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I

CONTENTS

ACKNOWLEDGEMENTS VII

SUMMARY VIII

CHAPTER 1 INTRODUCTION

1.1 GENERAL 1

1.2 USES OF COUPLED PHENOLICS 4

1.2.1 Antioxidants 4

1.2.2 Other Uses 6

1.3 METHODS OF PREPARATION OF COUPLED PHENOLICS 6

1.3.1 General Types of Coupling Reaction Mechanisms 8

1.3.2 Chemical and Electrochemical Methods for Oxidatively

Coupling Phenolics 15

1.3.2.1 Chemical oxidative coupling 15

1.3.2.1.1 Vanadium(IV) and vanadium(V) 16

1.3.2.1.2 A (nitrosonaphtholato)metal complex 18

1.3.2.1.3 Activated manganese dioxide 21

1.3.2.1.4 Cupric salts 23

1.3.2.2 Electrochemical oxidative coupling 25 1.3.2.2.1 Direct electrochemical oxidations 25

1.3.2.2.2 Indirect electrochemical oxidations 29

1.4 OBJECTIVES AND MOTIVATION FOR THIS STUDY 32



II

CHAPTER 2 EXPERIMENTAL

2.1 MATERIALS 34

2.1.1 Reagents for Synthesis and Analysis 34

2.2 SYNTHETIC PROCEDURES 36

2.2.1 Reagents for Analysis 36

2.2.1.1 Preparation of 3,3’-di-t -butyl-4,4’-dihydroxybiphenyl 36 2.2.1.2 Preparation of 3,3’,5,5’-tetra-t -butyldiphenoquinone 36

2.2.1.3 Preparation of 3,3’,5,5’-tetra-t -butyl-4,4’-

dihydroxybiphenyl 37

2.2.1.4 Preparation of 3,3’,5,5’-tetra-t -butyl-2,2’-

dihydroxybiphenyl 37

2.2.1.5 Preparation of 3,3’,5,5’-tetramethyl-2,2’-

Dihydroxybiphenyl 38

2.2.2 Preparation of Coupling Agents 38

2.2.2.1 Preparation of silver carbonate/celite 38

2.2.2.2 Preparation of barium manganate 39

2.2.2.3 Preparation of a (nitrosonaphtholato)metal complex

(MnII(1-nnap)2) 39

2.2.2.4 Electrochemical preparation of cerium(IV) from

cerium(III) using a divided cell 40

2.2.2.5 Preparation of silver oxide 42

2.3 EXPERIMENTAL PROCEDURES 43

2.3.1 Oxidative Coupling Reactions 43

2.3.1.1 Oxidation of alkylphenols using silver



III

carbonate/celite 43

2.3.1.2 Oxidation of alkylphenols using copper complexes

of dicarboxylic acids 45 2.3.1.3 Oxidation of alkylphenols using manganese(III)

acetate 44

2.3.1.4 Oxidation of alkylphenols using barium manganate 44

2.3.1.5 Oxidation of alkylphenols using a (nitrosonaphtholato)-

metal complex 45

2.3.1.6 Oxidation of alkylphenols using FeCl3 in an organic

solvent 45

2.3.1.7 Oxidation of alkylphenols using FeCl3 without

solvent 45

2.3.1.8 Oxidation of alkylphenols using Ag2O 46

2.3.1.9 Oxidation of alkylphenols using lead tetra-acetate 46

2.3.1.10 Oxidation of alkylphenols using Ce4+ 46

2.3.1.11 Oxidation of alkylphenols using potassium

ferricyanide 47

2.3.2 Determination of Ce(III) Remaining After the Electrochemical

Oxidation of Ce(III) to Ce(IV) 47

2.3.3 Dealkylation of Dihydroxybiphenyls 48

2.4 ANALYTICAL TECHNIQUES 48

2.4.1 High Performance Liquid Chromatography (HPLC) 48

2.4.2 Nuclear Magnetic Resonance (NMR) Spectroscopy 50 2.4.3 Fourier Transform Infra Red (FTIR) Spectroscopy 50

2.4.4 Gas Liquid Chromatography-Mass Spectrometry (GC-MS) 51

2.4.5 Molecular Orbital Calculations 51

2.5 TERMS AND DEFINITIONS 52



IV

CHAPTER 3 DISCUSSION

3.1 MODES OF PHENOLIC COUPLING 53

3.1.1 Molecular Orbital Calculations for the Coupling of Phenol 56

3.2 THE OXIDATIVE COUPLING OF 2-t -BUTYLPHENOL 58

3.2.1 The Range of Possible Products During the OxidativeCoupling of 2-t -Butylphenol 60

3.2.2 Oxidative Coupling Reactions of 2-t -Butylphenol

using Various Oxidants 63

3.2.2.1 Vanadium(V) oxytrichloride and vanadium(IV)

tetrachloride as coupling agents 65

3.2.2.2 Silver carbonate supported on celite as coupling

Agent 65

3.2.2.3 Copper acetate, in the presence of a dicarboxylic acid,

as coupling agent 70

3.2.2.4 Manganese(III) acetate as coupling agent 71

3.2.2.5 Barium manganate as coupling agent 72

3.2.2.6 Ferric chloride as coupling agent 73

3.2.2.7 Silver oxide as coupling agent 74

3.2.2.8 Potassium ferric cyanide, lead tetra-acetate,

a (nitrosonaphtholato)metal complex and

cerium(IV) sulphate as oxidants 75

3.2.3 Concluding Remarks on the Oxidative Coupling of 2-t -

Butylphenol 75

3.3 THE OXIDATIVE COUPLING OF 2,6-DI-t -BUTYLPHENOL 76



V

3.3.1 Molecular Orbital Calculations for the Oxidative Coupling of

2,6-Di-t -Butylphenol 77

3.3.2 Oxidative Coupling Reactions of 2,6-Di-t -ButylphenolUsing Various Oxidants 81


3.3.2.2 Copper(II) acetate/oxalic acid as coupling agent 87

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

Butylphenol 88

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 90

3.4.2 Oxidative Coupling Reactions of 2,4-Di-t -Butylphenol Using

Various Oxidants 94



3.4.2.3 Potassium ferric cyanide as coupling agent 100

3.4.2.4 Cerium as coupling agent 104

3.4.2.4.1 Identification of Ce(IV) as the preferred

oxidant 104

3.4.2.4.2 Oxidation in MeSO3H mediated by

Ce(IV) ions 107

3.4.2.4.3 Reaction mechanism for the oxidative

coupling of 2,4-di-t -butylphenol usingCe(IV) 119


Butylphenol 126



VI

3.5 THE OXIDATIVE COUPLING OF 2,4-DIMETHYLPHENOL 127

3.5.1 Oxidative Coupling Reactions of 2,4-Dimethylphenol UsingVarious Oxidants 131


3.5.1.2 Potassium ferric cyanide as coupling agent 136

3.5.1.3 Cerium(IV) as coupling agent 138

3.5.1.3.1 Reaction mechanism for the oxidative coupling

of 2,4-dimethylphenol using Ce(IV) 138

3.5.2 Concluding Remarks on the Oxidative Coupling of 2,4-Dimethylphenol 148

3.6 BUTYLATED PHENOLIC COUPLINGS: COMPARISONS 149

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 CONCLUSION AND FINAL COMMENTS

REFERENCES 159

APPENDIX 169



VII

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, Daniël, 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.



VIII

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 mono-

and disubstituted 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-t -

butylphenol, 2,6-di-t -butylphenol, 2,4-di-t -butylphenol and 2,4-dimethylphenol, using arange of different oxidizing 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 andselectivities 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 MeSO3H 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



IX

using 2,6-di-t -butylphenol as the substrate. However, it was not as effective with 2,4-

dimethylphenol, 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 thepreferred 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.



1

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 currentlywell established and one that continues to grow.1

From an initial slow start in the 1850’s, 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.



2

SO3H OH

1. NaOH, 300°C

2. H3O+

Cl OH

1. aq. NaOH, 340°C, 2500 psi

2. H3O++ NaCl

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

Scheme 2: Preparation of phenol from chlorobenzene

The Mitsui group is the world’s 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 tert -

hydroperoxide, which is then ultimately cleaved to yield phenol and acetone (Scheme

3).



3

OH

[O]

OOH

H3O+

+

O

cumene cumenehydroperoxide

acetone

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)

Chemical/Year 1996 1997 1998 1999 2000

Increase

1999/2000

Phenol 768 833 851 888 916 3.2%

Phenol Resins 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 then be reacted further by oxidative coupling to form the



4

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 serveas raw materials for varnishes, herbicides and insecticides.

1.2 USES OF COUPLED PHENOLICS

1.2.1 Antioxidants

One of the more important uses of many phenolic materials is their ability to serve asantioxidants. 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, α-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



5

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).

Initiation: production of RO• (1)

Propagation: R• + O2 → ROO• (2)

ROO• + RH → ROOH + R• (3)

Termination: ROO•

+ RO•

→ products (4)ROO• + PhOH → ROOH + PhO• (5)

While reaction 1 is very fast, having a rate constant of approximately 109 M-1s-1,

reaction 4 is much slower at 101 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.



6

1.2.2 Other Uses

Dihydroxybiphenyls are used in toner resins to increase surface additive adhesionand 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 moulding19 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 1950’s 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 extremelyimportant 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)



7

OH

R

OH

R

+ HO OH

R R

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 phenolicmolecules 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.

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

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

OH

R

OH

R

+ OHO

R

R



8

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 aretransferred 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) Direct coupling of two phenoxyl radicals (FR1)

ii) Homolytic aromatic substitution (FR2)iii) Heterolytic coupling preceded by two successive one-electron oxidation

steps (FR3)

b) Mechanisms which are non-radical in character

i) Heterolytic coupling preceded by a single two-electron transfer (NR1)

ii) Concerted coupling and electron transfer (NR2)



9

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). Most

reviewers have included the FR3 mechanism in their discussions but have attachedlittle importance to it. 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 (Scheme6) highlights the FR1, FR2 and FR3 mechanisms.



10

OH

RR

(1)

-e -, -H+RR

O

RR

O

+ (1)

FR2

FR1 coupling of two

FR3-e-

O

RR

+

O

RR

H H

H

OH

RR

-e-

-H+

O

R R

HH

O

R R

(2)

R R

OH

R R

OH

(3)

disproportionation

RR

OH

RR

OH

H

HH

-2e-, -2H+

-H+

pathway (a)

(4)

phenoxy radicals

+ (1)

phenoxy radical

tautomerization

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



11

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).

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 inprotic 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

R R

O

R R

O

R R

O

RR

O



12

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 metalion (M3+), which forms an initial metal-phenolate complex with (1).



13

RR

OH

(1)

+ M3+ - H+

O

RR

M2+

O

RR

+ M++ (1), - H+

RR

HH

O

O

RR

RR

OH

RR

OH

(3)

(2)

+

tautomerization

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



14

OH

RR

(1)

-H+

R R

OM

R R

OH

2+

O

R

R

H

H

O

R

R

RR

OH

R

OH

R

(3)

(2)

- M+

+ M+32

tautomerization

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) whichundergoes tautomerization, and so the desired product (3) is a result.

Objections, based on energetic 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.

Scheme 9: The NR2 mechanistic pathway



15

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 Thvagarajan59 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 oxidative coupling

From about as early as the 1920’s, 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,



16

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 thetypes 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 beenused 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 4,4’-

diphenol (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).

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

OH

+ VCl4

OH

OH

OH

OH OH

HO

(5)

(6)

(7)(8)

+ +



17

When the hydrolysis step was carried out in the presence of deuterium oxide, no

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 becoupled 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/dimerizationstep 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).



18

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

+ VOCl3-HCl

O

R R

V

O

Cl

Cl

OH

R R

O

O

HH

RR

R R

+

VOCl3

2VOCl2 + HCl

OH

OH

RR

RR

OH

RR

tautomerization

V

OH

ClCl



19

C(CH3)3(CH3)3C

OH

O2

[Mn(II)

(1-nnap)n]-R3P

O

O

(CH3)3C C(CH3)3

C(CH3)3(CH3)3C

(9)

(10)

Thus when 2,6-di-tert -butylphenol (9) was reacted with

(nitrosonaphtholato)manganese [Mn(II)(1-nnap)2] at 23°C under an oxygen

atmosphere, in the presence of triphenylphosphine, the diphenoquinone (10) was

formed (Scheme 12).

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 irreversibleMn(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.



20

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

C(CH 3)3(CH3)3C

OH

(9)O

N

N

O

O

O

O

MnIII

Mn-cycle

O

N

N

O

O

O

MnII

Ph3P=O+ HO

.

.

PPh3

+ O2

O

(CH3)3C

(CH3)3C

HO

H

(CH3)3C

(CH3)3C

O

(11) (12)

(13)

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

(16) [Mn-cycle]

(10)

(14)

PPh3

O

N

N

O

O

O

OH

MnIII

O

PPh3

[MnII(1-nnap)2]

O

(CH3)3C

(CH3)3C

H

H

C(CH 3)3

C(CH 3)3

OH

+(9)

MnIII species

tautomerizationHO

(CH3)3C

(CH3)3C

H

C(CH 3)3

C(CH 3)3

OH

HO

(CH3)3C

(CH3)3C

C(CH 3)3

C(CH 3)3

OH HO

(CH3)3C

(CH3)3C

C(CH 3)3

C(CH 3)3

O

(17)

MnIII species

[MnII(1-nnap)2]

O

(CH3)3C

(CH3)3C

C(CH 3)3

C(CH 3)3

O

(15)



21

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 phenoxylradical (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).

1.3.2.1.3 Activated manganese dioxide

37

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’,5,5’-

tetramethyl-p ,p ’-biphenol (20) and 3,3’,5,5’-tetramethyldiphenoquinone (21) [Scheme

14].

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

MeMe

OH

MnO2

(19)

n

+

Me Me

Me Me

OH

OH

O

O

Me Me

MeMe

+

(18)

(20) (21)

MeMe

OH

O

MeMe

O

MeMe



22

OH

Me MeO

O

Me Me

O

Me Me

H

(22) + (23) O

Me

O

Me

H

Me

Me

(19) (where n = 0)

(23) + (23)

Me

O

Me

H

Me

Me

O

H

(21)

(23) + O

Me

O

Me Me

Me

(19) (where n = 1)

(23)

(18) (22)

tautomer-

ization

O

OH

Me Me

Me Me

O

MeMe

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 carbon-

carbon coupling, whilst (19) is formed exclusively by carbon-oxygen coupling

(Scheme 15).

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



23

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., carbon-oxygen 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 salts46

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).



24

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 used 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).

R

R

OH

R

R R

R

OHOH

+ ...(1)

1/2 O2 + H2O

R

R

OH

2

(24)

(24)

+ 1/2 O2

(25)

R

R R

R

OHOH

(25)

2C

O

R)22Cu(OC

O

R2CuO

C

O

R2HO+

C

O

R2CuO C

O

R2HO+ + C

O

R)22Cu(O ...(2)

+ H2ONett: ...(3)



25

OH OH OH

OH

OH

OH

OH

(26)

C

O

R)22Cu(O

(6)

(7)

2 + +

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.



26

• 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 phenolitself, 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



27

OH

CPE: +0.9Vvs SCE

25% acetone buffer (pH 5), (C)

OH

+

O

-H+

-e-

O

++H2O

OH

OH

-H+

-2e-, -2H+

O

O

C-C coupling

OH

OH

O

O

(28)

(27)

andtautomerization

-2e-

-2H+

(6)

-e-

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 2,6-

dimethylphenol also leads to the rapid formation of a linear polymer chain. However,



28

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 infraredspectroscopy (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

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 Pummerer’s ketone (30) in 74 % yield, as seen in thefollowing scheme (Scheme 20).69

CCE: 1.0 mA cm-1

LiClO4, MeOH-CH 2Cl2

(Pt)

OH

C(CH3)3(CH3)3C

(9)

OH

C(CH3)3(CH3)3C

C(CH3)3(CH3)3C

OH

(16)

O

C(CH3)3(CH3)3C

C(CH3)3(CH3)3C

O

(10)

-2e-, -2H+

+2e-, +2H+



29

Scheme 20: Oxidation of p -cresol to Pummerer’s 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 Ce3+/Ce4+,

Mn2+/Mn3+ and Cr 3+/Cr 2O72-. These redox couples are used primarily for oxidations of

organic compounds.

Indirect electrosyntheses may be carried out using one of two methods:

OH

Me

CPE: +0.25 V vs SCE

(1 F mol-1)NaClO4

MeCN-H2O-NaOH

(C)O

Me

O

Me

o-p coupling

O O

HMe

Me

H+

(29)

(30)

Me

OH

O

Me

followed

bytautom.



30

• 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-6-

methylphenol (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 2,6-

diphenylphenol (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 (4.0M) 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.



31

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

Table 1.2 Oxidation of disubstituted phenols by cerium(IV)

Phenol Procedurea MolarRatiob

Concentrationof HClO4 (M)

Time(min)

Product (yield)(% )

31a A 1:2.15 0.5 0 32a (85), 33a (4), 34a (8)

31a B 1:4.00 4.0 30 32a (3), 34a (90)

31b A 1:2.25 0.5 180 32b (54), 33b (37)

31b B 1:3.75 4.0 90 32b (12), 33b (21), 34b (56)

31c A 1:2.25 0.5 0 32c (70), 33c (23)

31d A 1:1.75 0.5 0 32d (30), 33d (65)

aReactions were either in homogeneous (A) or heterogeneous (B) reaction systems

b Phenolic substrate:cerium(IV) molar ratio

R1

HO

R2

Ce(IV)

H2O-ANHClO4 (0.5-4.0 M)

O

O

R1 R2

R2R1

O O

R1

R2

R1

R2

R1

HO

R2

n33a-d

O O

R1

R2

31a: R1 = R2 = isopropyl31b: R1 =t -Bu; R2 = CH331c: R1 = R2 = Ph31d: R1 = R2 = Cl

+

32a-d

31a or 31b Ce(IV)CCl4/aq. CH 3CN

HClO4 (4.0 M)

34a or 34b



32

1.4 OBJECTIVES AND MOTIVATION FOR THIS STUDY

Dihydroxybiphenyls, as mentioned previously, have many important uses aschemicals 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 coupling of 2,4- or 2,6- disubstituted phenols is reallypossible 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 time-

consuming 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

mechanisms 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 becoupled. 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 di-

substituted phenols using chemical and indirect electrochemical oxidation methods.



33

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.



34

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 FORMULA SOURCE GRADE

4,4’-Dihydroxybiphenyl C12H10O2 Aldrich CP

Carbon tetrachloride CCl4 Holpro AR

t -Butyl bromide (CH3)3CBr Aldrich CP

Ethyl acetate CH3CO2C2H5 Saarchem CP

Hexane C6H14 BDH Technical

Methanol CH4O BDH HPLC2-Naphthol C10H7OH Saarchem CP

Dichloromethane CH2Cl2 Saarchem AR

Toluene C6H5CH3 Merck Technical

Oxalic acid HO2CCO2H Riedel-de Haen AR

Acetonitrile CH3CN BDH HPLC

Acetic acid CH3CO2H Merck AR

2-t -Butylphenol C10H14O Aldrich AR

2,4-Dimethylphenol C8H10O Riedel-de Haen CP

2,4-Di-t -butylphenol C14H22O Aldrich AR

2,6-Di-t -butylphenol C14H22O Fluka CP

Chloroform CHCl3 Saarchem CP

Succinic acid HO2C(CH2)2CO2H Riedel-de Haen AR



35

Table 2.2 Inorganic and organometallic reagents for synthesis

CHEMICAL NAME FORMULA SOURCE GRADE

Silicon dioxide SiO2 Fluka Technical

Sodium carbonate Na2CO3 Saarchem AR

Celite N/A Hopkin&Williams AR

Potassium ferric cyanide K3Fe(CN)6 Merck AR

Hydrochloric acid HCl Saarchem AR

Silver nitrate AgNO3 Saarchem AR

Barium hydroxide Ba(OH)2 Protea Chemicals CP

Sodium hydroxide NaOH Saarchem CPSodium nitrite NaNO2 Saarchem CP

Sulphuric acid H2SO4 Saarchem Technical

Manganese chloride MnCl2 M&B CP

Cupric acetate Cu(OAc)2 Mallinckcroft AR

Manganese acetate Mn(OAc)3 Merck AR

Triphenylphosphine P(Ph)3 Aldrich AR

Ferric chloride FeCl3 Riedel-de Haen CP

Silver oxide Ag2O Fluka AR

Cerium carbonate Ce2(CO3 )3 Aldrich AR

Methanesulphonic acid CH3SO3H Acros Technical

Ferrous sulphate FeSO4 Unilab Technical

Sodium hydrosulphite Na2S2O4 M&B Technical

Manganese dioxide MnO2 Unilab AR

Ammonium persulphate (NH4)2S2O8 Saarchem CP

Potassium hydroxide KOH Saarchem CP

Ferroin N/A Saarchem AR

Magnesium sulphate MgSO4

Saarchem 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.



36

2.2 SYNTHETIC PROCEDURES

2.2.1 Reagents for Analysis

2.2.1.1 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

Na2CO3 (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 70°C. The

SiO2 was filtered off and washed with ethyl acetate. The ethyl acetate washings andfiltrate 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-4,4’-

dihydroxybiphenyl, was thus obtained, and had m.p. 182-183°C (lit.71, m.p. 181-

183°C); ?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 -butylphenol (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 theprimary product, which was further purified by recrystallization using ethyl

acetate:petroleum ether (b.p. 60-80°C); m.p. 247-248°C (lit.28, m.p. 248°C); ?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).



37

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) inether (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-4,4’-

dihydroxybiphenyl (99.00 %), which was further purified by recrystallization using

ethyl acetate:petroleum ether (b.p. 60-80°C); m.p. 187-188°C (lit.72, m.p. 185-

186.5°C); ?max (CCl4)/cm

-1

3650 (OH), 2800-3050 (C-H) and 1592 (C=C); m/z 410(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-2,2’-

dihydroxybiphenyl (83.95 %), which was purified by recrystallization using ethyl

acetate:petroleum ether (b.p. 60-80°C); m.p. 199.5-202.5°C (lit.46, m.p. 200-202°C);

?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).



38

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

A Ce4+ 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. 130-134°C (lit.4, m.p.

133-134°C); ?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

2.2.2.1 Preparation of silver carbonate/celite28

Celite was first purified by successively washing with methanol containing 10%

concentrated HCl, and distilled water, until neutral. It was then dried at 120°C 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). A solution of

Na2CO3·10H2O (30.00 g, 104.9 mmol) in distilled water (300 mL) was then added

slowly to the resulting homogeneous solution. 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 Ag2CO3.

28



39

2.2.2.2 Preparation of barium manganate73

Preparation 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 350°C 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 100°C for 24

h to afford active barium manganate.

2.2.2.3 Preparation of a (nitrosonaphtholato)metal complex (Mn II(1-

nnap)2)27

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 0ºC. 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. 60-80ºC) to afford 1-nitroso-2-naphthol

as reddish brown needles; m.p. 107-109ºC (lit.75, m.p. 106-108ºC).



40

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 0ºC 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(1-

nnap)2 with a m.p. > 300°C (lit.27, m.p. >300°C).

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.



41

A = Anode compartment

B = Cathode compartmentC = 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 (60°C) and stirred (500 rpm)

for the designated time period. After completion of this time period, the reactionmixture 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 Ce4+ 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.



42

Table 2.3 Moles of Ce4+ at various MeSO3H concentrations

Methanesulphonic

Acid

Concentration

Moles of Ce 4+

Titration 1 Titration 2 Titration 3 Average

(mmol) (mmol) (mmol) (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 Ce3+ to Ce4+

Methanesulphonic Acid

Concentration

Initial Ce3+

Concentration

Volts

(V)

Amperes

(A)

Time

(h)

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 oxide75

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



43

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 EXPERIMENTAL PROCEDURES

2.3.1 Oxidative Coupling Reactions

2.3.1.1 Oxidation of alkylphenols using silver carbonate/celite73

General procedure

Before use, the silver carbonate/celite reagent (0.2 mmol of Ag2CO3) 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

acids76

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 80 °C. Sodium

hydroxide (0.4 M, 100 mL) was added during the course of the reaction to maintain



44

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 approximately 30 min, the gas flow was reduced and maintained at a levelsufficient 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 100°C 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 manganate73

General procedure

The alkylphenol (10.00 mmol) in toluene (50 mL) was added to barium manganate

(12.81 g, 50.00 mmol) in a 100 mL round-bottomed flask. The reaction mixture wasthen 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.



45

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 23°C 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 rotaryevaporator 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 50°C 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 FeCl3·6H2O (2.271 g, 14.00 mmol) were mixedtogether without any solvent, and the mixture then placed in a test tube and kept at

50°C 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.



46

2.3.1.8 Oxidation of alkylphenols using Ag2O78

General procedureThe 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 toluene (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 Ce4+

General procedure

The required amount of Ce4+ 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 (3x 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 GC-

MS and HPLC.



47

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) was added drop-wise during 30 min to a

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.,

Ce3+) 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 Ce3+ to Ce4+. 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 Ce4+ now present in the

solution (denoted as B in Table 2.5). The difference between the initial Ce4+ and final

Ce4+

values (B-A), therefore, was a measure of the amount of Ce3+

that remainedafter the electrochemical oxidation of the Ce3+ solution.



48

Table 2.5 Determination of the amount of Ce3+ ions present after

electrochemical oxidation of Ce3+ to Ce4+

Titration No. Ce4+

amount before

persulphate treatment

(A)

Ce4+

amount after

persulphate treatment

(B)

Moles Ce3+

present

(B)-(A)

1 1.119 mmol 1.860 mmol 0.7410 mmol

2 1.113 mmol 1.876 mmol 0.7630 mmol

3 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 round-

bottomed 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



49

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 five-

level calibration using standard solutions containing known amounts of the analytes.

Table 2.6 HPLC Conditions for 2-tert -butylphenol reactions

Injector Volume 5 µL

Column µBondpak C18 3.9 mm x 300 mm (Waters)

Wavelength 253 nm

Flow Rate 0.7 cm3 min-1

Mobile Phase 80% MeCN : 20% H2O

Table 2.7 HPLC Conditions for 2,4-dimethylphenol reactions



Wavelength 289 nm





50

Table 2.8 HPLC Conditions for 2,6-di-tert -butylphenol reactions



Wavelength 267 nm


Mobile Phase 100% MeCN

Table 2.9 HPLC Conditions for 2,4-di-tert -butylphenol reactions



Wavelength 289 nm



2.4.2 Nuclear Magnetic Resonance (NMR) Spectroscopy

Proton NMR spectra were recorded on a Brücker 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 Brücker Tensor 27 FTIR linked to a Bell

personal computer, equipped with Opus Software version 4.2. All samples were

analyzed using CCl4 as solvent.



51

2.4.4 Gas Liquid Chromatography-Mass Spectrometry (GC-MS)

GC-MS Analyses were performed on a Thermo-Finnigan Trace GC coupled to aQuadropole 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. The

temperature program used is summarized in Table 2.10.

Table 2.10 GLC Temperature program

Initial Temperature 50°C

Initial Hold Time 2.0 min

Program Rate 15 °C min-1

Second Temperature 250°C

Second Hold Time 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/Å.



52

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.

100arg

2 x

remainingsubstratemolesed chsubstratemoles

x product moles ySelectivit

−=

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.

100arg

arg x

ed chsubstrateof moles

remainingsubstrateof molesed chsubstrateof molesConversion

−=



53

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, (A-

E) 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 theimmediate product upon coupling is the dienone form of the dimer, which then

rearomatizes to form the phenolic analogues.



54

O OH

OH

phenoxyl radical dienone dimer phenolic dimer

A

HH

O

O

OH

OH

B

OH

OH

OH

H

OOH

OH

OH

O

OH

O

OH

O

C

D

E

O

OH

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

radicals



55

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.

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 theradical is centered at the ortho position couples with the oxygen-centered

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

FO O

O

phenoxyl radical peroxide



56

• O-O coupling (F): two phenoxyl moieties combine through their oxygen-

centered 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 (? f H) directly. Given in Table 3.1 are the theoretical heats of formation for

the coupled dienones (? f Hd) and phenols (? f Hp), calculated at the PM3 semi-empirical

molecular orbital (MO) level. In the final column of the table, the difference betweenthe heats of formation of the phenolic dimers and their corresponding dienones has

also been calculated.



57

Table 3.1 PM3 Heats of formation for phenol coupling products

Coupling

mode

? fHd

(kcal/mol)

? fHp

(kcal/mol)

? fHp - ? fHd

(kcal/mol)

E -6.53 -24.52 -17.99

C -5.87 -41.86 -35.99

D -5.61 -23.97 -18.36

B -5.08 -42.19 -37.11

A -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.)



58

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 4-positions, 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



59

C(CH3)3

OH

1

2

3

4

5

6

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.

(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-t -

butylphenol in order to attempt to form the para-para C-C coupled product, 3,3’-di-t -

butyl-4,4’-dihydroxybiphenyl (molecule (39) in Scheme 25), in high yield and

selectivity.

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 itspara position despite the additional availability of its ortho position.



60

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-t -

butylphenoxyl radical that is formed. Due to resonance stabilization, the radical maybe 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.



61

Scheme 24: Modes of coupling of the 2-t -butylphenoxyl radical when the radical

is centered on position 6

OO

O

O

O

OH

OH

(36)

OHOH

OH

O

(37)

(38)



62

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

OO

O

O

O

OH

OH

(37)

OHOH

(39)

(40)

O

HO



64

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)

(%)

1 Ag2CO3/Cel ite 1 PhCH3 R.T. 10.98 25.57

2 Ag2CO3/Cel ite 20 PhCH3 R.T. 78.58 3.56

3 Cu(OAc)2/

Oxalic acid

10 H2O 60°C 86.32 1.30

4 Mn(OAc)3 1 CH3CO2H 100°C 85.38 2.14

5 BaMnO4 2 CHCl3 50°C 66.96 4.55

6 FeCl3 2 CH2Cl2 R.T. 100.00 0.00

7 Ag2O 1 MeOH R.T. 96.00 7.29

8 K3Fe(CN)6 1 MeOH R.T. 62.20 0.85

9 Ce(SO4)2 1 H2O R.T. 26.61 25.99



65

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 theprohibitive 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 formof 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,



66

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). From standard curves using HPLCanalyses, it was determined that in reaction 1, the selectivity to (39) was only 25.57

%.

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 maybe observed in Figure 3.1 and Appendices 3.1-3.4, respectively.

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



67

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 wasnot 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 theconversion 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’-di-t -butyl-4,4’-dihydroxybiphenyl (39) formed in

reactions 1 and 2

Reaction

No.

Time

(h)

Mass of (35) used

(g)

Moles of (35) used

(mmol)

Moles of (39) formed

(mmol)

1 1 0.1576 1.049 0.0147

2 20 0.1611 1.072 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.



68

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 atthe 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 product (41) in

Scheme 26 (where n=1), had this required mass. Other workers using 2,6-

dimethylphenol 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

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

OH

(CH3)3C

O

O

(CH3)3C

(CH3)3C

n=1,2,3,.....

OH

(CH3)3C

Ag2CO3/celite

(35)

(41)



69

(CH3)3C

OH

C(CH3)3

OH

(CH3)3C

OH

(42)

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.

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



70

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 60°C. 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):



71

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 O2

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



72

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 100°C. 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 timesof 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 isomericproducts 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).



73

It was concluded that BaMnO4 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, despitetotal 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 phenoxyl–iron 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. FeCl3 was thus not investigated further in thisinstance.



74

3.2.2.7 Silver oxide as coupling agent

Silver oxide provided high yields and selectivities to the desired C-C coupled productswhen 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 withaqueous 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-t -

butyl-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).



75

3.2.2.8 Potassium ferric cyanide, lead tetra-acetate, a

(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-t -

butylphenol was observed although the reaction was repeated several times, and so

this reaction was not investigated further. The reaction of lead tetra-acetate79 with 2-

t -butylphenol gave a large variety of products, but the selectivity to the coupledproduct (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-t -

butylphenol 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,



76

OH

C(CH3)3(CH3)3C1

4

(9)

2

35

6

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 possibilityfor 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 substratereacts 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.

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 comeinto 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 C-

para 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



77

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 -Di-

t -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 thishad 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 semi-

empirical MO calculations.



78

Scheme 27a: Dienone and phenolic dimers from the coupling of 2,6-di-t -

butylphenoxyl 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.)


HH

O

O

t -But -Bu

t -But -Bu

OH

OH

t -Bu

t -Bu t -Bu

t -Bu

H

OH

O

t -Bu t -Bu

t -Bu

t -Bu

O

OH

t -But -Bu

t -Bu

t -Bu

O

t -But -Bu G



79

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-K were obtained by comparing their heats of formation (? f H)directly. Thus the heats of formation obtained for the coupled dienones (? f Hd) and

phenols (? f Hp) are summarized in Table 3.4.

phenoxyl radical dienone dimer

O t -Bu

Ot -Bu

t -Bu t -Bu

Ot -Bu

H

O

t -Bu

t -Bu t -Bu

O t -Bu

Ot -Bu

t -Bu

t -Bu

I

J

O

t -But -Bu

K



80

Table 3.4 PM3 Heats of formation for 2,6 -di-t -butylphenol coupled products

Coupling

mode

? fHd

(kcal/mol)

? fHp

(kcal/mol)

? fHp - ?fHd

(kcal/mol)

G -84.34 -119.24 -34.90

H -80.29 -94.17 -13.88

I -76.39 N/A N/A

J -59.89 N/A N/A

K -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 (? f Hp = -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



81

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 Ag2O 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.


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 quinoneform (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.



82

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 Ag2O and Cu(OAc)2/oxalic acid, in

separate experiments, and the results so-obtained are summarized in Table 3.5.

HO OHoxidation

reductionO O

(16) (10)



83

Table 3.5 Reactions of 2,6-di-t -butylphenol with various oxidizing agents

Reaction

No.

Oxidant Time

(h)


of (9)

(%)

Selectivity

to (10)

(%)

Selectivity

to (16)

(%)

10 Ag2O 1 MeOH R.T. 100 99.00 1.00

11 Cu(OAc)2/

Oxalic acid

10 PhCH3 60°C 100 96.25 3.75


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).



84


The major product (99 %) at a retention time of 13.77 min was identified as 3,3’,5,5’-

tetra-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). Theother 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 retention 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 (para C-para C), the overall selectivity of this oxidative

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



85

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].

Scheme 29: Oxidation of 2,6-di-t -butylphenol using Ag2O

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 Conversion(%)

Selectivity to (16)(% )

Selectivity to (10)(% )

1:2 100 1.00 99.001:1 98.80 4.05 95.95

1:0.5 71.01 8.75 91.25

OH

O

O

OH

OH

(9)

(16) (10)

2 mol Ag +

22 mol Ag+



86

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 amore facile reaction than the coupling of (9) to form (16). In addition, the overall

selectivity topara 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 reported88 that the oxidative coupling of 2,6-di-t -

butylphenol with silver oxide, in the absence of air, afforded isolation of this dienoneform 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, Blanchard78 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 non-

polar solvent.

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

O O

H

H

(43)



87

side reactions occurring. No para C-O coupling was ever observed in our

investigations. 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 60°C. 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, respectively.

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 wasalso high enough to oxidize the initially formed product (16) further to form (10).

These results are thus very similar to those achieved when using Ag2O, 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



88

para C-para C coupled products (16) and (10) is 100 % (3.75 % + 96.25 %), with no

para C-O coupled products being observed.


Butylphenol

From the above information, it is clear that the number of modes in which 2,6-di- t -

butylphenol can theoretically couple is numerous, though, in practice, this substrate is

highly selective when placed under oxidative coupling conditions. High selectivities to

the desired para C-para C coupled products (16) and (10) were achieved with both Ag2O 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-t -

butylphenol (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 asthat of 2,6-di-t -butylphenol. However, 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.



89

OH

C(CH3)3

C(CH3)3

1

6 25 3

4

(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 unsubstitutedortho 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 2,4-

analogue, but two such bulky groups in the 2,6-analogue. One may propose that 2-t -

butylphenol (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 140°C for 24 h, the coupled product 3,3’,5,5’-tetra-t -butyl-

2,2’-dihydroxybiphenyl (45) was solely formed, and no C-O coupled products wereobserved.



90

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 -Di-

t -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.



91

O

t -Bu

t -Bu

L

t -But -Bu

t -But -Bu

O

OH H

t -Bu t -Bu

t -Bu t -Bu

HO

OH

M

t -Bu

t -Bu

O

O

t -Bu

t -Bu

Ht -Bu

t -Bu

O

HO

t -Bu

t -Bu


Scheme 30a: Dienone and phenolic dimers from the coupling of 2,4-di-t -

butylphenoxyl 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 moret -butyl groups and it was assumed that this would not constitute a significant reaction

pathway.



92

t -Bu

t -Bu

O

Nt -Bu

t -Bu

H

t -Bu

OO

t -Bu

O

O

t -Bu

t -Bu O

t -Bu

t -Bu

P

t -Bu

t -Bu t -Bu

O

O

t -Bu


t -Bu

t -Bu

t -Bu

O

t -Bu

O

Q

Scheme 30b: Dienone dimers from the coupling of 2,4-di-t -butylphenoxyl

radicals by modes N, O, P and Q



93

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 Table3.7.

Table 3.7 PM3 Heats of formation for 2,4 -di-t -butylphenol coupled products

Coupling

mode

? fHd

(kcal/mol)

? fHp

(kcal/mol)

? fHp - ?fHd

(kcal/mol)

L -93.67 -123.31 -29.63

M -90.30 -105.61 -15.31

N -83.61 N/A N/A

O -78.63 N/A N/A

P -59.32 N/A N/A

Q -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



94

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 likelyto 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.


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 predictedto 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



95

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)


(%)

Selectivity

to (45)

(%)

12 FeCl3 2 PhCH3 50°C 92.00 0

13 Ag2O 1 MeOH R.T. 96.52 5.06

14 K3Fe(CN)6 2 MeOH R.T 96.04 83.95

15 Ce4+ 1 H2O/

MeOH

Reflux 100.00 90.35


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 50°C in either chloroform or toluene as the solvent.



96

Table 3.9 Reactions of 2,4-di-t -butylphenol with FeCl3

Reaction No. Ratio

(oxidant:substrate)

Time

(h)


(%)

Selectivity

to (45)

(%)

12 2:1 2 PhCH3 50°C 92.00 0

16 2:1 2 CHCl3 50°C 83.00 0

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).




97

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 t -

butyltoluene 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 themode 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.


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



98

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-di-

t -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).


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).



99

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 30.74min 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.

O

O

(46)



100

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 2,4-

di-t -butylphenol with Ag2O 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 one-

electron 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)

t -Bu

OH

t -Bu

Ag 2O

OH

t -Bu

t -Bu

O

O

t -Bu

t -Bu

t -Bu

t -Bu

n=1,2,3,...

(47)



101

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 K3Fe(CN)6

Reaction

No.

Oxidant Time

(h)


(%)

Selectivity

to (45)

(%)

14 K3Fe(CN)6 2 MeOH/H2O R.T 96.04 83.95

17 K3Fe(CN)6 1 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.



102

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).

O

anion of

K3Fe(CN)

6

O O

X 2

FR1 mechanism

OH OH

followed by

(45)

_

basic conditions

(44)

tautomerization



103


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.

O

OH

(48)



104

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 K3Fe(CN)6 gavesatisfactory 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+/Ce4+, 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+/Ce3+ 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



105

with cerium(IV) behaving as a one-electron oxidant.83,97 The oxidation potential of the

Ce4+/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

Figure 3.7: Electron flow in the indirect electrochemical oxidation process

using the Ce3+/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. Grace’s 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).

Ce4+

Ce3+

2,4-disubstituted phenol

Coupled product

cathode

anode



107

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 surveyfailed to indicate that oxidative coupling of disubstituted phenols, including 2,4-di-t -

butylphenol, 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 oxidant 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 MeSO3H 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



108

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.

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

ReactionNo.

[MeSO3H](M)

Time(h)

Solvent Ratio(substrate:oxidant)

Conversionof (44)

(%)

Selectivityto (45)

(%)

18 0.5 1 H2O 1:2 31.06 18.60

19 1.0 1 H2O 1:2 43.68 42.71

20 2.0 1 H2O 1:2 17.05 25.21



109

assumed that this problem required addressing before optimal results would be

achieved.

To decrease this solubility effect, the reaction temperature was increased to 80°C,

whilst keeping all other variables constant (Table 3.12).

Table 3.12 Oxidative coupling of (44) by Ce(IV) at various [MeSO3H] at 80°C

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 80°C 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 results 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 co-

solvent to the aqueous medium, the co-solvent obviously being one in which the

ReactionNo.

[MeSO3H](M)

Time(h)


Conversionof (44)

(%)

Selectivityto (45)

(%)

21 0.5 1 H2O 1:2 48.47 34.93

22 1.0 1 H2O 1:2 96.11 76.22

23 2.0 1 H2O 1:2 73.43 64.61



110

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 phasereaction 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.

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 H2O/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.

ReactionNo.

[MeSO3H](M)


Conversionof (44)

(%)

Selectivityto (45)

(%)

24 1.0 H2O/MeOH 1:2 94.80 69.28

25 1.0 H2O/CH3CN 1:2 93.29 62.37

26 1.0 H2O/CH2Cl2 1:2 41.87 85.22



111

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 co-solvent

Reaction No. MeOHvolume

Ratio(substrate:oxidant)

Temperature Conversionof (44)

(%)

Selectivityto (45)

(%)

27 20 mL 1:2 0°C 92.29 73.72

28 20 mL 1:2 R.T. 93.42 78.76

29 20 mL 1:2 45°C 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 0°C, ambient temperature, 45°C and reflux (65°C), it wasfound that high conversions were obtained throughout, even at 0°C (92.29 %). The

highest conversion occurred at the highest temperature (65°C, 96.96 %). A plot of

conversion versus temperature more clearly summarizes the results obtained (Figure

3.9):



112

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 45°C (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 %). Of

interest is the observed decreased selectivity to (45) at the lower temperatures (73.72

% at 0°C and 78.76 % at R.T.). This is a possible indication that the rate of thecoupling 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

92

93

94

95

96

97

98

0 10 20 30 40 50 60 70

Temperature in Deg. C

C o n v e r s i o n ( % )



113

is decreased, the rate of the desired coupling reaction slows down, therefore

increasing the possibility of side reactions.

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.

73

74

75

76

77

78

79

80

81

82

83

84

0 10 20 30 40 50 60 70

Temperature in Deg. C

S e l e c t i v i t y ( % )



114

Table 3.15 Reaction time effect on the coupling of (44) using Ce(IV)

ReactionNo.

MeOHvolume


Time(min)


(%)

Selectivityto (45)

(%)

30 20 mL 1:2 60 Reflux 96.96 80.50

31 20 mL 1:2 5 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)/MeSO3H 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).



115

Table 3.16 Effect of substrate loading on the coupling of (44) using Ce(IV)




(%)

Selectivityto (45)

(%)

32 5 mL 1:2 Reflux 55.98 84.86

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

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

conversion and selectivity

0

20

40

60

80

100

120

0 10 20 30 40 50

Volume of MeOH (mL)

P e r c e n t a g e

Conversion Selectivity



116

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 5mL), 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 substrateloading 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.



117

Table 3.17 Effect of substrate:oxidant ratio on the coupling of (44) usingCe(IV)




(%)

Selectivityto (45)

(%)

35 20 mL 1:0.5 Reflux 35.50 94.25

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 was obviously available for side reactions or further oxidation of the

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.



118

0

20

40

60

80

100

120

0 1 2 3 4 5 6

Molar ratio of Ce(IV) to substrate

P e r c e n t a g e ( % )

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 reactionmixture over a time period of 30 min.



119

Table 3.18 Effect of rate of oxidant addition

Reaction

No.

Oxidant Time

(h)


(%)

Selectivity

to (45)

(%)

15 Ce4+

1 MeOH reflux 100.00 90.35

It is clear from this result that these reaction conditions afford superior results in termsof conversion, which is quantitative, and the associated selectivity 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-t -

butylphenol (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.



120

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 inScheme 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)

O

OH

(48)

OH OH

(45)

OH

t -Bu

t -Bu

O

O

t -Bu

t -Bu

t -Bu

t -Bu(47)

n=1

O

O

(49)

OH

OH

(50)



121

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).

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

OH OH

+-H+

O

Ce4+ Ce3+

O

H

(51)

(52)

O

H

OOH H

tautomerization

OHOH

(53)(45)



122

Compounds (47) and (48) are readily accounted for: their formation is through C-O

coupling as shown clearly in Scheme 34.

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

O

(52)

O

H

OH

O

O

OH

(48)

tautomerization

Ce4+

Ce3+

O

OH

H

+

O

O

t -Bu

t -Bu

OH

t -Bu

t -Bu

O

t -But -Bu

H

+-H+

O

t -Bu

t -Bu

OH

t -Bu

t -Bu

O

t -But -Bu

(47)

(54)

(55)

(56)



123

(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

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.

OH

R

+H2O

OH

OH2

H

R

+

-H+

OH

OH

H

R

-e-

-H+

OH

OH

R(57)



124

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 t -

butyl 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, werenot formed in amounts significant enough to state that this was a facile process

compared with that of the formation of (45).) Hydroquinone (50) is then readily

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

OH -e -

OH

+

(44)

(51)

+H2O-H+

OH

OH

-e -

OH

OH

(50)

-2e -

-2H+

O

O

(49)

-t -Bu+

(58)



125

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 accountingfor 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.



126


Butylphenol

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

K3Fe(CN)6 and Ce(IV) oxidants [86.10 and 96.96 %, respectively]. The use of other

oxidants such as FeCl3 and Ag2O 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 Ag2O, 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 andconversions 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 65°C (at reflux, giving high selectivities and conversions and implying

ease of application), and lengthy reaction times were not necessary, probably



127

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

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 oxidizedwith 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

OH

Me

Me(59)



128

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 availableunsubstituted 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

Anexamination of the staggered approach (60) for the ortho-ortho coupling of 2,4-

dimethylphenoxyl radicals revealed that there were two sets of non-bonding

interactions between the methyl groups.109

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 thelatter 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

Me

Me

O

.

MeO

Me

.

(60)



129

PM3 semi-empirical MO calculations, the possible coupling modes are illustrated in

Schemes 37a and 37b.

phenoxyl radical phenolic dimer

Scheme 37a: Phenolic dimers from the coupling of 2,4-dimethylphenoxyl

radicals by modes R and S

O

Me

Me

HO

OH

Me Me

Me Me

O

HO

Me

Me

Me

Me

R

S

.



130


Scheme 37b: Dienone dimers from the coupling of 2,4-dimethylphenoxyl

radicals by modes T, U, V and W

O

Me

Me

.

H

OO

Me

Me

MeMe

O

O

Me

Me Me

Me

O

O

Me

Me Me

Me

T

U

V

W

Me

Me

Me

Me

OO



131

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 avariety 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-2,2’-

dihydroxybiphenyl (61).

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.

OH

Me

Me Me

Me

OH

(61)



132

The standard 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 bymeans 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)


(%)

Selectivity

to (61)

(%)

39 FeCl3 2 CHCl3 50°C 90.98 49.11

40 K3Fe(CN)6 2 MeOH R.T. 70.86 26.72

41 Ce4+

1 H2O R.T. 76.04 57.58


The one-electron oxidant, ferric chloride, was reacted with 2,4-dimethylphenol even

though 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 50°C in various solvents (Table 3.20).



133

Table 3.20 Reaction of 2,4-dimethylphenol with FeCl3 in various solvents

ReactionNo.


Time(h)

Solvent Temp. Conversion(%)

Selectivityto (61)

(%)

39 1:2 2 CHCl3 50°C 90.98 49.11

42 1:2 2 MeOH 50°C 34.71 11.05

43 1:2 2 PhCH3 50°C 77.88 38.84

44 1:2 2 EtOAc 50°C 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 2,4-

dimethylphenol 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



135

O

Me

Me

O

Me

Me

(64)

OH

Me

Me

O

Me

Me

(65)

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 Pummerer’s ketone (64) or ortho C-O coupled product (65):

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.)

OH

Me

Me

OH

Me

C O

H

(63)



136


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-t -

butylphenol (and 2-t -butylphenol), is certainly further evidence that the bulk of the t -

butyl 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-t -

butylphenol (44), with a high conversion and selectivity (96.04 and 83.95 %,

respectively) to the desired coupled product (45) being achieved. 2,4-Dimethylphenol 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.



137

Table 3.21 Reactions of 2,4-dimethylphenol with K3Fe(CN)6

Reaction

No.

Oxidant Time

(h)


(%)

Selectivity

to (45)

(%)

40 K3Fe(CN)6 2 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.


This is indicative again that polymeric materials 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 Pummerer’s 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



138

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 with an M+ of 360 mass

units, i.e., compounds that were higher than dimeric in nature. The success of thereaction 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.



139

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 describedearlier, 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 80°C, with all other variables remaining constant.

Table 3.22 Oxidative coupling of (59) by Ce(IV) at various [MeSO3H] at R.T.

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) wassignificantly 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 80°C to increase

its solubility in this medium (Table 3.23).

ReactionNo.

[MeSO3H](M)

Time(h)


Conversionof (59)

(%)

Selectivityto (61)

(%)

45 0.5 1 H2O 1:2 86.32 24.20

41 1.0 1 H2O 1:2 76.04 57.58

46 2.0 1 H2O 1:2 89.92 22.17



140

Table 3.23 Oxidative coupling of (59) by Ce(IV) at various [MeSO3H] at 80°C

In general, a decrease in terms of both the conversion of (59) and the selectivity 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 80°C. 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 2,4-

dimethylphenol 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, various organic co-solvents were also added to

each of the aqueous mixtures. To this end, MeOH and CH3CN were used in order toafford 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).

Reaction

No.

[MeSO3H](M)

Time

(h)

Solvent Ratio

(substrate:oxidant)

Conversion

of (59)(%)

Selectivity

to (61)(%)

47 0.5 1 H2O 1:2 86.12 17.59

48 1.0 1 H2O 1:2 69.58 57.19

49 2.0 1 H2O 1:2 71.47 16.72



141

Table 3.24 Effect of co-solvents on oxidative coupling of (59) by Ce(IV) at R.T.

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 MeSO3H was also kept constant (40

mL) for all these reactions. It was predicted that increased temperatures in the

presence of this co-solvent would merely decrease selectivities even further. Table

3.25 summarizes the results obtained.

ReactionNo.

[MeSO3H](M)


Conversionof (59)

(%)

Selectivityto (61)

(%)

50 1.0 H2O/MeOH 1:2 90.65 8.32

51 1.0 H2O/CH3CN 1:2 86.17 23.08

52 1.0 H2O/CH2Cl2 1:2 92.46 6.83



142

Table 3.25 Temperature effect on coupling of (59) by Ce(IV) with CH3CN asco-solvent

Reaction No. CH3CNvolume



(%)

Selectivityto (61)

(%)

51 20 mL 1:2 R.T. 86.17 23.08

53 20 mL 1:2 80°C 87.03 34.22

54 20 mL 1:2 reflux 78.85 42.81

However, 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.



143

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] wasadded 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.)


(%)

Selectivity

to (61)

(%)

55 Ce4+

15 CH3CN R.T. 61.10 49.85

55 Ce4+ 60 CH3CN 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-dimethylphenolusing 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):



144

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 theseproducts 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.



145

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 MeSO3H.

The formation of products (62) and (65) is similar to the mechanism proposed for 2,4-

O

Me

Me

O

MeMe

(64)

OH

Me

Me

O

Me

Me

(65)

OH

Me

Me

OH

Me

Me

(61)

Me

OH

Me

O

O

Me

Me

Me

Me(62)

OH

OHMe

Me

OH

Me

C O

H (67)

(66)



146

di-t -butylphenol to form the products (48) and (47) [Scheme 34]. Pummerer’s ketone

(64) is most likely to be formed by means of the following mechanism (Scheme 38).


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.

OH

Me

Me

.Ce4+ Ce3+

-H+

O

Me

Me

Me

O

Me

.

o-p coupling

O

MeH

Me

Me Me

O H+

tautomerization

Me

Me

Me Me

OHOH

(59)

(64)

Me

Me

Me Me

OOH



147

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

Me

Ce4+ Ce3+

-H+

(59)

O

Me

Me

Me

CH2

OH

OH

Me

CH2OH

OH

Me

CHO

(68)(69)

(70)(66)

CH2

OH

Me

+

-e-

H2O -H+

-2e-

-2H+



148

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 2,4-

di-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 t -

butyl 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

K3Fe(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 theefficiency 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.



149

3.6 BUTYLATED PHENOLIC COUPLINGS: COMPARISONS

In this section, a brief comparison of some of the more important results that have notthus 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 Ag2O

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 C-

C coupled products. The results of these reactions are summarized in Table 3.27.

Table 3.27 Comparative data obtained for silver oxide

Reaction

No.

Substrate Oxidant Time

(h)


(%)

Selectivity to p/p

coupled products

(%)

7

2-t -

butylphenol Ag2O 1 MeOH R.T. 96.00 7.29

102,6-di-t -

butylphenol Ag2O 1 MeOH R.T. 100.00 100.00a

aThe 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 %,



150

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.Substrate Oxidant Solvent Temp. Conversion

(%)

Selectivity to p/p

coupled products

(%)

3 2-t -butylphenol

Cu(OAc)2/

Oxalic acid PhCH3 60°C 86.32 1.30

11

2,6-di-t -

butylphenol

Cu(OAc)2/

Oxalic acid PhCH3 60°C 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 2,6-

di-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 4-

and 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-t -

butylphenol, 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



151

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-t -

butylphenol, may be ascribed to the fact that 2-t -butylphenol, with only one electron-

donating 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 theformer. 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). This is possibly a further

indication of the difference in oxidation potential of the two substrates, as well as of

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).



152

Table 3.29 Comparative data obtained for Ce(IV)

Reaction

No.

Oxidant Time

(h)


(%)

Selectivity to

desired coupled

products

(%)

15 Ce4+ 1 H2O/ MeOH Reflux 100.00 90.35b

56 Ce4+

1 H2O/ MeOH Reflux 45.01 100.00c

b Selectivity to (45).c

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 exclusively, whereas 2,4-

di-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-t -

butylphenol undergoes para C-oxygen coupling [2,6 p,O]), L (where the substrate 2,4-

di-t -butylphenol undergoes ortho C-ortho C coupling [2,4 o,o]) and M (where 2,4-di-t -

butylphenol 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 x-

axis. All values plotted are relative to the heat of formation of the phenolic form for



153

0

5

10

1520

25

30

35

40

45

50

0 1 2

R e l a t i v e E

n e r g y ( k c a l / m o l )

2,4 o,o

2,4 o,O

2,6 p,p

2,6 p,O

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.)

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 2,4-

analogue 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 calculationsalso 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



154

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 2,6-

analogue favours C-C coupling over C-O coupling to a greater extent than the 2,4-analogue 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

Ag2O 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.



155

CHAPTER 4

CONCLUSION AND FINAL COMMENTS

During the investigation into the oxidative coupling of various mono- and di-

substituted 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-t -

butylphenol 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-4,4’-

dihydroxybiphenyl (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 reactionconditions 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.



156

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 resultsobtained 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-t -

butylphenol (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 coupledproducts). 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 Ag2O 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



157

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 the undesired 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 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 65°C (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 beregenerated 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



158

modes R and S. Only moderate selectivities to the desired 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]. Once again, the difference in the results obtained for 2,4-di-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 t -

butyl 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-Hgroups, 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 various 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-t -

butylphenol, 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.



159

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169

APPENDIX

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

min


min



170


min


min



171

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


min



172


min


min




min

luan van cac chat chong oxy hoa

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