Selective NaOH-catalysed hydration of aromatic nitriles to amides

Article abstract of DOI:10.1039/c5cy00313j

The selective synthesis of aromatic and heteroaromatic amides through base-catalysed hydration of nitriles was achieved using inexpensive and commercially available NaOH as the only catalyst. A wide range of nitriles was selectively converted to their corresponding amides. Kinetic studies show that the double hydration of nitriles towards undesirable carboxylic acids is negligible under our reaction conditions.

Full text of DOI:10.1039/c5cy00313j

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Selective NaOH-catalysed hydration of aromatic
nitriles to amides†‡
Cite this: DOI: 10.1039/c5cy00313j
Thibault E. Schmid, Alberto Gómez-Herrera, Olivier Songis, Deborah Sneddon,
*
Antoine Révolte, Fady Nahra and Catherine S. J. Cazin
Received 3rd March 2015,
Accepted 18th March 2015
The selective synthesis of aromatic and heteroaromatic amides through base-catalysed hydration of nitriles
was achieved using inexpensive and commercially available NaOH as the only catalyst. A wide range of
nitriles was selectively converted to their corresponding amides. Kinetic studies show that the double
hydration of nitriles towards undesirable carboxylic acids is negligible under our reaction conditions.
DOI: 10.1039/c5cy00313j
www.rsc.org/catalysis
The selective hydration of nitriles leading to the formation of
amides is of great interest to both academia and industry.1
Due to an increasing demand for amides as versatile building
performance and suitability for a large variety of synthetic
needs. In spite of these remarkable advances, the simpler
acid- or base-catalysed hydration of nitriles still remains the
most desirable approach, due to its simplicity and low opera-
tional costs. Alami and co-workers have reported the synthe-
sis of a variety of aromatic and heteroaromatic amides in
good to excellent yields using Cs2CO3 (1.5 equivalents) in
pyrrolidinone.4c In the same year, Tu and co-workers reported
a microwave-assisted process using 5 to 50 mol% of K2CO3
in water,4d with a wider scope of substrates. Recently, the
catalytic use of a NHC (N-heterocyclic carbene) precursor,
the 1,3-dimethylimidazolium bicarbonate (IMe·HCO3), in an
EtOH/H2O mixture4e and CsOH in a DMSO/water mixture4f
has been described as efficient promoter of this reaction.
Despite these latest breakthroughs, there is still a need to fur-
ther improve this process.
As part of our work on mixed N-heterocyclic carbene/
phosphine palladium systems for the aqueous Suzuki–Miyaura
reaction,12 and in the course of testing some nitrile-containing
aromatic substrates, surprising results were obtained. The
isolated cross-coupling products using such substrates were
found to bear an amide group rather than the initial nitrile
functionality. After some background experiments supporting
the non-involvement of a catalytic Pd species in such a trans-
formation, the role of NaOH as a selective hydrolysis pro-
moter of aromatic nitriles was identified as the culprit for the
observed transformation. To validate this hypothesis, the
hydrolysis of benzonitrile using hydroxide bases (M = Li, Na,
K, Cs) as catalysts was first investigated (Table 1).
blocks,2 the hydration of nitriles has emerged as
a
straightforward and atom-economical methodology for the
preparation of such compounds. Typically, hydration reac-
tions have been carried out in the presence of acids,3
although a strict control of the reaction time, temperature,
concentration and other parameters is required for optimal
results (in particular to avoid over-hydrolysis to the related
carboxylic acids). In addition, an excess of the acid is usually
required, which leads to difficult amide purification and sub-
stantial waste generation. Recently, base-catalysed procedures
have attracted considerable attention.4
The use of peroxides under basic conditions has been
widely reported as an efficient and selective variation for the
base-promoted synthesis of amides.5 Nevertheless, the special
handling required for peroxides6 and the low functional
group tolerance of these protocols have progressively
decreased the overall interest in this approach, particularly
for industrial applications. Similar inconveniences have been
found with other reported hydration systems, such as the use
of sodium superoxide,7 despite its good performance under
mild conditions. In order to overcome these significant draw-
backs, enzymatic systems8 and transition-metal catalysts9–11
have been developed, and these protocols are nowadays
extensively used in this reaction due to their excellent
Several solvents were tested using 1 mol% of NaOH
(Table 1, entries 1–6) at 110 °C. EtOH and MeOH were shown
to perform optimally in 1 : 1 mixtures with H2O (27% and
35% conversion, respectively). EtOH was selected for further
optimisation due to its lower toxicity and environmental
impact. Next, the ratio of the EtOH/H2O mixture was varied
(Table 1, entries 7–11), and an optimal value of 7 : 3 was
EaStCHEM School of Chemistry, University of St Andrews, St Andrews, KY16 9ST,
UK. E-mail: cc111@st-andrews.ac.uk; Fax: +44 (0)1334 463808
† The authors gratefully acknowledge the Royal Society (University Research
Fellowship to CSJC) and Dr David J. Nelson for his help conducting the kinetic
studies and for helpful discussions.
‡ Electronic supplementary information (ESI) available: Experimental
procedures, GC calibration, IR plots and products NMR spectra. See DOI:
10.1039/c5cy00313j
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Table 1 Optimisation of benzonitrile hydration catalysed by MOHa
Entry
Solvent
Base
Loading (mol%)
Conversion (%)b
1
2
3
4
5
6
7
8
EtOH/H2O (1 : 1)
CH3CN/H2O (1 : 1)
1,4-Dioxane/H2O (1 : 1)
MeOH/H2O (1 : 1)
THF/H2O (1 : 1)
H2O
EtOH/H2O (8 : 2)
EtOH/H2O (7 : 3)
EtOH/H2O (6 : 4)
EtOH/H2O (3 : 7)
EtOH/H2O (2 : 8)
EtOH/H2O (7 : 3)
EtOH/H2O (7 : 3)
EtOH/H2O (7 : 3)
EtOH/H2O (7 : 3)
EtOH/H2O (7 : 3)
EtOH/H2O (7 : 3)
EtOH/H2O (7 : 3)
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
LiOH
1
1
1
1
1
1
1
1
1
1
1
1
1
1
5
27
15
3
35
15
4
28
45
42
15
8
25
33
52
80
9
10
11
12
13
14
15
16
17
18
KOH
CsOH
NaOH
NaOH
NaOHd
NaOH
10
10
10
>99 (82)c
>99
>99 (81)c,e
a
b
Reaction conditions: benzonitrile (1 mmol), base (1 M stock solution), solvent (0.5 mL), 110 °C (external temperature), 17 h. Conversion
c
d
e
determined by GC based on benzonitrile, average of two reactions. Isolated yield. Semiconductor grade NaOH used. 90 °C (external
temperature).
determined. The role of the cation associated with the hydrox-
ide base was also examined (Table 1, entries 12–14).
with trace amounts of sodium benzoate (ca. 2%). Benzoic
acid was not observed. Using sodium benzoate instead of
NaOH as the reaction catalyst, under our optimal conditions,
did not allow for any reactivity. Thus, these results suggest
that the hydrolysis of benzamide is a negligible side-reaction,
under our reaction conditions. Experimental data were suc-
cessfully fitted to a pseudo-first order rate equation (Fig. 1),
with a rate constant k1 of 1.1 × 10−2 M−1 s−1 and t1/2 ≈ 39 min.
A similar approach was followed to study the second hydroly-
sis step, by monitoring the hydration of benzamide under the
optimal reaction conditions. Results confirmed that this sec-
ond hydration reaction was significantly slower than the first
hydration process (see ESI‡).
To test whether the methodology could be further
extended, the reactivity of aliphatic nitriles was next exam-
ined. Acetonitrile was selected as a model substrate, and after
conducting IR-monitored tests, under our optimal reaction
conditions, very low concentrations of an acetamide/acetate
mixture were detected. The low catalytic efficiency of the sys-
tem was explained by the complete consumption of OH− in
the second hydration step, as the amide species were over-
hydrolysed to their carboxylate derivatives. The hydration of
isobutyronitrile, pivalonitrile and hexanenitrile, under the
same conditions, also led to very low isolated yields of their
related amides (5%, 8% and 13%, respectively). Based on
these findings, we conclude that aliphatic nitriles are not
suitable substrates for the synthesis of amides using the pres-
ent system.
While CsOH led to the best result (52% conversion) com-
pared to NaOH (45% conversion), NaOH was selected for fur-
ther optimisation due to its lower cost and ease of handling.
Increasing the catalyst loading to 10 mol% (Table 1, entry 16)
gave full conversion of benzonitrile to the desired benzamide,
with 82% isolated yield. In order to rule out any catalytic spe-
cies other than NaOH being operative in this process (such
as metal traces contaminating low grade NaOH), the same
reaction was repeated using semiconductor grade NaOH
(Table 1, entry 17).13 Moreover, decreasing the reaction tem-
perature to 90 °C afforded the amide product with no signifi-
cant decrease in the isolated yield (Table 1, entry 18).
In order to demonstrate the versatility of the method, a
reaction scope was explored. The optimised conditions were
tested on a wide range of substituted aromatic nitriles, bear-
ing either electron-donating or electron-withdrawing substitu-
ents. Some heteroaromatic nitriles were also tested. These
results are summarised in Scheme 1. Ortho-, meta- and para-
substituted amides were all obtained in high yields. The
transformation of some challenging heteroaromatic nitriles
also proceeded with good yields. To our delight, the reaction
with benzonitrile was reproduced on a 1 g scale with no
apparent loss in efficiency or selectivity (86% isolated yield, no
chromatographic separation needed). All reactions were carried
out in air using distilled water and reagent grade ethanol.14
Kinetic studies were conducted in order to understand the
selectivity of this catalytic system. The catalytic hydration of
benzonitrile using 10 mol% of NaOH in EtOH/H2O (7 : 3) at
90 °C was monitored in situ using IR (see ESI‡). Results
showed that benzamide was the major species present, along
To understand the difference in reactivity between aro-
matic and aliphatic nitriles, an analysis of the well described
base-catalysed nitrile hydration mechanism has to be consid-
ered. As the base only acts catalytically in the first hydration
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Scheme 2 Base-catalysed hydration of aromatic and aliphatic nitriles
under the described reaction conditions.
Conclusions
In conclusion, we have demonstrated the efficiency of a
simple base-catalysed hydration of aromatic nitriles leading
to the selective synthesis of the corresponding amides. A
wide range of aromatic nitriles bearing a variety of electron-
donating and electron-withdrawing substituents, as well as
challenging heteroaromatic nitriles, were successfully converted
to their corresponding amides in good to excellent yields,
using 10 mol% of NaOH as catalyst and a EtOH/H2O (7 : 3)
solvent mixture. This methodology represents a highly practi-
cal, economical and straightforward protocol for the prepara-
tion of aromatic amides.
Notes and references
1 Comprehensive Organic Transformations, ed. R. C. Larock,
Wiley-VCH, New York, 2nd edn, 1999, p. 1988.
2 (a) The Chemistry of Amides, ed. J. Zabicky, Wiley-
Interscience, New York, 1970; (b) Polyesters and Polyamides,
ed. B. L. Deopura, B. Gupta, M. Joshi and R. Alagirusami,
CRC Press, Boca Raton, 2008.
Scheme 1 Scope of the NaOH-catalysed hydration of nitriles. Reaction
conditions: nitrile (1 mmol), NaOH (0.1 mmol), EtOH/H2O (7: 3, 0.5 mL),
90 °C (external temperature), 17 h. Isolated yields, average of 2 reactions.
3 For examples of acid-catalysed hydration methods, see: (a)
H. R. Snyder and C. T. Elston, J. Am. Chem. Soc., 1954, 76,
3039; (b) C. R. Hauser and C. J. Eby, J. Am. Chem. Soc.,
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Smith and J. March, Wiley & sons, Hoboken, 6th edn, 2007,
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4 For examples of base-catalysed hydration methods, see: (a)
J. H. Hall and M. Gisler, J. Org. Chem., 1976, 41, 3769; (b)
K. J. Merchant, Tetrahedron Lett., 2000, 41, 3747; (c) S.
Sahnoun, S. Messaoudi, J.-F. Peyrat, J.-D. Brion and M.
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Z. Liu, X. Feng and Q. Wang, Green Chem., 2012, 14, 921; (e)
P. K. Verma, U. Sharma, M. Bala, N. Kumar and B. Singh,
RSC Adv., 2013, 3, 895; ( f ) H. Chen, W. Dai, Y. Chen, Q. Xu,
J. Chen, L. Yu, Y. Zhao, M. Yea and Y. Pan, Green Chem.,
2014, 16, 2136; (g) H. Veisi, B. Maleki, M. Hamelian and S.
Ashrafi, RSC Adv., 2014, 5, 6365; (h) P. Casara, A.-M. Chollet,
A. Daihnaut, J.-M. Henlin, P. Lestage and F. Panayi, PCT Int.
Appl., 2011, WO2011070252A1.
Fig. 1 IR monitoring data for the hydration of benzonitrile. Reaction
conditions: benzonitrile (24 mmol), base (2.4 mmol), EtOH/H2O (7 : 3,
12 mL), 90 °C (external temperature).
step, a rapid second hydration to the corresponding carboxyl-
ates would consume this species, thus decreasing the rate of
the amide synthesis. A slower second hydration step would
afford more available base for the conversion of nitriles to
amides, and also a better selectivity towards the latter. These
conclusions are supported by our experimental data (see
ESI‡). The proposed kinetics of the hydration of aromatic
and aliphatic nitriles are thus presented in Scheme 2.
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5 For examples of peroxide-catalysed hydration methods, see:
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Org. Lett., 1999, 1, 189.
6 The oxygen–oxygen bond in peroxides is unstable and can
be easily cleaved into reactive radicals. For that reason,
organic and inorganic peroxides are known to be powerful
oxidising, bleaching and explosive substances, and they have
to be stored in cool dark containers, avoiding contact with
ketones or ether solvents.
7 N. Kornblum and S. Singaram, J. Org. Chem., 1979, 44, 4727.
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13 Semiconductor grade NaOH was purchased from Sigma-
Aldrich (product code 306576, 99.99% purity).
10 For examples of homogeneous transition metal systems, see:
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14 General procedure for the nitriles hydration: a vial was
charged in air with the nitrile (1 mmol), NaOH (0.1 mmol)
and EtOH/H2O (7 : 3, 0.5 mL). The reaction mixture was
stirred at 90 °C for 17 h, and then allowed to cool to room
temperature. A saturated aqueous solution of NaCl (5 mL)
and AcOEt (5 mL) were added. The phases were separated,
and the aqueous layer was extracted with EtOAc (5 × 5 mL).
The combined organic extracts were dried over MgSO4,
filtered and dried in vacuo. If necessary, the crude product
was purified by flash column chromatography (SiO2,
pentane/EtOAc, gradient 7 : 3 to 0 : 1). Terephthalamide and
isophthalamide were successfully recovered by simple
crystallisation at 4 °C for 24 h, washed with water (4 mL)
and acetone (4 mL) and further dried at 80 °C for 5 h.
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