Catalytic investigations of calix[4]arene scaffold based phase transfer catalyst

Article abstract of DOI:10.1016/j.tetlet.2007.05.001

Calix[4]arene scaffold based quaternary ammonium salts as multi-site phase transfer catalysts were prepared and their catalytic activities were investigated for Darzens condensation, O/N-alkylation reactions and ethyl benzene oxidation. These calix[4]arene based multi-site phase transfer catalysts showed significant high catalytic activity as compared to single-site phase transfer catalysts.

Full text of DOI:10.1016/j.tetlet.2007.05.001

Tetrahedron Letters 48 (2007) 4489–4493
Catalytic investigations of calix[4]arene scaffold based
phase transfer catalyst
Pallavi Srivastava and Rajendra Srivastava*
Department of Chemistry, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Republic of Korea
Received 20 March 2007; revised 26 April 2007; accepted 1 May 2007
Available online 5 May 2007
Abstract—Calix[4]arene scaffold based quaternary ammonium salts as multi-site phase transfer catalysts were prepared and their
catalytic activities were investigated for Darzens condensation, O/N-alkylation reactions and ethyl benzene oxidation. These
calix[4]arene based multi-site phase transfer catalysts showed significant high catalytic activity as compared to single-site phase
transfer catalysts.
ꢀ 2007 Elsevier Ltd. All rights reserved.
The reaction between two reactants present in two sep-
arate phases is often inhibited because of inability of
the reagents to interact with each other. The rate of such
reactions can be enhanced by using a catalyst known as
a phase transfer catalyst. The phase-transfer catalysis is
a well-known concept, in which, a reactant (organic-sol-
uble component) and an anionic reactant (aqueous sol-
uble reactant) are brought together by the use of a
small quantity of catalyst which transports one reactant
across the interface into the other phase to enhance the
reaction rate.1 Quaternary ammonium salt has unique
capability to dissolve in both organic and aqueous solu-
tion and hence widely used as a phase-transfer catalyst.2
Phase transfer catalytic processes are industrially impor-
tant and environmentally friendly since they produce
less industrial waste and consume less energy than tradi-
tional processes.3,4 Recently, efforts have been made to
develop more eco-friendly phase transfer catalysts by
immobilizing on the polymer or solid supports.5
very important to develop new phase-transfer catalysts
(PTCs) that can be used in smaller proportions. In order
to overcome this problem novel multi-site PTCs have
been developed.8 Multi-site PTCs were applied in small
proportion to obtain a catalytic effect. Syntheses of the
multi-site PTCs have been less explored than the sin-
gle-site PTCs. The objective of this work is to develop
an efficient multi-site quaternary ammonium salt as
PTC and investigate its catalytic efficiency in various
organic transformations.
In the present study, calix[4]arene based multi-site PTCs
were synthesized. Multi-site PTCs I and II (Scheme 1)
were prepared as per the reported procedure.9 For com-
parison, single-site PTCs (III and IV) were also prepared
using p-methoxy benzylchloride and trialkylamine. All
1
the compounds were well characterized by H NMR,
elemental analysis, melting point and were confirmed
with the reported value in the literature.
The potential value of the quaternary ammonium cata-
lyst was exploited in various organic transformations.6
The application of phase-transfer catalysis to the Wil-
liamson synthesis of ethers has been widely investigated
and is far superior to any classical method for the syn-
thesis of aliphatic ethers.7 The drawback of the existing
process is that it requires a large amount of quaternary
ammonium salt as a phase-transfer catalyst. Hence, it is
In the present study, the catalytic activity of calix[4]-
arene based quaternary ammonium salts was investigated
for the Darzens condensation, O/N-alkylation reactions
and ethylbenzene oxidation. The Darzens condensation
is one of the most potential synthetic tool available to
organic chemists for the preparation of a,b-epoxy car-
bonyl compounds (Scheme 2).10 Various attempts have
been made for the phase transfer catalyzed Darzens con-
densation of chloroketones and sulfones.11
Keywords: Calixarenes; Phase transfer catalysts; Quaternary ammo-
nium salts.
First set of experiments were designed to obtain the opti-
mum reaction condition. Solvents and bases have strong
influence on the reaction. Among the bases and solvent
*
Corresponding author. Tel.: +82 42 869 5830; e-mail: chemi_
rajendra@yahoo.co.in
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.05.001

4490
P. Srivastava, R. Srivastava / Tetrahedron Letters 48 (2007) 4489–4493
and II were highly active (Table 1, entries 2–5). The chain
-
-
+
+
NR3Cl
NR3 Cl
length of the alkyl group in the multi-site phase transfer
catalysts influenced the catalytic activity. The long ali-
phatic chain (tert-butyl) substituted salts were found to
be more active than the short alkyl chain (tert-methyl)
substituted salts. However, diastereoselectivity was simi-
lar for all the phase transfer catalysts investigated in the
present study. Aromatic aldehydes having an electron
donating group such as –CH3 offered higher yields (Ta-
ble 1, compare entries 11 and 12), whereas an electron
withdrawing group such as –NO2 offered lower yields
for Darzens adduct (Table 1, compare entries 11 and
13). However, the product yield can be improved by car-
rying out the reaction for a longer time. The aromatic
aldehydes reactivity is faster with a-chloroacetonitrile
than with ethyl chloroacetate (Table 1, compare entries
13 and 15).
CH2
4
OCH3
OCH3
III, IV
I, II
I, III = R = CH3
II, IV = R = CH2CH2CH2CH3
Scheme 1. Multi-site and single-site phase transfer catalysts.
CHO
O
The catalytic activity of calix[4]arene based quaternary
ammonium salt was investigated for O-alkylation of
phenol and N-alkylation of pyrrole (Scheme 3). First
set of experiments were carried out between sodium
phenolate and benzylbromide at 298 K in 1,2-dichloro-
methane solvent. In this case also, single-site quaternary
ammonium salts were found to be less active than the
calix[4]arene based multi-site catalysts (Table 2). Since,
the pyrrole being more reactive than phenol, a high yield
of the product was obtained in a short reaction time
(5 min instead of 30 min in case of phenol). Similar to
Darzens condensation, the long aliphatic chain (tert-
butyl) substituted salts were found to be more active
than the short alkyl chain (tert-methyl) substituted salts
(Table 2).
PTC
EWG
+
EWG
Cl
R
R
Scheme 2. Darzens condensation of benzaldehyde derivatives with
a-chloroester and nitrile.
studied, KOH and THF were found to be the best (Table
1). Having found the optimum reaction condition, vari-
ous phase transfer catalysts were examined for the reac-
tion. A very low yield of product was obtained when the
reaction was performed without catalyst (Table 1, entry
1). Single-site phase transfer catalyst such as III and IV
were found to be weakly active for this reaction, whereas
calix[4]arene derived multi-site phase transfer catalyst I
The slow atmospheric oxidation of a C–H bond to a C–
O–O–H group (hydroperoxide) is called autoxidation.
Table 1. Catalytic investigation of multi-site PTCs in Darzens condensation
O
CHO
EWG
PTC
+
EWG
Cl
R
R
Entry
R
EWG
Solvent
Base
Catalyst
Yielda (%)
Cis/trans
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
H
H
H
H
H
H
H
H
H
H
H
4-CH3
4-NO2
4-NO2
4-NO2
–COOEt
–COOEt
–COOEt
–COOEt
–COOEt
–COOEt
–COOEt
–COOEt
–COOEt
–COOEt
–COOEt
–COOEt
–COOEt
–COOEt
–CN
THF
THF
THF
THF
THF
THF
THF
CH2Cl2
(C2H5)2O
C6H6
THF
THF
THF
THF
THF
KOH
KOH
KOH
KOH
KOH
NaOH
LiOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
None
I
9.0
43.9
72.0
8.7
12.3
65.2
35.9
39.5
8:1
8:1
7:1
II
III
IV
II
7.9:1
7.5:1
7.5:1
14:1
4.5:1
6.7:1
6.4:1
6.5:1b
1:1b
II
II
II
59.2
54.2
II
II
35.8b
42.0b
10.5b (29.3)a
No reaction
24.0b
II
II
3:1b (2.9:1)a
—
3.5:1b
IV
II
a Reaction condition: aldehyde (5 mmol), a-chloroester or a-chloroacetonitrile (6.0 mmol), base (6.0 mmol), catalyst (2.0 mol %), solvent (10 ml),
reaction temperature (298 K), run time (24 h).
b Reactions were carried out for 8 h.

P. Srivastava, R. Srivastava / Tetrahedron Letters 48 (2007) 4489–4493
4491
radical initiator. A blank experiment was performed
under the same reaction conditions without adding PTCs.
The oxidation of ethylbenzene at 403 K in the presence
of 1.0 wt % of ethylbenzene hydroperoxide is a typical
autocatalytic chain reaction. At this temperature, the
decomposition of the EBHP to produce free radicals
(Scheme 4) is one of the key steps in the oxidation reac-
tion because it leads to an increase in the chain initiation
rate and hence in the overall reaction rate. Because of
this reason, a small amount of hydroperoxides were
added in liquid-phase hydrocarbon oxidations, which
act as a radical initiator and remove the induction peri-
od just at the beginning of the reaction with molecular
oxygen. With this low concentration of EBHP, the
amount of radicals in the reaction medium are enough
to maintain the reaction rate at an almost constant level
from the very beginning with no detectable induction
period. Figure 1a shows that the single-site PTCs III
and IV do not catalyze the EB oxidation as efficiently
as multi-site PTCs I and II. It may be noted that EBHP
form autocatalytic under the reaction condition, but its
rate can be influenced by the addition of PTCs. The
activity of catalysts and the selectivity of EBHP forma-
tion are highly dependent on the chain length of quater-
nary ammonium salts. The long alkyl chain (tert-butyl)
substituted salt such as compound II hinders interaction
and favours interaction of Clꢀ with the EBHP, leading
to its decomposition (Eq. 1). Whereas the short alkyl
chain (tert-methyl) substituted PTC such as compound
I seems to be more appropriate and allow the interaction
with EBHP and favours the formation of ethylbenzyl
and hydroperoxy radicals which are the active species
in the propagation step (Scheme 4) in which EBHP is
formed.
OH
OCH2Ph
PTC
PTC
PhCH2Br
PhCH2Br
+
+
N
N
H
CH2-Ph
Scheme 3. O/N-Alkylation reaction of phenol and pyrrole over phase
transfer catalysts.
Table 2. Catalytic investigation of multi-site PTCs in O/N-alkylation
reaction
Entry Substrate Alkylating
reagents
Catalyst Run time Yield
(min)
(%)
1
2
3
4
Phenol
Benzylbromide
I
30
30
30
30
70.0
98.0
10.0
18.0
II
III
IV
5
6
7
8
Pyrrole
Benzylbromide
I
5
5
5
5
77.0
96.0
16.0
24.0
II
III
IV
Reaction condition: phenol/pyrrole (5 mmol), benzylbromide
(5.0 mmol), NaOH (6.0 mmol), catalyst (2.0 mol %), CH2Cl2 (10 ml),
reaction temperature (298 K).
Oxygen itself is very unreactive, which can abstract the
proton. However, if a trace amount of free radicals are
produced by some initiating processes, then they react
with oxygen to give R–O–OÅ and thereby the radical
chain reaction propagates (Scheme 4). Hydrocarbon
oxidation by O2 is highly dependent on the concentra-
tion of hydrocarbon peroxides because these hydrocar-
bon peroxides are radical initiators for the formation
of oxidized products. Various surfactants12 and onium
salts13 were reported to accelerate the hydrocarbon oxi-
dation. The mechanism of onium salts catalyzed hydro-
carbon oxidation is well documented.14
½R–OOH þ Clꢀ ! R–OÅ þ OHꢀ þ ClÅꢁ
ð1Þ
In addition, the hydroxyl group generated in reaction 1
is responsible to produce radicals that drive the reaction
towards the formation of oxidized products (ACP and
PE). Figure 1b shows the result obtained after 6 h of
the reaction. EB oxidation is highly dependent on the
EBHP concentration. After 6 h, a large amount of
EBHP remained in the reaction medium when com-
pound I was used in the reaction. The low concentration
of EBHP in the reaction medium in case of compound II
indicates that EBHP was utilized in the formation of
oxidized products. Hence, it can be concluded that com-
pound II is the promoter in EB oxidation, whereas com-
pound I is the inhibitor. From Figure 1b it is inferred
that compound II reacts with the formed EBHP, until
compound II is completely consumed. After this, the
formed EBHP is stable in the reaction medium. These
observations are in keeping with the previous studies
addressing the decomposition of organic hydroper-
oxides with quaternary ammonium salts.14,15
The role of multi-site phase transfer catalysts was also
investigated in the oxidation of ethylbenzene (EB) using
molecular oxygen. Three products, that is, ethylbenzene
hydroperoxide (EBHP), acetophenone (ACP) and 1-
phenylethanol (PE) were formed during the oxidation
reaction of ethylbenzene. Under the reaction condition,
1.0 wt % of ethylbenzene hydroperoxide was added as a
2 In .
In2
Initiation
In . + RH
R . + InH
R . + O2
ROO .
Propagation
Termination
In summary, calix[4]arene based multi-site quaternary
ammonium salts were prepared and used as phase trans-
fer catalysts. The catalytic activity of calix[4]arene based
phase transfer catalysts was investigated for Darzens
condensation, O/N-alkylation reactions and ethyl-
benzene oxidation. For comparison, single-site phase
R . + ROOH
ROO . + RH
Non radical products
2 ROO .
Scheme 4. Auto-oxidation of organic compounds.

4492
P. Srivastava, R. Srivastava / Tetrahedron Letters 48 (2007) 4489–4493
30
25
20
15
10
5
30
a
b
Catalyst I
Catalyst II
Without catalyst
Catalyst II
Catalyst I
Catalyst IV
Catalyst III
Without catalyst
25
20
15
10
5
0
0
0
1
2
3
4
5
6
Oxidized products
EBHP
Run time (h)
Products distribution
Figure 1. Ethylbenzene oxidation at 403 K over various catalysts: (a) ethylbenzene conversion plot verses reaction time and (b) products distribution
after 6 h.
transfer catalysts were also prepared. The multi-site
phase transfer catalyst showed significant high catalytic
activity as compared to the single-site phase transfer
catalyst. The chain length of the alkyl group present in
the PTCs also influences the catalytic activity. Long
chain (tert-butyl) substituted quaternary salt was found
to be more active.
S, 2H), 3.66 (OCH3, S, 3H), 2.96 (N+CH3, S, 9H). Anal.
Calcd for (C11H18NOCl)4: C, 61.25; H, 8.21; N, 6.49.
Found: C, 61.01; H, 7.96; N, 6.75.
p-Methoxy-(tri-butylammonio)-benzylcholoride
(IV):
7.25 (ArH, d, 2H), 6.90 (ArH, d, 2H), 3.86 (N+CH2,
S, 2H), 3.65 (OCH3, S, 3H), 2.90 (N+CH2, t, 6H), 1.58
(N+CH2–CH2, m, 6H), 1.36 (N+CH2–CH2–CH2, m,
6H), 0.88 (N+CH2–CH2–CH2–CH3, t, 9H). Anal. Calcd
for (C20H36NOCl): C, 70.25; H, 10.61; N, 4.10. Found:
C, 70.01; H, 10.36; N, 4.41.
Experimental
Phase transfer catalysts preparation and characterization
Catalysts were prepared by the reported procedure.9 All
Catalytic measurements
1
the compounds were well characterized by H NMR,
Darzens condensation. In a typical Darzens condensa-
tion, a mixture of aldehyde (5.0 mmol), a-chloroester
(6.0 mmol) and catalyst (2 mol %) was suspended in a
solvent (10 ml) and stirred for 30 min. Base (6.0 mmol)
was added to the above reaction mixture. After stirring
for a stipulated period of time at room temperature, the
reaction was quenched with water and was extracted
with ethyl acetate (15 ml · 3). The combined organic
layer was washed with brine and solvent, dried with
anhydrous sodium sulfate and concentrated under re-
duced pressure. Following purification by a flash col-
umn chromatography, the isolated yield was obtained.
elemental analysis, melting point and they matched well
with the reported values in the literature. 1H NMR
(300 MHz) and elemental analysis results of calix[4]-
arene based multi-site PTCs (I and II) and single-site
PTCs (III and IV) are given below.
5,11,17,23-tetrakis(trimethylammoniomethyl)-25,26,27,
28-tetramethoxycalix[4]arene tetracholoride (I): 7.3
(ArH, S, 2H), 4.37 (PhCH2Ph, s, 2H), 3.88 (N+CH2,
S, 2H), 3.67 (OCH3, S, 3H), 2.98 (N+CH3, S, 9H). Anal.
Calcd for (C12H18NOCl)4: C, 63.29; H, 7.97; N, 6.15.
Found: C, 62.81; H, 7.76; N, 6.35.
O/N-Alkylation. Typical alkylation reaction was con-
ducted by mixing benzyl bromide (5 mmol) in 10 ml of
CH2Cl2 and phenol/pyrrol (5 mmol) and NaOH
(5.2 mmol) in 10 ml of water. Catalyst (2 mol %) was
added and the reaction was conducted for a stipulated
time period (Table 2) at 298 K. Reaction mixture was
quenched with dilute HCl solution and extracted with
CH2Cl2 (15 ml · 3). The combined organic layer was
washed with brine and solvent, dried with anhydrous so-
dium sulfate and concentrated under reduced pressure.
Following purification by a flash column chromato-
graphy, the isolated yield was obtained.
5,11,17,23-tetrakis(tributylammoniomethyl)-25,26,27,
28-tetramethoxycalix[4]arene tetracholoride (II): 7.3
(ArH, S, 2H), 4.37 (PhCH2Ph, s, 2H), 3.88 (N+CH2,
S, 2H), 3.67 (OCH3, S, 3H), 2.93 (N+CH2, t, 6H), 1.61
(N+CH2–CH2, m, 6H), 1.38 (N+CH2–CH2–CH2, m,
6H), 0.86 (N+CH2–CH2–CH2–CH3, t, 9H). Anal. Calcd
for (C21H36NOCl)4: C, 71.29; H, 10.18; N, 3.96. Found:
C, 72.01; H, 10.06; N, 4.11.
p-Methoxy-(tri-methylammonio)-benzylcholoride (III):
7.27 (ArH, d, 2H), 6.90 (ArH, d, 2H), 3.86 (N+CH2,

P. Srivastava, R. Srivastava / Tetrahedron Letters 48 (2007) 4489–4493
4493
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cylindrical vessel attached with glass stirrer
a
(800 rpm) and a gas inlet system, a thermocouple and
a reflux condenser cooled with water were used for the
experiments. Gases were fed to the reactor through mass
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ethylbenzene containing 1.0 wt % of ethylbenzene
hydroperoxide was used. The reactions were performed
at 403 K. Once the temperature had reached at a con-
stant value, 2 mmol of catalyst was added into the reac-
tor and an air flow of 200 ml/min was set and kept
constant during the experiment. The concentration of
EBHP was measured by standard iodometric titration.
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gas chromatography (Hewlett-Packard 5890 Series II
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