Kinetics of selective formation of ibuprofenamide by phase transfer catalyzed oxidation of 2-(4-isobutylphenyl)propionitrile with basic hydrogen peroxide

Article abstract of DOI:10.1021/op7002425

Ibuprofenamide(benzeneacetamide-α-methyl-4-(2-methylpropyl)) is an ibuprofen analogue having anti-inflammatory activity itself and a precursor of many N-derivatives, all of which have good anti-inflammatory activities. The conventional process to prepare this amide is by the conversion of ibuprofen to acid chloride by thionyl chloride followed by ammonolysis or careful hydrolysis of the nitrile with H₂SO₄/CH₃COOH mixture. In this paper, the preparation of ibuprofenamide was achieved by the hydrolysis of 2-(4-isobutylphenyl)propionitrile with basic hydrogen peroxide under liquid-liquid phase transfer catalysis, under safe conditions with high conversion and selectivity. A systematic study was conducted to study the effects of various parameters such as different phase transfer catalysts, catalyst loading, substrate loading, and temperature on the conversion and rates of reaction. A kinetic model has been developed and validated against experimental data. With the 2-(4-isobutylphenyl)propionitrile to hydrogen peroxide mole ratio 1:4 at 60°C, the conversion and selectivity were found to be 70% and 90%, respectively, in 2 h. This is a first report of its kind on mechanism and kinetics of PTC hydrolysis of nitriles. The results are novel.

Full text of DOI:10.1021/op7002425

Organic Process Research & Development 2008, 12, 740–747
Kinetics of Selective Formation of Ibuprofenamide by Phase Transfer Catalyzed
Oxidation of 2-(4-Isobutylphenyl)propionitrile with Basic Hydrogen Peroxide
Ganapati D. Yadav* and J. Leo Ceasar
Department of Chemical Engineering, UniVersity Institute of Chemical Technology, UniVersity of Mumbai, Matunga,
Mumbai - 400 019, India
Abstract:
are used to prepare them on a laboratory scale.9–11 The general
method of preparing amides involves either the conversion of
Ibuprofenamide (benzeneacetamide-r-methyl-4-(2-methylpropyl))
is an ibuprofen analogue having anti-inflammatory activity itself
and a precursor of many N-derivatives, all of which have good
anti-inflammatory activities. The conventional process to prepare
this amide is by the conversion of ibuprofen to acid chloride by
thionyl chloride followed by ammonolysis or careful hydrolysis of
12,13
acid to acid chloride followed by ammonolysis
or the
hydrolysis of nitriles to amides and carboxylic acids, which is
14
one of the best methods. Some of the industrial examples cover
15
the hydrolysis of amino nitriles to amino acids, acrylonitrile
to acrylamide and acetone cyanohydrin to the corresponding
16
amide, en route to methyl methacrylate.
the nitrile with H
preparation of ibuprofenamide was achieved by the hydrolysis of
-(4-isobutylphenyl)propionitrile with basic hydrogen peroxide
2 4 3
SO /CH COOH mixture. In this paper, the
Selective hydrolysis of nitrile to amide is complicated to
achieve because the amide is often more easily hydrolyzed than
the nitrile from which it is formed and it requires stringent
2
under liquid-liquid phase transfer catalysis, under safe conditions
with high conversion and selectivity. A systematic study was
conducted to study the effects of various parameters such as
different phase transfer catalysts, catalyst loading, substrate
loading, and temperature on the conversion and rates of reaction.
A kinetic model has been developed and validated against
experimental data. With the 2-(4-isobutylphenyl)propionitrile to
hydrogen peroxide mole ratio 1:4 at 60 °C, the conversion and
selectivity were found to be 70% and 90%, respectively, in 2 h.
This is a first report of its kind on mechanism and kinetics of PTC
hydrolysis of nitriles. The results are novel.
1
1,14
conditions.
Commonly used methods for nitrile hydrolysis
17
to amides use strong acid (96% H
2 4
SO ) or base (50% KOH
18
/t-BuOH). In order to activate nitrile groups, strong inorganic
acid/alkaline base and high temperatures are usually required.
Yields range typically from poor to good, depending on the
substrates and conditions. As stoichiometric amounts of acid
or base are used, large amounts of salts are formed after workup,
which is neither economic nor environmental friendly. In
general, selective hydrolysis of nitriles to amides is fraught with
problems, and yields are reasonable at best due to two reasons:
(1) It is hard to stop the hydrolysis at the amide stage, and (2)
consecutive hydrolysis to the carboxylic acid often proceeds
because the rate constant of amide hydrolysis is usually larger
than that for nitrile hydrolysis, especially under dilute acidic or
basic conditions. Conversely, in concentrated acid or base the
relationship is inverted. Since the nitrile group is not very
reactive, harsh conditions using strong acids or bases at high
1
. Introduction
Phase transfer catalysis (PTC) has attained an incredible
maturity with several interesting applications in the last 35 years,
19
1
–6
ever since Charles Starks coined the terminology. PTC has
been extensively applied for the synthesis of organic chemicals
useful in agrochemical, dyestuff, pharmaceutical, polymer,
perfumes, flavor, and other fine chemical industries. However,
the literature on the use of PTC for amide synthesis is rather
scarce, and nothing is so far reported on kinetic modeling.
Amides are industrially very important, and several methods
(
9) Furniss, B. S., Hannaford, A. J. , Smith, P. W. G., Tatchell A. R. ,
Eds. Vogel’s Textbook of Practical Organic Chemistry, 5th ed.;
Longman: London, 1989.
1–8
(
(
10) (a) Dopp, D., Dopp, H., Eds. Methoden der Organischen Chemie
Houben-Weyl); Thieme: Stuttgart, 1985; Vol. E5, 2, p 1024. (b)
Brown, B. R., Ed.; The Organic Chemistry of Aliphatic Nitrogen
Compounds; Oxford University Press: Oxford, 1994; pp217-342.
11) March, J. AdVanced Organic Chemistry, 3rd ed.; Wiley-Interscience:
New York, 1985; p 788.
(
*
Author to whom correspondence should be addressed.: Telephone: 91-22-
4102121Fax: 91-22-24102121. E-mail: gdyadav@yahoo.com, gdyadav@
udct.org.
2
(12) Doshi, A.; Samant, S. D.; Deshpande, S. G. Indian J. Pharm. Sci.
2002, 64, 440–444.
(
1) Stark, C. M.; Liotta, C.; Halpern, M. Phase Transfer Catalysis:
Fundamentals, Application, and Industrial perspectiVes; Chapman and
Hall Publication: New York, 1994.
2) Sasson, Y., Neumann, R., Eds. Handbook of Phase Transfer Catalysis;
Blackie Academic and Professional: London, 1997.
3) Dehmlow, E. V.; Dehmlow, S. S. Phase Transfer Catalysis, 3rd ed.;
VCH: New York, 1993.
(13) Rajasekaran, A.; Sivakumar, P.; Jayakar, B. Indian J. Pharm. Sci. 1999,
61, 158–161.
(14) Schaefer, F. C. In The Chemistry of the Cyano Group; Rappaport, Z.,
Ed.; Interscience: New York, 1970; p 239.
(
(
(
(
(15) Bauer, W., Jr. In Ullmann’s Encyclopedia of Industrial Chemistry,
5th ed.; Wiley: New York, 1990; Vol. A16, p 441.
(16) Mckenzie, B. F.; Kendall, E. C. In Organic Syntheses; Gilman, H.,
Blatt, A. H., Eds.; Wiley: New York, 1941; Collect. Vol. 1, p 21.
(17) (a) Li, L.; Lin, K. H.; Hung, Y. T.; Kang, S. A. J. Chin. Chem. Soc.
1942, 9, 1. 14; 31; Chem. Abstr. 1944, 335. (b) Westfahl, J. C.;
Gresham, T. L. J. Am. Chem. Soc. 1955, 77, 3961.
4) Weber, W. P.; Gokel, G. W. Phase Transfer Catalysis in Organic
Synthesis; Springer-Verlag: Berlin, 1977.
5) Halpern, M. E. Phase Transfer Catalysis: Mechanisms and Syntheses;
American Chemical Society: Washington, DC, 1997.
6) Yadav, G. D. Chem. Ind. Digest 2004, 17, 52.
7) Yadav, G. D. Top. Catal 2004, 29, 143–158.
(
(
(
(18) (a) Hall, J.; Gisler, M. J. Org. Chem. 1976, 41, 3769. (b) Linke, S.
Synthesis 1978, 303.
8) Yadav, G. D. Chim. Ind. 2000, 1.
(19) Edward, J. T.; Meacock, S. C. R. J. Chem. Soc. 1957, 2000.
7
40
•
Vol. 12, No. 4, 2008 / Organic Process Research & Development
10.1021/op7002425 CCC: $40.75  2008 American Chemical Society
Published on Web 06/27/2008

temperatures are generally required, which precludes the pres-
ence of acid- or base-sensitive functional groups in the substrate.
The hydrogen halides in alcohol, mineral acids, sodium
superoxide in DMSO, manganese dioxide, potassium fluoride
supported on alumina and metals such as copper have been
N-pyrroline, N-morpholine, etc. also show good anti-inflam-
12,13
matory and ulcerogenic activity.
Another derivative N-(2-
aryl propionyl)sulfonamides is an inhibitor of neutrophil chemo-
35
taxis. With enzymes, asymmetric hydrolysis or dynamic
36
kinetic resolution of nitriles is possible. Enzyme hydrolysis
using nitrile hydatases is the best industrial method for conver-
20–24
employed for hydrolysis of nitriles to amides.
In addition
37
to strong base or acid, enzymes and transition metal catalysts
are also used to convert a variety of nitriles to amides. With
enzymes, asymmetric hydrolysis or dynamic kinetic resolution
of nitriles is possible. Transition metal coordination compounds
are reported as catalysts for nitrile hydrolysis leading to good
sion of nitriles to amides (e.g., nitro process for acrylamide).
Thus, the preparation of ibuprofenamide by using PTC under
mild conditions was considered to be an interesting and
contemporary topic for research. Different parameters have been
studied, and a suitable kinetic model has been proposed to
explain the collected data.
2
5,26
selectivity to amide.
Certain platinum complexes have also
27
been shown to catalyze this reaction. Among these, the
hydration of nitrile with metallic and ionic copper as well as
copper oxide have been found very effective to catalyze the
2
. Experimental Section
2.1. Chemicals and Catalysts. 2-(4-Isobutylphenyl)propi-
28,29
onitrile was obtained as a gift sample from Dr. Reddy’s
Laboratories Ltd., Hyderabad, India. Hydrogen peroxide (30%
w/v) and toluene of AR grade were obtained from M/s. s.d.
Fine Chem. Pvt. Ltd., Mumbai, India. Tetrabutylammonium
bromide (TBAB), tetrabutylammonium iodide (TBAI), ethyl-
triphenylphosphonium bromide (ETPPB), and tetrabutylam-
monium hydrogen sulfate (TBAHS), of pure grade, were
procured as gift samples from M/s. Dishman Pharmaceuticals
and Chemicals Ltd., Ahmedabad, India. All other chemicals
were analytical grade obtained from M/s s.d. Fine Chem. Pvt.
Ltd.
hydration of aromatic nitriles.
Hydrogen peroxide is a very good oxidation-reduction
agent. Basic hydrogen peroxide is used for hydrolysis by using
30–32
suitable mixtures of solvents.
2 2
H O in dilute aqueous alkali
can also be used to hydrolyze nitriles to the amides and finally
to the acids. This procedure can be stopped at the amide stage
2 2
by using different alkaline conditions with H O in aqueous
32a
ethanol. Compared to the method using 50% KOH in
refluxing t-BuOH, the reaction conditions are much milder. The
-
effective species is thought to be HO
2
, which is a much
stronger nucleophile than hydroxide ion (R-effect nucleo-
3
2a
2.2. Setup and Reaction Procedure. The experimental
setup consisted of a 3 cm i.d. fully baffled mechanically agitated
reactor of 50 mL capacity, equipped with four baffles and a
six-bladed turbine impeller and a reflux condenser. The stirrer
was centrally located, and the dimensions of the impeller were
as follows: disc turbine impeller of 1.0 cm o.d., made of stainless
steel 316, located at a distance of 0.8 cm from the bottom. The
entire reactor assembly was immersed in a thermostatic water
bath, which was maintained at the desired temperature with an
accuracy of (1 °C. Standard runs were conducted with 0.02
mol 2-(4-isobutylphenyl)propionitrile dissolved in toluene to
phile). A method based on a combination of urea/H
CO was also reported providing reasonable yields of amides
50-60%). It was found that the hydrolysis with basic
2 2
O /
K
(
2
3
30
hydrogen peroxide may be conveniently carried out under phase
transfer catalyzed conditions in dichloromethane, tetra-n-butyl-
33
2 2
hydrogen sulfate and excess H O .
In this work, 2-(4-isobutylphenyl)propionitrile was oxidized
with basic hydrogen peroxide under phase transfer conditions
to synthesize ibuprofenamide. There is literature available on
this reaction. Ibuprofenamide is an analogue of ibuprofen,
34
having a very good anti-inflammatory activity. Its N-deriva-
tives such as N-pyridinyl, N-methyl pyridinyl, N-methyl-phenyl,
3
make up 7 cm volume of organic phase. To the organic phase
was added a 10% solution of NaOH (0.005 mol) with 10 mol
(
(
20) Matsuda, F. Chem. Technol. 1977, 7, 306.
%
of catalyst based on the nitrile. For a standard reaction, 0.08
21) Ravindranathan, M.; Kalyanam, N.; Sivaram, S. J. Org. Chem. 1982,
mol of 30% w/v aqueous H was added with an addition
2 2
O
4
7, 4812.
(
(
(
22) Zil’berman, E. N. Russ. Chem. ReV. Engl. Transl. 1984, 53, 900.
23) Izumi, Y. Catal. Today 1997, 33, 371.
rate of 0.1 mL/min at 1000 rpm at 60 °C. The reaction scheme
is given below.
24) Brown, B. R. The Organic Chemistry of Aliphatic Nitrogen Com-
pounds; Oxford University Press: New York, 1994; pp 175-259.
25) Jensen, C. M.; Trogler, W. C. J. Am. Chem. Soc. 1986, 108, 723.
26) Kaminskaia, M. V.; Kostic, N. M. J. Chem. Soc., Dalton Trans. 1996,
(
(
3
677.
(
(
27) Ghaffar, T.; Parkins, A. W. Tetrahedron 1995, 40, 8657.
28) Watanabe, K. Bull. Chem. Soc. Jpn. 1959, 32, 1280. Watanabe, K.
Bull. Chem. Soc. Jpn. 1964, 37, 1325. Watanabe, K. Bull. Chem. Soc.
Jpn. 1967, 40, 1660. Watanabe, K. Bull. Chem. Soc. Jpn. 1971, 44,
1
440.
(
(
(
(
29) Bernard, B. J. Chem. Soc. (A) 1969, 2140.
30) Katrizky, A. R.; Pilarski, B.; Urogei, L. Synthesis 1989, 949.
31) Krewson, C. F.; Couch, J. F. J. Am. Chem. Soc. 1943, 65, 2256.
32) (a) Noller, C. R. Organic Syntheses; Wiley: New York, 1943; Collect.
Vol. 2, p 586. (b) Buck, J. S. Organic Syntheses; Wiley: New York,
(35) (a) WO 2000 0024 710, 2000. (b) WO 2002 062 330, 2002. (c) U.S.
Patent 2004 102 520, 2004.
(36) (a) Snell, D.; Colby, J. Enzyme Micro. Technol. 1999, 24, 160. (b)
Bornscheuer, U. T.; Kazluaskas, R. J. Hydrolases in Organic Synthesis,
2nd ed.; Wiley-ECH: New York, 2006. (c) Roberts, S. M.,. Ed.
Biocatalysis for Organic Synthesis; Wiley: New York, 1999. (d)
Yadav, G. D.; SajgureA. D.;.; Dhoot, S. B. Enzyme Catalysis in Fine
Chemical and Pharmaceutical Industries. In Enzyme Mixtures and
Complex Biosynthesis; Bhattacharya, S. K., Ed.; Landes Bioscience:
New York, 2007; Chapter 8, pp 79-106.
1
943; Collect. Vol. 2, p 44. (c) Wiberg, K. B. J. Am. Chem. Soc.
953, 75, 3961. (d) Mcisaac, J. E., Jr.; Ball, R. E.; Behrman, E. J. J.
1
Org. Chem. 1971, 36, 3048.
(
(
33) (a) Hendrickson, J. B.; Blair, K. W.; Keehn, P. M. Tetrahedron Lett.
1
976, 17, 603. (b) Cacci, C.; Misiti, D.; La Torre, F. Synthesis 1980,
2
43.
34) Spickett, R. G. W.; Vega, A.; Prieto, J.; Moragues, J.; Marquez, M.;
Roberts, D. J. Eur. J. Med. Chem. - Chim. Ther. 1976, 11, 7.
(37) Wiberg, K. B. J. Am. Chem. Soc. 1953, 75, 3961.
Vol. 12, No. 4, 2008 / Organic Process Research & Development
•
741

2.3. Method of Analysis. Samples of the organic phase
were withdrawn periodically and analyzed by gas chromatog-
raphy (Chemito model 8510). A 2.0 m × 3.2 mm i.d. stainless
steel column packed with Chromosorb WHP, which was
impregnated with 5% SE-30, was used for analysis in conjunc-
tion with a FID. Synthetic mixtures were prepared for calibration
and used to calculate the concentrations of 2-(4-isobutylphe-
nyl)propionitrile and ibuprofenamide quantitatively. The rates
of reaction were based on the disappearance of 1-(4-isobu-
tylphenyl)propionitrile. After the reaction, the toluene layer was
separated and cooled to precipitate the solid product. The solid
product was filtered and purified by crystallization with
methanol. The melting point was found to be 112-114 °C,
12
which matches with the literature value 114-116 °C. The
product was also confirmed by GC-MS.
Figure 1. Effect of rate of addition of H O , 2-(4-isobutylphe-
2
2
2 2
nyl)propionitrile 0.02 mol, toluene 3.3 mL, H O (30%) 0.08
mol, NaOH 0.005 mol (10% w/v solution), TBAB 0.002 mol,
temperature 60 °C, speed of agitation 1000 rpm.
3. Results and Discussion
3
.1. Reaction Mechanism. Hydrogen peroxide behaves as
an unusual reagent, with both oxidation and reduction properties
and in the case of reaction of aromatic nitrile in weakly basic
solution, it involves an oxidation-reduction of hydrogen
peroxide with simultaneous hydration of the nitrile. A clue for
the reaction mechanism was obtained from the work of
Wiberg, according to whom in a homogeneous reaction
containing nitrile and basic hydrogen peroxide in acetone or
ethanol, the rate of reaction is first order in the nitrile, hydrogen
peroxide, and hydroxyl ion.
There are four different reaction regimes possible for L-L
PTC as has been discussed by us earlier. These are (i) slow
reaction (kinetically controlled, rate of diffusion is very high),
7,39
(
ii) diffusion controlled (reaction rate is high), (iii) pseudofast
reaction (diffusion and reaction simultaneously occur in the film
next to L-L interface), and (iv) instantaneous reaction in the
film (diffusion controlled). The details are avoided and can be
37
7,38
seen in our work. If the concentration of the diffusing species
-
HOO in the organic phase remains constant, which is equal
to its saturation concentration, then the rate of addition of
hydrogen peroxide beyond a certain rate will not affect the
conversion and selectivity. As against a homogeneous reaction,
kobs
RC ≡ N(org) + 2H O
8 RCONH2(org) + O2(g)
+
2
2(aq)
+
-
the diffusing species will be an ion-pair Q HOO . If on the
contrary RCN diffuses from the organic phase to the aqueous
phase, then the aqueous phase will be always saturated with
RCN, due to its limited solubility, and the reaction kinetics
would show apparent zero order in RCN.
H O
(a)
(aq)
2
Experiments were done in such a manner as to provide
additional support for the mechanism and the kinetic model.
Aqueous NaOH solution with the phase transfer agent was taken
along with the organic phase containing the nitrile RCN in the
batch reactor. Initially experiments were done with aqueous
Therefore, a semibatch mode of operation was adopted, and
the effect of rate of addition on conversion and selectivity was
studied. The speed of agitation was maintained at 1000 rpm to
ensure absence of mass transfer resistance, which will be
discussed later. Several experiments were done, and a window
of operation for the flow rate of hydrogen peroxide was selected.
Aqueous hydrogen peroxide was added continuously to the
2 2 2 2
H O by taking in a molar ratio of RCN/H O of 1:4. It was
observed that there was too much frothing due to the oxygen
generated in situ and the exothermicity would lead to further
hydrolysis to the acid, along with ammonia, thereby affecting
the selectivity.
-
batch of the nitrile in toluene, aqueous base OH and phase
+
-
transfer agent Q X as a biphasic mixture. The rate of addition
of hydrogen peroxide to the reaction mass was varied from 0.1
kobs
3
to 0.3 cm /min (Figure 1). The conversions and selectivity were
RCONH2(org) + 2H O
8 RCOOH(org) + O2(g)
+
2
2(aq)
3
found to be practically the same at 0.1 and 0.15 cm /min for
3
2
h. With the higher rate of addition of 0.3 cm /min, the initial
NH3(g) + H O (b)
(aq)
2
rate is faster, and frothing was seen to some extent, indicating
3
the onset of reaction b above. Thus, a rate of 0.1 cm /min was
Under the liquid-liquid PTC, it was also necessary to
ascertain the locale of the reaction and whether kinetic informa-
tion could be extracted from the collected data. Under basic
used for further reaction to study the effects of various other
parameters. The conversion in 2 h was 70%, and selectivity to
the product was 90%. The selectivity up to 90 min was closer
to 98%. It indicates that the concentration of the ion-pair
-
-
conditions, typically the OH and HOO ions will coexist in
the aqueous phase, and for the hydrolysis reaction to occur,
+
-
Q HOO in the organic phase was always finite and at its
-
preferential transfer of HOO to the organic phase should occur
(
normal L-L PTC mechanism) or RCN must diffuse across
(
38) Yadav, G. D.; Jadhav, Y. B. Langmuir 2002, 18, 5995.
-
the interface into the aqueous phase to react with HOO .
(39) Yadav, G. D.; Jadhav, Y. B. J. Mol. Cat. A: Chem. 2002, 184, 151.
7
42
•
Vol. 12, No. 4, 2008 / Organic Process Research & Development

saturation value and the reaction locale was the organic phase.
This allowed the development of the kinetic model.
Thus, steps 1 and 2 produce the ion-pair with peroxo species,
and it is transferred to the organic phase.
hydrogen peroxide is such that it would render this term a
constant, as was discussed earlier. Thus,
-
d[A]org
dt
)
kp[A]org
(14)
+ OH( a HOO -( + H O (aq) (1)
-
H O
2
2 aq
( )
aq
)
aq
)
2
This is a typical first-order reaction, giving the following
integrated form:
HOO-(
+
Q( a Q HOO(
+
+
-
aq
(2)
(3)
aq
)
aq
)
)
+
-
+
-
aq
Q HOO( h Q HOO(
-ln(1 - X ) ) k t
(15)
aq
)
)
A
p
+
-
where k
p
is a pseudo-first-order rate constant. On the contrary,
[
Q HOO ]
org
K )
(4)
(5)
1
if there is a lot of dilution of the aqueous phase and the
equilibrium constant is affected, then it is necessary to account
for it.
+
-
[
Q HOO ]
aq
korg
+
-
From eqs 1, 2, and 4:
RC ≡ N(org) + Q HOO
8
(
RDS
)
-
-
+
[
HOO ] [H O]
RC d (OOH)N Q (org)
aq
2
aq
K )
(16)
(17)
3
-
[
H O ] [OH ]
2 2 aq aq
Assuming this step 5 is rate determining (RDS) and all
subsequent steps are fast and have no influence on the rate of
the reaction, these are as follows:
+
-
[
Q HOO ]
aq
K )
4
-
+
[
HOO ] [Q ]
aq
aq
-
+
RC d (OOH)N Q u RC(OOH)NH(aq)
(6)
(7)
+
-
-
+
[
Q HOO ] ) K [HOO ] [Q ] )
aq 4 aq aq
-
+
RC d (OOH)N Q + H O
f
2
(aq)
-
[
H O ] [OH ]
2 2 aq aq
+
-
(aq)
+
RC(OOH)NH(aq) + Q OH
K [Q ] K
aq 3
(18)
4
[
H O]
2
aq
The formation of peroxyimidic acid in step 6 above is important.
The homogeneous reaction using ethanol and acetone also
mentions the reaction 5 as RDS.
-
37
[H2O2]aq[OH ]aq
+
-
+
[
Q HOO ] ) K K K [Q ]
aq
)
org
1
3
4
[
H O]
2 aq
+
-
K [Q ] [H O ] [OH ] (19)
e
aq
2
2 aq
aq
RC(OOH) d NH(aq) + H O f
2
2
+
-
(aq)
RCONH + O
+ H + OH
(8)
(9)
2
2(aq)
-d[A]org
dt
+
-
)
k K [A] [Q ] [H O ] [OH ] (20)
org e org aq 2 2 aq aq
O2(aq) f O2(g)
The catalyst amount in moles (N
two phases.
Q
) is distributed between the
RCONH2(aq) f RCONH2(aq)
(10)
(11)
+
-
+
-
(aq)
Q OH
a Q OH
+
+
(
aq)
N ) [Q ] V + [Q ] V
(21a)
(22a)
(22b)
Q
aq aq
org org
+
-
[
Q OH ]
(org)
+
+
-
+
-
K )
(12)
[Q ] ) [Q HOO ] + [Q OH ]
aq aq aq
2
+
-
[
Q OH ]
(aq)
+
+
-
+
-
[
Q ] ) [Q HOO ] + [Q OH ]
org org org
The overall or observed rate of reaction is equal to that of the
RDS:
+
-
N ) (V + K V )[Q HOO ] + (V +
Q
aq
1
org
aq
aq
-
d[A]org
dt
+
-
+
-
K V )[Q OH ] (22c)
2
org
aq
)
k [A] [Q HOO ]
org
(13)
org
org
+
-
+
N - [Q ] V
Q org org
Let RC ) (OOH)N Q (org) be denoted by species A with
+
[
Q ] )
(21b)
aq
corresponding factional conversion X
be integrated provided the term [Q HOO ]org remains constant
A
. The above equation can
Vaq
+
-
throughout the reaction phase; that is, the rate of addition of
Here
Vol. 12, No. 4, 2008 / Organic Process Research & Development
•
743

Vaq ) Vaq-0 + q
· t
(23)
H O
2
2
V
aq-0 is the initial volume of the aqueous phase, qH2O the
2
volumetric rate of addition of aqueous hydrogen peroxide, and
t is the time of addition.
-
d[A]org
-
)
k K [A] [H O ] [OH ]
×
org
e
org
2
2 aq
aq
dt
+
N - [Q ] V
Q
org org
(
24)
(
Vaq-0 + q
· t
)
H O
2
2
Equation 24 needs a numerical method of analysis and can also
be integrated under certain conditions.
If the term in the large brackets on the right-hand side of eq
24 remains constant, then an analytical solution is possible. This
can be argued from the following perspective.
Figure 2. Effect of different catalysts 2-(4-isobutylphenyl)pro-
pionitrile 0.02 mol, toluene 3.3 mL H (30%) 0.08 mol, NaOH
0.005 mol (10% w/v solution), catalyst 0.002 mol, temperature
2 2
O
+
+
-
+
-
[
Q ] ) [Q HOO ] + [Q OH ]
(25)
(26)
aq
aq
aq
6
0 °C, rate of addition of H
2
O
2
0.1 mL/min.
-
-
I is a much bulkier anion than Br and better partitioned in
+
+
-
+
-
[
Q ] ) [Q HOO ] + [Q OH ]
org org org
organic phase. Thus, the model was tested for these catalysts
(
Figure 3) to find that the data fit very well, and in all cases,
+
-
+
-
N ) (V + K V )[Q HOO ] + (V +
the concentration of the ion-pair Q HOO in the organic phase
is constant in each case during the course of the reaction, and
the rate is controlled by the intrinsic kinetics. Thus, further
experiments were conducted with TBAB, since it is inexpensive
and commercially available in high purity.
Q
aq
1
org
aq
aq
+
-
K V )[Q OH ] (27)
2
org
aq
It is well-known that hydroxyls are preferentially partitioned
in aqueous phase when the organic phase is nonpolar and the
ion pairs are lose. So most of the quaternary cation is available
to make ion pairs with peroxy ions. Further, the peroxy ion-
pair [Q HOO ]org concentration in organic phase also remains
constant and is not affected by the slow rate of addition of
hydrogen peroxide. Thus, 15 can be written as follows:
3.3. Effect of Speed of Agitation. To ascertain the influence
of external mass transfer resistance on the transfer of reactants
to the reaction phase, the speed of agitation was varied in the
range of 600 to 1200 rpm under otherwise similar conditions
in the presence of TBAB as the catalyst. Figure 4 shows that
conversion is practically the same as the increase in speed of
agitation from 600 to 1200 rpm. This shows that there is no
external mass-transfer resistance above 600 rpm. Therefore, a
speed of agitation of around 1000 rpm was employed in all
further experiments. The model also fits the data at and beyond
+
-
’
-
ln(1 - X ) ) k N t
(28)
A
p Q
or
1
000 rpm; this data point is already shown in Figure 3 for
TBAB.
.4. Effect of Catalyst Concentration. The quantity of
-
ln(1 - X ) ) k t
A obs
(29)
3
-4
-3
where kobs is the observed (pseudo-first-order) rate constant in
catalyst (TBAB) was varied from 3 × 10 to 6 x10 mol
under otherwise similar experimental conditions. The conversion
of 2-(4-isobutylphenyl) propionitrile is plotted against time for
different catalyst concentrations (Figure.5). As the catalyst
loading is increased, the conversion also increased, due to the
fact that the concentration of Q OOH extracted into the
organic phase increases with increasing catalyst concentration.
The validity of the model was tested to find that it fits the data
well up to 10 mol % catalyst loading ()0.0002 mol) (Figure
6) and beyond it the fit is not as good since mass transfer effects
are set in due to excessive reaction rate (e.g., 20 mol%).
-1
time .
Now the model could be validated by conducting different
sets of experiments.
.2. Effect of Different Catalysts. Various catalysts with
3
+
-
different cationic as well as anionic structures, such as TBAB,
ETPPB, TBAHS, and TBAI were employed under otherwise
similar experimental conditions (Figure.2). Out of these, TBAB
gave the maximum rates of reaction and conversion. The order
of activity of these catalysts was as follows:
3
.5. Effect of molar ratio. The effect of change in molar
TBAI = TBAB > ETPPB > TBAHS
ratio of 2-(4-isobutylphenyl) propionitrile: H was studied
2 2
O
TBAI is marginally better than TBAB (5.1% as the slopes,
obs, indicate). However, TBAI is almost 3 times more expensive
by varying in the range of 1:1 to 1:6, with reference to the total
quantity added, under otherwise similar conditions (Figure 7).
At a given time, the concentration of [Q HOO ]org is main-
k
+
-
on a commercial scale. Indeed, in many cases KI is added along
+
-
+ -
1,39
with Q X to enhance the rate, where Q I is generated in situ.
tained constant because of the adequate rate of addition of the
7
44
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Vol. 12, No. 4, 2008 / Organic Process Research & Development

Figure 3. Validity of model against experimental data for different catalysts 2-(4-isobutylphenyl)propionitrile 0.02 mol, toluene 3.3
mL H (30%) 0.08 mol, NaOH 0.005 mol (10% w/v solution), catalyst 0.002 mol, temperature 60 °C, rate of addition of H 0.1
mL/min.
2
O
2
2 2
O
Figure 4. Effect of speed of agitation 2-(4-isobutylphenyl)
propionitrile 0.02 mol, toluene 3.3 mL, H (30%) 0.08 mol,
NaOH 0.005 mol (10% w/v solution), TBAB 0.002 mol, tem-
Figure 5. Effect of catalyst concentration 2-(4-isobutylphenyl)
propionitrile 0.02 mol, toluene 3.3 mL, H (30%) 0.08 mol,
NaOH 0.005 mol (10% w/v solution), temperature 60 °C, speed
of agitation 1000, rate of addition of H 0.1 mL/min.
2
O
2
2
O
2
perature 60 °C rate of addition of H
2
O
2
0.1 mL/min.
2
O
2
+
-
peroxide, then the substrate to [Q HOO ]org, the molar ratio
1
constant K is affected at lower mole ratios and the saturation
concentration for [Q HOO ]org is not achieved and therefore
lower conversions are obtained after 2 h.
of the substrate with reference to hydrogen peroxide in the
+
-
+
-
reactor is very large, because [Q HOO ]org is very small. Up
to 30 min, the conversions are not affected in all cases and
remain practically the same for all mole ratios. At mole ratios
3.6. Effect of NaOH Concentration. The sodium hydrox-
ide concentration was varied from 0.005 to 0.03 mol under
otherwise similar conditions (Figure 8). As the concentration
of sodium hydroxide increased, the conversion decreased due
to the fact that the decomposition of hydrogen peroxide is
greater with higher concentration of sodium hydroxide. This is
1
:4 and 1:6, at all times the conversions are the same.
+
-
[Q HOO ]org is a saturation (constant) value and all transferred
+
-
[Q HOO ]org reacts with RCN. For lower values of 1:1 and
1:2, based on the stoichiometry of the reaction, the maximum
conversion would be 50% and 100%, provided all peroxo ion
pair generated in situ is transferred from the aqueous to organic
phase. However, as the reaction proceeds, the equilibrium
17
also known from published literature. So 0.005 mol of sodium
hydroxide was used for further reactions.
Vol. 12, No. 4, 2008 / Organic Process Research & Development
•
745

Figure 8. Effect of NaOH concentration 2-(4-isobutylphenyl)-
propionitrile 0.02 mol, toluene 3.3 mL, H (30%) 0.08 mol,
TBAB 0.002 mol, temperature 60 °C speed of agitation 1000
rpm, rate of addition of H 0.1 mL/min.
2
O
2
2
O
2
Figure 6. Validity of model for different catalyst loadings in
mol % of substrate 2-(4-isobutylphenyl)propionitrile 0.02 mol,
toluene 3.3 mL, H
w/v solution), temperature 60 °C, speed of agitation 1000, rate
of addition of H 0.1 mL/min.
2 2
O (30%) 0.08 mol, NaOH 0.005 mol (10%
2
O
2
Figure 9. Effect of temperature 2-(4-isobutylphenyl)propioni-
trile 0.02 mol, toluene 3.3 mL, H (30%) 0.08 mol, NaOH
.005 mol (10% w/v solution) TBAB 0.002 mol, speed of
agitation 1000 rpm rate of addition of H 0.1 mL/min.
2
O
2
0
2
O
2
Figure 7. Effect of mole ratio 2-(4-isobutylphenyl)propionitrile
.02 mol, toluene 3.3 mL, NaOH 0.005 mol (10% w/v solution),
TBAB 0.002 mol, temperature 60 °C, speed of agitation 1000
rpm rate of addition of H 0.1 mL/min.
0
2
O
2
3.7. Effect of Temperature. The effect of temperature on
the rate of the reaction of 2-(4-isobutylphenyl) propionitrile was
studied in the range of 40 to 70 °C under otherwise similar
conditions. The conversion of 2-(4-isobutylphenyl) propionitrile
was observed to increase with an increase in the reaction
temperature from 40 to 60 °C (Figure 9). But at 70 °C it was
found that reaction rate decreases since hydrogen peroxide
decomposes fast at higher temperature.
Thus, the plots could be made to verify the validity of the
above model for three temperatures (Figure 10) to obtain kobs
.
Figure 10. Validation of model at different temperatures.
There is a good fit. Arrhenius plot was made to extract the
apparent energy of activation as 5.50 kcal/mol (Figure 11). This
value also confirms that the reaction is kinetically controlled
under the conditions employed.
4. Conclusion
The oxidation of 2-(4-isobutylphenyl)propionitrile with basic
hydrogen peroxide under phase transfer conditions was studied
7
46
•
Vol. 12, No. 4, 2008 / Organic Process Research & Development

3
[A]org
concentration of A in the organic phase, mol/cm of organic
phase
+
-
+
-
K
1
[Q HOO ]org/[Q HOO ]aq
+
-
+
-
K
2
[Q OH ](org)/[Q OH ](aq)
{[HOO-]aq [H
O]aq}/{[H
[Q HOO ]aq/{[HOO-]aq [Q ]aq
}
2
2 2
O ] }
aq [OH-]aq
+
K
3
+
-
K
4
K
e
1 3 4
K K K
1
k
obs
k
org
k
p
observed first-order reaction rate constant, min-
3
second-order reaction rate constant, cm /mol/min
pseudo-first-order rate constant, min-
1
N
Q
total moles of catalyst added to the system, mol
volumetric rate of addition of aqueous hydrogen peroxide,
cm /min
q
H O
2 2
3
Figure 11. Arrhenius plot.
t
time of reaction, min
V
V
V
X
aq
volume of aqueous phase at time t, cm3
initial volume of aqueous phase in the reactor, cm3
to synthesize ibuprofenamide. A mechanistic model was
developed to understand the progress of the reaction and
selectivity to ibuprofenamide. Semibatch reaction was selected
as the batch experiments result in more frothing, loss of the
hydrogen peroxide, and less conversion. With the 2-(4-isobu-
tylphenyl)propionitrile to hydrogen peroxide mole ratio 1:4 at
aq-0
org
A
volume of organic phase taken initially in the reactor, cm
3
A
NA0 - N /NA0, fractional conversion of A
Acknowledgment
60 °C, the conversion and selectivity were observed to be 70%
G.D.Y. acknowledges support from the Darbari Seth Profes-
sor Endowment for personal chair. J.L.C. received Gujarat
Ambuja SRF from Ambuja Research Institute. G.D.Y. also
thanks the Purdue University for inviting him as Distinguished
Visiting Scholar under the President’s Asian Initiative Program,
which allowed him to indulge in creative pursuits.
and 90%, respectively, in 2 h. Effects of various parameters
were studied on the rate of reaction and conversion to confirm
the validity of the model. The apparent activation energy was
found to be 5.05 kcal/mol. This is a first study on mechanism
and kinetics of phase transfer catalyzed oxidation of nitriles
using basic hydrogen peroxide. The results are novel.
Received for review October 26, 2007.
OP7002425
Nomenclature and Symbols
A
2-(4-isobutylphenyl)propionitrile
Vol. 12, No. 4, 2008 / Organic Process Research & Development
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