Perfluoroalkanesulfonic acid catalyzed acylations of alkylbenzenes: Synthesis of alkylanthraquinones

Article abstract of DOI:10.1055/s-2000-7102

The acylation of alkylbenzenes 1 with benzoyl chloride 2 and catalytic amounts of perfluorobutanesulfonic acid affords the corresponding 2-, 3-, and 4-alkylbenzophenones 3 with unusually high amounts of ortho products. Surprisingly, even tert-butylbenzene reacts under these reaction conditions without any acid catalyzed dealkylation. The yield of benzoylation of p-xylene 4 with benzoic acid in the presence of 5 mol% C₄F₉SO₃H to give 2,5-dimethylbenzophenone 5 could significantly be improved from 14% to 90% by continuous removal of water formed during the acylation. Also in the preparation of alkylanthraquinones 7 by reaction of alkylbenzenes with phthalic anhydride, water removal is the decisive factor to obtain satisfactory yields for the second acylation, allowing to cyclize 6 with catalytic amounts (10 mol%) of CF₃SO₃H in organic solvents to the corresponding alkylanthraquinones 7.

Full text of DOI:10.1055/s-2000-7102

PAPER
1427
Perfluoroalkanesulfonic Acid Catalyzed Acylations of Alkylbenzenes:
Synthesis of Alkylanthraquinones1
2
a
2b
2c
Franz Effenberger,* Frank Buckel, Andreas H. Maier, Judith Schmider
Institut für Organische Chemie, Universität Stuttgart, Pfaffenwaldring 55, D-70569 Stuttgart, Germany
Fax +49(711)6854269; E-mail: franz.effenberger@po.uni-stuttgart.de
Received 11 May 2000
5
ously described should be extended to the alkylbenzenes
Abstract: The acylation of alkylbenzenes 1 with benzoyl chloride
and catalytic amounts of perfluorobutanesulfonic acid affords the
1
b-d (Scheme 1).
2
corresponding 2-, 3-, and 4-alkylbenzophenones 3 with unusually
high amounts of ortho products. Surprisingly, even tert-butylben-
zene reacts under these reaction conditions without any acid cata-
lyzed dealkylation. The yield of benzoylation of p-xylene 4 with
benzoic acid in the presence of 5 mol% C F SO H to give 2,5-di-
4
9
3
methylbenzophenone 5 could significantly be improved from 14%
to 90% by continuous removal of water formed during the acyla-
tion. Also in the preparation of alkylanthraquinones 7 by reaction of
alkylbenzenes with phthalic anhydride, water removal is the deci-
sive factor to obtain satisfactory yields for the second acylation, al-
lowing to cyclize 6 with catalytic amounts (10 mol%) of CF SO H
3
3
in organic solvents to the corresponding alkylanthraquinones 7.
Key words: acylation, alkylbenzophenones, alkylanthraquinones,
perfluoroalkanesulfonic acid catalysis
Scheme 1
2
2
-Alkylanthraquinones (e. g., 2-tert-butyl, 2-isopropyl or
-ethylanthraquinone) are important catalysts for the pro-
5
3
Following the known procedure, alkylbenzenes 1a-d
have been reacted with benzoyl chloride 2 in the presence
of perfluorobutanesulfonic acid (C F SO H, 5 mol%) to
duction of hydrogen peroxide, therefore many proce-
dures for their preparation have been developed. The
acylation of alkylbenzenes with phthalic anhydride and
subsequent cyclization of the primarily formed benzophe-
none-2-carboxylic acids is one important route to prepare
4
4
9
3
give the alkylbenzophenones 3. After 15 hours reaction
time, the conversion was determined by isolation of the
unreacted benzoyl chloride as benzoic acid. The results
are listed in Table 1.
4
2
-alkylanthraquinones. Disadvantages of this procedure
are the great excess of AlCl (more than two molar) nec-
3
essary for the first acylation step, and the large amounts of Table 1 reveals that the alkylbenzophenones 3 are ob-
concentrated sulfuric acid required for the cyclization.
tained in good yields (referred to conversion). In the case
of the benzoylation of isopropylbenzene 1c to 3c'–c''', the
isolated yield of 3c'–c''' amounts to only 65% after 15
hours. Reducing the reaction time to 5 hours slightly in-
creases the yield of 3c'–c''' to 68% at decreased conver-
sion of 78%. The benzoylation of tert-butylbenzene 1d
afforded 3d'–d''' in 86% yield. Obviously, the acid cata-
lyzed acylation of 1d is faster than its dealkylation.
In previous publications we have demonstrated that aro-
matics can also be acylated with carboxylic acid chlorides
and catalytic amounts of perfluoroalkanesulfonic acids
5
avoiding large amounts of AlCl . As expected, the perflu-
3
oroalkanesulfonic acid catalyzed acylation is especially
favorable for donor-substituted aromatics (toluene, xy-
5
lene, etc.). Therefore, the acid catalyzed acylation of
alkylbenzenes with phthalic anhydride should also be pos- The isomeric ratios of products 3 were determined from
sible. However, in acid catalyzed acylations of isopropyl- the crude products by gas chromatography (Table 1). The
benzene and, even more pronounced, of tert- percentage of ortho products is conspicuously high com-
butylbenzene, undesired side-reactions of the alkylben- pared to benzoylations of alkylbenzenes with AlCl as cat-
3
8
zenes, especially dealkylation but also isomerizations, alyst, giving mainly para products. With increasing size
6
could occur. Applications of the tert-butyl group as a po- of the alkyl group from methyl to tert-butyl, the amount of
sitional protective group in reactions of aromatics is based ortho products 3a'-d' decreased mainly in favor of the
7
on easy debutylation.
corresponding para products 3a'''-d''': from 30% (3a')
and 68% (3a''') to 5% (3d') and 86% (3d'''). Also the per-
centage of meta products 3a''-d'' increases slightly: from
First, we have therefore investigated in general the acyla-
tion of alkylbenzenes with acid chlorides under perfluoro-
alkanesulfonic acid catalysis. The acylations of toluene
and p-xylene, respectively, with benzoyl chloride previ-
2
% (3a'') to 9% (3d'').
Synthesis 2000, No. 10, 1427–1430 ISSN 0039-7881 © Thieme Stuttgart · New York

1
428
F. Effenberger et al.
PAPER
Table 1 Acylation of Alkylbenzenes 1a–d with Benzoyl Chloride 2 in the Presence of 5% C F SO H
4
9
3
Reaction Conditions
Temp (°C) Time (h)
Educt
Conversion
%)
Products
Yield (%)
Isomeric Ratio
o:m:p
(
1
1
1
1
a
b
c
110
136
153
153
168
15
15
15
5
91
87
89
78
92
3a’, a’’, a’’’
3b’, b’’, b’’’
3c’,c’’,c’’’
85
77
65
68
86
30:2:68a
21:4:75
c
3c’, c’’, c’’’
3d’, d’’, d’’’
17:5:78
5:9:86
1d
15
a
Data from literature.5
The second step in the formation of anthraquinones from sulfuric acid, we have investigated this step separately in
benzenes with phthalic anhydride is the cyclization of the more detail applying the knowledge of the acid catalyzed
benzophenone ortho acids with an excess of sulfuric acid. benzoylation of p-xylene 4 with benzoic acid (Scheme 2).
Since we were also interested in a catalytic process for this The results of the cyclization of 6a to 7a in various sol-
ring closure, we first investigated the acid catalyzed acy- vents and with varying CF SO H concentrations are sum-
3
3
lation of p-xylene with benzoic acid as a model reaction. marized in Table 2. The use of 1,2-dichloroethane as
Under C F SO H catalysis (5 mol%) the acylation of solvent and 10 mol% of CF SO H was found to give the
4
9
3
3
3
p-xylene 4 with benzoic acid gives the acylation product best results: The cyclization of 6a afforded 7a in 89%
5
5
in only 14% yield. For the acylation of aromatics with yield. For large batch size, effective removal of the water
catalytic amounts of perfluoroalkanesulfonic acids, the formed is decisive for a high conversion of 6a to 7a as il-
formation of a mixed carboxylic perfluoroalkanesulfonic lustrated in the Figure.
9
anhydride is essential. Since the formation of water dur-
ing the reaction was probably the main reason for the low
5
yields of acylation product, water was removed from the
reaction mixture by azeotropic distillation and adsorption
onto molecular sieves in the back flow (see experimental
part). By this procedure the yield of acylation product 5
formed by reacting xylene 4 with benzoic acid in the pres-
ence of 10 mol% C F SO H could be improved to
4
9
3
9
2
0% when referred to conversion. After distillation,
,5-dimethylbenzophenone 5 was obtained in 71% yield
(
Scheme 2).
Based on these results, the acylation of 4 with phthalic an-
hydride in presence of trifluoromethanesulfonic acid
(
CF SO H) to give the corresponding anthraquinone 7a
3 3
was investigated (Scheme 2). The reaction occurred in
one step, but equimolar amounts of CF SO H are neces-
3
3
sary for completion. Moreover, product 7a obtained con-
tains many impurities, and thus it was isolated after
purification in only 15% yield. Obviously, phthalic anhy-
dride is too stable to react with catalytic amounts of
CF SO H, giving the reactive mixed anhydride.
3
3
Better results were achieved in the acylation of 4 with ph-
thaloyl chloride (Scheme 2). Compound 4 was acylated in
one step with phthaloyl chloride under CF SO H catalysis
3
3
(
5 mol%) to anthraquinone 7a in 52% yield after chro-
matographic purification. An increased appearance of
1
0
byproducts due to phthalide formation was not ob-
served.
Since the cyclization of the intermediate keto acid 6a to
anthraquinone 7a requires large amounts of concentrated
Scheme 2
Synthesis 2000, No. 10, 1427–1430 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Perfluoroalkanesulfonic Acid Catalyzed Acylations of Alkylbenzenes: Synthesis of Alkylanthraquinones
1429
Table 2 Cyclization of 2-(2,5-Dimethylbenzoyl)benzoic Acid (6a)a
to Anthraquinone 7a in Different Solvents (10 mL) under CF SO H
3
3
Catalysis
Reaction Conditions Product 7a
CF SO H Solvent
Temp
Time
(h)
Yield
g (%)
3
3
(
mol%)
(°C)
85
o-dichloroben-
180
7.5
0.70 (74)
zene
8
8
4
1
1
5
5
0
0
0
chlorobenzene
dichloroethane
dichloroethane
dichloroethane
dichloroethaneb
131
83
83
83
83
18.0
2.5
0.49 (52)
0.78 (82)
0.65 (69)
0.54 (57)
0.84 (89)
18.0
18.0
46.0
a
Scheme 3
Batch size 4.0 mmol each.
Only 5 mL of solvent.
b
formed by acylation of the solvent chlorobenzene. The an-
thraquinone 7b was obtained after crystallization from
ethanol in 17% yield.
In summary, the perfluoroalkanesulfonic acid catalyzed
acylation of alkylbenzenes 1 with benzoyl chloride 2 gave
the corresponding alkylbenzophenones 3 in high yields
without any acid catalyzed dealkylation. The application
of benzoic acid as acylating agent under acid catalysis is
possible, if, as shown for the acylation of p-xylene 4, the
water formed in the course of the reaction is continuously
removed. The one-step acylation of 4 with phthalic anhy-
dride via intermediate methylbenzoylbenzoic acid 6a to
anthraquinone 7a requires equimolar amounts of perfluo-
roalkanesulfonic acid. Regarding only the second step, it
could be demonstrated that cyclization of 2-(4-alkylben-
zoyl)benzoic acids 6 to the corresponding anthraquinones
7
in various solvents with catalytic amounts of perfluoro-
Figure
alkanesulfonic acid is possible. Again, removal of the wa-
ter formed is essential for obtaining satisfactory yields of
Finally, the CF SO H catalyzed cyclization of 2-(4-iso- anthraquinones.
3
3
propylbenzoyl)- and 2-(4-tert-butylbenzoyl)benzoic
1
1
acid to the corresponding anthraquinones in toluene as
solvent, and with removal of water was studied. In the
case of 2-(4-isopropylbenzoyl)benzoic acid after 3 days at
nearly complete conversion only a product mixture was 0.032-0.063 mm (Riedel-de Haen). Gas chromatography was per-
isolated, which could not be separated and characterized.
Mps were determined on a Büchi SMP 20 apparatus and are uncor-
rected. Preparative column chromatography was performed using
glass columns of different sizes packed with silica gel S, grain size
formed with a Carlo Erba Fractovap 4160 with FID and Spectra
Physics Minigrator. All solvents and starting materials were puri-
fied and dried.
2
-(4-tert-Butylbenzoyl)benzoic acid 6b also did not cy-
clize to the desired anthraquinone neither in toluene nor in
dichloroethane. The diminished reactivity of 4-alkyl-sub-
stituted benzoylbenzoic acids indicates that higher reac- To nonafluorobutanesulfonic acid (300 mg, 1.0 mmol) in a flame-
Alkylbenzophenones 3; General Procedure
1
2
tion temperatures are required. Therefore, chlorobenzene dried flask under Ar atm was added the respective alkylbenzene 1
(
200 mmol) followed by addition of 2 (2.81 g, 20 mmol). After be-
was used as solvent for the cyclization of 6b (Scheme 3).
ing stirred at reflux for 15 h (5 h for 1c), the reaction mixture was
poured into aqueous 2 N KOH (25 mL) and stirred vigorously for
6 h. After addition of Et O (200 mL), the phases were separated.
As shown in Scheme 3, after 72 hours reaction time in
presence of 10 mol% CF SO H a product mixture was
3
3
2
isolated, consisting of 4-tert-butylanthraquinone 7b and The organic phase was washed with H O, and concentrated. The
2
2
-(4-chlorobenzoyl)-4-tert-butylbenzophenone 8 in a ra- residue was chromatographed on silica gel with petroleum ether/
CH Cl (6:4). The isomeric ratio of compounds 3 was determined
tio of 2:1 (determined by NMR). The byproduct 8 is
2
2
by gas chromatography (Table 1).
Synthesis 2000, No. 10, 1427–1430 ISSN 0039-7881 © Thieme Stuttgart · New York

1
430
F. Effenberger et al.
PAPER
In order to isolate benzoic acid, the alkaline aqueous phase was
Following of the Cyclization of 6a to 7a
A solution of 6a (284 g, 1.12 mol) and CF SO H (16.81 g, 0.11 mol)
acidified with aqueous 6 N HCl and extracted with Et O. The com-
2
3
3
bined extracts were concentrated, and the remaining benzoic acid
was dried over P O and weighed out.
in DCE (1.25 L) was heated to reflux. After 48 h, a dropping funnel
filled with molecular sieve 4 Å and equipped with reflux condenser
2
5
was used for H O removal. At given time intervals samples of the
reaction mixture (1 mL) were taken, worked up as described above,
and the amount of 7a and unreacted 6a were determined.
2
Determination of Isomeric Ratio of 3 by Gas Chromatography13
GC was performed on a SDPE 08 capillary column (20 m) at
0
1
.45 bar H ; temperature programme 40-300 °C, 10° per min and
2
0 min at 300 °C. The correction factor (not given) was determined
Cyclization of 2-(4-tert-Butylbenzoyl)benzoic Acid (6b) to 2-tert-
Butylanthraquinone (7b)
To 6b (10.53 g, 37.3 mmol) in chlorobenzene (35 mL) (in an appa-
by weighed portion of reference substance for each reaction compo-
nent.
ratus described above with molecular sieve 4 Å for H O removal)
2
was added CF SO H (0.55 g, 3.65 mmol), and the reaction mixture
was heated under reflux for 72 h. Workup was performed as de-
scribed above for acylation of 4. The crude product was chromato-
Acylation of p-Xylene (4) with Azeotropic Removal of H O;
General Procedure
To a solution of the acylation agent in 4 in a flask with dropping fun-
nel, which was filled with molecular sieves 4 Å and equipped with
reflux condenser, was added the respective perfluoroalkanesulfonic
3
3
2
graphed on silica gel with petroleum ether/CH Cl (7:3) to yield a
2
2
mixture of 7b and 2-(4-chlorobenzoyl)-4-tert-butylbenzophenone
8) in a ratio 2:1. Crystallization from EtOH gave 1.67 g (17%) of
(
acid, and the reaction mixture was heated to reflux. H O formed
2
1
1
during the reaction was removed by adsorption onto molecular
sieves in the back flow. In order to complete the reaction, the reac-
tion mixture was cooled to r.t., and diluted with Et O or CH Cl to
7b with 99% GC purity; mp: 103 °C (Lit. mp: 104 °C).
2
2
2
Acknowledgement
double volume. The mixture was washed twice with aqueous KOH
and H O. The organic phase was dried (MgSO ), and concentrated
2
4
We would like to thank the Fonds der Chemischen Industrie for fi-
nancial support.
under vacuum. The residue was purified by distillation or recrystal-
lization.
2
,5-Dimethylbenzophenone (5)
References
From benzoic acid (10 g, 82 mmol) in 4 (40 mL, 324 mmol), and
C F SO H (2.4 g, 8 mmol) in 48 h was obtained 12.3 g (71%) of 5;
bp: 173 °C/10 torr (Lit. bp: 171-174 °C/11 torr).
(
1) Electrophilic Aromatic Substitution, 42. Part 41: Effenberger,
F.; Maier, A. H. publication in preparation.
4
9
3
5
(2) a) Buckel, F. Forschungspraktikum, Universität Stuttgart,
From the alkaline aqueous phase benzoic acid was re-isolated as de-
scribed above.
1995.
b) Maier, A. H. Dissertation, Universität Stuttgart, 1996.
c) Schmider, J. Forschungspraktikum, Universität Stuttgart,
1994.
1
,4-Dimethylanthraquinone (7a)
From phthalic anhydride (1.18 g, 8 mmol) in 4 (9.8 mL, 80 mmol),
(3) Düsing, G.; Kleinschmit, P.; Knippschild, G.; Kunkel, W. In
Ullmanns Encyklopädie der Technischen Chemie, 4th ed.,
Vol. 17; Bartholomé, E., Ed.; Verlag Chemie: Weinheim,
1979; p 697.
(4) Bayer, O. Houben-Weyl, 4th ed., Vol. VII/3c; Thieme:
Stuttgart, 1979; p 46, and references cited therein.
(5) Effenberger, F.; Epple, G. Angew. Chem., Int. Ed. Engl. 1972,
11, 299.
and CF SO H (1.19 g, 8 mmol) in 7.5 h; followed by chromatogra-
3
3
phy on silica gel with petroleum ether/CH Cl (7:3) and recrystalli-
2
2
4
zation was obtained 0.28 g (15%) of 7a; mp: 136 °C (Lit. mp:
41 °C).
1
CF SO H Catalyzed Acylation of 4 with Phthaloyl Chloride to
3
3
Anthraquinone 7a
To a solution of phthaloyl chloride (1.16 mL, 8.0 mmol) in 4
Effenberger, F.; Epple, G. Angew. Chem., Int. Ed. Engl. 1972,
11, 300.
(
9.8 mL, 80 mmol) was added CF SO H (5 mol% referred to phth-
3 3
aloyl chloride), and the stirred reaction mixture was heated to
38 °C for 18 h. After being cooled to r.t., the reaction mixture was
Effenberger, F.; Sohn, E.; Epple, G. Chem. Ber. 1983, 116,
1195.
1
poured on ice and stirred for a further 3 h. Et O (50 mL) was added,
and the phases were separated. The aqueous phase was extracted
(6) Olah, G. A.; Prakash, G. K. S.; Iyer, P. S.; Tashiro, M.;
Yamato, T. J. Org. Chem. 1987, 52, 1881.
(7) Tashiro, M. Synthesis 1979, 921.
2
with Et O (3 x 10 mL). The combined organic phases were washed
2
with H O (3 x 10 mL), dried (MgSO ), and concentrated under
vacuum. The residue was chromatographed on silica gel with petro-
(8) Stock, L. M.; Brown, H. C. Adv. Phys. Org. Chem. 1963, 1,
35.
2
4
leum ether/CH Cl (6:4) to yield 0.99 g (52%) of 7a, mp: 140 °C.
(9) Effenberger, F. Angew. Chem., Int. Ed. Engl. 1980, 19, 151.
10) Schellhammer, C. -W. In Houben-Weyl, 4th ed., Vol. VII/2a;
Müller, E., Ed.; Thieme: Stuttgart, 1973; p 332.
11) Peters, A. T.; Rowe, F. M. J. Chem. Soc. 1945, 181.
2
2
(
(
Cyclization of 2-(2,5-Dimethylbenzoyl)benzoic Acid (6a) to An-
thraquinone 7a
To 6a14 (1.02 g, 4.0 mmol) in 10 mL of solvent (Table 2) was added
(12) Noyce, D. S.; Kittle, P. A. J. Org. Chem. 1967, 32, 2459.
(
13) Schomburg, G. Gaschromatographie: Grundlagen, Praxis,
Kapillartechnik, 2nd ed.; Verlag Chemie: Weinheim, 1987; p
CF SO H (Table 2), and the reaction mixture was heated to reflux
3
3
for the times given in Table 2. (Due to the small batch size, molec-
62.
ular sieves for H O removal were not necessary.) After being cooled
2
(
14) Meyer, F. Ber. Dtsch. Chem. Ges. 1882, 15, 636.
to r.t., CH Cl was added, the reaction mixture was poured into
2
2
Beilsteins Handbuch der organischen Chemie, 4th ed., Vol.
aqueous 2 N KOH (10 mL) and stirred for a further 6 h. Et O
2
10 E II; Springer-Verlag: Berlin, 1949; p 531.
(50 mL) was added, and the phases were separated. The aqueous
phase was extracted with Et O (3 x 10 mL). The combined organic
2
phases were washed with H O (3 x 10 mL), dried (MgSO ), and
concentrated under vacuum. The residue was recrystallized from
EtOH.
2
4
Article Identifier:
437-210X,E;2000,0,10,1427,1430,ftx,en;H03100SS.pdf
1
Synthesis 2000, No. 10, 1427–1430 ISSN 0039-7881 © Thieme Stuttgart · New York