PD/C-CATALYZED SUZUKI CROSS- AND SELF- COUPLINGS & THE
DEVELOPMENT OF A LAB-SCALE HYDROGENATION SYSTEM
by
JENG-SHIOU CHEN
A Dissertation submitted to the
Graduate School-New Brunswick
Rutgers, The State University of New Jersey
In partial fulfillment of the requirements
For the degree of
Doctor of Philosophy
Graduate Program in Chemical and Biochemical Engineering
Written under the direction of
Professor Johannes G. Khinast
And approved by
______
______
______
______
New Brunswick, New Jersey
Jan. 2008 ABSTRACT OF THE DISSERTATION
PD/C-CATALYZED SUZUKI CROSS- AND SELF- COUPLINGS &
THE DEVELOPMENT OF A LAB-SCALE HYDROGENATION SYSTEM
By JENG-SHIOU CHEN
Dissertation Directors:
Professor Johannes G. Khinast
Suzuki couplings have become an efficient and clean strategy for the preparation of biologically active functionalized biphenyls, which are important building blocks for pharmaceutical and agricultural compounds. Among all catalysts of choice for
Suzuki couplings, palladium on carbon (Pd/C) is most frequently used for industrial applications due to its high catalytic activity, low cost and easy removal from the reaction mixture. Using a model coupling reaction of biphenylacetic acid, we intended to provide a thorough understanding of Pd/C-catalyzed Suzuki couplings for a straightforward industrial implementation.
A detailed investigation of the reaction parameters was carried out in Chapter 2.
The experimental observations indicate that excess amount of the borate is helpful to accelerate the reaction and 2 moles eq. of a strong base is the best choice for the reaction. Furthermore, our results suggest that transmetalation is the rate-limiting step of the Pd/C-catalyzed Suzuki couplings and also show that [OH-] is a critical factor
affecting the reaction rate.
ii In Chapter 3, the mechanism of Pd-leaching from Pd/C was investigated. The
filtration test was used to prove that oxidative addition of aryl-bromides is the main
cause for Pd-leaching, which is independent of the reaction solvent and temperature.
In addition, the oxidative addition of aryl-borates is another cause for Pd-leaching.
PVPy adsorption studies suggest that the activity of Pd/C is mainly due to leached Pd.
Furthermore, PVPy was proven to be a good reagent for complete removal of
Pd-residuals from the reaction mixture.
In Chapter 4, homocoupling of arylboronic acids was successfully carried out
with Pd/C in water/2-propanol (9:1 in volume ratio) under air, to obtain symmetric
biaryls in good yield. This novel system was discovered during Pd-leaching studies
and optimized in our work. The experimental observations suggest that higher water
fractions in the co-solvent and higher reaction temperature are beneficial for the
reaction. DFT calculations suggest that the overall reactivity of the different
arylboronic acids is independent of the oxidative addition of Pd to the arylboronic acid.
Lastly, we successfully established a lab-scale hydrogenation system at Rutgers
University to carry out chiral hydrogenation, which is presented in Chapter 5. The system allows reactions operated under 120 bars at a wide range of reaction temperatures (-80~350 oC).
iii ACKNOWLEDGEMENT
First of all, I wish to thank my advisor, Dr. Johannes Khinast, not only for his guidance and support in the academic work but also for the friendship we developed over the last four years. I really appreciate and treasure this opportunity to work with you. It is always joyful to talk to you. You are patient, always listen to me, and allow me to try all kinds of ideas. No matter if I obtained good or bad results, you provided me with the positive thinking all the times and guided me to go forward in the correct, optimistic direction. Moreover, thank you so much for your time on instructing my writing and speaking. I learned a lot from our discussions and communications through hundreds of emails. Although you are not in New Jersey for two years, I always feel that you are with me and support me. I really appreciate it.
To my committee member, Dr. Henrik Pedersen, thanks for your advice and help to operate and maintain HPLC, which is an important tool for me to obtain experimental results. Thanks to Dr. Marianthi Ierapetritou for your help and consideration. You always gave me your best smiles and encouraged me to look forward in research. To Dr. Karsten Krogh-Jespersen, thanks for your guidance and help in computational chemistry. This work could not have been accomplished without your assistance. It is very pleasant to discuss with you at all times.
A special thank to Dr. Yee Chiew and Anne. You not only guided me in the academic path but also helped me to root my life in New Jersey. With your help, I could adapt myself quickly to this new place and love everything happening in this beautiful place.
Furthermore, I would like to thank my parents and my sisters for always supporting me to do anything that interested me. Without your support, it is
iv impossible for me to fully concentrate on pursuing a Ph.D. degree in the most distant place from Taiwan. Thank you so much for listening to my complaints, giving me positive opinions, and for encouraging me to look forward. Although you cannot be close to me, it is always my most wonderful time to have your calls and emails. I feel as if I were still in that warm and cozy home. I love you!!
I-Ling, thank you for sharing my happiness and sadness for more than 12 years.
Before or after the wedding, you always put a smile on my face and give me your best support. Thank you for establishing a new family with me in this new place. Although
I cannot provide you with attractive and expensive things, I will always love you! For
Shang-Jiun, I am so happy to have you in the family although you do not understand anything yet.
Another special thanks to Anthony Panarello. You’re just like my big brother.
Thank you for teaching me everything in the lab and for getting me acquainted with
American life. I am glad that we had great times in the lab, in the bar, at the BBQs and at the football games.
Last but not the least: thanks to my fellow co-workers: Oleksiy, Natalia,
Athanas, and Jane, as well as the many departmental friends: Zhenya, Marggret,
Yangyang, Marcos, Eric, Eddie, Alan, Steve, Hong, Patty, and Frank. You all have taught me more than you can imagine. I will miss the many interesting conversations.
Thank you so much!
v TABLE OF CONTENTS
ABSTRACT...... ii
AKNOWLEGDEMENT...... iv
TABLE OF CONTENTS ...... vi
LIST OF TABLES ...... x
LIST OF FIGURES AND SCHEMES...... xi
1. INTRODUCTION...... 1
1.1 HETEROGENEOUS CATALYSIS...... 1
1.2 COUPLING REACTIONS...... 2
1.3 SUZUKI COUPLINGS ...... 3
1.4 HOMOCOUPLING OF ARYLBORONIC ACIDS ...... 6
1.5 COMPUTATIONAL CHEMISTRY BY DFT METHOD...... 7
1.6 BIMETALLIC CATALYSTS CATALYZED ENANTIOSELECTIVE
HYDROGENATION ...... 8
1.7 RESEARCH OBJECTIVES ...... 10
2. INVESTIGATION OF PD/C-CATALALYZED SUZUKI COUPLINGS
...... 14
2.1 EXPERIMENTAL...... 14
2.1.1 MATERIALS...... 14
2.1.2 MODEL REACTIONS FOR SUZUKI COUPLINGS ...... 15
2.1.3 RC1 CALORIMETRIC ASSAY ...... 15
2.1.4 HPLC ANALYSES ...... 16
2.1.5 EXPERIMENTAL VALIDATION...... 17
vi 2.2 INVESTIGATION OF REACTION PARAMETERS ...... 18
2.2.1 INFLUENCE OF AGITATION ...... 18
2.2.2 INFLUENCE OF CATALYST LOADING ...... 18
2.2.3 INFLUENCE OF BASE LOADING...... 19
2.2.4 INFLUENCE OF BASE LOADING...... 20
2.2.5 INFLUENCE OF REACTION TEMPERATURE ...... 20
2.3 DERIVATION OF THEORETICAL RATE EXPRESSIONS...... 22
2.3.1 SEVEN ELEMENTARY REACTIONS ...... 22
2.3.2 RATE EXPRESSIONS OF THE ASSUMED RATE-LIMITING STEPS23
2.4 PH-EFFECTS ON PD/C-CATALYZED SUZUKI COUPLINGS...... 25
2.4.1 INFLUENCE OF BASE SPECIES ...... 25
2.4.2 INFLUENCE OF REACTION CO-SOLVENT ...... 26
2.5 CONCLUSION...... 27
3. PD-LEACHING & PD-REMOVAL IN PD/C-CATALYZED SUZUKI
COUPLINGS...... 40
3.1 EXPERIMENTAL...... 41
3.1.1 MATERIALS...... 41
3.1.2 MODEL REACTIONS FOR SUZUKI COUPLINGS IN SMALL SCALE
...... 41
3.1.3 ANALYTICAL MEASUREMENTS ...... 42
3.2 PD-LEACHING OF PD/C...... 42
3.2.1 OBSERVATION OF PD-LEACHING FROM PD/C ...... 42
3.2.2 INFLUENCE OF REACTION CO-SOLVENT & TEMPERATURE ....43
3.2.3 INFLUENCE OF REACTANTS...... 44
3.3 ACTIVE MATERIAL OF PD/C ...... 46
vii 3.3.1 PD DEACTIVATION BY POLY(4-VINYLRIDINE)...... 46
3.3.2 MECHANISM OF PD DEACTIVATION BY PVPY...... 48
3.3.3 QUANTIFICATION OF THE HOMO- AND HETERO-GENEOUS
CATALYTIC PATHWAY ...... 50
3.4 REMOVAL OF LEACHED HOMOGENEOUS PD ...... 52
3.5 OXYGEN EFFECT ON THE PD/C-CATALYZED REACTION ...... 54
3.6 PD-LEACHING IN ORGANIC SOLVENTS...... 55
3.7 CONCLUSION...... 57
4. BASE- AND LIGAND-FREE PD/C-CATALYZED HOMOCOUPLING
OF ARYLBORONIC ACIDS ...... 70
4.1 EXPERIMENTAL...... 71
4.1.1 MATERIALS...... 71
4.1.2 MODEL REACTION FOR HOMOCOUPLING REACTIONS ...... 71
4.2 INVESTIGATION OF MODEL REACTIONS ...... 72
4.2.1 INFLUENCE OF WATER/2-PROPANOL RATIO...... 72
4.2.2 INFLUENCE OF REACTION TEMPERATURE ...... 73
4.2.3 I INFLUENCE OF CATALYST LOADING...... 74
4.2.4 PD(OAC)2 USED IN THE OPTIMAL CONDITIONS ...... 74
4.3 PD/C-CATALYZED HOMOCOUPLINGS OF ARYLBORONIC ACIDS ...... 75
4.3.1 EXPERIMENTAL OBSERVATIONS ...... 75
4.3.2 INFLUENCE OF FUNCTIONAL GROUPS BY DFT STUDIES ...... 75
4.3.3 EXPLORATION OF PALLADIUM-SULFUR AFFINITY ...... 76
4.4 CONCLUSION...... 77
5. DEVELOPMENT OF A LAB-SCALE HYDROGENATION SYSTEM.85
5.1 SAFETY OF HYDROGEN OPERATION...... 85
viii 5.2 DESIGN AND INSTITUTION OF HYDROGENATION SYSTEM ...... 86
5.3 ENANTIOSELECTIVE HYDROGENATION OF ETHYLPYRUVATE...... 87
5.3.1 EXPERIMENTAL...... 87
5.3.2 RESULTS AND DISCUSSION...... 88
6. CLOSURE AND FUTURE WORK...... 101
7. APPENDIX...... 103
7.1 APPENDIX 1: DERVIATIONS OF THE THEORETICAL RATE EXPRESSION
FOR HOMOGENEOUS PD-CATALYZED SUZUKI COUPLINGS ...... 103
7.2 APPENDIX 2: DERVIATIONS OF THE THEORETICAL RATE EXPRESSION
FOR HETEROGENEOUS PD-CATALYZED SUZUKI COUPLINGS ...... 109
8. REFERENCES...... 116
9. CURRICULUM VITAE...... 123
ix LIST OF TABLES
Table 1-1: Selected coupling reactions...... 11
Table 2-1: Measurement of the molar enthalpy of the preparation of biphenylacetic
acids in an RC1 ...... 28
Table 3-1: Conversions for premixing schemes with different components of the
reaction mixture...... 59
Table 3-2: Conversions of the Pd/C-catalyzed reaction in pure organic solvents and
Na2CO3 or triethylamine...... 60
Table 4-1: Optimization of conditions for Pd/C-catalyzed homocoupling reactions of
phenylboronic acid...... 79
Table 4-2: Base- and ligand free Pd/C-catalyzed homocoupling of substituted
arylboronic acids...... 80
Table 4-3: Computed free energy differences (B3LYP/SDD/6-31+G(d,p) and PCM
water solvation model) for species involved in the oxidative addition of Pd(0) to
boronic acid...... 81
Table 5-1: Safety of hydrogen operation ...... 90
x LIST OF FIGURES AND SCHEMES
Figure 2-1: Conversion of 4-bromophenylacetic acid as a function of time for
reactions at 55 oC and 65 oC from RC1 data and time-corrected HPLC
measurement ...... 29
Figure 2-2: (a) RC1 conversion data of 4-bromophenylacetic acid as a function of
time at different agitation speeds. (b) Initial rates from RC1 conversion data at
different agitation speeds...... 30
Figure 2-3: (a) RC1 conversion data of 4-bromophenylacetic acid as a function of
time with different Pd/C loadings. (b) Initial rates from RC1 conversion data
with different Pd/C loadings...... 31
Figure 2-4: (a) RC1 conversion data of 4-bromophenylacetic acid as a function of
time with different Na2CO3 loadings. (b) Initial rates from RC1 conversion
data with different Na2CO3 loadings...... 32
Figure 2-5: (a) RC1 conversion data of 4-bromophenylacetic acid as a function of
time with different 4-bromophenylacetic acid loadings. (b) Initial rates from
RC1 conversion data with different 4-bromophenylacetic acid loadings...... 33
Figure 2-6: (a) RC1 conversion data of 4-bromophenylacetic acid as a function of
time with different phenylboronic acid loadings. (b) Initial rates from RC1
conversion data with different phenylboronic acid loadings...... 34
Figure 2-7: (a) RC1 conversion data of 4-bromophenylacetic acid as a function of
time at different reaction temperatures. (b) Arrhenius Plot to estimate the
activation energy and Arrhenius constant of the model reaction...... 35 xi Figure 2-8: (a) RC1 conversion data of 4-bromophenylacetic acid as a function of
time with different base species. (b) pH as a function of time with different
base species...... 36
Figure 2-9: (a) RC1 conversion data of 4-bromophenylacetic acid as a function of
time with different water/2-propanol ratios. (b) pH as a function of time with
different water/2-propanol ratios...... 37
Figure 2-10: (a) RC1 conversion data of 4-bromophenylacetic acid as a function
of time with different organic solvents. (b) pH as a function of time with
different organic solvents...... 38
Figure 3-1: Conversion of 4-bromophenylacetic acid as a function of time under
standard conditions (■) and removed Pd/C after 8 minutes (•)...... 61
Figure 3-2: (a) RC1 conversion data of 4-bromophenylacetic acid as a function
time for different amounts of PVPy. (b) RC1 conversion data of
4-bromophenylacetic acid as a function time for different amounts of PVPy
(Enlarged) ...... 62
Figure 3-3: RC1 conversion data of 4-bromophenylacetic acid as a function of
time for different PVPy addition schemes with Pd(OAc)2 ...... 63
Figure 3-4: Conversion of 4-bromophenylacetic acid as a function of time under
PVPy treatment at 65 oC (■) and at room temperature (•) when Pd/C was
removed after 8 minutes...... 64
Figure 3-5: Conversions of 4-bromophenylacetic acid as a function of time under
regular conditions (■), N2 purged (•), sparging Air during the entire reaction
(▲), and sparging N2 during the entire reaction (▼) ...... 65
xii Figure 4-1: Conversion of phenylboronic acid (▼) and yields of biphenyl (▲),
benzene(●), and phenol( ) as a function of time...... 82
Figure 4-2: Optimal geometries of Pd-boronic acid complex, transition state for Pd
insertion into the C-B bond, and the insertion (rearrangement) product ...... 82
Figure 5-1: Picture of the reaction system ...... 91
Figure 5-2: Picture of the central part of the reaction system...... 91
Figure 5-3: Picture of the calcination system ...... 92
Figure 5-4: Picture of the control board for the calcinations system...... 92
Figure 5-5: Picture of the gas chromatograph system ...... 93
Figure 5-6: Picture of the rear part of the GC system...... 93
Figure 5-7: GC spectrum of the first testing model reaction ...... 94
Figure 5-8: GC spectrum of the second testing model reaction...... 95
Figure 5-9: GC spectrum of the third testing model reaction ...... 96
Figure 5-10: GC spectrum of the forth testing model reaction...... 97
Scheme 1-1: Suzuki couplings...... 12
Scheme 1-2: Homocoupling of Arylboronic acids ...... 12
Scheme 1-3: Enantioselective hydrogenation of α-ketoesters with cinchona
alkaloid modifiers ...... 13
Scheme 2-1: The model reaction for Pd/C-catalyzed Suzuki couplings...... 39
xiii Scheme 2-2: Proposed catalytic cycle for homogeneous Suzuki couplings...... 39
Scheme 3-1: Proposed catalytic cycle of Pd/C-catalyzed Suzuki couplings ...... 66
Scheme 3-2: Schematic of heterogeneous and homogeneous Suzuki couplings,
catalyzed by Pd/C ...... 67
Scheme 3-3: Schematic of the proposed mechanism of Pd deactivation by PVPy
for heterogeneous Pd and homogeneous Pd, respectively...... 68
Scheme 3-4: Optimal geometries of the complexes of Pd(II) species and pyridines
by DFT calculation with model B3LYP/SDD/6-31G...... 69
Scheme 3-5: The pathways of Pd after leaching. kl, kde are the leaching and
deactivation constants ...... 69
Scheme 4-1: Model reaction for base- and ligand-free Pd/C-catalyzed
homocoupling of aryl-boronic acids ...... 83
Scheme 4-2: Competition between homocoupling and protodeboronation of
arylboronic acids: a higher yield of biaryls at higher temperature implies Eah
> Eap1, Eap2...... 83
Scheme 4-3: Proposed mechanism for the oxidative addition of Pd(0) to
arylboronic acid...... 84
Scheme 4-4: Energy comparisons of Pd(0) complexes formed with
p-MeS-PhB(OH)2 and p-MeO-PhB(OH)2...... 84
Scheme 5-1: First process flow diagram (PFD) of the hydrogenation system ...... 98
Scheme 5-2: Second revised PFD of the hydrogenation system ...... 98
xiv Scheme 5-3: Third revised PFD of the hydrogenation system...... 99
Scheme 5-4: Model reaction for enantioselective hydrogenation using
Cinchonidine-modified Pt catalysts ...... 100
xv 1
1. INTRODUCTION
1.1 Heterogeneous Catalysis
Catalysis, which is a term created by Baron J. J. Berzelius in 1835, describes the ability of a substance (called the catalyst) to accelerate a chemical reaction without being consumed or chemically altered in the process [1]. During the catalytic process, catalysts can significantly affect the rate of a reaction by providing an alternative route, although the equilibrium composition of reactants and products remains the same due to thermodynamic constraints. Compared to an uncatalyzed reaction, the catalytic route has lower activation energies, which enhances the rate of the reaction. Typically, a catalytic cycle contains three steps: (1) unoccupied active sites of the catalyst adsorb reactants to form activated complexes, (2) the activated complexes undergo chemical conversions to products; and (3) the products desorb from the active sites. Then the unoccupied active sites adsorb reactants again to repeat these three steps.
Depending on the physical properties of the catalysts, catalysis can be divided into homogeneous and heterogeneous systems. Each system has its own specific advantages and disadvantages. Homogeneous catalysts typically offer high catalytic activity and selectivity, but complicate separation and may lead to metal contamination, which makes homogenous catalysts less favorable. For all practical consideration, heterogeneous catalysts offer easy separation, minimize metal contamination and allow recycling of the expensive catalysts. In order to reduce metal contamination, the pharmaceutical industry is interested in heterogeneous catalysis.
Heterogeneous catalysts usually contain transition-metals, supported on alumina, carbon, silica or zeolites, such as Cr2O3/Al2O3 for dehydrogenations, Pd/C
2
or Pt/C for hydrogenations, V2O5/silica for oxidations and Pt/zeolite for
acid-catalyzed reactions [2]. In addition to metal- or metal oxide-supported
catalysts, there has been a significant interest in the immobilization of homogeneous
catalysts. Immobilization of homogeneous catalysts was first demonstrated
successfully by [Ru(BINAP- 4SO3Na(C6H6)Cl)Cl] porous glass particle (CPG-240),
which is used commercially for the synthesis of (S)-naproxan [3].
1.2 Coupling Reactions
Coupling reactions, which involve the formation of carbon-carbon bonds, are a
class of catalytic reactions where two hydrocarbons are coupled in the presence of
metal catalysts with or without bases [4-9]. They have become important tools not
only for the preparation of basic organic molecules in chemical industry but also for
the synthesis of complex bio-active compounds in pharmaceutical and agricultural
industries.
Depending on the initial reactants, coupling reactions can be divided into two
coupling types, i.e., homo-couplings (R-X + R-X R-R, R usually refers to aryl- or
alkyl- groups) and cross-couplings, which can be expressed as follows:
Homo-couplings: R-X + R-X R-R
Cross-copulings: R-X + R’-Y R-R’
(R, R’ usually refer to aryl- or alkyl- groups.) The homo-coupling refers to a reaction where two molecules of the same type react to form a new symmetric compound, such as the Wurtz reaction and the Ullmann reactions (See Table 1-1).
Cross-coupling reactions are the coupling reaction where two different molecules react to generate a new asymmetric compound. Examples include Suzuki couplings and Heck reactions (See Table 1-1).
3
The study of coupling reactions can be tracked back to the middle of the nineteenth century [10]. During the past 150 years, numerous types of coupling reactions under diverse conditions have been developed and named after the scientists who first reported them. A few essential and commonly used coupling reactions are listed in Table 1-1. The Wurtz reaction [10] reported in 1855 is the homocoupling of alkyl-halides, which can be carried out under anhydrous conditions using metal sodium. Later, a few copper-catalyzed homocoupling reactions were reported, such as the Glaser reactions (1869) [11] and Ullmann reactions (1901)
[12,13]. In 1924, an early cross-coupling reaction was reported as
Gomberg-Bachmann reaction [14], where aromatic hydrocarbons can couple with diazonium salts in the presence of the base to obtain many asymmetric biaryls for the first time. However, the yields of the desired products at that moment were less than 40%. In 1970s, when palladium catalysts were introduced for coupling reactions, several important cross-coupling reactions were established, in which products were obtained in good to excellent yields. Typical examples are Heck reactions (1972) [18,19], Sonogashira reactions (1973) [20], Stille reactions (1977)
[21] and the Suzuki couplings (1979) [22].
Among those commonly used coupling reactions, Suzuki couplings are the most popular and widely-adopted in diverse applications in the pharmaceutical industry.
1.3 Suzuki Couplings
Suzuki coupling (Scheme 1-1), i.e., the formation of carbon-carbon bonds between organo-borates and organo-halides, organo-triflates or organo-tosylates, has been an efficient and practical strategy for the preparation of functionalized biaryls
4
[24-26]. Because of the mild reaction conditions (water can be used) and the ability
to tolerate a variety of organic functionality, Suzuki couplings help to simplify the
synthetic steps for known compounds and novel fine chemicals in various
applications. Examples include efficient coupling of heteroaryl bromides with
arylboronic acids [27], the development of new antiangiogenic tyrosine kinase for
anti-tumor-growth [28] and phosphodiesterase IV inhibitors for the intervention of
arthritis, asthma, and colitis [29]. Suzuki couplings are also important for the
synthesis of functional materials and supported catalysts, e.g., for the immobilization
of organometallic complexes onto heterogeneous supports [30].
From the perspective of catalysis science, Suzuki coupling is a versatile
reaction, which can be catalyzed with all forms of palladium with/without various
ligands as catalysts or precatalysts [9]. Moreover, in many cases, a minute amount of
palladium (at ppm or ppb level) is sufficient to obtain good product yields [31-33],
whereas in others, 10 mole % or higher catalyst loading is required to observe
significant amounts of products [9]. In addition to palladium, nickel-[34] and
platinum-containing catalysts [35] are used for Suzuki couplings.
The first Suzuki coupling was carried out by a homogeneous catalyst,
Pd(PPh3)4, with EtONa-EtOH as base in boiling benzene [22]. After that, Pd(PPh3)4 became the most commonly used catalyst for Suzuki couplings [25]. However,
PdCl2(PPh3)2 and Pd(OAc)2 with phospine ligands were also frequently used due to the stability to air and favorable activity [36-38]. In the early 1990s, Pd(OAc)2 [39]
or PdCl2[40] were applied to successfully carry out the coupling of arylboronic acids with haloarene. In order to prevent the side effects of phosphine in Suzuki couplings
(e.g., phosphine contamination), the use of ligandless Pd-catalysts and non-phosphorus ligands was of interest [41,42]. For each catalyst, a different
5
combination of bases and solvents has to be used in order to achieve favorable
- 2- activity and selectivity: different bases, which contain basic groups of OH , CO3 ,
2- 3- - - - HCO3 , PO4 , F , OBu or OEt cations, have been utilized for Suzuki couplings
with alcohols (methanol, ethanol, isopropanol or butanol), toluene,
dimethylacetamide (DMA) dimethyl ether(DME), dimethyl-formamide (DMF), and
tetrahydrofuran (THF) as a solvent [25,26]. In recent years, ligands for palladium
catalysts (either phosphorus-based or nonphosphorus) were continuously explored to
improve activation of aryl chlorides [43-45] and the stability of Pd-species [46,47]
and to develop-soluble ligands [48,49].
Although homogeneous Pd-catalysts provide high reactivity, the problems with
ligand pollution, catalyst removal and metal leaching make the use of heterogeneous
catalysts desirable.
Heterogeneous palladium on carbon (Pd/C) was first reported for the coupling
of 4-bromophenylacetic acid and phenylboronic acid [50]. Easy removal from the
reaction mixture by filtration offers significant practical advantages. By using a co-solvent water/alcohol (9:1 in volume ratio), hazardous reaction solvents can be avoided. Pd/C is also a reusable catalyst. For example, Sakurai et al. [51] studied the
Suzuki coupling of 4-iodophenol and phenylboronic acid in water and observed favorable activities of Pd/C even after the fifth run. However, recent studies showed that Pd/C is not a truly heterogeneous catalyst [52,33]. Instead, palladium leaches from the carbon support and after the reaction is completed, re-adsorbs back on the carbon support. Although Pd-leaching was observed, a detailed understanding of the
Pd-leaching mechanism is still lacking.
In addition to Pd/C, Pd nanoparticles supported by silica [53], zeolites [54], polymers [55], and layered hydroxides [56] were explored and successfully applied
6
for Suzuki couplings. In addition to act as a support for Pd, homogeneous Pd
complexes immobilized onto solid materials (such as silicas [57,58], zeolites [59,60]
and polymers [61,62]) are of interest to develop truly heterogeneous systems.
Although every system shows remarkable reactivity for selected Suzuki couplings,
metal-leaching is a general problem in many cases. One study reported that solvent
selection may be a way of reducing Pd-leaching [59].
1.4 Homocoupling of Arylboronic Acids
Homocoupling of arylboronic acids (Scheme 1-2), also called the “Suzuki-type
self-coupling reaction” [63,64], is the formation of carbon-carbon bonds during the
coupling of two molecules of the same arylboronic acid. This provides a
straightforward method to synthesize symmetrical biaryls. Similar to asymmetrical
biaryls, symmetrical biaryls are also important building blocks for natural products,
ligands in catalysis, and advanced pharmaceuticals, such as steganone [65], chiral
6,6’-bis(oxazolyl)-1,1’-biphenyls [66], and glucocorticoid receptor antagonists [67].
Homocoupling of arylboronic acids, which can be observed during some
Suzuki couplings, was first reported by Miyaura and Suzuki in 1987 [63]. They
carried out homocoupling of phenylboronic acid to biphenyl in anhydrous conditions
using Pd(OAc)2 with PPh3 as catalyst and Cu(OAc)2 under N2. Later, some catalysts commonly used for Suzuki couplings were applied to the homocoupling of arylboronic acids, such as Pd(PPh3)4 [68], Pd(OAc)2 [69], and Pd(II) complexes
(e.g., PdCl2(PPh3)2, PdCl2(dppb), Pd(MeCN)2) [70]. Typically, homocouplings of
arylboronic acids are carried out using homogeneous Pd catalysts with bases and/or
oxidants dissolved in organic solvents or solvent mixtures. However, in 1995,
Moreno-Manas et al. [64] reported that neither bases nor oxidants were necessary in
7 the homocoupling reaction. They also observed that the reaction can perform well under air, without excluding oxygen. After 2000, when environmental concerns were emphasized, several reaction systems using water or aqueous media as a reaction solvent were developed [71-73].
Although the known catalytic systems result in excellent yields, they have several disadvantages: (1) the ligands of the homogeneous catalysts may react to form undesired products, such as mono-substitued biaryls (R-Ph-Ph-H); (2) homogeneous catalysts are difficult to recover and to reuse; (3) the required reagents constitute additional costs for materials and for product separations; and (4) the use of some organic solvents, such as toluene and dimethylether, poses environmental concerns. A novel system, that eliminates these disadvantages, would be ideal for the synthesis of biaryls in terms of economics and efficiency.
1.5 Computational chemistry by DFT method
Computational chemistry, based on molecular and quantum mechanics, can be used for calculating the optimal geometries of molecules, electronic structures, bond energy between two atoms, enthalpies of reactions and activation energies of reactions, which are useful for predicting properties and the reactivity of a given system. It is a powerful tool to complement and support experimental work.
The fundamental equations, which govern computational chemistry, are
Newton’s 2nd Law (the equation of motion in classical mechanics) and the
Schroedinger Equation (the equation of motion in quantum mechanics) [74]. Based on these two equations and some other theories (e.g., Born-Oppenheimer
Approximation and Pauli principle), a theory was developed and several methods were established, such as molecular mechanics, semi-empirical and empirical,
8
Hartree-Fork (HF), and Density Functional Theory (DFT) methods. Among them, probably the most popular method nowadays is DFT.
DFT depends on two theorems proposed by Pierre Hohenberg and Walter
Kohn in 1964 [75,76]. The Hohenberg-Kohn existence theorem demonstrates that the electronic energy of the system may be written as a function of the electron density; the Hohenberg-Kohn variational theorem describes that choosing different electron densities, which provide lower energies, may minimize the total electronic energy of the system approaching the correct one. The method based on this theory allows us to obtain chemically more accurate thermo-information of a large-size system from computational chemistry. For example, by DFT calculations in vacuo with model B3LYP/6-311+G(d,p) for the coupling of 4-bromophenylboronic acids and phenylboronic acid, a molar heat of reaction of -233.64 KJ/mole was obtained, which is in good agreement with the experimental data (-224.01 KJ/mole) [33].
Nowadays, there are dozens of software tools supporting DFT calculations.
The software used in our research is Gaussian 03, which is developed by Gaussian,
Inc [77].
For Suzuki couplings, computational studies were carried out in the literature.
For example, Davies et al. [78] performed a theoretical study of the intermediate palladium complexes and their influence on various borates with various
β-chlorovinamidimium salts. Piechaczyk et al. [79] used computational analysis for analyzing experimental work on catalyst-development of palladium complexes.
1.6 Bimetallic Catalysts Catalyzed Enantioselective Hydrogenation
In addition to coupling reactions, enantioselective hydrogenations are another important strategy to synthesize optically pure chiral compound for pharmaceuticals,
9
agrochemicals, flavors and fragrances [80,81]. They are useful for several important
reactions, such as the reduction of functionalized C=O, C=C, and C=N groups.
Although some selective homogeneous catalysts [82,83] exist for enantioselective
hydrogenations, either their activity and stability are low, or they are not favorable
for industrial use, because of economic and practical consideration. Heterogeneous
enantioselective hydrogenations are thus gaining importance.
Heterogeneous enantioselective hydrogenations typically utilize single-metal
catalysts, such as Pt, Ni, or their supported catalysts. Only a few studies using
bimetallic catalysts for enantioselective hydrogenations were reported, such as
Ru/(Pd, Pt, Sn, Cu, or Ag) [84], Ni/Au [85], and Ni/Pd [86]. However, these
catalysts operate at high temperature, 333~373 K. Ni/Pt(111) surface [87] and
Co/Pt(111) surface [88], developed by Chen’s group at Chemical Engineering
Department in University of Delaware, showed low-temperature activity, which is
not seen with pure Ni, Co, or Pt metal surfaces. Especially for Co/Pt(111), the
desorption of hydrogen on the surface of Co/Pt(111) (Co is at 0.4~0.8 monolayer on
Pt(111)) occurs at 148 K, which is lower than pure Pt(111) (283 K) or a thick Co file
on Pt (111) (270 K) [88]. This shows the possibility for low-temperature
hydrogenations. In addition, Englisch et al. [89] observed that the addition of Co or
Ni to Pt/SiO2 increases three times the hydrogenation activity of the catalyst. Hence, applying Co/Pt/γ-Al2O3 to enantioselective hydrogenation is expected to achieve a
o higher conversion and a higher selectivity than Pt/Al2O3 below 0 C.
In the area of heterogeneous enantioselective hydrogenations, there exist two essential catalytic systems, i.e., the hydrogenation of α-ketoesters with cinchona alkaloids modified Pt [90] (Scheme 1-3) and β-ketoesters with tartaric acid modified
10
Ni [91]. In our work, we intend to develop a system for the use of Co/Pt/γ-Al2O3 as a catalyst for the hydrogenation of α-ketoesters with cinchona alkaloids modifiers.
1.7 Research Objectives
Our research aims to explore Pd/C-catalyzed Suzuki couplings in detail,
including kinetic studies, mechanism investigations, and the development of a rate
expression. Furthermore, we intend to provide a more detailed understanding of
Pd/C-catalyzed homocoupling of arylboronic acids (Suzuki self-couplings), which is
an exciting finding during the study of Suzuki couplings. Chapter 2, by using a
model coupling reaction of biphenylacetic acid, discusses the influence of reactants,
bases, solvents and temperature on the reaction kinetics and the mechanisms. In
addition, a rate expression for Pd/C-catalyzed Suzuki couplings is developed.
Chapter 3 describes a detailed investigation of Pd-leaching from Pd/C in Suzuki
couplings and provides a novel method to remove Pd-residues using PVPy
(Poly(4-vinylpyridine)). Chapter 4 demonstrates that Pd/C can catalyze
homocoupling of arylboronic acids under a base- and ligand-free condition, which
was observed during the Pd-leaching study in Chapter 3. Lastly, Chapter 5 presents
the development of a lab-scale hydrogenation system for the hydrogenation of
ethylpyruvate catalyzed by Pt bimetallic catalysts.
11
Tables
Table 1-1. Selected coupling reactions
Reactions Year Reactant A Reactant B Catalyst Base requirement
Wurtz Reaction[10] 1855 Alkyl-X Na No
Glaser Reaction[11] 1869 Alkynyl-H Cu Yes
Ullmann Reaction[12,13] 1901 Aryl-X Cu Yes
Gomberg-Bachmann 1924 Aryl-N2-X Aryl-H Yes Reaction[14]
Cadiot-Chodkiewicz 1957 Alkynyl-X Alkynyl-H Cu No Coupling[15]
Kumada Coupling[16,17] 1972 Aryl-X Aryl-Mg-X Ni, Pd No
Vinyl-X
Heck Reaction[18,19] 1972 Aryl-X Alkene Pd Yes
Vinyl-X
Sonogashira 1973 Aryl-X Alkynyl-H Pd, Cu Yes Reaction[20] Vinyl-X
[21] Stille Reaction 1977 Aryl-X Aryl-SnR3 Pd Yes
Vinyl-X
[22] Suzuki Coupling 1979 Aryl-X Aryl-B(OH)2 Pd Yes
Vinyl-X
[23] Hiyama Coupling 1988 Aryl-X Aryl-SiR3 Pd Yes
Vinyl-X * X refers to halide species, such as Cl, Br, and I.
12
Schemes
Scheme 1-1 Suzuki couplings.
Scheme 1-2 Homocoupling of Arylboronic acids.
13
Scheme 1-3 Enantioselective hydrogenation of α-ketoesters with cinchona alkaloid modifiers.
14
2. INVESTIGATION OF PD/C-CATALALYZED SUZUKI COUPLINGS
In 1997, Gala et al. [50] first introduced heterogeneous palladium on carbon
for use in Suzuki couplings by demonstrating the coupling of 4-bromophenylacetic
acid and phenylboronic acid. They revealed several advantages of Pd/C in this type
of reaction: (1) favorable activity at 65 oC, (2) easy catalyst removal from the reaction mixture by filtration with minimal metal leaching, and (3) the possibility of using a water/alcohol mixture as the reaction solvent to avoid the use of hazardous organic solvents.
While a number of publications have demonstrated the effectiveness of heterogeneous Pd/C as a suitable catalyst for Suzuki couplings, a detailed investigation of various reaction factors, e.g., the effect of the base or solvents, on the performance of Pd/C has not been reported in the literature. Moreover, the catalytic mechanism of Pd/C-catalyzed Suzuki coupling also remains unclear. Thus, by using the model coupling reaction of biphenylacetic acid (Scheme 2-1), we aimed to provide a better understanding of the reaction mechanism and to determine which parameter(s) may influence the catalyst performance. We also intended to derive a rate expression to describe the reaction behavior of Pd/C-catalyzed Suzuki couplings.
2.1 Experimental
2.1.1 Materials
In this study we used commercially available 4-bromophenylacetic acid
(Aldrich, 98%), phenylboronic acid (Aldrich, 95%), Pd/C (Aldrich, 5wt%, Degussa type, particle size 28~34 µm), sodium carbonate (Fisher), potassium carbonate
(Aldrich), sodium hydroxide (Fisher), sodium bicarbonate (Fisher), Na2HPO4
15
(Fisher), DMA (Aldrich, 99%), DMF (Acros, 99%), methanol (Fisher), Ethanol
(Fisher), 2-propanol (Fisher). No materials required further purification.
2.1.2 Model Reactions for Suzuki Couplings
Model Suzuki couplings were carried out in an RC1 (Mettler Toledo Reaction
Calorimeter), i.e., a 1-liter jacketed round-bottom glass reactor containing a
Hasteloy head and a 10 cm-length anchor impeller. Both the reactor and the impeller
were cleaned thoroughly with acetone, 6 M hydrogen chloride solution, and
de-ionized water followed by drying at room temperature before use. Phenylacetic
acid 1 (29 mmole) and phenylboronic acid 2 (32 mmole) were added to 500 ml
reaction solvent (water:2-PROPANOL 9:1 volume ratio) at room temperature. The
reaction mixture was then heated to 65 oC with 250 rpm agitation. When the temperature reached the set point, sodium carbonate (64 mmole) was added. After
15 minutes, Pd/C (0.22 mmole of Pd) was added to carry out the reaction.
2.1.3 RC1 Calorimetric Assay
The RC1 was used to carry out the reaction and to analyze the reaction kinetics.
In the RC1, a dynamic heat transfer system can identify and monitor any thermal events where a heat-flow-over-time plot is generated. Isothermal conditions (dTr/dt
= 0, Tr is the temperature inside the reactor) were achieved by determining and calibrating all external thermal influences except for the desired reaction, including mixing events. An energy balance around the isothermal reactor shows that heat flow is directly proportional to the reaction rate:
dC q(t) = ∆H V (1) Rxn dt
where q(t) is the instantaneous heat flow (w), ∆HRxn is the heat of reaction (J/mol).
V represents the reactor volume (l) and dC/dt is the reaction rate (M/s). However, as
seen in Equation 2, the heat transfer properties of the reactor, as defined by a second
16 energy balance around the outer surface of the reactor, identifies two contributions; the reaction, as well as the heat flow to the jacket, i.e.,
dTr q = UA(Tr − Tj) + mC , (2) p dt where U is the heat transfer coefficient (W/m2/K). A represents the total surface area, and Cp is the heat capacity of the reactor and its contents. Calibration experiments before the addition of the catalyst and at the completion of the reaction are necessary to determine Cpr and U. By using a heating probe immersed in the reactor to provide a known heat flow under isothermal conditions and by measuring the temperature of the reactor, Tr, and jacket, Tj, the heat transfer coefficients for the reactor were calculated. Heat capacities were measured by subjecting the reactor contents to a known temperature ramp, while the heat flow through the reactor wall equals the enthalpy accumulation (q = 0). Comparison of Cpr and U values before and after the reaction were used to make sure that no significant changes occurred. Consistent values over the course of the study were found, which validates the experiment.
q(ti )dr Conversion(%) = ∫ ×100 (3) ∫ q(t)dr
Reaction conversion was calculated directly by the measured heat flow.
Dividing the partial heat flow or area under the heat flow curve at any time ti by the total heat flow for the entire reaction equals conversion, as shown in Equation 3.
2.1.4 HPLC Analyses
HPLC (High Performance Liquid Chromatograph) analyses were performed on a Shimadzu SP-10 liquid chromatograph equipped with a UV-Vis absorption detector and an Aligent zorbax eclipse XDB-C8 column. The HPLC mobile phases were 40% deionized water with 0.05% formic acid (Aldrich, 96%) and 60% methanol (Fisher) in volume ratio. The flow rate of the mobile phase was 1.2 ml per
17 minute. The wavelength of the detection light was set to 208 nm. 0.1 ml samples were extracted from the reactor over the course of the reaction. The samples were diluted in 20 ml of a 60% methanol/40% water solution and then filtered to remove the catalyst. The conversion of the reaction was based on the consumption of the aryl-halide. If cA is the concentration of the aryl-halide, the conversion Y is defined as Y = [(cA,0-cA)/cA,0].
2.1.5 Experimental Validation
The enthalpy of the reaction, ∆h, is defined as the entire heat flow over the whole reaction; molar enthalpy of reaction, ∆H, is defined as ∆h divided by the mole number of reagents, n. For the same reaction in an isothermal batch reactor with no formation of side reaction, ∆h is proportional to n, and ∆H should be a constant value, i.e.,
∆h1 ∆h2 ∆H1 = = = ∆H 2 (4) n1 n2 where the subscripts represent different reactions.
In order to test the RC1, three reactions with different initial concentrations of the reagents were carried out, as shown in Table 2-1. Good consistency was observed, with the average molar enthalpy being -224.01 KJ/mole and the maximum deviation less than 1%. DFT calculations in vacuo with the model
B3LYP/6-311+G(d,p) were carried out with Gaussian 03. A molar heat of reaction of -233.64 KJ/mole was obtained, which is in good agreement with the experimental data, given that no detailed solvation model was used.
HPLC analysis was also used to validate the calorimetry data. Since the reaction continued until the catalyst was removed by filtration, the HPLC data had to be corrected by a two-minute delay. Fig. 2-1 compares the time-corrected HPLC
18 conversion data with those generated by the RC1. As can be seen, the agreement is excellent.
2.2 Investigation of Reaction Parameters
2.2.1 Influence of Agitation
The performance of a reaction is affected by extrinsic and intrinsic factors at the same time. Extrinsic factors refer to mass transfer issues, which should be excluded from the kinetic study. In order to choose a proper stirring-speed, we first investigated the influence of agitation on reaction performance in order to ensure that the reactions are not under mass-transfer control.
Five experiments were carried out in RC1 with the stirring-speed at 50 rpm,
125 rpm, 200 rpm, 250 rpm, and 300 rpm, respectively. As shown in Fig. 2-2, the initial reaction rate depended on agitation at lower stirring-speed, but it became independent when agitation was over 200 rpm. This indicates that the stirring-speed should be over 200 rpm to prevent diffusion limitation from the reaction performance. Therefore, we chose 250 rpm in our system.
2.2.2 Influence of Catalyst Loading
Next, we examined the influence of catalyst loading on the Suzuki couplings.
Three experiments were carried out at 250 rpm agitation in which the base-case
Pd/C loading of 0.76 mole % (i.e., 0.22 mmole of Pd) was doubled, halved, or quartered. As shown in Fig. 2-3, the initial reaction rates were proportional to the catalyst loading. This indicates again that the reactions were run under a kinetically-controlled regime. Moreover, from the ln(rate) vs. ln(cat) plot, it shows that the reaction rate is proportional to the first order of catalyst loading, i.e., rate ∝ [cata.]1 .
19
2.2.3 Influence of Base Loading
After excluding the effect of mixing, we started exploring the influences of the reactants, i.e., the base, the bromide, and the borate.
The base is important for Suzuki couplings, as it is involved in the catalytic step of metathesis and the activation of the borate. According to the proposed catalytic cycle of homogeneous Suzuki couplings (Scheme 2-2), typically 2 moles eq. of OH- w.r.t the bromide are required for a reaction to be completed, where one mole is consumed in the metathesis and the other is used for the borate activation. In
2- our model reaction, we chose sodium carbonate as a base, where CO3 in water
- - produces OH , HCO3 and H2CO3. Considering the first and second dissociation
2- -4 -8 constants of CO3 (Kb1 is 2.1·10 , and Kb2 is 8.3·10 ), we assumed that 1 mole of sodium carbonate only yields 1 mole eq. of OH- in the reaction mixture. Therefore, initially we used 2.2 moles eq. of Na2CO3 to carry out a model reaction, in order to increase the reaction rate. To test this idea, three experiments were carried out with
1.1, 3.3, and 4.4 mole eq. of sodium carbonate. The RC1 conversion data and the initial reaction rates are shown in Fig. 2-4. It was interesting to observe that the initial rate slows down in both the cases of insufficient and excess base loading. This indicates that ca. 2 moles eq. of the base is the best choice for the system. Less or excess amount of the base reduces the reaction rate. This also may imply that [OH-] in the reaction mixture plays an important role in the reaction performance. A more detailed study of the influence of OH- will be discussed in Section 2.4.
Moreover, from the ln(rate) vs. ln(base) plot, it can be seen that rate ∝ [base]1 in the case of insufficient base loading, and that rate ∝ [base]−0.8 in the case of excess base loading.
20
2.2.4 Influences of Bromide and Borate Loading
Subsequently, we explored the influences of bromide and borate loading, respectively, in order to determine which catalytic step is the rate-limiting one.
To investigate the influence of bromide loading, three experiments were carried out in the RC1, one with a regular amount and two with different excess amounts of 1 (i.e., bromide:borate is 1, 2, and 3 to 1 in molar equivalence). In order to provide sufficient base loading, in this investigation, two times the regular amount of Na2CO3 (i.e., 4.4 moles eq.) was used in each reaction. The results are shown in
Fig. 2-5. The RC1 conversion data show small differences of the initial rate for various amounts of 1, which suggests that the reaction rate is independent of bromide concentration. This may imply that oxidative addition of Pd(0) to the bromide is not the rate-limiting step of Suzuki couplings.
In order to investigate the influence of borate loading, two more experiments were carried out with excess amount of 2 (bromide:borate is 1 to 2 and 3 in molar equivalence). Two times the regular amount of Na2CO3 was used in each experiment. Results are shown in Fig. 2-6. RC1 conversion curves clearly show that the reaction performance strongly depends on the borate concentration in comparison to the bromide. This suggests that transmetalation is the rate-limiting step of the Suzuki coupling. Moreover, the ln(rate) vs. ln(borate) plot indicates that the reaction rate is of 1.4 order of borate concentration, i.e., rate ∝ [borate]1,4 .
2.2.5 Influence of Reaction Temperature
After exploring each reaction parameter, except for the temperature, the reaction rate can be expressed as:
rate = f ([catalyst],[base],[borate]) (5)
21
Based on our experimental results
rate = k[base][borate]1.4 = Ae −Ea / RT [base][borate]1.4 (6) [catalyst] where the rate constant (i.e., k), is described by the Arrhenius equation. A refers to pre-exponential factor, Ea is the activation energy (KJ/mole), R refers to ideal gas constant (J/Kmole), and T refers to temperature (K). This equation can only describe the reaction behavior when the base loading is less or equal to 2.2 moles eq.
From Equation 6, we can conclude: (1) 2 moles eq. of base should be used in a reaction. A lower amount of the base will result in a slower reaction. (2) Since rate ∝ [borate]1,4 , an excess amount of borate is recommended to accelerate the reaction.
In order to estimate the values of the activation energy and the pre-exponential factor three experiments were carried out at 45, 55, and 75 oC. The results are shown in Fig. 2-7. Based on these results we estimated that Ea is 100.0 KJ/mole and A is
5.73·1019. Inserting these two values into Equation 6, we get:
rate = 5.73×1019 e−100.0 / RT [base][borate]1.4 (7) [catalyst]
Equation 7 is a lumped/combined, experimental rate expression for describing
Pd/C-catalyzed Suzuki couplings based on our experimental observations. It is interesting to observe a “1.4” order on the borate concentration. A non-integer order indicates that there still exist some unexplained factors, which might be related to borate species, affecting the reaction performance. In order to elucidate the reaction mechanism, a theoretical derivation of the rate expression was performed.
22
2.3. Derivation of Theoretical Rate Expressions
Before deriving a theoretical expression, it was the goal to understand the catalytic pathways of Pd/C-catalyzed Suzuki couplings. In the literature (i.e., the group of Sun at Merck [52]) there are reports that Pd/C is a quasi-heterogeneous catalyst in Suzuki couplings. By monitoring the variation of free Pd concentration in the reaction mixture, they observed that palladium leaches from the support into the solution, catalyzes the reaction, reaches a maximum around the reaction conversion of 90%, and deposits back onto the support after completion of the reaction. This observation and the work by other groups led us to believe heterogeneous Pd/C actually catalyzes the reaction through a homogeneous pathway (for a detailed study see below).
Thus, we adopted the homogeneous catalytic cycle to derive the rate expression and we neglected Pd-leaching process.
2.3.1 Seven Elementary Reactions
The catalytic cycle can be divided into 7 elementary reactions, which can be expressed as follows:
Step I: Oxidative addition
Pd + R-Br ⎯⎯→k1 R-Pd-Br
r1 = k1[Pd][R-Br] (8)
Step II: Metathesis
R-Pd-Br + OH- ⎯⎯→k2 R-Pd-OH + Br-
- r2 = k2[R-Pd-Br][OH ] (9)
Step III: Transmetalation
- k3 - R-Pd-OH + R’-B(OH)3 ⎯⎯→ R-Pd-R’ + B(OH)4
23
- r3 = k3[R-Pd-OH][R’-B(OH)3 ] (10)
Step IV: Reductive elimination
R-Pd-R’ ⎯⎯→k4 R-R’ + Pd
r4 = k4[R-Pd-R’] (11)
Step V: Generation of hydroxide ion
CO 2- +H O ←⎯⎯⎯ ⎯⎯→k 5 HCO - + OH- 3 2 k5−1 3
3− − -1 [HCO ][OH ] K5 = k5/k5 = 2− (12) [CO3 ]
Step VI: Arylborate activation
R’-B(OH) + OH- ←⎯⎯⎯ ⎯⎯→k 6 R’-B(OH) - 2 k 6−1 3
− -1 [R'−B(OH )3 ] K6 = k6/k6 = − (13) [R'−B(OH ) 2 ][OH ]
Step VII: Compensation of hydroxide ion
B(OH) - ←⎯⎯⎯ ⎯⎯→k 7 B(OH) + OH- 4 k 7−1 3
− -1 [B(OH )3 ][OH ] K7 = k7/k7 = − (14) [B(OH ) 4 ]
2.3.2 Rate Expressions of the Assumed Rate-limiting Step
In the literature the oxidative addition [92] or transmetalation [52] were suggested as the possible rate-limiting step. Therefore, we intended to derive two theoretical rate expressions depending on these two possible steps, respectively.
(1) If oxidative addition is the rate-limiting step
the theoretical reaction rate would be expressed as:
rateT1 = r1 = [Pd][R − Br] (15)
24
By using mass balances of each species and the steady state assumption, the above equation becomes:
[Pd] rate = 0 (16) T1 1 1 1 1 + − + − + k1[R − Br] k2 [OH ] k3[R'−B(OH )3 ] k4 where [Pd]0 refers to initial concentration of Pd.
Because Step I is the RLS, we may further assume that k2, k3 and k4 are larger than k1. Then, the rate equation simplifies to:
[Pd] rate ≅ 0 = k [Pd] [R − Br] (17) T1 1 1 0
k1[R − Br]
By rearrangement we get
rateT1 = k1[R − Br] (18) [Pd]0
Equation 18 shows that the reaction mainly depends on the concentration of the bromide, if oxidative addition is the rate-limiting step.
(2) If transmetalation is the rate-limiting step
the reaction rate would be expressed as:
rateT 2 = r3 = k3[R − Pd − OH][R'−B(OH )3 ] (19)
Using the same procedure and by assuming that k1, k1 and k4 are >> k3, we obtain:
[Pd] rate ≅ 0 = k [Pd] [R'−B(OH ) − ] (20) T 2 1 3 0 3 − k3[R'−B(OH )3 ]
rateT 2 − i.e., = k3[R'−B(OH )3 ] (21) [Pd]0
- Because [R’-B(OH)3 ] in the equation can be expressed by a combination of
- [R’-B(OH)2] and [OH ] (Equation 13), Equation 21 becomes
25
rateT 2 − = k3 K 6 [OH ][R − B(OH ) 2 ] (22) [Pd]0
Equation 22 shows that the reaction depends on the concentration of hydroxide ion and the borate when transmetalation is the rate-limiting step. [OH-] is formed by various species, i.e., :
k [CO 2− ] + k −1[R'−B(OH ) − ] + k [B(OH ) − ] [OH − ] = 5 3 6 3 7 4 (23) −1 − −1 k1k2 [Pd][R − Br] + k5 [HCO3 ] + k6 [R'−B(OH ) 2 ] + k7 [B(OH )3 ]
Comparing the experimental rate expression one (Equation 7) with the two theoretical rate expressions (Equation 18 and 22), we find consistency between
Equation 7 and Equation 22, which confirms that transmetalation is the rate-limiting step in the Suzuki couplings.
Furthermore, Equation 23 clearly shows that the concentration of [OH-]
- depends on many factors such as [B(OH)4 ] and [B(OH)3] and the acidity of the bromide and the borate. This might explain the observation of a non-integer order on the borate concentration. In other words, the rate dependence [base][borate]0.4 derived from experimental observations might represent the influence of the overall
[OH-] concentration on the reaction.
2.4 pH-Effects on Pd/C-Catalyzed Suzuki Couplings
As previously described, OH- concentration plays an important role in the reaction performance. Therefore, in this section we investigate two pH-related factors, i.e., the species of the base and the reaction solvents.
2.4.1 Influence of Base species
Boronic acids without the addition of a base are not active for Suzuki couplings, because of the weak nucleophilicity of the organic groups on the boron.
The coordination of a negatively charged base to the boron atom is a key step to
26 increase its nucleophilicity, which activates boronic acids in the reaction. However, after we observed that an excess amount of the base does not accelerate the reaction, the question was raised if the hydroxyl ions (OH-) in the solution might be more important than the base.
To answer this question, four selected bases were used (Fig. 2-8(a)), and the reaction pH was monitored (Fig. 2-8(b)). The results clearly indicate that [OH-] strongly affects the reaction performance. The strong bases of K2CO3 and NaOH support the reaction much better than the weak bases NaHCO3 and Na2HPO4.
2.4.2 Influence of Reaction Co-solvent
[OH-] concentration in the solution may be affected not only by the base but also by the solvent. Consequently, we examined the effect of reaction solvents on the reaction performance. The solvent used in Suzuki couplings is a water/organic-solvent mixture. Different co-solvent ratios and organic solvents may change the reaction pH. To test the influence of co-solvent ratios, four experiments were carried out with water/2-propanol volume ratios of 20:1, 5:5, 3:7, and 1:9, respectively. The results were shown in Fig. 2-9. The reaction pH during the entire course of the reactions was in the range of 7.5~9.0. However, the variation of pH among various co-solvent ratios did not correlate with the reaction conversions. This investigation shows that higher fractions of 2-propanol are detrimental to the reaction and reduce the activity of Pd/C.
Furthermore, to test the influence of different organic solvents, MeOH, EtOH,
DMA, and DMF, were selected and mixed, respectively, with water in volume ratio
1:9. The reaction pH in Fig. 2-10(b) shows little variation for various organic solvents, which may be due to the high fraction of water in the co-solvent. However, small amounts of different organic solvents still result in different reaction
27 performance. The reaction conversion curves indicate that the reaction rates are IPA
> EtOH > MeOH and DMA >DMF. This may be due to the polarity of organic solvents, where the dielectric constant is IPA < EtOH < MeOH and DMA < DMF.
2.5 Conclusions
Pd/C-catalyzed Suzuki coupling was investigated using a model coupling reaction to form biphenylacetic acid. The main results of this work are:
Careful investigation of reaction parameters shows that the reaction rate mainly
depends on the concentration of the borate and the base for the same catalyst
loading and reaction temperature.
An excess amount of the borate is recommended to accelerate the reaction.
2 mole eq. of the base w.r.t the bromide is the best choice for Suzuki couplings.
Less or excess amount of the base are detrimental for the reaction.
Both experimental observations and theoretical derivations suggest that
transmetalation is the rate-limiting step for this type of Suzuki couplings.
Theoretical derivations also suggest that the derivatives of the borate and the
acidities of the bromide and borate may affect the reaction performance.
The investigation of the nature of the base shows that a sufficient amount of
hydroxide ion in the solvent is a critical factor for the reaction.
Higher fractions of organic solvents in the reaction mixture are detrimental for
the reaction and reduce the activity of Pd/C.
Organic solvents with lower dielectric constants may better support the reaction.
28
Tables
Table 2-1 Measurement of the molar enthalpy of the preparation of biphenylacetic
acids in an RC1.
Runs Condition [a] ∆H (kJ/mol) [b] Deviation
1 1x, 65 oC -225.85 0.8%
2 2x, 65 oC -223.61 -0.2%
3 4x, 65 oC -222.57 -0.6%
[a] 1x refers to 29 mmole 1, 36 mmole 2, 68 mmole of Na2CO3, and 0.45 mmole Pd/C in 500ml mixture of 10% 2-propanol in water. 2x and 4x stand for two and four times the amounts of 1 and 2 with the same amount of Pd/C. [b] Molar enthalpy calculated from reaction enthalpy of the RC1. [c] Deviation from the average molar heat of reaction, which equals -224.01 kJ/mol.
29
Figures
Fig. 2-1 Conversion of 4-bromophenylacetic acid as a function of time for reactions at 55 oC and 65 oC from RC1 data and time-corrected HPLC measurement
30
Fig. 2-2 (a) RC1 conversion data of 4-bromophenylacetic acid as a function of time at different agitation speeds. (b) Initial rates from RC1 conversion data at different agitation speeds.
31
Fig. 2-3 (a) RC1 conversion data of 4-bromophenylacetic acid as a function of time with different Pd/C loadings. (b) Initial rates from RC1 conversion data with different Pd/C loadings.
32
Fig. 2-4 (a) RC1 conversion data of 4-bromophenylacetic acid as a function of time with different Na2CO3 loadings. (b) Initial rates from RC1 conversion data with different Na2CO3 loadings.
33
Fig. 2-5 (a) RC1 conversion data of 4-bromophenylacetic acid as a function of time with different 4-bromophenylacetic acid loadings. (b) Initial rates from RC1 conversion data with different 4-bromophenylacetic acid loadings.
34
Fig. 2-6 (a) RC1 conversion data of 4-bromophenylacetic acid as a function of time with different phenylboronic acid loadings. (b) Initial rates from RC1 conversion data with different phenylboronic acid loadings.
35
Fig. 2-7 (a) RC1 conversion data of 4-bromophenylacetic acid as a function of time at different reaction temperatures. (b) Arrhenius Plot to estimate the activation energy and Arrhenius constant of the model reaction.
36
Fig. 2-8 (a) RC1 conversion data of 4-bromophenylacetic acid as a function of time with different base species. (b) pH as a function of time with different base species.
37
Fig. 2-9 (a) RC1 conversion data of 4-bromophenylacetic acid as a function of time with different water/2-propanol ratios. (b) pH as a function of time with different water/2-propanol ratios.
38
Fig. 2-10 (a) RC1 conversion data of 4-bromophenylacetic acid as a function of time with different organic solvents. (b) pH as a function of time with different organic solvents. Water/organic solvent is 9:1 in volume ratio.
39
Schemes
Scheme 2-1 The model reaction for Pd/C-catalyzed Suzuki couplings
RR' RBr 1 3 Pd(0)
IV I
- OH B(OH)3 RPd Br RPd R' VII
- - OH B(OH)4 II III V
- RPd OH - Na2CO3 R' B(OH)3 Br
OH- VI
R' B(OH)2 2
Scheme 2-2 Proposed catalytic cycle for homogeneous Suzuki couplings. I:
Oxidative addition; II: Metathesis; III: Transmetalation; IV: Reductive elimination. V: OH- generation; VI: boronic acid activation; VII: OH- compensation.
40
3. PD-LEACHING & PD-REMOVAL IN PD/C-CATALYZED SUZUKI
COUPLINGS
Pd/C is most frequently used for industrial applications among the catalysts of choice in Suzuki couplings, due to its high catalytic activity, low cost and commercial availability. Scanning transmission electron microscopy (STEM) pictures of commercial Pd/C catalysts show irregular palladium clusters of different sizes, randomly located on the carbon surface [93]. Thus, Pd/C is considered a heterogeneous catalyst, enabling straightforward removal of the catalyst from the reaction mixture with insignificant Pd-residuals [50,94]. This notion, however, has been challenged by several groups during recent years. For example, the group of
Sun at Merck proposed that Pd/C is a quasi-heterogeneous catalyst [52], where leached Pd catalyzes the reaction and re-adsorbs onto the carbon support after completion of the reaction.
Pd-leaching from Pd/C was also observed in Heck reactions [95-98], hydrodechlorinations [99] and during the isobutanol synthesis [100]. Particularly for
Heck reactions, detailed studies of the Pd-leaching from the heterogeneous catalyst
[97,98,101,102] and the Pd-reabsorption by the support [103,104] have been conducted.
In contrast to Heck reactions, a detailed experimental study of Pd-leaching during Suzuki couplings with Pd/C has not been performed. The objective of this work is to achieve a detailed understanding and offer experimental evidence of
Pd-leaching in Pd/C-catalyzed Suzuki couplings. Furthermore, we intended to provide a strategy for homogeneous Pd (Pd-residual) removal from the reaction mixture after the reaction has been completed. This is of interest especially for
41 pharmaceutical applications, where carryover of metal impurities may cause serious problems in the production of many formulations.
3.1 Experimental
3.1.1 Materials
In our study we used commercially available 4-bromophenylacetic acid
(Aldrich, 98%), 4-iodiobenzoic acid (Aldrich, 99%), phenylboronic acid (Aldrich,
95%), Pd/C (Aldrich, 5wt%, Degussa type, particle size 28~34 µm), palladium(II) acetate (Aldrich, 99.9%), sodium carbonate (Fisher), trimethylamine (Aldrich,
99.5%), 1,4 dioxanes (Fisher), DMA (Aldrich, 99%), DMF (Acros, 99%), methanol
(Fisher), 2-propanol (Fisher), THF (Alfa Aesar, 99.8%), toluene (Fisher), PVPy
(Aldrich, 2% crosslinked, powder, 60 mesh). No materials required further purification.
3.1.2 Model Reactions for Suzuki Couplings in a Small Scale
Model Suzuki couplings in this section were carried out in a 100 ml round-bottom glass reactor with a 1 cm-length stirring bar. Both the reactor and the stirring bar were cleaned thoroughly with acetone and 6 M hydrogen chloride solution and dried in a 110 oC oven for 4 hours before use. Phenylacetic acid (2.9 mmole), phenylboronic acid (3.2 mmole) and sodium carbonate (6.4 mmole) were added to 50 ml reaction solvent (IPA:water 1:9 volume ratio) at room temperature.
After adding Pd/C (0.01 mmole), the reaction mixture was heated to 65 oC to carry out the reaction. The reaction temperature was controlled by a light mineral oil
(Fisher) bath. Reactions were carried out at least twice to verify reproducibility of
42 the data. Variations were less than 5% (in one experiment 7%) of the reported values.
3.1.3 Analytical Measurements
The analytical tools for this work are HPLC (High Performance Liquid
Chromatograph) analyses and reaction calorimeter (ASI/Mettler-Toledo RC1). The detailed information is described in Section 2.1.3 and 2.1.4.
3.2 Pd-leaching of Pd/C
Biffis et al. [105] studied Heck reactions with Pd-supported catalysts and observed Pd-leaching only in the presence of an aryl-halide. On the basis of their work, Conlon et al. [52] proposed the hypothesis that Pd-leaching from Pd/C occurs after oxidative addition of the bromide. In this study, using the model coupling reaction of biphenylacetic acid 3 (Scheme 2-1) again, we provided experimental evidence to (partially) support this hypothesis. Furthermore, we carried out a detailed investigation of the mechanism of Pd-leaching from Pd/C during Suzuki coupling reactions.
3.2.1 Observation of Pd-leaching from Pd/C
First, the existence of Pd-leaching during our model reaction was verified using the filtration test, which is a straightforward method to distinguish homogeneous and heterogeneous catalytic activity, based on the comparison of the reaction progress before and after removal of the solid phase [106]. If the reaction proceeds after the removal of the solid catalyst - in this case Pd/C - by filtration, this is clear evidence that leaching forms homogeneous Pd in the filtrate which catalyzes the reaction. As shown in Fig. 3-1, nearly complete conversion of 1 was observed
43 around 15-20 minutes after the catalyst was removed using 0.45 µm syringe filters, which guaranteed a complete removal of solids (Pd/C particle size is 28~34µm). In another experiment, a reaction was carried out under standard conditions. After 8 minutes, Pd/C was removed from the reaction mixture, at a point when the conversion of 1 was 30%, but the reaction continued and reached 91% conversion after another 32 minutes. ICP (Inductively Coupled Plasma) analysis indicated that less than 1 ppm leached Pd existed in the filtrate after catalyst removal. These results clearly show that (1) a minute amount of leached Pd can catalyze a reaction and that (2) Pd-leaching does occur. Furthermore, this implies that leached Pd plays an important role in the high activity of Pd/C for Suzuki couplings.
(Note: there may be concern that vigorous mixing in the reaction flask could produce small Pd/C fragments that may pass through the syringe filter, thus biasing our results. However, experiments carried out without some of the reactants initially present (reported below) give no conversion after filtration and after all reactants were added. Had small fragments of Pd/C passed the syringe, the conversion would have been high. Consequently, the syringe filter effectively removes 100% of the solid phase and remaining activity is due to leached Pd.)
3.2.2 Influence of Reaction Co-solvent and Temperature
Since Pd leaching was observed during the reaction, we wanted to understand the cause of it. Various components may affect Pd-leaching, such as the aqueous co-solvent, the aryl-bromide, the aryl-borate and the base. All of these factors were examined and screened one by one. The impact of the aqueous co-solvent and of the reaction temperature was first examined. In order to observe significant Pd-leaching,
1 gram of Pd/C (i.e., 15 times the regular amount) was used in each experiment.
Two experiments were set up, where Pd/C was added to two flasks with only 50 ml
44 of IPA/water (1:9 volume ratio). These mixtures were then stirred for one hour at room temperature (RT) and at 75 oC. Then, Pd/C was removed by filtration and the filtrate was used as the reaction solvent for a regular reaction without adding any additional catalyst. If both experiments showed a low conversion, this would mean that both the solvent and the temperature have no effect on Pd-leaching, i.e., leaching is not caused by the dissolution of Pd atoms or clusters. The conversions of the reactions at RT and at 75 oC runs after 2 hours were 6% and 4% (Table 3-1), which indicates Pd-leaching does not occur during the premixing. This strongly suggests that Pd-leaching does not depend on the aqueous co-solvent and the temperature.
3.2.3 Influence of Reactants
These experiments clearly suggest that one or more of the reactants, i.e., the aryl-halide, the aryl-borate or the base, are the factors causing Pd-leaching. To investigate these possibilities, we tested which reactant premixed with Pd/C in
IPA/water causes Pd-leaching. Three experiments were carried out, where in each flask 1 gram of Pd/C was added to 50 ml of IPA/water (1:9 volume ratio) together with either phenylacetic acid 1, phenylboronic acid 2, or Na2CO3. The mixtures were stirred for one hour at 75 oC. Then, Pd/C was removed by filtration and the filtrate was used as the reaction solvent for a new reaction by adding the remaining reactants (for example, 2 and Na2CO3 were added, when 1 was premixed with Pd/C) without an additional catalyst. Conversions of these runs are shown in Table 2. The conversions of the runs of premixing Pd/C with 1 or 2 after 1 hour were 96% and
98%, which shows that homogeneous Pd exists in the filtrates and that Pd-leaching occurs in the presence of both aryl-bromide and aryl-borate. 0% conversion after premixing with Na2CO3 indicates that the base did not cause Pd-leaching.
45
In the case of premixing Pd/C with 1 (initially, only Pd/C and the aryl-bromide are in the reaction solvent), oxidative addition of the bromide to the heterogeneous
Pd clusters could occur. Thus, this experiment indicates that oxidative addition of the aryl-bromide is one critical step causing Pd-leaching, which also supports
Conlon et al.’s hypothesis. However, it was interesting to see that Pd-leaching also occurred in the presence of the aryl-borate, which is different from the previous case, as in this system no step in the proposed catalytic cycle (see Scheme 3-1 in section
3.3) should occur. We thus further analyzed the reaction mixture and found 42% yield of biphenyls, which is the product of the self-coupling of 2. This indicates that self-coupling of aryl-borates occurred during the premixing phase. In accordance with Moreno-Manas et al.’s proposed catalytic cycle for the self-coupling of aryl-borates [64], this run demonstrates that oxidative addition of aryl-borate is another factor causing Pd-leaching.
These results showed that Pd-leaching from Pd/C is mainly caused by oxidative addition, which occurs independently both with the bromide and the borates. This motivated us to test if the self-coupling of aryl-borates occurs in parallel to the Suzuki coupling. If it does, both 3 and the biphenyl should be seen after completion of the reaction. However, HPLC analysis confirmed the absence of biphenyls for our model system, which suggests that self-coupling of the aryl-borates is either suppressed by the competitive addition of the halide, or is significantly slower than the Suzuki coupling pathway. Clearly, oxidative addition of the aryl-bromides is the main factor causing Pd-leaching during Suzuki couplings.
However, when the aryl-bromide is absent, self-coupling of aryl-borates becomes dominant, and oxidative addition of aryl-borates is the main factor for leaching. This has to be considered during the setup of reaction protocols.
46
In addition, we studied Suzuki couplings of aryl-iodides and aryl-borates.
Instead of 1, 4-iodobenzoic acid was used together with 2 in IPA/water and Na2CO3 under standard conditions. The conversions of the regular reaction after 10 minutes and 1 hour were 42% and 100%, respectively. In the filtration test, the conversion still reached 100% after 1 hour, when Pd/C was removed after 10 minutes. This indicates that Pd-leaching also occurs during this reaction. Therefore, Pd-leaching can be observed in Suzuki couplings of both aryl-bromide and aryl-iodides.
3.3 Active Material of Pd/C
As shown in the literature and confirmed by our experiments, Pd/C can no longer be viewed as an entirely heterogeneous catalyst. There are two possible scenarios: (1) there is both a homogeneous (leached Pd) and a heterogeneous
(supported Pd) contribution or (2) only leached Pd is active and catalyzes the reactions. The proposed mechanism of Pd/C-catalyzed Suzuki coupling reactions by
[52] is shown in Scheme 3-1. Four steps occur in the main cycle: oxidative addition
(I), metathesis (II), transmetalation (III) and reductive elimination (IV). Steps I’ and
VI describe Pd-leaching due to oxidative addition of the halides and the re-adsorption on the support after completion of the reaction. Thus, the proposed cycle implies that leached Pd is the only active material catalyzing the reaction.
However, there is a lack of experimental evidence supporting this. Thus, in order to rule out the “two-pathway scenario”, PVPy adsorption experiments were carried out.
3.3.1 Pd Deactivation by Poly(4-vinylridine)
Poly(4-vinylpyridine) or PVPy, a solid polymer which is insoluble under reaction conditions, has been used to investigate Pd-leaching from Pd catalysts in
Heck reactions [98]. In their work PVPy was shown to deactivate free Pd(II)
47
(leached palladium) in the solution, bringing to a halt homogeneous palladium activity. Furthermore, a mechanism of Pd deactivation by PVPy was proposed [98] and it was reported that high catalyst activity was observed in the presence of molecular pyridine, while there was no reactivity in the presence of PVPy. Because pyridines are known to easily bind to Pd(II) [107] and molecular pyridine is a liquid under the reaction conditions, Yu et al. [98] concluded that PVPy deactivates homogeneous Pd by adsorbing and removing it from the solution. Therefore, by impeding the homogeneous pathway, PVPy can be helpful to distinguish between heterogeneous and homogeneous contributions to the reaction.
In performing the experiments, we initially assumed that both types of palladium, i.e., the leached and the heterogeneous species, are active. Scheme 3-2 illustrates the heterogeneous reaction pathway and the homogenous one. The heterogeneous reaction occurs only on the surface of the palladium nano-clusters adsorbed on the carbon support. In this pathway, the surface atoms of the palladium nano-clusters participate in the first step of the Suzuki couplings, the oxidative addition of aryl-bromides. Palladium then becomes Pd(II) and catalyzes the rest of the cycle. It is assumed that the carbon support and the adjacent Pd(0) firmly bond the Pd(II) species and prevent it from leaching during the course of the reaction. In the homogenous pathway, palladium leaches from the support to the solution, after becoming a soluble Pd(II) species [52], and then catalyzes the remaining steps of the reaction.
Although PVPy is known to deactivate homogeneous Pd, a priori there is the possibility that PVPy deactivates heterogeneous Pd as well. However, PVPy is in the form of large insoluble polymer particles (250 µm), which may hardly interact with the nanoclusters on the carbon support. Furthermore, the light soluble reactants can
48 react much faster (based on diffusivity and steric arguments) than the PVPy. Thus, we conclude that the possibility of PVPy interacting with heterogeneous Pd is negligible. Scheme 3-3 illustrates our proposed mechanism of PVPy poisoning of the Suzuki reaction, indicating that only the homogeneous pathway is affected.
3.3.2 Mechanism of Pd Deactivation by PVPy
The mechanism of homogeneous Pd deactivation by PVPy was further investigated by using the units of PVPy, i.e., 4-ethylpyridine, instead of molecular pyridine. 4-ethylpyridine is liquid under reaction conditions. With an excess of
4-ethylpyridine (150 eq. to Pd), 0% conversion was obtained after 2 hours. The complete deactivation of Pd/C with 4-ethylpyridine indicates that 4-ethylpridine deactivates Pd by blocking the access to the metal center. This result is in contrast to
Yu et al.’s finding [18] that the Pd catalyst still showed activity for Heck reactions in the presence of molecular pyridine. In order to understand the difference between their results and ours, we modeled both the 4-ethylpyridine-Pd and pyridine-Pd complexes using Gaussian 03 (DFT with B3LYP/(6-31G,SDD)). Leached Pd(II) species was assumed in the form of R-Pd-Br, where R refers to the aryl-group of 1.
Then, one, two or four molecules of 4-ethylpyridine were added to Pd center, respectively. DFT calculations yielded a molar heat of reaction of -196.80 KJ/mole for the addition of one 4-ethylpyridine molecule to Pd(II) species and -261.19
KJ/mole for cis-addition of two molecules and –355.29 KJ/mole for the trans-addition. However, we could not obtain any optimal geometry of Pd(II) octahedral complexes with four 4-ethylpyridine molecules, which is consistent with the planar coordination geometry of the Pd(II) complexes. The same trend was observed for molecular pyridine (-192.32 KJ/mole for one molecule addition,
-255.81 KJ/mole for cis-addition of two molecules, -348.76 KJ/mole for
49 trans-addition). In both cases, the results suggest trans-addition of two
(ethyl)pyridine molecules being the preferred form of the complex [108]. Scheme
3-4 shows these structures. Comparison of the HOMO-LUMO gap, bond lengths, bond angles, and dihedral angles of the two complexes revealed little difference; in fact they were almost identical. This suggest that molecular pyridine should deactivate Pd in the same way as 4-ethylpyridine in Pd/C-catalyzed Suzuki coupling reactions.
Thus, two additional experiments in the presence of molecular pyridine were carried out. In the first experiment with excess pyridine (150 eq. to Pd), 0% conversion was obtained after 1 hour. In the second experiment the conversion remained at only 35% after 1 hour, when the same amount of excess molecular pyridine was added after 8 minutes. Both experiments clearly indicate that molecular pyridine also deactivates Pd(II).
The discrepancy between Yu et al.’s [98] and our results may be due to the difference in reaction kinetics and the reaction solvents. The Heck coupling of n-butyl acrylate and iodobenzene is a much faster reaction, which reaches completion in merely 10 minutes. A careful analysis of their results shows that the presence of molecular pyridine did slow down the reaction by 15 minutes (the reaction reached completion in ca. 25 minutes). This implies that the fast Heck reaction is competing with the complex formation (deactivation). In other words, the observed activity of the catalyst in the presence of molecular pyridine might be due to active leached Pd from the catalyst before being poisoned. Another possible explanation for the discrepancy of the results is the use of different solvents in the two studies. In summary, it can be concluded that PVPy deactivates Pd by forming complexes with homogeneous Pd(II), thus inhibiting the catalytic cycle.
50
3.3.3 Quantification of the Homo- and Heterogeneous Catalytic Pathway
By comparing reactions in the presence and absence of PVPy, we intended to quantify the ratio of the homogeneous and heterogeneous catalytic pathway. Four experiments were carried out in the RC1, one without PVPy addition and three with different excess amounts of PVPy (PVPy:Pd is 100, 200 and 300 to 1 in molar equivalence, based on the molecular weight of 4-vinylpyridine.) PVPy was added first, followed by Pd/C to start the reaction. RC1 data indicated that the conversion of biphenylacetic acid after 10 minutes was 99%, 12%, 1% and 4%, and the time to reach 99% conversions was 0.2, 1.6, 6.9 and 12.7 hours, respectively. The conversion plots are shown in Fig. 3-2. The plots clearly show that the more PVPy is added, the slower the reaction becomes. The fact that PVPy reduces dramatically the activity of Pd/C indicates that the main activity of Pd/C is due to the homogeneous pathway. In addition, the initial lag phases (see Fig. 3-2b) suggest that at first a certain homogeneous Pd concentration has to build up in order to catalyze the reaction. Nevertheless, even large excess amounts PVPy are not able to stop the reaction completely, which may be explained by three possible scenarios: (I) heterogeneous Pd still catalyzes the reactions, albeit very slowly, (II) Pd in the form of PVPy-Pd is still slightly active, or (III) the adsorption of Pd is slow compared to the reaction, i.e., Pd molecules have a statistical time window to catalyze a few cycles before being captured by PVPy.
Scenario II can be excluded, since there is a clear inverse relation between reaction rate and PVPy concentration. Since PVPy is in excess, its concentration should not influence the rate, if indeed a PVPy-Pd complex catalyzes the reaction. In order to discriminate between the other possible mechanisms, additional tests were performed. However, this time Pd(OAc)2 was used. Pd(OAc)2, palladium(II)
51 acetate, is a well-known homogeneous catalyst for Suzuki couplings. Four reactions catalyzed by Pd(OAc)2 were carried out as follows: (1) Reaction without PVPy; (2)
200eq. PVPy was added initially, followed by Pd(OAc)2; (3) 200eq. PVPy and
Pd(OAc)2 were premixed in the reaction solvent overnight. Then the filtered and dried solid mixture of PVPy and Pd(OAc)2 was used for a reaction; (4) the solid mixture from reaction 3 (used PVPy+ Pd(OAc)2) was recycled and used as the catalyst for another reaction. RC1 studies indicated that the conversion after 10 minutes was 99%, 99%, 96% and 0%, respectively. Also, the reaction was very fast, i.e., the time required to reach 99% conversion was 2.5, 4.5, 20 minutes and infinity.
The trends are shown in Fig. 3-3. From this series of reactions, three conclusions can be drawn. First, reactions 1 and 2 show almost identical reactivity, which indicates that the catalytic reaction dominates Pd-capture by PVPy. This explains why PVPy cannot completely poison the system, as the homogeneously catalyzed Suzuki coupling is a fast reaction. Second, the high reactivity of reaction 3 indicates that
PVPy is not able to bind Pd(II) from Pd(OAc)2 in the absence of a reaction occurring. This may be due to the protection by the acetyl groups. Third, 0% conversion of reaction (4) proves that Pd in the form of PVPy-Pd is entirely inactive.
In summary, our careful experiments indicate that Pd-leaching is a critical step in the Pd/C-catalyzed Suzuki couplings in aqueous solvents, and that Pd adsorption by PVPy is not fast enough to entirely deactivate leached Pd. This is consistent with
Yu et al.’s finding [97] that PVPy cannot completely poison the catalyst in Heck reactions. Therefore, we conclude that the remaining reactivity we observed during the Pd/C reactions with PVPy is due to leached, homogeneous Pd that has not yet been captured by PVPy. Pd has two possible pathways after leaching from the support: one is to react with reactants and to contribute to the reaction, and the other
52 is to bind to PVPy and become inactive. These two mechanisms compete with one another, as shown in Scheme 3-5. This observation also implies that there should be a pseudo-steady state between heterogeneous Pd on the support and homogeneous
Pd in the solution, which is determined by the leaching and adsorption rate.
3.4 Removal of leached homogeneous Pd
Pd/C is an increasingly important catalyst for the preparation of fine chemicals and pharmaceuticals. However, only a few ppm of Pd detected in the reaction mixture may seriously contaminate the products, violating FDA guidelines. This is due to the possibility of Pd forming complexes with drug molecules, thus inactivating the drug, and to the general wish to deliver heavy-metal-free drugs, as metals are considered toxic and/or carcinogenic. Thus, it is important to develop a technique for removing Pd-residual from the final reaction mixture. The ability of
PVPy to bind to homogeneous Pd is a potential solution, as it is a straightforward method for removing Pd-residuals from the reaction mixture. Two experiments with
PVPy at 65 oC and at room temperature were carried out to demonstrate this approach. In both cases, the reactions were set up under standard conditions. After 8 minutes Pd/C was removed, and PVPy (200 eq. to Pd by assuming 1 ppm leached
Pd in the filtrate) was added and mixed at 65 oC or RT, respectively, to observe
PVPy effects on the leached-Pd-catalyzed reaction. After another 1 hour, PVPy was removed from solution by filtration and the conversion was monitored for another hour. The results are shown in Fig. 3-4. After removal of Pd/C and addition of PVPy, the reactions in both cases stopped within 10 minutes. Comparison to the reaction of removed Pd/C (without adding PVPy) in section 3.2.1 implies that PVPy is adsorbing and deactivating leached/homogeneous palladium. Taking a closer look at
53 the 65 oC case, a slight increase of the conversion during the first ten minutes (29% to 33%) shows that at a higher reaction temperature the adsorption of Pd by PVPy is slow compared to the reaction. After removal of PVPy, the reaction mixture was kept at 65 oC in both cases for one more hour. In both cases, the conversion remained constant and no further reaction occurred after removing PVPy. This indicates that PVPy can successfully and irreversibly remove homogeneous palladium from the reaction mixture. Since Pd adsorption by PVPy works in both cases, for economic and practical consideration, using PVPy at RT is sufficient for removing palladium.
Furthermore, the absorption capacity of PVPy for Pd was investigated. A solution of 1001 ppm of Pd in a 5% HCl solution (from Aldrich) was prepared. The orange-brown color of the Pd solution showed abundant free Pd(II) in the solution.
First, two experiments were carried out, where twice 10 ml of the Pd solution was added to two flasks. Excess PVPy (50 and 10eq. to Pd) was added to the flasks, respectively, and the mixtures were stirred at RT for 3 hours. Then, PVPy was filtered and the color of the filtrate was observed. In both cases, the filtrates were observed to be colorless, which implies that Pd was completely removed. As a result, one more experiment was carried out. The PVPy amount was reduced to 2 eq. Pd and the mixture was stirred for 2 hours only. In this run, the filtrate still had a light yellow-orange color. By ICP analysis of the light yellow-orange filtrate, Pd amount was determined to be 172 ppm. This shows that the equilibrium molar ratio of Pd removed to PVPy is 0.38/1 after two hours, which is the maximum ability of PVPy for Pd removal. Thus, for complete Pd removal from the solution, approximately 3.0 equiv. of PVPy should be sufficient. PVPy is commercially available for about 700
U.S. dollars per kilogram. Assuming a typical 400-gal batch with 10 ppm
54
Pd-residual in the solution, about 45g of PVPy are required to completely remove Pd.
This would translate into costs of about 30$.
3.5 Oxygen Effect on the Pd/C-Catalyzed Reaction
Dissolved gas from the headspace of the reactor is usually considered an important factor that may affect the reaction performance. Because palladium is an easily oxidized metal, Pd-catalyzed reactions are typically carried out under inert gas atmosphere [97,98] or vacuum [52] to prevent oxygen from poisoning the Pd catalysts. For Pd/C-catalyzed Suzuki couplings, the system is usually degassed before the experimental study. However, Gala et al. [50] noted in their study of
Pd/C-catalyzed Suzuki couplings that degassing of the solvents is unnecessary. This motivated us to investigate the impact of oxygen on the reaction.
In one experiment, a regular reaction was set up under air atmosphere. The flask was stirred for 20 minutes at RT and then heated up to 60 oC to carry out the reaction. As shown in Fig. 3-5, the reaction went to completion after about 20 minutes. Another reaction was set up under the same conditions but purged with N2 for 20 minutes, and then heated up to 60 oC. The conversion plots show that the reaction in the absence of oxygen is very similar (slightly slower), compared to the reaction in the presence of oxygen. This implies that oxygen may have little or no effect on the reactions. Moreover, under the same conditions as the regular reaction at 60 oC, two more reactions were carried out, one by sparging air and one by sparging N2 during the entire reactions (gas flowrate: 650 ml/min). The conversion plots, as shown in Fig 3-5, also showed an almost identical behavior. This confirms that oxygen has little or no effect on the reactions. The reduced reaction rates in the sparged system were due to cooling of the reaction mixture by the sparging gas (RT).
55
Therefore, we suggest that it is not necessary to exclude air/oxygen during the reaction, i.e., that Pd/C catalyzed reactions are not air-sensitive.
3.6 Pd-Leaching in Organic Solvents
Pd-leaching of Pd/C-catalyzed Suzuki couplings in an aqueous environment was carefully examined above. In addition, we intended to explore whether
Pd-leaching also occurs in pure organic solvents and whether leached Pd catalyzes the reactions as well in such a system. Four organic solvent systems, i.e., DMA, dioxane, THF and toluene, which all were used in the past by different groups to carry out homogeneous Pd-catalyzed Suzuki couplings [25,109] were selected.
Together with these four organic solvents, two different bases were tested, one being the inorganic base, Na2CO3, the other one the organic base, triethylamine (TEA).
The reactions were set up under regular conditions. Results are shown in Table 3-2.
Among the eight combinations of reaction solvents and bases, only THF/Na2CO3, toluene/Na2CO3, and toluene/TEA showed some reactivity, with the conversion after
4 hours being 4 %, 4% and 9%, respectively.
Since our studies suggest that the activity of Pd/C is mainly due to leached Pd, the cases yielding 0% conversion may be due to a lack of Pd-leaching. In order to examine whether Pd leached during these reactions, the reaction mixture of
DMA/TEA was filtered and a sample after 4-hour reaction was analyzed. ICP analysis showed that the amount of Pd in DMA/TEA was 3ppm, which is known to be sufficiently high for Suzuki couplings in aqueous solvents according to section
3.2.1. This indicates that Pd-leaching from Pd/C also occurs in organic solvents.
Conlon et al. [52] observed the absence of Pd-leaching in a mixture of only Pd/C and DMF at 80 oC. Thus, also in organic solvents, presence of 1 and 2 in the organic
56 solvent is necessary for leaching to occur. Again the oxidative addition of the aryl-bromide and/or the aryl-borate must be the cause for this phenomenon.
However, it is notable that leached Pd is inactive or only slightly active under these conditions.
Homogeneous Pd-catalysts usually have ligands or there are ligands dissolved in the solution. Therefore, we assumed that the low activity of leached Pd is due to the lack of ligands in the reaction mixture. In order to test this hypothesis, a homogeneous catalyst, tetrakis(triphenylphosphine) palladium (Pd(PPh3)4), and the ligand triphenylphosphine (PPh3) were used. Pd(PPh3)4 (0.01g/10ml solution) instead of Pd/C at 90 oC showed 8% conversion after 100 hours for the model reaction in DMA/TEA. This indicates that Pd(PPh3)4 is somewhat active. Next, two experiments were carried out, where Pd/C was added together with 1 and 2 in DMA.
The two mixtures were then stirred for 20 minutes at 80 oC. After that, in the first mixture PPh3 was added (100 eq. to Pd), followed by TEA after 2 hours. In the other mixture TEA was added first, followed by PPh3 after 2 hours. In both runs, the leached palladium and PPh3 were expected to form Pd(PPh3)4, which could catalyze the reaction. Finding a non-zero conversion would indicate that leached Pd in pure organic solvents needs a ligand to carry out the reaction. Nevertheless, in both cases no desired product was found even after 100 hours.
In order to further explore the behavior of leached Pd in different solvents,
DFT calculations with the model B3LYP/(6-31+G(d,p),SDD) were carried out. The fact that leached Pd is active in the aqueous co-solvent but not active in the pure organic solvent might be due to water, which stabilizes Pd(II) in solutions. By modeling the step of metathesis, the molar heat of formation of -170.14 KJ/mole was obtained for R-Pd(II)-OH without a hydration shell. -179.53 KJ/mole was
57
obtained for the formation of R-Pd(II)-OH with two associated H2O molecules. Thus, the hydration of the complex has little effect on stabilizing Pd(II). Therefore, the role of water is still somewhat unclear, although it is known that Pd/C-catalyzed
Suzuki couplings are best carried out in a combination of organic solvents and water
[110].
A plausible explanation for the effect of water may stem from the ability to stabilize Pd nanoparticles in water. Cassol et al. [111] studied Heck reactions with
Pd nanoparticles in an ionic-liquid/organic-phase system. They observed active Pd nanoparticles in the ionic liquid and inactive leached Pd in the organic phase.
However, no Pd nanoparticles were detected in the organic phase. Thus, the authors concluded that the reaction possibly proceeds on the surface of Pd nanoparticles, which are stabilized in an ionic solvent. Thus, we conjecture that the presence of water stabilizes Pd nanoparticles in our multisolvent system, which act as a reservoir for active dissolved Pd.
3.7 Conclusion
Pd-leaching in Pd/C-catalyzed Suzuki couplings was investigated using a model coupling reaction to form biphenylacetic acid. The main results of our work are:
Careful PVPy adsorption experiments show that the activity of Pd/C is only due
to leached Pd(II) species. There is no heterogeneous contribution to the reaction.
PVPy adsorption is slow compared to the homogeneous reaction. Thus, PVPy
cannot completely suppress the homogenous reaction. This also implies that
there exists a pseudo-steady state between heterogeneous Pd on the support and
58
homogeneous Pd in the solution, which is determined by the leaching and
adsorption rate.
PVPy was shown to be a good reagent to completely remove Pd-residuals from
the reaction mixture at very low costs. Excess PVPy (approximately 3.0 equiv.
to Pd) is sufficient.
Both 4-ethylpyridine (the monomer of PVPy) and pyridine bring to a stop the
activity of Pd/C. Modeling studies suggest the formation of a stable Pd-complex.
By premixing Pd/C with different components of the reaction mixture followed
by filtration tests, the oxidation addition of aryl-bromides was confirmed to be
the main cause for Pd-leaching. Dissolution of Pd clusters is not a factor in the
leaching mechanism.
It was shown that the oxidative addition of aryl-borates to form biphenyls is
another cause for Pd-leaching in the self-coupling of aryl-borates in the absence
of aryl-bromides.
The influence of oxygen on Pd/C-catalyzed Suzuki couplings was proved to be
negligible. Thus, this reaction is not air-sensitive.
Water as a co-solvent is required to obtain a certain catalytic activity. Although
leaching occurs in organic solvents, the reaction is very slow without addition of
water. This may be due to the easier formation of Pd nanoparticles in the
presence of water.
59
Tables
Table 3-1 Conversions for premixing schemes with different components of the reaction mixture.
Runs Premixing conditions with Pd/C Conversion[a] (%)/Reaction hours
1 IPA/water, at RT 6 / 2 hrs
2 IPA/water, at 75 oC 4 / 2 hrs
3 1, IPA/water, at 75 oC 96[b] / 1 hr
4 2, IPA/water, at 75 oC 98[b] / 1 hr
o 5 Na2CO3, IPA/water, at 75 C 0 / 4 hrs [a] Conversions refer to the conversion of 1. [b] Conversions were calculated based on different limiting reactants in each run. In Run 3, 1 was ca. 93% recovered from the premixing and while 2 was ca. 52% recovered in Run 4; thus, the limiting reactant in Run 3 was 1 and that in Run 4 was 2.
60
Table 3-2 Conversions of the Pd/C-catalyzed reaction in pure organic solvents and
Na2CO3 or triethylamine.
Runs Organic Solvent Bass Rxn 4 hours Conversion (%)
1 Dioxane Na2CO3 0
2 Dioxane Triethylamine 0
3 Dimethylacetimide Na2CO3 0
4 Dimethylacetimide Triethylamine 0
5 Tetrahydrofuran Na2CO3 4
6 Tetrahydrofuran Triethylamine 0
7 Toluene Na2CO3 4
8 Toluene Triethylamine 9
61
Figures
Fig. 3-1 Conversion of 4-bromophenylacetic acid as a function of time under standard conditions (■) and removed Pd/C after 8 minutes (•).
62
(a)
(b)
Fig. 3-2 (a) RC1 conversion data of 4-bromophenylacetic acid as a function time for different amounts of PVPy. (b) RC1 conversion data of 4-bromophenylacetic acid as a function time for different amounts of PVPy (Enlarged).
63
Fig. 3-3 RC1 conversion data of 4-bromophenylacetic acid as a function of time for different PVPy addition schemes with Pd(OAc)2
64
Fig. 3-4 Conversion of 4-bromophenylacetic acid as a function of time under PVPy treatment at 65oC (■) and at room temperature (•) when Pd/C was removed after 8 minutes.
65
Fig. 3-5 Conversions of 4-bromophenylacetic acid as a function of time under regular conditions (■), N2 purged (•), sparging Air during the entire reaction (▲), and sparging N2 during the entire reaction (▼).
66
Scheme 3-1 Proposed catalytic cycle of Pd/C-catalyzed Suzuki couplings. I:
Oxidative addition; I’: Pd-leaching due to oxidative addition; II:Metathesis; III:
Transmetalation; IV: Reductive elimination; V:Arylborate activation; VI:
Pd-readsorption. The hydroxide ion, OH-, comes from dissociation of the base,
Na2CO3, NaOH, K2CO3 etc.
67
Scheme 3-2 Schematic of heterogeneous and homogeneous Suzuki couplings, catalyzed by Pd/C. The proposed mechanisms for Pd-leaching is shown.
68
Scheme 3-3 Schematic of the proposed mechanism of Pd deactivation by PVPy for heterogeneous Pd and homogeneous Pd, respectively.
69
Scheme 3-4 Optimal geometries of the complexes of Pd(II) species and pyridines by
DFT calculation with model B3LYP/SDD/6-31G.
Scheme 3-5 The pathways of Pd after leaching. kl, kde are the leaching and deactivation constants.
70
4. BASE- AND LIGAND-FREE PD/C-CATALYZED HOMOCOUPLING OF
ARYLBORONIC ACIDS
In Chapter 3, we carried out a detailed mechanistic investigation of
Pd-leaching from heterogeneous Pd/C catalysts during Suzuki coupling reactions.
During these studies, we observed homocoupling of phenylboronic acids occurring in a mixture of phenylboronic acid 1 and water/2-propanol (9:1 volume ratio) with
Pd/C at 75 oC under air. Further investigation showed excellent yields of biphenyl 2, reaching 50% and 92% after 30 minutes and 2 hours, respectively (Fig. 4-1); in addition, small amounts of benzene 3 and phenol 4 were observed. The latter species are formed by protodeboronation of phenylboronic acid, a side reaction of arylboronic acids occurring in water or alcohols. The rate of protodeboronation is a function of the arylboronic acid type, the reaction solvent and the reaction temperature.[25,69,112]
This catalytic system offers significant potential and provides several advantages for homocoupling of arylboronic acids under base- and ligand-free conditions. First, no extra reagents are needed, thus simplifying the overall reaction at reduced cost. Second, Pd/C is a reusable catalyst. For example, Sakurai et al. [51] studied the Suzuki coupling of 4-iodophenol and phenylboronic acid in water and observed favorable activities of Pd/C even after the fifth run. Furthermore, the absence of any ligands on the transition metal catalyst should prevent the formation of undesired biaryls. The goal of this part of the PhD work is to provide a more detailed understanding of Pd/C-catalyzed homocoupling reactions, using the model coupling of biphenyls shown in Scheme 4-1, and to optimize the reaction conditions in order to allow for a straightforward industrial implementation.
71
4.1 Experimental
4.1.1 Materials
In this study we used commercially available phenylboronic acid (Aldrich,
95%), Pd/C (Aldrich, 5wt%, Degussa type, particle size 28~34 µm), palladium(II) acetate (Aldrich, 99.9%), 2-propanol (Fisher), methanol (Fisher), p-tolyboronic acid
(Aldrich, 97%), m-tolyboronic acid (Aldrich, 97%) 4-methoxyphenylboronic acid
(Aldrich), 4-(methylthio)phenylboronic acid (Aldrich), 4-chlorophenylboronic acid
(Aldrich, 95%). No materials required further purification.
4.1.2 Model Reaction for Homocoupling Reactions
The model coupling reaction of biphenyl was carried out in a 100 mL round-bottom glass reactor equipped with a stirring bar (1 cm length).
Phenylboronic acid (0.64 mmol) was added to 10 mL reaction solvent
(water/2-propanol in 9:1 volume ratio) at room temperature, while vigorously stirring for 15 minutes. After adding Pd/C (5 wt%, Degussa, 50% water-wet, amount of catalyst: 4.6 mole% of Pd w.r.t. phenylboronic acid), the reaction mixture was heated to 75 oC to carry out the reaction. After 3 hours, Pd/C was removed by filtration through a 0.45 µm filter (Fisher brand), and 2-propanol (2 × 35 mL) was used to wash the filter cake and to extract the products into the filtrate. The filtrate was analyzed by high-performance liquid chromatography (HPLC) to determine the concentrations of the reagent 1, the product 2 and the side products 3 and 4. HPLC analyses were performed on a Shimadzu SP-10 liquid chromatograph equipped with a UV-Vis absorption detector and an Agilent zorbax eclipse XDB-C8 column. The
HPLC mobile phase program was (a) 0 ~ 9 minutes, 60% deionized water with
0.05% formic acid and 40% acetonitrile (volume ratios), and (b) 9 ~ 30 minutes,
40% deionized water with 0.05% formic acid and 60% acetonitrile. The flow rate of
72 the mobile phase was 1.2 ml per minute. The wavelengths of the detection light were set from 190 nm to 250 nm. The conversion of 1 and the yields of 2-4 were calculated based on a mass balance. For example, if cA, cB, cC and cD are the mole concentrations of 1-4, respectively, then the yield of biphenyl YB is defined as YB =
[2cB/(cA + 2cB + cC + cD)].
4.2 Investigation of the Model Reactions
4.2.1 Influence of Water/2-propanol Ratio
First, the influence of the water/2-propanol ratio was studied. In the literature, the solvents used for Pd-catalyzed homocouplings of arylboronic acids are typically organic solvents or water/organic solvent mixtures in a 1:1 volume ratio. In order to optimize the reaction conditions, five experiments were carried out with water/2-propanol volume ratios of 9:1, 7:3, 5:5, 3:7 and 1:9, respectively. The results are shown in entries 1-5 of Table 4-1. The conversion of 1 decreased gradually from 100% to 19%, when the solvent fraction of 2-propanol was increased from 10% to 90%. In parallel, the yield of 2 also decreased from 93% to 16%. These results clearly indicate that a higher fraction of the organic solvent is detrimental to the desired reaction and reduces its rate. The overall yields of 3 and 4 increased slightly, relative to the yield of 2, with increasing concentration of 2-propanol. This indicates that side reactions are enhanced at higher 2-propanol fractions, consistent with the finding of Miyaura and Suzuki [25] that “the protodeboronation of
1-alkenylboronic compounds in alcohols is faster than in water.” Moreover, the reaction was carried out in pure water. The results are reported in entry 6 of Table
4-1 and show that both yield and selectivity are excellent even in pure water.
However, due to solubility limitations of the arylboronic acids containing
73 hydrophobic functional groups, a certain solvent fraction of 2-propanol may be necessary in an industrial implementation. In summary, we recommend that the
Pd/C-catalyzed homocoupling reaction of arylboronic acids is carried out with a water/2-propanol volume ratio of 9:1, since for these conditions both the yield and selectivity were excellent, while allowing for sufficient solubility of the reagents.
4.2.2 Influence of Reaction Temperature
The reaction temperature is another important factor. Smith et al. [69] studied the homocoupling of arylboronic acids with Pd(OAc)2 and observed an increased contribution from protodeboronation, when they carried out the reaction at higher temperatures (80 oC). On the basis of their work, we conjectured that higher yields of 2 should be obtained at lower temperatures. To test this hypothesis, five reaction runs were carried out at different temperatures (85 oC, 65 oC, 55 oC, 45 oC and RT).
The results are shown in entries 7-11 of Table 4-1. The reaction almost reached completion after 3 hours, when the temperature was higher than 55 oC. However, at
55 oC, the yield of 2 decreased from 93% to 88%, while the total yield of 3 and 4 increased from 7% to 12%. In a long-term experiment at RT (entry 12 in Table 4-1), the conversion and the yield of 2 after 24 hours reached 98% and 88%, respectively, and the total yield of impurities 3 and 4 was 10%. The higher yield of side products at lower temperatures contrasts the observations by Smith et al.[69] The increased rate of byproduct formation at lower temperatures indicates that protodeboronation of arylboronic acids has a lower activation energy than the homocoupling reaction
(Scheme 4-2). By considering both the yield of desired biaryls and the reaction kinetics (conversion rate), 75 oC seems to be the optimal temperature for the homocoupling reaction in our system.
74
4.2.3 Influence of Catalyst Loading
Subsequently, we examined the influence of catalyst loading on the homocoupling reaction. Two experiments were carried out at 75 oC in which the base-case Pd/C loading of 4.6 mole % was doubled or halved, respectively (entries
13 and 14 in Table 4-1). The reaction reached completion within 1 hour at the higher catalyst loading of 9.2 mole % and gave similar product yields. The reduced catalyst loading of 2.3 mole % resulted, as expected, in a lower reaction rate and less conversion (compared to the model reaction after 2 hours, Fig. 4-1). However, it is noteworthy that the reduced catalyst loading resulted in a faster protodeboronation
(higher overall yield of side products). This may imply that protodeboronation is a non-catalytic reaction, competing with the catalytic homocoupling.
4.2.4 Pd(OAc)2 Used Under Optimal Conditions
Recently, Yamamoto et al. [113] studied the Pd(II)-catalyzed carbonylation of arylboronic acid esters. They observed that arylboronic acids can undergo homocoupling by Pd(OAc)2 under base- and ligand-free conditions; for example, 5 mole % Pd(OAc)2 in methanol at RT under air with the reagent 1 afforded 2 in a
99% yield after 5 hours. The excellent yield motivated us to test whether our system can be improved upon by the use of Pd(OAc)2. A model reaction was carried out
o with 4.6 mole % Pd(OAc)2 in water/2-propanol at a volume ratio of 9:1 at 75 C under air (entry 15 in Table 4-1). The conversion after 3 hours was only 47%, which illustrates how strongly dependent the homocoupling reaction of arylboronic acids is on the proper selection of solvent.
75
4.3. Pd/C-Catalyzed Homocouplings of Arylboronic Acids
4.3.1 Experimental Observations
In order to establish the versatility of our method, homocoupling of five meta- or para-substituted arylboronic acids was examined. The results are summarized in
Table 4-2. Good to excellent yields of the desired products were obtained for arylboronic acids containing both electron donating (m- and p-Me-, p-MeO-) and electron withdrawing groups (p-Cl-). However, incorporation of the methylthio group (p-MeS-) resulted in a very low yield (entry 5, Table 4-2).
4.3.2 Influence of Functional Groups by DFT Studies
In order to further explore the influence of functional groups on reaction performance and mechanism, we modeled the Pd-arylboronic acid system using computational electronic structure methods implemented in the Gaussian 03 software package [77]. The first reaction step in the catalytic cycle proposed by
Moreno-Manas et al. [64] for homocoupling of arylboronic acids is oxidative addition of Pd to the arylboronic acid. This step can be further divided into two sub-steps (Scheme 4-3): a Lewis acid-base complexation reaction followed by rearrangement (Pd insertion into the C-B bond). Geometry optimization
(B3LYP/SDD/6-31+G(d,p) with PCM water solvation model) showed that the electron-rich Pd(0) atom coordinates without an activation barrier to the phenyl ring of the arylboronic acids, not to the B atom [64]. The Pd(0) atom preferentially interacts with the phenyl π-system and is located symmetrically between ipso and ortho C atoms (C-Pd ~ 2.16 Å, B-Pd ~ 2.79 Å), Fig. 4-2. No minimum could be found in which Pd(0) coordinated with the B atom; all such initial trial structures rearranged upon energy minimization to the phenylic π-complex without crossing an activation barrier. The LUMO of boronic acid is a phenylic π*-orbital with some
76 contribution from the B atom, and strong π-donation from the OH groups probably renders the B center a weaker electron acceptor (acid) than the phenyl π-system. The computed free energies of complex formation are shown in Table 4-3. They are all favorably negative (~ -110 kJ/mol) without much variation among the various substituents. We conclude, in agreement with Moreno-Manas et al., [64] that the initial step of the homocoupling reaction (complex intermediate formation, Scheme
4-3) is fast and, furthermore, not particularly sensitive to substituents on the aryl group.
However, the reactivity of the different arylboronic acids might depend on the second step, the rearrangement of the R-Ph group. Although the rearrangement step is endothermic, the computed enthalpies fall in a narrow range (30-35 kJ/mol) which suggests small activation energy differences between different Pd-arylboronic acid pairs. The modest and quite similar activation energies actually computed (Table 4-3) indicate that the insertion step should be facile at ambient temperatures. However, the computed activation energies do unfortunately not provide any particular reason for the poor performance of the p-MeS boronic acid.
4.3.3 Palladium-Sulfur Affinity
A plausible explanation for the low yield observed during the homocoupling of p-MeS-Ph-B(OH)2 may be found in the strong affinity shown by sulfur for palladium [114], which could result in poisoning of the active palladium sites. To test this hypothesis, a model reaction (entry 1 in Table 4-1) was carried out under the addition of p-MeS-Ph-B(OH)2 (5 mole %). The conversion of 1 and the yield of 2 after 3 hours were 99% and 89%, respectively. The high conversion indicates that the Pd catalyst was not poisoned by sulfur. Also, a new biaryl, i.e., MeS-Ph-Ph, was
77 observed at about 2% yield. Thus, we conclude that sulfur does not poison the palladium sites.
DFT calculations were carried out focusing on a comparison of Pd complexes formed with p-MeS-Ph-B(OH)2 and p-MeO-Ph-B(OH)2. A complex in which Pd(0) bonded to the S atom of p-MeS-Ph-B(OH)2 was found to be only 7.2 kJ/mol higher in energy than the phenylic π−complex discussed above (Scheme 4-4). Thus, the calculations suggest that sulfur does not irreversibly bind to Pd. However, the small energy difference computed between the two types of complexes suggests that both
(Pd-S and Pd-phenyl) may form at comparable rates, thus reducing catalyst activity.
In contrast, for the corresponding Pd(0) complex with p-MeO-Ph-B(OH)2 acid a much larger energy difference of 80.0 kJ/mol was computed (Pd-O versus
Pd-phenyl).
4.4 Conclusion
A base- and ligand-free catalytic system to synthesize symmetrical biaryls by
Pd/C-catalyzed homocoupling of arylboronic acids was developed. Using a model coupling reaction of biphenyl, the main results of our work are:
o Using 4.6 mole % Pd/C in water/2-propanol (9:1 volume ratio) at 75 C under air,
excellent yields of the desired products can be obtained after 3 hours for
phenylboronic acid derivatives containing electron-donating and
electron-withdrawing groups. However, a p-MeS substituent resulted in
extremely low yields.
Experimental observations show increasing activity of Pd/C when the solvent
fraction of water was increased from 10% to 90%
78
A higher yield of biaryls at higher temperature implies that the homocoupling
reaction has higher activation energy than the protodeboronation.
DFT calculations indicate that the presence of sulfur in the functional group
reduces catalyst activity by competing for the active metal site.
The calculations suggest that the reactivity of different arylboronic acids may be
relatively independent of the first step in the homocoupling reaction, oxidative
addition of Pd to the arylboronic acid.
79
Tables
Table 4-1. Optimization of conditions for Pd/C-catalyzed homocoupling reactions of phenylboronic acid
Entry Conditionsa Reaction Conversion Yield Yield Yield Time of 1, % 2, % 3, % 4, % 1 9:1b, 75 oC, 4.6 mole % Pd/C 3 hrs 100 93 6 1 2 7:3, 75 oC, 4.6 mole % Pd/C 3 hrs 99 91 3 5 3 5:5, 75 oC, 4.6 mole % Pd/C 3 hrs 83 74 6 2 4 3:7, 75 oC, 4.6 mole % Pd/C 3 hrs 54 49 4 1 5 1:9, 75 oC, 4.6 mole % Pd/C 3 hrs 19 16 2 1 6 water, 75 oC, 4.6 mole % Pd/C 2 hrs >99 92 6 1 7 9:1, 85 oC, 4.6 mole % Pd/C 3 hrs 100 93 6 1 8 9:1, 65 oC, 4.6 mole % Pd/C 3 hrs >99% 90 4 6 9 9:1, 55 oC, 4.6 mole % Pd/C 3 hrs >99% 88 7 5 10 9:1, 45 oC, 4.6 mole % Pd/C 3 hrs 82 72 5 5 11 9:1, RT, 4.6 mole % Pd/C 3 hrs 21 18 2 1 12 9:1, RT, 4.6 mole % Pd/C 24 hrs 98 88 4 6 13 9:1, 75 oC, 9.2 mole % Pd/C 1 hrs 100 94 5 <1 14 9:1, 75 oC, 2.3 mole % Pd/C 2 hrs 89 78 4 7 o 15 9:1, 75 C, 4.6 mole % Pd(OAc)2 3 hrs 47 42 1 4 [a] Basic parameters: 0.64 mmol phenylboronic acid and 10 mL water/2-propanol solvent. [b] Volume ratio of water/2-propanol solvent.
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Table 4-2. Base- and ligand free Pd/C-catalyzed homocoupling of substituted arylboronic acidsa
Entry Reactant Conversion, % Product Yield, % 1 100 93 B(OH)2
2 100 95 B(OH)2
3 100 96 B(OH)2
4 90 80 MeO B(OH)2 MeO OMe
5 29 18 MeS B(OH)2 MeS SMe
6 100 95 Cl B(OH)2 Cl Cl
[a] Reaction conditions: 0.64 mmol arylboronic acid, 4.6 mole % Pd/C, 10 mL water/2-propanol (9:1 volume ratio) at 75 oC under air for 3 hours.
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Table 4-3. Computed free energy differences (B3LYP/SDD/6-31+G(d,p) and PCM water solvation model) for species involved in the oxidative addition of Pd(0) to boronic acid (Fig. 4-2).
Boronic acid ∆G(complex)a ∆G‡(insert.)b ∆G(product)a
B(OH)2 -109.0 57.9 -79.8
B(OH)2 -103.3 54.6 -70.4
B(OH)2 -108.1 51.4 -76.4
MeO B(OH)2 -115.5 53.7 -84.3
MeS B(OH)2 -104.7 58.3 -71.5
Cl B(OH)2 -107.2 60.1 -75.5
[a] Free energy differences are in kJ/mol and relative to the energies of separated reactants (one Pd atom plus one boronic acid molecule). The free energy differences were computed using a reference state of 1 M concentration for each species participating in the reaction, and T = 298.15 K. [b] Activation free energy (kJ/mol) measured relative to complex.
82
Figures
Fig. 4-1. Conversion of phenylboronic acid (▼) and yields of biphenyl (▲), benzene(●), and phenol( ) as a function of time. Reaction conditions: 0.084 g phenylboronic acid and 0.2 g Pd/C in 10 mL water/2-propanol (9:1 volume ratio) at
75 oC.
Pd-acid complex Transition state Product
Fig. 4-2. Optimal geometries of Pd-boronic acid complex, transition state for Pd insertion into the C-B bond, and the insertion (rearrangement) product.
83
Schemes
Scheme 4-1. Model reaction for base- and ligand-free Pd/C-catalyzed homocoupling of aryl-boronic acids.
Scheme 4-2. Competition between homocoupling and protodeboronation of arylboronic acids: a higher yield of biaryls at higher temperature implies Eah > Eap1,
Eap2.
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Scheme 4-3. Proposed mechanism for the oxidative addition of Pd(0) to arylboronic acid. The step can be divided into two sub-steps, i.e., a Lewis acid-base complexation reaction followed by rearrangement.
Scheme 4-4. Energy comparisons of Pd(0) complexes formed with p-MeS-PhB(OH)2 and p-MeO-PhB(OH)2. The small energy difference between the two p-MeS-PhB(OH)2 complexes suggests that sulfur may interfere with the activity of Pd.
85
5. DEVELOPMENT OF A LAB-SCALE HYDROGENATION SYSTEM
In addition to Suzuki cross- and self-couplings, enantioselective hydrogenations are another important class of reactions for preparing pharmaceuticals, agrochemicals, flavors and fragrances. The group of Chen at the
University of Delaware prepared a series of bimetallic catalysts containing Pt, such as Ni/Pt/γ-Al2O3 [115], Co/Pt/γ-Al2O3 [116,117], and W/Pt/γ-Al2O3, and showed the ability of these surfaces to desorb hydrogen at 200~230K. Thus, hydrogenations could be carried out at low temperatures, which may be beneficial for chiral reactions since the rate of racemization is very small. In 2005, we obtained
Pt/γ-Al2O3 and Co/Pt/γ-Al2O3 from Chen’s group and intended to test those catalysts for real enantioselective hydrogenations. We expected to observe higher yields and selectivity of the desired chiral products using bimetallic Pt catalysts which are treated with chiral modifiers.
In order to carry out these reactions, we built a lab-scale hydrogenation system in our laboratory.
5.1 Safety of Hydrogen Operation
Hydrogen is a flammable gas, which is a serious hazard under improper operation conditions. Based on the material safety data sheets (MSDS) of hydrogen, selected safety information is listed in Table 5-1. The most important fact is that hydrogen has an extremely low ignition energy (0.017 mJ), which indicates that hydrogen could be ignited by an electrostatic spark. If a hydrogen explosion happens, the detonation pressure may break the equipment and result in tremendous injury.
Therefore, in order to prevent electrostatic sparks and friction heat, the process of
86 purging/releasing hydrogen becomes very important. Less than 20 ml/sec of hydrogen and gas dilution by nitrogen are recommended during hydrogen release.
The most suitable material for hydrogen piping is austenitic stainless steel with >7% nickel, which may hold pressures of up to 200 bars.
5.2 Design and Construction of the Hydrogenation System
A complete hydrogenation system includes three sub-systems: the reaction system, the calcination system (for catalyst activation) and the gas chromatographic
(GC) system for sample analysis. Schemes 5-1 to 5-3 show the process of designing the reaction and calcination systems. The design focused on developing simple, clear routes for nitrogen and hydrogen in and out of the hydrogen reservoir, the reactor, and the tube furnace. For safety concerns, the whole reaction system and gas tanks containing hydrogen were placed inside the laminar flow hood. The furnace is
3 meters away from the reactor.
Based on Scheme 5-3, a reaction system was built. The hydrogenation reactor is a 100 ml general purpose vessel from Parr Instrument Company, which can be operated under 200 bars and 350 oC. The hydrogen reservoir is a 150 ml double-ended cylinder from Swagelok®, in which the maximum operating pressure is 124 bars. The piping and valves made of 316 stainless steel were used for the entire system. Several checking valves were installed to prevent countercurrent flow of gas inside the system. A static-electricity-free mat on the ground was used to prevent electrostatic sparks caused by operators. Fig. 5-1 and 5-2 show the pictures of the real reaction system.
The calcination system was installed about 2 meters away from the hood. The furnace from Mellen can calcine catalysts up to 1200 oC. The piping allows use of
87 pure hydrogen or 5% hydrogen/95% nitrogen to activate the catalysts (metal reduction). The maximum flow rate is 42 ml/sec. Fig. 5-3 and 5-4 show pictures of the calcination system.
The GC system was set up on the bench in front of the hood. The HP 6850
Series GC system is used with a flame ionization detector (FID) and an Aligent
Cyclodex-B column. The analyzed data are printed out by HP 3396 Series II integrator. Hydrogen and air are provided to support the flame inside the FID, and nitrogen serves as a carrier and make-up gas. Fig. 5-5 and 5-6 show pictures of the
GC system.
5.3 Enantioselective Hydrogenation of Ethylpyruvate
To test the system and the bimetallic Pt catalysts after completing the construction of the hydrogenation system, we initially chose the hydrogenation of ethylpyruvate [118] (Scheme 5-4) as the model reaction, which is well-known among cinchona-alkaloid-modified Pt catalyzed enantioselective hydrogenations.
The reaction may achieve enantiomeric excess (e.e.) of 69% to 87% with various modifiers under 70 bar. This is a good test system to explore the possibility and reactivity of bimetallic Pt catalysts in the field of enantioselective hydrogenations.
By obtaining the kinetic data with different reaction parameters, such as modifier species, modifier amount, reaction pressure, and reaction temperature, the results can be applied to other complex enantioselective hydrogenations.
5.3.1 Experimental
In this study we used commercially available ethylpyruvate (Aldrich, 98%), ethyl (S)-(-)-lactate (Aldrich, 98%), cinchonidine (Aldrich, 98.5-101%), acetic acid
88
(Galcial). The materials did not require further purification. 5 wt% Pt/γ-Al2O3 and 5 wt% Co/Pt/γ-Al2O3 (Co:Pt = 1:1) are were obtained from Chen’s group.
At first, 25 mg 5 wt% Pt/γ-Al2O3 were pretreated in flowing nitrogen (50 ml/sec) at 450 oC for 30 mins, followed by a reductive treatment in 50 ml/sec hydrogen for another 90 mins. The catalyst then was cooled down to room temperature in hydrogen (50 ml/sec) and transferred to the vessel without exposure to air. The model hydrogenation of ethylpyruvate was carried out in a 100 ml general purpose vessel equipped with a cross-shape stirring bar (2 cm length).
Cinchonidine (6 mg) was added to 10 ml acetic acid at room temperature (RT), while vigorously stirring for 5 minutes. After adding the catalyst for 2 minutes, 5 ml ethylpyruvate was added to the reaction mixture to carry out the reaction under hydrogen at 80 bar. During the initial tests, the reaction temperature was maintained at RT. After 3 hours, the catalyst was removed by filtration through a 0.45 µm filter
(Fisher brand). 0.4 µm filtrate was withdrew and analyzed by GC to determine the concentrations of the reagent 1, the (S)-form product 2, and (R)-form product 3. The
GC mobile phase was nitrogen with 1.1 ml/min flow rate and 60.0 splitting ratio.
The inlet temperature was 220 oC. The column/oven temperature program was (a) 0
~ 5 minutes, 90 oC, (b) 5 ~ 17 minutes, heat to 210 oC by 10 oC/min, (c) 17 ~ 22 minutes, 210 oC, and (d) 22~27 minutes, a post-treatment at 220 oC. The detector temperature was 320 oC.
5.3.2 Results and Discussion
In order to test the hydrogenation system, two experiments were carried out.
The first experiment was run with less amount of the modifier (3 mg cinchonidine) and the catalyst (10 mg 5 wt% Pt/γ-Al2O3, which was reduced in 5% hydrogen/95% nitrogen) under hydrogen of 80 bar. The GC spectrum is shown in Fig. 5-7. The
89 conversion and e.e. after 3 hours were 3% and 33%. During this experiment, two drawbacks were observed: (1) hydrogen pressure was not stable due to several gas leaks in the system; (2) the agitation stopped due to an inappropriate stirring bar.
After fixing the problem related to the gas leak, we tested several sizes and shapes of stirring bars in the reactor. A 2-cm-length cross-shape stirring bar provided continuous stable agitation. After solving the drawbacks of the system, we carried out the second experiment with regular amounts of the modifier and catalyst. The conversion and e.e. after 3 hours were 6% and 42% (Fig. 5-8). We conjectured that the low conversions of the first two experiments might be due to the poor activation of the catalyst using 5% hydrogen/95% nitrogen.
To test our hypothesis, we used Pt/γ-Al2O3, which was reduced by pure hydrogen, to carry out the third experiment. The GC spectrum (Fig. 5-9) showed a significant improvement. The conversion and e.e. after 3 hours were 18% and 70%.
This indicates that the catalyst was activated much better by pure hydrogen. To further test bimetallic Pt catalysts for enantioselective hydrogen, a fourth experiment was carried out. Following the same procedure and treatment, Co/Pt/γ-Al2O3 was used to carry out the model reaction. The results are shown in Fig. 5-10. The conversion and e.e. after 3 hours were 17% and only 24%. The low enantioselectivity may be due to the reaction temperature. It can be expected that higher ee’s may be obtained at lower temperatures.
In summary, we successfully designed and constructed a lab-scale system to carry out enantioselective hydrogenations. However, more investigations should be done to further explore the catalytic ability of Co/Pt/g-Al2O3 in real hydrogenations at low temperature.
90
Tables
Table 5-1. Safety of hydrogen operation
Entry Safety Data
1 Flammability limit in air: 4% ~ 75%
2 Minimum ignition energy: 0.017 mJa
3 Auto-ignition temperature: 572 oC
4 Flame temperature: 2045 oC
5 Detonation pressure: 20 times initial pressure
6 Suitable Metal for hydrogen operation: austenitic stainless steel with >7% nickel, copper and its alloys.
7 Incompatible materials: Oxidizers, fluorine, chlorine, and lithium. [a] An electrostatic spark is ca. 10 mJ.
91
Figures
Fig. 5-1. Picture of the reaction system, in which enantioselective hydrogenations are carried out.
Fig. 5-2 Picture of the central part of the reaction system to illustrate the main routes of hydrogen and nitrogen.
92
Fig. 5-3 Picture of the calcination system, in which the catalyst is activated by hydrogen.
Fig. 5-4 Picture of the control board for the calcination system.
93
Fig. 5-5 Picture of the gas chromatograph system, where hydrogenation samples are analyzed.
Fig. 5-6 Picture of the rear part of the GC system to illustrate the connections of gases.
94
Fig. 5-7 GC spectrum of the first test model reaction. Reaction conditions: cinchonidine (3 mg) and Pt/γ-Al2O3 (10 mg) in the mixture of 10 ml acetic acid and
5 ml ethylpyruvate under hydrogen of 80 bar (pressure was unstable). The catalyst was reduced by 5% hydrogen/95% nitrogen.
95
Fig. 5-8 GC spectrum of the second test model reaction. Reaction conditions: cinchonidine (3 mg) and Pt/γ-Al2O3 (10 mg) in the mixture of 10 ml acetic acid and
5 ml ethylpyruvate under hydrogen of 80 bar. The catalyst was reduced by 5% hydrogen/95% nitrogen.
96
Fig. 5-9 GC spectrum of the third test model reaction. Reaction conditions: cinchonidine (6 mg) and Pt/γ-Al2O3 (25 mg) in the mixture of 10 ml acetic acid and
5 ml ethylpyruvate under hydrogen of 80 bar. The catalyst was reduced by pure hydrogen.
97
Fig. 5-10 GC spectrum of the forth test model reaction. Reaction conditions: cinchonidine (6 mg) and Co/Pt/γ-Al2O3 (25 mg) in the mixture of 10 ml acetic
acid and 5 ml ethylpyruvate under hydrogen of 80 bar. The catalyst was
reduced pure hydrogen.
98
Schemes
Scheme 5-1 First process flow diagram (PFD) of the hydrogenation system.
Scheme 5-2 Second revised PFD of the hydrogenation system.
99
Scheme 5-3 Third revised PFD of the hydrogenation system
100
Scheme 5-4 Model reaction for enantioselective hydrogenation using cinchonidine-modified Pt catalysts.
101
6. SUMMARY AND FUTURE WORK
The main purpose of our research was to provide the basis for an industrial implementation, including experimental studies and computational work. Therefore, we focused on relevant systems of industrial importance, e.g., Pd/C, used for Suzuki cross- and self-couplings.
In the studies of Pd/C-catalyzed Suzuki cross-couplings, our work not only thoroughly investigated the reaction parameters, but also provided significant experimental evidence to clarify the catalytic nature of Pd/C. Those findings may help to improve existing Suzuki coupling systems and will help develop truly heterogeneous Pd catalysts. Furthermore, during the study of Pd-leaching of Pd/C, we discovered a new application of Pd/C, i.e., the Pd/C catalyzed Suzuki self-coupling under base- and ligand-free conditions. We successfully developed optimal reaction conditions to obtain the desired biaryls in good to excellent yields.
This novel system may improve the homocoupling of arylboronic acids in terms of economics and efficiency.
In addition to the studies regarding the synthesis of biaryls, we also worked on the development of an experimental system to study enantioselective hydrogenations.
We successfully built up a lab-scale hydrogenation system at Rutgers University.
This is an important step to successfully explore high-pressure reactions in the near future.
Thus, the directions of future work should be:
102
(1) To explore the mechanism of Suzuki couplings using computational chemistry.
A completely thermodynamic study with diverse functional groups on
aryl-halides may help to determine the rate-limiting step in various cases.
(2) To apply base- and ligand-free Pd/C system to the preparation of complex
symmetric aromatic compounds. The new system might improve the reaction
processes with lower cost and faster reaction performance.
(3) To continue DFT studies on the catalytic cycle of homocouplings of arylboronic
acids.
(4) To continue the investigation of reaction parameters for the enantioselective
hydrogenation of ethylpyruvate using Pt/γ-Al2O3. This may improve yield and
selectivity of bimetallic Pt catalyst systems for enantioselective hydrogenations.
(5) To carry out low-temperature enantioselective hydrogenation using bimetallic Pt
catalysts to obtain a system with very high enantiomeric excesses.
103
7. APPENDIX
7.1 Appendix 1: Derivations of the theoretical rate expression for homogeneous
Pd-catalyzed Suzuki couplings
Seven elementary reactions:
I : Pd + R-Br ⎯⎯→k1 R-Pd-Br;
r1 = k1[Pd][R-Br] (A.1)
II: R-Pd-Br + OH- ⎯⎯→k2 R-Pd-OH + Br-;
- r2 = k2[R-Pd-Br][OH ] (A.2)
- k3 - III: R-Pd-OH + R’-B(OH)3 ⎯⎯→ R-Pd-R’ + B(OH)4 ;
- r3 = k3[R-Pd-OH][R’-B(OH)3 ] (A.3)
IV: R-Pd-R’ ⎯⎯→k4 R-R’ + Pd;
r4 = k4[R-Pd-R’] (A.4)
V: CO 2- +H O ←⎯⎯⎯ ⎯⎯→k 5 HCO - + OH- 3 2 k5−1 3
3− − -1 [HCO ][OH ] K5 = k5/k5 = 2− (A.5) [CO3 ]
VI: R’-B(OH) + OH- ←⎯⎯⎯ ⎯⎯→k 6 R’-B(OH) - 2 k 6−1 3
− -1 [R'−B(OH )3 ] K6 = k6/k6 = − (A.6) [R'−B(OH ) 2 ][OH ]
VII: B(OH) - ←⎯⎯⎯ ⎯⎯→k 7 B(OH) + OH- 4 k 7−1 3
− -1 [B(OH )3 ][OH ] K7 = k7/k7 = − (A.7) [B(OH ) 4 ]
104
Species Balance: d[Pd] = r4-r1 = -k1[Pd][R-Br] + k4[R-Pd-R’] =0 (A.8) dt d[R − Pd − Br] - = r1-r2 = k1[Pd][R-Br] – k2[R-Pd-Br][OH ] =0 (A.9) dt d[R − Pd − OH ] = r2-r3 dt
- - = k2[R-Pd-Br][OH ] - k3[R-Pd-OH][R’-B(OH)3 ]=0 (A.10) d[R − Pd − R'] - = r3-r4 = k3[R-Pd-OH][R’-B(OH)3 ] -k4[R-Pd-R’]=0 (A.11) dt
d[R'−B(OH ) 2 ] -1 -1 - - = r6 -r6 = k6 [R’-B(OH)3 ] -k6[R’-B(OH)2][OH ]=0 (A.12) dt
− d[R'−B(OH )3 ] -1 =r6-r6 -r3 dt
- -1 - - = k6[R’-B(OH)2][0H ] – k6 [R’-B(OH)3 ] –k3[R-Pd-OH][R’-B(OH)3 ] =0 (A.13)
− d[B(OH ) 4 ] -1 = r3-r7+r7 dt
- - -1 - - = k3[R-Pd-OH][R’-B(OH)3 ]-k7[B(OH)4 ] + k7 [B(OH)3 ][OH ] =0 (A.14)
− d[OH ] -1 -1 -1 = -r2 + (r5-r5 )+(-r6+r6 )+(r7-r7 ) dt
- 2- -1 - - - = -k2[R-Pd-Br][OH ] +k5[CO3 ] –k5 [HCO3 ][OH ] – k6[R’-B(OH)2][OH ]
-1 - - -1 - +k6 [R’-B(OH)3 ] +k7[B(OH)4 ] –k7 [B(OH)3][OH ] =0 (A.15)
− d[HCO3 ] -1 2- -1 - - = r5-r5 = k5[CO3 ] – k5 [HCO3 ][OH ] = 0 (A.16) dt
(I) When oxidative addition (Step I) is assumed as rate-limiting step, then:
reaction rate = k1[R − Br][Pd] (A.1)
105
From material balance of Pd species:
[Pd]0 = [Pd] + [R-Pd-Br] + [R-Pd-OH] + [R-Pd-R’]
k [R'−B(OH ) − ] = [Pd] + [R-Pd-Br] + [R-Pd-OH] + 3 3 [R − Pd − OH ] k4
⎪⎧ k [R'−B(OH ) − ]⎪⎫ k [OH − ] = [Pd] + [R-Pd-Br] + ⎨1+ 3 3 ⎬ 2 [R − Pd − Br] k − ⎩⎪ 4 ⎭⎪ k3[R'−B(OH )3 ]
⎪⎧ k [OH − ] k [OH − ]⎪⎫ = [Pd] + ⎨1+ 2 + 2 ⎬[R − Pd − Br] − k ⎩⎪ k3[R'−B(OH )3 ] 4 ⎭⎪
⎪⎧ k [OH − ] k [OH − ]⎪⎫ k [R − Br] =[Pd] + ⎨1+ 2 + 2 ⎬ 1 [Pd] − k − ⎩⎪ k3[R'−B(OH )3 ] 4 ⎭⎪ k2 [OH ]
⎪⎧ 1 1 1 1 ⎪⎫ = k1[Pd][R − Br]× ⎨ + + + ⎬ (A.17) k [R − Br] − − k ⎩⎪ 1 k2 [OH ] k3[R'−B(OH)3 ] 4 ⎭⎪
Therefore, from (A.17), reaction rate = k1[Pd ][R − Br]
[Pd] = 0 (A.18) 1 1 1 1 + − + − + k1[R − Br] k2 [OH ] k3[R'−B(OH )3 ] k4
Assume k2, k3, and k4 are much larger than k1, because oxidative addition is the RLS, then:
[Pd] reaction rate = 0 = k [Pd] [R − Br] (A.19) 1 1 0
k1[R − Br]
(A.19) is the theoretical rate expression when oxidative addition is assumed as the rate-limiting step.
(II) When transmetalation (Step III) is assumed as rate-limiting step, then:
106
− reaction rate r= k3[R'−B(OH )3 ][R − Pd − OH ] (A.3)
Calculate [R-Pd-OH] from material balance of Pd species:
[Pd]0 = [Pd]+[R-Pd-Br]+[R-Pd-OH]+[R-Pd-R’]
k1[Pd][R − Br] = [Pd]+ − +[R-Pd-OH]+[R-Pd-R’] k2 [OH ]
⎛ k [R − Br]⎞ = ⎜1+ 1 ⎟ [Pd]+[R-Pd-OH]+[R-Pd-R’] ⎜ − ⎟ ⎝ k2 [OH ] ⎠
⎛ k [R − Br]⎞ k [R − Pd − R'] =⎜1+ 1 ⎟ 4 +[R-Pd-OH]+[R-Pd-R’] ⎜ − ⎟ ⎝ k2 [OH ] ⎠ k1[R − Br]
⎛ k k ⎞ =⎜ 4 + 4 +1⎟ [R-Pd-R’]+[R-Pd-OH] ⎜ − ⎟ ⎝ k1[R − Br] k2 [OH ] ⎠
⎛ k k ⎞ k [R − Pd − OH ][R'−B(OH ) − ] =⎜ 4 + 4 +1⎟ 3 3 +[R-Pd-OH] ⎜ − ⎟ ⎝ k1[R − Br] k2 [OH ] ⎠ k4
⎛ k [R'−B(OH ) − ] k [R'−B(OH ) − ] k [R'−B(OH ) − ] ⎞ =⎜ 3 3 + 3 3 + 3 3 +1⎟ [R-Pd-OH] (A.20) ⎜ − ⎟ ⎝ k1[R − Br] k2 [OH ] k4 ⎠
Therefore, from (A.20),
⎛ k [R'−B(OH ) − ] k [R'−B(OH ) − ] k [R'−B(OH ) − ] ⎞ [R-Pd-OH] = [Pd] /⎜ 3 3 + 3 3 + 3 3 +1⎟ 0 ⎜ − ⎟ ⎝ k1[R − Br] k2 [OH ] k4 ⎠
[Pd] = 0 (A.21) − 1 1 1 1 k3[R'−B(OH )3 ]( + − + − + ) k1[R − Br] k2 [OH ] k3[R'−B(OH )3 ] k4
Insert (A.21) into reaction rate, then:
- reaction rate = k3[R-Pd-OH][R’-B(OH)3 ]
107
[Pd]0 =k3* − 1 1 1 1 k3[R'−B(OH )3 ]( + − + − + ) k1[R − Br] k2 [OH ] k3[R'−B(OH )3 ] k4
- *[R’-B(OH)3 ]
[Pd] = 0 (A.18) 1 1 1 1 + − + − + k1[R − Br] k2 [OH ] k3[R'−B(OH )3 ] k4 which is the same equation we obtained when oxidative addition is assumed as RLS.
However, we assume k1, k2, and k4 >>k3 in this case, because transmetalation is the assumed RLS. Hence,
[Pd] reaction rate = 0 = k [Pd] [R’-B(OH) -] (A.22) 1 3 0 3 − k3[R'−B(OH )3 ]
(A.21) could be the theoretical rate expression when transmetalation is assumed as the
- rate-limiting step. However, R’-B(OH)3 is the intermediate, not an initial reactant.
Thus, we would like to eliminate it from the rate equation.
- Calculation of [R’-B(OH)3 ]:
- From the species balance of [R’-B(OH)3 ], (A.13), we may obtain
− − - k6 [R'−B(OH ) 2 ][OH ] [R'−B(OH ) 2 ][OH ] [R’-B(OH)3 ] = = (A.23) k −1 + k [R − Pd − OH ] k −1 k [R − Pd − OH ] 6 3 6 + 3 k6 k6
k3[R − Pd − OH ] - We may further obtain ≅ 0 from the calculation of [B(OH)4 ] k7 and [B(OH)3]. This implies that k7>>k3, i.e., the equilibrant rate of [OH-] at step VII is much faster than step III (the RLS).
108
Therefore, we may also assume that the equilibrant rate of [OH-] at step VI is much
k [R − Pd − OH ] faster than step III to obtain 3 ≅ 0 . (A.24) k6
− - [R'−B(OH ) 2 ][OH ] Then [R’-B(OH)3 ] = −1 k6
k6
- = K6[R’-B(OH)2][OH ] (A.25)
Insert (A.25) back to (A.22), we may get
- reaction rate = k3K6[Pd]0[R’-B(OH)2][OH ] (A.26)
Calculate [OH-]:
From the species balance of [OH-],
k [CO 2− ] + k −1[R'−B(OH ) − ] + k [B(OH ) − ] [OH − ] = 5 3 6 3 7 4 (A.27) −1 − −1 k2 [R − Pd − Br] + k5 [HCO3 ] + k6 [R'−B(OH ) 2 ] + k7 [B(OH )3 ]
This shows that [OH-] is affected by the concentration of reactants and intermediates.
As a result, we obtain (A.26) as the theoretical rate expression, when transmetalation is assumed as the RLS.
109
7.2 Appendix 2: Derivations of theoretical rate expression for heterogeneous
Pd-catalyzed Suzuki couplings
Based on the catalytic cycle for homogeneous Pd-catalyzed Suzuki couplings, we obtained a theoretical rate expression (A.26), which matches the experimental observations, when transmetalation is assumed as the rate-limiting step. In addition, it is the goal to describe the behavior of heterogeneous Pd/C in Suzuki couplings. In this case, we assumed that both oxidative addition and transmetalation are reversible steps.
Assumptions:
1. Oxidative addition is reversible due to the adsorption effect of heterogeneous
catalysts.
2. k2 is comparable to k1/k-1 to support the first assumption.
3. Transmetalation is reversible because the excess amount of base would slow
down the reaction rate.
4. k4 is comparable to k3/k-3 to support the third assumption.
5. Transmetalation is assumed as RLS. Therefore, k1/k-1 and k2 are much larger
than k3/k-3 and k4.
Elementary steps of proposed catalytic cycle:
k1 I: Pd + R-Br ←⎯⎯k−1 ⎯⎯→ R-Pd-Br
r1 = k1[Pd][R − Br] (A.1)
r−1 = k−1[R − Pd − Br] (A.28)
II: R-Pd-Br + OH- ⎯⎯→k2 R-Pd-OH + Br
110
− r2 = k2 [R − Pd − Br][OH ] (A.2)
- k−3 k3 - III: R-Pd-OH + R’-B(OH)3 ←⎯⎯ ⎯⎯→ R-Pd-R’ + B(OH)4 − r3 = k3[R − Pd − OH ][R'−B(OH )3 ] (A.3) − r−3 = k−3[R − Pd − R'][B(OH ) 4 ] (A.29)
IV: R-Pd-R’ ⎯⎯→k4 Pd + R-R’
r4 = k4 [R − Pd − R'] (A.4)
V: CO 2- +H O ←⎯⎯⎯ ⎯⎯→k 5 HCO - + OH- 3 2 k5−1 3 3− − -1 [HCO ][OH ] K5 = k5/k5 = 2− (A.5) [CO3 ]
VI: R’-B(OH) + OH- ←⎯⎯⎯ ⎯⎯→k 6 R’-B(OH) - 2 k 6−1 3 − -1 [R'−B(OH )3 ] K6 = k6/k6 = − (A.6) [R'−B(OH ) 2 ][OH ]
VII: B(OH) - ←⎯⎯⎯ ⎯⎯→k 7 B(OH) + OH- 4 k 7−1 3 − -1 [B(OH )3 ][OH ] K7 = k7/k7 = − (A.7) [B(OH ) 4 ]
Species balance and steady state assumption: d[Pd] = r4 – r1 + r-1 dt = k4[R-Pd-R’] – k1[Pd][R-Br] + k-1[R-Pd-Br]=0 (A.30) d[R − Pd − Br] = r1 – r-1 – r2 dt - = k1[Pd][R-Br] – k-1[R-Pd-Br] – k2[R-Pd-Br][OH ] =0 (A.31) d[R − Pd − OH ] = r2 – r3 + r-3 (A.32) dt - - - = k2[R-Pd-Br][OH ] – k3[R-Pd-OH][R’-B(OH)3 ] + k-3[R-Pd-R’][B(OH)4 ]=0 d[R − Pd − R'] = r3 – r-3 – r4 dt - - = k3[R-Pd-OH][R’-B(OH)3 ] – k-3[R-Pd-R’][B(OH)4 ] – k4[R-Pd-R’] =0 (A.33)
Because transmetalation is the RLS:
111
reaction rate = r3 – r-3
− − = k3[R'−B(OH )3 ][R − Pd − OH ] − k−3[R − Pd − R'][B(OH ) 4 ] (A.34)
− Calculate k3 [R'−B(OH ) 3 ][R − Pd − OH ]:
[Pd]0 = [Pd] + [R-Pd-Br] + [R-Pd-OH] + [R-Pd-R’]
k4 [R − Pd − R'] ⎧ k−1 ⎫ k4 [R − Pd − R'] = ⎨1+ − ⎬+ − +[R-Pd-OH]+[R-Pd-R’] k1[R − Br] ⎩ k2 [OH ]⎭ k2 [OH ]
⎧ k4 k−1k4 k4 ⎫ = ⎨ + − + − +1⎬[R − Pd − R'] + [R − Pd − OH ] ⎩k1[R − Br] k1[R − Br]k2 [OH ] k2[OH ] ⎭
⎧ k4 k−1k4 k4 ⎫ ⎨ + − + − +1⎬× ⎩k1[R − Br] k1[R − Br]k2 [OH ] k2 [OH ] ⎭ = − k3[R'−B(OH )3 ] − [R − Pd − OH )] + [R − Pd − OH ] k−3[B(OH ) 4 ] + k4
⎧ k k k ⎫ 4 + −1 4 ⎪ − − ⎪ ⎪k1[R − Br]()k−3[B(OH ) 4 ] + k4 k1[R − Br]k2 [OH −]()k−3[B(OH ) 4 ] + k4 ⎪ ⎨ ⎬× = k 1 1 ⎪+ 4 + + ⎪ ⎪ − − − − ⎪ ⎩ k2 [OH ]()k−3[B(OH ) 4 ] + k4 k3[R'−B(OH )3 ] k−3[B(OH ) 4 ] + k4 ⎭ − k3[R'−B(OH )3 ][R − Pd − OH ]
− Therefore, k3 [R'−B(OH ) 3 ][R − Pd − OH ]
[Pd] = 0 k k k 4 + −1 4 − − − k1[R − Br]()k−3[B(OH ) 4 ] + k4 k1[R − Br]k2 [OH ]()k−3[B(OH ) 4 ] + k4 k 1 1 + 4 + + − − − − k2 [OH ]()k−3[B(OH ) 4 ] + k4 k3[R'−B(OH )3 ] k−3[B(OH ) 4 ] + k4
− [Pd]0 (k−3[B(OH ) 4 ] + k4 ) = − (A.35) k4 k−1k4 k4 ()k−3[B(OH ) 4 ] + k4 + − + − + − +1 k1[R − Br] k1[R − Br]k2 [OH ] k2 [OH ] k3[R'−B(OH )3 ]
112
− Calculate k−3[R − Pd − R'][B(OH) 4 ]:
[Pd]0 = [Pd] + [R-Pd-Br] + [R-Pd-OH] + [R-Pd-R’]
k4 [R − Pd − R'] ⎧ k−1 ⎫ k4 [R − Pd − R'] = ⎨1+ − ⎬+ − + k1[R − Br] ⎩ k2 [OH ]⎭ k2 [OH ]
− {k−3[B(OH ) 4 ] + k4 }[R − Pd − R'] − +[R-Pd-R’] k3[R'−B(OH )3 ]
− ⎪⎧ k k k k (k 3[B(OH ) 4 ] + k4 ) ⎪⎫ ⎨ 4 + −1 4 + 4 + − +1⎬× = k [R − Br] − − − ⎩⎪ 1 k1[R − Br]k2 [OH ] k2 [OH ] k3[R'−B(OH )3 ] ⎭⎪ [R − Pd − R']
Therefore, [R-Pd-R’]
[Pd]0 = − (A.36) k4 k−1k4 k4 ()k−3[B(OH ) 4 ] + k4 + − + − + − +1 k1[R − Br] k1[R − Br]k2 [OH ] k2 [OH ] k3[R'−B(OH )3 ]
− And k−3[R − Pd − R'][B(OH ) 4 ] − k−3[Pd]0 [B(OH ) 4 ] = − (A.37) k4 k−1k4 k4 ()k−3[B(OH ) 4 ] + k4 + − + − + − +1 k1[R − Br] k1[R − Br]k2 [OH ] k2 [OH ] k3[R'−B(OH )3 ]
Combine (A.35) and (A.37), reaction rate becomes:
− − reaction rate = k3[R'−B(OH ) 4 ][R − Pd − OH ] − k−3[R − Pd − R'][B(OH ) 4 ] − [Pd]0 (k−3[B(OH ) 4 ] + k4 ) = − – k4 k−1k4 k4 ()k−3[B(OH ) 4 ] + k4 + − + − + − +1 k1[R − Br] k1[R − Br]k2 [OH ] k2 [OH ] k3[R'−B(OH )3 ]
− k−3[Pd]0 [B(OH ) 4 ] − k4 k−1k4 k4 ()k−3[B(OH ) 4 ] + k4 + − + − + − +1 k1[R − Br] k1[R − Br]k2 [OH ] k2 [OH ] k3[R'−B(OH )3 ]
113
− − [Pd]0 (k−3[B(OH ) 4 ] + k4 )− k−3[Pd]0 [B(OH ) 4 ] = − k4 k−1k4 k4 ()k−3[B(OH ) 4 ] + k4 + − + − + − +1 k1[R − Br] k1[R − Br]k2 [OH ] k2 [OH ] k3[R'−B(OH )3 ]
[Pd]0 k4 = − k4 k−1k4 k4 ()k−3[B(OH ) 4 ] + k4 + − + − + − +1 k1[R − Br] k1[R − Br]k2 [OH ] k2 [OH ] k3[R'−B(OH )3 ]
[Pd]0 = − (A.38) 1 k−1 1 ()k−3[B(OH ) 4 ] + k4 1 + − + − + − + k1[R − Br] k1[R − Br]k2 [OH ] k2 [OH ] k4 k3[R'−B(OH )3 ] k4
reaction_rate Therefore, [Pd]0 1 = − (A.39) 1 k−1 1 ()k−3[B(OH ) 4 ] + k4 1 + − + − + − + k1[R − Br] k1[R − Br]k2 [OH ] k2 [OH ] k4 k3[R'−B(OH )3 ] k4
Because k1, k2 are much larger than k3, k4, (A.39) can be simplified as:
rr 1 = − (A.40) [Pd]0 [B(OH ) 4 ] 1 1 − + − + k4 K 3[R'−B(OH )3 ] k3[R'−B(OH )3 ] k4
Because transmetalation is assumed as the RLS, we further assume that k4 is bigger than k3, and 1/k4 is negligible:
rr 1 = − [Pd]0 [B(OH ) 4 ] 1 − + − k4 K 3[R'−B(OH )3 ] k3[R'−B(OH )3 ] − k3[R'−B(OH )3 ] = − (A.41) (k−3 / k4 )[B(OH ) 4 ] +1
114
- [R’-B(OH)3 ] in numerator may explain that reaction rate is faster with higher concentration of the boronic acid.
- [B(OH)4 ] in dominator may explain that reaction rate slows down while the excess amount of base is added (i.e., pH reaches a certain high level). When [OH-] is
- high, the accumulation of B(OH)4 would slow down transmetalation and result in a slower reaction.
- - Further calculations of [R-B(OH)3 ] and [B(OH)4 ]:
- - [R-B(OH)3 ] and [B(OH)4 ] are involved in the following two reactions:
- k−6 k6 - VI: R-B(OH)2 + OH ←⎯⎯ ⎯⎯→ R-B(OH)3
- k−3 k3 - III: R-Pd-OH + R’-B(OH)3 ←⎯⎯ ⎯⎯→ R-Pd-R’ + B(OH)4
- [R-B(OH)3 ]:
When we assume that step VI is much fast than step III (RLS), which implies
- K6(k6/k-6) is much larger than K3(k3/k-3), [R-B(OH)3 ] can be accounted by
- K6[R-B(OH)2][OH ] directly. (See (A.25))
- [B(OH)4 ]:
- Actually, B(OH)4 is the by-product of the reaction, and the whole formula of it would be NaB(OH)4. When we re-arrange it, it could be viewed as
- NaOH*H3BO3 and become NaH2BO3 + H2O. Therefore, [B(OH)4 ] would be equal to [NaH2BO3], which is a salt.
As a result, the final rate expression would become:
115
rr k K [R − B(OH ) ][OH − ] = 3 6 2 (A.42) [Pd]0 k−3 [NaH 2 BO3 ] +1 k4
Comparing to (A.26), (A.42) provides us more information about [OH-]/salt effect on the reaction performance, which better describes the experimental observations.
116
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123
9. CURRICULUM VITAE
Jeng-Shiou Chen, PhD
EDUCATION
NATIONAL TAIWAN UNIVERSITY, Taipei, Taiwan
1998 B.S. in Chemical Engineering
1998 B.S. in Public Health
2000 M.S. in Chemical Engineering
RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY, New Brunswick,
New Jersey
2005 M.S. in Chemical and Biochemical Engineering
2008 Ph.D. in Chemical and Biochemical Engineering
PUBLICATIONS Chen, J.-S., Krogh-Jespersen, K., and Khinast J.G, Base- and ligand-free heterogeneously catalyzed homocoupling of arylboronic acids. (Submitted to J. Mol. Cata. A in Nov. 2007)
Chen, J.-S., Vassylyev, O., Panarello, A.P., and Khinast, J.G., Pd-leaching and Pd-removal of Pd/C-catalyzed Suzuki couplings. Applied. Catalysis. A, 2007, 325:76-86
Vasiliev, A., Golovko, L.V., Povazhny, V.A., Zlotnikov, E., Chen J.-S., Khinast, J.G., Functionalized nanoporous carbon as a catalyst for Suzuki coupling reactions. Microporous and Mesoporous Materials, 2007, 101:342-347
Vassylyev, O., Chen, J.-S., Hall, G.S. and Khinast, G., Efficient surface functionalization of zeolites via esterification. Microporous and Mesoporous Materials, 2006, 92:101-108
Vassylyev, O., Chen, J.-S., Panarello, A.P. and Khinast, J.G. Catalytic properties of several supported Pd(II) complexes for Suzuki coupling reactions. Tetrahedron Letters, 2005, 46:6865-6869
124
Tai, Y.-W., Chen, J.-S., Yang, C.-C., and Wan, B.-Z., Preparation of nano-gold
on K2La2Ti3O10 for producing hydrogen from photo-catalytic water splitting. Catalysis Today, 2004, 97:95-101
Chen, J.-S., Reduction of CO2 in the daily life and study of layered titanium catalysts for photo-catalytic water decomposition. Master Thesis, National Taiwan University, Taiwan, 2000
MEMBERSHIPS • Catalysis Society of Metropolitan New York • ISPE Engineering Pharmaceutical Innovation