Ultrasonics Sonochemistry 18 (2011) 2831

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Ultrasonics Sonochemistry
journal homepage: www.elsevier.com/locate/ultsonch

Short Communication

Swift and efcient sono-hydrolysis of nitriles to carboxylic acids under basic

condition: Role of the oxide anion radical in the hydrolysis mechanism
Pascal Lignier, Julien Estager, Nathalie Kardos, Lydie Gravouil, Julien Gazza, Emmanuel Naffrechoux,
Micheline Draye *
Universit de Savoie, Laboratoire de Chimie Molculaire et Environnement, Campus Scientique de Savoie Technolac, 73376 Le Bourget du Lac Cedex, France

a r t i c l e i n f o a b s t r a c t

Article history: Carboxylic acids are promising candidates for new sustainable strategies in organic synthesis. In this
Received 25 November 2008 paper, we ascertain the potential of ultrasound for the hydrolysis of nitriles into carboxylic acids through
Received in revised form 8 March 2010 the study of key parameters of the reaction: pH, hydrolysis medium, reaction time and activation tech-
Accepted 20 April 2010
nique. The positive inuence of ultrasound under basic conditions is due to more than mechanical effects
Available online 29 April 2010
of cavitation. Indeed, the rate of hydrolysis is dramatically increased under sonication in NaOH solutions.

A radical mechanism involving the oxide anion radical O is proposed.
Keywords:
2010 Elsevier B.V. All rights reserved.
Sonochemistry
Nitrile hydrolysis
Carboxylic acid
Benzoic acid
Adipic acid

1. Introduction micro-mixing, mass transport or reduction of particles size [11].

Hydrolysis of nitriles enables the synthesis of amides and car-
boxylic acids such as aminoacids, acrylamide or adipic acid [1].
Carboxylic acids are promising compounds for sustainable synthe-
sis [2]. Because of their low reactivity, the transformation of start-
ing materials usually requires harsh conditions, such as a strong
acidic [3] or basic media [4], leading to the amide intermediate that
is generally quickly hydrolysed as described in Fig. 1.
Moreover, these products are rarely stable under these condi-
tions of pH and sustainable development requires softer condi-
tions. Thus, some alternatives have been proposed including
enzymatic biocatalysis [5] and heterogeneous organometallic
catalysis [6].
Sonochemistry is an alternative to replace these catalysts. In-
deed, ultrasound is sometimes considered as a sort of physical cat-
alyst that produces specic physical and chemical effects [7].
Actually, it is known to enhance some processes through a physical
phenomenon called cavitation, which is the formation, growth and
collapse of bubbles in an elastic liquid [8]. By imploding, these bub-
bles create locally high pressure (up to 1000 bars) and temperature
(up to 5000 K) [9] that lead to high-energy radical mechanisms
[10] and also generate some interesting physical effects, such as
* Corresponding author. Address: University of Savoie, Polytech Annecy-
Chambry, Scientic Campus of Savoie Technolac, 73376 Le Bourget du Lac Cedex,
France. Tel.: +33 4 79 75 88 59; fax: +33 4 79 75 86 74.
E-mail address: Micheline.draye@univ-savoie.fr (M. Draye).
There exists a growing list of organic reactions which take advan-
tage of this phenomenon, as for example, thiocyanation of aro-
matic compounds [12], halogenation of alcohol [13] or benzoin
condensation [14]. Because of the very harsh environment that is
produced upon cavitation in solution, sonochemistry is commonly
associated with radical chemistry as it has been observed, for in-
stance, for hydroxystannation of alkenes [15].
In the present paper, we have studied the effect of ultrasound
on the hydrolysis of nitriles under both basic and acidic conditions.
2. Experimental
2.1. Reagent, apparatus and analysis
All reagents, purchased from Aldrich, are of analytical grade and
used without further purication.
Concentrated hydrochloric acid and sodium hydroxide (Acros
organics) were used to adjust the pH of the solutions.
An ultrasonic horn operating at a frequency of 30 kHz was used
for the sonochemical experiments. Its acoustic power of
1.9 W mL 1 was determined by calorimetry using a procedure de-
scribed in the literature [16].
A HewlettPackard model 1100 HPLC equipped with a UV
detector was used for separation and for qualitative and quantita-
tive analyses of the experiments. The products were separated on a
5 lm Interchim C18-ODS2 column and eluted with a phosphoric
acid/acetonitrile (80/20) buffer (pH 2.5). The detection wavelength

1350-4177/$ - see front matter 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.ultsonch.2010.04.006
 P. Lignier et al. / Ultrasonics Sonochemistry 18 (2011) 2831 29

O O O icated for 30 min and bis(trimethylsilyl)hexadioate is obtained

OH- or H+ H2O, -NH4+ or -NH3
R N
Slow R NH2 Fast R OH
Fig. 1. Hydrolysis of a nitrile in acidic or basic conditions.
of UV detector was set at 220 nm, corresponding to the maximum
absorption wavelength of benzonitrile, benzamide and benzoic
acid.
The products were isolated and characterized by physical and
spectral data. 1H NMR and 13C NMR spectra were recorded on a
Brucker AMX 300 MHz spectrometer in CDCl3 (benzamide and
benzoic acid characterization) or DMSO-d6 (adipic acid character-
ization) with chemical shifts (d) given in ppm relative to tetra-
methylsilane (TMS). FTIR spectra were recorded using a Perkin
Elmer spectrometer with KBr pellets and reported in cm 1. GC
MS spectra were recorded on an Agilent 7973N MS coupled to an
Agilent 6890 GC equipped with a HP 5 column. Adipic acid was
previously silylated using N,O-bis(trimethylsilyl)triuoroaceta-
mide (BSTFA) as derivatization reagent. Melting points were deter-
mined on a Koer bench device (Wagner & Munz) and were not
corrected.
2.2. Synthesis of benzoic acid
2.2.1. Experimental procedure using ultrasonic activation
Hydrochloric acid or sodium hydroxide solution (9.5 mL) with
the appropriate pH are sonicated for a determined time with
0.5 mL (5 mmol) of benzonitrile. Argon or air is bubbled in water
during sodium hydroxide solution preparation. Control of temper-
ature is ensured by a thermocouple. Reaction is then performed
under ambient air or Argon atmosphere.
or with 100% yield.
R O
Bis(trimethylsilyl)hexanedioate: MS (EI) m/z (%): 275 (19), 247
(2), 231 (2), 217 (6), 204 (4), 185 (6), 172 (14), 159 (11), 147
(38), 141 (22), 129 (10), 117 (12), 111 (62), 99 (4), 83 (17), 73
(100), 67 (4), 55 (41), 45 (20), 29 (5).
3. Results and discussion
Benzonitrile was chosen as model compound to enable moni-
toring of the reaction by UV absorption. Moreover, its degradation
products due to sonication have already been determined and their
structures have been described previously [17,18].
In order to investigate a possible inuence of ultrasound on
benzonitrile hydrolysis, two sets of experiments have been per-
formed. In the rst set, reactions have been carried out without
sonication. In the second set, the reaction has been performed in
the same experimental conditions but under sonication. These con-
ditions are summarized in Fig. 2.
In each case, yields have been determined by HPLC with UV
detection (k = 220 nm) and after calibration. Results are given in
Table 1.
Results show a great inuence of pH on the feasibility of the
reaction and on its mechanism under ultrasonic conditions since
N )))), 30 kHz, 1.90 WmL -1
CO2H 100C, 45 min. CO2H
100C, 8h.
NaOH 2M or HCl 2M NaOH 2M or HCl 2M
Fig. 2. Experimental conditions for hydrolysis of benzonitrile under thermal or
ultrasonic activation in acidic or basic conditions.

2.2.2. Experimental procedure using thermal activation

Hydrochloric acid or sodium hydroxide solution (40 mL) with Table 1
the appropriate concentration are mixed with 2.5 mL (25 mmol) Conversion percentage of benzonitrile in benzoic acid in basic and acidic conditions,
with or without sonication: P = 19 W, F = 30 kHz, [HCl] = 2 M, [NaOH] = 2 M.
of benzonitrile at reux for 8 h. Control of temperature is insured
by a thermal regulator. Entry Activation method Catalyst Time, h Benzoic acid yield, %
Benzoic acid: m.p. 122 C. 1H NMR (CDCl3, 300 MHz): d = 7.50 1 Ultrasound NaOH 0.75 95
(m, 2H), d = 7.64 (m, 1H), d = 8.15 (d (J = 7.71 Hz), 2H). 13C NMR 2 Thermal NaOH 8 93
(CDCl3, 75 MHz): d = 128.41 (Csp2meta), d = 130.58 (Csp2-COOH), 3 Ultrasound HCl 0.75 0
4 Ultrasound HCl 1.5 0
d = 130.11 (Csp2ortho), d = 133.73 (Csp2para), d = 172.01 (COOH). FTIR
5 Thermal HCl 8 74
(1% in KBr): OH: 3405 cm 1, C@O: 1698 cm 1, Csp2Csp2: 1598,
1452 cm 1, Csp2-H: 3070 cm 1.
Benzamide: m.p. 129 C. 1H NMR (CDCl3, 300 MHz): d = 7.47 (m,
1H), d = 7.49 (m, 2H), d = 7.86 (d (J = 7.17 Hz), 2H), d = 6.10 (s, 2H).
13 100 0.25M
C NMR (75 MHz, CDCl3): d = 127.59 (Csp2ortho), d = 128.56 0.5M
(Csp2meta), d = 131.48 (Csp2para), d = 133.25 (Csp2-CONH2), 1M
d = 168.98 (CONH2). FTIR (1% in KBr): NH: 3369 cm 1, C@O: 2M
1680 cm 1, Csp2Csp2: 1625, 1464 cm 1, Csp2-H: 3070 cm 1. 80

2.3. Synthesis of adipic acid

Conversion (%)

60

Sodium hydroxide (9.5 mL) with the appropriate concentration

are sonicated for 45 min with 0.5 mL (4.4 mmol) of adiponitrile.
40
Control of temperature is insured by a thermal regulator.
Adipic acid: m.p. 151 C. 1H NMR (DMSO-d6, 300 MHz): d = 1.51
(m, 4H, CH2CH2), d = 2.23 (m, 4H, CH2-COOH), d = 11.8 (s, 1H, 20
COOH). 13C NMR (DMSO-d6, 75 MHz): d = 24.32 (CH2CH2),
d = 33.12 (CH2-COOH), d = 173.54 (COOH). FTIR (1% in KBr): OH:
3038 cm 1, Csp3-H: 2994, C@O: 1699 cm 1, Csp3Csp3: 1445 cm 1. 0
0 10 20 30 40 50 60
2.4. Synthesis of bis(trimethylsilyl)hexanedioate Time (min)

Fig. 3. Inuence of time and NaOH concentration on the conversion of benzonitrile

To 10 lL (0.19 mmol) of adipic acid diluted in 800 lL of diethyl in benzoic acid under ultrasonic irradiation, in basic conditions, under air
ether are added 100 lL (0.97 mmol) of BSTFA. The mixture is son- atmosphere. F = 30 kHz and P = 1.9 W mL 1.
30
CO2H
))))
HO
H2O H + HO
HO + - OH H2O + O-
- OH H + O-

Fig. 5. Formation of anionic radical O in basic medium under sonication
pH P 11.9.
C6 H5 CN OH-
HOC6 H5 CN .OH
k = 3.9.109 Lmol-1 s -1 k = 1.3.1010 Lmol-1 s -1

Fig. 6. Reactivity of OH radical in presence of hydroxide anion and benzonitrile.
hydrolysis only occurs under basic conditions whereas, acidic
catalysis, under classical conditions, yields benzoic acid.
We decided to optimize the reaction under basic conditions in
terms of NaOH concentration and reaction time to understand
the importance of each of these parameters. Experiments were rst
carried out at various NaOH concentrations (0.25, 0.5, 1 and
2 mol L 1) and during four reaction times (15, 30, 45, and
60 min). Yields of benzoic acid as a function of the reaction time
for 0.252 mol L 1 of NaOH are summarized in Fig. 3.
Fig. 3 shows a signicant increase in the rate of the reaction
when NaOH concentration increases. This observation tends to
support the notion that OH takes part into the hydrolysis mecha-
nism. In addition, reaction yields do not monotonously increase
with reaction time. For any NaOH concentration, maximum yields
are obtained after 45 min. However, a decrease of the overall yield
is observed for longer reaction times, and this observation can be
explained by the degradation of benzoic acid into hydroxybenzoic
acid, maleic acid and/or oxalic acid as described in Fig. 4 [18,19].
After optimization of the experimental conditions, the same
experiment was performed under argon atmosphere. For a 2 M so-
dium hydroxide concentration and after 45 min of sonication, a
maximum yield of 85% in benzoic acid is obtained instead of the
95% obtained in the presence of air.
All these results give very interesting information that may jus-
tify a specic mechanism for nitrile hydrolysis under ultrasonic
irradiation. First, the difference between the reaction in acidic
and basic conditions tends to prove that the effect of ultrasound
are potentially of chemical origin. Indeed, the physico-chemical
properties of the system (heterogeneity, viscosity, surface ten-
N .
N O
.O -
Fig. 7. Hypothesis on the mechanism of sono-hydrolysis of nitrile in basic conditions.
P. Lignier et al. / Ultrasonics Sonochemistry 18 (2011) 2831
O
CO2H HO CO2H O
)))) )))) OH OH
+ HO
OH
HO O
O
Fig. 4. Equation for sono-degradation of benzoic acid.
sion. . .) are equivalent in both cases and, as a consequence, the
physical effects usually recalled at low frequency cannot explain
this high variation in reactivity. During the collapse of the cavita-
tion bubble, high pressure and temperature are generated leading
to the formation of OH and H radicals [19]. In addition, the com-
position of water under sonication is somewhat different and de-
pends on its pH. In acidic conditions (HCl, pH 2), Jason et al.
observed that OH radicals are trapped by chloride anions with a
rate constant of 4.3  109 L mol 1 s 1 [20]. This observation could
explain the failure of the nitrile hydrolysis reaction in acidic condi-
H2 O + O.- tions under sonication. Under strongly basic conditions, because
the couple O /OH has a pKa of 11.9 [21] the anionic radical O
can play a role in the hydrolysis mechanism. The formation of
oxide anion radical is described on Fig. 5.
The rate constant of the second step was determined to be
1.3  1010 L mol 1 s 1 [22] which is an order of magnitude higher
than the one determined for the reaction of benzonitrile with
OH (3.9  109 L mol 1 s 1) [23,24]. The two reactions are de-
scribed on Fig. 6.
We then determined the OH concentration in pure water and
  
the O concentration (O is the basic form of OH above pH
11.9) in a 2 M NaOH solution with or without air by using a UV
methodology described in the literature [16]. The results show that
in the presence of air, more than 58 lmol L 1 of O are produced
within 40 min, while 38 lmol L 1 O are produced under argon

atmosphere and only 13 lmol L 1 O exist in pure water after this
time.
Benzonitrile is slightly soluble in water (15 mg mL 1 at room
temperature). Considering the maximum solubility of benzonitrile
in pure water and the experimental conditions used in our work,
0.02 mol of benzonitrile competed with 0.02 mol of hydroxide an-
ion to react with the hydroxyl radical. However, hydroxyl radical
reacts more rapidly with hydroxide anion than with benzonitrile
and this observation can lead to a mechanism that may explain
the formation of sodium benzoate under strong basic conditions.
This mechanism is described in Fig. 7.
Following this hypothesis, benzonitrile hydrolysis under ultra-
sonic irradiation can occur under basic conditions only through
the formation of an oxide anion radical O which reacts with ben-
zonitrile and enables the formation of an amide anion radical. Fur-
ther protonation by H radical and reaction with O leads to the
formation of benzoate. Of course, this mechanism remains hypo-
thetical since the identication of each of these short-lived inter-
mediates is not possible.
HN O HN OH O NH2
NH2
.
.O - O
H.
O
H. NH2
O
OH
O - NH3
O
 P. Lignier et al. / Ultrasonics Sonochemistry 18 (2011) 2831
)))), 30 kHz, 1.90 WmL-1
CN 100C, 45 min.
NC HO2C
NaOH 2M
Fig. 8. Hydrolysis of adiponitrile under ultrasonic activation.
To conrm the ability of ultrasound to directly hydrolyse any
nitrile group into a carboxylic acid one, this methodology was used
for the conversion of adiponitrile in adipic acid, a compound of
industrial importance [25]. The reaction and the experimental con-
ditions are described in Fig. 8.
Due to the absence of a stabilizing aromatic ring, adiponitrile
was supposed to be more reactive than benzonitrile. As expected,
in 45 min, adipic acid was successfully synthesised with a quanti-
tative yield. This result underlines the very high potentiality of our
methodology using ultrasound for the direct conversion of nitriles
into carboxylic acids.
4. Conclusion
In this paper, we prove that ultrasonic irradiation may be a very
promising method for hydrolysis of nitriles in basic conditions. In-
deed, after optimization of different parameters, a 95% yield in
benzoic acid is obtained from benzonitrile and, under the same
conditions, adiponitrile quantitatively reacts to give adipic acid.
The high yields and fast kinetics cannot be justied only by
mechanical effects due to sonication. Based on kinetic studies re-
ported in the literature, a catalytic effect implying the formation
of oxide anion radical O is then considered, and a radical mecha-
nism for the hydrolysis is proposed.
31
Acknowledgement
CO2H
The authors are very grateful to the Ecole Nationale Suprieure
de Chimie de Paris for nancial support.
References
[1] J. Crosby, J. Moilliet, J.S. Parratt, N.J. Turner, J. Chem. Soc., Perkin Trans. I (1994)
16792.
[2] L. Gooen, N. Rodriguez, K. Gooen, Angew. Chem., Int. Ed. 47 (2008) 3100.
[3] G.R. Newkome, C.N. Mooreeld, K.J. Thoriot, J. Org. Chem. 53 (1988) 5553.
[4] P.A. Aristoff, P.D. Johnson, A.W. Harrison, J. Am. Chem. Soc. 107 (1985) 7967.
[5] K. Faber, Biotransformations in Organic Chemistry, Springer-Verlag, 2004.
[6] V. Kukushkin, A. Pombeiro, Inorg. Chim. Acta 358 (2005) 1.
[7] P. Cintas, J.L. Luche, Green Chem. 1 (1999) 115.
[8] E.A. Neppiras, Phys. Reports 61 (1980) 159.
[9] K. Suslick, D.A. Hammerton, R.E. Cline Jr., J. Am. Chem. Soc. 108 (1986) 5641.
[10] K. Suslick, P. Schubert, J. Goodale, J. Am. Chem. Soc. 103 (1981) 7342.
[11] J.L. Luche, in: Synthetic Organic Sonochemistry, Plenum Press, New York, 1998,
p. 169.
[12] H.R. Memarian, I. Mohammadpoor-Baltork, K. Nikoofar, Ultrason. Sonochem.
15 (2008) 459.
[13] B.C. Ranu, R. Jana, Eur. J. Org. Chem. (2005) 705.
[14] J. Estager, J.-M. Lvque, R. Turgis, M. Draye, Tetrahedron Lett. 48 (2007) 755.
[15] E. Nakamura, Y. Imanishi, D. Machii, J. Org. Chem. 59 (1994) 8178.
[16] K. Shinobu, T. Kimura, T. Sakamoto, T. Kondo, H. Mitome, Ultrason. Sonochem.
10 (2003) 149.
[17] A.N. Nikopoulos, O. Igglessis-Markopoulou, N. Papayannakos, Ultrason.
Sonochem. 11 (2004) 183.
[18] R.H. de Lima Leite, P. Cognet, A.M. Wilhelm, H. Delmas, Chem. Eng. Sci. 57
(2002) 767.
[19] N.H. Ince, Appl. Catal. B: Environ. 29 (2001) 167.
[20] G.G. Jayson, B.J. Parsons, A.J. Swallow, J. Chem. Soc., Faraday Trans. I 69 (1973)
1597.
[21] C. Chatgilialoglu, M. Ioele, Q.G. Merlazzani, Radiat. Phys. Chem. 72 (2005) 251.
[22] D. Zehavi, J. Rabani, J. Phys. Chem. 75 (1971) 1738.
[23] P. Neta, R.H. Schuler, Radiat. Res. 64 (1975) 2847.
[24] B. Chutny, A.J. Swallow, Trans. Faraday Soc. 66 (1970) 2847.
[25] A. Casellan, J.C.J. Bart, S. Cavallaro, Catal. Today 9 (1991) 237.