2
Tetrahedron Letters
various reaction conditions. Different reaction parameters for
Next, we carried out the comparison study with
different oxidants on oxidation of 1a to 2a (Table 2). Oxidizing
agents such as m-CPBA and TBHP provided only 77% and 66%
conversions respectively in 7 h (Table 2, entry 1-2). Benzoyl
peroxide showed only 58% conversion of 1a in to 2a in 7 h
(Table 2, entry 3). Similarly, lower conversion was observed i.e.
only 50% in 7 h while using UHP (Table 2, entry 4). It was also
noticed that there is increase in impurity formation 4a and 3a
along with 2a during oxidation. This confirms that H2O2 is
exceptional oxidant for oxidation of 1a affording maximum
conversion and excellent selectivity of 2a with its eco-friendly
properties.
oxidation of 1a (1 mmol) with lactic acid (1 mL) as a solvent and
30 % H2O2 as an oxidant at room temperature were optimized
(Table 1). During this study, initially we carried out the oxidation
of 1a using lactic acid in the absence of oxidant H2O2 at room
temperature. It has been observed that there was no conversion
up to 8 h (Table 1, entry 1). Next, we added H2O2 (1 equiv.) in to
the mixture of 1a and lactic acid and found 72% conversion of
reaction mixture after 7 h (Table 1, entry 2). Increasing the
amount of H2O2 from 1 to 1.03 and 1.06 equiv. and conversion
also increased from 89% to 95% respectively (Table 1, entry 3,4).
When conc. of H2O2 was increased to 1.07 equiv. in to mixture of
1a and lactic acid, 100% conversion of 1a was observed with
formation of the desired product selectively benzaldehyde 2a
99.6% with slight impurity formation benzoic acid 3a 0.1% and
phenyl formate 4a 0.3% in 7 h (Table 1, entry 5). With further
increase in the amount of H2O2 from 1.07 to 1.10 equiv. it was
observed that selectivity of 2a decreases with increase in
selectivity of 3a and 4a (Table 1, entry 6). This oxidant
equivalent study indicates that H2O2 is the key oxidant for proper
transformation and 1.07 equiv. is suitable for maximum
conversion and excellent selectivity of 2a.
Table 2 aComparison with different oxidants and temperature
Entry
Oxidants
(equiv.)
Temp.
(°C)
Conv.b
(%)
Sele.b
(%)
2a
3a
4a
Oxidants study
1
2
m-CPBA
30
77
66
75
63
0.8
1.3
12
70%
TBHP
1.7
3
Benzoyl
peroxide
58
50
55
49
0.5
0.2
3.5
0.8
Subsequently, we checked out the solvent effects on
oxidation of 1a in to 2a (Table 1, entry 7-14). Solvent less
reaction mixture gave only 9% conversion of 1a in to 2a (Table
1, entry 7). Several polar and non-polar solvents were also tested
for this oxidation. We carried out the oxidation of 1a in to 2a
using polar aprotic solvents, 48% and 42% conversion of 1a to
2a was observed with acetonitrile (MeCN) and acetone
respectively (Table 2, entry 8-9) while using ethyl acetate
(EtOAC) only 38% conversion was obtained (Table 1, entry 12).
It was observed that oxidation of 1a in polar protic solvents like
methanol (MeOH) and water gave 55% and 46% conversion in 7
h respectively (Table 1, entry 10-11). Moreover, we performed
this oxidation in non-polar solvents such as hexane and
chloroform (CHCl3) and obtained less conversion of 1a in to 2a
(Table 1, entry 13-14). This above solvent study showed that bio
based lactic acid is the best solvent for the complete conversion
of 1a in to 2a.
4
UHP
Temperature study
5
6
7
8
H2O2
15
20
25
35
43
61
43
61
0
0
0
0
89
88.9
0
0.1
100
99.4
0.2
0.4
aReaction conditions: 1a (1 mmol), Lactic acid (1 mL), oxidants (1.07 equiv.),
Time (7 h), temperature (°C),
bconversion and selectivity determined by GC with the area normalization
method.
The next parameter optimized was oxidation at different
temperatures. Oxidation of 1a at 15 and 20°C showed 43% and
61% conversion to 2a in 7 h (Table 2, entry 5-6). Whereas at
25°C only 89% conversion of 1a in 8 h was observed (Table 2,
entry 7). When the temperature was increased to 35°C, maximum
conversion was obtained but selectivity of 2a decreased as
compared to 30°C (Table 2, entry 8). Thus, increase in the
reaction temperature causes impurity formation of 3a and 4a in
this oxidation. We also observed effect of time on desired
product formation [i.e. selectivity of 2a (%)] by carrying out
reaction at regular time intervals. It was found that 7 h was
sufficient to complete the reaction whereas keeping reaction for
more than 7 h causes formation of 3a and 4a at room temperature
Fig. 1.
Table 1 aOptimization of reaction parameters
Entry
Solvent
Oxidant
(equiv.)
Time
(h)
Conv.b
(%)
Sel.b
(%)
3a
2a
4a
In this protocol, kinetic study of reaction was carried
out at temperature range of 15-35°C. The kinetic plots of X /(1-
X) vs. time at varying temperatures are presented in Fig. 2. It was
observed from results that the oxidation reaction follows second
order kinetic model. The rate constants are given in Fig. 2 and
were calculated by using the formulae stated in supplementary
information [Calculation of kinetic rate constant]. The results in
Table 3 suggested that the rate constant increased from 0.09 to
0.63 L/ (mol min) for temperature range of 15-35°C respectively.
The plot of ln (K) vs T is represented in Fig. 3 that gives a
straight line and slope enables to calculate activation energy. The
activation energy was found to be 73.02 kJ/mol and the pre-
exponential factor was found to be 1.04 L/(mol min). Therefore,
the optimized reaction parameters for this process are 1a (1
mmol), Lactic acid (1 mL), H2O2 (1.07 equiv.) at 30°C and
reaction time 7 h.
Oxidant equiv. Study
1
2
3
4
5
6
Lactic
acid
--
8
7
7
7
7
7
--
72
--
72
--
0
--
0
1.00
1.03
1.06
1.07
1.10
89
95
100
100
89
0
0
94.8
99.6
97
0.1
0.1
1.2
0.1
0.3
1.8
Solvent study
7
--
1.07
8
7
7
7
8
7
7
7
09
48
42
55
46
38
35
22
08
47
41
52
44
38
34
20
1
1
1
3
2
0
1
2
0
0
0
0
0
0
0
0
8
9
MeCN
Acetone
MeOH
H2O
10
11
12
13
14
EtOAc
Hexane
CHCl3
aReaction conditions: 1a (1 mmol), Solvent (1 mL), 30% H2O2 (equiv.),
temperature (30°C),
bconversion and selectivity determined by GC with the area normalization
method.