The Chemoselective Catalytic Oxidation of Alcohols, Diols, and Polyols to Ketones and Hydroxyketones

THE CHEMOSELECTIVE CATALYTIC OXIDATION OF ALCOHOLS, DIOLS, AND POLYOLS TO KETONES AND HYDROXYKETONES

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

Ronald Michael Painter

March 2011

This work is licensed under a Creative Commons Attribution- Noncommercial 3.0 United States License. http://creativecommons.org/licenses/by-nc/3.0/us/

This dissertation is online at: http://purl.stanford.edu/ds322sz8050

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

Robert Waymouth, Primary Adviser

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

Justin Du Bois

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

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 in University Archives.

iii

Abstract

The chemoselective oxidation of vicinal diols to α-hydroxyketones is a challenge in organic syntheses because not only does the diol need to be oxidized selectively to a monocarbonyl compound, but diols are also prone to overoxidation and oxidative cleavage. Employing a cationic palladium complex, [(neocuproine)Pd(OAc)]2(OTf)2 (1), we were able to demonstrate the selective oxidation of glycerol to dihydroxyacetone mediated by either benzoquinone or O2 as the terminal oxidant, an accomplishment that has little precedent in homogeneous catalysis. Mechanistic studies were undertaken to uncover the nature of this remarkable chemoselectivity. Kinetic and deuterium-labeling studies implicate reversible β-hydride elimination from isomeric Pd alkoxides and turnover-limiting displacement of the dihydroxyacetone product by benzoquinone. We successfully extended this methodology to other terminal 1,2-diols and symmetric vicinal

1,2-diols and have carried out aerobic oxidation of these substrates catalyzed by 1.

Examination of the reactivity of 1 with conformationally-restricted 1,2-cyclohexanediols suggests that the diol must chelate to the Pd center for effective oxidation to the hydroxyketone product.

In a separate project, we have also investigated the electrocatalytic reduction of dioxygen by several dinuclear copper complexes, an important reaction for fuel cell applications.

Acknowledgments

My parents, Mike and Shannan Painter, have long played a crucial role in shaping me for who I am today. I would never have gotten as far in my education if it hadn't been for their undying efforts to provide me with the best education possible. Being the parents of a deaf child has its own challenges, and they have risen to the task by being outstanding parents and role models. They have provided me with many opportunities that are available to few other deaf children, and I would not be who I am today without them.

For that, they have earned my unending gratitude.

Perhaps the most important person in my graduate career at Stanford has been my advisor, Professor Robert M. Waymouth. He has demonstrated time and again his patience and understanding with me especially when it comes to working with a deaf graduate student. In addition, he is honestly one of the (if not the) smartest people I know, and has made himself available as a indispensable resource for me to learn chemistry from. Moreover, he has been an excellent mentor and advisor for the people who work in his lab, and I am very proud to have him as my advisor.

My colleagues in the Waymouth lab have been instrumental to making the lab operational. While I have never had the opportunity to personally collaborate with anyone in the lab on a project, I am confident that every person that I have worked with in the lab will go on to be successful scientists.

I could not have been successful in my Stanford graduate career without the opportunity to have worked with several outstanding ASL interpreters. When I came to Stanford in my first year, I had already studied chemistry for four years, but none of the interpreters in the area have had that luxury. They have spent countless hours learning how to mediate the transfer of chemical information, and that is not an easy task - organic chemistry is practically a language of its own! I am proud to have gotten to know six interpreters on a professional and personal basis: Debbie Mancuso and Mary Walsh, who have been with me since the very beginning (2004-2010), Laura Winick (2004-2005),

Debby Kajiyama (2005-2010), Alicia Davidovich (2004-2010), and Joseph Cartwright

(2008-2010). Stanford's Office of Accessible Education has contracted their services through an outstanding interpreter agency, Deaf Services Palo Alto, of which Janet Lewis is the owner. Janet has shown the utmost care for providing the very best interpreters for her clients, and I am confident that I would not be as successful as I have been without these six fantastic interpreters.

I'd also like to thank the members of my dissertation committee, Professor Barry M.

Trost and Professor Justin Du Bois. They are both extremely bright and dedicated chemists, and have taught me much over the last six years. The chemistry department's student services officer, Roger Kuhn, has been an indispensable resource for me relating to various aspects of my career at Stanford, and I am grateful for his assistance over the years. Our lab's adminstrative associate, Dewi Fernandez, has been instrumental to keeping the lab running smoothly - nothing would get done without her. Patricia Dwyer

has done the herculean task of putting together chemistry events, and despite her always having a full plate, she always remembers to set a chair aside for my interpreters to use.

Over the past two years, I have been proud to be part of the inaugural cohort of fellows for the Diversifying Academia, Recruiting Excellence fellowship program. The other eleven members of the group have been nothing but outstanding colleagues who have enriched my understanding of the importance of diversity in academia and provided me with support during the last portion of my career at Stanford. Anika Green and Chris

Golde have put in so much work to making the fellowship program successful, and I am grateful to them for giving us their time and resources to help us succeed in our future academic careers.

Finally, I would like to give heartfelt thanks to my partner, William White. When we met four and a half years ago, I never dreamed that I would be so lucky to have a partner who has been extremely supportive and encouraging despite the many, many, many frustrations that I've had in my Stanford graduate career. His being a biology major and now a medical student has helped me broaden my interests in science, and I know that I will continue to learn things from him as time goes on. I don't know where I will be going or what I will be doing after I graduate from Stanford, but I am happy to face the new challenges before us together.

vii

Preface

"I do not write books; I write pages."

-Dan Fante

viii

Table of Contents

ABSTRACT ...... iv

ACKNOWLEDGMENTS ...... v

PREFACE ...... viii

TABLE OF CONTENTS ...... ix

LIST OF TABLES ...... xii

LIST OF FIGURES ...... xiii

LIST OF SCHEMES ...... xiv

SYMBOLS AND ABBREVIATIONS ...... xvi

CHAPTER 1. An overview of the chemoselective oxidation of vicinal diols to

hydroxyketones.

1.1 Introduction ...... 1

1.2 Transition-metal catalyzed alcohol oxidation: mechanism ...... 2

1.3 Intermolecular selectivity in alcohol oxidation ...... 5

1.4 Intramolecular selectivity in alcohol oxidation ...... 8

1.5 The oxidation of vicinal diols to hydroxyketones ...... 9

1.6 References ...... 14

CHAPTER 2. The selective catalytic oxidation of glycerol to dihydroxyacetone.

2.0 Preface ...... 18

2.1 Introduction ...... 18

2.2 Results ...... 21

2.3 Discussion ...... 24

2.4 Discussion of reaction mechanism...... 26

2.5 Conclusion and future directions ...... 28

2.6 Experimental section ...... 28

2.7 References ...... 42

CHAPTER 3 The selective catalytic oxidation of diols and polyols to

hydroxyketones.

3.0 Preface ...... 45

3.1 Introduction ...... 45

3.2 The oxidation of activated diols ...... 46

3.3 The oxidation of aliphatic, unactivated diols ...... 48

3.4 Stereoelectronic effects on cyclohexane-1,2-diol oxidation ...... 52

3.5 Conclusions and future directions ...... 56

3.6 Experimental section ...... 57

3.7 References ...... 68

CHAPTER 4 The electrocatalytic reduction of dioxygen using dinuclear copper

complexes.

4.0 Preface ...... 70

4.1 Introduction ...... 70

4.2 Towards a dicopper electrocatalyst ...... 72

4.3 The 3,5-di(2-pyridyl)pyrazole ligand system ...... 74

4.4 A 3,6-di(2-pyridylthio)pyrazine dicopper complex ...... 81

4.5 Some 3,5-di(2-pyridyl)-1,2,4-triazole ligand systems ...... 81

4.6 Conclusions and future directions ...... 85

4.7 Experimental section: ligand syntheses ...... 86

4.8 Experimental section: electrochemical studies ...... 87

4.9 References ...... 88

APPENDIX

A.0 General remarks ...... 90

A.1 1H NMR spectrum of the oxidation products for trans,trans-3-methyl-1,2- cyclohexanediol...... 91

A.2 1H NMR spectrum of the oxidation products for trans,cis-3-methyl-1,2- cyclohexanediol...... 92

List of Tables

Table 2.1 Catalytic oxidation of glycerol and 1,2-propanediol with complex 1 ...... 22

Table 3.1 The Pd-catalyzed oxidation of 4'-substituted phenylethane-1,2-diols ...... 47

Table 3.2 NMR-scale screening of the oxidation for a variety of alcohols, diols, and polyols with 1 and benzoquinone in CD3CN/D2O at room temperature ...... 49

Table 3.3 The oxidation of six polyols to hydroxyketones on a 2 mmol scale ...... 52

xii

List of Figures

Figure 2.1 Comparison of conversion vs. time for 1,2-propanediol with air or O2 as the terminal oxidant ...... 32

Figure 2.2 First order kinetic plot for oxidation of 1,2-propanediol ...... 37

Figure 2.3 Second order kinetic plot for oxidation of 1,2-propanediol ...... 38

Figure 2.4 Plot of kobs vs. [Pd] ...... 38

Figure 2.5 Plot of initial rate vs. [BQ] ...... 39

Figure 2.6 Second order plots for d0, d1, and d2-1,2-propanediols ...... 40

Figure 2.7 Plot of 1/kobs vs. [HOAc] ...... 41

Figure 4.1 Cyclic voltammogram of (dppy)Cu2(OAc)3 at pH 4.7 ...... 76

Figure 4.2 Dependences of the peak current on scan rate for (dppy)Cu2(OAc)3 at (a) its redox potential at -170 mV and (b) its electrocatalytic O2 reduction peak with maximum current at -25 mV ...... 76

Figure 4.3 (a) Voltammograms of (dppy)Cu2(OAc)3 with varying rotation rates for the rotating disk electrode; (b) Plot of the current at -650 mV as a function of the square root of the rotation rate for the disk electrode ...... 78

Figure 4.4 Cyclic voltammograms at pH 4.7 for (a) the (4-NO2dppy)Cu2(OAc)3 complex and (b) the (4-NH2dppy)Cu2(OAc)3 complex ...... 79

Figure 4.5 Cyclic voltammograms of a copper 3,6-dipyridyl-1,2,5,6-dihydrotetrazine complex using (a) N2 saturated solution; (b) air saturated solution ...... 82

Figure 4.6 Cyclic voltammograms of a copper 3,6-dipyridyl-1,2,5,6-tetrazine complex using (a) N2 saturated solution; (b) air saturated solution ...... 83

Figure 4.7 Cyclic voltammograms of a copper 4-amino-3,5-dipyridyl-1,2,4-triazole complex using (a) N2 saturated solution; (b) air saturated solution ...... 83

Figure 4.8 Cyclic voltammograms of a copper 3,5-dipyridyl-1,2,4-triazole complex using (a) N2 saturated solution; (b) air saturated solution ...... 84

xiii

List of Schemes

Scheme 1.1 Multiple oxidation products from glycerol oxidation ...... 1

Scheme 1.2 Several possible mechanisms for hydride abstraction from alcohols ...... 3

Scheme 1.3 Studies on the β-hydride elimination from metal alkoxides ...... 4

Scheme 1.4 Methods for the preparation of α-hydroxyketones ...... 10

Scheme 2.1 Catalyst systems ...... 20

Scheme 2.2 Selective oxidation of glycerol to dihydroxyacetone ...... 21

Scheme 2.3 Oxidation of deuterium-labeled 1,2-propanediols ...... 25

Scheme 2.4 Proposed mechanism for the catalytic oxidation of 1,2-propanediol ...... 26

Scheme 2.5 Stoichiometric oxidation of 1,2-propanediol with 1 ...... 27

Scheme 3.1 The [(neocuproine)Pd(OAc)]2(OTf)2 complex ...... 46

Scheme 3.2 Preparation of substituted phenylethane-1,2-diols and their oxidation to the corresponding α-hydroxyacetophenone product ...... 46

Scheme 3.3 Preparation of 4-tert-butylcyclohexane-1,2-diols ...... 53

Scheme 3.4 Preparation and reactivity of 3-methyl-1,2-cyclohexanediols ...... 54

Scheme 3.5 The oxidation of 4-tert-butylcyclohexane1,2-diols by 1 ...... 55

Scheme 3.6 The oxidation of 3-methyl-1,2-cyclohexanediols by 1 ...... 56

Scheme 4.1 Proposed dinuclear copper electrocatalysts ...... 72

Scheme 4.2 Proposed catalytic cycle for the reduction of dioxygen ...... 73

Scheme 4.3 The oxidation of water to dioxygen with a dinuclear Ru complex ...... 74

Scheme 4.4 Synthesis of the 3,5-di(2-pyridyl)pyrazole ligand ...... 75

Scheme 4.5 Preparation of 4-substituted dppy ligands ...... 79

Scheme 4.6 Preparation of 3,6-di(2-pyridylthio)pyrazine dicopper tetrachloride ...... 81

xiv

Scheme 4.7 Preparation of 3,5-di(2-pyridyl)-1,2,4-triazole ...... 82

Scheme 4.8 Preparation of 3,5-di(2-pyridyl)-1,2,4-triazole derivatives ...... 85

Symbols and abbreviations

Anal. Calcd calculated elemental analysis aq. aqueous

β-H beta-hydride/hydrogen

BQ benzoquinone

DHA dihydroxyacetone dmso dimethylsulfoxide eq. equivalents

ESI electron-spray ionization

Et ethyl h hours

HOAc acetic acid

KIE kinetic isotope effect

M molar

Me methyl

MeO methoxy mM millimolar

MS mass spectroscopy m/z mass to charge ratio neocuproine 2,9-dimethyl-1,10-phenanthroline

NHE normal hydrogen electrode

NMR nuclear magnetic resonance

xvi

OAc acetate

OTf trifluoromethanesulfonate

PD or PG propylene glycol / 1,2-propanediol

Ph phenyl ppm parts per million

RDE rotating disk electrode

Rf retention factor

RT room temperature s seconds

TLC thin layer chromatography

V volt

xvii Chapter 1 An overview of the chemoselective oxidation of vicinal diols to hydroxyketones

1.1 Introduction

The oxidation of alcohols to carbonyl compounds is a fundamental and important transformation in organic synthesis; such a broadly useful reaction necessarily carries with it countless reagents that can serve in this capacity.1-4 One inherent challenge that comes with further development of this reaction is the ability for a reagent to selectively oxidize one alcohol group in the presence of other alcohol functional groups in the same molecule.5 In the case of chemoselective oxidation of polyols, several difficulties present themselves: lack of chemoselectivity, lack of control over the level of oxidation taking place (i.e. overoxidation), and, in the case of vicinal diols, oxidative cleavage of the carbon-carbon bond. Scheme 1.1 gives an illustrative example of these complications as they relate to glycerol (a problem that is specifically addressed in Chapter 2).

O O HO OH HO OH O O OH OH HO HO OH O O O HO H HO OH OH OH

Scheme 1.1. Multiple oxidation products from glycerol oxidation

1 This chapter is designed to give an overview of the fundamental problem of the chemoselective oxidation of polyols. The chapter will first delineate studies that have been done on intermolecular selectivity for primary vs. secondary alcohols, and then discuss chemoselective intramolecular examples of diols where the two alcohol groups are remote from each other. Finally, this chapter will discuss the specific case of the oxidation of 1,2-diols, where oxidative cleavage of this moiety is especially problematic.

1.2. Transition-metal catalyzed alcohol oxidation: mechanism

A common mechanism for homogeneous transition metal-mediated alcohol oxidations involves hydride abstraction from the β position of a metal alkoxide intermediate. This can take place via an electrophilic metal center (such as Pd) to form a metal hydride (vide infra), or, in the case of some metal oxos, via decomposition of metal esters (i.e. chromic acid oxidation) to form a metal hydroxo complex.6-10 Another class of homogeneous transition metal-catalyzed alcohol oxidations where hydride abstraction takes place invokes a transfer hydrogenation mechanism where there is at least a stoichiometric amount of sacrificial hydride acceptor present in the reaction solution.11-13 Finally, there are some examples of alcohol oxidations that go through a radical mechanism for abstraction of the alcohol’s β hydrogen (i.e. permanganate oxidation).14-17 The latter two classes of alcohol oxidation reagents are beyond the scope of this chapter, though they are known to chemoselectively oxidize certain types of alcohol functional groups.5

2 H H O + [M] [M] R O R H

H O OH O + R OH [M] [M] R O R H R' O H O [M] R' O + [M] R H R O

H H H O [M] [M] + [M] R O R O R H

Scheme 1.2. Several possible mechanisms for hydride abstraction from alcohols.

There have been few studies that compare the rates for β-H elimination of transition metal alkoxides derived from primary and secondary alcohols, owing to the difficulty in preparing stable metal alkoxide complexes. Milstein has synthesized a number of

31 (Me3P)3Ir(H)(Cl) alkoxides and studied the rates for Ir-H2 formation by P NMR; he reports that the rates for decomposition of these Ir alkoxide complexes follows the trend: isopropoxide > ethoxide >> methoxide.18 Bergman has made a series of stable

Cp*Ir(Ph)(PMe3) alkoxides that only undergo β-H elimination when a catalytic amount of cationic Ir is introduced to the solution as an hydride acceptor.19 In this case, the Ir methoxide complex is decomposed immediately at ambient temperatures where the neopentyl analog requires 4 h, likely because of the increased difficulty for the cationic Ir catalyst to access the Ir alkoxide and subsequently abstract the β-hydride. Hartwig has studied the thermolysis of trans-(Ph3P)2Ir(CO)(alkoxide) complexes; in contrast to the preceding two studies, there is an unusual lack of dependence for the nature of the alkoxide ligand on the rate constant at 95ºC.20 This is attributed to the relatively open

3 nature of the coordination around Ir after dissociation of the PPh3 ligand, such that steric bulk plays a much smaller role in the β-H elimination rates of these alkoxides.

H H O Me P RCH2OH Me P Me P H 3 Ir Cl 3 Ir OCH2R 3 Ir + Me3P PMe3 Me3P PMe3 Me3P PMe3 H Cl Cl R

Ir Me3P OTf Ir 0.1 eq. Ph Me3P H Ir Ir R Ph Me3P OCH2R Me3P O Ph Ph + [Ir ] H Ir R Me3P O Ph H

95ºC Ph3P + PPh O Ph P OCH R 3 Ph P H 3 Ir 2 Ir OCH2R 3 Ir + OC PPh3 - PPh3 OC OC PPh3 R H

iPr iPr CH4 iPr iPr P CH cat. NiIII-H P 3 R P H Ni 3 Ni Ni OCH Ph R P OCH Ph 2 P OCH2Ph 3 2 P CH3 iPr iPr iPr iPr

Ph H

Ph H Ar N N Ar Ar N N Ar Pd Pd O O O H O H Ph O

Scheme 1.3. Studies on the β-hydride elimination from metal alkoxides.

In a similar vein, Cámpora has shown that, when (dippe)Ni(CH3)(alkoxide) complexes are thermolyzed at 60ºC, there is little difference in the initial β-hydride elimination rates

4 for the complexes derived from benzyl alcohol and 1-phenylethanol.21 The proposed mechanism involves a catalytic amount of a NiI/III complex where β-H elimination takes place from a three-coordinate NiI alkoxide that is presumably not sensitive to the steric bulk on the alkoxide. Finally, Sigman has conducted elegant theoretical and experimental studies on the energetics of β-H elimination of alkoxides from a N- heterocyclic carbene-Pd complex using benzyl alcohol and 1-phenylethanol as substrates.22 He has found experimentally that there is little difference in ∆G‡ for the two substrates (21.1 and 21.2 kcal/mol, respectively) at 50ºC.

1.3 Intermolecular selectivity in alcohol oxidation

The oxidation of vicinal diols to hydroxyketones represents an intramolecular selectivity challenge, as it requires the oxidation of the secondary alcohol in the presence of a primary alcohol. It is therefore useful to compare this type of selectivity to intermolecular chemoselective alcohol oxidations that have been reported in the literature.

A variety of transition metal catalysts have been reported for alcohol oxidation, and, in contrast to stoichiometric reagents, the large majority of catalysts that show any selectivity favor primary alcohols over secondary alcohols, generally for steric reasons.

For instance, Naoto has reported a water-soluble dimeric Ru2(OAc)3(CO3) complex that aerobically oxidizes an equimolar mixture of 1- and 2-decanol to a 14:1 mixture of aldehyde and ketone products.23 Ishii has demonstrated that this same equimolar mixture is aerobically oxidized by Ru(PPh3)3Cl2 and hydroquinone as cocatalyst to a 28:1 mixture

5 of the corresponding products;24 Sheldon has demonstrated that this same catalyst with

TEMPO favors the oxidation of benzyl alcohol versus 1-phenylethanol by a factor of 20 while a mixture of 1- and 2-octanol gives the aldehyde product in a 8:1 ratio.25 Katsuki has shown that (salen)Ru(Cl)(NO) complexes can, once photolyzed, efficiently and aerobically oxidize primary aliphatic and benzylic alcohols to the corresponding aldehyde; secondary aliphatic alcohols are practically unreactive (>30 times slower than primary alcohols), and 1-phenylethanol is 12 times slower than 1-decanol to react under these conditions.26-28 Finally, a Ru-Co-hydroxyapatite catalyst can aerobically oxidize a mixture of 1- and 2-octanols to give the carbonyl products in a 3:1 selectivity for the aldehyde product.29

Copper systems have also shown a preference for primary vs. secondary alcohols. For instance, Semmelhack's early work on CuCl/TEMPO oxidation of alcohols shows that secondary alcohols are very slow to oxidize under catalytic conditions: a mixture of cyclohexanol and 1-octanol gives solely the aldehyde in 60% yield after two hours.30

Further mechanistic studies demonstrate that the copper is responsible for the oxidation of alcohol to product, and not the TEMPO cocatalyst. For comparison, the reaction of 1- and 2-octanol with catalytic TEMPO and stoichiometric NaOCl is nine times slower for

2-octanol versus 1-octanol.31 Similarly, Sheldon has reported on the ability of

Cu(bpy)Br2/TEMPO to oxidize benzyl alcohol in the presence of 1-phenylethanol selectively to benzaldehyde in 63% yield.32 Wieghardt has reported a hydroquinone- based copper catalyst for the oxidation of primary alcohols at ambient temperatures; secondary and benzylic alcohols are unreactive under the catalytic conditions.33

6 Palladium-catalyzed alcohol oxidants typically do not have as dramatic of a difference in chemoselectivity for aerobic alcohol oxidation though most of the studies conducted with these systems have been limited to benzylic alcohols. For instance, aerobic oxidation with Sheldon's (neocuproine)Pd(OAc)2 catalyst favors primary alcohols in up to 3:1 selectivity for the aldehyde product. Aerobic oxidation employing Pd(OAc)2 in dmso qualitatively favors primary benzylic and allylic alcohols, as base additives are needed to promote oxidation of secondary activated alcohols.34 Shimazu has reported a Pd catalyst supported on a solid mixture of Ni and Zn hydroxides; aerobic oxidation of benzylic alcohols under forcing conditions strongly favors the aldehyde product in a 29:1 ratio.35

In contrast, PdCl2-polyoxometallate complexes show a modest selectivity (2:1) selectivity

36 for primary versus secondary aliphatic alcohols. Pd(OAc)2 can also be made electrocatalytic with benzoquinone as the redox mediator; 1-phenylethanol is five times slower to react compared to benzyl alcohol though both substrates are eventually oxidized to the ketone and aldehyde in 60% and 77% yield, respectively.37

There are few examples where transition metal catalysts show a strong preference for secondary alcohols in the presence of primary ones. For instance, V2O5 can catalyze the aerobic oxidation of a mixture of cyclohexanol and 1-decanol, furnishing cyclohexanone as the sole product in 87% after 16 hours with a trace amount of decanal.38 A heterogeneous Ru-Co-Al-CO3 hydrotalcite catalyst can aerobically oxidize a mixture of

1- and 2-octanol to give the ketone in 82% yield; the primary alcohol is unreactive under these conditions.39 Finally, Navarro has reported a N-heterocyclic carbene Pd-allyl chloride complex for the oxidation of secondary alcohols with chlorobenzene as the

7 terminal oxidant; primary aliphatic alcohols are unreactive with this catalyst, and primary benzylic alcohols are also ineffective substrates for this system.40 Employing Ni instead of Pd with this carbene catalyst and using a higher catalyst loading shows similar reactivity.

1.4 Intramolecular selectivity for alcohol oxidation

The majority of stoichiometric alcohol oxidants show little to no selectivity for primary versus secondary alcohols because of the small magnitude of difference in reaction rates for oxidation of either functional group. For those that do show any selectivity, secondary alcohols are typically favored over primary alcohols.5 For instance, potassium ferrate, or barium or potassium manganate in the presence of copper sulfate and alumina under phase transfer conditions cleanly oxidizes the secondary alcohol group in terminal

1,3-diols without overoxidation of the molecule.41-42 These observations, and others, is the subject of an excellent review by Arterburn, who lists numerous examples of stoichiometric reagents that demonstrate superb intramolecular selectivity.5 Relevant examples include the oxidation of diols with positive halogen reagents, peroxide- mediated molybdate catalysts, dioxiranes, or transfer hydrogenation catalysts to obtain the corresponding hydroxyketone in high yields. One of the most impressive transformations reported in this review is the ability for dimethyldioxirane to selectively oxidize 1,2,3-cyclohexanetriol to the 2,3-dihydroxycyclohexanone product in greater than

90% yield.43

8 There are similarly few examples of transition-metal catalyzed oxidations that show intramolecular selectivity for alcohol oxidation. For instance, Pd(OAc)2 in the presence of triethylamine under certain conditions can show moderate intramolecular selectivity for 6-hydroxy-1-heptanol favoring the ketone product in a 6:1 ratio but overoxidation to the dicarbonyl compound is a significant problem.44 This system can also oxidize primary and secondary allylic alcohols in the presence of primary aliphatic alcohols by taking advantage of the superior binding properties that allylic alcohols offer over saturated aliphatic alcohols.45 More examples of selective transition-metal catalyzed oxidation of diols are supplied in the next section regarding oxidation of vicinal diols.

1.5 The oxidation of vicinal diols to hydroxyketones

Alpha-hydroxy ketones can be prepared by oxidation of the enol ether of the corresponding ketone by peracids,46 α-oxidation of ketones,47 acyloin condensation,48 from epoxides,49 or by the direct oxidation of alkenes.50-52 However, there are few examples of general protocols that can oxidize vicinal diols to the hydroxyketone without overoxidation to the diketone or oxidative cleavage.

As mentioned in Section 1.2, there are several stoichiometric reagents that can effect the oxidation of diols to hydroxyketones. An early example is Fétizon's reagent, which is silver carbonate supported on Celite; this protocol is limited to symmetric diols, however, and despite the mild conditions for oxidation, an excess of silver carbonate is required.53

Pyridinium chlorochromate has been reported to oxidize vicinal diols to hydroxyketones for certain substrates, but oxidative cleavage of the product is commonly observed.54

9 O R R R R

OSiR3 O OH R R R R R R OH OH

O 2 R OR' O R R

Scheme 1.4. Methods for the preparation of α-hydroxyketones.

Positive halogen reagents, such as N-bromosuccinimide, N-bromoacetamide, iodoxybenzoic acid or Dess-Martin periodinane, sodium bromate mediated by sodium bisulfite or cerium ammonium nitrate, tetraethylammonium trichloride, or bromine/aqueous base have all shown selective oxidation of 1,2-diols to the hydroxyketone, but they suffer from concomitant overoxidation, functional group incompatibilites, and/or lack of selectivity.5 An effective protocol for the stoichiometric oxidation of 1,2-diols is reaction of the diol with dibutyltin oxide in hot methanol to form the stannylene acetal and subsequent oxidation with bromine, but one equivalent of each toxic reagent is required.55 An electrocatalytic version of this reaction has been reported where a mixture of dimethyltin chloride (0.1 equiv) and diol substrate in methanol is electrolyzed at an unspecified (but presumably high) potential.56 Finally, dimethyldioxirane is a powerful oxidant for a variety of diols and selectively oxidizes

10 secondary alcohols in the presence of primary alcohols, as is the case for terminal 1,2- diols.43 Beyond this, the oxidation of internal vicinal diols is neither predictable nor well- behaved, and the preceding high selectivity is lost in some of these latter substrates.

More recently, Konwar has demonstrated that a combination of dimethyl sulfoxide, hydrazine, and iodine can selectively oxidize terminal 1,2-diols to hydroxyketones in moderate yields.57

Few catalytic examples are known that efficiently oxidize vicinal diols to the hydroxyketone product. Molybdate- or tungstate-based catalysts with either hydrogen peroxide or tert-butylhydroperoxide as the terminal oxidant are known to effect this oxidation, but cyclic diols are prone to C-C bond cleavage under catalytic conditions.5

Ikariya reports that Cp*Ir(diamine)(Cl) complexes are capable of aerobically and selectively oxidizing 1,2-diols, albeit with lower yields.58 Similarly, Martin reports that

Fe(NO3)2 promoted by FeBr3 can aerobically oxidize 1,2-octanediol to the hydroxyketone product in 74% yield.59 Very recently, Oberhauser and Lee have reported on the ability of

N-heterocyclic carbene Pd complexes to aerobically oxidize 1,2-propanediol and 1,2- butanediol selectively to the hydroxyketone product in moderate yields.60

The electrocatalytic oxidation of aliphatic diols on Pt-based electrodes can, under carefully controlled conditions, produce hydroxyketones, but this method is prone to overoxidation to diketone compounds and oxidative cleavage.61 De Giovani has demonstrated the ability for (dppe)Ru(polypyridyl) complexes to electrocatalytically oxidize 1,2-butanediol to 1-hydroxy-2-butanone at 1.18 V vs. NHE in 62% yield.62

11 2+ Romero has shown that trans-Ru(terpy)(O)2(OH2) can oxidize this same substrate to give the hydroxyketone in 78% yield at 0.8 V; other Ru-polypyridyl complexes were also

63 selective but gave the product in lower yields. Finally, Ishii has shown that Co(acac)3 in the presence of N-hydroxyphthalamide and 3-chlorobenzoic acid can oxidize various diols to the hydroxyketone product; however, oxidation of 1,2-diol substrates leads to oxidative cleavage as the major product in most cases.64

Heterogeneous catalysts can selectively oxidize diols to hydroxyketones. Taylor and

Hutchings has reported on the ability for Au-Pd nanoparticles supported on CeO2 to aerobically oxidize 1,2-butanediol at 160ºC to the hydroxyketone product with a turnover

-1 65 frequency of 2150 h . Hache has reported an Au-Pd catalyst supported on TiO2 to selectively oxidize 1,2-butanediol at 160ºC, with a somewhat lower turnover frequency of

1,520 h-1.66 These two reports are noteworthy because aliphatic alcohols are typically very poor substrates for heterogeneous Au-Pd catalysts.

1,2-diols are challenging substrates for catalytic oxidation of alcohols due to their propensity to form stable chelate complexes with various metals. In the case of Pd- catalyzed alcohol oxidations, similar chelating substrates are ineffective substrates for

44 Pd(OAc)2/triethylamine and N-heterocyclic carbene Pd complexes, and

67-68 Pd(OAc)2/sparteine systems. Indeed, a series of Pd diolate complexes are known that are quite stable,69 and, upon subjection to elevated temperatures, oxidative cleavage takes place instead of oxidation to the hydroxyketone product.70

12 1.6 References

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17 Chapter 2 The selective catalytic oxidation of glycerol to dihydroxyacetone

2.0 Preface

This chapter describes research done by David Pearson and me. D. Pearson made the initial discovery that glycerol could be oxidized to dihydroxyacetone under the catalytic conditions reported. I subsequently did most of the studies outlined in this chapter, including the preparation of all deuterated compounds. D. Pearson did a benzoquinone dependence study and an acetic acid dependence study on the reaction rate.

2.1 Introduction

The advent of biodiesel as an attractive and renewable alternative to dwindling fossil fuel supplies has led to an increased market for its consumption on a global scale. A major consequence from this recent development has been a corresponding acute increase in the supply of glycerol as the major byproduct of this process.1-2 Glycerol is an attractive and versatile feedstock as it is nontoxic, edible, and biodegradable, and it can be used as a building block for value-added chemicals.3-5 The development of novel, selective chemistry that can provide new applications to glycerol-derived products to meet the increased supply of glycerol itself remains a key challenge.5-7

18 The chemoselective, catalytic transformation of glycerol to dihydroxyacetone remains an unsolved problem. Dihydroxyacetone is currently produced on an industrial scale by microbial oxidation of glycerol with Gluconobacter oxydans, with the major limitations to this process being long reaction times and difficulty in removing unreacted glycerol from the desired product.8-9 While there has been considerable effort in investigating the oxidation of glycerol to glyceric acid, very few systems have shown any selectivity towards the formation of dihydroxyacetone.10 Kimura has shown that a bismuth- promoted platinum catalyst supported on carbon at acidic pH leads to an initial selectivity of 80% for dihydroxyacetone but the catalyst is eventually deactivated by glyceric acid that is formed as a byproduct.11 Gallezot reports a 37% yield of DHA at 75% conversion using a similar Bi/Pt catalyst system with significant amounts of overoxidation byproducts, mainly glyceric acid.12 Very recently, Varma has reported obtaining DHA in

13 48% yield at 80% conversion with this Bi/Pt catalyst using 30 psig O2 at 80ºC. Finally,

Crimmina reports an electrochemical method that produces DHA in 65% yield after 20 hours, but longer reaction times led to a concomitant increase in overoxidation products.14

To the best of our knowledge, there are no homogeneous catalytic systems that can promote the selective formation of dihydroxyacetone in satisfactory yields and conversions. Farnetti has recently demonstrated that a (PNP)Ir(cod)(H) complex can dehydrogenate glycerol through a transfer hydrogenation mechanism with benzaldehyde as the hydride acceptor, but yields are low (< 25% yield after 3 h at 100ºC).15-16 In addition, Wolfson has reported on the use of glycerol as a sacrificial hydrogen donor for

19 Ru-catalyzed transfer hydrogenation of ketones and suggests that dihydroxyacetone is formed selectively, but there is no evidence that this is actually observed.17

A variety of palladium complexes are known to be robust catalysts for alcohol oxidation.18-25 We have developed a catalyst inspired from Sheldon's work on aerobic oxidation of alcohols with (neocuproine)Pd(OAc)2 in dmso. While acetate is a competent internal base for deprotonation of the alcohol substrate, we envisioned that a noncoordinating ion would be necessary to provide the requisite open coordination site for β-hydrogen elimination of the Pd alkoxide complex. Consequently, we have reported the use of our cationic dimeric palladium complex [(neocuproine)Pd(OAc)]2(OTf)2 (1) in the aerobic alcohol oxidation of 2-heptanol with high initial rates at ambient temperature.26 More recently, we have demonstrated that 1 is a competent catalyst for the dehydrogenation of methanol to methyl formate at 50ºC.27 Key features of our proposed mechanism for both transformations include a noncoordinating counterion that provides an open coordination site for the binding of alcohols, and an internal base for the requisite deprotonation of the bound alcohol.

2+ 2+

(OTf)2 (OTf)2 N N N N N N Pd Pd Pd AcO AcO OAc H3CCN NCCH3

1 2 3

Scheme 2.1. Catalyst systems.

20 Herein we describe the chemoselective catalytic oxidation of glycerol and 1,2- propanediol with the Pd complex 1 in the presence of either benzoquinone or air as a terminal oxidant. We show that these vicinal polyols exhibit both faster rates and higher chemoselectivities than other primary and secondary alcohols, enabling the rapid chemoselective oxidation of glycerol to dihydroxyacetone under very mild conditions

(RT, 1 atm air).

Scheme 2.2. Selective oxidation of glycerol to dihydroxyacetone.

2.2. Results

The catalytic oxidation of glycerol with 5 mole % Pd (2.5 mol % 1) and 3 equivalents of benzoquinone (BQ) in acetonitrile at RT proceeds with 97% conversion in 24 h with

>96% selectivity to dihydroxyacetone (Table 1). The nature of the solvent has a significant influence on the rate: addition of water to the solvent as a 7/1 CH3CN/H2O

(v/v) mixture results in a significant acceleration in the reaction rate and complete conversion of glycerol in 3 h. When the reaction is conducted in dmso, the oxidation is complete within 15 minutes with complete selectivity for dihydroxyacetone. The selective oxidation of glycerol with 1 can readily be operated on a 10 mmol scale in wet acetonitrile: oxidation of 0.92 g (10 mmol) of glycerol afforded dihydroxyacetone in 92% yield after chromatography, or 58% yield after crystallization of the product as its dimer.

21 Despite high reaction rates and conversions with dmso as a solvent, the dihydroxyacetone product was inseparable from the solvent and thus could not be isolated in pure form.

Table 2.1. Catalytic oxidation of glycerol[a] and 1,2-propanediol with complex 1.

Time Conversion Selectivity Yield Entry Solvent Diol Oxidant [h] [%] [%] [%]

1 CH3CN glycerol BQ 24 97 99 [b] 2 CH3CN/H2O glycerol BQ 3 97 96 3 dmso glycerol BQ 0.25 97 99 4 dmso 1,2-PD BQ 0.3 98 96 5 dmso glycerol air 24 47 80 [c] 6 CH3CN/H2O glycerol BQ 4 97 92 [d] 7 CH3CN/H2O glycerol O2 4 95 69 [e] 8 CH3CN/H2O glycerol air 18 73 [a] standard conditions: 0.1 mmol glycerol, 0.3 mmol BQ, 5 mol % Pd, 0.7 mL solvent, 23 ºC. [b] 7:1 CH3CN:H2O. [c] 10:1 CH3CN:H2O, 10 mmol scale. [d] 10 mol % Pd, 1atm O2, 10:1 CH3CN:H2O, 1 mmol scale [e]10 mol % Pd, sparged with air, 10:1 CH3CN:H2O, 10 mmol scale

Significantly, the selective oxidation of glycerol can also be carried out aerobically. The oxidation of glycerol in wet acetonitrile under a balloon of O2 with 10 mol% Pd (1 mmol scale) affords dihydroxyacetone in 69% isolated yield; on a larger scale (10 mmol glycerol) under a continuous stream of air, dihydroxyacetone can be isolated in 73% isolated yield after chromatography. Monitoring the progress of the reaction by NMR with aliquots of the reaction solution reveals that there is little difference in reaction rate for either case. However, it is considerably more convenient to use O2 because, in large- scale reactions, the rate-limiting mass transfer of air diffusing throughout the solution becomes a significant problem; if the O2 concentration is not high enough in the solution

22 to promote turnover of the Pd catalyst, the latter decomposes to Pd black and precludes further conversion of the alcohol substrate to the desired oxidation product.

Attempts to perform the aerobic oxidation of glycerol at lower catalyst concentrations led to high selectivity for dihydroxyacetone, but low conversions: with 5 mol% Pd under a balloon of air only 47% conversion was observed after 24 hours in CD3CN/D2O.

Competitive oxidative decomposition of the catalyst is a likely cause of the lower conversions and yields: the 1H NMR spectrum of the final reaction mixture exhibited resonances characteristic of the Pd carboxylate 2 that we have previously shown to be inactive for alcohol oxidation. Thus, high conversions of glycerol to dihydroxyacetone can be achieved under aerobic conditions, but only at relatively high Pd concentrations.

The oxidation of glycerol and 1,2-propanediol is faster and more selective than that of

1,3-diols or a mixture of primary/secondary alcohols. Under similar conditions (5 mol%

Pd, 3 equiv. BQ, dmso, 23 °C), oxidation of glycerol is complete within 15 minutes and oxidation of 1,2-propanediol to hydroxyacetone is complete within 20 minutes in dmso

(Table 1). In contrast, oxidation of a 1:1 mixture of 1-heptanol and 2-heptanol was both slower and non-selective, requiring 10 hours to reach 78% conversion and affording a

45:55 ratio of the ketone/aldehyde. Similarly, oxidation of 1,3-butanediol proceeded to only 55% conversion after 4 h, yielding a 2:3 mixture of the ketone and aldehyde products.

23 2.3. Discussion

The high chemoselectivity for the oxidation of the secondary alcohol of glycerol in the presence of two primary alcohols is noteworthy. While many stoichiometric oxidants exhibit a preference for secondary over primary alcohols, few chemoselective catalytic alcohol oxidations are known.

The lower rates and selectivities observed in the inter- and intramolecular competition experiments suggest that vicinal diols exhibit unusual reactivity with 1. The kinetics of

1 1,2-propanediol oxidation with benzoquinone were monitored by H NMR in dmso-d6.

With 1.5 - 3.0 equivalents of benzoquinone (relative to diol), the disappearance of diol conforms to a mixed second-order kinetics analysis (eq. 1):

(1)

where [BQ] and [PG] are the concentrations of benzoquinone and 1,2-propanediol respectively, and t = time in seconds. Plots of kobs vs. [Pd] and the initial rates vs. [BQ] confirm that the rates are first order in both [Pd] and [BQ] for [BQ] ≤ 0.3 M, yielding a rate law (eq. 2)

(2)

-2 -1 where kobs = k'[Pd] and k' = 1.9(3) M s in dmso-d6 at 23ºC.

In the presence of three equivalents of benzoquinone in either acetonitrile-d3 or dmso-d6, a trace amount of lactaldehyde (< 5%) is observed to build up during the course of the reaction, but disappears after approximately 80% conversion. The relative concentration

24 of lactaldehyde appears to inversely correlate with the amount of water present in the reaction, as the highest amount of lactaldehyde (5% of the mass balance) is observed in dry acetonitrile.

While NMR studies indicate that lactaldehyde is formed during the course of the oxidation of 1,2-propanediol, deuterium-labeling studies suggest that generation of a mixture of hydroxyacetone/lactaldehyde and subsequent isomerization of the aldehyde does not contribute significantly to the high selectivity for hydroxyacetone. Catalytic oxidation of 2-d-1,2-propanediol with 1 in dmso-d6 affords unlabeled hydroxyacetone

(<1% d-scrambling) and oxidation of 1-d2-1,2-propanediol yields d2-hydroxyacetone with

96% selectivity at 98% conversion. These experiments suggest that liberation of free lactaldehyde, followed by Pd- or acid-catalyzed tautomerization is not a major contributor to the high selectivity for hydroxyacetone. The second-order rate constants for oxidation of 2-d-1,2-propanediol and that for the undeuteriated diol are within experimental error (kH/kD = 1.0(2)), implicating that β-H elimination is not rate limiting.

However, an inverse isotope effect of kH/kD = 0.7(2) is evident from the ratio of rate constants for 1-d2-1,2-propanediol and 1,2-propanediol (Fig. 2).

O O OH k /k = 1.0(2) H D HO HO HO + < 1% D D

OH O k /k = 0.7(2) HO H D HO D D D D

Scheme 2.3. Oxidation of deuterium-labeled 1,2-propanediols.

25 2.4. Discussion of reaction mechanism.

On the basis of previous work, we propose that isomeric Pd alkoxides are formed by liberation of acetic acid from the cationic Pd acetate derived from dimeric 1. β-H elimination from the alkoxides would generate a Pd hydride that reacts with benzoquinone to generate a cationic Pd hydroquinone complex. Reaction of this hydroquinone complex with the diol regenerates the Pd alkoxides.

1/2 1 O HO N N N N Pd Pd N N O Pd H O H HO OH O OH O HOAc HO HO

N N N N Pd Pd O AcO S O N N (S = solvent) HO Pd N N O Pd N N O HO OH Pd H O H H OH H HO O HO H HO OH HO

Scheme 2.4. Proposed mechanism for the catalytic oxidation of 1,2-propanediol.

To investigate the role of proton-transfer equilibria on the rate, we investigated the kinetics of 1,2-propanediol oxidation with benzoquinone in the presence of 5, 10, and 20 mol% acetic acid (HOAc, relative to diol) and found that the rates are inverse first order in [HOAc] (k' = k"/[HOAc]). This is consistent with the reversible generation of the alkoxide from the reaction of the cationic Pd acetate (Fig. 3). The first-order dependence on benzoquinone implies that reoxidation of Pd0 or the Pd-H is rate-limiting in dmso.

This is unusual for Pd-mediated alcohol oxidation, but consistent with the absence of a primary kinetic isotope effect. The origin of the inverse secondary isotope effect is not clear at present.

We have also conducted one-turnover experiments with stoichiometric Pd and 1,2- propanediol in dmso-d6. In this experiment, we observed 40% conversion with a 4:1 selectivity in favor of hydroxyacetone after 18 hours with the appearance of a Pd mirror

(presumably from the accumulation of (neocuproine)Pd0 after deprotonation of the Pd hydride). Addition of 25 equivalents of carbon tetrachloride in an attempt to trap the Pd-

H species resulted in lower conversion (25%) and the same 4:1 selectivity observed in the previous experiment. We were able to identify the Pd products as a mixture of

(neocuproine)PdCl2 and dmso-solvated chloropalladium species by comparison to authentic samples. A key observation is that, when benzoquinone is added to either reaction mixture, the previously reported high selectivity for hydroxyacetone is restored.

0.5 equiv. Pd dimer OH 25 equiv. CCl4 O OH + 25% conversion OH OH after 18 hours dmso-d6, rt CHO 4 : 1

OH 0.5 equiv. Pd dimer O OH 40% conversion OH OH + after 18 hours dmso-d6, rt CHO + Pd mirror 4 : 1 0.5 equiv. Pd dimer OH 3 equiv. benzoquinone O OH + > 97% conversion OH OH after 20 minutes dmso-d6, rt CHO > 25 : 1

Scheme 2.5. Stoichiometric oxidation of 1,2-propanediol with 1.

The higher selectivities observed for the oxidation of glycerol/1,2-propanediol relative to

1- and 2-heptanol implies that the product-determining steps for the intra- and

27 intermolecular oxidations are different. One possibility is that β-H elimination is not the sole product-determining step; but that both the reversible formation of the Pd alkoxides and β-H elimination contribute to the selectivities. Alternatively, if β-H elimination were reversible, selective displacement of the bound ketone from the Pd-H intermediate could explain the high selectivity for hydroxyketone formation. Further kinetic and mechanistic studies are ongoing to test these hypotheses.

2.5. Conclusion and future directions.

In summary, glycerol is selectively and rapidly oxidized to dihydroxyacetone with the cationic Pd catalyst 1 using benzoquinone or oxygen as the terminal oxidant. Vicinal diols appear to be privileged substrates with this catalyst system, and are oxidized with high rates and selectivities to hydroxyketones. Studies to explore the mechanism and generality of the oxidation of polyols are currently underway.

2.6. Experimental section.

General considerations

The dimeric Pd complex 1 was prepared as previously reported.26 All alcohols were obtained commercially, stored over 3Å molecular sieves, and used without further

purification. CD3CN and dmso-d6 were obtained from Cambridge Isotope Laboratories, distilled from CaH2, and stored over 3Å molecular sieves. Acetonitrile was dried by passage through a pair of alumina columns, and collected and stored under N2.

Benzoquinone was purified by Soxhlet extraction with heptane and subsequent recrystallization, or sublimed three times under vacuum at ambient temperature.

Thin-layer chromatography (TLC) was conducted with Whatman precoated silica gel plates (0.25 mm, PE SIL E/UV) and visualized with potassium permanganate staining.

Flash column chromatography was performed as described by Still et al.28 using Silicycle

SiliaFlash silica gel 60 (40-63 µm mesh).

1H NMR spectra were recorded on a Varian Mercury-400 (400 MHz) or Varian Inova-

500 (500 MHz) spectrometer and are reported in ppm using residual solvent as an internal

reference (CD3CN: 1.93 ppm, dmso-d6: 2.49 ppm). The data is reported as: s = singlet, d

= doublet, t = triplet, q = quartet, p = quintet, m = multiplet; coupling constant(s) in Hz, integration. Proton-decoupled 13C NMR spectra were recorded on a Varian Mercury-400

(100 MHz) or Varian Inova-500 (125 MHz) spectrometer, and are reported in ppm using

residual solvent as an internal reference (dmso-d6: 39.5 ppm).

Reaction optimization

Table 1, entry 1: Glycerol (9 mg, 0.1 mmol), benzoquinone (32 mg, 0.3 mmol), and p- xylene (10.6 mg, 0.1 mmol) were weighed in a tared 1 dram vial and dissolved in 0.7 mL

CD3CN. The yellow solution was transferred to a tared NMR tube containing 2.6 mg 1

(2.5 µmol), the tube shaken, and the reaction monitored by 1H NMR. Dihydroxyacetone was identified by its characteristic 1H NMR resonance at 4.16 ppm.29

Table 1, entry 2: This was carried out exactly as in entry 1, but 0.1 mL D2O and 0.7 mL

CD3CN was used as the solvent.

Table 1, entry 3: This was carried out exactly as in entry 1, but 0.7 mL dmso-d6 was used as the solvent.

Table 1, entry 4: This was carried out exactly as in entry 1, but 7.6 mg 1,2-propanediol

was used as the substrate, and 0.7 mL dmso-d6 was used as the solvent. Hydroxyacetone

1 30 was identified by H NMR (dmso-d6): 2.02 ppm (s, 3 H) and 4.02 ppm (s, 2 H).

Table 1, entry 5: Glycerol (0.92 g, 10 mmol) and benzoquinone (3.24 g, 30 mmol) were

dissolved in a mixture of 60 mL CH3CN and 6 mL H2O. 260 mg 1 (0.25 mmol) was then added to the solution resulting in a reddish-brown solution. The solution was stirred at room temperature until complete consumption of glycerol was evident by TLC. The solution was then poured into 300 mL diethyl ether to precipitate out the catalyst and then filtered through a plug of silica (60 g), eluting with ether and collecting 30 mL fractions until the eluent was colorless. The dihydroxyacetone was then eluted with acetone, and the acetone solution was concentrated. If any dihydroxyacetone coeluted with benzoquinone, it was purified by column chromatography using acetone as the eluent.

The acetone solution was concentrated to yield 0.83 g of dihydroxyacetone as a colorless and extremely hygroscopic oil (92%).

Alternatively, the acetonitrile solution was poured into 300 mL diethyl ether, filtered, and concentrated. The residue was taken up in 30 mL acetonitrile, seeded with 5 mg dihydroxyacetone dimer, and allowed to stand overnight at 5ºC. The white precipitate

30 was filtered, washed with acetonitrile, and dried to yield 410 mg of the dihydroxyacetone dimer, characterized by comparison to an authentic sample. A second crop could be obtained by concentrating the mother liquor and dissolving the residue in a minimal amount of diethyl ether, seeding with 5 mg dihydroxyacetone dimer, and allowing to stand at 5ºC overnight. This results in 110 mg of dihydroxyacetone dimer as a white powder, with an overall net yield of 522 mg (58%). 31

Table 1, entry 6: Glycerol (0.92 g, 10 mmol) was dissolved in a mixture of 60 mL

CH3CN and 6 mL H2O in a 100 mL round-bottom flask fitted with a rubber septum. The solution was saturated with air by sparging with a stream of air through a needle for 20 minutes, then 520 mg 1 (0.5 mmol) was added to the solution, resulting in an orange solution. The reaction was monitored via TLC until complete consumption of glycerol was observed. The solution was directly filtered through a plug of 60 g silica, eluting with acetonitrile, and the acetonitrile solution was concentrated to obtain 663 mg dihydroxyacetone as a colorless oil (73%).

This reaction was also carried out on a 1 mmol scale (92 mg glycerol) as described

above, but with a balloon of O2 as the terminal oxidant. Upon consumption of glycerol by TLC, the solution was filtered through a plug of silica (10 g) eluting with acetonitrile to remove catalyst, and concentrated to obtain 62 mg of dihydroxyacetone (69%).

Qualitative comparison of reaction rates with air or O2: 60.8 mg 1,2-propanediol (0.8

mmol) was dissolved in 5.6 mL 9:1 (v/v) CD3CN/D2O in a 20 mL vial sealed with a

31 rubber septum, and sparged with dioxygen or air (via a balloon attached to a syringe affixed with a 18-gauge needle) for 20 minutes. 41.6 mg catalyst (40 µmol) was then added to the clear solution, and the balloon quickly replaced. 0.5 mL aliquots of the reaction solution were taken over time and monitored by 1H NMR. Using p-xylene as an internal standard was ineffective in this experiment as it appears to slowly be lost to evaporation over time.

0.8

0.7

0.6

0.5

0.4 air

Conversion 0.3 O2 0.2

0.1

0 0 50 100 150 200 250 300 Time (minutes)

Figure 2.1. Comparison of conversion vs. time for 1,2-propanediol oxidation with air or

O2 as the terminal oxidant.

Mechanistic studies

Intermolecular selectivity: oxidation of 1-heptanol and 2-heptanol: 1-heptanol (5.8 mg, 0.05 mmol) and 2-heptanol (5.8 mg, 0.05 mmol), along with benzoquinone (32 mg,

0.3 mmol) and p-xylene (10.6 mg, 0.1 mmol) were dissolved in either dmso-d6 or CD3CN

32 (0.7 mL). This solution was transferred to a tared NMR tube containing 2.6 mg 1 (5

µmol Pd), the tube shaken, and the course of the reaction monitored by 1H NMR.

Integration of the alpha-CH2 protons of both carbonyl compounds (1.49 ppm for heptaldehyde, 1.43 ppm for 2-heptanone) reveals a 55:45 ratio of aldehyde to ketone in

dmso-d6, and a 1:1 ratio for both products in CD3CN after 10 hours.

Intramolecular selectivity: oxidation of 1,3-butanediol: 1,3-butanediol (9 mg, 0.1

mmol) and benzoquinone (32 mg, 0.3 mmol) were dissolved in 0.7 mL CD3CN and the solution transferred to a tared NMR tube containing 2.6 mg 1 (5 µmol Pd). The reaction

1 was monitored by H NMR by integration of the CH3 resonances for the diol (1.10 ppm, d), and the aldehyde (1.16 ppm, d) and ketone products (2.09 ppm, s). After 4 hours, there was 45% conversion, with the product mixture containing 42% 4-hydroxy-2- butanone31 and 58% 3-hydroxybutanal.32

Preparation of 1,1-d2-1,2-propanediol: 700 mg LiAlD4 (16.7 mmol) was dissolved in

30 mL THF at 0ºC. 2 g rac-lactide (13.9 mmol) was dissolved in 10 mL THF and added to the stirring solution over 5 minutes. The colorless solution was stirred at 0ºC for one hour then at 23ºC for one hour longer. The solution was cooled again to 0ºC and quenched by adding 0.7 mL water, 2.1 mL 15% aqueous NaOH, and finally 0.7 mL water, and stirred overnight. The aluminum salts were filtered, washed thoroughly with

THF, and the filtrate concentrated to obtain 2.1 g of a slightly yellow oil that was pure by

1H NMR (97% yield).

33 1 H NMR (500 MHz, dmso-d6): 0.98 (d, 3H, J = 6.5 Hz), 3.53 (q, 1 H, J = 5.5 Hz), 4.39 (d,

13 1 H, J = 4.5 Hz), 4.41 (s, 1H) C NMR (125 MHz, dmso-d6): 20.0, 66.5 (p, J = 21 Hz),

67.1

+ HRMS (m/z): M calc’d for C3H6D2NaO2, 101.0548; found, 101.0547

Preparation of 2-d-1,2-propanediol: 813 mg LiAlD4 (19.4 mmol) was dissolved in 20 mL diethyl ether at 0ºC. 2 g acetoxyacetone (17.2 mmol) was added to the stirring solution dropwise over 5 minutes, and the solution heated to reflux for 4 h. The solution was cooled to 23ºC, diluted with 20 mL diethyl ether, and quenched with 1 mL water, 3 mL 15% aqueous NaOH, and 1 mL water, and the slurry stirred for one hour. The aluminum salts were filtered out, washed thoroughly with THF, and the slightly yellow filtrate concentrated. The residue was purified by column chromatography (60 g silica,

CH3CN eluent, Rf = 0.45) to obtain 740 mg of a colorless oil (56% yield).

1 H NMR (500 MHz, dmso-d6): 0.97 (s, 3 H), 3.13 (dd, 1 H, J = 5.6 Hz, 10.5 Hz), 3.23

(dd, 1 H, J = 5.6 Hz, 10.5 Hz), 4.38 (s, 1 H), 4.46 (t, 1 H, J = 6 Hz) 13C NMR (125 MHz,

dmso-d6): 19.9, 66.7 (t, J = 21 Hz), 67.2

+ HRMS (m/z): M calc’d for C3H7DNaO2, 100.0485; found, 100.0487

Representative kinetic run: A stock solution was made consisting of 43.4 mg 1,2- propanediol (0.57 mmol), 183 mg benzoquinone (1.70 mmol), and 56.1 mg p-xylene (0.5

mmol) dissolved in enough dmso-d6 to make a solution with 4 mL total volume. 0.7 mL

34 of this stock solution was dispensed into a tared NMR tube consisting of 2.6 mg 1 (2.5

µmol) and monitored by NMR.

A 400 MHz Varian Mercury NMR spectrometer was used to record the spectra for every

kinetic run. The longest T1 relaxation time for all reagents in solution is 6.9 seconds for the benzoquinone protons. Each spectrum during a typical kinetic run was recorded 60 seconds apart via a programmed array, with each spectrum consisting of one pulse with a d1 delay of 45 seconds to ensure complete relaxation of all protons. Relevant peaks: 1,2- propanediol (0.93 ppm, d, 3 H, J = 6 Hz); lactaldehyde (1.14 ppm, d, 3 H, J = 7.2 Hz); hydroxyacetone (2.02 ppm, s, 3 H); p-xylene (2.21 ppm, s, 6 H); hydroquinone (6.58 ppm, s, 4 H); benzoquinone (6.80 ppm, s, 4 H). All peak areas were integrated relative to

the CH3 proton for p-xylene.

The kinetics were analyzed by mixed second-order plots that show the consumption of alcohol and benzoquinone as a function of time. The relevant equation for this dependence is described as follows:

where: [BQ]0 and [BQ]t are the concentrations of benzoquinone at time t = 0 and t= t, respectively;

[PG]0 and [PG]t are the concentration of 1,2-propanediol at time t = 0 and t= t, respectively; kobs is the observed rate constant; t is time in seconds

35 Error analysis: Due to the long delay times, error in estimates of integration are assumed to 2%. Standard propagation of error algebra,33 and least-squares analysis was used to obtain estimates of the variance of each variable:

where

σ = error in a specified variable y = the y-axis of the mixed second-order plot = ln(BQ/PG) = ln(BQ) - ln(PG)

PG and BQ refer to the integrations from the NMR spectra.

For the linear fits, a least squares analysis7 was used; y = kt + b

for

Kinetics

Shown in Figure S1 is a representative first-order plot for the consumption of 1,2-

propanediol in dry dmso-d6 as a function of time

36 10234"526/2"'784"&9:);+<=>?%=

!"#"$%$$&'(" &" )*"#"$%+++&&"

-%'" ," +

,%'" !"#$%&'()*&'()

$%'"

$" $" ,$$" -$$" &$$" .$$" '$$" /$$" 0$$" 1$$" +$$" -./"%.0$,"

Figure 2.2. First order kinetic plot for oxidation of 1,2-propanediol

Shown in Figure 2.3 are mixed second-order plots for the consumption of 1,2-

propanediol and benzoquinone as a function of time in dry dmso-d6.

There is a linear dependence of kobs on the concentration of Pd in the reaction solution:

k obs = k'[Pd]

where:

! [Pd] is the concentration of Pd in the reaction solution (assumed to be a monomeric

species)

k' is the rate constant of the reaction independent of [Pd], [BQ], and [PD].

Figure 2.3. Second order kinetic plot for oxidation of 1,2-propanediol.

Shown in Figure 2.4 is a plot of Pd concentration versus kobs (determined through

Equation 1 and the slope of the second order plot in Figure 2.4) is shown below:

!"#$%$&'"()*"+)&+,**-$.*/0)1**

,%,$-"

,%,$/"

,%,$."

!"#"$%&''()" ,%,$(" *+"#",%&-(,$"

,%,$"

,%,,-" 5678"9:;2$"8;2$<" ,%,,/"

,%,,."

,%,,("

," ,%,01,," $%,02,3" (%,02,3" 3%,02,3" .%,02,3" 4%,02,3" /%,02,3" '%,02,3" -%,02,3" &%,02,3" =>?@"9:<"

Figure 2.4: Plot of kobs vs. [Pd].

38 Shown in Figure 2.6 is a plot of initial rate vs. [BQ] concentration, confirming the first order dependence in BQ for 0.2M < [BQ] < 0.4M

!"#$&'($)&*345&67"8.&8-%&/012& $%$$$1" $%$$$0" !"#"$%$$&'(" )*"#"$%+++,-" $%$$$/" $%$$$'" $%$$$," $%$$$." !"#$%&'($)&*+,-.& $%$$$&" $" $" $%&" $%." $%," $%'" $%/" $%0" $%1" /012&

Figure 2.5. Plot of initial rate vs. [BQ].

Oxidation of d-labeled 1,2-propanediols: 7.7 mg of 2-d1-1,2-propanediol or 7.8 mg of

1-d2-1,2-propanediol (0.1 mmol), 32 mg benzoquinone (0.3 mmol), and 8.8 mg p-xylene

(0.08 mmol) was dissolved in dmso-d6 to make a total volume of 0.7 mL. This was then transferred to a tared NMR tube containing 2.6 mg 1 (2.5 µmol), and monitored by 1H

NMR, as above.

In the d1-alcohol experiments, the principal product was hydroxyacetone with peaks at

2.02 ppm (s, CH3) and 4.02 ppm (s, CH2). No incorporation of deuterium at the alpha

1 13 2 carbon could be observed by either H, C or H NMR. In the d2-alcohol experiments, the principal product was 1-d2-hydroxyacetone with a peak at 2.02 ppm (s, CH3). A very small triplet could be observed at the shoulder of the peak at 2.02 ppm, representing the

d1-hydroxyacetone product, but this was < 1% of the mass balance of the reaction.

The kinetic isotope effect for each of the two deuterated alcohols was determined by

directly calculating kH/kD, both obtained through mixed second-order plots. Shown in

-2 -1 -1 Figure S5 are mixed second-order plots for d0(kobs = 1.1(1) x 10 M s ) , d1(kobs = 1.1(1)

-2 -1 -1 -2 -1 -1 x 10 M s ), and d2 (kobs = 1.5(1) x 10 M s ) 1,2-propanediols:

Figure 2.6. Second order plots for d0, d1, and d2 1,2-propanediols

40 Shown in Figure 2.8 is a plot of the mixed second-order rate constant 1/kobs vs. added

[HOAc]:

Figure 2.7. Plot of 1/kobs vs. [HOAc]

41 2.7 References

(1) Tyson, K. S.; Bozell, J.; Wallace, R.; Petersen, E.; Moens, L.; (National

Renewable Energy Laboratory NREL/TP-510-34796, Boulder , Co, June 2004,

available at www1.eere.energy.gov/biomass/pdfs/34796.pdf): 2004.

(2) Gong, C. S.; Du, J. X.; Cao, N. J.; Tsao, G. T. Applied Biochemistry and

Biotechnology 2000, 84-6, 543.

(3) Werpy, T.; Petersen, G.; (US Department of Energy, Oak Ridge, TN, August

2004, available at www.eere.energy.gov/biomass/pdfs/35523.pdf): 2004.

(4) Zhou, C. H. C.; Beltramini, J. N.; Fan, Y. X.; Lu, G. Q. M. Chem. Soc. Rev. 2008,

37, 527.

(5) Behr, A.; Eilting, J.; Irawadi, K.; Leschinski, J.; Lindner, F. Green Chem. 2008,

10, 13.

(6) Christensen, C. H.; Rass-Hansen, J.; Marsden, C. C.; Taarning, E.; Egeblad, K.

Chemsuschem 2008, 1, 283.

(7) Pagliaro, M.; Ciriminna, R.; Kimura, H.; Rossi, M.; Della Pina, C. Eur. J. Lipid

Sci. Tech. 2009, 111, 788.

(8) Hekmat, D.; Bauer, R.; Neff, V. Process Biochemistry 2007, 42, 71.

(9) Mishra, R.; Jain, S. R.; Kumar, A. Biotechnology Advances 2008, 26, 293.

(10) Pagliaro, M.; Ciriminna, R.; Kimura, H.; Rossi, M.; Della Pina, C. Angew. Chem.

Int. Ed. 2007, 46, 4434.

(11) Kimura, H. Applied Catalysis A - General 1993, 105, 147.

(12) Fordham, P.; Garcia, R.; Besson, M.; Gallezot, P. Studies in Surface Science and

Catalysis 1996, 101, 161.

42 (13) Hu, W. B.; Knight, D.; Lowry, B.; Varma, A. Ind Eng Chem Res 2010, 49, 10876.

(14) Ciriminna, R.; Palmisano, G.; Della Pina, C.; Rossi, M.; Pagliaro, M. Tetrahedron

Lett. 2006, 47, 6993.

(15) Farnetti, E.; Kaspar, J.; Crotti, C. Green Chem. 2009, 11, 704.

(16) Crotti, C.; Kaspar, J.; Farnetti, E. Green Chem. 2010, 12, 1295.

(17) Wolfson, A.; Dlugy, C.; Shotland, Y.; Tavor, D. Tetrahedron Lett. 2009, 50,

5951.

(18) Lloyd, W. G. J. Org. Chem. 1967, 32, 2816.

(19) Nishimura, T.; Kakiuchi, N.; Onoue, T.; Ohe, K.; Uemura, S. J. Chem. Soc.

Perkin Trans. 1 2000, 1915.

(20) Stahl, S. S. Angew. Chem. Int. Ed. 2004, 43, 3400.

(21) Stoltz, B. M. Chem. Lett. 2004, 33, 362.

(22) Sigman, M. S.; Jensen, D. R. Acc. Chem. Res. 2006, 39, 221.

(23) Schultz, M. J.; Sigman, M. S. Tetrahedron 2006, 62, 8227.

(24) ten Brink, G. J.; Arends, I. W. C. E.; Sheldon, R. A. Adv. Synth. Catal. 2002, 344,

355.

(25) Arends, I. W. C. E.; ten Brink, G. J.; Sheldon, R. A. J. Mol. Catal. A - Chem.

2006, 251, 246.

(26) Conley, N. R.; Labios, L. A.; Pearson, D. M.; McCrory, C.; Chidsey, C. E. D.;

Waymouth, R. M. Organometallics 2007, 26, 5447.

(27) Pearson, D. M.; Waymouth, R. M. Organometallics 2009, 28, 3896.

(28) Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923.

(29) Kobayashi, Y.; Takahashi, H. Spectrochimica Acta A 1979, 35, 307.

43 (30) Glushonok, G. K.; Glushonok, T. G.; Maslovskaya, L. A.; Shadyro, O. I. Russ. J.

Gen. Chem. 2003, 73, 1027.

(31) Shei, C. T.; Chien, H. L.; Sung, K. Synlett 2008, 1021.

(32) Hintermann, L.; Kribber, T.; Labonne, A.; Paciok, E. Synlett 2009, 2412.

(33) Bevington, P. R.; Robinson, D. K. Data Reduction and Error Analysis for the

Physical Sciences; 2nd ed.; McGraw-Hill: New York, 1992.

44 Chapter 3 The selective catalytic oxidation of diols and polyols to hydroxyketones

3.0 Preface

The experiments conducted in this chapter were performed by Steven M. Banik and me.

S. M. Banik conducted all of the initial screening of the diols discussed in this chapter, and I scaled up all of the diol oxidations. I did all of the other studies reported in this chapter.

3.1 Introduction

The controlled and chemoselective oxidation of polyols to carbonyl compounds remains a fundamental challenge in organic synthesis.1 The problems associated with selective oxidation of alcohol functional groups in polyols include oxidative cleavage of a diol group, overoxidation to polycarbonyl compounds, and/or lack of chemoselectivity for one alcohol group over another. This problem, and the solutions that have been developed to address these problems, has been discussed in detail in Chapter 1 of this thesis.

We have recently disclosed the chemoselective catalytic oxidation of glycerol to dihydroxyacetone in high conversions, selectivities, and yields by a cationic

(neocuproine)Pd(OAc)(OTf) catalyst developed in our laboratory (Chapter 2).2 The chemoselectivity behind this transformation is remarkable in the face of many efforts by

45 other investigators towards the selective oxidation of glycerol to value-added products.3

The aerobic oxidation with a heterogeneous Pt/Bi catalyst leads to the best selectivity reported to date for dihydroxyacetone with 48% yield at 80% conversion.4 Herein, we report the extension of our diol oxidation methodology to other vicinal diols and polyols, with additional mechanistic insight into the nature of our catalyst’s intrinsic chemoselectivity for α-hydroxyketone products.

(OTf) N N 2 Pd AcO 2

Scheme 3.1. The [(neocuproine)Pd(OAc)]2(OTf)2 complex (1).

3.2 The oxidation of activated diols

We began this study by investigating the oxidation of a series of para-substituted-1,2- phenylethanediols, which are readily accessible from the corresponding para-substituted styrene by the Sharpless dihydroxylation protocol. In addition, by observing the oxidation of these substrates, we anticipated the ability to construct a Hammett plot and gain further mechanistic insight into the chemoselective oxidation of 1,2-diols to the corresponding hydroxyketone.

OH O 2.5 mol% 1 AD-mix alpha OH 3 eq. benzoquinone OH t BuOH/H2O, rt CD3CN/D2O, rt Y Y Y Y = CH3O, CH3, Cl, CF3, NO2

Scheme 3.2. Preparation of substituted phenylethane-1,2-diols and their oxidation to the corresponding α-hydroxyacetophenone product.

46 We discovered that the aryl-substituted 1,2-diols exhibit poor chemoselectivity under the catalytic conditions (5 mol% Pd, 3 equivalents benzoquinone, 9:1 acetonitrile:water, RT).

In contrast to glycerol and 1,2-propanediol, we observed overoxidation of the initial 2- hydroxyacetophenone product in all cases to phenylglyoxal (as the hydrate), and, after longer reaction times, to phenylglyoxalic acid. The product distribution for the various substituted phenylethanediols after two hours is shown in Figure 3.1 - no significant amount of phenylglyoxalic acid could be detected at this point.

Table 3.1. The Pd-catalyzed oxidation of para-substituted phenylethane-1,2-diols.a

Substituent Conversion (%) Hydroxyketone (%) Glyoxal (%) methoxy 55 21 33 methyl 71 10 60 chloro 61 8 53 nitrob 40 30 -- a Conditions: 0.1 mmol substrate, 5 µmol (5 mol%) Pd, 0.3 mmol benzoquinone, 0.63 b mL CD3CN/0.07 mL D2O, rt, 2 hours. after 6 hours of reaction time.

As can be discerned from Table 3.1, the reactivities of the four diols screened are similar, with the methoxy- and nitro-substituted diols being somewhat more selective than the other two diols. We attribute this similarity in reactivity of the diols as evidence for our hypothesis that β-hydride elimination of the Pd alkoxides to the carbonyl product is not the turnover-limiting step of the catalytic cycle for diol oxidation (see Chapter 2 for the proposed mechanism for 1,2-diol oxidation by 1). The methoxy and nitro-substituted diols' somewhat lower reactivities under the catalytic conditions is possibly due to binding of the substituent to the Pd center, inhibiting the reaction's progress. Due to the lower conversion for these two diols, it is plausible that the selectivities for the hydroxyketone product is higher due to a corresponding lower reactivity for the

47 hydroxyketone product for overoxidation. Sheldon has shown that, despite obtaining an excellent linear free energy relationship with (neocuproine)Pd(OAc)2-catalyzed aerobic oxidation of a range of substituted benzyl alcohols (ρ = -0.58), p-methoxybenzyl alcohol is significantly less reactive than predicted from this correlation.5 The dramatic lack of reactivity for the nitro-substituted diol relative to the other diols is unclear at present.

We also investigated the oxidation of 3-butene-1,2-diol under the prescribed conditions, and discovered that it gave a complex mixture of products, none of which could be readily identified. We attribute this mixture to several possible side reactions: overoxidation of the substrate, Wacker-type oxidation of the olefin, and possible allylic rearrangement. Thus, we conclude that diols with an activated C-H bond (allylic, benzylic) are poor substrates for our catalyst and prone to overoxidation.

3.3. The oxidation of aliphatic, unactivated diols.

We wish to report in this section the comparable effectiveness of this catalyst system for other vicinal diols. Oxidation of the 1,2-diol with 5 mol% Pd (2.5 mol% dimer) and 3 equivalents of benzoquinone in 9:1 (v/v) CD3CN/D2O at room temperature afforded the hydroxyketone as the major product with little to no overoxidation to the dicarbonyl compound. Table 3.2 shows the results of the NMR-scale oxidations conducted for a variety of substrates after 2 hours.

48 Table 3.2. NMR-scale screening of the oxidation for a variety of alcohols, diols, and a polyols with 1 and benzoquinone in CD3CN/D2O at room temperature .

Entry Substrate Conversion (%) NMR yield(%) Major product

OH O 1 95 95 OH OH

2 94 59

OH O 3 OH 62 62 OH HO HO OH O OH >99 OH 4 HO 72 HO (in dmso-d6) OH OH

5 57 38

OH O 6 87 76 O O

7 0 0 -

OH O 8 OH 55 55 OH

O 9 94 94 OH a 0.1 mmol substrate, 2.5 µmol 1 (5 mol% Pd), 0.3 mmol benzoquinone, 0.7 mL 9:1 (v/v) CD3CN/D2O, RT, 2 hours. Note: all of these substrates were screened by Steven M. Banik.

As previously reported,2 1,2-propanediol is oxidized under the catalytic conditions to hydroxyacetone in two hours with 95% conversion and 95% yield (entry 1). Replacing the methyl group with a more sterically demanding group (entry 2) does not affect the conversion, but the selectivity is lower; the NMR spectrum of the final product mixture

49 shows two products, the second of which cannot clearly be identified. 1,2,4-butanetriol and meso-erythritol (1,2,3,4-butanetetraol) were efficiently oxidized to the hydroxyketone product shown with minimal amounts of overoxidation products (entries 3 and 4, respectively). However, the oxidation of 1,3,5-pentanetriol (entry 5) was significantly slower and less selective than 1,2,4-butanetriol, suggesting that the chemoselective oxidation characteristic of this system is unique to 1,2-diols.

We hypothesized that the selectivity for 1,2-diol oxidation that comes with our catalytic system was partly due to the ability for the diol to chelate efficiently to Pd and effect conversion to the hydroxyketone. To test this hypothesis, we subjected 1-methoxy-2- propanol (entry 6) to our catalytic conditions and discovered that reaction rates and conversions were similar to the 1,2-propanediol case. However, the dimethylamino- substituted analog (entry 7) appears to bind irreversibly to Pd; a dark red solid immediately precipitated out of solution when the substrate was added.

We also tested cyclic 1,2-diols and discovered that these diols were equally effective substrates for oxidation. cis-Cyclopentane-1,2-diol and trans-cyclohexane-1,2-diol produce the corresponding racemic hydroxyketone product with similar selectivities, despite the former being somewhat less reactive than the latter. However, the geometry of substituted cyclohexane-1,2-diols has a significant effect on reactivity and selectivity

(vide infra). We attribute the equal selectivity observed for either geometry in the case of the unsubstituted diols to rapid interconversion between both possible conformers such that a favorable geometry for chelation to Pd is readily accessible. In contrast, when 1,2-

50 butanediol was subjected to the catalytic conditions, we observed an approximately 1:1 mixture of 3-hydroxy-2-butanone and 2,3-butanedione products. This suggests that cyclic internal 1,2-diols are superior to acyclic substrates; the reasons for this are unclear at present.

To evaluate the synthetic potential of this chemoselective oxidation, the oxidations were carried out on a preparative scale. We chose six substrates to be subjected to the reaction conditions (Table 3.3), and in preliminary scale-up attempts (2 mmol scale), we found it difficult to separate the hydroxyketone product from the large excess of benzoquinone.

We have previously reported that glycerol can be aerobically oxidized to dihydroxyacetone but at lower conversions and higher catalyst loading due to known catalyst decomposition.2 Despite this liability, the diols we chose were selectively oxidized to the hydroxyketone products in three hours, and were readily isolated in pure form by filtering out the catalyst through a silica plug (Figure 3.3) followed by chromatography if necessary. The yields for the polyols did not improve when subjected to longer reaction times. A remarkable observation is that, while the aerobic oxidation of acyclic vicinal diols typically stops at ~80% conversion, the cyclohexane-1,2-diols screened were significantly more reactive with nearly quantitative conversion to the hydroxyketone product in less than 2 hours.

51 Table 3.3. The oxidation of six polyols to hydroxyketones on a 2 mmol scale.a

Entry Substrate Product Isolated yield (%) OH O 1 76 OH OH OH O 2 75 O O OH O 3 OH OH 71 HO HO OH O OH OH 4 HO HO 65 OH OH OH O 5 OH OH 95

OH O 6 OH OH 94 a Conditions: 2 mmol diol, 0.1 mmol 1 (10 mol% Pd), 1 atm O2 balloon, 9 mL CH3CN/1 mL H2O, rt, 3 hours

3.4 Stereoelectronic effects on cyclohexane-1,2-diol oxidation

We conducted two additional studies to probe the reactivity of cyclic diols to the hydroxyketone product. First, we prepared conformationally restricted cyclohexane-1,2- diols to probe whether there was a significant effect of diol geometry on reactivity under catalytic conditions. Second, we conducted preliminary screenings of unsymmetrical 3- methyl-1,2-cyclohexanediol compounds to determine whether the oxidation of these substrates would be regioselective for one hydroxyketone over another.

52 We prepared three of the four possible geometric isomers for 4-tert-butylcyclohexane-

1,2-diol from 4-tert-butylcyclohexene (Scheme 3.2). The conformationally locked trans diaxial cyclohexanediol was accessible through regioselective ring-opening of the cyclohexene oxide formed from performic acid followed by alkaline hydrolysis of the formate ester products. Osmium-catalyzed dihydroxylation of 4-tert-butylcyclohexene gave both cis diastereomers in a 1:1 ratio that was inseparable by chromatography despite a previous report outlining their successful separation via their benzoate diesters.6

OH H2O2, HCO2H, 45ºC tBu OH then KOH/H2O OH 1. MsCl, Et3N

2. collidine, !

AD-mix alpha OH t Bu OH + tBu t OH BuOH/H2O, rt OH

Scheme 3.3. Preparation of 4-tert-butylcyclohexane-1,2-diols.

Subjection of the diaxial cyclohexanediol to our catalytic conditions with benzoquinone as the terminal oxidant resulted in very little reaction even after extended reaction times

(< 20% conversion over 2 days). This suggests that chelation of the diol to Pd that takes place via an accessible diol geometry is necessary for efficient oxidation to take place.

Since the cis-diols could unfortunately not be isolated in pure form, they were carried forward as a 1:1 mixture. Subjection of the mixture to the same catalytic conditions resulted in a complex mixture of products that could not be readily identified.

53 Two of the four possible unsymmetric 3-methyl-1,2-cyclohexanediol diastereomers were prepared by sodium borohydride reduction of the corresponding diketone in cold ethanol

(Scheme 3.3).

O O NaBH4 Me + Me HO OH OH EtOH/H2O OH

2.5 mol% 1 2.5 mol% 1 3 eq. benzoquinone 3 eq. benzoquinone CD3CN/D2O, rt CD3CN/D2O, rt

Me Me Me + HO O OH O OH O

Scheme 3.4. Preparation and reactivity of 3-methyl-1,2-cyclohexanediols

Each diastereomer was readily separable from the other by chromatography and was subjected to the catalytic conditions using benzoquinone as the terminal oxidant. The cis-diol was oxidized with good chemoselectivity, with the 2-hydroxy-6- methylcyclohexanone product predominating over the other possible regioisomer. The oxidation of the trans-diol was unfortunately not regioselective, with both ketone products being present in an ~1:1 mixture. It appears that the regiochemistry of these two oxidations is also sensitive to the ability of the diols to chelate to the Pd center; in the latter case, the axial alcohol is preferentially oxidized over the equatorial alcohol, reminiscent of other alcohol oxidation systems.7-8

The propensity for only specific cyclohexanediols to undergo chemoselective oxidation to the hydroxyketone deserves comment. The current hypothesis is that an accessible

54 chelating geometry for the diols is required for the reaction to proceed with this catalytic system (Scheme 3.5); for the diaxial isomer, no chelation is possible without forcing the diol to assume an extremely unfavorable conformer with an axial tert-butyl group. In contrast, for the cis-diastereomer shown, chelation is possible and the reaction proceeds normally to afford what is likely the product shown in the Scheme.

N N Pd NCCH O OH - AcOH O 3 t tBu + tBu // Bu N N + AcOH OH Pd OH OH AcO NCCH3

N N O OH - AcOH Pd tBu OH O OH tBu + + AcOH OH N N Pd AcO NCCH3 tBu

Scheme 3.5. The oxidation of 4-tert-butylcyclohexane-1,2-diols by 1.

The oxidation of the 3-methyl-1,2-cyclohexanediols, shown in Scheme 3.6, follows a similar hypothesis; the trans-diol can chelate to Pd, but the β-hydrogen for either alkoxide are roughly equally accessible, leading to the observed lack of selectivity for either hydroxyketone product. In contrast, the β-hydrogen for the axial alcohol in the cis- diol case is significantly more accessible than that for the equatorial alcohol group, leading to the observed regiochemistry.

55 N N O OH - AcOH Pd Me Me O H OH + + AcOH OH OH N N Pd Me H AcO NCCH3

Me O N N - AcOH Pd OH Me O + OH + + AcOH HO OH N N H Pd H Me AcO NCCH OH 3 Me O

Scheme 3.6. The oxidation of 3-methyl-1,2-cyclohexanediols by 1.

3.5. Conclusions and future directions.

We have successfully demonstrated the ability of our catalyst system to oxidize a variety of alcohols, diols, and polyols selectively to the hydroxyketone product. The aerobic oxidation of polyols is an attractive catalytic transformation, but further studies need to be conducted to improve conversions and yields with this system. Employing a more oxidatively-resistant ligand for this catalyst system that affords the same or better chemoselectivity for the hydroxyketone product would be an advance in this direction.

We have also conducted preliminary mechanistic investigations to determine how stereoelectronic effects affect the competency of the catalyst system for diol oxidation.

More mechanistic studies need to be conducted to better understand the origin of our catalyst system's ubiquitous reactivity with vicinal diols.

56 Being able to oxidize biomass-derived polyols, such as carbohydrates, selectively to a single ketone product would be an impressive and very desirable achievement with this catalyst system. Finally, developing a chiral catalyst system for the stereospecific oxidation of chiral or prochiral diols to optically pure ketones is a desirable goal in our laboratory. Investigations in both directions are currently underway in our laboratory.

3.6. Experimental section

9 The preparation of [(neocuproine)Pd(OAc)]2(OTf)2 has previously been described. All alcohol substrates and solvents were obtained commercially and used without further

purification. CD3CN and dmso-d6 were obtained from Cambridge Isotope Laboratories and used without further purification.

Thin-layer chromatography (TLC) was conducted with Whatman precoated silica gel plates (0.25 mm, PE SIL E/UV) and visualized with potassium permanganate staining except in the case of methoxyacetone, where a 2,4-dinitrophenylhydrazine stain was used. Flash column chromatography was performed as described by Still et al.24 using

Silicycle SiliaFlash silica gel 60 (40-63 µm mesh).

1H NMR spectra were recorded on a Varian Mercury-400 (400 MHz) or Varian Inova-

500 (500 MHz) spectrometer and are reported in ppm using residual solvent as an internal

reference (CD3CN: 1.93 ppm, dmso-d6: 2.49 ppm). The data is reported as: s = singlet, d

= doublet, t = triplet, q = quartet, p = quintet, m = multiplet; coupling constant(s) in Hz, integration. Proton-decoupled 13C NMR spectra were recorded on a Varian Mercury-400

57 (100 MHz) or Varian Inova-500 (125 MHz) spectrometer, and are reported in ppm using

residual solvent as an internal reference (dmso-d6: 39.5 ppm).

Para-substituted phenylethane-1,2-diols: These diols were prepared on a 1 mmol scale from the corresponding styrene by the Sharpless dihydroxylation protocol with AD-mix

25 α, as described in the literature. The NMR spectra of each diol prepared was identical to that previously reported in the literature.10-12

Representative procedure [for 1-(4-methoxyphenyl)ethane-1,2-diol]:

1.4 g AD-mix α (1 mmol) was added to 5 mL tert-butyl alcohol and 5 mL water and stirred until completely dissolved. 4-methoxystyrene (134 mg, 1 mmol) was then added to the biphasic yellow solution, and the solution stirred vigorously for 18 hours. Solid sodium sulfite (1.5 g, 12 mmol) was added to the now heterogeneous solution and the reaction stirred for 1 hour longer. The product was extracted from the now gray solution with 4 x 5 mL EtOAc, and the extracts dried over MgSO4, filtered, and evaporated. The residue was purified by chromatography (5 g SiO2, EtOAc) to yield a white solid (159 mg, 95% yield) that was pure by 1H and 13C NMR; the spectra were consistent with that reported in the literature.10

1-(4-methylphenyl)ethane-1,2-diol: 118 mg of 4-methylstyrene yielded 149 mg diol as a white solid (98%). Spectra were consistent with that reported in the literature.11

58 1-(4-chlorophenyl)ethane-1,2-diol: 139 mg of 4-chlorostyrene yielded 145 mg diol as a white solid (84%). Spectra were consistent with that reported in the literature.11

1-(4-nitrophenyl)ethane-1,2-diol: 149 mg of 4-nitrostyrene yielded 175 mg diol as a white solid (96%). Spectra were consistent with that reported in the literature.12

Oxidation of 4'-substituted phenylethane-1,2-diols: 0.1 mmol of the diol, 32 mg (0.3 mmol) benzoquinone, and 10.6 mg p-xylene (0.1 mmol, internal standard) were dissolved in 0.63 mL CD3CN and 0.7 mL D2O. This solution was transferred to a tared NMR tube containing 2.6 mg (5 µmol Pd) [(neocuproine)Pd(OAc)]2(OTf)2, the NMR tube capped and shaken, and the reaction monitored by 1H NMR. The 3 ppm to 6 ppm window was examined for the presence of the following compounds: diol (~3.8 ppm, 2 H), hydroxyketone (~4.8 ppm, 2 H), and phenylglyoxal hydrate (~5.9 ppm, 1 H); these peaks were integrated against the methyl peak of p-xylene (2.2 ppm). These chemical shifts are based on spectra obtained of authentic samples for the corresponding unsubstituted compounds; the products arising from oxidation of these four substituted diols are not known in the literature. Over time, the mass balance based on these three peaks decreases but that of the aromatic region remains roughly constant - this is presumably because of the formation of the phenylgloyxalic acid product, which only has NMR peaks in the aromatic region.

59 NMR screening of the oxidation of diols in Figure 3.2

A representative procedure is outlined for the oxidation of 1,2-propanediol. 1,2-

Propanediol (7.6 mg, 0.1 mmol) is carefully weighed into a vial containing p-xylene

(15.2 mg, 0.143 mmol). To this vial is added 0.7 mL of 9:1 v/v CD3CN:D2O. The mixture is transferred to an NMR tube and an initial reference 1H NMR is taken. Into a vial is weighed 2.6 mg [(neocuproine)Pd(OAc)]2(OTf)2 (2.5 µmol, 5 mol% Pd) and 32.4 mg benzoquinone (0.3 mmol). The NMR tube mixture is carefully transferred by pipette to this vial, and the resulting brown mixture is then transferred back to the NMR tube. A

1H NMR is taken after 2 hours to determine product conversion and product yield. Yield is determined by comparison to the p-xylene internal standard concentration. All products had spectra consistent with that reported in the literature.

In the case of meso-erythritol (1,2,3,4-butanetetraol), the substrate was not soluble in 9:1

(v/v) CD3CN/D2O, so 0.7 mL dmso-d6 was used in place of CD3CN/D2O.

Representative procedure for the aerobic oxidation of diols and polyols on a 2 mmol scale.

232 mg (2 mmol) cis-cyclohexanediol was dissolved in 9 mL CH3CN and 1 mL H2O.

The vial was sealed with a rubber septum, and the solution was placed under an O2-filled balloon (prepared by affixing an O2-filled balloon onto one end of a disposable plastic syringe, then affixing a 20-gauge needle on the other end, followed by piercing the septum with the needle). The solution was bubbled with O2 for 20 minutes, then 104 mg

(0.2 mmol) [(neocuproine)Pd(OAc)]2(OTf)2 was added to the reaction solution, and the

60 septum quickly replaced. The reaction was monitored by TLC (EtOAc, KMnO4 stain) for disappearance of alcohol (Rf = 0.48) and emergence of hydroxyketone (Rf = 0.73).

After the reaction is complete, the solution is evaporated to near-dryness with rotary evaporation (bath temperature 50ºC), resulting in a viscous opaque brown oil. 10 mL ethyl acetate is then added to this residue and this residue is triturated for 1 hour with vigorous stirring. The now yellow supernatant is then filtered through a plug of silica gel

(5 g) and the product eluted with ethyl acetate. The 10 mL fractions containing product were combined and evaporated to yield 215 mg of an pale yellow oil that gradually solidified into a white solid (95%). Spectra of the hydroxyketone product were consistent with that in the literature.17

1-hydroxy-2-butanone

180 mg of 1,2-butanediol, when subjected to the procedure outlined above, yielded a 4:1 mixture of the ketone and diol by 1H NMR. This was further purified by chromatography

(5 g SiO2, 2:1 hexanes:EtOAc to 1:1 hexanes:EtOAc) to obtain 134 mg of the hydroxyketone product as a colorless oil (76%). Spectra of this compound were consistent with that in the literature.13

1-methoxy-2-propanone (methoxyacetone)

180 mg 1-methoxy-2-propanol was subjected to the representative procedure outlined above to obtain 130 mg of the ketone isolated as a colorless oil (74%). Spectra of this compound were consistent with that in the literature.14

61 1,4-dihydroxy-2-butanone

212 mg 1,2,4-butanetriol was subjected to the representative procedure outlined above to obtain 146 mg isolated as a colorless oil (71%). Spectra of this compound were consistent with that in the literature.15

1,3,4-trihydroxy-2-butanone (erythrulose)

244 mg meso-erythritol was subjected to the representative procedure outlined above, with the following modifications: 9 mL CH3CN and 2 mL H2O were used as the reaction solvent, and the hydroxyketone product was extracted from the product mixture with 3 x

10 mL EtOAc. 156 mg erythrulose was isolated as a colorless oil (65%). Spectra of this compound were consistent with that in the literature.15

2-hydroxycyclohexanone

232 mg cis-1,2-cyclohexanediol yielded 215 mg (95%) of the hydroxyketone as a white solid. Oxidation of 232 mg trans-1,2-cyclohexanediol yields 211 mg (94%) as a white

17 solid. Spectra of the hydroxyketone product were consistent with that in the literature.

Preparation of 4-tert-butylcyclohexene: This preparation was based on the procedure by Sicher and coworkers;18 however, they did not specify reagent quantities or solvent volumes, so the procedure is outlined below. Sicher's method for preparing the mesylate intermediate was also much lower-yielding, so it was prepared by a different and more convenient method.19

62 4-tert-butylcyclohexanol mesylate: 1.56 g 4-tert-butylcyclohexanol (2.3:1 cis/trans mixture) was dissolved in 50 mL dichloromethane and cooled to 0ºC. Triethylamine (2.1 mL, 15 mmol) was added in one portion followed by dropwise addition of methanesulfonyl chloride (0.85 mL, 11 mmol) via an additional funnel. The solution was stirred at 0ºC for one hour; a white precipitate came out of solution. The solution was quenched by slow addition of 1 mL water, and then 30 mL water was added to the solution; the biphasic mixture was transferred to a separatory funnel where the aqueous layer was separated and discarded. The dichloromethane layer was washed with 1 x 30 mL 10% aqueous HCl, 1 x 30 mL water, and 1 x 30 mL saturated aqueous sodium bicarbonate. The organic layer was dried over magnesium sulfate, filtered, and the solvent evaporated to obtain 2.31 g of a slightly yellow oil that solidified into a white, crystalline solid (99%) that was used without further purification. Spectra of this

20 compound were consistent with that found in the literature.

4-tert-butylcyclohexene

4-tert-butylcyclohexanol mesylate (3.0 g, 12.8 mmol) was dissolved in 15 mL collidine and refluxed for 2 hours (150ºC bath temperature, exothermic reaction!). The solution turned orange-brown and a brown oil separated out. After cooling to room temperature, the solution was poured into 25 mL 6 M aqueous HCl and stirred until the exothermic reaction subsided. 20 mL pentane was added to the cool soution and the solution transferred to a separatory funnel (the flask was washed with an additional 20 mL pentane and added to the funnel). The pentane layer was separated and the aqueous solution was extracted with 3 x 40 mL pentane. The pentane extracts were washed with 1

63 x 40 mL 10% aqueous HCl, 1 x 40 mL water, and 1 x 40 mL saturated aqueous sodium bicarbonate. The pentane extracts were dried with magnesium sulfate, filtered, and the solvent evaporated. 1.6 g of a clear, colorless oil was obtained (91%), which was combined with two other runs and distilled under house vacuum (b.p. 80ºC / ~ 40 mm

Hg). Spectra of this compound were consistent with that reported in the literature.20

Preparation of 3-cis-4-trans-1-tert-butylcyclohexanediol (diaxial diol):

30% aqueous hydrogen peroxide (0.42 mL, 3.7 mmol) and 2 mL 95% aqueous formic acid were combined in a 20 mL scintillation vial, and immersed in an ambient temperature water bath. Under vigorous stirring, 415 mg 4-tert-butylcyclohexene (3 mmol) was added to the solution in ten 50 µL portions over 30 minutes, a new portion being added once most of the previous portion had come into solution. After addition was complete, the solution was heated to 45ºC for 1 hour with stirring, then allowed to stir at room temperature overnight. 1 mL of concentrated aqueous NaOH (4 g in 7.5 mL water) was then added to the reaction solution (exothermic). The aqueous solution was heated to 45ºC, and 2 mL ethyl acetate was added to the warm solution. After stirring vigorously to mix the layers, the ethyl acetate layer was drawn off with a pipet. This was repeated six more times, each with 2 mL ethyl acetate. The extracts were dried (sodium sulfate), filtered, and evaporated to yield a clear oil that was chromatographed on silica gel (30 g, 10:1 hexanes:EtOAc) to yield 316 mg of a colorless oil that solidified on standing (61% yield). Rf = 0.3 (10:1 hexanes:EtOAc). Spectra were consistent with that reported in the literature.21

64 Preparation of a mixture of 3-cis-4-cis-1-tert-butylcyclohexanediol and 3-trans-4- trans-1-tert-butylcyclohexanediol:

4.2 g AD-mix α (3 mmol) and 285 mg methanesulfonamide (3 mmol) was added to 15 mL tert-butyl alcohol and 15 mL water, and stirred until completely dissolved. 4-tert- butylcyclohexene (415 mg, 3 mmol) was then added to the biphasic yellow solution, and the solution stirred vigorously for 18 hours. Solid sodium sulfite (4.5 g, 48 mmol) was added to the now heterogeneous solution and the reaction stirred for 1 hour longer. The product was extracted from the now gray solution with 4 x 15 mL EtOAc. The extracts were washed with 3 x 10 mL 1 M aqueous NaOH to remove the sulfonamide, and the organic extracts dried over MgSO4, filtered, and evaporated. The cinchona ligand was removed by chromatography (20 g SiO2, EtOAc) to yield a white solid (400 mg, 77% yield) containing a mixture of both diols that were inseparable by chromatography.

The diastereomers (400 mg, 2.3 mmol) were converted to their benzoate diesters with

980 mg benzoyl chloride (6.96 mmol) and 10 mg 4-(dimethylamino)pyridine in 8 mL pyridine. After stirring overnight at room temperature, 10 mL 6 M aqueous HCl was added, and, after the exotherm subsided, 10 mL dichloromethane was added and the contents poured into a separatory funnel. The aqueous solution was extracted with 3 x 10 mL dichloromethane, and the extracts washed with 1 x 20 mL 10% aqueous HCl, 1 x 20 mL water, and 1 x 20 mL saturated aqueous bicarbonate. The extracts were dried

(magnesium sulfate), filtered, and the solvent evaporated to yield a white solid that was chromatographed on silica (30 g, 20:1 hexanes:EtOAc). The diester so obtained (489 mg,

65 56%) also could not be separated by chromatography; 1H NMR shows a roughly 1:1 mixture of both diastereomers.

Preparation of 1-cis-2-cis-3-methylcyclohexanediol and 1-cis-2-trans-3- methylcyclohexanediol.

This preparation was based on a textbook preparation for sodium borohydride reduction of alcohols.23

1 g 3-methyl-1,2-cyclohexanedione (7.9 mmol) was dissolved in 10 mL methanol at 0ºC, and a solution of 400 mg sodium borohydride (10.5 mmol) in 2 mL 2 M aqueous NaOH, also cooled to 0ºC, was added in 200 µL portions to the solution. After addition was complete, the solution was warmed to room temperature, and vigorously stirred overnight at that temperature. After the reaction was complete, 5 mL water was added to the viscous solution and the product extracted with 3 x 5 mL ethyl acetate. The extracts were washed with 1 x 5 mL brine, dried over magnesium sulfate, filtered, and the solvent evaporated. The two diol products were purified by column chromatography (50 g SiO2,

3:1 hexanes:ethyl acetate -> 1:1 hexanes:ethyl acetate) to obtain the diol products as colorless oils. The cis,cis isomer was the less polar isomer (Rf = 0.4, 1:1 hexanes:ethyl acetate), while the cis,trans isomer was more polar (Rf = 0.25, 1:1 hexanes:ethyl acetate).

Spectra were consistent with that reported in the literature.22

66 Oxidation of cyclohexanediol substrates: representative procedure cis, cis-3-methyl-1,2-cyclohexanediol (13 mg, 0.1 mmol) was carefully weighed into a vial, and 15.2 mg p-xylene (0.143 mmol) and 32.4 mg benzoquinone (0.3 mmol) were added. These compounds were dissolved in 0.7 mL of 9:1 v/v CD3CN:D2O. This solution was then transferred to a tared NMR tube containing 2.6 mg

[(neocuproine)Pd(OAc)]2(OTf)2 (2.5 µmol, 5 mol% Pd). The reaction was monitored by

1H NMR after 3 hours to determine product conversion and product yield.

The hydroxyketone products (1-hydroxy-3-methyl-2-cyclohexanone, A, and 2-hydroxy-

3-methyl-1-cyclohexanone, B) are not known in the literature, and no definitive assignments could be made for either product. When the trans-diol substrate was subjected to the procedure above, two products emerged in a roughly 1:1 ratio (based on the peak corresponding to the methyl group for each compound). In contrast, when the cis-diol substrate was oxidized, one product was strongly favored in a ~10:1 ratio, the major product being tentatively assigned as A based on the relative chemical shift of the methyl peaks for the two hydroxyketone products.

An NMR of the two reactions can be found in the Appendix. Page 91 contains the 1H

NMR spectrum from oxidation of the trans-diol to give a mixture of both A and B. Page

92 contains the 1H NMR spectrum from oxidation of the cis-diol to give predominantly one product, tentatively assigned as A.

67 3.7 References

(1) Arterburn, J. B. Tetrahedron 2001, 57, 9765.

(2) Painter, R. M., Pearson, D. M., Waymouth, R. M. Angew. Chem. Int. Ed. 2010, in

press.

(3) Pagliaro, M.; Ciriminna, R.; Kimura, H.; Rossi, M.; Della Pina, C. Angew. Chem.

Int. Ed. 2007, 46, 4434.

(4) Hu, W. B.; Knight, D.; Lowry, B.; Varma, A. Ind Eng Chem Res 2010, 49, 10876.

(5) ten Brink, G. J.; Arends, I. W. C. E.; Hoogenraad, M.; Verspui, G.; Sheldon, R. A.

Adv. Synth. Catal. 2003, 345, 497.

(6) Maki, T.; Iikawa, S.; Mogami, G.; Harasawa, H.; Matsumura, Y.; Onomura, O.

Chem. Eur. J. 2009, 15, 5364.

(7) Schreiber, J.; Eschenmoser, A. Helv. Chim. Acta. 1955, 38, 1529.

(8) Trost, B. M.; Masuyama, Y. Tetrahedron Lett. 1984, 25, 173.

(9) Conley, N. R.; Labios, L. A.; Pearson, D. M.; McCrory, C.; Chidsey, C. E. D.;

Waymouth, R. M. Organometallics 2007, 26, 5447.

(10) Junttila, M. H.; Hormi, O. E. O. J. Org. Chem. 2007, 72, 2956.

(11) Griffith, J. C.; Jones, K. M.; Picon, S.; Rawling, M. J.; Kariuki, B. M.; Campbell,

M.; Tomkinson, N. C. O. J. Am. Chem. Soc. 2010, 132, 14409.

(12) Kim, J.; De Castro, K. A.; Lim, M.; Rhee, H. Tetrahedron 2010, 66, 3995.

(13) Matsumoto, T.; Ohishi, M.; Inoue, S. J. Org. Chem. 1985, 50, 603.

(14) Wang, X. L.; Liu, R. H.; Jin, Y.; Liang, X. M. Chem. Eur. J. 2008, 14, 2679.

(15) Kaptein, B.; Barf, G.; Kellogg, R. M.; Vanbolhuis, F. J. Org. Chem. 1990, 55,

1890.

68 (16) Simonov, A. N.; Matvienko, L. G.; Pestunova, O. P.; Parmon, V. N.;

Komandrova, N. A.; Denisenko, V. A.; Vas'kovskii, V. E. Kinetics and Catalysis

2007, 48, 550.

(17) Zhang, W.; Shi, M. Chem. Commun. 2006, 1218.

(18) Sicher, J.; Sipos, F.; Tichy, M. Collect. Czech. Chem. Commun. 1961, 26, 847.

(19) Crosslan.Rk; Servis, K. L. J. Org. Chem. 1970, 35, 3195.

(20) Aciro, C.; Claridge, T. D. W.; Davies, S. G.; Roberts, P. M.; Russell, A. J.;

Thomson, J. E. Org. Biomol. Chem. 2008, 6, 3751.

(21) Trainor, R. W.; Deacon, G. B.; Jackson, W. R.; Giunta, N. Aust. J. Chem. 1992,

45, 1265.

(22) Ziffer, H.; Seeman, J. I.; Highet, R. J.; Sokoloski J. Org. Chem. 1974, 39, 3698.

(23) Vogel, A. I.; Furniss, B. S. Vogel's Textbook of Practical Organic Chemistry, 5th

ed. Longman Scientific & Technical, Wiley: London, New York, 1989.

(24) Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923.

(25) Sharpless, K. B., Amberg, W., Bennani, Y. L., Crispino, G. A., Hartung, J., Jeong,

K.-S., Kwong, H.-L., Morikawa, K., Wang, Z.-M., Xu, D., Zhang, X.-L. J. Org.

Chem. 1992, 57, 2768.

69 Chapter 4

The electrocatalytic reduction of dioxygen using dinuclear copper complexes

4.0 Preface

This chapter describes research done by Charles C. L. McCrory and me. I prepared all of the ligands and the complexes studied in this chapter and did the preliminary electrochemical screening of all three ligand systems reported here with the assistance of

C. C. L. McCrory. C. C. L. McCrory did more detailed characterization of the electrochemistry for the 3,5-di(2-pyridyl)-pyrazole ligand system himself, including the

Koutecky-Levich analysis described later in the chapter.

4.1 Introduction

The four-electron reduction of dioxygen to water is a fundamental reaction in biological systems and low temperature fuel cell devices.1-3 The standard redox potential of dioxygen at 1.23 V showcases its thermodynamic potency as a terminal oxidant in fuel cells. However, limitations relating to reaction inefficiency, voltage losses, and poor mass transfer of O2 to the electrode results in at least a 30% loss in cell efficiency at the cathode. Because of these difficulties, the development of a system that is able to rapidly and efficiently reduce dioxygen at the cathode remains a significant and unsolved problem.

70 State-of-the-art fuel cells routinely employ platinum nanoparticulate electrodes, and while they are effective catalysts for the reduction of oxygen, they require an overpotential of at least 350 mV to operate at acceptable current densities.3 Furthermore, less than 10% of the total platinum metal of a given electrode is catalytically active at the surface of the electrode. Because of the high cost of this precious metal coupled with the necessity for operating the cathode at a relatively large overpotential, a more effective solution to the dioxygen reduction problem needs to be developed.

Heller and coworkers have shown that fungal laccase enzymes, when tethered to the surface of a graphite electrode, are able to reduce dioxygen to water at an overpotential of only 70 mV at high current densities.4-6 These enzymes, which employ a trinuclear copper active site, operate at a turnover frequency of 2.1 dioxygen molecules reduced per laccase enzyme per second. This closely resembles the turnover frequency for platinum electrodes (2.5 O2 molecules reduced per surface Pt atom per second), but the former electrode operates at one-fifth of the overpotential for the latter electrode.3 Synthetic mononuclear copper phenanthroline complexes adsorbed on the surface of a graphite surface have demonstrated promising catalytic activity with a high turnover frequency of

10 O2 molecules per Cu catalyst per second, but unfortunately, this reaction also operates at high overpotentials (1.1 V).7-10 Given the efficiency of laccase enzymes at dioxygen reduction, synthetic dinuclear dicopper complexes are a viable next step towards solving the problem of rapid dioxygen reduction at low overpotentials.

71 4.2 Towards a dicopper electrocatalyst

Chidsey and coworkers has shown that mononuclear phenanthroline copper complexes are competent oxygen reduction electrocatalysts.11 The redox potential at this electrocatalytic reduction takes place is quite sensitive to the nature of the ligand; adding electron-withdrawing groups to the ligand or sterically demanding groups ortho to the 2/9 positions of the ligand allows the reaction to be operated at more positive potentials (200-

300 mV vs. NHE, compared to 10 mV for phenanthroline). However, due to very unfavorable and inefficient binding of dioxygen to these copper complexes, the reaction rate for dioxygen reduction drops off significantly relative to the unsubstituted phenanthroline copper complex (0.4-2 s-1 compared to 16 s-1).

R N S S Cl N N N N N N N N N N Cu Cu N Cu Cu N Cu Cu AcO AcO O OAc O O O OAc O Cl H Cl

Scheme 4.1. Proposed dinuclear copper electrocatalysts.

Thus, we envisioned that the proposed dicopper complexes in Scheme 2.1 would be efficient electrocatalysts for dioxygen reduction because of the unique binding environment that dinucleating ligands offer. We propose that using dinuclear copper complexes would be more effective electrocatalysts to this end for the following reasons:

(1) doubling the number of CuI sites would facilitate dioxygen binding to the complex;

(2) the adjacent, uncoordinated CuI center would help to stabilize the reduced CuI peroxide radical species by binding to it; and (3) the presence of two CuI centers that both

72 bind to the reduced dioxygen ligand would facilitate electron transfer to effect further reduction of dioxygen to water.

With these features in mind, the proposed mechanism for dicopper-mediated dioxygen reduction is shown in Scheme 4.2. The bis-CuII complex is reduced by two electrons to a bis-CuI intermediate, which then reversibly binds to dioxygen. After oxygen binds to one of the CuI centers in the catalyst, a single-electron reduction of dioxygen takes place to generate a CuII superoxide radical. The superoxide radical can then immediately bind to the adjacent CuI center and be reduced to a bis-CuII peroxide species.

N N N N N N N N CuI CuI CuI CuI H O O OH H O OH 2 2 2 H2O 2 H2 O2 H2O

2 e-

3+ N N N N N N N N CuII CuI II II Cu Cu H O OH 2 O H2O 2 H2O H O OH2 OH2 2 O

H2O

2 H+ N N N N N N N N I I II II Cu Cu 2 e- Cu Cu H2O O O OH2 H2O O O OH2 H H

Scheme 4.2. Proposed catalytic cycle for the reduction of dioxygen.

The structure of this peroxide interemediate deserves some comment. Crystal structures of known 3,5-di(2-pyridyl)pyrazolato dicopper(II) complexes reveal that the two copper

73 centers are approximately 4.05 Å apart.12-13 Known dicopper complexes bearing a "end- on" peroxo ligand have an average Cu-Cu distance of 4.36 Å, while those that have an

"side-on" peroxo ligand have an average Cu-Cu distance of 3.51 Å.1 Thus, we propose that the peroxo ligand binds to the dicopper complex in an "end-on" fashion since that is a more geometrically accessible intermediate.

In any event, the bis-CuII peroxide intermediate can go through one of two pathways: (1) the peroxo ligand is protolyzed and released from the CuI complex as hydrogen peroxide, or (2) the peroxo ligand undergoes two-electron reduction and subsequent protolysis to form the bis-CuII aquo complex. In either pathway, the initial bis-CuII aquo complex is regenerated, closing the catalytic cycle.

4.3. The 3,5-di(2-pyridyl)pyrazole ligand system

We began this study by investigating the synthesis of dicopper complexes employing the

3,5-di(2-pyridyl)-pyrazole (dppy) ligand. A variety of homobimetallic and heterobimetallic complexes are known for this ligand system, including dicopper complexes.14 Particularly relevant to the preceding discussion for the reduction of dioxygen is Llobet's report of a bis-Ru complex being able to oxidize water, the reverse reaction (Scheme 4.3).15

3+ 3+ 3+ -4 H+ 1.23 V N N N N N N N N N N N N Ru Ru -4 e- Ru Ru Ru Ru L OH2 H O L L O O L L OH2 H O L 2 2 H2O O2 2 L = terpyridine

Scheme 4.3. The oxidation of water to dioxygen with a dinuclear Ru complex.

74 He proposes that both RuII aquo centers are oxidized to RuIV-oxos, and that, when the final electron for the four-electron process is removed at 1.23 V vs. SCE, a synergistic phenomenon takes place with expulsion of both oxo ligands on Ru as dioxygen. Key evidence for this hypothesis is the fact that this final electron-transfer step (with oxygen evolution) is first-order in catalyst; in addition, independent synthesis of an unlabeled bis-

18 16 Ru aquo complex and its electrolysis in O-labeled water produces O2 as 99.5% of the isotopic mixture.16-17 A common feature that delineates bimetallic dppy complexes is that a bridging ligand readily coordinates to both metal centers - this is central to our hypothesis that the bound dioxygen will bridge both Cu centers as a superoxide, enabling rapid reduction of this substrate to hydrogen peroxide or water.

O O NaOEt H2NNH2 + OCH N N 3 toluene benzene N N N N NH N O O reflux

Scheme 4.4. Synthesis of the 3,5-di(2-pyridyl)pyrazole ligand.

The dppy ligand is readily synthesized in two steps from the cross-condensation of methyl 2-picolinate and 2-acetylpyridine in toluene and subsequent cyclization of the 1,3- diketone with hydrazine hydrate in hot benzene (Scheme 4.4).18 We were able to prepare the dicopper complex by reaction of the ligand with Cu(OAc)2 in ethanol, as reported by

Pons and coworkers,19 though the paramagnetic nature of the bis-CuII complex defied ready characterization. Elemental analysis of the complex suggests that the compound synthesized is (dppy)Cu2(OAc)3*H2O, and based on known dppy copper complexes, we propose that one acetate ligand bridges both Cu centers.

Figure 4.1. Cyclic voltammogram of (dppy)Cu(OAc)3 at pH 4.7.

Figure 4.2. Dependences of the peak current on scan rate for (dppy)Cu(OAc)3 at (a) its redox potential at -170 mV and (b) its electrocatalytic O2 reduction peak with maximum current at -25 mV.

76 The electrochemistry of the dicopper complex adsorbed on an edge-plane graphite surface is shown in Figure 4.1 (acetate buffer, pH 4.7, using Bu4NClO4 as electrolyte).

When the aqueous solution is saturated with N2, the complex demonstrates a single, reversible, two- electron peak at -170 mV vs. NHE (Figure 4.2a). This suggests that, once one CuII center is reduced, the other CuII is then rapidly reduced - hence, the redox peaks for each of the CuII centers are not well-resolved. The peak current at this potential is linear with the scan rate, confirming that the species is adsorbed onto the surface.20

Switching the N2-saturated buffer solution to an air-saturated solution effects a new broad peak with its onset at 170 mV and a maximum current at -25 mV - this peak appears to represent the electrocatalytic reduction of dioxygen. The peak current at -25 mV varies with the square root of the scan rate, indicating that a diffusing species is being reduced.20

To better characterize the electrocatalytic reduction taking place, a rotating-disk electrode was used to more precisely control the mass transport rate of oxygen diffusing to the surface of an electrode. By varying the rotation rate of the electrode and scanning the electrode at given rotation rates, a sigmoidal curve can be obtained that represents the steady-state current at that rotation rate if oxygen binding to the dicopper complex at the surface of the electrode is rate-limiting. Plotting the steady-state current at a given potential (-650 mV) as a function of the square root of the rotation rate should then give a straight line, with the slope being proportional to the number of electrons in the reduction and the intercept being the current that would arise in the absence of diffusion.20

Figure 4.3. (a) Voltammograms of (dppy)Cu(OAc)3 with varying rotation rates for the rotating disk electrode; (b) Plot of the current at -650 mV as a function of the square root of the rotation rate for the disk electrode. Dashed lines are theoretical lines representing a

2-electron and 4-electron process (labeled "2 e-" and "4 e-", respectively).

By using the Koutecky-Levich equation,20 the slope of the line so obtained can be compared to theoretical values. Analyzing such a plot shows that the electrocatalytic dioxygen reduction reaction more closely matches the theoretical curve for a four- electron reduction than that for a two-electron reduction. This suggests that the dicopper complex catalyzes the reduction of oxygen directly to water instead of stopping at the hydrogen peroxide stage.

We also examined the effect of substituted dppy ligands for dioxygen reduction.

Nitration of the dppy ligand under standard conditions (HNO3/H2SO4, 55ºC) selectively nitrated the pyrazole ring at the 4-position with no evidence of nitration on either pyridine ring. Reduction of the nitro group under several conditions (SnCl2/aq. HCl; H2, Pd/C,

EtOAc) only led to decomposition of the ligand, so preparation of the aminopyrazole was

78 not pursued further. The 4-aminodppy dicopper complex was, however, prepared in situ on the surface from the 4-nitrodppy dicopper complex by holding the potentiostat at a constant potential of -600 mV at pH 4.7 (vide infra).

NO2 NH2 HNO3 [H] // N N NH N H2SO4 N N NH N N N NH N

Scheme 4.5. Preparation of 4-substituted dppy ligands.

Figure 4.4. Cyclic voltammograms at pH 4.7 for (a) the (4-NO2dppy)Cu(OAc)3 complex and (b) the (4-NH2dppy)Cu(OAc)3 complex. The voltammogram for (a) is truncated at -

200 mV due to irreversible reduction of the nitro group on the ligand.

The redox potential for the 4-nitrodppy complex under N2 is shifted positive to -60 mV vs. NHE. In addition, subjection of the complex to a potential of below -300 mV resulted in an irreversible reduction of the nitro group to the amino group. The amino-dppy complex prepared in situ by reduction of the 4-nitrodppy dicopper complex at -600 mV had a more negative redox potential than the unsubstituted dppy complex, at -230 mV vs.

79 NHE. What is particularly striking about these three complexes is that, despite the dependence of the complex's redox potential on the nature of the ligand, there is practically no difference in the onset potential for dioxygen reduction (~160-170 mV vs.

NHE) or redox potential where there is a maximum current (~ -25 mV vs. NHE). It is not clear why there is a dependence of the ligand on the redox potential, but not for the potential of the electrocatalytic reaction - it is possible, however, that the perturbation of the electronics of the ligand does not significantly affect the rate of binding for oxygen to the dicopper complex.

There are two directions that can be taken with the dinuclear ligand system. First, it would be worthwhile to compare the redox potential of the dppy dicopper complex against dppy ligands that are more sterically demanding. For instance, the 2,9- dimethylphenanthroline copper complex shows a positive shift of 280 mV for the electrocatalytic reaction relative to the phenanthroline copper complex but with a concomitant 10-fold drop in reaction rate.11 However, the six-step synthesis of the analogous dimethyl dppy complex from 2,6-lutidine (since 6-methyl-2-picolinic acid is not commercially available)19 was extremely troublesome and ultimately failed to give a pure sample of the desired ligand for electrocatalytic studies. Second, the negative redox potentials for the dppy copper complexes could be due to the anionic nature of the pyrazolate ring, so neutral dinucleating ligands should shift the redox potential to more positive potentials. To this end, two neutral ligand systems were investigated for the electrocatalytic reduction of dioxygen.

80 4.4. A 3,6-di(2-pyridylthio)-pyrazine dicopper complex

Thompson has reported neutral pyridazine dicopper complexes with a more favorable redox potential of 0.6 V vs. NHE.21-22 Little is known about these complexes' reactivity towards dioxygen though it is a competent and stable catalyst for the aerobic oxidation of

3,5-di-tert-butylcatechol to the orthoquinone product. This ligand system is also attractive because the ligand can easily be prepared in one step by nucleophilic aromatic displacement with various thiols on 3,6-dichloropyrazine. The modular nature of this preparation could then give rise to a library of ligands from a variety of 2- mercaptopyridine compounds for screening towards the electrocatalytic reduction of dioxygen. However, in our hands, the preparation of Thompson's reported copper complex was not reproducible, and the in-situ preparation of the copper complex on the surface of the electrode failed to give satisfactory results, likely due to the ligand's very poor solubility in polar solvents. Thus, the investigation of this ligand system was abandoned.

Cl Cl N N EtOH S S CuCl2 S S Cl + N N N N EtOH reflux N N N Cu Cu N Cl Cl Cl N SH

Scheme 4.6. Preparation of 3,6-di(2-pyridylthio)pyrazine copper tetrachloride

4.5. Some 3,5-di(2-pyridyl)-1,2,4-triazole ligand systems

The second neutral ligand system investigated in this project is a triazole-based ligand reported by Brooker and coworkers,23-29 but no copper complexes are known employing this ligand. This ligand is accessible in three steps from 2-cyanopyridine; the

81 intermediate tetrazine-based ligands were also screened.30 While all of the ligands were readily prepared and adsorbed well on the graphite surface, none of the copper complexes showed promising electrochemistry. The CVs of each of the four copper acetate complexes were complex, indicating poorly-defined coordination chemistry, and had peaks at negative potentials (-200 mV vs. NHE). The complexes are able to reduce dioxygen, but consistently did so at very negative potentials (-200 mV to -400 mV vs.

NHE).

H2NNH2 N NH NaNO2 N N

N CN reflux N HN N N HOAc N N N N

aq. HCl !

NH 2 H N NaNO2 N HNO N N N N 3 N N N N

Scheme 4.7. Preparation of 3,5-di(2-pyridyl)-1,2,4-triazole.

Figure 4.5. Cyclic voltammograms of a copper 3,6-dipyridyl-1,2,5,6-dihydrotetrazine complex using (a) N2 saturated solution; (b) air-saturated solution.

Figure 4.6. Cyclic voltammograms of a copper 3,6-dipyridyl-1,2,5,6-tetrazine complex using an (a) N2-saturated solution; (b) air-saturated solution.

Figure 4.7. Cyclic voltammograms of a copper 4-amino-3,5-dipyridyl-1,2,4-triazole complex using an (a) N2-saturated solution; (b) air-saturated solution.

Figure 4.8. Cyclic voltammograms of a copper 3,5-dipyridyl-1,2,4-triazole complex using an (a) N2-saturated solution; (b) air-saturated solution.

To minimize the issues associated with multiple possible coordination environments for the dicopper triazole complexes, the nitrogen atom at the 4-position of the triazole ring needs to be alkylated. However, the triazole ring cannot be regioselectively N-alkylated at the 4-position based on literature precedent; alkylation at the undesired 2 position of the triazole ring is strongly favored.31 We took on two approaches to circumvent this issue. First, reaction of 2,6-dipyridyl-4-amino-1,2,4-triazole with 2,5- dimethoxytetrahydrofuran would produce 2,6-dipyridyl-4-pyrrolyl-1,2,4-triazole, a known compound; however, the reported preparation could not be reproduced in our hands. Second, a longer synthetic route to prepare the 2,6-dipyridyl-4-methyl-1,2,4- triazole in 4 steps from 2-picoline and methyl 2-picolinate24 proceeded smoothly until the final condensation step, which produced an intractable reaction mixture. Given the difficulty in the preparation of these heterocycles, this ligand system was also abandoned.

84 NH 2 MeO OMe N O N N N N N N dioxane/AcOH, ! N N N N

S8, Na2S NaOEt, EtOH NHMe NHMe N then EtBr, 50ºC N N reflux S S

H2NNH2 OMe NHNH2 N ! N O O Me n-BuOH N NHMe + NHNH2 N N ! N N N N S O

Scheme 4.8. Preparation of 3,5-dipyridyl-1,2,4-triazole derivatives.

4.6 Conclusions and future directions

We have synthesized a number of dinucleating ligands and formed the corresponding dicopper complexes, and characterized their ability to electrocatalytically reduce dioxygen at the surface of a graphite electrode. The dipyridylpyrazole copper complex is the most promising of the dicopper systems investigated since it reduces dioxygen at the most positive potentials of all of the ligand systems examined. This system needs to be further studied to better understand the role of both copper centers in the reduction reaction since it is not clear how this dicopper complex is an improvement over other mononuclear copper complexes previously studied.

To this end, several useful comparisons can be made with the dipyridylpyrazole system.

First, if a 4-substituted dipyridyltriazole system becomes more synthetically accessible

85 with well-behaved copper coordination chemistry, then a direct comparison of these two ligand systems can be made, since the dipyridyltriazole copper complex should be reduced at a more positive potential than the dppy copper complex. Second, the preparation of more sterically demanding dppy ligands would serve as an useful probe for examining the binding of dioxygen to the dicopper complex, as Chidsey has done with his studies of the electrochemistry for phenanthroline copper complexes.11 Third, it would be useful to directly compare the dipyridylpyrazole ligand system with a monopyridylpyrazole ligand, the latter of which should form a monocopper complex.

This comparison would be the most direct of the three since it explicitly evaluates whether a dinuclear copper complex is an improvement in terms of reaction rate and/or overpotentials over a mononuclear copper complex with a similar ligand environment.

4.7. Experimental considerations: ligand syntheses

All starting materials and solvents were obtained commercially and used without further purification unless otherwise specified. The ligands were prepared as previously reported: 3,5-di(2-pyridyl)pyrazole33, 4-nitro-3,5-di(2-pyridyl)pyrazole34, and 3,6-di(2- pyridylthio)pyrazine.21

3,5-di(2-pyridyl)pyrazolatodicopper(II) triacetate hydrate was prepared identically as reported.19

Elemental analysis: calc'd for C19H21Cu2N4O7: C, 41.91; H, 3.89; N, 10.29, found: C,

41.86; H, 3.77; N, 10.84. An alternative formula corresponds to Cu(dppy)(OAc)2(OH), calc'd for C17H17Cu2N4O5: C, 42.15; H, 3.54; N, 11.57.

86 Complexation of 3,6-(2-pyridylthio)pyrazine with two equivalents of CuCl2*2 H2O in ethanol yielded a green solid that was filtered, and then precipitated from ethanol/ether and dried in vacuo.

This product had the following elemental analysis data: calc'd for C14H10Cl4Cu2N4S2: C,

29.64; H, 1.78; N, 9.88, found: C, 25.39; H, 1.80; N, 8.31. Note that Thompson's reported analysis results is also inconsistent with his reported synthesis: (C, 32.30; H,

2.88; N, 9.42).21

4.8. Experimental considerations: electrochemical measurements

All electrochemical measurements were identical to that reported in Chidsey's studies of mononuclear copper phenanthroline complexes,11 and their experimental considerations are reproduced here:

Edge-plane graphite disk electrodes with a 0.195 cm2 macroscopic surface area

purchased from Pine Instrument Company were used. The electrodes were

ground by hand with a 600-grit silicon carbide paper followed by sonication in

pure water before each ligand deposition. Ligands were adsorbed onto the

electrode surface by exposing the surface to 1 mM acetonitrile solutions; the

II ligands were complexed with Cu by exposure to 1 M aqueous Cu(NO3)2

solutions and then rinsing the electrode with water. Electrochemical

measurements were recorded with a Pine Instrument Company AFCBP1

bipotentiostat with a MSR rotator, an auxilary Pt-mesh electrode, and a

87 Ag/AgCl/NaCl(saturated) reference electrode. The reference was calibrated

against Cu(NO3)2 in 1 M KBr and all reported values are referenced to NHE.

All electrochemical measurements were conducted in an aqueous acetate buffer (1:1 glacial acetic acid/sodium acetate, each at 0.04 M concentration). In addition, sodium perchlorate was used as the electrolyte, and was present in the buffered solution at 0.1 M concentration. Prior to recording electrochemical measurements, the solution was purged with either air or N2 for at least 20 minutes, and for the latter case, a blanket of N2 was maintained throughout the measurement. Cyclic voltammograms were recorded with a scan rate of 100 mV/s.

4.9. References

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90 Appendix

A.0 General remarks

The following two pages are the 1H NMR spectra of the oxidation products for trans,trans-3-methyl-1,2-cyclohexanediol and trans,cis-3-methyl-1,2- cyclohexanediol. See section 3.4 for discussion and section 3.6 for experimental details (p. 68).

Below are the peaks that do not correspond to either the cyclohexanediol starting material or hydroxycyclohexanone products:

1.93 ppm CHD2CN residual solvent peak (quintet, 1 H)

4.31 ppm HDO solvent peak (s, 1 H)

6.67 ppm hydroquinone (C-H) (s, 4 H)

6.81 ppm benzoquinone (C-H) (s, 4 H)

91 STANDARD PROTON PARAMETERS

Pulse Sequence: s2pul Solvent: cd3cn Ambient temperature INOVA-500 "ui50O1'

Pulse 30.5 degrees Acq. time 4.000 sec

Width 8000.0 Hz A.1. 16 repetitions OBSERVE Hl, 499.7512044 MHz DATA PROCESSING trans,trans-3-methyl-1,2-cyclohexanediol. FT Size 65536 Proton Total time 1 min, 4 sec NMR spectrum of 92 the oxidation products for STANDARD PROTON PARAMETERS

Pulse Sequence: s2pul Solvent: cd3cn Ambient temperature INOVA-500 "ui500"

Pulse 30.5 degrees

Acq. time 4.000 sec A.2. Width 8000.0 HZ 16 repetitions OBSERVE Hl, 499.7512044 MHz DATA PROCESSING Proton FT size 65536 trans,cis-3-methyl-1,2-cyclohexanediol. Total time 1 min, 4 sec NMR spectrum of 93 the oxidation products for