PART A:
IRIDIUM CATALYZED C-H BORYLATION OF ARENES; ENGINEERING SELECTIVITY
BY LIGAND DESIGN.
PART B:
Z-SELECTIVE PALLADIUM CATALYZED CROSS COUPLING OF E-VINYL
GERMANES.
By
Susanne L. Miller

A DISSERTATION
Submitted to
Michigan State University
in partial fulfillment of the requirements
for the degree of
Chemistry-Doctor of Philosophy
2017

ABSTRACT
PART A: IRIDIUM CATALYZED C-H BORYLATION OF ARENES; ENGINEERING
SELECTIVITY BY LIGAND DESIGN.
By
Susanne L. Miller
Iridium catalyzed C-H borylation has gained popularity as a means to functionalize simple
aromatic and heterocyclic substrates under mild conditions which tolerate a variety of functional
groups. Initial efforts to develop this chemistry made use of sterically driven selectivity to achieve
contra-electronic substitution patterns of aromatic and heterocyclic building blocks that were not
easily obtainable by conventional organic chemistry prevalent before the discovery of this
chemistry in 1999. As methodology and substrate scope rapidly expanded, steric selectivity
became a limitation, as more diverse substitution patterns and higher selectivities were sought.
These limitations were partially overcome by the extensive development of directing groups which
enabled more traditional ortho substitution patterns to be accessed by the same mild conditions
that made Ir-C-H borylation popular. While steric limitations that result in mixtures by the standard
borylation protocols can now be overcome by directing groups, a serious challenge remains for
the meta-functionalization of substrates which lack common directing groups or have small
substituents. This work seeks to address this limitation by ligand-directed selectivity which can be
instituted by the rational design of catalysts and ligands to achieve different selectivity outcomes
depending on the desired product. The design and development of ligands which make use of either
steric or electronic properties to achieve a given outcome was realized, and borylation meta to
fluorine in simple arenes which lack directing groups was achieved. By varying the substituents
on this ligand framework, the selectivity of the borylation can be shifted from steric to electronic
selectivity.

	

PART B: Z-SELECTIVE PALLADIUM CATALYZED CROSS COUPLING OF E-VINYL
GERMANES.
Germanium cross coupling reactions were born out of efforts to replace toxic organo-tin
reagents used in the Stille cross coupling reaction for the construction of C-C bonds. Initial interest
in germanium as a transmetalation partner peaked in the mid to late 1990s, but eventually waned
due to poor reactivity of organo-germanium reagents and the harsh conditions needed to activate
Ge-C bonds towards cross coupling. One such effort from the Maleczka group in the early 2000s,
although suffering from poor conversion and unreliable results, gained modest attention by
displaying a reactivity distinct from typical Stille coupling selectivity. Instead of retention of
geometry, the major product of the E-vinyl germanium coupling reaction exhibited inverted Zolefin geometry. In the reverse case, Z-vinylgermanes likewise gave inverted E-olefins as the
major coupling products. Early studies of the reaction led to the hypothesis of a Heck-like insertion
with subsequent germyl elimination to form the inverted product. The proposed mechanism
featured a palladium-germyl elimination in preference to a possible b-H elimination. Based on the
substrate scope and the organo-germane’s required possession of a tertiary allylic alcohol, the PdGe elimination theory was discarded in favor of the formation of a reactive epoxide intermediate,
which eliminated germanium upon carbopalladation. The observation of the unactivated cross
coupling of allylic germanium epoxides with iodo-arenes supported this hypothesis. Expansion of
this chemistry was hampered by inconsistent results and a very narrow substrate scope. Further
investigation suggested involvement of Pd nanoparticles.

	

Copyright by
SUSANNE L. MILLER
2017

	

	
	
	
	
	

I dedicate this dissertation to my parents, Bob and Mary, who never gave me any reason to think
there is anything I can’t do. I also dedicate this dissertation to my sisters, Lorenda, Dianne and
Judy, smart and lovely women who are strong, positive role models for their baby sister. I also
thank my husband Mitch for his mostly constructive criticism and unwavering support, and my
kids, Fred and Milton, who taught me the fine art of work-life triage.

	

v	

ACKNOWLEDGMENTS

I would like to acknowledge the chemists who influenced me the most in my early years
and gave me a firm foundation on which I built my current knowledge and deep appreciation for
science. Thanks to Dean Lantero, my undergraduate mentor, who taught me the art of air-free
Schlenk-line techniques, mastery of laboratory equipment and the skills to follow any experimental
procedure. Thanks to G. Abbas Chotana who guided me through my first C-H borylation and
taught me how the results of one experiment flow into the design of the next. Thanks to Luis
Sanchez and Monica Norberg for teaching an inorganic chemist the finer points of organic
synthesis, and to Rob Maleczcka for teaching me how to run a proper silica gel flash
chromatography column. Thanks to Paul Herrinton, my former supervisor and colleague at
BoroPharm, who taught me how to scale up reactions safely, how to stream line and improve
procedures, and most importantly, when to throw a reaction away and start over. He helped me
prioritize projects to make the best use of my time, because, as he would tell me often, time is
always the most expensive reagent.
I would also like to acknowledge the world-class support staff at MSU, most notably Dr.
Dan Holmes, a true NMR genius, and his talented assistant Dr. Li Xie. They helped me set up and
run no-D NMR kinetic studies and, most importantly, kept the instruments running so I always
had access to a spectrometer when I needed crucial data. Dr. Holmes has helped me design and
interpret numerous NMR experiments, and this thesis would not be the same without his help.
I also would like to acknowledge Dr. Richard Staples, a crystallographer of extraordinary
talent, for solving all the crystal structures produced in my graduate work. I am grateful for the
opportunity to work with him and learn from him.

	

vi	

I also wish to acknowledge Dr. Dan Jones, director of the Mass Spectrometry and
Metabolomic Core Facility at MSU, and his assistant Lijun Chen, in addition to Todd Liddick, the
director of the biochemistry mass spec facility in the Chemistry Building, and my colleague YuLing Lien, all of whom helped me help collect HRMS data. Thanks also to Olivia Chesniak for
her invaluable help with transmission electron microscopy, and to Olivia and Yu-Ling for their
help in preparing samples for TEM analysis.
Many thanks are due to Scott Bankroff in the glass shop and Glenn Weseley in the machine
shop. An integral part of my research is contingent on having a good vacuum line and manifold,
and I have depended on Scott to keep my vacuum manifold free of leaks and Glenn to change my
worn-out drive belts. Thanks also to Dean Shooltz for rebuilding my pump and keeping it running
like new. Without their support, I could not do the same high caliber work.
I must also acknowledge the Computer and Technology office for saving the day during
several computer emergencies. Thanks to Tom Carter for help with poster design and printing, and
helping me to set up a backup drive. Thanks to Paul Reed for keeping our ancient GC computer
running on the network, and for helping me fix rogue printers, find lost emails and solve
networking problems. Thanks to Chris Pfeiffer for helping with posters, web posting and email
issues.
This section would not be complete without acknowledging the many specialists and
support staff that keep the department running with a high level of efficiency and professionalism
so that students can focus on research and teaching. I would like to acknowledge the main office
and graduate office staff, the purchasing and business office staff, and building staff for keeping
me on track and our labs in good functioning order. Thanks especially to Marvy Olson and Beth
McGaw in purchasing; and Bob Rasico, Eric Smariege, Bill Flick, and Melissa Parsons of the

	

vii	

building staff. A special thanks to Heidi Warden in the graduate office for always knowing what
the actual MSU policy is and what I needed to do to follow it!
I would also like to acknowledge the many supportive lab-mates, friends and colleagues
who have made my life richer and more fun during my time in graduate school. Special thanks go
to my boron project collaborators Behnaz Ghaffari and Jonathan Dannatt. Thanks to my
germanium project collaborators, Kio Tanemura, Shawn Haldar and Maryam Abbas. Thanks also
to my favorite current and former coworkers Damith Perera, Kristin Gore, Tim Shannon, Yu-Ling
Lien, Hao Li, Ruwi Jayasundara, Olivia Chesniak, Rosario Amado-Hennessey, Aaron Baker,
Fangyi Shen, Luis Mori, Pepe Montero, Badru-Deen Barry, David Vogelsang, Gayanthi
Attanayake, Buddhadeb Chattopadhayay, Dmitry Sabasovs, Jon Fritz, Jacob Stricker, and Beth
Schoen.
Many thanks go out to my committee members, all of whom are accomplished chemists
and good people whose work I admire. They have inspired and challenged me professionally and
personally, and they are truly great teachers, role models, and friends. Thanks to Rob Maleczka,
my advisor, Aaron Odom, my second reader, Ned Jackson, Tom Hamann and Viktor Poltavets.
My final acknowledgements go out to Dr. Steve Carlson from Lansing Community College
and Dr. Todd Zahn from BoroPharm, guys who trusted me enough to hire me as a chemist at
different times in my life. Those jobs gave me valuable confidence and experience that allowed
me to get where I wanted to go.

	

viii	

TABLE OF CONTENTS

LIST OF TABLES.........................................................................................................................xi
LIST OF FIGURES......................................................................................................................xiii
LIST OF SCHEMES.....................................................................................................................xv
KEY TO ABBREVIATIONS.......................................................................................................xix
CHAPTER 1....................................................................................................................................1
INTRODUCTION...........................................................................................................................1
Electrophilic Aromatic Substitution (EAS)..............................................................2
Directed ortho-Metalation........................................................................................5
The Difficulty of Meta Substitution..........................................................................7
Metal Catalyzed C-H Activation - Functionalization...............................................8
C-H Activation by Iridium Catalyzed Borylation...................................................12
Ortho C-H Borylation by Chelate Direction...........................................................20
Ortho C-H Borylation by Relay Direction..............................................................23
Ortho C-H Borylation by Outer Sphere Direction..................................................24
Examples of Directed Meta C-H Borylation..........................................................25
Meta Selective Borylation by Ion Pair Direction....................................................27
Borylation Ortho to Fluorine by Sacrificial Blocking Group..................................29
Diborylation followed by Selective Monodeborylation.........................................29
Para Selective Borylation by Direction of Bulky Phosphine Ligand.....................30
REFERENCES...................................................................................................... 32
CHAPTER 2...................................................................................................................................39
ENGINEERING SELECTIVITY WITH LIGANDS AND BORANE.........................................39
Steric Effects of Substrates and Regioselective Outcomes.....................................39
Electronic Effects of Ligands on Borylation...........................................................41
Quantification of Electronic and Steric Effects of Ligands.....................................42
Ligand Selectivities of 3-Fluorochlorbenzene .......................................................43
Regioselective Effects of Borane Source on 3-Fluorchlorobenzene.......................44
Regioselective Outcomes for 5 and 6-Memebered Arenes and Heterocycles........45
Improving Regioselective Outcomes by Ligand Design........................................51
Expanding Synthetic Options for C-H vs C-X Borylation Routes.........................52
Variation of Regioisomer Ratios with Borane Concentration................................53
Kinetic Studies of Ligand and Borane Combinations............................................54
KIE Studies of Ligands and Borane.......................................................................65

	

ix	

APPENDIX.............................................................................................................69
REFERENCES........................................................................................................91
CHAPTER 3...................................................................................................................................95
IMPROVEMENTS IN SELECTIVITY AND REACTIVITY.......................................................95
Reactivity vs Selectivity of Ligands.......................................................................95
The Pyridyl-Imine Ligand Framework...................................................................96
Synthesis of a Reactive Pyridyl-Imine Ligand........................................................97
Testing Ligands for Reactivity...............................................................................99
Hydrazone Interaction with HBpin.......................................................................103
Crystal Structure of DMAP Hydrazone Ligand....................................................105
Effect of Ligand Structure on Borylation Selectivity of 1,3-Difluorobenzene.....105
Effect of Solvent Polarity and Borane Source on Selectivity................................109
Borylation of Electron-Rich Substrates................................................................110
REFERENCES.....................................................................................................113
CHAPTER 4.................................................................................................................................115
GERMANIUM CROSS-COUPLING.........................................................................................115
Background and Significance...............................................................................115
Previously Proposed Catalytic Cycle...................................................................117
Substrate Scope....................................................................................................119
Probe of Steric Effects on the Inversion of Geometry..........................................123
Updated Putative Mechanism Based on Reactive Intermediate Hypothesis.........124
Cross-Coupling with Allylic Germyl Epoxides....................................................126
Investigation of Oxidative Heck Conditions........................................................129
Substrate Scope from Updated Optimization.......................................................131
Mercury Poisoning Test.......................................................................................132
Catalyst Recycling Test........................................................................................133
Confirmation of Pd Nanoparticles by TEM and EDS...........................................133
REFERENCES.....................................................................................................137

	

x	

LIST OF TABLES

Table 1.1. Experimental Regioisomer Ratios vs Ratios Calculated with DDHs(Z)..........................19
Table 2.1. Electronic Effects on Borylation Regioselectivity........................................................41
Table 2.2: Brønsted Basicities of Related Oxazoles and Pyridines................................................43
Table 2.3. Boron Reagent Effects on the Borylation Regioselectivity of 1.....................................44
Table 2.4. Ligand Selectivities of C-H Borylation of 6-Membered Arenes and Heterocycles.......46
Table 2.5. Ligand Selectivities of C-H Borylation of 5-Membered Heterocycles...........................49
Table 2.6. Comparison of dmadpm Selectivities of Selected Substrates.......................................51
Table 2.7. Changes in 2a:2b GC Ratio over Time as Concentration of HBpin Changes.................53
Table 2.8. Selectivity of dmadpm in the Borylation of 1 Varies with Borane Reagent....................54
Table 2.9. Results of Borylation KIE Experiments for dtbpy and dmadpm with B2pin2 and
HBpin........................................................................................................................68
Table 2.10. Experiment 1 Table of Reactants.................................................................................70
Table 2.11. Experiment 2 Table of Reactants.................................................................................72
Table 2.12. Experiment 3 Table of Reactants.................................................................................73
Table 2.13. Experiment 4 Table of Reactants.................................................................................74
Table 2.14. Experiment 5 Table of Reactants.................................................................................75
Table 2.15. Experiment 6 Table of Reactants.................................................................................76
Table 2.16. Experiment 7 Table of Reactants.................................................................................77
Table 2.17. Experiment 8 Table of Reactants.................................................................................79
Table 2.18. Experiment 9 Table of Reactants.................................................................................81
Table 2.19. Experiment 10 Table of Reactants...............................................................................85
Table 2.20. Experiment 11 Table of Reactants...............................................................................86

	

xi	

Table 2.21. Experiment 12 Table of Reactants...............................................................................87
Table 2.22. Experiment 13 Table of Reactants...............................................................................89
Table 3.1. Reactivity Test by Borylation of 1,3-Dicyanobenzene................................................100
Table 3.2. Comparison of NNH2 Substitution on Reactivity........................................................101
Table 3.3. Prior Ligand Studies of the Borylation of 1,3-Difluorobenzene..................................106
Table 3.4. Selectivity Test of the Borylation of 1,3-Difluorobenzene..........................................107
Table 3.5. Test of Solvent Polarity and Borane Source on Selectivity..........................................109
Table 3.6. Borylation of Electron Rich Substrates........................................................................111
Table 4.1. Substrate Scope of Germyl-Heck Coupling Reaction..................................................119
Table 4.2. Investigation of Additives for Oxidative Heck Reactions............................................130
Table 4.3. Substrate Scope of Germanium Cross-Coupling Reaction..........................................131

	

xii	

LIST OF FIGURES

Figure 1.1. The Interaction of Steric and Electronic Directing Effects...........................................18
Figure 1.2. Calculation of Steric Parameters are Based on Benzamide Model...............................19
Figure 2.1. C-H Functionalization of 3-Fluorochlorobenzene.......................................................40
Figure 2.2. Variation of Ligand Steric and Electronic Effects........................................................42
Figure 2.3. Comparisons Between C–H and C–X Borylation Routes............................................52
Figure 2.4. Borylation of 17 with B2pin2 by generating the catalyst from [Ir(OMe)cod]2 gives the
similar result as catalysis from 26. (Exp. 3)..................................................................60
Figure 2.5. Borylation of 1 with generated catalyst gives comparable data. (Exp. 5).....................61
Figure 2.6. Borylation reactions with HBpin appear to be second order in arene. (Exp. 8)...........62
Figure 2.7. Borylation of 1 with dmadpm and HBpin. (Experiments 9 and 10)..............................63
Figure 2.8. First order Plot of Borylation Reaction with 1.0 equiv B2pin2 (Exp. 12)....................65
Figure 2.9. Experiment 1 First Order Plot.......................................................................................70
Figure 2.10. Experiment 1 First Order Plot at First Half-Life.........................................................71
Figure 2.11. Experiment 2 First Order Plot.....................................................................................72
Figure 2.12. Experiment 3 First Order Plot....................................................................................73
Figure 2.13. Experiment 4 First Order Plot.....................................................................................74
Figure 2.14. Experiment 5 First Order Plot.....................................................................................75
Figure 2.15. Experiment 6 First Order Plot.....................................................................................76
Figure 2.16. Experiment 7 First Order Plot.....................................................................................77
Figure 2.17. Experiment 7 Comparison of First Order and Second Order Plots.............................78
Figure 2.18. Experiment 8 First Order Plot.....................................................................................79

	

xiii	

Figure 2.19. Experiment 8 Comparison of First Order and Second Order Plots at 2 HalfLives.......................................................................................................................80
Figure 2.20. Experiment 9 First Order Plot....................................................................................81
Figure 2.21. Experiment 9 Second Order Plot................................................................................82
Figure 2.22. Experiment 9 Comparison of First Order and Second Order Plots.............................83
Figure 2.23. Experiment 9 Ratio of a:b over Time..........................................................................84
Figure 2.24. Experiment 10 Comparison of First Order and Second Order Plots.........................85
Figure 2.25. Experiment 11 First Order Plot...................................................................................86
Figure 2.26. Experiment 12 First Order Plot..................................................................................87
Figure 2.27. Experiment 12 First Order Plot at 3 Half-Lives..........................................................88
Figure 2.28. Experiment 13 First Order Plot..................................................................................89	
Figure 2.29. Experiment 13 Comparison of First Order and Second Order Plots..........................90	
Figure 3.1. Dpm-Ir Complexes Compared to dtbpy-Ir Complexes.................................................95
Figure 3.2. Ligands with Diimine and Pyridyl Imine Backbones in the Literature.........................96
Figure 3.3. DMAP-Imine Substituted Ligand forms a Hydrazone-HBpin Complex....................103
Figure 3.4. Methyl-Imine Substituted Ligand does not form a Hydrazone-HBpin Complex........104
Figure 3.5. Crystal Structure of DMAP-Imine Hydrazone Ligand...............................................105
Figure 4.1. NMR of the Cross-Coupled Unhindered Allylic Germyl Epoxide............................128
Figure 4.2. TEM Images of Poorly Controlled Pd Nanoparticles................................................134
Figure 4.3. Elemental Analysis of Pd Nanoparticles by EDS Spectrum.......................................134

	

xiv	

LIST OF SCHEMES

Scheme 1.1. ElectrophilicAromatic Substitution (EAS)...................................................................2
Scheme 1.2. Aromatic Substitution According to EAS....................................................................3
Scheme 1.3. EAS Substitution Patterns............................................................................................4
Scheme 1.4. The Selectivity of Directed Metalation, DoM..............................................................5
Scheme 1.5. Electronic Effects Reinforce ortho Selectivity.............................................................7
Scheme 1.6. Arene Functionalization...............................................................................................8
Scheme 1.7. A Better Term for “Activation” is Oxidative Addition................................................9
Scheme 1.8. Oxidative Addition of Naphthalene Reported in 1965...............................................10
Scheme 1.9. Oxidative Addition Exhibits Steric Selectivity..........................................................11
Scheme 1.10. First Reported Catalytic C-H Functionalization.......................................................11
Scheme 1.11. First Stoichiometric Photolyzed Metal Mediated CHB...........................................12
Scheme 1.12. First Reported Catalytic Ir CHB of Benzene...........................................................13
Scheme 1.13. 2002 Putative Catalytic Cycle of Ir CHB with Ir(III) to Ir(V) Manifold.................15
Scheme 1.14. Old Fashioned EAS Synthesis of Contra-Electronic Phenol...................................16
Scheme 1.15. One-pot Synthesis of Contra-Electronic Phenol Attained by Ir CHB.......................16
Scheme 1.16. Accepted Mechanism for Ir CHB.............................................................................17
Scheme 1.17. Chelate Directed Mechanism Employing Hemilabile Ligand..................................20
Scheme 1.18. Chelate Directed Borylation vs Undirected Borylation...........................................21
Scheme 1.19. Heterogeneous Chelate Directed Mechanism..........................................................21
Scheme 1.20. Ortho Borylation by Silica SMAP............................................................................22
Scheme 1.21. Donor Chelates Achieve 14 e- Intermediates under Homogeneous Conditions......23

	

xv	

Scheme 1.22. Relay Directed Mechanism......................................................................................24
Scheme 1.23. Outer Sphere Directed Mechanism.........................................................................25
Scheme 1.24. Outer Sphere Borylation Achieved by Recognition of Carbonyl Functionality......26
Scheme 1.25. Directed Meta or Ortho Borylation by Ligand-Based Selectivity...........................27
Scheme 1.26. Meta Borylation by Ion Pair Direction.....................................................................28
Scheme 1.27. Selective Borylation by Steric Blocking Group.......................................................29
Scheme 1.28. Alternate Functionalization by Poly-borylation / Selective Deborylation................30
Scheme 1.29. Para Borylation by Bulky Ligands that Mimic Enzyme Sites..................................31
Scheme 2.1. Sterically Directed C–H Borylation Regioselectivities.............................................39
Scheme 2.2. C–H Borylation of 3-Fluorochlorobenzene................................................................41
Scheme 2.3. Boron Reagent Effects on the Borylation Regioselectivity of 1................................44
Scheme 2.4. Highly Selective Borylation Meta to Fluorine............................................................52
Scheme 2.5. (coe)Ir(dtbpy)Bpin3, 26, does not enter the catalytic cycle or impact the order of
Borane......................................................................................................................55
Scheme 2.6. Dissociation of 26, (coe)Ir(dtbpy)Bpin3 generates the active catalyst, 27.................56
Scheme 2.7. Intermediate 27 enters the catalytic cycle after dissociation of 26.............................56
Scheme 2.8. NMR Tube Conditions: Experiment 1 of Kinetics Study..........................................59
Scheme 2.9. Borylation with B2pin2 by generation of catalyst from [Ir(OMe)cod]2 gives same result
as catalysis from 26...................................................................................................60
Scheme 2.10. Borylation of 3-Fluorochlorobenzene, 1, with B2pin2 by generating the catalyst from
[Ir(OMe)cod]2 gives the same result as catalysis from 26. (Exp. 5)...........................60
Scheme 2.11. 26-catalyzed Borylation of 1 with HBpin is not zero order in borane. (Exp. 8).......62
Scheme 2.12. Comparison of 2 Equiv HBpin vs Pseudo-First Order HBpin with dmadpm
(Experiments 9 and 10)............................................................................................63
Scheme 2.13. Borylation Reactions with 1.0 equiv B2pin2.............................................................64

	

xvi	

Scheme 2.14. The Modified Conditions for the Competitive Borylation Experiment of the KIE
Studies.....................................................................................................................67
Scheme 2.15. Experiment 1............................................................................................................70
Scheme 2.16. Experiment 2............................................................................................................72
Scheme 2.17. Experiment 3............................................................................................................73
Scheme 2.18. Experiment 4............................................................................................................74
Scheme 2.19. Experiment 5............................................................................................................75
Scheme 2.20. Experiment 6............................................................................................................76
Scheme 2.21. Experiment 7............................................................................................................77
Scheme 2.22. Experiment 8............................................................................................................79
Scheme 2.23. Experiment 9............................................................................................................81
Scheme 2.24. Experiment 9 at Room Temperature.........................................................................83
Scheme 2.25. Experiment 10..........................................................................................................85
Scheme 2.26. Experiment 11..........................................................................................................86
Scheme 2.27. Experiment 12..........................................................................................................87
Scheme 2.28. Experiment 13..........................................................................................................89
Scheme 3.1. Synthesis of the Dipyridyl Methane Ligand...............................................................97
Scheme 3.2. Lassaletta’s Substituted Hydrazone Ligands Exhibit Directed Borylation.................98
Scheme 3.3. DMAP-Imine Substituted Ligand does not Exhibit Directed Borylation...................98
Scheme 3.4. Substituted vs. Unsubstituted Hydrazone Ligands.....................................................99
Scheme 4.1. Germyl-Stille Cross-Coupling Results in Inversion................................................116
Scheme 4.2. Optimized Heck Conditions for Published Germanium Cross-Coupling...............117
Scheme 4.3. Putative Mechanism of Germyl Cross-Coupling Reaction as published in 2009......118
.
Scheme 4.4. Hiyama’s Activation vs. Carbopalladation Mechanisms..........................................120

	

xvii	

Scheme 4.5. Degermylation of Vinyl Germanes makes Allylic Alcohols...................................121
Scheme 4.6. The First Reported Heck-Coupling of Allylic Alcohol 4.9.....................................121
Scheme 4.7. Modern Heck-Coupling Protocols are E Selective..................................................122
Scheme 4.8. Germanium Cross-Coupling under Fluoride Activation.........................................123
Scheme 4.9. Proposed Mechanism for Inversion of Stereochemistry of Ge Cross-Coupling......124
Scheme 4.10. Germyl Allylic Epoxides Degermylate under Acidic Conditions..........................125
Scheme 4.11. Reaction of an Allylic Germyl Epoxide in the Cross-Coupling Reaction.............126
Scheme 4.12. Allylic Germyl Epoxide Reaction with Iodotoluene.............................................127
Scheme 4.13. Cross-Coupling Reaction of an Unhindered Allylic Germyl Epoxide..................127
Scheme 4.14. Germyl Allylic Epoxides Participate in Heck-Coupling.......................................128
Scheme 4.15. Nanoparticle Recycling Test.................................................................................133

	

xviii	

KEY TO ABBREVIATIONS

Ac

Acetate

AIBN

Azobisisobutyronitrile

Ar

Aryl

-BCat

Catecholate Ester of Boron, also called Catechol boronate

HBCat

Catechol Borane

-Bpin

Pinacolate Ester of Boron, also called Pinacol boronate

HBpin

Pinacol Borane

B2pin2

Bispinacolatodiborane

Bn

Benzyl

Bozo

2,2’-Bis-2-oxazoline

Bnbozo

2,2′-Bis[(4S)-4-benzyl- -2-oxazoline]

bpy

Bipyridine

BQ

1,4-Benzoquinone

Br

Bromine atom

Bu

Butyl

Bu4NBr

Tetrabutyl Ammonium Bromide

t-Bu

Tertiary Butyl, also called tert-Butyl

°C

Degrees Celsius

Cp

Cyclopentadiene or Cyclopentadienyl

Cp*

Pentamethyl Cyclopentadiene or Pentamethyl Cyclopentadienyl

C-C

Carbon-Carbon Single Bond

	

xix	

C=C

Carbon-Carbon Double Bond

C-H

Carbon-Hydrogen Single Bond

C-F

Carbon-Fluorine Single Bond

C-Ge

Carbon-Germanium Single Bond

C-Si

Carbon-Silicon Single Bond

C-X

Carbon Singly Bonded to any Halogen (Group 7)

Si-H

Silicon-Hydrogen Single Bond

cal

Calorie

CDCl3

Deuterated Chloroform, NMR solvent

Cy

Cyclohexane

cod

1,5-Cyclooctadiene

coe

cyclooctene

CHB

C-H Borylation

D

Deuterium atom

d

delta, NMR Chemical shift

d

doublet, double peak in NMR spectrum

dd

doublet of doublets

dba

Dibenzylideneacetone

DCM

Dichloromethane

4-DMAP

4-Dimethylaminopyridine

dmadpm

Dimethylaminodipyridyl Methane

dpm

Dipyridyl Methane

dtbpy

4,4’-Di-tert-butyl-2,2’- bipyridine

	

xx	

dmpe

Dimethylphosphinoethane

DMG

Directed Metalation Group

DoM

Directed ortho Metalation

e–

A Single Electron

E+

Electrophile

-E

Electrophilic Group

(E)

Trans-Double Bond

EAS

Electrophilic Aromatic Substitution

EDG

Electron Donating Group

EDS

Energy Dispersive X-ray Spectroscopy

EI

Electron Impact

EI-MS

Electron Impact Mass Spectroscopy

EWG

Electron Withdrawing Group

F

Fluorine atom

FG

Functional Group

GC

Gas Chromatograph

GC-FID

Gas Chromatograph with Flame Ionizing Detector

GC-MS

Gas Chromatograph with Mass Spectrometer

H

Hydrogen atom

h

Hour

Hg

Mercury

Hz

Hertz (cycles per second)

DH

Enthalpy, or Change in Enthalpy

	

xxi	

DDHs(Z)

Steric Enthalpy of a Substituent, Z

HCl

Hydrochloric Acid

HRMS

High Resolution Mass Spectroscopy

Ir

Iridium atom

Ir CHB

Iridium-Catalyzed C-H Borylation

J

NMR Coupling Constant

KIE

Kinetic Isotope Effect

kcal

Kilocalorie

L

Ligand

LDA

Lithium Diisopropyl Amide

m

Multiplet peak in NMR spectrum

m-

meta-Substituted or directing to the meta position

M

Metal atom

M+

Molecular Ion peak in Mass Spectrum

m/z

Mass divided by Charge of an ion in mass spectroscopy

Me

Methyl

MeCN

Acetonitrile

MHz

Mega Hertz

mol

Mole

NMP

N-Methyl pyrrolidone

NMR

Nuclear Magnetic Spectroscopy

Nu:

Nucleophile

o

ortho-Substituted or directing to ortho position

	

xxii	

o/p

Directing to the ortho or para positions

P

Phosphorous atom

PCy3

Tricyclohexyl Phosphine

Pd

Palladium Metal

Pd(OAc)2

Palladium (II) Acetate

Pd2(dba)3

Tris(dibenzylidene)dipalladium (0)

Ph

Phenyl

PMe3

Trimethyl Phosphine

PPh3

Triphenyl Phosphine

PMHS

Polymethylhydroxysilane

QX

Quaternary Halogen Salt

rt

Room Temperature

s

singlet peak in NMR spectrum

SMAP

Silica-constrained Monodentate triAlkyl Phosphine

s

second

TBAB

Tetra Butyl Ammonium Bromide

TBAF

Tetra Butyl Ammonium Fluoride

TEM

Transmission Electron Microscope

TFA

Trifluoroacetic Acid

THF

Tetrahydrofuran

tmp

3,4,7,8-tetramethyl-1,10-phenanthroline

TNT

2,4,6-Trinitrotoluene

tol

Toluene

	

xxiii	

TPPO

Triphenyl Phosphine Oxide

(Z)

Cis-double bond

	

xxiv	

CHAPTER 1
INTRODUCTION
Ir-catalyzed borylation (Ir CHB) has been utilized in many applications for the production
of fine chemicals,1-2 but it is especially suitable for the construction of small molecule building
blocks used in the fields of pharmaceutical, agricultural and advanced materials. There are many
strategies for arene functionalization,3 most of which have been improved and refined over decades
and are still being reliably used in industry today. Ir-catalyzed C-H borylation is a new technology
in comparison, and has earned its place in the top drawer of the synthetic chemist’s tool box
because it offers easy, one-step functionalization of arenes under mild conditions, and it provides
a selectivity that many older methods of functionalization cannot easily achieve.4
The most widely used methods of aromatic functionalization are electrophilic or
nucleophilic aromatic substitution, C-H deprotonation, and transition metal C-H activationfunctionalization.5 In recent years, innovations in all of these functionalization methodologies have
developed at a rapid pace. Most selective functionalization methods make use of electronic
properties resulting from the inductive or activating effects of existing electron-withdrawing or
electron-donating substituents. Because the regiochemistry of Ir CHB is sterically driven, this
methodology has been used as a complement to traditional selectivities that were unattainable by
other types of arene functionalization. The mild conditions, high yields and simplicity of Ir CHB
have resulted in efforts to develop methods that can attain all types of substitution patterns,
including the ortho substitution patterns of EAS and DoM in order to avoid the harsh reagents or
inconvenient reaction conditions of these older protocols.6
The selectivity of Ir CHB is primarily governed by sterics, but harnessing electronic factors
to direct functionalization has also been a successful strategy. Most newer directed borylation

	

1	

methodology has resulted in ortho functionalization by utilization of the conventional ortho/para
directing effects of EAS chemistry6-7. Far less common is meta selective borylation of unhindered
simple arenes lacking directing groups, and only since 2015 has meta-selective borylation been
reported.8 The origin of electronic effects lies in the properties of the arenes and their substituents,
and to use these properties to gain an advantage in selectivity requires an understanding of how
electronic effects arise from molecular structure.
Electrophilic Aromatic Substitution (EAS). The first method of aromatic C-H
functionalization discovered is known as electrophilic aromatic substitution, (EAS).
The first report of EAS was made by Michael Faraday in 1825.9 EAS involves an attack
on the π-system of an aromatic ring by an electrophile, E+, thus breaking the aromaticity of the
ring and allowing cleavage of the C-H bond, as seen in Scheme 1.1
Scheme 1.1. Electrophilic Aromatic Substitution (EAS)
E+
H

H

[NO2+]

E
H

-H+

NO2

-H

H

E

NO2

HNO3 / H2SO4

Scheme 1.1. Electrophilic aromatic substitution proceeds by an attack on the
aromatic π-system. The first reported aromatic C-H functionalization was the
nitration of benzene, reported in 1825 by Michael Faraday.	

Substitution happens through interactions of the electronic properties of the reactants and
any functional groups (FGs) that are already on the aromatic ring. Since benzene in Scheme 1.1
has no substituents, the NO2 group can replace the H atom on any C atom of the benzene ring.

	

2	

Once NO2 is on the ring, however, where the next substituent goes will be determined by the rules
of EAS.
Groups like NO2 are referred to as Electron Withdrawing Groups (EWG) because they
draw electron density out of the ring, causing incoming FGs to only substitute at the 3 or 5 positions
on the ring. This is called meta substitution, also denoted by m.
In contrast to EWG, electron donating groups (EDG) donate p-electron density into the
ring, making it more active towards substitution. This causes incoming FGs to substitute at 2, 4
and 6 positions on the ring. This is called ortho/para substitution, also denoted by o/p. Often o/p
directors have lone pairs on the atom next to the ring, and although halogens are electron
withdrawing, they also are o/p directors due to the presence of their unpaired electrons, and the
ability of those electrons to donate into the ring via resonance. In order to effect substitution,
reactants must be electron deficient and electrophilic, denoted as E+. The positive E+ group seeks
electron density, and so substitution is not favorable at positions where there is a build-up of
positive charge on the ring. Scheme 1.2 illustrates the substitution patterns of ortho/para and meta
directing groups.
Scheme 1.2. Aromatic Substitution According to EAS	
m-substitution
NO2

o/p-substitution
NO2

[NO2+]

Cl

HNO3 / H2SO4

NO2

Cl2 / AlCl3

Cl

EDG

EWG

E

Cl

Cl
+

Cl

(ortho)

(meta)
EWG

[Cl+]

E

EDG
+
E

E

(para)
EDG

E

EDG = O-, NR2, OR, OH
Halogens (X) = F, Cl, Br, I are weak EWG
EDG and Halogens are ortho/para-directors

EWG = NO2, C(OR), NR3+, SO3H, CN
EWG are meta-directors

Scheme 1.2. Meta directors pull electron density out of the aromatic ring, thus partially deactivating
it. Ortho/para directors release more electron density into the ring, thus partially activating it.

	

3	

The selectivity rules of EAS are determined in large part by where electron density
accumulates on the aromatic ring in conjunction with the steric accessibility of that site. In
substrates with multiple FGs harboring contrasting steric and electronic properties, the
accumulation of negative charge is a significant contributing factor in the substitution of the
incoming substituent. When the electronics of two or more sites are similar, or if an electronically
preferred site is sterically hindered, mixtures are often obtained.
Planning the synthesis of complex aromatic molecules around EAS rules can be very
challenging, and for some combinations, EAS cannot produce the desired product, such as the
meta substitution of structure a in Scheme 1.3. Particularly difficult is the functionalization of 1,3dihaloarenes. Their synthesis is usually accessed from substitution of NO2 meta directing groups
which are then transformed into halogens through Sandmeyer reactions, which produce potentially
explosive intermediates, and are generally avoided if possible.
Scheme 1.3. EAS Substitution Patterns
!-

EDG

EDG
EDG
!-

!-

a

EWG
!-

g

±

!EDG

EDG
!-

!-

!-

c
±
EWG

EWG

EWG
±

±

±

!-

!-

EWG

EWG

d

!-

!-

b

EWG

EDG

!-

f

e ±
EDG
EDG

!- ±

± !EWG EWG

!-

EDG
± !-

i

h ± !-

Scheme 1.3. Meta functionalized molecules like structure a are particularly
challenging to prepare due to a lack of negative charge polarization at meta positions.

	

4	

Directed ortho-Metalation. The second method of C-H activation offered an improvement
in selectivity over EAS. Although aromatic C-H bonds have high pKas that do not deprotonate
with aqueous bases, they can be deprotonated by strong organometallic bases such as alkyl
derivatives of lithium, sodium and potassium metals. This is known as metalation, defined broadly
as the substitution reaction in which an acidic H atom is replaced by a metal to produce a true
organometallic compound.10 The metal-carbon bond is reactive and can be functionalized by
trapping with an electrophile. The first C-H deprotonation and subsequent Li-functionalization
was reported in 1928 by Schlenk, for whom the famous side-armed flask is named, and his student
Bergmann.11
Scheme 1.4. The Selectivity of Directed Metalation, DoM
DMG

RLi

DMG

E+

Li
OMe

PhLi

OMe
Li

DMG
E

CO2

OMe

O2

CO2H

Scheme 1.4. DoM provides a selectivity advantages over EAS, but substitution is limited to
ortho positions. Attempts to achieve meta substitution with combinations of directed
metalation groups (DMGs) are substrate specific cannot be applied in a general way.

In 1930, work published by Zeigler made the preparation of standard organometallic
reagents such as butyllithium and phenyllithium from alkyl halides routine,12 and this led to a rapid
development of metalation as a practical tool in organic synthesis. Early efforts of C-H
deprotonation relied on functionalizing aromatic molecules with acidic protons, and lacked
selectivity.
In 1938, the observation that methoxy-substituents coordinate to metals and direct selective
deprotonation of C-H bonds ortho to the methoxy group was independently reported by Gilman13
	

5	

and Wittig.14 This led to rapid development of ortho-lithiation as a reliable method of C-H
functionalization. This reactivity is summarized in Scheme 1.4. Groups that direct C-H
deprotonation by chelation, such as the methoxy example, are called directed ortho metalation
groups (DMGs).
Halogen substituents generally do not survive metalation with strong organolithium
reagents, and instead undergo lithium halogen exchange. Exchange can be circumvented by the
use of less basic and bulkier non-nucleophilic bases, such as lithium diisopropyl amide, LDA,
which leaves halogens intact. Because of the inductive effects of halogen substituents, C-H bonds
ortho to halogens are more acidic, thus halogens are themselves directing groups for metalation.
Like EAS, selectivity in a molecule with two competing directing groups leads to mixtures.
Research into developing new DMGs has expanded rapidly in recent years and now
includes diverse functionalities such as tertiary amines, amides, alcohols, oxazolines, mesylates,
anilines, benzylamines and thiophenols, to name just a few of almost 50 classes of DMG groups.15
A complex set of rules based on DMG strength and number of DMGs present and the type
of organometallic reagents employed along with reaction conditions can direct substitution in
ingenious ways, providing enormous diversity in selectivity,16 including complex substitutions and
enantioselective transformations. Ortho directed metalation offers many options to build complex
organic molecules, but it is not a general or mild method suitable for late stage functionalization.
Often reagents are substrate specific and cannot be applied in a general way, and effective use of
the most recent DoM advances requires specialization in medicinal chemistry. For basic
functionalization of simple arenes like the example in Scheme 1.4, DoM groups still give useful
alternate selectivity to EAS, although simple meta functionalization is not an option.

	

6	

The Difficulty of Meta Substitution. The challenge of meta substitution is two-fold in that
substituents which activate the ring, thus making it amenable to either EAS or DoM substitution,
are ortho/para directors, and the accumulation of negative charge at the 2-, 4- and 6- positions
poses serious competition to the unactivated sites at 3 and 5. When meta-directors are present, the
presence of positive charge hampers reactions at the unactivated 3 and 5 sites, so meta
functionalization is not easy even if there are no competing contra electronic substituents. This
electronic effect is illustrated in Scheme 1.15.
Scheme 1.5. Electronic Effects Reinforce ortho Selectivity
otho/para substitution
EDG

4

EDG

EDG

EDG

6

"-

E+
"-

5

"+
EDG

⤉

2
3

"-

meta substitution

⤉

⤉

2

EWG

3

EWD

EWD

"+

EWD

6

4

E+

5

"+

"EWD

"+

Scheme 1.5. Meta direction does not have electronic enhancement to reinforce sterically driven
selectivity. Ortho/para direction enhances reactivity by accumulation negative charge at the 2, 4, and
6 positions thus reinforcing ortho direction.

Reliance on steric direction can only go so far, as the name implies, large or bulky
substituents are required. When substituents are small, such as F, there is currently no way to
achieve perfect steric selectivity. The best strategy to eliminate mixtures in the functionalization
of arenes with F substituents is to direct ortho to F. Achieving direction meta to F is a serious
challenge, and it is also a problem that has attracted the attention of medicinal chemists due to the
importance of F atoms in pharmaceutical products.17

	

7	

Metal Catalyzed C-H Activation - Functionalization. C-H activation offers an alternative
to the traditional electronics based selectivity of EAS and DoM because it is a concerted process
which takes place in one step without a chemical intermediate. Unlike EAS or DoM, which are
step-wise, the stabilities of reactive intermediates, such as radicals or carbocations, do not govern
formation of the products. (This selectivity is considered kinetically determined in contrast to
thermodynamically determined selectivity of organic step-wise reactions).
It is necessary to differentiate between the terms C-H activation and C-H functionalization.
C-H functionalization refers to breaking a C-H bond and replacing the H atom with a non-H
substituent or functional group (FG). C-H functionalization is generally not reversible and
transforms the substrate into a different compound.
Scheme 1.6. Arene Functionalization
H

FG

FG reagent
[-H]

Scheme 1.6. C-H functionalization is the irreversible breaking of a C-H bond and the
replacement of H with a non-H atom or functional group. Functionalization changes
the substrate into a different molecule.

C-H activation, on the other hand, is not a precise or descriptive term; mid-century
coordination chemistry pioneer, Lauri Vaska defined the term as a reversible binding of a substrate
to a metal to form a metal-substrate complex. It was originally used to describe the behavior of
enzymes or hemoglobin in the binding of small molecules. In the case of aromatic C-H activation,
the metal inserts into the C-H bond to form an organic metal hydride complex18-19 as shown in
Scheme 1.7. In Ir CHB, this is the step where C-H bond scission happens. “Activation” is more
precisely referred to as “Oxidative addition” for which Vaska is credited for describing. Oxidative
addition describes the process whereby a low-valent metal inserts into a bond, thereby breaking

	

8	

the bond and increasing in oxidation state by +2. “Activation” or oxidative addition in the case of
C-H activation-borylation, only refers to the reversible formation of the metal hydride complex.
Any additional reaction to form an organic product is the “functionalization,” or in the case of Ir
CHB, the reductive elimination is the “borylation” part.
Scheme 1.7. A Better Term for “Activation” is Oxidative Addition
Ln
H

M

Ln[M]

H

Scheme 1.7. C-H Activation (also called oxidative addition) is the insertion
of a metal into a C-H bond and the subsequent reversible binding of the
substrate to the metal to form a metal hydride-substrate complex. Activation
is reversible and under favorable thermodynamic conditions the substrate can
be regenerated again.
Oxidative addition has been known in the literature since the early 60s. One of the earliest
examples of an isolated complex formed by metal-mediated C-H activation was reported by Chatt
and Davidson in 1965.20 Treatment of a dichloro-bis-dimethylphosphinoethane (dmpe) ruthenium
complex, [Ru(dmpe)2Cl2], with sodium naphthalide resulted in C-H activation of naphthalene onto
the Ru metal center to form a naphthyl ruthenium hydride, which was isolated and characterized.
Addition of 2 equiv HCl regenerated the complex and liberated naphthalene. Also observed was
b-hydride elimination from the adjacent methyl of a dmpe ligand resulting in the liberation of
naphthalene and the formation of a Ru(dmpe)2 complex.

	

9	

Scheme 1.8. Oxidative Addition of Naphthalene Reported in 1965
P
sodium naphthalide

P
P

P Ru
P

hexane

Cl

P Ru
P
H

HCl

P

P
P Ru
P

P

+

Cl

Cl

Cl

P
P Ru
P
H

H
P C H
H

P
P Ru
P
H

P Ru
P

P
C

H
H

P

+

P

H

Scheme 1.8. C-H activation (oxidative addition) of naphthalene was observed by Chatt
and Davidson in 1965. The oxidative addition was reversible by addition of HCl or
by b-hydride elimination.
As mentioned before, the oxidative addition of substrates to coordinatively unsaturated
low-valent metals is a concerted process, thus the electronic stability of intermediates does not
play a role in selectivity, and metals favor activation of strong bonds over weak bonds. Hints of
this concept were observed by Chatt and Ittel in 1976 with the report that the C-H activation of
toluene by a phosphine ligated Fe complex did not take place at a benzylic position or ortho to
methyl at the most substituted carbon, but at unsubstituted sites in a statistical 2:1 distribution
with the methyl group meta or para to the metal.21 Many examples of C-H activated metal
hydride complexes were isolated and in the following years, but functionalization of activated
complexes was not realized until much later in the 1980s.

	

10	

Scheme 1.9. Oxidative Addition Exhibits Steric Selectivity
Me

P

P

P

P Fe
P
H

P

P Fe
P
H

P

P
P

P

Fe
H

Me

Me
2

:

1

Scheme 1.9. Chatt and Ittel observed that oxidative addition of toluene does not take place
at benzylic positions or the carbon of highest substitution like traditional organic chemistry
selectivity, but at the least sterically hindered carbons resulting in a statistical mixture.
The first catalyzed functionalization of an activated organometallic arene complex was
reported by Jones and Kosar22 in 1986 using Chatt’s (dmpe)2RuH(C10H7). Jones displaced
naphthalene to add 2,6-dimethylphenylisocyanide, which underwent an intermolecular
cyclometalation to make 7-methyl indole.
Scheme 1.10. First Reported Catalytic C-H Functionalization
P
CN

P
P Ru
P
H

P

P
P Ru
P
H

P

P
C

N

H H
H C
P Ru
P
C N

—

P
P
P

Ru

P

P

H
P Ru P
P

P

N

H

P

P Ru
P
N

N
H

Scheme 1.10 The driving force for functionalization of the isocyanide complex is an
intermolecular cyclometalation reaction in Jones and Kosar’s 1986 synthesis of 7methylindole.

	

11	

Although research into C-H activation had advanced rapidly, and many kinds of organic
compounds, including alkanes, had been activated and characterized, functionalization remained
elusive with few examples until the 1990s. In 1995, the next breakthrough came when Hartwig
reported that while irradiating Mn and Re pentacarbonyl complexes of catechol borane (Bcat) of
the form (CO)5M-Bcat (M = Mn or Re), stoichiometric functionalization of the solvent benzene
was observed to give phenyl-Bcat, and a minor amount of HBcat.23 When irradiation experiments
were repeated in toluene, toluene was also functionalized to give a mixture of meta and para BCat
substituted toluene along with some minor amounts of HBcat. Loss of a CO ligand enabled
oxidative addition of the solvent and rapid functionalization to make a B-C bond from the C-H
bond of an arene. These results led Hartwig to photolyze CpFe(CO)2Bcat, which provided higher
yields and greater efficiencies of stoichiometric Ph-Bcat generation, resulting only in the
[CpFe(CO)2]2 dimer as the metal reaction product.
Scheme 1.11. First Stoichiometric Photolyzed Metal Mediated CHB
benzene

O

Bcat

B
O

hν 1h
(-CO)

Bcat = Catechol borane

Fe Bcat

OC
OC

Me
toluene
Bcat

+ Me

Bcat

hν 1h
(-CO)

Scheme 1.11. Hartwig reported stoichiometric functionalization of benzene and
toluene in 1995 by irradiation of metal carbonyl complexes.
C-H Activation by Iridium Catalyzed Borylation. At the end of the 90s and the early 2000s,
rapid progress in catalyzed arene functionalization was made and many new developments were
reported.
	

In

1999,

Smith

reported

the
12	

first

thermal

Ir-catalyzed

thermal

C-H

activation/functionalization of benzene with Cp*Ir(PMe3)Bpin(H).24 Although turnovers were
low, this report provided the template for the successful development of catalytic C-H
activation/functionalization efforts that followed.
Scheme 1.12. First Reported Catalytic Ir CHB of Benzene

+

O

20 mol%

HB
O

Me3P

Ir

Bpin
H

O
B

150 °C, 120 h

O
53% yield

Scheme 1.12. In 1999 Iverson and Smith reported the first thermal Ircatalyzed CH functionalization of an arene.
In that same year, Hartwig reported stoichiometric functionalization of alkanes and some
arenes with W, Ru, and Re carbonyl complexes.25-26 In 2000, Hartwig reported the catalytic
functionalization of alkanes with Cp*Ru(h4-C6Me6).27 In the same year, Cho and Smith reported
the first regioselectivity study of C-H borylation of arenes catalyzed by Cp*Ru(h4-C6Me6), and
compared the results obtained with a less active iridium precatalyst.28 In this paper, the Smith and
coworkers showed that the product distribution of isomers obtained in C-H borylation were
kinetically determined, and the selectivity was primarily governed by the sterics of the substituents
for both catalytic systems. Also of note was the first reported borylation of a heterocycle, 2,6lutidine, and F substituted arenes.
Although the iridium catalyst was less active, the advantages became clear upon
comparison. C-F bonds did not survive Rh catalysis, and underwent preferential oxidative addition
over C-H bonds. Also Rh catalysis was less tolerant of benzylic C-H bonds, resulting in more
benzylic activation of toluene, compared to the Ir catalyst. Although both systems exhibited
roughly the same steric ratios of isomers for most substrates, some notable exceptions to statistical

	

13	

distributions for anisole, esters and dimethylaniline were observed. Smith attributed these
deviations to chelate directing effects, thus setting the stage for the investigation of competing
steric and electronic directing effects in later C-H borylation studies.
In a 2001, Smith and Tse published a borylation overview aimed at a wider audience of
synthetic organic chemists, in order to offer a practical guide for arene functionalization.29 The use
of an inert solvent, cyclohexane, rather than a large excess of substrate, was a marked improvement
for those seeking to functionalize small amounts of material such as natural products or the late
stage precursors of total synthesis, or the functionalization of expensive arenes where using the
substrate as solvent would be impractical. A diverse substrate scope of 1,3-disubstituted arenes
spanning a wide spectrum of electron-withdrawing to electron-donating functionality was featured
to showcase the versatility of Ir CHB as a viable synthetic method.
In a subsequent 2002 Science paper,30 Smith and Maleczka began a collaboration with the
introduction of important synthetic refinements that propelled Ir CHB onto the radar screens of
organic chemists seeking to find practical routes to improved arene functionalization. One-pot
Suzuki coupling and polyphenylene synthesis examples were included, which demonstrated the
high selectivity of C-H borylation towards aromatic C-H bonds, leaving the weaker C-X and
benzylic C-H bonds untouched, unlike similar rhodium-based catalysis. In addition, the first
putative mechanism for an Ir(III) to Ir(V) catalytic cycle was presented with the observations that
supported it, as featured in Scheme 1.13 on the following page. Among the convincing evidence
that cast doubt upon an Ir(I) to Ir(III) catalytic cycle was the observation that C-I bonds do not
survive stoichiometric borylations with the Ir(I) complex [IrI(H)(PMe3)4], but survived both
stoichiometric borylation by [IrIII(Bpin)3(PMe3)3] and catalytic borylation by other Ir(III)
catalysts.

	

14	

Scheme 1.13. 2002 Putative Catalytic Cycle of Ir CHB with Ir(III) to Ir(V) Manifold
E−E
(PR3)2IrIII(Bpin)(E)2
C-H activating species

Bpin

(PR3)nIrV(Bpin)(E)4
(PR3)n
E

E
IrV
H

H2

H−Bpin

(PR3)2IrIII(H)(E)2

+
E−E

Bpin
E = H, Bpin
n = 1, 2

Scheme 1.13. In 2002, Smith and Cho offered a putative mechanism for Ir catalyzed
CH borylation operating on an Ir(III) to Ir(V) catalytic manifold based on observations
of reactivity.
Also reported in 2002 by Ishiyama and Hartwig was the introduction of Ir catalysis with
bpy ligands, which soon became the most commonly used conditions for C-H borylation.31 In
2003, Maleczka and Smith expanded on the development of practical applications of this new
chemistry with their publication of one-pot synthesis of contra-electronically substituted phenols,
which bore witness to the circumvention of long-standing electronic limitations in the preparation
of contra-electronically substituted phenols.32 This ground breaking synthesis is shown in Scheme
1.15.

	

15	

Scheme 1.14. Old Fashioned EAS Synthesis of Contra-Electronic Phenol
Me
O2N

NO2

NO2

O2N
1. H2SO4, Na2Cr2O7
2. HOAc, heat
3. KOCN, MeOH

NO2
Br
4. Na2S, EtOH
OMe

5. NaNO2
6. CuBr

NO2 7. Sn, HCl
Br
8. conc. H2SO4
OMe

9. NaNO2
10. CuCl

Cl

1

OH

Scheme 1.14. The only synthesis of 3-bromo-5-chlorophenol reported before 2000
was published in 1926, featuring 10 steps starting from TNT and employing 4
potentially explosive Sandmeyer reactions.
	

The synthesis of 3,5-bromochlorophenol underscores the problem of functionalization
meta to di-substituted 1,3-o/p directors, as shown in Scheme 1.14. The toxic and dangerous 10step synthesis of this simple phenol provides a dramatic illustration of the advantages gained by
the sterically driven regioselectivity of Ir CHB. Simple phenols such as 1 eluded synthetic chemists
for almost a century. The preparation of 3-bromo-5-chlorophenol was reported only once, in 1926
following the 10-step process in Scheme 1.14 starting from the explosive material 2,4,6trinitrotoluene, known commercially as TNT.33 The next time it was reported was in 2001,34
prepared in mg quantities from enzymatic hydroxylation.
Scheme 1.15. One-pot Synthesis of Contra-Electronic Phenol Attained by Ir CHB

Br

Cl

1) 2.0 equiv HBpin
2 mol % (ind)Ir(cod)
2 mol % dmpe 150 °C 3.5 h;
2) aqueous oxone® acetone
25 °C 7 min (83%)

Br

Cl

1

OH

Scheme 1.15. The one-pot synthesis of 3-bromo-5-chlorophenol was
reported in 2003 by Maleczka and Smith, thus sparking intense interest and
development in aromatic functionalization by Ir CHB.
	
In this paper, 3-bromo-5-chlorophenol was prepared in 83% yield in a single day,
employing the one-pot process shown in Scheme 1.15.

	

16	

In 2005, Boller and Hartwig published a kinetic study with isolated intermediates of the
catalytic cycle in agreement with the Ir(III) to Ir(V) mechanism published by Maleczka and Smith
in 2002.30 The isolated intermediates helped to better define the cycle in what came to be widely
accepted as the mechanism of Ir CHB.
Scheme 1.16. Accepted Mechanism for Ir CHB

(dtbpy)Ir(Bpin)3(coe)
26

K1
(- coe)
K-1
(+ coe)

HBpin

L
L

Bpin
Bpin
Ir Bpin

27

arene

K2
K-2

Bpin
Bpin
L Ir H
L
Bpin

Bpin
Bpin
L
Ir H
L
Bpin
Bpin

B2pin2
L
L

Bpin
Bpin
Ir H

Bpin

Scheme 1.16. The accepted mechanism of the catalytic manifold of Ir
catalyzed CH borylation runs through Ir(III) to Ir(V) and involves a 5coordinate trisboryl intermediate.
	
The kinetics of this system will be discussed more in Chapter 2.
By 2005, Ir CHB had just begun to be utilized as a synthetic method in organic chemistry
for the functionalization of arenes outside the organometallic community. By this time, it was
apparent that there were limitations to steric selectivities when substituents were not sufficiently
large to block ortho-borylation, resulting in mixtures that were difficult to separate. Smith and
Chotana embarked on an investigation of the steric and electronic properties of 1,4-benzonitriles,

	

17	

due to the inherent difficulty functionalizing ortho to deactivating nitrile groups.35 In this study,
they sought to differentiate between steric and electronic effects, and, although it is not possible to
completely disentangle the two properties, the borylation of 4-substituted benzonitriles presented
a unique opportunity to quantify the influence of EAS-based electronic properties vs the “size” of
a substituent. According to EAS selectivities, nitrile groups are deactivating meta directors, but in
steric terms, nitriles are relatively small substituents. In order to quantify what constitutes a
substituent as “small” or “large,” Smith and Chotana established a measure of steric “size” that
can be compared widely among different groups, which they termed “steric enthalpies.” The
concept of competing steric and electronic substituent effects is illustrated in Figure 1.1.
Figure 1.1. The Interaction of Steric and Electronic Directing Effects
meta directors

Zm

Zm

Deactivated to EAS,
poor regioselectivity

steric and electronics
reinforce selectivity

Zo/p

Zm

ortho/para directors

Zo/p

Excellent
regioselectivity

Zo/p

Activated to EAS,
poor regioselectivity

Figure 1.1. The selectivity study of 4-substituted benzonitriles presented
the opportunity to evaluate the effects of electronics on the steric
selectivity of Ir CHB as seen above. Isomer ratios were indicative of the
competition between steric and electronic influence.
	
The concept of steric enthalpy is based on computational work by Fujita and coworkers for
the acid catalyzed hydration of o-benzamides.36-37 The parameter is based on calculations of the
difference in enthalpies between 2-substituted benzamides and unsubstituted benzamide, and the
difference between enthalpies of 2-substituted toluene and unsubstituted toluene. The parameter is
denoted DDHs(Z), where Hs is called the steric enthalpy and Z refers to the substituent.

	

18	

Smith postulates that since the transition states for ortho C-H borylation and ortho
hydration of benzamides are similar, as illustrated in Figure 1.2, the DDHs(Z) values should predict
calculated ortho:para ratios of the borylation of 4-substituted benzonitriles. After borylation of
several 4-benzonitriles, the calculated ratios are in good agreement with experimental ratios for
most substituents except for methoxy and thiol, as seen in Table 1.1.
Figure 1.2. Calculation of Steric Parameters are Based on Benzamide Model

OH2

Bpin
Bpin
Ir
Bpin

N
N

H 2N

H

OH Z

Z

Figure 1.2. The transition state of Ir CHB is similar in structure to the
acid catalyzed hydration of benzamides, thus modified calculated steric
parameters used for their study provides a good model for the prediction
of isomer distribution in Ir CHB.
	
Table 1.1. Experimental Regioisomer Ratios vs Ratios Calculated with DDHs(Z)
Z

THF, 25 °C

Z

H
CN
F
Cl
Br
I
CH3
OMe
SMe
NMe2
CO2Me
NHAc
CF3
	

ΔΔHs(Z)
kcal·mol-1

0
3.211
1.535
4.133
5.405
7.759
5.532
2.013
3.682
5.039
4.856
5.166
8.845

%a : %b
calc’d

—
—
6:94
83:17
98:2
>99:1
98:2
31:69
66:34
96:4
94:6
96:4
>99:1
19	

Bpin

+
a

CN

Z

Z

1.5 mol % [Ir(OMe)cod]2
3.0 mol % dtbpy

Bpin
CN

%a : %b
observed

—
—
8:92
81:19
97:3
>99:1
92:8
67:33
87:13
>99:1
>99:1
>99:1
>99:1

b CN

Erosion of steric selectivity was recognized as a serious limitation of Ir CHB and many
groups have sought to improve selectivity and eliminate mixtures with innovations that can be
categorized into three main strategies; Chelate direction, relay direction and outer-sphere
direction.7, 38-39 Of the three strategies, chelate and relay direction are inner-sphere processes,
taking place through a chemical bridge from ligand to substrate. Outer sphere direction, in contrast,
makes use of a ligand on the catalyst to recognize functionality in the substrate and position the
substrate by H-bonding. The borylation takes place between two distinct chemical entities rather
than two species chemically linked by a bond.
Ortho C-H Borylation by Chelate Direction. This strategy involves substrates with DMG
groups that coordinate to the metal to form 16 electron (e–) intermediates. Heterogeneous catalysis
of surface supported ligands uses a variation of this type of chelate direction that supports 14 e–
intermediates. Chelate directed borylation with hemilabile ligands are also able to access the 14 e–
intermediate by dissociation of the weakly coordinating half of the ligand to leave two vacant sites,
as shown in Scheme 1.17, where the boxes represent vacant coordination sites.
Scheme 1.17. Chelate Directed Mechanism Employing Hemilabile Ligand
L

Bpin

L

L

Ir

Bpin
Bpin

L

Bpin
L
Bpin
Ir
Bpin
DMG
H

Bpin
Ir

Bpin

DMG

Bpin

DMG

Bpin

Scheme 1.17. Chelate directed C-H borylation generates a 14 e– intermediate with a
hemilabile bidentate ligand that dissociates one side to accommodate a DMG. The
squares in the figure represent vacant coordination sites.
The first example of chelate direction in a borylation reaction was reported by Smith and
Cho in the year 2000 for the borylation of Benzamide while using the catalyst system of
Cp*Rh(h4C6Me6). A statistical ratio of meta:para borylated isomers was not observed, and instead
	

20	

the ortho isomer was the major product with a ratio of 4:2:1.28 In 2010, Smith, Maleczka and
Vanchura described the electronics of the chelate effect with striking examples of the borylations
of veratrole and benzodioxole, as seen in Scheme 1.18. The constrained benzodioxole gave only
the conventional borylation products while veratrole gave only ortho borylated product.40
Scheme 1.18. Chelate Directed Borylation vs Undirected Borylation
Bpin
P Ir
P
Bpin

O

O

Bpin
Bpin

O

O

Bpin

O

+ 1 equiv (dippe)Ir(Bpin)3 +

O

O

O

8 equiv

8 equiv

Scheme 1.18. In 2000 Smith and Vanchura provided insight into the mechanism of chelate
directed borylation.
Around this time, several chelate directed ortho borylations were discovered. Ishiyama and
Miyaura described ortho borylation of esters by use of bulky, monodentate phosphine ligands,41
followed by Ito and Ishiyama’s report of the ortho borylation of ketones,42 and Lassaletta’s
observation of N-directed ortho borylations of 2-phenylpyridines using hemilabile ligands.43 Clark
soon reported N-directed ortho borylation of benzylamines and phosphines.44-45
Scheme 1.19. Heterogeneous Chelate Directed Mechanism

L

E
Ir

Bpin

DMG

E
L
Ir
L
H

Bpin
L

DMG

Bpin

DMG

Bpin

Scheme 1.19. Heterogeneous chelate directed C-H borylation operates through by a 14
e– intermediate with 2 open coordination sites, which are represented by empty squares.

	

21	

In 2009, Sawamura reported a surface supported system of phosphines for heterogeneous
Rh catalysis that was highly active and ortho-selective with a much wider substrate scope,46 using
N heteroatoms as directing groups. The general mechanism for heterogeneous catalysis is shown
in Scheme 1.19, where L is the siloxane linker, and E is an electrophilic P donor group on the
ligand. A general depiction of how the tethered catalyst operates is shown in Scheme 1.20. The
synthesis of the supported medium, called silica SMAP proved to be challenging to synthesize,
thus limiting attempts to modify the system in order to engineer selectivity.
Scheme 1.20. Ortho Borylation by Silica SMAP
Bpin
Bpin

Bpin

Bpin

Bpin

Rh

Si

SiMe3

O

Si
O
O

O Si O
O

DMG

Bpin

O

O
O

H

DMG

Si

SiMe3

DMG

O

O

Rh
P

PH

Bpin

O Si O
O

Si
O
O

SiO2
SiO2

Scheme 1.20. Sawamura’s solid supported Silica SMAP tethers the catalyst to a solid surface
to block coordination of the tris boryl intermediate, and thus leaves two vacant coordination
sites, stabilizing a 14 e– intermediate. The vacant coordination sites are shown as boxes in the
scheme.
In 2014, Ghaffari and Smith reported ortho borylation by the use of silyl N or silyl P donor
ligands which can access the 14 e– intermediate without hemilabile ligands as shown in Scheme
1.21. The substrate scope is broad, and many arenes with typical directed metalation (DMG)
groups such as tertiary amides, esters, methoxy and 2-pyridines, were successfully ortho-borylated
with high selectivity and yields. This system operates with a 14 e– intermediate analogous to silica
SMAP, however it is a much more flexible system where the ligands can be modified easily to tune

	

22	

selectivity or to change directing effects to work with a with a different DMG. For example,
Scheme 1.21 shows how meta or ortho selectivity can be accessed depending on reaction
conditions.
Scheme 1.21. Donor Chelates Achieve 14 e- Intermediates under Homogeneous Conditions

R1
P
R1

Si

1.25 mol % [Ir(OMe)cod]2
2.5 mol % NR2PR2Ph F
1.0 equiv B2pin2

R2
R2

Ir

Bpin

CO2Me
Bpin

THF 80 °C 16 h

CO2Me

Br

F

Bpin

Br

1.25 mol % [Ir(OMe)cod]2
2.5 mol % dtbpy
F
1.0 equiv B2pin2

CO2Me

Bpin

THF 80 °C 16 h

Br

Scheme 1.21. In 2014 Ghaffari and Smith developed easily-synthesized and modified donor
chelates in order to access 14 e– intermediates without hemilabile ligands or supported media
that is impractical and inconvenient synthesize. The open coordination sites are shown as empty
squares.
This method meets the test for achieving a switch in selectivity under identical conditions
by just changing the ligand used. The ligand synthesis is simple, and can be easily modified. The
use of directing groups is necessary for this chemistry, but it is not limited to just one kind of
directing group, so this method is more general than many of the directed borylation methods
produced so far.
Ortho C-H Borylation by Relay Direction. This type of directed borylation relies on a
substituent on the substrate to reversibly bind to the metal by s bond metathesis. Substrates that
exhibit relay directed borylation have pendant Si-H bonds. The first reported ortho C-H borylation
using a silyl directing group was reported by Hartwig and Boebel in 2008,47 as seen in Scheme
1.22.

	

23	

Scheme 1.22. Relay Directed Mechanism

L
L

Bpin
Ir

Bpin

Bpin
L
Bpin
Ir
L
H SiR2

HR2SiO

HR2SiO

Bpin

O

Bpin

Scheme 1.22. Relay directed borylation relies on sigma bond metathesis between
a pendant silyl group and the metal in order to form a chemical linker to direct
borylation. Since the relay links to the ligand, a second open coordination site
(depicted as an empty square) is not necessary,
	
The strategy involves the protection of a phenol with a silyl protecting group, R2SiH. After
the borylation the protecting group can be removed.
Ortho C-H Borylation by Outer Sphere Direction. The transition state of this reaction
resembles relay direction, but there is a distinction that this reaction is directed by H-bond
interactions of the substrate with the ligand, and the mechanism is considered in light of
descriptions of hydrogen transfer.48 Also distinct from relay direction, the substrate and ligand
remain separate chemical entities and are not linked by a formal bond. Maleczka, Smith and
Singleton have used H-bond direction of boc protected anilines to selectively borylate ortho to the
bulky N-H boc group.49 Boc groups have been known to function as steric blocking groups in the
borylation of pyrrole and indoles, so H-bond directed borylation ortho to N-H boc is intriguing.
When a second boc group is put onto the aniline, thus removing the possibility for H-bonding,
ortho borylation is not seen, and the only product is borylated meta to the boc group. The general
mechanism of outer-sphere directed borylation is illustrated in Scheme 1.23.

	

24	

Scheme 1.23. Outer Sphere Directed Mechanism

L
L

Bpin
Ir

Bpin
Bpin

FG

Bpin
L
Bpin
Ir
L
H L
FG

FG

Bpin

Scheme 1.23. Outer sphere direction is guided by recognition of functionality by a
ligand. The ligand and substrate are chemically distinct, unlike relay direction. Here
the substrate contains a FG that coordinates to a ligand, thus only requires one open
coordination site (depicted as an empty square).
	

Examples of Directed Meta C-H Borylation. In the early development of C-H borylation,
it became clear that Ir CHB of mono-substituted arenes gave statistical mixtures of meta and para
isomers, and the only truly meta selective C-H borylations were of 1,3 di-substituted arenes with
large substituents. In 2015, however, the first Ir catalyzed meta selective borylation of a monosubstituted arene was reported by Kanai and coworkers.8 The borylation is directed by a bpy ligand
with a pendant urea substituent that “recognizes” carbonyl groups on the substrate. The substrate
is guided by H-bonding from the pendant urea, as pictured in Scheme 1.24. A large substrate scope
of heterocyclic and aryl compounds and tolerance for wide variety of functional groups was
demonstrated. Selectivity was generally good although some mixtures were obtained.

	

25	

Scheme 1.24. Outer Sphere Borylation Achieved by Recognition of Carbonyl Functionality

O

O

N
H

N
Bpin

N
H

H

N

Ligand =

O

N

NH2

Bpin
Ir H
N Bpin

N

O

O
NH2

N
H

pinB

1.5 mol % [Ir(OMe)cod]2
3.0 mol% ligand L

O
NH2

NH2

+

p-xylene, 25 °C 16 h

Bpin

Scheme 1.24. Kanai reported Ir meta CHB by use of a pendant urea group to direct from
the ligand rather than the substrate, sometimes called molecular recognition.
The synthesis of a complicated ligand and the requirement of xylene as a solvent is a
significant drawback, since xylene is expensive and difficult to remove. This is an important step
in the quest for selective chemistry based molecular recognition, but the need for a carbonyl
directing groups and very specific ligands render this methodology not general or practical for
most applications.
In 2016, Chattopadhyay reported a simpler, more general system using commercially
available ligands for directed meta selective borylation of benzaldehydes, protected with tert-butyl
amine. When tetramethylphenanthroline (tmp) was used as the ligand, aldehydes underwent orthoselective borylation. When 8-aminoquinoline was used as the ligand, reminiscent of Ghaffari and
Smith’s N donor ligands published in 2014,39 the reaction gave meta borylation as the major
product.50
This approach is simple, and meets the criteria of ligand based selectivity where, under
identical reaction conditions, changing the ligand leads to a switch in the major product. The

	

26	

reagents are widely available and the methodology is convenient and accessible to most organic
chemistry labs. The only drawback is the need to install a protected aldehyde director in order to
facilitate the selectivity. If the aldehyde is already in place and part of a larger synthetic strategy,
this is a very good strategy to achieve selective meta borylation. This ligand based approach and
examples of substrate scope is shown in Scheme 1.25.
Scheme 1.25. Directed Meta or Ortho Borylation by Ligand-Based Selectivity

N
N
1) 4 equiv t-BuNH2
(remove solent)
2) 1.5 mol% [Ir(OMe)cod]2
3.0 mol % tmp

CHO

CHO

CHO

0.1 mol% HBpin
0.7 equiv B2pin2
THF, 90 °C, 12 h

1) 4 equiv t-BuNH2
(remove solent)
2) 1.5 mol% [Ir(OMe)cod]2
3.0 mol % 8-AQ
0.1 mol% HBpin
0.7 equiv B2pin2
THF, 90 °C, 12 h

CHO

CHO

CHO

Bpin
MeO

Bpin

NC

Bpin

Bpin
CN

Bpin
F

A sampling of the substrate scope
showcasing the difficult substitution patterns
obtained from this chemistry is presented
here, however an example of borylation meta
to F was not among them.

CHO

Bpin

N
NH2

Scheme 1.25. Chattopadhyay discovered a directed borylation strategy to achieve either
ortho or meta selective borylation using commercially available ligands.
With an eye towards meta borylation to small electronegative substrates like F and CN, an
excellent range of borylated products are accessed, including borylation both meta and ortho to
CN, but meta borylation to F is missing from the substrate scope, as seen in Scheme 1.25.
Meta Selective Borylation by Ion Pair Direction. In 2016, Phipps achieved meta-selective
borylation of a variety of arenes including fluoarenes by installation of a quaternary amine group
on the substrate.51 A complimentary negatively charged sulfonate tether was installed on a bpy
ligand to produce a productive ion-pairing effect which would impose a desired interaction

	

27	

between the substrate and the active catalyst complex. In 4-fold improvement in meta selectivity
over dtbpy was realized with this approach.
Scheme 1.26. Meta Borylation by Ion Pair Direction
N

F

O
O

H

O S pinB
N

Bpin
N
OTs

Bpin

OTs
N

Ir

F

1.5 mol % [Ir(OMe)cod]2
3.0 mol % Ligand
1.5 equiv B2pin2

OTs

N

F

N

F
Bpin

THF 50 °C 20 h
Bpin
20:1

(dtbpy in THF 5:1)

Scheme 1.26. Use of modified ligands and substrates to produce an ionic pair facilitates
selective borylation meta to many substituents, including F. A drawback to this technology
is that there is no easy was to remove the quaternary directing group, although it successfully
participates in cross-coupling reactions, and can be left in place for that purpose.
Although this approach has achieved good meta selectivity for arenes, it does not produce
selectivity for pyridines or indoles, and is prone to over-borylation resulting in mixtures of
diborylated heterocycles. Fluoroarenes without the ortho position blocked were also prone to
diborylation. The anionic substituent is left in place to use as a Suzuki coupling partner, but no
way to remove the substituent is offered. While this is an important innovation in borylation of
arenes, it is not good for general functionalization of library compounds or small molecule building
blocks unless the anionic group is desired in the final product. In addition, the installation requires
the presence of a methyl or ethyl group already in place on the molecule. For bulk haloarenes,
there is no quick or simple way to install the directing group. Many borylation strategies to achieve

	

28	

selective borylation of pyridines and indoles already exist, and this strategy offers no improvement
for that application. This strategy is useful primarily to functionalize arenes that are slated for cross
coupling, and will likely develop into a useful specialized application of C-H borylation.
Borylation Ortho to Fluorine by Sacrificial Blocking Group. During ongoing ligand
studies, the Maleczka and Smith groups investigated the borylation of poly-halogenated substrates
in collaboration with Dow Chemical Company.52 Chathurika Jayasundara of the Maleczka group
and Dr. Jossian Oppenheimer of Dow explored borylation of 3-fluoro-substituted arenes with a
halogen blocking group (Br or Cl) para to F, with later removal of the halogen. The selective
borylation ortho to F was achieved with a para-Br blocking group and subsequent removal of Br
by Pd catalyzed reduction with polymethylhydrosiloxane (PMHS). A wide variety of difficult
substitution patterns was achieved, as illustrated in Scheme 1.27.
Scheme 1.27. Selective Borylation by Steric Blocking Group
CF3

Br

CF3

5 mol % Pd(OAc)2
2 equiv KF, 4 equiv PMHS

F
Bpin

F
Bpin

H2O, THF. rt, 24 h
(83%)

F

NH2

Me

F

F

Bpin

Bpin

N

F

F F3C

F

Bpin

Bpin

Bpin

Me

F
Bpin

Scheme 1.27. Obtaining difficult substitution patterns for fluoroarenes has been
accomplished by use of Br as a blocking group with subsequent removal of the blocking
group by polymethylhydroxysiloxane (PMHS) reduction.
	
Diborylation followed by Selective Monodeborylation. While working on selective
deutero-deborylation,53 a method was developed to prepare single isomer batches of 3-cyano

	

29	

substituted arenes and heterocycles which gave 1:1 mixtures of ortho and meta borylated products
under standard borylation conditions with [Ir(OMe)cod]2 and dtbpy. Substrates were diborylated
then subjected to selective mono-deborylation conditions to achieve single isomer products. This
method, while not atom economical, greatly simplifies the preparations of the surviving product
by destroying the unwanted isomer, thus, making isolation by a short silica plug possible.
In work published while the selective deborylation work was ongoing, Movassaghi and
coworkers independently published a 2,7-diborylation, selective 2-deborylation procedure on
indoles using two different conditions of trifluoroacetic acid in CH2Cl2 (TFA) and 5% Palladium
acetate in acetic acid.54 Also, in 2016 another selective deborylation of indoles was published by
Shen and coworkers using bismuth acetate.55 These strategies are highlighted for the selective
functionalization of indoles in Scheme 1.28.
Scheme 1.28. Alternate Functionalization by Poly-borylation / Selective Deborylation
A) Movassaghi
5 mol% Pd(OAc)2
AcOH, 30 °C, 10 h
72 - 82%
R

N
H

1.5 mol% [Ir(OMe)cod]2
3.0 mol% dtbpy
2.0 equiv B2pin2

B) Maleczka-Smith
1.5 mol % [Ir(OMe)cod]2
MeOH / CH2Cl2, 60 °C 2 h
58%

R
Bpin
Bpin

N
H

C) Maleczka-Smith-Merck collaboration
1.2 equiv BiCl3
MeCN/H2O (50:1) 60 °C 2 h
60-90%

R

Bpin

N
H

Scheme 1.28. Several methods have been reported for the selective deborylation of diborylated
substrates.
	
Para Selective Borylation by Direction of Bulky Phosphine Ligand. In 2015 use of a
bulky phosphate ligand enabled para borylation of mono-substituted substrates with very bulky
substituents. While selectivity and yields for the substrates featured are generally very good, all
substrates have a very bulky substituent, the smallest being a tert-butyl group. This method likely

	

30	

does not work for smaller substrates or haloarenes. It also makes use of a specialized complex
ligand not useful for other borylations. This is an innovative synthetic technique that will be useful
for very specialized applications, but will not be useful for general purpose borylations.
Scheme 1.29. Para Borylation by Bulky Ligands that Mimic Enzyme Sites

H
MeO
MeO

P

Bpin

Ir

P

Bpin
Bpin

1.0 equiv B2pin2
1.5 mol % [Ir(cod)OH]2
3.0 mol % Ligand
hexane 85 °C 20 h
Bpin

Scheme 1.29. Bulky ligands have been used to selectively functionalize
bulky substrates at the para position. The inspiration for this model is
based on the binding pocket of enzymes.
	
New strategies for selective C-H functionalization are being published rapidly, and Ir
catalyzed CH borylation is not the only method that shows promise. Many strategies for Zn,56
Co,57-58 Cu59-60 and Pd61 catalyzed meta selective functionalizations have also been developed,
which will not be discussed here, but nonetheless, remain as vital additions in the chemical tool
box.

	

31	

	

REFERENCES

	

32	

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(C5Me5)Rh(PMe3)(H)Ph. Evidence for arene precoordination. Journal of the American Chemical
Society 1982, 104 (15), 4240-4242.
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Chatt, J.; Davidson, J. M., 154. The tautomerism of arene and ditertiary phosphine
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ruthenium(II). Journal of the Chemical Society (Resumed) 1965, (0), 843-855.
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Ittel, S. D.; Tolman, C. A.; English, A. D.; Jesson, J. P., Novel carbon-hydrogen bond
cleavage by bis(dimethylphosphino)ethane complexes of iron, ruthenium, and osmium. Journal of
the American Chemical Society 1976, 98 (19), 6073-6075.
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Jones, W. D.; Kosar, W. P., Carbon-hydrogen bond activation by ruthenium for the
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Waltz, K. M.; He, X.; Muhoro, C.; Hartwig, J. F., Hydrocarbon Functionalization by
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Iverson, C. N.; Smith, M. R., Stoichiometric and Catalytic B-C Bond Formation from
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(33), 7696-7697.

	

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Waltz, K. M.; Muhoro, C. N.; Hartwig, J. F., C-H Activation and Functionalization of
Unsaturated Hydrocarbons by Transition-Metal Boryl Complexes. Organometallics 1999, 18 (17),
3383-3393.
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Chen, H.; Hartwig, J. F., Catalytic, Regiospecific End-Functionalization of Alkanes:
Rhenium-Catalyzed Borylation under Photochemical Conditions. Angewandte Chemie
International Edition 1999, 38 (22), 3391-3393.
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Chen, H.; Schlecht, S.; Semple, T. C.; Hartwig, J. F., Thermal, Catalytic, Regiospecific
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Cho, J.-Y.; Iverson, C. N.; Smith, M. R., Steric and Chelate Directing Effects in Aromatic
Borylation. Journal of the American Chemical Society 2000, 122 (51), 12868-12869.
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Tse, M. K.; Cho, J.-Y.; Smith, M. R., Regioselective Aromatic Borylation in an Inert
Solvent‚. Organic Letters 2001, 3 (18), 2831-2833.
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Cho, J.-Y.; Tse, M. K.; Holmes, D.; Maleczka, R. E.; Smith, M. R., Remarkably Selective
Iridium Catalysts for the Elaboration of Aromatic C-H Bonds. Science 2002, 295 (5553), 305-308.
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Ishiyama, T.; Takagi, J.; Ishida, K.; Miyaura, N.; Anastasi, N. R.; Hartwig, J. F., Mild
Iridium-Catalyzed Borylation of Arenes. High Turnover Numbers, Room Temperature Reactions,
and Isolation of a Potential Intermediate. Journal of the American Chemical Society 2001, 124 (3),
390-391.
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Maleczka, R. E.; Shi, F.; Holmes, D.; Smith, M. R., C−H Activation/Borylation/Oxidation: 
A One-Pot Unified Route To Meta-Substituted Phenols Bearing Ortho-/Para-Directing Groups.
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Chotana, G. A.; Rak, M. A.; Smith, M. R., Sterically Directed Functionalization of
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Sotomatsu, T.; Fujita, T., The steric effect of ortho substituents on the acidic hydrolysis of
benzamides. The Journal of Organic Chemistry 1989, 54 (18), 4443-4448.

	

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Smith, M. R., Outer-Sphere Direction in Iridium C–H Borylation. Journal of the American
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Ghaffari, B.; Preshlock, S. M.; Plattner, D. L.; Staples, R. J.; Maligres, P. E.; Krska, S. W.;
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Ortho Borylation Catalysis. Journal of the American Chemical Society 2014, 136 (41), 1434514348.
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Vanchura, I. I. B. A.; Preshlock, S. M.; Roosen, P. C.; Kallepalli, V. A.; Staples, R. J.;
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borylations: insights from unencumbered substrates and variation of boryl ligand substituents.
Chemical Communications 2010, 46 (41), 7724-7726.
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Ishiyama, T.; Isou, H.; Kikuchi, T.; Miyaura, N., Ortho-C-H borylation of benzoate esters
with bis(pinacolato)diboron catalyzed by iridium-phosphine complexes. Chemical
Communications 2010, 46 (1), 159-161.
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Hiroshi, I.; Takao, K.; Tatsuo, I.; Norio, M., Iridium-catalyzed ortho-C–H Borylation of
Aryl Ketones with Bis(pinacolato)diboron. Chemistry Letters 2011, 40 (9), 1007-1008.
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Crawford, K. M.; Ramseyer, T. R.; Daley, C. J. A.; Clark, T. B., Phosphine-Directed C-H
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Kawamorita, S.; Ohmiya, H.; Hara, K.; Fukuoka, A.; Sawamura, M., Directed Ortho
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Boebel, T. A.; Hartwig, J. F., Silyl-Directed, Iridium-Catalyzed ortho-Borylation of
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Kallepalli, V. A.; Shi, F.; Paul, S.; Onyeozili, E. N.; Maleczka, R. E.; Smith, M. R., Boc
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Bisht, R.; Chattopadhyay, B., Formal Ir-Catalyzed Ligand-Enabled Ortho and Meta
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Jayasundara, C. R. K.; Unold, J. M.; Oppenheimer, J.; Smith, M. R.; Maleczka, R. E., A
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61.
Dey, A.; Agasti, S.; Maiti, D., Palladium catalysed meta-C-H functionalization reactions.
Organic & Biomolecular Chemistry 2016, 14 (24), 5440-5453.
	

	

38	

CHAPTER TWO
ENGINEERING SELECTIVITY WITH LIGANDS AND BORANE
Steric Effects of Substrates and Regioselective Outcomes. C–H borylation has gained
popularity because the direct coupling of C–H with B–H or B–B bonds is the most atom
economical route to boronate esters.1 Another appealing feature is that sterically directed
regioselectivity, typically observed for aromatic substrates, complements selectivities of
electrophilic aromatic substitutions (EAS) and directed ortho metalations (DoM).2 Scheme 2.1
shows how steric directing effects can be utilized to achieve selective functionalizations in 1,3and 1,4-substituted benzenes. For 1,3-substituted benzenes, high meta selectivities are found when
the benzene substituents are sufficiently large to block functionalization of their ortho C–H bonds.
For 1,4-substituted benzenes, selective sterically directed C–H borylation can be achieved when
the sterics of the substituents differ significantly.3
Scheme 2.1. Sterically Directed C–H Borylation Regioselectivities
high selectivity

RL

low selectivity

C–H
borylation

R1

C–H
borylation

RL

Bpin
Bpin
R2

RM

RL

C–H
borylation

RS

R1

C–H
borylation

RM
Bpin

Bpin

	

									

RS

R2

RS

	

When these requirements are not met, selectivities can erode. Although recent work shows
promise for borylation of C–H bonds ortho to F,4-7 this tendency makes borylation meta to F
particularly challenging when a sterically accessible ortho H is present. Some recent efforts in
directed borylation have achieved success with borylation meta to F,
	

39	

8-11

however simple arenes

that lack common directing groups or that have multiple C-X bonds remain problematic. Given
the importance of fluorinated organic molecules, this is a serious limitation of C–H borylation.
Here we show that ligand design makes it possible to achieve good selectivities for combinations
of substrate classes, substituents, and substitution patterns that are daunting for C–H borylation
and other C–H or C–X transformations.
The chemistry of 3-fluorochlorobenzene (1) illustrates some of the challenges that remain
in aromatic functionalization (Chart 2.1).
Figure 2.1. C–H Functionalizations of 3-Fluorochlorobenzene
FG
F

Cl

EAS

F

Cl

F

DoM

Cl

FG
1

A
F

B

Cl

FG
C

F
2 direct routes
>45,000 known
strucutres

2 direct routes
>10,000 known
strucutres

															

Cl

FG
D

	

While the 2-position can be selectively transformed via DoM, and EAS can be used to
functionalize the 6-position,12-15 selective derivatizations at the 4-position are limited to an
enzymatic hydroxylation16,17 and the electrophilic borylation recently reported by Ingleson and coworkers.18 Likewise only two reports, both C–H activations, describe functionalization at the 5position.19-20 Given that >45,000 4-substituted and >10,000 5-substituted compounds have been
reported, the dearth of direct routes from 1 is remarkable.21 Limitations in the substrate scopes of
promising Co-catalyzed ortho C-H borylations reported by Cherik7 and meta C-H borylation
reported by Cui11 likewise fails to achieve dihalogenated structures C or D by direct
functionalization of 1.

	

40	

In

contrast,

Ir-catalyzed

C–H

borylation

using

the

commonly

employed

dtbpy/[Ir(OMe)(cod)]2 ligand/precatalyst combination gives a mixture of 4 and 5-borylated
products as shown in Scheme 2.2.
Scheme 2.2. C–H Borylation of 3-Fluorochlorobenzene
0.1 equiv HBpin,
0.5 equiv B2pin2
Cl
1.5 mol% [Ir(OMe)COD]2,
3 mol% dtbpy

Cl

Cl
Bpin

+

hexanes, r.t., 24 h

F

F
1

F
2a
1.8

Bpin
2b
1

:
					
	
Electronic Effects of Ligands on Borylation. Despite low selectivity, C–H borylations

clearly provide opportunities for these challenging transformations. Since electronic effects can
influence C–H borylation regioselectivities,22-23 Ir catalyzed C-H borylations of 1 were performed
using 4,4’-disubstuted-2,2’-dipyridyl (bpy) ligands. The remote 4’-substitution site on the bpy
ligand ensures that selectivities will be electronically determined. Although the changes in
selectivities are modest, Table 2.1 shows that 2a is favored for the most electron-rich ligand while
2b is the major isomer for the most electron- poor ligand. Based on calculated pKas of halogenated
benzenes,22 the C–H bond at the 4-position should be more acidic than the C–H at the 5-position.
Table 2.1. Electronic Effects on Borylation Regioselectivitya
1.5 mol% [Ir(OMe)(cod)] 2,
R
Cl

R
Cl

3 mol%
N

F

1
4 equiv
entry

a

	

Cl

N

0.1 equiv HBpin,
0.5 equiv B 2pin 2
hexanes, rt, 24 h

Bpin
F

2a

+
F

2b

R

2a:2b

1

t-Bu

1.8:1

2

NMe 2

2.2:1

3

CF 3

1:1.6

Bpin

1 equiv reflects the number of transferable Bpin groups (i.e., 2 Bpin groups per B2pin2).

41	

Quantification of Electronic and Steric Effects of Ligands. Using the results in Table 2.1
and estimations of ligand steric effects, the ligand design approach in Chart 2.2 was devised for
selective functionalization at the 4 or 5-positions of 1. Specifically, hindered, electron rich ligands
should favor isomer 2a, while less encumbered electron poor ligands should select for isomer 2b.
Chart 2.2 shows a palette of chelating ligands ordered by their steric and electronic properties.
Figure 2.2. Variation of Ligand Steric and Electronic Effects
hindered,
electron
rich ligands

Cl
Bpin
F

F

2a

Steric hindrance
N

F

1

CH2Ph
O

N
>

O

Bpin

O

N

O

N

>
N

N
t-Bu

CH2Ph
bnbozo

dpm

2b

t-Bu

N

,

N

unhindered, Cl
electron poor
ligands

Cl

dtbpy

bozo

Basicity
Me 2N
CH2Ph

t-Bu
N

N
>

O

N

>

N

N

O

t-Bu

O

N

O

N

~
N
CH2Ph

Me 2N

dmadpm
								
	
The ligands with a methylene spacer between the pyridine rings, denoted as dipyridyl

methane, (dpm) and dimethylaminodipyridyl methane (dmadpm), will form puckered sixmembered metalacyclic rings when chelated to the Ir, as opposed to the 5-membered planar
metalacycles that result from 4,4’-di-tertbutyl-2,2’-bipyridine (dtbpy) or 2,2’-bisoxazoline (bozo)
coordination to Ir.23 Therefore dpm and dmapm will be the most sterically demanding ligands. The
bozo ligand will be less sterically hindered than dtbpy because the five-membered oxazoline rings
of bozo are smaller than the pyridine rings in dtbpy. When ligated to the Ir center, the benzyl

	

42	

substituted bisoxazoline ligand, 2,2′-bis[(4S)-4-benzyl]-2-oxazoline (bnbozo) projects a benzyl
group below the ligand plane into the region where the substrate approaches during borylation.
Thus it should be more hindered than dtbpy and bozo.
Table 2.2: Brønsted Basicities of Related Oxazoles and Pyridines:
2-methyl
oxazolium

2-methyl
pyridinium

2,4-dimethyl
pyridinium

N,N’-(dimethyl)-4aminopyridinium

O

N

NH

pKa 5.52
ref. 26

+HN

+HN

pKa 5.97
ref. 28

pKa 6.71
ref. 27

HN

pKa 9.86
ref. 29

	

Table 2.2. Ranking of the bacisity is based on calculated pKas of analogous monomers of the
ligands. Calculations for the 2-methyl analogue of 4-dimethylamino pyridinium were not found in
the literature, so the unsubstituted pyridinium is included to illustrate the significant increase in
bacicity imparted by the NMe2 substituent. Scifinder predicted properties estimates 4(dimethylamino)-2-methyl pyridinium pKa = 10.71.
Ligand Selectivities of 3-Fluorochlorbenzene. From the Brønsted basicities of related
oxazoles and pyridines, (Table 2.2) the ligand’s capacities for sigma donation should increase in
the order bozo24 < dtbpy25 ~ dpm26 < dmadpm.27 If the steric and electronic effects on selectivity
for borylations of 1 map as predicted, preference for 2a should increase in the order bozo < dtbpy
< dpm < dmadpm, with the positioning of bnbozo being difficult to predict a priori. The results for
borylations with these ligands are shown in Table 2.3.
The selectivities follow the order predicted from the model, validating the notion that steric
and electronic effects can work in concert. When bnbozo is compared to less hindered dtbpy,
electronic effects for bnbozo trump sterics and the electronic product 2b is favored. The
electronically similar and less hindered bozo ligand is even more selective for 2b.

	

43	

Table 2.3. Boron Reagent Effects on the Borylation Regioselectivity of 1
Cl

Cl

1.5 mol % [Ir(OMe)(cod)] 2,
3 mol % ligand

Cl
Bpin

F

1
4 equiv

0.1 equiv HBpin,
0.5 equiv B 2pin 2
hexanes, 24 h, rt

F

+
F

2a

2b

Bpin

ligand

% conversiona

2a:2b

1

bozo

74

1:3.3

2

bnbozo

79

1:2.4

3

dtbpy

>99

1.8:1

4

dpm

86

2.3:1

5

dmadpm

>99

2.9:1

entry

a

% conversion was determined by integrating the 19F NMR resonances for
1, 2a, and 2b of aliquots from the reaction mixture.
Regioselective Effects of Borane Source on 3-Fluorchlorobenzene. It has previously been
documented that B2pin2 is more reactive than HBpin in borylations.28 Thus, borylation with 0.5
equiv of B2pin2 results in a rapid borylation of arene with production of HBpin. Once the B2pin2
is consumed, the second stage of borylation proceeds. In the case of dpm and dmadpm, the
selectivity for isomer 2a improves as the reaction with 0.5 equiv of B2pin2 proceeds, suggesting
that the selectivities with B2pin2 and HBpin differ (Scheme 2.3).
Scheme 2.3. Boron Reagent Effects on the Borylation Regioselectivity of 1
F

Cl

1

1.5 mol % [Ir(OMe)(cod)]2
3.0 mol % dmadpm
1.0 equiv B2pin2 or HBpin
THF, rt

F

Cl

F

Cl

+

pinB
Bpin

Boron reagent

2a

2b

1.0 equiv B2pin2

2.5

1

2.0 equiv HBpin

11

1

This was confirmed by examining HBpin and B2pin2 as the borylating agents in THF, where
the selectivity for 2a is slightly higher. Remarkably, the isomer ratio for dmadpm / HBpin improves

	

44	

to 11:1. This is the first time a significant difference in selectivity between B2pin2 and HBpin has
been observed. Selectivities with B2pin2 and HBpin were essentially identical for other ligands in
Chart 2.2. The disparity between B2pin2 and HBpin with dpm and dmadpm must result from a
change in catalyst resting state and/or mechanism—the details of which will be discussed later in
the chapter.
Ultimately, ligand design makes the synthesis of 2a or 2b from 1 possible and demonstrates
that Ir-catalyzed borylations can be tuned to complement EAS and DoM in Chart 2.1. Isomerically
pure 2a and 2b can be economically prepared by Miyaura borylation of the commercially available
bromides,29 or by addition of boron electrophiles in the case of 2b.18 Nevertheless, the design
principles that emerge from studying borylation of 1 can be applied to synthesize compounds
where the requisite halides for Miyaura borylation are prohibitively expensive or unknown, or
desired regioisomers are not accessible by Ingleson borylation.
Regioselective Outcomes for 5 and 6-Memebered Arenes and Heterocycles. A selection
of 5 and 6-membered ring compounds that give isomer mixtures in borylations with dtbpy were
screened against the ligands, dpm, bnbozo, and bozo, and the results are shown in Tables 2.4 and
2.5.
The ligand study was designed so that each parent substrate gave two primary products
denoted as a and b regioisomers with a isomers (red) being sterically favored, and b isomers (blue)
being electronically favored. Results are split between two tables, 6-membered arenes and
heteroarenes in Table 2.4, and 5-membered heterocycles in Table 2.5. The products in the first
entry of Table 2.4 are derived from the test substrate, 3-fluorochlorobenzene, 1. Even with the
modest selectivities gained from changing ligands, it is enough to isolate pure 2a by use of dpm

	

45	

or 2b by use of bozo, albeit in low yields. 2a an oil, can be eluted off a silica column with hexane
and 2b, a crystalline solid can be crystalized from the isomeric mixture dissolved in hexanes.
Table 2.4. Ligand Selectivities of C-H Borylation of 6-Membered Arenes and Heterocycles
1.5 mol % [Ir(OMe)(cod)]2
3 mol % ligand
THF or Et2O, rt, 1-48 h

HBpin or
H +
B2pin2

Het

Bpin

dtbpy
pinB

1
F

2a

Cl

F

Cl

dpm

bnbozo

1.8:1a 2.3:1b 1:2.4
28% 2a

4.5:1c
CN NC

F

3a

Br

pinB
F

pinB

2

F

Br

3b

7:1
60%
(7:1)

1:1.6

6.8:1
60%
(6.8:1)

1:1.3

1:1.8

7b

Cl

Cl

F

7a

pinB

3:1

NC

Cl
NC

8a

pinB

pinB

3:1
F

4a

I

F

I

4b

1:2.6

8

NC

N
9a

F

pinB
F

N

5a

Cl

6.5:1
F

N

Cl

23:1
4.5:1
90% 5a

1.9:1

1.2:1c

Cl

5b

N
10a

99:1d
89% 7a

27:1

4:1

5.6:1

13:1
60%
(13:1)

4.5:1

2:1

1:1e

13:1e
74%
(16:1)f

2.8:1e

1:4.5

1:8.5
66%
(1:9)f

Br
NC

Bpin

9

38:1

32:1a

8b
Bpin

Br

Bpin

4

3:1c
12:1
74% 6a

7b
Bpin

Cl

Bpin

3

74%a74%a

bozo

Bpin
6b

2b

Bpin

CN

bnbozo

6b

6a

bozo
1:3.3
16% 2b

dpm

pinB

5
CN

Bpin

dtbpy

Bpin

Het

N
9b
Bpin

F

Cl

1:1.6

N
10b

1.5:1
30%
(3:1)f

Standard conditions: 1 mmol substrate, 1.5 mol% [Ir(OMe)cod]2, 3 mol% ligand, 1.5-2 equiv HBpin,
3 mL THF, reaction times vary from 1-48 h as detailed in SI. Isomer ratios (GC-FID) or single isomer
isolated material in parenthesis where applicable. Yields without ratios are single isomer. a Hexane as
solvent. bEther as solvent. cCatalyst pregenerated in neat HBpin with 6 mol% Ir. No reaction was
observed without catalyst pregeneration. dStoichiometric conversion (6%). eLow conversion, 40-50%.
f
6 mol% Ir. g[GC ratio] in brackets from10-fold excess substrate to eliminate diborylation. hPractical
conditions use 2-fold excess substrate to minimize diborylation to <2%. iPractical conditions use 1
equiv substrate resulting in 12-19% diborylation. jDiborlation changes a:b ratio. kRatio improved by
silica plug. lRecrystallized form hexane. ma:b ratio determined by NMR. n5 mmol scale. o1 equiv
B2pin2	

Since many recent C-H borylation methods are prone to competing C-X activation, and
many dihalo-substituted arenes, particularly fluoroarenes, are either incompatible or suffer from
intrusive dehalogenation, we also tested the bromo and iodo analogues to 1, shown in Entries 2
and 3 of Table 2.4. These substrates are of interest because the iodo and bromo substituents would
render attempts to synthesize 3a,b and 4a,b by Miyaura coupling problematic. Borylation of
substrates 3 and 4 by dpm proceeds smoothly to 85 – 95% completion in 24 hours and a significant

	

46	

improvement in steric selectivity is seen over dtbpy. Dehalogenation is not observed in the
reactions.
Boronate products 5a,b and 6a,b (Entries 4 and 5) are derived from parent substrates that
most closely resemble 1 in that the least hindered site is flanked by two Hs, and the second site of
reactivity has a more acidic C–H bond juxtaposed between H and a relatively small substituent, F
or CN. As was the case for borylations of 1, dpm selects for the less sterically hindered site favoring
5a and 6a. In the borylation of 6-chloro-2-fluoropyridine, the bozo ligand shifts selectivity towards
5b, but 5a is still the major isomer. While bozo increases borylation ortho to CN in 1,3dicyanobenzene (Entry 5), conversions for bozo (and bnbozo) are very poor.
Entry 6 (compounds 7a,b) is illustrative of a combination of steric and electronic factors
working in concert to enhance selectivity of a single isomer.

The parent substrate, p-

chlorofluorobenzene, presents a competition between a more acidic H ortho to a smaller
substituent (resulting in product 7a) and a slightly less acidic H ortho to a larger substituent
(resulting in product 7b). All the ligands greatly favor isomer 7a with bnbozo exhibiting essentially
single isomer selectivity.
Entries 7 and 8 (8a,b and 9a,b) assess selectivities for borylations ortho to CN vs. heavier
halogens, Cl and Br, in six-membered ring systems.
With dtbpy, selectivity for borylation ortho to CN in Entry 7 is modest and drops
significantly for the pyridine in Entry 8. The diminished selectivity in Entry 8 is due to electronic
differences between arene and pyridine substrates, as borylation ortho to CN in 4bromobenzonitrile has previously been shown to be favored relative to 4-chlorobenzonitrile.3 The
electronics of the pyridine in Entry 8 render the 4-position electronically activated, although it is
ortho to a bulky Br group. Consequently, the ligands only modestly favor 9a, surprisingly with the

	

47	

most sterically demanding ligand, dpm, resulting in a 1:1 mixture. Bnbozo provides the highest
selectivity despite presenting a high steric demand. In contrast, the aryl substrate of Entry 7 has a
smaller chloro-substituent, yet exerts greater steric direction in the absence of competing electronic
influence, and all ligands favor steric isomer 8a.
The pyridine in Entry 9 (10a,b) presents a competition between the activated 4-position
ortho to a small F substituent, and illustrates the consequence of decreasing the steric bulk of a
pyridyl 3-substituent. Interestingly, dpm modestly favors the steric isomer 10a while the other
ligands favor 10b borylated at the electronically enhanced 4-position, with bozo giving
synthetically useful selectivity of 9:1.
For the 6 membered ring systems, these ligands produce some useful sterically driven shifts
in selectivity when electronic factors are either working in concert or largely absent. For 5membered ring heterocycles, steric effects from neighboring substituents are mitigated, hence
selectivities with dtbpy diminish. Results for the borylation of several 5-membered heterocycles
are shown in Table 2.5. The first three entries are 2,5-disubstituted heterocyclic substrates where
borylation is favored ortho to the smaller CN group. For bnbozo, selectivity is high for 11b, 12b,
and 13b.
It is important to note, that for Entry 2, 2-bromo-5-cyanothiophene, bnbozo is the only
ligand that can efficiently borylate this substrate under the standard conditions.
The dtbpy reaction for Entry 2 turns black and exhibits only stoichiometric borylation of
2-bromo-5-cyanothiophenene. For dpm and bozo, catalyst loading is increased to 6 mol % Ir, and
the catalyst must be generated in HBpin before diluting with solvent, or no reaction occurs. Even
though catalytic turnover is achieved, conversion is low at 40 – 50%.

	

48	

Entry 4 is another 2,5-disubstituted thiophene where borylation competes between a large
iodo substituent and a medium-sized chloro substituent. Again, bnbozo displays high Steric
selectivity for product 14a, though the substrate is less active towards borylation and higher
catalyst loading is needed.
Table 2.5. Ligand Selectivities of C-H Borylation of 6-Membered Arenes and Heterocycles
Het

1

NC

O

Me NC

pinB 11a

2

NC

S

NC

Br

NC

Cl

Me
N Me NC

S

pinB
14a

S

Br

12b Bpin

Me
N Me

I

Cl

S

14b

I
Bpin

[Ir(OMe)(cod)]2

dtbpy

dpm

bnbozo

bozo

5.7:1a

4.8:1

>99:1b
96%
(11a)

17:1

4.6:1c,d 4.9:1c,e 40:1
81%
(55:1)k

5.7:1

2.7:1

13b Bpin

pinB 13a
4f

Me

+ HBpin or
B2pin2

11b Bpin

pinB 12a

3f

O

H

5.7:1a

3.2:1

Het

S

pinB

13:1

12:1b
89%
(14a)

6:1

Bpin

5
15b CN

S

pinB
6h,m

S

16a Cl

32:1b
66%
(13a)

dtbpy

S

15a CN

6.1:1c,e

Bpin

7m

N

Me
N

17a

8

N
Bpin

bozo

(1:4.9)

11:1
82%
(11:1)

6.1:1

1.0:1

Me
N
Bpin 1:9.0a

1:6.3

1:9.0b

1:32n,o
63%l
(17b)

4:1

17b

Bpin
18a

bnbozo

16bCl

O

O

Bpin

dpm

g
[1:1.1]g,h [2.3:1] [1:1]g,h [1:3.2]g
74%i.j
70%i,j
k
(5.5:1)k

Bpin

1:32

1:18

1: >99
93%
(18b)

1:14

18b

Standard conditions: 1 mmol substrate, 1.5 mol% [Ir(OMe)cod]2, 3 mol% ligand, 1.5-2 equiv HBpin,
3 mL THF, reaction times vary from 1-48 h as detailed in SI. Isomer ratios (GC-FID) or single isomer
isolated material in parenthesis where applicable. Yields without ratios are single isomer. a Hexane as
solvent. bEther as solvent. cCatalyst pregenerated in neat HBpin with 6 mol% Ir. No reaction was
observed without catalyst pregeneration. dStoichiometric conversion (6%). eLow conversion, 40-50%.
f
6 mol% Ir. g[GC ratio] in brackets from10-fold excess substrate to eliminate diborylation. hPractical
conditions use 2-fold excess substrate to minimize diborylation to <2%. iPractical conditions use 1
equiv substrate resulting in 12-19% diborylation. jDiborlation changes a:b ratio. kRatio improved by
silica plug. lRecrystallized form hexane. ma:b ratio determined by NMR. n5 mmol scale. o1 equiv
B2pin2	

Entries 5 and 6 are 3-substituted thiophenes where borylation at the 2 and 5 positions
compete. In both cases, dpm favors borylation at the less hindered 5 position, although with the
small CN substituent of Entry 5, significant amounts of 2-borylation occurs. Entry 6 has a Cl
substituent, which is larger than CN, and consequently dpm selectivity for 16a is greater than 15a.

	

49	

Bozo, on the other hand favors borylation at the electronically more activated 2-position. With 3cyanothiophene (Entry 5), pure 15a is isolated by crystallization from the dpm reaction, and pure
15b is isolated by crystallization form the bozo reaction, both in moderate yields. The interesting
feature of Entry 5 is that the selectivity advantage is modest when all diborylation is prevented by
running the reaction with a 10-fold excess of substrate, as the ratios in brackets show. However,
when diborylation occurs, the ratio is enhanced for 15a to 5.5:1 in the dpm system, thus making
crystallization easy after separating diborylated material with a short silica plug in a 1:1
dichloromethane : hexane solvent mixture.
A good illustration of the contrasting effects of sterically driven regioselectivity between
bnbozo and bozo is seen when Entries 5 and 6 are compared. For Entry 5, which has a small 3-CN
substituent, bnbozo gives 1:1 selectivity for 15a:15b (borylation at the 5 vs 2 position), while bozo
is selective for 2-borylation. For the larger 3-Cl substituent in Entry 6, bnbozo gives good
selectivity for 16a, (6.1:1) while bozo gives poor 1:1 selectivity.
For Entry 7, N-methylpyrazine, the steric position is substantially less acidic than the
electronic position, but the electronic positon is ortho to a bulky methyl group.
All ligands favor 2-borylation, 17b, with the smallest ligand, bozo, giving the best selectivity.
Dpm, while still favoring 17b, produces more of isomer 17a than the other ligands. For the last
entry, benzofuran, all ligands greatly favor borylation at the more activated 2-position, 18b, with
bnbozo essentially displaying single isomer selectivity. The intriguing result, however, is bozo, the
smallest of the ligands, shows the lowest ratio for 18b when the only steric demand presented is
the electron pairs of the O atom. Even though bozo produces the lowest ratio at 14:1, it is still
highly selective for 18b.

	

50	

Improving Regioselective Outcomes by Ligand Design. For each substrate in Tables 2.4
and 2.5, the entries with the highest selectivities are highlighted for products that are major
isomers, and isolated yields are given, most resulting in moderate to excellent single isomer
products. Significantly, there is no example where dtbpy, the most commonly used ligand in Ircatalyzed C-H borylation gives superior selectivity.
For the cases where dpm favored the sterically preferred product, comparisons were made
with the more electron rich ligand, dmadpm. The comparisons are shown in Table 2.6.
Improvement in selectivity was seen for products 2a, 3a, 4a, 5a, and 13a, whereas dmadpm
selectivity for 6a and 14a was worse.
Table 2.6. Comparison of dmadpm Selectivities of Selected Substrates
Het

H

Het

or

[Ir(OMe)(cod)]2

H

Het

HBpin or B2pin2

Bpin
or

Het

Bpin

dtbpy

Bpin
pinB

4)
dtbpy

dpm

bnbozo

bozo

6a

pinB
1)

1.8:1a

F

2a

Cl

F

Cl

2.3:1a,b
(28% 2a)c

1:2.4

2b

1:3.3a,b,d
(65% 1:3.6)e
(34% 2b)f

11:1
(71% 2a)c

F
Cl

N
10a

pinB

S

pinB
3:1
4a
Bpin

F

I

6.8:1

1:1.3

1:2.6

I

16:1
(65% 4a)c

pinB
3)

6.5:1

F

N
5a

Cl

F

N

Cl

23:1
(91% 5a)c

4.5:1

4.8:1

3:1

1.2:1

6:1
(79% 7.5:1)e
(32% 6a)h

1:1.6

1.5:1
(30% 3:1)c

1:4.5

1:8.5
(66% 1:9)c

2.3:1
60% (2:1)e
38% (17:1)i
16% (10a)f

1:1.1j

5.5:1j
(74% 5.5:1)e
(43% 13a)i

1.0:1j

1:3.2j
(70% 1:3.2)e
(36% 13b)i

5:1k
(80% 10:1)c

1.0:1k,l

10:1k,l
(84% 10:1)e

N
10b

Cl
S

13a CN

pinB

38:1
(97% 5a)c

S

Bpin

13b CN

S

Bpin
4:1k,l

7)

5b

14a

Cl

dmadpm

6b
Bpin

6)

4b

bozo

CN

Bpin F

5)

Bpin
2)

F

CN NC

CN

bnbozo

12:1
(74% 6a)g

4.5:1

dmadpm

Bpin

dpm

14b

Cl

11:1k,l
6.1:1k,l
(97% 11:1)e

Standard conditions: 1 mmol substrate, 1.5 mol% [Ir(OMe)cod]2, 3 mol% ligand, 2 equiv HBpin, 3 mL
THF, reaction times vary from 1-48 h as detailed in SI. Isomer ratios (GC-FID) or single isomer isolated
a
b
material in parenthesis where applicable. Yields without ratios are single isomer. Hexane as solvent. 4
c
d
e
equiv substrate. Isolation by silica plug with hexane. 1 equiv B2pin2. Isolated by silica plug with
h
f
g
CH2Cl2. Recrystallized twice from hexane. Isolation by kugelrohr distillation. Recrystallized from
i
j
ethanol. Recrystallized once from hexane. 12-15% diborylation. Ratio of 13a:13b is changed
k
l
significantly by diborylation when dpm is used as ligand. 2 equiv substrate, 2-5% diborylation. Ratio
a:b determined by NMR.	

In the case of 5a, the selectivity was sufficiently high that a 95% isolated yield of pure 5a
could be obtained at a low catalyst loading (Scheme 2.4).

	

51	

Scheme 2.4. Highly Selective Borylation Meta to Fluorine	
Bpin

0.25 mol % [Ir(OMe)(cod)]2
0.5 mol % dmadpm
2.0 equiv HBpin

Cl

N

THF, rt, 5 h

F

95% yield,
isomeric purity > 99:1

Cl

N
5a

F

Expanding Synthetic Options for C-H vs C-X Borylation Routes. The utility of the ligand
and borane reagent-modulated selectivity that we have developed is showcased in Figure 2.3. C-H
borylations are compared to putative C–X borylations (X = Br or I) of the type pioneered by
Miyaura. Factors that would be considered in choosing between these routes are selectivity for the
desired product and the price of reagents.
Figure 2.3. Comparisons Between C–H and C–X Borylation Routes
Y

Y

Y

Y

CN
F

Cl
Y

$/g

H
Br

0.69
0.50
Bpin
Het

N

Cl
Y

F

NC

CN

S
Br
Y

$/g

Y

$/g

H 2.30
Br 1500

H
Br

0.11
428

H 7.50
I unknown

B2pin2 or
HBpin,
Ir catalyst

Bpin

B2pin2 or
HBpin,
Pd catalyst
Y = Br, I

Y
Het

Y=H

$/g

Het

For the synthesis of 2a, the high regio-specificity of the Miyaura borylation and the low
cost of the aryl bromide substrate make it the route of choice. In contrast the aryl and heteroaryl
halides that would be required for Miyaura coupling routes to 5a, 6a, or 12a range from being
costly to nonexistent. It is noteworthy that directed ortho metalations of substrates where Y = H
followed by trapping with boron electrophiles will not give 5a or 6a as major isomers, and bromothiophenes are known for halogen dance rearrangements. Therefore, Ir-catalyzed C–H borylation
is the best option for the synthesis of isomers 5a, 6a, and 12a.

	

52	

Variation of Regioisomer Ratios with Borane Concentration. These Studies show that
ligand modifications can dramatically improve regioselectivity in C–H borylations of substrates
where the most commonly used ligand, dtbpy, gives isomer mixtures that can limit synthetic utility.
In addition, we have shown for the first time that the nature of the boron reagent can significantly
affect the regioselectivity in C–H borylation. Considering the dramatic effect that the borane
source has on the selectivity of dpm and dmadpm borylation reactions, we decided to further probe
the source of this disparate reactivity between HBpin and B2pin2 with the dpm-type ligands.
Table 2.7. Changes in 2a:2b GC Ratio over Time as Concentration of HBpin Changes
1.5 mol % [Ir(OMe)(cod)]2
3.0 mol % dmadpm
0.5 equiv B2pin2

Cl

Bpin

THF, rt, 48 h

F

F

F

1

Entry

Cl

Cl

2a

Bpin
2b

Time (h)

Conversion

Ratio 2a:2b

1

1

2

2

6%
10%

1.3:1.0
1.4:1.0

3

6

16%

1.8:1.0

4

12

31%

3.7:1.0

5

20

55%

4.8:1.0

6

24

64%

4.8:1.0

This effect was first noticed when preliminary borylation tests performed on 1 with
dmadpm ligand suffered a lack of consistency among various reaction conditions with varied
amounts of HBpin used to pre-generate the catalyst, and the choice of 1.0 equiv B2pin2 or 0.5 equiv
B2pin2. In order to eliminate the variability of dispensing HBpin, no HBpin was added to
subsequent reactions, and 0.5 equiv B2pin2 was chosen as the borane stoichiometry for the next
round of experiments. When the reactions were monitored by GC over time, the ratios of 2a:2b
changed as the reaction proceeded, as seen in a Table 2.7.

	

53	

A summary of the range of ratios obtained based on the type and amounts of borane reagent
used in the reaction is seen in Table 2.8. This result is striking in itself, but it is particularly
noteworthy in context of the well-established borylation kinetics of Boller and Hartwig,30
published in 2005. In their paper, it was established that borylation reactions of [Ir(OMe)cod]2 /
dtbpy with B2pin2 are zero order in B2pin2, and the reaction rates are dependent only on the
concentration of arene present in the reaction. The borylation of 3-fluorochlorobenzene with the
ligand dmadpm as seen in Tables 2.7 and 2.8 did not seem consistent with a reaction that is zero
order in borane, so we wondered if the catalytic cycle for dmadpm and HBpin is significantly
different than that of dtbpy.
Table 2.8. Selectivity of dmadpm in the Borylation of 1 Varies with Borane Reagent.
1.5 mol % [Ir(OMe)cod]2
3.0 mol % dmadpm
Boron Reagent

F

F

F

Bpin

Bpin

THF rt

Cl

Cl 1

Boron source

2a

Cl

2b

Ratio a : b

1.0 equiv B2pin2

2.4 : 1.0

0.5 equiv B2pin2

3.6 : 1.0

1.1 equiv B2pin2

10.3 : 1.0

2.0 equiv HBpin

11.1 : 1.0

Kinetic Studies of Ligand and Borane Combinations. We decided to subject the ligand
dmadpm to the kinetics experiments performed in the Boller-Hartwig studies to see if dmadpm
adhered to the accepted catalytic cycle where C-H activation is the rate limiting step and the
catalytic cycle is zero order in borane. A key difference between our studies and the work of
Boller and Hartwig is that their work employed the isolated cyclooctene (coe) adduct of the dtbpy
ligated Ir tris-boryl intermediate (26) as the catalyst instead of generating a catalytic species from
[Ir(OMe)cod]2 and dtbpy.
	

54	

Scheme 2.5. (coe)Ir(dtbpy)Bpin3, 26, does not enter the catalytic cycle or impact the order
of borane.

L
L

Bpin
Bpin
Ir Bpin

26

-coe

K1
K-1

L
L

Bpin
Bpin + coe
Ir Bpin

27
coe = 1,2-cis-cyclooctadiene

Unfortunately, the isolation of an analogous dmadpm ligated Ir trisboryl complex is
ongoing, and so an isolated intermediate was not available to our kinetics study. Instead, we
generated the catalyst from [Ir(OMe)cod]2 and dmadpm ligand at the beginning of each kinetics
experiment.
The purpose of using the preassembled dtbpy tris-boryl iridium complex in the 2005
kinetics studies was to avoid complications arising from the kinetics of catalyst assembly from
[Ir(OMe)cod]2 and free dtbpy. In keeping with Halpern’s maxim31 that true reaction intermediates
are almost never isolable, Boller and Hartwig showed that 26 is a catalyst resting state, and there
is a rapid and reversible dissociation (shown in Scheme 2.6) of coe to form a 16-electron
intermediate, 27, which is the actual participant in the proposed catalytic cycle, as shown in
Scheme 2.7.30 Since 26 does not directly react with arenes, or participate in the catalyst cycle, it
cannot give us information about the order in borane. Although it may affect the rates of reactions,
generation of the active catalyst species from [Ir(OMe)cod]2 and free ligand instead of a dmadpm
analogue of 26 should reliably provide an accurate assessment of whether borylation reactions
with dmadpm are zero order in borane.

	

55	

Scheme 2.6. Dissociation of 26, (coe)Ir(dtbpy)Bpin3 generates the active catalyst, 27.
-coe

Bpin
Bpin
Ir Bpin

L
L

K1
L
L

K-1

26

Bpin
Bpin + coe
Ir Bpin

27

K1 =

[27][coe]
[26]
[27]2
[26]

K1 =

since [27] = [coe]

Scheme 2.7. Intermediate 27 enters the catalytic cycle after dissociation of 26.

(dtbpy)Ir(Bpin)3(coe)
26

K1
(- coe)
K-1
(+ coe)

HBpin

L
L

Bpin
Bpin
Ir Bpin

27

arene

K2
K-2

Bpin
Bpin
L Ir H
L
Bpin

Bpin
Bpin
Ir H
L
Bpin
Bpin

L

B2pin2
L
L

Bpin
Bpin
Ir H

Bpin

The rate equation of Ir catalyzed borylation was determined experimentally by Boller and
Hartwig from stoichiometric reactions of 26 and benzene,30 as shown below labeled as equation 1.

rate = K1k2[Ir][arene]/[coe]

	

56	

(eq. 1)

Although equation 1 forms the foundation for understanding the catalytic cycle of the
[Ir(OMe)cod]2/dtbpy system, in practice, catalytic borylation reactions do not have a direct
dependence on coe concentration due to the low catalyst loadings of 1 – 3 mol % that are
typically employed. Boller and Hartwig also showed that the equilibrium for the dissociation of
26 into (27 + coe) lies far to the left, favoring the associated coe-adduct over the dissociated
active species, 27, which results in a concentration dynamic of [coe] << [26] << [arene].30 The
rate equation for catalytic borylation with 26 can be simplified and rearranged to equation 2.

rate = K1½ k2[26]½[arene]

(eq. 2)

For Ir-catalyzed reactions, the rate can be expressed in terms of an experimentally observed
rate constant, kobs, which encompasses the pre-catalyst assembly into 26 and dissociation into 27.
After the establishment of the initial catalytic cycle, kinetic studies demonstrate the reaction
depends only on how much arene is present, and exhibits rates consistent with equation 3.30

rate = kobs [arene]

(eq. 3)

set eq. 1 = eq. 2: kobs = K1½ k2 [26]½

By setting equations 1 and 2 equal to each other, an expression is derived where the rate
constants can be calculated if the concentration of the precatalyst 26 is known. This is another
advantage to using an isolated precatalyst rather than in situ generation of an active species.
Detailed mechanistic and kinetics experiments by Boller and Hartwig demonstrate a clear
first order dependence in arene concentration and a zero order dependence in B2pin2

	

57	

concentration.30 Changing the ligand of the active catalyst species from one substituted pyridylbased ligand to another would be expected to follow a similar reaction profile, though the observed
rate would vary according to the properties imparted by the ligand.
In the case of dmadpm, however, the considerable difference in rate and selectivity seen
between HBpin and B2pin2 does not support Boller and Hartwig’s observed zero order behavior in
borane concentration. The effect of HBpin as the boron source was not investigated in Hartwig’s
paper, and the authors chose 1.6 equiv of B2pin2 as a standard condition in the kinetic studies, thus
ensuring that B2pin2 was always available as a boron source. They offered the observation that
“The simplest data were obtained when the concentration of B2pin2 exceeded the concentration of
arene.”30
The search for a plausible explanation behind the divergent reactivity of HBpin vs B2pin2
in the dmadpm ligated system led to the design of a series of experiments analogous to the kinetic
studies detailed in the 2005 Boller-Hartwig paper,30 where a series of NMR tube reactions were
performed with fluorine-containing substrates, and the borylation reactions were monitored by 19F
NMR. This approach was adapted to the dmadpm system using the substrate of interest, 3fluorochlorobenzene, and the boron reagents HBpin and B2pin2.
The starting point for this investigation was to replicate the published results in the lab and
then adapt a procedure suitable to the dmadpm system. Since we did not have an isolated dmadpm
tris-boryl intermediate, the first task in the investigation was to ensure that the assembly of the
active catalyst from [Ir(OMe)cod]2 and dmadpm did not significantly change the outcome of Boller
and Hartwig’s experimental observations.
We first synthesized 26 and repeated Hartwig’s initial experiment of the borylation of 3trifluomethyltoluene 17, with 1.6 equiv (0.49 M) B2pin2 in cyclohexane, (Experiment 1, Scheme

	

58	

2.8). The reactions were assembled in the glove box, transferred into screw cap NMR tubes, and
the substrate was injected just before monitoring of the reaction by an arrayed

19

F NMR

experiment.
Scheme 2.8. NMR Tube Conditions: Experiment 1 of Kinetics Study
Me

CF3

0.00188 M (dtbpy)Ir(Bpin)3(coe)
0.492 M B2pin2

Me

CF3

Cyclohexane 30°C 19F NMR
0.299 M

Bpin
18

17

The first order plot was linear and kobs was on the order of Hartwig’s reported value. See
the Chapter 2 appendix for all detailed information regarding the kinetics experiments, including
concentrations of reagents and graphs and kobs values.
Next, 17 was borylated under pseudo-first order conditions with 26 and 4.5 equiv (1.3 M)
B2pin2 in cyclohexane (Experiment 2). The kobs was slightly lower than Experiment 1, but matched
Hartwig’s reported values. Although they were not the same, the kobs values of Experiments 1 and
2 were on the same order of magnitude, within a multiple of 3, and the first order plots for both
were linear over 4 half–lives.
Next, the catalyst was generated from [Ir(OMe)cod]2 and dtbpy (Ir/dtbpy) for the standard
borylation of 17 with 1.6 equiv (0.49 M) B2pin2 (Experiment 3, Scheme 2.9 and the graph seen in
Figure 2.4).
This produced a linear first order plot with the same kobs that Hartwig reported, so it seemed
that catalyst generation did not affect the behavior of the reaction. The substrate of interest for the
dmadpm system is 3-fluorochlorobenzene, 1, and so the next step required the borylation of 1
using complex 26 and 0.49 M B2pin2 in cyclohexane (Experiment 4).

	

59	

Scheme 2.9. Borylation with B2pin2 by generating the catalyst from [Ir(OMe)cod]2
gives the same result as catalysis from 26. (Exp. 3)
Me

3 mol % [Ir(OMe)cod]2
6 mol % dtbpy
1.6 equiv B2pin2

CF3

Me

THF, 25°C 1 h
monitored by 19F NMR

17

CF3

Bpin

18

Figure 2.4. Borylation of 17 with B2pin2 by generating the catalyst from
[Ir(OMe)cod]2 gives the similar result as catalysis from 26. (Exp. 3)
ln[Ar]t/[Ar]0 vs	time	
Ir	/dtbpy	 +	3-CF 3-toluene	 +	1.6	B2pin2
-0.1

ln[Ar]t/[Ar]0

-0.3
-0.5
-0.7
-0.9

y	=	-2.110E-04x	+	1.006E-01
R²	=	9.957E-01

-1.1
-1.3

0

1000

2000

3000

4000

5000

6000

Time	(seconds)

A second borylation of substrate 1 with the active catalyst generated from Ir/dtbpy with
0.49 M B2pin2 in a different solvent, THF, was also run (Experiment 5, as seen in Scheme 2.10).
The reactions progressed too rapidly to be followed by NMR with the same conditions as
the more electron rich substrate 17. The temperature was lowered from 30°C to 25°C and the
catalyst load was halved from 0.018 M to 0.009 M (6 mol % lowered to 3 mol %). The kobs values
of the reactions catalyzed by 26 in cyclohexane and the reaction of Ir/dtbpy in THF were within
5% of each other, with the THF reaction slightly faster.
Both first order plots were linear, both with R2 values of 0.997. The ratios of 2a:2b for
Experiment 4 (catalyzed by 26 in cyclohexane) was 1.5:1, compared to Experiment 5 (Ir/dtbpy
reaction in THF) 2a:2b ratio of 1.9:1. This solvent effect is consistent with observed ratio
differences of 2a:2b in the borylation reactions of 1 run in THF compared to hexane.

	

60	

Scheme 2.10. Borylation of 3-Fluorochlorobenzene, 1, with B2pin2 by generating the catalyst
from [Ir(OMe)cod]2 gives the same result as catalysis from 26. (Exp. 5)
F

Cl

1.5 mol % [Ir(OMe)cod]2
3 mol % dtbpy
1.6 equiv B2pin2

F

Cl

F

Cl
+

Bpin

THF, 25°C 1 h
monitored by 19F NMR

Bpin

1

2a

2b

Figure 2.5. Borylation of 1 with generated catalyst gives comparable data. (Exp. 5)
ln[Ar]t /[Ar]0 vs	time
Fluorochlorobenzne	 +	1.6	B2pin2 3	mol%	Ir	/	dtbpy
0.5
0
-0.5
-1

ln[Ar]t /[Ar]0

-1.5
-2
-2.5
-3
-3.5
-4

y	=	-1.04E-03x	+	1.75E-02
R²	=	9.93E-01

-4.5
-5

0

1000

2000

3000

4000

5000

Time	(seconds)

Next, 1 was borylated with Ir/dmadpm, and 0.49 M B2pin2 in THF (Experiment 6). The
reaction was too slow to provide useful kinetic data, so the temperature was increased from 25 °C
to 50 °C, while the catalyst concentration was kept 0.009 M. The reaction was much slower than
dtbpy ligated reaction, with a kobs of 6.5 x 10-5 s-1. In 5 hours, 57% conversion was observed with
a 2a:2b ratio of 2.5:1. The first order plot was linear with an R2 of 0.990.
The fact that the first order plots were linear, the kobs values were repeatable, the data was
reasonable and in line with reported values, it was determined that these kinetics conditions were
suitable to study the dmadpm system of the borylation of 1 in THF. After confirmation that
dmadpm provided useful kinetic data, and was zero order in B2pin2 for the prescribed B2pin2
concentrations, the next step was to test whether HBpin likewise exhibits zero order behavior in
borylation reactions.

	

61	

Experiment 7 was a repeat of Experiment 1 (catalyzed by 26 with B2pin2 and substrate 17
in cyclohexane) except using 2 equivalents of HBpin (0.64 M) instead of B2pin2. (2 equiv is the
stoichiometry where the 2a:2b ratio is the greatest, 11:1). Even though 17 will not form mixtures,
the borane was kept at the same stoichiometry as the reaction of interest. Experiment 7 was carried
out at 30 °C and 0.018 M in 26. The reaction was very slow and in 2.5 hours, only 30% conversion
was realized. The first order graph was not linear. This reaction was not zero order in borane.
Experiment 7 conditions were repeated with substrate 1 in cyclohexane with 0.64 M HBpin
at 50 °C (Experiment 8, shown in Scheme 2.11). In 2 h, 88% conversion was realized with a 2a:2b
ratio of 2:1. The first order plot was not linear. The second order plot, however, appeared linear
with an R2 of 0.999. The second order kobs was 0.04 M-1s-1. To compare the effect of HBpin to
B2pin2 on selectivity, the ratios of reactions 4 and 8 are compared, Reaction 4 (26-catalyzed
borylation of 1 with B2pin2 in cyclohexane) gave a ratio of 1.5 :1. The same reaction conditions
with HBpin in experiment 8 gave a 2:1 ratio.
Scheme 2.11. 26-catalyzed Borylation of 1 with HBpin is not zero order in borane. (Exp. 8)
3 mol % (dtbpy)Ir(Bpin)3(coe)
2 equiv HBpin

F

Cl

+

Bpin

cyclohexane, 50°C 2 h
monitored by 19F NMR

0.296 M
1

F

F Cl

Cl

Bpin

2a

2b

Figure 2.6. Borylation reactions with HBpin appear to be second order in arene. (Exp. 8)
(coe)Ir(dtbpy)Bpin3 +	2	equiv	HBpin	
3-Fluorochlorobenzene:	 1/[Ar]	vs	time	(seconds)	

(coe)Ir(dtbpy)Bpin3 +	2	equiv	HBpin
3-Fluorochlorobenzene:	 ln[At]t/[Ar]0 vs	time	

1800
1600
1400

-0.6

1/[Ar]	M -1

ln	[Ar]t	/	[Ar]0

-0.1

-1.1

1200
1000

-1.6
-2.1

y	=	3.85E-01x	+	3.56E+02
R²	=	9.98E-01

600
400
0

500

1000

1500

2000

2500

3000

3500

200

4000

0

Time	(seconds)	

	

800

1000

2000
Time	(seconds)

62	

3000

4000

It was confirmed that borylation reactions with 2 equiv HBpin are not zero order in borane,
and this behavior holds among different substrates, ligands and solvents, not just dpm type ligands.
Figure 2.2 shows the first and second order plots for the borylation of 1 with 2 equiv HBpin
catalyzed by the isolated intermediate 26. Even for with the assembled precatalyst, the order in
borane depends on the boron source.
After control experiments were evaluated, borylation of 1 with HBpin and the ligand
dmadpm was tested. Ir/dmadpm catalyzed borylation of 1 with 0.64 M HBpin at 30 °C was very
slow and less than 50% conversion was reached in 12 h. The reaction was repeated at 40°C but it
was still too slow. These two initial experiments did not provide usable kinetic data, but the ratios
of 2a:2b were both 11:1 as determined by integration of 19F NMR.
Scheme 2.12. Comparison of 2 Equiv HBpin vs Pseudo-First Order HBpin with dmadpm
(Experiments 9 and 10)	
1.5 mol %[Ir(OMe)cod]2
3 mol % dmdpm

F

Cl

Exp. 9: 2 equiv HBpin
Exp. 10: 5 equiv HBpin

F

Cl
+

Bpin

THF, 50°C 2.5 h
monitored by 19F NMR

1

F

Cl

Bpin

2a

2b
																	
	
Figure 2.7. Borylation of 1 with dmadpm and HBpin. (Experiments 9 and 10)

0
-0.2

ln[Ar]t/[Ar]0 vs	time
3-Fluorochlorobenzne	 +	Ir	/	dmadpm	+	5	equiv	HBpin

ln[Ar]t/[Ar]0 vs	time	
3-Fluorochlorobenzne	 +	Ir	/	dmadpm		+	2	equiv	 HBpin	
0

10000

20000

30000

0

40000

0

2000

3000

4000

5000

6000

-0.5

-0.4
-0.6

ln[Ar]t/[Ar]0

ln[Ar]t/[Ar]0

1000

-0.8
-1
-1.2
-1.4

-1
-1.5
-2

-1.6

-2.5

-1.8

Time	(seconds)

y	=	-3.59E-04x	- 1.06E-01
R²	=	9.92E-01
Time	(seconds)

The first order plots were not linear, but there was not enough conversion to make any
inference from the experiments. The experimental conditions were repeated at 50°C (Experiment

	

63	

9), and 79% conversion was reached in 12 h. The first order plot was not linear, while the second
order plot was linear with an R2 of 0.998. The second order kobs was 0.0029 M-1s-1. Heating the
reaction to 50°C resulted in a lower 2a:2b ratio of 7.5:1.
The next reaction (Experiment 10) explored the borylation of 1 under pseudo first order
HBpin concentration. Ir/dmadpm catalyzed borylation of 1 with 1.6 M HBpin in THF at 50°C over
5 h resulted in 97% conversion, and a 2a:2b ratio of 11:1. The first order plot was approximately
linear over 3 half-lives with an R2 value of 0.982. The kobs over the reaction was 0.00029 s-1. The
second order plot was not linear.
It was interesting to observe that 2 equivalents of HBpin resulted in a non- zero order in
borane, with a linear second order plot, but the borylation of 1 under pseudo first order
concentrations of HBpin (Experiment 11) produced an approximate zero order behavior, yet also
exhibited the increased 2a:2b ratio of 11:1.
Since these experiments infer that concentrations of borane do matter, we wondered what
effect would be seen from the 26-catalyzed reaction of 1 in cyclohexane with exactly 1.0 equiv
B2pin2 (0.3 M), (Experiment 12). Over 3 half-lives, the first order plot is linear with R2 value of
0.997 and kobs of 0.0017 s-1. 3 half-lives are reached in 20 minutes. After that, the rate slows rapidly
and the linearity is lost. Full conversion is seen over 2 h, with a 2a:2b ratio of 1.6:1.

Scheme 2.13. Borylation Reactions with 1.0 equiv B2pin2 (Exp. 12)	
F

Cl

3 mol % (dtbpy)Ir(Bpin)3(coe)
1 equiv B2pin2
cyclohexane rt 2 h
monitored by 19F NMR

1

	

F

Cl

Bpin
Bpin
2a

64	

F

Cl
+

2b

Figure 2.8. First order Plot of Borylation Reaction with 1.0 equiv B2pin2 (Exp. 12)		
3-Fluorochlorobenzene	 +	1.0	 equiv	B2pin2 +	
(coe)Ir(dtbpy)Bpin3 ln[Ar]t/[Ar]0 vs	Time
0
-0.5
-1

ln[Ar]t/[Ar]0

-1.5
-2
-2.5
-3
-3.5

0

1000

2000

3000

4000

Time	(seconds)

The last kinetics experiment (Experiment 13) repeated the conditions of Experiment 12
with 0.5 equiv B2pin2 (0.16 M). The initial rate was rapid, and 11% conversion was seen by the
first spectrum about 60 s after the substrate was injected. The first half life was reached at 9
minutes, but then the reaction began to slow rapidly and over 2 h, only 67% conversion was
realized, less than 2 half-lives. The first and second order plots are not linear over any part of them.
The differences in rate and the non-linear first order graphs made us wonder if the HBpin
borylation went through a different catalytic cycle than B2pin2. We carried out competitive
borylation experiments on an equimolar mixture of D6-benzene and H6-benzene. The results were
compared to KIE studies from the Boller-Hartwig paper.30
KIE Studies of Ligands and Borane. The linear nature of the second order plots
constructed from reactions with excess HBpin suggests that the rate depends not only on the
concentration of arene but also on the concentration of another reaction species. If a large primary
isotope effect is observed, it will suggest that the CH activation step is still rate limiting but has
been slowed or subjected to an equilibrium involving another species somehow. If there is no large
isotope effect, it will suggest the possibility, (although not the certainty), that a different catalytic
cycle has been activated and C-H activation is no longer the rate limiting step.

	

65	

The KH/KD is calculated from the ratio of protiated to deuterated products. These products
can be separated by a slow ramping GC-MS method with a long isothermal plateau. The products
can then be quantified by a quantitative integration program based on calibration curves of the
pure H5 and D5 phenyl-Bpin products. Conversion was assessed by

11

B NMR and by use of

dodecane as an internal standard for quantitative mass spec analysis.
The initial reactions were followed as written in the Boller-Hartwig paper, but significant
amounts of diborylation, both protiated and deuterated resulted.
It was not clear if the investigators missed diborylated byproducts by having too short of a
GC-MS method or if it was an oversight where the wrong protocol was included in the manuscript
by mistake. The first task of this investigation was to determine if the published KIEs were
accurate. To that end, a procedure was developed that avoided diborylation, and a quantitative GCMS method was developed to accurately measure the amounts of D5- and H5-phenyl Bpin
produced.
The faulty procedure is most likely an oversight in the manuscript preparation rather than
missing diborylated byproducts, as the KIE values from our early attempts with significant
diborylation produced KH/KD ratios the range of 3.0 – 3.4, lower than the reported range of 5.0 ±
0.4.
In an attempt to optimize the reaction, the ratio of the mix of benzenes was increased from
a 6-fold excess (3 equiv per benzene species) to a 10-fold increase (5 equiv per benzene species).
Still, intrusive amounts of diborylation (~10%) plagued the reaction. The reaction times were
significantly shortened to an hour and still diborylation was not eliminated, though it was limited
to about 2-5%. In the reactions with a 10-fold excess of benzenes, the diborylated products did not

	

66	

contain the mass of 334 by GC-MS, indicating no deuterated diborylated phenyl-Bpin was
produced.
To avoid wasting large amounts of deuterated benzene, the amount of B2pin2 in the reaction
was decreased from 1.5 mmol to 0.1 mmol, a reduction from 200 mg to 25 mg. Under 10 mmol of
benzenes per 0.1 mmol B2pin2, essentially at 100-fold excess, the reaction did not produce
diborylation. These conditions were used for all subsequent analyses in this investigation. Also, to
check for variation of KIE ratios, the reactions were sampled at various points in the reaction, from
very early conversion to late conversion up to a day after completion of the reaction.
The optimized conditons under which all KIE experiments were run is shown in Scheme
2.14.
Scheme 2.14. The Modified Conditions for the Competitive Borylation Experiment of the
KIE Studies

D6

+ H6

50 equiv

1.5 mol% [Ir(OMe)cod]2
3.0 mol% dmadpm
2.0 equiv Boron
dodecane rt

D5

Bpin
+ H5

Bpin

50 equiv

Scheme 2.14. The modified conditions used for competitive borylation in the KIE study of
dmadpm. Benzene and d6-benzene ratios were increased, and the reaction scale was reduced to 0.1
mmol B2pin2 to prevent diborylation. (1 equiv B2pin2 = 2 equiv Boron).
The reactions were carried out in 20 mL vials equipped with stir bars or put into NMR
tubes to monitor conversion by 11B NMR. Rate and conversion of the NMR tube reactions were
much lower than the reactions in vials, but KIE ratios remained within a small range of values, and
KIE values did not change significantly over the course of the reactions nor did they differ
depending in which reaction vessel the reactions were run.
Reaction conversion was assessed by 11B NMR and GC-MS. KH/KD ratios were determined
by quantitative GC-MS methods using dodecane as internal standard as described in the supporting

	

67	

information. The average KIE values for the ligands dtbpy and dmadpm for the competative
borylation of C6D6 / C6H6 with HBpin and B2pin2 are summarized in Table 2.9.
Table 2.9. Results of Borylation KIE Experiments for dtbpy and dmadpm with B2pin2 and HBpin

Entry

ligand

Borane

Avg. KIE

1

dtbpy

B2pin2

5.0 ± 0.4

2

dtbpy

HBpin

5.0 ± 0.4

3
4

dmadpm
dmadpm

B2pin2
HBpin

3.8 ± 0.3
4.2 ± 0.3

The KIEs obtained for Ir-catalyzed C-H borylation with dmadpm as the ligand and HBpin
or B2pin2 as the borane are on par with dtbpy KIE values for the same systems, as they are large
primary isotope effects. Both dtbpy and dmadpm catalytic cycles appear to have C-H activation as
the rate limiting step and that does not change when HBpin is the borane source.
In summary, the order in borane for both dtbpy and dmadpm ligands is zero order when
B2pin2 is in excess, but deviates significantly when HBpin concentration becomes dominant. When
HBpin is present in pseudo first order amounts, the order in borane is roughly zero again. The
deviation in the catalytic cycle appears to be related to HBpin and not the ligand. Noteworthy,
however, for dtbpy, the product ratios do not differ significantly between borylation with B2pin2
vs HBpin, whereas there is a considerable difference in ratios for dmadpm. The reason behind this
behavior is not clear, and more kinetic studies are needed to clarify the role of HBpin, although it
is clear that the reaction rates are inhibited as the concentration of HBpin becomes significant.

	

68	

APPENDIX

	

69	

Kinetics Experiment 1: (coe)Ir(dtbpy)Bpin3 with Excess B2pin2 on 3-Trifluoromethyltoluene
Scheme 2.15. Experiment 1
Me

0.00188 M (coe)Ir(dtbpy)Bpin3
0.492 M B2pin2

CF3

Cyclohexane 30°C
monitored by 19F NMR

0.299 M

Table 2.10. Experiment 1 Table of Reactants
FW
Reagent
vol(mL) d (g/mL) (g/mol)
3-CF3-tol
0.025
[(COE)Ir(dtbpy)bpin3]
B2pin2
xxxx
C6F6
0.009
cyclohexane
0.60

Me

1.148
xxxx
xxxx
1.612

160.14
886.62
253.94
186.06

CF3

Bpin

mass
(g)

mols

rxn vol
(mL)

0.029
0.010
0.075
1.45E-02

1.79E-04
1.13E-05
2.95E-04
7.80E-05

0.60
0.60
0.60
0.60

[reagent] M

sm14-6	:	ln[Ar]t	/[Ar]0		vs	;me	
3-CF3-toluene	+	6	mol%	[1]	+	1.6	B2pin2		
0	

ln[Ar]t	/[Ar]0				

0	

500	

1000	

1500	

2000	

2500	

-0.4	
-0.6	

ln	[Ar]t/[Ar]0	

-0.8	
-1	
-1.2	
-1.4	

	

3000	

y	=	-3.42E-04x	-	4.45E-02	
R²	=	9.97E-01	
Time	(seconds)	

70	

3500	

mol ratio

2.99E-01
1.000
1.88E-02
0.063
4.92E-01
1.648
1.30E-01
0.435
70% conversion

Figure 2.9. Experiment 1 First Order Plot

-0.2	

(6 mol% Ir)

4000	

Kinetics Experiment 1 continued: (coe)Ir(dtbpy)Bpin3 with Excess B2pin2 on 3-Trifluoromethyltoluene at One Half-Life
Scheme 2.15. Experiment 1 continued

Me

CF3

0.299 M

0.00188 M (coe)Ir(dtbpy)Bpin3
0.492 M B2pin2

Me

Cyclohexane 30°C
monitored by 19F NMR

CF3

Bpin

Conversion = 70%
Figure 2.10. Experiment 1 First Order Plot at First Half-Life

sm14-6:	ln[Ar]t	/[Ar]0		vs	;me	at	first	half	life	
3-CF3-toluene	+	6	mol%	[1]	+	1.6	B2pin2		
0	
-0.1	

0	

500	

1000	

1500	

2000	

ln[Ar]t	/[Ar]0			

-0.2	
ln	[Ar]t/[Ar]0	

-0.3	
-0.4	
-0.5	
-0.6	

y	=	-3.78E-04x	-	1.27E-02	
R²	=	9.99E-01	

-0.7	
-0.8	

	

Time	(seconds)	

71	

Kinetics Experiment 2: (coe)Ir(dtbpy)(Bpin)3 Pseudo-First Order in B2pin2 on 3-Trifluoromethyltoluene

	
Scheme 2.16. Experiment 2
	

Me

CF3

0.00188 M (coe)Ir(dtbpy)Bpin3
1.31 M B2pin2

Me

CF3

cyclohexane, 30°C
monitored by 19F NMR

0.299 M

Bpin

Table 2.11. Experiment 2 Table of Reactants
Reagent
vol(mL)
3-CF3-tol
0.025
[(COE)Ir(dtbpy)bpin3]
B2pin2
xxxx
C6F6
0.009
cyclohexane

FW
(g/mol)
160.14
886.62
253.94
186.06

d (g/mL)
1.148
xxxx
xxxx
1.612

mass (g)
0.029
0.010
0.200
1.45E-02

rxn vol
(mL)
0.60
0.60
0.60
0.60
0.60

mols
1.79E-04
1.13E-05
7.88E-04
7.80E-05

[reagent]
M
mol ratio
2.99E-01
1.000
1.88E-02
0.063
1.31E+00
4.395
1.30E-01
0.435
72% conversion

Figure 2.11. Experiment 2 First Order Plot
sm14-12: ln[Ar]t/[Ar]0 vs time
CF3-toluene + [1] + 4.5 B2pin2 at 30°C
0	
-0.2	

0	

1000	

2000	

3000	

ln [Ar]t /[Ar]0

-0.4	

4000	

5000	

y	=	-1.930E-04x	-	5.221E-02	
R²	=	9.978E-01	

-0.6	
-0.8	
-1	
-1.2	
-1.4	
-1.6	

	

6000	

Time in seconds

72	

7000	

8000	

	

Kinetics Experiment 3: Catalyst Pre-Generated from [Ir(OMe)cod]2 and dtbpy on 3-Trifluoromethyltoluene
Scheme 2.17. Experiment 3
Me

CF3

0.299 M

0.0063 M [Ir(OMe)cod]2
0.0124 M dtbpy
0.492 M B2pin2

Me

cyclohexane, 31°C 2 h
monitored by 19F NMR

CF3

Bpin

Table 2.12. Experiment 3 Table of Reactants
FW
stock soln
Reagent
vol(mL) d (g/mL) (g/mol)
mass (g)
mols
M
3-CF3-tol
0.0250
1.148
160.14
0.029
1.79E-04
xxxx
[Ir(OMe)cod]2 2.50E-01
xxxx
663
2.50E-03
3.78E-06
1.51E-02
dtbpy
xxxx
xxxx
268.4
0.002
7.45E-06
xxxx
B2pin2
xxxx
xxxx
253.94
0.075
2.95E-04
xxxx
C6F6
not added
cyclohexane
0.600
Figure 2.12. Experiment 3 First Order Plot

rxn vol
(mL)
0.60
0.60
0.60
0.60

sm14-9:	ln[Ar]t/[Ar]0	vs	;me	
4	mol%	in-situ	Ir	/dtbpy	+	3-CF3-toluene	+	1.6	B2pin2	
0.1	
-0.1	 0	

1000	

2000	

3000	

4000	

5000	

6000	

ln[Ar]t/[Ar]0		

-0.3	
-0.5	

ln[Ar]t/[Ar]0	

-0.7	
-0.9	

y	=	-2.11E-04x	+	1.06E-01	
R²	=	9.96E-01	

-1.1	
-1.3	

	

Time	(seconds)	

73	

7000	

[reagent] mol
M
ratio
2.99E-01 1.00
6.29E-03 0.02
1.24E-01 0.04
4.92E-01 1.65
xxxx
xxxx
72% conversion

Kinetics Experiment 4: (coe)Ir(dtbpy)(Bpin)3 with Excess B2pin2 on 3-Fluorochlorobenzene
Scheme 2.18. Experiment 4
F

Cl

0.0094 M (coe)Ir(dtbpy)Bpin3
0.492 M B2pin2

F

F Cl

Cl

cyclohexane 25°C 1h
monitored by 19F NMR

0.296 M

Bpin
Bpin

Table 2.13. Experiment 4 Table of Reactants

Reagent
vol(mL)
C6H4ClF
0.019
[(COE)Ir(dtbpy)bpin3]
B2pin2
xxxx
C6F6
0.009
cyclohexane

FW
(g/mol)
130.55
886.62
253.94
186.06

d (g/mL)
1.219
xxxx
xxxx
1.612

mass (g)
0.023
0.005
0.075
1.45E-02

rxn vol
(mL)
0.60
0.60
0.60
0.60
0.60

mols
1.77E-04
5.64E-06
2.95E-04
7.80E-05

[reagent]
M
2.96E-01
9.40E-03
4.92E-01
1.30E-01

ratio
1.000
0.032
1.665
0.440

conversion = 84%
a:b ratio = 1.5 : 1
Figure 2.13. Experiment 4 First Order Plot

sm14-1:	ln[Ar]t/[Ar]0	vs	:me	
Fluorochlorbenzene	+	3	mol%	[1]	+	1.6	equivB2pin2	
0	
-0.2	

0	

200	

400	

600	

800	

1000	

1200	

1400	

1600	

1800	

ln[Ar]t/[Ar]0		

-0.4	
-0.6	
-0.8	
-1.2	
-1.4	
-1.6	
-1.8	
-2	

	

ln[Ar]t/[Ar]0	

-1	

y	=	-9.271E-04x	-	1.068E-01	
R²	=	9.968E-01	
Time	(seconds)	

74	

2000	

Kinetics Experiment 5: Catalyst Pre-Generated from [Ir(OMe)cod]2 and dtbpy with Excess B2pin2 in THF on 3-Fluorochlorobenzene
Scheme 2.19. Experiment 5

0.00943 M [Ir(OMe)cod]2
0.0186 M dtbpy
0.492 M B2pin2

F

Cl

F

Cl

+
Bpin

THF, 25°C 1 h
monitored by 19F NMR

0.296 M

Table 2.14. Experiment 5 Table of Reactants
FW
Reagent
vol(mL) d (g/mL) (g/mol)
cl-f-bz
0.019
1.219
130.55
[Ir(OMe)cod]2
0.150
xxxx
663
dtbpy
0.050
xxxx
268.4
B2pin2
xxxx
xxx
253.94
C6F6
0.013
1.612
186.06
THF
0.400

mass (g)
0.023
0.004
0.003
0.075
0.021

Bpin

mols
1.77E-04
5.66E-06
1.12E-05
2.93E-04
1.13E-04

stock soln
M
xxxx
3.77E-02
2.24E-01
xxxx
xxxx

Figure 2.14. Experiment 5 First Order Plot

0.5	
0	
-0.5	 0	

sm14-20:	ln[Ar]t	/[Ar]0	vs	;me	
Fluorochlorobenzne	+	1.6	B2pin2		6	mol%	Ir	/	dtbpy	
	(in-situ	catalyst,	no	HBpin,	THF	25°C)	
500	

1000	

1500	

2000	

2500	

3000	

3500	

4000	

4500	

5000	

-1	

ln[Ar]t	/[Ar]0		

-1.5	
-2	

-2.5	
ln[Ar]t/[Ar]0	

-3	

-3.5	
-4	

y	=	-1.04E-03x	+	1.75E-02	
R²	=	9.93E-01	

-4.5	
-5	

	

Time	(seconds)	

75	

F

Cl

rxn vol
(mL)
0.600
0.600
0.600
0.600
0.600

[reagent]
mol
M
ratio
2.96E-01
1.000
9.43E-03
0.032
1.86E-02
0.063
4.92E-01
1.651
1.88E-01
0.635
conversion = 100%
a:b ratio = 1.9:1

Kinetics Experiement 6: Catalyst Pre-Generated from [Ir(OMe)cod]2 and dmadpm with Excess B2pin2 in THF on 3Fluorochlorobenzene
	

Scheme 2.20. Experiment 6

0.0094 M [Ir(OMe)cod]2
0.0186 M dmadpm
0.492 M B2pin2

F

Cl

Cl

F

+
Bpin

THF, 50°C 5 h
monitored by 19F NMR

0.296 M

F

Cl

Bpin

Table 2.15. Experiment 6 Table of Reactants

Reagent
C6H4ClF
[Ir(OMe)cod]2
dmadpm
B2pin2
C6F6
THF

vol(mL)
0.019
0.150
0.050
xxxx
0.013
0.400

d
(g/mL)
1.219
xxxx
xxxx
xxx
1.612

FW
(g/mol)
130.55
663
256.35
253.94
186.06

mass
(g)
0.023
0.004
0.003
0.075
0.021

mols
1.77E-04
5.66E-06
1.12E-05
2.93E-04
1.13E-04

stock soln
M
xxxx
3.77E-02
2.24E-01
xxxx
xxxx

rxn vol
[reagent]
(mL)
M
mol ratio
0.600
2.96E-01
1.000
0.600
9.43E-03
0.032
0.600
1.86E-02
0.063
0.600
4.92E-01
1.651
0.600
1.88E-01
0.635
conversion = 57% a:b ratio = 2.5:1

Figure 2.15. Experiment 6 First Order Plot
sm14-21:	ln[Ar]t/[Ar]0	vs	;me	
chlorofluorobenzene	+	6	mol%	Ir	/	dmadpm	+	1.6	B2pin2		
THF	50°C	at	5	h	
0	

ln	[Ar]t/[Ar]0	

-0.1	

0	

2000	

4000	

-0.2	

6000	

-0.4	
-0.5	

	

10000	

y	=	-6.470E-05x	-	8.267E-03	
R²	=	9.895E-01	

-0.3	

-0.6	

8000	

Time	(seconds)	

76	

Kinetics experiment 7: (coe)Ir(dtbpy)Bpin3 with 2 equiv HBpin on Trifluoromethyltoluene
	
Scheme 2.21. Experiment 7
Me

CF3

cyclohexane, 30°C
monitored by 19F NMR 2h

0.299 M

Table 2.16. Experiment 7 Table of Reactants
Reagent
vol(mL)
3-CF3-tol
0.025
[(COE)Ir(dtbpy)bpin3]
Hbpin
0.055
C6F6
0.009
cyclohexane

FW
(g/mol)
160.14
.886.62
126.97
186.06

d (g/mL)
1.148
xxxx
0.882
1.612

Me

0.0188 M [1]
0.637 M HBpin

mass
(g)
0.0287
0.01
0.049
0.015

Bpin

mols
1.79E-04
1.13E-05
3.82E-04
7.80E-05

rxn vol (mL)
0.6
0.6
0.6
0.6
0.6

Figure 2.16. Experiment 7 First Order Plot
sm14-7:	ln	[Ar]t/[Ar]0	vs	;me		
CF3-toluene	+	6	mol%	[1]	+	2	HBpin	30°C	2.5h	
0	
-0.05	

0	

1000	

2000	

3000	

4000	

5000	

6000	

7000	

8000	

ln	[Ar]t/[Ar]0		

-0.1	
-0.15	
ln[Ar]t/[Ar]0	

-0.2	

-0.25	
-0.3	
-0.35	
-0.4	

	

Time	(seconds)	

77	

CF3

[reagent]
M
equiv
0.2987
1.00
0.0188
0.063
0.6368
2.13
0.1300
0.44
conversion = 30%

Kinetics Experiment 7 continued: (coe)Ir(dtbpy)Bpin3 with 2 equiv HBpin on 3-Trifluoromethyltoluene
Scheme 2.21. Experiment 7 continued
Me

CF3

Me

0.0188 M coe)Ir(dtbpy)Bpin3
0.637 M HBpin
cyclohexane, 30°C
monitored by 19F NMR 2h

0.299 M

CF3

Bpin

Conversion = 30%

Figure 2.17. Experiment 7 Comparison of First Order and Second Order Plots
sm14-4:	2nd	order	plot:	1/[Ar]	vs	<me	
CF3-tol	+6	mol%	[1]	+	2	HBpin	30°C	2.5	h	
2	half	lives	

sm14-7:	ln	[Ar]t/[Ar]0	vs	;me		
CF3-toluene	+	6	mol%	[1]	+	2	HBpin	30°C	(~1000	sec)	
0	
-0.02	

0	

200	

400	

600	

800	

1000	

1200	

600	
500	
400	

-0.06	
ln[Ar]t/[Ar]0	

-0.08	

1/[A]	M	-1	

ln	[Ar]t/[Ar]0		

-0.04	

-0.1	
-0.12	

	

1/[Ar]	

200	
100	

-0.14	
-0.16	

300	

0	
0	

Time	(seconds)	

500	

1000	

1500	

Time	(seconds)	

78	

2000	

2500	

	

Kinetics Experiment 8: (coe)Ir(dtbpy)Bpin3 with Excess HBpin on 3-Fluorochlorobenzene at 50 °C
Scheme 2.22. Experiment 8
0.0188 M (dtbpy)Ir(Bpin)3(coe)
0.637 M HBpin

F

Cl

F Cl

Cl

+
Bpin

cyclohexane, 50°C 2 h
monitored by 19F NMR

0.296 M

F

Bpin

6 mol% Ir

Table 2.17. Experiment 8 Table of Reactants
Reagent
vol(mL)
C6H4ClF
0.019
[(COE)Ir(dtbpy)bpin3]
Hbpin
0.055
C6F6
0.009
cyclohexane

FW
(g/mol)
130.55
886.62
126.97
186.06

d (g/mL)
1.219
xxxx
0.882
1.612

mass (g)
0.023
0.010
0.049
1.45E-02

rxn vol
(mL)
0.60
0.60
0.60
0.60

mols
1.77E-04
1.13E-05
3.82E-04
7.80E-05

0.600

0.60
Figure 2.18. Experiment 8 First Order Plot
	
sm14-3:	ln[Ar]t	/[Ar]0	vs	;me	(2.5	half	lives)	
Fluorochlorobenzene	+	6	mol%	[1]	+	2	HBpin	50°C	
0	
-0.2	

0	

500	

1000	

1500	

2000	

2500	

3000	

3500	

4000	

4500	

ln[Ar]t	/[Ar]0		

-0.4	
-0.6	
-0.8	
ln[Ar]t/[Ar]0	

-1	
-1.2	
-1.4	
-1.6	
-1.8	

	

Time	(seconds)	

79	

[reagent]
mol
M
ratio
2.96E-01
1.000
1.88E-02
0.064
6.37E-01
2.154
1.30E-01
0.440
88% conversion
a:b ratio = 2 : 1

Kinetics Experiment 8 continued: (coe)Ir(dtbpy)Bpin3 with Excess HBpin on 3-Fluorochlorobenzene at 50°C
Scheme 2.22. Experiment 8 continued
F

Cl

0.0188 M mol% (coe)Ir(dtbpy)Bpin3
0.637 M HBpin

+

Bpin

cyclohexane, 50°C 2 h
monitored by 19F NMR

0.296 M

F

F Cl

Cl

Bpin

conversion = 88%
a:b ratio = 2 : 1

Figure 2.19. Experiment 8 Comparison of First Order and Second Order Plots at 2 Half-Lives
sm14-3:	1/[Ar]	vs	9me	(second	order	plot	over	2	half	lives)	
Fluorochlorobenzene	+	6	mol%	[1]	+	2	equiv	HBpin	50°C	2	h	
	

sm14-3:	ln[Ar]t/[Ar]0	vs	;me	at	2	half	lives	
Fluorochlorobenzene	+	6	mol%	[1]	+	2	HBpin	50°C	
0	
-0.2	

0	

500	

1000	

1500	

2000	

2500	

3000	

1600	
1400	

-0.6	
ln[Ar]t/[Ar]0	

-0.8	
-1	
-1.2	
-1.4	
-1.6	

	

1200	
1/[Ar]	M	-1	

ln[Ar]t/[Ar]0	

-0.4	

1000	
800	

1/[Ar]	

600	

y	=	4.02E-01x	+	3.39E+02	
R²	=	9.99E-01	

400	

y	=	-5.25E-04x	-	1.92E-01	
R²	=	9.66E-01	

200	
0	
0	

Time	(seconds)	

500	

1000	

1500	
Time	(seconds)	

80	

2000	

2500	

3000	

Kinetics Experiment 9: [Ir(OMe)cod]2 and dmadpm with 2 equiv HBpin on 3-Fluorochlorbenzene
Scheme 2.23. Experiment 9
0.00943 M [Ir(OMe)COD]2
0.0010 M dmadpm
0.704 M HBpin

F

Cl

F Cl
+

Cl

Bpin

THF, 50°C 12 h
monitored by 19F NMR

0.341 M

F

Bpin

conversion = 79%
a:b ratio = 7.5:1

Table 2.18. Experiment 9 Table of Reactants
Reagent
C6H4ClF
[Ir(OMe)cod]2
dmadpm
Hbpin
C6F6
THF

vol(mL)
0.027
0.500
0.240
0.075
0.009
0.040

d
(g/mL)
1.219
xxxx
xxxx
0.882
1.612

FW
(g/mol) mass (g)
130.55
0.033
663
xxxx
256.35
xxxx
126.97
0.066
186.06
0.015

mols
2.52E-04
3.75E-06
7.49E-06
5.21E-04
7.80E-05

Figure 2.20. Experiment 9 First Order Plot
sm13-39	First	Order	Plot:	ln[Ar]t/[Ar]0	vs	>me	over	12	h	
Fluorochlorobenzne	+	2	HBpin	+	3	mol%	Ir	/	dmadpm		
in-situ	catalyst	THF	50°C	
	

0	
-0.2	

0	

5000	

10000	 15000	 20000	 25000	 30000	 35000	 40000	 45000	

ln[Ar]t/[Ar]0	

-0.4	
-0.6	
-0.8	
-1	
-1.2	
-1.4	
-1.6	
-1.8	

	

stock soln
M
xxxx
7.50E-03
3.12E-02
xxxx
xxx

Time	(seconds)	

81	

rxn vol
(mL)
0.740
0.740
0.740
0.740
0.740
0.074

[reagent]
M
3.41E-01
9.43E-03
1.01E-02
7.04E-01
1.05E-01

ratio
1.00E+00
1.49E-02
2.97E-02
2.05E+00
3.09E-01

Kinetics Experiment 9 continued: [Ir(OMe)cod]2 and dmadpm with 2 equiv HBpin on 3-Fluorochlorobenzene
Scheme 2.23. Experiment 9 continued
0.00943 M [Ir(OMe)COD]2
0.0010 M dmadpm
0.704 M HBpin

F

Cl

THF, 50°C 12 h
monitored by 19F NMR

0.341 M

F Cl
+

Cl

F
Bpin

Bpin

79% conversion
a:b ratio = 7.5 : 1

Figure 2.21. Experiment 9 Second Order Plot
sm13-39	second	order	plot:	1/[Ar]	vs	<me	
Fluorochlorobenzne	+	2	HBpin	+	3	mol%	Ir	/	dmadpm		
in-situ	catalyst	THF	12	h	50°C	
1600	
1400	

y	=	2.91E-02x	+	2.56E+02	
R²	=	9.98E-01	

1200	

1	/[Ar]	M-1	

1000	
800	
600	

1/[Ar]	

400	
200	
0	
0	

	

5000	 10000	 15000	 20000	 25000	 30000	 35000	 40000	 45000	
Time	(seconds)	

82	

Kinetics Experiment 9 continued: [Ir(OMe)cod]2 and dmadpm with 2 equiv HBpin - Previous Low-Conversion Trials
(Earlier trial runs at room temperature or below 40°C had better a:b ratios)
Scheme 2.24. Experiment 9 at Room Temperature
F

Cl

0.341 M

0.00943 M [Ir(OMe)COD]2
0.0010 M dmadpm
0.704 M HBpin

F

Cl

Cl

F

+

Bpin

THF, rt 12 h
monitored by 19F NMR

Bpin

only 30 % conversion
a:b ratio = 11:1
Figure 2.22. Experiment 9 Comparison of First Order and Second Order Plots
sm13-31	2nd	order	plot:	1/[Ar]	vs	<me	
3	mol%	Ir/dmadpm	+	2	HBpin	THF	rt	12h	

sm13-31:	ln[Ar]t/[Ar]0vs	:me	
3	mol%	Ir/dmadpm	+	2	HBpin	THF	rt	12h	
4.6	

6	

4.5	

5	
4	

ln	{Ar]t	/	[Ar]0	

4.3	
4.2	

1/[Ar]	M	-1	

ln[Ar]t/[Ar]0	

4.4	

y	=	-1E-05x	+	4.5373	
R²	=	0.99162	

4.1	

10000	

20000	

30000	

40000	

2	

1/[Ar]	

0	

50000	

0	

5000	 10000	 15000	 20000	 25000	 30000	 35000	 40000	 45000	
Time	(seconds)	

Time	(seconds)	

	

y	=	5E-05x	+	3.04	
R²	=	0.99894	

1	

4	
0	

3	

83	

Kinetics Experiment 9 continued: [Ir(OMe)cod]2 and dmadpm with 2 equiv HBpin – Ratio of a : b over time
Earlier trial run at room temperature or below 40°C had better a:b ratios
Scheme 2.24. Experiment 9 at Room Temperature

F

Cl

0.00943 M [Ir(OMe)COD]2
0.0010 M dmadpm
0.704 M HBpin
THF, rt 12 h
monitored by 19F NMR

0.341 M

F

Cl

Cl

F

+

Bpin
Bpin

only 30 % conversion
a:b ratio = 11:1
Figure 2.23. Experiment 9 Ratio of a:b over Time
sm13:31	ra#o	a/b	vs	#me	
12.00	

ra#o	of	a	/	b	

11.00	
10.00	
9.00	
ra/o	a/b	

8.00	
7.00	
6.00	
0	

5000	 10000	 15000	 20000	 25000	 30000	 35000	 40000	 45000	
Time	(secondsP	

	

84	

Kinetics Experiment 10: [Ir(OMe)cod]2 and dmadpm Pseudo First-Order in HBpin on 3-Fluorochlorbenzene
Scheme 2.25. Experiment 10
0.01885 M [Ir(OMe)cod]2
0.0195 M dmadpm
1.62 M HBpin

F

Cl

F

Cl

F

+
Bpin

THF, 50°C 5 h
monitored by 19F NMR

0.311 M

Cl

Bpin

Table 2.19. Experiment 10 Table of Reactants
Reagent
vol(mL)
C6H4ClF
0.020
[Ir(OMe)cod]2 0.150
dmadpm
0.150
Hbpin
0.140
C6F6
0.000
THF
0.200

d (g/mL)
1.219
xxxx
xxxx
0.882
1.612

FW
(g/mol)
130.55
663
268.4
126.97
186.06

mass (g)
0.024
0.004
0.003
0.123
0.000

stock
soln M
xxxx
3.77E-02
7.80E-02
xxxx
xxxx

mols
1.87E-04
5.66E-06
1.17E-05
9.73E-04
0.00E+00

rxn vol
[reagent]
(mL)
M
mol ratio
0.600
3.11E-01
1.000
0.600
9.43E-03
0.030
0.600
1.95E-02
0.063
0.600
1.62E+00
5.208
0.600
0.00E+00
0.000
conversion =97% a:b ratio = 11: 1

Figure 2.24. Experiment 10 Comparison of First Order and Second Order Plots	
sm14-37:	ln[Ar]t/[Ar]0	vs	<me	
Fluorochlorobenzne	+	6	mol%		Ir/	dmadpm	+5	equiv	HBpin	
	THF	50°C	3h	
0	
0	

2000	

4000	

6000	

8000	

10000	

70	

12000	

60	
1/[A]	M-1	

-0.5	
ln[Ar]t/[Ar]0		

-1	

-1.5	
-2	

-3.5	
-4	

	

50	
40	
30	

-2.5	
-3	

sm14-37:1/[A]	vs	9me	
dmadpm	Pseudeo	first	order	in	HBpin	

80	

20	

y	=	-2.93E-04x	-	2.92E-01	
R²	=	9.82E-01	

10	
0	
0	

Time	(seconds)	

85	

2000	

4000	 6000	 8000	
Time	(seconds)	

10000	 12000	

	

Kinetics Experiment 11: [Ir(OMe)cod]2 and dtbpy Pseudo First-Order in HBpin on 3-Fluorochlorbenzene
Scheme 2.26. Experiment 11

0.01885 M [Ir(OMe)cod]2
0.0186 M dtbpy
1.47 M HBpin

F

Cl

F

Cl

Bpin
Bpin

Table 2.20. Experiment 11 Table of Reactants
FW
stock
Reagent
vol(mL) d (g/mL)
(g/mol)
mass (g)
mols
soln M
cl-f-benzene
0.019
1.219
130.55
0.023
1.77E-04
xxxx
[Ir(OMe)cod]2 0.150
xxxx
663
0.004
5.66E-06 3.77E-02
dtbpy
0.050
xxxx
268.4
0.003
1.12E-05 2.24E-01
Hbpin
0.128
0.882
128
0.113
8.82E-04
xxxx
C6F6
0.015
1.612
186.06
0.024
1.30E-04
xxx
THF
0.040
Figure 2.25. Experiment 11 First Order Plot	

rxn vol
(mL)
0.60
0.60
0.60
0.60
0.60
0.06

sm14-26:	ln[Ar]t	/[Ar]0	vs	<me	
3-Chlorofluorobenzene	+	5	equiv	HBpin,	THF,	50°C	
in-situ-6mol%	Ir/dtbpy	
0	
-0.2	 0	

2000	

4000	

6000	

8000	

10000	

12000	

ln[Ar]t	/[Ar]0			

-0.4	
-0.6	
-0.8	

ln[Ar]t/[Ar]0	

-1	
-1.2	
-1.4	
-1.6	
-1.8	

y	=	-1.31E-04x	-	1.91E-01	
R²	=	9.96E-01	

-2	
Time	(seconds)	

	

86	

F

85 % conversion
a:b ratio = 2.4 : 1

+

THF 50°C 2.5 h
monitored by 19F NMR

0.296 M

Cl

14000	

	

[reagent]
M
2.96E-01
9.43E-03
1.86E-02
1.47E+00
2.17E-01

mol ratio
1.000
0.032
0.063
4.972
0.733

	

Kinetics Experiment 12: (coe)Ir(dtbpy)Bpin3 and 1.0 equiv B2pin2 on 3-Fluorochlorobenzene
Scheme 2.27. Experiment 12
F 0.00943 M (dtbpy)Ir(Bpin)3(coe)
0.295 M B2pin2

Cl

F
Bpin

cyclohexane rt 2 h
monitored by 19F NMR

0.296 M

F Cl
+

Cl

Bpin

Table 2.21. Experiment 12 Table of Reactants
Reagent
vol(mL)
C6H4ClF
0.019
[(COE)Ir(dtbpy)bpin3]
B2pin2
xxxx
C6F6
0.009
cyclohexane
0.60

FW
(g/mol)
130.55
886.62
253.94
186.06

d (g/mL)
1.219
xxxx
xxxx
1.612

rxn vol
mols
(mL)
1.77E-04
0.60
5.64E-06
0.60
1.77E-04
0.60
7.80E-05
0.60
full conversion

mass (g)
0.023
0.005
0.045
1.45E-02

Figure 2.26. Experiment 12 First Order Plot	
sm14-4:	ln[Ar]t/[Ar]0	vs	Time	
3-Chlrorfluorobenzene	+	1.0	equiv	B2pin2		+	6	mol%	[1]	
cyclohexane	rt	1	h	
0	

ln[Ar]t/[Ar]0			

-0.5	

0	

500	

1000	

1500	

2000	

2500	

3000	

3500	

4000	

-1	

-1.5	
ln[sm]t/[sm]0	

-2	
-2.5	
-3	
-3.5	

	

Time	(seconds)	

87	

[reagent]
M
mol ratio
2.96E-01
1.000
9.40E-03
0.032
2.95E-01
0.999
1.30E-01
0.440
a:b ratio = 1.6 :1

Kinetics Experiment 12 continued: (coe)Ir(dtbpy)Bpin3 and 1.0 equiv B2pin2 on 3-Fluorochlorobenzene
Scheme 2.27. Experiment 12 continued
F 0.00943 M (dtbpy)Ir(Bpin)3(coe)
0.295 M B2pin2

Cl

F
Bpin

cyclohexane rt 2 h
monitored by 19F NMR

0.296 M

F Cl
+

Cl

Bpin

Full Conversion
a:b ratio = 1.6 : 1

Figure 2.27. Experiment 12 First Order Plot at 3 Half-Lives
sm14-4:	ln[Ar]t/[Ar]0	vs	Time	
3-Chlorofluorobenzene	+	1.0	equiv	B2pin2		+	6	mol%	[1]	
cyclohexane	rt	at	3	half	lives	(~20	min.)	
0	
0	

200	

400	

600	

800	

1000	

1200	

1400	

ln[Ar]t/[Ar]0			

-0.5	
-1	
ln[Ar]t/[Ar]0	

-1.5	
-2	
-2.5	

	

y	=	-1.69E-03x	-	1.92E-01	
R²	=	9.97E-01	
Time	(seconds)	

88	

Kinetics Experiment 13: (coe)Ir(dtbpy)Bpin3 and 0.5 equiv B2pin2 on 3-Fluorochlorobenzene
Scheme 2.28. Experiment 13
F

Cl

0.0094 M (dtbpy)Ir(Bpin)3(coe)
0.158 M B2pin2

Table 2.22. Experiment 13 Table of Reactants
d (g/mL)
1.219
xxxx
xxxx
1.612

FW
(g/mol)
130.55
886.62
253.94
186.06

Bpin

mass (g)
0.023
0.005
0.024
1.45E-02

rxn vol
[reagent]
mols
(mL)
M
mol ratio
1.77E-04
0.60
2.96E-01
1.000
5.64E-06
0.60
9.40E-03
0.032
9.45E-05
0.60
1.58E-01
0.533
7.80E-05
0.60
1.30E-01
0.440
conversion = 67% a:b ratio = 1.6:1

Figure 2.28. Experiment 13 First Order Plot	
sm14-10:	ln[Ar]t/[Ar]0	vs	Time	
Fluorochlorobenzene	+	0.5	equiv	B2pin2	+	6	mol%	[1]	
cyclohexane	rt	2	h		
0	
0	

1000	

2000	

3000	

4000	

5000	

6000	

-0.2	

ln[Ar]t/[Ar]0		

-0.4	
ln[Ar]t/[Ar]0	

-0.6	
-0.8	
-1	
-1.2	

Time	in	seconds	

	

89	

F
Bpin

cyclohexane rt 2 h
monitored by 19F NMR

0.296 M

Reagent
vol(mL)
Fluorochlorobenzene
0.019
[(COE)Ir(dtbpy)bpin3]
B2pin2
xxxx
C6F6
0.009
cyclohexane
0.60

F Cl
+

Cl

7000	

8000	

Kinetics Experiment 13 continued: (dtbpy)Ir(Bpin)3(coe) and 0.5 equiv B2pin2 on 3-Fluorochlorobenzene
Scheme 2.28. Experiment 13 continued
F

Cl

0.0094 M (dtbpy)Ir(Bpin)3(coe)
0.158 M B2pin2

F Cl
+

Cl

Bpin

cyclohexane rt 2 h
monitored by 19F NMR

0.296 M

F

Bpin

Conversion = 100%
a:b ratio = 1.6 : 1
Figure 2.29. Experiment 13 Comparison of First Order and Second Order Plots	

0	

sm14-10:	ln[Ar]t/[Ar]0	vs	Time	at	half	life	
Fluorochlorobenzene	+	0.5	equiv	B2pin2	+	6	mol%	[1]	cyclohexane	rt	
	first	half	life	~9	min.	
0	

100	

200	

300	

400	

500	

sm14-10:	2nd	order	plot:	1/[Ar]	vs	=me	
6	mol%	[1]	+	0.5	B2pin2	CyH	rt	2	h	
12	

600	

-0.1	

10	

-0.3	

ln[Ar]t/[Ar]0	

-0.4	

8	
6	

-0.5	

4	

-0.6	

2	

-0.7	

0	

-0.8	

	

1/[Ar]	M	-1	

ln[Ar]t/[Ar]0		

-0.2	

y	=	1.2425ln(x)	-	1.7291	
R²	=	0.97721	

0	
Time	in	seconds	

2000	

4000	
Tine	(seconds)	

90	

6000	

8000	

	
	
	

REFERENCES

	

91	

REFERENCES

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Mkhalid, I. A. I.; Barnard, J. H.; Marder, T. B.; Murphy, J. M.; Hartwig, J. F., C−H
Activation for the Construction of C−B Bonds. Chemical Reviews 2010, 110 (2), 890-931.
2.
Ros, A.; Fernandez, R.; Lassaletta, J. M., Functional group directed C-H borylation. Chem.
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3.
Chotana, G. A.; Rak, M. A.; Smith, M. R., III, Sterically Directed Functionalization of
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Obligacion, J. V.; Semproni, S. P.; Chirik, P. J., Cobalt-Catalyzed C–H Borylation. Journal
of the American Chemical Society 2014, 136 (11), 4133-4136.
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Furukawa, T.; Tobisu, M.; Chatani, N., C–H Functionalization at Sterically Congested
Positions by the Platinum-Catalyzed Borylation of Arenes. Journal of the American Chemical
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Takaya, J.; Ito, S.; Nomoto, H.; Saito, N.; Kirai, N.; Iwasawa, N., Fluorine-controlled C-H
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Obligacion, J. V.; Bezdek, M. J.; Chirik, P. J., C(sp2)–H Borylation of Fluorinated Arenes
Using an Air-Stable Cobalt Precatalyst: Electronically Enhanced Site Selectivity Enables
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Bisht, R.; Chattopadhyay, B., Formal Ir-Catalyzed Ligand-Enabled Ortho and Meta
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Kuninobu, Y.; Ida, H.; Nishi, M.; Kanai, M., A meta-selective C–H borylation directed by
a secondary interaction between ligand and substrate. Nat Chem 2015, 7 (9), 712-717.
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Davis, H. J.; Mihai, M. T.; Phipps, R. J., Ion Pair-Directed Regiocontrol in TransitionMetal Catalysis: A Meta-Selective C–H Borylation of Aromatic Quaternary Ammonium Salts.
Journal of the American Chemical Society 2016, 138 (39), 12759-12762.
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Cui, C.; Ren, H.; Zhou, Y.-P.; Bai, Y.-P.; Driess, M., Cobalt-Catalyzed Regioselective
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Schlienger, N.; Lund, B. W.; Pawlas, J.; Badalassi, F.; Bertozzi, F.; Lewinsky, R.; Fejzic,
A.; Thygesen, M. B.; Olsson, R.; Tabatabaei, A.; Bradley, S. R.; Gardell, L. R.; Piu, F., Synthesis,
structure-activity relationships, and characterization of novel nonsteroidal and selective androgen
receptor modulators. J. Med. Chem. 2009, 52 (22), 7186-7191.
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Belsham, M. G.; et al., J. Chem. Soc., Perk. Trans. 2 1974, 119-125.

14.

Diep, B. K.; et al., J. Chem. Soc. 1963, 2784-2787.

15.
Joshi, K. C.; Dubey, K.; Dandia, A., Possible psychopharmacological agents. Part XIII:
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16.
Soffers, A. E. M. F.; Veeger, C.; Rietjens, I. M. C. M., Influence of the type of halogen
substituent on in vivo and in vitro phase II metabolism of 2-fluoro-4-halophenol metabolites
formed from 3-halo-fluorobenzenes. Xenobiotica 1994, 24 (8), 759-774.
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Keenan, M.; Abbott, M. J.; Alexander, P. W.; Armstrong, T.; Best, W. M.; Berven, B.;
Botero, A.; Chaplin, J. H.; Charman, S. A.; Chatelain, E.; von Geldern, T. W.; Kerfoot, M.; Khong,
A.; Nguyen, T.; McManus, J. D.; Morizzi, J.; Ryan, E.; Scandale, I.; Thompson, R. A.; Wang, S.
Z.; White, K. L., Analogues of Fenarimol Are Potent Inhibitors of Trypanosoma cruzi and Are
Efficacious in a Murine Model of Chagas Disease. J. Med. Chem. 2012, 55 (9), 4189-4204.
18.
Del Grosso, A.; Ayuso Carrillo, J.; Ingleson, M. J., Regioselective electrophilic borylation
of haloarenes. Chemical Communications 2015, 51 (14), 2878-2881.
19.

Shul'pin, G. B.; Kitaigorodskii, A. N., J. Organomet. Chem. 1981, 212, 275-282.

20.
Wencel-Delord, J.; Nimphius, C.; Wang, H.; Glorius, F., Rhodium(III) and
Hexabromobenzene-A Catalyst System for the Cross-Dehydrogenative Coupling of Simple
Arenes and Heterocycles with Arenes Bearing Directing Groups. Angew. Chem., Int. Ed. 2012, 51
(Copyright (C) 2013 American Chemical Society (ACS). All Rights Reserved.), 13001-13005.
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Carey, J. S.; Laffan, D.; Thomson, C.; Williams, M. T., Analysis of the reactions used for
the preparation of drug candidate molecules. Organic & Biomolecular Chemistry 2006, 4 (12),
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Shen, K.; Fu, Y.; Li, J. N.; Liu, L.; Guo, Q. X., What are the pKa values of C-H bonds in
aromatic heterocyclic compounds in DMSO? Tetrahedron 2007, 63 (7), 1568-1576.
23.
Webster-Gardiner, M. S.; Fu, R.; Fortman, G. C.; Nielsen, R. J.; Gunnoe, T. B.; Goddard,
W. A., III, Arene C-H activation using Rh(i) catalysts supported by bidentate nitrogen chelates.
Catal. Sci. Technol. 2015, 5 (1), 96-100.

	

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Porter, G. R.; Rydon, H. N.; Schofield, J. A., Transformations of 2-methyl-∆ 2-oxazoline
in aqueous solution. Journal of the Chemical Society (Resumed) 1960, (0), 2686-2690.
25.
Soovali, L.; Rodima, T.; Kaljurand, I.; Kutt, A.; Koppel, I. A.; Leito, I., Basicity of some
P1 phosphazenes in water and in aqueous surfactant solution. Organic & Biomolecular Chemistry
2006, 4 (11), 2100-2105.
26.
Menger, F. M.; Singh, T. D.; Bayer, F. L., Nitrogen to nitrogen proton transfer. The
significance of large negative entropies of activation. Journal of the American Chemical Society
1976, 98 (16), 5011-5012.
27.
Rochester, C. H.; Waters, J. A., Thermodynamic study of the acid dissociation of
substituted pyridinium ions in methanol. Journal of the Chemical Society, Faraday Transactions
1: Physical Chemistry in Condensed Phases 1982, 78 (4), 1303-1312.
28.
Ishiyama, T.; Takagi, J.; Hartwig, J. F.; Miyaura, N., A stoichiometric aromatic C-H
borylation catalyzed by iridium(I)/2,2 '-bipyridine complexes at room temperature. Angew. Chem.
Int. Ed. 2002, 41 (16), 3056-3058.
29.
Ishiyama, T.; Murata, M.; Miyaura, N., Palladium(O)-Catalyzed Cross-Coupling Reaction
of Alkoxydiboron with Haloarenes - a Direct Procedure for Arylboronic Esters. J. Org. Chem.
1995, 60 (23), 7508-7510.
30.
Boller, T. M.; Murphy, J. M.; Hapke, M.; Ishiyama, T.; Miyaura, N.; Hartwig, J. F.,
Mechanism of the Mild Functionalization of Arenes by Diboron Reagents Catalyzed by Iridium
Complexes. Intermediacy and Chemistry of Bipyridine-Ligated Iridium Trisboryl
31.
Halpern, J., Mechanism and Stereoselectivity of Asymmetric Hydrogenation. Science
1982, 217 (4558), 401-407.

	

94	

CHAPTER 3
IMPROVEMENTS IN SELECTIVITY AND REACTIVITY
Reactivity vs Selectivity of Ligands. Although the design of the dpm ligand framework was
successful in that it resulted in a significant shift towards steric selectivity, the dpm ligands did not
exhibit a level of reactivity suitable for general, all-purpose use. Dpm and dmadpm have lower
catalytic activity than dtbpy, resulting in longer reaction times and lower conversions. Although
borylation studies1 established a correlation between electron donation, (i.e. basicity) with better
reactivity, dmadpm does not follow that trend. It is the most basic of the ligand series, yet the least
active. Although far more basic than 3,4,7,8-tetramethyl-1,10-phenanthrolene (tmp) (pKa
measured at 6.0),2 dmadpm is unsuitable for electron rich arenes, which tmp borylates with ease.
Unlike tmp, dpm-type ligands do not form stable catalyst complexes at elevated temperatures, thus
heating reactions does not improve conversion, and hastens catalyst decomposition.
Figure 3.1. Dpm-Ir Complexes Compared to dtbpy-Ir Complexes
tBu

N

N

tBu

N

Ir

N

Ir

H
H

N

N

N
Ir

Ir

N

Figure 3.1. The non-planar Ir-dpm complex results in diminished electron
donation to the metal compared to the planar complex of Ir-dtbpy.
The challenge of designing a more sterically selective yet sufficiently reactive catalyst
remained to be solved. Although the 4,4’ substitution of NMe2 improved steric selectivity of
dmadpm over dpm and introduced an interesting kinetic effect with HBpin that may provide a path

	

95	

to engineer greater selectivity through shifting catalytic cycles, the general reactivity remained low
with long reaction times and the same thermal instability that plagued dpm.
The Pyridyl-Imine Ligand Framework. The source of decreased reactivity, as depicted in
Figure 3.1, is likely the flexible 6-membered transition structure diminishing the electron donation
to the metal, and stability may also be affected by the disruption of aromaticity by the methylene
spacer between the pyridyl rings. Active pyridyl ligands such as dtbpy and tmp are rigid and planar,
thus locking electron donation in place. The objective to construct a pyridyl based ligand with bulk
near the metal, yet having a planar coordination with the metal, turned our attention away from
dpm and shifted focus towards pyridyl-imine ligands.
Figure 3.2. Ligands with Diimine and Pyridyl Imine Backbones in the Literature
tBu

Hartwig

N

Nishida

31

N

R

32

Lassaletta
N

N

N

tBu

N NR'2

33 R = H, R' = Bn
34 R = NMe2, R' = Bn

Figure 3.2. Ligands with imine backbones that have been reported in the literature.
The first reported use of pyridyl imine ligands for C-H borylation was made by Nishida in
20043 from the recognition of the bpy framework as a diimine system. Nishida substituted the
imine arm of his ligands with bulky R groups. Substrates were symmetric arenes and pyridines
and indoles unsubstituted at the 2-position, so selectivity was not addressed. Later Lassaletta and
others developed similar pyridyl imine ligands for use as hemilabile directing groups in
borylation,4-5 resulting in another method for ortho borylation. Some diimine ligands that have
been reported in the literature are seen in Figure 3.2 on the previous page..
	

96	

As part of the project to design a meta selective ligand, Smith and Maleczka began a
collaboration to investigate several ligand frameworks, notably imine, 2,2’-bisoxazoline (box) and
bipyridyl (bpy) ligands. This collaboration was instructive in the recognition and classification of
a useful imine ligand that was fortuitously discovered during the dpm project.
Synthesis of a Reactive Pyridyl-Imine Ligand. When dmadpm became a ligand design
target, the chosen synthetic route required reduction of the corresponding dipyridyl ketone, 28, in
order to install the methylene spacer. The ketone was converted to the hydrazone, 29, and reduced
according to a Wolf-Kischner protocol, as seen in Scheme 3.1. During the conversion to dmadpm,
30, it was noted that the intermediate hydrazone was unusually stable and not easily reduced. In
preliminary ligand tests, early batches of dmadpm contained traces of the intermediate hydrazone
29.
Scheme 3.1. Synthesis of the Dipyridyl Methane Ligand
N
N
N
N

N
N
N

O

N

N

28

29

N NH2

H2NNH2•H2O
KOH, 150°C 2 h

N
N
N

30

Scheme 3.1. Pyridyl imine ligands were synthesized in the Smith and Maleczka
labs for ligand selectivity studies. 29 features a 4-dimethylaminopyridine (4DMAP) substituted at the imine carbon.
Although dmadpm is easily purified by sublimation, as a precaution, 29 was synthesized
and isolated to test whether its trace presence influenced catalytic activity. The catalytic activity
of dmadpm remained the same in the absence of 29. When 29 was tested as a ligand, however, the
initial catalytic reactivity was far greater than dpm-type ligands, and on par with dtbpy.
Furthermore, the steric selectivity was superior to both dtbpy and the dpm ligands for several

	

97	

substrates. The similarity of 29 to ligands possessing imine backbones reported by Nishida and
Lassaletta was noticed. It is interesting to consider, that although 29 is similar to 33 and 34,
Lassaletta’s ligands are only used for chelate-directed borylation, in stark contrast to the steric
selectivity observed from ligand 29.
Scheme 3.2. Lassaletta’s Substituted Hydrazone Ligands Exhibit Directed Borylation
N

N NBn2
33
1.0 mol % [Ir(OMe)cod]2
2.0 mol% Ligand 33

N

N
Bpin

1.0 equiv B2pin2, 5.0 mol % HBpin
THF 80°C 48h

64%
44

43

Scheme 3.2. Lassaletta’s directed borylation with ligand 33 results in borylation
directed to the 2-phenyl position.
In order to test whether 29 would react according to a chelate directed mechanism, 2-phenyl
pyridine (43) was subjected to borylation under Lassaletta’s conditions. As seen in Scheme 3.2,
the Ir-catalyzed borylation of 43 with 33 as the ligand produces only borylation at the 2-poition of
the phenyl group as directed by the N atom of the pyridine ring.
Scheme 3.3. DMAP-Imine Substituted Ligand does not Exhibit Directed Borylation
N
N
N
N
N

N NH2

29
Bpin

1.0 mol % [Ir(OMe)cod]2
2.0 mol% Ligand 29

N

N

pinB

1.0 equiv B2pin2, 5.0 mol % HBpin
THF 80°C 1 h
2 monoborylated
28%

43

Bpin

2 diborylated
72%

Scheme 3.3. Ligand 29 does not exhibit directed borylation under Lassaletta’s conditions.

	

98	

When 29 was used as the ligand with B2pin2 under Lassaletta’s conditions, over-borylation
of the pyridine and phenyl rings was observed, as shown in Scheme 3.3, resulting in two monoborylated isomers and two diborylated isomers. When 2-phenylpyridine was borylated at room
temperature with 29 as ligand and 2 equiv HBpin, according to the standard conditions previously
established for dpm-type ligands, over-borylation of substrate also occurred within 12 h, resulting
in another mixture of mono and diborylated products. When HBpin was limited to 1 equiv, the
result was a 1:3 mixture of 45:46.
To compare the effect of N-benzyl substitution on the function of the ligand, an
unsubstituted hydrazone analog (35) of the dibenzyl ligand 34 was synthesized.
Scheme 3.4. Substituted vs. Unsubstituted Hydrazone Ligands
N

Lassaletta
34
N

N

N NBn2

Bpin

1.0 mol % [Ir(OMe)cod]2
2.0 mol% Ligand 34
1.0 equiv B2pin2, 5.0 mol % HBpin
THF 80°C 48h

44

N

N
43

Bpin
Hydrazone
35
N
N NH2

pinB

1.0 mol % [Ir(OMe)cod]2
2.0 mol% Ligand 35
1.0 equiv B2pin2, 5.0 mol % HBpin
THF 80°C 1h

N

N

1.5
45

:

1
46

Scheme 3.4. N,N-dibenzyl substitution of the hydrazone in ligand 33 leads to directed
borylation. The bare NH2 of ligand 35 does not facilitate directed borylation.
Testing Ligands for Reactivity. Borylations of 43 were carried out under Lassaletta’s
conditions with ligands 34 and 35 to observe if directed borylation resulted with the bare
hydrazone, as seen in Scheme 3.4. Dibenzyl ligand 34 gave only directed borylation product 44.

	

99	

The free hydrazone 35 gave only monoborylated 45 and 46, and no directed product 44 was
observed in the reaction mixture.
Table 3.1. Reactivity Test by Borylation of 1,3-Dicyanobenzene
2 equiv HBpin
CN 1 mol% [Ir(OMe)cod]2 NC
2 mol% Ligand

NC

Ligand

entry

CN

Bnip

rt solvent time

14

CN NC

Ligand #

14a Bpin

14b

conversion

14a : 14b

Me2N

DMAP
N

1.

29

THF rt 1h

>99%

16:1

2.

31

THF rt 1h

>99%

4:1

3.

33

THF rt 24h

38%

3:1

4.

34

THF rt 24h

68%

5:1

5.

32

Cy rt 24h

40%

1.6:1

29 N NH2

tBu

tBu

N

N

31

Bn
N

33

N N

Bn

Me2N

Bn
N

N N

34

Bn

ipr
N

Me

N

32
ipr

Table 3.1. The hydrazone ligand 29 is compared to known imine ligands from the literature in the
borylation of 1,3-dicyanobenzene.
In order to gauge the reactivity of 29, a borylation test of 1,3-dicyanobenzene (14) was
devised, a substrate that had proven difficult and slow for dpm-type ligands Also included in the
test were ligands 31 (dtbpy), Nishida’s bulky ligand 32 and Lassaletta’s ligands, 33 and 34.
The results are summarized in Table 3.1. Of the ligands featured in Table 3.1, Entries 1
(29), and 2 (31) demonstrate significant reactivity, completing the borylation reaction in just 1
hour. Entries 3 (33) and 5 (35) exhibit low reactivity.

	

100	

Moderate reactivity of 68% is shown by 34 in Entry 4. Ligands 31, 33, and 34, dtbpy and
Lassaletta’s ligands, all have similar selectivity producing a range of about 3-5 :1 14a:14b
borylation. Nishida’s 32 has the least selectivity at 1.6:1. The two most reactive ligands, 29 and
31, show equal reactivity, however 29 produces four times more meta borylation with a ratio of
16:1.
Table 3.2. Comparison of NNH2 Substitution on Reactivity
NC

CN

2 equiv HBpin
1 mol% [Ir(OMe)cod]2 NC
2 mol% Ligand

entry

CN

Bnip

rt solvent time

14

CN NC

14a Bpin

conversion

Ligand

14b

14a : 14b

Me2N

DMAP
N

tBu

1.

29

THF rt 1h

>99%

16:1

2.

31

THF rt 1h

>99%

4:1

3.

36

THF rt 15h

63%

4:1

4.

37

THF rt 24h

13%

not
integrable

5.

35

THF rt 1h

96%

N NH2
29
tBu

N

N
31

Me2N

N
Me2N

H
N N
36
Me
Me

N
37
Me2N

N

N N
Me

35

N NH2

4.6:1

Table 3.2. Reactivity and selectivity decrease with N-substitution of the hydrazone.
With the recognition that only ligand 29 contained a free NH2 functional group, the effect
of substitution of the N atom was tested next. The N-methyl hydrazone substituted ligand, 36, and
N,N-dimethyl hydrazone substituted ligand, 37, and free, hydrazone with unsubstituted NH2, 35,

	

101	

were synthesized. Borylation reactions of dicyanobenzene with 35, 36, and 37 were performed and
compared to 29 and 31, as seen in Table 3.2.
Entry 5 of Table 3.2 indicates that free hydrazone 35, is almost as active as 29 and 31,
with 93% conversion in 1 hour. The meta selectivity of 35 is better than 31, but at 16:1, 29 remains
the most meta-selective ligand tested. The N-methyl 36, shows moderate reactivity with 63%
conversion in 15 hours, but the N,N-dimethyl 34, shows poor reactivity. The GC-FID for Entry 4
is messy, and does not integrate well. These results indicate that the high reactivity exhibited by
29 and 35 is diminished when the N atom is substituted with non-H groups. Counterintuitively,
the free NH2 of 29 and 35 gives higher steric selectivity than the more hindered ligands 32, 33, 34,
36, and 37.
Although the 36 and 37 show diminished reactivity, the bulky N,N- dibenzyl 34, exhibits
moderately better reactivity than N-methyl 36. This likely due to the benzyl groups being farther
away and more flexible, and ultimately creating less steric pressure close to the metal, in contrast
to methyl groups.
Hydrazone Interaction with HBpin. In order to probe the high reactivity imparted by the
free NH2 of hydrazone ligands, an NMR experiment was devised to monitor the interaction
between 29 and HBpin. 29 was dissolved in CDCl3 and 2 equiv HBpin were added. The mixture
was stirred then transferred to an NMR tube, and 11B and 1H NMR spectra were taken immediately.
The mixture was monitored at 3, 24 and 48 hours.
The first NMR showed HBpin as a large doublet at 27 ppmin the 11B spectrum. There was
a small sharp peak at 2.9 ppm. The 1H NMR integrated properly with the NH peak integrating to
2 protons. The NMR at 3 h showed the sharp peak at 2.9 ppm growing slowly in the 11B spectrum,
and the NH peak in the 1H spectrum was integrating as less than 2 protons. At 24 h the NH peak

	

102	

integrated to 1 proton and the aromatic peaks had shifted. The 11B spectrum showed the doublet
of HBpin and a large sharp peak at 2.9 ppm, and the two peaks integrated 1:1. The sharp peak is
consistent with boron in a tetrahedral environment. After 48 h, the NMR did not change. The NH
peak remained at the same integration.
Figure 3.3. DMAP-Imine Substituted Ligand forms a Hydrazone-HBpin Complex

Figure 3.3. Ligand 29 reacts with 1 equivalent of HBpin to form a complex. The sharp peak at 2.9
in the 11B NMR indicates a boron in a tetrahedral environment.
This NMR study was compared to a study that was previously conducted on the methyl
imine substituted ligand 38 (shown in Table 3.2). To investigate if the unsubstituted pyridine ring
of the ligand was likely undergo borylation during a reaction, ligand 38 was subjected to borylation
conditions with 5 mol % [Ir(OMe)cod]2 and 2 equiv HBpin in THF and monitored by 11B NMR.
After 1 hour, the 11B spectrum showed the large doublet of HBpin at 27 ppm and a large, broad
peak at 24.2 ppm, signifying N-B bond formation. No sharp peak was present at 2.9 ppm. After

	

103	

24 h, a broad peak at 30 ppm was apparent, evidence that borylation on the pyridine ring had
occurred.
Figure 3.4. Methyl-Imine Substituted Ligand does not form a Hydrazone-HBpin Complex

Figure 3.4. The methyl imine substituted hydrazone ligand 38 does not form a tetrahedral boron
complex with HBpin. Ligand 35 undergoes N-B borylation instead, and no tetrahedral boron
environments are evident in the 11B NMR.
These experiments suggest that 29 does not readily undergo N-borylation like typical
hydrazone ligands, such as ligand 38. Further NMR studies showed that 29 forms a complex
rapidly in the presence of [Ir(OMe)cod]2, but one proton remains visible in the 1H NMR. The
spectrum did not change 24 or 48 h later, thus indicating that only 1 equivalent of HBpin formed
an adduct in the presence of the Ir catalyst, and 1 H remains on the N atom of the hydrazone.
Attempts to crystallize the 29-HBpin complex are ongoing.

	

104	

s
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r ap F o
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ith
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Figure 3.5. The crystal structure of 29 shows the pyridyl face and imine arm locked in the
same plane by an H bonding interaction.
Effect of Ligand Structure on Borylation Selectivity of 1,3-Difluorobenzene. Considering
the different mode of binding observed for 29, the borylation of 1,3-difluorobenzene (47) was
undertaken with various ligands to investigate the selectivity differences between the ligands.
Previous work by Chotana and Rak6 enables us to compare dtbpy (31) to Nishida’s ligand (32)
under forcing conditions.
They found that while dtbpy exhibits low selectivity resulting in four isomers, ligands
bulkier than dtbpy achieve better selectivity and avoid 2-borylation between the F substituents.6
We sought to expand this work in order to identify properties more subtle than large steric blocking
groups on the ligands that shift selectivity. The ratios of products are listed in Table 3.3. The long

	

105	

reaction times and high temperature of these conditions are unnecessary for this reactive substrate,
so the conditions were modified in the current round of borylation studies, which were performed
in collaboration with Behnaz Ghaffari and Jonathan Dannatt.
Table 3.3. Prior Ligand Studies of the Borylation of 1,3-Difluorobenzene
F

F

1.5 mol % [Ir(OMe)cod]2
3.0 mol % Ligand
1.0 mmol HBpin

F

12 h 80 °C

Bpin

47

tBu

F

Bpin
F

F

F

Bpin
F

F

F

pinB
Bpin

Ligand

47 A

47 B

47 C

47 D

31

50%

34%

16%

0%

50%

0%

0%

tBu

N

N

N

N

32

50%

Me

Table 3.3. Previous work by Chotana and Rak show selectivity for ligands 31 and
32. The bulky ligand 32 does not borylate the 2-position between the F atoms.
The pyridyl NMe2 substituted and DMAP imine substituted ligands were prepared in the
Maleczka group and included in the Smith group’s ongoing imine ligand studies. The results
relevant to the function of hydrazone activity and selectivity are presented on the next page in
Table 3.4.
The first test was designed to probe the effect of substitution on the imine backbone, and
the methyl imine substituted ligand 38, was compared to the bare pyridyl imine hydrazone 39.
Substitution of the methyl group at the imine carbon increases conversion and selectivity.
The methyl imine substituted ligand 38 has greater selectivity for product 47C, the 2-borylated
isomer.
Within the second set of reactions, the effect of DMAP substitution at the imine carbon of
29 is examined and compared to imine-Me substitution of 38 and lack of imine substitution of 35
and 40. The DMAP imine substituent improves reactivity and conversion, as the reaction is

	

106	

complete within 2 h. The ratio of meta-substituted product 47A obtained from 29 is dramatically
increased, and is 18.2 times greater than the meta borylated product of unsubstituted 35 and 40
and Me substituted 38.
Table 3.4. Selectivity Test of the Borylation of 1,3-Difluorobenzene

F

F

1.0 mol % [Ir(OMe)cod]2
2.0 mol % Ligand

F

Bpin

2.0 equiv HBpin
THF rt

47

F

Bpin
F

F

Ligand structures

Me
1)

N

N

N NH2

38

39
Me2N

Me2N
Me2N

N

N
N
2)

29

N NH2

35

N NH2
Me

N NH2
N

Me

38

N
41

N NH2

40

Br
N
N

N NH2
41

F

Bpin
47 B

47 C

47 D

Ligand

Time

Conversion

38

4h

63 %

1.0 : 0.6 : 5.0 : 0.2

39

4h

36 %

1.0 : 0.8 : 2.4 : 0.4

29

2h

>99 %

18.2 : 1.7 : 1.0 : 2.3

35

2h

91 %

1.0 : 0.4 : 2.8 : 1.3

38

2h

63 %

1.0 : 0.6 : 5.0 : 0.2

40

2h

62 %

1.0 : 0.5 : 2.2 : 0.75

41

2h

50 %

1.0 : 1.2 : 4.9 : 0.95

Ratio A : B : C : D

N NH2

Br
3)

F

N NH2

Br

N

Bpin
F

pinB

47 A

set

F

41

3h

67 %

1.0 : 2.0 : 8.0 : 0.8

42

3h

65 %

1.0 : 1.8 : 13.0: 0.6

N NH2
42

Table 3.4. First set of experiments (1) tests the effect of an imine substituent on the ligand
framework. Second set of experiments (2) compares pyridyl substituents vs effect of imine
substituent, as well as the effect of electron donating or electron withdrawing substituents. Also
considered, effect of borylation of pyridyl ring of 38 compared to pyridyl substituted ligands. Last
set of experiments (3) tests the effect of 3 or 4 substitution of pyridyl ring.
The comparison of 35, 40 and 38 within the second set of reactions is a good means to
compare the of the effect of imine substitution to the effect of 4-substitution on the pyridine ring.

	

107	

35 and 40 have no imine substituent, but have different electron donating group substituents on
the pyridine ring. Ligand 38 has no pyridine ring substituent but has a Me imine substituent.
Also considered, it was shown that 38 itself is borylated in the course of an Ir-catalyzed
reaction. Now the effect of borylated ligand 38 is compared to ligands where borylation is blocked
by pyridyl substituents. The effect of pyridyl borylation is seen in the ratios of
47C:(47A+47B+47D) for 35, 40 and 38. The results indicate that, while all three ligands favor 2borylation over any other single product, 38 produced the highest ratio of 47C:(47A+47B+47D)
at 2.7:1. The other two ligands, 35 and 40 produce 1:1 ratios of 47C:(47A+47B+47D). This lends
support to the observation that methyl substitution of the imine carbon increases electronic
selectivity, and also the borylation of pyridyl rings may shift selectivity to electronic products.
When comparing pyridine substituents of 35 (NMe2) and 40 (Me), the selectivity is about
the same, but the conversion is improved for NMe2 substituted 35, achieving 91% compared to
63%. The unsubstituted 38 and electron withdrawing group Br-substituted 41 fare the worst with
63% and 50% conversion respectively. 41 has slightly improved selectivity for 2-borylated product
47C, with ratio 47C:(47A+47B+47D) observed at 1.6:1. Br substitution of the pyridine ring
appears have roughly the same effect as methyl substitution of the imine carbon. It is difficult to
assign the increased product 47C to borylation of the ring or the methyl imine substituent.
It was previously shown that ligand 38 undergoes borylation of the pyridine ring during
borylation reactions, and Bpin is considered an electronegative group. Comparing 38 to 41 is an
indirect probe of the effect of an electron withdrawing group, like Bpin, on the reactivity and
selectivity of the ligand. The selectivities of 38 and 41 are approximately the same, hence
borylation of the pyridyl rings likely influences selectivity. Br-substituted ligands 41 and 42 are

	

108	

slated to be converted to Bpin substituted ligands by Miyaura coupling in order to test the real
borylated ligands. These efforts are ongoing.
When borylation experiments were carried out on pyridyl ligands as substrates, two
borylated isomers result, 4-borylation and 3-borylation on the pyridine ring, as seen with the
borylation of 2-phenyl pyridine. In order to determine if the mixture of borylated ligands might
shift selectivity of product 47C for ligand 38 over the 47C-selectivity of ligand 41, a third set of
experiments was designed. Using a Br substituent as an approximation of a Bpin substituent, 3-Br
substituted 42 was synthesized. The reaction time was increased from 2h to 3h, and the ratio for
47C:(47A+47B+47D) by 41 increased from 1.6:1 to 2:1, possibly from conversion of product 47D
into product 47C. 42 achieved less conversion than 41, but product 47C selectivity is greater at a
ratio of 3.8:1 for 47C:(47A+47B+47D). When the Br-substituted ligands are converted to Bpin
substituted ligands, they will be re-tested to see if selectivity for 47C increases.
Effect of Solvent Polarity and Borane Source on Selectivity. Since free NH2 can interact
with solvents through H bonding, a last set of experiments was designed to observe the effects on
Table 3.5. Test of Solvent Polarity and Borane Source on Selectivity

F

F

1.0 mol % [Ir(OMe)cod]2
2.0 mol % Ligand

F

F

Bpin

1.0 equiv B2pin2
rt pentane

47

47 A
Ligand structures

Me
Me
N

Br
N
N

41

N NH2

40

38

N NH2

Bpin
F

F

F

Bpin
F

F

F

pinB
Bpin
47 C

47 B

47D

Ligand

Time

Conversion

38

3h

76%

1.0 : 1.3 : 18.0 : 01.0

40

3h

70%

1.0 : 1.0 : 6.5 : 0.8

41

3h

65 %

1.0 : 1.8 : 13.0: 0.6

Ratio A : B : C : D

N NH2

Table 3.5. The effect of decreasing solvent polarity and the borane source are tested.

	

109	

reactivity and selectivity of decreasing the solvent polarity from THF to pentane. Since many
pyridyl imines also form complexes with HBpin, B2pin2 was used as the boron source, to minimize
influence on the hydrazone from the environment. The results are presented in Table 3.5.		
The decrease in polarity and use of B2pin2 resulted in a shift in selecitivty of product 47C
for for all ligands. 41 saw the largest increase in the ratio of 47C:(47A+47B+47D) from 1.6:1 to
3.8:1 Non polar solvents and B2pin2 as the boron source favors electronic selectivity.
The borylation studies of 1,3-difluorobenzene indicate that 4-pyridyl substitution of NMe2
improves conversion and reactivity. 4-Pyridyl methyl substitution improved conversion over
unsubstituted pyriydyl imine ligands, but was not as advantageous as NMe2. 4-pyridyl bromo
substitution decreased conversion and resulted in a shift towards electronic selectivity. Imine
substitution with 4-DMAP greatly enhances reactivity and meta selectivity, while methyl
substitution at the imine shifts selectivity toward electronic products and improves conversion and
reactivity.
Borylation of Electron-Rich Substrates. After probing the function of the pyridyl imine
backbone, attention was turned to comparison of the pyridyl imine to bpy and tmp frameworks. A
series of 1,3-disubstituted electron rich arenes was borylated with 29, 31 and tmp as ligands in
order to compare the reactivity of 29 to widely-used, general purpose ligands of good reactivity.
The substrates chosen were 1,3-dimethoxybenzene (48), 1,3-diisopropylbenzene (49) and 3dimethylaminotoluene (50). The reactions were heated to 65°C and stirred for 22 h. The results
are presented in Table 3.6.
For dimethoxy benzene, 29 gave the most conversion. Tmp gave the best conversion for
the other two substrates. In general 29 performed as well or better than dtbpy. Tmp produced more
conversion in the time allowed. For these substrates, there was not a real test of selectivity so, the

	

110	

next step is to test the ligands on electron rich substrates that give mixtures to compare the
selectivity of tmp to the hydrazone, 29. Efforts in this area are ongoing.
Table 3.6. Borylation of Electron Rich Substrates
R

R

1.0 mol % [Ir(OMe)cod]2
2.0 mol % Ligand

R

2.0 equiv HBpin
THF 65°C 22 h

R

Bpin

conversion
R group

29

31

R1 = R2 = OMe

61%

31%

34%

R1 = R2 = ipr

27%

16%

60%

R1 = NMe2, R2 = Me

13%

13%

33%

tmp

Table 3.6. Borylation comparisons of electron rich substrates between ligand 29,
dtbpy and tmp show that ligand 29 is a viable ligand for electron rich substrates,
performing as well or better than dtbpy.
In summary, the ligand design project is continuing to study ligand 29 with the aim of
developing a highly active, meta selective ligand that is useful for a wide variety of substrates. The
pyridyl imine framework has proven to be more active than the dpm framework, and pyridyl imines
are thermally stable allowing borylation reactions to be heated, whereas dpm type ligated catalyst
complexes break down when heated.
Preliminary tests indicate 29 is as reactive as dtbpy for neutral and electron withdrawing
substrates, and more reactive towards electron rich substrates, though not as reactive towards these
substrates as tmp. Studies are on-going to investigate whether 29 is more selective than tmp for
borylation of non-symmetric elecron rich substrates that produce mixtrues of isomers.

	

111	

The structure and reactivity studies of the pyridyl imine framework indicate that electron
rich imine substituents increase activity and conversion. Methyl imine substitution shifts
selectivity towards electronic products, while the DMAP imine substituent shifts to a high degree
of

steric selectivity. Electron donating 4-pyridyl substituents also increase reactivity and

conversion of borylation reactions. The most beneficial 4-pyridyl substituent was found to be
NMe2. Electron withdrawing substituents decrease conversion, but are more selective for
electronic products. 3-pyridyl substitution is not as beneficial as 4-pyridyl substitution. Efforts to
enhance reactivity and meta selectivity hint that a larger, more electron donating aromatic
substituent at the imine position may improve selectivity.
The 1,3-dicynobenzene borylation tests showed that the increased reactivity of ligand 29
is partly from the free NH2 of the hydrazone. Substitution of the NH2 leads to decreased reactivity,
hemilabile behavior, and directed borylation with substrates that posess chelate directing
functionality. The free NH2 also facilitates HBpin complex formation which may block some
electronic ortho borylation, and shifts selectivity towards steric products. The steric effect of
HBpin is evident, as the tetrahedral boron complex provides a steric demand near the metal. It is
not yet known what kind of electronic effects the HBpin complex engenders, and that will be
explored by computaional modeling in the near future. Ligand 29 represents the design of a
succesful ligand framework, and efforts to modify that framework to engineer selectivity are
ongoing.
Although the dpm framework is much less reactive than the pyridyl imine framework, a
unique opportunity exists to study the kinetics of HBpin borylation wth dpm ligands and to probe
the catalytic cycles in order to shift selectivity outcomes.

	

112	

REFERENCES

	

113	

REFERENCES

1.
Vanchura, I. I. B. A.; Preshlock, S. M.; Roosen, P. C.; Kallepalli, V. A.; Staples, R. J.;
Maleczka, J. R. E.; Singleton, D. A.; Smith, I. I. I. M. R., Electronic effects in iridium C-H
borylations: insights from unencumbered substrates and variation of boryl ligand substituents.
Chemical Communications 2010, 46 (41), 7724-7726.
2.
Gasque, L.; Medina, G.; Ruiz-Ramı́rez, L.; Moreno-Esparza, R., Cu–O stretching
frequency correlation with phenanthroline pKa values in mixed copper complexes. Inorganica
Chimica Acta 1999, 288 (1), 106-111.
3.
Tagata, T.; Nishida, M., Aromatic C-H Borylation Catalyzed by Iridium/2,6-DiisopropylN-(2-pyridylmethylene)aniline Complex. Advanced Synthesis & Catalysis 2004, 346 (13-15),
1655-1660.
4.
Ros, A.; Estepa, B.; López-Rodríguez, R.; Álvarez, E.; Fernández, R.; Lassaletta, J. M.,
Use of Hemilabile N,N Ligands in Nitrogen-Directed Iridium-Catalyzed Borylations of Arenes.
Angewandte Chemie International Edition 2011, 50 (49), 11724-11728.
5.
Ros, A.; López-Rodríguez, R.; Estepa, B.; Álvarez, E.; Fernández, R.; Lassaletta, J. M.,
Hydrazone as the Directing Group for Ir-Catalyzed Arene Diborylations and Sequential
Functionalizations. Journal of the American Chemical Society 2012, 134 (10), 4573-4576.
6.
Chotana, G. A.; Rak, M. A.; Smith, M. R., Sterically Directed Functionalization of
Aromatic C-H Bonds: Selective Borylation Ortho to Cyano Groups in Arenes and Heterocycles.
Journal of the American Chemical Society 2005, 127 (30), 10539-10544.

	

114	

CHAPTER 4
GERMANIUM CROSS-COUPLING
Background and Significance. Harnessing the reliability of palladium-catalyzed Stille
cross-coupling reactions while eliminating the health hazards and costs associated with handling
and disposal of tin waste byproducts has been an interest in synthetic organic chemistry since the
late 1980s and early 1990s, and efforts to replace tin with a less toxic alternative from group 14
have been on-going since that time.1 The bulk of efforts have been directed towards silicon
coupling chemistry, and the field has developed many successful and useful protocols from the
primary work of Hiyama and Denmark and others.2
In the early 2000s, the Maleczka group took an interest in reducing the impact of tin in
Stille couplings by developing the first Stille coupling process catalytic in tin, employing 6 mol%
trialkyl tin rather than the standard stoichiometric transmetalating reagents.3-5 With an eye towards
eliminating toxicity concerns altogether, attention was turned to the study of germanium crosscoupling reactions with the aim of developing a similar catalytic coupling cycle employing
germanium instead of tin. The results of the initial studies were published in 2009 by Torres, Lavis
and Maleczka and formed the basis for this project.6
Several unusual features mark this germanium cross-coupling reaction compared to all
other germyl cross-coupling efforts pursued up to that time. Like the early Si coupling efforts,
directly replacing trialkyl tin reagents with analogous R3Si or R3Ge silyl or germyl reagents did
not afford transmetalation. Activation of the more nonpolar C-Si and C-Ge bonds had to be
accomplished by addition of fluoride ions to form a pentacoordinte intermediate which then could
undergo cross-coupling. To the best of our knowledge, unlike all other published germanium cross-

	

115	

coupling reports, Torres’ account is the only direct R3Ge analogue without fluoride additives or
activation steps.
During the initial investigation of the cross-coupling reaction, an unexpected result was
obtained. E-tributylvinyl germanes analogous to typical trialkyl stannane reagents were subjected
to standard Stille arylation conditions in order to obtain vinyl arenes. Instead of the expected Evinylarene product, however, the major product was the inverted Z-aryl olefin, as shown in
Scheme. 4.1.
Scheme 4.1. Germyl-Stille Cross-Coupling Results in Inversion
20 mol % Pd2dba3
80 mol% AsPh3
2 equiv Ph-I
Bu3Ge

OH

Ph

OH

NMP, 70 °C 48 h

4.1

4.2
30 % yield

Scheme 4.1. The initial germyl-Stille reactions resulted in inversion of stereo chemistry to obtain
Z isomer 4.2 as the major isomer.
Although the yield was low, if optimized, this unexpected result could offer a new tin-free
Stille-type coupling with stereo control complementary to conventional Stille methodology. The
early attempts by Torres to optimize this reaction under Stille conditions resulted in little
improvement. Adding CuI, a typical means of rate acceleration for Stille reactions,7 caused the
reaction to fail altogether. Drawing insight from previous suggestions of Heck involvement in
other contemporary Ge coupling studies,8 it was recognized that a Heck mechanism could better
explain the inversion of the olefin geometry found in the coupling product. Heck reaction
conditions were subsequently investigated.
The standard conditions as shown in Scheme 4.2 were determined based on optimization
studies with carbonate bases and quaternary ammonium additives previously tabulated for Heck
reactions as catalogued by Jefferey in the mid 1990s.9-10 This palladium Heck type system is also
	

116	

referred to as [Pd/M2CO3/QX] where Pd is a simple palladium salt, usually palladium acetate,
Pd(OAc)2. M is an alkali metal, usually potassium or sodium, and QX is a quaternary ammonium
halide, tetrabutylammonium bromide (TBAB) in this case. Triphenylphosphine (PPh3) was
utilized as the ligand, which is typical for this system, and iodobenzene (PhI) was the coupling
partner.
Scheme 4.2. Optimized Heck Conditions for Published Germanium Cross-Coupling
20 mol % Pd(OAc)2
40 mol% PPh3
2 equiv Ph-I
Bu3Ge

Ph

OH
4.1

1 equiv TBAB, 2.5 equiv K2CO3
9:1 MeCN:H2O (~0.05 M)
70°C 16 h

OH

Ph

OH

Ph
OH

4.2

4.3

4.4

(Z)
major product

(E)

internal

Scheme 4.2. The optimized conditions for the germyl Heck coupling published by Torres, Lavis
and Maleczka in 20096 were similar to the conditions developed by Jeffrey10 in the early 1990s.
Previously Proposed Catalytic Cycle. Operating under the premise that the reaction
proceeded predominantly by a Heck-type insertion rather than a Stille-type transmetalation,
Scheme 4.3 expands upon the putative mechanism offered in the 2009 paper. The mechanism is
unusual in that instead of the expected b-H elimination which retains E olefin geometry, a bond
rotation is suggested that puts Ge and Pd syn to each other, in preference to the usual coplanar
arrangement of Pd and H. Instead of a b-hydride elimination, a b-germyl elimination is
hypothesized, thus giving rise to the inverted Z olefin geometry. There is no precedence for this
type of reaction in the literature, but over the next few years, after the project lapsed, attempts to
rationalize the mechanism in order to explain the inversion prompted a reexamination of the
proposed Pd-Ge elimination.

	

117	

Alternate explanations involving reinsertion of a hydride,11 oxy-palladation,12-13 or Pd Ochelation14 failed to account for the inversion of geometry. A look at the substrate scope provided
hints for the basis of this unique reactivity.
Scheme 4.3. Putative Mechanism of Germyl Cross-Coupling Reaction as published in 2009
Bu3GeX

Ph X
Pd(0)

Bu3GePd(ΙΙ)X

Ph

(ΙΙ) Ph
LnPd
X

Oxidative
Addition

Reductive
Elimination

Bu3Ge

R

R

Elimination

Coordination
Bu3Ge

Pd(ΙΙ)X

Ph
H

H

R
Syn-Coplanar
Addition

Rotation

Ph X
LnPd(ΙΙ)
H

R

Bu3Ge

H

Ph Pd(ΙΙ)X
H
R
Bu3Ge
H

Scheme 4.3. The mechanism proposed by Torres, Lavis and Maleczka in 2009 involved a bgermyl elimination instead of the usual b-hydride elimination.
As seen in Table 4.1, successful coupling required the presence of a tertiary allylic alcohol,
unlike simple Heck reactions which apply across a wide range of olefins and tolerate a variety of
functional groups.15-16 When the alcohol was protected, as compound 4.7, no reaction occurred.
This specific substrate scope cast doubt upon hydride reinsertion, as no oxygen functionality is
required for the addition of a palladium hydride species. The failure of the ether to couple ruled
out chelation chemistry,14 as ethers and esters form a large part of the substrate scope of reported
chelation chemistry. Oxy-palladation or cyclic germanium intermediates were ruled out, as

	

118	

following the mechanisms for both possibilities leads to retention of stereochemistry, not
inversion.
Table 4.1. Substrate Scope of Germyl-Heck Coupling Reaction.

Table 4.1. The substrate scope of Torres’ coupling reaction was limited to
vinyl germanes bearing an unprotected allylic alcohol.
Substrate Scope. Torres used vinyl germanes with unhindered allylic alcohol groups, like
compound 4.8 in Table 4.1, as a probe of competition for b-hydride elimination against the
proposed b-germyl elimination, with the predicted outcome being retention of stereochemistry for
b-hydride elimination and inversion for b-germyl elimination. When the allylic carbon is not
tertiary, however, the reaction results in a complicated mixture, and Torres isolated only 15%
internal product, with no formation of either E or Z coupling product, and no recovery of unreacted

	

119	

starting material. The reaction mechanism is not straight forward, and may operate by a competing
mixture of pathways.
Looking back to literature on desilylative couplings from the 1980s, Hiyama presents his
observations of unactivated silanes coupling with allylic carbonates and epoxides under Pd
catalyzed conditions which result in inversion of configuration, while activation with fluoride ion
sources result in retention of configuration with the same substrates.17 Scheme 4.4 shows his
mechanistic reasoning for activation vs palladation.
Scheme 4.4. Hiyama’s Activation vs. Carbopalladation Mechanisms
F

Pd(Ar)Ln

Me

H

Ph

Pd(Ar)Ln

Ph

[Si]

– [Si]–F

H

Me

– PdLn

Ar

Ph

Me

H

Activation

[Si]
Me

Ph
H

Ph

Pd(Ar)(F)Ln
– [Si]

Me

Ph

Pd(Ar)Ln
H

– Pd(F)Ln

Me

Ar
H

Carbopalladation

Scheme 4.4. Hiyama noticed that geometry of some desilylative couplings depended on reaction
conditions. If a pentacoordinate species was generated by activation with fluoride additives, the
geometry was retained. If the mechanism went through a direct carbopalladation across a C=C
double bond without a fluoride ion source, the geometry was inverted. Only allylic carbonates and
epoxides underwent unactivated coupling.
In Hiyama’s mechanism, he shows the desilyation step for unactivated substrates as
concurrent with the carbopalladation step. The first coupling reactions on the reboot of this project
involved looking for evidence of degermylation to determine whether degermylation happened
before or after carbopalladation. The initial reactions gave low conversion, and so careful recovery
and quantification of the starting material was done in order to be sure than the vinyl germane was
not degermylating or forming intermediates that were difficult to detect by NMR. In all cases,

	

120	

the starting material recovery was nearly equal to the amount left over as indicated by GC-FID
and 1H NMR. We concluded that the starting material was not degermylating prior to the coupling
reaction to liberate an allylic alcohol. This was consistent with the degermylation of a reaction
intermediate.
Scheme 4.5. Degermylation of Vinyl Germanes makes Allylic Alcohols
degermylation
Bu3Ge

OH
4.1

OH

–Bu3Ge

4.9
2-methyl-3-butene-2-ol

The allylic alcohol that would result from degermylation of vinyl germane 4.1 is 2-methyl3-butene-2-ol, shown in Scheme 4.5 (referred to here as compound 4.9). Looking back to the early
Heck coupling reports from the 1970s, Chalk18 and Heck18 reported the first Heck coupling
reactions of 2-methyl-3-butene-2-ol (4.9) in 1976, The results are shown in scheme 4.6.
Scheme 4.6. The First Reported Heck-Coupling of Allylic Alcohol 4.9.
3 mol % Pd(OAc)2(PPh3)2
2.7 mol% PPh3

1.25 equiv

OH
4.9

Ph

OH

Ph

Ph
OH

1.2 equiv NaHCO3
2 M Et3N 140 °C 4h

98% E
4.3

1% internal
4.4

1% dehyd.
4.10

In the Heck coupling of the free allylic alcohol 4.9, the Z isomer is not seen among the
products. The E isomer is overwhelmingly the major product with only internal and dehydration
products seen as side products. In the years that followed with successive improvements to Heck
coupling, almost all coupling reactions with 4.9 produce 100% E isomer, with no traces of internal
or Z isomer. A typical example of modern Heck coupling conditions are shown on the next page
in Scheme 4.7.19

	

121	

Scheme 4.7. Modern Heck-Coupling Protocols are E Selective
3 mol % PdCl2(PCy3)2
Ph

OH
4.9

1.1 equiv Cs2CO3
0,75 M dioxane

OH
100% E
4.3

In all the literature searches we conducted of Heck reactions with allylic alcohols and
similar vinyl silanes, Torres’ coupling reaction was the only Heck reaction that afforded the Z
isomer at all, let alone as the major product. Any coupling of the free allylic alcohol 4.9 under
Heck conditions does not result in formation of the Z isomer. This suggests that the vinyl germane
starting material forms a reactive intermediate that participates in the Heck reaction instead of
liberating the alcohol.
Looking at the structures of the successful coupling partners, compounds 4.1 and 4.5 in
Table 4.1, both can form an epoxide intermediates, reminiscent of Hiyama’s early unactivated
allylic epoxide and allylic carbonate substrates for desilyative coupling.17, 20-21 Compound 4.6 does
not have an allylic O atom, and 4.7 cannot form an epoxide due to the bulky O protection group.
In our subsequent studies, we tried protecting the alcohol with a smaller methyl group, and that
also resulted in no reaction. Formation of intermediate epoxides is a plausible reaction path since
the substrate scope shows vinyl germanes lacking allylic oxygens or having protected allylic O
atoms do not participate in the Heck coupling reaction.
The unhindered compound 4.8 has an allylic alcohol but the position is also flanked by bH atoms. b-H elimination would result in a tautomerization likely to form a ketone or aldehyde. In
our resumed studies, we found ketones present in some reaction mixtures, and the tell-tale CH2
protons that are usually hidden under tetrabutylammoniumbromide (TBAB) peaks in the NMRs
of the crude material and are difficult to see. The ketone products also come off the column near

	

122	

the solvent front with the left over iodobenzene in the normal silica columns eluted with
dichloromethane that were employed to analyze the reaction products. These less polar products
can be easily missed without careful analysis of all eluted fractions. Investigation of unhindered
vinyl germane alcohols is a priority of this project to enable a wider the substrate scope beyond
tertiary allylic alcohols.
Probe of Steric Effects on the Inversion of Geometry. To test whether the O atom is
directly involved in the inversion of the stereochemistry and to rule out steric influence, the
analogous tributylvinyl germane with tertiary allylic carbon of 3,3-dimethylbutane, 4.11, was
synthesized and subjected to coupling conditions. Under the standard conditions, no coupling
reaction occurred. Under the Torres’ initial Stille coupling conditions with Pd2(dba)3 in NMP, still
no coupling resulted. Adding tetrabutylammoniumfluoride (TBAF) to both the standard Stille and
Heck reaction conditions from Torres’ 2009 report6 also resulted in no reaction.
Scheme 4.8. Germanium Cross-Coupling under Fluoride Activation
1.1 equiv Ph-I
10 mol% Pd2(dba)3
7 equiv TBAF
Ph

Bu3Ge
4.11

toluene 100°C 16 h

4.12
20% conversion
100% E

Scheme 4.8. When the vinyl germane lacks an allylic alcohol functional group, cross-coupling
conditions must be harsher and activated with fluoride ions. Only E coupling product is observed
under these conditions.
After searching for optimized conditions that might work, 4.11 was subjected to Stille
coupling according to Wnuk’s moist toluene approach using TBAF as an activating source, as
detailed in Scheme 4.8.22 The reaction exhibited only 20% conversion and only E product was
seen by NMR and GC-FID. Although not much conversion was realized, the coupling product was
isolated for a 16% yield and 72% of the starting vinyl germane 4.11 was recovered.

	

123	

Updated Putative Mechanism Based on Reactive Intermediate Hypothesis. The recovery
of the starting material supports the idea that the vinyl germane is robust and does not degermylate
from fluoride attack under the reaction conditions to undergo subsequent coupling as a free allylic
alcohol. In all cases of vinyl germane coupling, the unreacted vinyl germane is seen in the mass
spec as a single peak m/z = 272 which corresponds to the molecular ion minus a butyl radical
group (m/z = 56).
Scheme 4.9. Proposed Mechanism for Inversion of Stereochemistry of Ge Cross-Coupling
Ar

Pd

X

[Pd]
Ar-X
Bu3Ge

OH
4.1

Base

syn-addition
Bu3Ge

OH

H
Bu3Ge

Ar
PdX
OH
H
4.13

Pd(0) + X
X
Ph

OH

GeBu3

degermylation
Ar
H

4.2

H
O

Bu3Ge-X

degermylation of
intermediate 4.14

Ar

rotation
H
Bu3Ge

H
O

4.14

Scheme 4.9. The proposed mechanism of the germyl-coupling reaction proceeds through the
generation of a reactive epoxide intermediate with subsequent degermylation of the intermediate.
The unreacted starting material is easily isolated and quantified to verify that it is not
degermylating or forming an intermediate that is not detected by GC-MS or NMR. The ejected
Bu3Ge fragment is also seen in the GCMS with an m/z = 245. The mass of iodine is not found with
it, so it is not unequivocally verified that degermylation occurs with attack of iodide to the
intermediate, as illustrated with the proposed degermylation of 4.15, as shown in Scheme 4.9.

	

124	

Further support for the degermylation of an intermediate is found in the fact that the Bu3Ge
fragment does not occur in the GC-MS of the starting material as a fragment pattern or artifact,
nor does it appear in coupling reactions that have failed. The fact that this tributylgermyl fragment
is only found in reactions where coupling products have been formed lends support to the fact that
degermylation happens to an intermediate and not directly to the starting material.
Attempts to synthesize the putative secondary allylic germyl epoxide, 4.14 (as shown in
Scheme 4.9) have not yet succeeded, and are ongoing. While work on the proposed intermediate
progresses, primary allylic germyl epoxides were synthesized in the meantime. Although primary
epoxides cannot provide information about the retention or inversion of stereochemistry, these
reagents provided a means to test whether allylic germyl epoxides can undergo coupling reactions
under the prescribed reaction conditions.
Scheme 4.10. Germyl Allylic Epoxides Degermylate under Acidic Conditions
H

O

OH

GeBu3
4.15

– GeBu3

4.16

Scheme 4.10. The allylic germyl epoxide 4.15 was shown to degermylate on silica to
generate an allylic alcohol. Efforts were made to determine whether the starting vinyl
germane underwent degermylation to liberate the allylic alcohol or if degermylation
occurred on a carbopalladated intermediate.
When epoxide 4.15 was passed through an activated silica plug, degermylation to the
allylic alcohol 4.16 was seen. The NMR matched the reported spectrum of the known compound
and GC-FID and GC-MS standards were taken in order to look for the free alcohol in the crude
reactions. The epoxide survived passage through grade 2 silica (~3% water) and neutral and basic
alumina.

	

125	

Cross-Coupling with Allylic Germyl Epoxides. To test if the allylic germyl epoxide could
undergo coupling in a reaction under the current conditions, a standard coupling reaction with
vinyl germane 4.1 and iodobenzene was begun. After verification of coupling product formation
around 4 - 8 hours, the vinyl germane was injected into the reaction. The analogous Heck coupling
product of iodobenzene with 1-phenyl-prop-2-en-1-ol, 4.15, was found in the literature to be the
ketone 1,3-diphenylpropan-1-one, 4.16 (Scheme 4.9)23. After 24 hours, the GC-MS of the crude
reaction was analyzed for the masses of the free allylic alcohol and the coupling product. The
allylic alcohol was not found in the NMR or GC-MS, but the coupling product was seen in both
NMR and GC-MS, and the spectrum of the isolated compound matched reported NMR data.
Traces of unreacted germyl epoxide also remained in the crude reaction, but were not isolated.
Scheme 4.11. Reaction of an Allylic Germyl Epoxide in the Cross-Coupling Reaction

Bu3Ge

OH

+ 2.0 equiv

I

standard coupling condtions

Ph

4.1

OH

Ph

4.2

O

OH
4.3

Ph
4.4

OH

O

GeBu3
4.15

4.17
add epoxide at t = 4 h

1,3-diphenylpropan-1-one

Scheme 4.11. The allylic germyl epoxide was injected into a coupling reaction already in progress
to ensure the coupling conditions were viable upon addition of the epoxide, and to be sure the
reaction was not hindered or stopped by the addition of the epoxide.
The procedure was repeated with iodotoluene as the coupling partner, and epoxide 4.15
was added into the reaction by syringe after 8 hours. The expected coupling product, 4.1823 was
found in the GCMS and NMR of the crude reaction. Less conversion occurred for this reaction,
and significant amounts of epoxide were seen remaining in the GC-MS and NMR of the crude
reaction. The free allylic alcohol was not found in the crude reaction.

	

126	

Scheme 4.12. Allylic Germyl Epoxide Reaction with Iodotoluene

Bu3Ge

OH

I

+ 2.0 equiv

standard coupling condtions
Tol

Me

4.1

OH

OH Tol

Tol

4.2

4.3

O

4.4

OH

O

GeBu3
4.15
add epoxide at t = 8 h

4.18
Me
1-phenyl-3-(p-tolyl)propan-1-one

Scheme 4.12. The reaction was repeated with iodotoluene as the coupling partner to ensure no
phenyl transfer reactions from PPh3 or other reagents occurred.
These reactions showed that allylic germyl epoxides are capable of undergoing unactivated
coupling reactions, thus lending support to the proposed epoxide intermediate in Scheme 4.7. In
order to investigate the fate of unhindered allylic alcohols of vinyl germanes in the coupling
reaction, the unhindered allylic vinyl germane 4.19 (Scheme 4.11) was synthesized and subjected
to a coupling reaction under the same conditions with vinyl germane 4.1 and iodobenzene.
Scheme 4.13. Cross-Coupling Reaction of an Unhindered Allylic Germyl Epoxide
Bu3Ge

OH

+ 2.0 equiv

I

standard coupling condtions

4.1

Ph

OH

Ph

4.2

O

GeBu3
4.19

add epoxide at t = 4 h

OH
4.3

Ph
4.4

OH

O
H
4.20

OH
4.21

cinnamaldehyde (E)-3-phenylprop-2-en-1-ol
(cinnamyl alcohol)

Scheme 4.13. The undhindered allylic germyl epoxide serves as a test to probe what might happen
to unhindered vinyl germanes under the current coupling conditions.
At 4 hours, the epoxide was added into the reaction. After 24 h, the crude reaction smelled
like cinnamon. Cinnamaldehyde and cinnamyl alcohol were found in the crude NMR and GCMS.
The unhindered epoxide formed cinnamaldehyde and cinnamyl alcohol as byproducts of the
coupling reaction.
	

127	

Figure 4.1. NMR of the Cross-Coupled Unhindered Allylic Germyl Epoxide

Figure 4.1. NMR of coupling reaction compared to known samples of cinnamaldehyde and
cinnamyl alcohol show that the unhindered epoxide undergoes degermylative cross- coupling with
iodobenzene
Scheme 4.14. Germyl Allylic Epoxides Participate in Heck-Coupling.
O
Ph

O
GeBu3

X-Ar

Ph

Pd, base

4.15

O
Ph

H

−Bu3GeX

X

H HH
Ar
PdX
rotation

Ar

Ph

β-hydride
elimination

OH

O
Ph

Ar

4.17

−H-PdX

Ph O

H

H
Ar

H
PdX

Scheme 4.14. Allylic germyl epoxides participate in Heck-coupling with aryl halides, thus lending
support to the proposed reactive intermediate.
After support was found for the generation of a transient allylic germyl epoxide
intermediate, an effort was made to improve the conversion and repeatability of the reaction, and
to expand the substrate scope to include allylic carbonates, amines or thiols and vinyl germanes

	

128	

with secondary allylic alcohols. Other catalysts systems less prone to b-hydride elimination may
be investigated for the purpose of broadening the substrate scope.
The first task for optimization however, was to obtain consistent conversion and isomer
ratios of Z to E, and to improve overall repeatability in general. Some early results indicated that
water was necessary in higher ratios than 1:9 for the solvent. The best acetonitrile to water ratio
was found to be 2:1. Greater solvent volume also helped to increase conversion and sparging with
O2 gas was also beneficial. Stirring the reaction for at least an hour before heating was found to
increase conversion. Despite numerous optimization attempts, the reaction remained frustratingly
inconsistent in conversion and Z:E ratios.
In collaboration with Kiyoto Tanemura, oxidative Heck-coupling conditions were
investigated to see if improvements could be made. The results of some of these studies are
presented in Table 4.2, seen on the following page.
Investigation of Oxidative Heck Conditions. When comparing additives and changes in
conditions, it seems adding the oxidant benzoquinone, (BQ) was helpful for both conversion and
yield, except in entry 10 when used in combination with O2 sparging. Adding a radical initiator
AIBN in Entry 11 resulted in no reaction. Bidentate ligand bis(diphenylphosphino)propane, dppp,
decreased the Z:E ratio significantly for Entry 6. Triphenylphosphine oxide, TPPO, worked as a
ligand in place of triphenylphosphine. Table 4.2 represents a sampling of Tanemura’s
optimizations. See the supporting information for more details. No clear trends emerged from
studying the effect of additives or conditions designed to work in accordance with known Heck
mechanisms, and again, the results were inconsistent.

	

129	

Table 4.2. Investigation of Additives for Oxidative Heck Reactions

OH
Bu3Ge

+ 2.0 Ph

20 mol% Pd(OAc)2
1.0 equiv. Bu3NBr
2.5 equiv. K2CO3
additives (1-13)

OH

I

Ph
2:1 MeCN/H2O,

70oC,

24 hr

+

Z

Entry

Additive

1

OH +
Ph

Ph
E

OH
internal

Z:E:internal

40 mol % Ph3P

NMR
conversion
40 %

2

40 mol % Ph3P, O2 sparge

76 %

10:1:0.3

3

40 mol % Ph3P, air sparge

77 %

5.5:1:0.2

4

40 mol % Ph3PO

60 %

13:1:0.2

5

20 mol % Ph3P,
20 mol % Ph3PO

52 %

6.5:1:0.2

6

40 mol % dppp, O2 sparge

30 %

2.5:1:0.1

7

40 mol % Ph3P, 20 mol % BQ

49 %

35:1:2

8

O2 sparge

0%

-

9

20 mol % BQ, O2 sparge

55 %

14:1:0.2

10

20 mol % BQ,
40 mol % Ph3P, O2 sparge

11 %

2:1:trace

11

40 mol % Ph3P, 10 mol % AIBN

0%

-

12

40 mol % S-Phos, O2 sparge

71 %

14:1:0.4

13

40 mol % Ph3P, 2.5 equiv. Ag2CO3

85 %

5:1:trace

46:1:2

Table 4.2. Additives typically used for oxidative Heck additions produced no clear trends. BQ =
1,4 benzoquinone, dppp = bis(diphenylphosphino) propane, a bidentate ligand, AIBN =
azobisisobutylnitrile, a radical initiator, SPHOS = 2-Dicyclohexylphosphino-2′,6′-dimethoxy
biphenyl, a bulky monodentate phosphine ligand.
When we turned to the literature for guidance on the conditions for the coupling, it became
clear that the [Pd/M2CO3/QX] Heck coupling system was likely generating Pd nanoparticles,24 and
the coupling reaction was operating under a mixture of homogeneous and heterogeneous
conditions.

	

130	

Next, in collaboration with Shawn Haldar and Maryam Abbas, investigation of the
substrate scope, effect of O2 on the reaction, and testing for the presence of nanoparticles began.
Substrate Scope from Updated Optimization. A summary of the substrate scope is
presented in Table 4.3. In keeping with the generation of nanoparticles, Abbas found that stirring
the reagents for at least an hour, and making sure all solids were dissolved before adding the
Pd(OAc)2 was beneficial for higher yields and better Z:E ratio..
Table 4.3. Substrate Scope of Germanium Cross-Coupling Reaction
Entry

Substrate

Conversion

Z:E ratio

Yield

84%

20:1

78%

Br

12%

14:1

5%

Me

I

57%

10:1

47%

4) O N
2

I

0%

—

—

Br

15%

5:1

7%

I

12%

5:1

5%

Br

22%

8:1

10%

1)

I

2)
3)

5)

O2N

6) MeO
7)
O

Table 4.3. General Conditions for 0.25 mmol: 1 equiv vinyl germane (4.1), 2 equiv Ar-X, 40
mol % PPh3, 1 equiv Bu4NBr, 2.5 equiv K2CO3, 2:1 MeCN:H2O, 20 mL (0.0125 M). Sparge
O2 gas (one balloon volume), 20 mol % Pd(OAc)2 added after stirring and sparging with O2,
but before heating. Stir under O2 balloon 1 hour, heat 70 °C 23 more hours.
The reaction worked best for iodobenzene, then showed moderate to good conversion for
electron donating groups, but the coupling barely worked for electron withdrawing coupling

	

131	

partners like para-nitro-bromobenzene, resulting in low conversions of 5 -15%. No conversion was
seen for para-nitro-iodobenzene
During the substrate screening, a test to determine the effect of O2 atmosphere on the
coupling reactions was conducted. One reaction of 4.1 with iodobenzene was made up with all
reagents except Pd(OAc)2 and allowed to stir for a half hour. Half of the reaction was removed to
another flask by pipette. The flasks were labeled 1 and 2. Flask 1 was sparged with house N2 gas
for 2 hours, while flask 2 was sparged with two large balloon volumes of O2 for a half hour then
put under an O2 balloon atmosphere. After 2 hours, the Pd(OAc)2 was added. Flask 1 turned black
immediately, while flask 2 looked normal, a bright orange color. The reactions were then stirred
at room temperature for 3 hours. A GC-FID sample was taken and both reactions had about 10%
conversion. The reactions were heated to 70°C overnight for 18 h, a total of 24 h since the reactions
were started. Flask 1, carried out in the absence of O2, achieved 55% conversion with 6:1 Z:E ratio.
Flask 2, carried out under O2, achieved 70% conversion with 14:1 Z:E ratio. It seems as if O2
improves conversion and Z:E ratio, but is not crucial for the reaction to proceed.
Mercury Poisoning Test. The first test for nanoparticles was a Hg poisoning test in which
a coupling reaction was set up and stirred for an hour, then half of the reaction was removed by
pipette to another flask. A GC-FID sample was taken to ensure coupling products were being
formed, with about 7% conversion seen in both. A drop of mercury was added to one flask while
the other was allowed to proceed according to the standard conditions. The flask with mercury
immediately turned clear and the conversion was low, around 10%, while the second flask without
Hg showed 77% conversion. This was indicative that nanoparticles were probably being formed,
and both heterogeneous and homogeneous conditions were operating.

	

132	

Catalyst Recycling Test. A second test was done where germane 4.1 and iodotoluene were
coupled to make product 4.22, as shown in Scheme 4.12. The reaction was allowed to settle for 24
hours and then the reaction was slowly decanted out. The dirty flask and magnet were used for a
subsequent coupling reaction of iodobenzene and 4.1 under standard conditions except no
additional palladium was added. Conversion to 4.2 was seen and 4.22, coupling product of the
previous reaction, was not present in the GC or NMR. Although the conversion was low, the
product was isolated and weighed to be sure the yield was consistent with the GC and NMR
conversion. 10% isolated yield of pure 4.2 was obtained.
Scheme 4.15. Nanoparticle Recycling Test

Bu3Ge

2 equiv Tol-I
20 mol% Pd(OAc)2
40 mol% PPh3

OH
4.1

2:1 MeCN : H2O
2.5 equiv K2CO3
70 °C 24 h

Tol

OH

Tol

OH
4.23

4.22

50% conversion
10:1 Z:E ratio

Reaction decanted
No Pd added!
Ph

OH
4.2

Ph

OH
4.3

15% conversion
>50:1 Z:E

Flask and stirbar used
without washing

2 equiv Ph-I
40 mol% PPh3
2:1 MeCN : H2O
2.5 equiv K2CO3
70 °C 24 h

Confirmation of Pd Nanoparticles by TEM and EDS. Taken together, the results of the
poisoning test and the catalyst recycling test were persuasive. A sample was prepared for
Transmission Electron Microscopy (TEM). Images of the samples revealed the presence of poorly
controlled nanoparticles varying in size from about 50 nm to 500 nm. An elemental analysis
indicated about 1.9 % Pd present by weight in the sample, amidst organic residue.
	

133	

Figure 4.2. TEM Images of Poorly Controlled Pd Nanoparticles

Figure 4.3. Elemental Analysis of Pd Nanoparticles by EDS Spectrum	
Spectrum	processing	:		
No	peaks	omitted	
	
Quantitation	method	:	Cliff	Lorimer	thin	
ratio	section.	
Processing	option	:	All	elements	analyzed	
(Normalised)	
Number	of	iterations	=	3	
	
Standardless	
	
Element	 Weight%	
Atomic%	
	
C	K	
88.74	
94.63	
	
O	K	
4.78	
3.82	
	
Al	K	
0.57	
0.27	
	
P	K	
0.46	
0.19	
	
K	K	
2.18	
0.71	
	
Pd	L	
1.90	
0.23	
	
I	L	
1.38	
0.14	
	
	
	
	
	
Totals	
100.00	
	
	
Deconvolution	Elements	:	
Copper	
Sample	thickness:			20.0	nm	
Sample	density:						 3.32	g/cm3	
Density	estimate:			 2.40	g/cm3	
Beam	broadening:		0.32	nm	
No	optimization	has	been	
performed.	
Detector	efficiency	:	Calculation	
Pulse	pile	up	correction	performed.	

	

134	

Although the discovery of Pd nanoparticles has complicated the investigation of this
germanium cross-coupling reaction, there are still more interesting features to be discovered about
the mechanism. When running a slow, long method in the GC-MS to look for intermediates and
byproducts that can offer clues to the mechanism, a large acetamide peak was found. The reagent
bottle of acetonitrile was tested and acetamide was absent. The reagents for a coupling reaction of
4.1 and iodobenzene were combined and stirred together for an hour, then a sample was removed
and tested by GC-MS before the addition of Pd(OAc)2. The combination of reagents did not contain
any detectable aetamide. The Pd(OAc)2 was added and the reaction was heated to 70 °C for 24 h.
When a reaction sample was tested, a large acetamide peak was present. The reaction appears to
catalyze the hydration of MeCN, and the solvent may be functioning as a ligand, thus becoming
oxidized in the way that PPh3 is oxidized to TPPO.
At the present time, efforts to quantify how much acetamide is produced from the reaction
are in progress. We also wanted to know if the hydration of nitriles is general or if only acetonitrile
can be hydrated. In a preliminary test for nitrile hydration, para dicyanobenzene was added into a
coupling reaction. The next day the material was absent in the GC-MS and a peak of mass
consistent with para cyanobenzoic acid was found. The results are preliminary and efforts to access
the extent of hydration and conduct a brief test to determine the types of nitriles that will undergo
hydration in this system are underway.
We are also working to test if nitrile hydration is linked to the mechanism of the germanium
cross-coupling reaction, and if finding a better nitrile hydration catalyst will enable the crosscoupling reaction to proceed more reliably.
In summary, we have discovered that the palladium-catalyzed cross-coupling reaction of
aryl halides and vinyl germanes bearing an allylic alcohol likely proceeds through a transient

	

135	

intermediate, most likely an allylic epoxide species, which undergoes carbopalladation before
degermylation. The structure of the allylic epoxide likely contributes to the ability to cross-couple
without fluoride activation. The reaction has given inconsistent results due to the generation of
poorly controlled Pd nanoparticles. The reaction has also been found to catalyze nitrile hydration,
but it is not yet known if the reaction will proceed without the reagents for the cross-coupling
present in the flask. Controls are being planned to determine if the nitrile hydration is a tandem
cycle or if it operates independently of the coupling reaction. It has been noted previously that the
reaction does not proceed without a mixture of acetonitrile and water, and other solvents such as
methanol also have failed to facilitate cross- coupling.

	

136	

REFERENCES

	

137	

REFERENCES

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LIST OF FIGURES

Figure 1.1. The Interaction of Steric and Electronic Directing Effects...........................................18
Figure 1.2. Calculation of Steric Parameters are Based on Benzamide Model...............................19
Figure 2.1. C-H Functionalization of 3-Fluorochlorobenzene.......................................................40
Figure 2.2. Variation of Ligand Steric and Electronic Effects........................................................42
Figure 2.3. Comparisons Between C–H and C–X Borylation Routes............................................52
Figure 2.4. Borylation of 17 with B2pin2 by generating the catalyst from [Ir(OMe)cod]2 gives the
similar result as catalysis from 26. (Exp. 3)..................................................................60
Figure 2.5. Borylation of 1 with generated catalyst gives comparable data. (Exp. 5).....................61
Figure 2.6. Borylation reactions with HBpin appear to be second order in arene. (Exp. 8)...........62
Figure 2.7. Borylation of 1 with dmadpm and HBpin. (Experiments 9 and 10)..............................63
Figure 2.8. First order Plot of Borylation Reaction with 1.0 equiv B2pin2 (Exp. 12)....................65
Figure 2.9. Experiment 1 First Order Plot.......................................................................................70
Figure 2.10. Experiment 1 First Order Plot at First Half-Life.........................................................71
Figure 2.11. Experiment 2 First Order Plot.....................................................................................72
Figure 2.12. Experiment 3 First Order Plot....................................................................................73
Figure 2.13. Experiment 4 First Order Plot.....................................................................................74
Figure 2.14. Experiment 5 First Order Plot.....................................................................................75
Figure 2.15. Experiment 6 First Order Plot.....................................................................................76
Figure 2.16. Experiment 7 First Order Plot.....................................................................................77
Figure 2.17. Experiment 7 Comparison of First Order and Second Order Plots.............................78
Figure 2.18. Experiment 8 First Order Plot.....................................................................................79

	

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