2
12
W. Li et al. / Applied Catalysis A: General 419–420 (2012) 210–214
hydrochloride (7). To optimize the reaction conditions, the alkyla-
tion reaction was carried out with a range of inverse phase-transfer
catalysts, agitation speeds, reaction times, reaction temperatures,
mole ratios and catalyst loadings. The results are discussed in the
following sections.
100
80
60
8
8
0C
5C
40
3.1. Choice of inverse phase transfer catalysts
90C
5C
20
9
In the preliminary studies, the reaction was assessed in the pres-
0
ence and absence of a phase transfer catalyst. Different agents were
then tested as the inverse phase transfer catalyst in an aqueous
medium. The results are summarized in Table 1.
As shown in Table 1, the type of the inverse phase trans-
fer catalyst employed has a significant effect on the reaction.
For instance, when 6-[(3-chloropropyl)amino]-1,3-dimethyluracil,
0
30
60
90
120
150
180
210
240
Time (min)
Fig. 2. The effect of temperature. Substrate 6, 1.0 mol; compound 7, 1.01 mol;
Na2CO3, 2.0 mol; catalyst, -cyclodextrin; catalyst loading, 0.02 mol; solvent, water;
agitation speed, 1500 rpm.
1
-(2-methoxyphenyl)piperazine hydrochloride and sodium car-
◦
increasing the reaction temperature from 85 to 95 C. This indi-
◦
bonate were reacted in water for 9 h at 100 C, Urapidil was
obtained in 38.5% yield with 89.5% purity (entry 1). However, the
same reaction in the presence of -cyclodextrin (0.02 mol), led to
a 82.1% yield of urapidil with 98.6% purity (entry 2). To evaluate
the catalytic ability of -cyclodextrin, reactions with other inverse
and non-inverse phase-transfer catalysts were carried out, (entries
cates that increasing temperature further facilitate the alkylation,
by enhancing the rate of reaction. Although a higher temperature
usually tends to favor side reactions, no side products were found
◦
at 95 C in this study.
3.4. Effect of substrate mole ratios
3
–15), -cyclodextrin was seen to be the most efficient catalyst
by factors of 1.6, 1.2 and 1.5 for tetra-butyl-ammomium bromide,
cetylpyridinium chloride monohydrate and PEG-600, respectively
6
-[(3-chloropropyl) amino]-1,3-dimethyluracil to 1-(2-
methoxy phenyl) piperazine hydrochloride mole ratios between
:1 and 1:1.1, under otherwise similar experimental conditions
(
entries 6, 7 and 10). As little as 0.01 mol -cyclodextrin was suf-
1
ficient for successful reaction, which emphasizes its remarkable
catalytic activity (entry 3). In this context, -cyclodextrin was used
for all further experiments.
were also screened (Fig. 3). The best results were obtained with
a mole ratio of 1:1.01, and minimum conversions were obtained
with a mole ratio of 1:1.1. This suggests that further addition
of 1-(2-methoxyphenyl) piperazine hydrochloride do no lead to
enhancements in reaction rate.
3.2. Effect of agitation speed
To ascertain the influence of resistance to mass transfer of the
3
.5. Effect of catalyst loading
reactants to the reaction phase, the agitation speed was varied over
a range of 500–2000 rpm under otherwise similar conditions. The
results are shown in Fig. 1. This figure suggests that the conversion
of 6-[(3-chloropropyl) amino]-1,3-dimethyluracil increases with
increasing agitation speed from 500 to 1500 rpm. However, the
conversion remains almost constant at agitation speeds beyond
The reaction was carried out with a range of catalyst loadings
(from 11 to 44 g). The conversions are plotted against time for the
different loadings, under otherwise similar conditions (Fig. 4). The
results indicate that the conversion of 6-[(3-chloropropyl) amino]-
1
,3-dimethyluracil increases with increasing catalyst loading up to
3 g. However, further increases in loading lead to reduced conver-
1
500 rpm. This result indicates that the interfacial mass transfer
3
resistance between the organic and aqueous phases is negligible at
agitation speeds above 1500 rpm. Therefore, further experiments
were conducted at 1500 rpm.
sions. A yield of only 38.5% was observed in the absence of catalyst.
The results suggest that a catalyst loading of 22 g is optimal for a
high conversion.
3.3. Effect of reaction temperature
3.6. Rate expression
The effect of reaction temperature on the alkylation was stud-
The rate expression is obtained by plotting −ln(1 − X) versus
◦
ied at 80, 85, 90 and 95 C under otherwise similar experimental
conditions. The results shown in Fig. 2 indicate that the conversion
of 1-(2-methoxyphenyl) piperazine hydrochloride increases with
reaction time (where X is the fractional conversion of 6-[(3-
chloropropyl) amino]-1,3-dimethyluracil) for reactions carried out
100
100
80
80
6
0
1mol:1mol
6
0
5
00rpm
1
1
mol:1.01mol
mol:1.05mol
40
40
100rpm
1
500rpm
000rpm
20
20
1mol:1.1mol
2
0
0
0
30
60
90
120
Time (min)
150
180
210
240
0
30
60
90
120
Time (min)
150
180 210
240
Fig. 1. The effect of agitation speed. Substrate 6, 1.0 mol; compound 7, 1.01 mol;
Na2CO3, 2.0 mol; catalyst, -cyclodextrin; catalyst loading, 0.02 mol; solvent, water;
temperature, 95 C.
Fig. 3. The effect of mole ratio. Substrate 6, 1.0 mol; compound 7, 1.0–1.1 mol; com-
pound 6: Na2CO3 = 1 mol: 2 mol; catalyst, -cyclodextrin; catalyst loading, 0.02 mol;
solvent, water; temperature, 95 C; agitation speed, 1500 rpm.
◦
◦