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Investigation of mechanisms of complex catalytic reactions from obtaining and analyzing experimental data to mechanistic modeling
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Investigation of mechanisms of complex catalytic reactions from obtaining and analyzing experimental data to mechanistic modeling
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Content
INVESTIGATION OF MECHANISMS OF COMPLEX CATALYTIC REACTIONS:
FROM OBTAINING AND ANALYZING EXPERIMENTAL DATA TO MECHANISTIC
MODELING
by
Antonina L. Nazarova
A Dissertation Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
[CHEMISTRY]
December 2020
Copyright 2020 Antonina L. Nazarova
D E D I C A T I O N
To my beloved parents.
ii
ACKNOWLEDGEMENTS
Successful research is not solely the product of the researcher alone, but also those who provide
support and guidance throughout the process. Therefore, I would like to take this opportunity to
thank the talented individuals who have supported me throughout my five years of research as part
of the University of Southern California’s Chemistry Department. Without your direction and
mentorship, my accomplishments as a researcher would not have been possible.
First, I would like to thank my Ph.D. advisor, Professor Valery Fokin, for his unique,
unprecedented, and unforgettable lessons in life and science. He taught me that to be a successful
researcher, one must exude mutual strength and independence. His guidance throughout this
process have instilled within me the confidence needed as I continue along my career path.
Next, I convey my gratitude to Professor Sri Narayan whose openness and enthusiasm toward my
idea of performing electrochemical studies on the catalytic system carried me along the project.
His expertise, straightforward directions, and step-by-step guidance saw to the success of my
cyclic voltammetry studies, and for that I am grateful. From providing robust feedback before and
after setting up each experiment to taking time away from his busy schedule to answer my
questions, Prof. Narayan went above and beyond the call of duty to support me as a researcher.
I would also like to acknowledge Professor Anna Krylov who served as a successful female role
model during my time in the department. She supported me in both my career and outside life,
always offering her support for the computation section of my research, as well as encouraging me
to become a leader in our field. She provided me direction on how to communicate my
computational results to a purely synthetic chemistry auditorium with maximum effect.
iii
Furthermore, as a committee member for my qualification exam, Professor Chao Zhang afforded
me valuable advice and guidance during his Advanced Organic Chemistry course and Ph.D.
candidacy times. His passionate teaching style and ability to deliver material in an inspiring
manner were key triggers in my interest to pursue a career in higher education.
As an Assistant Lecture during my time in the Burg Teaching Fellowship program, I was lucky to
have Professor Thomas Bertolini as an incredible mentor. Giving lectures to over two-hundred
students is easier said than done, and his guidance during this unique experience provided me the
confidence and skillset needed for a future career in academia. I still remember my first lecture—
palms sweaty and unable to see the slides fully as my glasses had fogged up—Prof. Bertolini came
to me and said, “the students will not eat you. They like you!” I will remember this sentiment on
many first days to come.
In addition to the aforementioned individuals, I would like to express my gratitude to Professor
G. K. Surya Prakash who warmly welcomed me to the Chemistry Department and Loker
Hydrocarbon Research Institute when I have first arrived, and still through to this day. His door
was always open to solve any kind of issue, challenge, or problem an international student might
face. In addition, Professor Prakash is very cheerful regardless of the topic, let it be science,
research-related challenges, or even cooking recipes. He taught me the fundamentals of NMR
spectrometry and advised me on how to apply this powerful analytic technique to kinetic profiling
studies. I feel incredibly honored to have met such great mentor this early in my scientific career.
I will deeply miss him once I moved on to my next chapter of life but am confident our paths will
cross again.
iv
Another fantastic person I met during my Ph.D. studies was Professor Aiichiro Nakano. I would
like to express my sincere gratitude for his strong support in computational field of my Ph.D.
studies. He was incredibly inspiring and supportive of the statistical and numerical approaches I
used for the modeling of reaction mechanism. Prof. Nakano also exposed me to a world of high-
performance computing (which significantly improved my computational method of chemical
kinetic analysis and data processing), as well as machine learning for chemical structure-activity
relationship studies. With great enthusiasm he mentored me through the processes of compiling,
writing, and submitting my first research paper.
Lastly, I am incredible grateful to Professor Karl O. Christe. The current thesis would not be where
it is today without him. He eagerly gave constructive critiques to my research and extensively
polished my write-up. Karl always found time to discuss and teach me to solve and communicate
scientific problems in an understandable manner. When I was feeling exhausted, he always found
ways to cheer me up by telling funny stories and was equally there to listen when I happily shared
my successes. Karl picks up the phone regardless of the day or time and listen to my concerns and
provided me with invaluable advice. I am more that grateful to be able to call Karl a friend.
I would like to acknowledge the administrative staff of the USC Chemistry Department who tried
their best to simplify any bureaucracy experienced during my time in the Ph.D. program. I never
forget the kindness of Magnolia who gave me a pillow my first day in the United States and always
cheerfully addressed my questions. I would also like to thank Michele Dea for working hard to
ease life of everyone in the department and maintaining oversight large amount of documentation
graduate students are facing.
v
During my time at USC I met incredible people whom without my Ph.D. would have been way
less enjoyable. I would like to thank my lab mates, Joice Thomas, Jeff Celaje, Jitendra Gurjar,
Jingjing Lee, Jorick Bater, Haley Rossiter, Sydney Hiller, Shelby Heller, William Richards and
many more. The many memories we created together will never be forgotten. Also, worth
mentioning a second time are our postdocs Joice and Jeff who taught me a lot in practical organic
chemistry. I would like to also thank my friends and collaborators, Anastasiia A, Arman, Anastasia
G, Aleksander N, Billal, Sayan, Socrates, Piyush, Vincent, Colby, Archith, Alexander S, Adam U,
Valeriy, Kevin, Nicholas, Sanket, Robert P, Robert N, Liqiu, Pankaj, Aravind, Ankit, Kuang, Ken-
Ishi, Amir, Golnas, Yiing, Nikita, Debanjan, Saltanat, Alex M, Jin, Jet, Rene, Ophelia, Yang,
Narcisse, Betsy, Seyma, Xue, Zhiyao, Simon, Kainan, Carolina, Carlos, Geovanni and many more
for their company and participation in helping me mature as a researcher and person.
Finally, I would like to thank my family for their endless support and not letting me down in the
most difficult moments of my Ph.D. journey. As such, I am very thankful to my aunt Ludmila and
uncles Eugenie and Valeriy for their love and valuable guidance at every stage.
No words can express my gratitude to Thomas. I am incredibly thankful for your love and carry,
and for being my very best friend as we travel together through chemistry and life. I certainly could
have not accomplished this journey without you.
To my mom and dad, I am eternally grateful for your support in all my endeavors, for your
unconditional love, and for your unbeatable encouragement. You both stood by me through
difficult times, and always built me back up when needed. Thank you both for teaching me to
never give up, never to despond, and to only move forward to achieve my goals.
vi
TABLE OF CONTENTS
Dedication ....................................................................................................................................... i
Acknowledgements ....................................................................................................................... ii
List of Tables ................................................................................................................................ xi
List of Figures .............................................................................................................................. xv
List of Schemes .......................................................................................................................... xxii
List of Abbreviations ............................................................................................................... xxiv
Abstract ................................................................................................................................... xxviii
Preface ....................................................................................................................................... xxxi
Chapter I ........................................................................................................................................ 1
1. A Chemical Space and Analytical Tools to Probe it .......................................................... 2
1.1 The field of CuAAC reaction in synthetic chemistry .................................................................... 2
1.2 Bioorthogonal reactions ................................................................................................................ 4
1.3 The field of CuAAC reaction in bioimaging studies .................................................................... 6
1.4 Methods of in situ (online) and ex situ (offline) monitoring of reaction progress in
homogeneous catalysis ................................................................................................................. 8
1.4.1 Spectroscopic methods ......................................................................................................................... 8
1.4.2 Chromatographic methods .................................................................................................................. 13
1.4.3 Methods of data processing and analysis for chemical kinetics information. ..................................... 17
1.4.4 Models of enzyme kinetics: Utilization of the Michaelis-Menten model in complex catalytic
reactions .............................................................................................................................................. 19
1.4.5 Visual Kinetic Analysis (VKA) methods for reaction progress profiling ........................................... 25
1.5 References ................................................................................................................................... 28
Chapter II .................................................................................................................................... 33
2. Mechanistic and Kinetic Investigation of 1-Iodoaryl Alkynes with Organic Azides in
the Copper (I)-catalyzed Cycloaddition Reaction ............................................................ 34
2.1 Introduction into methods of kinetic studies of complex catalytic reactions .............................. 34
2.2 Global heat and spectroscopic methods: preliminary studies of the
I
CuAAC reaction mechanism
................................................................................................................................................... 37
2.3 In situ
1
H NMR reaction monitoring ........................................................................................... 40
2.4 Deterministic approach to the staged kinetic model representation ............................................ 42
vii
2.5 Kinetic model parameters estimation from the experimental data .............................................. 44
2.6 Deterministic reaction progress analysis ..................................................................................... 48
2.7 Relative energy studies: Eyring equation .................................................................................... 50
2.8 Tris(triazolyl)amine ligands screening ........................................................................................ 52
2.9 Limiting conditions for the numerical estimation of the reaction rate parameters ..................... 53
2.10 Open Multi-Processing interface for computational speedup ..................................................... 57
2.11 Conclusions ................................................................................................................................. 58
2.12 References ................................................................................................................................... 60
Chapter III ................................................................................................................................... 62
3. Kinetic Studies and Mechanistic Elucidation of the Copper(I)-Catalyzed
Cycloaddition Reaction of bismuth(III) acetylides with Organic Azides ...................... 63
3.1 Introduction to organobismuth(III) compounds in drug design .................................................. 63
3.2 Bismuth type of copper(I)-catalyzed azide-alkyne cycloaddition as a potential biolabeling
strategy ....................................................................................................................................... 64
3.3 Synthesis and Characterization of diphenyl sulfone bismuth(III) acetylides .............................. 66
3.4 Preliminary reactivity studies: X-ray structural information ...................................................... 73
3.5 Dynamic exchange processes as a function of temperature ........................................................ 75
3.6
1
H NMR kinetic studies .............................................................................................................. 77
3.7 Independent reaction progress analysis as a method for exploring the evolution of the reactive
intermediates. Substrate-dependent shift in the rate determining step ....................................... 78
3.8 “Different excess” studies: Conversion-dependent shift in the rate determining step ................ 83
3.9 Catalyst robustness studies.......................................................................................................... 86
3.10 Competitive
1
H NMR kinetic studies of bismuth(III)-acetylide and terminal acetylenes
reactivities under copper(I) catalyzed conditions ...................................................................... 86
3.11 Evaluation of a mechanistic model of a
Bi
CuAAC catalytic reaction based on kinetic cyclic
voltammetry data ....................................................................................................................... 88
3.12 Conclusions ................................................................................................................................. 93
3.13 References ................................................................................................................................... 94
Chapter IV ................................................................................................................................... 97
4. “On Water” Synthesis of Fluorosulfonyl 1,2,3-Triazoles ................................................ 98
4.1 Organic synthesis “On Water” .................................................................................................... 98
4.2 Sulfonamide-containing drugs .................................................................................................... 99
4.3 Synthetic protocols towards sulfonamide drugs development .................................................. 100
4.4 SuFEx “click reaction” for the synthesis of sulfonamide-containing drugs ............................. 102
viii
4.5 Methodology development and optimization of water promoted 1,3-dipolar cycloaddition
reactions ................................................................................................................................... 103
4.6 Kinetic studies of the water-assisted regioselective synthesis of SO 2F-functionalized triazoles
................................................................................................................................................. 106
4.7 Substrate scope of water-assisted 1,3-dipolar cycloaddition reactions ..................................... 110
4.8 Conclusion ................................................................................................................................ 114
4.9 References ................................................................................................................................. 115
Chapter V .................................................................................................................................. 117
5. Signal Processing Methods for Kinetic Data derived from Heat Flow Calorimetry .. 118
5.1 Reaction Calorimetry in industrial research .............................................................................. 118
5.2 The calorific output quantification ............................................................................................ 119
5.3 Heat flow calorimetry experiment for kinetic studies of complex catalytic transformations ... 121
5.4 Numerical treatment of inverse problems in chemical kinetics ................................................ 123
5.5 Heat Flow Calorimetry for global parameter studies of multistep reactions ............................ 130
5.6 Step-by-step protocol for processing the calorific output ......................................................... 132
5.7 Conclusions ............................................................................................................................... 132
5.8 Experimental details .................................................................................................................. 133
5.9 References ................................................................................................................................. 135
Appendices ................................................................................................................................. 137
Appendix A Additional Information on Chapter II .......................................................... 138
A.1
1
H NMR kinetic studies ............................................................................................................ 138
A.1.2 General procedure B – rate-orders experiments ............................................................................... 145
A.1.3 General procedure C – VT experiments ........................................................................................... 154
A.1.4 General Procedure D - influence of the used catalytic system on the substrate reactivity ................ 161
A.1.5 General Procedure E - probing catalyst robustness for off-cycle species scenarios ......................... 163
A.1.6 General Procedure F - probing catalyst robustness for deactivation scenarios ................................. 165
A.1.7 Deriving of the rate equation for a complex catalytic reaction by the Deterministic method. Solving
the System of ordinary differential equations (ODEs) ...................................................................... 167
A.1.8 Graphical representation of experimentally determined and theoretically calculated reaction profiles
.......................................................................................................................................................... 169
A.2 Heat-flow calorimetry studies ................................................................................................... 173
A.2.1 Calibration Curves for HPLC studies ............................................................................................... 174
A.2.2 General Procedure A - individual reaction kinetic protocol with the Cu(I)-TTTA catalytic system 178
A.2.3 General Procedure B - individual reaction kinetic protocol with the CuI-TBTA catalytic system ... 180
A.2.4 General Procedure C – competition Experiments ............................................................................. 182
A.2.5 General Procedure D - “multiple injection” experiment ................................................................... 186
ix
A.2.6 General Procedure E - competitive reactivity experiment ................................................................ 187
A.3 Synthesis and Characterization ................................................................................................. 189
A.3.1 General procedure 1 for the synthesis of 1-iodoalkynes ................................................................... 190
A.3.2 General procedure 2 for the synthesis of 1-iodo-3,4,5-triazoles ....................................................... 194
A.3.3
1
H and
13
C NMR spectra ................................................................................................................... 200
A.4 References ................................................................................................................................. 212
Appendix B Additional Information on Chapter III ......................................................... 213
B.1
1
H NMR kinetic reactivity studies ............................................................................................ 213
B.1.1 General procedure A – independent bismuth(III)-acetylide reactivity experiments ......................... 214
B.1.2 General procedure B- rate orders experiments ................................................................................. 219
B.1.3 Molecular dynamics NMR spectroscopic study ............................................................................... 223
B.1.4 General Procedure C - protoalkyne/ bismuth(III) acetylide competitive experiments ..................... 224
B.1.5 Moisture compatibility experiments ................................................................................................. 226
B.1.6 General procedure D - hydrogen/diphenylsulfone bismuth(III) transmetallation experiments using
the CuOTf toluene complex as catalyst ............................................................................................ 227
B.1.7 General procedure E – catalyst robustness experiments ................................................................... 236
B.2 Cyclic Voltammetric (CV) kinetic studies ................................................................................ 238
B.2.1 General procedure F – Determination of the rate constant of bismuth(III)-acetylide – copper(I)
catalyst π-complex formation ........................................................................................................... 239
B.2.2 General procedure G – Determination of the apparent rate constant of the bismuth(III) triazolide[X]
formation .......................................................................................................................................... 240
B.2.3 Determination of reaction rate parameters ........................................................................................ 242
B.3 Synthesis and characterization of bismuth(III)-acetylides and 5-bismuth-1,2,3-triazolides ..... 246
B.4 X-Ray Crystallographic Details ................................................................................................ 282
B.5
1
H,
13
C and
19
F NMR spectra .................................................................................................... 335
B.6 References ................................................................................................................................. 382
Appendix C Additional Information on Chapter IV ......................................................... 383
C.1 Synthesis and characterization .................................................................................................. 383
C.2 General Procedure A - Kinetic
1
H NMR aliquot study ............................................................. 384
C.3 General Procedure B - synthesis of 1H-1,2,3-triazole-4-sulfonyl fluorides from 1-bromoethene-
1-sulfonyl fluoride (BESF) ...................................................................................................... 385
C.4 General Procedure C - synthesis of 1H-1,2,3-triazole-4-sulfonyl fluorides from 1,2-
dibromoethane-1-sulfonyl fluoride (DBESF) .......................................................................... 385
C.5 General Procedure D - synthesis of 5-(fluorosulfonyl)-1H-pyrazoles from 1,2-dibromoethene-1-
sulfonyl fluoride (DBESF) ....................................................................................................... 386
C.6 General Procedure E - synthesis of 1H-pyrazoles and isoxasoles from ethenesulfonyl fluoride
(ESF) ........................................................................................................................................ 386
C.7 General Procedure F – Diels-Alder cycloaddition with ethenesulfonyl fluoride (ESF) ........... 387
x
C.8 Product scope. Synthesis and characterization.......................................................................... 388
C.9
1
H,
13
C and
19
F NMR spectra .................................................................................................... 404
C.10 References ................................................................................................................................. 462
xi
LIST OF TABLES
Table 2.1 Rate constants derived from the
1
H NMR kinetic measurements corresponding to the independent
reactivity kinetic profiles. Deterministic method of kinetic analysis.
a
........................................................ 45
Table 2.2 Activation parameters determined by variable temperature (VT) 1H NMR kinetic studies. The
apparent rate constant was derived at temperature ranges 0–40 ℃ for A[1] and 10–50 ℃ for A[4]. ........ 51
Table 2.3 OpenMP and single core CPU computational approaches for solving chemical kinetics of
I
CuAAC complex catalytic reactions. ......................................................................................................... 58
Table 3.1 Comparison of acetylene group C(1)≡C(2) IR stretching vibration frequencies of the derivatized
bismuth(III) acetylides. ............................................................................................................................... 72
Table 3.2 Distances of the transannular Bi(1)···O(1) interactions, and lengths of Bi(III)–C(1) and
C(1)≡C(2) key covalent bonds of the synthesized bismuth(III) acetylides [1-10]. ..................................... 73
Table 3.3 Rate parameters, derived from the cyclic voltammogram kinetic studies of the
Bi
CuAAC reaction
at 25 °C in dry DMSO at 100 mV/sec. Conditions: 3-electrode cell with glassy carbon as the working
electrode, copper foils as counter and reference electrodes. ....................................................................... 92
Table 4.1 Reaction optimization. Reaction conditions were ((azidomethyl)benzene, BESF, in water (1 ml,
unless stated otherwise, 1 eq. is equal to 0.3 mmol), room temperature and at maximum stirring rate).
Corresponding yields were calculated by GC-MS calibration procedures after 6 hours of continuous stirring.
.................................................................................................................................................................. 105
Table 5.1 Conditions and reactivity data of calorimetry heat flow experiments between different 1-
iodoalkyne substrates A[1-3] and (2-azidoethyl)benzene [Z] in the presence of the CuI-TTTA catalytic
system. ...................................................................................................................................................... 122
Table 5.2 Characteristics of narrowband noise accompanied by the heat flow calorimetry experimental
output. ....................................................................................................................................................... 126
Table 5.3 Reaction rate constants for iodoalkynes A[1], A[2] and A[3] in
I
CuAAC reaction catalyzed by
the CuI-TTTA system. .............................................................................................................................. 131
Table 5.4 Exponential decay function parameters represented in Figure 5.6. .......................................... 131
xii
Table A.1 Reaction conditions of experiments following general procedure A. Independent reactivity
I
CuAAC experiments. ............................................................................................................................... 141
Table A.2 Reaction conditions of experiments following general procedure B. Variable [Azide]
concentration experiments. ....................................................................................................................... 147
Table A.3 Reaction conditions of the experiments following general procedure B. Variable [Alkyne]
concentration experiments. ....................................................................................................................... 151
Table A.4 Reaction conditions for the experiments following general procedure C. Variable-temperature
NMR kinetic studies of
I
CuAAC reaction mechanism with 1-chloro-4-(iodoethynyl)benzene substrate A[4].
.................................................................................................................................................................. 155
Table A.5 Reaction conditions of the experiments following general procedure C. Variable-temperature
NMR kinetic studies of
I
CuAAC reaction mechanism with 1-methoxy-4-(iodoethynyl)benzene substrate
A[1]. .......................................................................................................................................................... 158
Table A.6 Reaction conditions of experiments following general procedure D. Variable catalytic systems
studies. ...................................................................................................................................................... 162
Table A.7 Reaction conditions of experiments following general procedure E. Variable catalytic systems.
.................................................................................................................................................................. 164
Table A.8 Reaction conditions of experiments following general procedure F. Catalyst robustness studies.
.................................................................................................................................................................. 166
Table A.9 Calibration curve data of 1-iodoalkynes and 5-iodo-1,2,3-triazoles. ...................................... 175
Table A.10 Reaction conditions and parameters of calorimetry heat flow experiments between different [1-
5] alkyne substrates and [Z] azide and CuI-TTTA catalytic system. General procedure A. .................... 179
Table A.11 Reaction conditions and parameters of heat flow calorimetry experiments between different [1-
5] alkyne substrates and [Z] azide in the presence CuI-TBTA as catalyst. General procedure B. ........... 181
Table A.12 Conditions and results for competition calorimetry heat flow experiments between different 1-
ioadoalkynes [1-5] and azide [Z] in the presence of Cu(I)-TTTA as the catalyst. General procedure C. 184
Table A.13 Heat flow calorimetry “multiple injection experiment” with 1-iodoalkyne [4] and azide [Z] as
substrates and the CuI-TTTA catalyst system. General procedure D. ...................................................... 187
Table A.14 Iodo-proto exchange experiment with 1-ethynyl-4-(trifluoromethyl)benzene, 1-iodoalkyne [4]
and azide [Z] substrates and the Cu(I)-TTTA catalyst system. ................................................................ 188
xiii
Table B.1 Reactions conditions of experiments following general procedure A. Independent bismuth(III)-
acetylide reactivity experiment. ................................................................................................................ 215
Table B.2 Reactions conditions of experiments following general procedure B. Variable [Alkyne]
concentration experiment. Kinetic profiles shown in Figure B.1 ............................................................. 220
Table B.3 Reactions conditions of experiments following general procedure C. Kinetic profiles are shown
in Figure B.3. ........................................................................................................................................... 225
Table B.4 Moisture compatibility experiment. Reaction conditions of experiments following general
procedure A. .............................................................................................................................................. 226
Table B.5 Equilibrium measurements at 27
°
C with the CuOTf toluene complex as catalyst. General
procedure D. .............................................................................................................................................. 230
Table B.6 Equilibrium measurements at 69
°
C with CuOTf toluene complex as catalyst. General procedure
D. ............................................................................................................................................................... 231
Table B.7 Catalyst robustness experiments. Reactions conditions of the experiments following general
procedure E. .............................................................................................................................................. 236
Table B.8 Crystal data and structure refinement for compound 42......................................................... 282
Table B.9 Bond lengths [Å] and angles [°] for compound 42. ................................................................ 283
Table B.10 Crystal data and structure refinement for compound 39....................................................... 287
Table B.11 Bond lengths [Å] and angles [°] for compound 39. .............................................................. 288
Table B.12 Crystal data and structure refinement for compound 40....................................................... 291
Table B.13 Bond lengths [Å] and angles [°] for compound 40. .............................................................. 292
Table B.14 Crystal data and structure refinement for compound 34....................................................... 295
Table B.15 Bond lengths [Å] and angles [°] for compound 34. .............................................................. 296
Table B.16 Crystal data and structure refinement for compound 35....................................................... 299
Table B.17 Bond lengths [Å] and angles [°] for compound 35. ............................................................. 300
Table B.18 Crystal data and structure refinement for 32. ....................................................................... 302
Table B.19 Bond lengths [Å] and angles [°] for 32. ................................................................................ 303
Table B.20 Crystal data and structure refinement for compound 33....................................................... 308
Table B.21 Bond lengths [Å] and angles [°] for compound 33. ............................................................. 309
xiv
Table B.22 Crystal data and structure refinement for compound 36....................................................... 312
Table B.23 Bond lengths [Å] and angles [°] for compound 36. ............................................................. 313
Table B.24 Crystal data and structure refinement for compound 27....................................................... 317
Table B.25 Bond lengths [Å] and angles [°] for compound 27. .............................................................. 318
Table B.26 Crystal data and structure refinement for compound 21....................................................... 321
Table B.27 Bond lengths [Å] and angles [°] for compound 21. .............................................................. 322
Table B.28 Crystal data and structure refinement for compound 18....................................................... 326
Table B.29 Bond lengths [Å] and angles [°] for compound 18. .............................................................. 327
Table B.30 Crystal data and structure refinement for compound 37....................................................... 330
Table B.31 Bond lengths [Å] and angles [°] for compound 37. .............................................................. 331
xv
LIST OF FIGURES
Figure 1.1 (A) Classification of 1,3-dipole structures of the allyl- and allenyl- types. (B) Acetylide scope
being employed in CuAAC reaction. Highlighted in blue and red have been used in this work. ................. 3
Figure 1.2 The electromagnetic spectrum and related spectroscopic methods.
45
......................................... 9
Figure 1.3 Absorbance of NBB (the azo group (618 nm) and the aromatic rings (320 nm) over reaction
time while treated with oxygen peroxide and iron sulfate. ......................................................................... 10
Figure 1.4 Multiple band monitoring of methyl nicotinate hydrogenation with an IR flow cell under the
fast flow (5 ml/min) conditions.
50
............................................................................................................... 11
Figure 1.5
1
H NMR kinetic study of the copper(I)-catalyzed azide-1-iodoalkyne cycloaddition reaction
I
CuAAC (experimental data derived by the author). .................................................................................. 13
Figure 1.6 Off-line HPLC reaction progress monitoring of the copper(I)-catalyzed azide-1-iodoalkyne
cycloaddition reaction
I
CuAAC (experimental data is derived by author). ................................................ 15
Figure 2.1 Graphical representations of the variable-conditions kinetic profiles of the
I
CuAAC reactions
derived with differential and integral methods.
1
H NMR kinetics. (A) Same excess protocol; Conditions:
A[3]=0.075M; [Z]=0.105 M; 8.75 mM cat[2] (red line); A[3]=0.10 M; [Z]=0.13 M; 8.75 mM cat[2] (black
line); 0.8 ml of THF-d8, 35 °C; (B) Reaction rate vs A [4]; Conditions: 0.1 M A [4]; 0.13 M [Z] ; 0.8 ml of
THF-d8, 28.7 °C, using 5mM (grey line) and 7.5mM (black line) of cat[1]; Heat Flow Calorimetry. (C)
Catalyst stability experiment. Conditions: 0.10 M A[4], 0.10 M P[4] (grey) or 0.10 M A[4] (black); 0.11 M
[Z], 10 mol % cat[2]; (D) Non-time dependent instantaneous rates vs conversion for A [5] and A [4]
substrates. First kinetic regime (blue), second kinetic regime (red). Conditions: 0.1 M A[5] (grey) or 0.10
M A[4] (black); 0.11 M [Z], 10 mol % cat[2]. ............................................................................................ 39
Figure 2.2 Graphical representations of the kinetic profiles of the independent
I
CuAAC reactions derived
via real time
1
H NMR spectroscopy. Reaction conversion versus time. ..................................................... 41
Figure 2.3 The Hammett plot derived from the
1
H NMR kinetic experiment. Apparent rate constants were
normalized regarding the electron-neutral (iodoethynyl)benzene substrate. A free energy relationship
exhibited a linear trend with a scope of ρ = 1.34 (0.13).............................................................................. 42
Figure 2.4 Experimental data analysis algorithm using numerical methods of statistical data processing.
.................................................................................................................................................................... 44
xvi
Figure 2.5 Results of the proposed deterministic approach for
I
CuAAC mechanism modelling. Comparison
of experimental and predicted concentration-time profiles. The set of rate parameters was considered to be
accurate, once the experimental values of the reactant concentrations vs time were in exact agreement with
the computed ones derived with the classic Runge-Kutta method. Conditions: 0.10 M A [4]; 0.122 M [Z];
10 mol % CuI-TCPTA; 0.8 ml of THF-d8, 28.7 °C. .................................................................................. 47
Figure 2.6 Plots of catalytically active species [A·cat], [A·cat·Z], [cat] during the course of the reaction.
The continuous concentration curves were calculated using the set of derived rate constants (Table 2.1). A)
Advantages of the deterministic approach in kinetic studies; B) Evolution profiles of involved the key
catalytic species. ......................................................................................................................................... 49
Figure 2.7 (A) Calculation of the activation parameters for the electron-rich 1-iodo-alkyne[1] (initial rates):
∆H
ǂ
=3.2 (0.9) kcal/mol and ∆S
ǂ
= -70.0 (3.1) cal/mol·K; (B) Calculation of activation parameters for
electron-deficient 1-iodo-alkyne [4] (initial rates): ∆H
ǂ
=5.8 (1.1) kcal/mol and ∆S
ǂ
= -58.1 (0.2) cal/mol·K.
.................................................................................................................................................................... 51
Figure 2.8 Various catalytic systems experiment. Graphical representations of the kinetic profiles of the
I
CuAAC reactions catalyzed by CuI-TCPTA/TTTA/TBTA systems obtained by real time
1
H NMR
spectroscopy. Conditions: 0.10 M A [4]; 0.13 M [Z]; 10 mol % CuI-TCPTA (blue); 10 mol % CuI-TBTA
(purple); 10 mol % CuI-TCPTA (red); 0.8 ml of THF-d8, 28.7 °C. ........................................................... 52
Figure 2.9 The following code fragment represents the classic RK integration method for computing
concentration profiles from eq.(4)-(6) employing optimized rate parameters. ........................................... 56
Figure 3.1 Selected bond Bi(1)–I and transannular Bi(1)···O(1) interaction distances [Å] of the synthesized
iodobismines ([27] and [28]) and correspondent isolated yields. Thermal ellipsoids are set at 50%
probability. .................................................................................................................................................. 70
Figure 3.2 Selected bond and transannular Bi(1)–O(1) interaction distances [Å] of the synthesized
bismuth(III) acetylides. Thermal ellipsoids are set at 50% probability. A) Crystal structures of the most
reactive bismuth(III) acetylide [3] and the least reactive acetylide [5]; B) Crystal structures of para-phenyl
substituted bismuth(III) acetylides; C) Crystal structures of diphenylsulfone substituted
bismuth(III)acetylides. ................................................................................................................................ 71
Figure 3.3 Infrared spectroscopy as a diagnostic tool for observing the disappearance of the -C≡C-
stretching band. Comparison of the absorbance data for 1-bismuth(III) acetylide [2] and the corresponding
5-bismuth(III) triazolide [2]. ....................................................................................................................... 72
xvii
Figure 3.4
1
H NMR signal coalescence/decoalescence demonstrate intermolecular processes of bond
rotations as a function of temperature for 5-bismuth(III) triazole[2]. ......................................................... 76
Figure 3.5 Kinetic progress monitored by
1
H NMR spectra of
Bi
CuAAC reaction. .................................. 77
Figure 3.6 Kinetic profiles of
Bi
CuAAC independent experiments catalyzed by the copper(I)-triflate toluene
complex. Conditions: A[X] = 0.025M; [Z] = 0.043 M; [cat] = 0.375 mM; 0.8 ml volume DMSO-d6;
T = 59.5 °C. A) Standard reaction conversion versus time; B) Reaction rates versus time. ....................... 80
Figure 3.7 Kinetic profile of the
Bi
CuAAC reaction catalyzed by the copper(I)-triflate toluene complex.
Double exponential approximation. A) Reaction concentration versus time. Variable [Alkyne]
concentration experiment. B) Reaction rate versus bismuth(III) acetylide A [2] concentration. C) ʋ/[Z]
versus A[2]. D) ʋ/A[2] versus [Z]. .............................................................................................................. 85
Figure 3.8 Graphical representation of probing the catalyst robustness in the
Bi
CuAAC reaction.
Conditions: 0.012 M A[4], 0.014 M [Z], 0.386 mM (light blue) and 0.773 mM (dark blue), DMSO-d6,
60 °C. .......................................................................................................................................................... 86
Figure 3.9 Cyclic voltammogram kinetic studies of the
Bi
CuAAC reaction with the copper(I)-triflate
toluene complex at 25 °C in dry DMSO at 100 mV/sec. Conditions: 3-electrode cell with glassy carbon as
the working electrode, copper foils as counter and reference electrodes. (A) Kinetic studies of catalyst-
bismuth(III) acetylide coordination; (B) Kinetic studies of azide insertion; (C) Voltamperrograms in the
presence of the indicated reagents, added in the order specified; (D) Average of onset oxidation and
reduction potential values for variable [A[X]·cat] complexes. ................................................................... 91
Figure 3.10 Cyclic voltammograms in the presence of the copper catalyst [CuOTf], bismuth(III) acetylide
A[X] and azide [Z] reagents, added in the order indicated. (A) 1-Bismith(III) acetylide [1]; (B) 1-
bismith(III) acetylide [2]; (C) 1-bismith(III) acetylide [3]; (D) 1-bismith(III) acetylide [4]; (E) 1-
bismith(III) acetylide [5]; (F) 1-bismith(III) acetylide [6]. ......................................................................... 92
Figure 4.1: (A) Relative composition of sulfur-containing functionalities in pharmaceutical drugs
employed for the treatment of twelve frequently occurring disease categories; (B) Examples of US FDA-
approved sulfonamide-containing pharmaceuticals, possessing a heterocyclic scaffold. ........................... 99
Figure 4.2 Kinetic studies of the water-assisted reaction of SO 2F-functionalized triazoles. A) Surfactant
effect on the sulfonyl triazoles formation. (Reaction conditions: 1 eq. = 0.5 mmol, DBESF (1.5 eq.),
(azidomethyl)benzene (1.0 eq.), triethylamine (1.5 eq.), Aliquat®336 (0.0 eq.; 0.03 eq.; 0.05 eq.; 0.10 eq.;
0.15 eq.; 0.20 eq.; 0.23 eq.; 0.24 eq.; 0.30 eq.), water (2 ml), spin rate of the stir bar (1400 rpm), r.t., aliquots
were taken after 8 h of continuous stirring; B) Influence of the spin rate on the reaction rates (Reaction
xviii
conditions: DBESF (1.5 eq.), (azidomethyl)benzene (1.0 eq.), triethylamine (1.5 eq.), water ( 2 ml), spin
rates of the stir bar(400; 800; 1100, 1400 rpm), r.t., aliquot withdrawal was performed every 50 min).
Conversion vs. time; C) Ratio of 5-bromol triazole to 5-sulfonyl triazole as a function of spin rate. Same
conditions as in B); D) The difference in reactivity due to solvent polarity and base loading. (Reaction
conditions: entry 1 (DBESF (1.5 eq.), (azidomethyl)benzene (1.0 eq.), triethylamine (1.5 eq.), DMF (2 ml),
Aliquat®336 (0.15 eq.)), entry 2 (DBESF (1.5 eq.), (azidomethyl)benzene (1.0 eq.), triethylamine (1.5 eq.),
water (2 ml), Aliquat®336 (0 eq.)), entry 3 (DBESF (1.5 eq.), (azidomethyl)benzene (1.0 eq.), triethylamine
(1.5 eq.), water (2 ml), Aliquat®336 (0.15 eq.)), spin rate of the stir bar(1400 rpm), r.t., aliquot withdrawal
was performed every 50 min). .................................................................................................................. 107
Figure 4.3 The scope of sulfonyl triazoles formed from DBESF and organic azides. Reaction conditions:
Spin rate – 1400 rpm.
a
(0.74 mM) DBESF (0.74 mM), azide (0.49 mM), Aliquat®336 (30 mg), 1 ml H 2O,
8 h, r.t.;
b
DBESF (0.94 mM), azide (0.47 mM), Aliquat®336 (50 mg), 1 ml H 2O, 8 h, r.t.;
c
DBESF (1.88
mM), azide (0.47 mM), Aliquat®336 (50 mg), 1 ml H 2O, 8 h, r.t............................................................ 112
Figure 4.4 5-Fluorosulfonyl and 5-bromo-functionalized pyrazoles, non-substituted pyrazoles and various
derivatives of Diels-Alder additions formed from ESF, DBESF and organic azides. (A) Diels-Alder
adducts; (B) ESF and DBESF-promoted 1,3-dipolar cycloadditions. ...................................................... 113
Figure 5.1 OmniCal multi-reactor calorimeter (Insight-CPR-210) (exployed for current studies ) impulse
response represented in A)time and B) frequency domains. ..................................................................... 125
Figure 5.2 Noise representation for fast (entry 1), medium (entry 2) and slow (entry 3) kinetics (Table 5.1)
in A-C) frequency and A1-C1) time domains. .......................................................................................... 126
Figure 5.3 Dynamic correction of the heat released done with the dynamic correction operation as part of
the OmniCal Winsight calorimetry software (green) and self-developed FFT-based computational protocol
(blue). ........................................................................................................................................................ 127
Figure 5.4 Comparison ratio of the experimentally gained heat flow profile r(t) with it’s polynomial fit
functions 𝑟𝑡 for slow, medium and fast kinetics reaction profiles (Table 5.1). ........................................ 128
Figure 5.5 Heat flow kinetic profiles for the
I
CuAAC reactions shown in Scheme 5.1. A) Polynomial fit
(𝑟𝑡 ) of the experimentally derived heat flow data (𝑟𝑡 ) (entry 1, Table 5.1); Calorific data processing results:
B) slow kinetics (entry 1, Table 5.1); C) medium kinetics (entry 2, Table 5.1); D) fast kinetics (entry 3,
Table 5.1). (Red – experimental instantaneous heat flow data (𝑟𝑡 ); green – approximated function (20th
order polynomial curve) ( 𝑟𝑡𝑖 ); black – dynamically corrected calorific output (𝑈𝑟𝑒𝑎𝑙 (𝑡 )) administering
self-developed regularization protocol with 𝑟𝑡 ) input data; blue – dynamically corrected calorific output
(estimated 𝑈𝑟𝑒𝑎𝑙 (𝑡 )) derived with operation calorimetry Winsight software (with 𝑟𝑡 as input data). .... 129
xix
Figure 5.6 Reaction rates derived from eq.(1) employing dynamically corrected heat flow sequences
obtained with the self-developed regularization protocol. ........................................................................ 131
Figure A.1 Kinetic profiles obtained from the experiment described in the general procedure B. Variable
[Azide] concentration experiments. A-E) reactant concentrations vs time; F) reaction conversion versus
time. Method of initial rates. ..................................................................................................................... 150
Figure A.2 Plot of Ln(rate) vs Ln([Azide]) shows a non-zero order in the azide concentration in the reaction
rate (n=1.31). ............................................................................................................................................. 150
Figure A.3 Kinetic profiles obtained from the experiment described by the general procedure B. Variable
[Alkyne] concentration experiments. A) Reaction conversion vs. time; B1-B4) 5-iodo-1,2,3-triazole P[4]
concentration vs. time. .............................................................................................................................. 152
Figure A.4 Ln(rate) vs. Ln([Alkyne]) reveals a change in 1-iodoalkyne rate orders (from n=0.84 to
n=0.013). ................................................................................................................................................... 153
Figure A.5 Kinetic profiles obtained from the experiment described by the general procedure C. A) 5-iodo-
1,2,3-triazole P[4] concentration vs. time; B1-B4) Initial concentrations of P[4] vs. time. ..................... 156
Figure A.6 Activation parameters for electron-deficient 1-iodo-alkyne [4]. Results of Eyring plot: ∆H
ǂ
=5.8
(1.1) kcal/mol and ∆S
ǂ
=-58.1 (0.2) cal/mol·K. ......................................................................................... 157
Figure A.7 Kinetic profiles for reactions described in the general procedure C. A) Product P[1]
concentration vs. time; B1-B5) Initial concentrations of the 5-iodo-1,2,3-triazole [P] vs. time. .............. 159
Figure A.8 Activation parameters for the electron-rich 1-iodo-alkyne[1]. Results of Eyring plot: ∆Hǂ =3.2
(0.9) kcal/mol and ∆Sǂ =-70.0 (3.1) cal/mol·K. ........................................................................................ 160
Figure A.9 Kinetic profiles for reactions described in general procedure E. A) 4.37 mM of [cat]; B)
6.56 mM of [cat]. ...................................................................................................................................... 164
Figure A.10 Kinetic profiles for reactions performed following general procedure F. A1) A[3]=0.075 M;
[Z]=0.105 M; A2) A[3]=0.105 M; [Z]=0.135 M ...................................................................................... 166
Figure A.11 Derived theoretical profiles for 1-iodoalkyne, azide and 5-iodotriazole substrates match the
experimental ones. .................................................................................................................................... 169
Figure A.12 Intermediate [A·cat] and [cat] evolution curves determined by
1
H kinetic NMR experiments
described in Table A.1, entries 1, 2, 3, 4 and 5. Data collection was performed via
1
H NMR signal
integration of the corresponding to reactants. ........................................................................................... 172
xx
Figure A.13 Intermediate [A·cat] and [cat] evolution curves determined by
1
H kinetic NMR studies for
experimental conditions described in Table A.1, entry 4. Comparison of the computationally and
experimentally derived data. ..................................................................................................................... 172
Figure A.14 Calibration curves of 1-iodoalkynes and 5-iodo-1,2,3-triazoles. ......................................... 177
Figure A.15 Kinetic profiles for experiments following general procedure A. A) Reaction rates vs. time
plot; B) Reaction rates vs. [Azide] plot. .................................................................................................... 179
Figure A.16 Kinetic profiles for experiments following general procedure B. A) Reaction rates vs. time
plot; B) Reaction rates vs. [Azide] plot. .................................................................................................... 181
Figure A.17 “Multiple injection” experiment. A) heat flow vs. time; B) reaction rate vs. [Azide]. ........ 187
Figure B.1 Kinetic profiles of reactions studied following general procedure B. .................................... 221
Figure B.2 Substrate rate order kinetic study performed following general procedure B. Method of initial
rates. (A1-A5) Product P[2] concentration vs. time; (B) LN(rate) vs. LN([A]). ...................................... 222
Figure B.3 Kinetic profiles of reactions studied following general procedure C. .................................... 225
Figure B.4 Kinetic profiles of reactions studied following general procedure A. A) Conversion profiles of
reactions (Table B.4), entries 1 and 2; B1-B2) Dry and ‘wet’ DMSO-d6 as solvent. .............................. 226
Figure B.5 Exchange reaction progress spectra. Equilibrium measurements at 27
°
C with CuOTf toluene
complex as catalyst. General procedure D. ............................................................................................... 230
Figure B.6 Exchange reaction progress spectra. Equilibrium measurements with CuOTf toluene complex
as catalyst at 69 °C. General procedure D. ............................................................................................... 235
Figure B.7 Kinetic profiles for experiments performed following general procedure E. A) [cat]=0.386 mM;
B) [cat]=0.773 mM. .................................................................................................................................. 237
Figure B.8 Kinetic profiles of the cyclic voltammograms obtained by following general procedure F. . 240
Figure B.9 Kinetic profiles of the cyclic voltammograms obtained by following general procedure G. 241
Figure B.10 Asymmetric unit in the crystal structure of compound 42. .................................................. 282
Figure B.11 Asymmetric unit in the crystal structure of compound 39. .................................................. 287
Figure B.12 Asymmetric unit in the crystal structure of compound 40. .................................................. 291
Figure B.13 Asymmetric unit in the crystal structure of compound 34. .................................................. 295
Figure B.14 Asymmetric unit in the crystal structure of compound 35. .................................................. 299
xxi
Figure B.15 Asymmetric unit in the crystal structure of compound 32. .................................................. 302
Figure B.16 Asymmetric unit in the crystal structure of compound 33. .................................................. 308
Figure B.17 Asymmetric unit in the crystal structure of compound 36. .................................................. 312
Figure B.18 Crystal structure of compound 27. ....................................................................................... 317
Figure B.19 Crystal structure of compound 21. ....................................................................................... 321
Figure B.20 Crystal structure of compound 18. ....................................................................................... 326
Figure B.21 Crystal structure of compound 37. ....................................................................................... 330
xxii
LIST OF SCHEMES
Scheme 1.1 Bio-orthogonal Click reactions have been used for biolabeling and imaging. (A) Staudinger
ligation; (B) Cu-catalyzed azide-alkyne cycloaddition (CuAAC); (C) strain-promoted azide-alkyne
cycloaddition (SPAAC); (D) inverse-electron-demand Diels–Alder reaction (IEDDA). ............................. 6
Scheme 1.2 Catalytic scheme of Michaelis-Menten kinetic model. ........................................................... 19
Scheme 1.3 Generalized mechanism of a complex catalytic reaction with two substrates and two
intermediates. .............................................................................................................................................. 23
Scheme 2.1 Copper(I)-catalyzed azide-1-Iodoalkyne cycloaddition reaction (
I
CuAAC). Previous and
current studies. ............................................................................................................................................ 36
Scheme 2.2 Copper(I)-catalyzed cycloadditions of 1-iodoalkynes[X] to Azide[Z] catalyzed by CuI-TTTA,
CuI-TBTA or CuI-TCPTA catalytic systems. ............................................................................................ 38
Scheme 2.3 Proposed mechanism of the
I
CuAAC reaction with evaluated rate-determining step changes.
.................................................................................................................................................................... 47
Scheme 3.1 5-Bismuth(III)-triazolides in the
Bi
CuAAC reaction. Previous report and current study. ....... 66
Scheme 3.2 (A) Synthetic route for the synthesis of diphenylsulfone bismuth(III) acetylides (a) CuI, K 2CO 3,
i-propanol/ethylene glycol, 80 °C; (b) m-CPBA, DCM, MgSO 4 10 eq., 0 °C-> r.t.; (c) 1)BiBr 3, BiPh 3, Et 2O,
2) n-BuLi, THF, –78 °C-> r.t.; (d) I 2, Et 2O, r.t.; (e) 1) n-BuLi, THF, –78 °C-> r.t. 2) para-substituted
phenylacetylene; (B) diphenylsulfone bismuth(III) acetylides; (C) 1-ethynyl-4-methylbenzene bismuth(III)
acetylides with functionalized diphenylsulfone ligands. ............................................................................ 69
Scheme 3.3 (A) General scheme for
Bi
CuAAC reactions of bismuth(III) acetylides A[1-6] with (2-
azidoethyl)benzene; (B) Product scope for the copper(I)-catalyzed bismuth(III) acetylide-azide
cycloaddition reaction. ................................................................................................................................ 74
Scheme 3.4 Proposed mechanistic model of the azide-bismuth(III) acetylide copper(I)-catalyzed
cycloaddition reaction (
Bi
CuAAC). ............................................................................................................. 82
Scheme 4.1 Synthetic procedures for the synthesis of sulfonyl chloride heterocycles amenable to further
amination. ................................................................................................................................................. 101
Scheme 4.2 Sulfur-Fluoride Exchange reaction (SuFEx).
28
A) SuFEx mediated formation of sulfonamides
and sulfonates; B) Common hubs for SuFEx ligation; C) Synthetic protocol for the generation of DBESF
and BESF from ESF.
29
.............................................................................................................................. 103
xxiii
Scheme 4.3 Water-assisted formation of 4-sulfonyl and 4-bromo triazoles from organic azides and DBESF.
.................................................................................................................................................................. 108
Scheme 5.1 Copper(I)-catalyzed cycloaddition of 1-iodoalkynes to organic azides (
I
CuAAC). ............. 121
xxiv
LIST OF ABBREVIATIONS
1D 1-dimensional
2D 2-dimensional
Å Ångstrom, 10
-10
meter
A 1-iodoalkyne or bismuth(III) acetylide
aq aqueous
cat catalyst
A·cat alkyne(acetylide)-catalyst π-complex
A·cat·Z catalyst-iodoalkyne-azide complex
ATR attenuated total reflectance
AZ·cat transition state complex
BSS bismuth subsalicylate
Brij
®
L4 polyethylene glycol dodecyl ether
13
C NMR carbon nuclear magnetic resonance
CBS colloidal bismuth subcitrate
CPU central processing unit
CuI-TBTA copper(I) iodide-tris-((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)amine catalyst
CuI-TCPTA copper(I) iodide-tris-((1-cyclopentyl-1H-1,2,3- triazol-4-yl)methyl)amine catalyst
CuI-TTTA copper(I) iodide-tris-((1-tert-butyl-1H-1,2,3-triazolyl)methyl)amine catalyst
CuOTf trifluoromethanesulfonic acid copper(I) salt toluene complex
CV Cyclic Voltammetry
d doublet (NMR spectroscopy notation)
DCM dichloromethane
DMF N,N-dimethylformamide
E enzyme
Eav average of the onset oxidation and reduction potentials
xxv
ESI-MS Electrospray Ionization-Mass Spectrometry
ES enzyme-substrate complex
EtOAc ethyl acetate
FT Fourier Transform
FFT Fast Fourier Transform
FTIR Fourier Transform Infrared Spectroscopy
g gram
GC Gas Chromatography
MHz Megahertz
h hour
HMBC Heteronuclear Multiple Bond Coherence
1
H NMR Proton Nuclear Magnetic Resonance
HPLC High Performance Liquid Chromatography
HSQC Heteronuclear Single Quantum Coherence
Hz hertz
IR infrared
J coupling constant (NMR spectroscopy notation)
LFER Linear Free Energy Relationships
LMS Least Square Means
M concentration (moles/liter)
m- meta-substituent
m-CPBA meta-chloroperoxybenzoic acid
Me methyl
MeCN acetonitrile
mg milligram
ml milliliter
mM concentration (millimoles/liter)
xxvi
mol mole
MS Mass Spectrometry
n- normal
NA nucleic acid
NIR near-infrared
NMR Nuclear Magnetic Resonance
Nuc nucleophile
o ortho-substituent
˚ degree
OMe methoxy
OpenMP Open Multi-Processing
OTf trifluoromethanesulfonate
p- para-substituent
P 5-iodo-1,2,3-triazole or 5-bismuth(III)-1,2,3-triazolide
PET Positron Emission Tomography
q quartet (NMR spectroscopy notation)
QE quasi-equilibrium
R organic group
RDS rate-determining step
ROS reactive oxygen species
RPKA Reaction Progress Kinetic Analysis
r.t. room temperature
S substrate
s singlet (NMR spectroscopy notation)
sec second
SI international system of units
SPAAC “strain-promoted” cycloaddition of azide and cyclooctynes dipolarophiles
xxvii
SS steady-state
t triplet (NMR spectroscopy notation)
TBTA tris-((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)amine
t
Bu tert-butyl
TCPTA tris-((1-cyclopentyl-1H-1,2,3- triazol-4-yl)methyl)amine
TEA triethylamine
THF tetrahydrofuran
TLC thin layer chromatography
TTTA tris-((1-tert-butyl-1H-1,2,3-triazolyl)methyl)amine
VKA Visual Kinetic Analysis
VT variable temperature
VTNA Variable Time Normalization Analysis
UV ultraviolet
UV-Vis Ultraviolet-Visible
W watts
[xs] concentration excess
Z azide
[ ] concentration
β beta
δ chemical shift in ppm
µ micro (10
-6
)
µL microliter
ρ rho
σ sigma
xxviii
ABSTRACT
A better understanding of the fundamental transformations and processes in reaction profiles can
help a scientist to improve a method or synthetic model without additional cost and efforts. Results
from the mechanistic investigations of existing transformations can improve the optimization or
development of novel, more efficient techniques and protocols. In the current thesis, various
kinetic studies were performed to gain insights into the iodo- and bismuth(III)-types of copper (I)-
catalyzed azide-alkyne cycloaddition (CuAAC) transformations. A quantitative mechanistic
model is outlined for the copper(I)-catalyzed azide-iodoalkyne cycloaddition reaction (
I
CuAAC)
by applying a mathematical system of statistics and data analysis. During the modeling part, two
problems required to be solved in order to improve existing or new catalytic cycloadditions: 1) the
evaluation of how electronic and steric properties of reactants affect the rate and selectivity of the
triazole formation; and 2) the gaining of insight into the mechanism of the catalytic activation
when employing the coordinative triazolyl(amine)ligands, tris-((1-tert-butyl-1H-1,2,3-
triazolyl)methyl)amine, (TTTA), and tris-((1-cyclopentyl-1H-1,2,3-triazol-4-yl)methyl)amine,
(TCPTA). Even though the mechanism of the copper(I)-catalyzed cycloaddition of iodoalkynes
was proposed to proceed via two different reaction pathways, i.e., the cleavage of the carbon–
iodine bond versus the formation of Cu(I)-iodoalkyne π-complex, much uncertainly remained
about the rate-limiting step and the nature of the interactions of the catalyst with the iodoalkyne.
For both catalytic systems, competitive reactions revealed that electron withdrawing groups
increase the rate of the 5-iodo-1,2,3-triazole formation, while electron donating groups slow down
the reaction. The kinetic profiles for both the CuI-TTTA and the CuI-TCPTA catalytic systems
were consistent with the hypothesis of the 1-iodo-2,3,4-triazoles formation following the general,
linear, free-energy relationship trend with positive ρ values for both 1-iodo-alkyne- and azide-
xxix
substrates. Computational protocols using extensive experimental data sets allowed an entire
conversion-profiled kinetic elucidation and revealed fine differences between reaction regimes.
While my study was in progress, similar results on iodine/hydrogen exchange in 1-iodo- and
terminal alkynes were published by Hein et al. (ACS Catal., 2017) and Fokin, Hein and co-workers
(ACS Catal., 2018). The conclusions from their independent work regarding competitive kinetics
are in good agreement with my results which are summarized below.
Mechanistic investigations were also performed for the copper(I)-catalyzed azide-bismuth(III)
acetylide cycloaddition reaction, (
Bi
CuAAC). Similar to the iodo-alkyne CuAAC reaction, the rate-
determining step was identified. However, the use of a set of different diphenyl sulfone
bismuth(III) acetylides resulted not only in a conversion-dependent, rate-determining step, but also
revealed a substrate-dependent relationship. Employing variable “excess” concentrations, the
catalyst robustness, reaction rate orders as well as the independent substrate reactivity were studied
either by spectroscopy or cyclic voltammetry. Based on X-ray crystallographic data for the
synthesized bismuth(III)-acetylides, a correlation between the transannular O(1)···Bi(1)
interaction and reactivity is indicated. The possibility to turn on the activity of such coupling
substrates under copper(I)-catalytic conditions and the development of biocompatible synthetic
protocols will be the subject of separate study.
Throughout the kinetic studies, the question of a more detailed reaction rate-law elucidation for
the complex catalytic reactions remained one of the key concerns. The analysis of intermittently
taken sample aliquots showed that incomplete kinetic data produce either misleading results or
restrict the process of parameter elucidation. However, more detailed kinetic studies were
previously considered too tough and time-consuming. These two factors are a major concern for a
xxx
chemist interested in kinetic and mechanistic computations. Programming software was developed
for the analysis of detailed experimental data sets, obtained by variable instrumental techniques.
During attempts to improve the signal to noise ratio in calorific and spectroscopic output data, the
inverse problem in chemical kinetics was solved for the differential approach of heat flow
calorimetry. Particularly, the importance of data smoothing was demonstrated when applying
dynamic correction procedures.
Mechanistic studies were also performed for the on-water catalyzed synthesis of fluorosulfonyl-
substituted 1,2,3-triazoles from dibromovinylsulfonyl building blocks (DBESF) and organic
azides. DBESFs were also successfully employed for a methodology development and procedure
optimization for the synthesis of functionalized pyrazoles, isoxazoles and Diels-Alder
cycloaddition adducts.
xxxi
PREFACE
CHAPTER 2
“Mechanistic and Kinetic Investigation of 1-Iodoaryl Alkynes with Organic Azides in the
Copper(I)-catalyzed Cycloaddition Reaction” has not been published. I performed all experimental
work and data analysis.
CHAPTER 3
“Mechanistic and Kinetic Studies of the Copper(I)-Catalyzed Cycloaddition Reaction of
Bismuth(III)-acetylides with Organic Azides” has not been published. I performed all
experimental work and data analysis.
CHAPTER 4
“On-water catalysis” has not been published. The project was initiated by Dr. Joice Thomas. I have
been working on this project in collaboration with Dr. Joice Thomas since December 2017. I
performed the methodology optimization, acquired and analyzed all the kinetic data and performed
the bulk of the syntheses and characterization.
CHAPTER 5
“Importance of Signal Processing Methods for Abundant Kinetic Data derived from Heat Flow
Calorimetry” has not been published. I performed all experimental work and data analysis.
C H A P T E R I
2
1 A CHEMICAL SPACE AND ANALYTICAL TOOLS TO PROBE IT
1.1 THE FIELD OF CUAAC REACTION IN SYNTHETIC CHEMISTRY
In recent years, chemical academic research has shifted from being curiosity-driven and “pure
science” to applying that research to project-based collaborations within industrial partnerships. In
particular for synthetic organic chemistry, the development of novel reagents and synthetic
protocols and methodologies have a tremendous impact on the entire drug discovery process in the
pharmaceutical industry and are directly benefiting humanity.
1, 2
Most of the attention to decipher
chemical problems has been focused on metal-catalyzed cross-coupling reactions,
3
C-H
activation
4, 5
and chiral biocatalysis
6, 7
. In 2002, a cycloaddition reaction of terminal alkynes to
organic azides, mediated by the copper (I), was reported.
8, 9
It was operationally robust, performing
well under non-ideal conditions, and regioselective with exclusive formation of 1,4-substituted
1,2,3-triazole, it proceeded fast at room temperature and, in general, demonstrated quantitative
yields and significantly enhanced rates, compared to any other previously reported cycloaddition.
This catalytic transformation became an essential part of the newly introduced concept of “Click
Chemistry”.
10
Since the time is was first reported copper(I)-mediated azide-alkyne ligation has
been applied to diverse chemical-biology systems, pharmaceuticals and drug delivery,
11
material
science,
12
functionalized nano-particles for biochemical assays
13
and supramolecular chemistry.
14
In 1893, Arthur Michael discovered a simple protocol for the synthesis of 1,2,3-triazoles by simply
heating ethereal solutions of acetylenedicarboylic esters and phenyl azide in a sealed tube.
15
Mechanistic studies of the addition of diazoalkanes to angularly strained double bonds by Rolf
Huisgen in the 1960s led to the concept of 1,3-dipolar cycloadditions
16
In this study, a pericyclic
mechanism of 1,3-dipolar addition was postulated involving a concerted reaction between 1,3-
3
dipolar moieties, such as nitrile oxide, ozone or azide, with dipolarophiles, i.e., unsaturated
molecules. While the thermal cycloaddition was forming both 1,4- and 1,5- regioisomers with
yields directly proportional to electronic and steric factors, a wise choice of reactive 1,3 dipoles,
transition-metal catalyst, and solvent medium resulted in the development of regioselective and
efficient protocols, amenable to room temperature. The unique ability of copper to increase the
nucleophilicity of the internal β-carbon allows coordination of the organic azide with the
subsequent formation of the first covalent C-N bond between the β-C of the alkyne and the terminal
N(1) atom of the azide moiety. Particularly in the field of organic synthesis, the copper(I)-catalyzed
cycloaddition of acetylenes and organic azides has been successfully employed for the synthesis
of mulit-functionalized complexes linked via triazolate (in iClick cycloaddition)
17
or triazolide (in
CuAAC cycloaddition), also allowing further derivatization.
17-21
Figure 1.1 (A) Classification of 1,3-dipole structures of the allyl- and allenyl- types. (B) Acetylide scope
being employed in CuAAC reaction. Highlighted in blue and red have been used in this work.
4
While some of the terminal acetylenes required elevated temperatures and prolonged reaction
times, others exhibited exceptionally fast kinetics at room temperature. Before proceeding further,
it would be necessary to list the classifications of all types of 1,3-dipoles that have been employed
so far in the synthetic field (in addition to click reactions) so far (Figure 1.1) and to highlight those
directly employed in the current work. The acetylide scope of reported “click” acetylides is
represented in Figure 1.1. While the discussion of the scope and usage of current reactions for
synthetic organic applications is far beyond this thesis, I would like to focus the attention on the
biomedically relevant key aspect of click chemistry.
1.2 BIOORTHOGONAL REACTIONS
It did not take long until Sharpless and Finn reported a enzyme-driven screening procedure for the
generation of 1,2,3-triazoles by using alkynes and azides under -biologically relevant conditions.
22
The in situ generation of the triazole scaffolds from alkynes and azides gained extensive attention
and has evolved significantly.
23
In 2015 M.-H. Hu et al. successfully applied the kinetic, target-
guided, in situ, click chemistry approach for the synthesis of fluorescent probes for selective
binding to G-quadruplex nucleic acid structures.
24
Two years later, Bhardwaj et al. reported the
kinetic target-guided synthesis of a cyclooxygenase-2-isozyme inhibitor employing the binding
pocket of a cyclooxygenase-2 as a reaction vessel.
25
Taking into account the ligation rates, high
chemoselectivity and stability of substituted 1,2,3-triazoles, K. Bertozzi came up with the idea of
copper-free or “strain-promoted” cycloaddition of azide and cyclooctyne dipolarophiles
(SPAAC).
26
While pursuing a compromise between the rate acceleration and robustness of the
linkage forming approach she developed, Bertozzi performed a derivatization of cyclooctyne units
by incorporating fluorine containing electron-withdrawing functional groups besides other
heteroatoms.
27-29
For bioimaging purposes, these drawbacks forced SPAAC to remain in a non-
5
permanent status for bioorganic chemists, while creating room for improved strategies.
27, 30
The
novel subclass of cycloaddition reactions was termed “bioorthogonal”. The basic principle for this
concept was to allow for no interaction nor intervention with the biological milieu this approach
are operating in.
31
A schematic summary of existing bio-orthogonal click reactions is represented
in Scheme 1.1. These approaches have been extensively used for metabolic labelling and the
discovery of novel structures with a strong affinity to nucleic acids (NAs) and peptides.
32
In the
context of functionalization methods, such as CuAAC, SPAAC, Staudinger ligation and IEDDA,
the copper-promoted synthesis of small and macromolecular conjugates remains a hot topic.
Thus, the main objective of this work was the exploration and advancements in understanding the
mechanism of metal(Cu)-catalyzed cycloaddition (CuAAC) in a biologically relevant context.
6
Scheme 1.1 Bio-orthogonal Click reactions have been used for biolabeling and imaging. (A) Staudinger
ligation; (B) Cu-catalyzed azide-alkyne cycloaddition (CuAAC); (C) strain-promoted azide-alkyne
cycloaddition (SPAAC); (D) inverse-electron-demand Diels–Alder reaction (IEDDA).
1.3 THE FIELD OF CUAAC REACTION IN BIOIMAGING STUDIES
The major problem precluding further research of
copper(I)-catalyzed azide-alkyne cycloaddition
reactions in mammalian cells is the deactivation of the copper species by thiol linkages, present in
the cytosolic milieu.
33, 34
Furthermore, cytotoxicity of copper promotes the formation of reactive
oxygen species (ROS).
35-37
In addition, the cycloaddition rates are also restricted by an increase in
density and heterogeneity of crowding molecules, when employing limiting concentrations of the
reagents. Therefore, up to now, only two crucial accounts of CuAAC potentially thriving inside
the complex interior of mammalian cells have been disclosed.
38, 39
The development of variable
7
copper binding ligands, as well as the derivatization of the azide structure to induce chelated
functionality, allowed for protein visualization and tracking with click techniques. Without
tailoring the full spectra of synthesized ligands, we will prominently discuss in this work the class
of polytriazole ligands, found to effectively complex copper(I). Tris-((1-benzyl-1H-1,2,3-triazol-
4-yl)methyl)amine, (TBTA), was the first efficient oligotriazole derivative, demonstrating
significant acceleration of cycloaddition rates while remaining Cu(I) stable under oxygen-exposed
conditions.
40
Hence, tetradentate chelation of copper with tertiary amine and triazole moieties was
shown to be strong yet being reactive enough to allow access to copper(I) by another, π-fashion
binding acetylene unit. A TBTA-assisted CuAAC reaction was performed for the biotinylated
labelling studies of an E.coli membrane protein.
41
Since then, a variety of functionalized
tris(triazolyl)amine ligand analogs have been synthesized, applicable to hydrophilic or
hydrophobic solvent medias and promoting cycloaddition with variable acetylide scaffolds.
42, 43
A
wise choice of copper(I)-stabilizing ligand will boost the CuAAC-type biorthogonal approach in
terms of sensitivity and sensory modality. Indeed, to become a potentially reliable method for
biomolecule labelling and imaging, a reaction protocol should satisfy the following criteria:
44
▪ High selectivity;
▪ Stability at physiological conditions (air and humidity);
▪ Non-toxicity and biocompatibility;
▪ Solubility and relatively small size (to facilitate transport through a cellular
membrane)
Mechanistic studies of the iodo- and bismuth-variations of the copper(I) catalyzed cycloaddition
(
I
CuAAC and
Bi
CuAAC) will provide insides into the catalytic cycle; the role of the copper catalyst
as driving force as well as the rate orders of the reaction kinetics for these types of CuAAC. An
8
in-depth understanding of every step in the catalytic mechanism can trigger a boost in the
development of more effective metal-mediated approaches and protocols with application ranging
from synthetic organic chemistry to biological systems.
1.4 METHODS OF IN SITU (ONLINE) AND EX SITU (OFFLINE) MONITORING
OF REACTION PROGRESS IN HOMOGENEOUS CATALYSIS
Reliable and high precision instrumentation is important for performing mechanistic studies of
reactions. The choice of an appropriate instrument for monitoring of the kinetic progress is
typically made based on the exothermicity, reactivity, sensitivity to moisture and light, as well as
homogeneity of the reaction. Additionally, other potentially limiting factors can include the lack
of the studying materials or a need to work in the diluted conditions. This would require the
employment of the very sensitive techniques, such as spectroscopic or mass spectroscopy-related
ones. Generation of a solid product, one that is not soluble in the reaction media nor releases gas,
release will call for global heat or open vessel operational methods. The following paragraphs will
describe the advantages and disadvantages of the existing methods for kinetic studies as well as
shine a light on the kinetic data processing and analysis approaches.
1.4.1 SPECTROSCOPIC METHODS
Spectroscopic techniques employ the quantum phenomena of electromagnetic interaction to probe
molecular features of the subject matter. Depending on the properties of the electromagnetic
interaction (e.g., wavelength λ, frequency ʋ), different spectroscopic techniques can be applied to
solve various biological and chemical problems (Figure 1.2). As such, every region of the
electromagnetic spectrum (corresponding to a certain technique) is related to specific transitions
of an electron within particular molecular orbitals. In the following sections, ultraviolet-visible
9
(UV-Vis), Fourier-transform infrared (FT-IR) and nuclear magnetic resonance (NMR)
spectroscopic techniques, being the most informative tools for monitoring organic reactions, will
be discussed in detail.
Figure 1.2 The electromagnetic spectrum and related spectroscopic methods.
45
1.4.1.1 ULTRAVIOLET-VISIBLE SPECTROSCOPY (UV-VIS)
Ultraviolet–visible spectrophotometry (UV–Vis) refers to a spectroscopic method that utilizes UV
and adjacent visible electromagnetic radiation to excite bonding and non-bonding electrons. travel
to higher anti-bonding molecular orbitals. Due to electronic transitions, the absorption in the
visible range for certain molecules directly correlates with color changes. Since the discovery of
the Bouguer-Lambert-Beer law in 1852, quantification of UV-Vis measurements has revealed new
horizons for that method of spectroscopy.
46
Spectrophotometric kinetic analysis of reactions has
gained interest among the scientific community due to the unique balance between the robustness
of its set-up, the richness of information, and the simplicity of data processing. The only time-
consuming process can might be development calibration curves to relate absorbance with
concentration. Poster and Mauser were the first to use UV-Vis for the evaluation of the second
10
order reaction of amidation of o-nitrophenyl acetate with n-butylamine in acetonitrile at room
temperature.
47
More recently, in situ UV-Vis was successfully applied to assess reaction kinetics
of the Fenton oxidation of naphthol blue black (NBB), demonstrating an adaptability, which will
be implemented into undergraduate course study as a 2-3 hour laboratory experiment (Figure
1.3).
48
Figure 1.3 Absorbance of NBB (the azo group (618 nm) and the aromatic rings (320 nm) over reaction
time while treated with oxygen peroxide and iron sulfate.
1.4.1.2 FOURIER TRANSFORM INFRARED SPECTROSCOPY (FT-IR)
Fourier transform infrared spectroscopy (FT-IR) employs infrared radiation passed through a
sample while recording absorbance (transmission) as a function of the wavelength. The output
signal allows the detection of functional groups by characteristic absorbance peaks related to the
corresponding bending or stretching frequencies.
49
Due to the relative simplicity of the
experimental set-up, rapidity of the information collection as well as the straightforwardness of
kinetic information extraction, FT-IR has been recently transformed from a method of structure
characterization to one of reaction monitoring, such as ReactIR (Figure 1.4).
50
Online monitoring
of product appearance and evolution of intermediate has been observed for fluorination and
hydrogenation reactions, oxazole synthesis, Curtius rearrangement, acyl azide formation and even
11
peptide coupling. Such a broad variety of investigated systems became possible due to a DiComp
- microscale flow cell using a diamond window for integrating attenuated total reflection (ATR).
Figure 1.4 Multiple band monitoring of methyl nicotinate hydrogenation with an IR flow cell under the
fast flow (5 ml/min) conditions.
50
The continuous monitoring of chemical processes has been achieved under real reaction conditions
involving continuous stirring. The potential drawbacks of the current approach might be the “blind
spot” windows and relatively noisy signal. Furthermore, overlapping peaks together with the
relatively broad wavelength ranges of certain functional groups can undoubtedly be additional
obstacles for a variety of complex reaction systems. In situ FT-IR, in combination with other
analytical techniques, became a method of choice for obtaining information on a system, especially
for batch processes.
12
1.4.1.3 NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY (NMR)
NMR spectroscopy is as an indispensable analytical tool for chemical research and the life
sciences. It is the most commonly and widely used technique for the in situ monitoring and the
systematic investigation of complex chemical transformations taking place in homogeneous
solutions.
51
High-pressure NMR has been used for measuring kinetics of reactions involving
substantial gas release.
52, 53
Thus, high-pressure NMR has been applied to the study of reaction
kinetics of reactions involving a gas-solution interphase.
54
NMR active nuclei with short relaxation
delays, such as
1
H and
19
F, and the ability to automate serial experiments offer the opportunity to
monitor chemical reactions in situ and real-time.
55
Acquiring NMR data of two nuclei
simultaneously can provide additional insights in the reaction progress without incurring additional
time or cost.
56
The minimal set-up requirements in combination with almost ubiquitous, easy-to-
use automation packages in modern NMR acquisition software, make NMR spectroscopy a very
powerful analytical tool for the quantitative investigations of reactions (Figure 1.5). Like for all
spectroscopic methods, an internal or external reference compound is required for quantitative
analysis. In NMR spectroscopy, the area of a resonance peak correlates with concentration and
generally requires the use of an internal standard which does not interfere with the resonances of
interest. Furthermore, the signals of interest are required to be well separated.
Interference from solvent signals can be reduced by the use of deuterated solvents or solvent
suppression techniques, while MestreNova’s deconvolution function provides additional peak
separation. Due to the persistent magnetic field inside of the spectrometer, additional drawbacks
of the current methods are the lack of continuous stirring required for strictly homogeneous
conditions. However, the development of in-line benchtop NMR spectrometers has provided a
unique analytical tool for the flow-type analysis of reaction mixtures
57
While possessing small
13
permanent magnets capable to functioning at a low magnetic field, low-field (LF) NMR has
successfully become a reaction monitoring tool for process control.
58, 59
The inconsistence in the
obtaining data out of the three different types of kinetics NMR studies can be another downside of
this method. Thus, both static NMR and periodic manual shaking of the NMR-tube by sporadic
inversion, provided the same kinetic profiles as the online NMR experiments (classic stirred flask
conditions with periodic sample withdrawal).
60
In addition, the processes quantified in static NMR
are considered to be diffusion limited, which may affect the interpretations of the observed results.
Figure 1.5
1
H NMR kinetic study of the copper(I)-catalyzed azide-1-iodoalkyne cycloaddition reaction
I
CuAAC (experimental data derived by the author).
1.4.2 CHROMATOGRAPHIC METHODS
Chromatographic technique is generally based on the principle of compound separation depending
on their polarity and the characteristics of the mobile and stationary phases. Due to the variability
of these factors, some components of the investigated mixture tend to stay longer in the
14
chromatographic column, while the retention time of others is relatively short.
61
The
chromatographic method provides not only qualitative but also a quantitative information. Based
on the chemical nature of the stationary phase (for example, liquid or solid support), mobile phase
(liquid (LC) or gas (GC)), separated mixture (polymers, proteins exc.) various types of
chromatographic techniques have been developed. Hydrophobic Interaction Chromatography
(HIC) is broadly employed for protein purification due to its ability to differentiate proteins not
only by their binding capability but also by their size and shape and total charge as well as the
number of present hydrophobic groups.
62
1.4.2.1 HIGH PERFORMANCE LIQUID CHROMATOGRAPHY AND LIQUID
CHROMATOGRAPHY-MASS SPECTROSCOPY
High performance liquid chromatography (HPLC) uses high pressure (10-400 atm) and therefore
has a fast solvent throughput rate (0.1-5 ml/min).
63
Since a mobile phase makes a column to be
tightly packed, the separation ability increases, leading to a higher analytic efficiency. When
performing reaction monitoring, HPLC analysis as well as NMR is often used to follow the product
conversion in the off-line aliquoted samples (Figure 1.6). However, organic molecules without
UV-active chromophores cannot be detected and measured by HPLC. Thus, GC (gas
chromatography) analysis can be an option here, otherwise manual sample preparation and
acquisition is usually time-consuming and introduces unnecessary errors into the signal
measurements, unless being attached with the liquid handling robotic setup.
64
15
Figure 1.6 Off-line HPLC reaction progress monitoring of the copper(I)-catalyzed azide-1-iodoalkyne
cycloaddition reaction
I
CuAAC (experimental data is derived by author).
This way, automated on-line analysis arrangements, such as HPLC-MS systems, have been
successfully demonstrated to provide in-line reaction kinetics.
65, 66
While previously liquid
chromatography–mass spectrometry (LC-MS) has been quite widespread for the characterization
of small molecules, only recently this dual analysis platform has become available for reaction
monitoring.
The disadvantage of chromatographic systems was mainly the factor of system-dependent
response values for the compounds of the interest. The researcher was required to provide
calibration curves together with the concentration values. Mass spectrometry became a unique
addition as a tandem method of choice since many compounds can be fragmented by a certain
ionization method to become detectable. The group of Hein reported an example of off-line HPLC-
MS-connected sampling instrumentation for probing kinetics of proton/iodine exchange between
terminal acetylenes and 1-iodoalkynes, mediated by copper(I).
43
The group of McIndoe reported
16
the utilization of a push-pull capillary and inert gas to transfer diluted reaction mixtures via HPLC
into the mass-spectrometer (ESI-MS).
67
This technique opened new horizons into the mechanistic
studies while detecting intermediates and other catalytic species forming in low concentration
limits.
1.4.2.2 HEAT-FLOW CALORIMETRY
Heat-flow calorimetry refers to the global parameter measurement technique due to the inability
to measure the separate outcome of each component during the automated kinetic profiling. The
recorded signal is the instantaneously released heat being plotted as a function of time.
68
The
amount of the released heat is considered as the reaction enthalpy and is directly proportional to
the reaction rate together with the volume of the reaction vessel and reaction conversion. While
integrating the rate versus time, one converts differential data (reaction rate) to the integral –
reactant concentration. Presently, commercially available multi-slot heat-flow calorimeters allow
simultaneous heat profiling for up to ten samples. For adiabatic systems, the generated heat is
considered to be entirely detectable in the jacket. The reaction endpoint is related to the time when
the heat curve approaches the zero point and remains constant. However, it is recommended that
a sample aliquot is taken and analyzed by any other available analytical technique to ascertain that
the generated calorific output corresponds to the expected reaction outcome. Since the first report
in 1996 by D. G. Blackmond et al. exemplifying reaction calorimetry as an in situ method for
deriving high-quality kinetic information for multi-step reactions, heat flow data profiling became
a common approach for divergent types of mechanistic elucidations.
69
Advantages of this
technique boosted the development of variable data analysis protocols for determination of
substrate rate orders, catalyst deactivation/robustness experiments and screening of the reaction
conditions. Due to the possibility of high loading reactant, heat flow calorimetry presents real
17
reactant concentration limits out of all the described methods. This makes calorimetry method the
most useful one for methodology development studies in chemical engineering.
68
1.4.3 METHODS OF DATA PROCESSING AND ANALYSIS FOR CHEMICAL
KINETICS INFORMATION.
The known mechanisms of complex organometallic reactions generally involve the same type of
fundamental transformations, yet vary by the reaction rate-determining steps, catalyst resting state
and by the presence of off-cycle processes, inhibiting the overall process. Performing kinetic
studies requires two coherent actions: data collection with appropriate instrumentation (discussed
above) and data processing (to be discussed below).
1.4.3.1 INTEGRAL AND DIFFERENTIAL METHODS IN REACTION PROGRESS
STUDIES
As was pointed out earlier, a variety of automated laboratory tools are available for in situ on-line
monitoring of reaction performance including chromatography, thermal and spectroscopic
techniques. The way one analyzes kinetic data is directly related to the experimental method with
which these data were collected.
68
The instrumental methods which use the species concentration
as the measured parameter (UV-Vis, NMR, FT-IR, fluorescence) are related to the group of integral
methods. In this case, the reaction rate is derived as the first differential of the concentration at a
certain time-step and is considered to be a processed parameter. As an example, NMR
spectroscopic studies show the reactant concentration to be directly proportional to the signal
intensity as a complex function of the chemical shift and time. The rate is calculated by taking a
first derivative of the experimental concentration versus time data. Due to this reverse
manipulation, reaction rate is considered to be a “processed” parameter, whereas concentration is
denoted as a “primary” one. In heat flow calorimetry, differential methods use the derivative
18
experimental data, such as calorific output, and require integration to process concentration or
reaction conversion information. The methods of experimental data fitting with the mathematical
functions are applied to eliminate the influence of the inherent noise during differentiation.
1.4.3.2 PROS AND CONS OF THE DIFFERENTIAL AND INTEGRAL METHODS WITH
DENSE EXPERIMENTAL DATA SETS.
Improvement of a device characteristics together with the analyte sample optimization can
improve the signal to noise ratio of derived raw experimental data. However, some methods lack
the flexibility of external adjustments. NMR spectra are useful for determining reaction kinetics
component-wise. To derive a reliable NMR spectrum in a kinetic run, even with decent
concentration limits, one must manipulate set-up parameters, such as sample loading, appropriate
spectral width, sample volume, and number of scans. Thus, among the frequently employed in situ
profiling methods, NMR analytics is among the most informative ones. Despite the indisputable
advantages of spectroscopic methods (multivariable data set, ability to follow reactants'
independent evolution), these studies require considerable time and resources for obtaining useful
kinetic information, when carrying out quantitative mechanism modelling studies. Integral
methods require noise reduction procedures prior to or during differentiation of measured
concentration profiles. Linear regression analysis employing approximation with a high order
polynomial function assert methods of theory of probability.
70
When approximating with the
polynomial function, the found order must satisfy critical Z-score values of Fischer statistics
(corresponding to a 99% confidence level) for a reliable representation when solving mechanistic
models. Approximation with an exponential function is more relevant for understanding the
chemical nature of a current reaction process, as it gives insights into the internal mechanistic
changes happening during the reaction profile.
71
For the heat flow calorimetric method, reaction
19
rates can be readily calculated from the reaction heat values. However, here we must assert a more
sophisticated mathematical scheme as we are facing the problem of inverse problem in kinetic
analysis when solving a convolution integral.
1.4.4 MODELS OF ENZYME KINETICS: UTILIZATION OF THE MICHAELIS-
MENTEN MODEL IN COMPLEX CATALYTIC REACTIONS
The first mathematical description of the catalytic model was achieved by Michaelis and Menten
in 1913 for the example of a ferment catalyzed reaction. While taking place as a noncyclic process,
the model still sufficiently described basic principles of the kinetic methodology such as substrate
– enzyme changes, rate-determining parameters and reversibility. Presently, the same concepts are
utilized in complex catalytic reaction studies, even though the enzymatic one is just a
generalization of the catalytic cycle. The rate of the enzyme[E] catalysis with the product[P]
formation is dependent on the substrate[S] concentration following the scheme shown in Scheme
1.2:
Scheme 1.2 Catalytic scheme of Michaelis-Menten kinetic model.
The Michaelis-Menten model accounts for the formation of the substrate-enzyme intermediate
complex [ES] which then undergoes a rate-limiting transformation with the generation of product
[P]. An enzyme [E] binds the substrate [S] with the corresponding direct rate constant k1, while
the generated [ES] complex can either release product [P] or dissociate back to the separated
enzyme [E] and substrate [S]. By default, the Michaelis-Menten model considers k2 as the rate-
limiting step and the corresponding process to be non-equilibrium. It was found that depending on
20
the relative values of involved rate parameters, the experimentally derived rate law matched the
calculated value derived with one of two approximate approaches: Steady-State (SS) or Quasi-
Equilibrium (QE).
72
The steady-state approximation is referring to the case of direct rate k1 to be
the slowest: k−1 ≫ k1 and k2 ≫ k1, meaning the disappearance of the intermediate (ES) to be faster
than it’s accumulation.
𝑑 [𝐸𝑆 ]
𝑑𝑡
≅ 0 (1)
When considering the second step to be irreversible and slow, i.e. k1≫ k2 and k−1 ≫ k2, the model
can be approached with Quasi-Equilibrium:
𝑘 1
[𝐸 ][𝑆 ] = 𝑘 −1
[𝐸𝑆 ] (2)
1.4.4.1 STEADY-STATE APPROACH FOR THE MICHAELIS-MENTEN EQUATION
The steady-state approach postulates the rate of consumption of the intermediate species to be
much higher than its accumulation. Thus, assuming that the concentration of the [ES] intermediate
complex changes insignificantly, the corresponding differential rate law is equal to zero:
d[ES]
dt
= k
1
[E][S] − k
−1
[ES] − k
2
[ES] (3)
Following (1):
k
1
[E][S] = (k
−1
+ k
2
)[ES] (4)
Applying the conservation law for the enzyme component:
[E]
o
= [E] + [ES] (5)
Combining (4) and (5):
21
[ES] =
[S][E]
o
k
1
+k
2
k
−1
+[S]
=
[S][E]
o
K
M
+[S]
, where (6)
K
M
is a Michaelis-Menten constant.
As the rate law of the product formation can be denoted as:
d[P]
dt
= k
2
[ES] (7)
The equation (7) for the product formation via Michaelis-Menten constant can be defined:
d[P]
dt
= k
2
[S][E]
o
K
M
+[S]
(8)
The numerical value of the Michaelis-Menten parameter resembles the affinity of the
ferment (catalyst) to a substrate and is a constant property of the enzyme when existing near to the
physiological concentration. The traditional way of evaluation is normally accessed in the frames
of the initial rates, when only up to 20% of the kinetic profile is taken under consideration. This
type of impeded kinetic profiling might lead to misleading information and introduce systematic
errors for poor data representation.
1.4.4.2 QUASI-EQUILIBRIUM APPROACH FOR THE MICHAELIS-MENTEN
EQUATION
The quasi-equilibrium approach results in the forward and backward reactions being referred to as
an equilibrium, when the process of activated complex formation is considered to be completely
reversible. For the Michaelis-Menten kinetics, the rate law can be derived via a quasi-equilibrium
approach as well.
73
From (2):
k
1
[S][E] = k
−1
[ES] (9)
22
When substituting with (5):
[ES] =
[S][E]
o
k
1
k
−1
+[S]
=
[S][E]
o
K
eq.
+[S]
, where (10)
K
eq.
is an equilibrium rate parameter or a dissociation rate constant of the [ES] complex.
Following equation (7) the rate order can be formulated as:
d[P]
dt
= k
2
[S][E]
o
K
eq.
+[S]
(11)
Initially, the kinetic Michaelis-Menten equation was represented in the form of (11). Indeed, when
k1≫ k2 and k−1 ≫ k2 (QE approach), then k2 is considered small and 𝐾 𝑀 =
k
1
+k
2
k
−1
can be simplified
to 𝐾 𝑒𝑞 .
=
k
1
k
−1
.
74
1.4.4.3 QUASI-EQUILIBRIUM APPROACH FOR A GENERALIZED CATALYTIC
CYCLE OF TWO SUBSTRATES WITH TWO INTERMEDIATES
In reality, the general cycle of complex catalytic transformations, which the researcher must work
on under laboratory conditions, consists of one or more off- and in-cycle processes. While most
chemists focus on the isolated yield of a particular reaction, mechanistic investigations can help to
mitigate or take advantage of off-cycle processes to maximize the desired product formation.
Furthermore, identifying optimal conditions is not possible without a complete understanding of
the catalytic speciation evolution and catalyst resting state, and without quantitative information
regarding the reaction progress at each step. Here we demonstrate the common strategy of kinetic
modelling of a certain type of copper(I)-catalyzed reaction of azide-alkyne cycloaddition. The
proposed example was chosen due to its relative complexity yet graphical robustness to guide a
reader into the specification of the catalytic models. Thus, the reaction was assumed to be initiated
23
with the formation of the [A·Cu(I)-L], followed by insertion of the Z component and formation of
the transition state [A·Cu(II)-L·Z], which upon copper(III) reductive oxidation leads to the triazole
formation [P] and CuI-L catalyst regeneration (Scheme 1.3). Further analysis represents a standard
methodology for deriving reaction rate laws in mechanism modelling studies. The following
example is given in the frames of the quasi-equilibrium approach having been discussed above.
The kinetic modelling was built based on the experimental data, which tells whether the system
accumulates the catalyst-containing species, has stable and detectable or highly reactive
intermediates, has catalytic impurities or involves catalyst decomposition or formation of the pre-
catalyst, which results in an initiation period.
Scheme 1.3 Generalized mechanism of a complex catalytic reaction with two substrates and two
intermediates.
Based on the QE assumption, the concentration of the substrate is in an instantaneous equilibrium
with other species of the catalytic cycle:
k
A
[A][cat] = k
−A
[A∙ cat]; (12)
k
−Z
[A∙ cat∙ Z] = k
Z
[A∙ cat][Z]; (13)
24
Following the conservation law:
[cat] = [cat]
0
− [A∙ cat] − [A∙ cat∙ Z]; (14)
Deriving intermediate concentration from (13):
[A∙ cat] =
k
−Z
[A∙cat∙Z]
k
Z
[Z]
; (15)
Introducing (15) to (14) with the following derivatization of (12):
k
A
[A]([cat]
0
−
k
−Z
[A∙cat∙Z]
k
Z
[Z]
− [A∙ cat∙ Z]) = k
−A
k
−Z
[A∙cat∙Z]
k
Z
[Z]
; (16)
In accordance with (7), the rate of the reaction can be derived:
d[P]
dt
= k
2
[A∙ cat∙ Z] =
k
2
k
A
[A][cat]
0
k
A
[A]k
−Z
k
Z
[Z]
+k
A
[A]+
k
−A
k
−Z
k
Z
[Z]
; (17)
Upon the simplification of (17):
d[P]
dt
= k
2
[A∙ cat∙ Z] =
k
2
k
A
k
Z
[Z][A][cat]
0
k
A
[A]k
−Z
+k
A
[A]k
Z
[Z]+k
−A
k
−Z
; (18)
When employing the equilibrium constants for the formation of the [A·cat] and [A·cat·Z]
complexes, (K
A
=
k
A
k
−A
and K
Z
=
k
Z
k
−Z
), the reaction rate in the quasi-equilibrium approximation
can be calculated as (19):
d[P]
dt
= k
2
[A∙ cat∙ Z] =
k
2
K
A
K
Z
[Z][A][cat]
0
K
A
[A]+K
A
[A]K
Z
[Z]+1
; (19)
The novel mechanistic insights can be extracted from the experimental data once tested with the
mathematically derived rate laws. Thus, the current approach is a probe to test if a specific reaction
has a catalyst resting state shift. For the calculated values of KA, the equilibrium rates are
25
significantly larger than the KZ one. Then equation (19) can be simplified to support the
assumption of first order kinetics (for the regime of low conversion, when the corresponding
concentration of [A] is still high enough to be cancelled out):
d[P]
dt
= k
2
K
Z
[Z][cat]
o
= k
obs
[Z] (20)
The ultimate goal of a chemical engineer is to develop or optimize a process to follow fast, first-
order kinetics. The rule of thumb for a catalytic process in this case is to remain in the regime of
first-order rates as long as possible, as the appearance of the denominator reduces the rate functions
by an order of a magnitude.
75
1.4.5 VISUAL KINETIC ANALYSIS (VKA) METHODS FOR REACTION
PROGRESS PROFILING
The level of the experimental data interrogation during a kinetic analysis directly depends on the
complexity of the system, the depth of the investigating problem, and the quality and the quantity
of the experimental data. Graphical approaches in kinetic data analysis allow access to the
experimental data and mathematical manipulations to fully reveal the mechanistic story of a
catalytic system. Reaction Progress Kinetic Analysis (RPKA)
68
and Variable Time Normalization
Analysis (VTNA)
76
remain the most common graphical approaches of Visual Kinetic Analysis
(VKA).
77
They allow a simplified interrogation of the kinetic data, following a qualitative and
quantitative assessment of the reaction mechanism model. While employing different strategies
for graphical data overlaying, both methods identify catalytic system robustness as well as the
reaction order for any reactant.
26
1.4.5.1 REACTION PROGRESS KINETIC ANALYSIS (RPKA)
The key to the robustness and low time requirement of RPKA, compared to the classical kinetic
approach of initial rate studies, lies in the unique ability to provide information when inspecting
kinetic graphs in the “reaction coordinate” mode. Reaction progress kinetic analysis was developed
to simplify the access to dense data and the corresponding rate law.
68
Although Blackmond’s
approach originated as a training set for the calorific output of the differential measurements,
RPKA can be applied to streamlined spectroscopic and chromatographic experiments. The basic
principle of RPKA analysis consists of extracting the maximum information from a minimum
number of experiments. Thus, classical kinetics necessitates multiple repetitive experiments,
whereas for the RPKA approach one needs to perform only a couple “excess” experiments to
develop a quantitative kinetic model. The “excess” kinetics cut down the analysis to only one
dependent (typically concentration) parameter, while leaving the other ones constant.
78
Particularly in organocatalysis, the RPKA approach allows to monitor the progression of the entire
reaction over time, the detection of concentration changes of certain catalytic species and their role
in the catalytic cycle, as well as the changes in the mechanism or formation of the by-products.
The graphical illustration of employed protocols allows a visual analysis which does not require
knowledge of an advanced mathematical and statistical knowledge.
However, the use of visual techniques for predicting the extent of graphical overlapping,
coincidences, etc. does not allow complete quantitative modelling and is limited to only degenerate
substrate and catalyst rate orders.
27
1.4.5.2 VARIABLE TIME NORMALIZATION ANALYSIS (VTNA)
Another modern kinetic data analysis method employing naked-eye capability to capture patterns
of the graphically plotted profiles is a variable time normalization analysis (VTNA). The method
was first reported by J. Burés and can be used to determine the kinetic order of any component in
the reaction.
76
The analysis uses the normalized time scale of the substrate concentration raised to
a certain power (the rate order) versus the concentration of another reactant. The disadvantage of
this method is the lack of high precision. Thus, it usually gives the range of orders satisfying the
overlapping of the normalized reaction concentration profiles and makes it impossible to measure
the standard deviation error. Furthermore, the method was initially tested on computationally
simulated data for a relatively straightforward, one-substrate, catalytic system. Real high-dense
experimental data processing might be a daunting task, as it would require prior denoising and
other data treatment procedures.
28
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33
C H A P T E R II
34
2 MECHANISTIC AND KINETIC INVESTIGATION OF 1-IODOARYL
ALKYNES WITH ORGANIC AZIDES IN THE COPPER (I)-
CATALYZED CYCLOADDITION REACTION
2.1 INTRODUCTION INTO METHODS OF KINETIC STUDIES OF COMPLEX
CATALYTIC REACTIONS
Complex multi-step catalytic reactions represent a major class of synthetic and biological
transformations where the determination of intermolecular interactions remains challenging and
sometimes impossible to elucidate.
1-3
This problem is caused mostly by the complexity of the
catalytic models typically involving two or more substrates and intermediate species. Mechanistic
investigations in homogeneous or heterogeneous conditions are usually carried out in a qualitative
rather than quantitative manner, employing visual analysis when examining whether derived
kinetic functions graphically overlay.
4-7
When quantitation is desired, the computation of the key
rate constants and parameters is frequently restricted to quasi-equilibrium (QE) or steady-state
(SS) assumptions to simplify the problem solution.
8
The use of the quasi-equilibrium approach
allows to compute the reaction rate law which captures the patterns of the catalytic mechanism
only in terms of equilibria constants. On the other hand, the steady-state approach restricts
determination of the reaction rate by forcing the changes in the formation of the intermediates to
be inherently negligible, thus also minimizing the possible number of computed rate parameters
determining the catalytic reactivity. The rate of formation of the catalytically active species for
both QE and SS approaches is assumed to be constant or negligibly small, thus resulting in their
elimination from the set of involved rate equations. Withdrawal of the computed “variables”, rate
parameters, inevitably results either in the loss of or false information when probing an “equation”
35
of the chemical bonding interactions – catalytic cycle. Therefore, the nature of the processes
involved in the formation of the intermediates or catalytic inner-cycle interactions are ignored or,
in the best case, survive in the form of an unsupported hypothesis. The earliest attempts of using
approach-free or deterministic kinetic studies have been reported when examining the intermediate
formation in the reduction of chromium (VI) by glutathione (GSH). The mechanism was
investigated neither in a steady-state nor in equilibrium, with the initial constants deduced by a
matrix formulation.
9, 10
Reaction rate parameters corresponding to the Michaelis Menten type of
enzyme-substrate complex formation and decomposition were derived computationally from the
spectrophotometrically obtained concentration versus time assays. Other approaches, such as
matrix representation, were also applied to reduce the complexity. However, while the square
coefficient matrix approach is unable to fully characterize a complex chemical process, this
formalistic method can introduce additional complications.
11
Therefore, novel, robust methods are
needed for the mechanistic quantification of the detailed catalytic reaction models, which are
capable of complexity reduction without important data loss.
12
In our study, the mechanism of the
copper(I)-catalyzed azide-1-iodoalkyne cycloaddition reaction (
I
CuAAC) was modeled in the
form of ordinary differential equations denoting independent substrate rate profiles, and solved
numerically using the classic Runge-Kutta iterative method (Figure 2.4).
13
The
I
CuAAC example
of a two-substrate two-intermediate catalytic reaction highlights the case where the calculation of
the entire set of rate parameters reveals the key interactions responsible for the observed reactivity
which otherwise is not obtainable with steady-state or quasi-equilibrium assumptions. In this case,
modelling of all elementary stages of the emerged mechanistic profile was performed via the grid
search among all possible yet chemically sensible values of kinetic parameters. Upon gradient
36
refinement the direct solution was required to satisfy the minimum criteria of experimental and
calculated data juxtaposition in the metrics of the least squares’ sums (LSM).
In this chapter, the inverse problem in chemical kinetics was solved with the method of quasi-
solutions when performing
I
CuAAC reaction mechanism modelling studies.
14
More detailed
discussion regarding inverse problems, particularly ill-posed ones, is presented in Chapter V .
15
Scheme 2.1 Copper(I)-catalyzed azide-1-Iodoalkyne cycloaddition reaction (
I
CuAAC). Previous and
current studies.
37
2.2 GLOBAL HEAT AND SPECTROSCOPIC METHODS: PRELIMINARY
STUDIES OF THE
I
CUAAC REACTION MECHANISM
Previously reported mechanistic studies of 1-iodoalkyne type of CuAAC reactions, did not
elucidate the evolution of the catalytic species within the catalytic cycle, nor the nature of the
Cu(I)-iodoalkyne π-complex formation (Scheme 2.1).
To develop a quantitative mechanistic model of the
I
CuAAC reaction, the panel of the
electronically diverse 1-iodoalkyne substrates was synthesized and introduced into the
cycloaddition reaction following kinetic study protocols. To elucidate possible inner cycle
deactivation processes or get insights into intermediate kinetics over the course of a catalytic
reaction, instantaneous changes in the transformation progress were monitored by means of in situ
heat flow calorimetry and
1
H NMR spectroscopic techniques. The protocol of a standard progress
kinetic analysis (RPKA) was employed to extract preliminary mechanistic fingerprints, detectable
visually upon graphical manipulations (Scheme 2.2).
4, 5, 16, 17, 18
38
Scheme 2.2 Copper(I)-catalyzed cycloadditions of 1-iodoalkynes[X] to Azide[Z] catalyzed by CuI-TTTA,
CuI-TBTA or CuI-TCPTA catalytic systems.
As illustrated in Figure 2.1(A), results of “same excess” cycloaddition experiments exhibited no
inhibition as the outcome of both kinetic profiles were matched. However, here we observed that
the rate profile of 5-iodotriazole formation possesses dual behavior, approaching almost zero-
kinetics at higher conversions. When examining the robustness of the copper(I) iodide- tris-((1-
cyclopentyl-1H-1,2,3- triazol-4-yl)methyl)amine catalytic system (CuI-TCPTA), the data in
Figure 2.1 (B) revealed only a slight difference between the reaction rate functions corresponding
to 5.0 mM (grey) and 7.5 mM (black) of initial copper(I) catalyst concentrations.
39
Furthermore, upon comparison of two concentration-adjusted kinetic trials with and without
addition of the reaction product in the beginning of the reaction, no significant changes in reactivity
were detected Figure 2.1 C. Concentration-dependent reaction rate profiles, derived from the heat
flow calorimetry studies, resulted in a pair of linear curves as a reliable approximate fit (Figure
Figure 2.1 Graphical representations of the variable-conditions kinetic profiles of the
I
CuAAC reactions
derived with differential and integral methods.
1
H NMR kinetics. (A) Same excess protocol; Conditions:
A[3]=0.075M; [Z]=0.105 M; 8.75 mM cat[2] (red line); A[3]=0.10 M; [Z]=0.13 M; 8.75 mM cat[2] (black
line); 0.8 ml of THF-d8, 35 °C; (B) Reaction rate vs A [4]; Conditions: 0.1 M A [4]; 0.13 M [Z] ; 0.8 ml
of THF-d8, 28.7 °C, using 5mM (grey line) and 7.5mM (black line) of cat[1]; Heat Flow Calorimetry. (C)
Catalyst stability experiment. Conditions: 0.10 M A[4], 0.10 M P[4] (grey) or 0.10 M A[4] (black); 0.11
M [Z], 10 mol % cat[2]; (D) Non-time dependent instantaneous rates vs conversion for A [5] and A [4]
substrates. First kinetic regime (blue), second kinetic regime (red). Conditions: 0.1 M A[5] (grey) or 0.10
M A[4] (black); 0.11 M [Z], 10 mol % cat[2].
40
2.1 D). For reactions performed under identical conditions, such dual kinetic behavior likely
implies changes in substrate rate orders or changes in the turnover-limiting step. Without the
existence of confirmed inhibition processes, changes in the catalyst resting state or in the order of
the kinetic behavior were proposed as an explanation for the dual kinetic behavior. For the
completeness of the preliminary kinetic studies and further elucidation of the two graphically
expressed characteristic regions of the rate profile, variable “excess” experiments were performed
(Figure A.2 and Figure A.4). A plot of [Z] concentrations as natural logarithm versus rates
resulted in a straight line with a slope value of 1.3, revealing near to first order kinetics in azide
substrate.
2.3 IN SITU
1
H NMR REACTION MONITORING
Spectroscopic and especially spectrophotometric methods are considered to be the most efficient
analytical techniques for monitoring the reaction progress as they simultaneously provide both
structural and quantitative information regarding reactants, products and intermediate species
present in the reaction media.
19, 20
In our study,
1
H NMR spectroscopy was used as a control tool
for the continuous integration of distinctive changes of both reactants – alkyne[X] and azide[Z]
and the corresponding 5-iodotriazole product P[X] throughout the
I
CuAAC course of
cycloaddition (Figure 2.2).
41
Figure 2.2 Graphical representations of the kinetic profiles of the independent
I
CuAAC reactions derived
via real time
1
H NMR spectroscopy. Reaction conversion versus time.
An independent reactivity protocol revealed electron-withdrawing groups to increase the rate of 5-
iodo-1,2,3-triazole formation, while electron-donating groups were slowing down the reaction.
Hammett equation supported the linear free-energy correlation of the para-substituents in the
aromatic ring of the iodoalkyne substrates with the corresponding reactivity, providing a
qualitative explanation for electron-withdrawing groups to stabilize the negative charge on the
reaction transition state (refers by default to the transition state preceding the rate-determining
step) (Figure 2.3). In view of the previous data for the further characterization of the mechanistic
model, the following questions needed to be answered:
42
1) What is the reason for the observed drastic difference in substrate reactivity? In other
words, why does a trifluoro-substituted alkyne A[5] exhibit an almost 8–10 times higher
reactivity (in terms of time), whereas electron-donating and electron-neutral
functionalities exhibit nearly identical rates?
2) What is the nature of the coexistence of two kinetic regimes or dual kinetic behavior?
Does the mechanism change or is it just a shift in the rate-determining step?
To adequately answer these questions, an accurate quantitative analysis was required.
2.4 DETERMINISTIC APPROACH TO THE STAGED KINETIC MODEL
REPRESENTATION
Classic mechanistic modelling strategies for homogeneous catalytic systems imply unambiguity
in the rate-controlling processes as well as in component rate orders. When performing in-depth
mechanistic studies, these assumptions can potentially lead to misconceptions in the interpretation
of observed reactivity trends. The problem becomes even more controversial when applying model
Figure 2.3 The Hammett plot derived from the
1
H NMR kinetic experiment. Apparent rate constants were
normalized regarding the electron-neutral (iodoethynyl)benzene substrate. A free energy relationship
exhibited a linear trend with a scope of ρ = 1.34 (0.13).
43
reduction methods of the quasi-equilibrium approximation QE or steady-state SS.
21
Since the
reaction rate is a function of multiple parameters, a direct (assumption-free) mechanistic analysis
would allow accurate and reliable accounting of all factors that influence the evolution of the rate-
determining changes throughout the course of the reaction. By direct analysis one implies
subsuming concentration variations of all involved catalytic species and reactants. For the purpose
of the direct and reverse rate constants elucidation and their impact on the equilibrium processes,
a set of ordinary differential equations (ODEs) was compiled to solve the mechanistic model of
the
I
CuAAC reaction:
𝑑 [𝐴 ]
𝑑𝑡
= −𝑘 𝑎 [𝐴 ][𝑐𝑎𝑡 ] + 𝑘 −𝑎 [𝐴 ∙ 𝑐𝑎𝑡 ]; (1)
𝑑 [𝑍 ]
𝑑 𝑡 = 𝑘 −𝑧 [𝐴 ∙ 𝑐𝑎𝑡 ∙ 𝑍 ] − 𝑘 𝑧 [𝐴 ∙ 𝑐𝑎𝑡 ][𝑍 ]; (2)
𝑑 [𝑃 ]
𝑑𝑡
= 𝑘 2
[𝐴 ∙ 𝑐𝑎𝑡 ∙ 𝑍 ], (3)
where [X] is an instantaneous concentration, kx – the forward rate constant, and k-x – the reverse
rate constant.
Considering the mass law formulation of active species, the ODEs set can be expressed by the
following expressions:
𝑑 [𝐴 ]
𝑑𝑡
= −𝑘 𝑎 [𝐴 ]([𝑃 ] + [𝐴 ] + 𝑐𝑜𝑛𝑠𝑡 1
)+ 𝑘 −𝑎 (−[𝐴 ] + [𝑍 ] + 𝑐𝑜𝑛𝑠𝑡 0
) (4)
𝑑 [𝑍 ]
𝑑𝑡
= −𝑘 𝑧 (−[𝐴 ] + [𝑍 ] + 𝑐𝑜𝑛𝑠𝑡 0
)[𝑍 ] + 𝑘 −𝑧 (−[𝑃 ] − [𝑍 ] + 𝑐𝑜𝑛𝑠𝑡 2
) (5)
𝑑 [𝑃 ]
𝑑𝑡
= 𝑘 2
(−[𝑃 ] − [𝑍 ] + 𝑐𝑜𝑛𝑠𝑡 2
), (6)
where 𝑐𝑜𝑛𝑠𝑡 0
= [𝐴 ]
0
− [𝑍 ]
0
; 𝑐𝑜𝑛𝑠𝑡 1
= −0.9[𝐴 ]
0
; 𝑐𝑜𝑛𝑠𝑡 2
= [𝑍 ]
0
(7)
44
The current set of substrate independent routes represents a methodology of kinetic data analysis,
where the reactivity of the complex transformation system can be expressed via a number of
substantially simplified routes (non-linear parametrized functions).
2.5 KINETIC MODEL PARAMETERS ESTIMATION FROM THE
EXPERIMENTAL DATA
As mentioned previously, the profiles of experimentally derived concentration versus time for the
semi-batch experiments can be construed in form of a system of ordinary differential equations
(ODEs). In the developed approach, differential equations (4)-(6) were solved with the initial
conditions as given by eq. (7) and by the use of a hybrid optimization coarse grid search algorithm
following the local gradient refinement on the basis of a fourth order classical Runge-Kutta
iterative method (Figure 2.4).
Figure 2.4 Experimental data analysis algorithm using numerical methods of statistical data processing.
The reliable solution of the unknown kinetic parameters was found in the metrics of the LMS
optimization. The theoretically estimated concentrations were found to be in exact agreement with
the experimental values of the [A], [Z] and [P] profiles until 100% conversion (Figure 2.5). The
45
developed approach enabled the determination of a unique and unambiguous solution on the basis
of data-dense experimental sets of concentration data. The numerical trend of the computed rate
constants for the entire experimental batch of five different iodoalkyne substrates revealed a direct
correlation with the electronic nature of the emerged substrates (Table 2.1).
Table 2.1 Rate constants derived from the
1
H NMR kinetic measurements corresponding to the independent
reactivity kinetic profiles. Deterministic method of kinetic analysis.
a
a
0.8 ml volume; THF-d8, 0.10M A[X], 0.13 M [Z], 10 mol % cat[1], 28.7 °C.
b
KA=kA/k-A; KZ=kZ/k-Z – equilibrium constants.
The investigation of the observed reactivity throughout the entire selection of studied iodoakyne
partners was performed within the frames of the equilibrium rate constants. The π-intermediate
formation equilibrium rate constant KA demonstrated that the breakdown of the [A·cat] complex
is prevalent over the formation for electron-rich 1-iodoalkynes. However, for electron-deficient
A[4] and A[5] substrates the rate of a π-intermediate formation strongly favored a direct reaction,
with the corresponding equilibrium rate constant KA to be 17 (for Cl-substituted iodolkyne A[4])
and 77 times (for CF3-functionalysed iodolkyne A[5]) higher than the one of electron rich
iodoalkynes. This indicates the electron-donating functionality of the corresponding iodoalkyne to
increasing reactivity
[1] [2] [3] [4] [5]
kA, M
-1
sec
-1
1.00 1.00 1.50 5.01 5.16
k-A, sec
-1
5.50 5.50 5.50 1.50 0.33
KA
b
, M
-1
0.18 0.18 0.27 3.37 15.54
kZ, M
-1
sec
-1
1.01 1.50 1.50 4.00 5.35
k-Z, sec
-1
1.01 1.00 2.00 2.98 4.33
KZ
b
, M
-1
1.00 1.50 0.75 1.34 1.24
k2, sec
-1
4.51 4.50 4.50 0.54 0.38
46
be undesirable for the π-coordination with copper(I). Furthermore, the rate constant k2 was almost
identical for the electron-rich and neutral iodoalkynes A[1–3], while it decreases almost nine-fold
for the electron-deficient substrates A[4] and A[5]. Since the π-intermediate forming equilibrium
rate KA for alkyne [5] and [4] is significantly higher than for the substrates A[1–3], the formation
of the [A·cat] species is, presumably, a turnover-limiting step for electron-rich iodoalkynes with
the free catalyst serving as the resting state. Whereas, the k2 rate constant reveals to be rate-limiting
for electron-deficient alkynes A[4] and A[5]. When considering, that azide ligation and migratory
insertion are possibly merged events
22
, the catalyst resting state can be considered to be spread
between the [A·cat] and [A·cat·Z] catalytic species for the electron-deficient aryl iodoalkynes A[4]
and A[5].
Previously, Watson et al. have reported that the rate-determining step in the parent CuAAC to
depend on the alkyne functionality subtype.
22
Moreover, the same pattern of a substrate-dependent,
rate-determining step was previously also found in enzyme-catalyzed reactions.
23-25
Similarly,
upon examination of the reaction progress data, we detected the rate-determining step changes to
depend on the electronic nature of the iodoalkyne substrates (Scheme 2.3).
47
Figure 2.5 Results of the proposed deterministic approach for
I
CuAAC mechanism modelling. Comparison
of experimental and predicted concentration-time profiles. The set of rate parameters was considered to be
accurate, once the experimental values of the reactant concentrations vs time were in exact agreement with
the computed ones derived with the classic Runge-Kutta method. Conditions: 0.10 M A [4]; 0.122 M [Z];
10 mol % CuI-TCPTA; 0.8 ml of THF-d8, 28.7 °C.
Scheme 2.3 Proposed mechanism of the
I
CuAAC reaction with evaluated rate-determining step changes.
48
2.6 DETERMINISTIC REACTION PROGRESS ANALYSIS
In addition to the estimation of the reaction rate parameters, the developed computational
modelling approach was also used for the prediction of the evolution of the catalytic intermediates,
particularly their quantitative changes over the course of the reaction. The independently integrated
concentration changes of both the azide [Z] and 1-iodo-alkyne A[X] reactants in the NMR kinetic
studies, demonstrated a certain non-constant delay while being represented in the same time-
dependent fashion. Changes in concentration of both, azide [Z] and 1-iodo-alkyne A[X],
components were integrated independently. In the set of equations (4), (5) and (6) (the use of the
computed substrate concentrations is required due to the impact of the instrumental noise), the
difference between substrate concentrations indirectly determines the evolution of the intermediate
[A·cat] and catalyst [cat] evolution and is shown in Figure 2.6 (A)
13
:
[𝐴 ·𝑐𝑎𝑡 ] = −[𝐴 ] + [𝑍 ] + 𝑐𝑜𝑛𝑠𝑡 0
(7)
[𝐴 ·𝑐𝑎𝑡 ·𝑍 ] = −[𝑃 ] − [𝑍 ] + 𝑐𝑜𝑛𝑠𝑡 2
(8)
[𝑐𝑎𝑡 ] = [𝐴 ] + [𝑃 ] + 𝑐𝑜𝑛𝑠𝑡 1
(9)
The implementation of numerical methods to solve the ODEs allows a discrete minimization which
enables kinetic monitoring the reaction from the start. The time required to reach the maximum
concentration of an intermediate [A·cat] was found to directly coincide with the electronic
functionality of the corresponding 1-iodoalkynes. Thus, a “saddle point” of expression [7] tends
to be delayed for electron-deficient substrates, rather than for electron-rich ones. Indeed, in
comparison with the unsubstituted 1-iodophenylacetylene A[3], the generation of maximum
concentration of the [A[1]·cat] intermediate π-complexes resulted in a shorter interim period
49
(Figure A.12). The prolonged times of the intermediate accumulation-consumption periods for
electron-deficient substrates could be explained by a careful examination of the numerical values
of the calculated equilibrium rate constants (Table 2.1). The larger the equilibrium rate of the π-
intermediate generation, the longer it was required to reach the maximum concentration of [A·cat].
Figure 2.6 Plots of catalytically active species [A·cat], [A·cat·Z], [cat] during the course of the reaction.
The continuous concentration curves were calculated using the set of derived rate constants (Table 2.1). A)
Advantages of the deterministic approach in kinetic studies; B) Evolution profiles of involved the key
catalytic species.
50
In this way, the developed deterministic kinetic approach was successfully applied when detecting
dynamic changes in kinetic profile and understanding the
I
CuAAC mechanism on a molecular
level. The inability of unambiguously superimposing the computationally obtained evolutions of
the catalyst and the intermediates with the unprocessed experimental data is caused primarily by
instrumental noise and, maybe, by the roughness of the mathematical model representation for low
reactivity substrates (Figures A.11 and A.13).
2.7 RELATIVE ENERGY STUDIES: EYRING EQUATION
While being the central theorem of the transition state theory (TST), the Eyring equation
determines thermodynamic and kinetic parameters of an activated complex.
26
As described, the
complex catalytic
I
CuAAC reaction involves numerous key catalytic intermediates. We used the
Eyring plot to elucidate the reactivity parameters for the first transition state (TS
ǂ
), which forms
prior to the [A·cat] intermediate complex. Previous developments in the area of estimating entropy
∆S
ǂ
and enthalpy ∆H
ǂ
parameters were given by S. Benson in 1976.
27
Reaction coordinates were
shown to be directly dependent of the natural logarithm of the constant of first TS
ǂ
formation versus
inverse temperature to achieve a linear fit:
𝑙𝑛
𝑘 𝑇 = −
∆𝐻 ǂ
𝑅 1
𝑇 𝑙𝑛
𝑘 𝐵 ℎ
+
∆𝑆 ǂ
𝑅 , (10)
where ∆𝐻 ǂ
and ∆𝑆 ǂ
were the activation complex enthalpy and entropy correspondingly;
R = 8.3144598 J/K·mol; 𝑘 𝐵 = 1.38064852·10
−23
J/K; h = 6.62607004·10
−34
J·s.
51
Figure 2.7 (A) Calculation of the activation parameters for the electron-rich 1-iodo-alkyne[1] (initial rates):
∆H
ǂ
=3.2 (0.9) kcal/mol and ∆S
ǂ
= -70.0 (3.1) cal/mol·K; (B) Calculation of activation parameters for
electron-deficient 1-iodo-alkyne [4] (initial rates): ∆H
ǂ
=5.8 (1.1) kcal/mol and ∆S
ǂ
= -58.1 (0.2) cal/mol·K.
Table 2.2 Activation parameters determined by variable temperature (VT) 1H NMR kinetic studies. The
apparent rate constant was derived at temperature ranges 0–40 ℃ for A[1] and 10–50 ℃ for A[4].
Alkyne
∆G
ǂ
exp, 25℃
(kcal/mol)
∆H
ǂ
exp, 25℃
(kcal/mol)
∆S
ǂ
exp, 25 ℃
(cal/mol/K)
A[1] 24.1 (1.3) 3.2 (0.9) -70.0 (3.1)
A[4] 23.0 (1.1) 5.8 (1.1) -58.1 (0.2)
An alternate derivation of the Eyring equation as Rln(k/T)-Rln(h/kB) versus 1000/T allows the
straightforward calculation of the key activation rate parameters (Figure 2.7). As such, the slope
is now considered to be directly proportional to the enthalpy of activation and the y-intercept
determines the entropy of the activated complex. Based on the obtained values of the
thermodynamic parameters, presumably σ-donation from the π-bonding orbital of the triple bond
to copper(I) in cooperation with the back bonding from the d-filled orbital of copper species to the
52
π* of acetylenic moiety is more favorable in the case of substrates possessing electron-poor
functionalities.
2.8 TRIS(TRIAZOLYL)AMINE LIGANDS SCREENING
Up to date, numerous different types of copper(I) coordinating ligands have been reported to
increase the rates of the CuAAC cycloaddition, yet no detailed kinetic analysis has been shown.
Therefore, we studied the steric effect of various tris(triazolyl)amine ligands on the exhibited
catalytic reactivity in the
I
CuAAC reaction (Figure 2.8).
Figure 2.8 Various catalytic systems experiment. Graphical representations of the kinetic profiles of the
I
CuAAC reactions catalyzed by CuI-TCPTA/TTTA/TBTA systems obtained by real time
1
H NMR
spectroscopy. Conditions: 0.10 M A [4]; 0.13 M [Z]; 10 mol % CuI-TCPTA (blue); 10 mol % CuI-TBTA
(purple); 10 mol % CuI-TCPTA (red); 0.8 ml of THF-d8, 28.7 °C.
53
In 2009, J. Hein et al. demonstrated a direct correlation of the Lewis base complexes with the
observed reaction rates and chemoselectivity of copper(I)-catalyzed azide-iodoalkyne
cycloaddition.
28
Thus, the overall yields of the 5-iodo-1,2,3-triazole were significantly increased
when exposed to almost two equivalents of tertiary amine ligands, becoming to almost quantitative
when switched to the triazolyl-amine ones.
29
Para-substituted (iodoethynyl)benzene derivatives
have been demonstrated to exhibit noncovalent halogen bonding(XB) interaction with potential
XB acceptors, such as pyridine and triethylamine.
30
Computational simulations supported the
“sigma-hole” assumption for the partial positive charge forming on large and soft iodine atom in
a iodoalkyne structure
31
which boosts simultaneous activation with a π- fashion (via the copper(I)
species) and a σ-fashion (via N3 of the triazole moiety with iodine).
32
For (benzyl-substituted
triazolyl) - TBTA, halogen bonding between iodoalkynes and tris(triazolyl)amine (N(sp
2
)
triazolide long pair was stronger and not sterically hindered, as it is the case for the
tris(cyclopropyl-) TCPTA and tris(tert-butyl-) substituted TTTA analogs of triazolyl(amine).
Possibly, this favors formation of the off-cycle oligomeric species, slowing down the overall rate
of the reaction with the CuI-TBTA system.
2.9 LIMITING CONDITIONS FOR THE NUMERICAL ESTIMATION OF THE
REACTION RATE PARAMETERS
As mentioned earlier, calculation of the reaction rate constants (parameters of the system of ODEs
depicting the mechanistic model) was performed with the grid search algorithm. Prior to that, the
rough estimation of the kA, k-A, kz, k-z and k2 values was performed to evaluate the limitations of
the grid search protocol. The deviation of the roughly estimated values from the real ones was
influenced by several factors, including instrumental noise and computational errors associated
with the nonoptimal discrete time step.
33
Thus, a rough estimation of the direct constant kA of
54
[A·cat] intermediate formation can be determined by using eq. (1). For the initial time t=0 the
expression (1) can be transformed to eq. (12):
(
𝑑 [𝐴 ]
𝑑𝑡
)
𝑡 0
= −𝑘 𝐴 [𝐴 ]
𝑡 0
([𝑃 ]
𝑡 0
+ [𝐴 ]
𝑡 0
+ 𝑐𝑜𝑛𝑠𝑡 1
)+ 𝑘 −𝐴 (−[𝐴 ]
𝑡 0
+ [𝑍 ]
𝑡 0
+ 𝑐𝑜𝑛𝑠𝑡 0
), (12)
where 𝑐𝑜𝑛𝑠𝑡 1
= [𝑐𝑎𝑡 ]
𝑡 0
− [𝐴 ]
𝑡 0
; 𝑐𝑜𝑛𝑠𝑡 0
= [𝐴 ]
𝑡 0
− [𝑍 ]
𝑡 0
From the other side, (
𝑑 [𝐴 ]
𝑑𝑡
)
𝑡 0
=
[𝐴 ]
𝑡 1
−[𝐴 ]
𝑡 0
𝑡 1
−𝑡 2
, (13)
where [𝐴 ]
𝑡 1
is identified as next experimentally derived concentration value and 𝑡 1
is the time step
corresponding to it. Simplifying the right section of eq. (12):
(
𝑑 [𝐴 ]
𝑑𝑡
)
𝑡 0
= −𝑘 𝐴 [𝐴 ]
𝑡 0
([𝑐𝑎𝑡 ]
𝑡 0
) (14)
This way, the rough estimate of the direct rate of the π-complex formation would be represented
by (15):
𝑘 𝐴 = −(
𝑑 [𝐴 ]
𝑑𝑡
)
𝑡 0
/([𝐴 ]
𝑡 0
∙ [𝑐𝑎𝑡 ]
𝑡 0
(15)
Employing 2
dn
and 3
rd
order derivative functions, the rest of the reaction rate parameters could be
estimated taking into account other ODEs expressions:
𝑘 −𝐴 =
(
𝑑 2
[𝐴 ]
𝑑 𝑡 2
)
𝑡 0
+𝑘 𝐴 ∙(
𝑑 [𝐴 ]
𝑑𝑡
)
𝑡 0
∙[𝑐𝑎𝑡 ]
𝑜 +𝑘 𝐴 ∙[𝐴 ]
𝑡 0
∙(
𝑑 [𝐴 ]
𝑑𝑡
)
𝑡 0
((
𝑑 [𝐴 ]
𝑑𝑡
)
𝑡 0
∙[𝑍 ]
𝑡 0
)
;
𝑘 𝑍 = −
(−
𝑑 2
[𝑍 ]
𝑑 𝑡 2
)
𝑡 0
((
𝑑 [𝐴 ]
𝑑𝑡
)
𝑡 0
∙[𝑍 ]
𝑡 0
)
;
55
𝑘 −𝑍 =
(
𝑑 3
[𝑍 ]
𝑑 𝑡 3
)
𝑡 0
+𝑘 𝑍 ∙((−
𝑑 2
[𝐴 ]
𝑑 2
𝑡 )
𝑡 0
+(
𝑑 2
[𝑍 ]
𝑑 2
𝑡 )
𝑡 0
)∙[𝑍 ]
𝑡 0
(−(
𝑑 2
[𝑍 ]
𝑑 𝑡 2
)
𝑡 0
)
;
𝑘 2
=
(
𝑑 3
[𝑃 ]
𝑑 𝑡 3
)
𝑡 0
𝑘 𝑍 ∙(
𝑑 [𝐴 ]
𝑑𝑡
)
𝑡 0
·[𝑍 ]
𝑡 0
.
Following another alternative, the estimation of the k2, kz, k-z, k-A rate parameters can be
accomplished autonomously, employing metrics of the least squares sum in the frames of the
integrated representations in the reactants kinetic equations:
∑ ([𝐴 ]
𝑒𝑥𝑝 − [𝐴 ]
𝑡 ℎ𝑒𝑜𝑟 )
2
→ 𝑚𝑖𝑛 𝑛 𝑖 =1
(16)
∑ ([𝑍 ]
𝑒𝑥𝑝 − [𝑍 ]
𝑡 ℎ𝑒 𝑜 𝑟 )
2
→ 𝑚𝑖𝑛 𝑛 𝑖 =1
(17)
∑ ([𝑃 ]
𝑒𝑥𝑝 − [𝑃 ]
𝑡 ℎ𝑒𝑜𝑟 )
2
→ 𝑚𝑖𝑛 𝑛 𝑖 =1
(18)
Thus, the optimized values of the unknown constants were computed to satisfy the following
minimization criteria:
∑ ([𝐴 ]
𝑒𝑥𝑝 − ∫ (−𝑘 𝐴 ([𝑃 ]
𝑖 + [𝐴 ]
𝑖 + 𝑐𝑜𝑛𝑠𝑡 1
)[𝐴 ]
𝑖 + 𝑘 −𝐴 ([𝑍 ]
𝑖 − [𝐴 ]
𝑖 + 𝑐𝑜𝑛𝑠𝑡 0
))
𝑛 𝑖 =1
)
2
→ 𝑚𝑖𝑛 𝑛 𝑖 =1
(19)
∑ ([𝐴 ]
𝑒𝑥𝑝 − ∫ (−𝑘 𝐴 ([𝑃 ]
𝑖 + [𝐴 ]
𝑖 + 𝑐𝑜𝑛𝑠𝑡 1
)[𝐴 ]
𝑖 + 𝑘 −𝐴 ([𝑍 ]
𝑖 − [𝐴 ]
𝑖 + 𝑐𝑜𝑛𝑠𝑡 0
))
𝑛 𝑖 =1
)
2
→ 𝑚𝑖𝑛 𝑛 𝑖 =1
(20)
∑ ([𝐴 ]
𝑒𝑥𝑝 − ∫ (−𝑘 𝐴 ([𝑃 ]
𝑖 + [𝐴 ]
𝑖 + 𝑐𝑜𝑛𝑠𝑡 1
)[𝐴 ]
𝑖 + 𝑘 −𝐴 ([𝑍 ]
𝑖 − [𝐴 ]
𝑖 + 𝑐𝑜𝑛𝑠𝑡 0
))
𝑛 𝑖 =1
)
2
→ 𝑚𝑖𝑛 𝑛 𝑖 =1
(21)
With the present approach, the estimated direct rate constant kZ of the [A·cat·Z] complex formation
did not exceed the limit of ≈ 1.7 for most of the substrates, whereas the maximum value for other
parameters k-A, k2, k-Z did not exceeded the level of 0.5. Considering these results, the grid search
algorithm for the system ODEs (4)–(6) was performed within the numerical limits of 0 and 6, as a
56
three-fold extended interval (𝑘 𝑥 𝜖 [0;6]). The discrete value of 0.5 was chosen for the purpose of
time efficiency of the calculation. Once the set of the rate parameters, satisfying the minimum
criteria in the metrics of LMS, was found, the further refinement involving the gradient descend
optimization protocol, was used to derive the reaction rate parameters satisfying the global
maximum criteria. This way, the computed concentration profiles of both iodoalkyne A[X] and
azide [Z] reactants, as well as the 5-iodo-1,2,3-triazole P[X], matched the experimentally derived
concentration data. The fragment of the computational protocol computing the concentration
values of [A], [Z] and [P] employing the Runge-Kutta algorithm, is shown below.
Figure 2.9 The following code fragment represents the classic RK integration method for computing
concentration profiles from eq.(4)-(6) employing optimized rate parameters.
//2._________________ Runge_Kutta Procedure for calculation of ka, kma, kz, kmz, k2 _________________
h=0.01;
a1=a0;
z1=z0;
p1=p0;
sum=0.;
for(i=0;i<5000000;i++)
{
r8=(int)(i*h);
k11=h*(-ka*(p1+a1+c1)*a1+kma*(-a1+z1+c0));
k12=h*(-kz*(-a1+z1+c0)*z1+kmz*(-p1-z1+c2));
k13=h*(k2*(-p1-z1+c2));
k21=h*(-ka*((p1+0.5*k13)+(a1+0.5*k11)+c1)*(a1+0.5*k11)+kma*(-(a1+0.5*k11)+(z1+0.5*k12)+c0));
k22=h*(-kz*(-(a1+0.5*k11)+(z1+0.5*k12)+c0)*(z1+0.5*k12)+kmz*(-(p1+0.5*k13)-(z1+0.5*k12)+c2));
k23=h*(k2*(-(p1+0.5*k13)-(z1+0.5*k12)+c2));
k31=h*(-ka*((p1+0.5*k23)+(a1+0.5*k21)+c1)*(a1+0.5*k21)+kma*(-(a1+0.5*k21)+(z1+0.5*k22)+c0));
k32=h*(-kz*(-(a1+0.5*k21)+(z1+0.5*k22)+c0)*(z1+0.5*k22)+kmz*(-(p1+0.5*k23)-(z1+0.5*k22)+c2));
k33=h*(k2*(-(p1+0.5*k23)-(z1+0.5*k22)+c2));
k41=h*(-ka*((p1+k33)+(a1+k31)+c1)*(a1+k31)+kma*(-(a1+k31)+(z1+k32)+c0));
k42=h*(-kz*(-(a1+k31)+(z1+k32)+c0)*(z1+k32)+kmz*(-(p1+k33)-(z1+k32)+c2));
k43=h*(k2*(-(p1+k33)-(z1+k32)+c2));
a1=a1+1./6.*(k11+2.*k21+2.*k31+k41);
z1=z1+1./6.*(k12+2.*k22+2.*k32+k42);
p1=p1+1./6.*(k13+2.*k23+2.*k33+k43);
57
2.10 OPEN MULTI-PROCESSING INTERFACE FOR COMPUTATIONAL
SPEEDUP
The time efficiency of a straightforward grid search for the calculation of reaction rate parameters
(kA, k-A, kZ, k-Z, k2) was directly proportional to the experimental set volume and required more
than 24 hours of computing time in some cases. The disadvantage of implementing smaller discreet
values was considered to be directly proportional to an exponential increase in calculation time for
the grid search approach. However, the tactic of discrete time increase improves time performance
but gives a rough estimate of emerged parameters, which is usually the case when performing
single-core computing. Further refinement of rate parameters was accomplished with a gradient
descent method, which often resulted in biased solutions (dependent on the initial conditions which
correspond to the resulting values derived from the grid search). This way, we investigated the
performance of the OpenMP-based grid search algorithm implementing the 4
th
order classic RK
solver for the kinetic study of
I
CuAAC. The total number of threads was equaled to i1 - maximum
number of computed different rate parameters ka [i1 max = 12 (discretization step h=0.5) or 22
(discretization step h=0.25)]. The grid search employed the LSM minimization protocol when
comparing computed results (concentration profile) with the experimental data within one thread.
The reliability of the corresponding coefficients was confirmed by graphical superposition of the
derived computed concentration profiles with the experimental ones. Initial conditions were
selected based on the experimental data assuming 2% of the standard deviation error. Table 2.3
compares the performance of RK integration algorithms, run with and without parallelization.
OpenMP parallelization (#pragma statements places in C code) with 12 threads required 4m
15.774s of global time for the computing of the minimization condition, whereas 1 thread (regular
grid search) required 44m 1.761s for the execution of the same task. LSM corresponding minimum
58
sums were slightly different for the 12 and the 1 thread run, however the values of the rate constants
were identical. Implementation of the 22 threads with a 0.25 discretization step required 67m
51.703s of computing time. Obviously, the derived kA, k-A, kZ, k-Z, k2 rate parameters values
differed from those computed with 0.5 (Table 2.3). The values that correspond to the lower
minimum of LSM sum parameter were taken as the correct ones.
Table 2.3 OpenMP and single core CPU computational approaches for solving chemical kinetics of
I
CuAAC complex catalytic reactions.
N
o
entry n of threads discretization. step h computing time
1 1 0.5 44m 14.761s
2 12 0.5 4m 15.774s
3 22 0.25 67m 51.703s
As an outcome of the developed computational approach, an effective usage of different levels of
heterogeneous parallelism on multiple CPU cores version implemented for the rate law integration
algorithms, was demonstrated to greatly improve the reaction mechanism modelling performance,
while also reducing the computation time.
2.11 CONCLUSIONS
The developed approach of deterministic analysis of chemical kinetics allows solving the reaction
rate parameters for further refinement of the standard reaction profiling and system design with
improved reactivity characteristics.
The developed protocol has been probed and optimized for the comprehensive mechanistic
analysis of the copper(I)-catalyzed azide-1-iodoalkyne cycloaddition (
I
CuAAC). As such, methods
of continuous reaction progress monitoring were used to obtain data-dense kinetic profiles. The
59
numerical method of Runge-Kutta analysis was applied to access a quantitative mechanistic model
for the investigated
I
CuAAC complex catalytic reaction. Computationally derived rate constants
and parameters, as well as the time frames of intermediate species accumulation and consumption,
were in a good agreement with the electronic functionality of the investigated 1-iodo-alkyne
substrates. The analysis of the intermediate profiling data revealed that the catalyst resting state is
substrate-dependent.
Considering the time efficiency of the used search algorithms, the high-fidelity OpenMP grid
search method was developed, optimized and probed for increased performance mechanistic
studies of organometallic reactions, involving multiple substrates and intermediate complexes. A
further investigation of other types of ODEs systems for complex catalytic transformation studies
and catalytic networks development is required.
Progress in the sensitivity of spectroscopic techniques and advanced computational modelling
could significantly improve the elucidation of complex catalytic reaction mechanisms and provide
more adequate and reliable kinetic models. Particularly, this would help to reveal special cases of
reaction kinetics complexities, such as phase equilibrium instabilities or substrate-induced rate-
determining shifts. The use of advanced computational techniques in kinetic data analysis is
essential to achieve fast yet reliable correlations between the proposed kinetic models for the
catalytic cycles and the experimental data.
60
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Combinatorial Analysis of C1 Chemistry. J. Chem. Inf. Model. 2000, 40 (3), 833-838.
(2) Lee, C. H.; Othmer, H. G., A multi-time-scale analysis of chemical reaction networks: I.
Deterministic systems. J. Math. Biol. 2009, 60 (3), 387-450.
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Knowledge from Data through Catalysis Informatics. ACS Catal. 2018, 8 (8), 7403-7429.
(4) Blackmond, D. G., Reaction Progress Kinetic Analysis: A Powerful Methodology for
Mechanistic Studies of Complex Catalytic Reactions. Angew. Chem. Int. Ed. 2005, 44 (28), 4302-
4320.
(5) Blackmond, D. G., Kinetic Profiling of Catalytic Organic Reactions as a Mechanistic Tool.
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(6) Burés, J., A Simple Graphical Method to Determine the Order in Catalyst. Angew. Chem.
Int. Ed. 2016, 55 (6), 2028-2031.
(7) Burés, J., Variable Time Normalization Analysis: General Graphical Elucidation of
Reaction Orders from Concentration Profiles. Angew. Chem. Int. Ed. 2016, 55 (52), 16084-16087.
(8) Perez-Benito, J. F., Some Considerations on the Fundamentals of Chemical Kinetics:
Steady State, Quasi-Equilibrium, and Transition State Theory. J. Chem. Educ. 2017, 94 (9), 1238-
1246.
(9) Perez-Benito, J. F.; Arias, C.; Lamrhari, D.; Anhari, A., The determination of kinetic data
for the reactions of chromium(VI) with glutathione and other thiols. Int. J. Chem. Kinet. 1994, 26
(5), 587-591.
(10) Pogliani, L.; Terenzi, M., Matrix formulation of chemical reaction rates: A mathematical
chemical exercise. J. Chem. Educ. 1992, 69 (4).
(11) Berberan-Santos, M. N.; Martinho, J. M. G., The integration of kinetic rate equations by
matrix methods. J. Chem. Educ. 1990, 67 (5), 375.
(12) Zeigarnik, A. V .; Valdés-Pérez, R. E.; White, B. S., Proposed Methodological
Improvement in the Elucidation of Chemical Reaction Mechanisms Based on Chemist-Computer
Interaction. J. Chem. Educ. 2000, 77 (2).
(13) Ernst Hairer, G. W., Syvert P. Nørsett, Solving Ordinary Differential Equations I. Springer,
Berlin, Heidelberg: 1993.
(14) Bock, H. G., Numerical Treatment of Inverse Problems in Chemical Reaction Kinetics. In
Modelling of Chemical Reaction Systems, 1981; pp 102-125.
(15) Tikhonov, A. N., Goncharsky, A., Stepanov, V .V ., Yagola, A.G., Numerical Methods for the
Solution of Ill-Posed Problems. Springer Science+Business Media: Dordrecht 1995.
(16) Mathew, J. S.; Klussmann, M.; Iwamura, H.; Valera, F.; Futran, A.; Emanuelsson, E. A.
C.; Blackmond, D. G., Investigations of Pd-Catalyzed ArX Coupling Reactions Informed by
Reaction Progress Kinetic Analysis. J. Org. Chem. 2006, 71 (13), 4711-4722.
(17) Ferretti, A. C.; Mathew, J. S.; Blackmond, D. G., Reaction Calorimetry as a Tool for
Understanding Reaction Mechanisms: Application to Pd-Catalyzed Reactions. Ind. Eng. Chem.
Res. 2007, 46 (25), 8584-8589.
(18) Susanne, F.; Smith, D. S.; Codina, A., Kinetic Understanding Using NMR Reaction
Profiling. Org. Process Res. Dev. 2011, 16 (1), 61-64.
61
(19) Zheng, X.; Bi, C.; Li, Z.; Podariu, M.; Hage, D. S., Analytical methods for kinetic studies
of biological interactions: A review. J. Pharm. Biomed. Anal. 2015, 113, 163-180.
(20) Susanne, F.; Smith, D. S.; Codina, A., Kinetic Understanding Using NMR Reaction
Profiling. Org. Process Res. Dev. 2012, 16 (1), 61-64.
(21) Gorban, A. N., Model reduction in chemical dynamics: slow invariant manifolds, singular
perturbations, thermodynamic estimates, and analysis of reaction graph. Curr. Opin. Chem. Eng.
2018, 21, 48-59.
(22) Seath, C. P.; Burley, G. A.; Watson, A. J. B., Determining the Origin of Rate-Independent
Chemoselectivity in CuAAC Reactions: An Alkyne-Specific Shift in Rate-Determining Step.
Angew. Chem. Int. Ed. 2017, 56 (12), 3314-3318.
(23) Kirsch, J. F.; Hinkle, P. M., Demonstration of a change in the rate-determining step in
papain- and ficin-catalyzed acyl-transfer reactions. Biochemistry 1971, 10 (14), 2717-2726.
(24) Casey, A. K.; Schwalm, E. L.; Hays, B. N.; Frantom, P. A., V-Type Allosteric Inhibition
Is Described by a Shift in the Rate-Determining Step for α-Isopropylmalate Synthase from
Mycobacterium tuberculosis. Biochemistry 2013, 52 (39), 6737-6739.
(25) Machado, T. F. G.; Gloster, T. M.; da Silva, R. G., Linear Eyring Plots Conceal a Change
in the Rate-Limiting Step in an Enzyme Reaction. Biochemistry 2018, 57 (49), 6757-6761.
(26) Lente, G.; Fábián, I.; Poë, A. J., A common misconception about the Eyring equation. New
J. Chem. 2005, 29 (6).
(27) Benson, S. W., Thermochemical Kinetics. John Wiley & Sons: New York, 1976.
(28) Hein, J. E.; Tripp, J. C.; Krasnova, L. B.; Sharpless, K. B.; Fokin, V . V ., Copper(I)-
Catalyzed Cycloaddition of Organic Azides and 1-Iodoalkynes. Angew. Chem. Int. Ed. 2009, 48
(43), 8018-8021.
(29) Hong, V .; Presolski, S. I.; Ma, C.; Finn, M. â. G., Analysis and Optimization of Copper-
Catalyzed Azideâ “Alkyne Cycloaddition for Bioconjugation. Angew. Chem. Int. Ed. 2009, 48
(52), 9879-9883.
(30) Dumele, O.; Wu, D.; Trapp, N.; Goroff, N.; Diederich, F., Halogen Bonding of
(Iodoethynyl)benzene Derivatives in Solution. Org. Lett. 2014, 16 (18), 4722-4725.
(31) Gao, K.; Goroff, N. S., Two New Iodine-Capped Carbon Rods. J. Am. Chem. Soc. 2000,
122 (38), 9320-9321.
(32) Elliott, P. I. P., Chapter 1. Organometallic complexes with 1,2,3-triazole-derived ligands.
In Organomet. Chem., 2014; pp 1-25.
(33) El Seoud, O. A.; Baader, W. J.; Bastos, E. L., Practical Chemical Kinetics in Solution. In
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62
C H A P T E R III
63
3 KINETIC STUDIES AND MECHANISTIC ELUCIDATION OF THE
COPPER(I)-CATALYZED CYCLOADDITION REACTION OF
BISMUTH(III) ACETYLIDES WITH ORGANIC AZIDES
3.1 INTRODUCTION TO ORGANOBISMUTH(III) COMPOUNDS IN DRUG
DESIGN
As one of the rarest chemical elements in the earth’s crust, bismuth possesses a negligibly low
level of toxicity and carcinogenicity, relative to those of its highly abundant neighbors on the
periodic table (tin, lead, antimony, arsenic).
1, 2
Due to these qualities, the number of applications
for bismuth in the area of catalysis, photovoltaics and quantum dots has increased significantly
during the past two decades.
3, 4
However, the biochemical and industrial applications involving
bismuth metal-organic frameworks frameworks remain rather limited.
3, 5
Presently, commercially
available bismuth(III) compounds are mostly inorganic salts (used as Lewis acid catalysts for
organometallic reactions) or those involved in the construction of nanoparticle scaffolds.
6-9
As
such, bismuth subsalicylate (BSS) (trade name – Pepto-Bismol), which is used for the treatment
of gastrointestinal problems and some bacterial infections, is one of the few examples of a
commercially available pharmaceutical containing bismuth.
10, 11
Rare cases of toxicity from
organobismuth drugs, resulting in cytotoxic effects as well as reversible renal failure, have only
occurred in cases of high doses and prolonged intake.
12, 13
Apart from drug development
applications, bismuth has gained attention in the area of metal frameworks for bioimaging and
biolabeling purposes. It has recently been discovered that coordination with donor atoms, such as
sulfur (S) and nitrogen (N), increases the thermal, air and hydrolytic stability of bismuth, opening
up new opportunities for its use.
14, 15
With the increased interest in the area of novel, nontoxic and
64
biocompatible nanomaterials, Bi-doped systems have become a hot topic in the area of near-
infrared (NIR)-emitting or drug-delivery materials.
16-18
Nanocapsules containing bismuth were
reported as a potential X-ray contrast agent for cellular imaging in micro-computed tomography.
19
Bismuth was chosen due to its prolonged efficacy in encapsulation and its non-toxicity due to
acceptable bio-elimination. Sun et al. reported the first near-infrared bismuth-doped nanoparticles,
which were successfully tested as in vivo photoluminescent(PL) bioimaging probes in living
mice.
20
In fact, all the Bi-containing materials used for biolabeling applications have been
nanoparticle composites consisting of either transition metals or inorganic oxides from group 13,
14 and 15.
21-23
3.2 BISMUTH TYPE OF COPPER(I)-CATALYZED AZIDE-ALKYNE
CYCLOADDITION AS A POTENTIAL BIOLABELING STRATEGY
Copper(I)-catalyzed azide-terminal alkyne cycloaddition (CuAAC) has been reported as a bio-
orthogonal, regioselective and fast molecular labeling method for tracking bio-molecular
processes.
24, 25
However, current labeling approaches still possess some limitations, requiring
further improvements in the area of bio-orthogonal click reactions.
26-29
Herein, we report a
synthetic procedure for a unique class of organobismuth reactants, which were recently
demonstrated to undergo copper(I)-catalyzed cycloaddition with organic azides to form
trisubstituted 5-bismuth(III) triazolides at a decent rate. This novel type of internal acetylides (R–
C≡C–BiAr2) has a high potential for bio-oriented medicinal applications, such as advanced
diagnostic bioimaging, positron emission tomography (PET), NIR or isotopically-labeled reactive
probes.
6, 20
65
The purpose of the current research was to investigate the mechanism of the copper(I)-catalyzed
azide-bismuth(III) acetylide cycloaddition reaction. Two types of derivatization strategies were
employed for the synthesis of various organobismuth acetylide reactants: 1) diphenylsulfonyl
ligand immobilization with different functional groups; and 2) para-position phenylacetylene
substitution with electron-deficient, neutral and electron-rich functionalities. Crystallographic
characterization of the bismuth acetylides revealed the nucleophilicity of the acetylene moiety to
be dependent on the ligand design. Surprisingly, the variation of Bi(III)···O(1) bond formation
was further found to be in agreement with the observed reactivity detected by NMR analysis in the
solution phase. The experimental strategy to elucidate this reactivity involved independent kinetic
studies with para-functionalized bismuth(III)-derivatized acetylides and competitive between
bismuth(III) acetylides and parent terminal phenylacetylenes. A copper(I) trifluoromethane-
sulfonate toluene complex was used as an electron deficient copper(I) catalytic system. A
mechanistic model of a two-substrate two-intermediate
Bi
CuAAC transformation was proposed on
the basis of previously reported and current studies (Scheme 3.1)
30
. Kinetic cyclic voltammetry
(CV) together with
1
H NMR spectroscopy were used to derive kinetic parameters and the rate law
of the transformations that emerged. For some substrates, thermally induced cycloaddition at 60 °C
(mapped with NMR data) demonstrated first-order kinetics in azide, whereas for others it was
permanently a zero-order pattern. Taking into account bismuth coordination chemistry as well as
the coordination to the backbone sulfonyl group, we predicted the relative geometry of the high-
valent intermediates which were confirmed by electrochemistry studies. A comparison between
the reactivity of 1-bismuth(III) acetylides and that of 1-iodoalkynes under copper(I)-catalyzed
conditions is briefly discussed as well.
66
Scheme 3.1 5-Bismuth(III)-triazolides in the
Bi
CuAAC reaction. Previous report and current study.
3.3 SYNTHESIS AND CHARACTERIZATION OF DIPHENYL SULFONE
BISMUTH(III) ACETYLIDES
Bismuth(III) acetylides [1] through [6] were synthesized employing a synthetic route previously
reported for acetylide compound [3]
31
(Scheme 3.2 B). Acetylides [7] through [10] were
synthesized using protocols similar to those of Bi-C(sp
2
) and Bi-C(sp) bond formation, reported
previously in the literature (Scheme 3.2 C). A copper-catalyzed C(aryl)-S bond forming reaction
between aryliodides and arylsulfides, followed by oxidation with m-CPBA, metalation with n-
butyllithium, and subsequent treatment with in situ generated Bi(OTf)2Ph yielded triphenylsulfone
67
bismuth derivatives (Scheme 3.2 A). Iodination followed by C(sp)-Bi coupling afforded the final
bismuth(III) acetylides [7–10]. The scope of the corresponding transformations was in accordance
with a single crystal X-ray diffraction study demonstrating the electronic functionality of
substituents to influence the stability of C(sp
2
)-Bi, I(iodine)-Bi or C(sp)-Bi covalent bonds (Figure
3.1). The electron-rich dimethoxy-substituted iodo-diphenylsulfone bismuth(III) derivative 27
exhibited a less covalent I(1)-Bi bond, with a distance of 2.871(1) Å, than that of the 2-methoxy-
8-trifluoromethyl-functionalized diphenyl-iodobismine, 28, which had a distance of 2.862(1) Å.
The yield of 27 was almost one and a half times higher than that of 28. This confirmed both the
influence of the electron withdrawing nature of the sulfone group at the ortho-position and the
ability of the trifluoromethyl group at the meta-position to render the Bi center electrophilic. The
extent of Bi(III)–I(1) bond formation further impacts transmetallation and C(sp)–Bi coupling with
para-functionalized phenylacetylenes. The protocol proved to be universal with a variety of para-
substituted arylbismuth(III) acetylides, including methoxy- (1, 79% of total yield), tert-butyl- (2,
76%), methyl- (3, 54%), proto- (4, 90%), bromo- (5, 79%), trifluoromethyl- (6, 56%) substituents.
Additionally, diphenyl sulfone meta-substituents, such as methoxy- (7, 60%), chloro- (8, 66%) and
trifluoromethyl- (10, 51%) groups were also tolerated. The results of the IR analysis of compounds
[1]–[10] showed no linear free energy pattern with the corresponding absorbance bands of the
acetylenic C(sp)–C(sp) bonds (Table 3.1, Figure 3.3). In addition, in the row of para-substituted
diphenylsulfone bismuth(III) acetylides ranging from [1] to [6], the distance of transannular
interactions between the Bi(1) and O(1) atoms or the C(sp)–C(sp) triple bond did not follow the
Hammett trend as well
32
(Table 3.2, Figure 3.2). The electron-poor chloro- and trifluoromethyl-
substituted diphenylsulfonyl bismuth(III) acetylides [8] and [7] showed greater elongation of the
oxygen(1)-bismuth interactions (bond lengths were 2.878(3) Å and 2.874(2) Å respectively) than
68
those of the electron-rich methoxy-functionalized bismuth(III) acetylides [9] and [10] (C(1)-Bi(1)
bond distances were 2.908(3) Å and 3.035(3) Å, respectively). Previously, the functionality of the
triarylbismuth(V) derivative ligands was reported to directly influence their reactivity.
33
Therefore,
we were expecting higher yields from the cycloaddition process when employing bismuth(III)
acetylide [3] than when using bismuth(III) acetylide [5] because stronger transannular electron
donation between Bi(1) and O(1) was thought to induce additional nucleophilicity at the C(β)
acetylenic carbon. As we will see further on, the trend of the distances of the transannular
interactions between Bi(1) and O(1) atoms reflects the factors influencing copper-mediated 5-
bismuth(III)-1,2,3-triazole formation.
69
Scheme 3.2 (A) Synthetic route for the synthesis of diphenylsulfone bismuth(III) acetylides (a) CuI, K 2CO 3,
i-propanol/ethylene glycol, 80 °C; (b) m-CPBA, DCM, MgSO 4 10 eq., 0 °C-> r.t.; (c) 1)BiBr 3, BiPh 3, Et 2O,
2) n-BuLi, THF, –78 °C-> r.t.; (d) I 2, Et 2O, r.t.; (e) 1) n-BuLi, THF, –78 °C-> r.t. 2) para-substituted
phenylacetylene; (B) diphenylsulfone bismuth(III) acetylides; (C) 1-ethynyl-4-methylbenzene bismuth(III)
acetylides with functionalized diphenylsulfone ligands.
70
Figure 3.1 Selected bond Bi(1)–I and transannular Bi(1)···O(1) interaction distances [Å] of the synthesized
iodobismines ([27] and [28]) and correspondent isolated yields. Thermal ellipsoids are set at 50%
probability.
71
Figure 3.2 Selected bond and transannular Bi(1)–O(1) interaction distances [Å] of the synthesized
bismuth(III) acetylides. Thermal ellipsoids are set at 50% probability. A) Crystal structures of the most
reactive bismuth(III) acetylide [3] and the least reactive acetylide [5]; B) Crystal structures of para-phenyl
substituted bismuth(III) acetylides; C) Crystal structures of diphenylsulfone substituted
bismuth(III)acetylides.
72
Table 3.1 Comparison of acetylene group C(1)≡C(2) IR stretching vibration frequencies of the derivatized
bismuth(III) acetylides.
Figure 3.3 Infrared spectroscopy as a diagnostic tool for observing the disappearance of the -C≡C-
stretching band. Comparison of the absorbance data for 1-bismuth(III) acetylide [2] and the corresponding
5-bismuth(III) triazolide [2].
Bismuth(III)-acetylide IR (υ[cm
-1
]) Bismuth(III)-acetylide IR (υ[cm
-1
])
para-phenyl substituted bismuth(III)acetylides
[1], R = OMe 2099 [2], R =
t
Bu 2108
[3], R = Me 2099 [4], R = H 2111
[5], R = Br 2105 [6], R = CF3 2114
diphenylsulfone substituted bismuth(III)acetylides
[7], R’ = CF3 2045 [8], R’ = Cl 2098
[9], R’ = OMe 2107 [10], R’ = OMe, OMe 2051
73
Table 3.2 Distances of the transannular Bi(1)···O(1) interactions, and lengths of Bi(III)–C(1) and
C(1)≡C(2) key covalent bonds of the synthesized bismuth(III) acetylides [1-10].
Bismuth(III)-acetylide O⋯Bi / Å Bi ̶ C (1) C(1)≡C(2) C(2)–C(sp
2
)
para-phenyl substituents
[1], R = OMe 2.896(2) 2.243(3) 1.180(3) 1.453(3)
[2], R =
t
Bu 2.998(2) 2.225(3) 1.195(5) 1.453(5)
[3], R = Me 2.962(2) 2.256(4) 1.135(6) 1.483(6)
[4], R = H 2.936(2) 2.236(3) 1.202(5) 1.449(5)
[5], R = Br 2.972(2) 2.231(4) 1.175(6) 1.458(6)
[6], R = CF3 2.940(2) 2.210(5) 1.222(6) 1.434(6)
diphenylsulfone ligand substituents
[7], R’ = CF3 2.874(2) 2.230(3) 1.211(3) 1.440(3)
[8], R’ = Cl 2.878(3) 2.230(4) 1.196(5) 1.444(4)
[9], R’ = OMe 2.908(3) 2.221(4) 1.153(6) 1.477(7)
[10], R’ = OMe, OMe 3.035(3) 2.209(4) 1.198(6) 1.447(6)
3.4 PRELIMINARY REACTIVITY STUDIES: X-RAY STRUCTURAL
INFORMATION
To probe the relative reactivity of acetylides employed in the
Bi
CuAAC process, we charged the
reaction vessel with a series of acetylides[X], (2-azidoethyl)benzene and the catalyst following the
described protocol and worked-up the reactions after a specified time (Scheme 3.3 A). While
performing end-point reactivity studies in bulk, no correlation between the Hammett sigma values
and the observed reactivity was observed (Scheme 3.3 B). The isolated yields clearly demonstrated
74
acetylides [3], [4] and [6] to be more reactive than acetylides [1], [2] and [5]. Based on our previous
knowledge, gained from 1-iodoalkyne CuAAC studies, this observation indicates either unusual
forms of induced nucleophilicity on the C(β) atom or an inconsistent pattern in the rate-
determining step (RDS) of the reaction for the corresponding methyl-, proto- and trifluoromethyl-
substituted acetylides [2], [4] and [6].
Scheme 3.3 (A) General scheme for
Bi
CuAAC reactions of bismuth(III) acetylides A[1-6] with (2-
azidoethyl)benzene; (B) Product scope for the copper(I)-catalyzed bismuth(III) acetylide-azide
cycloaddition reaction.
Thus, bismuth(III) triazolide [6] was synthesized with close to a 81% yield, while the conversion
of the similarly electron-deficient bismuth(III) acetylide [5] was almost halved. However, the
reactivity of the resulting bismuth(III) acetylides was not directly dependent on electronic factors,
75
as we found for 1-iodoalkynes. Additionally, in our previous study (Chapter II), electron-deficient
iodoacetylenes exhibited significantly higher reactivity than that of substrates with positive
Hammett constant values. Here, the para-bromo-functionalized bismuth(III) acetylide[5] was the
least reactive substrate, whereas the methyl-substituted substrate was as efficient as the
trifluoromethyl-functionalized acetylide [6]. No precipitation nor any sort of heterogeneity was
observed in the reaction mixture when the reaction was performed in bulk in tetrahydrofuran
(THF) solution with continuous stirring at 35 °C. This interesting observation is in accord with the
X-ray analysis of the bismuth(III) acetylides, showing an unusual trend in the bond distances
(Table 3.2). Indeed, the transannular Bi(1)-O(1) coordinative bond distance for the least reactive
acetylide, A[5], was one of the largest, implying electron donation from the para-bromo
substituent. Vice versa, more reactive substrates, [3], [4] and [6], demonstrated shorter Bi(1)-O(1)
bond distances, providing more electron density to the corresponding triple bond π-systems.
Hence, the additional supply of electron density to the C(β)-acetylene carbon via the bismuth
“transmitter” possibly induced the nucleophilicity of the latter, accelerating C(β)–N(1) bond
formation during the azide insertion step. A similar type of geometry-dependent nucleophilicity
demonstrated by X-ray crystallography data has been previously reported for pentacoordinated
trimethylsilyl lactams.
34
3.5 DYNAMIC EXCHANGE PROCESSES AS A FUNCTION OF
TEMPERATURE
The possibility of positional exchanges of bismuth(III) ligands is supported by the observation that
corresponding ortho-hydrogens of sulfone ligands are broadened. Previously, P(V) complexes
have been reported to participate in positional exchanges by the Berry pseudorotation (BPR) and
Turnstile rotation (TR) mechanisms.
35
Both processes involve apical and equatorial ligand
76
rotations. The same type of positional exchange was observed for C(sp)–Bi bonds. At –43 °C, the
1
H NMR spectra of the bismuth(III) triazolide[2] showed two singlets in the aliphatic range,
corresponding to a pair of tert-butyl signals from both conformers (Figure 3.4). Moreover, an
analogous situation was found for the methyl signals of the azide residues: we observed four
different signals at –43 C, whereas at 91 °C only two singlets were detected (the same occurred
with the
t
Bu-group). To simplify peak integration, the kinetic monitoring was carried out at
elevated temperatures.
Figure 3.4
1
H NMR signal coalescence/decoalescence demonstrate intermolecular processes of bond
rotations as a function of temperature for 5-bismuth(III) triazole[2].
77
3.6
1
H NMR KINETIC STUDIES
From a variety of experimental tools available for the reaction mechanism elucidation, we chose
1
H NMR spectroscopy due to the opportunity for multidimensional control and its relatively high
accuracy
36-38
. Although previous experiments were performed in tetrahydrofuran (THF),
1
H NMR
kinetic studies were carried out in deuterated dimethylsulfoxide (DMSO-d6,
1
H δ = 2.50 ppm) due
to its advantages of allowing variable temperature that result in better signal separation. While
observing the effect of hydrogen-induced intermolecular rotation of azide-related ethylene groups
(Figure 3.4), heating of the sample up to 60 °C was required for the kinetic monitoring to minimize
coalescent effects.
39
The progress of the reaction was monitored by the changes in the characteristic doublets of the
acetylide reactant (for A[3], δ = 7.62–7.57 ppm), azide ([Z], δ = 2.89–2.84 ppm), 5-bismuth(III)-
1,2,3-triazole (P[3], δ = 8.29–8.24 ppm) and the singlet of the 1,4-dimethoxybenzene reference
Figure 3.5 Kinetic progress monitored by
1
H NMR spectra of
Bi
CuAAC reaction.
78
compound ([R], δ = 6.87–6.82 ppm) (Figure 3.5). The above signals were chosen because they
were well separated and allowed for accurate integration. The concentration changes of the
reactants as a function of time were obtained by referencing the integrated signal ratios to a known
concentration of 1,4-dimethoxybenzene (reference). For entry 3 (Scheme 3.3 A), a strong decrease
of the aromatic and aliphatic triplet signals, displayed in red and blue, respectively, in Figure 3.5,
indicated the consumption of the acetylide A[3] and azide [Z] reagents and corresponded to a linear
increase of the symmetric hydrogen signal of the bismuth(III) triazolide P[3], highlighted in green.
3.7 INDEPENDENT REACTION PROGRESS ANALYSIS AS A METHOD FOR
EXPLORING THE EVOLUTION OF THE REACTIVE INTERMEDIATES.
SUBSTRATE-DEPENDENT SHIFT IN THE RATE DETERMINING STEP
In bulk studies, an accurate quantification of the bismuth(III) acetylide reactivity was restricted by
the use of recrystallization as a purification technique at the final stage of the reaction work-up.
The performance of the recrystallization procedure is depending on the physicochemical properties
of the purified substance, such as its morphology, crystallinity and purity. Continuous monitoring
of the reaction progress was required to provide insights into the
Bi
CuAAC reaction mechanism.
However, several mechanistic key aspects remained unclear:
▪ What type of electronic functionalities of the used bismuth(III) acetylides
determine the rate order dependencies of the substrate? Para-phenyl
functionalization or transannular interaction?
▪ What is the chemical nature of the first- or zero-order kinetic patterns for certain
bismuth(III) acetylides? Should one anticipate the same type of catalytic reactivity
79
as for 1-iodoalkyne
I
CuAAC? If so, will the rate-determining changes be
substrate- or conversion-dependent?
To answer these questions, time-dependent concentration profiles for the acetylide A[X], azide [Z]
and bismuth(III) triazolide P[X] reactants were obtained and computationally processed to perform
independent RPKA studies as well as to gain insights into reaction intermediate evolution
40
.
Bismuth(III) acetylides possessing diphenyl sulfone ligands [1-6] were independently reacted with
a 0.48 M excess of (2-azidoethyl)benzene in the presence of an electron-deficient copper(I)
trifluoromethanesulfonate toluene complex under the studied temperature conditions (Figure
3.6 A). Concentration ranges were optimized to allow for sufficient monitoring time, taking into
account drastically different rates of reactivity of the individual substrates.
In theory, all members of the same class of chemical transformations follow similar mechanistic
features and exhibit identical kinetic patterns.
41
Our work has shown that differences in reaction
profiles are an inevitable characteristic of a reaction class where the catalyst resting state changes
over the course of the reaction and remains substrate dependent. Based on the conversions, a
drastic difference was observed in the mechanistic pathway of P[6], P[4] and P[3] formation versus
the rest of the 5-bismuth(III)-1,2,3-triazoles (Figure 3.6 B). The resulting linear and exponential
rise curves permit differentiation between zero-order kinetics and positive rate orders for high and
low reactivity acetylides, respectively.
80
Figure 3.6 Kinetic profiles of
Bi
CuAAC independent experiments catalyzed by the copper(I)-triflate toluene
complex. Conditions: A[X] = 0.025M; [Z] = 0.043 M; [cat] = 0.375 mM; 0.8 ml volume DMSO-d6;
T = 59.5 °C. A) Standard reaction conversion versus time; B) Reaction rates versus time.
The concentration-dependent reaction rates of entries [3], [4] and [6] (Scheme 3.3 A) suggest
relatively long steady periods followed by an immediate drop upon the complete consumption of
the acetylide (Figure 3.6 B). These observations suggest positive, close to zero-order kinetics for
the acetylide[5] and near first-order kinetic behavior for acetylide [4]. The time-independent
reaction rate for the bismuth(III) triazolide[6] demonstrates horizontal dependence, signalizing that
81
the bismuth(III) acetylide [6] kinetics follow a zero-order pattern. For the acetylides [1], [2] and
[5], a slow decay of merged two-phased dependence was observed instead. This nonlinear behavior
was unusual but has already been observed in standard transformations involving a shift in the
RDS. A plausible scenario for the existence of a two-step kinetic regime was postulated to involve
a substrate-based RDS fluctuation between [A·cat] and [cat] species. The acetylide rate order for
substrates [3] and [4] was graphically elucidated to be non-zero and comparable to that of
substrates [1], [2] and [5] for the first kinetic regime of the π-complex formation when participating
in the RDS. When reaching higher conversions, the RDS tended to shift from an acetylide-binding
to an azide-dependent regime, leading to zero-order alkyne kinetics and [A·cat] as a resting state
(causing a dual slope curve). This resulted in the reaction order to be changed in the interval of 0
and 1 depending on the concentration of acetylide [A]. Conversely, the highly reactive substrates
[3] and [4] proceed exclusively in one regime with non-zero-order kinetics. A possible rationale
for this difference might be the higher affinity of transannular-based electron transfer,
strengthening the copper(I)-acetylide triple bond coordination. This favors the fast formation of
the intermediate [A·cat] or [A·cat] being the catalyst-resting phase. As such, azide coordination
becomes the turn-over limiting step during the entire bismuth(III) triazolide[6] formation reaction.
Notably, no unexpected precipitation or gas release was observed during the course of the reaction
for entry 1 (Scheme 3.3 A); thus, the nature of the formation of the bismuth(III) acetylide [1]
“hump” is presumably a physical phenomenon. However, spectroscopic measurements were
performed at 60 °C and might have resulted in perturbed, heterogeneous conditions not visible
otherwise. When cyclic voltammetry studies using bismuth(III) acetylide [1] were performed at
room temperature, a small amount of precipitation was observed. This may have been the result of
82
the poor solubility of the formed bismuth(III) triazolide [1] or formation of an oligomeric species
inhibiting the catalyst.
Scheme 3.4 Proposed mechanistic model of the azide-bismuth(III) acetylide copper(I)-catalyzed
cycloaddition reaction (
Bi
CuAAC).
83
3.8 “DIFFERENT EXCESS” STUDIES: CONVERSION-DEPENDENT SHIFT IN
THE RATE DETERMINING STEP
Different excess experiments were performed to probe a conversion-dependent shift in the RDS.
While being related to the subgroup of low reactivity bismuth(III) acetylides, para-tert-butyl
substituted acetylide[2] was chosen for this study. In our experiment, the “excess” value was
defined as the difference between the concentrations of azide and acetylide[2] components at the
initial time, to:
[𝑍 ]
𝑥 = [𝐴 ]
𝑥 + "𝑒𝑥𝑐𝑒𝑠𝑠 " (1)
The value of the “excess” concentration was chosen to be on the order of 0.5 M, to avoid a “pseudo-
zero-order” approach, resulting in synthetically irrelevant conditions. The plot in Figure 3.7 (A)
displays an exponential dependence of reaction conversion on both excess and limiting acetylide
concentrations, indicating positive order kinetics. Upon replotting these data as a function of
reaction rate versus bismuth(III) acetylide A [2] concentration, we observed single and dual kinetic
functionality profiles (Figure 3.7 B). Concentration-dependent rates for the 0.087 M and 0.054 M
[“excess”] entries 1 and 2, respectively, exhibited smooth decay, signalizing approximately non-
zero-order kinetics for acetylide for the entire reaction process. For entries with an comparable
amount or an excess of bismuth(III) acetylide (entries -0.01 M [“excess”] (blue), -0.031 M
[“excess”] (cyan) and 0.024 M [“excess”] (olive)) the two-step linear curves with distinguishably
distinct slope values were measured (Figure 3.7 B). From this, we can estimate that the acetylide
rate order lies between 0 and 1 with its value alternating as a complex function of the electronic
nature of the used bismuth(III) acetylide A[X]. Numerical values of substrate rate orders were
obtained from graphical plots of the derived reactivity in natural logarithm coordinates (f(x) =
84
ln(x)) under the conditions of initial rates. This allowed for the calculation of the substrate rate
orders via the slope value from the “straight-line” method. For the regime of low conversion rates,
acetylide[2] was exhibiting negative-order kinetics (n = -0.05) for experiments where the
concentration of azide was limiting. As a visible characteristic of complex catalytic reactions,
bismuth(III) acetylide was in the denominator in the rate law depicted in equation (19)
(Figure B.2 B). For the initial kinetic regime of excess azide (entries 4 and 5), the
bismuth(III) acetylide[2] remained negative (n = -0.2) yet suggested a higher rate order. To
elucidate the situation further, reaction progress data were plotted as the time-honored or
“normalized” double reciprocal coordinates of rate·[A]
-1
versus [Z] or rate·[Z]
-1
versus [A] as
shown in Figure 3.7 C and D. Normalized data for all experiments indicate that the first kinetic
regime for the low reactivity bismuth(III) acetylides depends on the addition of both [Z] and [A],
while disproving saturation in the intermediate [A·cat], even under acetylide[2] “excess”
conditions. If that were the case, a graphical rate equation shown in Figure 3.7 D would exhibit a
straight horizontal line representing data from “different excess” experiments all overlaying each
other. However, the reaction is displaying zero-order or non-acetylide-dependent but azide
dependent kinetics during the regime of higher conversion rates, as a consequence of the
overlaying dependencies in Figure 3.7 D.
85
Figure 3.7 Kinetic profile of the
Bi
CuAAC reaction catalyzed by the copper(I)-triflate toluene complex.
Double exponential approximation. A) Reaction concentration versus time. Variable [Alkyne]
concentration experiment. B) Reaction rate versus bismuth(III) acetylide A [2] concentration. C) ʋ/[Z]
versus A[2]. D) ʋ/A[2] versus [Z].
As previously mentioned, such inconsistent linear behavior in the plot of rate versus [A] (Figure
3.7) is a sign of a shift in the resting state (from the free [cat] stage to the [A·cat] formation) for
low reactivity bismuth(III) acetylides (Scheme 3.4). One rationale for a non-integer-order for an
acetylide[2] may be that during the kinetic regime with low conversion rates, the catalytic cycle is
saturated with the copper(I) species, making the alkyne approach a turn-over limiting step.
Towards the higher conversions period, the reaction becomes saturated with the [A·cat]
intermediate, shifting the predominant RDS to azide addition.
86
3.9 CATALYST ROBUSTNESS STUDIES
The reactions with 0.36 mM and 0.77 mM catalyst concentrations demonstrated an overlay when
carried out at the same “excess” ratio and different copper(I) trifluoromethanesulfonate toluene
complex concentrations (Figure 3.8). Because the corresponding blue and purple curves show
little to no deviation from a straight line, the first-order dependence of the catalyst concentration
was confirmed.
Figure 3.8 Graphical representation of probing the catalyst robustness in the
Bi
CuAAC reaction.
Conditions: 0.012 M A[4], 0.014 M [Z], 0.386 mM (light blue) and 0.773 mM (dark blue), DMSO-d6,
60 °C.
3.10 COMPETITIVE
1
H NMR KINETIC STUDIES OF BISMUTH(III)-
ACETYLIDE AND TERMINAL ACETYLENES REACTIVITIES UNDER
COPPER(I) CATALYZED CONDITIONS
Competitive studies with proto-alkynes show the ultra-high affinity of the copper(I)
trifluoromethanesulfonate toluene complex towards bismuth(III) acetylides, leading to the
formation of π-bismuth(III) acetylide upon mixing them together (canary yellow solution) and
87
causing quantitative yields of 5-bismuth(III)-triazolide.
1
H NMR monitoring of the reaction
progress, employing a 1:1 equivalent ratio of terminal acetylene and bismuth(III) acetylide with
equal para-functionality, resulted in only 3-5% of proto-triazole formation with Cu(I) triflate
complex catalysis (Figure B.3). When introducing reactive acetylide A[3] together with its
terminal acetylene analog into a catalyst activation protocol (without the presence of an azide
component), the rates of bismuth(III) acetylide hydrolysis were inversely proportional to its
corresponding reactivity in copper(I)-induced cycloadditions with azides. Thus, negligibly small
amounts of hydrolyzed substrate were observed for acetylide A [3], compared to those of the
entries using low reactivity bismuth(III) acetylides (Figures B.5 and B.6). A detailed analysis of
the copper-catalyzed equilibrium between the terminal acetylenic proton and bismuth(III) ligated
moiety of diphenyl sulfone bismuth(III) acetylides showed a complete inertness of proto-alkynes
towards π-complex formation in the presence of organobismuth(III) reactants at room temperature,
and only a slight increase upon heating. Furthermore, in the presence of residual water, no
significant changes in the substrate reactivity or hydrolysis-product formation were detected. In
terms of data reliability, the entire kinetic setup was performed in the inert atmosphere of a
glovebox, as reactivity measurements of triazolide[6] formation showed slightly lower values for
the concentration profile when performed a moisture-containing solvent (Figure B.4). Neither
moisture-free nor wet protocols formed a proto-triazolide product.
88
3.11 EVALUATION OF A MECHANISTIC MODEL OF A
BI
CUAAC
CATALYTIC REACTION BASED ON KINETIC CYCLIC VOLTAMMETRY
DATA
Detailed mechanistic modelling was performed in the context of cyclic voltammetry (CV)-
independent reactivity experiments. This method allowed for further investigation of the
intermolecular transannular effect on bismuth(III) acetylide reactivity. Numerically dissecting the
reaction rate expressions from the spectroscopy data via the system of ordinary differential
equations (ODEs) would have allowed for the rationalization of the
Bi
CuAAC mechanism, as we
demonstrated for
I
CuAAC studies. However, instead of solving the set of ODEs, a kinetic analysis
methodology based on unique opportunities of cyclic voltammetry studies was developed and
applied for in-depth mechanistic studies of the
Bi
CuAAC reaction. The rate constant measurements
consisted of two sets of experimental data processing: first set – measurement of the equilibrium
constant of the π-complex formation; second set – the averaged rate parameter of azide binding
and 5-bismuth(III) triazolide formation.
Each kinetic electrochemical experiment was first initiated with redox studies of CuOTf catalytic
solutions, followed consistently with the addition of bismuth(III) acetylide and organic azide.
Cyclic voltammetry at 100 mV/s in dry DMSO with 0.58 mM CuOTf (used as the salt as well as
the catalyst) showed reduction potentials for the Cu(I)/Cu(0) redox system to be around -0.2 V
versus the Cu
+
/Cu
o
reference electrode (Figure 3.9 C, black). Next, a 10× solution of bismuth(III)
acetylide was injected to obtain a substrate concentration of 5.0 mM , and the kinetics of the [A·cat]
complex formation were monitored (Figure 3.9 A). A final CV measurement was used for the
graphical representation of collected information on the redox characteristics of the first π-
intermediate complex (Figure 3.9 C) Upon binding to the π-system of the bismuth-containing
89
ligand, the copper reduction potentials were shifted relative to the electronic features of the
employed acetylides, whereas the oxidative potentials remained the same and were not changeable
over the time course of the coordination (Table 3.3). Thus, the average of the onset oxidation and
reduction potentials for the [A[5]·cat] complex (Eav) was 0.15 V higher than for [A[6]·cat],
indicating copper to be easier to reduce, and hence, to be more electropositive to begin with
(Figure 3.9 D, Table 3.3). This further justifies our hypothesis regarding non-electronic factors
influencing the observed reactivity, as measured by NMR. Whenever there is a linear correlation
between the structure and the observed reactivity for para-substituted derivatives, the
trifluoromethyl-substituted bismuth(III) acetylide would make copper(I) more electron deficient
than the bromine-functionalized bismuth(III) acetylide would do. The formation of the
Cu(I)acetylide complex was mild enough to be detectable and to derive rate parameters responsible
for the corresponding kinetics (Table 3.3). Thus, the observed rate of π-complex formation was in
agreement with the spectroscopically derived reactivity trend. Kinetic parameters of the redox
changes for (ethylbenzyl)azide coordination reactions (or triazolide[X] formation) were also
probed by cyclic voltammetry. When the stabilized redox cycle signalized the completed formation
of the [A·cat] intermediate of the bismuth(III) acetylide and copper triflate catalytic mixture, the
azide was injected into the system (Figure 3.9 B). Upon injection, a slight fading of the
characteristic canary yellow color was observed together with an immediate increase of the
current. The stabilized CV plot for the azide binding/5-bismuth(III) triazolide formation
overlapped with the final plot of [A·cat] formation, indicating some acetylide remained bound with
the copper(I) catalyst. Presumably, the equilibrium of the azide insertion was shifted towards
product formation when proceeding at elevated temperatures. Thus, this quantitative conversion
was observed when monitored by NMR at 60 °C, in contrast to the electrochemistry kinetics
90
observed at room temperature. Reaction yields derived upon potential stabilization in azide-
addition CV studies were confirmed by
1
H NMR. However, the time of acquisition under heating
conditions might be enough to drive an experiment to full conversion.
Reaction rate parameters were calculated, and a substrate-selective shift of the turn-over limiting
step was confirmed to follow the same trend as that found by the spectroscopic data, i.e. substrate-
dependent (Table 3.3). Thus, among the acetylides[1–6], the methyl-functionalized A[3] was
shown to have the lowest KA intermediate [A·cat] forming rate constant, simultaneously
demonstrating that azide insertion is the rate limiting step (KZ·k2 = kobs = 0.024, which is the
highest value among the other Kz values). Among the used acetylide substrates, the kobs apparent
reaction rate constant was shown to be significantly higher for A[3] (-Me), A[4] (-H) and A[5] (-
Br) than for A[1] (-OMe), A[2] (-
t
Bu) and A[6] (-CF3) bismuth(III) acetylides, demonstrating a
non-Hammett dependent correlation with the observed reactivity. Conversely, the rate constants
for catalyst-acetylide coordination of reactants A[1], A[2] and A[5] were generally higher than
those for bismuth(III) acetylides A[3], A[4] and A[6], making the bromo-derivative of bismuth(III)
acetylide the reactant with the highest affinity for copper(I), yet the slowest at azide insertion.
91
Figure 3.9 Cyclic voltammogram kinetic studies of the
Bi
CuAAC reaction with the copper(I)-triflate
toluene complex at 25 °C in dry DMSO at 100 mV/sec. Conditions: 3-electrode cell with glassy carbon as
the working electrode, copper foils as counter and reference electrodes. (A) Kinetic studies of catalyst-
bismuth(III) acetylide coordination; (B) Kinetic studies of azide insertion; (C) Voltamperrograms in the
presence of the indicated reagents, added in the order specified; (D) Average of onset oxidation and
reduction potential values for variable [A[X]·cat] complexes.
92
Figure 3.10 Cyclic voltammograms in the presence of the copper catalyst [CuOTf], bismuth(III) acetylide
A[X] and azide [Z] reagents, added in the order indicated. (A) 1-Bismith(III) acetylide [1]; (B) 1-
bismith(III) acetylide [2]; (C) 1-bismith(III) acetylide [3]; (D) 1-bismith(III) acetylide [4]; (E) 1-
bismith(III) acetylide [5]; (F) 1-bismith(III) acetylide [6].
Table 3.3 Rate parameters, derived from the cyclic voltammogram kinetic studies of the
Bi
CuAAC reaction
at 25 °C in dry DMSO at 100 mV/sec. Conditions: 3-electrode cell with glassy carbon as the working
electrode, copper foils as counter and reference electrodes.
Entry KA·10
-3
, M
-1
σ kobs = Kz·K2, M
-1
·sec
-1
σ Eav, V
[1], R = OMe 1.80 1.30E-4 1.60E-3 0.80E-4 0.35
[2], R =
t
Bu 0.91 0.13E-4 1.23E-3 0.29E-3 0.32
[3], R = Me 0.093 0.10E-3 0.024 0.41E-3 0.30
[4], R = H 1.28 0.12E-3 7.50E-3 0.55E-3 0.30
[5], R = Br 4.93 0.90E-3 6.68E-3 0.25E-3 0.38
[6], R = CF3 1.02 0.52E-3 9.70E-3 0.40E-3 0.25
93
3.12 CONCLUSIONS
As a result of the mechanistic studies employing kinetic CV and
1
H NMR approaches, a catalytic
model for the
Bi
CuAAC reaction was developed. Taking into account “same excess” and catalytic
robustness studies, we postulate the active π-complex of the copper(I)catalytic species and the
acetylide to serve as the initially formed intermediate, the reactive stability of which dictates the
overall reaction reactivity. Accumulation of the intermediate [A·cat] is proposed during the initial
regime of low conversion rates (slow rates) for low reactivity substrates (alkyne insertion is an
RDS and the free copper(I) catalyst is a resting state). This is followed by a regime of high
conversion rates (fast rates) with the rate-limiting reaction being the consumption of the [A·cat]
intermediate species (which are spread out between [cat] and [A·cat] with the catalyst resting state
predominantly located in [A·cat]). For fast reacting substrates, the reaction profile was more
independent from the acetylide, leading in some cases to the azide insertion being the only rate-
limiting factor for the entire reaction sequence. Transannular interaction between the oxygen atom
O(1) of the diphenyl sulfone ligand and bismuth might influence the reversibility of this type of
interaction while revealing an experimentally observed correlation between the extension of
B(III)···O(1) coordinative bond distances and reaction rates.
Our observations show that bromo-substituted A[5], tert-butyl-substituted A[2] and methoxy-
substituted A[1] bismuth(III) acetylides exhibit restricted binding abilities with the
copper(I)triflate complex. By contrast, para-derivatized methyl-A[3], proto-A[4] and
trifluoromethyl-[6] acetylides exhibit enhanced reactivity towards azide addition. Numerical
values of the corresponding π-intermediate and triazolide apparent reaction rate constants obtained
by kinetic cyclovoltammetry studies are in agreement with the proposed quantitative model of the
Bi
CuAAC reaction mechanism.
94
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97
C H A P T E R IV
98
4 “ON WATER” SYNTHESIS OF FLUOROSULFONYL 1,2,3-
TRIAZOLES
4.1 ORGANIC SYNTHESIS “ON WATER”
The unique properties of water have been previously reported to enhance the rates and improve
the regioselectivity of organic transformations, showing in some cases almost quantitative yields.
1-
3
The phenomenon of accelerated reaction rates in water was first reported by Breslow and Rideout
in 1980. They found that Diels-Alder reactions in aqueous media occur substantially faster than
those under traditional neat conditions.
4
It was postulated by the authors that the hydrophobic
effect is the major driving force behind the acceleration of the observed reaction speed. More than
two decades later, Otto and Engberts showed that the transition state energy is not affected by
hydrophobic interactions.
5
Later Sharpless, Kolb, Fokin, Finn and colleagues reported a water-
enhanced cycloaddition between water-insoluble quadricyclane and dimethyl azodicarboxylate.
6
The reported synthetic protocol involved vigorous stirring of the reaction mixture. This resulted in
the formation of finely dispersed minute droplets, which inevitably enlarged the interfacial area
between the reactants and the aqueous reaction media. Such fast dispersion of both organic and
aqueous phases was considered to be crucial for the rate acceleration, leading to a complete
reaction conversion within 10 minutes. Performing the reaction in organic media (toluene)
increased the reaction time almost twelve-fold. Mechanistic studies have shown that shifting to a
homogenous environment with the addition of methanol was significantly diminishing the reaction
rates. Further experiments with deuterium oxide as well as with the perfluorinated solvents showed
that interface layers between the reactants and water play a crucial role. This led to the
development of the term, “on water” reactivity instead of “in water”. Thus, “on water” reactions
99
can be identified as those transformations that occur between water-insoluble reactants in the water
solvent, driven by hydrogen bonding on the water-organic interface.
2
However, economic and
environmental efficiency of “on water” organic transformations remain in question since the
workup conditions still commonly require organic solvents.
7
Nonetheless, the current “on water”
synthetic protocol represents a milestone for organic synthesis in laboratory research.
1, 8
The scope of these findings motivated us to extend “on water” chemistry to other synthetic
protocols where reactions result in low yields when performed under neat or organic solvent
conditions.
4.2 SULFONAMIDE-CONTAINING DRUGS
Over the past several decades, sulfur-containing drugs have constituted almost one fifth of all
known pharmaceutical architectures.
9
As of December 2016, the US Food and Drug
Administration (FDA) had approved 285 sulfur-containing pharmaceuticals.
10
Sulfur-containing
Figure 4.1: (A) Relative composition of sulfur-containing functionalities in pharmaceutical drugs
employed for the treatment of twelve frequently occurring disease categories; (B) Examples of US FDA-
approved sulfonamide-containing pharmaceuticals, possessing a heterocyclic scaffold.
100
functional patterns are commonly used for chemo- and acquired immune deficiency syndrome
(AIDS) therapy as well as for the treatment of other common medical conditions, such as arthritis,
diabetes and depression. Among the various sulfur-containing medicinal drugs and agrochemicals,
sulfonamide derivatives remain the most pervasive (Figure 4.1 A). The evolution of “sulfa drugs”
began in 1932 when Gerhard Domagk found sulfamidochrysoidine (the sulfanilamide prodrug
Prontosil®) to exhibit antagonistic activity against a wide spectrum of bacteria.
11, 12
The broad
antibacterial effect was later explained by the unique structural and electronic property of the
sulfanilamide group, found to be a bioisostere of certain carboxylic acid functionalities.
13
In
addition to other properties, such as antibacterial, hypoglycemic, antithyroid and anticancer
activities
9
, sulfonamide derivatives were recently found to inhibit central nervous system
activity.
14
4.3 SYNTHETIC PROTOCOLS TOWARDS SULFONAMIDE DRUGS
DEVELOPMENT
A brief survey of commercially available “sulfa” drugs showed benzyl- and alkyl groups to be the
major scaffold constituents,
10
leaving only several sulfonamide drugs possessing heterocyclic
backbones. Some examples are represented in (Figure 4.2 B). Plausible strategies for the synthesis
of sulfonamide-functionalized heterocycles involve sulfonyl chloride, as a versatile intermediate,
commonly generated through direct sulfonation.
15
However, sulfonation of certain heterocycles,
such as triazole, leads to N-protonation with further deactivation of electrophilic substitution. This
restricts the formation of sulfonyl chloride derivatives, which are also known to be unstable and
readily decompose, eliminating SO2 (Scheme 4.1).
16, 17
A 4-step synthetic route starting from
triazole thiol, proposed by Hunt et al., resulted in 10-30% total yields of corresponding sulfonyl
chlorides, depending on the precursor used.
18
Recent oxidative chlorination of thiols in the
101
presence of H2O2-TMSCl mixtures allowed for their efficient conversion into sulfonyl chlorides.
However, this method was shown to be sustainable only for aliphatic or derivatized phenylthiols.
19
As of now, only a limited number of heterocyclic sulfonyl chloride-functionalized compounds are
commercially available for further amination. In view of these obstacles, we concentrated on the
development of a robust and efficient synthesis of other reactive substitutes for sulfonyl chlorides,
such sulfonyl fluorides.
Scheme 4.1 Synthetic procedures for the synthesis of sulfonyl chloride heterocycles amenable to further
amination.
102
4.4 SUFEX “CLICK REACTION” FOR THE SYNTHESIS OF SULFONAMIDE-
CONTAINING DRUGS
The development of novel synthetic methodologies for common pharmaceutical scaffolds is a
continuing effort in the pharmaceutical industry. During the past several years sulfonyl fluoride
chemistry has become an area of increasing interest.
20
Simultaneously, a novel transformation for
assembling functionally diverse molecules – the Sulfur (VI) Fluoride Exchange (SuFEx) reaction
(Scheme 4.2 A) – was developed.
21
Since 2014, SuFEx chemistry has gained a reputation for being
a “privileged warhead”, enabling the metal-free, fast and efficient synthesis of small molecules,
peptide-type structures and polymers with a large structural diversity.
22-24
The success of the
SuFEx approach is due to the chemical nature of sulfonyl fluorides.
25
Unlike sulfonyl chlorides,
SO2F-reagents are resistant to reduction conditions, are stable at high temperatures and possess a
high affinity for hydrogen bonding (Scheme 4.2 B).
21
This allows for the use of the SO2F group
for the synthesis of pharmaceutically important SO2-NH2 sulfonamides. Presently, a variety of
aliphatic, aromatic and heterocyclic SuFEx reagents are commercially available with
ethenesulfonyl fluoride (ESF) being the most common. It is stable under ambient conditions, yet
very reactive upon substitution with common nucleophiles.
26
1-bromo-ESF (BESF) was also
reported to serve as a novel SuFExable coupling block while being compatible with a variety of
azide functionalities. Reactive BESF can be generated in situ from 1,2-dibromoethane-1-sulfonyl
fluoride (DBESF) upon dehydrobromination with any Hünig’s base, such as N,N-
diisopropylethylamine (DIPEA) or triethylamine (TEA) (Scheme 4.2 C).
27
103
Scheme 4.2 Sulfur-Fluoride Exchange reaction (SuFEx).
28
A) SuFEx mediated formation of sulfonamides
and sulfonates; B) Common hubs for SuFEx ligation; C) Synthetic protocol for the generation of DBESF
and BESF from ESF.
29
4.5 METHODOLOGY DEVELOPMENT AND OPTIMIZATION OF WATER
PROMOTED 1,3-DIPOLAR CYCLOADDITION REACTIONS
To expand the synthetic procedures for sulfonyl-containing pharmaceutics, we started with the
development of reliable procedures for sulfonyl fluoride functionalization of 5-membered
heterocycles, in particular, triazoles, isoxazoles and pirazoles. The 1,4-regioselectivity of triazole
substitution, resulting from the cycloaddition of BESF and organic azides, has already been
104
reported.
29
We started our optimization study with 1,3-dipolar cycloadditions, using BESF as a
dipolarophile and (2-azidoethyl)benzene as a 1,3-dipole. The structure of the final products was
established with GC-MS and NMR, demonstrating mild regioselectivity in the triazole formation
under aqueous conditions. As shown in Table 4.1, the use of toluene favored the formation of Br-
substituted triazole. Indeed, increasing the hydrophobicity of the reaction media has favored the
formation of 4-bromo-1,2,3-triazole (tracked with the GC-MS). Further experimentation with
variations in the pH, solvent polarity and addition of different salts did not reveal any significant
improvements in the reaction regioselectivity.
105
Table 4.1 Reaction optimization. Reaction conditions were ((azidomethyl)benzene, BESF, in water (1 ml,
unless stated otherwise, 1 eq. is equal to 0.3 mmol), room temperature and at maximum stirring rate).
Corresponding yields were calculated by GC-MS calibration procedures after 6 hours of continuous stirring.
Entry BESF,eq. Azide,eq. Conditions
Product, Yield (%)
A B
1 2 1 water 2 ml 60.0 20.0
2 2 1 LiCl (3M), water 2ml 67.0 29.0
3 2 1 TFA (1 eq.), water 2 ml 67.0 29.0
4 2 1 Brij
®
L4 (0.13 eq.) 58.8 39.0
5 2 1
30% aq. solution Cocamidopropyl betaine
(0.13 eq.)
39.0 58.9
6 2 1
30% aq. solution Cocamidopropyl betaine
(0.04 eq.), toluene (0.5 eq.)
36.9 55.9
7 2 1
30% aq. solution Cocamidopropyl betaine
(0.20 eq.), toluene (0.5 eq.)
47.3 51.2
8 2 1
30% aq. solution Cocamidopropyl betaine
(1.30 eq.)
23.0 64.7
9 2 1 Methanol (1.5 eq.) 73.4 22.1
10 2 1 Methanol (0.5 ml.) 62.5 24.5
11 2 1 1ml pH 7 buffer 43.2 54.9
12 2 1 Octanol-1 (0.06 eq.) 70.9 28.0
13 2 1 Dodecanol-1 (0.04 eq.) 71.2 24.5
14 2 1 Aliquat
®
336 (0.04 eq.) 7.3 91.2
15 2 1 Aliquat
®
336 (0.24 eq.) 0.0 99.9
16 1.6 1 Aliquat
®
336 (0.24 eq.) 1.3 94.7
17 1 1 Aliquat
®
336 (0.24 eq.) 1.7 87.8
18 0.5 1 Aliquat
®
336 (0.24 eq.) 1.2 54.5
19 2 1 ZnCl 2 (0.02 eq.) 71.5 26.4
20 2 1 1 ml Fructose (1M) solution in water 74.8 24.0
21 2 1 ZnCl 2 (0.02 eq.), toluene (0.5 eq.) 75.5 23.6
22 2 1 Glucose (0.3 eq.) 75.9 22.3
23 2 1 1 ml Glucose (0.5M) solution in water 59.9 40.1
24 2 1 Chloroform (0.4 eq.) 66.2 32.2
25 2 1 Thiourea (1M) 3.0 1.6
26 1 1 Toluene (0.5 eq.) 48.0 25.8
27 2 1 Toluene (0.5 eq.) 78.3 18.8
28 2 1
t
BuOH (2.25 eq.) 53.9 28.8
29 2 1 pH4 buffer
56.8 28.6
30 2 1 Toluene (0.5 eq.), 50
o
C
64.6 18.6
31 2 1 Toluene (0.5 eq.), drop-wise addition
56.5 24.3
106
To our surprise, the addition of Aliquat
®
336 completely shifted the selectivity resulting in an
almost quantitative (99%) yield of 1,2,3-triazole-4-sulfonyl fluoride. Variable “excess” entries 15-
18 demonstrated the azide component to be the limiting factor with an almost two-fold reduction
of the almost quantitative yield of sulfonyl triazole. The effect of rate enhancement upon addition
of Aliquat
®
336 was probably due to the limited ability of the fluoride atom to form hydrogen bonds
with water, thus, becoming a better leaving group in the toluene media. Whereas in the presence
of surfactants, bromine is eliminated due to the restricted ability of fluoride and oxygen atoms of
the SO2F functionality to produce intermolecular bonds.
4.6 KINETIC STUDIES OF THE WATER-ASSISTED REGIOSELECTIVE
SYNTHESIS OF SO 2F-FUNCTIONALIZED TRIAZOLES
When ESF was replaced with the DBESF reagent (in situ generation of BESF), no significant
difference in reaction yields was detected. In both cases - ESF and DBESF - in the absence of an
organic solvent, the azide reagent was completely consumed in an average of four hours. In the
presence of an organic solvent, the complete conversion required more than one day (Figure 4.2 D,
red).
1
H NMR kinetic experiments were performed by sampling aliquots from the reaction at
certain time intervals in the presence of a reference compound. In particular, we examined the
amount of phase transfer agent required for the predominant formation of SO2F-triazole (Figure
4.2 A).
107
Figure 4.2 Kinetic studies of the water-assisted reaction of SO 2F-functionalized triazoles. A) Surfactant
effect on the sulfonyl triazoles formation. (Reaction conditions: 1 eq. = 0.5 mmol, DBESF (1.5 eq.),
(azidomethyl)benzene (1.0 eq.), triethylamine (1.5 eq.), Aliquat®336 (0.0 eq.; 0.03 eq.; 0.05 eq.; 0.10 eq.;
0.15 eq.; 0.20 eq.; 0.23 eq.; 0.24 eq.; 0.30 eq.), water (2 ml), spin rate of the stir bar (1400 rpm), r.t., aliquots
were taken after 8 h of continuous stirring; B) Influence of the spin rate on the reaction rates (Reaction
conditions: DBESF (1.5 eq.), (azidomethyl)benzene (1.0 eq.), triethylamine (1.5 eq.), water ( 2 ml), spin
rates of the stir bar(400; 800; 1100, 1400 rpm), r.t., aliquot withdrawal was performed every 50 min).
Conversion vs. time; C) Ratio of 5-bromol triazole to 5-sulfonyl triazole as a function of spin rate. Same
conditions as in B); D) The difference in reactivity due to solvent polarity and base loading. (Reaction
conditions: entry 1 (DBESF (1.5 eq.), (azidomethyl)benzene (1.0 eq.), triethylamine (1.5 eq.), DMF (2 ml),
Aliquat®336 (0.15 eq.)), entry 2 (DBESF (1.5 eq.), (azidomethyl)benzene (1.0 eq.), triethylamine (1.5 eq.),
water (2 ml), Aliquat®336 (0 eq.)), entry 3 (DBESF (1.5 eq.), (azidomethyl)benzene (1.0 eq.), triethylamine
(1.5 eq.), water (2 ml), Aliquat®336 (0.15 eq.)), spin rate of the stir bar(1400 rpm), r.t., aliquot withdrawal
was performed every 50 min).
108
For maximum sulfonyl triazole formation, the borderline value of Aliquat®336 was found to be
0.05 eq. with respect to the limiting reagent. Higher loadings did not lead to an improvement in
the reaction selectivity. We also varied the stirring speed to examine its impact on the formation
of the 5-sulfonyl fluoride triazole. (Figure 4.2 B) When exploring hydrodynamic effects posed by
vigorous stirring, only small changes in the conversion rates were observed when varying the rates
of the stirring rates between 200, 400, 800, 1100 and 1400 rpm. The relative ratio of 5-sulfonyl
fluoride triazole versus the 5-bromotriazole formation was found to depend strongly on the spin
rate at low spin rates but leveled out at higher spin rates. At a spin rate of 1400 rpm, the formation
of SO2F-triazole was seven times higher than that of the bromo-derivative (Figure 4.2 C). Thus,
we believe that in the presence of Aliquat®336, the sulfurylfluoride group is shielded from
forming hydrogen bonds with water molecules, resulting in bromine becoming a better leaving
group. The addition of toluene favors the formation of microdroplets in which the SO2F-group can
become solvated more readily and more prone to leave (Scheme 4.3).
Scheme 4.3 Water-assisted formation of 4-sulfonyl and 4-bromo triazoles from organic azides and DBESF.
The procedure, previously reported by our group, for the formation of 4-fluorosulfonyl 1,2,3-
triazoles by 1,3-dipolar cycloaddition with DBESF, has already demonstrated a high-yield and
broad scope. However, the reaction required high temperatures and long reaction times.
29
Compared to the previous procedure using DMF as a solvent, our kinetic studies using an aqueous
109
system and Aliquat®336 were three times faster under comparable conditions, while conserving
quantitative selectivity (Figure 4.2 D). One interesting observation was that the reaction vessel
warmed up upon the addition of azide during the in situ pre-generation of BESF. Thus, the reaction
is thermodynamically driven to undergo dehydrobromination during the formation of the
substituted triazole moiety.
110
4.7 SUBSTRATE SCOPE OF WATER-ASSISTED 1,3-DIPOLAR
CYCLOADDITION REACTIONS
By varying the nature of the organic azide functionality, a versatile library of 1,2,3-triazole-4-
sulfonyl fluorides was generated (Figure 4.3). Para-, meta- and ortho-substituted phenyl azides
generally resulted in lower yields than the yields of those having alkyl groups. Functional group
position was detrimental to product formation, especially when posing steric hinderances. The
reaction performed well for both para- [6a] and ortho-substituted [7a] azidomethoxy benzenes.
Azides with electron-donating substituents in para-position [9a] generally led to higher yields than
those with electron-withdrawing functionalities [4c]. The current protocol was performed in
accordance with Hammett sigma constants with para-substituted phenyl azides [4], [6] to give
electron-deficient sulfonyl triazoles [4a–c], [6a]. The formation of disubstituted products, such as
aromatic [15a] and aliphatic [23a] and [24a], was also possible with the current method. Scaffolds
with double azide functionalities were studied using a four-fold excess of DBESF. The protocol
also worked with relatively bulky adamantane and cyclohexane azides [20] and [21], as well as
with other aromatic compounds [13] and [15] allowing for the synthesis of quinolinone and
naphthalene derivatives in good yields. As outlined in Figure 4.4, the synthesis of isoxazole and
pyrazole SO2F-derivatized heterocycles was also accomplished employing one-pot ESF and
DBESF optimized protocols. Non-substituted
1
H-pyrazoles [27a] and isoxazoles [30a] were
readily generated employing ESF without Aliquat®336 addition. For sulfonyl fluoride
derivatization, the DBESF protocol, in the presence of TEA and a phase transfer catalyst, was
employed [27c]. The yields in that case were generally lower than for SO2F-functionalized triazole
scaffolds. An excess of ESF led to 1N-substituted SO2F-functionalized pyrazoles amenable for
further amination on both sites, as well [27b], [27a]. The Diels-Alder reaction with quadricyclane
111
and furan exhibited good yields [25a] and [25b] and supremacy of endo-product formation.
However, when probed, the versatility of DBESF in 1,3-dipolar cycloaddition with 4-chloro-N-
hydroxybenzimidoyl chloride (the nitrile oxide was generated in situ), 5-bromo isoxazole [30b]
was predominantly isolated (41% of isolated yield). Such a unique phenomenon is a topic of further
investigations. The structural characteristics of the reported cycloaddition products were
determined by extensive
1
D and
2
D NMR spectroscopy analyses.
112
Figure 4.3 The scope of sulfonyl triazoles formed from DBESF and organic azides. Reaction conditions:
Spin rate – 1400 rpm.
a
(0.74 mM) DBESF (0.74 mM), azide (0.49 mM), Aliquat®336 (30 mg), 1 ml H 2O,
8 h, r.t.;
b
DBESF (0.94 mM), azide (0.47 mM), Aliquat®336 (50 mg), 1 ml H 2O, 8 h, r.t.;
c
DBESF (1.88
mM), azide (0.47 mM), Aliquat®336 (50 mg), 1 ml H 2O, 8 h, r.t.
113
Figure 4.4 5-Fluorosulfonyl and 5-bromo-functionalized pyrazoles, non-substituted pyrazoles and various
derivatives of Diels-Alder additions formed from ESF, DBESF and organic azides. (A) Diels-Alder
adducts; (B) ESF and DBESF-promoted 1,3-dipolar cycloadditions.
114
4.8 CONCLUSION
In this chapter, a unique, metal-free, environmentally sustainable synthesis of fluorosulfonyl-
substituted heterocycles is presented. Optimization studies revealed that the use of water as a
solvent and of 5–10 mol% of a quaternary ammonium salt phase-transfer agent, Aliquat®336,
provides a protocol for more efficient sulfonylfluoride-triazole formation. Kinetic studies
elucidated the observed reactivity and reduced the reaction time for the generation of
fluorosulfonyl-functionalized triazoles from 42 hours (when performed in organic solvents) to 8
hours.
This on-water and phase transfer catalyst-assisted regioselective protocol was successfully applied
to the synthesis of other sulfonylfluoride substituted heterocyclic azoles, which had been difficult
to access. Thus,
1
H-pyrazoles, 5-(fluorosulfonyl)-1H-pyrazoles, and Diels-Alder adducts were
synthesized in decent to good yields employing bromoethenylsulfonyl fluoride (BESF) and
ethenesulfonyl fluoride (ESF) with variable 1,3-dipole structures.
115
4.9 REFERENCES
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748.
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(3) Zuo, Y .-J.; Qu, J., How Does Aqueous Solubility of Organic Reactant Affect a Water-
Promoted Reaction? J. Org. Chem. 2014, 79 (15), 6832-6839.
(4) Rideout, D. C.; Breslow, R., Hydrophobic acceleration of Diels-Alder reactions. J. Am.
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(5) Otto, S.; Engberts, J. B. F. N., Hydrophobic interactions and chemical reactivity. Org.
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(7) Blackmond, D. G.; Armstrong, A.; Coombe, V .; Wells, A., Water in Organocatalytic
Processes: Debunking the Myths. Angew. Chem. Int. Ed. 2007, 46 (21), 3798-3800.
(8) Butler, R. N.; Coyne, A. G., Understanding “On-Water” Catalysis of Organic Reactions.
Effects of H+ and Li+ Ions in the Aqueous Phase and Nonreacting Competitor H-Bond Acceptors
in the Organic Phase: On H2O versus on D2O for Huisgen Cycloadditions. J. Org. Chem. 2015,
80 (3), 1809-1817.
(9) Ilardi, E. A.; Vitaku, E.; Njardarson, J. T., Data-Mining for Sulfur and Fluorine: An
Evaluation of Pharmaceuticals To Reveal Opportunities for Drug Design and Discovery. J. Med.
Chem. 2013, 57 (7), 2832-2842.
(10) Scott, K. A.; Njardarson, J. T., Analysis of US FDA-Approved Drugs Containing Sulfur
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(11) Jean-Paul, G., The First Miracle Drugs: How the Sulfa Drugs Transformed Medicine. Bull.
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(12) Domagk, G., Ein Beitrag zur Chemotherapie der bakteriellen Infektionen. Dtsch med
Wochenschr 1935, 61 (7), 250-253.
(13) Anderson, R. G., P.; Todd, A.; Worsley, A. J., Antibacterial Agents: Chemistry, Mode of
Action, Mechanisms of Resistance, and Clinical Applications. John Wiley & Sons: Chichester,
U.K., 2012.
(14) Haruki, H.; Pedersen, M. G.; Gorska, K. I.; Pojer, F.; Johnsson, K., Tetrahydrobiopterin
Biosynthesis as an Off-Target of Sulfa Drugs. Science 2013, 340 (6135), 987-991.
(15) Cremlyn, R. J.; Swinbourne, F. J.; Yung, K.-M., Some heterocyclic sulfonyl chlorides and
derivatives. J. Heterocycl. Chem. 1981, 18 (5), 997-1006.
(16) Roblin, R. O.; Clapp, J. W., The Preparation of Heterocyclic Sulfonamides1. J. Am. Chem.
Soc. 1950, 72 (11), 4890-4892.
(17) Bornholdt, J.; Fjære, K. W.; Felding, J.; Kristensen, J. L., Heterocyclic pentafluorophenyl
sulfonate esters as shelf stable alternatives to sulfonyl chlorides. Tetrahedron 2009, 65 (45), 9280-
9284.
(18) Hunt, H. J.; Belanoff, J. K.; Walters, I.; Gourdet, B.; Thomas, J.; Barton, N.; Unitt, J.;
Phillips, T.; Swift, D.; Eaton, E., Identification of the Clinical Candidate (R)-(1-(4-Fluorophenyl)-
6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-
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4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone (CORT125134): A Selective Glucocorticoid
Receptor (GR) Antagonist. J. Med. Chem. 2017, 60 (8), 3405-3421.
(19) Sohrabnezhad, S.; Bahrami, K.; Hakimpoor, F., High yielding protocol for direct
conversion of thiols to sulfonyl chlorides and sulfonamides. J. Sulfur Chem. 2019, 40 (3), 256-
264.
(20) Narayanan, A.; Jones, L. H., Sulfonyl fluorides as privileged warheads in chemical biology.
Chem. Sci. 2015, 6 (5), 2650-2659.
(21) Dong, J.; Krasnova, L.; Finn, M. G.; Sharpless, K. B., Sulfur(VI) Fluoride Exchange
(SuFEx): Another Good Reaction for Click Chemistry. Angew. Chem. Int. Ed. 2014, 53 (36), 9430-
9448.
(22) Jones, L. H., Emerging Utility of Fluorosulfate Chemical Probes. ACS Med. Chem. Lett.
2018, 9 (7), 584-586.
(23) Liu, Z.; Li, J.; Li, S.; Li, G.; Sharpless, K. B.; Wu, P., SuFEx Click Chemistry Enabled
Late-Stage Drug Functionalization. J. Am. Chem. Soc. 2018, 140 (8), 2919-2925.
(24) Brooks, K.; Yatvin, J.; Kovaliov, M.; Crane, G. H.; Horn, J.; Averick, S.; Locklin, J.,
SuFEx Postpolymerization Modification Kinetics and Reactivity in Polymer Brushes.
Macromolecules 2018, 51 (2), 297-305.
(25) Martín-Gago, P.; Olsen, C. A., Arylfluorosulfate-Based Electrophiles for Covalent Protein
Labeling: A New Addition to the Arsenal. Angew. Chem. Int. Ed. 2019, 58 (4), 957-966.
(26) Zheng, Q.; Dong, J.; Sharpless, K. B., Ethenesulfonyl Fluoride (ESF): An On-Water
Procedure for the Kilogram-Scale Preparation. J. Org. Chem. 2016, 81 (22), 11360-11362.
(27) Smedley, C. J.; Giel, M.-C.; Molino, A.; Barrow, A. S.; Wilson, D. J. D.; Moses, J. E., 1-
Bromoethene-1-sulfonyl fluoride (BESF) is another good connective hub for SuFEx click
chemistry. Chem. Commun. 2018, 54 (47), 6020-6023.
(28) Barrow, A. S.; Smedley, C. J.; Zheng, Q.; Li, S.; Dong, J.; Moses, J. E., The growing
applications of SuFEx click chemistry. Chem. Soc. Rev. 2019, 48 (17), 4731-4758.
(29) Thomas, J.; Fokin, V . V ., Regioselective Synthesis of Fluorosulfonyl 1,2,3-Triazoles from
Bromovinylsulfonyl Fluoride. Org. Lett. 2018, 20 (13), 3749-3752.
117
C H A P T E R V
118
5 SIGNAL PROCESSING METHODS FOR KINETIC DATA
DERIVED FROM HEAT FLOW CALORIMETRY
5.1 REACTION CALORIMETRY IN INDUSTRIAL RESEARCH
The chemical industry continues to demand robust and versatile instruments to probe complex
systems at the preliminary phases of process development. The quantification of heat release to
understand the mechanistic underpinnings of the chemical processes has become a prevalent
direction of both laboratory and industrial research.
1-3
In particular, reaction calorimetry analysis
has become a widely employed method for delving into the mechanisms of homogeneous
4
and
heterogeneous catalytic reactions.
5
One of the most well studied and commonly employed methods of heat flux monitoring is still
heat flow calorimetry, a generalized model of which was reported back in 1970 by K. Amaya et
al.
6
In 1994, the method was implemented in practical studies by R. Landau et al.
7
Pioneered by
D. G. Blackmond, this robust and user-friendly type of reaction profiling has been successfully
employed for mechanistic studies in organocatalysis
8
. The rational selection and employment of
available devices and settings, such as vessels with a relatively small volume, preheating
conditions, and an opportunity to run multiple reactions simultaneously, allow for continuous
monitoring within well-stirred conditions. In addition, heat flow calorimetry injection system
provides immediate dispersal of catalyst species, substantially lowering the impact of the
molecular-diffusion processes. Additionally, reaction calorimetry analysis is quite often employed
as a tool for delving into heterogeneous reaction mechanisms, when aliquot-withdrawal sampling
is not an option.
119
However, the experimental calorific output is always accompanied with instrumental and
environmental noise, with a power directly proportional to thermodynamic features of a catalytic
system and thermal insulation parameters. These factors can be considered disadvantageous when
deriving the actual time dependent heat flow profile. Although there are many analytical methods
for reaction profiling, this chapter aims to cover techniques of manipulating and processing “high
dense” kinetic data derived from the heat flow calorimeter reactor
9, 10
.
5.2 THE CALORIFIC OUTPUT QUANTIFICATION
Following the basic principle of microcalorimetry studies, the heat produced from the reaction is
directly proportional to the catalytic activity or, in other words, to the rate of the product
formation:
11
ℎ𝑒𝑎𝑡 (𝑡 ) = 𝑉 𝑟𝑥𝑛 ∙ ∆𝐻 𝑟𝑥𝑛 ∙ 𝑟𝑎𝑡𝑒 (𝑡 ), (1)
where heat(t) – heat liberated at the certain time step; 𝑉 𝑟𝑥𝑛 – volume of the reaction vessel; ∙
∆𝐻 𝑟𝑥𝑛 ∙- reaction enthalpy (kcal/mol); rate (t) – instantaneous reaction rate.
As such, calorific measurements operate with the differential as “primary” data, whereas, for
example, spectroscopy or chromatography techniques treat reaction rate as the processed
parameter of interest. Even though the benefits of reaction calorimetry in chemical process
profiling are extensive (calculation of reaction rates and maximum of the heat release, indication
of reaction completion, reduced experimental time for batch analysis, monitoring of the maximum
heat capacity of reactor contents)
12,13
, the calculation of reaction rate parameters remains restricted
due to instrumental noise. As such, the basis for instrumental errors in calorific experimental
output is threefold
14-16
:
120
1) Instability in the temperature control system;
2) Low sensitivity towards exhibited low level exothermic output;
17
3) Noise (narrowband and broadband) interference amplified during dynamic
correction procedures.
The noise level due to the first factor can be reduced by the appropriate choice of external cooling
system with adequate control of the thermoelectric output. Amplification of noise inherent to the
second and third factors remains a significant problem, especially for experiments that measure
compounds with a low reactivity, where deriving the actual heat flow 𝑈 𝑟𝑒𝑎𝑙 (𝑡 ) requires the
measurement of heat loss from the reactor sector (𝑞 𝑓 ), heat accumulation in the reaction mass
(𝑞 𝑎𝑐𝑐 ) and the environmental impact caused by the heating of the surrounding environment
(𝑞 𝑙𝑜𝑠𝑠 ).
17
When solving this heat balance issue, employment of the dynamic correction technique
through off-system software (in this work, OmniCal Winsight) amplifies the noise, especially for
reactions exhibiting an exothermic effect of less than 50 mW/l. Inevitably, this restricts the
estimation of parameters and propagates further errors in the model of the mechanism.
14
More
sensitive modifications of commercially available heat flow calorimeters have been developed;
however, they were oriented to the research of specific laboratories and difficult to operate.
17, 18
Thus, this chapter will refer to developed processing protocols for the fine analysis of noisy
instantaneous heat values to address the fact that the available software (Winsight 5.6) creates
distortions in the representation of the original signal.
In this work, mechanistic insights into a complex catalytic cycle of
I
CuAAC transformation were
probed via quantitative analysis of heat flux data presented in a time-dependent domain. Statistical
analysis of reaction rates revealed polynomial approximation to be an adequate fit for experiments
121
that measure compounds with fast, medium and slow reactivities fast, medium and slow reactivity
experiments, as well as applicable for instrumental noise reduction and artifact removal. Current
procedures for the accurate processing of calorific data could be applied by both the scientific and
industrial communities.
5.3 HEAT FLOW CALORIMETRY EXPERIMENT FOR KINETIC STUDIES OF
COMPLEX CATALYTIC TRANSFORMATIONS
As of Chapter II, the schematic representation of the
I
CuAAC reaction profile was probed and
reported to initiate with [A·cat] π-complex formation following azide coordination resulting in the
[A·cat·Z] transitional state and ending with the 5-iodotriazole [P] product formation.
19
In order to
obtain thermodynamic parameters as well as to identify the apparent parameters responsible for
the observed catalytic reactivity, reaction profiles spanning the entire conversion for the panel of
para-substituted iodo-phenyl-alkyne substrates A[5] (p-CF3-), A[4] (p-Cl-), A[3] (p-H-) were
acquired (Scheme 5.1). Apart from the NMR kinetic studies, discussed in Chapter II, the CuI-
TTTA catalytic system was employed in the heat flow calorimetry experimental trials.
Scheme 5.1 Copper(I)-catalyzed cycloaddition of 1-iodoalkynes to organic azides (
I
CuAAC).
122
Table 5.1 Conditions and reactivity data of calorimetry heat flow experiments between different 1-
iodoalkyne substrates A[1-3] and (2-azidoethyl)benzene [Z] in the presence of the CuI-TTTA catalytic
system.
Entry A[X],M [Z], M [CuI·TTTA], M 𝑯𝒆𝒂𝒕 𝒎𝒂𝒙 ,𝐦𝐖 time, min conv, %
1 (slow) [3], 0.1 0.113 0.01 33.83 100 100
2 (medium) [2], 0.1 0.113 0.01 85.85 35 100
3 (fast) [1], 0.1 0.113 0.01 132.10 25 100
However, when performing a simultaneous run of independent
I
CuAAC catalytic transformations,
one can face ambiguity when processing calorific outputs following eq. (1). In particular, the
dynamic correction procedure required for obtaining an actual heat flow function might produce
unreliable, distorted data, especially for low exothermicity entry 1, Table 5.1. As such, Figure 5.3
shows both experimentally derived heat flow (red) and a dynamically corrected heat flow profile
(𝑈 𝑟𝑒𝑎𝑙 (𝑡 ) – blue) possessing harmonic fluctuations.
The next chapter will deal with the nature of the inverse problem in heat flow data analysis as it
relates to the family of ill-posed problems. The methodology of rate profiling will be explained
and demonstrated on the experimentally obtained kinetic results of three different complex
catalytic reactions (Table 5.1 Conditions and reactivity data of calorimetry heat flow experiments
between different 1-iodoalkyne substrates A[1-3] and (2-azidoethyl)benzene [Z] in the presence
of the CuI-TTTA catalytic system. For the purpose of simplification, the maximum instantaneous
heat value was used as the primary criterion to determine whether the kinetics of the processes
were fast, slow or medium.
123
5.4 NUMERICAL TREATMENT OF INVERSE PROBLEMS IN CHEMICAL
KINETICS
Inverse problems in chemical kinetics refer to the estimation of unknown parameters from
experimentally derived kinetic data (in Chapter II, solving the system of ODEs for optimal
𝑘 𝐴 ,𝑘 −𝐴 ,𝑘 𝑍 ,𝑘 −𝑍 ,𝑘 2
rate constants).
20-22
In the presence of noise, the inverse problem is related to
the family of ill-posed problems where small changes in the input values cause dramatically
diverse outputs.
20-22
Tackling the inverse problem while inputting noisy data is commonly
addressed using approaches adopted for ill-posed problems. In heat flow calorimetry studies,
experimental values of detected instantaneous heat 𝑈 𝑒𝑥𝑝 (𝑡 ) and the real heat released 𝑈 𝑟𝑒𝑎𝑙 (𝑡 )
(also referred to as the dynamically corrected heat value) are determined in the form of a
convolution integral (2). As such, the convolution integral (2) estimates 𝑈 𝑟𝑒𝑎𝑙 (𝑡 ) depending on
experimentally derived 𝑈 𝑒𝑥𝑝 (𝑡 ):
∫ 𝐾 (𝑡 − 𝜏 )𝑈 𝑟𝑒𝑎𝑙 (𝜏 )𝑑𝜏 𝑡 0
= 𝑟 (𝑡 ) = 𝑈 𝑒𝑥𝑝 (𝑡 )+ 𝑛 (𝑡 ) (2)
where, 𝐾 (𝑡 ) is a convolution kernel (heat flow calorimetry impulse response) for a linear filter;
and 𝑛 (𝑡 ) is the total noise (instrumental and directly related to the chemical process itself).
Theoretically in the noise free scenario,
𝑈 𝑟𝑒𝑎𝑙 (𝑡 ) = 𝑈 𝑡𝑟𝑢𝑒 (𝑡 ), (3)
where 𝑈 𝑡𝑟𝑢𝑒 (𝑡 ) is considered to be an exact solution.
When solving an inverse problem (2), one can face two potential obstacles:
1) The solution of 𝑈 𝑟𝑒𝑎𝑙 (𝑡 ) may not be available for experimentally derived 𝑟 (𝑡 );
124
2) Small changes in 𝑟 (𝑡 ) reflect dramatically different values of 𝑈 𝑟𝑒𝑎𝑙 (𝑡 ) causing instability
issues.
Various methods for solving ill-posed problems have been developed. Currently, the regularization
and quasi-solution techniques remain the most pervasive among the scientific community. In
particular, the regularization approach is based on the direct relationship between real(true) and
information measured in the frequency domain:
𝐾 (𝜔 )∙ 𝑈 𝑟𝑒𝑎𝑙 (𝜔 ) = 𝑟 (𝜔 ) = 𝑈 𝑒𝑥𝑝 (𝜔 )+ 𝑛 (𝜔 ) (4)
resulting in 𝑈 𝑟𝑒𝑎𝑙 (𝜔 ) =
𝑈 𝑒𝑥𝑝 (𝜔 )
𝐾 (𝜔 )
+
𝑛 (𝜔 )
𝐾 (𝜔 )
, with 𝐾 (𝜔 ) denoting the Fourier transformation (FT) of
the calorimetry apparatus impulse response,
𝐾 (𝜔 ) = ∫ 𝐾 (𝑡 )𝑒 𝑗𝜔𝑡 𝑑𝑡 +∞
−∞
(5)
and 𝑈 𝑟𝑒𝑎𝑙 (𝜔 ), 𝑈 𝑒𝑥𝑝 (𝜔 ) and 𝑛 (𝜔 ) representing the Fourier transformation of 𝑈 𝑟𝑒𝑎𝑙
(𝑡 ), 𝑈 𝑒𝑥𝑝
(𝑡 )
and 𝑛 (𝑡 ). Considering representations obtained in the frequency domain, estimated 𝑈
𝑟𝑒𝑎𝑙 (𝑡 ) can
be derived as:
𝑈 𝑟𝑒𝑎𝑙 (𝑡 ) =
1
2𝜋 ∫ (
𝑈 𝑒𝑥𝑝 (𝜔 )
𝐾 (𝜔 )
+
𝑛 (𝜔 )
𝐾 (𝜔 )
)𝑒 −𝑗𝜔𝑡 𝑑𝜔 = 𝑈 𝑡𝑟𝑢𝑒 (𝑡 )+
1
2𝜋 ∫
𝑛 (𝜔 )
𝐾 (𝜔 )
𝑒 −𝑗𝜔𝑡 𝑑𝜔 +∞
−∞
+∞
−∞
(6)
As it was previously pointed out, the process of addressing 𝑈 𝑟𝑒𝑎𝑙 (𝑡 ) can be significantly distorted
for trials with high noise interference. To overcome that issue, the regularized solution 𝑈 𝑟𝑒𝑎𝑙 (𝑡 ) is
determined in the form of (7):
𝑈 𝑟𝑒𝑎𝑙 (𝑡 ) =
1
2𝜋 ∫
𝑓 (𝜔 )
𝐾 (𝜔 )
(𝑈 𝑒𝑥𝑝 (𝜔 )+ 𝑛 (𝜔 ))𝑒 −𝑗𝜔𝑡 𝑑 𝜔 +∞
−∞
, (7)
where 𝑓 (𝜔 ) is a regularization function (for example, a sigmoid curve).
125
In the current study, the fast Fourier transform (FFT) algorithm was implemented to solve eq. (7).
At first, the impulse response 𝐾 (𝑡 ) was experimentally defined as a complex exponential function
in the continuous time domain (8):
𝐾 (𝑡 ) = 𝛼 1
𝑒 −𝑡 /𝜏 1
+ 𝛼 2
𝑒 −𝑡 /𝜏 2
, (8)
where 𝛼 1
= 0.0148; 𝛼 2
= 0.0156; 𝜏 1
= 3.220; and 𝜏 2
= 0.090.
Figure 5.1 reveals a graphical representation of an impulse response both for time (𝐾 (𝑡 )) and
frequency modes (𝐾 (𝜔 )). Since experimentally derived data set was provided in 0.05 minute-
fashion time scale, the frequency scale was illustrated in Hertz notation.
Figure 5.1 OmniCal multi-reactor calorimeter (Insight-CPR-210) (exployed for current studies ) impulse
response represented in A)time and B) frequency domains.
The protocol for calculating 𝑛 (𝜔 ) for three different types of reaction kinetics profiles (Table 5.1,
entries 1, 2, 3) utilized the difference between experimentally generated 𝑟 (𝑡 ) = 𝑈 𝑒𝑥𝑝 (𝑡 )+ 𝑛 (𝑡 )
and theoretically approximated 𝑟 ̂(𝑡 ) functions (20
th
order polynomial fit) with subsequent
numerical transformation into the frequency domain. Narrowband noise signals were derived for
126
all of the above mentioned types of calorific output and characterized with main frequency (𝑓 0
)
and frequency bandwidth (∆𝑓 ) parameters (Figure 5.2, Table 5.2).
Table 5.2 Characteristics of narrowband noise accompanied by the heat flow calorimetry experimental
output.
Entry 𝒇 𝟎 , Hz ∆𝒇 , Hz
1 (slow) 0.0212 0.0013
2 (medium) 0.0247 0.0018
3 (fast) 0.0201 0.0039
Figure 5.2 Noise representation for fast (entry 1), medium (entry 2) and slow (entry 3) kinetics (Table 5.1)
in A-C) frequency and A1-C1) time domains.
When performing dynamic correction (solving expression (7)), utilizing the dynamic correction
operation as part of the OmniCal Winsight calorimetry software, the presence of narrowband noise
127
not only impedes analysis by amplifying signal distortions but contributes to significant
deformation of estimated heat values 𝑈 𝑟𝑒𝑎𝑙 (𝑡 ) (Figure 5.3, blue). A similar result was obtained
when applying self-developed software based on FFT claiming 𝑓 (𝜔 ) = 1 (for |𝜔 | < 0.05) and
𝑓 (𝜔 ) = 0 (for |𝜔 | > 0.05). The FT dimension (quantity of the spectral components) was taken as
n = 2
15
.
Figure 5.3 Dynamic correction of the heat released done with the dynamic correction operation as part of
the OmniCal Winsight calorimetry software (green) and self-developed FFT-based computational protocol
(blue).
Thus, the rationale of performing further calculations with the polynomial approximation functions
(𝑟 ̂(𝑡 )) was dictated by the observation of narrowband noise 𝑛 (𝑡 ) being a solution of eq. (6) as
well, and thus, being magnified when computing eq. (7). Approximation with the theoretically
derived function returns noise-free experimental data amenable to further alteration. The
estimation of parameters of theoretically derived approximations 𝑟 ̂(𝑡 ) was obtained based on the
agreement of LSM metrics relative to the following functional (9) minimization:
128
min
𝑎⃗
∑ (𝑟 ̂(𝑡 𝑖 )− 𝑟 (𝑡 𝑖 ))
2 𝑛 𝑖 =1
, (9)
where 𝑟 ̂(𝑡 𝑖 ) = ∑ 𝑎 𝑖 𝑥 𝑖 ,
𝑁 𝑖 =0
𝑎 = (𝑎 0
,𝑎 1
,…,𝑎 𝑛 ).
The data in Figure 5.4 shows the ratio of experimentally gained instantaneous heat values to
approximation values to be slightly mismatched due to the noise inheritance n(t).
Figure 5.4 Comparison ratio of the experimentally gained heat flow profile r(t) with it’s polynomial fit
functions 𝑟 ̂(𝑡 ) for slow, medium and fast kinetics reaction profiles (Table 5.1).
The ratio, close to 1 throughout the entire conversion, demonstrates a fine fit of the experimental
dataset with the curving function. Employing a polynomial function, the integral (6) was solved
and the dynamically corrected 𝑈 𝑟𝑒𝑎𝑙 (𝑡 ) calorific outputs for all three trials are represented in
Figure 5.5 (B, C and D). Here, we demonstrated the influence of narrowband noise on the derived
instantaneous data, leading to incorrect data interpretation.
129
Figure 5.5 Heat flow kinetic profiles for the
I
CuAAC reactions shown in Scheme 5.1. A) Polynomial fit
(𝑟 ̂(𝑡 )) of the experimentally derived heat flow data (𝑟 (𝑡 )) (entry 1, Table 5.1); Calorific data processing
results: B) slow kinetics (entry 1, Table 5.1); C) medium kinetics (entry 2, Table 5.1); D) fast kinetics (entry
3, Table 5.1). (Red – experimental instantaneous heat flow data (𝑟 (𝑡 )); green – approximated
function (20th order polynomial curve) ( 𝑟 ̂(𝑡 𝑖 )); black – dynamically corrected calorific output
(𝑈 𝑟 𝑒 𝑎 𝑙 (𝑡 )) administering self-developed regularization protocol with 𝑟 ̂(𝑡 )) input data; blue – dynamically
corrected calorific output (estimated 𝑈 𝑟𝑒𝑎𝑙 (𝑡 )) derived with operation calorimetry Winsight software (with
𝑟 (𝑡 ) as input data).
130
5.5 HEAT FLOW CALORIMETRY FOR GLOBAL PARAMETER STUDIES OF
MULTISTEP REACTIONS
Previous kinetic investigations of the (iodoethynyl)benzene derivatives in the
I
CuAAC reaction
featured aromatic para-substituents to directly affect reaction rates. Indeed, the heat flow analysis
revealed significantly higher values of instantaneous heat for trifluoro-substituted electron-
deficient substrate A[3], whereas the adjacent value for electron-rich (iodoethynyl)benzene A[1]
has been progressively reduced almost seven fold (≈300 mW versus 45 mW, respectively) (Figure
5.5 B and D). Together with the maximum value of released instantaneous heat, the self-developed
dynamic correction procedure demonstrated that the signal area, in other words, the enthalpy of
the reaction, is also a reliable criterion for considering reaction kinetics to be fast, medium, or slow
(Table 5.1).
For precise quantification of experimental mechanistic profiles, heat flow measurements were
analytically processed to derive kinetic parameters, distinguishable by the observed substrate
reactivity. As such, corresponding instantaneous rates were plotted in time domain to obtain kinetic
parameters in quasi-equilibrium approximation in asymptotic time form (Figure 5.6). The
exponential decay arguments deduced the trend for apparent rate constants to be consistent with
the detected chemical reactivity of the claimed substrates. As such, the 𝑘 𝑜𝑏𝑠 constant of the iodo-
triazolide P[1] formation was calculated to be the lowest with that of electron-deficient triazole
P[3] being almost five times greater (Table 5.3).
131
Figure 5.6 Reaction rates derived from eq.(1) employing dynamically corrected heat flow sequences obtained with
the self-developed regularization protocol.
Table 5.3 Reaction rate constants for iodoalkynes A[1], A[2] and A[3] in
I
CuAAC reaction catalyzed by
the CuI-TTTA system.
Entry 𝒌 𝒐𝒃𝒔
= 𝜷 𝒙 , min
-1
𝛔 × 𝟏𝟎
−𝟑
1 (slow); P[1] 0.053 0.21
2 (medium); P[2] 0.175 0.43
3 (fast); P[3] 0.292 1.96
Table 5.4 Exponential decay function parameters represented in Figure 5.6.
Entry 𝜶 𝒙 × 𝟏𝟎
−𝟑 𝝈 𝜶 × 𝟏𝟎
−𝟒 𝜷 𝒙 𝝈 𝜷 × 𝟏𝟎
−𝟑 𝜸 𝒙 × 𝟏𝟎
−𝟒 𝝈 𝜸 × 𝟏𝟎
−𝟔
rate(t); P[1] 3.81 0.11 0.053 0.21 1.34 2.54
rate(t); P[2] 11.61 0.27 0.175 0.43 8.05 3.17
rate(t); P[3] 26.71 1.42 0.292 1.96 7.63 121.80
132
5.6 STEP-BY-STEP PROTOCOL FOR PROCESSING THE CALORIFIC
OUTPUT
1) Experimental heat flow data versus time were extracted from OmniCal Winsight
software and plotted in a time-related domain without additional processing in an
available numerical software package (Excel, MATLAB, Origin).
2) The heat flow data was approximated with the polynomial function (the order is
determined by F-statistic criteria and usually does not exceed 20
th
order) on the
entire conversion profile.
3) Impulse convolution K(t) and approximated experimental input 𝑟 ̂(𝑡 ) were
transferred to the frequency domain, employing the Fourier transform.
4) Derived frequency-mode representations of K(ω) and 𝑟 ̂(𝜔 ) were introduced into
the fast Fourier transform algorithm when deconvoluting integral expression (7).
The regularization function 𝑓 (𝜔 ) = 1 was employed.
5) Obtained estimated values of 𝑈 𝑟𝑒𝑎𝑙 (𝑡 ) were used as the true dynamically corrected
heat flow for further kinetic investigations.
5.7 CONCLUSIONS
The algorithm of dynamically corrected heat flow values taken from the experimentally derived
instantaneous heat output was developed and probed using the example of a complex catalytic
reaction - a copper(I)-catalyzed reaction of azide-1-iodoalkyne cycloaddition. The algorithms of
fast Fourier transformation were employed to obtain a regularized solution of the convolution
integral denoting an ill-posed problem in mechanistic (kinetic) modelling. Obtained
thermodynamic and kinetic parameters demonstrated a structure-dependent reactivity for the
133
spectra of para-substituted (iodoethynyl)-benzene derivative substrates. As such, a Hammett-type
linear energy trend among rate constant values and the electronic nature of 1-iodoalkyne substrates
involved in
I
CuAAC transformation were observed to coincide with the results of the
1
H NMR
studies in Chapter II.
5.8 EXPERIMENTAL DETAILS
Employed computational protocols and FFT-based software were developed in C++ and applied
for a dense data calorimetry analysis for solving an ill-posed problem in chemical kinetics with
the subsequent outlining of the reaction rate parameters in a quasi-equilibrium approach.
Experiments were performed on an OmniCal multi-reactor calorimeter, Insight-CPR-210. Julabo
circulator FS18-MC was employed as an external temperature control system. Prior to data
acquisition, all reaction components were mixed in a 12 ml glass vial equipped with a septum cap.
The system temperature was equilibrated before the injection of the catalyst. The reactor
temperature was kept constant at 35 °C until the entire heat flow profile was acquired. The rate of
stirring was 90 rpm and was applied equally within the same experimental batch. Reaction
progress monitoring and data collection were performed in OmniCal Winsight software (version
2004-2005). For the purpose of narrowband noise influence studies, dynamic correction procedure
was employed to raw heat flow measurements employing cell time constants of the reaction station
as τ1 = 2.00 and τ2 = 0.13 min. All the reaction setups were well-stirred, and a mixing vessel with
glass walls was employed. The total heat of reactions was found based on the reaction conversions
verified with HPLC analysis.
For the entire experimental batch, the initial concentrations of (2-azidoethyl)benzene [Z], 1-
iodoalkyne A[X] and catalyst [CuI∙ 𝑇𝑇𝑇𝐴 ] components were 0.113 M, 0.1 M and 0.01 M,
134
respectively. The copper(I)-ligand [cat∙ 𝑇𝑇𝑇𝐴 ] solution in tetrahydrofuran (THF) was injected as
a clear solution to a mixture of azide and alkyne components. THF was dried by passing
commercially available solvents through the activated alumina columns of the solvent purification
system. 1-chloro-4-ethynylbenzene and 1-ethynyl-4-(trifluoromethyl)benzene were purchased
from Sigma-Aldrich for subsequent iodination procedures employing N-iodosuccinimide
23
.
Copper iodide was purchased from Sigma-Aldrich. Tris-((1-tert-butyl-1H-1,2,3-
triazolyl)methyl)amine (TTTA) triazolyl containing ligand was synthesized following the
previously reported literature procedure
19
.
135
5.9 REFERENCES
(1) Ferretti, A. C.; Mathew, J. S.; Blackmond, D. G., Reaction Calorimetry as a Tool for
Understanding Reaction Mechanisms: Application to Pd-Catalyzed Reactions. Ind. Eng. Chem.
Res. 2007, 46 (25), 8584-8589.
(2) Garbett, N. C.; Chaires, J. B., Thermodynamic studies for drug design and screening.
Expert Opin. Drug Discov. 2012, 7 (4), 299-314.
(3) Chaires, J. B., Calorimetry and Thermodynamics in Drug Design. Annu. Rev. Biophys.
2008, 37 (1), 135-151.
(4) Zogg, A.; Stoessel, F.; Fischer, U.; Hungerbühler, K., Isothermal reaction calorimetry as
a tool for kinetic analysis. Thermochim. Acta 2004, 419 (1-2), 1-17.
(5) Gravelle, P. C., Heat-Flow Microcalorimetry and Its Application to Heterogeneous
Catalysis. In Advances in Catalysis, Elsevier: 1972; pp 191-263.
(6) Hattori, M.; Tanaka, S.; Amaya, K., A One-dimensional Model of a Conduction
Calorimeter. Bull. Chem. Soc. Jpn. 1970, 43 (4), 1027-1032.
(7) Landau, R. N.; Blackmond, D. G.; Tung, H.-H., Calorimetric Investigation of an
Exothermic Reaction: kinetic and Heat Flow Modeling. Ind. Eng. Chem. Res. 1994, 33 (4), 814-
820.
(8) Burés, J.; Armstrong, A.; Blackmond, D. G., The interplay of thermodynamics and kinetics
in dictating organocatalytic reactivity and selectivity. Pure Appl. Chem. 2013, 85 (10), 1919-1934.
(9) Fitzpatrick, D. E.; Ley, S. V ., Engineering chemistry: integrating batch and flow reactions
on a single, automated reactor platform. React. Chem. Eng. 2016, 1 (6), 629-635.
(10) Porta, R.; Benaglia, M.; Puglisi, A., Flow Chemistry: Recent Developments in the
Synthesis of Pharmaceutical Products. Org. Process Res. Dev. 2015, 20 (1), 2-25.
(11) Blackmond, D. G., Reaction Progress Kinetic Analysis: A Powerful Methodology for
Mechanistic Studies of Complex Catalytic Reactions. Angew. Chem. Int. Ed. 2005, 44 (28), 4302-
4320.
(12) Stoessel, F., Applications of reaction calorimetry in chemical engineering. J. Therm. Anal.
1997, 49 (3), 1677-1688.
(13) Regenass, W., The development of heat flow calorimetry as a tool for process optimization
and process safety. J. Therm. Anal. 1997, 49 (3), 1661-1675.
(14) Stefan M. Sarge, G. W. H. H., Wolfgang Hemminger, Calorimetry: Fundamentals,
Instrumentation and Applications. Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, 2014.
(15) Wadsö, L.; Gómez Galindo, F., Isothermal calorimetry for biological applications in food
science and technology. Food Control 2009, 20 (10), 956-961.
(16) Wadsö, I.; Goldberg, R. N., Standards in isothermal microcalorimetry (IUPAC Technical
Report). Pure Appl. Chem. 2001, 73 (10), 1625-1639.
(17) Marison, I.; Linder, M.; Schenker, B., High-sensitive heat-flow calorimetry1Presented at
the Twelfth Ulm-Freiberg Conference, Freiberg, Germany, 19–21 March 19971. Thermochim.
Acta 1998, 310 (1-2), 43-46.
(18) Richner, G. C.-A. Dynamic study of a new small scale reaction calorimeter and its
application to fast online heat capacity determination. Ph.D. Thesis, ETH Zurich, Switzerland,
2008.
136
(19) Hein, J. E.; Tripp, J. C.; Krasnova, L. B.; Sharpless, K. B.; Fokin, V . V ., Copper(I)-
Catalyzed Cycloaddition of Organic Azides and 1-Iodoalkynes. Angew. Chem. Int. Ed. 2009, 48
(43), 8018-8021.
(20) Lopez-Sandoval, E.; Mello, A.; Godina-Nava, J. J.; Samana, A. R. Power Series Method
applied to Inverse Analysis in Chemical Kinetics Problem arXiv e-prints [Online], 2012, p.
arXiv:1203.3800. (accessed April 12, 2020).
(21) Ferreira, B. D. L.; Paulo, J. M.; Braga, J. P.; Sebastião, R. C. O.; Pujatti, F. J. P., Methane
combustion kinetic rate constants determination: an ill-posed inverse problem analysis. Quim.
Nova 2013, 36, 262-266.
(22) Santosa, F.; Weitz, B., An inverse problem in reaction kinetics. J. Math. Chem. 2011, 49
(8), 1507-1520.
(23) Lehnherr, D.; Alzola, J. M.; Lobkovsky, E. B.; Dichtel, W. R., Regioselective Synthesis
of Polyheterohalogenated Naphthalenes via the Benzannulation of Haloalkynes. Chem. Eur. J.
2015, 21 (50), 18122-18127.
137
A P P E N D I C E S
138
Appendix A ADDITIONAL INFORMATION ON CHAPTER II
A.1
1
H NMR KINETIC STUDIES
General information
THF-d8 was purchased in ampules from Cambridge Isotope Laboratories, Inc., opened inside a
glovebox and stored over molecular sieves. Copper(I) iodide was purchased from Sigma-Aldrich
and used as received. The 1-iodoalkynes as well as tris-((1-cyclopentyl-1H-1,2,3- triazol-4-
yl)methyl)amine (TCPTA)
1
, tris-((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)amine (TBTA) and tris-
((1-tert-butyl-1H-1,2,3-triazolyl)methyl)amine (TTTA) were prepared following reported
literature procedures.
2
Experimental details
Kinetic experiments were carried out in 5mm thin wall precision NMR tubes (7”, 600 MHz, 535-
PP-7, Wilmad LabGlass). All glassware was oven-dried (140 °C) and purged by vacuum-N2 cycles
in the antechamber of the glovebox before use. Stock solutions of corresponding 1-iodoalkynes,
(2-azidoethyl)benzene and CuI-TCPTA were prepared using volumetric flasks with a 1 ml or 2 ml
volume and stored in LCMS-capped vials for the duration of one batch of experiments.
1
H spectra
were recorded either on a Varian VNMRS-500 or a Varian VNMRS-600 spectrometer. Chemical
shifts are reported in ppm referenced to 3.28 ppm one solvent residual peak of THF in deuterated-
THF. Conversion rates were determined from the NMR data and were verified by either by HPLC,
GC-MS or LC-MS analysis
Data analysis
For manipulation of the NMR spectra and signal peak integration MestReNova (Version 9.0.0,
Mestrelab Research S.L.) was used. Further data processing, calculation of the rate constants as
139
well as validity verification was accomplished by using a self-developed protocols C++ or the
Origin 9.0 data analysis and graphing software package (OriginLab Corporation). Graphical
analysis and interpretation of the processed experimental data was done using Origin 9.0 or
Microsoft Excel 2016 software. The Hammett free energy relationship, comparison of the kinetic
profiles for concentration excess as well as variable temperature experiments were derived using
the initial rates method.
140
A.1.1.1 GENERAL PROCEDURE A - INDEPENDENT REACTIVITY STUDIES FOR
1-IODOALKYNES [1]-[5]
Independent reactivity experiments: Stock solutions of 0.4 M 1-iodoalkynes A[X], 0.52 M (2-
azidoethyl)benzene (0.115 mg, 0.78 mmol, 1.3 eq. in 1.5 ml), 0.045M of TCPTA and 0.04 M 1,4-
dimethoxybenzene (internal standard) in THF-d8 were prepared and handled in the dry nitrogen
atmosphere of a glove box. The amount of CuI necessary for a 0.04 M catalyst solution was weight
out and mixed with the corresponding volume of TCPTA stock solution to prepare the CuI-TCPTA
catalytic mixture. The mixture was agitated until of a clear pale-yellow solution was formed. The
total volume in the NMR tube for one experiment was 0.8 ml.
NMR kinetic experiments were recorded on a Varian VNMRS-500 spectrometer with no spinning.
1
H-NMR data was collected with the following acquisition parameters: 2 transients (scans), 5 sec.
relaxation delay time, acquisition time of 3.2768 sec. Between the spectra was a 1 sec pre-
acquisition delay. The data was collected at 28.5°C. The temperature was calibrated against a
temperature standard (ethylene glycol). Each individual experiment was performed twice. All
reagents were dried before use. All manipulations were performed in the dry nitrogen atmosphere
of a glove box. Reaction conversions were integrated relative to an internal reference standard.
141
Table A.1 Reaction conditions of experiments following general procedure A. Independent reactivity
I
CuAAC experiments.
Entry A [X], M [Z], M [CuI], M [TCPTA], M [Ref], M [excess], M
Time
(averaged),
sec
Conv,
%
1 [1], 0.1 0.130
0.01 0.0123 0.0098 0.03
42653 89.8
2 [2], 0.1 0.130 49931 100.0
3 [3], 0.1 0.130 33539 100.0
4 [4], 0.1 0.130 5287 100.0
5 [5], 0.1 0.127 1944 100.0
Rate of [1]
Kinetic data was obtained by following the general procedure A: 200 μl of the 0.04 M catalyst
solution were added to a mixture consisting of each 200 μl of the stock solutions of 1-
(iodoethynyl)-4-methoxybenzene (0.4 M, 0.021 mg, 0.079 mmol, 1 eq.), (2-azidoethyl) benzene
(0.52 M) and the internal reference (0.04 M). The rate constant k= 2.11E-5(6.00E-7) was derived
as the slope of the initial rate curve.
y = 0.0000210968x + 0.0088318449
R² = 0.9507348790
0
0.005
0.01
0.015
0.02
0.025
0.03
0.035
0.04
0 200 400 600 800 1000 1200 1400 1600
concentration, M
time, sec
P[1], M
142
Rate of [2]
Kinetic data was obtained by following the general procedure A: 200 μl of the 0.04 M catalyst
solution were added to a mixture consisting of each 200 μl of the stock solutions of 1-(tert-butyl)-
(iodoethynyl)benzene (0.4 M, 0.023 mg, 0.079 mmol, 1 eq.), (2-azidoethyl) benzene (0.52 M) and
the internal reference (0.04 M). The rate constant k=2.86E-5 (7.38E-7) was derived as the slope of
the initial rate curve
Rate of [3]
Kinetic data was obtained by following the general procedure A: 200 μl of the 0.04 M catalyst
solution were added to a mixture consisting of each 200 μl of the stock solutions of
(iodoethynyl)benzene (0.4 M, 0.018 mg, 0.079 mmol, 1 eq.), (2-azidoethyl) benzene (0.52 M) and
the internal reference (0.04 M). The rate constant k= 4.03E-5 (2.04E-6) was derived as the slope
of the initial rate curve.
y = 0.0000285621x + 0.0049789079
R² = 0.9740089829
0
0.005
0.01
0.015
0.02
0.025
0.03
0.035
0 200 400 600 800 1000
concentration, M
time, sec
P[2], M
143
Rate of [4]
Kinetic data was obtained by following the general procedure A: 200 μl of the 0.04 M catalyst
solution were added to a mixture consisting of each 200 μl of the stock solutions of 1-chloro-4-
(iodoethynyl)benzene (0.4 M, 0.021 mg, 0.079 mmol, 1 eq.), (2-azidoethyl) benzene (0.52 M) and
the internal reference (0.04 M). The rate constant k=1.31E-4 (4.30E-6) was derived as the slope of
the initial rate curve.
144
Rate of [5]
Kinetic data was obtained by following the general procedure A: 200 μl of the 0.04 M catalyst
solution were added to a mixture consisting of each 200 μl of the stock solutions of 1-
(iodoethynyl)-4-(trifluoromethyl)benzene (0.4 M, 0.024 mg, 0.079 mmol, 1 eq.), (2-azidoethyl)
benzene (0.52 M) and the internal reference (0.04 M). The rate constant k=2.43E-4 (8.92E-6) was
derived as the slope of the initial rate curve.
145
A.1.2 GENERAL PROCEDURE B – RATE-ORDERS EXPERIMENTS
For evaluation of [Azide] rate order: A 0.4 M stock solution of 1-chloro-4-(iodoethynyl)benzene
in THF-d8 was prepared. 0.014 M, 0.045 M, 0.067 M, 0.135 M and 0.235 M solutions of (2-
azidoethyl)benzene (final sample concentration) in THF-d8 were prepared by sequential dilutions.
For evaluation of [Alkyne] rate order: A 0.45 M stock solution of (2-azidoethyl)benzene and
0.13 M, 0.16 M, 0.21 M, 0.05 M solutions of 1-chloro-4-(iodoethynyl)benzene (final sample
concentration) in THF-d8 were prepared. In addition, a 0.045 M stock solution of TCPTA in THF-
d8 was prepared. The amount of CuI necessary for a 0.04 M catalyst solution was weight out and
used together with the TCPTA stock solution for the preparation of the CuI-TCPTA catalytic
mixture. The mixture was agitated until of a clear pale-yellow solution was obtained. The total
volume in the NMR tube for one experiment was 0.8 ml.
NMR kinetic experiments were recorded on a Varian VNMRS-500 spectrometer with no spinning.
1
H-NMR data was collected with the following acquisition parameter: 4 transients (scans), 2 sec.
relaxation delay time, acquisition time of 2.7263 sec. Between the spectra was a 1 sec pre-
acquisition delay. The data was collected at 35.8˚C. The temperature was calibrated against a
temperature standard (ethylene glycol). Each individual experiment was performed twice. All
reagents were dried before use. All manipulations were performed in the dry nitrogen atmosphere
of a glove box. Reaction conversions were determined by signal integration relative to an internal
reference standard.
146
A.2.1.1 (2-AZIDOETHYL)BENZENE RATE ORDER EXPERI MENTS
Evaluation of the azide rate order:1 ml of a stock solution of 1-chloro-4-(iodoethynyl)benzene in
THF-d8 was prepared inside of a glovebox (0.105 g, 0.04 mmol), transferred to a dry LCMS- glass
vial and sealed with a septum cap. Solutions with various concentrations of (2-azidoethyl)benzene
in THF-d8 were prepared and transferred to a dry LCMS-glass vials and closed with a septum cap
(250 μl each). A 0.208 M stock solution of the internal reference standard in THF-d8 was prepared
(0.029 g, 0.2 mmol). For the NMR kinetic experiment 200 μl of every stock solution was
transferred into an NMR tube equipped with a septum cap and agitated. The rate constants were
determined from the slope of the line in the plot of product concentration of P[X] versus time. All
experiments were repeated twice.
Preparation of the catalyst mixture
The tris-((1-cyclopentyl-1H-1,2,3- triazol-4-yl)methyl)amine (TCPTA) ligand was synthesized
following a procedure reported by Jason Hein and co-workers.
3
The catalyst solution was prepared
with CuI (7.6 mg, 0.04 mmol) and TCPTA (0.021 g, 0.045 mmol) in 2 ml of dry THF-d8. The
mixture was agitated until of a clear pale-yellow solution was formed.
147
Table A.2 Reaction conditions of experiments following general procedure B. Variable [Azide]
concentration experiments.
Entry A[4], M [Z], M [CuI], M [TCPTA], M [excess], M conv, % kobs, sec
-1
σ
1
0.1
0.014
0.01 0.0113
-0.086 81.4 % 6.54E-6 2.89E-7
2 0.045 -0.055 72.2 % 1.80E-5 5.48E-7
3 0.067 -0.033 75.0 % 2.93E-5 5.35E-7
4 0.135 0.035 100.0 % 1.49E-4 9.48E-6
5 0.248 0.135 100.0 % 2.07E-4 5.41E-6
A
148
B
C
149
D
E
150
F
Figure A.1 Kinetic profiles obtained from the experiment described in the general procedure B. Variable
[Azide] concentration experiments. A-E) reactant concentrations vs time; F) reaction conversion versus
time. Method of initial rates.
Figure A.2 Plot of Ln(rate) vs Ln([Azide]) shows a non-zero order in the azide concentration in the reaction
rate (n=1.31).
151
A.2.1.2 DEPENDENCE ON 1-CHLORO-4-(IODOETHYNYL)BENZENE
CONCENTRATION
Evaluation of 1-iodoalkyne rate order: 1 ml of a stock solution of (2-azidoethyl)benzene in 2 ml
of THF-d8 was prepared inside of a glovebox (0.066 g, 0.45 mmol), transferred to a dry LCMS-
glass vial and closed with a septum cap. Solutions with various concentrations of 1-chloro-4-
(iodoethynyl)benzene in THF-d8 were prepared through multiple dilution cycles and transferred
to a dry LCMS-type glass vial equipped with a septum cap (250 μl each).
For the NMR kinetic experiment 200 μl of every reagent stock solution was transferred into an
NMR tube which is closed with a NMR tube septum cap and properly agitated. The rate constants
were determined from the slope of the line in the plot of product concentration of P[X] versus time.
All the experiments were repeated twice.
Preparation of the catalyst
The tris-((1-cyclopentyl-1H-1,2,3- triazol-4-yl)methyl)amine (TCPTA) ligand was synthesized
following procedure reported by Jason Hein and co-workers.
3
The catalyst solution was prepared
with CuI (7.6 mg, 0.04 mmol) and TCPTA (0.021 g, 0.045 mmol) in 2 ml of dry THF-d8. The
mixture was agitated until of a homogeneous pale-yellow solution was formed.
Table A.3 Reaction conditions of the experiments following general procedure B. Variable [Alkyne]
concentration experiments.
Entry A [4], M [Z], M [CuI], M [TCPTA], M [excess], M kobs, sec
-1
σ
1 0.127
0.1125 0.01 0.0113
0.0145 1.46E-4 6.12E-6
2 0.160 0.0475 1.43E-4 6.85E-6
3 0.209 0.0965 1.47E-4 6.11E-6
4 0.047 -0.0655 1.08E-4 7.90E-6
152
Figure A.3 Kinetic profiles obtained from the experiment described by the general procedure B. Variable
[Alkyne] concentration experiments. A) Reaction conversion vs. time; B1-B4) 5-iodo-1,2,3-triazole P[4]
concentration vs. time.
153
Figure A.4 Ln(rate) vs. Ln([Alkyne]) reveals a change in 1-iodoalkyne rate orders (from n=0.84 to
n=0.013).
154
A.1.3 GENERAL PROCEDURE C – VT EXPERIMENTS
Stock solutions of 1-iodoalkynes [1] and [4], (2-azidoethyl)benzene and 1,4-dimethoxybenzene
(internal standard) stock solutions were prepared in THF-d8 and handled in the dry nitrogen
atmosphere of a glove box. The CuI-TCPTA catalyst solution was prepared with TCPTA being in
5.0mM concentration excess. For the NMR kinetic experiment 200 μl of every reagent stock
solution was transferred to an NMR tube which is closed with a NMR tube septum cap and
properly agitated.
Variable temperatures NMR kinetic experiments were recorded on a Varian VNMRS-500 or a
Varian VNMRS-600 spectrometer without sample spinning. The NMR data was collected with the
following acquisition parameter: 4 transients (scans), 2 sec. relaxation delay time. Between the
spectra was a 1 sec pre-acquisition delay. The temperatures were calibrated against a temperature
standard (neat ethylene glycol or methanol). Each individual experiment was performed twice. All
reagents were dried before use to ensure anhydrous conditions. All manipulations were performed
in the dry nitrogen atmosphere of a glove box to avoid oxidation of CuI by an atmospheric oxygen.
Reaction conversions were determined by integration relative to an internal reference standard or
by the sum of reactant-product integral values. The rate constants were determined from the slope
of the line in the plot of product concentration of P[X] versus time. All the experiments were
repeated twice.
155
A.3.1.1 EYRING PLOT FOR 1-CHLORO-4-(IODOETHYNYL)BENZENE
Kinetic data was obtained by following general procedure C using stock solutions of 1-chloro-4-
(iodoethynyl)benzene (0.130 mg, 0.5 mmol, 0.95 eq.) in 1.3 ml of THF-d8 and (2-
azidoethyl)benzene (0.076 mg, 0.52 mmol, 1.0 eq.) in 1.3 ml of THF-d8. Temperatures were
277.1 K, 287.9 K, 301.0 K, 318.5 K.
Preparation of the catalyst
The tris-((1-cyclopentyl-1H-1,2,3- triazol-4-yl)methyl)amine (TCPTA) ligand was synthesized
following procedure reported by Jason Hein and co-workers.
3
The catalyst solution was prepared
with CuI (7.6 mg, 0.04 mmol) and TCPTA (0.021 g, 0.045 mmol) in 2 ml of dry THF-d8. The
mixture was agitated until of a homogeneous pale-yellow solution was formed.
Table A.4 Reaction conditions for the experiments following general procedure C. Variable-temperature
NMR kinetic studies of
I
CuAAC reaction mechanism with 1-chloro-4-(iodoethynyl)benzene substrate A[4].
Entry A[4], M [Z], M T, K [CuI], M [TCPTA], M [Ref], M kobs , sec
-1
σ
1 0.095 0.1 277.1
0.01 0.0113 0.030
3.24E-5 4.16E-7
2 0.095 0.1 287.9 4.99E-5 9.75E-7
3 0.095 0.1 301.0 7.98E-5 2.75E-6
4 0.095 0.1 318.5 1.46E-4 1.51E-5
156
Figure A.5 Kinetic profiles obtained from the experiment described by the general procedure C. A) 5-iodo-
1,2,3-triazole P[4] concentration vs. time; B1-B4) Initial concentrations of P[4] vs. time.
157
Figure A.6 Activation parameters for electron-deficient 1-iodo-alkyne [4]. Results of Eyring plot: ∆H
ǂ
=5.8
(1.1) kcal/mol and ∆S
ǂ
=-58.1 (0.2) cal/mol·K.
158
A.3.1.2 EYRING PLOT FOR 1-(IODOETHYNYL)-4-METHOXYBENZENE
Kinetic data was obtained by following general procedure C using stock solutions of 1-
(iodoethynyl)-4-methoxybenzene (0.100 mg, 0.38 mmol, 0.83 eq.) in 1.3 ml of THF-d8 and (2-
azidoethyl)benzene (0.068 mg, 0.46 mmol, 1.0 eq.) in 1.3 ml of THF-d8. The experiments were
performed at 287.6 K, 297.8 K, 308.1 K, 318.0 K and 331.9 K, respectively.
Preparation of the catalyst
The tris-((1-cyclopentyl-1H-1,2,3- triazol-4-yl)methyl)amine (TCPTA) ligand was synthesized
following procedure reported by Jason Hein and co-workers.
3
The catalyst solution was prepared
by dissolving CuI (7.6 mg, 0.04 mmol) and TCPTA (0.021 g, 0.045 mmol) in 2 ml of dry THF-
d8. The mixture was agitated until of a homogeneous pale-yellow solution was formed.
Table A.5 Reaction conditions of the experiments following general procedure C. Variable-temperature
NMR kinetic studies of
I
CuAAC reaction mechanism with 1-methoxy-4-(iodoethynyl)benzene substrate
A[1].
Entry A[1], M [Z], M T, K [CuI], mM [TCPTA],
mM
[Ref], M kobs , sec
-1
σ
1
0.074 0.089
287.6
7.4 8.32 0.0348
1.19E-05 5.47E-07
2 297.8 1.40E-05 6.66E-07
3 308.1 1.90E-05 5.28E-07
4 318.0 2.24E-05 6.35E-07
5 331.9 2.79E-05 8.31E-07
159
Figure A.7 Kinetic profiles for reactions described in the general procedure C. A) Product P[1]
concentration vs. time; B1-B5) Initial concentrations of the 5-iodo-1,2,3-triazole [P] vs. time.
160
Figure A.8 Activation parameters for the electron-rich 1-iodo-alkyne[1]. Results of Eyring plot: ∆Hǂ =3.2
(0.9) kcal/mol and ∆Sǂ =-70.0 (3.1) cal/mol·K.
161
A.1.4 GENERAL PROCEDURE D - INFLUENCE OF THE USED CATALYTIC
SYSTEM ON THE SUBSTRATE REACTIVITY
Evaluation of the influence on substrate reactivity of the different coordinating ligands use in the
catalyst solution: 0.05 M solutions of tris-((1-cyclopentyl-1H-1,2,3- triazol-4-
yl)methyl)amine (TCPTA), tris-((1-tert-butyl-1H-1,2,3-triazolyl)methyl)amine (TTTA) and tris-
((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)amine (TBTA) in CD3CN-d3 were prepared and mixed
with the corresponding to 0.044 M amount of CuI. The catalyst mixtures were agitated until of
homogeneous solutions were formed. The solutions were yellow color when TCPTA and TTTA
ligands were used and only very pale yellow in case of the TBTA ligand. The catalyst solutions
were transferred to a dry LCMS-glass vial and closed with a septum cap. 0.55 ml of a 0.53 M
solution of 1-chloro-4-(iodoethynyl)benzene, a 0.58 M solution of (2-azidoethyl)benzene, and a
0.153 M solution of 1,4-dimethoxybenzene in dry CD3CN-d3 was prepared and transferred to a
dry LCMS glass vial and sealed with a septum cap. The kinetic measurements were started once
150 μl of every reagent stock solution and 200 μl of the catalyst-solution (CuI-TCPTA, CuI-TTTA
or CuI-TBTA) was transferred to an NMR tube closed with a NMR septum cap. The reaction was
monitored by
1
H NMR kinetic experiments with the following acquisition parameter: 1 transient
(scan), 1 sec. relaxation delay time, acquisition time of 3.2768 sec. Between the spectra was a 1 sec
pre-acquisition delay. The data was collected at 24.0˚C. The temperature was calibrated against a
temperature standard (ethylene glycol). All the experiments were repeated twice. A HPLC/DAD
analysis of the aliquots taken from the reaction mixture was performed to verify the accuracy of
the NMR spectroscopic determined conversion values.
162
Preparation of the catalytic mixtures
For Cu(I)-TCPTA catalyst:
The tris-((1-cyclopentyl-1H-1,2,3- triazol-4-yl)methyl)amine (TCPTA) ligand was synthesized by
following a procedure reported by Jason Hein and co-workers.
3
A homogeneous solution of CuI
(1.5 mg, 0.008 mmol) and TCPTA (4.6 mg, 0.01 mmol) in 2 ml of dry CD3CN-d3 was prepared.
The mixture was agitated until of a clear pale-yellow solution was formed.
For Cu(I)-TTTA catalyst:
A homogeneous solution of CuI (1.5 mg, 0.008 mmol) and TTTA (4.3 mg, 0.01 mmol) in 2 ml of
dry CD3CN-d3 was prepared. The mixture was agitated until of a clear pale-yellow solution was
formed.
For Cu(I)-TBTA catalyst:
A homogeneous solution of CuI (1.5 mg, 0.008 mmol) and TBTA (5.3 mg, 0.01 mmol) in 2 ml of
dry CD3CN-d3 was prepared. The mixture was agitated until of a clear pale-yellow solution was
formed.
Table A.6 Reaction conditions of experiments following general procedure D. Variable catalytic systems
studies.
Entry A[4], M [Z], M [CuI], M Ligand, M time, sec Conv, %
1
0.1231 0.1338 0.01
[TCPTA], 0.0123 2451 100.0
2 [TTTA], 0.0123 3432 100.0
3 [TBTA], 0.0123 6327 100.0
163
A.1.5 GENERAL PROCEDURE E - PROBING CATALYST ROBUSTNESS FOR OFF-
CYCLE SPECIES SCENARIOS
For the study of a possible formation of oligomeric alkyne-catalyst π-complexes species, kinetic
profiling experiments with various catalyst loadings were performed. Stock solutions of 0.35 M 1-
chloro-4-(iodoethynyl)benzene and 0.53 M (2-azidoethyl)benzene and 0.042 M 1,4-
dimethoxybenzene in THF-d8 were prepared.
1
st
sample: 200 μl of a 0.35 M solution of 1-chloro-4-(iodoethynyl)benzene, 200 μl of a 0.53 M
solution of (2-azidoethyl)benzene, 50 μl of pure THF-d8, 150 μl of the CuI-TCPTA catalyst
solution and 200 μl of a 0.042 M solution of 1,4-dimethoxybenzene were transferred to a NMR
tube closed with a NMR septum cap. In situ NMR reaction monitoring was immediately initiated
after all reactants were added and sporadically agitated.
2
nd
sample: 200 μl of a 0.35M solution of 1-chloro-4-(iodoethynyl)benzene, 200 μl of a 0.53 M
solution of (2-azidoethyl)benzene, 100 μl of pure THF-d8, 100 μl of the CuI-TCPTA catalytic
mixture and 200 μl of a 0.042 M solution of 1,4-dimethoxybenzene were transferred to a NMR
tube closed with a NMR septum cap. In situ NMR reaction monitoring was immediately initiated
after all reactants were added and sporadically agitated.
1
H-NMR kinetic data was collected with the following acquisition parameters: 1 transient (scan),
5 sec. relaxation delay time, acquisition time of 3.2768 sec. Between the spectra was a 1 sec pre-
acquisition delay. The data was collected at 35.5˚C.
164
Preparation of the CuI-TCPTA catalyst:
Tris-((1-cyclopentyl-1H-1,2,3- triazol-4-yl)methyl)amine (TCPTA) ligand was synthesized by
following a procedure reported by Jason Hein and co-workers.
3
A homogeneous solution of
CuI (0.010 g, 0.052 mmol) and TCPTA (0.031 g, 0.067 mmol) in 1.5 ml of THF-d8 was prepared.
The mixture was agitated until of a clear pale-yellow solution was formed.
Table A.7 Reaction conditions of experiments following general procedure E. Variable catalytic systems.
Entry A[4], M [Z], M [CuI-TCPTA]
mM
[Ref], M time
(averaged), sec
Conv, %
1
0.087 0.132
6.56
0.0105
8407 100.0
2 4.37 14107 100.0
Figure A.9 Kinetic profiles for reactions described in general procedure E. A) 4.37 mM of [cat]; B)
6.56 mM of [cat].
165
A.1.6 GENERAL PROCEDURE F - PROBING CATALYST ROBUSTNESS FOR
DEACTIVATION SCENARIOS
For the evaluation of a possible catalyst deactivation in the active catalyst cycle, ‘same excess’
experiments were performed. Stock solution of 0.4 M iodoethynyl)benzene ([Alkyne]) and 0.54 M
(2-azidoethyl)benzene ([Azide]) and 0.042 M 1,4-dimethoxybenzene in THF-d8 were prepared.
The ‘excess’ parameter was defined as [ex]=[Azide]-[Alkyne]. Plots of experimental
concentration versus time were approximated by double exponential decay or rise functions. For
the graphical representation of the kinetic profiles approximated curves were used.
1
st
sample: 200 μl of a 0.4M solution of (iodoethynyl)benzene, 200 μl of a 0.54 M solution of (2-
azidoethyl)benzene, 200 μl of the CuI-TCPTA catalyst solution and 200 μl of a 0.042 M solution
of 1,4-dimethoxybenzene were transferred to a NMR tube closed with a NMR septum cap. In situ
NMR reaction monitoring was immediately initiated after all reactants were added and
sporadically agitated. Calculated value of excess [excess]=0.035M.
2
nd
sample: 0.15ml of a 0.4 M solution of (iodoethynyl)benzene, 150 μl of a 0.54 M solution of (2-
azidoethyl)benzene, 100 μl of pure THF-d8, 200 μl of the CuI-TCPTA catalyst solution and 200 μl
of a 0.042 M solution of 1,4-dimethoxybenzene were transferred to a NMR tube closed with a
NMR septum cap. In situ NMR reaction monitoring was immediately initiated after all reactants
were added and sporadically agitated. Calculated value of excess [excess]=0.035 M.
1
H-NMR kinetic data was collected with the following acquisition parameter: 1 transient (scan),
5 sec. relaxation delay time, acquisition time of 3.2768 sec. Between the spectra was a 1 sec pre-
acquisition delay. The data was collected at 35.5˚C.
166
Preparation of the CuI-TCPTA catalyst:
Tris-((1-cyclopentyl-1H-1,2,3- triazol-4-yl)methyl)amine (TCPTA) ligand was synthesized by
following a procedure reported by Jason Hein and co-workers.
3
A homogeneous solution of
Cu(I) (0.010 g, 0.052 mmol) and TCPTA (0.031 g, 0.067 mmol) in 1.5 ml of THF-d8 was
prepared. The mixture was agitated until of a clear pale-yellow solution was formed.
Table A.8 Reaction conditions of experiments following general procedure F. Catalyst robustness studies.
Entry A[3], M [Z], M [CuI-TCPTA],
mM
[Ref], M [excess], M time
(averaged),
sec
Conv, %
1 0.105 0.135
8.75 0.0105 0.030
8407 100.0
2 0.075 0.105 14107 100.0
Figure A.10 Kinetic profiles for reactions performed following general procedure F. A1) A[3]=0.075 M;
[Z]=0.105 M; A2) A[3]=0.105 M; [Z]=0.135 M
167
A.1.7 DERIVING OF THE RATE EQUATION FOR A COMPLEX CATALYTIC
REACTION BY THE DETERMINISTIC METHOD. SOLVING THE SYSTEM OF
ORDINARY DIFFERENTIAL EQUATIONS (ODES)
Based on the proposed catalytic cycle (Scheme 2.3) of the copper(I)-catalyzed cycloaddition of 1-
iodoalkynes to organic azides, the following rate expressions can be derived:
𝑑 [𝑐𝑎𝑡 ]
𝑑𝑡
= 𝑘 2
[𝐴 ∙ 𝑐𝑎𝑡 ∙ 𝑍 ] + 𝑘 −𝐴 [𝐴 ∙ 𝑐𝑎𝑡 ] − 𝑘 𝐴 [𝐴 ][𝑐𝑎𝑡 ]; [1]
𝑑 [𝐴 ]
𝑑𝑡
= −𝑘 𝐴 [𝐴 ][𝑐𝑎𝑡 ] + 𝑘 −𝐴 [𝐴 ∙ 𝑐 𝑎 𝑡 ]; [2]
𝑑 [𝑃 ]
𝑑𝑡
= 𝑘 2
[𝐴 ∙ 𝑐𝑎𝑡 ∙ 𝑍 ]; [3]
𝑑 [𝑍 ]
𝑑𝑡
= 𝑘 −𝑧 [𝐴 ∙ 𝑐𝑎𝑡 ∙ 𝑍 ] − 𝑘 𝑧 [𝐴 ∙ 𝑐𝑎𝑡 ][𝑍 ]; [4]
By introducing [2] into [1] one can derive a simplified equation:
𝑑 [𝑐𝑎𝑡 ]
𝑑𝑡
= 𝑘 2
[𝐴 ∙ 𝑐𝑎𝑡 ∙ 𝑍 ] + 𝑘 −𝐴 [𝐴 ∙ 𝑐𝑎𝑡 ] − 𝑘 𝐴 [𝐴 ][𝑐 𝑎 𝑡 ] = 𝑘 2
[𝐴 ∙ 𝑐𝑎𝑡 ∙ 𝑍 ] +
𝑑 [𝐴 ]
𝑑𝑡
; [5]
𝑑 [𝑐𝑎𝑡 ]
𝑑𝑡
=
𝑑 [𝐴 ]
𝑑𝑡
+
𝑑 [𝑃 ]
𝑑𝑡
; [6]
Upon integration, equation [6] is converted to:
[𝑐𝑎𝑡 ]
0
= [𝐴 ]
0
+ [𝑃 ]
0
+ 𝑐𝑜𝑛𝑠𝑡 1
; 𝑐𝑜𝑛𝑠𝑡 1
= −0.9[𝐴 ]
0
[𝒄𝒂𝒕 ] = [𝑨 ] + [𝑷 ] + 𝒄𝒐𝒏𝒔𝒕 𝟏 ; [7]
The following rate expressions for the intermediate species can be determined:
𝑑 [𝐴 ∙𝑐𝑎𝑡 ]
𝑑𝑡
= 𝑘 𝐴 [𝐴 ][𝑐𝑎𝑡 ] + 𝑘 −𝑧 [𝐴 ∙ 𝑐𝑎𝑡 ∙ 𝑍 ] − 𝑘 𝑧 [𝐴 ∙ 𝑐𝑎𝑡 ][𝑍 ] − 𝑘 −𝐴 [𝐴 ∙ 𝑐𝑎𝑡 ]; [8]
𝑑 [𝐴 ∙𝑐𝑎𝑡 ∙𝑍 ]
𝑑𝑡
= −𝑘 2
[𝐴 ∙ 𝑐𝑎𝑡 ∙ 𝑍 ] + 𝑘 𝑧 [𝐴 ∙ 𝑐𝑎 𝑡 ][𝑍 ] − 𝑘 −𝑧 [𝐴 ∙ 𝑐𝑎𝑡 ∙ 𝑍 ]; [9]
168
With [1], [2], [3] and [4] in mind, eq. 10 and 11 can be obtained:
𝑑 [𝐴 ∙𝑐𝑎𝑡 ]
𝑑𝑡
=
𝑑 [𝑍 ]
𝑑𝑡
−
𝑑 [𝐴 ]
𝑑𝑡
; [10]
𝑑 [𝐴 ∙𝑐𝑎𝑡 ∙𝑍 ]
𝑑𝑡
= −
𝑑 [𝑃 ]
𝑑𝑡
−
𝑑 [𝑍 ]
𝑑𝑡
; [11]
The following equations result for the very beginning of the reaction progress (at t=0):
[𝐴 ∙ 𝑐𝑎𝑡 ]
0
= [𝑍 ]
0
− [𝐴 ]
0
+ 𝑐𝑜𝑛𝑠𝑡 0
= 0; [12]
𝑐𝑜𝑛𝑠𝑡 0
= [𝐴 ]
0
− [𝑍 ]
0
; [13]
[𝐴 ∙ 𝑐𝑎𝑡 ∙ 𝑍 ]
0
= −[𝑃 ]
0
− [𝑍 ]
0
+ 𝑐𝑜𝑛𝑠𝑡 2
= 0; [14]
𝑐𝑜𝑛𝑠𝑡 2
= [𝑍 ]
0
; [15]
This way,
[𝑨 ∙ 𝒄𝒂 𝒕 ] = [𝒁 ] − [𝑨 ] + 𝒄𝒐𝒏𝒔𝒕 𝟎 ; [16]
[𝑨 ·𝒄𝒂𝒕 ·𝒁 ] = −[𝑷 ] − [𝒁 ] + 𝒄 𝒐 𝒏𝒔𝒕 𝟐 ; [17]
After introducing [16] and [17], the differential equations [2], [3] and [4] can be simplified to:
𝒅 [𝑨 ]
𝒅𝒕
= −𝒌 𝑨 [𝑨 ]([𝑷 ] + [𝑨 ] + 𝒄𝒐𝒏𝒔𝒕 𝟏 )+ 𝒌 −𝑨 (−[𝑨 ] + [𝒁 ] + 𝒄𝒐𝒏𝒔𝒕 𝟎 ); [18]
𝒅 [𝒁 ]
𝒅𝒕
= −𝒌 𝒛 (−[𝑨 ] + [𝒁 ] + 𝒄𝒐𝒏𝒔𝒕 𝟎 )[𝒁 ] + 𝒌 −𝒛 (−[𝑷 ] − [𝒁 ] + 𝒄𝒐𝒏𝒔𝒕 𝟐 ); [19]
𝒅 [𝑷 ]
𝒅𝒕
= 𝒌 𝟐 [𝑨 ∙ 𝒄𝒂𝒕 ∙ 𝒁 ] = 𝒌 𝟐 (−[𝑷 ] − [𝒁 ] + 𝒄𝒐𝒏𝒔𝒕 𝟐 ). [20]
169
A.1.8 GRAPHICAL REPRESENTATION OF EXPERIMENTAL LY DETERMINED AND
THEORETICALLY CALCULATED REACTION PROFILES
The calculations were performed with a self-developed computational protocol on the basis of the
4
th
order Runge–Kutta classic method with a subsequent gradient descent minimization procedure.
Figure A.11 Derived theoretical profiles for 1-iodoalkyne, azide and 5-iodotriazole substrates match the
experimental ones.
170
171
172
Figure A.12 Intermediate [A·cat] and [cat] evolution curves determined by
1
H kinetic NMR experiments
described in Table A.1, entries 1, 2, 3, 4 and 5. Data collection was performed via
1
H NMR signal
integration of the corresponding to reactants.
Figure A.13 Intermediate [A·cat] and [cat] evolution curves determined by
1
H kinetic NMR studies for
experimental conditions described in Table A.1, entry 4. Comparison of the computationally and
experimentally derived data.
173
A.2 HEAT-FLOW CALORIMETRY STUDIES
General information
Heat flow calorimetry data was acquired on an Insight_CPR_210 calorimeter (OmniCal, Inc.) and
monitored and controlled using OmniCal Winsight
TM
software package.
Experimental details
All the kinetic experiments were performed inside of the 12 ml glass vials equipped with a
magnetic stir bar and closed with a septum screw caps. The stir rate was 60 rpm. The internal
temperature of the calorimeter was kept constant at 35˚C (due to the external chiller). The sample
mixture was allowed to equilibrate to the internal temperature prior the experiment. The catalyst
solution was injected with a syringe which was also left inside of the calorimeter injection hole for
some time to regulate the contents temperature (needle was capped with a small rubber cap to
prevent leaking of the catalytic mixture). All stock solutions were prepared under inert gas
atmosphere and the transfer of reagents was done with glass syringes of different volumes (1-
5 ml). HPLC/DAD analysis of aliquots taken from the reaction mixture was performed to verify
the reaction conversion. High resolution mass spectra were recorded on an Agilent LC/MS Q-TOF
spectrometer. HPLC analysis was performed on a Agilent HPLC 1100 Series system using aliquots
taking from the reaction mixture (1 μl of reaction mixture per 500 μl of acetonitrile) on an Eclipse
Plus C18 Column (2.1 x 50 mm; 1.8 micron) using a gradient solvent medium of water/acetonitrile
(with 0.1% trifluoroacetic acid) with a flow rate of 0.500 ml/min at 35
o
C.
Data analysis
The calorific output was collected and dynamically processed via OmniCal Winsight
TM
software.
Graphical analysis and interpretation of the processed data was done using Origin 9.0 data analysis
and graphing software package (OriginLab Corporation) or Microsoft Excel 2016 software.
174
A.2.1 CALIBRATION CURVES FOR HPLC STUDIES
In reaction calorimetry, the reaction rate is directly proportional to the consumed or released heat
flow, allowing the calculation of the rate parameters of the reaction:
4
𝑞 ̇ = ∆𝐻 𝑟𝑥𝑛 ∙ 𝑉 ∙ 𝑟
𝑥 =
∫ 𝑞 ̇𝑑𝑡 𝑡 𝑥 𝑡 0
∫ 𝑞 ̇𝑑𝑡 𝑡 𝑓 𝑡 0
where 𝑞 ̇ is a reaction heat flow (kcal/min); 𝐻 𝑟𝑥𝑛 is the heat of the reaction (kcal/mol); V is a
reaction volume; r is a reaction rate (mol/ml/min); χ is a fractional heat flow; 𝑡 𝑥 and 𝑡 0
are reaction
start and end time points.
Furthermore, the heat of the reaction released during a particular time period is directly
proportional to the conversion of reaction.
𝑋 (𝑡 )
𝑋 𝑓𝑖𝑛𝑎𝑙 =
∫ 𝑞 (𝑡 )𝑑𝑡 𝑡 𝑜 ∫ 𝑞 (𝑡 )𝑑𝑡 𝑡 (𝑓𝑖𝑛𝑎𝑙 )
𝑜
Yields of the cycloaddition reactions were confirmed by analyzing aliquots taken immediately
after no changes in the heat profile could be noticed anymore.
𝑦𝑖𝑒𝑙𝑑 % =
5−𝐼 𝑡𝑟𝑖𝑎𝑧𝑜𝑙𝑒 𝑎𝑟𝑒𝑎 𝑟𝑒𝑓𝑒𝑟𝑒𝑛𝑐𝑒 𝑎𝑟𝑒𝑎 ∗𝛼 1
5−𝐼 𝑡𝑟𝑖𝑎𝑧𝑜 𝑙𝑒 𝑎𝑟𝑒𝑎 𝑟𝑒𝑓𝑒𝑟𝑒𝑛𝑐𝑒 𝑎𝑟𝑒𝑎 ∗𝛼 1
+
1−𝐼 𝑎𝑙𝑘𝑦𝑛𝑒 𝑟𝑒𝑓𝑒𝑟𝑒𝑛𝑐𝑒 𝑎𝑟𝑒𝑎 ∗𝛼 2
∗ 100, where α1 and α2 are the slope coefficients of the
corresponding 5-iodo-1,2,3-triazole/1-iodoalkyne pair derived from the calibration curves data.
175
Table A.9 Calibration curve data of 1-iodoalkynes and 5-iodo-1,2,3-triazoles.
[𝑋 ]
[𝑅𝑒𝑓 ]
= 𝑎 ·
𝐴𝑏𝑠 (𝑋 )
𝐴𝑏𝑠 (𝑟𝑒𝑓 )
+ 𝑏
Entry 1-Iodoalkynes a b
1 1 0.1202 -0.0028
2 2 0.1194 -0.0047
3 3 0.1668 -0.0491
4 4 0.1277 -0.0136
5 5 0.1294 0.0042
5-iodo-1,2,3-
triazoles
a b
6 A 0.1249 -0.0039
7 B 0.1471 0.0001
8 C 0.1983 0.0003
9 D 0.1377 -0.0042
10 E 0.1845 -0.0009
176
177
Figure A.14 Calibration curves of 1-iodoalkynes and 5-iodo-1,2,3-triazoles.
178
A.2.2 GENERAL PROCEDURE A - INDIVIDUAL REACTION KINETIC PROTOCOL
WITH THE CU(I)-TTTA CATALYTIC SYSTEM
A dry 5 ml volumetric flask was equipped with a septum cap, charged with 1-iodoalkyne[X] and
exposed to three vacuum-nitrogen purge cycles. Dry THF was added to the vial via syringe and
properly mixed until a pale-yellow solution (0.4 M) was formed. Identically, stock solutions of
0.45 M of azide[Z] and 0.4 M of diethyl 1-benzyl-1H-1,2,3-triazole-4,5-dicarboxylate (reference
compound) were prepared. A dry 12 ml glass vial was equipped with stir bar, closed with a septum
cap, purged with dry nitrogen and loaded with a reactant mixture consisting each 900 μl of the
stock solutions of the iodoalkynes (0.4 M), the azide (0.45 M) and the reference compound
(0.4 M). 900 μl of the catalyst solution was injected to the reactant mixture (3x900 μl) which was
preconditioned to 35˚C inside the sample well of the calorimeter. Thus, the total sample volume
for one experiment was 3.6 ml. The reaction mixture was stirred until the reaction progress curve
reached the baseline plateau, indication the completion of the reaction. HPLC/DAD analysis of an
aliquot taken from the reaction mixture was performed to verify reaction conversion.
Preparation of the CuI-TTTA catalyst:
Tris-((1-tert-butyl-1H-1,2,3-triazolyl)methyl)amine(TTTA) was synthesized following a literature
procedure
2
. A homogeneous solution of CuI (0.034 g, 0.18 mmol) and TTTA (0.087 g,
0.203 mmol) in 4.5 ml of dry THF was prepared. The mixture was agitated until of a clear pale-
yellow solution was formed and left in a dry 12 ml glass vial with a closed septum cap until needed.
179
Table A.10 Reaction conditions and parameters of calorimetry heat flow experiments between different [1-
5] alkyne substrates and [Z] azide and CuI-TTTA catalytic system. General procedure A.
Figure A.15 Kinetic profiles for experiments following general procedure A. A) Reaction rates vs. time
plot; B) Reaction rates vs. [Azide] plot.
Entry A[X], M [Z], M Triazole[X], M [CuI], M ΔHrxn, kcal/mol Conv, % Time, min
1 0.1 [1]
0.1125
0.01
29.32 100 153
2 0.1 [2] 33.59 100 153
3 0.1 [3] 47.68 100 153
4 0.1 [4] 58.22 100 45
5 0.1 [5] 56.51 100 35
6 0.1 [4] 0.1 [D] 56.87 100 45
180
A.2.3 GENERAL PROCEDURE B - INDIVIDUAL REACTION KINETIC PROTOCOL
WITH THE CUI-TBTA CATALYTIC SYSTEM
A dry 5 ml volumetric flask was equipped with a septum cap, charged with of 1-iodoalkyne[X]
and exposed to three vacuum-nitrogen purge cycles. Dry THF was added to the vial via syringe
and properly mixed until the pale yellow solution was formed. Similarly, stock solutions of 0.45 M
azide[Z] and 0.4 M diethyl 1-benzyl-1H-1,2,3-triazole-4,5-dicarboxylate (reference compound)
were prepared. A dry 12 ml glass vial was equipped with stir bar, closed with a septum cap, purged
with dry nitrogen and loaded with a reactant mixture consisting each 900 μl of the stock solutions
of the iodoalkynes (0.4 M), the azide (0.45 M) and the reference compound (0.4 M). 900 μl of the
catalyst solution was injected to the reactant mixture (3x900 μl ) which was preconditioned to 35
˚
C
inside the sample well of the calorimeter. Thus, the total sample volume for one experiment was
3.6 ml. The reaction mixture was stirred until the reaction progress curve reached the baseline
plateau, indication the completion of the reaction. A HPLC/DAD analysis of an aliquot taken from
the reaction mixture was performed to verify the reaction conversion.
Preparation of the CuI-TBTA catalyst:
Tris-((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)amine (TBTA) ligand was prepared following a
literature procedure.
2
A homogeneous solution of CuI (0.034 g, 0.18 mmol) and TTTA (0.108 g,
0.203 mmol) in 4.5 ml of dry THF was prepared. The mixture was agitated until of a clear pale-
yellow solution was formed and left in a dry 12 ml glass vial with a closed septum cap until needed.
181
Table A.11 Reaction conditions and parameters of heat flow calorimetry experiments between different [1-
5] alkyne substrates and [Z] azide in the presence CuI-TBTA as catalyst. General procedure B.
Entry A[X], M [Z], M [cat], M ∆Hrxn, kcal/mol Conv, % Time, min
1 0.1 [3] 0.1125 0.01 39.10 59.2 127
2 0.1 [4] 0.1125 0.01 47.17 94.0 180
3 0.1 [5] 0.1125 0.01 62.95 100.0 178
Figure A.16 Kinetic profiles for experiments following general procedure B. A) Reaction rates vs.
time plot; B) Reaction rates vs. [Azide] plot.
182
A.2.4 GENERAL PROCEDURE C – COMPETITION EXPERIMENTS
A dry 5 ml volumetric flask was equipped with a septum cap, charged with 1-iodoalkyne[X] and
exposed to three vacuum-nitrogen purge cycles. Dry THF was added to the vial via syringe and
properly mixed until a pale-yellow solution (0.4 M) was formed. Identically, stock solutions of
0.4 M and 0.9 M of azide[Z] and 0.4 M of diethyl 1-benzyl-1H-1,2,3-triazole-4,5-dicarboxylate
(reference compound) were prepared. A dry 12 ml glass vial was equipped with stir bar, closed
with a septum cap, purged with dry nitrogen and loaded with a reactant mixture consisting each:
For entries 1-4: 800 μl of the stock solutions of the iodoalkyne[X] (0.4 M), the azide (0.4 M), dry
THF and iodoalkyne[3] (0.4 M) (for entries 1 and 3 instead of iodoalkyne[3] 800 μl of THF were
added). 800 μl of the catalyst solution was injected to the reactant mixture (4x800 μl) which was
preconditioned to 35˚C inside the sample well of the calorimeter. Thus, the total sample volume
for one experiment was 4.0 ml. The reaction mixture was stirred until the reaction progress curve
reached the baseline plateau, indication the completion of the reaction. A certain amount of the
external reference compound was added an aliquot taken from the reaction mixture and
HPLC/DAD analysis was performed to verify the reaction conversion.
For entries 5-8: 900 μl of the stock solutions of the iodoalkyne[X] (0.4 M), the azide (0.45 M,
prepared from 0.9M stock solution), dry THF (for entries 6 and 8) or iodoalkyne[3] (0.4 M) (for
entries 5 and 7). 900 μl of the catalyst solution was injected to the reactant mixture (3x900 μl)
which was preconditioned to 35˚C inside the sample well of the calorimeter. Thus, the total sample
volume for one experiment was 3.6 ml. The reaction mixture was stirred until the reaction progress
curve reached the baseline plateau, indication the completion of the reaction. The certain amount
of the external reference compound was added an aliquot taken from the reaction mixture and
HPLC/DAD analysis was performed to verify the reaction conversion.
183
For entry 9-10: 900 μl of the stock solutions of the iodoalkyne[X] (0.4 M), the azide (0.9 M),
iodoalkyne[3] (0.4 M) or iodoalkyne[4] (0.4 M). 900 μl of the catalyst solution was injected to the
reactant mixture (3x900 μl) which was preconditioned to 35˚C inside the sample well of the
calorimeter. Thus, the total sample volume for one experiment was 3.6 ml. The reaction mixture
was stirred until the reaction progress curve reached the baseline plateau, indication the completion
of the reaction. The certain amount of the external reference compound was added an aliquot taken
from the reaction mixture and HPLC/DAD analysis was performed to verify the reaction
conversion.
For entry 11: 700 μl of the stock solution of the iodoalkyne[1] (0.4 M), 900 μl of the stock solution
of the azide (0.9 M), 700 μl of the stock solution of iodoalkyne[5] (0.4 M) and 400 μl of dry THF.
900 μl of the catalyst solution was injected to the reactant mixture (2.7 ml) which was
preconditioned to 35˚C inside the sample well of the calorimeter. Thus, the total sample volume
for one experiment was 3.6 ml. The reaction mixture was stirred until the reaction progress curve
reached the baseline plateau, indication the completion of the reaction. The certain amount of the
external reference compound was added an aliquot taken from the reaction mixture and
HPLC/DAD analysis was performed to verify the reaction conversion.
Preparation of the CuI-TTTA catalyst:
Tris-((1-tert-butyl-1H-1,2,3-triazolyl)methyl)amine (TTTA) was synthesized following a
literature procedure
2
. A homogeneous solution of CuI (0.034 g, 0.18 mmol) and TTTA (0.087 g,
0.203 mmol) in 4.5 ml of dry THF was prepared. The mixture was agitated until of a clear pale-
yellow solution was formed and left in a dry 12 ml glass vial with a closed septum cap until needed.
184
Table A.12 Conditions and results for competition calorimetry heat flow experiments between different 1-
ioadoalkynes [1-5] and azide [Z] in the presence of Cu(I)-TTTA as the catalyst. General procedure C.
Entry A1[X], M A2[X], M [Z], M [cat], M
ΔHrxn,
kcal/mol
Conv, %
1 [2], 0.08 0.08 0.008 52.31 77.40
2 [2], 0.08 [3], 0.08 0.08 0.008 46.93 34.20; 46.23
3 [1], 0.08 0.08 0.008 44.26 51.83
4 [1], 0.08 [3], 0.08 0.08 0.008 57.23 17.68; 40.30
5 [4], 0.1 0.1125 0.01 60.07 100.00
6 [4], 0.1 [3], 0.1 0.1125 0.01 61.07 74.89; 31.37
7 [5], 0.1 0.1125 0.01 59.93 100.00
8 [5], 0.1 [3], 0.1 0.1125 0.01 59.85 85.48; 24.12
9 [5], 0.1 [4], 0.1 0.225 0.01 81.28 100.0; 100.0
10 [4], 0.1 [3], 0.1 0.225 0.01 83.73 98.59; 76.60
11 [1], 0.0727 [5], 0.0727 0.225 0.01 89.84 96.61; 100.00
A.4.2.1 STANDARD ERROR FOR CALORIMETRY EXPERIMENTS
Experiments 2, 3 and 8, Table A.12, following the general procedure C were used in the
calculation of the standard deviation as they involved the identical substrates with different
concentrations.
185
Mean value ∆𝐻 =
61,86+61,70+59,99
3
= 61.18
𝑘𝑐𝑎𝑙 𝑚𝑜𝑙
standard deviation 𝜎 = √1/3∑ (∆𝐻 𝑖 − 𝜇 )
2 2
1
= 0.85kcal/mol
Therefore, we assume a standard deviation when calculating reaction enthalpies of 0.85 kcal/mol.
186
A.2.5 GENERAL PROCEDURE D - “MULTIPLE INJECTION” EXPERIMENT
A dry 5 ml volumetric flask was equipped with a septum cap, charged with 1-iodoalkyne[X] and
exposed to three vacuum-nitrogen purge cycles. Dry THF was added to the vial via syringe and
properly mixed until a pale-yellow solution (0.6 M) was formed. Identically, stock solutions of
1.0 M of azide[Z] was prepared and 0.4 M of diethyl 1-benzyl-1H-1,2,3-triazole-4,5-dicarboxylate
(reference compound) were prepared. A dry 12 ml glass vial was equipped with a stir bar, closed
with a septum cap, purged with dry nitrogen and loaded with a reactant mixture.
Initially (1
st
injection), 900 μl of the catalyst mixture CuI-TTTA (0.04M in THF) was injected into
the mixture consisting of 900 μl of the 1-iodoalkyne[4] stock solution, 900 μl azide[Z] stock
solution and 900 μl of dry THF preconditioned to 35˚C inside of sample well of the calorimeter.
Once the reaction kinetic profile reached completion, a second portion (2
nd
injection) of the
substrate mixture was injected in one portion (900 μl of 0.75 M [4] and 1.25 M [Z] in THF) again
preconditioned prior to 35
o
C. The 3
rd
injection of 900 μl of iodoalkyne-azide mixture (900 μl of
0.15 M [4] and 0.25 M [Z] in THF) was added once the reaction kinetic profile reached the baseline
level after the second injection. The reaction mixture was stirred until the reaction progress curve
reached the baseline plateau, indication the completion of the reaction. A certain amount of the
external reference compound was added an aliquot taken from the reaction mixture and
HPLC/DAD analysis was performed to verify the reaction conversion.
187
Table A.13 Heat flow calorimetry “multiple injection experiment” with 1-iodoalkyne [4] and azide [Z] as
substrates and the CuI-TTTA catalyst system. General procedure D.
Figure A.17 “Multiple injection” experiment. A) heat flow vs. time; B) reaction rate vs. [Azide].
A.2.6 GENERAL PROCEDURE E - COMPETITIVE REACTIVITY EXPERIMENT
200 μl of the catalyst mixture (CuI-TTTA 0.04 M in THF) was injected to mixture consisting of
each 200 μl of 1-iodoalkyne[5] (0.13 M), 1-ethynyl-4-(trifluoromethyl)benzene (0.13 M) and
azide[6] (0.13 M) in THF inside a closed LC-MS vial equipped with stir bar. Thus, the
concentration of the reactants in the reaction mixture of the 1-iodoalkyne[5] was 0.10 M, 1-
ethynyl-4-(trifluoromethyl)benzene was 0.10 M, azide[Z] was 0.15 M and CuI-TTTA was 0.04 M
in THF. Concurrently, the same amount of the catalytic mixture was added to a mixture consisting
of each 200 μl of 1-iodoalkyne[5] (0.156 M), 1-ethynyl-4-(trifluoromethyl)benzene (0.13 M) and
azide[6] (0.13 M) in THF. Thus, the final concentration of the 1-iodoalkyne[5] was 0.12 M, 1-
№ Injection
A[4], M in the
vessel
[Z], M in the
vessel
[cat], M in the
vessel
ΔHrxn,
kcal/mol
Conversion,
%
1
st
- 0.15 M [4]; 0.25 M [Z] 0.150 0.250
0.01
57.52 100
2
nd
- 0.75 M [4]; 1.25 M [Z] 0.150 0.330 58.72 100
3
rd
- 0.15 M [4]; 0.25 M[Z] 0.025 0.192 58.74 100
188
ethynyl-4-(trifluoromethyl)benzene was 0.10 M, azide[Z] was 0.15 M and CuI-TTTA was 0.04 M
in THF. Both mixtures were vigorous stirred while heating to 35˚C. Aliquots were taken at five
times (beginning of the reaction, after 25 min, after 50 min, after 75 min and after 120 min). A
specific amount of the external reference compound was added an aliquot taken from the reaction
mixture and HPLC/DAD analysis was performed to verify the reaction conversion.
Table A.14 Iodo-proto exchange experiment with 1-ethynyl-4-(trifluoromethyl)benzene, 1-iodoalkyne [4]
and azide [Z] substrates and the Cu(I)-TTTA catalyst system.
#
[Iodo-
alkyne], M
[Proto-
alkyne], M
[Z], M T 0, min T 25, min T 50, min T 75, min T 120, min
1 [5], 0.12M
[5-H], 0.1M 0.1
[5]=0.12M
[5-H]=0.1M
[5-triazole]= 0 M
[5-H-triazole]=0 M
[5]=0.025M
[5-H]=0.025M
[2-triazole]=0.095 M
[5-H-triazole]=0 M
[5]=0.02M
[5-H]=0.1M
[2-triazole]= 0.1 M
[5-H-triazole]= 0 M
[5]=0.02M
[5-H]=0.1M
[2-triazole]= 0.1 M
[5-H-triazole]= 0 M
[5]=0.02M
[5-H]=0.1M
[2-triazole]= 0.1 M
[5-H-triazole]= 0 M
2 [5], 0.1M
[5]=0.1M
[5-H]=0.1M
[5-triazole]= 0 M
[5-H-triazole]= 0 M
[5]=0.0019M
[5-H]=0.1M
[5-triazole]=0.098 M
[5-H-triazole]≤1% M
[5]=0M
[5-H]=0.1M
[5-triazole]= 0.1 M
[5-H-triazole]≤1% M
[5]=0M
[5-H]=0.1M
[5-triazole]= 0.1 M
[5-H-triazole]≤1% M
[5]=0M
[5-H]=0.1M
[5-triazole]= 0.1 M
[5-H-triazole]≤1% M
189
A.3 SYNTHESIS AND CHARACTERIZATION
General Information
All reactions were carried out under nitrogen atmosphere with dry solvents ensuring anhydrous
reaction conditions, unless otherwise stated. Dry tetrahydrofuran (THF) and acetone were obtained
by passing commercially available pre‐dried, oxygen-free formulations through activated alumina
columns. Yields describe chromatographically and spectroscopically (
1
H NMR) pure materials,
unless otherwise stated. 1-ethynyl-4-methoxybenzene, 1-(tert-butyl)-4-ethynylbenzene,
ethynylbenzene, 1-chloro-4-ethynylbenzene, 1-ethynyl-4-(trifluoromethyl)benzene and copper(I)
iodide were all purchased from Sigma-Aldrich and used as received. Tris-((1-tert-butyl-1H-1,2,3-
triazolyl)methyl)amine (TTTA) and tris-((1-cyclopentyl-1H-1,2,3- triazol-4-yl)methyl)amine
(TCPTA) triazolyl containing ligands were prepared following literature procedures.
1, 2
E. Merck
silica gel (60, particle size 0.040–0.063 mm) was used for flash column chromatography.
Reactions progress was monitored both by thin‐layer chromatography (TLC) on 0.25 mm E. Merck
silica gel plates (60F‐254) and by Agilent LC/MSD as well as Agilent HPLC/DAD spectroscopy.
Experimental Details
NMR spectra were recorded on Varian Mercury 400, Varian VNMRS-500 or Varian VNMRS-
600 spectrometer. Chemical shifts were referenced to residual solvent signals (Chloroform-d: δH
= 7.26 ppm, δC = 77.16 ppm) as an internal reference. The following abbreviations were used to
describe NMR signal multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, quin = quintet,
m = multiplet, b = broad. High resolution mass spectra were recorded on an Agilent LC/MS Q-
TOF instrument. HPLC analysis was performed on an Agilent HPLC 1100 Series system using
aliquots taking from the reaction mixture (1 μl of reaction mixture per 500 μl of acetonitrile) on
an Eclipse Plus C18 Column (2.1 x 50 mm; 1.8 micron) using a gradient solvent medium of
190
water/acetonitrile (with 0.1% trifluoroacetic acid) with a flow rate of 0.500 ml/min at 35˚C
temperature. Infrared spectra were recorded in the range 4000-400 cm
-1
on Bruker Alpha
spectrometer using a diamond ATR unit. IR intensities are described as vw (very weak), w (weak),
m (medium), s (strong), vs (very strong).
A.3.1 GENERAL PROCEDURE 1 FOR THE SYNTHESIS OF 1-IODOALKYNES
Adapted from a procedure of Iannazzo L. and co-workers
5
.
1-(iodoethynyl)-4-methoxybenzene. To a 50 ml round-bottom flask equipped with a magnetic
stir bar, 1.00 g (7.56 mmol, 1.00 eq.) of 1-ethynyl-4-methoxybenzene in 25ml of reagent grade
acetone was added. After the addition of 1.79 g (7.94 mmol, 1.05 eq.) of N-iodosuccinimide (NIS)
a clear solution was formed. Subsequently 64 mg of silver(I) nitrate (0.347 mmol, 0.050 eq.) as
initiation reagent was added. The mixture was stirred for 4 hours. During which a large amount of
white precipitate was formed, and an absence of the starting material was identified by TLC
(hexane, Rf (product) = 0.47, Rf (reagent) = 0.5). The solvent was evaporated, the solid residue was
dissolved in ethyl acetate (100 ml), transferred to a 250 ml separator funnel, and washed twice
with a saturated sodium thiosulfate solution (2x25 ml). The organic layer was dried over MgSO4,
filtered, and concentrated to yield a light-yellow oil. This crude material was purified by column
191
chromatography using hexane as eluent to give 1-(iodoethynyl)-4-methoxybenzene as a pale
yellow solid (1.13 g, 4.38 mmol, 58 % yield).
IR (υ[cm-1]) 3051 (vw), 3011w, 2963 (m), 2926 (m), 2838 (m), 2586 (w), 2540 (w), 2509 (w),
2344 (w), 2156 (m), 2036 (m), 1989 (m), 1883 (m), 1865 (m), 1756 (m), 1695 (m), 1636 (m), 1600
(vs), 1570 (vs), 1501 (vs), 1456.13 (vs), 1438 (vs), 1415 (vs), 1338 (m), 1303 (s), 1290 (vs), 1246
(vs), 1189 (s), 1170 (vs), 1124 (vs), 1107 (vs), 1020 (vs), 954 (s), 933 (s), 822 (vs), 783 (vs), 744
(vs), 699 (s), 642 (s), 598 (s), 551 (vs), 527 (vs), 504 (vs), 443 (m), 408 w;
1
H NMR (600 MHz, Chloroform-d) δ 7.38 (d, J = 9.0 Hz, 2H), 6.83 (d, J = 8.9 Hz, 2H), 3.80 (s,
3H).
13
C NMR (151 MHz, Chloroform-d) δ 160.03, 133.88, 129.15, 115.64, 113.94, 94.07, 55.41.
1-(tert-butyl)-4-(iodoethynyl)benzene. Synthesized from 1-(tert-butyl)-4-ethynylbenzene
(2.00 g, 12.64 mmol) using general procedure 1, 3.12 g, 11.0 mmol, 87 %, 4 hours, colorless solid:
IR (υ[cm-1])3085 (w), 3039 (vw), 2962 (vs), 2900 (m), 2863 (m), 2158 (w), 1912 (w), 1792 (vw),
1783 (vw), 1684 (w), 1665 (w), 1601 (w), 1515 (m), 1501 (s), 1458 (s), 1406 (m), 1390 (m), 1362
(vs), 1267 (s), 1236 (w), 1201 (m), 1106 (s), 1015 (s), 963 (w), 949 (w), 925 (m), 831 (vs), 735
(m), 698 (w), 667 (vw), 645 (vw), 603 (w), 559 (vs), 515 m;
1
H NMR (600 MHz, Chloroform-d) δ 7.44 (d, J = 8.5 Hz, 2H), 7.40 (d, J = 8.5 Hz, 2H), 1.38 (s,
9H).
13
C NMR (151 MHz, Chloroform-d) δ 152.07, 132.13, 125.29, 120.43, 94.34, 34.83, 31.24, 5.63.
192
(Iodoethynyl)benzene. Synthesized from ethynylbenzene (1.00 g, 9.80 mmol) using general
procedure 1, 1.97 g, 8.62 mmol, 88 %, 3 hours, yellow oil:
IR (υ[cm-1]) 3079 (w), 3056 (w), 3030 (w), 2925 (vw), 2173 (vw), 1968 (vw), 1949 (vw), 1880
(vw), 1802 (vw), 1779 (vw), 1750 (w), 1671 (w), 1596 (m), 1572 (w), 1507 (vw), 1487 (vs), 1442
(s), 1384 (w), 1328 (w), 1276 (w), 1239 (w), 1220 (w), 1175 (m), 1157 (w), 1097 (w), 1068 (m),
1025 (s), 999 (m), 986 (w), 967 (w), 914 (m), 880 (w), 840 (w), 814 (w), 752 (vs), 687 (vs), 609
(m), 584 (m), 555 (m), 521 (vs), 448 w;
1
H NMR (400 MHz, Chloroform-d) δ 7.48 – 7.38 (m, 2H), 7.32 (dd, J = 5.8, 1.5 Hz, 3H);
13
C NMR (101 MHz, Chloroform-d) δ 132.51, 132.41, 128.92, 128.39, 128.33, 123.51, 94.27,
77.16, 6.27.
1-chloro-4-(iodoethynyl)benzene. Synthesized from 1-chloro-4-ethynylbenzene (1.50 g,
11.0 mmol) using general procedure 1, 2.71 g, 10.3 mmol, 94 %, 2 hours, pale yellow solid:
IR (υ[cm-1]) 3083 (w), 3056 (vw), 2963 (vw), 2923 (vw), 2779 (vw), 2571 (w), 2535 (vw), 2309
(w), 2290 (w), 2159 (w), 2026 (w), 1996 (w), 1893 s ,1763 (m), 1639 (s), 1587 (s), 1561 (m), 1483
(vs), 1459 (vs), 1394 (vs), 1365 (s), 1337 (s), 1266 (s), 1177 (m), 1106 (s), 1079 (vs), 1040 (s),
1012 (vs), 954 (s), 820 (vs), 702 (m), 663 (vs), 636 (s), 518 (vs), 438 (m), 409 (m);
1
H NMR (600 MHz, Chloroform-d) δ 7.38 – 7.34 (m, 2H), 7.31 – 7.26 (m, 2H);
193
13
C NMR (151 MHz, Chloroform-d) δ 135.04, 133.66, 128.73, 121.96, 93.09, 7.85.
1-(iodoethynyl)-4-(trifluoromethyl)benzene. Synthesized from 1-ethynyl-4-
(trifluoromethyl)benzene (0.75 g, 4.41 mmol) using general procedure 1, 1.20 g, 4.05 mmol,
92 %, 1 hour, colorless solid:
IR (υ[cm-1]) 3110 (vw), 3083 (vw), 2930 (vw), 2637 (vw), 2294 (vw), 2195 (vw), 2167 (w), 2074
(vw), 2001 (vw), 1972 (vw), 1920 (w), 1795 (w), 1699 (vw), 1665 (w), 1613 (s), 1572 (w), 1512
(vw), 1403 (s), 1382 (vw), 1318 (vs), 1232 (m), 1187 (s), 1163 (vs), 1124 (vs), 1104 (vs), 1065
(vs), 1015 (vs), 969 (s), 954 (s), 840 (vs), 752 (s), 735 (m), 724 (m), 665 (w), 647 (m), 627 (vs),
593 (vs), 549 (m), 518 (s), 443 m;
1
H NMR (400 MHz, Chloroform-d) δ 7.55 (q, J = 8.2 Hz, 4H);
13
C NMR (101 MHz, Chloroform-d) δ 132.76, 130.63 (q, J = 32.7 Hz), 127.19, 125.36, 122.57,
92.98, 10.32;
19
F NMR (564 MHz, Chloroform-d) δ -62.76.
194
A.3.2 GENERAL PROCEDURE 2 FOR THE SYNTHESIS OF 1-IODO-3,4,5-
TRIAZOLES
Adapted from a procedure of Hein and co-workers
6
.
CuI (9.52 mg, 0.05 mmol) was added to the vigorously stirred solution of TTTA (0.02 g,
0.05 mmol) in THF (4.5 mL) at room temperature. After formation of a clear homogeneous
solution (after roughly 20 min), a mixture of 1-ethynyl-4-methoxybenzene (0.23 g, 1.00 mmol)
and (2-azidoethyl)benzene (0.20 g, 1.00 mmol) dissolved in THF (0.5 mL) was added in one
portion. The mixture was allowed to stir for 45 min and was then quenched by the addition of
1.0 mL of 10% NH4OH solution. V olatile components were removed by evaporation in vacuo, and
the resulting solid residue was purified by column chromatography yielding a white powder
(0.40 g, 0.93 mmol, 93%).
5-iodo-4-(4-methoxyphenyl)-1-phenethyl-1H-1,2,3-triazole.
IR (υ[cm-1]) 2897 (vw), 2875 (vw), 1986 (w), 1617 (vs), 1596 (vs), 1580 (vs), 1484 (s), 1437 (vs),
1371 (s), 1341 (m), 1292 (s), 1254 (m), 1225 (w), 1188 (w), 1174 (w), 1162 (w), 1122 (s), 1108
(vs), 1070 (w), 1027 (m), 997 (s), 972 (s), 955 (s), 842 (s), 831 (m), 822 (m), 799 (vs), 752 (s),
721 (vs), 687 (vs), 651 (s), 614 (m), 566 (vw), 524 (vs), 481 (s), 461 (w), 451 (w), 437 w;
195
1
H NMR (500 MHz, Chloroform-d) δ 7.85 (d, J = 8.1 Hz, 2H), 7.32 (t, J = 7.6 Hz, 2H), 7.28 (d,
J = 6.6 Hz, 1H), 7.21 (d, J = 8.0 Hz, 2H), 7.00 (d, J = 8.0 Hz, 2H), 4.65 (t, J = 8.0 Hz, 2H), 3.86
(s, 3H), 3.26 (t, J = 8.2, 7.5 Hz, 2H);
13
C NMR (126 MHz, Chloroform-d) δ 160.01, 149.78, 136.91, 129.04, 129.00, 128.97, 127.31,
122.97, 114.11, 76.07, 55.48, 52.16, 36.72.
HRMS (ESI-TOF) (m/z): [M + H]
+
calc. for C17H16IN3O, 405.03; found 406.0452.
4-(4-(tert-butyl)phenyl)-5-iodo-1-phenethyl-1H-1,2,3-triazole. Synthesized from 1-(tert-
butyl)-4-(iodoethynyl)benzene (0.20 g, 0.70 mmol) using general procedure 2, 0.28 g, 0.65 mmol,
93 %, 1 hour, colorless solid:
IR (υ[cm-1]) 3083 (w), 3061 (m), 3036 (w), 3025 (m), 2957 (vs), 2901 (s), 2864 (s), 1915 (w),
1877 (w), 1826 (vw), 1810 (w), 1670 (w), 1616 (w), 1602 (m), 1583 (w), 1543 (m), 1495 (s), 1479
(vs), 1454 (vs), 1440 (s), 1418 (s), 1392 (s), 1365 (s), 1342 (vs), 1317 (m), 1289 (m), 1268 (vs),
1223 (vs), 1201 (m), 1158 (s), 1126 (s), 1108 (s), 1083 (m), 1068 (vs), 1031 (s), 1018 (s), 999 (vs),
983 (vs), 967 (m), 951 (m), 934 (w), 913 (m), 862 (w), 837 (vs), 801 (m), 776 (s), 744 (vs), 716
(vs), 698 (vs), 667 (s), 638 (m), 621 (w), 573 (vs), 554 (vs), 515 (vs), 497 (vs), 427 m;
1
H NMR (500 MHz, Chloroform-d) δ 7.87 (d, J = 8.6 Hz, 2H), 7.49 (d, J = 8.6 Hz, 2H), 7.32 (t, J
= 7.1 Hz, 2H), 7.27 (d, J = 7.6 Hz, 1H), 7.20 (d, J = 7.9 Hz, 2H), 4.64 (t, J = 8.0, 7.5 Hz, 2H), 3.26
(t, J = 7.9 Hz, 2H), 1.36 (s, 9H);
196
13
C NMR (126 MHz, Chloroform-d) δ 151.76, 149.73, 136.90, 129.04, 128.96, 127.53, 127.30,
127.24, 125.62, 76.34, 52.13, 36.71, 34.88, 31.44.
HRMS (ESI-TOF) (m/z): [M + H]
+
calc. for C20H22IN3, 431.09; found 432.1010.
197
5-iodo-1-phenethyl-4-phenyl-1H-1,2,3-triazole. Synthesized from (iodoethynyl)benzene
(0.20 mg, 0.88 mmol) using general procedure 2, 0.31 g, 0.83 mmol, 94 %, 1 hour, colorless solid:
IR (υ[cm-1]) 3085 (vw), 3044 (w), 3026 (m), 2962 (w), 2940 (m), 2858 (vw), 1956 (w), 1889 (w),
1826 (w), 1759 (w), 1690 (w), 1669 (w), 1602 (m), 1577 (w), 1537 (w), 1489 (m), 1473 (s), 1454
(s), 1446 (s), 1410 (m), 1364 (s), 1347 (s), 1317 (m), 1288 (m), 1224 (vs), 1182 (w), 1155 (s), 1128
(m), 1067 (s), 1030 (m), 1023 (m), 1002 (s), 982 (s), 917 (s), 854 (m), 844 (m), 815 (w), 772 (vs),
745 (vs), 712 (vs), 696 (vs), 680 (vs), 659 (s), 569 (m), 540 (s), 507 (vs), 474 (s), 406 s;
1
H NMR (500 MHz, Chloroform-d) δ 7.92 (t, J = 8.0 Hz, 2H), 7.47 (t, J = 7.5 Hz, 2H), 7.40 (t, J =
7.4 Hz, 1H), 7.32 (t, J = 7.2 Hz, 2H), 7.28 (d, J = 7.5 Hz, 1H), 7.21 (d, J = 7.1 Hz, 2H), 4.67 (t, J
= 7.6 Hz, 2H), 3.27 (t, J = 8.0 Hz, 2H);
13
C NMR (126 MHz, Chloroform-d) δ 149.82, 136.84,
130.43, 129.02, 128.96, 128.70, 128.67, 127.64, 127.32, 76.79, 52.17, 36.69.
HRMS (ESI-TOF) (m/z): [M + H]
+
calc. for C16H14IN3, 375.02; found 376.0562.
4-(4-chlorophenyl)-5-iodo-1-phenethyl-1H-1,2,3-triazole. Synthesized from 1-chloro-4-
(iodoethynyl)benzene (0.20 g, 0.76 mmol) using general procedure 2, 0.30 g, 0.74 mmol, 97 %, 1
hour, colorless solid:
198
IR (υ[cm-1]) 3065 (w), 3048 (w), 3023 (m), 3000 (w), 2988 (w), 2942 (m), 2864 (vw), 2821 (vw),
2754 (vw), 2723 (vw), 2641 (vw), 2434 (vw), 1961 (w), 1908 (m), 1823 (w), 1772 (w), 1661 (w),
1603 (s), 1533 (m), 1492 (s), 1469 (vs), 1454 (vs), 1417 (s), 1397 (s), 1366 (s), 1342 (vs), 1293
(m), 1266 (w), 1222 (vs), 1179 (m), 1153 (vs), 1128 (s), 1094 (vs), 1067 (vs), 1030 (s), 1013 (s),
1000 (vs), 982 (vs), 960 (m), 919 (s), 846 (m), 833 (vs), 777 (m), 745 (vs), 726 (vs), 700 (vs), 663
(vs), 628 (m), 573 (s), 541 (vs), 510 (vs), 501 (vs), 477 (vs), 420 m;
1
H NMR (600 MHz, Chloroform-d) δ 7.87 (d, J = 8.6 Hz, 2H), 7.44 (d, J = 8.5 Hz, 2H), 7.32 (t, J
= 7.2 Hz, 2H), 7.28 (d, J = 7.3 Hz, 1H), 7.20 (d, J = 6.7 Hz, 2H), 4.66 (t, J = 7.8 Hz, 2H), 3.26 (t,
J = 7.8 Hz, 2H);
13
C NMR (151 MHz, Chloroform-d) δ 148.79, 136.72, 134.67, 129.01, 128.98, 128.92, 128.90,
128.84, 127.37, 76.88, 52.22, 36.66.
HRMS (ESI-TOF) (m/z): [M + H]
+
calc. for C16H13IN3Cl, 408.98; found 409.9918.
199
5-iodo-1-phenethyl-4-(4-(trifluoromethyl)phenyl)-1H-1,2,3-triazole. Synthesized from 1-
(iodoethynyl)-4-(trifluoromethyl)benzene (0.20 g, 0.68 mmol) using general procedure 2, 0.29 g,
0.66 mmol, 98 %, 1 hour, colorless solid:
IR (υ[cm-1]) 3024 (w), 2945 (w), 2857 (vw), 2637 (vw), 1926 (w), 1822 (vw), 1801 (vw), 1791
(vw), 1684 (vw), 1667 (vw), 1621 (m), 1584 (w), 1549 (vw), 1499 (m), 1491 (w), 1455 (s), 1439
(w), 1420 (s), 1401 (w), 1330 (vs), 1237 (s), 1227 (s), 1173 (vs), 1156 (s), 1127 (vs), 1106 (vs),
1084 (s), 1068 (vs), 1032 (s), 1015 (vs), 1001 (vs), 984 (vs), 921 (m), 845 (vs), 784 (m), 763 (m),
742 (vs), 713 (s), 703 (vs), 691 (vs), 664 (vs), 633 (w), 604 (s), 569 (s), 530 (m), 506 (vs), 485 (s),
458 (vs), 406 m;
1
H NMR (500 MHz, Chloroform-d) δ 8.07 (d, J = 8.1 Hz, 2H), 7.73 (d, J = 7.8 Hz, 2H), 7.32 (t, J
= 7.5 Hz, 2H), 7.28 (d, J = 7.5 Hz, 1H), 7.19 (d, J = 7.7 Hz, 2H), 4.68 (t, J = 7.6 Hz, 2H), 3.27 (t,
J = 7.8 Hz, 2H);
13
C NMR (126 MHz, Chloroform-d) δ 148.41, 136.66, 133.95, 130.56 (q, J=32.6 Hz), 129.02,
129.01, 127.73, 127.42, 125.67(q, J=3.8 Hz), 124.24 (q, J=281.0 Hz), 52.27, 36.66.
19
F NMR (470 MHz, Chloroform-d) δ -62.68.
HRMS (ESI-TOF) (m/z): [M + H]
+
calc. for C17H13IN3F3, 443.01; found 444.0183.
200
A.3.3
1
H AND
13
C NMR SPECTRA
201
202
203
204
205
206
207
208
209
210
211
212
A.4 REFERENCES
(1) Chung, R.; V o, A.; Hein, J. E., Copper-Catalyzed Hydrogen/Iodine Exchange in Terminal
and 1-Iodoalkynes. ACS Catal. 2017, 7 (4), 2505-2510.
(2) Hein, J. E.; Krasnova, L. B.; Iwasaki, M.; Fokin, V . V ., Cu-Catalyzed Azide-Alkyne
Cycloaddition: Preparation of Tris((1-Benzyl-1H-1,2,3-Triazolyl)Methyl)Amine. In Organic
Syntheses, 2012; pp 238-246.
(3) Malig, T. C.; Koenig, J. D. B.; Situ, H.; Chehal, N. K.; Hultin, P. G.; Hein, J. E., Real-
time HPLC-MS reaction progress monitoring using an automated analytical platform. React.
Chem. Eng. 2017, 2 (3), 309-314.
(4) Blackmond, D. G., Reaction Progress Kinetic Analysis: A Powerful Methodology for
Mechanistic Studies of Complex Catalytic Reactions. Angew. Chem. Int. Ed. 2005, 44 (28), 4302-
4320.
(5) Iannazzo, L.; Kotera, N.; Malacria, M.; Aubert, C.; Gandon, V ., Co(I)- versus Ru(II)-
Catalyzed [2+2+2] cycloadditions involving alkynyl halides. J. Organomet. Chem. 2011, 696 (24),
3906-3908.
(6) Hein, J. E.; Tripp, J. C.; Krasnova, L. B.; Sharpless, K. B.; Fokin, V . V ., Copper(I)-
Catalyzed Cycloaddition of Organic Azides and 1-Iodoalkynes. Angew. Chem. Int. Ed. 2009, 48
(43), 8018-8021.
213
Appendix B ADDITIONAL INFORMATION ON CHAPTER III
B.1
1
H NMR KINETIC REACTIVITY STUDIES
General information
DMSO-d8 was purchased in ampules from Cambridge Isotope Laboratories, Inc., opened inside a
glovebox and stored over molecular sieves. Copper(I) trifluoromethanesulfonate toluene complex
(CuOTf) was purchased from Sigma-Aldrich. 1,4-dimethoxybenzene and 1,2,3,4,5,6-
hexamethylbenzene were obtained from commercial sources (Sigma-Aldrich).
Experimental details
Kinetic experiments were carried out in 5mm thin wall precision NMR tubes (7”, 600 MHz, 535-
PP-7, Wilmad LabGlass). All glassware was oven-dried (140 C) and purged by three vacuum-N2
cycles in the antechamber of the glovebox before use. Stock solutions of corresponding
bismuth(III) acetylides, (2-azidoethyl)benzene and CuOTf toluene complex were prepared using
1 ml volumetric flasks volume and stored in LCMS-capped vials for the duration of one batch of
experiments.
1
H NMR spectra were recorded on a Varian VNMRS-600 spectrometer. Chemical
shifts are reported in ppm referenced to 2.5 ppm the solvent residual peak of DMSO in deuterated-
DMSO.
Data analysis
For manipulation and analysis of the NMR data and signal peak integration MestReNova (Version
9.0.0, Mestrelab Research S.L.) was used.The substrates rate orders from the excess experiments
were derived in the frames of the first kinetic regime (initial rates).
214
B.1.1 GENERAL PROCEDURE A – INDEPENDENT BISMUTH(III)-ACETYLIDE
REACTIVITY EXPERIMENTS
For independent reactivity experiments: Stock solutions for the corresponding bismuth(III)
acetylides (0.10 M), (2-azidoethyl)benzene (0.688 M), 1,4-dimethoxybenzene (internal standard)
(0.054 M) and copper(I) triflate toluene complex (2.5 mM) were prepared in DMSO-d6. Of these
stock solutions: 200 μl of the alkyne, 50 μl of the azide and 50 μl of the reference stock solutions
were transferred to an NMR tube and diluted with 450 μl of DMSO-d6 capped with a gas-tight
rubber NMR septum and agitated. Lastly, 50 μl of the CuOTf catalyst solution were added to the
NMR tube and immediately agitated. The total volume in the NMR tube for one experiment was
800 μl.
Kinetic NMR measurements were recorded on a Varian VNMRS-600 spectrometer. The sample
spinning rate was 20 Hz.
1
H-NMR data was collected with the following acquisition parameters:
1 transients (scans), 5 sec. relaxation delay time, acquisition time of 5.824 sec. Between the spectra
was a 1 sec pre-acquisition delay. Data was collected at 60.0˚C. The temperature was calibrated
against a temperature standard (ethylene glycol). Each individual experiment was performed twice.
All reagents were dried before use. All manipulations were performed in the dry nitrogen
atmosphere of a glove box. Reaction conversions were integrated relative to an internal reference
standard.
215
Table B.1 Reactions conditions of experiments following general procedure A. Independent bismuth(III)-
acetylide reactivity experiment.
Entry A [X], M [Z], M [cat], mM [ref], mM [ex],M Time
(averaged),
sec
T,
°
C Conv, %
1 [1], 0.025 0.043
0.625 3.375 0.018
14725
60
100.0
2 [2], 0.025 0.043 9281 100.0
3 [3], 0.025 0.043 1331 100.0
4 [4], 0.025 0.043 2092 100.0
5 [5], 0.025 0.043 22168 94.6
6 [6], 0.025 0.043 1509 100.0
216
Rate of [1]
Kinetic data was obtained by following general procedure A; using 10-((4-
methoxyphenyl)ethynyl)-10H-dibenzo[b,e][1,4]thiabismine 5,5-dioxide (bismuth(III)
acetylide[1]). The rate constant k= 1.14E-5(1.17E-6) was derived as the slope of the initial rate
curve.
Rate of [2]
Kinetic data was obtained by following general procedure A; using 10-((4-(tert-
butyl)phenyl)ethynyl)-10H-dibenzo[b,e][1,4]thiabismine 5,5-dioxide (bismuth(III) acetylide[2]).
The rate constant k=7.11E-6 (1.18E-7) was derived as the slope of the initial rate curve.
217
Rate of [3]
Kinetic data was obtained by following general procedure A; using 10-(p-tolylethynyl)-10H-
dibenzo[b,e][1,4]thiabismine 5,5-dioxide (bismuth(III) acetylide[3]). The rate constant k=2.35E-5
(4.50E-7) was derived as the slope of the initial rate curve.
Rate of [4]
Kinetic data was obtained by following general procedure A; using 10-(phenylethynyl)-10H-
dibenzo[b,e][1,4]thiabismine 5,5-dioxide (Bi(III)acetylide[4]). The rate constant k=2.16E-5
(3.96E-7) was derived as the slope of the initial rate curve.
218
Rate of [5]
Kinetic data was obtained by following general procedure A; using 10-((4-bromophenyl)ethynyl)-
10H-dibenzo[b,e][1,4]thiabismine 5,5-dioxide (bismuth(III) acetylide[5]). The rate constant
k=3.06E-6 (2.57E-8) was derived as the slope of the initial rate curve.
Rate of [6]
Kinetic data was obtained by following general procedure A; using 10-((4-bromophenyl)ethynyl)-
10H-dibenzo[b,e][1,4]thiabismine 5,5-dioxide (bismuth(III) acetylide[6]). The rate constant
k=1.35E-5 (1.30E-7) was derived as the slope of the initial rate curve.
219
B.1.2 GENERAL PROCEDURE B- RATE ORDERS EXPERIMENTS
Evaluation of 1-bismuth(III) acetylide component rate order: Stock solutions of (2-
azidoethyl)benzene (0.6 M), of bismuth(III) acetylide[2], 1,2,3,4,5,6-hexamethylbenzene (0.23 M,
as internal standard) and copper(I) triflate toluene complex (0.015 M) were prepared in DMSO-
d6. Of these stock solutions: x μl of the bismuth(III) acetylide, 200 μl of azide, 50 μl of reference
stock solution were solutions were transferred to an NMR tube and diluted with (150+180+200-
x) μl of DMSO-d6 agitated and closed with a gas-tight rubber NMR septum. Lastly, 20 μl of the
CuOTf catalyst solution were added to the NMR tube and immediately agitated. The total volume
in the NMR tube for one experiment was 800 μl.
Kinetic NMR measurements were recorded on a Varian VNMRS-600 spectrometer. The sample
spinning rate was 20 Hz.
1
H-NMR data was collected with the following acquisition parameters:
3 transients (scans), 5 sec. relaxation delay time, acquisition time of 2.7263 sec. Between the
spectra was a 1 sec pre-acquisition delay. Data was collected at 69.0˚C. The temperature was
calibrated against a temperature standard (ethylene glycol). Each individual experiment was
performed twice. All reagents were dried before use. All manipulations were performed in the dry
nitrogen atmosphere of a glove box. Reaction conversions were integrated relative to an internal
reference standard.
220
Table B.2 Reactions conditions of experiments following general procedure B. Variable [Alkyne]
concentration experiment. Kinetic profiles shown in Figure B.1
Entry
A[2], M [Z], M [cat], mM [excess], M
Time
(averaged),
sec
Conv, %
1 0.063 0.150
3.75
0.087 3294 100.0
2 0.096 0.150 0.054 6393 100.0
3 0.126 0.150 0.024 16000 100.0
4 0.160 0.150 -0.10 30000 100.0
5 0.181 0.150 -0.31 45000 100.0
221
Figure B.1 Kinetic profiles of reactions studied following general procedure B.
222
Figure B.2 Substrate rate order kinetic study performed following general procedure B. Method of initial
rates. (A1-A5) Product P[2] concentration vs. time; (B) LN(rate) vs. LN([A]).
223
B.1.3 MOLECULAR DYNAMICS NMR SPECTROSCOPIC STUDY
The experiment was by recording
1
H-NMR of one identical sample at different temperatures. No
quantitative interpretation of the changes in the spectra was performed. Bismuth(III) triazolide [2]
in DMF-d7 was chosen as representative sample. A restricted rotation around the C(sp2)-Bi bond
was confirmed by the variability of resonances for slow, intermediate and fast exchange regions.
At low temperature all aromatic protons of the diphenyl sulfone unit exhibit different unique
chemical shifts. Is the temperature gradually raised, an similar observation was made for the two
methylene groups of the ‘azido’ fragment. Close to room temperature these signals are broad and
overlapping. The existence of two structural isomers is supported by the fact of two characteristic
singlets representing the
t
Bu substituent.
224
B.1.4 GENERAL PROCEDURE C - PROTOALKYNE/ BISMUTH(III) ACETYLIDE
COMPETITIVE EXPERIMENTS
Evaluation of catalytic activity in the presence of terminal acetylenes: Stock solutions of the
corresponding bismuth(III) acetylides (0.06 M), terminal alkyne (0.06 M), (2-azidoethyl)benzene
(0.06 M), 1,4-dimethoxybenzene (0.012 M, internal standard) and copper(I) triflate toluene
complex (2.50 mM) were prepared in DMSO-d6. Of these stock solutions: 200 μl of bismuth(III)-
acetylide, 200 μl of terminal alkyne and 50 μl of reference the stock solutions were transferred into
an NMR tube, diluted with 300 μl of DMSO-d6 agitated and closed with a gas-tight rubber NMR
septum. Lastly, 50 μl of the CuOTf catalyst solution was added to the NMR tube and immediately
agitated. The total volume in the NMR tube for one experiment was 800 μl.
Kinetic NMR measurements were recorded on a Varian VNMRS-600 spectrometer. The sample
spinning rate was 20 Hz.
1
H-NMR data was collected with the following acquisition parameters:
1 transient (scan), 5 sec. relaxation delay time, acquisition time of 5.824 sec. Between the spectra
was a 1 sec pre-acquisition delay. Data was collected at 27.0˚C. After about 1 hour of data
acquisition the temperature was raised to 69.0˚C. After which 200 μl of the (2-azidoethyl)benzene
stock solution were injected and immediately agitated. The total volume inside NMR tube
experiment increased to 1 ml. Temperatures were calibrated against a temperature standard
(ethylene glycol). Each individual experiment was performed twice. All reagents were dried before
use. All manipulations were performed in the dry nitrogen atmosphere of a glove box. Reaction
conversions were integrated relative to an internal reference standard.
225
Table B.3 Reactions conditions of experiments following general procedure C. Kinetic profiles are shown
in Figure B.3.
Entry A[X], M A[Y],M [Z], M [cat], mM yield A, % H-exchanged Alkyne, %
1 [-Br], 0.012 [-H], 0.012
0.012 0.147
100.0 7.0
2 [-H], 0.012 [-Br], 0.012 58.33 0.0
3 [-Me], 0.012 [-H], 0.012 100.0 5.0
4 [-H], 0.012 [-Me], 0.012 100.0 0.0
Figure B.3 Kinetic profiles of reactions studied following general procedure C.
0
0.002
0.004
0.006
0.008
0.01
0.012
0.014
0 1000 2000 3000 4000 5000 6000
concentration, M
time, sec
BrBi/HH HBi/MeH
MeBi/HH HBi/BrH
226
B.1.5 MOISTURE COMPATIBILITY EXPERIMENTS
Table B.4 Moisture compatibility experiment. Reaction conditions of experiments following general
procedure A.
№ A [6], M [Z], M [cat], mM Water, % [Ref], mM Time, sec T,
°
C Conv, %
1
0.025 0.043 0.625
2% H 2O
3.375
1509
60
100.0
2 12% H 2O 1685 100.0
Figure B.4 Kinetic profiles of reactions studied following general procedure A. A) Conversion profiles of
reactions (Table B.4), entries 1 and 2; B1-B2) Dry and ‘wet’ DMSO-d6 as solvent.
227
B.1.6 GENERAL PROCEDURE D - HYDROGEN/DIPHENYLSULFONE BISMUTH(III)
TRANSMETALLATION EXPERIMENTS USING THE CUOTF TOLUENE
COMPLEX AS CATALYST
Evaluation of exchange processes: stock solutions of 1-ethynyl-4-methylbenzene (0.20 M), 1-
bromo-4-ethynylbenzene (0.20 M), ethynylbenzene (0.20 M), bismuth(III)-acetylide[3] (0.20 M),
bismuth(III)-acetylide[4] (0.20 M), bismuth(III)-acetylide[5] (0.20 M) 1,4-dimethoxybenzene
(0.108 M) were prepared in DMSO-d6. Similarly, a catalyst solution of the copper(I) triflate
toluene complex (0.012 M) was prepared in DMSO-d6. Of these stock solutions: 200 μl of alkyne
and bismuth(III)-acetylide and 50 μl of reference were transferred to an NMR tube, diluted with
300 μl of DMSO-d6 agitated and closed with a gas-tight rubber NMR septum. Lastly, 50 μl of the
CuOTf catalyst solution was added to the NMR tube and immediately agitated. The total volume
in the NMR tube for one experiment was 800 μl.
Kinetic NMR measurements were recorded on a Varian VNMRS-600 spectrometer. The sample
spinning rate was 20 Hz.
1
H-NMR data was collected with the following acquisition parameters:
1 transient (scan), 5 sec. relaxation delay time, acquisition time of 5.824 sec. Between the spectra
was a 1 sec pre-acquisition delay. Data was collected either collected at 27.0 or 69.0˚C.
Temperatures were calibrated against a temperature standard (ethylene glycol). Each individual
experiment was performed twice. All reagents were dried before use. All manipulations were
performed in the dry nitrogen atmosphere of a glove box. Reaction conversions were integrated
relative to an internal reference standard.
228
229
230
Figure B.5 Exchange reaction progress spectra. Equilibrium measurements at 27
°
C with CuOTf toluene
complex as catalyst. General procedure D.
Table B.5 Equilibrium measurements at 27
°
C with the CuOTf toluene complex as catalyst. General
procedure D.
Entry A[X], M A[Y], M [cat], mM
1 [-Br], 0.012M [-H], 0.012M
0.3
2 [-H], 0.012M [-Br], 0.012M
3 [-Me], 0.012M [-H], 0.012M
4 [-H], 0.012M [-Me], 0.012M
231
Table B.6 Equilibrium measurements at 69
°
C with CuOTf toluene complex as catalyst. General procedure
D.
The
1
H NMR spectra data make clear that the difference in integration values upon injection of the
catalyst increases due to the presence of a small amount of paramagnetic Cu(II).
Entry A[X], M A[Y], M [cat],mM
1 [-Br], 0.012M [-H], 0.012M
0. 3
2 [-H], 0.012M [-Br], 0.012M
3 [-Me], 0.012M [-H], 0.012M
4 [-H], 0.012M [-Me], 0.012M
232
233
234
235
Figure B.6 Exchange reaction progress spectra. Equilibrium measurements with CuOTf toluene complex as catalyst at 69 °C. General procedure D.
236
B.1.7 GENERAL PROCEDURE E – CATALYST ROBUSTNESS EXPERIMENTS
Evaluation of catalyst rate order: Stock solutions of bismuth(III)-acetylide[4] (0.60 M), of 2-
azidoethylbenzene (0.063 M), 1,4-dimethoxybenzene (0.025 M) and copper(I) triflate toluene
complex (3.10 mM) were prepared in DMSO-d6. Of these stock solutions: 120 μl of azide, 100 μl
of bismuth(III)-acetylide, 100 μl of reference stock solution transferred to an NMR tube, diluted
with 200 μl (entry 1) or 300 μl (entry 2) of pure DMSO-d6 agitated and closed with a gas-tight
rubber NMR septum. Lastly, 100 μl (entry 1) or 200 μl (entry 2) of the CuOTf catalyst solution
was added to the NMR tube and immediately agitated. The total volume in the NMR tube for one
experiment was 800 μl.
Kinetic NMR measurements were recorded on a Varian VNMRS-600 spectrometer. The sample
spinning rate was 20 Hz.
1
H-NMR data was collected with the following acquisition parameters:
2 transients (scans), 5 sec. relaxation delay time, acquisition time of 5.824 sec. Between the spectra
was a 1 sec pre-acquisition delay. Data was collected either collected at 60.0˚C. The temperature
was calibrated against a temperature standard (ethylene glycol). Each individual experiment was
performed twice. All reagents were dried before use. All manipulations were performed in the dry
nitrogen atmosphere of a glove box. Reaction conversions were integrated relative to an internal
reference standard.
Table B.7 Catalyst robustness experiments. Reactions conditions of the experiments following general
procedure E.
Entry A [4], M [Z], M [cat],
mM
[Ref],
mM
[excess], M Time
(averaged),
sec
T,
o
C Conv, %
1
0.012 0.014
0.386
3.1 0.002
4436
60
100.0
2 0.773 2336 100.0
237
Figure B.7 Kinetic profiles for experiments performed following general procedure E. A) [cat]=0.386 mM;
B) [cat]=0.773 mM.
238
B.2 CYCLIC VOLTAMMETRIC (CV) KINETIC STUDIES
General information
Anhydrous DMSO was purchased from MilliporeSigma and used without further purification.
Copper(I) trifluoromethanesulfonate toluene complex (CuOTf) was purchased from Sigma-
Aldrich.
Experimental details
All glassware was oven-dried (140 C) and purged by vacuum-N2 cycles in the antechamber of the
glovebox before use. All electrochemical measurements were performed inside a glovebox under
nitrogen atmosphere. Anhydrous DMSO served as solvent. A 3-electrode glass cell with a glassy
carbon working electrode (BASi, MF-2012), copper foil as the counter and reference electrodes,
and copper (I) triflate (0.58 mM in anhydrous DMSO) was used for the measurements.
Electrochemical data was collected on a multi-channel potentiostat (AMETEK Scientific
Instruments, VersaSTAT 4). Voltammogram at a scan rate of 100 mV s
-1
was performed on the
copper compound between -0.3 V and 0.8 V vs. Cu
+
/Cu.
1
H NMR spectra were obtained on a Varian 600Hz. Chemical shifts were reported in ppm
referenced at 2.5 ppm of DMSO-d6 solvent.
Data analysis
Kinetic cyclic voltammetry measurements were processed as current versus time dependences.
Graphical interpretation of processed experimental data was performed in Origin 9.0 data analysis
and graphing software package (OriginLab Corporation) or Microsoft Excel 2016.
239
B.2.1 GENERAL PROCEDURE F – DETERMINATION OF THE RATE CONSTANT
OF BISMUTH(III)-ACETYLIDE – COPPER(I) CATALYST Π-COMPLEX
FORMATION
Independent reactivity experiments: Stock solutions of the corresponding bismuth(III) acetylides
(0.075 M), (2-azidoethyl)benzene (0.135 M) and copper(I) triflate toluene complex (8.12 mM)
were prepared in anhydrous DMSO. 0.5 ml of the copper(I) triflate toluene complex stock solution
and 6.0 ml of DMSO were transferred into the 3-electrode cell, agitated and used to performed
cyclic voltammetry studies of three redox cycles (to ensure reproducibility of the data and the
stability of copper(I) triflate complex).
Kinetic CV measurements were recorded in the same 3-electrode cell with a glassy carbon working
electrode, copper foils as counter and reference electrodes. A solution of the
bismuth(III) acetylide[X] stock solution in anhydrous DMSO (0.5 ml) was introduced into
electrochemical cell and agitated for some time prior the start of the electrochemistry data
acquisition. Continuous electrochemical data collection at 100 mV s
-1
was performed until no
further changes in the redox cycles were observed.
240
Figure B.8 Kinetic profiles of the cyclic voltammograms obtained by following general procedure F.
B.2.2 GENERAL PROCEDURE G – DETERMINATION OF THE APPARENT RATE
CONSTANT OF THE BISMUTH(III) TRIAZOLIDE[X] FORMATION
Kinetic CV experiments were recorded in a 3-electrode cell with a glassy carbon working
electrode, copper foils as counter and reference electrodes. A solution of the
bismuth(III) acetylide[X] stock solution in anhydrous DMSO (0.5 ml) was introduced into
electrochemical cell and agitated for some time prior the start of the electrochemistry data
acquisition. Continuous electrochemical data collection at 100 mV s
-1
was performed until no
further changes in the redox cycles were observed.
A solution of the (2-azidoethyl)benzene in anhydrous DMSO (0.5 ml) was introduced to a
electrochemical cell with already preformed π-intermediate (general procedure F). The mixture
was agitated for some time prior the start of the electrochemistry data acquisition. Continuous
241
electrochemical data collection at 100 mV s
-1
was performed until no further changes in the redox
cycles were observed. Electrochemical measurements were recorded at 100 mV s
-1
between -0.3
V and 0.8 V vs. Cu
+
/Cu. An aliquot sample was taken and analyzed by
1
H NMR to confirm the
conversion rate of the reaction.
Figure B.9 Kinetic profiles of the cyclic voltammograms obtained by following general procedure G.
242
B.2.3 DETERMINATION OF REACTION RATE PARAMETERS
Rate of [1]
Kinetic data was obtained following general procedures F and G using 10-((4-
methoxyphenyl)ethynyl)-10H-dibenzo[b,e][1,4]thiabismine 5,5-dioxide (bismuth(III)
acetylide[1]). The rate constants of the acetylide coordination and the apparent rate constant of the
triazolide[1] formation were defined as the lowest value of exponential factors in the double
exponential rise approximation (KA = 1.21E-3 (1.3E-4) M
-1
; kobs = 1.60E-3(0.80E-4) M
-1
·sec
-1
).
Rate of [2]
Kinetic data was obtained following general procedures F and G using 10-((4-(tert-
butyl)phenyl)ethynyl)-10H-dibenzo[b,e][1,4]thiabismine 5,5-dioxide (bismuth(III) acetylide[2]).
The rate constants of the acetylide coordination and the apparent rate constant of the triazolide[2]
formation were defined as the lowest value exponential factors in the double exponential rise
approximation (KA = 0.91E-3 (0.13E-3) M
-1
; kobs = 1.23E-3(0.29E-3) M
-1
·sec
-1
).
243
Rate of [3]
Kinetic data was obtained following general procedures F and G using 10-(p-tolylethynyl)-10H-
dibenzo[b,e][1,4]thiabismine 5,5-dioxide (bismuth(III) acetylide[3]). The rate constants of the
acetylide coordination and the apparent rate constant of the triazolide[3] formation were defined
as the lowest value exponential factors in the double exponential rise approximation (KA = 0.093E-
3 (0.10E-4) M
-1
; kobs = 2.40E-2(0.41E-3) M
-1
·sec
-1
).
Rate of [4]
Kinetic data was obtained following general procedures F and G using 10-(phenylethynyl)-10H-
dibenzo[b,e][1,4]thiabismine 5,5-dioxide (bismuth(III) acetylide[4]). The rate constants of the
acetylide coordination and the apparent rate constant of the triazolide[4] formation were defined
244
as the lowest value exponential factors in the double exponential rise approximation (KA = 1.28E-
3 (0.12E-3) M
-1
; kobs = 7.50E-3 (0.55E-3) M
-1
·sec
-1
).
Rate of [5]
Kinetic data was obtained following general procedures F and G using 10-((4-
bromophenyl)ethynyl)-10H-dibenzo[b,e][1,4]thiabismine 5,5-dioxide (bismuth(III) acetylide[5]).
The rate constants of the acetylide coordination and the apparent rate constant of the triazolide[5]
formation were defined as the lowest value exponential factors in the double exponential rise
approximation (KA = 4.93E-3 (0.90E-3) M
-1
; kobs = 6.68E-3 (0.25E-3) M
-1
·sec
-1
).
245
Rate of [6]
Kinetic data was obtained following general procedures F and G using 10-((4-
bromophenyl)ethynyl)-10H-dibenzo[b,e][1,4]thiabismine 5,5-dioxide (bismuth(III) acetylide[6]).
The rate constants of the acetylide coordination and the apparent rate constant of the triazolide[6]
formation were defined as the lowest value exponential factors in the double exponential rise
approximation (KA = 1.02E-3 (0.52E-3) M
-1
; kobs = 9.70E-3 (0.40E-3) M
-1
·sec
-1
).
246
B.3 SYNTHESIS AND CHARACTERIZATION OF BISMUTH(III)-ACETYLIDES
AND 5-BISMUTH-1,2,3-TRIAZOLIDES
All reactions were carried out under nitrogen atmosphere with dry solvents ensuring anhydrous
reaction conditions, unless otherwise stated. Dry tetrahydrofuran (THF), acetone, diethyl ether
(Et2O), and methylene chloride (CH2Cl2) were obtained by passing commercially available pre‐
dried, oxygen-free formulations through activated alumina columns. Chemical reagents were
purchased at the highest commercially available purity and used without further purification,
unless otherwise stated. Copper(I) iodide (98% purity), bismuth(III) bromide (98% purity),
copper(I) trifluoromethanesulfonate toluene complex (90% technical grade) were purchased from
Sigma-Aldrich. Triphenylbismuth (99+% purity) and 3-chloroperbenzoic acid (<77% purity) were
purchased from Alfa Aesar. Anhydrous potassium carbonate and ethylene glycol were purchased
from Fischer Scientific. LCMS grade 2-propanol, hexane and ethyl acetate were purchased from
Fischer Scientific and used directly without drying or degassing. Aryl thiols and aryl halides were
used as received and without additional purification. Silica gel (230-400 mesh) was purchased
from Merck. Reactions progress was monitored both by thin‐layer chromatography (TLC) on 0.25
mm E. Merck silica gel plates (60F‐254) using UV light as visualizing agent and by Agilent
LC/MSD as well as Agilent HPLC/DAD spectrometer. E. Merck silica gel (60, particle size 0.040–
0.063 mm) was used for flash column chromatography. NMR spectra were recorded on Varian
Mercury 400, Varian VNMRS-500 or Varian VNMRS-600 spectrometer. Chemical shifts were
referenced to residual solvent signals (Chloroform-d: δH = 7.26 ppm, δC = 77.16 ppm) as an
internal reference.
19
F NMR spectra were externally referenced to 80% CFCl3 in chloroform-d.
The following abbreviations were used to describe NMR signal multiplicities: s = singlet, d =
doublet, t = triplet, q = quartet, quin = quintet, m = multiplet, b = broad. Infrared spectra were
247
recorded in the range 4000-400 cm
-1
on Bruker Alpha spectrometer using a diamond ATR unit. IR
intensities are described as vw (very weak), w (weak), m (medium), s (strong), vs (very strong).
X-ray crystallographic analysis was performed at UCSD on a Bruker Apex II Ultra2 CCD
diffractometer equipped with Mo Kα radiation (crystallographic details for all structures are given
X-Ray crystallographic details section). Yields refer to chromatographically and spectroscopically
(
1
H NMR) pure materials, unless otherwise is stated.
B.1.3.1 GENERAL PROCEDURE 1. SYNTHESIS OF DIPHENYLSULFANES
Adapted from a procedure of S. L. Buchwald and co-workers
1
.
(4-methoxyphenyl)(phenyl)sulfane 1. A dry 12-ml screw-capped glass vial sealed with rubber
septum was purged with dry nitrogen, equipped with magnetic stirring bar and charged with
copper(I) iodide (70.0 mg, 0.35 mmol), potassium carbonate (1.95 g, 14.0 mmol) and 1-iodo-4-
methoxybenzene (1.30 g, 7.0 mmol). The vial and its contents were exposed to three vacuum-
nitrogen cycles. Subsequently, 2-propanol (7.0 ml) and ethylene glycol (0.77 ml) were added
together with the 4-methoxybenzenethiol (0.77 mg, 7.0 mmol) with a syringe. The stirred reaction
mixture was heated up to 80 °C and kept at this temperature overnight. The reaction mixture was
allowed to cool to room-temperature, filtered and concentrated to give yellow liquid, which was
purified by flashed column chromatography to yield a pale yellow liquid as a product (yield:
0.65 g, 43 %). NMR characterization data was consistent with those previously reported
2
.
248
phenyl(p-tolyl)sulfane. Synthesized from 4-methylbenzenethiol (0.87 g, 7.0 mmol) and
iodobenzene (1.43 g, 7.0 mmol) following general procedure 1, 1.08 g, 77 %, overnight, colorless
liquid. NMR characterization data is consistent with those previously reported
2
(4-chlorophenyl)(phenyl)sulfane. Synthesized from benzenethiol (0.77 g, 7.0 mmol) and 1-
chloro-4-iodobenzene (1.97 g, 7.0 mmol) using general procedure, 1.5 g, 97 %, overnight,
colorless liquid. NMR characterization data is consistent with those previously reported
3
.
phenyl(4-(trifluoromethyl)phenyl)sulfane. Synthesized from benzenethiol (0.77 g, 7.0 mmol)
and 1-iodo-4-(trifluoromethyl)benzene (1.90 g, 7.0 mmol) following general procedure 1, 0.88 g,
50 %, overnight, colorless liquid:
IR (υ[cm-1]) 3089 (vw), 3050 (vw), 2921 (vw), 1926 (vw), 1602 (m), 1582 (m), 1568 (w), 1496
(vw), 1477 (m), 1440 (m), 1401 (m), 1320 (s), 1189 (w), 1161 (s), 1127 (s), 1106 (vs), 1094 (vs),
249
1061 (vs), 1024 (m), 1011 (s), 997 (m), 959 (m), 908 (m), 833 (vs), 778 (w), 743 (vs), 727 (s), 695
(s), 687 (s), 631 (m), 615 (w), 592 (m), 522 (m), 494 (m), 480 (s), 435 (m), 403 (w).
1
H NMR (500 MHz, Chloroform-d) δ 7.50 – 7.46 (m, 4H), 7.42 – 7.36 (m, 3H), 7.28 (d, J = 0.9
Hz, 2H).
13
C NMR (126 MHz, Chloroform-d) δ 142.97, 133.68, 132.65, 129.82, 128.66, 128.18 (q, J = 32.5
Hz) , 125.95 (q, J = 3.8 Hz) , 124.37 (q, J = 273.7 Hz).
19
F NMR (470 MHz, Chloroform-d) δ -62.51.
(4-methoxyphenyl)(4-(trifluoromethyl)phenyl)sulfane. Synthesized from 4-
methoxybenzenethiol (0.98 g, 7.0 mmol) and 1-iodo-4-(trifluoromethyl)benzene (1.90 g,
7.0 mmol) following general procedure 1, 1.20 g, 60 %, overnight, colorless liquid:
IR (υ[cm-1]) 3086 (vw), 3029 (w), 2973 (w), 2948 (w), 2846 (w), 2084 (vw), 2054 (vw), 1923
(w), 1670 (vw), 1601 (m), 1588 (m), 1569 (m), 1490 (m), 1466 (m), 1451 (m), 1441 (m), 1400
(m), 1356 (vw), 1327 (s), 1288 (m), 1252 (m), 1189 (m), 1165 (s), 1107 (vs), 1082 (vs), 1060 (s),
1030 (s), 1009 (s), 957 (m), 830 (vs), 811 (s), 799 (m), 776 (m), 724 (m), 699 (m), 644 (m), 627
(m), 590 (m), 532 (m), 505 (m), 492 (m), 430 (m).
1
H NMR (500 MHz, Chloroform-d) δ 7.47 (d, J = 8.9 Hz, 2H), 7.44 (d, J = 8.2 Hz, 2H), 7.14 (d, J
= 8.2 Hz, 2H), 6.96 (d, J = 8.9 Hz, 2H), 3.85 (s, 3H).
250
13
C NMR (126 MHz, Chloroform-d) δ 160.77, 144.97, 136.85, 127.35 (q, J = 32.7 Hz), 126.55,
125.77 (q, J = 3.8 Hz), 124.32 (q, J = 271.7 Hz), 121.82, 115.52, 55.57.
19
F NMR (470 MHz, Chloroform-d) δ -62.39.
bis(4-(trifluoromethyl)phenyl)sulfane. Synthesized from 4-(trifluoromethyl)benzenethiol
(0.89 g, 5.0 mmol) and 1-iodo-4-(trifluoromethyl)benzene (1.36 g, 5.0 mmol) following general
procedure 1, 1.21 g, 75 %, overnight, colorless solid:
IR (υ[cm-1]) 3094 (vw), 3063 (vw), 2924 (vw), 1604 (m), 1574 (w), 1496 (w), 1401 (m), 1318
(vs), 1162 (s), 1119 (vs), 1103 (vs), 1082 (s), 1060 (vs), 1012 (s), 951 (w), 824 (s), 778 (m), 724
(w), 699 (m), 632 (w), 590 (m), 515 (m), 486 (m), 414 (w).
1
H NMR (500 MHz, Chloroform-d) δ 7.60 (d, J = 8.2 Hz, 1H), 7.46 (d, J = 8.5 Hz, 1H).
13
C NMR (126 MHz, Chloroform-d) δ 139.68, 131.17, 129.85 (q, J = 32.8 Hz), 126.42 (q, J = 3.8
Hz), 124.06 (q, J = 272.0 Hz).
19
F NMR (470 MHz, Chloroform-d) δ -62.77.
251
B.1.3.2 GENERAL PROCEDURE 2. SYNTHESIS OF SULFONYLDIBENZENES
Adapted from a procedure of J. Thomas and co-workers
4
.
1-methoxy-4-(phenylsulfonyl)benzene. To a 50 ml round-bottom flask equipped with a magnetic
stir bar, 1.00g (4.62 mmol, 1.00 eq.) of (4-methoxyphenyl)(phenyl)sulfane in 25 ml of reagent
grade DCM were added. To the clear solution 5.56 g (46.2 mmol, 10.0 eq.) of anhydrous MgSO4
were added followed by the slow addition 2.40g of m-CPBA (oxidizing reagent) (13.86 mmol,
3.00 eq.). The reaction mixture was stirred at room temperature for 8 hours. Complete conversion
of starting material was ensured monitoring of the reaction progress by TLC (hexane,
Rf(product)=0.5, Rf (reagent)=0.4). The reaction mixture was transferred to a 250 ml separatory
funnel and washed with sat. NaHCO3 (2×40 ml) to ensure complete removal of any residual m-
CPBA. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo to yield a
pale yellow oil. The crude material was purified by flash column chromatography using hexane as
eluent to give 1-methoxy-4-(phenylsulfonyl)benzene as an pale yellow solid (0.70 g, 98% yield).
IR (υ[cm-1]) 3076 (w), 2847 (w), 2655 (w), 2595 (w), 2550 (w), 1689 (m), 1591 (m), 1574 (m),
1497 (m), 1468 (w), 1446 (m), 1416 (m), 1298 (s), 1261 (s), 1192 (w), 1183 (w), 1148 (s), 1105
252
(s), 1071 (m), 1018 (m), 997 (m), 914 (m), 897 (m), 850 (m), 833 (m), 803 (m), 748 (s), 730 (s),
719 (s), 711 (m), 687 (m), 667 (m), 656 (m), 627 (m), 575 (s), 554 (vs), 493 (m), 451 (w), 416 (w).
1
H NMR (500 MHz, Chloroform-d) δ 7.92 (d, J = 8.3 Hz, 2H), 7.88 (d, J = 8.2 Hz, 2H), 7.56 –
7.51 (m, 1H), 7.48 (t, J = 7.5 Hz, 2H), 6.96 (d, J = 9.0 Hz, 2H), 3.84 (s, 3H).
13
C NMR (126 MHz, Chloroform-d) δ 163.51, 142.52, 133.28, 132.96, 130.04, 129.33, 127.46,
114.65, 55.79.
1-chloro-4-(phenylsulfonyl)benzene. Synthesized from (4-chlorophenyl)(phenyl)sulfane
(0.80 g, 3.60 mmol) following general procedure 2, 0.91 g, 98%, 4 hours, colorless solid. NMR
characterization data is consistent with those previously reported
5
.
IR (υ[cm-1]) 3091 (w), 3068 (w), 2956 (w), 2956 (w), 2923 (w), 2853 (w), 1693 (m), 1596 (w),
1576 (m), 1474 (m), 1446 (m), 1417 (w), 1390 (m), 1319 (m), 1308 (s), 1279 (m), 1263 (m), 1176
(w), 1152 (s), 1106 (m), 1084 (s), 1069 (s), 1049 (m), 1026 (m), 1011 (m), 998 (m), 953 (w), 932
(w), 897 (w), 851 (w), 833 (m), 823 (m), 765 (m), 747 (vs), 718 (s), 700 (m), 685 (s), 653 (w), 608
(vs), 564 (vs), 521 (m), 496 (s), 486 (m), 467 (m), 435 (m).
1-(phenylsulfonyl)-4-(trifluoromethyl)benzene. Synthesized from phenyl(4-
(trifluoromethyl)phenyl)sulfane (0.88 g, 3.40 mmol) following general procedure 2, 0.89 g, 91%,
4 hours, colorless solid.
253
IR (υ[cm-1]) 3108 (vw), 3090 (vw), 3063 (vw), 1608 (vw), 1583 (vw), 1500 (vw), 1477 (vw),
1446 (w), 1404 (m), 1317 (s), 1296 (m), 1145 (s), 1106 (s), 1071 (s), 1058 (s), 1017 (m), 998 (m),
978 (w), 967 (w), 928 (w), 846 (m), 839 (m), 787 (m), 758 (m), 742 (m), 720 (s), 700 (s), 684 (s),
593 (vs), 557 (s), 497 (w), 480 (w), 456 (w), 421 (m).
1
H NMR (500 MHz, Chloroform-d) δ 8.07 (d, J = 8.2 Hz, 2H), 7.96 (d, J = 7.6 Hz, 2H), 7.75 (d, J
= 8.2 Hz, 2H), 7.63 – 7.56 (m, 1H), 7.53 (t, J = 7.6 Hz, 2H).
13
C NMR (126 MHz, Chloroform-d) δ 145.33, 140.65, 134.89 (q, J=33.2 Hz), 133.89, 129.64,
128.28, 127.98, 126.54 (q, J=3.7 Hz), 123.20 (q, J=273.5 Hz).
4,4'-sulfonylbis(methoxybenzene). Synthesized from 4.4’-sulfonyldiphenol (0.50 g, 2.0 mmol)
and iodomethane (2.84 g, 20.0 mmol) following a literature procedure
6
, 0.54 g, 97 %, 4 hours,
colorless solid:
IR (υ[cm-1]) 2996 (w), 2982 (w), 2949 (w), 2921 (w), 2901 (w), 2841 (w), 1592 (m), 1576 (m),
1496 (m), 1458 (s), 1437 (s), 1386 (vs), 1317 (s), 1295 (s), 1253 (vs), 1185 (m), 1178 (m), 1145
(s), 1103 (s), 1020 (s), 973 (m), 939 (w), 846 (s), 829 (m), 819 (m), 801 (s), 717 (m), 677 (s), 642
(w), 630 (m), 623 (w), 566 (s), 547 (vs), 484 (m), 411 (vw).
254
1
H NMR (500 MHz, Chloroform-d) δ 7.85 (d, J = 9.1 Hz, 4H), 6.95 (d, J = 9.0 Hz, 4H), 3.83 (s,
6H).
13
C NMR (126 MHz, Chloroform-d) δ 163.22, 134.13, 129.66, 114.55, 55.76.
1-methoxy-4-((4-(trifluoromethyl)phenyl)sulfonyl)benzene. Synthesized from (4-
methoxyphenyl)(4-(trifluoromethyl)phenyl)sulfane (1.20 g, 3.70 mmol) following general
procedure 2, 1.16 g, 99 %, 4 hours, colorless solid:
IR (υ[cm-1]) 3101 (vw), 2955 (vw), 2850 (vw), 1591 (m), 1575 (m), 1497 (m), 1463 (w), 1445
(w), 1415 (w), 1403 (m), 1322 (s), 1302 (m), 1261 (s), 1188 (m), 1155 (s), 1122 (s), 1105 (vs),
1074 (m), 1058 (vs), 1014 (s), 959 (w), 944 (w), 838 (m), 801 (m), 734 (w), 721 (s), 706 (s), 661
(s), 627 (w), 590 (vs), 549 (s), 515 (m), 479 (m), 424 (s).
1
H NMR (500 MHz, Chloroform-d) δ 8.04 (d, J = 9.0 Hz, 2H), 7.89 (d, J = 8.7 Hz, 2H), 7.74 (d, J
= 8.9 Hz, 2H), 6.99 (d, J = 8.8 Hz, 2H), 3.85 (s, 3H).
13
C NMR (126 MHz, Chloroform-d) δ 164.00, 146.13, 134.65 (q, J = 33.1 Hz), 132.11, 130.31,
127.99, 126.50 (q, J = 3.8 Hz), 123.26 (q, J = 273.0 Hz), 114.92, 55.86.
4,4'-sulfonylbis((trifluoromethyl)benzene). Synthesized from bis(4-
(trifluoromethyl)phenyl)sulfane (1.0 g, 3.10 mmol) following general procedure 2, 0.55 g, 50 %,
4 hours, colorless solid:
255
IR (υ[cm-1]) 3105 (vw), 3056 (vw), 2927 (vw), 1609 (vw), 1406 (m), 1316 (s), 1158 (s), 1129
(vs), 1105 (vs), 1073 (s), 1058 (vs), 1015 (s), 962 (m), 840 (s), 790 (m), 734 (m), 716 (s), 703 (s),
676 (w), 616 (s), 600 (s), 560 (s), 499 (w), 471 (w), 427 (s).
1
H NMR (500 MHz, Chloroform-d) δ 8.08 (d, J = 8.2 Hz, 4H), 7.81 (d, J = 8.4 Hz, 4H).
13
C NMR (126 MHz, Chloroform-d) δ 144.34, 135.59 (q, J = 33.2 Hz), 128.60, 126.85 (q, J = 3.7
Hz), 123.11 (q, J = 273.2 Hz).
19
F NMR (470 MHz, Chloroform-d) δ -63.34.
256
B.1.3.3 GENERAL PROCEDURE 3. SYNTHESIS OF 10-PHENYL-10H-
DIBENZO[B,E][1,4]THIABISMINE 5,5-DIOXIDES
Adapted from a procedure of Suzuki H. and co-workers
7
.
2-methoxy-10-phenyl-10H-dibenzo[b,e][1,4]thiabismine 5,5-dioxide. Synthesized from 1-
methoxy-4-(phenylsulfonyl)benzene (0.65 g, 2.60 mmol) following a literature procedure
7
, 1.23 g,
87 %, 4 hours, colorless solid:
IR (υ[cm-1]) 3047 (w), 3005 (vw), 2958 (w), 2922 (m), 2851 (w), 1720 (w), 1567 (s), 1496 (vw),
1460 (m), 1427 (m), 1291 (s), 1265 (s), 1236 (m), 1221 (s), 1183 (w), 1145 (s), 1116 (s), 1094 (s),
1074 (s), 1025 (s), 1011 (s), 996 (m), 909 (w), 874 (m), 828 (m), 760 (m), 727 (vs), 715 (s), 706
(m), 695 (s), 661 (m), 650 (s), 582 (s), 561 (vs), 543 (s), 513 (m), 495 (m), 483 (m), 460 (m), 445
(m), 431 (m).
1
H NMR (500 MHz, Chloroform-d) δ 8.34 (d, J = 7.7 Hz, 1H), 8.32 (d, J = 8.6 Hz, 1H), 7.85 (d, J
= 7.2 Hz, 1H), 7.79 (d, J = 7.9 Hz, 2H), 7.47 – 7.40 (m, 2H), 7.42 – 7.35 (m, 3H), 7.33 (t, J = 7.4
Hz, 1H), 6.85 (dd, J = 8.6, 2.6 Hz, 1H), 3.69 (s, 3H).
257
13
C NMR (126 MHz, Chloroform-d) δ 167.88, 166.20, 163.65, 160.47, 142.74, 138.80, 137.61,
133.32, 133.22, 130.99, 129.11, 128.73, 128.24, 126.73, 123.51, 112.90, 55.68.
10-phenyl-10H-dibenzo[b,e][1,4]thiabismine 5,5-dioxide. Synthesized from sulfonyldibenzene
(1.8 g, 8.5 mmol) following general procedure 3, 2.07 g, 63 %, overnight, colorless solid. NMR
characterization data is consistent with those previously reported
8
.
2-chloro-10-phenyl-10H-dibenzo[b,e][1,4]thiabismine 5,5-dioxide. Synthesized from 1-chloro-
4-(phenylsulfonyl)benzene (0.78 g, 3.10 mmol) following general procedure 3, 0.79 g, 47 %,
overnight, colorless solid:
IR (υ[cm-1]) 3056 (w), 3039 (w), 2978 (vw), 2932 (vw), 1651 (vw), 1548 (m), 1474 (w), 1427
(m), 1362 (w), 1298 (s), 1284 (m), 1249 (m), 1150 (s), 1122 (m), 1086 (s), 1075 (s), 1055 (m),
1012 (m), 996 (m), 953 (w), 912 (w), 877 (w), 851 (w), 821 (m), 780 (m), 754 (m), 728 (s), 711
(m), 694 (s), 649 (m), 638 (m), 612 (vs), 568 (vs), 527 (m), 502 (m), 476 (m), 467 (m), 442 (m),
426 (m).
258
1
H NMR (500 MHz, Chloroform-d) δ 8.37 (d, J = 7.6 Hz, 1H), 8.30 (d, J = 8.3 Hz, 1H), 7.87 (d, J
= 7.0 Hz, 1H), 7.82 (d, J = 2.0 Hz, 1H), 7.78 (d, J = 7.9 Hz, 2H), 7.47 (t, J = 7.7 Hz, 2H), 7.45 –
7.34 (m, 4H).
13
C NMR (126 MHz, Chloroform-d) δ 166.45, 159.23, 141.67, 140.90, 140.15, 138.74, 137.74,
137.32, 133.82, 131.29, 129.04, 128.51, 128.48, 128.41, 127.41.
10-phenyl-2-(trifluoromethyl)-10H-dibenzo[b,e][1,4]thiabismine 5,5-dioxide. Synthesized
from 1-(phenylsulfonyl)-4-(trifluoromethyl)benzene (2.44 g, 8.52 mmol) following general
procedure 3, 1.22 g, 25 %, overnight, colorless solid:
IR (υ[cm-1]) 3069 (w), 3052 (w), 1954 (w), 1911 (vw), 1852 (vw), 1786 (vw), 1587 (w), 1562
(m), 1475 (w), 1447 (w), 1427 (m), 1383 (m), 1320 (s), 1304 (vs), 1288 (s), 1256 (m), 1154 (s),
1118 (vs), 1097 (s), 1079 (s), 1064 (vs), 1022 (m), 1012 (m), 996 (m), 964 (m), 909 (w), 898 (m),
855 (w), 834 (m), 802 (m), 766 (m), 741 (m), 724 (s), 709 (s), 699 (s), 651 (m), 638 (w), 622 (m),
601 (s), 559 (s), 513 (m), 492 (w), 469 (m), 450 (w), 438 (m), 428 (m), 404 (w).
1
H NMR (500 MHz, Chloroform-d) δ 8.47 (d, J = 8.1 Hz, 1H), 8.40 (dd, J = 7.6, 1.5 Hz, 1H), 8.09
(s, 1H), 7.90 (dd, J = 7.2, 1.3 Hz, 1H), 7.76 (dd, J = 8.0, 1.4 Hz, 2H), 7.67 (d, J = 8.1 Hz, 1H),
7.50 – 7.33 (m, 5H).
259
13
C NMR (126 MHz, Chloroform-d) δ 166.48, 159.71, 145.43, 141.01, 138.67, 137.82, 134.80 (q,
J = 32.4 Hz), 134.50 (q, J = 3.6 Hz), 134.02, 131.31, 129.15, 128.62, 127.79, 127.35, 127.20,
125.49 (q, J = 3.7 Hz), 123.55 (q, J = 273.2 Hz).
19
F NMR (470 MHz, Chloroform-d) δ -62.92.
2,8-dimethoxy-10-phenyl-10H-dibenzo[b,e][1,4]thiabismine 5,5-dioxide. Synthesized from
4,4'-sulfonylbis(methoxybenzene) (1.0 g, 3.60 mmol) following general procedure 3, 1.20 g, 59
%, overnight, colorless solid:
IR (υ[cm-1]) 3107 (w), 3059 (w), 2934 (w), 1609 (w), 1593 (w), 1570 (m), 1497 (w), 1460 (w),
1427 (w), 1406 (m), 1314 (s), 1265 (m), 1221 (m), 1156 (s), 1128 (vs), 1104 (vs), 1074 (s), 1058
(s), 1015 (s), 963 (m), 839 (s), 791 (m), 734 (m), 716 (s), 704 (m), 680 (m), 654 (w), 616 (m), 600
(m), 560 (s), 503 (w), 472 (w), 452 (vw), 427 (m).
1
H NMR (500 MHz, Chloroform-d) δ 8.28 (d, J = 8.6 Hz, 2H), 7.81 (d, J = 7.9 Hz, 2H), 7.44 (t, J
= 7.6 Hz, 2H), 7.39 – 7.35 (m, 3H), 6.84 (dd, J = 8.6, 2.5 Hz, 2H), 3.69 (s, 6H).
13
C NMR (126 MHz, Chloroform-d) δ 172.32, 163.52, 160.04, 138.80, 134.23, 131.00, 128.76,
128.59, 123.50, 112.75, 55.68.
260
2,4-dimethoxy-10-phenyl-10H-dibenzo[b,e][1,4]thiabismine 5,5-dioxide. Synthesized from
2,4-dimethoxy-1-(phenylsulfonyl)benzene (0.80 g, 2.80 mmol ) following general procedure 3,
0.75 g, 47 % , 4 hours, colorless solid:
IR (υ[cm-1]) 3086 (vw), 3051 (w), 3033 (w), 2999 (w), 2980 (w), 2941 (w), 2829 (w), 2067 (vw),
1955 (vw), 1878 (vw), 1820 (vw), 1574 (m), 1556 (s), 1473 (w), 1462 (m), 1445 (m), 1419 (m),
1399 (m), 1298 (s), 1272 (vs), 1208 (s), 1181 (m), 1173 (m), 1142 (vs), 1109 (s), 1083 (m), 1067
(s), 1029 (s), 1009 (s), 995 (m), 951 (m), 923 (m), 854 (s), 845 (s), 754 (m), 728 (vs), 708 (s), 698
(s), 636 (s), 607 (s), 587 (vs), 576 (s), 537 (m), 512 (s), 484 (m), 449 (m), 426 (m), 414 (m).
1
H NMR (400 MHz, Chloroform-d) δ 8.35 (d, J = 6.4 Hz, 1H), 7.75 (d, J = 7.3 Hz, 1H), 7.65 (dd,
J = 7.9, 1.5 Hz, 2H), 7.54 (d, J = 2.2 Hz, 1H), 7.37 – 7.20 (m, 5H), 6.54 (d, J = 2.2 Hz, 1H), 3.82
(s, 3H), 3.25 (s, 3H).
13
C NMR (101 MHz, Chloroform-d) δ 164.39, 162.32, 162.13, 157.19, 143.07, 141.64, 138.06,
137.90, 137.04, 133.27, 130.29, 128.02, 127.67, 126.57, 104.29, 103.03, 55.94, 55.57.
261
B.1.3.4 GENERAL PROCEDURE 4. SYNTHESIS OF 10-IODO-10H-
DIBENZO[B,E][1,4]THIABISMINE 5,5-DIOXIDES
Adapted from a procedure of H. Suzuki and co-workers
7
.
10-iodo-2-methoxy-10H-dibenzo[b,e][1,4]thiabismine 5,5-dioxide. Synthesized from 2-
methoxy-10-phenyl-10H-dibenzo[b,e][1,4]thiabismine 5,5-dioxide (0.06 g, 11.4 mmol) following
a literature procedure
7
, 0.61 g, 10.8 mmol, 92 %, 4 hours, off-white solid:
IR (υ[cm-1]) 2969 (m), 2953 (m), 2928 (m), 1592 (s), 1551 (s), 1496 (m), 1470 (m), 1445 (m),
1425 (s), 1384 (vs), 1267 (s), 1198 (m), 1145 (s), 1106 (m), 1090 (m), 1070 (m), 1017 (m), 962
(w), 898 (w), 874 (w), 831 (m), 803 (w), 760 (m), 731 (s), 684 (m), 671 (m), 658 (m), 577 (m),
513 (s), 430 (w), 408 (w).
1
H NMR (500 MHz, Chloroform-d) δ 9.21 – 9.18 (m, 1H), 8.81 (d, J = 2.4 Hz, 1H), 8.27 (d, J =
7.6 Hz, 1H), 8.24 (d, J = 8.4 Hz, 1H), 7.60 (t, J = 7.4 Hz, 1H), 7.47 (t, J = 7.6 Hz, 1H), 6.91 (dd, J
= 8.5, 2.4 Hz, 1H), 3.89 (s, 3H).
262
13
C NMR (126 MHz, Chloroform-d) δ 166.31, 165.77, 163.62, 141.19, 140.29, 135.75, 131.12,
129.68, 128.84, 127.21, 126.39, 114.23, 56.02.
10-iodo-10H-dibenzo[b,e][1,4]thiabismine 5,5-dioxide. Synthesized from 10-phenyl-10H-
dibenzo[b,e][1,4]thiabismine 5,5-dioxide (3.310 g, 6.0 mmol) following general procedure 4,
2.07 g, 63 %, 4 hours, colorless solid. NMR characterization data is consistent with those
previously reported
8
.
2-chloro-10-iodo-10H-dibenzo[b,e][1,4]thiabismine 5,5-dioxide. Synthesized from 2-chloro-
10-phenyl-10H-dibenzo[b,e][1,4]thiabismine 5,5-dioxide (0.65 g, 1.11 mmol) following general
procedure 4, 0.66 g, 69 %, 4 hours, off-white solid:
IR (υ[cm-1]) 3076 (w), 3046 (vw), 3031 (vw), 1547 (m), 1437 (w), 1423 (m), 1362 (w), 1302 (s),
1285 (m), 1248 (m), 1146 (m), 1135 (m), 1116 (m), 1087 (s), 1066 (s), 1024 (m), 1007 (m), 957
(w), 884 (m), 832 (m), 781 (m), 760 (s), 728 (m), 709 (m), 648 (m), 636 (w), 612 (s), 567 (vs),
524 (m), 500 (m), 483 (m), 463 (s), 424 (m).
263
1
H NMR (500 MHz, Chloroform-d) δ 9.23 (d, J = 7.4 Hz, 1H), 9.13 (dd, J = 2.0, 1.0 Hz, 1H), 8.30
(d, J = 7.7 Hz, 1H), 8.21 (d, J = 8.2 Hz, 1H), 7.65 (t, J = 7.4 Hz, 1H), 7.54 – 7.48 (m, 1H), 7.45 –
7.42 (m, 1H).
13
C NMR (126 MHz, Chloroform-d) δ 163.84, 157.42, 143.99, 140.65, 140.54, 140.11, 138.41,
136.28, 129.22, 129.10, 128.70, 127.86.
10-iodo-2-(trifluoromethyl)-10H-dibenzo[b,e][1,4]thiabismine 5,5-dioxide. Synthesized from
10-phenyl-2-(trifluoromethyl)-10H-dibenzo[b,e][1,4]thiabismine 5,5-dioxide (1.0 g, 1.75 mmol)
following general procedure 4, 0.46 g, 42 %, 4 hours, off-white solid:
IR (υ[cm-1]) 3105 (vw), 3062 (vw), 3031 (vw), 1561 (w), 1440 (w), 1425 (w), 1390 (w), 1311
(vs), 1294 (m), 1254 (m), 1173 (s), 1148 (s), 1118 (vs), 1093 (m), 1073 (m), 1064 (s), 1029 (m),
1010 (m), 985 (w), 971 (w), 894 (m), 878 (w), 844 (m), 823 (w), 802 (w), 762 (m), 738 (m), 723
(m), 707 (m), 652 (w), 638 (w), 623 (m), 601 (m), 588 (m), 558 (s), 526 (w), 513 (m), 491 (w),
470 (m), 442 (m), 428 (m).
1
H NMR (500 MHz, Chloroform-d) δ 9.41 (s, 1H), 9.28 – 9.21 (m, 1H), 8.41 – 8.29 (m, 2H), 7.75
(d, J = 7.9 Hz, 1H), 7.67 (tt, J = 7.5, 1.5 Hz, 1H), 7.56 – 7.49 (m, 1H).
13
C NMR (126 MHz, Chloroform-d) δ 143.63, 140.51, 137.56, 136.36 129.07, 128.10, 127.38,
126.05, 123.36 (q. J = 274 Hz), 77.25, 76.99, 76.74.
264
19
F NMR (470 MHz, Chloroform-d) δ -62.81.
10-iodo-2,8-dimethoxy-10H-dibenzo[b,e][1,4]thiabismine 5,5-dioxide. Synthesized from 2,8-
dimethoxy-10-phenyl-10H-dibenzo[b,e][1,4]thiabismine 5,5-dioxide (0.56 g, 1.78 mmol)
following general procedure 4, 0.56 g, 51%, 4 hours, colorless solid:
IR (υ[cm-1]) 3083 (w), 3011 (w), 2968 (w), 2930 (w), 2829 (w), 1561 (s), 1472 (w), 1452 (m),
1424 (m), 1400 (m), 1317 (m), 1294 (s), 1269 (s), 1223 (vs), 1189 (m), 1178 (m), 1157 (m), 1139
(m), 1124 (s), 1102 (s), 1071 (s), 1020 (s), 954 (m), 884 (m), 876 (m), 819 (vs), 712 (m), 681 (s),
652 (m), 636 (m), 581 (m), 567 (vs), 548 (s), 539 (vs), 504 (s), 466 (m), 435 (m).
1
H NMR (600 MHz, Chloroform-d) δ 8.79 (d, J = 2.4 Hz, 2H), 8.20 (d, J = 8.6 Hz, 2H), 6.89 (dd,
J = 8.5, 2.5 Hz, 2H), 3.89 (s, 6H).
13
C NMR (151 MHz, Chloroform-d) δ 166.14, 165.60, 132.21, 129.12, 126.33, 114.08, 56.00.
10-iodo-2-methoxy-8-(trifluoromethyl)-10H-dibenzo[b,e][1,4]thiabismine 5,5-dioxide.
Synthesized from 2-methoxy-10-phenyl-8-(trifluoromethyl)-10H-dibenzo[b,e][1,4]thiabismine
5,5-dioxide (0.40 g, 0.67 mmol) following general procedure 4, 0.16 g, 10.8 mmol, 37%, 4
hours, off-white solid:
265
IR (υ[cm-1]) 3107 (w), 3015 (w), 2969 (w), 2934 (w), 2833 (w), 1566 (m), 1455 (m), 1425 (m),
1397 (m), 1381 (m), 1318 (s), 1302 (s), 1271 (s), 1255 (s), 1227 (s), 1177 (m), 1145 (s), 1122 (vs),
1103 (s), 1075 (s), 1064 (vs), 1019 (s), 1006 (s), 974 (m), 950 (m), 893 (m), 882 (m), 849 (m), 826
(m), 817 (s), 802 (m), 731 (w), 717 (s), 708 (m), 664 (m), 652 (s), 621 (m), 594 (s), 558 (m), 548
(s), 516 (m), 494 (m), 474 (m), 440 (m), 421 (w), 411 (w).
1
H NMR (500 MHz, Chloroform-d) δ 9.39 (s, 1H), 8.84 (d, J = 2.5 Hz, 1H), 8.34 (d, J = 8.2 Hz,
1H), 8.26 (d, J = 8.6 Hz, 1H), 7.73 (d, J = 8.5 Hz, 1H), 6.94 (dd, J = 8.6, 2.4 Hz, 1H), 3.91 (s, 3H).
13
C NMR (126 MHz, Chloroform-d) δ 166.72, 166.21, 163.06, 137.58 (q, J = 3.6 Hz), 137.07 (q,
J = 33.0 Hz), 130.26, 130.16, 126.98, 126.70, 126.16 (q, J = 3.7 Hz), 123.44 (q, J = 272.8 Hz),
114.52, 56.11.
10-iodo-10H-dibenzo[b,e][1,4]thiabismine. Synthesized from 10-phenyl-10H-
dibenzo[b,e][1,4]thiabismine (1.30 g, 2.70 mmol) following general procedure 4, 0.71 g,
1.37 mmol, 51 %, overnight, pale yellow solid:
266
1
H NMR (500 MHz, Chloroform-d) δ 8.99 (d, J = 7.5 Hz, 2H), 7.83 (d, J = 7.6 Hz, 2H), 7.50 (tt, J
= 7.4, 1.0 Hz, 2H), 7.29 (tt, J = 7.5, 1.1 Hz, 2H).
13
C NMR (126 MHz, Chloroform-d) δ 165.06, 144.80, 139.61, 136.84, 134.10, 132.90, 129.01,
77.16.
10-iodo-2,4-dimethoxy-10H-dibenzo[b,e][1,4]thiabismine 5,5-dioxide. Synthesized from 2,4-
dimethoxy-10-phenyl-10H-dibenzo[b,e][1,4]thiabismine 5,5-dioxide (0.75 g, 1.33 mmol )
following general procedure 4, 0.8 g, 98 %, 4 hours, olive solid:
IR (υ[cm-1]) 3079 (w), 2998 (vw), 2954 (w), 2929 (w), 2828 (w), 1575 (m), 1554 (m), 1463 (m),
1456 (m), 1421 (m), 1397 (m), 1309 (s), 1278 (vs), 1251 (m), 1212 (s), 1189 (m), 1180 (m), 1160
(m), 1139 (s), 1108 (s), 1083 (m), 1073 (m), 1038 (s), 1027 (m), 1004 (m), 944 (m), 931 (m), 838
(s), 756 (m), 724 (s), 696 (m), 635 (m), 602 (vs), 572 (s), 541 (m), 511 (s), 473 (m), 449 (w), 432
(m).
1
H NMR (500 MHz, Chloroform-d) δ 10.33 (d, J = 7.7 Hz, 1H), 8.04 – 7.96 (m, 1H), 7.81 (dd, J
= 2.7, 1.0 Hz, 1H), 7.68 (d, J = 4.8 Hz, 2H), 6.66 (d, J = 1.7 Hz, 1H), 3.97 (s, 3H), 3.87 (s, 3H).
13
C NMR (126 MHz, Chloroform-d) δ 161.84, 159.81, 148.80, 142.97, 142.39, 140.57, 130.45,
129.61, 110.15, 108.33, 103.94, 57.34, 56.40.
267
B.1.3.5 GENERAL PROCEDURE 5. SYNTHESIS OF SULFONYLDIBEN ZENES
Adapted from a procedure of H Suzuki and co-workers
7
.
10-((4-methoxyphenyl)ethynyl)-10H-dibenzo[b,e][1,4]thiabismine 5,5-dioxide. Synthesized
from 1-ethynyl-4-methoxybenzene and 24 (0.90 g, 1.63 mmol) following a literature procedure
7
,
0.72 g, 79%, 4 hours, colorless solid:
IR (υ[cm-1]) 3036 (w), 2972 (w), 2939 (w), 2844 (w), 2099 (m), 1601 (m), 1561 (m), 1504 (m),
1459 (m), 1438 (m), 1285 (s), 1248 (s), 1208 (m), 1182 (m), 1171 (m), 1164 (m), 1143 (s), 1114
(m), 1085 (m), 1069 (m), 1025 (s), 1010 (m), 951 (m), 830 (s), 807 (m), 757 (m), 737 (s), 715 (s),
700 (m), 637 (m), 587 (vs), 563 (vs), 536 (m), 510 (m), 466 (m), 423 (m).
1
H NMR (500 MHz, Chloroform-d) δ 8.74 (d, J = 7.5 Hz, 2H), 8.33 (d, J = 7.7 Hz, 2H), 7.52 (t, J
= 7.4 Hz, 2H), 7.46 – 7.36 (m, 4H), 6.83 (d, J = 8.2 Hz, 2H), 3.81 (s, 3H).
268
13
C NMR (126 MHz, Chloroform-d) δ 160.60, 159.91, 141.21, 138.19, 134.17, 133.71, 128.53,
127.65, 115.61, 114.06, 112.85, 83.62, 55.43.
10-((4-(tert-butyl)phenyl)ethynyl)-10H-dibenzo[b,e][1,4]thiabismine 5,5-dioxide.
Synthesized from 1-ethynyl-4-tert-butylbenzene and 24 (1.0 g, 1.81 mmol) following general
procedure 5, 0.80 g, 76%, 4 hours, colorless solid:
IR (υ[cm-1]) 3044 (vs), 2960 (vs), 2108 (vs), 1562 (vs), 1501 (vs), 1461 (vs), 1438 (vs), 1393 (vs),
1364 (vs), 1301 (s), 1287 (s), 1268 (vs), 1251 (vs), 1209 (vs), 1183 (vs), 1147 (s), 1133 (vs), 1117
(vs), 1106 (vs), 1086 (vs), 1072 (vs), 1012 (vs), 952 (vs), 874 (vs), 831 (vs), 793 (vs), 759 (vs),
737 (s), 715 (vs), 701 (vs), 654 (vs), 637 (vs), 586 (s), 561 (s), 511 (s), 464 (s), 423 (vs).
1
H NMR (500 MHz, Chloroform-d) δ 8.74 (d, J = 7.2 Hz, 2H), 8.33 (d, J = 7.7 Hz, 2H), 7.51 (t, J
= 7.4 Hz, 2H), 7.45 – 7.37 (m, 4H), 7.32 (d, J = 8.2 Hz, 2H), 1.30 (s, 9H).
13
C NMR (126 MHz, Chloroform-d) δ 160.66, 152.01, 141.19, 138.21, 134.19, 131.97, 128.53,
127.66, 125.45, 120.46, 112.80, 83.96, 34.95, 31.31.
10-(p-tolylethynyl)-10H-dibenzo[b,e][1,4]thiabismine 5,5-dioxide. Synthesized from 1-
ethynyl-4-methylbenzene and 24 (0.77 g, 1.39 mmol) following general procedure 5, 0.41 g, 54%,
4 hours, colorless solid:
269
IR (υ[cm-1]) 3025 (w), 2956 (w), 2924 (w), 2099 (m), 1603 (w), 1562 (m), 1503 (m), 1436 (m),
1375 (w), 1285 (s), 1250 (m), 1201 (m), 1178 (m), 1163 (m), 1144 (s), 1117 (m), 1105 (m), 1086
(m), 1069 (m), 1027 (m), 1010 (m), 941 (m), 833 (w), 811 (m), 756 (s), 739 (s), 715 (s), 700 (m),
637 (m), 586 (vs), 563 (vs), 529 (m), 511 (m), 486 (m), 463 (m), 415 (m).
1
H NMR (500 MHz, Chloroform-d) δ 8.75 (d, J = 7.4 Hz, 2H), 8.33 (d, J = 7.7 Hz, 2H), 7.52 (t, J
= 7.4 Hz, 2H), 7.43 (t, J = 7.6 Hz, 2H), 7.35 (d, J = 7.6 Hz, 2H), 7.11 (d, J = 7.9 Hz, 2H), 2.35 (s,
3H).
13
C NMR (126 MHz, Chloroform-d) δ 160.64, 141.20, 138.85, 138.20, 134.20, 132.11, 129.84,
129.19, 128.54, 127.67, 120.42, 112.89, 21.66.
10-(phenylethynyl)-10H-dibenzo[b,e][1,4]thiabismine 5,5-dioxide. Synthesized from
ethynylbenzene and 24 (1.0 g, 1.81 mmol) following general procedure 5, 0.85 g, 90%, 4 hours,
colorless solid:
IR (υ[cm-1]) 3054 (vw), 3036 (vw), 2111 (w), 1634 (vw), 1596 (w), 1561 (w), 1486 (m), 1437
(m), 1299 (s), 1287 (m), 1249 (m), 1204 (m), 1177 (w), 1165 (w), 1147 (s), 1133 (m), 1116 (m),
270
1087 (m), 1071 (m), 1026 (m), 1011 (m), 951 (w), 919 (w), 875 (w), 844 (w), 800 (w), 785 (m),
758 (s), 738 (s), 712 (m), 692 (m), 636 (m), 585 (vs), 562 (vs), 538 (m), 530 (m), 509 (m), 465
(m), 424 (m).
1
H NMR (500 MHz, Chloroform-d) δ 8.75 (d, J = 7.3 Hz, 2H), 8.33 (d, J = 7.7 Hz, 2H), 7.52 (t, J
= 7.4 Hz, 2H), 7.49 – 7.40 (m, 4H), 7.32 – 7.29 (m, 3H).
13
C NMR (126 MHz, Chloroform-d) δ 160.66, 141.19, 140.45, 138.18, 134.23, 132.20, 128.95,
128.58, 128.44, 127.70, 123.51, 112.53.
10-((4-bromophenyl)ethynyl)-10H-dibenzo[b,e][1,4]thiabismine 5,5-dioxide. Synthesized
from 1-bromo-4-ethynylbenzene and 24 (1.0 g, 1.81 mmol) following general procedure 5, 0.86 g,
79%, 4 hours, colorless solid:
IR (υ[cm-1]) 3056 (vw), 3038 (vw), 2105 (w), 1636 (w), 1582 (w), 1562 (w), 1482 (m), 1466 (w),
1438 (m), 1391 (w), 1285 (s), 1250 (m), 1200 (m), 1177 (w), 1165 (w), 1143 (m), 1118 (m), 1106
(m), 1086 (m), 1069 (m), 1028 (m), 1009 (m), 943 (w), 819 (m), 785 (w), 759 (m), 741 (s), 715
(m), 700 (m), 637 (m), 598 (m), 586 (vs), 563 (vs), 525 (m), 512 (m), 463 (m), 421 (w), 408 (w).
1
H NMR (500 MHz, Chloroform-d) δ 8.73 (d, J = 7.3 Hz, 2H), 8.34 (d, J = 7.7 Hz, 2H), 7.53 (t, J
= 7.4 Hz, 2H), 7.44 (t, J = 7.6 Hz, 4H), 7.31 (d, J = 7.7 Hz, 2H).
271
13
C NMR (126 MHz, Chloroform-d) δ 160.66, 141.17, 138.18, 134.28, 133.60, 131.71, 128.65,
127.78, 127.71, 122.86, 122.48, 115.55, 111.21.
10-((4-bromophenyl)ethynyl)-10H-dibenzo[b,e][1,4]thiabismine 5,5-dioxide. Synthesized
from 1-ethynyl-4-(trifluoromethyl)benzene and 24 (1.0 g, 1.81 mmol) following general
procedure 5, 0.60 g, 56 %, 4 hours, colorless solid:
IR (υ[cm-1]) 3056 (vw), 2960 (vw), 2921 (vw), 2114 (vw), 1609 (m), 1562 (w), 1509 (vw), 1437
(w), 1427 (w), 1403 (w), 1319 (s), 1299 (m), 1285 (s), 1254 (m), 1207 (m), 1179 (m), 1166 (m),
1151 (s), 1123 (s), 1103 (s), 1087 (m), 1064 (s), 1027 (m), 1014 (m), 946 (w), 869 (vw), 845 (m),
838 (m), 815 (w), 769 (m), 760 (m), 737 (s), 713 (m), 700 (m), 638 (w), 596 (m), 585 (vs), 564
(vs), 523 (m), 514 (m), 464 (s), 422 (m).
1
H NMR (500 MHz, Chloroform-d) δ 8.74 (d, J = 7.3 Hz, 2H), 8.35 (d, J = 7.7 Hz, 2H), 7.58 –
7.51 (m, 6H), 7.44 (t, J = 7.6 Hz, 2H).
13
C NMR (126 MHz, Chloroform-d) δ 160.80, 141.13, 138.08, 134.31, 132.37, 130.17 (q, J = 32.6
Hz), 128.68, 127.80, 127.33, 125.35 (q, J = 3.5 Hz), 123.97 (q, J = 272.3 Hz), 115.72, 110.58.
19
F NMR (470 MHz, Chloroform-d) δ -62.85.
272
2,8-dimethoxy-10-(p-tolylethynyl)-10H-dibenzo[b,e][1,4]thiabismine5,5-dioxide. Synthesized
from 1-ethynyl-4-methylbenzene and 27 (0.50 g, 0.82 mmol) following general procedure 5,
0.30 g,0.550 mmol, 61 %, overnight, pale yellow solid:
IR (υ[cm-1]) 3062 (w), 2937 (w), 2838 (w), 2051 (vw), 1592 (m), 1573 (m), 1494 (s), 1457 (m),
1438 (m), 1414 (m), 1318 (m), 1308 (m), 1292 (s), 1256 (vs), 1176 (m), 1146 (vs), 1102 (vs), 1072
(s), 1014 (s), 831 (m), 804 (s), 717 (m), 679 (s), 637 (m), 626 (m), 553 (vs), 486 (m), 436 (w), 414
(vw).
1
H NMR (500 MHz, Chloroform-d) δ 8.30 (d, J = 2.5 Hz, 2H), 8.22 (d, J = 8.6 Hz, 2H), 7.36 (d, J
= 7.8 Hz, 2H), 7.11 (d, J = 7.8 Hz, 2H), 6.86 (dd, J = 8.6, 2.5 Hz, 2H), 3.84 (s, 6H), 2.35 (s, 3H).
13
C NMR (126 MHz, Chloroform-d) δ 164.22, 162.21, 138.85, 133.46, 132.05, 129.23, 129.01,
123.81, 120.45, 113.49, 113.15, 110.15, 55.84, 21.66.
2-chloro-10-(p-tolylethynyl)-10H-dibenzo[b,e][1,4]thiabismine 5,5-dioxide. Synthesized from
1-ethynyl-4-methylbenzene and 27 (0.20 g, 0.34 mmol) following general procedure 5, 0.13 g,
66%, overnight, pale-yellow solid:
273
IR (υ[cm-1]) 2957 (m), 2920 (vs), 2851 (s), 2098 (w), 1710 (w), 1601 (m), 1548 (m), 1504 (w),
1461 (m), 1439 (w), 1376 (w), 1305 (m), 1285 (m), 1248 (m), 1147 (m), 1117 (m), 1086 (s), 1071
(s), 1010 (m), 956 (w), 915 (vw), 884 (w), 854 (vw), 818 (m), 779 (m), 761 (s), 728 (m), 711 (m),
650 (w), 638 (w), 611 (vs), 568 (vs), 526 (m), 501 (w), 477 (m), 465 (m), 420 (w).
1
H NMR (500 MHz, Chloroform-d) δ 8.75 (d, J = 7.3 Hz, 1H), 8.71 (d, J = 2.0 Hz, 1H), 8.32 (d, J
= 7.7 Hz, 1H), 8.24 (d, J = 8.2 Hz, 1H), 7.54 (t, J = 7.3 Hz, 1H), 7.44 (t, J = 7.6 Hz, 1H), 7.40 (dd,
J = 8.3, 2.0 Hz, 1H), 7.37 (d, J = 7.7 Hz, 2H), 7.13 (d, J = 8.6 Hz, 2H), 2.36 (s, 3H).
13
C NMR (126 MHz, Chloroform-d) δ 161.88, 161.16, 141.75, 141.04, 139.42, 139.07, 138.24,
138.10, 134.45, 132.14, 129.25, 128.74, 120.14, 113.80, 113.16, 21.68.
2-trifluoro-10-(p-tolylethynyl)-10H-dibenzo[b,e][1,4]thiabismine 5,5-dioxide. Synthesized
from 1-ethynyl-4-methylbenzene and 27 (0.20 g, 0.32 mmol) following general procedure 5,
0.10 g, 51%, overnight, pale-yellow solid:
274
IR (υ[cm-1]) 3099 (w), 3081 (w), 3062 (w), 2045 (vw), 1607 (vw), 1582 (vw), 1476 (w), 1446
(m), 1403 (m), 1321 (vs), 1294 (s), 1156 (vs), 1122 (s), 1104 (vs), 1071 (s), 1060 (vs), 1016 (m),
997 (m), 962 (w), 849 (m), 838 (m), 787 (w), 764 (m), 740 (m), 720 (vs), 701 (m), 689 (m), 604
(s), 593 (s), 557 (s), 422 (m).
1
H NMR (500 MHz, Chloroform-d) δ 9.02 (s, 1H), 8.76 (d, J = 7.3 Hz, 1H), 8.41 (d, J = 8.0 Hz,
1H), 8.35 (d, J = 7.5 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.56 (t, J = 7.4 Hz, 1H), 7.46 (t, J = 7.5 Hz,
1H), 7.34 (d, J = 7.8 Hz, 2H), 7.12 (d, J = 7.8 Hz, 2H), 2.36 (s, 3H).
13
C NMR (126 MHz, Chloroform-d) δ 161.60, 161.51, 144.74, 140.40, 139.13, 138.33, 135.38,
135.18 (q, J=3.27 Hz), 134.69, 132.07, 129.27, 128.86, 128.23, 127.53, 125.78 (q, J=3.67 Hz),
120.03, 113.88, 77.16, 21.68.
19
F NMR (470 MHz, Chloroform-d) δ -62.80.
2-methoxy-10-(p-tolylethynyl)-10H-dibenzo[b,e][1,4]thiabismine 5,5-dioxide. Synthesized
from 1-ethynyl-4-methylbenzene and 27 (0.47 g, 0.80 mmol) following general procedure 5,
0.35 g, 60%, overnight, colorless solid:
IR (υ[cm-1]) 3063 (w), 2943 (w), 2846 (w), 2107 (w), 1591 (m), 1571 (m), 1497 (m), 1459 (m),
1446 (m), 1312 (s), 1297 (s), 1262 (vs), 1229 (m), 1192 (w), 1183 (w), 1148 (vs), 1105 (vs), 1070
275
(s), 1017 (s), 997 (m), 931 (w), 862 (w), 833 (s), 821 (m), 803 (m), 764 (m), 755 (m), 730 (s), 710
(m), 687 (m), 657 (m), 627 (m), 575 (s), 554 (vs), 485 (m), 454 (m), 424 (w).
1
H NMR (500 MHz, Chloroform-d) δ 8.72 (d, J = 6.1 Hz, 1H), 8.32 (d, J = 2.5 Hz, 1H), 8.29 (d, J
= 6.4 Hz, 1H), 8.26 (d, J = 8.6 Hz, 1H), 7.92 (d, J = 7.0 Hz, 0.5H), 7.88 (d, J = 8.8 Hz, 0.5H), 7.50
(t, J = 8.2 Hz, 1H), 7.41 (td, J = 7.6, 1.2 Hz, 1.5H), 7.35 (d, J = 7.9 Hz, 2H), 7.11 (d, J = 7.8 Hz,
2H), 6.96 (d, J = 8.8 Hz, 0.5H), 6.87 (dd, J = 8.6, 2.5 Hz, 1H), 3.84 (s, 3H), 2.35 (s, 3H).
13
C NMR (126 MHz, Chloroform-d) δ 164.36, 162.60, 160.29, 142.14, 138.85, 138.11, 133.96,
132.08, 130.03, 129.53, 129.33, 129.21, 128.48, 127.46, 127.15, 123.80, 120.43, 114.64, 113.64,
113.01, 55.85, 21.66.
276
B.1.3.6 GENERAL PROCEDURE 6. SYNTHESIS OF 5-BISMUTH(III)
TRIAZOLIDES
Adapted from a procedure of B. T. Worrell and co-workers
9
.
10-(4-(4-methoxyphenyl)-1-phenethyl-1H-1,2,3-triazol-5-yl)-10H-
dibenzo[b,e][1,4]thiabismine 5,5-dioxide. To a 50 ml round-bottom flask equipped with a
magnetic stir bar, 0.139 g (0.25 mmol, 1.00 equiv.) of 10-((4-methoxyphenyl)ethynyl)-10H-
dibenzo[b,e][1,4]thiabismine 5,5-dioxide 31 and 0.055 g (0.37 mmol, 1.50 equiv.) of (2-
azidoethyl)benzene in 3 ml of reagent grade dry THF were added. 1 ml of a copper(I)
trifluoromethanesulfonate toluene complex solution in dry THF (0.05 mmol, 0.2 equiv.) was
injected directly to the clear solution of 31 and (2-azidoethyl)benzene. Immediately, the solution
turned bright yellow (for all substrates) signalizing the formation of a bismuth(III)-acetylenide-
Cu(I) π-complex. The reaction mixture was stirred for 2-3 hours at room temperature. After this
time, the reaction mixture was dissolved with reagent grade DCM (30 ml), transferred to 250 ml
separatory funnel and washed with birne:NH4OH(10%) solution (5:1) 2⨯30 ml NH4OH to ensure
complete removal of any residual catalytic species. The organic phase was dried over MgSO4,
filtered, and concentrated in vacuo. The residue was dissolved in 1 ml of dry DCM and added
dropwise to 200 ml of vigorously stirred hexanes. The formed precipitate was filtered and dried in
277
a vacuum to yield a colorless solid (0.113 g, 64 %). Due to the mediocre performance of
recrystallization as a purification technique, the observable yields are considered to be higher.
IR (υ[cm-1]) 3032 (w), 2991 (w), 2957 (w), 2929 (w), 2851 (w), 2834 (w), 1614 (m), 1576 (w),
1561 (w), 1536 (m), 1498 (m), 1440 (m), 1427 (m), 1398 (w), 1336 (w), 1306 (m), 1290 (m), 1243
(s), 1197 (w), 1174 (m), 1152 (s), 1120 (m), 1106 (m), 1087 (m), 1073 (m), 1037 (m), 1023 (m),
1011 (m), 982 (m), 950 (w), 909 (w), 876 (vw), 834 (m), 810 (m), 775 (w), 759 (m), 734 (s), 717
(m), 696 (s), 669 (m), 636 (w), 614 (m), 586 (vs), 564 (vs), 547 (m), 532 (m), 512 (m), 498 (m),
462 (m), 426 (w).
1
H NMR (500 MHz, Chloroform-d) δ 8.53 (d, J = 7.7 Hz, 2H), 7.97 (s, 2H), 7.51 (t, J = 7.9 Hz,
2H), 7.41 (s, 2H), 7.26 (s, 4H), 6.72 (s, 5H), 3.88 (s, 5H), 3.11 (s, 2H).
13
C NMR (126 MHz, Chloroform-d) δ 159.54, 157.08, 156.44, 152.42, 141.10, 138.05, 137.30,
134.01, 129.55, 129.23, 128.73, 128.60, 127.78, 127.05, 124.89, 113.82, 77.16, 55.39, 53.34,
36.74.
10-(4-(4-(tert-butyl)phenyl)-1-phenethyl-1H-1,2,3-triazol-5-yl)-10H-
dibenzo[b,e][1,4]thiabismine 5,5-dioxide. Synthesized from (2-azidoethyl)benzene and 32
(0.146 g, 0.25 mmol) following general procedure 6, 0.127 g, 70 %, 2 hours, colorless solid:
278
IR (υ[cm-1]) 3062 (vw), 3034 (w), 2950 (m), 2903 (w), 2866 (w), 1561 (w), 1538 (vw), 1494 (w),
1472 (m), 1458 (m), 1442 (m), 1427 (m), 1404 (m), 1365 (m), 1333 (w), 1305 (s), 1289 (m), 1270
(m), 1256 (m), 1228 (w), 1199 (m), 1178 (m), 1153 (m), 1134 (m), 1119 (m), 1106 (m), 1088 (m),
1074 (m), 1051 (w), 1027 (m), 1011 (m), 983 (m), 912 (w), 889 (w), 878 (w), 842 (m), 764 (m),
740 (s), 715 (m), 697 (s), 637 (m), 585 (vs), 576 (s), 565 (vs), 518 (m), 509 (m), 501 (m), 461 (m),
426 (w).
1
H NMR (500 MHz, Chloroform-d) δ 8.40 (d, J = 7.7 Hz, 2H), 7.85 (s, 2H), 7.37 (t, J = 7.5 Hz,
2H), 7.29-7.27 (m, 2H), 7.12 (s, 6H), 6.55 (s, 2H), 3.82 (s, 2H), 2.97 (s, 2H), 1.28 (s, 9H).
13
C NMR (126 MHz, Chloroform-d) δ 156.95, 156.59, 152.39, 150.98, 141.04, 137.88, 137.17,
133.90, 129.32, 129.22, 128.60, 128.45, 127.93, 127.67, 126.91, 125.24, 77.02, 53.21, 36.49,
34.52, 31.26.
10-(1-phenethyl-4-(p-tolyl)-1H-1,2,3-triazol-5-yl)-10H-dibenzo[b,e][1,4]thiabismine 5,5-
dioxide. Synthesized from (2-azidoethyl)benzene and 33 (0.135, 0.25 mmol) following general
procedure 6, 0.121 g, 71 %, 4 hours, colorless solid:
IR (υ[cm-1]) 3060 (vw), 3033 (w), 2960 (w), 2921 (w), 2852 (w), 1561 (w), 1538 (vw), 1497 (w),
1457 (m), 1425 (m), 1409 (w), 1397 (m), 1332 (vw), 1308 (m), 1289 (m), 1253 (m), 1194 (m),
1181 (w), 1151 (s), 1135 (m), 1120 (m), 1107 (m), 1087 (m), 1073 (m), 1029 (m), 1011 (m), 984
(m), 964 (w), 949 (w), 909 (w), 900 (w), 876 (w), 839 (w), 823 (m), 797 (w), 780 (m), 759 (m),
733 (s), 716 (m), 694 (s), 669 (w), 636 (m), 612 (w), 587 (vs), 564 (vs), 542 (m), 510 (m), 479
(w), 462 (m), 425 (w), 408 (w).
1
H NMR (500 MHz, Chloroform-d) δ 8.54 (s, 2H), 8.00 (s, 2H), 7.67 – 7.28 (m, 7H), 7.19 – 6.22
(m, 6H), 3.95 (s, 2H), 3.09 (s, 2H), 2.43 (s, 3H).
279
13
C NMR (126 MHz, Chloroform-d) δ 157.28, 156.71, 152.80, 141.05, 138.01, 137.88, 137.23,
133.98, 129.45, 129.13, 128.64, 128.50, 128.22, 127.71, 126.95, 77.37, 77.16, 53.25, 36.59, 21.20.
10-(1-phenethyl-4-phenyl-1H-1,2,3-triazol-5-yl)-10H-dibenzo[b,e][1,4]thiabismine 5,5-
dioxide. Synthesized from (2-azidoethyl)benzene and 34 (0.138 g, 0.25 mmol) following general
procedure 6, 0.10 g, 59 %, 4 hours, colorless solid:
IR (υ[cm-1]) 3062 (w), 3026 (w), 2950 (w), 1605 (w), 1581 (w), 1562 (w), 1497 (w), 1483 (w),
1447 (m), 1427 (m), 1395 (w), 1372 (w), 1298 (s), 1286 (m), 1251 (m), 1223 (m), 1179 (m), 1151
(s), 1106 (m), 1087 (m), 1073 (m), 1050 (m), 1026 (m), 1013 (m), 999 (m), 977 (m), 912 (w), 845
(w), 760 (s), 727 (s), 714 (m), 697 (vs), 690 (vs), 637 (m), 586 (vs), 562 (vs), 517 (m), 508 (m),
462 (m), 427 (w), 404 (vw).
1
H NMR (500 MHz, Chloroform-d) δ 8.53 (d, J = 7.8 Hz, 2H), 8.00 (s, 2H), 7.51 (t, J = 8.0 Hz,
2H), 7.41 (s, 3H), 7.36-7.11 (m, 6H), 6.70 (s, 3H), 3.98 (s, 2H), 3.11 (s, 2H).
13
C NMR (126 MHz, Chloroform-d) δ 157.20, 156.67, 152.74, 141.10, 137.99, 137.24, 134.06,
132.37, 129.32, 128.71, 128.56, 128.40, 128.33, 128.08, 127.80, 127.03, 77.16, 53.34, 36.66.
10-(4-(4-bromophenyl)-1-phenethyl-1H-1,2,3-triazol-5-yl)-10H-
dibenzo[b,e][1,4]thiabismine 5,5-dioxide. Synthesized from (2-azidoethyl)benzene and 35
(0.151 g, 0.25 mmol) following general procedure 6, 0.075 g, 40 %, 2 hours, pale-yellow solid:
280
IR (υ[cm-1]) 3118 (vw), 3091 (vw), 3055 (w), 2918 (vw), 2855 (vw), 1599 (w), 1564 (w), 1498
(w), 1481 (w), 1454 (m), 1402 (w), 1364 (w), 1334 (w), 1301 (m), 1288 (m), 1254 (m), 1222 (m),
1178 (w), 1148 (s), 1133 (m), 1117 (m), 1106 (m), 1088 (m), 1070 (m), 1051 (m), 1028 (m), 1011
(m), 977 (m), 838 (m), 824 (m), 756 (m), 739 (s), 712 (m), 697 (s), 637 (m), 584 (vs), 564 (vs),
507 (m), 480 (m), 461 (m), 443 (m), 423 (w).
1
H NMR (500 MHz, Chloroform-d) δ 8.38 (d, J = 7.7 Hz, 2H), 7.68 (s, 2H), 7.38 (t, J = 7.4 Hz,
2H), 7.23 – 7.15 (m, 4H), 7.08 – 6.42 (m, 7H), 4.33 (s, 2H), 3.18 (s, 2H).
13C NMR (126 MHz, Chloroform-d) δ 157.26, 154.98, 152.45, 141.67, 140.85, 137.41, 134.01,
131.28, 131.04, 129.53, 129.29, 129.05, 128.97, 127.91, 127.45, 121.99, 77.16, 53.75, 37.28.
10-(1-phenethyl-4-(4-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-5-yl)-10H-
dibenzo[b,e][1,4]thiabismine 5,5-dioxide. Synthesized from (2-azidoethyl)benzene and 36
(0.297 g, 0.5 mmol) following general procedure 5, 0.298 g, 80 %, 3 hours, colorless solid:
IR (υ[cm-1]) 3036 (w), 2941 (w), 2873 (vw), 1618 (w), 1562 (w), 1493 (w), 1457 (w), 1436 (w),
1427 (w), 1413 (w), 1323 (s), 1310 (s), 1256 (m), 1196 (w), 1168 (m), 1152 (s), 1134 (s), 1106
(s), 1088 (s), 1063 (s), 1029 (m), 1011 (m), 983 (m), 915 (w), 878 (w), 850 (m), 781 (w), 761 (m),
281
737 (s), 714 (m), 699 (s), 665 (m), 636 (m), 608 (w), 586 (vs), 564 (vs), 509 (m), 488 (w), 463
(m), 452 (m), 425 (w).
1
H NMR (600 MHz, Chloroform-d) δ 8.33 (d, J = 7.8 Hz, 2H), 7.71 – 7.55 (m, 2H), 7.30 (t, J =
7.6 Hz, 2H), 7.20 (t, J = 7.4 Hz, 2H), 7.15 (t, J = 7.3 Hz, 3H), 7.13 – 7.06 (m, 6H), 4.58 (s, 2H),
3.23 (s, 2H).
13
C NMR (126 MHz, Chloroform-d) δ 157.65, 154.29, 152.81, 140.70, 137.98, 137.40, 135.87,
133.89, 129.29, 129.05, 127.99, 127.74, 127.47, 127.29 (q, J=4.9 Hz), 124.53, 123.94 (q, J=272.1
Hz), 77.16, 53.78, 37.35.
19
F NMR (470 MHz, Chloroform-d) δ -63.00.
282
B.4 X-RAY CRYSTALLOGRAPHIC DETAILS
B.1.4.1 X-RAY CRYSTALLOGRAPHIC ANALYSIS OF BISMUTH(III) ACETYLIDE
42
The single crystal X-ray diffraction studies were carried out on a Bruker Apex II Ultra2 CCD diffractometer equipped
with Mo Kα radiation (λ = 0.71073). A 0.090 x 0.070 x 0.040 mm colorless crystal was mounted on a Cryoloop with
Paratone oil. Data were collected in a nitrogen gas stream at 100(2) K using ϕ and ϖ scans. Crystal-to-detector distance
was 40 mm using exposure time 1.0s with a scan width of 0.80°. Data collection was 100.0% complete to 25.242° in
θ. A total of 32975 reflections were collected covering the indices, -16<=h<=16, -9<=k<=9, -25<=l<=20. 4097
reflections were found to be symmetry independent, with a Rint of 0.0705. Indexing and unit cell refinement indicated
a Primitive, Monoclinic lattice. The space group was found to be P21/c. The data were integrated using the Bruker
SAINT Software program and scaled using the SADABS software program. Solution by direct methods (SHELXT)
produced a complete phasing model consistent with the proposed structure. All nonhydrogen atoms were refined
anisotropically by full-matrix least-squares (SHELXL-2014). All carbon bonded hydrogen atoms were placed using a
riding model. Their positions were constrained relative to their parent atom using the appropriate HFIX command in
SHELXL-2014.
Notes: Proposed structure in agreement with model derived from diffraction data. Excellent data and refinement
Figure B.10 Asymmetric unit in the crystal structure of compound 42.
Table B.8 Crystal data and structure refinement for compound 42.
Empirical formula C22 H17 Bi O3 S
Molecular formula C22 H17 Bi O3 S
Formula weight 570.39
Temperature 100.0 K
Wavelength 0.71073 Å
Crystal system Monoclinic
283
Space group P 1 21/c 1
Unit cell dimensions a = 12.7269(4) Å α = 90°.
b = 7.4850(2) Å β = 104.6713(8)°.
c = 20.1551(6) Å γ = 90°.
Volume 1857.39(9) Å3
Z 4
Density (calculated) 2.040 Mg/m3
Absorption coefficient 9.625 mm-1
F(000) 1088
Crystal size 0.09 x 0.07 x 0.04 mm3
Crystal color, habit colorless block
Theta range for data collection 1.654 to 27.101°.
Index ranges -16<=h<=16, -9<=k<=9, -25<=l<=20
Reflections collected 32975
Independent reflections 4097 [R(int) = 0.0705]
Completeness to theta = 25.242° 100.0 %
Absorption correction Semi-empirical from equivalents
Max. and min. transmission 0.2622 and 0.1787
Refinement method Full-matrix least-squares on F2
Data / restraints / parameters 4097 / 0 / 246
Goodness-of-fit on F2 1.047
Final R indices [I>2sigma(I)] R1 = 0.0208, wR2 = 0.0521
R indices (all data) R1 = 0.0220, wR2 = 0.0531
Largest diff. peak and hole 0.591 and -0.923 e.Å-3
Table B.9 Bond lengths [Å] and angles [°] for compound 42.
Bi(1)-C(1) 2.294(3)
Bi(1)-C(12) 2.270(3)
Bi(1)-C(14) 2.230(3)
S(1)-O(1) 1.453(2)
S(1)-O(2) 1.437(2)
S(1)-C(6) 1.764(3)
S(1)-C(7) 1.768(3)
O(3)-C(3) 1.365(3)
O(3)-C(13) 1.430(4)
C(9)-H(9) 0.9500
C(9)-C(8) 1.390(5)
C(9)-C(10) 1.390(5)
C(2)-H(2) 0.9500
C(2)-C(1) 1.390(4)
C(2)-C(3) 1.401(4)
C(21)-H(21) 0.9500
C(21)-C(20) 1.393(5)
C(21)-C(16) 1.391(4)
C(1)-C(6) 1.393(4)
C(3)-C(4) 1.395(4)
C(13)-H(13A) 0.9800
C(13)-H(13B) 0.9800
284
C(13)-H(13C) 0.9800
C(8)-H(8) 0.9500
C(8)-C(7) 1.399(4)
C(15)-C(16) 1.440(4)
C(15)-C(14) 1.210(4)
C(20)-H(20) 0.9500
C(20)-C(19) 1.384(5)
C(12)-C(11) 1.386(4)
C(12)-C(7) 1.395(4)
C(6)-C(5) 1.393(4)
C(19)-C(22) 1.503(4)
C(19)-C(18) 1.392(5)
C(16)-C(17) 1.404(4)
C(10)-H(10) 0.9500
C(10)-C(11) 1.400(4)
C(4)-H(4) 0.9500
C(4)-C(5) 1.385(4)
C(11)-H(11) 0.9500
C(5)-H(5) 0.9500
C(17)-H(17) 0.9500
C(17)-C(18) 1.382(4)
C(22)-H(22A) 0.9800
C(22)-H(22B) 0.9800
C(22)-H(22C) 0.9800
C(18)-H(18) 0.9500
C(12)-Bi(1)-C(1) 86.77(9)
C(14)-Bi(1)-C(1) 88.38(11)
C(14)-Bi(1)-C(12) 92.22(10)
O(1)-S(1)-C(6) 106.17(14)
O(1)-S(1)-C(7) 106.10(14)
O(2)-S(1)-O(1) 120.01(14)
O(2)-S(1)-C(6) 110.18(13)
O(2)-S(1)-C(7) 110.24(14)
C(6)-S(1)-C(7) 102.69(13)
C(3)-O(3)-C(13) 117.5(2)
C(8)-C(9)-H(9) 120.0
C(8)-C(9)-C(10) 120.0(3)
C(10)-C(9)-H(9) 120.0
C(1)-C(2)-H(2) 120.4
C(1)-C(2)-C(3) 119.3(3)
C(3)-C(2)-H(2) 120.4
C(20)-C(21)-H(21) 120.0
C(16)-C(21)-H(21) 120.0
C(16)-C(21)-C(20) 120.0(3)
C(2)-C(1)-Bi(1) 122.6(2)
C(2)-C(1)-C(6) 119.0(3)
C(6)-C(1)-Bi(1) 118.1(2)
O(3)-C(3)-C(2) 124.1(3)
285
O(3)-C(3)-C(4) 115.0(2)
C(4)-C(3)-C(2) 120.9(3)
O(3)-C(13)-H(13A) 109.5
O(3)-C(13)-H(13B) 109.5
O(3)-C(13)-H(13C) 109.5
H(13A)-C(13)-H(13B) 109.5
H(13A)-C(13)-H(13C) 109.5
H(13B)-C(13)-H(13C) 109.5
C(9)-C(8)-H(8) 120.9
C(9)-C(8)-C(7) 118.3(3)
C(7)-C(8)-H(8) 120.9
C(14)-C(15)-C(16) 174.9(3)
C(21)-C(20)-H(20) 119.4
C(19)-C(20)-C(21) 121.2(3)
C(19)-C(20)-H(20) 119.4
C(11)-C(12)-Bi(1) 123.5(2)
C(11)-C(12)-C(7) 117.6(3)
C(7)-C(12)-Bi(1) 118.7(2)
C(1)-C(6)-S(1) 117.6(2)
C(1)-C(6)-C(5) 122.0(3)
C(5)-C(6)-S(1) 120.4(2)
C(20)-C(19)-C(22) 120.4(3)
C(20)-C(19)-C(18) 118.5(3)
C(18)-C(19)-C(22) 121.0(3)
C(21)-C(16)-C(15) 122.0(3)
C(21)-C(16)-C(17) 118.5(3)
C(17)-C(16)-C(15) 119.2(3)
C(9)-C(10)-H(10) 119.7
C(9)-C(10)-C(11) 120.6(3)
C(11)-C(10)-H(10) 119.7
C(3)-C(4)-H(4) 120.0
C(5)-C(4)-C(3) 119.9(3)
C(5)-C(4)-H(4) 120.0
C(12)-C(11)-C(10) 120.7(3)
C(12)-C(11)-H(11) 119.7
C(10)-C(11)-H(11) 119.7
C(6)-C(5)-H(5) 120.6
C(4)-C(5)-C(6) 118.8(3)
C(4)-C(5)-H(5) 120.6
C(8)-C(7)-S(1) 119.9(2)
C(12)-C(7)-S(1) 117.3(2)
C(12)-C(7)-C(8) 122.8(3)
C(16)-C(17)-H(17) 119.7
C(18)-C(17)-C(16) 120.6(3)
C(18)-C(17)-H(17) 119.7
C(19)-C(22)-H(22A) 109.5
C(19)-C(22)-H(22B) 109.5
C(19)-C(22)-H(22C) 109.5
H(22A)-C(22)-H(22B) 109.5
286
H(22A)-C(22)-H(22C) 109.5
H(22B)-C(22)-H(22C) 109.5
C(15)-C(14)-Bi(1) 156.9(2)
C(19)-C(18)-H(18) 119.6
C(17)-C(18)-C(19) 120.7(3)
C(17)-C(18)-H(18) 119.6
287
B.1.4.2 X-RAY CRYSTALLOGRAPHIC ANALYSIS OF BISMUTH(III) ACETYLIDE
39
The single crystal X-ray diffraction studies were carried out on a Bruker Apex II Ultra2 CCD diffractometer equipped
with Mo Kα radiation (λ = 0.71073). A 0.160 x 0.140 x 0.040 mm colorless crystal was mounted on a Cryoloop with
Paratone oil. Data were collected in a nitrogen gas stream at 100(2) K using ϕ and ϖ scans. Crystal-to-detector distance
was 40 mm using exposure time 1.0s with a scan width of 0.80°. Data collection was 100.0% complete to 25.242° in
θ. A total of 18974 reflections were collected covering the indices, -16<=h<=16, -9<=k<=9, -20<=l<=25. 3886
reflections were found to be symmetry independent, with a R int of 0.0508. Indexing and unit cell refinement indicated
a Primitive, Monoclinic lattice. The space group was found to be P21/c. The data were integrated using the Bruker
SAINT Software program and scaled using the SADABS software program. Solution by direct methods (SHELXT)
produced a complete phasing model consistent with the proposed structure. All nonhydrogen atoms were refined
anisotropically by full-matrix least-squares (SHELXL-2014). All carbon bonded hydrogen atoms were placed using
a riding model. Their positions were constrained relative to their parent atom using the appropriate HFIX command
in SHELXL-2014.
Notes: Proposed structure in agreement with model derived from diffraction data. Excellent data and refinement
Figure B.11 Asymmetric unit in the crystal structure of compound 39.
Table B.10 Crystal data and structure refinement for compound 39.
Empirical formula C21 H14 Bi Cl O2 S
Molecular formula C21 H14 Bi Cl O2 S
Formula weight 574.81
Temperature 100.0 K
Wavelength 0.71073 Å
Crystal system Monoclinic
Space group P 1 21/c 1
288
Unit cell dimensions a = 12.7458(6) Å α = 90°.
b = 7.3360(3) Å β = 105.2780(10)°.
c = 20.2483(8) Å γ = 90°.
Volume 1826.37(14) Å3
Z 4
Density (calculated) 2.090 Mg/m3
Absorption coefficient 9.927 mm-1
F(000) 1088
Crystal size 0.16 x 0.14 x 0.04 mm3
Crystal color, habit colorless irregular
Theta range for data collection 1.656 to 26.730°.
Index ranges -16<=h<=16, -9<=k<=9, -20<=l<=25
Reflections collected 18974
Independent reflections 3886 [R(int) = 0.0508]
Completeness to theta = 25.242° 100.0 %
Absorption correction Semi-empirical from equivalents
Max. and min. transmission 0.2612 and 0.1459
Refinement method Full-matrix least-squares on F2
Data / restraints / parameters 3886 / 0 / 236
Goodness-of-fit on F2 1.050
Final R indices [I>2sigma(I)] R1 = 0.0194, wR2 = 0.0487
R indices (all data) R1 = 0.0214, wR2 = 0.0499
Largest diff. peak and hole 1.068 and -0.449 e.Å-3
Table B.11 Bond lengths [Å] and angles [°] for compound 39.
Bi(1)-C(1) 2.284(3)
Bi(1)-C(12) 2.270(3)
Bi(1)-C(13) 2.230(3)
Cl(1)-C(3) 1.749(3)
S(1)-O(2) 1.452(2)
S(1)-O(1) 1.436(2)
S(1)-C(6) 1.770(3)
S(1)-C(7) 1.767(3)
C(20)-H(20) 0.9500
C(20)-C(19) 1.395(5)
C(20)-C(15) 1.391(5)
C(6)-C(1) 1.394(4)
C(6)-C(5) 1.389(4)
C(17)-H(17) 0.9500
C(17)-C(18) 1.395(5)
C(17)-C(16) 1.382(4)
C(21)-H(21A) 0.9800
C(21)-H(21B) 0.9800
C(21)-H(21C) 0.9800
C(21)-C(18) 1.500(4)
C(1)-C(2) 1.393(4)
C(11)-H(11) 0.9500
C(11)-C(12) 1.384(4)
289
C(11)-C(10) 1.396(4)
C(12)-C(7) 1.397(4)
C(5)-H(5) 0.9500
C(5)-C(4) 1.395(4)
C(8)-H(8) 0.9500
C(8)-C(9) 1.386(4)
C(8)-C(7) 1.394(4)
C(9)-H(9) 0.9500
C(9)-C(10) 1.392(5)
C(3)-C(2) 1.386(4)
C(3)-C(4) 1.383(4)
C(14)-C(13) 1.196(4)
C(14)-C(15) 1.444(4)
C(19)-H(19) 0.9500
C(19)-C(18) 1.391(5)
C(2)-H(2) 0.9500
C(10)-H(10) 0.9500
C(4)-H(4) 0.9500
C(15)-C(16) 1.401(4)
C(16)-H(16) 0.9500
C(12)-Bi(1)-C(1) 86.63(9)
C(13)-Bi(1)-C(1) 87.84(11)
C(13)-Bi(1)-C(12) 94.46(10)
O(2)-S(1)-C(6) 105.40(13)
O(2)-S(1)-C(7) 106.16(14)
O(1)-S(1)-O(2) 119.79(14)
O(1)-S(1)-C(6) 110.36(13)
O(1)-S(1)-C(7) 110.34(14)
C(7)-S(1)-C(6) 103.46(13)
C(19)-C(20)-H(20) 119.8
C(15)-C(20)-H(20) 119.8
C(15)-C(20)-C(19) 120.4(3)
C(1)-C(6)-S(1) 117.0(2)
C(5)-C(6)-S(1) 120.2(2)
C(5)-C(6)-C(1) 122.8(3)
C(18)-C(17)-H(17) 119.6
C(16)-C(17)-H(17) 119.6
C(16)-C(17)-C(18) 120.8(3)
H(21A)-C(21)-H(21B) 109.5
H(21A)-C(21)-H(21C) 109.5
H(21B)-C(21)-H(21C) 109.5
C(18)-C(21)-H(21A) 109.5
C(18)-C(21)-H(21B) 109.5
C(18)-C(21)-H(21C) 109.5
C(6)-C(1)-Bi(1) 118.7(2)
C(2)-C(1)-Bi(1) 123.0(2)
C(2)-C(1)-C(6) 118.2(3)
C(12)-C(11)-H(11) 119.8
C(12)-C(11)-C(10) 120.5(3)
290
C(10)-C(11)-H(11) 119.8
C(11)-C(12)-Bi(1) 123.6(2)
C(11)-C(12)-C(7) 117.9(3)
C(7)-C(12)-Bi(1) 118.4(2)
C(6)-C(5)-H(5) 120.7
C(6)-C(5)-C(4) 118.6(3)
C(4)-C(5)-H(5) 120.7
C(9)-C(8)-H(8) 120.8
C(9)-C(8)-C(7) 118.3(3)
C(7)-C(8)-H(8) 120.8
C(8)-C(9)-H(9) 119.9
C(8)-C(9)-C(10) 120.1(3)
C(10)-C(9)-H(9) 119.9
C(2)-C(3)-Cl(1) 118.1(2)
C(4)-C(3)-Cl(1) 118.9(2)
C(4)-C(3)-C(2) 123.0(3)
C(13)-C(14)-C(15) 176.4(3)
C(14)-C(13)-Bi(1) 155.6(3)
C(20)-C(19)-H(19) 119.5
C(18)-C(19)-C(20) 121.0(3)
C(18)-C(19)-H(19) 119.5
C(1)-C(2)-H(2) 120.6
C(3)-C(2)-C(1) 118.8(3)
C(3)-C(2)-H(2) 120.6
C(17)-C(18)-C(21) 120.9(3)
C(19)-C(18)-C(17) 118.3(3)
C(19)-C(18)-C(21) 120.7(3)
C(11)-C(10)-H(10) 119.8
C(9)-C(10)-C(11) 120.5(3)
C(9)-C(10)-H(10) 119.8
C(12)-C(7)-S(1) 117.7(2)
C(8)-C(7)-S(1) 119.7(2)
C(8)-C(7)-C(12) 122.6(3)
C(5)-C(4)-H(4) 120.7
C(3)-C(4)-C(5) 118.6(3)
C(3)-C(4)-H(4) 120.7
C(20)-C(15)-C(14) 121.9(3)
C(20)-C(15)-C(16) 118.4(3)
C(16)-C(15)-C(14) 119.5(3)
C(17)-C(16)-C(15) 120.9(3)
C(17)-C(16)-H(16) 119.6
C(15)-C(16)-H(16) 119.6
291
B.1.4.3 X-RAY CRYSTALLOGRAPHIC ANALYSIS OF BISMUTH(III) ACETYLIDE
40
The single crystal X-ray diffraction studies were carried out on a Bruker Apex II Ultra CCD diffractometer equipped
with Mo Kα radiation (λ = 0.71073). A 0.220 x 0.15 x 0.125 mm colorless crystal was mounted on a Cryoloop with
Paratone oil.Data were collected in a nitrogen gas stream at 100(2) K using ϕ and ϖ scans. Crystal-to-detector distance
was 40 mm using exposure time 1s with a scan width of 0.80°. Data collection was 100.0% complete to 25.242° in θ.
A total of 31005 reflections were collected covering the indices, -17<=h<=17, -12<=k<=12, -18<=l<=18. 3995
reflections were found to be symmetry independent, with a Rint of 0.0705. Indexing and unit cell refinement indicated
a Primitive, Monoclinic lattice. The space group was found to be P2 1/c. The data were integrated using the Bruker
SAINT Software program and scaled using the SADABS software program. Solution by direct methods (SHELXT)
produced a complete phasing model consistent with the proposed structure. All nonhydrogen atoms were refined
anisotropically by full-matrix least-squares (SHELXL-2014). All carbon bonded hydrogen atoms were placed using
a riding model. Their positions were constrained relative to their parent atom using the appropriate HFIX command
in SHELXL-2014.
Notes: Proposed structure in agreement with model derived from diffraction data. Slightly higher residual density 3.38
e.Å-3 possibly due to minor disorder
Figure B.12 Asymmetric unit in the crystal structure of compound 40.
Table B.12 Crystal data and structure refinement for compound 40.
Empirical formula C22 H14 Bi F3 O2 S
Molecular formula C22 H14 Bi F3 O2 S
Formula weight 608.37
Temperature 100.0 K
Wavelength 0.71073 Å
292
Crystal system Monoclinic
Space group P 1 21/c 1
Unit cell dimensions a = 14.1582(7) Å α = 90°.
b = 9.6556(5) Å β = 100.4560(10)°.
c = 14.5266(7) Å γ = 90°.
Volume 1952.90(17) Å3
Z 4
Density (calculated) 2.069 Mg/m3
Absorption coefficient 9.179 mm-1
F(000) 1152
Crystal size 0.22 x 0.15 x 0.125 mm3
Crystal color, habit colorless irregular
Theta range for data collection 1.463 to 26.370°.
Index ranges -17<=h<=17, -12<=k<=12, -18<=l<=17
Reflections collected 31005
Independent reflections 3995 [R(int) = 0.0705]
Completeness to theta = 25.242° 100.0 %
Absorption correction Semi-empirical from equivalents
Max. and min. transmission 0.2607 and 0.1761
Refinement method Full-matrix least-squares on F2
Data / restraints / parameters 3995 / 0 / 263
Goodness-of-fit on F2 1.031
Final R indices [I>2sigma(I)] R1 = 0.0242, wR2 = 0.0628
R indices (all data) R1 = 0.0264, wR2 = 0.0639
Largest diff. peak and hole 3.380 and -0.951 e.Å-3
Table B.13 Bond lengths [Å] and angles [°] for compound 40.
Bi(1)-C(1) 2.277(4)
Bi(1)-C(12) 2.271(4)
Bi(1)-C(14) 2.209(4)
S(1)-O(1) 1.446(3)
S(1)-O(2) 1.439(3)
S(1)-C(6) 1.768(4)
S(1)-C(7) 1.763(4)
F(1)-C(13) 1.322(5)
F(2)-C(13) 1.331(5)
F(3)-C(13) 1.349(5)
C(1)-C(2) 1.394(5)
C(1)-C(6) 1.398(5)
C(2)-C(3) 1.390(5)
C(3)-C(4) 1.384(6)
C(3)-C(13) 1.497(6)
C(4)-C(5) 1.397(6)
C(5)-C(6) 1.388(5)
C(7)-C(8) 1.390(5)
C(7)-C(12) 1.398(5)
C(8)-C(9) 1.388(6)
C(9)-C(10) 1.388(6)
293
C(10)-C(11) 1.397(6)
C(11)-C(12) 1.396(5)
C(14)-C(15) 1.198(6)
C(15)-C(16) 1.447(6)
C(16)-C(17) 1.404(6)
C(16)-C(21) 1.401(6)
C(17)-C(18) 1.380(6)
C(18)-C(19) 1.384(6)
C(19)-C(20) 1.396(6)
C(19)-C(22) 1.509(6)
C(20)-C(21) 1.387(5)
C(12)-Bi(1)-C(1) 86.56(13)
C(14)-Bi(1)-C(1) 86.97(14)
C(14)-Bi(1)-C(12) 92.50(14)
O(1)-S(1)-C(6) 105.38(17)
O(1)-S(1)-C(7) 107.05(18)
O(2)-S(1)-O(1) 119.73(17)
O(2)-S(1)-C(6) 109.47(18)
O(2)-S(1)-C(7) 110.08(18)
C(7)-S(1)-C(6) 103.93(18)
C(2)-C(1)-Bi(1) 122.3(3)
C(2)-C(1)-C(6) 117.2(3)
C(6)-C(1)-Bi(1) 120.2(3)
C(3)-C(2)-C(1) 120.1(4)
C(2)-C(3)-C(13) 120.8(4)
C(4)-C(3)-C(2) 121.9(4)
C(4)-C(3)-C(13) 117.3(4)
C(3)-C(4)-C(5) 119.0(4)
C(6)-C(5)-C(4) 118.5(4)
C(1)-C(6)-S(1) 118.1(3)
C(5)-C(6)-S(1) 118.6(3)
C(5)-C(6)-C(1) 123.3(3)
C(8)-C(7)-S(1) 118.8(3)
C(8)-C(7)-C(12) 122.9(4)
C(12)-C(7)-S(1) 118.3(3)
C(9)-C(8)-C(7) 118.6(4)
C(10)-C(9)-C(8) 119.7(4)
C(9)-C(10)-C(11) 121.2(4)
C(12)-C(11)-C(10) 120.1(4)
C(7)-C(12)-Bi(1) 120.5(3)
C(11)-C(12)-Bi(1) 122.0(3)
C(11)-C(12)-C(7) 117.5(4)
F(1)-C(13)-F(2) 108.1(4)
F(1)-C(13)-F(3) 105.9(3)
F(1)-C(13)-C(3) 113.5(3)
F(2)-C(13)-F(3) 105.0(3)
F(2)-C(13)-C(3) 112.6(3)
F(3)-C(13)-C(3) 111.2(3)
C(15)-C(14)-Bi(1) 166.1(4)
294
C(14)-C(15)-C(16) 176.1(4)
C(17)-C(16)-C(15) 119.9(4)
C(21)-C(16)-C(15) 121.9(4)
C(21)-C(16)-C(17) 118.1(4)
C(18)-C(17)-C(16) 120.8(4)
C(17)-C(18)-C(19) 121.2(4)
C(18)-C(19)-C(20) 118.4(4)
C(18)-C(19)-C(22) 121.0(4)
C(20)-C(19)-C(22) 120.6(4)
C(21)-C(20)-C(19) 121.1(4)
C(20)-C(21)-C(16) 120.4(4)
295
B.1.4.4 X-RAY CRYSTALLOGRAPHIC ANALYSIS OF BISMUTH(III) ACETYLIDE
34
The single crystal X-ray diffraction studies were carried out on a Bruker Kappa Apex II CCD diffractometer equipped
with Mo Kα radiation (λ = 0.71073). A 0.120 x 0.050 x 0.040 mm colorless crystal was mounted on a Cryoloop with
Paratone oil. Data were collected in a nitrogen gas stream at 100(2) K using ϕ and ϖ scans. Crystal-to-detector distance
was 40 mm using exposure time 20s with a scan width of 0.70°. Data collection was 100.0% complete to 25.242° in
A total of 26572 reflections were collected covering the indices, -10<=h<=10, -12<=k<=12, -25<=l<=25. 3488
reflections were found to be symmetry independent, with a R int of 0.0413. Indexing and unit cell refinement indicated
a Primitive, Monoclinic lattice. The space group was found to be P2 1/c. The data were integrated using the Bruker
SAINT Software program and scaled using the SADABS software program. Solution by direct methods (SHELXT)
produced a complete phasing model consistent with the proposed structure. All nonhydrogen atoms were refined
anisotropically by full-matrix least-squares (SHELXL-2014). All carbon bonded hydrogen atoms were placed using a
riding model. Their positions were constrained relative to their parent atom using the appropriate HFIX command in
SHELXL-2014.
Notes: Proposed structure in agreement with model derived from diffraction data. Excellent data and refinement
Figure B.13 Asymmetric unit in the crystal structure of compound 34.
Table B.14 Crystal data and structure refinement for compound 34.
Empirical formula C20 H13 Bi O2 S
Molecular formula C20 H13 Bi O2 S
Formula weight 526.34
Temperature 100.0 K
Wavelength 0.71073 Å
Crystal system Monoclinic
296
Space group P 1 21/c 1
Unit cell dimensions a = 8.535(4) Å α = 90°.
b = 9.906(5) Å β = 94.941(17)°.
c = 20.213(11) Å γ = 90°.
Volume 1702.7(15) Å3
Z 4
Density (calculated) 2.053 Mg/m3
Absorption coefficient 10.486 mm-1
F(000) 992
Crystal size 0.12 x 0.05 x 0.04 mm3
Crystal color, habit colorless plank
Theta range for data collection 2.023 to 26.359°.
Index ranges -10<=h<=10, -12<=k<=12, -25<=l<=25
Reflections collected 26572
Independent reflections 3488 [R(int) = 0.0413]
Completeness to theta = 25.242° 100.0 %
Absorption correction Semi-empirical from equivalents
Max. and min. transmission 0.4910 and 0.3028
Refinement method Full-matrix least-squares on F2
Data / restraints / parameters 3488 / 0 / 217
Goodness-of-fit on F2 1.029
Final R indices [I>2sigma(I)] R1 = 0.0172, wR2 = 0.0348
R indices (all data) R1 = 0.0232, wR2 = 0.0364
Largest diff. peak and hole 0.594 and -0.485 e.Å-3
Table B.15 Bond lengths [Å] and angles [°] for compound 34.
Bi(1)-C(13) 2.236(3)
Bi(1)-C(1) 2.288(3)
Bi(1)-C(12) 2.290(3)
S(1)-O(2) 1.456(2)
S(1)-O(1) 1.444(2)
S(1)-C(7) 1.766(3)
S(1)-C(6) 1.772(3)
C(13)-C(14) 1.202(4)
C(3)-H(3) 0.9500
C(3)-C(4) 1.395(5)
C(3)-C(2) 1.393(4)
C(1)-C(2) 1.400(4)
C(1)-C(6) 1.396(4)
C(7)-C(12) 1.406(4)
C(7)-C(8) 1.394(4)
C(17)-H(17) 0.9500
C(17)-C(16) 1.402(4)
C(17)-C(18) 1.363(4)
C(14)-C(15) 1.450(4)
C(4)-H(4) 0.9500
C(4)-C(5) 1.381(4)
C(5)-H(5) 0.9500
297
C(5)-C(6) 1.398(4)
C(2)-H(2) 0.9500
C(20)-H(20) 0.9500
C(20)-C(15) 1.406(4)
C(20)-C(19) 1.379(5)
C(16)-H(16) 0.9500
C(16)-C(15) 1.406(4)
C(12)-C(11) 1.393(5)
C(11)-H(11) 0.9500
C(11)-C(10) 1.395(5)
C(10)-H(10) 0.9500
C(10)-C(9) 1.385(5)
C(8)-H(8) 0.9500
C(8)-C(9) 1.385(5)
C(18)-H(18) 0.9500
C(18)-C(19) 1.380(5)
C(19)-H(19) 0.9500
C(9)-H(9) 0.9500
C(13)-Bi(1)-C(1) 92.23(11)
C(13)-Bi(1)-C(12) 90.07(12)
C(1)-Bi(1)-C(12) 86.04(11)
O(2)-S(1)-C(7) 105.90(14)
O(2)-S(1)-C(6) 106.96(14)
O(1)-S(1)-O(2) 119.21(14)
O(1)-S(1)-C(7) 110.45(15)
O(1)-S(1)-C(6) 109.92(15)
C(7)-S(1)-C(6) 103.15(15)
C(14)-C(13)-Bi(1) 170.0(3)
C(4)-C(3)-H(3) 119.5
C(2)-C(3)-H(3) 119.5
C(2)-C(3)-C(4) 121.0(3)
C(2)-C(1)-Bi(1) 123.6(2)
C(6)-C(1)-Bi(1) 119.4(2)
C(6)-C(1)-C(2) 117.0(3)
C(12)-C(7)-S(1) 117.8(2)
C(8)-C(7)-S(1) 120.1(3)
C(8)-C(7)-C(12) 122.1(3)
C(16)-C(17)-H(17) 119.9
C(18)-C(17)-H(17) 119.9
C(18)-C(17)-C(16) 120.3(3)
C(13)-C(14)-C(15) 177.4(3)
C(3)-C(4)-H(4) 120.0
C(5)-C(4)-C(3) 120.1(3)
C(5)-C(4)-H(4) 120.0
C(4)-C(5)-H(5) 121.0
C(4)-C(5)-C(6) 118.1(3)
C(6)-C(5)-H(5) 121.0
C(3)-C(2)-C(1) 120.4(3)
298
C(3)-C(2)-H(2) 119.8
C(1)-C(2)-H(2) 119.8
C(15)-C(20)-H(20) 120.2
C(19)-C(20)-H(20) 120.2
C(19)-C(20)-C(15) 119.6(3)
C(17)-C(16)-H(16) 120.1
C(17)-C(16)-C(15) 119.8(3)
C(15)-C(16)-H(16) 120.1
C(7)-C(12)-Bi(1) 118.6(2)
C(11)-C(12)-Bi(1) 123.1(2)
C(11)-C(12)-C(7) 118.2(3)
C(20)-C(15)-C(14) 119.5(3)
C(20)-C(15)-C(16) 118.8(3)
C(16)-C(15)-C(14) 121.6(3)
C(12)-C(11)-H(11) 120.2
C(12)-C(11)-C(10) 119.7(3)
C(10)-C(11)-H(11) 120.2
C(1)-C(6)-S(1) 117.3(2)
C(1)-C(6)-C(5) 123.5(3)
C(5)-C(6)-S(1) 119.2(2)
C(11)-C(10)-H(10) 119.4
C(9)-C(10)-C(11) 121.3(3)
C(9)-C(10)-H(10) 119.4
C(7)-C(8)-H(8) 120.7
C(9)-C(8)-C(7) 118.6(3)
C(9)-C(8)-H(8) 120.7
C(17)-C(18)-H(18) 119.9
C(17)-C(18)-C(19) 120.2(3)
C(19)-C(18)-H(18) 119.9
C(20)-C(19)-C(18) 121.3(3)
C(20)-C(19)-H(19) 119.4
C(18)-C(19)-H(19) 119.4
C(10)-C(9)-H(9) 119.9
C(8)-C(9)-C(10) 120.1(3)
C(8)-C(9)-H(9) 119.9
299
B.1.4.5 X-RAY CRYSTALLOGRAPHIC ANALYSIS OF BISMUTH(III) ACETYLIDE
35
The single crystal X-ray diffraction studies were carried out on a Bruker APEX II ULTRA CCD diffractometer
equipped with Mo Kα radiation (λ= 0.71073 Å ). Crystals of the subject compound were used as received. A 0.150 x
0.050 x 0.050 mm colorless prism crystal was mounted on a Cryoloop with Paratone N oil. Data were collected in a
nitrogen gas stream at 100(2) K using ϖ scans. Crystal-to-detector distance was 40 mm using an exposure time of 8
seconds with a scan width of 1°. Data collection was 100.0% complete to 25.242° in θ. A total of 23898 reflections
were collected. 3274 reflections were found to be symmetry independent, with a Rint of 0.0319. Indexing and unit
cell refinement indicated a Primitive Triclinic lattice. The space group was found to be P-1. The data were integrated
using the Bruker SAINT Software program and scaled using the SADABS software program. Solution by direct
methods (SHELXT) produced a complete phasing model consistent with the proposed structure. All non-hydrogen
atoms were refined anisotropically by full-matrix least-squares (SHELXL-2014). All carbon bonded hydrogen atoms
were placed using a riding model. Their positions were constrained relative to their parent atom using the appropriate
HFIX command in SHELXL-2014.
Notes: Excellent data and refinement. There is minor chemical disorder at the Br1 atom (93 % Br, 7 %H).
Figure B.14 Asymmetric unit in the crystal structure of compound 35.
Table B.16 Crystal data and structure refinement for compound 35.
Empirical formula C20 H12.07 Bi Br0.92 O2 S
Formula weight 599.17
Temperature 100.0 K
Wavelength 0.71073 Å
Crystal system Triclinic
300
Space group P-1
Unit cell dimensions a = 8.3788(8) Å α= 69.917(3)°.
b = 9.4899(9) Å β= 87.930(3)°.
c = 12.4028(11) Å γ= 74.563(3)°.
Volume 891.15(15) Å3
Z 2
Density (calculated) 2.233 Mg/m3
Absorption coefficient 12.093 mm-1
F(000) 559
Crystal size 0.15 x 0.05 x 0.05 mm3
Theta range for data collection 1.751 to 25.393°.
Index ranges -10<=h<=10, -11<=k<=11, -14<=l<=14
Reflections collected 23898
Independent reflections 3274 [R(int) = 0.0319]
Completeness to theta = 25.242° 100.0 %
Absorption correction Semi-empirical from equivalents
Max. and min. transmission 0.4901 and 0.3629
Refinement method Full-matrix least-squares on F2
Data / restraints / parameters 3274 / 0 / 228
Goodness-of-fit on F2 1.074
Final R indices [I>2sigma(I)] R1 = 0.0168, wR2 = 0.0320
R indices (all data) R1 = 0.0205, wR2 = 0.0329
Extinction coefficient n/a
Largest diff. peak and hole 0.733 and -0.509 e.Å-3
Table B.17 Bond lengths [Å] and angles [°] for compound 35.
Bi(1)-C(8) 2.231(3)
Bi(1)-C(9) 2.271(3)
Bi(1)-C(20) 2.281(3)
Br(1)-C(1) 1.900(3)
S(1)-O(1) 1.437(2)
S(1)-O(2) 1.456(2)
S(1)-C(14) 1.767(3)
S(1)-C(15) 1.763(3)
C(1)-C(2) 1.380(5)
C(1)-C(6) 1.380(5)
C(2)-C(3) 1.381(5)
C(3)-C(4) 1.402(5)
C(4)-C(5) 1.390(5)
C(4)-C(7) 1.458(5)
C(5)-C(6) 1.377(5)
C(7)-C(8) 1.175(5)
C(9)-C(10) 1.390(5)
C(9)-C(14) 1.388(4)
C(10)-C(11) 1.396(5)
C(11)-C(12) 1.389(5)
C(12)-C(13) 1.373(5)
C(13)-C(14) 1.394(5)
301
C(15)-C(16) 1.391(4)
C(15)-C(20) 1.393(4)
C(16)-C(17) 1.385(5)
C(17)-C(18) 1.384(5)
C(18)-C(19) 1.392(5)
C(19)-C(20) 1.387(5)
C(8)-Bi(1)-C(9) 90.76(12)
C(8)-Bi(1)-C(20) 95.13(12)
C(9)-Bi(1)-C(20) 87.10(11)
O(1)-S(1)-O(2) 119.00(14)
O(1)-S(1)-C(14) 110.21(15)
O(1)-S(1)-C(15) 109.69(15)
O(2)-S(1)-C(14) 105.80(14)
O(2)-S(1)-C(15) 105.77(14)
C(15)-S(1)-C(14) 105.48(15)
C(2)-C(1)-Br(1) 119.9(3)
C(2)-C(1)-C(6) 121.6(3)
C(6)-C(1)-Br(1) 118.5(3)
C(1)-C(2)-C(3) 119.1(3)
C(2)-C(3)-C(4) 120.5(3)
C(3)-C(4)-C(7) 119.9(3)
C(5)-C(4)-C(3) 118.8(3)
C(5)-C(4)-C(7) 121.3(3)
C(6)-C(5)-C(4) 121.0(3)
C(5)-C(6)-C(1) 119.0(3)
C(8)-C(7)-C(4) 178.2(4)
C(7)-C(8)-Bi(1) 159.8(3)
C(10)-C(9)-Bi(1) 123.1(2)
C(14)-C(9)-Bi(1) 119.3(2)
C(14)-C(9)-C(10) 117.7(3)
C(9)-C(10)-C(11) 120.3(3)
C(12)-C(11)-C(10) 120.3(3)
C(13)-C(12)-C(11) 120.4(3)
C(12)-C(13)-C(14) 118.4(3)
C(9)-C(14)-S(1) 117.8(2)
C(9)-C(14)-C(13) 122.8(3)
C(13)-C(14)-S(1) 119.3(2)
C(16)-C(15)-S(1) 118.8(2)
C(16)-C(15)-C(20) 122.6(3)
C(20)-C(15)-S(1) 118.6(2)
C(17)-C(16)-C(15) 118.6(3)
C(18)-C(17)-C(16) 119.8(3)
C(17)-C(18)-C(19) 120.9(3)
C(20)-C(19)-C(18) 120.3(3)
C(15)-C(20)-Bi(1) 118.3(2)
C(19)-C(20)-Bi(1) 123.9(2)
C(19)-C(20)-C(15) 117.8(3)
302
B.1.4.6 X-RAY CRYSTALLOGRAPHIC ANALYSIS OF BISMUTH(III) ACETYLIDE
32
The single crystal X-ray diffraction studies were carried out on a Bruker Kappa Apex II CCD diffractometer equipped
with Mo K α radiation (λ = 0.71073). A 0.180 x 0.125 x 0.060 mm colorless crystal was mounted on a Cryoloop with
Paratone oil. Data were collected in a nitrogen gas stream at 100(2) K using ϕ and ϖ scans. Crystal-to-detector distance
was 40 mm using exposure time 15s with a scan width of 0.60°. Data collection was 100.0% complete to 25.242° in
θ. A total of 24144 reflections were collected covering the indices, -12<=h<=12, -10<=k<=10, -30<=l<=30. 4322
reflections were found to be symmetry independent, with a Rint of 0.0350. Indexing and unit cell refinement indicated
a Primitive, Monoclinic lattice. The space group was found to be P21/c. The data were integrated using the Bruker
SAINT Software program and scaled using the SADABS software program. Solution by direct methods (SHELXT)
produced a complete phasing model consistent with the proposed structure. All nonhydrogen atoms were refined
anisotropically by full-matrix least-squares (SHELXL-2014). All carbon bonded hydrogen atoms were placed using
a riding model. Their positions were constrained relative to their parent atom using the appropriate HFIX command
in SHELXL-2014.
Notes: Proposed structure in agreement with model derived from diffraction data. Excellent data and refinement
Disorder on the t-Bu group, SADI, RIGU…
Figure B.15 Asymmetric unit in the crystal structure of compound 32.
Table B.18 Crystal data and structure refinement for 32.
Empirical formula C24 H21 Bi O2 S
Molecular formula C24 H21 Bi O2 S
Formula weight 582.45
Temperature 100.0 K
Wavelength 0.71073 Å
303
Crystal system Monoclinic
Space group P 1 21/c 1
Unit cell dimensions a = 10.2166(5) Å 90°.
b = 8.6731(4) Å 97.570(2)°.
c = 24.1194(11) Å 90°.
Volume 2118.58(17) Å
3
Z 4
Density (calculated) 1.826 Mg/m
3
Absorption coefficient 8.437 mm
-1
F(000) 1120
Crystal size 0.18 x 0.125 x 0.06 mm
3
Crystal color, habit colorless plank
Theta range for data collection 2.011 to 26.371°.
Index ranges -12<=h<=12, -10<=k<=10, -30<=l<=30
Reflections collected 24144
Independent reflections 4322 [R(int) = 0.0350]
Completeness to theta = 25.242° 100.0 %
Absorption correction Semi-empirical from equivalents
Max. and min. transmission 0.2607 and 0.1603
Refinement method Full-matrix least-squares on F
2
Data / restraints / parameters 4322 / 76 / 296
Goodness-of-fit on F
2
1.028
Final R indices [I>2sigma(I)] R1 = 0.0198, wR2 = 0.0336
R indices (all data) R1 = 0.0321, wR2 = 0.0364
Largest diff. peak and hole 0.481 and -0.415 e.Å
-3
Table B.19 Bond lengths [Å] and angles [°] for 32.
Bi(1)-C(1) 2.277(3)
Bi(1)-C(12) 2.274(3)
Bi(1)-C(13) 2.225(3)
S(1)-O(1) 1.453(2)
S(1)-O(2) 1.440(2)
S(1)-C(6) 1.769(3)
S(1)-C(7) 1.766(3)
C(1)-C(2) 1.389(4)
C(1)-C(6) 1.390(4)
C(2)-H(2) 0.9500
C(2)-C(3) 1.391(4)
C(3)-H(3) 0.9500
C(3)-C(4) 1.392(5)
C(4)-H(4) 0.9500
C(4)-C(5) 1.382(5)
C(5)-H(5) 0.9500
C(5)-C(6) 1.391(4)
C(7)-C(8) 1.387(4)
C(7)-C(12) 1.399(4)
304
C(8)-H(8) 0.9500
C(8)-C(9) 1.390(4)
C(9)-H(9) 0.9500
C(9)-C(10) 1.389(4)
C(10)-H(10) 0.9500
C(10)-C(11) 1.387(4)
C(11)-H(11) 0.9500
C(11)-C(12) 1.385(4)
C(13)-C(14) 1.195(4)
C(14)-C(15) 1.453(4)
C(15)-C(16) 1.397(4)
C(15)-C(20) 1.395(4)
C(16)-H(16) 0.9500
C(16)-C(17) 1.384(4)
C(17)-H(17) 0.9500
C(17)-C(18) 1.399(5)
C(18)-C(19) 1.400(4)
C(18)-C(21) 1.535(7)
C(18)-C(21B) 1.531(7)
C(19)-H(19) 0.9500
C(19)-C(20) 1.382(4)
C(20)-H(20) 0.9500
C(21)-C(22) 1.533(7)
C(21)-C(23) 1.526(7)
C(21)-C(24) 1.535(7)
C(22)-H(22A) 0.9800
C(22)-H(22B) 0.9800
C(22)-H(22C) 0.9800
C(23)-H(23A) 0.9800
C(23)-H(23B) 0.9800
C(23)-H(23C) 0.9800
C(24)-H(24A) 0.9800
C(24)-H(24B) 0.9800
C(24)-H(24C) 0.9800
C(21B)-C(22B) 1.538(7)
C(21B)-C(23B) 1.529(7)
C(21B)-C(24B) 1.530(7)
C(22B)-H(22D) 0.9800
C(22B)-H(22E) 0.9800
C(22B)-H(22F) 0.9800
C(23B)-H(23D) 0.9800
C(23B)-H(23E) 0.9800
C(23B)-H(23F) 0.9800
C(24B)-H(24D) 0.9800
C(24B)-H(24E) 0.9800
C(24B)-H(24F) 0.9800
C(12)-Bi(1)-C(1) 85.87(11)
C(13)-Bi(1)-C(1) 90.39(11)
305
C(13)-Bi(1)-C(12) 93.72(11)
O(1)-S(1)-C(6) 105.64(14)
O(1)-S(1)-C(7) 106.87(14)
O(2)-S(1)-O(1) 119.31(13)
O(2)-S(1)-C(6) 109.76(14)
O(2)-S(1)-C(7) 109.92(14)
C(7)-S(1)-C(6) 104.24(14)
C(2)-C(1)-Bi(1) 122.4(2)
C(2)-C(1)-C(6) 118.0(3)
C(6)-C(1)-Bi(1) 119.5(2)
C(1)-C(2)-H(2) 119.9
C(1)-C(2)-C(3) 120.2(3)
C(3)-C(2)-H(2) 119.9
C(2)-C(3)-H(3) 119.8
C(2)-C(3)-C(4) 120.3(3)
C(4)-C(3)-H(3) 119.8
C(3)-C(4)-H(4) 119.7
C(5)-C(4)-C(3) 120.6(3)
C(5)-C(4)-H(4) 119.7
C(4)-C(5)-H(5) 121.0
C(4)-C(5)-C(6) 118.0(3)
C(6)-C(5)-H(5) 121.0
C(1)-C(6)-S(1) 118.0(2)
C(1)-C(6)-C(5) 122.8(3)
C(5)-C(6)-S(1) 119.1(2)
C(8)-C(7)-S(1) 118.8(2)
C(8)-C(7)-C(12) 122.6(3)
C(12)-C(7)-S(1) 118.6(2)
C(7)-C(8)-H(8) 120.8
C(7)-C(8)-C(9) 118.3(3)
C(9)-C(8)-H(8) 120.8
C(8)-C(9)-H(9) 119.9
C(10)-C(9)-C(8) 120.2(3)
C(10)-C(9)-H(9) 119.9
C(9)-C(10)-H(10) 119.8
C(11)-C(10)-C(9) 120.3(3)
C(11)-C(10)-H(10) 119.8
C(10)-C(11)-H(11) 119.5
C(12)-C(11)-C(10) 120.9(3)
C(12)-C(11)-H(11) 119.5
C(7)-C(12)-Bi(1) 118.8(2)
C(11)-C(12)-Bi(1) 123.6(2)
C(11)-C(12)-C(7) 117.6(3)
C(14)-C(13)-Bi(1) 170.3(3)
C(13)-C(14)-C(15) 178.1(4)
C(16)-C(15)-C(14) 120.1(3)
C(20)-C(15)-C(14) 121.8(3)
C(20)-C(15)-C(16) 118.1(3)
C(15)-C(16)-H(16) 119.7
306
C(17)-C(16)-C(15) 120.6(3)
C(17)-C(16)-H(16) 119.7
C(16)-C(17)-H(17) 119.0
C(16)-C(17)-C(18) 121.9(3)
C(18)-C(17)-H(17) 119.0
C(17)-C(18)-C(19) 116.7(3)
C(17)-C(18)-C(21) 123.6(5)
C(17)-C(18)-C(21B) 120.7(5)
C(19)-C(18)-C(21) 118.9(5)
C(19)-C(18)-C(21B) 122.5(5)
C(18)-C(19)-H(19) 119.1
C(20)-C(19)-C(18) 121.9(3)
C(20)-C(19)-H(19) 119.1
C(15)-C(20)-H(20) 119.6
C(19)-C(20)-C(15) 120.8(3)
C(19)-C(20)-H(20) 119.6
C(22)-C(21)-C(18) 104.6(13)
C(22)-C(21)-C(24) 112.1(13)
C(23)-C(21)-C(18) 112.4(7)
C(23)-C(21)-C(22) 108.5(11)
C(23)-C(21)-C(24) 108.7(8)
C(24)-C(21)-C(18) 110.6(8)
C(21)-C(22)-H(22A) 109.5
C(21)-C(22)-H(22B) 109.5
C(21)-C(22)-H(22C) 109.5
H(22A)-C(22)-H(22B) 109.5
H(22A)-C(22)-H(22C) 109.5
H(22B)-C(22)-H(22C) 109.5
C(21)-C(23)-H(23A) 109.5
C(21)-C(23)-H(23B) 109.5
C(21)-C(23)-H(23C) 109.5
H(23A)-C(23)-H(23B) 109.5
H(23A)-C(23)-H(23C) 109.5
H(23B)-C(23)-H(23C) 109.5
C(21)-C(24)-H(24A) 109.5
C(21)-C(24)-H(24B) 109.5
C(21)-C(24)-H(24C) 109.5
H(24A)-C(24)-H(24B) 109.5
H(24A)-C(24)-H(24C) 109.5
H(24B)-C(24)-H(24C) 109.5
C(18)-C(21B)-C(22B) 114.7(15)
C(23B)-C(21B)-C(18) 113.1(8)
C(23B)-C(21B)-C(22B) 109.7(12)
C(23B)-C(21B)-C(24B) 108.0(9)
C(24B)-C(21B)-C(18) 105.2(8)
C(24B)-C(21B)-C(22B) 105.5(14)
C(21B)-C(22B)-H(22D) 109.5
C(21B)-C(22B)-H(22E) 109.5
C(21B)-C(22B)-H(22F) 109.5
307
H(22D)-C(22B)-H(22E) 109.5
H(22D)-C(22B)-H(22F) 109.5
H(22E)-C(22B)-H(22F) 109.5
C(21B)-C(23B)-H(23D) 109.5
C(21B)-C(23B)-H(23E) 109.5
C(21B)-C(23B)-H(23F) 109.5
H(23D)-C(23B)-H(23E) 109.5
H(23D)-C(23B)-H(23F) 109.5
H(23E)-C(23B)-H(23F) 109.5
C(21B)-C(24B)-H(24D) 109.5
C(21B)-C(24B)-H(24E) 109.5
C(21B)-C(24B)-H(24F) 109.5
H(24D)-C(24B)-H(24E) 109.5
H(24D)-C(24B)-H(24F) 109.5
H(24E)-C(24B)-H(24F) 109.5
308
B.1.4.7 X-RAY CRYSTALLOGRAPHIC ANALYSIS OF BISMUTH(III) ACETYLIDE
33
The single crystal X-ray diffraction studies were carried out on a Bruker APEX II ULTRA CCD diffractometer
equipped with Mo Kα radiation (λ = 0.71073 Å ). Crystals of the subject compound were used as received. A 0.220
x 0.160 x 0.110 mm colorless block crystal was mounted on a Cryoloop with Paratone N oil. Data were collected in a
nitrogen gas stream at 100(2) K using ϕ and ϖ scans. Crystal-to-detector distance was 40 mm using an exposure time
of 5 seconds with a scan width of 1.5°. Data collection was 99.9% complete to 25.242° in θ. A total of 11108
reflections were collected. 4447 reflections were found to be symmetry independent, with a Rint of 0.0314. Indexing
and unit cell refinement indicated a Primitive Triclinic lattice. The space group was found to be P-1. The data were
integrated using the Bruker SAINT Software program and scaled using the SADABS software program. Solution by
direct methods (SHELXT) produced a complete phasing model consistent with the proposed structure. All non-
hydrogen atoms were refined anisotropically by full-matrix least-squares (SHELXL-2014). All carbon bonded
hydrogen atoms were placed using a riding model. Their positions were constrained relative to their parent atom using
the appropriate HFIX command in SHELXL-2014.
Notes: Excellent data and refinement. There is one molecule per asymmetric unit.
Figure B.16 Asymmetric unit in the crystal structure of compound 33.
Table B.20 Crystal data and structure refinement for compound 33.
Empirical formula C21 H15 Bi O2 S
Formula weight 540.37
Temperature 100.0 K
Wavelength 0.71073 Å
Crystal system Triclinic
Space group P-1
309
Unit cell dimensions a = 8.4656(5) Å 𝛼 = 70.606(2)°.
b = 9.4514(5) Å β= 87.545(2)°.
c = 12.2813(6) Å γ= 75.602(2)°.
Volume 896.93(8) Å3
Z 2
Density (calculated) 2.001 Mg/m3
Absorption coefficient 9.956 mm-1
F(000) 512
Crystal size 0.22 x 0.16 x 0.11 mm3
Theta range for data collection 1.760 to 28.292°.
Index ranges -11<=h<=11, -12<=k<=12, -16<=l<=16
Reflections collected 11108
Independent reflections 4447 [R(int) = 0.0314]
Completeness to theta = 25.242° 99.9 %
Absorption correction Semi-empirical from equivalents
Max. and min. transmission 0.7457 and 0.5814
Refinement method Full-matrix least-squares on F2
Data / restraints / parameters 4447 / 0 / 227
Goodness-of-fit on F2 1.038
Final R indices [I>2sigma(I)] R1 = 0.0205, wR2 = 0.0463
R indices (all data) R1 = 0.0242, wR2 = 0.0472
Extinction coefficient n/a
Largest diff. peak and hole 1.429 and -0.802 e.Å-3
Table B.21 Bond lengths [Å] and angles [°] for compound 33.
Bi(1)-C(9) 2.256(3)
Bi(1)-C(10) 2.274(3)
Bi(1)-C(16) 2.275(3)
S(1)-O(1) 1.445(2)
S(1)-O(2) 1.459(2)
S(1)-C(15) 1.767(3)
S(1)-C(17) 1.771(3)
C(1)-H(1A) 0.9800
C(1)-H(1B) 0.9800
C(1)-H(1C) 0.9800
C(1)-C(2) 1.520(4)
C(2)-C(3) 1.391(5)
C(2)-C(7) 1.391(5)
C(3)-H(3) 0.9500
C(3)-C(4) 1.387(4)
C(4)-H(4) 0.9500
C(4)-C(5) 1.400(5)
C(5)-C(6) 1.396(5)
C(5)-C(8) 1.483(5)
C(6)-H(6) 0.9500
C(6)-C(7) 1.377(4)
C(7)-H(7) 0.9500
C(8)-C(9) 1.135(5)
310
C(10)-C(11) 1.391(4)
C(10)-C(15) 1.399(4)
C(11)-H(11) 0.9500
C(11)-C(12) 1.397(5)
C(12)-H(12) 0.9500
C(12)-C(13) 1.392(4)
C(13)-H(13) 0.9500
C(13)-C(14) 1.392(4)
C(14)-H(14) 0.9500
C(14)-C(15) 1.381(4)
C(16)-C(17) 1.390(4)
C(16)-C(21) 1.399(4)
C(17)-C(18) 1.393(4)
C(18)-H(18) 0.9500
C(18)-C(19) 1.384(4)
C(19)-H(19) 0.9500
C(19)-C(20) 1.395(4)
C(20)-H(20) 0.9500
C(20)-C(21) 1.395(4)
C(21)-H(21) 0.9500
C(9)-Bi(1)-C(10) 91.74(11)
C(9)-Bi(1)-C(16) 94.53(11)
C(10)-Bi(1)-C(16) 86.35(11)
O(1)-S(1)-O(2) 118.94(13)
O(1)-S(1)-C(15) 110.15(14)
O(1)-S(1)-C(17) 109.64(14)
O(2)-S(1)-C(15) 106.19(14)
O(2)-S(1)-C(17) 106.05(14)
C(15)-S(1)-C(17) 104.92(14)
H(1A)-C(1)-H(1B) 109.5
H(1A)-C(1)-H(1C) 109.5
H(1B)-C(1)-H(1C) 109.5
C(2)-C(1)-H(1A) 109.5
C(2)-C(1)-H(1B) 109.5
C(2)-C(1)-H(1C) 109.5
C(3)-C(2)-C(1) 121.4(3)
C(7)-C(2)-C(1) 120.6(3)
C(7)-C(2)-C(3) 117.9(3)
C(2)-C(3)-H(3) 119.2
C(4)-C(3)-C(2) 121.6(3)
C(4)-C(3)-H(3) 119.2
C(3)-C(4)-H(4) 120.0
C(3)-C(4)-C(5) 119.9(3)
C(5)-C(4)-H(4) 120.0
C(4)-C(5)-C(8) 120.2(3)
C(6)-C(5)-C(4) 118.5(3)
C(6)-C(5)-C(8) 121.2(3)
C(5)-C(6)-H(6) 119.6
311
C(7)-C(6)-C(5) 120.8(3)
C(7)-C(6)-H(6) 119.6
C(2)-C(7)-H(7) 119.4
C(6)-C(7)-C(2) 121.2(3)
C(6)-C(7)-H(7) 119.4
C(9)-C(8)-C(5) 178.3(4)
C(8)-C(9)-Bi(1) 161.7(3)
C(11)-C(10)-Bi(1) 123.0(2)
C(11)-C(10)-C(15) 117.3(3)
C(15)-C(10)-Bi(1) 119.7(2)
C(10)-C(11)-H(11) 119.8
C(10)-C(11)-C(12) 120.5(3)
C(12)-C(11)-H(11) 119.8
C(11)-C(12)-H(12) 119.6
C(13)-C(12)-C(11) 120.9(3)
C(13)-C(12)-H(12) 119.6
C(12)-C(13)-H(13) 120.2
C(12)-C(13)-C(14) 119.5(3)
C(14)-C(13)-H(13) 120.2
C(13)-C(14)-H(14) 120.7
C(15)-C(14)-C(13) 118.6(3)
C(15)-C(14)-H(14) 120.7
C(10)-C(15)-S(1) 116.9(2)
C(14)-C(15)-S(1) 119.8(2)
C(14)-C(15)-C(10) 123.3(3)
C(17)-C(16)-Bi(1) 118.9(2)
C(17)-C(16)-C(21) 117.3(3)
C(21)-C(16)-Bi(1) 123.8(2)
C(16)-C(17)-S(1) 118.1(2)
C(16)-C(17)-C(18) 123.2(3)
C(18)-C(17)-S(1) 118.7(2)
C(17)-C(18)-H(18) 120.8
C(19)-C(18)-C(17) 118.4(3)
C(19)-C(18)-H(18) 120.8
C(18)-C(19)-H(19) 120.0
C(18)-C(19)-C(20) 120.0(3)
C(20)-C(19)-H(19) 120.0
C(19)-C(20)-H(20) 119.7
C(19)-C(20)-C(21) 120.6(3)
C(21)-C(20)-H(20) 119.7
C(16)-C(21)-H(21) 119.8
C(20)-C(21)-C(16) 120.5(3)
C(20)-C(21)-H(21) 119.8
312
B.1.4.8 X-RAY CRYSTALLOGRAPHIC ANALYSIS OF BISMUTH(III) ACETYLIDE
36
The single crystal X-ray diffraction studies were carried out on a Bruker APEX II ULTRA CCD diffractometer
equipped with Mo Kα radiation (λ = 0.71073 Å ). Crystals of the subject compound were used as received. A 0.190
x 0.100 x 0.050 mm colorless prism crystal was mounted on a Cryoloop with Paratone N oil. Data were collected in
a nitrogen gas stream at 100(2) K using ϕ and ϖ scans. Crystal-to-detector distance was 45 mm using an exposure
time of 2 seconds with a scan width of 0.70°. Data collection was 100.0% complete to 25.242° in θ. A total of 18762
reflections were collected. 3830 reflections were found to be symmetry independent, with a Rint of 0.0335. Indexing
and unit cell refinement indicated a Primitive Monoclinic lattice. The space group was found to be P21/c. The data
were integrated using the Bruker SAINT Software program and scaled using the SADABS software program. Solution
by direct methods (SHELXT) produced a complete phasing model consistent with the proposed structure. All non-
hydrogen atoms were refined anisotropically by full-matrix least-squares (SHELXL-2014). All carbon bonded
hydrogen atoms were placed using a riding model. Their positions were constrained relative to their parent atom using
the appropriate HFIX command in SHELXL-2014.
Notes: Excellent data and refinement. There is minor chemical disorder with approximately 3% of the iodo-Bi starting
material present.
Figure B.17 Asymmetric unit in the crystal structure of compound 36.
Table B.22 Crystal data and structure refinement for compound 36.
Empirical formula C21 H12 Bi F3 I0.03 O2 S
Formula weight 598.15
Temperature 100.0 K
Wavelength 0.71073 Å
Crystal system Monoclinic
313
Space group P 1 21/c 1
Unit cell dimensions a = 7.7441(5) Å α= 90°.
b = 9.9411(7) Å β= 98.4280(10)°.
c = 24.6103(16) Å γ = 90°.
Volume 1874.2(2) Å3
Z 4
Density (calculated) 2.120 Mg/m3
Absorption coefficient 9.611 mm-1
F(000) 1126
Crystal size 0.19 x 0.1 x 0.05 mm3
Theta range for data collection 1.673 to 26.368°.
Index ranges -9<=h<=8, -12<=k<=12, -30<=l<=30
Reflections collected 18762
Independent reflections 3830 [R(int) = 0.0335]
Completeness to theta = 25.242° 100.0 %
Absorption correction Semi-empirical from equivalents
Max. and min. transmission 0.2607 and 0.1551
Refinement method Full-matrix least-squares on F2
Data / restraints / parameters 3830 / 0 / 258
Goodness-of-fit on F2 1.079
Final R indices [I>2sigma(I)] R1 = 0.0189, wR2 = 0.0412
R indices (all data) R1 = 0.0219, wR2 = 0.0420
Extinction coefficient n/a
Largest diff. peak and hole 0.985 and -0.521 e.Å-3
Table B.23 Bond lengths [Å] and angles [°] for compound 36.
Bi(1)-C(10) 2.263(3)
Bi(1)-C(16) 2.267(3)
Bi(1)-C(9) 2.210(5)
Bi(1)-I(1) 2.931(17)
S(1)-O(2) 1.449(2)
S(1)-O(1) 1.439(2)
S(1)-C(15) 1.765(3)
S(1)-C(21) 1.778(3)
F(1)-C(1) 1.322(4)
C(15)-C(10) 1.393(4)
C(15)-C(14) 1.393(4)
F(3)-C(1) 1.325(5)
F(2)-C(1) 1.333(5)
C(5)-C(4) 1.395(5)
C(5)-C(6) 1.403(5)
C(5)-C(8) 1.434(5)
C(5)-I(1) 2.122(17)
C(10)-C(11) 1.384(4)
C(16)-C(21) 1.382(4)
C(16)-C(17) 1.390(4)
C(21)-C(20) 1.390(4)
C(20)-H(20) 0.9500
314
C(20)-C(19) 1.385(5)
C(14)-H(14) 0.9500
C(14)-C(13) 1.385(5)
C(12)-H(12) 0.9500
C(12)-C(13) 1.380(5)
C(12)-C(11) 1.394(5)
C(18)-H(18) 0.9500
C(18)-C(19) 1.382(5)
C(18)-C(17) 1.393(5)
C(4)-H(4) 0.9500
C(4)-C(3) 1.383(5)
C(13)-H(13) 0.9500
C(2)-C(7) 1.392(5)
C(2)-C(3) 1.383(5)
C(2)-C(1) 1.477(5)
C(19)-H(19) 0.9500
C(9)-C(8) 1.222(7)
C(7)-H(7) 0.9500
C(7)-C(6) 1.366(5)
C(17)-H(17) 0.9500
C(6)-H(6) 0.9500
C(3)-H(3) 0.9500
C(11)-H(11) 0.9500
C(10)-Bi(1)-C(16) 85.21(10)
C(10)-Bi(1)-I(1) 89.2(3)
C(16)-Bi(1)-I(1) 89.6(3)
C(9)-Bi(1)-C(10) 92.67(13)
C(9)-Bi(1)-C(16) 92.72(12)
O(2)-S(1)-C(15) 106.45(13)
O(2)-S(1)-C(21) 106.44(14)
O(1)-S(1)-O(2) 118.82(14)
O(1)-S(1)-C(15) 110.52(15)
O(1)-S(1)-C(21) 109.77(14)
C(15)-S(1)-C(21) 103.72(14)
C(10)-C(15)-S(1) 117.5(2)
C(14)-C(15)-S(1) 119.8(3)
C(14)-C(15)-C(10) 122.7(3)
C(4)-C(5)-C(6) 118.6(3)
C(4)-C(5)-C(8) 121.1(3)
C(4)-C(5)-I(1) 115.3(5)
C(6)-C(5)-C(8) 120.1(3)
C(6)-C(5)-I(1) 125.9(4)
C(15)-C(10)-Bi(1) 119.0(2)
C(11)-C(10)-Bi(1) 123.2(2)
C(11)-C(10)-C(15) 117.8(3)
C(21)-C(16)-Bi(1) 118.9(2)
C(21)-C(16)-C(17) 117.6(3)
C(17)-C(16)-Bi(1) 123.4(2)
315
C(16)-C(21)-S(1) 117.7(2)
C(16)-C(21)-C(20) 123.0(3)
C(20)-C(21)-S(1) 119.4(2)
C(21)-C(20)-H(20) 120.9
C(19)-C(20)-C(21) 118.2(3)
C(19)-C(20)-H(20) 120.9
C(15)-C(14)-H(14) 121.0
C(13)-C(14)-C(15) 118.0(3)
C(13)-C(14)-H(14) 121.0
C(13)-C(12)-H(12) 119.6
C(13)-C(12)-C(11) 120.8(3)
C(11)-C(12)-H(12) 119.6
C(19)-C(18)-H(18) 119.9
C(19)-C(18)-C(17) 120.3(3)
C(17)-C(18)-H(18) 119.9
C(5)-C(4)-H(4) 120.0
C(3)-C(4)-C(5) 120.0(3)
C(3)-C(4)-H(4) 120.0
C(14)-C(13)-H(13) 119.8
C(12)-C(13)-C(14) 120.4(3)
C(12)-C(13)-H(13) 119.8
C(7)-C(2)-C(1) 120.1(3)
C(3)-C(2)-C(7) 119.8(3)
C(3)-C(2)-C(1) 120.1(3)
C(20)-C(19)-H(19) 119.8
C(18)-C(19)-C(20) 120.4(3)
C(18)-C(19)-H(19) 119.8
C(8)-C(9)-Bi(1) 160.8(4)
C(2)-C(7)-H(7) 120.1
C(6)-C(7)-C(2) 119.8(3)
C(6)-C(7)-H(7) 120.1
C(16)-C(17)-C(18) 120.6(3)
C(16)-C(17)-H(17) 119.7
C(18)-C(17)-H(17) 119.7
C(5)-C(6)-H(6) 119.4
C(7)-C(6)-C(5) 121.2(3)
C(7)-C(6)-H(6) 119.4
C(4)-C(3)-H(3) 119.7
C(2)-C(3)-C(4) 120.6(3)
C(2)-C(3)-H(3) 119.7
C(9)-C(8)-C(5) 175.0(4)
C(10)-C(11)-C(12) 120.3(3)
C(10)-C(11)-H(11) 119.9
C(12)-C(11)-H(11) 119.9
F(1)-C(1)-F(3) 106.2(3)
F(1)-C(1)-F(2) 104.3(4)
F(1)-C(1)-C(2) 113.7(3)
F(3)-C(1)-F(2) 105.8(4)
F(3)-C(1)-C(2) 112.7(3)
316
F(2)-C(1)-C(2) 113.3(3)
C(5)-I(1)-Bi(1) 141.4(7)
317
B.1.4.9 X-RAY CRYSTALLOGRAPHIC ANALYSIS OF 10-IODO-10H-
DIBENZO[B,E][1,4]THIABISMINE 5,5-DIOXIDE 27
The single crystal X-ray diffraction studies were carried out on a Bruker Apex II Ultra CCD diffractometer equipped
with Mo Kα radiation (λ = 0.71073). A 0.140 x 0.025 x 0.025 mm colorless crystal was mounted on a Cryoloop with
Paratone oil. Data were collected in a nitrogen gas stream at 100(2) K using ϕ and ϖ scans. Crystal-to-detector distance
was 60 mm using exposure time 3s with a scan width of 0.60°. Data collection was 99.9% complete to 25.242° in θ.
A total of 14363 reflections were collected covering the indices, -11<=h<=11, -6<=k<=6, -44<=l<=29. 3213
reflections were found to be symmetry independent, with a Rint of 0.0204. Indexing and unit cell refinement indicated
a Primitive, Monoclinic lattice. The space group was found to be P21/n. The data were integrated using the Bruker
SAINT Software program and scaled using the SADABS software program. Solution by direct methods (SHELXT)
produced a complete phasing model consistent with the proposed structure. All nonhydrogen atoms were refined
anisotropically by full-matrix least-squares (SHELXL-2014). All carbon bonded hydrogen atoms were placed using
a riding model. Their positions were constrained relative to their parent atom using the appropriate HFIX command
in SHELXL-2014.
Notes: Proposed structure in agreement with model derived from diffraction data. Excellent data and refinement
Figure B.18 Crystal structure of compound 27.
Table B.24 Crystal data and structure refinement for compound 27.
Empirical formula C14 H12 Bi I O4 S
Molecular formula C14 H12 Bi I O4 S
Formula weight 612.18
Temperature 100.0 K
Wavelength 0.71073 Å
Crystal system Monoclinic
Space group P 1 21/n 1
318
Unit cell dimensions a = 9.1914(6) Å α = 90°.
b = 4.8207(3) Å β = 91.7600(10)°.
c = 35.739(2) Å γ = 90°.
Volume 1582.82(18) Å3
Z 4
Density (calculated) 2.569 Mg/m3
Absorption coefficient 13.232 mm-1
F(000) 1120
Crystal size 0.14 x 0.025 x 0.025 mm3
Crystal color, habit colorless plank
Theta range for data collection 2.272 to 26.372°.
Index ranges -11<=h<=11, -6<=k<=6, -44<=l<=29
Reflections collected 14363
Independent reflections 3213 [R(int) = 0.0204]
Completeness to theta = 25.242° 99.9 %
Absorption correction Semi-empirical from equivalents
Max. and min. transmission 0.2607 and 0.1503
Refinement method Full-matrix least-squares on F2
Data / restraints / parameters 3213 / 0 / 192
Goodness-of-fit on F2 1.251
Final R indices [I>2sigma(I)] R1 = 0.0186, wR2 = 0.0395
R indices (all data) R1 = 0.0190, wR2 = 0.0396
Largest diff. peak and hole 0.855 and -1.101 e.Å-3
Table B.25 Bond lengths [Å] and angles [°] for compound 27.
Bi(1)-I(1) 2.8715(3)
Bi(1)-C(1) 2.275(4)
Bi(1)-C(12) 2.270(4)
S(1)-O(2) 1.459(3)
S(1)-O(3) 1.433(3)
S(1)-C(6) 1.763(4)
S(1)-C(7) 1.761(4)
O(1)-C(3) 1.363(4)
O(1)-C(13) 1.433(4)
O(4)-C(10) 1.364(4)
O(4)-C(14) 1.434(5)
C(1)-C(2) 1.379(5)
C(1)-C(6) 1.398(5)
C(2)-H(2) 0.9500
C(2)-C(3) 1.407(5)
C(3)-C(4) 1.392(5)
C(4)-H(4) 0.9500
C(4)-C(5) 1.394(5)
C(5)-H(5) 0.9500
C(5)-C(6) 1.384(5)
C(7)-C(8) 1.383(5)
C(7)-C(12) 1.400(5)
C(8)-H(8) 0.9500
319
C(8)-C(9) 1.395(5)
C(9)-H(9) 0.9500
C(9)-C(10) 1.391(5)
C(10)-C(11) 1.402(5)
C(11)-H(11) 0.9500
C(11)-C(12) 1.384(5)
C(13)-H(13A) 0.9800
C(13)-H(13B) 0.9800
C(13)-H(13C) 0.9800
C(14)-H(14A) 0.9800
C(14)-H(14B) 0.9800
C(14)-H(14C) 0.9800
C(1)-Bi(1)-I(1) 91.33(9)
C(12)-Bi(1)-I(1) 93.48(9)
C(12)-Bi(1)-C(1) 87.54(13)
O(2)-S(1)-C(6) 104.41(17)
O(2)-S(1)-C(7) 104.26(17)
O(3)-S(1)-O(2) 119.25(16)
O(3)-S(1)-C(6) 110.53(17)
O(3)-S(1)-C(7) 111.58(17)
C(7)-S(1)-C(6) 105.74(17)
C(3)-O(1)-C(13) 118.3(3)
C(10)-O(4)-C(14) 117.4(3)
C(2)-C(1)-Bi(1) 123.4(3)
C(2)-C(1)-C(6) 118.7(3)
C(6)-C(1)-Bi(1) 117.9(3)
C(1)-C(2)-H(2) 120.2
C(1)-C(2)-C(3) 119.6(3)
C(3)-C(2)-H(2) 120.2
O(1)-C(3)-C(2) 114.5(3)
O(1)-C(3)-C(4) 124.2(3)
C(4)-C(3)-C(2) 121.3(3)
C(3)-C(4)-H(4) 120.6
C(3)-C(4)-C(5) 118.9(3)
C(5)-C(4)-H(4) 120.6
C(4)-C(5)-H(5) 120.3
C(6)-C(5)-C(4) 119.4(3)
C(6)-C(5)-H(5) 120.3
C(1)-C(6)-S(1) 116.9(3)
C(5)-C(6)-S(1) 121.0(3)
C(5)-C(6)-C(1) 122.1(3)
C(8)-C(7)-S(1) 121.0(3)
C(8)-C(7)-C(12) 122.2(3)
C(12)-C(7)-S(1) 116.8(3)
C(7)-C(8)-H(8) 120.4
C(7)-C(8)-C(9) 119.2(3)
C(9)-C(8)-H(8) 120.4
C(8)-C(9)-H(9) 120.4
320
C(10)-C(9)-C(8) 119.2(3)
C(10)-C(9)-H(9) 120.4
O(4)-C(10)-C(9) 123.9(3)
O(4)-C(10)-C(11) 115.0(3)
C(9)-C(10)-C(11) 121.1(3)
C(10)-C(11)-H(11) 120.1
C(12)-C(11)-C(10) 119.8(3)
C(12)-C(11)-H(11) 120.1
C(7)-C(12)-Bi(1) 117.9(3)
C(11)-C(12)-Bi(1) 123.6(3)
C(11)-C(12)-C(7) 118.5(3)
O(1)-C(13)-H(13A) 109.5
O(1)-C(13)-H(13B) 109.5
O(1)-C(13)-H(13C) 109.5
H(13A)-C(13)-H(13B) 109.5
H(13A)-C(13)-H(13C) 109.5
H(13B)-C(13)-H(13C) 109.5
O(4)-C(14)-H(14A) 109.5
O(4)-C(14)-H(14B) 109.5
O(4)-C(14)-H(14C) 109.5
H(14A)-C(14)-H(14B) 109.5
H(14A)-C(14)-H(14C) 109.5
H(14B)-C(14)-H(14C) 109.5
321
B.1.4.10 X-RAY CRYSTALLOGRAPHIC ANALYSIS OF 10-PHENYL-10H-
DIBENZO[B,E][1,4]THIABISMINE 5,5-DIOXIDE 21
The single crystal X-ray diffraction studies were carried out on a Bruker Kappa Apex II CCD diffractometer equipped
with Mo Kα radiation (λ = 0.71073). A 0.180 x 0.150 x 0.130 mm colorless crystal was mounted on a Cryoloop with
Paratone oil. Data were collected in a nitrogen gas stream at 100(2) K using ϕ and ϖ scans. Crystal-to-detector distance
was 40 mm using exposure time 2s with a scan width of 0.70°. Data collection was 99.9% complete to 25.242° in θ.
A total of 13836 reflections were collected covering the indices, -12<=h<=11, -12<=k<=9, -13<=l<=10. 3650
reflections were found to be symmetry independent, with a Rint of 0.0323. Indexing and unit cell refinement indicated
a Primitive, Triclinic lattice. The space group was found to be P-1. The data were integrated using the Bruker SAINT
Software program and scaled using the SADABS software program. Solution by direct methods (SHELXT) produced
a complete phasing model consistent with the proposed structure. All nonhydrogen atoms were refined anisotropically
by full-matrix least-squares (SHELXL-2014). All carbon bonded hydrogen atoms were placed using a riding model.
Their positions were constrained relative to their parent atom using the appropriate HFIX command in SHELXL-
2014.
Notes: Proposed structure in agreement with model derived from diffraction data. Excellent data and refinement
Figure B.19 Crystal structure of compound 21.
Table B.26 Crystal data and structure refinement for compound 21.
Empirical formula C20 H17 Bi O4 S
Molecular formula C20 H17 Bi O4 S
Formula weight 562.38
Temperature 100.0 K
Wavelength 0.71073 Å
322
Crystal system Triclinic
Space group P-1
Unit cell dimensions a = 9.9992(7) Å α = 69.723(2)°.
b = 10.2711(7) Å β = 86.066(2)°.
c = 10.5288(7) Å γ = 62.662(2)°.
Volume 895.70(11) Å3
Z 2
Density (calculated) 2.085 Mg/m3
Absorption coefficient 9.982 mm-1
F(000) 536
Crystal size 0.175 x 0.035 x 0.02 mm3
Crystal color, habit colorless plank
Theta range for data collection 2.074 to 26.372°.
Index ranges -12<=h<=11, -12<=k<=9, -13<=l<=10
Reflections collected 13836
Independent reflections 3650 [R(int) = 0.0323]
Completeness to theta = 25.242° 99.9 %
Absorption correction Semi-empirical from equivalents
Max. and min. transmission 0.2607 and 0.1758
Refinement method Full-matrix least-squares on F2
Data / restraints / parameters 3650 / 0 / 237
Goodness-of-fit on F2 1.050
Final R indices [I>2sigma(I)] R1 = 0.0164, wR2 = 0.0359
R indices (all data) R1 = 0.0183, wR2 = 0.0364
Largest diff. peak and hole 0.638 and -0.661 e.Å-3
Table B.27 Bond lengths [Å] and angles [°] for compound 21.
Bi(1)-C(1) 2.263(3)
Bi(1)-C(12) 2.288(3)
Bi(1)-C(15) 2.265(3)
S(1)-O(3) 1.450(2)
S(1)-O(4) 1.441(2)
S(1)-C(6) 1.778(3)
S(1)-C(7) 1.767(3)
O(1)-C(2) 1.370(3)
O(1)-C(13) 1.439(3)
O(2)-C(4) 1.366(3)
O(2)-C(14) 1.439(3)
C(1)-C(2) 1.399(4)
C(1)-C(6) 1.392(4)
C(2)-C(3) 1.387(4)
C(3)-H(3) 0.9500
C(3)-C(4) 1.401(4)
C(4)-C(5) 1.392(4)
C(5)-H(5) 0.9500
C(5)-C(6) 1.387(4)
C(7)-C(8) 1.395(4)
C(7)-C(12) 1.395(4)
323
C(8)-H(8) 0.9500
C(8)-C(9) 1.384(4)
C(9)-H(9) 0.9500
C(9)-C(10) 1.389(4)
C(10)-H(10) 0.9500
C(10)-C(11) 1.382(4)
C(11)-H(11) 0.9500
C(11)-C(12) 1.390(4)
C(13)-H(13A) 0.9800
C(13)-H(13B) 0.9800
C(13)-H(13C) 0.9800
C(14)-H(14A) 0.9800
C(14)-H(14B) 0.9800
C(14)-H(14C) 0.9800
C(15)-C(16) 1.390(4)
C(15)-C(20) 1.390(4)
C(16)-H(16) 0.9500
C(16)-C(17) 1.394(4)
C(17)-H(17) 0.9500
C(17)-C(18) 1.384(4)
C(18)-H(18) 0.9500
C(18)-C(19) 1.385(4)
C(19)-H(19) 0.9500
C(19)-C(20) 1.400(4)
C(20)-H(20) 0.9500
C(1)-Bi(1)-C(12) 87.99(10)
C(1)-Bi(1)-C(15) 97.72(10)
C(15)-Bi(1)-C(12) 87.27(10)
O(3)-S(1)-C(6) 106.45(13)
O(3)-S(1)-C(7) 107.06(13)
O(4)-S(1)-O(3) 118.80(12)
O(4)-S(1)-C(6) 109.07(13)
O(4)-S(1)-C(7) 109.00(13)
C(7)-S(1)-C(6) 105.69(13)
C(2)-O(1)-C(13) 117.8(2)
C(4)-O(2)-C(14) 117.0(2)
C(2)-C(1)-Bi(1) 121.2(2)
C(6)-C(1)-Bi(1) 122.2(2)
C(6)-C(1)-C(2) 116.3(2)
O(1)-C(2)-C(1) 114.3(2)
O(1)-C(2)-C(3) 123.8(3)
C(3)-C(2)-C(1) 121.8(3)
C(2)-C(3)-H(3) 120.4
C(2)-C(3)-C(4) 119.2(3)
C(4)-C(3)-H(3) 120.4
O(2)-C(4)-C(3) 114.6(2)
O(2)-C(4)-C(5) 124.4(3)
C(5)-C(4)-C(3) 121.0(3)
324
C(4)-C(5)-H(5) 121.4
C(6)-C(5)-C(4) 117.3(3)
C(6)-C(5)-H(5) 121.4
C(1)-C(6)-S(1) 118.3(2)
C(5)-C(6)-S(1) 117.1(2)
C(5)-C(6)-C(1) 124.2(3)
C(8)-C(7)-S(1) 118.9(2)
C(8)-C(7)-C(12) 122.6(3)
C(12)-C(7)-S(1) 118.5(2)
C(7)-C(8)-H(8) 120.8
C(9)-C(8)-C(7) 118.4(3)
C(9)-C(8)-H(8) 120.8
C(8)-C(9)-H(9) 120.1
C(8)-C(9)-C(10) 119.8(3)
C(10)-C(9)-H(9) 120.1
C(9)-C(10)-H(10) 119.6
C(11)-C(10)-C(9) 120.9(3)
C(11)-C(10)-H(10) 119.6
C(10)-C(11)-H(11) 119.6
C(10)-C(11)-C(12) 120.8(3)
C(12)-C(11)-H(11) 119.6
C(7)-C(12)-Bi(1) 121.4(2)
C(11)-C(12)-Bi(1) 121.1(2)
C(11)-C(12)-C(7) 117.3(3)
O(1)-C(13)-H(13A) 109.5
O(1)-C(13)-H(13B) 109.5
O(1)-C(13)-H(13C) 109.5
H(13A)-C(13)-H(13B) 109.5
H(13A)-C(13)-H(13C) 109.5
H(13B)-C(13)-H(13C) 109.5
O(2)-C(14)-H(14A) 109.5
O(2)-C(14)-H(14B) 109.5
O(2)-C(14)-H(14C) 109.5
H(14A)-C(14)-H(14B) 109.5
H(14A)-C(14)-H(14C) 109.5
H(14B)-C(14)-H(14C) 109.5
C(16)-C(15)-Bi(1) 115.8(2)
C(20)-C(15)-Bi(1) 124.6(2)
C(20)-C(15)-C(16) 118.9(3)
C(15)-C(16)-H(16) 119.8
C(15)-C(16)-C(17) 120.5(3)
C(17)-C(16)-H(16) 119.8
C(16)-C(17)-H(17) 119.9
C(18)-C(17)-C(16) 120.2(3)
C(18)-C(17)-H(17) 119.9
C(17)-C(18)-H(18) 120.0
C(17)-C(18)-C(19) 120.0(3)
C(19)-C(18)-H(18) 120.0
C(18)-C(19)-H(19) 120.2
325
C(18)-C(19)-C(20) 119.6(3)
C(20)-C(19)-H(19) 120.2
C(15)-C(20)-C(19) 120.7(3)
C(15)-C(20)-H(20) 119.7
C(19)-C(20)-H(20) 119.7
326
B.1.4.11 X-RAY CRYSTALLOGRAPHIC ANALYSIS OF 10-PHENYL-10H-
DIBENZO[B,E][1,4]THIABISMINE 5,5-DIOXIDE 18
The single crystal X-ray diffraction studies were carried out on a Bruker Apex II Ultra CCD diffractometer equipped
with Mo Kα radiation (λ = 0.71073). Crystals of the subject compound were used as received. A 0.200 x 0.030 x
0.030 mm colorless crystal was mounted on a Cryoloop with Paratone oil. Data were collected in a nitrogen gas stream
at 100(2) K using ϕ and ϖ scans. Crystal-to-detector distance was 50 mm using exposure time 4s with a scan width
of 0.70°. Data collection was 99.9% complete to 25.242° in θ. A total of 23456 reflections were collected covering
the indices, -30<=h<=29, -17<=k<=17, -6<=l<=6. 3614 reflections were found to be symmetry independent, with a
R int of 0.0393. Indexing and unit cell refinement indicated a Primitive, Orthorhombic lattice. The space group was
found to be Pna2 1. The data were integrated using the Bruker SAINT Software program and scaled using the
SADABS software program. Solution by direct methods (SHELXT) produced a complete phasing model consistent
with the proposed structure. All nonhydrogen atoms were refined anisotropically by full-matrix least-squares
(SHELXL-2014). All carbon bonded hydrogen atoms were placed using a riding model. Their positions were
constrained relative to their parent atom using the appropriate HFIX command in SHELXL-2014.
Notes: Proposed structure in agreement with model derived from diffraction data. Minor twin component tried hkl5
but return to single domain integration
Figure B.20 Crystal structure of compound 18.
Table B.28 Crystal data and structure refinement for compound 18.
Empirical formula C19 H12 Bi F3 O2 S
Molecular formula C19 H12 Bi F3 O2 S
Formula weight 570.33
Temperature 100.0 K
Wavelength 0.71073 Å
Crystal system Orthorhombic
Space group Pna21
327
Unit cell dimensions a = 24.2413(8) Å α = 90°.
b = 14.1185(5) Å β = 90°.
c = 5.1234(2) Å γ = 90°.
Volume 1753.49(11) Å3
Z 4
Density (calculated) 2.160 Mg/m3
Absorption coefficient 10.214 mm-1
F(000) 1072
Crystal size 0.2 x 0.03 x 0.03 mm3
Crystal color, habit colorless plank
Theta range for data collection 1.669 to 26.437°.
Index ranges -30<=h<=29, -17<=k<=17, -6<=l<=6
Reflections collected 23456
Independent reflections 3614 [R(int) = 0.0393]
Completeness to theta = 25.242° 99.9 %
Absorption correction Semi-empirical from equivalents
Max. and min. transmission 0.0452 and 0.0204
Refinement method Full-matrix least-squares on F2
Data / restraints / parameters 3614 / 37 / 235
Goodness-of-fit on F2 1.092
Final R indices [I>2sigma(I)] R1 = 0.0259, wR2 = 0.0546
R indices (all data) R1 = 0.0290, wR2 = 0.0556
Absolute structure parameter -0.007(6)
Largest diff. peak and hole 1.276 and -2.343 e.Å-3
Table B.29 Bond lengths [Å] and angles [°] for compound 18.
Bi(1)-C(1) 2.292(9)
Bi(1)-C(12) 2.260(8)
Bi(1)-C(14) 2.273(9)
S(1)-O(1) 1.436(10)
S(1)-O(2) 1.439(6)
S(1)-C(6) 1.778(9)
S(1)-C(7) 1.752(8)
F(1)-C(13) 1.285(13)
F(2)-C(13) 1.308(13)
F(3)-C(13) 1.261(12)
C(1)-C(2) 1.390(12)
C(1)-C(6) 1.396(12)
C(2)-C(3) 1.398(15)
C(3)-C(4) 1.383(13)
C(3)-C(13) 1.501(13)
C(4)-C(5) 1.389(12)
C(5)-C(6) 1.395(12)
C(7)-C(8) 1.401(11)
C(7)-C(12) 1.398(11)
C(8)-C(9) 1.395(12)
C(9)-C(10) 1.383(12)
C(10)-C(11) 1.423(11)
328
C(11)-C(12) 1.395(12)
C(14)-C(15) 1.383(11)
C(14)-C(19) 1.398(11)
C(15)-C(16) 1.383(13)
C(16)-C(17) 1.367(13)
C(17)-C(18) 1.377(12)
C(18)-C(19) 1.390(12)
C(12)-Bi(1)-C(1) 86.4(3)
C(12)-Bi(1)-C(14) 97.7(3)
C(14)-Bi(1)-C(1) 89.3(3)
O(1)-S(1)-O(2) 118.8(3)
O(1)-S(1)-C(6) 105.7(3)
O(1)-S(1)-C(7) 107.7(4)
O(2)-S(1)-C(6) 109.9(4)
O(2)-S(1)-C(7) 109.9(4)
C(7)-S(1)-C(6) 103.7(4)
C(2)-C(1)-Bi(1) 121.9(7)
C(2)-C(1)-C(6) 117.5(8)
C(6)-C(1)-Bi(1) 120.6(6)
C(1)-C(2)-C(3) 120.1(8)
C(2)-C(3)-C(13) 119.2(8)
C(4)-C(3)-C(2) 121.2(8)
C(4)-C(3)-C(13) 119.6(10)
C(3)-C(4)-C(5) 119.9(9)
C(4)-C(5)-C(6) 118.1(8)
C(1)-C(6)-S(1) 117.4(7)
C(5)-C(6)-S(1) 119.5(7)
C(5)-C(6)-C(1) 123.1(8)
C(8)-C(7)-S(1) 118.9(6)
C(12)-C(7)-S(1) 118.9(6)
C(12)-C(7)-C(8) 122.2(8)
C(9)-C(8)-C(7) 119.1(8)
C(10)-C(9)-C(8) 120.2(8)
C(9)-C(10)-C(11) 120.0(8)
C(12)-C(11)-C(10) 120.6(8)
C(7)-C(12)-Bi(1) 120.1(6)
C(11)-C(12)-Bi(1) 122.1(6)
C(11)-C(12)-C(7) 117.9(8)
F(1)-C(13)-F(2) 103.0(11)
F(1)-C(13)-C(3) 111.6(10)
F(2)-C(13)-C(3) 113.2(9)
F(3)-C(13)-F(1) 107.4(10)
F(3)-C(13)-F(2) 106.1(11)
F(3)-C(13)-C(3) 114.7(9)
C(15)-C(14)-Bi(1) 125.0(6)
C(15)-C(14)-C(19) 119.5(8)
C(19)-C(14)-Bi(1) 115.4(6)
C(16)-C(15)-C(14) 119.3(9)
329
C(17)-C(16)-C(15) 121.7(11)
C(16)-C(17)-C(18) 119.2(10)
C(17)-C(18)-C(19) 120.5(8)
C(18)-C(19)-C(14) 119.6(8)
330
B.1.4.12 X-RAY CRYSTALLOGRAPHIC ANALYSIS OF 2,8-DIMETHOXY-10-(P-
TOLYLETHYNYL)-10H-DIBENZO[B,E][1,4]THIABISMINE 5,5-DIOXIDE 37
The single crystal X-ray diffraction studies were carried out on a Bruker Apex II Ultra CCD diffractometer equipped
with Mo Kα radiation (λ= 0.71073). Crystals of the subject compound were used as received. A 0.140 x 0.140 x 0.050
mm colorless crystal was mounted on a Cryoloop with Paratone oil. Data were collected in a nitrogen gas stream at
100(2) K using ϕ and ϖ scans. Crystal-to-detector distance was 40 mm using exposure time 5s with a scan width of
0.70°. Data collection was 100.0% complete to 25.242° in θ. A total of 25165 reflections were collected covering the
indices, -9<=h<=9, -23<=k<=23, -16<=l<=16. 3952 reflections were found to be symmetry independent, with a Rint
of 0.0281. Indexing and unit cell refinement indicated a Primitive, Monoclinic lattice. The space group was found to
be P21/c. The data were integrated using the Bruker SAINT Software program and scaled using the SADABS
software program. Solution by direct methods (SHELXT) produced a complete phasing model consistent with the
proposed structure. All nonhydrogen atoms were refined anisotropically by full-matrix least-squares (SHELXL-2014).
All carbon bonded hydrogen atoms were placed using a riding model. Their positions were constrained relative to
their parent atom using the appropriate HFIX command in SHELXL-2014.
Notes: Proposed structure in agreement with model derived from diffraction data. Minor disorder or chemical
impurity/co-crystalized has not been modeled
Figure B.21 Crystal structure of compound 37.
Table B.30 Crystal data and structure refinement for compound 37.
Empirical formula C23 H19 Bi O4 S
Molecular formula C23 H19 Bi O4 S
Formula weight 600.42
Temperature 100.0 K
Wavelength 0.71073 Å
331
Crystal system Monoclinic
Space group P 1 21/c 1
Unit cell dimensions a = 7.6537(3) Å = 90°.
b = 19.4904(8) Å = 90.9170(10)°.
c = 13.9017(6) Å = 90°.
Volume 2073.50(15) Å3
Z 4
Density (calculated) 1.923 Mg/m3
Absorption coefficient 8.630 mm-1
F(000) 1152
Crystal size 0.14 x 0.14 x 0.05 mm3
Crystal color, habit colorless block
Theta range for data collection 1.799 to 25.680°.
Index ranges -9<=h<=9, -23<=k<=23, -16<=l<=16
Reflections collected 25165
Independent reflections 3952 [R(int) = 0.0281]
Completeness to theta = 25.242° 100.0 %
Absorption correction Semi-empirical from equivalents
Max. and min. transmission 0.0926 and 0.0606
Refinement method Full-matrix least-squares on F2
Data / restraints / parameters 3952 / 15 / 265
Goodness-of-fit on F2 1.088
Final R indices [I>2sigma(I)] R1 = 0.0261, wR2 = 0.0606
R indices (all data) R1 = 0.0305, wR2 = 0.0624
Largest diff. peak and hole 3.365 and -1.161 e.Å-3
Table B.31 Bond lengths [Å] and angles [°] for compound 37.
Bi(1)-C(1) 2.287(4)
Bi(1)-C(12) 2.266(5)
Bi(1)-C(15) 2.221(5)
S(1)-O(1) 1.450(3)
S(1)-O(2) 1.443(3)
S(1)-C(6) 1.761(5)
S(1)-C(7) 1.764(5)
O(3)-C(3) 1.360(6)
O(3)-C(13) 1.430(6)
O(4)-C(10) 1.362(5)
O(4)-C(14) 1.431(6)
C(1)-C(2) 1.382(7)
C(1)-C(6) 1.399(6)
C(2)-H(2) 0.9500
C(2)-C(3) 1.401(7)
C(3)-C(4) 1.395(7)
C(4)-H(4) 0.9500
C(4)-C(5) 1.386(7)
C(5)-H(5) 0.9500
C(5)-C(6) 1.389(7)
C(7)-C(8) 1.385(6)
332
C(7)-C(12) 1.397(6)
C(8)-H(8) 0.9500
C(8)-C(9) 1.384(7)
C(9)-H(9) 0.9500
C(9)-C(10) 1.390(7)
C(10)-C(11) 1.398(6)
C(11)-H(11) 0.9500
C(11)-C(12) 1.400(6)
C(13)-H(13A) 0.9800
C(13)-H(13B) 0.9800
C(13)-H(13C) 0.9800
C(14)-H(14A) 0.9800
C(14)-H(14B) 0.9800
C(14)-H(14C) 0.9800
C(15)-C(16) 1.153(6)
C(16)-C(17) 1.478(7)
C(17)-C(18) 1.398(7)
C(17)-C(22) 1.393(7)
C(18)-H(18) 0.9500
C(18)-C(19) 1.385(7)
C(19)-H(19) 0.9500
C(19)-C(20) 1.390(8)
C(20)-C(21) 1.399(8)
C(20)-C(23) 1.507(7)
C(21)-H(21) 0.9500
C(21)-C(22) 1.385(7)
C(22)-H(22) 0.9500
C(23)-H(23A) 0.9800
C(23)-H(23B) 0.9800
C(23)-H(23C) 0.9800
C(12)-Bi(1)-C(1) 85.38(16)
C(15)-Bi(1)-C(1) 87.64(16)
C(15)-Bi(1)-C(12) 89.16(17)
O(1)-S(1)-C(6) 107.4(2)
O(1)-S(1)-C(7) 106.9(2)
O(2)-S(1)-O(1) 119.0(2)
O(2)-S(1)-C(6) 109.6(2)
O(2)-S(1)-C(7) 109.7(2)
C(6)-S(1)-C(7) 103.0(2)
C(3)-O(3)-C(13) 118.3(4)
C(10)-O(4)-C(14) 118.4(4)
C(2)-C(1)-Bi(1) 122.9(3)
C(2)-C(1)-C(6) 117.9(4)
C(6)-C(1)-Bi(1) 118.7(3)
C(1)-C(2)-H(2) 119.7
C(1)-C(2)-C(3) 120.7(4)
C(3)-C(2)-H(2) 119.7
O(3)-C(3)-C(2) 115.2(4)
333
O(3)-C(3)-C(4) 124.2(4)
C(4)-C(3)-C(2) 120.5(5)
C(3)-C(4)-H(4) 120.4
C(5)-C(4)-C(3) 119.3(4)
C(5)-C(4)-H(4) 120.4
C(4)-C(5)-H(5) 120.3
C(4)-C(5)-C(6) 119.5(4)
C(6)-C(5)-H(5) 120.3
C(1)-C(6)-S(1) 116.9(4)
C(5)-C(6)-S(1) 120.8(4)
C(5)-C(6)-C(1) 122.1(4)
C(8)-C(7)-S(1) 121.3(3)
C(8)-C(7)-C(12) 121.9(4)
C(12)-C(7)-S(1) 116.6(3)
C(7)-C(8)-H(8) 120.5
C(9)-C(8)-C(7) 119.0(4)
C(9)-C(8)-H(8) 120.5
C(8)-C(9)-H(9) 120.0
C(8)-C(9)-C(10) 120.1(4)
C(10)-C(9)-H(9) 120.0
O(4)-C(10)-C(9) 115.6(4)
O(4)-C(10)-C(11) 123.4(4)
C(9)-C(10)-C(11) 121.0(4)
C(10)-C(11)-H(11) 120.4
C(10)-C(11)-C(12) 119.2(4)
C(12)-C(11)-H(11) 120.4
C(7)-C(12)-Bi(1) 119.4(3)
C(7)-C(12)-C(11) 118.8(4)
C(11)-C(12)-Bi(1) 121.5(3)
O(3)-C(13)-H(13A) 109.5
O(3)-C(13)-H(13B) 109.5
O(3)-C(13)-H(13C) 109.5
H(13A)-C(13)-H(13B) 109.5
H(13A)-C(13)-H(13C) 109.5
H(13B)-C(13)-H(13C) 109.5
O(4)-C(14)-H(14A) 109.5
O(4)-C(14)-H(14B) 109.5
O(4)-C(14)-H(14C) 109.5
H(14A)-C(14)-H(14B) 109.5
H(14A)-C(14)-H(14C) 109.5
H(14B)-C(14)-H(14C) 109.5
C(16)-C(15)-Bi(1) 168.9(4)
C(15)-C(16)-C(17) 172.4(5)
C(18)-C(17)-C(16) 121.7(4)
C(22)-C(17)-C(16) 119.2(4)
C(22)-C(17)-C(18) 119.0(5)
C(17)-C(18)-H(18) 119.8
C(19)-C(18)-C(17) 120.4(5)
C(19)-C(18)-H(18) 119.8
334
C(18)-C(19)-H(19) 119.5
C(18)-C(19)-C(20) 120.9(5)
C(20)-C(19)-H(19) 119.5
C(19)-C(20)-C(21) 118.3(5)
C(19)-C(20)-C(23) 121.3(5)
C(21)-C(20)-C(23) 120.4(5)
C(20)-C(21)-H(21) 119.4
C(22)-C(21)-C(20) 121.2(5)
C(22)-C(21)-H(21) 119.4
C(17)-C(22)-H(22) 119.9
C(21)-C(22)-C(17) 120.1(5)
C(21)-C(22)-H(22) 119.9
C(20)-C(23)-H(23A) 109.5
C(20)-C(23)-H(23B) 109.5
C(20)-C(23)-H(23C) 109.5
H(23A)-C(23)-H(23B) 109.5
H(23A)-C(23)-H(23C) 109.5
H(23B)-C(23)-H(23C) 109.5
335
B.5
1
H,
13
C AND
19
F NMR SPECTRA
336
337
338
339
340
341
342
343
344
345
346
347
348
349
350
351
352
353
354
355
356
357
358
359
360
361
362
363
364
365
366
367
368
369
370
371
372
373
374
375
376
377
378
379
380
381
382
B.6 REFERENCES
(1) Kwong, F. Y .; Buchwald, S. L., A General, Efficient, and Inexpensive Catalyst System for
the Coupling of Aryl Iodides and Thiols. Org. Lett. 2002, 4 (20), 3517-3520.
(2) Bahekar, S. S.; Sarkate, A. P.; Wadhai, V . M.; Wakte, P. S.; Shinde, D. B., CuI catalyzed
CS bond formation by using nitroarenes. Catal. Commun. 2013, 41, 123-125.
(3) Sikari, R.; Sinha, S.; Das, S.; Saha, A.; Chakraborty, G.; Mondal, R.; Paul, N. D.,
Achieving Nickel Catalyzed C–S Cross-Coupling under Mild Conditions Using Metal–Ligand
Cooperativity. J. Org. Chem. 2019, 84 (7), 4072-4085.
(4) Thomas, J.; Van Hecke, K.; Robeyns, K.; Van Rossom, W.; Sonawane, M. P.; Van
Meervelt, L.; Smet, M.; Maes, W.; Dehaen, W., Homothiacalix[4]arenes: Synthetic Exploration
and Solid-State Structures. Chem. Eur. J. 2011, 17 (37), 10339-10349.
(5) Margraf, N.; Manolikakes, G., One-Pot Synthesis of Aryl Sulfones from Organometallic
Reagents and Iodonium Salts. J. Org. Chem. 2015, 80 (5), 2582-2600.
(6) Chang, Y .; Lee, H. H.; Kim, S. H.; Jo, T. S.; Bae, C., Scope and Regioselectivity of
Iridium-Catalyzed C–H Borylation of Aromatic Main-Chain Polymers. Macromolecules 2013, 46
(5), 1754-1764.
(7) Suzuki, H.; Murafuji, T.; Azuma, N., Synthesis and reactions of some new heterocyclic
bismuth-(III) and -(V) compounds. 5,10-Dihydrodibenzo[b,e]bismine and related systems. J.
Chem. Soc., Perkin Trans. 1 1992, (13).
(8) Worrell Brady, T.; Ellery Shelby, P.; Fokin Valery, V ., Copper(I)‐Catalyzed Cycloaddition
of Bismuth(III) Acetylides with Organic Azides: Synthesis of Stable Triazole Anion Equivalents.
Angew. Chem. Int. Ed. 2013, 52 (49), 13037-13041.
(9) Worrell, B. T.; Ellery, S. P.; Fokin, V . V ., Copper(I)-Catalyzed Cycloaddition of
Bismuth(III) Acetylides with Organic Azides: Synthesis of Stable Triazole Anion Equivalents.
Angew. Chem. Int. Ed. 2013, 52 (49), 13037-13041.
383
Appendix C ADDITIONAL INFORMATION ON CHAPTER IV
C.1 SYNTHESIS AND CHARACTERIZATION
General Information
All reactions were carried out in capped 5 ml screw cap vials, unless otherwise stated. LCMS-
grade water and methanol were purchased from sigma-Aldrich and used as received. Diethyl ether
(Et2O), ethyl acetate (EtOAc) and methylene chloride (CH2Cl2) were obtained from Fischer
Scientific and used without further purification. Organic azides and other azo derivatives were in
part obtained with the highest possible purity from Sigma-Aldrich or synthesized following
literature procedures and analyzed for purity before use. Aliquat 336 (Starks' catalyst) was
purchased from Alfa Aesar. Anhydrous potassium carbonate and ethylene glycol were purchased
from Fischer Scientific. 1,2-dibromoethane-1-sulfonyl fluoride(DBESF) and 1-bromoethane-1-
sulfonyl fluoride (BESF) were used while being prior synthesized following a literature
procedure.
1
Silica gel (230-400 mesh) was purchased from Merck. Reactions were monitored by
either thin‐layer chromatography (TLC), carried out on 0.25 mm E. Merck silica gel plates (60F‐
254) using UV pale as visualizing agent, or on Agilent LC/MSD and Agilent HPLC/DAD
instruments. E. Merck silica gel (60, particle size 0.040–0.063 mm) was used for flash column
chromatography. NMR spectra were recorded on Varian Mercury 400, Varian VNMRS 500 and
Varian VNMRS 600 spectrometer. Chemical shifts were referenced to residual signals in the
deuterated solvent (Chloroform-d: δH = 7.26 ppm, δC = 77.16 ppm) as an internal reference.
19
F
NMR spectra were externally referenced to 80% CFCl3 in chloroform-d. The following
abbreviations were used to describe NMR signal multiplicities: s = singlet, d = doublet, t = triplet,
q = quartet, quin = quintet, m = multiplet, b = broad. . Infrared spectra were recorded in the range
4000-400 cm
-1
on Bruker Alpha or Agilent Cary 630 FT-IR spectrometer using a diamond ATR
384
unit. IR intensities are described as vw (very weak), w (weak), m (medium), s (strong), vs (very
strong). Yields refer to chromatographically and spectroscopically (
1
H NMR) pure materials,
unless otherwise stated.
General Information for NMR kinetic experiments
Chloroform-d was purchased from Cambridge Isotope Laboratories, Inc., 1,4-dimethoxybenzene
was used an internal standard and purchased from Sigma-Aldrich. Kinetic experiments were
carried out in 5mm thin wall precision NMR tubes (7”, 600 MHz, 535-PP-7, Wilmad LabGlass).
All glassware was oven-dried (140 C) and purged by vacuum-N2 cycles in the antechamber of the
glovebox before use.
For manipulation of the NMR spectra and signal peak integration MestReNova (Version 9.0.0,
Mestrelab Research S.L.) was used. Spectra manipulations include a base line correction along f1
using Whittaker Smoother with automatically adjusted filter window and a smooth factor of 20000
unless otherwise is mentioned. Graphical analysis and interpretation of the processed experimental
data was done using the Origin 9.0 data analysis and graphing software package (OriginLab
Corporation). or Microsoft Excel 2016 software.
C.2 GENERAL PROCEDURE A - KINETIC
1
H NMR ALIQUOT STUDY
A 5ml glass vial equipped with a stir bar was charged with 1,2-dibromoethane-1-sulfonyl fluoride
DBESF (0.2 g, 0.71 mmol, 1.50 eq.), triethylamine (0.075 g, 1.5 eq.) and 1 ml of LC-MS graded
water. After 10 min of continuous stirring, (azidomethyl)benzene (0.50 mmol, 1.0 eq.) and
Aliquat®336 (0.03 g, 0.074 mmol, 0.15 eq.) were added. The mixture was immediately
continuously stirred. The stirring speed, the solvent media or the base loading were controlled
according the purpose of the experiment. Aliquots were periodically taken from the reaction
385
mixture, dissolved in a deuterated chloroform, dried over MgSO4 and analyzed by
1
H NMR
spectroscopy. For the kinetic profile of the reaction progress, the ratio of the integral of the
corresponding product and reference signals was plotted vs. time.
C.3 GENERAL PROCEDURE B - SYNTHESIS OF 1H-1,2,3-TRIAZOLE-4-
SULFONYL FLUORIDES FROM 1-BROMOETHENE-1-SULFONYL
FLUORIDE (BESF)
A 5ml glass vial equipped with a stir bar was charged with the corresponding azide (0.66 mmol,
1.0 eq.), 2 ml of LCMS-grade water, Aliquot@336 (0.06 mg, 0.15 mmol, 0.22 eq.) and 1-
bromovinyl sulfonylfluoride (BESF) (0.275 g, 1.45 mmol, 2.20eq.). The resulting mixture was
immediately agitated by vigorous stirring with the highest possible stirring speed (1400 rpm). After
12 hours of vigorous stirring (or after the formation of a brown viscous/solid precipitate was
observed), the mixture was extracted with 3х2 ml of ethyl acetate. The combined organic fractions
were dried over MgSO4 and ethyl acetate was evaporated in vacuo. The residue was purified by
silica column chromatography using hexane:ethyl acetate as an eluent (starting from 10:0 and
continuously decreasing to 8:2).
C.4 GENERAL PROCEDURE C - SYNTHESIS OF 1H-1,2,3-TRIAZOLE-4-
SULFONYL FLUORIDES FROM 1,2-DIBROMOETHANE-1-SULFONYL
FLUORIDE (DBESF)
A 5ml glass vial equipped with a stir bar was charged with 1,2-dibromoethane-1-sulfonyl fluoride
(DBESF) ((a) 0.200 g, 0.741 mmol, 1.50 eq. or (b) 0.254 g, 0.941 mmol, 2.0 eq. or (c) 0.507 g,
1.88 mmol, 4.0 eq.), 1 ml of LC-MS grade water and triethylamine ((a) 0.075 g, 1.5 eq. or (b)
0.095 g, 2.0 eq. or (c) 0.19 g, 4.0 eq.). After 10 min of vigorous stirring, azide ((a) 0.494 mmol,
1.0 eq. or (b),(c) 0.471 mmol, 1.0 eq.) and Aliquat®336 ((a) 0.030 g, 0.074 mmol, 0.15 eq. or (b),
386
(c) 0.050 g, 0.124 mmol, 0.26 eq.) were added. The mixture was immediately agitated by vigorous
stirring with the highest possible stirring speed (1400 rpm). After 8 hours (or after the formation
of brown precipitate was observed), the reaction mixture was extracted twice with 3х2 ml of ethyl
acetate. The combined organic fractions were dried over MgSO4 and the ethyl acetate was removed
in vacuo. The residue was purified by silica flash chromatography using hexane: dichloromethane
as an eluent (starting from 10:0 continuously decreasing to 8:2).
C.5 GENERAL PROCEDURE D - SYNTHESIS OF 5-(FLUOROSULFONYL)-1H-
PYRAZOLES FROM 1,2-DIBROMOETHENE-1-SULFONYL FLUORIDE
(DBESF)
A 5ml glass vial equipped with a stir bar was charged with 1,2-dibromoethane-1-sulfonyl fluoride
(DBESF) (0.367 g, 1.36 mmol, 1.0 eq.), 1 ml of LC-MS grade water and triethylamine (0.137 g,
1.0 eq.). After 10 min of continuous stirring the 1,3-dipole (0.87 mmol, 1.0 eq.) and Aliquat®336
(0.04 g, 0.10 mmol, 0.11 eq) were added. The mixture was immediately agitated by vigorous
stirring with the highest possible stirring speed (1400 rpm). After 4 hours (or after formation of
brown precipitate was observed), the reaction mixture was extracted twice with 3х2 ml of ethyl
acetate. The combined organic fractions were dried over MgSO4 and the ethyl acetate was removed
in vacuo. The residue was purified by silica column chromatography using hexane:ethyl acetate as
an eluent (starting from 10:0 continuously decreasing to 8:2).
C.6 GENERAL PROCEDURE E - SYNTHESIS OF 1H-PYRAZOLES AND
ISOXASOLES FROM ETHENESULFONYL FLUORIDE (ESF)
A 5ml glass vial equipped with a stir bar was charged with 1,3-dipole (1.36 mmol, 1.0 eq.), 1 ml
of LC-MS grade water, Aliquat®336 (0.04 g, 0.10 mmol, 0.075 eq.), ethenesulfonyl fluoride
(ESF) (0.164g, 1.50 mmol, 1.1 eq.). The mixture was immediately agitated by vigorous stirring
387
with the highest possible stirring speed (1400 rpm). After 4 hours, triethylamine (0.137 g, 1.0 eq.)
was added followed by 10 min of vigorous stirring. The reaction mixture was extracted with
3х2 ml of ethyl acetate. The combined organic fractions were dried over MgSO4 and ethyl acetate
was removed in vacuo. The oily residue was purified by silica flash chromatography using hexane:
ethyl acetate as an eluent (starting from 10:0 continuously decreasing to 8:2) to yield a solid as
product after the solvent was removed in vacuo.
C.7 GENERAL PROCEDURE F – DIELS-ALDER CYCLOADDITION WITH
ETHENESULFONYL FLUORIDE (ESF)
A 5ml glass vial equipped with a stir bar was charged with furan or quadricyclane (0.91 mmol,
1.0 eq.), 1 ml of LC-MS grade water, ethenesulfonyl fluoride (ESF) (0.2 g, 1.81 mmol, 2.0 eq.).
The mixture was immediately agitated by vigorous stirring with the highest possible stirring speed
(1400 rpm). After 1 hour the reaction mixture was extracted with 3х2 ml of ethyl acetate. The
combined organic fractions were dried over MgSO4 and ethyl acetate was removed in vacuo. The
oily residue was purified by silica flash chromatography using hexane to yield a solid as product
after the solvent was removed in vacuo.
388
C.8 PRODUCT SCOPE. SYNTHESIS AND CHARACTERIZATION
1-phenethyl-1H-1,2,3-triazole-4-sulfonyl fluoride. Synthesized from 1,2-dibromoethane-1-
sulfonyl fluoride (0.741 mmol, 0.200 g) and (2-azidoethyl)benzene (0.072 g, 0.494 mmol) using
procedure C, 95 %, 8 hours, colorless solid.
1
H NMR (500 MHz, Chloroform-d) δ 7.81 (s, 1H) 7.35 – 7.29 (m, 3H), 7.06 (d, J = 7.5 Hz, 2H),
4.73 (t, J = 7.0 Hz, 2H), 3.27 (t, J = 7.0 Hz, 2H).
13
C NMR (126 MHz, Chloroform-d) δ 139.71 (d, J = 36.7 Hz), 135.59, 129.20, 128.53, 128.40 (d,
J = 3.0 Hz), 127.78, 77.26, 77.00, 76.75, 52.90, 36.31.
19
F NMR (470 MHz, Chloroform-d) δ 66.48.
1-(4-methylbenzyl)-1H-1,2,3-triazole-4-sulfonyl fluoride. Synthesized from 1,2-
dibromoethane-1-sulfonyl fluoride (0.741 mmol, 0.200 g) and 1-(azidomethyl)-4-methylbenzene
(0.073 g, 0.494 mmol) using procedure C, 41 %, 8 hours, colorless solid.
1
H NMR (500 MHz, Chloroform-d) δ 8.04 (s, 1H), 7.27 – 7.21 (m, 4H), 5.59 (s, 2H), 2.39 (s,
3H).
13
C NMR (126 MHz, Chloroform-d) δ 140.24, 130.52, 128.84, 127.98 (d, J = 2.6 Hz), 55.33,
21.38.
19
F NMR (470 MHz, Chloroform-d) δ 66.32.
389
1-benzyl-1H-1,2,3-triazole-4-sulfonyl fluoride. Synthesized from 1,2-dibromoethane-1-sulfonyl
fluoride (0.741 mmol, 0.200 g) and (azidomethyl)benzene (0.066 g, 0.494 mmol) using procedure
C, 80 %, 8 hours, colorless solid.
1
H NMR (500 MHz, Chloroform-d) δ 8.09 (s, 1H), 7.47 – 7.43 (m, 3H), 7.36 – 7.32 (m, 2H),
5.64 (s, 2H).
13
C NMR (126 MHz, Chloroform-d) δ 135.93 (d, J = 39.6 Hz), 132.40, 130.01, 129.84, 128.77,
128.12 (d, J = 3.1 Hz)., 55.50.
19
F NMR (470 MHz, Chloroform-d) δ 66.35.
1-(4-iodophenyl)-1H-1,2,3-triazole-4-sulfonyl fluoride. Synthesized from 1,2-dibromoethane-
1-sulfonyl fluoride (0.741 mmol, 0.200 g) and 1-azido-4-iodobenzene (0.121 g, 0.494 mmol)
using procedure C, 67 %, 8 hours, off-white solid.
1
H NMR (500 MHz, Chloroform-d) δ 8.65 (s, 1H), 7.96 (d, J = 8.6 Hz, 2H), 7.52 (d, J = 8.7 Hz,
2H).
13
C NMR (126 MHz, Chloroform-d) δ 141.27 (d, J = 37.5 Hz), 139.62, 135.26, 126.32 (d, J = 3.1
Hz), 122.66, 96.30, 77.41, 77.16, 76.91.
19
F NMR (470 MHz, Chloroform-d) δ 66.67.
390
1-(4-bromophenyl)-1H-1,2,3-triazole-4-sulfonyl fluoride. Synthesized from 1,2-
dibromoethane-1-sulfonyl fluoride (0.941 mmol, 0.254 g) and 1-azido-4-bromobenzene (0.093 g,
0.470 mmol) using procedure C, 51 %, 8 hours, off-white solid.
1
H NMR (500 MHz, Chloroform-d) δ 8.65 (s, 1H), 7.76 (d, J = 8.9 Hz, 2H), 7.66 (d, J = 8.9 Hz,
2H).
13
C NMR (126 MHz, Chloroform-d) δ 141.30 (d, J = 37.6 Hz), 134.59, 133.69, 126.39 (d, J = 2.6
Hz), 124.91, 122.66, 77.41, 77.16, 76.91.
19
F NMR (470 MHz, Chloroform-d) δ 66.37.
1-(4-chlorophenyl)-1H-1,2,3-triazole-4-sulfonyl fluoride. Synthesized from 1,2-
dibromoethane-1-sulfonyl fluoride (0.941 mmol, 0.254 g) and 1-azido-4-chlorobenzene (0.070 g,
0.470 mmol) using procedure C, 33 %, 8 hours, colorless solid.
1
H NMR (600 MHz, Chloroform-d) δ 8.63 (s, 1H), 7.73 (d, J = 8.9 Hz, 2H), 7.60 (d, J = 8.8 Hz,
2H).
13
C NMR (151 MHz, Chloroform-d) δ 141.30 (d, J = 37.8 Hz), 136.98, 134.10, 130.71, 126.42
(d, J = 2.7 Hz), 122.49, 77.37, 77.16, 76.95.
19
F NMR (564 MHz, Chloroform-d) δ 66.62.
1-(3,4-dimethoxyphenyl)-1H-1,2,3-triazole-4-sulfonyl fluoride. Synthesized from 1,2-
dibromoethane-1-sulfonyl fluoride (0.741 mmol, 0.200 g) and 4-azido-1,2-dimethoxybenzene
(0.086 g, 0.494 mmol) using procedure C, 65 %, 8 hours, colorless solid.
1
H NMR (500 MHz, Chloroform-d) δ 8.60 (s, 1H) 7.31 (d, J = 2.4 Hz 1H), 7.22 (dd, J = 8.6, 2.4
Hz, 1H), 7.00 (d, J = 8.6 Hz, 1H), 3.97 (s, 3H), 3.96 (s, 3H).
391
13
C NMR (126 MHz, Chloroform-d) δ 150.93, 150.26, 140.64 (d, J = 37.1 Hz), 128.92, 126.62
(d, J = 2.8 Hz), 113.44, 111.46, 105.29, 56.51, 56.42.
19
F NMR (470 MHz, Chloroform-d) δ 66.63.
1-(4-methoxyphenyl)-1H-1,2,3-triazole-4-sulfonyl fluoride. Synthesized from 1,2-
dibromoethane-1-sulfonyl fluoride (0.741 mmol, 0.200 g) and 1-azido-4-methoxybenzene
(0.074 g, 0.494 mmol) using procedure C, 85 %, 8 hours, colorless solid.
1
H NMR (500 MHz, Chloroform-d) δ 8.60 (s, 1H), 7.65 (d, J = 9.1 Hz, 2H), 7.07 (d, J = 9.1 Hz,
2H), 3.89 (s, 3H)
13
C NMR (126 MHz, Chloroform-d) δ 161.27, 140.55 (d, J = 36.9 Hz), 128.79, 126.58 (d, J = 2.8
Hz), 122.91, 115.36, 55.89.
19
F NMR (470 MHz, Chloroform-d) δ 66.65.
1-(2-methoxyphenyl)-1H-1,2,3-triazole-4-sulfonyl fluoride. Synthesized from 1,2-
dibromoethane-1-sulfonyl fluoride (0.741 mmol, 0.200 g) and 1-azido-2-methoxybenzene
(0.073 g, 0.494 mmol) using procedure C, 83 %, 8 hours, colorless solid.
1
H NMR (600 MHz, Chloroform-d) δ 8.85 (s, 1H), 7.86 (dd, J = 7.7, 1.7 Hz, 1H), 7.53 (td, J =
7.8, 1.6 Hz, 1H), 7.20 – 7.14 (m, 2H), 3.97 (s, 3H).
13
C NMR (151 MHz, Chloroform-d) δ 150.83, δ 139.77 (d, J = 36.4 Hz), 131.81, 130.31 (d, J =
2.8 Hz), 125.29, 124.68, 121.69, 112.64, 77.37, 77.16, 76.95, 56.37.
19
F NMR (564 MHz, Chloroform-d) δ 66.58.
392
1-(3-methoxybenzyl)-1H-1,2,3-triazole-4-sulfonyl fluoride. Synthesized from 1,2-
dibromoethane-1-sulfonyl fluoride (0.741 mmol, 0.200 g) and 1-(azidomethyl)-3-
methoxybenzene (0.081 g, 0.494 mmol) using procedure C, 73 %, 8 hours, colorless solid.
1
H NMR (500 MHz, Chloroform-d) δ 8.12 (s, 1H), 7.36 (t, J = 8.0 Hz, 1H), 6.97 (d, J = 8.4 Hz,
1H), 6.91 (d, J = 7.6 Hz, 1H), 6.90 (s, 1H), 5.59 (s, 2H), 3.82 (s, 3H).
13
C NMR (126 MHz, Chloroform-d) δ 160.57, 140.47 (d, J = 36.8 Hz), 133.73, 130.96, 128.20
(d, J = 2.9 Hz), 120.82, 115.18, 114.56, 55.54, 55.42.
19
F NMR (470 MHz, Chloroform-d) δ 66.38.
1-(p-tolyl)-1H-1,2,3-triazole-4-sulfonyl fluoride. Synthesized from 1,2-dibromoethane-1-
sulfonyl fluoride (0.741 mmol, 0.200 g) and 1-azido-4-methylbenzene (0.066 g, 0.494 mmol)
using procedure C, 82%, 8 hours, colorless solid.
1
H NMR (500 MHz, Chloroform-d) δ 8.74 (s, 1H), 8.21 (d, J = 8.6 Hz, 2H), 7.92 (d, J = 8.3 Hz,
2H), 2.69 (s, 3H).
13
C NMR (126 MHz, Chloroform-d) δ 196.24, 141.50 (d, J = 37.7 Hz), 138.60, 138.55, 130.58,
126.45 (d, J = 3.1 Hz), 121.09, 26.91.
19
F NMR (470 MHz, Chloroform-d) δ 66.68.
393
1-(4-(azidomethyl)benzyl)-1H-1,2,3-triazole-4-sulfonyl fluoride. Synthesized from 1,2-
dibromoethane-1-sulfonyl fluoride (0.941 mmol, 0.254 g) and 1,4-bis(azidomethyl)benzene
(0.088 g, 0.470 mmol) using procedure C, 31 %, 8 hours, colorless solid.
1
H NMR (500 MHz, Chloroform-d) δ 8.17 (s, 1H), 7.49 – 7.44 (m, 2H), 7.41 (d, J = 6.9 Hz, 1H),
7.35 (d, J = 7.0 Hz, 1H), 5.75 (s, 2H), 4.46 (s, 2H).
13
C NMR (126 MHz, Chloroform-d) δ 140.44 (d, J = 36.9 Hz), 134.36, 131.42, 131.22, 130.89,
130.57, 130.14, 128.46 (d, J = 3.1 Hz), 77.41, 77.16, 76.91, 52.71, 52.36.
19
F NMR (470 MHz, Chloroform-d) δ 66.14.
1-(4-((4-(fluorosulfonyl)-1H-1,2,3-triazol-1-yl)methyl)benzyl)-1H-1,2,3-triazole-4-sulfonyl
fluoride. Synthesized from 1,2-dibromoethane-1-sulfonyl fluoride (1.882 mmol, 0.508 g) and 1,4-
bis(azidomethyl)benzene (0.088 g, 0.470 mmol) using procedure C, 55 %, 8 hours, colorless solid.
1
H NMR (600 MHz, DMSO -d6) δ 9.39 (s, 1H), 7.38 (d, J = 10.0 Hz, 1H), 5.97 (s, 2H).
13
C NMR (151 MHz, DMSO -d6) δ 138.28 (d, J = 35.9 Hz)., 132.54, 130.94, 130.16, 129.40,
78.42, 51.01, 39.52.
19
F NMR (564 MHz, DMSO -d6) δ 67.22.
394
1-(naphthalen-2-ylmethyl)-1H-1,2,3-triazole-4-sulfonyl fluoride. Synthesized from 1,2-
dibromoethane-1-sulfonyl fluoride (0.941 mmol, 0.254 g) and 2-(azidomethyl)naphthalene
(0.086 g, 0.470 mmol) using procedure C, 65 %, 8 hours, colorless oil.
1
H NMR (500 MHz, Chloroform-d) δ 8.01 (s, 1H), 7.99 (d, J = 8.2 Hz, 1H), 7.96 – 7.86 (m, 1H),
7.60 – 7.55 (m, 1H), 7.53 (td, J = 8.0, 6.9, 1.8 Hz, 4H), 6.08 (s, 2H).
13
C NMR (126 MHz, Chloroform-d) δ 140.09 (d, J = 36.5 Hz), 134.15, 131.19, 130.92, 129.38,
129.08, 128.34 (d, J = 3.2 Hz), 127.98, 127.70, 126.88, 125.56, 122.32, 77.41, 77.16, 76.91,
53.34.
19
F NMR (470 MHz, Chloroform-d) δ 66.18.
1-(3-(4-formylphenoxy)propyl)-1H-1,2,3-triazole-4-sulfonyl fluoride. Synthesized from 1,2-
dibromoethane-1-sulfonyl fluoride (0.741 mmol, 0.200 g) and 4-(3-azidopropoxy)benzaldehyde
(0.101 g, 0.494 mmol) using procedure C, 33%, 8 hours, colorless solid.
1
H NMR (500 MHz, Chloroform-d) δ 9.88 (s, 1H), 8.34 (s, 1H), 7.83 (d, J = 8.1 Hz, 2H), 6.96 (d,
J = 8.7 Hz, 2H), 4.76 (t, J = 6.9 Hz, 2H), 4.14 (t, J = 5.5 Hz, 2H), 2.54 (p, J = 6.4 Hz, 2H).
13
C NMR (126 MHz, Chloroform-d) δ 190.83, 163.03, 40.27 (d, J = 36.8 Hz), 132.20, 130.68,
128.83 (d, J = 2.9 Hz), 114.76, 64.42, 48.71, 29.55.
19
F NMR (470 MHz, Chloroform-d) δ 66.20.
395
1-(3-((1-methyl-2-oxo-1,2-dihydroquinolin-4-yl)oxy)propyl)-1H-1,2,3-triazole-4-sulfonyl
fluoride. Synthesized from 1,2-dibromoethane-1-sulfonyl fluoride (0.941 mmol, 0.254 g) and 4-
(3-azidopropoxy)-1-methylquinolin-2(1H)-one (0.121 g, 0.470 mmol) using procedure C, 37 %,
8 hours, colorless solid.
1
H NMR (600 MHz, DMSO-d6) δ 9.58 (s, 1H), 7.69 (dd, J = 8.0, 1.6 Hz, 1H), 7.64 (td, J = 8.7,
7.2, 1.6 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.22 (t, J = 7.2 Hz, 1H), 6.02 (s, 1H), 4.79 (t, J = 6.7
Hz, 2H), 4.23 (t, J = 5.7 Hz, 2H), 3.55 (s, 3H), 2.51 (p, J = 6.2 Hz, 2H).
13
C NMR (151 MHz, DMSO-d6) δ 162.23, 160.66, 139.38, 137.77 (d, J = 34.7 Hz), 131.58 (d, J
= 2.8 Hz), 131.44, 122.55, 121.39, 115.35, 114.62, 96.85, 65.84, 39.52, 28.59, 28.33.
19
F NMR (564 MHz, DMSO-d6) δ 62.39.
2-(2-(4-(fluorosulfonyl)-1H-1,2,3-triazol-1-yl)ethoxy)ethyl 4-methylbenzenesulfonate.
Synthesized from 1,2-dibromoethane-1-sulfonyl fluoride (0.941 mmol, 0.254 g) and 2-(2-
azidoethoxy)ethyl 4-methylbenzenesulfonate (0.134 g, 0.470 mmol) using procedure C, 51 %, 8
hours, pale yellow oil.
1
H NMR (600 MHz, Chloroform-d) δ 8.41 (s, 1H), 7.78 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.0 Hz,
2H), 4.66 (t, J = 5.1, 4.4 Hz, 2H), 4.16 (t, J = 4.1 Hz, 2H), 3.88 (t, J = 4.5 Hz, 2H), 3.71 (t, J = 4.5
Hz, 2H), 2.45 (s, 3H).
13
C NMR (151 MHz, Chloroform-d) δ 145.41, 140.24 (d, J = 36.7 Hz), 132.93, 130.15, 129.82 (d,
J = 2.9 Hz), 127.98, 77.37, 77.16, 76.95, 69.08, 68.81, 68.67, 51.42, 21.78.
19
F NMR (564 MHz, Chloroform-d) δ 71.12.
396
1-cyclohexyl-1H-1,2,3-triazole-4-sulfonyl fluoride. Synthesized from 1,2-dibromoethane-1-
sulfonyl fluoride (0.741 mmol, 0.200 g) and azidocyclohexane (0.062 g, 0.494 mmol) using
procedure C, 63 %, 8 hours, colorless solid.
1
H NMR (500 MHz, Chloroform-d) δ 8.28 (s, 1H), 4.57 (tt, J = 11.8, 3.9 Hz, 1H), 2.28 (d, J =
11.2 Hz, 2H), 1.97 (dt, J = 14.0, 2.9 Hz, 2H), 1.79 (qd, J = 12.4, 3.7 Hz, 3H), 1.50 (qt, J = 12.8,
3.4 Hz, 2H), 1.31 (qt, J = 12.9, 3.7 Hz, 1H).
13
C NMR (126 MHz, Chloroform-d) δ 139.59 (d, J = 36.2 Hz), 126.47 (d, J = 2.8 Hz), 61.79,
33.38, 24.98, 24.89.
19
F NMR (470 MHz, Chloroform-d) δ 66.32.
1-((3s,5s,7s)-adamantan-1-yl)-1H-1,2,3-triazole-4-sulfonyl fluoride. Synthesized from 1,2-
dibromoethane-1-sulfonyl fluoride (0.941 mmol, 0.254 g) and (3s,5s,7s)-1-azidoadamantane
(0.083 g, 0.470 mmol) using procedure C, 90 %, 8 hours, colorless solid.
1
H NMR (500 MHz, Chloroform-d) δ 8.27 (s, 1H), 2.33 (s, 3H), 2.28 (s, 6H), 1.83 (dd, J = 13.1
Hz, 6H).
13
C NMR (126 MHz, Chloroform-d) δ 139.32 (d, J = 35.9 Hz), 125.25 (d, J = 2.6 Hz), 62.44,
42.94, 35.69, 29.51.
19
F NMR (470 MHz, Chloroform-d) δ 66.02.
397
1-(((1R,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)methyl)-1H-1,2,3-triazole-4-sulfonyl
fluoride. Synthesized from 1,2-dibromoethane-1-sulfonyl fluoride (0.941 mmol, 0.254 g) and
(1R,5S)-2-(azidomethyl)-6,6-dimethylbicyclo[3.1.1]hept-2-ene (0.070 g, 0.470 mmol) using
procedure C, 33 %, 8 hours, colorless oil.
1
H NMR (600 MHz, Chloroform-d) δ 8.23 (s, 1H), 5.73 – 5.71 (m, 1H), 4.98 (s, 2H), 2.41 (dt, J
= 8.9, 5.7 Hz, 1H), 2.39 – 2.27 (m, 3H), 2.12 (ttd, J = 5.8, 2.8, 1.2 Hz, 1H), 2.02 (td, J = 5.6, 1.7
Hz, 1H), 1.23 (s, 3H), 1.12 (d, J = 8.9 Hz, 1H), 0.72 (s, 3H).
13
C NMR (151 MHz, Chloroform-d) δ 140.53, δ 140.13 (d, J = 36.4 Hz), 128.18 (d, J = 2.9 Hz),
125.54, 77.37, 77.16, 76.95, 56.50, 43.61, 40.33, 38.18, 31.70, 31.40, 25.85, 20.98.
δ 140.13 (d, J = 36.4 Hz), 128.18 (d, J = 2.9 Hz).
19
F NMR (564 MHz, Chloroform-d) δ 66.43.
1-(5-(4-(fluorosulfonyl)-1H-1,2,3-triazol-1-yl)pentyl)-1H-1,2,3-triazole-4-sulfonyl fluoride.
Synthesized from 1,2-dibromoethane-1-sulfonyl fluoride (1.882 mmol, 0.508 g) and 1,5-
diazidopentane (0.072 g, 0.470 mmol) using procedure C, 71 %, 8 hours, colorless solid.
1
H NMR (600 MHz, Chloroform-d) δ 8.24 (s, 2H), 4.50 (t, J = 7.1 Hz, 4H), 2.02 (p, J = 7.8 Hz,
4H), 1.44 (p, J = 3.6 Hz, 4H).
13
C NMR (151 MHz, Chloroform-d) δ 140.50 (d, J = 37.0 Hz), 128.13 (d, J = 1.9 Hz), 77.37,
77.16, 76.95, 51.34, 29.86, 25.79.
19
F NMR (564 MHz, Chloroform-d) δ 66.33.
398
1-(2-((1s,4s)-4-(4-(fluorosulfonyl)-1H-1,2,3-triazol-1-yl)-4-methylcyclohexyl)propan-2-yl)-
1H-1,2,3-triazole-4-sulfonyl fluoride. Synthesized from 1,2-dibromoethane-1-sulfonyl fluoride
(1.882 mmol, 0.508 g) and (1s,4s)-1-azido-4-(2-azidopropan-2-yl)-1-methylcyclohexane
(0.105 g, 0.470 mmol) using procedure C, 50 %, 8 hours, colorless solid.
1
H NMR (600 MHz, DMSO-D6-d6) δ 9.62 (s, 1H), 9.47 (s, 1H), 2.72 (d, J = 14.5 Hz, 2H), 2.08
(dd, J = 12.2, 9.7 Hz, 2H), 1.80 (td, J = 14.0, 3.6 Hz, 6H), 1.56 (s, 3H), 1.43 (s, 2H), 1.29 (d, J =
13.4 Hz, 2H), 0.83 (q, J = 13.2 Hz, 2H).
13
C NMR (151 MHz, DMSO-d6) δ 138.80 (d, J = 34.4 Hz), 137.98 (d, J = 34.4 Hz), 130.34 (d, J
= 1.7 Hz), 130.26 (d, J = 1.6 Hz), 67.76, 64.36, 46.19, 45.42, 40.39, 40.25, 40.11, 39.97, 39.83,
39.69, 39.56, 35.62, 35.37, 31.72, 31.53, 24.48, 22.38.
19
F NMR (564 MHz, DMSO-d6) δ 67.34, 67.33.
399
(1S,2S,4S)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonyl fluoride. Synthesized from ethenesulfonyl
fluoride (1.81 mmol, 0.20 g) and furan (0.062 g, 0.910 mmol) using procedure F (Rf = 0.89 in
hexane:EtOAc = 9:1), 64 %, 8 hours, colorless oil.
1
H NMR (500 MHz, Chloroform-d) δ 6.57 (s, 1H), 6.45 – 6.41 (m, 1H), 5.45 (s, 1H), 5.26 (s,
1H), 3.43 – 3.34 (m, 1H), 2.38 – 2.32 (m, 1H), 1.91 (dd, J = 12.5, 8.3 Hz, 1H).
13
C NMR (126 MHz, Chloroform-d) δ 139.09, 133.70, 79.47, 78.21, 77.41, 77.16, 76.91, 60.09
(d, J = 13.0 Hz), 28.71.
19
F NMR (470 MHz, Chloroform-d) δ 50.92.
(1S,2R,4S)-7-oxabicyclo[2.2.1]hept-5-ene-2-sulfonyl fluoride. Synthesized from ethenesulfonyl
fluoride (1.81 mmol, 0.20 g) and furan (0.062 g, 0.910 mmol) using procedure F (Rf = 0.51 in
hexane:EtOAc = 9:1), 20 %, 8 hours, colorless oil.
1
H NMR (500 MHz, Chloroform-d) δ 6.62 (d, J = 5.8 Hz, 1H), 6.41 (d, J = 5.7 Hz, 1H), 5.33 (s,
1H), 5.19 (s, 1H), 4.06 – 3.95 (m, 1H), 2.52 – 2.36 (m, 1H), 1.79 – 1.67 (m, 1H).
13
C NMR (126 MHz, Chloroform-d) δ 138.52, 131.33, 79.64, 78.27, 58.43 (d, J = 12.8 Hz),
29.25.
19
F NMR (470 MHz, Chloroform-d) δ 57.74.
400
ethyl 1H-pyrazole-3-carboxylate. Synthesized from ethenesulfonyl fluoride (1.50 mmol,
0.164 g) and ethyl 2-diazoacetate (0.070 g, 1.36 mmol) using procedure E, 87 %, 1 hour, pale
yellow oil.
1
H NMR (600 MHz, Chloroform-d) δ 13.21 (s, 1H), 7.78 (d, J = 2.2 Hz, 1H), 6.84 (d, J = 2.2 Hz,
1H), 4.41 (q, J = 7.1 Hz, 2H), 1.40 (t, J = 7.2 Hz, 3H).
13
C NMR (151 MHz, Chloroform-d) δ 162.11, 141.68, 132.88, 107.98, 77.37, 77.16, 76.95,
61.13, 14.53.
2-(3-cyano-1H-pyrazol-1-yl)ethane-1-sulfonyl fluoride. Synthesized from ethenesulfonyl
fluoride (0.941 mmol, 0.254 g) and 2-diazoacetonitrile (0.070 g, 0.470 mmol) and addition of
2 eq.of triethylamine 10 min prior the end of the reaction, using procedure E (reactants loading
was changed), 18%, 8 hours, colorless powder.
1
H NMR (500 MHz, Chloroform-d) δ 7.68 (s, 1H), 6.86 (s, 1H), 4.84 (t, J = 6.6 Hz, 2H), 4.06 (q,
J = 6.2, 5.6 Hz, 2H).
13
C NMR (126 MHz, Chloroform-d) δ 141.04, 115.86, 114.55, 109.89, 77.41, 77.16, 76.91, 49.74
(d, J = 18.9 Hz), 44.98.
19
F NMR (470 MHz, Chloroform-d) δ 56.82.
401
3-(4-chlorophenyl)isoxazole. Synthesized from ethenesulfonyl fluoride (1.50 mmol, 0.164 g) and
(Z)-4-chloro-N-hydroxybenzimidoyl chloride (0.258 g, 1.36 mmol) using procedure E, 61 %,
1 hour, colorless solid.
1
H NMR (600 MHz, Chloroform-d) δ 8.47 (s, 1H), 7.70 (d, J = 8.6 Hz, 2H), 7.45 (d, J = 8.5 Hz,
2H), 6.57 (s, 1H).
13
C NMR (151 MHz, Chloroform-d) δ 163.40, 142.27, 136.86, 129.53, 128.12, 126.65, 104.47.
ethyl 5-(fluorosulfonyl)-1H-pyrazole-3-carboxylate. Synthesized from 1,2-dibromoethane-1-
sulfonyl fluoride (1.36 mmol, 0.367 g) and ethyl 2-diazoacetate (0.100 g, 0.870 mmol) using
procedure D, 55.0 %, 1 hour, colorless solid.
1
H NMR (600 MHz, Chloroform-d) δ 12.04 (s, 1H), 7.42 (s, 1H), 4.48 (q, J = 7.2 Hz, 2H), 1.43
(t, J = 7.2 Hz, 3H).
13
C NMR (151 MHz, Chloroform-d) δ 158.05, 145.66 (d, J = 35.3 Hz), 136.50, 111.29, 77.37,
77.16, 76.95, 63.09, 14.26.
19
F NMR (564 MHz, Chloroform-d) δ 65.12.
402
5-bromo-3-(4-chlorophenyl)isoxazole. Synthesized from 1,2-dibromoethane-1-sulfonyl fluoride
(1.36 mmol, 0.367 g) and (Z)-4-chloro-N-hydroxybenzimidoyl chloride (0.165 g, 0.870 mmol)
using procedure D, 41 %, 1 hour, colorless solid.
1
H NMR (600 MHz, Chloroform-d) δ 7.70 (d, J = 8.6 Hz, 2H), 7.45 (d, J = 8.5 Hz, 2H), 6.57 (s,
1H).
13
C NMR (151 MHz, Chloroform-d) δ 163.40, 142.27, 136.86, 129.53, 128.12, 126.65, 104.47,
77.37, 77.16, 76.95.
ethyl 1-(2-bromo-2-(fluorosulfonyl)ethyl)-1H-pyrazole-3-carboxylate. Synthesized from 1,2-
dibromoethane-1-sulfonyl fluoride (0.941 mmol, 0.254 g) and ethyl 2-diazoacetate (0.070 g,
0.470 mmol), using procedure D (reactants loading was changed), 18 %, 1 hour, pale yellow oil.
1
H NMR (600 MHz, Chloroform-d) δ 7.48 (s, 1H), 5.75 (ddd, J = 8.2, 6.0, 1.9 Hz, 1H), 5.61 (dd,
J = 14.4, 6.0 Hz, 1H), 5.41 (dd, J = 14.4, 8.5 Hz, 1H), 4.46 (q, J = 7.1 Hz, 2H), 1.43 (t, J = 7.1
Hz, 3H).
13
C NMR (151 MHz, Chloroform-d) δ 158.10, 144.39 (d, J = 36.4 Hz), 136.08, 114.18, 77.37,
77.16, 76.95, 63.31, 54.26 (d, J = 23.2 Hz), 53.46, 14.16.
19
F NMR (564 MHz, Chloroform-d) δ 65.29, 46.69.
403
ethyl (E)-1-(2-(fluorosulfonyl)vinyl)-1H-pyrazole-3-carboxylate. Synthesized from 1,2-
dibromoethane-1-sulfonyl fluoride (0.941 mmol, 0.254 g) and ethyl 2-diazoacetate (0.070 g,
0.470 mmol) and addition of 2 eq.of triethylamine 10 min prior the end of the reaction using
procedure D (reactants loading was changed), 15 %, 1 hour, pale yellow oil.
1
H NMR (600 MHz, Chloroform-d) δ 9.81 (s, 1H), 7.62 (s, 1H), 4.49 (q, J = 7.1 Hz, 2H), 1.44 (t,
J = 7.1 Hz, 3H).
13
C NMR (151 MHz, Chloroform-d) δ 157.25, 146.97 (d, J = 38.0 Hz), 137.42, 136.39, 115.02,
108.36 (d, J = 35.8 Hz), 77.37, 77.16, 76.95, 63.83, 14.18.
19
F NMR (564 MHz, Chloroform-d) δ 65.00, 53.64.
404
C.9
1
H,
13
C AND
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F NMR SPECTRA
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C.10 REFERENCES
(1) Thomas, J.; Fokin, V . V ., Regioselective Synthesis of Fluorosulfonyl 1,2,3-Triazoles from
Bromovinylsulfonyl Fluoride. Org. Lett. 2018, 20 (13), 3749-3752.
Abstract (if available)
Abstract
A better understanding of the fundamental transformations and processes in reaction profiles can help a scientist to improve a method or synthetic model without additional cost and effort. Results from the mechanistic investigations of existing transformations can improve the optimization or development of novel, more efficient techniques and protocols. In the current thesis, various kinetic studies were performed to gain insights into the iodo- and bismuth(III)-types of copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) transformations. A quantitative mechanistic model is outlined for the copper(I)-catalyzed azide-iodoalkyne cycloaddition reaction (ᴵCuAAC) by applying a mathematical system of statistics and data analysis. During the modeling part, two problems required to be solved in order to improve existing or new catalytic cycloadditions: 1) the evaluation of how electronic and steric properties of reactants affect the rate and selectivity of the triazole formation; and 2) the gaining of insight into the mechanism of the catalytic activation when employing the coordinative triazolyl(amine)ligands, tris-((1-tert-butyl-1H-1,2,3-triazolyl)methyl)amine, (TTTA), and tris-((1-cyclopentyl-1H-1,2,3-triazol-4-yl)methyl)amine, (TCPTA). Even though the mechanism of the copper(I)-catalyzed cycloaddition of iodoalkynes was proposed to proceed via two different reaction pathways, i.e., the cleavage of the carbon-iodine bond versus the formation of Cu(I)-iodoalkyne π-complex, much uncertainly remained about the rate-limiting step and the nature of the interactions of the catalyst with the iodoalkyne. For both catalytic systems, competitive reactions revealed that electron-withdrawing groups increase the rate of the 5-iodo-1,2,3-triazole formation, while electron donating groups slow down the reaction. The kinetic profiles for both the CuI-TTTA and the CuI-TCPTA catalytic systems were consistent with the hypothesis of the 1-iodo-2,3,4-triazoles formation following the general, linear, free-energy relationship trend with positive ρ values for both 1-iodo-alkyne- and azide-substrates. Computational protocols using extensive experimental data sets allowed an entire conversion-profiled kinetic elucidation and revealed fine differences between reaction regimes. While my study was in progress, similar results on iodine/hydrogen exchange in 1-iodo- and terminal alkynes were published by Hein et al. (ACS Catal., 2017) and Fokin, Hein, and co-workers (ACS Catal., 2018). The conclusions from their independent work regarding competitive kinetics are in good agreement with my results which are summarized below.
Mechanistic investigations were also performed for the copper(I)-catalyzed azide-bismuth(III) acetylide cycloaddition reaction, (ᴮⁱCuAAC). Similar to the iodo-alkyne CuAAC reaction, the rate-determining step was identified. However, the use of a set of different diphenyl sulfone bismuth(III) acetylides resulted not only in a conversion-dependent, rate-determining step, but also revealed a substrate-dependent relationship. Employing variable "excess" concentrations, the catalyst robustness, reaction rate orders as well as the independent substrate reactivity were studied either by spectroscopy or cyclic voltammetry. Based on X-ray crystallographic data for the synthesized bismuth(III)-acetylides, a correlation between the transannular O(1)···Bi(1) interaction and reactivity is indicated. The possibility to turn on the activity of such coupling substrates under copper(I)-catalytic conditions and the development of biocompatible synthetic protocols will be the subject of a separate study.
Throughout the kinetic studies, the question of a more detailed reaction rate-law elucidation for the complex catalytic reactions remained one of the key concerns. The analysis of intermittently taken sample aliquots showed that incomplete kinetic data produce either misleading results or restrict the process of parameter elucidation. However, more detailed kinetic studies were previously considered too tough and time-consuming. These two factors are a major concern for a chemist interested in kinetic and mechanistic computations. Programming software was developed for the analysis of detailed experimental data sets, obtained by variable instrumental techniques. ⧠During attempts to improve the signal to noise ratio in calorific and spectroscopic output data, the inverse problem in chemical kinetics was solved for the differential approach of heat flow calorimetry. Particularly, the importance of data smoothing was demonstrated when applying dynamic correction procedures.
Mechanistic studies were also performed for the on-water catalyzed synthesis of fluorosulfonyl-substituted 1,2,3-triazoles from dibromovinylsulfonyl building blocks (DBESF) and organic azides. DBESFs were also successfully employed for methodology development and procedure optimization for the synthesis of functionalized pyrazoles, isoxazoles, and Diels-Alder cycloaddition adducts.
Linked assets
University of Southern California Dissertations and Theses
Asset Metadata
Creator
Nazarova, Antonina L.
(author)
Core Title
Investigation of mechanisms of complex catalytic reactions from obtaining and analyzing experimental data to mechanistic modeling
School
College of Letters, Arts and Sciences
Degree
Doctor of Philosophy
Degree Program
Chemistry
Degree Conferral Date
2020-12
Publication Date
05/19/2022
Defense Date
04/20/2020
Publisher
University of Southern California. Libraries
(digital)
Tag
"on water" transformations,1,2,3-triazoles,1-iodoalkyne,bismuth(III) acetylide,catalytic model development,computational approaches for solving chemical kinetics,continuous reaction progress monitoring,copper(I)-catalyzed azide-alkyne cycloaddition reaction,cyclic voltammetry,fluorosulfonyl 1,gas chromatography-mass spectrometry (GS-MS),gradient descent algorithm,greed search algorithm,heat flow calorimetry,high performance liquid chromatography (HPLC),in-situ kinetic studies,inverse problem in chemical kinetics,kinetic nuclear magnetic resonance spectroscopy (NMR),kinetic studies of multistep processes,liquid chromatography-mass spectrometry (LS-MS),OAI-PMH Harvest,Open Multi-Processing interface,quantitative mechanistic model,rate parameters estimation,Runge-Kutta numerical method of analysis,signal to noise ratio,system of ordinary differential equations (ODEs),X-ray crystallography
Format
application/pdf
(imt)
Language
English
Contributor
Electronically uploaded by the author
(provenance)
Advisor
Fokin, Valery V. (
committee chair
), Nakano, Aiichiro (
committee member
), Prakash, G. K. Surya (
committee member
)
Creator Email
antonazarova@icloud.com,nazarova@usc.edu
Permanent Link (DOI)
https://doi.org/10.25549/usctheses-c89-397727
Unique identifier
UC11666486
Identifier
etd-NazarovaAn-9131.pdf (filename),usctheses-c89-397727 (legacy record id)
Legacy Identifier
etd-NazarovaAn-9131
Dmrecord
397727
Document Type
Dissertation
Format
application/pdf (imt)
Rights
Nazarova, Antonina L.
Internet Media Type
application/pdf
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 author, as the original true and official version of the work, but does not grant the reader permission to use the work if the desired use is covered by copyright. It is the author, as rights holder, who must provide use permission if such use is covered by copyright. The original signature page accompanying the original submission of the work to the USC Libraries is retained by the USC Libraries and a copy of it may be obtained by authorized requesters contacting the repository e-mail address given.
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
Repository Email
cisadmin@lib.usc.edu
Tags
"on water" transformations
1,2,3-triazoles
1-iodoalkyne
bismuth(III) acetylide
catalytic model development
computational approaches for solving chemical kinetics
continuous reaction progress monitoring
copper(I)-catalyzed azide-alkyne cycloaddition reaction
cyclic voltammetry
fluorosulfonyl 1
gas chromatography-mass spectrometry (GS-MS)
gradient descent algorithm
greed search algorithm
heat flow calorimetry
high performance liquid chromatography (HPLC)
in-situ kinetic studies
inverse problem in chemical kinetics
kinetic nuclear magnetic resonance spectroscopy (NMR)
kinetic studies of multistep processes
liquid chromatography-mass spectrometry (LS-MS)
Open Multi-Processing interface
quantitative mechanistic model
rate parameters estimation
Runge-Kutta numerical method of analysis
signal to noise ratio
system of ordinary differential equations (ODEs)
X-ray crystallography