Engineering selectivity in novel synthesis of 3-(phenylmethoxy)phenol from resorcinol and benzyl chloride under liquid-liquid-liquid phase transfer catalysis

Article abstract of DOI:10.1021/op7002369

Monobenzyl ether of resorcinol, namely, 3-(phenylmethoxy)phenol is used as an intermediate for the synthesis of various chemically and biologically active molecules. The synthesis of 3-(phenylmethoxy)phenol can be accomplished by using phase transfer catalysis (PTC), either as liquid-liquid (L-L) or solid-liquid (S-L) PTC. Creation of a third phase in a biphasic reaction leads to several advantages in this type of reaction. A catalyst rich middle phase is formed between the other two phases wherein the main reaction takes place in the liquid-liquid-liquid (L-L-L) PTC and this offers a number of advantages over L-L PTC in terms of intensification of rate, higher selectivity and the possibility to reuse the catalyst. It is an excellent way for waste reduction and improving profitability. The catalyst rich phase is recovered and reused to up to six times with little impact to reactivity. This also helps in waste minimization which is a major theme of Green Chemistry. In the current work, synthesis of 3-(phenylmethoxy)-phenol was accomplished by the reaction of resorcinol with benzyl chloride using tetrabutylammonium bromide (TBAB) under liquid-liquid-liquid phase transfer catalysis (L-L-L PTC) at 90 °C. The studies cover the effects of various kinetic and process parameters which lead to enhancement in rates and selectivities. A theoretical model was developed and validated against experimental data. It follows zero-order kinetics in the mono-O-benzylation of resorcinol. There is 100% selectivity for 3-(phenylmethoxy)phenol with no discernible amount of bis-alkylated product detectable. O-Alkylation of hydroquinone and catechol were also studied using the same technique to realise the same high selectivity. The order of reactivity and apparent activation energy is as follows: hydroquinone 〉 resorcinol 〉 catechol.

Full text of DOI:10.1021/op7002369

Organic Process Research & Development 2008, 12, 755–764
Engineering Selectivity in Novel Synthesis of 3-(Phenylmethoxy)phenol from
Resorcinol and Benzyl Chloride under Liquid–Liquid-Liquid Phase Transfer Catalysis
Ganapati D. Yadav* and Omprakash V. Badure
Department of Chemical Engineering, UniVersity Institute of Chemical Technology, UniVersity of Mumbai, Matunga,
Mumbai - 400 019, India
1
Abstract:
ration of an intermediate for an oral bactericide drug. Most of
the routes for the manufacture of the 3-(phenylmethoxy)phenol
involve reaction of resorcinol with benzyl chloride in presence
Monobenzyl ether of resorcinol, namely, 3-(phenylmethoxy)phenol
is used as an intermediate for the synthesis of various chemically
and biologically active molecules. The synthesis of 3-(phenyl-
methoxy)phenol can be accomplished by using phase transfer
catalysis (PTC), either as liquid–liquid (L-L) or solid–liquid (S-L)
PTC. Creation of a third phase in a biphasic reaction leads to
several advantages in this type of reaction. A catalyst rich middle
phase is formed between the other two phases wherein the main
reaction takes place in the liquid–liquid-liquid (L-L-L) PTC
and this offers a number of advantages over L-L PTC in terms
of intensification of rate, higher selectivity and the possibility to
reuse the catalyst. It is an excellent way for waste reduction and
improving profitability. The catalyst rich phase is recovered and
reused to up to six times with little impact to reactivity. This also
helps in waste minimization which is a major theme of Green
Chemistry. In the current work, synthesis of 3-(phenylmethoxy)-
phenol was accomplished by the reaction of resorcinol with benzyl
chloride using tetrabutylammonium bromide (TBAB) under
liquid–liquid-liquid phase transfer catalysis (L-L-L PTC) at 90
2
of potassium carbonate. Other synthetic routes include: (a)
demethylation of the bis-methyl ether of resorcinol, (b)
hydrogenolysis of resorcinol dibenzyl ether using hydrogen and
Pd/C acetic acid, (c) reaction of benzyl bromide with 10-fold
excess of resorcinol, (d) using PEG as a multipurpose soluble
polymer, monoprotection group and phase transfer catalyst, and
e) Mitsunobu reaction of resorcinol monobenzoate and alcohol
followed by hydrolysis using a strong base. All of these
methods give low yields of 3-(phenylmethoxy)phenol, and some
methods require expensive and not readily available reagents.
O-Alkylation can be most conveniently carried out by using
phase transfer catalysis (PTC), and in the case of dihydroxy-
benzenes, the reaction needs to be engineered to get only the
monoether. In this paper, a very convenient method is reported
to synthesize monobenzyl ether of resorcinol by using
liquid–liquid-liquid (L-L-L) PTC, and also a mechanistic
and kinetic analysis of the process is presented to generalize
the findings for other dihydroxybenzenes.
3
4
5
6
(
7
°C. The studies cover the effects of various kinetic and process
PTC is now a text-book technique, which is practised in over
00 processes in different industries such as intermediates,
dyestuffs, agrochemicals, perfumes, flavours, pharmaceuticals,
parameters which lead to enhancement in rates and selectivities.
A theoretical model was developed and validated against experi-
mental data. It follows zero-order kinetics in the mono-O-
benzylation of resorcinol. There is 100% selectivity for 3-(phenyl-
methoxy)phenol with no discernible amount of bis-alkylated
product detectable. O-Alkylation of hydroquinone and catechol
were also studied using the same technique to realise the same
high selectivity. The order of reactivity and apparent activation
energy is as follows: hydroquinone > resorcinol> catechol.
6
8–11
and polymers.
A majority of PTC reactions are conducted
under liquid–liquid (L-L) conditions. L-L PTC is also
disadvantageous for systems where the presence of water can
lead to side reactions, such as hydrolysis; for instance, when
halides are used as alkylating agents it leads to byproduct
formation such as alcohols and ethers. In order to suppress
byproduct formation and also to intensify the rates, the biliquid
PTC ought to be converted to triliquid PTC. In the case of
1
. Introduction
(
1) Wissner, A.; Carrol, M. L.; Green, K. E.; Kerwar, S. S. J. Med. Chem.
992, 35, 1650.
1
O-Alkylation of dihydroxybenzenes leads to mono- and
(
2) Fitton, A. O.; Ramage, G. R. J. Chem. Soc. 1962, 4870.
dialkylated products which are highly valuable in the fine
chemical and pharmaceutical industry. Catechol, resorcinol, and
hydroquinone have been used to create a family of intermediates
and fine chemicals though C- and O-alkylations, by using a
variety of alkylating agent, both through acid catalysis and phase
transfer catalysis (PTC). Monobenzyl ether of resorcinol, namely
(3) Karpov, O. N.; Fedosyuk, L. G. Khim. Tekhnol. 1976, 3, 59;Chem.
Abstr. 1976, 85:159566r.
(
(
4) Maleski, R. J.; Kluge, M.; Sicker, D. Synth. Commun. 1995, 25, 2327.
5) Amabilino, D. B.; Ashton, P. R.; Boyd, S. E.; Gómez-López, M.;
Hayes, W.; Stoddart, J. F. J. Org. Chem. 1997, 62, 3062.
(
(
6) Yang, G.; Chen, Z.; Zhang, Z.; Qiu, X. Synth. Commun. 2002, 3, 3637.
7) Boxhall, J. Y.; Page, P. C. B.; Chan, Y.; Hayman, C. M.; Heaney, H.;
McGrath, M. J. Synlett 2003, 7, 997.
(
8) Starks, C. M.; Liotta, C.; Halpern, M. Phase Transfer Catalysis:
Fundamentals, Applications and PerspectiVes; Chapman and Hall:
New York, 1994.
3-(phenylmethoxy)phenol, for instance, is used as a precursor
for the synthesis of various chemically and biologically active
molecules. 3-(Phenylmethoxy)phenol is also used in the prepa-
(9) Sasson, Y., Neumann, R., Eds. Handbook of Phase Transfer Catalysis;
Blackie Academic and Professional: New York, 1997.
(
10) Dehmlow, E. V.; Dehmlow, S. S. Phase Transfer Catalysis, 3rd ed.;
*
Author to whom correspondence should be addressed. Telephone: 91-22-
10 2121. Fax: 91-22-414-5614. E-mail: gdyadav@yahoo.com, gdyadav@
udct.org.
VCH: New York, 1993.
4
(11) (a) Yadav, G. D. Top. Catal. 2004, 29, 145. (b) Yadav, G. D.; Naik,
S. S. Catal. Today 2001, 66, 345.
1
0.1021/op7002369 CCC: $40.75

2008 American Chemical Society
Vol. 12, No. 4, 2008 / Organic Process Research & Development
•
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Published on Web 06/18/2008

L-L-L PTC, the middle phase (or the so-called third phase)
is the catalyst-rich phase, with two interfaces on either side,
namely,(i)aqueousphase-middlephase,(ii)organicphase-middle
phase, which prohibit direct contact of aqueous and organic
phases. Therefore, there is no coextraction of water and the
aqueous-phase promoted reactions are totally suppressed.
Indeed, we have found in a number of reactions, not only the
rates of reaction but also the selectivity can be enhanced
dramatically thereby reducing reaction times; reactor volumes
11–19
and separation costs.
Besides, the catalyst phase can be
recycled along with the aqueous phase to reuse the catalyst,
which leads to waste minimization, one of the tenets of Green
Chemistry. The third liquid phase is the main reaction phase
and, the recovery and reuse of the catalyst is easier since it
Figure 1. Photograph of the L-L-L PTC Reactor. The stirrer
is stationary.
11–23
forms an immiscible middle liquid phase.
The current work
addresses L-L-L PTC catalyzed monobenzylation of resor-
cinol with benzyl chloride to produce 3-(phenylmethoxy)phenol.
The mono-O-benzylation of catechol and hydroquinone was
also studied since the corresponding products are also important
in fine chemical and pharmaceutical industry.
out at 90 °C and 1000 rpm for which the reactions were
intrinsically kinetically controlled, which will be discussed later.
L-L PTC reactions were also conducted at a catalyst concen-
tration a little lower than the critical concentration which formed
the third phase.
2
.3. Method of Analysis. Samples of the organic phase
2
. Experimental Section
.1. Materials. Benzyl chloride, toluene, resorcinol, cat-
echol, hydroquinone, potassium hydroxide, potassium chloride,
-(phenylmethoxy)phenol of AR grade were obtained from M/S
were withdrawn periodically and analysed by gas chromatog-
raphy on a Chemito 8510 model. A 2 m × 3.18 mm internal
diameter stainless steel column packed with 10% SE-30 on
chromosorb WHP was used for analysis in conjunction with a
flame ionization detector. The conversion was based on the
disappearance of benzyl chloride in the organic phase. Synthetic
mixtures of pure components and possible products were made
and used to quantify the data. Under three liquid phases, only
2
3
s.d. Fine Chem. Pvt. Ltd. Mumbai, India. Tetrabutylammonium
bromide (TBAB) of pure grade was obtained as a gift sample
from M/s Dishman Pharmaceuticals and Chemicals Ltd.,
Ahmedabad, India. All other chemicals were A.R. grade
procured from reputed firms.
3
-(phenylmethoxy)phenol was produced. The product was
confirmed by GC-MS and also by product isolation and
purification.
2.2. Experimental Procedure. The reaction was studied in
a 5 cm. i.d. fully baffled mechanically agitated glass reactor of
3
100 cm total capacity which was equipped with four baffles
2.4. Determination of the Composition of the Third
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 1.7 cm o.d., made of
s.s. 316, located at a distance of 0.9 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. The reaction mixture was agitated mechani-
cally with the help of an electric motor. Typical L-L-L PTC
runs were conducted by taking 0.04 mol resorcinol, 0.02 mol
Phase. The composition of the third phase was analyzed on
gas phase chromatography by using a thermal conductivity
detector with a stainless steel column (3.25 mm × 2 m) packed
with a liquid stationary phase of 10% SE-30. A Karl Fischer
apparatus was used to analyze the amount of water present in
the third phase. The third phase contains 14.87% toluene,
22.56% TBAB, 0.89% benzyl chloride, 20.79% resorcinol,
1.24-3% (phenylmethoxy)phenol, 39.65% water. In a typical
experiment, the third-phase volume was 7.0 mL.
.5. Reaction Scheme. The overall reaction is shown in
potassium hydroxide, 0.13 mol of potassium chloride, and
2
3
0
.0062 mol TBAB in 30 cm of water. This ensured that the
Scheme 1 for dihydroxybenznes. Resorcinol reacts with benzyl
chloride in the presence of the phase transfer catalysis to give
selectively 3-(phenylmethoxy)phenol in triliquid PTC. When
dihydroxybenzene is taken as a limiting reactant with reference
to KOH and benzyl chloride, byproduct formation is significant
due to a series (consecutive) reaction of dihydroxybezene and
a parallel reaction of benzyl chloride as shown in Scheme 1,
particularly in L-L PTC.
formation of the third liquid phase took place at room temper-
ature and also at reaction temperature (Figure 1). The organic
phase was composed of 0.02 mol benzyl chloride which was
3
made up to 30 cm toluene. All the typical runs were carried
(
(
12) Yadav, G. D.; Reddy, C. A. Ind. Eng. Chem. Res. 1999, 38, 2245.
13) Yadav, G. D.; Jadhav, Y. B. Clean Technol. EnViron. Policy 2003, 6,
3
2.
(
(
(
(
(
(
(
(
(
(
14) Yadav, G. D.; Bisht, P. M. J. Mol. Catal. A: Chem. 2004, 223, 93.
15) Yadav, G. D.; Lande, S. V. Appl. Catal., A. 2005, 287 (2), 267.
16) Yadav, G. D.; Lande, S. V. AdV. Synth. Catal. 2005, 347 (9), 1235.
17) Yadav, G. D.; Desai, N. M. Org. Process. Rec. DeV. 2005, 9, 749.
18) Yadav, G. D.; Desai, N. M. Catal. Commun. 2006, 7, 325.
19) Wang, D. H.; Weng, H. S. Chem. Eng. Sci. 1988, 43, 2019.
20) Wang, D. H.; Weng, H. S. Chem. Eng. Sci. 1995, 50, 3477.
21) Neumann, R.; Sasson, Y. J. Org. Chem. 1984, 49, 3448.
3. Results and Discussion
Figure 1 shows the photograph of the reactor with three
distinct liquid phases. The photograph was taken without any
agitation at the reaction temperature. These phases were stable
under experimental conditions, and only the desired monoalkyl-
ated product was formed. Scheme 2 depicts the mechanism of
22) Masson, D.; Magdassi, S.; Sasson, Y. J. Org. Chem. 1991, 56, 7229.
23) Huang, C. C.; Yang, H. M. Appl. Catal., A 2005, 290, 65.
7
56
•
Vol. 12, No. 4, 2008 / Organic Process Research & Development

Scheme 1. O-Alkylation of dihydroxybenzene with benzyl chloride; complex reaction network consisting of two parallel
reactions of benzyl chloride and a consecutive reaction of dihydroxybenzene; L-L-L allows only one reaction (b) to give the
desired product; L-L also leads to byproduct formation
Scheme 2. Mechanism of L-L-L PTC mono-O-benzylation of resorcinol with benzyl chloride
the L-L-L PTC. It shows the various reactions taking place
in different phases and the products getting transferred across
the two interfaces. The locale of the rate-controlling reaction
here because benzyl chloride is not allowed to transfer to the
aqueous third-phase interface. Scheme 3 depicts the L-L PTC
mechanism and shows why there are byproducts in the biphasic
system where the rate-controlling reaction takes place in the
(reaction b) is the middle phase, and no side reactions occur
Vol. 12, No. 4, 2008 / Organic Process Research & Development
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757

Scheme 3. Mechanism of L-L PTC alkylation of resorcinol with benzyl chloride
+
-
organic phase (reaction b). The formation of the Q OH ion-
pair due to ion exchange (reaction c in Scheme 3) near the
interface influences the selectivity. This ion-pair has a very
limited partitioning into the organic phase; hence, benzyl
chloride is hydrolyzed to benzyl alcohol at the interfacial region
no mass transfer effects at and beyond 1000 rpm. Thus, further
experiments were carried out at 1000 rpm. The inspection of
the data suggested that the conversions were linear with the
time, suggesting a zero-order kinetics. As will be discussed
later, the effect of temperature on rates of reaction also
showed that the activation energy was much greater (i.e.,
15.52 kcal/mol) than a typical value, which is realized
for mass transfer controlled reaction (i.e., 4 kcal/mol). The
reaction was intrinsically kinetically controlled, and hence,
the reaction mechanism and kinetic model could be
developed and tested through the effects of various
parameters.
(
reaction d) and subsequently a series of reactions take place
such as e, f, and g (in that order). As a result, byproducts are
formed which are benzyl alcohol [2], 3-(phenylmethoxy)benzyl
ether [3], and dibenzyl ether [4], apart from some C-alkylated
products. Particularly when resorcinol was used as a limiting
reactant with a little excess of KOH and BzCl in the L-L PTC,
all byproducts were formed in the current work. When the moles
of KOH and BzCl were taken equivalent to, or less than, half
of resorcinol, the byproduct formation was reduced in L-L
PTC. No byproduct was formed, when the L-L PTC system
was converted into a L-L-L PTC. The comparison of
Schemes 2 and 3 also reveals why there is 100% selectivity in
L-L-L PTC, whereas the selectivity to 3-phenylmethoxy
phenol was 80% in L-L PTC.
3.2. Mechanism and Kinetic Model. The reaction mech-
anism for L-L-L PTC system is shown in Scheme 2. Since
3.1. Effect of Speed of Agitation. To ascertain the influence
of mass transfer resistance for the transfer of reactants to the
reaction phase and products into the organic phase, the speed
of agitation was varied from 800 to 1200 rpm under otherwise
similar conditions, with TBAB as the catalyst, at 90 °C (Figure
2). Experiments were also done at 500 rpm to find that there
was a reduction in conversion (23% after 25 min), but there
was no change in selectivity. The conversion was found to be
nearly the same within experimental errors as that at 1000 and
1200 rpm. Further increase in the speed of agitation had
practically no effect on the conversion. So there was no mass
transfer resistance, and all further experiments were conducted
at 1000 rpm. A typical analysis was done for mass transfer rates
and overall reaction rates by using theoretical correlations on
overall mass transfer coefficients; also to reiterate, there were
Figure 2. Effect of speed of agitation on conversion of benzyl
3
chloride - 0.02 mol; organic phase made up to 30 cm with
-3
toluene. Resorcinol - 0.04 mol. TBAB - 6.21 × 10 mol. KOH
3
-
0.02 mol. Aqueous phase made up to 30 cm with water. KCl
- 0.13 mol. Temperature - 90 °C.
7
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Vol. 12, No. 4, 2008 / Organic Process Research & Development

the selectivity to 3-(phenylmethoxy)phenol (R′OR) [1] was
00%, the mechanism depicted here is straightforward. Here
1
-
+
The potassium 3-hydroxyphenoxide ion-pair (RO K ) gener-
ated in situ in the aqueous phase is equivalent to moles of KOH,
and the anion exchange takes place between the quaternary salt
+
-
-
+
(
(
Q Cl ) and RO K in the aqueous phase to form an ion-pair
-
+
RO Q ) (reaction a in Scheme 2), which is then transferred
into the third liquid phase (or the middle phase, which is referred
to as the third phase for the sake of consistency). All the species
involved have equilibrium concentrations. The substrate benzyl
chloride R′Cl is transferred from the organic phase to the third
phase, where the subsequent reaction occurs between
Figure 3. Effect of resorcinol:KOH mole ratio on conversion
of benzyl chloride. Mole ratio: resorcinol:KOH, resorcinol:BzCl
2:1. Benzyl chloride - 0.02 mol. Organic phase made up to 30
3
-3
cm with toluene. TBAB - 6.21 × 10 mol. KCl - 0.13 mol.
3
-
+
Aqueous phase made up to 30 cm with water. Speed of
RO Q and R′Cl to produce the desired product, R′OR [1]
reaction bin Scheme 2), which is transferred to the organic
phase.
Thus, the overall reaction is:
agitation - 1000 rpm. Temperature - 90 °C.
(
L - L - L PTC
KOR(aq) + R ′ Cl(org)
8 R ′ OR(org) + KCl(aq)
(1)
The rate equation is derived as given in the Appendix.
Equation 27) becomes
(
dX
dt
)
kapp(1 - X)NQtot
(29)
where X is the fractional conversion of R′Cl (benzyl chloride),
app is the apparent rate constant for the third phase reaction,
k
Figure 4. Effect of catalyst loading on conversion of benzyl
chloride. Benzyl chloride - 0.02 mol. Organic phase made up
and NQtot is the total moles of catalyst added to the reaction
mass. When the third phase was saturated with R′Cl for the
conditions employed in these studies, it was observed that the
conversions were linear in time. Thus, from eq 10, by following
the above procedure, the rate of change of fractional conversion
is given by:
3
to 30 cm with toluene. Resorcinol - 0.04 mol. KOH - 0.02 mol.
3
Aqueous phase made up to 30 cm with water. KCl - 0.13 mol.
Temperature - 90 °C. Agitation speed - 1000 rpm
3.3. Effect of Mole Ratio of Resorcinol to KOH. The
amount of resorcinol was varied from 0.02 to 0.05 mol, which
corresponds to a mole ratio of 1 to 2.5 of resorcinol to potassium
hydroxide by keeping the amount of potassium hydroxide
constant. Increasing the concentration of resorcinol increases
the selectivity of monobenzylated product (Figure 3). Inspection
of Figure 3 shows that the conversions are linear in time only
when the mole ratio of resorcinol to KOH was above 1:1.5,
thereby showing a zero-order reaction. At a mole ratio of 1:1,
there is no zero-order dependence; the reaction follows a first-
order dependence as given by eq 32, and there was a formation
of the byproducts. After 0.04 mol of resorcinol there is no
increase in the selectivity under otherwise similar conditions.
Therefore, 0.04 mol of resorcinol was taken as the optimum
quantity for further experiments. The selectivity to 3-(phenyl-
methoxy)phenol was 100%.
dX
dt
k0N
Qtot
)
) k′ ) constant
(30)
0
NR′Cl0
Integrating eq 30 leads to:
X ) X ) k′ NQtott
(31)
A
0
Thus, conversion of R′Cl is linear in time with apparent zero-
order reaction.
When the concentrations of KOH and benzyl chloride are
taken in stoichiometrically excess over 0.5 mol of resorcinol,
the second hydroxyl group is also converted; then by integrating
eq 29 it leads to
3
.4. Effect of Catalyst Loading. The catalyst amount was
-3
-3
-
ln(1 - X) ) kappNQtot
t
(32)
varied from 1.6 × 10 mol to18.6 × 10 mol under otherwise
similar conditions. It was observed that the formation of the
third phase takes place only after a certain critical amount of
catalyst was added to the reaction mixture. In the present case,
The above theory was tested by conducting further
experiments.
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Figure 5. Effect of resorcinol:benzyl chloride mole ratio on
Figure 7. Effect of temperature on conversion of benzyl
conversion of benzyl chloride. Mole ratio - resorcinol:BzCl.
3
chloride for monobenzylation of resorcinol. Benzyl chloride -
Resorcinol:KOH - 2:1. Organic phase made up to 30 cm with
3
-3
0.02 mol. Organic phase made up to 30 cm with toluene. TBAB
toluene. TBAB - 6.21 × 10 mol. Aqueous phase made up to
-3
3
- 6.21 × 10 mol. Resorcinol - 0.04 mol. KOH - 0.02 mol.
3
0 cm with water. KCl - 0.13 mol. Speed of agitation - 1000
3
Aqueous phase made up to 30 cm with water. KCl - 0.13 mol.
rpm. Temperature - 90 °C.
Agitation speed - 1000 rpm.
Figure 8. Arrhenius plot for monobenzylation of resorcinol.
3
.5. Effect of Concentration Benzyl Chloride as a Limit-
Figure 6. Effect of potassium chloride on conversion of benzyl
chloride. Benzyl chloride - 0.02 mol. Organic phase made up to
ing Reactant. The effect of the mole ratio of benzyl chloride
to resorcinol (with a resorcinol to KOH mole ratio of 2:1) was
studied from 0.5:2 to 2:2. The conversion was found to decrease
with increasing mole ratio up to 1:2 (Figure 5). The rate constant
3
-3
3
0 cm with toluene. Resorcinol - 0.04 mol. TBAB - 6.21 × 10
3
mol. KOH - 0.02 mol. Aqueous phase made up to 30 cm with
water. Speed of agitation - 1000 rpm. Temperature - 90 °C.
0 0
k′ contains the term NR′Cl0, and thus, the constant k is calculated
the formation of the third phase takes place at the catalyst
from the slopes of the lines in Figure 5 to get an average value
by the fit within 98% correlation coefficient.
-3
concentration of 6.2 × 10 mol TBAB. At any amount of
catalyst below this value, the third phase disappears, and the
system becomes L-L PTC system. Figure 4 shows the
percentage conversion as a function of time at different catalyst
3.6. Effect of Potassium Chloride Concentration. The
amount of potassium chloride was varied from 0.13 to 0.26
mol under similar reaction conditions (Figure 6). The role of
KCl is to salt out the catalyst along with the nucleophile in the
-
3
amounts. It was observed that at amounts less than 1.6 × 10
-
+
mol, the third phase rich in catalyst was not formed. Only at
form of the RO Q ion-pair from the aqueous phase into the
third phase as well as to increase the rate of aqueous phase
ion-exchange reaction, which leads to equilibrium. As the
concentration of potassium chloride was increased from 0.13
mol, no significant increase in the rate of reaction was observed,
and almost constant conversions were obtained as is seen in
Figure 6. This is because there was no further increase in the
-3
higher amounts of catalyst, i.e. at and beyond 1.6 × 10 mol,
was the third phase formation observed. When the catalyst
-3
-3
amount increased from 6.2 × 10 to 18.6 × 10 mol, the rate
of reaction increased substantially. The conversions were linear
with time at all catalyst loadings as predicted by the model (see
Figure 4).
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Vol. 12, No. 4, 2008 / Organic Process Research & Development

Figure 11. Effect of temperature on conversion of benzyl
Figure 9. Effect of temperature on conversion of benzyl
chloride for monobenzylation of hydroquinone. Benzyl chloride
chloride for monobenzylation of catechol. Benzyl chloride - 0.02
3
-
0.02 mol. Organic phase made up to 30 cm with toluene.
3
mol. Organic phase made up to 30 cm with toluene. TBAB -
TBAB - 6.21 × 10–3 mol. Hydroquinone - 0.04 mol. KOH -
3
6
.21 × 10 mol. Catechol - 0.04 mol. KOH - 0.02 mol. Aqueous
3
0
-
.02 mol. Aqueous phase made up to 30 cm with water. KCl
0.13 mol. Agitation speed - 1000 rpm.
3
phase made up to 30 cm with water. KCl - 0.13 mol. Agitation
speed - 1000 rpm.
Figure 12. Arrhenius plot for monobenzylation of hydroquinone.
Figure 10. Arrhenius plot for monobenzylation of catechol.
studied under identical conditions by using TBAB as a catalyst.
The effect of temperature on the rate of reaction of benzyl
chloride was studied in the range of 75-90 °C. The conversion
of benzyl chloride was observed to increase with an increase
in the reaction temperature. Once again it was observed that
the reaction followed zero-order kinetics. Catechol was found
to be more reactive and hydroquinone was found to be less
reactive towards benzyl chloride. The effect of temperature on
the conversion of benzyl chloride is given in Figure 9 for
catechol with the corresponding Arrhenius plot in Figure 10.
Similar plots are also made for hydroquinone (Figure 11 and
Figure 12, respectively). The energy of activation has been
found to be 12.74 ( 0.1 kcal/mol and 23.13 ( 0.1 kcal/mol
for catechol and hydroquinone, respectively. Activation energy
for the monobenzylation of catechol was found to be lower than
that for monobenzylation of resorcinol and hydroquinone. The
reactivity of dihydroxybenzenes as well as activation energy is
in the following order:
catalyst concentration in the middle phase. Addition of KCl
beyond the saturation concentration has no significant effect
on the rate of reaction because it forms an additional solid phase.
3.7. Effect of Temperature. The effect of temperature on
the rate of reaction between resorcinol and benzyl chloride was
studied under otherwise similar conditions. The temperature was
varied from 75 to 90 °C.The conversion of benzyl chloride was
observed to increase with an increase in the reaction temper-
ature. The effect of temperature on the conversion of benzyl
chloride is given in Figure 7. The conversions were linear with
time at all temperatures. These observations show that the
reaction is zero order in substrate concentration and the model
is validated at different temperatures. The Arrhenius plot was
made to determine the energy of activation (Figure 8). The
energy of activation has been found to be 15.52 ( 0.1 kcal/
mol.
3.8. Effect of Different Dihydroxybenzene Isomers. Re-
actions of hydroquinone and catechol with benzyl chloride were
Hydroquinone> resorcinol > catechol
Vol. 12, No. 4, 2008 / Organic Process Research & Development
•
761

th
QCl
3
.9. Catalyst Reusability. The catalyst-rich phase along
C
C
+
-
+
-
with the aqueous phase was used six times in which the organic
phase along with the solvent was replenished with benzyl
chloride. The reaction mass was cooled to 1ower temperatures
Q Cl a Q Cl K )
(3)
(4)
(5)
1
aq
QCl
(
<15 °C) while maintaining the three phases, and the organic
th
QOR
C
+
-
+
-
phase was recovered and processed to get the product. The
middle phase and the aqueous phase were reused. The purpose
of using the aqueous phase was to use the catalyst distributed
in the aqueous phase using the conditions of the control
experiment. The merits of such a strategy are discussed
elsewhere. The selectivity to the product 3-(phenylmethox-
y)phenol was 100% in all cases. There was a marginal decrease
in conversion (5%) from the first use to the sixth use. This is
reasonable.
Q O R a Q O RK )
(
aq)
2
aq
QOR
C
th
KOR
C
C
K )
3
17
aq
KOR
+
-
+
-
3
. Ion-exchange reaction of K O R and Q Cl can also
take place in the third liquid phase to form catalytic intermediate
Q O R and K Cl , transferring into aqueous phase with
equilibrium constants K and K respectively:
4
. Conclusion
+
-
+
-
3-(Phenylmethoxy)phenol is used in the preparation of a drug
4
5
intermediate used in the inhibition of oral bacteria. This reaction
can be accomplished by L-L-L PTC instead of L-L or S-L
PTC. The synthesis of this compound was done under L-L-L
PTC by using resorcinol and benzyl chloride. The best results
were obtained by employing 0.02 mol of each benzyl chloride
and potassium hydroxide, 0.04 mol of resorcinol, and 0.0062
mol of TBAB. A theoretical model has been proposed and
validated against experimental data. The reaction follows zero-
order kinetics. The studies were also extended to catechol and
hydroquinone for monobenzylation.
Creation of a third phase from the two-phase reaction leads
to several advantages in PTC. A catalyst-rich third phase or
the middle phase is formed between other two phases, wherein
the main reaction takes place, and it intensifies the rates of
reaction as well as offers better selectivity including catalyst
reusability unlike the L-L PTC. L-L-L PTC is an excellent
technique for reducing waste, reactor volume, and processing
time, and thus increasing profitability. The catalyst-rich phase
is recovered and reused to some extent. This also helps in waste
minimization which is a major theme of green chemistry. The
reactivity of dihydroxybenzenes with benzyl chloride for the
mono-O-alkylation as well as activation energy is in the
following order:
+
-
+
-
+
-
+
-
K O R + Q Cl f Q O R + K Cl
(6)
(7)
(
th)
(th)
aq
KCl
C
+
-
+
-
K Cl a K Cl K )
4
th
KCl
C
org
QOR
C
+
-
+
-
Q O R a Q O R K )
(8)
(
th)
(org) 5
th
C
QOR
+
-
4. Reaction of Q O R with R′Cl in the third liquid
phase:
kth
+
-
+
-
Q O R
+ R ′ Cl (org)
9
8 R ′ OR (th) + Q Cl
(
th)
(th)
(
9)
There is a very insignificant contribution by the reaction in
organic phase, although it is shown in Scheme 2 for the sake
of clarity and for comparison with an L-L PTC process. The
critical analysis of rate data suggested that the conversions of
benzyl chloride were linear in time, suggesting zero-order
reaction.
The rate of formation of R′OR can be written from eq 9. At
the same time, the stoichiometry suggests that for every one
mole of R′Cl, one mole of product R′OR is formed. Here,
Hydroquinone > resorcinol > catechol
Acknowledgment
This work was made possible by the UGC award of SRF to
O.V.B. Thanks are also due to the Darbari Seth Professor
Endowment for a personal Chair to G.D.Y. Thanks are also
due to Purdue University for inviting G.D.Y. as distinguished
visiting scholar under the President’s Asian Initiative program
which enabled him to spend considerable time on creativity.
Appendix
Derivation of Kinetic Equation
The steps involved in the overall reaction 1 are as follows:
+
-
+
-
1
. Ion-exchange reaction of K O R and Q Cl in the
aqueous phase to form the ion-pair with the nucleophile
+
-
Q O R:
+
-
+
-
+
-
+
-
K O R + Q Cl a Q O R + K Cl
(2)
(aq)
+
-
+
-
+
-
2
. Mass transfer of Q Cl , K O R and Q O R from the
aqueous phase into the third liquid phase with equilibrium
constants K1, respectively:
Thus, the rate of formation of the product per unit volume
of the third phase is given by:
K
2, and K
3
7
62
•
Vol. 12, No. 4, 2008 / Organic Process Research & Development

th
R′OR
th
Q
th
QOR
th
QCl
dC
C ) C
+ C
(21)
(22)
th
th
)
k C
C
(10)
(11)
th QOR R′Cl
dt
th
th
C
) ηCQ
QOR
th
th
R′OR
C
C
C
R′Cl
Further K )
and K )
+
7
8
In eq 23, η is the molar ratio of Q in the form of QOR at
any time in the third-phase.
org
org
R′OR
C
R′Cl
Substituting eqs 3, 4, and 23 into eq 21, the following is
obtained.
The fractional conversion of R′Cl is given by:
NR′Cl0 - NR′Cl
th
th
X )
(12)
1
K2
V
1
K1
V
1 - η
η
th
QOR
aq
NR′Cl0
NQtot
)
+
+
+
C
V
(23)
(24)
[
(
aq) (
aq
)
(
)]
V
V
where 0 denotes the zero time or initial condition.
The rate of formation of R′OR in mol/time is equal to that
of reaction of R′Cl as shown below.
N
Qtot
aq
th
QOR
N
th
QOR
V
C
)
)
th
th
th
V
1
K2
V
1
V
1 - η
th
R′OR
+
+
+
dNR′OR
dt
thdC
-dNR′Cl
dt
[
(
aq) (
aq
)
(
)
]
K1
η
th
th
th
V
V
(13)
)
V
) V k C
C
)
th QOR R′Cl
dt
th
k K N
NR′Cl
k K N
-
dN
th
7
QOR
th
7
R′Cl
-
dNR′Cl
dt
)
)
×
th
th
org
R′Cl
org
th
org
th
)
V k C K C
(14)
dt
th QOR
7
(V + K V ) (V + K V )
7
7
th
NQtot
V
The volumes of the aqueous, third, and organic phases are given
aq
aq
th
org
V
by V , V , and V , respectively. The total number of moles
of R′ Cl at any time are distributed between the organic and
third phase and none in the aqueous phase:
(
25)
th
th
1
K2
V
1
V
1 - η
(
)])
+
+
+
[
(
aq) (K1
aq)(
η
V
V
th
R′Cl
org
R′Cl
th
QOR
NR′Cl ) N + N
(15)
(16)
-dNR’Cl k K N NR′Cl
th
7
)
)
org
th
dt
(
V
+ K V )
7
th
R′Cl
th
R′Cl
org
C
C
N
V
K )
)
Rk K NR′ClN
th 7 Qtot
7
org
R′Cl
org th
R′Cl
N
V
(26)
(27)
org
1
K2
1
1 - η
V (1 + K ꢀ)
+ R +
+ R
7
(
)]
[
(
) (K1
)
η
therefore, the following can be derived:
th
th
V
V
NR′Cl
org
R′Cl
R )
aq
and
ꢀ )
C
)
(17)
(18)
org
org
th
V
V
(
V
+ K V )
7
7
In eq 27, R, ꢀ, K and kthare constant and hence can be suitably
th
th
QOR
th
QOR
-
dNR′Cl
V k K C
NR′Cl
k K N
NR′Cl
th
org
7
th
7
written as an apparent rate constant kapp constant. The volume
of the third phase remains practically the same since the product
is transported back into the organic phase. This was also
confirmed through measurements and is assumed to be constant.
Further NQtot, the catalysts quantity added is also constant.
In terms of fractional conversion, eq 27 becomes,
)
)
th
org
th
dt
(
V
+ K V )
(V + K V )
7
7
Taking mass balance for the catalyst (NQtot, the total moles
added initially) which is distributed in six different species in
the three phases:
aq aq
aq
QCl
th th
th
NQtot ) V (C
+ C ) + V (C
+ C ) +
QCl
QOR
QOR
org org
dX
dt
)
kapp(1 - X)NQtot
(28)
org
QCl
V (C
+ C ) (19)
QOR
Nomenclature and Symbols
As stated earlier, the contribution of the organic phase
reaction is negligible since the amount of Q in the organic phase
is negligible, and thus eq 20 becomes:
A
benzyl chloride
Corg
concentration of benzyl chloride in the organic phase, mol/
cm of organic phase
A
3
aq aq
aq
th th
th
QCl
Cth
concentration of benzyl chloride in the third phase, mol/cm3
NQtot ) V (C
+ C ) + V (C
QCl QOR
+ C ) (20)
A
QOR
of third phase
CaqQOR
concentration of RO Q (also QOR) in aqueous phase, mol/
-
+
Let the amount of catalyst in the third phase be denoted
3
by
cm aqueous phase
Vol. 12, No. 4, 2008 / Organic Process Research & Development
•
763

CaqQCl
+
-
zero-order constant, mol-1 s-1
apparent zero-order constant, s-1
concentration of Q Cl (also QCl) in aqueous phase, mol/
k
0
3
cm aqueous phase
k
0
CthQOR
CthQCl
concentration of RO Q (also QOR) in third phase, mol/cm
-
+
3
3
k
th
rate of reaction in the third phase, cm /(mol of catalyst s)
total moles of catalyst added to the system, mol
moles of A in third phase, mol
moles of A in organic phase, mol
moles of QOR in third phase, mol
benzyl chloride
third phase
N
Qtot
+
-
3
concentration of Q Cl (also QCl) in third phase, mol/cm
Nth
Norg
A
third phase
A
CorgQOR
CorgQCl
concentration of RO Q (also QOR) in organic phase, mol/
-
+
NthQOR
R′Cl
ROH
R′OR
t
3
cm organic phase
+
-
3
concentration of Q Cl (also QCl) in organic phase, mol/cm
dihydroxybenzene
organic phase
mono-O-benzylated product
th
QCl
C
time of reaction, s
volume of aqeous phase, cm3
K
1
aq
QCl
C
Vaq
th
Vorg
Vth
volume of organic phase, cm3
volume of the third phase, cm3
C
C
C
C
QOR
aq
QOR
K
2
th
ROK
NA0 - NA
, fractional conversion
X
a
NA0
aq
ROK
K
3
aq
KCl
C
Greek symbols
th
KCl
Vth/Vaq ) ratio of third to aqueous phase volumes
Vth/Vorg ) ratio of third to organic phase volumes
R
K
4
C
org
QOR
ꢀ
C
th
QOR
th
QOR
C
K
5
C
+
)molar ratio of Q in the form of
η
th
QOR
th
QCl
th
R′Cl
C
+ C
C
QOR at any time in the third phase
org
R′Cl
K
7
C
th
R′OR
C
C
org
R′OR
K
8
Received for review October 22, 2007.
OP7002369
3
k
app
apparent first-order reaction rate constant, cm /(mol of
catalyst s)
7
64
•
Vol. 12, No. 4, 2008 / Organic Process Research & Development