Swift and efficient_sono-hydrolysis_of_n

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Short Communication
Swift and efficient 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 *
Université de Savoie, Laboratoire de Chimie Moléculaire et Environnement, Campus Scientifique de Savoie Technolac, 73376 Le Bourget du Lac Cedex, France
a r t i c l e i n f o
Article history:
Received 25 November 2008
Received in revised form 8 March 2010
Accepted 20 April 2010
Available online 29 April 2010
Keywords:
Sonochemistry
Nitrile hydrolysis
Carboxylic acid
Benzoic acid
Adipic acid
a b s t r a c t
Carboxylic acids are promising candidates for new sustainable strategies in organic synthesis. In this
paper, we ascertain the potential of ultrasound for the hydrolysis of nitriles into carboxylic acids through
the study of key parameters of the reaction: pH, hydrolysis medium, reaction time and activation tech-
nique. The positive influence of ultrasound under basic conditions is due to more than mechanical effects
of cavitation. Indeed, the rate of hydrolysis is dramatically increased under sonication in NaOH solutions.
A radical mechanism involving the oxide anion radical O
ÅÀ
is proposed.
Ó 2010 Elsevier B.V. All rights reserved.
1. Introduction
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 specific 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
micro-mixing, mass transport or reduction of particles size [11].
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 purification.
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 mLÀ1
was determined by calorimetry using a procedure de-
scribed in the literature [16].
A Hewlett–Packard 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 Ó 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.ultsonch.2010.04.006
* Corresponding author. Address: University of Savoie, Polytech Annecy-
Chambéry, Scientific 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).
Ultrasonics Sonochemistry 18 (2011) 28–31
Contents lists available at ScienceDirect
Ultrasonics Sonochemistry
journal homepage: www.elsevier.com/locate/ultsonch

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. 1
H NMR and 13
C 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 cmÀ1
. 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)trifluoroaceta-
mide (BSTFA) as derivatization reagent. Melting points were deter-
mined on a Kofler 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.
2.2.2. Experimental procedure using thermal activation
Hydrochloric acid or sodium hydroxide solution (40 mL) with
the appropriate concentration are mixed with 2.5 mL (25 mmol)
of benzonitrile at reflux for 8 h. Control of temperature is insured
by a thermal regulator.
Benzoic acid: m.p. 122 °C. 1
H NMR (CDCl3, 300 MHz): d = 7.50
(m, 2H), d = 7.64 (m, 1H), d = 8.15 (d (J = 7.71 Hz), 2H). 13
C NMR
(CDCl3, 75 MHz): d = 128.41 (Csp2meta), d = 130.58 (Csp2-COOH),
d = 130.11 (Csp2ortho), d = 133.73 (Csp2para), d = 172.01 (COOH). FTIR
(1% in KBr): O–H: 3405 cmÀ1
, C@O: 1698 cmÀ1
, Csp2–Csp2: 1598,
1452 cmÀ1
, Csp2-H: 3070 cmÀ1
.
Benzamide: m.p. 129 °C. 1
H 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
C NMR (75 MHz, CDCl3): d = 127.59 (Csp2ortho), d = 128.56
(Csp2meta), d = 131.48 (Csp2para), d = 133.25 (Csp2-CONH2),
d = 168.98 (CONH2). FTIR (1% in KBr): N–H: 3369 cmÀ1
, C@O:
1680 cmÀ1
, Csp2–Csp2: 1625, 1464 cmÀ1
, Csp2-H: 3070 cmÀ1
.
2.3. Synthesis of adipic acid
Sodium hydroxide (9.5 mL) with the appropriate concentration
are sonicated for 45 min with 0.5 mL (4.4 mmol) of adiponitrile.
Control of temperature is insured by a thermal regulator.
Adipic acid: m.p. 151 °C. 1
H NMR (DMSO-d6, 300 MHz): d = 1.51
(m, 4H, CH2–CH2), d = 2.23 (m, 4H, CH2-COOH), d = 11.8 (s, 1H,
COOH). 13
C NMR (DMSO-d6, 75 MHz): d = 24.32 (CH2–CH2),
d = 33.12 (CH2-COOH), d = 173.54 (COOH). FTIR (1% in KBr): O–H:
3038 cmÀ1
, Csp3-H: 2994, C@O: 1699 cmÀ1
, Csp3–Csp3: 1445 cmÀ1
.
2.4. Synthesis of bis(trimethylsilyl)hexanedioate
To 10 lL (0.19 mmol) of adipic acid diluted in 800 lL of diethyl
ether are added 100 lL (0.97 mmol) of BSTFA. The mixture is son-
icated for 30 min and bis(trimethylsilyl)hexadioate is obtained
with 100% yield.
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 influence of ultrasound on
benzonitrile hydrolysis, two sets of experiments have been per-
formed. In the first 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 influence of pH on the feasibility of the
reaction and on its mechanism under ultrasonic conditions since
N
CO2H CO2H
100°C, 8h.
NaOH 2M or HCl 2M NaOH 2M or HCl 2M
)))), 30 kHz, 1.90 WmL-1
100°C, 45 min.
Fig. 2. Experimental conditions for hydrolysis of benzonitrile under thermal or
ultrasonic activation in acidic or basic conditions.
Table 1
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.
Entry Activation method Catalyst Time, h Benzoic acid yield, %
1 Ultrasound NaOH 0.75 95
2 Thermal NaOH 8 93
3 Ultrasound HCl 0.75 0
4 Ultrasound HCl 1.5 0
5 Thermal HCl 8 74
0 10 20 30 40 50 60
0
20
40
60
80
100
Conversion(%)
Time (min)
0.25M
0.5M
1M
2M
Fig. 3. Influence of time and NaOH concentration on the conversion of benzonitrile
in benzoic acid under ultrasonic irradiation,
in basic conditions, under air
atmosphere. F = 30 kHz and P = 1.9 W mLÀ1
.
R N
R
O
NH2 R
O
OH R
O
O
OH- or H+
Slow
H2O, -NH4
+ or -NH3
Fast
or
Fig. 1. Hydrolysis of a nitrile in acidic or basic conditions.
P. Lignier et al. / Ultrasonics Sonochemistry 18 (2011) 28–31 29

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 first
carried out at various NaOH concentrations (0.25, 0.5, 1 and
2 mol LÀ1
) and during four reaction times (15, 30, 45, and
60 min). Yields of benzoic acid as a function of the reaction time
for 0.25–2 mol LÀ1
of NaOH are summarized in Fig. 3.
Fig. 3 shows a significant increase in the rate of the reaction
when NaOH concentration increases. This observation tends to
support the notion that OHÀ
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 specific 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-
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 OHÅ
and HÅ
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 OHÅ
radicals are trapped by chloride anions with a
rate constant of 4.3 Â 109
L molÀ1
sÀ1
[20]. This observation could
explain the failure of the nitrile hydrolysis reaction in acidic condi-
tions under sonication. Under strongly basic conditions, because
the couple OÅÀ
/OHÅ
has a pKa of 11.9 [21] the anionic radical OÅÀ
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 Â 1010
L molÀ1
sÀ1
[22] which is an order of magnitude higher
than the one determined for the reaction of benzonitrile with
OHÅ
(3.9 Â 109
L molÀ1
sÀ1
) [23,24]. The two reactions are de-
scribed on Fig. 6.
We then determined the OHÅ
concentration in pure water and
the O
ÅÀ
concentration (O
ÅÀ
is the basic form of OH
Å
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 LÀ1
of OÅÀ
are produced
within 40 min, while 38 lmol LÀ1
O
ÅÀ
are produced under argon
atmosphere and only 13 lmol LÀ1
OÅÀ
exist in pure water after this
time.
Benzonitrile is slightly soluble in water (1–5 mg mLÀ1
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 OÅÀ
which reacts with ben-
zonitrile and enables the formation of an ‘amide anion radical’. Fur-
ther protonation by HÅ
radical and reaction with OÅÀ
leads to the
formation of benzoate. Of course, this mechanism remains hypo-
thetical since the identification of each of these short-lived inter-
mediates is not possible.
CO2H CO2H
OH
CO2H
OH
OH
OH
OH
O
O
OH
OH
O
O
+
)))) )))) ))))
Fig. 4. Equation for sono-degradation of benzoic acid.
H2O H° + HO°
HO° +-OH H2O + O°-
-OH H° + O°-
Fig. 5. Formation of anionic radical O
ÅÀ
in basic medium under sonication
pH P 11.9.
.OH
k = 3.9.109
Lmol-1
s-1
k = 1.3.1010
Lmol-1
s-1
C6H5CN OH-
H2O + O.-
HOC6H5CN .
k = 3.9.10 Lmol-1
s-1 -1
Fig. 6. Reactivity of OH
Å
radical in presence of hydroxide anion and benzonitrile.
N
N O NH O NH OH O NH2
NH2
O
O
NH2
O
OH
O
O
.O-
H. .O-
H.
.
.
- NH3
Fig. 7. Hypothesis on the mechanism of sono-hydrolysis of nitrile in basic conditions.
30 P. Lignier et al. / Ultrasonics Sonochemistry 18 (2011) 28–31

To confirm 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 justified 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 OÅÀ
is then considered, and a radical mecha-
nism for the hydrolysis is proposed.
Acknowledgement
The authors are very grateful to the Ecole Nationale Supérieure
de Chimie de Paris for financial support.
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CN
HO2C
CO2H
)))), 30 kHz, 1.90 WmL-1
100°C, 45 min.
NaOH 2M
Fig. 8. Hydrolysis of adiponitrile under ultrasonic activation.
P. Lignier et al. / Ultrasonics Sonochemistry 18 (2011) 28–31 31

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