Trifluoromethanesulfonic acid catalyzed novel friedel-crafts acylation of aromatics with methyl benzoate

Article abstract of DOI:10.1016/S0040-4020(00)00633-5

Methyl benzoate, protolytically activated by superacidic trifluoromethanesulfonic acid, reacts with aromatic compounds to give benzophenone derivatives in good to excellent yields (70-93%). Even highly deactivated nitrobenzene as well as benzotrifluoride

Full text of DOI:10.1016/S0040-4020(00)00633-5

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 7199–7203
Trifluoromethanesulfonic Acid Catalyzed Novel Friedel–Crafts
Acylation of Aromatics with Methyl Benzoate1
†
*
*
Je Pil Hwang, G. K. Surya Prakash and George A. Olah
Donald P. and Katherine B. Loker Hydrocarbon Research Institute and Department of Chemistry, University of Southern California,
Los Angeles, CA 90089-1661, USA
Dedicated to Professor Rolf Huisgen on the occasion of his 80th birthday
Received 22 June 2000; accepted 17 July 2000
Abstract—Methyl benzoate, protolytically activated by superacidic trifluoromethanesulfonic acid, reacts with aromatic compounds to give
benzophenone derivatives in good to excellent yields (70–93%). Even highly deactivated nitrobenzene as well as benzotrifluoride underwent
smooth benzoylation under the reaction conditions to respective meta-substituted benzophenones. ᭧ 2000 Elsevier Science Ltd. All rights
reserved.
Introduction
resulting mixture was heated to 85ЊC (see Table 1 for
reaction time). Two and a half molar amount of trifluoro-
methanesulfonic acid compared to methylbenzoate was
necessary to achieve suitable reaction which involves super-
electrophilic activation. A number of substituted aromatics
including benzene gave the respective benzophenones as
major isolable products (Eq. (1)). In no case was there
further electrophilic reaction of benzophenones with the
aromatics observed. The yield of benzophenones obtained
ranged from 70 to 93%. Even highly deactivated nitro-
benzene and benzotrifluoride showed good reactivity and
gave the corresponding meta-substituted benzophenones in
high yield. The results are summarized in Table 1.
Friedel–Crafts reactions2 are widely used in organic synthe-
sis for carbon–carbon bond formation. Friedel–Crafts
acylation is a very important method for the preparation
of aromatic ketones. Aromatic ketones have been prepared
by the reaction of carboxylic acids with aromatic hydro-
carbons catalyzed by a wide variety of catalysts (generally
used in excess of molar amounts) such as methanesulfonic
acid,3 zeolite,4 palladium catalyst,5 trimethylsilyl poly-
phosphate,6 Nafion-H7 and SiCl4–Silver salts.8 Aromatic
acylations have also been achieved with carboxylic acid
anhydrides and acid chlorides with various active Lewis
acid catalysts (with more than one molar equivalent
basis).9 Recently, we have focused our attention on super-
electrophilic activation of electrophiles using frequently
trifluoromethanesulfonic acid as the superacid.10,11 We
wish to report now that methyl benzoate is activated in
trifluoromethanesulfonic acid to a highly reactive benzoyl-
ating reagent that reacts with aromatic compounds to give
benzophenone derivatives in good to excellent yields.
Although the Friedel–Crafts preparation of benzophenone
derivatives is well known,12,13 direct acylation of aromatic
compounds using benzoic acid esters was not well explored.
ꢀ1†
A possible mechanism of acylation involving activated
dicationic intermediates such as VII or VIII are shown in
Scheme 1. It is also possible that diprotonated ester inter-
mediates V or VI may also directly react with the aromatic
substrate to give the product. Possible formation of such
activated intermediates in strong acids have been earlier
explored.11,14–16 Benzoic acid itself does not react with
benzene under similar reaction conditions. After three
days of reflux, only a trace of benzophenone (2a) was
obtained indicating that a carboxylic acid is much less
reactive than its methyl ester under the reaction conditions.
Results and Discussion
Methyl benzoate and the corresponding aromatic compound
were mixed with trifluormethanesulfonic acid and the
Keywords: methyl benzoate; benzoylation; trifluoromethanesulfonic acid;
benzo-phenones; superelectrophilic activation.
* Corresponding authors. Tel.: ϩ1-213-740-5976; fax: ϩ1-213-740-5087;
e-mail: olah@methyl.usc.edu
†
Post-doctoral fellow.
0040–4020/00/$ - see front matter ᭧ 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00633-5

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J. P. Hwang et al. / Tetrahedron 56 (2000) 7199–7203
Table 1. Acylation of artomatics with methyl benzonate using trifluoromethanesulfonic acid
a
Isolated yields.
Aliphatic esters, under the reaction conditions, are less reac-
tive than benzoic acid esters. For example, methyl phenyl
acetate (4) reacted with benzene only under prolonged
reflux for three days in the presence of trifluoromethane-
sulfonic acid to give deoxybenzoin (5) as the major product
(Eq. (2)) in 54% yield. Ethyl acetate with benzene under
similar reaction conditions gave exclusively ethylated
products (Eq. (3)). Ethyl trifluoroacetate, on the other
hand, gave besides ethylated products also acylation
products that underwent further arylation to give 10
(Eq. (4)).
ꢀ2†
ꢀ3†
ꢀ4†

J. P. Hwang et al. / Tetrahedron 56 (2000) 7199–7203
7201
Scheme 1.
ꢀ5†
Diesters such as 1,4-dimethyl terephthalate (11)
under similar reaction conditions with benzene (reflux
for 8 h) gave a mixture of 4-benzoyl methyl benzoate
(12) and 1,4-dibenzoyl benzene (13) as major products
(Eq. (5)). In the case of 1,2-diethyl phthalate (14),
however, phthalic anhydride (15) was the major
product along with some 1,2-dibenzoyl benzene (16)
(Eq. (6)).
In summary, we have shown that methylbenzoate can be
activated in trifluormethanesulfonic acid to a superelectro-
philic benzoylating agent that reacts with both activated and
ꢀ6†

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J. P. Hwang et al. / Tetrahedron 56 (2000) 7199–7203
1
deactivated aromatics to give their respective benzo-
phenones in preparatively useful yields.
p-Fluorobenzophenone (2c). 85%; Mp 48ЊC; H NMR: d
7.85–7.80 (m, 3H), 7.76 (s, 2H), 7.74–7.73 (t, 1H, Jˆ7 Hz),
7.48–7.44 (t, 2H, Jˆ7 Hz), 7.16–7.10 (t, 2H, Jˆ9 Hz); 13C
NMR: d 195.26 (CO), 167.04, 163.67, 137.47, 132.71,
132.59, 132.45, 129.86, 128.34, 115.58, 115.29; MS (%)
200 (M, 100), 181 (0.7), 170 (10), 123 (61), 105 (33), 95
(47), 77 (39), m/e calcd for C13H10OF (M) 200.22, found
200.05.
Experimental
General
Methyl benzoate, benzene, fluorobenzene and trifluoro-
toluene were obtained from Aldrich Chemical Co. and
used as received. Chlorobenzene, toluene, anisole, nitro-
benzene and o-xylene were obtained from Fluka and
Mallinckrodt Chemical Co. and were also used without
further purification. Trifluoromethanesulfonic acid was
obtained from 3M Co. and distilled under a dry nitrogen
atmosphere before use (bp:162ЊC). Column chromato-
graphy was carried out on silica gel, Merck grade 60
(230–400 mesh). Melting points were determined on a
Mel-Temp II (Laboratory devices) apparatus with a micro-
p-Methylbenzophenone (2d). 70%; Mp 57ЊC; 1H NMR: d
7.79–7.76 (d, 2H, Jˆ7 Hz), 7.73–7.70 (d, 2H, Jˆ8 Hz),
7.59–7.54 (t, 1H, Jˆ6 Hz), 7.48–7.43 (t, 2H, Jˆ7 Hz),
7.29–7.26 (d, 2H, Jˆ8 Hz), 2.42 (s, 3H); 13C NMR: d
196.35 (CO), 134.14, 137.86, 134.79, 132.08, 130.22,
129.85, 128.90, 128.13, 21.63 (Me); MS (%) 196 (M, 63),
181 (12), 119 (100), 105 (27), 77 (23), m/e calcd for
C14H12O (M) 196.25, found 196.00.
1
p-Methoxybenzophenone (2e). 93%; Mp 62ЊC; H NMR:
1
scope attachment. H, 13C NMR spectra were measured in
d 7.82–7.79 (d, 2H, Jˆ9 Hz), 7.74–7.71 (d, 2H, Jˆ8 Hz),
7.60–7.53 (t, 1H, Jˆ7 Hz), 7.46–7.41(t, 2H, Jˆ7 Hz),
6.95–6.92 (d, 2H, Jˆ9 Hz), 3.87 (s, 3H); 13C NMR: d
197.17 (CO), 163.18, 138.24, 132.55, 131.86, 130.10,
129.70, 128.16, 113.52, 55.48 (OMe); MS (%) 212 (M,
20), 181 (7), 135 (100), 105 (11), 92 (25), 77 (55), m/e
calcd for C14H12O2 (M) 212.25, found 212.05.
CDCl3 solutions on a Varian Unity-300 spectrometer and
the chemical shifts are referenced to TMS. MS spectra were
taken on a HP 5890 GC-HP 5971 mass spectrometer system.
Exact mass measurements were made at the UC Riverside
Mass Spectroscopic facilities. Caution: Trifluoromethane-
sulfonic acid is a corrosive and hygroscopic liquid that
should be handled under a dry atmosphere.
3,4-Dimethylbenzophenone (2f). 76%; Mp 46ЊC; 1H
NMR: d 7.80–7.75 (d, 2H, Jˆ7 Hz), 7.60 (s, 1H), 7.56–
7.49 (q, 2H, Jˆ7 Hz), 7.48–7.40 (t, 2H, Jˆ8 Hz), 7.22–7.18
(t, 2H, Jˆ7 Hz), 2.33 (s, 3H), 2.30 (s, 3H); 13C NMR: d
196.54 (CO), 141.87, 137.98, 136.64, 135.21, 131.99,
131.09, 129.84, 129.35, 128.09, 127.95, 19.98 (Me), 19.73
(Me); MS (%) 210 (M, 97), 195 (31), 165 (16), 133 (100),
105 (33), 95 (47), 77 (71), m/e calcd for C15H14O (M)
210.29, found 210.15.
Preparation of benzophenone (2a) from methyl benzoate
and benzene under trifluormethanesulfonic acid
catalysis (typical procedure)
Trifluromethanesulfonic acid (5.0 mmol; 750 mg) was
added slowly to a solution of methyl benzoate (2.0 mmol;
272 mg) in dry benzene (5 mL) at room temperature under a
dry nitrogen atmosphere. The heterogeneous solution was
stirred vigorously for 8 h under reflux, gradually the reac-
tion mixture turned deep brown in color. Progress of the
reaction was monitored by thin layer chromatography
(silica) using hexane/ethyl acetate (20:1) as eluent. After
the completion of the reaction, the reaction mixture was
neutralized with ice-water (20 mL) containing saturated
NaHCO3 solution and extracted carefully with 3×25 mL
of ethyl acetate. The organic layer was separated, washed
with brine solution, dried over anhydrous MgSO4, and
concentrated under reduced pressure. After removal of the
organics a low melting solid remained. The solid was further
purified by column chromatography (hexane/ethyl acetate,
20:1) to obtain 254.8 mg of benzophenone (75% yield) as a
white solid.
1
m-Nitrobenzophenone (2g). 82%; Mp 93ЊC; H NMR: d
8.61–8.60 (s, 1H), 8.45–8.44 (d, 1H, Jˆ8 Hz), 8.14–8.11
(d, 1H, Jˆ7 Hz), 7.80–7.77 (d, 2H, Jˆ7 Hz), 7.72–7.62 (m,
2H), 7.54–7.49 (t, 2H, Jˆ7 Hz), 7.16 (s, 1H); 13C NMR: d
199.72 (CO), 139.02, 136.21, 135.44, 133.36, 130.00,
129.63, 128.72, 126.72, 124.70; MS (%) 227 (M, 30), 150
(12), 105 (100), 77 (40), m/e calcd for C13H9NO3 (M)
227.23, found 227.10.
m-Trifluoromethylbenzophenone (2h). 84%; Mp 53ЊC; 1H
NMR: d 8.12–8.10 (d, 1H, Jˆ7 Hz), 7.63–7.58 (t, 2H,
Jˆ8 Hz), 7.49–7.44 (t, 2H, Jˆ7 Hz), 7.16 (s, 1H); 13C
NMR: d 195.14 (CO), 138.24, 136.71, 133.11, 132.99,
131.60, 131.17, 130.73, 130.30, 130.00, 129.08, 128.93,
128.83, 128.79, 128.54, 126.66, 125.49, 121.88, 118.27;
MS (%) 250 (M, 98), 231 (15), 173 (43), 145 (41), 105
(100), 77 (37), m/e calcd for C14H12O2 (M) 250.23, found
249.90.
Benzophenone (2a). 75%; Mp 49ЊC; 1H NMR: d 7.77–7.74
(d, 4H, Jˆ7 Hz), 7.55–7.50 (t, 2H, Jˆ7 Hz), 7.45–7.40 (t,
2H, Jˆ7 Hz); 13C NMR: d 196.61 (CO), 137.49, 132.33,
128.19; MS (%) 182 (M, 58), 105 (100), 77 (57), m/e calcd
for C13H10O (M) 182.22, found 182.00.
1
Deoxybenzoin (5). 53%; Mp 55ЊC; H NMR: d 8.14–8.10
p-Chlorobenzophenone (2b). 78%; Mp 75ЊC; 1H NMR: d
7.77–7.71 (m, 4H), 7.64–7.57 (t, 1H, Jˆ7 Hz), 7.53–7.44
(q, 5H, Jˆ6.8 Hz); 13C NMR: d 195.18 (CO), 135.76,
134.10, 132.73, 129.53, 128.34, 126.89, 125.51, 125.28;
MS (%) 216 (M, 100), 181 (23), 139 (74), 105 (64), 77
(74), m/e calcd for C13H10OCl (M) 216.68, found 216.00.
(d, 1H, Jˆ7 Hz), 8.04–7.95 (d, 3H, Jˆ7 Hz), 7.64–7.41 (m,
1H), 7.36–7.22 (m, 4H), 4.24 (s, 2H); 13C NMR: d 196.49
(CO), 136.51 134.47, 133.70, 133.13, 130.14, 129.72,
129.41, 128.62, 128.56, 128.45, 126.84, 45.46 (–CH2–);
MS (%) 196 (M, 2), 105 (100), 91 (7), 77 (36), m/e calcd
for C14H12O (M) 196.25, found 196.10.

J. P. Hwang et al. / Tetrahedron 56 (2000) 7199–7203
7203
1
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Phthalic anhydride (15). 40%; Mp 132ЊC; H NMR: d
8.04–7.96 (m, 4H), 7.76–7.71 (m, 1H), 7.56–7.53 (m,
1H); 13C NMR: d 168.58 (–CO–O), 163.20 (–CO–O),
136.52, 131.18, 129.21, 125.78; MS (%) 148 (M, 16), 104
(100), 76 (73), m/e calcd for C8H4O3 (M) 148.12, found
147.95.
Acknowledgements
Support of this work by the National Science Foundation
and Korea Science and Engineering Foundation is gratefully
acknowledged.
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