Heterogeneous phase alkylation of phenols making use of phase transfer catalysis and microwave irradiation

Article abstract of DOI:10.2174/157017809789869500

The benzylation of cresol was studied under liquid-liquid and solid-liquid phase transfer catalytic conditions. Microwave irradiation was useful only in the solid-liquid phase benzylations. Using acetonitrile as the solvent, the benzylations were fully O-selective, but complete conversions were obtained only in the presence of Cs₂CO₃. There was no need to use an onium salt. In the absence of solvent, an O-selectivity of ca. 90% could be obtained in the presence of an alkali carbonate and an onium salt. The optimum set of conditions was extended to the reaction of other phenol derivatives and alkylating agents.

Full text of DOI:10.2174/157017809789869500

Letters in Organic Chemistry, 2009, 6, 535-539
535
Heterogeneous Phase Alkylation of Phenols Making Use of Phase Transfer
Catalysis and Microwave Irradiation
György Keglevich*,a, Erika Bálinta, Éva Karsaib, Judit Vargaa, Alajos Grüna,c, Mária Bálintb and
István Greinerd
aDepartment of Organic Chemistry and Technology, Budapest University of Technology and Economics, H-1521
Budapest, Hungary
bBálint Analytics, H-1116 Budapest, Fehérvári Street 144, Hungary
cResearch Group of the Hungarian Academy of Sciences at the Department of Organic Chemistry and Technology,
Budapest University of Technology and Economics, H-1521 Budapest, Hungary
dGedeon Richter Plc., H-1475 Budapest, Hungary
Received February 19, 2009: Revised April 29, 2009: Accepted September 09, 2009
Abstract: The benzylation of cresol was studied under liquid–liquid and solid–liquid phase transfer catalytic conditions.
Microwave irradiation was useful only in the solid–liquid phase benzylations. Using acetonitrile as the solvent, the
benzylations were fully O-selective, but complete conversions were obtained only in the presence of Cs2CO3. There was
no need to use an onium salt. In the absence of solvent, an O-selectivity of ca. 90% could be obtained in the presence of
an alkali carbonate and an onium salt. The optimum set of conditions was extended to the reaction of other phenol
derivatives and alkylating agents.
Keywords: O-alkylation, selectivity, phase transfer catalysis, microwave synthesis.
1. INTRODUCTION
was found that the O- versus C-selectivity can be fine-tuned
by the presence or absence of the base and PT catalyst [15].
In this paper, we wish to investigate in detail, how the
efficiency and selectivity of the alkylation of phenols can be
influenced.
The use of microwave (MW)-assisted phase transfer (PT)
catalytic methods represents an attractive alternative in
environmentally friendly chemistry [1,2]. In heterogeneous-
phase C-alkylations, the PT catalyst can be substituted by
MW irradiation [3,4]. In N-alkylations, the MW and PT
catalytic techniques complete well each other [5]. Regarding
O-alkylations, the PT catalyzed reactions can be
synergistically enhanced by MW irradiation. The alkylation
of phenols can be carried out in solid-liquid phase
conditions, using organic solvents and an alkali hydroxide as
the base [6,7]. Solvent-free alkylations in the presence of
K2CO3 or K2CO3 /NaOH have also been described [8,9].
Sodium phenolate may also form the solid phase [10].
Liquid–liquid phase alkylation, using aqueous NaOH and
e.g. toluene is another possibility [11]. In some cases there
was no need for a PT catalyst [12-14]. The combination of
PT catalytic and MW techniques is beneficial from the point
of view of rate enhancement, but details on the selectivity
have not been disclosed. Selectivity is generally a crucial
problem from the point of view of efficient accomplishment
of any reaction. Reproduction of the data may be difficult, as
the early experiments were accomplished in domestic MW
ovens. We made efforts to clarify the exact role of the PT
catalysts in MW-assisted alkylations [2-4,15], including the
benzylation of phenols [2,15]. In our preliminary study, it
2. RESULTS AND DISCUSSION
The benzylation of cresol was carried out first in a liquid-
liquid two phase system using toluene and 30% NaOH
solution at 60 °C, with vigorous stirring. In the absence of
the phase transfer catalyst, triethylbenzyl-ammonium
chloride (TEBAC), and in the presence of 1.5 eq. of NaOH,
not all of the cresol was consumed after 2.5 h and four
products, 4-methylphenyl benzyl ether (2a, 35%), 2-benzyl-
4-methylphenol (3a, 43%), 2-benzyl-4-methylphenyl benzyl
ether (4a, 7%), and 2,5-dibenzyl-4-methylphenol (5a, 11%)
were formed (Table 1/entry 1). Using 3.0 eq. of NaOH, the
conversion was complete and the quantity of products 2a,
3a, 4a, and 5a was 31, 12, 19, and 38%, respectively (Table
1/entry 2). As compared to the previous experiment (entry
1), the quantity of benzylcresol 3a decreased, while that of
dibenzyl products 4a and 5a increased. The benzylations
were also carried out in the presence of 5, 10, and 15% of
TEBAC using 1.5 eq. NaOH. In the above order, the quantity
of cresyl benzyl ether 2a was 62, 73, and 83%, respectively,
while that of the dibenzyl by-product 4a was 26, 25, and
13%, respectively. The quantity of phenols 3a and 5a was in
the range of 0–8% (Table 1/entries 3-5). In the presence of
TEBAC, an increase in the quantity of NaOH from 1.5 to 3
eq. did not have a significant impact on the outcome. The
isolated yield of cresyl benzyl ether 2a from the experiment
*Address correspondence to this author at the Department of Organic
Chemistry and Technology, Budapest University of Technology and
Economics, H-1521 Budapest, Hungary; Tel: +36 1 4631111/5883;
Fax: +36 1 4633648; E-mail: keglevich@mail.bme.hu
1570-1786/09 $55.00+.00
© 2009 Bentham Science Publishers Ltd.

536 Letters in Organic Chemistry, 2009, Vol. 6, No. 7
Keglevich et al.
Table 1. The Alkylation of Cresol with Benzyl Bromide in Liquid–Liquid Two Phase System Using Toluene and Aqueous Sodium
Hydroxide
60 °C
TEBAC
OH
OBn
OH
OBn
OH
Bn
Bn
Bn
NaOH / H2O
+
BnBr
+
+
+
PhMe
(1.2 eq.)
Bn
Me
Me
Me
Me
Me
2a
3a
4a
5a
1a
2a
3a
4a
5a
NaOH [eq.]
TEBAC [%]
Reaction Time [h]
Entry
[%]
1.5
3.0
1.5
1.5
1.5
-
-
2.5 a,b
2.5
35
31
62
73
83
43
12
8
7
11
38
4
1
2
3
4
5
19
26
25
13
5
~1.5 b
~1.0
~1.0
10
15
<1
4
2
0
a4% of cresol was also detected that does not disappear on further stirring.
bMW irradiation enhanced the reaction, but the product composition did not change significantly.
shown in entry 5 was 75%. It can be seen that the reaction of
cresol with benzyl bromide is complete and selective mostly
only in the presence of TEBAC. The maximum of the
desired O-selectivity was 83% (Table 1/entry 5). The C-
selectivity was the most significant (54%) in the experiment
shown in entry 1. Repeating a few of the above liquid-liquid
phase transfer benzylations under MW conditions (at 60 °C)
showed no advantage.
In the hope of better O-selectivities, the benzylations
were carried out under solid-liquid phase transfer conditions,
using acetonitrile as the solvent, in the presence of an alkali
carbonate, and in the absence or presence of an onium salt,
by traditional heating or by MW irradiation. The thermal
(control) experiments were carried out in boiling acetonitrile
in the presence of K2CO3. The use of 5% of TEBAC
somewhat shortened the reaction time (4 vs. 2.5 h). Both
Table 2. The Alkylation of Cresol with Benzyl Bromide in Solid–Liquid Two Phase System Using Acetonitrile and Alkali
Carbonate
ꢀ or MW
T, t
onium salt
base (1.0 eq.)
OH
OBn
+
BnBr
MeCN
(1.2 eq.)
Me
Me
1a
2a
Base
Onium Salt [%]
Mode of Heating
T [°C]
t
Conversion of 1a to 2a [%]
Entry
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
Cs2CO3
-
ꢀ
82
82
4 h
2.5 h
1.5 h
1.5 h
1 h
100
100
92a
1
2
3
4
5
6
7
8
9
TEBAC (5)
-
ꢀ
MW
MW
MW
MW
MW
MW
MW
80
TEBAC (5)
-
80
94a
100
100
100
80
92a
TEBAC (5)
TPEPB (5)
1 h
93a
1 h
92a
b
-
45 min
30 min
100c
100c
b
-
100
ano complete conversion on further irradiation.
bno effect of 5% of TEBAC added.
cisolated yields were ca. 90%.

Heterogeneous Phase Alkylation of Phenols Making Use
Letters in Organic Chemistry, 2009, Vol. 6, No. 7
537
reactions (Table 2/entries
1
and 2) were entirely
4). By applying Cs2CO3 instead of K2CO3 and carrying out
the benzylations at 80 or 100 °C, the conversions were
almost quantitative and the O-selectivity increased to ꢀ79%
(Table 3/entries 5–7). In the absence of an onium salt, the O-
selectivity of 79% was somewhat surprising. The use of 5%
of onium salts was beneficial; on the one hand, the O-
selectivity further improved, and on the other hand the
conversions were complete (Table 3/entries 6 and 7).
chemoselective. To shorten further the reaction times, the
solid–liquid phase alkylations were carried out under MW
irradiation. Using K2CO3, incomplete conversions (~92%)
were observed at 80 and 100 °C (Table 2/entries 3 and 5).
The presence of 5% of TEBAC was not useful in attaining
complete conversions (Table 2/entries 4 and 6). The
application of triphenylethylphosphonium bromide (TPEPB)
instead of TEBAC had no beneficial effect on the course of
the reaction (Table 2/entry 7). Then K2CO3 was replaced by
the more organophilic Cs2CO3. Carrying out the reaction at
80 °C, the benzylation was complete after 45 min (Table
2/entry 8). At 100 °C the reaction time was 30 min (Table
2/entry 9). The use of 5% of TEBAC had no impact on the
outcome of the benzylation. Isolated yields of cresyl benzyl
ether 2a from the experiments shown in entries 8 and 9 were
ca. 90%. One can conclude that the benzylations carried out
in acetonitrile in the presence of alkali carbonates under MW
conditions are selective, but the conversion is incomplete if
K2CO3 is applied as the base. However, no unreacted cresol
remains in the reaction mixture if Cs2CO3 is used.
It can be seen that MW irradiation offers advantages in
combination with solid–liquid PT catalytic methods in the
alkylation of phenol derivatives. The conversions are
complete, the reaction times become shorter and the
alkylations are at least 90% O-selective. If the alkylations are
carried out in acetonitrile, there is no need for an onium salt.
In this case, the MW irradiation replaces the PT catalyst.
Under solventless conditions, the presence of an onium salt
ensures O-selectivity.
The optimum set of conditions found for cresol were then
applied to other model compounds, such as phenol and 4-
chlorophenol. Using Cs2CO3 in acetonitrile at 100 °C, the
corresponding ether (2b and 2c, respectively) was obtained
quantitatively (Table 4/entries 1 and 2). The PT catalyst
added had no impact on the benzylation. The alkylation of
cresol with benzyl chloride under similar conditions was
complete in the presence of 5% of TEBAC (Table 4/entry 3).
We then wished to study the benzylations carried out
under solventless and MW conditions in detail. It had been
shown by our preliminary studies [15] that in such
alkylations the outcome, namely the selectivity of O- versus
C-benzylation, can be controlled by the absence or presence
of K2CO3 and TEBAC. If neither of them is present in the
reaction mixture, only the C-benzylated product (3a) is
formed (Table 3/entry 1), while if both the base and the
catalyst are present in the mixture, a pronounced O-
selectivity, resulting in ether 2a (89%), can be achieved at
100 °C (Table 3/entry 3). The alkylation carried out in the
presence of K2CO3 without any catalyst represents an
intermediate case (Table 3/entry 2). The use of TPEPB
instead of TEBAC led to similar results (see Table 3/entry
Going to solventless alkylations, the benzylation of
phenol carried out at 100 °C in the absence of TEBAC
resulted in the formation of a mixture containing 85% of
ether 2b and 15% of C-benzylated phenols and dialkylated
derivatives (Table 4/entry 4). In this instance, the presence of
a PT catalyst had not much impact on the results (Table
4/entry 5). In the benzylation of 4-chlorophenol at 110 °C,
the absence or presence of TEBAC had a significant impact
on the O-selectivity: in the absence of catalyst, 84% of the
Table 3. The Alkylation of Cresol with Benzyl Bromide in Solid–Liquid Two Phase System under Solventless and MW Conditions
MW
T, t
onium salt
base
1a
+
BnBr
2a
+
3a + 4a + 5a
no solvent
(1.2 eq.)
1a
2a
3a
4a
5a
Base
Onium Salt [%]
T [°C]
t [min]
Ref.
Entry
[%]
-
-
100
100
100
80b
60
40
35
45
40
30
30
79
12a
0
21
24
1
[15]
[15]
[15]
1
2
3
4
5
6
7
K2CO3
K2CO3
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
-
52
89
93
79
89e
93
6
10
6
6
0
0
1
0
0
TEBAC (5)
TPEPB (5)
-
0
1
100c
100d
100
4
5
11
9
TEBAC (5)
0
2
TPEPB (5)
0
1
6
adid not disappear of further irradiation.
bsimilar results were obtained at 100 °C after a reaction time of 35 min.
csimilar results were obtained at 80 °C after a reaction time of 50 min.
dsimilar results were obtained at 80 °C after a reaction time of 40 min.
ethe isolated yield was 81%.

538 Letters in Organic Chemistry, 2009, Vol. 6, No. 7
Keglevich et al.
Table 4. Extension of the MW-Assisted Solid–Liquid Phase Benzylation to Phenol Derivatives
MW
T, t
onium salt
OH
OBn
Cs2CO3 (1.0 eq.)
+
BnX
solvent
(1.2 eq.)
Y
Y
1
2
Y
X
Solvent
Onium Salt [%]
T [°C]
t [min]
Proportion of Ether 2 [%]
Entry
a
H
Cl
Me
H
Br
Br
Cl
Br
Br
Br
Br
Cl
MeCN
-
100
100
100
100
100
110
110
100
40
40
40
40
40
35
35
40
100,b 2b
100,b 2c
100, 2a
85,c 2b
88,c 2b
84,d 2c
96, 2c
1
2
3
4
5
6
7
8
a
MeCN
-
MeCN
TEBAC (5)
-
-
-
-
-
-
H
TEBAC (5)
-
Cl
Cl
Me
TEBAC (5)
TEBAC (5)
96, 2a
ano effect of 5% TEBAC added.
bisolated yields were ca. 95%.
cthe remaining part comprised C-benzylated phenols and dialkylated derivatives.
dthe reaction mixture contained 8% of unreacted chlorophenol and 8% of benzyl 2-benzyl-4-chlorophenyl ether.
ether (2c) was formed, while in the presence of TEBAC the
proportion was 96% (Table 4/ entries 6 and 7). The reaction
of cresol with benzyl chloride at 100 °C was complete when
5% of catalyst was used (Table 4/entry 8).
presence of an alkali carbonate and an onium salt using a
variety of alkylating agents.
3. EXPERIMENTAL
3.1. General
Finally, the solid-liquid phase alkylation of cresol was
extended to other alkylating agents. The reaction of cresol
with ethyl iodide was selective at 140 °C in the presence of
K2CO3 to give ether 6d, but the conversions were not
complete (Table 5/entries 1 and 2). The replacement of
K2CO3 by Cs2CO3 led, however, to a complete conversion.
There was no need to use a PT catalyst (Table 5/entry 3).
The situation was similar when n-propyl bromide was used
as the alkylating agent (Table 5/entries 4 and 5). The best
result was obtained when Cs2CO3 was the base (Table
5/entry 5). The reaction of cresol with isopropyl bromide at
140 °C in the presence of K2CO3 led to a mixture containing
only 61% of the expected ether (6f), 32% of cresol and 7%
of 4-methyl-2-isopropylphenol (Table 5/entry 6). The use of
TEBAC had not much impact on the outcome, but in this
case an additional by-product, isopropyl 4-methyl-2-
isopropylphenyl ether also appeared in the mixture (Table
5/entry 7). The best result was obtained using Cs2CO3 as the
base. In this case, the O-selectivity was ca. 90% (Table
5/entry 8).
The alkylations were carried out in a CEM Discover
microwave reactor equipped with a pressure controller using
20-30 W irradiation.
GC was carried out on an HP5890 series 2 GC-FID
chromatograph, using a 15 m ꢀ 0.18 mm Restek, Rtx-5
column with a film layer of 0.20 μm. The temperature of the
column was initially held at 40 °C for 1 min, followed by
programming at 25 °C/min. up to 300 °C, and a final period
at 300 °C (isothermal) for 10 min. The temperature of the
injector was 290 °C, and of the FID detector 300 °C. The
carrier gas was H2.
GC-MS was also carried out on an Agilent 6890 N-GC-
5973 N-MSD chromatograph, using a 30 m ꢀ 0.25 mm
Restek, Rtx-5SILMS column with a film layer of 0.25 μm.
The initial temperature of column was 45 °C for 1 min,
followed by programming at 10 °C/min. up to 310 °C and a
final period at 310 °C (isothermal) for 17 min. The
temperature of the injector was 250 °C. The carrier gas was
He and the operation mode was splitless.
It can be seen that during the solventless alkylations
applying alkyl halogenides, the most appropriate is to use
Cs2CO3 without an onium salt.
3.2. General Procedure for Liquid-Liquid Phase
Benzylation of Cresol
In conclusion, choosing the appropriate conditions, the
alkylation of phenol derivatives can be accomplished
selectively under MW irradiation. Carrying out the
benzylations in acetonitrile in the presence of Cs2CO3, the
reactions are O-selective. In the absence of solvent, an O-
selectivity of ca. 90% could be achieved in most cases, in the
4.63 mmol (0.50 g) of cresol, TEBAC [5% (0.23 mmol,
0.053 g), 10% (0.46 mmol, 0.11 g), 15% (0.70 mmol, 0.16
g)] and 5.55 mmol (0.70 ml) of benzyl bromide were
dissolved in 10 ml of toluene and the mixture was stirred at

Heterogeneous Phase Alkylation of Phenols Making Use
Letters in Organic Chemistry, 2009, Vol. 6, No. 7
539
Table 5. MW-Assisted Solid–Liquid Phase Alkylation of Cresol with Different Alkylating Agents
MW
140 °C, 1.5 h
onium salt
OH
OR
M2CO3 (1.0 eq.)
+
RX
no solvent
(1.2 eq.)
Me
Me
1a
6
RX
Base
Onium Salt [%]
Proportion of Ether 6 [%]
Entry
EtI
EtI
K2CO3
K2CO3
Cs2CO3
K2CO3
Cs2CO3
K2CO3
K2CO3
Cs2CO3
-
79,a 6d
87,b 6d
100, 6d
81,d 6e
97, 6e
61,e 6f
64,f 6f
87,g 6f
1
2
3
4
5
6
7
8
TEBAC
c
EtI
-
nPrBr
nPrBr
iPrBr
iPrBr
iPrBr
TEBAC
c
-
-
TEBAC
c
-
athe reaction mixture comprised 21% of unreacted cresol.
bthe reaction mixture comprised 13% of unreacted cresol.
cno effect of 5% of TEBAC added.
dthe reaction mixture comprised 19% of unreacted cresol.
ethe reaction mixture comprised 32% of unreacted cresol and 7% of 4-methyl-2-isopropylphenol.
fthe reaction mixture comprised 26% of unreacted cresol, 3% of 4-methyl-2-isopropylphenol and 7% of isopropyl 4-methyl-2-isopropylphenyl ether.
gthe reaction mixture comprised 9% of unreacted cresol and 4% of 4-methyl-2-isopropylphenol.
60 °C with 30% NaOH solution [(1.5 eq. (6.95 mmol, 0.30 g
of NaOH and 0.70 ml of water) or 3.0 eq. (13.90 mmol, 0.60
g of NaOH and 1.40 ml of water)] for the appropriate time.
The organic phase was separated, washed with sodium
hydrogen carbonate solution and dried (Na2SO4).
Evaporation of the volatile components provided the crude
product which was analysed by GC-MS or GC.
ACKNOWLEDGEMENT
The above project was supported by Gedeon Richter Plc.
and partially by the Hungarian Scientific Research Fund
(OTKA T067679).
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3.3. General Procedure for Solid-Liquid Phase Alkylation
of Phenol Derivatives or Phenol Under Solventless and
MW Conditions
A mixture of 1.0 mmol of phenol derivatives (0.11 g of
cresol, 0.13 g of 4-chlorophenol, 0.15 g of 4-tert-
butylphenol) or 1.0 mmol (0.09 g) of phenol, 0.14 g (1.0
mmol) of K2CO3 or 0.33 g (1.0 mmol) of Cs2CO3, 11.4 mg
(0.05 mmol) of TEBAC or 18.6 mg (0.05 mmol) of TPEPB
and 1.2 mmol of benzyl halide (0.14 ml of benzyl bromide,
0.14 ml of benzyl chloride, 0.10 ml of ethyl iodide, 0.11 ml
of 1-bromopropane or 0.11 ml of 2-bromopropane) in a
closed vial was irradiated in a CEM Discover [300 W]
Microwave Reactor at 20-30 W for the appropriate time. The
reaction mixture was taken up in 25 ml of ethyl acetate and
the suspension was filtered. Evaporation of the volatile
components provided the crude product that was passed
through a thin (ca. 2 cm) layer of silica gel using 3% MeOH
in CH2Cl2 as the eluant to give an oil that was analysed by
GC–MS or GC.
[9]
[10]
[11]
[12]
[13]
[14]
[15]
Similar reactions were carried out in 3 ml of acetonitrile
as the solvent. The work-up was similar to that described for
the solventless alkylations.