Novelties of solid-liquid phase transfer catalysed synthesis of α-isopropyl-p-chlorophenyl acetonitrile from p-chlorophenyl acetonitrile

Article abstract of DOI:10.1021/op025538z

C-Alkylation is an important class of synthetic reaction employed in the fine chemical industry. Although a number of C-alkylation reactions are reported under liquid-liquid (L-L) phase transfer catalysis (PTC) leading to intensification of reaction rates, there is a dearth of information on similar reactions under the solid-liquid (S-L) PTC including kinetics and mechanism. S-L PTC offers higher rates of reaction and better selectivities to the desired product vis-a-vis L-L PTC. This contribution reports the novelties of S-L PTC for C-alkylation of p-chlorophenyl acetonitrile to α-isopropyl-p-chlorophenyl acetonitrile which is an important intermediate in the synthesis of a pyrethroid insecticide named fenvalerate. p-Chlorophenyl acetonitrile can be mono- or dialkylated, depending on the reaction conditions, and it is a versatile synthetic intermediate in the sense that the nitrile function can be hydrolysed, reduced, or added to by organometallics after an alkylation has been carried out. It is found that the S-L PTC process is more intensified and selective. The mechanistic details of C-alkylation under basic conditions and the unexpected side reaction of oxidative decyanation are studied. The production of water as a byproduct in the reaction to form the omega (ω) phase and the mechanism in reference to the S-L-ω-phase system is described. A numerical model is composed to calculate the values of various pseudo rate constants and validate the simulated profiles against experimental data. The finer aspects of selectivity in C-alkylation reaction are analysed.

Full text of DOI:10.1021/op025538z

Organic Process Research & Development 2003, 7, 588−598
Technology Reports
Novelties of Solid-Liquid Phase Transfer Catalysed Synthesis of
r-Isopropyl-p-chlorophenyl Acetonitrile from p-Chlorophenyl Acetonitrile
Ganapati D. Yadav* and Yogeeta B. Jadhav
Department of Chemical Engineering, UniVersity Institute of Chemical Technology (UICT) UniVersity of Mumbai,
Matunga, Mumbai-400019, India
Abstract:
reactions under the solid-liquid (S-L) PTC including
kinetics and mechanism. In general, S-L PTC offers higher
rates of reaction in comparison with the L-L PTC. An added
advantage of carrying out reactions in the presence of a base
in S-L biphasic systems is that it suppresses alkaline
hydrolysis of halogenated reactant leading to higher yield
of the C-alkylated product.
This work is concerned with S-L PTC of C-alkylation
of p-chlorophenyl acetonitrile to R-isopropyl-p-chlorophenyl
acetonitrile which is an important intermediate in the
synthesis of a pyrethroid insecticide named fenvalerate.
Approximately 4000 tonnes of fenvalerate are used annually
worldwide. India alone produces about 2300 tonnes/year. It
is used primarily in agriculture but also in homes and gardens
for insect control, and on cattle, alone or in combination with
other insecticides.
C-Alkylation is an important class of synthetic reaction em-
ployed in the fine chemical industry. Although a number of
C-alkylation reactions are reported under liquid-liquid (L-
L) phase transfer catalysis (PTC) leading to intensification of
reaction rates, there is a dearth of information on similar
reactions under the solid-liquid (S-L) PTC including kinetics
and mechanism. S-L PTC offers higher rates of reaction and
better selectivities to the desired product vis- a` -vis L-L PTC.
This contribution reports the novelties of S-L PTC for
C-alkylation of p-chlorophenyl acetonitrile to r-isopropyl-p-
chlorophenyl acetonitrile which is an important intermediate
in the synthesis of a pyrethroid insecticide named fenvalerate.
p-Chlorophenyl acetonitrile can be mono- or dialkylated,
depending on the reaction conditions, and it is a versatile
synthetic intermediate in the sense that the nitrile function can
be hydrolysed, reduced, or added to by organometallics after
an alkylation has been carried out. It is found that the S-L
PTC process is more intensified and selective. The mechanistic
details of C-alkylation under basic conditions and the unex-
pected side reaction of oxidative decyanation are studied. The
production of water as a byproduct in the reaction to form the
omega (ω) phase and the mechanism in reference to the S-L-
ω-phase system is described. A numerical model is composed
to calculate the values of various pseudo rate constants and
validate the simulated profiles against experimental data. The
finer aspects of selectivity in C-alkylation reaction are analysed.
Apart form its commercial value, p-chlorophenyl aceto-
nitrile is a good substrate for study because it is reasonably
acidic, but not alkylated by aqueous metal hydroxide in the
absence of a catalyst at any synthetically useful rate. Another
advantage is that it can be mono or dialkylated depending
on the reaction conditions. It is a versatile synthetic
intermediate in the sense that the nitrile function can be
hydrolysed, reduced, or added to by organometallics after
an alkylation has been carried out. The C-alkylation of
p-chlorophenyl acetonitrile has reportedly been done under
L-L PTC conditions using various phase transfer catalysts
such as tetramethylammonium bromide, PEG, tetrabutylam-
monium hydrogen sulphate, benzyltriethylammonium chlo-
2
-8
ride, and tetrabutylammonium chloride.
A few of these
Introduction
reports deal with the mechanistic details of the process.
Alkylation reactions, particularly C-alkylations, are among
the most useful synthetic transformations in organic chem-
istry, typically performed under alkaline conditions with or
(
2) Qui, Z.; Liu, Z.; Zhou, H.; Cheng, M. Xiandai Huagong 1995 15, 32-33;
Chem. Abstr. 1996, 124, 260526.
1
(3) Li, Y.; Chen, J.; Li, M. Xueyuan Xuebao Ziran Kexueban 1986, 23, 479;
Chem. Abstr. 1987, 106, 175898.
without a phase transfer catalyst. Although a number of
C-alkylation reactions under liquid-liquid (L-L) phase
transfer catalysis (PTC) leading to intensification of reaction
rates are reported, there is a dearth of information on similar
(
(
(
4) Lu, Z.; Ma, W. Guangzhou Shiyun Xuebao Ziran Kexueban 1991, 41-44;
Chem. Abstr. 1994, 120, 133982.
5) Verbrugge, P. A.; Uurbananus, E. W.; Kramer, P. A.; Terlouw, W. Br.
Patent 1,528,043, 1978; Chem. Abstr. 1979, 91, 123576.
6) Moreno, L.; Maria, J. Span. Es 537,684, 1985; Chem. Abstr. 1986, 105,
42501.
*
Corresponding author. Telephone: 91-22-2412 2121. Fax: 91-22-2414-
5
614. E-mail: gdyadav@yahoo.com, gdy@udct.ernet.in.
(7) Grasso, Charles, P. U.S. Patent 4,377,531, 1983; Chem. Abstr. 1984, 99,
(
1) Starks, C. M.; Liotta, C. L.; Halpern, M. Phase Transfer Catalysis:
Fundamentals, Applications and Industrial PerspectiVes; Academic Press:
New York, 1994.
87838.
(8) Ohno, N.; Umemura, T.; Watanabe, T. Canada 1,043,811, 1978; Chem.
Abstr. 1976, 90, 151846.
5
88
•
Vol. 7, No. 4, 2003 / Organic Process Research & Development
10.1021/op025538z CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/29/2003

Synthesis under S-L PTC conditions is not reported. The
current work brings out the novelties of the S-L PTC
synthesis including mechanism and kinetics of this reaction.
Scheme 1. Reaction scheme of solid-liquid phase transfer
catalysed C-alkylation of p-chlorophenyl acetonitrile with
isopropyl bromide under alkaline conditions
Experimental Section
Chemicals and Catalysts. p-Chlorophenyl acetonitrile
and isopropyl bromide were gift samples from Rallis India
Ltd., Mumbai, India. Potassium hydroxide (solid pellets, 15%
water content) and toluene of AR grade were obtained from
M/s S.D. Fine Chem. Pvt. Ltd., Mumbai, India.
Tetrabutylammonium bromide (TBAB) of pure grade was
obtained as a gift sample from M/s. Dishman Pharmaceu-
ticals and Chemicals Ltd., Ahmedabad, India. These were
used as such without further purification.
Setup and Reaction Procedure. The reactions were
studied in a 5.4 cm i.d. fully baffled mechanically agitated
3
contactor of 150 cm total capacity, which was equipped with
a six-blade turbine-impeller and a reflux condenser. The
reactor height was 8.7 cm and the clearance of the stirrer
blade from the baffles was 1.8 cm. The reactor was kept in
an isothermal bath whose temperature could be maintained
at a desired value by using a temperature indicator controller.
The control experiment was conducted with 0.02 mol of
p-chlorophenyl acetonitrile and 0.04 mol isopropyl bromide
3
dissolved in toluene to make 25 cm volume of organic
phase. A known quantity of tetrabutylammonium bromide
Table 1. Control reaction
(TBAB) was added. Solid potassium hydroxide (KOH)
pellets (0.02 mol) were added to the reaction mixture and
the reaction temperature was maintained at 60 °C.
Method of Analysis. Samples of the organic phase were
withdrawn periodically and analysed by gas chromatography
Reaction Conditions
p-chlorophenyl acetonitrile
isopropyl bromide
potassium hydroxide
tetrabutylammonium bromide
toluene
0.02 mol
0.04 mol
0.02 mol
0.002 mol
25 cm
60 °C
2 h
[
Chemito model 8510]. A 2.0 m × 3.2 mm i.d. stainless
3
steel column packed with Chromosorb WHP, which was
impregnated with 10% OV-17 was used for analysis in
conjunction with a FID. Rates of reaction were calculated
on the basis of the disappearance of p-chlorophenyl aceto-
nitrile. Quantification of data was done through calibration
by using synthetic mixtures.
temperature
time
speed of agitation
1000 rpm
Selectivity, %
monoalkylated
conversion %
dialkylated
ester
16
45
84
-
The reaction products were confirmed by GC-MS
analysis. The GC-MS data showed that the C-alkylation
under S-L PTC conditions was highly selective towards the
monoalkylated product, R-isopropyl-p-chlorophenyl aceto-
nitrile. The other two minor products were identified as R,R′-
diisopropyl-p-chlorophenyl acetonitrile and p-chlorobenzoic
acid methylethyl ester. Neither isopropyl alcohol nor diiso-
propyl ether was detected in the reaction mixture.
as given in Table 1, at the end of 4 h, the monoalkylated
product was detected in 84% selectivity and the residual 16%
was the ester whereas there was no dialkylated product.
Consequently, it is beneficial to conduct the C-alkylation
under S-L PTC if the desired product is the monoalkylated
R-isopropyl-p-chlorophenyl acetonitrile.
Reaction Scheme. Scheme 1 depicts the products formed
in the reaction under S-L PTC conditions, namely, R-iso-
propyl-p-chlorophenyl acetonitrile, R,R′-diisopropyl-p-chlo-
rophenyl acetonitrile and p-chlorobenzoic acid methylethyl
ester. In general, for C-alkylations under L-L conditions,
the dialkylated product is formed in significant amounts and
also hydrolysis of p-chlorophenyl acetonitrile occurs to give
the corresponding amide or acid. However, in the current
work on S-L PTC under controlled conditions the monoalky-
lated R-isopropyl-p-chlorophenyl acetonitrile was obtained
as the major product and the dialkylated product was totally
suppressed. Formation of p-chlorobenzoic acid methylethyl
ester was observed unanticipatedly. For the control reaction,
Confirmation of Formation of p-Chlorobenzoic Acid
Methylethyl Ester. In the presence of atmospheric oxygen
and under alkaline conditions, oxidative decyanation of
p-chlorophenyl acetonitrile leads to the formation of the ester.
This was confirmed by GC-MS. This was further established
through independent experiments in which the reactions were
conducted separately under oxygen and nitrogen blankets.
Bubbling pure oxygen gas through the reaction mixture
increased the formation of the ester (31% in 4 h). Conversely,
when the reaction was conducted in an autoclave under
nitrogen atmosphere, the ester was not at all detected in the
reaction mixture. Thus, the formation of the ester indicates
the necessity of rigorously excluding oxygen from the
Vol. 7, No. 4, 2003 / Organic Process Research & Development
•
589

reaction mixture, when other desired reactions are sought.
However, since formation of the ester was a novel observa-
tion, it was decided to conduct the experiments under normal
atmospheric conditions and observe the effect of varying
parameters on the formation of the ester. A plausible
mechanism is provided in what follows.
Different observations have led to different theories, which
explain the role of ω-phase in S-L system. A few papers
have reported the increase in rates of the S-L PTC reaction
with increasing amounts of water in the system.1
0-11
A
comprehensive discussion of the ω-phase theory in ac-
cordance with the S-(ω)-L PTC cyanide displacement of
p-chlorobenzyl chloride has been published recently by us.12
According to the ω-phase theory, trace quantities of water
aid dissolution of the solid salt by forming a thin aqueous
film (known as the ω-phase) around the solid particle. In
S-L PTC, only minute quantities of the PT catalyst are
present in the organic phase while most of it is translocated
on the surface of the inorganic nucleophilic salt. Trace
quantities of water facilitate interaction between the quat and
the salt by breaking down the crystal lattice structure and
thus augment the ion-exchange reaction which in turn
enhances the reaction rates. On the basis of the ω-phase
theory, a general mechanism for the S-(ω)-L reaction can
be represented as shown in Scheme 2, which involves the
Reaction Mechanism
Although a wide variety of PTC reactions are conducted
in the presence of a base, the mechanism of these reactions
under S-L PTC conditions is obscure. PTC systems operate
1
via different mechanisms in the presence of bases. In L-L
PTC reactions involving strong bases, it is believed that the
mechanism involves extraction of hydroxide ion pair into
the organic phase followed by deprotonation and alkylation
of the substrate. However, the extraction of hydroxide is
difficult because of its limited solubility and partitioning in
the organic phase. Alkylation reactions have been proposed
+
-
to be mediated through [Q OH ] intermediate and probably
+
-
-
involve reaction between [Q OH ] and the organic substrate
dissolution of solid OH into the ω-phase followed by the
at the liquid-liquid interface in the case of L-L PTC and
in the bulk organic phase after formation of [Q OH ] at the
solid-liquid interface in the case of S-L PTC.
anion-exchange reaction with the catalyst to form the active
+
-
+
-
ion-pair Q OH which is then transferred to the organic
phase where it can abstract a proton from the nitrile to form
-
+
Presently, there is relatively little information available
on alkylation by the S-L phase transfer method. S-L PTC
reactions can follow two mechanisms based on the solubility
of the solid in the organic phase and the location of the ion-
exchange reaction, namely, homogeneous and heterogeneous
solubilisation.9
One of the important aspects of S-L PTC systems is the
role of trace quantities of water and its effect on the
mechanism and kinetics of the PTC cycle. In most solid-
liquid PTC/OH systems, water is always formed, and thus
the formation a thin film aqueous phase, called the “omega
the active species [RCH CNQ ] which reacts with isopropyl
bromide to give the monoalkylated product. Abstraction of
another proton from the monoalkylated product and subse-
quent reaction with isopropyl halide leads to the formation
of the dialkylated product. This is depicted in Scheme 3.
Most of the reports on phase transfer catalysed oxidative
decyanation are in reference to the transformation of
R-secondary nitriles to ketones and involve the use of strong
bases and is proposed to proceed via formation of the
1
3-14
1-cyanoalkyl peroxide anion intermediate.
The mecha-
nism of formation of p-chlorobenzoic acid methylethyl ester
involves the abstraction of the proton from the nitrile
followed by the oxidation of the resulting active species by
molecular oxygen. The unstable peroxy species thus formed
(ω)-phase” is almost certain. In the present system, water is
a byproduct of the reaction and it has to be deliberated in
reference to the formation of ω-phase. Here the maximum
quantity of water (15% w/w water content in solid KOH
taken initially plus water generated in situ during the reaction
considering maximum conversion of 45%) in the reaction
+
-
rapidly dissociates to p-chlorobenzoic acid and [Q CN ].
The acid instantaneously reacts with isopropyl bromide to
give p-chlorobenzoic acid methylethyl ester and HBr which
3
+
-
+
-
mixture will be 0.65 cm . Considering the following calcula-
reacts instantaneously with [Q OH ] to give [Q OBr ] and
water. To support the proposed mechanism, a control reaction
with p-chlorobenzoic acid and isopropyl bromide in the
presence of an alkali under the reaction conditions was
performed, and it was observed that the reaction does yield
the ester quantitatively and that no other product was formed.
Further, esterification of phenylacetic acid and derivatives
under S-L PTC conditions using triethylbenzylammonium
tions, it can be seen that a ω-phase of 0.4 mm thickness
surrounds the KOH particle. Typical calculations are given
below:
For solid KOH,
rp ) average pellet radius ) 0.27 cm
N ) average number of pellets in 1.12 g KOH loading )
1
5-16
chloride and solid KOH is reported,
and these reports
13. (The particles are not broken and remain as such during
describe PTC esterification of carboxylic acid, C-alkylation,
the course of reaction and shrink as the reaction proceeds.
Hence the number of particles remain constant.)
(9) Naik, S. D.; Doraiswamy, L. K. Chem. Eng. Sci. 1997, 52, 4533.
3
Volume of water available for ω-phase ) 0.65 cm .
(10) Liotta, C. L.; Burgess, E. M.; Ray, C. C.; Black, E. D.; Fair, B. E. ACS
Symp. Ser. 1987, 15, 326.
3
3
p
(
(
(
(
(
11) Zahalka, H. A.; Sasson, Y. J. Chem. Soc., Chem. Commun. 1984, 1652.
12) Yadav, G. D.; Jadhav, Y. B. Langmuir 2002, 18, 5995-6002.
13) Donetti, A.; Boniardi, O.; Ezhaya, A. Synthesis 1980, 12, 1009.
14) Kulp, S. S.; McGee, M. J. J. Org. Chem. 1983, 48, 4097.
15) Starks, C. M.; Liotta, C. L.; Halpern, M. Phase Transfer Catalysis:
Fundamentals, Applications and Industrial PerspectiVes; Academic Press:
New York, 1994, pp 392-393.
4/3 π N(r
- r ) ) 0.65
p+ω
where rp+ω ) radius of particle + ω-phase. Therefore, rp+ω
0.31 cm. Hence, r ) 0.4 mm. This means that a ω-phase
)
ω
thickness of 0.4 mm is available, which shows that the
reaction is indeed a solid-liquid PTC reaction with ω-phase.
(16) Canicio J.; Ginebreda A. Canellia R. Anal. Quim. Ser. C 1985, 81, 181.
590
•
Vol. 7, No. 4, 2003 / Organic Process Research & Development

Scheme 2. Mechanism of S-(ω)-L PTC C-alkylation of p-chlorophenyl acetonitrile
Scheme 3. Mechanism of solid-liquid phase transfer
catalysed C-alkylation of p-chlorophenyl acetonitrile with
isopropyl bromide
Scheme 4. Mechanism of solid-liquid phase transfer
catalysed oxidative decyanation of p-chlorophenyl
acetonitrile under alkaline conditions
of p-chlorophenyl acetonitrile under alkaline conditions is
proposed and represented in Scheme 4.
and hydrolysis all under S-L PTC conditions by using solid
KOH. On the basis of the experimental observations and
reported literature, the mechanism for oxidative decyanation
Effect of Different Parameters
To validate the proposed mechanism, effects of various
parameters on the rate of reaction were studied, and
Vol. 7, No. 4, 2003 / Organic Process Research & Development
•
591

Figure 2. Effect of catalyst concentration.
Figure 1. Effect of speed of agitation.
Table 3. Effect of catalyst concentration on selectivitya
Table 2. Effect of speed of agitation on selectivitya
Selectivity, %
[
TBAB] mol conversion % monoalkylated dialkylated ester
Selectivity, %
speed of
agitation, rpm conversion % monoalkylated dialkylated ester
0.001
.002
0.003
0.004
43
45
48
52
86
84
81
80
-
-
2
14
16
17
18
0
5
7
000
00
00
36
44
45
89
85
84
-
-
-
11
15
16
2
1
a
p-CBCN: 0.02 mol, IPB: 0.04 mol, KOH: 0.02 mol, toluene: 25 cm3,
a
temperature: 60 °C, speed of agitation: 1000 rpm.
p-CBCN: 0.02 mol, IPB: 0.04 mol, KOH: 0.02 mol, TBAB: 0.002 mol,
3
toluene: 25 cm , temperature: 60 °C.
that the solid-(ω)-liquid mass transfer is very fast vis- a` -
vis the reaction in the organic phase.
selectivity towards each product was calculated from the
moles of product formed to the moles of reactant converted
at the end of the reaction. All the reactions were conducted
for a period of 120 min. A standard reaction was performed
for 5 h, but it was observed that under standard reaction
conditions, the reaction slowed considerably after 3 h. Also
the standard reaction was a part of a more extensive research
on cascade-engineered PTC reaction systems and hence was
studied under the mentioned conditions with the formation
of the ester being explored as an interesting outcome.
(
b) Effect of Catalyst Concentration. There was no
reaction in the absence of PTC. The concentration of catalyst
TBAB) was varied from 0.001 to 0.004 mol, maintaining
(
all other experimental conditions constant. Figure 2 shows
the effect of catalyst loading on the conversion of p-
chlorophenyl acetonitrile. As is typical for all PTC reactions,
the conversion is found to increase with increasing catalyst
loading but the increase is marginal. The selectivity towards
C-alkylated product decreases and the formation of the ester
increases with increasing catalyst concentration. The dialky-
lated product is formed in small amounts at higher concen-
trations of the PTC (Table 3).
(a) Effect of Speed of Agitation. The theory of mass
transfer with reaction for phase transfer catalysed reactions
is discussed in our earlier paper on L-L PTC oxidation of
benzyl chloride.17 This theory is also applicable to S-L
reactions. To ascertain the influence of external mass transfer
resistance on the transfer of the reactants to the reaction
phase, the speed of agitation was varied in the range of 500-
(c) Effect of p-Chlorophenyl Acetonitrile Concentra-
tion. The concentration of p-chlorophenyl acetonitrile was
-4
-3
3
varied from 4 × 10 to 1.2 × 10 mol/cm organic phase
at 60 °C. The conversion of p-chlorophenyl acetonitrile is
plotted against time in Figure 3. The selectivity values at
the end of 2 h of reaction shows that the C-alkylated product
formation is favoured with increasing p-chlorophenyl aceto-
nitrile concentration (Table 4).
1
000 rev/min. As is seen from Figure 1, the conversion
increases with an increase in speed of agitation from 500 to
00 rev/min. However, when the speed of agitation was
7
increased from 700 to 1000 rev/min, the increase in conver-
sion was marginal which suggests elimination of external
resistance to mass transfer. All further experiments were
conducted at 1000 rpm. The selectivity of various products
at the end of 2 h of reaction is given in Table 2. It is obvious
(d) Effect of Solid Potassium Hydroxide Loading.
Figure 4 shows the effect of increase in solid KOH loading
on the conversion of p-chlorophenyl acetonitrile. The study
was conducted over a range of 0.01-0.03 mol loading of
solid KOH pellets. As the loading of solid alkali is increased,
conversion increases drastically. This is because more and
(17) Yadav, G. D.; Haldavanekar, B. V. J. Phys. Chem. 1997, 101, 36.
5
92 Vol. 7, No. 4, 2003 / Organic Process Research & Development
•

Table 5. Effect of solid KOH loading on selectivitya
Selectivity, %
[
KOH] mol conversion % monoalkylated dialkylated ester
0
0
0
0
.01
.02
.025
.03
33
45
60
70
88
84
84
84
-
-
3
12
16
13
13
3
a
p-CBCN: 0.02 mol, IPB: 0.04 mol, TBAB: 0.002 mol, toluene: 25 cm3,
temperature: 60 °C, speed of agitation: 1000 rpm.
Figure 3. Effect of p-CBCN concentration.
Table 4. Effect of p-CBCN on selectivitya
Selectivity, %
[
p-CBCN] mol conversion % monoalkylated dialkylated ester
0.01
0.02
0.025
0.03
86
45
40
35
82
84
85
88
-
-
-
-
18
16
15
12
a
IPB: 0.04 mol, KOH: 0.02 mol, TBAB: 0.002 mol, toluene: 25 cm3,
Figure 5. Effect of Isopropyl bromide concentration.
temperature: 60 °C, speed of agitation: 1000 rpm.
Table 6. Effect of IPB concentration on selectivitya
Selectivity, %
[
IPB] mol conversion % monoalkylated dialkylated ester
0.02
0.03
0.04
0.05
0.06
41
42
45
54
54
85
84
84
84
81
-
-
-
2
15
16
16
14
12
7
a
p-CBCN: 0.02 mol, KOH: 0.02 mol, TBAB: 0.002 mol, toluene: 25 cm3,
temperature: 60 °C, speed of agitation: 1000 rpm.
greater, there is no corresponding increase in the amount of
caustic available for deprotonation; hence, the increase in
conversion is insignificant. For better conversion values, both
the IPB and KOH concentrations have to be increased
simultaneously. At higher IPB concentrations of 0.05 and
0
.06 mol some of the monoalkylated product is further
converted to dialkylated product. However, the change in
selectivity is not very significant (Table 6).
Figure 4. Effect of solid KOH loading.
+
-
more nucleophile in the [Q OH ] form is available for proton
abstraction. The selectivity of various products is not altered
much except that the formation of dialkylated product is
observed at higher alkali concentrations (Table 5).
(f) Effect of Increasing IPB and Solid KOH Concen-
tration. Since increasing the strength of IPB and solid alkali
individually did not have a substantial effect on conversion,
it was decided to increase their loading simultaneously.
Therefore, both IPB and KOH at equimolar concentrations
were varied at 0.02, 0.03, 0.04, and 0.06 mol. As seen from
Figure 6, it was observed that almost complete conversion
could be achieved when the loading of IPB and KOH was
in triple molar excess to p-chlorophenyl acetonitrile. The
selectivity towards monoalkylated product, however, suffered
(e) Effect of Isopropyl Bromide Concentration. The
effect on conversion of increasing the concentration of
isopropyl bromide is represented in Figure 5. There is a
marginal increase in conversion from 41 to 54% as the moles
of IPB are increased from 0.02 to 0.06 mol. Even though
the quantity of IPB available for the reaction has become
Vol. 7, No. 4, 2003 / Organic Process Research & Development
•
593

Table 8. Effect of temperature on selectivitya
Selectivity, %
temperature °C conversion % monoalkylated dialkylated ester
30
40
50
60
24
36
40
45
88
88
88
84
-
-
-
-
12
12
12
16
a
p-CBCN: 0.02 mol, IPB: 0.04 mol, KOH: 0.02 mol, TBAB: 0.002 mol,
3
toluene: 25 cm , speed of agitation: 1000 rpm.
8
). It is well-known that heterogeneous reactions with
activation energy values lower than 4 kcal/mol are mass-
transfer limited and systems above 6 kcal/mol are kinetically
controlled. The current system is thus kinetically controlled.
Mathematical Modeling
Figure 6. Effect of varying IPB and KOH concentration.
The various steps involved in C-alkylation and oxidative
decyanation of p-chlorophenyl acetonitrile can be represented
as:
Table 7. Effect of varying IPB and KOH concentration on
selectivitya
KQX
Selectivity, %
+
-
+
-
[
Q X ]
{
} [Q X ]
ω
(1)
(2)
(3)
[
IPB] and [KOH] conversion
org
mol
%
monoalkylated dialkylated ester
K1
+
-
-
+
-
-
[
Q X ] + [OH ] {\ } [Q OH ] + [X ]
ω ω ω ω
0.02
0.03
0.04
0.06
41
62
82
98
85
84
83
79
-
2
5
15
14
12
9
KQOH
+
-
+
-
[
Q OH ] { } [Q OH ]
ω
org
H
O2
11
O2(g)
{
} O2(org)
(4)
a
3
p-CBCN: 0.02 mol, TBAB: 0.002 mol, toluene: 25 cm , temperature: 60
C, speed of agitation: 1000 rpm.
°
In the above equation, [O
the organic phase. [O
2
]org is the solubility of oxygen in
2
]
org is approximately taken as 8.47 ×
-
5
3
18
1
0
mol/cm toluene at 90 °C which is a constant.
H
O
is
2
2
the Henry’s law solubility constant for O .
Reactions Occurring in the Organic Phase:
K2
S + QOH {
\
} S + H O
(5)
1
2
k
9
r1
S1 + A
8 M + QX
(6)
(7)
K3
M + QOH {
\
} S + H O
2 2
k
9
r2
S2 + A
8 D + QX
(8)
(9)
K4
\} S
S + O {
1
2
3
K5
S3
9
8 B + QCN
(10)
(11)
k
r3
B + A
98 E + HX
Figure 7. Effect of temperature.
+
-
+
-
HX + [Q OH ] f [Q X ] + H O
(11a)
(12)
(13)
org
org
2
at higher concentration of IPB and KOH. Table 7 depicts
the selectivity of various products.
KQCN
{
+
-
+
-
[Q CN ]org
} [Q CN ]
ω
(
g) Effect of Temperature. The effect of temperature
on the rate of the reaction was studied in the range of 30-
0 °C. The conversion of p-chlorophenyl acetonitrile was
K6
9
+
-
-
+
-
-
[
Q CN ] + [OH ]
8 [Q OH ] + [CN ]
ω
ω
ω
ω
6
Derivation of the Rate Equation
On the basis of the proposed mechanism, the rate equation
for the S-L PTC C-alkylation reaction can be derived.
observed to increase with an increase in the reaction
temperature (Figure 7). There was no significant change in
selectivity of various products with increase in reaction
temperature (Table 8). The energy of activation from the
Arrhenius plot was calculated to be 6.82 kcal/mol (Figure
(
18) Green, D. W.; Maloney J. O. Perry’s Chemical Engineers’ Handbook;
McGraw-Hill: New York, 1997
594
•
Vol. 7, No. 4, 2003 / Organic Process Research & Development

Thus, the final rate equation for the monoalkylated product,
R-isopropyl-p-chlorophenyl acetonitrile [M] can be given as:
d[M]org
[A]org[S]org[QX]org[OH-]
ω
r )
) kM
(24)
M
-
dt
[
X ] [H O]
ω
2
org
M
1 2 QOH
where k ) kr1K K K KQX, pseudorate constant. Similarly,
for the dialkylated product, R,R′-diisopropyl-p-chlorophenyl
acetonitrile [D], the rate equation can be given as:
d[D]org
dt
[A]org[M]org[QX]org[OH-]
ω
r )
) k K K KQOHK
r 1 3 QX
2
D
-
[
X ] [H O]
ω
2
org
(25)
Figure 8. Arrhenius plot.
d[D]org
dt
[A]org[M]org[QX]org[OH- ]
ω
r )
) kD
(26)
D
-
Rate of Formation of the Monoalkylated Product [M]:
[X ] [H O]
ω
2
org
d[M]org
where k
1 3 QOH
) kr2K K K KQX, pseudorate constant.
D
r )
) k [S ] [A]org
(14)
M
r
1 org
1
Rate of Consumption of Isopropyl Bromide [A]:
dt
From eq 5,
d[A]org
-rA ) -
) [A]org{k [S ] + k [S ] + k [B]org}
r 1 org r 2 org r
1 2 3
dt
[
S ] [H O]
1 org 2 org
(27)
K )
(15)
(16)
2
[S]org[QOH]org
From eq 5,
From eq 7,
[S]org[QOH]org
[
S ] ) K2
[S]org[QOH]org
1
org
[
H O]
[S ] ) K2
2
org
1 org
[
H O]
2 org
Substituting in eq 14, we get
d[M]org
[A]org[S]org[QOH]org
[H O]
)
k K
(17)
[M]org[QOH]org
r
2
1
dt
[S ] ) K3
2
org
2 org
[
H O]
2 org
From eq 2,
Substituting for [S
d[A]org
1 2
]org and [S ]org in eq 27,
-
[
QOH] [X ]
ω
ω
[S]org
K )
(18)
(19)
1
-
-r ) -
) [A]org[QOH]org k K
+
A
r
1
2
[
QX] [OH ]
{
ω
ω
dt
[H O]
2
org
-
[M]org
[B]org
[
QX] [OH ]
ω
ω
k K
+ kr3
(28)
r
3
2
}
[
QOH] ) K
[H O]
[QOH]org
ω
1
-
2
org
[
X ]
ω
Substituting for [QOH] org from eq 22, eq 28 leads to the
following:
from eq 3,
from eq 1,
[
QOH]org
d[A]org
[
QOH] )
(20)
(21)
ω
-r ) -
KQOH
A
dt
[
A]org[QX]org[OH-]
[S]org
ω
)
K KQOHKQX
k K
2
+
1
-
r
{
1
[H O]
org
[
QX] ) KQX[QX]org
[X ]
2
ω
ω
[
M]org
[B]org[X-]
ω
By substituting eqs 20 and 21 in eq 19, the following is
obtained
k K
+ K KQOHK kr3
(29)
r
3
1
QX
-
2
}
[H O]
2 org
[QX]org[OH ]
ω
[A]org[QX]org[OH-]
[S]org
[
QX
QX]org[OH-]
ω
d[A]org
ω
[
QOH]org ) K KQOHK
(22)
1
-
-r ) -
) Ka
Kb
+
A
-
[X ]
dt
{
[H O]
ω
[X ]
2
org
ω
-
[
M]org
[B] [X ]
Substituting for [QOH]org in eq 17, we get
org
ω
Kc
+ Kd
(30)
-
}
[
H O]
2 org
[QX]org[OH ]
ω
[A]org[S]org[QX]org[OH-]
d[M]org
ω
r )
) k K K KQOHK
r 1 2 QX
1
M
-
dt
where K
a
) K
1 QOH
K
K
QX, K
b
) kr1
K , K
2
c
) kr2K
3
and K
d
)
[
X ] [H O]
ω
2
org
(23)
1 QOH r3
K K K k .
QX
Vol. 7, No. 4, 2003 / Organic Process Research & Development
•
595

Table 9. Rate equations used for numerical solution for C-alkylation
equation
equation no.
rate of formation of monoalkylated product [M]:
d[M]org
[A]org[S]org[QX]org[OH-]
ω
rM
)
) kM
24
26
-
dt
[
X ] [H O]
ω 2 org
rate of formation of dialkylated product [D]:
d[D]org
dt
[A]org[M]org[QX]org[OH-]
ω
r )
) kD
D
-
[
X ] [H O]
ω
2
org
rate of consumption of isopropyl bromide [A]:
d[A]org
[A]org[QX]org[OH-]
[S]org
[M]org
+ Kd
[H O]
org
[QX]org[OH ]
[B]org[X-]
ω
ω
-rA ) -
) Ka
Kb
+ Kc
30
35
36
-
{
-
}
dt
[H O]
2 org
[
X ]
2
ω
ω
rate of formation of p-chlorobenzoic acid methylethyl ester [E]:
d[E]org
[A]org[O ] [S]org[QX]org[OH-]
2 org
ω
rE )
) kE
-
dt
rate of consumption of p-chlorophenyl acetonitrile [S]:
[
H O] [X ] [QCN]
2
org
ω
org
d[S]org
-
) K [S]org[QOH]org
2
dt
Rate of Formation of p-Chlorobenzoic Acid Methyl-
Substituting the above in eq 33, the following is obtained:
ethyl Ester [E]:
[
O2]org[S]org[QX]org[OH-]
ω
[
B]org ) K K KQOHK K K
d[E]org
1 2 QX 4 5
-
[
H O] [X ] [QCN]
rE )
) k [B]org[A]org
(31)
2
org
ω
org
r
3
dt
[
O ] [S]org[QX]org[OH-]
ω
From eq 10,
2 org
[
B]org ) KC
(34)
-
[
H O] [X ] [QCN]
2
org
ω
org
[
B]org[QCN]org
K )
5
[
S ]
where K
1 2 QOH QX 4 5
) K K K K K K .
3
org
C
Substituting the above in eq 31 leads to
[
S ]
3
org
[B]org ) K5
(32)
[A]org[O ] [S]org[QX]org[OH-]
[
QCN]org
d[E]org
2 org
ω
rE )
) k K
r C
3
-
dt
[
H O] [X ] [QCN]
2
org
ω
org
From eq 9,
[
S ]
d[E]org
[A]org[O ] [S]org[QX]org[OH-]
ω
3
org
2 org
K )
rE )
) kE
(35)
4
-
[
S ] [O ]
dt
1
org
2 org
[H O] [X ] [QCN]
2
org
ω
org
[
S ] ) K [S ] [O ]
3 org 4 1 org 2 org
where k
Rate of Consumption of p-Chlorophenyl Acetonitrile
S]:
E
C
) kr3K ) pseudorate constant.
Substituting in eq 32, we get
[
[
S ] [O ]
1 org 2 org
[
B]org ) K K
(33)
d[S]org
4
5
[QCN]org
-
) K [S]org[QOH]org
(36)
2
dt
[
S ] [H O]
1
org
2
org
Now, the various equations as given in Table 9 can be solved
to get the concentration profiles of individual species. The
profiles of A, M, D, E, and S are interrelated, and the
pertinent equations can be solved simultaneously. Owing to
their complex nature, these equations cannot be analytically
solved; hence, a numerical method was employed.
K )
2
[S]org[QOH]org
[
S]org[QOH]org
[
S ] ) K2
1 org
[
H O]
2 org
Again,
The values of various rate constants and distribution
coefficients were calculated with a numerical computing
program that uses Euler’s method. The basic concept for
Euler’s method is to add small increments to the given
functions corresponding to derivatives multiplied by step
QX]org[OH-]
[
ω
19
[
QOH]org ) K KQOHKQX
1
-
[
X ]
ω
[
S]org[QX]org[OH-]
ω
[
S ] ) K K KQOHK
1 org 1 2 QX
-
(19) Press, W. H.; Teukolsky, S. A.; Vetterling, W. T.; Flannery, B. P.
[
H O] [X ]
2
org
ω
Numerical Recipes in C; Cambridge University Press: New York, 1992.
596
•
Vol. 7, No. 4, 2003 / Organic Process Research & Development

Table 10. Values of pseudorate constants by Euler’s method
concentration
k
M
K
a
k
E
k
D
3
3
3
3
parameter studied
mol
K
2
cm /mol‚s
cm /mol‚s
K
b
cm /mol‚s
cm /mol‚s
K
c
p-CBCN
27
25
-
-
-
3
3
3
0
.02
4.98 × 10
4.26 × 10
3.6 × 10
2
2
2
38
35
32.5
2
2
2
-
-
-
-
-
-
0
0
.025
.03
23.2
IPB
33
23
20
25.2
-
-
-
-
3
3
3
3
0.03
0.05
0.06
4.56 × 10
6.48 × 10
6.48 × 10
5.058 × 10
2
2
2
2
38
20
20
30.58
2
2
1
1.83
-
18
4.8
11.4
-
23
23
23
average values
The known values of initial concentrations of each species
were used as input, and the above equations were defined
as functions. The values of various pseudorate constants and
equilibrium constants for varying p-CBCN and IPB concen-
trations were calculated independently and are summarised
in Table 10. The relative error was found to be negligible.
It can be seen from Figure 9a, that the simulated conversion
profile of p-chlorophenyl acetonitrile matches with the
experimental curve within the range of reasonable accuracy.
The concentration profiles of each species obtained from
numerical analysis are shown in Figure 9b.
Conclusions
The alkylation of p-chlorophenyl acetonitrile with iso-
propyl bromide under solid-liquid phase transfer conditions
is an enticing system from the mechanistic perspective. The
C-alkylation reaction is accompanied by oxidative decya-
nation of the nitrile, resulting in the generation of p-
chlorobenzoic acid methylethyl ester as the byproduct. The
monoalkylated compound is the major product, and the
dialkylated product results only at higher concentrations of
catalyst, alkali, and alkylating agent. The reaction following
S-L numerical analysis was performed using Euler’s method
to get the values of various rate constants, equilibrium
constants, and the concentration profile of each species.
Acknowledgment
G.D.Y. acknowledges the Darbari Seth Professorship
Endowment, and AICTE and Ambuja Cement Ltd. for
research funding. Y.B.J. thanks AICTE and Ambuja Cements
for the award of JRF and SRF, respectively. Assistance of
Sanket Salgaonkar in numerical calculations is gratefully
acknowledged. G.D.Y. also thanks the Michigan State
University, East Lansing, MI, for hosting him as the
Johansen-Crosby Visiting Chair Professor of Chemical
Engineering which provided ample time for creative writing.
Figure 9. (a) Conversion profile for simulated and experi-
mental results. (b) Concentration profile resulting from nu-
merical analysis.
sizes. The formula for Euler’s method is
yn+1 ) y + hf(x ,y )
(37)
NOMENCLATURE
n
n
n
K
K
K
K
1
Equilibrium constant for anion-exchange reaction in the
ω-phase, dimensionless
where yn+1 is the increment in y
increment of h in x
n
corresponding to an
n
.
+
-
QOH
QX
QCN
Distribution coefficient of Q OH between ω and organic
The formula is unsymmetrical. It advances the solution
through an interval h but uses derivative information only
at the beginning of that interval. This means that the steps
error is only one power of h smaller than the correction.
This method was selected because of its simplicity and
accuracy to solve simple differential equations.
phase, dimensionless
+
-
Distribution coefficient of Q X between ω and organic
phase, dimensionless
+
-
Distribution coefficient of Q CN between ω and organic
phase, dimensionless
Vol. 7, No. 4, 2003 / Organic Process Research & Development
•
597

k
r1
k
r2
k
r3
Rate constant for formation of R-isopropyl-p-chlorophe-
nylacetonitrile in organic phase, cm /mol‚s
[M]org
[D]org
[E]org
Concentration of R-isopropyl-p-chlorophenylacetonitrile in
3
organic phase, mol/cm3
Rate constant for formation of R,R′-diisopropyl-p-chlo-
Concentration of R,R′-diisopropyl-p-chlorophenylaceto-
nitrile in organic phase, mol/cm3
3
rophenyl acetonitrile in organic phase, cm /mol‚s
Rate constant for formation of p-chlorobenzoic acid
Concentration of p-chlorobenzoic acid methylethyl ester
in organic phase, mol/cm3
3
methylethyl ester in organic phase, cm /mol‚s
[
[
[
[
[
[
[
OH-]
ω
Concentration of OH- in ω-phase, mol/cm3
Concentration of QX in organic phase, mol/cm3
Concentration of QX in ω-phase, mol/cm3
Concentration of QOH in organic phase, mol/cm3
Concentration of QOH in ω-phase, mol/cm3
Moles of X- in ω-phase, mol/cm3
r
M
Rate of formation of R-isopropyl-p-chlorophenylacetoni-
trile, cm /mol‚s
3
QX]org
rD
Rate of formation of R,R′-diisopropyl-p-chlorophenylac-
QX]
ω
3
etonitrile in organic phase, cm /mol‚s
QOH]org
r
E
Rate of formation of p-chlorobenzoic acid methylethyl
QOH]
ω
3
ester in organic phase, cm /mol‚s
-
X ]
ω
3
r
A
Rate of consumption of isopropyl bromide, cm /mol‚s
A]org
Concentration of isopropyl bromide in organic phase, mol/
cm3
3
k
D
Pseudorate constant, cm /mol‚s
3
k
M
Pseudorate constant, cm /mol‚s
[
[
S]org
Concentration of p-chlorophenylacetonitrile in organic
phase, mol/cm3
Received for review April 5, 2002.
OP025538Z
3
H
2
O]org
2
Concentration of H O in organic phase, mol/cm of organic
phase
598
•
Vol. 7, No. 4, 2003 / Organic Process Research & Development