Novel highly selective catalytic oxychlorination of phenols

Article abstract of DOI:10.1039/b513329g

The highly selective oxychlorination of various phenols catalyzed by CuCl₂ under mild conditions, in which chloride ions are used as chlorinating agents and dioxygen as a final oxidant, has been developed. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b513329g

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Novel highly selective catalytic oxychlorination of phenols
Luciano Menini and Elena V. Gusevskaya*
Received (in Berkeley, CA, USA) 19th September 2005, Accepted 18th October 2005
First published as an Advance Article on the web 17th November 2005
DOI: 10.1039/b513329g
completely characterized by GC/MS (Hewlett-Packard MSD
1
The highly selective oxychlorination of various phenols
catalyzed by CuCl2 under mild conditions, in which chloride
ions are used as chlorinating agents and dioxygen as a final
oxidant, has been developed.
5890/Series II, 70 eV) and H and 13C-NMR (Bruker DRX-400,
tetramethylsilane, CDCl3, COSY, HMQC, DEPT and NOESY
experiments). The obtained data revealed that under the conditions
used, a selective chlorination of the aromatic nucleus of eugenol
occurred resulting in monochlorinated product 1b with chlorine
being in the ortho-position.
Chlorophenols are widely used in pharmaceutical, agricultural and
dye industries for the production of various drugs, insecticides,
herbicides, dyestuffs, etc.1,2 Common methods for their synthesis
involve electrophilic aromatic halogenation reactions using various
chlorinating agents such as chlorine,3 sulfuryl chloride (which
readily dissociates into SO2 and chlorine)4,5 and hypochlorites.6 An
alternative pathway to chlorinated phenols is oxidative chlorina-
This oxidative transformation of eugenol formally consists of a
nucleophilic substitution of aromatic hydrogen by Cl2 and a
further oxidation of H2 by CuCl2, i.e. oxychlorination (Scheme 1).
Reduced copper(I) species are readily re-oxidized back by
dioxygen. Under optimized conditions at 80 uC and an oxygen
pressure of 1 atm,{ nearly complete conversion of eugenol
occurred after a 6 h reaction (Table 1, run 1). The remarkable
selectivity of this reaction should be mentioned: no traces of meta-
isomer or polychlorinated products were observed, with chemo-
selectivity being virtually 100%.
tion, which uses chloride ions as
a
chlorine source.
Oxychlorination has many advantages compared to the conven-
tional chlorination, such as fuller utilization of chlorine atoms and
the use of low value and easy to handle chlorinating agents rather
than more expensive and toxic ones, like chlorine. These reactions
become especially attractive if dioxygen, the most abundant and
cheapest oxidant, is involved.
The reactivities of various aromatic compounds were examined
under similar conditions. Some of these results are collected in
Table 1. The reaction with phenol itself occurs much slower than
that with eugenol resulting in a 93% conversion for 24 h (run 2). A
high selectivity of 90% for para-chlorophenol 2b has been obtained
in this reaction under non-optimized conditions, with only small
amounts of ortho-isomer being detected. On the other hand,
phenols having at least one more electron donating group, i.e.,
meta-cresol 3a, guaiacol 4a and thymol 5a, undergo the CuCl2
catalyzed oxychlorination at much higher rates, like eugenol.
Nearly complete conversions and excellent selectivities for para-
chlorinated products were achieved in most of the reactions after
4–6 h (runs 3–5). Only in the case of guaiacol (run 4) have some
secondary products been detected by GC, however at lower
temperature (60 uC) selectivity increases to 97% at 82% conversion
(run 6). Although these side products have not been fully identified
yet, GC/MS analyses show that they contain no or only one
chlorine atom, indicating that no polychlorination occurred.
Although the catalytic oxychlorination of ethylene with
dioxygen has been developed into the important industrial
synthesis of 1,2-dichloroethane,7 little was achieved with oxychlor-
ination of aromatics. In most of the published works,8–11 peroxo
compounds were used as oxidants, with complex mixtures of
isomeric mono- and polychlorinated aromatics being usually
obtained. Moreover, in substituted aromatics, the reactions are
strongly complicated by the concomitant oxidation of side chains.
The present communication reports the remarkable activity of
CuCl2 to catalyze under mild conditions the oxychlorination of
various phenols with dioxygen, affording monochlorinated
products with high chemo- and regioselectivity. The presence of
the hydroxy group attached to the aromatic nucleus was found
essential for the reactivity of the aromatic substrate for
oxychlorination, so that non-phenolic aromatics undergo no
reaction at all in these systems. Thus, the method can be applied
to perform a specific chlorination of phenols present in a mixture
of various aromatic compounds.
We have recently been involved in palladium catalyzed aerobic
oxidations of naturally occurring olefins.12–14 Studying the PdCl2–
CuCl2 catalyzed oxidation of eugenol (1a), which is an allylbenzene
easily available from biomass, we have observed that its solutions
in acetic acid containing CuCl2 and LiCl readily consume dioxygen
even in the absence of palladium. Gas chromatography (GC)
showed the formation of only one product, which was isolated
from the reaction solution by column chromatography and
Departamento de Qu´ımica, Universidade Federal de Minas Gerais,
31270-901, Belo Horizonte, MG, Brazil. E-mail: elena@ufmg.br;
Fax: +55 31 34995700; Tel: +55 31 34995755
Scheme 1
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Chem. Commun., 2006, 209–211 | 209

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a
Table 1 Oxychlorination of phenols catalyzed by CuCl2
Run Substrate (0.40 M) Time (h) Conversion (%) Product
Selectivity (isolated yield) (%)
99 (82)
1
2
Eugenol
Phenol
6
94
93
24
90
3
4
meta-Cresol
6
6
90
94
99 (81)
Guaiacol
52
5
Thymol
4
7
92
82
99 (87)
6b
Guaiacol
97
a
Conditions: solvent: acetic acid, [CuCl2] = 0.05 M, [LiCl] = 0.80 M, 80 uC, O2 (1 atm). Conversion and selectivity were determined by GC.
60 uC.
b
As mentioned above, the para-isomers of monochlorinated
In the absence of CuCl2, no chlorination products are formed
and no other reactions occur with phenols under the conditions
shown in Table 1. The oxychlorination of eugenol is approximately
first order in the catalyst concentration. Moreover, when CuCl2
was substituted by CoCl2, no reaction was observed. These results
show the important and specific role of the copper catalyst.
It is known that most oxidative transformations of phenols
catalyzed by copper complexes involve, as a key feature, the one-
electron oxidation of phenolate by Cu(II) to the corresponding
phenoxy radical.15 Thus, although the mechanism of copper
catalyzed oxychlorination of phenols is not clear so far, it can be
suggested that a free radical mechanism is likely to operate in these
systems. Mechanistic aspects of this reaction are under investiga-
tion in our laboratory.
products are exclusively formed from all studied phenols, except
eugenol, in which the para-position is occupied by the allylic
group. Although ortho-chlorination of eugenol occurs smoothly,
no significant amounts of corresponding ortho-isomers are formed
from substituted phenols having the para-position available. Also,
no further ortho-chlorination of para-chlorophenols 3b–5b has
been observed even at longer reaction times. Thus, the presence of
the electron withdrawing chlorine atom attached to aromatic
nucleus in primarily formed products virtually suppresses their
further chlorination.
The results obtained clearly demonstrate the generality of
the catalyst in the para- or ortho-oxychlorination of phenol
and electron-rich phenolic compounds. The catalytic system
shows not only high regioselectivity but also a remarkable
chemoselectivity for monochlorination. It is also important that
no products of the oxidation of phenols are formed in detectable
amounts.
Preliminary studies show that the method can be extended to
solvents other than acetic acid, such as water, methanol,
acetonitrile, etc. In particular, performing the process in water
offers not only important technological and environmental
advantages, but also makes possible the use of sodium chloride
as the chlorine source rather than the more expensive lithium
chloride. We have found that the oxychlorination of eugenol 1a in
aqueous solutions of NaCl and CuCl2 (cat.) results exclusively in
monochlorinated product 1b.
Non-phenolic compounds examined in this reaction, both with
electron withdrawing and with electron donating groups, i.e.
anisole, nitrobenzene, toluene and safrol, undergo no transforma-
tion at all under the conditions used for oxychlorination of
phenols. Thus, the method is highly substrate specific and could be
applicable to the chlorination of phenols in mixtures with other
aromatics.
In summary, CuCl2 efficiently catalyzes the oxychlorination of
phenols under mild conditions in various solvents including water.
210 | Chem. Commun., 2006, 209–211
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2 Kirk-Othmer Encyclopedia of Chemical Technology, Wiley, New York,
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Chloride ions are used as the halogenating agent and dioxygen as
the final oxidant. These novel reactions are relatively fast, specific
for monochlorination and highly regioselective for para- or ortho-
substitution. The method might be applied to the synthesis of
chlorophenols, which are widely used in pharmaceutical, agricul-
tural and dye industries.
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We acknowledge the financial support from CNPq and
FAPEMIG and scholarship from CNPq (LM). The authors wish
to thank Luciana Alves Parreira for technical assistance.
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Notes and references
{ The reactions were carried out in a stirred glass reactor and followed by
measuring the dioxygen uptake and by gas chromatography using
dodecane as an internal standard (Shimadzu 17 instrument, Carbowax
20 M capillary column, flame ionization detector). In a typical run, a
solution of the aromatic compound, dodecane, CuCl2 and LiCl in acetic
acid was intensively stirred under oxygen at 80 uC for a specified time.
´
1 Ullmanns Encyclopedia of Industrial Chemistry, Wiley-VCH, Weinheim,
6th edn, 1998.
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