CONTENTS

ACKNOWLEDGEMENTS SUMMARY VII VIII

CHAPTER 1
1.1 GENERAL

INTRODUCTION
1

1.2

USES OF COUPLED PHENOLICS 1.2.1 Antioxidants 1.2.2 Other Uses

4 4 6

1.3

METHODS OF PREPARATION OF COUPLED PHENOLICS 1.3.1 General Types of Coupling Reaction Mechanisms 1.3.2 Chemical and Electrochemical Methods for Oxidatively Coupling Phenolics 1.3.2.1 1.3.2.1.1 1.3.2.1.2 1.3.2.1.3 1.3.2.1.4 1.3.2.2 1.3.2.2.1 1.3.2.2.2 Chemical oxidative coupling Vanadium(IV) and vanadium(V) A (nitrosonaphtholato)metal complex Activated manganese dioxide Cupric salts Electrochemical oxidative coupling Direct electroche mical oxidations Indirect electrochemical oxidations

6 8

15 15 16 18 21 23 25 25 29 32

1.4

OBJECTIVES AND MOTIVATION FOR THIS STUDY

CHAPTER 2
2.1 MATERIALS

EXPERIMENTAL
34

2.1.1 Reagents for Synthesis and Analysis 2.2 SYNTHETIC PROCEDURES

34 36

2.2.1 Reagents for Analysis 2.2.1.1 2.2.1.2 2.2.1.3 Preparation of 3,3-di-t-butyl-4,4-dihydroxybiphenyl Preparation of 3,3,5,5-tetra -t-butyldiphenoquinone Preparation of 3,3,5,5-tetra -t-butyl-4,4dihydroxybiphenyl 2.2.1.4 2.2.1.5 Preparation of 3,3,5,5-tetra -t-butyl-2,2dihydroxybiphenyl Preparation of 3,3,5,5-tetramethyl-2,2Dihydroxybiphenyl

36 36 36 37 37 38

2.2.2 Preparation of Coupling Agents 2.2.2.1 2.2.2.2 2.2.2.3 2.2.2.4 Preparation of silver carbonate/celite Preparation of barium manganate Preparation of a (nitrosonaphtholato)metal complex (MnII(1-nnap)2) Electrochemical preparation of cerium(IV) from cerium(III) using a divided cell 2.2.2.5 2.3 Preparation of silver oxide

38 38 39 39 40 42 43 43

EXPERIMENTAL PROCEDURES 2.3.1 Oxidative Coupling Reactions 2.3.1.1 Oxidation of alkylphenols using silver

II

carbonate/celite 2.3.1.2 2.3.1.3 2.3.1.4 2.3.1.5 Oxidation of alkylphenols using copper complexes of dicarboxylic acids Oxidation of alkylphenols using manganese(III) acetate Oxidation of alkylphenols using barium manganate Oxidation of alkylphenols using a (nitrosonaphtholato)metal complex 2.3.1.6 Oxidation of alkylphenols using FeCl3 in an organic solvent 2.3.1.7 2.3.1.8 2.3.1.9 2.3.1.10 2.3.1.11 Oxidation of alkylphenols using FeCl3 without solvent Oxidation of alkylphenols using Ag2O Oxidation of alkylphenols using lead tetra -acetate Oxidation of alkylphenols using Ce4+ Oxidation of alkylphenols using potassium ferricyanide 2.3.2 Determination of Ce(III) Remaining After the Electrochemical Oxidation of Ce(III) to Ce(IV) 2.3.3 Dealkylation of Dihydroxybiphenyls 2.4 ANALYTICAL TECHNIQUES

43

45 44 44 45

45 45 46 46 46

47 47 48 48

2.4.1 High Performance Liquid Chromatography (HPLC) 2.4.2 Nuclear Magnetic Resonance (NMR) Spectroscopy 2.4.3 Fourier Transform Infra Red (FTIR) Spectroscopy 2.4.4 Gas Liquid Chromatography-Mass Spectrometry (GC -MS) 2.4.5 Molecular Orbital Calculations 2.5 TERMS AND DEFINITIONS

48 50 50 51 51 52

III

CHAPTER 3
3.1

DISCUSSION
53 56 58

MODES OF PHENOLIC COUPLING 3.1.1 Molecular Orbital Calculations for the Coupling of Phenol

3.2

THE OXIDATIVE COUPLING OF 2-t-BUTYLPHENOL

3.2.1 The Range of Possible Products During the Oxidative Coupling of 2 -t-Butylphenol 3.2.2 Oxidative Coupling Reactions of 2-t-Butylphenol using Various Oxidants 3.2.2.1 3.2.2.2 3.2.2.3 3.2.2.4 3.2.2.5 3.2.2.6 3.2.2.7 3.2.2.8 Vanadium(V) oxytrichloride and vanadium(IV) tetrachloride as coupling agents Silver carbonate supported on celite as coupling Agent Copper acetate, in the presence of a dicarboxylic acid, as coupling agent Manganese(III) acetate as coupling agent Barium manganate as coupling agent Ferric chloride as coupling agent Silver oxide as coupling agent Potassium ferric cyanide, lead tetra-acetate, a (nitrosonaphtholato)metal complex and cerium(IV) sulphate as oxidants 3.2.3 Concluding Remarks on the Oxidative Coupling of 2-tButylphenol 3.3 THE OXIDATIVE COUPLING OF 2,6-DI-t-BUTYLPHENOL 75 76 75 70 71 72 73 74 65 65 63 60

IV

3.3.1 Molecular Orbital Calculations for the Oxidative Coupling of 2,6-Di-t-Butylphenol 3.3.2 Oxidative Coupling Reactions of 2,6-Di-t-Butylphenol Using Various Oxidants 3.3.2.1 3.3.2.2 Silver oxide as coupling agent Copper(II) acetate/oxalic acid as coupling agent Butylphenol 81 83 87 88 77

3.3.3 Concluding Remarks on the Oxidative Coupling of 2,6-Di-t-

3.4

THE OXIDATIVE COUPLING OF 2,4-DI-t-BUTYLPHENOL

88

3.4.1 Molecular Orbital Calculations for the Oxidative Coupling of 2,4-Di-t-Butylphenol 3.4.2 Oxidative Coupling Reactions of 2,4-Di-t-Butylphenol Using Various Oxidants 3.4.2.1 3.4.2.2 3.4.2.3 3.4.2.4 Ferric chloride as coupling agent Silver oxide as coupling agent Potassium ferric cyanide as coupling agent Cerium as coupling agent 3.4.2.4.1 3.4.2.4.2 Identification of Ce(IV) as the preferred oxidant Oxidation in MeSO3 H mediated by Ce(IV) ions 3.4.2.4.3 Reaction mechanism for the oxidative coupling of 2,4-di-t-butylphenol using Ce(IV) 3.4.3 Concluding Remarks on the Oxidative Coupling of 2,4-Di-tButylphenol 126 119 107 104 94 95 97 100 104 90

3.5

THE OXIDATIVE COUPLING OF 2,4-DIMETHYLPHENOL

127

3.5.1 Oxidative Coupling Reactions of 2,4-Dimethylphenol Using Various Oxidants 3.5.1.1 3.5.1.2 3.5.1.3 3.5.1.3.1 Ferric chloride as coupling agent Potassium ferric cyanide as coupling agent Cerium(IV) as coupling agent Reaction mechanism for the oxidative coupling of 2,4-dimethylphenol using Ce(IV) 3.5.2 Concluding Remarks on the Oxidative Coupling of 2,4Dimethylphenol 3.6 BUTYLATED PHENOLIC COUPLINGS: COMPARISONS 148 149 138 131 132 136 138

3.6.1 Reactions of 2-t-Butylphenol and 2,6-Di-t-Butylphenol with Ag2O and Cu(OAc)2 /Oxalic Acid 149 3.6.2 Reactions of 2,4-Di-t-Butylphenol and 2,6 -Di-t-Butylphenol with Ce(IV) in MeSO3H 151

CHAPTER 4
REFERENCES APPENDIX

CONCLUSION AND FINAL COMMENTS

159 169

VI

ACKNOWLEDGEMENTS
The author wishes to express his sincere appreciation to:

My promoters, Dr B. Barton and Prof B. Zeelie, for their assistance and enthusiasm for this work. The NRF and Port Elizabeth Technikon for financial support. My fellow students, Mteza, Nigel, Danil, Melissa and Knowledge for their moral support. Dr S. Gouws, Dr G. Rubidge and Prof P. Loyson for their assistance. The staff and students of the Department of Chemistry at the Port Elizabeth Technikon for their assistance and moral support.

VII

SUMMARY
The oxidative coupling of 2,6-di-t-butylphenol under mild reaction conditions is well documented and the subject of many patents. However, the coupling of other monoand di- substituted phenols is not as well documented and thus there is scope for further investigation for providing a convenient, environmentally friendly and economically viable method for the oxidative coupling of these phenols. In this study, the oxidative coupling of a variety of alkylated phenolic substrates, 2-tbutylphenol, 2,6-di-t-butylphenol, 2,4 -di-t-butylphenol and 2,4-dimethylphenol, using a range of different oxi dizing agents, were investigated by means of experimental and/or theoretical means. The dibutylated aromatics provided the highest selectivities to their respective coupled products, with results obtained with the dimethyl analogue being only satisfactory, and that for 2 -t-butylphenol being totally inefficient. PM3 Molecular orbital (MO) calculations were used to predict the possible modes of coupling for the substrates 2,6 -di-t-butylphenol and 2,4-di-t-butylphenol, and these results were then compared with those obtained experimentally in the laboratory. Preliminarily, the coupling of unsubstituted phenolics was also assessed by means of MO calculations.

Much emphasis was placed on Ce(IV) as the oxidant, and the reaction conditions under which it was used and the results that were obtained have not been reported before and are therefore novel. The oxidation of 2,4-di-t-butylphenol using Ce(IV) in the presence of methanesulphonic acid was optimized to afford high yields and selectivities to the desired ortho C-ortho C coupled product under mild reaction conditions. Various reaction parameters were also investigated in this case, such as varying the MeSO3 H concentration, the solvent, the reaction temperature, the reaction time, the substrate loading, the rate of oxidant addition and the substrate to oxidant ratio. Ce(IV) also gave a high selectivity to the para C-para C coupled product when

VIII

using 2,6-di-t-butylphenol as the substrate. However, it was not as effective with 2,4dimethylphenol, and even less so with 2-t-butylphenol. The oxidation reactions of 2-t-butylphenol and 2,4-dimethylphenol with various coupling agents were also investigated with the intention of obtaining high selectivities to the respective desired coupled products. In these studies, 2-t-butylphenol afforded a large number of products, irrespective of the oxidant used. The dimethyl analogue was more selective, but results were not optimal. It was clear that the number of substituents on the phenol ring, their nature and their position with regards to the hydroxyl moiety was of great importance and made a significant impact on the preferred coupling mode of the substrate. It was observed that steric effects also played a major role in the outcome of these reactions: 2,6-di-t-butylphenol never afforded any C-O coupled products whereas 2-t-butylphenol, 2,4-di-t-butylphenol and 2,4-dimethylphenol all appeared to undergo some C-O coupling. Finally, reaction mechanisms were provided for both the K3Fe(CN)6 and Ce(IV) work, these reacting in basic and acidic media, respectively. It was proposed that both of these mechanisms operate through the initial formation of the phenoxyl radical.

IX

CHAPTER 1 INTRODUCTION
1.1 GENERAL

The chemical industry today is faced with major economic and environmental challenges. We as scientists have a responsibility towards the efficiency and profitability of the industry. We thus have to look at developing sustainable processes that have long -term economic and environmental viability. The chemical industry has been continually driven by this need for better quality products and much more effective and efficient production procedures, resulting in an industry that is currently well established and one that continues to grow.1

From an initial slow start in the 1850s, the chemical industry has made tremendous strides in the field of organic synthesis, this being primarily due to enhanced competition between the various chemical companies, leading to increased numbers of products becoming commercially available.2 During the twentieth century, the industry has experienced exponential growth and this has led to a major improvement in both our living standards and life expectancy.

Phenol and other phenolics are currently some of the more versatile and important industrial organic chemicals. Phenol itself was first isolated from coal tar by Runge.3 In 1843, C.F. Gerhardt prepared phenol by heating salicylic acid with lime; the resulting product was given the name phenol.4 Until World War II, phenol was essentially a coal tar extraction product, but due to an increased demand, synthetic methods replaced extraction from natural resources. Currently, only small amounts of phenol are obtained from coal tar (SASOL); larger quantities are being formed in coking or by the low pressure carbonization of wood and brown coal, as well as from oil cracking. The earlier methods of phenol synthesis via benzenesulphonic acid using alkali fusion (Scheme 1) and via chlorobenzene (Scheme 2)5 have since been replaced by more economically and environmentally friendly processes such as the Hock process, which utilizes cumene as substrate.

SO3H 1. NaOH, 300C 2. H 3O+

OH

Scheme 1: Preparation of phenol from benzenesulphonic acid (alkali fusion)

Cl 1. aq. NaOH, 340C, 2500 psi 2. H 3O +

OH

NaCl

Scheme 2: Preparation of phenol from chlorobenzene

The Mitsui group is the worlds second largest producer of phenol through the Hock process. Acetone is produced as a byproduct in this process, but this is not deemed a disadvantage of the Hock method since there is also a high demand for acetone worldwide. The Hock process involves the alkylation of benzene with propene to afford isopropylbenzene (cumene); cumene is oxidized to the corresponding terthydroperoxide, which is then ultimately cleaved to yield phenol and acetone (Scheme 3).

OOH OH [O] H3O+ O + acetone

cumene

cumene hydroperoxide

Scheme 3: The Hock process for the production of phenol

Plants operating the cumene process are found in the USA, Canada, France, Italy, Japan, Spain, Eastern Europe and Germany, with an overall capacity of 5 000 000 tons per annum.6 By noting the Japanese production output and usage of phenol and phenolic resins (in tons) through the years 1996 to 2000, merely as an example, as contained in Table 1.1, one can better comprehend the importance of these compounds in an industrial capacity (Table 1.1).7 Table 1.1 Japanese production of phenol and phenolic resins (in tons)

Increase Chemical/Year Phenol Phenol Resins 1996

768

1997
833

1998
851

1999
888

2000
916

1999/2000
3.2%

294

303

259

250

262

4.8%

Alkylphenols, such as xylenols, cresols, octylphenols and tert-butylphenols are generally produced by the alkylation of phenol with methanol or the corresponding olefins. Alkyphenols can the n be reacted further by oxidative coupling to form the 3

dihydroxybiphenyls, the focus of this investigation.

All of these products have

considerable economic importance because they are used to manufacture thermosets, insulating foams, adhesives, laminates, impregnating resins, and serve as raw materials for varnishes, herbicides and insecticides. 1.2 1.2.1 USES OF COUPLED PHENOLICS Antioxidants

One of the more important uses of many phenolic materials is their ability to serve as antioxidants. Antioxidants are merely compounds that are added to, or occur in, various materials, both living organisms and synthetic organic materials antioxidants then readily react with free radicals that would otherwise damage the materials prematurely. The free radicals are normally the result of autoxidation, a process that occurs spontaneously all around us all the time due to the oxygen in the air. In human blood plasma, -tocopherol, well known as a component of vitamin E, has proved to be the most efficient phenol derivative to date to trap damaging phenoxyl radicals (ROO ),8,9 caused by autoxidation, and therefore acts as an efficient antioxidant. Uninhibited free radical peroxidation in vivo is implicated in a wide variety of degenerate diseases such as cancer, heart disease, inflammation and even aging. Thus, over the last two decades, there has been a tremendous increase in the research of phenols as antioxidants.10,11

Phenols owe their efficient antioxidant activity to their ability to scavenge radicals by hydrogen or electron transfer in processes that are much faster than radical attacks on the substrate. The antioxidant property can be related to the readily abstractable phenolic hydrogen as a consequence of the relatively low bond dissociation enthalpy of the phenolic O-H group. Thus phenols and dihydroxybiphenyls are an extremely important class of antioxidants.12,13

To understand the antioxidant strength of phenols and diols, we need to discuss the reaction of molecular oxygen with organic molecules under mild conditions (autoxidation). It may be represented by the following chemical reactions (1 5). production of RO R RH RO PhOH ROO ROOH + R

Initiation:

(1)

Propagation:

O2 +

(2) (3)

ROO ROO ROO

Termination:

+ +

products ROOH + PhO

(4) (5)

While reaction 1 is very fast, having a rate constant of approximately 109 M-1s-1, reaction 4 is much slower at 10 1 M-1s-1. Oxidative degradation can therefore occur readily, and the use of low concentrations of antioxidants is thus important for all living organisms and for many commercial products in order to reduce the rate of degradation.

Both phenols and dihydroxybiphenyls behave as antioxidants because of their ability to undergo reactions such as that shown in reaction 5, thus trapping potentially damaging peroxyl radicals. This is a much faster reaction than the attack of the peroxyl radicals on the organic substrate (reaction 3) due to the low bond dissociation energies for the oxygen-hydrogen bond in the hydroxyaromatic. The substituents on the aromatic ring have a profound effect on the ability of the phenol/diol to donate a hydrogen atom. Only those phenols bearing electron-

donating substituents are active as antioxidants, particularly if these are at the ortho and/or para positions relative to the hydroxyl moiety. This is not unexpected since electron-donating groups are expected to lower the phenolic O-H bond dissociation enthalpy and thus increase the reaction rates with peroxyl radicals, implying a more efficient antioxidant.

1.2.2

Other Uses

Dihydroxybiphenyls are used in toner resins to increase surface additive adhesion and to optimize cohesion between the toner particles.14 It also acts as a binder resin, thus eliminating the need for gels to be present in the toner, and enabling the magnetic brush development system to achieve consistent, high quality copy images.15

They are also used as inexpensive and simple starting materials for producing polycarbonate resins,16 which are used to reinforce rubber vulcanizates.17 Dihydroxybiphenyls are extensively used in coating agents,18 glass moulding 19 and infrared-reflecting colourants,20 and they are reacted with acid catalysts to form polymers which are used as a polymer scale deposition preventative agent.21 1.3 METHODS OF PREPARATION OF COUPLED PHENOLICS

The diversity of phenol oxidation products offers interesting synthetic possibilities for the preparation of simple and polymeric molecules containing phenolic and/or quinoid structural elements; these can be formed from both like and unlike radical species.13,22 The successful synthesis of various natural products from phenols has been well documented from the 1950s to the present.23-28 Biogenetic oxidative coupling routes were first investigated in 1957,29,30 and the prevalence of the overall coupling process in the biosynthesis of natural products was authenticated. Thus the oxidative coupling step has been found to be extremely important in the natural formation of compounds as diverse as lignins,31 lignans,32 tannins,33 plant pigments,22 and an estimated 10% of all known alkaloids.23 (Lignin is a complex biopolymer that accounts for 20-30% of the dry weight of wood. It is formed by the free radical polymerization of substituted phenylpropane units to yield polymers which have a number of functional groups such as aryl ethers, phenols and benzyl alcohols.34)

The major difficulty with oxidative coupling reactions of phenols is that a large variety of potential products are possible from a single substrate when carried out in the presence of various chemical or biological oxidants. This is because the phenolic molecules are able to undergo both carbon-carbon (Scheme 4 shows para-para coupling, though ortho-para coupling may also occur) and carbon-oxygen (Scheme 5) coupling reactions.

OH

OH

HO

OH

Scheme 4: Carbon-carbon oxidative coupling (showing para-para coupling)

OH

OH

HO

R R

Scheme 5: Carbon-oxygen oxidative coupling

The type of coupled product (whether C-C or C-O coupled) is also dependent on whether the ortho or para positions bear substituents or not. In addition to these two potential reaction products, the oxidative coupling of phenols also often allows for the formation of polymeric materials which, in general, are undesirable (though there are a few industrial processes where these are of great importance35,36). It has been reported that when carbon-oxygen coupling occurs, there is a tendency for further coupling to occur on the resultant substrate, and this leads to the formation of polymeric products.37

To understand the effect that both the nature of the reactant and oxidant has on the type of products that are formed, one must have an understanding of the various reaction pathways that are possible, from a mechanistic point of view. A summary of literature reports dealing with the various mechanisms is now briefly discussed. 1.3.1 General Types of Coupling Reaction Mechanisms

The reaction pathway for the oxidative coupling of phenols has been extensively investigated.38,39 There are two main modes of coupling that may be highlighted. These are an external and an internal oxidation process. In the former, electrons are transferred from the phenolic compound to an external oxidizing agent, whilst the internal oxidation process involves an internal oxidation-reduction reaction in which one substrate molecule is oxidized whilst another is simultaneously reduced. Since there is no change in the net overall oxidation state, this process may be termed a non-oxidative coupling (NOC) reaction.

In our investigations, only the external oxidative coupling process was studied. For this reason, literature reports dealing only with this mode are summarized here. External oxidative coupling reactions may be grouped into two separate classes, those involving free radical intermediates, and those that are non-radical in nature. These may further be subdivided into several general mechanistic types.

a)

Mechanisms involving free radical intermediates i) ii) iii) Direct coupling of two phenoxyl radicals (FR1) Homolytic aromatic substitution (FR2) Heterolytic coupling preceded by two successive one-electron oxidation steps (FR3)

b)

Mechanisms which are non-radical in character i) ii) Heterolytic coupling preceded by a single two-electron transfer (NR1) Concerted coupling and electron transfer (NR2)

It has previously been widely accepted that, in the field of phenol oxidations, the FR1 mechanism is the most viable (without discounting the FR2 mechanism). little importance to it. Most

reviewers have included the FR3 mechanism in their discussions but have attached Until recently, no one has considered the NR1 and NR2 mechanisms as significant enough to warrant a discussion of them in this context. The para-para (C-C) coupling of a simple 2,6-disubstituted phenol is used to illustrate the five general types of processes (FR1, FR2, FR3, NR1 and NR2) as listed above. In all cases, the oxidized phenolic species is written as the neutral phenol molecule, and only intermediates are shown as unprotonated. The following scheme (Scheme 6) highlights the FR1, FR2 and FR3 mechanisms.

OH R R -e -, -H + pathway (a) (1) + (1) O R R FR2 R

O R R

O R

phenoxy radical

FR1 coupling of two phenoxy radicals

FR3 -eO

O R R H H H -eR OH R disproportionation O (2) R R -H+ H H + (1) -H+ + R R

tautomerization OH R R R H H H -2e- , -2H+ R OH (4) OH (3) R R R OH R

Scheme 6: The FR1, FR2 and FR3 free radical mechanisms

10

The degree of protonation of the phenolic species in each of these mechanisms depends on various factors, such as the acidity of the species, the nature of the solvent and the pH of the solution. The free radical processes are initiated by means of pathway (a) shown in Scheme 6. The first one-electron transfer from the disubstituted phenol (1) to an oxidant results in the formation of the phenoxyl radical which is stabilized by resonance, as shown in the following scheme (Scheme 7).

O R R R

O R R

O R R

O R

Scheme 7: Resonance stabilization of the phenoxyl radical The formation of the phenoxyl radical is well attested, for example by ESR.40,41,42 (It has been shown9 that the subsequent dimerization thereof fits a diffusion-controlled model.) The phenoxyl radical is able to react in one of three ways, each leading to the same product (Scheme 6). Firstly, it may homolytically combine with another phenoxyl radical by mechanism FR1 to afford compound (2). This dicyclohexadienone rapidly tautomerizes in protic media to the more stable aromatic biphenol product (3). Secondly, the phenoxyl radical may react with the initial substrate (1) via mechanism FR2 to generate a dimeric radical. Upon loss of an electron and a proton from this new radical, (2) is formed once again. However, the dimeric radical may also disproportionate, leading to a dihydro product (4) as well as to (2). As yet, compounds such as (4), although analogous to similar products produced

11

in free radical aromatic substitutions,45 have not yet been observed in oxidative coupling reactions. This may perhaps be due to the fact that the conversion of (4) to (3) is a facile one since (3) has enhanced stability due to its aromaticity. Thirdly, the phenoxyl radical may be further oxidized by removal of an electron, to yield a phenoxyl cation, according to mechanism FR3. The initial substrate (1), with concomitant hydroxyl proton loss, may then heterolytically couple with the cation to afford (2). Examples of the NR1 and NR2 non-radical processes are shown in Schemes (8) and (9), respectively. In both illustrations, the oxidant is represented as a tripositive metal ion (M 3+), which forms an initial metal-phenolate complex with (1).

12

OH R R + M3+ - H+ R

M O

2+

(1) O R R O R H H
+ + (1), - H

R + M+ +

R O (2)

tautomerization

OH R R

R OH (3)

Scheme 8: The NR1 (non-radical) mechanistic pathway

13

As shown in Scheme 8, the metal complex decomposes into a phenoxyl cation with concurrent reduction of the metal ion. Subsequently, heterolytic coupling similar to that shown in Scheme 6 (the FR3 mechanism) affords compound (2) which undergoes tautomerization, and so the desired product (3) is a result.

Objections, based on energ etic grounds, to the formation and stabilization of cationic intermediates in this mechanism may be obviated by considering the possibility of a concerted electron transfer, as for the simple NR2 mechanism shown in Scheme 9.
M 2+ O R OH R 2 R + M+3 -H+ R

(1) R O OH R R R H tautomerization O H R R OH (3) R (2) R O H - M+ R R

Scheme 9: The NR2 mechanistic pathway

14

1.3.2

Chemical and Electrochemical Methods for Oxidatively Coupling Phenolics

There has been a tremendous amount of research carried out on the oxidative coupling of phenols that involves the use of a wide variety of chemical oxidants and/or catalysts. These include manganese(III) complexes,26,27 silver carbonate/celite,28 molybdenum(VI) and (V),45 cupric salts,46 amongst numerous others.47-55 The oxidative coupling of phenols through the use of electricity has been documented for both direct56,57 and indirect58 electrochemical means, but these occur to a much lesser extent as compared to that of chemical methods. The wide variety of possible oxidation products that may be obtained under oxidative coupling conditions is clearly indicated by examples from work done earlier by scientists such as Barton, 29 Thvagaraja n59 and Pummerer.60 Subsequent research has mainly concentrated on the coupling of di- and tri- substituted phenols, and the literature is virtually devoid of reactions using mono-substituted substrates. Furthermore, reports suggest that higher selectivities to the carbon-carbon coupled products are achieved when the substituents on the aromatic ring are large and bulky, such as the t-butyl moiety, since they prevent carbon-oxygen coupling due to the steric hindrance that their bulk offers. In the next sections, research utilizing both the chemical and electrochemical methods (direct and indirect) for the oxidative coupling of phenols, is summarized. 1.3.2.1 Chemical oxidativ e coupling

From about as early as the 1920s, chemists have been researching the oxidative coupling of phenols using chemical oxidizing systems. It was thought that all oxidative coupling reactions involved one electron transfers, and therefore that these oxidations were all free radical reactions. The mechanisms by which the reactions occurred, and the characteristics of the various oxidizing agents and/or catalysts,

15

were not investigated successfully because they were not well understood; it was always assumed that coupling occurred through the bonding of two phenoxyl radicals (FR1) to form the coupled biphenol. However, it has since become clear that the types of mechanisms involved are extremely dependent on the nature of the oxidant and/or catalyst used. Some of these, including vanadium (IV) and (V), a

(nitrosonaphtholato)metal complex, activated manganese dioxide, and cupric salts, and the reaction pathways they are involved in, will now be discussed further.

1.3.2.1.1

Vanadium(IV) and vanadium(V)

Vanadium(V) oxytrichloride (VOCl3) and vanadium(IV) tetrachloride (VCl4) have been used to oxidatively couple phenols in aprotic solvents.61 When phenol (5) was used as the substrate in the presence of VCl4, a dark insoluble residue was initially formed which was accompanied by the vigorous evolution of HCl gas. This residue was shown to be a form of vanadium -phenolate species, but when analyzed, the elemental composition was not consistent with any simple structure. Acid hydrolysis thereof afforded high yields of the para-para coupled product, identified as 4,4diphenol (6). Also observed were the para-ortho and ortho-ortho coupled products, identified as 2,4-diphenol (7) and 2,2-diphenol (8), as shown in the following scheme (Scheme 10).
OH OH

OH HO + VCl 4 + OH (5) (7) (8) + OH

OH (6)

Scheme 10: The oxidative coupling of phenol using VCl4 as oxidant

16

When the hydrolysis step was carried out in t e presence of deuterium oxide, no h carbon-deuterium bonds were formed, indicating that the vanadium is bonded to the phenolic oxygen. Furthermore, it was found that phenol (5) itself could not be coupled oxidatively using vanadium(V) oxytrichloride but ra ther only those substituted phenolics, such as the naphthols, that have oxidation potentials lower than (5). A simple mechanism involving the formation of a vanadium phenolate compound has previously been proposed, but does not provide explanations for all observations made. In this proposal, the vanadium -phenolate decomposes to form the phenoxyl radical and a lower valence vanadium species, whereafter the coupling/dimerization step occurs to afford the biphenol. It has been suggested by Carrick61 that phenolic coupling occurs by a rearrangement of electrons in a complex containing at least two phenoxide residues and one metal center. Whether vanadium(V) or vanadium(IV) acts as one or two electron oxidizing agents here is not clear and, furthermore, the course of the phenolic coupling itself is also not clear. However, the existence of metal-phenolate compounds has been established, enhancing the possibility that a non-radical (two electron oxidation) pathway may be involved. The NR2 mechanism can be used to explain the existence of a metal-phenolate derivative (Scheme 11).

17

O Cl V OH R R + VOCl3 -HCl R O R Cl

R O H

OH R R R

O R

tautomerization H

OH H + Cl VOCl3 V Cl

R OH

R O

R 2VOCl2 + HCl

Scheme 11: The oxidative coupling of a substituted phenol using VOCl3 1.3.2.1.2 A (nitrosonaphtholato)metal complex16

Over the past three decades, the use of a (nitrosonaphtholato)metal complex in these reactions were investigated both spectroscopically and physically.62,63 However, little was known about the catalytic ability of these complexes in organic oxidation reactions,46 and so the coupling reactions of both 2,4- and 2,6- disubstituted phenols, due to their structural simplicity, were investigated in the presence of this complex.26

18

Thus

when

2,6-di-tert-butylphenol

(9) at

was 23C

reacted under an

with oxygen

(nitrosonaphtholato)manganese

[Mn(II)(1-nnap)2]

atmosphere, in the presence of triphenylphosphine, the diphenoquinone (10) was formed (Scheme 12).
O OH (CH3)3C C(CH3)3 O2 [Mn (II) (1-nnap) n]-R3P (9) (CH3)3C O (10) C(CH3)3 (CH3)3C C(CH3)3

Scheme 12: The oxidative coupling of 2,6-di-t-butylphenol using a (nitrosonaphtholato)metal complex Some phosphine compounds are known to activate metal catalysts,64-67 and the addition of triphenylphosphine as co-ligand to the above reaction increased the yield of (10) from 5 % (after 10 h) to 93 %. This catalytic activity of [Mn(II) (1 -nnap)2] was demonstrated in a variety of organic solvents such as acetonitrile, tetrahydrofuran, methanol and ethyl acetate. However, no oxidation products were obtained in

reactions using benzene or acetic acid as solvents. The data obtained from the cyclic voltammogram of [Mn(II) (1-nnap)2] showed reversible Mn(II) ? Mn(III) and irreversible Mn(III) Mn(IV) processes. This indicates that [Mn(II) (1-nnap)2] tends to be oxidized to a Mn(III) species, implying that it could therefore behave as a one electron transfer catalyst in these reactions. It was proposed that [Mn(II) (1-nnap)2 ], after activation by phosphine, traps molecular oxygen to form complex (11), as shown in Scheme 13.

19

(CH 3)3C OH (CH 3)3C C(CH 3)3

O O O

.
O N O

Mn-cycle O O

OH O Mn
III

(CH 3)3C

(9)

N O

Mn

III

N O

PPh3

PPh3

N O

(CH 3)3C

(11)

(12)
O N O N O II [Mn (1-nnap)2]

O
Mn
II

PPh3 + O2

Ph3P=O + HO

(CH 3)3C
(13)

+(9) (CH 3)3C H tautomerization HO (15) (CH 3)3C

MnIII -H +

C(CH 3)3

(CH 3)3C H

C(CH 3)3

OH

O H

OH

C(CH 3)3
species

(CH 3)3C

(14)

C(CH 3)3

[MnII(1-nnap)2]

(CH 3)3C

C(CH 3)3

(CH 3)3C

C(CH 3)3

HO

OH

HO

(CH 3)3C

(16)

C(CH 3)3

[Mn-cycle]

(CH 3)3C

(17)

C(CH 3)3
MnIII species [MnII(1-nnap)2]

(CH 3)3C

C(CH 3)3

(CH 3)3C

(10)

C(CH 3)3

Scheme 13: Coupling mechanism using a (nitrosonaphtholato)metal complex

20

Complex (11) has manganese in the 3+ oxidation state since this metal ion was found to be electrochemically stable. It was suggested that complex (11) then abstracts a hydroxyl hydrogen from (9) to yield the peroxymanganese (12) and the phenoxyl radical (13). Complex (12) immediately decomposes to afford phosphine oxide and a hydroxyl radical. Radical (13) then reacts with (9) to yield the coupled product (14) which tautomerizes to (15). Thereafter, after a similar oxidation cycle, radical (15) affords the diphenyl diol (16), which is oxidized by the same catalytic cycle to give (17). The latter compound is ultimately transformed to the diphenoquinone (10). Activated manganese dioxide37

1.3.2.1.3

When activated manganese dioxide was reacted with 2,6 -xylenol (18), the analysis of the product mixture showed the presence of a polyphenylene ether (19), 3,3,5,5tetramethyl-p,p-biphenol (20) and 3,3,5,5-tetramethyldiphenoquinone (21) [Scheme 14].

OH Me Me OH Me OH Me Me MnO 2 Me O Me + + Me Me O Me

(18) O

n Me OH Me Me (20) Me Me O (21) Me

(19)

Scheme 14: Oxidation of 2,6-xylenol using MnO2 The molecular weight of polymer (19) varied substantially, depending on the reactant ratio and the reaction solvent used, ranging from 2 000 to 20 000. The polymer was

21

the major product, with diol (20) and diphenoquinone (21) being formed in much smaller amounts, when a molar ratio of 3:1 (oxide:xylenol) was used. However, when (18) was used in molar excess, (21) was the principle product, with a low molecular weight oligomer also being formed. Products (20) and (21) are formed by carboncarbon coupling, whilst (19) is formed exclusively by carbon-oxygen coupling (Scheme 15).
OH Me Me O Me O Me Me O Me

(18) Me

(22) Me H tautomerization Me Me H Me Me

H (23)

(22) + (23)

(19) (where n = 0)

(23) + (23)

O H Me Me

(21)

O Me Me

Me

Me

(23) +

O O Me Me Me

H Me

(19) (where n = 1)

O Me Me

Scheme 15: Reactions showing C-C and C-O coupling using MnO2 as oxidant

22

Scheme 15 shows that the phenoxyl radical may couple with another phenoxyl radical through either the oxygen (22) or carbon (23) atoms. It was found that when excess manganese dioxide was used, coupling occurred mainly head to tail (i.e., carbonoxygen coupling), and thus the main product in this case was (19).

Polymerization may be prevented, if so desired, by using phenolics with large groups in the 2 and 6 positions, since steric hindrance prevents the phenoxyl oxygen radical from combining with (23) in such cases. Thus reacting 2,6-di-tert-butylphenol with manganese dioxide, and having the reactant in excess, results mainly in products (10) and (16) [see Scheme 13 for structures of (10) and (16)]. 1.3.2.1.4 Cupric salts 46

Cupric salts of carboxylic acids have been found to oxidize phenols in a manner that is characteristic of single electron oxidizing agents to yield products coupled at the ortho or para positions, depending on the substitution of the initial substrate. In this study, only disubstituted phenols were used. It was with cupric salts that the more highly oxidized products, like the quinones, were generally not produced (Scheme 16).

23

OH R 2 O R 2Cu(O C R)2

OH

OH R O + 2CuO C R O ...(1)

R (24) O O

R (25) O

+ 2HO C R

2CuO C R + 2HO C R + 1/2 O2 OH R Nett: 2 + 1/2 O2 R

2Cu(O C R)2 + H2O OH OH R

...(2)

+ H2O ...(3)

R (24)

R (25)

Scheme 16: Oxidation of 2,4-disubstituted phenols using cupric salts

In these reactions, the phenolic compound was in excess and also served as the solvent. The cupric salt was regenerated by bubbling air through the solution (Equation 2) and, as a result, could be us ed in catalytic amounts, with oxygen serving as the principal oxidizing agent. In the above scheme, when R = H or CH3, it was found that larger amounts of resinous materials were produced in the presence of oxygen. Phenol itself gave polymeric products exclusively but, in the absence of oxygen, a light amber oil was produced which consisted mainly of the coupled dimer (26) [Scheme 17]. Small amounts of other coupled products were also formed such as the para-para (6) and ortho-para (7) coupled products (Scheme 17).

24

OH O 2 2Cu(O C R)2

OH

OH

OH

OH

(26) OH

OH (6)

(7)

Scheme 17: Oxidative coupling of phenol in the presence of cupric salts 1.3.2.2 Electrochemical oxidative coupling

Electrochemical methods present another useful avenue that may be investigated for synthesizing organic molecules, particularly for the oxidative coupling of phenols. Both direct and indirect electrochemical oxidation reactions have been carried out by other workers in this context, and these are briefly summarized below. 1.3.2.2.1 Direct electrochemical oxidations

Direct electrochemical oxidations involve electron transfer between an organic reactant and the anode of an electrochemical cell. This results in an intermediate which then reacts further to form the product. The characteristic features of direct electrochemical oxidations are as follows: The redox reagent is the electron itself; electrons are removed either directly or indirectly from the reactant via an electrode. The selectivity of the electrochemical step can be greatly increased by careful selection of the conditions at the phase boundary, e.g., potential, current densities, etc.

25

 Electrochemical methods can be used to synthesize a wide variety of organic chemicals: any oxidation that can be carried out using conventional chemical oxidizing agents can theoretically be carried out in an electrochemical cell. Electrochemical syntheses often have a lower environmental impact than conventional oxidation methods since electrolytic routes often replace toxic reagents and hazardous process conditions.68 Generally, the phenolic substrate forms an electrogenerated radical species, the dimerization of which (to afford the desired product) is in competition with a further one electron oxidation that results in the corresponding cation. In the case of phenol itself, electropolymerization is known to occur at the anode surface resulting in the formation of a passivating film on the electrode surface.56,57 In addition to polymeric products, both p-benzoquinone and 4,4-diphenoquinone are also produced as minor products (in 20 and 10% yields, respectively) as shown in the following scheme (Scheme 18). 56

26

OH OH CPE: +0.9V vs SCE 25% acetone buffer (pH 5), (C) -e+ OH -H+ O

C-C coupling and tautomerization -e-

O -2e-, -2H+

OH

O OH +H2O -H+ (6) + -2e-2H+ O

O (27)

OH

O (28)

Scheme 18: The direct electrochemical oxidation of phenol

The 4,4-diphenoquinone (28) is formed through biphenol (6). The (27)/(28) ratio may be controlled to a certain extent: if the electrolysis is carried out at a higher anodic potential, the amount of (27) may be increased. In addition to reactions using phenol as substrate, the anodic oxidation of 2,6dimethylphenol also leads to the rapid formation of a linear polymer chain. However,

27

phenolic substrates bearing bulkier alkyl substituents afford radicals that are expected to have enhanced stability. For example, the radical species of 2,6-di-sec-

butylphenol was detected using multiple internal reflection Fourier transform infrared spectroscopy (MIRFTIRS), thus confirming the radical mechanism during the anodic oxidation of this substrate. When 2,6-di-tert-butylphenol (9) was reacted under constant current electrolysis conditions (1.0 mA.cm-2; 2.5 F.mol-1) in MeOH-CH2Cl2, using a divided cell, it was converted to the corresponding 4,4-diphenoquinone (10) in 84.7 % yield. A subsequent electroreduction, achieved by merely altering the current direction, resulted in the formation of biphenol (16) in 92.5 % yield (Scheme 19).53

OH (CH 3 )3 C OH (CH 3) 3C C(CH 3) 3 CCE: 1.0 mA cm-1 LiClO 4 , MeOH-CH 2 Cl 2 (Pt) (9) (CH 3 )3 C OH (16) C(CH 3 )3 (CH3 )3 C -2e-, -2H+ +2e-, +2H+ C(CH 3 )3 (CH3 )3 C

O C(CH 3 ) 3

C(CH 3 ) 3 O (10)

Scheme 19: Direct electrochemical oxidation of 2,6-di-t-butylphenol

p-Cresol (29) was also electrolyzed at a controlled potential (+0.25 V vs SCE) in a basic medium to afford Pummerers ketone (30) in 74 % yield, as seen in the following scheme (Scheme 20). 69

28

OH CPE: +0.25 V vs SCE (1 F mol-1) NaClO 4 MeCN-H 2O-NaOH (C) Me (29) Me Me Me followed by tautom. O H (30) H o-p coupling Me O O Me Me

O H+

Scheme 20: Oxidation of p-cresol to Pummerers ketone

1.3.2.2.2

Indirect electrochemical oxidations

In an indirect electrode reaction, a redox couple is used as a catalyst (electron carrier) for the oxidation or reduction of another species in the system. In such a system, the electrode can be used to reconvert the redox reagent to an oxidation state where it can again react with an organic compound. In other words, indirect electrolysis has distinct advantages over the direct method: firstly, the redox reagent can be recycled, thus decreasing the problems associated with the use of toxic reagents and, secondly, the redox catalyst may have increased solubility in water, thus allowing the reaction to be carried out at high current density in an aqueous electrolyte. Generally, the most suitable redox couples are inorganic, and include Ce 3+/Ce4+, Mn2+ /Mn3+ and Cr3+/Cr2O72-. These redox couples are used primarily for oxidations of organic compounds. Indirect electrosyntheses may be carried out using one of two methods:

29

 The in-cell method: The reaction between the organic substrate and the redox reagent, in its active oxidation state, occurs within the cell. The ex-cell method: The reaction is carried out in a reactor separate to the cell. This approach has advantages over the in-cell method in that the conditions for the electrode reaction and the chemical step may be optimized separately and, furthermore, that the electrolyte may be purified between the reactor and the cell. One redox catalyst that has been used successfully for oxidative coupling is the Ce +3/Ce+4 couple.69 The cerium(IV) ions were generated from cerium(III) in the presence of perchloric acid. Using 2,6-dimethylphenol as the substrate in aqueous or aqueous-acetonitrile solutions of perchloric acid (0.5 - 1.0 M) at room temperature, the corresponding 4,4-diphenoquinone and 1,4-benzoquinone were obtained as the main products.70 Under similar conditions, the oxidation of 2,6-diisopropylphenol (31a), 2-tert-butyl-6methylphenol (31b), 2,6-diphenylphenol (31c) and 2,6 -dichlorophenol (31d) resulted in the formation of the corresponding 4,4-diphenoquinones (32a-d) in addition to oligomeric poly(1,4-phenylene) oxides (33a-d) [Scheme 21]. In the case of 2,6diphenylphenol (31c), the quantity of carbon-oxygen coupled product was low due to the steric hindrance associated with the large phenyl groups adjacent to the oxygen atom. When 2,6-diisopropylphenol (31a) and 2-tert-butyl-6-methylphenol (31b) were oxidized by cerium(IV) in a two phase system, namely, in CCl4 and an aqueous acetonitrile solution of perchloric acid, at a high concentration of perchloric acid (4.0 M) in the reacting phase, this afforded the corresponding 1,4-benzoquinones in good yields. This was not observed with 2,6-diphenylphenol and 2,6-dichlorophenol. The results obtained from these reactions are summarized in Table 1.2.

30

O R1 R1 Ce(IV) H2O-AN HClO 4 (0.5-4.0 M) R2 31a: R 1 = R2 = isopropyl 31b: R 1 = t -Bu; R2 = CH 3 31c: R1 = R2 = Ph 31d: R 1 = R2 = Cl R1 O 32a-d R1 Ce(IV) CCl 4/aq. CH 3CN HClO 4 (4.0 M) R2 33a-d R2 R1 R1 R1

HO

HO

R2

R2 n

R2

31a or 31b

R2 34a or 34b

Scheme 21: Indirect oxidation of 2,6 -disubstituted phenols

Table 1.2

Oxidation of disubstituted phenols by cerium(IV)

Phenol

Procedure a

Molar Ratio b
1:2.15

Concentration of HClO4 (M)

0.5

Time (min)
0

Product (yield) (% )
32a (85), 33a (4), 34a (8)

31a

31a

1:4.00

4.0

30

32a (3), 34a (90)

31b

1:2.25

0.5

180

32b (54), 33b (37)

31b

1:3.75

4.0

90

32b (12), 33b (21), 34b (56)

31c

1:2.25

0.5

32c (70), 33c (23)

31d
a b

1:1.75

0.5

32d (30), 33d (65)

Reactions were either in homogeneous (A) or heterogeneous (B) reaction systems Phenolic substrate:cerium(IV) molar ratio

31

1.4

OBJECTIVES AND MOTIVATION FOR THIS STUDY

Dihydroxybiphenyls, as mentioned previously, have many important uses as chemicals in their own right, but also as intermediates in the manufacture of other materials. Dihydroxybiphenyls are often prepared by means of oxidative coupling procedures. However, the reaction is only efficient for disubstituted phenols such as 2,6-di-t-butyphenol and 2,4-dimethylphenol. The literature contains many reports on the successful coupling of these substrate types, but is, however, virtually devoid of studies carried out on monosubstituted phenols such as 2-t-butylphenol. The reasons for this are clear: the C-C coup ling of 2,4- or 2,6- disubstituted phenols is really possible only in the 6- and 4- positions, respectively, leading to reactions that afford high yields of the desired coupled product. In contrast, a monosubstituted phenol such as 2-t-butylphenol has two positions available through which C-C coupling may occur, the 4- and 6 - positions. Hence, in the latter case, complex oxidative coupling reaction mixtures are obtained. These often contain significant proportions of polymeric materials, and thus low selectivities to the desired product are a result. This in turn implies tedious and timeconsuming purification steps. There thus appears to be a need to study these reactions more closely with the view to developing a better understanding as to the mecha nisms at work so that the knowledge base for this reaction type may be enhanced, and ultimately a better process may be devised.

In addition, it must be mentioned that another factor that has fuelled our interest in this investigation is the ready availability of the starting materials that are to be coupled. SASOL produces phenol during its petroleum cracking process, and alkylated phenols may readily be prepared from it. These alkylated phenols serve as substrates in our coupling reactions. This study is therefore concerned with the oxidative coupling of various mono - and disubstituted phenols using chemical and indirect electrochemical oxidation methods.

32

The effect of the various substituents already on the aromatic ring on the oxidative process is also investigated and, furthermore, attention is given to achieving high conversions and selectivities to specifically carbon-carbon coupled products.

33

CHAPTER 2 EXPERIMENTAL
2.1 MATERIALS

2.1.1

Reagents for Synthesis and Analysis

All materials used in the oxidation procedures and syntheses, with their sources and respective grades, are listed in Tables 2.1 and 2.2, and were used as received. Table 2.1 Organic reagents for synthesis

CHEMICAL NAME
4,4-Dihydroxybiphenyl Carbon tetrachloride t-Butyl bromide Ethyl acetate Hexane Methanol 2-Naphthol Dichloromethane Toluene Oxalic acid Acetonitrile Acetic acid 2-t-Butylphenol 2,4-Dimethylphenol 2,4-Di-t-butylphenol 2,6-Di-t-butylphenol Chloroform Succinic acid

FORMULA
C12H10O2 CCl4 (CH3)3CBr CH3 CO2 C2H5 C6H14 CH4O C10H7OH CH2 Cl2 C6H5 CH3 HO2CCO2 H CH3 CN CH3CO2 H C10H14O C8H10O C14H22O C14H22O CHCl3 HO2C(CH 2)2 CO2 H

SOURCE
Aldrich Holpro Aldrich Saarchem BDH BDH Saarchem Saarchem Merck Riedel-de Haen BDH Merck Aldrich Riedel-de Haen Aldrich Fluka Saarchem Riedel-de Haen

GRADE
CP AR CP CP Technical HPLC CP AR Technical AR HPLC AR AR CP AR CP CP AR

34

Table 2.2

Inorganic and organometallic reagents for synthesis

CHEMICAL NAME
Silicon dioxide Sodium carbonate Celite Potassium ferric cyanide Hydrochloric acid Silver nitrate Barium hydroxide Sodium hydroxide Sodium nitrite Sulphuric acid Manganese chloride Cupric acetate Manganese acetate Triphenylphosphine Ferric chloride Silver oxide Cerium carbonate Methanesulphonic acid Ferrous sulphate Sodium hydrosulphite Manganese dioxide Ammonium persulphate Potassium hydroxide Ferroin Magnesium sulphate

FORMULA
SiO2 Na2 CO3 N/A K 3Fe(CN)6 HCl AgNO3 Ba(OH)2 NaOH NaNO2 H2SO 4 MnCl2 Cu(OAc)2 Mn(OAc)3 P(Ph)3 FeCl3 Ag2O Ce2(CO3 )3 CH3SO 3 H FeSO4 Na2S 2O4 MnO2 (NH4)2S 2O8 KOH N/A MgSO4

SOURCE
Fluka Saarchem Hopkin&Williams Merck Saarchem Saarchem Protea Chemicals Saarchem Saarchem Saarchem M&B Mallinckcroft Merck Aldrich Riedel-de Haen Fluka Aldrich Acros Unilab M&B Unilab Saarchem Saarchem Saarchem Saarchem

GRADE
Technical AR AR AR AR AR CP CP CP Technical CP AR AR AR CP AR AR Technical Technical Technical AR CP CP AR CP

The reagents used as standard materials for high performance liquid chromatography (HPLC) are also listed in Table 2.1 (shown before). All standard materials were used as received. Acetonitrile (Chromasolve), used as mobile phase for HPLC analyses, was obtained from Merck and also used as received.

35

2.2

SYNTHETIC PROCEDURES

2.2.1 2.2.1.1

Reagents for Analysis Preparation of 3,3-di-t-butyl-4,4-dihydroxybiphenyl71

To a mixture of 4,4-dihydroxybiphenyl (0.3701 g, 1.987 mmol), SiO2 (1.013 g), and Na 2CO3 (1.935 g, 18.25 mmol) in CCl4 (7 mL) was added t-butyl bromide (0.7867 g, 5.741 mmol), and the reaction mixture was stirred vigorously for 24 h at 70C. The SiO2 was filtered off and washed with ethyl acetate. The ethyl acetate washings and filtrate were then combined and the solvent was removed under vacuum. The product was isolated using thin-layer chromatography with hexane:ethyl acetate (90:10) as the developing solvent system. The desired product, 3,3-di-t-butyl-4,4dihydroxybiphenyl, was thus obtained, and had m.p. 182-183C (lit. 71, m.p. 181183C); ?max (CCl4)/cm-1 3600 (OH), 2750-3100 (C -H) and 1583 (C=C); m/z 298 (M+), 283 (M+-15) and 255 (M+-43); dH (CDCl3)/ppm 1.47 (18H, s, CH3), 4.81 (2H, s, OH) and 6.65-7.50 (6H, m, Ar). 2.2.1.2 Preparation of 3,3,5,5-tetra-t-butyldiphenoquinone

2,6-Di-t-butylphe nol (0.222 g, 1.075 mmol) was added to silver oxide (0.5147 g, 2.222 mmol) in methanol (25 mL), after which the reaction mixture was stirred for 1 h. The solids were removed by filtration and washed with hot toluene, the toluene then being combined with the filtrate. This solution was then concentrated down on the rotary evaporator to afford crude 3,3,5,5-tetra-t-butyldiphenoquinone (99.00 %) as the primary product, which was further purified by recrystallization using ethyl acetate:petroleum ether (b.p. 60-80C); m.p. 247-248C (lit. 28 , m.p. 248C); ?max (CCl4)/cm-1 2800-3100 (C-H), 1631 (C=O) and 1603 (C=C); m/z 408 (M+), 393 (M+15), 366 (M+-42), 351 (M+-57) and 309 (M+-99); dH (CDCl3)/ppm 1.40 (36H, s, CH3) and 7.73 (4H, s, Ar).

36

2.2.1.3

Preparation of 3,3,5,5-tetra-t-butyl-4,4-dihydroxybiphenyl

To a suspension of 3,3,5,5-tetra-t-butyldiphenoquinone (1.169 g, 2.861 mmol) in ether (50 mL) was added a solution of sodium hydrosulphite (8.030 g, 46.12 mmol) in aqueous NaOH (1.0 M, 100 mL). After stirring the reaction mixture for 1 h, the

aqueous layer was acidified with concentrated HCl (15 mL). The organic layer was separated, dried (MgSO4) and concentrated to give 3,3,5,5-tetra-t-butyl-4,4dihyd roxybiphenyl (99.00 %), which was further purified by recrystallization using ethyl acetate:petroleum ether (b.p. 60-80C); m.p. 187-188C (lit.72, m.p. 185186.5C); ? (CCl4)/cm-1 3650 (OH), 2800-3050 (C-H) and 1592 (C=C); m/z 410 max (M+), 395 (M+-15), 190 (M+ -220) and 162 (M+-248); dH (CDCl3)/ppm 1.50 (36H, s, CH3), 5.20 (2H, s, OH) and 7.30 (4H, s, Ar). 2.2.1.4 Preparation of 3,3,5,5-tetra-t-butyl-2,2-dihydroxybiphenyl

A solution of potassium ferricyanide (6.690 g, 20.32 mmol) and sodium hydroxide (2.944 g, 73.61 mmol) in water (100 mL) was added drop-wise over 30 min to a vigorously stirred solution of 2,4 -di-t-butylphenol (4.058 g, 19.67 mmol) in methanol (100 mL). After stirring for a further 90 min, the mixture was poured into water and extracted with ethyl acetate (3 x 50 mL). The organic layer was then dried (MgSO4) and concentrated on a rotary evaporator to give 3,3,5,5-tetra-t-butyl-2,2dihydroxybiphenyl (83.95 %), which was purified by recrystallization using ethyl acetate:petroleum ether (b.p. 60-80C); m.p. 199.5-202.5C (lit.46, m.p. 200-202C); ?max (CCl4)/cm-1 3538 (OH), 2800-3050 (C-H) and 1586 (C=C); m/z 410 (M +), 395 (M+-15), 354 (M+-56), 339 (M +-76), 283 (M +-127), 227 (M+-183) and 190 (M+-220); dH (CDCl3)/ppm 1.35 (18H, s, CH3), 1.48 (18H, s, CH3), 5.24 (2H, s, OH) and 7.12-7.43 (4H, m, Ar).

37

2.2.1.5

Preparation of 3,3,5,5-tetramethyl-2,2-dihydroxybiphenyl

A Ce 4+ solution (20 mL, 2.057 mmol) was added to 2,4-dimethylphenol (0.1366 g, 1.118 mmol) in a 50 mL round-bottomed flask and stirred vigorously at 750 rpm for 1 h. The reaction mixture was then extracted using ethyl acetate (3 x 25 mL), and the organic layer washed with water (3 x 25 mL) and dried (MgSO4). The solvent was removed under vacuum, and the product was isolated using column chromatography, with hexane:ethyl acetate (90:10) as the developing solvent system. The desired product, 3,3,5,5-tetramethyl-2,2-dihydroxybiphenyl, had m.p. 130-134C (lit.4, m.p. 133-134C); ?max (CCl4)/cm-1 3558 (OH), 2858-3050 (C-H) and 1547 (C=C); m/z 242 (M+), 227 (M+-15), 199 (M+-43), 165 (M+-77) and 91 (M +-151); dH (CDCl3)/ppm 2.38 (12H, s, CH3), 5.04 (2H, s,OH), 6.63 (2H, s, Ar) and 6.92 (2H, s, Ar). 2.2.2 Preparation of Coupling Agents Preparation of silver carbonate/celite 28

2.2.2.1

Celite was first purified by successively washing with methanol containing 10% concentrated HCl, and distilled water, until neutral. It was then dried at 120C for 12 h. This purified celite (30.00 g) was then added to a mechanically stirred solution of silver nitrate (34.00 g, 200.1 mmol) in distilled water (200 mL). slowly to the resulting homogeneous solution. A solution of Na 2CO310H2 O (30.00 g, 104.9 mmol) in distilled water (300 mL) was then added When the addition was complete, stirring was continued for a further 10 min. The yellow-green precipitate that formed was filtered off and finally dried on a rotary evaporator over a period of several hours. Every 0.57 g of this silver carbonate/celite reagent contained 1.00 mmol of Ag 2CO3.28

38

2.2.2.2

Preparation of barium manganate73

Preparati on of potassium manganate Potassium hydroxide (5.675 g, 101.1 mmol) was thoroughly mixed with manganese dioxide (4.345 g, 54.62 mmol) and left in an oven at 350C for 3 h. The fused green potassium manganate that so formed was filtered and then used for the preparation of barium manganate.

Preparation of barium manganate To a 500 mL flask containing distilled water (100 mL) was added barium hydroxide (7.698 g, 24.40 mmol), and the pH was adjusted to 7 with dilute hydrochloric acid. To the resulting warm solution was added potassium manganate (8.236 g, 41.78 mmol) with stirring. The colour of the reaction mixture immediately changed to dark purple. The reaction mixture was filtered with suction and the so-obtained dark blue crystals were washed several times with distilled water, and placed in an oven at 100C for 24 h to afford active barium manganate. 2.2.2.3 Preparation nnap)2)27 of a (nitrosonaphtholato)metal complex (Mn II(1-

Preparation of 1-nitroso -2-naphthol

After 2-naphthol (14.68 g, 101.8 mmol) was dissolved in hot NaOH (0.6 M, 340 mL), the solution was cooled to 0C. NaNO2 (7.054 g, 102.2 mmol) was added, and 6 M H2SO4 (16 mL) was carefully dropped into the resulting solution during 1.5 h with stirring. The mixture was stirred for a further 1 h. The brown solid that formed was filtered, washed with water (250 mL) and dried in a desiccator. The crude material was recrystallized from petroleum ether (b.p. 60-80C) to afford 1-nitroso-2-naphthol as reddish brown needles; m.p. 107-109C (lit.75, m.p. 106-108C).

39

Preparation of nitrosonaphthol sodium salt

1-Nitroso-2-naphthol (4.015 g, 21.28 mmol) was dissolved in a 10 M NaOH solution (50 mL) at 0C during 2 h, and the mixture was stirred at room temperature overnight. The green solid that formed was filtered, washed with 2 M NaOH solution, and dried in a desiccator to afford the corresponding sodium salt (3.613 g, 17.11 mmol, 76.25%). Preparation of MnII(1-nnap)2

Nitrosonaphthol sodium salt (3.182 g, 14.29 mmol) was dissolved in water (200 mL), and MnCl2 (1.880 g, 9.520 mmol) was added. After stirring for 2 h, the solid that formed was filtered, thoroughly washed with water and dried in a desiccator. The solid was recrystallized from CH2Cl2 -hexane to give dark brown crystals of MnII(1nnap)2 with a m.p. > 300C (lit.27 , m.p. >300C). 2.2.2.4 Electrochemical preparation of cerium(IV) from cerium(III) using a divided cell

The required amount of methanesulphonic acid was added to both the anode and cathode compartments to approximately the same level in each, after which the required amount of cerium carbonate was slowly added to the anode compartment. The experimental setup is shown in Figure 2.1.

40

A = Anode compartment B = Cathode compartment C = Amp meter D = Power supply E = Heater/stirrer

Figure 2.1: Experimental setup for the electrochemical generation of Ce(IV)

Both the anode and cathode compartments were heated (60C) and stirred (500 rpm) for the designated time period. After completion of this time period, the reaction mixture from the anode compartment was filtered, and a 5 mL sample of the filtrate was titrated against a ferrous sulphate solution with ferroin as indicator. This was done in order to determine the Ce 4+ concentration. The results obtained for the oxidation of Ce3+ to Ce4+ in various methanesulphonic acid solutions of varying concentrations may be observed in Table 2.3, where the data from triplicate titrations and their averages are listed.

41

Table 2.3

Moles of Ce4+ at various MeSO3H concentrations

4+

Methanesulphonic Acid Concentration Titration 1 (mmol)

Moles of Ce Titration 2 (mmol)

Titration 3 (mmol)

Average (mmol)

0.5 M

2.975

2.488

2.528

2.664

1.0 M

3.886

3.716

3.454

3.685

2.0 M

3.065

3.564

4.122

3.548

The electrochemical reaction conditions for the oxidation of Ce3+ to Ce4+ in the divided cell, in various methanesulphonic acid solutions of varying concentrations, are listed in Table 2.4. Table 2.4 Conditions for oxidation of Ce 3+ to Ce4+
3+

Methanesulphonic Acid Concentration

Initial Ce

Volts (V)

Amperes (A)

Time (h)

Concentration

0.5 M

0.1 M

24.0-26.0

0.4

72

1.0 M

0.1 M

10.0-13.5

0.4

48

2.0 M

0.1 M

5.0-6.8

0.4

24

2.2.2.5

Preparation of silver oxide 75

Sodium hydroxide (2.67 g, 66.75 mmol) was added to silver nitrate (10.62 g, 62.52 mmol) in water (100 mL) in a 250 mL round -bottomed flask. The reaction mixture

42

was stirred for 1 h, after which it was filtered. The so-recovered solid was washed repeatedly with water (200 mL) to result in a brown solid of Ag2O, which was dried in a vacuum desiccator for 48 h. 2.3 2.3.1 EXPERIMENTAL PROCEDURES Oxidative Coupling Reactions Oxidation of alkylphenols using silver carbonate/celite73

2.3.1.1

General procedure Before use, the silver carbonate/celite reagent (0.2 mmol of Ag 2CO3) was freed from residual water azeotropically by distillation with toluene. The alkylphenol (0.1 mmol) was then added to the silver carbonate/celite reagent and the reaction mixture was stirred in toluene (200 mL) for various reaction times. The reaction mixture was then filtered to remove the solid phase, the solvent evaporated with a rotary evaporator, and the resulting mixture analyzed by HPLC and GC-MS. 2.3.1.2 Oxidation of alkylphenols using copper complexes of dicarboxylic acids 76

General procedure Into a 250 mL reaction vessel, which was fitted with a gas addition tube, a condenser, a thermometer, and a stirrer capable of operating at speeds ranging from approximately 800 rpm to 10 000 rpm, was added sodium lauryl sulphate (0.10 g, 0.35 mmol), deionised water (75 mL) and the alkylphenol (approximately 65 mmol). To the resulting slurry (which was stirred between 800 and 10 000 rpm depending on the experiment), was added a mixture of cupric acetate (1.0 -50.0 mmol) and a dicarboxylic acid (1.0-50.0 mmol) in deionised water (50 mL). The resulting mixture was stirred for 5 min while heating to temperatures ranging from 60 to 80C. Sodium hydroxide (0.4 M, 100 mL) was added during the course of the reaction to maintain

43

the pH of the reaction mixture at 9. The mixture was stirred under oxygen or nitrogen depending on the experiment. The flow of gas was initially rapid to flush the system. After approxi mately 30 min, the gas flow was reduced and maintained at a level sufficient to cause slow bubbling. The reaction mixture was stirred and maintained under oxygen or nitrogen for time periods varying from 6 to 30 h. The reaction

mixture was then cooled to room temperature and then acidified to pH 3 with HCl (3 M). The reaction mixture was extracted using ethyl acetate (3 x 50 mL), and the organic layer washed with water (3 x 50 mL) and dried (MgSO4). The organic layer was then concentrated on a rotary evaporator and analyzed by HPLC and GC -MS. 2.3.1.3 Oxidation of alkylphenols using manganese(III) acetate26

General procedure The alkylphenol (7.00 mmol) was added to a mixture containing glacial acetic acid (130 mL) and manganese (III) acetate (3.753 g, 14.00 mmol). The reaction mixture was then heated to 100C for 1 h after which it was cooled down, extracted with chloroform (3 x 50 mL), and the organic layer washed with water (3 x 50 mL) and dried (MgSO4). The organic layer was concentrated on a rotary evaporator and analyzed by HPLC and GC-MS. 2.3.1.4 Oxidation of alkylphenols using barium manganate 73

General procedure The alkylphenol (10.00 mmol) in toluene (50 mL) w added to barium manganate as (12.81 g, 50.00 mmol) in a 100 mL round-bottomed flask. The reaction mixture was then stirred at room temperature for 1 h, and then vacuum filtered. The solid was washed repeatedly with ethyl acetate (total volume of 150 mL), and the combined organic washings concentrated on a rotary evaporator and analyzed by HPLC and GC-MS.

44

2.3.1.5

Oxidation of alkylphenols using a (nitrosonaphtholato)metal complex27

General procedure A mixture of the alkylphenol (1.00 mmol), the (nitrosonaphtholato)manganate complex (0.0399 g, 0.100 mmol) and triphenylphosphine (0.2885 g, 1.100 mmol), in dry CHCl3 (30 mL), was stirred for 5 h at 23C under an oxygen atmosphere (1 atm). The reaction mixture was then quenched with 2 M HCl (50 mL). The aqueous mixture was extracted with CHCl3 (3 x 25 mL), and the organic layer washed with water (3 x 25 mL) and dried (MgSO4). The organic layer was then concentrated on a rotary evaporator and analyzed by HPLC and GC -MS. 2.3.1.6 Oxidation of alkylphenols using FeCl3 in an organic solvent77

General procedure A mixture of the alkylphenol (7.0 mmol) and FeCl3 (2.271 g, 14.00 mmol), in an appropriate solvent (20 mL), was stirred in a round-bottomed flask at 50C for 2 h. The reaction mixture was then decomposed with dilute HCl (50 mL), and the organic layer washed with water (3 x 20 mL) and dried (MgSO4). The organic layer was then concentrated on a rotary evaporator and analyzed by HPLC and GC-MS. 2.3.1.7 Oxidation of alkylphenols using FeCl3 without solvent77

General procedure The alkylphenol (7.0 mmol) and FeCl36H2O (2.271 g, 14.00 mmol) were mixed together without any solvent, and the mixture then placed in a test tube and kept at 50C for 2 h. The reaction mixture was then decomposed with dilute HCl (50 mL), and the aqueous layer extracted with ethyl acetate (3 x 25 mL). The organic layer was washed with water (3 x 25 mL), dried (MgSO4), concentrated on a rotary evaporator and analyzed by HPLC and GC -MS.

45

2.3.1.8

Oxidation of alkylphenols using Ag 2O78

General procedure The alkylphenol (10.00 mmol) was added to silver oxide (4.635 g, 20.00 mmol) in 150 mL of methanol, after which the reaction mixture was stirred for 1 h at room temperature. The solids were removed by filtration and washed with hot toluene, the toluene then being combined with the filtrate. The resulting organic solution was concentrated on a rotary evaporator and the reaction mixture analyzed by GC-MS and HPLC. 2.3.1.9 Oxidation of alkylphenols using lead tetra-acetate79

General procedure The alkylphenol (7.00 mmol) was dissolved in to luene (100 mL) and stirred while lead tetra-acetate (6.2058 g, 13.997 mmol) was slowly added to the reaction mixture over 1 h. The reaction mixture was then washed with water (3 x 75 mL) and the organic layer dried (MgSO4) and concentrated on a rotary evaporator. Analysis was carried out using GC-MS and HPLC. 2.3.1.10 Oxidation of alkylphenols using Ce 4+

General procedure The required amount of Ce 4+ solution and the alkylphenol were added together in a round-bottomed flask in the required solvent and stirred vigorously at 750 rpm for the required time period. The reaction mixture was then extracted using ethyl acetate (3 x 25 mL), and the organic layer washed with water (3 x 25 mL) and dried (MgSO4). The organic layer was then concentrated on a rotary evaporator and analyzed by GCMS and HPLC.

46

2.3.1.11

Oxidation of alkylphenols using potassium ferricyanide

General procedure A solution of potassium ferricyanide (6.585 g, 20.00 mmol) and sodium hydroxide (2.840 g, 71.00 mmol) in water (100 mL) w added drop-wise during 30 min to a as vigorously stirred solution of the alkylphenol (20.0 mmol) in methanol (100 mL). After stirring for the required reaction time at room temperature, the mixture was poured into water and extracted with ethyl acetate (3 x 50 mL), the organic layer washed with water (3 x 50mL) and then dried (MgSO4). The organic layer was concentrated on a rotary evaporator and analyzed by GC -MS and HPLC. 2.3.2 Determination of Ce(III) Remaining after the Electrochemical Oxidation of Ce(III) to Ce(IV)80

Water (140 mL) and concentrated sulphuric acid (1 mL) were added to 20 mL of the cerium solution obtained after the electrochemical oxidation of cerium carbonate (i.e., Ce 3+) to Ce4+. (The number of moles of Ce4+ in this amount of solution had already been determined by titration as described in Section 2.2.2.4, and is denoted as A in Table 2.5 overleaf.) The reaction mixture was then treated with ammonium persulphate (1.241 g, 5.438 mmol) and 7 drops of 0.1 M AgNO3, and boiled for 30 min, in order to oxidize any remaining Ce 3+ to Ce 4+. The reaction mixture was then cooled down and titrated again against a ferrous sulphate solution (0.0860 M) with ferroin as the indicator, in order to determine the amount of Ce 4+ now present in the solution (denoted as B in Table 2.5). The difference between the initial Ce4+ and final Ce 4+ values (B-A), therefore, was a measure of the amount of Ce 3+ that remained after the electrochemical oxidation of the Ce3+ solution.

47

Table 2.5

Determination

of

the

amount

of

Ce 3+

ions

present

after

electrochemical oxidation of Ce3+ to Ce 4+

4+ 4+ 3+

Titration No.

Ce

amount before

Ce

amount after

Moles Ce

present

persulphate treatment (A)

persulphate treatment (B)

(B)-(A)

1.119 mmol

1.860 mmol

0.7410 mmol

1.113 mmol

1.876 mmol

0.7630 mmol

1.115 mmol

1.857 mmol

0.7420 mmol

Average

1.115 mmol

1.864 mmol

0.7490 mmol

2.3.3

Dealkylation of Dihydroxybiphenyls

3,3,5,5-Tetra -t-butyl-4,4-dihydroxybiphenyl (0.2345 g, 0.5711 mmol) and one drop of sulphuric acid were added to o-dichlorobenzene (20 mL) in a two-necked roundbottomed flask (50 mL), which was fitted with a reflux condenser and a tube introducing nitrogen. The reaction mixture was refluxed for 3 h under an N2 atmosphere, after which it was cooled, washed with water (3 x 25 mL) and the organic layer dried (MgSO4). The organic layer was then analyzed by GC-MS. 2.4 ANALYTICAL TECHNIQUES

2.4.1

High Performance Liquid Chromatography (HPLC)

HPLC Analyses were carried out on a Hewlett Packard 1100 series HPLC chromatograph with a dual pump system (G 1312A), equipped with a variable UV Visible detector (G 1314A) and an auto sampler unit (G 1313A). Data was acquired from the detector by means of a personal computer equipped with HP Chemstation

48

Acquisition software, version A.06.03.

All solvents were HPLC grade and were

degassed prior to analysis with a Millipore vacuum-degassing unit. A discovery C8 (serial no. 59354-u) column was used for the analysis of the reaction samples. As different substrates were used in the reactions, analysis of the mixtures required different LC conditions. These settings are summarized in Tables 2.6 2.9. Response factors for the compounds of interest were determined by means of a fivelevel calibration using standard solutions containing known amounts of the analytes.

Table 2.6

HPLC Conditions for 2-tert-butylphenol reactions

Injector Volume Column Wavelength Flow Rate Mobile Phase

5 L Bondpak C18 3.9 mm x 300 mm (Waters) 253 nm 0.7 cm3 min-1 80% MeCN : 20% H2 O

Table 2.7

HPLC Conditions for 2,4-dimethylphenol reactions

Injector Volume Column Wavelength Flow Rate Mobile Phase

1 L Bondpak C18 3.9 mm x 300 mm (Waters) 289 nm 0.5 cm3 min-1 90% MeCN : 10% H2 O

49

Table 2.8

HPLC Conditions for 2,6-d i-tert-butylphenol reactions

Injector Volume Column Wavelength Flow Rate Mobile Phase

5 L Bondpak C18 3.9 mm x 300 mm (Waters) 267 nm 0.7 cm3 min-1 100% MeCN

Table 2.9

HPLC Conditions for 2,4-d i-tert-butylphenol reactions

Injector Volume Column Wavelength Flow Rate Mobile Phase

1 L Bondpak C18 3.9 mm x 300 mm (Waters) 289 nm 0.5 cm3 min-1 90% MeCN : 10% H2 O

2.4.2

Nuclear Magnetic Resonance (NMR) Spectroscopy

Proton NMR spectra were recorded on a Brcker AX (300 MHz) spectrometer using X Win NMR software for data analysis. All samples were analyzed using CDCl3 as solvent. 2.4.3 Fourier Transform Infra Red (FTIR) Spectroscopy

Infra red spectra were recorded on a Brcker Tensor 27 FTIR linked to a Bell personal computer, equipped with Opus Software version 4.2. All samples were analyzed using CCl4 as solvent.

50

2.4.4

Gas Liquid Chromatography-Mass Spectrometry (GC-MS)

GC-MS Analyses were performed on a Thermo -Finnigan Trace GC coupled to a Quadropole Trace MS+ detector. The GLC was equipped with a Restek-RTX 5 MS (15 m x 0.25 mm i.d.) column. Data was acquired from the detector by means of a Bell personal computer equipped with Excaliber version 1.3 software. temperature program used is summarized in Table 2.10. Table 2.10 GLC Temperature program The

Initial Temperature Initial Hold Time Program Rate Second Temperature Second Hold Time

50C 2.0 min 15 C min-1 250C 45.0 min

The mass range capability of the mass spectrometer was from 50 to 1000 atomic mass units. 2.4.5 Molecular Orbital Calculations

Calculations were carried out using Spartan 02 (version 119) running under Linux 2.2 on a QuantumStation QS4-1800S machine. Structures were initially partially refined using the MMFF molecular mechanics facility, where a conformational search was carried out in order to identify the lowest energy conformer in each case, before these structures were refined at the PM3 semi-empirical MO level. All geometry

optimisations achieved energy gradient norms of at least 0.01kcal/mol/.

51

2.5

TERMS AND DEFINITIONS

Terms and definitions like selectivity and conversion need to be clarified. These are: Selectivity: defined as the ratio of a particular product to the amount of substrate consumed, and this is expressed as a percentage.

Selectivity =

moles product x 2 moles substrate ch arg ed moles substrate remaining

x 100

Conversion: defined as the total amount of substrate originally charged that has been consumed in the formation of the reaction products, expressed as a percentage.

Conversion =

moles of substrate ch arg ed moles of substrate remaining moles of substrate ch arg ed

100

52

CHAPTER 3 DISCUSSION
3.1 MODES OF PHENOLIC COUPLING

There are several mechanisms that may be proposed by which phenolic substrates may oxidatively couple with one another to form dimers. Naturally, the nature of the phenolic substrate plays a crucial role in the mode by which it ultimately combines with another substrate molecule. Of significant importance in this regard is the nature of substitution of the phenolic ring, not only encompassing the number and type of substituents, but also the positions they occupy relative to the hydroxyl moiety and each other.

When one considers, for simplicity sake, the coupling of an unsubstituted phenol with another such substrate, six modes of coupling may be identified. In five of these, (AE) shown in Scheme 22, the immediate precursor to the coupled product is shown as the phenoxyl radical (which is resonance stabilized, see previous Scheme 7), and the immediate product upon coupling is the dienone form of the dimer, which then rearomatizes to form the phenolic analogues.

53

phenoxyl radical O

dienone dimer O H A H O O

phenolic dimer OH

OH OH

O O O H C H OH

OH OH

O H O D

OH O

OH

E H O O

Scheme 22: Dienone and phenolic dimers from the coupling of phenoxyl radicals

54

Scheme 23 is an illustration of the sixth possible mode of coupling (F) in which two phenoxyl radicals combine through oxygen, resulting in the peroxide as shown.

phenoxyl radical O

peroxide

F O O

Scheme 23: Peroxide formation from the coupling of phenoxyl radicals

Thus when two phenoxyl radicals couple with another, they may do so in one of the following ways: Ortho C-ortho C coupling (A): A resonance form of the phenoxyl radical in which the radical is centered at the ortho position couples with another identical species; Para C-para C coupling (B): A resonance form of the phenoxyl radical in which the radical is centered at the para position couples with another identical species; Ortho C-para C coupling (C): A resonance form of the phenoxyl radical in which the radical is centered at the ortho position couples with another resonance form of the phenoxyl radical in which the radical is centered at the para position; Ortho C-O coupling (D): A resonance form of the phenoxyl radical in which the radical is centered at the ortho position couples with the oxygen-cente red radical of another phenoxyl species; Para C-O coupling (E): A resonance form of the phenoxyl radical in which the radical is centered at the para position couples with the oxygen-centered radical of another phenoxyl moiety; and

55

O-O coupling (F): two phenoxyl moieties combine through their oxygencentered radicals.

Because of the numerous pathways through which phenoxyl radicals may react with one another to form dimers, the oxidative coupling of unsubstituted phenol itself results in numerous products, and there is no known process in which the yield and selectivity to one specific product is high enough to term the process a successful one. In addition to the above six modes of coupling, one must also bear in mind that dimeric products that form are also capable of reacting further with either the substrate and/or dimeric products in the reaction mixture, forming polymeric species. Oxidation mixtures of unsubstituted phenols thus result in a complex mixture of dimeric, polymeric and unreacted compounds, often with poor carbon accountability. All of these factors make the oxidative coupling of unsubstituted phenol itself a very unattractive prospect when the desired product is a specific dimeric form, for example, the industrially useful compound 4,4 -dihydroxybiphenyl (6). 3.1.1 Molecular Orbital Calculations for the Coupling of Phenol

In order to ascertain the likelihood that the phenoxyl radicals will couple as shown in Schemes 22 and 23, it was deemed appropriate to calculate the relative stabilities of the dienone dimers as well as the phenolic dimers. Since these species are all isomeric, their relative stabilities can be obtained by comparing their heats of formation (? fH) directly. Given in Table 3.1 are the theoretical heats of formation for the coupled dienones (? f Hd) and phenols (? fHp), calculated at the PM3 semi-empirical molecular orbital (MO) level. In the final column of the table, the difference between the heats of formation of the phenolic dimers and their corresponding dienones has also been calculated.

56

Table 3.1

PM3 Heats of formation for phenol coupling products

Coupling mode

? fHd (kcal/mol)

? fHp (kcal/mol)

? fHp - ? fHd (kcal/mol)

-6.53

-24.52

-17.99

-5.87

-41.86

-35.99

-5.61

-23.97

-18.36

-5.08

-42.19

-37.11

-4.99

-39.48

-34.49

It is clear from these results that the relative stabilities of the primary coupling products, the dienones, are very similar. As a result, one would expect to obtain a distribution of all the possible dienones (C-C and C-O coupled), assuming that their rates of formation are similar. These calculations also show that the C-C coupled phenolic products, i.e., coupling modes A, B and C (where ? f Hp is 39.48, -42.19 and 41.86 kcal/mol, respectively), are significantly more stable than the C-O coupled products, i.e., coupling modes D and E (where ? f Hp is 23.97 and 24.52 kcal/mol, respectively), and one would expect, thus, a predominance of C-C coupled products in the product mixture. However, the rates at which the dienones are converted to the phenolic dimers are not known, and so one cannot ultimately make predictions about the final phenolic dimer product distribution. (It is assumed here that the dienone -phenolic dimer conversion is irreversible and that no equilibrium exists in this transformation.)

57

The peroxide PhOOPh, formed by means of O-O coupling (mode F), can be shown to be much less stable, having a calculated heat of formation of +34.61 kcal/mol. From this investigation, it may be concluded that both C-C and C-O dienone products are likely to form in the oxidative coupling of unsubstituted phenol. Hence their corresponding phenolic forms are also likely, though it must be reiterated that these calculations do not convey any information on relative rates of formation, and so the actual product distribution cannot really be predicted. The peroxide, PhOOPh, on the other hand, appears unlikely to form due to its low stability relative to the other products. These calculations thus confirm reports that the oxidative coupling of

phenol results in a wide product distribution, both C-C and C-O coupled, and cannot be used with much success when a single dimer is the desired product. Experimentally, this work did not involve unsubstituted phenol as a substrate for the above reasons. However, the above MO study was extrapolated to two other substrates, 2,4 -di-t-butylphenol and 2,6 -di-t-butylphenol, the results of which are discussed in the relevant sections. 3.2 THE OXIDATIVE COUPLING OF 2-t-BUTYLPHENOL

The literature contains many reports that deal with the successful C-C coupling of disubstituted phenols, such as 2,4- and 2,6- dialkylphenols, but is, however, virtually devoid of studies carried out on monosubstituted phenols, such as 2-t-butylphenol. This is certainly because both 2,4- and 2,6 - disubstituted phenols can each only effectively C-C couple at one particular carbon position, namely the 6- and 4positions, respectively, thus affording high yields and selectivities to the desired product with these substrate types. (This is obviously assuming that C-C coupling is less likely to take place at aromatic carbon positions that already bear a substituent, this assumption having been confirmed by PM3 semi-empirical MO calculations which are discussed later). However, in the case of the monosubstituted phenols, such as 2-t-butylphenol (35), there are two positions available through which C-C coupling can

58

occur, the 4- and 6- positions, and so the number of possible products increases and therefore results in low yields and selectivities to any one desired product. Thus these substrate types generally result in reactions that are not significantly successful, and hence their virtual absence of mention in the literature.

OH 1 6 5 4
(35) There therefore exists a need to investigate the oxidative coupling of monosubstituted phenols in more depth in order to, at best, develop a process that leads to higher yields of the required materials or, at worst, contribute positively towards this field of chemistry by obtaining further information associated with this reaction, since there does not appear to be much mention of it in the literature. To this end, a variety of oxidizing agents were used in the investigation of the oxidative coupling of 2-tbutylphenol in order to attempt to form the para-para C-C coupled product, 3,3-di-tbutyl-4,4-dihydroxybiphenyl (molecule (39) in Scheme 25), in high yield and selectivity.

C(CH3)3 2 3

The aim of this section of the work was to determine whether any one particular oxidizing agent afforded optimal results compared with the other agents used, and whether the substrate molecule could, in fact, be C-C coupled selectively through its para position despite the additional availability of its ortho position.

59

3.2.1

The Range of Possible Products During the Oxidative Coupling of 2-t-Butylphenol

The reaction mechanisms possible for the oxidative coupling of substituted (mainly disubstituted) phenols have been discussed at length in the literature.22,23 As mentioned previously, the number of products possible with 2-t-butylphenol as a substrate is most likely to be greater than that with 2,4 - or 2,6- disubstituted phenols as substrates. In order to hypothetically predict the types of coupling products

possible with (35), one needs to look at the possible coupling modes of the initial 2-tbutylphenoxyl radical that is formed. Due to resonance stabilization, the radical may be centered at either the 6- or the 4- position, or on oxygen itself. In either of the two cases where the radical is centered on an aromatic carbon atom, a number of products can form, as is illustrated in Schemes 24 and 25. In these schemes, only the phenolic forms of the coupled products are given, and not the primary dienone products, for the sake of brevity.

Scheme 24, in which the radical is centered at position 6, shows how the monosubstituted phenoxyl radical can couple with either another radical in which the unpaired electron is centered at the 6- or 4- position, or also on oxygen, affording phenolic dimers (36), (37) and (38) as products, respectively. Scheme 25 is similar but the initial phenoxyl radical is centered at position 4, thus affording compounds (37), (39) and (40) upon combining with the various species as shown.

60

OH

OH
O

(36)

OH O O OH

(37)

OH O

(38)

Scheme 24: Modes of coupling of the 2 -t-butylphenoxyl radical when the radical is centered on position 6

61

OH OH

(37)

OH
O

OH (39)

HO (40)

Scheme 25: Modes of coupling of the 2 -t-butylphenoxyl radical when the radical is centered on position 4

There are therefore three possible modes of C-C coupling when 2-t-butylphenol is oxidatively coupled, namely para-para, ortho-para and ortho-ortho coupling, as was the case for unsubstituted phenol. In this study, due to its industrial uses and importance, the desired product was 3,3-di-t-butyl-4,4-dihydroxybiphenyl (39). Already it is apparent that the number of possible products using 2-di-t-butylphenol as the substrate are numerous, with, in addition to the three different C-C coupled

62

products, two C-O coupled products also being possible, as are products resulting from polymerization (see previous Schemes 14 and 15). The lengths of the polymeric chains may also vary depending on the oxidant used,81 and so the reaction mixture may become rathe r complex indeed. (Note that MO calculations were not performed on any of the C-C, C-O or O-O coupled products in this instance, the reason being that this substrate could not be effectively coupled selectively to any one desired compound, as will become apparent in the next sections.)

2-t-Butylphenol was thus subjected to the action of various oxidizing agents in order to assess their effect on the product distribution in this coupling reaction. results are discussed in the following section. 3.2.2 Oxidative Coupling Reactions of 2-t-Butylphenol Using Various Oxidants These

After a thorough scrutiny of the available literature, a number of coupling agents were selected upon the basis that they were, according to the various reports (though these deal mainly with 2,4- or 2,6- disubstituted phenols), primarily para-directing. In addition, and where appropriate, we considered issues such as environmental impact and economic viability in our selection. Since the selected agents effect on compound (35) ha s never been reported, it was envisaged that information obtained from this study would be invaluable to the knowledge base of this field of chemistry. The aim of these experiments was to determine how effectively each of the selected oxidizing agents was in terms of preparing the para-para C-C coupled product (39) from (35). A standard material of (39) was prepared by treating 4,4-dihydroxybiphenyl with tbutyl bromide in the presence of SiO2 and Na 2CO3 for purposes of analysis in this section. The compound required purification by means of thin-layer chromatography, and its structure was confirmed to be that of (39) by means of a melting point

63

determination (where this compared favourably with that given in the literature), as well as NMR, IR and GC -MS experiments. The reaction conditions and results for the reaction of 2-t-butylphenol with the various oxidizing agents are summarized in Table 3.2. Table 3.2 Reactions of 2-t-butylphenol with various oxidizing agents

Reaction No.

Oxidant

Time (h)

Solvent

Temp.

Conversion of (35) (%)

Selectivity to (39) (%)

Ag2CO3/Celite

PhCH3

R.T.

10.98

25.57

Ag2CO3/Celite

20

PhCH3

R.T.

78.58

3.56

Cu(OAc)2/ Oxalic acid

10

H2O

60C

86.32

1.30

Mn(OAc)3

CH3CO2 H

100C

85.38

2.14

BaMnO4

CHCl3

50C

66.96

4.55

FeCl3

CH2 Cl2

R.T.

100.00

0.00

Ag2O

MeOH

R.T.

96.00

7.29

K 3Fe(CN)6

MeOH

R.T.

62.20

0.85

Ce(SO4)2

H2O

R.T.

26.61

25.99

64

3.2.2.1

Vanadium(V) oxytrichloride and vanadium(IV) tetrachloride as coupling agents

As discussed previously, literature reports show that vanadium(V) oxytrichloride61 and vanadium(IV) tetrachloride react with phenol to give exclusively para-coupled products, thus implying that these agents are highly selective and para -directing in their action. Furthermore, vanadium(V) is reported to follow a non-radical mechanism in which an intermediate with a considerable cationic character is developed, ultimately ensuring the exclusive formation of para -coupled products (see previous Schemes 8 and 9).82 However, for the purposes of our investigation, due to the prohibitive costs of these oxidants, and due to the fact that a vigorous evolution of HCl gas is accompanied by their reaction with the substrate, implying both economical and environmental non-viability, it was decided not to assess their effect on 2-t-butylphenol as substrate. 3.2.2.2 Silver carbonate supported on celite as coupling agent

Silver carbonate on a celite support is also known28 to be a highly specific and selective oxidizing agent for C-C coupling when reacted with disubstituted phenols. For example, when silver carbonate/celite was reacted with 2,6-di-t-butylphenol, the diphenoquinone (10) was the primary product formed. The redox potential of the oxidant (Ag+ + e- ? Ag ~0.80 V) is thus high enough to oxidize the initially formed 4,4-dimer (16) to the corresponding 4,4-diphenoquinone (10). An attractive prospect with this agent is that the reactions were performed under very mild conditions. Though the cost of the agent is rather high, it was deemed plausible that some form of recycle would circumvent this disadvantage, and so it was decided to investigate silver carbonate/celite as the coupling agent for 2-t-butylphenol, and thus to compare the results obtained with those achieved with disubstituted phenols. Thus a water-free silver carbonate/celite oxidant was prepared and the substrate added to it, and the mixture stirred at room temperature for either 1 h (reaction 1,

65

Table 3.2) or 20 h (reaction 2, Table 3.2 ). From the results in Table 3.2, it can be seen that reaction 1 did not afford a high selectivity to the desired coupled product 3,3-di-t-butyl-4,4-dihydroxybiphenyl (39). %. A GC-MS experiment of the reaction mixture (from reaction 1) showed that there were four products, at retention times of 12.76, 13.29, 14.18 and 15.27 min, that had the same molecular ion mass (M +) of 298 mass units (the mass of the desired product). The GC trace and the associated mass spectra of these four isomeric products may be observed in Figure 3.1 and Appendices 3.1-3.4, respectively. From standard curves using HPLC analyses, it was determined that in reaction 1, the selectivity to (39) was only 25.57

Figure 3.1: GC trace of product mixture obtained in reaction 1, Table 3.2

An injection of the standard material for (39) showed that it eluted at 15.27 min, confirming the presence of the desired product in the reaction mixture. The MS fragmentation patterns of each of these products (Appendices 3.1-3.4) were found to be, unsurprisingly, somewhat similar in that many of the mass fragments were common to all four products. The main difference between these mass spectra was the relative abundance of the various mass fragments in one spectrum compared to

66

that in another spectrum. It should be noted that products (36), (37), (38) and (40) all have the same M+ (298 mass units) as the desired product (39). However, to identify the exact structures of the products from their MS fragmentation patterns alone was not possible, and an exhaustive separation procedure would be required followed by individual characterization. This was not deemed necessary since the objective of this study was to increase the selectivity to (39). In an attempt to increase the yield of (39) that was obtained in reaction 1, the reaction time was extended from 1 h to 20 h, with all other variables remaining constant (reaction 2, Table 3.2). The effect of this change was a dramatic increase in the conversion of the substrate (from 10.98 to 78.58 %), but with an equally dramatic decrease in selectivity to (39) [from 25.57 to 3.56 %]. The number of moles of (39) formed in each of these two reactions was calculated from standard curves using HPLC analyses, and may be observed in Table 3.3. Table 3.3 Amount of 3,3-d i-t-butyl-4,4-dihydroxybiphenyl (39) formed in reactions 1 and 2

Reaction No. 1 2

Time (h) 1 20

Mass of (35) used (g) 0.1576 0.1611

Moles of (35) used (mmol) 1.049 1.072

Moles of (39) formed (mmol) 0.0147 0.0150

It is clear that in both reactions in which the amounts of substrate used was very similar, irrespective of the reaction time, the same amount of product was formed. Reaction time did not seem to have an effect on the yield of the desired product (39). This may imply that the desired reaction is rather fast, and that an increase in time after the formation of (39) merely resulted in side product formation, and hence the overall decrease in selectivity to (39). However, it may also be probable that the increased reaction time allowed the formed product to react further, thus also accounting for the decrease in selectivity. 67

Further scrutiny of the GC trace from reaction 1 (Figure 3.1) revealed the two products at retention times 20.67 and 21.79 min. MS Data showed both these
+ products to have an M of 446 mass units, and their retention times alone hinted at

the possibility that these were large molecules. When the possible products with m/z = 446 mass units were investigated, it was found that the C-O coupled produc t (41) in Scheme 26 (where n=1), had this required mass. Other workers using 2,6dimethylphenol as the substrate and manganese oxide as the coupling agent also found these types of compounds in their reaction mixtures (see Schemes 14 and 15).37
OH (CH3) 3C

OH (CH3) 3C Ag 2CO3 /celite (CH3) 3C O

(35) n=1,2,3,..... O (CH3 )3C

(41)

Scheme 26: The C-O coupling of 2-t-butylphenol to afford (41)

When C-O coupling occurs, the reaction mixture becomes much more complex with side product formation becoming even more significant. It must also be noted that when an oxidizing agent is reacted with 2-t-butylphenol, the polyether (41) is only one

68

of the possible products that could have m/z = 446 mass units. Another possibility is the following C -C coupled product, which is also deemed highly feasible.

OH OH (CH3)3C C(CH3)3

(CH3)3C OH (42)

Furthermore, a product having both C-O and C-C coupling may also account for the mass of 446, but mass fragmentation patterns alone do not suffice for the exact structure determination of such molecules. Upon completion of reaction 2, i.e., after 20 h reaction time, it was noted that these two products with m/z = 446 mass units disappeared, an indication that they reacted further to form longer chain polymers, and which could then not be detected by this technique. To add credence to the latter statement, reaction mixture 2, upon workup, was very tarry, dark in colour and had a high viscosity, an indication of the presence of polymers. It was thus concluded that silver carbonate/celite was not suitable as a coupling agent for 2-t-butylphenol under the conditions investigated in this study, despite its reported success with disubstituted phenolics: the reaction was very inefficient and the

69

selectivity to (39) was unacceptably low. No further work was thus conducted using this oxidant and 2-t-butylphenol. 3.2.2.3 Copper acetate, in the presence of a dicarboxylic acid, as coupling agent Copper acetate, in the presence of the dicarboxylic acid oxalic acid,46,76 was also investigated as a coupling agent for 2-t-butylphenol. Cupric salts of dicarboxylic acids have been reported to couple phenolic substrates, the products of which were combined at unsubstituted ortho- and para- positions in a manner characteristic of single-electron oxidizing agents. The higher oxidized products such as the diphenoquinones were generally not produced with this coupling agent. Furthermore, only reactions of disubstituted phenols have been reported,46 due to the increased possibility of polymer formation with substrates that are less substituted. A slurry of the substrate and sodium lauryl sulphate in deionised water was treated with a mixture of cupric acetate and oxalic acid, also in deionised water, and the resultant mixture stirred rapidly for 5 min while heating to 60C. After the addition of sodium hydroxide (in order to achieve a pH of 9), the mixture was heated and stirred for 10 h under an oxygen atmosphere, cooled and worked up. Reaction 3 in Table 3.2 summarizes the result of this experiment. Disappointingly, this was not promising: although the conversion of the substrate was high (86.32 %), the amount of (39) formed was extremely low, with a selectivity to (39) of 1.30 % being calculated. This implied that side product formation in this reaction was highly significant. Consider the HPLC trace obtained upon analysis of the reaction mixture (Figure 3.2):

70

Figure 3.2: HPLC of product mixture obtained in reaction 3, Table 3.2

It is obvious from this trace that the reaction mixture for reaction 3 is highly complex with many different products visible. It was virtually impossible to isolate/characterize all of these products due to their great number, and their low occurrence. The reaction conditions were then varied in order to assess their effect on the reaction: various other dicarboxylic acids, such as succinic and glutaric acid, were used in place of oxalic acid, and the reaction was carried out under an N2 rather than O 2 atmosphere. Furthermore, the oxidant:substrate molar ratios were varied. None of these variations provided any significant improvements. Once again, it was concluded that the cupric salts of dicarboxylic acids were not suitable as coupling agents for 2-t-butylphenol under the reaction conditions investigated, despite the positive results reported for 2,6-di-t-butylphenol.46

3.2.2.4

Manganese(III) acetate as coupling agent

It has been reported in the literature 26 that Mn(OAc)3 can be used successfully as a coupling agent for 2,6-disubstituted phenolic substrates, with quantitative yields to the desired products being claimed. However, this oxidant, when reacted with

monosubstituted phenols such as p-cresol, p-chlorophenol and 4-t-butylphenol, is

71

also reported to afford mostly polymeric products.26 Despite these reports, an investigation of this oxidant with 2-t-butylphenol was undertaken. 2-t-Butylphenol was thus treated with a manganese(III) acetate/glacial acetic acid mixture for 1 h at 100C. Reaction 4 in Table 3.2 is a summary of the obtained results. A high conversion (85.38 %) indicated the high reactivity of 2-t-butylphenol with managanese(III) acetate, but the selectivity to (39) was, once again, extremely low at 2.14 %. From the GC trace, the products at retention times 12.76, 13.29, 14.18 and 15.27 min (with m/z = 298 mass units) were again prominent (as they were in the Ag2CO3/celite work), with no trimeric species being observed at retention times of 20.65 and 21.79 min (with m/z = 446 mass units). The reaction mixture was very tarry upon work-up, and the presence of long chain polymers was thus a distinct possibility (these not usually being observable under the GC-MS conditions used). Thus manganese(III) acetate proved also to be unsuitable for the oxidative coupling reactions of 2-t-butylphenol under the reaction conditions employed. 3.2.2.5 Barium manganate as coupling agent

Barium manganate is known to effectively couple substituted phenolics,73 and it was thus decided to investigate its effect on 2-t-butylphenol. This substrate, in CH2Cl2 as solvent, was treated with excess BaMnO 4 at room temperature for 1 h. The results obtained are summarized in Table 3.2 (reaction 5). These show, once again, a very low selectivity to (39) [4.55 %], despite a reasonable conversion of the substrate (66.96 %). Once again, the GC and HPLC traces indicated that a large number of products had formed in the reaction. From the GC trace (Appendix 3.5), the isomeric products at retention times 12.79, 14.21 and 15.30 min were again prominent (as they were in the silver carbonate/celite work). In addition, products at retention times 20.84, 22.00, 26.41 and 38.04 min all had the same M+ value (446 mass units), and it has already been speculated that these compounds are isomeric trimeric species (see the silver carbonate /celite investigation).

72

It was concluded that BaMnO 4 was therefore not an ideal coupling agent for (35) in these conditions due to the low selectivity to (39). 3.2.2.6 Ferric chloride as coupling agent

2-Naphthol has been successfully coupled using FeCl3, known as a one-electron oxidant, as coupling agent. 77 2-t-Butylphenol was thus treated with this ferric species for 2 h at room temperature with chloroform as the solvent. Table 3.2, reaction 6, illustrates that no p-p coupled product was formed under these conditions, as was observed from standard HPLC data, and confirmed by GC -MS experiments, despite total substrate conversion. The nature of the products obtained in this reaction also varied substantially from those experiments already discussed, as was apparent from the lack of common retention times and m/z values when comparing the various traces. However, due to the poor results achieved in this reaction, these products were not characterized.

Reports exist that claim that many phenols having steric bulk in the vicinity of the hydroxyl moiety do not couple successfully in the presence of FeCl3. It has been stated that this is due to prevention of formation of the phenoxyliron complex that is required to form for an efficient reaction.22 Thus carbon-carbon coupling is only favoured when the phenoxyl radicals that are produced remain complexed through oxygen to the respective iron atoms during the coupling step. This may offer a reasonable explanation for our findings using (35) as the substrate, since this compound does have steric bulk, in the form of the tert-butyl group, in the ortho position to the hydroxyl group. instance. FeCl3 was thus not investigated further in this

73

3.2.2.7

Silver oxide as coupling agent

Silver oxide provided high yields and selectivities to the desired C-C coupled products when disubstituted substrates such as 2,6-di-t-butylphenol were employed in its presence.78 The mechanism of this reaction, however, is possibly the least well understood of all the oxidative coupling processes, though it is postulated to occur on the metal surface.22

In our investigation, commercially available silver oxide was used in addition to silver oxide that had been prepared in our laboratories by treatment of silver nitrate with aqueous sodium hydroxide. The use of this oxidant implies exorbitant costs (unless some form of recycle may be used for the silver metal so-produced), irrespective of the results achieved. The alkylphenol was added to silver oxide in methanol, and the resultant reaction mixture was stirred at ambient temperature for 1 h. Reaction 7 in Table 3.2 thus showed a high conversion of the substrate (96.00 %), but with a selectivity of only 7.29 % to (39). The kinds of products obtained were similar to those from the silver carbonate/celite work, as concluded from GC data. The coupled product 3,3-di-tbutyl-4,4-dihydroxybiphenyl (39) was the most prominent on the GC trace, and no other products were observed above the retention time of 16 min. It thus initially appeared as though the selectivity to (39) would be high, but standard calculations proved otherwise: once again, the conditions under which the GC-MS experiments were conducted were not conducive to the detection of polymeric materials, as must have been present in this case to account for the low calculated selectivity. Silver oxide as coupling agent was thus set aside due to its inefficient action in this reaction to afford (39).

74

3.2.2.8

Potassium

ferric

cyanide,

lead

tetra-acetate,

(nitrosonaphtholato)metal complex and cerium(IV) sulphate as oxidants

The final oxidants that were investigated for substrate (35) were potassium ferric cyanide, lead tetra-acetate, a (nitrosonaphtholato)metal complex and cerium(IV) sulphate. No reactivity between the (nitrosonaphtholato)metal complex27 and 2-tbutylphenol was observed although the reaction was repeated several times, and so this reaction was not investigated further. The reaction of lead tetra -acetate79 with 2t-butylphenol gave a large variety of products, but the selectivity to the coupled product (39) was not quantified. The use of K3Fe(CN)6 and Ce(SO4)2 as oxidative coupling agents with disubstituted phenols is well documented.50,83 These reactions were carried out according to Sections 2.3.1.10 and 2.3.1.11, and the results so-obtained are summarized in Table 3.2, reactions 8 and 9. The first of these was disappointing: potassium ferric cyanide (reaction 8) allowed the formation of only 0.85 % of (39) of the 62.20 % of substrate that had been converted. Ce4+, which is generated electrochemically from cerium(III) carbonate and is thus economically viable and environmentally friendly due to the potential for regeneration, gave a reasonable selectivity to (39) of 25.99%, but only 26.61 % of the substrate was converted. GC-MS Data showed, once again, that the range of products was similar to those of the many oxidants discussed previously. 3.2.3 Concluding Remarks on the Oxidative Coupling of 2-t-Butylphenol

From all of the above information, it is clear that the number of modes in which 2-tbutylphenol can couple is vast, irrespective of the oxidant used, resulting in experiments that generally produced low selectivities to (39). The highest selectivities were achieved with silver carbonate on celite, and cerium(IV) sulphate, but these too were unacceptably low (for purposes of industrial interest). The other oxidants were virtually totally ineffective at producing the desired result. In most of the cases,

75

conversion of the substrate was reasonable, and it appeared that the higher conversions were associated with the lowest selectivities. This was not surprising since high conversions, in these reactions, generally implied an increased possibility for side product and polymer formation. No further work was thus conducted on (35) as substrate since none of the results obtained showed any promise. 3.3 THE OXIDATIVE COUPLING OF 2,6-DI-t-BUTYLPHENOL

The literature contains many reports that deal with the successful para C-para C coupling of 2,6-di-t-butylphenol (9). 84-87 In order to understand why this substrate reacts so successfully, we may predict that the reasons are due to the fact that (9) can only effectively couple at one particular carbon position, namely the 4-position, assuming that coupling at a carbon position already bearing a substituent is less favoured (as is likely, due to steric implications). This latter assumption, however, will be investigated further in order to assess its validity.

OH (CH3)3C 6 5 4 (9)
Furthermore, we may also assume that para C-O coupling will be less likely to occur than para C-para C coupling because of the increased steric effect that would come into play in such a situation, due to the proximity of the t-butyl groups to the hydroxyl moiety (and thus their proximity to the subsequent O-centered phenoxyl radical species, effectively hindering its reaction with other radical species). We may thus predict that side reactions, such as those resulting from para C-O coupling, ortho Cpara C coupling etc., will be less favoured, and that the resultant product mixture in the oxidative coupling of (9) will show a high yield and selectivity to the desired

1 2 3

C(CH3)3

76

product, 3,3,5,5-tetra -t-butyl-4,4-dihydroxybiphenyl (16), via the corresponding dienone form. (Note that, depending on the oxidant, 3,3,5,5-tetra -t-

butyldiphenoquinone (10), may also be the isolated product, which is formed by over oxidation of (16), and that this product may readily be reduced back to the phenolic form (16).) Previous studies have been conducted to investigate the effect of various substituents on the aromatic ring in coupling reactions. It has been reported87 that when larger groups, such as t-butyl, are present, then carbon-carbon coupling predominates. However, when the phenolic bears smaller substituents, such as a methyl group, carbon-oxygen coupling becomes more predominant. It was further reported that the relative rate of this competitive reaction depended largely on the reaction conditions. As confirmation of the above predictions and thus the success with which (9) can be oxidatively coupled, this substrate has been reported to predominantly form the para C-para C dimer in very high yields when subjected to electrochemical oxidation, as shown in Scheme 19 previously.53 3.3.1 Molecular Orbital Calculations for the Oxidative Coupling of 2,6 -Dit-Butylphenol

Predictions made in the preceding section required some theoretical backup and verification, and MO calculations were thus carried out in order to determine the preferential mode of coupling of (9). All possible modes were taken into account, with one exception, the oxygen-oxygen coupling mode to afford the peroxide, since this had been shown in previous calculations to be highly unlikely. Schemes 27a and 27b are an illustration of the coupling reactions investigated by means of PM3 semiempirical MO calculations.

77

phenoxyl radical

dienone dimer O t -Bu t -Bu t -Bu

phenolic dimer OH t -Bu

O t -Bu t -Bu G H H

t -Bu O O t -Bu

t -Bu

t -Bu OH OH

t -Bu

t -Bu

t -Bu

t -Bu

t -Bu H H O O

t -Bu

t -Bu

t -Bu

Scheme 27a: Dienone and phenolic dimers from the coupling of 2,6-di-tbutylphenoxyl radicals by modes G and H

Of the five modes possible, only two are able to result in a final phenolic form of the product (where both rings are aromatic), modes G and H (Scheme 27a), with the other modes (I, J and K, Scheme 27b) forming only the dienone form of the dimers (where at least one of the rings is not aromatic), due to the nature of their structures. (Dienones from modes I, J and K would require the leaving of one or more t-butyl groups in order to form phenolic products, which we assume will not be a highly significant reaction pathway.)

78

phenoxyl radical

dienone dimer t -Bu

O O t -Bu t -Bu I t -Bu H t -Bu

t -Bu

O t -Bu J t -Bu t -Bu O

t -Bu

O t -Bu t -Bu K t -Bu O t -Bu

Scheme 27b: Dienone dimers from the coupling of 2,6-di-t-butylphenoxyl radicals by modes I, J and K

As done previously for phenol, the relative stabilities of the various dimeric species for coupling modes G were obtained by comparing their heats of formati on (? f H) -K directly. Thus the heats of formation obtained for the coupled dienones (? f Hd) and phenols (? f Hp) are summarized in Table 3.4.

79

Table 3.4

PM3 Heats of formation for 2,6 -di-t-butylphenol coupled products

Coupling mode

? fHd (kcal/mol)

? fHp (kcal/mol)

? fHp - ? fH d (kcal/mol)

-84.34

-119.24

-34.90

-80.29

-94.17

-13.88

-76.39

N/A

N/A

-59.89

N/A

N/A

-47.35

N/A

N/A

It is obvious from the data contained in Table 3.4 that the most stable dienone intermediate product is the one that results through coupling mode G (where ?f Hd is -84.34 kcal/mol), i.e., through unsubstituted para C-para C coupling, as predicted earlier. Approximately 4 kcal/mol less stable is the para C-O coupled dienone through mode H (with ? f Hd = -80.29 kcal/mol). The relative stabilities of the phenolic tautomers of these dienone dimers follow the same trend in that mode G affords the more stable substituted phenolic dimer (? fHp = -119.24 kcal/mol), with the phenol from mode H being significantly less stable (by 25.07 kcal/mol with ? f Hp = -94.17 kcal/mol). A plausible reason for these stability differences is the enhanced steric congestion experienced by products formed through mode H.

Coupling via the substituted ortho C and an unsubstituted para C (mode I) is about 8 kcal/mol less favourable than para C-para C coupling (with ?f Hd = -76.39 kcal/mol). Steric congestion, once again, is most likely the major contributing factor for this observation. Similarly, the other two modes of coupling (J and K) that also involve a

80

carbon atom already bearing a substituent are even less favourable, as was predicted earlier, and for similar reasons. In conclusion, we may therefore say that the formation of the para C-para C coupled product will be the most likely when considering calculated heats of formation of the various species. These MO calculations add credence to previous predictions made regarding which mode of coupling will be the predominant one when (9) is used as the substrate of choice.

2,6-Di-t-butylphenol was subjected to the action of a couple of oxidizing agents, namely Ag 2O and Cu(OAc) 2 /oxalic acid, in order to confirm the previous predictions experimentally in our laboratories, and to compare with the results obtained for other substrate oxidations. The results of this investigation are reported in the next section. 3.3.2 Oxidative Coupling Reactions of 2,6-Di-t-Butylphenol Using

Various Oxidants

As mentioned previously, the successful oxidative coupling of 2,6-di-t-butylphenol has been extensively reported in the literature.84-87 In our case, the aim of this investigation was to determine specifically both conversion and selectivity to the desired para C-para C coupled products, in order to be able to compare the results with those obtained when using other substrates, and to confirm data obtained from MO calculations. Note that, in this case, there are two possible desired products,

3,3-5,5-tetra-t-butyl-4,4-biphenol (16) and 3,3-5,5-tetra-t-butyl-4,4-diphenoquinone (10). Both of these are obtained by means of coupling mode G, with the quinone form (10) merely being an oxidized form of the biphenol. Both forms are readily interchangeable by simple reduction or oxidation (Scheme 28), and hence the formation of either of these two compounds or a mixture of both is equally desirable, and a mixture of the two is not necessarily deemed a disadvantage in this reaction.

81

oxidation HO OH reduction O O

(16)

(10)

Scheme 28: The ready interchangeability of desired products (16) and (10)

The two oxidizing agents that were assessed were Ag2O and Cu(OAc)2/oxalic acid (which were also used previously for 2 -t-butylphenol as substrate). Both standard materials, (16) and (10), required separate preparation so that reaction mixtures from this investigation could be effectively quantified. The quinone (10) was prepared by reacting 2,6-di-t-butylphenol with Ag2O resulting in the required product being virtually quantitatively obtained, and which was further purified by means of recrystallization. The biphenol (16) was prepared by reducing (10) with sodium

hydrosulphite in the presence of aqueous NaOH, followed by recrystallization. The structures of both standards were confirmed to be that of (10) and (16) by means of melting point determinations and the successful comparison of these with reported values, as well as NMR, IR and GC-MS experiments.

2,6-Di-t-butylphenol (9) was then treated with Ag 2O and Cu(OAc)2 /oxalic acid, in separate experiments, and the results so-obtained are summarized in Table 3.5.

82

Table 3.5

Reactions of 2,6-di-t-butylphenol with various oxidizing agents

Reaction No.

Oxidant

Time (h)

Solvent

Temp.

Conversion of (9) (%)

Selectivity to (10) (%)

Selectivity to (16) (%)

10

Ag2O

MeOH

R.T.

100

99.00

1.00

11

Cu(OAc)2/ Oxalic acid

10

PhCH3

60C

100

96.25

3.75

3.3.2.1

Silver oxide as coupling agent

It was previously reported that silver oxide provided high yields and selectivities to the desired coupled product when disubstituted substrates such as 2,6-di-t-butylphenol were employed in its presence.78 As described earlier, the mechanism of this reaction is not well understood, though it is postulated to occur on the metal surface.22 The alkylphenol was added to silver oxide in methanol, and the resultant reaction mixture was stirred at ambient temperature for 1 h. It was noted in this reaction (reaction 10, Table 3.5) that 2,6-di-t-butylphenol (9) was highly reactive under the reaction conditions employed, with a conversion of 100 % being achieved. Upon analysis by GC, only two products were observed (Figure 3.3).

83

Figure 3.3: GC trace of product mixture obtained in reaction 10, Table 3.5

The major product (99 %) at a retention time of 13.77 min was identified as 3,3,5,5tetra-t-butyldiphenoquinone (10) by using both retention time and mass fragmentation pattern comparisons with that of the prepared standard material. The molecular ion had a mass of 408 mass units as is required for this product (see Appendix 3.6). The other product present in the reaction mixture to a much lesser extent, with a retention time of 14.11 min, was identified as the biphenol (16), whose retenti on time and mass fragmentation pattern corresponded with that of its standard material (with M+ = 410 mass units, Appendix 3.7). The selectivity to (16) was calculated to be only 1.00 % (Table 3.5). Since both (16) and (10) are desired products, both resulting from the same coupling mode G ( ara C-para C), the overall selectivity of this oxidative p coupling reaction may be said to be 100 % (1 % + 99 %). The predominance of (10) in this reaction is not surprising since the reaction was carried out with sufficient oxidant for the overall transformation to (10). The substrate:Ag2O ratio used was 1:2, which is effectively a 1:4 substrate:Ag+ ratio. It is presumed that one mole equivalent of Ag + per substrate molecule is required for the coupling process itself (i.e., two moles of Ag+ are used to form every biphenol product molecule), while two mole equivalents of Ag+ are then required for the oxidation of the 84

so-formed biphenol (16) to the diphenoquinone (10). Thus the amount of oxidant used was sufficient to ensure the further oxidation of (16) all the way through to (10) [Scheme 29].

OH OH

2 mol Ag +

2 mol Ag +

(9)

OH (16)

O (10)

Scheme 29: Oxidation of 2,6-di-t-butylphenol using Ag 2O

In addition, silver oxide has a high redox potential (approximately 0.80 V) and thus has the power to oxidize (16) to (10). The ratio of the substrate to oxidant was increased to both 1:1 and 1:0.5, and the results compared with that of 1:2 (Table 3.6). Table 3.6 The effect of substrate:oxidant ratio variations

Substrate:Oxidant 1:2 1:1 1:0.5

Conversion (%) 100 98.80 71.01

Selectivity to (16) Selectivity to (10) (% ) (% ) 1.00 4.05 8.75 99.00 95.95 91.25

85

As the ratio of substrate to oxidant is increased, it is clear that the conversion of substrate decreases, not unexpectedly. The diphenoquinone (10) remains the

predominant final product, implying that the oxidation of (16) to (10) is possibly a more facile reaction than the coupling of (9) to form (16). In addition, the overall selectivity to para C-para C coupling remained 100 % in all cases. The intermediate dienone, i.e., 3,3,5,5-tetra-t-butyl-1,1-dihydro-2,2,5,5-

biscyclohexadiene-4,4-dione (43) [see also Scheme 27a] was never observed in any of our reaction mixtures. It has been reported 88 that the oxidative coupling of 2,6-di-tbutylphenol with silver oxide, in the absence of air, afforded isolation of this dienone form of (16), and that this keto tautomer is stable in non-polar solvents,53 but tautomerizes immediately to (16) in hydroxylic solvents such as methanol. In addition, Blanchard 78 reported that the coupled product (43) was also formed in the presence of oxygen when 2,6 -di-t-butylphenol was oxidized by silver oxide in a nonpolar solvent.

H O H O

(43)

Due to the fact that methanol (a hydroxylic solvent) was our solvent of choice, the absence of observation of (43) in any of our reaction mixtures (irrespective of substrate:oxidant ratio) was thus not surprising. Overall, our findings are thus in agreement with other reports that used silver oxide as coupling agent, giving para C-para C coupling (mode G) exclusively, with no other

86

side reactions occurring. investigations.

No para C-O coupling was ever observed in our

The previously shown MO calculation data predicted this behaviour.

The bulky t-butyl groups, and thus steric factors, play a significant role in the mode of coupling that (9) preferably undergoes. 3.3.2.2 Copper(II) acetate/oxalic acid as coupling agent

The reaction of copper acetate46,76 in the presence of a dicarboxylic acid, oxalic acid, with 2,6-di-t-butylphenol was investigated. As reported previously, cupric salts of dicarboxylic acids have been used to couple phenolic substrates in a manner characteristic of a single-electron oxidizing agent.46 A substrate/sodium lauryl sulphate/deionised water slurry was treated with a cupric acetate/oxalic acid/deionised water mixture, and stirred rapidly for 5 min while heating at 60C. After sodium hydroxide addition (pH 9), the mixture was heated and stirred for 10 h under an oxygen atmosphere, and then cooled and worked up. Reaction 11 in Table 3.5 summarizes the result of this experiment. (For this reaction, the molar ratio of the substrate:oxidant was 50:1, the copper salt of oxalic acid thus acting in a catalytic fashion.) After the required reaction time, no starting material remained, with the conversion of 2,6-di-t-butylphenol to products being complete. A GC-MS analysis of the reaction mixture showed that, once again, as with the silver oxide work, only two products were formed, at retention times of 13.76 and 14.14 min, respective ly. These corresponded with the standards (10) and (16), and the analysis showed again that (10) was the predominant product (with a selectivity of 96.25 %) as compared to (16) [with a selectivity of 3.75 %]. Thus the redox potential of the copper salt was also high enough to oxidize the initially formed product (16) further to form (10). These results are thus very similar to those achieved when using Ag 2O, reiterating the ease with which (9) can be oxidatively coupled with high selectivity and yield to the desired para C-para C coupled product. Once again, the overall selectivity to the

87

para C-para C coupled products (16) and (10) is 100 % (3.75 % + 96.25 %), with no para C-O coupled products being observed. 3.3.3 Concluding Remarks on the Oxidative Coupling of 2,6-Di-tButylphenol

From the above information, it is clear that the number of modes in which 2,6-di-tbutylphenol can theoretically couple is numerous, though, in practice, this substrate is highly selective when placed under oxidative coup ling conditions. High selectivities to the desired para C-para C coupled products (16) and (10) were achieved with both Ag 2O and Cu(OAc)2 /oxalic acid (100 % selective in both instances). This is in agreement with results obtained in the literature.46,78 No para C-O coupled products were ever observed. Molecular orbital calculations confirmed these observations. In addition, it was stated earlier that dealkylation of the coupled product and/or substrate would not be a significant reaction pathway, and this was found to be so since no dealkylated products were ever evident. In conclusion, it may thus be said that the presence of the additional t-butyl group in (9), as compared with that of 2-tbutylphenol (35), obviously plays a critical role in its choice of mode of coupling, and steric congestion is also a major consideration in these reactions. No further work was conducted on (9) as substrate since the results were optimal and well known to the field, and there was thus no need for further investigation. 3.4 THE OXIDATIVE COUPLING OF 2,4-DI-t-BUTYLPHENOL

The oxidative coupling of 2,4-di-t-butylphenol has not been as well documented as that of 2,6-di-t-butylphenol. Howe ver, as with the 2,6 -analogue, it is envisaged that 2,4-di-t-butylphenol (44) will carbon-carbon couple primarily at one particular carbon position, namely the 6-position, for similar reasons to those discussed earlier for the 2,6-analogue. Thus the oxidative coupling of (44) should lead to the ortho C-ortho C coupled product (45) with high yield and selectivity.

88

OH 1 6 5 4 C(CH3)3 (44)
Having said this, it must be bourne in mind that although (44) has only one available unsubstituted carbon position available for coupling, the possibility of unsubstituted ortho C-O coupling occurring may be greater than that for 2,6-di-t-butylphenol since the hydroxyl moiety (and hence the phenoxyl radical) of the 2,4 -analogue has decreased steric hindrance compared with that of the 2,6-analogue. This is because there is only one bulky t-butyl group in close proximity to the OH group in the 2,4analogue, but two such bulky groups in the 2,6-analogue. One may propose that 2-tbutylphenol (35) has similar hindrance in the vicinity of the hydroxyl moiety as that of (44), and thus when one considers that (35), under oxidative coupling conditions, afforded no less than four products having the same mass as that of the desired coupled product (39) [see relevant previous section], one may come to the conclusion that it is highly likely that some unsubstituted C-O coupling did indeed occur with (35) [though these four isomeric products were not isolated and characterized]. It therefore appears likely that some unsubstituted C-O coupling should also be likely with (44). However, in previous reports,89 it was stated that when (44) was oxidized with di-t-butyl peroxide at 140C for 24 h, the coupled product 3,3,5,5-tetra-t-butyl2,2-dihydroxybiphenyl (45) was solely formed, and no C-O coupled products were observed.

C(CH3) 3 2 3

89

OH

OH

(45)
The primary aim of this investigation was to study the oxidative coupling of (44) using a variety of oxidizing agents. The desired product in these reactions was (45), and an attempt was made to obtain optimal yields and selectivities to this product. A further aim was to compare and analyze results obtained here with those obtained for the other substrates under the same oxidative reaction conditions. 3.4.1 Molecular Orbital Calculations for the Oxidative Coupling of 2,4 -Dit-Butylphenol

As before, MO calculations were carried out to determine the preferential mode of coupling of (44). The heat of formation calculated for 2,4-di-t-butylphenol ( 59.90 kcal/mol) suggested that it was marginally more stable than 2,6-di-t-butylphenol (having a heat of formation of -58.78 kcal/mol), presumably due to the greater steric crowding associated with the 2,6 -analogue. The possible coupling modes with respect to available carbon positions available for coupling were similar to those of 2,6 -di-t-butylphenol, with oxygen-oxygen coupling also being discounted. Schemes 30a and 30b are an illustration of the coupling reactions investigated by means of PM3 semi-empirical MO calculations.

90

phenoxyl radical

dienone dimer t -Bu

phenolic dimer t -Bu

O t -Bu L

t -Bu

t -Bu

O H O H HO

OH

t -Bu t -Bu t -Bu t -Bu t -Bu

t -Bu

t -Bu

t -Bu M O H t -Bu

t -Bu O t -Bu

O t -Bu

HO t -Bu

Scheme 30a: Dienone and phenolic dimers from the coupling of 2,4-di-tbutylphenoxyl radicals by modes L and M

There are only two possible reaction modes (L and M) that are able to afford phenolic products with both rings aromatic in nature, via the tautomeric rearrangement of the corresponding dienone forms. The other modes (N, O, P and Q, Scheme 30b) result only in the dienone forms of the dimers: as with 2,6-di-t-butylphenol, the formation of the phenolic products for these latter modes would require the leaving of one or more t-butyl groups and it was assumed that this would not constitute a significant reaction pathway.

91

phenoxyl radical O t -Bu N t -Bu

dienone dimer O O H t -Bu t -Bu

t -Bu

t -Bu O t -Bu

O t -Bu O t -Bu

t -Bu

O t -Bu

t -Bu

t -Bu

t -Bu O O O t -Bu Q t -Bu t -Bu

t -Bu

Scheme 30b: Dienone dimers from the coupling of 2,4-di-t-butylphenoxyl radicals by modes N, O, P and Q

92

The relative stabilities of the various dimeric species for the coupling modes L-Q were obtained by comparing their heats of formation (? f H), as before. The results thus obtained for the coupled dienones (? f Hd) and phenols (? f Hp) are summarized in Table 3.7. Table 3.7 PM3 Heats of formation for 2,4 -di-t-butylphenol coupled products

Coupling mode

? fHd (kcal/mol)

? fHp (kcal/mol)

? fHp - ? fH d (kcal/mol)

-93.67

-123.31

-29.63

-90.30

-105.61

-15.31

-83.61

N/A

N/A

-78.63

N/A

N/A

-59.32

N/A

N/A

-52.67

N/A

N/A

From this data, it can be observed that the most stable dienone intermediate is the one that results through coupling mode L (where (? f Hd) is -93.67 kcal/mol), formed through ortho C-ortho C coupling in which both of these ortho positions are unsubstituted. The unsubstituted ortho C-O coupled dienone (mode M) was

approximately 3.4 kcal/mol less stable than the corresponding ortho C-ortho C dienone (mode L). The stabilities of the corresponding phenolic tautomers followed the same trend, with mode L affording the more stable phenolic dimer (? f Hp = -123.31 kcal/mol), followed next by the phenol from mode M. Again, this latter phenol was

93

significantly less stable than that from mode L (by 17.70 kcal/mol with ? f Hp = -105.61 kcal/mol). Coupling via the unsubstituted ortho C and a substituted para C (mode N) is approximately 10 kcal/mol less favourable than ortho C-ortho C (with ? f Hd = -83.61 kcal/mol), obviously as a result of steric interactions. Mode O, coupling between a substituted para C and oxygen is less desired still, having ?f Hd = -78.63 kcal/mol. Finally, when both coupling carbons are substituted, i.e., modes P and Q, the coupling reaction is highly disfavoured, as would be expected. In conclusion, we may therefore say that the formation of the ortho C-ortho C coupled product is most likely to be the favoured one according to these heats of formation data of the various species. 2,4-Di-t-butylphenol was then subjected to the action of a variety of oxidizing agents, and the results of these reported in the next section, and compared with the data obtained from other substrates in a later section.

3.4.2

Oxidative

Coupling

Reactions

of

2,4-Di-t-Butylphenol

Using

Various Oxidants

In the course of this investigation, a number of oxidizing agents were selected for study. Naturally, agents that were considered both economically and environmentally advantageous were given priority. Furthermore, the aim here was to obtain optimal results in terms of the coupling of (44) to (45). The experimental results obtained were compared to those obtained from MO calculations (with mode L being predicted to be the most favourable), and to results obtained from reactions with other substrates, where appropriate. The standard material of the desired product, 3,3,5,5-tetra-t-butyl-2,2-

dihydroxybiphenyl (45), was prepared by reacting 2,4-di-t-butylphenol with K3Fe(CN)3. The product thus formed required purification by recrystallization. The structure of

94

this compound was confirmed to be that of (45) by means of a melting point determination, and the successful comparison of this with reported values, as well as NMR, IR and GC-MS experiments. 2,4-Di-t-butylphenol (44) was then treated with various oxidants, and the optimum results achieved with each are summarized in Table 3.8. Table 3.8 Reactions of 2,4-di-t-butylphenol with various oxidizing agents

Reaction No.

Oxidant

Time (h)

Solvent

Temp.

Conversion (%)

Selectivity to (45) (%)

12

FeCl3

PhCH3

50C

92.00

13

Ag2O

MeOH

R.T.

96.52

5.06

14

K 3Fe(CN)6

MeOH

R.T

96.04

83.95

15

Ce4+

H2O/ MeOH

Reflux

100.00

90.35

3.4.2.1

Ferric chloride as coupling agent

Ferric chloride, known as a one -electron transfer oxidant, has been used extensively for the oxidative coupling of various phenols.90-92 2,4-Di-t-butylphenol was treated with this ferric species for 2 h at 50C in either chloroform or toluene as the solvent.

95

Table 3.9

Reactions of 2,4-di-t-butylphenol with FeCl3

Reaction No.

Ratio (oxidant:substrate)

Time (h)

Solvent

Temp.

Conversion (%)

Selectivity to (45) (%)

12

2:1

PhCH3

50C

92.00

16

2:1

CHCl3

50C

83.00

The results (Table 3.9) showed that 2,4-di-t-butylphenol proved to be highly reactive with FeCl3 under the reaction conditions employed (reaction 12 and 16), with conversions of 92.00 and 83.00 % being obtained, respectively. However, in neither solvent was any desired coupled product (45) formed. A variety of other products were evident upon analysis of the reaction mixture by GC (Figure 3.4).

Figure 3.4: GC trace of product mixture obtained in reaction 12, Table 3.9 96

Data obtained from MS experiments suggested that, in the case of this substrate, the products obtained stemmed not only from the oxidative coupling process, but also from their subsequent dealkylation, as well as that of the starting material. For example, when toluene was used as the reaction solvent, the presence of tbutyltoluene at the retention time of 7.11 min was very significant, contrary to our initial assumption that dealkylation would not be a main consideration in these reactions. In addition, the product at 9.60 min was identified as t-butylphenol, most likely from the dealkylation of the substrate. Furthermore, products at retention times 15.27 and 13.51 min were identified as the tri- and tetra- debutylated coupled products, respectively, though these were not isolated and characterized, and so the mode of coupling that occurred could not be ascertained. When CHCl3 was used as the reaction solvent (reaction 16), a large variety of products were noted, including chlorinated 2,4 -di-t-butylphenol, t-butylphenol (due to dealkylation) and various dealkylated coupled products. It seems that coupling does indeed occur in these conditions but that the resultant products are further debutylated. Once again, the steric bulk afforded by the t-butyl group in the vicinity of the OH group was not conducive to a clean oxidative coupling process, as verified by results obtained in the 2 -t-butylphenol work and as claimed by other workers in the field.22

Due to the poor results achieved with FeCl3, it was therefore deemed appropriate to sideline this reaction, and not investigate its use any further with 2,4-di-t-butylphenol as substrate. 3.4.2.2 Silver oxide as coupling agent

Silver oxide is a known one-electron transfer oxidant that converts phenols to phenoxyl radicals.12,90 These phenoxyl radicals can then undergo the characteristic C-C and/or C-O coupling processes. Since silver oxide showed high selectivity to the

97

diphenoquinone coupled product (10) when reacted with 2,6 -di-t-butylphenol, its reaction with 2,4-di-t-butylphenol was considered to be of great interest. The alkylphenol was added to silver oxide in methanol, and the resulting reaction mixture stirred at ambient temperature for 1 h. Reaction 13 in Table 3.8 indicated the high reactivity of the substrate in these conditions, with 96.52 % conversion of 2,4 -dit-butylphenol being observed. However, the reaction was not a selective one, as is seen by the many products formed according to GC analysis (Figure 3.5).

Figure 3.5: GC trace of product mixture obtained in reaction 13, Table 3.8 The product at retention time 17.51 min had a molecular ion mass (M+) of 438 mass units and could not be identified, but that at 17.71 min had an M+ of 410 mass units and was confirmed to be the desired C-C coupled product (45) by comparison with the standard material. However, the selectivity to biphenol (45) was only 5.06 %. This was not necessarily surprising since silver oxide, in the case of the 2,6-analogue (9), afforded mainly the overoxidized diphenoquinone derivative (10), with only a very small amount of the biphenol (16) being observed. Thus it may appear probable that (46) could dominate over (45) here also, though its stability (as is known for ortho versus para quinones) is most likely to be lower than that of (10). 98

(46)

Two products at retention times 23.84 and 25.70 min had an M+ of 408 mass units, the required mass for (46). However, because it was not a priority in this investigation, a separation of these was not carried out, and it is thus not certain which of the two products was (46), if any. Whatever the case, it is obvious from this study that the 2,4- and 2,6 - di-t-butylphenols behave very differently under identical conditions when treated with silver oxide. The 2,6-analogue was coupled highly

successfully whilst the 2,4 -analogue provided rather disappointing results, with a number of unwanted side products being formed. Reasons for this are not clear the mechanism at work here, as has been stated before, is not well known, but from this investigation, it may be concluded that the positioning of the alkyl substituents on the aromatic moiety plays a role in the subsequent reaction of the substrate. It is plausible that steric hindrance is a factor since one would expect the 4-position of the 2,6-analogue to be less crowded than that of the 6 -position in the 2,4 -analogue.

As an aside, and of peripheral interest, was the product at the retention time of 30.74 min which MS data showed to have an M+ of 615 mass units (Appendix 3.8). This is possibly due to a product of multiple coupling such as, for example, the triaryl species (47) shown in Scheme 31 (where n=1), though the exact nature of the coupling (whether C-C or C-O) was not verified by further characterization.

99

OH OH t -Bu Ag 2O t -Bu O

t -Bu

t -Bu

n=1,2,3,... O t -Bu t -Bu

t -Bu

t -Bu (47)

Scheme 31: A plausible multi-coupled product (47) with M+ = 615 mass units

Therefore, due to the disappointingly low selectivity to the coupled product (45) and the subsequent significance of side reactions in these conditions, the reaction of 2,4di-t-butylphenol with Ag 2O was not investigated further. 3.4.2.3 Potassium ferric cyanide as coupling agent

Ferric cyanide is one of the most widely used oxidizing agents for the generation of phenoxyl radicals in alkaline solutions.90,92,93 Previous studies94 indicate that the

oxidant must be in excess relative to the substrate, and that K3Fe(CN)6 acts as a oneelectron transfer agent [reaction (A)] involving phenoxide anions (present due to the basic medium) as the oxidizable substrate. Furthermore, it was found that the rate of oxidation was largely dependent on the basicity of the solution and on the ferricyanide/ferrocyanide ratio.
-

ArO

[Fe(CN) 6 ]3-

ArO

[Fe(CN)6]4-

(A)

100

2,4-Di-t-butylphenol was thus treated with this ferric species in a basic medium (NaOH) with the reaction conditions and results summarized in Table 3.10. Table 3.10 Reactions of 2,4-di-t-butylphenol with K 3Fe(CN)6

Reaction No.

Oxidant

Time (h)

Solvent

Temp.

Conversion (%)

Selectivity to (45) (%)

14

K 3Fe(CN)6

MeOH/H2O

R.T

96.04

83.95

17

K 3Fe(CN)6

MeOH/H2O

R.T

84.53

86.10

It was noted in this reaction that 2,4-di-t-butylphenol (44) was highly reactive under the reaction conditions employed, with conversions of 96.04 and 84.53 % for reactions 14 and 17, respectively. These reactions were carried out under identical reaction conditions except that reaction 14 was continued for 2 h, whilst reaction 17 was quenched after only 1 h. The longer reaction (14) afforded the higher conversion of substrate (not surprisingly), but the selectivity to (45) decreased from 86.10 (after 1 h, reaction 17) to 83.95 % (after 2 h, reaction 14). These results were, however, significantly superior to those achieved with ferric chloride and silver oxide. Since potassium ferric cyanide is a known one -electron oxidizing agent, and since the reaction takes place in a basic medium, the phenoxyl radical is thought to form from the phenoxide anion (see (A) before). After this, the direct coupling (the FR1

mechanism highlighted earlier, Scheme 6) of two such phenoxyl radicals, in which the radical is centered at the 6-position (through resonance), takes place to ultimately afford (45) after tautomerization. Scheme 32 depicts the proposed mechanism at work in this reaction. 101

_ O O O

K3Fe(CN)6 basic conditions X2

anion of (44) FR1 mechanism followed by tautomerization

OH

OH

(45)

Scheme 32: Mechanism for the coupling of (44) using potassium ferric cyanide

GC Analysis thus showed a considerable decrease in side product formation when compared with reactions using Ag2O and FeCl3 (Figure 3.6).

102

Figure 3.6: GC trace of product mixture obtained in reaction 14, Table 3.9

The product at a retention time of 17.97 min was the major product and was identified as the desired ortho C-ortho C coupled product (45) by comparison with a standard. The product at retention time 17.52 min had the same molecular ion mass (M+) of 410 mass units as (45), though the MS fragmentation pattern differed. This product is obviously an isomeric form of (45) in which the coupling mode differed, perhaps being formed by ortho C-O coupling, and affording, as a likely product, dimer (48), though no isolation was carried out.

OH O

(48)

103

Also notable was the presence of products at retention times of 24.13 and 31.39 min, their mass fragmentation patterns being indicative, as before, of products (46) and (47), respectively, which can only form by coupling modes L or M. 3.4.2.4 Cerium(IV) as coupling agent

3.4.2.4.1

Identification of Ce(IV) as the preferred oxidant

In this investigation, two considerations that had to be bourne in mind were the economic viability and environmental impact of the oxidant of choice. Although the oxidative coupling reaction of 2,4-di-t-butylphenol (44) with K 3Fe(CN)6 gave satisfactory results, it is not an environmentally acceptable oxidant nor would it be industrially attractive. The indirect electrochemical oxidation of organic substrates is becoming more and more economically viable, and there are many compounds that are known to be capable of acting as indirect oxidants, including transition metal salts, cobalt, manganese, iron, lead, silver and cerium. Examples of redox couples that have been studied include Ce3+/Ce 4+, Mn2+/Mn3+, and Mn2+ /MnO2.95 An alternative oxidant was thus sought, one that can be regenerated, implying that recycling thereof would be feasible, and thus being advantageous from an economic point of view. Furthermore, if the oxidant could be re-used, this would directly have a positive bearing on the environment since the potential amount of waste requiring treatment/storage would be minimized. However, the regeneration of many spent metals to their higher oxidation states is not always effective, since many metal ion oxidants have certain properties that make this process difficult. However, the

indirect electrochemical oxidation of phenols using a redox couple remains attractive and, to this end, we investigated it further. For the purposes of this study, the Ce4+/Ce 3+ couple was extensively investigated, with its recycle (Figure 3.7) being the driving force for our interest. Among the electron carriers most commonly used for indirect oxidations, cerium salts appear to be the most suitable when oxidations must be carried out under mild reaction conditions. The most common electron valencies of cerium salts are three and four,96

104

with cerium(IV) behaving as a one-electron oxidant.83,97 The oxidation potential of the Ce 4+/Ce3+ couple is reported to be dependent on the reaction conditions, such as the ligand. For example, the oxidation potential of this couple in 1 N perchloric, nitric, sulphuric and hydrochloric acids was observed to be -1.70, -1.61, -1.44 and -1.28 volts, respectively.98-101
Ce4+

cathode

2,4-disubstituted phenol

anode Ce3+

Coupled product

Figure 3.7: Electron flow in the indirect electrochemical oxidation process using the Ce 3+/Ce4+ couple

The oxidative coupling of 2,6-disubstituted phenols using Ce(IV) in the presence of perchloric acid is well documented.69,70 However, an alternative acid would be preferred since perchloric acid has the potential to lead to the formation of perchlorates which can be hazardous when in contact with organic chemicals.102 It was thus decided to investigate the use of W.R. Graces technology,103 where Ce(IV) would be reacted with our substrate in the presence of methanesulphonic acid. There are a number of advantages of using methanesulphonic acid rather than sulphuric and perchloric acid. These are:

It is unreactive with both reactants and products. It is stable to anodic and cerium oxidations. Ce(III) and Ce(IV) are highly soluble in aqueous methanesulphonic acid. It has a high current efficiency (>90 %) at high current density (>400 mA/cm2).

105

The solubility of the Ce(III) ion in the acid plays an extremely important role in these indirect electrochemical reactions, since a greater solubility of the oxidant implies a higher substrate loading in the reaction mixture. A study on the solubility of Ce(III) in both methanesulphonic and sulphuric acid showed that its solubility in the former is by far superior to its solubility in sulphuric acid at the same concentrations of each of the acids (Figure 3.8). 103

2.5 Ce(III) Concentration (M)

1.5

0.5

0 0 2 4 6 8 10 Acid Concentration (M) Methanesulphonic acid Sulphuric acid

Figure 3.8: Solubility of Ce(III) in aqueous methanesulphonic and sulphuric acids

For both acids though, it is obvious from this diagram that the greater the acid concentration, the lower the solubility of Ce(III) in the acid. However, by increasing the acid concentration, the oxidation of Ce(III) to Ce(IV) is facilitated. On the basis of these solubility results, it was decided that the Ce(IV) ions would be generated in the presence of methanesulphonic acid using cerium carbonate as the

106

source of Ce(III). The experimental setup was given previously (Figure 2.1). The Ce(III) concentration was kept constant (0.1 M) whilst varying the methanesulphonic acid concentration initially between 0.5 and 2.0 M. An extensive literature survey failed to indicate that oxidative coupling of disubstituted phenols, including 2,4-di-tbutylphenol, had been previously investigated with Ce(IV) in the presence of methanesulphonic acid. This work is thus entirely novel, and information gathered from it is deemed to add to the knowledge base of this field of chemistry.

The aim of this investigation was thus to extensively investigate the oxidative coupling of 2,4-di-t-butylphenol (44) using Ce(IV) as the oxi dant in methanesulphonic acid and, in so doing, to determine the effect of the following on this oxidative coupling process:

Varying the MeSO3H concentration. One or two phase systems with or without added co-solvent. Varying the reaction temperature. Varying the reaction time. Substrate loading. Varying the substrate:oxidant ratio. Varying the rate of oxidant addition to the reaction mixture.

On completion of these studies, it will then be possible to optimize reaction conditions so as to improve the yield and selectivity to the desired coupled product (45). 3.4.2.4.2 Oxidation in MeSO3 H mediated by Ce(IV) ions

For this investigation, the cerium carbonate concentration was kept constant at 0.1 M, irrespective of the methanesulphonic acid concentration. The minimum concentration of methanesulphonic acid was set at 0.5 M (MeSO3H is a mono-protic acid). Hence the methanesulphonic acid concentration was varied between 0.5 and 2.0 M for the electrochemical oxidation of Ce(III) to Ce(IV). The results obtained are summarized in Table 2.3 (Experimental section). It was noted that the highest conversion of Ce(III) to Ce(IV) occurred when the MeSO3H concentration was 1.0 M (when

107

considering the average titration values). The rate of the electrochemical oxidation of Ce(III) to Ce(IV) also depended on the methanesulphonic acid concentration, with slower oxidations occurring at lower acid concentrations, as is evident from Table 2.4. It has been well documented that an increase or decrease in the acid concentration affects the oxidation strength of the Ce(IV) ions.70,104 The effect of the MeSO3H concentration on the oxidative coupling of 2,4 -di-t-butylphenol (44) to form (45) in the presence of Ce(IV) ions at room temperature (R.T.) was thus investigated, and the results summarized in Table 3.11. Table 3.11 Oxidative coupling of (44) by Ce(IV) at various [MeSO3H] at R.T.

Reaction No.

[MeSO 3H]

(M)

Time (h)

Solvent

Ratio (substrate:oxidant)

Conversion of (44) (%) 31.06

Selectivity to (45) (%) 18.60

18

0.5

H2O

1:2

19

1.0

H2O

1:2

43.68

42.71

20

2.0

H2O

1:2

17.05

25.21

Reactions 18 to 20 were all one hour reactions carried out in aqueous media at ambient temperature. The ratio of substrate:oxidant was also kept constant at 1:2. The only variable was the methanesulphonic acid concentration. Initial investigations under these conditions showed that the highest conversion of (44) and selectivity to (45) was achieved when the MeSO3H concentration was 1.0 M (reaction 19, Table 3.11), where these values were 43.68 and 42.71 %, respectively. However, due to the reaction solvent being aqueous, the solubility of the substrate was poor as was evident from the adherence of the organic substrate to the stirrer bar and the glass walls of the reaction vessel. This low solubility of the substrate in aqueous media was presumed to have a deleterious effect on the reactivity of (44) with Ce(IV), and it was

108

assumed that this problem required addressing before optimal results would be achieved. To decrease this solubility effect, the reaction temperature was increased to 80C, whilst keeping all other variables constant (Table 3.12). Table 3.12 Oxidative coupling of (44) by Ce(IV) at various [MeSO3H] at 80C

Reaction No.

[MeSO 3H]

(M)

Time (h)

Solvent

Ratio (substrate:oxidant)

Conversion of (44) (%) 48.47

Selectivity to (45) (%) 34.93

21

0.5

H2O

1:2

22

1.0

H2O

1:2

96.11

76.22

23

2.0

H2O

1:2

73.43

64.61

A significant improvement was noted in terms of both the conversion of (44) and the selectivity to (45) in each of these reactions when compared with those obtained at R.T. Once again, as at R.T., the reaction using 1.0 M MeSO3H (reaction 22) gave the best results in terms of conversion of 2,4 -di-t-butylphenol and selectivity to the coupled product (45). In conclusion then, it may be said that an increase in the reaction temperature from ambient to 80C increased both conversion and selectivity, irrespective of the acid concentration. Thus far, the optimal reaction was one carried out at the elevated temperature using 1.0 M methanesulphonic acid (reaction 22, Table 3.12). Not unexpectedly, therefore, these resul ts imply that the solubility of the substrate is important in the reaction. As above, an increase in reaction temperature is one method by which the solubility may be increased. Another method is to add a cosolvent to the aqueous medium, the co -solvent obviously being one in which the

109

substrate is very soluble, such as methanol, acetonitrile or dichloromethane. The first two of these are water-soluble organic solvents and would ultimately afford a one phase reaction system, whilst dichloromethane is not and would result in a two phase reaction system. To investigate the effects of these co-solvents on the coupling process, the reactions were initially performed at R.T. for 1 hour. Since previous results showed that optimal conversions and selectivities were obtained using 1.0 M methanesulphonic acid concentrations, this was the concentration of choice in the following reactions. Results so-obtained are summarized in Table 3.13. Table 3.13 Effect of co-solvents on oxidative coupling of (44) by Ce(IV) at R.T.

Reaction No.

[MeSO3H]

Solvent

(M)

Ratio (substrate:oxidant)

Conversion of (44) (%) 94.80

Selectivity to (45) (%) 69.28

24

1.0

H2O/MeOH

1:2

25

1.0

H2O/CH3CN

1:2

93.29

62.37

26

1.0

H2O/CH2Cl2

1:2

41.87

85.22

The conversion of 2,4-di-t-butylphenol in aqueous solvent with added MeOH or CH3CN was similar and high at 94.80 and 93.29 %, respectively. However, the acetonitrile-containing system afforded a lower selectivity to (45) of 62.37 %, whereas the methanol-containing system was higher at 69.28 %. When CH2Cl2 was used as the organic co-solvent, there was a significant decrease in the conversion of (44) [reaction 26, 41.87 %] compared with MeOH and CH3CN. The selectivity to the coupled product (45) was, however, much higher (85.22 %). This low reactivity of 2,4-di-t-butylphenol with Ce(IV) in H2 O/CH2Cl2 is most likely due to the presence of the two phases, where the substrate prefers to reside within the organic solvent, implying that reaction can only occur effectively at the boundary surface of the two phases. In such a system, stirring efficiency would be an important consideration.

110

Overall, MeOH as co-solvent thus gave the most promising results at ambient temperatures. In the next study, using 1.0 M MeSO3H and MeOH as co -solvent, the reaction was carried out at various reaction temperatures in order to determine whether an optimum point could be defined. All other variables were kept constant. The results obtained are contained in Table 3.14. Table 3.14 Temperature effect on coupling of (44) by Ce(IV) with MeOH as cosolvent

Reaction No.

MeOH volume

Ratio (substrate:oxidant)

Temperature

Conversion of (44) (%) 92.29

Selectivity to (45) (%) 73.72

27

20 mL

1:2

0C

28

20 mL

1:2

R.T.

93.42

78.76

29

20 mL

1:2

45C

95.09

82.76

30

20 mL

1:2

Reflux

96.96

80.50

The total volume of the MeOH and aqueous MeSO3H was also kept constant (40 mL) for all of these reactions. After assessing reactions at 0C, ambient temperature, 45C and reflux (65C), it was found that high conversions were obtained throughout, even at 0C (92.29 %). The highest conversion occurred at the highest temperature (65C, 96.96 %). A plot of conversion versus temperature more clearly summarizes the results obtained (Figure 3.9):

111

98

97

Conversion (%)

96

95

94

93

92 0 10 20 30 40 50 60 70 Temperature in Deg. C

Figure 3.9: Plot of conversion versus temperature

Similarly, Figure 3.10 is a graphical summary of the results obtained in terms of selectivity, where selectivity was plotted against temperature. From this plot, an optimal selectivity to (45) was achieved at the reaction temperature of 45C (reaction 29, 82.76 %). However, as seen above, the conversion of (44) at this temperature (95.09 %) was slightly lower than that obtained at reflux (reaction 30, 96.96 %). O f interest is the observed decreased selectivity to (45) at the lower temperatures (73.72 % at 0C and 78.76 % at R.T.). This is a possible indication that the rate of the coupling reaction to afford (45) increases with increasing temperature, implying that the lower coupling rates at the lower temperatures provides the reactive species time to undergo other side reactions, and hence resulting in the observed lower selectivity at the lower temperatures. In other words, it appears as though the coupling reaction to form (45) occurs rapidly at the higher temperatures and less so at the lower temperatures relative to other side reactions: hence, when the reaction temperature

112

is decreased, the rate of the desired coupling reaction slows down, therefore increasing the possibility of side reactions.

84 83 82 81 Selectivity (%) 80 79 78 77 76 75 74 73 0 10 20 30 40 50 60 70 Temperature in Deg. C

Figure 3.10: Plot of selectivity versus temperature

Since the results obtained for reactions 29 and 30 were very similar in terms of both conversion and selectivity, reflux temperature, due to its ease of application, was selected as the temperature of choice for further investigations. A study of the effect of reaction time was then carried out: the substrate (44) was reacted in 1.0 M MeSO3H for 5 min rather than the usual 1 h, with all other variables being identical. The comparative result obtained is given in Table 3.15.

113

Table 3.15

Reaction time effect on the coupling of (44) using Ce(IV)

Reaction No.

MeOH volume

Ratio (substrate:oxidant)

Time (min)

Temperature

Conversion of (44) (%) 96.96

Selectivity to (45) (%) 80.50

30

20 mL

1:2

60

Reflux

31

20 mL

1:2

Reflux

94.96

82.97

From this data, it is obvious that there is very little difference between the results obtained for a reaction of 1 h compared with that of a reaction carried out for 5 min. Reaction 31 showed only a slight decline in the conversion (from 96.96 to 94.96 %), but a slight increase in selectivity (from 80.50 to 82.97 %) relative to reaction 30. Once again, this is probably because the ortho C-ortho C coupling reaction is a rather rapid one, and so the longer the reaction time, the greater the opportunity for side product formation. The next reaction variable that was investigated was the substrate loading by varying the co-solvent (MeOH) volume, yet keeping the Ce(IV)/MeSO3 H volume constant (i.e., 20 mL) and the amount of 2,4 -di-t-butylphenol (44) constant also. Reaction time and temperature were maintained at the same values throughout. Table 3.16 contains the obtained results. This data was then displayed graphically (Fig. 3.11) by plotting the percentage selectivity and conversion against the volume of methanol used (which is then directly related to the substrate loading, with higher methanol volumes implying lower loadings).

114

Table 3.16

Effect of substrate loading on the coupling of (44) using Ce(IV)

Reaction No.

MeOH volume

Ratio (substrate:oxidant)

Temperature

Conversion of (44) (%) 55.98

Selectivity to (45) (%) 84.86

32

5 mL

1:2

Reflux

33

10 mL

1:2

Reflux

94.47

82.45

30

20 mL

1:2

Reflux

96.96

80.50

34

40 mL

1:2

Reflux

92.93

60.70

120 100

80 Percentage 60

40 20

0 0 10 20 30 40 50 Volume of MeOH (mL) Conversion Selectivity

Figure 3.11: Plot showing the effect of substrate loading on percentage conversion and selectivity

115

The best results were obtained in reactions 30 and 33 (Table 3.16) where the volume of MeOH used was 20 and 10 mL, respectively. It is clear from Figure 3.11 that when the substrate loading was high (reaction 32, where the MeOH volume used was 5 mL), the conversion was a low 55.98 %, while the selectivity was high (84.86 %). This was surprising since one would have expected that a high substrate loading would afford high conversions of the starting material. A possible explanation for this phenomenon is that the substrate solubility in the aqueous medium containing only small volumes of added co-solvent is low and hence its low conversion. A low

substrate loading, when the volume of MeOH used was 40 mL (reaction 34), showed a significant decrease in selectivity (60.70 %). This data shows that the substrate loading in these reactions is critical, and should not be too high nor too low for optimal conversions and selectivities. The reaction variable investigated next was the oxidant to substrate ratio. In this part of the investigation, the following reaction variables were kept constant:

Temperature (reflux). Substrate loading (20 mL of MeOH). Reaction time (1 hour). MeSO3H concentration (1.0 M).

Hence, whilst maintaining a constant substrate amount (moles) in each reaction, the number of moles of Ce(IV) was varied so that substrate:oxidant molar ratios of 1:0.5, 1:1, 1:1.5, 1:2 and 1:5 were achieved. Refer to Table 3.17 for the results obtained.

116

Table 3.17

Effect of substrate:oxidant ratio on the coupling of (44) using Ce(IV)

Reaction No.

MeOH volume

Ratio (substrate:oxidant)

Temperature

Conversion of (44) (%) 35.50

Selectivity to (45) (%) 94.25

35

20 mL

1:0.5

Reflux

36

20 mL

1:1

Reflux

72.90

91.74

37

20 mL

1:1.5

Reflux

83.35

79.29

30

20 mL

1:2

Reflux

96.96

80.50

38

20 mL

1:5

Reflux

97.12

60.31

The poorest results in terms of conversion were achieved in reaction 35 (35.50 %), where the substrate to oxidant ratio was 1:0.5. However, this reaction also gave the greatest selectivity to the coupled product (45) of 94.25 %. The highest conversion of the starting material was achieved in reaction 38 where the substrate to oxidant molar ratio was the greatest (1:5). This result was to be expected since a larger amount of oxidant in the reaction mixture increases the availability of the Ce(IV) ions to the substrate (44), thus increasing the conversion. Furthermore, and as expected, the selectivity to the coupled product in this reaction was also the lowest (60.31 %): excess oxidant w obviously available for side reactions or further oxidation of the as formed product. A graph of both percentage selectivity and conversion versus oxidant:substrate ratio was then plotted (Fig. 3.12) by using the information in Table 3.17.

117

120 100 80 60 40 20 0 0 1 2 3 4 5 6 Molar ratio of Ce(IV) to substrate conversion selectivity

Figure 3.12: Plot showing the effect of oxidant:substrate ratio on percentage conversion and selectivity

A molar ratio of 1:2 (substrate:oxidant) thus afforded both high conversion of (44) and high selectivity to (45), and was thus deemed the optimal ratio in this reaction. The last variable that was investigated was the rate of addition of the oxidant to the reaction mixture. In all the previous reactions, the Ce(IV) was added to the reaction mixture within 30 seconds, except for reaction 15 in Table 3.8 (repeated (Table 3.18) for convenience), in which the Ce(IV) [in 20 mL MeSO3H] was added to the reaction mixture over a time period of 30 min.

Percentage (%)

118

Table 3.18

Effect of rate of oxidant addition

Reaction No.

Oxidant

Time (h)

Solve nt

Temp.

Conversion (%)

Selectivity to (45) (%)

15

Ce

4+

MeOH

reflux

100.00

90.35

It is clear from this result that these reaction conditions afford superior results in terms of conversion, which is quantitative, and the associated selectivi ty to the desired coupled product (45) is still very high at 90.35 %. Thus slow oxidant addition is clearly favoured over that of its rapid addition. 3.4.2.4.3 Reaction mechanism for the oxidative coupling of 2,4-di-t-butylphenol using Ce(IV) To propose a feasible reaction mechanism for the oxidative coupling of 2,4-di-tbutylphenol (44) using Ce(IV) in the presence of MeSO3H, all the reaction products need to be identified. The mechanism must then account for these products. Upon a thorough examination of the reaction mixtures in the various oxidative coupling reactions using 2,4-di-t-butylphenol (44) as the substrate and Ce(IV) as oxidant, the following products [(45), (47), (48), (49) and (50)] were identified from their molecular ion masses and their mass fragmentation patterns. With the exception of (49) and (50), all of these products were common to those found in reactions using K3Fe(CN)6 as oxidant.

119

OH

OH
OH t -Bu O

t -Bu

t -Bu

n=1
O t -Bu t -Bu

(45)

t -Bu

OH O

(47) O OH

(48)

O (49)

OH (50)

Since Ce(IV) is reacted with (44) in acidic media, the reaction mechanism probably differs from that established for potassium ferric cyanide (basic media). (When potassium ferric cyanide is reacted with (44) in basic medium, the hydrogen of the phenolic OH is abstracted by base to form the anion (Scheme 32), which is then oxidized to form the phenoxyl radical.) Since Ce(IV) acts as a one -electron oxidant and the reaction takes place in acidic medium, the assumption can be made that one electron is removed from the aromatic ring to form the radical cation (51), as shown in Scheme 33. This is most likely a facile process due to the electron rich nature of the aromatic ring due to the presence of electron-donor substituents such as the hydroxyl and alkyl groups. This radical cation may then lose a proton to afford the phenoxyl radical (52). One resonance form of (52) is where the unpaired electron is centered at carbon position 6. Two of these then couple directly together to afford dimer (53)

120

which, upon tautomerization, affords (45), the desired product in this reaction, and the product that was obtained in high yields throughout (relative to any other products).

OH

OH

+ Ce4+ Ce3+

-H+

(51) (52) O H

O H

OH

OH

O H tautomerization H

(45)

(53)

Scheme 33: Reaction mechanism for the formation of (45)

121

Compounds (47) and (48) are readily accounted for: their formation is through C-O coupling as shown clearly in Scheme 34.
O H

O O tautomerization O H O OH

(52)

(54)

(48) Ce4+ Ce 3+

t -Bu OH

t -Bu OH
O

OH t -Bu O O t -Bu -H+

t -Bu H O

O O + t -Bu H +

t -Bu

t -Bu t -Bu (47)

t -Bu

t -Bu t -Bu (56)

(55)

Scheme 34: Reaction mechanism for the formation of (47) and (48)

It is thus plausible that (48) is formed through the direct coupling of radical (52), where the unpaired electron is centered on oxygen, with another (52) species, but where the unpaired electron is centered on carbon position 6, thus affording the C-O coupled product (54). This then tautomerizes to form (48). This product may then be further oxidized to afford the radical cation (55). Its reaction with (52) yields the cation

122

(56) which may then lose a proton to form trimer (47), the driving force being rearomatization. It has been reported that the radical cations are also capable of reacting with water to ultimately afford dihydroxybenzenes (57) by the pathway shown in Scheme 35.69

OH H 2O + R R

OH + OH 2 H -H+

OH OH H R -e-H+ R

OH OH

(57)

Scheme 35: Radical cation reaction with water to form dihydroxybenzenes (57)

Using the same ideology, the formation of products (49) and (50) must certainly be due to intermediate radical cations reacting with the water that is in the reaction medium. A possible pathway to explain their formation is presented in Scheme 36.

123

OH +H2O + -H+

OH

OH

-e -

OH (58) (51) -e -t -Bu+ O OH

-2e (44) -2H+

O (49)

OH (50)

Scheme 36: Formation of products (49) and (50) from a radical cation

From this scheme, the radical cation (51) produced reacts with water and, after proton loss, affords the radical (58), which then also undergoes oxidation by losing an electron. The cation which so forms is then transformed into (50) by the loss of a tbutyl cation. (Since this is a tertiary carbocation, its stability is reasonably high, and this step is thus more than plausible. However, since high selectivities to (45) were observed in these reactions, these debutylated products, though not quantified, were not formed in amounts significant enough to state that this was a facile process compared with that of the formation of (45).) oxidized to the quinone (49). A general trend observed is that an increase in reaction temperature allowed for an increase in the amount of desired product (45) formed after the same amount of Hydroquinone (50) is then readily

124

reaction time (Table 3.14). The desired reaction appears to be a rapid one, and an increase in reaction temperature plausibly increases it even further, providing less opportunity for side reactions (such as C-O coupling), and thus possibly accounting for this general observation. The rate of the desired coupling reaction thus generally increases with increasing temperature, implying that at lower temperatures, the lower rate of formation of the desired dimer results in an increased possibility for side product formation. The statement that the desired coupling reaction is proposed to occur rather rapidly was also implied by a comparison of the reaction when carried out for 60 min relative to the reaction when carried out for only 5 min (reaction 30 versus reaction 31, Table 3.15): after only 5 min, a high conversion and selectivity to (45) was obtained, and extending the reaction time to 60 min made no significant difference to the result. The effect of substrate loading was also significant in this reaction: the lowest selectivity to (45) was obtained when the reaction mixture had the lowest substrate loading (reaction 34, Table 3.16). When the substrate loading was increased, the selectivity to the desired C-C coupled product also increased. Once again, it may be concluded that reaction conditions that favour the rapid formation of (45) via the desired coupling reaction, i.e., by increasing reaction temperature (see above) or increasing the substrate concentration, disfavour side product formation, and thus an increase in the selectivity to (45) was observed in these instances. It must be kept in mind that too high substrate loadings are not ideal since substrate conversions are rather low in such cases.

Schemes 33-36 therefore account for the products observed in our reaction mixtures, and they hence represent viable pathways by which these products were all formed.

125

3.4.3

Concluding Remarks on the Oxidative Coupling of 2,4-Di-tButylphenol

From the results obtained, it is clear that 2,4-di-t-butylphenol coupled primarily by modes L and M. This substrate was not as selective as 2,6-di-t-butylphenol, but high selectivities to the ortho C-ortho C coupled product (45) were achieved with both the K 3Fe(CN) 6 and Ce(IV) oxidants [86.10 and 96.96 %, respectively]. The use of other oxidants such as FeCl3 and Ag 2O afforded results that were less than satisfactory, with very little, if any, desired product being formed, despite high conversions. This was rather surprising, especially in the case of Ag 2O, since this oxidant was 100 % selective towards the para C-para C coupled product when the 2,6-analogue was the substrate. These oxidants are obviously not suitable for the purposes of forming (45), quite possibly due to the mechanisms by which they react in combination with the positioning of the substituents on the aromatic rings. Molecular orbital calculations confirmed the preference for coupling mode L and, to a lesser extent, mode M. The difference in results obtained for the 2,4- and 2,6-analogues may only be explained in terms of steric crowding, in which the hydroxyl moiety of the 2,6-analogue is well surrounded by the two bulky t-butyl groups, thus disallowing the formation of C-O coupled products. The 2,4 -analogue, on the other hand, is less crowded in the vicinity of the OH group, and can thus also form some of the C-O coupled product, resulting in the observed lower selectivities to the C-C coupled product as compared with the 2,6-analogue.

The work conducted using Ce(IV) as the oxidant is entirely novel, and the results obtained in these reactions were very promising indeed, with high selectivities and conversions to the desired coupled dimer (45) being achieved. Optimal reaction conditions included the use of 1 M aqueous methanesulphonic acid as the medium of choice with added co-solvent (methanol) such that the resultant solution is a single phased reaction mixture. Furthermore, the optimal reaction temperature was approximately 65C (at reflux, giving high selectivities and conversions and implying ease of application), and lengthy reaction times were not necessary, probably

126

because the desired coupling reaction takes place rather rapidly. The substrate loading was an important factor: too high loadings afforded low conversions, and too low loadings afforded low selectivities. The optimal substrate:oxidant ratio was 1:2, with a slow addition of the oxidant to the reaction medium being slightly favoured over that of rapid addition. Finally, a mechanism was proposed for this work that

accounted for all the products observed in the reaction mixtures. 3.5 THE OXIDATIVE COUPLING OF 2,4-DIMETHYLPHENOL

From the literature, it was ascertained that the reaction of 2,4-dimethylphenol (59) with various oxidative coupling agents gave complex reaction mixtures.52,105

OH Me

Me (59)
Furthermore, it was shown that, in the case of the 2,6-dialkylphenols, the bulkiness of the substituents played an important role in the types of products formed, with the larger groups, such as t-butyl, giving C-C coupled products almost exclusively.106,107 However, with smaller substituents, such as methyl, C-O coupling has been reported to occur more readily, and long chain ethers of high molecular weight have been obtained as products in these cases. When various 2,6-dialkylphenols were oxidized with cuprous chloride in nitrobenzene/pyridine, the yield of long chain ethers was decreased to zero with an increase in bulk of the substituents [-CH3, -CH(CH3 )2, C(CH3)3].108 Thus the decreased steric effect of the methyl groups of 2,4 -dimethylphenol (59), compared with the t-butyl groups of 2,4-di-t-butylphenol, implies that the course that

127

the oxidative coupling process takes by the former substrate may be different to that taken by the latter substrate, and so resulting in different relative product ranges for the two substrates. Although 2,4 -dimethylphenol (59) has only one available unsubstituted carbon position available for coupling, the possibility for ortho C-O coupling occurring may be greater than for 2,4-di-t-butylphenol since the hydroxyl moiety (and hence the phenoxyl radical) of (59) has decreased steric hindrance. From the literature, it was also ascertained that the non-bonding interactions between methyl groups in the transition state for coupling of methyl -substituted phenoxyl radicals are important.109 It was observed that the oxidation of 2,4-dimethylphenol gave a much higher yield of C-O coupled products than obtained with p-cresol.110 An examination of the staggered approach (60) for the ortho-ortho coupling of 2,4dimethylphenoxyl radicals revealed that there were two sets of non-bonding interactions between the methyl groups.109
Me O Me

. .
O (60)

Me

Me

Due to these methyl group interactions, a higher energy pathway for C-C coupling results, and consequently more C-O coupling occurs because the formation of the latter bond is much less dependent on efficient SOMO-SOMO interactions between the two radicals. However, the possible coupling modes of 2,4 -dimethylphenol (59) with respect to available carbon positions for coupling are similar to those of 2,4-di-t-butylphenol. Although the oxidative coupling reactions of (59) were not investigated by means of

128

PM3 semi-empirical MO calculations, the possible coupling modes are illustrated in Schemes 37a and 37b.
phenoxyl radical phenolic dimer

O Me

.
R

Me

Me

OH HO

Me Me Me Me

Me S O

HO

Me

Me

Scheme 37a: Phenolic dimers from the coupling of 2,4-dimethylphenoxyl radicals by modes R and S

129

phenoxyl radical

dienone dimer

. O Me T Me

O O H Me Me

Me

Me O U Me

Me

Me

Me O Me

Me

Me

Me O O O W Me Me Me

Me

Scheme 37b: Dienone dimers from the coupling of 2,4-dimethylphenoxyl radicals by modes T, U, V and W

130

The assumption is made (as for the 2,4-di-t-butyl analogue) that there are two main reaction modes that can afford phenolic products, namely modes R and S. The assumption is also made that, for 2,4 -dimethylphenol, the other coupling modes (T, U, V and W, Scheme 37b) result only in the dienone forms of the dimers, with the loss of methyl groups not being considered to be a pathway that will be favoured by these dienones, and thus the phenolic forms thereof not being considered significant in these cases. (The phenolic forms of the dienones can only be formed by methyl substituents being lost from these dienone substrates.)

The oxidative coupling of (59) was thus assessed by reacting this substrate with a variety of coupling agents, and analyzing the reaction mixtures in order to determine percentage conversions and yields to the desired product, 3,3,5,5-tetramethyl-2,2dihydroxybiphe nyl (61).

OH Me

OH Me

Me (61)

Me

3.5.1

Oxidative Coupling Reactions of 2,4-Dimethylphenol Using Various Oxidants

The oxidizing agents considered during the course of this investigation were the same as those used for 2,4-di-t-butylphenol (with the omission of Ag2O), the aim being to be able to compare results obtained here with those obtained for the 2,4-di-t-butyl analogue. This would then provide information on the comparative effect of the

various substituents on the aromatic ring on the coupling process.

131

The

sta ndard

material

for

the

desired

product,

3,3,5,5-tetramethyl-2,2-

dihydroxybiphenyl (61), was prepared by reacting 2,4 -dimethylphenol with Ce(IV) in the presence of methanesulphonic acid. The product thus formed was purified by means of column chromatography. The structure was confirmed to be that of (61) by means of a melting point determination, and the successful comparison of this with reported values, as well as NMR, IR and GC-MS experiments. The optimum results obtained when 2,4-dimethylphenol (59) was treated with each of the various oxidants are summarized in Table 3.19. Table 3.19 Reactions of 2,4-dimethylphenol with various oxidizing agents

Reaction No.

Oxidant

Time (h)

Solvent

Temp.

Conversion (%)

Selectivity to (61) (%)

39

FeCl3

CHCl3

50C

90.98

49.11

40

K 3Fe(CN)6

MeOH

R.T.

70.86

26.72

41

Ce

4+

H2O

R.T.

76.04

57.58

3.5.1.1

Ferric chloride as coupling agent

The one-electron oxidant, ferric chloride, was reacted with 2,4 -dimethylphenol even thoug h it was not successful at all in coupling the 2,4-di-t-butyl analogue to the desired coupled product (45). 2,4-Dimethylphenol was treated with this ferric species for 2 h at 50C in various solvents (Table 3.20).

132

Table 3.20

Reaction of 2,4-dimethylphenol with FeCl3 in various solvents

Reaction No.

Ratio (substrate:oxidant)

Time (h)

Solvent

Temp.

Conversion (%)

Selectivity to (61) (%) 49.11

39

1:2

CHCl 3

50C

90.98

42

1:2

MeOH

50C

34.71

11.05

43

1:2

PhCH3

50C

77.88

38.84

44

1:2

EtOAc

50C

36.83

9.59

The results showed that the reactivity of FeCl3 with 2,4-dimethylphenol depended largely on the solvent employed. The best results for the reaction of FeCl3 with 2,4dimethylphenol was achieved when CHCl3 was used as the solvent (reaction 39), with this affording the highest conversion of (59) and selectivity to (61) of 90.98 and 49.11 %, respectively. Although the selectivity was low and conversion high, no other major products were detected upon analysis of the reaction mixture by GC (Figure 3.13).

Figure 3.13: GC trace of product mixture from reaction 39, Table 3.20

133

The low selectivity, despite the lack of observation of any other major product on the GC trace (Figure 3.13), is most likely an indication of the presence of longer chain polymeric ethers, these not normally observable by means of this analytical technique. The product at a retention time of 15.42 min, with a molecular mass (M+) of 242 mass units (by MS analysis) was identified as the desired coupled product (61), by comparison with the standard material, with the starting material (59) eluting at 8.32 min. Of significance was the total absence of dealkylated products in reaction 39 (recall that the t-butyl analogue did und ergo dealkylation). The product at a retention time of 16.58 min with an M+ of 282 was not further characterized, but that at 22.20 min with m/z = 362 mass units corresponded to the polymeric ether (62). No isolation was carried out here, but whatever the case, this product was polymeric/oligomeric in nature, as indicated by its M+.
OH Me O Me Me

O Me Me

Me (62)

Of interest was the product at the retention time of 18.07 min, which had a molecular ion mass of m/z = 256, and whose mass fragmentation pattern (Appendix 3.9) corresponded to that of (63).

134

OH Me

OH Me

Me

C H (63)

Product (63) appears to be one in which one of the methyl substituents has been oxidized to an aldehydic group. The product at retention time 18.15 min has an identical m/z value compared with that of (61) (i.e., 242 mass units), and is possibly either the isomeric Pummerers ketone (64) or ortho C-O coupled product (65):

OH Me Me Me Me O O Me (64) O Me (65)

Me

Me

When MeOH and ethyl acetate were used as solvents (reactions 42 and 44) in place of CHCl3, the results obtained in terms of conversion (34.71 and 36.83 %, respectively) and selectivity (11.05 and 9.59 %, respectively) were very poor, and these reactions were not further investigated. With toluene as the solvent (reaction 43), a large variety of dealkylated products were obtained, including mono-, di- and tri- demethylated coupled products at retention times 15.23, 15.17 and 12.86 min respectively (Figure 3.14). (These dealkylated products were not present in reaction 39 where CHCl3 was the solvent.)

135

Figure 3.14: GC trace of product mixture from reaction 43, Table 3.20

The fact that the reaction of FeCl3 with 2,4 -dimethylphenol gave at least some of the desired product, despite being totally ineffective when reacted with 2,4-di-tbutylphenol (and 2-t-butylphenol), is certainly further evidence that the bulk of the tbutyl group does indeed prevent formation of the phenoxyl-iron complex,22 whereas the decreased steric effect associated with the methyl groups allows such an interaction to some extent. 3.5.1.2 Potassium ferric cyanide as coupling agent

Potassium ferric cyanide gave very promising results when reacted with 2,4-di-tbutylphenol (44), with a high conversion and selectivity (96.04 and 83.95 %, respectively) to the desired coupled product (45) being achieved. 2,4Dimethylphenol was treated with this ferric species under identical reaction conditions, in basic media (NaOH), and the reaction conditions and results are summarized in Table 3.21.

136

Table 3.21

Reactions of 2,4-dimethylphenol with K 3Fe(CN)6

Reaction No.

Oxidant

Time (h)

Solvent

Temp.

Conversion (%)

Selectivity to (45) (%)

40

K 3Fe(CN)6

MeOH/H2O

R.T

70.86

26.72

The selectivity (26.72 %) to the desired coupled product (61) was thus poor with this coupling agent. The GC trace, however, shown in Figure 3.15, did not indicate that many products were formed in this reaction.

Figure 3.15: GC trace of product mixture from reaction 40, Table 3.21

This is indicative again that polymeric materi als were formed under these conditions. GC-MS Experiments suggested that the product eluting at 15.25 min was, once again, either the ortho C-O coupled product (65) or Pummerers ketone (64), since their M+ values were identical to that of (61) at 242 mass units, but isolation and further characterization was not considered important here. (The product at retention

137

time 15.54 min was identified as the desired coupled product (61).)

Higher elution

times 21.78 and 25.34 min both corresponded to products w an M+ of 360 mass ith units, i.e., compounds that were higher than dimeric in nature. The success of the reaction of this ferric species with the 2,4-di-t-butyl analogue could thus not be mimicked in this case, and all evidence obtained in this reaction hinted at the significant presence of higher oligomeric species, most likely emanating from C-O coupling (due to its greater propensity for occurring when the substituents are methyl groups). 3.5.1.3 Cerium(IV) as coupling agent

For 2,4-di-t-butylphenol (44), coupling mode L (ortho C-ortho C) was found to be the most dominant, but the dominance of this mode in the oxidation of (44) with Ce(IV) depended on a number of factors such as temperature, concentration of the oxidant, the substrate:oxidant ratio, the reaction time and substrate loading. Under the correct reaction conditions, Ce(IV) in methanesulphonic acid afforded high conversions and selectivities to the desired product (45) when reacted with 2,4 -di-t-butylphenol (44). However, and as discussed earlier, in the case of the 2,4-dimethyl analogue, it is highly probable that coupling mode S (ortho C-O) may become more prominent due to the associated decreased steric effects around the hydroxyl group. In order to investigate this, 2,4-dimethylphenol was treated with Ce(IV) in methanesulphonic acid. (This reaction is novel in terms of the reaction conditions used for the coupling of this substrate by Ce(IV).) The effect of the following reaction parameters on this oxidative coupling process was investigated:

Varying the MeSO3H concentration. One or two phase systems with or without added co-solvent. Varying the reaction temperature. Varying the rate of oxidant addition to the reaction mixture.

138

Once again, the cerium carbonate concentration was kept constant at 1.0 M, irrespective of the methanesulphonic acid concentration, which was varied between 0.5 and 2.0 M for the electrochemical oxidation of Ce(III) to Ce(IV). As described earlier, an increase or decrease in the acid concentration affects the oxidation strength of the Ce(IV) ions.70,104 The substrate to oxidant ratio (1:2) was also kept constant throughout. Tables 3.22 and 3.23 show what effect a change in the MeSO3H concentration has on the coupling of 2,4-dimethylphenol (59) by Ce(IV) ions to form (61) at both room temperature (R.T.) and 80C, with all other variables remaining constant. Table 3.22 Oxidative coupling of (59) by Ce(IV) at various [MeSO3H] at R.T.

Reaction No.

[MeSO 3H] (M)

Time (h)

Solvent

Ratio (substrate:oxidant)

Conversion of (59) (%) 86.32

Selectivity to (61) (%) 24.20

45

0.5

H2O

1:2

41

1.0

H2O

1:2

76.04

57.58

46

2.0

H2O

1:2

89.92

22.17

It can be seen that when the concentration of MeSO3H was 1.0 M (reaction 41), the lowest conversion of (59) was obtained (76.04%), but the selectivity to (61) was significantly higher (57.58%) than in the other reactions. (One will recall that for the 2,4-t-butyl analogue, this reaction under identical conditions gave much lower conversions and selectivities as compared to this current study.) As found in prior investigations, the solubility of 2,4-dimethylphenol was found to be low in the aqueous reaction mixture, and so the reaction temperature was increased to 80C to increase its solubility in this medium (Table 3.23).

139

Table 3.23

Oxidative coupling of (59) by Ce(IV) at various [MeSO3H] at 80C

Reaction No.

[MeSO 3H]

(M)

Time (h)

Solvent

Ratio (substrate:oxidant)

Conversion of (59) (%) 86.12

Selectivity to (61) (%) 17.59

47

0.5

H2O

1:2

48

1.0

H2O

1:2

69.58

57.19

49

2.0

H2O

1:2

71.47

16.72

In general, a decrease in terms of both the conversion of (59) and the selectivi ty to (61) was noted in each of these reactions when compared to those results at R.T. This was surprising and in stark contrast to results obtained with the 2,4-di-t-butyl analogue that afforded much higher conversions and selectivities upon raising the reaction temperature from ambient to 80C. Thus, in the case where (59) is the substrate, an increased reaction temperature is not beneficial to the desired outcome of the reaction. The reasons for this are not clear, but perhaps the fact that 2,4dimethylphenol is a liquid at room temperature whilst 2,4 -di-t-butylphenol is a solid may affect the reaction in some way. However, it is still very surprising that

conversions dropped upon reaction temperature increase.

As with the 2,4-di-t-butyl analogue, v arious organic co-solvents were also added to each of the aqueous mixtures. To this end, MeOH and CH3CN were used in order to afford single-phased reaction systems, whilst CH2Cl2 was used for the biphasic system. These reactions were performed at R.T. for 1 h while keeping the MeSO3H concentration constant at 1.0 M (Table 3.24).

140

Table 3.24

Effect of co-solvents on oxidative coupling of (59) by Ce(IV) at R.T.

Reaction No.

[MeSO3H]

Solvent

(M)

Ratio (substrate:oxidant)

Conversion of (59) (%) 90.65

Selectivity to (61) (%) 8.32

50

1.0

H2O/MeOH

1:2

51

1.0

H2O/CH3CN

1:2

86.17

23.08

52

1.0

H2O/CH2Cl2

1:2

92.46

6.83

The reactivity of 2,4-dimethylphenol towards Ce(IV) ions in the presence of the organic solvents was high, with reactions 50, 51 and 52 achieving high conversions of (59) [90.65, 86.17 and 92.46 %, respectively], as expected. These conversions were much higher than those obtained earlier. However, selectivities dropped significantly. In the next study, using 1.0 M MeSO3H and CH3CN as co-solvent, the reaction was carried out at various reaction temperatures with all other variables kept constant. The total volume of the CH3CN and aqueous MeSO3 H was also kept constant (40 mL) for all these reactions. It w predicted that increased temperatures in the as presence of this co-solvent would merely decrease selectivities even further. Table 3.25 summarizes the results obtained.

141

Table 3.25

Temperature effect on coupling of (59) by Ce(IV) with CH 3CN as co-solvent

Reaction No.

CH3 CN volume

Ratio (substrate:oxidant)

Temperature

Conversion of (59) (%) 86.17

Selectivity to (61) (%) 23.08

51

20 mL

1:2

R.T.

53

20 mL

1:2

80C

87.03

34.22

54

20 mL

1:2

reflux

78.85

42.81

Howe ver, though reasonably high conversions were obtained at all three temperature settings, the highest selectivity was obtained at the highest temperature (reflux, reaction 54). Furthermore, the highest conversion was obtained at the lowest

temperature setting (R.T., reaction 51). It is not surprising that increased conversions are associated with decreased selectivities, but what is surprising is the decreased conversion at higher reaction temperatures; one would have expected higher temperatures to be accompanied by higher conversions unless, of course, the solubility of the substrate decreases with increasing reaction temperature, which hypothetically appears unlikely. Once again, the reasons for these observations are thus not clear, and may warrant further investigation in the future.

The optimum reaction conditions for this reaction may therefore be summarized as follows: The use of 1.0 M methanesulphonic acid concentration, In aqueous solvent with no added co-solvent (i.e., monophasic), At room temperature.

When co-solvents were added, reflux temperature afforded the better results.

142

The last variable that was investigated was the rate of addition of the oxidant to the reaction mixture. In all the previous reactions, the Ce(IV) was added to the mixture within 30 seconds, but in reaction 55 (Table 3.26), the Ce(IV) [in 20 mL MeSO3H] was added to the substrate (in 20 mL CH3CN) over a time period of 30 min. Samples were taken at 15 min and 60 min of reaction time. Table 3.26 Effect of rate of oxidant addition

Reaction No.

Oxidant

Time (min.)

Solvent

Temp.

Conversion (%)

Selectivity to (61) (%)

55

Ce

4+

15

CH3 CN

R.T.

61.10

49.85

55

Ce4+

60

CH3 CN

R.T.

82.81

19.24

When one compares the result obtained after 60 min (where the oxidant was added over 30 min) with that of reaction 51 (where the oxidant was added within 30 seconds), there is no advantage gained with the slower oxidant addition, contrary to that found for the coupling of the 2,4 -di-t-butyl analogue. In fact, slight decreases were observed in terms of both the conversion and the selectivity to (61). Reaction 51 thus remains the reaction having the optimal results.

3.5.1.3.1

Reaction mechanism for the oxidative coupling of 2,4 -dimethylphenol using Ce(IV)

In order to propose a feasible mechanism by which this reaction occurs, all the products of reaction 41 (Table 3.22) were identified. The GC trace has the following appearance (Figure 3.16):

143

Figure 3.16: GC trace of product mixture in reaction 41, Table 3.22

By making use of data obtained in mass spectral experiments and thus by determining the molecular ion peaks and interpreting their mass fragmentation patterns, the products (61), (62), (64), (65), (66) and (67) are proposed to have formed in this reaction. Products eluting at 8.13 and 8.81 min were identified as (66) and (67), respectively, while those at 14.64, 15.05 and 18.17 min all had the same M+ of 242 mass units. It is obviously not possible to fully characterize and identify these products from their mass fragmentation patterns alone, but it was deemed feasible that these peaks could be assigned to compounds (64), (65) and some other isomeric form thereof, such as any of the dienone dimers shown in Scheme 37b. Compounds eluting at 8.30 and 15.39 min corresponded with the starting material (59) and desired coupled product (61), respectively.

144

OH Me

OH Me Me

OH O

Me

Me

O Me (61) Me Me Me

Me (62) OH Me Me O O Me (64) O Me (65) OH Me Me OH Me Me

Me Me

OH

C H (66)

Me (67)

The formation of (61) will follow the same mechanism as proposed for the oxidative coupling of 2,4 -di-t-butylphenol (Scheme 33) by Ce(IV) in the presence MeSO3 H. The formation of products (62) and (65) is similar to the mechanism proposed for 2,4-

145

di-t-butylphenol to form the products (48) and (47) [Scheme 34]. Pummerers ketone (64) is most likely to be formed by means of the following mechanism (Scheme 38).
OH Me Ce4+ Ce3+ Me

.
O Me

Me Me

-H + O Me (59) o-p coupling

Me Me Me

H Me

Me Me

O H Me tautomerization Me Me

OH Me

H+

Me

O H Me (64)

Scheme 38: Reaction mechanism for the formation of (64)

The catechol (67) is possibly a result of the reaction of the radical cation with water, as shown previously in Scheme 35, and it may therefore readily be accounted for.

146

Though the amount of product (66) formed in these reactions was very small, its formation is of interest. One proposed mechanism that results in this product is shown in Scheme 39.
OH Me Ce4+ Ce3+ O Me

-H+ Me (59) Me

OH Me -e-

OH Me

CH2
+

CH2 (68)

(69) H2O -H+

OH OH Me Me -2e-2H+ CH2OH (70) CHO (66)

Scheme 39: Reaction mechanism for the formation of (66)

147

From this scheme, the radical (68) undergoes oxidation by losing an electron to afford the benzylic cation (69), which then reacts with the water present to form the primary alcohol (70). This is then further oxidized to form the benzaldehyde (66). (Compound (63), detected in reactions using FeCl3 as oxidant, may thus have been a result of the coupling of (59) with 4-hydroxy-3-methylbenzaldehyde, formed in a similar fashion to (66) shown in Scheme 39). 3.5.2 Concluding Remarks on the Oxidative Coupling of 2,4-

Dimethylphenol

From the results obtained, it is clear that 2,4-dimethylphenol coupled primarily by modes R and S. This substrate was not as selective as 2,6-di-t-butylphenol and 2,4di-t-butylphenol. Only moderate selectivities to the ortho C-ortho C coupled product (61) were achieved with oxidants FeCl3, K3Fe(CN)6 and Ce(IV) [49.11, 26.72 and 57.58 %, respectively]. The difference in the results obtained for 2,4-di-t-butylphenol and 2,4-dimethylphenol can be explained in terms of steric crowding, in which the hydroxyl moiety of 2,4-di-t-butylphenol is more sterically hindered by the two bulky tbutyl groups, thus disallowing the formation of the C-O coupled products which are more prevalent in the oxidation reactions of 2,4-dimethylphenol. In the case of K 3Fe(CN) 6, the major product seems to be that formed by C-O coupling. Furthermore, the methyl groups themselves are quite plausibly more reactive than the t-butyl groups of the other substrates, resulting also in the lower observed selectivities.

Results from the work conducted using Ce(IV) as the oxidant are novel, though the efficiency of the coupling in this reaction was found to be only moderately successful in terms of selectivity to the coupled product (61). Finally, a mechanism proposed for this work accounted for all the products observed in the reaction mixtures.

148

3.6

BUTYLATED PHENOLIC COUPLINGS: COMPARISONS

In this section, a brief comparison of some of the more important results that have not thus far been discussed and compared, is provided for cases where common oxidants were used for the various butylated phenol substrates, in order to draw conclusions from similarities and/or differences observed in the results so-obtained. (Note that many comparisons have been made in sections prior to this one, but it was deemed inappropriate to include the discussion that now follows in those self-same sections.) 3.6.1 Reactions of 2-t-Butylphenol and 2,6 -Di-t-Butylphenol with Ag 2O and Cu(OAc)2/Oxalic Acid Silver oxide was reacted with both 2-t-butylphenol and 2,6-di-t-butylphenol under identical reaction conditions. The results obtained for these substrates were significantly different with regards to their selectivity towards the respective desired CC coupled products. The results of these reactions are summarized in Table 3.27. Table 3.27 Comparative data obtained for silver oxide

Selectivity to p/p Reaction No. 2-t7 butylphenol 2,6-di-t10

a

Substrate

Oxidant

Time (h)

Solvent

Temp.

Conversion (%)

coupled products (%)

Ag2O

MeOH

R.T.

96.00

7.29
a

butylphenol

Ag2O

MeOH

R.T.

100.00

100.00

The diphenoquinone (10) and diol (16) percentages were 96.25 and 3.75 %, respectively.

From these results, it is obvious that when silver oxide is reacted with 2-t-butylphenol and 2,6-di-t-butylphenol under identical reaction conditions, the selectivity to the desired para C-para C coupled products is vastly different (7.29 % and 100.00 %,

149

respectively). (Note that with 2,6-di-t-butylphenol, a mixture of the diphenoquinone (10) and diol (16) were obtained, both resulting from para C-para C coupling, and the sum of their selectivities equalled 100 %.) When 2-t-butylphenol and 2,6 -di-t-butylphenol were oxidized using a copper(II) acetate/oxalic acid complex, the results obtained followed the same general trend as with Ag2O with regards to conversion of starting material and selectivity to the desired coupled products (Table 3.28). Table 3.28 Comparative data obtained for copper acetate/oxalic acid

Reaction No.

Selectivity to p/p Substrate Oxidant Solvent Temp. Conversion (%) Cu(OAc)2/ coupled products (%)

2-t-butylphenol 2,6-di-t-

Oxalic acid Cu(OAc)2/ Oxalic acid

PhCH3

60C

86.32

1.30

11

butylphenol

PhCH3

60C

100.00

100.00

In this case, with 2-t-butylphenol as substrate, the selectivity to the desired coupled product was extremely low (1.30 %), whereas when the oxidant was reacted with 2,6di-t-butylphenol, the desired para C-para C coupled products were formed exclusively [(16) and (10)].

The fact that 2-t-butylphenol has two unsubstituted carbon positions available (the 4and 6-positions) for oxidative coupling plays a significant role in these reactions when compared with the case when both the 2- and 6- positions are occupied by t-butyl groups. When the 6-position is blocked by such a bulky group, such as in 2,6-di-tbutylphenol, it prevents a large variety of C-C and C-O coupled side products from being formed, therefore accounting for the observed high selectivity. More especially, C-O coupling would be disfavoured by the proximity of the two bulky groups in the case of the 2,6-analogue. However, both C-O and C-C coupling (in more than one 150

position) are highly likely for the mono-substituted phenol, thus resulting in the myriad of products that was observed. It was further noted that 2-t-butylphenol was less reactive in terms of conversion than 2,6-di-t-butylphenol in the presence of both silver oxide and copper acetate/oxalic acid. The decreased reactivity of 2-t-butylphenol, as compared to 2,6-di-tbutylphenol, may be ascribed to the fact that 2-t-butylphenol, with only one electrondonating alkyl group (by the inductive effect), is most likely less easily oxidized than 2,6-di-t-butylphenol, which has two such alkyl groups, the latter aromatic ring being, therefore, more electron dense (and thus more readily oxidized) than that of the former. It was further noted that no diphenoquinone formation was observed in the oxidation of 2-t-butylphenol, whereas with 2,6-di-t-butylphenol, the diphenoquinone derivative was the major product (reactions 10 and 11). their resultant coupled products. 3.6.2 Reactions of 2,4-Di-t-Butylphenol and 2,6-Di-t-Butylphenol with Ce(IV) in MeSO3H For the sake of this comparative study and in retrospect, it was thought appropriate to carry out a reaction (reaction 56, Table 3.29) in which 2,6 -di-t-butylphenol (9) was reacted with Ce(IV) under identical reaction conditions to that of reaction 15, in which the substrate was 2,4-di-t-butylphenol (44). This is possibly a further indication of the difference in oxidation potential of the two substrates, as well as of

151

Table 3.29

Comparative data obtained for Ce(IV)

Reaction No.

Oxidant

Time (h)

Solvent

Temp.

Conversion (%)

Selectivity to desired coupled products (%)

15

Ce4+
4+

H2O/ MeOH

Reflux

100.00

90.35b
c

56

Ce

H2O/ MeOH

Reflux

45.01

100.00

b c

Selectivity to (45). The diphenoquinone (10) and diol (16) percentages were 82.50 and 17.50 %, respectively.

It was observed that 2,6-di-t-butylphenol was significantly less reactive with Ce(IV) than 2,4-di-t-butylphenol (conversions of 45.01 and 100 %, respectively). However, 2,6-di-t-butylphenol formed para C-para C coupled products exclusive ly, whereas 2,4di-t-butylphenol did not form the desired ortho C-ortho C product (45) exclusively (with a selectivity of only 90.35 %). This may be due to the increased potential for C-O coupling in the 2,4-analogue as compared to the 2,6-analogue due to steric hindrance. In order to investigate possible theoretical reasons for these observations, MO calculations were carried out on the relevant dienone and phenolic products of these two reactions. The relative energy profiles associated with coupling modes G (where the substrate 2,6-di-t-butylphenol undergoes para C-para C coupling [2,6 p,p]), H (where 2,6-di-tbutylphenol undergoes para C-oxygen coupling [2,6 p,O]), L (where the substrate 2,4di-t-butylphenol undergoes ortho C-ortho C coupling [2,4 o,o]) and M (where 2,4-di-tbutylphenol undergoes ortho C-oxygen coupling [2,4 o,O]) that lead to phenolic products can be depicted in the following graph (Figure 3.17). (In this figure, dienone intermediates are denoted as 1 and their corresponding phenolic forms as 2 on the xaxis. All values plotted are relative to the heat of formation of the phenolic form for

152

the ortho C-ortho C coupled product of 2,4-di-t-butylphenol (denoted as 2,4 o,o in the figure), which was arbitrarily assigned a value of 0 kcal/mol for the purposes of ease of comparison.)

50 Relative Energy (kcal/mol) 45 40 35 30 25 20 15 10 5 0 0 1 2 2,4 o,o 2,4 o,O 2,6 p,p 2,6 p,O

Figure 3.17: Relative energies of dienones (1) and coupled phenols (2)

From these relative energy profiles, it can be seen that the intermediate dienones, when coupling the 2,4 -analogue, have lower relative energies as compared to the corresponding 2,6-analogue, implying that the 2,4-analogue more readily forms these intermediates (because of their greater stability) than the 2,6-analogue. This is in agreement with experimental findings (Table 3.29) where the conversion of the 2,4analogue was much higher than that of the 2,6-analogue in the presence of Ce(IV) as the oxidant. The driving force for the subsequent tautomerization of these dienones is their gain in aromaticity, and thus an increase in their stability. These calculations also show that the ortho C-O coupling (2,4-di-t-butylphenol) of a pair of the appropriate phenoxyl radicals is about 10 kcal/mol more favourable than the corresponding para C-O (2,6-di-t-butylphenol) derivative, as suggested earlier and as a consequence of the greater steric crowding around oxygen in the 2,6-analogue. The greater energy difference (4.05 kcal/mol, Table 3.4) between dienones formed by para C-para C and para C-O coupling reactions of 2,6-di-t-butylphenol as compared

153

with the smaller energy difference (3.37 kcal/mol, Table 3.7) of dienones formed by ortho C-ortho C and ortho C-O coupling of 2,4-di-t-butylphenol suggests that the 2,6analogue favours C-C coupling over C-O coupling to a greater extent than the 2,4analogue favours C-C coupling over C-O coupling. This may be an explanation for the observed selectivity difference between these two substrates (when using Ce(IV) and Ag 2O as oxidants), and also for the observation that the 2,4-analogue afforded C-O coupled product whereas the 2,6-analogue did not. (Note that these MO calculations do not provide any information on rates of reaction, but only on thermodynamic aspects thereof.)

Overall, these theoretical considerations thus add credence to experimental findings obtained in our laboratories.

154

CHAPTER 4 CONCLUSION AND FINAL COMMENTS

During the investigation into the oxidative coupling of various mono- and disubstituted phenols under a variety of reaction conditions using a range of different coupling agents, a number of conclusions were drawn from the observed results.

The oxidative coupling reactions of 2-t-butylphenol (35) using various oxidants produced a large number of products, and so the number of coupling modes that 2-tbutylphenol prefers is numerous under the conditions that were investigated. There was no observed selectivity to any single product, and both C-C and C-O coupling appeared to take place in these reactions, amongst others. Although a large variety of oxidants were assessed, the selectivity to the coupled product 3,3-di-t-butyl-4,4dihydroxybiphenyl (39) was found to be low irrespective of the oxidant used. The highest selectivities were achieved with cerium(IV) sulphate (25.99 %) and silver carbonate on celite (25.57 %), but these selectivities were obtained at low conversions of 2 -t-butylphenol (26.61 and 10.98 %, respectively). (The reaction conditions under which the cerium work was conducted in this case is novel and has not been reported elsewhere, as indicated by an extensive literature survey.) All the other oxidants that were used were found to be totally ineffective in producing the desired coupled product (39). In many of these latter cases, though, the conversion of the substrate was reasonable. A general trend that was observed was that higher conversions were usually associated with lower selectivities. It was therefore concluded that 2-t-butylphenol (35), due to the number of feasible coupling modes available to this substrate, showed no promise as a substrate for the selective coupling to afford (39) as the desired product under the reactions conditions that were investigated. It therefore appears highly unlikely that 2-t-butylphenol may be used as a substrate in order to form the desired para C-para C coupled product in an economically viable process due to the non-selectivity displayed by the substrate, irrespective of the employed oxidant.

155

The oxidative coupling reactions of 2,6-di-t-butylphenol (9) can theoretically produce numerous products through a number of different coupling modes (G-K). Of these modes, however, G and H were predicted to be more facile, as shown by molecular orbital calculations. When experimentally investigated, it was found that this substrate was indeed highly selective when placed under oxidative coupling conditions. It was observed that high selectivities to the desired para C-para C coupled products (16) and (10) using Ag2O, Cu(OAc)2/oxalic acid and Ce(IV) sulphate (100 % selectivity in all instances) were achieved. Both Ag2O and Cu(OAc)2/oxalic acid also gave high conversions of (9) [both 100 %], but Ce(IV) sulphate only achieved a 45.01 % conversion of (9) after a reaction time of 1 h. These results obtained are in agreement with those reported in the literature,46,78 and the molecular orbital calculations further confirmed these observations. Thus the presence of an additional t-butyl group in 2,6-di-t-butylphenol (9), as compared with that of 2-tbutylphenol (35), has a significant effect on the course of the reaction and on the preferred mode of coupling of (9). The number of feasible coupling modes for (9) is thus reduced by the additional substituent, and steric congestion also comes into play when considering the absence of any C-O coupling for (9) [which was present when the substrate was (35)]. (Note that results obtained from reactions of Ce(IV) with (9) have not been reported previously.) When 2,4 -di-t-butylphenol (44) was oxidatively coupled using agents potassium ferric cyanide and cerium(IV) sulphate, a high selectivity to the desired ortho C-ortho C coupled product (coupling mode L) was observed. The C-O coupling mode also

appears to occur in these reactions (mode M). This substrate was, however, not as selective as 2,6-di-t-butylphenol (showing 100 % selectivity to para C-para C coupled products). The use of other oxidants such as FeCl3 and Ag2O afforded results that were less than satisfactory in terms of selectivity to the preferred coupled product (45), despite high conversions of the substrate. Thus both FeCl3 and Ag 2O were found to be unsuitable for the purposes of forming (45), quite possibly due to the mechanisms by which they react in combination with the positioning of the substituents on the aromatic rings. Molecular orbital calculations confirmed the

156

preference for coupling mode L and, to a lesser extent, mode M. The difference in results obtained for the 2,4- and 2,6 -analogues may onl y be explained in terms of steric crowding, in which the hydroxyl moiety of the 2,6-analogue is well surrounded by the two bulky t-butyl groups, thus disallowing the formation of the undesired C-O coupled products. The 2,4 -analogue, on the other hand, s less crowded in the i

vicinity of the OH group, and can thus also form some of the C-O coupled product, resulting in the observed lower selectivities to the C-C coupled product as compared with the 2,6-analogue. The amount of steric congestion around the OH group in both 2-t-butylphenol and 2,4 -di-t-butylphenol is probably somewhat similar, thus explaining the propensity for both substrates to undergo C-O coupling in these conditions. Once again, the work conducted with 2,4 -di-t-butylphenol using Ce(IV) as the oxidant is entirely novel, and the results obtained in these reactions were found to be very promising indeed, with high selectivites and conversions to the desired coupled dimer (45) being achieved. Investigation of the various reaction conditions then produced the optimal reaction conditions which included the use of 1 M aqueous methanesulphonic acid as the medium of choice with added co-solvent (methanol) such that the resultant solution is a single phased reaction mixture. Furthermore, the optimal reaction temperature was found to be approximately 65C (at reflux), and lengthy reaction times were not necessary, probably because the desired coupling reaction takes place rather rapidly. The substrate loading was an important factor: too high loadings afforded low conversions, and too low loadings afforded low selectivities. The optimal substrate:oxidant ratio was 1:2, with a slow addition of the oxidant to the reaction medium being favoured over that of rapid addition. This

process can be further investigated in terms of industrial viability since Ce(IV) can be regenerated electrochemically from Ce(III) successfully and since 2,4-di-t-butylphenol as a substrate gave high selectivities to the desired coupled product. The oxidative coupling reactions of 2,4-dimethylphenol (59) were not as selective as that of 2,4-di-t-butylphenol or 2,6-di-t-butylphenol under identical reaction conditions. From the results obtained, it is clear that 2,4-dimethylphenol coupled primarily by

157

modes R and S. Only moderate selectivities to the desired ortho C-ortho C coupled product (61) were achieved with oxidants FeCl3, K 3Fe(CN) 6 and Ce(IV) [49.11, 26.72 and 57.58 %, respectively]. Once again, the difference in the results obtained for 2,4di-t-butylphenol and 2,4-dimethylphenol can be explained in terms of steric crowding: the hydroxyl moiety of 2,4-di-t-butylphenol is more sterically hindered by the bulky tbutyl group, thus decreasing the amount of C-O coupling, which is more prevalent in the oxidation reactions of 2,4-dimethylphenol (which only has the smaller methyl substituent in the OH region). (In the case of K3Fe(CN)6, the major product seems to be that formed by C-O coupling.) Furthermore, the lower selectivities observed for the dimethyl derivative is also very likely a result of the presence of the benzylic C-H groups, which are normally rather activated, especially under radical conditions. Results from the work conducted using Ce(IV) as the oxidant are again novel, though the efficiency of the coupling in this reaction was found to be only moderately successful in terms of selectivity to the coupled product (61). The aims of this investigation have thus been realized, and the study of the various coupling reactions, the reaction conditions and the v arious oxidants and substrates has led to much new knowledge that may now be added to this field of chemistry. Many promising results were observed, and feasible reasons given for those reactions that were not successful. One of the major goals of these investigations was to find an oxidant that was both environmentally and economically viable, that afforded high conversions of the substrates and selectivities to the desired coupled products. From this work, Ce(IV), in the presence of methanesulphonic acid,

appears to be just such a coupling agent, and many promising, novel results were obtained in oxidative coupling reactions carried out in its presence. The feasibility of its electrochemical regeneration from Ce(III), the fact that substrates such as 2,4-di-tbutylphenol, when reacted with Ce(IV), gave high conversions and selectivities to the desired product, and the mild reaction conditions used, makes it an oxidant that may be feasible for scale-up operations, though scale-up itself will require a separate intensive study.

158

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168

APPENDIX

Appendix 3.1: MS Fragmentation pattern for product with retention time 12.76 min

Appendix 3.2: MS Fragmentation pattern for product with retention time 13.29 min

169

Appendix 3.3: MS Fragmentation pattern for product with retention time 14.18 min

Appendix 3.4: MS Fragmentation pattern for product with retention time 15.27 min

170

Appendix 3.5: GC trace obtained for BaMnO4 reaction with (35)

Appendix 3.6: MS Fragmentation pattern for product with retention time 13.77 min

171

Appendix 3.7: MS Fragmentation pattern for product with retention time 14.11 min

Appendix 3.8: MS Fragmentation pattern for product with retention time 30.74 min

172

Appendix 3.9: MS Fragmentation pattern for product with retention time 18.07 min

173