Development of Green and of Polymer-Supported

Home , Alcohol oxidation, Oppenauer oxidation, Swern oxidation

DEVELOPMENT OF GREEN AND OF POLYMER-SUPPORTED

OXIDIZING AGENTS FOR OXIDATION OF ALCOHOLS

SYED JAVED ALI, M.Tech., B.Tech.

A THESIS

CHEMISTRY

Submitted to the Graduate Faculty of Texas Tech University in Partial Fulfillment of the Requirements for the Degree of

MASTER OF SCIENCE

Approved

David Birney Chairperson of the Committee

Satomi Niwayama

Accepted

John Borrelli Dean of the Graduate School

May, 2006 ACKNOWLEDGEMENTS

I would like to express my sincere gratitude to my mentor, Dr. David Birney, for his ever-inspiring scientific guidance, for his constant encouragement and support and for his unfathomable patience. I hold him in very high esteem for being such an excellent teacher and a wonderful human being. Words would only depreciate my admiration and my gratitude for all that he has done. I would like to thank Dr. Satomi Niwayama for agreeing to be my thesis committee member and for her valuable comments on my work. My thanks are also due to Dr. Pramod Chopade for helping me understand some of the chemistry, Ms. Paramakalyani Martinelango for being a great friend and for help with this manuscript. I thank my very best friend, Pradip, and Anwesa for their moral support and always being there for me. I would like to thank my parents for their love, sacrifice and continued prayers and blessings, and my friends back home who I know genuinely care for my well-being.

ii TABLE OF CONTENTS

ACKNOWLEDGEMENTS……………………………………………………………….ii LIST OF SCHEMES……………………………………………………………………...v LIST OF TABLES………………………………………………………………………..vi LIST OF FIGURES……………………………………………………………………...vii CHAPTER 1. INTRODUCTION…………………………………………………………………...…1 1.1 An Overview of Oxidizing Agents for Alcohols……………………………...1 1.1.1 With Strong Oxidizing Agents……………………………………....1 1.1.1.1 Chromium Compounds…………………………………….1 1.1.1.2 Manganese Compounds……………………………………3 1.1.1.3 Ruthenium Compounds……………………………………4 1.1.1.4 Other Metal-Based Oxidants……………………………….5 1.1.2 By Catalytic Dehydrogenation………………………………………5 1.1.3 The Oppenauer Oxidation…………………………………………...7 1.1.4 With Dimethyl Sulfoxide Reagents…………………………………8 1.1.5 With Hypervalent Iodine Reagents………………………………….9 1.2. Use of Nitroxyl Radicals…………………………………………………….11 1.2.1 Structure and Stability……………………………………………...11 1.2.2 Synthesis of Nitroxyl Radicals……………………………………..12 1.2.3 Redox Reactions…………………………………………………...13 1.2.4 Mechanistic considerations………………………………………...14 1.2.5 Significance of this research……………………………………….18 2. EXPERIMENTAL…………………………………………………………………….19 2.1 General Methods……………………………………………………………..19 2.2 Synthesis of PEG-supported TEMPO………………………………………..19 2.3 General procedure for oxidation of alcohols with PEG-TEMPO……………24 2.4 General procedure for TEMPO-TCCA oxidation of alcohols……………….25

iii 3. RESULTS AND DISCUSSION………………………………………………………26 3.1 Factors Affecting Frequency of Absorption of the C=O Group……………..26 3.1.1 Inductive and Resonance Effects…………………………………..26 3.1.2 Effects of Conjugation……………………………………………..27 3.1.3 Steric Effects……………………………………………………….27 3.1.4 Ring strain effects………………………………………………….28 3.2 Discussion of experimental data……………………………………………..28 3.2.1 Oxidation of benzylic alcohols to aromatic ketones……………….28 3.2.2 Oxidation of alcohols to aliphatic and unsaturated ketones……….32 3.2.3 Oxidation of alcohols to cyclic aliphatic ketones………………….33 3.2.4 Oxidation of alcohols to form aromatic aldehydes………………...35 3.2.5 Oxidation of alcohols to form aliphatic/ unsaturated aldehydes…..39 4. CONCLUSION………………………………………………………………………..41 REFERENCES…………………………………………………………………………..42

iv LIST OF SCHEMES

1.1 Oxidation of alcohols to carbonyl compounds……………………………...... 1 1.2 Preparation of pyridinium chlorochromate (PCC)………………………………...... 2 1.3 Oppenauer oxidation of an alcohol to a carbonyl compound……………………... ..7 1.4 Alcohol oxidation with DMSO…………………………………………………… ..8 1.5 Synthesis of the Dess-Martin periodinane……………………………………….... 10 1.6 Disproportionation of a nitroxyl radical with an α- hydrogen………………….…..12 1.7 Redox reactions of TEMPO………………………………………………………. 13 1.8 Disproportionation of the nitroxyl radical……………………………………….....14 1.9 Possible mechanistic pathways for oxidation with TEMPO……………………… 15 1.10 Mechanism of the TEMPO-TCCA oxidation system…………………………….17 2.1 Synthesis of PEG-supported TEMPO…………………………………………….. 20 2.2 Synthesis of mesylate of modified PEG……………………………………….…...23

v LIST OF TABLES

3.1 Oxidation of Alcohols to form Aromatic Ketones...... 30 3.2 Oxidation of Alcohols to form Aliphatic and Unsaturated Ketones...... 32 3.3 Oxidation of Alcohols to form Cyclic Aliphatic Ketones...... 33 3.4 Oxidation of Alcohols to form Aromatic Aldehydes...... 35 3.5 Oxidation of Alcohols to form Aliphatic/Unsaturated Aldehydes...... 39

vi LIST OF FIGURES

1.1 Structures of some chromium based oxidizing agent...... 2 1.2 Structure of IBX...... 10 1.3 Resonance structure of the nitroxyl radical...... 11 1.4 Conjugated and non-conjugated nitroxyl radicals...... 11 1.5 Complex formation in the acyclic intermediate...... 16 3.1 Inductive and resonance effects influencing C=O shift…...... 27 3.2 Effect of conjugation...... 27 3.3 A resonance structure for 4-methoxybenzaldehyde showing decreased double bond character...... 38 3.4 s-cis conformation for (Z)-hex-2-enal...... 40

vii CHAPTER 1 INTRODUCTION

The selective oxidation of primary alcohols and secondary alcohols into their corresponding aldehydes (or carboxylic acids) and ketones is one of the most important transformations in modern organic synthesis. A myriad of oxidizing agents have been developed to affect this transformation shown in Scheme 1. Tertiary alcohols resist oxidation by conventional oxidizing agents unless they are dehydrated in acidic media to alkenes, which subsequently undergo oxidation. In modern synthetic chemistry there is still a demand for mild and selective reagents for the oxidation of alcohols in presence of other oxidizable groups.

R1 O R1 CHOH C O

R2 R2

R1= H, Alkyl or Aryl R2= Alkyl or Aryl Scheme 1.1 Oxidation of alcohols to carbonyl compounds

1.1 An overview of oxidizing agents for alcohols Primary and secondary alcohols can be oxidized to the corresponding carbonyl compounds in five main ways1

1.1.1 With strong oxidizing agents

1.1.1.1 Chromium compounds Traditionally, the reagents most commonly used are based on high oxidation state

transition metals, particularly Cr(VI). Chromic acid (H2CrO4), a strong oxidizing agent, 2- can be prepared by acidification of sodium or potassium salts of chromate (CrO4 ) or 2- dichromate (Cr2O7 ). Oxidation of primary alcohols by this method leads to the

1 formation of carboxylic acids in most instances, due to the rapid hydration and subsequent oxidation of aldehydes with chromic acid. Pyridinium chlorochromate (PCC), prepared by dissolving chromium trioxide in aqueous HCl and adding pyridine2 (Scheme 2), was developed for the oxidation of primary alcohols to aldehydes. Secondary alcohols are oxidized to ketones by chromic acid as well as by PCC.3

CrO3 + HCl + CrO3Cl

N N

H Scheme 1.2 Preparation of pyridinium chlorochromate (PCC) Pyridinium chlorochromate, tetra-n-butylammonium hydrogen chromate (Fig 1a) and pyridinium dichromate (Fig 1b) are typical representatives of an important series of chromium (VI) oxidants that may be formally regarded as lipophilic derivatives of the

monomer form of chromic acid H2CrO4 or of the dimeric form H2Cr2O7. They find increasing use as mild reliable oxidants for alcohols.4

O n-Bu N-O O N 4 2- Cr2O7 Cr Cr O N HO O N O

H 2

a b c

Figure 1.1 Structures of some chromium based oxidizing agents

2 Jones’ reagent is a solution of chromium trioxide in dilute H2SO4 which also affects the oxidation of primary allylic alcohols to aldehydes and secondary alcohols to ketones. Other chromium trioxide reagents have been prepared by adsorption of chromium trioxide on Celite, silica gel, or on anion exchangers. Among non-acidic reagents which are suitable for oxidations of acid-sensitive substrates, is Collin’s reagent (Fig 1c), a complex of chromium trioxide with two molecules of pyridine. It is prepared by the addition of chromium trioxide in small portions to pyridine, with continuous stirring and cooling the mixture in an ice bath.2 The disadvantages of this reagent are that a) it is very hygroscopic and is easily converted into the insoluble dipyridinium dichromate b) a six fold quantity of the reagent might be required to obtain best yields in some instances and c) saturated aliphatic alcohols often give low yields. Though chromium based oxidations are effective, they are relatively expensive and have serious drawbacks in terms of green chemistry and environmental impact. They generate stoichiometric amounts of heavy-metal waste and Cr(VI) is a proven carcinogen.5,6

1.1.1.2 Manganese compounds The best known manganese based oxidants are manganese dioxide and the permanganate ion. Manganese dioxide is used as a suspension in petroleum ether,

hexane, benzene, chloroform or CCl4. Saturated alcohols are less readily oxidized compared to allylic, benzylic alcohols and α-keto alcohols.4 The reactions are carried out at room temperature and yields vary widely depending on the substrate, ratio of substrate to oxidant, solvent and reaction time. Manganates and permanganates are seldom used for the conversion of alcohols to aldehydes as permanganate oxidizes aldehydes to carboxylic acids. Aldehydes can be obtained using potassium permanganate if adsorbed on molecular sieves and the reaction is done in benzene at 70 ºC. However, saturated alcohols give very low yields of aldehydes. Barium manganate has also been used in certain instances as an alternative to manganese dioxide.

3 1.1.1.3 Ruthenium compounds Among the earliest known ruthenium based oxidizing agents was ruthenium tetroxide,2,4 which was successfully used for the oxidation of secondary alcohols to ketones. Though it was used to oxidize benzyl alcohol to benzaldehyde,4 aliphatic primary alcohols were oxidized to the corresponding carboxylic acids. It is a strong and effective oxidant which may be used under mild conditions for the conversion of secondary alcohols to ketones. This reagent has been specifically useful in the field of carbohydrate chemistry, where the oxidation of alcohol groups in partially protected derivatives of saccharides poses a problem. Ruthenium tetroxide oxidation of such compounds provides a viable route to the corresponding keto-sugars, subsequently used in the synthesis of many important derivatives whose syntheses are based on the chemistry of the carbonyl group. In order to minimize difficulties in the handling of pure ruthenium tetraoxide, it has been prepared and used in solution. Chloroform and dichloromethane are the solvents of choice for the reaction medium, though carbon tetrachloride is preferable. It reacts violently with diethyl ether, benzene and pyridine. An alternative to ruthenium tetraoxide, which is rather expensive and required in stoichiometric amounts, is the use of ruthenium trichloride in catalytic amounts with sodium hypochlorite as reoxidant. Sodium ruthenate and potassium ruthenate, synthesized respectively from ruthenium dioxide and sodium periodate in sodium hydroxide and from ruthenium trichloride and potassium persulfate, effect the oxidation of secondary alcohols to ketones at room temperature. Tetrapropylammonium perruthenate (also known as TPAP) can be used to convert some primary alcohols to aldehydes. TPAP is prepared by the initial formation of RuO4 by the reaction of hydrated ruthenium chloride and sodium periodate in water, and then transferring the product into a solution of tetra-n-propylammonium hydroxide containing sodium hydroxide. N-methyl morpholine oxide (NMO) was used as

the co-oxidant. Another ruthenium compound, RuCl2(PPh3)3 in benzene, was found to be highly effective for the selective oxidation of primary alcohol groups in presence of a secondary one : 1-dodecanol was oxidized fifty times faster than 4-dodecanol.7

4 1.1.1.4 Other metal-based oxidants Cerium (IV) salts are strong oxidants that show selectivity for the oxidation of secondary alcohols relative to primary alcohols.4 Cerium (IV) sulfate oxidation, done in acidic media, is a selective oxidant for the preparation of quinones. Ceric ammonium nitrate (CAN) in water or in 50% acetic acid oxidizes benzylic alcohols at 90 ºC in very good yields. NaBrO3 used in stoichiometric amounts with catalytic amounts of CAN selectively oxidizes secondary alcohols in presence of primary ones. Commercial silver carbonate in excess of 300 mol% has been found to be a satisfactory oxidant if the reaction was performed in refluxing toluene. Precipitating silver carbonate in the presence of Celite results in a supported reagent, commonly known as Fetizon’s reagent. It is a very versatile and useful oxidizing agent, its chief advantages being its ease of use, selectivity and mild conditions under which it is used. Lead tetraacetate finds major application in the cleavage of 1,2-diols. The reaction is virtually quantitative and leads to the formation of two carbonyl compounds. In the oxidation of primary and secondary monohydric alcohols, product composition depends upon the structure of the substrate and the reaction solvent. Aldehydes and ketones are formed in good yields for reactions performed with an excess of the alcohol or in polar solvents such as pyridine. For reactions carried out in non-polar solvents, fragmentation reactions and formation of cyclic ethers, if the substrate is of suitable structure, are more often observed. Molar equivalents of lead tetraacetate are required, and the reaction time varies from 10-20 h at room temperature. The reaction medium acts as its own indicator, turning from deep red to pale yellow when all the oxidant has been reduced. An important feature of this oxidation is that the reaction stops at the aldehyde or the ketone stage, and the product is stable under the reaction conditions for several days.

1.1.2. By catalytic dehydrogenation Catalytic dehydrogenation is much more valuable as an industrial method than on a laboratory scale. It is especially advantageous in the oxidation of primary alcohols2 as it prevents their over-oxidation to carboxylic acids. This method is also useful for the

5 oxidation of secondary alcohols as ketones are more stable at the higher temperatures at which the reactions are usually conducted, resulting in higher yields and fewer by- products. Besides, secondary alcohols are more reactive towards the dehydrogenation process than primary alcohols. The catalytic dehydrogenation of alcohols to yield carbonyl compounds can generally be performed either in the absence or in the presence of a hydrogen acceptor. In the absence of a hydrogen acceptor, the process is endothermic and is favored by high temperatures. In the latter case, oxygen may be used as a hydrogen acceptor and the reaction is exothermic. An extremely large number of dehydrogenation catalysts have been described, copper chromite being the most commonly used. Reactions can be carried out in the gas phase or in the liquid phase. Aliphatic alcohols with three to eight carbons are converted to aldehydes using copper chromite on Celite at 300-350 ºC. Quantitative yields can be obtained when reactions are carried out over copper, silver or both in an insufficient amount of air or oxygen at 300-380 ºC. For aldehydes which are stable at high temperatures of 250-300 ºC, vapor-phase dehydrogenation of the corresponding alcohol can be done over cupric oxide in a current of helium. Besides copper chromite, catalysts that have found laboratory use include Raney nickel, platinum, palladium and copper- silver on pumice. Liquid phase reactions are operationally simpler than gas phase reactions for laboratory use, though convenient experimental arrangements that use a simple heated reaction tube are available. For alcohols that cannot be vaporized and that contain double bonds, a catalytic oxidation can be carried out by passing a current of air or oxygen through solutions of alcohols in solvents like heptane or ethyl acetate, in the presence of platinum, or preferably platinum oxide, or active cobalt oxide. Aliphatic, aromatic and unsaturated alcohols can be oxidized in the liquid phase from -10 to 60 ºC with argentic oxide in nitric or acetic acid. Benzylic alcohols can be oxidized in very good yields at 90 ºC in water or in 50% acetic acid with ceric ammonium nitrate.

6 1.1.3. The Oppenauer oxidation The Oppenauer oxidation is essentially the reverse of the Meerwein-Ponndorf- Verley reduction.4 This method involves the use of a carbonyl compund as a hydrogen acceptor in the presence of a base. Aluminum alkoxides such as aluminum isopropoxide and aluminum phenoxide are bases used often; aluminum tert-butoxide being the most commonly used. Carbonyl compounds used as hydrogen acceptors are acetone, cyclohexanone, benzaldehyde, cinnamaldehyde and benzophenone. Fluorenone can also be used as the hydrogen acceptor as it effects a considerable reduction in time and temperature of the reaction. The oxidation potential of the carbonyl compound affects its efficiency as a hydrogen acceptor, which can be overcome by using the oxidant in large excess. The metal alkoxide converts the alcohol into its corresponding alkoxide, which is converted into a carbonyl compound by hydride ion transfer to a carbonyl compound as shown in Scheme 3. The reaction is reversible and leads to an equilibrium and systematic removal of the product drives the reaction to completion. The product or byproduct is removed by distillation or azeotropic distillation. Hence, high boiling alcohols such as hydroxy steroids may be oxidized with considerable selectivity; equatorial hydroxyl groups are oxidized more rapidly than axial ones.

R R 1 1 R1 OH t-BuO- O C C C O R R C=O R2 3 4 R2 H H R2 + + R3 R3 CO CH O

R4 R4

Scheme 1.3 Oppenauer oxidation of an alcohol to a carbonyl compound

7 Only catalytic amounts of the metal alkoxide base are needed to initiate the - reaction, as the byproduct R3R4CH-O formed acts as a strong base. Carbonyl compounds containing α-hydrogen atoms can undergo self-condensation under the alkaline conditions of the oxidation, and can also undergo condensation reactions with the product. The use of inert solvents can minimize these reactions in instances where it is desirable. Commonly used oxidant-solvent combinations are acetone-benzene and cyclohexanone-toluene. For compounds which are sufficiently stable to heat, reaction times may be significantly reduced in the cyclohexanone-toluene system by conducting the oxidations under reflux conditions. In general, the Oppenauer oxidation finds better application in the oxidation of secondary alcohols than primary alcohols.

1.1.4 With dimethyl sulfoxide based reagents Dimethyl sulfoxide (DMSO) is a versatile and mild reagent for the oxidation of alcohols of widely different structural types and complexities to carbonyl compounds. Successful use of DMSO as an oxidant for alcohols requires8 a) activation of DMSO by a suitable electrophilic reagent (E+A-) below the rearrangement temperature of the requisite intermediate 1; b) facile attack by an alcohol on the electropositive sulfur atom of intermediate 1 with the departure of a leaving group to form a dimethylalkoxysulfonium salt 2; c) reaction of the salt 2 with a base, typically triethylamine, to form dimethyl sulfide and the carbonyl product; and d) isolation of the carbonyl product from by-products.

+ - - Me2SO+EA Me2SOE A 1 "activated" DMSO

R1R2CHOH

base - Me2S + R1R2C O + R1R2CHOCH2SCH3 Me2SOCHR1R2 A 2 Scheme 1.4 Alcohol oxidation with DMSO

8 Most oxidations involving DMSO are accomplished at temperatures well below 0 ºC and require an acid catalyst. The Moffatt oxidation involves the oxidation of an alcohol with DMSO, dicyclohexylcarbodiimide (DCC) and anhydrous phosphoric acid. It provides a method for the conversion of a primary alcohol to an aldehyde without the formation of the carboxylic acid. There are a number of variants to this reaction, where DCC is replaced with other reagents. The use of oxalyl chloride with DMSO, where the + oxidizing species, (CH3)2S Cl is generated by the reaction between these two reagents, is known as the Swern oxidation. A major drawback of the Swern oxidation is that it suffers from the use of activated DMSO as a reagent and very low temperatures, and mainly from the presence of dimethyl sulfide as a byproduct. Moreover, the oxidation is not chemoselective. In the Corey-Kim modification9, the oxidizing species is generated using dimethyl sulfide and N-chlorosuccinimide, as the latter is more convenient to use on a laboratory scale. The formation of HCl is avoided which results in a milder and a more generally useful method, and the reaction products appeared somewhat cleaner. Some of the other reagents used in place of DCC are acetic anhydride, SO3-pyridine-triethylamine, trifluoroacetic anhydride, methane sulfonic anhydride, tosyl chloride, trichloromethyl chloroformate and trimethylamine N-oxide.

1.1.5 With hypervalent iodine reagents The Dess-Martin periodinane10 is an iodine containing oxidizing agent by treating

2-iodobenzoic acid with KBrO3 in sulfuric acid, and then heating the resultant product with acetic acid and acetic anhydride to 100 ºC. The reagent so formed is stable, with an indefinite shelf life. However, it can be shock sensitive under some conditions and can be explosive at temperatures exceeding 200 ºC.11

9 OAc O OH HOAc AcO KBrO3 Ac2O I I I H2SO4 100 ºC O O OAc COOH

O O Scheme 1.5 Synthesis of the Dess-Martin periodinane Another iodine containing reagent that can affect smooth oxidations of primary as well as secondary alcohols at room temperature is o-iodoxybenzoic acid12 (Fig 2). 1,2- Diols can also be oxidized to α-ketols or α-diketones without any oxidative cleavage of the glycol bond. HO O I

O Figure 1.2 Structure of IBX However, these reactions can only be conducted in DMSO as IBX is sparingly soluble in commonly used solvents such as dichloromethane, acetonitrile, chloroform, acetone, THF and DMF. THF can be used as a co-solvent for compounds that are not readily soluble in DMSO. In contrast to the Dess-Martin periodinane, IBX is not sensitive to moisture and the oxidations can be carried out in an open flask without the need for an inert atmosphere or a dry solvent. However, like the Dess-Martin periodinane, it is also explosive upon heavy impact and heating over 200 ºC. A newer oxidation protocol that involves the use of [bis(acetoxy)iodo]benzene (BAIB) as the stoichiometric oxidant with catalytic quantities of TEMPO has also been developed.13 The reaction worked well at room temperature in dichloromethane, but no oxidation process was observed in the absence of TEMPO. Oxidation of alcohols in high

10 yields under solvent-free conditions has been achieved by using iodobenzene diacetate supported on alumina, the reaction being accelerated by microwaves.14

1.2. Use of Nitroxyl Radicals 1.2.1 Structure and stability Nitroxyl radicals are compounds containing the N-O group with one unpaired electron15. Resonance structures for this fragment can be drawn as shown in Fig 2.

N O N O

Figure 1.3 Resonance structure of the nitroxyl radical The major contributing structure depends on the polarity of the medium and the effects of conjugation. In conjugated nitroxyl radicals (Fig 4a), the unpaired electron is delocalized over the entire molecule. Such radicals, unlike non-conjugated radicals, are not used for the oxidation of alcohols. In non-conjugated nitroxyl radicals (Fig 4b and 4c), the unpaired electron is only delocalized over the nitrogen-oxygen bond. The high stability of the non conjugated radicals is demonstrated by the fact that these radicals underwent chemical reactions without involving the unpaired electron.16 Similar radicals have been synthesized and used in the biological field as spin labels and spin trapping agents.

N N N

O O O

a b c Figure 1.4 Conjugated and non-conjugated nitroxyl radicals

11 In general, these radicals are stable only in molecules lacking α-hydrogens. The presence of one or more hydrogens in the α-position results in a disproportionation reaction leading to the formation of a hydroxylamine and a nitrone as shown in Scheme 6. Either or both of the species so formed may undergo further reaction.

2 + N N N H H O OH O

Scheme 1.6 Disproportionation of a nitroxyl radical with an α- hydrogen The most stable nitroxyl radicals among the piperidine series are the ones where the α- positions are completely substituted. The most simple radical of this class, 2,2,6,6- tetramethylpiperidin-1-oxyl (Fig 4b), commonly known as TEMPO, was the first non- conjugated nitroxyl radical to be synthesized.

1.2.2 Synthesis of nitroxyl radicals In general, nitroxyl radicals have been obtained by the dehydrogenation of hydroxylamines, oxidation of amines, reduction of nitro or nitroso compounds and addition of free radicals to nitrones.15 Preparation of nitroxyls by the oxidation of amines is particularly useful in the preparation of cyclic dialkyl nitroxyls. The oxidative method was first reported when an ESR signal resulted from the diphenylnitroxyl radical when oxygen was bubbled into a diphenylamine solution.17 Following this result, a number of nitroxyls were prepared by oxidation of the corresponding aromatic, aromatic-aliphatic, aliphatic and alicyclic amines. Oxidation of secondary amines with hydrogen peroxide in the presence of tungstates is among the more convenient methods for the synthesis of nitroxyls. Highly stable nitroxyls of piperidines, pyrolidines, hydrogenated pyrrols, tetrahydroquinoline derivatives and tetrahydrobenzoquinoline derivatives, besides other cyclic compounds and biradicals have been synthesized by this method. The oxidation of suitable amines with

12 phosphotungstic acid and ammonium molybdate as catalyst also readily yields nitroxyl radicals. TEMPO was prepared by this method. Phototungstic acid accelerated the oxidation, but resulted in decreased nitroxyl yields. It was shown mechanistically that the pertungstate ion is the oxidizing agent.

1.2.2.1 Synthesis of TEMPO Among the earliest reported syntheses,18 a solution of 2,2,6,6- tetramethylpiperidine (1 mol), ethylenediamine-N,N,N',N'-tetraacetic acid (0.05 mol), 800 ml of 45% methanol, 0.3 g of sodium tungstate, and 250 ml of 30% hydrogen peroxide was cooled in a flat-bottomed flask. The mixture was left at room temperature for 10 days. It was then diluted two fold with water, saturated with potassium carbonate and extracted with ether. The ether extract was dried with magnesium sulfate. The ether was evaporated and the residue was sublimed in vacuum to obtain the radical in a 61% yield. The product was dark red, transparent prisms.

1.2.3 Redox reactions The nitroxyl radical represents only one stage in a series of compounds interrelated by oxidation and reduction products as shown, for TEMPO, in Scheme 7.19,20 These are: the secondary amine (a), the hydroxyl amine (b), the nitroxyl radical (c) and the nitrosonium salt (d).

-2e- -1e- -1e-

N N N N

H OH O O

a b c d Scheme 1.7 Redox reactions of TEMPO Mild reducing agents like phenylhydrazine or ascorbic acid react with the radical to give the hydroxylamine, while stronger reducing agents like sodium sulfide yield the

13 secondary amine. Two of the above species, the radical (c) and the nitrosonium salt (d), are oxidizing agents, the latter being much stronger of the two. The oxammonium salt is the reactant in the oxidation of primary and secondary alcohols. Yet another redox reaction of significant importance is the reversible and acid catalyzed disproportionation of the radical to yield the hydroxylamine and the nitrosonium salt19 as shown in Scheme 8. In acidic media, the equilibrium is shifted to the right as the hydroxylamine is basic enough to form a salt and the hydroxide ion formed can be neutralized. This reaction is favored at a pH below 2.0.

+ OH- 2 + H2O +

N N N

O OH O

Scheme 1.8 Disproportionation of the nitroxyl radical At a pH above 3.0, the reverse of the disproportionation reaction occurs, i.e. a syn proportionation between the oxammonium salt and the hydroxylamine occurs to give two nitroxyl radicals.

1.2.4 Mechanistic considerations Many functional groups such as amines, phosphines, phenols and anilines can be oxidized using nitroxyl radicals. Nitroxyl radicals, as shown earlier, are oxidized into nitrosonium salts which, in turn, function as oxidizing agents and have been used as oxidants for alcohols (to form aldehydes or ketones), primary amines (to form aldehydes, and in some cases RCH2NH2 to nitriles), ketones (to α-diketones), and phenols (to quinones).21 The use of nitroxyl radicals has recently emerged as a metal-free alternative for the oxidation of alcohols. Two possible mechanistic pathways for the TEMPO oxidation of alcohols have been considered as shown in Scheme 9. Initial mechanistic investigations by Semmelhack and co-workers favored the formation of 2.22 The possibility of a radical mechanism as

14 well that of a direct hydride abstraction were excluded. It was suggested that a Cope-like cyclic elimination could be expected in this transition state. An alternate mechanism with an acyclic transition state 4 was proposed by Ma and Bobbit.23 The acyclic form was considered more favorable for two reasons. First, the acyclic form appeared sterically less confining than the cyclic form and it seemed that fewer steric effects were involved in oxammonium oxidations.

O R N 2 R O 1 -H+ H 2

H OH N + HO N H O R2 R1 3 1 +

O B H O N R1 R2 OH R R1 2 4 Scheme 1.9 Possible mechanistic pathways for oxidation with TEMPO Secondly, the acyclic intermediate also shows how a β-oxygen may hinder the reaction by complexing with the positively charged nitrogen as shown in Fig 5, which is less likely to occur in the cyclic intermediate because of a negatively charged oxygen. The complex formation may hinder or slow the reaction in two ways. It may reduce the positive charge on the nitrogen and decrease the driving force of the reaction. Alternatively, complex formation may force the hydrogen out of the anti-periplanar conformation required for the reaction.

15 O H N H OH δ− H O H R Figure 1.5 Complex formation in the acyclic intermediate Steric effects become more important in nitroxyl radical based oxidations under alkaline conditions.24 Reactions rates are comparable for primary and secondary alcohols under acidic conditions, while under alkaline conditions, the more sterically hindered secondary alcohols are oxidized at a slower rate. It was proposed by van Bekkum and co- workers that a sterically confining cyclic reaction mechanism as proposed by Semmelhack could be possible under alkaline conditions, while an acyclic mechanism as proposed by Bobbit could be possible under acidic conditions. Also, under acidic conditions, the primary hydrogen isotope effect (kH/kD) was 3.1 while under alkaline conditions, it was 1.8, and is hence consistent with the pathways suggested. Abstraction of the α- proton is expected to be the rate limiting step in acidic conditions while under basic conditions equilibrium formation of the complex might occur at a rate comparable with that of elimination. TEMPO can be used in catalytic amounts with 1,3,5-trichloro-2,4,6- triazinetrione25 (trichloroisocyanuric acid – TCCA), a relatively inexpensive reagent to provide an oxidation system that operates rapidly, and gives near quantitative yields of aldehydes and ketones at room temperature. A proposed mechanism26 for this reaction is as shown in Scheme 10.

TCCA R OH

N N 1 O O Cl H

O N O N Cl O OH NN O N O Cl Cl H O NN Cl Cl H R

O H H2O

O R N 2 H OH

O N O OH R O + HOCl + HCl NN Cl H R O O

Scheme 1.10 Mechanism of the TEMPO-TCCA oxidation system

17 1.2.5 Significance of this research The purpose of this research is to find at least one oxidation system that can oxidize a wide variety of alcohols within a reasonable time frame so it can used in an Organic Chemistry teaching lab. The oxidation systems explored would be mild and environmentally friendly methods that would introduce to students comparatively newer and modern oxidation techniques, thereby replacing traditional oxidation experiments which are over half a century old. These experiments would enable students to prepare a different aldehyde or a ketone from a primary or a secondary alcohol. Using the infrared (IR) spectra of the resultant carbonyl products, the pedagogical goal can be further extended to enable students study trends in carbonyl peak shifts based on the structure of the compound. These experiments would be similar to a parallel combinatorial synthesis of esters that has been previously developed.27

18 CHAPTER 2 EXPERIMENTAL

2.1 General methods All commercially available materials were used as received, unless otherwise mentioned. Tetrahydrofuran was dried over anhydrous MgSO4 and distilled from sodium

and benzophenone under N2. Diethyl ether was refluxed with sodium and benzophenone and distilled immediately before use. Acetone and N,N-dimethylformamide were distilled with 4Å molecular sieves onto 4Å molecular sieves just before use. Polyethylenegylcol monomethylether was dried by melting at 80 °C under vacuum until the disappearance of bubbles. All glassware used for the reactions was oven dried and cooled in desiccators prior to use. IR spectra of all compounds were recorded as films cast on a salt plate from -1 solutions in CH2Cl2. A Thermo Nicolet IR100 spectrometer with a resolution of 4 cm was used for this purpose. NMR spectra were obtained on a Varian UNITYplus 300 instrument. All spectra were obtained using CDCl3 as the NMR solvent with residual

CHCl3 as the internal reference. Mass spectra were done on a Finnigan AQA Mass Spectrometer by the electrospray ionization (ESI) method.

2.2 Synthesis of PEG-supported TEMPO The synthesis of polymer supported TEMPO is accomplished by a convergent synthesis by the reaction of products 5 and 6 as depicted in Scheme 2.1. The reaction scheme for the synthesis of the mesylate of modified PEG (product 6) is provided in Scheme 2.2. This is a modification of the published procedure.28

19 OH OH O O

N Br 4 CBr4, PPh3 O K2CO3, KI THF, 0 C, 30min aq NaOH, Bu NBr Acetone, reflux 24h 4

OH OH Br 123

O OH

Pd(OAc) , PPh 2 3 + O OMs EtOH O O

N N

O O

5 6

Cs2CO3 O O DMF O N O

8 = CH3O-(CH2CH2O)n-CH2-CH2- Polyethyleneglycol monomethylether Mw = 5000 Da

Scheme 2.1 Synthesis of PEG-supported TEMPO (8)

20 Synthesis of p-(Allyloxy)benzyl Alcohol (2) A mixture of 4-hydroxybenzyl alcohol (1) (12.41 g, 100 mmol), potassium carbonate (17.91 g, 130 mmol) and potassium iodide (0.22g, 1.3 mmol) was weighed in a three-necked flask and dry acetone (80 mL) was added. Allyl bromide (11.3 mL, 130 mmol) dissolved in dry acetone (60 mL) was added dropwise with continuous stirring. The reaction mixture was refluxed for 24 h under nitrogen. The reaction was then cooled to room temperature and an insoluble portion was filtered off. The filtrate was dried over

MgSO4 and the solvent was evaporated to give a yellow liquid. The yield of 2 was 15.86 1 g (96.6%). H NMR (CDCl3) δ = 6.91, 7.21 (d, J= 7.8 Hz, ArH, 4H), 6-6.2 (m, -CH=,

1H), 5.3, 5.5 (dd, J= 18.1, 1.9, 11.4, 1.3 Hz =CH2, 2H), 4.61 (s, -CH2-, 2H), 4.51 (d, J =

5.5 Hz, -CH2-, 2H).

Synthesis of p-(Allyloxy)benzyl Bromide (3) p-(Allyloxy)benzyl alcohol (9.16 g, 56 mmol) and tetrabromomethane (23.22 g, 70 mmol) in THF (60 mL) were placed in a three-necked flask under nitrogen and cooled in an ice bath. Triphenylphosphine (18.36 g, 70 mmol) was added dropwise with continuous stirring. The reaction mixture was stirred for 30 min in the ice bath. The solution was filtered and the filtrate was evaporated. The residue, a thick brown liquid, was transferred to a separatory funnel. The crude product was extracted from the residue with 4 x 25 mL washes of hexane. An insoluble portion remained, and the organic layer

was dried over MgSO4. Removal of solvent provided 11.39 g of crude material. Purified 3 was obtained by vacuum distillation. An aliquot of 1.23 g of the crude material gave 0.15 g of pure product. The yield was extrapolated to be 1.38 g (10.85 %). 1 H NMR (CDCl3) δ = 6.79, 7.23 (d, J= 8.2 Hz, ArH, 4H), 6-6.2 (m, -CH=, 1H), 5.31,

5.53 (dd, J= 19.3, 1.6, 11.5, 1.8 Hz, =CH2, 2H), 4.61 (d, J= 5.3 Hz, -CH2-, 2H), 4.5 (s, -

CH2-, 2H).

21 Synthesis of 4-(p-(Allyloxy)benzyloxy)-2,2,6,6-tetramethyl piperidinyl-1-oxy (5) Hydroxy-TEMPO (4) (1.17 g, 5.16 mmol) was dissolved in dry toluene (1 mL), and p-(allyloxy)benzyl bromide (3) (0.89 g, 5.16 mmol), tetrabutylammonium bromide (0.08 g, 0.258 mmol) and a two-fold excess of 50% aq. NaOH were added. The mixture was stirred and heated at 70 °C for 20 h. The solution was cooled to room temperature

and stirred with the addition of toluene (5 mL), hexanes (5 mL) and H2O (10 mL). The

organic phase was separated, dried over Na2SO4 and the solvent evaporated under vacuum. Purification was done by flash chromatography on a silica gel column (hexanes : ethyl acetate 9:1) to obtain product 4. The yield was 1.64 g. (12.7 %). IR (selected peaks): 2875, 2937, 1612, 1512, 1241, 1083 cm-1.

Synthesis of product 6 Product 5 (0.21 g, 0.6 mmol) was dissolved in ethanol (10 mL). Triphenylphosphine (0.07 g, 0.27 mmol) and palladium(II) acetate (0.013 g, 0.06 mmol) were added, and the mixture was refluxed for 2 h with stirring. The mixture was cooled to

room temperature, SiO2 (1 g) was added and the contents were stirred for 60 min. The mixture was stirred through Celite and the solvent evaporated under vacuum. The residue was purified by flash chromatography on a silica gel column (hexanes : ethyl acetate 4:1) to yield product 6. The yield was 0.17 g (70.3 %). IR (selected peaks): 3000, 2975, 2937, 1614, 1517, 1462, 1354, 1239, 1173, 1081 cm-1. ESI MS: m/z was found at 277.8; + formula weight calculated for [C16H24NO3] was 278.18.

Synthesis of product 7 Product 7 was synthesized in three steps as depicted in Scheme 2.2. Polyethylene glycol monomethylether (MW=5000 Da) (9) (5.0 g, 1 mmol) was dissolved in dry

CH2Cl2 (15 mL) and tri-n-octylamine (0.53 mL, 1.2 mmol) was added. The mixture was stirred for 5 min before the addition of methanesulfonyl chloride (0.09mL, 1.2 mmol). The mixture was stirred for 20 h. The resultant PEG-mesylate (10) was precipitated by the addition of diethyl ether (200 mL), and filtered over a Büchner funnel. The precipitate

22 was washed thrice with diethyl ether (150 mL) and any residual ether was removed under vacuum. The yield was 4.78 g (95.6%). 1H NMR (with presaturation of methylene signals

at δ =3.6, relaxation delay = 6 s, acquisition time = 4 s) MeSO2 signal resonated at δ =3.08. To a solution of (10) (4.22 g, 0.83 mmol) in dry DMF (30 mL) were added cesium carbonate (0.87 g, 2.7 mmol) and 3-(4-hydroxyphenyl)-1-propanol (11) (0.38 g, 2.49 mmol) and stirred for 18 h at room temperature. The mixture was concentrated to half its original volume under vacuum. Addition of diethyl ether (80 mL) resulted in a

oily product at the bottom of the flask. Evaporation of ether by blowing a stream of N2 over the mixture induced the formation of a precipitate. The process was continued till no significant increase in the formation of precipitate was observed. The precipitate was washed with diethyl ether (150 mL) after filtration over a Büchner funnel. Residual ether was dried over vacuum, resulting in a 2.08 g yield (48.2%) of product (12).

The modified PEG (12) (2.21 g, 0.42 mmol) was dissolved in CH2Cl2 (20 mL) and stirred with trioctylamine (0.88 mL, 2 mmol) and methanesulfonyl chloride (0.16 mL, 2 mmol) for 18 h. The mesylate was precipitated by the addition of diethyl ether (80 mL), filtered over a Büchner funnel and washed with ether (100 mL). The residual solvent was evaporated and 2.15 g of 7 was obtained (99.5 %).

HO OH CH3SO2Cl, TOA OH OSO2CH3 11 CH2Cl2 Cs2CO3, DMF 9 10

CH3SO2Cl, TOA O OH O OMs CH2Cl2

12 7

= CH3O-(CH2CH2O)n-CH2-CH2- Polyethyleneglycol monomethylether Mw = 5000 Da Scheme 2.2 Synthesis of mesylate of modified PEG

23 Synthesis of product 8 A solution of the modified PEG-mesylate 7 (1.31 g, 0.25 mmol) was dissolved in

dry DMF (6 mL) and stirred at 50 °C under N2. The TEMPO-attached phenol 6 (0.083 g, 0.3 mmol) and cesium carbonate (0.24 g, 0.75 mmol) were added and stirred for 72 h at 70 °C. Most of the DMF was evaporated under vacuum, and after cooling to room

temperature, CH2Cl2 (6 mL) was added. The solution was filtered to remove an insoluble portion, and diethyl ether (120 mL) was added to precipitate PEG-supported TEMPO 8.

Again, evaporation of ether by blowing a stream of N2 resulted in an increased amount of precipitate, which was filtered over a Büchner funnel and washed with ether. Any residual solvent was evaporated and the yield was found to be 0.89 g (64 %). IR (selected peaks): 2882, 1646, 1511, 1467, 1467, 1359, 1280, 1241cm-1

2.3 General procedure for oxidation of alcohols with PEG-TEMPO In a reaction vial equipped with a stirrer, 1 mmol of the alcohol was weighed and

CH2Cl2 (1-2 mL) was added to completely dissolve the alcohol. The solution was cooled to 0 °C. To the cold solution, PEG-TEMPO (varying from 0.01 mmol to 0.001 mmol) was added and stirred for 5 min. Trichloroisocyanuric acid (TCCA) (0.244 g, 1.05 mmol) was added and the mixture was stirred for 15 min. The progress of the reaction was monitored by TLC (before spotting on the TLC plate, an aliquot of the reactant solution was filtered through a Celite plug) until the alcohol was completely oxidized. Reaction times are indicated in the table below. At the end of the reaction, the CH2Cl2 solution was filtered through Celite, and cold ether (10 mL) was added. The polymer precipitate was collected on a Büchner funnel, and the filtrate was collected in a test tube placed at the bottom of the funnel inside the suction flask. A TLC of the filtrate was done to ensure no residual polymer catalyst was present in the ether. The ether layer was then dried over

MgSO4 and the solvent was removed under vacuum. An IR spectrum of the product was

obtained by dissolving it in CH2Cl2 and casting a thin film on a salt plate.

24 2.4 General procedure for TEMPO-TCCA oxidation of alcohols In a round bottomed flask containing a magnetic stirrer, a solution of alcohol (2.5 mmol) and the solvent dichloromethane (10 mL) was prepared. The oxidant, trichloroisocyanuric acid, was added to the solution in excess (2.6 mmol, 0.6043 g). The flask was then cooled in an ice water bath and stirred in a nitrogen atmosphere. TEMPO, or 2,2,6,6-tetramethyl-1-piperidinyloxy, was weighed out in a shell vial (0.025 mmol, 0.0040 g). TEMPO was then dissolved in about 1-2 mL of dichloromethane and added to the solution at approximately 0˚C. After the addition of TEMPO, the solution was removed from the ice bath and allowed to warm to room temperature while stirring. The solution was then allowed to stir for 20 to 25 minutes and filtered over Celite. The

mixture was washed with 15 mL of Na2CO3, followed by HCl, and brine in a separatory funnel. The organic layers were combined and dried over MgSO4. The solvent was evaporated under vacuum and an IR spectrum of the product was obtained by dissolving

it in CH2Cl2 and casting a thin film on a salt plate.

25 CHAPTER 3 RESULTS AND DISCUSSION

Functional groups such as ketones, aldehydes, carboxylic acids, esters, lactones, acid halides, anhydrides, amides and lactams show a strong C=O stretching absorption band in the region of 1870 to 1540 cm-1. The C=O stretching mode is always intense owing to the large dipole moment of the carbon-oxygen double bond. The absorption frequency occurring at approximately 1715 cm-1 for a saturated aliphatic ketone is often referred to as the “normal” absorption frequency.29 Changes in the environment of the carbonyl group effect an increase or a decrease in the absorption frequency from this “normal” value. Conversely, changes in the observed absorption frequency can be interpreted as reflecting changes in the environment of the carbonyl group.

3.1 Factors affecting frequency of absorption of the C=O group The position of the C=O stretching band is determined by a number of factors29 including: (1) the physical state, (2) electronic and mass effects of neighboring substituents, (3) conjugation, (4) hydrogen bonding30 (intermolecular and intramolecular), and (5) ring strain. Intermolecular hydrogen bonding between the carbonyl group and a hydroxylic solvent causes a slight decrease in the absorption frequency. The physical state of the carbonyl compound, ex. the crystal packing structure can effect a slight increase in the absorption frequency.

3.1.1 Inductive and resonance effects The C=O absorption frequency shifts when the alkyl group in a saturated aliphatic ketone is replaced by a heteroatom (G). The direction of the shift is determined by the predominance of the inductive effect or the resonance effect.29

26 G G

CO CO

R R (a) (b) Figure 3.1 Inductive and resonance effects influencing C=O shift A strongly electronegative group attached to the C=O group results in the predominance of the inductive effect (Figure 3.1 a). This reduces the length of the C=O bond and increases the force constant, resulting in a higher frequency of absorption. On the other hand, electron donation via the resonance effect (Figure 3.1 b) decreases the double bond character in the carbonyl group, thereby weakening the bond. The C=O bond length consequently increases, and the frequency of absorption is reduced.

3.1.2 Effects of conjugation Conjugation of the C=O group with a C=C bond of an alkene or phenyl group results in delocalization of the π electrons of both the unsaturated groups (Figure 3.2). Again, delocalization of the π electrons of the C=O group diminishes its double bond character31, thus causing conjugated C=O groups to have lower absorption frequencies than their saturated counterparts.

O O

CCC CCC

Figure 3.2 Effect of conjugation

3.1.3 Steric effects The effect of conjugation is reduced by sterically bulky groups that reduce the coplanarity of the system. A conjugated system tends towards a planar conformation in

27 the absence of steric hindrance. Inductive and/or resonance effects from the neighboring group affect the frequency of absorption as described above.

3.1.4 Ring strain effects Ring strain can be interpreted as changing the hybridization of atoms in the ring. In a small, and hence more strained ring, σ bonds should have more p- orbital character and thus, exocyclic σ bonds should have more s- orbital character. This makes the C=O stronger and results in an increase in absorption frequency.

3.2 Discussion of experimental data The following sections provide a list of alcohols that have been oxidized by both the TEMPO-TCCA system, as well as by the PEG-TEMPO method. The carbonyl frequency used in the discussion is the observed value, recorded by taking an IR of a liquid film. The observed values reported have been obtained after the TEMPO-TCCA oxidation. Selected alcohols were oxidized by the PEG-TEMPO oxidation system, and IR absorptions obtained from this system have been indicated. The reference value, unless otherwise indicated, is that of a liquid film of the compound.

3.2.1 Oxidation of benzylic alcohols to aromatic ketones Table 1 lists the alcohols that were oxidized in quantitative yields to their corresponding ketones. The oxidation of 1-phenylethanol (entry 1) results in the formation of acetophenone. The absorption frequency of acetophenone (1686 cm-1) is lower than that of an aliphatic saturated ketone due to the electron withdrawing effect of the phenyl group. Propiophenone, formed by the oxidation of 1-phenylpropan-1-ol (entry 2), has a comparable absorption frequency (1687 cm-1) as the neighboring ethyl group does not have a significant effect on the C=O group. A comparatively more significant change in the absorption frequency is observed in the case of 1-(2- methoxyphenyl)ethanone, obtained by the oxidation of 1-(2-methoxyphenyl)ethanol (entry 3). The lowered absorption frequency of 1678 cm-1 can be explained by the

28 combined electron withdrawing effects of the benzene ring and the methoxy group, present in the ortho position. The absorption frequency of 1-(4-fluorophenyl)ethanone and 1,2-diphenyl ethanone (entries 5 and 6 respectively) are similar to that of acetophenone. In the case of 1-(4-fluorophenyl)ethanone, the presence of a fluorine atom in the para position does not affect the absorption frequency. Similarly, the C=O group of 1,2-diphenyl ethanone is affected only by the neighboring benzene ring, as the second benzene ring is one carbon atom away, accounting for the comparable absorption frequency. For 1-(2,4-dichlorophenyl)ethanone (entry 7), a substantial increase in absorption frequency – 1698 cm-1 is observed. It is possible that the relatively bulkier chlorine atom in the ortho position causes the C=O group to bend out of plane of the benzene ring, thereby decreasing the conjugation with the ring, resulting in an increase of absorption frequency. Another contributing factor is that chlorine, though electron withdrawing by induction, is electron donating by resonance, resulting in a higher frequency of absorption as explained in Section 3.1.1. Both 1-(2-chlorophenyl)propan-1-one and 2-chloro-1-(2,4-dichlorophenyl) ethanone (entries 8 and 9 respectively) have comparable absorption frequencies, but higher than that of acetophenone. Again, this can be explained by the loss of co-planarity of the system owing to the Cl atom and also due to its electron donating effect.

29 Table 3.1 Oxidations of Alcohols to form Aromatic Ketones Frequency (cm-1) Entry Alcohol Product of Carbonyl peak Observed Reference OH O 1686, 1 1686 32 1687@

OH O 1687, 2 1688 32 1687@

OH O

3 1678 1675 32

O O O OH O O 1681 4 (orig), - 1709

OH O

1686, 1687, 5 1688@ 1698 32

F F

1686, 6 1686 32 1686@ OH O OH O

1698, 7 1698 32 1698@

Cl Cl Cl Cl

30 Table 3.1 Continued

Frequency (cm-1) Entry Alcohol Product of Carbonyl peak Observed Reference OH O

1702, 8 Cl Cl - 1705@

OH O

Cl Cl 1703, 9 1699 32 1703@

Cl Cl Cl Cl OH O

10 1722 1660 32

O O @ Obtained by PEG-TEMPO oxidation

31 3.2.2 Oxidation of alcohols to aliphatic and unsaturated ketones Table 3.2 Oxidation of alcohols to form aliphatic and unsaturated ketones

Frequency (cm-1) Entry Alcohol Product of Carbonyl peak Observed Reference

1685, 11 1710 1704 32 OH O OH O 1712, 12 - 1714@

1712, 33 13 @ 1730 OH O 1712

OH O 1716, 14 1717 32 1717@

15 1716 1716 32 HO O OH O 16 1758 1722 32

OH O 1759, 17 1708 32 1770

@ Obtained by PEG-TEMPO oxidation The absorption of pent-1-en-3-one (entry 11), hept-1-en-4-one (entry 12) and heptane-3-one (entry 16) occur, as expected in the “normal” absorption region. 1- Phenylpropan-2-one and 4-phenylbutan-2-one (entries 13 and 14) also exhibit absorption frequencies closer to the “normal” value of 1715 cm-1. Evidently, the C=O group is away from the influence of the benzene ring in both cases, resulting in an absorption frequency similar to that of a saturated aliphatic ketone. However, the absorption frequencies for

32 butan-2-one and 3,3-dimethylbutan-2-one do not fit the anticipated trends, and have unexpectedly high absorption values.

3.2.3 Oxidation of alcohols to cyclic aliphatic ketones Table 3.3 Oxidation of alcohols to form Cyclic Aliphatic Ketones

Frequency (cm-1) Entry Alcohol Product of Carbonyl peak Observed Reference OH O 1714, 18 1716 32 1716@

OH O

1718, 19 1712 32 1720@

1717 20 OH O 1723* 32 1721@

HO CH3 O CH3 1724, 21 1711 1724@ (H3C)2HC (H3C)2HC H3C H3C

H3C H3C

# 32 22 CH3 CH3 H 1717 1722

H H H H

HO O H H

1742, 32 23 OH O 1744 1742@

* Absorption frequency determined by Nujol Mull method # Absorption frequency determined by KBr method @ Obtained by PEG-TEMPO oxidation

33 In cyclic ketones, the C=O stretch is affected by the adjacent C-C stretch. The bond angle of the –C-CO-C- group influences the absorption frequency of the C=O group. In acyclic ketones and in ketones with a 6-membered ring, this angle is nearly 120°. In rings where the angle is less than 120°, ring strain results in increased s- character at the C=O carbon, and strengthens the C=O bond because of increased overlap between orbitals on C and O atoms. The force constant increases, resulting in an increased frequency of absorption. Cyclohexanone, 2-methylcyclohexanone and 4-tert- butyl cyclohexanone (entries 18, 19 and 20 respectively) are some examples of 6- membered rings where there is no ring strain. Hence, they show absorption frequencies similar to that of aliphatic ketones. The same can be said of ketones formed by the oxidation of (2S,5R)-2-isopropyl-5-methyl cyclohexanol and cholesterol (entries 21 and 22), where the change in absorption frequency is negligible. A drastic increase in the absorption frequency to 1742 cm-1 is observed in the oxidation of borneol to camphor (entry 23). As explained earlier, the ring strain in the system causes an increase in energy required to produce the C=O stretch, resulting in an increased frequency of absorption.

34 3.2.4 Oxidation of alcohols to form aromatic aldehydes Table 3.4 Oxidation of alcohols to form aromatic aldehydes

Frequency (cm-1) of Carbonyl peak Entry Alcohol Product Observed Reference

OH O H

1691, 24 F F 1702 33 1690@

OH O H

1694, 32 25 NO2 NO2 1699 1697@

O O

26 H 1695 ~1700 34

OH O O O2N OH O2N 27 H 1698 1699# 32 Cl Cl O

OH 1696, 28 H - 1699@ I I O Br OH Br 29 H 1715 1676# 32 OH OH

35 Table 3.4 Continued

Frequency (cm-1) of Carbonyl peak Entry Alcohol Product Observed Reference

O OH H 30 1713, 1693* 32 HO HO OCH3 OCH3 OH H O

31 1728 1702 32

OCH3 OCH3 OH H 1721, 32 32 @ 1724 O 1721

O OH 33 33 H 1709 1745 + acid OH O 34 1720 - H H CO H3CO 3 OH O 35 1727 - H F F H

36 OH 1723 - O

36 Table 3.4 Continued

Frequency (cm-1) of Carbonyl peak Entry Alcohol Product Observed Reference

H OH 1721, 37 O @ - H CO 1721 H CO 3 3

OH O 1724, 1724, 38 1724@ 1734 32 H

OH O 39 1726 - H Cl Cl

* Absorption frequency determined by Nujol Mull method # Absorption frequency determined by KBr method @ Obtained by PEG-TEMPO oxidation 2-Fluorobenzaldehyde (entry 24) shows a decreased frequency of carbonyl absorption at 1691 cm-1 due to a bulky halogen, viz. a fluorine atom, at the ortho position causing the aldehyde to have some electrostatic interaction. The absorption frequencies of 2-nitrobenzaldehyde, 4-phenoxybenzaldehyde and 2-iodobenzaldehyde (entries 25, 26 and 28) are, within instrumental error, at relatively the same position as that of 2- fluorobenzaldehyde. In the case of 2-chloro-5-nitrobenzaldehyde (entry 27), the carbonyl absorption frequency is slightly increased (1698 cm-1). It would appear that the presence of the nitro group at the meta position has little effect, while the presence of a bulky Cl atom, at the ortho position, accounts for the observed increase. A significant increase in absorption frequency is observed in 5-bromo-2-hydroxybenzaldehyde (1715 cm-1) and 4-hydroxy-3- methoxybenzaldehyde (1713 cm-1) (entries 29 and 30 respectively). In both instances, it

37 appears that the substituents at the meta position has little effect on the absorption frequency, while the presence of an OH group in the ortho and para position can result in a decrease of double bond character of the carbonyl group as explained using Fig 3.3. A still sharper increase in absorption frequency is observed in the case of 4- methoxybenzaldehyde (entry 31) and a resonance structure that contributes to this effect is shown in Fig 3.3. In all three cases, the absorption frequency should be expected to decrease; the increased frequency does not fit the anticipated trend.

H O H O

OCH3 OCH3

Figure 3.3 A resonance structure for 4-methoxybenzaldehyde showing decreased double bond character Oxidation of 2-p-tolylethanol (entry 33) resulted in the formation of 2-p- tolylacetaldehyde and 2-p-tolylacetic acid, as observed by TLC and NMR. The resultant intermolecular hydrogen bonding could cause the observed decrease in absorption frequency. 2-4-(Methoxyphenyl)-acetaldehyde (entry 34) and the aldehydes in entries 35 through 39 exhibit absorption frequencies in the range of 1721 cm-1 to 1727 cm-1. In all these cases, the aldehyde functionality is at least one C atom away from the benzene ring, and the neighboring alkyl group caused the absorption frequency to occur at slightly above the “normal” range.

38 3.2.5 Oxidation of alcohols to form aliphatic/ unsaturated aldehydes Table 3.5 Oxidation of alcohols to form aliphatic/unsaturated aldehydes

Frequency (cm-1) of Carbonyl peak Entry Alcohol Product Observed Reference

H HO O 1668, 40 - 1670@

41 OH O 1717 - H H 42 1729 1695 32 HO O H 32 43 HO 1729 1694 O H

OH O 44 1724 -

H 1711, 45 1729 32 HO 1715@ O H OH O 46 HO O 1730 - H @ Obtained by PEG-TEMPO oxidation The absorption frequency of (E)-3,7-dimethylocta-2,6-dienal (entry 40) is observed at a sharply decrease value of 1668 cm-1 due to the effect of conjugation as explained in Section 3.1.2. However, in (Z)-hex-2-enal (entry 41), (E)-hex-2-enal (entry 42), and (E)-oct-2-enal (entry 43), there is an increase in absorption frequency, possibly due to the s-cis conformation of the α,β-unsaturated aldehyde as shown in Fig 3.4.

39 H

Figure 3.4 s-cis conformation for (Z)-hex-2-enal Octanal (entry 45) shows the absorption frequency expected for an aliphatic aldehyde, at 1711 cm-1, while decanedial (entry 46) shows an unanticipated higher absorption frequency.

40 CHAPTER 4 CONCLUSION

The oxidation of alcohols to their corresponding carbonyl compounds was carried out by the TEMPO-TCCA oxidation system as well as by the PEG-supported TEMPO. The reactions proceeded to completion without over-oxidation to the corresponding carboxylic acid in most cases. Polymer supported catalysts are being currently regarded as amenable alternatives to improve the efficiency of a catalytic process in that they allow catalyst recovery and recycling. Removal of the catalyst can be achieved by mere precipitation, making the purification of the product much easier. Both methods provide mild conditions for oxidation of alcohols, and are viable alternatives to metal based oxidants. The IR spectra of the carbonyl compounds obtained have been studied, and trends in absorption frequencies of the carbonyl group have been discussed.

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