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METHODS OF PREPARATION OF COUPLED PHENOLICS

The diversity of phenol oxidation products offers interesting synthetic possibilities for
the preparation of simple and polymeric molecules containing phenolic and/or quinoid
structural elements; these can be formed from both like and unlike radical
species.13,22 The successful synthesis of various natural products from phenols has
been well documented from the 1950s to the present. 23-28
Biogenetic oxidative coupling routes were first investigated in 1957, 29,30 and the
prevalence of the overall coupling process in the biosynthesis of natural products was
authenticated. Thus the oxidative coupling step has been found to be extremely
important in the natural formation of compounds as diverse as lignins, 31 lignans,32
tannins,33 plant pigments,22 and an estimated 10% of all known alkaloids. 23 (Lignin is
a complex biopolymer that accounts for 20-30% of the dry weight of wood. It is
formed by the free radical polymerization of substituted phenylpropane units to yield
polymers which have a number of functional groups such as aryl ethers, phenols and
benzyl alcohols.34)
The major difficulty with oxidative coupling reactions of phenols is that a large variety
of potential products are possible from a single substrate when carried out in the
presence of various chemical or biological oxidants. This is because the phenolic
molecules are able to undergo both carbon-carbon (Scheme 4 shows para-para
coupling, though ortho-para coupling may also occur) and carbon-oxygen (Scheme 5)
coupling reactions.

Scheme 4: Carbon-carbon oxidative coupling (showing para-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 importance 35,36). It has been
reported that when carbon-oxygen coupling occurs, there is a tendency for further
coupling to occur on the resultant substrate, and this leads to the formation of
polymeric products.37
To understand the effect that both the nature of the reactant and oxidant has on the
type of products that are formed, one must have an understanding of the various
reaction pathways that are possible, from a mechanistic point of view. A summary of
literature reports dealing with the various mechanisms is now briefly discussed.
General Types of Coupling Reaction Mechanisms
The reaction pathway for the oxidative coupling of phenols has been extensively
investigated.38,39 There are two main modes of coupling that may be highlighted.
These are an external and an internal oxidation process. In the former, electrons are
transferred from the phenolic compound to an external oxidizing agent, whilst the
internal oxidation process involves an internal oxidation-reduction reaction in which
one substrate molecule is oxidized whilst another is simultaneously reduced. Since
there is no change in the net overall oxidation state, this process may be termed a
non-oxidative coupling (NOC) reaction.
In our investigations, only the external oxidative coupling process was studied. For
this reason, literature reports dealing only with this mode are summarized here.
External oxidative coupling reactions may be grouped into two separate classes,
those involving free radical intermediates, and those that are non-radical in nature.
These may further be subdivided into several general mechanistic types.
a) Mechanisms involving free radical intermediates
i) 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)
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 attached
little 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 (Scheme
6) highlights the FR1, FR2 and FR3 mechanisms.
Gambar
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 in
protic media to the more stable aromatic biphenol product (3).
Secondly, the phenoxyl radical may react with the initial substrate (1) via
mechanism FR2 to generate a dimeric radical. Upon loss of an electron and a
proton from this new radical, (2) is formed once again. However, the dimeric
radical may also disproportionate, leading to a dihydro product (4) as well as to (2).
As yet, compounds such as (4), although analogous to similar products produced in free
radical aromatic substitutions,45 have not yet been observed in oxidative
coupling reactions. This may perhaps be due to the fact that the conversion of (4)
to (3) is a facile one since (3) has enhanced stability due to its aromaticity.
Thirdly, the phenoxyl radical may be further oxidized by removal of an electron, to
yield a phenoxyl cation, according to mechanism FR3. The initial substrate (1),
with concomitant hydroxyl proton loss, may then heterolytically couple with the
cation to afford (2).
Examples of the NR1 and NR2 non-radical processes are shown in Schemes (8) and
(9), respectively. In both illustrations, the oxidant is represented as a tripositive metal
ion (M3+), which forms an initial metal-phenolate complex with (1).

As shown in Scheme 8, the metal complex decomposes into a phenoxyl cation with
concurrent reduction of the metal ion. Subsequently, heterolytic coupling similar to
that shown in Scheme 6 (the FR3 mechanism) affords compound (2) which
undergoes tautomerization, and so the desired product (3) is a result.
Objections, based on energ etic grounds, to the formation and stabilization of cationic
intermediates in this mechanism may be obviated by considering the possibility of a
concerted electron transfer, as for the simple NR2 mechanism shown in Scheme 9.

Scheme 9: The NR2 mechanistic pathway


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.
Chemical oxidative coupling
From about as early as the 1920s, chemists have been researching the oxidative
coupling of phenols using chemical oxidizing systems. It was thought that all
oxidative coupling reactions involved one electron transfers, and therefore that these
oxidations were all free radical reactions. The mechanisms by which the reactions
occurred, and the characteristics of the various oxidizing agents and/or catalysts, were not
investigated successfully because they were not well understood; it was
always assumed that coupling occurred through the bonding of two phenoxyl radicals
(FR1) to form the coupled biphenol. However, it has since become clear that the
types of mechanisms involved are extremely dependent on the nature of the oxidant
and/or catalyst used. Some of these, including vanadium (IV) and (V), a
(nitrosonaphtholato)metal complex, activated manganese dioxide, and cupric salts,
and the reaction pathways they are involved in, will now be discussed further.