Quaternary ammonium salt-assisted organic reactions in water: Alkylation of phenols

Article abstract of DOI:10.1081/SCC-100000172

A series of quaternary ammonium salts has been tested as phase transfer agents to promote reactions between phenols and alkyl halides in an aqueous solution of sodium hydroxide in the absence of organic solvent. Methyltrioctylammonium chloride emerges as the most effective catalyst.

Full text of DOI:10.1081/SCC-100000172

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QUATERNARY AMMONIUM SALT-ASSISTED ORGANIC
REACTIONS IN WATER: ALKYLATION OF PHENOLS
a
a
Jean Jacques Vanden Eynde & Isabelle Mailleux
a
Organic Chemistry Department, University of Mons-Hainaut, Place du Parc 20, B-7000,
Mons, Belgium
Available online: 09 Nov 2006
To cite this article: Jean Jacques Vanden Eynde & Isabelle Mailleux (2001): QUATERNARY AMMONIUM SALT-ASSISTED
ORGANIC REACTIONS IN WATER: ALKYLATION OF PHENOLS, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 31:1, 1-7
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SYNTHETIC COMMUNICATIONS, 31(1), 1–7 (2001)
QUATERNARY AMMONIUM
SALT-ASSISTED ORGANIC REACTIONS IN
WATER: ALKYLATION OF PHENOLS
∗
Jean Jacques Vanden Eynde and Isabelle Mailleux
University of Mons-Hainaut, Organic Chemistry
Department, Place du Parc 20, B-7000 Mons, Belgium
ABSTRACT
A series of quaternary ammonium salts has been tested as
phase transfer agents to promote reactions between phenols and
alkyl halides in an aqueous solution of sodium hydroxide in the ab-
senceoforganicsolvent. Methyltrioctylammoniumchlorideemerges
as the most effective catalyst.
Nowadays, thereisanincreasingawarenessoftheurgentnecessitytolimit, as
far as possible, any source of pollution. Consequently and in response to the public
pressure, the environmental legislation is becoming ever more severe. Facing up
to those facts, chemists have to dedicate numerous efforts to the development of
clean technologies.
That new challenge has led recently to a growing interest in the displacement
of organic reactions to aqueous media (1–3), which has been achieved successfully
in the Ruhr Chemie Rh oˆ ne-Poulenc hydroformylation process (4).
Waterisanabundant, cheap, nontoxic, andnondangeroussolvent. Obviously,
it does not dissolve most of the organic reactants, but that fact has been recognized
∗
To whom correspondence should be addressed. E-mail: jjvde@umh.ac.be
1
Copyright ꢀC 2001 by Marcel Dekker, Inc.
www.dekker.com

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2
VANDEN EYNDE AND MAILLEUX
as a benefit on rates and selectivities of several transformations (1–3). Moreover,
the addition of a phase transfer agent, generally a quaternary ammonium salt,
enables to improve an intimate contact with an organic layer (3–11).
The aim of this paper is to disclose suitable experimental conditions to
promote alkylation of phenols in an aqueous solution of sodium hydroxide and in
the absence of any organic solvent. That reaction yields aryl ethers, a functionality
that is a key constituent in the structures of many pharmaceutically important
chemicals.
RESULTS
The reaction between phenols and alkyl halides in an aqueous solution of
sodium hydroxide requires the contact between two nonmiscible phases and yields
a water-insoluble product. Therefore, its course can be monitored readily by UV
spectroscopy on samples of the aqueous phase, as the phenolates are the sole
species that absorb in that wavelength region. That method was used to select the
most attractive phase transfer catalyst from a kinetic point of view in a model
−
1
−1
reaction involving 1,2-dihydroxybenzene (1a-Fig. 1; ꢀ = 2870 l mol cm
;
λ max = 275 nm) and iodomethane. By that way, we observed that 1a reacts
slowly with an excess (3 eq) of iodomethane in an aqueous solution of sodium
◦
hydroxide (5M) at 50 C.
After 1 h, only 5% of the starting material 1a is consumed. Addition of a
quaternary ammonium salt (10% mol relative to 1a) accelerates the process as
indicated by inspection of the results collected in Table 1. Among the transfer
ꢀ
R
agents we tested, methyltrioctylammonium chloride (Aliquat 336) emerges as
the most effective catalyst. Interestingly, in contrast with conclusions (12) dealing
with other phase transfer catalysis experiments, no synergistic effect of a crown
ether-quaternary ion salt pair takes place.
To evaluate the synthetic potential of the method, we performed the same
experiments in a boiling solution of sodium hydroxide, extending the reaction time
arbitrarily to 1 h. After cooling, the mixture was extracted with dichloromethane.
Before evaporation of the solvent, the organic layer was filtered through a cake
of alumina to retain the ammonium salt. Yields in 1,2-dimethoxybenzene, deter-
1
mined by H NMR, are collected in Table 1. The data parallel the results of the
Figure 1.

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ALKYLATION OF PHENOLS
3
Table 1. Influence of the Catalyst on the Alkylation of 1a with Methyl Iodide
1a] (mol/l) after Isolated Yieldb,
a
[
Catalyst (10% mol relative to 1a)
30 mn
60 mn
%
None
0.78
0.68
0.44
0.54
0.45
0.45
0.76
0.56
0.38
0.51
0.35
0.33
25
40
65
60
80
90
Benzyltriethylammonium chloride
Tetrabutylammonium hydrogenosulfate (TBA)
TBA/15-crown-5
Cetyltrimethylammonium bromide
Methyltrioctylammonium chloride
a
−1
−1
−1
−1
◦
C
C
0
(1a) = 0.8 mol l ; C
0
(CH
(CH
3
I) = 2.4 mol l ; T = 50 C.
b
0
(1a) = 0.8 mol l ; C
0
3
I) = 1.6 mol l ; T = reflux; time = 1 hour.
kinetic study. Indeed, the highest yield in isolated product was obtained by using
methyltrioctylammonium chloride as the transfer agent. Cetyltrimethylammonium
bromide is also efficient, but its tendancy to foam complicates the experimental
procedure. The other salts give lower yields so we did not use them. Experimen-
tally, we also noticed that the stoechiometric amount of iodomethane is sufficient
to effect the dialkylation. In agreement with the mechanism of the reaction, which
requires the formation of phenolate anions, a lower concentration of NaOH (0.5
M) or the use of sodium hydrogenocarbonate (5 M, 0.5 M) as the base (in the pres-
ence of 10% mol of methyltriocylammonium) dramatically decreases the yield in
1,2-dimethoxybenzene to 30, 20, or 5%, respectively. In that sense, too, sodium
dodecylsulfate (10% mol), a popular anionic surfactant, exhibits a poor but positive
activity (35%).
Having a simple procedure to methylate 1,2-dihydroxybenzene, we wished
toestimateitsrangeofapplicability. Underourexperimentalconditions, compound
Figure 2.

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4
VANDEN EYNDE AND MAILLEUX
Table 2. Results for the Alkylation of 1a, 1b, and Various
Phenols in the Presence of Methyltrioctylammonium Chloride
Product
Isolated Yield, %
Lit. Ref.
2
2
3
3
3
3
3
4
4
4
4
4
4
a
b
a
b
c
d
e
a
b
c
90
55
60
65
75
95
50
90
90
55
65
95
70
21–24
23–26
23, 24, 27, 28
14, 29
14, 30
14, 29
23, 24, 31
23, 24, 32, 33
23, 24, 34, 35
23, 24, 36, 37
38
d
e
f
39–41
42–44
1a readily reacts with 1,2-dibromoethane, 1,3-dibromopropane, 1,4-dibromo-
butane, and even 1,5-dibromopentane. Yields vary from 50 to 95%. In particu-
lar, derivative 3c has been obtained in 75% yield, whereas Ziegler (7) reports that
its preparation requires two steps and that the yield of the second step does not
exceed 40%. 3,4-Dihydroxybenzaldehyde (1b) and other phenols also can be alky-
lated under our experimental conditions, as indicated by the examples presented
in Figure 2 (isolated yields are reported in Table 2). Mention should be made that
in all cases the crude final products were isolated by decantation or filtration, thus
limiting the use of an organic solvent to the purification by recrystallization when
the expected compound is a solid.
CONCLUSION
Elegant protocols for the preparation of aryl ethers have recently been pub-
lished. They recommend the use of polymer-supported bases (15) or irradiation
of dry media with microwaves (16,17). This paper presents another simple ex-
perimental procedure (that could readily be scaled up) to alkylate phenols in an
aqueous basic solution in the presence of a catalytic amount of methyltrioctylam-
monium and in the absence of any organic solvent. It is characterized by its wide
range of applicability as it enables, e.g., the formation of 6- to 9-membered benzo
fused systems, as well as the use of long chain alkyl halides. Our experimental
conditions largely differ from those described by Bashall and Collins (18) as the

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ALKYLATION OF PHENOLS
5
ammonium salt does not play the role of a solvent. Let us also emphasize that we
did not observe any poisoneous effect of the iodide ion when alkyl iodides were
involved (18, 19), and that by-products from a Cannizzaro reaction (20) were not
detected when starting from hydroxybenzaldehydes.
EXPERIMENTAL SECTION
All reagents, catalysts, and solvents are commercially available (Aldrich,
Acros Organics). All products (2, 3, 4) have been described in the literaure and
were fully characterized by their melting point (hot-stage microscope) or boiling
point, and by their spectral data (NMR: Varian EM 360-L, Bruker AMX; IR:
Perkin-Elmer 1760K).
Quantitative Study
A stirred mixture of 1,2-dihydroxybenzene (5.51 g; 50 mmol) and a catalyst
(
see Table 1; 5 mmol) in a 5 M aqueous solution (62.50 mL) of sodium hydroxide
◦
was held under thermostatic control at 50 C for two hours. Iodomethane (9.34 mL;
1
50 mmol) was added. A sample of the mixture was taken every 10 minutes, rapidly
◦
cooled down to 0 C, and diluted (2000 X) for UV analysis (Varian Cary 118).
General Procedure for the Alkylation
A mixture of the phenol (100 mmol), the alkyl halide (one or two equiva-
lents), and methyltrioctylammonium chloride (10 mmol) in a 5 M aqueous solution
(100 mL) of sodium hydroxide was stirred and heated under reflux for one hour. Af-
ter cooling, the crude product was separated (decantation or filtration) and purified
by distillation or recrystallization.
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