O-acylation of substituted phenols with various alkanoyl chlorides under phase-transfer catalyst conditions

Article abstract of DOI:10.1080/00397911.2011.584007

Esterification of several types of mono-and disubstituted phenols with various mono-and dialkanoyl chlorides was performed in phase-transfer catalysis conditions, using tetrabutylammonium chloride in a mixture of aqueous NaOH and dichloromethane. The process is particularly efficient (almost quantitative yields) as well as rapid (only 5 min reaction time, at a temperature of0°C). Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911.2011.584007

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O-Acylation of Substituted Phenols with
Various Alkanoyl Chlorides Under Phase-
Transfer Catalyst Conditions
Alina Marieta Simion a , Iwao Hashimoto b , Yoshiharu Mitoma c ,
Naoyoshi Egashira c & Cristian Simion a
a “Politehnica” University of Bucharest, Department of Organic
Chemistry, Bucharest, Romania
b Department of Material Science, Wakayama National College of
Technology, Goboh City, Wakayama, Japan
c Department of Environmental Sciences, Faculty of Life and
Environmental Sciences, Prefectural University of Hiroshima,
Shobara City, Hiroshima, Japan
Accepted author version posted online: 20 Sep 2011.Version of
record first published: 11 Nov 2011.
To cite this article: Alina Marieta Simion, Iwao Hashimoto, Yoshiharu Mitoma, Naoyoshi Egashira &
Cristian Simion (2012): O-Acylation of Substituted Phenols with Various Alkanoyl Chlorides Under
Phase-Transfer Catalyst Conditions, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 42:6, 921-931
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Synthetic Communications1, 42: 921–931, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.584007
O-ACYLATION OF SUBSTITUTED PHENOLS WITH
VARIOUS ALKANOYL CHLORIDES UNDER
PHASE-TRANSFER CATALYST CONDITIONS
Alina Marieta Simion,1 Iwao Hashimoto,2 Yoshiharu Mitoma,3
Naoyoshi Egashira,3 and Cristian Simion1
1‘‘Politehnica’’ University of Bucharest, Department of Organic Chemistry,
Bucharest, Romania
2Department of Material Science, Wakayama National College of
Technology, Goboh City, Wakayama, Japan
3Department of Environmental Sciences, Faculty of Life and Environmental
Sciences, Prefectural University of Hiroshima, Shobara City, Hiroshima,
Japan
GRAPHICAL ABSTRACT
Abstract Esterification of several types of mono- and disubstituted phenols with various
mono- and dialkanoyl chlorides was performed in phase-transfer catalysis conditions, using
tetrabutylammonium chloride in a mixture of aqueous NaOH and dichloromethane. The
process is particularly efficient (almost quantitative yields) as well as rapid (only 5 min
reaction time, at a temperature of 0 ꢀC).
Keywords Hindered phenols; O-acylation; phase-transfer catalyst; tetrabutylammonium
chloride
INTRODUCTION
The -COOR moiety is a key figure in a large number of organic compounds,
both natural and synthetic.[1] Therefore, it is understandable that the esterification
reaction is one of the most studied and frequently used organic processes, generating
an impressive number of reports each year in a large number of chemical journals.[1,2]
Among the various methods used for obtaining esters, one of the most useful and
Received April 14, 2011.
This paper is dedicated to the memory of Professor Iwao Hashimoto (1942–2011).
Address correspondence to Cristian Simion, ‘‘Politehnica’’ University of Bucharest, Department of
Organic Chemistry, Spl. Independentei 313, 060042 Bucharest, Romania. E-mail: c_simion@chim.upb.ro
921

922
A. M. SIMION ET AL.
versatile transformation is the acylation of alcohols and=or phenols.[2] However,
some major inconveniences are present: either long duration and harsh reaction con-
ditions are necessary for the direct esterification, or essentially anhydrous conditions
when using anhydrides or acyl chlorides instead of the carboxylic acid. A notable
exception is the well-known Schotten–Baumann procedure,[3] a reaction that implies
acylation of a phenol using an acyl chloride and can be carried out in anhydrous
organic solvents as well as in aqueous media.[4] Several variations of the method were
proposed to accommodate the sensitivity of acyl chlorides toward aqueous con-
ditions. The 1980s–1990s recorded a first volley of reports dealing with esterification
processes under phase-transfer catalyst (PTC) methods,[5] which tend to be replaced
nowadays with several types of procedures in solvent-free conditions.[6] A major
requirement of these numerous solvent-free methodologies is the use of anhydrides
and, quite often, sophisticated and sensitive catalysts. However, we noticed in the
past few years a return of interest in practical and useful O-acylation method using
a PTC in studies of the kinetics of phenol benzoylation.[7] Starting from Direktor
and Effenberger’s procedure,[5e,h] we developed our own protocol for the O-acylation
of phenols,[8] with main advantages versus previously PTC esterification process of
the use of equimolecular amounts of phenol and acyl chloride (instead of an excess
of phenol), the use of sodium hydroxide (instead of NaHCO3, avoiding thus the risk
of effervescence), dichloromethane (instead of the more viscous chlorobenzene), less
toxic tetrabutylammonium chloride (instead of tetrabutylammonium bromide), low
temperatures (0 ꢀC), extremely short reaction time (only 5 min), and kinetical evalu-
ation of the scope and limitations of this process.[8c] We report the extent of our study
to various substituted phenols in the O-acylation reaction under PTC conditions
with different acyl chlorides.
RESULTS AND DISCUSSION
Our aim was to study the effect of the reagents (substituted phenols 1 and acyl
chloride 2) on the O-acylation process (Scheme 1).
A series of experiments was conducted using different acyl chlorides in reaction
with equimolecular amounts of phenol 1a at 0 ꢀC for 5 min. The results are presented
in Table 1.
All acylation processes afforded, after a simple separation procedure, the cor-
responding phenyl esters in excellent yields, even for greater acyl chlorides. The
obtained results (e.g., formation of phenyl benzoate—entry 9, Table 1) are superior,
in respect to yield and reaction time, to those previously reported for different PTC
reactions.[5k,m]
The second step of our research was to switch the phenol 1 in the O-acetylation
process with acetyl chloride, under PTC conditions, at 0 ꢀC for 5 min. Table 2
summarizes these results.
Scheme 1. O-Acylation of p-phenols with various alkanoyl chlorides under PTC conditions.

PHENOLIC ESTER FORMATION
923
Table 1. O-Acylation of phenol 1a with various acyl chlorides under PTC conditions, at 0 ꢀC for 5 min
Acyl chloride
CH3-
Reaction product
Yield (%)
Entry
Cpd
R-
Cpd
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
3a
3b
3c
3d
3e
3f
92
88
CH3CH2-
CH3CH2CH2-
CH3(CH2)2CH2-
(CH3)2CH-
89
84
96
(CH3)2CHCH2-
(CH3)3C-
100
75
2g
2h
2i
3g
3h
3i
cyclo-C6H11
C6H5-
-
89
100
O-Acetylation of p-substituted phenols gave the corresponding esters in fair to
good yields. It is interesting to note that for hydrocarbon substituents, as the chain
becomes longer, the yields decrease. However, substrates bearing branched substitu-
ents presented better results (entries 6 and 7, Table 2). At the same time, for heteroa-
tom substituents, yields are greater for an electron-withdrawing substituent than for
a donor one. At this point, we should also mention that compounds 3s and 3q could
not be obtained by classical Schotten–Baumann procedures. Moreover, when a small
substituent like the methyl group was shifted from para- position to meta- and
ortho-, the yields of the esterification reaction product dropped, showing that steric
hindrance plays a certain role in the process. We decided to see if the O-acylation of
specially hindered substrates such as 2,6-disubstituted phenols 4 can occur using our
reaction protocol. The obtained results are presented in Table 3.
With the exception of entry 7, when steric hindrance in both 2,6-disubstituted
phenol and acyl chloride proved to be decisive in preventing the transformation, O-
acylation with phenols bearing bulky groups is effective in only 5 min of stirring, at
0 ꢀC. For comparison, the classical Schotten–Baumann reaction carried out
Table 2. O-Acetylation of p-substituted phenols under PTC conditions, at 0 ꢀC for 5 min
p-Substituted phenol
Reaction product
Yield (%)
Entry
Cpd
X-
Cpd
1
2
1a
1b
1c
1d
1e
1f
H
CH3-
3j
3k
3l
92
95
70
63
62
91
80
51
63
71
59
76
3
CH3CH2-
CH3CH2CH2-
CH3CH2(CH3)CH-
4
3m
3n
3o
3p
3q
3r
5
6
(CH3)2CH-
(CH3)3C-
CH3O-
Cl-
7
1g
1h
1i
8
9
10
11
12
1j
NO2-
o-CH3-
m-CH3-
3s
1k
1l
3t
3u

924
A. M. SIMION ET AL.
Table 3. O-Acylation of 2,6-disubstituted phenols with various alkanoyl chlorides under PTC conditions,
at 0 ꢀC for 5 min
2,6-Disubstituted phenol
Acyl chloride
Cpd R-
CH3-
Reaction product
Cpd Yield (%)
Entry
Cpd
2,6-Substituent
1
2
4a
4a
4a
4b
4c
4b
4c
4d
4e
4f
CH3-
CH3-
CH3-
2a
2g
2i
5a
5b
5c
5d
5e
5f
97
94
86
80
78
64
0
(CH3)3C-
C6H5-
CH3-
3
4
(CH3)2CH-
(CH3)3C-
(CH3)2CH-
(CH3)3C-
Cl-
2a
2a
2g
2g
2a
2a
2a
5
CH3-
6
(CH3)3C-
(CH3)3C-
CH3-
7
5g
5h
5i
8
54
75
45
9
10
Br-
CH3O-
CH3-
CH3-
5j
simultaneously with our experiments for reactants in entries 4 and 5 showed no
occurrence of any reaction product. It is interesting to note that Mukayama and
coworkers obtained 2,6-dimethylphenyl 4-methoxybenzoate from the corresponding
dimethylphenol, via phenoxydiphenylphosphines formed in situ from various
n-BuLi-treated phenols and chlorodiphenylphosphine in only 23% yield, when the
reaction was carried out for 6.0 h at 110 ꢀC, and in 76% yield when the reaction
was carried out for 2 h at 160 ꢀC using a solvent such as p-xylene.[9] It is noteworthy
that acid-catalyzed esterification of 2,6-disubstituted phenols is a process difficult to
achieve, irrespective of the nature of the substituents,[10] and on more than one
occasion a ring C-acylation product has been detected. However, some successes
were recorded when using a polymer-supported PTC in solid–liquid PTC condit-
ions[5e,h] or on when acetic anhydride was used as acylating reagent, either on
2,6-dimethylphenol in the presence of copper perchlorate[6n] or ruthenium chloride
(after a 3-h treatment),[11] or on 2,6-di-tbutyl-4-methylphenol in the presence of scan-
dium triflate.[12] In the case of phenols substituted with heteroatoms, the yields we
obtained after only 5 min are fair. However, better yields were achieved for
2,6-dichlorophenyl acetate, but working with acetic anhydride, in the presence of
o-benzenedisulfonimide, for much longer reaction time: ꢁ4 h.[13] Without any cata-
lyst, 2,6-dimethoxyphenyl acetate was obtained in comparative yields after an even
longer treatment: 24 h treatment at room temperature.[14]
Our system, which is much simpler because it is a liquid–liquid PTC reaction sys-
tem, permitted the formation of only the O-acylation reaction product, remarkably
free of other side-reaction products. Moreover, in our process, esterification of bulky
phenols is completed in only 5 min instead of hours for other O-acylation processes.
Over the years, PTC gained its lettre de noblesse by overriding the difficulties of
some classical chemical processes and permitting a large number of industrial appli-
cations.[15] One such potential application is the bis-esterification of dialkanoyl
chlorides, aiming to synthesize oligomers and polymers with a predetermined num-
ber of units (such a practical application of polyesterification has been already
tested[16]). We studied such a reaction between several dialkanoyl chlorides and
phenol in PTC conditions at 0 ꢀC and 5 min reaction time (Table 4).

PHENOLIC ESTER FORMATION
925
Table 4. O-Acylation of phenol 1a with various dicarboxylic acyl chlorides
under PTC conditions, at 0 ꢀC for 5 min
Acyl dichlorides ClCO-(CH2)n-COCl
Reaction product
Entry
Cpd
n
Cpd
Yield (%)
1
2
3
6a
6b
6c
2
3
4
7a
7b
7c
95
100
96
Straightforward isolation of pure reaction products is the main characteristic
of this process. As a comparison, we performed a classic esterification, which
afforded the corresponding diesters in 53%, 77%, and 71% yields.
Although optimum conditions for this PTC process have been established
in our previous papers,[8] some considerations have to be made to outline the
differences and advantages of our procedure over the existing ones.[5]
We targeted a simpler and shorter approach to the PTC process (most of the
previous investigations[5] reported reaction times of several hours). We soon noticed
the importance of NaOH concentration as well as of the speed of stirring. Our fin-
dings[8c] were later confirmed by the study of Yang and Huang[7] and by the present
research. Thus, a violent shaking of the biphasic system will increase the surface of
the interphase area, allowing a higher rate of mass transfer of the carrier PTC. On
the other hand, a greater NaOH concentration than the 10% we used proved to
be damaging for the process, because the hydroxide anion could compete with the
phenoxide anion for the tetrabutylammonium cation. Nevertheless, compared with
previous investigations,[5e,h,m] we used an excess of NaOH (0.015 mmol phenol–
0.05 mmol NaOH, instead of equimolecular amounts), which favors the complete
transformation of phenol in phenoxide in the aqueous phase.
Another advantage of our method is the use of dichloromethane instead of
dichlorobenzene.[5e,h] Although there is a difference in polarity between the two
chlorinated solvents, the mass transfer will be favored in the case of CH2Cl2 by
the viscosity of the solvent: Dichloromethane is less viscous, thus allowing better
passage through the interphase of the tetrabutylammonium chloride or tetrabuty-
lammonium phenoxide, respectively. Yang and Huang obtained similar results when
comparing the effectiveness of dichloromethane, dichlorobenzene, heptane, and
hexane,[7a] and before them, Lee, Yeh, and Shih reported a similar pattern when
comparing dichloromethane with dichlorobenzene, benzene, and toluene.[5m]
The nature of the PTC catalyst is important: tetrabutylammonium chloride
confirmed our expectations to be more suitable for this type of process than the pre-
viously used tetrabutylammonium bromide. Indeed, for the benzoylation of phenol
with tetrabutylammonium chloride, in our reaction conditions we obtained a quan-
titative transformation (Table 1, entry 9) in only 5 min at 0 ꢀC, while in an extensive
study of the same process, Yang and Huang obtained only 67.4% after 1 h of treat-
ment with tetrabutylammonium bromide at 35 ꢀC.[7a] For their part, Lee, Yeh, and
Shih reported 96% conversion for the same benzoylation process, after 2.5 h at 17 ꢀC,
using the same tetrabutylammonium bromide.[5m] However, we worked with a 10:1

926
A. M. SIMION ET AL.
ratio of phenol–PTC, while the previously mentioned authors used a 20:1 ratio.
Increased content of PTC in the reaction mixture was confirmed to improve the yield
of phenyl benzoate,[7a] as well as of all O-acylation products.[8] Moreover, the
process can be successfully applied to other derivatives, such as the thioesters.[17]
Last but not least, an undoubtful advantage of this method over the
‘‘free-solvent’’ ones is the use of acyl chlorides instead of anhydrides, because only
1 equivalent of carboxylic acid is needed instead of 2 (one of them being completely
lost in the process using anhydrides).
CONCLUSION
The PTC process for O-acylation of substituted phenols in the presence of 10%
tetrabutylammonium chloride in a mixture of 10% aqueous NaOH and dichloro-
methane is rapid and extremely effective, superior to the previously described meth-
ods and unrivalled by other classic methods of esterification. Indeed, for a large
number of mono- and disubstituted phenols, the reaction with mono- and dialkanoyl
chlorides was almost quantitative at 0 ꢀC after only 5 min.
EXPERIMENTAL
In all reactions, commercially available substituted phenols and alkanoyl chlor-
ides were used after a prior purification step (generally, distillation or recrystalliza-
tion). Analytical gas–liquid chromatograms (GLC) were carried out on a
Yanagimoto G-180 F fitted with a FS-WCOT column (0.25 mm i.d., length 25 m)
coated silicon OV-1701 or Yanagimoto G-80 packed column gas-chromatograph
(Apiezon grease L, 10%, 1.5 m or silicone SE-30, 10%, 1 m). All reaction products
were identified by comparison with GLC retention times of authentic samples, pre-
viously obtained through classic Schotten–Baumann or other suitable esterification
procedures.
In a typical procedure, substituted phenol (15 mmol) was dissolved in 20 ml of
10% aqueous sodium hydroxide (50 mmol NAOH) solution in a 100-ml flask. Solu-
tions of tetra-n-butylammonium chloride (1.5 mmol) in 5 mL of dichloromethane
and acyl chloride (15 mmol) in 15 mL of dichloromethane were prepared. After cool-
ing all solutions at 0 ꢀC, they were mixed at once. The reaction mixture was kept
under vigorous magnetic stirring (400 rpm) at 0 ꢀC for 5 min and then poured over
50 mL of icy water. The organic layer was separated and the aqueous layer was
extracted twice with 40 mL of diethyl ether. The combined organic extracts were
washed with saturated NaCl solution. After drying on Na2SO4, the solvent was eva-
porated, and the residue was analyzed directly by gas chromatrography (GC), liquid
chromatography (LC) and=or GC–mass spectrometry (MS). Quantitative determi-
nations were carried out using the internal standard method. The product structures
were also identified by infrared (IR), NMR spectra, and GC-mass analysis.
All NMR spectra were recorded on a Jeol JNM-LA 300, 300 MHz, for samples
in CDCl3 with Me4Si as internal standard. Coupling constants (J values) are given in
hertz (Hz). Identification of esters was made by GC (Shimadzu GC-17A GC instru-
ment, carrier gas N2, pressure 135 kgf=cm2, flow 55 mL=min on a J&W Scientific
DB-1 fused silica capillary column, length 30 m, i.d. 0.32 mm with film thickness

PHENOLIC ESTER FORMATION
927
of 0.25 mm) and GC-MS (Hewlett-Packard HP6890 GC, carrier gas He, flow
1.5 mL=min, velocity 48 cm=s and pressure 10.3 psi, J&W Scientific DB-1 fused silica
capillary column and Jeol Automass system II MS). Mass spectra and
high-resolution mass spectra (HRMS) were recorded on a Jeol JMS-700 T, with
45 eV ionization energy and 600 mA current.
A certain number of esters are already known and have been previously
described in the literature. Thus, the following compounds have been identified by
comparison of their spectral data: phenyl acetate, 3a,[6a] phenyl propionate, 3b,[18]
phenyl butyrate, 3c,[19] phenyl pentanoate, 3d,[9] phenyl isobutyrate (phenyl
2-methylpropanoate), 3e,[20] phenyl isopentanoate (phenyl 3-methylbutyrate), 3f,[20]
phenyl pivalate (phenyl 2,2-dimethylpropanoate), 3 g,[20,21] phenyl cyclo-hexanecar-
boxylate, 3 h,[22] phenyl benzoate, 3i,[23] p-tolyl acetate (4-methylphenyl acetate, p-
cresyl acetate), 3j,[24] p-tertbutylphenyl acetate, 3o,[25] p-methoxyphenyl acetate,
3p,[6a,26] p-chlorophenyl acetate, 3q,[24] p-nitrophenyl acetate, 3r,[27] o-tolyl acetate
(2-methylphenyl acetate, o-cresyl acetate), 3 s,[28] m-tolyl acetate (3-methylphenyl
acetate, m-cresyl acetate), 3 t,[29] 2,6-dimethylphenyl acetate, 5a,[13] 2,6-dichlorophe-
nyl acetate, 5 h,[30] 2,6-dimethoxyphenyl acetate, 5j,[31] diphenyl succinate, 7a,[32,33]
diphenyl glutarate, 7b,[33] diphenyl adipate, 7c.[33]
All other compounds presented in their IR spectra a characteristic absorbtion
of the ester moiety around 1750 cmÀ1 and were fully described by their 1H NMR and
MS spectra.
Selected Data
p-Ethylphenyl acetate, 3l. 1H NMR (d, J, Hz, CDCl3): 1.21 (t, 3H), 2.23 (s,
3H), 2.61 (q, 2H), 6.97 (d, 2H), 7.16 (d, 2H); MS (m=z): 164 (MP), 122, 107 (BP), 77,
43.
p-sec-Butylphenyl acetate, 3n. 1H NMR (d, J, Hz, CDCl3): 0.81 (t, 3H),
1.21 (d, 3H), (dt, 2H), 2.24 (s, 3H), 2.58 (m, 1H), 6.99 (d, 2H), 7.16 (d, 2H); MS
(m=z): 192 (MP), 150, 121 (BP), 91, 77, 43.
p-Isopropylphenyl acetate, 3o. 1H NMR (d, J, Hz, CDCl3): 1.22 (d, 6H),
2.23 (s, 3H), 2.88 (q, 1H), 6.98 (d, 2H), 7.20 (d, 2H); MS (m=z): 178 (MP), 136,
121 (BP), 91, 43.
2,6-Dimethylphenyl pivalate, 5b. 1H NMR (d, J, Hz, CDCl3): 1.40 (s, 9H),
2.12 (s, 6H), 7.03 (m, 3H); MS (m=z): 206 (MP), 153, 136, 122 (BP), 107, 84, 77.
2,6-Dimethylphenyl benzoate, 5c. 1H NMR (d, J, Hz, CDCl3): 2.19 (s, 6H),
7.09 (m, 3H), 7.52 (m, 2H), 7.65 (m, 1H), 8.23 (m, 2H); MS (m=z): 226 (MP), 153,
136, 121, 105 (BP), 81, 77.
2,6-Diisopropylphenyl acetate, 5d. 1H NMR (d, J, Hz, CDCl3): 1.21 (d,
13.4, 12H), 2.35 (s, 3H), 2.91 (hp, 13.4, 2H), 6.96 (m, 1H), 7.25 (m, 2H); MS
(m=z): 220 (MP), 178, 163 (BP), 91.
2,6-Ditertbutylphenyl acetate, 5e. 1H NMR (d, J, Hz, CDCl3): 1.34 (s,
18H), 2.33 (s, 3H), 7.14 (m, 1H), 7.32 (m, 2H); MS (m=z): 248 (MP), 205, 191
(BP), 163, 131, 115, 91, 77, 57.

928
A. M. SIMION ET AL.
2,6-Diisopropylphenyl pivalate, 5g. 1H NMR (d, J, Hz, CDCl3): 1.19 (d,
6.9, 12H), 1.41 (s, 9H), 2.88 (hp, 6.9, 2H), 7,16 (m, 3H); MS (m=z): 262 (MP),
178, 163, 85, 57 (BP).
2,6-Dichlorophenyl acetate, 5h. 1H NMR (d, J, Hz, CDCl3): 2.39 (s, 3H),
7.13 (m, 1H), 7.34 (m, 2H); MS (m=z): 204=06=08 (MP), 162=64=66 (BP), 126=28, 84.
2,6-Dibromophenyl acetate, 5i. 1H NMR (d, J, Hz, CDCl3): 2.37 (s, 3H),
7.03 (m, 1H), 7.26 (m, 2H); MS (m=z): 292=94=96 (MP), 250=52=54, 170=72, 91,
63, 47.
2,6-Dimethoxyphenyl acetate, 5j. 1H NMR (d, J, Hz, CDCl3): 2.34 (s, 3H),
3.81 (s, 6H), 6.61 (d, 2H), 7.12 (t, 1H); MS (m=z): 196 (MP), 154 (BP), 139, 107, 89,
77.
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