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  • Theoretical Study on Pd-catalyzed

    Cross-Coupling Reactions.

    Maximiliano Garca Melchor

    Ph.D. Thesis

    Ph.D. in Chemistry

    Supervisors:

    Gregori Ujaque Prez

    Agust Lleds Falc

    Departament de Qumica,

    Facultat de Cincies

    2012

  • Universitat Autnoma de BarcelonaDepartament de QumicaUnitat de Qumica Fsica

    Memria presentada per aspirar al Grau de Doctor per Max Garca Melchor.

    Max Garca Melchor

    Vist i plau,

    Gregori Ujaque Prez Agust Lleds Falc

    Bellaterra, 9 de Mar de 2012.

  • List of abbreviations

    Abbreviation Meaning

    Ar Any aromatic group

    B3LYP Becke's three-parameter, Lee-Yang-Parr exchange-correlationfunctional

    tBu tert-butyl

    dba dibenzylideneacetone

    DCM Dichloromethane

    DMF N,N-Dimethylformamide

    DFT Density Functional Theory

    DMSO Dimethyl sulfoxide

    ee Enantiomeric excess

    GGA Generalized Gradient Approximation

    HF Hartree-Fock

    IUPAC International Union of Pure and Applied Chemistry

    KS Kohn-Sham

    LDA Local Density Approximation

    LSDA Local Spin Density Approximation

    MA Maleic Anhydride

    Me Methyl

    MeCN Acetonitrile

    MM Molecular Mechanics

    MP2 Mller-Plesset perturbation theory to second order

    NHC N-Heterocyclic Carbene

    NMR Nuclear Magnetic Resonance

    ONIOM Our own N-layered integrated molecular orbital+ molecular mechanics

    PCM Polarizable Continuum Model

    vii

  • Abbreviation Meaning

    PES Potential Energy Surface

    Ph PhenyliPr Isopropyl

    QM Quantum Mechanics

    SDD Stuttgart-Dresden eective core potential

    Sn2 Bimolecular nucleophilic substitution

    THF TetrahydrofuranZPE Zero Point Energy

    viii

  • Contents

    Chapter 1 : General introduction 1

    1.1 Catalysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31.1.1 Origin and basic concepts . . . . . . . . . . . . . . . . . . . . 31.1.2 Transition state stabilization . . . . . . . . . . . . . . . . . . . 41.1.3 The catalytic cycle . . . . . . . . . . . . . . . . . . . . . . . . 51.1.4 Quantication of the activity and eciency of catalytic processes 6

    1.2 CC cross-coupling reactions . . . . . . . . . . . . . . . . . . . . . . . 91.2.1 What are CC cross-coupling reactions? . . . . . . . . . . . . 91.2.2 The catalytic cycle . . . . . . . . . . . . . . . . . . . . . . . . 111.2.3 Oxidative addition . . . . . . . . . . . . . . . . . . . . . . . . 121.2.4 Transmetalation . . . . . . . . . . . . . . . . . . . . . . . . . . 191.2.5 Reductive elimination . . . . . . . . . . . . . . . . . . . . . . 23

    Chapter 2 : Computational methods 31

    2.1 Quantum mechanics basis . . . . . . . . . . . . . . . . . . . . . . . . 332.1.1 Origin and basic concepts . . . . . . . . . . . . . . . . . . . . 332.1.2 The Schrdinger equation . . . . . . . . . . . . . . . . . . . . 34

    2.2 Theory applied to reactivity . . . . . . . . . . . . . . . . . . . . . . . 362.2.1 The Born-Oppenheimer approximation and the concept of elec-

    tronic structure . . . . . . . . . . . . . . . . . . . . . . . . . . 362.2.2 The potential energy surface (PES ) . . . . . . . . . . . . . . . 392.2.3 Approximate resolution of the Schrdinger equation . . . . . . 41

    2.3 The density functional theory (DFT ) . . . . . . . . . . . . . . . . . . 422.3.1 The Hohenberg-Kohn theorems . . . . . . . . . . . . . . . . . 432.3.2 The Kohn-Sham method . . . . . . . . . . . . . . . . . . . . . 452.3.3 Exchange-correlation functionals . . . . . . . . . . . . . . . . . 502.3.4 Self-interaction error . . . . . . . . . . . . . . . . . . . . . . . 58

    2.4 Computation of solvent eects . . . . . . . . . . . . . . . . . . . . . . 59

    ix

  • Chapter 3 : Objectives 63

    Chapter 4 : The Negishi reaction mechanism 67

    4.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 694.2 The transmetalation step in the Negishi coupling of trans-

    [PdMeCl(PMePh2)2] with ZnMeCl . . . . . . . . . . . . . . . . . . . 724.2.1 Experimental data . . . . . . . . . . . . . . . . . . . . . . . . 734.2.2 Computational details . . . . . . . . . . . . . . . . . . . . . . 764.2.3 The concerted mechanism to the trans product . . . . . . . . 774.2.4 The concerted mechanism to the cis product . . . . . . . . . . 794.2.5 Comparing theoretical and experimental results . . . . . . . . 814.2.6 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82

    4.3 The transmetalation step in the Negishi coupling of trans-[PdMeCl(PMePh2)2] with ZnMe2 . . . . . . . . . . . . . . . . . . . . 844.3.1 Experimental data . . . . . . . . . . . . . . . . . . . . . . . . 844.3.2 Computational details . . . . . . . . . . . . . . . . . . . . . . 874.3.3 The concerted mechanism to the trans product . . . . . . . . 884.3.4 The concerted mechanism to the cis product . . . . . . . . . . 904.3.5 The ionic mechanism to the trans product (L = THF) . . . . 934.3.6 The ionic mechanism to the trans product (L = PMePh2) . . 954.3.7 Comparing theoretical and experimental results . . . . . . . . 984.3.8 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99

    Chapter 5 : The Cu-free Sonogashira reaction mechanism 103

    5.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1055.2 Computational details . . . . . . . . . . . . . . . . . . . . . . . . . . 1095.3 Selection of the model . . . . . . . . . . . . . . . . . . . . . . . . . . 1105.4 The oxidative addition step . . . . . . . . . . . . . . . . . . . . . . . 1115.5 The carbopalladation mechanism . . . . . . . . . . . . . . . . . . . . 1125.6 The deprotonation mechanism . . . . . . . . . . . . . . . . . . . . . . 115

    5.6.1 The cationic mechanism . . . . . . . . . . . . . . . . . . . . . 1155.6.2 The anionic mechanism . . . . . . . . . . . . . . . . . . . . . . 1185.6.3 Cationic mechanism vs. anionic mechanism . . . . . . . . . . 121

    5.7 An alternative mechanism: the ionic mechanism . . . . . . . . . . . . 1225.8 The eect of the alkyne R substituent from experiments . . . . . . . 1255.9 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127

  • Chapter 6 : An asymmetric Suzuki-Miyaura reaction mechanism 129

    6.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1316.2 Experimental data . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1346.3 Computational details . . . . . . . . . . . . . . . . . . . . . . . . . . 1376.4 The oxidative addition step . . . . . . . . . . . . . . . . . . . . . . . 1386.5 The transmetalation step . . . . . . . . . . . . . . . . . . . . . . . . . 1426.6 The reductive elimination step . . . . . . . . . . . . . . . . . . . . . . 1466.7 Where is the enantioselectivity dened? . . . . . . . . . . . . . . . . . 1486.8 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151

    Chapter 7 : General conclusions 153

    Bibliography 157

    Chapter A: Appendix A: Published articles on the topics includedin this Ph.D. Thesis 175

    A.1 Article I: Chem. Eur. J. 2010, 16, 8596-8599 . . . . . . . . . . . . . 177A.2 Article II: J. Am. Chem. Soc. 2011, 133, 13519-13526 . . . . . . . . 183A.3 Article III: ACS Catal. 2012, 2, 135-144 . . . . . . . . . . . . . . . . 193

    Chapter B: Appendix B: Published articles on related topics andthat are not included in this Ph.D. Thesis 205

    B.1 Article IV: J. Am. Chem. Soc. 2009, 131, 3650-3657 . . . . . . . . . 207B.2 Article V: Chem. Eur. J. 2011, 17, 13847-13853 . . . . . . . . . . . . 217B.3 Article VI: Catalysis by Metal Complexes, 2011, 37, 57-84 . . . . . . 225

  • In all science, error precedes the truth, and

    it is better it should go rst than last.

    Hugh Walpole

    1General introduction

    As the title above suggests, this rst chapter is devoted to make a general introductionto the main topic of this present thesis: the Pd-catalyzed cross-coupling reactions.With this aim, in the rst part of this chapter the concept of catalysis, its origin, aswell as other related topics will be briey introduced.

    Next, in the second part of this chapter, the denition of cross-coupling reactionsand a summary of their generally accepted reaction pathway will be presented.

    Finally, the elementary steps that take part in this type of reactions will be de-scribed separately. Furthermore, for each of these steps, the most relevant mechanis-tic studies on Pd-catalyzed cross-coupling reactions reported in the last years, withparticular attention to the theoretical ones, will be reviewed.

    In principle, all the concepts provided in this rst chapter may be more thanenough to contextualize all the results obtained in the course of this thesis, and thatare presented in Chapters 4, 5 and 6.

    1

  • 1.1 Catalysis 3

    1.1 Catalysis

    1.1.1 Origin and basic concepts

    The term catalysis was introduced by Berzelius when in 1836 in an eort of ac-counting for a series of chemical transformations and decompositions, wrote:[1, 2]

    This new force, which was unknown until now, is common to organic and inor-ganic nature. I do not believe that this is a force entirely independent of the electro-chemical anities of matter; I believe, on the contrary, that it is only a new mani-festation, but since we cannot see their connection and mutual dependence, it will beeasier to designate it by a separate name. I will call this force catalytic force. Simi-larly, I will call the decomposition of bodies by this force catalysis, as one designatesthe decomposition of bodies by chemical anity analysis.

    Hence, Berzelius used the concept of catalysis to bring together a series of phe-nomena that could not be explained with the common conception of that time

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