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Iridium and ruthenium complexes for catalytic hydrogen transfer reactions
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Iridium and ruthenium complexes for catalytic hydrogen transfer reactions
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Content
IRIDIUM AND RUTHENIUM COMPLEXES FOR CATALYTIC HYDROGEN TRANSFER
REACTIONS
by
Long Zhang
A Dissertation Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
in Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(CHEMISTRY)
August 2024
Copyright 2024 Long Zhang
ii
Acknowledgements
It’s my fortune to join the Williams Group, especially as one who loves chemistry and
hopes to employ chemical knowledge to improve the environment and the quality of human life.
My mentor Dr. Zhiyao Lu has a deep understanding of homogeneous catalytic hydrogenation and
dehydrogenation. With Dr. Lu’s introduction and help, I quickly adapted to the rhythm of the
chemistry laboratory and fell in love with the field of hydrogen energy. After that, under the
guidance of my advisor Dr. Travis J. Williams, I completed my first work described in Chapter 2.
I am grateful to Dr. Van Do for inviting me to join the project she proposed and for working with
me to complete the work described in Chapter 3. I am also grateful to Dr. Valeriy Cherepakhin
and Dr. Anju Nalikezhathu for giving me advice and guidance in the early stages of the project
described in Chapter 4.
The sincerest thanks to my advisor Dr. Travis J. Williams. I am honored to work with him
over the years. His professionalism, tolerance, patience and pure love for chemistry have always
encouraged me to move forward on the road of scientific research. He can always help me in my
most difficult time. No matter what field I work in in the future, I believe his scientific research
attitude will always influence and encourage me.
I am grateful to every member of the Williams Group for their important contributions to
our academic community. It is a pleasure to work with such energetic and kind colleagues: Anju
Nalikezhathu, Adriane Tam, Alexander Maertens, A.J. Chavez, Ben Miller, Carlos Navarro,
Clarissa Olivar Magallanes, Cass Giffin, Ding-Yuan Lim, Ivan Demianets, Justin Lim, Rice
(Andrew) Rander, Stephanie Sun, Talya Kapenstein, Valery Cherepakhin, Van Do, Yuhao Chen
and Zhiyao Lu.
iii
Much gratitude must be given to my graduate committee members: Professors Chi H. Mak,
Chao Zhang, Elias Picazo, Smaranda C. Marinescu, Steve R. Nutt, and Valery Fokin for their time,
suggestion and support.
Thanks to the excellent staff of LHI and USC Department of Chemistry: Allan Kershaw,
Carole Phillips, David Hunter, Dr. Robert Anizfeld, Michele Dea, Marie de la Torre, and Claudia
Cortez.
Particularly, my parents have been very supportive of my college career for the past 11
years. I am also grateful to my entire family for their encouragement and support in my study
career.
iv
Table of Contents
Acknowledgements......................................................................................................................... ii
List of Tables ................................................................................................................................. vi
List of Schemes............................................................................................................................. vii
List of Figures..............................................................................................................................viii
Abstract......................................................................................................................................... xii
Chapter 1 Green Chemistry and Recent Advances in Homogeneous Catalysis ........................... 1
1.1 Introduction .........................................................................................................................................1
1.2 Hydrogenation .....................................................................................................................................2
1.2.1 CO2 Hydrogenation......................................................................................................................2
1.2.2 Hydrogenation of Carboxylic Acid Derivatives ..........................................................................5
1.3 Dehydrogenation .................................................................................................................................8
1.4 Hydrogen Borrowing C-N bond formation .......................................................................................10
1.5 Overview ...........................................................................................................................................12
1.6 References .........................................................................................................................................13
Chapter 2 An Ambient Pressure, Direct Hydrogenation of Ketones .......................................... 19
2.1 Introduction .......................................................................................................................................19
2.2 Results and Discussion ......................................................................................................................20
2.2.1 Optimization of Reaction Conditions.........................................................................................21
2.2.2 Substrate Scope ..........................................................................................................................23
2.2.3 Mechanistic Studies ...................................................................................................................26
2.3 Conclusion.........................................................................................................................................35
2.4 References .........................................................................................................................................35
Chapter 3 Pressurized Formic Acid Dehydrogenation: An Entropic Spring Replaces
Hydrogen Compression Cost ........................................................................................................ 37
3.1 Introduction .......................................................................................................................................37
3.2 Results and Discussion ......................................................................................................................39
3.2.1. Catalysts for FA Dehydrogenation at Ambient and Self-Pressurizing Conditions...................40
3.2.2 Impact of Applied H2 and CO....................................................................................................44
3.2.3 Regeneration, Activity, and Selectivity of 3.11 in High Pressure Gas Stream Production. ......49
3.3 Conclusion.........................................................................................................................................51
3.4 References .........................................................................................................................................52
Chapter 4 Optimization and Study of the Ligands Effects on the Selectivity and Reactivity of
Ruthenium Catalysts for Alcohol-Amine Coupling ..................................................................... 57
4.1 Introduction .......................................................................................................................................57
4.2 Results and Discussion ......................................................................................................................59
4.2.1 Coupling of Amines and Alcohols.............................................................................................59
4.2.2 Mechanistic Study......................................................................................................................61
4.2.3 Substrate Scope ..........................................................................................................................68
4.3 Conclusion.........................................................................................................................................70
4.4 References .........................................................................................................................................70
Chapter 5 Experimental and Spectral Data ................................................................................. 73
5.1 General Methods ...............................................................................................................................73
5.2 Experimental and Spectral Data: Ketones and Aldehydes Hydrogenation .......................................75
v
5.3 Experimental and Spectral Data: Formic Acid Dehydrogenation...................................................132
5.4 Experimental and Spectral Data: Alcohol-Amine Coupling ...........................................................134
5.5 References .......................................................................................................................................166
Bibliography .............................................................................................................................. 167
Appendix X-Ray Crystallography Data..................................................................................... 181
Crystal Structure of 2.5 (CCDC 2142636)............................................................................................181
Crystal Structure of 2.6 (CCDC 2258133)............................................................................................183
Crystal Structure of 4.1 (CCDC 2354122)............................................................................................185
vi
List of Tables
Table 2.1 Optimization of the Hydrogenation of Acetophenone................................................. 22
Table 2.2 Substrate Scope. ........................................................................................................... 24
Table 2.3 Kinetic Dependence on Ketone Concentration............................................................ 27
Table 2.4 Kinetic Dependence on Base. ...................................................................................... 28
Table 2.5 Kinetic Dependence on Catalyst Concentration. ......................................................... 29
Table 3.1 Dehydrogenation of Neat FA at Ambient Pressure Versus under Pressurized
Operation....................................................................................................................................... 42
Table 3.2 Aqueous Methanol Photodehydrogenation Experiment. ............................................. 47
Table 4.1 Optimization of the Coupling of Amines and Alcohols............................................... 61
Table 4.2 CO Effect in Catalytic Coupling of Amines and Alcohols.......................................... 63
Table 4.3 Reaction Site Selectivity of Catalyst 4.1 and 4.2......................................................... 67
Table 4.4 Substrate Scope of Amine Monoalkylation. ................................................................ 69
Table 5.1 Crystal Data and Structure Refinement for 2.5.......................................................... 182
Table 5.2 Crystal Data and Structure Refinement for 2.6.......................................................... 184
Table 5.3 Crystal Data and Structure Refinement for 4.1.......................................................... 187
vii
List of Schemes
Scheme 1.1 CO2 Hydrogenation Processes: A) CO2 Hydrogenation to Formic Acid; B) CO2
Hydrogenation to Methanol; C) CO2 Hydrogenation to Alkanes................................................... 3
Scheme 1.2 Proposed Catalytic Cycle for Hydrogenation of CO2 by Ir Catalyst 1.1. ................... 4
Scheme 1.3 Proposed Catalytic Cycle for CO2 Hydrogenation to Methanol by Catalyst 1.10...... 5
Scheme 1.4 A) Methanol Reforming; B) Envisioned Catalytic Dehydrogenation of Methanol.... 9
Scheme 1.5 Basic Scheme of the Hydrogen Borrowing Methodology........................................ 11
Scheme 2.1 Hydrogen Molecule Cleavage and Dihydride Iridium Formation. ORTEP
Diagram of 2.5 (CCDC 2142636) with 50% Ellipsoids. .............................................................. 21
Scheme 2.2 Catalyst Precursor 2.6 and Iridium Trihydride 2.7. ORTEP Diagram of 2.6
(CCDC 2258133) with 50% Ellipsoids. ....................................................................................... 26
Scheme 2.3 Proposed Mechanism of Catalysis............................................................................ 34
Scheme 3.1 Synthesis and Molecular Structures of 3.11-CO. ORTEP Diagram of 3.11-CO
(CCDC 2142637) with 50% Ellipsoids. ....................................................................................... 49
Scheme 4.1 Reaction Intermediate Study of Complex 4.1........................................................... 62
Scheme 4.2 Complexes 4.1 and 4.2 Mixture................................................................................ 65
Scheme 4.3 Kinetic Isotope Effect Study..................................................................................... 66
Scheme 4.4 A Metal-Catalyzed Hydrogen Transfer Via a Monohydride or a Dihydride
Intermediate. ................................................................................................................................. 68
Scheme 5.1 Initiation of Catalyst 2.1. ........................................................................................ 115
Scheme 5.2 Initiation of Catalyst 2.6. ........................................................................................ 117
viii
List of Figures
Figure 2.1 Four Iridium-based Catalyst Precursors. .................................................................... 20
Figure 2.2 Eyring Plot of Benzophenone Hydrogenation by Catalyst 2.1................................... 31
Figure 2.3 Hammett Plot of Hydrogenation of a Series of Para-substituted Acetophenones
with Different Hydride Affinities. ................................................................................................ 32
Figure 3.1 Late-transition Metal Complexes Tested for Formic Acid Dehydrogenation............ 39
Figure 3.2 Gas Evolution of Formic Acid Dehydrogenation by Complex 3.7 Over Time.......... 40
Figure 3.3 Structural Analogy between the Common Noyori-type, Milstein-type Pincer and
our Pseudo-pincer Active Catalytic Species................................................................................. 43
Figure 3.4 Pressurized Dehydrogenations of FA: Control (Black Squares), Pretreated with 8
Bars of H2 (Green Triangles), (Orange Circles) Pretreated with 1 Bar of CO Following by N2
Purging. Top Left. Complex 3.5; Top Right. Complex 3.15; Bottom Left. Complex 3.10;
Bottom Right. Complex 3.14........................................................................................................ 45
Figure 3.5 Kinetic Profile of Formic Acid Dehydrogenation by 3.9 – Black Circles and
3.9-CO – Orange Triangles. ......................................................................................................... 48
Figure 3.6 Gas Evolution of Formic Acid Dehydrogenation by Complexes 3.1-3.21 at
Ambient Pressure over Time (0 - 5 Hours)................................................................................... 50
Figure 4.1 Two Ruthenium-based Catalyst Precursors................................................................ 59
Figure 4.2 Hammett Plot of Aniline Alkylation using a Series of para-Substituted Benzyl
Alcohols with Complex 4.1 as Catalyst........................................................................................ 64
Figure 4.3 Hammett Plot of Aniline Alkylation using a Series of para-Substituted Benzyl
Alcohols with Complex 4.2 as Catalyst........................................................................................ 64
Figure 5.1 Apparatus Set Up for Hydrogenation Reactions. ....................................................... 75
Figure 5.2 1
H NMR Spectrum of Compound 2.4 in CD2Cl2. ...................................................... 78
Figure 5.3 13C NMR Spectrum of Compound 2.4 in CDCl3........................................................ 78
Figure 5.4 Infrared Spectrum of Compound 2.4.......................................................................... 79
Figure 5.5 1
H NMR Spectrum of Compound 2.6 in CD2Cl2. ...................................................... 81
Figure 5.6 13C NMR Spectrum of Compound 2.6 in CD2Cl2. ..................................................... 81
Figure 5.7 Infrared Spectrum of Complex 2.6............................................................................. 82
Figure 5.8 1
H NMR Spectrum of Table 2.2, Entry 1 Product 2.11aa in CDCl3. Data are
Consistent with a Commercial Compound. .................................................................................. 84
Figure 5.9 1
H NMR Spectrum of Table 2.2, Entry 2 Product 2.11ba in CDCl3. Data are
Consistent with a Commercial Compound. .................................................................................. 86
Figure 5.10 1
H NMR Spectrum of Table 2.2, Entry 3 Product 2.11ca in CDCl3. Data are
Consistent with a Commercial Compound. .................................................................................. 88
ix
Figure 5.11 1
H NMR Spectrum of Table 2.2, Entry 4 Product 2.11da in CDCl3. Data are
Consistent with a Commercial Compound. .................................................................................. 90
Figure 5.12 1
H NMR Spectrum of Table 2.2, Entry 5 Product 2.11ea in CDCl3. Data are
Consistent with a Commercial Compound. .................................................................................. 92
Figure 5.13 1
H NMR Spectrum of Table 2.2, Entry 6 Product 2.11fa in CDCl3. Data are
Consistent with a Commercial Compound. .................................................................................. 94
Figure 5.14 1
H NMR Spectrum of Table 2.2, Entry 7 Product 2.12a in CDCl3. Data are
Consistent with a Commercial Compound. .................................................................................. 96
Figure 5.15 1
H NMR Spectrum of Table 2.2, Entry 8 Product 2.13a in CDCl3. Data are
Consistent with a Commercial Compound. .................................................................................. 98
Figure 5.16 1
H NMR Spectrum of Table 2.2, Entry 9 Product 2.14a in CDCl3. Data are
Consistent with a Known Compound.5
....................................................................................... 100
Figure 5.17 1
H NMR Spectrum of Table 2.2, Entry 10 Product 2.15a in CDCl3. Data are
Consistent with a Commercial Compound. ................................................................................ 102
Figure 5.18 1
H NMR Spectrum of Table 2.2, Entry 11 Product 2.16a in CDCl3. Data are
Consistent with a Commercial Compound. ................................................................................ 104
Figure 5.19 1
H NMR Spectrum of Table 2.2, Entry 12 Product 2.17a in CDCl3. Data are
Consistent with a Commercial Compound. ................................................................................ 106
Figure 5.20 1
H NMR Spectrum of Table 2.2, Entry 16 Product 2.20a in CDCl3. Data are
Consistent with a Commercial Compound. ................................................................................ 108
Figure 5.21 1
H NMR Spectrum of Table 2.2, Entry 17 Product 2.21a in D2O. Data are
Consistent with a Commercial Compound. ................................................................................ 110
Figure 5.22 1
H NMR Spectrum of Table 2.2, Entry 18 Product 2.22a in CDCl3. Data are
Consistent with a Commercial Compound. ................................................................................ 112
Figure 5.23 1
H NMR Spectrum of Table 2.2, Entry 19 Product 2.23a in CD3OD. Data are
Consistent with a Commercial Compound. ................................................................................ 114
Figure 5.24 1
H NMR Spectrum of Compound 2.5 in CD2Cl2. .................................................. 116
Figure 5.25 13C NMR Spectrum of Compound 2.7 in CD3CN.................................................. 116
Figure 5.26 1
H NMR Spectrum of Ir-H Species in CD2Cl2....................................................... 118
Figure 5.27 Kinetic Profile of Hydrogenation of Four Different Amounts of Acetone. ........... 120
Figure 5.28 Kinetic Dependence of Acetone............................................................................. 121
Figure 5.29 Kinetic Profile of Hydrogenation of Acetone using Four Different Amounts of
Base............................................................................................................................................. 123
Figure 5.30 Kinetic Dependence of Base................................................................................... 124
Figure 5.31 Kinetic Profile of Hydrogenation of Acetone using Four Different Amounts of
Catalyst 2.1. ................................................................................................................................ 126
Figure 5.32 Kinetic Dependence of Catalyst 2.1. ...................................................................... 127
x
Figure 5.33 KIE Study of Benzophenone Hydrogenation by Catalyst 2.1................................ 128
Figure 5.34 Hammett Plot of Hydrogenation of a Series of para-Substituted Acetophenones
with Different Hydride Affinities. .............................................................................................. 129
Figure 5.35 Eyring Plot of Benzophenone Hydrogenation by Catalyst 2.1............................... 130
Figure 5.36 Kinetic Profile of Hydrogenation of 4'-Dimethylaminoacetophenone with or
without Alcohol. ......................................................................................................................... 131
Figure 5.37 Gas Evolution of Formic Acid Dehydrogenation by Complexes 3.1-3.21 at
Ambient Pressure over Time (0 - 25 hours)................................................................................ 133
Figure 5.38 1
H NMR Spectrum of Compound 4.1 in CD2Cl2. .................................................. 135
Figure 5.39 13C NMR Spectrum of Compound 4.1 in CD2Cl2. ................................................. 135
Figure 5.40 19F NMR Spectrum of Compound 4.1 in CD2Cl2................................................... 136
Figure 5.41 MALDI-MS Spectrum of Compound 4.1............................................................... 136
Figure 5.42 Kinetic Dependence of Benzyl Alcohol. ................................................................ 137
Figure 5.43 Kinetic Dependence of Hexylamine....................................................................... 138
Figure 5.44 Kinetic Dependence of Benzyl Alcohol. ................................................................ 139
Figure 5.45 1
H NMR Spectrum of Table 4.4, Entry 1 Product 4.3aa in CDCl3. Data are
Consistent with a Commercial Compound. ................................................................................ 141
Figure 5.46 1
H NMR spectrum of Table 4.4, Entry 2 Product 4.3ab in CDCl3. Data are
Consistent with a Commercial Compound. ................................................................................ 143
Figure 5.47 1
H NMR Spectrum of Table 4.4, Entry 3 Product 4.3ac in CDCl3. Data are
Consistent with a Commercial Compound. ................................................................................ 145
Figure 5.48 1
H NMR Spectrum of Table 4.4, Entry 4 Product 4.3ad in CDCl3. Data are
Consistent with a Commercial Compound. ................................................................................ 147
Figure 5.49 1
H NMR Spectrum of Table 4.4, Entry 5 Product 4.3ae in CDCl3. Data are
Consistent with a Commercial Compound. ................................................................................ 149
Figure 5.50 1
H NMR Spectrum of Table 4.4, Entry 6 Product 4.3af in CDCl3. Data are
Consistent with a Commercial Compound. ................................................................................ 151
Figure 5.51 1
H NMR Spectrum of Table 4.4, Entry 7 Product 4.3ag in CDCl3. Data are
Consistent with a Commercial Compound. ................................................................................ 153
Figure 5.52 1
H NMR Spectrum of Table 4.4, Entry 8 Product 4.4b in CDCl3. Data are
Consistent with a Commercial Compound. ................................................................................ 155
Figure 5.53 1
H NMR Spectrum of Table 4.4, Entry 9 Product 4.5b in CDCl3. Data are
Consistent with a Commercial Compound. ................................................................................ 157
Figure 5.54 1
H NMR Spectrum of Table 4.4, Entry 10 Product 4.6b in CDCl3. Data are
Consistent with a Commercial Compound. ................................................................................ 159
Figure 5.55 1
H NMR Spectrum of Table 4.4, Entry 11 Product 4.7b in CDCl3. Data are
Consistent with a Commercial Compound. ................................................................................ 161
xi
Figure 5.56 1
H NMR Spectrum of Table 4.4, Entry 13 Product 4.9b in CDCl3. Data are
Consistent with a Commercial Compound. ................................................................................ 163
Figure 5.57 1
H NMR Spectrum of Table 4.4, Entry 14 Product 4.10b in CDCl3. Data are
Consistent with a Commercial Compound. ................................................................................ 165
xii
Abstract
Our group develops new catalysts and conditions to manipulate hydrides such as various
C-H and other X-H bonds. To achieve these goals, we employ strategies of catalyst design, thus
exploring novel organometallic and coordination chemistry, and target-oriented new organic
reaction development. Some examples include iridium complex-catalyzed hydrogenation of
ketones and aldehydes, formic acid dehydrogenation, and ruthenium complex-catalyzed aminealcohol coupling.
Chapter 1 reviews the catalytic chemistry of hydride manipulation, such as hydrogenation
and dehydrogenation processes. Research projects mainly involve the design and synthesis of new
catalysts and mechanism analysis of catalytic processes. Such mechanistic understanding can
improve catalytic efficiency, selectivity, and catalyst lifetime. Interest in hydride manipulation is
explained by its atom economy, which is consistent with the principles of sustainability and green
chemistry. Chapter 2 describes a catalytic hydrogenation system that affects carbonyl
hydrogenation with ambient hydrogen pressure at up to quantitative yield on a diverse set of
ketones and aldehydes. Direct hydrogenation of carbonyl groups is a 100% atom efficient,
environmentally benign synthetic process. Many well-defined molecular catalysts for
hydrogenation, transfer hydrogenation of C=O groups, and dehydrogenation systems have
emerged, yet most rely on hydrogen gas pressure or a hydrogen donor/acceptor to obtain useful
rates. Such requirements for pressurization limit the utility of these methods and make them
inconvenient for users without pressurization tools. Chapter 3 presents the first general study of
how formic acid dehydrogenation catalysts respond to self-pressurizing conditions. We
demonstrate a broad survey of activity and stability of catalysts in both ambient and pressurized
reaction conditions and find striking reactivity improvements for some catalysts when pressurized.
xiii
We ultimately show how such improvements are realized, sometimes by transforming a
monomeric catalyst into a two-metal pseudo-pincer type species upon carbonylation. Chapter 4
introduces our previously reported strong s-donating (pyridyl)methylcarbene ligand to modify
precursor [RuCl2(h6
-cymene)]2 to form a new ruthenium complex which is an efficient catalyst
for the amine-alcohol coupling reaction. We find neither that this new complex will self-poison
nor that CO generated during the reaction is enough to poison it. We also propose a monomeric
catalytic mechanism of this ruthenium catalyst and extend the reaction scope to include several
kinds of amides, less nucleophilic amines, and cyclic amine products. We experimentally compare
the effects of two ligands (pyridyl-carbene and pyridyl-phosphine) connected to ruthenium on the
selectivity of catalytic reactions. In addition, we envision this new ruthenium complex as a useful
tool both for organic synthesis at scale and preparation for drug synthesis.
1
Chapter 1 Green Chemistry and Recent Advances in Homogeneous Catalysis
1.1 Introduction
Chemistry occupies a special place in the development of civilization, and its role in industrial
world is particularly important. Chemistry is relevant to the development of alternative energy
sources (particularly hydrogen), drug synthesis, design of new materials, sustainable harvesting in
agriculture, and more. Chemistry, however, has been accused of polluting the environment,
including air, water and soil pollution. Waste generated during the manufacturing of organic
compounds consists mainly of inorganic salts. This is a direct result of the use of stoichiometric
inorganic reagents in organic synthesis, particularly in fine chemicals and pharmaceutical
manufacturing. For example, stoichiometric reduction with metal hydride reagents (LiAlH4,
NaBH4), and oxidation with permanganate, manganese dioxide, and chromium(VI) reagents.
Many reactions such as sulfonation, nitration, halogenation, and diazotization using stoichiometric
amounts of inorganic acids (H2SO4, HF, H3PO4) and Lewis acids (AlCl3, ZnCl2, BF3) are major
sources of waste.
Green chemistry offers a way out. The authors of this concept, Anastas and Warner proposed
12 principles of green chemistry in 1998.1,2 Research and development is driven by the necessity
to reduce waste, use less toxic reagents and solvents, improve energy efficiency, recycle catalysts
and reagents, and combine unit operations to reduce costs and achieve more sustainable processes.
Catalytic processes can reduce reactor volume, shorten reaction time, lower reaction temperature,
and avoid unnecessary waste, thereby significantly reducing the environmental pollution.
2
1.2 Hydrogenation
Catalytic hydrogenation is undoubtedly the most widely used method for the reduction of
organic compounds and is among the most important transformations in the chemical industry.
Homogeneous catalysts are often used for highly selective transformations, especially
enantioselective reductions. Hydrogenation with molecular hydrogen is an atom-economic
transformation and the cleanest method of reducing compounds with complete recovery of
heterogeneous or homogeneous catalysts. Homogeneous catalysts have achieved astonishing
progress over the past three decades, culminating in the 2001 Nobel Prize in Chemistry being
awarded to W.S. Knowles and R. Noyori developed catalytic asymmetric hydrogenation and K.B.
Sharpless developed asymmetric oxidation catalysis.3 Recent trends in the application of catalytic
hydrogenation in the production of fine chemicals, focusing on the use of chemo-, regio-, and
stereo-selective heterogeneous and homogeneous catalysts.4
1.2.1 CO2 Hydrogenation
In recent years, the utilization of carbon dioxide is emerging as a promising field from the
perspective of green chemistry and sustainable development. In fact, CO2 fixation and conversion
hold great promise for recycling CO2 into chemicals, fuels and materials due to its huge potential
as a non-toxic, sustainable and ubiquitous C1 resource.5-7 Therefore, using CO2 as a chemical
feedstock to prepare large-scale production of useful products such as urea, organic carbonates,
formic acid (FA), methanol, and polycarbonates would be ideal for industrial applications (Scheme
1.1).
8 Additionally, CO2 can be used as a green alternative to traditional carbon monoxide and
phosgene processes for the preparation of organic carbonates, carboxylic acids, and their
derivatives. Cycloaddition of epoxides with CO2 provides an industrial route to produce cyclic
3
carbonates using CO2 instead of phosgene or carbon monoxide.9 Despite this, the chemical
industry currently consumes only a small fraction of the total abundance of CO2 (∼0.1%);10 mainly
due to the establishment of selective catalytic and economical carbon neutralization processes with
high turnover numbers (TON) due to the thermodynamic stability and kinetic inertness are
challenging issues. In fact, most reactions involving CO2 require the use of stoichiometric amounts
of organometallic reagents, excess additives/solvents, harsh reaction conditions, and tedious workup procedures due to the unavoidable formation of by-products, resulting in economical lower.
Therefore, how to effectively, selectively and greenly utilize CO2 is significant in the future.
Scheme 1.1 CO2 Hydrogenation Processes: A) CO2 Hydrogenation to Formic Acid; B) CO2
Hydrogenation to Methanol; C) CO2 Hydrogenation to Alkanes.
In 2009, Nozaki et al. demonstrated that Ir-PNP-H3 (1.1) is the most efficient catalytic
system for CO2 hydrogenation and FA dehydrogenation, where the studied catalytic process was
tuned to achieve reversibility by using the base triethanolamine (Scheme 1.2).
8d The strength of
the base and the pressure of H2 and CO2 play a crucial role in achieving higher catalytic activity.
Catalyst 1.1 performed well with KOH at 120 °C, 60 bar pH2/pCO2 (1:1) in THF, achieving 94%
yield with a TON of 470,000. Reducing the catalyst loading by a factor of ten resulted in an
increase in TON of 3,500,000 and TOF of 73,000 h−1
. DFT studies revealed two pathways for CO2
hydrogenation: a deprotonation step from 1.5 to 1.6 and a hydrogenolysis step from 1.9 to 1.1 as
rate-determining steps.8e The deprotonation seems less likely to be the rate-determining step
CO2 + H2 HCOOH
CO2 + 3 H2 CH3OH + H2O
(n+2) CO2 + [3(n+2)+1] H2 CH3(CH2)nCH3 + 2(n+2) H2O
A:
B:
C:
4
because they observed that a higher concentration of KOH resulted in lower reactivity. This work
presents an outstanding homogeneous iridium system for CO2 hydrogenation to formate.
Scheme 1.2 Proposed Catalytic Cycle for Hydrogenation of CO2 by Ir Catalyst 1.1.
Ru(triphos)(TMM) (Triphos = 1,1,1-tris(diphenylphosphinomethyl)ethane, TMM =
trimethylene methane) 1.10 might be one of the best single catalysts for CO2 hydrogenation known
to date (Scheme 1.3). In the study published by Leitner et al. in 2012,8a at 140 °C, under 80 bar
H2/CO2 (3:1), Ru(triphos)(TMM) 1.10 hydrogenates CO2 to methanol with a TON of 221 in 24
hours. The reduction of CO2 to methanol goes through multiple oxidation states, which might be
out of the reaction scope of a single catalyst. In the follow-up study, Leitner and co-workers studied
5
the mechanism of this Ru(triphos)(TMM) catalyzed CO2 hydrogenation to methanol reaction by
in situ FT-IR, NMR, X-ray spectroscopy, and DFT calculations.8b NMR spectroscopic studies
revealed that formation of a formate adduct 1.11 from the precatalyst 1.10 immediately after
pressurized under H2 and CO2. Notably, this cationic 1.11 can be obtained from readily available
catalyst precursor 1.10 and formic acid. The resting state of the catalyst is a dihydride bridged
dimer 1.12.
Beller and colleagues further expanded triphos ligand-based molecular catalysts from
ruthenium to cobalt metal.8c As expected, Co(triphos) showed interesting results in CO2
hydrogenation, with methanol selectivity above 97%, but low stability and productivity (TON 78
after 96 h) were observed under mild reaction conditions (70 bar of H2, 20 bar of CO2, 100 °C).
Characterization of the formed cobalt complex by high-resolution electrospray ionization mass
spectrometry and in situ high pressure phosphorus NMR spectroscopy showed that the reaction
follows an inner-sphere mechanism, possibly similar to Ru(triphos)(TMM) 1.10.
Scheme 1.3 Proposed Catalytic Cycle for CO2 Hydrogenation to Methanol by Catalyst 1.10.
1.2.2 Hydrogenation of Carboxylic Acid Derivatives
In the context of upgrading bio-based feedstocks, the hydrogenation of carboxylic acids
and their esters has received increasing attention. Seed and vegetable oils are important biological
resources that can be converted into fatty alcohols and other bulk chemicals.11 Fatty alcohols are
used as intermediates in the production of pharmaceuticals,12 fragrances,13 detergents,14
1.10 1.11 1.12
6
emulsifiers15 and lubricants16. Common routes used to produce fatty alcohols are direct
hydrogenation of oils and fats17 or hydrogenation of fatty acids and their methyl esters (e.g.
biodiesel). Many bulk chemicals, including polyesters and polyurethanes, can be synthesized using
diols obtained by hydrogenation of dicarboxylic acids and their esters.18, 19
Hydrogenation of carboxylic acid derivatives is a powerful tool in synthetic organic
chemistry. The alcohol products typically formed in such reduction reactions offer great potential
for further synthetic functionalization. These alcohols can be derivatized by selective
dehydrogenation,20 oxidation,21 amination,22 and acceptor-free dehydrogenative coupling of esters,
amides, and imines.23-25 Therefore, the catalytic hydrogenation of carboxylic acids and their esters
can yield a huge number of useful products such as bulk platform chemicals or fine-synthesis
intermediates. Ester hydrogenation is also one of the key steps in potential pathways for CO2
valorization26 and green methanol production.27 In the presence of a homogeneous catalyst, CO2
can be reduced to methylformate, which can then be further reduced to methanol at low
temperatures.28
Bouveault-Blanc reduction involves reaction with elemental sodium in absolute ethanol.29
In this process, a total of four equivalents of sodium metal are required to convert the ester to the
corresponding alcohol. Due to the risks associated with alkali metal handling and the generation
of large amounts of waste, this method has been largely replaced by other processes involving
metal hydrides as reducing agents.30 Hydride species such as LiAlH4 or NaBH4 can be used
successfully for the reduction of many esters. However, the stoichiometric nature of such processes
results in large amounts of waste. Other disadvantages include cumbersome reprocessing
procedures and the hazards associated with handling highly reactive hydrides.31 Compared to
stoichiometric methods, catalytic processes are more attractive from an environmental and
7
economic perspective. They provide greater atomic and energy efficiency. In particular, 100%
atomic efficiency can be achieved using molecular H2 as reducing agent.
The catalytic hydrogenation of carboxylic acids and their esters is a challenging
transformation, particularly due to the low electrophilicity of the carbonyl carbon and difficulties
associated with substrate carbonyl polarization.32 Additional complexity arises from the fact that
esters, lactones, and carboxylic acids can interconvert under the applied reaction conditions. Since
carboxylic acids, esters, and lactones are resistant to reduction, efficient catalyst formulations are
required. Current heterogeneous catalytic processes operate under harsh conditions, with
temperatures ranging from 200-300 °C and hydrogen pressures of 140-300 bars. Therefore, side
reactions and degradation of reaction substrates and products may occur. Although this may not
be a problem for the production of many bulk or industrial-grade chemicals, it limits the
applicability of this approach to the conversion of highly functionalized compounds in fine
chemical synthesis. Heterogeneous catalytic hydrogenation of carboxylic acid derivatives mainly
focuses on the conversion of biomass-derived substrates, such as oils and levulinic acid. The
substrate range of homogeneous catalysts is much wider than that of heterogeneous catalysts. In
addition to aliphatic and aromatic esters and lactones, some homogeneous catalysts are capable of
hydrogenating substrates containing chiral centers, various reducible groups, or heteroatom
functional groups. Modern state-of-the-art homogeneous catalysts typically operate at much lower
temperatures than heterogeneous catalysts, resulting in unique selectivity for alcohol products.33
8
1.3 Dehydrogenation
Dehydrogenation is a major frontier of hydrogen transfer, with well-established
dehydrogenation of alkanes to olefins and alcohols to carbonyl compounds being important
examples of such transformations.34 The hydrogen produced in these reactions can be used as a
carbon-free energy carrier,35 but mastering hydrogen fuel requires improved methods for its high
weight-efficiency and reversible storage on liquid media, which in turn motivates further work in
hydrogen transfer catalysis. Such developments in catalysts lead to high-value new reactions that
can be useful in all areas of synthesis, including fuel upgrading, fine chemicals, and even complex
molecule synthesis.
Hydrogen has a high energy content (120 MJ/kg), almost three times that of gasoline (44
MJ/kg),36 making it well suited for chemical energy storage.37 It can be oxidized in fuel cells,
producing electricity with water as the only by-product. In addition, hydrogen fuel cell-powered
vehicles offer other advantages, such as quieter operation and greater efficiency, making them
particularly suitable for urban communities.
38 Utilizing hydrogen as a fuel on a large scale is
challenging, because it is a gas under ambient conditions. Compression, cryogenic liquefaction,
and absorption are available hydrogen storage strategies; however, all are known to have
undesirable cost, capacity, and safety issues.39 Small molecule dehydrogenation is an attractive
method to release hydrogen on demand. Liquid organic hydrogen carriers such as methanol or
formic acid have high hydrogen storage densities and can be distributed through existing fuel
infrastructure. Furthermore, selective dehydrogenation of these compounds will produce only
hydrogen and carbon dioxide. The latter can be recycled through known systems,40 achieving a
carbon-neutral fuel cycle.
9
In the context of methanol economy, methanol has attracted extensive research interest as a
potential energy carrier and hydrogen storage material (12.6 wt%). Heterogeneous methanol
reforming produces three molecules of H2 and one molecule of CO2 from one molecule of
methanol and one molecule of H2O. However, traditional methanol reforming requires harsh
conditions such as high temperature and high pressure.41 Therefore, energy consumption is high
and on-site hydrogen production is very inconvenient. Entering the 21st century, alcohol
dehydrogenation and oxidation technology is booming, providing a more mature platform for the
development of methanol dehydrogenation catalysts under reasonable conditions. One reasonably
envisions stepwise water-assisted methanol dehydrogenation as shown in Scheme 1.4. According
to this scheme, three catalytic steps produce three molecules of H2: 1) dehydrogenation of
methanol to form formaldehyde, which then adds H2O to methanol; 2) dehydrogenation of
methanol to form FA; and 3) dehydrogenation of FA to form H2 and CO2.
Scheme 1.4 A) Methanol Reforming; B) Envisioned Catalytic Dehydrogenation of Methanol.
Formic acid has received much research interest as a hydrogen carrier. Despite a lower
hydrogen storage density (4.4 wt%) than methanol, formic acid has its own prominent advantages.
It is a potential solar fuel because efficient synthesis of formic acid from CO2 and H2 is known.42
In addition, hydrogen evolution from FA can be achieved under mild conditions, which is a crucial
premise for on-demand hydrogen release. Furthermore, formic acid is an environmentally benign
CH3OH + H2O CO2 + 3 H2
CH3OH
H2
cat.
HCHO
H2O
C
H
OH
H OH
H2
cat.
HCOOH
H2
cat. CO2
A )
B )
10
chemical. There are many heterogeneous43 and homogeneous44,45 systems for catalytic
dehydrogenation of formic acid. Heterogeneous catalysts are known to be reusable and easily
separated from the reaction mixture.46 However, these catalysts usually require forcing conditions
and have poor selectivity. Homogeneous catalysts are generally more efficient and selective, but
their limited lifetime and high recycling costs make them impractical.
1.4 Hydrogen Borrowing C-N bond formation
Most catalysts are designed to act on only one transformation, and little is known about
multifunctional catalysts. If the same catalyst could be used for a variety of independent reactions
or could enable the entire synthesis in one pot, chemistry would reach a new level because more
complex molecules could be made with greater material and energy efficiency.
The hydrogen borrowing principle is a powerful method that combines transfer hydrogenation
with one or more intermediate reactions to synthesize more complex molecules without the need
for tedious separation or isolation processes. This strategy generally relies on three steps: (i)
dehydrogenation, (ii) intermediate reactions and (iii) hydrogenation (Scheme 1.4), making it an
excellent and widely recognized process from synthetic, economic and environmental perspectives.
Grieg et al.47 and Watanabe et al.48 introduced the first homogeneous catalyst in 1981 for the Nalkylation of amines with alcohols. Grieg et al. reported N-alkylation of primary and secondary
amines with primary alcohols to give secondary and tertiary amines, with rhodium catalyst
[RhH(PPh3)4] being the most active catalyst.47 Meanwhile, Watanabe and co-workers reported
ruthenium-catalyzed alkylation and N-heterocyclization of N-anilines with alcohols and aldehydes.
11
Scheme 1.5 Basic Scheme of the Hydrogen Borrowing Methodology.
The development of hydrogen borrowing catalysis has paralleled the design of homogeneous
transition metal complexes in the search for more active catalysts. Iridium and ruthenium
complexes are the most common catalysts for this transformation. Hydrogen borrowing strategies
begin with metal-catalyzed dehydrogenation, typically by temporarily converting a less reactive
donor molecule into a more reactive substrate (e.g., alcohols to aldehydes, or ketones and amines
to imines). The more reactive intermediates can be further converted into unsaturated compounds,
which will be reduced with the intervention of the metal hydride produced in the first
dehydrogenation step. Considering that the intermediate reaction steps are common organic
reactions involving dehydrogenation substrates, the participation of metals is not absolutely
necessary at this point, although this assumption may not necessarily hold since an electrophilic
metal component of the catalyst can increase the electrophilic nature of the carbonyl group and
thus enhance its reactivity.
Alcohols are generally poor electrophiles for alkylation reactions, requiring activation of the
hydroxyl group into a suitable leaving group to promote nucleophilic substitution.49 Another
method of activating alcohols involves removal of hydrogen from the alcohol to form an aldehyde,
R1 X
R1 X
[M]
[MH2]
1-2 steps
transformation
R Y
R2
R Y
R2
X = C, N, O
Y = C, N, S
dehydrogenation hydrogenation
12
usually via dehydrogenation in a hydrogen self-transfer process. In this case, the alcohol is
temporarily converted to an aldehyde or ketone, forming an alkene or imine (or enamine), which
is then reduced to a C−C or C−N bond.50,51 The amination of alcohols with primary amines by
hydrogen borrowing method has the advantage of promoting the formation of secondary amines
because primary amines react more readily with aldehydes. This fact is in contrast to traditional
alkylation methods, which tend to produce over-alkylated products because secondary amines are
more reactive toward alkyl bromides than primary amines. The hydrogen borrowing process
produces water as the only by-product and allows alcohols to replace more traditional but toxic
alkyl halides as the alkylating agent.52
Some recent applications confirm the interest this reaction has generated in large-scale
synthesis, namely a one-kilogram-scale application of this strategy to the synthesis of an inhibitor
for the treatment of schizophrenia, named PF-03463275. In particular, a GlyT1 inhibitor was
prepared under optimized conditions in the presence of (Cp*
IrCl2)2 with a catalyst loading below
0.05 mol% while requiring moderate reaction times.53
1.5 Overview
Green chemistry involves redesigning chemical processes to avoid the use and generation of
hazardous substances and the formation of waste. The application of catalysis is fundamental to
the concept of green chemistry and the sustainability of chemical products and processes. The
application of catalytic technology enables processes to use energy and raw materials more
efficiently and produce less waste. The use of homogeneous catalysis helps to understand the
mechanism of a catalysis and further helps design an improved process. Thanks to the hard work
13
of the chemistry community, we have made many exciting new advances over the past few years,
particularly in the field of pharmaceutical manufacturing and energy delivery and storage.
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14
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alcohol dehydrogenation: interplay of theoretical and experimental studies. ACS Catalysis
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22. Zhang, Y.; Lim, C.; Sim, D. S. B.; Pan, H.; Zhao, Y. Catalytic enantioselective amination of
alcohols by the use of borrowing hydrogen methodology: cooperative catalysis by iridium and
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23. Gunanathan, C.; Milstein, D. Metal–ligand cooperation by aromatization–dearomatization:
a new paradigm in bond activation and “green” catalysis. Accounts of Chemical Research
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24. Gunanathan, C.; Milstein, D. Applications of acceptorless dehydrogenation and related
transformations in chemical synthesis. Science 2013, 341 (6143).
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amines with liberation of H2. Angewandte Chemie International Edition 2010, 49 (8), 1468–
1471.
26. Maeda, C.; Miyazaki, Y.; Ema, T. Recent progress in catalytic conversions of carbon dioxide.
Catalysis Science & Technology 2014, 4 (6), 1482.
27. Oláh, G. A. Beyond oil and gas: the methanol economy. Angewandte Chemie International
Edition 2005, 44 (18), 2636–2639.
28. Huff, C. A.; Sanford, M. S. Cascade catalysis for the homogeneous hydrogenation of CO2 to
methanol. Journal of the American Chemical Society 2011, 133 (45), 18122–18125.
29. Bouveault, L.; Blanc, G. Preparation of primary alcohols by means of the corresponding acids.
Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences 1903, 136, 1676–
1678.
30. Bodnar, B. S.; Vogt, P. F. An improved Bouveault−Blanc ester reduction with stabilized alkali
metals. Journal of Organic Chemistry 2009, 74 (6), 2598–2600.
16
31. Young, J. A. Bretherick’s Handbook of Reactive Chemical Hazards, 7th Edition (Peter G.
Urben, ed., assisted by Malcolm J. Pitt). Journal of Chemical Education 2007, 84 (5), 768.
32. Clayden, J.; Greeves, N.; Warren, S. Organic chemistry; Oxford University Press, 2012.
33. Gunanathan, C.; Milstein, D. Bond activation and catalysis by ruthenium pincer complexes.
Chemical Reviews 2014, 114 (24), 12024–12087.
34. Kumar, A.; Bhatti, T. M.; Goldman, A. S. Dehydrogenation of alkanes and aliphatic groups by
pincer-ligated metal complexes. Chemical Reviews 2017, 117 (19), 12357–12384.
35. Bossel, U.; Eliasson, B.; Taylor, G. The future of the hydrogen economy: bright or bleak?
Cogeneration & Distributed Generation Journal 2003, 18 (3), 29–70.
36. Abbasi, S. A. ‘Renewable’ hydrogen: prospects and challenges. Renewable & Sustainable
Energy Reviews 2011, 15 (6), 3034–3040.
37. Zhang, X.; Lü, Z.; Foellmer, L. K.; Williams, T. J. Nitrogen-based ligands accelerate ammonia
borane dehydrogenation with the Shvo catalyst. Organometallics 2015, 34 (15), 3732–3738.
38. Sharaf, O. Z.; Orhan, M. F. An overview of fuel cell technology: Fundamentals and
applications. Renewable & Sustainable Energy Reviews 2014, 32, 810–853.
39. Enthaler, S. Carbon Dioxide—The Hydrogen-storage material of the future? ChemSusChem
2008, 1 (10), 801–804.
40. Tanaka, R.; Yamashita, M.; Nozaki, K. Catalytic hydrogenation of carbon dioxide using
Ir(III)−pincer complexes. Journal of the American Chemical Society 2009, 131 (40), 14168–
14169.
41. Palo, D. R.; Dagle, R. A.; Holladay, J. D. Methanol steam reforming for hydrogen production.
Chemical Reviews 2007, 107 (10), 3992–4021.
42. (a) Federsel, C.; Jackstell, R.; Boddien, A.; Laurenczy, G.; Beller, M. Ruthenium-catalyzed
hydrogenation of bicarbonate in water. ChemSusChem 2010, 3 (9), 1048–1050. (b) Federsel,
C.; Boddien, A.; Jackstell, R.; Jennerjahn, R.; Dyson, P. J.; Scopelliti, R.; Laurenczy, G.; Beller,
M. A well-defined iron catalyst for the reduction of bicarbonates and carbon dioxide to
formates, alkyl formates, and formamides. Angewandte Chemie International Edition 2010, 49
(50), 9777–9780. (c) Federsel, C.; Ziebart, C.; Jackstell, R.; Baumann, W.; Beller, M. Catalytic
hydrogenation of carbon dioxide and bicarbonates with a well-defined cobalt dihydrogen
complex. Chemistry 2011, 18 (1), 72–75.
43. Zheng, Z.; Tachikawa, T.; Majima, T. Plasmon-enhanced formic acid dehydrogenation using
anisotropic Pd–Au nanorods studied at the single-particle level. Journal of the American
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17
44. Bertini, F.; Mellone, I.; Ienco, A.; Peruzzini, M.; Gonsalvi, L. Iron(II) complexes of the linear
rac-tetraphos-1 ligand as efficient homogeneous catalysts for sodium bicarbonate
hydrogenation and formic acid dehydrogenation. ACS Catalysis 2015, 5 (2), 1254–1265.
45. Barnard, J. H.; Wang, C.; Berry, N. G.; Xiao, J. Long-range metal–ligand bifunctional
catalysis: cyclometallated iridium catalysts for the mild and rapid dehydrogenation of formic
acid. Chemical Science 2013, 4 (3), 1234.
46. Zhang, S.; Metin, Ö.; Su, D.; Sun, S. Monodisperse AgPd alloy nanoparticles and their superior
catalysis for the dehydrogenation of formic acid. Angewandte Chemie International Edition
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47. Grigg, R.; Mitchell, T. R. B.; Sutthivaiyakit, S.; Tongpenyai, N. Transition metal-catalysed Nalkylation of amines by alcohols. Journal of the Chemical Society. Chemical Communications
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48. Watanabe, Y.; Tsuji, Y.; Ohsugi, Y. The ruthenium catalyzed N-alkylation and Nheterocyclization of aniline using alcohols and aldehydes. Tetrahedron Letters 1981, 22 (28),
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49. Smith, M. B. March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure;
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50. Yang, Q.; Wang, Q.; Yu, Z. Substitution of alcohols by N-nucleophiles via transition metalcatalyzed dehydrogenation. Chemical Society Reviews 2015, 44 (8), 2305–2329.
51. Huang, F.; Liu, Z.; Yu, Z. C‐Alkylation of ketones and related compounds by alcohols:
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52. Crabtree, R. H. An organometallic future in green and energy chemistry? Organometallics
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53. Berliner, M. A.; Dubant, S.; Makowski, T. W.; Ng, K.; Sitter, B.; Wager, C.; Zhang, Y. Use of
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18
19
Chapter 2 An Ambient Pressure, Direct Hydrogenation of Ketones
2.1 Introduction
I would like to take this opportunity to acknowledge my co-authors. Dr. Zhiyao Lu
contributed to experimental design throughout the project. Moreover, he acquired a crystal
structure of ruthenium complex 2.1. Andrew R. Rander acquired a crystal structure of ruthenium
complex 2.6. Some images in this chapter are reproduced from Ref. 1 with permission from the
Royal Society of Chemistry.1
Direct hydrogenation of carbonyl groups is a 100% atom efficient, environmentally benign
synthetic process. While hydride reagents like LiAlH4 and NaBH4 are effective and expedient for
this transformation, these are accompanied by the cost and separation issues that accompany a
stoichiometric portion of any metallic reagent, which makes direct hydrogenation an important
option at scale.2 As highlighted in Chapter 1, catalytic hydrogenation is undoubtedly the most
widely used method for the reduction of organic compounds and is among the most important
transformations in the chemical industry. Homogeneous catalysts are often used for highly
selective transformations and have achieved astonishing progress over the past three decades.
Since Noyori’s milestone discovery of asymmetric ketoester direct hydrogenation,3 many welldefined molecular catalysts for hydrogenation, transfer hydrogenation, and dehydrogenation of
C=O systems have emerged,4 yet most rely on hydrogen gas pressure or a hydrogen donor/acceptor
to obtain useful rates.5 Frustrated Lewis-pair species have also been demonstrated,6 although also
rely on elevated gas pressure.7 Such requirements for pressurization limit the utility of these
methods and make them inconvenient for users without pressurization tools. Base metals (Fe, Co,
Ni, and Cu) are emerging in this space;8 in fact, the Hanson PNP–Co complexes catalyze ambient
20
pressure hydrogenation of some ketones in THF at 60 °C,8b but room remains to introduce high
reactivity, highly functional group tolerant catalysts for ambient pressure carbonyl hydrogenation.
Thus, we reported a catalytic hydrogenation system that affects carbonyl hydrogenation with
ambient hydrogen pressure at up to quantitative yield on a diverse set of ketones and aldehydes.1
We previously reported complexes 2.1-2.3 (Figure 2.1) as pre-catalysis for glycerol
dehydrogenation.9 Therein we found that backbone deprotonation of 2.2 with concurrent pyridine
dearomatization plays a mechanistic role in cleaving glycerol’s O—H bond, apparently through a
metal-ligand cooperative step. We further found that electron withdrawing CO ligands slowed
dehydrogenation by comparing rates of reactions of 2.1 and 2.3. We propose that the opposite
should be true in the reductive direction, and that the apparent bifunctional nature of the backbone
of 2.1-2.3 could facilitate H2 cleavage as highlighted in Scheme 2.1.5d
Figure 2.1 Four Iridium-based Catalyst Precursors.
2.2 Results and Discussion
When we treated precursor 2.1 with KOt
Bu and one bar H2 in a J. Young tube at room
temperature, we found that precursor 2.1 rapidly splits hydrogen and forms iridium dihydride
complex 2.5 (Scheme 2.1).10 The same reaction is unsuccessful with iridium complex 2.4 that lacks
a pyridyl methylene arm, which is consistent with our view that the backbone CH group is
important to hydrogen cleavage.
2.1 2.2 2.3 2.4
21
Scheme 2.1 Hydrogen Molecule Cleavage and Dihydride Iridium Formation. ORTEP Diagram of
2.5 (CCDC 2142636) with 50% Ellipsoids.
2.2.1 Optimization of Reaction Conditions
Whereas complexes 2.1-2.3 readily cleave H2 at ambient temperature and pressure as
shown in Scheme 2.1, we screened them for ambient pressure acetophenone hydrogenation.
Complex 2.1 has the highest reactivity among the three (Table 2.1). By contrast, complex 2.4 has
no reactivity in acetone hydrogenation, again consistent with a role for the backbone CH group.
Further consistent, none of these four iridium complexes has reactivity for acetone hydrogenation
if base is removed from this reaction, although the role of the base could be to deprotonate a
coordinated H2 ligand. We therefore expect that ligand deprotonation and dearomatization play a
role in hydrogen splitting and catalyst precursor activation for these precursors.
Ir
N
N
N CO
CO
Ir
N
N
N H
CO
Mes
CO
H
H
Mes
2.1 2.5
H
H2 (1 atm)
KOt
Bu
22
Table 2.1 Optimization of the Hydrogenation of Acetophenone.
Entry [Ir] Base Solvent T (°C) NMR Yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
2.1
2.2
2.3
2.4
2.1
2.1
2.1
2.1
2.1
2.1
2.1
2.1
2.1
2.1
2.1
2.1
KOt
Bu
KOt
Bu
KOt
Bu
KOt
Bu
K2CO3
NaOEt
KOH
KH
—
KOt
Bu
KOt
Bu
KOt
Bu
KOt
Bu
KOt
Bu
KOt
Bu
KOt
Bu
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
benzene
THF
MeOH
toluene
toluene
toluene
toluene
40
40
40
40
40
40
40
40
40
40
40
40
60
80
100
120
40
3
13
0
3
37
8
11
0
13
3
5
46
78
88
61
Condition optimization for the hydrogenation of acetophenone with 2.1 are outlined in
Table 2.1. Various bases were tested for the hydrogenation of acetophenone, using 3 mol% 2.1, 10
mol% base and 1 atm hydrogen pressure at 40 °C. This taught us that effective bases have a pKa
above ca. 16, which is appropriate for ligand backbone deprotonation: KOt
Bu, KH, and NaOEt
afforded productive reaction where KOH and K2CO3 did not. We next turned to solvent and
temperature. Increasing the temperature provided a modest increase in the reaction yield, but the
yield at 120 °C is lower than that at 100 °C, thus leaving toluene as a suitable solvent for this
reaction system. Gratifyingly, the system operates efficiently down to ambient pressure.
O
Ph H2 (1 atm), base, solvent,
T (°C), 48 h
OH
Ph
[Ir] (3 mol%)
23
2.2.2 Substrate Scope
With optimized reaction conditions, we screened a series of ketones and aldehydes to
understand the rection’s scope. Studying a series of differentially para-substituted acetophenones
(Table 2.2, entries 1-7) enabled calculation of a negative (nucleophilic substrate) Hammett reaction
parameter of ρ = -0.93 (Figure 2.3). This negative ρ value is atypical for reduction, which should
normally involve an electrophilic accepter receiving a nucleophilic hydride in a kineticallyrelevant step: for example, the ρ value for NaBH4 reduction of this reaction is +3.06,11 and LiAlH4
reduction of benzophenones +1.95.12 Catalytic ketone hydrogenation with the Shvo’s system has
ρ = +1.77, +0.91 under two conditions studied.13,14 These undergo a concerted, outer-sphere
hydrogen transfer mechanism. The ρ for Noyori type catalyst [RuCl2(diphosphine)(1,2-diamine)]
is ρ = +1.03.15 Lewis acid-catalyzed acetophenone hydrogenation also has a positive ρ >1.16
24
Table 2.2 Substrate Scope.
O
R1 R2
3 mol % [Ir]
10 mol % base
H2 (1 atm), toluene
100 °C, 48 h
OH
R1 R2
2.11a-g, 2.12-2.23 2.11aa-ga, 2.12a-2.23a
Entry Yield (%)a
1
2
3
4
5
6
8
9
10
11
O
Substrates Products
R
OH
R
R = H
R = NMe2
R = OMe
R = OH
R = Br
R = Cl
>95
>95
R = H
R = NMe2
R = OCH3
R = OH
R = Br
R = Cl
68
>95
83
40
81
42
83
O
MeO
MeO
OMe
OH
MeO
MeO
OMe
77
O OH
O
Ph Ph
OH
Ph Ph
85
77c
84d
48
88
64
89
O
N
OH
N
>95
[Ir]
2.1
2.6
2.1
2.6
2.1
2.1
2.1
2.6
2.1
2.6
2.1
2.1
2.1
2.6
2.1
2.6
2.11aa
2.11ba
2.11ca
2.11da
2.11ea
2.11fa
2.12a
2.13a
2.14a
2.15a
2.11a
2.11b
2.11c
2.11d
2.11e
2.11f
2.12
2.13
2.14
2.15
7 R = NO2 R = NO2 2.1
2.11g 2.11ga
9b
12
O
3 3
OH
3 3
13
33
72
21
2.1
2.6
2.1
14
O OH
2.16a
2.17a
2.16
2.17
O
73 2.1 b
2.18 2.18a
OH
16
N
O
N
OH
43b
85b
17
O
OH
52b
80
2.1
2.6
2.1
2.6
2.22a
2.23a
2.22
2.23
18
19
O
O
OH
HO
OH
HO
>95
>95
2.1
2.1
2.20a
2.21a
2.20
2.21
15
O OH
32 2.1 b
2.19 2.19a
Entry Yield (%)a Substrates Products [Ir]
aIsolated yield, 100 mg substrate scale. bNMR yield. c500 mg scale. dReagents weighed out in air.
25
Continuing our study of substrate scope (Table 2.2), we examined ketones with increased
steric demand. These are well tolerated (entries 8-9). Particularly, benzophenone was reduced at
the larger 500 mg scale (entry 9) to show that scaling the biphasic reaction does not significantly
retard the yield. Furthermore, we tested the out-of-box hydrogenation of benzophenone, all
reagents were weighed out of the glove box, and then the Schlenk flask was purged with H2. The
results (entry 9) showed that the glove box is not necessary for our reaction system.
Diphenylcyclopropenone was reduced chemoselectively at the C=O bond, with no evidence of
C=C reduction (entry 10). To gain insight into the chemoselectivity of catalyst 2.1, a competition
experiment was performed in which a 1:1 mixture of styrene and benzaldehyde was hydrogenated
using 2.1. Benzaldehyde was hydrogenated more rapidly, with complete conversion of
benzaldehyde and only 8% conversion of styrene observed over 48 hours. Heteroaryl-substituted
ketones and aldehydes were also hydrogenated (entries 11, 18). For aliphatic ketones such as 5-
nonanone and 2,2,4,4-tetramethyl-3-pentanone, lower activity was observed (entries 12, 13). We
also explored the activity of the complex 2.1 towards a collection of aldehydes. Benzaldehyde and
4-hydroxybenzaldehyde were effectively reduced (entries 16, 17). Complex 2.1 has lower activity
for heterocyclic aldehydes, possibly due to coordination of the heterocycle to the iridium center
competing with H2.
While complex 2.1 operates efficiently with many substrates, we sought a faster and more
efficient catalyst to address cases that are not well-served by 2.1. Suspecting that carbonylation in
2.1 reduces the basicity of the intermediate that must receive a proton in the slow step, we designed
and synthesized chloride-substituted pre-catalyst (CN)IrCl(CO), 2.6. Unlike Nozaki’s pincer
iridium system [k3
-[2,6-(iPr2PCH2)2(C6H3N)]IrH3], which takes 20 hours to form its active iridium
trihydride complex,17 precursor 2.6 immediately transforms to trihydride 2.7 at ambient
26
temperature and pressure (Scheme 2.2). While it is less shelf stable and must be prepared shortly
prior to use, we find that complex 2.6 enables more rapid reactions than 2.1. Table 2.2 shows
compared yields of hydrogenations with catalysts 2.1 and 2.6 in which the more rapid reactivity
of 2.6 enables significantly superior performance.
Scheme 2.2 Catalyst Precursor 2.6 and Iridium Trihydride 2.7. ORTEP Diagram of 2.6 (CCDC
2258133) with 50% Ellipsoids.
2.2.3 Mechanistic Studies
A series of experiments were conducted to establish the reaction mechanism. We have
measured the kinetic order of reaction for ketone, base, and catalyst. A log-log plot (Table 2.3)
gives us a slop of 0.94(5), indicating the reaction is first order on the ketone substrate. In the same
way, we found base (Table 2.4) and catalyst (Table 2.5) are in first order for this reaction.
Ir
N
N
N CO
Cl
Ir
N
N
N H
H
Mes
CO
H
H
Mes
2.6 2.7
H
H2 (1 atm)
NaOH
27
Table 2.3 Kinetic Dependence on Ketone Concentration.
Amount of acetone (mmol) Rate (s-1
)
0.135 5.0(1) x 10-6
0.270 5.1(2) x 10-6
0.405 4.2(9) x 10-6
0.540 4.8(5) x 10-6
y = 0.9424x - 15.403
-17.4
-17.2
-17
-16.8
-16.6
-16.4
-16.2
-16
-15.8
-2.5 -2 -1.5 -1 -0.5 0 ln(-d[A]0/dt)
ln([A]0)
Substrate Reaction Order
O
+ H2
2.1 (0.009 mmol)
KOt
Bu (0.03 mmol)
100 °C
OH
28
Table 2.4 Kinetic Dependence on Base.
Amount of KOt
Bu (mol%) Rate (s-1
)
5 5.0(1) x 10-6
10 5.3(3) x 10-6
15 5.0(1) x 10-6
20 5.0(1) x 10-6
y = 0.7599x - 12.96
-16.4
-16.2
-16
-15.8
-15.6
-15.4
-15.2
-15
-4.5 -4 -3.5 -3 -2.5 ln(-d[A]0/dt)
ln([base]0)
Base Reaction Order
O
+ H2
2.1 (0.008 mmol)
KOt
Bu
100 °C
OH
29
Table 2.5 Kinetic Dependence on Catalyst Concentration.
Amount of 2.1 (mol%) Rate (s-1
)
0.5 5.1(2) x 10-6
2.5 5.2(3) x 10-6
5 5.0(2) x 10-6
10 5.3(3) x 10-6
O
+ H2
2.1
KOt
Bu (0.09 mmol)
100 °C
OH
y = 0.8806x - 10.149
-16.5
-16
-15.5
-15
-14.5
-14
-13.5
-13
-12.5
-7 -6.5 -6 -5.5 -5 -4.5 -4 -3.5 -3 ln(-d[A]0/dt)
ln([C]0)
Catalyst Reaction Order
30
2.2.3.1 Isotope Effects
We performed a kinetic isotope effect study by parallel reactions with complex 2.1 and
benzophenone to investigate whether the H2 coordinating step is a rate-determining step. For the
H2 experiment, a rate constant of 5.3(3) × 10-6 s-1 could be obtained, while for the D2 run, we
observed a rate constant of 5.6(4) × 10-6 s-1
. This gives us a KIEH2/D2 = 1.06(11). This observed
KIE value is inconsistent with a rate-determining step of H2 metal complex coordination and
cleavage. These typically have KIE > 2.18 Further, hydrogen pressure does not effect this reaction
rate.
31
2.2.3.2 Eyring Plot
An Eyring plot (Figure 2.2), constructed using acetone as the substrate over a temperature
range of 60-90 °C results in ∆S‡ = -42.70(25) cal mol-1 K-1 and ∆H‡ = 9.5(7) kcal mol-1
. This
indicates a very low enthalpic (bond cleavage) component, but a significant entropic cost, in or
before the rate-limiting transition state. We see this body of data as consistent with a reversible H2
activation and a fast, facile hydride transfer early in the mechanism, both preceding a slow proton
transfer or alcohol dissociation step.
Figure 2.2 Eyring Plot of Benzophenone Hydrogenation by Catalyst 2.1.
y = -9.4577x - 42.794
R² = 0.99893
-72
-71.5
-71
-70.5
-70
-69.5
-69
-68.5
2.7 2.75 2.8 2.85 2.9 2.95 3 3.05
Rln(k/T) - Rln(kB/h)
1000/T (K-1)
32
2.2.3.3 Hammett Analysis
We tested hydrogenation of a series of para-substituted acetophenones with different
hydride affinities. The Hammett plot (Figure 2.3) gives us the reaction constant ρ = -0.93. The
negative ρ value in our system is consistent with kinetic relevance of a proton transfer step, rather
than a hydride transfer as in the above cases. Its magnitude, ρ < -0.5, is consistent with the
involvement of an anionic phenonone-containing fragment in or before our rate-limiting step.19
Such a species could be a metal alkoxide,20 which is protonated in a slow step (vide infra).
Figure 2.3 Hammett Plot of Hydrogenation of a Series of Para-substituted Acetophenones with
Different Hydride Affinities.
-NO2
-Br -Cl
H
-OMe
y = -0.9306x + 0.0283
R² = 0.98178
-0.9
-0.8
-0.7
-0.6
-0.5
-0.4
-0.3
-0.2
-0.1
0
0.1
0.2
0.3
0.4
-0.4 -0.2 0 0.2 0.4 0.6 0.8 1 log(kR/kH)
!
33
2.2.3.4 Mechanistic Proposal
Based our combined kinetic data, we propose the mechanistic cycle shown in Scheme 2.3.
We propose that species 2.5 transfers a hydride to substrate in a kinetically invisible step to form
iridium alkoxide intermediate 2.8. Then, a kinetically relevant proton transfer from the methylene
arm to the alkoxide occurs. We suspect that a second equivalent of alcohol or the conjugate base
is involved in this step as a proton shuttle. A neutral product alcohol is formed and released. We
suspect that the rate-limiting step is in this proton transfer/shuttle and alcohol dissociation
sequence. The strong ∆S‡ is more consistent proton shuttling than ligand dissociation. The ratio of
reaction rates with and without added alcohol, kROH/kno ROH = 1.625, illustrates that added
isopropanol accelerates the reaction overall, which is consistent with the role of an alcohol in the
proton shuttle. We calculated the energetic advantage of such a proton shuttle in ketone
hydrogenation by an analogous bifunctional iridium complex.21 Following alcohol loss, H2 rapidly
coordinates to the dearomatized iridium species and form complex 2.10. A proton can then be
transferred from H2 to the linking arm to regenerate the aromatized iridium-dihydride 2.5. Again,
a proton shuttle would be logical.
34
Scheme 2.3 Proposed Mechanism of Catalysis.
2.1
Ir N
NMes
N CO
CO
Ir N
N
N H
CO
H
CO
Mes
Ir N
N
N H
CO
O
CO
Mes
H
R2 R1
Ir N
N
N H
CO
O
CO
Mes
H
R2 R1
Ir N
N
N H
CO
CO
Mes
H H
KOt
Bu
H2, H+
O
R1 R2
H2
OH
R1 R2
H
2.5
2.8
2.9
2.10
slow
H
H
O
R
35
2.3 Conclusion
In conclusion, we have developed efficient iridium catalysts 2.1 and 2.6 for the
hydrogenation of ketones and aldehydes at ambient pressure. Importantly, finding a kinetic scheme
in which H2 is zero order enables facile ambient pressure reactions, which avoid the use of
expensive autoclave reactors that are not readily available in every lab. Further, reactions can be
accomplished using traditional Schlenk techniques without need for freeze-pump-thaw conditions.
These attributes improve the safety and operability convenience of the reaction. A less shelf stable
complex, 2.6, which differs from 2.1 by substitution of a CO for a chloride, has higher catalytic
hydrogenation reactivity, affording useful results for some systems that are not easily reduced with
2.1. We envision these catalysts as useful tools both for organic synthesis at scale, where the byproduct of NaBH4 or LiAlH4 reduction creates operational costs and challenges, or small-scale
practitioners needing to eliminate by-product separation, as in radiopharmaceutical synthesis.
2.4 References
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Zhang, X. Asymmetric hydrogenation catalyzed by first-row transition metal complexes.
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hydrogenation of ketones catalyzed by BINAP/1,2-diamine−ruthenium(II) complexes. Journal
of the American Chemical Society 2003, 125 (44), 13490–13503. (b) Casey, C. P.; Guan, H.
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David, Y.; Milstein, D. Efficient hydrogenation of ketones catalyzed by an iron pincer complex.
Angewandte Chemie International Edition 2011, 50 (9), 2120–2124. (d) Zhang, G.; Scott, B.
L.; Hanson, S. K. Mild and homogeneous cobalt-catalyzed hydrogenation of C-C, C-O, and CN bonds. Angewandte Chemie International Edition 2012, 51 (48), 12102–12106. (e)
Lagaditis, P. O.; Sues, P. E.; Sonnenberg, J. F.; Wan, K. Y.; Lough, A. J.; Morris, R. H. Iron(II)
complexes containing unsymmetrical P–N–P′ pincer ligands for the catalytic asymmetric
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1367 – 1380. (f) Butschke, B.; Feller, M.; Diskin ‐ Posner, Y.; Milstein, D. Ketone
hydrogenation catalyzed by a new iron(ii)–PNN complex. Catalysis Science & Technology
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6. Scott, D. J.; Fuchter, M. J.; Ashley, A. E. Designing effective ‘frustrated Lewis pair’
hydrogenation catalysts. Chemical Society Reviews 2017, 46 (19), 5689–5700.
7. Wei, S.; Du, H. A highly enantioselective hydrogenation of silyl enol ethers catalyzed by chiral
frustrated Lewis pairs. Journal of the American Chemical Society 2014, 136 (35), 12261–
12264.
8. (a) Sui-Seng, C.; Freutel, F.; Lough, A. J.; Morris, R. H. Highly efficient catalyst systems using
iron complexes with a tetradentate PNNP ligand for the asymmetric hydrogenation of polar
bonds. Angewandte Chemie International Edition 2008, 47 (5), 940–943. (b) Zhang, G.; Scott,
B. L.; Hanson, S. K. Mild and homogeneous cobalt-catalyzed hydrogenation of C-C, C-O, and
C-N bonds. Angewandte Chemie International Edition 2012, 51 (48), 12102–12106. (c)
Hamada, Y.; Koseki, Y.; Fujii, T.; Maeda, T.; Hibino, T.; Makino, K. Catalytic asymmetric
hydrogenation of α-amino-β-keto ester hydrochlorides using homogeneous chiral nickelbisphosphine complexes through DKR. Chemical Communications 2008, No. 46, 6206. (d)
Krabbe, S. W.; Hatcher, M. A.; Bowman, R. K.; Mitchell, M. B.; McClure, M. S.; Johnson, J.
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2013, 15 (17), 4560–4563.
37
9. Lü, Z.; Demianets, I.; Hamze, R.; Terrile, N. J.; Williams, T. J. A prolific catalyst for selective
conversion of neat glycerol to lactic acid. ACS Catalysis 2016, 6 (3), 2014–2017.
10. K, V., DO; Vargas, N. A.; Chavez, A.; Zhang, L.; Cherepakhin, V.; Lu, Z.; Currier, R. P.; Dub,
P. A.; Gordon, J. C.; Williams, T. J. Pressurized formic acid dehydrogenation: an entropic
spring replaces hydrogen compression cost. Catalysis Science & Technology 2022, 12 (23),
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11. Bowden, K.; Hardy, M. A. The reduction of substituted acetophenones by sodium borohydride.
Tetrahedron 1966, 22 (4), 1169–1174.
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alkoxyaluminohydride reductions of ketones in diethyl ether. Journal of the American
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13. Casey, C. P.; Strotman, N. A.; Beetner, S. E.; Johnson, J. J.; Priebe, D. C.; Guzei, I. A. PPh3-
Substituted [2,5-Ph2-3,4-Tol2(η5
-C4COH)]Ru(CO)(PPh3)H exhibits slower stoichiometric
reduction, faster catalytic hydrogenation, and higher chemoselectivity for hydrogenation of
aldehydes over ketones than the dicarbonyl Shvo catalyst. Organometallics 2006, 25 (5),
1236–1244.
14. Koren-Selfridge, L.; Londino, H. N.; Vellucci, J. K.; Simmons, B. J.; Casey, C. P.; Clark, T.
A boron-substituted analogue of the Shvo hydrogenation catalyst: catalytic hydroboration of
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15. Sandoval, C. A.; Shi, Q.; Li, S.; Noyori, R. NH/π Attraction: a role in asymmetric
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38
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A new mechanism of metal-ligand cooperative catalysis in transfer hydrogenation of ketones.
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37
Chapter 3 Pressurized Formic Acid Dehydrogenation: An Entropic Spring
Replaces Hydrogen Compression Cost
3.1 Introduction
I would like to take this opportunity to acknowledge my co-authors Van K. Do, Nicolas
Alfonso Vargas, Anthony J. Chavez, Valeriy Cherepakhin, Zhiyao Lu, Robert P. Currier, Pavel A.
Dub, John C. Gordon. Dr. Van K. Do contributed to experimental design throughout the project.
Moreover, she acquired a crystal structure of ruthenium complex 3.11-CO. Some portions of this
chapter are reproduced from Ref. 1 with permission from the Royal Society of Chemistry.1
The production of hydrogen gas on demand is an enabling technology for the widespread
deployment of hydrogen fuel cell vehicles. One approach to providing H2 on demand is to release
it catalytically from a liquid organic hydrogen carrier (LOHC), provided that the economics of
such a system can overcome the costs of pressurizing and delivering the gas. Gas compression
contributes 49% to 83% of the total refueling cost for light-duty and heavy-duty vehicles,
respectively, in US retail cases.2 Thus, the ability to produce pressurized H2 on demand reduces
the cost of H2 in vehicle refueling. Yet, to our view, most catalyst development work on LOHC
dehydrogenation has been under ambient pressure conditions.
Formic acid (FA, available from biomass fermentation or CO2 electrolysis), is a low cost,
sustainable hydrogen carrier with desirable volumetric density (1.22 g/mL) and H2 content (4.4
wt%).3 Its dehydrogenation is significantly entropically driven, with ∆rxnH° = + 7.4 kcal/mol and
∆rxnS° = + 51 cal/mol·K, so entropic energy released upon dehydrogenation serves as a type of
spring, capable of delivering compressed hydrogen without the cost of compression. Selfpressurization of FA or alcohol dehydrogenation creates a unique environment for catalysis, where
38
H2, CO2, and/or CO can govern catalyst initiation (e.g. in-situ catalyst synthesis), speciation, and
decomposition. While carbonylation is a known poisoning pathway in many cases,4, 5 we find that
it can be essential to catalyst activation in others: for example, CO can play a healing role,
extending the life of systems that would be deactivated without it. Despite these key advantages,
we know of no broad studies of how closed-reactor conditions impact dehydrogenation catalysis;5
the healing role of CO has been missed; and there are not generalizations for when this behavior
might be expected or what the role of pressurization might have in directing it.
Hydrogen release from FA has been studied extensively in homogeneous and
heterogeneous systems based on precious (Ir,6, 7, 8 Ru,8, 9, 10 Pd,11, 12 and Au13, 14) and non-precious
(Fe15, 16 and Mn17, 18) metal catalysts, but we see only a few systems that are known to produce
pressurized products while maintaining catalytic reactivity and selectivity.19-24 Pioneering work by
Fellay et al. described one of the first examples of high-pressure dehydrogenation of aqueous
formic acid using a ruthenium catalyst.23, 24 Since then, several groups have reported similar
findings,19-22 however, industrially relevant turnover frequencies (TOF) and turnover numbers
(TON) have not been achieved using neat formic acid. Most recently, Milstein recently reported a
ruthenium PNP pincer catalyst for the dehydrogenation of neat FA, demonstrating the catalyst’s
tolerance of headspace H2/CO2 pressure (10-100 bar).25
We provide here the first general study of how FA dehydrogenation catalysts respond to
self-pressurizing conditions. We demonstrate a broad survey of activity and stability of catalysts
in both ambient and pressurized reaction conditions and find striking reactivity improvements for
some catalysts when pressurized. We ultimately show how such improvements are realized,
sometimes by transforming a monomeric catalyst into a two-metal pseudo-pincer type species
upon carbonylation.
39
Figure 3.1 Late-transition Metal Complexes Tested for Formic Acid Dehydrogenation.
3.2 Results and Discussion
We surveyed a wide range of complexes that generally fit into four classes: (1) Noyoritype tridentate complexes 3.1-3.8, (2) bidentate chelates complexes 3.9-3.12 and their analog 3.13,
(3) cyclopentadienyl piano stools complexes 3.14-3.17, and (4) metal precursors for the ligated
complexes 3.18-3.21 (Figure 3.1). Each was examined in FA dehydrogenation both under ambient
pressure and self-pressurizing conditions to determine catalyst activity and efficiency (Table 3.1).
While every complex is different under these conditions, some generalizations of each class can
be identified.
O
Ph
Ph
Ph
Ph
Ru
CO OC
H
H Ru
CO
CO
O
Ph Ph
Ph
Ph
Ir N
N
N
OTf
Ir N
N
L
L
Mes
N
OTf
N Ru
P Cl
tBu tBu
3.12
3.14
3.10
Cl
Ir Cl Ir
Cl
Cl
3.15
Cl
Ru Cl Ru
Cl
Cl
3.21
3.4 (X = Cl)
3.5 (X = H)
Ir P
N
tBu tBu
OTf
3.11
HN
EtS Ru SEt
PPh3
Cl
Cl
3.2 (X = Cl)
3.3 (X = BH4)
3.17
3.1 3.6
Rh
OC Cl Rh
CO
OC Cl CO
M Cl
Cl M
3.20
Ir Cl
NH2
TsN
3.16
Ir Cy3P
N
PF6
3.13
3.7
Me N Ir H
N
Cl
S Me
Me
3.8 3.9 (L2 = COD)
3.9-CO (L2 = CO)
Ir Cl
N
TsN
3.18 (M = Rh)
3.19 (M = Ir)
HN
P Ru P
CO
X
H
Ph
Ph
Ph
Ph
HN
P Ru S
PPh3
X
X
Ph
Ph
Ph
HN
P Ru P
CO
Cl
H
i-Pr
i-Pr
i-Pr
i-Pr
HN
P Ru S
PPh3
Cl
Cl
Ph
Ph
O Ph
OTf
40
3.2.1. Catalysts for FA Dehydrogenation at Ambient and Self-Pressurizing Conditions
Table 3.1 shows the results of FA dehydrogenation conducted under both ambient and selfpressurizing conditions. All twenty-one complexes react with FA at a higher rate when pressurized
than they do at ambient pressure, each without detectable reversibility. The overall improvement
in conversion efficiency varied between a minimum of +13% (Table 3.1, entries 15 and 16) and a
maximum of +72% (Table 3.1, entry 14) as conditions changed from open to closed vessels. For
example, mildly active complex 3.20 at ambient pressure promoted complete conversion when in
a closed system (Table 3.1, entry 20). Perhaps most startling, complexes 3.1-3.6, 3.8, 3.10, 3.13,
and 3.21 exhibit little reactivity at ambient pressure but are dramatically more reactive under selfpressurizing conditions. An exception was observed in complex 3.726, 27, 28 which has competitive
reaction conversion at both ambient and pressurized conditions (Figure 3.2). For Figure 3.2, grey
triangles represent an ambient pressure (opened system) condition and blue diamonds represent a
self-pressurized condition (closed system).
Figure 3.2 Gas Evolution of Formic Acid Dehydrogenation by Complex 3.7 Over Time.
41
Complexes 3.1-3.8 in the well-studied Noyori-type tridentate family, generally featuring
M(PNL) (L = PPh2, P(i
Pr)2, S(CH3)2) structures, tend to have lower reactivity than other catalysts
at ambient pressure, giving conversions between 2% and 10%; but they are the highly impacted
by pressurization relative to the other classes, reaching conversions from 58% to 84% under selfpressurizing conditions. Complex 3.7 is a notable exception to both of these generalizations,
possibly owing to the semi-lability of its phosphine oxide and the lower hydricity of its active form;
whereas in an ester hydrogenation reaction, complex 3.7 is one order of magnitude less efficient
than complex 3.4.
26 Often, complexes in this class require pre-activation via hydrodechlorination
with KOH or KOt
Bu to generate their active hydride forms.9, 26, 31, 32, 33 Nevertheless, under selfpressurizing conditions, there was an increase in conversion from 21% (Table 3.1, entry 2a) to 75%
(Table 3.1, entry 6a) without such pre-activation. For example, self-pressurization enables
complex 3.4 (Table 3.1, entry 4b) to achieve 79% conversion, comparable to its activated dihydride
derivative 3.5 (Table 3.1, entry 5, 79%). Complex 3.6 can be initiated under pressurizing
conditions without any base to convert 84% FA, while at ambient pressure only 3.4% FA is
converted, even if the catalyst is activated with KOt
Bu. This dramatic enhancement of reactivity
upon pressurization suggests that one of the reaction products, like H2 or CO, is necessary to enable
or maintain catalytic activity. Hydrogenation is known to activate amine-containing Noyori-type
complexes such as 3.1-3.6 in the presence of base,9, 31, 32, 33 which is a possible explanation. Further,
we observe that thermal decarbonylation of FA is possible at our operating temperature (vide infra).
We expect that the trace CO generated through this pathway is oxidized rapidly by the catalyst,
but that its continued supply installs or maintains a CO ligand on the catalyst.
42
Table 3.1 Dehydrogenation of Neat FA at Ambient Pressure Versus under Pressurized Operation.
Entrya Catalyst precursor Conversion at
ambient pressurec
Conversion in pressurized vessel
(Evolved pressure in bar)d
1a
1b
2a
2bb
3
4a
4bb
5
6a
6bb
7
8
9a
9b
10
11
12
13
14
15
16
17
18
19e
20
21
3.1
3.1
3.2
3.2
3.3
3.4
3.4
3.5
3.6
3.6
3.7
3.8
3.9
3.9-CO
3.10
3.11
3.12
3.13
3.14
3.15
3.16
3.17
3.18
3.19
3.20
3.21
6%
6%
8%
9%
9%
2%
3%
3%
9%
3%
63%
10%
12%
35%
6%
99%
99%
0%
1%
2%
3%
23%
3%
99%
33%
5%
42% (16)
82% (31)
29% (11)
58% (22)
71% (27)
40% (15)
79% (30)
79% (30)
84% (32)
84% (32)
74% (28)
32% (12)
86% (33)
92% (35)
55% (21)
100% (38)
100% (38)
32% (12)
74% (28)
16% (6)
16% (6)
42% (16)
32% (12)
100% (38)
100% (38)
84% (32) a
Conditions: catalyst (0.00795 mmol, 100 ppm), FA (3.0 mL, 79.5 mmol), and NaO2CH (1.2 g,
17.6 mmol) at 110 °C. b
Pre-activation with 2.0 eq. of KOt
Bu in toluene (0.5 mL) at 25 °C. c
FA
conversion in opened system. d
FA conversion in closed system (3.0 ml) calculated based on full
conversion (38 bar) of entry 11. e
Reported best yield of 3 replications.
Bidentate chelate complexes 3.9-CO, 3.11,
6, 29, 34, 35, 36 and 3.12 are the most reactive
precursors that we encountered at ambient pressure.37 Complex 3.11 exhibits the highest rate of
the entire library, where in 79.5 mmol of FA were fully converted within 1.2 hours. We found
these complexes to be pressure-tolerant, but with little enhancement in reactivity because of their
high baseline efficiency at ambient pressure. We believe the unique reactivity of these complexes
to be a function of a novel self-assembly pathway: these convert to two-metal pseudo-pincer
43
structures in the presence of a CO (isolated and characterized from reaction mixtures), exemplified
by cases of our (pyridyl)phosphine ligand bound to ruthenium and iridium (Figure 3.3).6, 37 These
pathways are available at ambient pressure either from FA or an alcohol.6, 29, 34, 35, 36 The resulting
bimetallic complexes have high activity and stability at ambient or elevated pressure. The active
complexes have structural homology with some prolific Noyori-type and Milstein-type pincer
complexes, where one arm of the tridentate ligand is replaced by the second metal.38, 39
Figure 3.3 Structural Analogy between the Common Noyori-type, Milstein-type Pincer and our
Pseudo-pincer Active Catalytic Species.
Carbene-ligated compound 3.10 in this class lacks the reactivity of 3.9-CO, 3.11, or 3.12.
While the reactivity of carbene-ligated systems 3.9-CO and 3.10 should be different than their
phosphine-ligated congeners 3.11 and 3.12, it is surprising that 3.10 does not react analogously to
3.9-CO under pressurized conditions, especially whereas 3.9-CO is prepared from its
cyclooctadiene-ligated precursor 3.9 at ambient pressure. Crabtree’s catalyst 3.13 also exhibits low
reactivity compared to its bidentate analog 3.11. We infer that tethering the pyridine and phosphine
groups is important for proper catalyst self-assembly.
Piano stool Cp*
Ir complexes 3.15-3.17 are not very efficient in this study, although they
are moderately aided by pressure. Complexes 3.16 and 3.17 have been known to have excellent
reactivity in alcohol dehydrogenation,30, 39 but their activity towards FA is moderate, respectively
44
16% and 42% conversion under pressurizing conditions. Notably, Shvo’s cyclopentadienoneligated catalyst 3.14 is much more reactive than Cp*
Ir systems under pressurizing condition. The
Shvo system is known to rest in its dimeric form 3.14 in the presence of H2,
40, 41, 42 so we reason
that the availability of CO to trap the system’s oxidized monomer and prevent formation of 3.14
could account for its rate advantage upon pressurization, because it is known that H2 pressure will
drive the system back to dimer 3.14.
41, 42, 43
While several of the ligated species in Table 3.1 are efficient catalysts—they were designed
as such—we were surprised to find that their synthetic precursors 3.18-3.216, 36, 37 have reactivity
that rivals their ligated congeners. We find, however, that unlike the ligated congeners, the unligated precursors seem to deactivate easily. Overall, one piece of traditional wisdom that seems
to be preserved is that ligated complexes tend to have good stability, sometimes at the cost of
reaction rate. For example, we had difficulty replicating entries 18-21 in Table 3.1 whilst other
entries were very reliable. Apparently, these more naked species tend to react quickly, yet the
reactivity is short-lived and difficult to replicate.
3.2.2 Impact of Applied H2 and CO
Whereas many of the complexes we screened are more productive under self-pressurizing
conditions, we conclude that initially formed products, probably CO and H2, are involved in
activating the precatalysts5, 37 and healing the active catalyst by preempting deactivation processes.
We propose that these processes could be emulated by adding CO or H2 at the outset of the reaction.
To test this, reactions involving four catalyst precursors, 3.5, 3.10, 3.14 and 3.15, were examined
representing the three respective classes of ligated precatalysts that benefitted significantly from
self-pressurizing conditions. These were alternatively pretreated with H2 or CO in FA and their
catalytic activity was evaluated (Figure 3.4).
45
Figure 3.4 Pressurized Dehydrogenations of FA: Control (Black Squares), Pretreated with 8 Bars
of H2 (Green Triangles), (Orange Circles) Pretreated with 1 Bar of CO Following by N2 Purging.
Top Left. Complex 3.5; Top Right. Complex 3.15; Bottom Left. Complex 3.10; Bottom Right.
Complex 3.14.
Neither H2 (green triangles) nor CO (orange circles) uniformly improved catalytic activity
over baseline (black squares) of every catalyst tested. While complexes 3.15 and 3.10 benefit
respectively from H2 and CO pretreatment, other combinations of catalyst and treatment did not
46
significantly improve reactivity: there is not a generalization that explains why these four
complexes are accelerated by pressure. By contrast, both 3.5 and 3.10 are deactivated by H2
pretreatment. In the case of the Shvo system 3.14, H2 pressure slows the reaction but did not affect
maximum total pressure (27-28 bars), consistent with the above proposal of dimer formation.
Notably, after 3.10 was pretreated with CO, the activity was significantly improved,
reaching 89% conversion in five hours, surpassing its carbonylated homolog 3.9-CO. This is an
interesting contrast to the relatively low reactivity of 3.9 under self-pressurizing conditions:
apparently insufficient CO is generated by formic acid dehydrogenation to realize the full benefit
of carbonylation. Interesting about this catalyst system is that at ambient pressure, reactivity slows
after about 3 minutes, which is not observed under pressurizing conditions. We view this as
evidence that CO heals the catalyst and maintains fast kinetics when it does not have the
opportunity to escape the reactor. Despite numerous cases of catalyst poisoning by metal
carbonylation,4, 5 complexes 3.9-CO and 3.10 exhibit the opposite effect: in the absence of CO,
3.10 has low activity for FA decomposition, but when CO is introduced, either by self-generation
or pretreatment, complex 3.10 performed ca. three times (added CO, Figure 3.4) to four times (selfgenerated CO, Table 3.1, entry 9b) better.
Whereas CO is essential to the activation of these catalyst systems, it must be available in
the reactor, although it is not detected in the product stream of FA dehydrogenation as reported in
many studies from our lab and others.5 Although there has not been a full explanation of this, we
believe that formation of CO occurs thermally,44, 45 possibly catalyzed by traces of metals in the
reactor vessel, and that CO is oxidized rapidly by the catalyst in our conditions. We tested these
ideas with two experiments: (1) when the reaction was run with precursor 3.11 under pressurizing
conditions and utilizing rapid heating, the reactor reaching over 129 °C at times, we detected CO
47
concentration up to 0.63%, concurrent with fast H2 generation (107 L/h). No CO (< 10 ppm) is
observed under analogous conditions below 100 °C. This suggests that thermal decarbonylation of
FA can produce significant CO concentration if not controlled;44, 45 (2) In an aqueous methanol
photodehydrogenation experiment (Table 3.2), 6% of CO was generated in the absence of catalyst
3.10, whereas none can be detected when 3.10 is present. Complex 3.10 was chosen for this
experiment for its relatively slow reactivity in FA dehydrogenation, thus to allow longer life and
easier observation of C1 intermediates. We infer from this observation that, when CO is produced
by a non-catalytic reaction, the presence of an appropriate metal complex will reform the CO
efficiently: CO is available, but not detectable. We suspect that this is a general feature of
homogeneous catalysts for formic acid dehydrogenation that has not previously been described.
Table 3.2 Aqueous Methanol Photodehydrogenation Experiment.
Catalyst 3.10 loading Quinolone loading Conversion of COa Conversion of H2
b
40 ppm
40 ppm
—
5 mol%, (R = CN)
5 mol%, (R = OMe)
5 mol%, (R = CN)
—
—
6 %
33 %
trace
13 % a
CO collected as Na2CO3. b
1 mL MeOH, 3 mL H2O, 300 nm hv, room temperature.
Whereas CO is vital to the initiation and speciation of some catalysts, we attempted to
prepare species by independent synthesis that could be responsible for the observations. Upon
treating 3.10 with 1 atm CO, we found that 3.10-CO was not stable to isolation. Treatment of 3.11
with CO results in a broad diversity of structures, which we have previously reported.29 While
these systems failed, the clean carbonylated species 3.9 readily yielded 3.9-CO upon
carbonylation.29 We measured the kinetics of dehydrogenation with 3.9 and 3.9-CO at ambient
pressure to test the hypothesis that CO plays a role in precatalyst activation. At ambient pressure,
MeOH + H2O + [Ir] (3.10)
N
+
R
6M NaOH
hv
CO2 + CO + H2
48
complex 3.9-CO dehydrogenates FA faster than precursor 3.9 (Figure 3.5): both show saturation
catalysis through a 4-hour experiment, with 3.9-CO (black circles) at 24.6% conversion (16.5(1)
x 10-2 TOF) relative to 3.9 (orange triangles) at 11.7% conversion (8.3(1) x 10-2 TOF). These data
indicate an important role for CO in the reactivity of catalyst 3.9.
Figure 3.5 Kinetic Profile of Formic Acid Dehydrogenation by 3.9 – Black Circles and 3.9-CO –
Orange Triangles.
Further investigation of CO pressure revealed the expected inhibitory role at higher loading
(Figure 3.6). At low concentration of CO either from FA decomposition or treatment with 2 bars
of CO, 3.9 initiates at a faster rate than in the absence of CO. By contrast, under 8 bars of CO, we
observe slower conversion of the catalytic reaction following rapid initiation as shown in Figure
3.6. As expected, 3.9-CO performed substantially similar to 3.9 when 3.9 is treated with 2 bars
CO, but like 3.9, 3.9-CO exhibits inhibited rate when 8 bars CO is applied.
While seeking to understand the activation pathway of our most active precursor 3.11, a
stable species 3.11-CO was isolated from a FA dehydrogenation reaction at ambient pressure
(Scheme 3.1). Complex 3.11-CO was characterized by 1
H, 13C, 19F, and 31P NMR spectroscopy
and its molecular structure was established by single-crystal X-ray diffraction. Formation of
0
500
1000
1500
2000
2500
3000
0 5000 10000 15000
Turnover numbers (TON)
Time (s)
Kinetic Profile of Formic Acid Dehydrogenation
49
carbonyl complex 3.11-CO under these conditions is a remarkable development, since FA
dehydrogenation catalyzed by 3.11 is known to produce no free CO gas (< 10 ppm) and returns
non-carbonylated catalytic species when operated at 90 °C.6 This teaches us that at sufficient
temperature and pressure, the previously characterized resting species from the 3.11-catalyzed
dehydrogenation of FA can be further converted into a carbonylated system 3.11-CO. Again, we
see that while FA decarbonylation happens during catalysis, CO is reformed rapidly to products
and remains undetectable in the product stream.
Scheme 3.1 Synthesis and Molecular Structures of 3.11-CO. ORTEP Diagram of 3.11-CO
(CCDC 2142637) with 50% Ellipsoids.
3.2.3 Regeneration, Activity, and Selectivity of 3.11 in High Pressure Gas Stream Production.
To the best of our knowledge, precursor 3.11 continues to demonstrate comparable or
superior activity to all known homogeneous systems for dehydrogenation of neat FA (Figure 3.7).
It also provides excellent stability, longevity (TON > 2 million) and selectivity6 (H2:CO2 1:1, CO
< 10 ppm). We thus scaled this system to generate a pressurized product stream (> 103 bars) while
demonstrating longevity and exceptional kinetics. To acquire high resolution data, we used a 600
mL stirred pressure vessel equipped with an internal temperature probe and a pressure transducer.
Ir P
N
tBu
tBu
3.11
OTf
1. HCO2H, HCO2Na,
25 °C, 1 h
2. 90 °C, 4 h
3.11-CO
N Ir+
P
CO
H
Ir
N
OC P
tBu tBu
tBu tBu
F3C SO3
H2C Cl
2
50
We report volumetric flow rate (standardized to 1 atm at 0 °C) in units of liters per hour (L/hour
corrected to ambient conditions) for all H2 evolution rates. For Figure 3.7, gas evolution of formic
acid dehydrogenation by complexes 3.1-3.21 at ambient pressure over time (0 - 5 hours): complex
3.1 – lavender crosses; complex 3.1 w/ t
BuOK – purple squares; complex 3.2 – orange asterisks;
complex 3.2 w/tBuOK – grey circles; complex 3.3 – yellow plusses; complex 3.4 – blue squares;
complex 3.4 w/ tBuOK – peach squares; complex 3.5 – green triangles; complex 3.6 – cream
crosses; complex 3.7 – red asterisks; complex 3.8 – red circles; complex 3.9-CO – blue plusses;
complex 3.10 – orange hyphens; complex 3.11 – black triangles; complex 3.12 – navy diamonds;
complex 3.13 – grey hyphens; complex 3.14 – yellow crosses; complex 3.15 – blue asterisks;
complex 3.16 – lavender diamonds; complex 3.17 – pink squares; complex 3.18 – green hyphens;
complex 3.19 – grey triangles; complex 3.20 –green circles; complex 3.21 – yellow diamonds.
Figure 3.6 Gas Evolution of Formic Acid Dehydrogenation by Complexes 3.1-3.21 at Ambient
Pressure over Time (0 - 5 Hours).
51
3.3 Conclusion
Among a library of late-transition metal complexes, we found that in every case studied
the dehydrogenation of neat FA is more productive under self-pressurizing reaction conditions.
This is a stunning outcome, whereas the cost of hydrogen provided for retail vehicle filling is
dominated by the cost of compressing the gas yet we have few detailed and broad-based studies
that show how pressure evolution impacts the efficacy of homogeneous FA dehydrogenation
catalysts. We grouped catalysts for neat FA dehydrogenation into four general classes, pincers,
bidentate chelates, piano stool complexes, and metal precursors. Each structural class uniquely
responds to pressurized condition. The bidentate chelates excel beyond others, which we attribute
to a transformation from monomers to two-metal pseudo-pincer complexes in which the second
metal seems to impart special reactivity. We find an enabling role for CO and/or H2 in a number
of cases, typically impacting catalyst initiation (in-situ catalyst synthesis) and defining the course
of catalyst speciation. This hypothesis is supported by previous studies,5, 37 namely, the observation
and isolation of the carbonylation derivative of 3.11, and the three-fold increase in a healing
process of 3.10 by CO. In addition, complex 3.11, which exhibits exceptional catalytic activity,
stability, and selectivity, supersedes existing systems in the production of a high-pressure product
stream from neat FA dehydrogenation. This catalyst was used to convert over 1 L of formic acid
into pressurized H2/CO2 product over the course of 30 hours, proving that the catalytic activity
could be maintained at a high level for 200,000 turnovers at 117 bars without any loss of reactivity.
Due to the favorable economics of producing H2 at pressure, fully automated H2 generation using
a continuous feed, stirred tank reactor will be developed to evaluate the ultimate longevity of the
catalyst. This technology and the discovery of a detailed mechanism and speciation of 3.11 will be
reported in future work.
52
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56
57
Chapter 4 Optimization and Study of the Ligands Effects on the Selectivity
and Reactivity of Ruthenium Catalysts for Alcohol-Amine Coupling
4.1 Introduction
This chapter represents an ongoing project in the group. I would like to acknowledge my
co-authors. Andrew R. Rander acquired a crystal structure of ruthenium complex 4.1. Yuhao Chen
acquired the MALDI spectrum for clusters of ruthenium complex 4.2.
Developing sustainable C–N bond formation methods is an important challenge in
synthetic chemistry.1 The reaction of amines with organohalides to form alkylated amines is a
basic method for the synthesis of amine derivatives. However, this method uses toxic
organohalides as reactants and produces a mixture of different amines and inevitable ammonium
salts as by-products, which brings serious problems to product isolation and purification.2 Nalkylation of amines/amides using alcohols as alkylating reagents is a relatively environmentally
benign reaction, not only because relatively high atomic efficiency can be achieved by producing
water as the only by-product, but also because alcohols are more available, lower toxicity and
lower cost, they are a class of chemicals that are more environmentally friendly than corresponding
organohalides or carbonyl compounds.3
Over the past decade, a number of ruthenium-based catalytic systems have been developed
that enable alcohol-amine coupling by hydrogen-borrowing methods.3, 4 This reaction is crucial,
because it is related to efficient preparation for drug synthesis.5 In addition, hydrogen-borrowing
methods are often selective for mono-alkylation, complementing many traditional alkylation
methods. The development of hydrogen-borrowing catalysis has paralleled the design of
homogeneous transition metal complexes in the search for more active catalysts.3
58
Although the development of hydrogen-borrowing catalysis has paralleled the design of
homogeneous transition metal complexes in the search for more active catalysts, few studies have
reported the impact of ligands on catalyst selectivity. Analyzing the way different ligands control
the catalytic selectivity and activity of homogeneous catalysts is critical for fine chemical
synthesis.4 This understanding could ultimately guide the design of new, more specialized catalytic
systems.
We recently reported a ruthenium complex [(h6
-cymene)RuCl(PyCH2Pt
Bu2)]OTf (4.2)
that efficiently catalyzes the coupling of primary amines and benzylic alcohols without the aid of
a strong base.6 We have demonstrated that the formation of an active cluster is facilitated by a high
ruthenium loading (> 2.5 mol% Ru) and catalyst poisoning is caused by the reaction with CO
derived from starting alcohol.7 In this study, we introduce our previously reported strong sdonating bidentate (pyridyl)methylcarbene ligand8 to modify the precursor [RuCl2(h6
-cymene)]2
to form complex 4.1 and we prove a monomeric catalytic mechanism and a catalyst loading
breakthrough. We find that a catalytic amount of potassium hydroxide is required, which displaces
the cymene group of complex 4.1 and initiates it to an active species. We propose that complex
4.1 will not self-poison and that CO generated during the reaction is not enough to poison complex
4.1. We also extend the reaction scope and experimentally compared the effects of these two
ligands on the selectivity of catalytic reactions. In addition, we found that this ruthenium complex
is a catalyst for acceptorless dehydrogenation of alcohols and possesses a complementary
selectivity to that of our previously reported catalyst.
59
Figure 4.1 Two Ruthenium-based Catalyst Precursors.
4.2 Results and Discussion
4.2.1 Coupling of Amines and Alcohols
Heating complex 4.1 in air with hexylamine, benzyl alcohol, and catalytic amount of KOH
results in the selective formation of secondary amine and water with no other products detectable.
Using the reaction conditions in our previous report,
6 the reaction yield was limited to less than
50% (Table 4.1, entry 1).
Comparing results of entry 1 and entry 3 in Table 4.1, we find that increasing the amount
of catalyst 4.1 can increase the reaction conversion. Entry 4b of Table 1 shows that reaction
temperature increasing can significantly increase the conversion. From the perspective of green
chemistry,
9 low catalyst loading and reaction temperature close to room temperature are what we
expect, because high catalyst loading reduces atom efficiency and high reaction temperature limits
solvent selection in industrial applications. Adding a catalytic amount of inorganic base
significantly improves the reactivity and reaction conversion (Table 4.1, entry 5). Although the
addition of base is not in line with the principles of green chemistry,
9 it reduces the amount of
catalyst used and ultimately increasesthe atom efficiency. Unlike previously reported complex 4.2,
whose catalytic activity is limited at high loading,7 complex 4.1 tolerates a higher loading, enabling
Ru P
N
tBu
tBu
Cl
OTf
Ru
Cl
N
N
Mes
4.1 4.2
OTf
60
shorter reaction time (Table 4.1, entry 10). Adding inorganic base and increasing temperature
inhibits reaction conversion (Table 4.1, entry 15). We achieve a reaction at 70 °C (Table 4.1, entry
16), which provides an opportunity to use a wider variety of solvents for this type of reaction in
industrial applications. Although the reaction is slow, an acceptable conversion can be obtained
by extending the reaction time to 72 hours (Table 4.1, entry 17). We think that the greater stability
and longevity of catalyst 4.1 is due, in part, to the bidentate architecture of the (pyridyl)carbine
which appears to inhibit ligand scrambling processes.
10 According to the results of Table 4.1, we
find that the optimal reaction condition is an amine-to-alcohol ratio of 1 to 1.5, 1 mol% catalyst, 3
mol% KOH, and a reaction temperature of 100 °C. These are the default reaction conditions for
subsequent substrate scope and mechanistic studies.
61
Table 4.1 Optimization of the Coupling of Amines and Alcohols.
Entry [Ir] catalyst (mol%) base time (hour) NMR Yield
1
2
3
4b
5
6
7
8
9
10
11
12
13
14
15b
16c
17c
18d
19e
20f
4.1
4.2
4.1
4.1
4.1
4.1
4.1
4.1
4.1
4.1
4.1
4.2
4.2
4.1
4.1
4.1
4.1
4.1
4.1
4.1
1
1
3
3
3
3
3
3
3
6
6
6
6
1
1
1
1
1
1
1
—
—
—
—
KOH (10 mol%)
KOt
Bu (10 mol%)
KH (10 mol%)
K2CO3 (10 mol%)
KOH (10 mol%)
KOH (20 mol%)
KOH (20 mol%)
—
KOH (20 mol%)
KOH (3 mol%)
KOH (3 mol%)
KOH (3 mol%)
KOH (3 mol%)
KOH (3 mol%)
KOH (3 mol%)
KOH (3 mol%)
24
24
24
24
24
24
24
24
3
2
24
24
24
12
12
12
72
12
12
12
23%
72%
67%
99%
100%
82%
95%
42%
78%
94%
100%
49%
38%
100%
76%
21%
67%
91%
89%
47% a
Hexylamine is the limiting reagent and 1.5 eq. of the benzyl alcohol is used. Reaction temperature
is 100 °C. b
Reaction temperature is 130 °C. c
Reaction temperature is 70 °C. d
2 eq. of the benzyl
alcohol is used. e
1.2 eq. of the benzyl alcohol is used. f
1 eq. of the benzyl alcohol is used.
4.2.2 Mechanistic Study
In our previous report, we showed that the backbone methylene of the
(pyridyl)methylcarbene ligand of complex 2.1 can be deprotonated.8 Interestingly, the backbone
of complex 4.1 is not deprotonated by hydroxide. When we use a stronger base, KOt
Bu, instead of
KOH, the (pyridyl)methylcarbene ligand of 4.1 is still not deprotonated. When we attempt to
obtain a reaction intermediate of complex 4.1, we utilize the reaction conditions used previously
to study complex 4.2 (i.e., [4.1]:[HexNH2]:[BuOH] is 1:6.5:144), then removed volatiles under
vacuum and analyzed the residue by NMR.7
We find from this that the chloride of 4.1 is replaced
+ HO
sealed flask
neat
NH2 + H2O N
H
[Ru]
62
by hydride, but the cymene group of 4.1 remains connected to ruthenium after 10 minutes (Scheme
4.1). As a comparison, adding a catalytic amount of base (i.e. KOH) readily displaces cymene from
4.1. Interestingly, in the absence of alcohol, Ru-cymene bonds are hard to break, even with the
addition of KOH. We propose that the combination of base and alcohol facilitates the activation
of the catalyst 4.1 in this catalytic amine-alcohol coupling reaction.
Scheme 4.1 Reaction Intermediate Study of Complex 4.1.
We propose that the (pyridyl)carbene ligand of 4.1 preempts metal carbonylation, which
leads to the death of 4.2. This improves catalyst survival and provides the ability to use higher
catalysts loadings. We do not find a Ru−CO fragment in the reaction mixture after a reaction using
complex 4.1 as observed by 1
H NMR and MALDI. Further, when we purge a sealed reactor with
CO gas, reaction rate is significantly reduced (Table 4.2, entry 2). On the contrary, when we treat
complex 4.2 with CO gas, rate is accelerated at low CO loading, even though CO eventually
poisons catalyst 4.2 (Table 4.2, entry 4).
Ru
Cl
N
N
Mes
4.1
OH
NH2
110 °C
10 min
OTf
Ru
H
N
N
N
Mes
4.3
OTf
63
Table 4.2 CO Effect in Catalytic Coupling of Amines and Alcohols.
entry [Ru] CO base conversion
1 4.1 - KOH (3 mol%) 60%
2 4.1 1 bar KOH (3 mol%) 5%
3 4.2 - - 35%
4 4.2 1 bar - 48%
4.2.2.1 Hammett Analysis
The electronic influence on the rate of the alcohol amination is studied using aniline and
several para-substituted benzyl alcohols, i.e. a Hammett study. For catalyst 4.1, this study enabled
calculation of a positive Hammett reaction parameter of r = 0.88 (Figure 4.2). This positive r
value means an electrophilic accepter receiving a nucleophilic hydride in a kinetically-relevant
step.11 We did a Hammett study for catalyst 4.2 and calculated a negative Hammett reaction
parameter of r = -0.37 (Figure 4.3) which is opposite to catalyst 4.1. We realize that catalyst 4.1
using (pyridyl)carbene ligand not only breaks through the loading limitation of catalyst 4.2, it also
provides a complementary substrate selectivity. Furthermore, this also gives us an opportunity to
explore the effects of different ligands on the selectivity and activity of organometallic catalysts.
+ HO
sealed flask
100 °C
neat
6 hours
NH2 + H2O N
H
[Ru] (1 mol %)
64
Figure 4.2 Hammett Plot of Aniline Alkylation using a Series of para-Substituted Benzyl Alcohols
with Complex 4.1 as Catalyst.
Figure 4.3 Hammett Plot of Aniline Alkylation using a Series of para-Substituted Benzyl Alcohols
with Complex 4.2 as Catalyst.
-CF3
-H
-MeO
-Cl
-Me
y = 0.8753x - 0.0271
R² = 0.99576
-0.4
-0.3
-0.2
-0.1
0
0.1
0.2
0.3
0.4
0.5
0.6
-0.4 -0.3 -0.2 -0.1 0 0.1 0.2 0.3 0.4 0.5 0.6 log(kR/kH)
!
-CF3
-H
-OMe
-Cl
-Me
y = -0.3749x - 0.0139
R² = 0.99507
-0.3
-0.2
-0.1
0
0.1
0.2
-0.4 -0.3 -0.2 -0.1 0 0.1 0.2 0.3 0.4 0.5 0.6 log(kR/kH)
!
65
4.2.2.2 Ruthenium Clusters
In our previous report, we synthesized ruthenium clusters (e.g. 4.4) from complex 4.2, and
proved that two of the clusters illustrated there are the dead catalyst forms.7 Here we applied the
same reaction conditions (i.e., [4.1]:[HexNH2]:[BuOH] is 1:6.5:144) used to form 4.4 to complex
4.1, and characterized the results by matrix-assisted laser desorption/ionization (MALDI). No
ruthenium clusters are detected, as we only find monomeric complexes. Under these reaction
conditions, complexes 4.1 and 4.2 were combined in a ratio of 1 to 2, then volatiles were removed
under vacuum and the residue was analyzed by 1
H and 31P NMR spectroscopy and MALDI. We
found that complex 4.1 does not react with complex 4.2, and complex 4.2 still forms clusters 4.4
(Scheme 4.2).
Scheme 4.2 Complexes 4.1 and 4.2 Mixture.
4.2.2.3 Isotope Effects
We performed a kinetic isotope effect study by parallel reactions with complex 4.1 and
benzylamine to investigate whether the alcohol dehydrogenation step is a rate-determining step
(Scheme 4.3). For methanol, Scheme 4.3A obtains a rate constant of 2.8(2) x 10-5 s
-1
. For
deuterated methanol, Scheme 4.3B obtains a rate constant of 2.4(1) x 10-5 s
-1
. The observed KIE
value of 1.17(11) is inconsistent with a rate-determining step of alcohol deprotonation and hydride
metal complex coordination.12
Ru P
N
t
Bu
t
Bu
Cl
OTf
Ru
Cl
N
N
Mes
4.1
OTf
4.2
110 °C
1 hour
Ru Ru
Ru H Cl
N
Cl
Pt
Bu2
P CO
N
P N
H +
OTf
4.4
Ru
H
N
N
N
Mes
4.3
+
OTf n-Butanol
n-Hexylamine
66
Scheme 4.3 Kinetic Isotope Effect Study.
4.2.2.4 Mechanistic Proposal
Liu and co-workers reported DFT calculations of the catalytic N-alkylation reaction.12
They found that the initial alcohol dehydrogenation to aldehyde and the subsequent aldehydeamine condensation steps are thermodynamically endergonic. By contrast, the final imine
reduction to product amine step is highly exergonic, thus making it the driving force for the
catalytic cycle. We find that when the reaction temperature is lower than the optimal reaction
temperature, the reaction conversion decreases slightly (Table 4.1, entry 16); while the reaction
conversion decreases significantly when the reaction temperature is higher than the optimal
reaction temperature (Table 4.1, entry 15).
In order to analyze the catalytic mechanism of complex 4.1 and understand the difference
between 4.1 and 4.2, we designed a reaction using 4-aminobenzylamine and benzyl alcohol as
substrates. The general hydrogen borrowing reaction process includes three steps (Scheme 1.5). If
the alcohol dehydrogenation is the rate-limiting step, 4.3c in Table 4.3 should not form because
the generated benzaldehyde reacts with the more nucleophilic aliphatic amine first; if the aldehydeamine condensation is the rate-limiting step, the imine product should not be detected; if the imine
reduction is the rate-limiting step, 4.3a has the opportunity to react with benzaldehyde to produce
4.3c. For catalyst 4.1, we find that during the reaction, 4.3c becomes the main component of the
NH2 + CH3OH N
H +
CH3
A: H2O
[4.1] (1 mol%)
KOH (3 mol%)
100 °C
B: NH2 + CD3OD + H2O
[4.1] (1 mol%)
KOH (3 mol%)
100 °C N
D
CD3
67
product, and we propose that the imine reduction is the reaction rate-limiting step. For catalyst 4.2,
the data in Table 4.3 indicate that dehydrogenation of benzyl alcohol is the rate-limiting step of
this catalytic hydrogen borrowing reaction, because 4.3a is reduced to product 4.3b before 4.3c or
4.3d can appear.
Table 4.3 Reaction Site Selectivity of Catalyst 4.1 and 4.2.
entry [Ru] Time (hour) NMR Conversion
4.3a 4.3b 4.3c 4.3d 4.3e
1 4.1 0.5 23% 7% 18% 8% 0%
2 4.2 7% 25% 0% 0% 0%
3 4.1 1 11% 0% 42% 18% 5%
4 4.2 10% 34% 0% 0% 0%
5 4.1 6 0% 0% 18% 59% 14%
6 4.2 18% 54% 0% 0% 0%
7 4.1 12 0% 0% 0% 71% 26%
8 4.2 13% 71% 0% 0% 0%
To investigate whether metal-catalyzed hydrogen transfers go via a monohydride or a
dihydride intermediate, 1-deutero-1-phenylethanol is synthesized13 (4.4, 92% D by NMR) and is
subjected to complex 4.1 in the presence of an equimolar amount of acetophenone (Scheme 4.4).
Heating this mixture to 100 °C and analyzing by NMR after five hours (4.5, 72% D by NMR)
reveals the absence of deuterium scrambling from the O-H of 4.4 to carbon of the C=O of
acetophenone, suggesting a monohydride intermediate, where deuterium is always extracted from
C-D bond of 4.4 and transferred to the carbon atom of the carbonyl group of acetophenone, by
NH2
NH2
OH
N
N N
NH
HN
NH [Ru] (1 mol %)
KOH (0.03 eq)
d-Toluene
100 °C
+ + +
4.3c 4.3d 4.3e
N
NH2 NH2
NH
+
4.3a 4.3b
+
2 eq
68
contrast, complete scrambling would suggest a dihydride intermediate, where H and D can
exchange on metal atoms. 1
H NMR spectroscopy revealed a proton incorporation (4.5, 72% D by
NMR), which is an indication that a dihydride intermediate is involved. (Scheme 4.4)
Scheme 4.4 A Metal-Catalyzed Hydrogen Transfer Via a Monohydride or a Dihydride
Intermediate.
4.2.3 Substrate Scope
Table 4.5 shows N-alkylation of a wide range of amines, such as primary amines, anilines,
and amides, that are enabled by catalyst 4.1. Entries 1-4 and entry 9 realize monoalkylation of
different amides, including sulfonamide, phosphoramide, aliphatic primary amide, and
picolinamide groups. We successfully alkylated an aniline with strong electron-withdrawing
groups (entry 5). Amines containing a guanidine or guanidine-like structure undergo
monoalkylation of the primary amine group (entry 6-7). An important category of alcohol-amine
coupling via hydrogen borrowing processes is amine methylations using methanol. These are
challenging processes, partly due to the relatively high activation enthalpy of methanol
dehydrogenation.
14 Here, we successfully activate methanol (entry 9). Other short chain aliphatic
alcohols are used as reactants (entry 8 and 14). Entry 10-11 show catalyzed tandem alcohol
amination/Pictet-Spengler/cycloamination reactions that enable direct synthesis of
indoloquinolizidine and azapyridoindole. 4.7b is determined with NMR and MALDI data of
product mixture. We used these conditions to synthesize a benzodiazepine in one step (entry 13).
The product of entry 15 is a potential anti-Parkinson agent.
15
OH
D
O
+
4.1 (5 mol %)
KOH (15 mol %)
d-Toluene
110 °C
OH
H(D)
Ln-1Ru D
H
4.4
(92% D by NMR)
4.5
(72% D by NMR)
69
Table 4.4 Substrate Scope of Amine Monoalkylation.
R1 NH2 + HO R2
4.1 (1 mol %)
KOH (0.03 eq.)
sealed flask
neat, 100 °C
12 hours
R1 NH
R2 + H2O
Entry Nitrogen Nucleophile Alcohol Producta
S
O
O
NH2 S
O
O
NH
(82%)
HO
1
NH2
F F
F
F F
5 NH
F F
F F
(71%)
H
N
N
NH2
S
N
NH2
H
N
N
NH
S
N
NH
(65%)
(76%)
6
7
8 NH2 NH
(85%)
P
O
O NH2 O
NH2
O
N
O
NH2
2
3
4
P
O
N
H
O
O
N
H
O
N
O
N
H
(87%)
(68%)
(56%)
HO
4.3 4.3a
4.4
4.5
4.6
4.7
4.8
4.9
4.10
4.3a
4.3a
4.3a
4.3a
4.3a
4.4a
4.3aa
4.3ab
4.3ac
4.3ad
4.3ae
4.3af
4.3ag
4.4b
F
N
H
NH2
HO OH
N
H
N
(66%)
10
12
13
NH2
OH
NH2
OH N
H
H
N
NH2
OH
HO
HN
Ph
N
H
N
Ph
(82%)b
(88%)
NH2
HO HN
(38%)
15
NH2 HO
14 N
H
(72%)
4.12
4.13
4.14
4.15
4.16
4.6a
4.13
4.9a
4.10a
4.11a
4.6b
4.8b
4.9b
4.10b
4.11b
aIsolated yield, 50 mg substrate scale. bNMR yield, 50 mg substrate scale,
mesitylene as the internal standard.
Entry Nitrogen Nucleophile Alcohol Producta
N
H
NH2
HO
N
H
N
(30%)b
11
4.12 4.7a 4.7b
OH
S
O
O
NH2 S
O
O
NH
(77%)
9 HO
4.11 4.5a 4.5b
70
4.3 Conclusion
In conclusion, we introduce our previous reported strong s-donating
(pyridyl)methylcarbene ligand8 to modify precursor [RuCl2(h6
-cymene)]2 to form complex 4.1
which is an efficient ruthenium catalyst for the amine alcohol coupling reaction. We find that 4.1
breaks through the catalyst loading limit of catalyst 4.2. We find that a catalytic amount of
potassium hydroxide is required for dissociating cymene from complex 4.1 and initiating it to an
active species. We find that complex 4.1 will not self-poison and that CO generated during the
reaction does not poison it. We apply catalyst 4.1 to extend the scope of hydrogen borrowing
amine-alcohol coupling. We experimentally compared catalysts 4.1 and 4.2 and summarize the
effects of their respective bidentate ligands on the selectivity of catalytic reactions. Complex 4.1
can be used as a complementary catalyst choice for 4.2. In addition, we envision catalyst 4.1 as a
useful tool both for organic synthesis at scale and preparation for drug synthesis.
4.4 References
1. Reed-Berendt, B. G.; Latham, D. E.; Dambatta, M. B.; Morrill, L. C. Borrowing hydrogen for
organic synthesis. ACS Central Science 2021, 7 (4), 570–585.
2. Guillena, G.; Ramón, D. J.; Yus, M. Hydrogen autotransfer in the N-alkylation of amines and
related compounds using alcohols and amines as electrophiles. Chemical Reviews 2009, 110
(3), 1611–1641.
3. Corma, A.; Navas, J.; Sabater, M. J. Advances in one-pot synthesis through borrowing
hydrogen catalysis. Chemical Reviews 2018, 118 (4), 1410–1459.
4. Sabo-Etienne, S.; Grellier, M. Ruthenium: inorganic & coordination chemistry. Encyclopedia
of Inorganic and Bioinorganic Chemistry, 1st ed.; Wiley, 2011. Updated December 15, 2011.
5. Berliner, M. A.; Dubant, S. P. A.; Makowski, T.; Ng, K.; Sitter, B.; Wager, C.; Zhang, Y. Use
of an iridium-catalyzed redox-neutral alcohol-amine coupling on kilogram scale for the
synthesis of a GLYT1 inhibitor. Organic Process Research & Development 2011, 15 (5),
1052–1062.
71
6. (a) Celaje, J. J. A.; Zhang, X.; Zhang, F.; Kam, L.; Herron, J. R.; Williams, T. J. A base and
solvent-free ruthenium-catalyzed alkylation of amines. ACS Catalysis 2017, 7 (2), 1136–1142.
(b) Nalikezhathu, A.; Cherepakhin, V.; Williams, T. J. Ruthenium catalyzed tandem Pictet–
Spengler reaction. Organic Letters 2020, 22 (13), 4979–4984.
7. Cherepakhin, V.; Williams, T. J. Catalyst evolution in ruthenium-catalyzed coupling of amines
and alcohols. ACS Catalysis 2019, 10 (1), 56–65.
8. Zhang, L.; Lu, Z.; Rander, A. R.; Williams, T. J. An ambient pressure, direct hydrogenation of
ketones. Chemical Communications 2023, 59 (52), 8107–8110.
9. Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and Practice; Oxford University Press,
USA, 2000.
10. Stewart, R.; Yates, K. The protonation of the carbonyl group. i. The basicity of substituted
acetophenones. Journal of the American Chemical Society 1958, 80 (23), 6355–6359.
11. Zeng, G.; Sakaki, S.; Fujita, K.-I.; Sano, H.; Yamaguchi, R. Efficient catalyst for acceptorless
alcohol dehydrogenation: interplay of theoretical and experimental studies. ACS Catalysis
2014, 4 (3), 1010–1020.0
12. Zhao, G.-M.; Liu, H.-L.; Huang, X.-R.; Zhang, D.-D.; Yang, X. Mechanistic study on the
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iridium-catalyzed N-alkylation of amines with alcohols. RSC Advances 2015, 5 (29),
22996–23008.
13. Delgado-Abad, T.; Martínez-Ferrer, J.; Caballero, A.; Olmos, A.; Mello, R.; González-Núñez,
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bond heterolysis. Angewandte Chemie International Edition 2013, 52 (50), 13298–13301.
14. Donthireddy, S. N. R.; Illam, P. M.; Rit, A. Ruthenium(II) complexes of heteroditopic Nheterocyclic carbene ligands: efficient catalysts for C–N bond formation via a hydrogenborrowing strategy under solvent-free conditions. Inorganic Chemistry 2020, 59 (3), 1835–
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72
73
Chapter 5 Experimental and Spectral Data
5.1 General Methods
General Procedures
Reproduced from Ref. 1 with permission from the Royal Society of Chemistry.1
All air and water sensitive procedures were carried out either in a Vacuum Atmosphere
glove box under nitrogen (2-10 ppm O2 for all manipulations) or using standard Schlenk
techniques under nitrogen. Sensitive liquids and solutions were transferred via syringe or stainlesssteel cannula. Reactions were run using Teflon-coated magnetic stir bars. Elevated temperatures
were maintained in temperature regulated oil baths. Organic solutions were concentrated using a
Buchi rotary evaporator. Thin layer chromatography plates were visualized by ultraviolet light.
Chromatographic purification of products was accomplished by flash chromatography.
Dichloromethane and hexanes are purchased from VWR and dried in a J. C. Meyer solvent
purification system with alumina/copper(II) oxide columns; toluene was dried using sodium
benzophenone ketyl. Other solvents were used directly from commercial suppliers, unless
otherwise specified. Chloro(1,5-cyclooctadiene)iridium(I) dimer (Strem), sodium
trifluoromethanesulfonate (Sigma-Aldrich), potassium tert-butoxide (Sigma-Aldrich) were purged
with nitrogen and stored under nitrogen atmosphere; pyridine-imidazolium ligands and
corresponding silver carbenes were synthesized using a literature procedure.2
74
Reagents, Solvents, and other Starting Materials
Deuterated NMR solvents were purchased from Cambridge Isotopes Laboratories. Unless
otherwise stated, all reagents were purchased from major commercial suppliers (Sigma-Aldrich,
Merck, Fluorochem, Apollo Scientific, Fischer Scientific, Tokyo Chemical Industry, Acros
Organics) and used without further purification. CO was supplied by Airgas through USC Mailing
and Material Management.
Spectroscopic Measurements
NMR spectra were recorded on a Varian Mercury 400, Varian VNMRS 500, or VNMRS
600, spectrometer processed using MestReNova. All chemical shifts are reported in units of ppm
and referenced to the residual 1
H or 13C solvent peak and line-listed according to (s) singlet, (bs)
broad singlet, (d) doublet, (t) triplet, (dd) double doublet, etc. 13C spectra are delimited by carbon
peaks, not carbon count. Air-sensitive NMR spectra were taken in 8” J-Young tubes (Wilmad or
Norell) with Teflon valve plugs. Data were collected and graphed was plotted with Microsoft Excel
or JMP Pro 15.
Analytical Chromatography
Infrared spectra were recorded on Bruker OPUS FTIR spectrometer. GC-MS analysis on
Agilent HPLC/Q TOF MS/MS Spectrometer. MALDI-MS spectra were acquired on Bruker
Autoflex Speed MALDI Mass Spectrometer.
75
5.2 Experimental and Spectral Data: Ketones and Aldehydes Hydrogenation
Hydrogenation Procedures
Iridium catalysts for carbonyl group hydrogenation are stored in a glovebox for long term
purpose (less than one year). In a typical reaction, iridium catalyst, base (i.e. KOt
Bu) and solid
substrates are weighed inside the glovebox, added to a Schlenk flask equipped with a magnetic stir
bar (Figure 2.4). Liquid substrates and toluene are added to the same flask with a disposable plastic
syringe. An oil bath is used for reactions at 100 °C. Bath temperature is monitor using an alcohol
thermometer. Normally < ±2.5 °C temperature fluctuation is observed for oil baths.
Figure 5.1 Apparatus Set Up for Hydrogenation Reactions.
1 atm H2
O
R1 R2
OH
R1 R2
H
[Ir] + Base
R1 = Aryl, Heteroaryl, Alkyl
R2 = Aryl, Heteroaryl, Alkyl, H [Ir] =
Base= KOt
Bu
N
N
N H
H
Ir
CO
CO
Mes
OTf
76
Organometallic Compounds
[2-(3-Mesityl-imidazol-1-yl)pyridine]Ir(cod)OTf, 2.4:
In the glovebox under nitrogen, in a 100 mL Schlenk flask wrapped in foil to avoid light,
dibromo-di(3-mestiyl-1H-imidazol-2-ylidene)-disilver(I) (100 mg, 0.111 mmol)3 was added in
small portions to a stirring solution of chloro(1,5-cyclooctadiene)Iridium(I) dimer (74.6 mg, 0.222
mmol) in dry dichloromethane (20 mL). After 6 hours, sodium trifluoromethanesulfonate (38.2
mg, 0.222 mmol) was also added to the mixture. After stirring for 30 minutes, the solution was
filtered through a dry pad of celite to remove the byproducts. The solvent was evaporated under
reduced pressure to yield a red glassy solid. This red solid was dissolved in dry dichloromethane
(10 mL), and dry hexanes (20 mL) was added to the solution to facilitate a precipitation. A red
crystalline solid was acquired and dried under vacuum (54 mg, 35%). This sample was
spectroscopically pure by 1
H NMR.
This synthetic step can be done without a glove box as follows. Pyridine-imidazolium
ligands were synthesized in a laboratory reflux apparatus out of the glove box.4 For [Ag]1 synthesis
out in air, pyridine-imidazolium ligand (500 mg, 1.59 mmol), Ag2O (222 mg, 0.960 mmol, 0.600
eq) and 50 mL dichloromethane were put in a 250 mL round bottom flask wrapped in foil. This
flask was purged with N2 and connected to a N2 balloon. After stirring for 48 hours, the solution
was filtered through a pad of celite to remove byproducts. Half of the solvent was evaporated under
reduced pressure and then 50 mL hexanes was dropped into this solution using a pressureequalizing dropping funnel. The top of the dropping funnel was connected to a N2 balloon. A grey
crystalline solid was acquired and dried under vacuum (520 mg, 77.6%). [Ag]1 can be used without
further protection.
For complex 2.4 synthesis out in air, in a 100 mL round bottom flask, chloro(1,5-
cyclooctadiene)Iridium(I) dimer (100 mg, 0.300 mmol) was dissolved in dichloromethane (10 mL).
Then, a pressure-equalizing dropping funnel was used to drop a solution of [Ag]1 (134 mg, 0.150
mmol) in dichloromethane (10 mL) into this stirring solution. The apparatus was connected to a
N2 balloon. After 6 hours, sodium trifluoromethanesulfonate (51.2 mg, 0.300 mmol) was also
added to the mixture. After stirring for another 30 minutes, the solution was filtered through a pad
of celite to remove byproducts. Half of the solvent was evaporated under reduced pressure and
then 25 mL hexanes was dropped into this solution using a pressure-equalizing dropping funnel.
The top of the dropping funnel was connected to a N2 balloon. A red solid was acquired and dried
under vacuum (68 mg, 33%).
2.4
N
N
Ag
Mes
Cl
Cl Ag
N
N
Mes
[Ag]1
N
N
[Ir(COD)Cl]2
then NaOTf
DCM
35%
77
1
H NMR (600 MHz, cd2cl2) δ 8.47 (ddd, J = 4.7, 1.8, 0.9 Hz, py 1H), 7.95 (d, J = 1.2 Hz, py 1H),
7.61 (td, J = 7.7, 1.8 Hz, py 1H), 7.45 (d, J = 1.9 Hz, py 1H), 7.25 (s, mesityl-ar 2H), 6.88 (d, J =
2.0 Hz, COD sp2 1H), 6.77 (d, J = 2.0 Hz, COD sp2 1H), 5.71 (d, J = 16.1 Hz, Im 1H), 5.49 (d, J
= 4.7 Hz, Im 1H), 4.21 (td, J = 6.2, 3.5 Hz, COD sp2 1H), 3.99 (m, COD sp3 2H), 3.64 (m, COD
sp3 4H), 3.60 – 3.53 (m, COD sp2 1H), 2.26 (s, mesityl-para-methyl 3H), 2.14 (s, mesityl-orthomethyl 3H), 1.83 (s, mesityl-ortho-methyl 3H).
13C NMR (126 MHz, cdcl3) δ 172.87 (carbene C), 154.55 (py), 147.49 (py), 144.99 (py), 141.00
(mesityl-ar), 134.37 (mesityl-ar), 133.64 (mesityl-ar), 130.01 (mesityl-ar), 125.81 (Im), 124.40
(py), 119.53 (Im), 114.33 (py), 86.42 (COD sp2
), 65.99 (COD sp2
), 33.80 (COD sp3
), 29.24 (COD
sp3
), 21.41 (mesityl-CH3), 17.74 (mesityl-CH3), 14.27 (mesityl-CH3).
IR (thin film/cm-1
) ν 3533, 3109, 3052, 2914, 2831, 1734, 1591, 1570, 1470, 1435, 1394, 1263,
1223, 1150, 1030, 730, 700, 636.
MS (MALDI) calc’d for [C25H29IrN3]
+ 563.7, found 563.2.
78
Figure 5.2 1
H NMR Spectrum of Compound 2.4 in CD2Cl2.
Figure 5.3 13
C NMR Spectrum of Compound 2.4 in CDCl3.
13 12 11 10 9 8 7 6 5 4 3 2 1 0 -1
f1 (ppm)
0
100
200
300
400
500
600
700
800
900
1000
1100
2.53
3.21
3.32
1.24
3.76
1.57
1.89
1.25
0.86
1.20
1.20
1.20
1.19
1.96
1.03
1.17
1.00
1.13
1.81
1.80
1.82
1.83
1.85
2.03
2.04
2.04
2.06
2.06
2.14
2.16
2.15
2.16
2.16
2.17
2.17
2.18
2.25
2.25
2.26
2.26
2.27
2.27
2.27
2.28
2.29
2.29
2.29
3.56
3.57
3.58
3.64
3.80
3.98
3.99
3.99
4.20
4.21
4.22
4.21
4.22
4.23
5.48
5.49
5.70
5.73
6.77
6.77
6.88
6.89
6.99
7.01
7.25
7.45
7.45
7.60
7.60
7.61
7.61
7.62
7.63
7.95
7.95
8.46
8.46
8.46
8.46
8.47
8.47
8.47
8.47
180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0
f1 (ppm)
-10
0
10
20
30
40
50
60
70
80
90
100
110
120
130
140
150
160
1.01
14.10
17.57
21.24
22.64
29.08
31.58
33.64
65.83
76.74 cdcl3
77.00 cdcl3
77.20
77.25 cdcl3
86.25
114.16
119.36
124.24
125.64
129.85
133.47
134.21
140.83
144.82
147.32
154.38
172.71
79
Figure 5.4 Infrared Spectrum of Compound 2.4.
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
3730 3330 2930 2530 2130 1730 1330 930 530
Absorbance
Wavenumbers (cm-1)
80
[2-((3-Mesityl-imidazol-1-yl)methyl)pyridine]Ir(CO)Cl, 2.6:
In the glovebox under nitrogen, in a 100 mL Schlenk flask, chloro(1,5-
cyclooctadiene)iridium(I) dimer (100 mg, 0.150 mmol) was dissolved in dry acetonitrile (20 mL).
The flask was purged with 1 atm CO gas. After 5 min, dichloro-di(1-(2,4,6-trimethylphenyl)-3-(2-
picolyl)-imidazol-2-ylidene)-disilver(I)4 ([Ag]2, 125 mg, 0.150 mmol) was added in small portions
to this stirring solution. After stirring for 1 hour, the solution was filtered through a pad of dry
cotton, apparently to remove the silver chloride byproduct. The solvent was evaporated under
reduced pressure to yield a yellow glassy solid. This yellow solid was dissolved in dry
dichloromethane (10 mL), and dry hexanes (20 mL) was added to the solution to facilitate
precipitation. A yellow crystalline solid was acquired and dried under vacuum (104 mg, 65.0%).
This sample was spectroscopically pure by 1
H NMR.
This synthetic step can be done without a glove box as follows. [Ag]2 can be synthesized
in air and the procedure is the same as the steps mentioned in preparation of complex 2.4.
For complex 2.6 synthesis out in air, chloro(1,5-cyclooctadiene)iridium(I) dimer (100 mg,
0.150 mmol) was dissolved in acetonitrile (20 mL) in a 100 mL Schlenk flask. After 5 min, using
a pressure-equalizing dropping funnel to drop a solution of [Ag]2 (125 mg, 0.150 mmol) in
acetonitrile (10 mL) into this stirring solution. After 1 hour, the solution was filtered through a pad
of celite to remove byproducts. The solvent was evaporated under reduced pressure to yield a
yellow glassy solid. This yellow solid was dissolved in dichloromethane (10 mL) and then 25 mL
hexanes was dropped into this solution using a pressure-equalizing dropping funnel. The top of
the dropping funnel is connected with a N2 balloon. A yellow solid was acquired and dried under
vacuum (93 mg, 58%).
1
H NMR (400 MHz, cd2cl2) δ 9.31 – 9.22 (m, py 1H), 7.92 (td, J = 7.7, 1.7 Hz, py 1H), 7.54 (d, J
= 7.7 Hz, py 1H), 7.46 (ddd, J = 7.4, 5.7, 1.4 Hz, py 1H), 7.16 (d, J = 2.1 Hz, Im 1H), 6.98 (s,
mesityl-ar 2H), 6.76 (d, J = 2.0 Hz, Im 1H), 5.26 (s, methylene 2H), 2.34 (s, mesityl-para-methyl
3H), 2.04 (s, mesityl-ortho-methyl 6H).
13C NMR (126 MHz, cd2cl2) δ 176.02 (carbene C), 162.09 (CO), 154.13 (py), 153.58 (py), 139.81
(py), 139.60 (mesityl), 136.26 (py), 135.97 (mesityl), 129.32 (mesityl), 125.05 (py), 123.92
(mesityl), 121.31 (Im), 120.38 (Im), 55.42 (py-CH2), 21.25 (mesityl-CH3), 18.64 (mesityl-CH3).
IR (thin film/cm-1
) ν 3055, 2992, 2939, 2252 (CO), 1558, 1505, 1435, 1416, 1374, 1270, 1035,
917, 734, 702.
MS (MALDI) calc’d for [C18H19IrN3]
+ 469.6, found 469.7.
N
N Ir
N
Cl
O N
N
Ag
Mes
Br
Br Ag
N
N
Mes
[Ir(CO)2Cl]2
MeCN
65%
[Ag]2
N
N
2.6
81
Figure 5.5 1
H NMR Spectrum of Compound 2.6 in CD2Cl2.
Figure 5.6 13
C NMR Spectrum of Compound 2.6 in CD2Cl2.
11.0 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5 -1.0
f1 (ppm)
-200
-100
0
100
200
300
400
500
600
700
800
900
1000
1100
1200
1300
1400
1500
1600
1700
1800
1900
2000
2100
2200
2300
2400
6.08
3.19
1.87
0.96
2.14
0.97
1.14
1.07
1.00
0.99
230 220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10
f1 (ppm)
0
10000
20000
30000
40000
50000
60000
70000
80000
90000
100000
18.64
21.25
53.30 cd2cl2
53.57 cd2cl2
53.84 cd2cl2
54.11 cd2cl2
54.31
54.38 cd2cl2
55.42
120.38
121.31
123.92
125.05
129.32
136.26
139.81
153.59
154.14
82
Figure 5.7 Infrared Spectrum of Complex 2.6.
0
0.05
0.1
0.15
0.2
0.25
0.3
3530 3030 2530 2030 1530 1030 530
Absorbance
Wavenumbers (cm-1)
83
Spectral Data: Ketones and Aldehydes Hydrogenation
All compounds formed in Table 2.2 are known compounds, and most are commercially available.
1-Phenylethanol 2.11aa:
Inside the glovebox, a 50 mL Schlenk reactor with a conical bottom was charged with
2.11a (50 mg, 0.42 mmol), 10% KOt
Bu (4.70 mg, 41.6 µmol) and 3 mol% iridium complex 2.1
(8.40 mg, 12.5 µmol). The reactor was sealed, taken out of the glovebox, purged with 1 bar
hydrogen gas and heated to 100 °C for 48 hours. The toluene was removed by a rotary evaporator
after the reaction. After that, the dark yellow mixture was poured over 20 mL brine, and the organic
material was extracted three times by dichloromethane (30 mL), and dried over anhydrous sodium
sulfate. The resulting solution was concentrated by rotary evaporation and purified by auto column
chromatography, eluting with ethyl acetate/ hexanes. Product-containing fractions were identified
and concentrated by rotary evaporation to yield 34.7 mg (68%) of product 2.11aa as light yellow
oil.
1
H NMR (500 MHz, cdcl3) δ 7.38 – 7.30 (m, 4H), 7.28 – 7.24 (m, 1H), 4.87 (q, J = 6.5 Hz, 1H),
1.48 (d, J = 6.4 Hz, 3H).
O
H2 (1 atm)
2.1 (3 mol%)
KOt
Bu (10 mol%)
toluene, 100 °C, 48 h
68%
OH
2.11a 2.11aa
84
Figure 5.8 1
H NMR Spectrum of Table 2.2, Entry 1 Product 2.11aa in CDCl3. Data are Consistent
with a Commercial Compound.
8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5
f1 (ppm)
0
100
200
300
400
500
600
700
800
900
1000
1100
4.00 1.05 1.00 3.13
0.83
0.84
0.85
0.86
0.87
0.87
0.87
0.88
0.89
0.90
0.96
0.97
1.23
1.24
1.26
1.26
1.27
1.28
1.47
1.48
2.02
2.02
2.08 H2O
4.08
4.09
4.11
4.12
4.85
4.86
4.87
4.89
5.27
7.24
7.24
7.24
7.25
7.25
7.25
7.26
7.26
7.26 cdcl3
7.26
7.27
7.27
7.27
7.27
7.31
7.32
7.32
7.32
7.33
7.33
7.33
7.34
7.34
7.34
7.35
7.35
7.36
7.36
7.36
7.36
7.36
7.37
OH
85
2-[4-(Dimethylamino)phenyl]ethanol 2.11ba:
Inside the glovebox, a 50 mL Schlenk reactor with a conical bottom was charged with
2.11b (50 mg, 0.31 mmol), 10% KOt
Bu (3.40 mg, 30.6 µmol) and 3 mol% iridium complex 2.1
(6.2 mg, 9.2 µmol). The reactor was sealed, taken out of the glovebox, purged with 1 bar hydrogen
gas and heated to 100 °C for 48 hours. The toluene was removed by a rotary evaporator after the
reaction. After that, the dark yellow mixture was poured over 20 mL brine, and the organic material
was extracted three times by dichloromethane (30 mL), and dried over anhydrous sodium sulfate.
The resulting solution was concentrated by rotary evaporation and purified by auto column
chromatography, eluting with ethyl acetate/ hexanes. Product-containing fractions were identified
and concentrated by rotary evaporation to yield 47.7 mg (95%) of product 2.11ba as light yellow
oil.
1
H NMR (400 MHz, cdcl3) δ 7.30 – 7.25 (m, 2H), 6.78 – 6.73 (m, 2H), 4.82 (q, J = 6.4 Hz, 1H),
2.96 (s, 6H), 1.50 (d, J = 6.4 Hz, 3H).
O
H2 (1 atm)
2.1 (3 mol%)
KOt
Bu (10 mol%)
toluene, 100 °C, 48 h
95%
OH
Me2N Me2N
2.11b 2.11ba
86
Figure 5.9 1
H NMR Spectrum of Table 2.2, Entry 2 Product 2.11ba in CDCl3. Data are Consistent
with a Commercial Compound.
8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5
f1 (ppm)
-500
0
500
1000
1500
2000
2500
3000
3500
4000
4500
5000
5500
2.03 2.11 1.00 6.09 3.00
1.21
1.23
1.25
1.25
1.26
1.27
1.29
1.30
1.46
1.47
1.49
1.99 H2O
2.05
2.92
2.93
2.93
2.94
2.95
2.95
3.06
3.07
3.11
4.10
4.12
4.14
4.16
4.79
4.80
4.82
4.83
6.69
6.71
6.72
6.72
6.73
6.74
6.75
6.75
7.24
7.25
7.25
7.26 cdcl3
7.26
7.27
7.27
7.28
OH
N
H3C
CH3
87
1-(4-Methoxyphenyl)ethanol 2.11ca:
Inside the glovebox, a 50 mL Schlenk reactor with a conical bottom was charged with 2.11c
(50 mg, 0.33 mmol), 10% KOt
Bu (3.70 mg, 33.3 µmol) and 3 mol% iridium complex 2.1 (6.70
mg, 10.0 µmol). The reactor was sealed, taken out of the glovebox, purged with 1 bar hydrogen
gas and heated to 100 °C for 48 hours. The toluene was removed by a rotary evaporator after the
reaction. After that, the dark yellow mixture was poured over 20 mL brine, and the organic material
was extracted three times by dichloromethane (30 mL), and dried over anhydrous sodium sulfate.
The resulting solution was concentrated by rotary evaporation and purified by auto column
chromatography, eluting with ethyl acetate/ hexanes. Product-containing fractions were identified
and concentrated by rotary evaporation to yield 42.1 mg (83%) of product 2.11ca as light yellow
oil.
1
H NMR (500 MHz, cdcl3) δ 7.29 – 7.24 (m, 2H), 6.88 – 6.83 (m, 2H), 4.81 (q, J = 6.4 Hz, 1H),
3.78 (s, 3H), 1.45 (d, J = 6.4 Hz, 3H).
O
H2 (1 atm)
2.1 (3 mol%)
KOt
Bu (10 mol%)
toluene, 100 °C, 48 h
83%
OH
MeO MeO
2.11c 2.11ca
88
Figure 5.10 1
H NMR Spectrum of Table 2.2, Entry 3 Product 2.11ca in CDCl3. Data are Consistent
with a Commercial Compound.
8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5
f1 (ppm)
-200
0
200
400
600
800
1000
1200
1400
1600
1800
2000
2200
2400
2600
2800
3000
2.05 2.01 1.00 3.05 3.07
1.23
1.24
1.26
1.26
1.44
1.45
1.93
2.02
2.18 H2O
3.76
3.78
3.78
4.07
4.09
4.10
4.12
4.79
4.80
4.82
4.83
6.84
6.85
6.85
6.86
6.87
6.87
7.25
7.25
7.25
7.26 cdcl3
7.26
7.26
7.26
7.27
7.27
7.28
7.28
7.28
7.28
OH
O
H3C
89
4-(1-Hydroxyethyl)phenol 2.11da:
Inside the glovebox, a 50 mL Schlenk reactor with a conical bottom was charged with
2.11d (50 mg, 0.37 mmol), 10% KOt
Bu (4.10 mg, 36.7 µmol) and 3 mol% iridium complex 2.1
(7.40 mg, 11.0 µmol). The reactor was sealed, taken out of the glovebox, purged with 1 bar
hydrogen gas and heated to 100 °C for 48 hours. The toluene was removed by a rotary evaporator
after the reaction. After that, the dark yellow mixture was poured over 20 mL brine, and the organic
material was extracted three times by dichloromethane (30 mL), and dried over anhydrous sodium
sulfate. The resulting solution was concentrated by rotary evaporation and purified by auto column
chromatography, eluting with ethyl acetate/ hexanes. Product-containing fractions were identified
and concentrated by rotary evaporation to yield 48.2 mg (83%) of product 2.11da as light yellow
oil.
1
H NMR (500 MHz, cdcl3) δ 7.10 – 7.04 (m, 2H), 6.84 – 6.78 (m, 2H), 6.15 – 6.09 (q, 1H), 1.23
(m, J = 7.6 Hz, 3H).
O
H2 (1 atm)
2.1 (3 mol%)
KOt
Bu (10 mol%)
toluene, 100 °C, 48 h
95%
OH
HO HO
2.11d 2.11da
90
Figure 5.11 1
H NMR Spectrum of Table 2.2, Entry 4 Product 2.11da in CDCl3. Data are
Consistent with a Commercial Compound.
8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0
f1 (ppm)
-100
0
100
200
300
400
500
600
700
800
900
1000
1100
1200
1300
1400
1500
1600
1700
1800
1900
2000
2100
2200
1.98 2.00 1.00 3.05
1.21
1.23
1.24
1.27
1.29
1.30
1.32
1.33
1.34
2.09
2.10
2.36
2.58
2.59
2.61
2.62
4.15
4.16
4.18
4.19
6.11
6.12
6.12
6.13
6.13
6.79
6.80
6.80
6.81
6.81
6.82
7.06
7.07
7.07
7.07
7.07
7.08
7.08
7.08
7.09
7.26 cdcl3
OH
HO
91
1-(4-Bromophenyl)ethanol 2.11ea:
Inside the glovebox, a 50 mL Schlenk reactor with a conical bottom was charged with 2.11e
(50 mg, 0.25 mmol), 10% KOt
Bu (2.80 mg, 25.1 µmol) and 3 mol% iridium complex 2.1 (5.1 mg,
7.5 µmol). The reactor was sealed, taken out of the glovebox, purged with 1 bar hydrogen gas and
heated to 100 °C for 48 hours. The toluene was removed by a rotary evaporator after the reaction.
After that, the dark yellow mixture was poured over 20 mL brine, and the organic material was
extracted three times by dichloromethane (30 mL), and dried over anhydrous sodium sulfate. The
resulting solution was concentrated by rotary evaporation and purified by auto column
chromatography, eluting with ethyl acetate/ hexanes. Product-containing fractions were identified
and concentrated by rotary evaporation to yield 20.3 mg (40%) of product 2.11ea as light yellow
oil.
1
H NMR (400 MHz, cdcl3) δ 7.53 – 7.46 (m, 2H), 7.28 – 7.22 (m, 2H), 4.86 (q, J = 6.5 Hz, 1H),
1.48 (d, J = 6.5 Hz, 3H).
O
H2 (1 atm)
2.1 (3 mol%)
KOt
Bu (10 mol%)
toluene, 100 °C, 48 h
40%
OH
Br Br
2.11e 2.11ea
92
Figure 5.12 1
H NMR Spectrum of Table 2.2, Entry 5 Product 2.11ea in CDCl3. Data are Consistent
with a Commercial Compound.
8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0
f1 (ppm)
-500
0
500
1000
1500
2000
2500
3000
3500
4000
4500
5000
5500
6000
1.97 2.01 1.00 3.01
1.43
1.45
4.80
4.81
4.83
4.84
7.21
7.21
7.22
7.21
7.22
7.23
7.23
7.26 cdcl3
7.43
7.44
7.45
7.46
7.46
7.47
Br
OH
93
1-(4-Chlorophenyl)ethanol 2.11fa:
Inside the glovebox, a 50 mL Schlenk reactor with a conical bottom was charged with 2.11f
(50 mg, 0.32 mmol), 10% KOt
Bu (3.60 mg, 32.3 µmol) and 3 mol% iridium complex 2.1 (6.6 mg,
9.7 µmol). The reactor was sealed, taken out of the glovebox, purged with 1 bar hydrogen gas and
heated to 100 °C for 48 hours. The toluene was removed by a rotary evaporator after the reaction.
After that, the dark yellow mixture was poured over 20 mL brine, and the organic material was
extracted three times by dichloromethane (30 mL), and dried over anhydrous sodium sulfate. The
resulting solution was concentrated by rotary evaporation and purified by auto column
chromatography, eluting with ethyl acetate/ hexanes. Product-containing fractions were identified
and concentrated by rotary evaporation to yield 21.3 mg (42%) of product 2.11fa as light yellow
oil.
1
H NMR (400 MHz, cdcl3) δ 7.83 – 7.86 (m, 2H), 7.39 – 7.42 (m, 2H), 4.82 (q, J = 6.4 Hz, 1H),
1.41 (d, J = 6.4 Hz, 3H).
O
H2 (1 atm)
2.1 (3 mol%)
KOt
Bu (10 mol%)
toluene, 100 °C, 48 h
42%
OH
Cl Cl
2.11f 2.11fa
94
Figure 5.13 1
H NMR Spectrum of Table 2.2, Entry 6 Product 2.11fa in CDCl3. Data are Consistent
with a Commercial Compound.
13 12 11 10 9 8 7 6 5 4 3 2 1 0 -1
f1 (ppm)
-100
0
100
200
300
400
500
600
700
800
900
1000
1100
1200
1300
2.00 2.00 1.14 3.28
0.09
0.87
1.21
1.23
1.25
1.25
1.26
1.41
1.43
1.94
2.00
2.49
2.53
2.54
2.56
2.69
4.05
4.07
4.09
4.10
4.78
4.80
4.82
4.83
7.23
7.24
7.24
7.25
7.26
7.26 cdcl3
7.27
7.27
7.28
7.28
7.39
7.39
7.40
7.41
7.42
7.42
7.83
7.84
7.84
7.85
7.86
7.86
Cl
OH
95
1-(3,4,5-Trimethoxyphenyl)ethanol 2.12a:
Inside the glovebox, a 50 mL Schlenk reactor with a conical bottom was charged with 2.12
(50 mg, 0.24 mmol), 10% KOt
Bu (2.70 mg, 23.8 µmol) and 3 mol% iridium complex 2.1 (4.8 mg,
7.1 µmol). The reactor was sealed, taken out of the glovebox, purged with 1 bar hydrogen gas and
heated to 100 °C for 48 hours. The toluene was removed by a rotary evaporator after the reaction.
After that, the dark yellow mixture was poured over 20 mL brine, and the organic material was
extracted three times by dichloromethane (30 mL), and dried over anhydrous sodium sulfate. The
resulting solution was concentrated by rotary evaporation and purified by auto column
chromatography, eluting with ethyl acetate/ hexanes. Product-containing fractions were identified
and concentrated by rotary evaporation to yield 39.0 mg (77%) of product 2.12a as light yellow
oil.
1
H NMR (600 MHz, cdcl3) δ 6.58 (t, J = 0.7 Hz, 2H), 4.82 (tdd, J = 6.4, 6.1, 1.1 Hz, 1H), 3.85 (d,
J = 1.0 Hz, 6H), 3.82 (d, J = 0.9 Hz, 3H), 1.47 (dd, J = 6.5, 0.9 Hz, 3H).
O H2 (1 atm)
2.1 (3 mol%)
KOt
Bu (10 mol%)
toluene, 100 °C, 48 h
77%
OH
MeO
MeO
OMe
MeO
MeO
OMe
2.12 2.12a
96
Figure 5.14 1
H NMR Spectrum of Table 2.2, Entry 7 Product 2.12a in CDCl3. Data are Consistent
with a Commercial Compound.
9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0
f1 (ppm)
-200
-100
0
100
200
300
400
500
600
700
800
900
1000
1100
1200
1300
1400
1500
1600
1700
1800
1900
2000
2100
2200
2300
2400
2500
2.00 1.00 6.03 3.02 3.00
1.46
1.47
1.48
1.48
1.75 H2O
3.82
3.85
4.80
4.80
4.80
4.81
4.81
4.81
4.82
4.82
4.82
4.83
4.83
6.58
6.58
6.59
7.26 cdcl3
O
OH
O
O
H3C
CH3 CH3
97
Diphenylmethanol 2.13a:
Inside the glovebox, a 50 mL Schlenk reactor with a conical bottom was charged with 2.13
(50 mg, 0.27 mmol), 10% KOt
Bu (3.10 mg, 27.4 µmol) and 3 mol% iridium complex 2.1 (5.6 mg,
8.2 µmol). The reactor was sealed, taken out of the glovebox, purged with 1 bar hydrogen gas and
heated to 100 °C for 48 hours. The toluene was removed by a rotary evaporator after the reaction.
After that, the dark yellow mixture was poured over 20 mL brine, and the organic material was
extracted three times by dichloromethane (30 mL), and dried over anhydrous sodium sulfate. The
resulting solution was concentrated by rotary evaporation and purified by auto column
chromatography, eluting with ethyl acetate/ hexanes. Product-containing fractions were identified
and concentrated by rotary evaporation to yield 43.0 mg (85%) of product 2.13a as light yellow
oil.
1
H NMR (600 MHz, cdcl3) δ 7.41 – 7.36 (m, 4H), 7.34 (dd, J = 8.5, 6.8 Hz, 4H), 7.30 – 7.26 (m,
2H), 5.86 (s, 1H).
O
H2 (1 atm)
2.1 (3 mol%)
KOt
Bu (10 mol%)
toluene, 100 °C, 48 h
85%
OH
2.13 2.13a
98
Figure 5.15 1
H NMR Spectrum of Table 2.2, Entry 8 Product 2.13a in CDCl3. Data are Consistent
with a Commercial Compound.
10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0
f1 (ppm)
-200
0
200
400
600
800
1000
1200
1400
1600
1800
2000
2200
2400
2600
2800
3000
3200
3400
3600
3800
4.01 4.00 2.08 1.00
5.86
7.26
7.26
7.26 cdcl3
7.27
7.27
7.27
7.28
7.28
7.28
7.33
7.33
7.34
7.34
7.35
7.35
7.36
7.38
7.38
7.38
7.38
7.39
7.39
7.40
OH
99
2,3-diphenylcycloprop-2-en-1-ol 2.14a:
Inside the glovebox, a 50 mL Schlenk reactor with a conical bottom was charged with 2.14
(50 mg, 0.24 mmol), 10% KOt
Bu (2.70 mg, 24.2 µmol) and 3 mol% iridium complex 2.1 (4.9 mg,
7.3 µmol). The reactor was sealed, taken out of the glovebox, purged with 1 bar hydrogen gas and
heated to 100 °C for 48 hours. The toluene was removed by a rotary evaporator after the reaction.
After that, the dark yellow mixture was poured over 20 mL brine, and the organic material was
extracted three times by dichloromethane (30 mL), and dried over anhydrous sodium sulfate. The
resulting solution was concentrated by rotary evaporation and purified by auto column
chromatography, eluting with ethyl acetate/ hexanes. Product-containing fractions were identified
and concentrated by rotary evaporation to yield 44.6 mg (88%) of product 2.14a as light yellow
oil.
1
H NMR (500 MHz, cdcl3) δ 7.69 – 7.64 (m, 4H), 7.50 (t, J = 7.7 Hz, 4H), 7.43 – 7.40 (m, 2H),
3.07 (s, 1H).
O
H2 (1 atm)
2.1 (3 mol%)
KOt
Bu (10 mol%)
toluene, 100 °C, 48 h
88%
OH
2.14 2.14a
100
Figure 5.16 1
H NMR Spectrum of Table 2.2, Entry 9 Product 2.14a in CDCl3. Data are Consistent
with a Known Compound.5
10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0
f1 (ppm)
-50
0
50
100
150
200
250
300
350
400
450
500
550
600
650
700
750
800
850
4.10 4.05 2.03 1.00
1.63 H2O
3.07
7.26 cdcl3
7.39
7.39
7.39
7.41
7.41
7.41
7.42
7.42
7.42
7.43
7.43
7.44
7.44
7.49
7.49
7.51
7.52
7.52
7.65
7.65
7.66
7.66
7.67
7.67
7.67
OH
101
4-(1-Hydroxyethyl)pyridine 2.15a:
Inside the glovebox, a 50 mL Schlenk reactor with a conical bottom was charged with 2.15
(50 mg, 0.41 mmol), 10% KOt
Bu (4.60 mg, 41.3 µmol) and 3 mol% iridium complex 2.1 (8.40
mg, 12.4 µmol). The reactor was sealed, taken out of the glovebox, purged with 1 bar hydrogen
gas and heated to 100 °C for 48 hours. The toluene was removed by a rotary evaporator after the
reaction. After that, the dark yellow mixture was poured over 20 mL brine, and the organic material
was extracted three times by dichloromethane (30 mL), and dried over anhydrous sodium sulfate.
The resulting solution was concentrated by rotary evaporation and purified by auto column
chromatography, eluting with ethyl acetate/ hexanes. Product-containing fractions were identified
and concentrated by rotary evaporation to yield 32.8 mg (64%) of product 2.15a as light yellow
oil.
1
H NMR (400 MHz, cdcl3) δ 8.51 – 8.31 (m, 2H), 7.34 – 7.19 (m, 2H), 4.85 (q, J = 6.5 Hz, 1H),
1.45 (d, J = 6.5 Hz, 3H).
N
O
H2 (1 atm)
2.1 (3 mol%)
KOt
Bu (10 mol%)
toluene, 100 °C, 48 h
64%
N
OH
2.15 2.15a
102
Figure 5.17 1
H NMR Spectrum of Table 2.2, Entry 10 Product 2.15a in CDCl3. Data are Consistent
with a Commercial Compound.
9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5
f1 (ppm)
0
500
1000
1500
2000
2500
3000
3500
4000
2.00 2.09 1.00 3.00
1.19
1.20
1.21
1.21
1.23
1.23
1.43 H2O
1.43
1.45
1.99
3.93
4.04
4.06
4.08
4.10
4.82
4.84
4.85
4.87
7.26
7.26 cdcl3
7.27
7.27
8.40
8.41
8.41
N
OH
103
2-Hexanol 2.16a:
Inside the glovebox, a 50 mL Schlenk reactor with a conical bottom was charged with 2.16
(50 mg, 0.50 mmol), 10% KOt
Bu (5.60 mg, 49.9 µmol) and 3 mol% iridium complex 2.1 (10.1
mg, 15.0 µmol). The reactor was sealed, taken out of the glovebox, purged with 1 bar hydrogen
gas and heated to 100 °C for 48 hours. The toluene was removed by a rotary evaporator after the
reaction. After that, the dark yellow mixture was poured over 20 mL brine, and the organic material
was extracted three times by dichloromethane (30 mL), and dried over anhydrous sodium sulfate.
The resulting solution was concentrated by rotary evaporation and purified by auto column
chromatography, eluting with ethyl acetate/ hexanes. Product-containing fractions were identified
and concentrated by rotary evaporation to yield 17.1 mg (33%) of product 2.16a as light yellow
oil.
1
H NMR (600 MHz, cdcl3) δ 3.83 – 3.74 (m, 1H), 1.47 – 1.28 (m, 6H), 1.18 (d, J = 6.2 Hz, 3H),
0.92 – 0.89 (m, 3H).
O
H2 (1 atm)
2.1 (3 mol%)
KOt
Bu (10 mol%)
toluene, 100 °C, 48 h
33%
OH
2.16 2.16a
104
Figure 5.18 1
H NMR Spectrum of Table 2.2, Entry 11 Product 2.16a in CDCl3. Data are Consistent
with a Commercial Compound.
8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0
f1 (ppm)
-100
0
100
200
300
400
500
600
700
800
900
1000
1100
1200
1300
1400
1500
1600
1700
1800
1900
2000
2100
2200
2300
1.00 6.20 3.09 3.06
0.87
0.89
0.89
0.89
0.90
0.90
0.91
0.91
0.91
1.17
1.17
1.18
1.19
1.22
1.23
1.25
1.25
1.25
1.25
1.26
1.27
1.27
1.28
1.28
1.29
1.29
1.30
1.30
1.30
1.31
1.31
1.31
1.32
1.32
1.32
1.32
1.33
1.33
1.34
1.34
1.34
1.34
1.35
1.35
1.35
1.35
1.36
1.37
1.37
1.37
1.37
1.38
1.38
1.39
1.39
1.39
1.39
1.40
1.40
1.40
1.41
1.41
1.41
1.42
1.42
1.43
1.43
1.44
1.45
1.45
1.45
1.46
1.46
1.46
1.46
1.47
1.47
1.47
1.48
1.98
2.17 H2O
2.33
2.35
3.77
3.78
3.78
3.78
3.79
3.79
3.80
5.29
6.88
6.89
6.96
7.26 cdcl3
OH
105
5-Nonanol 2.17a:
Inside the glovebox, a 50 mL Schlenk reactor with a conical bottom was charged with 2.17
(50 mg, 0.35 mmol), 10% KOt
Bu (3.90 mg, 35.2 µmol) and 3 mol% iridium complex 2.1 (7.10
mg, 10.5 µmol). The reactor was sealed, taken out of the glovebox, purged with 1 bar hydrogen
gas and heated to 100 °C for 48 hours. The toluene was removed by a rotary evaporator after the
reaction. After that, the dark yellow mixture was poured over 20 mL brine, and the organic material
was extracted three times by dichloromethane (30 mL), and dried over anhydrous sodium sulfate.
The resulting solution was concentrated by rotary evaporation and purified by auto column
chromatography, eluting with ethyl acetate/ hexanes. Product-containing fractions were identified
and concentrated by rotary evaporation to yield 10.8 mg (21%) of product 2.17a as light yellow
oil.
1
H NMR (400 MHz, cdcl3) δ 3.56 (h, J = 4.3 Hz, 1H), 1.49 – 1.21 (m, 12H), 0.98 – 0.80 (t, 6H).
O
H2 (1 atm)
2.1 (3 mol%)
KOt
Bu (10 mol%)
toluene, 100 °C, 48 h
21%
OH
2.17 2.17a
106
Figure 5.19 1
H NMR Spectrum of Table 2.2, Entry 12 Product 2.17a in CDCl3. Data are Consistent
with a Commercial Compound.
7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5
f1 (ppm)
-50
0
50
100
150
200
250
300
350
400
450
500
550
600
650
700
1.00 12.13 5.93
0.87
0.88
0.90
0.90
0.91
1.25
1.25
1.27
1.28
1.29
1.30
1.31
1.31
1.32
1.32
1.33
1.34
1.35
1.37
1.38
1.38
1.39
1.40
1.40
1.41
1.42
1.43
1.43
1.44
1.44
1.45
1.45
1.47
1.48
1.52 H2O
3.52
3.54
3.55
3.55
3.57
3.57
3.58
5.27
7.26 cdcl3
OH
3 3
107
Phenylmethanol 2.20a:
Inside the glovebox, a 50 mL Schlenk reactor with a conical bottom was charged with 2.20
(50 mg, 0.47 mmol), 10% KOt
Bu (5.30 mg, 47.1 µmol) and 3 mol% iridium complex 2.1 (9.60
mg, 14.1 µmol). The reactor was sealed, taken out of the glovebox, purged with 1 bar hydrogen
gas and heated to 100 °C for 48 hours. The toluene was removed by a rotary evaporator after the
reaction. After that, the dark yellow mixture was poured over 20 mL brine, and the organic material
was extracted three times by dichloromethane (30 mL), and dried over anhydrous sodium sulfate.
The resulting solution was concentrated by rotary evaporation and purified by auto column
chromatography, eluting with ethyl acetate/ hexanes. Product-containing fractions were identified
and concentrated by rotary evaporation to yield 48.4 mg (95%) of product 2.20a as light yellow
oil.
1
H NMR (400 MHz, cdcl3) δ 7.50 – 7.04 (m, 5H), 4.52 (s, 2H).
H2 (1 atm)
2.1 (3 mol%)
KOt
Bu (10 mol%)
toluene, 100 °C, 48 h
2.20 95% 2.20a
O OH
108
Figure 5.20 1
H NMR Spectrum of Table 2.2, Entry 16 Product 2.20a in CDCl3. Data are Consistent
with a Commercial Compound.
9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0
f1 (ppm)
-200
-100
0
100
200
300
400
500
600
700
800
900
1000
1100
1200
1300
1400
1500
1600
1700
1800
1900
2000
2100
2200
2300
5.05 2.00
1.17
1.19
1.21
1.73
1.94
1.94
3.45
4.01
4.03
4.04
4.06
4.52
7.19
7.19
7.20
7.21
7.21
7.21
7.22
7.22
7.23
7.24
7.25
7.26 cdcl3
7.27
7.27
7.28
7.28
7.29
7.29
7.30
OH
109
4-(Hydroxymethyl)phenol 2.21a:
Inside the glovebox, a 50 mL Schlenk reactor with a conical bottom was charged with 2.21
(50 mg, 0.41 mmol), 10% KOt
Bu (4.60 mg, 40.9 µmol) and 3 mol% iridium complex 2.1 (8.30
mg, 12.3 µmol). The reactor was sealed, taken out of the glovebox, purged with 1 bar hydrogen
gas and heated to 100 °C for 48 hours. The toluene was removed by a rotary evaporator after the
reaction. After that, the dark yellow mixture was poured over 20 mL brine, and the organic material
was extracted three times by dichloromethane (30 mL), and dried over anhydrous sodium sulfate.
The resulting solution was concentrated by rotary evaporation and purified by auto column
chromatography, eluting with ethyl acetate/ hexanes. Product-containing fractions were identified
and concentrated by rotary evaporation to yield 49.2 mg (95%) of product 2.21a as light yellow
oil.
1
H NMR (400 MHz, d2o) δ 7.30 (dd, J = 8.5, 2.3 Hz, 2H), 7.00 – 6.83 (m, 2H), 4.55 (d, J = 2.2
Hz, 2H).
H2 (1 atm)
2.1 (3 mol%)
KOt
Bu (10 mol%)
toluene, 100 °C, 48 h
2.21 95% 2.21a
O OH
HO HO
110
Figure 5.21 1
H NMR Spectrum of Table 2.2, Entry 17 Product 2.21a in D2O. Data are Consistent
with a Commercial Compound.
10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5
f1 (ppm)
-100
0
100
200
300
400
500
600
700
800
900
1000
1100
1200
1300
1400
1500
1600
1700
1800
1900
2000
2.06 1.93 2.00
4.55
4.56
4.79 d2o
6.90
6.91
6.92
6.92
6.93
7.10
7.29
7.29
7.31
7.32
OH
HO
111
(1-Methyl-1H-pyrrol-2-yl)methanol 2.22a:
Inside the glovebox, a 50 mL Schlenk reactor with a conical bottom was charged with 2.22
(50 mg, 0.46 mmol), 10% KOt
Bu (5.10 mg, 45.8 µmol) and 3 mol% iridium complex 2.1 (9.30
mg, 13.7 µmol). The reactor was sealed, taken out of the glovebox, purged with 1 bar hydrogen
gas and heated to 100 °C for 48 hours. The toluene was removed by a rotary evaporator after the
reaction. After that, the dark yellow mixture was poured over 20 mL brine, and the organic material
was extracted three times by dichloromethane (30 mL), and dried over anhydrous sodium sulfate.
The resulting solution was concentrated by rotary evaporation and purified by auto column
chromatography, eluting with ethyl acetate/ hexanes. Product-containing fractions were identified
and concentrated by rotary evaporation to yield 22.0 mg (43%) of product 2.22a as light yellow
oil.
1
H NMR (600 MHz, cdcl3) δ 6.67 – 6.61 (m, 1H), 6.11 (dd, J = 3.6, 1.8 Hz, 1H), 6.05 (dd, J = 3.5,
2.7 Hz, 1H), 4.59 (s, 2H), 3.69 (s, 3H).
H2 (1 atm)
2.1 (3 mol%)
KOt
Bu (10 mol%)
toluene, 100 °C, 48 h
43%
O
N
OH
N
2.22 2.22a
112
Figure 5.22 1
H NMR Spectrum of Table 2.2, Entry 18 Product 2.22a in CDCl3. Data are Consistent
with a Commercial Compound.
9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0
f1 (ppm)
-100
0
100
200
300
400
500
600
700
800
900
1000
1100
1200
1.09 1.00 0.98 2.05 3.00
1.50 H2O
1.68
2.36
2.71
3.00
3.63
3.69
3.69
3.72
3.93
3.95
3.95
3.95
3.95
3.95
3.95
3.95
3.95
3.96
3.97
3.97
3.97
3.97
3.97
3.97
3.97
3.98
3.98
3.98
3.98
4.53
4.59
5.30
5.30
6.05
6.05
6.05
6.05
6.06
6.06
6.10
6.11
6.11
6.11
6.21
6.21
6.21
6.22
6.22
6.22
6.22
6.22
6.23
6.62
6.63
6.64
6.64
6.88
6.88
6.88
6.91
6.91
6.91
6.92
6.92
6.92
6.92
6.92
7.15
7.16
7.16
7.17
7.17
7.17
7.17
7.17
7.17
7.18
7.18
7.18
7.19
7.19
7.24
7.24
7.25
7.26
7.26 cdcl3
7.26
7.27
7.27
N
OH
113
1-Pentanol 2.23a:
Inside the glovebox, a 50 mL Schlenk reactor with a conical bottom was charged with 2.23
(50 mg, 0.58 mmol), 10% KOt
Bu (6.50 mg, 58.1 µmol) and 3 mol% iridium complex 2.1 (9.30
mg, 17.4 µmol). The reactor was sealed, taken out of the glovebox, purged with 1 bar hydrogen
gas and heated to 100 °C for 48 hours. The toluene was removed by a rotary evaporator after the
reaction. After that, the dark yellow mixture was poured over 20 mL brine, and the organic material
was extracted three times by dichloromethane (30 mL), and dried over anhydrous sodium sulfate.
The resulting solution was concentrated by rotary evaporation and purified by auto column
chromatography, eluting with ethyl acetate/ hexanes. Product-containing fractions were identified
and concentrated by rotary evaporation to yield 41.1 mg (43%) of product 2.23a as light yellow
oil.
1
H NMR (600 MHz, cd3od) δ 3.54 (t, J = 6.7 Hz, 2H), 1.58 – 1.49 (m, 2H), 1.40 – 1.30 (m, 4H),
0.96 – 0.89 (m, 3H).
O
H2 (1 atm)
2.6 (3 mol%)
KOt
Bu (10 mol%)
toluene, 100 °C, 48 h
80%
OH
2.23 2.23a
114
Figure 5.23 1
H NMR Spectrum of Table 2.2, Entry 19 Product 2.23a in CD3OD. Data are
Consistent with a Commercial Compound.
7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0
f1 (ppm)
-200
0
200
400
600
800
1000
1200
1400
1600
1800
2000
2200
2400
2600
2800
3000
3200
3400
3600
3800
4000
4200
2.00 2.02 4.01 3.00
0.91
0.91
0.92
0.92
0.92
0.93
0.93
0.93
0.93
0.94
0.94
0.94
0.95
1.31
1.32
1.32
1.32
1.33
1.33
1.33
1.33
1.34
1.34
1.34
1.34
1.34
1.35
1.35
1.35
1.36
1.36
1.36
1.36
1.37
1.38
1.39
1.39
1.51
1.52
1.52
1.53
1.53
1.53
1.53
1.54
1.54
1.54
1.55
1.55
1.55
1.55
1.56
1.56
3.31 cd3od
3.31 cd3od
3.31 cd3od
3.53
3.54
3.55
4.86 HDO
5.19
OH
115
Catalyst Initiation
Scheme 5.1 Initiation of Catalyst 2.1.
In a glovebox, iridium compound 2.1 (20 mg, 0.030 mmol) and KOt
Bu (11 mg, 3.3 eq) are
added to a J. Young tube. Dichloromethane-d2 (1.0 mL) solvent is added to dissolve the solid
mixture. The J. Young tube is then gently evacuated, refilled with 1 atm H2 and placed at room
temperature for 10 min. 1
H NMR shows a kind of Ir-dihydride (compound 2.5) formed after 1
minute (Figure 5.22). Data are consistent with a known compound.1 CCDC# 2142636 contains
supplementary crystallographic data for 2.5.
1
H NMR (600 MHz, cd2cl2) δ 8.94 – 8.90 (m, 1H), 8.22 (d, J = 1.4 Hz, 1H), 8.11 (td, J = 7.8, 1.6
Hz, 1H), 8.03 (d, J = 2.0 Hz, 1H), 7.40 (td, J = 7.4, 5.5, 1.5 Hz, 1H), 7.12 (d, J = 2.0 Hz, 1H), 7.03
(s, 2H), 5.89 (d, J = 15.5 Hz, 1H), 5.28 (d, J = 15.5 Hz, 1H), 2.35 (s, 3H), 1.97 (s, 3H), 1.89 (s,
3H), -8.00 (d, J = 3.8 Hz, 1H), -17.94 (dd, J = 3.9, 1.3 Hz, 1H).
13C NMR (151 MHz, cd3cn) δ 180.10 (CO), 169.06 (carbene C), 165.31 (CO), 154.00 (py), 150.84
(py), 139.94 (py), 136.41 (mesityl), 129.70 (py), 129.54 (mesityl), 125.56 (mesityl), 125.16 (py),
124.85 (mesityl), 123.61 (Im), 123.06 (Im), 55.68 (py-CH2), 21.14 (mesityl-CH3), 18.55 (mesitylCH3).
MS (MALDI) calc’d for [C20H21IrN3O2]
+ 528.1, found 527.9.
Ir
N
N
N CO
CO
Ir
N
N
N H
CO
Mes
CO
H
H
Mes
2.1 2.5
H
H2 (1 atm)
KOt
Bu
116
Figure 5.24 1
H NMR Spectrum of Compound 2.5 in CD2Cl2.
Figure 5.25 13
C NMR Spectrum of Compound 2.7 in CD3CN.
14 13 12 11 10 9 8 7 6 5 4 3 2 1 0 -1 -2 -3 -4 -5 -6 -7 -8 -9 -10 -11 -12 -13 -14 -15 -16 -17 -18 -19 -20 -21 -22 -23 -24
f1 (ppm)
0
100
200
300
400
500
600
700
800
900
1000
1.00
1.00
3.17
3.12
3.16
1.12
1.18
2.02
1.13
1.43
1.12
1.24
1.06
1.11
190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0
f1 (ppm)
-5
0
5
10
15
20
25
30
35
40
45
50
55
60
65
70
75
80
85
0.84
0.91
1.04
1.18 cd3cn
1.32 cd3cn
1.46 cd3cn
1.60
1.73
17.47
18.41
18.55
18.67
21.14
21.17
28.65
55.25
56.45
118.30
121.71
121.84
123.06
123.59
124.17
124.85
125.16
125.55
129.54
129.70
129.94
130.29
130.44
136.31
136.41
136.93
139.94
141.10
150.84
154.00
154.73
117
Scheme 5.2 Initiation of Catalyst 2.6.
In a glovebox, iridium compound 2.6 (20 mg, 0.038 mmol) and NaOH (4.6 mg, 3.3 eq) are
added to a J. Young tube. Acetonitrile-d3 (1.0 mL) solvent is added to dissolve the solid mixture.
J. Young tube is then gently evacuated, refilled with 1 atm H2 and placed at room temperature for
60 min. 1
H NMR shows three Ir-H signals (Figure 5.26).
1
H NMR (400 MHz, cd3cn) δ 9.12 (d, J = 5.7 Hz, 1H), 8.07 (td, J = 8.2, 1.8 Hz, 1H), 7.54 (d, J =
2.0 Hz, 1H), 7.38 (td, J = 7.4, 5.5, 1.5 Hz, 1H), 7.21 (d, J = 1.8 Hz, 1H), 6.92 (s, 2H), 6.83 (d, J =
1.4 Hz, 1H), 5.32 (s, 2H), 2.29 (s, 3H), 2.08 (s, 6H), -7.10 (d, J = 4.1 Hz, 1H), -18.28 (d, J = 3.8
Hz, 1H), -19.95 (d, J = 4.2 Hz, 1H).
Further spectra were not collected as this is a transient species.
Ir
N
N
N Cl
CO
Ir
N
N
N H
H
Mes
CO
H
H
Mes
2.6 2.7
H
H2 (1 atm)
NaOH
118
Figure 5.26 1
H NMR Spectrum of Ir-H Species in CD2Cl2.
13 12 11 10 9 8 7 6 5 4 3 2 1 0 -1 -2 -3 -4 -5 -6 -7 -8 -9 -10 -11 -12 -13 -14 -15 -16 -17 -18 -19 -20 -21 -22 -23
f1 (ppm)
0
10
20
30
40
50
60
70
80
90
100
0.89
0.57
1.00
6.45
2.97
2.04
0.93
2.11
0.86
1.06
1.11
1.06
1.30
119
Reaction Orders of Ketones Hydrogenation
Kinetic Dependence on Ketone Concentration
In a glovebox, four different amounts of acetone (0.0100 mL, 0.135 mmol, or 0.0200 mL,
0.270 mmol, or 0.0300 mL, 0.405 mmol, or 0.0400 mL, 0.540 mmol), iridium compound 2.1 (6
mg, 0.009 mmol) and KOt
Bu (3.37 mg, 0.0300 mmol) are added to a J. Young tube. Toluene-d8
(1.0 mL) is added to dissolve the solid mixture. The J. Young tube is then gently evacuated, refilled
with 1 atm H2. The NMR tube is heated to 100 °C for a kinetic run. Rate constant of each kinetic
run is calculated based on the consumption of the acetone substrate. Rate constants are calculated
to be 5.0(1) × 10-6 s
-1
, 5.1(2) × 10-6 s
-1
, 4.2(9) × 10-6 s
-1
, 4.8(5) × 10-6 s
-1 (Figure 5.27). A log-log
plot (Figure 5.28) gives us a slop of 0.94(5), indicating the reaction is first order on the ketone
substrate.
120
Figure 5.27 Kinetic Profile of Hydrogenation of Four Different Amounts of Acetone.
121
Figure 5.28 Kinetic Dependence of Acetone.
y = 0.9424x - 15.403
-17.4
-17.2
-17
-16.8
-16.6
-16.4
-16.2
-16
-15.8
-2.5 -2 -1.5 -1 -0.5 0 ln(-d[A]0/dt)
ln([A]0)
Substrate Reaction Order
122
Kinetic Dependence on Base Concentration
In a glovebox, four different amounts of KOt
Bu (1.50 mg, 0.0134 mmol, or 3.00 mg, 0.0267
mmol, or 4.50 mg, 0.0401 mmol, or 6.00 mg, 0.0534 mmol), iridium compound 2.1 (5.4 mg,
0.0080 mmol) and acetone (0.020 mL, 0.27 mmol) are added to a J. Young tube. Toluene-d8 (1.0
mL) is added to dissolve the solid mixture. The J. Young tube is then gently evacuated, refilled
with 1 atm H2. The NMR tube is heated to 100 °C for a kinetic run. Rate constant of each kinetic
run is calculated based on the consumption of the acetone substrate. Rate constants are calculated
to be 5.0(1) × 10-6 s
-1
, 5.3(3) × 10-6 s
-1
, 5.0(1) × 10-6 s
-1
, 5.0(1) × 10-6 s
-1 (figure 5.29). A log-log
plot (Figure 5.30) gives us a slop of 0.76(12), indicating the reaction is first order on the base
KOt
Bu.
123
Figure 5.29 Kinetic Profile of Hydrogenation of Acetone using Four Different Amounts of Base.
124
Figure 5.30 Kinetic Dependence of Base.
y = 0.7599x - 12.96
-16.4
-16.2
-16
-15.8
-15.6
-15.4
-15.2
-15
-4.5 -4 -3.5 -3 -2.5 ln(-d[A]0/dt)
ln([base]0)
Base Reaction Order
125
Kinetic dependence on catalyst concentration
In a glovebox, four different amounts of iridium compound 2.1 (0.930 mg, 0.00138 mmol,
or 4.65 mg, 0.00690 mmol, or 9.32 mg, 0.0138 mmol, or 18.7 mg, 0.0276 mmol), KOt
Bu (10.3
mg, 0.0920 mmol) and acetone (0.0200 mL, 0.276 mmol) are added to a J. Young tube. Toluened8 (1.0 mL) is added to dissolve the solid mixture. The J. Young tube is then gently evacuated,
refilled with 1 atm H2. The NMR tube is heated to 100 °C for a kinetic run. Rate constant of each
kinetic run is calculated based on the consumption of the acetone substrate. Rate constants are
calculated to be 5.1(2) × 10-6 s
-1
, 5.2(3) × 10-6 s
-1
, 5.0(2) × 10-6 s
-1
, 5.3(3) × 10-6 s
-1 (Figure 5.31).
A log-log plot (Figure 5.32) gives us a slop of 0.88(4), indicating the reaction is first order on the
iridium compound 2.1.
126
Figure 5.31 Kinetic Profile of Hydrogenation of Acetone using Four Different Amounts of
Catalyst 2.1.
127
Figure 5.32 Kinetic Dependence of Catalyst 2.1.
y = 0.8806x - 10.149
-16.5
-16
-15.5
-15
-14.5
-14
-13.5
-13
-12.5
-7 -6.5 -6 -5.5 -5 -4.5 -4 -3.5 -3 ln(-d[A]0/dt)
ln([C]0)
Catalyst Reaction Order
128
KIE Study
In a glovebox, benzophenone (16.0 mg, 0.0878 mmol), iridium catalyst 2.1 (1.78 mg,
0.00263 mmol, 3 mol%) and KOt
Bu (0.990 mg, 0.00878 mmol) are added to a J. Young tube.
Toluene-d8 (1.0 mL) is added to dissolve the solid mixture. The J. Young tube is then gently
evacuated, refilled with 1 atm H2 or D2 and heated to 100 °C for a kinetic study. Rate constant of
each kinetic run is calculated based on the consumption of the benzophenone substrate (Figure
5.33). For the H2 experiment, a rate constant of 5.3(3) × 10-6 s
-1 could be obtained, while for the
D2 run, we observed a rate constant of 5.6(4) × 10-6 s
-1
. This gives us a KIEH2/D2 = 1.06(11).
Figure 5.33 KIE Study of Benzophenone Hydrogenation by Catalyst 2.1.
235
240
245
250
255
260
265
270
275
280
0 1000 2000 3000 4000 5000 6000
Conc. (µmol/mL)
time (min)
KIE Study
H2
D2
129
Hammett Analysis
In four parallel runs, 0.06 mmol substrate (acetophenone, 4'-methoxyacetophenone, 4'-
chloroacetophenone, 4'-bromoacetophenone, 4'-nitroacetophenone), iridium catalyst 2.1 (1.2 mg,
1.8 × 10-3 mmol) and KOt
Bu (0.67 mg, 6.0 × 10-3 mmol) are added to a J. Young tube. 1.0 mL
toluene-d8 is added to dissolve the solid mixture. The J. Young tube is then gently evacuated,
refilled with 1 atm H2. The NMR tube is heated to 100 °C for a kinetic run. The Hammett plot
(Figure 5.34) gives us the reaction constant ρ = -0.93.
Figure 5.34 Hammett Plot of Hydrogenation of a Series of para-Substituted Acetophenones with
Different Hydride Affinities.
-NO2
-Br -Cl
H
-OMe
y = -0.9306x + 0.0283
R² = 0.98178
-0.9
-0.8
-0.7
-0.6
-0.5
-0.4
-0.3
-0.2
-0.1
0
0.1
0.2
0.3
0.4
-0.4 -0.2 0 0.2 0.4 0.6 0.8 1 log(kR/kH)
!
130
Eyring Plot
In a glovebox, benzophenone (16.0 mg, 0.0878 mmol), iridium catalyst 1 (1.8 mg, 0.0026
mmol) and KOt
Bu (0.99 mg, 0.0088 mmol) are added to a J. Young tube. 1.0 mL toluene-d8 is
added to dissolve the solid mixture. The J. Young tube is then gently evacuated, refilled with 1
atm H2. The tubes are heated to four temperatures (60 °C, 70 °C, 75 °C, 90 °C) for kinetic runs.
Rate constant of each kinetic run is calculated based on the consumption of the acetone substrate.
Eyring plot (figure 5.35) gives us the ∆H‡ = +9.5(7) kcal mol-1 and ∆S‡ = -42.8(3) cal mol-1 K-1
.
Figure 5.35 Eyring Plot of Benzophenone Hydrogenation by Catalyst 2.1.
y = -9.4577x - 42.794
R² = 0.99893
-72
-71.5
-71
-70.5
-70
-69.5
-69
-68.5
2.7 2.75 2.8 2.85 2.9 2.95 3 3.05
Rln(k/T) - Rln(kB/h)
1000/T (K-1)
131
Proton Shuttle
In a glovebox, iridium compound 2.1 (2.6 mg, 0.0039 mmol), KOt
Bu (1.4 mg, 0.013 mmol),
4'-dimethylaminoacetophenone (21.0 mg, 0.129 mmol) and isopropanol (0.010 mL, 0.13 mmol,
1.0 eq to ketone substrate or 0 mL) are added to a J. Young tube. Toluene-d8 (1.0 mL) is added to
dissolve the solid mixture. The J. Young tube is then gently evacuated, refilled with 1 atm H2. The
NMR tube is heated to 100 °C for a kinetic run. Rate constants of are calculated based on the
consumption of the ketone substrate. Rate constants are calculated to be 3.9(1) × 10-6 s
-1 and 2.4(6)
× 10-6 s
-1 (Figure 5.36). This gives us a ratio of these two different reaction rates kROH/kno ROH =
1.625.
Figure 5.36 Kinetic Profile of Hydrogenation of 4'-Dimethylaminoacetophenone with or without
Alcohol.
132
5.3 Experimental and Spectral Data: Formic Acid Dehydrogenation
5.3.1 Theoretical Yield & Reaction Rate Calculations
Based on the Ideal gas law equation and assuming 100% FA conversion from 3.00 mL
(79.5 mmol) of FA, we would yield:
Ambient Pressure:
nevolved gases = 159 mmol
P = 1 atm
R = 0.08206 L·atm·K-1
·mol-1
T = 25 °C + 273 = 298 K
V = (n • R • T) / P = 3.89 L
FA conversion % = (Vevolved gas / 3.89) * 100 %
Self-Pressurized Conditions:
nevolved gases = 0.159 mol
R = 0.08206 L·atm·K-1
·mol-1
T = 110°C + 273.15 = 383.15 K
V = 0.125 L
P = (n • R • T) / V = 39.99 atm = 40.5 bar
FA conversion % = (Pevolved gas /38 bar) * 100 %
All volumetric rate data is always expressed in normal liters per hour, (L/hour)
standardized to 0 °C and 1 atm. An example calculation of a volumetric rate from pressure is
shown below:
P1 = 990 psi; T1 = 118 °C
P2 = 1005 psi; T2 = 120 °C
V = 600 mL
Δt = 8 s
Δn = [P2 / (273.15 K + T2) - P1 / (273.15 K + T1)] / 14.7 • V / 1000 / R
Rate (L/hour) = Δn • R • 273.15 K / 1 atm / (Δt / 3600) = 126.8 L/hour
133
5.3.2 Catalysts Kinetic Profile under Ambient Pressure
Figure 5.37 Gas Evolution of Formic Acid Dehydrogenation by Complexes 3.1-3.21 at Ambient
Pressure over Time (0 - 25 hours). Complex 3.1 – lavender crosses; complex 3.1 w/ tBuOK –
purple squares; complex 3.2 – orange asterisks; complex 3.2 w/tBuOK – grey circles; complex 3.3
– yellow plusses; complex 3.4 – blue squares; complex 3.4 w/ tBuOK – peach squares; complex
3.5 – green triangles; complex 3.6 – cream crosses; complex 3.7 – red asterisks; complex 3.8 – red
circles; complex 3.9-CO – blue plusses; complex 3.10 – orange hyphens; complex 3.11 – black
triangles; complex 3.12 – navy diamonds; complex 3.13 – grey hyphens; complex 3.14 – yellow
crosses; complex 3.15 – blue asterisks; complex 3.16 – lavender diamonds; complex 3.17 – pink
squares; complex 3.18 – green hyphens; complex 3.19 – grey triangles; complex 3.20 –green
circles; complex 3.21 – yellow diamonds.
134
5.4 Experimental and Spectral Data: Alcohol-Amine Coupling
Organometallic Compounds 4.1
[(2-((3-Mesityl-imidazol-1-yl)methyl)pyridine)Ru(h6
-cymene)Cl]OTf, 4.1:
In the glovebox under nitrogen, in a 100 mL in a Schlenk flask, dichloro-di(1-(2,4,6-
trimethylphenyl)-3-(2-picolyl)-imidazol-2-ylidene)-disilver(I)4 ([Ag]3, 125 mg, 0.150 mmol) was
added in small portions to a stirring solution of dichloro(p-cymene)ruthenium(II) dimer (91.9 mg,
0.150 mmol) in 20 mL dry dichloromethane. After 1 hour, sodium trifluoromethanesulfonate (51.6
mg, 0.300 mmol) was also added to the mixture. After stirring for 30 minutes, the solution was
filtered through a dry pad of celite to remove the sodium chloride byproduct. The solvent was
evaporated under reduced pressure to yield a yellow glassy solid. This red solid was dissolved in
5 mL dry dichloromethane, and 20 mL dry hexanes was added to the solution to facilitate a
precipitation. A deep yellow crystalline solid was acquired and dried under vacuum (182 mg, 87%).
This sample was later determined to be spectroscopically pure under NMR.
1
H NMR (600 MHz, cd2cl2) δ 9.33 (dd, J = 5.9, 1.5 Hz, 1H), 7.91 (td, J = 7.7, 1.7 Hz, 1H), 7.76
(d, J = 7.7 Hz, 1H), 7.72 (d, J = 2.0 Hz, 1H), 7.38 (t, J = 7.0 Hz, 1H), 7.08 (s, 1H), 6.99 (d, J = 1.9
Hz, 1H), 6.98 (s, 1H), 5.70 (d, J = 15.8 Hz, 1H), 5.63 (t, J = 6.0 Hz, 2H), 5.27 (t, J = 5.6 Hz, 2H),
5.10 (d, J = 15.7 Hz, 1H), 2.35 (s, 3H), 2.30 (p, J = 6.9 Hz, 1H), 2.24 (s, 3H), 2.01 (s, 3H), 1.68 (s,
3H), 1.14 (d, J = 6.9 Hz, 3H), 0.61 (d, J = 6.9 Hz, 3H).
13C NMR (151 MHz, cd2cl2) δ 175.24 (carbene C), 159.39 (py), 156.55 (py), 140.15 (cymene-ar),
139.99 (py), 138.64 (mesityl-ar), 135.86 (cymene-ar), 135.59 (mesityl-ar), 130.12 (mesityl-ar),
128.63 (mesityl-ar), 125.74 (mesityl-ar), 125.56 (py), 124.88 (Im), 124.28 (py), 122.50 (Im),
120.37 (mesityl-ar), 90.28 (cymene-ar), 89.11(cymene-ar), 87.83 (cymene-ar), 84.27 (cymene-ar),
55.24 (CH2), 31.73 (cymene-CH), 23.97 (cymene-CH3), 21.10 (mesityl-CH3), 20.35 (mesityl-CH3),
19.71 (cymene-CH3), 18.56 (cymene-CH3), 18.51 (mesityl-CH3).
19F NMR (564 MHz, cd2cl2) δ: -78.87.
IR (thin film/cm-1) ν 3055, 2992, 2939, 1558, 1505, 1435, 1416, 1374, 1263, 1159,1031, 917, 734,
702, 638.
MS (MALDI) for C29H34ClN3Ru calc’d 549.164 g/mol; found m/z = 548.511 [M]+
.
Ru
Cl
N
N
N
Mes
4.1
OTf
N
N Ag
Mes
Cl
Cl Ag
N
N
Mes
[(cymene)RuCl2]2
DCM
87%
[Ag]3
N
N
135
Figure 5.38 1
H NMR Spectrum of Compound 4.1 in CD2Cl2.
Figure 5.39 13
C NMR Spectrum of Compound 4.1 in CD2Cl2.
13 12 11 10 9 8 7 6 5 4 3 2 1 0 -1
f1 (ppm)
-500
0
500
1000
1500
2000
2500
3000
3500
4000
4500
5000
5500
6000
3.00
3.05
3.02
3.01
3.00
1.06
3.04
1.00
2.01
2.02
1.00
0.96
0.97
1.02
0.99
0.99
1.00
1.00
1.00
0.60
0.62
1.11
1.13
1.14
1.68
2.01
2.24
2.27
2.29
2.30
2.31
2.32
2.33
2.35
5.08
5.11
5.26
5.27
5.28
5.62
5.63
5.64
5.69
5.72
6.98
6.99
6.99
7.08
7.37
7.37
7.38
7.39
7.72
7.72
7.75
7.76
7.90
7.90
7.91
7.91
7.92
7.92
9.33
9.33
9.34
9.34
230 220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10
f1 (ppm)
-100
0
100
200
300
400
500
600
700
800
900
1000
1100
18
1200 .51
18.56
19.71
20.35
21.10
23.05
23.97
31.73
53.48 cd2cl2
53.66 cd2cl2
53.84 cd2cl2
54.02 cd2cl2
54.20 cd2cl2
55.24
84.27
87.83
89.11
90.28
120.37
122.50
124.28
124.88
125.56
125.74
128.63
130.12
135.59
135.86
138.64
139.99
140.15
156.55
159.39
175.24
136
Figure 5.40 19
F NMR Spectrum of Compound 4.1 in CD2Cl2.
Figure 5.41 MALDI-MS Spectrum of Compound 4.1.
137
Reaction Orders of Amine-Alcohol Coupling Catalyzed by Ruthenium Complex 4.1
Kinetic Dependence on Benzyl Alcohol Concentration
In a glovebox, four different amounts of benzyl alcohol (0.0120 mL, 0.114 mmol; 0.0240
mL, 0.228 mmol; 0.0350 mL, 0.342 mmol; 0.0470 mL, 0.456 mmol), hexylamine (0.010 mL,
0.076 mmol), ruthenium complex 4.1 (1.6 mg, 0.0020 mmol) and KOH (0.43 mg, 0.0076 mmol)
are added to a J. Young tube. Toluene-d8 (1.0 mL) is added to dissolve the solid mixture. The
NMR tube is heated to 100 °C for a kinetic run. The rate constant of each kinetic run is calculated
based on the consumption of the amine substrate. Rate constants are calculated to be 6.4(1) × 10-5
s
-1
, 6.7(2) × 10-5 s
-1
, 5.9(9) × 10-5 s
-1
, 6.4(3) × 10-5 s
-1
. A log-log plot (Figure 5.42) gives us a slop
of 0.99(4), indicating the reaction is first order on the alcohol substrate.
Figure 5.42 Kinetic Dependence of Benzyl Alcohol.
y = 0.9918x - 12.56
-15
-14.8
-14.6
-14.4
-14.2
-14
-13.8
-13.6
-13.4
-13.2
-2.5 -2 -1.5 -1 -0.5 0 ln(-d[A]0/dt)
ln([A]0)
Alcohol Reaction Order
138
Kinetic Dependence on Hexylamine Concentration
In a glovebox, four different amounts of benzyl alcohol (0.0480 mL, 0.456 mmol),
hexylamine (0.010 mL, 0.076 mmol; 0.0200 mL, 0.152 mmol; 0.0300 mL, 0.228 mmol; 0.0400
mL, 0.304 mmol), ruthenium compound 4.1 (6.3 mg, 0.0090 mmol) and KOH (1.70 mg, 0.0304
mmol) are added to a J. Young tube. Toluene-d8 (1.0 mL) is added to dissolve the solid mixture.
The NMR tube is heated to 100 °C for a kinetic run. Rate constant of each kinetic run is calculated
based on the consumption of the amine substrate. Rate constants are calculated to be 6.3(3) × 10-5
s
-1
, 6.4(3) × 10-5 s
-1
, 6.8(1) × 10-5 s
-1
, 6.5(1) × 10-5 s
-1
. A log-log plot (Figure 5.43) gives us a slop
of 1.09(5), indicating the reaction is first order on the alcohol substrate.
Figure 5.43 Kinetic Dependence of Hexylamine.
y = 1.0479x - 12.037
-15
-14.8
-14.6
-14.4
-14.2
-14
-13.8
-13.6
-13.4
-13.2
-3 -2.5 -2 -1.5 -1 -0.5 0 ln(-d[A]0/dt)
ln([A]0)
Amine Reaction Order
139
Kinetic dependence on catalyst concentration
In a glovebox, benzyl alcohol (0.0120 mL, 0.114 mmol), hexylamine (0.010 mL, 0.076
mmol), four different amounts of ruthenium compound 4.1 (0.80 mg, 0.0010 mmol; 1.6 mg, 0.0020
mmol; 2.4 mg, 0.0030 mmol; 3.2 mg, 0.0040 mmol) and KOH (0.43 mg, 0.0076 mmol) are added
to a J. Young tube. Toluene-d8 (1.0 mL) is added to dissolve the solid mixture. The NMR tube is
heated to 100 °C for a kinetic run. Rate constant of each kinetic run is calculated based on the
consumption of the amine substrate and rate constants are calculated to be 6.4(1) × 10-5 s
-1
, 6.7(2)
× 10-5 s
-1
, 7.3(2) × 10-5 s
-1
, 8.1(1) × 10-5 s
-1
. A log-log plot (Figure 5.44) gives us a slop of 0.947(2),
indicating the reaction is first order on the ruthenium compound 4.1.
Figure 5.44 Kinetic Dependence of Benzyl Alcohol.
y = 0.9472x - 7.2008
-13.5
-13
-12.5
-12
-11.5
-11
-10.5
-7 -6.5 -6 -5.5 -5 -4.5 -4 -3.5 -3 ln(-d[A]0/dt)
ln([C]0)
Catalyst Reaction Order
140
Spectral Data: Alcohol-Amine Coupling
All compounds formed in Table 4.5 are known compounds, and most are commercially available.
N-Benzylbenzenesulfonamide 4.33aa:
Inside the glovebox, a 5 mL Schlenk reactor with a conical bottom was charged with 4.3
(50 mg, 0.32 mmol), benzyl alcohol 4.3a (51.6 mg, 0.48 mmol), 0.03 equivalents KOH (0.53 mg,
9.6 µmol) and 1 mol% ruthenium complex 4.1 (2.2 mg, 3.2 µmol). The reactor was sealed, taken
out of the glovebox, and was heated to 100 °C for 12 hours. After that, the dark brown mixture
was poured over 20 mL brine, and the organic material was extracted three times by
dichloromethane (30 mL), and dried over anhydrous sodium sulfate. The resulting solution was
concentrated by rotary evaporation and purified by auto column chromatography, eluting with
ethyl acetate (1 wt% triethylamine)/ hexanes (1 wt% triethylamine). Product-containing fractions
were identified and concentrated by rotary evaporation to yield 65 mg (82%) of product 4.3aa as
light yellow oil.
1
H NMR (400 MHz, cdcl3) δ 7.70 (dt, J = 6.9, 2.8 Hz, 2H), 7.33 (tt, J = 4.6, 1.9 Hz, 3H), 7.26 (t,
J = 3.8 Hz, 4H), 7.18 (t, J = 4.2 Hz, 1H), 4.74 (s, 2H). Data are consistent with a commercial
compound.
S
O
O
NH2 S
O
O
NH
HO
4.3 4.3a 4.3aa
4.1 (1 mol%)
KOH (0.03 eq.)
neat, 100 °C, 12 hours
82%
+ + H2O
141
Figure 5.45 1
H NMR Spectrum of Table 4.4, Entry 1 Product 4.3aa in CDCl3. Data are Consistent
with a Commercial Compound.
8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0
f1 (ppm)
-100
0
100
200
300
400
500
600
700
800
900
1000
1100
1200
1300
1400
1500
1600
1700
1800
1.85 2.83 3.99 1.11 2.00
142
Diethyl benzylphosphoramidate 4.33ab:
Inside the glovebox, a 5 mL Schlenk reactor with a conical bottom was charged with 4.4
(50 mg, 0.33 mmol), benzyl alcohol 4.3a (54.1 mg, 0.50 mmol), 0.03 equivalents KOH (0.56 mg,
9.9 µmol) and 1 mol% ruthenium complex 4.1 (2.3 mg, 3.3 µmol). The reactor was sealed, taken
out of the glovebox, and was heated to 100 °C for 12 hours. After that, the dark brown mixture
was poured over 20 mL brine, and the organic material was extracted three times by
dichloromethane (30 mL), and dried over anhydrous sodium sulfate. The resulting solution was
concentrated by rotary evaporation and purified by auto column chromatography, eluting with
ethyl acetate (1 wt% triethylamine)/ hexanes (1 wt% triethylamine). Product-containing fractions
were identified and concentrated by rotary evaporation to yield 69 mg (87%) of product 4.3ab as
light yellow oil.
1
H NMR (400 MHz, cdcl3) δ 7.36 – 7.22 (m, 5H), 4.13 – 4.05 (tdd, J = 8.6, 7.0, 5.0 Hz, 4H), 3.83
– 3.78 (s, 2H), 1.31 – 1.22 (m, 6H). Data are consistent with a commercial compound from
Chemieliva Pharmaceutica Co., Ltd.
P
O
O O NH2
P
O
N
H
O O
4.4 4.3ab
+ H2O HO
4.3a
+
4.1 (1 mol%)
KOH (0.03 eq.)
neat, 100 °C, 12 hours
87%
143
Figure 5.46 1
H NMR spectrum of Table 4.4, Entry 2 Product 4.3ab in CDCl3. Data are Consistent
with a Commercial Compound.
9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0
f1 (ppm)
-50
0
50
100
150
200
250
300
350
400
450
500
550
600
1.07 4.07 3.84 2.00 5.77
144
N-Benzylhexanamide 4.3ac:
Inside the glovebox, a 5 mL Schlenk reactor with a conical bottom was charged with 4.5
(50 mg, 0.43 mmol), benzyl alcohol 4.3a (70.3 mg, 0.65 mmol), 0.03 equivalents KOH (0.73 mg,
13.0 µmol) and 1 mol% ruthenium complex 4.1 (3.0 mg, 4.3 µmol). The reactor was sealed, taken
out of the glovebox, and was heated to 100 °C for 12 hours. After that, the dark brown mixture
was poured over 20 mL brine, and the organic material was extracted three times by
dichloromethane (30 mL), and dried over anhydrous sodium sulfate. The resulting solution was
concentrated by rotary evaporation and purified by auto column chromatography, eluting with
ethyl acetate (1 wt% triethylamine)/ hexanes (1 wt% triethylamine). Product-containing fractions
were identified and concentrated by rotary evaporation to yield 60 mg (68%) of product 4.3ac as
light yellow oil.
1
H NMR (400 MHz, cdcl3) δ 7.38 – 7.22 (m, 5H), 3.87 – 3.85 (s, 2H), 2.20 (td, J = 7.8, 2.8 Hz,
2H), 1.64 (qd, J = 7.8, 2.8 Hz, 2H), 1.52 (m, 2H), 1.32 (dq, J = 7.6, 3.6 Hz, 3H), 0.91 (tt, J = 6.5,
2.9 Hz, 2H). Data are consistent with a commercial compound.
N
H
O
4.3ac
+ H2O HO
4.3a
+
NH2
O
4.1 (1 mol%)
KOH (0.03 eq.)
neat, 100 °C, 12 hours
4.5 68%
145
Figure 5.47 1
H NMR Spectrum of Table 4.4, Entry 3 Product 4.3ac in CDCl3. Data are Consistent
with a Commercial Compound.
9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0
f1 (ppm)
-50
0
50
100
150
200
250
300
350
400
450
500
550
600
650
700
5.22 2.00 1.74 1.79 2.24 3.18 2.29
146
N-Benzylpicolinamide 4.3ad:
Inside the glovebox, a 5 mL Schlenk reactor with a conical bottom was charged with 4.6
(50 mg, 0.41 mmol), benzyl alcohol 4.3a (66.0 mg, 0.61 mmol), 0.03 equivalents KOH (0.67 mg,
12.0 µmol) and 1 mol% ruthenium complex 4.1 (2.9 mg, 4.1 µmol). The reactor was sealed, taken
out of the glovebox, and was heated to 100 °C for 12 hours. After that, the dark brown mixture
was poured over 20 mL brine, and the organic material was extracted three times by
dichloromethane (30 mL), and dried over anhydrous sodium sulfate. The resulting solution was
concentrated by rotary evaporation and purified by auto column chromatography, eluting with
ethyl acetate (1 wt% triethylamine)/ hexanes (1 wt% triethylamine). Product-containing fractions
were identified and concentrated by rotary evaporation to yield 49 mg (56%) of product 4.3ad as
light yellow oil.
1
H NMR (400 MHz, cdcl3) δ 8.69 (m, 1H), 8.41 (dq, J = 7.9, 1.4 Hz, 1H), 8.05 (dtd, J = 9.9, 5.0,
2.1 Hz, 1H), 7.63 (ddt, J = 7.5, 4.4, 2.8 Hz, 1H), 7.52 (dq, J = 6.0, 1.9 Hz, 4H), 7.48 – 7.40 (m,
1H), 4.06 (s, 2H). Data are consistent with a commercial compound.
N
O
NH2
N
O
N
H
4.6 4.3ad
+ H2O HO
4.3a
+
4.1 (1 mol%)
KOH (0.03 eq.)
neat, 100 °C, 12 hours
56%
147
Figure 5.48 1
H NMR Spectrum of Table 4.4, Entry 4 Product 4.3ad in CDCl3. Data are Consistent
with a Commercial Compound.
14 13 12 11 10 9 8 7 6 5 4 3 2 1 0 -1
f1 (ppm)
-100
0
100
200
300
400
500
600
700
800
900
1000
1100
1200
0.92 0.92 1.17 0.95 4.10 1.07 2.00
148
N-Benzyl-2,3,4,5,6-pentafluoroaniline 4.3ae:
Inside the glovebox, a 5 mL Schlenk reactor with a conical bottom was charged with 4.7
(50 mg, 0.27 mmol), benzyl alcohol 4.3a (44.3 mg, 0.41 mmol), 0.03 equivalents KOH (0.46 mg,
8.2 µmol) and 1 mol% ruthenium complex 4.1 (1.9 mg, 2.7 µmol). The reactor was sealed, taken
out of the glovebox, and was heated to 100 °C for 12 hours. After that, the dark brown mixture
was poured over 20 mL brine, and the organic material was extracted three times by
dichloromethane (30 mL), and dried over anhydrous sodium sulfate. The resulting solution was
concentrated by rotary evaporation and purified by auto column chromatography, eluting with
ethyl acetate (1 wt% triethylamine)/ hexanes (1 wt% triethylamine). Product-containing fractions
were identified and concentrated by rotary evaporation to yield 53 mg (71%) of product 4.3ae as
light yellow oil.
1
H NMR (600 MHz, acetone) δ 7.28 (dtt, J = 7.2, 1.5, 0.8 Hz, 2H), 7.25 – 7.21 (m, 2H), 7.16 –
7.12 (m, 1H), 4.57 (s, 2H). Data are consistent with a commercial compound.
NH2
F F
F
F F
NH
F F
F
F F
4.7 4.3ae
+ H2O HO
4.3a
+
4.1 (1 mol%)
KOH (0.03 eq.)
neat, 100 °C, 12 hours
71%
149
Figure 5.49 1
H NMR Spectrum of Table 4.4, Entry 5 Product 4.3ae in CDCl3. Data are Consistent
with a Commercial Compound.
9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5
f1 (ppm)
-1000
0
1000
2000
3000
4000
5000
6000
7000
8000
9000
10000
11000
12000
13000
2.04 2.04 1.05 1.99
150
N-Benzyl-1H-benzimidazol-2-amine 4.3af:
Inside the glovebox, a 5 mL Schlenk reactor with a conical bottom was charged with 4.8
(50 mg, 0.38 mmol), benzyl alcohol 4.3a (60.6 mg, 0.56 mmol), 0.03 equivalents KOH (0.63 mg,
11.3 µmol), 1 mol% ruthenium complex 4.1 (2.6 mg, 3.8 µmol), and 1.5 mL toluene. The reactor
was sealed, taken out of the glovebox, and was heated to 100 °C for 12 hours. The toluene was
removed by a rotary evaporator after the reaction. After that, the dark brown mixture was poured
over 20 mL brine, and the organic material was extracted three times by dichloromethane (30 mL),
and dried over anhydrous sodium sulfate. The resulting solution was concentrated by rotary
evaporation and purified by auto column chromatography, eluting with ethyl acetate (1 wt%
triethylamine)/ hexanes (1 wt% triethylamine). Product-containing fractions were identified and
concentrated by rotary evaporation to yield 54 mg (65%) of product 4.3af as light yellow oil.
1
H NMR (400 MHz, dmso) δ 7.34 (q, J = 4.8 Hz, 3H), 7.32 – 7.28 (m, 2H), 7.21 (ddd, J = 11.4,
5.9, 2.1 Hz, 1H), 7.16 – 7.10 (m, 1H), 6.91 – 6.85 (m, 2H), 3.73 (d, J = 2.9 Hz, 2H). Data are
consistent with a commercial compound.
H
N
N
NH2
H
N
N
NH
4.8 4.3af
+ H2O HO
4.3a
+
4.1 (1 mol%)
KOH (0.03 eq.)
toluene, 100 °C, 12 hours
65%
151
Figure 5.50 1
H NMR Spectrum of Table 4.4, Entry 6 Product 4.3af in CDCl3. Data are Consistent
with a Commercial Compound.
8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0
f1 (ppm)
-100
0
100
200
300
400
500
600
700
800
900
1000
1100
2.82 1.54 1.08 1.55 1.58 2.00
152
N-Benzyl-1,3-benzothiazol-2-amine 4.3ag:
Inside the glovebox, a 5 mL Schlenk reactor with a conical bottom was charged with 4.9
(50 mg, 0.33 mmol), benzyl alcohol 4.3a (54.1 mg, 0.50 mmol), 0.03 equivalents KOH (0.56 mg,
10.0 µmol) and 1 mol% ruthenium complex 4.1 (2.3 mg, 3.3 µmol). The reactor was sealed, taken
out of the glovebox, and was heated to 100 °C for 12 hours. The toluene was removed by a rotary
evaporator after the reaction. After that, the dark brown mixture was poured over 20 mL brine, and
the organic material was extracted three times by dichloromethane (30 mL), and dried over
anhydrous sodium sulfate. The resulting solution was concentrated by rotary evaporation and
purified by auto column chromatography, eluting with ethyl acetate (1 wt% triethylamine)/
hexanes (1 wt% triethylamine). Product-containing fractions were identified and concentrated by
rotary evaporation to yield 61 mg (76%) of product 4.3ag as light yellow oil.
1
H NMR (400 MHz, cdcl3) δ 7.57 (t, J = 8.0 Hz, 2H), 7.38 (d, J = 9.6 Hz, 4H), 7.32 (d, J = 7.7 Hz,
2H), 7.13 – 7.06 (m, 1H), 4.65 (s, 2H). Data are consistent with a commercial compound.
S
N
NH2
S
N
NH
4.9 4.3ag
+ H2O HO
4.3a
+
4.1 (1 mol%)
KOH (0.03 eq.)
toluene, 100 °C, 12 hours
76%
153
Figure 5.51 1
H NMR Spectrum of Table 4.4, Entry 7 Product 4.3ag in CDCl3. Data are Consistent
with a Commercial Compound.
10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0
f1 (ppm)
-50
0
50
100
150
200
250
300
350
400
450
500
550
600
650
700
750
2.01 4.07 2.11 0.99 2.00
154
N-Ethylaniline 4.4b:
Inside the glovebox, a 5 mL Schlenk reactor with a conical bottom was charged with 4.10
(50 mg, 0.54 mmol), ethanol 4.4a (37.3 mg, 0.81 mmol), 0.03 equivalents KOH (0.90 mg, 16.1
µmol) and 1 mol% ruthenium complex 4.1 (3.8 mg, 5.4 µmol). The reactor was sealed, taken out
of the glovebox, and was heated to 100 °C for 12 hours. After that, the dark brown mixture was
poured over 20 mL brine, and the organic material was extracted three times by dichloromethane
(30 mL), and dried over anhydrous sodium sulfate. The resulting solution was concentrated by
rotary evaporation and purified by auto column chromatography, eluting with ethyl acetate (1 wt%
triethylamine)/ hexanes (1 wt% triethylamine). Product-containing fractions were identified and
concentrated by rotary evaporation to yield 55 mg (85%) of product 4.4b as a light yellow oil.
1
H NMR (400 MHz, cdcl3) δ 7.25 – 7.18 (m, 2H), 6.77 – 6.70 (m, 1H), 6.67 – 6.62 (m, 2H), 3.19
(dddd, J = 8.8, 7.0, 5.3, 2.6 Hz, 2H), 1.33 – 1.25 (m, 3H). Data are consistent with a commercial
compound.
NH2 HO NH
4.10 4.4a 4.4b
+ + H2O
4.1 (1 mol%)
KOH (0.03 eq.)
neat, 100 °C, 12 hours
85%
155
Figure 5.52 1
H NMR Spectrum of Table 4.4, Entry 8 Product 4.4b in CDCl3. Data are Consistent
with a Commercial Compound.
8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0
f1 (ppm)
-200
0
200
400
600
800
1000
1200
1400
1600
1800
2000
2200
2400
1.92 0.97 1.92 2.00 2.93
156
N-Methylbenzenesulfonamide 4.5b:
Inside the glovebox, a 5 mL Schlenk reactor with a conical bottom was charged with 4.11
(50 mg, 0.54 mmol), methanol 4.5a (37.3 mg, 0.81 mmol), 0.03 equivalents KOH (0.90 mg, 16.1
µmol) and 1 mol% ruthenium complex 4.1 (3.8 mg, 5.4 µmol). The reactor was sealed, taken out
of the glovebox, and was heated to 100 °C for 12 hours. After that, the dark brown mixture was
poured over 20 mL brine, and the organic material was extracted three times by dichloromethane
(30 mL), and dried over anhydrous sodium sulfate. The resulting solution was concentrated by
rotary evaporation and purified by auto column chromatography, eluting with ethyl acetate (1 wt%
triethylamine)/ hexanes (1 wt% triethylamine). Product-containing fractions were identified and
concentrated by rotary evaporation to yield 42 mg (77%) of product 4.5b as light yellow oil.
1
H NMR (400 MHz, cdcl3) δ 7.75 (dt, J = 8.4, 1.7 Hz, 2H), 7.31 (dd, J = 8.6, 2.6 Hz, 2H), 2.64
(dt, J = 5.4, 1.8 Hz, 3H), 2.45 – 2.41 (m, 3H). Data are consistent with a commercial compound.
S
O
O
NH2 S
O
O
MeOH NH
4.11 4.5a 4.5b
+ + H2O
4.1 (1 mol%)
KOH (0.03 eq.)
neat, 100 °C, 12 hours
77%
157
Figure 5.53 1
H NMR Spectrum of Table 4.4, Entry 9 Product 4.5b in CDCl3. Data are Consistent
with a Commercial Compound.
9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0
f1 (ppm)
-100
0
100
200
300
400
500
600
700
800
900
1000
1100
1200
1300
1400
1500
1600
1700
1800
2.00 2.02 3.12 3.18
158
Indolo(2,3-a)quinolizidine 4.6b:
Inside the glovebox, a 5 mL Schlenk reactor with a conical bottom was charged with 4.12
(50 mg, 0.33 mmol), 1,5-pentanediol 4.6a (54.1 mg, 0.50 mmol), 0.03 equivalents KOH (0.56 mg,
10.0 µmol) and 1 mol% ruthenium complex 4.1 (2.3 mg, 3.3 µmol). The reactor was sealed, taken
out of the glovebox, and was heated to 100 °C for 1 hour. After that, the Schlenk reactor was
charged with indium(III) trifluoromethanesulfonate (18.5 mg, 0.033 mmol) and then reacted for
another 11 hours. The toluene was removed by a rotary evaporator after the reaction. After that,
the dark brown mixture was poured over 20 mL brine, and the organic material was extracted three
times by dichloromethane (30 mL), and dried over anhydrous sodium sulfate. The resulting
solution was concentrated by rotary evaporation and purified by auto column chromatography,
eluting with ethyl acetate (1 wt% triethylamine)/ hexanes (1 wt% triethylamine). Productcontaining fractions were identified and concentrated by rotary evaporation to yield 61 mg (76%)
of product 4.6b as off-white crystals. Melting point of 4.6b is 147 °C.
1
H NMR (400 MHz, cdcl3) δ 7.49 – 7.43 (m, 1H), 7.30 – 7.23 (m, 1H), 7.09 (dtd, J = 17.2, 7.2,
1.3 Hz, 2H), 3.21 (d, J = 10.9 Hz, 1H), 3.10 – 2.94 (m, 3H), 2.75 – 2.57 (m, 2H), 2.37 (td, J = 11.2,
3.9 Hz, 1H), 2.03 (dd, J = 12.2, 3.3 Hz, 1H), 1.88 (d, J = 12.0 Hz, 1H), 1.74 (dp, J = 10.5, 3.7 Hz,
2H), 1.64 – 1.52 (m, 1H), 1.47 (tt, J = 12.3, 3.7 Hz, 1H). Data are consistent with a commercial
compound from Aurora Fine Chemicals LLC.
N
H
NH2
HO OH
N
H
N
4.12 4.6a 4.6b
1. 4.1 (1 mol%), KOH (0.03 eq.)
2. In(OTf)3 (10 mol%)
toluene, 100 °C, 12 hours
66%
+ + H2O
159
Figure 5.54 1
H NMR Spectrum of Table 4.4, Entry 10 Product 4.6b in CDCl3. Data are Consistent
with a Commercial Compound.
8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5
f1 (ppm)
-100
0
100
200
300
400
500
600
700
800
900
1000
1100
1200
1.00 1.22 2.10 1.03 3.24 2.06 0.93 0.98 0.95 2.01 1.10 1.05
160
Piperazine 4.7b:
Inside the glovebox, a 5 mL Schlenk reactor with a conical bottom was charged with 4.13
(100 mg, 1.64 mmol), 0.03 equivalents KOH (2.76 mg, 49.1 µmol) and 1 mol% ruthenium
complex 4.1 (11.4 mg, 16.4 µmol). The reactor was sealed, taken out of the glovebox, and was
heated to 100 °C for 12 hours. After that, the dark brown mixture was poured over 20 mL brine,
and the organic material was extracted three times by dichloromethane (30 mL), and dried over
anhydrous sodium sulfate. The resulting solution was concentrated by rotary evaporation and
purified by auto column chromatography, eluting with ethyl acetate (1 wt% triethylamine)/
hexanes (1 wt% triethylamine). Product-containing fractions were identified and concentrated by
rotary evaporation to yield 62 mg (88%) of product 4.7b as light yellow oil.
1
H NMR (400 MHz, cdcl3) δ 2.78 (dd, J = 3.0, 1.4 Hz, 8H). Data are consistent with a commercial
compound.
NH2
OH N
H
H
N
4.13 4.7b
+ 2 H2O
4.1 (1 mol%)
KOH (0.03 eq.)
neat, 100 °C, 12 hours
88%
2
161
Figure 5.55 1
H NMR Spectrum of Table 4.4, Entry 11 Product 4.7b in CDCl3. Data are Consistent
with a Commercial Compound.
7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0
f1 (ppm)
-100
0
100
200
300
400
500
600
700
800
900
1000
1100
1200
1300
1400
1500
1600
1700
1800
2.02
162
N-Isopropylbenzylamine 4.9b:
Inside the glovebox, a 5 mL Schlenk reactor with a conical bottom was charged with 4.15
(50 mg, 0.47 mmol), isopropanol 4.9a (42.1 mg, 0.70 mmol), 0.03 equivalents KOH (0.78 mg,
13.9 µmol) and 1 mol% ruthenium complex 4.1 (3.3 mg, 4.7 µmol). The reactor was sealed, taken
out of the glovebox, and was heated to 100 °C for 12 hours. After that, the dark brown mixture
was poured over 20 mL brine, and the organic material was extracted three times by
dichloromethane (30 mL), and dried over anhydrous sodium sulfate. The resulting solution was
concentrated by rotary evaporation and purified by auto column chromatography, eluting with
ethyl acetate (1 wt% triethylamine)/ hexanes (1 wt% triethylamine). Product-containing fractions
were identified and concentrated by rotary evaporation to yield 50 mg (72%) of product 4.9b as
light yellow oil.
1
H NMR (400 MHz, cdcl3) δ 7.24 (m, 3H), 7.20 – 7.17 (m, 2H), 3.82 (dt, J = 13.3, 1.9 Hz, 1H),
3.70 – 3.66 (m, 2H), 3.62 (dt, J = 13.2, 2.0 Hz, 1H), 2.78 – 2.66 (m, 1H), 2.60 (dt, J = 12.4, 3.5
Hz, 1H), 1.05 – 1.00 (m, 3H). Data are consistent with a commercial compound.
NH2 HO N
H
4.15 4.9a 4.9b
+ + H2O
4.1 (1 mol%)
KOH (0.03 eq.)
neat, 100 °C, 12 hours
72%
163
Figure 5.56 1
H NMR Spectrum of Table 4.4, Entry 13 Product 4.9b in CDCl3. Data are Consistent
with a Commercial Compound.
9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0
f1 (ppm)
-50
0
50
100
150
200
250
300
350
400
450
500
550
600
650
700
750
800
3.04 2.08 1.03 2.00 1.03 0.95 0.97 3.01
164
N-(2-Propynyl)-2,3-dihydroinden-1-amine 4.10b:
Inside the glovebox, a 5 mL Schlenk reactor with a conical bottom was charged with 4.16
(50 mg, 0.91 mmol), 1-indanol 4.10a (182.7 mg, 1.36 mmol), 0.03 equivalents KOH (1.53 mg,
27.2 µmol) and 1 mol% ruthenium complex 4.1 (6.3 mg, 9.1 µmol). The reactor was sealed, taken
out of the glovebox, and was heated to 100 °C for 12 hours. After that, the dark brown mixture
was poured over 20 mL brine, and the organic material was extracted three times by
dichloromethane (30 mL), and dried over anhydrous sodium sulfate. The resulting solution was
concentrated by rotary evaporation and purified by auto column chromatography, eluting with
ethyl acetate (1 wt% triethylamine)/ hexanes (1 wt% triethylamine). Product-containing fractions
were identified and concentrated by rotary evaporation to yield 59 mg (38%) of product 4.10b as
light yellow oil.
1
H NMR (400 MHz, cdcl3) δ 7.37 (dt, J = 5.6, 2.4 Hz, 1H), 7.23 – 7.17 (m, 3H), 5.22 – 5.16 (m,
1H), 3.36 (s, 2H), 3.07 – 2.95 (m, 1H), 2.83 – 2.72 (m, 1H), 2.49 – 2.38 (m, 1H), 1.96 – 1.84 (m,
1H). Data are consistent with a commercial compound.
NH2
HO HN
4.16 4.10a 4.10b
+ + H2O
4.1 (1 mol%)
KOH (0.03 eq.)
neat, 100 °C, 12 hours
38%
165
Figure 5.57 1
H NMR Spectrum of Table 4.4, Entry 14 Product 4.10b in CDCl3. Data are
Consistent with a Commercial Compound.
8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0
f1 (ppm)
0
50
100
150
200
250
300
0.99 2.93 1.00 2.08 1.04 1.08 1.11 1.27
166
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181
Appendix
X-Ray Crystallography Data
Crystal Structure of 2.5 (CCDC 2142636)
Yellow single crystals of C21H21IrN3O5F3S 2.5 were prepared from slow liquid diffusion
of dichloromethane and diethyl ether. A suitable crystal was selected and mounted on a loop on
a XtaLAB Mini II diffractometer. The crystal was kept at 100.00(10) K during data collection. The
X-ray intensity data were measured on a Bruker APEX DUO system equipped with a fine-focus
tube (MoKα, λ = 0.71073 Å) and a TRIUMPH curved-crystal monochromator.
182
Table 5.1 Crystal Data and Structure Refinement for 2.5.
Bond precision: C-C = 0.0076 A Wavelength=0.71073
Cell: a=7.824(2) b=10.972(3) c=14.212(4)
alpha=95.459(5) beta=94.385(5) gamma=98.090(5)
Temperature: 100 K
Calculated Reported
Volume 1197.4(6) 1197.4(6)
Space group P -1 P -1
Hall group -P 1 -P 1
Moiety formula C20H21IrN3O2, CF3O3S C20H21IrN3O2, CF3O3S
Sum formula C21H21F3IrN3O5S C21H21F3IrN3O5S
Mr 676.69 676.67
Dx, g cm-3 1.877 1.877
Z 2 2
Mu (mm-1
) 5.723 5.723
F000 656.0 656.0
F000' 653.78
h, k, lmax 11, 15, 20 11, 15, 20
Nref 7465 6673
Tmin, Tmax 0.475, 0.892 0.548, 0.746
Tmin' 0.420
Correction method= # Reported T Limits: Tmin=0.548
Tmax=0.746 AbsCorr = MULTI-SCAN
Data completeness= 0.894 Theta(max)= 30.740
R(reflections)= 0.0349( 6189) wR2(reflections)= 0.0669( 6673)
S = 1.036 Npar= 317
183
Crystal Structure of 2.6 (CCDC 2258133)
Yellow single crystals of C19H19ClIrN3O 2.6 were prepared from slow liquid diffusion of
dichloromethane and diethyl ether. A suitable crystal was selected and mounted on a loop on
a XtaLAB Mini II diffractometer. The crystal was kept at 100.00(10) K during data collection. The
X-ray intensity data were measured on a Bruker APEX DUO system equipped with a fine-focus
tube (MoKα, λ = 0.71073 Å) and a TRIUMPH curved-crystal monochromator.
184
Table 5.2 Crystal Data and Structure Refinement for 2.6.
Identification code Iridium CN carbonyl chloride
Empirical formula C19H19ClIrN3O
Formula weight 533.02
Temperature/K 100.00(10)
Crystal system monoclinic
Space group P21/c
a/Å 8.7180(2)
b/Å 15.1641(3)
c/Å 14.4976(3)
α/° 90
β/° 106.108(2)
γ/° 90
Volume/Å3 1841.35(7)
Z 4
ρcalcg/cm3 1.923
µ/mm-1 7.408
F (000) 1024.0
Crystal size/mm3 0.173 × 0.095 × 0.058
Radiation Mo Kα (λ = 0.71073)
2Θ range for data collection/° 5.372 to 64.818
Index ranges -13 ≤ h ≤ 12, -22 ≤ k ≤ 20, -20 ≤ l ≤ 21
Reflections collected 50998
Independent reflections 5943 [Rint = 0.0498, Rsigma = 0.0296]
Data/restraints/parameters 5943/0/232
Goodness-of-fit on F2 1.041
Final R indexes [I>=2σ (I)] R1 = 0.0251, wR2 = 0.0457
Final R indexes [all data] R1 = 0.0377, wR2 = 0.0501
Largest diff. peak/hole / e Å-3 2.65/-1.10
185
Crystal Structure of 4.1 (CCDC 2354122)
A clear yellowish prism like crystal of C58H66Cl2F6N6O6Ru2S2, approximate dimensions
0.471 mm x 0.16 mm x 0.139 mm was used for X-ray crystallographic analysis grown from slow
diffusion of hexanes and dichloromethane. The X-ray intensity data was collected on a XtaLAB
Synergy, Dualflex, HyPix diffractometer using a Mo Kα fine-focus tube (λ = 0.71073) and kept at
100.00(10) K during data acquisition. The crystal was mounted on a MiTiGen 50um.
A total of 1248 frames were collected; the total exposure time was 3 hours and 37 minutes.
The frames were integrated using Rigaku CrysAlisPro software. The integration of the data using
a monoclinic crystal system resulted in 134659 reflections to a maximum θ angle of 32.472° (0.75
Å resolution), of which 18833 were independent (completeness = 88.5 %, Rint = 0.0493, Rsigma =
186
0.0326) and used in all calculations. The final cell constants are a = 14.4987(2) Å, b = 13.8436(2)
Å, c = 29.3646(3) Å, b = 90.5070(10) °, γ = α = 90°, volume = 5893.66(13) Å3
, are based upon the
refinement. Data was corrected for absorption effects using the multi-scan method. The ration of
minimum to maximum apparent transmission was 0.64389.
The structure was solved using olex2.solve structure solution program using Charge
Flipping, and refined with the SHELXL refinement package using Least Squares minimization.
The space group P21/n was used with Z = 4 for the formula unit, C58H66Cl2F6N6O6Ru2S2. The final
R1 = 2.70% and wR2 = 6.01% (I>2σ(I)) while for all data R1 = 3.65% and wR2 = 6.35%. The
goodness-of-fit was 1.038. The largest peak in the final difference electron density synthesis was
1.16 e-
/ Å3 and the largest hole was -0.73 e-
/ Å3. On the basis of the final model, the calculated
density was 1.571 g/cm3 and F(000), 2848.0.
187
Table 5.3 Crystal Data and Structure Refinement for 4.1.
Identification code Ruthenium CN-Mesityl
Empirical formula C58H66Cl2F6N6O6Ru2S2
Formula weight 1394.32
Temperature/K 100.00(10)
Crystal system monoclinic
Space group P21/n
a/Å 14.4987(2)
b/Å 13.8436(2)
c/Å 29.3646(3)
α/° 90
β/° 90.5070(10)
γ/° 90
Volume/Å3 5893.66(13)
Z 4
ρcalcg/cm3 1.571
µ/mm-1 0.749
F (000) 2848.0
Crystal size/mm3 0.471 × 0.16 × 0.139
Radiation Mo Kα (λ = 0.71073)
2Θ range for data collection/° 4.29 to 64.944
Index ranges -18 ≤ h ≤ 21, -20 ≤ k ≤ 20, -43 ≤ l ≤ 42
Reflections collected 134659
Independent reflections 18833 [Rint = 0.0493, Rsigma = 0.0326]
Data/restraints/parameters 18833/0/751
Goodness-of-fit on F2 1.038
Final R indexes [I>=2σ (I)] R1 = 0.0270, wR2 = 0.0601
Final R indexes [all data] R1 = 0.0365, wR2 = 0.0635
Largest diff. peak/hole / e Å-3 1.16/-0.73
Abstract (if available)
Abstract
Our group develops new catalysts and conditions to manipulate hydrides such as various C-H and other X-H bonds. To achieve these goals, we employ strategies of catalyst design, thus exploring novel organometallic and coordination chemistry, and target-oriented new organic reaction development. Some examples include iridium complex-catalyzed hydrogenation of ketones and aldehydes, formic acid dehydrogenation, and ruthenium complex-catalyzed amine- alcohol coupling.
Chapter 1 reviews the catalytic chemistry of hydride manipulation, such as hydrogenation and dehydrogenation processes. Research projects mainly involve the design and synthesis of new catalysts and mechanism analysis of catalytic processes. Such mechanistic understanding can improve catalytic efficiency, selectivity, and catalyst lifetime. Interest in hydride manipulation is explained by its atom economy, which is consistent with the principles of sustainability and green chemistry. Chapter 2 describes a catalytic hydrogenation system that affects carbonyl hydrogenation with ambient hydrogen pressure at up to quantitative yield on a diverse set of ketones and aldehydes. Direct hydrogenation of carbonyl groups is a 100% atom efficient, environmentally benign synthetic process. Many well-defined molecular catalysts for hydrogenation, transfer hydrogenation of C=O groups, and dehydrogenation systems have emerged, yet most rely on hydrogen gas pressure or a hydrogen donor/acceptor to obtain useful rates. Such requirements for pressurization limit the utility of these methods and make them inconvenient for users without pressurization tools. Chapter 3 presents the first general study of how formic acid dehydrogenation catalysts respond to self-pressurizing conditions. We demonstrate a broad survey of activity and stability of catalysts in both ambient and pressurized reaction conditions and find striking reactivity improvements for some catalysts when pressurized. We ultimately show how such improvements are realized, sometimes by transforming a monomeric catalyst into a two-metal pseudo-pincer type species upon carbonylation. Chapter 4 introduces our previously reported strong s-donating (pyridyl)methylcarbene ligand to modify precursor [RuCl2(h6-cymene)]2 to form a new ruthenium complex which is an efficient catalyst for the amine-alcohol coupling reaction. We find neither that this new complex will self-poison nor that CO generated during the reaction is enough to poison it. We also propose a monomeric catalytic mechanism of this ruthenium catalyst and extend the reaction scope to include several kinds of amides, less nucleophilic amines, and cyclic amine products. We experimentally compare the effects of two ligands (pyridyl-carbene and pyridyl-phosphine) connected to ruthenium on the selectivity of catalytic reactions. In addition, we envision this new ruthenium complex as a useful tool both for organic synthesis at scale and preparation for drug synthesis.
Linked assets
University of Southern California Dissertations and Theses
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Asset Metadata
Creator
Zhang, Long
(author)
Core Title
Iridium and ruthenium complexes for catalytic hydrogen transfer reactions
School
College of Letters, Arts and Sciences
Degree
Doctor of Philosophy
Degree Program
Chemistry
Degree Conferral Date
2024-08
Publication Date
08/27/2024
Defense Date
08/02/2024
Publisher
Los Angeles, California
(original),
University of Southern California
(original),
University of Southern California. Libraries
(digital)
Tag
dehydrogenation,green chemistry,homogeneous organometallic catalysis,hydrogen,hydrogen borrowing reactions,hydrogenation,OAI-PMH Harvest
Format
theses
(aat)
Language
English
Contributor
Electronically uploaded by the author
(provenance)
Advisor
Williams, Travis (
committee chair
), Nutt, Steve (
committee member
), Picazo, Elias (
committee member
)
Creator Email
nbzl9595@outlook.com,zhanglon@usc.edu
Permanent Link (DOI)
https://doi.org/10.25549/usctheses-oUC113999U1Q
Unique identifier
UC113999U1Q
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etd-ZhangLong-13437.pdf (filename)
Legacy Identifier
etd-ZhangLong-13437
Document Type
Dissertation
Format
theses (aat)
Rights
Zhang, Long
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application/pdf
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texts
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20240828-usctheses-batch-1203
(batch),
University of Southern California
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University of Southern California Dissertations and Theses
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The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the author, as the original true and official version of the work, but does not grant the reader permission to use the work if the desired use is covered by copyright. It is the author, as rights holder, who must provide use permission if such use is covered by copyright.
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Repository Email
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Tags
dehydrogenation
green chemistry
homogeneous organometallic catalysis
hydrogen
hydrogen borrowing reactions
hydrogenation