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Catalytic applications of palladium-NHC complexes towards hydroamination and hydrogen-deuterium exchange and development of acid-catalyzed hydrogen-deuterium exchange methods for preparative deut...
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Catalytic applications of palladium-NHC complexes towards hydroamination and hydrogen-deuterium exchange and development of acid-catalyzed hydrogen-deuterium exchange methods for preparative deut...
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Content
CATALYTIC APPLICATIONS OF PALLADIUM-NHC COMPLEXES TOWARDS
HYDROAMINATION AND HYDROGEN-DEUTERIUM EXCHANGE AND
DEVELOPMENT OF ACID-CATALYZED HYDROGEN-DEUTERIUM EXCHANGE
METHODS FOR PREPARATIVE DEUTERATION AND CHEMICAL EDUCATION
by
Richard A. Giles
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 2015
Copyright 2015 Richard A. Giles
ii
Epigraph
“Well, although I do not suppose that either of us knows anything
really beautiful and good, I am better off than he is - for he knows nothing,
and thinks that he knows. I neither know nor think that I know.”
–Plato, Ἀπολογία Σωκράτους [Apology] (B. Jowett, Trans.)
iii
Dedication
In memory of
Ida Mae Giles
iv
Acknowledgements
I would like to thank my advisor, Prof. Kyung Woon Jung, for his patience,
guidance, and support throughout my graduate school career. Through him I have learned
the virtues of diligence and independent thought as well as the reasoning processes
necessary to formulate elegant solutions to complex problems.
Current and former graduate students in the Jung research group have been very
influential in my life and research, including Chris Meyer, Prasanna Pullanikat, Victor
Hadi, Anne-Marie Finaldi, Janet Olsen, Jamie Jarusiewicz, Justin O’Neill, Adam
Schanen, and Nima Zargari. I am grateful for their assistance and camaraderie; especially
Anne-Marie, with whom I have shared many long talks over coffee. I would also like to
thank Dr. Joo Ho Lee and the late Dr. Kyung Soo Yoo for sharing their research
experience with me to help augment my own.
Numerous undergraduate students have assisted me in my research over the years,
and I am thankful for their contributions to my work. I would especially like to thank
Michael Chiu, Iris Kim, and Eric Chao, whose tireless efforts were vital in the
completion of projects mentioned in this dissertation.
I am also indebted to other faculty and staff at the University of Southern
California, including Prof. Travis Williams, Dr. James Ellern, and Dr. Jennifer Moore,
for their wisdom and guidance. A special thanks also goes to Michele Dea for her
indispensable administrative support during my graduate school career.
v
I must also thank faculty in the Department of Chemistry at my alma mater, The
College of Wooster, especially Prof. Paul Bonvallet, my undergraduate Independent
Study advisor, and Prof. Mark Snider, who was instrumental in awarding me the
scholarship that would allow me to attend Wooster. Both continue to have profound
influences on my life as educators and mentors.
To my closest friends during my tenure in graduate school, including Ken
Hanson, Lance Pickens, Ronoldo Appleton, and Jim Witter – thank you for your roles in
my continued intellectual and personal development. Whether times were at their best or
most challenging, I was fortunate to have your companionship.
Finally, the support of my family, both immediate and extended, has been
unconditional and unwavering, and for that I am eternally grateful. The boundless love
and encouragement from my parents Teri and Rick and my brothers Rob and Mike has
made all the difference in the world to me.
vi
Table of Contents
Epigraph .............................................................................................................................. ii
Dedication .......................................................................................................................... iii
Acknowledgements ............................................................................................................ iv
List of Tables ..................................................................................................................... ix
List of Figures ..................................................................................................................... x
List of Schemes ................................................................................................................ xiii
Abstract ............................................................................................................................. xv
Chapter 1. Introduction. Palladium NHC Catalysis and H-D Exchange. .......................... 1
1.1 Background of NHCs and their metal complexes ..................................................... 1
1.2 Catalytic and synthetic applications of palladium NHC complexes ......................... 4
1.3 Development of the Jung-Sakaguchi NHC-amidate-alkoxide catalytic scaffold ...... 6
1.4 Background of deuterium isotope effects.................................................................. 9
1.5 Important applications of deuterated compounds ................................................... 11
1.6 Methods for H-D exchange ..................................................................................... 15
1.7 References for Chapter 1 ......................................................................................... 18
Chapter 2. Chemoselective hydroamination of vinyl arenes catalyzed by an NHC-
amidate-alkoxide Pd(II) complex and p-TsOH................................................................. 24
2.1 Introduction ............................................................................................................. 24
2.2 Initial work .............................................................................................................. 26
2.3 Results and Discussion ............................................................................................ 29
2.4 Conclusion ............................................................................................................... 35
2.5 References for Chapter 2 ......................................................................................... 36
Chapter 3. Hydrogen–deuterium exchange of aromatic amines and amides using
deuterated trifluoroacetic acid........................................................................................... 38
3.1 Introduction ............................................................................................................. 38
3.2 Results and Discussion ............................................................................................ 40
3.3 Conclusion ............................................................................................................... 45
3.4 References for Chapter 3 ......................................................................................... 46
vii
Chapter 4. H-D exchange in deuterated trifluoroacetic acid via ligand-directed NHC-
palladium catalysis: a powerful method for deuteration of aromatic ketones, amides, and
amino acids. ...................................................................................................................... 48
4.1 Introduction ............................................................................................................. 48
4.2 Results and Discussion ............................................................................................ 50
4.3 Conclusion ............................................................................................................... 60
4.4 References for Chapter 4 ......................................................................................... 61
Chapter 5. Dual Studies on a Hydrogen-Deuterium Exchange of Resorcinol and the
Subsequent Kinetic Isotope Effect. ................................................................................... 64
5.1 Introduction ............................................................................................................. 64
5.2 Experimental Design ............................................................................................... 66
5.3 Results and Discussion ............................................................................................ 67
5.4 Student Experiences ................................................................................................ 72
5.5 References for Chapter 5 ......................................................................................... 74
Appendix 1. Chemoselective hydroamination of vinyl arenes catalyzed by an NHC-
amidate-alkoxide Pd(II) complex and p-TsOH................................................................. 75
A1.1 Experimental Section ........................................................................................... 75
A1.2 Spectral Data for New Compounds Synthesized ................................................. 76
A1.2
1
H and
13
C NMR Spectra For New Compounds Synthesized .............................. 80
Appendix 2. Hydrogen–deuterium exchange of aromatic amines and amides using
deuterated trifluoroacetic acid......................................................................................... 100
A2.1 Experimental Section ......................................................................................... 100
A2.2 Spectral Data for Substrates Used in Deuterium Labeling Studies .................... 104
A2.3 NMR Spectra for Substrates Used in Deuterium Labeling Studies ................... 108
Appendix 3. H-D exchange in deuterated trifluoroacetic acid via ligand-directed NHC-
palladium catalysis: a powerful method for deuteration of aromatic ketones, amides, and
amino acids. .................................................................................................................... 127
A3.1 Experimental Section ......................................................................................... 127
A3.2 Spectral Data for Substrates Used in Deuterium Labeling Studies .................... 132
A3.3 NMR Spectra for Substrates Used in Deuterium Labeling Studies ................... 141
A3.4 References for Appendix 3 ................................................................................. 183
viii
Appendix 4. Dual Studies on a Hydrogen-Deuterium Exchange of Resorcinol and the
Subsequent Kinetic Isotope Effect. ................................................................................. 184
A4.1 Student Handout ................................................................................................. 184
A4.2 Instructor Notes .................................................................................................. 194
A4.3 Experimental Section ......................................................................................... 198
Appendix 5. Synthesis of NHC-amine ligands for palladium. ...................................... 202
A5.1 Introduction ........................................................................................................ 202
A5.2 Results and Discussion – Synthesis of complexes 9a and 9b ............................ 204
A5.3 Results and Discussion – Efforts towards synthesis of complex 23. ................. 213
A5.4 Experimental Section ......................................................................................... 218
A5.5
1
H NMR Spectra ................................................................................................. 230
A5.6 Supplementary crystallographic information for complex 9a ............................ 248
A5.7 References for Appendix 5 ................................................................................. 260
Comprehensive Bibliography ......................................................................................... 262
ix
List of Tables
Table 2.1. Determination of catalyst role in the hydroamination reaction. ...................... 28
Table 2.2. Effect of acids and palladium complexes on hydroamination of 4-
methylstyrene. ................................................................................................................... 30
Table 2.3. Effect of solvents and substrate ratios. ............................................................ 31
Table 2.4. Effect of catalyst and acid at different temperatures. ...................................... 32
Table 2.5. Hydroamination of various vinyl arenes with benzenesulfonamide. .............. 34
Table 4.1. Effect of palladium salts and AgTFA additive on H-D exchange. ................. 51
Table 4.2. Effect of reaction conditions on H-D exchange. ............................................. 53
Table A4.1. Activating and deactivating substituents on an aromatic ring. ................... 184
Table A5.1. Crystal data and structure refinement for C
21
H
28
N
3
O
4
Pd. ........................ 248
Table A5.2. Atomic coordinates ( x 10
4
) and equivalent isotropic displacement
parameters (Å
2
x 10
3
) for C
21
H
28
N
3
O
4
Pd. U(eq) is defined as one third of the trace of
the orthogonalized U
ij
tensor. ......................................................................................... 249
Table A5.3. Bond lengths [Å] and angles [°] for C
21
H
28
N
3
O
4
Pd. .................................. 251
Table A5.4. Anisotropic displacement parameters (Å
2
x 10
3
) for C
21
H
28
N
3
O
4
Pd. The
anisotropic displacement factor exponent takes the form: -2π
2
[ h
2
a*
2
U
11
+ ... + 2 h k
a* b* U
12
]...................................................................................................................... 256
Table A5.5. Hydrogen coordinates ( x 10
4
) and isotropic displacement parameters (Å
2
x
10
3
) for C
21
H
28
N
3
O
4
Pd. .................................................................................................. 258
x
List of Figures
Figure 1.1. Early metal carbene complexes prepared by Tschugajeff, Fischer, and
Schrock. .............................................................................................................................. 1
Figure 1.2. Early metal NHC complexes prepared by Öfele and Wanzlick and the dimer
prepared by Wanzlick. ........................................................................................................ 2
Figure 1.3. Synthesis of the first crystalline NHC by Arduengo. ...................................... 3
Figure 1.4. First Pd-NHC catalysts synthesized by Herrmann for use in Heck-Mizoroki
coupling............................................................................................................................... 4
Figure 1.5. Representative carbon-carbon bond-forming cross-coupling reactions
catalyzed by palladium-NHC complexes............................................................................ 5
Figure 1.6. NHC-amidate-alkoxide complexes synthesized by Jung ................................ 7
Figure 1.7. Derivatives of the Pd NHC-amidate-alkoxide catalyst 11 synthesized by Jung
et al. and representative examples of their reactivity. ......................................................... 8
Figure 1.8. Tetrabenazine and its deuterated derivative dutetrabenazine (SD-809). ....... 14
Figure 1.9. Ligand-directed ortho deuteration of ketones and acetanilides using
Crabtree’s iridium catalyst by Hesk et al .......................................................................... 17
Figure 1.10. Representative examples of H-D exchange reactions catalyzed by
homogeneous palladium complexes. ................................................................................ 18
Figure 2.1. NHC-amidate Pd(II) catalyst 1. ..................................................................... 26
Figure 3.1. H-D exchange of anilines and acetanilide without ring substituents............. 42
Figure 3.2. H-D exchange of para-substituted anilines and acetanilides. ....................... 43
Figure 3.3. H-D exchange of ortho and meta-substituted anilines. .................................. 44
xi
Figure 4.1. NHC-amidate palladium catalyst 1................................................................ 50
Figure 5.1.
1
H NMR spectra of resorcinol prior to (left) and after (right) H-D exchange.
........................................................................................................................................... 69
Figure 5.2. Representative UV-Vis absorbance data (at 460 nm) for the experiment. .... 72
Figure A2.1. NMR signals and total deuterium incorporation in m-anisidine. ............. 103
Figure A2.2.
1
H NMR spectra of m-anisidine 15 showing the disappearance of proton
signals after the catalytic H-D exchange reaction in CF
3
COOD. ................................... 104
Figure A3.1. NMR signals and total deuterium incorporation in benzophenone
(condition b).................................................................................................................... 130
Figure A3.2.
1
H NMR spectra of 2-acetonaphthone 6 showing the disappearance of
proton signals after catalytic H-D exchange reactions in CF
3
COOD (condition a) and in
CF
3
COOD with palladium catalyst 1 (10 mol%) and AgTFA (10 mol%) (condition b).
......................................................................................................................................... 131
Figure A4.1. Ortho, meta, and para addition of an electrophile E
+
to an aromatic ring.
......................................................................................................................................... 185
Figure A4.2. Substitution patterns in dihydroxybenzenes. ............................................ 186
Figure A4.3. Mechanism and resonance forms of acid-catalyzed aromatic H-D exchange.
......................................................................................................................................... 187
Figure A4.4. Relative rates of iodination of resorcinol.................................................. 188
Figure A5.1. Representative examples of synthesized NHC-AA complexes. ............... 203
Figure A5.2. Representative NHC-amidate-alkoxide palladium complex 7 synthesized by
Jung and Sakaguchi......................................................................................................... 204
xii
Figure A5.3. Crystal structure of 9a determined by single crystal X-ray diffraction
analysis. Hydrogen atoms have been omitted for clarity. (Data collected by Timothy
Stewart.) .......................................................................................................................... 212
Figure A5.4. Previously synthesized palladium NHC-amidate complex 22 and its
proposed amine variant 23. ............................................................................................. 214
xiii
List of Schemes
Scheme 2.1. An example of competitive hydroamination and vinyl arene homocoupling
reactions under acidic conditions. ..................................................................................... 26
Scheme 2.2. Hydroamination of 4-methylstyrene along with formation of homocoupled
side product. ...................................................................................................................... 29
Scheme 2.3. General scheme for hydroamination of vinyl arenes. .................................. 33
Scheme 3.1. CF
3
COOD-catalyzed H–D exchange of acetaminophen. ............................ 40
Scheme 3.2. H-D exchange of diclofenac. ....................................................................... 45
Scheme 4.1. H-D exchange of aromatic ketones with CF
3
COOD (condition a) and
CF
3
COOD with catalyst 1 and AgTFA (condition b). ...................................................... 55
Scheme 4.2. H-D exchange of aromatic amides and their derivatives with CF
3
COOD
(condition a) and CF
3
COOD with catalyst 1 and AgTFA (condition b). ......................... 56
Scheme 4.3. H-D exchange of amino acids and derivatives with CF
3
COOD (condition a)
and CF
3
COOD with catalyst 1 and AgTFA (condition b). ............................................... 58
Scheme 5.1. Acid-catalyzed H-D exchange of resorcinol in D
2
O. .................................. 68
Scheme 5.2. Simplified mechanism for electrophilic iodination of resorcinol. ............... 70
Scheme A5.1. Original proposed synthesis of NHC-AA palladium complex 2. ........... 205
Scheme A5.2. Reductive amination of L-valinol followed by reductive amination with
benzaldehyde................................................................................................................... 206
Scheme A5.3. Methylation of secondary amine 4 under different conditions. .............. 206
Scheme A5.4. Initial attempts at converting the primary alcohol of 5 to a halide. ........ 207
Scheme A5.5. Attempted tosylation of primary alcohol of 5 ......................................... 208
xiv
Scheme A5.6. Coupling of alkyl chloride 8 with benzimidazole. .................................. 209
Scheme A5.7. Synthesis of palladium complex 9a. ....................................................... 210
Scheme A5.8. Synthesis of palladium complex 9b. ....................................................... 211
Scheme A5.9. Heck-Mizoroki coupling catalyzed by complex 9a. ............................... 213
Scheme A5.10. Failed attempts at reduction of intermediates in the synthesis of complex
22 towards synthesis of 23. ............................................................................................. 214
Scheme A5.11. Coupling of benzimidazole with 1,2-dichloroethane, methylation of the
resulting compound with methyl iodide, and attempted coupling of the iodide salt with
with 2-methoxyethylamine. ............................................................................................ 215
Scheme A5.12. Attempted coupling of alkyl chloride 29 with 2-methoxyethylamine 31.
......................................................................................................................................... 216
Scheme A5.13. Boc-protection of 33 followed by methylation of the benzimidazole
nitrogen and deprotection of the resultant iodide salt with TFA in CH
2
Cl
2
. .................. 217
Scheme A5.14. Formation of silver carbene complex 37 and attempted palladation to 38.
......................................................................................................................................... 218
xv
Abstract
The research efforts discussed herein encompass two broad subjects, the
development of catalytic methodologies using palladium-NHC complexes and the
hydrogen-deuterium exchange of aromatic molecules under acidic conditions. The
introduction (Chapter 1) gives a brief overview of the history, progress, and recent
developments in these fields.
In Chapter 2, the development of a method for the hydroamination of vinyl arenes
using a palladium-NHC complex is discussed. This methodology selectively furnished
the cross-coupled hydroamination products in a Markovnikov fashion while greatly
reducing undesired acid-catalyzed homocoupling of the vinyl arenes.
Chapter 3 describes the trifluoroacetic acid-d
1
-catalyzed hydrogen-deuterium
exchange of aromatic amines and amides. While this method was amenable to efficient
deuterium incorporation for numerous substrates, best results were seen with less basic
anilines and highly activated acetanilides, reflecting the likelihood of different
mechanistic pathways.
Chapter 4 represents the intersection of these methods by employing a palladium-
NHC complex under the conditions described in Chapter 3 to effect the ortho-selective
ligand-directed hydrogen-deuterium exchange of aromatic ketones, amides, and amino
acids, accompanied in some cases by concurrent acid-catalyzed electrophilic deuteration.
Experimental evidence strongly suggests that palladium facilitates C-H activation of the
aromatic substrates, a mechanism seldom observed under strongly acidic conditions.
xvi
In Chapter 5, the application of hydrogen-deuterium exchange methods to a
pedagogical context is examined. Using acidic deuterium oxide, efficient deuterium
incorporation into resorcinol was possible during the course of a single undergraduate
laboratory session, and iodination of the deuterated product allowed for a visual
representation of a kinetic isotope effect.
Appendix 5 contains supplementary research regarding the synthesis of various
NHC ligands for palladium incorporating sp
3
amine substituents. The crystal structure
and reactivity of one of these palladium complexes is also discussed.
1
Chapter 1. Introduction. Palladium NHC Catalysis and H-D Exchange.
1.1 Background of NHCs and their metal complexes
The reactivity of carbenes, divalent electronically neutral carbon species with two
nonbonding electrons, has been studied in the context of synthetic chemistry since the
mid-19
th
century.
1
However, early efforts to isolate stable carbenes or their metal
complexes were met with little success. A platinum metal-carbene complex 1, although
not fully recognized as such at time, was synthesized as early as 1925
2
although it was
not unambiguously characterized and recognized as such until 1970.
3
Later efforts by
Fischer and Schrock successfully prepared metal-carbene complexes of tungsten
4
2 and
tantalum
5
3 respectively (Figure 1.1).
Figure 1.1. Early metal carbene complexes prepared by Tschugajeff (1), Fischer (2),
and Schrock (3).
Around the same time, the work of Öfele
6
and Wanzlick
7
identified the N-
heterocyclic carbene (NHC) as a ligand for chromium 4 and mercury 5, respectively
(Figure 1.2). These types of carbenes were found to be highly thermodynamically stable
compared to other examples. Previously, Wanzlick had attempted to isolate the free
2
imidazolium carbene via a deprotonation strategy but invariably synthesized dimer 6
instead.
8
These NHC metal complexes were largely seen as synthetic curiosities, and
isolation of a free NHC remained elusive for years to come.
Figure 1.2. Early metal NHC complexes prepared by Öfele (4) and Wanzlick (5) and
the dimer prepared by Wanzlick (6).
The realization of NHCs as synthetically valuable catalysts and ligands is
relatively recent. Arduengo finally prepared the first stable, isolable NHC 8 (Figure 1.3)
in 1991,
9
successfully employing a similar deprotonation strategy to the one postulated
by Wanzlick decades prior, but utilizing the extreme steric bulk of the adamantyl groups
bonded to nitrogen to inhibit the dimerization that hindered earlier efforts. What followed
can be described as exponential growth in the field of N-heterocyclic carbenes and their
applications. Reviews within the past two years alone encompass their coordination
chemistry with group 1 and 2 elements and early transition metals,
10
late transition
metals
11
(especially nickel
12
and palladium
13
) and main group elements
14
as well as their
reactivity with esters,
15
unsaturated carbon-carbon bonds,
16
organofluorine compounds,
17
and silicon reagents.
18
Other recent reviews focus on synthetic modification of metal-
NHC complexes
19
, their photoluminescent properties,
20
and the use of NHCs as
asymmetric organocatalysts
21
and anti-tumor agents.
22
3
Figure 1.3. Synthesis of the first crystalline NHC by Arduengo.
While NHCs make up a highly diverse group of compounds, they are loosely
defined as cyclic compounds possessing a carbene carbon and at least one nitrogen atom.
The exceptional stability of NHCs is primarily due to π electron donation from the lone
pairs on these nitrogen atoms with some contribution from double bonds within the
ring.
23
The nitrogen atoms are also σ-electron withdrawing, inductively reducing the
energy of the occupied carbene σ orbital.
24
These properties allow for stabilization of the
carbene electrons in a paired (singlet) state, causing them to exhibit nucleophilic rather
than electrophilic character. As a result, NHCs act as strong σ donors, allowing them to
react with metals to form strongly bound ligands or with electrophilic organic compounds
directly to generate reactive adducts.
24
The high structural diversity of NHCs allows for
fine-tuning of their steric and electronic properties depending on the desired application.
Several different strategies have been employed for the synthesis of NHCs and
their metal complexes. Direct deprotonation of the NHC salt, as suggested by Wanzlick
and first successfully utilized by Arduengo, is the simplest and most common method.
Other methods to generate free NHCs include dissolved metal reduction of imidazole
derivatives or thermal decomposition of various NHC adducts with other organic
compounds.
13
The isolated free NHC can then directly react with a metal center to
generate a metal-NHC complex. In cases where isolation of the free NHC is difficult, the
4
free NHC can be prepared in situ via deprotonation and reacted directly with the metal.
Alternatively, a silver carbene complex can be generated via reaction of the appropriate
NHC salt with Ag
2
O, and transmetalation of this complex with a different metal will
yield the desired NHC compound. However, this method has certain disadvantages,
including the relative sensitivity of the silver carbene complex towards light.
13
1.2 Catalytic and synthetic applications of palladium NHC complexes
As discussed previously, an extremely diverse set of NHC complexes with a
number of different metals have been prepared and characterized. Some of the most
important of these are the palladium-NHC complexes. Since their first catalytic
application towards Heck-Mizoroki coupling by Herrmann
25
in 1995 (Figure 1.4), Pd-
NHC complexes have been utilized for a variety of other important carbon-carbon bond-
forming reactions, including the Suzuki-Miyaura, Negishi, Kumada-Tamao-Corriu, Stille,
Hiyama, and Sonogashira cross-coupling reactions (Figure 1.5).
26
Of these, Pd-NHC
catalysis of Heck-Mizoroki, Suzuki-Miyaura, Negishi, and Sonogashira reactions has
been studied extensively, while the scope of Kumada-Tamao-Corriu, Stille, and Hiyama
reactions catalyzed by Pd-NHC complexes remains limited.
26b
Figure 1.4. First Pd-NHC catalysts synthesized by Herrmann for use in Heck-
Mizoroki coupling.
5
Figure 1.5. Representative carbon-carbon bond-forming cross-coupling reactions
catalyzed by palladium-NHC complexes.
Pd-NHC complexes have numerous other applications besides the aforementioned
cross-coupling reactions. The Buchwald-Hartwig amination, a direct coupling of amines
and aryl halides, has been investigated using several different Pd-NHC complexes.
26
Other important transformations catalyzed by Pd-NHC complexes include allylic
alkylation (the Tsuji-Trost reaction),
26a
allylic amination,
26a
hydroamination,
27
alpha
arylation,
26a
and various polymerization reactions.
26a
Notably, many of these reactions
can be conducted stereoselectively via the use of chiral NHC ligands, allowing for the
synthesis of highly enantiomerically-enriched products.
27
One report even investigated
the effect of various two Pd-NHC complexes on three different cancer cell lines and
examined their mechanism of action in some detail.
28
6
As ligands for palladium, NHCs are routinely compared to phosphine ligands in
terms of their activity and electronic properties. On a basic level, they share some similar
characteristics, including their tendencies to act as strong σ donors and weak π acceptors
when bound to a metal.
24
However, there are several key differences between these
classes of ligands. NHC ligands are significantly stronger σ-donators than phosphines,
resulting in a stronger and thus more stable (less labile) bond to the metal center.
24
Additionally, the steric environment of NHC ligands and phospine ligands are profoundly
dissimilar, such that NHC ligands are not adequately described by the “cone angle”
terminology applied to many phosphine ligands.
24
Finally, as mentioned previously,
synthetic modification of NHC ligands is usually straightforward, allowing for a high
degree of steric and electronic diversity, whereas alteration of phosphine ligands can be
challenging and less predictable.
24
1.3 Development of the Jung-Sakaguchi NHC-amidate-alkoxide catalytic scaffold
In 2008, the synthesis of a novel NHC-amidate-alkoxide complex 11 and its
dimer 12 (Figure 1.6) was reported by Sakaguchi and Jung.
29
This tridentate catalyst
scaffold was designed to counteract the comparatively low thermodynamic stability and
enantioselectivity afforded by more traditional monodentate or bidentate Pd-NHC
complexes. Jung emphasized the strong σ donation of the NHC, additional chelation
provided by the amide and alkoxide, and chirality and steric bulk from the isopropyl side
chain as key features of the catalyst design.
29
Other reports suggest that N/O-
functionalized NHC ligands may interact with incoming substrates to improve the
7
catalytic activity and enantioselectivity of various reactions.
30
The catalyst was first
synthesized as monomer 11, which in the presence of base homocoupled to dimer 12.
This dimer was easily split back into monomer 11 by adding stoichiometric amounts of
HCl. Dimer 12 efficiently catalyzed the oxidative boron Heck-type cross-coupling of
arylboronic acids and acyclic alkenes, generating products with up to 98% enantiomeric
excess.
29
These impressive results suggested that this catalytic scaffold could be useful
for other challenging palladium-catalyzed reactions.
Figure 1.6. NHC-amidate-alkoxide complexes synthesized by Jung.
29
As Jung envisioned, the developed NHC-amidate-alkoxide scaffold proved to be
an unusually versatile catalytic system. The diverse transformations catalyzed by
derivatives of palladium complex 11 (Figure 1.7) include the aforementioned boron
Heck-type coupling of arylboronic acids and olefins,
31
the Strecker reaction of aldehydes
and ketones,
32
aliphatic hydroxylation of ketones and carboxylic acids,
33
oxidative
degradation of glycerol to formic acid,
34
and hydrogen-deuterium (H-D) exchange of
aromatic and aliphatic compounds.
35
Both the boron-Heck coupling and hydroxylation
reactions reactions proceeded with a high degree of stereoselectivity. Separately, using
8
the NHC-amidate-alkoxide scaffold, Sakaguchi prepared several iridium complexes that
were employed as catalysts for various enantioselective transformations, including
transfer hydrogenation,
36
hydrosilane reduction,
37
and hydrosilylation of ketones.
38
Sakaguchi also synthesized palladium, ruthenium, and copper complexes with this ligand
system and applied them towards enantioselective allylic alkylation,
39
transfer
hydrogenation,
40
and conjugate addition reactions,
41
respectively.
Figure 1.7. Derivatives of the Pd NHC-amidate-alkoxide catalyst 11 synthesized by
Jung et al. and representative examples of their reactivity.
9
The H-D exchange conditions, which were highly effective for aromatic
hydrocarbons such as benzene and toluene as well as aliphatic alkanes such as
cyclopentane and cyclohexane, are of particular interest, due to the reaction proceeding
through C-H activation of otherwise unreactive hydrocarbons by the Pd-NHC complex.
This direct C-H activation of hydrocarbons is attractive and atom-economical, but very
challenging due to its high activation barrier. The comparatively high electron density on
the palladium center due to strong donation from the NHC, amidate, and alkoxide of
complex 16 was given as the primary reason this transformation was feasible.
35
1.4 Background of deuterium isotope effects
Deuterium is a relatively uncommon (0.015% natural abundance)
42
isotope of
hydrogen with double the mass of the more common protium (>99.98% natural
abundance) due to the presence of a single neutron in its nucleus. Since the first report by
Urey of the existence of deuterium in 1932,
43
a discovery for which he won the 1934
Nobel Prize in Chemistry, chemists have been intrigued by its unique properties and
potential applications. Synthetic chemists have long sought to incorporate deuterium into
organic molecules through the displacement of existing hydrogen atoms, a process known
as H-D exchange. Development of methods for H-D exchange reactions has seen a
dramatic increase in research interest since the late 1990s due to rapidly increasing
demand for deuterated compounds.
44
10
The utility of deuterated compounds is a result of the unique properties of the
carbon-deuterium bond relative to the carbon-protium bond. Consider the simplified
analogy of a chemical bond as an oscillator with various vibrational modes. As
oscillators, all chemical bonds possess some zero-point energy; i.e. a certain amount of
inherent vibrational energy present even at 0 K.
45
The zero-point energy of an oscillator
is dependent on the mass of the oscillator, and more massive atoms (e.g. deuterium
versus protium) in an otherwise identical chemical bond reduce the amount of zero-point
energy.
45
The reduced zero-point energy of the carbon-deuterium bond means that in
general, more energy must be applied to overcome the barrier to reaction and break that
bond than would be required for a carbon-protium bond. Because deuterium has twice the
mass of protium, the extent of this difference in reactivity is exaggerated compared to
reactions involving isotopes of heavier chemical elements, such as oxygen and nitrogen,
which have a proportionally smaller difference in mass.
45
For this reason, carbon–
deuterium bonds tend to be around an order of magnitude stronger than their protium
counterparts.
46
Other factors such as involvement of multiple nuclei and quantum
tunneling can affect the reactivity of a carbon-deuterium bond,
45
but these influences are
beyond the scope of this discussion.
The difference in rate between the reaction of a carbon-protium bond and a
carbon-deuterium bond is a primary kinetic isotope effect (KIE) often referred to as the
deuterium isotope effect (DIE).
47
The impact of the deuterium isotope effect can be
considerable; for example, the autooxidation of cumene was observed to have k
H
/k
D
=
76.
48
However, the vast majority of reactions in which the breaking of a carbon-hydrogen
11
bond is rate limiting exhibit a DIE substantially less than 10.
49
Not all isotope effects are
the result of breaking a chemical bond to the isotope of interest. Secondary kinetic
isotope effects, the result of isotopic substitution at one part of a molecule affecting
reactivity at another part of the molecule, are prevalent but typically much lower in
magnitude.
46
Further complicating matters, many reactions exhibit no measurable DIE,
and others may actually exhibit an increase in rate when protium is replaced by
deuterium (DIE <1).
49
Despite the substantial work accomplished in the study of
deuterium isotope effects, the magnitude of these effects is dependent on numerous
factors and cannot be predicted with any degree of certainty, even if the mechanism of
the reaction of interest is well-understood.
49
1.5 Important applications of deuterated compounds
Deuterated compounds have been widely adopted as internal standards for trace
analysis of samples from metabolic, toxicological, and pharmacokinetic studies
50
as well
as environmental samples.
51
The popularity of mass spectrometry (MS) as an
investigative tool for quantification of very small amounts of compounds in complex
matrices has resulted in high demand for deuterated internal standards for comparison
purposes. The primary advantage of deuterium-labeled standards is their nearly identical
physical properties to the non-deuterium enriched analyte of interest, resulting in few
differences in chromatographic retention times or ionization behavior but noticeable mass
differences easily detectable using MS techniques.
50
These properties make deuterated
standards useful when compensating for matrix effects and mechanical losses during
12
preparation of complex biological samples.
51
Ideally, deuterated compounds used as MS
internal standards would have highly selective deuterium incorporation, as mixtures of
isotopomers (isomers differing in the regioselectivity of isotopic incorporation) and/or
isotopologues (isomers differing in total isotopic composition) broaden MS signals and
make accurate sample quantification difficult or impossible.
50
Thus highly active and
selective H-D exchange techniques effective for a wide variety of different substrates are
of great interest to researchers in these fields (vide infra).
The increasing relevance of MS techniques for proteomics, the macroscale study
of proteins, has also led to development of deuterium-labeled amino acids and proteins.
To this end, proteins are generally deuterated for much the same reason as the
aforementioned analytes of interest in metabolic and environmental studies; i.e. to
provide a convenient basis of comparison for MS studies.
52
One technique first proposed
by Aebersold et al. is the isotope-coded affinity tag (ICAT) method.
53
Using this strategy,
an affinity tag labeled with deuterium is affixed to specific amino acid residues within a
protein, and upon digestion of the protein to its constituent peptides, this label aids
purification and also allows for quantification using MS. Another method developed by
Mann et al. is referred to as SILAC (stable isotope labeling by amino acids in cell
culture).
52
This strategy forms deuterium-labeled proteins by utilizing cell cultures to
construct proteins from deuterium-labeled amino acids, and thus no additional H-D
exchange is necessary. Together, these methods encompass the majority of studies with
deuterium-labeled proteins and peptides. However, not all deuterium labeling of proteins
is done to aid MS analysis; for example, other studies have utilized deuterium-labeled
13
proteins to quantitatively examine their structure and hydrogen-bonding interactions
using NMR techniques.
54
A more recent application of deuterated compounds is the emergence of
deuterium-labeled pharmaceuticals. Deuterated drugs are in many ways indistinguishable
from their non-deuterated isotopologues, including their mechanism of action, target
binding affinity, and cellular activity.
49
However, due to the increased strength of the
carbon-deuterium bond and resulting KIE (vide supra), deuterated pharmaceuticals can
have some beneficial properties, including reduced formation of harmful metabolites,
increased therapeutic window, and retention of activity at lower dosages.
49
The concept
of labeling drugs with deuterium to alter their pharmacokinetic properties is not a new
one, as a review from the 1970s discussed that very topic.
55
However, as recently as
1999, the prospects of a deuterated drug entering the market were grim, as no quantifiable
progress had been reported in the ensuing decades.
46
Since then, explosive progress has
been made in the field of deuterated pharmaceuticals,
56
and several deuterium-labeled
drugs are currently in clinical trials. One compound, SD-809 (Figure 1.8), has shown
promise in phase 3 clinical trials and is expected to enter the market soon as an improved
treatment for Huntington’s disease.
57
A limitation of deuterated pharmaceuticals is the
dependence of the DIE on the reaction mechanism. Depending on how the drug is
metabolized in vivo, substitution of protium with deuterium may not have a noticeable
biological effect; best results so far have been observed with deuteration of carbon-
hydrogen bonds which are oxidized in vivo by enzymes such as cytochrome P450 and its
14
derivatives.
49
Nonetheless, future prospects for deuterated drugs are extremely promising,
and research in this field is still in its infancy.
Figure 1.8. Tetrabenazine and its deuterated derivative dutetrabenazine (SD-809).
Finally, and perhaps most fundamentally, deuterium-labeled compounds are
frequently employed to probe the mechanistic details of various organic reactions. In
general, these studies make use of the aforementioned DIE to determine rate-limiting
steps for organic transformations or monitor where deuterium labels are incorporated or
lost during a reaction to elucidate specific mechanistic steps. These methods were already
well-established by 1961, when an extensive review of the topic was written;
58
a
comprehensive book on the subject was published two decades later.
59
These strategies
are still extensively utilized, and representative examples are far too numerous to
summarize here. Selected recent examples include the proposal of a new mechanism for
the extensively studied formose reaction,
60
an examination of regioselectivity in the
palladium-catalyzed fluorination of aryl triflates,
61
and determination of product
distribution in the Fischer-Tropsch synthesis.
62
A review by Baldwin, which provides
details of deuterium labeling studies used to examine the otherwise complicated reactions
of simple hydrocarbons, is of particular interest.
63
15
1.6 Methods for H-D exchange
The extensive applications of deuterium-labeled compounds mentioned above
have necessitated the development of methods to efficiently and selectively incorporate
deuterium into organic compounds. H-D exchange methods can be broadly classified into
four (sometimes overlapping) categories: Brønsted and Lewis acid-catalyzed methods,
base-catalyzed methods, homogeneous metal-catalyzed methods, and heterogeneous
metal-catalyzed methods.
44
Some rare exceptions exist, such as the hydrothermal
deuteration of arenes at 380-430 °C in neutral D
2
O
64
and highly selective enzymatic
deuteration of DNA.
65
The rate, specificity, functional group tolerance, and degree of
deuterium incorporation of each method are not necessarily generalizable or easily
predictable. As a result, the choice of H-D exchange method depends strongly upon the
substrate(s) of interest. Due to the relevance of each to the research discussed in
subsequent chapters (vide infra), Brønsted-acid catalyzed and homogeneous metal-
catalyzed methods will be discussed in greater detail here.
One of the first H-D exchange methods, Brønsted acid catalysis, has been a
subject of research interest since the 1950s.
66
This method is frequently employed for
aromatic substrates, which react to form deuterated products primarily via an
electrophilic aromatic substitution mechanism. Strong mineral acids such as DCl, DBr, or
D
2
SO
4
in D
2
O are common catalysts for these reactions, and have been used to
effectively deuterate substrates ranging from alkanes
67
to natural products.
68
However,
several disadvantages to use of these acids have been observed, especially unwanted side
reactions and substrate decomposition.
44
High temperature dilute acid (HTDA)
16
conditions, which employ low concentrations of acid at temperatures up to 400 °C, were
developed to avoid these complications, and are especially effective for aromatic
compounds such as aniline, phenol, and benzoic acid.
69
Other limitations of Brønsted
acid H-D exchange catalysis include low substrate solubility and frequently poor
regioselectivity of deuterium incorporation. Regioselectivity is sometimes improved by
employing less potent acid catalysts such as TFA, HOAc, H
3
PO
4
, or their deuterated
derivatives.
44
Perhaps the most important drawback of acid-catalyzed H-D exchange is
the substrate scope, as many compounds are simply unstable or unreactive under the
described conditions.
Homogeneous metal-catalyzed H-D exchange has several advantages over acid-
catalyzed techniques, including improved selectivity, higher regiospecificity, and milder
reaction conditions.
44
Depending on the catalyst, various deuterium sources can be
employed for these transformations, including D
2
O, deuterated organic solvents such as
benzene-d
6
or acetone-d
6
, or even deuterium gas (D
2
). The most commonly employed
transition metal for homogeneous metal-catalyzed H-D exchange is iridium, as a number
of cationic iridium complexes have shown high activity for the C-H activation of organic
compounds, especially arenes.
70
A representative example of iridium-catalyzed ligand-
directed ortho deuteration is the work conducted by Hesk et al. (Figure 1.9) which
reported successful deuteration of simple ketones and acetanilides as well as a
pharmaceutically-useful β-lactam compound.
71
Much recent H-D exchange work using
iridium has employed NHC ligands to increase the catalytic activity of the iridium
complexes.
72
Rhodium and ruthenium complexes
73
have also been used for H-D
17
exchange applications, albeit to a lesser extent than iridium. Additionally, although
homogeneous platinum-catalyzed H-D exchange reactions were discovered by Garnett
and co-workers in the late 1960s,
74
the synthetic applications of soluble platinum
complexes towards H-D exchange reactions remain limited.
50
A common disadvantage of
homogeneous metal-catalyzed H-D exchange reactions is the cost and sensitivity of the
metal catalysts, which frequently must be used under anhydrous, air-free conditions.
Figure 1.9. Ligand-directed ortho deuteration of ketones and acetanilides using
Crabtree’s iridium catalyst by Hesk et al.
71
Examples of homogeneous palladium-catalyzed H-D exchange reactions (Figure
1.10) are exceedingly rare, as most work with palladium has focused on heterogeneous
catalysis.
50
Anderson et al. first reported an example of H-D exchange via homogeneous
palladium catalysis in the mid 1980s, achieving rapid deuteration of nitromethane and
other organic molecules using Pd(0) phosphine complexes.
75
As mentioned previously,
Jung et al. utilized a palladium–NHC complex to conduct H-D exchange reactions of
various organic molecules, with benzene and toluene giving superior results.
35
Sanford et
al. employed a dicationic pyridine-based ligand to effect the H-D exchange of benzene
with PdCl
2
.
76
Finally, recent work by Yu et al. disclosed the use of Pd(OAc)
2
to effect
18
regioselective ligand-directed ortho deuteration of phenylacetic acids and related
compounds
77
in a conceptually similar strategy to previous work with iridium. These
extremely limited examples of homogeneous palladium-catalyzed H-D exchange, spread
out over four decades, suggest that there is much work remaining to be done in this field.
Figure 1.10. Representative examples of H-D exchange reactions catalyzed by
homogeneous palladium complexes.
1.7 References for Chapter 1
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Chapter 2. Chemoselective hydroamination of vinyl arenes catalyzed by an
NHC-amidate-alkoxide Pd(II) complex and p-TsOH.
Work presented in this chapter is demonstrated in the following publication:
Giles, R.; O’Neill, J.; Lee, J. H.; Chiu, M. K.; Jung. K. W. Tetrahedron Lett. 2013, 54,
4083-4085. DOI: 10.1016/j.tetlet.2013.05.101
2.1 Introduction
The formation of carbon-nitrogen bonds is an exceptionally active area of organic
chemistry, especially due to the prevalence of carbon-nitrogen bonds in molecules of
biological interest. In particular, hydroamination, the direct intermolecular or
intramolecular addition of an amine or amide across an unsaturated carbon-carbon bond,
is of great synthetic interest.
1
Hydroamination is particularly attractive due to its elegance
and atom economy; i.e. no leaving group is required for addition of nitrogen to occur.
However, while this transformation is typically thermodynamically favorable, it has a
high barrier of activation,
1
necessitating the use of various catalysts to facilitate the
addition.
The degree of diversity of hydroamination catalysts and reagents is exceptional,
encompassing homogeneous and heterogeneous metallic and other inorganic catalysts as
well as Brønsted acids and bases. Inorganic catalysts for hydroamination include alkaline
25
earth and rare-earth metals, the group 4 and group 5 metals, late transition metals,
zeolites and clays, and other solid-supported inorganic compounds.
1
Brønsted acids
catalyzing hydroamination reactions include, among others, triflic acid,
2
hydrogen
iodide,
3
and tungstophosphoric acid,
4
while bases used for hydroamination are generally
limited to lithium amides and other lithiated compounds.
1
Transition metals in particular have been extensively employed in hydroamination
reactions due to their combination of exceptional stability and distinguished reactivity as
well as their tolerance towards a wide variety of functional groups. Among the scope of
homogeneous intermolecular hydroamination reactions of vinyl arenes and weakly basic
nitrogen sources such as sulfonamides, various metal catalysts have been employed
including complexes of platinum, copper, bismuth, hafnium, iron, gold, silver, and
zirconium.
5
However, these methods have several limitations including an abbreviated
substrate scope, especially with electron-rich vinyl arenes, unavoidable concomitant
formation of undesirable side products, and air and moisture sensitivity.
Hydroamination reactions of vinyl arenes and sulfonamides are not limited to
conditions that employ transition metals. Other catalysts and stoichiometric reagents
including N-bromosuccinimide,
6
molecular iodine,
7
N-fluorobenzenesulfonimide,
8
ionic
liquids,
9
gallium
10
and Amberlyst-15
11
have also been utilized in similar hydroamination
reactions. Interestingly, this reaction was also show to be possible using simple Brønsted
acid catalysts, albeit limited to simple unsubstituted vinyl arenes.
2
These acid-catalyzed
examples were hampered by reaction of the nitrogen source with the acid, resulting in
formation of an unreactive intermediate, as well as a lack of selectivity between the
26
desired hydroamination product and a side product formed via the homocoupling of two
equivalents of the vinyl arene substrate (Scheme 2.1).
5d,11
Scheme 2.1. An example of competitive hydroamination and vinyl arene homocoupling
reactions under acidic conditions.
11
2.2 Initial work
During the initial studies, it became clear that palladium had never before been
utilized in the hydroamination of vinyl arenes with sulfonamides. However, the
pioneering work of Hartwig et al. revealed that the palladium-catalyzed intermolecular
hydroamination of vinyl arenes with various other nitrogen sources such as anilines was
indeed facile under the proper conditions.
12
The Pd-NHC-amidate catalyst scaffold
developed by our research group had previously shown efficacy in various
transformations including the Strecker reaction,
13
boron Heck-type additions,
14
and the
H-D exchange of benzene,
15
and application of catalyst 1 (Figure 1) towards direct C-N
bond formation using vinyl arenes and sulfonamides was considered.
Figure 2.1. NHC-amidate Pd(II) catalyst 1.
27
To determine if a methodology employing catalyst 1 was capable of overcoming
the shortcomings with previous hydroamination reactions, the hydroamination of styrene
with benzenesulfonamide was examined (Table 2.1). Initially, styrene 2 and
benzenesulfonamide 3 did not furnish any hydroamination product in the presence of
catalyst 1 alone (entry 1). However, a moderate yield of hydroamination product was
achieved by adding stoichiometric AgBF
4
, with abstraction of the chloride from 1 by
silver to generate an open site on palladium considered as a likely mechanism. Acidic co-
catalysts further improved the yield (entries 3-4), with p-toluenesulfonic (p-TsOH) acid
yielding superior results compared to tetrafluoroboric acid (HBF
4
). Unexpectedly,
however, a control experiment (entry 5) revealed that p-TsOH alone was an effective
hydroamination catalyst. It was speculated that trace amounts of HBF
4
generated from
AgBF
4
may have provided the driving force for the observed reactivity with palladium
(entry 2). The necessity to utilize a palladium catalyst at all was questioned.
28
Table 2.1. Determination of catalyst role in the hydroamination reaction.
ab
Entry Catalyst (10
mol %)
Additive (10 mol %) Acid (20 mol %) Yield
1 PdOMe - - 0%
2 PdOMe AgBF
4
- 44%
3 PdOMe AgBF
4
HBF
4
55%
4 PdOMe AgBF
4
p-TsOH 71%
5 - - p-TsOH 82%
a
Each reaction employed a 3:1 excess of the olefin to the sulfonamide.
b
General
conditions: to a mixture of 3 (0.25 mmol), 1 (10 mol%), AgBF
4
(10 mol%), and acid
(5.00×10
-2
mmol) in a 2 dram vial were added toluene (3 mL) and 2 (0.75 mmol). After
stirring for 18 h at 100 °C, the reaction mixture was diluted with CH
2
Cl
2
(3 mL),
neutralized with Et
3
N (5.00×10
-2
mmol), and filtered through diatomaceous earth. The
resulting solution was concentrated in vacuo then purified using flash column
chromatography with silica gel (4:1 hexanes/EtOAc).
However, when screening various styrene derivatives, an interesting observation
was made that elucidated a different role played by the palladium complex. As reported
previously under acid-catalyzed conditions,
11
unavoidable concomitant homocoupling of
the vinyl arene was an issue with this methodology (Scheme 2.2). When acids were used
as the sole catalysts, 4-methylstyrene 2 underwent homocoupling to furnish dimer 7
predominantly. However, when using catalyst 1 in conjunction with p-TsOH,
Markovnikov-type hydroamination was facilitated efficiently, improving the yields of the
hydroamination product (6 in Scheme 2.2) while minimizing undesired homocoupling
side product (7 in Scheme 2.2). This intriguing result gave rise to further investigation of
the phenomenon.
29
Scheme 2.2. Hydroamination of 4-methylstyrene along with formation of
homocoupled side product.
2.3 Results and Discussion
As shown in Table 2.2, a comparative study on hydroamination and homocoupling was
conducted. Using N,N-dimethylformamide (DMF) as an internal NMR standard,
conversion yields of 6 were recorded based on the sulfonamide as the limiting reagent
and the mole ratios of 6 and 7 as the measure of chemoselectivity. Among several acids
examined including triflic acid (TfOH) and trifluoroacetic acid (TFA), p-TsOH turned
out to be the most effective for hydroamination but still gave the dimer 7 as the major
product (entry 1). The use of palladium complexes as co-catalysts was then investigated.
When known palladium complexes were used (entries 2 and 3), both the yield of
hydroamination product and the chemoselectivity remained similar to those of the acid-
only conditions (entry 1). In sharp contrast, the addition of catalyst 1 led to a great
improvement in hydroamination conversion and considerable reversal of
chemoselectivity. Comparable results were observed with MeSO
3
H (entry 5). Unlike
known catalysts, our catalyst 1 inhibited undesired Brønsted acid-catalyzed
homocoupling of the olefin while promoting the desired hydroamination, implying that
30
the structure and electronic properties of the ligand, rather than the simple presence of a
palladium salt, could be the driving force behind the unique reactivity and selectivity.
Table 2.2. Effect of acids and palladium complexes on hydroamination of 4-
methylstyrene.
a
entry Pd catalyst
b
Acid 4 (yield) 4 : 5 (mol ratio)
1 - p-TsOH 71% 1 : 1.6
2 Pd(PPh
3
)
2
Cl
2
p-TsOH 81% 1 : 1.6
3 Pd(OAc)
2
p-TsOH 71% 1 : 1.7
4 1 p-TsOH 95% 7.9 : 1
5 1 MeSO
3
H 91% 5.1 : 1
a
All reactions were run using 0.25 mmol of benzenesulfonamide, 0.75 mmol of 4-
methylstyrene, 10 mole % of palladium catalyst, and 20 mol% of acid in toluene at 60
o
C.
With these trends noted, the influence of several other factors, including solvent and
substrate ratios, was determined (Table 2.3). Three distinct outcomes based on solvent
effects were observed; the reaction was very active but not selective (1,2-dichloroethane,
entry 1), no reaction occurred (dioxane, entry 2), and the reaction was efficient and
highly selective towards the hydroamination product (toluene, entry 3). When the amount
of the olefin was decreased to limit formation of dimer 7, much higher selectivities were
observed, as anticipated. However, the yields of 6 diminished significantly, revealing the
importance of using an excess of the olefin for optimal results (entries 4 – 5).
31
Table 2.3. Effect of solvents and substrate ratios.
a
entry Ratio (5 : 3) Solvent 6 (yield) 6 : 7 (mol ratio)
1 3 : 1 DCE 81% 1.2 : 1
2 3 : 1 dioxane 0% 0 : 0
3 3 : 1 toluene 81% 20 : 1
4 1 : 1 toluene 67% 67 : 1
5 1 : 3 toluene 61% 61 : 1
a
All reactions were run using 10 mol% of both the catalyst and acid at 60
o
C.
Subsequently, the effect of lowering catalyst 1 and acid loading at different
temperatures was investigated (Table 2.4). When 5 mol% of p-TsOH was used, the
chemoselectivities improved dramatically but the reactions were sluggish and provided
much lower yields of the hydroamination product (entries 1 and 2). With 10 mol% of the
acid and 2 – 5 mol% of the Pd catalyst, reasonably high yield and selectivity in favor of
the hydroamination product was observed (entry 3). Lower temperatures improved the
selectivity despite slightly lower yield (entry 4) while higher temperatures gave
comparable yields with slightly lower selectivity (entry 5). Thus depending on the nature
of the substrate, the temperature could be varied to improve either selectivity or yield as
desired.
32
Table 2.4. Effect of catalyst and acid at different temperatures.
a
entry 1 (mol%) p-TsOH (mol%) Temp (°C) 4 (yield) 4 : 5 (mol ratio)
1 5 5 60 55% 55 : 1
2 10 5 60 30% 30 : 1
3 5 10 60 93% 13 : 1
4 5 10 40 80% 40 : 1
5 5 10 100 91% 7 : 1
a
All reactions were run using 0.25 mmol of benzenesulfonamide and 0.75 mmol of 4-
methylstyrene in toluene.
Under the optimized catalytic conditions, the substrate scope of this methodology
was examined by screening various different vinyl arenes (Scheme 2.3 and Table 2.5).
16
Electron-rich vinyl arenes, including 4-methylstyrene (entry 1), 2,4-dimethylstyrene
(entry 2), and 4-methoxystyrene (entry 3), furnished the hydroamination products in good
yields and selectivities at relatively low temperatures (40–60
o
C). 2,4-Dimethylstyrene in
particular reacted in essentially quantitative yield under these conditions. 4-
Methoxystyrene, in comparison, was much more sensitive to polymerization than any
other substrates and required very mild conditions, including increased catalyst loading
and a lower temperature, to give the hydroamination product in a moderate yield. When
the substitution pattern was changed from 4-methoxy to 3-methoxy (entry 4), the
reactivity decreased dramatically and higher temperatures were required to afford
comparable yields. 3-Methoxystyrene behaved similarly to unsubstituted and electron-
neutral substrates encompassing styrene (entry 5) and 2-vinylnaphthalene (entry 6),
which reacted smoothly at higher temperatures than electron-rich styrenes. Higher
33
temperatures or increased amounts of p-TsOH resulted in significantly lower
chemoselectivities, yielding increased amounts of homocoupled product 10.
Scheme 2.3. General scheme for hydroamination of vinyl arenes.
4-F-, Cl-, and Br-substituted vinyl arenes were subjected to the developed catalytic
conditions and each of these substrates provided high yields and selectivities under
conditions similar to those used for electron-neutral examples (entries 7-9).
34
Table 2.5. Hydroamination of various vinyl arenes with benzenesulfonamide.
entry vinyl arene p-TsOH
(mol%)
solvent temp
(°C)
products yield
9 (%)
ratio
9 : 10
1 4-methylstyrene (8a) 10 toluene 60 9a, 10a 93 13 : 1
2 2,4-dimethylstyrene (8b) 10 toluene 60 9b, 10b 99 9 : 1
3 4-methoxystyrene
a
(8c) 5 toluene 40 9c, 10c 70 7.8 : 1
4 3-methoxystyrene (8d) 15 toluene 100 9d, 10d 73 12 : 1
5 styrene (8e) 15 toluene 100 9e, 10e 84 9.3 : 1
6 2-vinylnaphthalene (8f) 10 toluene 100 9f, 10f 57 14 : 1
7 4-fluorostyrene (8g) 15 toluene 100 9g, 10g 95 9.5 : 1
8 4-chlorostyrene (8h) 15 toluene 100 9h, 10h 83 28 : 1
9 4-bromostyrene (8i) 15 toluene 100 9i, 10i 87 15 : 1
10 2-fluorostyrene (8j) 20 chloro-
benzene
130 9j, 10j 70 23 : 1
11 2-bromostyrene (8k) 20 chloro-
benzene
130 9k, 10k 63 16 : 1
12 2-chlorostyrene
b
(8l) 20 chlorob-
enzene
130 9l, 10l 31 4.4 : 1
13 3-chlorostyrene (8m) 20 chloro-
benzene
130 9m, 10m 41 8.2 : 1
14 cis-β-methylstyrene (8n) 20 chlorob-
enzene
130 9n, 10n 13 13 : 1
a
10% catalyst loading was required.
b
Significant polymerization of starting material was
observed.
As expected based on the aforementioned examples, the reactivities dropped
significantly when the substitution pattern was changed from para to ortho. These
substrates required higher temperatures in chlorobenzene solvent with higher loading of
p-TsOH (entries 10-12). 2-Fluoro- and 2-bromostyrenes provided decent yields and
selectivities at 130
o
C. In contrast, 2-chlorostyrene underwent significant polymerization
35
as well as hydroamination and dimerization (entry 11). 3-Chlorostyrene was a poor
substrate (entry 13) while additional styrenes with electron withdrawing groups were also
resistant to hydroamination conditions. These results suggest that the vinyl arenes play an
electrophilic role in the hydroamination reaction and the electron-withdrawing
substituents on the styrenes would slow their reactivities. In pursuit of wider applications,
hydroamination on disubstituted styrenes were attempted but failed to acquire satisfactory
results. For instance, cis-β-methylstyrene barely generated the desired product because of
almost complete isomerization to the more stable trans-olefin (entry 14) which was
largely resistant to these conditions.
2.4 Conclusion
The combination of the tridentate NHC-amidate-alkoxide palladium complex 1 and p-
TsOH efficiently catalyzed the Markovnikov-type hydroamination of electronically
varying vinyl arenes with benzenesulfonamide. The developed hybrid method improved
the yields of the hydroamination products while minimizing the undesired homocoupling
side products, which existing methods commonly produced in the presence of strong
acids. In addition, while existing methods were generally limited to unsubstituted or
para-substituted substrates, the described method was highly efficient for vinyl arenes
with ortho-, meta-, and para-substitutions. Electron-rich and electron-neutral vinyl arenes
were well suited for the intended selective hydroamination.
36
2.5 References for Chapter 2
1
Müller, T. E.; Hultzsch, K. C.; Yus, M.; Foubelo, F.; Tada, M. Chem. Rev. 2008, 108,
3795–3892.
2
(a) Li, Z.; Zhang, J.; Brouwer, C.; Yang, C.-G.; Reich, N. W.; He, C. Org. Lett. 2006, 8,
4175–4178. (b) Rosenfeld, D. C.; Shekhar, S.; Takemiya, A.; Utsunomiya, M.; Hartwig,
J. F. Org. Lett. 2006, 8, 4179–4182.
3
Marcseková, K.; Doye, S. Synthesis 2007, 145–154.
4
Lingaiah, N.; Seshu Babu, N.; Mohan Reddy, K.; Sai Prasad, P.; Suryanarayana, I.
Chem. Commun. 2007, 278–279.
5
(a) Qian, H.; Widenhoefer, R. A. Org. Lett. 2005, 7, 2635–2638; (b) Taylor, J. G.;
Whittall, N.; Hii, K. K. Org. Lett. 2006, 8, 3561–3564; (c) Qin, H.; Yamagiwa, N.;
Matsunaga, S.; Shibasaki, M. Chem. Asian. J. 2007, 2, 150–154; (d) Michaux, J.;
Terrasson, V.; Marque, S.; Wehbe, J.; Prim, D.; Campagne, J.-M. Eur. J. Org. Chem.
2007, 2601–2603; (e) Zhang, X.; Corma, A. Dalton Trans. 2008, 7, 397–403; (f) Yang,
L.; Xu, L.-W.; Zhou, W.; Gao, Y.-H.; Sun, W.; Xia, C.-G. Synlett 2009, 7, 1167–1171;
(g) Dal Zotto, C.; Michaux, J.; Zarate Ruiz, A.; Gayon, E.; Virieux, D.; Campagne, J.-M.;
Terrasson, V.; Pieters, G.; Gaucher, A.; Prim, D. J. Organomet. Chem. 2011, 696, 296–
304; (h) Giner, X.; Nájera, C.; Kovács, G.; Lledós, A.;Ujaque, G. Adv. Synth. Catal.
2011, 353, 3451–3466.
6
Talluri, S. K.; Sudalai, A. Org. Lett. 2005, 7, 855–857.
7
Yadav, J. S.; Reddy, B. V. S.; Rao, T. S.; Krishna, B. B. M. Tetrahedron Lett. 2009, 50,
5351–5353.
8
Xu, T.; Qiu, S.; Liu, G. J. Organomet. Chem. 2011, 696, 46–49.
9
Yang, L.; Xu, L.-W.; Xia, C.-G. Synthesis 2009, 12, 1969–1974.
10
Jaspers, D.; Kubiak, R.; Doye, S. Synlett 2010, 8, 1268–1272.
11
Qureshi, Z. S.; Deshmukh, K. M.; Tambade, P. J.; Dhake, K. P.; Bhanage, B. M. Eur.
J. Org. Chem. 2010, 6233–6238.
12
Johns, A. M.; Utsunomiya, M.; Incarvito, C. D.; Hartwig, J. F. J. Am. Chem. Soc. 2006,
128, 1828-1839.
37
13
Jarusiewicz, J.; Choe, Y.; Yoo, K. S.; Park, C. P.; Jung, K. W. J. Org. Chem. 2009, 74,
2873–2876.
14
Yoo, K. S.; O’Neill, J.; Sakaguchi, S.; Giles, R.; Lee, J. H.; Jung, K. W. J. Org. Chem.
2010, 75, 95–101.
15
Lee, J. H.; Yoo, K. S.; Park, C. P.; Olsen, J. M.; Sakaguchi, S.; Prakash, G. K. S.;
Mathew, T.; Jung, K. W. Adv. Synth. Catal. 2009, 351, 563–568.
38
Chapter 3. Hydrogen–deuterium exchange of aromatic amines and amides
using deuterated trifluoroacetic acid.
Work presented in this chapter is demonstrated in the following publication:
Giles, R.; Lee, A.; Jung, E.; Kang, A.; Jung. K. W. Tetrahedron Lett. 2015, 56, 747-749.
DOI: 10.1016/j.tetlet.2014.12.102
3.1 Introduction
Increasing demand for deuterated compounds, especially due to a renewed
interest in the therapeutic prospects of so-called “heavy drugs”,
1
has spurred development
of novel methods for hydrogen-deuterium exchange. One group of compounds with
significant research interest for H-D exchange is the aromatic amines and amides, due to
the presence of these moieties in numerous clinically important pharmaceuticals,
including such mainstays as acetaminophen (paracetamol), diclofenac, and acebutolol.
The former two compounds are of particular importance with respect to aromatic isotopic
exchange due to their metabolism to potentially toxic ring-oxygenated metabolites in the
liver by cyctochrome P450 and related enzymes. Several in vitro and in vivo studies
performed using deuterated analogs of these compounds have had profound mechanistic
implications.
2
As a result, various syntheses of ring-deuterated variants of
acetaminophen
3
and diclofenac
4
have been reported. However, these methods generally
39
require several synthetic steps from expensive deuterated starting materials. Efforts have
been made towards exploring the direct aromatic H-D exchange of both of these
compounds to varying degrees of success.
5
In particular, a rapid, direct, and metal-free
method for labeling acetaminophen with deuterium has proven elusive.
Acid-catalyzed H-D exchange conditions encompass some of the most powerful
and efficient methods for incorporating deuterium into an aromatic ring.
6
While these
methods can employ a wide variety of acidic catalysts, including heterogeneous and
Lewis acids, homogeneous Brønsted systems are the most common. Under these
conditions, reactivity typically proceeds through an electrophilic aromatic substitution
mechanism and the aromatic ring is selectively deuterated at the most electron-rich
positions. Commonly-used systems for H-D exchange include a solvent, usually D
2
O, as
well as a deuterated mineral acid catalyst such as DCl, DBr, or D
2
SO
4
. However, the use
of these harsh reagents has several disadvantages, including unwanted side reactions, low
substrate solubility in aqueous solution, and potential substrate decomposition.
The use of deuterated trifluoroacetic acid (CF
3
COOD) has several benefits over
other acidic H-D exchange methods, including its ease of preparation, simple removal in
vacuo, low nucleophilicity, and high solubility properties for a wide variety of substrates.
CF
3
COOD can be prepared quantitatively from trifluoroacetic anhydride and D
2
O in
essentially anhydrous fashion. Since the pioneering efforts of Lauer et al.,
7
CF
3
COOD
has found use as a highly versatile and effective deuterating agent for hormones,
8
natural
products,
9
and various other biologically relevant aromatic systems.
10
The viability of this
reagent was considered for the deuteration of aromatic amines and amides such as
40
acetaminophen. A handful of examples can be found in the chemical literature, including
the CF
3
COOD-catalyzed H-D exchange of tryptophan and its derivatives
11
along with a
single report each regarding H-D exchange of naphthalene-diamines,
12
reserpine
13
and
pteroylglutamic acid.
14
However, to the best of our knowledge, the H-D exchange of
other aromatic amines and amides in CF
3
COOD has not been studied extensively. Herein
the generalized use of CF
3
COOD as a source of deuterium and reaction solvent is
reported for the preparation of several deuterated aromatic amine and amide derivatives.
3.2 Results and Discussion
During investigation of palladium-catalyzed H-D exchange of pharmaceutically
relevant compounds, CF
3
COOD was found be highly effective at deuterating
acetaminophen absent any metal catalyst at 110° C (Scheme 3.1). Since efficient and
direct H-D exchange of this compound has only been conducted using the assistance of
rhodium salts
5c
it was decided to investigate this unexpected transformation further.
Scheme 3.1. CF
3
COOD-catalyzed H–D exchange of acetaminophen.
At reflux without any additional catalyst or co-solvent, acetaminophen was
deuterated extensively at the aromatic positions ortho to the hydroxyl substituent and
more slowly at the positions ortho to the amide. The selectivity of deuteration is opposite
41
that observed in the previously reported metal-catalyzed example and is unprecedented in
the direct H-D exchange of acetaminophen.
Encouraged by these results, an effort was made to determine the scope of this
methodology and thus simple aniline and acetanilide, as well as aniline derivatives
substituted only at nitrogen, were subjected to the same CF
3
COOD conditions used for
acetaminophen (Figure 1). Aniline 1 and N-ethylaniline 2 underwent H-D exchange
smoothly under these conditions at the positions ortho and para to the nitrogen atom, a
result consistent with a standard EAS mechanism. However, the H-D exchange of N,N-
diethylaniline 3 under the same conditions was poor despite the enhanced induction from
the alkyl substituents on nitrogen. This low rate of exchange was also observed in
previous work on the acid-catalyzed proton exchange of N,N-diethylaniline
15
and
attributed to its high basicity and at least partially to steric interference from the ethyl
groups. Interestingly, 1-phenylpiperazine 4 was even more reactive towards CF
3
COOD–
catalyzed H-D exchange than aniline, indicating that dialkylation of the amine is not
inherently detrimental towards the exchange process. Acetanilide 5 was similarly reactive
towards H-D exchange as aniline, suggesting that acetylation of the nitrogen does not
necessarily deactivate the aromatic ring towards reaction with CF
3
COOD.
42
Figure 3.1. H-D exchange of anilines and acetanilide without ring substituents.
To test the effect of various ring substituents, para-substituted substrates were
then investigated under the reaction conditions (Figure 2). The reactivity of p-toluidine 6
was similar but not enhanced compared to aniline, despite the presence of an activating
methyl substituent on the ring. However, the reactivity of both p-anisidine 7 and p-
aminophenol 8 was significantly lower than that of p-toluidine, and deuteration of both of
these substrates proceeded with very low selectivity. Interestingly, 4-nitroaniline 9
underwent H-D exchange analogously to p-toluidine despite the very different electronic
properties of these aromatic systems. Thus a strong correlation between the basicity of
the amine and the rate of H-D exchange can be seen, with more basic anilines reacting
somewhat less efficiently and with lower selectivity. Acid-catalyzed H-D exchange of
aromatic anilines can proceed via aromatic substitution of either the protonated anilinium
ion (slow) or its free-base counterpart (fast) which exists in equilibrium. In strongly
acidic solution, electron-rich anilines are more likely to react through the former
pathway, and with deactivated anilines, the latter pathway predominates.
16
The observed
selectivity differences in this experiment likely reflect these mechanistic differences.
43
Figure 3.2. H-D exchange of para-substituted anilines and acetanilides.
Further support of this hypothesis can be drawn from the reactivity of the N-
acetylated derivatives of each compound. Acetylation of the amine inhibits protonation at
nitrogen, essentially eliminating one of the two possible H-D exchange pathways from
consideration. The reactivity of 4′-methylacetanilide 10 was comparable to its non-
acetylated counterpart 6, reflecting a minor inductive effect from the methyl substituent.
In contrast, the H-D exchange of 4-methoxyacetanilide 11 was very efficient and highly
selective compared to p-anisidine 7, and the observed H-D exchange pattern was opposite
that of 4′-methylacetanilide. The reactivity and deuteration selectivity of acetaminophen
12 was analogous to that of 4-methoxyacetanilide and similarly improved relative to 4-
aminophenol 8. The reactivity of 11 and 12 revealed the strong directing influence of the
hydroxy and methoxy functional groups in the absence of protonation at nitrogen.
However, the more-deactivated 4-nitroacetanilide 13 barely reacted at all compared to 4-
nitroaniline 9. Thus, while optimal H-D exchange results occur with less electron-rich
44
anilines, acetanilides react with greater efficiency with an activating substituent on the
aromatic ring.
The effect of the substitution pattern of the ring on H-D exchange was
investigated by reacting other anisidine isomers with CF
3
COOD (Figure 3). The
influence of the amine group dominated the H-D exchange selectivity of o-anisidine 14,
and the positions ortho and para to the amine exchanged rapidly under these conditions
while the positions ortho and para to the methoxy group had significantly lower
deuterium incorporation. A similar pattern was observed in m-anisidine 15, which
underwent rapid exchange throughout the ring excepting the single position meta to both
the amine and methoxy substituents. The effect of an electron-withdrawing substituent
nitro substituent in place of the methoxy was pronounced, as 3-nitroaniline 16 exchanged
at a much lower rate than m-anisidine.
Figure 3.3. H-D exchange of ortho and meta-substituted anilines.
The applicability of this method to more complex pharmaceutical compounds was
investigated using diclofenac as an example (Scheme 3.2). Like acetaminophen,
diclofenac is an aromatic amine or amide-containing NSAID with wide-ranging
therapeutic applications. Upon subjecting the sodium salt of diclofenac to the described
45
experimental conditions, cyclization was observed to the amide derivative 18. This
transformation was precedented in another acid-catalyzed H-D exchange experiment of
diclofenac, and the original sodium salt can be recovered using a simple base-catalyzed
procedure.
5a
Significant H-D exchange was observed in the ring annulated to the newly-
formed lactam at the positions ortho and para to nitrogen. However, little H-D exchange
was observed at the other aromatic positions.
Scheme 3.2. H-D exchange of diclofenac.
15
3.3 Conclusion
Using deuterated trifluoroacetic acid, the rapid and efficient H-D exchange of a
wide variety of aromatic amines and amides was achieved without the need for metal
salts or other co-catalysts. Direct H-D exchange of valuable pharmaceutically relevant
compounds such as acetaminophen and diclofenac was conducted, engendering the
possibility of applying this technique towards deuteration of other biologically active
compounds. The exchange reaction generally proceeded according to typical EAS
patterns, but was inhibited by strongly basic amines or highly deactivated acetanilides.
46
3.4 References for Chapter 3
1
(a) Timmins, G. S. Expert Opin. Ther. Patents 2014, 24, 1067-1075; (b) Katsnelson, A.
Nat. Med. 2013, 19, 656.
2
(a) Grunwald, H.; Hargreaves, P.; Gebhardt, K.; Klauer, D.; Serafyn, A.; Schmitt-
Hoffmann, A.; Schleimer, M.; Schlotterbecks, G.; Wind, M. J. Pharmaceut. Biomed.
2013, 85, 138-144; (b) Kozakai, K.; Yamada, Y.; Oshikata, M.; Kawase, T.; Suzuki, E.;
Haramaki, Y.; Taniguchi, H. Drug Metab. Pharmacokinet. 2012, 27, 520-529; (c)
Hoffmann, K.-J.; Axworthy, D. B.; Baillie, T. A. Chem. Res. Toxicol. 1990, 3, 204-211;
(d) Forte, A. J.; Wilson, J. M.; Slattery, A. J.; Nelson, S. D. Drug Metab. Dispos. 1984,
12, 484-491.
3
(a) Johnston, D.; Elder, D. J. Labelled Comp. Rad. 1988, 25, 1315-1318. (b) Freed, C.
R.; Murphy, R. C. J. Labelled Comp. Rad. 1978, 15, 637-643.
4
(a) Wu, K.; Tian, L.; Li, H.; Li, J.; Chen, L. J. Labelled Comp. Rad. 2009, 52, 535-537;
(b) Leroy, D.; Richard, J.; Godbillon, J. J. Labelled Comp. Rad. 1993, 33, 1019–1027.
5
(a) Atzrodt, J; Blankenstein, J.; Brasseur, D.; Calvo-Vicente, S.; Denoux, M.; Derdau,
V.; Lavisse, M.; Perard, S.; Roy, S.; Sandvoss, M.; Schofield, J.; Zimmermann. J.
Bioorgan. Med. Chem. 2012, 20, 5658-5667; (b) Tuck, K. L.; Tan, H.-W.; Hayball, P. J.
J. Labelled Comp. Rad. 2000, 43, 817–823; (c) Lockley, W. J. S. J. Labelled Comp. Rad.
1985, 22, 623-630.
6
Junk, T.; Catallo, W. J. Chem. Soc. Rev. 1997, 26, 401-406.
7
Lauer, W. M.; Matson, G. W.; Stedman, G. J. Am. Chem. Soc. 1958, 80, 6433–6437.
8
(a) Stack, D. E.; Ritonya, J.; Jakopovic, S.; Maloley-Lewis, B. Steroids 2014, 92, 32-38;
(b) Kiuru, P. S.; Wähälä, K. Tetrahedron Lett. 2002, 43, 3411-3412.
9
(a) Betts, J. W.; Kitney, S. P.; Fu, Y.; Peng, W.-M.; Kelly, S. M.; Haswell, S. J. Chem.
Eng. J. 2011, 167, 545-547. (b) Kamounah, F. S.; Christensen, P.; Hansen, P. E. J.
Labelled Comp. Rad. 2010, 54, 126-131. (c) Jordheim, M.; Fossen, T.; Songstad, J.;
Andersen, Ø. M. J. Agric. Food Chem. 2007, 55, 8261–8268.
10
(a) Fan, D.; Taniguchi, M.; Lindsey, J. S. J. Org. Chem. 2007, 72, 5350-5357. (b)
Taylor, P. J. M.; Bull, S. D. Tetrahedron-Asymmetr. 2006, 17, 1170-1178.
11
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Matthews, H. R.; Matthews, K. S.; Opella, S. J. Biochim. Biophys. Acta 1977, 497, 1-13.
47
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Dambmann, C.; Nicolaisen, F. Acta Chem. Scand. 1967, 21, 1674-1675.
12
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13
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14
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Comp. Rad. 1978, 14, 479–486.
15
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16
Bean, G. P.; Katritzky, A. R. J. Chem. Soc. B 1968, 864-866.
48
Chapter 4. H-D exchange in deuterated trifluoroacetic acid via ligand-
directed NHC-palladium catalysis: a powerful method for deuteration of
aromatic ketones, amides, and amino acids.
Work presented in this chapter is in final preparations as a scientific manuscript.
4.1 Introduction
Development of efficient, practical methods for H-D exchange has accelerated as
a result of the rapidly increasing commercial importance of deuterated compounds. Of
particular interest are deuterated pharmaceuticals, the commercial value of which is
expected to eventually exceed 1 billion USD.
1
One deuterated drug, the tetrabenazine
derivative SD-809, has shown promising results during phase 3 clinical trials for chorea
associated with Huntington’s disease.
2
A number of catalytic processes have been
investigated to produce these valuable deuterium-labeled compounds, including metal-
free conditions as well as both homogeneous and heterogeneous metallic catalysts.
3
Of
the homogenous transition metal-catalyzed methods for H-D exchange of
pharmaceutically relevant compounds, most have focused on the use of rhodium and
iridium
4
although H-D exchange of other small molecules by homogenous ruthenium,
5
palladium
5a,6
and platinum
5a,6b,7
species has also been reported. These reactions are
frequently conducted in deuterated acidic media such as acetic acid-d
4
or trifluoroacetic
acid-d
1
(CF
3
COOD). However, recent studies have called into question whether certain
49
metal-catalyzed H-D exchange reactions in acidic solvents proceed through C-H
activation or electrophilic aromatic substitution mechanisms; in CF
3
COOD, the latter
mechanism has been suggested to predominate.
5a,8
Ligand-directed C-H activation by palladium is a versatile method for highly
selective functionalization of otherwise unreactive C-H bonds. Numerous challenging
transformations have been carried out using this approach, including alkylation,
olefination, alkynylation, arylation, and amidation reactions, among others.
9
While
several different mechanistic pathways are possible depending on the specific reaction,
generally the substrate undergoes cyclopalladation with the ligated palladium catalyst to
generate the reactive intermediate.
9a
Weakly-coordinating ligands such as ketones and
carboxylic acids have recently emerged as promising directing groups for palladium-
catalyzed organic synthesis. Because palladacycles formed using weakly-coordinating
directing groups are generally less thermodynamically stable than their tightly-bound
counterparts, they are thus more reactive towards functionalization.
9c
A few reports of ligand-directed H-D exchange using rhodium
10
and ruthenium
5b-c
catalysts have been published, although most studies employ iridium complexes.
11
Recently, a report of ligand-directed palladium-catalyzed ortho-selective H-D exchange
of benzoic acids and phenylacetic acids using weak coordination has been published.
6a
The H-D exchange of benzene and other hydrocarbons in D
2
O with NHC-amidate
palladium catalyst 1
6c
has been previously investigated. The use of CF
3
COOD as a
solvent, catalyst, and source of deuterium label for anilines and acetanilides has also been
established.
12
Herein is reported an H-D exchange methodology that utilizes both of these
50
strategies simultaneously to effect the ortho-selective H-D exchange of aromatic amides,
ketones, and amino acids. In several cases, this ligand-directed C-H activation process
occurs in conjunction with electrophilic H-D exchange by CF
3
COOD, allowing for
complete H-D exchange of pharmaceutically relevant compounds such as acetaminophen.
This distinguished reactivity provides a complimentary strategy for previously
inaccessible deuterated substrates.
Figure 4.1. NHC-amidate palladium catalyst 1.
4.2 Results and Discussion
Our previously reported electrophilic H-D exchange method using CF
3
COOD
without any additional metal catalyst
12
was highly effective for aromatic amides and
amines. However, this method was ineffective for more electron-poor substrates such as
acetophenone and its derivatives, and the use of a homogeneous palladium catalyst in
conjunction with CF
3
COOD was considered to improve the extent of deuteration.
51
Table 4.1. Effect of palladium salts and AgTFA additive on H-D exchange.
a
Entry Catalyst Additive % D (H
1
) % D (H
2
)
1 none - 6 2
2 PdCl
2
- 6 2
3 Pd(MeCN)
2
Cl
2
- 6 2
4 Pd(OAc)
2
- 7 4
5 Pd(PPh
3
)
2
Cl
2
- 5 1
6 Pd(TFA)
2
- 9 9
7 1 - 6 13
8 Pd(PPh
3
)
2
Cl
2
AgTFA
b
6 1
9 none AgTFA 6 1
10 1 AgTFA 11 86
11 1 AgOTf -
c
-
c
a
H-D exchange of other positions on the aromatic rings has been omitted for clarity.
b
0.04 mmol AgTFA was added.
c
Significant degradation of the substrate was observed.
Ketones have been employed as directing groups for numerous different metal-
catalyzed transformations, including ortho-selective H-D exchange with iridium
11
and
ruthenium.
5b
To determine the viability of a palladium-catalyzed H-D exchange method
using a ketone as a directing group, 2-acetonaphthone was subjected to reaction with
52
CF
3
COOD in the presence of several different palladium(II) complexes and additives
(Table 4.1).
In the absence of any palladium catalyst, no significant H-D exchange occurred
on the aromatic rings although extensive H-D exchange was observed on the acetyl group
(entry 1). Most common palladium salts showed negligible improvement over the control
experiment (entries 2 – 5), although Pd(TFA)
2
exhibited minor activity (entry 6). While
these known catalysts favored regioselective H-D exchange of H
1
, Pd-NHC catalyst 1 (10
mol%) effected an improved rate of deuteration at H
2
preferentially (entry 7). Activation
of the palladium salts with AgTFA was then investigated. When activated Pd(PPh
3
)
2
Cl
2
(generated via addition of two equivalents of AgTFA) and AgTFA alone were used as
catalysts, reactivity was unchanged relative to the control experiment (entries 8 – 9).
However, the use of catalyst 1 with AgTFA (10 mol%) resulted in a significant
increase in the extent of H-D exchange observed, far superior to any of the other
palladium salts tested. Substitution of deuterium was selective, occurring predominantly
at one position (H
2
), ortho to the ketone (entry 10). Adding AgOTf in place of AgTFA
resulted in reduced H-D exchange as well as partial degradation of the substrate (entry
11).
53
Table 4.2. Effect of reaction conditions on H-D exchange.
a
Entry 1 (mol%) AgTFA (mol%) solvent % D
1 10 10 CF
3
COOD 86
2 10 20 CF
3
COOD 82
3 5 5 CF
3
COOD 72
4
b
10 10 CF
3
COOD 9
5
c
10 10 CF
3
COOD 77
6
d
10 10 CF
3
COOD 76
7 10 10 DOAc-d
3
0
8 10 10 MeOD-d
3
1
9
e
10 10 CF
3
COOD 85
a
H-D exchange of other positions on the aromatic rings has been omitted for clarity.
b
Reaction conducted at 60 °C.
c
0.5 mL of CF
3
COOD was added.
d
2 mL of CF
3
COOD
was added.
e
Reaction proceeded for 36 h.
In the presence of Pd-NHC catalyst 1, various reaction conditions were then
investigated (Table 4.2). Additional AgTFA resulted in no improvement (entry 1 vs entry
2), and reducing the catalyst loading lowered the extent of H-D exchange somewhat
(entry 3). At lower temperatures, very low amounts of deuterium incorporation were
observed (entry 4). Increasing or decreasing the volume of CF
3
COOD gave
approximately a 10% reduction in deuterium incorporation (entries 5 – 6). Little or no H-
D exchange was observed when deuterated acetic acid or methanol was used in place of
CF
3
COOD as a solvent (entries 7 – 8). Longer reaction times did not result in a
54
proportional increase in deuterium incorporation (entry 9). It was concluded that the
original conditions did not require further optimization.
The substrate scope of this method was evaluated by testing several different
aromatic ketones in the presence of catalyst 1 and AgTFA (Scheme 4.1). The method was
less effective for unsubstituted acetophenone 2 compared to 2-acetonaphthone 6,
resulting in 25% total ortho-selective deuterium incorporation. The aliphatic protons
adjacent to the carbonyl (acetyl protons) were mostly exchanged with deuterium (>90%);
this H-D exchange occurred with all substrates tested independent of palladium catalyst.
Similarly, deuterium incorporation in 4 ′-methoxyacetophenone 3 was marginally
improved by the palladium catalyst. Interestingly, while the Pd-NHC catalyst efficiently
deuterated highly activated ketone 4 more effectively than CF
3
COOD, the nitro-
substituted ketone 5 was unresponsive to the developed conditions, suggesting a strong
dependence on the electronic properties of the aromatic ring. As explained above, 2-
acetonaphthone 6 exhibited far superior reactivity and selectivity under the palladium-
catalyzed conditions. Other bicyclic ketones such as 7 and 8 were moderately deuterated
with a high degree of ortho selectivity. However, when the ketone was distal to the
aromatic ring such as in dibenzyl ketone 9, almost no ortho incorporation of deuterium
was observed.
55
Scheme 4.1. H-D exchange of aromatic ketones with CF
3
COOD (condition a) and
CF
3
COOD with catalyst 1 and AgTFA (condition b).
a
The bracketed numbers
adjacent to each aromatic position represent percent deuterium incorporation at that
position (combined in the case of a symmetrical structure.) Isolated yields are given in
parentheses.
Encouraged by these promising results with ketones, acetanilide derivatives were
investigated (Scheme 4.2). Acetanilides have been extensively utilized as directing
groups for palladium-catalyzed C-H functionalization reactions and have also been
employed to direct H-D exchange reactions with rhodium,
10c
iridium,
11
and ruthenium.
5c
The palladium-catalyzed ortho-selective H-D exchange of acetanilides was envisaged
56
proceeding in a similar fashion to ketones under identical conditions. Previous work
12
identified acetanilides as substrates well-suited for electrophilic H-D exchange in
CF
3
COOD, so care was taken to identify any improvement in ortho-selective deuterium
incorporation by catalyst 1.
Scheme 4.2. H-D exchange of aromatic amides and their derivatives with CF
3
COOD
(condition a) and CF
3
COOD with catalyst 1 and AgTFA (condition b).
a
Results 10a-
14a are from our previous work
12
using identical conditions and are shown for
comparison purposes.
b
No deuterium incorporation was observed at the amide
substituents after workup.
c
The bracketed numbers adjacent to each aromatic position
57
represent percent deuterium incorporation at that position (combined in the case of a
symmetrical structure.) Isolated yields are given in parentheses.
d
Keto-enol
tautomerism prevents accurate determination of deuterium incorporation at the
pyrazolone methylene position.
Electron-rich and electron-neutral acetanilides 10-13 were deuterated efficiently
under the described conditions, although electron-poor acetanilide 14 had significantly
lower deuterium incorporation. Notably, one-step, nearly complete ring deuteration of
pharmaceutically-relevant acetaminophen 13 was achieved, which was a significant
improvement over existing literature methods which required multiple inefficient
synthetic steps
13
or only partially deuterated the aromatic ring.
10c,11e,14
As with ketone
substrate 9, distal amide substrate 15 was ineffective at promoting H-D exchange.
Conversely, pyrazolone-substituted substrate 16, the pharmaceutically-relevant
compound edaravone, was selectively ortho-deuterated in good yield in the presence of
catalyst. Benzamide 17 was somewhat reactive towards the palladium catalyst but was
deuterated much less efficiently than the acetanilides. In summary, the palladium-
catalyzed conditions led to a high degree of H-D exchange selectively ortho to the amide
group, a significant improvement over the previously developed CF
3
COOD conditions.
The H-D exchange of aromatic amino acids using this method was also
considered. Various methods for ring deuteration of phenylalanine and tyrosine
derivatives, generally employing acid catalysis, have been reported in the literature.
7f-g,15
Palladium-catalyzed ortho functionalization of aromatic amino acids such as
phenylalanine and tyrosine and their derivatives has been conducted
16
but typically uses
methyl esters
17
or sulfonamides
18
to efficiently direct C-H activation. It was found that
58
simple unmodified α-phenylglycine 18 and phenylalanine 19 were deuterated selectively
at the ortho positions by the developed catalytic method (Scheme 4.3). Previously,
aromatic deuterium incorporation ortho to the side chain of phenylalanine was achieved
by selective protonation of ring-perdeuterated tyrosine followed by reduction to
phenylalanine,
15c
an inefficient and deuterium-uneconomical strategy. However,
palladium-catalyzed ortho deuteration was not as effective for tyrosine 20, and
electrophilic H-D exchange by CF
3
COOD was predominant. Varying amounts of
deuterium incorporation were observed at the stereocenters, and thus some racemization
of the amino acids may have occurred. Interestingly, neither phenylacetic acid 21 nor
benzylamine 22 showed selectivity towards H-D exchange by the palladium catalyst,
suggesting that efficient ligand direction does not occur in the absence of the amine or
carboxylic acid functional groups.
Scheme 4.3. H-D exchange of amino acids and derivatives with CF
3
COOD (condition
a) and CF
3
COOD with catalyst 1 and AgTFA (condition b).
a
The bracketed numbers
adjacent to each aromatic position represent percent deuterium incorporation at that
position (combined in the case of a symmetrical structure.) Isolated yields are given in
parentheses.
59
Based on the experimental evidence collected, a catalytic cycle was envisioned
involving coordination of the palladium-NHC complex 1 to the substrate of interest,
followed by C-H activation of an accessible aromatic proton. This process may involve
formation of an agostic complex with assistance from coordinated trifluoroacetate, as
evidenced in several computational studies.
19
Subsequent deuterolysis would furnish the
deuterated substrate and regenerate the catalyst. This proposed mechanism is
conceptually very similar to that suggested by Yu et al. in the palladium-catalyzed H-D
exchange of phenylacetic acids and other arenes.
6a
The active intermediate for such a C-
H activation reaction would presumably be a cyclopalladated aryl-Pd(II) complex;
however, this proposed intermediate could not be isolated. Acid-catalyzed H-D exchange
by CF
3
COOD, following a simple electrophilic aromatic substitution pathway, would be
concomitant with several substrates.
While evidence suggests metal-catalyzed H-D exchange reactions of arenes in
strong acids such as CF
3
COOD, especially with additives such as AgTFA, are in many
cases predominantly electrophilic,
5a,8
a Lewis-acid type H-D exchange mechanism under
the described conditions is unlikely for several reasons. First, Lewis-acid catalyzed H-D
exchange is typically restricted to nonpolar arenes
3a
without functional groups that the
Lewis acid could coordinate to preferentially. Moreover, simple palladium salts were not
nearly as effective catalytically as the NHC-palladium complex 1, which exhibits
increased thermal stability and electron density on palladium due to strong σ donation
from the NHC ligand. This complex has previously been utilized for H-D exchange
reactions under neutral conditions.
6c
In this case, the role of the AgTFA is thus to abstract
60
chloride from palladium to generate an open coordination site, not to increase the Lewis
acidity of the metal center. Additionally, the high degree of ortho selectivity observed for
H-D exchange of ketones, without comparable meta or para reactivity, further suggests a
C-H activation mechanism. Finally, when AlCl
3
was utilized in place of palladium with
2-acetonapthone 6, no improvement over simple acid-catalyzed conditions were seen,
both with and without stoichiometric AgTFA additive.
4.3 Conclusion
Using a palladium-NHC catalyst in deuterated trifluoroacetic acid, one-step
ligand-directed ortho-selective H-D exchange of aromatic ketones, amides, and amino
acids has been conducted. The Pd-NHC complex tested showed distinguished reactivity
compared to other palladium salts, which were ineffective deuteration catalysts. In
general, acetanilides were more reactive than ketones, and a strong correlation of
reactivity with the electronic properties of the aromatic ring was observed. Direct ortho
deuteration of amino acids was possible without prior functionalization at nitrogen or
oxygen. Experimental data supports the intermediacy of an aryl-palladium species
generated by C-H activation of the coordinated substrate rather than Lewis acid-type
catalysis. With highly activated substrates, substantial concurrent acid-catalyzed
electrophilic H-D exchange also occurred, resulting in nearly complete ring deuteration
of several acetanilides, including pharmaceutically-relevant acetaminophen.
The potential catalytic applications of this method are significant. The Pd-NHC
catalyst 1 is air and water-stable and retains high activity in refluxing trifluoroacetic acid,
revealing its robust thermodynamic stability under considerably harsh reaction
61
conditions. As a result, ortho-selective aromatic functionalization with other electrophiles
besides deuterium cation may be possible using a variant of this method. Further work
will explore these possibilities and investigate synthetic modification of the catalyst
scaffold and development of additional NHC ligands to improve catalytic activity and
selectivity.
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J. Biochim. Biophys. Acta 1977, 497, 1-13. (i) Griffiths, D.B., Feeney, J., Roberts,
G.C.K.; Burgen, A.S.V. Biochim. Biophys. Acta 1976, 446, 479-485.
16
Noisier, A. F. M.; Brimble, M. A. Chem. Rev. 2014, 114, 8775−8806.
17
(a) Albert, J.; Ariza, X.; Calvet, T.; Font-Bardia, M.; Garcia, J.; Granell, J.; Lamela, A.;
López, B.; Martinez, M.; Ortega, L.; Rodriguez, A.; Santos, D. Organometallics 2013,
32, 649-659. (b) López, B.; Rodriguez, A.; Santos, D.; Albert, J.; Ariza, X.; Garcia, J.;
Granell, J. Chem. Commun. 2011, 47, 1054-1056. (c) Nieto, S.; Arnau, P.; Serrano, E.;
Navarro, R.; Soler, T.; Cativiela, C.; Urriolabeitia, E. P. Inorg. Chem. 2009, 48, 11963–
11975. (d) Vicente, J.; Saura-Llamas, I.; García-López, J.-A.; Calmuschi-Cula, B.;
Bautista, D. Organometallics 2007, 26, 2768-2776.
18
(a) García-Rubia, A.; Laga, E.; Cativiela, C.; Urriolabeitia, E. P.; Gómez-Arrayás, R.;
Carretero, J. C. J. Org. Chem. 2015, 80, 3321-3331. (b) He, G.; Zhao, Y.; Zhang, S.; Lu,
C.; Chen, G. J. Am. Chem. Soc. 2012, 134, 3-6. (c) Vickers, C. J.; Mei, T.-S.; Yu, J.-Q.
Org. Lett. 2010, 12, 2511-2513. (d) Mei, T.-S.; Wang, X.; Yu, J.-Q. J. Am. Chem. Soc.
2009, 131, 10806–10807. (e) Li, J.-J.; Mei, T.-S.; Yu, J.-Q. Angew. Chem. Int. Ed. 2008,
47, 6452–6455.
19
(a) Jiang, J.; Yu, J-Q.; Morokuma, K. ACS Catal. 2015, 5, 3648–3661. (b) Munz, D.;
Strassner, T. Chem. Eur. J. 2014, 20, 14872-14879. (c) Aullón, G.; Chat, R.; Favier, I.;
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8292–8300. (d) Davies, D. L.; Donald, S. M. A.; Macgregor, S. A. J. Am. Chem. Soc.
2005, 127, 13754-13755.
64
Chapter 5. Dual Studies on a Hydrogen-Deuterium Exchange of Resorcinol
and the Subsequent Kinetic Isotope Effect.
Work presented in this chapter is demonstrated in the following publication:
Giles, R.; Kim, I.; Chao, W. E.; Moore, J.; Jung. K. W. J. Chem. Educ. 2014, 91, 1220-
1223. DOI: 10.1021/ed500093g
5.1 Introduction
It is well-understood that hydrogen-deuterium (H-D) exchange reactions are
efficient and selective on numerous activated aromatic compounds in D
2
O with a
catalytic amount of acid. These reactions typically follow general trends for electrophilic
aromatic substitution. H-D exchange of aromatic systems has been extensively reviewed
in the chemical literature
1
but implemented sparingly in experiments within the Journal of
Chemical Education.
2
Moreover, simple isotopic labeling laboratory experiments with
clear results are underrepresented in a teaching context outside of upper-level physical,
physical organic, and inorganic chemistry laboratories. Growing interest in deuterated
pharmaceuticals
3
presents a fascinating application for this avenue of chemistry.
While a handful of kinetic isotope effect (KIE) laboratory experiments and lecture
demonstrations with organic compounds suitable for lower-level undergraduate students
have been reported in the Journal of Chemical Education,
4
they employ deuterated
65
compounds that have been previously synthesized and/or highly toxic metal catalysts or
reagents that are undesirable for use in a teaching laboratory. In contrast, the
methodology described herein utilizes simple reagents under metal-free conditions and
allows students to both conduct an H-D exchange experiment and subsequently examine
the kinetic isotope effect within a single laboratory session. It is a versatile methodology
suitable for students at the secondary and undergraduate levels to explore the process of
isotopic substitution and its effect on further reactivity.
Aromatic hydrogen-deuterium exchange seems to be under-utilized in teaching
laboratories because such reactions often take an impractical amount of time for
sufficient deuterium incorporation or require undesirable metal catalysts. There is
generally no visual confirmation that exchange has taken place, as the product and
starting material possess identical appearances and may be difficult to resolve apart from
analysis from advanced instrumentation, such as mass spectrometry and NMR.
Additionally, most common electrophilic or nucleophilic aromatic substitution
reactions do not exhibit meaningful KIE values, as elimination of hydrogen or deuterium
from the intermediate species is rapid compared to the slow addition of electrophiles or
nucleophiles to the aromatic ring. Under normal circumstances, for example, there are
few, if any, easily observable kinetic isotope effects for nitration, chlorination, or
bromination of aromatic systems.
5
However, there are notable exceptions to this trend,
including azo-coupling
4a
and iodination. Specifically, a substantial KIE for the iodination
of phenol with molecular iodine in buffered solution was reported with an observed k
H
/k
D
up to 6.3 depending on the concentration of iodide.
6
Under these conditions, the initial
66
addition of iodide to the aromatic ring was rapid and highly reversible, making
elimination of hydrogen or deuterium the slow step in comparison.
Resorcinol is deuterated much more rapidly under acidic conditions than phenol
while retaining a comparable isotope effect. Much like phenol, resorcinol is inexpensive
and highly soluble in acidic D
2
O solution. These qualities make it an optimal substrate
for a laboratory experiment that combines an H-D exchange reaction with a subsequent
visualization of the kinetic isotope effect. Herein is described a convenient way to label a
simple aromatic molecule with deuterium and demonstrate its reactivity compared to the
unmodified starting material. The pedagogic goal of the experiment is to improve student
understanding of several important concepts, including electrophilic aromatic substitution
(EAS), the kinetic isotope effect, and
1
H NMR spectroscopy. The described reactions can
be examined with or without advanced instrumentation. While employed primarily as
part of the laboratory curriculum for undergraduate students in organic chemistry, the
chemistry involved is accessible by students at multiple levels of instruction and can also
be discussed from several perspectives depending on the intended audience.
5.2 Experimental Design
Students worked in pairs. The reactant was resorcinol, a highly activated aromatic
molecule that reacts quickly and efficiently by electrophilic aromatic substitution under
acidic conditions. Each student prepared a solution of resorcinol (0.60 mmol) in D
2
O (1
mL) containing H
2
SO
4
(20 μL). Both solutions were refluxed for 30 minutes then were
cooled to room temperature. One reaction solution was analyzed by
1
H NMR
67
spectroscopy, and the other solution was used in the iodination reaction (as the reaction
mixture).
Students prepared another solution of resorcinol in acidic D
2
O that is not refluxed
as a (non-deuterated) control. Students conducted iodination of resorcinol at room
temperature by adding a dilute solution of molecular iodine and potassium iodide in
ethanol simultaneously to two vials, one containing the reaction mixture and the other
containing the (non-deuterated) control.
6,7
The reaction progress was monitored visually
via the disappearance of iodine color in the reaction solutions due to the formation of 2-
iodoresorcinol and 4-iodoresorcinol. The kinetic isotope effect of the iodination reactions
were quantified by analysis of UV-Vis spectroscopic data
6,7
provided to students.
5.3 Results and Discussion
This experiment has been completed once in a laboratory session of 3 hours by a
total of 15 first-semester undergraduate organic chemistry students. The C-H bonds in
resorcinol did not undergo significant H-D exchange in refluxing D
2
O in a time frame
reasonable for use in a classroom setting. However, when D
2
O and sulfuric acid were
mixed together, the concentration of D
3
O
+
in solution and subsequent reactivity were
greatly increased. To conduct the reaction, a microscale reflux apparatus, consisting of a
small vial containing a spin vane (a boiling chip would be sufficient) with a reflux
condenser, was heated on a hot plate. The reaction typically reached equilibrium within
30 minutes of heating, after which no further net deuteration would occur. The
appearance of the reaction mixture did not change over the course of the experiment.
68
Resorcinol underwent >95% H-D exchange at the 2-, 4-, and 6-positions on the
ring (Scheme 5.1). This result was in accord with a typical EAS mechanism involving
slow addition of D+ to the aromatic ring to form an intermediate arenium ion followed by
rapid elimination of the proton. Though there was a negligible kinetic preference for
elimination of the proton over the deuteron, the high concentration of deuterium in
solution resulted in preferential formation of the trideuterated species. The alcohol
protons were also exchanged, but this had no effect on the outcome of the experiment.
Scheme 5.1. Acid-catalyzed H-D exchange of resorcinol in D
2
O.
Students transferred the reaction mixture to an NMR tube for
1
H NMR analysis.
The extent of deuteration was determined by integrating the remaining proton at the 5-
position and comparing it to any remaining proton signals (Figure 5.1). This proton was
meta to the activating hydroxyl groups on the ring and thus not activated towards
electrophilic exchange. As a result, deuterium incorporation at this position was
negligible during the course of the experiment. The NMR signal associated with this
proton collapsed from a triplet into a broad singlet, providing strong evidence that
neighboring protons were exchanged with deuterium. The inability to observe any H-D
coupling in the spectrum, despite deuterium being NMR active (I = 1), typified important
differences between H-H and H-D spin-spin coupling and can provide an introduction to
69
more advanced NMR concepts such as the magnetogyric ratio. The spectrum was used as
an effective explanation of electrophilic aromatic substitution trends due to the clear
distinction between near complete exchange at the positions ortho and para to the
activating hydroxyl groups and very minor exchange at the meta position. Representative
spectra are in the Supporting Information.
Figure 5.1.
1
H NMR spectra of resorcinol prior to (left) and after (right) H-D
exchange.
By adapting the procedure from a previous work
7
students visualized the kinetic
isotope effect by adding a dilute ethanolic solution of iodine and sodium iodide to the
reaction mixture containing deuterated resorcinol and a control mixture of resorcinol and
sulfuric acid in D
2
O at ambient temperature (Scheme 5.2). Before adding the iodine
solution, the deuterated mixture and control (non-deuterated) mixture were clear, nearly
colorless, and visually indistinguishable. After initial addition of the iodine solution, both
the deuterated mixture and control mixture were translucent and dark orange-red in color.
The color faded and the solutions clarified as the iodine reacted with the resorcinol. In
70
each case, after completion of the reaction, the solution was clear and very light yellow in
color, indicating that a trace amount of unreacted iodine may remain.
In the control experiment, the iodine color of the solution faded much more
rapidly (i.e., a change was apparent within five minutes) compared to the deuterated
example, and the reaction was nearly complete after approximately half an hour.
Comparatively, the isotopically labeled resorcinol-d
5
reacted much more slowly, and the
reaction remained incomplete after well over an hour. The concentration of iodine
remained consistently higher in the vial containing deuterated resorcinol throughout the
duration of the experiment, providing a qualitative visual representation of the
comparative reactivities of each substrate. The effect was best observed when the
experimental and control reactions were conducted side-by-side and a student could
observe both results simultaneously. While reaction time and the concentration of iodine
varied somewhat from student to student, the trend was very clear in each case and the
effect was easily visualized.
Scheme 5.2. Simplified mechanism for electrophilic iodination of resorcinol.
The kinetic isotope effect k
H
/k
D
of the iodination reaction was also determined
quantitatively (Figure 5.2). The reaction of iodine with resorcinol under the
aforementioned conditions was found to be second-order overall, providing an excellent
71
opportunity to quantify the KIE by monitoring the UV-Vis absorption spectrum of iodine
as it reacted at 460 nm. However, because a significant amount of time was required to
collect sufficient UV-Vis data and the outcome appeared to be somewhat sensitive to
minor variances in preparation, previously obtained data were given to students for
interpretation. By plotting 1/[I
2
] versus time for the control and experimental conditions
and comparing the slopes of these plots, a k
H
/k
D
of approximately 3.4 was calculated.
72
Figure 5.2. Representative UV-Vis absorbance data (at 460 nm) for the experiment.
5.4 Student Experiences
A key aspect of this experimental methodology is its adaptability to fit the target
audience. This experiment was primarily utilized as part of the lab curriculum for first-
semester undergraduate organic chemistry students. Prior to conducting the experiment,
73
most students only had a cursory understanding of isotopes and their effect on chemical
reactivity. Students were introduced to the concepts of electrophilic aromatic substitution,
isotopic exchange, and the kinetic isotope effect as part of the required reading before the
experiment. By performing the experiment, students were able to better comprehend EAS
and isotopic exchange. Using
1
H NMR, they were able to familiarize themselves with the
instrumentation and its utility in characterizing such isotopic exchange reactions.
Additionally, they interpreted UV-Vis absorbance data to quantify the kinetic isotope
effect of the iodination reaction and rationalize its rate and mechanism. After the
experiment, post-lab write-ups indicated that all students had a significantly greater
understanding of EAS and the kinetic isotope effect, and many were interested in the
potential applications of the chemistry, including the production of deuterated drugs.
As a secondary project, the deuteration and iodination reactions were successfully
performed and the results interpreted by ambitious high school students looking to gain
experience with undergraduate-level chemistry. These students had previous experience
with chemistry courses but were not familiar with isotopic substitution reactions or their
effects. While some of the more complicated aspects of the transformation were omitted,
the fundamental aspects of isotopic exchange could be understood and demonstrated
experimentally. Isotope effects were explained by comparing the physical properties of
D
2
O and H
2
O (slightly different molar masses and densities), as well as by monitoring
the iodination reaction visually. In each case, students saw firsthand that isotopically
substituted compounds often have very similar physical properties but can be
differentiated through experimentation. This methodology is amenable to a diverse
74
audience of chemistry students and educators, with the complexity of the material highly
adaptable to the desired outcome.
5.5 References for Chapter 5
1
(a) Junk, T.; Catallo, W. J. Chem. Soc. Rev. 1997, 26, 401–406. (b) Atzrodt, J.; Derdau,
V.; Fey, T.; Zimmermann, J. Angew. Chem., Int. Ed. 2007, 7744–7765.
2
(a) Hanson, J. R. J. Chem. Educ. 1982, 59, 342–343. (b) Murray, C. J.; Duffin, K. L. J.
Chem. Educ. 1991, 68, 683–684. (c) Field, L. D.; Sternhell, S.; Wilton, H. V. J. Chem.
Educ. 1999, 76, 1246–1247.
3
(a) Yarnell, A. T. Chem. Eng. News 2009, 87, 36–39. (b) Katsnelson, A. Nat. Med.
2013, 19, 656.
4
(a) Zollinger, H. J. Chem. Educ. 1957, 34, 249. (b) Henderson, J. J. Chem. Educ. 1988,
65, 349. (c) Harding, C. E.; Mitchell, C. W.; Devenyi, J. J. Chem. Educ. 2000, 77, 1042-
1044. (d) Iskenderian-Epps, W. S.; Soltis, C.; O’Leary, D. J. J. Chem. Educ. 2013, 90,
1044-1047.
5
Zollinger, H. Adv. Phys. Org. Chem. 1964, 2, 163–200.
6
(a) Grovenstein Jr., E.; Kilby, D. C. J. Am. Chem. Soc. 1957, 79, 2971–2972. (b)
Grovenstein Jr., E.; Aprahamian, N. S.; Bryan, C. J.; Gnanapragasam, N. S.; Kilby, D. C.;
McKelvey Jr., J. M.; Sullivan, R. J. J. Am. Chem. Soc. 1973, 95, 4261–4270.
7
Macháček, V.; Štěrba, V.; Valter, K. Collect. Czech. Chem. Commun. 1972, 37, 3073–
3080.
75
Appendix 1. Chemoselective hydroamination of vinyl arenes catalyzed by
an NHC-amidate-alkoxide Pd(II) complex and p-TsOH.
A1.1 Experimental Section
General considerations
All reactions were conducted under an ambient atmosphere. Palladium-NHC catalyst 1
was prepared according to a literature procedure.
[1]
All other solvents and reagents were
obtained from commercial vendors (Sigma-Aldrich, Alfa Aesar, Acros, TCI, or BDH)
and used without further purification.
1
H NMR spectra were obtained using a Varian
Mercury 400 spectrometer at 400 MHz or a Varian 500S spectrometer at 500 MHz.
13
C
NMR spectra were obtained using a Mercury 400 spectrometer at 100 MHz or a Varian
500S spectrometer at 125 MHz. Chemical shifts (δ) are given in ppm and are referenced
to the residual CDCl
3
solvent peak. Flash column chromatography was conducted using
SiliaFlash® P60 40-63µm (230-400 mesh) silica gel.
Typical procedure
To a mixture of benzenesulfonamide 3 (0.25 mmol), palladium catalyst 1 (10 mol%), and
p-TsOH (5.00×10
-2
mmol) in a 2 dram (7.39 mL) vial were added toluene (3 mL) and
vinyl arene 8 (0.75 mmol). After stirring for 18 h at 100 °C, the reaction mixture was
diluted with CH
2
Cl
2
(3 mL), neutralized with Et
3
N (5.00×10
-2
mmol), and filtered
76
through diatomaceous earth. The resulting solution was concentrated in vacuo then
purified using flash column chromatography with silica gel (4:1 hexanes/EtOAc).
Product conversions were determined via comparison of
1
H NMR peak integrations with
a DMF internal NMR standard. For isolation of analytically pure compounds, further
purification using preparatory TLC was generally required.
A1.2 Spectral Data for New Compounds Synthesized
N-(1-(2,4-dimethylphenyl)ethyl)benzenesulfonamide 7b
White solid.
1
H NMR: δ 7.73-7.69 (m, 2H, ArCH), 7.50-7.44 (m, 1H, ArCH), 7.39-7.33
(m, 2H, ArCH), 7.02-6.97 (m, 1H, ArCH), 6.86-6.81 (m, 2H, ArCH), 4.76-4.74 (d, J =
6.4 Hz, 1H, NH), 4.74-4.66 (m, 1H, CH), 2.23 (s, 3H, CH
3
), 2.13 (s, 3H, CH
3
), 1.41-1.37
(d, J = 6.8 Hz, 3H, CH
3
).
13
C NMR: 140.79, 137.26, 137.08, 134.50, 132.34, 131.31,
128.86, 127.22, 127.09, 125.38, 49.77, 23.26, 20.99, 18.98.
(E)-4,4'-(but-1-ene-1,3-diyl)bis(1,3-dimethylbenzene) 8b
Colorless oil.
1
H NMR: δ 7.39-7.35 (m, 1H, ArCH), 7.25-7.20 (m, 1H, ArCH), 7.10-7.05
(m, 2H, ArCH), 7.03-6.97 (m, 2H, ArCH), 6.65-6.59 (d, J = 16 Hz, 1H, C=CH), 6.27-
6.20 (dd, J
1
= 16.5 Hz, J
2
= 6.5 Hz, 1H, C=CH), 3.94-3.86 (m, 1H, CH), 2.42 (s, 3H,
CH
3
), 2.37 (s, 1H, CH), 2.35 (s, 6H, CH
3
), 1.52-1.49 (d, J = 7.0 Hz, 3H, CH
3
).
13
C NMR:
140.89, 136.63, 135.73, 135.54, 135.00, 134.14, 131.34, 131.02, 127.01, 126.85, 126.35,
126.14, 125.60, 38.24, 21.14, 21.10, 20.85, 19.85, 19.52.
77
N-(1-(3-methoxyphenyl)ethyl)benzenesulfonamide 7d
Colorless oil.
1
H NMR: δ 7.75-7.71 (d, 2H, ArCH), 7.51-7.46 (m, 1H, ArCH), 7.42-7.36
(m, 2H, ArCH), 7.14-7.07 (m, 1H, ArCH), 6.73-6.65 (m, 2H, ArCH), 6.61-6.56 (s, 1H,
ArCH), 4.92-4.86 (d, J = 6.5 Hz, 1H, NH), 4.51-4.43 (m, 1H, CH), 3.72-3.67 (s, 3H,
OCH
3
), 1.45-1.41 (d, J = 7.0 Hz, 3H, CH
3
).
13
C NMR: 159.83, 143.52, 140.78, 132.49,
129.78, 128.95, 127.18, 118.50, 113.22, 111.86, 55.28, 53.83, 23.68.
N-(1-(naphthalen-2-yl)ethyl)benzenesulfonamide 7f
1
H NMR: δ 7.76-7.74 (m, 1H, ArCH), 7.72-7.65 (m, 4 H, ArCH), 7.52-7.51 (m, 1H,
ArCH), 7.47-743 (m, 2H, ArCH), 7.41-7.37 (m, 1H, ArCH), 7.31-7.27 (m, 2H, ArCH),
7.19-7.16 (m, 1H, ArCH), 4.76-4.74 (d, J = 7.0 Hz, 1H, NH), 4.69-4.66 (m, 1H, CH),
1.54-1.52 (d, J = 7.0 Hz, 3H, CH
3
).
13
C NMR: 140.73, 139.09, 133.22, 132.88, 132.49,
128.90, 128.69, 127.99, 127.70, 127.18 126.43, 126.23 125.22, 124.12, 53.98, 23.59.
N-(1-(4-fluorophenyl)ethyl)benzenesulfonamide 7g
White solid.
1
H NMR: δ 7.71-7.69 (m, 2H, ArCH), 7.51-7.48 (m, 1H, ArCH), 7.41-7.37
(m, 2H, ArCH), 7.07-7.04 (m, 2H, ArCH), 6.88-6.82 (m, 2H, ArCH), 4.93 (d, J = 6.8 Hz,
1H, NH), 4.53-4.46 (m, 1H, CH), 1.41 (d, J = 6.8 Hz, 3H, CH
3
).
13
C NMR: 161.39,
160.94, 140.70, 137.78, 137.74, 132.59, 129.00, 128.01, 127.92, 127.15, 115.59, 115.37,
53.18, 23.73.
78
N-(1-(4-chlorophenyl)ethyl)benzenesulfonamide 7h
White solid.
1
H NMR: δ 7.72-7.68 (m, 2H, ArCH), 7.53-7.47 (m, 1H, ArCH), 7.42-7.34
(m, 2H, ArCH), 7.13-7.09 (m, 2H, ArCH), 7.05-7.00 (m, 2H, ArCH), 5.49-5.45 (d, J =
7.2 Hz, 1H, NH), 4.50-4.42 (m, 1H, CH), 1.39-1.36 (d, J = 7.2 Hz, 3H, CH
3
).
13
C NMR:
140.63, 140.50, 133.45, 132.62, 129.04, 128.78, 127.70, 127.14, 53.21, 23.61.
N-(1-(4-bromophenyl)ethyl)benzenesulfonamide 7i
White solid.
1
H NMR: δ 7.71-7.67 (m, 2H, ArCH), 7.54-7.49 (m, 1H, ArCH), 7.42-7.36
(m, 2H, ArCH), 7.32-7.27 (m, 2H, ArCH), 6.99-6.94 (m, 2H, ArCH), 4.84-4.78 (d, J =
6.8 Hz, 1H, NH), 4.51-4.43 (m, 1H, CH), 1.42-1.38 (d, J = 6.8 Hz, 3H, CH
3
).
13
C NMR:
140.99, 140.61, 132.63, 131.75, 129.05, 128.05, 127.15, 121.57, 53.26, 23.58.
N-(1-(2-fluorophenyl)ethyl)benzenesulfonamide 7j
White solid.
1
H NMR: δ 7.69-7.65 (m, 2H, ArCH), 7.44-7.39 (m, 1H, ArCH), 7.34-7.28
(m, 2H, ArCH), 7.14-7.04 (m, 2H, ArCH), 6.96-6.91 (m, 1H, ArCH), 6.84-6.77 (m, 1H,
ArCH), 5.07-5.00 (d, J = 6.8 Hz, 1H, NH), 4.73-4.63 (m, 1H, CH), 1.49-1.45 (d, J = 5.6
Hz, 3H, CH
3
).
13
C NMR: 161.18, 159.22, 140.28, 132.43, 129.37, 129.30, 128.85,
128.29, 128.25, 127.03, 124.37, 124.34, 115.95, 115.78, 50.35, 50.34, 23.05, 23.04.
79
N-(1-(2-bromophenyl)ethyl)benzenesulfonamide 7k
Light yellow solid.
1
H NMR: δ 7.75-7.70 (m, 2H, ArCH), 7.46-7.41 (m, 1H, ArCH),
7.38-7.31 (m, 3H, ArCH), 7.20-7.16 (m, 1H, ArCH), 7.14-7.08 (m, 1H, ArCH), 7.01-6.96
(m, 1H, ArCH), 5.37-531 (d, J = 7.2 Hz, 1H, NH), 4.94-4.86 (m, 1H, CH), 1.44-1.39 (d, J
= 7.2 Hz, 3H, CH
3
).
13
C NMR: 140.94, 140.10, 133.11, 132.56, 128.92, 128.90, 127.88,
127.85, 127.21, 122.08, 53.37, 23.07.
N-(1-(3-chlorophenyl)ethyl)benzenesulfonamide 7m
White solid.
1
H NMR: δ 7.71-7.69 (m, 2H, ArCH), 7.51-7.47 (m, 1H, ArCH), 7.41-7.37
(m, 2H, ArCH), 7.12-7.11 (m, 2H, ArCH), 7.01-6.98 (m, 2H, ArCH), 4.89-4.87 (d, J =
7.2 Hz, 1H, NH), 4.50-4.47 (m, 1H, CH), 1.41-1.40 (d, J = 7.2 Hz, 3H, CH
3
).
13
C NMR:
143.91, 140.52, 134.52, 132.73, 129.97, 129.01, 127.82, 127.12, 126.57, 124.49, 53.36,
23.65.
80
A1.2
1
H and
13
C NMR Spectra For New Compounds Synthesized
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
A1.3 References for Appendix 1
1
J. H. Lee, K. S. Yoo, C. P. Park, J. M. Olsen, S. Sakaguchi, G. K. S. Prakash, T.
Mathew, K. W. Jung, Adv. Synth. Catal. 2009, 351, 563-568
100
Appendix 2. Hydrogen–deuterium exchange of aromatic amines and
amides using deuterated trifluoroacetic acid.
A2.1 Experimental Section
General considerations
All reactions were conducted under an ambient atmosphere. Deuterated trifluoroacetic
acid (CF
3
COOD) was prepared from D
2
O and trifluoroacetic anhydride according to a
literature procedure
[1]
and used without distillation. Palladium-NHC catalyst 1 was also
prepared according to a literature procedure.
[2]
All other solvents and reagents were
obtained from commercial vendors (Sigma-Aldrich, Alfa Aesar, Acros, TCI, or BDH)
and used without further purification.
1
H NMR spectra were obtained using a Varian
Mercury 400 spectrometer at 400 MHz or a Varian 500S spectrometer at 500 MHz.
13
C
NMR spectra were obtained using a Varian 500S spectrometer at 125 MHz.
2
H NMR
spectra were obtained using a Varian 500S spectrometer at 77 MHz. Chemical shifts (δ)
are given in ppm and are referenced to the residual solvent peak (CDCl
3
, MeOH, or
DMSO). Flash column chromatography was conducted using SiliaFlash® P60 40-63µm
(230-400 mesh) silica gel.
General procedure for the H-D exchange reaction of amines
To the substrate (0.2 mmol) in a 2 dram (7.39 mL) glass vial was added CF
3
COOD (1.0
mL, 12.98 mmol). A magnetic stir bar was added and the sealed vial was heated with
101
stirring to 110° C for 16 h. After cooling, the mixture was diluted with 2 mL of TFA and
filtered through diatomaceous earth. The solvent was evaporated in vacuo and the residue
was stirred in 2 M KOH solution (0.5 mL) for 0.1-4.0 h. The deuterium-labeled substrate
was extracted with CH
2
Cl
2
or EtOAc, and the organic layer was dried with Na
2
SO
4
then
removed in vacuo. The crude product was purified using flash column chromatography
with silica gel (CH
2
Cl
2
, EtOAc, or MeOH). The purified product was analyzed by
1
H
NMR spectroscopy. The amount of deuterium incorporation was determined via
comparison of
1
H NMR peak integrations with a control sample of the substrate using a
1,3,5-trimethoxybenzene internal NMR standard of known concentration.
General procedure for the H-D exchange reaction of acetanilides
To the substrate (0.2 mmol) in a 2 dram (7.39 mL) glass vial was added CF
3
COOD (1.0
mL, 12.98 mmol). A magnetic stir bar was added and the sealed vial was heated with
stirring to 110° C for 16 h. After cooling, the mixture was diluted with 2 mL of TFA and
filtered through diatomaceous earth. The solvent was evaporated in vacuo and the residue
was stirred in saturated aqueous NaHCO
3
solution (1 mL) for 0.5 h. The deuterium-
labeled substrate was extracted with CH
2
Cl
2
or EtOAc, and the organic layer was dried
with Na
2
SO
4
then removed in vacuo. The crude product was purified using flash column
chromatography with silica gel (CH
2
Cl
2
, EtOAc, or MeOH). The purified product was
analyzed by
1
H NMR spectroscopy. The amount of deuterium incorporation was
determined via comparison of
1
H NMR peak integrations with a control sample of the
102
substrate using a 1,3,5-trimethoxybenzene internal NMR standard of known
concentration.
Determination of Deuterium Content
The degree of deuterium incorporation for all substrates was determined using
1
H NMR.
This was accomplished by comparison of the experimental
1
H NMR spectrum of each
purified substrate after the H-D exchange reaction to a control
1
H NMR spectrum of the
substrate before the reaction. In each case, integration of the substrate peaks was
referenced to an identical 1,3,5-trimethoxybenzene internal NMR standard of known
concentration. Reductions in the integration of product peaks from their expected values
based on the internal standard correspond proportionally to the amount of deuterium
incorporation. In the case of a symmetrical structure, the total percent deuterium
incorporation at all NMR-equivalent positions is reported. These numbers are given in
brackets adjacent to each substrate in the main text. H-D exchange of labile protons, such
as those on amines and alcohols, was not considered. The following formula was used to
calculate total deuterium incorporation:
Percentage deuterium incorporation = (1 – (actual integration/expected integration))×100
103
Example: H-D exchange of m-anisidine 15
Figure A2.1. NMR signals and total deuterium incorporation in m-anisidine.
Expected NMR integration of H
A
(relative to internal NMR standard): 4.37
Actual NMR integration of H
A
(relative to internal NMR standard): 0.35
Percentage deuterium incorporation at H
A
= (1 – (0.35/4.37))×100 = 92%.
This indicates an average deuterium incorporation of 0.92 at this position on the aromatic
ring.
104
Representative
1
H NMR spectra of m-anisidine 15
Figure A2.2.
1
H NMR spectra of m-anisidine 15 showing the disappearance of proton
signals after the catalytic H-D exchange reaction in CF
3
COOD.
A2.2 Spectral Data for Substrates Used in Deuterium Labeling Studies
Aniline 1
1
H NMR (CDCl
3
) δ 7.16 (br s, 1.84H, ArCH), 6.77 (t, J = 7.6 Hz, 0.15H, ArCH), 6.70 (d,
J = 7.6 Hz, 0.34H, ArCH).
13
C NMR: 145.78, 129.07, 118.82, 118.76, 118.56, 118.37,
115.31, 115.22, 115.03, 114.84.
2
H NMR: 6.83 (br s), 6.77 (br s).
105
N-ethylaniline 2
1
H NMR (DMSO-d
6
) δ 7.30 (m, 1.66H, ArCH), 7.09 (m, 0.42H, ArCH), 7.02 (m, 0.16H,
ArCH), 3.16 (q, J = 7.2 Hz, 2H, CH
2
), 1.18 (t, J = 7.2 Hz, 3H, CH
3
).
N,N-diethylaniline 3
1
H NMR (DMSO-d
6
) δ 7.11 (m, 1.84H, ArCH), 6.62 (m, 1.56H, ArCH), 6.52 (m, 0.76H,
ArCH), 3.29 (q, J = 7.2 Hz, 4H, CH
2
), 1.05 (t, J = 7.2 Hz, 6H, CH
3
).
1-phenylpiperazine 4
1
H NMR (DMSO-d
6
) δ 7.18 (br s, 1.58H, ArCH), 6.88 (d, J = 8.8 Hz, 0.14H, ArCH),
6.73 (t, J = 7.2 Hz, 0.07H, ArCH), 2.99 (m, 4H, CH
2
), 2.80 (m, 4H, CH
2
).
Acetanilide 5
1
H NMR (CDCl
3
) δ 7.49 (d, J = 8.4 Hz, 0.46H, ArCH), 7.45 (br s, 1H, NH), 7.30 (br s,
1.56H, ArCH), 7.10 (d, J = 7.2 Hz, 0.19H, ArCH), 2.16 (s, 3H, CH
3
).
p-toluidine 6
1
H NMR (CDCl
3
) δ 6.97 (m, 1.60H, ArCH), 6.62 (m, 0.60H, ArCH), 2.25 (s, 3H, CH
3
).
p-anisidine 7
1
H NMR (CDCl
3
) δ 6.75 (m, 1.54H, ArCH), 6.65 (m, 0.98H, ArCH), 3.74 (s, 3H, OCH
3
).
106
4-aminophenol 8 (converted to hydrochloride salt)
1
H NMR (DMSO-d
6
) δ 7.17 (m, 1.16H, ArCH), 6.83 (m, 0.98H, ArCH).
4-nitroaniline 9
1
H NMR (MeOD-d
3
) δ 7.97 (m, 1.86H, ArCH), 6.61 (m, 0.54H, ArCH).
4′-methylacetanilide 10
1
H NMR (DMSO-d
6
) δ 9.79 (br s, 1H, NH), 7.43 (m, 0.58H, ArCH), 7.06 (br s, 1.82H,
ArCH), 2.22 (s, 3H, CH
3
), 1.99 (s, 3H, CH
3
).
4-methoxyacetanilide 11
1
H NMR (CDCl
3
) δ 7.54 (br s, 1H, NH), 7.38 (br s, 1.74H, ArCH), 6.84 (m, 0.12H,
ArCH), 3.78 (s, 3H, OCH
3
), 2.16 (s, 3H, CH
3
).
Acetaminophen 12
1
H NMR (DMSO-d
6
) δ 9.62 (br s, 1H, NH), 9.10 (br s, 1H, OH), 7.31 (br s, 1.28H,
ArCH), 6.65 (m, 0.14H, ArCH), 1.95 (s, 3H, CH
3
).
4-nitroacetanilide 13
1
H NMR (DMSO-d
6
) δ 10.53 (br s, 1H, NH), 8.19 (m, 1.88H, ArCH), 7.80 (m, 1.86H,
ArCH), 2.10 (s, 3H, CH
3
).
107
o-anisidine 14 (converted to hydrochloride salt)
1
H NMR (DMSO-d
6
) δ 7.47 (m, 0.09H, ArCH), 7.37 (m, 0.09H, ArCH), 7.19 (m, 0.83H,
ArCH), 7.01 (m, 0.66H, ArCH), 3.86 (s, 3H, OCH
3
).
m-anisidine 15
1
H NMR (CDCl
3
) δ 7.08 (br s, 0.74H, ArCH), 6.34 (d, J = 6.4 Hz, 0.09H, ArCH), 6.31 (d,
J = 6.4 Hz, 0.10H, ArCH), 6.26 (br s, 0.08H, ArCH), 3.78 (s, 3H, OCH
3
).
3-nitroaniline 16
1
H NMR (DMSO-d
6
) δ7.36 (t,
4
J = 2.2 Hz, 0.73H, ArCH), 7.28 (m, 0.45H, ArCH), 7.23
(t, J = 7.8 Hz, 0.84H, ArCH), 6.93 (m, 0.79H, ArCH).
Diclofenac 17 (converted to lactam derivative 18)
1
H NMR (CDCl
3
) δ 7.54-7.50 (d, J = 6.4 Hz, 1.80H, ArCH), 7.41-7.37 (t, J = 6.4 Hz,
0.89H, ArCH), 7.35 (br s, 0.85H, ArCH), 7.22 (br s, 0.75H, ArCH), 7.11 (t, J = 6.0 Hz,
ArCH), 6.42 (d, J = 6.0 Hz, ArCH), 3.77 (br s, 0.04H, CH
2
).
108
A2.3 NMR Spectra for Substrates Used in Deuterium Labeling Studies
1
H NMR of aniline 1.
109
13
C NMR of aniline 1 (detail, inset).
110
2
H NMR of aniline 1 (detail, inset).
111
112
113
114
115
116
117
118
119
120
121
122
123
124
125
126
A2.4 References for Appendix 2.
1
R. J. Smith, R. M. Pagni, J. Org. Chem. 1982, 47, 3180–3183.
2
J. H. Lee, K. S. Yoo, C. P. Park, J. M. Olsen, S. Sakaguchi, G. K. S. Prakash, T.
Mathew, K. W. Jung, Adv. Synth. Catal. 2009, 351, 563-568
127
Appendix 3. H-D exchange in deuterated trifluoroacetic acid via ligand-
directed NHC-palladium catalysis: a powerful method for deuteration of
aromatic ketones, amides, and amino acids.
A3.1 Experimental Section
General considerations
All reactions were conducted under an ambient atmosphere. Deuterated trifluoroacetic
acid (CF
3
COOD) was prepared from D
2
O and trifluoroacetic anhydride according to a
literature procedure
[1]
and used without distillation. Palladium-NHC catalyst 1 was also
prepared according to a literature procedure.
[2]
All other solvents and reagents were
obtained from commercial vendors (Sigma-Aldrich, Alfa Aesar, Acros, TCI, or BDH)
and used without further purification.
1
H NMR spectra were obtained using a Varian
Mercury 400 spectrometer at 400 MHz or a Varian 500S spectrometer at 500 MHz.
Chemical shifts (δ) are given in ppm and are referenced to the residual solvent peak
(CDCl
3
, D
2
O, MeOH, DMSO, or MeCN). Flash column chromatography was conducted
using SiliaFlash® P60 40-63µm (230-400 mesh) silica gel.
128
General procedure for the non palladium-catalyzed H-D exchange reaction (condition a)
To the substrate (0.2 mmol) in a 2 dram (7.39 mL) glass vial was added CF
3
COOD (1.0
mL, 12.98 mmol). A magnetic stir bar was added and the sealed vial was heated with
stirring to 110° C for 16 h. After cooling, the mixture was diluted with 2 mL of TFA and
filtered through diatomaceous earth. The solvent was evaporated in vacuo and the residue
was stirred in saturated aqueous NaHCO
3
solution (1 mL) for 0.5 h. The deuterium-
labeled substrate was extracted with CH
2
Cl
2
or EtOAc, and the organic layer was dried
with Na
2
SO
4
then removed in vacuo. The crude product was purified using flash column
chromatography with silica gel (CH
2
Cl
2
, EtOAc, or MeOH). The purified product was
analyzed by
1
H NMR spectroscopy. The amount of deuterium incorporation was
determined via comparison of
1
H NMR peak integrations with a control sample of the
substrate using a 1,3,5-trimethoxybenzene internal NMR standard of known
concentration.
General procedure for the palladium-catalyzed H-D exchange reaction (condition b)
To the substrate (0.2 mmol) in a 2 dram (7.39 mL) glass vial was sequentially added
catalyst 1 (0.02 mmol), AgTFA (0.02 mmol), and CF
3
COOD (1.0 mL, 12.98 mmol). A
magnetic stir bar was added and the sealed vial was heated with stirring to 110° C for 16
h. After cooling, the mixture was diluted with 2 mL of TFA and filtered through
diatomaceous earth. The solvent was evaporated in vacuo and the residue was stirred in
saturated aqueous NaHCO
3
solution (1 mL) for 0.5 h. The deuterium-labeled substrate
129
was extracted with CH
2
Cl
2
or EtOAc, and the organic layer was dried with Na
2
SO
4
then
removed in vacuo. The crude product was purified using flash column chromatography
with silica gel (CH
2
Cl
2
, EtOAc, or MeOH). The purified product was analyzed by
1
H
NMR spectroscopy. The amount of deuterium incorporation was determined via
comparison of
1
H NMR peak integrations with a control sample of the substrate using a
1,3,5-trimethoxybenzene internal NMR standard of known concentration.
Purification of Amino Acids
Amino acids underwent H-D exchange reactions as described above. After cooling, the
reaction mixture was diluted with 2 mL of TFA and filtered through diatomaceous earth.
The solvent was evaporated in vacuo and the residue was stirred in Et
3
N (1 mL) for 0.5 h.
The Et
3
N was evaporated in vacuo and acetone (3 mL) was added to the residue to
precipitate the free amino acid. The precipitated product was isolated via vacuum
filtration on a fine fritted glass funnel and washed with acetone and CH
2
Cl
2
. The purified
product was analyzed by
1
H NMR spectroscopy.
Determination of Deuterium Content
The degree of deuterium incorporation for all substrates was determined using
1
H NMR.
This was accomplished by comparison of the experimental
1
H NMR spectrum of each
purified substrate after the H-D exchange reaction to a control
1
H NMR spectrum of the
130
substrate before the reaction. In each case, integration of the substrate peaks was
referenced to an identical 1,3,5-trimethoxybenzene internal NMR standard of known
concentration. Reductions in the integration of product peaks from their expected values
based on the internal standard correspond proportionally to the amount of deuterium
incorporation. In the case of a symmetrical structure, the total percent deuterium
incorporation at all NMR-equivalent positions is reported. These numbers are given in
brackets adjacent to each substrate in the main text. H-D exchange of labile protons, such
as those on amines and alcohols, was not considered. The following formula was used to
calculate total deuterium integration:
Percentage deuterium incorporation = (1 – (actual integration/expected integration))×100
Example: H-D exchange of benzophenone 7b using Pd-NHC catalyst 1 (condition b)
Figure A3.1. NMR signals and total deuterium incorporation in benzophenone
(condition b).
Expected NMR integration of H
A
(relative to internal NMR standard): 13.29
Actual NMR integration of H
A
(relative to internal NMR standard): 6.04
131
Percentage deuterium incorporation at H
A
= (1 – (6.40/13.29))×100 = 52%.
As there are 4 H
A
protons in total, this indicates an average deuterium incorporation of
2.1 (of a potential 4) at this position on the aromatic ring.
Representative
1
H NMR spectra of 2-acetonaphthone 6 (condition a and condition b)
Figure A3.2.
1
H NMR spectra of 2-acetonaphthone 6 showing the disappearance of
proton signals after catalytic H-D exchange reactions in CF
3
COOD (condition a) and in
CF
3
COOD with palladium catalyst 1 (10 mol%) and AgTFA (10 mol%) (condition b).
132
A3.2 Spectral Data for Substrates Used in Deuterium Labeling Studies
Spectral Data for Catalyst 1
[1]
1
H NMR (MeCN-d
3
) δ 7.61 (m, 1H, ArCH), 7.51 (m, 1H, ArCH), 7.46-7.37 (m, 2H,
ArCH), 5.53 (s, 2H, CH
2
), 4.33 (s, 3H, CH
3
), 3.40-3.30 (m, 4H, CH
2
), 3.22 (s, 3H, CH
3
).
Acetophenone 2a
1
H NMR (CDCl
3
) δ 7.97 (m, 1.90H, ArCH), 7.58 (m, 1.94H, ArCH), 7.47 (m, 1.96H,
ArCH), 2.61 (m, 0.60H, CH
3
).
Acetophenone 2b
1
H NMR (CDCl
3
) δ 7.96 (m, 1.50H, ArCH), 7.57 (m, 1.96H, ArCH), 7.46 (m, 1.92H,
ArCH), 2.58 (m, 0.33H, CH
3
).
4′-Methoxyacetophenone 3a
1
H NMR (CDCl
3
) δ 7.93 (m, 1.68H, ArCH), 6.92 (m, 0.76H, ArCH), 3.86 (s, 3H, OCH
3
),
2.52 (m, 0.27H, CH
3
).
4′-Methoxyacetophenone 3b
1
H NMR (CDCl
3
) δ 7.93 (m, 1.34H, ArCH), 6.93 (m, 0.66H, ArCH), 3.86 (s, 3H, OCH
3
),
2.52 (m, 0.21H, CH
3
).
133
3′,4′-(Methylenedioxy)acetophenone 4a
1
H NMR (CDCl
3
) δ 7.54 (dd, J = 8.4 Hz,
4
J = 2 Hz, 0.78H, ArCH), 7.42 (d,
4
J = 2 Hz,
0.77H, ArCH), 6.84 (d, J = 8.4 Hz, 0.77H, ArCH), 6.03 (s, 1.64H, CH
2
), 2.49 (m, 0.16H,
CH
3
).
3′,4′-(Methylenedioxy)acetophenone 4b
1
H NMR (CDCl
3
) δ 7.54 (d, J = 8.4 Hz, 0.54H, ArCH), 7.42 (d,
4
J = 2 Hz, 0.06H, ArCH),
6.84 (d, J = 8.4 Hz, 0.74H, ArCH), 6.03 (s, 1.60H, CH
2
), 2.50 (m, 0.20H, CH
3
).
4′-Nitroacetophenone 5a
1
H NMR (DMSO-d
6
) δ 8.30 (m, 2H, ArCH), 8.10 (m, 1.92H, ArCH), 2.64 (m, 0.20H,
CH
3
).
4′-Nitroacetophenone 5a
1
H NMR (DMSO-d
6
) δ 8.30 (m, 1.98H, ArCH), 8.10 (m, 1.92H, ArCH), 2.64 (m, 0.22H,
CH
3
).
2-Acetonaphthone 6a
1
H NMR (CDCl
3
) δ 8.47 (s, 0.93H, ArCH), 8.04 (m, 0.98H, ArCH), 7.97 (m, 0.99H,
ArCH), 7.90 (m, 0.96H, ArCH), 7.88 (m, 0.97H, ArCH), 7.61 (m, 1H, ArCH), 7.56 (m,
0.99H, ArCH), 2.70 (m, 0.21H, CH
3
).
134
2-Acetonaphthone 6b
1
H NMR (CDCl
3
) δ 8.46 (s, 0.89H, ArCH), 8.03 (m, 0.14H, ArCH), 7.97 (m, 0.97H,
ArCH), 7.90 (m, 0.93H, ArCH), 7.88 (m, 0.97H, ArCH), 7.60 (m, 1H, ArCH), 7.55 (m,
1H, ArCH), 2.70 (m, 0.28H, CH
3
).
Benzophenone 7a
1
H NMR (CDCl
3
) δ 7.81 (m, 4H, ArCH), 7.59 (m, 2H, ArCH), 7.49 (m, 4H, ArCH).
Benzophenone 7b
1
H NMR (CDCl
3
) δ 7.81 (m, 1.88H, ArCH), 7.59 (m, 1.98H, ArCH), 7.49 (m, 3.84H,
ArCH).
Cyclohexyl phenyl ketone 8a
1
H NMR (CDCl
3
) δ 7.94 (m, 1.76H, ArCH), 7.53 (m, 0.96H, ArCH), 7.45 (m, 1.86H,
ArCH), 3.26 (m, 0.05H, CH), 1.91-1.80 (m, 4H, CH
2
), 1.78-1.20 (m, 6H, CH
2
).
Cyclohexyl phenyl ketone 8b
1
H NMR (CDCl
3
) δ 7.94 (m, 0.92H, ArCH), 7.54 (m, 0.95H, ArCH), 7.46 (m, 1.78H,
ArCH), 3.26 (m, 0.06H, CH), 1.91-1.80 (m, 4H, CH
2
), 1.78-1.20 (m, 6H, CH
2
).
135
Dibenzyl ketone 9a
1
H NMR (DMSO-d
6
) δ 7.30 (m, 4H, ArCH), 7.24 (m, 1.98H ArCH), 7.16 (m, 3.96H,
ArCH). 3.81 (m, 0.40H, CH
2
).
Dibenzyl ketone 9b
1
H NMR (DMSO-d
6
) δ 7.30 (m, 4H, ArCH), 7.24 (m, 1.98H, ArCH), 7.16 (m, 3.80H,
ArCH). 3.81 (m, 0.40H, CH
2
).
Acetanilide 10a
1
H NMR (CDCl
3
) δ 7.58 (br s, 1H, NH), 7.49 (d, J = 8.4 Hz, 0.46H, ArCH), 7.30 (br s,
1.56H, ArCH), 7.10 (d, J = 7.2 Hz, 0.19H, ArCH), 2.16 (s, 3H, CH
3
).
Acetanilide 10b
1
H NMR (CDCl
3
) δ 7.49 (d, J = 8.8 Hz, 0.16H, ArCH), 7.27 (br s, 1H, NH), 7.31 (br s,
1.88H, ArCH), 7.10 (d, J = 7.2 Hz, 0.16H, ArCH), 2.16 (s, 3H, CH
3
).
4′-Methylacetanilide 11a
1
H NMR (DMSO-d
6
) δ 9.79 (br s, 1H, NH), 7.43 (m, 0.58H, ArCH), 7.06 (br s, 1.82H,
ArCH), 2.22 (s, 3H, CH
3
), 1.99 (s, 3H, CH
3
).
4′-Methylacetanilide 11b
1
H NMR (CDCl
3
) δ 7.35 (m, 0.16H, ArCH), δ 7.17 (br s, 1H, NH), 7.10 (br s, 1.78H,
ArCH), 2.30 (s, 3H, CH
3
), 2.14 (s, 3H, CH
3
).
136
4′-Methoxyacetanilide 12a
1
H NMR (CDCl
3
) δ 7.54 (br s, 1H, NH), 7.38 (br s, 1.74H, ArCH), 6.84 (m, 0.12H,
ArCH), 3.78 (s, 3H, CH
3
), 2.16 (s, 3H, CH
3
).
4′-Methoxyacetanilide 12b
1
H NMR (CDCl
3
) δ 7.37 (br s, 0.16H, ArCH), 7.28 (br s, 1H, NH), 6.84 (m, 0.12H,
ArCH), 3.78 (s, 3H, CH
3
), 2.14 (s, 3H, CH
3
).
Acetaminophen ( 4′-hydroxyacetanilide) 13a
1
H NMR (DMSO-d
6
) δ 9.62 (br s, 1H, NH), 9.10 (br s, 1H, OH), 7.31 (br s, 1.28H,
ArCH), 6.65 (m, 0.14H, ArCH), 1.95 (s, 3H, CH
3
).
Acetaminophen ( 4′-hydroxyacetanilide) 13b
1
H NMR (DMSO-d
6
) δ 9.62 (br s, 1H, NH), 9.10 (br s, 1H, OH), 7.30 (m, 0.18H, ArCH),
6.65 (m, 0.18H, ArCH), 1.95 (s, 3H, CH
3
).
4′-Nitroacetanilide 14a
1
H NMR (DMSO-d
6
) δ 10.53 (br s, 1H, NH), 8.19 (m, 1.88H, ArCH), 7.80 (m, 1.86H,
ArCH), 2.10 (s, 3H, CH
3
).
137
4′-Nitroacetanilide 14b
1
H NMR (DMSO-d
6
) δ 10.53 (br s, 1H, NH), 8.18 (m, 1.68H, ArCH), 7.79 (m, 1.42H,
ArCH), 2.10 (s, 3H, CH
3
).
N-benzylacetamide 15a
1
H NMR (MeCN-d
3
) δ 7.35 (m, 2H, ArCH), 7.31-7.24 (m, 3H, ArCH), 6.86 (br s, 1H,
NH), 4.33 (d, 2H, CH
2
), 1.93 (s, 3H, CH
3
).
N-benzylacetamide 15b
1
H NMR (MeCN-d
3
) δ 7.35 (m, 2H, ArCH), 7.31-7.24 (m, 3H, ArCH), 6.84 (br s, 1H,
NH), 4.33 (d, 2H, CH
2
), 1.93 (s, 3H, CH
3
).
Edaravone (5-Methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one) 16a (keto-enol tautomers)
1
H NMR (DMSO-d
6
) δ 11.43 (br s, 1H, enol OH), 7.69 (d, J = 7.6 Hz, 1.90H, ArCH),
7.39 (t, J = 7.6 Hz, 1.88H, ArCH), 7.18 (t, J = 7.6 Hz, 0.95H, ArCH), 5.33 (br s, 1H, enol
CH), 3.68 (br s, 2H, keto CH
2
), 2.09 (s, 3H, CH
3
).
Edaravone (5-Methyl-2-phenyl-2,4-dihydro-3H-pyrazol-3-one) 16b (keto-enol tautomers)
1
H NMR (DMSO-d
6
) δ 11.44 (br s, 1H, enol OH) 7.69 (m, 0.12H, ArCH), 7.39 (d, J = 7.6
Hz, 1.52H, ArCH), 7.18 (t, J = 7.6 Hz, 0.82H, ArCH), 5.33 (br s, 1H, enol CH), 3.68 (br
s, 2H, keto CH
2
), 2.10 (s, 3H, CH
3
).
138
Benzamide 17a
1
H NMR (DMSO-d
6
) δ 7.86 (m, 2H, ArCH), 7.53 (m, 1H, ArCH), 7.45 (m, 2H, ArCH).
Benzamide 17b
1
H NMR (DMSO-d
6
) δ 7.86 (m, 1.40H, ArCH), 7.53 (m, 0.99H, ArCH), 7.45 (m, 2H,
ArCH).
L-(+)- α-phenylglycine 18a
(converted to potassium carboxylate salt)
[3]
1
H NMR (D
2
O/DMSO-d
6
) δ 7.31 (d, J = 7.2 Hz, 1.96H, ArCH), 7.20 (t, J = 7.2 Hz, 2H,
ArCH), 7.12 (t, J = 7.2 Hz, 0.98H, ArCH), 4.04 (s, 0.61H, CH).
L-(+)- α-phenylglycine 18b
(converted to potassium carboxylate salt)
[3]
1
H NMR (D
2
O/DMSO-d
6
) δ 7.28 (d, J = 7.2 Hz, 0.38H, ArCH), 7.21 (t, J = 7.2 Hz,
1.76H, ArCH), 7.13 (t, J = 7.2 Hz, 0.96H, ArCH), 4.04 (s, 0.17H, CH).
L-phenylalanine 19a (converted to HCl salt)
1
H NMR (D
2
O) δ 7.23-7.13 (m, 2.97H, ArCH), 7.11 (m, 1.92H, ArCH), 4.15 (m, 0.98H,
CH), 3.17-2.95 (m, 2H, CH
2
).
L-phenylalanine 19b (converted to HCl salt)
1
H NMR (D
2
O) δ 7.22-7.12 (m, 2.88H, ArCH), 7.09 (m, 0.62H, ArCH), 4.15 (m, 0.92H,
CH), 3.17-2.95 (m, 2H, CH
2
).
139
L-tyrosine 20a (converted to HCl salt)
1
H NMR (D
2
O) δ 6.89 (br s, 1.84H, ArCH), 6.58 (m, 0.18H, ArCH), 4.02 (m, 0.90H,
CH), 3.01-2.81 (m, 2H, CH
2
).
L-tyrosine 20b
(converted to HCl salt)
1
H NMR (D
2
O) δ 6.89 (br s, 1.48H, ArCH), 6.59 (m, 0.18H, ArCH), 4.02 (m, 0.80H,
CH), 3.04-2.82 (m, 2H, CH
2
).
4-methoxyphenylacetic acid 21a
1
H NMR (CDCl
3
) δ 7.20 (br s, 1.84H, ArCH), 6.87 (m, 0.18H, ArCH), 3.80 (s, 3H,
OCH
3
), 3.59 (m, 1.48H, CH
2
).
4-methoxyphenylacetic acid 21b
1
H NMR (CDCl
3
) δ 7.20 (br s, 1.90H, ArCH), 6.87 (m, 0.20H, ArCH), 3.80 (s, 3H,
OCH
3
), 3.59 (m, 1.60H, CH
2
).
4-methoxybenzylamine 22a
1
H NMR (CDCl
3
) δ 7.23 (br s, 1.06H, ArCH), 6.87 (m, 0.16H, ArCH), 3.81 (br s, 1.10H,
CH
2
), 3.79 (s, 3H, OCH
3
).
140
4-methoxybenzylamine 22a
1
H NMR (CDCl
3
) δ 7.23 (br s, 1.02H, ArCH), 6.87 (m, 0.18H, ArCH), 3.81 (br s, 1.22H,
CH
2
), 3.80 (s, 3H, OCH
3
).
141
A3.3 NMR Spectra for Substrates Used in Deuterium Labeling Studies
4
1
H NMR spectrum of acetophenone 2a after reaction (condition a).
142
1
H NMR spectrum of acetophenone 2b after reaction (condition b).
143
1
H NMR spectrum of 4′methoxyacetophenone 3a after reaction (condition a).
144
1
H NMR spectrum of 4′methoxyacetophenone 3b after reaction (condition b).
145
1
H NMR spectrum of 3′,4′-(methylenedioxy)acetophenone 4a after reaction (condition a).
146
1
H NMR spectrum of 3′,4′-(methylenedioxy)acetophenone 4b after reaction (condition
b).
147
1
H NMR spectrum of 4′-nitroacetophenone 5a after reaction (condition a).
148
1
H NMR spectrum of 4′-nitroacetophenone 5b after reaction (condition b).
149
1
H NMR spectrum of 2-acetonaphthone 6a after reaction (condition a).
150
1
H NMR spectrum of 2-acetonaphthone 6b after reaction (condition b).
151
1
H NMR spectrum of benzophenone 7a after reaction (condition a).
152
1
H NMR spectrum of benzophenone 7b after reaction (condition b).
153
1
H NMR spectrum of cyclohexyl phenyl ketone 8a after reaction (condition a).
154
1
H NMR spectrum of cyclohexyl phenyl ketone 8b after reaction (condition b).
155
1
H NMR spectrum of dibenzyl ketone 9a after reaction (condition a).
156
1
H NMR spectrum of dibenzyl ketone 9b after reaction (condition b).
157
1
H NMR spectrum of acetanilide 10a after reaction (condition a).
158
1
H NMR spectrum of acetanilide 10b after reaction (condition b).
159
1
H NMR spectrum of 4′-methylacetanilide 11a after reaction (condition a).
160
1
H NMR spectrum of 4′-methylacetanilide 11b after reaction (condition b).
161
1
H NMR spectrum of 4′-methoxyacetanilide 12a after reaction (condition a).
162
1
H NMR spectrum of 4′-methoxyacetanilide 12b after reaction (condition b).
163
1
H NMR spectrum of acetaminophen 13a after reaction (condition a).
164
1
H NMR spectrum of acetaminophen 13b after reaction (condition b).
165
1
H NMR spectrum of 4′-nitroacetanilide 14a after reaction (condition a).
166
1
H NMR spectrum of 4′-nitroacetanilide 14b after reaction (condition b).
167
1
H NMR spectrum of N-benzylacetamide 15a after reaction (condition a).
168
1
H NMR spectrum of N-benzylacetamide 15b after reaction (condition b).
169
1
H NMR spectrum of edaravone 16a after reaction (condition a).
170
1
H NMR spectrum of edaravone 16b after reaction (condition b).
171
1
H NMR spectrum of benzamide 17a after reaction (condition a).
172
1
H NMR spectrum of benzamide 17b after reaction (condition b).
173
1
H NMR spectrum of L-(+)-α-phenylglycine 18a after reaction (condition a).
174
1
H NMR spectrum of L-(+)-α-phenylglycine 18b after reaction (condition b).
175
1
H NMR spectrum of L-phenylalanine 19a after reaction (condition a).
176
1
H NMR spectrum of L-phenylalanine 19b after reaction (condition b).
177
1
H NMR spectrum of L-tyrosine 20a after reaction (condition a).
178
1
H NMR spectrum of L-tyrosine 20b after reaction (condition b).
179
1
H NMR spectrum of 4-methoxyphenylacetic acid 21a after reaction (condition a).
180
1
H NMR spectrum of 4-methoxyphenylacetic acid 21b after reaction (condition b).
181
1
H NMR spectrum of 4-methoxybenzylamine 22a after reaction (condition a).
182
1
H NMR spectrum of 4-methoxybenzylamine 22b after reaction (condition b).
183
A3.4 References for Appendix 3
1
R. J. Smith, R. M. Pagni, J. Org. Chem. 1982, 47, 3180–3183.
2
J. H. Lee, K. S. Yoo, C. P. Park, J. M. Olsen, S. Sakaguchi, G. K. S. Prakash, T.
Mathew, K. W. Jung, Adv. Synth. Catal. 2009, 351, 563-568
3
While H-D exchange at the stereocenter of L-(+)-α-phenylglycine at elevated
temperatures in D
2
O under basic conditions is known, this process did not occur to an
appreciable extent in the preparation of this NMR sample. The stereocenter H-D
exchange observed in this case is due entirely to the experimental conditions. This was
confirmed by repeating the experiment, converting the product to the hydrochloride salt,
and preparing another NMR sample in a mixture of methanol-d
4
and DMSO-d
6
.
4
1
H NMR spectra 10a-14a are identical to those for the same compounds in Chapter 3
(Appendix 2) and are included for comparison purposes.
184
Appendix 4. Dual Studies on a Hydrogen-Deuterium Exchange of
Resorcinol and the Subsequent Kinetic Isotope Effect.
A4.1 Student Handout
Aromatic hydrocarbons such as benzene are referred to as arenes. Because these
compounds have π electrons available to react, like alkenes, they are similarly susceptible
to reactions with electrophiles. However, because aromatic molecules are exceptionally
stable, they tend to participate in substitution reactions rather than elimination reactions
so that they retain their aromaticity. The rate by which arenes react with electrophiles is
affected by their functional group substituents. Functional groups on arenes are broadly
classified as activating or deactivating (Table 1). Activating functional groups donate
electron density to the aromatic ring while deactivating groups withdraw electron density
from the ring. It follows that arenes with activating groups tend to react more rapidly with
electrophiles while those with deactivating groups react more slowly.
Table A4.1. Activating and deactivating substituents on an aromatic ring.
Strongly activating: amine, alcohol Strongly deactivating: nitro, CF
3
, CCl
3
Activating: amide, ether Deactivating: carboxylic acid, ester, aldehyde,
ketone
Weakly activating: alkyl, phenyl Weakly deactivating: halide
185
The position of a substituent on an arene ring can be ortho¸ meta, or para to
another group. These terms refer to how many carbons away from each other the
substituents are. Thus when electrophiles add to an aromatic ring, they can add ortho,
meta, or para to an existing functional group (Figure 1). Where they add depends on the
presence and nature of pre-existing functional groups. In general, activating functional
groups induce the electrophile to add preferentially at the ortho and para positions, and
these functional groups are referred to as ortho-para directors. Likewise, deactivating
functional groups cause the electrophile to add at the meta position on an aromatic ring
(halides are an exception) and are called meta directors.
Figure A4.1. Ortho, meta, and para addition of an electrophile E
+
to an aromatic ring.
Resorcinol (meta-dihydroxybenzene, Figure 2) is a simple arene that can be
isolated from a wide variety of biological sources. While most resorcinol produced
commercially is utilized for industrial applications, it is also commonly employed in skin
creams in combination with sulfur for the treatment of acne and other dermatological
conditions. Resorcinol is a derivative of benzene with hydroxyl groups at the 1 and 3
positions. Because the two hydroxyl groups are activating (electron-donating) and ortho-
para directing, the carbon atoms ortho and para to these groups are susceptible to
186
reaction with various electrophiles. The remaining carbon meta to each of the hydroxyls
is not nearly as reactive with electrophiles.
Figure A4.2. Substitution patterns in dihydroxybenzenes.
The ortho-para reactivity of resorcinol is due to the stability of the intermediate.
The electrophilic aromatic substitution (EAS) of aromatic systems such as resorcinol
generally proceeds through a stepwise mechanism (Figure 3). The electrons within the
aromatic ring attack an electrophile (in this case, D
3
O
+
,
see below), forming an unstable
carbocation intermediate called an arenium ion. The compound is no longer aromatic but
is somewhat stabilized by resonance (this is called a resonance effect), allowing the
positive charge to be spread amongst several atoms in the molecule. Note that the
positive charge can only be delocalized to the oxygens if the electrophile is attacked by
the carbons ortho or para to the hydroxyls. Attack by the meta carbon would result in a
far less stable arenium ion, which is why that position is unreactive towards electrophiles.
Finally, a base can pull off a proton from the arenium ion, relieving the instability and
allowing the ring to regain its aromaticity.
187
Figure A4.3. Mechanism and resonance forms of acid-catalyzed aromatic H-D exchange.
Hydrogen-deuterium exchange (H-D exchange) reactions can proceed through
this mechanism. In these reactions, one of the protons (
1
H) in the aromatic ring is
exchanged with a heavier deuterium (
2
H or D) isotope by using a large excess of
deuterium electrophile. By Le Chatlier’s principle, even though there is an equilibrium
between the rates at which deuterium and hydrogen are added to the ring, the large excess
of deuterium pushes this equilibrium strongly towards formation of the deuterated
product.
A kinetic isotope effect (KIE) is the ratio of reaction rates (k) between reactants
with two different isotopes of the same atom. A simple example is that of hydrogen and
deuterium. Often, organic compounds which contain carbon-deuterium bonds rather than
carbon-hydrogen bonds react more slowly, because the deuterium nucleus is heavier,
resulting in a shorter bond length and a stronger bond. You can make the analogy that the
carbon-proton and carbon-deuterium bonds behave like springs which oscillate back and
188
forth and until eventually reaching a breaking point. Because deuterium has about double
the mass of hydrogen, the spring is compressed further and the carbon-deuterium bond
oscillates at a lower frequency. This additional mass thus increases the activation energy
required to oscillate and break the bond during the reaction. This is called a primary
kinetic isotope effect. Secondary kinetic isotope effects, in which the bond to the isotope
in the reactant is not changed during the course of the reaction, are much smaller in
magnitude and will not be discussed here.
Generally, only the slowest step of a reaction mechanism is significantly affected
by isotopic substitution. Most common electrophilic aromatic substitution reactions such
as nitration or chlorination do not exhibit a KIE, as elimination of hydrogen or deuterium
from the intermediate arenium species by a base is rapid compared to the slow addition of
electrophiles to the aromatic ring. Because breaking the C-H or C-D bond is not the slow
step, there is no observable difference in the rate. However, electrophilic iodination
(Figure 4) can be an exception, because the initial addition of iodide to the aromatic ring
is (k
1
) rapid and highly reversible (k
-1
), making elimination of hydrogen or deuterium (k
B
)
the slow step in comparison.
Figure A4.4. Relative rates of iodination of resorcinol.
189
In this experiment, you will investigate the electrophilic aromatic substitution and
H-D exchange of resorcinol under acidic conditions by using catalytic amounts of
sulfuric acid in deuterium-enriched water (D
2
O or “heavy water”). The H-D exchange
reaction will be confirmed by examining the
1
H NMR spectrum of the product after the
reaction is complete. Subsequently, you will examine the kinetic isotope effect visually
and calculate the difference in the rate of reactivity of C-H and C-D bonds (the ratio
k
H
/k
D
) using absorbance data from a UV-Vis spectrometer.
Chemicals and CAS Registry Numbers
Chemical CAS number
Deuterium oxide (D
2
O)
7789-20-0
Sulfuric acid, 98% 7664-93-9
Resorcinol 108-46-3
Iodine 7553-56-2
Potassium iodide 7681-11-0
Ethanol 64-17-5
Hazards
Concentrated sulfuric acid is highly corrosive and should be handled cautiously.
A solution of sulfuric acid in D
2
O can be prepared in advance for students to use.
Resorcinol is harmful if swallowed, inhaled, or absorbed through the skin. No safety
information is available for resorcinol-d
3
, but similar safety concerns are reasonably
190
expected. D
2
O is mild in toxicity. Molecular iodine is corrosive to skin and eyes and
harmful if inhaled. The solution of iodine/iodide in ethanol may be corrosive and should
be handled with care. The iodination products of resorcinol, including 2-iodoresorcinol,
are harmful if swallowed, inhaled, or absorbed through the skin. Wear proper personal
protective equipment at all times when performing this experiment, including gloves, a
lab coat, and safety goggles. Chemical manipulations are recommended to be done in an
appropriate fume hood if possible.
Pre-Experiment Questions
(1) What is the ratio of deuterium to hydrogen in the reaction mixture prior to adding
resorcinol? Assume that both protons in sulfuric acid freely exchange with the
solvent. Hint: the molarity of D
2
O solution is approximately 55.3M and the
molarity of concentrated sulfuric acid is approximately 18.4M.
(2) If resorcinol is deuterated exclusively at the positions ortho and para to the
alcohols during this experiment, how many aromatic peaks would you expect to
see in a
1
H (proton) NMR spectrum of the resulting compound? If the answer isn’t
clear, you may need to conduct a little research on deuterium in
1
H NMR spectra.
Hint: why are
1
H NMR solvents deuterated?
191
(3) Is the rate of the reaction between resorcinol and iodine (Figure 4) zero order, first
order, or second order overall? Assuming you know the concentration of iodine
over time, what would you plot versus time to get a straight line? Hint: a zero
order reaction, for example, would directly plot the concentration of iodine versus
time.
(4) Resorcinol is an organic compound, but it is very soluble in water. Why?
Procedure
Work in pairs for this experiment, but each student should set up their own
reaction. Using a pipettor in a fume hood, each student should add 1 mL of D
2
O to a
conical vial followed by 20 μL (0.37 mmol) of concentrated sulfuric acid (caution –
concentrated sulfuric acid is very corrosive to skin and mucous membranes). Measure out
66 mg (0.60 mmol) of resorcinol and add it to the vial along with a small spin vane.
Equip the vial with a reflux condenser, then heat on a hot plate with an aluminum block
for 30 minutes. Allow the reaction vessel to cool to room temperature. One sample
should be pipeted into an NMR tube and submitted for
1
H NMR analysis. The other
sample should be pipeted into a standard 2 dram vial and set aside.
In a separate 2 dram vial, prepare a second sample using 1 mL of D
2
O, 20 μL of
sulfuric acid, and 66 mg of resorcinol, but do not heat this sample. Instead, seal the vial
and briefly shake it to dissolve the resorcinol, and then set it adjacent to the original vial.
Use a pipettor to withdraw 300 μL of the iodine (0.033M) and potassium iodide (0.033M)
192
solution in ethanol, and then prepare to add the solution. Uncap the vials then add the
solution simultaneously. Cap the vials, briefly shake them to disperse the ethanol, then
carefully observe the color change in each vial over 10-15 minutes. In which vial does the
color fade most rapidly? Why does this happen?
The rate at which iodine has been consumed during a typical reaction has been
calculated by measuring its absorbance at a certain wavelength with a UV-Vis
spectrometer. Using the supplied UV-Vis absorbance data, calculate the magnitude of the
kinetic isotope effect k
H
/k
D
of the iodination reaction. Consider that the supplied plot
represents the inverse of the concentration of iodine over time (1/[I
2
] vs. time), and that
the slope should represent the rate of the reaction. Since this slope is a straight line, what
does it imply about the overall rate of the reaction (i.e. what order is the reaction)? Does
the KIE you calculated make sense in terms of what you observed during the experiment?
Postlab Questions
(1) In which vial did the iodine color fade most rapidly? Why did this occur? Hint: I
2
is dark red to orange while 2-iodoresorcinol and 4-iodoresorcinol are colorless in
solution.
(2) During a sample iodination reaction, the amount of light absorbed by iodine at a
particular wavelength was recorded over time using a UV-Vis spectrometer.
193
Higher concentrations of iodine absorb more light (and vice versa). Use the
supplied absorbance data to answer the following questions.
a. Determine the order of the iodination reaction (e.g. first-order, second-
order). Hint: Carefully observe what is being plotted versus time. Consider
that absorbance corresponds to the concentration of iodine.
b. Calculate the magnitude of the kinetic isotope effect k
H
/k
D
of the
iodination reaction. Does the result make sense in terms of what you
observed during the experiment? Hint: k
H
and k
D
are reaction rates. What
do the slopes of these plots indicate?
(3) Consider your
1
H NMR spectrum of resorcinol after reflux. Compare it to the
supplied
1
H NMR spectrum of undeuterated resorcinol. What major differences
do you note in the spectrum of resorcinol after it was subjected to H-D exchange?
Interpret these results, including changes in integration and multiplicity.
194
A4.2 Instructor Notes
The experiment can be completed during the equivalent of a standard 3-hour lab
period. Students should work in pairs. The experiment can proceed quickly if the
student is well-prepared.
The 2, 4, and 6-positions on the aromatic ring should be >95% deuterated under
these conditions and the result should be immediately apparent by NMR. The
remaining proton, corresponding to a peak at around δ 6.8, should remain but
collapse into a singlet. It can be integrated in comparison to the small residual
proton peaks remaining to determine a rough percentage of deuterium
incorporation into the aromatic ring. Sample
1
H NMR spectra are provided.
The iodination reaction can have somewhat subtle color differences depending on
how accurately it is set up. As the iodine reacts, the iodine color in the vial will
fade, and the deuterated sample is expected to react more slowly than the control.
Students should pay close attention to how rapidly the color fades in each vial.
This reaction is very time-sensitive, and the rate increases significantly if less
potassium iodide is used.
The acidic D
2
O solution can be prepared in advance by adding 20 μl of H
2
SO
4
per
every mL of D
2
O required for the experiment. This allows the experiment to be
conducted without students working with concentrated sulfuric acid.
195
The UV-Vis portion of the experiment can be conducted by the students if
desired. Instead of adding the iodine and potassium iodide solution to each vial
simultaneously, it can be added to one of the vials, the vial can be sealed and
shaken, then the solution can quickly be pipeted into a cuvette, placed in the
instrument, and the absorbance measured at 460 nm over 15-20 minutes. This
wavelength is in the visible range, so most common spectrophotometers should be
usable for this experiment. Due to time and instrument constraints, we provided a
sample data set which students can use to calculate the kinetic isotope effect
k
H
/k
D
. As a second-order reaction, the absorbance data can be plotted as
1/[absorbance] to achieve a straight line, and k
H
/k
D
can be calculated by
comparing the slopes in each case. The observed KIE is about 3.4.
Infrared spectroscopy was not discussed but sample spectra are provided should
the instructor wish to incorporate them into the experiment. To conduct such an
experiment, the deuterated resorcinol must be extracted from the aqueous solvent.
This can be accomplished by using a minimal amount of diethyl ether to conduct
a standard microscale extraction. After the solvent is completely evaporated, the
resulting solid product can be isolated and further characterized using infrared
spectroscopy. Interestingly, substantial changes are apparent in the IR spectrum.
As expected, several peaks associated with C-H bonds disappear in the spectrum
of the deuterated compound, presumably shifted to lower frequencies, while other
196
peaks from C=C bonds are shifted 30-40 cm
-1
due to an isotope effect. While the
result is undoubtedly more subtle than that of the NMR spectrum, it could be
utilized as a supplemental piece of information to further elucidate the effects of
H-D exchange.
Teaching this experiment at a pre-college level was accomplished by omitting the
NMR and UV-Vis portions of the experiment. The experiment was framed as a
way to explain what chemical isotopes are, how they can be added to an organic
molecule, and how their effects can be seen by carefully constructing an
experiment that could tell them apart even though they were invisible to the naked
eye. High school students noted that they were not taught about isotopes in their
classes and that this experiment helped them understand what isotopes were and
how they react.
Answers to pre-lab questions:
o (1) 0.74 mmol protons from H
2
SO
4
, 110.6 mmol deuterons from D
2
O
gives a ratio of approximately 149:1 deuterium to hydrogen.
o (2) You would expect to see one aromatic NMR peak remaining in the
spectrum.
197
o (3) The reaction would be first order in resorcinol and iodine and thus
second order overall. You would plot the inverse of absorbance versus
time to get a straight line plot.
o (4) The two hydroxyl groups on resorcinol make the compound very polar,
and are also capable of hydrogen bonding with water. These factors make
resorcinol very soluble in water.
Answers to post-lab questions:
o (1) The color should fade most rapidly in the vial which has not been
refluxed. As iodine adds to the aromatic ring, the orange color fades. The
slow kinetic step in this reaction, k
B
, occurs more rapidly with a C-H bond
compared to a C-D bond.
o (2) a. The data suggests that the reaction is second order, in agreement
with the prediction made in the pre-lab. b. k
H
/k
D
from the plots is
calculated to be ~3.4, meaning that iodine adds about three times faster to
a C-H bond as compared to a C-D bond. This should agree well with
observation of the rate by which the orange color fades during the
experiments.
o (3) Two peaks almost disappear completely (integrate to a very small
value) due to extensive deuteration at those positions on the ring. The
remaining peak collapses to an apparent singlet due to the lack of splitting
by adjacent protons.
198
A4.3 Experimental Section
General considerations
All solvents and reagents were obtained from commercial vendors and used without
further purification. UV-Vis data was collected using an Ocean Optics Red Tide USB-
650 spectrometer at 460 nm. IR data was collected using a Shimadzu FTIR spectrometer.
1
H NMR spectra were obtained using a Varian 400 spectrometer at 400 MHz and
chemical shifts (δ) are given in ppm.
Representative spectral data for resorcinol after reaction
1
H NMR (D
2
O) δ 6.90 (br s, 1H, ArCH), 6.22 (d, J = 8 Hz, 0.10 H, ArCH), 6.15 (br s,
0.05H, ArCH).
199
Representative full
1
H NMR spectrum of resorcinol after reaction
200
Representative IR spectra of resorcinol before and after reaction (optional)
201
202
Appendix 5. Synthesis of NHC-amine ligands for palladium.
A5.1 Introduction
Due to their strong σ-donating properties as well as their versatility towards
synthetic modification, N-heterocyclic carbene (NHC) ligands have been extensively
utilized for numerous transition metal-catalyzed transformations. Specifically, palladium
complexes with chiral NHC ligands have been utilized for enantioselective
hydroamination, alkylation, and cross-coupling reactions.
1
One class of NHC ligands
which has received some attention for enantioselective reactions is the NHC-N-donor
ligands, which incorporates additional chelating nitrogen atoms within the ligand
backbone. These ligands are typically hemilabile in that while the NHC remains strongly
bound to the metal, binding of the amine to the metal center is highly reversible,
especially under acidic conditions.
A relatively small subclass of these ligands, herein referred to as NHC-alkylamine
(NHC-AA) ligands, feature chelating primary, secondary, or tertiary sp
3
-hybridized
amines, rather than pyridine derivatives or other aromatic nitrogen substituents. NHC-AA
ligands can be synthetically altered at nitrogen, enabling facile modification of their steric
and electronic properties and potentially producing beneficial results for enantioselective
catalytic reactions.
2
It has also been suggested that in certain acid-catalyzed reactions,
such as hydroamination, the amine substituent could improve reactivity by acting as a
proton shuttle, thus assisting in proton transfer to the metal.
2
The first reported example of an NHC-AA ligand was synthesized by Cavell et al.
in 2001, where it was utilized in C-C cross-coupling reactions.
3
However, the synthetic
203
utility of this complex was hindered by its low stability under the explored conditions.
Douthwaite et al. later developed several NHC-AA palladium complexes
4
and tested their
catalytic competence in Heck-Mizoroki and hydroamination coupling reactions.
2
Some
improvement over existing Pd-NHC complexes incorporating pyridine moieties was
noted. Other examples of NHC-AA palladium complexes have been reported by Roland
et al.,
5
Luo et al.,
6
and Hizari et al.
7
(Figure A5.1).
Figure A5.1. Representative examples of synthesized NHC-AA complexes.
In 2008, Jung and Sakaguchi reported the synthesis of an NHC-amidate-alkoxide
complex 7 which was utilized for the highly stereoselective oxidative boron Heck-type
cross-coupling of arylboronic acids and acyclic alkenes.
8
Derivatives of this complex
showed an unusual versatility towards the catalysis of other transformations ranging from
the Strecker reaction
9
to H-D exchange of hydrocarbons.
10
The amidate moiety of this
204
ligand scaffold was noted as a key feature, providing strong chelation to palladium and
increasing the thermodynamic stability of the complex. To further investigate the role of
the amide, the development of novel NHC-AA ligands was proposed so that their
structure and function could be compared to the aforementioned amidate complexes.
Substitution of the amide with an alkyl amine would presumably have a strong impact on
the catalytic capabilities of the resulting palladium complexes. Herein are discussed
efforts undertaken towards the syntheses of novel NHC-AA ligands and their palladium
complexes.
Figure A5.2. Representative NHC-amidate-alkoxide palladium complex 7 synthesized by
Jung and Sakaguchi.
A5.2 Results and Discussion – Synthesis of complexes 9a and 9b
The first catalytic NHC-AA ligand envisioned was a chiral bidentate scaffold
similar to the ligand of complex 4 prepared by Roland et al.
5
with some key differences
(Scheme A5.1). The proposed catalyst would use L-valine as a starting material, resulting
in a stereocenter with an isopropyl group rather than a phenyl group. Additionally, like
the original NHC-AA ligand 1 prepared by Cavill et al., the proposed ligand would
feature a tertiary amine moiety, which could allow for different binding modes compared
to more common primary and secondary amines. Finally, the NHC moiety would utilize
205
benzimidazole rather than imidazole, and one benzimidazole nitrogen would be
functionalized with different alkyl groups to determine the effect of this substitution on
the structure of the resulting palladium complex.
Scheme A5.1. Original proposed synthesis of NHC-AA palladium complex 2.
Reduction of L-valine 8 to L-valinol 10 using NaBH
4
and I
2
in refluxing THF
proceeded smoothly in 85% yield (Scheme A5.2). Because alkylation at nitrogen using an
alkyl halide could give a mixture of products, installation of a benzyl group on nitrogen
using a reductive amination procedure was conducted. The imine was pre-formed by
adding benzaldehyde to L-valinol in CH
2
Cl
2
using 4Å molecular sieves, isolated from the
reaction mixture, then redissolved in EtOH and reduced using sodium borohydride. This
reaction furnished the desired secondary amine product 11 in good yield (79%) without
difficulty.
206
Scheme A5.2. Reductive amination of L-valinol followed by reductive amination with
benzaldehyde.
Initially, methylation of secondary amine 11 was problematic (Scheme A5.3).
Using Ag
2
O as a base, the methylation was unselective, resulting in a mixture of N-
methylated and N,O-dimethylated products that was difficult to resolve. After several
attempts to separate these products and modify the reaction conditions, a new approach
was conducted using Eschweiler-Clarke conditions. This strategy was synthetically
desirable due to the mechanism of the reaction, which inherently prevents formation of
undesirable quaternary ammonium salts and does not methylate alcohols. Under these
conditions, the desired product 12 was isolated in reasonable (70%) yield.
Scheme A5.3. Methylation of secondary amine 4 under different conditions.
207
The next step involved conversion of the resulting alcohol 12 to a halide or other
leaving group followed by coupling with benzimidazole. Unfortunately, the two steps
required to conduct this transformation were fraught with difficulty. Initial efforts
focused on conversion of the alcohol to a bromide (Scheme A5.4). However, despite the
use of several different conditions, only the hydrobromide salt 13 was isolated in each
case. It was not immediately clear if the bromide was prone to decomposition back to the
alcohol or if the starting material was simply unreactive under the attempted conditions.
Similarly, attempted iodination of 12 under Appel conditions was unsuccessful, returning
only starting material.
Scheme A5.4. Initial attempts at converting the primary alcohol of 5 to a halide.
Conversion of the alcohol to a tosylate rather than a halide was then examined
(Scheme A5.5). The alcohol 12 was reacted with tosyl chloride using Et
3
N as a base and
208
DMAP as a catalyst in CH
2
Cl
2
at 0 °C, and the resulting product was isolated and
purified. However, after careful examination of the
1
H NMR spectrum of the product, it
was concluded that chloride 15 was isolated instead in outstanding (95%) yield. This
product was presumably the result of rapid nucleophilic attack by chloride on the
incipient tosylate (completely absent by
1
H NMR). This alkyl chloride product was
carried on to the next step.
Scheme A5.5. Attempted tosylation of primary alcohol of 5.
Under the first several sets of conditions attempted, chloride 15 failed to couple
efficiently with benzimidazole (Scheme A5.6). Modification of reaction time and
temperature did not increase the amount of product; instead, nucleophilic addition of
hydroxyl to the alkyl halide returned increasingly large amounts of alcohol 12. The
necessity for a better leaving group than chloride was considered. Gratifyingly, using a
catalytic amount of tetrabutylammonium iodide to convert the alkyl chloride to a more
reactive alkyl iodide in situ was successful, furnishing the desired coupling product 17 in
moderate (70%) yield.
209
Scheme A5.6. Coupling of alkyl chloride 8 with benzimidazole.
From ligand scaffold 17, two different palladium complexes, 9a and 9b, were
prepared according to similar procedures (Schemes A5.7 and A5.8). Upon reaction with
methyl iodide in refluxing THF, compound 10 was methylated at the benzimidazole
nitrogen, generating ammonium salt 18 in excellent (95%) yield. No undesirable
methylation at the tertiary alkyl nitrogen was observed. This iodide salt was reacted with
Ag
2
O to generate silver carbene complex 19 in a facile manner. Although reaction of this
silver carbene complex with Pd(OAc)
2
was unsuccessful, transmetalation of 19 with
Pd(MeCN)
2
Cl
2
furnished the desired Pd-NHC complex 9a. Similarly, coupling of 17 with
benzyl bromide proceeded in acceptable (53%) yield to furnish bromide salt 20. This
product was reacted with Ag
2
O and Pd(MeCN)
2
Cl
2
in subsequent reactions in the same
manner as iodide salt 21, successfully generating Pd-NHC complex 9b. Both 9a and 9b
were characterized by
1
H NMR.
210
Scheme A5.7. Synthesis of palladium complex 9a.
211
Scheme A5.8. Synthesis of palladium complex 9b.
To confirm the structure of 9a, it was necessary to grow a single crystal of the
palladium complex so that X-ray diffraction studies could be conducted. By layering
hexanes into a solution of 9a in CH
2
Cl
2
, followed by slow evaporation of the resultant
solution, a single crystal of acceptable quality was grown and analyzed by X-ray
diffraction (Figure A5.3). The results confirmed that the structure was a cis-dichloro
palladium(II) complex as predicted, co-crystallized with CH
2
Cl
2
, and that the amine
moiety did coordinate to the palladium center, with a Pd-N distance of 2.153(2) Å. The
Pd-N coordination distance is somewhat longer than the Pd-N coordination distance in
the NHC-AA complex 4 reported by Roland (2.117(5) Å), which featured a chelating
secondary amine.
5
Both distances are significantly longer than the amido Pd-N bond
212
substituent in complex 5 (2.006(4) Å).
6
The increased distance between palladium and
nitrogen relative to complex 4 may be due to the increased steric bulk of the tertiary
amine. The Pd-C bond length was 1.947(2) Å, slightly shorter than 1.975(5) Å bond
length of the analogous carbene bond in complex 4. However, unlike complex 4, which
adopted a boat conformation, the six-membered palladacycle ring of 9a adopted an
unusual distorted skew-boat (twist) conformation. Additionally, a significant trans effect
due to the NHC was observed, with the Pd-Cl bond length trans to the NHC significantly
longer (2.3792(7) Å) than the Pd-Cl bond trans to the amine (2.3156(7) Å). This effect is
due to strong σ-donation from the NHC and has previously been observed in other NHC-
AA complexes.
4b,5
Figure A5.3. Crystal structure of 9a determined by single crystal X-ray diffraction
analysis. Hydrogen atoms have been omitted for clarity. (Data collected by Timothy
Stewart.)
213
Complex 9a was tested for catalytic competence in several different reactions.
Disappointingly, it was not an effective catalyst for most transformations, including
Suzuki-Miyaura coupling, the Tsuji-Trost reaction, or α-arylation of cyanoacetates.
However, complex 9a did effectively catalyze the Heck-Mizoroki coupling of 4-
iodoanisole with cyclohexene, albeit with unremarkable activity or regioselectivity.
Further studies of this complex and its properties are ongoing.
Scheme A5.9. Heck-Mizoroki coupling catalyzed by complex 9a.
A5.3 Results and Discussion – Efforts towards synthesis of complex 23.
A highly versatile derivative of palladium complex 7 is the achiral complex 22
(Figure A5.4). This compound has been employed as a catalyst for reactions ranging
from oxidative degradation of glycerol
11
to hydroamination
12
and H-D exchange.
10
To
further investigate the distinguished reactivity of this complex, the synthesis of palladium
NHC-AA ligand 23 was proposed. This ligand would be structurally analogous to the
amidate complex 22 but would incorporate a secondary amine moiety, rather than an
amidate, to coordinate to palladium. The structure and catalytic activity of complex 23
could shed further light on the precise role of the amidate in the aforementioned catalytic
transformations.
214
Figure A5.4. Previously synthesized palladium NHC-amidate complex 22 and its
proposed amine variant 23.
The most direct route towards synthesis of palladium complex 23 would be the
reduction of either 24 or 26, known intermediates towards the synthesis of complex 22
(Scheme A5.10).
10
Adopting the NaBH
4
/I
2
reduction strategy previously used for amino
acids (Scheme A5.2), which has also been shown to be effective for amides,
13
both
neutral compound 24 and iodide salt 26 were utilized as starting materials. However, both
reactions failed to give the desired amine in appreciable yield; instead, intractable
mixtures of products were observed. It was concluded that an entirely new synthetic route
towards 23 should be developed.
Scheme A5.10. Failed attempts at reduction of intermediates in the synthesis of complex
22 towards synthesis of 23.
215
The proposed route started with benzimidazole 16, which was coupled with 1,2-
dichloroethane 28 in poor (32%) but acceptable yield to furnish the alkyl chloride 29
(Scheme A5.11). This chloride complex was easily methylated by methyl iodide to
furnish the iodide salt 30. However, repeated attempts to couple this iodide salt with 2-
methoxyethylamine 31 failed to generate the desired amine product, despite screening of
various solvents, additives, and conditions.
Scheme A5.11. Coupling of benzimidazole with 1,2-dichloroethane, methylation of the
resulting compound with methyl iodide, and attempted coupling of the iodide salt with
with 2-methoxyethylamine.
Due to the difficulties in this coupling reaction, a somewhat lengthier synthetic
route was explored. An initial attempt to couple alkyl chloride 29 with 2-
methoxyethylamine 31 under cesium hydroxide conditions, a known condition for mono-
alkylation of amines,
14
instead gave primarily elimination product 32 (Scheme A5.12).
Various other conditions were explored, including the use of catalytic
216
tetrabutylammonium iodide (see also Scheme A5.6), but all resulted in intractable
mixtures of products which could not be resolved. Finally, the desired coupling product
33 was synthesized in good yield by heating 29 in a solution of neat 31, thus utilizing 2-
methoxyethylamine as solvent, reactant, and base.
Scheme A5.12. Attempted coupling of alkyl chloride 29 with 2-methoxyethylamine 31.
As direct methylation of compound 33 using methyl iodide would result in
undesirable methylation at the secondary amine, it was concluded that protection of this
vulnerable amine with a tert-butyloxycarbonyl (Boc) group was required (Scheme
A5.13). Facile reaction of the amine with di-tert-butyl dicarbonate in MeOH afforded the
Boc-protected compound 34 in excellent (90%) yield. This was followed by
straightforward methylation of 34 using methyl iodide to give iodide salt 35 and
deprotection of the secondary amine to afford the completed ligand 36.
217
Scheme A5.13. Boc-protection of 33 followed by methylation of the benzimidazole
nitrogen and deprotection of the resultant iodide salt with TFA in CH
2
Cl
2
.
With the completed ligand scaffold 36 in hand, formation of silver carbene
complex 37 was straightforward, and conducted as before (see Schemes A5.7 and A5.8)
in good yield. This silver carbene complex, as with the previously synthesized silver
complexes 19 and 21, was soluble in organic solvents and was characterized by
1
H NMR.
However, transmetalation of compound 37 with Pd(MeCN)
2
Cl
2
was problematic, and
desired NHC-palladium complex 23 could not be isolated, despite screening of various
reaction conditions. The formation of complex 23 in situ was inconclusive based on
NMR evidence. Further attempts at synthesis and purification of palladium complex 23
are underway.
218
Scheme A5.14. Formation of silver carbene complex 37 and attempted palladation to 38.
A5.4 Experimental Section
General considerations
All solvents and reagents were obtained from commercial vendors and used without
further purification.
1
H NMR spectra were obtained using a Bruker AC-250 spectrometer
at 250 MHz, a Varian Mercury 400 spectrometer at 400 MHz or a Varian 500S
spectrometer at 500 MHz. Chemical shifts (δ) are given in ppm and are referenced to the
residual solvent peak (CDCl
3
, D
2
O, MeOH, DMSO, or MeCN). X-ray crystallography
studies were conducting using a Bruker APEX DUO single-crystal diffractometer
equipped with an APEX2 CCD detector. Flash column chromatography was conducted
using SiliaFlash® P60 40-63µm (230-400 mesh) silica gel.
219
L-valinol 10
To a 250 mL round-bottom flask equipped with a reflux condenser was added L-valine
(10 g, 85.3 mmol), NaBH
4
(7.11g, 187.7 mmol) and THF (50 mL). Iodine (21.68 g, 85.3
mmol) was dissolved in THF (90 mL) in an addition funnel. The iodine solution was
added dropwise to the L-valine suspension with cooling in an ice bath. After the
evolution of gas ceased, the reaction was heated at reflux for 12 h. With cooling in an ice
bath, the solution was slowly quenched with MeOH, and the mixture was concentrated in
vacuo. The resulting residue was dissolved in 20% KOH solution (60 mL), stirred for two
hours, then extracted three times with CH
2
Cl
2
. The organic layer was dried with sodium
sulfate, filtered and concentrated to yield crude 10, which was purified using column
chromatography on silica gel to yield pure 10 as a slightly yellow oil (85%, 7.49 g).
1
H NMR (CDCl
3
) δ 3.63 (m, 1H, CH
2
), 3.28 (m, 1H, CH
2
), 2.55 (m, 1H, CH), 1.93 (m,
1H, OH), 1.56 (m, 1H, CH), 0.91 (m, 6H, CH
3
).
(S)-2-(benzylamino)-3-methylbutan-1-ol 11
To a 250 mL round-bottom flask was added 10 (2 g, 19.4 mmol), benzaldehyde (2.06 g,
19.4 mmol), activated 4Å molecular sieves (1 g) and CH
2
Cl
2
(40 mL). After strirring for
3 hours, the solution was filtered and the solvent removed in vacuo. EtOH (40 mL) was
added to the residue followed by NaBH
4
(1.32 g, 34.9 mmol) in three portions over 1
hour. The mixture stirred for two hours, after which saturated NaHCO
3
solution (20 mL)
220
was added. The solution was extracted three times with CH
2
Cl
2
, the organic layer dried
with sodium sulfate, and solvent removed in vacuo to yield crude 11, which was purified
using column chromatography on silica gel to yield pure 11 as a colorless oil (79%, 2.96
g).
1
H NMR (CDCl
3
) δ 7.60 (m, 2H, ArCH), 7.39 (m, 3H, ArCH), 4.18 (s, 2H, CH
2
), 3.83 (d,
J = 5.4 Hz, 1H, CH
2
), 2.79 (m, 1H, CH), 2.07 (m, 1H, CH), 1.02 (m, 6H, CH
3
).
(S)-2-(benzyl(methyl)amino)-3-methylbutan-1-ol 12
To a 25 mL round-bottom flask equipped with a reflux condenser was added 11 (1.70 g,
8.80 mmol), formic acid (1.21 g, 26.4 mmol), and 37.5% formalin solution (0.85 g, 10.56
mmol formaldehyde). The resulting solution was heated at reflux for 3 hours. The solvent
was removed in vacuo, and the residue neutralized with saturated NaHCO
3
solution (20
mL). The resulting solution was extracted three times with CH
2
Cl
2
, the organic layer
dried with sodium sulfate, and solvent removed in vacuo to yield crude 12, which was
purified using column chromatography on silica gel to yield pure 12 as a colorless oil
(70%, 1.27 g).
1
H NMR (CDCl
3
) δ 7.99 (m, 1H, ArCH), 7.89 (m, 1H, ArCH), 7.74 (m, 3H, ArCH), 5.39
(m, 2H, CH
2
), 4.19 (s, 3H, CH
3
), 3.77 (m, 1H, CH), 3.63 (m, 2H, CH
2
), 1.90 (m, 1H,
CH), 0.97 (m, 6H, CH
3
).
221
(S)-N-benzyl-1-chloro-N,3-dimethylbutan-2-amine 15
To a 250 mL round-bottom flask was added 12 (1.51 g, 7.29 mmol), DMAP (0.089 g,
0.729 mmol), Et
3
N (1.22 mL, 8.75 mmol), and CH
2
Cl
2
(60 mL) followed by p-
toluenesulfonyl chloride (1.67 g, 8.75 mmol) with cooling in an ice bath. The resulting
solution was stirred for 12 hours, gradually warming to ambient temperature, then
washed three times with water. The organic layer was dried with sodium sulfate and the
solvent removed in vacuo to yield crude 15, which was purified using column
chromatography on silica gel to yield pure 15 as a colorless oil (95%, 1.56 g).
1
H NMR (CDCl
3
) δ 7.38-7.26 (m, 5H, ArCH), 4.04 (m, 1H, CH), 3.57 (m, 2H, CH
2
),
2.69 (m, 2H, CH
2
), 2.29 (s, 3H, CH
3
), 2.20 (m, 1H, CH), 1.08-0.86 (m, 3H, CH
3
).
(S)-1-(1H-benzo[d]imidazol-1-yl)-N-benzyl-N,3-dimethylbutan-2-amine 17
To a 25 mL round-bottom flask equipped with a reflux condenser was added
benzimidazole (0.72 g, 6.13 mmol), tetrabutylammonium iodide (0.23 g, 0.613 g), finely
ground KOH (0.35 g, 6.13 mmol), and DMF (13 mL). After this solution stirred for 2
hours, 15 (1.38 g, 6.13 mmol) was added, and the resulting reaction mixture stirred for 12
hours at 50 °C. The solvent was removed in vacuo, and the resulting residue was
dissolved in CH
2
Cl
2
(30 mL). The organic layer was washed three times with water, dried
with sodium sulfate and the solvent removed in vacuo to yield crude 17, which was
222
purified using column chromatography on silica gel to yield pure 17 as an off-white solid
(70%, 1.32 g).
1
H NMR (CDCl
3
) δ 7.94 (s, 1H, CH), 7.88 (m, 1H, ArCH), 7.30 (m, 3H, ArCH), 7.11 (m,
3H, ArCH), 6.86 (m, 2H, ArCH), 4.23 (m, 2H, CH
2
), 3.53 (m, 2H, CH
2
), 2.88 (m, 1H,
CH), 2.35 (s, 3H, CH
3
), 2.06 (m, 1H, CH), 1.15 (m, 6H, CH
3
).
(S)-1-(2-(benzyl(methyl)amino)-3-methylbutyl)-3-methyl-1H-benzo[d]imidazol-3-ium
iodide 18
To a 25 mL round-bottom flask equipped with a reflux condenser was added 17 (1 g, 3.25
mmol), methyl iodide (1.85 g, 13 mmol), and THF (50 mL). The resulting solution was
heated at reflux for 12 hours. The solvent was removed in vacuo, and the residue was
dissolved in CH
2
Cl
2
(10 mL). The product was precipitated from the solution by adding
hexanes (30 mL) and isolated by vacuum filtration, yielding essentially pure 18 as a light
yellow solid (95%, 1.39 g).
1
H NMR (CDCl
3
) δ 7.70 (m, 1H, ArCH), 7.62 (m, 1H, ArCH), 7.54 (m, 1H, ArCH), 7.41
(m, 1H, ArCH), 6.92 (m, 1H, ArCH), 6.85 (m, 2H, ArCH), 6.52 (m, 2H, ArCH), 4.47 (m,
2H, CH
2
), 4.17 (s, 3H, CH
3
), 3.56 (m, 2H, CH
2
), 2.69 (m, 1H, CH), 2.65 (s, 3H, CH
3
),
2.19 (m, 1H, CH), 1.17 (m, 6H, CH
3
).
223
(S)-3-(2-(benzyl(methyl)amino)-3-methylbutyl)-1-methyl-1H-benzo[d]imidazol-2-ylidene
AgI 19
To a 250 mL round-bottom flask was added 18 (1.46 g, 3.25 mmol), Ag
2
O (0.376 g, 1.62
mmol) and CH
2
Cl
2
(70 mL). The resulting reaction mixture stirred in a dark environment
for 4 hours. The solution was gravity filtered and the solvent removed in vacuo, yielding
essentially pure 19 as a light yellow solid with some foaming (90%, 1.55 g).
1
H NMR (CDCl
3
) δ 7.53-7.27 (m, 4H, ArCH), 7.10-6.90 (m, 3H, ArCH), 6.68 (m, 2H,
ArCH), 4.48 (m, 2H, CH
2
), 4.08 (m, 3H, CH
3
), 3.61 (m, 2H, CH
2
), 3.08 (m, 1H, CH),
2.48 (m, 3H, CH
3
), 2.12 (m, 1H, CH), 1.19 (m, 6H, CH
3
).
(S)-3-(2-(benzyl(methyl)amino)-3-methylbutyl)-1-methyl-1H-benzo[d]imidazol-2-ylidene
PdCl
2
9a
To a 25 mL round-bottom flask was added 19 (0.1358 g, 0.244 mmol), Pd(MeCN)
2
Cl
2
(0.0602 g, 0.232 mol), and MeCN (9 mL). The resulting solution was stirred for 12 hours.
The mixture was filtered through diatomaceous earth, and the solvent removed in vacuo.
The residue was dissolved in CH
2
Cl
2
(4 mL), and the product was precipitated from the
solution by adding hexanes (20 mL) and isolated by vacuum filtration, yielding
essentially pure 9a as an orange-brown powdery solid (62%, 0.0755 g).
1
H NMR (MeCN-d
3
) δ 7.64 (d, J = 8.2 Hz, 1H, ArCH), 7.51 (d, J = 8.2 Hz, 1H, ArCH),
7.39 (t, J = 7.8 Hz, 1H, ArCH), 7.29 (t, J = 8.2 Hz, 1H, ArCH), 7.03 (t, J = 7.4 Hz, 1H,
224
ArCH), 6.93 (t, J = 7.6 Hz, 2H, ArCH), 6.54 (d, J = 7.4 Hz, 1H, ArCH), 5.06 (m, 1H,
CH
2
), 4.53 (m, 1H, CH
2
), 4.38 (s, 3H, CH
3
), 4.21 (m, 1H, CH), 3.76 (m, 2H, CH
2
), 2.32
(m, 3H, CH
3
), 2.29-2.15 (m, 1H, CH), 1.45-1.30 (m, 6H, CH
3
).
(S)-3-benzyl-1-(2-(benzyl(methyl)amino)-3-methylbutyl)-1H-benzo[d]imidazol-3-ium
bromide 20
To a 25 mL round-bottom flask was added 17 (0.4161 g, 1.353 mmol), benzyl bromide
(0.4630 g, 2.707 mmol), and dimethylacetamide (7 mL). The resulting reaction mixture
was heated at reflux for 12 hours, and the solvent was removed in vacuo, yielding crude
20, which was purified using column chromatography on silica gel to yield pure 20 as a
slightly yellow solid (53%, 0.3434 g).
1
H NMR (CDCl
3
) δ 7.65-7.57 (m, 3H, ArCH), 7.55-7.32 (m, 6H, ArCH), 6.82 (m, 1H,
ArCH), 6.65(m, 2H, ArCH), 6.38 (m, 2H, ArCH), 5.82 (m, 2H, CH
2
), 4.71 (m, 1H, CH
2
),
4.37 (m, 1H, CH
2
), 3.55 (m, 2H, CH
2
), 2.75 (m, 1H, CH), 2.66 (s, 3H, CH
3
), 2.22 (m, 1H,
CH), 1.17 (m, 6H, CH
3
).
225
(S)-1-benzyl-3-(2-(benzyl(methyl)amino)-3-methylbutyl)-1H-benzo[d]imidazol-2-ylidene
AgBr 21
This complex was prepared in the same fashion as 19 above, with 20 (0.3434 g, 0.7177
mmol), Ag
2
O (0.0831 g, 0.3588 mmol), and CH
2
Cl
2
(15 mL), to yield 21 as a slightly
yellow solid (88%, 0.3716 g).
1
H NMR (CDCl
3
) δ 7.40-7.25 (m, 9H, ArCH), 6.98 (m, 1H, ArCH), 6.85 (m, 2H, ArCH),
6.59 (m, 2H, ArCH), 5.62 (s, 2H, CH
2
), 4.46 (m, 2H, CH
2
), 3.57 (m, 2H, CH
2
), 3.05 (m,
1H, CH), 2.14 (m, 1H, CH), 1.21 (m, 6H, CH
3
).
(S)-1-benzyl-3-(2-(benzyl(methyl)amino)-3-methylbutyl)-1H-benzo[d]imidazol-2-ylidene
PdCl
2
9b
This complex was prepared in the same fashion as 9a above, with 21 (0.2317 g, 0.3958
mmol), Pd(MeCN)
2
Cl
2
(0.0996 g, 0.3839 mmol), and MeCN (15 mL), to yield 9b as an
orange-brown solid (84%, 0.182 g).
1
H NMR (MeCN-d
3
) δ 7.62 (m, 2H, ArCH), 7.50 (m, 1H, ArCH), 7.45-7.25 (m, 4H,
ArCH), 7.21 (m, 2H, ArCH), 7.02 (m, 1H, ArCH), 6.89 (m, 2H, ArCH), 6.53 (m, 2H,
ArCH), 6.45-6.29 (m, 1H, CH
2
), 6.17-5.99 (m, 1H, CH
2
), 5.15 (m, 1H, CH
2
), 4.56 (m,
1H, CH
2
), 4.29 (m, 1H, CH), 3.96-3.68 (m, 2H, CH
2
), 2.33 (m, 3H, CH
3
), 2.27 (m, 1H,
CH), 1.50-1.30 (m, 6H, CH
3
).
226
1-(2-chloroethyl)-1H-benzo[d]imidazole 29
To a 100 mL round-bottom flask was added benzimidazole (2.36 g, 20 mmol), KOH
(2.24 g, 40 mmol), 1,2-dichloroethane (60 mL, 635 mmol), tetrabutylammonium iodide
(0.222 g, 0.600 mmol) and water (0.4 mL). The resulting mixture was stirred for 48
hours, then was dried with MgSO
4
and gravity filtered. The solvent was removed in
vacuo, yielding crude 29, which was purified using column chromatography on silica gel
to yield pure 29 as white solid (32%, 1.16 g).
1
H NMR (CDCl
3
) δ 8.35 (s, 1H, CH), 7.88 (m, 1H, ArCH), 7.44 (m, 1H, ArCH), 7.38 (m,
3H, ArCH), 4.60 (t, J = 6.0 Hz, CH
2
), 3.91 (t, J = 6.0 Hz, CH
2
).
1-(2-chloroethyl)-3-methyl-1H-benzo[d]imidazol-3-ium iodide 30
This complex was prepared in the same fashion as 18 above, with 29 (0.5 g, 2.768
mmol), methyl iodide (1.179 g. 8.304 mmol), and THF (5 mL) to yield 30 as a yellow
solid (87%, 0.777 g).
1
H NMR (CDCl
3
) δ 11.09 (s, 1H, CH), 7.87 (m, 1H, ArCH), 7.76-7.67 (m, 3H, ArCH),
5.11 (m, 2H, CH
2
), 4.28 (s, 3H, CH
3
), 4.23 (m, 2H, CH
2
).
227
N-(2-(1H-benzo[d]imidazol-1-yl)ethyl)-2-methoxyethan-1-amine 33
To a 10 mL round-bottom flask equipped with a reflux condenser was added 29 (0.4547
g, 2.517 mmol) and 2-methyoxyethylamine (2.62 mL, 30.2 mmol). The resulting mixture
was heated at 100 °C for 12 hours, and the solvent was removed in vacuo. The crude 33
was purified using column chromatography on silica gel to yield pure 29 as a light yellow
oil which crystallized upon standing (82%, 0.4524 g).
1
H NMR (CDCl
3
) δ 8.15 (s, 1H, CH), 7.60 (d, J = 8.0 Hz, 1H, ArCH), 7.46 (d, J = 8.0 Hz,
1H, ArCH), 7.28-7.14 (m, 2H, ArCH), 4.54 (m, 2H, CH
2
), 3.69 (m, 1H, CH
2
), 3.57 (m,
2H, CH
2
), 3.30 (s, 3H, CH
3
), 3.21 (m, 1H, CH
2
), 2.98 (m, 2H, CH
2
).
tert-butyl (2-(1H-benzo[d]imidazol-1-yl)ethyl)(2-methoxyethyl)carbamate 34
To a 100 mL round-bottom flask was added 33 (0.800 g, 3.648 mmol), di-tert-butyl
dicarbonate (1.592 g, 7.296 mmol), and MeOH (20 mL). The resulting solution stirred for
2 hours, and the solvent was removed in vacuo, yielding crude 34, which was purified
using column chromatography on silica gel to yield pure 34 as a colorless oil (90%, 1.049
g).
1
H NMR (CDCl
3
) δ 7.84 (m, 1H, ArCH), 7.46 (m, 1H, ArCH), 7.28 (m, 2H, ArCH), 4.39
(m, 2H, CH
2
), 3.64 (m, 2H, CH
2
), 3.51 (m, 1H, CH
2
), 3.36 (s, 3H, CH
3
), 3.24 (m, 2H,
CH
2
), 3.03 (m, 1H, CH
2
), 1.52-1.17 (m, 9H, CH
3
).
228
1-(2-((tert-butoxycarbonyl)(2-methoxyethyl)amino)ethyl)-3-methyl-1H-benzo[d]imidazol-
3-ium iodide 35
This complex was prepared in the same fashion as 18 above, with 34 (0.5 g, 1.565
mmol), methyl iodide (0.666 g. 4.695 mmol), and THF (5 mL) to yield 35 as a yellow
solid (92%, 0.6642 g).
1
H NMR (CDCl
3
) δ 10.94 (s, 1H, CH), 8.00-7.60 (m, 4H, ArCH), 4.85 (m, 2H, CH
2
),
4.24 (s, 3H, CH
3
), 3.84 (m, 2H, CH
2
), 3.57-3.44 (m, 4H, CH
2
), 3.37 (s, 3H, CH
3
), 1.40-
1.08 (m, 9H, CH
3
).
1-(2-((2-methoxyethyl)amino)ethyl)-3-methyl-1H-benzo[d]imidazol-3-ium iodide 36
To a 50 mL round-bottom flask was added TFA (10 mL), CH
2
Cl
2
(10 mL), and 35
(0.6642 g, 1.440 mmol) with cooling in an ice bath. The resulting solution stirred for 2
hours, and the solvent was removed in vacuo, yielding crude 36, which was purified
using column chromatography on silica gel to yield pure 36 as a brown oil (86%, 0.4473
g).
1
H NMR (MeOD- d
3
) δ 8.04-7.91 (m, 2H, ArCH), 7.74 (m, 2H, ArCH), 4.60 (m, 2H,
CH
2
), 4.16 (s, 3H, CH
3
), 3.45 (m, 2H, CH
2
), 3.36 (s, 3H, CH
3
), 3.16 (m, 2H, CH
2
), 2.80
(m, 2H, CH
2
).
229
1-(2-((2-methoxyethyl)amino)ethyl)-3-methyl-1H-benzo[d]imidazol-2-ylidene AgI 37
This complex was prepared in the same fashion as 19 above, with 36 (0.2 g, 0.5537
mmol), Ag
2
O (0.0647 g, 0.2768 mmol), and CH
2
Cl
2
(10 mL), to yield 37 as a yellow
solid (90%, 0.2333 g).
1
H NMR (MeOD- d
3
) δ 7.81 (m, 1H, ArCH), 7.75 (m, 1H, ArCH), 7.53 (m, 2H, ArCH),
5.00 (m, 2H, CH
2
), 4.11 (s, 3H, CH
3
), 3.58 (m, 2H, CH
2
), 3.39 (m, 2H, CH
2
), 3.34 (s, 3H,
CH
3
), 3.00 (m, 2H, CH
2
).
230
A5.5
1
H NMR Spectra
231
232
233
234
235
236
237
238
239
240
241
242
243
244
245
246
247
248
A5.6 Supplementary crystallographic information for complex 9a
15
Table A5.1. Crystal data and structure refinement for C
21
H
28
N
3
O
4
Pd.
Identification code pdcl2m
Empirical formula C
22
H
29
C
l4
N
3
Pd
Formula weight 583.68
Temperature 138(2) K
Wavelength 0.71073 Å
Crystal system Monoclinic
Space group P2(1)
Unit cell dimensions a = 10.0697(9) Å α= 90°.
b = 22.6147(19) Å β= 89.9750(10)°.
c = 10.8754(9) Å γ= 90°.
Volume 2476.6(4) Å
3
Z 4
Density (calculated) 1.565 Mg/m
3
Absorption coefficient 1.196 mm
-1
F(000) 1184
Crystal size 1.10 x 0.50 x 0.50 mm
3
Theta range for data collection 1.80 to 27.52°.
Index ranges -13<=h<=11, -23<=k<=29, -13<=l<=14
Reflections collected 17195
Independent reflections 8807 [R(int) = 0.0205]
Completeness to theta = 27.52° 97.6 %
Absorption correction Semi-empirical
Max. and min. transmission 0.5863 and 0.3530
Refinement method Full-matrix least-squares on F
2
Data / restraints / parameters 8807 / 1 / 549
Goodness-of-fit on F
2
1.060
Final R indices [I>2sigma(I)] R1 = 0.0208, wR2 = 0.0531
R indices (all data) R1 = 0.0211, wR2 = 0.0533
Absolute structure parameter -0.014(14)
Largest diff. peak and hole 0.523 and -0.371 e.Å
-3
249
Table A5.2. Atomic coordinates ( x 10
4
) and equivalent isotropic displacement
parameters (Å
2
x 10
3
) for C
21
H
28
N
3
O
4
Pd. U(eq) is defined as one third of the trace of
the orthogonalized U
ij
tensor.
________________________________________________________________________
x y z U(eq)
________________________________________________________________________
Pd(1) -497(1) 2407(1) 2705(1) 22(1)
N(1) -830(2) 1842(1) 1143(2) 22(1)
N(2) 1914(2) 1712(1) 2423(2) 23(1)
N(3) 1319(2) 1711(1) 4340(2) 24(1)
Cl(1) -2467(1) 2958(1) 2324(1) 31(1)
Cl(2) 116(1) 3090(1) 4186(1) 36(1)
C(1) 999(2) 1921(1) 3217(2) 23(1)
C(2) 532(3) 1769(2) 5466(2) 32(1)
C(3) 2456(2) 1358(1) 4260(2) 25(1)
C(4) 3162(3) 1046(1) 5148(2) 32(1)
C(5) 4262(3) 732(1) 4745(3) 34(1)
C(6) 4650(3) 736(1) 3510(3) 33(1)
C(7) 3950(3) 1049(1) 2621(2) 28(1)
C(8) 2843(2) 1356(1) 3027(2) 24(1)
C(9) 1633(2) 1700(1) 1096(2) 24(1)
C(10) 283(2) 1410(1) 889(2) 22(1)
C(11) 214(3) 1075(1) -358(2) 30(1)
C(12) 785(4) 454(2) -169(3) 47(1)
C(13) 933(3) 1372(2) -1437(2) 41(1)
C(14) -1007(3) 2255(1) 80(2) 28(1)
C(15) -2140(2) 1522(1) 1300(2) 27(1)
C(16) -2091(3) 1011(1) 2189(2) 26(1)
C(17) -2214(3) 434(1) 1776(3) 38(1)
C(18) -2154(4) -37(2) 2582(4) 46(1)
C(19) -1953(3) 57(2) 3821(3) 44(1)
C(20) -1864(3) 634(2) 4258(3) 38(1)
C(21) -1931(3) 1105(1) 3452(2) 30(1)
250
Pd(2) 5497(1) 1997(1) 7706(1) 22(1)
N(4) 5832(2) 2562(1) 6144(2) 22(1)
N(5) 3084(2) 2691(1) 7425(2) 22(1)
N(6) 3680(2) 2693(1) 9341(2) 24(1)
Cl(3) 7467(1) 1446(1) 7325(1) 31(1)
Cl(4) 4886(1) 1316(1) 9187(1) 36(1)
C(22) 4004(2) 2483(1) 8218(2) 24(1)
C(23) 4469(3) 2635(2) 10467(2) 31(1)
C(24) 2539(2) 3047(1) 9264(2) 25(1)
C(25) 1838(3) 3359(1) 10151(2) 32(1)
C(26) 739(3) 3670(1) 9747(3) 35(1)
C(27) 350(3) 3668(1) 8512(3) 33(1)
C(28) 1050(3) 3355(1) 7624(2) 28(1)
C(29) 2157(2) 3048(1) 8029(2) 23(1)
C(30) 3369(2) 2702(1) 6098(2) 25(1)
C(31) 4717(2) 2993(1) 5892(2) 22(1)
C(32) 4788(3) 3327(1) 4644(2) 30(1)
C(33) 4212(4) 3947(2) 4837(3) 46(1)
C(34) 4068(3) 3031(2) 3564(2) 41(1)
C(35) 6008(3) 2148(1) 5081(2) 29(1)
C(36) 7138(2) 2882(1) 6298(2) 26(1)
C(37) 7094(2) 3392(1) 7189(2) 25(1)
C(38) 6933(3) 3298(1) 8455(2) 29(1)
C(39) 6863(3) 3770(2) 9258(3) 38(1)
C(40) 6954(3) 4344(2) 8823(3) 44(1)
C(41) 7153(4) 4440(2) 7577(4) 47(1)
C(42) 7218(3) 3969(1) 6775(3) 38(1)
C(43) 1563(4) 9376(2) 6838(4) 53(1)
Cl(5) 3024(1) 9669(1) 7466(1) 74(1)
Cl(6) 923(1) 9829(1) 5662(1) 58(1)
C(44) 3433(4) 5026(2) 1834(4) 52(1)
Cl(7) 1977(1) 4734(1) 2467(1) 74(1)
Cl(8) 4076(1) 4576(1) 662(1) 58(1)
________________________________________________________________________
251
Table A5.3. Bond lengths [Å] and angles [°] for C
21
H
28
N
3
O
4
Pd.
_____________________________________________________
Pd(1)-C(1) 1.947(2)
Pd(1)-N(1) 2.153(2)
Pd(1)-Cl(2) 2.3156(7)
Pd(1)-Cl(1) 2.3792(7)
N(1)-C(14) 1.498(3)
N(1)-C(10) 1.513(3)
N(1)-C(15) 1.513(3)
N(2)-C(1) 1.348(3)
N(2)-C(8) 1.398(3)
N(2)-C(9) 1.471(3)
N(3)-C(1) 1.349(3)
N(3)-C(3) 1.399(3)
N(3)-C(2) 1.464(3)
C(3)-C(4) 1.391(3)
C(3)-C(8) 1.396(3)
C(4)-C(5) 1.386(4)
C(5)-C(6) 1.399(4)
C(6)-C(7) 1.390(4)
C(7)-C(8) 1.386(4)
C(9)-C(10) 1.526(3)
C(10)-C(11) 1.554(3)
C(11)-C(12) 1.532(4)
C(11)-C(13) 1.534(4)
C(15)-C(16) 1.507(4)
C(16)-C(17) 1.387(4)
C(16)-C(21) 1.399(4)
C(17)-C(18) 1.380(5)
C(18)-C(19) 1.380(5)
C(19)-C(20) 1.391(5)
C(20)-C(21) 1.382(4)
Pd(2)-C(22) 1.944(3)
Pd(2)-N(4) 2.152(2)
252
Pd(2)-Cl(4) 2.3120(7)
Pd(2)-Cl(3) 2.3794(7)
N(4)-C(35) 1.497(3)
N(4)-C(36) 1.511(3)
N(4)-C(31) 1.512(3)
N(5)-C(22) 1.351(3)
N(5)-C(29) 1.397(3)
N(5)-C(30) 1.471(3)
N(6)-C(22) 1.350(3)
N(6)-C(24) 1.403(3)
N(6)-C(23) 1.466(3)
C(24)-C(25) 1.388(4)
C(24)-C(29) 1.398(3)
C(25)-C(26) 1.383(4)
C(26)-C(27) 1.399(4)
C(27)-C(28) 1.389(4)
C(28)-C(29) 1.387(4)
C(30)-C(31) 1.525(4)
C(31)-C(32) 1.554(3)
C(32)-C(33) 1.532(4)
C(32)-C(34) 1.534(4)
C(36)-C(37) 1.507(4)
C(37)-C(42) 1.386(4)
C(37)-C(38) 1.403(4)
C(38)-C(39) 1.381(4)
C(39)-C(40) 1.385(5)
C(40)-C(41) 1.387(5)
C(41)-C(42) 1.377(5)
C(43)-Cl(5) 1.751(4)
C(43)-Cl(6) 1.760(4)
C(44)-Cl(7) 1.749(4)
C(44)-Cl(8) 1.755(4)
C(1)-Pd(1)-N(1) 90.65(9)
253
C(1)-Pd(1)-Cl(2) 88.36(7)
N(1)-Pd(1)-Cl(2) 170.69(6)
C(1)-Pd(1)-Cl(1) 172.34(7)
N(1)-Pd(1)-Cl(1) 92.50(6)
Cl(2)-Pd(1)-Cl(1) 89.65(3)
C(14)-N(1)-C(10) 110.49(19)
C(14)-N(1)-C(15) 106.33(18)
C(10)-N(1)-C(15) 111.0(2)
C(14)-N(1)-Pd(1) 104.89(16)
C(10)-N(1)-Pd(1) 114.34(14)
C(15)-N(1)-Pd(1) 109.34(15)
C(1)-N(2)-C(8) 110.93(19)
C(1)-N(2)-C(9) 120.24(19)
C(8)-N(2)-C(9) 125.4(2)
C(1)-N(3)-C(3) 109.9(2)
C(1)-N(3)-C(2) 126.6(2)
C(3)-N(3)-C(2) 123.1(2)
N(2)-C(1)-N(3) 107.1(2)
N(2)-C(1)-Pd(1) 122.90(16)
N(3)-C(1)-Pd(1) 130.01(18)
C(4)-C(3)-C(8) 121.6(2)
C(4)-C(3)-N(3) 131.6(2)
C(8)-C(3)-N(3) 106.8(2)
C(5)-C(4)-C(3) 116.6(3)
C(4)-C(5)-C(6) 121.6(3)
C(7)-C(6)-C(5) 121.9(3)
C(8)-C(7)-C(6) 116.2(3)
C(7)-C(8)-C(3) 122.1(2)
C(7)-C(8)-N(2) 132.6(2)
C(3)-C(8)-N(2) 105.3(2)
N(2)-C(9)-C(10) 108.95(19)
N(1)-C(10)-C(9) 110.8(2)
N(1)-C(10)-C(11) 116.12(19)
C(9)-C(10)-C(11) 112.3(2)
254
C(12)-C(11)-C(13) 109.0(3)
C(12)-C(11)-C(10) 108.2(2)
C(13)-C(11)-C(10) 115.7(3)
C(16)-C(15)-N(1) 114.2(2)
C(17)-C(16)-C(21) 118.1(3)
C(17)-C(16)-C(15) 120.8(2)
C(21)-C(16)-C(15) 121.1(3)
C(18)-C(17)-C(16) 121.1(3)
C(19)-C(18)-C(17) 120.6(3)
C(18)-C(19)-C(20) 119.1(3)
C(21)-C(20)-C(19) 120.3(3)
C(20)-C(21)-C(16) 120.7(3)
C(22)-Pd(2)-N(4) 90.67(9)
C(22)-Pd(2)-Cl(4) 88.37(8)
N(4)-Pd(2)-Cl(4) 170.79(6)
C(22)-Pd(2)-Cl(3) 172.28(7)
N(4)-Pd(2)-Cl(3) 92.47(6)
Cl(4)-Pd(2)-Cl(3) 89.64(3)
C(35)-N(4)-C(36) 106.43(19)
C(35)-N(4)-C(31) 110.58(18)
C(36)-N(4)-C(31) 110.9(2)
C(35)-N(4)-Pd(2) 104.87(16)
C(36)-N(4)-Pd(2) 109.45(14)
C(31)-N(4)-Pd(2) 114.17(14)
C(22)-N(5)-C(29) 111.02(19)
C(22)-N(5)-C(30) 119.9(2)
C(29)-N(5)-C(30) 125.5(2)
C(22)-N(6)-C(24) 110.1(2)
C(22)-N(6)-C(23) 126.4(2)
C(24)-N(6)-C(23) 123.0(2)
N(6)-C(22)-N(5) 106.9(2)
N(6)-C(22)-Pd(2) 130.14(18)
N(5)-C(22)-Pd(2) 122.97(17)
C(25)-C(24)-C(29) 121.8(2)
255
C(25)-C(24)-N(6) 131.7(2)
C(29)-C(24)-N(6) 106.5(2)
C(26)-C(25)-C(24) 116.5(2)
C(25)-C(26)-C(27) 121.8(3)
C(28)-C(27)-C(26) 121.8(3)
C(29)-C(28)-C(27) 116.3(2)
C(28)-C(29)-N(5) 132.7(2)
C(28)-C(29)-C(24) 121.8(2)
N(5)-C(29)-C(24) 105.5(2)
N(5)-C(30)-C(31) 108.95(19)
N(4)-C(31)-C(30) 110.8(2)
N(4)-C(31)-C(32) 116.0(2)
C(30)-C(31)-C(32) 112.2(2)
C(33)-C(32)-C(34) 109.0(3)
C(33)-C(32)-C(31) 108.0(2)
C(34)-C(32)-C(31) 115.8(2)
C(37)-C(36)-N(4) 114.4(2)
C(42)-C(37)-C(38) 118.2(3)
C(42)-C(37)-C(36) 120.6(3)
C(38)-C(37)-C(36) 121.2(2)
C(39)-C(38)-C(37) 120.6(3)
C(38)-C(39)-C(40) 120.4(3)
C(39)-C(40)-C(41) 119.3(3)
C(42)-C(41)-C(40) 120.4(3)
C(41)-C(42)-C(37) 121.1(3)
Cl(5)-C(43)-Cl(6) 111.8(2)
Cl(7)-C(44)-Cl(8) 112.1(2)
_____________________________________________________________
Symmetry transformations used to generate equivalent atoms:
256
Table A5.4. Anisotropic displacement parameters (Å
2
x 10
3
) for C
21
H
28
N
3
O
4
Pd. The
anisotropic displacement factor exponent takes the form: -2π
2
[ h
2
a*
2
U
11
+ ... + 2 h k
a* b* U
12
]
________________________________________________________________________
U
11
U
22
U
33
U
23
U
13
U
12
________________________________________________________________________
Pd(1) 19(1) 26(1) 22(1) 0(1) -1(1) 1(1)
N(1) 19(1) 26(1) 21(1) 3(1) -2(1) 3(1)
N(2) 20(1) 30(1) 18(1) 2(1) -2(1) 1(1)
N(3) 21(1) 32(1) 20(1) 2(1) 1(1) 0(1)
Cl(1) 26(1) 34(1) 35(1) -1(1) -2(1) 8(1)
Cl(2) 31(1) 42(1) 35(1) -14(1) -7(1) 5(1)
C(1) 20(1) 28(1) 21(1) 1(1) -1(1) -4(1)
C(2) 28(1) 48(2) 20(1) 3(1) 3(1) -2(1)
C(3) 21(1) 28(1) 26(1) 3(1) -2(1) -3(1)
C(4) 29(1) 36(2) 29(1) 10(1) -6(1) -4(1)
C(5) 29(1) 33(2) 41(2) 11(1) -11(1) 0(1)
C(6) 22(1) 29(2) 49(2) 5(1) -4(1) 1(1)
C(7) 22(1) 29(2) 33(1) 2(1) 0(1) -2(1)
C(8) 19(1) 26(1) 26(1) 2(1) -3(1) -3(1)
C(9) 22(1) 34(2) 17(1) 3(1) 2(1) 1(1)
C(10) 23(1) 24(1) 19(1) 2(1) 0(1) 4(1)
C(11) 35(1) 33(2) 23(1) -3(1) -3(1) 6(1)
C(12) 60(2) 38(2) 42(2) -7(1) -3(2) 18(2)
C(13) 43(2) 59(2) 21(1) -1(1) 2(1) 11(2)
C(14) 33(1) 29(1) 23(1) 7(1) -4(1) 5(1)
C(15) 21(1) 30(2) 29(1) 0(1) -3(1) -2(1)
C(16) 19(1) 25(1) 33(1) 1(1) 1(1) -2(1)
C(17) 41(2) 34(2) 38(2) -7(1) 7(1) -6(1)
C(18) 43(2) 23(2) 73(2) -4(1) 14(2) -1(1)
C(19) 32(2) 39(2) 62(2) 18(2) 2(1) -2(1)
C(20) 32(1) 44(2) 38(2) 11(1) -2(1) -10(1)
C(21) 26(1) 32(2) 32(1) -1(1) 4(1) -7(1)
257
Pd(2) 19(1) 26(1) 22(1) 0(1) 1(1) 1(1)
N(4) 20(1) 25(1) 22(1) -3(1) 2(1) 2(1)
N(5) 20(1) 28(1) 19(1) -2(1) 3(1) 1(1)
N(6) 22(1) 30(1) 21(1) -3(1) 0(1) 1(1)
Cl(3) 26(1) 33(1) 35(1) 1(1) 2(1) 8(1)
Cl(4) 33(1) 40(1) 36(1) 13(1) 7(1) 5(1)
C(22) 22(1) 29(1) 19(1) -1(1) 1(1) -5(1)
C(23) 30(1) 44(2) 20(1) -2(1) -3(1) -1(1)
C(24) 21(1) 27(1) 27(1) -2(1) 3(1) -3(1)
C(25) 30(1) 36(2) 30(1) -9(1) 6(1) -3(1)
C(26) 29(1) 33(2) 42(2) -12(1) 10(1) -1(1)
C(27) 23(1) 30(2) 47(2) -3(1) 3(1) 2(1)
C(28) 22(1) 29(2) 33(1) -2(1) -1(1) -3(1)
C(29) 19(1) 25(1) 26(1) -4(1) 4(1) -3(1)
C(30) 23(1) 33(2) 18(1) -3(1) -2(1) 2(1)
C(31) 23(1) 26(1) 18(1) -2(1) 0(1) 3(1)
C(32) 34(1) 33(2) 22(1) 3(1) 4(1) 4(1)
C(33) 59(2) 38(2) 41(2) 8(1) 4(2) 16(2)
C(34) 45(2) 59(2) 19(1) 1(1) -2(1) 10(2)
C(35) 34(1) 31(2) 22(1) -7(1) 5(1) 4(1)
C(36) 20(1) 30(2) 30(1) 0(1) 2(1) -2(1)
C(37) 18(1) 24(1) 33(1) 0(1) -2(1) -1(1)
C(38) 24(1) 30(2) 32(1) 0(1) -4(1) -6(1)
C(39) 32(1) 46(2) 37(2) -10(1) 0(1) -9(1)
C(40) 31(2) 37(2) 63(2) -18(2) 1(1) -4(1)
C(41) 45(2) 22(2) 73(2) 3(1) -13(2) -1(1)
C(42) 40(2) 32(2) 41(2) 8(1) -9(1) -6(1)
C(43) 50(2) 45(2) 62(2) 4(2) -9(2) -1(2)
Cl(5) 46(1) 105(1) 71(1) 7(1) -9(1) -16(1)
Cl(6) 51(1) 57(1) 65(1) 14(1) -1(1) 7(1)
C(44) 50(2) 48(2) 59(2) -4(2) 7(2) -2(2)
Cl(7) 47(1) 105(1) 70(1) -7(1) 8(1) -16(1)
Cl(8) 51(1) 57(1) 65(1) -14(1) 1(1) 7(1)
________________________________________________________________________
258
Table A5.5. Hydrogen coordinates ( x 10
4
) and isotropic displacement parameters (Å
2
x
10
3
) for C
21
H
28
N
3
O
4
Pd.
________________________________________________________________________
x y z U(eq)
________________________________________________________________________
H(2A) -248 2016 5303 48
H(2B) 1074 1953 6108 48
H(2C) 243 1377 5740 48
H(4) 2904 1048 5989 38
H(5) 4764 510 5321 41
H(6) 5414 518 3271 40
H(7) 4215 1052 1783 34
H(9A) 2332 1473 662 29
H(9B) 1626 2107 765 29
H(10) 205 1098 1537 27
H(11) -744 1032 -586 36
H(12A) 725 231 -940 70
H(12B) 278 249 472 70
H(12C) 1717 484 83 70
H(13A) 1884 1400 -1253 61
H(13B) 570 1769 -1566 61
H(13C) 806 1135 -2183 61
H(14A) -1288 2031 -646 42
H(14B) -163 2454 -94 42
H(14C) -1684 2550 284 42
H(15A) -2814 1809 1589 32
H(15B) -2431 1373 487 32
H(17) -2342 361 924 45
H(18) -2253 -429 2280 55
H(19) -1875 -268 4370 53
H(20) -1758 704 5113 46
H(21) -1869 1497 3759 36
H(23A) 5244 2385 10305 47
259
H(23B) 3926 2455 11114 47
H(23C) 4766 3027 10734 47
H(25) 2098 3359 10990 38
H(26) 234 3892 10324 42
H(27) -413 3887 8274 40
H(28) 784 3353 6786 33
H(30A) 2670 2927 5662 29
H(30B) 3380 2294 5770 29
H(31) 4794 3305 6540 27
H(32) 5745 3371 4416 36
H(33A) 4264 4170 4065 69
H(33B) 4723 4153 5473 69
H(33C) 3283 3916 5095 69
H(34A) 3123 2989 3761 61
H(34B) 4454 2640 3414 61
H(34C) 4167 3276 2826 61
H(35A) 5160 1955 4897 43
H(35B) 6671 1847 5292 43
H(35C) 6308 2370 4359 43
H(36A) 7815 2596 6584 32
H(36B) 7427 3032 5486 32
H(38) 6873 2906 8762 35
H(39) 6750 3700 10113 46
H(40) 6882 4669 9373 52
H(41) 7244 4832 7275 56
H(42) 7350 4042 5923 45
H(43A) 890 9334 7496 63
H(43B) 1748 8978 6502 63
H(44A) 4107 5069 2490 63
H(44B) 3246 5424 1497 63
________________________________________________________________________
260
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Abstract (if available)
Abstract
The research efforts discussed herein encompass two broad subjects, the development of catalytic methodologies using palladium-NHC complexes and the hydrogen-deuterium exchange of aromatic molecules under acidic conditions. The introduction (Chapter 1) gives a brief overview of the history, progress, and recent developments in these fields. ❧ In Chapter 2, the development of a method for the hydroamination of vinyl arenes using a palladium-NHC complex is discussed. This methodology selectively furnished the cross-coupled hydroamination products in a Markovnikov fashion while greatly reducing undesired acid-catalyzed homocoupling of the vinyl arenes. ❧ Chapter 3 describes the trifluoroacetic acid-d1-catalyzed hydrogen-deuterium exchange of aromatic amines and amides. While this method was amenable to efficient deuterium incorporation for numerous substrates, best results were seen with less basic anilines and highly activated acetanilides, reflecting the likelihood of different mechanistic pathways. ❧ Chapter 4 represents the intersection of these methods by employing a palladium-NHC complex under the conditions described in Chapter 3 to effect the ortho-selective ligand-directed hydrogen-deuterium exchange of aromatic ketones, amides, and amino acids, accompanied in some cases by concurrent acid-catalyzed electrophilic deuteration. Experimental evidence strongly suggests that palladium facilitates C-H activation of the aromatic substrates, a mechanism seldom observed under strongly acidic conditions. ❧ In Chapter 5, the application of hydrogen-deuterium exchange methods to a pedagogical context is examined. Using acidic deuterium oxide, efficient deuterium incorporation into resorcinol was possible during the course of a single undergraduate laboratory session, and iodination of the deuterated product allowed for a visual representation of a kinetic isotope effect. ❧ Appendix 5 contains supplementary research regarding the synthesis of various NHC ligands for palladium incorporating sp3 amine substituents. The crystal structure and reactivity of one of these palladium complexes is also discussed.
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Giles, Richard A.
(author)
Core Title
Catalytic applications of palladium-NHC complexes towards hydroamination and hydrogen-deuterium exchange and development of acid-catalyzed hydrogen-deuterium exchange methods for preparative deut...
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College of Letters, Arts and Sciences
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Doctor of Philosophy
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Chemistry
Publication Date
08/20/2015
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08/04/2015
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catalysis,chemical education,deuterium,H-D exchange,hydroamination,OAI-PMH Harvest,palladium
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English
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Jung, Kyung Woon (
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), Nakano, Aiichiro (
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rgiles788@gmail.com,richarag@usc.edu
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Tags
catalysis
chemical education
deuterium
H-D exchange
hydroamination
palladium