A one-pot conversion of carboxylic acids into nitriles catalysed by PEG400 under microwave irradiation

Article abstract of DOI:10.3184/030823410X12795488698174

A new efficient method for the synthesis of nitriles is reported. Carboxylic acids were converted into nitriles by a onepot reaction with hydroxylamine sulfate and zinc catalysed by PEG400 under microwave irradiation in excellent yields. The most suitable condition was 20 minutes under the microwave power of 231 W with 5 mol% PEG400.

Full text of DOI:10.3184/030823410X12795488698174

414 RESEARCH PAPER
JULY, 414–415
JOURNAL OF CHEMICAL RESEARCH 2010
A one-pot conversion of carboxylic acids into nitriles catalysed by
PEG400 under microwave irradiation
Yu-Qing Cao*, An-Li Qu, Rui-Yan Liu and Chun-Ming Duan
College of Pharmacy, Hebei University, Baoding-071002, P. R. China
A new efficient method for the synthesis of nitriles is reported. Carboxylic acids were converted into nitriles by a one-
pot reaction with hydroxylamine sulfate and zinc catalysed by PEG400 under microwave irradiation in excellent
yields. The most suitable condition was 20 minutes under the microwave power of 231 W with 5 mol% PEG400.
Keywords: carboxylic acids, nitriles, hydroxylamine sulfate, PEG400, microwave irradiation
Table 1 Effect of the power to benzoic acid
Nitriles are important reagents for organic synthesis, which
serve as a pharmacophore and intermediate for pharmaceuti-
cals, agricultural chemicals, dyes, and material sciences.
In recent years, it showed that nitriles could be converted to
thiazole derivatives as inhibitors of superoxide,1 benzamidines
possessing activity of fibrinogen antagonists,2 tetrazole deriva-
tives as antipicornavirus drugs3 and the commercially impor-
tant angiotensin II receptor antagonist, losartan and valsartan.4
A number of methods are known for the preparation of
this useful class of compounds. They can be divided into
three routes: (1) by dehydration of aldoximes,5–7 or directly
from aldehydes via hydroxylamine hydrochloride/phthalic
anhydride,8 ammonia/MgSO4/MnO29 or hydroxylamine
hydrochloride/KF/Al2O3;10 (2) by treating acids chlorides with
sulfonamide;11 and (3) by treating carboxylic acids with urea/
aminosulfonic acid,12–16 ethyl carbamate/thionyl chloride17 or
diphosphorus tetraiodide/ammonium carbonate.18 Among all
of the reactants, carboxylic acids are more stable and inexpen-
sive. In addition, a number of drawbacks may be encountered
using some of the above methods, such as low yields, harsh
reaction conditions, tedious work-up procedures, and opaque
reaction mechanism.
Microwave irradiation has been widely applied in organic
synthesis.19–21 Microwave activation has been reported for the
one-pot synthesis of nitriles from aldehydes.22–24 However,
only one method for conversion of carboxylic acids into nitriles
under the microwave was found by our team.25 We now report
a new method for the one-pot conversion of carboxylic acids
into nitriles with hydroxylamine sulfate as amidation reagent
and zinc as reductant catalysed by PEG400 under microwave
irradiation and the results shown in Table 2. In this method, the
yields are higher for some products and save much time with
comparison to the general methods.
Entry
Power/W
Time/min
Yield/%
1
2
3
4
5
6
7
8
9
119
119
119
231
231
231
385
385
385
20
40
60
15
20
25
10
15
20
45
57
61
78
93
92
55
63
62
reason may be the higher power input, the energy is too high to
make the reaction completely effective, some of others chemi-
cal bonds or compounds (hydroxylamine sulfate) would be
broken at the same time; On the other hand, if the power input
is too low, hydroxylamine would decompose so the reaction
would be unable to progress completely and the yield would be
too low.
In Table 2, most of aromatic (entries 1–12) and heteroaro-
matic (entries 13–15) carboxylic acids could be converted to
the corresponding nitriles in excellent yields. The aryl carbox-
ylic acids with electron-donating groups such as –CH3 and –
OCH3 are more reactive than those with electron-withdrawing
groups such as –Cl, –I, –NO2 in the aromatic ring, mainly
because electron-donating groups increased the electron
density of carbonyl promoting the easier reaction, and produc-
ing heteroaromatic carboxylic acids. The amino group as an
electron-donating group resulted in 4-aminobenzoic acid
Table 2 Conversions of carboxylic acids into nitriles
Results and discussion
Entry Carboxylic acids
Time Yield
/min /%
M.p./oC
These reactions are very difficult, and there may even be no
reaction if there is no catalyst. So, PEG400 as a phase transfer
to this reaction has been studied and the best amount to use is
5 mol%. It was found that a lower dosage of PEG400 did not
catalyse the reaction effectively and a higher dosage would
undoubtedly lead to more loss of products during the washing
procedure. In our opinion, PEG400 should work as a solvent
and disperse reactants hence making the reactions easier.
As shown in Table 1, the power of microwave had an
obvious effect on the yields. The most suitable condition for
benzoic acid was 20 minutes with the power of 231W. The
Found Report12,13,26
1
2
C6H5.COOH
20
19
24
27
17
93 187–189a 188–191
91 110–112 110–113
4-HO.C6H4.COOH
4-Cl.C6H4.COOH
4-O2N.C6H4.COOH
2-CH3.C6H4.COOH
3
89 92–95
94–96
4
85 146–149 146–149
5
93 204–206a
96 55–57
205
57–59
6
4-H3CO.C6H4.COOH 14
7
3-O2N.C6H4.COOH
4-I.C6H4.COOH
2-Cl.C6H4.COOH
4-H2N.C6H4.COOH
C6H5.CH2COOH
C6H5.CH2CH2COOH
3-C5H4N.COOH
2-C4H3S.COOH
3-C4H3O.COOH
(CH3)3C.COOH
CH3CH2CH2CH2.
COOH
27
22
25
25
20
20
25
14
16
20
21
87 115–117 115–117
88 126–128 128–129
8
9
90 43–45
82 83–85
43–46
83–85
10
11
12
13
14
15
16
17
92 232–234a 233–234
90 259–260a
89 50–51
261
50–52
192
93 190–192a
91 149–151a
(NH2OH)2·H2SO4/Zn
RCOOH
RCN
151
PEG400/MW
80 104–105a 105–106
88 138–140a 139–141
Scheme 1
a Boiling points were determined.
* Correspondent: E-mail: pharm_hbu@yahoo.com

JOURNAL OF CHEMICAL RESEARCH 2010 415
(10) having a lower yield than other acids. The aliphatic car-
boxylic acids (entries 16–17) have lower yields and longer
reaction periods, especially for pivalic acid (16). We suggest
that the main reason for the low yields of pivalic acid (16) is
volatilisation and decarboxylation to form the hydrocarbon.
In summary, a new method for the conversion of carboxylic
acids into nitriles catalysed by PEG400 under microwave irra-
diation in satisfactory yields with hydroxylamine sulfate as
amidation reagent and zinc as reductant has been developed.
This method is inexpensive, practical and with less pollution
and easy work-up.
Received 14 April 2010; accepted 25 June 2010
Paper 1000070 doi: 10.3184/030823410X12795488698174
Published online: 28 July 2010
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Benzonitrile; general preparation
A mixture of benzoic acid (2.44 g, 20 mmol), hydroxylamine sulfate
(2.46 g, 15 mmol ), zinc dust (1.94 g,30 mmol) and PEG400(5 mol%)
was irradiated at middle low power(231W) for 20 min. Upon comple-
tion, the solids were filtered and extracted with dried dichloromethane
(2×10 mL).The organic phase was washed with H2O (3×10 mL) and
dried with magnesium sulfate. After the solvent was removed by
distillation, the benzonitrile 1.92 g (93% yield) was collected at
1
187–1890C. H NMR(CDCl3,) δ: 7.44 (d, 2H, 2×CH), 7.51 (d, 2H,
2×CH),7.54 (t, 1H, CH); IR (KBr) ν: 3067, 2229, 1599, 1490, 1447,
1287, 1223, 1178, 1070, 1026, 927, 760, 688, 548 cm−1.
We thank the Hebei Province Science and Technology Agency
(grant No. 4213006) for financial support.
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