s, 9H).

67

(Z)-N-2-Bromobenzylidene-tert-butanamine oxide (2b).

White solid.
1
H NMR (400 MHz, CDCl 3) δ 9.35-9.33 (m, 1H), 8.08 (s, 1H), 7.62-7.59 (m, 1H),
7.38-7.37 (m, 1H), 7.22 (m, 1H), 1.63 (s, 9H).
(Z)-N-3-Cyanobenzylidene-tert-butanamine oxide (2c).

White solid.
1
H NMR (400 MHz, CDCl 3) δ 8.37-8.36 (m, 2H), 7.67-7.61 (m, 2H), 7.61 (s, 1H),
1.61 (s, 9H).
(Z)-N-3-Fluorobenzylidene-tert-butanamine oxide (2d).

White solid.
1
H NMR (400 MHz, CDCl 3) δ 8.38-8.34 (m, 1H), 7.77-7.75 (m, 1H), 7.56 (s, 1H),
7.37-7.33 (m, 1H), 7.11-7.09 (m, 1H), 1.61 (s, 9H).
(Z)-N-4-Fluorobenzylidene-tert-butanamine oxide (2e).

White solid.
1
H NMR (400 MHz, CDCl 3) δ 8.35-8.31 (m, 2H), 7.52 (s, 1H), 7.11-7.07 (m, 2H),
1.61 (s, 9H).
68

(Z)-N-2,6-Dimethylbenzylidene-tert-butanamine oxide (2f).

White solid.
1
H NMR (400 MHz, CDCl 3) δ 7.74 (s, 1H), 7.17-7.15 (m, 1H), 7.05-7.03 (m, 2H),
2.25 (s, 6H), 1.64 (s, 9H).
(Z)-N-2,4,6-Trimethoxybenzylidene-tert-butanamine oxide (2g).

Yellow oil.
1
H NMR (400 MHz, CDCl 3) δ 7.48 (s, 1H), 6.12 (s, 2H), 3.81 (s, 9H), 1.59 (s, 9H).
(Z)-N-(E)-3-Phenylallylidene-tert-butanamine oxide (2h).

Yellow oil.
1
H NMR (400 MHz, CDCl 3) δ 7.56-7.50 (m, 3H), 7.45-7.42 (m, 1H), 7.37-7.29 (m,
3H), 7.05-6.98 (m, 1H), 1.56 (s, 9H).
13
C NMR (100 MHz, CDCl 3) δ 138.4, 136.4, 132.7, 129.1,
128.9, 127.3, 119.4, 69.3, 28.2. Exact mass calcd for C 13H 18NO [M+H]
+
: 204.1383. Found:
204.1386.
(Z)-N-Naphthalen-2-ylmethylene-tert-butanamine oxide (2i).

Yellow oil.
1
H NMR (400 MHz, CDCl 3) δ 9.43 (s, 1H), 7.93-7.91 (m, 1H), 7.84-7.80 (m, 3H),
7.71 (s, 1H), 7.52-7.48 (m, 2H), 1.67 (s, 9H).

69

(Z)-N-Naphthalen-1-ylmethylene-tert-butanamine oxide (2j).

Yellow oil.
1
H NMR (400 MHz, CDCl 3) δ 9.43-9.42 (m, 1H), 8.33 (s, 1H), 7.93-7.91 (m, 1H),
7.82-7.79 (m, 2H), 7.50-7.43 (m, 3H), 1.54 (s, 9H).
2.4.4 General Procedure for Reaction between Ethyl monofluorobromoacetate 3a
and (Z)-aryl-N-phenylnitrones 1 and (Z)-aryl-N-tert-butylnitrones 2
Nitrones 1, or 2 and NaHMDS were massed under nitrogen atmosphere (nitrogen filled glovebox)
in a 20 mL sealed tube. To a solution of nitrones 1 or 2 (1 mmol) and NaHMDS (2 mmol) in THF (2
mL) at - 78
o
C was added BrFCHCOOEt 3a (2 mmol in 3 mL) with syringe pump during 3 hrs. The
reaction mixture was then warmed to room temperature. PhCF 3 (0.5 mL 0.1 M solution in THF) was
added and the
19
F NMR spectrometry was obtained. HCl (1 M, 2 mL, in the case of nitrones 1) or NH 4Cl
(aq, 2 mL, in the case of nitrones 2) was added and the solution was extracted with EtOAc (3× 2 mL).
The combined organic phase was dried over MgSO 4, evaporated under vacuum and purified with
preparative thin layer chromatography (Hexane/CH 2Cl 2 10:1).
(E)-Ethyl-2-fluoro-3-phenylacrylate (4a).

56% yield. Colorless oil. E/Z: 90:10.
1
H NMR (400 MHz, CDCl 3) δ 7.47-7.44 (m, 2H), 7.36-7.34
(m, 3H), 6.92 (d, J = 22.2 Hz, 1H), 4.25 (q, J = 7.1 Hz, 2H), 1.24 (t, J = 7.1 Hz, 3H).
19
F NMR (376
MHz, CDCl 3) δ -117.3 (d, J = 22.2 Hz, E), -125.4 (d, J = 35.2 Hz, Z).

70

(E)-Ethyl-2-fluoro-3-(2-bromophenyl)acrylate (4b).

10% yield. White solid. E/Z: 90:10.
1
H NMR (400 MHz, CDCl 3) δ 7.58-7.18 (m, 4H), 6.92 (d, J =
19.2 Hz, 1H), 4.18 (q, J = 7.1 Hz, 2H), 1.15 (t, J = 7.1 Hz, 3H).
19
F NMR (376 MHz, CDCl 3) δ -117.0
(d, J = 19.2 Hz, E), -124.8 (d, J = 34.1 Hz, Z).
13
C NMR (100 MHz, CDCl 3)

δ 160.2 (d, J = 36.1 H),
148.2 (d, J = 258.2 Hz), 132.4, 131.4 (d, J = 2.2 Hz), 130.0, 128.9 (d, J = 12.7 Hz), 126.9, 120.5 (d, J =
27.1 Hz), 115.8, 61.9, 13.9. Exact mass calcd for C 11H 10O 2FBr [M]: 271.9848. Found: 271.9844.
(E)-Ethyl-2-fluoro-3-(3-cyanophenyl)acrylate (4c).

28% yield. White solid. E/Z: 96:4.
1
H NMR (400 MHz, CDCl 3) δ 7.76-7.75 (m, 1H), 7.64-7.59 (m,
1H), 7.48-7.44 (m, 1H), 7.26-7.21 (m, 1H), 6.85 (d, J = 20.7 Hz, 1H), 4.24 (q, J = 7.1 Hz, 2H), 1.24 (t,
J = 7.1 Hz, 3H).
19
F NMR (376 MHz, CDCl 3) δ -117.3 (d, J = 20.6 Hz, E), -121.6 (d, J = 33.8 Hz, Z).
(E)-Ethyl-2-fluoro-3-(3-fluorophenyl)acrylate (4d).

43% yield. White solid. E/Z: 92:8.
1
H NMR (400 MHz, CDCl 3) δ 7.34-7.26 (m, 1H), 7.26-7.11 (m,
1H), 7.19-7.17 (m, 1H), 7.05-7.00 (m, 1H), 6.86 (d, J = 21.7 Hz, 1H), 4.25 (q, J = 7.1 Hz, 2H), 1.25 (t,
J = 7.1 Hz, 3H).
19
F NMR (376 MHz, CDCl 3) δ -112.3 (dd, J = 12.1, 7.7 Hz, Z), -113.4 (tt, J = 28.9,
13.1 Hz, 1F, E), -115.7 (d, J = 21.7 Hz, 1F, E), -123.3 (d, J = 34.3 Hz, Z). Exact mass calcd for
C 11H 10O 2F 2 [M]: 212.0649. Found: 212.0644.

71

(E)-Ethyl-2-fluoro-3-(4-fluorophenyl)acrylate (4e).

44% yield. White solid. E/Z: 99:1.
1
H NMR (400 MHz, CDCl 3) δ 8.32-8.162 (m, 1H), 7.55-7.40 (m,
2H), 7.06-7.02 (m, 1H), 6.86 (d, J = 22.3 Hz, 1H), 4.26 (q, J = 7.1 Hz, 2H), 1.26 (t, J = 7.1 Hz, 3H).
19
F
NMR (376 MHz, CDCl 3) δ -109.7 (m, Z), -112.0 (ddq, J = 10.6, 5.4, 2.3 Hz, 1F, E), -117.2 (dd, J = 22.3,
2.3 Hz, 1F, E), -126.5 (d, J = 35.0 Hz, Z).
(E)-Ethyl-2-fluoro-3-(4-nitrophenyl)acrylate (4f).

21% yield. White solid. E/Z: 90:10.
1
H NMR (400 MHz, CDCl 3) δ 8.22-8.19 (m, 2H), 7.61-7.59 (m,
2H), 6.92 (d, J = 20.9 Hz, 1H), 4.26 (q, J = 7.1 Hz, 2H), 1.25 (t, J = 7.1 Hz, 3H).
19
F NMR (376 MHz,
CDCl 3) δ -112.5 (d, J = 20.4 Hz, E), -119.7 (d, J = 33.7 Hz, Z).
(2E, 4E)-Ethyl 2-fluoro-5-phenylpenta-2, 4-dienoate (4i).

24% yield. Colorless oil. E/Z: 70:30.
1
H NMR (400 MHz, CDCl 3) δ 7.74 (dd, J 1 = 15.7 Hz, J 2 = 11.6
Hz, 1H), 7.48 (m, 2H), 7.39-7.27 (m, 3H), 6.78 (d, J = 15.7 Hz, 1H), 6.60 (dd, J 1 = 19.4 Hz, J 2 = 11.6
Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H).
19
F NMR (376 MHz, CDCl 3) δ -123.3 (d, J
= 19.4 Hz, E), -128.6 (d, J = 30.9 Hz, Z).
13
C NMR (100 MHz, CDCl 3) δ 163.3 (d, J = 42.6 Hz), 163.2
(d, J = 249.9 Hz), 129.8 (d, J = 8.3 Hz), 115.6 (d, J = 21.7 Hz), 109.0, 111.6, 68.5 (d, J = 23.9 Hz), 62.4,
60.2, 23.5 (d, J = 0.8 Hz), 13.7.

72

(E)-Ethyl-2-fluoro-3-(naphthalen-2-yl)acrylate (4j).

80% yield. White solid. E/Z: 93:7.
1
H NMR (400 MHz, CDCl 3) δ 7.95 (s, 1H), 7.85-7.81 (m, 3H),
7.61-7.58 (m, 1H), 7.52-7.50 (m, 2H), 7.08 (d, J = 22.4 Hz, 1H), 4.28 (q, J = 7.1 Hz, 2H), 1.24 (t, J =
7.1 Hz, 3H).
19
F NMR (376 MHz, CDCl 3) δ -116.6 (d, J = 22.4 Hz, E), -125.2 (d, J = 35.3 Hz, Z).
13
C
NMR (100 MHz, CDCl 3) δ 160.7 (d, J = 36.1 Hz), 147.3 (d, J = 255.0 Hz), 133.3, 133.0, 129.6, 128.5
(d, J = 9.4 Hz), 128.4, 127.8, 127.7, 127.2 (d, J = 2.3 Hz), 126.9, 126.5, 121.8 (d, J = 26.2 Hz), 61.8,
14.1.
(E)-Ethyl-2-fluoro-3-(naphthalen-1-yl)acrylate (4k).

61% yield. White solid. E/Z: 97:3.
1
H NMR (400 MHz, CDCl 3) δ 7.69-7.63 (m, 4H), 7.32-7.30 (m,
2H), 7.26-7.25 (m, 1H), 7.15 (d, J = 19.3 Hz, 1H), 3.85 (q, J = 7.1 Hz, 2H), 0.73 (t, J = 7.1 Hz, 3H).
19
F
NMR (376 MHz, CDCl 3) δ -116.0 (d, J = 19.3 Hz, E), -125.9 (d, J = 33.1 Hz, Z).
13
C NMR (100 MHz,
CDCl 3) δ 160.4 (d, J = 36.9 Hz), 148.5 (d, J = 256.0 Hz), 133.4, 131.5 (d, J = 2.5 Hz), 128.9, 128.9 (d,
J = 9.1 Hz), 128.6, 127.3 (d, J = 2.6 Hz), 126.5, 126.1, 125.1, 124.6, 119.0 (d, J = 24.0 Hz), 61.6, 13.6.
(E)-Ethyl-2-fluoro-3-(6-methoxynaphthalen-2-yl)acrylate (4l).

63% yield. White solid. E/Z: 94:6.
1
H NMR (400 MHz, CDCl 3) δ 7.91 (s, 1H), 7.73-7.69 (m, 2H),
7.59-7.57 (m, 1H), 7.16-7.12 (m, 2H), 7.04 (d, J = 22.7 Hz, 1H), 4.28 (q, J = 7.1 Hz, 2H), 3.93 (s, 3H),
1.25 (t, J = 7.1 Hz, 3H).
19
F NMR (376 MHz, CDCl 3) δ -118.1 (d, J = 22.7 Hz, E), -127.0 (d, J = 35.6
Hz, Z).
13
C NMR (100 MHz, CDCl 3) δ 160.9 (d, J = 35.9 Hz), 158.6, 146.8 (d, J = 253.5 Hz), 134.7,
130.0, 129.8 (d, J = 3.6 Hz), 128.5, 127.9 (d, J = 2.2 Hz), 126.5, 126.2 (d, J = 9.4 Hz), 122.2 (d, J =
26.5 Hz), 119.4, 105.8, 61.8, 55.5, 14.1. Exact mass calcd for C 16H 16O 3F [M+H]
+
: 275.1078. Found:
275.1081.
73

(E)-Ethyl-2-fluoro-3-(6-methoxynaphthalen-2-yl)acrylate (4l).

52% yield. White solid. E/Z: 90:10.
1
H NMR (400 MHz, CDCl 3) δ 8.34-8.31 (m, 1H), 7.84-7.82 (m,
1H), 7.55-7.46 (m, 3H), 7.33 (d, J = 20.1 Hz, 1H), 6.81 (d, J = 8.0 Hz, 1H), 4.12 (q, J = 7.1 Hz, 2H),
4.02 (s, 3H), 1.06 (t, J = 7.1 Hz, 3H).
19
F NMR (376 MHz, CDCl 3) δ -117.3 (d, J = 20.1 Hz, E), -128.6
(d, J = 33.8 Hz, Z).
13
C NMR (100 MHz, CDCl 3) δ 160.6 (d, J = 36.4 Hz), 156.2, 147.9 (d, J = 254.5
Hz), 132.5, 128.2 (d, J = 2.5 Hz), 127.0, 125.4, 124.2, 122.6 (d, J = 5.8 Hz), 120.5 (d, J = 9.2 Hz), 119.4
(d, J = 24.5 Hz), 103.1, 61.4, 55.6, 13.8. Exact mass calcd for C 16H 16O 3F [M+H]
+
: 275.1078. Found:
275.1080.
4-Bromo-2-(tert-butyl)-4-fluoro-3-phenylisoxazolidin-5-one (5a).

40% yield. White solid.
1
H NMR (400 MHz, CDCl 3) δ 7.77 (br, 1H), 7.42-7.26 (br, 4H), 4.62 (d, J
= 18.2 Hz, 1H), 1.12 (s, 9H).
19
F NMR (376 MHz, CDCl 3) δ -122.86 (d, J = 18.2 Hz).
13
C NMR (126
MHz, CDCl 3) δ 164.9 (d, J = 24.7 Hz), 134.2, 129.9, 128.6 (br), 128.3, 99.4 (d, J = 269.9 Hz), 72.5 (d,
J = 21.2 Hz), 62.6, 26.1. Exact mass calcd for C 13H 15NO 2FBr [M]: 315.0270. Found: 315.0284.
2-(tert-Butyl)-4-fluoro-3-phenylisoxazol-5(2H)-one (6a).

28% yield. White solid.
1
H NMR (400 MHz, CDCl 3) δ 7.53-7.41 (m, 5H), 1.14 (s, 9H).
19
F NMR
(376 MHz, CDCl 3) δ -177.94 (s).
13
C NMR (126 MHz, CDCl 3) δ 162.7 (d, J = 25.3 Hz), 151.4 (d, J =
12.6 Hz), 133.4 (d, J = 256 Hz), 131.2, 129.0, 128.7 (d, J = 1.4 Hz), 127.3 (d, J = 3.4 Hz), 65.9, 27.0.
Exact mass calcd for C 13H 14NO 2F [M]: 235.1009. Found: 235.1015.

74

4-Bromo-2-(tert-butyl)-4-fluoro-3-(2-bromophenyl)isoxazolidin-5-one (5b).

48% yield. White solid.
1
H NMR (400 MHz, CDCl 3) δ 7.77 (dd, J = 8.0, 1.7 Hz, 1H), 7.55 (dd, J =
8.0, 1.3 Hz, 1H), 7.33 (td, J = 7.6, 1.3 Hz, 1H), 7.22 (td, J = 7.6, 1.7 Hz, 1H), 5.38 (d, J = 16.9 Hz, 1H).
1.03 (s, 9H).
19
F NMR (376 MHz, CDCl 3) δ -119.3 (d, J = 16.9 Hz).
13
C NMR (101 MHz, CDCl 3) δ
164.7 (d, J = 24.9 Hz), 133.8, 133.2, 133.1, 131.2, 126.8, 123.8, 100.1 (d, J = 272.5 Hz), 70.2 (d, J =
21.7 Hz), 62.9, 26.1. Exact mass calcd for C 13H 15NO 2FBr 2 [M+H]
+
: 393.9448. Found: 393.9449.
4-Bromo-2-(tert-butyl)-4-fluoro-3-(3-cyanophenyl)isoxazolidin-5-one (5c).

25% yield. White solid.
1
H NMR (500 MHz, CDCl 3) δ 7.92 (br, 1H), 7.73 (d, J = 7.1 Hz, 2H), 7.37
(br, 1H), 4.69 (d, J = 18.2 Hz, 1H), 1.12 (s, 9H).
19
F NMR (376 MHz, CDCl 3) δ-122.0 (d, J = 18.3 Hz).
13
C NMR (126 MHz, CDCl 3) δ 164.2 (d, J = 24.7 Hz), 139.7, 132.5 (br), 132.0 (br), 130.9 (br), 129.1
(br), 118.2, 114.1, 98.6 (d, J = 271.4 Hz), 71.9 (d, J = 21.5 Hz), 63.0, 26.1. Exact mass calcd for
C 14H 14N 2O 2FBr [M]: 340.0223. Found: 340.0209.
2-(tert-Butyl)-4-fluoro-3-(3-cyanophenyl)phenylisoxazol-5(2H)-one (6c).

11% yield. White solid.
1
H NMR (400 MHz, CDCl 3) δ 7.84-7.78 (m, 2H), 7.63-7.61 (m, 2H), 1.16
(s, 9H).
19
F NMR (376 MHz, CDCl 3) δ-174.57 (s).
13
C NMR (126 MHz, CDCl 3) δ 161.9 (d, J = 25.3
Hz), 148.9 (d, J = 11.9 Hz), 134.3 (d, J = 260.2 Hz), 133.0, 132.8, 131.6 (d, J = 3.5 Hz), 129.6, 129.4
(d, J = 1.5 Hz), 117.7, 115.2, 66.4, 27.0. Exact mass calcd for C 14H 13N 2O 2F [M]: 260.0961. Found:
260.0974.

75

4-Bromo-2-(tert-butyl)-4-fluoro-3-(3-fluorophenyl)isoxazolidin-5-one (5d).

43% yield. White solid.
1
H NMR (399 MHz, CDCl 3) δ 7.48-7.38 (br, 2H), 7.14-7.03 (br, 2H), 4.62
(d, J = 17.5 Hz, 1H), 1.13 (s, 9H).
19
F NMR (376 MHz, CDCl 3) δ -111.8 (br, two signals for two
conformers), -122.4 (d, J = 17.2 Hz).
13
C NMR (100 MHz, CDCl 3) δ 164.6 (d, J = 24.8 Hz), 162.4 (d,
J = 247.0 Hz), 136.8 (br), 130.3 (br), 123.9 (br, two signals for two isomers), 117.0 (br), 115.1 (br), 98.9
(d, J = 270.5 Hz), 71.9 (d, J = 21.8 Hz), 62.8, 26.0. Exact mass calcd for C 13H 14NO 2F 2Br [M]: 333.0176.
Found: 333.0170.
2-(tert-Butyl)-4-fluoro-3-(3-fluorophenyl)phenylisoxazol-5(2H)-one (6d).

13% yield. White solid.
1
H NMR (400 MHz, CDCl 3) δ 7.49 (td, J = 8.0, 5.6 Hz, 1H)., 7.28-7.18 (m,
3H). 1.17 (s, 9H).
19
F NMR (376 MHz, CDCl 3) δ -110.7 (td, J = 8.6, 5.6 Hz, 1F), -176.2 (s, 1F).
13
C
NMR (126 MHz, CDCl 3) δ 162.7 (d, J = 248 Hz), 162.3 (d, J = 25 Hz), 149.7 (dd, J = 9.8, 2.9 Hz),
133.7 (d, J = 256 Hz), 130.9 (d, J = 8.3 Hz), 129.0 (dd, J = 8.7, 3.5 Hz), 124.5 (dd, J = 3.4, 1.9 Hz),
118.3 (d, J = 21.0 Hz), 116.0 (d, J = 23.5 Hz), 66.2, 27.0. Exact mass calcd for C 13H 13NO 2F 2 [M]:
253.0914. Found: 253.0920.
4-Bromo-2-(tert-butyl)-4-fluoro-3-(4-fluorophenyl)isoxazolidin-5-one (5e).

30% yield. White solid.
1
H NMR (400 MHz, CDCl 3) δ 7.77 (br, 1H), 7.21-7.01 (br, 3H), 4.61 (d, J
= 18.1 Hz, 1H). 1.11 (s, 9H).
19
F NMR (376 MHz, CDCl 3) δ -111.0 (m, 1F), -123.0 (d, J = 18.1 Hz, 1F).
13
C NMR (100 MHz, CDCl 3) δ 164.6 (d, J = 24.7 Hz), 163.6 (d, J = 249 Hz), 131.8, 130.0 (d, J = 3.2
Hz), 115.5 (d, J = 21.8 Hz), 99.3 (d, J = 268.9 Hz), 71.8 (d, J = 21.5 Hz), 62.6, 26.1. Exact mass calcd
for C 13H 14NO 2F 2Br [M]: 333.0176. Found: 333.0167.

76

2-(tert-Butyl)-4-fluoro-3-(4-fluorophenyl)phenylisoxazol-5(2H)-one (6e).

14% yield. White solid.
1
H NMR (400 MHz, CDCl 3) δ 7.47 (dd, J = 8.5, 5.2 Hz, 1H), 7.20 (t, J =
8.5 Hz, 1H). 1.15 (s, 9H).
19
F NMR (376 MHz, CDCl 3) δ -107.7 (m, 1F), -177.5 (s, 1F).
13
C NMR (100
MHz, CDCl 3) δ 164.3 (d, J = 253.0 Hz), 162.4 (d, J = 25.2 Hz), 150.4 (d, J = 12.5 Hz), 133.5 (d, J =
255.8 Hz), 130.8 (dd, J = 8.7, 1.6 Hz), 123.2 (t, J = 3.5 Hz), 116.5 (d, J = 22.2 Hz), 66.0 (d, J = 0.9 Hz),
27.0. Exact mass calcd for C 13H 13NO 2F 2 [M]: 253.0914. Found: 253.0923.
Ethyl-2-(tert-butyl)-4-fluoro-3-(4-fluorophenyl)-1,2-oxazetidine-4-carboxylate (7e).

15% yield. White solid.
1
H NMR (400 MHz, CDCl 3) δ 7.61-7.51 (m, 2H), 7.13-6.98 (m, 2H), 5.05
(d, J = 25.3 Hz, 1H), 3.95 (q, J = 7.1 Hz, 2H), 1.16 (s, 1H), 0.91 (t, J = 7.1 Hz, 3H).
19
F NMR (376 MHz,
CDCl 3) δ -90.7 (d, J = 25.3 Hz), -112.6 (tt, J = 8.5, 5.4 Hz).
13
C NMR (100 MHz, CDCl 3) δ 163.3 (d, J
= 42.6 Hz), 163.2 (d, J = 247 Hz), 129.9 (d, J = 3 Hz), 129.8 (d, J = 8.3 Hz), 115.6 (d, J = 21.7 Hz),
110.3 (d, J = 261 Hz), 68.5 (d, J = 23.9 Hz), 62.4, 60.2, 23.5 (d, J = 0.8 Hz), 13.7. Exact mass calcd for
C 15H 20NO 3F 2 [M+H]
+
: 300.1406. Found: 300.1406.
4-Bromo-2-(tert-butyl)-4-fluoro-3-( naphthalen-1-yl)isoxazolidin-5-one (5k).

21% yield. White solid.
1
H NMR (400 MHz, CDCl 3) δ 8.06-8.03 (m, 2H), 7.95-7.92 (m, 2H), 7.63-
7.55 (m, 3H), 5.62 (d, J = 18.5 Hz, 1H). 1.11 (s, 9H).
19
F NMR (376 MHz, CDCl 3) δ -119.3 (d, J = 17.5
Hz).
13
C NMR (100 MHz, CDCl 3) δ 165.2 (d, J = 25.4 Hz), 133.8, 130.7, 130.2, 129.5 (d, J = 2.9 Hz),
128.6, 127.5, 126.2, 125.0, 124.6, 121.7 (d, J = 2.7 Hz), 101.2 (d, J = 270.1 Hz), 66.8 (d, J = 21.2 Hz),
63.0, 26.1. Exact mass calcd for C 13H 14NO 2F 2Br [M]: 333.0176. Found: 333.0167.

77

2.4.5 Elucidation of the Formation of Imine Side-products

78

Aromatic region showed no significant change upon the addition of NaHMDS.

79

80

2.4.6 DFT Calculations on reaction mechanisms
The DFT calculations were performed at the M06-2X/6-311+G(d,p)//B3LYP/6-31+G(d,p) level of
theory in Gaussian 09.
26,28
Solvent effects of THF were included implicitly through the self-consistent
reaction field approach, as implemented in the default PCM model.
29
Thermal and entropic corrections
were obtained by frequency analysis at the B3LYP/6-31+G(d,p) level in THF. The frequency analysis
confirmed that all considered ground structures were true minima on the PES. The transition state
structures were indicated by a single imaginary frequency.
Energetically preferential reaction intermediates and transition states are indicated in red.
Species
Calculations at B3LYP/6-
31+G(d,p) level
Single point calculations at M06-
2X/6-311+G(d,p) level
Thermal
correction
G E
G (E +
Thermal
correction)
Starting materials and products
F -0.014159 -99.992394 -99.962511 -99.976670
Br -0.016176
-
2571.908041 -2574.347474 -2574.363650
Na -0.014429
-
162.235349 -162.189925 -162.204354
NaBr -0.023495
-
2734.171186 -2736.564918 -2736.588413
NaF -0.020582
-
262.263737 -262.198389 -262.218971
NaOMe 0.011234
-
277.472403 -277.421007 -277.409773
enolateNa1 0.022887
-
3100.479282 -3102.869800 -3102.846913
enolateNa2 0.021624
-
3100.479036 -3102.867904 -3102.846280
81

enolateNa3 0.022870
-
3100.479298 -3102.869802 -3102.846932
enolateNa4 0.022891
-
3100.473349 -3102.865201 -3102.842310
enolateNa5 0.021905
-
3100.477247 -3102.865241 -3102.843336
PhNOCHPh 0.168517
-
631.798977 -631.815251 -631.646734
BuNOCHPh 0.200509
-
557.975816 -558.028517 -557.828008
VinylNOCHPh 0.124851
-
478.180160 -478.18505272
-
478.06020172
MeNOCHPh 0.121340
-
440.101073 -440.109849 -439.988509
PhNO 0.066745
-
361.502603 -361.486587 -361.419842
BuNO 0.097017
-
287.676694 -287.697096 -287.600079
VinylNO 0.022906
-
207.879445 -207.85308494
-
207.83017894
MeNO 0.018527
-
169.794767 -169.774548 -169.756021
Eolefin 0.128235
-
636.672255 -636.679452 -636.551217
Zolefin 0.129531
-
636.679876 -636.689212 -636.559681
IMPh4 0.221218
-
924.339294 -998.205318 -997.984100
IMBu4 0.252592
-
924.339294 -924.416688 -924.164096
82

Ph5memproduct 0.180982
-
3454.808502 -3457.270524 -3457.089542
Bu5membproduct 0.214496
-
3380.980153 -3383.482590 -3383.268094
Vinyl5memprd 0.164198
-
3578.651019 -3581.063937 -3580.899739
Me5memprd 0.161161
-
3540.574895 -3542.993361 -3542.832200

Species
Calculations at B3LYP/6-31+G(d,p)
level
Single point calculations at
M06-2X/6-311+G(d,p) level
Thermal correction G E
G (E +
Thermal
correction)
Transition states and intermediates in aldol reaction
Ph3plus2Z 0.216424
-
3732.248544
-
3734.684554
-
3734.468130
Ph3plua2E 0.215722
-
3732.249326
-
3734.687902
-
3734.472180
Ph2 0.213524
-
3732.263788
-
3734.699690
-
3734.486166
Ph2P 0.216393
-
3732.287086
-
3734.735785
-
3734.519392
Ph3 0.213801
-
3732.265713
-
3734.700394
-
3734.486593
Ph3P 0.216891
-
3732.288047
-
3734.736789
-
3734.519898
Ph4 0.214111
-
3732.267662
-
3734.704143
-
3734.490032
83

Ph4P 0.216867
-
3732.288402
-
3734.740858
-
3734.523991
Ph9 0.214853
-
3732.262656
-
3734.701184
-
3734.486331
Ph9P 0.216448
-
3732.289996
-
3734.738832
-
3734.522384
Bu3plus2Z 0.248578
-
3658.411148
-
3660.888956
-
3660.640378
Bu3plua2E 0.247239
-
3658.412895
-
3660.890718
-
3660.643479
Bu9 0.246584
-
3658.424218
-
3660.902797
-
3660.656213
Bu9P 0.248761
-
3658.447844
-
3660.936757
-
3660.687996
Bu14 0.247576
-
3658.424513
-
3660.901434
-
3660.653858
Bu14P 0.249360
-
3658.444246
-
3660.932087
-
3660.682727
Bu3 0.246527
-
3658.428892
-
3660.905111
-
3660.658584
Bu3P 0.249966
-
3658.442668
-
3660.933441
-
3660.683475
Bu4 0.247344
-
3658.430601
-
3660.909790
-
3660.662446
Bu4P 0.249385
-
3658.444320
-
3660.936714
-
3660.687329
Vinyl4b 0.169836
-
3578.650579
-
3581.075045
-
3580.905209
Vinyl4P2 0.172815
-
3578.665694
-
3581.106727
-
3580.933912
84

Me4b 0.167483
-
3540.560654
-
3542.993456
-
3542.825973
Me4P 0.170101
-
3540.577022
-
3543.021647
-
3542.851546
Transition states in olefination reaction
Ph2CNcleave 0.213043
-
3732.255278
-
3734.687523
-
3734.474480
Ph2Brleave 0.217371
-
3732.265445
-
3734.697656
-
3734.480285
Ph4PCNleave 0.214192
-
3732.258185
-
3734.692304
-
3734.478112
Ph9CNcleave 0.214213
-
3732.267506
-
3734.704921
-
3734.490708
Ph4P1stepc 0.214358
-
3732.258869
-
3734.697756
-
3734.483398
Bu4PCNcleave 0.250564
-
3658.438410
-
3660.931300
-
3660.680736
Bu4PBrleaving 0.255406
-
3658.433567
-
3660.891194
-
3660.635788
Bu14PBrleave 0.248294
-
3658.430933
-
3660.899650
-
3660.651356
Bu2PCNcleave 0.247169
-
3658.413821
-
3660.884924
-
3660.637755
Bu9PCNcleave 0.246062
-
3658.427743
-
3660.903008
-
3660.656946
Vinylolefination 0.168904
-
3578.634423
-
3581.054587
-
3580.885683
Meolefination 0.166249
-
3540.551075
-
3542.977956
-
3542.811707

85

Species
Calculations at B3LYP/6-
31+G(d,p) level
Single point calculations at
M06-2X/6-311+G(d,p) level
Thermal
correction
G E
G (E +
Thermal
correction)
Transition states and intermediates in 4-membered and 5-membered ring forming reactions
Ph5memSM1 0.218831
-
3732.289192
-
3734.746178
-
3734.527347
Ph5memSM1E 0.218057
-
3732.287110
-
3734.742745
-
3734.524688
Ph5memTS1 0.213682
-
3732.260766
-
3734.700427
-
3734.486745
Ph5memTS1E2 0.211909
-
3732.263406
-
3734.698898
-
3734.486989
Bu5memSM1 0.250553
-
3658.456830
-
3660.950953
-
3660.700400
Bu5memTS1 0.246732
-
3658.432734
-
3660.911438
-
3660.664706
All5memSM1 0.174076
-
3578.671117
-
3581.113889
-
3580.939813
All5memTS 0.169897
-
3578.641325
-
3581.070128
-
3580.900231
Me5memSM1 0.171033
-
3540.585782
-
3543.033172
-
3542.862139
Me5memTS 0.167817
-
3540.560819
-
3542.994371
-
3542.826554
Ph4PBrleaving2 0.217574
-
3732.263634
-
3734.713329
-
3734.495755
86

4-Membered intermediate decomposition
Calculated at B3LYP/6-31+G(d,p) level with implicit consideration of THF solvent effects
Species
Thermal
correction
E G
ΔG
IMPh4 0.221217
-
998.3902745
-
998.1690575 0.0
PhTSC1 (C-O
cleavage) 0.21813
-
998.309967
-
998.091837 +48.5
PhTSC2 (C-C
cleavage) 0.219653
-
998.3135992
-
998.0939462 +47.1
IMBu4 0.253069
-
924.5940863
-
924.3410173 0.0
BuTSC1 (C-O
cleavage) 0.249709
-
924.506061
-
924.256352 +53.1
BuTSC2 (C-C
cleavage) 0.250743
-
924.5129474
-
924.2622044 +49.5

Coordinates details can be found in the supporting information of published article: Chem. Eur. J.
2014, 20, 831–838.

Bu4memformTS 0.250125
-
3658.416872
-
3660.904154
-
3660.654029
87

2.4.7. Elucidation of N-substituent effects based on linear free energy relationship
analysis
Correlation between electronegativity and activation barriers of aldol reactions.

Correlation between electronegativity and relative Gibbs free energies of aldol adducts.

y = -22.967x + 58.502
R² = 0.6756
0.0
3.0
6.0
9.0
2.2 2.3 2.4 2.5
ΔG
TS
‡
(kcal/mol)
χ
P
(Pauling Scale)
χ
P
-ΔG
TS
‡
Aldol Addition Correlation
y = -45.769x + 94.565
R² = 0.8837
-20.0
-16.0
-12.0
-8.0
2.2 2.3 2.4 2.5
ΔG
IM
(kcal/mol)
χ
P
(Pauling Scale)
χ
P
-ΔG
IMAldol Addition Correlation
88

Correlation between electronegativity and activation barriers of olefination reactions.

Correlation between electronegativity and relative Gibbs free energies of the reactant toward
5-membered ring formation (conformational isomers of aldol adducts).

y = -35.742x + 97.226
R² = 0.7617
5.0
9.0
13.0
17.0
2.2 2.3 2.4 2.5
ΔG
TS
‡
Olefination
(kcal/mol)
χ
P
(Pauling Scale)
χ
P
-ΔG
TS
‡
Olefination
y = -21.978x + 33.268
R² = 0.8853
-22.0
-20.0
-18.0
-16.0
2.2 2.25 2.3 2.35 2.4 2.45 2.5
ΔG
IM 5membered-ring formation
(kcal/mol)
χ
P
(Pauling Scale)
χ
P
-ΔG
IM 5membered-ring formation
89

Correlation between electronegativity and activation barriers of 5-membered ring formation

Correlation between σ para and activation barriers of aldol reactions.

y = -7.967x + 23.952
R² = 0.7198
4.0
5.0
6.0
7.0
2.2 2.25 2.3 2.35 2.4 2.45 2.5
ΔG
TS
‡
5membered-ring formation
χ
P
(Pauling Scale)
χ
P
-ΔG
TS
‡
5membered-ring formation
y = -31.245x + 1.0192
R² = 0.9103
0.0
3.0
6.0
9.0
-0.25 -0.2 -0.15 -0.1 -0.05 0
ΔG
TS
‡
(kcal/mol)
σ
Para
σ
Para
-ΔG
TS
‡
Aldol Addition Correlation
90

Correlation between σ para and relative Gibbs free energies of aldol adducts.

Correlation between σ para and activation barriers of olefination reactions.

y = -56.943x - 19.429
R² = 0.9958
-20.0
-16.0
-12.0
-8.0
-0.25 -0.2 -0.15 -0.1 -0.05 0
ΔG
IMAldol Addition Correlation
(kcal/mol)
σ
Para
σ
Para
-ΔG
IMAldol Addition Correlation
y = -40.358x + 8.6374
R² = 0.707
5.0
9.0
13.0
17.0
-0.25 -0.2 -0.15 -0.1 -0.05 0
ΔG
TS
‡
Olefination
(kcal/mol)
σ
Para
σ
Para
-ΔG
TS
‡
Olefination
91

Correlation between σ para and relative Gibbs free energies of the reactant toward 5-membered
ring formation (conformational isomers of aldol adducts)

Correlation between σ para and activation barriers of 5-membered ring formation

y = -27.358x - 21.473
R² = 0.9987
-22.0
-20.0
-18.0
-16.0
-0.25 -0.2 -0.15 -0.1 -0.05 0
ΔG
IM 5membered-ring formation
(kcal/mol)
σ
Para
σ
Para
-ΔG
IM 5membered-ring formation
y = -10.717x + 4.0247
R² = 0.9482
4.0
5.0
6.0
7.0
-0.25 -0.2 -0.15 -0.1 -0.05 0
ΔG
TS
‡
5membered-ring formation
(kcal/mol)
σ
Para
σ
Para
-ΔG
TS
‡
5membered-ring formation
92

Correlation between Es and activation barriers of aldol reactions.

Correlation between Es and relative Gibbs free energies of aldol adducts.

y = 1.3982x + 6.2889
R² = 0.2297
0.0
2.0
4.0
6.0
8.0
10.0
-2.6 -2.3 -2 -1.7 -1.4 -1.1 -0.8 -0.5 -0.2 0.1
ΔG
TS
‡
Aldol Addition Correlation
(kcal/mol)
E
s
E
s
-ΔG
TS
‡
Aldol Addition Correlation
y = 3.3132x - 8.7369
R² = 0.4249
-20.0
-16.0
-12.0
-8.0
-2.6 -2.3 -2 -1.7 -1.4 -1.1 -0.8 -0.5 -0.2 0.1
ΔG
IMAldol Addition Correlation
(kcal/mol)
E
s
E
s
-ΔG
IMAldol Addition Correlation
93

Correlation between Es and activation barriers of olefination reactions.

Correlation between Es and relative Gibbs free energies of the reactant toward 5-membered
ring formation (conformational isomers of aldol adducts)

y = 2.8804x + 16.972
R² = 0.4539
5.0
9.0
13.0
17.0
-2.6 -2 -1.4 -0.8 -0.2
ΔG
TS
‡
Olefination
(kcal/mol)
E
s
E
s
-ΔG
TS
‡
Olefination
y = 1.62x - 16.296
R² = 0.4414
-22.0
-20.0
-18.0
-16.0
-2.6 -2 -1.4 -0.8 -0.2
ΔG
IM 5membered-ring formation
(kcal/mol)
E
s
E
s
-ΔG
IM 5membered-ring formation
94

Correlation between Es and activation barriers of 5-membered ring formation

Correlation between Charton’s parameters and activation barriers of aldol reactions.

y = 0.4798x + 5.8325
R² = 0.2395
4.0
5.0
6.0
7.0
-2.6 -2.0 -1.4 -0.8 -0.2
ΔG
TS
‡
5membered-ring formation
(kcal/mol)
E
s
E
s
-ΔG
TS
‡
5membered-ring formation
y = -3.2179x + 8.1052
R² = 0.2501
0.0
2.0
4.0
6.0
8.0
10.0
0.5 0.8 1.1 1.4 1.7
ΔG
TS
‡
Aldol Addition Correlation
(kcal/mol)
υ (Charton's parameter)
υ-ΔG
TS
‡
Aldol Addition Correlation
95

Correlation between Charton’s parameters and relative Gibbs free energies of aldol adducts.

Correlation between Charton’s parameters and activation barriers of olefination reactions.

y = -7.312x - 4.8036
R² = 0.4253
-20.0
-16.0
-12.0
-8.0
0.5 0.8 1.1 1.4 1.7
ΔG
IMAldol Addition Correlation
(kcal/mol)
υ (Charton's parameter)
υ-ΔG
IMAldol Addition Correlation
y = -6.0217x + 19.996
R² = 0.4078
5.0
9.0
13.0
17.0
0.5 0.8 1.1 1.4 1.7
ΔG
TS
‡
Olefination
(kcal/mol)
υ (Charton's parameter)
υ-ΔG
TS
‡
Olefination
96

Correlation between Charton’s parameters and relative Gibbs free energies of the reactant
toward 5-membered ring formation (conformational isomers of aldol adducts)

Correlation between Charton’s parameters and activation barriers of 5-membered ring
formation reaction

y = -3.6112x - 14.33
R² = 0.4508
-22.0
-20.0
-18.0
-16.0
0.5 0.8 1.1 1.4 1.7
ΔG
IM 5membered-ring formation
(kcal/mol)
υ (Charton's parameter)
υ-ΔG
IM 5membered-ring formation
y = -1.0787x + 6.4256
R² = 0.2488
4.0
5.0
6.0
7.0
0.5 0.8 1.1 1.4 1.7
ΔG
TS
‡
5membered-ring formation
(kcal/mol)
υ (Charton's parameter)
υ-ΔG
TS
‡
5membered-ring formation
97

2.4.8. NMR Spectra

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

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149

2.5 References
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153

Chapter 3

N,N-Dimethyl-S-difluoromethyl-S-
phenylsulfoximinium Tetrafluoroborate: A
Versatile Electrophilic Difluoromethylating
Reagent

154

3.1 Introduction
Fluoroorganics have been found to possess unique chemophysical and biological properties.
1

Among fluoromethyl functionalities, the difluoromethyl moiety is of particular interest due to its
isostericity and isopolarity to an ethereal oxygen, and has been utilized to replace specific oxygen
atoms in various bioactive species to increase their metabolic stability and bioavailability.
2
Over
the past ten years, sulfur-based fluoromethyl containing compounds have been extensively
investigated as versatile fluoroalkylating reagents by Prakash, Hu, as well as many others.
3

Particularly, S-(difluoromethyl)diarylsulfonium tetrafluoroborate was first synthesized and
exploited in our laboratory as an efficient electrophilic difluoromethylating reagent towards a series
of nucleophilic species to accommodate the corresponding difluoromethylated products.
4
Despite
its feasible synthetic applications under many chemical ré gimes, the drawback of this reagent was
found to be its slow decomposition over time even under low temperatures.
On the other hand, sulfoximines have been widely employed in synthetic chemistry as versatile
reagents and valuable ligands.
5
Johnson and co-workers treated N,N-dimethyl-S-methyl-S-
phenylsulfoximinium tetrafluoroborate, which is known as the Johnson reagent, with bases to
afford the corresponding sulfur ylide, which is capable of transferring the methylene group to
various substrates.
6
The preparation of fluorinated sulfoximines has been pioneered by Shreeve and
co-workers, who have investigated the properties of a series of bis(perfluoromethyl)sulfoximines.
7

In 1988, Finch reported α-fluoromethyl-N-methyl-phenylsulfoximine as a fluoromethylenation
reagent for ketones and aldehydes.
8
Lately, Shibata and co-workers demonstrated the synthetic
utility of the trifluoromethylated and the monofluoromethylated counterparts of Johnson reagents
in the electrophilic fluoromethylation of various nucleophilic species.
4
It is worth mentioning that
Hu et al. have exploited N-tosyl-S-difluoromethyl-S-phenylsulfoximine as a difluorocarbene
precursor, which readily reacts with a variety of S-, N-, and C-nucleophiles.
4c

155

3.2 Results and Discussion
Herein, we would like to report the development of N, N-dimethyl-S-difluoromethyl-S-
phenylsulfoximinium tetrafluoroborate salt (1) as a robust electrophilic difluoromethylating
reagent. Generated in situ from shelf-stable N-methyl-S-difluoromethyl-S-phenylsulfoximine (3),
the present reagent has exhibited good reactivity toward a broad scope of nucleophiles (N-, P-, S-,
and O-nucleophiles).
The preparation of 2 was initially conducted by treating difluoromethyl phenyl sulfoxide
(PhSOCF 2H) with sodium azide (NaN 3) in 25% fuming H 2SO 4 as the reaction medium,
4d,9
which
unfortunately led to a minor explosion (Scheme 3.1). In contrast, PhSOCF 2H was intact when
subjected to NaN 3 and 98% H 2SO 4 in chloroform.
8
After several attempts, we were able to obtain
that the desired product 2 in quantitative yield by using a combination of NaN 3/oleum/CH 2Cl 2 as
the oxidative imination system.
10
The subsequent methylation of 2 was first performed under the
one-pot procedure described by Johnson,
11
which resulted in the rapid decomposition of the parent
sulfoximine. Further attempts to transform 2 via an established methylation protocol,
4d
however,
only gave the title products with unsatisfactory yields. Eventually, the methylation of 2 was
achieved through a stepwise route utilizing trimethyloxonium tetrafluoroborate as the methylating
reagent (Scheme 3.1). Obtained in high yields, salt 1 is a white solid possessing reasonable stability
that allows its storage for several hours at room temperature.
12
Interestingly, in contrast to its
trifluoromethylated analogue that was inert in MeOH,
4d
a rapid reaction between 1 and CD 3OD has
been observed via
1
H and
19
F NMR spectroscopy implying its remarkable reactivity.
13
Noticeably,
despite the slight lability of sulfoximinium 1, its precursor 3 has exhibited sufficient stability under
ambient conditions permitting a facile access to 1.

Scheme 3.1. Preparation of N,N-dimethyl-S-difluoromethyl-S-phenylsulfoximinium
tetrafluoroborate (1).
Having the difluoromethylated Johnson reagent 1 on hand, we were able to systematically
investigate its difluoromethyl-transfer ability to an arsenal of nucleophilic species. An examination
156

of various reaction media revealed that anhydrous dichloromethane is the optimal solvent for the
difluoromethylation of triphenylphosphine (Table 3.1). Other solvents such as tetrahydrofuran
(THF) and dimethylformaldehyde (DMF) were found to promote the decomposition of the reagent
presumably due to their slight nucleophilicity. After a careful modification of the reaction
parameters such as the addition sequences of the reagents and the proportions of substrates, the
optimized yields were achieved by the treatment of 1 with 1.5 equivalents of various nucleophiles
in dichloromethane at room temperature.
Table 3.1. Optimization of the reaction conditions.

We subsequently explored the scope of current protocol with a wide range of phosphorus
nucleophiles. As depicted in Table 3.2, the difluoromethylation reaction underwent smoothly with
both aromatic and aliphatic phosphines to afford the corresponding difluoromethyl phosphonium
salts in moderate to good yields (Entries 1-6 and 8, Table 3.2). Intriguingly, the steric characters of
phosphorus nucleophiles seem to be crucial to the outcome of the reaction (Entries 7, Table 3.2).
Although the meta- and the para-substituted aryl phosphines exhibited satisfactory reactivity
toward sulfoximinium 1, the presence of ortho substituents on the aromatic rings dramatically
inhibits the reactivity of the phosphines.

157

Table 3.2. Difluoromethylation of phosphines using 1.

Intriguingly, the electrophilic difluoromethylating reagent 1 was also found to act as an
ambident species capable of oxidizing phosphorous nucleophiles. Because the transformation from
158

3 to 1 was performed under heterogeneous conditions, control experiments have been performed
to exclude the possible involvement of Me 3O
+
BF 4
-
residue that can account for the observed side
reaction. As depicted in Figure 3.1-B, the reaction between 3 and Me 3O
+
BF 4
-
, in a molar ratio of
2:1, gave a mixture of 3, 1, and a small amount of impurities in 4.1:2.7:0.7 ratio according to the
19
F NMR spectrum, which provides compelling evidence for the complete consumption of
Me 3O
+
BF 4
-
under the present reaction conditions. Further treatment of the same mixture with a
stoichiometric amount of Ph 3P afforded the difluoromethyl phosphonium salt and the
corresponding phosphine oxide in a ratio of approximately 3:1, which was similar to the
observation in the reaction employing a slightly excess amount of Me 3O
+
BF 4
-
. This striking
observation was found to resemble the previously described oxidation of phosphines with
sulfoxides in the presence of Lewis acids, and a similar mechanism has been proposed (Scheme
3.2).
14

Scheme 3.2. Plausible mechanism of the oxidation of Ph 3P.

Figure 3.1. Investigation of the difluoromethylation and oxidation ability of 1 with Ph 3P. (A)
19
F
NMR spectrum of 3; (B)
19
F NMR spectrum of the reaction mixture of 3 and Me 3O
+
BF 4
-
in 2:1
ratio; (C)
19
F NMR spectrum of the reaction mixture of 3 and Me 3O
+
BF 4
-
in 1:1 ratio; (D)
31
P NMR
spectrum of the reaction mixture B and Ph 3P. All the spectra were taken in CD 3CN.
159

Table 3.3. Difluoromethylation of nitrogen nucleophiles using 1.

160

In addition to the phosphorus nucleophiles, a series of amines and several nitrogen-containing
heterocyclic compounds were subjected to the reaction expecting the formation of difluoromethyl
ammonium salts. Gratifyingly, tertiary amines were also found to readily react with 1 under the
optimized reaction conditions. As shown in Table 3.3, the difluoromethylation of the tertiary
amines generally gave the corresponding ammonium salts in moderate to good yields as monitored
by
19
F NMR spectroscopy (Entries 1-4 and 7-10, Table 3.3). Similar to the difluoromethylation of
the phosphines, the reactivity of the amines toward 1 was also affected by the steric demand of the
ortho-substituents. In particular, when highly bulky 2,2-diisopropyl aniline was subjected to the
reaction, 1 was found to be intact. Noticeably, although 1-phenyl-1H-imidazole reacted with
sulfoximinium 1 smoothly, the similar difluoromethylation of 1H-imidazole and pyridine was
found to be rather sluggish. This observation, however, has not been rationalized yet. In particular,
substantially differing from the reaction between 1 and phosphorous nucleophiles, oxidation of
amines was not observed under the current reaction conditions.
We further investigated the reaction of reagent 1 with various oxygen and sulfur nucleophiles.
Derived from the corresponding aryl thiols and NaH, sodium aryl thiolates displayed low to
moderate reactivity toward sulfoximinium 1 (Entries 1-4, Table 3.4). In contrast, it has been
observed that the treatment of 1 with sodium alkoxides and phenolates led to the rapid
decomposition of the reagent instead of affording the corresponding difluoromethyl ethers.
Surprisingly, the desired difluoromethyl ethers were achieved, when sulfoximinium 1 was reacted
with a large excess amount of aliphatic alcohols (10 equiv.) under neutral conditions (Entries 5-8,
Table 3.4). As depicted in Table 3.4, the current synthetic approach was applicable not only for the
difluoromethylation of primary alcohols, but also for secondary and tertiary alcohols. It is worth
noting that, in addition to (2-difluoromethoxyethyl)benzene, 2-phenylethyl ether was also isolated
as the side product when 2-phenylethanol was employed as the substrate. Such an outcome
evidently indicates that the coupling reaction of nucleophiles towards the formation of the
corresponding ethers is one of the significant competing reactions of the difluoromethylation
process, which may account for the low yields observed in the reaction of 1 with alcohols. In
particular, phenols were found to be inert under the present reaction conditions.
In an effort to gain the mechanistic insight into the protocol, isotope-labeling experiments have
been performed to determine the pathway involved in the present reaction (Scheme 3.3). In theory,
the difluoromethyl group is believed to undergo a deprotonation-protonation process in the
difluorocarbene pathway. Hence, significant amounts of deuterated products (CF 2D) are anticipated
in the presence of deuterated methanol under such mechanism. In contrast, such a proton-deuterium
161

Table 3.4. Difluoromethylation of sulfur and oxygen nucleophiles using 1.

exchange is presumably unable to take place under the electrophilic difluoromethylation pathway
due to the absence of the C-H cleavage. As demonstrated in Scheme 3.3, the results have ruled out
difluorocarbene as a plausible intermediate under the current reaction conditions since no
162

deuterated difluoromethyl group was detectable via
19
F NMR spectroscopy, which experimentally
confirmed sulfoximinium 1 as a de facto electrophilic difluoromethylating reagent.
15

Scheme 3.3. Mechanistic studies based on isotope-labeling experiments.

3.3 Conclusion
In conclusion, we have successfully prepared the unprecedented N, N-dimethyl-S-
difluoromethyl-S-phenylsulfoximinium tetrafluoroborate as a versatile electrophilic
difluoromethylating reagent. In situ generated from the shelf-stable N-methyl-S-difluoromethyl-S-
phenylsulfoximine, difluoromethylated sulfoximinium salt has enabled a feasible synthetic
approach toward a variety of difluoromethylated compounds. As a difluoromethylated analogue of
the Johnson reagents, the compound has been found to transfer the difluoromethyl group via an
electrophilic alkylation fashion instead of the commonly adopted difluorocarbene pathway.
3.4 Experimental
Unless otherwise mentioned, all chemicals were purchased from commercial sources.
1
H NMR
spectra were recorded on 400 MHz and 500 MHz superconducting NMR spectrometers.
13
C NMR
163

spectra were recorded on 101 MHz and 126 MHz superconducting NMR spectrometers.
19
F NMR
spectra were recorded on 376 MHz and 470 MHz superconducting NMR spectrometers.
31
P NMR
spectra were recorded on 162 MHz and 202 MHz superconducting NMR spectrometers. All the
unknown compounds have been fully characterized by NMR spectroscopy and high resolution MS
analysis, whereas structures of all known products were confirmed by comparison of their
1
H NMR
and
19
F NMR spectra with reported data.
1
H NMR chemical shifts (δ) 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.
19
F NMR chemical shifts were determined relative to
internal CFCl 3 at δ 0.0 ppm.
31
P NMR chemical shifts were determined relative to internal H 3PO 4
(85%) at δ 0.0 ppm.
3.4.1 General procedure for the preparation of S-difluoromethyl-S-
phenylsulfoximine (2).
PhSOCF 2H (3.52 g, 20 mmol) was mixed with sodium azide (NaN 3, 2.6 g, 40 mmol) in
dichloromethane (20 mL) under N 2. To the stirred reaction mixture, oleum (20 %, 7.5 mL) was
added dropwise within 15 min at -10
o
C. The reaction was slowly warmed to room temperature and
stirred over night. The resulting suspension was slowly poured into ice water (ca. 100 mL) and
neutralized with NaOH (solid, 4.73 g, 120 mmol). NaHCO 3 was subsequently added in small
portions until bubbling ceased. The mixture was then extracted with dichloromethane (50× 3 mL).
The combined organic phase was washed with water (20 mL) and dried over Na 2SO 4 before the
removal of the solvent. The crude product was further purified by flash column chromatography
(silicon gel) using hexane and ethyl acetate (4:1) as the eluent to afford an colorless oil (3.80 g,
99 %).
1
H NMR (CDCl 3):  6.14 (t, J = 54.8 Hz, 1H), 7.57-7.66 (m, 2H), 7.73-7.77 (m, 1H), 8.06-
8.08 (m, 2H).
19
F NMR (CDCl 3):  -119.3 (dd, J = 258.5 Hz, J = 54.8 Hz, 1F), -122.4 (dd, J = 258.5,
Hz J = 54.8 Hz, 1F).
13
C NMR (CDCl 3):  115.4 (t, J = 287.1 Hz), 129.5, 130.6, 133.3, 135.0.
HRMS: calculated for C 7H 8F 2NOS
+
(MH
+
) 192.0289, found: 192.0289.
3.4.2 Preparation of N-methyl-S-difluoromethyl-S-phenyl sulfoximine (3)
S-difluoromethyl-S-phenylsulfoximine 2 (3.80 g, 19.9 mmol) was dissolved in anhydrous
dichloromethane (20 mL) under N 2. Trimethyloxonium tetrafluoroborate (3.25 g, 22 mmol) was
added into the stirred solution in small portions. The reaction was monitored by thin layer
chromatography until the completion. The resulting mixture was then quenched with saturated
NaHCO 3 aqueous solution and extracted with dichloromethane (50× 3 mL). The combined organic
164

layer was dried over Na 2SO 4 before evaporation of the solvent. The crude product was purified by
column chromatography (silica gel) using hexane and ethyl acetate (5:1) as the eluent to
accommodate 2 as a colorless oil (2.8 g, 68 %).
1
H NMR (CDCl 3):  2.98 (s, 3H), 6.20 (t, J = 54.4
Hz, 1H), 7.55-7.65 (m, 2H), 7.68-7.78 (m, 1H), 7.95-8.05 (m, 2H).
19
F NMR (CDCl 3):  -118.0 (dd,
J = 259.8 Hz, J = 54.3 Hz, 1F), -120.5 (dd, J = 259.7 Hz, J = 54.5 Hz, 1F).
13
C NMR (CDCl 3): 
29.3, 115.6 (t, J = 287.8 Hz), 129.6, 130.8, 132.3, 134.7. HRMS: calculated for C 8H 10F 2NOS
+
(MH
+
)
206.0446, found: 206.0447.
3.4.3 General procedure for the preparation of N,N-dimethyl-S-difluoromethyl-S-
phenyl sulfoximinium tetrafluoroborate (1)
To a stirred solution of N-methyl-S-difluoromethyl-S-phenylsulfoximine 2 (3.08 g, 15 mmol) in
anhydrous dichloromethane (15 mL), trimethyloxonium tetrafluoroborate (2.43 g, 16.5 mmol) was
added all at once under N 2. The reaction mixture was stirred for 30 min before the removal of
volatile substances under vacuum. A white solid was obtained and subject to the
difluoromethylations reaction without further purification (4.3 g, 99%).
1
H NMR (CD 3CN):  3.24
(s, 6H), 7.70 (t, J = 51.5 Hz, 1H), 7.94-8.00 (m, 2H), 8.14-8.21 (m, 3H).
19
F NMR (CD 3CN):  -
108.9 (dd, J= 249.4 Hz, J = 51.9 Hz, 1F), -115.3 (dd, J = 248.5 Hz, J = 51.1 Hz, 1F), -154.0 (b,
4F).
13
C-NMR (CD 3CN):  40.3, 117.2 (t, J = 295.8 Hz), 121.2, 132.6, 133.0, 141.0. HRMS
calculated for C 9H 12F 2NOS
+
(M
+
) 220.0602, found: 220.0601.

3.4.4 General Procedure for difluoromethylations of phosphorus nucleophiles
To the in situ generated 1 (0.2 mmol), a solution of phosphines (4a-4i) (0.3 mmol) in anhydrous
CH 2Cl 2 (0.5 mL) was quickly added under N 2 protection and the reaction mixture was stirred for 1 h.
The reaction was monitored via
19
F NMR spectroscopy with PhCF 3 as an internal standard. The solvent
was then evaporated under vacuum and the residue was purified by flash column chromatography or
thin layer chromatography (silica gel) using CH 2Cl 2 and MeOH as the eluent.
P-(Difluoromethyl)triphenylphosphonium Tetrafluoroborate (5a). Yield = 82%.
1
H NMR (DMSO-
d 6):  7.85-7.93 (m, 12H), 8.04-8.06 (m, 3H), 8.40 (dt, J = 47.1 Hz, J = 29.3 Hz, 1H).
19
F NMR (DMSO-
d 6):  -125.7 (dd, J = 77.3 Hz, J = 47.1 Hz, 2F), -147.65 (s, 1F), -147.70 (s, 3F).
P-(Difluoromethyl)tri(n-butyl)phosphonium Tetrafluoroborate (5b). Yield = 53%.
1
H NMR
(CD 3OD):  1.01 (t, J = 7.2 Hz, 9H), 1.54 (sextet, J = 7.1 Hz, 6H), 1.65 (quintet, J = 7.1 Hz, 6H), 2.50-
2.57 (m, 6H), 7.16 (dt, J = 47.3 Hz, J = 26.8 Hz, 1H).
19
F NMR (CD 3OD):  -129.30 (dd, J = 68.9 Hz,
J = 47.4 Hz, 2F), -153.95 (s, 1F), -154.00 (s, 3F).
31
P-NMR (CD 3OD):  38.2 (t, J = 68.9 Hz).
13
C NMR
(CD 3OD):  12.1 (d, J = 0.8 Hz), 15.0 (d, J = 41.9 Hz), 22.7 (d, J = 5.0 Hz), 23.6 (d, J = 16.2 Hz),
165

113.95 (dt, J = 265.4 Hz, J = 75.4 Hz). HRMS calculated for C 13H 28F 2P
+
(M
+
) Expected: 253.1891.
Found: 253.1894.
P-(Difluoromethyl)dimethylphenylphosphonium Tetrafluoroborate (5c). Yield = 70%.
1
H NMR
(CD 3OD):  2.54 (d, J = 14.7 Hz, 6H), 7.10 (dt, J = 48.5 Hz, J = 28.8 Hz, 1H), 7.78-7.83 (m, 2H), 7.94
(t, J = 7.8 Hz, 1H), 8.04 (dd, J = 13.3 Hz, J = 8.2 Hz, 1H).
19
F-NMR (CD 3OD):  -126.55 (dd, J = 77.7
Hz, J = 47.3 Hz, 2F), -153.95 (s, 1F), -154.00 (s, 3F).
31
P-NMR (CD 3OD):  28.0 (t, J = 77.9 Hz).
13
C
NMR (CD 3OD):  2.54 (d, J = 52.2 Hz), 114.9 (dt, J = 265.3 Hz, J = 84.4 Hz), 123.3 (d, J = 87.5 Hz),
131.4 (d, J = 13.1 Hz), 134.0 (d, J = 10.4 Hz), 137.2 (d, J = 3.3 Hz). HRMS calculated for C 9H 12F 2P
+
(M
+
) Expected: 189.0639. Found: 189.0639.
P-(Difluoromethyl)tricyclohexylphosphonium Tetrafluoroborate (5d). Yield = 69%.
1
H-NMR
(CD 3OD):  2.59-3.00 (m, 30H), 2.93 (m, 3H), 7.32 (dt, J = 46.8 Hz, J = 26.3 Hz, 1H).
19
F-NMR
(CD 3OD):  -126.9 (dd, J = 61.1 Hz, J = 47.0 Hz, 2F), -153.95 (s, 1F), -154.00 (s, 3F).

P-(Difluoromethyl)tri(p-tolyl)phosphonium Tetrafluoroborate (5e). Yield = 61%.
1
H NMR
(CD 3OD):  2.54 (s, 9H), 7.34-7.71 (m, 12 H), 7.95 (dt, J = 47.3 Hz, J = 29.6 Hz).
19
F NMR (CD 3OD):
 -126.72 (dd, J = 76.9 Hz, J = 47.4 Hz, 2F), -153.95 (s, 1F), -154.00 (s, 3F).
31
P-NMR (CD 3OD): 
18.7 (t, J = 77.0 Hz).
13
C-NMR (CD 3OD):  21.9, 110.2 (d, J = 88.8 Hz), 115.9 (dt, J = 268.3 Hz, J =
87.0 Hz), 132.8 (d, J = 13.6 Hz), 135.8 (d, J = 10.8 Hz), 150.1 (d, J = 3.2 Hz). HRMS calculated for
C 22H 22F 2P
+
(M
+
) Expected: 355.1422. Found: 355.1421.
P-(Difluoromethyl)tri(m-tolyl)phosphonium Tetrafluoroborate (5f). Yield = 78 %.
1
H NMR
(CD 3OD):  2.47 (s, 9H), 7.58-7.65 (m, 6H), 7.70-7.74 (m, 3H), 7.84-7.85 (m, 3H), 7.96 (dt, J = 47.3
Hz, J = 29.6 Hz, 1H).
19
F NMR (CD 3OD):  -126.24 (dd, J = 77.0 Hz, J = 47.3 Hz, 2F), -153.95 (s, 1F),
-154.00 (s, 3F).
31
P NMR (CD 3OD):  19.1 (t, J = 77.0 Hz).
13
C NMR (CD 3OD):  21.3, 113.6 (d, J =
85.0 Hz), 115.9 (dt, J = 272.0 Hz, J = 89.5 Hz), 132.0 (d, J = 14.1 Hz), 133.2 (d, J = 10.3 Hz), 135.7 (d,
J = 10.3 Hz), 138.8 (d, J = 3.2 Hz), 143.0 (d, J = 13.3 Hz). HRMS calculated for C 22H 22F 2P
+
(M
+
)
Expected: 355.1422. Found: 355.1423.
P-(Difluoromethyl)tri(p-methoxyphenyl)phosphonium Tetrafluoroborate (5h). Yield = 48 %.
1
H-
NMR (CD 3OD):  3.96 (s, 9H), 7.33-7.36 (m, 6H), 7.69-7.74 (m, 6H), 7.76 (dt, J = 47.7 Hz, J = 29.1
Hz, 1H).
19
F-NMR (CD 3OD):  -127.62 (dd, J = 76.5 Hz, J = 47.6 Hz, 2F), -153.95 (s, 1F), -154.00 (s,
3F).
31
P-NMR (CD 3OD):  17.7 (t, JP-F = 76.5 Hz).
13
C-NMR (CD 3OD):  56.7, 103.8 (d, J = 95.3 Hz),
115.9 (dt, J = 266.8 Hz, J = 88.5 Hz), 117.8 (d, J = 14.3 Hz), 137.9 (d, J = 12.1 Hz), 167.7 (d, J = 3.1
Hz). HRMS calculated for C 22H 22F 2O 3P
+
(M
+
) Expected: 403.1269. Found: 403.1268.

166

3.4.5 General procedure for difluoromethylations of nitrogen nucleophiles
To the in situ generated 1 (0.2 mmol), a solution of amines or nitrogen-containing heterocyclics
(6a-6j) (0.3 mmol) in anhydrous CH 2Cl 2 (0.5 mL) was quickly added under N 2 protection and the
reaction mixture was stirred for 1 h. The reaction was monitored via
19
F NMR spectroscopy with
PhCF 3 as an internal standard. The solvent was then evaporated under vacuum and the residue was
purified by flash column chromatography or thin layer chromatography (silica gel) using CH 2Cl 2
and MeOH as the eluent.
N-(Difluoromethyl)triethylammonium Tetrafluoroborate (7a). Yield: 69%.
1
H-NMR
(CD 3OD):  1.42 (q, J = 5 Hz, 9H), 3.67(t, J = 5 Hz, 6H), 7.14 (t, J = 55.0 Hz, 1H).
19
F-NMR
(CD 3OD):  -112.97 (d, J = 56.0 Hz, 2F), -153.95 (s, 1F), -154.00 (s, 3F).
N-(Difluoromethyl)-N,N-dimethylanilinium Tetrafluoroborate (7b). Yield: 71%.
1
H-NMR
(DMSO-d 6):  3.77 (s, 6H), 7.56 (t, J = 58.6 Hz, 1H), 7.61-7.62 (m, 3H), 7.86-7.88 (m, 2H).
19
F-
NMR (DMSO-d 6):  -115.04 (d, J = 61.0 Hz, 2F), -153.95 (s, 1F), -154.00 (s, 3F).
N-(Difluoromethyl)-N,N-dimethyl-p-toluenedinium Tetrafluoroborate (7c). Yield: 70 %.
1
H-NMR (DMSO-d 6):  2.40 (s, 3H), 3.78 (s, 6H), 7.41-7.52 (m, 2H), 7.55 (t, J = 60.0 Hz, 1H),
7.81-7.87 (m, 2H).
19
F-NMR (DMSO-d 6):  -117.10 (d, 2F, J = 56 Hz), -153.95 (s, 1F), -154.00 (s,
3F).
N-(Difluoromethyl)-N,N-dimethyl-m-toluenedinium Tetrafluoroborate (7d). Yield: 83%.
1
H-NMR (DMSO-d 6):  3.02 (s, 3H), 4.25 (t, J = 1.5 Hz, 6H), 7.60 (t, J = 58.8 Hz, 1H), 8.06-8.09
(m, 1H), 8.11-8.16 (m, 1H), 8.20-8.23 (m, 1H).
19
F-NMR (DMSO-d 6):  -114.5 (dt, J = 58.8 Hz, J
= 1.5, Hz, 2F), -153.95 (s, 1F), -154.00 (s, 3F).
13
C-NMR (CD 3OD):  21.4, 49.1, 117.0 (t, J = 277.6
Hz), 120.2, 123.6, 131.7, 133.6, 141.4, 143.1. HRMS calculated for C 10H 14F 2N
+
(M
+
) Expected:
186.1089. Found: 186.1089.
N-(Difluoromethyl)-N,N-dimethyl-m-aminoanisolium Tetrafluoroborate (7g). Yield: 53%.
1
H-NMR (CD 3OD):  3.83 (s, 6H), 3.92 (s, 3H), 7.29 (d, J = 8.4 Hz, 1H), 7.44 (t, J = 58.9 Hz, 1H,
partially overlapping with aromatic signals), 7.43-7.50 (m, 2H), 7.63 (t, J = 8.4 Hz, 1H).
19
F-NMR
(CD 3OD):  -112.16 (d, J = 58.7 Hz, 2F), -153.95 (s, 1F), -154.00 (s, 3F).
13
C-NMR (CD 3OD): 
49.2 (partially overlapping with solvent signal), 56.7, 109.8, 114.8, 117.0 (t, J = 277.5 Hz, partially
overlapping with aromatic signals), 142.4, 162.7. HRMS calculated for C 10H 14F 2NO
+
(M
+
)
Expected: 202.1038. Found: 202.1038.
167

N-(Difluoromethyl)-N,N-dimethyl-m-chloroanilinium Tetrafluoroborate (7h). Yield: 47%.
1
H-NMR (CD 3OD):  3.87 (t, J = 2.4 Hz, 6H), 7.45 (t, J = 58.6 Hz, 1H), 7.71-7.79 (m, 2H), 7.93
(d, J = 8.1 Hz, 1H), 8.11 (pseudo t, J = 2.1 Hz, 1H).
19
F-NMR (CD 3OD):  -111.2 (d, J = 58.6 Hz,
2F), -153.95 (s, 1F), -154.00 (s, 3F).
13
C-NMR (CD 3OD):  49.2, 109.8, 114.8, 117.0 (t, J = 280.7
Hz), 118.1, 132.8, 142.4, 162.7. HRMS calculated for C 9H 11ClF 2N
+
(M
+
) Expected: 206.0543.
Found: 206.0543.
N-(Difluoromethyl)-3-phenylimidazolium Tetrafluoroborate (7i). Yield: 68%.
1
H NMR
(CD 3CN): 7.61 (t, J = 59.1 Hz, 1H), 7.66 (5H), 7.94 (s, 1H), 7.96 (s, 1H), 9.41 (s, 1H).
19
F NMR
(CD 3CN): 95.5 (d, J = 59.0 Hz), -153.95 (s, 1F), -154.00 (s, 3F).
3.4.6 General procedure for difluoromethylations of sulfur nucleophiles
To a stirred solution of aryl thiols (8a-8d) (0.3 mmol) in anhydrous THF, NaH (0.3 mmol) was added
in small portions under N 2. The solvent was evaporated under vacuum until the bubbling ceased. The
residue was added to freshly prepared 1 (0.2 mmol) in one portion under N 2 and the reaction mixture
was stirred for 1 h. The reaction was monitored via
19
F NMR spectroscopy with PhCF 3 as an internal
standard, and the yields were calculated on the basis of substrate 1 used.
3.4.7 General procedure for difluoromethylations of oxygen nucleophiles
To the in situ generated 1 (0.2 mmol), a solution of alcohols (8e-8h) (2 mmol) in anhydrous CH 2Cl 2
(0.5 mL) was quickly added under N 2 protection and the reaction mixture was stirred for 1 h. The
reaction was monitored via
19
F NMR spectroscopy with PhCF 3 as an internal standard, and the yields
were calculated on the basis of substrate 1 used.
3.4.8 NMR Spectra

168

169

170

171

172

173

174

175

3.5 References
[1] (a) Kirsch, P. Modern Fluoroorganic Chemistry: Synthesis, Reactivity, Applications, Wiley-
VCH: Weinheim, 2004; (b) Uneyama, K. Organofluorine Chemistry, Blackwell, Oxford,
2006; (c) Müller, K.; Faeh, C.; Diederich, F. Science, 2 007, 317, 1881.
[2] Bégué, J.-P.; Bonnet-Delpon, D. Bioorganic and Medicinal Chemistry of Fluorine, Wiley-
VCH, Weinheim, 2008.
[3] (a) Prakash, G. K. S.; Hu, J. Acc. Chem. Res. 200 7, 40, 921-930; (b) Hu, J.; J. Fluorine
Chem. 2009, 130, 1130-1139; (c) Hu, J.; Zhang, W.; Wang, F. Chem. Common. 2009, 7465-
7478.
[4] (a) Prakash, G. K. S.; Weber, C.; Chacko, S.; Olah, G. A. Org. Lett. 2007, 9, 1863-1866.
(b) Prakash, G. K. S.; Weber, C.; Chacko, S.; Olah, G. A. J. Comb. Chem. 2007, 9, 920–
923. (c) Zhang, W.; Wang, F.; Hu, J. Org. Lett. 2 009, 11, 2109-2112. (d) Noritake, S.;
Shibata, N.; Nakamura, S.; Toru, T.; Shiro, M. Eur. J. Org. Chem. 20 08, 20, 3465-3468. (e)
Nomura, Y.; Tokunaga, E.; Shibata, N. Angew. Chem. Int. Ed. 2011, 50, 1885-1889.
[5] Reggelin, M.; Zur, C. Synthesis 2000, 1-64.
[6] Johnson, C. R.; Janiga, E. R.; Haake, M. J. Am. Chem. Soc. 196 8, 90, 3890-3891.
[7] (a) Sauer, D. T.; Shreeve, J. M. Inorg. Chem. 1972, 11, 238-242; (b) Abe, T.; Shreeve, J. M.
Chem. Comm. 1981 242-243. (c) Abe, T.; Shreeve, J. M. Inorg. Chem. 1981, 20, 2432-
2434. (d) Abe, T.; Shreeve, J. M. Inorg. Chem. 1 981, 20, 2894-2899.
[8] Boys, M. L.; Collington, E. W.; Finch, H.; Swanson, S.; Whitehead, J. F. Tetrahedron Lett.
1988, 29, 3365-3368.
[9] Kondratenko, N. V.; Radchenko, O. A.; Yagupol'skii, L. M. Zh. Org. Khim. 1 984, 20, 2250-
2251.
[10] Magnier, E.; Wakselman, C. Synthesis 20 03, 565-569.
[11] Johnson, C. R.; Haake, M.; Schroeck, C. W. J. Am. Chem. Soc. 1970, 92, 6594-6598.
[12] Compound 1 was synthesized as a white solid, which was found to be rather labile even
under inert conditions. Approximately 30 % of the reagent was found to decompose after
the overnight storage in a glove box.
[13] Zheng, J.; Li, Y.; Zhang, L.; Hu, J.; Meuzelaar, G. J.; Federsel, H. Chem. Commun. 2007,
5149-5151.
[14] Kikuchi, S.; Konishi, H.; Hashimoto, Y. Tetrahedron 2005, 61, 3587-3591. And the
references therein.
[15] Brahms, D. L. S.; Dailey, W. P. Chem. Rev. 1996, 96, 1585-1632.

176

Chapter 4

Nucleophilic Trifluoromethylation of
Carbonyl Compounds: Trifluoroacetaldehyde
Hydrate as a Trifluoromethyl Source

177

4.1 Introduction
Among various synthetic pathways, the nucleophilic trifluoromethylation of carbonyl
compounds has offered a facile access to α-trifluoromethyl alcohols.
1-4
Although TMSCF 3 (also
known as the Ruppert-Prakash reagent) is a versatile reagent, which is capable of transferring the
CF 3 group (Scheme 4.1-a),
5,6
chemists have also strived for alternative nucleophilic
trifluoromethylating reagents that are applicable to various synthetic purposes.
7-10
In recent years,
a series of nucleophilic trifluoromethylation reactions has been established based on the in situ
formation of transient negatively charged species, which can release trifluoromethyl anion (CF 3
-
)
along with a stable by-product (Scheme 4.1-b).
11
Langlois and others have demonstrated the direct
trifluoromethylation of various electrophiles using trifluoromethane (CF 3H) in DMF through a
trifluoromethylated hemiaminal derivative (CF 3
-
-DMF adduct analogue).
12-19
Prakash et al. utilized
phenyl trifluoromethyl sulfone (PhSO 2CF 3) and phenyl trifluoromethyl sulfoxide (PhSOCF 3) in
nucleophilic trifluoromethylation reactions, which led to the generation of CF 3
-
via pentavalent and
tetravalent sulfur intermediates, respectively.
20
Similar to this work, an alkoxide-induced
trifluoromethylation was also reported by Beier and coworkers using diethyl
trifluoromethylphosphate [(EtO) 2POCF 3].
21
More recently, Colby et al. elegantly developed a novel
nucleophilic trifluoromethylating reagent using hexafluoroacetone hydrate amidinate complex.
22-24

By releasing thermodynamically stable trifluoroacetate anion (CF 3CO 2
-
), such a reagent was able
to incorporate the CF 3 moiety into various electrophiles. On the basis of these reactions, we
envisaged that ready available trifluoroacetaldehyde hemiacetal derivatives (1) could also enable
nucleophilic trifluoromethylation by expelling formates as leaving groups. Compared with other
similar reagents, the advantages of 1 lie in not only its high atom economy but also its maximum
utilization of the CF 3 motif (Scheme 4.1-c).

Scheme 4.1. Generation of "CF 3
-
" synthon through the release of neutral or stable species.

178

4.2 Results and Discussion
Our initial effort was focused on the trifluoromethylation of benzaldehyde (PhCHO, 2a) using
2,2,2-trifluoro-1-methoxyethanol (1a) and 2,2,2-trifluoro-1-ethoxyethanol (1b). By treating 1a and
1b with potassium tert-butoxide (tert-BuOK) in DMF, neither CF 3H nor the desired α-
trifluoromethyl alcohol (3a) was observed after numerous attempts (Scheme 4.2). This could be
ascribed to the plausible reverse addition of CF 3
-
to alkyl formates, which could significantly
impede the trifluoromethylation of benzaldehyde (Scheme 4.2, Eq. 1).

Scheme 4.2. Generation of CF 3
-
from different trifluoroacetaldehyde hemiacetal derivatives.
Considering the essential low electrophilicity of formate anion (HCO 2
-
), trifluoroacetaldehyde
hydrate (1c) was adopted in our further investigation to avoid the reverse CF 3
-
-by-product addition
(Scheme 4.2, Eq. 2). According to
19
F NMR spectroscopy, 3a was obtained in 64% yield by treating
1c (1.2 equiv.) with 6.0 equiv. of tert-BuOK in DMF (Table 4.1, Entries 1-4). Further reaction
condition screening was focused on alternative bases, reaction temperatures and the proportion of
reagents; however, the yields did not improve (Table 4.1, Entry 5-11).

179

Table 4.1. Reaction condition optimization using 1c [CF 3CH(OH) 2-2H 2O] as a CF 3
-
precursor.

Whereas the above mentioned results seemed to be satisfactory, its practicality was largely
limited by the requirement of large excess of base. This was presumably due to the fact that
commercial 1c was a dihydrate CF 3CH(OH) 2· 2H 2O.
25
To remove the excess amount of H 2O,
CF 3CH(OH) 2 was treated with various amines expecting the formation of the corresponding salts
similar to the hexafluoroacetone hydrate amidinate salts.
24
However, no solid complexes could be
obtained by these means, probably due to the lower acidity of CF 3CH(OH) 2 compared with
(CF 3) 2C(OH) 2. We further exploited 4Å molecular sieves as a drying agent, which unfortunately
absorbed majority of CF 3CH(OH) 2 along with water. After a brief screening, calcium chloride
(CaCl 2) was shown to be an efficient drying agent allowing recovery of 95% 1c with a composition
of CF 3CH(OH) 2· ½H 2O.
26
With such processed 1c in hand, the required amount of tert-BuOK was
significantly reduced (Table 4.2, Entries 1-4). The optimal reaction conditions were found by
treating 1c (1.5 equiv.) with tert-BuOK (6.0 equiv.) in DMF at -50 ° C for 30 min, followed by the
addition of PhCHO (1.0 equiv.) (Table 4.2, Entries 5-7). Noticeably, despite the fact that THF and
180

DMSO allowed the release of CF 3
-
from 1c, the nucleophilic trifluoromethylation of benzaldehyde
did not take place (Table 4.2, Entries 8 and 9).
Table 4.2. Reaction condition optimization using 1c [CF 3CH(OH) 2-½H 2O] as a CF 3
-
precursor.

With the optimal reaction conditions, the scope of substrates was investigated. As shown in
Table 4.3, various aldehydes and ketones readily reacted. Aryl aldehydes bearing electron-donating
substituents and halides were shown to participate in the reaction to afford products in good to
excellent yields (Table 4.3, Entries 1-5, 8-11, and 13). However, other strong electron-withdrawing
moieties, such as NO 2 and CF 3 groups, on the phenyl ring impeded the reaction (Table 4.3, Entries
6 and 7). In comparison with the significant electronic effects, the steric hindrance of substituents
did not play a major role in the reactivity of the substrates (Table 4.3, Entries 5 and 9-11). As
anticipated, the trifluoromethylation reaction with enolizable aldehydes was quite sluggish under
such strong basic conditions (Table 4.3, Entry 14). Similar to aryl aldehydes, various benzophenone
derivatives were also found to be reactive (Table 4.3, Entry 12, 14, 15). Bulky phenyl ketone (2s)
also reacted to yield the corresponding product in excellent yield (Table 4.3, Entry 19). Intriguingly,
although enolizable acetophenone was not a viable substrate in the present reaction, adamantan-2-
one (2t) was smoothly trifluoromethylated, due to its low enolizability (Table 4.3, Entry 20).
181

Table 4.3. Nucleophilic trifluoromethylation of carbonyl compounds 2 with trifluoroacetaldehyde
hydrate 1c [CF 3CH(OH) 2-½H 2O].

182

Scheme 4.3. Calculated thermodynamics of the nucleophilic trifluoromethylation reaction using 1c
and the related reactions.
To elucidate mechanistic aspects of the reaction, theoretical calculations were performed at the
B3LYP/6-31+G(d,p) level in DMF
27,28
using Gaussian 09 package.
29,30
As shown in Scheme 4.3,
trifluoroacetaldehyde hydrate 1c preferentially underwent deprotonation in the presence of tert-
BuOK. Although further deprotonated intermediate 1c-K2 was slightly higher in energy by +0.7
kcal/mol, ca. 60% of 1c-K could still be deprotonated with 4 eq. of tert-BuOK under the reaction
183

conditions (Scheme 4.3, Eq. 2). It has also been found that salts 1c-K and 1c-K 2 were
thermodynamically unstable species tending to expel CF 3
-
. Since these processes involve a Gibbs
free energy change of approximately -30 kcal/mol, the reversible addition of CF 3
-
to HCO 2K was
rather unlikely to occur (Scheme 4.3, Eq. 4 and 5). In contrast, the desired product 3a-K was found
to be more stable than the corresponding starting materials by -1.7 kcal/mol (Scheme 4.3, Eq. 6).
This has not only provided a theoretical support for the success in isolating 3a, but also agreed with
the observed essential stability of 3a in the presence of tert-BuOK in DMF. Overall, the Gibbs
energy change was calculated to be downhill by -52.2 kcal/mol, which is mainly due to the highly
exothermic deprotonation and degradation processes (Scheme 4.3, Eq. 6). Noticeably, the
analogous hydride transfer by releasing trifluoroacetate was also found to be an exothermic reaction,
which was however slightly less thermodynamically favorable (Table 4.1, Entry 9 and Scheme 4.3,
Eq. 7).
We further explored transition states to achieve a continuous reaction pathway from 1c to 3a-K
(Figure 4.1). As mentioned above, both 1c-K and 1c-K2 could irreversibly degrade to release CF 3H
and HCO 2K. However, such fragmentation was more likely to proceed via 1c-K2 intermediate due
to the significantly lower barrier involving TS2 than TS1 (+6.5 kcal/mol v.s. +21.0 kcal/mol).
Whereas T S2’ was also located on the reaction pathway suggesting the possible hydride transfer
and trifluoroacetate formation, it was substantially unfavorable compared with TS2. This is not
only in good agreement with the fact that the trifluoromethyl transfer predominated in the present
reaction, but also rationalizes the observed trifluoroacetate formation under certain reaction
conditions (Table 4.1, Entry 9). Presumably, the nucleophilic addition involved the deprotonation
of CF 3H by tert-BuOK, which was predicted to have a small barrier of +9.3 kcal/mol. In spite of
the endothermic deprotonation by +5.6 kcal/mol, the forward nucleophilic addition was both
thermodynamically favored and kinetically facile due to a rather small activation barrier of +19.4
kcal/mol (compared with CF 3H). Apparently, both of these two factors facilitated the nucleophilic
trifluoromethylation under the present reaction conditions.
184

Figure 4.1. Calculated reaction coordinate from 1c to 3a-K.
In addition to the above mentioned studies, we also performed theoretical calculations to explore
the mechanism of nucleophilic trifluoromethylations using trifluoroacetaldehyde hemiacetal (1a)
and hexafluoroacetone hydrate (5). As show in Figure 4.2-A, although the deprotonation of 1a was
thermodynamically feasible, the exothermicity of the subsequent CF 3 release was rather
insignificant (-2.9 kcal/mol), indicating a facile reverse addition of “CF 3
-
” to methyl formate. This
is indeed consistent with the observed low ability of trifluoroacetaldehyde hemiacetals to release
the “CF 3
-
” anion. Moreover, the formations of trifluoroacetaldehyde (via methoxide release) and
methyl trifluoromethylacetate (via hydride release) were found to be highly endothermic,
suggesting that the low reactivity of 1a was mainly due to the reversibility of the “CF 3
-
” release.
Kinetically, the barrier to the nucleophilic trifluoromethylation of benzaldehyde was found to be
fairly similar to nucleophilic trifluoromethylation of methyl formate (+21.5 kcal/mol versus +19.4
kcal/mol). Considering the overall Gibbs energy change from 1a-K to 3a-K was -4.6 kcal/mol, the
interconversion between these two species was essentially reversible (Figure 4.2-C).
185

Figure 4.2. Calculated reaction coordinate of nucleophilic trifluoromethylation of aldehyde using
trifluoroacetaldehyde hemiacetal (1a) and hexafluoroacetone hydrate (5).
As shown in Figure 4.2-B, both the first and the second deprotonations of hexafluoroacetone
hydrate (5) were highly exothermic due to the presence of geminal CF 3 groups. Although the release
of the “CF 3
-
” anion were thermodynamically downhill from both deprotonated products (5-K and
5-K 2), a significantly higher kinetic barrier was found during the course of CF 3 release from 5-K
(+24.6 kcal/mol versus +5.6 kcal/mol). This resembled the CF 3 release coordinate of 1c, therefore
implying that the primary kinetic driving force for CF 3 release was the formation of the highly ionic
dipotassium salts 1c-K 2 and 5-K 2. In contrast, 1a could only form a monopotassium-containing
species 1a-K, which thus retarded to expel CF 3
-
. Noticeably, the nucleophilic trifluoromethylation
using 5 was calculated to be thermodynamically more favorable than that using 1c by ca. 13
kcal/mol. This was presumably due to the generation of by-product CF 3CO 2K, whose conjugate
acid is more acidic than formic acid. However, since both reactions employing 1c and 5 were highly
186

exothermic processes, such difference in Gibbs free energy release did not have significantly
influence on the reversibility of these two reactions.

4.3 Conclusion
In conclusion, we have developed a novel nucleophilic trifluoromethylation of carbonyl
compounds using trifluoroacetaldehyde hydrate 1c as a CF 3
-
precursor. The utilization of readily
available trifluoroacetaldehyde hydrate has not only provided a facile synthetic access towards α-
trifluoromethyl alcohols, but also allowed maximum utilization of the CF 3 moiety in the precursor
(compared with hexafluoroacetone hydrate). Theoretical calculations have suggested that both
trifluoroacetaldehyde hydrate deprotonation and subsequent CF 3 release from potassium salt 1c-
K2 were highly exothermic processes. These two steps contributed ca. +50 kcal/mol Gibbs free
energy release as the actual driving force for the reaction. Further theoretical calculations of
nucleophilic trifluoromethylations using trifluoroacetaldehyde hemiacetal 1a and
hexafluoroacetone hydrate 5 provided mechanistic rationalizations of their different reactivity from
trifluoroacetaldehyde hydrate 1c.

4.4 Experimental
Unless otherwise mentioned, all the chemicals were purchased from commercial sources and
used without further purification. Preparative thin layer chromatography or flash column
chromatography were performed to isolate products with suitable 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 standard at δ 7.26 ppm.
13
C NMR shifts were
determined relative to CDCl 3 at δ 77.16 ppm.
19
F NMR chemical shifts were determined relative to
CFCl 3 at δ 0.00 ppm. Mass spectra were recorded on a high resolution mass spectrometer, in the
EI, FAB or ESI modes.
4.4.1 General procedure for Removal of Excess Water from Commercial
Trifluoroacetaldehyde Hydrate 1c.
Commercial trifluoroacetaldehyde hydrate 1c (5.00 g, 32.9 mmol) in 100 mL anhydrous Et 2O
was added CaCl 2 (1.21 g, 11.0 mmol) in small portions with vigorous stirring. The mixture was
stirred for 2 h and quickly subjected to suction filtration under air. The solvent of the filtrate was
removed under reduced pressure to give partially dried product (4.11 g).
19
F NMR spectrum of this
187

sample showed 1.5 equivalents of H 2O compared to the amount of CF 3CHO, therefore indicating a
formula of CF 3CH(OH) 2· ½H 2O and > 95% yield. The newly prepared trifluoroacetaldehyde
hydrate was transferred into a tightly sealed vial and stored in a glove box.
4.4.2 General Procedure for Nucleophilic Trifluoromethylation of Carbonyl
Compounds.
To a stirred solution of trifluoroacetaldehyde hydrate (1c, 1.5 mmol) in DMF (1.0 mL) at -50 ° C,
a solution of tert-BuOK (672.54 mg, 6.0 mmol) in DMF (3.0 mL) was added dropwise over 5 min.
The reaction was stirred for 30 min while maintaining the temperature at -50 ° C. A solution of
carbonyl compounds (2, 1 mmol) in DMF (1.0 mL) was then added into the reaction mixture at -
50 ° C and stirred for 1 h. The reaction mixture was allowed to gradually warm up to room
temperature before quenching with water. The resulting mixture was extracted with diethyl ether
(3× 10 mL). The combined organic phase was then washed with saturated NH 4Cl aqueous solution,
water, and dried over Na 2SO 4. The solvent was removed under reduced pressure and the residue
was purified with silica gel flash chromatography using pentane-diethyl ether as eluent.
1-Phenyl-2,2,2-trifluoroethanol (3a).
20
Colorless oil, 83% yield.
1
H NMR (400 MHz,
CDCl 3) δ. 7.55-7.37 (m, 5H), 5.00 (q, J = 6.7 Hz, 1H), 2.78 (br, 1H).
19
F NMR (376 MHz, CDCl 3)
δ -78.9 (d, J = 6.7 Hz, 3F).
1-(4-Fluoro-phenyl)-2,2,2-trifluoroethanol (3b).
20, 32
Colorless oil, 51% yield.
1
H NMR
(400 MHz, CDCl 3) δ 7.48-7.44 (m, 2H), 7.15-7.05 (m, 2H), 5.01 (q, J = 6.6 Hz, 1H), 2.74 (br, 1H).
19
F NMR (376 MHz, CDCl 3) δ -79.2 (d, J = 6.6 Hz, 3F).
1-(4-Chloro-phenyl)-2,2,2-trifluoroethanol (3c).
20,32
Colorless oil, 58% yield.
1
H NMR
(400 MHz, CDCl 3) δ 7.48-7.33 (m, 4H), 5.01 (q, J = 6.5 Hz, 1H), 2.72 (br, 1H).
19
F NMR (376
MHz, CDCl 3) δ -79.0 (d, J = 6.5 Hz, 3F).
1-(4-Bromo-phenyl)-2,2,2-trifluoroethanol (3d).
33
Colorless oil, 56% yield.
1
H NMR (400
MHz, CDCl 3) δ 7.57-7.53 (m, 2H), 7.36-7.33 (m, 2H), 4.98 (dq, J = 4.3, 6.6 Hz, 1H), 2.83 (d, J =
4.3 Hz, 1H).
19
F NMR (376 MHz, CDCl 3) δ -79.0 (d, J = 6.6 Hz, 3F).
1-(4-Methyl-phenyl)-2,2,2-trifluoroethanol (3e).
33
Colorless oil, 45% yield.
1
H NMR (400
MHz, CDCl 3) δ 7.36 (d, J = 7.9 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 4.98 (q, J = 6.7 Hz, 1H), 2.56
(br, 1H), 2.38 (s, 3H).
19
F NMR (376 MHz, CDCl 3) δ -78.9 (d, J = 6.7 Hz, 3F).
188

1-(4-Dimethylamino-phenyl)-2,2,2-trifluoroethanol (3h).
24
Colorless solid (reddish), 94%
yield.
1
H NMR (400 MHz, CDCl 3) δ 7.31 (d, J = 8.6 Hz, 2H), 6.73 (d, J = 8.8 Hz, 2H), 4.88 (q, J
= 6.8 Hz, 1H), 2.97 (s, 6H), 2.66 (br, 1H).
19
F NMR (376 MHz, CDCl 3) δ -78.9 (d, J = 6.8 Hz, 3F).
1-(3-Dimethylamino-phenyl)-2,2,2-trifluoroethanol (3i).
4
Colorless oil, 72% yield.
1
H
NMR (400 MHz, CDCl 3) δ 7.34-7.18 (m, 4H), 4.96 (q, J = 6.7 Hz, 1H), 2.68 (br, 1H), 2.39 (s, 3H).
19
F NMR (376 MHz, CDCl 3) δ -78.8 (d, J = 6.7 Hz, 3F).
1-(2-Dimethylamino-phenyl)-2,2,2-trifluoroethanol (3j).
34
Colorless oil, 53% yield.
1
H
NMR (400 MHz, CDCl 3) δ 7.66-7.56 (m, 1H), 7.34-7.19 (m, 3H), 5.31 (dq, J = 6.6, 4.3 Hz, 1H),
2.67 (d, J = 4.5 Hz, 1H), 2.39 (s, 3H).
19
F NMR (376 MHz, CDCl 3) δ -78.2 (d, J = 6.6 Hz, 3F).
1-(2,4,6-Trimethoxy-phenyl)-2,2,2-trifluoroethanol (3k). White solid, 70% yield.
1
H NMR
(400 MHz, CDCl 3) δ 6.17 (d, J = 11.6 Hz, 2H), 5.44 (dq, J = 11.8, 7.8 Hz, 1H), 4.86 (d, J = 11.8
Hz, 1H), 3.83 (s, 6H), 3.80 (s, 3H).
19
F NMR (376 MHz, CDCl 3) δ -78.6 (d, J =7.8 Hz, 3F).
13
C
NMR (125 MHz, CDCl 3) δ 162.1, 159.8, 125.3 (q, J =284.4 Hz), 103.0, 91.4, 67.1 (q, J =33.4 Hz),
56.1, 55.5. Exact mass calcd for C 11H 13O 4F 3 [M] : 266.0766, Found : 266.0770.
2,2,2-Trifluoro-1-(naphthalen-2-yl)ethanol (3m).
20
White solid, 57% yield.
1
H NMR (400
MHz, CDCl 3) δ 7.84 (d, J = 0.5 Hz, 1H), 7.81-7.73(m, 3H), 7.49-7.40 (m, 3H), 5.06 (dq, J = 6.7,
4.2 Hz, 1H), 2.76 (d, J = 4.2 Hz, 1H).
19
F NMR (376 MHz, CDCl 3) δ -78.6 (d, J =6.7 Hz, 3F).
2,2,2-Trifluoro-1,1-diphenylethanol (3p).
20
Colorless oil, 90% yield.
1
H NMR (400 MHz,
CDCl 3) δ. 7.58-7.53 (m, 4H), 7.43-7.37 (m, 6H), 3.06 (br, 1H).
19
F NMR (376 MHz, CDCl 3) δ -
74.3 (s, 3F).
2,2,2-Trifluoro-1,1-bis(4-methoxyphenyl)ethanol (3q).
24
Colorless oil, 80% yield.
1
H NMR
(400 MHz, CDCl 3) δ. 7.41 (d, J = 8.6 Hz, 4H), 6.89-6.85 (m, 4H), 3.80 (s, 6H), 3.03 (br, 1H).
19
F
NMR (376 MHz, CDCl 3) δ -75.1 (s, 3F).
2,2,2-trifluoro-1-(4-nitrophenyl)-1-phenylethanol (3r).
20
Colorless oil, 45% yield.
1
H
NMR (400 MHz, CDCl 3) δ. 8.17 (t, J = 11.5 Hz, 2H), 7.68 (dd, J = 17.5, 8.5 Hz, 2H), 7.54-7.51
(m, 2H), 7.4527.35 (m, 3H), 3.26 (s, 1H).
19
F NMR (376 MHz, CDCl 3) δ -74.7 (s, 3F).
1-Adamantan-1-yl-2,2,2-trifluoro-1-phenylethanol (3s). White solid, 96% yield.
1
H NMR
(400 MHz, CDCl 3) δ. 7.74-7.30 (m, 5H), 2.52 (s, 1H), 2.02 (s, 3H), 1.76 (dd, J = 49.5, 12.2 Hz,
6H), 1.61 (dd, J = 38.1, 12.2 Hz, 6H).
19
F NMR (376 MHz, CDCl 3) δ -66.8 (s, 3F).
13
C NMR (100
MHz, CDCl 3) δ 136.2, 128.1, 127.1 (q, J = 290.1 Hz), 127.9 (br), 127.3 (br), 127.2 (br), 82.4 (q, J
189

= 25.4 Hz), 39.8, 36.71, 36.68, 28.5. Exact mass calcd for C 18H 19F 3 [M-H 2O]
+
: 292.1433, Found :
292.1439.
2-(Trifluoromethyl)adamantan-2-ol (3t).
20
White solid, 95% yield.
1
H NMR (400 MHz,
CDCl 3) δ. 2.29-2.21 (m, 2H), 2.14-2.04 (m, 4H), 1.90 (s, 1H), 1.89-1.80 (m, 2H), 1.80-1.70 (m,
4H), 1.64-1.54 (m, 2H).
19
F NMR (376 MHz, CDCl 3) δ -75.7 (s, 3F).
4.4.3 Theoretical Calculations
Theoretical calculations were performed at the B3LYP/6-31+G(d,p) level in DMF using Gaussian
09 package.
29,30
Solvent effects were included implicitly through the self-consistent reaction field
approach, as implemented in the default Polarizable Continuum Model (PCM) in Gaussian 09.
27,28

Thermal and entropic corrections for PCM-optimized structures were obtained by frequency analysis at
the B3LYP/6-31+G(d,p) level. The frequency analyses confirmed that all considered ground state
structures were true minima on the PES. All transition states were also identified and validated using
vibrational frequency analysis.
Calculated Ground State Structures
Species Calculated Structure ε 0+G corr
ΔG
relative to
most stable
conformer
(kcal/mol)

-
345.526084
-

-
832.973349
-
190

-
233.601138
-

-
528.003924
+0.3

-
528.004364
+0.0

-
528.002437
+1.2

-
528.004226
+0.1

-
1127.406787
1.3

-
1127.408866
0.0
191

-
1127.405818
1.9

-
1726.776132
2.4

-
1726.779954
0.0

-
338.262183
-

-
937.625486
-

-
789.194834
-

-
1126.260750
-
192

-
1283.163263
-

-
946.086666
-

Calculated Transition State Structures
Species Calculated Structure ε 0+G corr
ΔG
‡
relative
to
corresponding
stable ground
state (kcal/mol)

-
1127.375327
+21.0
relative to

-
1726.769662
+6.5
relative to

193

-
1726.756709
+14.6
relative to

-
1283.129601
+13.8
relative to
the energy sum
( ε 0+G corr) of
CF 3K and
PhCHO

194

4.4.4 NMR Spectra

195

196

197

198

199

200

201

202

203

204

205

206

207

208

209

210

211

4.5 References
[1] Uneyama, K. Organofluorine Chemistry, Blackwell Publish, Oxford, 2006.
[2] The applications of organofluorine compounds have been thoroughly summarized, Kirsch,
P. Modern Fluoroorganic Chemistry: Synthesis, Reactivity, Applications, Wiley-VCH,
2004.
[3] Prakash, G. K. S.; Wang, F. Flourishing Frontiers in Organofluorine Chemistry, in
Organic Chemistry-Breakthroughs and Perspectives (eds K. Ding and L.-X. Dai), Wiley-
VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, pp. 413-473, 2012.
[4] Prakash, G. K. S.; Jog, P. V.; Batamack, P. T. D.; Olah, G. A. Science 2012, 338, 1324-
1327.
[5] Prakash, G. K. S.; Krishnamurti, R.; Olah, G. A. J. Am. Chem. Soc. 1989, 111, 393-395.
[6] Prakash, G. K. S.; Mandal, M. J. Fluorine Chem. 2001, 112, 123-131.
[7] Ait-Mohand, S.; Takechi, N.; Medebielle, M.; Dolbier Jr. W. R. Org. Lett. 2001, 3, 4271-
4273.
[8] Takechi, N.; Ait-Mohand, S.; Medebielle, M.; Dolbier Jr. W. R. Org. Lett. 2002, 4, 4671-
4672.
[9] Xu, W.; Dolbier Jr. W. R. J. Org. Chem. 2005, 70, 4741-4745.
[10] Zhao, Y.; Zhu, J.; Ni, C.; Hu, J. Synthesis 2010, 1899-1904.
[11] The mechanism of these reactions is also conceptually similar to the trifluoromethylation
using TMSCF 3, which is achieved via in situ formation of metastable pentavalent silicon
intermediates.
[12] Shono, T.; Ishifume, M.; Okada, T.; Kashimura S. J. Org. Chem. 1991, 56, 2-4.
[13] Barhdadi, R.; Troupel, M.; Perichon, J. Chem. Commun. 1998, 12, 1251-1252.
[14] Folleas, B.; Marek, I.; Normant, J.-F.; Saint-Jalmes, L. Tetrahedron Lett. 1998, 39, 2973-
2976.
[15] Folleas, B.; Marek, I.; Normant, J.-F.; Saint-Jalmes, L. Tetrahedron 2000, 56, 275-283.
[16] Russell, J.; Roques, N. Tetrahedron 1998, 54, 13771-13782.
[17] Large, S.; Roques, N.; Langlois, B. R. J. Org. Chem. 2000, 65, 8848-8856.
[18] Roques, N.; Mispelaere, C. Tetrahedron Lett. 1999, 40, 6411-6414.
[19] Billard, T. B.; Langlois, B. R. Org. Lett. 2000, 2, 2101-2103.
[20] Prakash, G. K. S.; Hu, J.; Olah, G. A. Org. Lett. 2003, 5, 3253-3256.
[21] Cherkupally, P.; Beier, P. Tetrahedron Lett. 2010, 51, 252-255.
[22] Han, C.; Kim, E. H.; Colby, D. A. J. Am. Chem. Soc. 2011, 133, 5802-5805.
212

[23] Han, C.; Kim, E. H.; Colby, D. A. Synlett 2011, 23, 1559-1563.
[24] Riofski, M. V.; Hart, A. D.; Colby, D. A. Org. Lett. 2013, 15, 208-211.
[25] The formula of 1c was determined via
19
F NMR spectroscopy by mixing 1c (of a given
mass, generally ca. 100 mg) with PhCF 3 (20 μL, 0.163 mmol, an internal standard) in 0.5
mL CD 3OD.
[26] The procedure was modified based on a known method. Junji, N.; Shozo, K.; Yoshifumi,
Y.; Yoshikazu, S.; Yukio, H.; Yuzuru, M. Brit. UK Pat. Appl. 1993, GB 2260322 A
19930414.
[27] Solvent effects were included implicitly through the self-consistent reaction field approach,
as implemented in the default Polarizable Continuum Model (PCM) in Gaussian 09.
Miertuš, S.; Scrocco, E.; Tomasi, J. Chem. Phys. 1981, 55, 117-129.
[28] Scalmani, G.; Frisch, M. J. J. Chem. Phys. 2010, 132, 114110-114115.
[29] Gaussian 09, Revision A.1, Frisch, M. J. et al. Gaussian, Inc., Wallingford CT, 2009. See
Supporting Information for the complete citation.
[30] Thermal and entropic corrections for PCM-optimized structures were obtained by
frequency analysis at the B3LYP/6-31+G(d,p) level. The frequency analyses also
confirmed that all considered structures were true minima on the PES.
[31] Tordeux, M.; Francese, C.; Wakselman, C.; J. Chem. Soc., Perkin Trans. 1 1990, 1951-
1957.
[32] Matsuda, T.; Harada, T.; Nakajima, N.; Itoh, T.; Nakamura, K. J. Org. Chem. 2000, 65,
157-163.
[33] Motherwell, W. M.; Storey, L. J. Synlett 2002, 4, 646-648.
[34] Chang, Y.; Cai, C. Tetrahedron Lett. 2005, 46, 3161-3164

213

Chapter 5

The Long-Lived Trifluoromethide Anion: A
Key Intermediate in Nucleophilic
Trifluoromethylations

214

5.1 Introduction
Because of the potential applications of fluorinated compounds in chemistry, biology, and
materials science,
[1-5]
fluorine substitution of organic compounds has become a vibrant research
area in synthetic organic chemistry.
[6-10]
Among various fluorinated substituents, the
trifluoromethyl group (CF 3) stands out not only because of its role as the parent of other fluoroalkyl
moieties, but also owing to its remarkable potential for modulating chemical, physical, and
biochemical properties of molecules.
[1,4,11]
Over the past several decades, significant advances have
been made for the synthetic incorporation of the trifluoromethyl moiety, such as cross-coupling
reactions or nucleophilic and electrophilic trifluoromethylations.
[8,9,12-16]
Mechanistically, a vast
majority of these transformations are proposed to involve, directly or indirectly, the
trifluoromethide, anion (CF 3
-
) (Figure 5.1-A). Despite evidence for CF 3
-
in the gas phase from mass
spectrometry
[17]
and photoelectron spectroscopy,
[18]
and tentatively from IR spectroscopy at 5 K in
a neon matrix,
[19]
it was widely accepted for more than six decades that CF 3
-
is an essentially
transient species, which can undergo swift α-defluorination to singlet difluorocarbene in the
condensed phase (Figure 5.1-B).
[5,8,15,20-27]
To date, the extreme low thermal stability of CF 3
-
has
been frequently invoked in the mechanisms of various reactions in organofluorine chemistry.

Figure 5.1. A. Central role of trifluoromethide in fluoroalkylation chemistry. B. Proposed
mechanisms for the decomposition of trifluoromethide and ionic metal-CF 3 complexes. C.
Calculated C-F bond dissociation enthalpies and free energies of CF 3
-
and the KCF 3 ion pair (1 M
concentration) in THF at 298 K.

215

5.2 Results and Discussion
Considering the high strength of C-F bonds among carbon halogen bonds
[20a]
and the relatively
strong Lewis acidity of singlet difluorocarbene (CF 2), as computed by its fluoride (F
-
) affinity of
46.7 kcal/mol in the gas phase
[28,29]
, the CF 3
-
is expected to be a rather persistent species at low
temperatures.

We have estimated the adiabatic C-F bond dissociation enthalpy and free energy of
CF 3
-
in THF to be 25.4 kcal/mol and 16.7 kcal/mol, respectively, at the COSMO-CCSD(T)/Def2-
TZVPPD//SMD-M06-2X/Def2-TZVPPD level of theory (Figure 5.1-C). Further calculations
predict that the α-defluorination enthalpy and free energy can be significantly reduced to +17.1
kcal/mol and +9.7 kcal/mol, respectively, in the presence of a potassium cation (Figure 5.1-C). In
addition, we have observed the decomposition of ethyl α-fluorobromo acetate after deprotonation
through α-debromination instead of α-defluorination in Chapter 2, indicating the fairly strength of
C-F bond (in contrast to the widely accepted interpretation of “spontaneous α-defluorination due
to Columbus repulsive force”). On the one hand, these results indicate that CF 3
-
might possess
sufficient thermal stability to allow its preparation and isolation at sub-ambient temperatures. On
the other hand, to suppress possible decomposition, it is necessary to diminish the metal-
trifluoromethide interactions through efficient coordination of the metal cation.
[30a]
Herein, we
report the generation and characterization of CF 3
-
with the [K(18-crown-6)]
+
cation

in a THF
solution as a long-lived key intermediate at sub-ambient temperatures.
Based on the discussions above, the generation of CF 3
-
was initially attempted by treating
fluoroform (CF 3H) with excess potassium tert-butoxide (tert-BuOK) in the presence of 18-crown-
6 in THF at -78 ° C (Scheme 5.1, Eq. 1 and Figure 5.3). Although CF 3
-
was previously not reported
as an observable species in the direct deprotonation of CF 3H using organic superbases
[26,27]
and
potassium-based strong bases,
[16,23-25,31]
a weak broad signal around -19 ppm was found by
19
F NMR
spectroscopy at -78 ° C under the present reaction conditions.
[30b]
Compared with the reported
19
F
NMR chemical shifts of transition metal-CF 3 complexes, such as CuCF 3
[25,32]
and the [Cu(CF 3) 2]
-
anion,
[33]
the observed broad signal is likely to correspond to exchange broadened CF 3
-
.
Considering that the reactions between trifluoromethyltrimethylsilane (TMSCF 3, the Ruppert-
Prakash reagent)
[34]
and Lewis bases can be energetically more favorable than those using CF 3H,
further investigation was focused on generating CF 3
-
using TMSCF 3. Similar to previous
observations in the literature,
[35,36]
initial attempts to treat TMSCF 3 with various fluoride sources
exclusively led to CF 3-containing pentacoordinated silicon adducts (Scheme 5.1, Eq. 2).

216

Scheme 5.1. Equations 1-3: Attempted preparations of CF 3
-
under various reaction conditions.
Equation 4: Equilibrium between CF 3
-
and the pentacoordinated [(CH 3) 3Si(CF 3) 2]
-
anion at different
temperatures in a THF solution. Equation 5: Optimal conditions for the synthesis of CF 3
-
.
In spite of using a bulky tert-butoxy anion as a Lewis base, the pentacoordinated
[(CH 3) 3Si(CF 3) 2]
-
anion was observed as the major product in the
19
F NMR spectrum (a singlet at -
65.6 ppm), along with CF 3H (a doublet at -81.0 ppm) possibly generated by the deprotonation of
the solvent or crown ether by CF 3
-
, and a sharp singlet at -18.8 ppm implying the formation of some
CF 3
-
(Scheme 5.1, Eq. 3 and Figure 5.4). Intriguingly, the [(CH 3) 3Si(CF 3) 2]
-
anion, dominant at -
78 ° C, was found to dissociate to CF 3
-
and TMSOtBu at -56 ° C (Scheme 5.1, Eq. 4, Figures 5.17
and 5.18). Although the preparation of CF 3
-
can thus be achieved in relatively high conversions,
complete dissociation of the [(CH 3) 3Si(CF 3) 2]
-
anion to CF 3
-
can be accomplished in this manner
only under strictly controlled reaction conditions.

Sterically bulky trifluoromethyltriisopropylsilane (TIPSCF 3)
[16]
was then employed to inhibit
the formation of undesired pentacoordinated silicon species. By reacting a mixture of tert-BuOK
and 18-crown-6 in THF at -78 ° C with TIPSCF 3, complete conversion to CF 3
-
was achieved within
minutes (Scheme 5.1, Eq. 5 and Figure 5.6). A sharp singlet was detected at -18.7 ppm in the
19
F
NMR spectrum, and this chemical shift was essentially identical to those observed with either CF 3H
or TMSCF 3 as the trifluoromethide sources (Figure 5.2 A). A small amount of CF 3H was also
observed due to protonation from the solvent or crown ether by CF 3
-
, along with a fairly weak
217

singlet at -116.1 ppm. The latter signal can be tentatively assigned to a CF 2-containing compound,
presumably arising from the singlet difluorocarbene formed by slow CF 3
-
decomposition.

Figure 5.2. A.
19
F NMR spectrum of CF 3
-
, generated according to Eq. 5 in Scheme 5.1, in THF at
-78 ° C with PhCF 3 as an internal standard at -63.0 ppm relative to CFCl 3. The CF 3H is due to
protonation from the solvent or crown ether by CF 3
-
. B.
13
C NMR spectrum of CF 3
-
, generated
according to Eq. 3 in Scheme 5.1, in THF at -56 ° C.
After meticulous efforts, the
13
C NMR spectrum of CF 3
-
was obtained at -56 ° C by using
TMSCF 3 as the trifluoromethide source. The
13
C NMR spectrum showed an explicit quartet at 175.0
ppm with a 1:2:2:1 intensity pattern, suggesting that the carbon atom is attached to three equivalent
fluorine atoms (Figure 5.2 B). The
1
J C-F coupling constant was determined to be 432.5 Hz, which
is among the largest
1
J C-F coupling constants ever observed (Figure 5.2 B and Figure 5.5).
[37]
This
value is in good agreement with the
1
J C-F coupling constant measured by the
13
C satellite signals in
the
19
F NMR spectra (429.3 Hz and 434.0 Hz with TMSCF 3 and TIPSCF 3 as CF 3
-
sources,
respectively). These results not only confirm the correspondence between the
19
F and
13
C NMR
signals, but also provide evidence that the reactions employing TMSCF 3 and TIPSCF 3 leads to the
same species, i.e. CF 3
-
at -18.7 ppm in the
19
F NMR spectra. The assignment of our NMR
spectroscopic data to CF 3
-
were validated by GIAO-PCM-B3LYP/aug-cc-pVTZ//PCM-B3LYP/6-
218

31+G(d,p) calculations.
[38,39]
The
19
F NMR and
13
C NMR chemical shifts of CF 3
-
were computed
to be -23.7 and 170.3 ppm, respectively, which are in good agreement with the experimental data.
Although the predicted
1
J C-F coupling constant of CF 3
-
of 393.0 Hz differs from the experimental
value by 9% likely due to reported systematic errors,
40
the significantly larger experimental and
calculated
1
J C-F coupling constants of CF 3
-
compared with that of CF 3H are consistent with the
expected higher pyramidalization of anionic carbon centers.
[37]
Similar observations have been
documented in the literature, such as those for CF 3CF 2Li
[41]
and (PhSO 2) 2CF
-
.
[42]

The thermal stability of CF 3
-
was investigated by variable temperature
19
F NMR experiments.
The trifluoromethide anion was found to have reasonable stability at -78 ° C for a few days, which
supports the relatively high decomposition barrier in THF predicted by our calculations. When
samples containing [K(18-crown-6)]
+
[CF 3]
-
in a THF solution were recorded at temperatures from
-50 to -35 ° C, the intensity of the CF 3
-
signal decreased with time while that of CF 3H increased,
and the sum of the areas of the two signals remained essentially constant (Figures 5.15 and 5.16).
This observation not only demonstrates the strong basic character of CF 3
-
enabling the
deprotonation of either THF or 18-crown-6, but also suggests that α-defluorination of CF 3
-
is a
relatively slow process than its protonation. On prolonged exposure to -35 ° C, the decomposition
of CF 3
-
was significantly accelerated as indicated by the appearance of two sets of signals, i.e. a
relatively simple one consisting of two singlets at -125.7 ppm and -129.1 ppm with an area ratio of
1.2:1.0, respectively and a more complex one in the -40 to -140 ppm range with several multiplets
probably due to F-F coupling (Figure 5.15). As mentioned above, a fairly weak singlet at -116.1
ppm was also observed in the range characteristic for CF 2 group containing compounds.
[37]

Although tetrafluoroethylene (C 2F 4, δ F = ca. -134 ppm)
[37]
was not observed in the current reactions,
an explicit interpretation of these spectral data remains difficult due to their complexity and the
paucity of literature data on the condensation reactions of difluorocarbene. The relatively long life
of CF 3
-
at low temperature, along with the recently observed high thermal stabilities of SnF 3
-
and
GeF 3
-
,
[43]
demonstrate that the widely invoked strong repulsion between the free valence electron
pair on carbon and the partial negative charges on the fluorine ligands in CF 3
-[5,8,20]
does not
necessarily lead to its spontaneous α-defluorination. (See 5.4.9 for detailed discussions on charge
distribution,
[44]
the lone pair of electrons in CF 3
-[45]
and its C 3V symmetry.)

219

Table 5.1. Capture of CF 3
-
with various electrophiles.
Entry
Electrophile
(equiv.)
Product
19
F NMR chemical shift
(ppm)
[a]

19
F NMR yield/
conv. (%)
[b]

1 PhSSPh (2.2) PhSCF 3 −43.4 70/70
2 I 2 (2.2) CF 3I −16.5 48/61
3 MeI (11.0) MeCF 3 −60.8 21/24
4 (PhSO 2) 2NF (2.2) PhSO 2CF 3 −79.5 41/72
5 PhCOMe (11.0)

−79.5 22/36
6 PhCHO (2.2)

−78.3 68/68
7 CO 2 (excess) CF 3CO 2K −75.2 76/76
8

−60.3 7/21
9 CuI (11.0) CuCF 3 −24.9 66/77
[a]
19
F NMR chemical shifts relative to PhCF 3 (−63.0 ppm) as an internal standard. [b]
19
F
NMR yields of product and conversion of TIPSCF 3 based on TIPSCF 3 with reference to PhCF 3
as an internal standard.
In addition to the unequivocal NMR spectroscopic characterization, a series of trapping
experiments was carried out to ascertain the reactivity of CF 3
-
in nucleophilic trifluoromethylations.
The experiments were performed by mixing TIPSCF 3 with tert-BuOK in the presence of 18-crown-
6 at -78 ° C for 0.5 h, which assured the complete conversion of TIPSCF 3 to CF 3
-
. The reaction
mixture was subsequently treated with electrophilic substrates to afford the corresponding
trifluoromethylated products. As shown in Table 5.1, various types of trifluoromethylation
reactions were achieved via the above mentioned reaction sequence, including nucleophilic
substitution reactions (Entries 1-4), nucleophilic addition reactions (Entries 5-7), aromatic
nucleophilic substitution reaction (Entry 8), and cupration (Entry 9). Due to the ubiquitous presence
of proton sources in the trapping experiments, CF 3H can be formed and possibly participate in the
trifluoromethylation reactions. As the concentration of CF 3
-
was shown, by NMR experiments, to
be generally higher than that of CF 3H, direct reactions between CF 3
-
and the substrates most likely
made a significant contribution to the overall trifluoromethylations, particularly in the high yielding
reactions 1, 6, 7, and 9. Given the considerable long life of CF 3
-
at low temperatures, the results
220

from the trapping experiments mentioned above, and recent observations of trifluoromethylations
in solvents other than DMF,
[16,26,27]
detailed mechanistic investigations may still be warranted for
nucleophilic trifluoromethylations that were postulated by assuming the inherent instability of
CF 3
-
.
[23,25,26]

5.3 Conclusion
In conclusion, the trifluoromethide anion with [K(18-crown-6)]
+
countercation has been
successfully observed and characterized for the first time in solution. Its formation was confirmed
by low-temperature
13
C and
19
F NMR spectroscopy in a THF solution. Contrary to previous
assumption, it is now shown that the CF 3
-
is not a transient species but possesses significant lifetime
at sub-ambient temperatures. The reaction chemistry of isolated CF 3
-
provides direct evidence, for
the first time, of the intermediacy of CF 3
-
in various nucleophilic trifluoromethylation reactions.
Previous failures to isolate this key intermediate can be attributed to its facile reaction with reactive
acceptors, such as TMSF and TMSCF 3, and ready protonation to form CF 3H due to its strong
basicity. Considering the central role of CF 3
-
in fluoroalkylation reactions, the present results not
only advance the understanding of the related chemistry, but are also expected to provide a
mechanistic basis for the development of novel synthetic protocols in organofluorine chemistry.

5.4 Experimental
Unless otherwise mentioned, all the chemicals were purchased from commercial sources and
used without further purification. THF was freshly distilled from potassium under argon
atmosphere and stored over sodium-potassium alloy. THF-d 8 was dried over sodium-potassium
alloy and transferred to NMR tubes via diffusion under reduced pressure. 18-Crown-6 was dried
by sublimation (1 mTorr, 120 ° C).
1
H,
13
C, and
19
F NMR spectra were recorded on Varian 400 MHz
or 600 MHz NMR spectrometers.
1
H NMR chemical shifts were determined relative to the NMR
solvent residual peak as internal standard (CHCl 3, δ = 7.26 ppm).
13
C NMR shifts were determined
relative to THF-d 8 as internal standard (δ = 67.6 and 25.4 ppm, respectively).
19
F NMR chemical
shifts were determined relative to CFCl 3 at δ = 0.0 ppm in CDCl 3 or PhCF 3 at δ = 63.0 ppm in THF
or THF-d 8 as internal standards. The NMR temperature calibration was carried by measuring the
chemical-shift separation between the OH and CD 2H resonances in CD 3OD to give an accuracy of
221

± 0.1 K. Known fluorine-containing compounds were confirmed by comparing their
19
F NMR
chemical shifts with literature reported values.
5.4.1 General procedure for the preparation of trifluoromethyl(triisopropyl)silane
(TIPSCF3).
16

To a 250 mL round bottom flask charged with a magnetic stir bar was added anhydrous diethyl
ether (140 mL) under nitrogen. The flask was cooled to -78 º C for 10 min before CF 3H (34.3 mmol,
2.4 g) was bubbled into the ether solution. Chlorotriisopropylsilane (5.32 g, 27.7 mmol) was then
added to the reaction mixture and the resulting reaction mixture was stirred at -78 º C for 10 min
before dropwise addition of a suspension of potassium hexamethyldisilazide (7.40 g, 37.1 mmol)
in anhydrous ether (60 mL). The resulting yellowish reaction mixture was stirred at -78 º C for 2 h.
The reaction mixture was gradually warmed to room temperature and further stirred for 1 h. Ether
was removed under reduced pressure, and the residue was dissolved in pentane (150 mL). The
mixture was washed with water (1 × 30 mL) and cold concentrated sulfuric acid (98%, 4 × 15 mL)
to remove silicon-containing by-products. The organic layer was then washed with water (5 × 50
mL) until pH ≈ 7. The organic layer was dried over sodium sulfate. After the removal of the solvent
by distillation, the crude product was purified via vacuum distillation to afford pure TIPSCF 3 (4.10
g, 65%, bp 34
o
C/5 mmHg).
1
H NMR (400 MHz): δ 1.15 (d,
3
J H-H = 7.2 Hz, 18H), 1.29 (sep,
3
J H-H
= 7.2 Hz, 3H);
19
F NMR (376 MHz): δ -55.5 (s).
5.4.2 General procedure for the preparation of the CF3
-
anion from CF3H in an
NMR tube.
In a glovebox, tert-BuOK (11.2 mg, 0.1 mmol) and 18-crown-6 (26.4 mg, 0.1 mmol) were
weighed into an NMR tube which was tightly capped with a rubber septum. Freshly distilled THF
(0.6 mL, with PhCF 3 as an internal standard) was added to the mixture with a syringe at room
temperature. The mixture was sonicated (ca. 5 min) until a homogeneous solution was formed. The
solution was cooled to -78 º C for 10 min. CF 3H (0.1 mL, ca. 1 M solution in THF) was added to
the NMR tube using a syringe through the rubber septum. The rubber septum was carefully sealed
with PTFE thread seal tape and parafilm. The mixture was then shaken gently at -78 º C to obtain a
homogenous solution, which was analyzed by
19
F NMR.
5.4.3 General procedure for the preparation of the CF3
-
anion from TMSCF3 in
an NMR tube.
In a glovebox, tert-BuOK (22.4 mg, 0.2 mmol) and 18-crown-6 (52.8 mg, 0.2 mmol) were
weighed into an NMR tube, which was tightly capped with a rubber septum. Freshly distilled THF
222

(0.6 mL, with PhCF 3 as an internal standard) was added to the mixture with a syringe at room
temperature. The mixture was sonicated (ca. 5 min) until a homogeneous solution was formed. The
solution was cooled to -78 º C for 10 min. TMSCF 3 (14.6 μL, 0.1 mmol) was added to the NMR
tube through the rubber septum using a syringe. (To maintain the low temperature during the
mixing, TMSCF 3 was preferentially added along the inner wall of the NMR tube). The rubber
septum was carefully sealed with PTFE thread seal tape and parafilm. The mixture was then shaken
gently at -78 º C to obtain a homogenous solution.
The sample for the
13
C NMR experiment was prepared via a similar procedure, in which tert-
BuOK (22.4 mg, 0.2 mmol) and 18-crown-6 (52.8 mg, 0.2 mmol) were weighed into an NMR tube.
The NMR tube was then attached to a Schlenk line and THF-d 8 (0.6 mL) was condensed into the
NMR tube at -78 º C under vacuum, and the tube was carefully shaken to achieve a homogenous
solution. TMSCF 3 (0.1 mmol, the amount was determined based on the ideal gas law) was
condensed into the NMR tube at -196 º C. The mixture was then shaken gently at -78 º C to obtain a
homogenous solution before flame sealing the tube. The
13
C NMR was measured on a Varian 600
MHz NMR spectrometer, which was precooled to -56 º C.
5.4.4 General procedure for the preparation of the CF3
-
anion from TIPSCF3 in an
NMR tube.
In a glovebox, tert-BuOK (11.2 mg, 0.1 mmol) and 18-crown-6 (26.4 mg, 0.1 mmol) were
weighed into an NMR tube, which was tightly capped with a rubber septum. Freshly distilled THF
or THF-d 8 (0.6 mL)
46
was added to the mixture via a syringe at room temperature. The mixture was
sonicated (ca. 5 min) until a homogeneous solution was formed. The solution was cooled to -78 º C
for 10 min. TIPSCF 3 (10 μL, 0.045 mmol) was added to the NMR tube through the rubber septum
using a syringe. (To maintain the low temperature during the mixing, TIPSCF 3 was preferentially
added along the inner wall of the NMR tube). The rubber septum was carefully sealed with PTFE
thread seal tape and parafilm. The mixture was then shaken gently at -78 º C to obtain a homogenous
solution, which was analyzed by
19
F NMR.
To exclude moisture, the samples used for kinetic studies were flame sealed with the following
procedure. After the addition TIPSCF 3, the rubber septum was removed under a positive argon flow,
and the NMR tube was immediately attached to a Schlenk line. The sample tube was carefully
evacuated for a few seconds, cooled with liquid nitrogen and flame sealed under vacuum.

223

5.4.5 Trapping the CF3
-
anion with various electrophiles.
5.4.5.1 General procedure for the reaction between the CF 3
-
anion and diphenyl disulfide.
R To a 10 mL Schlenk tube charged with a magnetic stir bar was added tert-BuOK (11.2 mg,
0.1 mmol) and 18-crown-6 (26.4 mg, 0.1 mmol). The tube was sealed in the glovebox with a septum.
A solution of PhCF 3 in freshly distilled THF (0.016 M, 1.0 mL) was added to the reaction mixture
via a syringe at room temperature. The mixture was sonicated (ca. 1 min) until a homogeneous
solution was formed. The solution was cooled to –78 ° C for 10 min before the addition of TIPSCF 3
(10 μL, 0.045 mmol) at –78 ° C. The reaction was maintained at the same temperature for 10 min
before a solution of diphenyl disulfide (21.8 mg, 0.1 mmol) in freshly distilled THF (0.2 mL) was
added. The reaction was kept at –78 ° C for an additional 60 min and gradually warmed up to room
temperature before the determination of the
19
F NMR yield with reference to PhCF 3 as an internal
standard.
19
F NMR yield of phenyl(trifluoromethyl)sulfide: 70%.
19
F NMR yield of TIPSCF 3: 70%.
19
F NMR (376 MHz): δ -43.4. The chemical shift is in good agreement with reported value of -42.7
ppm in CDCl 3.
47

5.4.5.2 General procedure for the reaction of the CF 3
-
anion with benzaldehyde.
The reaction was performed as described in 5.1 using benzaldehyde (10.6 mg, 0.1 mmol) as the
electrophile.
19
F NMR yield of 2,2,2-trifluoro-1-phenylethan-1-ol: 68%.
19
F NMR yield of TIPSCF 3:
68%.
19
F NMR (376 MHz): δ -78.3. The chemical shift is in good agreement with the reported
value of -78.9 ppm in CDCl 3.
31b

5.4.5.3 General procedure for the reaction of the CF 3
-
anion with iodine.
The reaction was performed as described in 5.1 using a solution of iodine (25.4 mg, 0.1 mmol)
in freshly distilled THF (0.2 mL) as the electrophile.
19
F NMR yield of trifluoroiodomethane: 48%.
19
F NMR yield of TIPSCF 3: 61%.
19
F NMR (376 MHz): δ -16.5. Due to the large divergence of
reported
19
F NMR chemical shifts (-11.5 ppm
48
and -3.7 ppm
49
), the formation of CF 3I was
confirmed by adding excessive CF 3I (1 M in CDCl 3) to the reaction mixture. Upon the addition of
excess CF 3I, the
19
F NMR showed only a single peak at -10.4 ppm along with PhCF 3 and CF 3H,
therefore confirming the formation of CF 3I.
5.4.5.4 General procedure for the reaction of the CF 3
-
anion with acetophenone.
The reaction was performed as described in 5.1 using acetophenone (12.0 mg, 0.1 mmol) as the
electrophile.
19
F NMR yield of 1,1,1-trifluoro-2-phenylpropan-2-ol: 22%.
19
F NMR yield of
224

TIPSCF 3: 36%.
19
F NMR (376 MHz): δ -79.5. The chemical shift is in good agreement with the
reported value of -81.8 ppm in CDCl 3.
50

5.4.5.5 General procedure for the reaction of the CF 3
-
anion with iodomethane.
The reaction was performed as described in 5.1 using iodomethane (71.0 mg, 0.5 mmol) as the
electrophile.
19
F NMR yield of 1,1,1-trifluoroethane: 21%.
19
F NMR yield of TIPSCF 3: 24%.
19
F
NMR (376 MHz): δ -60.8 (q,
3
J H-F = 15.0 Hz). The chemical shift is in good agreement with the
reported value of -61.7 ppm (q,
3
J H-F = 12.8 Hz) in CDCl 3.
51

5.4.5.6 General procedure for the reaction of the CF 3
-
anion with o-fluoronitrobenzene.
The reaction was performed as described in 5.1 using o-fluoronitrobenzene (70.5 mg, 0.5 mmol)
as the electrophile.
19
F NMR yield of o-nitro(trifluoromethyl)benzene: 7%.
19
F NMR yield of
TIPSCF 3: 21%.
19
F NMR (376 MHz): δ -60.3. The chemical shift is in good agreement with the
reported value of -61.1 ppm in CDCl 3.
52

5.4.5.7 General procedure for the reaction of the CF 3
-
anion with carbon dioxide.
The reaction was performed as described in 5.1 by introducing dry carbon dioxide (excess, in a
balloon) to the reaction mixture via a long needle.
19
F NMR yield of potassium trifluoroacetate:
76%.
19
F NMR yield of TIPSCF 3: 76%.
19
F NMR (376 MHz): δ -75.2. The chemical shift is in good
agreement with the reported value of -73.4 ppm in DMSO-d 6.
53

5.4.5.8 General procedure for the reaction of the CF 3
-
anion with N-
fluorobenzenesulfonimide.
The reaction was performed as described in 5.1 using a solution of N-fluorobenzenesulfonimide
(0.1 mmol) in freshly distilled THF (0.2 mL).
19
F NMR yield of (trifluoromethyl)phenylsulfone:
41%.
19
F NMR yield of TIPSCF 3: 72%.
19
F NMR (376 MHz): δ -79.5. The chemical shift is in good
agreement with reported value of -78.4 ppm in CDCl 3.
54

5.4.5.9 General procedure for the reaction of the CF 3
-
anion with CuI.
The CF 3
-
anion was generated in an NMR tube based on the procedure described in Section 4.
The yield of CF 3
-
anion was determined by
19
F NMR spectroscopy at -78 ° C with PhCF 3 as an
internal standard (60%
19
F NMR yield). A suspension of CuI (0.5 mmol) in anhydrous THF (0.2
mL, freshly distilled) was added to the NMR tube at -78 ° C with a syringe with a 16-gauge needle.
The reaction mixture was vigorously shaken at -78 º C and gradually warmed to room temperature.
The yield of CuCF 3 was determined by
19
F NMR at room temperature with PhCF 3 as an internal
standard (66%).
19
F NMR yield of TIPSCF 3: 77%.
19
F NMR (376 MHz): δ -26.9 ppm. This value
225

falls in the range of reported
19
F NMR chemical shifts for CuCF 3 in DMF (-24.9 ppm [Grushin]
25

and -28.8 ppm [Burton]
32
).
5.4.6 Trapping of the CF3
-
anion generated in situ with various electrophiles.
5.4.6.1 General procedure for reaction of the CF 3
-
anion generated in situ and iodine.
To a 10 mL Schlenk tube with a stir bar was added trifluoromethyl(trimethyl)silane (14.2 mg,
0.1 mmol) and iodine (50.8 mg, 0.2 mmol). A solution of PhCF 3 in freshly distilled THF (0.010 M,
0.5 mL) was added to the mixture with a syringe at room temperature. The solution was cooled to
-78 º C for 10 min before the addition of a solution of tetrabutylammonium difluorotriphenylsilicate
(54.0 mg, 0.1 mmol) in freshly distilled THF (0.5 mL) at -78 º C. The reaction was continued for
60 min at -78 º C and then gradually warmed up to room temperature before the determination of
the
19
F NMR yield.
19
F NMR yield of trifluoroiodomethane: 35%.
19
F NMR (376 MHz): δ -9.7.
The formation of CF 3I was confirmed as described in 3.3.
5.4.6.2 General procedure for the reaction of the CF 3
-
anion generated in situ with o-
fluoronitrobenzene.
The reaction was performed as described in 6.1 using o-fluoronitrobenzene (28.2 mg, 0.2 mmol)
as the electrophile.
19
F NMR yield of o-nitro(trifluoromethyl)benzene: 5%.
19
F NMR (376 MHz):
δ -60.3.
5.4.6.3 General procedure for the reaction of the CF 3
-
anion generated in situ with carbon
dioxide.
The reaction was performed as described in 6.1 by introducing dry carbon dioxide (excess, in a
balloon) to the reaction mixture via a long needle.
19
F NMR yield of potassium trifluoroacetate:
74%.
19
F NMR (376 MHz): δ -74.5.

226

Figure 5.3.
19
F NMR spectrum of the CF 3
-
anion generated from CF 3H at -78 ° C. A large amount of
CF 3H remained (a broad strong signal at -79.6 ppm).

Figure 5.4.
19
F NMR spectrum of the CF 3
-
anion generated from TMSCF 3 at -78 ° C. The
1
J C-F
coupling constant of the CF 3
-
anion is in good agreement with the value obtained from
13
C NMR. The
chemical shift (-65.6 ppm) and the coupling constant (377.1 Hz) of the observed pentacoordinated
silicon species are close to the values reported for [Me 3Si(CF 3) 2]
-
(-62.6 ppm and 378 Hz) and
[Me 3Si(CF 3)F]
-
(-63.9 ppm and 375 Hz). We therefore tentatively assign the species to [Me 3Si(CF 3) 2]
-
.
227

Figure 5.5.
13
C NMR spectrum of the CF 3
-
anion prepared from TMSCF 3 at -56 ° C.

Figure 5.6.
19
F NMR spectrum of the CF 3
-
anion generated from TIPSCF 3 at -78 ° C.
228

Figure 5.7.
19
F NMR spectrum of trapping the CF 3
-
anion with PhSSPh.

Figure 5.8.
19
F NMR spectrum of trapping the CF 3
-
anion with I 2.

Figure 5.9.
19
F NMR spectrum of trapping the CF 3
-
anion with benzaldehyde.
229

Figure 5.10.
19
F NMR spectrum of trapping the CF 3
-
anion with acetophenone.

Figure 5.11.
19
F NMR spectrum of trapping the CF 3
-
anion with CO 2.

Figure 5.12.
19
F NMR spectrum of trapping the CF 3
-
anion with CH 3I.
230

Figure 5.13.
19
F NMR spectrum of trapping the CF 3
-
anion with o-fluoronitrobenzene.

Figure 5.14.
19
F NMR spectrum of trapping the CF 3
-
anion with CuI.

.
231

Figure 5.15.
19
F NMR experiments at -35 ° C with a sample obtained from the reaction between
TIPSCF 3 and tert-BuOK in the presence of 18-crown-6 in THF (performed in a flame sealed NMR tube).

Figure 5.16.
19
F NMR experiments at -50 ° C with a sample obtained from the reaction between
TIPSCF 3 and tert-BuOK in the presence of 18-crown-6 in THF (performed in a flame sealed NMR tube).

232

Figure 5.17. Variable temperature
19
F NMR experiments of a sample from the reaction between
TMSCF 3 and tert-BuOK in the presence of 18-crown-6 in THF at -78 ° C from 0 h to 24 h and at -56 ° C
from 26 -70 h (performed in a flame sealed NMR tube).
233

Figure 5.18.
19
F NMR experiments at -50 ° C of a sample from the reaction between TMSCF 3 and
tert-BuOK in the presence of 18-crown-6 in THF at -78 ° C (performed in a flame sealed NMR tube and
the signal of the penta-coordinated silicon species is adjusted to be the highest peak in each spectrum).
5.4.7 Computational Details and Results
Theoretical calculations were performed at the B3LYP/6-31+G(d,p) level in DMF using Gaussian
09 package.
29,30
Solvent effects were included implicitly through the self-consistent reaction field
approach, as implemented in the default Polarizable Continuum Model (PCM) in Gaussian 09.
27,28

Thermal and entropic corrections for PCM-optimized structures were obtained by frequency analysis at
the B3LYP/6-31+G(d,p) level. The frequency analyses confirmed that all considered ground state
structures were true minima on the PES. All transition states were also identified and validated using
vibrational frequency analysis.
Estimated kinetic stability of CF 3
-
and KCF 3.
The adiabatic gas-phase bond dissociation enthalpy of CF 3
-
into singlet CF 2 and F
-
was evaluated
using Weizmann-1 (W1RO) theory
[55,56]
and was found to be 46.7 kcal/mol at 298 K. The free energy
of dissociation was calculated as 38.0 kcal/mol at 1 atm. W1RO is based on CCSD(T) calculations
extrapolated to the basis set limit, with corrections for inner-shell correlation, scalar relativistic effects
and spin-orbit coupling. The method has an estimated root-mean-square deviation from experiment of
0.57± 0.48 kcal/mol. W1RO was used as implemented in Gaussian 09, rev. A02.
[57]
Our value of 46.7
234

kcal/mol is in excellent agreement with Dixon’s result, which has estimated the fluoride affinity
[29]
of
CF 2 to be -46.0 kcal/mol using a comparable CCSD(T)/CBS//MP2/cc-pVTZ-based approach.
[28]

In the case of endothermic bond dissociation the existence of a transition state in the transitional
sense need not exist. Instead the activation energy often closely corresponds to the dissociation energy.
In order to test the consistency of the dissociation energy with the energy of activation, high-resolution
(0.05-0.1 Å) relaxed energy scans were performed along the reaction coordinate using UM06-2X/Def2-
TZVPPD calculations.
[58,59]
M06-2X calculations for main-group chemistry have been shown to have a
mean absolute deviation of 2.2 kcal/mol.
[60,]
As shown in Fig. S17, the scans did not show any tendency
for an additional barrier. The SCF energy obtained at large scan distances is close to and below the sum
of the SCF energies for the two species calculated separately. The introduction of an explicit K
+

counterion, acts as to lower the dissociation energy significantly (Fig. S17).

Figure 5.19. SCF energy of CF 3
-
as a function of the carbon–fluoride distance (kcal/mol). Energies
are obtained at the level of UM06-2X/Def2-TZVPPD. Maximum energy is obtained at infinite
separation of CF 2 and F
-
.
When concerned with the free energy of activation it is necessary to realize that the entropy which
arises due to the additional rotational and translational degrees of freedom associated with a full
dissociation, is largely gained after the dissociation barrier has been overcome. This has the practical
consequence of making the free energy of dissociation smaller than the free energy of activation.
Because of this, the bond dissociation enthalpy can be considered a more reasonable upper-
approximation to the factual free energy barrier. In our experience, this is a good approximation when
comparing calculated barriers with experimental observations.
To account for solvent effects in THF, we have corrected our W1RO gas-phase energies using
solvation free energies obtained through a series of single-point calculations (using standard
thermodynamic cycles). All our calculations are only marginally affected by thermal corrections at a
235

lower temperature, and the standard state for all calculations were set to 1 M and 298 K throughout,
unless otherwise specified. The single point energy calculations were performed at the COSMO-
CCSD(T)/Def2-TZVPPD level using the ORCA 3.0 code. The free energy solvent corrections utilized
density functional theory (M06-2X/Def2-TZVPPD) geometries and thermal corrections, which were
evaluated in both gas phase and in solution. Structural relaxation upon solvation is hence included. Our
calculated adiabatic solvent correction to the gas-phase bond dissociation amount to -21.3 kcal/mol. Our
best estimate to the adiabatic bond dissociation enthalpy of free CF 3
-
in solution is thus 25.4 kcal/mol.
The corresponding free energy change is estimated to 16.7 kcal/mol.
The universal SMD-PCM implicit solvation model, which was used for all optimizations and for the
DFT scans, has a reported mean absolute deviation of 4 kcal/mol from experimental solvation energies
for ions.
[58]
Our single point calculations at higher levels of theory utilized the comparable COSMO
method
[ 61 , 62 ]
because of its CCSD(T) implementation in ORCA 3. Whereas calculated absolute
solvation energies of ions are likely to have inherent errors, the effect on the overall relative energies
will be smaller due to error cancelation. Indeed, no marked difference (< 0.1 kcal/mol) in the overall
solvent correction terms were seen when comparing the SMD and COSMO methods.
We have studied the conformations of KCF 3 in solution by a series of calculations at the COSMO-
CCSD(T)/Def2-TZVPPD//SMD-M06-2X/Def2-TZVPPD level of theory. Four stable minima on the
potential energy surface of KCF 3 were identified within 1 kcal/mol of each other (Figure 5.20), implying
that rapid interconversion among them is possible.

Figure 5.20. The four predicted conformers of KCF 3 in THF solution. Energies are given in kcal/mol
and bond distances in Å.
When KCF 3 is considered, the bond dissociation enthalpy for the α-defluorination is lowered by 7.9
kcal/mol, to 17.1 kcal/mol, due to the specific potassium-fluorine interactions and the preferential
formation of the KF ion pair. The corresponding free energy change upon formation of separated KF
and CF 2 from KCF 3 is 9.7 kcal/mol. Our COSMO-CCSD(T) energies are in quantitative agreement with
the DFT scans presented in Figure 5.19. Whereas the exact value for the free energy barrier is arguable,
236

we can conclude that the lower calculated decomposition barrier of KCF 3, compared to CF 3
-
, stresses
the need to reduce K-CF 3 interactions in the preparation of the CF 3
-
anion, by introducing crown ethers.
5.4.8 Details on the Calculations of NMR Properties.
To validate the existence of the trifluoromethide anion, its NMR properties in THF solution were
computed at the GIAO-PCM-B3LYP/aug-cc-PVTZ//6-31+G(d,p) level of theory. Due to convergence
problems the NMR chemical shifts of CF 3Cu needed to be optimized using a different basis set (Def2-
TZVPP). The spin-spin coupling constants were calculated with the “mixed” approach
[63]
implemented
in Gaussian 09.
By correlating the calculated magnetic shielding tensors and experimental NMR chemical shifts of
a series of known compounds as references (Figure 5.21, left and middle), the
19
F NMR and
13
C NMR
chemical shifts of the free CF 3
-
anion were estimated to be -23.6 and 169.0 ppm, respectively. These
results are in good agreement with the observed
19
F NMR and
13
C NMR chemical shifts of -18.7 and
175.0 ppm, respectively. Using a similar correlation protocol, the
1
J C-F coupling constant of free CF 3
-

was predicted to be 393.0 Hz (Figure 5.21, right). Although this value differs from the experimental
value by 41 Hz (ca. 9% error), the divergence is likely to be a systematic error as described in
literature.
[63]
A similar error was also found in the calculation of the
1
J C-F value of the anionic CF 2 group
in CF 3CF 2Li using the same method, which also underestimates the
1
J C-F value by 19.6 Hz (ca. 6%).
Similar to other α-fluorocarbanions, such as CF 3CF 2
- [40]
and (PhSO 2) 2CF
-

[64]
anions,

the formation of
the CF 3
-
anion can also be inferred from the significantly increased
1
J C-F coupling constant as compared
with that of its protonated derivative (CF 3H,
1
J C-F = 293.3 Hz).

Such an increase can be ascribed to the
higher pyramidalization of fluorinated anionic carbon centers

compared with the corresponding
protonated carbon atoms.

Table 5.2. Summary of Calculated and Experimental NMR Properties of the CF 3
-
anion and
Reference Compounds.
Reference
Compound
19
F NMR
(ppm)
13
C NMR
(ppm)
1
J C-F Coupling Constant
(Hz)
SCF GIAO
magnetic
shielding
tensor
Exp.
Chemical
Shift
SCF GIAO
magnetic
shielding
tensor
Exp.
Chemical
Shift
Cal. Exp.
237

Acetone
(carbonyl)
- - -39.6 206.6 - -
CCl 3F 157.23 0.00 25.1 118.2 - -
PhCF 3 (CF 3) 235.42 -63.0 43.3 127.1 353.7 271.5
PhSCF 3
(CF 3)
219.73 -42.70 33.9 129.6 402.7 306.0
CF 3H 255.11 -80.88 53.4 122.2 359.7 293.3
LiCF 2CF 3
CF 2
311.12 -128.00 19.8 158.0 389.6 318.5
LiCF 2CF 3
CF 3
262.03 -85.00 43.2 126.0 363.9 273.0
TMSCF 3
(CF 3)
242.99 -65.80 34.8 131.8 410.9 321.9
CF 4 236.00 -62.50 47.8 119.8 366.4 260.0
CF 3Cl 198.37 -28.60 36.9 125.4 403.8 299.0
CuCF 3 196.36 -24.20 19.1 152.3 460.8 350.0
Compound
19
F NMR (ppm)
13
C NMR (ppm)
1
J C-F Coupling Constant
(Hz)
SCF GIAO
magnetic
shielding
tensor
Predicted
Chemical
Shift
SCF GIAO
magnetic
shielding
tensor
Predicted
Chemical
Shift
Cal. Predicted
CF 3
-
191.38 -23.69 -8.3 170.3 515.4 393.0

238

Figure 5.21. Top left. Correlation between calculated and experimental
19
F NMR chemical shifts.
Top right. Correlation between calculated and experimental
13
C NMR chemical shifts. Bottom.
Correlation between calculated and experimental
1
J C-F coupling constants.
5.4.9 Lone Pair and Bonding Analysis
By correlating It has been shown that lone pair domains can be quantified following topological
analysis of the electron localization function (ELF, η(r)).
[42]
The high-ELF localization domain
population (HELP)
[45]
is a measure of the most localized and chemically relevant regions of the
molecular space, and has been shown to correlate with a large number of physical properties and
quantum chemical constructs, such as atomic charge, NBO lone pair orbitals,
[ 65 ]
and molecular
geometry.
[45]
Here, we have applied the HELP analysis to compare the lone pair domain of CF 3
-
with
that of isoelectronic NF 3, which has been known to possess substantial thermal stability.
[66]
The effect
239

of a coordinating potassium cation on the lone pair domain has also been assessed. For complementary
charge analysis we have used the Quantum Theory of Atoms in Molecules (QTAIM) approach, which
allows for direct topological analysis of the electron density, ρ(r).
[45]

HELP reveals that, compared to NF 3, the lone pair domain of CF 3
-
is larger in volume, implying
more delocalization (Table 5.3). The more diffused lone pair in CF 3
-
may imply a stronger hypothetical
“charge-pair repulsion”, which could account for its lower thermal stability than NF 3. When CF 3
-
is
bound to K
+
(C-coordination), the lone pair domain contracts in size, and the HELP value decreases to
1.30 electrons (Table 5.3, Figure 5.22). This value is 90% that of the free species and offers an indication
of the ionic character of the bonding interaction. The charge of the CF 3 group in KCF 3 is 0.92 electrons,
when calculated with both NBO and QAIM methodologies, and suggest a highly ionic situation, in good
agreement with the HELP analysis.

Figure 5.22. The ionic KCF 3 bonding interaction visualized using ELF/HELP. η(r) = 1.0 (red)
denotes electrons which are alone with respect to their same spin counterparts (or “localized”). η(r) =
½ (blue) denotes electrons which on average exhibit kinetic energies due to Pauli repulsion equal to that
of a homogeneous electron gas of identical electron density (or “delocalized”).

240

Table 5.3. Selected lone pair domain and bond characteristics of NF 3, CF 3
-
and KCF 3.
Species HELP
[a]

e (Å
3
)
∇
2
ρ(r) @ BCP
[b]

e bohr
-5

charge on fluorine
[c]

e
NF 3 1.68 (3.6) - -0.31 (-0.20)
CF 3
-
1.42 (8.4) - -0.72 (-0.46)
KCF 3 1.30 (3.1) 0.075 -0.72 (-0.44)
[-0.92 (-0.92)]
[a]
Average number of electrons in the HELP lone pair domain on the CF 3-carbon and NF 3-nitrogen.
Domain volumes are limited to regions where ρ(r) > 0.001 e bohr
-1
and η(r) > 0.5 and are given within
parenthesis.
[b]
The Laplacian of the electron density at the K-C bond critical point (BCP).
[c]
QTAIM
charge of flourine with NBO charge within parenthesis. Corresponding charge of entire CF 3-group in
KCF 3 is given between brackets.

HELP and QTAIM analyses were performed on wave functions calculated using the M06-2X density
functional,
[58]
in conjunction with the Def2-TZVPPD basis set. Implicit consideration of tetrahydrofuran
solvent was included in all reported data. However, we have seen that negligible changes (0.01 electrons)
were observed when HELP for CF 3
-
was calculated with and without implicit solvation. The
corresponding changes in HELP lone pair volumes were 0.11 and 0.06 Å
3
, respectively. Generation and
analysis of η(r) and ρ(r) were performed over a 0.05 bohr (0.026 Å) grid in DGRID 4.6,
[67]
where η(r)
was calculated using the spin-polarized definition of Kohout and Savin.
[68]
Natural Bond Orbital (NBO)
analyses were performed using NBO version 3.0
[65]
in Gaussian 09.
5.4.10 Standard Orientation of Calculated Species.
Standard Orientation of Species in Sections 7&9
CF 3
-

SMD-ωB97X-D/Def2-TZVPPD geometry:
E(SMD-ωB97X-D): -337.763387047
F -0.83559 -0.93585 -0.11903
F 1.22809 -0.25564 -0.11912
241

F -0.39243 1.19167 -0.11913
C -0.00009 -0.00012 0.53611

SMD-M06-2X/Def2-TZVPPD geometry:
E(SMD-M06-2X): -337.746914326
E(COSMO-CCSD(T)): -337.414818017939
F 0.00015 1.24731 -0.11781
F -1.08037 -0.62379 -0.11783
F 1.08007 -0.62344 -0.11773
C 0.00015 -0.00008 0.53791

M06-2X/Def2-TZVPPD geometry:
E(M06-2X): -337.661619027
E(CCSD(T)): -337.332065647826
F -0.83273 -0.93319 -0.12138
F 1.22412 -0.25505 -0.12153
F -0.39114 1.18819 -0.12136
C -0.00028 0.00011 0.54309

W1RO geometry:
H(W1RO): -337.887066
F 0.00000 1.26895 -0.12514
F -1.09894 -0.63447 -0.12514
F 1.09894 -0.63447 -0.12514
C 0.00000 0.00000 0.55807

CF 2
242

SMD-M06-2X/Def2-TZVPPD geometry:
E(SMD-M06-2X): -237.720411339
E(COSMO-CCSD(T)): -237.492941662481
F 0.00000 1.02455 -0.19583
F 0.00000 -1.02455 -0.19583
C 0.00000 0.00000 0.59022

M06-2X/Def2-TZVPPD geometry:
E(M06-2X): -237.724361262
E(CCSD(T)): -237.491456308001
F 0.00000 1.02313 -0.19840
F 0.00000 -1.02313 -0.19840
C 0.00000 0.00000 0.59330

W1RO geometry:
H(W1RO): -237.877583
F 0.00000 1.03232 -0.19976
F 0.00000 -1.03232 -0.19976
C 0.00000 0.00000 0.59702

F
-

E(SMD-M06-2X): -99.9776007485
E(COSMO-CCSD(T)): -99.881078569725
E(M06-2X): -99.8546017794
E(CCSD(T)): -99.766083492154
H(W1RO): -99.935079

243

K
+

E(SMD-M06-2X): -599.821846667
E(COSMO-CCSD(T)): -599.271342608617

KCF 3 (C-coordination)
SMD-ωB97X-D/Def2-TZVPPD geometry:
E(SMD-ωB97X-D): -937.639221117
F -0.00055 1.25387 -1.33197
F -1.08547 -0.62652 -1.33100
F 1.08581 -0.62735 -1.33148
C 0.00044 0.00032 -0.69226
K -0.00023 -0.00033 2.14422

SMD-M06-2X/Def2-TZVPPD geometry:
E(SMD-M06-2X): -937.609513095,
E(COSMO-CCSD(T)): -936.725630605738
F -0.00014 1.24602 -1.32661
F -1.07924 -0.62291 -1.32761
F 1.07932 -0.62312 -1.32806
C 0.00025 -0.00052 -0.68976
K -0.00019 0.00053 2.12956

M06-2X/Def2-TZVPPD geometry:
E(M06-2X): -937.580785205
F 0.00000 1.24816 -1.29050
F -1.08094 -0.62408 -1.29050
F 1.08094 -0.62408 -1.29050
244

C 0.00000 0.00000 -0.68327
K 0.00000 0.00000 2.01205

KCF 3 (1F-coordination)
SMD-M06-2X/Def2-TZVPPD geometry:
E(SMD-M06-2X): -937.610852202
E(COSMO-CCSD(T)): -936.726984342743
F -1.05751 0.41145 0.00000
F 0.39480 1.62335 1.07209
C 0.34761 0.74860 0.00000
K 0.04235 -1.98407 0.00000
F 0.39480 1.62335 -1.07209

KCF 3 (2F-coordination)
SMD-M06-2X/Def2-TZVPPD geometry:
E(SMD-M06-2X): -937.609364580
E(COSMO-CCSD(T)): -936.726041857571
F -0.87703 2.07701 0.00000
F 0.32087 0.63517 1.08244
C -0.60828 0.73545 0.00000
F 0.32087 0.63517 -1.08244
K 0.28398 -1.83172 0.00000

KCF 3 (3F-coordination)
SMD-M06-2X/Def2-TZVPPD geometry:
E(SMD-M06-2X): -937.610288297
E(COSMO-CCSD(T)): -936.727781644771
245

F 0.00000 1.24574 -0.77440
F 1.07884 -0.62287 -0.77440
C 0.00000 0.00000 -1.46172
K 0.00000 0.00000 1.56206
F -1.07884 -0.62287 -0.77440

KF
SMD-M06-2X/Def2-TZVPPD geometry:
E(SMD-M06-2X): -699.850066248
E(COSMO-CCSD(T)): -699.203381276790
F -1.01046 0.25382 0.00000
K -0.03431 -1.86201 0.00000

NF 3
SMD-RM062X/Def2-TZVPPD geometry:
E(SMD-RM062X): -354.115356466
F 0.00000 1.21512 -0.12281
F -1.05232 -0.60756 -0.12281
F 1.05232 -0.60756 -0.12281
N 0.00000 0.00000 0.47371

246

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species is particularly
discounted based on the previously assumed extreme lability of CF 3
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[30] a) As expected, DFT calculations also show that Li
+
and Na
+
cations, compared with K
+

cation preferentially facilitate the defluorination of CF 3
-
,for discussions see, Luo, G.; Luo,
Y.; Qu, J. New J. Chem. 2013, 37, 3274-3280; b) Our experiments demonstrated that no
CF 3
-
was observed by treating CF 3H with [Li(12-crown-4)]
+
tBuO
-
and [Na(15-crown-
5)]
+
tBuO
-
systems in THF at -78 ° C and majority of the CF 3H remained unreacted under
such reaction conditions.
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[46] The
19
F NMR samples were prepared using THF or THF-d 8 with PhCF 3 as an internal
standard (0.008 M).
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249

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250

Chapter 6

On the Nucleophilicity of Persistent α-
Monofluoromethanide Derivatives

251

6.1 Introduction
Nucleophilic addition of α-fluorocarbanions to electrophilic substrates is a widely employed
synthetic strategy for fluoromethyl incorporation.
1
The presence of α-fluorine atom(s) can
dramatically change the chemical nature of nucleophilic fluoroalkylating reagents, thereby
mechanistically distinguishing nucleophilic fluoroalkylations from analogous non-fluorinated
transformations. Although, as inferred by reaction yields, many α-fluorocarbanions were assumed
to be lower in reactivity than their non-fluorinated counterparts,
2
contrary observations have also
been documented.
3,4,5
As both the acidity of pronucleophiles
6,7
and the thermal stability of α-
monofluoromethanide derivatives can be altered by α-fluorine substitution, the observed fluorine
effect on reaction yields can be in part associated with the decomposition, protonation, other
undesired side reactions of the key reactive species, and the reversibility of the addition reactions.
8

It is therefore debatable to assess the reactivity of α-fluorocarbanions, an intrinsic kinetic property
by definition,
9
based on reaction yields. To the best of our knowledge, how the reactivity of α-
monofluoromethanide derivatives contributes to the overall fluorine effect on nucleophilic
fluoroalkylating reactions has been scarcely explored. Herein, we disclose a quantitative evaluation
of the reactivity of a series of persistent α-monofluoromethanide derivatives on the basis of the
nucleophilicity scale. By comparing the nucleophilicity of these anions with their non-fluorinated
analogues, a structure-reactivity relationship has been established to provide the insight into the
effect of α-fluorine substitution on the reactivity of these carbanions.

6.2 Results and Discussion
The nucleophilicity of α-monofluoromethanide derivatives and their analogues was assessed by
investigating the kinetics of the reactions between α-substituted carbanions (1~4) and various
reference electrophiles, including quinone methides (5a~5h) and benzhydrylium ions (5i~5m).
Such reactions can be considered model reactions of conjugate addition and nucleophilic
substitution. Reagents (1−H~4−H) were chosen as carbanion precursors because of their synthetic
relevance
10
and the persistency of the corresponding carbanions. In addition to our previous
demonstration,
11
the persistency of the carbanions (1~4) was further confirmed by the high yielding
recovery of 1−H~4−H from the protonation of the corresponding stock solution of 1~4 (83-99%,
determined by NMR spectroscopy, (See 6.4.3 for details). Due to the relatively high reactivity of
malonate carbanions 4, reference electrophiles with small E values (5a~5g) were employed for
kinetic study.
252

Figure 6.1. Carbanions 1~4.
Table 6.1: Michael acceptors 5a~5h and benzhydrylium ions 5i~5m employed as reference
electrophiles.

Electrophile E max

R = p-NMe 2 5a −17.29 486 nm
R = p-OMe 5b ̶ 16.11 393 nm
R = p-Me 5c ̶ 15.83 371 nm
R = m-F 5d ̶ 15.03 354 nm
R = p-NO 2 5e -14.36 374 nm

R

= NMe 2 5f ̶ 13.39 533 nm
R = OMe 5g ̶ 12.18 422 nm
R = H 5h ̶ 11.87 384 nm

n = 1 5i ̶ 10.04 630 nm
n = 2 5j ̶ 9.45 635 nm

n = 1 5k ̶ 8.76 627 nm
n = 2 5l ̶ 8.22 618 nm

R = Pyrrol 5m ̶ 7.69
620 nm

Given electrophile-specific parameter, E, solvent-dependent nucleophile-specific parameters
(s N and N) can be derived based on Eq. 1.
12

log k 2 (20
o
C) = s N (N + E) (1)
By exploiting persistent carbanions (1~4), interference from the pronucleophile acidity and the
anion thermal stability can be well prevented in the kinetic study. Given the fact that the adducts
of 1~4 with 5j were isolated with relatively high yields (59~93%, see 6.4.4 for details), the observed
reaction kinetics was unlikely to be significantly altered by undesired side reactions. Moreover, the
253

addition of a stoichiometric amount of 18-crown-6 did not lead to derivation of expected reaction
kinetics, thus excluding notable counterion effect (see 6.4.5 for details). This observation is similar
to a previous study, in which the cation effect of potassium was absent at low reaction
concentrations (< 10
-3
M).
13

Figure 6.2. N/s N parameters of carbanions 1~4. The parameters were determined by applying log
k 2 = s N(N+E) with 3~5 proper reference electrophiles (see 6.4.6 for details).

254

Table 6.2: Rate constants k 2 for the reactions of the carbanions 1~4 with the reference electrophiles
5j or 5f in DMSO at 20
o
C.

X
a

Electrophile = 5j Electrophile = 5j Electrophile = 5j Electrophile = 5f
k 2 ΔΔG
‡
k 2 ΔΔG
‡
k 2 ΔΔG
‡
k 2 ΔΔG
‡

H 1.26× 10
4
0.00 1.57× 10
4
0.00 1.41× 10
5
0.00 2.96× 10
4 c
0.00
F 2.42× 10
5 b
-1.72 1.76× 10
5
-1.41 2.72× 10
6
-1.72 3.09× 10
5 b
-1.37
OMe 1.38× 10
5
-1.39 6.98× 10
5
-2.21
d
2.20× 10
5
-0.26 8.65× 10
4
-0.63
Ph 1.23× 10
4
+0.01 1.30× 10
4
+0.11 −
f
−
f

Cl −
e
−
f
−
f
4.17× 10
3
+1.14
a
The k 2 (M· s
-1
) was determined by the nucleophile concentration dependence of pseudo-first rate
constants k obs. Pseudo-first rate constant k obs (s
-1
) was obtained by fitting the mono-exponential
function A t = A 0e
-
k
obs
t
+ C to the observed time-dependent absorbance. The k 2 value of 1~3 and 4
refers to the reaction with 5j and 5f as the reference electrophile, respectively. ΔΔG
‡
(kcal· mol
-1
)
was estimated based on transition state theory and the assumption that the reactions of a given
series of nucleophiles have the same proportionality constants.
b
The value is determined by
extrapolation. k 2 was derived by applying known E-value of the reference electrophile to the
established equation log k 2 = C +s NE of the corresponding nucleophile.
c
The k 2 of 4a is obtained
from reference.
12b

d
Kinetic data of 2f was used.
e
Undesired hydrodechlorinated product was
obtained (see 6.4.4 for details).
f
Not determined due to the limited availability.
Compared with other α-substituents, fluorine leads to the most significant increase in the
nucleophilicity (N) of the carbanions (Figure 6.2, See 6.4.5 for details). As the reaction kinetics is
also closely associated with nucleophile-specific sensitivity (s N), to better demonstrate the α-
substitution effect, the reaction rate constants (k 2) of a given series of carbanions with respect to a
specific electrophile are listed. As shown in Table 2, α-fluorocarbanions (1b~4b) react significantly
faster than the parent anions (1a~4a) by ca. 10 to 20 fold. These results explicitly demonstrated
that the α-fluorine substitution indeed increases the reactivity of the nucleophilic reactivity of the
carbanions. α-Methoxy substitution also leads to reaction rate acceleration, however, to a smaller
extent. Compared with 4a, α-chlorine substitution results in a 7-fold decrease in the reaction rate.
Although α-phenyl substitution can significantly change the electronic and steric nature of the
anionic carbon center, α-phenylcarbanions (1d and 2d) indeed exhibit reaction rate constants and
N values very similar to those of the parent anions. Based on reaction rates, the activation Gibbs
free energy difference (ΔΔG
‡
) relative to that of the reaction with the parent anions was estimated
255

to be within a range of ± 2 kcal/mol. Although non-linear, a positive correlation of ΔΔG
‡
across the
four series can be clearly seen, indicating the observed α-substitution effect is likely to be a
ubiquitous phenomenon in related anions.
To rationalize this observation, the pyramidalization of the anionic carbon bearing an electron-
withdrawing α-substituent, i.e. ground state destabilization of the planar structure as predicted by
the Bent’s rule,
14
was previously invoked. Since previous investigations have shown that 1a
adopted planar geometry while 1b and 1c adopted pyramidal geometry.
11
Such a proposal can
seemingly account for the reactivity enhancement of bis(phenylsulfonyl)methanides and malonates,
in which the anions undergo (further) pyramidalization during the transition state. In order to verify
this assumption, we have investigated the conformational geometry of 1 by studying the NOE effect
of their counterparts 7 (Figure 6.3 and Figure 6.5~6.8), in which the two phenyl rings can be
differentiated with the introduction of a p-Me group.
15
With an established correlation between the
population of trans-planar geometry and the NOE intensity by employing the data from crystal
structure as well as DFT calculation respectively, the population of trans-planar configuration in
carbanion 7 can be derived. It is surprising to note that exceedingly strong NOE was observed for
7b which reached the interproton distance limit. This might be due to the extremely long mixing
time τ m which reached the plateau region of the NOE build up curve and the results are thus deviated
(see 6.4.7 for details).

Figure 6.3. Conformational study of carbanion 7 via NOESY 1D experiments.

256

6.3 Conclusion
In conclusion, we have conducted a systematic study of the nucleophilic reactivity of a series of
fluorine-substituted carbanions and their analogues. The α-substitution with one fluorine atom and
methoxy group increases the nucleophilic reactivity of the carbanions studied, while the extent of
influence is greater with fluorine substitution. The substitution with a phenyl group leads to
comparable results with the parental analogues. Ground state destabilization theory as predicted by
Bent’s rule are previously invoked to interpret such observations. Computational studies are under
way for the elucidation of the origin of the observed effects.

6.4 Experimental
General
Unless otherwise mentioned, all the chemicals were purchased from commercial sources. Flash
chromatography or preparative thin layer chromatography using 1500 microns preparative think
layer chromatography plates were performed to isolate the products.
1
H,
13
C, and
19
F, NOE, COSY
spectra were recorded on 400 MHz or 500 MHz Varian NMR spectrometers.
1
H NMR chemical
shifts were determined relative to DMSO-d 6 (δ 2.50) or to CDCl 3 (δ 7.26) as the internal standard.
13
C NMR shifts were determined relative to DMSO-d 6 (δ 39.50) or to CDCl 3 (δ 77.16) as the
internal standard.
19
F NMR chemical shifts were determined relative to CFCl 3 at δ 0.00, Mass
spectra were recorded on a high resolution mass spectrometer, in the EI, FAB or ESI modes. All
reactions were performed under an atmosphere of dry argon or nitrogen. Dry DMSO for kinetics
was purchased (<50 ppm H 2O). Other substrates were purchased from Sigma-Aldrich and used
without further purification.

6.4.1. Synthesis of Starting Materials
The reference electrophiles (Quinone Methides 5b-h and Benzhydrylium tetrafluoroborates 5i-m)
used in this work were prepared as described before.
16
1c-H,
17
3a-H,
18
2b-H
10k
were prepared
following the known procedure.
Preparation of 2a−H and 2d−H.
19

A catalytic amount of acetyl chloride (0.12 mL, 1.5 mmol) was added dropwise to a 0 ° C mixture
of benzaldehyde (1.5 mL, 15.0 mmol) and benzenethiol (3.5 mL, 33.0 mmol) or benzene-1,2-dithiol
(1.9 mL, 16.5 mmol). The reaction mixture was stirred at room temperature for 24. Then AcOH
(25 mL) and H 2O 2 (17 mL, 150 mmol, 30% in H 2O) were added. The resulting reaction mixture
257

was stirred for 2 h at room temperature and then overnight at 50 ° C. The mixture was cooled down
to 0 ° C and filtered. The solids were thoroughly washed with H 2O. The pure products were obtained
after trituration of the solids with ethanol.

(Phenylmethylenedisulfonyl)dibenzene 2a-H:
20
White solid. Yield: 3.42 g (9.2 mmol, 61%).
1
H
NMR (300 MHz, CDCl 3) δ 7.78 (d, J = 7.8 Hz, 5H), 7.63 (t, J = 7.6 Hz, 2H), 7.46 (t, J = 7.6 Hz,
5H), 7.41 – 7.32 (m, 1H), 7.32 – 7.16 (m, 2H), 5.43 (s, 1H).

2-Phenylbenzo[1,3]dithiole 1,1,3,3-tetraoxide 2d-H: White solid. Yield: 2.52 g (8.6 mmol, 57%).
1
H NMR (300 MHz, CDCl 3) δ 8.14–8.11 (m, 3H), 7.95 (dd, J = 5.9, 3.1 Hz, 1H), 7.71 (d, J = 6.7
Hz, 1H), 7.58 (dd, J = 14.8, 7.8 Hz, 2H), 7.48 (t, J = 7.6 Hz, 2H), 5.55 (s, 1H).
13
C NMR (75 MHz,
CDCl 3) δ 172.0, 138.4, 135.2, 134.0, 132.9, 131.7, 130.4, 129.4, 128.6, 123.3, 119.8, 79.2, 77.4.
HRMS (EI): m/z calcd for C 13H 10O 4S 2: 294.0021; found: 294.0015.

Preparation of 2-methoxy-2H-benzo[1,3]dithiole-1,1,3-trioxide 2f-H.
21

To a solution of benzene-1,2-dithiol (20 mmol) in acetonitrile (80 mL) under N 2 was added sodium
(40 mmol) in portion, while the temperature was kept below 30
o
C. The reaction mixture was stirred
overnight. Under vigorous stirring, a solution of dichloromethoxymethane (20 mmol) in
acetonitrile (20 mL) was added dropwise to the white suspension and the temperature was kept
below 30
o
C. After stirring overnight at room temperature the mixture was filtered and the filtrate
was concentrated under vacuum to give 2-methoxybenzodithiole which was used without further
purification. To a solution of 2-methoxybenzodithiole (10 mmol) in dichloromethane (50 mL) at 0
o
C was added peracetic acid (60 mmol) and the resulting mixture was stirred overnight. Cold water
was then added and the mixture was filtered and washed with cold water (5× 20mL). The crude
product was recrystallized in benzene to give the titled compound. White solid. 55% yield.
1
H NMR
(400 MHz, CDCl 3, 25 ° C, TMS) δ = 8.02-7.95 (m, 2H), 7.93-7.84 (m, 2H), 5.54 (s, 1H), 3.98 (s,
3H);
13
C NMR (100 MHz, CDCl 3, 25 ° C, TMS) δ = 137.7, 136.2, 135.5, 134.3, 129.2, 124.5, 108.5,
63.0. HRMS (ESI), m/z calcd for C 8H 8NaO 4S 2 [M+Na]
+
: 2254.9756. Found: 254.9761.

Preparation of ethyl 2-methoxy-2-(phenylsulfonyl)acetate 3c-H.
22

Ethyl 2-methoxy-2-(phenylthio)acetate was prepared with previously reported procedure. To a
solution of ethyl 2-methoxy-2-(phenylthio)acetate (3.5 mmol) in MeOH (15 mL) at 0
o
C was added
a solution of oxone (25 mmol) in water (25 mL). The resulting cloudy slurry was stirred for
overnight at room temperature, diluted with water and extracted with chloroform. The combined
258

organic layers were washed with water and brine, dried over anhydrous Na 2SO 4. The solvent was
removed in vacuo and the crude product was purified by flash chromatography to give the titled
compound. Colorless oil. 97% yield.
1
H NMR (400 MHz, CDCl 3, 25 ° C, TMS) δ =7.92-7.89 (m,
2H), 7.72-7.68 (m, 1H), 7.55-7.59 (m, 2H), 4.82 (s, 1H), 4.21 (q, 2H,
3
J H-H = 17.2 Hz), 3.73 (s, 3H),
1.25 (t, 3H,
3
J H-H = 17.2 Hz);
13
C NMR (100 MHz, CDCl 3, 25 ° C, TMS) δ =163.7, 135.7, 134.7,
129.9, 129.1, 96.0, 62.9, 61.6, 14.1. HRMS (ESI), m/z calcd for C 11H 14O 5NaS [M+Na]
+
: 281.0460.
Found: 281.0456.

Preparation of 7−H.
17

To a solution of 4-methylbenzenesulfonyl fluoride (2.1 mmol) and corresponding methyl phenyl
sulfone (2.1 mmol) in THF (4 mL), a solution of KHMDS (6 mmol) in THF (6 mL) was added
dropwise at -78
o
C. After 30 min, the reaction mixture was quenched with 4M HCl at 0
o
C. The
resulting solution was extracted with DCM, washed with brine, and dried over magnesium sulfate.
The crude product was further purified with flash chromatography.

1-methyl-4-(((phenylsulfonyl)methyl)sulfonyl)benzene 7a−H. White solid. 95% yield.
1
H NMR
(400 MHz, DMSO-d 6, 25 ° C, TMS) δ =7.85-7.81 (m, 2H), 7.75-7.73 (m, 3H), 7.63-7.61 (m, 2H),
7.42-7.39 (m, 2H), 5.87 (s, 2H), 2.41 (s, 3H).

1-((fluoro(phenylsulfonyl)methyl)sulfonyl)-4-methylbenzene 7b−H. White solid. 93% yield.
1
H
NMR (400 MHz, DMSO-d 6, 25 ° C, TMS) δ =7.93-7.91 (m, 2H), 7.91-7.86 (m, 1H), 7.82-7.80 (m,
2H), 7.74-7.70 (m, 2H), 7.54-7.51 (m, 2H), 7.39 (d,
3
J H-F = 42.8 Hz), 2.45 (s, 3H);
19
F NMR (376
MHz, DMSO-d 6, 25 ° C) δ = -172.4 (d,
3
J H-F = 42.8 Hz).

1-((methoxy(phenylsulfonyl)methyl)sulfonyl)-4-methylbenzene 7c−H. White solid. 87% yield.
1
H
NMR (400 MHz, DMSO-d 6, 25 ° C, TMS) δ =7.89-7.87 (m, 2H), 7.83-7.79 (m, 1H), 7.77-7.75 (m,
2H), 7.69-7.65 (m, 2H), 7.48-7.46 (m, 2H), 6.47 (s, 1H), 3.31 (s, 3H), 2.43 (s, 3H).

259

6.4.2. Selective isolation of carbanions as potassium salts
In a previously dried round bottom Schlenk flask the corresponding CH-Acidic sulfone (1.00
equiv.) was added to a solution of KO
t
Bu (0.95 equiv.) in ethanol (10 mL) under argon atmosphere.
The resulting solution was stirred at room temperature for 30 min and then concentrated under
reduced pressure to give a solid which was further washed with freshly distilled Et 2O (3  10 mL)
under argon. The solids were dried under vacuum for additional 2 hours to afford the corresponding
potassium salts which were stored in the glove box under argon atmosphere.

Potassium bis(phenylsulfonyl)methanide 1a was obtained according to the general procedure
described above starting from bis(phenylsulfonyl)methane 1a-H (605.0 mg,
2.04 mmol) and KO
t
Bu (217.0 mg, 1.93 mmol). White solid (  max = 287 nm).
Yield: 580.7 mg (1.74 mmol, 90%).
1
H NMR (400 MHz, DMSO-d 6) δ 7.74 – 7.67 (m, 4H), 7.34 –
7.27 (m, 7H).
13
C NMR (101 MHz, DMSO-d 6) δ 150.4, 129.0, 127.7, 125.2.

Potassium phenylbis(phenylsulfonyl)methanide 1d was obtained according to the general
procedure described above starting from 3-(phenylmethylenedisulfonyl)-
dibenzene 1d-H (550.0 mg, 1.47 mmol) and KO
t
Bu (157.0 mg, 1.40 mmol).
White solid (  max = 268 nm). Yield: 412.2 mg (1.00 mmol, 72%).
1
H NMR (400
MHz, DMSO-d 6) δ 7.94 – 7.86 (m, 5H), 7.45 – 7.28 (m, 10H).
13
C NMR (101
MHz, DMSO-d 6) δ 168.2, 136.7, 130.2, 129.0, 127.6, 54.6.
Potassium benzo[1,3]dithiol-2-ide 1,1,3,3-tetraoxide 2a was obtained according to the general
procedure described above starting from 1,3-Benzodithiole tetraoxide 2a-H (510.0
mg, 2.34 mmol) and KO
t
Bu (249.0 mg, 2.21 mmol). White solid (  max = 261 and 299
nm). Yield: 436.2 mg (1.70 mmol, 77%).
1
H NMR (400 MHz, DMSO-d 6) δ 7.63 (dt,
J = 6.3, 3.4 Hz, 2H), 7.61 – 7.55 (m, 2H), 2.99 (s, 1H).
13
C NMR (101 MHz DMSO-
d 6) δ 146.5, 131.3, 119.6, 60.9.

Potassium 2-phenylbenzo[1,3]dithiol-2-ide 1,1,3,3-tetraoxide 2d was obtained according to the
general procedure described above starting from 2-phenyl- benzo[d][1,3]dithiole
1,1,3,3-tetraoxide 2d-H (500.0 mg, 1.70 mmol) and KO
t
Bu (181.0 mg, 1.61 mmol).
White solid (  max = 278 and 349 nm). Yield: 375.1 mg (1.13 mmol, 70%).
1
H NMR
(400 MHz, DMSO-d 6) δ 8.25 – 8.13 (m, 1H), 8.05 – 7.94 (m, 1H), 7.92 – 7.84 (m,
2H), 7.63 – 7.53 (m, 1H), 7.49 – 7.40 (m, 1H), 7.39 – 7.29 (m, 3H).
13
C NMR (101
MHz DMSO-d 6) δ 168.5, 138.2, 137.2, 134.8, 130.1, 129.1, 128.8, 127.6, 122.1, 76.1.
260

6.4.3. Investigation of persistency of carbanions.
Initial NMR spectra was taken with a solution of substrate (0.05 mmol) and reference (0.2 M PhCF 3
solution in DMSO or 0.1 M PhCH 3 solution in DMSO, 0.01 mmol) in 0.5 mL DMSO-d 6. After
addition of 1.2 equiv. tBuOK (0.6 M in DMSO, 0.06 mmol), NMR spectra was performed to
confirm the complete deprotonation by the disappearance of methylene proton ((EWG) 2CHR) and
the chemical shift change of
19
F NMR if fluorine presents. Subsequently, acetic acid (0.2 mmol)
was added into the mixture and quantitative analysis of the recovery ratio was performed based on
the appropriate reference.
The recovery ratio is as follows:

1b−H, 91.1%; 1c−H, 89.0%; 2b−H, 99.0%; 2f−H, 94.3%; 3a−H, 90.4%; 3b−H, 83.2%; 3c−H,
87.9%; 4b−H, 92.2%; 4c−H, 96.6%; 4e−H, 87.0%.

261

6.4.4. General procedure for the synthesis of nucleophilic addition products.
Under an argon atmosphere potassium tert-butoxide (0.11 mmol) was added to a solution of 1−H
(0.10 mmol) in dry DMSO (2 mL). To the in situ generated carbanion solution was added the
benzhydrilium tetrafluoroborate 5j (0.10 mmol). After total decoloration (2-5 min), the product was
precipitated by adding H 2O (10 mL). The mixture was filtered off and the precipitate was
redissolved in EtOAc. The solution was washed with water (2 x 10 mL), dried over MgSO 4 and
evaporated under reduced pressure affording a crude product which was purified by flash
chromatography or preparative thin layer chromatography with EtOAc/Hexane as eluent.
9,9'-(2,2-bis(phenylsulfonyl)ethane-1,1-diyl)bis(2,3,6,7-tetrahydro-1H,5H-pyridoquinoline) 6a.
Pale yellowish solid. 59% yield.
1
H NMR (300 MHz, CDCl 3) δ 7.64 (d, J = 7.8 Hz, 4H), 7.53 (t, J
= 7.5 Hz, 2H), 7.37 (t, J = 7.5 Hz, 4H), 6.53 (s, 4H), 5.45 (d, J = 6.3 Hz, 1H), 4.79 (d, J = 5.8 Hz,
1H), 3.06 (t, J = 5.6 Hz, 8H), 2.54 (t, J = 6.3 Hz, 8H), 1.89 (p, J = 5.9 Hz, 8H).
13
C NMR (75 MHz,
CDCl 3) δ 141.9, 140.5, 133.3, 129.1, 128.4, 128.1, 126.4, 121.1, 90.7, 50.1, 49.3, 27.7, 22.3.

9,9'-(2-fluoro-2,2-bis(phenylsulfonyl)ethane-1,1-diyl)bis(2,3,6,7-tetrahydro-1H,5H-
pyridoquinoline) 6b. White solid. 57% yield.
13
C NMR could not be obtained due to the slow
decomposition of the titled compound during acquisition.
1
H NMR and
19
F NMR

contain 19% of
1b due to difficulty of separation. HRMS could not be obtained due to the slow decomposition.
1
H
NMR (400 MHz, CDCl 3, 25 ° C, TMS) δ = 7.54-7.56 (m, 4H), 7.46-7.49 (m, 2H), 7.29-7.33 (m,
4H), 3.90 (s, 4H), 4.82 (d,
3
J H-F = 41.6 Hz), 2.95-3.05 (m, 8H), 2.33-2.60 (m, 8H), 1.77-1.89 (m,
8H);
19
F NMR (376 MHz, CDCl 3, 25 ° C) δ = -141.0 (d,
3
J H-F = 38.7 Hz).

9,9'-(2-methoxy-2,2-bis(phenylsulfonyl)ethane-1,1-diyl)bis(2,3,6,7-tetrahydro-1H,5H-
pyridoquinoline) 6c. White solid. 83% yield.
1
H NMR (400 MHz, CDCl 3, 25 ° C, TMS) δ =7.64-
7.62 (m, 4H), 7.45-7.44 (m, 2H), 7.33-7.30 (m, 4H), 6.50 (s, 4H), 4.60 (s, 3H), 4.51 (s, 1H), 3.03-
2.91 (m, 8H), 2.58-2.37 (m, 8H), 1.87-1.77 (m, 8H);
13
C NMR (100 MHz, CDCl 3, 25 ° C, TMS) δ
=141.9, 141.6, 132.8, 129.6, 128.6, 127.9, 127.1, 120.8, 120.5, 59.1, 53.7, 50.0, 27.7, 22.3. HRMS
(ESI), m/z calcd for C 39H 43N 2O 5S 2 [M+H]
+
: 683.2608. Found: 683.2620.

9,9'-(2-Phenyl-2,2-bis(phenylsulfonyl)ethane-1,1-diyl)bis(1,2,3,5,6,7-hexahydropyrido[3,2,1-
ij]quinoline) 6d. Pale yellowish solid. 66% yield.
1
H NMR (599 MHz, CDCl 3) δ 7.76 (d, J = 9.0
Hz, 4H), 7.61 (t, J = 7.5 Hz, 2H), 7.45 (t, J = 7.9 Hz, 4H), 7.35 (t, J = 7.4 Hz, 1H), 7.24 – 7.20 (m,
4H), 6.77 (s, 4H ), 5.48 (s, 1H), 3.12 – 3.04 (m, 8H), 2.72 (t, J = 6.5 Hz, 8H), 1.94 (dt, J = 12.2, 6.4
262

Hz, 8H).
13
C NMR (151 MHz, CDCl 3) δ 142.3, 138.1, 134.6, 131.9, 130.6, 129.8, 129.0, 127.4,
125.8, 125.4, 121.5, 76.2, 50.2, 27.8, 22.3.

When 1e was examined, undesired product 6a was obtained: 9,9'-(2,2-bis(phenylsulfonyl)ethane-
1,1-diyl)bis(2,3,6,7-tetrahydro-1H,5H-pyridoquinoline). Pale yellowish solid. 61% yield.
1
H NMR
(300 MHz, CDCl 3) δ 7.63~7.65 (2H), 7.51~7.55 (2H), 7.36~7.40 (4H), 6.53 (s, 4H), 5.45 (d, J =
6.3 Hz, 1H), 4.79 (d, J = 6.4 Hz, 1H), 3.06 (t, J = 5.4 Hz, 8H), 2.54 (t, J = 6.3 Hz, 8H), 1.89 (p, J
= 5.6 Hz, 8H).

2-(bis(2,3,6,7-tetrahydro-1H,5H-pyridoquinolin-9-yl)methyl)-2H-benzo[1,3]dithiole-1,1,3,3-
tetraoxide 6e. Pale yellowish solid. 73% yield.
1
H NMR (300 MHz, CDCl 3) δ 7.97 – 7.74 (m, 4H),
6.85 (s, 4H), 5.30 (d, J = 11.9 Hz, 1H), 4.60 (d, J = 11.9 Hz, 1H), 3.17 – 2.96 (m, 8H), 2.73 (t, J =
6.5 Hz, 8H), 2.03 – 1.82 (m, 8H).
13
C NMR (75 MHz, CDCl 3) δ 142.6, 138.3, 134.8), 126.8, 124.9,
122.4, 121.5, ~77.0 (overlap with CDCl 3) 50.1, 46.3, 27.9, 22.2. HRMS (ESI): m/z calcd for
C 32H 34N 2O 4S 2: 574.1960; found: 574.1945.

2-(bis(2,3,6,7-tetrahydro-1H,5H-pyridoquinolin-9-yl)methyl)-2-fluoro-2H-benzo[1,3]dithiole-
1,1,3,3-tetraoxide 6f. White solid. 93% yield.
1
H NMR (400 MHz, CDCl 3, 25 ° C, TMS) δ = 7.93-
7.91 (m, 2H), 7.85-7.83 (m, 2H), 6.98 (s, 4H), 5.01 (d, 1H,
3
J H-F = 40.1 Hz), 3.10-3.08 (m, 8H),
2.75-2.72 (m, 8H), 1.95-1.90 (m, 8H);
19
F NMR (376 MHz, CDCl 3, 25 ° C) δ = -154.0 (d,
3
J H-F =
40.1 Hz).
13
C NMR (100 MHz, CDCl 3, 25 ° C, TMS) δ = 142.8, 136.2, 135.2, 138.2 (d,
3
J C-F = 1.9
Hz), 123.6, 121.9, 121.4, 109.2 (d,
1
J C-F = 276.5 Hz), 50.0, 46.9 (d,
2
J C-F = 15.1 Hz), 27.9, 22.1.
HRMS (ESI), m/z calcd for C 32H 34FN 2O 4S 2 [M+H]
+
: 593.1939. Found: 593.1944.

2-(bis(2,3,6,7-tetrahydro-1H,5H-pyridoquinolin-9-yl)methyl)-2-methoxy-2H-benzo[1,3]dithiole-
1,1,3-trioxide 6g. White solid. 69% yield.
1
H NMR (400 MHz, CDCl 3, 25 ° C, TMS) δ = 7.78-7.65
(m, 4H), 6.97 (s, 2H), 6.81 (s, 2H), 4.96 (s, 1H), 3.66 (s, 3H), 3.10-3.03 (m, 8H), 2.75-2.61 (m, 8H),
1.95-1.88 (m, 8H);
13
C NMR (100 MHz, CDCl 3, 25 ° C, TMS) δ = 142.5, 142.1, 140.2, 138.6, 134.6,
132.5, 128.8, 128.4, 126.7, 124.73, 124.70, 122.3, 121.2, 121.0, 114.9, 57.2, 52.1, 50.2, 50.0, 27.92,
27.86, 22.3, 22.2. HRMS (ESI), m/z calcd for C 33H 37N 2O 4S 2 [M+H]
+
: 589.2189. Found: 589.2192.

2-(Bis(1,2,3,5,6,7-hexahydropyrido[3,2,1-ij]quinolin-9-yl)methyl)-2-phenylbenzo[1,3]-dithiole-
1,1,3,3-tetraoxide 6h. Pale yellowish solid. 54% yield.
1
H NMR (400 MHz, CDCl 3) δ 8.12 (dd, J =
5.8, 3.2 Hz, 2H), 7.95 (dd, J = 5.8, 3.2 Hz, 2H), 7.74 – 7.52 (m, 5H), 7.26 (s, 2H), 6.73 (s, 2H),
263

5.10 (s, 1H,), 3.08 (dt, J = 12.2, 5.7 Hz, 2H), 2.97 (t, J = 5.5 Hz, 6H), 2.72 (q, J = 6.2 Hz, 2H), 2.50
(t, J = 6.6 Hz, 6H), 1.95 (p, J = 6.2 Hz, 2H), 1.81 (p, J = 6.3 Hz, 6H).
13
C NMR (101 MHz, CDCl 3)
δ 142.2, 141., 138.1, 135.1, 133.5, 132.7, 131.6, 129.8, 129.3, 127.9, 127.3, 125.2, 123.7, 122.1,
121.4, 120.3, 91.6, 50.2, 49.9, 27.7, 27.5, 22.3, 22.1.

Ethyl 2-(phenylsulfonyl)-3,3-bis(2,3,6,7-tetrahydro-1H,5H-pyridoquinolin-9-yl)propanoate 6i.
White solid. 89% yield.
1
H NMR (400 MHz, CDCl 3, 25 ° C, TMS) δ =7.47-7.43 (m, 3H), 7.30-7.28
(m, 2H), 6.61 (s, 2H), 6.39 (s, 1H), 4.87 (d, 1H,
3
J H-H = 12.2 Hz), 4.32 (d, 1H,
3
J H-H = 12.2 Hz),
4.13-4.03 (m, 2H), 3.01-2.98 (m, 8H), 2.64-2.32 (m, 8H), 1.88-1.82 (m, 8H), 1.06 (t, 3H,
3
J H-H =
7.1 Hz);
13
C NMR (100 MHz, CDCl 3, 25 ° C, TMS) δ = 165.1, 142.2, 142.0, 140.2, 132.7, 129.4,
128.7, 128.49, 128.45, 128.3, 126.7, 126.0, 121.6, 121.5, 76.1, 62.0, 50.13, 50.12, 27.8, 27.6, 22.31,
22.26, 13.9. HRMS (ESI), m/z calcd for C 35H 41N 2O 4S [M+H]
+
: 585.2782. Found: 585.2784.

Ethyl 2-fluoro-2-(phenylsulfonyl)-3,3-bis(2,3,6,7-tetrahydro-1H,5H-pyridoquinolin-9-
yl)propanoate 6j. White solid. 88% yield.
1
H NMR (400 MHz, CDCl 3, 25 ° C, TMS) δ =7.43-7.41
(m, 3H), 7.28-7.24 (m, 2H), 6.73 (s, 2H), 6.58 (s, 2H), 4.68 (d, 1H,
3
J H-F = 40.5 Hz), 4.21 (qd, 2H,
3
J H-H = 7.1 Hz,
3
J H-F = 2.3 Hz), 3.04-3.00 (m, 8H), 2.64-2.57 (m, 8H), 1.88-1.83 (m, 8H), 1.17 (t,
3H,
3
J H-H = 7.1 Hz);
19
F NMR (376 MHz, CDCl 3, 25 ° C) δ = -160.9 (d,
3
J H-F = 40.4 Hz).
13
C NMR
(100 MHz, CDCl 3, 25 ° C, TMS) δ =163.2 (d,
2
J C-F = 25.5 Hz), 142.4, 142.1, 135.9, 133.1, 130.1 (d,
3
J C-F = 2.1 Hz), 128.3 (d,
3
J C-F = 2.6 Hz), 127.8, 126.9 (d,
4
J C-F = 1.8 Hz), 125.6, 124.1, 121.4, 121.1,
112.3 (d,
1
J C-F = 241.2 Hz), 62.9, 52.5 (d,
2
J C-F = 16.2 Hz), 50.0, 49.9, 27.6, 27.5, 22.2, 22.0, 13.8.
HRMS (ESI), m/z calcd for C 35H 40FN 2O 4S [M+H]
+
: 603.2693. Found: 603.2684.

Ethyl 2-methoxy-2-(phenylsulfonyl)-3,3-bis(2,3,6,7-tetrahydro-1H,5H-pyridoquinolin-9-
yl)propanoate 6k. White solid. 83% yield.
1
H NMR (400 MHz, CDCl 3, 25 ° C, TMS) δ = 7.47-7.43
(m, 1H), 7.35-7.31 (m, 2H), 7.26-7.24 (m, 2H), 6.70 (s, 4H), 4.43 (s, 1H), 4.20 (q, 2H,
3
J H-H = 7.1
Hz), 4.06 (s, 3H), 3.04-2.99 (m, 8H), 2.64-2.41 (m, 8H), 1.89-1.87 (m, 8H), 1.25 (t, 3H,
3
J H-H = 7.1
Hz);
13
C NMR (100 MHz, CDCl 3, 25 ° C, TMS) δ = 166.0, 138.6, 132.7, 130.4, 129.3, 127.6, 121.2,
107.6, 62.2, 58.0, 55.4, 50.3, 50.2, 27.8, 27,7, 22.5, 22.3, 14.1. HRMS (ESI), m/z calcd for
C 36H 43N 2O 5S [M+H]
+
: 615.2887. Found: 615.2879.

Diethyl 2-(bis(2,3,6,7-tetrahydro-1H,5H-pyridoquinolin-9-yl)methyl)-2-fluoromalonate 6l. White
solid. 92% yield.
1
H NMR (400 MHz, CDCl 3, 25 ° C, TMS) δ = 6.77 (s, 4H), 4.63 (d, 1H,
3
J H-F =
36.6 Hz), 4.13 (q, 2H,
3
J H-H = 7.1 Hz), 3.06-3.03 (m, 8H), 2.69-2.66 (m, 8H), 1.93-1.87 (m, 8H),
264

1.12 (t, 3H,
3
J H-H = 7.1 Hz);
19
F NMR (376 MHz, CDCl 3, 25 ° C) δ = -173.9 (d,
3
J H-F = 36.5 Hz).
13
C NMR (100 MHz, CDCl 3, 25 ° C, TMS) δ =165.9 (d,
2
J C-F = 26.2 Hz), 142.0, 127.8 (d,
3
J C-F =
2.2 Hz), 126.0, 121.3, 98.5 (d,
1
J C-F = 209.8 Hz), 62.4, 54.4 (d,
2
J C-F = 18.1 Hz), 50.2, 27.8, 22.3,
14.0. HRMS (ESI), m/z calcd for C 32H3 9FN 2O 4 [M+H]
+
: 534.2894. Found: 534.2887.

Dimethyl 2-(bis(2,3,6,7-tetrahydro-1H,5H-pyridoquinolin-9-yl)methyl)-2-methoxymalonate 6m.
White solid. 91% yield.
1
H NMR (400 MHz, CDCl 3, 25 ° C, TMS) δ = 6.79 (s, 4H), 4.37 (s, 1H),
3.59 (s, 6H), 3.57 (s, 3H), 3.05-3.02 (m, 8H), 2.69-2.67 (m, 8H), 1.92-1.91 (m, 8H);
13
C NMR (100
MHz, CDCl 3, 25 ° C, TMS) δ = 169.3, 141.6, 128.4, 127.6, 120.9, 89.8, 57.2, 56.9, 52.3, 50.2, 27.8,
22.4. HRMS (ESI), m/z calcd for C 31H3 9N 2O 5 [M+H]
+
: 519.2859. Found: 519.2849.
Diethyl 2-(bis(2,3,6,7-tetrahydro-1H,5H-pyridoquinolin-9-yl)methyl)-2-chloromalonate 6n. White
solid. 91% yield.
1
H NMR (400 MHz, CDCl 3, 25 ° C, TMS) δ = 6.84 (s, 4H), 4.93 (s, 1H), 4.12 (q,
3
J H-H = 7.1 Hz, 4H), 3.07-3.04 (m, 8H), 2.70-2.67 (m, 8H), 1.93-1.90 (m, 8H), 1.14 (t,
3
J H-H = 7.1
Hz, 6H);
13
C NMR (100 MHz, CDCl 3, 25 ° C, TMS) δ = 166.4, 141.8, 128.8, 126.9, 120.8, 77.6,
63.0, 55.2, 50.2, 27.9, 22.4, 13.9. HRMS (ESI), m/z calcd for C 32H 40O 4N 2Cl [M+H]
+
: 551.2671.
Found: 551.2673.

Diethyl 2-chloro-2-((3,5-di-tert-butyl-4-hydroxyphenyl)(4-nitrophenyl)methyl)malonate 6o.
White solid. 67% yield.
1
H NMR (400 MHz, CDCl 3, 25 ° C, TMS) δ = 8.20 (d,
3
J H-H = 8.4 Hz, 2H),
7.40 (d,
3
J H-H = 8.5 Hz, 2H), 6.94 (s, 2H), 5.46 (s, 1H), 4.09 (dq,
3
J H-H = 14.4 Hz,
3
J H-H = 7.1 Hz,
4H), 1.36 (s, 18H), 1.07 (dt,
3
J H-H = 6.9 Hz,
3
J H-H = 6.9 Hz, 6H);
13
C NMR (100 MHz, CDCl 3, 25 ° C,
TMS) δ = 166.6, 165.1, 155.8, 154.7, 148.0, 147.4, 136.1, 130.2, 130.0, 126.6, 126.2, 123.4, 61.6,
61.5, 34.5, 30.3, 13.9, 13.8. HRMS (ESI), m/z calcd for C 28H 36O 7N [M−HCl]
+
: 498.2486. Found:
498.2491.

265

6.4.5 Kinetic Experiments
6.4.5.1 General procedure for the kinetic experiments.
The rates of all investigated reactions were determined photometrically. For the evaluation of the
kinetics stopped-flow spectrophotometer systems (Hi-Tech SF-61DX2 or Applied Photophysics
SX.18MV-R) were used. All kinetic measurements were carried out in DMSO (H 2O < 50 ppm)
under exclusion of moisture. The temperature of the solutions during all kinetic studies was kept
constant (20.0 ± 0.1 ° C) by using a circulating bath thermostat. The nucleophiles were always
employed as major component (high excess, typically at least 10 times higher) in the reactions with
the electrophiles to ensure first-order conditions with k obs = k 2[Nu] 0 + k 0. Pseudo-first rate constants
k obs (s
–1
) were obtained by fitting the mono-exponential function A t = A 0e
–kobst
+ C to the observed
time-dependent absorbance (average from 10 kinetic runs for each nucleophile concentration). In
order to obtain the second order reaction rates k 2 each electrophile-nucleophile combination was
measured with generally 5 different concentrations of the nucleophile. N and s N parameters were
determined applying the free energy relationship log k 2 = s N· (N+E). UV-VIS spectra were recorded
by using a J&M TIDAS diode array spectrophotometer controlled by Labcontrol Spectacle
software and connected to a Hellma 661.502-QX quartz Suprasil immersion probe (5 mm light
path) via fiber optic cables and standard SMA connectors.

The formation of the carbanions 1~4 from their conjugate acids 1−H~4−H were monitored by using
diode array UV-Vis spectrometers. The temperature during all experiments was kept constant by
using a circulating bath (20.0 ° C). Solutions of the CH acids in dry DMSO were added to a solution
of KO
t
Bu (1.1 eq.) in dry DMSO respectively. After the equilibration of the absorption (30 to 40
s) the mixtures were treated subsequently with various equivalents of KO
t
Bu (dissolved in DMSO).
In all cases a full deprotonation of the CH acid with one equivalent of base was monitored and the
UV-Vis Spectra of the anions were recorded.

266

6.4.5.2 Kinetics of the reactions of 1 with 2 in DMSO (20 ° C).
Table 6.3: Kinetics of the reactions of 1a with 5i in DMSO (20 ° C, stopped-flow,  = 630 nm).
Table 6.4: Kinetics of the reactions of 1a with 5j in DMSO (20 ° C, stopped-flow,  = 635 nm).
Table 6.5: Kinetics of the reactions of 1a with 5k in DMSO (20 ° C, stopped-flow,  = 627 nm).
Table 6.6: Kinetics of the reactions of 1a with 5l in DMSO (20 ° C, stopped-flow,  = 618 nm).
[5i] 0 /
mol· L
-1

[1a] 0 /
mol· L
-1

[18-Crown-6]
/
mol· L
-1

[1a] 0/
[5i] 0
k obs /
s
-1

1.01  10
-5
1.89  10
-4
--- 18.7 2.36  10
0

1.01  10
-5
3.77  10
-4
4.02  10
-4
37.4 4.70  10
0

1.01  10
-5
5.66  10
-4
--- 56.1 7.45  10
0

1.01  10
-5
7.55  10
-4
8.04  10
-4
74.8 1.01  10
1

k 2 = 1.38  10
4
L· mol
-1
·s
-1

[5j] 0 /
mol· L
-1

[1a] 0 /
mol· L
-1

[18-Crown-6]
/
mol· L
-1

[1a] 0/
[5j] 0
k obs /
s
-1

1.10  10
-5
1.89  10
-4
--- 17.1 6.41  10
0

1.10  10
-5
3.77  10
-4
4.02  10
-4
34.2 1.31  10
1

1.10  10
-5
5.66  10
-4
--- 51.3 1.98  10
1

1.10  10
-5
7.55  10
-4
8.04  10
-4
68.4 2.73  10
1

k 2 = 3.68  10
4
L· mol
-1
·s
-1

[5k] 0 /
mol· L
-1

[1a] 0 /
mol· L
-1

[18-Crown-6]
/
mol· L
-1

[1a] 0/
[5k] 0
k obs /
s
-1

2.02  10
-5
2.83  10
-4
--- 14.0 1.59  10
1

2.02  10
-5
3.77  10
-4
4.02  10
-4
18.7 2.80  10
1

2.02  10
-5
4.72  10
-4
--- 23.3 3.95  10
1

2.02  10
-5
5.66  10
-4
--- 28.0 5.30  10
1

2.02  10
-5
6.60  10
-4
6.96  10
-4
32.7 6.33  10
1

k 2 = 1.41  10
5
L· mol
-1
·s
-1

[5l] 0 /
mol· L
-1

[1a] 0 /
mol· L
-1

[18-Crown-6]
/
mol· L
-1

[1a] 0/
[5l] 0
k obs /
s
-1

1.30  10
-5
2.83  10
-4
--- 21.8 6.11  10
1

1.30  10
-5
3.77  10
-4
4.02  10
-4
29.0 8.72  10
1

1.30  10
-5
4.72  10
-4
--- 36.3 1.15  10
2

1.30  10
-5
5.66  10
-4
--- 43.5 1.49  10
2

1.30  10
-5
6.60  10
-4
6.96  10
-4
50.8 1.82  10
2

k 2 = 3.41  10
5
L· mol
-1
·s
-1

y = 13765x - 0.34
R
2
= 0.9989
0.0
2.0
4.0
6.0
8.0
10.0
12.0
0.0000 0.0001 0.0002 0.0003 0.0004 0.0005 0.0006 0.0007 0.0008
[Nu] / molL
-1
k
obs
/ s
-1
y = 36768x - 0.69
R
2
= 0.9992
0.0
5.0
10.0
15.0
20.0
25.0
30.0
0.0000 0.0001 0.0002 0.0003 0.0004 0.0005 0.0006 0.0007 0.0008
[Nu] / molL
-1
k
obs
/ s
-1
y = 141200x - 11.7
R
2
= 0.9977
0.0
10.0
20.0
30.0
40.0
50.0
60.0
70.0
80.0
90.0
0.0000 0.0001 0.0002 0.0003 0.0004 0.0005 0.0006 0.0007
[Nu] / molL
-1
k
obs
/ s
-1
y = 341340x - 5.2
R
2
= 0.9996
0.0
50.0
100.0
150.0
200.0
250.0
0.0000 0.0001 0.0002 0.0003 0.0004 0.0005 0.0006 0.0007
[Nu] / molL
-1
k
obs
/ s
-1
267

Table 6.7: Kinetics of the reactions of 1a with 5m in DMSO (20 ° C, stopped-flow,  = 620 nm).
Determination of the Reactivity Parameters N and s N of Potassium Salt 1a

Table 6.8: Rate Constants of the reactions of 1a with different electrophiles.
Table 6.9: Kinetics of the reactions of 1b with 5b in DMSO (20 ° C, stopped-flow,  = 620 nm).
Table 6.10: Kinetics of the reactions of 1b with 5f in DMSO (20 ° C, stopped-flow,  = 620 nm).
[5m] 0 /
mol· L
-1

[1a] 0 /
mol· L
-1

[18-Crown-
6] /
mol· L
-1

[1a] 0/
[5m]
0
k obs /
s
-1

1.19  10
-5
9.43  10
-5
9.82  10
-5
7.9 6.54  10
1

1.19  10
-5
1.89  10
-4
--- 15.8 1.23  10
2

1.19  10
-5
2.83  10
-4
--- 23.7 1.89  10
2

1.19  10
-5
3.77  10
-4
4.02  10
-4
31.6 2.64  10
2

k 2 = 7.01  10
5
L· mol
-1
·s
-1

Electrophile E
k 2 /
L· mol
-1
·s
-1

log k 2

5i ˗10.04 1.26  10
4
4.10
5j ˗9.45 3.54  10
4
4.55
5k ˗8.76 1.27  10
5
5.10
5l ˗8.22 3.22  10
5
5.51
5m ˗7.69 7.01  10
5
5.85
N = 15.50, s N = 0.75

[5b] 0 /
mol· L
-1

[1b] 0 /
mol· L
-1

[18-Crown-6]
/
mol· L
-1

[1b] 0/
[5b] 0
k obs /
s
-1

4.24  10
-5
4.37  10
-4
--- 10.3 2.77  10
-3

4.24  10
-5
9.54  10
-4
1.01  10
-3
22.5 7.43  10
-3

4.24  10
-5
1.47  10
-3
--- 34.6 1.17  10
-2

4.24  10
-5
1.78  10
-3
1.89  10
-3
42.0 1.42  10
-2

4.24  10
-5
2.15  10
-3
--- 50.8 1.85  10
0

k 2 = 8.95  10
0
L· mol
-1
·s
-1

[5f] 0 /
mol· L
-1

[1b] 0 /
mol· L
-1

[18-Crown-6]
/
mol· L
-1

[1b] 0
/
[5f] 0
k obs /
s
-1

8.94  10
-5
5.00  10
-4
--- 5.6 3.76  10
-1

8.94  10
-5
7.39  10
-4
7.76  10
-4
8.3 5.89  10
-1

8.94  10
-5
9.86  10
-4
--- 11.0 7.67  10
-1

8.94  10
-5
1.43  10
-3
1.50  10
-3
16.0 1.42  10
0

8.94  10
-5
1.83  10
-3
--- 17.8 1.78  10
0

k 2 = 1.10  10
3
L· mol
-1
·s
-1

y = 701338x - 4.9
R
2
= 0.9968
0.0
50.0
100.0
150.0
200.0
250.0
300.0
0.0000 0.0001 0.0001 0.0002 0.0002 0.0003 0.0003 0.0004 0.0004
[Nu] / molL
-1
k
obs
/ s
-1
y = 8.9530x - 0.0012
R
2
= 0.9960
0.000
0.005
0.010
0.015
0.020
0 0.0005 0.001 0.0015 0.002 0.0025
[Nu] / molL
- 1
k obs / s
-1
y = 1103.2x - 0.2221
R
2
= 0.9885
0.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
2.0
0.0000 0.0005 0.0010 0.0015 0.0020
[Nu] / molL
-1
k obs / s
-1
268

Table 6.11: Kinetics of the reactions of 1b with 5g in DMSO (20 ° C, stopped-flow,  = 620 nm).
Determination of the Reactivity Parameters N and s N of Potassium Salt 1b

Table 6.12: Rate Constants of the reactions of 1b with different electrophiles.
Table 6.13: Kinetics of the reactions of 1c with 5f in DMSO (20 ° C, stopped-flow,  = 533 nm).

[5g] 0 /
mol· L
-1

[1b] 0 /
mol· L
-1

[18-Crown-6]
/
mol· L
-1

[1b] 0
/
[5g] 0
k obs /
s
-1

8.94  10
-5
4.83  10
-4
--- 5.4 1.81  10
0

8.94  10
-5
7.14  10
-4
7.57  10
-4
8.0 3.56  10
0

8.94  10
-5
9.52  10
-4
--- 10.6 4.76  10
0

8.94  10
-5
1.38  10
-3
1.46  10
-3
15.5 7.50  10
0

8.94  10
-5
1.76  10
-3
--- 19.7 9.37  10
0

k 2 = 5.87  10
3
L· mol
-1
·s
-1

Electrophile E
k 2 /
L· mol
-1
·s
-1

log k 2

5b ˗16.11 8.95  10
0
0.95
5f ˗13.39 1.10  10
3
3.04
5g ˗12.18 5.87  10
3
3.77
N = 17.46
s N = 0.73

[5f] 0 /
mol· L
-1

[1c] 0 /
mol· L
-1

[1c] 0/
[5f] 0
k obs /
s
-1

1.80  10
-5
3.75  10
-4
20.8 2.11
1.80  10
-5
5.01  10
-4
27.8 2.18
1.80  10
-5
6.26  10
-4
34.7 2.25
1.80  10
-5
7.51  10
-4
41.7 2.32
1.80  10
-5
8.76  10
-4
48.6 2.39
k 2 = 5.59  10
2
L· mol
-1
·s
-1

y = 5873.4x - 0.8155
R
2
= 0.9961
0.0
2.0
4.0
6.0
8.0
10.0
12.0
0.0000 0.0005 0.0010 0.0015 0.0020
[Nu] / molL
-1
k obs / s
-1
y = 0.7254x + 12.666
R
2
= 0.9971
0.00
1.00
2.00
3.00
4.00
5.00
-17 -16 -15 -14 -13 -12 -11 -10
E -parameter
log k 2
269

Table 6.14: Kinetics of the reactions of 1c with 5g in DMSO (20 ° C, stopped-flow,  = 422 nm).
Table 6.15: Kinetics of the reactions of 1c with 5i in DMSO (20 ° C, stopped-flow,  = 630 nm).

Table 6.16: Kinetics of the reactions of 1c with 5j in DMSO (20 ° C, stopped-flow,  = 635 nm).

[5g] 0 /
mol· L
-1

[1c] 0 /
mol· L
-1

[1c] 0/
[5g] 0
k obs /
s
-1

1.73  10
-5
3.75  10
-4
21.7 2.43
1.73  10
-5
5.01  10
-4
29.0 2.84
1.73  10
-5
6.26  10
-4
36.2 3.33
1.73  10
-5
7.51  10
-4
43.4 3.60
1.73  10
-5
8.76  10
-4
50.7 3.97
k 2 = 3.07  10
3
L· mol
-1
·s
-1

[5i] 0 /
mol· L
-1

[1c] 0 /
mol· L
-1

[1c] 0/
[5i] 0
k obs /
s
-1

8.89  10
-6
1.25  10
-4
14.1 1.55  10
1

8.89  10
-6
1.50  10
-4
16.9 1.85  10
1

8.89  10
-6
1.88  10
-4
21.1 2.39  10
1

8.89  10
-6
2.50  10
-4
28.2 3.26  10
1

k 2 = 1.38  10
5
L· mol
-1
·s
-1

[5j] 0 /
mol· L
-1

[1c] 0 /
mol· L
-1

[1c] 0/
[5j] 0
k obs /
s
-1

8.10  10
-6
1.25  10
-4
15.4 3.28  10
1

8.10  10
-6
1.50  10
-4
18.5 3.94  10
1

8.10  10
-6
1.88  10
-4
23.2 5.10  10
1

8.10  10
-6
2.50  10
-4
30.9 7.34  10
1

k 2 = 3.27  10
5
L· mol
-1
·s
-1

270

Table 6.17: Kinetics of the reactions of 1c with 5k in DMSO (20 ° C, stopped-flow,  = 627 nm).

Table 6.18: Rate Constants of the reactions of 1c with different electrophiles.

Table 6.19: Kinetics of the reactions of 1d with 5i in DMSO (20 ° C, stopped-flow,  = 630 nm).
[5k] 0 /
mol· L
-1

[1c] 0 /
mol·L
-1

[1c] 0/
[5k] 0
k obs /
s
-1

9.34  10
-6
1.25  10
-4
13.4 5.94  10
1

9.34  10
-6
1.50  10
-4
16.1 7.46  10
1

9.34  10
-6
1.88  10
-4
20.1 1.02  10
1

9.34  10
-6
2.50  10
-4
26.8 1.52  10
1

k 2 = 7.44  10
5
L· mol
-1
·s
-1

Electrophile E
k 2 /
L· mol
-1
·s
-1

log k 2

5f ˗13.39 5.59  10
2
2.75
5g ˗12.18 3.07  10
3
3.49
5i ˗10.04 1.38  10
5
5.14
5j ˗9.45 3.27  10
5
5.51
5k ˗8.76 7.44  10
5
5.87
N = 17.29
s N = 0.70

[5i] 0 /
mol· L
-1

[1d] 0 /
mol· L
-1

[18-Crown-6] /
mol· L
-1

[1d] 0
/ [5i] 0
k obs /
s
-1

1.13  10
-5
1.51  10
-4
--- 13.4
3.31 
10
0

1.13  10
-5
3.02  10
-4
--- 26.8
5.33 
10
0

1.13  10
-5
3.78  10
-4
4.23  10
-4
33.4
6.31 
10
0

1.13  10
-5
6.04  10
-4
--- 53.5
8.96 
10
0

1.13  10
-5
7.55  10
-4
8.47  10
-4
66.9
1.08 
10
1

k 2 = 1.23  10
4
L· mol
-1
·s
-1

log k
2
= 0.6976E + 12.061
R² = 0.9971
0.0
1.0
2.0
3.0
4.0
5.0
6.0
7.0
-15.0 -13.0 -11.0 -9.0 -7.0
lg k2
E-Parameter
y = 12287x + 1.5611
R
2
= 0.9992
0.0
2.0
4.0
6.0
8.0
10.0
12.0
0.0000 0.0001 0.0002 0.0003 0.0004 0.0005 0.0006 0.0007 0.0008
[Nu] / molL
-1
k
obs
/ s
-1
271

Table 6.20: Kinetics of the reactions of 1d with 5j in DMSO (20 ° C, stopped-flow,  = 635 nm).
Table 6.21: Kinetics of the reactions of 1d with 5k in DMSO (20 ° C, stopped-flow,  = 627 nm).
Table 6.22: Kinetics of the reactions of 1d with 5l in DMSO (20 ° C, stopped-flow,  = 618 nm).

[5j] 0 /
mol· L
-1

[1d] 0 /
mol· L
-1

[18-Crown-6] /
mol· L
-1

[1d] 0
/
[5j] 0
k obs /
s
-1

1.49  10
-5
1.51  10
-4
--- 10.2
8.07 
10
0

1.49  10
-5
2.27  10
-4
--- 15.2
1.00 
10
1

1.49  10
-5
3.78  10
-4
4.23  10
-4
25.4
1.42 
10
1

1.49  10
-5
6.04  10
-4
--- 40.7
2.06 
10
1

1.49  10
-5
7.55  10
-4
8.47  10
-4
50.8
2.47 
10
1

k 2 = 2.77  10
4
L· mol
-1
·s
-1

[5k] 0 /
mol· L
-1

[1d] 0 /
mol· L
-1

[18-Crown-6]
/
mol· L
-1

[1d] 0
/
[5k] 0
k obs /
s
-1

1.51  10
-5
1.51  10
-4
--- 10.0 1.26  10
1

1.51  10
-5
3.02  10
-4
--- 20.0 2.44  10
1

1.51  10
-5
4.53  10
-4
5.29  10
-4
30.0 3.61  10
1

1.51  10
-5
6.04  10
-4
--- 40.0 4.58  10
1

1.51  10
-5
7.55  10
-4
8.47  10
-4
50.0 5.61  10
1

k 2 = 7.18  10
4
L· mol
-1
·s
-1

[5l] 0 /
mol· L
-1

[1d] 0 /
mol· L
-1

[18-Crown-6]
/
mol· L
-1

[1d]
/
[5l] 0
k obs /
s
-1

1.10  10
-5
1.51  10
-4
--- 13.8 4.23  10
1

1.10  10
-5
2.27  10
-4
--- 20.7 5.93  10
1

1.10  10
-5
3.02  10
-4
--- 27.6 7.50  10
1

1.10  10
-5
4.53  10
-4
5.29  10
-4
41.3 1.08  10
2

1.10  10
-5
6.04  10
-4
--- 55.1 1.36  10
2

k 2 = 2.08  10
5
L· mol
-1
·s
-1

y = 27702x + 3.8001
R
2
= 0.9999
0.0
5.0
10.0
15.0
20.0
25.0
30.0
0.0000 0.0001 0.0002 0.0003 0.0004 0.0005 0.0006 0.0007 0.0008
[Nu] / molL
-1
k
obs
/ s
-1
y = 71780x + 2.48
R
2
= 0.9982
0.0
10.0
20.0
30.0
40.0
50.0
60.0
0.0000 0.0001 0.0002 0.0003 0.0004 0.0005 0.0006 0.0007 0.0008
[Nu] / molL
-1
k
obs
/ s
-1
y = 207638x + 11.999
R
2
= 0.9988
0.0
20.0
40.0
60.0
80.0
100.0
120.0
140.0
160.0
0.0000 0.0001 0.0002 0.0003 0.0004 0.0005 0.0006 0.0007
[Nu] / molL
-1
k
obs
/ s
-1
272

Table 6.23: Kinetics of the reactions of 1d with 5m in DMSO (20 ° C, stopped-flow,  = 620 nm).

Determination of the Reactivity Parameters N and s N of Potassium Salt 1d

Table 6.24: Rate Constants of the reactions of 1d with different electrophiles.

Table 6.25: Kinetics of the reactions of 2a with 5i in DMSO (20 ° C, stopped-flow,  = 630 nm).
[5m] 0 /
mol· L
-1

[1d] 0 /
mol· L
-1

[18-Crown-6]
/
mol· L
-1

[1d] 0
/
[5m]
0
k obs /
s
-1

7.65  10
-6
7.55  10
-5
8.47  10
-4
9.9 7.42  10
1

7.65  10
-6
1.51  10
-4
--- 19.7 1.37  10
2

7.65  10
-6
2.27  10
-4
--- 29.6 1.92  10
2

7.65  10
-6
3.02  10
-4
--- 39.5 2.61  10
2

7.65  10
-6
3.78  10
-4
4.23  10
-4
49.4 3.29  10
2

k 2 = 8.39  10
5
L· mol
-1
·s
-1

Electrophile E
k 2 /
L· mol
-1
·s
-1

log k 2

5i ˗10.04 1.23  10
4
4.09
5j ˗9.45 2.77  10
4
4.44
5k ˗8.76 7.18  10
4
4.86
5l ˗8.22 2.08  10
5
5.32
5m ˗7.69 8.39  10
5
5.92
N = 15.30
s N = 0.76

[5i] 0 /
mol· L
-1

[2a] 0 /
mol· L
-1

[18-Crown-6]
/
mol· L
-1

[2a] 0/
[5i] 0
k obs /
s
-1

1.01  10
-5
1.98  10
-4
--- 19.6 3.06  10
0

1.01  10
-5
3.96  10
-4
4.02  10
-4
39.3 5.68  10
0

1.01  10
-5
5.95  10
-4
--- 58.9 8.36  10
0

1.01  10
-5
7.93  10
-4
8.04  10
-3
78.6 1.20  10
1

1.01  10
-5
9.91  10
-4
--- 98.2 1.55  10
1

k 2 = 1.57  10
4
L· mol
-1
·s
-1

y = 839111x + 8.56
R
2
= 0.9983
0.0
50.0
100.0
150.0
200.0
250.0
300.0
350.0
0.0000 0.0001 0.0001 0.0002 0.0002 0.0003 0.0003 0.0004 0.0004
[Nu] / molL
-1
k
obs
/ s
-1
y = 0.7612x + 11.649
R
2
= 0.9786
3.0
3.5
4.0
4.5
5.0
5.5
6.0
6.5
-10.5 -10.0 -9.5 -9.0 -8.5 -8.0 -7.5
E -Parameter
log k 2
y = 15744x - 0.44
R
2
= 0.994
0.0
2.0
4.0
6.0
8.0
10.0
12.0
14.0
16.0
18.0
0.0000 0.0002 0.0004 0.0006 0.0008 0.0010 0.0012
[Nu] / molL
-1
k
obs
/ s
-1
273

Table 6.26: Kinetics of the reactions of 2a with 5j in DMSO (20 ° C, stopped-flow,  = 635 nm).
Table 6.27: Kinetics of the reactions of 2a with 5k in DMSO (20 ° C, stopped-flow,  = 627 nm).
Table 6.28: Kinetics of the reactions of 2a with 5l in DMSO (20 ° C, stopped-flow,  = 618 nm).
Table 6.29: Kinetics of the reactions of 2a with 5m in DMSO (20 ° C, stopped-flow,  = 620nm).
[5j] 0 /
mol· L
-1

[2a] 0 /
mol· L
-1

[18-Crown-6]
/
mol· L
-1

[2a] 0/
[5j] 0
k obs /
s
-1

1.10  10
-5
1.98  10
-4
--- 18.0 7.87  10
0

1.10  10
-5
3.96  10
-4
4.02  10
-4
35.9 1.53  10
1

1.10  10
-5
5.95  10
-4
--- 53.9 2.19  10
1

1.10  10
-5
7.93  10
-4
8.04  10
-3
71.9 2.97  10
1

1.10  10
-5
9.91  10
-4
--- 89.8 3.72  10
1

k 2 = 3.69  10
4
L· mol
-1
·s
-1

[5k] 0 /
mol· L
-1

[2a] 0 /
mol· L
-1

[18-Crown-6]
/
mol· L
-1

[2a] 0/
[5k] 0
k obs /
s
-1

2.02  10
-5
2.97  10
-4
--- 14.7 1.94  10
1

2.02  10
-5
3.96  10
-4
4.11  10
-4
19.6 2.54  10
1

2.02  10
-5
4.95  10
-4
--- 24.5 3.17  10
1

2.02  10
-5
5.95  10
-4
6.25  10
-4
29.4 3.89  10
1

2.02  10
-5
6.94  10
-4
--- 34.3 4.63  10
1

k 2 = 6.79  10
4
L· mol
-1
·s
-1

[5l] 0 /
mol· L
-1

[2a] 0 /
mol· L
-1

[18-Crown-6]
/
mol· L
-1

[2a] 0/
[5l] 0
k obs /
s
-1

1.30  10
-5
2.97  10
-4
--- 22.9 7.29  10
1

1.30  10
-5
3.96  10
-4
4.11  10
-4
30.5 9.13  10
1

1.30  10
-5
4.95  10
-4
--- 38.1 1.15  10
2

1.30  10
-5
5.95  10
-4
6.25  10
-4
45.7 1.36  10
2

1.30  10
-5
6.94  10
-4
--- 53.3 1.59  10
2

k 2 = 2.19  10
5
L· mol
-1
·s
-1

[5m] 0 /
mol· L
-1

[2a] 0 /
mol· L
-1

[18-Crown-6]
/
mol· L
-1

[2a] 0/
[5m]
0
k obs /
s
-1

1.19  10
-5
9.91  10
-5
9.91  10
-5
8.3 7.95  10
1

1.19  10
-5
1.98  10
-4
--- 16.6 1.50  10
2

1.19  10
-5
2.97  10
-4
--- 24.9 2.15  10
2

1.19  10
-5
3.96  10
-4
4.11  10
-4
33.2 2.94  10
2

1.19  10
-5
4.95  10
-4
--- 41.5 3.66  10
2

k 2 = 7.24  10
5
L· mol
-1
·s
-1

y = 3.69E+04x + 4.68E-01
R
2
= 9.99E-01
0.0
5.0
10.0
15.0
20.0
25.0
30.0
35.0
40.0
0.0000 0.0002 0.0004 0.0006 0.0008 0.0010
[Nu] / molL
-1
k
obs
/ s
-1
y = 67920x - 1.31
R
2
= 0.9978
0.0
5.0
10.0
15.0
20.0
25.0
30.0
35.0
40.0
45.0
50.0
0.0000 0.0001 0.0002 0.0003 0.0004 0.0005 0.0006 0.0007 0.0008
[Nu] / molL
-1
k
obs
/ s
-1
y = 218696x + 6.41
R
2
= 0.9987
0.0
20.0
40.0
60.0
80.0
100.0
120.0
140.0
160.0
180.0
0.0000 0.0001 0.0002 0.0003 0.0004 0.0005 0.0006 0.0007 0.0008
[Nu] / molL
-1
k
obs
/ s
-1
y = 723605x + 5.8
R
2
= 0.9991
0.0
50.0
100.0
150.0
200.0
250.0
300.0
350.0
0.0000 0.0001 0.0002 0.0003 0.0004 0.0005 0.0006
[Nu] / molL
-1
k
obs
/ s
-1
274

Determination of the Reactivity Parameters N and s N of Potassium Salt 2a

Table 6.30: Rate Constants of the reactions of 2a with different electrophiles.
Table 6.31: Kinetics of the reactions of 2b with 5f in DMSO (20 ° C, stopped-flow,  = 533 nm).

Table 6.32: Kinetics of the reactions of 2b with 5g in DMSO (20 ° C, stopped-flow,  = 422 nm).

Electrophile E
k 2 /
L· mol
-1
·s
-1

log k 2

5i ˗10.04 1.57  10
4

4.20
5j ˗9.45 3.69  10
4
4.57
5k ˗8.76 6.79  10
5
4.83
5l ˗8.22 2.19  10
5
5.34
5m ˗7.69 7.24  10
5
5.86
N = 16.06
s N = 0.69

[5f] 0 /
mol· L
-1

[2b] 0 /
mol· L
-1

[2b] 0/
[5f] 0
k obs /
s
-1

1.83  10
-5
4.64  10
-4
25.4 1.24  10
0

1.83  10
-5
5.80  10
-4
31.7 1.42  10
0

1.83  10
-5
6.96  10
-4
38.1 1.63  10
0

1.83  10
-5
8.12  10
-4
44.4 1.84  10
0

1.83  10
-5
9.28  10
-4
50.8 2.06  10
0

k 2 = 1.78  10
3
L· mol
-1
·s
-1

[5g] 0 /
mol· L
-1

[2b] 0 /
mol· L
-1

[2b] 0/
[5g] 0
k obs /
s
-1

2.47  10
-5
4.64  10
-4
18.8 5.60  10
0

2.47  10
-5
5.80  10
-4
23.5 6.70  10
0

2.47  10
-5
6.96  10
-4
28.2 7.70  10
0

2.47  10
-5
8.12  10
-4
32.9 8.90  10
0

2.47  10
-5
9.28  10
-4
37.6 9.98  10
0

k 2 = 9.45  10
3
L· mol
-1
·s
-1

y = 0.6857x + 11.015
R
2
= 0.9697
0.0
1.0
2.0
3.0
4.0
5.0
6.0
7.0
-11.0 -10.5 -10.0 -9.5 -9.0 -8.5 -8.0 -7.5 -7.0
E-Parameter
lg k2
275

Table 6.33: Kinetics of the reactions of 2b with 5i in DMSO (20 ° C, stopped-flow,  = 630 nm).

Table 6.34: Kinetics of the reactions of 2b with 5j in DMSO (20 ° C, stopped-flow,  = 635 nm).

Table 6.35: Kinetics of the reactions of 2b with 5k in DMSO (20 ° C, stopped-flow,  = 627 nm).

[5i] 0 /
mol· L
-1

[2b] 0 /
mol·L
-1

[2b] 0/
[5i] 0
k obs /
s
-1

6.97  10
-6
1.04  10
-4
15.0 2.53  10
1

6.97  10
-6
1.51  10
-4
21.6 3.35  10
1

6.97  10
-6
1.74  10
-4
25.0 3.81  10
1

6.97  10
-6
2.09  10
-4
30.0 4.38  10
1

6.97  10
-6
2.32  10
-4
33.3 4.47  10
1

k 2 = 1.76  10
5
L· mol
-1
·s
-1

[5j] 0 /
mol· L
-1

[2b] 0 /
mol· L
-1

[2b] 0/
[5j] 0
k obs /
s
-1

1.06  10
-5
1.04  10
-4
9.9 4.23  10
1

1.06  10
-5
1.51  10
-4
14.3 5.66  10
1

1.06  10
-5
1.74  10
-4
16.4 6.41  10
1

1.06  10
-5
2.09  10
-4
19.7 7.52  10
1

1.06  10
-5
2.32  10
-4
21.9 8.15  10
1

k 2 = 3.10  10
5
L· mol
-1
·s
-1

[5k] 0 /
mol· L
-1

[2b] 0 /
mol·L
-1

[2b] 0/
[5k] 0
k obs /
s
-1

9.06  10
-6
1.04  10
-4
11.5 8.47  10
1

9.06  10
-6
1.51  10
-4
16.6 1.22  10
2

9.06  10
-6
1.74  10
-4
19.2 1.45  10
2

9.06  10
-6
2.09  10
-4
23.0 1.75  10
2

9.06  10
-6
2.32  10
-4
25.6 1.96  10
2

k 2 = 8.73  10
6
L· mol
-1
·s
-1

276

Table 6.36: Rate Constants of the reactions of 2b with different electrophiles.

Table 6.37: Kinetics of the reactions of 2f with 5a in DMSO (20 ° C, stopped-flow,  = 486 nm).
Table 6.38: Kinetics of the reactions of 2f with 5b in DMSO (20 ° C, stopped-flow,  = 393 nm).

Electrophile E
k 2 /
L· mol
-1
·s
-1

log k 2

5f ˗13.39 1.76  10
3
3.25
5g ˗12.18 9.45  10
3
3.98
5i ˗10.04 1.76  10
5
5.25
5j ˗9.45 3.10  10
5
5.49
5k ˗8.76 8.73  10
5
5.94
N = 19.03
s N = 0.58
[5a] 0 /
mol· L
-1

[2c] 0 /
mol· L
-1

[2c] 0/
[5a] 0
k obs /
s
-1

4.03  10
-5
8.23  10
-4
20.4 1.47  10
-1

4.03  10
-5
1.06  10
-3
26.3 1.91  10
-1

4.03  10
-5
1.29  10
-3
32.1 2.32  10
-1

4.03  10
-5
1.53  10
-3
37.9 2.67  10
-1

k 2 = 1.70  10
2
L· mol
-1
·s
-1

[5b] 0 /
mol· L
-1

[2c] 0 /
mol· L
-1

[2c] 0/
[5b] 0
k obs /
s
-1

4.44  10
-5
5.88  10
-4
13.3 8.76  10
-2

4.44  10
-5
8.23  10
-4
18.6 3.17  10
-1

4.44  10
-5
1.06  10
-3
23.9 5.15  10
-1

4.44  10
-5
1.29  10
-3
29.2 6.60  10
-1

4.44  10
-5
1.53  10
-3
34.5 8.29  10
-1

k 2 = 7.76  10
2
L· mol
-1
·s
-1

log k
2
= 0.5781E + 11.002
R² = 0.999
0.0
1.0
2.0
3.0
4.0
5.0
6.0
7.0
-14.0 -12.0 -10.0 -8.0
lg k2
E-Parameter
277

Table 6.39: Kinetics of the reactions of 2f with 5e in DMSO (20 ° C, stopped-flow,  = 374 nm).

Table 6.40: Kinetics of the reactions of 2f with 5f in DMSO (20 ° C, stopped-flow,  = 533 nm).

Table 6.41: Kinetics of the reactions of 2f with 5g in DMSO (20 ° C, stopped-flow,  = 422 nm).

[5e] 0 /
mol· L
-1

[2c] 0 /
mol· L
-1

[2c] 0/
[5e] 0
k obs /
s
-1

2.03  10
-5
8.23  10
-4
40.5 2.16  10
1

2.03  10
-5
1.06  10
-3
52.1 2.54  10
1

2.03  10
-5
1.29  10
-3
63.6 2.87  10
1

2.03  10
-5
1.53  10
-3
75.2 3.22  10
1

k 2 = 1.49  10
4
L· mol
-1
·s
-1

[5f] 0 /
mol· L
-1

[2c] 0 /
mol· L
-1

[2c] 0/
[5f] 0
k obs /
s
-1

1.59  10
-5
2.35  10
-4
14.8 2.35  10
0

1.59  10
-5
2.94  10
-4
18.5 4.91  10
0

1.59  10
-5
3.53  10
-4
22.2 7.00  10
0

1.59  10
-5
4.12  10
-4
25.9 9.50  10
0

1.59  10
-5
4.70  10
-4
29.6 1.19  10
1

k 2 = 4.03  10
4
L· mol
-1
·s
-1

[5g] 0 /
mol· L
-1

[2c] 0 /
mol· L
-1

[2c] 0/
[5g] 0
k obs /
s
-1

1.76  10
-5
2.35  10
-4
13.4 3.86  10
1

1.76  10
-5
2.94  10
-4
16.7 5.07  10
1

1.76  10
-5
3.53  10
-4
20.1 6.37  10
1

1.76  10
-5
4.12  10
-4
23.4 7.99  10
1

1.76  10
-5
4.70  10
-4
26.8 9.42  10
1

k 2 = 2.39  10
5
L· mol
-1
·s
-1

278

Table 6.42: Rate Constants of the reactions of 2f with different electrophiles.
Table 6.43: Kinetics of the reactions of 2d with 5i in DMSO (20 ° C, stopped-flow,  = 630 nm).
Table 6.44: Kinetics of the reactions of 2d with 5j in DMSO (20 ° C, stopped-flow,  = 635 nm).
Table 6.45: Kinetics of the reactions of 2d with 5k in DMSO (20 ° C, stopped-flow,  = 627 nm).
Electrophile E
k 2 /
L· mol
-1
·s
-1

log k 2

5a -17.29 1.70  10
2
2.23
5b ˗16.11 7.76  10
2
2.89
5e ˗14.36 1.49  10
4
4.17
5f ˗13.39 4.03  10
4
4.61
5g ˗12.18 2.39  10
5
5.38
N = 20.87, s N = 0.62

[5i] 0 /
mol· L
-1

[2d] 0 /
mol· L
-1

[18-Crown-6]
/
mol· L
-1

[2d] 0/
[5i] 0
k obs /
s
-1

1.68  10
-5
5.49  10
-4
--- 32.7 1.03  10
1

1.68  10
-5
8.24  10
-4
9.22  10
-4
49.0 1.36  10
1

1.68  10
-5
1.10  10
-3
--- 65.3 1.74  10
1

1.68  10
-5
1.37  10
-3
1.54  10
-3
81.7 2.09  10
1

k 2 = 1.30  10
4
L· mol
-1
·s
-1

[5j] 0 /
mol· L
-1

[2d] 0 /
mol· L
-1

[18-Crown-6]
/
mol· L
-1

[2d] 0
/ [5j] 0
k obs /
s
-1

1.58  10
-5
2.75  10
-4
--- 17.3 1.40  10
1

1.58  10
-5
5.49  10
-4
--- 34.7 2.46  10
1

1.58  10
-5
8.24  10
-4
9.22  10
-4
52.0 3.30  10
1

1.58  10
-5
1.10  10
-3
--- 69.3 4.27  10
1

1.58  10
-5
1.37  10
-3
1.54  10
-3
86.7 5.45  10
1

k 2 = 3.61  10
4
L· mol
-1
·s
-1

[5k] 0 /
mol· L
-1

[2d] 0 /
mol· L
-1

[18-Crown-6]
/
mol· L
-1

[2d] 0
/
[5k] 0
k obs /
s
-1

1.48  10
-5
2.75  10
-4
--- 18.5 2.29  10
1

1.48  10
-5
5.49  10
-4
--- 37.0 4.29  10
1

1.48  10
-5
8.24  10
-4
9.22  10
-4
55.6 6.01  10
1

1.48  10
-5
1.10  10
-3
--- 74.1 7.80  10
1

1.48  10
-5
1.37  10
-3
1.54  10
-3
92.6 1.05  10
2

k 2 = 7.26  10
4
L· mol
-1
·s
-1

y = 12963x + 3.09
R
2
= 0.9993
0.0
5.0
10.0
15.0
20.0
25.0
0.0000 0.0002 0.0004 0.0006 0.0008 0.0010 0.0012 0.0014 0.0016
[Nu] / molL
-1
k
obs
/ s
-1
y = 36084.1227x + 4.0300
R
2
= 0.9970
0.0
10.0
20.0
30.0
40.0
50.0
60.0
0.0000 0.0002 0.0004 0.0006 0.0008 0.0010 0.0012 0.0014 0.0016
[Nu] / molL
-1
k
obs
/ s
-1
y = 72569x + 1.99
R
2
= 0.9925
0.0
20.0
40.0
60.0
80.0
100.0
120.0
0.0000 0.0002 0.0004 0.0006 0.0008 0.0010 0.0012 0.0014 0.0016
[Nu] / molL
-1
k
obs
/ s
-1
279

Table 6.46: Kinetics of the reactions of 2d with 5l in DMSO (20 ° C, stopped-flow,  = 618 nm).
Table 6.47: Kinetics of the reactions of 2d with 5m in DMSO (20 ° C, stopped-flow,  = 620 nm).

Determination of the Reactivity Parameters N and s N of Potassium Salt 2d

Table 6.48: Rate Constants of the reactions of 2d with different electrophiles.

[5l] 0 /
mol· L
-1

[2d] 0 /
mol· L
-1

[18-Crown-6]
/
mol· L
-1

[2d] 0
/ [5l] 0
k obs /
s
-1

9.69  10
-6
1.37  10
-4
--- 14.2 4.10  10
1

9.69  10
-6
2.06  10
-4
2.30  10
-4
21.3 5.54  10
1

9.69  10
-6
2.75  10
-4
--- 28.3 7.70  10
1

9.69  10
-6
3.43  10
-4
3.84  10
-4
35.4 8.99  10
1

9.69  10
-6
4.12  10
-4
--- 42.5 1.07  10
2

k 2 = 2.41  10
5
L· mol
-1
·s
-1

[5m] 0 /
mol· L
-1

[2d] 0 /
mol· L
-1

[18-Crown-6]
/
mol· L
-1

[2d] 0
/
[5m]
0
k obs /
s
-1

1.22  10
-5
1.37  10
-4
--- 11.2 8.65  10
1

1.22  10
-5
2.06  10
-4
2.30  10
-4
16.8 1.19  10
2

1.22  10
-5
2.75  10
-4
--- 22.4 1.68  10
2

1.22  10
-5
3.43  10
-4
3.84  10
-4
28.1 1.91  10
2

1.22  10
-5
4.12  10
-4
--- 33.7 2.27  10
2

k 2 = 5.13  10
5
L· mol
-1
·s
-1

Electrophile E
k 2 /
L· mol
-1
·s
-1

log k 2

5i ˗10.04 1.30  10
4
4.11
5j ˗9.45 3.61  10
4
4.56
5k ˗8.76 7.26  10
4
4.86
5l ˗8.22 2.41  10
5
5.38
5m ˗7.69 5.13  10
5
5.71
N = 16.13
s N = 0.67

y = 241337.6035x + 7.7000
R
2
= 0.9950
0.0
20.0
40.0
60.0
80.0
100.0
120.0
0.0000 0.0001 0.0002 0.0003 0.0004 0.0005
[Nu] / molL
-1
k
obs
/ s
-1
y = 512824x + 17.4
R
2
= 0.9908
0.0
50.0
100.0
150.0
200.0
250.0
0.0000 0.0001 0.0002 0.0003 0.0004 0.0005
[Nu] / molL
-1
k
obs
/ s
-1
y = 0.6748x + 10.884
R
2
= 0.9893
0.0
1.0
2.0
3.0
4.0
5.0
6.0
-11.0 -10.5 -10.0 -9.5 -9.0 -8.5 -8.0 -7.5 -7.0
E-Parameter
lg k2
280

Table 6.49: Kinetics of the reactions of 3a with 5f in DMSO (20 ° C, stopped-flow,  = 533 nm).

Table 6.50: Kinetics of the reactions of 3a with 5g in DMSO (20 ° C, stopped-flow,  = 422 nm).

Table 6.51: Kinetics of the reactions of 3a with 5i in DMSO (20 ° C, stopped-flow,  = 630 nm).

[5f] 0 /
mol· L
-1

[3a] 0 /
mol· L
-1

[3a] 0/
[5f] 0
k obs /
s
-1

2.33  10
-5
9.52  10
-4
40.8 1.37  10
0

2.33  10
-5
1.27  10
-3
54.4 1.75  10
0

2.33  10
-5
1.59  10
-3
68.0 2.28  10
0

2.33  10
-5
1.90  10
-3
81.6 2.73  10
0

2.33  10
-5
2.22  10
-3
95.2 3.15  10
0

k 2 = 1.43  10
3
L· mol
-1
·s
-1

[5g] 0 /
mol· L
-1

[3a] 0 /
mol· L
-1

[3a] 0/
[5g] 0
k obs /
s
-1

3.24  10
-5
9.52  10
-4
29.4 9.20  10
0

3.24  10
-5
1.27  10
-3
39.2 1.13  10
1

3.24  10
-5
1.59  10
-3
49.0 1.49  10
1

3.24  10
-5
1.90  10
-3
58.8 1.79  10
1

3.24  10
-5
2.22  10
-3
68.6 2.12  10
1

k 2 = 9.65  10
3
L· mol
-1
·s
-1

[5i] 0 /
mol· L
-1

[3a] 0 /
mol· L
-1

[3a] 0/
[5i] 0
k obs /
s
-1

1.50  10
-5
1.59  10
-4
10.6 3.82  10
1

1.50  10
-5
2.38  10
-4
15.9 4.83  10
1

1.50  10
-5
3.17  10
-4
21.2 5.90  10
1

1.50  10
-5
3.96  10
-4
26.4 7.26  10
1

1.50  10
-5
4.76  10
-4
31.7 8.20  10
1

k 2 = 1.41  10
5
L· mol
-1
·s
-1

281

Table 6.52: Kinetics of the reactions of 3a with 5j in DMSO (20 ° C, stopped-flow,  = 635 nm).

Table 6.53: Kinetics of the reactions of 3a with 5k in DMSO (20 ° C, stopped-flow,  = 627 nm).

Table 6.54: Rate Constants of the reactions of 3a with different electrophiles.

[5j] 0 /
mol· L
-1

[3a] 0 /
mol· L
-1

[3a] 0/
[5j] 0
k obs /
s
-1

1.22  10
-5
1.59  10
-4
13.0 7.81  10
1

1.22  10
-5
2.38  10
-4
19.4 9.98  10
1

1.22  10
-5
3.17  10
-4
25.9 1.24  10
2

1.22  10
-5
3.96  10
-4
32.4 1.52  10
2

1.22  10
-5
4.76  10
-4
38.9 1.73  10
2

k 2 = 3.05  10
5
L· mol
-1
·s
-1

[5k] 0 /
mol· L
-1

[3a] 0 /
mol· L
-1

[3a] 0/
[5k] 0
k obs /
s
-1

1.32  10
-5
1.27  10
-4
9.6 1.23  10
2

1.32  10
-5
1.59  10
-4
12.0 1.65  10
2

1.32  10
-5
1.90  10
-4
14.4 1.73  10
2

1.32  10
-5
2.38  10
-4
18.0 2.15  10
2

1.32  10
-5
3.17  10
-4
24.1 3.04  10
2

k 2 = 9.13  10
5
L· mol
-1
·s
-1

Electrophile E
k 2 /
L· mol
-1
·s
-1

log k 2

5f ˗13.39 1.43  10
3
3.16
5g ˗12.18 9.65  10
3
3.98
5i ˗10.04 1.41  10
5
5.15
5j ˗9.45 3.05  10
5
5.48
5k ˗8.76 9.13  10
5
5.96
N = 18.81
s N = 0.59
log k
2
= 0.5901E + 11.099
R² = 0.9981
0.0
1.0
2.0
3.0
4.0
5.0
6.0
7.0
-14.0 -12.0 -10.0 -8.0
lg k2
E-Parameter
282

Table 6.55: Kinetics of the reactions of 3b with 5c in DMSO (20 ° C, stopped-flow,  = 371 nm).

Table 6.56: Kinetics of the reactions of 3b with 5e in DMSO (20 ° C, stopped-flow,  = 374 nm).

Table 6.57: Kinetics of the reactions of 3b with 5f in DMSO (20 ° C, stopped-flow,  = 533 nm).

[5c] 0 /
mol· L
-1

[3b] 0 /
mol· L
-1

[3b] 0/
[5c] 0
k obs /
s
-1

2.98  10
-5
1.32  10
-3
44.2 7.40  10
-1

2.98  10
-5
1.65  10
-3
55.2 1.05  10
0

2.98  10
-5
1.98  10
-3
66.3 1.32  10
0

2.98  10
-5
2.31  10
-3
77.3 1.65  10
0

2.98  10
-5
2.63  10
-3
88.3 1.94  10
0

k 2 = 9.11  10
2
L· mol
-1
·s
-1

[5e] 0 /
mol· L
-1

[3b] 0 /
mol· L
-1

[3b] 0/
[5e] 0
k obs /
s
-1

2.36  10
-5
1.65  10
-3
69.9 3.54  10
1

2.36  10
-5
1.98  10
-3
83.8 4.27  10
1

2.36  10
-5
2.31  10
-3
97.8 4.62  10
1

2.36  10
-5
2.63  10
-3
111.8 4.97  10
1

k 2 = 1.41  10
4
L· mol
-1
·s
-1

[5f] 0 /
mol· L
-1

[3b] 0 /
mol· L
-1

[3b] 0/
[5f] 0
k obs /
s
-1

2.65  10
-5
3.29  10
-4
12.4 1.26  10
1

2.65  10
-5
4.94  10
-4
18.6 1.78  10
1

2.65  10
-5
6.59  10
-4
24.9 2.22  10
1

2.65  10
-5
8.23  10
-4
31.1 2.48  10
1

k 2 = 2.49  10
4
L· mol
-1
·s
-1

283

Table 6.58: Kinetics of the reactions of 3b with 5g in DMSO (20 ° C, stopped-flow,  = 422 nm).

Table 6.59: Kinetics of the reactions of 3b with 5i in DMSO (20 ° C, stopped-flow,  = 630 nm).

Table 6.60: Rate Constants of the reactions of 3b with different electrophiles.
[5g] 0 /
mol· L
-1

[3b] 0 /
mol· L
-1

[3b] 0/
[5g] 0
k obs /
s
-1

2.74  10
-5
3.29  10
-4
12.0 6.31  10
1

2.74  10
-5
4.94  10
-4
18.0 1.09  10
2

2.74  10
-5
6.59  10
-4
24.0 1.45  10
2

2.74  10
-5
8.23  10
-4
30.0 1.86  10
2

2.74  10
-5
9.88  10
-4
36.0 2.28  10
2

k 2 = 2.47  10
5
L· mol
-1
·s
-1

[5i] 0 /
mol· L
-1

[3a] 0 /
mol· L
-1

[3a] 0/
[5i] 0
k obs /
s
-1

1.58  10
-5
1.65  10
-4
10.4 1.62  10
2

1.58  10
-5
1.98  10
-4
12.5 2.66  10
2

1.58  10
-5
2.47  10
-4
15.7 4.27  10
2

1.58  10
-5
2.96  10
-4
18.8 5.54  10
2

k 2 = 3.00  10
6
L· mol
-1
·s
-1

Electrophile E
k 2 /
L· mol
-1
·s
-1

log k 2

5c ˗15.83 9.12  10
2
2.96
5e ˗14.32 1.41  10
4
4.15
5f ˗13.39 2.49  10
4
4.40
5g ˗12.18 2.47  10
5
5.39
5i ˗10.04 2.72  10
6
6.43
N = 20.99
s N = 0.60

log k
2
= 0.5955E + 12.498
R² = 0.987
0.0
1.0
2.0
3.0
4.0
5.0
6.0
7.0
-17.0 -15.0 -13.0 -11.0 -9.0
lg k2
E-Parameter
284

Table 6.61: Kinetics of the reactions of 3c with 5f in DMSO (20 ° C, stopped-flow,  = 533 nm).
Table 6.62: Kinetics of the reactions of 3c with 5i in DMSO (20 ° C, stopped-flow,  = 533 nm).
Table 6.63: Kinetics of the reactions of 3c with 5j in DMSO (20 ° C, stopped-flow,  = 533 nm).
Determination of the Reactivity Parameters N and s N of Potassium Salt 3c

Table 6.64: Rate Constants of the reactions of 3c with different electrophiles.
[5f] 0 /
mol· L
-1

[3c] 0 /
mol· L
-1

[18-Crown-6]
/
mol· L
-1

[3c] 0/
[5f] 0
k obs /
s
-1

1.01  10
-5
2.47  10
-4
--- 24.5 6.27  10
-1

1.01  10
-5
3.70  10
-4
4.11  10
-4
36.7 9.60  10
-1

1.01  10
-5
4.93  10
-4
--- 49.0 1.23  10
0

1.01  10
-5
6.17  10
-4
6.95  10
-4
61.2 1.55  10
0

1.01  10
-5
7.40  10
-4
--- 73.5 1.89  10
0

k 2 = 2.53  10
3
L· mol
-1
·s
-1

[5i] 0 /
mol· L
-1

[3c] 0 /
mol· L
-1

[18-Crown-6]
/
mol· L
-1

[3c] 0/
[5i] 0
k obs /
s
-1

1.30  10
-5
1.23  10
-4
--- 9.5 2.33  10
1

1.30  10
-5
2.47  10
-4
--- 19.0 5.98  10
1

1.30  10
-5
3.70  10
-4
4.11  10
-4
28.5 7.99  10
1

1.30  10
-5
4.93  10
-4
--- 38.0 1.12  10
2

1.30  10
-5
6.17  10
-4
6.95  10
-4
47.5 1.33  10
2

k 2 = 2.20  10
5
L· mol
-1
·s
-1

[5j] 0 /
mol· L
-1

[3c] 0 /
mol· L
-1

[18-Crown-6]
/
mol· L
-1

[3c] 0/
[5j] 0
k obs /
s
-1

1.22  10
-5
1.85  10
-4
2.09  10
-4
15.2 5.98  10
1

1.22  10
-5
2.47  10
-4
--- 20.3 7.99  10
1

1.22  10
-5
3.08  10
-4
--- 25.4 1.12  10
2

1.22  10
-5
3.70  10
-4
4.11  10
-4
30.4 1.33  10
2

k 2 = 5.30  10
5
L· mol
-1
·s
-1

Electrophile E
k 2 /
L· mol
-1
·s
-1

log k 2

5f -13.39 2.53  10
3
3.40
5i ˗10.04 2.20  10
5
5.34
5j ˗9.45 5.30  10
5
5.72
N = 19.15, s N = 0.59

y = 2526.9439x + 0.0050
R
2
= 0.9987
0.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
2.0
0.0000 0.0001 0.0002 0.0003 0.0004 0.0005 0.0006 0.0007 0.0008
[Nu] / molL
-1
k obs / s
-1
y = 220256.088x + 0.120
R
2
= 0.991
0.0
20.0
40.0
60.0
80.0
100.0
120.0
140.0
160.0
0.0000 0.0001 0.0002 0.0003 0.0004 0.0005 0.0006 0.0007
[Nu] / molL
-1
k obs / s
-1
y = 530366.2794x + 10.6000
R
2
= 0.9962
0.0
50.0
100.0
150.0
200.0
250.0
0.0000 0.0001 0.0001 0.0002 0.0002 0.0003 0.0003 0.0004 0.0004
[Nu] / molL
-1
k obs / s
-1
285

Table 6.65: Kinetics of the reactions of 4b with 5a in DMSO (20 ° C, stopped-flow,  = 486 nm).

Table 6.66: Kinetics of the reactions of 4b with 5c in DMSO (20 ° C, stopped-flow,  = 393 nm).

Table 6.67: Kinetics of the reactions of 4b with 5d in DMSO (20 ° C, stopped-flow,  = 354 nm).

[5a] 0 /
mol· L
-1

[4b] 0 /
mol·L
-1

[4b] 0/
[5a] 0
k obs /
s
-1

1.37  10
-5
4.34  10
-4
31.7 1.41  10
-1

1.37  10
-5
5.79  10
-4
42.3 1.87  10
-1

1.37  10
-5
7.24  10
-4
52.9 2.48  10
-1

1.37  10
-5
8.69  10
-4
63.5 2.95  10
-1

1.37  10
-5
1.01  10
-3
74.1 3.75  10
-1

k 2 = 3.98  10
2
L· mol
-1
·s
-1

[5c] 0 /
mol· L
-1

[4b] 0 /
mol· L
-1

[4b] 0/
[5c] 0
k obs /
s
-1

1.49  10
-5
7.24  10
-4
48.6 2.28  10
0

1.49  10
-5
8.69  10
-4
58.3 2.82  10
0

1.49  10
-5
1.01  10
-3
68.0 3.18  10
0

1.49  10
-5
1.16  10
-3
77.7 3.63  10
0

1.49  10
-5
1.30  10
-3
87.4 4.14  10
0

k 2 = 3.13  10
3
L· mol
-1
·s
-1

[5d] 0 /
mol· L
-1

[4b] 0 /
mol· L
-1

[4b] 0/
[5d] 0
k obs /
s
-1

1.28  10
-5
7.24  10
-4
56.6 1.57  10
1

1.28  10
-5
8.69  10
-4
67.9 1.86  10
1

1.28  10
-5
1.01  10
-3
79.2 2.04  10
1

1.28  10
-5
1.16  10
-3
90.5 2.35  10
1

1.28  10
-5
1.30  10
-3
101.8 2.69  10
1

k 2 = 1.89  10
4
L· mol
-1
·s
-1

286

Table 6.68: Kinetics of the reactions of 4b with 5e in DMSO (20 ° C, stopped-flow,  = 374 nm).

Table 6.69: Rate Constants of the reactions of 4b with different electrophiles.

Table 6.70: Kinetics of the reactions of 4c with 5e in DMSO (20 ° C, stopped-flow,  = 374 nm).

[5e] 0 /
mol· L
-1

[4b] 0 /
mol·L
-1

[4b] 0/
[5e] 0
k obs /
s
-1

1.40  10
-5
4.34  10
-4
31.0 2.71  10
1

1.40  10
-5
5.79  10
-4
41.3 3.42  10
1

1.40  10
-5
7.24  10
-4
51.6 4.44  10
1

1.40  10
-5
8.69  10
-4
62.0 5.41  10
1

1.40  10
-5
1.01  10
-3
72.3 6.67  10
1

k 2 = 6.84  10
4
L· mol
-1
·s
-1

Electrophile
E
k 2 /
L· mol
-1
·s
-1

log k 2

5b ˗17.29 3.99  10
2
2.60
5d ˗15.83 3.13  10
3
3.50
5e ˗15.03 1.89  10
4
4.28
5f ˗14.32 6.84  10
4
4.84
N = 20.63
s N = 0.76
[5e] 0 /
mol· L
-1

[4c] 0 /
mol·L
-1

[4c] 0/
[5e] 0
k obs /
s
-1

1.00  10
-5
2.62  10
-4
26.1 1.74  10
-1

1.00  10
-5
3.92  10
-4
39.2 2.59  10
-1

1.00  10
-5
5.23  10
-4
52.2 3.53  10
-1

1.00  10
-5
6.54  10
-4
65.3 4.39  10
-1

k 2 = 6.80  10
2
L· mol
-1
·s
-1

log k
2
= 0.758E + 15.64
R² = 0.9898
0.0
1.0
2.0
3.0
4.0
5.0
6.0
-18.0 -17.0 -16.0 -15.0 -14.0 -13.0
lg k2
E-Parameter
287

Table 6.71: Kinetics of the reactions of 4c with 5f in DMSO (20 ° C, stopped-flow,  = 533 nm).

Table 6.72: Kinetics of the reactions of 4c with 5g in DMSO (20 ° C, stopped-flow,  = 422 nm).

Table 6.73: Kinetics of the reactions of 4c with 5i in DMSO (20 ° C, stopped-flow,  = 630 nm).

[5f] 0 /
mol· L
-1

[4c] 0 /
mol· L
-1

[4c] 0/
[5f] 0
k obs /
s
-1

1.19  10
-5
2.62  10
-4
22.0 9.50  10
-1

1.19  10
-5
3.92  10
-4
33.1 1.48  10
0

1.19  10
-5
5.23  10
-4
44.1 2.05  10
0

1.19  10
-5
6.54  10
-4
55.1 2.63  10
0

1.19  10
-5
7.85  10
-4
66.1 3.10  10
0

k 2 = 4.17  10
3
L· mol
-1
·s
-1

[5g] 0 /
mol· L
-1

[4c] 0 /
mol· L
-1

[4c] 0/
[5g] 0
k obs /
s
-1

9.88  10
-6
2.62  10
-4
26.5 6.43  10
0

9.88  10
-6
3.92  10
-4
39.7 9.60  10
0

9.88  10
-6
5.23  10
-4
53.0 1.29  10
1

9.88  10
-6
6.54  10
-4
66.2 1.69  10
1

9.88  10
-6
7.85  10
-4
79.4 1.98  10
1

k 2 = 2.60  10
4
L· mol
-1
·s
-1

[5i] 0 /
mol· L
-1

[4c] 0 /
mol· L
-1

[4c] 0/
[5i] 0
k obs /
s
-1

7.69  10
-6
7.85  10
-5
10.3 7.93  10
1

7.69  10
-6
1.05  10
-4
13.6 1.11  10
2

7.69  10
-6
1.31  10
-4
17.0 1.50  10
2

7.69  10
-6
1.57  10
-4
20.4 1.72  10
2

7.69  10
-6
1.83  10
-4
23.8 2.04  10
2

k 2 = 1.18  10
6
L· mol
-1
·s
-1

288

Table 6.74: Rate Constants of the reactions of 4c with different electrophiles.

Table 6.75: Kinetics of the reactions of 4e with 5a in DMSO (20 ° C, stopped-flow,  = 486 nm).

Table 6.76: Kinetics of the reactions of 4e with 5b in DMSO (20 ° C, stopped-flow,  = 393 nm).

Electrophile
E
k 2 /
L· mol
-1
·s
-1

log k 2

5e ˗14.36 6.80  10
2
2.83
5f ˗13.39 4.17  10
3
3.62
5g ˗12.18 2.60  10
4
4.42
5i ˗10.04 1.18  10
6
6.07
N = 18.19
s N = 0.74
[5a] 0 /
mol· L
-1

[4e] 0 /
mol· L
-1

[4e] 0/
[5a] 0
k obs /
s
-1

1.96  10
-5
7.29  10
-4
37.3 2.09  10
-1

1.96  10
-5
9.11  10
-4
46.6 2.20  10
-1

1.96  10
-5
1.09  10
-3
55.9 2.42  10
-1

1.96  10
-5
1.28  10
-3
65.2 2.74  10
-1

1.96  10
-5
1.46  10
-3
74.6 2.90  10
-1

k 2 = 1.19  10
2
L· mol
-1
·s
-1

[5b] 0 /
mol· L
-1

[4e] 0 /
mol· L
-1

[4e] 0/
[5b] 0
k obs /
s
-1

2.47  10
-5
7.29  10
-4
29.6 6.75  10
-1

2.47  10
-5
8.20  10
-4
33.3 7.38  10
-1

2.47  10
-5
9.11  10
-4
37.0 8.41  10
-1

2.47  10
-5
1.09  10
-3
44.4 9.60  10
-1

2.47  10
-5
1.28  10
-3
51.7 1.12  10
0

k 2 = 8.05  10
2
L· mol
-1
·s
-1

289

Table 6.77: Kinetics of the reactions of 4e with 5d in DMSO (20 ° C, stopped-flow,  = 354 nm).

Table 6.78: Kinetics of the reactions of 4e with 5f in DMSO (20 ° C, stopped-flow,  = 533 nm).

Table 6.79: Rate Constants of the reactions of 4e with different electrophiles.
[5d] 0 /
mol· L
-1

[4e] 0 /
mol· L
-1

[4e] 0/
[5d] 0
k obs /
s
-1

2.02  10
-5
7.29  10
-4
36.2 6.79  10
0

2.02  10
-5
9.11  10
-4
45.2 7.61  10
0

2.02  10
-5
1.09  10
-3
54.2 8.97  10
0

2.02  10
-5
1.28  10
-3
63.3 1.05  10
1

k 2 = 6.80  10
3
L· mol
-1
·s
-1

[5f] 0 /
mol· L
-1

[4e] 0 /
mol· L
-1

[4e] 0/
[5f] 0
k obs /
s
-1

1.51  10
-5
1.82  10
-4
12.1 5.10  10
0

1.51  10
-5
3.64  10
-4
24.1 2.19  10
1

1.51  10
-5
5.47  10
-4
36.2 3.68  10
1

1.51  10
-5
7.29  10
-4
48.3 5.41  10
1

k 2 = 8.89  10
4
L· mol
-1
·s
-1

Electrophil
e
E
k 2 /
L· mol
-1
·s
-1

log
k 2

5a
˗17.2
9
1.19 
10
2

2.0
7
5b
˗16.1
1
8.05 
10
2

2.9
1
5d
˗15.0
3
6.80 
10
3

3.8
3
5f
˗13.3
9
8.89 
10
4

4.9
5
N = 20.07
s N = 0.74
290

6.4.6. Structure-Reactivity Relationship.

Figure 6.4. Correlation of the second-order rate constants logk
2
for the reactions of the nucleophiles 1 with the electrophiles 2 in DMSO with
their electrophilicity parameters E.

291

6.4.7. Conformational study.
NMR samples were prepared in 5mm tubes with 0.6 mL anhydrous DMSO-d 6 and 0.03 mmol
7−H (2 equiv. of tBuOK were added to prepare 7 in situ), in air without degassing. 1D selective
transient NOESY spectra (1500 ms mixing time, 2.7329 sec. acquisition time, 4.5 s relaxation delay,
128 scans) were obtained using the Varian Vnmrj 3.2 NOESY1D sequence which is based on the
DPFGSEMOE (double-pulse field gradient spin-echo NOE) excitation.

The ratio of intensities of a pair of NOE signals, within that experiment can thus be assumed to
be proportional to the ratio of their internuclear distances.
15
The calculated ensemble-averaged
NOE intensity of H2−H2’ can be determined by
η
𝑜 𝑏𝑠 − 1
η
𝑜 𝑏𝑠 − 𝑟 𝑒 𝑓 =
𝑟 1 𝐴 − 6
× 𝑝 𝑜𝑝 1 𝐴 + 𝑟 1 𝐵 − 6
× 𝑝 𝑜𝑝 1 𝐵 𝑟 𝑟 𝑒 𝑓 − 6

where η obs-1 is the normalized NOE intensity between the proton of interest and the proton which
is being inversed (H2’−H2). η obs-ref is the normalized NOE intensity between the adjacent proton(s)
with known distance and the proton which is being inversed (H3−H2). r 1A is the internuclear
distance between proton of interest and the proton which is being inversed in conformation A.
pop 1A is the population of conformation A. r 1B is the internuclear distance between proton of interest
and the proton which is being inversed in conformation B. pop 1A is the population of conformation
B. r ref is the distance between the adjacent proton(s) with known distance and the proton which is
being inversed. A linear relationship can be drawn between the averaged NOE intensity and the
population of trans-conformation (100% − population of cis-conformation). By applying the
observed NOE intensity to the theoretical linear relationship equation the population of trans-
conformation can be thus derived.
292

The build-up of NOE of 7c is shown in Figure 6.8. As the τ m increases, the NOE build-up curve
deviates from initial linearity and reaches a plateau. With τ m of 1.5 s, NOE intensity is no longer
linearly correlated to the inverse of r
6
and the observed NOE effect can deviate from the real value
by a large extent.

Figure 6.5. NOE measurement of 7a.

Figure 6.6. NOE measurement of 7b.
293

Figure 6.7. NOE measurement of 7c.

Figure 6.8. NOE build up curve using 7c.

0
0.02
0.04
0.06
0.08
0.1
0.12
0.14
0.16
0.18
0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2
294

Table 6.80. Correlation between population of trans-planar geometry and the NOE intensity.

H2-H2'
distance-trans-
lower limit
(Å)(crystal)
H2-H2'
distance-trans-
upper
limit(Å)(crystal)
H2-H2'
distance-
trans-lower
limit (Å)(DFT)
H2-H2'
distance-
trans-upper
limit (Å)(DFT)

5.388 5.804 5.934 5.754
H2-H2'
distance-cis-
lower
limit(Å)(crystal)
H2-H2'
distance-cis-
upper
limit(Å)(crystal)
H2-H2'
distance-cis-
lower limit
(Å)(DFT)
H2-H2'
distance-cis-
upper limit
(Å)(DFT)
3.204 3.850 3.374 3.530
H2-H3 distance-ref(Å) (crystal) H2-H3 distance-ref(Å) (DFT)
2.357 2.500
pop-
trans
pop-cis
effective
distance
(crystal)
NOE intensity
(crystal)
effective
distance
(DFT)
NOE
intensity
(DFT)
0 1 3.4285 0.1057 3.4459 0.1458
0.1 0.9 3.4857 0.0957 3.5042 0.1319
0.2 0.8 3.5504 0.0857 3.5702 0.1179
0.3 0.7 3.6245 0.0757 3.6460 0.1039
0.4 0.6 3.7111 0.0657 3.7347 0.0900
0.5 0.5 3.8145 0.0557 3.8413 0.0760
0.6 0.4 3.9423 0.0457 3.9735 0.0620
0.7 0.3 4.1077 0.0357 4.1461 0.0481
0.8 0.2 4.3386 0.0257 4.3903 0.0341
0.9 0.1 4.7090 0.0157 4.7934 0.0201
1 0 5.5698 0.0057 5.8392 0.0062

Effective distance is calculated as :
1 / [ ( 𝑟 1 𝐴 − 6
× 𝑝 𝑜𝑝 1 𝐴 + 𝑟 1 𝐵 − 6
× 𝑝 𝑜𝑝 1 𝐵 )
1
6
]
Table 6.81. Population of trans-planar geometry of 7.
NOE Intesnsity (Exp) pop-trans
7a 0.0522 0.7019
7b 0.2907 -0.8701
7c 0.1546 0.0273

295

Figure 6.9. Correlation between population of trans-planar geometry and the NOE intensity
(Crystal).

Figure 6.10. Correlation between population of trans-planar geometry and the NOE intensity
(DFT).

y = -0.0999x + 0.1057
R² = 1
0.0000
0.0200
0.0400
0.0600
0.0800
0.1000
0.1200
0 0.2 0.4 0.6 0.8 1 1.2
NOE Intensity
pop-trans
Crystal
y = -0.1397x + 0.1458
R² = 1
0.0000
0.0200
0.0400
0.0600
0.0800
0.1000
0.1200
0.1400
0.1600
0 0.2 0.4 0.6 0.8 1 1.2
NOE Intensity
pop-trans
DFT
296

6.4.8. NMR Spectra

297

298

299

300

301

302

303

304

305

306

307

308

309

310

311

312

313

314

315

316

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Abstract (if available)

Abstract This dissertation mainly explored two aspects in organofluorine chemistry, the development of novel efficient fluoroalkylating protocols (CF−, C₂−, C₃−) and the related in-depth mechanistic studies. ❧ In chapter one a brief review of the history of organofluorine chemistry is given. The major achievements in organofluorine chemistry are discussed in a chronological order following the CF−, C₂−, C₃− sequence. ❧ Chapter two demonstrates the exploration of a versatile method of the stereoselective syntheses of bioactive fluoroalkenoates and oxazolidinones via the monofluoroolefination of nitrones. By altering N-substituents in nitrones, preparation of (E)-α-fluoroalkenoates and 4-fluoro-5-isoxazolidinones, respectively, can be achieved with high chemo- and stereoselectivities. Experimental and computational studies have been conducted to elucidate the reaction mechanisms. ❧ Chapter three reports the design and synthesis of novel electrophilic difluoromethylating reagent N,N-dimethyl-S-difluoromethyl-S-phenylsulfoximinium salt which is the difluoromethylated analogue of Johnson Reagent. The reagent provides excellent reactivity toward a broad spectrum of nucleophilic species (N-, P-, S-, and O-nucleophiles) to yield the corresponding difluoromethylated products with high efficacy under mild conditions. ❧ Chapter four describes the investigation of atom-economical nucleophilic trifluoromethylating method employing readily available reagent trifluoroacetaldehyde hydrate. A wide scope of carbonyl compounds are applicable to this reaction with high yields under mild condition. DFT calculations have been performed to provide mechanistic insight into the present and related reactions employing 2,2,2-trifluoro-1-methoxyethanol and hexafluoroacetone hydrate. ❧ Chapter five delivers the first bulk synthesis and characterization of C₃− anion. Based on high level theoretical calculations, the α-defluorination of the C₃− anion was found to possess a barrier of 25.4 kcal/mol in THF allowing direct observations via spectroscopic methods. NMR spectra collected at −78 ℃ clearly demonstrated the existence of the CF₃− anion as a persistent species in the presence of potassium cation and 18-crown-6 for the first time, which facilitates various nucleophilic trifluoromethylation reactions. ❧ Chapter six conveys the investigation of nucleophilicity of α-monofluoromethanide derivatives by comparing to a series of α-substituted carbanion analogues. The nucleophilicity parameters N and nucleophile specific parameter sN of a series of α-substituted nucleophiles have been determined. NOE experiments have been performed to understand the geometry configuration of carbanions. The effects of α-substituents (−F, −Cl, −OMe) on carbanions have been explicitly demonstrated.

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University of Southern California Dissertations and Theses

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Asset Metadata

Creator Zhang, Zhe (author)

Core Title Towards selective fluoroalkylating reactions: synthesis and mechanistic studies

School College of Letters, Arts and Sciences

Degree Doctor of Philosophy

Degree Program Chemistry

Publication Date 07/17/2015

Defense Date 06/11/2015

Publisher University of Southern California (original), University of Southern California. Libraries (digital)

Tag fluorine chemistry,mechanistic studies,OAI-PMH Harvest,synthesis

Format application/pdf (imt)

Language English

Contributor Electronically uploaded by the author (provenance)

Advisor Prakash, G. K. Surya (committee chair), Shing, Katherine (committee member), Thompson, Barry C. (committee member)

Creator Email zhangzhe@usc.edu

Permanent Link (DOI) https://doi.org/10.25549/usctheses-c3-598528

Unique identifier UC11299960

Identifier etd-ZhangZhe-3630.pdf (filename),usctheses-c3-598528 (legacy record id)

Legacy Identifier etd-ZhangZhe-3630.pdf

Dmrecord 598528

Document Type Dissertation

Format application/pdf (imt)

Rights Zhang, Zhe

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