An improved method for the conversion of nitriles to amides using N,N-disubstituted hydroxylamine

Article abstract of DOI:10.3184/174751911X13133294115830

An improved method for the selective hydration of nitriles to amides employing N,N-disubstituted hydroxylamine is described leading to a reduction in reaction time and improved yield. Amides having electron-donating groups, which were not reported using the original method, were obtained in excellent yields. The amount of N,N-disubstituted hydroxylamine was reduced from three equivalents to one equivalent and the use of water as the reaction medium is environmentally friendly.

Full text of DOI:10.3184/174751911X13133294115830

4
80 RESEARCH PAPER
AUGUST, 480–483
JOURNAL OF CHEMICAL RESEARCH 2011
An improved method for the conversion of nitriles to amides using
N,N-disubstituted hydroxylamine
Xiao-yun Ma and Ming Lu*
Chemical Engineering College, Nanjing University of Science andTechnology, Nanjing 210094, China
An improved method for the selective hydration of nitriles to amides employing N,N-disubstituted hydroxylamine is
described leading to a reduction in reaction time and improved yield. Amides having electron-donating groups,
which were not reported using the original method, were obtained in excellent yields. The amount of N,N-disubsti-
tuted hydroxylamine was reduced from three equivalents to one equivalent and the use of water as the reaction
medium is environmentally friendly.
Keywords: hydration, nitrile, amide, N,N-disubstituted hydroxylamine
The hydration of nitriles to the corresponding amides is an
important transformation from both the academic and indus-
or N,N-dibenzylhydroxylamine. We examined the effects of
solvent, reaction temperature, and reaction time on the yields
of the hydration reaction. The detailed results are listed in
Table 1.
1–3
trial points of view. Classically the reaction was carried out
in the presence of a strong acid or base catalyst, methods which
usually cause over-hydrolysis of the amide to the correspond-
ing carboxylic acids, a faster reaction particularly under basic
As shown in Table 1, we found that benzonitrile was easily
hydrated to benzamide by the action of N,N-disubstituted
hydroxylamine in water. The use of absolute methanol in
place of water resulted in no product (Table 1, entry 5), but
the subsequent addition of water lead to the formation of
benzamide at reflux. When we reduced the amounts of N,N-
diethylhydroxylamine to 2.5 mmol (0.5 equiv.), the yield was
significantly reduced (45%). Thus, both water and N,N-
diethylhydroxylamine were involved in the hydration of
nitriles. In addition, we found that the conversion and reaction
rate were improved significantly by increasing the reaction
temperature. Compared to the water-soluble N,N-diethylhy-
droxylamine, use of N,N-dibenzylhydroxylamine in the hydro-
lysis reaction gives a relatively low yield (Table 1, entry 6),
and an increase in the reaction time to 8 h had a minimal effect
on the product yield at 100 °C (Table 1, entry 7). In view of the
fact that N,N-dibenzylhydroxylamine is completely insoluble
in water at room temperature and only became partially solu-
ble at 100 °C, organic solvent was added as a cosolvent to
obtain a homogeneous solution at refluxing temperature. How-
ever, There was no detectable increase in the yield of benza-
mide (Table 1, entries 8–10). It should be noted that no benzoic
acid was detected in the reaction mixture at high temperatures.
On the basis of the above results, we can conclude that using
4–5
conditions. Although it is possible to stop the process at the
amide stage, in these cases it is necessary to control carefully
the temperature and stoichiometry employed in order to avoid
6
the formation of polymeric side products. It is also important
to note that, from an industrial perspective, the final neutra-
lisation step required in either the acid- or base-catalysed
reactions leads to extensive salt formation with inconvenient
7
contamination of the product and pollution effects. Several
catalysts or reagents have been developed To overcome these
limitations. For instance, a variety of homogeneous catalysts
8
,9
10,11
based on transition metals and heterogeneous catalysts
have been reported for the selective conversion of nitriles to
1
2
amides. Enzyme-mediated hydrations are also now known.
In 1984, Miyazawa and his co-workers reported a method
for the preparation of amides from nitriles by the use of some
1
3
hydroxylamine derivatives. In this method, nitriles were con-
verted to amides using dichloromethane as a reaction medium
under an inert atmosphere at reflux. In addition, the reaction
required 3 equivalents of the hydroxylamine derivative. Except
for a few nitriles having electron-withdrawing substituents,
the hydration of most nitriles such as heterocyclic nitriles and
aliphatic nitriles proceeded in low yield after long reaction
times. Nitriles having electron-donating groups had not been
reported in this literature.
Table 1 Reaction conditions
Following this method, we have previously converted 3-
chloro-4-arylpicolinonitrile which is sensitive to alkali and
acid to the corresponding amide. In strict accordance with the
literature, the reaction was carried out in anhydrous dichloro-
methane with the aid of N,N-diethylhydroxylamine under
a nitrogen atmosphere at 50 °C. However, only 10% of the
3
-chloro-4-arylpicolinonitrile was converted to the amide after
heating at this temperature for 12 h. To our surprise, when
water was used as solvent instead, 100% of 3-chloro-4-
arylpicolinonitrile was transformed into 3-chloro-4-arylpicoli-
noamide at room temperature for 6 h, and there was no need
for inert gas protection in this reaction. Thus, we found that the
hydrolysis of nitriles can proceed smoothly using water as a
solvent in the presence of the hydroxylamine derivatives. To
further understand the role of water, a comprehensive study of
the hydrolysis of nitriles was carried out.
Entrya Reagent system
Time/h
Temp/°C
Yield/%b
1
2
H
A+H
A+H
A+H O
A+CH
B+H
B+H
B+H
B+H
2
O
8
8
8
5
8
5
8
8
8
8
reflux
rt
0
2
O
O
25
3
2
50 °C
reflux
reflux
reflux
reflux
reflux
reflux
reflux
60
4
2
92(45)c
0
5
3
OH
6
2
2
2
2
O
O
64
7
70
8
O/Dioxane
O/DMF
71
9
70
Results and discussion
10
B+H O/DMSO
71
2
In the first stage of the study, we focused on the the hydrolysis
of benzonitrile with the aid of N,N-diethylhydroxylamine
a
Reaction conditions: benzonitrile (5 mmol); N,N-disubstituted
hydroxylamine (5 mmol); solvent (10 mL), the ratio of H O/
dioxane, H O/DMF, H O/DMSO is 1:1(entries 8–10).
Isolated yield.
2
2
2
b
c
*
Correspondent. E-mail: lumingnjust@163.com
2.5 mmol of N,N-diethylhydroxylamine (A) was used.

JOURNAL OF CHEMICAL RESEARCH 2011 481
Table 2 Hydration of various nitriles using N,N-diethylhydroxylaminea
Entry
1
Nitrile
Time/h
5
Yield/%b
90
Entry
8
Nitrile
Time/h
3
Yield/%b
95
2
3
4
4
5
5
94
93
96
9
10
11
4
4
4
95
96
96
5
5
60(88) c
12
3
5
96
92
6
7
a
5
5
55(85)c
40(83)c
13
14
CH
3
(CH
2
)
6
CN
5
5
5
91
90
90
1
5
6
CH
CH
3
(CH
(CH
2
)
)
10CN
16CN
1
3
2
Reaction conditions: nitrile (5 mmol), N,N-diethylhydroxylamine (5 mmol), H
2
O (15 mL), 100 °C.
b
c
Isolated yield.
1
0 mmol of N,N-diethylhydroxylamine were used.
N,N-diethylhydroxylamine in water at reflux is the optimal
condition for benzonitrile hydrolysis.
volume of N,N-diethylhydroxylamine (Table 2, entries 3, 8
and 12).
This protocol of hydration was subsequently applied to
various aromatic nitriles, heterocyclic nitriles and aliphatic
nitriles. As shown in Table 2, various nitriles including
aromatic nitriles having electron-donating or electron-
withdrawing substituents (Table 2, entries 1–7), heterocyclic
nitriles (Table 2, entries 8–12), and aliphatic nitriles (Table 2,
entries 13–16) were converted into the corresponding amides
in good to excellent yields. Substrates bearing strong electron-
donating groups (Table 2, entries 5–7) render the nitrile carbon
less electron-deficient and sensitive to nucleophilic attack by
N,N-diethylhydroxylamine, and exhibited slightly lower con-
versions. When the amount of N,N-diethylhydroxylamine was
increased, yield of amides was improved. For instance, good
conversions of 4-methoxybenzonitrile (Table 2, entry 5), 2-
Amino-4-bromobenzonitrile (Table 2, entry 6) and 4-hydroxy-
benzonitrile (Table 2, entries 7) to the corresponding amides
took place with two equivalents of N,N-diethylhydroxylamine.
In contrast, the hydration of nitriles with an electron-with-
drawing group proceeded faster and more effectively (Table 2,
entries 4, 9–12). In the case of aliphatic nitriles, the hydration
process was similar to aromatic nitriles and aliphatic nitriles
In the course of the study on hydration of nitriles with
electron-withdrawing groups to the corresponding amides,
we found that the hydrolysis of these nitriles can be achieved
in good yields in the presence of water at room temperature.
As shown in Table 3, treatment of nitriles with N,N-diethylhy-
droxylamine in a mixed solvent of methanol and water at room
temperature for a relatively long time gave amides in good
yield. When only water was used in this reaction a low yield
was obtained due to the poorly water-soluble nitrile (Table 3,
entry 1). It is interesting to note that increasing the electron-
withdrawing ability of the nitrile enhances the rate of the
reaction and improves the rate of conversion.
As can be seen from Table 1, both water and N,N-diethylhy-
droxylamine were involved in the hydration of nitriles. In addi-
tion, we found that one equivalent of diethylamine was formed
simultaneously in this reaction.Thus, according to the mecha-
nism proposed in ref.13, the mechanistic rationalisation is
suggested to account for the formation of amides according
to Scheme 1. Initially, the nucleophilic addition of N,N-
1
diethylhydroxylamine yields the intermediate, and then forms
11
11
acylamino radical and the aminyl radical and the acylamino
radical III by homolytic cleavage. Unlike the literature pro-
posal that the radicals abstract hydrogen from N,N-diethylhy-
droxylamine, we believe that both radicals may abstract
hydrogen from water, thus giveing diethylamine and the
corresponding amide.
(
Table 2, entries 13–16) were smoothly hydrated to give the
corresponding amides in excellent yields under the employed
reaction conditions. In addition, ortho substituents had only
slight effect on nitriles hydrolysis due to the small molecular

4
82 JOURNAL OF CHEMICAL RESEARCH 2011
Table 3 Hydration of nitriles at room temperaturea
Agilent-1100-JC/MSD-Trap spectrometer. Analytical TLC was
performed on precoated silica gel 60 F254 plates. Yields refer to the
isolated yields of the products after purification by silica-gel column
chromatography (300 mesh). All starting chemicals are commercially
available but 3,4-dichloropicolinonitrile (entry 12 in Table 2) was
14–15
synthesised according to the method reported in the literature.
Hydrolysis of the nitriles
The nitrile substrate (5 mmol), N,N-diethylhydroxylamine (5 mmol)
Entry
1
Nitrile
Time/h
10
Yield/%b
and H O (15 mL) were added to a 50 mL round-bottom flask equipped
2
89(55)c
with magnetic stirrer. The mixture was heated to reflux for 3–5 h
(
reaction times are given in Table 2.). After cooling to room tempera-
ture, the solution was subjected to continuous extraction with ethyl
acetate. The organic phase was washed with water and dried (Na SO ).
2
4
The solvent was removed in vacuo to give the crude product which
was purified by silica gel column chromatography (ethyl acetate/
n-hexane). In some instances (water-soluble amides), the solution was
directly evaporated to dryness and the residue was purified by a silica
gel column chromatography (ethyl acetate/n-hexane). The commer-
cially available amides were characterised by melting points, and the
others were characterised by NMR spectra.
2
8
93
3
4
10
10
86
87
Benzamide (Table 1, entry 4): Benzonitrile (515 mg, 5 mmol) was
used for the preparation of the title compound. After removal of the
solvent (H O) the residue was separated by column chromatography
2
(
hexanes/EtOAc = 1:1) to give benzamide as a white solid (557 mg,
10
9
2%); m.p. 127–128 °C (lit. m.p. 126–127 °C).
-Chlorobenzamide (Table 2, entry 1): 2-Chlorobenzonitrile (688
mg, 5 mmol) gave after column chromatography (hexanes/EtOAc =
5
6
10
6
90
95
2
1
1
:1) 2-chlorobenzamide as a white solid (700 mg, 90%); m.p. 140–
41 °C (lit. m.p. 138–140 °C).
16
4
-Chlorobenzamide (Table 2, entry 2): 4-Chlorobenzonitrile (688
mg, 5 mmol) gave after column chromatography (hexanes/EtOAc =
:1) to give 4-chlorobenzamide as a white solid (731 mg, 94%); m.p.
1
a
5
Reaction conditions: nitrile (5 mmol), N,N-diethylhydroxyl-
178–179 °C (lit. m.p. 178–180 °C).
amine (5 mmol), H
2
O (7.5 mL), CH
3
OH (7.5 mL), rt.
3-Methylbenzamide (Table 2, entry 3): 3-Methylbenzonitrile (585
mg, 5 mmol) gave after column chromatography (hexanes/EtOAc =
1:1) 3-methylbenzamide as a white solid (628 mg, 93%); m.p. 93–
b
Isolated yield.
Methanol was not used as a cosolvent.
c
17
9
4 °C (lit. m.p. 92–93 °C).
-Nitrobenzamide (Table 2, entry 4): 4-Nitrobenzonitrile (585 mg,
4
5
4
mmol) gave after column chromatography (hexanes/EtOAc = 2:1)
In conclusion, we report an improved method for the selec-
tive hydration of a nitrile to an amide using a commercially
available N,N-disubstituted hydroxylamine in environmentally
friendly water as a solvent. Under the improved protocol, the
hydration of nitriles to amides proceeded with a higher yield,
shorter reaction time and a wider substrate structure when
compared to the previously reported method. Thus, benzo-
amide was obtained in 92% yield after 5 h with the improved
method in comparison to 79% yield after 65 h according to the
previously reported method. Amides having electron-donating
groups, which were not been reported using the original
method, were obtained in excellent yields by hydrolysis of the
corresponding nitriles. The amount of N,N-diethylhydroxyl-
amine was reduced from three equivalents to one equivalent.
Nitriles having electron-withdrawing groups could be con-
verted into the corresponding amides in good yields at room
temperature and all reactions were carried out without inert
gas protection. Thus, compared to the original method, the
improved one has a wider application.
-nitrobenzamide as a white solid (799 mg, 96%); m.p. 199–201 °C
13
(
lit. m.p. 200–202 °C)
4
-Methoxybenzamide (Table 2, entry 5): 4-Methoxybenzonitrile
(666 mg, 5 mmol) gave after column chromatography (hexanes/EtOAc
= 1:1) 4-methoxybenzamide as a white solid (665 mg, 88%); m.p.
166–167 °C (lit. m.p. 166 °C).
18
23
2-Amino-4-bromobenzamide (Table 2, entry 6): 2-Amino-4-bro-
mobenzonitrile (985 mg, 5 mmol) was used for the preparation of
the title compound (two equivalents of N,N-diethylhydroxylamine
was used). The solution was subjected to extraction with 2 × 25 mL of
ethyl acetate, and the organic phases were combined, washed with
water, dried (Na SO ) and the solvent was removed in vacuo. The
2
4
residue was purified by column chromatography (hexanes/EtOAc =
23
3
:1) to give 2-amino-4-bromobenzamide as a white solid (914 mg,
85%); m.p. 176–177 °C; H NMR (DMSO-d ) δ 7.85 (1H, br), 7.71
(1H, d, J = 2.4 Hz), 7.26(1H, dd, J = 2.4, 8.8 Hz), 7.18 (1H, br), 6.71
1
6
13
(2H, br), 6.67 (1H, d, J = 8.8 Hz), C NMR (DMSO-d ) δ 105.2,
6
+
+
1
15.7, 119.0, 131.2, 134.8, 149.8, 170.4; MS (ESI ): 215.0 (M+H) .
-Hydroxybenzamide (Table 2, entry 7): 4-Hydroxybenzonitrile
596 mg, 5 mmol) was hydrolysed using 2 equivalents of N,N-
4
(
diethylhydroxylamine. After removal of the solvent (H O) the residue
2
was purified by column chromatography (hexanes/EtOAc = 1:4) to
give 4-hydroxybenzamide as a white solid (570 mg, 83%); m.p. 161–
162 °C (lit. m.p. 160–162 °C).
2-Chloronicotinamide (Table 2, entry 8): 2-Chloronicotinonitrile
(693 mg, 5 mmol) was hydrolysed as above. The solution was extracted
Experimental
16
Melting points were determined on a Thomas Hoover capillary
apparatus and were uncorrected. NMR spectra were obtained from
a Bruker DPX 400 spectrometer. MS spectra were obtained from a
Scheme 1 Proposed mechanism for nitrile hydration with N,N-diethylhydroxylamine.

JOURNAL OF CHEMICAL RESEARCH 2011 483
22
with 4 × 25 mL of ethyl acetate, and the organic phases were com-
bined, washed with 0.5 M hydrochloric acid and water, dried (Na SO )
as a white solid (1276 mg, 90%); m.p. 108–109 °C (lit. m.p. 108.5–
109 °C).
2
4
and the solvent was removed in vacuo. The residue was purified by
column chromatography (hexanes/EtOAc = 1:2) to give 2-chloronico-
tinamide as a white solid (744 mg, 95%); m.p. 161–163 °C (lit. m.p.
Financial support from the National Natural Science
Foundation of China-NSAF (grant no. 11076017) is gratefully
acknowledged.
19
1
60–162 °C).
Picolinamide (Table 2, entry 9): Picolinonitrile (520 mg, 5 mmol)
was hydrolysed as above. After removal of the solvent (H O) the resi-
due was purified by column chromatography (hexanes/EtOAc = 3:1)
2
Received 1 July 2011; accepted 12 August 2011
Paper 1100770 doi: 10.3184/174751911X13133294115830
Published online: 29 August 2011
to give picolinamide as a white solid (580 mg, 95%); m.p. 104–106 °C
5
(
lit. m.p. 105–106 °C).
Nicotinamide (Table 2, entry 10): Nicotinonitrile (520 mg, 5 mmol)
was hydrolysed as above. After removal of the solvent (H O) the resi-
2
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57–158 °C (lit. m.p. 158 °C).
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3
14
(
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2
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6
+
+
MS (ESI ): 191.0 (M+H) .
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2
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10
58 °C (lit. m.p. 158–159 °C).
15
16
17
18
19
20
21
Octanamide (Table 2, entry 14): Octanenitrile (626 mg, 5 mmol)
gave after column chromatography (hexanes/EtOAc = 1:2) octan-
amide as a white solid (652 mg, 91%); m.p. 105–106 °C (lit. m.p.
1
20
05 °C).
Dodecanamide (Table 2, entry 15): Dodecanenitrile (907 mg,
mmol) gave after column chromatography (hexanes/EtOAc = 1:2)
5
dodecanamide as a white solid (897 mg, 90%); m.p. 101–102 °C
(
21
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gave after column chromatography (hexanes/EtOAc = 1:2) stearamide