Towards the rehabilitation of the Mathews' 'dry' hydrolysis reaction using microwave technology

Article abstract of DOI:10.1016/S0040-4039(02)01127-9

The Mathews' reaction is a one-pot preparation of carboxylic acids from their corresponding nitriles or amides by a 'dry' hydrolysis with phthalic acid or anhydride in the absence of water and solvent. Excellent isolated yields and selectivity (up to 99%) were attained within short reaction times (typically, 30 minutes) when the reaction was performed under microwave heating.

Full text of DOI:10.1016/S0040-4039(02)01127-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 5555–5557
Towards the rehabilitation of the Mathews’ ‘dry’ hydrolysis
reaction using microwave technology
Farid Chemat*
Laboratoire de Chimie des Substances Naturelles et des Sciences des Aliments, Faculte´ des Sciences et Technologies,
Universite´ de la Re´union, 15 avenue Rene´ Cassin, B.P. 7151, F-97715 Saint Denis messag cedex 9, La Re´union, France D.O.M
Received 29 May 2002; revised 12 June 2002; accepted 13 June 2002
Abstract—The Mathews’ reaction is a one-pot preparation of carboxylic acids from their corresponding nitriles or amides by a
‘dry’ hydrolysis with phthalic acid or anhydride in the absence of water and solvent. Excellent isolated yields and selectivity (up
to 99%) were attained within short reaction times (typically, 30 minutes) when the reaction was performed under microwave
heating. © 2002 Elsevier Science Ltd. All rights reserved.
The Mathews’ reaction, a ‘dry’ hydrolysis procedure of
nitriles by phthalic acid or amides by phthalic anhy-
dride to give the corresponding carboxylic acid, is
roughly one century old1,2 and during this period, there
have been very few studies.3–7 The need of a high
reaction temperature, expensive co-reagents (tetra-
chloro and tetrafluoro phthalic acids or anhydrides)
and long reaction periods (6–7 days to obtain often
only low to moderate yields) have overshadowed its
main advantages: simplicity, high yield and selectivity,
and also use of inexpensive reagents.
perform reactions very efficiently in the absence of any
organic solvents (so called dry media conditions) and in
closed vessels. The use of microwaves provides fast
volumetric heating of the chemicals above their boiling
points thus enhancing reaction rates and dramatically
shortening preparation times.
A kinetic study, together with a GC/MS (gas chro-
matography with a mass spectrometer detector) investi-
gation of the crude reaction mixture, allowed the
reaction pathway illustrated in Scheme 1 to be estab-
lished. The reaction mixtures contains initially equimo-
lar quantities of nitrile 1 and phthalic acid 2. The
intermediate compounds 4 and 5, respectively, the
amide corresponding to the starting nitrile 1 and
phthalic anhydride, as well as the intermediates 3, 6 and
the expected compounds, carboxylic acid 7 and phthal-
imide 8, have been identified by GC/MS technique.11
The first reaction step is probably protonation of the
nitrile followed by a nucleophilic attack giving the
identified intermediate 3. An internal proton shift and
substitution give anhydride 5 and the intermediate
amide 4. Reaction of 4 and 5 by a similar pathway
gives 6 whose hydrolysis with the water generated in
situ gives the expected acid 7 and phthalimide 8. Fur-
thermore heating 4 and 5 under the same reaction
conditions gives also the expected acid 7 and phtalimide
8. The single water equivalent needed for complete
hydrolysis of the nitrile is provided in situ by phthalic
acid. Because this hydrolysis reaction is run without
addition of water, we call it ‘dry’ hydrolysis.
We have found that using microwave technology under
solvent- and water-free conditions, the hydrolysis of
nitriles with phthalic acid, or of amides with phthalic
anhydride, takes place in excellent yields (>98%) and
selectivity (>99%) and with short reaction times (<30
min). The reaction allows the presence of some func-
tional groups thanks to the rather mild acidic condi-
tions. The corresponding products are carboxylic acid
and phthalimide.
In recent decades microwave technology has taken an
undeniable place in chemical laboratory practice as a
very effective and non-polluting method of activating
reactions.8,9 Examples of this technology in organic
synthesis and to organo-metallic chemistry are numer-
ous.10 The greater successes achieved have been to
Keywords: hydrolysis; microwave; nitrile; amid; carboxylic acid.
* Fax: +262.262.93.81.83; e-mail: chemat@univ-reunion.fr
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01127-9

5556
F. Chemat / Tetrahedron Letters 43 (2002) 5555–5557
Scheme 1. Mechanism of the Mathews’ ‘dry’ hydrolysis reaction.
Microwave heating is used as a useful tool for prepara-
tive organic synthesis: reactions can be carried out in a
closed Teflon vessel under monitored pressure and tem-
perature. Higher temperatures could be attained with
microwave heating which reduce reaction times in com-
parison with conventional reflux reaction conditions.
Degradation reactions do not occur using microwave
technology, enhancing yields and selectivity.12,13
The generally drastic conventional conditions of nitrile
and amide hydrolysis lead to severe drawbacks with
compounds containing sensitive functional groups. The
method described here was tested as a possible alterna-
tive.14–16 Since nitriles or amides are more difficult to
hydrolyze than esters, chemo-selective hydrolysis of the
former functionality is an attractive objective. There-
fore an investigation was initiated with a series of
bi-functional compounds (see Table 1). Fairly good
yields are obtained simply by using microwave under
mild reaction conditions.
Figure 1. Microwave reactor suitable for organic prepara-
tions.
In order to gain more insight into this reaction, kinetic
studies have been carried out. Our results fit with a
second order kinetic equation: first partial order for
both nitrile and phthalic acid. Activation energy and
pre-exponential factor have been determined using the
Arrhenius equation: Ea=35.6 kJ/mole and ln A=9.1.
‘Dry’ hydrolysis of benzonitrile with phthalic acid is
complete after 7 days at 140°C. The same reaction can
be achieved after only 30 minutes at 250°C and 10 atm
using microwave heating.
In summary, an extremely simple method for the prepa-
ration of carboxylic acids and phthalimides has been
rediscovered using microwave technology. The
Mathews reaction allows the general, efficient, and
chemo-selective hydrolysis of primary and secondary
nitriles or amides to carboxylic acids. The reaction can
be carried out in the absence of water, solvent, added
acid or base even in the presence of an ester
functionality.

F. Chemat / Tetrahedron Letters 43 (2002) 5555–5557
5557
Table 1. ‘Dry’ hydrolysis of nitriles 1 and amides 4 to carboxylic acids 7 (MW, 250°C; 10 atm)
R (name)
Reaction time (min)
Yield (%)
Selectivity (%)
Nitrile with phthalic acid
PhCN (benzonitrile)
15
30
15
30
30
99
99
53
92
98
99
99
70
96
99
PhCH2CN (phenylacetonitrile)
C2H5OOCCH2CONH2 (ethyl cyanoacetate)
HOPhCH2CONH2 (p-hydroxyphenylacetonitrile)
(C3H7)2CHCN (valeronitrile)
Amide with phthalic anhydride
PhCONH2 (benzamide)
PhCH2CONH2 (phenylacetamide)
PhOCH2CONH2 (phenoxyacetamide)
(C3H7)2CHCONH2 (valeramide)
(CH3)3CCONH2 (pivalamide)
15
20
30
15
15
99
97
79
95
96
99
98
90
98
98
Acknowledgements
14. In a typical run, the nitrile (30 mmol) and phthalic acid
(30 mmol) were introduced in the microwave reactor
(Fig. 1), and heated under stirring. At the desired reac-
tion time, the reactor was rapidly cooled down in a
water/ice mixture, and chloroform (30 mL) is added. The
mixture is stirred for 5 min, and the solid filtered off. The
chloroform solution contains unreacted nitrile, amide and
carboxylic acid. The residual solid contains unchanged
phthalic acid, phthalic anhydride and phthalimide. The
volume of the chloroform solution is adjusted to 50 mL
and naphthalene is added as internal standard. The
resulting solution is analyzed by GC/MS (Hewlett Pack-
ard 3690; QC BP20 capillary column, 25 m).
The author thanks Professor Jacqueline Smadja and
Professor Bernard Vidal for their valuable comments
and helpful discussions.
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