Abstract: Under microwave irradiation a number of phenols
react remarkably fast with a number of primary alkyl halides to
give aromatic ethers. The procedure is alternative to those which
rely on the use of dipolar aprotic solvents, sodium, sodium hydride,
sodium amide and several procedure that rely on "standard"
Results and Discussion
In the last few years there has been a growing interest in the
use of microwave heating in organic synthesis [1-4]. The use of
such unconventional reaction conditions reveals several features
like: a short reaction time compared to conventional heating,
ease of work-up after a reaction, and reduction in the usual thermal
degradation and better selectivity.
The simplest method for conducting microwave-assisted reactions
involves irradiation of reactants in an open vessel. Such a method,
termed 'microwave-organic reaction enhancement (MORE)', was developed
by Bose at al.. During the reaction, reactants are heated by
microwave irradiation in a polar, high-boiling solvents so that
the temperature of reaction mixture does not reach the boiling
point of a solvent. Despite of convenience, a disadvantage of
the MORE technique its limitation to high-boiling polar solvents
such as DMSO, DMF, N-methylmorpholine, diglyme etc. However, the
approach has been adopted to lower-boiling points solvent (e.g.
toluene) , it generates a potentially serious fire hazard.
For reactions at reflux domestic microwave ovens have been modified
by making a shielded opening to prevent leakage, and through which
the reaction vessel has been connected to a condenser .
The pressurised conditions for microwave reactions first reported
by the groups of Gedye  and Giguere  also have been developed.
Gedye at al. used a domestic microwave oven, and commercially
available screw-up pressure vessels made from either PET or Teflon.
The 'bomb' strategy has been successfully applied to a number
of synthesis, but it always generates a risk of hazardous explosions.
Recently, Majetich and Hicks  reported 45 different reactions
with a commercial microwave oven and and PET vessels designed
for acid digestion.
Microwave heating has been proven to be of benefit particularly
for the reactions under "dry" media (i.e., in the absence
of a solvent, on solid support with or without catalysts) and
offers a number of advantages: solvents are often expensive, toxic,
difficult to remove in the case of aprotic solvents with high
boiling point. Liquid-liquid extraction can be avoided for the
isolation of reaction products. Moreover, the absence of solvent
reduce the risk of explosions when reaction takes place in a microwave
Reactions under "dry" conditions (i.e., in the absence
of a solvent, on a solid support with or without catalysts) were
originally developed in the late eighties . Synthesis without
solvents under microwave irradiation offers several advantages
. The absence of solvent reduces the risk of explosions when
the reaction takes place in a closed vessel in an oven. Moreover,
aprotic dipolar solvents with high boiling points are expensive
and difficult to remove from the reaction mixtures. During microwave
induction of reactions under dry conditions, the reactants adsorbed
on the surface of alumina, silica gel, clay, and others absorb
the microwaves whereas the support does not, nor does it restrict
the transmission of microwaves. Consequently, such supported reagents
efficiently induce reactions under safe and simple conditions
with domestic microwave ovens instead of specialised expensive
commercial microwave systems.
Results and Discussion
Preparation of aromatic ethers is an important synthetic reaction
for which a wide variety of procedure has been developed during
the last hundred years. Most of the commonly used method involve
alkylation of parent phenol or derived phenoxide ion, with the
latter type being by far the more important. The phenoxide ion
is generated by treatment of the phenol with a base such as sodium,
sodium hydride or sodium amide in a solvent such as benzene, toluene,
or dioxane; alkylation with the appropriate alkylu halide is then
normally carried out in the same solvent. This method is usually
highly efficient, although some care must be exercised in choice
of solvent in order to avoid formation of both C- and O-alkylated
products , .
There are few useful procedures available for the conversion of
phenols into aromatic ethers which do not neccesite initial formation
of the corresponding phenoxide ion. Direct alkylation with diazomethane
can be wide applied, but is seldom the method of choice because
of the obnoxious nature of the reagent. Alkylation can be also
accomplished with alkyl orthocarbonate esters , dialkyl oxolate
esters , and by treatment of phenols with alcohols in the
presence of dicyclohexylcarboimide . None of these methods
is, however, general with respect to the variety of alkyl groups
which can be introduced into aromatic alkyl ethers.
During the last years, several new procedures for Williamson synthesis have been developed  in which the PTC procedures appear to be the most useful in terms of mildness of conditions, yield, and convenience, .
We have sought to develop a general method of the O-alkylation
of phenols and alcohols. Such a procedure should retain the convenience
of PTC methods but should be free from some limitations related
to PTC systems  and much faster. Therefore we decided to explore
the use of microwave heating under solvent free PTC conditions
for O-alkylation of phenols.
We now report here the remarkable fast method of synthesis of
aromatic ethers in 'dry' media under microwave irradiation Fig.
Figure 1. The reaction of phenols with alkyl halides under
The reactions were carried out by simply mixing of phenol with
50% excess of an alkyl halide and a catalytic amount of tetrabutylammonium
bromide (TBAB). The mixtures were adsorbed either on the mixture
of potassium carbonate and potassium hydroxide or potassium carbonate
and then irradiated in an open vessel in a domestic microwave
oven for 25-65 s. The results are summarized in Table 1.
Table 1. The reactions of phenols with alkyl halides under
irradiation in a microwave oven.*
*Reagents ratio: phenol (5 mmol), alkylating agent
(6 mmol), tetrabutylammonium bromide(0.5mmol), K2CO3
(20 mmol), KOH (20 mmol).
Since the shape and size of the reaction vessel are important factors for the heating of dielectrics in a microwave oven, the preferred reaction vessel is a tall beaker of much larger capacity than the volume of the reaction mixture, and bearing a loose cover. A large Erlenmeyer flask with a funnel as a loose top cap can be used in place of the beaker. Superheating of liquids is common under microwave irradiation, thus the strategy of the reactions is to keep the reaction temperature substantially below the boiling point of each compound used for the reaction. Since it is difficult to measure temperature in a household microwave oven, one of the best solutions is to repeat an experiment several times increasing the power slowly so that vapours do not escape outside of the flask.
After the reaction, the work-up procedure is reduced to a treatment
with an appropriate solvent (e.g., THF or CH_2Cl_2), purification
by distillation in a Kugelrohr apparatus or recrystallization.
If necessary before recrystallization, compounds can be separated
from starting materials by means of flash chromatography. All
the products gave satisfactory IR, ^1 H - NMR, and MS data. Melting
and boiling points of all the compounds are in good agreement
with literature data. The reaction procedures are not optimised
In conclusion, we have developed a simple method for the synthesis
of aromatic ethers that occurs remarkable fast under mild conditions
using inexpensive reagents and a household microwave oven as the
irradiation source. Moreover, the procedure is alternative to
those which rely on the use of dipolar aprotic solvents, sodium,
sodium hydride, sodium amide and several procedure that rely on
"standard" PTC methods.
A mixture of a phenol (5.0 mmol), alkylating agent (6.0 mmol),
tetrabutyl-ammonium bromide - TBAB (0.17 g, 0.50 mmol), and the
mixture of potassium carbonate (2.8 g, 20 mmol) and potassium
hydroxide (1.1 g, 20 mmol) was heated in a domestic microwave
oven in an open Erlenmeyer flask for an appropriate time (see
Table ??). After being cooled down, the reaction mixture was extracted
with methylene chloride or THF (2 x 25 ml). Then the extract was
dried withMgSO_4, filtered, and the solvent was evaporated to
dryness. Liquid compounds were purified on Kugelrohr distillation
apparatus, while solid compounds were purified by means of flash
chromatography to afford desired an aromatic ether, yield: 64-92%.