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Seton Hall University Dissertations and Theses

Spring 5-2011

Scope and Mechanistic Studies of the Palladium on Carbon Catalyzed Suzuki Cross Coupling Reaction Carl LeBlond Seton Hall University

Follow this and additional works at: http://scholarship.shu.edu/dissertations Part of the Organic Chemistry Commons Recommended Citation LeBlond, Carl, "Scope and Mechanistic Studies of the Palladium on Carbon Catalyzed Suzuki Cross Coupling Reaction" (2011). Seton Hall University Dissertations and Theses (ETDs). Paper 1242.

SCOPE AND MECHANISTIC STUDIES OF THE PALLADIUM ON CARBON CATALYZED SUZUKI CROSS COUPLING REACTION

by Carl LeBlond

Ph.D. DISSERTATION Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Chemistry and Biochemistry of Seton Hall University

May 2001 South Orange, New Jersey

We certify that we have read this thesis and that in our opinion it is sufficient in scientific scope and quality as a dissertation for the degree of Doctor of Philosophy.

APPROVED

J ~ RSowa, . Jr., Ph.D. Research Advisor, Seton Hall University

Yongkui s&,Ph.D. Research Advisor, Merck Research Laboratories

Stephen P. Kelty, Ph.D. Member of Dissertation Committee, Seton Hall University

emistry and Biochemistry, Seton Hall University

To my parents and Lisa

"I call our world Flatland, not because we call it so, but to make its nature clearer to you, my happy readers, who are privileged to live in Space."

"Imagine a vast sheet of paper on which straight Lines, Triangles, Squares, Pentagons, Hexagons, and other figures, instead of remaining fixed in their places, move freely about, on or in the surface, but without the power of rising above or sinking below it, very much like shadows -- only hard and with luminous edges -- and you will then have a pretty correct notion of my country and countrymen. Alas, a few years ago, I should have said "my universe": but now my mind has been opened to higher views of things."

[E.A. Abbott, Flatland (6thEd.) Dover, New York, 19521

SCOPE AND MECHANISTIC STUDIES OF THE PALLADIUM ON CARBON CATALYZED SUZUKI CROSS COUPLING REACTION

Abstract

Due to its efficiency, mild reaction conditions and functional group tolerance, the Suzuki cross-coupling reaction, i.e., palladium-catalyzed carbon-carbon bond formation reaction between organoboron derivatives and organic halides, has become a major tool in synthesizing complex organic compounds. While the cross-coupling reaction has been predominantly catalyzed by homogeneous palladium catalysts such as Pd[P(Ph)s]4, there has been a limited number of reports where heterogeneously-supported Pd catalysts were found to catalyze the cross-coupling reaction. Heterogeneously-catalyzed Suzuki crosscoupling can be technically important due to the inherent advantages associated with the processing of heterogeneous catalysts.

At the same time, it is also a scientifically

challenging reaction to understand and optimize considering the complexity of the active sites on heterogeneous surfaces. We show that the coupling of a variety of para-substituted aryl bromides and aryl boronic acids occurs in yields of 79 - 94 % at temperatures as low as 25 "C. A Hammett study reveals that the reaction rates increase with electron-donating groups on the aryl boronic acid (p =-2.0) and increase moderately with electron-withdrawing groups on the aryl bromide. In addition, steric effects are more dominating during the transmetallation step because steric bulk on the boronic acid has a greater inhibitory affect on the reaction rate than on the aryl halide. Kinetic studies indicate the reaction is othorder in aryl halide and 1'' order in phenylboronic acid. These results are consistent with transmetallation as

the rate limiting step. A mechanism in which the phenylboronic acid reacts with a surface bound aryl halide is proposed and discussed. We have optimized the reaction to enable PdC, without added ligands, to catalyze the Suzuki cross-coupling reaction with aryl chlorides. Up to 95% yield was observed for aryl chlorides with electron-withdrawing substituents, whereas the yields of electron rich and neutral aryl chlorides are moderate. The high reactivity towards activation of the C-Cl or C-Br bond may result from unique catalytic properties associated with heterogeneous Pd catalysts, namely, cooperative anchimeric and electronic effects which occur upon adsorption of the aryl halide on the Pd catalytic surface.

Acknowledgements

I am grateful for the financial support provided by Merck and Co., Inc. during the research contained herein. To all my fiiends in the REL past and present; Dr. Michael Palucki, Dr. Dave Conlon, Dr. Ralph Landau and Dr. Jian Wang who have all contributed in one way or another over the past seven years. To Dr. Tiebang Wang and Jane Wu of Merck and Co. Inc. for AA analysis.

To John Sowa for his guidance, support and flexibility throughout this work. I am very gratefd to John for his friendship and mentoring during this work.

To Yongkui Sun, my co-advisor, mentor and good friend, who has shaped me into an excellent researcher and is primarily responsible for my conversion from an engineer to the hybrid I am today.

To Donna Blackmond who before this project was even conceived, believed in my abilities and gave me the opportunity to work with these brilliant people.

To Frank Gortsema not only for his work on catalyst characterization, but for providing excellent advice, a helping hand and tolerating my music in the lab.

To Dr. Stephen Kelty for serving on my Thesis Committee. To my Mom and Dad for their encouragement and support throughout my education.

Finally I want to thank my wife Lisa for putting up with the weekends I spent working and countless hours I've worked on manuscript preparation and data processing.

vii

Table of contents TABLE OF CONTENTS LIST OF FIGURES LIST OF TABLES

.................................................................................................8

.......................................................................................................10

..........................................................................................................12

ABBREVIATIONS

................................................................................................... 13 1

........................................................................14 A Review of the Suzuki Cross-Coupling Reaction.......................................................17

INTRODUCTION AND RATIONALE

Oxidative Addition Step ............................................................................................... 20 Role of the Base ..........................................................................................................25

Transmetallation Step ............................................................................................. 27 Reductive Elimination Step ......................................................................................... 30

.......................................................................

-77 PdIC. Physical Properties and Catalysis 31 Structure and Preparation .............................................................................................. 31

Safety ..............................

. . ...................................................................................... 33

Reactivity of PdIC ................................................................................................... 34 Nature of Metal-Substrate Interactions ..................................................................... 35 PdIC in Hydrogenations and Reductions ................................................................. 40 Heterogeneous Catalysis in C-C bond Formation Reactions .................................. 44

.................................................................................52 PdIC Catalyzed Suzuki Cross-Coupling with Aryl Bromides ....................................54 RESULTS AND DISCUSSION

Heterogeneous versus homogeneous catalysis............................................................ 55 Scope of the Pd/C Suzuki Cross-Coupling .................................................................

57

Substituent Electronic Effects ..................................................................................... 58 Reaction Order Studies ................................................................................................

64

Effect of [ArBr]......................................................................................................... 65 Effect of [ArB(OH)2]..............................................................................................66

. . Mechan~sticInterpretation ............................................................................................69 PdIC Catalyzed Suzuki Cross-Coupling with Aryl Chlorides ....................................79 Optimization .............................................................................................................. 80 Scope of Pd/C Suzuki Cross-Coupling using Aryl Chlorides ...................................... 82 Proposed Mechanism of C-C1 bond Activation ............................................................ 86

CONCLUSIONS

...........................................................................................................89

FUTURE EXPERIMENTATION............................................................................. 91 EXPERIMENTAL SECTION.......................................................................................94 Materials ..................................................................................................................... 94 Instrumentation .......................................................................................................... 94 Cross-Couplings with Aryl Bromides .Table 5 ........................................................... 95 Hammett Studies -Figure 7. Figure 10 and Figure I 1............................................... 101 Reaction Calorimetry Studies .Figure 12 and Figure 13 ........................................... 103 Cross-Couplings with Aryl Chlorides .Table 8 ......................................................... 104

. . . . . . . . .............................108

APPENDIX I .KINETIC MODEL..........................

APPENDIX I1 .H' NMR SPECTRA TABLE 5 AND TABLE 8 .............................113 APPENDIX I11 . ARBR LC DATA

...........................................................................142

..........................................148

APPENDIX IV . ARCL LC DATA ...........................

APPENDIX V .RATE CALCULATIONS FOR FIGURE 7 ................................... 156 APPENDIX VI . RATE CALCULATIONS FOR FIGURE 10 ...............................159 APPENDIX VII .RATE CALCULATIONS FOR FIGURE 11..............................161

List of figures Figure 1. Proposed SE2 coordination mechanism ............................................................ 28 Figure 2 . SE2 coordination mechanism in transmetallation from Sn to Pd ...................... 29 Figure 3 . Hydroxo p2-bridged transition state in transmetallation involving alkylboranes to palladium .............................................................................................................. 29 Figure 4 . Complexity of heterogeneous catalytic surfaces......................................... 32 Figure 5 . Dewar-Chatt-Duncanson model of olefin coordination to transition metals .... 36 Figure 6 . Saturation at corner, edge and terrace sites ...................................................... 38 Figure 7 . Hammett plots for the heterogeneous Suzuki coupling reaction using Pd/C at 25 "C . Effect of substituted aryl halides .................................................................. 59 Figure 8. Concentration profiles for para-substituted aryl bromides ............................... 61 Figure 9 . Effect of benzonitrile on cross-coupling of 4-bromobenzotrifluoride with phenylboronic acid .................................................................................................... 62 Figure 10. Hammett plot for the heterogeneous Suzuki cross-coupling reaction using Pd/C at 25 "C (p = -2.0). ........................................................................................... 63 Figure 11. Hammett plots for the heterogeneous Suzuki cross-coupling using Pd/C at 50 "C . Effect of substituted phenylboronic acids ......................................................... 64 Figure 12. Zero order rate dependence on aryl bromide concentration (CRC-90 data) . . 66 Figure 13. Positive order rate dependence on phenylboronic acid concentration (RC 1 data) ........................................................................................................................... 67 Figure 14. Conversion versus time plot ........................................................................... 68 Figure 15. Reaction order determination; a) ln(rate) versus ln(C) for initial induction period evaluated over 0- 10% conversion b) ln(rate) versus ln(C) following induction period evaluated over 40-60% conversion ................................................................ 69 Figure 16. SE2(cyclic)transmetallation mechanism in heterogeneous Suzuki crosscoupling .....................................................................................................................74 Figure 17. Proposed Suzuki cross-coupling mechanism over Pd/C ................................ 75 Figure 18. Comparison of steric effects on the phenylboronic acid and aryl bromide

substrates................................................................................................................... 77

Figure 19. Transmetallation on heterogeneous surface. a) effect of sterically hindered mesitylboronic acid and b) effect of sterically hindered mesitylbromide ...............

...... Figure 20 . Illustration of cooperative anchimeric and electronic effects ..............

78 87

List of tables Table 1. Common hydrogenation reactions employing Pd/C ...................... . .............. 41 Table 2 . Coupling Reactions Catalyzed by Pd/C ............................................................. 45 Table 3 . Pd/C catalyzed Suzuki cross-coupling results reported by Buchecker et a1...... 47 Table 4 . Activity of Pd Sources toward Suzuki cross-coupling of aryl bromides and phenylboronic acid .................................................................................................... 57 Table 5 . Yield and conversion results for Suzuki cross-coupling of substituted aryl bromides and substituted phenylboronic acids at catalyzed by Pd/C at 25 "C and 50

OC .............................................................................................................................. 58 Table 6. Acid dissociation constants for para-substituted phenylboronic acids in 25% aqueous ethanol solution........................................................................................... 74 Table 7 . Effect of solvent and amount of water in the PdIC catalyzed Suzuki crosscoupling of 4-chlorobenzotrifluoride and phenylboronic acid ................................. 81 Table 8. Pd/C-catalyzed Suzuki cross-couplings with aryl chlorides.............................. 82 Table 9. Self-coupling of Phenylboronic acid over Pd/C .........................................84

Abbreviations P

micro or bridging ligand as in p2

rl

hapticity

Ar

aryl group

9-BBN

9-borabicyclo[3.3. llnonane

CBA

concentration of phenylboronic acid

CY

cyclohexyl

dba

dibenzylidene acetone

DlMA

N,N-dimethylacetamide

DMF

N,N-dimethylformamide

dppf equiv

bis(dipheny1phosphino)ferrocene

i-Pr

isopropyl

h

hours

k

rate constant

ko

rate constant with H as substituent

L

ligand

L

Liter

M

molarity (molesIL)

mL

milliliter

mmol

millimole

n-Bu

n-Butyl

NMP

1-methylpyrolidinone

OAc

acetate

OTf

triflate

Ph

phenyl

9r

heat release rate (energyltime)

S E ~

bimolecular electrophilic substitution

S N ~

bimolecular nucleophilic substitution

molar equivalents