MECHANISTIC INSIGHTS TOWARDS NEW REACTIONS AND …dk657vx4442/Kiesewetter thesis - Stanford...Chapter 1 is a review of organocatalysis as it pertains to the polymer synthesis with

MECHANISTIC INSIGHTS TOWARDS NEW REACTIONS AND MATERIALS

A DISSERTATION

SUBMITTED TO THE DEPARTMENT OF CHEMISTRY

AND THE COMMITTEE ON GRADUATE STUDIES

OF STANFORD UNIVERSITY

IN PARTIAL FULFILLMENT OF THE REQUIREMENTS

FOR THE DEGREE OF

DOCTOR OF PHILOSOPHY

Matthew Karl Kiesewetter

October 2010

http://creativecommons.org/licenses/by-nc/3.0/us/

This dissertation is online at: http://purl.stanford.edu/dk657vx4442

© 2011 by Matthew Karl Kiesewetter. All Rights Reserved.

Re-distributed by Stanford University under license with the author.

This work is licensed under a Creative Commons Attribution-Noncommercial 3.0 United States License.

ii



http://purl.stanford.edu/dk657vx4442

I certify that I have read this dissertation and that, in my opinion, it is fully adequatein scope and quality as a dissertation for the degree of Doctor of Philosophy.

Robert Waymouth, Primary Adviser


Eric Kool


Barry Trost

Approved for the Stanford University Committee on Graduate Studies.

Patricia J. Gumport, Vice Provost Graduate Education

This signature page was generated electronically upon submission of this dissertation in electronic format. An original signed hard copy of the signature page is on file inUniversity Archives.

iii

iv

ABSTRACT

Catalysis is the enabling science of polymer synthesis, and new catalytic

mechanisms yield new materials. The development of organocatalysts for polymer

synthesis has, particularly in the last decade, spawned an impressive array of new

catalysts, processes and mechanistic insights. While the focus of most recent research

in organocatalysis has concentrated on enantioselective synthesis of small molecules,

organocatalysis offers a number of opportunities in polymer synthesis and was among

the earliest methods of catalyzing the synthesis of polyesters. The enthalpy of ring

opening of cyclic esters or carbonates drives the majority of organocatalytic

polymerization reactions catalyzed by a still-evolving array of organocatalysts.

Organocatalysts are thought to effect polymerization of cyclic esters by several

mechanisms. Some proceed via a monomer activated mechanism whereby the catalyst

activates the cyclic ester towards transesterification to the polymer chain. Others

operate by an alcohol activation mechanism where the alcoholic end group of the

growing polymer chain is activated to induce transesterification. Some are thought to

be operative by a combination of these mechanisms. The unique reactivity offered by

organocatalysts has provided access to precisely controlled macromolecular

architectures and well-defined (co)polymers including a wide array of functionality.

The notion that rate must be sacrificed to implement organocatalysts is fading with the

discovery of transesterification organocatalysts that rival in reaction rate even the most

active metal-containing catalysts.

Cyclopentadienyl ruthenium complexes with quinaldic acid-type ligands are

robust allylation catalysts in alcoholic solvents, but they are sensitive to dissolved

oxygen, requiring reactions to be conducted in an inert atmosphere. Moving from

alcoholic to neat aqueous solvents decreases the rate of deallylation but allows the

reaction to be conducted in air without loss of catalyst activity over the course of the

reaction. These complexes are also effective for the formation of allyl ethers, allowing

the synthesis of poly(2,5-dihydrofuran) from the condensation polymerization of 2-

cis-butene-1,4-diol. This material was previously deemed inaccessible via traditional

polycondensation catalysts.

v

PREFACE

Chapter 1 is a review of organocatalysis as it pertains to the polymer synthesis

with a particular emphasis on ring opening polymerization. It is intended to give the

reader a background in concepts pertaining to metal-free polymer synthesis and a

comparison between those methods. This article was published as a Perspective in

Macromolecules and was co-authored by Eun Ji Shin, Dr. James L. Hedrick and

Professor Robert M. Waymouth.

Chapter 2 pertains to the peculiar reactivity of a single N-heterocyclic carbene

and the specialized polymer architectures that can be generated from this catalyst and

specialized initiators. The initial work on this system was performed by Andrew

Mason, Prof. Philippe Dubois and Dr. Olivier Coulembier. The synthesis of the

macromolecular initiators, initial characterization (MALDI, and Mw versus time plots)

was performed by Andrew Mason and Dr. Olivier Coulembier. This chapter is largely

reproduced from an Angewandte Chemie communication.

Chapter 3 concerns the marked increase in reactivity of 1,5,7-

triazabicyclo[4.4.0]dec-5-ene (TBD) relative to another guanidine catalyst 1,4,6-

triazabicyclo[3.3.0]oct-4-ene (TBO). The reactivity of the two species in amidation

and polymerization reactions is explored and a kinetic analysis is performed. The

synthesis of TBO and the polymerization reactions with this catalyst were performed

by Dr. Marc Scholten. The kinetic analyses and reagent screening with TBD were

formed by undergraduate researchers Ryan Weber and Nicole Kirn, but the

experimental designs were my own. This chapter is largely reproduced from a J. Org.

Chem. publication.

Chapter 4 outlines the synthesis of the first in a new class of molecular

transporters made by the ring-opening polymerization of functionalized carbonates.

The initial syntheses of 4.4, 4.3 and 4.6a-c were performed by Dr. Fredrik Nederberg.

I devised the synthesis of 4.4b and 4.6d-e and synthesized all of 4.6 used in the

biological assays for publication. I performed all oligomerization reactions for

materials used in the final J. Am. Chem. Soc. publication. The experiments and

syntheses pertaining to quinine were performed by undergraduate researcher Justin

vi

Edward (with the exception of the MTC-quinine synthesis which I performed), but the

experimental designs were my own. The syntheses of 4.8, 4.11, and 4.12 were my

own design and execution. All other syntheses were performed by Christina Cooley

or Brian Trantow as were all biological experiments. The text of the original

communication was a collaborative effort between all co-authors (see the printed

communication: J. Am. Chem. Soc. 2009, 131, 16401).

Chapter 5 details the kinetic analysis of a deprotection of allyl alcohol reaction

by a cyclopentadienyl ruthenium kynurenic acid allylation catalyst that is stable in air

and water. A solid supported version of the catalyst is also discussed. All the work in

this chapter was performed by me. At the time of printing, this chapter was submitted

to Organometallics for publication.

Chapter 6 reports the synthesis of a heretofore unobtainable polymer from cis-

2-butene-1,4-diol formed with a Ru allylation catalyst. All of the experiments

described in this chapter were my own design although some experiments (small

molecule allylation reactions, lactide polymerizations and a repeated catalyst

synthesis) were performed by Justin Edward. At the time of printing, this chapter was

in final preparation for submission to J. Am. Chem. Soc.

Chapter 7 outlines out attempts to characterize the anion radicals of several N-

heterocyclic carbenes. The work in the chapter was performed by me.

vii

ACKNOWLEDGEMENTS

It is always the solvent.

I have many people to whom I owe a great deal of credit. To not miss a single

person would exceed the confines a reasonable acknowledgements section. First, I

would like to thank my committee for all the hard work they have done for me: Prof.

Wender (my de facto co-advisor on Chapters 4 and 5) and Prof. Contag, and especially

Profs. Kool and Trost for serving on my committee for 4 years. I would like to

express my gratitude to Prof. Robert (Bob) Waymouth. His enthusiasm for ‘cool’

science and his desire to always take a project to the next level are unbelievably

motivating. His sense of humor is a source of joy in the lab and has always driven me

to come up with some new ‘cute’ comment for Bob. Further, Bob possesses the best

quality in an advisor: you can always hear him coming.

As I construct the section on my wonderful lab mates, I come to realize the

trait that I most cherish in a person is their ability to take a joke. I will leave to others

the commentary about what that says about me. However, the quality of coworkers

that I have shared lab space with over the years far defies the statistics of random

coworker generators. Dr. Nahrain Kamber became a good friend in the couple years

that we were bench neighbors, and her influence has outlasted her physical presence in

my life. Dr. David Pearson and I have the ability to find humor and trouble in far

more obscure places than the average duo. I will never forget tremendous fun we have

had or the Variac that paid the ultimate price. Eun Ji (Eunj) Shin is one of the kindest

people that I have ever met, and consequently one of the people that I tease the least.

Once I finally got her to speak, we quickly became good friends. I will miss our

therapy sessions. It has been fun watching people grow as chemists over the years. I

would like to thank Hayley(meister) Brown for knowing all the rules. I trust that

Kristen Brownell’s relationship with gravity will improve even more with time, and

Jeff Simon (the youngest Waymite) has the drive to succeed in graduate school. Even

though they do not need it, I wish these people the best of luck at getting what they

want in life.

viii

Over my years at Stanford, I have had the opportunity to work with several

undergraduate researchers from whom I may have learned more than I taught. Ryan

Weber was (and continues to be) a gifted scientist, and I was forced to learn so much

just to stay a couple of paces ahead of him. Ryan so enjoyed his time with us that he

sent his friend, Ray Gipson, to us the next summer. Nicole Kirn became probably my

best friend from among all my undergraduate cohorts. I am sad that Nicole did not

like our country as much as we liked having her in it. Justin Edward is a typical

Stanford pre-med, but I tried not to hold it against him. It was a great joy to watch

Justin evolve from a Freshman, virtually without chemistry skills, into the great

scientist that he has become. Justin’s subtle synthetic technique and quiet disposition

mirrors my own, but he is just so cute that you cannot get too upset.

There are many friends from outside my Stanford world that continue to play

an important role in my life. Certainly one of my best friends, Nate Miller has been a

source of entertainment and companionship since our undergraduate days at Illinois

State (ISU). Things are never calm or quiet when Nate is around, and, unfortunately,

few people around the two of us have any idea what we are talking about. They,

perhaps, do not realize that neither do we. Audrey Butcher has been a long time friend,

and I have no doubt that we will continue to be each other’s cheerleader. Thanks

Maekers (Shirleyan, Val, Christine and Ruth) for all the afternoons and evenings I was

a fixture in your living room. Many of my friends from prior to college were my

teachers: Deb Voorhees (how do you always win at Scrabble?), Carl Byers (I think

we should all be more like Mr. Byers), Mary Sutter (who eased my transition from

Bloomington High to ISU) and Mike Gebhard (the source of all my Egyptian slave

labor analogies). I owe a special thanks to Angie Lawrence who took the time to feed

my addiction to chemistry even after I finished her sophomore chemistry class.

Before Mrs. Lawrence I wanted to teach science, but afterwards there was only

chemistry.

I will never be able to repay Distinguished Prof. Cheryl Stevenson (ISU) for

the impact that she has had on my life. Cheryl’s scientific enthusiasm sparked an

interest in me to pursue the degree of which this document is the culmination. The

ix

convergence of the right people at the right time produced for me at least a moderately

successful undergraduate research career that, I think without qualification, took me to

Stanford and the impacts of which will last far beyond this place. I will long

remember those times when we puled about the latest reviews as we quaffed those

kind nepenthes. The day that she retired from teaching, Illinois State lost the best

instructor in the institution. I also owe a great deal of thanks to my co-advisor from

Illinois State, Prof. Richard (Dick) Reiter. Dick is, without overstating the matter, the

world’s expert on EPR spectrum simulations. The patience that he displays while

looking at those spectra is simply inspiring, and exactly what he sees when he looks a

spectrum is at the heart of the indescribable thing that he possesses which makes him

so great. I want to acknowledge him for his input on the EPR simulations in Chapter

7; it is much appreciated.

Lastly, I would like to thank my family. My big sister, Michelle Kiesewetter,

was a constant support to me when we were growing up. She pretended that she did

not care about my well being, but I caught her doing just that every now and then. I

noticed, and I appreciate it. My parents, Pamela and Terrance Kiesewetter, were

always amazingly supportive of my adventures in kindergarten science and my

lingering fascination with spontaneous, highly exothermic, reactions. My dad,

especially, supported my budding scientific curiosity as a child. I remember when he

showed me the glow of a bottle of tonic in the sunlight – I was hooked. My family’s

knack for finding humor in almost every situation has served well in life even if it has

gotten me into trouble every now and then.

The last thing on my mind when I went of to California for graduate school

was getting married. On my first visit to the Waymouth lab, I met my future wife. I

recall that I was immediately smitten and that Elizabeth was not. We have had an

incredible adventure together so far, and the Drs. Kiesewetter are headed off to new

adventures in far colder environs. The places one goes in life and the milestones one

passes do not seem as important as the people with whom they are shared. Liz and I

agree that there may be no better place to live in this country than this little spot of the

San Francisco peninsula, and we have certainly cherished our time here. Stanford will

x

always hold a special place in our hearts. Perhaps we will return to this place some

day.

NMR is not a verb.

Matt Kiesewetter

Stanford, CA

September 24, 2010

xi

TABLE OF CONTENTS ABSTRACT iv

PREFACE v

ACKNOWLEDGEMENTS vii

LIST OF TABLES xvi

LIST OF FIGURES xvii

LIST OF SCHEMES xx

SYMBOLS AND ABBREVIATIONS xxii

CHAPTER 1: Organocatalysis: Opportunities and Challenges for 1

Polymer Synthesis

1.1 Introduction 2

1.2 Electrophilic Monomer Activation 5

1.3 Nucleophilic Monomer Activation. 5

1.4 Initiator or Chain-end Activation by a General Base 6

1.5 Bifunctional Activation of Monomer and Initiator/Chain-End 6

1.6 Organic Acids 7

1.7 Pyridine Bases and Nucleophiles 9

1.8 Phosphine and Carbene Bases and Nucleophiles 12

1.9 Strong Neutral Bases: Phosphazenes. 17

1.10 Nitrogen Bases 18

1.11 Bifunctional Activation 19

1.11.1 Thiourea / Amines 19

1.11.2 1,5,7-triazabicyclododecene (TBD) 21

1.12 Chemoselectivity, Substrate Tolerance 23

1.13 Architectural Control 25

1.14 Conclusions 28

1.15 References 31

xii

CHAPTER 2: A Distinctive Organocatalytic Approach to Complex

Macromolecular Architectures 45

2.1 Introduction 44

2.2 Results and Discussion 45

2.3 Conclusion 49

2.4 Experimental Section 49

2.4.1 General Considerations 49

2.4.2 Cyanoethylation of hydroxy-terminated PEG 50

2.4.3 Cyanoethylation of amine-terminated PEG 50

2.4.4 General procedure for nitrile reduction 51

2.4.5 Synthesis of diamine initiator 51

2.4.6 Synthesis of tetra-amine initiator 51

2.4.7 General polymerization procedure 52

2.4.8 ε-caprolactam initiated polymerization of lactide 53

2.5 References 56

CHAPTER 3: Cyclic Guanidine Organic Catalysts: What Is Magic About

Triazabicyclodecene? 59

3.1 Introduction 60


3.2.1 Kinetics and Mechanism 66

3.2.2 Effect of Catalyst Structure 68

3.2.3 Lactide Polymerization 71

3.3 Conclusion 72



3.4.2 Procedure for Kinetic Experiments 73

3.4.2.1 Kinetic and Thermodynamic Data 74

3.4.3 Typical Substrate Screening Experiment 77

3.4.4 Synthesis of n-butylacetamide (solution) 78

xiii

3.4.5 Synthesis of n-butylacetamide (neat) 79

3.4.6 Synthesis of (S)-n-butyl-2-hydroxypropanamide 79

3.4.7 Synthesis of the Mosher Ester 79

3.4.8 Synthesis of (S)-naproxen methyl ester 79

3.4.9 Synthesis of rac-naproxen methyl ester 80

3.4.10 Synthesis of (S)-naproxen butyl amide 80

3.4.11 Synthesis of 1,4,6-triazabicyclo[3.3.0]-oct-4-ene (TBO) 81

3.4.12 Synthesis of acyl-TBO 84

3.4.13 Polymerization of L-LA Using TBO catalyst 84

3.4.14 Computational Details 84

3.5 References 87

CHAPTER 4: Oligocarbonate Molecular Transporters: Oligomerization-

Based Syntheses and Cell-Penetrating Studies 93

4.1 Introduction 94


4.3 Conclusion 101

4.4 Preliminary Results for Future Directions 102



4.5.2 Synthesis of dansyl initiator 107

4.5.3 2-(tritylthio)ethanol 107

4.5.4 MTC-ethylguanidine-BOC 108

4.5.5 Synthesis of Oligomers 109

4.5.6 Synthesis of PMTC-guanidines 111

4.5.7 Synthesis of Luciferin Oligomers 113

4.5.8 Synthesis of Dansyl-r8 114

4.5.9 Octanol-Water Partitioning 116

4.5.10 Cellular Uptake Assays by Flow Cytometry 118

4.5.11 Cellular Uptake Assay at 4°C or in the Presence of Sodium Azide 118

xiv

4.5.12 Cellular Uptake Assay, High Potassium [K+] Buffer 118

4.5.13 Fluorescence Microscopy Studies 122

4.5.14 Cellular Assays for Luciferin Release 124

4.5.15 Hydrolytic Stabilities of the Dansylated Conjugates 124

4.5.17 Hydrolytic Stabilities and Luciferin Release of the Luciferin 126

4.5.18 Synthesis of MTC-pyrene 126

4.5.19 Synthesis of MTC-quinine 127

4.5.20 Synthesis of PMTC-quinine 128

4.5.21 Initiation of Oligomerization from Quinine 129

4.5.22 Initiation of Oligomerization from Taxol 129

4.5.23 MTC/amine “Click” Reaction 131

4.6 References 132

CHAPTER 5: Kinetics of an Air and Water Stable Ruthenium(IV)

Catalyst for the Deprotection of Allyl Alcohols 135

5.1 Introduction 136


5.3 Conclusion 146


5.4.1 General considerations 146

5.4.2 Synthesis of kynurenic acid allyl ester 146

5.4.3 Synthesis of methoxy substituted kynurenic acid allyl ester 147

5.4.4 Synthesis of RuIV catalyst 147

5.4.5 Synthesis of ligand for solid supported catalyst 148

5.4.6 Attachment of ligand to solid support 148

5.4.7 Synthesis of solid supported catalyst 149

5.4.8 Kinetic analysis to give the Ru loading PS bead 149

5.4.9 Determining Equilibrium 150

5.4.2 Kinetic Data 152

5.5 References 154

xv

CHAPTER 6: Poly(2,5-dihydrofuran) from 2-cis-butene-1,4-diol

and a Ruthenium Allylation Catalyst 157



6.3 Conclusions 166



6.4.2 General polymerization experiment 167

6.4.3 2-trans-1,4-butenediol 169

6.4.6 Reaction of CpRuIV-allyl with 2-cis-butene-1,4-diol 171

6.4.7 ROP of LA from the PDHF macroinitiator 171

6.4.8 2-cis-butene-1,4-diol Polymerization Experiment with Drying 172

6.4.8 Allylation of CD3OD with 2-cis-butene-1,4-diol 173

6.4.8 Allylation of CD3OD with 2-cis-pentene-1-ol 173

6.5 References 173

CHAPTER 7: Alkali Metal Reductions of N-Heterocyclic Carbenes

and Their HCl Salts 176



7.2.1 Reductions of NHCs and their HCl Salts 179

7.2.2 Decomposition Products 183

7.3 Conclusion 185



7.4.2 Example Reduction Experiment and Quenching 186

7.5 References 187

xvi

LIST OF TABLES Table 2.1 Polymerization of Lactide from Amine and Alcohol Initiators. 54

Table 3.1 Substrate Screening for the TBD Catalyzed Amidation of Esters 65

Table 3.2 Polymerization of L-lactide (L-LA) with TBO 72

Table 4.1 Oligomerization from Taxol with 4.3 103

Table 4.2 Synthesis and Characterization of 4.3 oligomers 110

Table 4.3 Toxicity and Stability of Oligoguanidines 4.6a-c 131

Table 4.4 Stability and Release of Luciferin oligomers 4.7a-b 132

xvii

LIST OF FIGURES Figure 1.1 Representative Organic Catalysts and Initiators 8

Figure 1.2 MTC-OR Monomers Accessible from MTC-OH 24

Figure 2.1 Reversible E-H insertion reactions of 2.1 45

Figure 2.2 Comparison of rates of LA polymerization with PEO-(NH2)2 and

PEO-(OH)2 catalyzed by 2.1 48

Figure 2.3 MALDI-TOF of PLA initated from 4-pyrene-methylamine 53

Figure 2.4 Chart of Molecular weight and Mw/Mn versus conversion 54

Figure 2.5 1H-NMR (CDCl3) of PLA2-PEO-PLA2 54

Figure 2.6 First-order plots for the rac-lactide polymerization 55

Figure 2.7 GPC of lactide polymerization carried out with an equimolar

mixture of PEO-(NH2)2 and PEO-(OH)2 56

Figure 3.1. Nucleophilic and basic organocatalysts for ROP 60

Figure 3.2. ROP of lactide with TBD is even faster than with NHC's 61

Figure 3.3 Model studies demonstrating the acylating ability of TBD 62

Figure 3.4 Hydrogen-bonding mechanism suggested by theoretical studies 63

Figure 3.5 Catalytic amidation of esters 64

Figure 3.6 Proposed mechanism for formation of n-butylacetamide

from benzyl acetate and butylamine 67

Figure 3.7 Generation of Acyl-TBD and acylation with amines and alcohols 68

Figure 3.8 B3LYP/6-31G* calculated geometries of ATBD and ATBO 71

Figure 3.9 Determining kobs(TBD) from kobs vs [alcohol]-1 74

Figure 3.10 Determining k2(TBD) from kobs vs. [amine]o 74

Figure 3.11 kobs vs. [TBD]o demonstrates first order in TBD 75

Figure 3.12 Determining k-1(TBD) 75

Figure 3.13 One of the [ROH] vs time used to construct Figure 3.9 76

Figure 3.14 Temperature dependent equilibrium between

benzyl acetate/TBD and benzyl alcohol/acyl-TBD 76

Figure 3.15 Determining kobs(TBO) 77

Figure 3.16 Determining k2(TBO) from ln([acylTBO]/[ acylTBO]o) vs time 77

xviii

Figure 3.17 1H-NMR spectra of the TBD-catalyzed reaction of

benzyl acetate with n-butylamine in toluene-d8 t minutes after

the addition of butylamine. 78

Figure 3.18 1H-NMR spectrum of acyl-TBO in CDCl3 82

Figure 3.19 13C-NMR spectrum of acyl-TBO in toluene-d8 83

Figure 4.1 Flow cytometry determined cellular uptake 98

Figure 4.2 Fluorescence microscopy images 99

Figure 4.3 Assay for measurement of intracellular luciferin delivery 100

Figure 4.4 Observed bioluminescence from HepG2 cells 101

Figure 4.5 Overlay of RI and UV detector signals of PMTC-guanidine-boc 110

Figure 4.6 1H-NMR spectrum of 4.5b 111

Figure 4.7 Stacked 1H-NMR of MTC-guanidine-boc, PMTC-guanidine-boc,

and PMTC-guanidine 112

Figure 4.8 1H-NMR (D2O) of 4.7a (n=8) 114

Figure 4.9 1H-NMR (D2O) of 4.7b (n=11) 115

Figure 4.10 1H-NMR of r8 dansyl 116

Figure 4.11 Dansyl ethanol calibration curve in water 117

Figure 4.12 Dansyl ethanol calibration curve in octanol 117

Figure 4.13 Partitioning of 4.6b into the octanol layer 117

Figure 4.14 Concentration dependence of cellular uptake into Jurkat - 1 119

Figure 4.15 Concentration dependence of cellular uptake into Jurkat - 2 120

Figure 4.16 Flow cytometry determined cellular uptake of oligocarbonates - 1 121



Figure 4.19 Uptake into Jurkat cells 123

Figure 4.20 1H-NMR MTC-quinine 128

Figure 4.21 1H-NMR of quinine-containing polymers 130

Figure 4.22 1H-NMR of taxol-PMTC 131

Figure 4.23 1H-NMR of the products of the reaction of 4.11 and 4.12 131

Figure 5.1 Plot of allyl methyl carbonate vs. time 138

xix

Figure 5.2 Plot of kobs (M•h-1) vs. Ru concentration 139

Figure 5.3 Plot of [allyl methyl carbonate] versus hours in CD3OD 142

Figure 5.4 Plots of [allyl methyl carbonate] versus hours 145

Figure 5.5 IR spectra of PS-supported materials 150

Figure 5.6 Slow approach to equilibrium of Ru complex and D2O 151

Figure 5.7 Slow approach to equilibrium of Ru complex and CD3OD 152

Figure 5.8 1H-NMR spectrum of partially converted allyl methyl carbonate 153

Figure 5.9 Plot of [allyl methyl ether] versus hours 153

Figure 6.1 ESI-MS of the crude polymerization material 162

Figure 6.2 Chain extension of PDHF with L-lactide 163

Figure 6.3 1H-NMR spectra of 2-butene-1,4-diol and PDHF 164

Figure 6.4 1H-1H COSY of PDHF 168

Figure 6.5 ESI of PDHF 169

Figure 6.6 ESI of the supernatant from the polymerization reaction 169

Figure 6.7 13C-NMR spectra of poly(2,5-DHF) and 2-cis-butene-1,4-diol 170

Figure 6.8 13C-NMR spectra of PDHF acquired with power-gated

decoupling and gated decoupling 170

Figure 6.9 1H-NMR spectra of allyl alcohol, allyl ether, and a solution

containing 6.1 and cis-2-buten-1,4-diol which is partially

converted to cis-3-(allyloxy)prop-2-en-1-ol. 171

Figure 6.10 1H-NMR spectrum of 6.3 172

Figure 7.1 X-band EPR signal observed upon the exposure of a THF

solution of 7.4 and 18-crown-6 to a K metal mirror in vacuo 180

Figure 7.2 X-band EPR spectra and computer generated simulations 181

Figure 7.3 Destructive decomposition pathways 182

Figure 7.4 Degenerate LUMOs of benzene substituted 183

Figure 7.5 Coupling constants of selected radicals 184

Figure 7.6 Proposed decomposition pathway 184

Figure 7.7 Apparatus used for the reduction of NHCs or their HCl salts 187

xx

LIST OF SCHEMES Scheme 1.1 Coordination-insertion Mechanism for Metal Catalyzed ROP 4

Scheme 1.2 Electrophilic Monomer Activation Mechanism for ROP 5

Scheme 1.3 Nucleophilic Monomer Activation Mechanism for ROP 5

Scheme 1.4 Initiator/Chain-End Activation Mechanism for ROP 6

Scheme 1.5 Bifunctional Activation Using Hydrogen Bonding for ROP 6

Scheme 1.6 ROP of Pivalolactone with Pyridine Initiators 10

Scheme 1.7 DMAP-Catalyzed ROP of LA and lac-OCA to produce PLA 10

Scheme 1.8 Proposed nucleophilic mechanism for ROP of Lactide with DMAP 11

Scheme 1.9 Proposed general-base mechanism for ROP of Lactide with DMAP 11

Scheme 1.10 Zwitterionic Ring-Opening Polymerization of Lactide by IMes 13

Scheme 1.11 Zwitterionic Polymerization of EO 14

Scheme 1.12 NHC-catalyzed poly-Benzoin Condensation 15

Scheme 1.13 Mechanisms of GTP of Acrylic Monomers 16

Scheme 1.14 ROP of TMOSC with Me2IPr 16

Scheme 1.15 Alcohol-activation Mechanism for the BEMP-catalyzed ROP of VL 17

Scheme 1.16 Mechanism for the ROP of Ethylene Oxide by t-BuP4 18

Scheme 1.17 MTBD Reversibly Associates with Benzyl Alcohol

but Does Not React with Vinyl Acetate 18

Scheme 1.18 Binding Constants of 1.1a with Selected Monomers 20

Scheme 1.19 ROP of VL by the Dual Activation of Monomer and Initiator

by 1.1a and MTBD 20

Scheme 1.20 TBD-catalyzed Acyl-transfer Reaction for Alcohols and Amines 22

Scheme 1.21 Nucleophilic Mechanism for the TBD-catalyzed ROP of LA 22

Scheme 1.22 TBD-catalyzed ROP of LA by the Hydrogen Bonding Mechanism. 23

Scheme 1.23 Synthesis of Guanidinylated Oligocarbonate Molecular Transporters 24

Scheme 1.24 Use of Dual-Function Initiators to generate poly(N,N-

dimethylacrylamide)-block-PLA by Tandem NMP-ROP, and

poly(vinyl pyridine)-block-PLA by Tandem RAFT-ROP 25

Scheme 1.25 ROP of -lactones using SIMes 27

xxi

Scheme 1.26 Reversible Activation and Deactivation of SIMes 27

Scheme 1.27 Reversible Activation of Triazolylidene Carbenes 28

Scheme 1.28 Organocatalysts possess the triad of versatility, convenience and

functional group tolerance and yield well-defined polymers of

precise architecture structures for a specific function 29

Scheme 2.1 Polymerization of LA initiated with PEO-(NH2)2 and PEO-(NH2)4

forming H-shaped and super-H-shaped polymers respectively 47

Scheme 4.1 Synthesis of molecular transporter 96

Scheme 4.2 Targeted Synthesis of a taxol-MoTr 103

Scheme 4.3 Synthesis of Two Oligomers Bearing Quinine Moieties 104

Scheme 4.4 Attachment of a Highly Fluorescent via a “Click” Reaction. 105

Scheme 5.1 Synthesis of Kitamura’s Catalyst 136

Scheme 5.2 Synthesis of the Ru complex 137

Scheme 5.3 Proposed mechanism for catalytic hydrolysis of allyl

methyl carbonate in water by RuIV-allyl complex 139

Scheme 5.4 Synthesis of the polystyrene supported Ru complex 144

Scheme 6.1 Conceptual polymerization of butene-1,4-diol 159

Scheme 6.2 Regioselectivity of the polymerization catalyst 165

Scheme 6.3 Polymerization Mechanism 166

Scheme 7.1 The Reduction of Triaz to Yield the Free Carbene 179

Scheme 7.2 Reaction Diagram of the Reduction Products Select NHCs 179

xxii

SYMBOLS AND ABBREVIATIONS [X]eff Effective concentration of X AIBN Azobisisobutyronitrile ATP Adenosine triphosphate aX Hyperfine coupling constant of nucleus X (gauss, G) BEMP 2-tert-butylimino-2-diethylamino-1,3-dimethyl-

perhydro-1,2,3-diazaphosphorine Bis-MPA 2,2-bis(methylol)propionic acid CL -caprolactone Cp cyclopentadienyl Cp* Pentamethylcyclopentadienyl DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCM dichloromethane DHF dihydrofuran DLA D-lactide DMAP 4-(dimethylamino)pyridine DME 1,2-dimethoxyethane DMF Dimethylformamide DMSO Dimethylsulfoxide DP Degree of polymerization (repeat units/initiator) DTT Dithiothreitol EC50 Half maximal effective concentration EDG Electron donating group EO Ethylene oxide EPR Electron Paramagnetic Resonance ESI-MS Electrospray ionization – mass spectrometry FBS Fetal bovine serum GC-MS Gas chromatography – mass spectrometry GR Guanidinium rich GTP Group transfer polymerization Hartrees 1 hartree = 627.509 kcal/mol HPLC High performance liquid chromatography IAd 1,3-bis(diadamantyl)imidazol-2-ylidene IdiMe 1,3-bis(-2,6-dimethylphenyl)imidazol-2-ylidene IMe 1,3-bis(dimethyl)imidazol-2-ylidene IMes 1,3-bis(-2,4,6-trimethylphenyl)imidazol-2-ylidene IPr 1,3-bis(diisopropyl)imidazol-2-ylidene IR Infrared (spectroscopy or spectrum) ItBu 1,3-bis(di-tert-butyl)imidazol-2-ylidene LA Lactide Lac-OCA 5-methyl-1,3-dioxolane-2,4-dione LLA L-lactide LUMO Lowest unoccupied molecular orbital M/I Monomer to initiator ratio

xxiii

MALDI-TOF Matrix-assisted laser desorption/ionization – time of flight (mass spectrometry)

MDR Multi-drug resistant Me2IMe 1,3,4,5-tetramethylimidazol-2-ylidene Me2IPr 1,3-diisopropyl-4,5-dimethylimidazol-2-ylidene MeOTf Methyl trifluoromethanesulfonate Mn Number average molecular weight MoTr(s) Molecular transporter(s) MTBD N-methyl-1,5,7-triazabicyclo[4.4.0]dec-1-ene MTC(-OH); (-OR) 5-methyl-2-oxo-1,3-dioxane-5-carboxylic acid; -R

ester MTT 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium

bromide Mw Weight average molecular weight NHC N-heterocyclic carbene NMP Nitroxide mediated polymerization NMR Nuclear Magnetic Resonance P1-t-Bu N’-tert-butyl-N,N,N’,N’,N”,N”-

hexamethylphosphorimidic triamide PBS Phosphate buffered saline PCL Poly(-caprolactone) PDHF Poly(dihydrofuran) PDI Polydispersity index PEG Poly(ethylene glycol) PEO Poly(ethylene oxide) PET Poly(ethyleneterephthalate) Ph2IMes 1,3-bis(-2,4,6-trimethylphenyl)-4,5-diphenylimidazol-

2-ylidene Poly(2,5-DHF) Poly(2,5-dihydrofuran) PPY pyrrolidinopyridine PS polystyrene PTHF Poly(tetrahydrofuran) r8 (R)-octa-arginine RAFT Reversible addition-fragmentation chain transfer

polymerization RI Refractive index ROP Ring-opening polymerization RPMI Roswell Park Memorial Institute SIMes 1,3-dimesitylimidazolin-2-ylidene TBD 1,5,7-triazabicyclo[4.4.0]dec-1-ene TBO 1,4,6- triazabicyclo[3.3.0]oct-4-ene t-BuP4 Schwesinger base TGA Thermogravimetric analysis THF Tetrahydrofuran TMC Trimethylene carbonate

xxiv

TMOSC 2,2,5,5-tetramethyl-1-oxa-2,5-disilacyclopentane TOF Turnover frequency (s-1) Triaz Triazol-5-ylidene TU Thiourea (generic) VL -valerolactone SR Muon Spin Resonance Electron spin density

1

CHAPTER 1

Organocatalysis: Opportunities and Challenges for Polymer Synthesis

Reprinted in part with permission from Macromolecules, 2010, 43, 2093 Copyright 2010 by the American Chemical Society

2

1.1 Introduction

Organocatalysis can be traced back at least a century to the enantioselective

synthesis of quinine alkaloids.1,2 Many enzymatic reactions are mediated by precise

arrays of organic functional groups, and much of the early work was inspired by an

effort to understand and mimic the remarkable rates and selectivities of enzymatic

catalysis.2-7 The application of chiral organocatalysts for enantioselective synthesis

has,1,8,9 particularly in the last decade, spawned an impressive array of new catalysts,

processes and mechanistic insights.10-30 While the focus of most recent research in

organocatalysis has concentrated on enantioselective synthesis of small molecules,

organocatalysis offers a number of opportunities in polymer synthesis and was among

the earliest methods of catalyzing the synthesis of polyesters.31

In the following perspective we attempt to highlight the opportunities and

challenges in the use of organic molecules as catalysts or initiators for polymerization

reactions. The ring-opening polymerization of cyclic monomers will be used as a

representative polymerization process to illustrate some of the features of organic

catalysts and initiators and to compare them to metal-based approaches.

Polymerization can occur by one of two general enchainment processes: step growth

or chain growth.32 Ring-opening polymerization is an example of a chain-growth

process where repeated addition of the monomer to the chain-end leads to an increase

in the molecular weight. The thermodynamics of ring-opening polymerization (ROP)

is driven by the enthalpy of ring opening; the kinetics and selectivity of the ring-

opening process is strongly influenced by the nature of the reactive chain ends, the

monomers, and the presence of catalysts.

Catalysis plays a critical role not only in enhancing the rate of chemical

reactions, but in controlling the selectivity of the reaction of interest relative to other

competing reactions. For fine chemical synthesis, the premium placed on high regio-,

chemo-, and stereoselectivities (particularly enantioselectivities) can compensate for

modest rates and turnover numbers.29 For polymerization catalysis, rate and turnover

number come to the fore, as catalyst residues are often left in the final material due to

the difficulty or added cost of separating these impurities from the resultant material.

3

Furthermore, the selectivities critical for the ideal polymer synthesis include those that

enable control over the molecular weight, molecular weight distribution, the nature

and number of polymer endgroups, the architecture, stereochemistry and topology of

the macromolecule (linear, branched, cyclic, degree of crosslinking), and the

functionality and sequence of monomers in the chain.33 Indeed, the number of

discrete catalytic steps in a ring-opening polymerization that must occur with the

correct relative rates to yield a well-controlled reaction is impressive. Under

conditions where the rates of initiation and propagation are higher than termination

and inter and intra chain reactions, exquisite control over the molecular weight and

molecular weight distribution is possible.32

“Living” polymerization reactions are those where termination is absent,

enabling control over the molecular weight by control of the monomer/initiator ratio

([M]ₒ/[I]ₒ) and monomer conversion. For living polymerizations where the rate of

initiation is faster or comparable to propagation and all other competing reactions are

minimized (inter and intra-chain reactions, etc.), very narrow distributions of

molecular weights are possible, and a linear relationship between molecular weight

and monomer conversion allows for precise tailoring of the molecular weight.

Deviations from the living behavior can be attributed to slow initiation or side

reactions such as chain transfer and termination reactions,32 and these processes

typically result in the broadening of molecular weight distribution (described by the

polydispersity index PDI = Mw/Mn, the weight average molecular weight and number

average molecular weight, respectively).34-38

If we consider the ring-opening polymerization of lactones as a representative

example, a variety of general strategies can be envisioned for enhancing the rate and

selectivity of enchainment either catalytically or stoichiometrically. For these

reactions, the lactone monomer is electrophilic and the initiator/chain-end is typically

a nucleophile such as an alcohol. The rates of these reactions can be increased by

activating the monomer, activating the initiator/chain end, or activating both

simultaneously.

4

Metal alkoxides represent the most widely used set of catalysts for the ROP of

cyclic esters, and they typically operate by a ‘coordination-insertion’ mechanism

(Scheme 1.1).39-47 A typical mechanism for these reactions involves activation of the

alcohol initiator (or chain-end) by formation of metal-alkoxide. Depending on the

Lewis-acidity of the metal (or the availability of open coordination sites), the metal

alkoxide can also activate the monomer by binding to the carbonyl (Scheme 1.1). 39-44

In cases where transesterifications of the propagating metal alkoxide are slow, the

metal alkoxide functions as an initiator (not a catalyst); however, if the metal alkoxide

reacts with alcohols to regenerate a new metal alkoxide, then chain formation is

catalytic in M-OR. A wide range of metal complexes, most commonly alkoxides,

have been developed using metals such as Al, Mg, Zn, Ca, Sn, Fe, Y, Sm, Lu, Ti, Zr

(Turnover frequencies = TOF ~ 0.01~0.1 s-1 for metal alkoxide complexes).39-42 The

applications of polyesters in packaging,48 biomedical44 and microelectronic49

applications have motivated efforts to develop more biocompatible metal catalysts50,51

or metal-free organic catalysts.24

O

O

[M]O

RORO

OO

O[M]

RO[M]

n

[M] X

O

R

H

H X

[M] OR

O

O

OR

H ORO

OH

n

Scheme 1.1. Coordination-insertion Mechanism for Metal Catalyzed ROP

Organic catalysts and initiators will typically operate by different mechanisms

of enchainment than metal alkoxides;24 this diversity of mechanistic pathways has

provided new opportunities for the control of polymerization reactions with organic

catalysts. In the following, we outline some general strategies for enhancing the rate

and selectivity of ring-opening polymerization by the activation of the monomer,

activation of the initiator/chain-ends or by cooperative dual activation.

5

1.2 Electrophilic Monomer Activation

Electrophiles can activate the monomer toward enchainment. In the case of

lactones, activation of the carbonyl by an electrophile facilitates nucleophilic attack by

the initiating or propagating alcohol (Scheme 1.2). This has been achieved by protic

acids (catalytic) or methylating agents (stoichiometric).

O

O

E-XO

OE

X ROH

O

OE

X

O

H

RO

RO O

E

H

X

RO O

OH

E-X

n

RO O

O

H

RO O

O

H O

OE

X

E-X

Scheme 1.2. Electrophilic Monomer Activation Mechanism for ROP

1.3 Nucleophilic Monomer Activation

Nucleophiles can activate the monomer by direct attack on the monomer to

generate more reactive chain-carrying intermediates. Protonation of the zwitterionic

alkoxide by the initiating or propagating alcohol followed by acylation of the incipient

alkoxide leads to the formation of a ring-opened alcohol that can propagate by

repeated attack on the activated monomer. This mechanism has been postulated for a

variety of nucleophiles including pyridines, imidazoles, phosphines, and N-

heterocyclic carbenes.

O

O

NuROH

RO

O

OH

NuO

O

+

OH

O

Nu OR

Nu

Scheme 1.3. Nucleophilic Monomer Activation Mechanism for ROP

6

1.4 Initiator or Chain-end Activation by a General Base

Rather than activating the monomer, the initiator or active chain-ends can be

activated by a variety of mechanisms. In classical anionic polymerization, the initiator

or chain-end is activated by deprotonation to generate an alkoxide,52,53 which is

reactive enough to mediate ring-opening even with non-coordinating counterions.54

Attack of the alkoxide at the carbonyl carbon of the monomer is followed by acyl-

oxygen bond scission. This forms an ester end-group and an active alcoholate species

which reacts with the monomer for further propagation. The high reactivity of alkali

metal alkoxides often leads to competitive transesterification.

Milder general bases can also activate the initiator or chain-end via H-

bonding. By hydrogen bonding to the alcohol, a general base can increase the

nucleophilicity of the initiating or propagating alcohol to facilitate nucleophilic attack

on the lactone monomer (Scheme 1.4). 55-57

B + ORH O

R

H

BO

O

O

OORH B

RO

O

OH

BO

OOR

HB

Scheme 1.4. Initiator/Chain-End Activation Mechanism for ROP

1.5 Bifunctional Activation of Monomer and Initiator/Chain-End

Dual activation of both the monomer and the chain-end is a very effective

strategy for enhancing the rate and selectivity of ring-opening polymerization; many

of the metal alkoxide catalysts are proposed to operate in this way (Scheme 1.1). The

combination of an electrophile to activate the monomer and a general base to activate

the initiator/chain-end can activate both partners to effect ring-opening (Scheme 1.5).

O

OOR

HB

E

O

O

B

H

OR

ERO

O

OH

B

E

O

OORH B

E

Scheme 1.5. Bifunctional Activation Using Hydrogen Bonding for ROP

7

The strategies described in Schemes 1.2-1.5 are not mutually exclusive and

different catalysts and initiators can operate by a combination of mechanisms; for

ring-opening reactions catalyzed or mediated by organic molecules, one or more of

these mechanisms may be operative. In the discussion below, we highlight situations

where this diversity of mechanistic pathways can provide new opportunities for

enhancing the rate of polymerization and influencing the selectivity to generate

polymer architectures that are difficult to access by metal-mediated processes.

The following discussion will focus primarily on the ring-opening of lactones,

but other monomers and processes will also be discussed. Representative organic

catalysts and initiators are shown in Figure 1.1.

1.6 Organic Acids

The simplest method to effect ROP is by the employment of a strong organic

acid.32,58 The polymerization is initiated by the protonation of the monomer and

subsequent ring-opening by reaction with a nucleophile, such as an alcohol (initiator).

The polymerization propagates by the terminal hydroxyl group of the polymer chain

acting as the nucleophile towards the protonated monomer. The use of a catalyst that

is free from the propagating polymer (whereas metal alkoxides remain attached to the

propagating species) represents a fundamental advantage of this strategy: less than

one catalyst per monomer chain.32,59 Stoichiometric activation of the monomer can be

achieved with strong methylating agents such as methyl trifluoromethanesulfonate

(MeOTf);58 this strategy has proven particularly effective for the ring-opening of 1,3-

oxazolin-2-enes32 but for lactones, this procedure requires further optimization to

control the molecular weights.

8

NH

N

N N

NN

N

N

MTBD

NH

NH

S

CF3

F3C

N

rac

1.1

NH

NH

S

CF3

F3CN

1.1a1.1b

N

N

DMAP

NP

N

N

N

NP

N

N

N

BEMP P1-t-Bu

N N

IMes

N N

SIMes

N N

Ph2IMes

NNN

Triaz

N N RR

N N

Me2IMe

N N

Me2IPr

P2-t-Bu

NP PN N

N

N

N

N

t-Bu

IPr : R = CH(CH3)2ItBu : R = C(CH3)3IAd : R = adamantyl

IMe : R = CH3

TBD DBU

P N

N

N

N

PN N

N

PN

NN P

N

NN

t-BuP4

HO

O

OH

R

NH2

OH

O HO

O

OH

O OH

OH

O

HO

O

OH

OH

OH

OS

O

OOH

lactic acid

tartaric acid

amino acids

citric acid

p-toluenesulfonic acid

Figure 1.1. Representative Organic Catalysts and Initiators

9

Acid catalyzed ROP has a distinct advantage in its simplicity and the wide

range of acids available, but as with many cationic processes, the selectivity for

propagation relative to other chain-termination or transfer reactions is dictated by the

reactivity of the protonated monomer.60 In the presence of an alcohol initiator,

HCl·Et2O polymerizes -valerolactone (VL) and -caprolactone (CL) with controlled

molecular weights (Mn ~ 3000) and low polydispersity index (< 1.20).61 Higher

molecular weights could be achieved by increasing the initial monomer

concentration.62 Amino acids (L-alanine, L-leucine, L-phenylalanine, L-proline) have

also been used as catalysts for the ROP of CL in the absence of initiators. 1H NMR

spectroscopy and titration of carboxyl end group showed that the polymerization was

initiated by the amino group of the amino acid.63 Other organic acids such as tartaric

acid, lactic acid, citric acid and fumaric acid have been used as catalysts for CL and

VL polymerization in the presence of alcohol and carbohydrate initiators.64 The acid

catalyzed polymerization of LA with trifluoromethanesulfonic acid (HOTf)58 was

faster and more highly controlled in the presence of a protic (alcohol) initiator.65 The

low molecular weights, slow rates and high catalyst loadings associated with organic

acids is compensated by the operational simplicity of this approach and the

observation that the polymerization of L-lactide was highly stereospecific.60,65

1.7 Pyridine Bases and Nucleophiles

Pyridines are moderate bases and good nucleophiles;66 they have been shown

to act as nucleophilic initiators in the zwitterionic ring-opening polymerization of

pivalolactone.32,67 Linear chains having one pyridinium ion and one CO2- ion as end

groups were observed as products, and no cyclic polymers were observed in the

MALDI-TOF mass spectra, which suggests that pyridine functions as a nucleophilic

initiator by ring-opening the lactone to generate a zwitterionic carboxylate, which

propagates by an anionic mechanism (Scheme 1.6).

10

NR

R = H, CH3, N(CH3)2

OO

NRCO2

OO

NRCO O CO O CO2

n

n-1NR

CO O CO O CO2Hn-1

+ ArOH

- ArO

Scheme 1.6. ROP of Pivalolactone with Pyridine Initiators

The more nucleophilic 4-(dimethylamino)pyridine (DMAP) and 4-

pyrrolidinopyridine (PPY), were shown to be very effective for the ROP of lactide

(LA) in solution and in the melt.54,68-72 In solution, DMAP loadings on the order of

initiator concentration produced PLA up to degree of polymerization (DP) = 100 with

PDI < 1.13 in days. PPY was shown to effect the ROP of LA only in the melt and

significantly slower than DMAP (20 h vs 20 m).69 DMAP was also shown to be

effective for the ROP of substituted lactides and lactide equivalents (Scheme 1.7).73-76

DMAP was originally proposed to react via a nucleophilic monomer activation

mechanism (Schemes 1.3 and 1.8),69,77 although subsequent computational studies

strongly suggest that an alcohol activation mechanism (either concerted or stepwise)

may be operative in the DMAP-catalyzed ROP of lactide (Schemes 1.4 and 1.9).78

OO

O

O

O

O

O

O

ROH

DMAP

ROO

OH

O

O n

CO2

NMe2N

Scheme 1.7. DMAP-Catalyzed ROP of LA and lac-OCA to produce PLA

11

N N

O

O

O

O

O

O

R O

O

OH

N N

O

O

O

O

N N ROH

O

OH

O

O

N N

OR

ROH

Scheme 1.8. Proposed nucleophilic mechanism for ROP of Lactide with DMAP

This mechanistic competition between nucleophilic and general-base

mechanisms is a recurrent theme for nucleophilic/basic organic catalysts. Calculations

suggest that both pathways are energetically accessible55-57,78 and predict the H-

bonded pathway to be lower in energy than the nucleophilic mechanism in the gas

phase or in polar aprotic solvents. However, in cases where alcohol initiators are

absent (Schemes 1.6 and 1.10) or at low concentration (high monomer/initiator ratio),

nucleophilic mechanisms can compete.

N N

O

O

O

O

ROHO

O

O

O

O

HN

N

HR

O

O

O

O

O

H

N

N

RO

O

R O

O

O

N

N

H

Scheme 1.9. Proposed general-base mechanism for ROP of Lactide with DMAP

Despite its low monomer scope and slow reaction times, DMAP marked two

fundamental advances in the development of polymerization catalysts: 1) these

catalysts show a high selectivity for transesterification of the monomer (propagation)

relative to the open chain esters of the polymer (chain-shuttling) and 2) these catalysts

are compatible with a range of different initiators and co-catalysts. DMAP does not

catalyze the transesterification of esters with secondary alcohols, which mitigates

transesterification of the PLA backbone by the propagating alcohol endgroups,

resulting in narrow polydispersities.68 This idea would be developed further, in much

more widely applicable catalysts, later see section 1.11. Also, DMAP was used in the

successful ROP of LA from a metalloinitiator when Al(OiPr)3 and Sn(Oct)2 failed to

12

produce the desired polymer.79 This trait, broadly denoted herein as compatibility

with functionality, was also to become a defining attribute of organocatalysts, see

section 1.12.

1.8 Phosphine and Carbene Bases and Nucleophiles

Phosphines, such as P(Bu)3, PPheMe2, PPh2Me, PPh3, catalyze the ROP of

lactide in the presence of an alcohol initiator.80 The substitution on the phosphine

controls the reactivity of the catalyst such that the alkyl-substituted phosphines are

more active (they are more basic and more nucleophilic) than the aryl-containing ones.

Polymerizations are effective at high temperatures (135°C) and in bulk (on the order

of 0.01 s-1 for P(Bu)3), which shows the potential for phosphine catalysts to be used in

industrial processes.80

N-heterocyclic carbenes (NHCs) are another class of potent neutral bases and

nucleophiles.18,81-84 They are widely used in place of phosphines in organometallic

complexes.85-88 Early work by Breslow,6 Wanzlick89 Sheehan,90 and Stetter91

demonstrated that they are also potent organocatalysts.18,24 In 2002, the groups of

Nolan,92 Hedrick and Waymouth93 demonstrated that NHC’s were potent

organocatalysts for transesterification reactions, studies which led to their

investigation as catalysts for the ring-opening polymerization of lactones.94,95

The ROP of lactide by the NHC IMes is considerably faster than that catalyzed

by DMAP. The polymerization of lactide is extremely rapid (TOF ~ 18 s-1), well-

controlled and exhibits features of a living polymerization.24,94-96 A variety of cyclic

monomers can be polymerized with NHC’s, including lactones,94-97 cyclic

carbonates,98,99 cyclic siloxanes,100,101 acrylates,102-104 dialdehydes,105 and epoxides.106

Both a nucleophilic mechanism (Scheme 1.3)94,95 and a H-bonding alcohol

activation mechanism (Scheme 1.4)57 have been proposed for the NHC-catalyzed

transesterifications92,93,107 and ring-opening polymerizations of lactide. Theoretical

calculations predicted that the H-bond alcohol activation mechanism has a lower

barrier than the nucleophilic mechanism.57 Mechanistic studies to test for the viability

of the nucleophilic mechanism demonstrated that in the absence of alcohol initiators,

13

the carbene IMes could mediate the zwitterionic ring-opening polymerization of

lactide to generate cyclic polylactides (Scheme 1.10).108 These studies strongly

support that a nucleophilic activation of the monomer by NHC’s is viable; moreover

these studies provided a new strategy to generate well-defined cyclic polyesters.

Kinetic and mechanistic investigations108b indicate that the NHC acts as a

catalyst/initiator; due to a slower rate of initiation relative to propagation only a small

fraction (approx. 30-50%) of the carbenes are converted to active zwitterions which

propagate rapidly and extrude the carbene to generate cyclic macrolactones.

N N

IMes

NN RR

O

OO

O

N

N

R

R

O

OO O

O

O

O

O

O

N

N

R

R

O 2n

kc

ki

kp

O

OO O

O O

O

O

O

O

O

O

OO

O

O

n-1

Z1 Zn

Cn

NN RR

Scheme 1.10. Zwitterionic Ring-Opening Polymerization of Lactide by IMes

In the presence of alcohol initiators, it is likely that the NHC-catalyzed ROP

operates by a combination of both mechanisms, particularly at high monomer/initiator

ratios. The carbenes are active for the polymerization of a variety of lactones and the

rates and selectivities depend sensitively on both the nature of the carbene and the

lactone monomer;24,95 for example, the aryl-substituted carbene IMes is very active for

lactide, but much less active for CL. For CL, the more basic and less sterically

hindered carbenes Me2IMe and Me2IPr are more effective than IMes.97

The ring-opening polymerization of ethylene oxide can also be catalyzed by

NHC’s such as IPr (Scheme 1.11).106 Under the conditions described (DMSO, 50oC),

linear PEO was exclusively obtained, unlike the zwitterionic polymerization of LA

14

described above. A nucleophilic mechanism to generate a zwitterionic imidazol-2-

ylidinium alkoxide was proposed. The appropriate choice of the terminating agent

gave a variety of ,-difunctionalized PEOs,106 and dendrimer-like PEOs could be

obtained by zwitterionic polymerization of EO followed by slow, semi-continuous

addition of glycidol and propylene oxide (sequentially or randomly) during the

arborization of the PEO chain ends.110

N

N O

N

N OOn-1

N

N

OO

n-1

NuH NuO

H

n

Nu = N3. OH, Bz

Scheme 1.11. Zwitterionic Polymerization of EO.

In addition to chain-growth ring-opening polymerizations, carbenes are

effective for the step-growth polymerization of diesters and diols93 and the

depolymerization of polyesters, including poly(ethyleneterephthalate) (PET).93,111

Poly(glycolide) and PCL, biodegradable and commodity polymers, were synthesized

by polycondensation of ethyl glycolate and ethyl 6-hydroxyhexanoate, respectively,

using IMe generated in situ.93

Carbenes are known to catalyze the benzoin and formoin condensation

reactions.18 This reactivity has been exploited for the step-growth polymerization of

dialdehydes to obtain polybenzoin polymers.105 Various carbenes, such as IPr, ItBu,

IAd and Triaz, were used in the step-growth polymerization of terephthaldehyde to

produce poly(1,4-phenylene-1-oxo-2-hydroxyethylene) under mild conditions (THF +

DMSO solution, 40oC) (Scheme 1.12).105 Optimization of reaction conditions to

achieve higher molecular weights, minimize possible cyclic byproducts and expanding

the catalyst and monomer scope are some of the challenges of step-growth

polymerization.

15

O

H

O

HO H

O

n

XNN

R'

RRX

N NR R

R'

HO

O

OH

CHOn

XN NR R

R'

O

O

OH

CHOn

O

H

O

HO H

O

m

XN NR R

R'

O

OH

O

OHC

OH

OHO

CHO

m

n

O

H

O

HO H

O

n+m

polybenzoin

Scheme 1.12. NHC-catalyzed poly-Benzoin Condensation

Group transfer polymerization (GTP) employs silyl ketene acetals as initiators

in the presence of either nucleophilic or Lewis acid catalysts for controlled

polymerization of acrylic monomers.112 NHCs such as Me2IPr,102 IPr and ItBu103,104

were found to be effective neutral nucleophilic catalysts for the GTP of methacrylates

and acrylates. Methylmethacrylate and t-butyl acrylate were successfully polymerized

in a controlled manner showing living characteristics enabling synthesis of block

copolymers. Such high degree of control was proposed to come from the modulation

of the concentration of the propagating enolates via reversible activation/deactivation

equilibrium involving dormant bis(enolate) siliconates in the case of the Me2IPr

(dissociative mechanism in Scheme 1.13).102 Later, for the case of IPr and ItBu, the

associative mechanism (an initiator activation mechanism) was proposed. The first-

order dependence of the initial polymerization rate on the initiator concentration and

the absence of enolate type species was offered to support the associative

mechanism.104

16

O

OSiMe3

NN RR

O

OSiMe3

NN RROO

R'

O

O

R = tBu, iPr

SiMe3

R' = H, Me

NN RR

R'O

O

n

O OSiMe3

O

R'

OO

R'

On

NN

O

O

N

HN

Si

O

ON

HN

Si

OO Si

OO

O

OSiMe3

N

HN

Si

Associative

Dissociative

Scheme 1.13. Mechanisms of Group Transfer Polymerization of Acrylic Monomers

NHCs were also shown to catalyze the ring-opening polymerization of

carbosiloxanes in the presence of initiating alcohols.100,101 The ROP of 2,2,5,5-

tetramethyl-1-oxa-2,5-disilacyclopentane (TMOSC) with Me2IPr was proposed to

occur by an alcohol activation mechanism where the strongly basic NHC activates the

alcohol toward nucleophilic attack by H-bonding (Scheme 1.14), but a nucleophilic

mechanism is also possible. The ROP reaction of TMOSC with 1 mol% Me2IPr is

extremely fast (99 % conv. in 1 min or 1.65 s-1) and yields poly(carbosiloxane) with a

molecular weight Mn = 10,200 g/mol and a polydispersity of Mw/Mn = 1.19. The aryl

substituted carbene IMes is slower, (80 % after 30 min or 0.044 s-1), but provides a

similar degree of control (Mw/Mn = 1.14).100

N NR' R'

R' = iPr

ROHN NR' R'

HO

R

OSi

Si

H OSi

SiOR

OSi

Si

OR

HN

N

R'

R'

Scheme 1.14. ROP of TMOSC with Me2IPr.

17

1.9 Strong Neutral Bases: Phosphazenes

The phosphazene bases P1-t-Bu, P2-t-Bu, t-BuP4 and BEMP (Figure 1.2)

developed by Schwesinger and Schlemper113,114 are potent neutral bases in aprotic

solvents. (MeCNpKa P1-t-BuH+ = 27.6, DMSOpKa t-BuP4H+ = 32)115 These bases are

effective catalyst for the ring-opening polymerization of lactones in the presence of

alcohol initiators. Both BEMP (MeCNpKa BEMPH+ = 27.6)116 and P1-t-Bu are active

for the polymerization of LA and VL, producing comparable polymers, but BEMP

offered enhanced rates (1 day versus several days). The ROP of CL was exceedingly

slow (> 10 d for 14% conversion). The BEMP-catalyzed ROP of L-LA was shown to

evolve Mn linearly with time and exhibited excellent chain end control,116 which is

consistent with a living polymerization. Based on experimental evidence, an alcohol

activated mechanism was proposed whereby the catalyst activates the alcohol toward

nucleophilic attack on the monomer, Scheme 1.15. BEMP is inert towards polymer

except at high conversion when broadening of PDI occurs due to transesterification of

the polymer backbone.116

NP

N N

N

O

O

R

OH

NP

N N

N

R

O

H

O

O

NP

N N

N

R

O

H

O

O

NP

N N

N

H

NP

N N

N

R

O

O

O

R

O

OO H

Scheme 1.15. Alcohol-activation Mechanism for the BEMP-catalyzed ROP of VL

These bases have been shown to be effective for the polymerization of

siloxanes. The catalyst P1-t-Bu offered improvement in reaction time over alkali metal

alkoxide alternatives, as is typical of softer cations, but retained the broad PDIs.114 A

similar catalyst, t-BuP4, was shown to be effective for the ROP of ethylene oxide in

the presence of acidic initiators (a phenol or benzyl cyanide); in these cases, it was

proposed that the phosphazene deprotonates the initator which concomitantly attacks

monomer and produces short oligomers (Mw ~3,000) of narrow PDI < 1.09, Scheme

1.16.117 Similar reports were made for propylene oxide monomer.118

18

OH

t-BuP4

O

OnO

OH

H

t-BuP4H

Scheme 1.16. Mechanism for the ROP of Ethylene Oxide by t-BuP4

1.10 Nitrogen Bases

The guanidines and amidines N-methyl-1,5,7-triazabicyclododecene (MTBD,

pKa MTBDH+ = 25.5)115 and diazabicycloundecene (DBU, MeCNpKa DBUH+ =

24.3)115, have similar basicities. Both MTBD119 and DBU120 are effective for the

polymerization of LA, producing polymers of up to DP = 500 with narrow PDI < 1.1

in less than 1 hour (TOF ~ 0.05 s-1). As with the phosphazenes, transesterification of

the polymer backbone and accompanying broadening of PDI occurs at high

conversion.120 An alcohol activated mechanism was proposed for the MTBD or DBU

catalyzed polymerization of LA.120 In such a mechanism, MTBD would activate the

initiating alcohol but be inert towards the monomer, and this was shown to be the case

in some model reactions. MTBD was shown to associate strongly with benzyl

alcohol: Keq=14±2 M-1 at 298 K, H° = -3.82±0.24 kcal mol-1, S° = -7.17±0.24 cal

mol-1, and neither MTBD nor DBU are potent enough nucleophiles to be acylated by

vinyl acetate, Scheme 1.17.121-124 While the alcohol activation executed by MTBD

and DBU is sufficient for the ROP of LA,100 DBU produced poly(ethylene oxide) in

very poor yield;117 neither catalyst is active for the polymerization of BL, VL or CL at

up to 20 mol% catalyst loading.120

NH

N

N

O

ON

N

N

CH3H

O

N

N

NK = 14 M-1

Ph

CH3H

O

Ph

Scheme 1.17. MTBD Reversibly Associates with Benzyl Alcohol but Does Not React

with Vinyl Acetate

19

1.11 Bifunctional Activation

The previous sections have highlighted the selective activation of monomer or

initiator, but the dual implementation of an electrophile and nucleophile should allow

for the simultaneous activation of both; the attenuation of the strength of each

interaction required to effect the transformation can lead to higher selectivities.

Catalytic reactions using weak electrophilic interactions (hydrogen bonding) to

activate the substrate have been demonstrated for small molecule transformations;21,125

this motif is also a powerful strategy for ring-opening polymerization. For lactones,

bifunctional activiation of the monomer by an electrophile and the initiator by a

nucleophile has been shown to facilitate the ROP of esters. Both unimolecular and

bimolecular catalysts have been employed.

1.11.1 Thiourea / Amines

A variety of ureas and thioureas activate carbonyl substrates7,21 in a fashion

similar to the hydrogen-bonding motifs in enzyme active sites.7,21,125-130 One

particular example combined the hydrogen bonding capabilities of a thiourea (TU) H-

bond donor and an amine base in a discrete catalyst, 1.1 (Figure 1.1).127-131 In the

ROP of LA, the thiourea 1.1 produced PLA of narrow PDI (<1.08) whose Mn is

dictated by [M]ₒ/[I]ₒ and evolves linearly with time (TOF ~ 0.8 h-1). The thiourea and

amine need not be linked; a combination of the thiourea 1.1a and the tertiary amine

1.1b was also active.132 Catalytic activity was modulated by changing the architecture

of the thiourea; 1.1a was the most effective of the thioureas tested,121 but amido-

indoles can also be used.133

Catalytic activity was significantly augmented when stronger bases are

substituted for 1.1b. Whereas DBU and MTBD alone or any TU-tertiary amine

combination are only active for the ROP of LA, TU/MTBD and TU/DBU were shown

to be active for the ROP of VL, CL, MTC and TMC.99,120,134 The combination of

MTBD or DBU and 1.1a (5mol% each) produced PVL with predictable molecular

weights up to DP ~200 (TOFMTBD/1.1a ~TOFDBU/1.1a ~ 5 h-1). However, MTBD/TU and

DBU/TU, required days (TOFs ~ 0.13 h-1) to reach 80% conversion in the ROP of

20

CL.120 The DBU/TU system demonstrated a higher TOF for the ring-opening

polymerization of the cyclic carbonates MTC-OR (Figure 1.2, TOFMTC-OBn ~ 19 h-1)

than for TMC.99 The proposed bifunctional mechanism of action, Scheme 1.19, was

supported by observed interactions between benzyl alcohol and MTBD (Scheme 1.17)

and between 1.1a and various monomers, Scheme 1.18.120,121,132

NH

NH

S

CF3

F3C

X O

O

n

+

N

N

SF3C

F3C X

OO

n

H

HKeq

VL: n=1, X=CH2, Keq= 39±5 M-1

CL: n=2, X=CH2, Keq= 42±5 M-1

TMC: n=1, X=O, Keq= 45 M-1

Scheme 1.18. Binding Constants of 1.1a with Selected Monomers

NH

NH

S

CF3

F3C

O

O

NN

S

CF3

F3C

H H

O

O

OHR

O

R

HN

N

NN

NN

R

O

O

OH

NH

NH

S

CF3

F3C

N

N

N

Scheme 1.19. ROP of VL by the Dual Activation of Monomer and Initiator by 1.1a

and MTBD

While the activities of the TU/amine (TU/A) catalysts are lower than that of

the carbenes, these catalysts are remarkably tolerant and selective, leading to polymers

of very narrow polydispersities. Transesterification of the polymer chain was shown

to be minimal; when fully converted reaction solutions were allowed to sit for days in

the presence of the catalyst, the polydispersities did not increase.120,121,132 The origin of

this high selectivity was investigated by NMR experiments measuring the binding

constants of lactones and esters with the thioureas. Cyclic lactones and cyclic

carbonates bind to the thiourea 1.1a (Scheme 1.18). In contrast, the open chain-ester

21

ethyl acetate exhibited no measurable binding affinity for 1.1a under similar

conditions.120 The higher H-bond basicity of s-cis esters of lactones/cyclic

carbonates135 relative to that of the acyclic s-trans esters of the polymer chain is the

likely origin of this high selectivity for ring-opening relative to transesterification of

the chain. This high selectivity is a defining attribute of the TU/A organic catalysts.

The selectivity of these catalysts, coupled with their broad substrate tolerance, has

created new opportunities for generating highly functionalized polymers with well-

defined molecular weights (vide infra).

1.11.2 1,5,7-triazabicyclododecene (TBD)

The bicyclic guanidine TBD has a slightly higher basicity (pKa TBDH+ =

26.0)115 than its substituted analog MTBD (Figure 1.1, Scheme 1.17) but its activity in

ring-opening polymerization reactions is considerably higher. The ROP of lactide

requires approx. 30 minutes in the presence of 0.5mol% MTBD (an average turnover

frequency of TOF ~0.002 s-1), whereas TBD is much more active. At 0.1 mol% TBD,

the ROP of lactide is complete in 1 min (TOF ~81 s-1).120 Similarly, the ring-opening

polymerization of the cyclic carbonate TMC (Figure 1.2) requires 6 days (TOF <0.1

h-1) for MTBD, but in the presence of TBD complete conversion is achieved in 15

min (TOF ~0.1s-1).134 This commercially available catalyst has been shown to be

active in the ROP of LA, VL, CL, MTC, TMC, and carbosiloxanes with rates that

exceed any other organocatalyst or, in some cases, any other catalyst known. For all

monomers tested, TBD exhibited characteristics of a living polymerization, but its

higher transesterification activity results in the broadening of the molecular weight

distribution upon full conversion for all monomers except carbosiloxanes.99,119,120,134

This is in marked contrast to the NHC catalyzed ROP of carbosiloxanes that, while

faster, broaden the PDI by transetherification. The methylated analog, MTBD, was

inactive in the ROP of carbosiloxanes.100

The much higher reactivity of TBD relative to DBU and MTBD stimulated

mechanistic and theoretical studies to illuminate the origin of the higher rates.

Treatment to TBD with vinyl acetate led to the rapid formation of acyl-TBD which

22

subsequently reacted with benzyl alcohol to regenerate TBD and the ester (Scheme

1.20A).119 This led to the proposal that TBD might function as a bifunctional

nucleophilic catalyst for tranesterification (Scheme 1.21). A nucleophilic mechanism

was also proposed for the TBD catalyzed formation of amides from esters (Scheme

1.20B);136 kinetic studies provide strong support for a nucleophilic mechanism

involving an acyl-TBD intermediate.137

NH

N

N

O

O+ N

N

N

O

HX

R NH

N

N

O

XR

+

X= O or NH

N

N

N

O OH

OH

H

O

R'O

O

H

HN

R

NH

N

N

+

O

NH

R + HO

R'

A

B

Scheme 1.20. TBD-catalyzed Acyl-transfer Reaction for Alcohols and Amines

NH

N

N

O

O

O

O

NN

N

O

O

O

O

N

N

N

O

O

O

OH

OHR

N

N

N

OOO

OH

OR

H

NH

N

N

R O

O

O

O

OH

H

Scheme 1.21. Nucleophilic Mechanism for the TBD-catalyzed ROP of LA

23

Theoretical studies55,56 implied that while a nucleophilic mechanism for TBD

catalyzed ring-opening polymerization is feasible, a H-bonding mechanism(Scheme

1.22) exhibited a lower calculated barrier for transesterification. Binding of the

alcohol to TBD100 simultaneously activates the alcohol and creates an incipient

guanidinium ion, which can function as a H-bond donor to the lactone carbonyl

(analogous to a thiourea). The unique structural and electronic features of TBD enable

it to catalyze transacylation reactions by a variety of mechanisms137 with high rates

and selectivities. Because TBD is commercially available, it is also operationally

quite simple and convenient.

NH

N

N

O

O

O

O

HOR

N

N

N

O

O

O

O

O RH H

N

NN

O

O

O

O

OR

H

HNH

N

N

R O

O

O

O

OH

Scheme 1.22. TBD-catalyzed ROP of LA by the Hydrogen Bonding Mechanism

1.12 Chemoselectivity, Substrate Tolerance

While achieving fast rates and high turnover numbers is highly desirable, the

selectivity and tolerance of the catalyst to other functional groups is also important.

For example, DMAP catalysts are effective for the ring-opening of lactones75,76 or O-

carboxyanhydrides73-76 functionalized with pendant esters. The TU/A catalyst systems

are particularly chemoselective and tolerant to a wide variety of functionalized

monomers.

The high selectivity of the TU/A catalysts for tranesterification of cyclic

lactones and carbonates relative to open-chain s-cis esters has created new

opportunities for generating highly functionalized polylactones and polycarbonates

with a diverse range of functionalities. For example, a wide range of functionalized

carbonates (MTC-OR) can be prepared from 2,2-bis(methylol)propionic acid (bis-

MPA);99,138,139 these functionalized carbonates are readily polymerized or

24

copolymerized in the presence of the TU/A catalysts to generate a family of

functionalized carbonates with a range of pendant functional groups (Figure 1.2).99

O O

O

OOH

MTC-OH

O O

O

OOR

MTC-OR

R =

Cl

SS N

StBu

NHBoc

NBoc

OOMe

(CF2)5CF3

OMTC

Figure 1.2. A Selection of the MTC-OR Monomers Accessible from MTC-OH

The ring-opening polymerization can be initiated from a wide variety of

functional groups including alcohols, thiols, primary amines and silanols.99,121,134

These highly controlled polymerizations led to a new synthesis of well-defined

guanidinylated oligocarbonates that were shown to act as molecular transporters140

that traverse cell membranes (Scheme 1.23).141

N

SO OHN

OH

O O

N

NH

NH

O

O

O

O

O O

O

1) TU/DBU

2) CF3CO2H

CH2Cl2

N

SO OHN

O O

O

OH

O O

NH

NH2H2N

n

TFAn

6 85%a: n=8b: n=11c: n=22+

Scheme 1.23. Synthesis of Guanidinylated Oligocarbonate Molecular Transporters

The high chemoselectivity of the TU/A catalysts also creates additional

opportunities for tandem polymerizations from multifunctional initiators. Hydroxy-

functionalized nitroxides or dithioesters can be used as initiators for tandem free-

radical and ring-opening polymerization reactions (Scheme 1.24).134 This is one

25

strategy for the synthesis of complex, multifunctional polymer architectures that is

enabled by the high functional group tolerance of the TU catalysts.

O NHONMP

O NHO

N

O ROPO

OO

O

OH

SSOH

NRAFT

SSOH

NNROP

SSO

NN

O

O

O

OH

O N

N

O

Scheme 1.24. Use of Dual-Function Initiators to generate (Upper) poly(N,N-

dimethylacrylamide)-block-PLA by Tandem NMP-ROP, and (Lower) poly(vinyl

pyridine)-block-PLA by Tandem RAFT-ROP

1.13 Architectural Control

The mechanistic diversity of organocatalytic polymerization reactions has

created new opportunities and strategies to control the architecture of macromolecules.

The zwitterionic polymerization with NHC’s to make cyclic polymers (Scheme

1.10)108,109,142 and the step-growth benzoin condensations (Scheme 1.12)105 are two

examples; below we highlight several other examples where the selectivity of organic

catalysts has provided new strategies for macromolecular design.

Stereoselectivity is critically important in fine-chemical synthesis; it is also

very important in polymerization catalysis as the relative stereochemistry of

stereogenic centers along the chain influences the physical properties of the

polymer.143,144 The stereoselective polymerization of the chiral monomer lactide has

attracted considerable interest and can be carried out with a variety of metal

catalysts.143,145-150

Several organic catalysts have been shown to influence the stereoselectivity of

enchainment of lactide. The sterically encumbered carbene, Ph2IMes, is very active

for the ROP of LA at room temperature (1.58 s-1) producing atactic poly(LA) from

rac-LA, however, when the temperature is lowered (-40 to -70°C) highly isotactic

(from rac-LA) and heterotactic (from meso-LA) polylactides are generated.151 Similar

26

stereoselectivities were observed with sterically demanding phosphazenes.116,121,152

The stereoselectivity of these polymerization catalysts was proposed to be due to a

chain-end control mechanism whereby the growing chain selectively attacks the

activated monomer of the same stereochemistry leading to isotactic enchainment.

In addition to the stereochemistry, the comonomer sequence is also an

important determinant for polymer properties. Due to their different mechanisms of

enchainment, organic catalysts exhibit a different chemoselectivity for

copolymerization than typical metal alkoxide catalysts.153-159 The catalysts

MTBD/TU, DBU/TU and TBD all show a selectivity for monomer wherein the fastest

propagating monomer (kLA >> kVL > kCL) is ring-opened to >95% conversion before

ring-opening of the second monomer begins.120 While extensive studies on the

copolymerization selectivity have not been done, these selectivities imply that block

copolymers might be accessible in one step. In the case of the cyclic carbonates

MTC-OR, more random copolymers were observed. Accordingly, block and random

MTC-OR copolymers could be generated simply by varying reaction conditions.99,160

Unsaturated carbenes such as IMes generate cyclic polyesters or polyamides in

the zwitterionic ring-opening of lactide108 or N-carboxyanhydrides.142 The saturated

carbene SIMes (Figure 1.1) also generates cyclic polyesters from -lactones,109 but

subtle differences in the reactivity between the unsaturated and saturated carbenes81

lead to different mechanisms. Treatment of the saturated carbene SIMes with one

equivalent of -butyrolactone generates the novel spirocycle 1.25S. This spirocycle

initiates the ring-opening polymerization of -lactones to yield cyclic polyesters.109 A

novel mechanism involving reversible collapse of the zwitterionic intermediate to a

neutral imidazolidine spirocycles was proposed (Scheme 1.25). 109,142 The

polymerization is highly selective due to the generation of small amount of

zwitterionic intermediate by the reversible formation of the spiro-macrocycles.

27

Scheme 1.25. ROP of -lactones using SIMes

Organic catalysts can also be used to generate telechelic poly(valerolactone) or

poly(THF) that could be cyclized into large cyclic polymers.161,162 These new

strategies for generating macromolecules with a cyclic topology offer new

opportunities for generating these architectures.163

Alkyl164 and alcohol165 adducts of saturated N-heterocyclic carbenes have been

used in the ROP of LA as a convenient method for generating the NHC catalyst in

situ. Chloroform and pentafluorobenzene adducts of saturated imidazolinylidene are

stable at room temperature but eliminate the carbene at elevated temperature.164,166

These NHCs polymerize LA in the presence of an alcohol initiator at elevated

temperatures (65 oC ~ 144 oC). In contrast, alcohol adducts of the saturated carbene

SIMes eliminate the alcohol reversibly at room temperature.165 In these adducts, the

alcohol initiator is liberated with the carbene; thus the adducts of SIMes act as single

component catalyst/initiators for the ROP of LA, Scheme 1.26. The liberation of the

alcohol is rapid in solution at room temperature and PLA is obtained within minutes in

high yield with narrow polydispersity.

+ CH3OH

O

OOO

100

CH3O

O

n

O

HOAc CH3O

O

n

OH

Mn = 16500 g/molPDI = 1.1689% yield

CH3O

O

n

OH

N N

CH3O H

Mes Mes

N NMes Mes

N

N

Mes

Mes

H

N

N

Mes

Mes

Scheme 1.26. Reversible Activation and Deactivation of SIMes

28

In contrast to the alcohol adducts of the saturated imidazolinylidene carbenes,

alcohol adducts of Enders’ triazol-5-ylidene are stable at room temperature and

reversibly eliminate the alcohol only at 90°C.167,168 At room temperature in the

presence of alcohols, the triazolylidenes are inactive; at 90°C they polymerize lactide

to give polymers of narrow polydispersities. This provides a means of regulating the

polymerization with temperature: at elevated temperature, polymerization proceeds;

at lower temperature the alcohol “clicks”169 back onto the alcohol terminus of the

polymer to give the dormant alcohol adduct (Scheme 1.27).168,170 The reversible

formation of the active and dormant carbene species is the key factor that contributes

to the exceptional control observed in these polymerizations.

NN

N PhPh

NN

N

O

H

Ph

Ph

O

OR

nNN

N

OR

H

Ph

Ph

ROO

O

O

OHO

O

O

O

- ROH

n

Ph

Ph Ph

Active, high T

Dormantlow T

Scheme 1.27. Reversible Activation of Triazolylidene Carbenes

The triazol-5-ylidene is also tolerant to a variety of initiators and, in

conjunction with telechelic macroinitiators, has been used to produce complex

architectures such as block copolymers, star copolymers168 and (super-) H-shaped

copolymers.171

1.14 Conclusions

The activity, selectivity, convenience and diverse reactivity of organic catalysts

have expanded the armamentarium of synthetic methods for polymer synthesis.

29

Organic catalysts have proven of broad utility for the generation of an ever-increasing

array of polymer architectures that have interesting properties in their own right, or

can be programmed to assemble into larger nanostructures of defined size, shape and

function (Scheme 1.28).24,60,98,121,160,172-174

Scheme 1.28. Organocatalysts possess the triad of versatility, convenience and

functional group tolerance and yield well-defined polymers of precise architecture

structures for a specific function.

The application of organocatalysts to polymer synthesis has provided new

mechanistic insights, new strategies for enchaining monomers and new families of

materials with a range of structure and function that continues to evolve. In the past

decade, the development of new families of organic catalysts has led to impressive

advances in the catalytic rates (DMAP to TBD) and selectivities (acids to TU/base).

Some organocatalysts exhibit rates that compare or exceed those of organometallic

catalysts.175

The development of new families of metal catalysts51 and enzymes176 for ring-

opening polymerization continues apace;47,50,60 recent advances in metallic, enzymatic

30

and organic catalysts have highlighted the important role of catalyst development for

advancing our ability to generate well-defined macromolecules with specific structure

and function.177 In this perspective, we have attempted to highlight where

investigations of organic catalysts have provided mechanistic insights and strategies

for activating monomers and chain-ends to generate new opportunities for

macromolecular design. Organic catalysts in many cases are complementary to metal

or enzyme catalysts; choosing between a particular catalyst will depend on a variety of

factors relevant to the specific challenge at hand. The use of organic catalysts can

provide advantages in microelectronic178-181 or biomedical applications where the

presence of metal residues in the final material can be deleterious to their end-

use.50,141,160,174,182 An additional advantage of organic species that activate monomers

or chain-ends catalytically is that they can be used in concentrations lower than that of

the polymer chains, further minimizing the amount of catalyst residues in the final

material.50,183

The wide substrate tolerance and exquisite selectivity of the thiourea organic

catalysts120,121,132 for ring-opening versus transesterification of open chain esters

provides a new strategy for precision polymer synthesis. The reversible capping of

endgroups with triazolylidene carbenes168,170,171 and the zwitterionic polymerization to

generate cyclic polymers108,109,142 are just a few examples of new strategies to complex

molecular architectures and topologies.

While the foregoing discussion highlights some of the advantages of

organocatalytic approaches, challenges remain. Melt polymerizations are industrially

attractive and compliant with the tenets of green chemistry.184,185 However,

organocatalysts have not been widely investigated in melt polymerizations and this

remains an attractive target for future research. Chiral phosphines have been used to

great success in small molecule reactions,186 but chiral phosphines for stereoselective

polymerization is an area still to be explored. The trifunctional catalyst for ROP may

be just around the corner. A trifunctional organocatalyst modeled on serine hydrolases

combines electrophilic activation, nucleophilic activation and a nucleophile in a

discrete catalyst and exhibits a million-fold enchancement in acyl-transfer rate from

31

vinyl trifluoroacetate to alcohols.187 A polymerization strategy can be envisaged.

This system extends concepts in multifunctional activation by precise arrays of

functional groups that mimics the behavior of many enzymatic processes. New

catalyst families that combine the attributes of organic and metal catalysis146 or that

employ new combinations of activation mechanisms (or a new mechanism entirely)

will create new opportunities for polymer synthesis. Many cues are evident from

Nature; the extraordinary rates, selectivities and exquisite multicomponent catalytic

cascades of natural catalysts inspire emulation. The convergence of convenience,

functional group tolerance, fast rates and selectivities will continue to drive

innovations in polymerization catalysis, and it is our perspective that organocatalysis

will continue to play an important role in these developments.

1.15 References

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(183) Williams, C. K.; Hillmyer, M. A. Polymer Reviews 2008, 48, 1-10.

(184) Horvath, I. T.; Anastas, P. T. Chem. Rev. 2007, 107, 2169-2173.

(185) Anastas, P. T.; Kirchhoff, M. M. Acc. Chem. Res. 2002, 35, 686-694.

(186) Methot, J. L.; Roush, W. R. Adv. Synth. Catal. 2004, 346, 1035.

(187) Ema, T.; Tanida, D.; Matsukawa, T.; Sakai, T. Chem. Commun. 2008, 957-

959.

43

CHAPTER 2

A Distinctive Organocatalytic Approach to Complex Macromolecular Architectures

Reprinted in part with permission from Angew. Chem. Int. Ed. 2007, 46, 4719.

Copyright 2007 by Wiley Interscience

44

2.1 Introduction

The assembly of precisely aggregated macromolecular assemblies has largely

been the domain of biological systems due to the exquisite architectural and

compositional makeup of natural macromolecules. Modern synthetic methods are

beginning to challenge Nature's monopoly on the creation of well-defined

macromolecules of defined architecture and composition.1-3 Living polymerization

methods enable the synthesis of a wide variety of block copolymers of different

structure and topology.3 In the case of block copolymers, the molecular architecture or

topology of the chain has a pronounced effect on the morphology and interfacial

activity. For example, ABC triblock copolymers, dendritic-linear hybrid copolymers,

radial star-shaped copolymers, comb, tadpole-shaped and linear-nanoparticle

copolymers all manifest unique morphologies as a result of their distinctive

architectures. 4-9 While the synthesis of linear block copolymers is facile with several

methods, the introduction of branch points at specific loci is more challenging and

requires multiple steps.3 H-shaped homopolymers, first reported by Roovers et al.,10

exhibit unique rheological behavior. Many variations of this architecture (super-H, -

shaped, graft, off-centered graft, etc.) have been prepared with anionic methods,3

typically from styrene, isoprene and butadiene monomers. More recently, controlled

radical polymerization and ring-opening metathesis methods have expanded the

comonomer classes that can be enchained into specifically branched copolymer

architectures, but the construction of branched structures requires multiple steps.11-14

In this contribution, we report an expedient approach to a H-shaped and super H-

shaped polymers by ring-opening polymerization from telechelic diamine or

polyamine macroinitiators.

New catalysts beget new patterns of reactivity for the enchainment of

monomers to structurally well defined macromolecules. Organocatalysts complement

transition metal catalysts due to their different mechanisms for effecting bond

constructions.15 Our research has focused on organocatalytic ring-opening

polymerization (ROP) of cyclic esters, primarily motivated to avoid metal

contaminants in polymers for microelectronic and biomedical applications.16-24 Recent

45

studies have shown that these catalysts enable the construction of novel polymer

architectures.17, 19 We have reported several classes of ROP organocatalysts, including

N-heterocyclic carbenes,18 bifunctional thiourea-amines,21, 25 and amidine or guanidine

superbases,16, 26 with user-selectable degrees of activity and selectivity. In this

contribution, we report a simple approach to a H-shaped and super H-shaped

architectures enabled by the unique reactivity of the commercially available 1,3,4-

triphenyl-4,5-dihydro-1H-1,2,4-triazol-5-ylidene (2.1).27 Primary amines were found

to function as bifunctional initiators for ROP in the presence of 2.1 to promote

polymerization of two chains, enabling the facile introduction of branch points in

block copolymers. This is in marked contrast to conventional organometallic

promoters where only one chain is initiated from an amine, generating an amide end-

group.28, 29

2.2 Results and Discussion

The triazole carbene 2.1 is an efficient catalyst for the ROP of lactide in the

presence of alcoholic initiators at 50 -90 °C.20, 23 Elevated temperatures are required

for 2.1 due to a competitive O-H insertion reactions of 2.1 with terminal alcohols of

the growing chains that lead to dormant alcohol adducts that are reactivated reversibly

at elevated temperatures (Figure 2.1).23, 27 As analogous N-H insertion reactions are

known for secondary amines,30, 31 we investigated the use of primary amines as

initiators for lactide polymerization with 2.1.

NN

NPh

Ph

Ph

+ E R

H

NN

NPh

Ph

Ph

ER

H

E = O, NR

Figure 2.1. Reversible E-H insertion reactions of 2.1

The polymerization of rac-lactide (LA) initiated by 4-pyrene-methylamine as

an initiator and 2.1 as catalyst in deuterated benzene (C6D6) was carried out at an

46

initial monomer-to-initiator ratio ([M]0/[I]0) of 100 at 90°C. After 15 hours (Conv. =

72.6%), the reaction was cooled to room temperature and directly quenched with a few

drops of carbon disulfide. The polymer was precipitated twice from cold methanol

and dried under vacuum until constant weight to give polylactide with a Mn = 10600

g/mol and Mw/Mn = 1.1. Analysis of the 1H NMR spectrum, MALDI-TOF mass

spectra, and GPC with a UV detector clearly show the presence of the 4-pyrene-

methylamino endgroup. Surprisingly, integration of the methine endgroups vs. the

pyrene aromatic signals revealed approx. two endgroups per pyrene, suggesting that

lactide polymerization was initiated from both N-H groups of the initiator (i.e., both

the amine and resulting amide functionality). This is surprising, as it suggests that the

N-heterocyclic carbene 2.1 can initiate lactide polymerization both from primary

amines and from amides.

To establish the competence of amides as initiators in the presence of 2.1, we

investigated the polymerization of rac-lactide(LA) initiated from the cyclic amide ε-

caprolactam (CLa) ([LA]0/[CLa]0 = 10). After 22 hrs in C6D6 at 90C, the reaction

was quenched with acetic acid and the resulting polymer analyzed by 1H, 13C-NMR

and electrospray ionization mass spectrometry (ESI-MS). The ESI-MS yields a series

of peaks corresponding to CLa-(LA)n with a parent ion at M/z = 1121.3 (M/z =

1122.03 g/mol for CLa-(LA)7) and the 1H- and 13C-NMR spectra clearly show the

presence of the CLa endgroup. The observation that amides can serve as initiators for

the polymerization of lactide with 2.1 is intriguing as initiation from both N-H bonds

of primary amines provides a facile means of generating branched polymers in a single

step.

47

H2N OO

NH2n

363 KO

OO

O

m

N O O Nn

O OO

O

O

OO O

OO

OO

OO

OO

H

HH

H

NN

NPh

PhPh

N OO

Nn

NH2

NH2

H2N

H2N

363 KOO

O

O

m

PEON N

N

NN

N

O

O

O

O

OO

O

O

OO

O

O

O

O

O

O

O

O

O

O

H

H

H H

H

H

H

O

O

O

O

O

O

O

O

O

O

H

NN

NPh

PhPh

y

y y

y y

y

y

y y

y

y

y

Scheme 2.1. Polymerization of LA initiated with (left) PEO-(NH2)2 and (right) PEO-

(NH2)4 forming H-shaped and super-H-shaped polymers respectively

To test the latter hypothesis, the polymerization of rac-lactide (LA) was

carried out with poly(ethylene glycol) bis(3-aminopropyl) (PEO-(NH2)2) as initiator

and 2.1 as catalyst ([M]0/[I]0 = 100, [2.1]0/ [I]0 = 4). in C6D6 at 90C (Scheme 2.1).

Analysis of aliquots of the reaction mixture revealed a linear dependence of molecular

weight Mn versus conversion. Plots of ln(([LA]0-[LA]eq)/([LA]t-[LA]eq)) vs time are

linear with zero intercepts (see 2.4 Experimental Section), indicating a first order

dependence on LA concentration and an absence of termination. The linear nature of

the plot, in conjunction with the narrow polydispersities (Mw/Mn < 1.1), suggests that

the polymerization of LA from the amino-adduct of 2.1 is living, as previously

described for LA ROP from the alcohol-adduct of 2.1.20, 23 At 71 hrs, the reaction had

reached 85% conversion, and a 1H-NMR spectrum (see see 2.4 Experimental Section)

of the purified polymer taken after quenching with CS2 revealed the formation of the

[poly(lactide)]2-poly(ethylene glycol)-[poly(lactide)]2 (PLA2-PEO-PLA2) triblock

polymer: DPPLA = 48 (by comparison of the PLA and PEO resonances at 5.14 ppm

and 3.61 ppm, respectively). Integration of the methine end group (4.34 ppm) versus

48

the PEO segment confirmed the presence of 4.0 end groups, indicated that

polymerization had occurred off all four N-H bonds of the initiator.

To confirm the initiation from all four N-H groups of the telechelic initiator

PEO-(NH2)2, we compared the kinetics of ROP from PEO-(NH2)2 to that of PEO-

(OH)2 in the presence of 2.1. The kinetics are consistent with the rate law: -d[LA]/dt =

kobs[LA] for kobs = k1[PEO][ 2.1], where [PEO] = PEO-(OH)2 or PEO-(NH2)2. These

studies reveal that the rate constant for monomer consumption (k1) is approximately

two times higher when LA is polymerized from PEO-(NH2)2 (k1-NH2) compared to

when LA is polymerized from PEO-(OH)2 (k1-OH), k1-NH2/ k1-OH = 1.97, consistent with

the doubling of the number of propagating –OH endgroups when polymerization is

initiated from the amine initiators (Figure 2.2). In addition, polymerization of lactide

from a 1:1 mixture of PEO-(OH)2 and PEO-(NH2)2 at 90°C with 2.1 in C6D6 yielded a

mixture of diblock copolymers of Mn = 20,000 g/mol and 9000 g/ mol (GPC vs.

polystyrene), consistent with the generation of a mixture of an H-shaped block

polymer of approximately twice the molar mass as the linear block copolymer.

y = 407 .53x

y = 797 .79x

0

500

1000

1500

2000

2500

3000

3500

4000

4500

0 1 2 3 4 5 6 7

tim e (h rs )

ln((

[LA

]o)/

([L

A]t

))/[

PE

O][

tria

zole

]

Figure 2.2. Comparison of rates of LA polymerization with (upper) PEO-(NH2)2 and

(lower) PEO-(OH)2 catalyzed by 2.1

49

This strategy also enables a facile synthesis of super H-shaped copolymers32

from a telechelic tetramino-functionalized PEO oligomers (Scheme 2.1). Tetra-amine-

functionalized PEO was synthesized by cyanoethylation of PEO-(NH2)2 followed by

nitrile reduction using BH3·THF. Polymerization of LA initiated from poly(ethylene

glycol) octa(3-aminopropyl) (PEO-(NH2)4) with eight equivalents of 2.1 and 100

equivalents of LA ([LA]0 = 1 M) in C6D6 was carried out at 90°C until near complete

conversion after 16 hours, (Scheme 2.1). 1H-NMR analysis confirms the

polymerization off each N-H bond (integration of the end groups versus the PEO

segment suggests 8.15 end groups) and DP= 93 (integration of PLA versus PEO

fragment).

2.3 Conclusion

These results indicate that 2.1 with any of a host of commercially available

amino-functionalized macroinitiators provide a general procedure for the generation a

variety of precisely branched block copolymer architectures. In addition, these results

suggest a novel means of functionalizing polyamides or proteins. Further studies are

underway to investigate the interfacial and self-assembly properties of these

hydrophilic / hydrophobic branched copolymer architectures.

2.4 Experimental Section

2.4.1 General Considerations

rac-Lactide was obtained from Purac and used without further purification

(water content < 0.02 %). Bis-hydroxyl terminated Poly(ethylene glycol)s (PEO-

(OH)2, Mn = 3400) were purchased from Aldrich and dried under vacuum at 60°C

overnight prior to three azeotropic distillations from toluene. Amino-terminated PEGs

were prepared by cyanoethylation of PEG-(OH)2 or PEG-(NH2)2 followed by

reduction. 1,3,4-triphenyl-4,5-dihydro-1H-1,2-triazol-5-ylidene (from Acros) was

purified by exposure to high vacuum at 90°C overnight. Benzene-d6, purchased from

Aldrich, was dried over Na/benzophenone and degassed by standard procedures.

50

2.4.2 Cyanoethylation of hydroxy-terminated PEG

(NCCH2CH2O(CH2CH2O)CH2CH2CN)

Hydroxy-terminated PEG (Mn = 3400, 10.0 g, 2.94 mmol) was dissolved in

excess acrylonitrile (25 mL) in a round-bottom flask. The clear solution was cooled to

0 °C in an ice water bath, and a small amount of sodium hydride (60% dispersion in

mineral oil, 15 mg, 0.4 mmol) was added to start the reaction. After 15 minutes at 0

°C, the pale yellow reaction mixture was quenched with a few drops of concentrated

hydrochloric acid. Excess acrylonitrile was removed under vacuum and the product

was dissolved in CH2Cl2. Insoluble poly(acrylonitrile) was removed by filtration

through a plug of Celite, giving a clear, colorless solution. Solvent removal gave the

nitrile-terminated PEG as a white solid (8.90 g, 86%). 1H NMR (CDCl3, 400 MHz): δ

3.70 (t, 4H, J = 6.4 Hz, OCH2CH2CN), 3.63 (br s, PEG CH2), 2.60 (t, 4H, J = 6.4 Hz,

OCH2CH2CN). 13C NMR (CDCl3, 100 MHz): δ 117.9 (OCH2CH2CN), 70.5 (PEG

CH2), 65.9 (OCH2CH2CN), 18.8 (OCH2CH2CN).

2.4.3 Cyanoethylation of amine-terminated PEG

(NCCH2CH2)2NCH2CH2CH2O(CH2CH2O)CH2CH2CH2N(CH2CH2CN)2

Amine-terminated PEG (Mn = 3510, 5.0 g, 1.42 mmol) was dissolved in

methanol (20 mL) and excess acrylonitrile (20 mL) to give a clear solution. The flask

was sealed and stirred at 60 °C for six hours. After cooling, the solvent was removed

under vacuum. The product was dissolved in CH2Cl2, filtered, and dried to give a

white solid (4.95 g, 93%). 1H NMR (CDCl3, 400 MHz): δ 3.63 (br s, PEG CH2), 3.52

(t, 4H, J = 6.0 Hz, OCH2CH2CH2N), 2.81 (t, 8H, J = 6.4 Hz, NCH2CH2CN), 2.61 (t,

4H, J = 6.4 Hz, OCH2CH2CH2N), 2.47 (t, 8H, J = 6.4 Hz, NCH2CH2CN), 1.68 (p, 4H,

J = 6.0 Hz, OCH2CH2CH2N). 13C NMR (CDCl3, 100 MHz): δ 118.6 (NCH2CH2CN),

70.3 (PEG CH2), 67.6 (OCH2CH2CH2N), 49.5 (NCH2CH2CN), 49.2

(OCH2CH2CH2N), 27.2 (OCH2CH2CH2N), 16.6 (NCH2CH2CN).

51

2.4.4 General procedure for nitrile reduction

A dry Schlenk flask equipped with a reflux condenser was placed under

nitrogen and charged with dry THF (50 mL). A syringe was used to add an excess

(usuall two- to four-fold) of BH3·THF solution (1.0 M in THF). This mixture was

cooled to 0 °C in an ice bath. The nitrile-terminated PEG was also dissolved in a

minimum amount of dry THF; in most cases heating was required to obtain a

homogeneous solution. The PEG solution was added slowly to the borane solution,

then allowed to stir for 30 minutes at 0 °C. The reaction was then heated at reflux

under nitrogen overnight. After cooling in an ice bath, the flask was opened and

methanol was slowly added to react with excess borane (with hydrogen evolution).

Concentrated HCl (2 mL) was added, and the mixture was stirred at 0 °C for one hour.

The solvent was removed under vacuum, residues were taken up in methanol and

dried under vacuum to remove trimethyl borate side products. The resulting polymer

was dissolved in aqueous sodium hydroxide (1M solution). The polymer was

thoroughly dried under vacuum, dissolved in CH2Cl2, filtered through Celite, and

precipitated in ether, giving a fine white powder.

2.4.5 Synthesis of H2NCH2CH2CH2O(CH2CH2O)CH2CH2CH2NH2

Nitrile-terminated PEG (5.00 g, 1.43 mmol) was reacted with excess BH3·THF

solution (20 mL, 20 mmol) as described above to give the desired amine-terminated

PEG as a white powder (4.30 g, 86%). 1H NMR (CDCl3, 400 MHz): δ 3.63 (br s, PEG

CH2), 3.56 (t, 4H, J = 6.4 Hz, OCH2CH2CH2NH2), 2.81 (t, 4H, J = 6.8 Hz,

OCH2CH2CH2NH2), 1.74 (p, 4H, J = 6.4 Hz, OCH2CH2CH2NH2), 1.10 (br s, 4H,

OCH2CH2CH2NH2). 13C NMR (CDCl3, 100 MHz): δ 70.5 (PEG CH2), 69.5

(OCH2CH2CH2NH2), 39.6 (OCH2CH2CH2NH2), 33.1 (OCH2CH2CH2NH2).

2.4.6 Synthesis of

(H2NCH2CH2CH2)2NCH2CH2CH2O(CH2CH2O)CH2CH2CH2N(CH2CH2CH2NH2)2

Tetranitrile-terminated PEG (2.50 g, 0.67 mmol) was reacted with excess

BH3·THF solution (20 mL, 20 mmol) as described above to give the desired

52

tetraamine-terminated PEG as a white powder (2.10 g, 84%). 1H NMR (CDCl3, 400

MHz): δ 3.63 (br s, PEG CH2), 3.46 (t, 4H, J = 6.4 Hz, OCH2CH2CH2N), 2.72 (t, 8H,

J = 6.8 Hz, NCH2CH2CH2NH2), 2.44 (t, 4H, J = 6.8 Hz, OCH2CH2CH2N), 2.42 (t, 8H,

J = 6.8 Hz, NCH2CH2CH2NH2), 1.69 (p, 4H, J = 6.4 Hz, OCH2CH2CH2N), 1.58 (p,

8H, J = 6.8 Hz, NCH2CH2CH2NH2), 1.15 (br s, NCH2CH2CH2NH2). 13C NMR

(CDCl3, 100 MHz): δ 70.5(PEG CH2), 69.6 (OCH2CH2CH2N), 51.9

(OCH2CH2CH2N), 50.8 (NCH2CH2CH2NH2), 40.6 (NCH2CH2CH2NH2), 30.4

(OCH2CH2CH2N), 27.1 (NCH2CH2CH2NH2).

2.4.7 General polymerization procedure

In a drybox, an NMR tube equipped with a J-Young valve was charged with rac-

lactide (29.7 mg, 2.06 x 10-1 mmol), 1,3,4-triphenyl-4,5-dihydro-1H-1,2-triazol-5-

ylidene (2.9 mg, 9.76 x 10-3 mmol) and PEO-(NH2)2 (9.2 mg, 2.40 x 10-3 mmol) in 0.6

ml of dry benzene-d6. The sealed NMR tube was then heated at 90°C in an oil bath.

After 3 days (conv = 84.3%), the reaction was cooled to room temperature and

quenched with ~0.5 mL of carbon disulfide and returned to reflux for 1 hr. The

polymer was precipitated twice from cold heptane. The resulting polymer, slightly

pink in color indicating the presence of CS2-triazole adduct, can be dissolved in CS2 at

90°C and precipitated by returning to room temperature. The red CS2 solution can be

decanted leaving behind white polymer. Isolated polymer is dried under high vacuum

until constant weight (31.3 mg, 80.5%, PDI = 1.09, Mn = 9,580), and the degree of

polymerization was determined by 1H-NMR spectroscopy (DP = 48). 300 MHz 1H-

NMR (CDCl3): 1.41-1.70 (m, -CH3 & -nCH3), 3.62 (s, -n(CH2-CH2-O)-), 4.32 (q, -

CH-), 5.07-5.22 (m, -nCH). For polymerizations with the diol, a single

catalyst/initiator species was made by stirring PEO-(OH)2 with excess 2.1 for 1 hour

in toluene, followed by precipitation from solution with cold heptane and isolation.

The PEO-(2.1)2 adduct is stable at room temperature. rac-Lactide polymerizations

with this species proceed identically to the telechelic polyamine species. Failure to

dry the PEO-(OH)2 in this manner results in short oligomeric fragments of PLA

(presumably initiated from H2O) mixed with the triblock polymer.

53

2.4.8 ε-caprolactam initiated polymerization of lactide

Using the identical polymerization procedure, rac-lactide (45.8 mg, 3.18 x 10-1

mmol), 1,3,4-triphenyl-4,5-dihydro-1H-1,2-triazol-5-ylidene (6.4 mg, 2.15 x 10-2

mmol) and ε-caprolactam (2.8 mg, 2.48 x 10-2 mmol) were heated in 0.6 mL of dry

benzene-d6 at 90°C for 22 hrs before quenching with 5 drops of 1M acetic acid. The

resulting polymer, after precipitation in cold heptane and isolation, was analyzed by

300 MHz 1H-NMR (CDCl3): CLa moiety: 2.41 (m, -CH2-), 2.18 (m, -CH2-), 1.18-

0.98 (m, -(CH2)3-); PLA moiety: 5.04 (m, -CH-), 4.27 (q, -CH-OH), 1.5 (m, -CH3).

Figure 2.3. MALDI-TOF Mass spectra of poly(rac-Lactide) initated from 4-pyrene-

methylamine ([LA]0 = 1 M, [pyr-NH2]0 = 0.02M, [2.1]0 = 0.02M, 68% conv, Mn =

6,400 (GPC vs PS), Mw/Mn = 1.06, degree of polymerization (a) entire spectra, (b)

blowup of spectra. Calculated m/z for n(Lactic acid repeat unit = 72) + pyrene amine

+ Na = 4791 (n = 63), 4862 (n = 64), 4935 (n = 65), 5007 (n = 66), 5079 (n = 67),

5152 (n = 68).

54

Table 2.1. Polymerization of Lactide from Amine and Alcohol Initiators.

Entries Initiator

[M]0/[I]0 Polym.

Time

(h)

Conv.

(%)

Mn(theory)

(g.mol-1)

MnNMR

(g.mol-1)

MnGPC

(g.mol-1)

Mw/Mn

1 Pyr-NH2a 100 22.5 70 10022 8064 8549 1.07

2 PEO(NH2)2 b 86 71 79 13612 11605 9580 1.09

3 PEO(NH2)4 c 105 18 ~100 19720 18099 19388 1.24

4 PEO(OH)2 d 101 46 75 16902 14058 12874 1.17

5 -Cla e 13 22 85 1984 1984 NA -

a [LA]0= 0.82 M, [Pyr-NH2]0/[2.1]0 = 1. b [LA]0= 0.35 M, [PEO(NH2)2]0/[2.1]0 = 0.25. c [LA]0= 1.31 M, [PEO(NH2)4]0/[2.1]0 = 0.125. d [LA]0= 1.31 M, [PEO(OH)2]0/[2.1]0 = 1. e [LA]0= 0.35 M, [-Cla]0/[2.1]0 = 1.

Figure 2.4. Chart of Molecular weight (-- GPC vs. Polystyrene) and Mw/Mn (-o-)

versus conversion for the polymerization of rac-lactide initiated from PEO-(NH2)2 in

C6D6 at 90°C using 2.1 as catalyst. Conditions: [LA]0 = 1M, [PEO]0 = 1.99 x 10-2M

and [2.1]0 = 3.99 x 10-2 M.

y = 100.71x + 5396.7

R2 = 0.9499

50006000700080009000

100001100012000130001400015000

0 20 40 60 80 100

Conv.(%)

MnG

PC

(g

/mo

l)

11.051.11.151.21.251.31.351.41.451.5

PD

I

55

Figure 2.5. 300 MHz 1H-NMR (CDCl3) of PLA2-PEO-PLA2 (Mn = 9,580; Mw/Mn =

1.09). The numbers under the brackets indicate the integration of the designated

peaks. See text for peak assignments.

y = 0.03184x

R2 = 0.99703

y = 0.6334x

R2 = 0.9501

0

0.5

1

1.5

2

2.5

3

3.5

0 1 2 3 4 5 6 7

hours

ln([

LA

]o/[

LA

]t)

Figure 2.6. First-order plots for the rac-lactide polymerization initiated with either

PEO-(NH2)2 (upper) or PEO-(OH)2 (lower) in C6D6 at 90°C using triazolium carbene

2.1 as catalyst. Conditions: PEO-(NH2)2 polymerization: [LA]0 = 1 M, [PEO]0 = 1.99

56

x 10-2 M and [2.1]0 = 3.99 x 10-2 M; PEO-(OH)2 polymerization: [LA]0 = 6.25 M,

[PEO]0 = 6.25 x 10-3 M and [2.1]0 = 1.25 x 10-2 M. As noted in text, k1-NH2/ k1-OH =

1.97, where kobs = k1[PEO][ 2.1], see ref. 6.

Figure 2.7. Gel Permeation Chromatogram of lactide polymerization carried out with

an equimolar mixture of PEO-(NH2)2 and PEO-(OH)2 in C6D6 at 90°C using

triazolium carbene 2.1 as catalyst. Conditions: [LA]0 = 1.16 M, [1]0 = 1.0 x 10-2 M,

PEO-(NH2)2, [PEO-(NH2)2]0 = [PEO-(OH)2]0 = 1.72 x 10-3 M

2.5 References

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(3) Hadjichristidis, N.; Pitsikalis, M.; Pispas, S.; Iatrou, H.; Chem. Rev 2001, 101,

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4

6

8

10

12

14

16

25 30 35 40

Ret. Vol. (ml)

Inte

nsity

8926

20703

57

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243-244.

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L. J. Am. Chem. Soc. 2006, 128, 4556-4558.

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H. C.; Waymouth, R. M.; Hedrick, J. L. Angew. Chem., Int. Ed. 2006, 45,

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(18) Dove, A. P.; Pratt, R. C.; Lohmeijer, B. G. G.; Culkin, D. A.; Hagberg, E. C.;

Nyce, G. W.; Waymouth, R. M.; Hedrick, J. L. Polymer 2006, 47, 4018-4025.

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Waymouth, R. M.; Hedrick, J. L. Chem. Commun. 2006, 2881-2883.

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Culkin, D. A.; Benight, S. J.; Dubois, P.; Waymouth, R. M.; Hedrick, J. L.


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58

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59

CHAPTER 3

Cyclic Guanidine Organic Catalysts: What Is Magic About Triazabicyclodecene?

Reprinted in part with permission from J. Org. Chem. 2009, 74, 9490. Copyright 2007 by the American Chemical Society

60

3.1 Introduction

Almost a century after its beginnings,1-4 the field of organocatalysis has

undergone a resurgence with the development of new classes of highly

enantioselective organocatalysts.5-8 Notwithstanding the extraordinary pace of

developments in transition metal and organometallic catalysis,9,10 it is clear that

organocatalytic reactions have evolved to provide a powerful addition to the

armamentarium of methods for chemical synthesis.5-8 Organocatalysis has also proven

a powerful strategy for polymer synthesis.11 We have investigated a variety of

nucleophilic and basic organic molecules as catalysts for transesterification12,13 and

ring-opening polymerization reactions (Figure 3.1).11 The highly basic and

nucleophilic N-heterocyclic carbenes are potent organocatalysts for the ring-opening

polymerization of lactones, generating polyesters of defined molecular weights in

seconds at room temperature.11,14 Mechanistic and theoretical studies indicate that N-

heterocyclic carbenes bind readily to alcohols,15,16 activating the alcohol for

nucleophilic attack and stabilizing the resultant tetrahedral intermediates.16,17 In the

absence of alcohols, the N-heterocyclic carbenes react directly with lactones and

mediate the zwitterionic ring-opening polymerization of esters by a nucleophilic

mechanism.14,18 This mechanistic duality is common to many acylation reactions

catalyzed by amines and nitrogen heterocycles.19,20

NH

N

N

N

N

TBD

PN

N

NtBu

NEt2

Me

Me

N

N

N

MTBDMe

DBU

BEMP

P N P

NMe2

NMe2

NtBu

Me2N

Me2N

Me2N

P2-tBu

N NR R

R' R'

NHC

Figure 3.1. Nucleophilic and basic organocatalysts for ring-opening polymerization

In addition to the N-heterocyclic carbenes, we have also surveyed a variety of

other potent neutral organic bases as catalysts for ring-opening polymerization

61

reactions. Guanidines such as 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD),21,22 N-

methyl-TBD (MTBD), and 1,4,6- triazabicyclo[3.3.0]oct-4-ene (TBO),21 amidines

such as 1,8-diazabicyclo[5.4.0]-undec-7-ene (DBU)23-25 and phosphazenes such as 2-

tert- butylimino- 2- diethylamino- 1,3- dimethyl-perhydro- 1,3,2- diazaphosphorine

(BEMP) and 1-tert-butyl-2,2,4,4,4-pentakis(dimethylamino)-2Λ5,4Λ5- catenadi-

(phosphazene) (P2-t-Bu)26 are all effective catalysts for the ring-opening

polymerization of lactones and cyclic carbonates27-32 (Figure 3.1).

TBD is among the most active ring-opening polymerization catalysts that we

have investigated to date. The ring-opening polymerization of lactide with 0.1% TBD

in THF exhibits a turnover frequency of 80 s-1 at room temperature,23,25 which is

comparable to those of the most active metal catalysts reported for ROP of lactide.33-35

These polymerizations are also remarkably well-controlled, yielding polylactide with

well-defined molecular weights and narrow polydispersities (Figure 3.2).

O

O

O

O

+N NMes Mes

0.5 % THF, 25 °C,

20 seconds!

O

OO

O

OH

n

OH

TOF = 18 s-1

N

N

NH

0.1%, 25�C 20 seconds!

OO

O

O

+

O

OO

OO

H

n

OH

TOF = 80 s-1

96 %, Mn = 23,000, PDI = 1.09

99 %, Mn = 63,000, PDI = 1.11

Figure 3.2. Ring-opening polymerization of lactide with TBD is even faster than with

NHC's

TBD is a more active catalyst than MTBD or DBU for lactide polymerization

and catalyzes the ring-opening polymerization of -valerolactone and -caprolactone

under conditions where MTBD and DBU are inactive.23,25 TBD (TBDH+, pKa = 26),

MTBD (MTBDH+, pKa = 25) and DBU (DBUH+, pKa = 24) have comparable

basicities in THF36 to those calculated for the N-aryl substituted N-heterocyclic

0.1%, 25°C

62

carbenes (pKa 27-28).37-39 The large differences in activity observed for TBD, MTBD

and DBU implies that thermodynamic basicity is not the sole criterion for predicting

catalytic activity.

Guanidines and amidines are effective catalysts for a variety of organic

reactions.22,40-44 These commercially available, easily handled bases have been

reported as transesterification catalysts.27,45-48 In water, guanidines and amidines are

readily protonated,36 and their biological activity49-51 and much of their reaction

chemistry is assumed to proceed via guanidinium or amidinium intermediates.42-44,51,52

However, several studies have shown that guanidines and amidines can act as

nucleophiles.22,53,54

We had previously shown that TBD can be acylated by vinyl acetate,

implicating that TBD can act as a nucleophile.23 Subsequent reaction of acyl-TBD

with benzyl alcohol yielded the ester, leading us to propose a nucleophilic mechanism

as a potential pathway for ring-opening by TBD (Figure 3.3).23,25 Subsequent

theoretical studies24,55 indicated that a nucleophilic mechanism was feasible, but had a

considerably higher barrier than a hydrogen-bond mediated mechanism (Figure 3.4)

for transesterification reactions.

N

N

NH

N

N

N

O N

N

NH

Ph O

O

O

O

H

O

Ph OH

Figure 3.3. Model studies demonstrating the acylating ability of TBD

63

N

N

N

H HO

R

O

N

N

N

H H

O

O

O

O

OO

OO

R

N

N

N

H H

O

OO

OO R

Figure 3.4. Hydrogen-bonding mechanism suggested by theoretical studies24,55

The implication that TBD can act as a bifunctional nucleophilic catalyst

suggests that it may be able to acylate other nucleophiles. The acylation of amines is

of particular interest as the formation of amides from esters is an exceedingly useful

reaction typically carried out under forcing conditions with highly basic catalysts.56-67

Maggi had previously demonstrated that TBD catalyzes the formation of ureas from

carbonates and primary amines,68,69 and while this work was ongoing, Mioskowski

reported the aminolysis of esters with amines to form amides under solvent-free

conditions.70

In this article, we report kinetic studies on the acylation of amines by esters

which strongly implicate a nucleophilic mechanism for the conversion of esters to

amides in the presence of TBD. Studies of the analogous bicyclic guanidine 1,4,6-

triazabicyclo[3.3.0]oct-4-ene (TBO)21 revealed it to be a much slower catalyst;

mechanistic and theoretical studies provide useful insights on the stereoelectronic

properties of TBD that contribute to its remarkable ability to catalyze acylation

reactions.


The amidation of vinyl acetate with 4 equiv. of n-butylamine with 10 mol %

TBD in toluene solution at 25°C affords n-butylacetamide quantitatively in 6 minutes

(Figure 3.5). While vinyl esters are known to acylate primary amines in the absence of

a catalyst,71,72 these reactions are significantly slower than that observed in the

presence of TBD (6 min vs. 24 hours). In the presence of four equivalents of n-

64

butylamine, benzyl acetate converted cleanly (99% conversion, 94.9% isolated yield)

to n-butylacetamide in 5 hours at 80°C in toluene in the presence of 10 mol% TBD.

Under solvent-free conditions reported by Mioskowski,70 neat benzyl acetate reacts

with 1.3 equiv. of butylamine in the presence of 22 mol % TBD to give n-

butylacetamide in 89% isolated yield after 2 hours. No special care is needed in the

purification of solvents: reactions in reagent grade toluene, THF, DMSO or CH2Cl2

proceeded in quantitative yield, albeit with slightly slower rates than those in dry

toluene. The conversion of benzyl acetate to n-butylacetamide did not proceed at an

appreciable rate when N-methylTBD (MTBD) or triethylamine were substituted for

TBD.

O

O+ Bu NH2

TBD (10%)

tol, 25¡C, 6 minBu

NH

O+ H

O

O

OBu

NH

OTBD (10%)

tol, 80¡C, 5 h25 ¡C, 10 h

+ Bu NH2 +Ph

PhCH2OH

O

O

OH OH

O

NH

BuTBD (10%)

tol, 80°C, 2.5 h+ Bu NH2

retention of configuration

O

OMe

OO

HN

Bu

O

HO+

TBD (10%)

tol, 80°C, 20 days+ Bu NH2

MeOH+

99%

95%

97%

64%

Figure 3.5. Catalytic amidation of esters

The amidation of (S)-ethyl lactate is considerably faster than benzyl acetate,

generating a 71% yield of n-butyl lactamide within 30 minutes at 80°C. Analysis of

the Mosher ester of n-butyl lactamide reveals it to be of high diastereomeric purity

(only one isomer observed by 19F NMR) and derived from (S)-n-butyl lactamide,

tol. 25°C, 6 min

tol. 80°C, 5 h 25°C, 10 h

65

indicating that the amidation of ethyl lactate proceeds with retention of configuration

with minimal epimerization. In contrast, amidation of the more acidic and sterically

demanding (S)-2-(6-Methoxy-naphthalen-2-yl)-propionic acid methyl ester was

considerably slower (20 days, 64% yield) and yielded racemic n-butyl 2-napthyl

propranamide. In the latter case, due to the much slower rate, TBD-catalyzed

epimerization of either the ester or amide can compete with amidation. Thus, while

we had anticipated that the basic nature of TBD might lead to the racemization of

acidic esters, it is clear that the extent of racemization depends sensitively on the

nature of the ester.

Screening experiments, Table 3.1, by 1H NMR revealed that catalytic

formation of amides from branched and secondary amines or from branched esters

exhibited much slower rates at 25°C in solution ([Ester]o = 0.23 M) than those of

benzyl acetate and ethyl lactate. However, under solvent-free conditions, the catalytic

amidation of methyl phenylacetate yields the amides in 94% yield after 12 hours at

75°C.70

Table 3.1. Substrate Screening for the TBD Catalyzed Amidation of Esters

entry R1 R2 R3 time (h) temperature (C)

conversion (%)b

1 Bz Me n-Bu 10 25 99 (94.9)f

2 vinyl Me n-Bu 0.1 25 99

3 Me Me n-Bu 48 25 97

4 i-Pr Me n-Bu 121 25 57

5 t-Bu Me n-Bu NRd -- --

6 Me i-Pr n-Bu 120 25 99

7 Me Et n-Bu 75 25 89

8 Me Ph n-Bu 121 25 76

66

9 Me cyclohexyl n-Bu 600 25 89

12 Bz Me

NH2

122 25 99

13e Me 2-naphthyl propionate

n-Bu 504 25 65(64)f

14 Me

HNHBoc

n-Bu 648 25 84

15 Et ethan-1-ol n-Bu 2.5 25 99 (97)f

1 Bz Me n-Bu 5 80 99

2 Me Me n-Bu 15 80 99

3 i-Pr Me n-Bu 21 80 57

4 t-Bu Me n-Bu NRd -- --

5 Me i-Pr n-Bu 24 80 99

6 Me Et n-Bu 31 80 99

7 Me Ph n-Bu 75 80 96

8 Et ethan-1-ol n-Bu <0.5 80 99 a Reaction Conditions: Amine (0.92M), ester (0.23M) and TBD (0.023M) in toluene-d8 at 25C.

b

Conversion based on 1H NMR analysis of crude reaction mixture. c Yield determined by integration

versus an internal standard, TBD. d No reaction observed after 96 h. e see experimental for naproxen

rxn conditions f Isolated yield.

3.2.1 Kinetics and Mechanism

Theoretical studies implicate that a hydrogen-bonded mechanism has a lower

barrier than a nucleophilic acylation mechanism for transesterification reactions

(Figure 3.4).24,55 For amine nucleophiles, an H-bonded mechanism analogous to

Figure 3.4 is less likely and motivated us to investigate the chemical and kinetic

competence of a nucleophilic mechanism for amine acylation.

To this end, kinetic investigations of the reaction of benzyl acetate with n-

butylamine were studied by 1H NMR in the presence of TBD. In toluene-d8 at 298K

under pseudo first order conditions, the rate of disappearance of benzyl acetate is first

order in benzyl acetate, first order in TBD, first order in amine and inverse first order

in benzyl alcohol, yielding a rate law described by eq. (1),

67

d[Ester]

dt kobs

[Ester][RNH2][TBD]

[ROH] (1)

where [Ester], [RNH2], [TBD], and [ROH] equal the concentrations of benzyl acetate,

n-butylamine, TBD, and benzyl alcohol, respectively; and kobs =1.9 ± 0.1 x 10-3 M-1s-1.

This rate law can be accommodated by the mechanism shown in Figure 3.6 involving

the reversible formation of an acyl-TBD intermediate, followed by irreversible

trapping of acyl-TBD with butylamine to generate n-butylacetamide and TBD.

N

N

NH

N

N

N

O

N

N

NH

BuNH

OPh O

O

Ph OH

+

k1

k-1

+

Bu NH2

k2

Figure 3.6. Proposed mechanism for formation of n-butylacetamide from benzyl

acetate and butylamine.

Application of the steady-state assumption to the mechanism described in

Figure 3.6 yields the rate law in eq (2):

][][

]TBD][][[][

221

221

RNHkROHk

RNHEsterkk

dt

Esterd

(2)

This rate equation would be consistent with the experimental rate law under

conditions where k-1[ROH] >> k2[RNH2], for which:

kobs k1k2

k1

. (3)

In an effort to demonstrate the validity of this assumption, we measured the

individual rate constants for some of the discrete steps of the proposed mechanism in

Figure 3.6. For these studies, acyl-TBD was generated in situ from the reaction of

TBD and vinyl acetate (Figure 3.7).23 When 10 equivalents of butylamine were added

to the in situ-generated acyl-TBD intermediate, we observed a first-order decay in

68

acyl-TBD concentration by 1H NMR with a rate constant of k2 = 0.9 ± 0.2 x 10-3 M-1s-1

(298K). The reaction of acyl-TBD with excess benzyl alcohol exhibited first-order

kinetics and provided an estimate for k-1 = 1.86 ± 0.39 x 10-2 M-1s-1 (298K). The

greater than tenfold difference between these two rate constants supports our

approximation used to derive equation 3, and is in accordance with an acyl transfer

mechanism defined by a steady-state concentration of acyl-TBD.

N

N

NH

N

N

N

O

O

O

H

O

BuNH

O+ TBD

Bu NH2

k2

k-1

Ph OH Ph O

O+ TBD

Figure 3.7. Generation of Acyl-TBD and acylation with amines and alcohols

Given the kinetic parameters reported above, equation 3 was employed to

estimate a value for k1 equal to 3.7 ± 0.5 x 10-2 M-1s-1 under the catalytic conditions

used to determine kobs. Independent measurement of k1 from the reaction of benzyl

acetate with TBD was unsuccessful, as a rapid approach to equilibrium did not permit

accurate measurement of the forward rate. The equilibrium constant for the formation

of the acyl-TBD intermediate in the absence of amine was determined Keq = 1.6 ± 0.2

x 10-4 (303K). Analysis of the temperature dependence of this equilibrium constant

yielded the following thermodynamic data: ∆H = 18.22 ± 0.01 kJ/mol, ∆S = -1.7 ±

0.3 J/mol. These data describe an endergonic reaction between benzyl acetate and

TBD, and are consistent with the inverse first order dependence of the catalytic rate on

benzyl alcohol concentration.

3.2.2 Effect of Catalyst Structure

The modest rates for the amidation of sterically demanding substrates with

TBD motivated us to investigate less sterically hindered bicyclic guanidines as

69

catalysts. We prepared 1,4,6-triazabicyclo[3.3.0]oct-4-ene (TBO),21,73 analogs of

which had been shown to be effective catalysts for enantioselective Strecker

reactions.40 We anticipated that the larger N-C-N angle of TBO22 and the lower

basicity of TBO relative to TBD74 might facilitate reactions with more sterically

hindered substrates and potentially mitigate the racemization of α-substituted esters.

However, the catalytic activity of TBO for the amidation of benzyl acetate with

butylamine was considerably slower than that of TBD. The amidation of benzyl

acetate with 10 equivalents of butylamine in toluene with 10 mol % TBO did not

proceed at a measurable rate at 25 °C, whereas under comparable conditions TBD

catalyzed the amidation of benzyl acetate to butylacetamide in 90% yield after 100

minutes. At higher temperatures (70 °C), TBO catalyzed the formation of

butylacetamide, but in only 20% conversion after 100 minutes. Kinetic analysis

revealed that the observed rate constant for amidation of benzyl acetate by TBO was

kobs(TBO, 343K) = 2.3 ± 0.4 x 10-4 M-1s-1, whereas that for TBD at 298K was

kobs(TBD, 298K) = 1.9 ± 0.1 x 10-3 M-1s-1.

Mechanistic studies were carried out to illuminate the origin of the lower rates

observed with TBO relative to TBD. In toluene solution at room temperature, TBD

reacts quantitatively with vinyl acetate within minutes to generate acyl-TBD. In

contrast the acylation of TBO with vinyl acetate requires over 16 hours to generate N-

acyl-TBO. Isolation of this intermediate provides support for the nucleophilic75 attack

of TBO on vinyl acetate to generate the acylated guanidine, but the slower rate implies

that TBO is a less potent nucleophile than TBD. This was supported by experiments

with benzyl acetate. Treatment of TBD with one equivalent of benzyl acetate led to a

very rapid reaction to generate an equilibrium mixture of acyl-TBD, benzyl alcohol,

and TBD. In contrast, the reaction between TBO and benzyl acetate was much slower,

even at elevated temperature. An equimolar mixture of TBO and benzyl acetate (both

0.13 M in toluene) slowly converted to acyl-TBO and benzyl alcohol but even after

100 hours at 343K equilibrium was not established. Likewise, acyl-TBO reacted

slowly with benzyl alcohol to generate benzyl acetate but this mixture did not reach

equilibrium even after 16 hours at 343K. These data imply that TBO is much less

70

reactive towards esters than TBD, and acyl-TBO is much less reactive towards

alcohols than acyl-TBD.

This was confirmed with kinetic studies for the reaction of acyl-TBO with

excess butylamine. Under pseudo-first order conditions, the rate of disappearance of

acyl-TBO followed first order kinetics at 343K, yielding a rate constant for acylation

of butylamine, k2(ATBO, 343K) = 2.6 ± 0.1 x 10-4 M-1s-1. This rate constant is lower

than that measured for TBD k2(ATBD, 298K) = 0.9 ±0.2 x 10-3 M-1s-1. These data

show that the slower rates observed for TBO are a consequence both of the lower

nucleophilicity of TBO relative to TBD as well as the slower rate of transacylation of

the acylguanidine intermediate.

We turned to computer simulations to elucidate the structural differences

between TBD, TBO and the acylated guanidines, acyl-TBD and acyl-TBO. Coles has

previously compared the coordination chemistry of TBD and TBO and has carried out

DFT calculations on the geometries and frontier molecular orbitals of these bicyclic

guanidines.76 On the basis of natural bond order analysis, Coles observed a higher

electron density on the imine nitrogen of TBD, relative to that of TBO, consistent with

our observations of the higher reactivity of TBD toward vinyl and benzyl acetate.

The structures of acyl-TBD and acyl-TBO were geometry optimized at the

B3LYP/6-31G* level using Spartan ’02. Analysis of the calculated structures of the

two acylated guanidines is revealing. For acyl-TBO, the acyl is coplanar with the

guanidine moiety (C1-C2-N3-C4 dihedral angle of 3°) which is consistent with a planar

amide. In contrast, the calculated C1-C2-N3-C4 dihedral angle of acyl-TBD is

approximately 15°, indicative of a twisted amide, Figure 3.8. This deviation from

amide planarity is also manifested in the loss of carbonyl-guanidine conjugation

(TBD: C2-N3 = 1.403Å, TBO C2-N3 = 1.393Å) and loss of conjugation within the

guanidine moiety (TBD: (C4-N)max–(C4-N)min = 0.036Å, TBO: (C4-N)max–(C4-N)min =

0.007Å). The twisted amide calculated for acyl-TBD might explain its enhanced

reactivity towards amine and alcohol nucleophiles. In particular, the much slower rate

at which the planar amide of acyl-TBO reacts with amines relative to the twisted

71

amide of acyl-TBD suggests that a planar amide acyl-guanidine intermediate is too

stable for effective catalysis.77

The same DFT protocol was used to optimize the geometries of TBD and

TBO76 so that an isodesmic acyl-exchange reaction could be calculated, eq. 4. The

acyl exchange from acyl-TBD to acyl-TBO is predicted to be E° = -7.2 kcal/mol,

indicating that the structural differences calculated for acyl-TBD and acyl-TBO are

also manifested in a greater thermodynamic stability for acyl-TBO.

N

N

N

O

N

NH

N+

54

63

21

E°(calc) = - 7.2 kcal/mol N

N

NH

N

NN+

O54

6

32

1

(4)

ATBD ATBO

Figure 3.8. B3LYP/6-31G* calculated geometries of ATBD and ATBO

3.2.3 Lactide Polymerization

The relative reactivity of TBD and TBO for amidation of esters is also

reflected in their relative reactivity for the ring-opening polymerization (ROP) of

lactide (Table 3.2). The ROP of lactide occurs within minutes in the presence of TBD

and an alcohol initiator.23,25 In contrast, TBO demonstrates much lower catalytic

activity. ROP of lactide with 2 mol % TBO proceeded to 16 % conversion after 1

hour at room temperature in CH2Cl2. To achieve complete conversion over a

reasonable time period, catalyst loading was increased to 4 mol %. Under these

conditions nearly quantitative monomer conversion was observed after 4 hours for

various targeted degrees of polymerization (Table 3.2) but the molecular weight

distributions were broad, Mw/Mn = 1.8-2.0. The molecular weights were close to that

predicted by the monomer to initiator ratio for target DP = 100 and 200, but were

72

lower than predicted for DP = 400. Transesterification of the formed polymer chain

could account for this lack of control, as the relative rate of polymerization would be

reduced due to the lower nucleophilicity of TBO.

Table 3.2. Polymerization of L-lactide (L-LA) with TBO

Entry Time

(hours)

[M]0/[I]0 Conversiona

(%)

Mn

predictedb

Mn

(GPC)c

PDI

1 1.0 100 92 13,200 15,800 1.84

2 2.5 200 82 23,600 18,900 1.90

3 2.5 400 95 54,700 19,500 2.02

Conditions: [M]0 = 1 M [TBO]0 = 0.04 M in CH2Cl2 at room temperature. [I]0 = 11, 5.3, 2.4

mM for entries, 1, 2, and 3, respectively (a) monomer conversion as determined by 1H NMR

using integration of methyl proton resonances of L-LA and the formed polymer. (b) PLA

molecular weight predicted based on ([M]0/[I]0)*144(g/mol)*conversion(%). (c) GPC

calibrated to polystyrene in THF.

3.3 Conclusion

The bicyclic guanidine TBD is a potent transacylation catalyst, mediating both

the transesterification of esters and the formation of amides from esters. Mechanistic

and theoretical studies reveal that TBD can act both as a bifunctional general base/H-

bond donor and as a nucleophile for transacylation reactions. For transesterification

reactions, a general base mechanism is predicted where H-bonding of the alcohol to

TBD simultaneously activates the alcohol toward nucleophilic attack and generates a

guanidinium species that stabilizes the tetrahedral intermediate. For amidation

reactions, kinetic studies implicate a nucleophilic acylation mechanism where TBD

reacts reversibly with the ester to generate a 'twisted amide' acyl-TBD intermediate,

which subsequently acylates the amine. Comparative investigations of the bicyclic

guanidine TBO provide further insights on the unusual geometric features of TBD that

render it such an effective acylation catalyst. TBD is both more basic and more

nucleophilic than TBO, facilitating the general base/H-bonding transesterification

reactions and nucleophilic acylation pathways. In addition, the acyl-guanidine

73

intermediate generated from TBD cannot adopt a planar amide structure, rendering it

more active for subsequent acylation by amines.

The unique structural and stereoelectronic features of TBD contribute to its

remarkable catalytic activity for transesterification and ring-opening polymerization

reactions. More generally, these studies provide further insights on the chemical and

biological role of bicyclic guanidine motifs in a number of natural products.49



All syntheses and kinetic studies were performed using standard glovebox and

Schlenk techniques, unless stated otherwise. All chemicals were ordered from Aldrich

and used as received unless stated otherwise. Toluene-d8 was distilled from

potassium/benzophenone prior to use. Benzyl alcohol was dissolved in THF, stirred

overnight over CaH2, filtered, and recovered by evaporation of the solvent before use.

1,4,6-triazabicyclo[3.3.0]oct-4-ene (TBO),21,73TBO and rac-N-butyl-2-hydroxy-

propanamide78 were prepared as described in the literature. For kinetic studies of acyl

transfer, conversion data were acquired by 300 MHz 1H NMR, using the integration of

the acyl methyl resonance on benzyl acetate and that of the formed acetamide versus

an internal standard (anisole).

3.4.2 Procedure for Kinetic Experiments

To a vial containing 0.8 mL of toluene-d8 was added 15.0 mg (0.11 mmol)

TBD, 0.1 mL (0.074 g, 1.0 mmol) n-butylamine, and 0.1 mL (0.11 g, 1.0 mmol)

benzyl alcohol. This solution was transferred to a J-Young NMR tube, and the

reaction was initiated with addition of benzyl actetate (15.4 μL, 16.2 mg, 0.11 mmol).

At this point the NMR tube was sealed, removed from the glove box, and assayed for

conversion by 1H NMR. Disappearance of benzyl acetate and appearance of n-

butylacetamide were monitored by integration of the benzylic methylene and acyl

methyl resonances, respectively.

74

3.4.2.1 Kinetic and Thermodynamic Data

kobs vs. [Alcohol]

y = 0.00032xR2 = 0.99189

0

0.00005

0.0001

0.00015

0.0002

0.00025

0.0003

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9

1/[Alcohol] (1/M)

kob

s (1

/sec

)

Figure 3.9. Determining kobs(TBD) from kobs vs [alcohol]-1. [amine]o = 1.28 M;

[TBD]o= 0.128 M; [alcohol]o= given in toluene-d8; where slope = kobs [TBD]o[amine]o

kobs vs. [Amine]

y = 0.000974x

R2 = 0.989175

0

0.0002

0.0004

0.0006

0.0008

0.001

0.0012

0 0.2 0.4 0.6 0.8 1 1.2

[Amine] (M)

kob

s (1

/sec

)

Figure 3.10. Determining k2(TBD) from kobs vs. [amine]o. [amine]o = given;

[acylTBD]o = 0.045 M in toluene-d8, where slope = k2 [amine]o

75

kobs vs. [TBD]^m y = 0.4585x

R2 = 0.9492

0

0.01

0.02

0.03

0.04

0.05

0.06

0.07

0.08

0 0.02 0.04 0.06 0.08 0.1 0.12 0.14 0.16

[TBD]^m

kob

s

kobs vs. [TBD]^1

Figure 3.11. kobs vs. [TBD]o demonstrates first order in TBD. [ROH]o = [amine]o =

1.276M, [ester]o = 0.1276M in toluene-d8

1st Order

y = -0.2024xR2 = 0.9863

-1.4

-1.2

-1

-0.8

-0.6

-0.4

-0.2

0

0 1 2 3 4 5 6 7

Time (min.)

ln(1

-co

nv)

Figure 3.12. Determining k-1(TBD) from first order plots of ln[ROH]/[ROH]o vs

time, [acylTBD]o= 0.02 M in toluene-d8. The slope = -k-1, and an average over several

[ROH]o was taken.

76

[ROH] vs time

0

0.02

0.04

0.06

0.08

0.1

0.12

0.14

0 2 4 6 8 10 12 14

min

[ben

zyl

alco

ho

l]

Figure 3.13. One of the [ROH] vs time used to construct Figure 3.9.

1/T (1/K)0.0024 0.0026 0.0028 0.0030 0.0032 0.0034 0.0036 0.0038

ln K

-9

-8

-7

room temp, K= 0.00016

y = -2191.9x - 1.6615R2 = 0.92

Figure 3.14. Temperature dependent equilibrium between benzyl acetate/TBD and

benzyl alcohol/acyl-TBD. [ester]o = 10•[TBD]o = 0.867M in toluene-d8, ∆H =

18.22±0.010 kJ/mol, ∆S = -1.662±0.316 J/mol

77

y = -0.002376x + 0.013741

R2 = 0.989617

-0.3

-0.25

-0.2

-0.15

-0.1

-0.05

0

0.05

0 20 40 60 80 100 120 140

min

ln(1

-co

nv)

Figure 3.15. Determining kobs(TBO) from ln([benzylacetate]/[ benzylacetate]o) vs

time. [amine]o = 1.26 M; [TBO]o= 0.135 M in toluene-d8; where slope = -kobs

[TBO]o[amine]o

y = -0.0196x + 0.1527

R2 = 0.9918

-2.5

-2

-1.5

-1

-0.5

0

0.5

0 20 40 60 80 100 120 140

min

ln(1

-co

nv)

Figure 3.16. Determining k2(TBO) from ln([acylTBO]/[ acylTBO]o) vs time.

[amine]o = 1.26; [acylTBD]o = 0.135 M in toluene-d8, where slope = -k2[amine]o

3.4.3 Typical Substrate Screening Experiment

In a dry box under N2 atmosphere, TBD (3.2 mg, 0.023 mmol) and n-

butylamine (67.2 mg, 90.8 L, 0.92 mmol) were dissolved in 0.5 mL toluene-d8 and

transferred to a J-Young NMR tube. To initiate the reaction, benzyl acetate (34.5 mg,

32.7 L, 0.23 mmol) was added to the NMR tube by micropipette.

78

Figure 3.17. 300 MHz 1H-NMR spectra of the TBD-catalyzed reaction of benzyl

acetate with n-butylamine in toluene-d8 t minutes after the addition of butylamine.

The peaks marked with * are due to TBD, with are due to benzyl acetate, are due

to butylamine, are due to benzyl alcohol and with red arrows are due to n-

butylacetamide. The inset shows the evolution of the reaction with time.

3.4.4 Synthesis of n-butylacetamide (solution)

Into an NMR tube in a dry box was loaded 0.0015 g (0.01 mmol) TBD, 0.45

mL toluene-d8, 0.043 mL (0.44 mmol) n-butylamine and 0.0155 mL (0.11 mmol)

benzyl acetate. Reaction progress was monitored by 1H NMR. The crude reaction

mixture was poured into water and extracted with 3x8 mL diethyl ether, dried with

MgSO4 and solvent was removed under reduced pressure, yielding 12 mg (94.9%).

Characterization matched the literature.79

79

3.4.5 Synthesis of n-butylacetamide (neat)

Into a vial in a dry box was loaded 67.3 mg (0.48 mmol) TBD, 0.3237 g (2.17

mmol) benzyl acetate, and 0.2099 mL (2.88 mmol) n-butylamine. After 2 hours, the

crude reaction mixture was poured into water and extracted with 3x8 mL diethyl ether,

dried with MgSO4 and solvent was removed under reduced pressure, yielding 0.221 g

(89%). Characterization matched the literature.79

3.4.6 Synthesis of (S)-n-butyl-2-hydroxypropanamide

Into an NMR tube in a dry box was loaded 0.0015 g (0.01 mmol) TBD, 0.7 mL

toluene-d8, 0.05 mL (0.5 mmol) n-butylamine and 0.011 mL (0.1 mmol) ethyl (S)-(-)-

lactate. Reaction progress was monitored by 1H NMR. The crude reaction mixture

was poured into water and extracted with 3x8 mL diethyl ether, organics dried with

MgSO4, filtered and solvent removed under reduced pressure. The residue was shaken

with pentane and the solution decanted off the product, yielding 14 mg (97%). 1H

NMR (CDCl3, 300 MHz, 25 °C) = 0.86 (t 3H), 1.16-1.49 (m 7H), 2.21 (s 1H), 3.21

(q 2H), 4.16 (q 1H).78

3.4.7 Synthesis of the Mosher Ester

n-butyl-2-hydroxypropanamide (0.003 g, 0.021 mmol, 1 eq.) and (R)-(−)-α-

methoxy-α-(trifluoromethyl)phenylacetyl chloride (0.0039 mL, 0.022 mmol, 1.01 eq.)

were mixed with carbon tetrachloride (5 drops) and dry pyridine (1 drop) and stirred in

a closed vial for 20 h. Reaction mixture was extracted with diethyl ether and water

and washed twice with ether. After washing with dilute hydrochloric acid and

saturated sodium carbonate solution, and drying with MgSO4 the mixture was filtered

and solvent evaporated under reduced pressure. NMR spectra were taken without

further purification.

3.4.8 Synthesis of (S)-naproxen methyl ester

In a three neck round bottom flask equipped with a reflux condenser, 0.94 g

(4.09 mmol) (S)-naproxen was stirred in 20 mL methanol under N2. The flask was

80

cooled to 0°C and 0.049 mL (0.68 mmol) thionyl chloride was added dropwise via

syringe. The mixture was warmed to room temperature over an hour and refluxed for

6 h. Volatiles were removed under high vacuum Yield 0.60 g, 60.5 %. 1H NMR

(CDCl3, 300 MHz, 25 °C) = 1.51 (d 3H), 3.59 (s 3H), 3.79 (q 1H), 3.84 (s 3H), 7.02-

7.66 (m 6H) []D24.5 = +79.65° (c = 26 mg/ 100mL; CH2Cl2), []D,Lit

= +76.9 (c = 20

mg/ 100mL; CDCl3).80

3.4.9 Synthesis of rac-naproxen methyl ester

Racemic naproxen methyl ester was made by dissolving 0.2 g (0.819 mmol)

(S)-naproxen methyl ester in 10 mL methanol with 0.02 g (0.164 mmol) 5-

diazabicyclo[4.3.0]non-5-ene and refluxing overnight. The methanol solution was

diluted with 50 mL water and extracted 3x25 mL methylene chloride, dried over

MgSO4 and solvent removed under reduced pressure, yielding 0.196 mg (97.9%).

[]D23.7 = +0.0018° (c = 26 mg/ 1mL; CH2Cl2).

3.4.10 Synthesis of (S)-naproxen butyl amide

In a dry box, an NMR tube was loaded with 1.6 mg (0.012 mmol) TBD, 1 mL

toluene-d8, 0.046 mL (0.46 mmol) n-butylamine and 28 mg (0.115 mmol) (S)-

naproxen methyl ester. Reaction conversion was monitored by 1H NMR. After

several days, the reaction had reached 65% conversion and was quenched by pouring

into water. The water was extracted with 3x8mL diethyl ether, organics dried with

MgSO4 and solvent removed under reduced pressure. The residue was purified by

silica gel column chromatography using ethyl acetate: hexanes (1:2). Yield: 21 mg

(0.073 mmol, 63.7%) 1H NMR (CDCl3, 300 MHz, 25 °C) δ = 0.77 (t 3H), 1.06-1.37

(m 4H), 1.53 (d 2H), 3.11 (q 2H), 3.61 (q 1H), 3.86 (s 3H),5.23 (s 1H), 7.05-7.69 (m

6H) []D24.5 = +1.11 (c = 20.9 mg/1 mL; CH2Cl2) HPLC; 99:10 Heptane / 2-

Propanol; flow rate = 0.8 mL/min; t1 = 12.3 min, t2 = 14.4 min. 81

81

3.4.11 Synthesis of 1,4,6-triazabicyclo[3.3.0]-oct-4-ene (TBO)

Synthesized by the method of Cotton, et al.73 With stirring at room

temperature under nitrogen atmosphere, xylenes (300 mL), diethylenetriamine (20.6 g,

21.7 mL, 0.2 mol), and carbon disulfide (15.2 g, 12.0 mL, 0.2 mol) were added to a

three-necked flask. A white precipitate formed immediately and the suspension was

heated to reflux. Evolution of H2S from the reaction exhaust was monitored using

filter paper soaked in a methanolic suspension of lead(II) acetate. After 10 days of

reflux under nitrogen, GC/MS analysis confirmed quantitative conversion to the target

compound. Upon cooling to room temperature a white solid crystallized from

solution, and the supernatant was decanted. The solid was washed with 2 x 50 mL

portions of acetone and pentane, respectively, and dried under vacuum overnight.

(8.65 g, 39 %). 1H NMR 400 MHz (CDCl3) = 6.02 (br s, 1H), 3.79 (t, 2H, J = 7.0

Hz), 3.05 (t, 2H, J = 7.0 Hz). 13C NMR 100 MHz (CDCl3) = 171.18, 52.62, 49.38.

LRMS (m/z): 112.1 (positive ion, M+H).

82

Figure 3.18. 400 MHz 1H NMR spectrum of acyl-TBO in CDCl3

PP

M 6.8

6.4 6.0

5.6 5.2

4.8 4.4

4.0 3.6

3.2 2.8

2.4

2.000

2.015

2.036

1.998

2.799

83

Figure 3.19. 100 MHz 13C NMR spectrum of acyl-TBO in toluene-d8.

PP

M 1

60.0

1

50.0

1

40.0

1

30.0

1

20.0

1

10.0

1

00.0

9

0.0

8

0.0

7

0.0

6

0.0

5

0.0

4

0.0

3

0.0

84

3.4.12 Synthesis of 1-(2,3,5,6-tetrahydro-1H-imidazo[1,2-a]-imidazol-1-

yl)ethanone (acyl-TBO)

With stirring at room temperature in a drybox, THF (5 mL), TBO (0.115 g,

1.03 mmol), and vinyl acetate (0.1 mL, 0.09 g, 1.1 mmol) were added to a 20 mL glass

vial. The solution was stirred for approximately 16 hours, at which point solvent and

all volatiles were removed under vacuum, yielding a slightly off-white solid (0.143 g,

0.93 mmol, 90.3 %). 1H NMR 400 MHz (toluene-d8) = 3.77 (t, 2H, J = 7.8 Hz),

3.62 (t, 2H, J = 7.0 Hz), 2.51 (s, 3H), 2.45 (t, 2H, J = 7.2 Hz), 2.14 (t, 2H, J = 7.0 Hz). 13C NMR 100 MHz (d8-toluene) = 168.54, 59.55, 50.76, 48.43, 44.34, 23.08. LRMS

(m/z): 154.2 (positive ion, M+H). Elemental analysis: calcd: C = 54.89 %, H = 7.24

%, N = 27.43 %. Found: C = 54.71 % H = 7.23 % N = 27.20 %.

3.4.13 Polymerization of L-LA Using TBO catalyst

L-LA (300 mg, 2.1 mmol) and TBO (10.0 mg, 0.1 mmol) were dissolved in

CH2Cl2 (2 mL). To initiate the polymerization benzyl alcohol (2.2 μL, 0.02 mmol) was

added. The polymerization was quenched after 1 h by addition of excess benzoic acid

(~20 mg, 0.16 mmol), and solvent was removed under vacuum. 1H-NMR (CDCl3): δ

= 8.15-7.45 (5H), 5.30-5.13 (m, ~200H), 4.4 (t, 2H), 1.67-1.43 (br d); GPC (RI

detection, polystyrene calibration): Mn = 15,800 g mol-1, PDI = 1.84.

3.4.14 Computational Details

Structures were built in the Spartan ’02 software package (Windows version,

Wavefunction Inc., Irvine, CA) and geometry optimized directly from the structure as

drawn. An “equilibrium geometry” calculation (in the gas phase) at the “ground state”

with “density functional” at the B3LYP/6-31G* level of theory, without enforcing

symmetry, was performed on each structure. Final, optimized, coordinates and

energies are given below.

TBD: -438.8240398 hartrees Coordinates (Angstroms) ATOM X Y Z 1 H -1.282304 -2.168556 0.265972

85

2 C -1.319915 -1.163419 -0.173160 3 C -2.418024 1.071767 -0.147267 4 C -2.492255 -0.363114 0.387051 5 H -2.739018 1.089336 -1.201981 6 H -2.427236 -0.356270 1.482174 7 H -1.433737 -1.292425 -1.264773 8 H -3.133390 1.707527 0.391737 9 H -3.440756 -0.840888 0.113446 10 N -0.064453 -0.490055 0.145651 11 C 1.142496 -1.243806 -0.183752 12 H 1.232515 -1.383437 -1.277493 13 H 1.042393 -2.245196 0.253927 14 C 2.395050 -0.552147 0.348030 15 H 3.287348 -1.082370 -0.003124 16 H 2.392273 -0.570872 1.443647 17 C 2.405079 0.895792 -0.131726 18 H 2.537381 0.921731 -1.229030 19 H 3.242643 1.447118 0.309544 20 N 1.164791 1.523688 0.300066 21 H 1.077402 2.516842 0.120072 22 C -0.070271 0.907130 0.089469 23 N -1.098010 1.671624 -0.038479 Point Group: c1 Number of degrees of freedom: 63 Acyl-TBD: -591.4776079 hartrees Coordinates (Angstroms) ATOM X Y Z 1 C -2.300469 0.337905 0.430541 2 H -3.093193 0.246347 -0.316843 3 H -2.743221 0.041186 1.387656 4 C -1.771120 1.771568 0.478470 5 H -1.354437 2.006558 1.464838 6 H -2.596916 2.467943 0.294165 7 C -0.664910 1.935492 -0.559917 8 H -0.260709 2.952659 -0.549580 9 H -1.052933 1.747786 -1.574197 10 N 0.413382 1.019983 -0.215664 11 C 0.133200 -0.293489 0.123324 12 N -1.245416 -0.630126 0.056016 13 C 1.802425 1.464834 -0.282334 14 H 1.836709 2.528426 -0.016546 15 H 2.186183 1.377859 -1.311753 16 C 2.666202 0.640359 0.671479 17 H 2.410001 0.897902 1.706552

86

18 H 3.724530 0.882687 0.520989 19 C 2.397355 -0.848848 0.434493 20 H 2.909191 -1.449275 1.196195 21 H 2.827588 -1.155290 -0.532963 22 N 0.982794 -1.192608 0.469040 23 C -1.726407 -1.915056 -0.224013 24 O -2.917325 -2.144127 -0.054330 25 C -0.805130 -2.971893 -0.798315 26 H -0.103552 -2.565740 -1.530519 27 H -1.446559 -3.725838 -1.260446 28 H -0.207264 -3.427203 -0.006338 Point Group: c1 Number of degrees of freedom: 78 TBO: -360.183104 1hartrees Coordinates (Angstroms) ATOM X Y Z 1 H -1.900046 -1.590023 0.630623 2 C -1.456111 -0.824610 -0.013264 3 C -2.198359 0.547129 0.044223 4 H -2.946729 0.644001 -0.749713 5 H -1.415076 -1.215907 -1.045077 6 H -2.721900 0.664085 1.004354 7 N -0.122795 -0.425241 0.440424 8 C 1.120537 -1.024257 -0.033610 9 H 1.036410 -1.339321 -1.089086 10 H 1.416231 -1.894542 0.560380 11 C 2.121703 0.155887 0.118483 12 H 2.845036 0.184538 -0.703168 13 H 2.680009 0.081772 1.059906 14 N 1.255408 1.342602 0.127227 15 C -0.061621 0.947367 0.142011 16 N -1.150131 1.579668 -0.091845 17 H 1.497435 2.166853 -0.401868 Point Group: c1 Number of degrees of freedom: 45 Acyl-TBO: -512.8505944 hartrees Coordinates (Angstroms) ATOM X Y Z 1 C 1.672412 1.864296 0.133099 2 H 1.882072 2.289272 1.124640 3 H 1.998230 2.593594 -0.614750 4 C 2.379037 0.483810 -0.034527 5 H 3.267008 0.368410 0.593522

87

6 H 2.662282 0.297182 -1.084527 7 N 1.294570 -0.408043 0.376978 8 C 0.130057 0.328365 0.146142 9 N 0.221985 1.597332 0.001549 10 C 1.075561 -1.772400 -0.088323 11 H 1.669233 -2.500356 0.472151 12 H 1.316281 -1.877411 -1.160254 13 N -0.939761 -0.555100 0.060740 14 C -0.439108 -1.939086 0.162017 15 H -0.646775 -2.340693 1.160107 16 H -0.937134 -2.573840 -0.572208 17 C -2.304713 -0.297278 -0.042720 18 O -3.085894 -1.236055 -0.065334 19 C -2.729715 1.150161 -0.127546 20 H -3.817122 1.174230 -0.211610 21 H -2.265778 1.646269 -0.984959 22 H -2.402725 1.707340 0.755811 Point Group: c1 Number of degrees of freedom: 60

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a]imidazole (H-tbo)..

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93

CHAPTER 4

Oligocarbonate Molecular Transporters: Oligomerization-Based Syntheses and Cell-

Penetrating Studies

Reprinted in part with permission from J. Am. Chem. Soc. 2009, 131, 16401.

Copyright 2009 by the American Chemical Society

94

4.1 Introduction

New strategies, devices and agents that enable or enhance the passage of drugs

or probes across biological barriers are required to address a range of major challenges

in chemotherapy, imaging, diagnostics, and mechanistic chemical biology.1 In 2000,

the Wender lab reported that the cellular uptake of the Tat49-57 peptide could be

mimicked by homooligomers of arginine.2 Uptake was shown to be a function of the

number and array of guanidinium groups, observations that led to the design and

synthesis of the first guanidinium-rich (GR) peptoids,2 GR-spaced peptides,3 GR-

oligocarbamates4 and GR-dendrimeric molecular transporters (MoTrs).5 Noteworthy

subsequent studies from several groups showed that a variety of other scaffolds,

including beta-peptides, carbohydrates, heterocycles, and peptide nucleic acids, upon

perguanidinylation, exhibit cell-penetrating activity.6 GR MoTrs have been shown to

carry a variety of cargos into cells, including small molecules, probes, metals,

peptides, proteins, siRNA, morpholino-RNAs, and DNA plasmids.7 Activatable

MoTrs have been reported for targeted therapy and imaging,8 a releasable

octaarginine-drug conjugate has been shown to overcome P-glycoprotein-mediated

resistance in animal models of cancer,9 and a drug-heptaarginine conjugate has been

advanced to phase II human clinical trials.10

While octaarginine MoTrs have been made on scale under good manufacturing

practice conditions and a step-saving segment doubling approach has been

introduced,11 the length and associated costs of these syntheses preclude some

anticipated applications. A solid phase synthesis of octaarginine requires ≥16 steps,

while the segment doubling approach involves 9 steps.11 Reported herein is a new

family of oligocarbonate GR MoTrs that can be flexibly and efficiently assembled in a

one-step organocatalytic ring opening oligomerization process that also allows for

concomitant probe (or drug) attachment and control over transporter length.

The Waymouth and Hedrick groups have previously shown that a metal-free,

organocatalytic ring-opening polymerization (ROP)12 of cyclic carbonates13 initiated

by a variety of nucleophiles, including alcohols, amines and thiols, provides narrowly

dispersed polymers of predictable molecular weights and end-group fidelity.14 We

95

reasoned that if cyclic carbonates incorporating a guanidinium side chain could be

used in this process, and if the initiator could be a drug or probe, then one-step

assembly of oligocarbonate MoTr-drug or -probe conjugates could be realized.

Significantly, unlike solid or solution phase syntheses of oligomeric MoTrs in which

step count increases with transporter length, this controlled catalytic oligomerization

strategy would provide access to various lengths in one step simply through

adjustment of the initiator-monomer ratio.15 Moreover, the metal-free nature of the

catalysts and low catalyst loadings (typically 5%) are anticipated to avoid the

cytotoxicity associated with catalyst residues.


The new guanidine-protected monomer 4.3 was prepared by coupling the

cyclic carbonate 4.1 and 1,3-di-Boc-2-(2-hydroxyethyl) guanidine 4.2. It is noteworthy

that alcohol 4.4 does not initiate oligomerization of monomer 4.3 in the absence of

catalyst. However, when the alcohol-tagged dansyl fluorophore initiator 4.4a or

protected sulfur alcohol 4.4b (Scheme 4.1) is mixed with monomer 4.3 in the presence

of the bifunctional thiourea/amine catalyst TU/DBU,16 ring opening oligomerization

readily occurs. This catalyst exhibits exquisite selectivity for ring-opening

oligomerization; no transesterification is observed. This exquisite control stems from

the high selectivity of this catalyst combination towards the strained cyclic carbonate

of the monomer relative to the acyclic carbonate and ester moieties of the

oligomers.14,16 Moreover, oligomers of various lengths are generated by simply

controlling the monomer-to-initiator ratio ([M]o/[I]o). Oligomers 4.5a-e exhibit well

defined molecular weights and narrow polydispersities (Mn = 3,800, 5,200, 10,000,

3,900, 5,100 g/mol; Mw/Mn = 1.16, 1.11, 1.15, 1.16, 1.16, respectively). With a 5 mol

% catalyst loading ([M]0 = 1M), full conversion is reached in 1.25 h at room

temperature. The process is highly reproducible over the range of scales studied (50mg

to 2.5g). 1H NMR spectroscopy showed that each oligomer was end-labeled with the

initiator, and the overlay of the GPC traces from the RI and UV detectors confirms

quantitative initiation and predictable molecular weights. Removal of the Boc groups

96

by simple exposure of 4.5a-e to TFA gave oligocarbonate MoTr conjugates 4.6a-e in

high yields from 4.3.

Scheme 4.1. Synthesis of molecular transporter

The new MoTr conjugates 4.6 incorporate a backbone scaffold (carbonate) and

side chain spacing (1,7) previously unexplored in cell uptake studies.3 A

distinguishing feature of these molecular transporters is their stability profile; while

they are stable for months as solids at room temperature or in buffer (PBS) at 4°C,

they degrade under physiologically relevant conditions (Hepes buffered saline, pH

7.4) with a half-life of ~8 h at 37°C. This affords excellent shelf stability, but also the

novel ability to degrade after cellular uptake. Additionally, the MoTrs are non-toxic at

concentrations required for uptake analysis (5 min incubation, EC50 4.6a=160M;

4.6b=48M). Like analogous oligoarginines, these transporters are highly water-

97

soluble, but as shown for 4.6a and 4.6b, they readily partition into octanol when

treated with sodium laurate (1.2 equiv. per charge).17

The ability of GR oligocarbonate MoTrs 4.6a-c to enter cells was initially

determined by flow cytometry with Jurkat cells that had been incubated for 5 min at

23ºC with the dansylated oligomers, washed with PBS to remove the remaining

oligomers, and resuspended in PBS for analysis (Figure 4.1). The uptake of 4.6a-c was

compared to that of a dansylated octaarginine derivative (r8) as a positive control and

the dansyl initiator 4.4a as a negative control using the same 5 min pulse strategy.

The dansyl probe initiator 4.4a alone does not enter Jurkat cells. In striking

contrast, dansyl-oligocarbonate conjugates 4.6a and 4.6b exhibited rapid and

concentration-dependent uptake similar to that of the dansylated r8 positive control.

The extended oligomer 4.6c showed uptake but also cell-cell adhesion behavior and

was excluded from further analysis. The significant increase in uptake observed for

4.6b relative to 4.6a at higher concentrations is consistent with the increase in uptake

observed for MoTrs with increasing guanidinium content (up to n=15)18 and provides

further evidence that the GR-oligocarbonates are functionally analogous to

oligoarginines.

98

0

50

100

150

200

250

300

350

400

450

0 5 10 15 20 25 30Concentration (μM)

Mea

n F

luo

resc

ence

r84.6a4.6b4.4a+r8 K+4.6a K+4.6b K+4.4a K

Figure 4.1. Flow cytometry determined cellular uptake of oligocarbonates 4.6a and

4.6b, dansylated-r8, and dansyl initiator 4.4 in either PBS or high [K+] PBS. Jurkat

cells were incubated with the various transporters or positive and negative controls for

5 minutes at 23ºC. Cell viability was >80% as determined by propidium iodide

analysis.

Not unlike the behavior of other GR MoTrs, the uptake of 4.6a and 4.6b was

drastically decreased when cells were incubated with modified PBS in which all

sodium ions were replaced with potassium ions (Figure 4.1), a protocol used to

decrease the voltage potential across the cell membrane.17 Additionally, incubating

cells with NaN3, conditions known to interfere with ATP dependent processes,19 led to

a decrease in uptake. Finally, decreased uptake (18-37%) was observed with cells

incubated at 4°C, suggesting a mixed mechanistic pathway in which endocytosis could

play a role.20

99

In addition to flow cytometry studies, fluorescence microscopy using a two-

photon excitation method established that both 4.6a and 4.6b were internalized into

Jurkat cells upon incubation for 5 minutes at 23ºC (Figure 4.2).

Figure 4.2. Fluorescence microscopy images showing internalization of 4.6b

throughout various layers (0.9 m wide) of a Jurkat cell (5 min incubation, 25 M at

23ºC). Panels A, G, L and O show a series of z-cuts through the cell as illustrated in

the diagram at top left.

To further probe the ability of the oligocarbonate MoTrs to function as

delivery vectors, experiments examining the delivery of the bioluminescent small

molecule luciferin were conducted. In this recently introduced assay,21 the ability of a

conjugate to enter cells and release its luciferin cargo is measured by the light emitted

when luciferin is converted by luciferase to oxyluciferin and a photon of detectable

light. Only free luciferin is measured and the analysis is independent of the

mechanism(s) of entry, providing a real-time measure of drug/probe availability. A

new strategy to access thiol-terminated oligomers 4.6d and 4.6e (Scheme 4.1) enabled

the facile synthesis of disulfide-releasable luciferin conjugates 4.7a and 4.7b (Figure

4.3). The ability of 4.7a and 4.7b to deliver luciferin into HepG2 cells expressing click

beetle luciferase was analyzed with a cooled charge-coupled device camera (photon

count). Importantly, alkylated luciferin is not a substrate for the luciferase enzyme,22

100

and all light observed is therefore derived from the intracellular release and turnover

of free luciferin.

O O

O

OH

O O

NH

NH2H2N

TFA

n

4.7a: n=8

b: n=11

S

N

N

S

HO2C O O

O

SS

luciferin - releasable linker - transporter

glutathione

S

N

N

S

HO2C O O

O

SH

glutathione-S-S-transporter

SO

O

S

N

N

S

HO2C OHluciferase

S

N

N

S

OHO

hv

Figure 4.3. Assay for measurement of intracellular luciferin delivery

Figure 4.4 shows the uptake and delivery of luciferin for 4.7a, 4.7b, an

analogous D-cysteine-r8 conjugate,21 and luciferin alone in Ringers (140 mM NaCl, 5

mM KCl, 10 mM HEPES, 10 mM D-glucose, 2 mM MgCl2, and 2 mM CaCl2) and

high [K+] Ringers (70 mM NaCl, 75 mM KCl, 10 mM HEPES, 10 mM D-glucose, 2

mM MgCl2, and 2 mM CaCl2) solutions, imaging buffers which contain a variety of

ions and glucose to maintain healthy cells during longer imaging times. Following a 5

min incubation of the luciferase-expressing cells with transporter, both oligocarbonate

MoTr conjugates 4.7a and 4.7b continuously release free luciferin over a period of

about one hour. This behavior is in contrast to the r8 control, which exhibits much

faster release kinetics both in cells (over about 20 minutes, Figure 4.4), and when

treated with DTT in buffer, as observed by analytical HPLC analysis (see 4.5

Experimental Section). The ability of these MoTrs to release cargo over time offers

several advantages, including the potential to avoid bolus effects associated with

101

administration of a free drug alone. The oligocarbonate MoTrs are able to deliver free

luciferin in a concentration-dependent manner that is inhibited by high [K+] conditions

associated with a diminished membrane potential. Free luciferin alone, while

marginally cell permeable, exhibits negligible light output after a 5 min incubation.

Taken together, these data demonstrate that the novel oligocarbonate MoTrs are able

to not only penetrate the cell membranes of multiple cell types, but also efficiently

deliver and release small molecule cargos where they are available for turnover by

intracellular targets.

0.00E+00

5.00E+05

1.00E+06

1.50E+06

2.00E+06

2.50E+06

3.00E+06

3.50E+06

0 10 20 30 40 50 60 70Time (min)

Flu

x (

ph

oto

ns/

sec)

cysr84.7a4.7bLuc +cysr8 K +4.7a K +4.7b K +Luc K

Figure 4.4. Observed bioluminescence from HepG2 cells expressing click beetle

luciferase following a 5 minute incubation with 25M 4.7a, 4.7b, cysr8 luciferin

derivative, or luciferin alone in either Ringers or [K+] Ringers solutions.

4.3 Conclusion

An expedient one-step, metal-free oligomerization route to a new family of

MoTrs is described. This strategy enables the direct conjugation of probes and, by

analogy, drug moieties as part of the oligomerization process. The monomers could

thus be used as “kit” reagents for transporter-conjugate synthesis. Importantly, these

102

oligocarbonate MoTrs show low cytotoxicity and exhibit uptake comparable to or

better than that of the parent oligoarginines as determined by flow cytometry and

fluorescence microscopy. In addition, their ability to intracellularly deliver and release

the bioluminescent small molecule probe luciferin was demonstrated, confirming the

intracellular availability of the free cargo to interact with its target enzyme. The facile

cellular uptake exhibited by these new MoTrs, the ease with which short to long

oligomers (and presumably mixed oligomers) can be prepared, and their ability to

degrade after uptake offer many advantages for drug/probe delivery, particularly for

biological and macromolecular cargos.

4.4 Preliminary Results for Future Directions

Having successfully initiated from a drug surrogate and delivered the resulting

probe-MoTr conjugates (4.6 and 4.7) to cells and released free probe, the labs of

Hedrick, Waymouth and Wender are interested in advancing the method to a

therapeutic system. Initial research into this broad goal has progressed along two

avenues: initiating the oligomerization reaction directly from a drug and determining

the release kinetics of a therapeutic moiety conjugated to the MoTr via an ester or

carbonate linkage.

A one step oligomerization from a drug would be beneficial in the

commercialization of a MoTr-drug construct.11 Taxol is an attractive target for direct

oligomer initiation; its poor water solubility (~0.4 g/mL)27 and marked

ineffectiveness (vis-à-vis other chemotherapeutics) against readily available MDR

(multi-drug resistant) cell lines facilitates the evaluation of MoTr constructs bearing

taxol moieties as a strategy for overcoming MDR.9 In previous studies, taxol-r8

constructs have been shown to be effective for the treatment of taxol resistant cell

lines,9 but the synthetic cost of r8 and low drug density per transporter make a

commercialized system costly.11 Taxol contains three alcohols (two 2° alcohols and

one 3° alcohol) that could serve as initiators, but one alcohol (the C2’ alcohol) is

significantly more reactive than the others, Scheme 4.2.

103

Scheme 4.2. Targeted Synthesis of a taxol-MoTr (4.8) with 4.3 from taxol at the C2’

position

The treatment of taxol with 4.3 and TU/sparteine (5 mol%) in anhydrous DCM

effected a polymerization reaction (the use of the TU/DBU combination degrades

taxol, as determined by 1H-NMR). The molecular weight of the resulting polymer,

however, was not predictable by [M]ₒ/[I]ₒ, Table 4.1.

Table 4.1. Oligomerization from Taxol with 4.3a

[M]ₒ/[I]ₒ Reaction time

(h)

Conversionb

(%)

DPb Mnc

(g/mol)

8 5 --- 7 3700

8 5 38 4 2700

8 15 ~100 15 5400

8 6 --- 4 2300

a) For reaction conditions, see Experimental. b) determined by 1H-NMR c) determined by

GPC after dialysis (no GPCs were taken before dialysis)

The TU/DBU catalyzed oligomerization of MTC-Bn from quinine exhibits a

broad PDI, 4.9a in Scheme 4.3 (the same is true of cholesterol), which is consistent

with quinine exhibiting a rate of propagation that is no longer (vis-à-vis 4.6) trivial

relative to the rate of initiation.28 However, when quinine is incorporated into the

monomer backbone to make 4.9b, the oligomerization reaction proceeds to DP ~

104

[M]ₒ/[I]ₒ with narrow PDI. In the future, the Waymouth/Hedrick labs are interested in

synthesizing the taxol containing polymer by means of a monomer of taxol, 4.10

(MTC-taxol). This strategy will allow for the incorporation of many drugs per

transporter chain.

Scheme 4.3. Synthesis of Two Oligomers Bearing Quinine Moieties, 4.9a and 4.9b

The lability of the MTC backbone towards amines provides another means of

incorporating functionality into 4.6 or 4.7. We observed that amines react with closed

MTC carbonates to form the ring opened species,30 constituting a “click” reaction.31

To test the viability of the guanidiniums of a modified version of 4.6, Scheme 4.4, as a

click handle, highly fluorescent monomer, 4.11, was prepared by known methods.14

When this monomer is mixed with a guanidine-containing polymer, 4.12, the

previously silent UV channel of the GPC trace of the polymer becomes active

indicating the conjugation of 4.11 to the polymer, Scheme 4.4. This same strategy

could be employed with 4.10 to attach taxol, or another drug, to a preformed polymer

chain.

105

Scheme 4.4. Attachment of the Highly Fluorescent 4.11 to 4.12 via a “Click”

Reaction.

Probes linked to 4.7 via a labile disulfide linker have a fast release from the

MoTr once they have entered cells, but we are interested in exploring the release

profile of a probe or drug attached to the MoTr via a hydrolyzable ester or carbonate

linkage. We have previously established the half life of the 4.6 as 8 hours in buffered

saline solution, as determined by disappearance of polymer signal in an HPLC assay

(see Results and Discussion section). We chose to explore the degradation release

kinetics of quinine from the polymer 4.9b. Quinine is a particularly attractive probe

because of its low cost, fluorescence32 and biological activity,33 and when in

concentrated solution (>1 mM) quinine is known to self quench.34 The effective

concentration of quinine on 4.9b is above the self quenching concentration, yet when

the ester linkages appending quinine to the polymer backbone are hydrolyzed free

quinine will be released into solution causing a solution fluorescence signal that is

proportional to free quinine. In pH 7 water, 15 M quinine•H2SO4 has a fluorescence

intensity 370 times that of 1 M 4.9b(n=16) •16 H2SO4 under the same conditions.

106

Refluxing 4.9b with base causes rapid hydrolysis and dramatic increase in

fluorescence signal in a matter of minutes, indicating the viability of the method, see

Experimental Section. The experiments to determine the degradation release kinetics

of quinine from 4.9b, and co-polymers (both block and random) with 4.3 were

underway as of the writing of this document.



All chemicals were purchased from Aldrich and used as received unless stated

otherwise. 1-(3,5-Bis-trifluoromethyl-phenyl)-3-cyclohexyl-thiourea (TU)23 and

octaarginine (r8)24 were prepared according to literature procedures. Dansyl

aminocaproic acid NHS ester and propidium iodide were obtained from Invitrogen.

Methylene chloride was stirred over CaH2 overnight, degassed by three freeze-pump-

thaw cycles and vacuum transferred into a flame-dried bomb. Gel permeation

chromatography (GPC) was performed in tetrahydrofuran (THF) at a flow rate of 1.0

mL/min on a Waters chromatograph equipped with four 5 μm Waters columns (300

mm x 7.7 mm) connected in series. A Viscotek S3580 refractive index detector,

VE3210 UV/vis detector and Viscotek GPCmax autosampler were employed. The

system was calibrated using monodisperse polystyrene standards (Polymer

Laboratories). Reverse-phase high performance liquid chromatography (RP-HPLC)

was performed with a Varian ProStar 210/215 HPLC using a preparative column

(Alltec Alltima C18, 250 x 22 mm). The products were eluted utilizing a solvent

gradient (solvent A = 0.1% TFA/H2O; solvent B = 0.1% TFA/CH3CN). NMR spectra

were recorded on Varian INOVA 500 MHz and Varian Mercury 400 MHz magnetic

resonance spectrometers.

107

4.5.2 Synthesis of 5-(dimethylamino)-N-(2-hydroxyethyl)naphthalene-1-

sulfonamide, 4.4a

N

S OO

HNOH

Under nitrogen, dansyl chloride (5.05g, 18.72mmol) was placed in a dry

250mL round bottom flask equipped with a stir bar. After dry methylene chloride

(50mL) was added via syringe, the flask was attached to an addition funnel and the

system was cooled to 0°C. Ethanolamine (1.25g, 1.24mL, 20.59mmol), triethylamine

(2.27g, 3.13mL, 22.46 mmol), and 75mL of dry methylene chloride were loaded into

the addition funnel, and the solution was added dropwise with stirring over 30 min.

The solution was stirred for an additional 30 min before the ice bath was removed, the

solution allowed to reach ambient temperature and left to stir for an additional 14

hours. The product was isolated using flash chromatography initially eluting with

methylene chloride before gradually increasing the polarity to 5% methanol in

methylene chloride. Following removal of the solvent, a yellow oil was obtained that

solidified upon standing. Yield 5.0g (83%). 1H-NMR (CDCl3) δ: 8.6-7.2 (m, 6H,

ArH), 5.45 (t, 1H, -NH), 3.62 (m, 2H, -CH2OH), 3.07 (m, 2H, -NHCH2-), 2.90 (s, 6H,

(-CH3)2), 2.25 (bs, 1H, -OH).

4.5.3 2-(tritylthio)ethanol

SOH

108

Mercaptoethanol (1 mL, 14.2 mmol) was added to a solution of trityl chloride

(4.317 g, 15.5 mmol) in 10 mL THF (ACS grade). The flask was equipped with a

reflux condenser and heated at reflux for 3 h. The volatiles were removed under high

vacuum yielding an off white solid which, when washed with about 50 mL ethyl

acetate/hexanes (1:2), yielded a pure white powder. Characterization matched the

literature.25

4.5.4 MTC-ethylguanidine-BOC

O

HN

N

HN

O

O

O

O

OO

OO

5-Methyl-2-oxo-[1,3]dioxane-5-carboxylic acid (MTC-OOH) (1.26g,

7.9mmol) was initially converted to MTC-Cl using standard procedures with

oxalylchloride.14 In a dry 250mL round bottom flask equipped with a stir bar, the

formed intermediate was dissolved in 75mL of dry methylene chloride. Under

nitrogen flow, an addition funnel was attached into which 1,3-di-boc-2-(2-

hydroxyethyl)guanidine (2.0g, 5.59mmol), pyridine (0.55g, 0.56mL, 6.92mmol), and

30mL of dry methylene chloride was charged. The flask was cooled to 0°C, and the

solution was added dropwise over 30 min. The formed solution was stirred for an

additional 30 min before the ice bath was removed, and the solution stirred for an

additional 4 hours under nitrogen. The crude product was placed directly onto a silica

gel column, and the product separated by eluting with 100% ethyl acetate. The product

fractions were removed and the solvent evaporated to yield the product as white

crystals. Yield 2.70g (92%). 1H-NMR (CDCl3) δ: 11.5 (s, 1H, NH), 8.65 (t, 1H, NH),

4.70 (d, 2H, CH2), 4.35 (t, 2H, CH2), 4.23 (d, 2H, CH2), 3.75 (q, 2H, CH2), 1.55 (s,

18H, CH3), 1.45 (s, 3H, CH3). HR-MS-ESI: m/z calculated for C19H31N3O9+Na 468.45

found 468.1952.

109

4.5.5 Synthesis of Oligomers: Dansyl 4.5a-c, Trityl 4.5d-e

N

SO OHN

O O

O O

OH

O

NH

N NHO O

OO

nR

S

dansyl initiator trityl initiator

R=

Representative Example 4.5b. In a glove box with N2 atmosphere using flame

dried glassware TU (21mg, 56mol), 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU)

(8.5mg, 56mol), and initiator (see Table 4.2) were charged in a 20mL glass vial

equipped with a stir bar. A small volume of methylene chloride was added, and the

formed solution stirred for 10 minutes. MTC-guanidine-boc 4.3 (0.5g, 1.12mmol)

dissolved in enough additional DCM for a final concentration of 1M monomer was

added to the catalyst/initiator solution, and the resulting solution kept stirring for 1.25

hours (conversion studied by 1H NMR analysis). Benzoic acid (15mg, 120μmol) was

added to quench the catalyst. The crude reaction solution was transferred into a

dialysis bag (1,000 g/mol cut off), and the solution dialyzed against methanol for 48

hours, the methanol solution was changed after 24 hours. The remaining solvent was

evaporated yielding 4.5b (0.425g) as an off white solid. Alternatively direct addition

of TFA in DCM (see next procedure) to the crude reaction mixture allowed for direct

conversion to the PMTC-Guanidines in 85% yield. 1H-NMR of boc-oligomers

(CDCl3) δ: For oligomer (same for trityl and dansyl): 11.49 (s, 11H, NH), 8.66 (t,

11H, NH), 4.30 (m, 65H, polyMTC-CH2), 3.75 (m, 22H, polyMTC-CH2), 1.51 (s,

200H, CH3-boc), 1.28 (s, 3H, polyMTC-CH3); For DP11 dansyl 4.5b: 8.32 (d, 1H,

ArH), 8.26 (d, 1H, ArH), 7.58 (m, 2H, ArH), 7.34 (m, 1H, ArH), 7.23 (d, 1H, ArH),

4.14 (t, 2H, CH2), 3.22 (q, 2H, CH2), 2.92 (s, 6H, CH3); For DP11 trityl 4.5e: 7.4 (d,

6H, ArH), 7.3 (d, 6H, ArH), 7.25 (t, 3H, ArH), 3.82 (t, 2H, CH2), 2.55, 2H, CH2).

110

Table 4.2: Synthesis and Characterization of PMTC-guanidine-boc oligomers

Initiator Initiator amount n MnNMR MnGPC PDIa Yield

4.5a Dansyl 41.5 mg, 141 μmol 8 3,854 3,029 1.16 85%

4.5b Dansyl 33 mg, 112 mol 11 5,189 3,160 1.11 85%

4.5c Dansyl 15.0 mg, 51 μmol 22 10,084 4,692 1.15 85%

4.5d Trityl 44.9 mg, 140 μmol 8 3,880 4,235 1.16 78%

4.5e Trityl 36.0 mg, 112 mol 11 5,215 3,342 1.16 78%

a) PDI (polydispersity index) = Mw/Mn

RI-detector

UV-detector

Figure 4.5. GPC overlay of RI and UV detector signals of 4.5b PMTC-guanidine-boc,

PDI~1.11

Ret. Vol. (mL)

Signal strength

111

Figure 4.6. 1H NMR spectrum of 4.5b with integrations displayed below selected

resonances. Degree of polymerization was determined by integration of the end group

resonances (i.e. b and e for the dansyl-initiated polymer) versus the polymer backbone

g and g’.

4.5.6 Synthesis of PMTC-guanidines Dansyl 4.6a-c, Trityl 4.6d-e:

N

SO OHNO O

O O

OH

O

NH

H2N NH2

nR

SH

dansyl initiator

from trityl initiatedoligomers

R=

TFA

PMTC-guanidine-boc (0.23g, 46mol) was charged in a 100mL round bottom flask

equipped with a stir bar and dissolved in 18mL of methylene chloride. Trifluoroacetic

acid (TFA) (2mL) was added and the flask sealed and left under stirring at ambient

112

temperature for 18 hours. For oligomers containing the trityl- group, 200 L

triisopropylsilane was added as a cation scavenger. Nitrogen gas was bubbled through

the solution for 30 minutes and the remaining solvent evaporated by rotational

evaporation yielding (0.20g, 85%) of 4.6b as a slightly yellow waxy solid. Further

purification (if needed for cell uptake analysis) was carried out by reverse-phase

HPLC (H2O:CH3CN, 5-60% gradient). The product containing fractions were

collected and lyophilized to yield 1H-NMR (DMSO-d6) δ: [from dansyl: 8.40 (d, 1H,

ArH), 8.20 (m, 2H, ArH), 7.55 (m, 2H, ArH), 3.92 (t, 2H, CH2), 2.99 (q, 2H, CH2),

2.79 (s, 6H, CH3)] 7.90 (bs, 11H, polyMTC-NH), 7.25 (bs, 44H, polyMTC-NH), 7.18

(m, 44H, polyMTC-CH2), 4.02 (m, 22H, polyMTC-CH2), 3.37 (m, 22H, polyMTC-

CH2), 1.10 (s, 33H, polyMTC-CH3). MALDI MS analysis: [M+] calculated for

Dansyl-PMTC-guanidine 4.6a (n=8, no TFA), 2264.29, found, 2256.203. 4.6b (n=11,

no TFA) calculated, 2991.13, found, 2995.

1234567891011

1234567891011

1234567891011

Figure 4.7. Stacked 1H-NMR of MTC-guanidine-boc (top, CDCl3), PMTC-

guanidine-boc (mid, CDCl3), and PMTC-guanidine (below, DMSO-d6).

ppm

113

For oligomers containing the trityl group, the deprotected PMTC-guanidine thiol 4.6d-

e could be purified similarly to the dansyl moieties (above) or taken on crude to the

next reaction (luciferin coupling). Verification of deprotection was observed by

MALDI MS analysis: [M+] calculated for HS-PMTC-guanidine oligomer 4.6d (n=8,

no TFA), 2048.06, found 2042. 4.6e (n=11, no TFA) calculated, 2786.77, found 2780.

4.5.7 Synthesis of Luciferin Oligomers 4.7a and 4.7b

To crude HS-PMTC-guan 4.6d (after solvent removal via stream of nitrogen

and high vacuum, 0.012873 mmol) was added luciferin carbonate aldrithiol (4.0 mg,

0.007668 mmol, for preparation and characterization see reference 5) in 400 L of

DMF which had been deoxygenated by 6 freeze-pump-thaw cycles. The reaction

stirred at rt for 12 hours then acetonitrile (0.5 mL) and deionized water (1.5 mL) were

added, and the reaction was purified by reverse-phase HPLC (H2O:CH3CN, 10-80%

gradient). The product containing fractions were collected and lyophilized to yield

luciferin oligomer 4.7a (7.5 mg, 29% over two steps) as a white/yellow amorphous

solid; Prep RP-HPLC (H2O:CH3CN) > 95% purity. 1H NMR (400 MHz, D2O): δ =

8.01 (d, J = 8.8 Hz, 1 H), 7.92 (d, J = 2.0 Hz, 1 H), 7.46 (d, J = 8.8 Hz, 1 H), 5.33 (t, J

= 8.8 Hz, 1 H), 4.37-4.22 (m, 42 H), 3.84-3.83 (m, 2H), 3.76-3.66 (m, 4H), 3.47 (bs,

14 H), 2.94 (m, 2H), 2.79-2.72 (m, 4H), 1.78 (bs, 4H), 1.20 (s, 24H) ppm. MALDI

MS: [M]+ calculated for C90H148N26O46S4 (no TFA), 2458.54; found, 2452.9.

Luciferin oligomer 4.7b was accessed in a similar fashion (5 mg, 24% over two steps)

as a white/yellow amorphous solid; Prep RP-HPLC (H2O:CH3CN) > 95% purity. 1H

NMR (400 MHz, D2O): δ = 8.14 (d, J = 8.8 Hz, 1 H), 7.95 (d, J = 2.0 Hz, 1 H), 7.48

(d, J = 8.8 Hz, 1 H), 5.35 (t, J = 8.8 Hz, 1 H), 4.40-4.29 (m, 80 H), 3.91-3.86 (m, 2 H),

3.77-3.69 (m, 4 H), 3.69 (bs, 24 H), 2.98 (m, 2 H), 2.77-2.75 (m, 4 H), 1.81 (bs, 4 H),

114

1.23 (s, 33 H) ppm. MALDI MS: [M]+ calculated for C117H196N35O61S4 (no TFA),

3197.25; found, 3190.135.

Figure 4.8. 1H-NMR (D2O) of 4.7a (n=8)

4.5.8 Synthesis of Dansyl-r8

O

HN

O

NH2

NH

H2N NH2

7

TFA

NH

NH

H2N NH2TFA

OHN

SO

O

N

Octaarginine (25 mg, 0.01834 mmol) was added to a small conical vial with

stirbar and deionized water, then lyophilized. Dansyl aminocaproic acid NHS ester

(10 mg, 0.021668 mmol, Invitrogen) was dissolved in 100 L DMF and added to the

ppm

115

conical vial. Diisopropylethylamine (2.8 L, 0.16251 mmol) was added and the

reaction stirred at rt for 22.4 hours, when DMF was blown off with a stream of

nitrogen. Acetonitrile (0.5 mL) and deionized water (1.5 mL) were added, followed

by trifluoroacetic acid (1.7 L, 20 equivalents), and the reaction was purified by

reverse-phase HPLC (H2O:CH3CN, 5-60% gradient). The product containing

fractions were collected and lyophilized to yield dansyl r8 (25 mg, 90%) as a

white/yellow amorphous solid; Prep RP-HPLC (H2O:CH3CN) > 95% purity. 1H

NMR (400 MHz, D2O): δ = 8.652 (d, J = 8.70 Hz, 2 H), 8,424 (d, J = 8.74, 1 H),

8.306 (d, J = 6.98, 2 H), 7.93 (d, J = 7.71, 1 H), 7.85-7.80 (m, 3 H), 4.33-4.18 (m, 8

H), 3.354 (s, 6 H), 3.18-3.11 (m, 14 H), 2.896 (t, J = 6.61, 2 H), 2.116 (t, J = 7.17, 3

H), 1.84-1.58 (m, 29 H), 1.38-1.29 (m, 4 H), 1.137 (d, J = 7.39, 3 H) ppm. MALDI

MS: [M]+ calculated for C66H129N35O11S (no TFA), 1620.04; found, 1615.365.

Figure 4.9. 1H-NMR (D2O) of 4.7b (n=11)

ppm

116

Figure 4.10. 1H-NMR of r8 dansyl, D2O.

4.5.9 Octanol-Water Partitioning

For the partitioning experiments calibration curves of dansyl ethanol in water

and octanol respectively were initially made (see below). The UV-vis spectra were

recorded using an Agilent 8453 spectrophotometer at λ=335nm. From the calibration

curves, ideal polymer concentrations were made which allowed absorbance between

1.0-1.5 instrumentation absorbance units (AU), this corresponded to initial polymer

concentration of ~ 0.1mM (in water). After the polymer was dissolved in water

(1mL), octanol (1mL) was added and the UV-spectra recorded in both the water and

octanol layer. Sodium laurate (1.2eq to the total guanidine concentration) was added,

the vial gently shaken, and the UV spectra recorded in both the water and octanol

layer. Following partitioning the water and octanol layers were separated after which

the aqueous phase was lyophilized and its contents analyzed with 1H-NMR.

ppm

117

y = 14940x + 0.0018

R2 = 0.9998

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

0 0.00002 0.00004 0.00006 0.00008 0.0001 0.00012

Concentration (M)

Ab

sorb

ance

(A

U)

Figure 4.11. Dansyl ethanol calibration curve in water

Figure 4.12. Dansyl ethanol calibration curve in octanol

Figure 4.13. Picture of the total partitioning of 4.6b (n = 11 dansyl functionalized

poly(MTC-guanidine)) into the octanol layer (top) following the addition of sodium

laurate and UV excitation.

Concentration (M) Absorbance (AU)

0.0001 1.5011

0.00005 0.73687

0.00001 0.15813

0.000001 0.016527

[M] Absorbance (AU)

0.0001 1.6526

0.00005 0.83922

0.00001 0.18729

0.000001 0.0097547

y = 1 6 4 8 1 x + 0 .0089

R 2 = 0 . 9 9 9 7

0 0 . 2 0 . 4 0 . 6 0 . 8

1 1 . 2 1 . 4 1 . 6 1 . 8

0 2 E- 0 5 4 E - 0 5 6 E - 05 8E-05 0.0001 0.0001

C o n c e n t r a tion (M)

(AU)

118

4.5.10 Cellular Uptake Assays by Flow Cytometry

Dansyl-tagged oligomers and octaarginine control were brought up in pH 7.2

PBS buffer at 5μM, 12.5μM, and 25μM concentrations. Jurkat cells grown in 10%

FBS in RPMI media 1640 (+ glutamine) were used for cellular uptake experiments.

Cells were plated on a microtiter plate at 3.0 x 106 cells/mL with 200L/well. The

plate was centrifuged (1300 rpm for 3 min), media removed, and cells resuspended in

PBS buffer twice. Compounds 4.6(a-c) and r8 control at varying concentrations were

incubated with the cells for 5 minutes at 23°C. The microtiter plates were centrifuged

and the cells were isolated, washed with PBS and resuspended in PBS containing

propidium iodide (3 g/mL, 0.01%). The cells were analyzed using a fluorescent flow

cytometer (Vantoo, Stanford University) equipped with a UV laser for excitation of

the dansyl fluorophore, and cells stained with propidium iodide were excluded from

the analysis. The data presented are the mean fluorescent signals for the 20,000 cells

analyzed.

4.5.11 Cellular Uptake Assay at 4°C or in the Presence of Sodium Azide

Uptake assays at 4°C were performed as described above except that solutions

were precooled at 4°C and cells were incubated on ice. Uptake assays in the presence

of sodium azide were performed as described above with the exception that cells used

were preincubated for 30 min with 0.5% sodium azide in 2% FBS/PBS buffer before

the addition of fluorescently labeled oligomers and cells were washed with 0.5%

sodium azide in PBS buffer.

4.5.12 Cellular Uptake Assay in the Presence of High Potassium [K+] Buffer

A high potassium PBS buffer was prepared by mixing 136.9 mmol KCl, 1.5

mmol KH2PO4, and 8.3 mmol K2HPO4*7 H2O and titrated to pH = 7.2. Stock

solutions of all oligomers were made in the high potassium PBS buffers. Uptake

assays were performed as described above with the exception that the cells were

washed twice with the high potassium buffer. The cells were then exposed to the

119

oligomer in high [K+] buffer, washed with the same buffer, and finally resuspended in

that buffer for analysis.

Figure 4.14. Concentration dependence of cellular uptake into Jurkat Cells in pH 7.2

PBS, incubated at 5 minutes with r8 dansyl, oligomers 4.6b or 4.6c, or the dansyl

alcohol initiator 4.4 at 23°C.

0

200

400

600

800

1000

1200

1400

0 5 10 15 20 25 30 Concentration (uM)

r87.6b7.6c4.4a

Mea

n F

luor

esce

nce

120

Figure 4.15. Concentration dependence of cellular uptake into Jurkat Cells in pH 7.2

PBS or K+ PBS, incubated at 5 minutes with r8 dansyl, oligomers 4.6b in two separate

batches, 1 or 2, or the dansyl alcohol initiator 4.4 at 23°C.

0

500

1000

1500

2000

2500

0 5 10 15 20 25 30 Concentration (uM)

r8 4.6b 1

r8 K+ 4.6b1K+

4.4a K+

4.6b 2 4.4a

4.6b2K+

Mea

n F

luor

esce

nce

121

Figure 4.16. Flow cytometry determined cellular uptake of oligocarbonates 4.6a,

4.6b, r8 dansyl, and dansyl alcohol initiator 4.4 in PBS. Jurkat cells were incubated

with the various transporters for 5 minutes at either 23°C or 4°C.


4.6b, r8 dansyl, and dansyl alcohol initiator 4.4 in PBS. Jurkat cells were incubated

with the various transporters for 5 minutes at 23°C, in the presence and absence of

sodium azide (NaN3).

0

50

100

150

200

250

300

350

400

450

4.6b 4.6a r8

4.4a 4.6b 4C 4.6a 4C r8 4C

4.4a 4C Sample

0

50

150

250

350

450

4.6b

4.6a

r8

4.4a

4.6b N3 4.6a N3 r8 N3

4.4a N3

Sample

Mea

n F

luor

esce

nce

Mea

n F

luor

esce

nce

122


4.6b, r8 dansyl, and dansyl alcohol 4.4 in PBS or [K+] PBS. Jurkat cells were

incubated with the various transporters for 5 minutes at 23°C.

4.5.13 Fluorescence Microscopy Studies

Cells were washed, incubated with oligomers, and suspended for analysis as

described above, with the exception that cells were not stained with propidium iodide

before analysis. Analysis was performed on a Zeiss LSM 510 with Ti:Sapphire laser

for 2-photon excitation to excite the dansyl fluorophore.

0

50

100

150

200

250

300

350

400

450

4.6b 4.6a r8 4.4a 4.6bK+ 4.6aK+ r8 K+ 4.4aK+

Sample

25 uM

Mea

n F

luor

esce

nce

123

Figure 4.19. Uptake of 4.6b into Jurkat cells, 5 min incubation, 25 M at 23°C

visualized by fluorescence microscopy using a two-photon excitation. Panels A-O

show varying Z-cuts through the cell (from top to bottom) with 0.9 m resolution and

0.7 m between cuts. Panel P shows the bright field image of the same cell.

124

4.5.14 Cellular Assays for Luciferin Release from Conjugates 4.7a and 4.7b

A hepatocellular carcinoma cell line stably transfected with click beetle

luciferase, Hep-G2, was plated at 25,000 cells per well in a 96 well, flat bottomed

plate 24 hours prior to the assay. The cells were washed once with 100 L of Ringers

solution (140 mM NaCl, 5 mM KCl, 10 mM HEPES, 10 mM D-glucose, 2 mM

MgCl2, and 2 mM CaCl2) or [K+] Ringers (70 mM NaCl, 75 mM KCl, 10 mM

HEPES, 10 mM D-glucose, 2 mM MgCl2, and 2 mM CaCl2), then incubated with

varying concentrations of either the potassium salt of luciferin (Xenogen Corp.,

Alameda, CA) r8-luciferin carbonate 7,5 or luciferin oligomers 4.7a or 4.7b, in

triplicate, for 5 minutes in Ringers or [K+] Ringers. The cells were washed,

resuspended with the appropriate buffer, and the resultant luminescence was measured

using a charge coupled device camera and Living Image Software (IVIS29, Xenogen,

Corp., Alameda, CA).

4.5.15 Assays Measuring the Hydrolytic Stabilities of the Dansylated Conjugates

4.6a-c:

Each of the conjugates was dissolved in 190 L HEPES buffered saline (HBS)

pH = 7.4 (1 mM) in 1.5 mL microfuge tubes and incubated at 37°C with 10 L of a

solution of 10 mg 1-naphthalenemethanol in 24 mL of methanol, which served as an

internal standard. At appropriate time points 20 L of the solution was removed and

analyzed by RP-HPLC. The percent decomposition was calculated from the

integrated peak areas of the conjugate, the internal standard, and the various

decomposition products.

4.5.16 MTT Toxicity Assays

Jurkat cells grown in 10% FBS in RPMI media 1640 (+ glutamine) were plated

at 5-10 x 104 cells/mL on a 96-well microtiter plate in the same media. In a second

96-well plate, compound was serially diluted in triplicate over 20 wells in columns 2-

11 and rows 1-3 and 5-7; typical dilutions spanned the concentration range of 400µM

to 20nM. Columns 1 and 12 contained no cells and no compound, respectively. Rows

125

4 and 8 contained a serial dilution of colchicine as internal control; colchicine

concentrations were generally much lower than compound concentrations in order to

obtain an EC50 (half-maximal effective concentration). Compounds were added to the

plate containing cells and the cells were incubated at 37˚C for 24 h or 5 min, at which

point the plate was centrifuged, compound removed, and the cells resuspended in fresh

media. The cells were incubated for an additional 48 h (72 h assay total), centrifuged,

media removed, and 150µL of 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium

bromide (MTT) solution (5mg/mL media) was added to each well. Cells were

incubated with MTT for 3 hours at 37˚C, 150μL solubilizing solution (10% triton X-

100, 90% 0.1N HCl in isopropanol) was added to each well, and colorimetry data

obtained on a plate reader. Numerical data from plate reader was standardized using

values from columns 1 and 12 and curve fitting was performed using Graph Pad Prism

software to obtain an EC50 for each compound.

Table 4.3. Toxicity and Stability of Oligoguanidines 4.6a-c

Compound EC50 (μM)

Jurkat cells,

24 hour

incubation

EC50 (μM)

Jurkat cells, 5

min

incubation

Stability (t1/2,

hours)

95% HBS pH

7.4, 5%

MeoH, 37ºC

Dansyl-DP8 4.6a 17.85 ± 1.07 160.3 ± 27.8 8.3 ± 1.4

Dansyl-DP11 4.6b 8.53 ± 0.75 48.0 ± 6.4 8.10 ± 0.14

Dansyl-DP22 4.6c 2.32 ± 0.63 ~4 15.9 ± 0.4

Dansyl initiator 4.4 311 -- --

126

4.5.17 Assays Measuring the Hydrolytic Stabilities and Luciferin Release of the

Luciferin Conjugates 4.7a-b

Each of the conjugates (0.5 mg) were dissolved in 200 L Hepes Buffered

Saline (HBS) pH 7.4 (1 mM) in 1.5 mL microfuge tubes and incubated at 37°C with

15 L of a solution of 10 mg p-methoxyphenol in 10 mL of methanol, which served as

an internal standard. At appropriate time points 20 L of the solution was removed

and analyzed by RP-HPLC. The percent decomposition was calculated from the

integrated peak areas of the conjugate, the internal standard, and the various

decomposition products. For release studies with DTT (dithiothreatol), 180 L of

HBS pH 7.4 was added, followed by 20 L of a 100 mM DTT solution in HBS

(giving 10 mM total DTT in solution). At appropriate time points 20 L of the

solution was removed and analyzed by RP-HPLC. The percent decomposition was

calculated from the integrated peak areas of the disulfide reduced luciferin

intermediate, the internal standard, and the appearance of free luciferin.

Table 4.4. Stability and Release of Luciferin oligomers 4.7a-b

Compound Stability (h)

HBS pH 7.4, 37°C

Release (min)

HBS pH 7.4, 37°C,

10 mM DTT

Luciferin-DP8 4.7a 4.5 8.6

Luciferin-DP8 4.7b 5.4 8.7

Luciferin-Cys-r8 33a 2.6 (3a) aLiterature value26

4.5.18 Synthesis of MTC-pyrene, 4.11

To a flame dried flask under N2 flow containing 4.1 (0.0073 mol), which was

prepared in situ according to established methods (ref. 14), and 25 mL anhydrous THF

was added a solution of pyrene butanol (2.0 g, 0.0073 mol), pyridine (0.76 mL, 0.0095

mol) in 25 mL anhydrous THF dropwise over 30 minutes at 0°C. The reaction was

stirred and allowed to warm to room temperature overnight. The contents of the flask

127

were filtered, and the solvent removed under reduced pressure. The solid was

dissolved in ~9 mL of DCM and loaded onto a silica gel column and eluted with ethyl

acetate/hexanes (2:1) yielding pure 4.11, yield: 1.939g (64%). 1H-NMR (300 MHz,

CDCl3) : 8.32-7.84 (m, 9H), 4.66 (d, 2H), 4.28 (t, 2H), 4.17 (d, 2H), 3.42 (t, 2H),

2.02-1.79 (m, 4H), 1.28 (s, 3H). 13C-NMR (100 MHz; CDCl3) : 171.32, 147.76,

136.17, 131.64, 131.08, 130.17, 128.81, 127.74, 127.63, 127.53, 126.97, 126.15,

125.33, 125.23, 125.09, 125.05, 123.42, 76.99, 73.20, 66.30, 40.36, 33.16, 28.60,

28.06, 17.75. ESI-MS: Experimental: 439.12 m/z (parent); Theoretical: C26H24O5 +

Na+ : 439.15 g/mol (parent)

4.5.19 Synthesis of MTC-quinine

To a flame dried flask under N2 flow containing 4.1 (0.0028 mol), which was

prepared in situ according to established methods (ref. 14), and 20 mL anhydrous THF

was added a solution of quinine (1.0 g, 0.0031 mol), triethyl amine (0.86 mL, 0.0062

mol) in 25 mL anhydrous THF dropwise over 30 minutes at 0°C. The reaction was

stirred and allowed to warm to room temperature overnight. The contents of the flask

were filtered, and the solvent removed under reduced pressure. The solid was washed

with ~50 mL of cold methanol under vacuum filtration yielding a pure white powder:

0.39 g (30%). 13C-NMR (125 MHz; CDCl3) : 170.83, 158.38, 147.76, 146.39,

145.13, 141.81, 132.27, 127.29, 122.27, 120.18, 118.84, 115.03, 101.34, 101.31,

73.24, 72.97, 59.59, 59.57, 56.62, 55.94, 42.56, 40.61, 39.81, 28.03, 27.52, 25.41,

17.57. ESI-MS: Experimental: 467.18 m/z (parent), 468.17 m/z (25%), 469.11 m/z

(10%); Theoretical: C26H30N2O6 + H+ : 467.22 g/mol (parent), 468.22 (30%), 469.22

(5%).

128

8 7 6 5 4 3 2 1Chemical Shift (ppm)

Figure 4.20. 1H-NMR (500 MHz, CDCl3) MTC-quinine

4.5.20 Synthesis of PMTC-quinine, 4.9b

In a glove box with N2 atmosphere using flame dried glassware TU (7.9 mg,

22 mol), 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) (3.3 mg, 22 mol), and benzyl

alcohol (1.8 L, 17.2 mol) were charged in a 20mL glass vial equipped with a stir

bar. A small volume of methylene chloride was added, and the formed solution was

stirred for 10 minutes. MTC-quinine (0.2 g, 0.43 mmol) dissolved in enough

additional DCM for a final concentration of 0.37 M monomer was added to the

catalyst/initiator solution, and the resulting solution was kept stirring for 0.75 hours

(73% conversion by 1H-NMR analysis). Benzoic acid (15 mg, 120 μmol) was added

to quench the catalyst. The crude reaction solution was transferred into a dialysis bag

(1,000 g/mol cut off), and the solution dialyzed against methanol for 48 hours, the

methanol solution was changed after 24 hours. The remaining solvent was evaporated

yielding 4.9b (0.05 g) as an off white solid. GPC: Mn=2,800; Mw=3,800; PDI = 1.212.

129

4.5.21 Initiation of Oligomerization from Quinine, 4.9a

In a glove box with N2 atmosphere using flame dried glassware TU (8.0 mg,

22 mol), 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) (4.4 mg, 29 mol), quinine (5.2

mg, 0.016 mmol) were charged in a 20mL glass vial equipped with a stir bar. A small

volume of methylene chloride was added, and the formed solution stirred for 10

minutes. MTC-benzyl (0.1002 g, 0.40 mmol) dissolved in enough additional DCM for

a final concentration of 1M monomer was added to the catalyst/initiator solution, and

the resulting solution kept stirring for 1.25. Benzoic acid (15 mg, 120 μmol) was

added to quench the catalyst. The solvent was evaporated yielding 4.9a as an off

white solid. GPC: Mn=3,900; Mw=6,700; PDI = 1.721.

4.5.22 Initiation of Oligomerization from Taxol, 4.8

In a representative polymerization, in a glove box with N2 atmosphere using

flame dried glassware TU (4.1 mg, 11 mol), sparteine (4.9 mg, 21 mol), taxol (21.9

mg, 0.026 mmol) were charged in a 20mL glass vial equipped with a stir bar. A small

volume of methylene chloride was added, and the formed solution stirred for 10

minutes. 4.3 (0.0961 g, 0.216 mmol) dissolved in enough additional DCM for a final

concentration of 1M monomer was added to the catalyst/initiator solution, and the

resulting solution kept stirring for 1.25. Benzoic acid (15 mg, 120 μmol) was added to

quench the catalyst. The crude reaction solution was transferred into a dialysis bag

(1,000 g/mol cut off) that had been rinsed with copious amounts of DI water and

soaked in 500 mL DI water for 10 minutes, and the solution dialyzed against methanol

for 48 hours, the methanol solution was changed after 24 hours. The solvent was

evaporated yielding 4.8 as an off white solid. GPC: Mn=2,700; Mw=3,000; PDI =

1.113.

130

9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5Chemical Shift (ppm)

9 8 7 6 5 4 3 2 1Chemical Shift (ppm)

Figure 4.21. 1H-NMR (500 MHz, CDCl3) of (upper) 4.9b and (lower) 4.9a

131

11 10 9 8 7 6 5 4 3 2 1Chemical Shift (ppm)

Figure 4.22. 1H-NMR (300 MHz, CDCl3) of 4.8a

4.5.23 MTC/amine “Click” Reaction, 4.11 + 4.12

To a vial containing 4.12 (40 mg, 0.009 mmol; PDI=1.146) was added 2 mL

methanol and 4.11 (3.4 mg, 0.0082 mmol) which was stirred for 2 h. The solution was

treated with DCM (~2 mL) which precipitated a white oily solid. The supernatant was

decanted and the residue washed with DCM (~2 mL). The residue was taken to

dryness under high vacuum yielding a white sticky solid. GPC: overlapping RI and

UV signals indicate Mn=250; Mw=275; PDI=1.10.

8.8 8.4 8.0 7.6 7.2 6.8 6.4 6.0 5.6 5.2 4.8 4.4 4.0 3.6 3.2 2.8 2.4 2.0 1.6 1.2 0.8 0.4

Figure 4.23. 1H-NMR (500 MHz, CD3OD) of the products of the reaction of 4.11 and

4.12

ppm

132

4.6 References

(1) a) Wender, P.A.; Galliher, W.C.; Goun, E.A.; Jones, L.R.; Pillow, T.H. Adv.

Drug Del. Rev. 2008, 60, 452-472. b) Snyder, E.L.; Dowdy, S.F. Expert Opin.

Drug Del. 2005, 2, 43-51. c) Langel, U.; Cell-Penetrating Peptides: Processes

and Applications; CRC Press: Boca Raton, FL, 2002.

(2) Wender, P. A.; Mitchell, D. J.; Pattabiraman, K.; Pelkey, E. T.; Steinman, L.;

Rothbard, J. B. Proc. Natl. Acad. Sci. U. S. A. 2000, 97, 13003-13008.

(3) Rothbard, J.B.; Kreider, E.; VanDeusen, C.L.; Wright, L.; Wylie, B.L.;

Wender, P.A. J. Med. Chem. 2002, 45, 3612-3618.

(4) Wender, P. A.; Rothbard, J. B.; Jessop, T. C.; Kreider, E. L.; Wylie, B. L. J.

Am. Chem. Soc. 2002, 124, 13382-13383.

(5) Wender, P. A.; Kreider, E.; Pelkey, E. T.; Rothbard, J.; VanDeusen, C. L. Org.

Lett. 2005, 7, 4815-4818.

(6) For a review and lead references on GR transporters from the groups of

Torchilin, Prochiantz, Langel, Futaki, Vives, Wender, Dowdy, Piwnica-

Worms, Lebleu, Seebach, Gellman, Goodman, Tor, Chung, Kiso, Mendoza

and others see: Adv. Drug Delivery Rev. 2008, 60, 452. For further lead

references see a) Hamilton, S.K.; Harth, E. ACS Nano 2009, 3, 402-410. b)

Geisler, I.; Chmielewski, J. J. Chem. Biol. Drug Des. 2009, 73, 39-45. c)

Seow, W.Y.; Yang, Y-Y. Adv. Mater. 2009, 21, 86-90. d) Daniels, D.S.;

Schepartz, A. J. Am. Chem. Soc. 2007, 129, 14578.

(7) For a recent review on arginine-rich peptides and their many cargos see:

Tung, C.H.; Weissleder, R. Adv. Drug Delivery Rev. 2003, 55, 281-294.

(8) a) Goun, E.A.; Shinde, R.; Dehnert, K.W.; Adams-Bond, A.; Wender, P.A.;

Contag, C.H.; Franc, B.L. Bioconjugate Chem. 2005, 17, 787-796. b) Jiang,

T.; Olson, E.S.; Nguyen, Q.T.; Roy, M.; Jennings, P.A.; Tsien, R.Y. Proc.

Natl. Acad. Sci. U.S.A. 2004, 101, 17867-17872.

(9) Dubikovskaya, E.A.; Thorne, S.H.; Pillow, T.H.; Contag, C.H.; Wender, P.A.

Proc. Natl. Acad. Sci. USA 2008, 105, 12128.

133

(10) Rothbard, J.; Garlington, S.; Lin, Q.; Kirschberg, T.; Kreider, E.; McGrane, P.;

Wender, P.; Khavari, P. Nat. Med. 2000, 6, 1253.

(11) Wender, P.A.; Jessop, T.C.; Pattabiraman, K.; Pelkey, E.T.; VanDeusen, C.L.

Org. Lett. 2001, 3, 3229-3232.



(13) Rokicki, G. Prog. Polym. Sci. 2000, 25, 259-342. (b) Al-Azemi, T. F.; Bisht,

K. S. Macromolecules 1999, 32, 6536-6540.

(14) (a) Pratt, R.C.; Nederberg, F.; Waymouth, R.M.; Hedrick, J.L. Chem. Comm.

2008, 114-116. (b) Nederberg, F.; Lohmeijer, B. G. G.; Leibfarth, F.; Pratt, R.

C.; Choi, J.; Dove, A. P.; Waymouth, R. M.; Hedrick, J. L.


(15) Guanidinylated oligomers have been generated by ring-opening metathesis to

provide cell or artificial membrane transporters with hydrocarbon backbones.

See Kolonko, E.M.; Kiessling, L.L. J. Am. Chem. Soc. 2008, 130, 5626-5627;

Kolonko, E.M.; Pontrello, J.K.; Mangold, S.H.; Kiessling, L.L. J. Am. Chem.

Soc. 2009, 131, 7327-7333; Gabriel, G. J.; Madkour, A. E.; Dabkowski, J. M.;

Nelson, C. F.; Nusslein, K.; Tew, G. N. Biomacromolecules 2008, 9, 2980-

2983; and Hennig, A.; Gabriel, G. J.; Tew, G. N.; Matile, S. J. Am. Chem.

Soc. 2008, 130, 10338-10344.

(16) (a) Pratt, R.C.; Lohmeijer, B.G.G.; Long, D.A.; Lundberg, P.N.P.; Dove,

A.P.; Li, H.; Wade, C.G.; Waymouth, R.M.; Hedrick, J.L.

Macromolecules, 2006, 39, 7863–7871. (b) Dove, A. P., Pratt, R.C.;

Lohmeijer, B.G.G.; Waymouth, R.M.; Hedrick, J.L, J. Am. Chem. Soc. 2005,

127, 13798-13799.

(17) Rothbard, J.B.; Jessop, T.C; Lewis, R.S.; Murray, B.A.; and Wender, P.A. J.

Am. Chem. Soc. 2004, 126, 9506-9507.

(18) Mitchell, D.J.; Kim, D.T.; Steinman, L.; Fathman, C.G.; Rothbard, J.B. J.

Peptide Res., 2000, 56, 318-325.

(19) Sandvig, K.; Olsnes, S. J. Biol. Chem. 1982, 257, 7504-7513.

134

(20) Silhol, M.; Tyagi, M.; Giacca, M.; Lebleu, B.; Vives, E. Eur. J. Biochem.

2002, 269, 494.

(21) Jones, L.R.; Goun, E.A.; Shinde, R.; Rothbard, J.B., Contag, C.H.,

Wender, P.A. J. Am. Chem. Soc. 2006, 128, 6526.

(22) Denburg, J.L.; Lee, R.T.; McElroy, W.D. Arch Biochem Biophys 1969, 134,

381.

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Li, H.; Wade, C.G.; Waymouth, R.M.; Hedrick, J.L.

Macromolecules, 2006, 39, 7863–7871

(24) Wender, P.A.; Jessop, T.C.; Pattabiraman, K.; Pekley, E.T.; VanDeusen, C.L.

Org. Lett. 2001, 3, 3229-3232.

(25) Maltese, M. J. Org. Chem. 2001, 66, 7615-7625.

(26) Jones, L.R.; Goun, E.A.; Shinde, R.; Rothbard, J.B.; Contag, C.H.; Wender,

P.A. J. Am. Chem. Soc. 2006, 128, 6526-6527.

(27) Richheimer, S. L.; Tinnermeier, D. M.; Timmons, D. W. Anal. Chem. 1992,

64, 2323-2326.

(28) (a) Kiesewetter, M. K.; Shin, E. J.; Hedrick, J. L.; Waymouth, R. M.

Macromolecules 2010, 43, 2093-2107. (b) Odian, G. Principles of

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Photochem. Photobio. A 1990, 51, 313-315.

135

CHAPTER 5

Kinetics of an Air and Water Stable Ruthenium(IV) Catalyst for the Deprotection of

Allyl Alcohols

136

5.1 Introduction

The rich reaction chemistry of transition metal allyl complexes has spawned a

diverse array of catalytic reactions for bond forming and cleaving reactions.1-4

Catalytic nucleophilic allylic substitution is a powerful synthetic method for the

selective formation of carbon-carbon and carbon heteroatom bonds.1-3 Allylic ethers,

esters, carbonates and carbamates are also versatile protecting groups due to their high

reactivity with many transition metals.1,5-9 Several metals are known to cleave allyl

esters/ethers in aprotic solvents,6,7,10 and Ru complexes, including commercially

available [CpRu(CH3CN)3]PF6,11,12 are particularly attractive due to their tolerance to

many functional groups.13-18 Kitamura reported Ru complexes derived from

[CpRu(CH3CN)3]PF6 and quinaldic acid that are particularly effective for deallylation

reactions that operate in protic solvents and feature an internal base, which obviates

the need for additives.5,10,19-21 Complex 5.1 exhibits a wide substrate tolerance in

alcoholic solvents10 and has been shown to reversibly allylate a variety biological

molecules, including peptides and nucleic acids.5,20,22 As part of a program on the

synthesis of water-soluble bioactive polymers,23 we sought a facile method for the

deprotection of allylic carbonates or carbamates in aqueous solution. Herein, we

report our investigations on the kinetics and mechanism of the hydrolysis of allyl

carbonates in water in the presence of both homogeneous and supported analogs of

complex 5.1. We also compare the rates of hydrolysis and methanolysis of allyl

methyl carbonate in both aqueous and methanol solutions.

N

O

OH RuNCMeMeCN

NCMe

PF6

+acetone

OH

NO

O

RuPF6

5.1

Scheme 5.1. Synthesis of Kitamura’s Catalyst, 5.1.


Quinaldic acid and pyridine carboxylic acids have proven to be effective

ligands for Ru-catalyzed allylation reactions and allyl alcohol/carbonate

137

deprotection.5,10,19-21 We sought a readily functionalized derivative of quinaldic acid

that might enable facile anchoring of Ru complexes to inorganic24 or organic supports.

Kynurenic acid (4-hydroxyquinoline-2-carboxylic acid), a metabolite of

tryptophan,25,26 provided an attractive and readily available synthon. The kynurenic

acid allyl ester can be readily alkylated with a variety of functional groups to generate

a series of substituted kynurenic acid derivatives. The kynurenic allyl ester, 5.2, reacts

with [CpRu(NCCH3)3]PF6 in dry acetone to yield the orange-yellow RuIV allyl, 5.4,

which precipitates from concentrated solution (Scheme 5.2).19,21,27

Scheme 5.2. Synthesis of the Ru complex 5.4.

The Ru allyl complex 5.1, derived from quinaldic acid, has been shown to be

an active catalyst for the deallylation of allyl carbonates10 and carbamates20 in

methanolic solutions under argon (eq 1). For these reactions, it was proposed that the

RuIV allyl species is the resting state and that attack of methanol on the Ru allyl is rate-

limiting.5,10,19

To assess the activity of the analogous Ru allyl complex 5.4 in aqueous

solution, we carried out the kinetics of deallylation of allyl methyl carbonate in D2O,

eq 1.

(1)

138

In the absence of Ru, allyl methyl carbonate is stable in water for more than a

week at room temperature. In the presence of the Ru complex 5.4 (0.6 - 10 mol%),

allyl methyl carbonate hydrolyzes to allyl alcohol, methanol and carbon dioxide. In

the solid-state, complex 5.4 is stable in air for months without the loss of activity.

Kinetic studies carried out in air at room temperature revealed that the hydrolysis of

allyl methyl carbonate was zero order in carbonate, Figure 5.1, and first order in Ru to

give a rate law:

-d[carbonate]/dt = R = kobs (2)

where kobs = k’[5.4] = 1.25 (± 0.05) x 10-3 M h-1 (20 °C), Figure 5.2.

Figure 5.1. Plot of allyl methyl carbonate [C] vs. time. Conditions: [5.4]ₒ=0.5 mM in

D2O with a) [C]ₒ = 0.105 M; b) [C]ₒ = 0.054 M; c) [C]ₒ = 0.025 M; d) [C]ₒ = 0.013 M

(a)

(b)

(c) (d)

139

Figure 5.2. Plot of kobs (M•h-1) vs. Ru concentration [5.4]0. Conditions: [allyl methyl

carbonate]ₒ = 0.10 M in D2O.

The mechanism proposed for the deprotection of allyl carbonates in alcohol

solvents was proposed to involve the nucleophilic attack of the alcohol on the RuIV

allyl species as a key step.5,10,20 An analogous mechanism for the aqueous hydrolysis

of allyl methyl carbonate is shown in Scheme 5.3. This mechanism assumes that

attack of water on the RuIV allyl generates allyl alcohol and a solvated RuII species

which subsequently reacts with allyl methyl carbonate to regenerate the RuIV allyl

species 5.4.

Scheme 5.3. Proposed mechanism for catalytic hydrolysis of allyl methyl carbonate

in water by RuIV-allyl complex 5.4. (PF6 anion omitted for clarity)

140

A rate law for the mechanism in Scheme 5.3 can be derived if a low steady-

state concentration of the RuII intermediate and the reversible formation of 5.4 from

allyl alcohol is assumed (eqs 3 and 4).19,27

(3)

(4)

With these assumptions, the rate of disappearance of allyl methyl carbonate can be

derived (eq 5):

][][

]][][4.5[][

21

221

CkAk

COHkk

dt

CdR

(5)

where [C] = concentration of allyl methyl carbonate, [A] = concentration of allyl

alcohol, and [5.4] = concentration of complex 5.4. This rate equation would be

consistent with the experimental rate law under conditions where the rate of formation

of 5.4 from the reaction of allyl methyl carbonate with RuII is faster than the formation

of 5.4 from the reaction of RuII with allyl alcohol19,27 (k2[C] >> k-1[A]), for which:

Rate = k1[H2O][5.4]; where k’ = k1[H2O] (6)

These results imply that the attack of water on the RuIV allyl complex 5.4 is

rate limiting, even in aqueous solution ([H2O] ~ 55.5 M; [D2O] ~ 55.5 M, 20 °C) and

that the RuIV allyl complex 5.4 is the resting state during the catalytic reaction (i.e.

[Ru]T ~ [5.4]0) under these conditions. Analysis of the kinetics of the catalytic

141

hydrolysis of allyl methyl carbonate reaction in a 1:1 mixture of H2O: D2O solvent

revealed a kinetic isotope effect of kH/kD = 2.5, which is consistent with proposals by

Kitamura5,19,27 that nucleophilic attack on the RuIV allyl is coupled to deprotonation of

the nucleophile (H2O in the present case, ROH in previous examples), presumably by

the Ru carboxylate (Scheme 5.3).

The rate law derived in eq (5) assumes the reversible formation of 5.4 from

allyl alcohol and the RuII, but an equally valid rate law could be derived without this

assumption (ie. k-1[A] = 0). As CpRu complexes ligated by pyridine carboxylic acids

or quinaldic acids have been shown to catalyze allylic substitutions of allyl

alcohols,19,27-31 we sought independent kinetic evidence for the equilibrium

represented in eq (3). To this end, we treated the Ru complex 5.4 with D2O in

acetone-d6, and measured both the equilibrium constant and the rate of approach to

equilibrium at 20 °C (see Experimental Section).32 Under these conditions, the

equilibrium constant (eq. 3) was determined to be Keq = [RuII][A]/[5.4][D2O] = 0.0075

± 0.0008 with k1= 0.036 ± 0.011 M-1 h-1 and k-1= 4.80 ± 1.53 M-1 h-1.

For comparison, the kinetics of the catalytic methanolysis of allyl methyl

carbonate with 5.4 were examined in CD3OD. When carried out in air at room

temperature, the methanolysis of allyl methyl carbonate with 5.4 only proceeds to 40%

conversion under these conditions. Kinetic studies revealed that the evolution of [allyl

methyl carbonate] with time is linear to approx. 25% conversion; at longer times, the

rate decays rapidly. Similar rates and conversions are observed in the presence and

absence of 5 equivalents of allyl methyl ether, implicating that product inhibition by

allyl methyl ether is not the cause of decaying rate. However, if the methanolysis of

allyl methyl carbonate with 5.4 is carried out under argon, the reaction proceeds to full

conversion in less than 90 minutes with a rate that is zero order in allyl carbonate,

kobs(methanol) = 6.6 (± 0.2) x 10-2 M h-1, Figure 5.3.

While we haven't unambiguously determined the cause of the low conversions

observed for the methanolysis in air, we propose that oxidative decomposition of the

catalyst is a likely cause, due to the higher conversions observed under argon. We

propose that the different behavior observed in water and methanol is due to the higher

142

solubility of oxygen in methanol relative to water: O2/water (298 K, 1 atm) =

2.3x10-5; O2/CH3OH (298 K, 1 atm) = 4.2x10-4.33-35 As the RuIV compounds 5.4 and

5.1 are shelf stable for months in air, it is likely that oxidation of the RuII species is

competitive with catalysis in methanol, whereas in water the lower solubility of O2

leads to longer catalysts lifetimes. If borne out in further studies, this hypothesis

highlights another potential advantage of water as reaction solvent.

Figure 5.3. Plot of [allyl methyl carbonate] ([C]) versus hours in CD3OD.

Conditions: under argon, 1 mM 5.4, 100 mM allyl methyl carbonate, 0.3 mL CD3OD.

A comparison of the rates of hydrolysis of allyl methyl carbonate in water

(under air) vs. the methanolysis (under argon) reveals that the deallylation of allyl

methyl carbonate is considerably faster in methanol. If we assume that ][' 1 ROHkk

(for R = H, or CH3) and that the concentration of [D2O] = 55.5 M and [CD3OH] = 24.6

M, then estimates for k1 reveal that the rate constant for nucleophilic attack by

methanol is approx. 60 times that of water (k1(methanol) = 2.68 ± 0.10 M-1 h-1;

(k1(water) = 0.045 ± 0.002 M-1 h-1). These estimates imply that methanol is

considerably more reactive than water toward the RuIV allyl.

Further insights were obtained from measurements of the equilibration of the

RuIV allyl 5.4 and methanol in acetone. The slow approach to equilibrium of the Ru

complex 5.4 treated with methanol in acetone-d6, eq 7, was examined at 20 °C.32

0

0.02

0.04

0.06

0.08

0.1

0.12

0 0.2 0.4 0.6 0.8 1 1.2 hours

[C]

143

Under these conditions, the equilibrium constant (eq 7) was determined to be

Keq(methanol) = [RuII][AE]/[5.4][CH3OH] = 0.0828 ± 0.0083 with k1’= 0.86 x ± 0.26

M-1 h-1 and k-1’= 10.4 ± 3.3 M-1 h-1 (where [AE] = concentration of allyl methyl ether).

These results confirm the higher rate of attack of methanol on the RuIV allyl 5.4. In

either methanol or water, 5.4 is the predominant species at equilibrium, but the

equilibrium constant is higher in the case of methanol than for water in acetone

solution.

(7)

Studies of the catalytic hydrolysis of allyl methyl carbonate suggest 5.4 is

air/water compatible. To facilitate removal of the catalyst from the products, we

generated a solid-supported version24 of the Ru catalyst. Solid supported catalysts

facilitate the removal and recycling of metal residues,36 and several heterogeneous

catalysts for (de)allylation have been reported.37-39 Indeed, among other solid

supported allylation catalysts,40,41 a heterogeneous version of 5.1 supported on silica

was developed by Kitamura and coworkers.24 The supported catalyst provided

comparable yields and rates to the homogeneous analogues24 and exhibited no

leaching from the solid support after nine reaction cycles in methanol solvent under

argon, but only one instance of water being used as a co-solvent was reported.24

The amino-functionalized ligand 5.3 was coupled to a chloromethyl

polystyrene resin (1% crosslinked, 200-400 mesh, 3.5-4.5 mmol Cl-/g) to generate the

polystyrene-supported ligand PS-5.3. Microanalysis of PS-5.3 provided an estimate

of 1.164 mmol/g for the amount of ligand loaded onto the polystyrene. Treatment of

PS-5.3 with excess [CpRu(CH3CN)3]PF6 for 1.5 hours in acetone generated the

polystyrene supported complex 5.5, Scheme 5.4.

144

Scheme 5.4. Synthesis of the polystyrene supported Ru complex 5.5.

The supported catalyst 5.5 is competent for the hydrolysis of allyl methyl

carbonate in aqueous solution. Conducting the hydrolysis of allyl methyl carbonate

under identical conditions with the supported Ru complex 5.5 and homogeneous

analogue 5.4 allowed for the direct comparison of the rates, enabling an estimate of

the Ru loading on the PS bead.42,43 When 0.9 mg of 5.5 was used for the hydrolysis of

allyl methyl carbonate in 0.32 mL D2O, the rate constant, kobs, from the zero order plot

of [allyl methyl carbonate] vs time of this reaction was compared to kobs vs [5.4] plot

(Figure 5.2) to determine an effective concentration of ruthenium, [Ru]eff = 1.847 ±

0.047 mM, and a catalyst loading of 0.66 ± 0.15 mmol/g of active RuIV on the 5.5

bead. Combustion analysis of 5.5 provided an independent estimate of the Ru content

in 5.5, [Ru] = 0.48 ± 0.04 mmol/g, which is within error of the loading determined by

kinetic analysis.

After 4 hours of reaction time, the supported catalyst was isolated from the

reaction solution by filtering, washed with allyl alcohol and acetone, removed of

volatiles under high vacuum and subjected to identical catalytic conditions. For the

second run, the rate was lower and the calculated catalyst loading on 5.5 was 0.53 ±

0.06 mmol/g. This process was repeated and on the third run the rate was even lower,

yielding an estimate of 0.31 ± 0.03 mmol/g, Figure 5.4.

145

Figure 5.4. Plots of [allyl methyl carbonate] versus hours for the deallylation of allyl

methyl carbonate in D2O catalyzed by 5.5, recycled over successive runs.

The lower rates observed on subsequent runs imply that Ru is leaching from

the polystyrene support. As a further test for leaching, the supernatant from the

washings was assessed for catalytic activity;43 these experiments revealed that the

supernatant was catalytically active albeit at a much slower rate than 5.5

(approximately 20 times slower). We could not detect any free kynurenic acid ligand

in the supernatant by 1H-NMR or ESI-MS, implying that in water, Ru is extracted off

of the bead, presumably by solvolysis of the kynurenic ligand, leaving PS-5.3 intact.

While similar leaching phenomenon have been observed with other PS-supported Ru

catalysts,44,45 this behavior is in contrast to that reported by Kitamura for a silica-

supported version of 5.1 that did not exhibit loss of catalytic activity over nine

recycling cycles under an argon atmosphere.24 To test whether the presence of air

might contribute to the higher leaching, we repeated the catalyst recycling experiments

with 5.5 in water under argon. For these experiments, leaching was attenuated but still

evident with each catalyst cycle giving catalyst loadings of: 0.84 ± 0.08 mmol/g,46

0.66 ± 0.15 mmol/g, and 0.31 ± 0.03 mmol/g over three successive runs.

The higher degree of leaching observed for the polystyrene catalyst 5.5 in

water, relative to the silica-supported analog24 could be due to the nature of the solvent

(water vs. methanol), the nature of the modified ligands (kynurenic acid vs. amide-

substituted pyridine carboxylic acid), or the support itself. Arenes are known to

146

displace coordinated ligands on RuII species.47 The phenyl-rich environment of the

PS-bead could labilize the Ru complexes; further studies are ongoing to test these

hypotheses.

5.3 Conclusions

Cyclopentadienyl ruthenium complexes of a modified natural product,

kynurenic acid, was found to be an effective catalyst for the deallylation of carbonates

in water. A variety of substituted kynurenic acid ligands is available using simple

procedures and commercially available materials. In the presence of air, catalyst 5.4

exhibits increased stability in water versus methanol; although methanol is a better

nucleophile towards 5.4. A kynurenic acid ligand bearing a pendant amine allows for

the attachment of the catalyst to a solid PS support. However, catalyst 5.5, a

heterogeneous version of 5.4, was observed to leach from the polystyrene support

upon several catalyst recycling experiments, suggesting that the stability of supported

versions of these homogeneous catalysts depends sensitively on the nature of the

support and reaction conditions.


5.4.1 General considerations

All materials were purchased from Aldrich and used as received unless stated

otherwise. Tris(acetonitrile)cyclopentadienylruthenium(II) hexafluorophosphate was

purchased from Strem and used as received. All preparations of ruthenium(IV)

compounds were carried out in an inert atmosphere using standard glove box or

Schlenk techniques but stored in atmosphere in closed vials. Combustion analyses

were conducted on a Perkin-Elmer TGA 7 Thermogravimetric Analyzer.

5.4.2 Synthesis of kynurenic acid allyl ester

Allyl bromide (1.4 mL, 16.6 mmol) was added in a single aliquot to a

vigorously stirred mixture of kynurenic acid (2.0 g, 10.6 mmol) and KHCO3 (1.7 g,

147

17.4 mmol) in 60 mL DMF. The single neck round bottom flask was equipped with

reflux condenser and heated to 40°C for 15h. Reaction was quenched with water (~60

mL) and extracted with 3x ethyl acetate. Combined organics were washed with 5%

aqueous NaCl, dried with MgSO4, filtered and removed of volatiles. Material was

taken on without further purification. Yield: 1.575g (65%). 1H-NMR (300 MHz,

CDCl3): 8.38 (1H, d, 8.37 Hz); 8.05 (1H, bs); 7.70 (1H, t, 7.75); 7.49 (1H, d, 8.40);

7.41 (1H, t, 7.75); 7.05 (1H, s); 6.4 (1H, m); 5.44 (2H, m); 4.93 (2H, d, 4.93). 13C-

NMR (125 MHz, CDCl3) 162.9; 136.6; 130.6; 133.4; 103.8; 126.7; 126.5; 126.4;

124.8; 120.2; 118.4; 112.0; 67.8.

5.4.3 Synthesis of 5.2 (R=CH3)

Methyl iodide (0.155 mL, 2.5 mmol) was added in a single aliquot to a

vigorously stirred mixture of kynurenic acid allyl ester (0.505 g, 2.2 mmol) and

Cs2CO3 (0.803 g, 2.5 mmol) in 130 mL acetone. The single neck round bottom flask

was fitted with a reflux condenser and heated to reflux for 15h. The reaction was

quenched with brine (~70 mL) and extracted with 3x ethyl acetate. The combined

organics were dried with MgSO4, filtered and removed of volatiles. Material was

taken on without further purification. Yield: 0.301g (56%). 1H-NMR (300 MHz,

acetone-d6): 8.22 (1H, d, 8.27 Hz); 8.12 (1H, d, 8.56 Hz); 7.84 (1H, t, 7.66 Hz);

7.68 (1H, t, 7.66 Hz); 7.59 (1H, s); 6.17 (1H, m); 5.44 (2H, m); 4.95 (2H, d, 5.83 Hz);

4.20 (3H, s). 13C-NMR (125 MHz, acetone-d6) 163.4; 149.9; 148.7; 132.9; 130.7;

130.2; 127.8; 122.2; 121.9; 118.2; 118.0; 100.3; 66.1; 56.1.

5.4.4 Synthesis of 5.4

5.2 (0.21 g, 0.86 mmol) and [CpRu(NCCH3)3]PF6 (0.316 g, 0.73 mmol) were

added to a flame-dried Schlenk flask with a stir bar and removed from the glove box

to a Schlenk line. Under N2, 10 mL extra-dry acetone (Aldrich) was added via

syringe. The red solution produced a yellow precipitate over 25 min. The stirring was

stopped and, under N2 flow, the supernatant was removed from the precipitate with a

pipette and discarded. The precipitate was washed with approximately 1 mL extra-dry

148

acetone, and the precipitate was removed of volatiles under high vacuum yielding pure

4: 0.218g (54%). 1H-NMR (300 MHz, acetone-d6): 8.43 (1H, d, 8.74 Hz); 8.10 (2H,

m); 7.91 (1H, t, 7.12); 7.59 (1H, s); 4.87 (2H, m); 4.70 (1H, d, 10.46 Hz); 4.45 (1H,

m); 4.40 (1H, m); 4.35 (1H, s). Elemental analysis for C19H18F6NO3PRu calcd:

41.16% C, 3.27% H, 2.53 % N; found: 41.26% C, 3.08% H, 2.53 % N.


2-bromoethylamine•HBr (0.21 g, 1.02 mmol) was added in a single aliquot to a

vigorously stirred mixture of kynurenic acid allyl ester (0.22 g, 0.87 mmol) and

Cs2CO3 (0.8 g, 2.5 mmol) in 65 mL acetone. The single neck round bottom flask was

fitted with a reflux condenser and heated to reflux for 15h. The reaction was

quenched with brine (~70 mL) and extracted with 3x ethyl acetate. The combined

organics were dried with MgSO4, filtered, removed of volatiles and taken into acetone

(material is self-labile when neat). Material was taken on without further purification.

Yield: 0.120g (46%). 1H-NMR (300 MHz, acetone-d6): 8.30 (1H, d, 8.4 Hz); 7.86

(1H, d, 8.4 Hz); 7.53 (1H, t, 7.8 Hz); 7.27 (1H, t, 7.8 Hz); 7.06 (1H, s); 6.04 (1H, m);

5.41 (1H, d, 17.4 Hz); 5.22 (1H, d, 10.7); 4.79 (2H, d, 5.6); 4.36 (2H, t, 7.8); 3.59 (2H,

t, 7.8 Hz); 3.48 (2H, bs). 13C-NMR (125 MHz, acetone-d6) 163.0; 132.3; 132.1;

126.8; 125.3; 124.2; 120.9; 118.5; 110.3; 66.8; 64.6; 54.9; 53.0; 40.6. IR (diamond

anvil cell) cm-1: 1708 (s, C=O); 1607 (m, 1°NH); 1564 (m, C-C aromatic); 1095 (s, C-

O ester); 760 (s, 1°NH).

5.4.6 Synthesis of PS-5.3

5.3 (1.23 g, 4.5 mmol) and Merrifield’s peptide resin, 1% crosslinked, 200-400

mesh (0.132 g, 0.49 mmol) were added to a round bottom flask with a stir bar.

Acetone (100 mL) and Cs2CO3 (0.169 g, 0.52 mmol) were added, and the reaction

mixture was stirred for 19 h. The crude reaction mixture was filtered and the filtrate

was washed with copious quantities of acetone. IR (diamond anvil cell) cm-1: 1708 (s,

C=O); 1564 (m, C-C aromatic); 1095 (s, C-O ester); 760 (s, 2°NH) (see Figure 5.5).

149


PS-5.3 (0.141 g, 0.52 mmol) and [CpRu(NCCH3)3]PF6 (0.5363 g, 1.24 mmol)

were added to a flame-dried Schlenk flask with a stir bar and removed from the glove

box to a Schlenk line. Under N2, 15 mL extra-dry acetone (Aldrich) was added via

syringe, and the reaction mixture was stirred for 1.5 h. The stirring was stopped and,

under N2 flow, the supernatant was removed from the precipitate with a pipette and

discarded. The precipitate was washed with copious extra-dry acetone and removed of

volatiles under high vacuum. IR (diamond anvil cell) cm-1: 1587 (m); 1334 (m); 833

(s) (see Figure 5.5). Combustion analysis of 5.5. Samples were loaded on to the

analytical balance of the TGA under air flow and subjected to an annealing program: 1

min hold at 50°C, temperature ramp to 100°C, 2 min hold at 100°C, temperature ramp

to 900°C, 1 min hold at 900°C, temperature ramp to 50°C; all temperature ramps were

50°C/min. Initial sample masses were taken after the 100°C temperature hold and

final masses at the end of the program. A sample of Merrifield’s peptide resin

subjected to the annealing program resulted in complete loss of mass. After subjecting

5.4 (1.2567 mg, 0.00227 mmol) to the annealing program, a black residue remained

(0.3341 mg) that provided a molecular weight of the fully oxidized material (0.3341

mg/0.00227 mmol = 147.3 g/mol; RuO2 is 133 g/mol). In a representative annealing,

5.5 (1.7490 mg) was reduced to a black residue (0.1202 mg) which was taken to be

147.3 g/mol in molecular weight, yielding a Ru loading on 5.5 of 0.467 mmol/g.

Triplicate measurements yield: 0.478 ± 0.034 mmol/g.

5.4.8 Kinetic analysis to give the Ru loading on 5.5

In a typical experiment, 5.5 (0.9 mg) was loaded directly into an NMR tube

along with D2O (0.32 mL) and allyl methyl carbonate (3.6 L, 0.032 mmol), the tube

was shaken to mix and reaction progress was monitored by 1H-NMR against an

internal standard (acetone). From a (zero order) plot of ‘[allyl methyl carbonate]

versus hours’ (Figure 5.1), the slope was taken to be kobs, and this value was divided

by k’ (the slope of the ‘kobs versus [Ru]’ plot generated from the solution catalysis,

Figure 5.2) to determine a [Ru] in solution, 1.847 mM. Accounting for the solution

150

volume and mass of 5.5 in the given experiment gives the loading of 5.5, 0.657

mmol/g of active RuIV on 5.5. The error of Ru loading was propagated from the rate

constant errors.

1000150020002500300035004000

Figure 5.5. IR spectra of A) IR spectrum of Merrifield’s peptide resin, 1%

crosslinked B) 5.3, and C) PS-5.3.

5.4.9 Determining Equilibrium

Into an NMR tube under argon was added 5.4 (2.6 mg, 0.0047 mmol), 1.0 mL

acetone-d6, and D2O (8.6 L, 0.4773 mmol), in order. (For methanol the amounts

were: 5.4 (2.7 mg, 0.0049 mmol), 0.5 mL acetone-d6, and CD3OD (2.0 L, 0.049

mmol) added in the given order). Tube was shaken to mix and reaction progress was

monitored by 1H-NMR (see Figure 5.8). Concentrations of allyl alcohol and 5.4 were

determined by integration against an internal standard. The concentration of RuII was

determined from mass balance: [RuII] = [5.4]ₒ – [5.4]. The reported rate and

equilibrium constant errors were propagated from the error of the NMR integrations,

which were taken to be ±10%.

A

B

C

cm-1

151

(8)

[A] = [A]e + t 9

CtkKt

t

11 )1(

ln (10)

where = [RuIV]e + [ROH]e + K-1([RuII]e + [allyl alcohol/ether]e)

y = -0.0497x - 6.6136

R2 = 0.9946

-12

-11

-10

-9

-8

-7

-6

-5

-4

0 20 40 60 80 100

h

ln(d

t/(1

-K-1

)+a

lph

a))

Figure 5.6. Slow approach to equilibrium of the reaction shown in eq 8, R=H, in

acetone-d6. Thermodynamic data extracted from plot using eqs 8-10: Keq = 0.0075;

G°=2.90 kcal/mol; [5.4]e=0.0047M; [RuII]e=0.0027M; [allyl alcohol]e=0.0027M;

[D2O]e= 0.48M, = 1.1898. k1=0.0116x10-3 M-1s-1 and k-1=1.54 x10-3 M-1s-1

152

Figure 5.7. Slow approach to equilibrium of 5.4 and CD3OD in acetone-d6 (eq 8,

R=Me). Thermodynamic data was extracted using eqs 8-10: Keq = 0.0828; G°=1.45

kcal/mol; [5.4]e=0.0042M; [RuII]e=0.0057M; [allyl methyl ether]e=0.0057M;

[CD3OD]e= 0.0933M, = 0.2341. k1=0.238x10-3 M-1s-1 and k-1=2.87 x10-3 M-1s-1

5.4.2 Kinetic Data

Typical kinetic experiment. 5.4 (1.8 mg, 0.0032 mmol) was stirred with 1.1

mL D2O (or other solvent) to yield a 2.95 mM stock solution. To an NMR tube, 0.22

mL of stock solution was diluted with 0.43 mL D2O to give a final concentration of 4

(0.65 mol, 0.001 M) to which was added allyl methyl carbonate (7.35 L, 0.065

mmol, 0.100 M) via syringe. Tube was capped and shaken to mix. Reaction was

monitored by 1H-NMR (see Figure 5.8), and concentrations were determined versus an

internal standard (acetone). The reported rate constant errors were propagated from

the error of the NMR integrations, which were taken to be ±10%. When reactions

were conducted under argon, the solvent was sparged with a submerged jet of gas for

2 min, and the reaction vessel was purged out before and after reagent addition.

153

5.8 5.6 5.4 5.2 5.0 4.8 4.6 4.4 4.2 4.0 3.8 3.6 3.4 3.2 Figure 5.8. 1H-NMR spectrum of partially converted allyl methyl carbonate. The

resonances marked with * are due to allyl methyl carbonate, with ● are due to

methanol and with ■ are due to allyl alcohol.

0.02

0.03

0.04

0.05

0.06

0.07

0.08

0.09

0 1 2 3 4 5

hours

[ally

l me

thy

l ca

rbo

na

te]

Figure 5.9. Plot of [allyl methyl ether] versus hours. Initial reaction conditions, all

reactions under air in methanol-d4:

(▲) [5.4]ₒ=1.8 mM, [allyl methyl carbonate]ₒ= 100 mM, [allyl methyl ether]ₒ= 0.0 M;

(X) [5.4]ₒ=1.8 mM, [allyl methyl carbonate]ₒ= 49 mM, [allyl methyl ether]ₒ= 0.0 M;

(♦) [5.4]ₒ=3.6 mM, [allyl methyl carbonate]o= 51mM, [allyl methyl ether]o= 0.274 M;

(■) [5.4]ₒ=3.6 mM, [allyl methyl carbonate]o= 51mM, [allyl methyl ether]o= 0.0 M;

■■

●*

*■

HOD

*

*

154

5.5 References

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(2) Trost, B. M.; Crawley, M. L. Chem. Rev. 2003, 103, 2921-2944.

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(7) Tsuji, J.; Mandai, T. Synthesis 1996, 1-24.

(8) Trost, B. M.; Fullerton, T. J. J. Am. Chem. Soc. 1973, 95, 292-294.

(9) Tsuji, J.; Takahashi, H.; Morikawa, M. Tetrahedron Lett. 1965, 6, 4387-4388.

(10) Tanaka, S.; Hajime, S.; Murase, T.; Ishibashi, Y.; Kitamura, M. J. Organomet.

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(11) Trost, B. M.; Older, C. M. Organometallics 2002, 21, 2544-2546.

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1061.

(13) Morisaki, Y.; Kondo, T.; Mitsudo, T.-a. Organometallics 1999, 18, 4742-4746.

(14) Hermatschweiler, R.; Ferandez, I.; Breher, F.; Pregosin, P. S.; Veiros, L. F.;

Calhorda, M. J. Angew. Chem. Int. Ed. 2005, 44, 4397-4400.

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Calhorda, M. J. Angew. Chem. Int. Ed. 2006, 45, 6386-6391.

(16) Achard, M.; Derrien, N.; Zhang, H.-J.; Demerseman, B.; Bruneau, C. Org.

Lett. 2008, 11, 185-188.

(17) Gruber, S.; Zaitsev, A. B.; WoÌˆrle, M.; Pregosin, P. S.; Veiros, L. F.

Organometallics 2008, 27, 3796-3805.

(18) Bruneau, C.; Renaud, J.-L.; Demerseman, B. Chem. Eur. J. 2006, 12, 5178-

5187.

(19) Saburi, H.; Tanaka, S.; Kitamura, M. Angew. Chem. Int. Ed. 2005, 44, 1730-

1732.

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(20) Tanaka, S.; Saburi, H.; Murase, T.; Yoshimura, M.; Kitamura, M. J. Org.

Chem. 2006, 71, 4682-4684.

(21) Tanake, S.; Saburi, H.; Kitamura, M. Adv. Synth. Catal. 2006, 348, 375-378.

(22) Tanaka, S.; Hirakawa, T.; Oishi, K.; Hayakawa, Y.; Kitamura, M. Tetrahedron

Lett. 2007, 48, 7320-7322.

(23) Cooley, C. B.; Trantow, B. M.; Nederberg, F.; Kiesewetter, M. K.; Hedrick, J.

L.; Waymouth, R. M.; Wender, P. A. J. Am. Chem. Soc. 2009, 131, 16401-

16403.

(24) Hirakawa, T.; Tanaka, S.; Usuki, N.; Kanzaki, H.; Kishimoto, M.; Kitamura,

M. Eur. J. Org. Chem. 2009, 789-792.

(25) Erhardt, S.; Schwieler, L.; Nilsson, L.; Linderholm, K.; Engberg, G.

Physiology & Behavior 2007, 92, 203-209.

(26) Barth, M. C.; Ahluwalia, N.; Anderson, T. J. T.; Hardy, G. J.; Sinha, S.;

Alvarez-Cardona, J. A.; Pruitt, I. E.; Rhee, E. P.; Colvin, R. A.; Gerszten, R. E.

J. Biol. Chem. 2009, 284, 19189-19195.

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2009, 38, 188-189.

(28) Tanaka, S.; Seki, T.; Kitamura, M. Angew. Chem. Int. Ed. 2009, 48, 8948-

8951.

(29) Sundararaju, B.; Achard, M.; Demerseman, B.; Toupet, L.; Sharma, G. V. M.;

Bruneau, C. Angew. Chem. Int. Ed. 2010, 49, 2782-2785.

(30) Gruber, S.; Pregosin, P. S. Adv. Synth. Catal. 2009, 351, 3235-3242.

(31) Zaitsev, A. B.; Caldwell, H. F.; Pregosin, P. S.; Veiros, L. F. Chem. Eur. J.

2009, 15, 6468-6477.

(32) Espenson, J. H. Chemical Kinetics and Reaction Mechanisms; 2nd ed.;

McGraw-Hill: New York, 2002.

(33) Fischer, K.; Wilken, M. J. Chem. Thermo. 2001, 33, 1285-1308.

(34) Battino, R.; Rettich, T. R.; Tominaga, T. J. Phys. Chem. Ref. Data 1983, 12,

163-178.

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156

(36) Bergbreiter, D. E.; Tian, J. H.; Hongfa, C. Chem. Rev. 2009, 109, 530-582.

(37) Miura, H.; Wada, K.; Hosokawa, S.; Sai, M.; Kondo, T.; Inoue, M. Chem.

Commun. 2009, 4112-4114.

(38) Li, G.; Zhao, G. Org. Lett. 2006, 8, 633-636.

(39) McNamara, C. A.; Dixon, M. J.; Bradley, M. Chem. Rev. 2002, 102, 3275-

3300.

(40) Uozumi, Y.; Danjo, H.; Hayashi, T. J. Org. Chem. 1999, 64, 3384-3388.

(41) Akiyama, R.; Kobayashi, S. Angew. Chem. Int. Ed. Engl. 2001, 40, 34693471.

(42) Demerseman, B.; Renaud, J. L.; Toupet, L.; Hubert, C.; Bruneau, C. Eur. J.

Inorg. Chem. 2006, 1371-1380.

(43) Phan, T. S.; Sluys, M. V. D.; Jones, C. M. Adv. Synth. Catal. 2006, 348, 609-

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(44) Nguyen, S. T.; Grubbs, R. H. J. Organomet. Chem. 1995, 497, 195-200.

(45) Nieczypor, P.; Buchowicz, W.; Meester, W. J. N.; Rutjes, F. P. J. T.; Mol, J. C.

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(46) The initial Ru loading estimated from the rates is higher under argon

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157

CHAPTER 6

Poly(2,5-dihydrofuran) from 2-cis-butene-1,4-diol and a Ruthenium Allylation Catalyst

158

6.1 Introduction

The ever shrinking dichotomy of organic and polymer synthesis has

engendered macromolecular syntheses increasingly reminiscent of their small

molecule congeners.1 Ongoing programs with the common theme of organocatalysis

for polymer synthesis have adopted the tools of sub-nanometer synthesis for the

generation of polymeric constructs.2-4 In the realm of transition metal catalysis, the

powerful C-C bond forming Tsuji-Trost reaction5 has been adopted for polymer

synthesis.6 Polymer constructs are available via a one monomer method, where each

allylic monomer possesses a nucleophilic and an electrophilic end,7 or a two monomer

method where a bis-nucleophile is combined with an allylic monomer that is telechelic

in leaving group.8 The Pd-allyl-containing reaction mechanism produces primarily

linear enchainments,6 but the recent entry of Ir-allyl polymerization catalysts

combined with similar synthons as the Pd-allyl reaction have provided access to

primarily branched products.9

The successful implementation of the Pd- and Ir-allyls as tools in

polymerization chemistry has not been paralleled in the rich chemistry of Ru-allyls

and their ability to form C-heteroatom bonds. As was previously noted, the ability of

cyclopentadienyl ruthenium (CpRu) complexes of quinaldic acid to activate allyl

alcohol to form RuIV-allyls10, 11 is remarkable,12 and a general approach to RuIV-allyl

cations was demonstrated.12 The allylation of alcohols via their nucleophilic attack on

a RuIV-allyl begs the possibility of implementing allylic alcohols as both the

electrophile and nucleophile for ether formation via RuIV-allyl intermediates. For

example, a CpRuIV-allyl catalyzed condensation of 2-butene-1,4-diol, which would

serve as both electrophile and nucleophile in this paradigm, would generate homo-

poly(2,5-dihydrofuran) (poly(2,5-DHF)) if the catalytic hydrolysis of allyl ethers were

slower than their formation, Scheme 6.1. While butenediols have been used in

condensation reactions to make urethanes or polyesters,13-15 we do not know of an

example of the homo-condensation of 2-butene-1,4-diol to make poly(2,5-DHF).

159

Scheme 6.1. Conceptual polymerization of butene-1,4-diol

Polytetrahydrofuran (PTHF) is a commodity telechelic polymer produced on

the order of 200,000 tons annually.16 Telechelic polymers are valuable building

blocks for the construction of higher molecular weight materials.17 One such class of

materials is ABA triblock copolymers generated by grafting or growing polymers

from the telechelic endgroup functionality.17-20 Such copolymers have been used in

applications such as adhesives, biomedical and elastomeric materials.21 The treatment

of THF with a Lewis acid results in the polymerization to PTHF.16 Large scale

commercial processes will produce PTHF of approximately 800-1,000 g/mol from

air/water free THF, and the post-polymerization formation of telechelic hydroxyl end

groups allows for the conjugation of PTHF into commercial products.16

(1)

(2)

(3)

(4) The treatment of 1,2-dihydrofuran (1,2-DHF) with BF3 produces poly(1,2-

DHF) homopolymer not of the ring opened product but one where the repeat unit is an

160

intact THF ring, eq 2.22, 23 The addition of BF3 to 2,5-dihydrofuran (2,5-DHF) and a

co-monomer (THF, epichlorohydrin, or propylene oxide) produces random co-

polymers of the ring opened 2,5-DHF, eq 3.24 It was observed that the rate of

polymerization is inversely proportional to the concentration of 2,5-DHF, which was

taken as an indication that homo-poly(2,5-dihydrofuran) (poly(2,5-DHF)) could not be

made.24 As far as we know, poly(2,5-DHF) has never been made. Despite their

structural similarities, PTHF and poly(2,5-DHF) require different synthetic strategies.

Poly(2,5-DHF) should be accessible via the promised bifunctional nature of 2-butene-

1,4-diol in Ru-allyl chemistry.

Kinetic investigations25 on 6.1 (see eq 5), a modified version of a RuIV

(de)allylation catalyst first reported by Kitamura,10, 26, 27 demonstrated that it possesses

both high activity and tolerance to air and water.25 We have shown that 6.1 is

effective for the deallylation of allyl carbonates in either aqueous or methanol solution,

and kinetic studies suggest a mechanism by which the catalyst is operative.25 In the

case of a water nucleophile, the reversible rate determining nucleophilic attack of

water on 6.1 generates a solvated RuII species, eq 5, and the back reaction dominates

the forward reaction (i.e. Keq<1). The rapid reaction of the RuII with allyl methyl

carbonate regenerates the RuIV-allyl, liberating methanol and carbon dioxide.25 The

equilibrium step (eq 5) lies further to the RuII product in the case of methanol versus

water, which suggests that ether products are favored at least in the condensation of

methanol and allyl alcohol.

161

(5)

(6)


As a preliminary test of the paradigm outlined in Scheme 6.1, 6.1 was treated

with one equiv. of cis-2-butene-1,4-diol resulting in the formation of 3-(allyloxy)prop-

2-en-1-ol as determined by 1H-NMR, see 6.4 Experimental Section. This suggests that

allylic alcohols are competent nucleophiles for 6.1. The molecular weight of a 50/50

solution of acetone/cis-2-butene-1,4-diol and 6.1 (0.10 mol% to diol) is observed to

increase with time, as determined by gel permeation chromatography (GPC). A

molecular weight plateau is reached at 48 hours (determined by GPC) which

corresponds to 80% conversion from monomer (1H-NMR). Evaporation of the

reaction solvent yields a mixture of products that can be shown by electrospray

ionization mass spectrometry (ESI-MS) to be composed of materials with masses

consistent with a mixture of cyclic (ESI: (C4H6O)n, n=3-10; for n=3+ H+, m/z =210.82

vs 211.12 g/mol) and telechelic, linear polymer chains (see 6.4.2 General

polymerization experiment) spaced by the mass of a buteneol monomer unit, Figure

6.1. Dissolution of the crude material in dichloromethane (DCM) followed by

treatment with hexanes causes the oiling out of an orange material (color is

presumably due to Ru products) from a turbid hexanes supernatant. Analysis of the

evaporated oil indicates the presence of telechelic polymer, 6.2, (GPC: Mn=770, PDI

=2.97; ESI: HO(C4H6O)nH, n=5-27; for n=16 + Na+, m/z =1161.59 vs 1161.64 g/mol),

while the concentrated supernatant contains primarily cyclic oligomers by ESI (see 6.4

162

Experimental Section). These cycles are the unsaturated versions of long-ago reported

5n-Crown-n series of crown ethers.28-30 Taken together, these results suggest that 6.1

is an effective catalyst for the polymerization of cis-2-butene-1,4-diol to make

poly(2,5-DHF), eq 7. Treatment of cis-2-butene-1,4-diol with BF3•(OC6H6)2 or

trifluoroacetic acid (TFA) does not result in the generation of polymer.

(7)

Figure 6.1. ESI-MS of the crude polymerization material. The signals marked with

the ▲are due to linear, telechelic oligomers + H+; the ■ to linear, telechelic oligomers

+ Na+; and * to cyclic oligomers + H+.

If 6.2 is telechelic, the symmetrical chain extension should be possible from

both ends of the polymer yielding a telechelic ABA triblock co-polymer. The GPC

trace of the polymer, 6.3, resulting from the addition of L-lactide (L-LA) (0.3004 g;

2.09 mmol) to a DCM solution of 1,5,7-triazabicyclo[4.4.0]dodec-1-ene (TBD)

163

(0.0021 mmol, 0.57 mM) and 6.2 (1.7 mg; 0.0027 mmol) suggests the chain extension

of 6.2 by a polymer of narrowly dispersed molecular weight (vis-à-vis 6.2), Figure 6.2.

In the 1H-NMR of 6.3, the integrations of the end group resonances of the

poly(lactide) (PLA) segments versus the polymer backbone indicate the presence of

1.92 endgroups per chain 1H-NMR, see 6.4 Experimental Section. This suggests that

6.3, as well as the macroinitiator 6.2, is a telechelic diol.

O

O

O

+

N

NDCM30 min.

OO

6O

OOO

O

O

x

HOO

H66.2

O

NH

TBD

O

O

HO

O

OH

Oy

x+y=240

two end groups

6.3

Figure 6.2. Chain extension of 6.2 with L-lactide to yield 6.3

The regiochemistry of polymerization reactions are often evident by the

information locked in the repeat units of the polymer. Dialysis of the crude 6.2 against

methanol (1,000 g/mol molecular weight cut off) leaves only the highest molecular

weight material, 6.2b. The 1H-NMR of 6.2b is consistent with the expected

symmetrical homoallylation product, Figure 6.3. In addition to the major resonances

associated with the buteneol repeat units in 6.2b, there are smaller resonances in the 1H-NMR spectrum (1/16th the intensity) indicative of a vinyl moiety. This would be

expected were the RuIV-allyl attacked by the alcoholic nucleophile at the more

substituted position, producing a 1,2-addition (branched) product rather than the

dominant 1,4-addition (linear) product. This assignment is corroborated by 13C-NMR

spectra using fully coupled and decoupled acquisitions. The cis-/trans- isomerization

was replicated in a small molecule study by altering the reaction conditions to a lower

164

concentration of cis-2-butene-1,4-diol in aqueous solvent (see 6.4 Experimental

Section), which prevents the formation of oligomers.

Figure 6.3. 1H-NMR spectra of (upper) 2-butene-1,4-diol and (lower) 6.2b, where the

insets are 10x enlargements of the spectrum below.

The high selectivity of 6.1 for linear enchainment of cis-2-butene-1,4-diol

became interesting to us particularly in light of the behavior of similar catalysts.

There is a great deal of interest in the reactivity of pentamethylcyclopentadienyl Ru

(Cp*Ru) complexes (including those ligated by quinaldic acid) because of the high

selectivity these catalysts typically exhibit for branched isomers: branched/linear (B/L)

ratios typically >>1.12, 31-34 Complexes of CpRu typically exhibit low regioselectivity

in favor of the linear isomer, 31,35 but CpRuIV-allyls have been used for

enantioselective ring closing allylations that obviate the regioselectivity issue.11 To

this end, we sought to examine the source of the high regioselectivity of 6.1. A

mixture of 6.1 (0.0065 mmol; 0.0036 M) and 2-cis-butene-1,4-diol (10 L, 0.122

mmol) in CD3OD is observed to generate butenyl methyl ethers in a B/L ratio 11/89,

similar to the polymerization reaction. The branched products are approximately 2/3

bisalkylated and 1/3 mono-alkylated. The linear products are primarily mono-

alkylated. The analogous reaction where cis-2-pentenol is the allyl source is observed

to generate pentenyl methyl ethers in a similar B/L ratio 19/81, Scheme 6.2. These

6 : 94

165

observations suggest the regioselectivity of 6.1 is not specific to allyl substitution nor

to the identity of the nucleophile.

Scheme 6.2. Regioselectivity of 6.1

We propose a mechanism of polymerization that proceeds through a RuIV-

allyl/RuII-solvent cycle, Scheme 6.3. Analogous to the small molecule study,25, 26 a

solvated RuII intermediate coordinates with a polymer chain end or monomer to

liberate water and generate the RuIV-allyl, 6.4. We have previously shown that

nucleophilic displacement of the allyl is coupled to a deprotonation step for the

incoming nucleophile, presumably from the internal carboxylate.25 Accordingly,

isomerization of the RuIV-allyl prior to the nucleophilic attack by a monomer/polymer

provides a Curtin-Hammett distribution of products from 6.4, resulting in chain

extension and regeneration of the RuII-solvent species. Alternatively, the -end of a

RuIV-allylic oligomer, 6.4 (R=(CH2CH=CHCH2O)nH), can attack its own allyl to

generate a cycle, Scheme 6.3. It is not clear whether the RuIV is preferentially

associated with monomer or growing polymer, but the presence of cyclic oligomers

suggests that the RuIV must be bound to the growing polymer some of the time. We

were not able to isolate the putative intermediate, 6.4.

166

OHRO

Solv.NOH

O

Ru

O

NO

O

Ru

O

HO OHO

OHRO

O

O

O

NO

O

Ru

OR

NO

O

Ru

NO

O

Ru

OR

OR

OR

O OHRO

OOHRO

-H2O

kb ~ 16(kc +kd) >>ka

6.4a

6.4b

6.4d

6.4c

Scheme 6.3. Polymerization Mechanism (PF6 anion omitted for clarity)

If the polymerization reaction is accurately described by eq 7, removal of water

should result in higher conversions. When a solution of cis-2-butene-1,4-diol (4 mL;

0.049 mol) and 6.1 (15.4 mg; 0.028 mmol) in a mixture of ethyl ether (2 mL) and

dichloromethane (4 mL) was refluxed beneath a condenser column packed with 4Å

molecular sieves, the solution reached 90% conversion in monomer after 48 h and the

molecular weight of the polymer was 2,300 g/mol (GPC). The polymer exhibited a

B/L ratio of 17/83. Changing the solvent has been previously observed to alter B/L

ratios.12 These results suggest that higher molecular weight polymer can be obtained

by implementing drying conditions, but that care must be taken to segregate the drying

agent and catalyst.35b

6.3 Conclusions

The suite of M-allyl catalysts that are adaptable to polymer synthesis was

expanded to Ru wherein 2-cis-butene-1,4-diol was employed as a nucleophile and

electrophile to make poly(2,5-DHF) via a RuIV-allyl mechanism. The CpRu-allyl

catalyst was found to be extremely regioselective for the linear product, and higher

molecular weight poly(2,5-DHF) can be accessed by implementing drying conditions.

The saturated version of this polymer, PTHF, is a commodity material that is produced

under air/water free conditions with post-polymerization modification.16 For four

decades it was thought that the polymer which is different from PTHF only by one H2

167

per repeat unit was inaccessible,24 but the application of old catalysts to old problems

begets new mechanisms and yields new materials.



All materials were purchased from Aldrich and used as received unless stated

otherwise. Dialysis bags were purchased from SpectraPor. The catalyst 6.1 was

prepared as previously described.25 The ROP experiments were performed in a glove

box under nitrogen atmosphere. Gel permeation chromatography (GPC) was

performed in tetrahydrofuran (THF) at a flow rate of 1.0 mL/min on a Waters

chromatograph equipped with four 5 μm Waters columns (300 mm x 7.7 mm)

connected in series. A Viscotek S3580 refractive index detector, Visotek VE3210

UV/vis detector and Viscotek GPCmax autosampler were employed. The system was

calibrated using monodisperse polystyrene standards (Polymer Laboratories).

Electrospray Ionization (ESI) Mass Spectra were collected on a ThermoFinnigan LCQ

ion trap mass spectrometer operated in positive ion electrospray.

6.4.2 General polymerization experiment

Catalyst 6.1 (16.3 mg, 0.029 mmol) was weighed directly into a glass vial with

a tightly fitting cap. To the vial was added reagent grade acetone (2 mL) and a stir bar,

and the mixture was stirred until homogeneous. In a single aliquot, 2-cis-butene-1,4-

diol was added (2 mL, 24.4 mmol), and the vial was tightly capped and left stirring for

48 hours. Acetonitrile was added (1 mL) to quench the reaction, and the reaction was

removed of volatiles under high vacuum. The crude polymer was taken up in reagent

grade dichloromethane (~2 mL), and the addition of wash hexanes (~5 mL) oils out

6.2 which was isolated from the turbid supernatant by pipette. Crude 6.2: ESI:

HO(C4H6O)nH, n=3-20; for n=7 + Na+, m/z =531.44 vs 531.28 g/mol (see Figure 6.5).

GPC: Mn=415; PDI=2.21. Yield: 1.715 g, 80%

168

6.2 was loaded into a dialysis bag (1,000 g/mol molecular weight cut off) with

approximately 10x volume of dichloromethane. The bag was closed and submerged in

a stirred vessel of methanol. The methanol was changed once after 5 h and the

contents of the bag were taken to dryness after 19 h. 6.2b: 1H-NMR (500 MHz,

acetone-d6) 5.80 (d, 1H); 5.70 (s, 32H); 5.31 (m, 2H); 4.08 (s, 64H); 4.00 (m, 1H);

3.46 (m, 2H). 13C-NMR (100 MHz, CDCl3) 135.9; 133.0; 129.6; 128.2; 118.8; 79.8;

73.3; 70.5; 66.2; 65.8; 65.7; 64.6; 58.8 (see Figure 6.8). GPC: Mn=4,987; PDI= 1.303.

Yield: 21 mg, 4%.

The supernatant (cyclic oligomer fraction) was removed of volatiles and analyzed: 1H-

NMR (400 MHz, CDCl3) 5.80 (d, 1H); 5.70 (s, 32H); 5.31 (m, 2H); 4.08 (s, 64H);

4.00 (m, 1H); 3.46 (m, 2H). 13C-NMR (100 MHz, CDCl3) 129.6; 66.2. ESI:

(C4H6O)n, n=3-10; for n=3+ H+, m/z =210.87 vs 211.12 g/mol (see Figure 6.6).

PPM (F2) 5.8 5.6 5.4 5.2 5.0 4.8 4.6 4.4 4.2 4.0 3.8 3.6 PPM (F1)

6.2

6.0

5.8

5.6

5.4

5.2

5.0

4.8

4.6

4.4

4.2

4.0

3.8

3.6

3.4

Figure 6.4. 1H-1H COSY (500 MHz, acetone-d6) of 6.2b

169

Figure 6.5. ESI of 6.2: HO(C4H6O)nH, n=3-20; for n=7 + Na+, m/z =531.44 vs

531.28 g/mol

Figure 6.6. ESI of the supernatant from the polymerization reaction. (C4H6O)n, n=3-

10; for n=3+ H+, m/z =210.87 vs 211.12 g/mol, the Na+ adducts are visible at +23 m/z

6.4.3 2-trans-1,4-butenediol

6.1 (1 mg, 0.0018 mmol) was weighed directly into an NMR tube to which

was added D2O (0.5 mL) and 3 drops of acetone-d6 (reference) and 2-cis-1,4-

butenediol (0.1 mL, 1.2 mmol). The tube was shaken to mix, and the isomerization

occurred over several hours yielding the trans- product: 1H-NMR (400 MHz, D2O)

200 400 600 800 1000 1200 1400 1600 1800 2000m/z

0

10

20

30

40

50

60

70

80

90

100

Re

lativ

e A

bu

nd

an

ce

303.20

280.89

210.87

373.26

443.29

545.23

615.32690.82

717.15

843.06 992.731087.08

1224.31 1434.68 1635.89 1764.76 1931.29

200 400 600 800 1000 1200 14000

500000

1000000

1500000

2000000

2500000

3000000

3500000

4000000

4500000

5000000

5500000

6000000

Inte

nsi

ty

531.44

461.45

601.42

671.42

391.41741.44

811.43

881.49321.36951.52

1021.501091.56

1092.59 1231.53251.29 1441.84

170

5.74 (t, 2H); 4.21 (d, 4H). 13C-NMR (100 MHz, D2O) 131.59; 58.37 (c.f. Figure

6.7)

Figure 6.7. 13C-NMR (D2O, acetone internal standard) spectrum of poly(2,5-DHF),

6.2b; (lower, a=CH; b=CH2) and 2-cis-butene-1,4-diol (upper, c=CH; b=CH2)

Figure 6.8. (upper) 13C-NMR (100 MHz, CDCl3) spectrum of 6.2b acquired with

power-gated decoupling. (lower) 13C-NMR (100 MHz, CDCl3) spectrum of 6.2b

acquired with gated decoupling

171

6.4.6 Reaction of 6.2 with 2-cis-butene-1,4-diol

To an NMR tube containing 6.1 (1.6 mg; 0.0029 mmol) in acetone-d6 (0.4 mL)

was added 2-cis-butene-1,4-diol (0.2 uL, 0.0029 mmol). The tube was shaken to mix,

and the reaction was monitored by 1H-NMR. Characterization matched the

literature.36

Figure 6.9. (upper) 1H-NMR (500 MHz, acetone-d6) spectrum of allyl alcohol

(Aldrich). (middle) 1H-NMR (500 MHz, acetone-d6) spectrum of allyl ether (Aldrich).

(bottom) 1H-NMR (500 MHz, acetone-d6) spectrum of a solution containing 6.1 (●)

and cis-2-buten-1,4-diol (■) partially converted to cis-3-(allyloxy)prop-2-en-1-ol (▲).

6.4.7 Synthesis of 6.3 (ROP of LA from the macroinitiator 6.2)

To a vial containing a stir bar, 6.2 (2.0 mg; 0.0048 mmol) and TBD (0.0021

mmol) in dichloromethane (DCM) (~2 mL) was added L-lactide (0.3004 g; 2.1 mmol)

in DCM in the balance of volume required to yield a final DCM volume of 3.54 mL.

The vial was sealed and stirred for 30 min. during which time the reaction had reached

55% conversion to polymer (1H-NMR). The reaction was quenched by the addition of

●● ●

●

▲ ▲▲▲

▲▲

■■

▲

172

10 mg (0.082 mmol) benzoic acid, and the addition of hexanes to the crude solution

precipitated a crystalline solid. 1H-NMR (400 MHz, CDCl3) d 5.8-5-6 (m, 12H); 5.2

(q, 480H); 4.35 (q, 1.92 H); 4.1-4.0 (m, 24H). GPC: Mn=16,900; PDI= 1.222. Yield:

150 mg, 50%.

ppm3.84.04.24.44.64.85.05.25.45.65.86.0

4.324.344.364.38

12 480 1.92 24 Figure 6.10. 1H-NMR (400 MHz, CDCl3) spectrum of 6.3. The integrations of the

resonances are given below the signals.

6.4.8 2-cis-butene-1,4-diol Polymerization Experiment with Drying

A round bottom flask loaded with a stir bar 6.1 (15.4 mg; 0.028 mmol), 2-cis-

1,4-butene-1,4-diol (4 mL; 0.049 mol), 4 mL DCM and 2 mL ethyl ether was

equipped with a reflux condenser packed with 4Å molecular sieves. The solution was

stirred at reflux for 48 h. Acetonitrile was added (1 mL) to quench the reaction. The

reaction was cooled, and conversion was assessed by 1H-NMR. The crude material

was placed under high vacuum until constant weight. 1H-NMR (300 MHz, acetone-

d6) 5.80 (d, 1H); 5.70 (s, 10H); 5.31 (m, 2H); 4.08 (s, 20H); 4.00 (m, 1H); 3.46 (m,

2H). GPC: Mn=2,300; PDI= 2.639. Yield: 2.99 g, 80%.

173

6.4.8 Allylation of CD3OD with 2-cis-butene-1,4-diol

To an NMR tube containing 6.1 (0.6 mg; 0.0011 mmol) was added 0.3 mL

CD3OD and 2-cis-butene-1,4-diol (10 L; 0.122 mmol). The tube was shaken to mix,

and the reaction was monitored by 1H-NMR. The reaction proceeded to 56%

conversion in 24 hours. The B/L ratio could be measured by integration of the vinyl

signal at 5.3 ppm and the methylene signal at 4.05 ppm. Characterization of the

branched (both bis- and mono- alkylated products) and linear products matched the

literature.37,38,39

6.4.8 Allylation of CD3OD with 2-cis-pentene-1-ol

To an NMR tube containing 6.1 (0.6 mg; 0.0011 mmol) was added 0.3 mL

CD3OD and 2-cis-pentene-1-ol (12 L; 0.119 mmol). The tube was shaken to mix,

and the reaction was monitored by 1H-NMR. The reaction proceeded to 44%

conversion in 24 hours. The B/L ratio could be measured by integration of the vinyl

signal at 5.23 ppm and the methylene signal at 4.02 ppm. NMR characterization of

the branched and linear products matched the literature.40,41

6.5 References

(1) Hawker, C. J.; Wooley, K. L. Science 2005, 309, 1200-1205.

(2) Kiesewetter, M. K.; Shin, E. J.; Hedrick, J. L.; Waymouth, R. M.

Macromolecules 2010, 43, 2093.

(3) Iha, R. K.; Wooley, K. L.; Nystrom, A. M.; Burke, D. J.; Kade, M. J.; Hawker,

C. J. Chem. Rev. 2009, 109 (11), 5620-5686.

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(5) Trost, B. M.; Van Vranken, D. L. Chem. Rev. 1996, 96 (1), 395-422.

(6) Nomura, N.; Tsurugi, K.; Okada, M. J. Am. Chem. Soc. 1999, 121 (31), 7268-

7269.

(7) Nomura, N.; Tsurugi, K.; Okada, M. Angew. Chem. Int. Ed. 2001, 40 (10),

1932-1935.

174

(8) Nomura, N.; Yoshida, N.; Tsurugi, K.; Aoi, K. Macromolecules 2003, 36 (9),

3007-3009.

(9) Nomura, N.; Komiyama, S.; Kasugai, H.; Saba, M. J. Am. Chem. Soc. 2008,

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(10) Tanaka, S.; Saburi, H.; Ishibashi, Y.; Kitamura, M. Organic Letters 2004, 6

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(11) Tanaka, S.; Seki, T.; Kitamura, M. Angew. Chem. Int. Ed. 2009, 48 (47), 8948-

8951.

(12) Zhang, H. J.; Demerseman, B.; Toupet, L.; Xi, Z.; Bruneau, C. Adv. Synth.

Catal. 2008, 350 (10), 1601-1609.

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173-183.

(15) Vlad, S.; Oprea, S.; Stanciu, A.; Ciobanu, C.; Bulacovschi, V. E. Poly. J.

2000, 36, 1495-1501.

(16) Zeitsch, K. J., The Chemistry and Technology of Furfural and its Many By-

products. Elsevier Science B.V.: Amsterdam, The Netherlands, 2000; p 358.

(17) Goethals, E. J., Telechelic Polymers: Synthesis and Applications. CRC Press:

Boca Raton, 1989; p 403.

(18) Phillips, J. P.; Deng, X.; Stephen, R. R.; Fortenberry, E. L.; Todd, M. L.;

McClusky, D. M.; Stevenson, S.; Misra, R.; Morgan, S.; Long, T. E. Polymer

2007, 48 (23), 6773-6781.

(19) Young, A. M.; Ho, S. M. J. Controlled Rel. 2008, 127, 162-172.

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(21) Thomas, R. M.; Grubbs, R. H. Macromolecules 2010, 43 (8), 3705-3709.

(22) Sanda, F.; Matsumoto, M. Macromolecules 1995, 28 (20), 6911-6914.

(23) Sanda, F.; Matsumoto, M. J. Appl. Poly. Sci. 1996, 59, 295-299.

(24) Minoura, Y.; Mitoh, M. Die Makromolekulare Chemie 1968, 119, 104-112.

(25) Kiesewetter, M. K.; Waymouth, R. M. see Chapter 5.

175

(26) Tanaka, S.; Saburi, H.; Murase, T.; Yoshimura, M.; Kitamura, M. J. Org.

Chem. 2006, 71 (12), 4682-4684.

(27) Kitamura, M.; Tanaka, S.; Yoshimura, M. J. Org. Chem. 2002, 67 (14), 4975-

4977.

(28) McKenna, J. M.; Wu, T. K.; Pruckmayr, G. Macromolecules 1977, 10 (4),

877-879.

(29) Pruckmayr, G.; Wu, T. K. Macromolecules 1978, 11 (1), 265-270.

(30) Thu, C. T.; Bastelberger, T.; Hocker, H. J. Mol. Catal. 1985, 28, 279-292.

(31) Bruneau, C.; Renaud, J. L.; Demerseman, B. Chem. Eur. J. 2006, 12 (20),

5178-5187.

(32) Gruber, S.; Zaitsev, A. B.; Worle, M.; Pregosin, P. S.; Veiros, L. F.

Organometallics 2009, 28 (12), 3437-3448.

(33) Achard, M.; Derrien, N.; Zhang, H.-J.; Demerseman, B.; Bruneau, C. Org.

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(34) Sundararaju, B.; Achard, M.; Demerseman, B.; Toupet, L.; Sharma, G. V. M.;

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1059-1061.

(35b) Attempting to remove the water to favor products by in situ chemical drying

(MgSO4, NaSO4, or 4Ǻ molecular sieves) did not increase the molecular

weight of the polymer.

(36) Ooi, T.; Hokke, Y.; Tayame, E.; Marouka, K. Tetrahedron 2001, 57 (1), 135-

144.

(37) Lu, K.; Huang, M.; Xiang, Z.; Liu, Y.; Chen, J.; Yang, Z. Org. Lett. 2006, 8

(6), 1193-1196.

(38) Baltes, H.; Steckhan, E.; Schafer, H. J. Chem. Ber. 1978, 111, 1294-1314.

(39) Kumaraswamy, G.; Sadaiah, K.; Ramakrishna, D. S.; Police, N.; Sridhar, B.;

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176

CHAPTER 7

Alkali Metal Reductions of N-Heterocyclic Carbenes and Their HCl Salts

177

7.1 Introduction

The use of N-heterocyclic carbenes (NHCs) experienced a renaissance with the

work of Arduengo in 1991.1 Their chemistry has recently been the subject of a

thematic issue of Chemical Reviews 2 and has been the subject of several independent

reviews.3-5 NHCs are used in almost every conceivable arena of chemistry from

transition metal ligands to organocatalysts5,6, where they are employed in our lab as

potent transesterification catalysts for polymerization.7 NHCs are renowned for their

potent nucleophilicity and strong -donation.3 However, the dearth of empirical

information on the electron distribution of NHCs is surprising, especially given the

debate over their aromaticity8 and -accepting abilities.9 Indeed, to our knowledge,

only one EPR spectrum has been recorded of an NHC parent anion radical (i.e. not

complexed to metal).10 In that case, the ‘odd’ electron was localized away from the

carbene carbon (see hyperfine coupling constants of triazole carbene below), which

suggests that the five-membered ring is too high in energy to accept an electron.2, 10

The electron distributions of NHC anion radicals that do not possess a phenyl moiety

in the backbone into which the added electron can diffuse would be of interest.

The large amount of interest in the exact nature of the NHC-M bond has

spurred many theoretical and experimental studies.3 Several studies to gauge the bond

donating abilities of NHCs have been performed.11-13 The anion radicals of complexes

of several imidazolylidene-type NHCs or their heavy atom congeners (at the carbene

carbon) as well as the gas phase anion radicals of chlorocarbenes have been studied to

probe their electrochemical activity and ability to participate in electron transfer

178

processes.14-17 However, many of these studies remain computational in nature due to

the elusive NHC anion radical, and the reluctance of the imidazolylidene moiety to

accept an electron is a common theme.18, 19 Taking the nature of the imidazolylidene

congener of [6]annulene or cyclopentadienyl anion as a cue, the -acidity of NHCs

would seem to be minimal for the aromatic8 NHCs.

The radical anion of a parent imidazolylidene-type NHC has not been

observed, but if these species are like [6]annulene (as they are predicted to be),8 their

radical anions would not be stable in most solvents at room temperature. The

unmistakable seven line pattern of the benzene anion radical, generated in THF with

K, is observable at 170 K but unobtainable at room temperature.20 Only with the

addition of crown ether (18-crown-6) is the radical stable at room temperature.21 The

signal intensity of organic ion radicals has been shown to be a function of the

concentration of alkali metal solvating agent.22 18-crown-6 also renders observable

the [8]annulene anion radical in THF, which undergoes disproportionation to

[8]annulene dianion and neutral molecules in the absence of crown ether.22, 23

The electrochemical or chemical reduction of imidazolium salts (7.1) is a

means of preparatively producing the free NHCs.24-26 In the case of 7.1, the purported

initial reduction product is the neutral radical of the imidazolium, 7.3a.24, 25 This

species has not been characterized by EPR spectroscopy due to its rapid elimination of

H. to form the free carbene, 7.4.24 Electrochemical investigation of the transformation

suggests an irreverisible one electron reduction of 7.1 and no further reduction signals

due to the reduction of 7.4.24 The five membered ring moiety is proposed to be

aromatic8 (4n+2 electrons), and the smaller ring (vis-à-vis benzene) would suggest a

higher reduction potential than the parent aromatic annulene.20, 27 However, it was our

reasoning that the strong reducing conditions of alkali metal in THF with crown ether

might sufficiently stabilize 7.3a and 7.4 to allow for the empirical characterization of

the electron distribution in the NHC radical anions and NHC-salt radicals. The

muonium addition product of 7.4 has been characterized by Muon Spin Resonance

(SR) which suggests that the muonium resides on the imidazolium ring,

preferentially on the carbenic carbon.28

179

Scheme 7.1. The Reduction of 7.1 to Yield the Free Carbene


7.2.1 Reductions of NHCs and their HCl Salts

Scheme 7.2. Reaction Diagram of the Reduction Products of 7.1, 7.2, 7.4 and 7.5

The EPR signal of the green solution that results from the exposure of 7.4 or

7.5 (Scheme 7.2) in THF with excess 18-crown-6 in vacuo to a freshly distilled K

mirror is shown in Figure 7.1. The three line pattern is well explained by an electron

coupling to a single nitrogen with aN = 40 G.29 This large hyperfine coupling constant

180

to a single nitrogen is ~2/3 the theoretical maximum from the McConnell equation (aN

= Q1Q2(), where Q1 = 30-35 G, Q2= -14 G and 1 is the spin density on the

N and 2 and 3 are the spin densities on the adjacent atoms),29, 30 and cannot be

explained in terms of the expected radical, 7.6. The signal is attributed to a

breakdown product, 7A, see 7.2.2 Decomposition Products. The preparative scale

synthesis of 7.4 with excess K suggests25 that 18-crown-6 facilitates the electron

transfer to 7.4 or 7.5 at room temperature as with [6]annulene, but the added electron

is extremely destabilizing to 7.4 or 7.5.20, 27 Further exposure of the solution to the K

mirror results in the EPR spectra of species attributed to the breakdown products of

the solvent system.31, 32 The 1H-NMR spectra of the fully reduced solutions (to the

solvated electron) do not indicate the presence of any resonances attributable to 7.6,

nor do the solutions that were quenched with D2O possess the D2O adducts/Birch

reduction products of 7.4 (or 7.5) by GC-MS, which corroborates a degradation

phenomenon.

Gauss3440 3460 3480 3500 3520 3540 3560 3580

Figure 7.1. X-band EPR signal observed upon the exposure of a THF solution of 7.4

and 18-crown-6 to a K metal mirror in vacuo.

Since the exposure of 7.4 to reducing conditions in the presence of 18-crown-6

gives access to different products than in the absence of crown ether, we were

interested in determining the effect of crown ether, if any, on the reduction of 7.1 (and

7.2). The exposure of 7.1 or 7.2 in THF with excess 18-crown-6 to a K metal mirror

yields at least two species that are observable by EPR. One of these species (7B) is

well simulated by 6 protons with aH= 6.83 G and the other (7C) by 3Hs at aH = 6.80 G

181

and 2Hs at aH = 6.15 G. There is no measurable g-shift between the two species.

When 7.1 is reduced, the two species occur in a ratio of 1:1 (7B:7C). Surprisingly, the

K metal reduction of 7.2 under identical conditions yields the same spectra albeit in

different relative intensities, 7B:7C = 2:1, Figure 7.2. There are no electron

distribution assignments conceivable to us that would account for 7B and 7C being

assigned as 7.3, see section 7.2.2 Decomposition Products.

Gauss3490 3500 3510 3520 3530

A)

B)

C)

D)

******

Figure 7.2. (A) X-band EPR spectrum of the K metal reduction products of 7.1; (B)

Computer generated simulation of two species, 7B and 7C, in a ratio of 1:1; (C) X-

band EPR spectrum of the K metal reduction products 7.2; (D) Computer generated

simulation of two species, 7B and 7C, in a ratio of 2:1. The species 7B and 7C are

simulated using the parameters given in the text. The resonances marked with (*) are

due to 7C and those with (■) to 7B.

However, the inconsistency that develops as a result of the reduction products

of 7.4 and 7.1 (which leads to 7.4 under reducing conditions)25 being different must be

due to the presence of 18-crown-6. In the preparative synthesis of 7.4 from 7.1, we

propose that Lewis acidic 7.4 is stabilized by coordination to K+ analogously to the

solvation of the cation by THF or DME in the absence of 18-crown-6.33, 34 In the

182

presence of crown ether, 7.4 is no longer stabilized by coordination to the K+ which is

being sequestered by the stronger interaction of K+ with the crown ether. To the

extent that the carbene character evolving concomitant with the loss of H. in the 7.3 to

7.4 (or 7.5) transformation is being stabilized by K+, the presence of 18-crown-6 will

attenuate that interaction resulting in destabilization of that transition state, Figure 7.3.

Further, the presence of the K+ encapsulated in the crown ether will hinder the

intermolecular loss of H2 (ion pairs or covalent-type interactions involving alkali metal

in the presence of crown ether involves the entire M+/18-crown-6 complex)35, 36. In

sum or separately, these processes allow 7.3 to access decomposition pathways that

lead away from 7.4, see 7.2.2 Decomposition Products.37 Also, the ability of crown

ether to attenuate the interaction of an alkali metal cation and an imidazolylidene has

been previously observed to induce decomposition.38 The exhaustive reduction (to

solvated electron) of the solutions that provided the EPR spectra in Figure 7.2 and

subsequent quenching with D2O indicates no trace of 7.1 or 7.2 by 1H-NMR.

N N

R RH

OO

O

OOO

R'N N

R'

H

N N

R R

K+ OO

N N

R HR'

N N

R R

+

N N

R R

OO

O

OOO

K+

7B

N

N H

OO

O

OOO

K+

OOO

OO

O

K+

NN

H

7.3

7.4 R=CH3 (IMes)7.5 R=H (IdiMe)

7.4 R=CH3 (IMes)7.5 R=H (IdiMe)

H

Figure 7.3. The addition of 18-crown-6 disfavors the path from 7.3 to 7.4 or 7.5

causing destructive decomposition pathways.

183

7.2.2 Decomposition Products

The features of the EPR spectra permit tentative assignment of the

decomposition products. The normal relative distributions of spin densities of phenyl

moieties substituted with electron donating groups are at odds with the phenyl

substitution patterns of 7.1 and 7.2 (the presence of a group of 3 protons is, of course,

indicative of a methyl group), Figure 7.4.30 Further, the wide spectral window

(spectral width > Q, aH = Q)30 indicates that 7B and 7C are radicals and not

radicals.30, 39 The ability of 7.3 to eliminate a radical to form a stable, neutral species

is well established,24-26 and the presence of 18-crown-6 is reasonably expected to

destabilize the pathway leading to 7.4 or 7.5 (see 7.2.1 Reductions of NHCs and their

HCl Salts) allowing other pathways to dominate. Species 7.3 could reasonably

eliminate a aryl radical to form a stable aryl imidazole if the H. elimination pathway

Figure 7.4. The degenerate LUMOs of benzene substituted with an electron pushing

group where the dashed lines represent nodes.

were disfavored. This aryl radical is assigned as 7B. The phenyl () radical40 has

been observed as has the p-tolyl radical41. In these molecules, the spin densities

rapidly decrease in magnitude away from the radical center, and the p-methyl of the p-

tolyl radical is not observed,39, 41 Figure 7.5, which would account for the identical

EPR spectra produced by 7B when R=H or CH3. The coupling constants ortho- to the

radical center are 17 G and 18 G for the phenyl and p-tolyl radicals respectively,39 and

one would expect a coupling constant of the protons of a methyl group in those

positions to be approximately one third those values, as observed in 7B, Figure 7.6.

The identical g-shift of 7C (to 7B) suggests a species that is structurally similar to 7B

(another neutral radical of similar structure).30 However, the assignment of a structure

does not seem possible without evoking reduction/rearrangement products of 7B.

184

17.4 G

6.25 G2.04 G

18.2 G

p-tolyl phenyl Figure 7.5. Coupling constants of selected s radicals.39

Coupling constants similar magnitude to those observed upon the reduction of

7.4 or 7.5 are often seen in nitroxide type radicals where the electron is considered to

be shared evenly between N and O atoms.39 In order to increase the magnitude of the

coupling constant from a nitroxide-type radical to aN = 40G, as observed for 7A,42 the

spin from the ‘odd’ electron must be more localized on the N atom. The proposed

homolysis of the N-C(aryl) bond in 7.3 does not occur in this system (leading to 7B)

presumably because the stable imidazolium cannot be easily formed from the free

NHC (as opposed to the 7.3 decomposition, see Figure 7.6). The 4N+3 electron 7.6

could, however, decompose along a retro-[3+2] cycloaddition43 pathway followed by a

proton migration to form a nitrogen centered radical whose unpaired electron is

predominately N in character, Figure 7.6. Any hyperfine coupling from the aryl

moieties would be hidden in the linewidth.42

Figure 7.6. Proposed decomposition pathway leading to 7A and 7B.

185

The extreme instability of 7.4 and 7.5 upon reduction is counter to the

observation of a stable triazole anion radical.10 We propose that the presence of the

phenyl ring on the triazole backbone is the source of that molecule’s marked stability

(vis-à-vis 7.4 or 7.5). In the imidazolylidenes, the nitrogen atoms and phenyl groups

are mutually destabilizing for single electron addition, and decomposition is the result

upon reduction. Taken together, these observations suggest that the N’s, which

stabilize the carbene carbon, are the source of the instability of NHC single electron

reduction products. Triazole can obviate this instability due to the phenyl moiety in

the backbone away from the electron pushing nitrogen atoms.

7.3 Conclusion

Much in the same manner as the prototypical aromatic system [6]annulene, the

exposure of 7.4 or 7.5 to K metal in THF does not produce a reduced species at room

temperature except in the presence of crown ether. The imidazol-2-ylidenes (7.4 and

7.5) are destabilized by the addition of an electron resulting in decomposition to a

paramagnetic species whose unpaired electron is predominately localized on a single

N. These results suggest that the imidazol-2-ylidenes are aromatic8 and would not

readily accept an electron through a backbonding interaction from a metal center.9

Likewise, the putative intermediate, 7.3, in the reductive formation of free carbene

from 7.1 or 7.2 is destabilized in the presence of 18-crown-6, preventing the formation

of free carbene and leading to putative intramolecular decomposition products.

Certainly, an experimental or theoretical treatment of the electron donating/accepting

abilities of NHCs requires the explicit consideration of solvent effects to give

meaningful data.



Tetrahydrofuran was dried over Na/benzophenone and distilled onto sodium-

potassium eutectic under high vacuum. 18-crown-6 was purchased from Aldrich and

stored under high active vacuum for several days before use. 7.1 was purchased from

186

Strem Chemicals and stored in a glove box under N2. 7.2 was prepared from standard

procedures, and characterization matched the literature.44 Potassium in mineral oil

was purchased from Aldrich.

7.4.2 Example Reduction Experiment and Quenching

A glass capillary with fragile ends containing 7.1 (2.2 mg, 0.0065 mmol) was

loaded into the custom apparatus shown in Figure 7.7 along with 18-crown-6 (5 mg,

0.019 mmol). A small amount of potassium was washed with hexanes and loaded into

the apparatus at #2 (numbers in Figure 7.7). The apparatus was evacuated under high

active vacuum by attaching to a vacuum line at #3. The apparatus was sealed shut at

#4, and a K metal mirror was formed at #5 by distilling the potassium through #6. The

arm #2 was sealed from the apparatus at #6. THF (1.5 mL) from sodium-potassium

eutectic was distilled into the apparatus at #7, and the apparatus was sealed from the

vacuum line at #7. The apparatus was gently agitated to dissolve the 18-crown-6 and

then shaken vigorously to break the capillary. The apparatus was rotated to allow the

solution to come into contact with the K mirror, and the solution was transferred to the

attached EPR tube which was inserted directly into the EPR cavity to record the

spectra. The apparatus could be removed from the cavity to allow the solution to be

re-exposed to the metal mirror and subsequent EPR spectra recorded. Quenching

reduction products: The end of the EPR tube was scored and snapped off when

submerged in water. The contents of the apparatus were extracted with chloroform,

and the concentrated fractions were analyzed by 1H-NMR and GC-MS.

187

Figure 7.7. Apparatus used for the reduction of NHCs or their HCl salts.

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190

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