Kinetics and mechanism of vanadium catalysed asymmetric cyanohydrin synthesis in propylene carbonate

Article abstract of DOI:10.3762/bjoc.6.119

Propylene carbonate can be used as a green solvent for the asymmetric synthesis of cyanohydrin trimethylsilyl ethers from aldehydes and trimethylsilyl cyanide catalysed by VO(salen)NCS, though reactions are slower in this solvent than the corresponding re

Full text of DOI:10.3762/bjoc.6.119

Kinetics and mechanism of vanadium catalysed
asymmetric cyanohydrin synthesis
in propylene carbonate
Michael North* and Marta Omedes-Pujol
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2010, 6, 1043–1055.
School of Chemistry and University Research Centre in Catalysis and
Intensified Processing, Bedson Building, University of Newcastle,
Newcastle upon Tyne, UK, NE1 7RU
doi:10.3762/bjoc.6.119
Received: 12 July 2010
Accepted: 15 October 2010
Published: 03 November 2010
Email:
Michael North* - michael.north@ncl.ac.uk
Guest Editor: J. Murphy
* Corresponding author
© 2010 North and Omedes-Pujol; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
cyanohydrin; Hammett; kinetics; propylene carbonate; vanadium
Abstract
Propylene carbonate can be used as a green solvent for the asymmetric synthesis of cyanohydrin trimethylsilyl ethers from alde-
hydes and trimethylsilyl cyanide catalysed by VO(salen)NCS, though reactions are slower in this solvent than the corresponding
reactions carried out in dichloromethane. A mechanistic study has been undertaken, comparing the catalytic activity of
VO(salen)NCS in propylene carbonate and dichloromethane. Reactions in both solvents obey overall second-order kinetics, the rate
of reaction being dependent on the concentration of both the aldehyde and trimethylsilyl cyanide. The order with respect to
VO(salen)NCS was determined and found to decrease from 1.2 in dichloromethane to 1.0 in propylene carbonate, indicating that in
propylene carbonate, VO(salen)NCS is present only as a mononuclear species, whereas in dichloromethane dinuclear species are
present which have previously been shown to be responsible for most of the catalytic activity. Evidence from 51V NMR spec-
troscopy suggested that propylene carbonate coordinates to VO(salen)NCS, blocking the free coordination site, thus inhibiting its
Lewis acidity and accounting for the reduction in catalytic activity. This explanation was further supported by a Hammett analysis
study, which indicated that Lewis base catalysis made a much greater contribution to the overall catalytic activity of VO(salen)NCS
in propylene carbonate than in dichloromethane.
Introduction
The last 15 years have witnessed an explosion of activity in the drins, which can readily be converted into other, pharmaceuti-
area of asymmetric cyanohydrin synthesis [1], mostly using cally important, bifunctional units, such as α-hydroxy acids and
trimethylsilyl cyanide (TMSCN) as the cyanide source to β-amino alcohols [2] (Scheme 1). Asymmetric cyanohydrin
produce enantiomerically enriched silyl-protected cyanohy- synthesis can be achieved by the use of a suitable chiral cata-
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Beilstein J. Org. Chem. 2010, 6, 1043–1055.
lyst, and a wide range of catalysts have been found to catalyse
this reaction including enzymes [3,4], organocatalysts [5,6] and
metal-based catalysts [1]. All of the most effective catalysts for
asymmetric cyanohydrin synthesis have been found to involve
cooperative catalysis [7-9], in which the aldehyde is activated
by an acidic group and the cyanide source is activated by a
basic group. The acid and base catalysts can be present within a
single catalyst unit, or can be in separate catalysts, either or
both of which may be chiral.
Scheme 1: Synthesis and transformation of nonracemic silyl-protected
cyanohydrins.
Figure 1: Highly active metal(salen) complexes for asymmetric
cyanohydrin synthesis.
Whilst enzymatic catalysts (oxynitrilases) have been exten-
sively developed [3,4] and commercialized [10], they do have bond, thus allowing transfer of cyanide to the carbonyl to occur
the disadvantage of requiring hydrogen cyanide which is toxic intramolecularly in a highly organized transition state structure.
and difficult to handle in a laboratory environment, and gives The mode of action of vanadium based catalysts such as 2 is
unprotected cyanohydrins which are prone to racemization. Pre- believed to involve two parallel catalytic cycles, the slower of
eminent amongst the synthetic catalysts are metal(salen) which involves only monometallic species, whilst the other
complexes, especially those based on titanium (1) and vana- involves bimetallic complexes [28]. Experimental evidence has
dium (2) [1] (Figure 1). Titanium complex 1 will catalyse the shown that formation of vanadium(IV) complexes in situ is
asymmetric addition of TMSCN to aromatic aldehydes with important [28,50], as is the formation of bimetallic complexes
80–90% enantiomeric excess at room temperature with just involving vanadium ions in both the +4 and +5 oxidation states
0.1 mol % of catalyst [11]. Complex 1 also catalyses the asym- [28,51]. Both Lewis acid and Lewis base catalysis are known to
metric addition of other cyanide sources including potassium be involved in the catalytic cycle, the latter possibly involving
cyanide [12-15], cyanoformates [15-20] and acyl cyanides the isothiocyanate counterion [52].
[17,19,21] to aldehydes, and will accept some ketones as
substrates [22,23]. Recently, a modified version of complex 1, Despite their many favourable properties, there is one draw-
in which the two salen ligands are covalently linked together back associated with catalysts 1 and 2; they exhibit highest
has been developed which allows the amount of catalyst used to activity and highest enantioselectivity in chlorinated solvents,
be reduced to 0.0005 mol % [24,25].
optimally dichloromethane. Recently however, we showed that
catalyst 2 could be used in propylene carbonate [53]. Propylene
Vanadium based catalysts such as 2 also catalyse the asym- carbonate and other cyclic carbonates are starting to attract
metric addition of TMSCN [26-28] and KCN [13] to aldehydes significant interest as green solvents [54-64], since they can be
and are more enantioselective, but less reactive than the tita- prepared by a 100% atom economical reaction between epox-
nium based catalyst 1. Complexes 1 and 2 have been commer- ides and CO2 (Scheme 2) [65]. The green credentials of propy-
cialized [10,29,30], immobilized to facilitate their recycling lene carbonate are enhanced by the commercialization of a low
[31-43] and used by other groups as part of synthetic studies temperature synthesis of propylene oxide from propene and
[44-46]. Mechanistically, the mode of action of catalyst 1 is hydrogen peroxide [66-70], by the development of a greener
well understood [15,20,47-49], involving a bimetallic transition synthesis of hydrogen peroxide [71], and by the combination of
state in which one titanium atom acts as a Lewis acid, coordi- these processes into a one-pot synthesis of propylene oxide
nating to the aldehyde, and the other forms a titanium–cyanide from propene, hydrogen and oxygen [72,73]. In addition, it has
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Beilstein J. Org. Chem. 2010, 6, 1043–1055.
been shown that in the presence of an appropriate catalyst, the dition of TMSCN to a range of aldehydes in both dichloro-
reaction between epoxides and carbon dioxide can be achieved methane and propylene carbonate under identical reaction
at atmospheric pressure and room temperature [74-77], or in a conditions. These reactions were all carried out at room
gas-phase continuous flow reactor [78], thus facilitating the use temperature for two hours with 0.1 mol % of catalyst, 1.1 equiv
of waste carbon dioxide in this process [79].
of TMSCN and a substrate concentration of 0.56 M. In each
case, the enantiomeric excess of the cyanohydrin product was
determined by chiral GC after conversion of the trimethylsilyl
ether into the corresponding acetate by the method of Kagan
[80], a process which is known to cause no racemization
(Scheme 3). The results of this study are presented in Table 1.
Scheme 2: Synthesis of cyclic carbonates.
In this paper we give full details of the use of catalyst 2 in
propylene carbonate, and describe kinetic studies, which allow
differences in the relative importance of Lewis acid and Lewis
base catalysis between reactions carried out in dichloromethane
and propylene carbonate to be elucidated.
Scheme 3: Synthesis of cyanohydrin trimethylsilyl ethers and
acetates.
Results and Discussion
Synthetic Studies
It is apparent from Table 1, that for reactions catalysed by tita-
Initially, the compatibility of catalysts 1 and 2 with propylene nium based catalyst 1, changing the solvent to propylene
carbonate was investigated by carrying out the asymmetric ad- carbonate had a severely detrimental effect on the enantio-
Table 1: Influence of solvent on cyanohydrin synthesis using catalysts 1 and 2.
Aldehyde
Solventa
Catalyst 1
Catalyst 2
Conversionb
eec
Conversionb
eec
PhCHO
CH2Cl2
PC
95
33
40
24
98
20
83
53
76
47
95
30
82
16
71
98
93
100
100
97
78
40
76
35
83
25
84
46
89
36
97
57
68
49
73
45
47
10
66
19
100
73
81
67
90
73
83
56
81
78
100
67
86
56
88
96
100
99
100
97
86
80
91
76
93
76
89
62
96
73
99
93
87
86
83
67
86
76
88
67
PhCHO
4-FC6H4CHO
4-FC6H4CHO
4-ClC6H4CHO
4-ClC6H4CHO
3-ClC6H4CHO
3-ClC6H4CHO
2-MeC6H4CHO
2-MeC6H4CHO
3-MeC6H4CHO
3-MeC6H4CHO
4-MeC6H4CHO
4-MeC6H4CHO
Me(CH2)7CHO
Me(CH2)7CHO
Me3CCHO
CH2Cl2
PC
CH2Cl2
PC
CH2Cl2
PC
CH2Cl2
PC
CH2Cl2
PC
CH2Cl2
PC
CH2Cl2
PC
CH2Cl2
PC
Me3CCHO
CyCHO
CH2Cl2
PC
CyCHO
aPC = propylene carbonate; bConversions were determined by 1H NMR spectroscopy; cEnantiomeric excesses were determined by chiral GC
analysis of the cyanohydrin acetates (data presented in Supporting Information File 1). The predominant cyanohydrin derivative always had the (S)-
configuration.
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Beilstein J. Org. Chem. 2010, 6, 1043–1055.
selectivity of the reactions. In some cases, the enantiomeric
excess of the cyanohydrin was more than halved when reac-
tions were carried out in propylene carbonate. For aromatic
aldehydes, there was also a substantial reduction in the conver-
sion obtained from reactions carried out in propylene carbonate,
though this was not apparent with the aliphatic aldehydes
studied. The reason for the lower reactivity and enantio-
selectivity displayed by catalyst 1 in propylene carbonate can be
related to the dissociation of the catalytically active bimetallic
complex 1 into the catalytically inactive monometallic complex
3 (Scheme 4). The position of this equilibrium is known to be
solvent dependent, with polar solvents favouring the formation
of the monometallic species [15]. Propylene carbonate is a polar
aprotic solvent with a dielectric constant of 65 [81], and there-
fore the concentration of catalytically active bimetallic com-
plex 1 will be reduced in this solvent resulting in less effective
catalysis.
Scheme 4: Equilibrium between bimetallic and monometallic Ti(salen)
complexes.
Reactions carried out with benzaldehyde at room temperature
Reactions catalysed by complex 2 also proceeded more slowly (entries 1 and 2) showed that increasing the reaction time
and less enantioselectively in propylene carbonate than in di- increased the conversion without lowering the enantio-
chloromethane (Table 1). However, the reduction in conversion selectivity. The conversion could also be increased by doubling
and enantioselectivity was much less pronounced than for reac- the catalyst concentration (entry 3), though this did not enhance
tions catalysed by complex 1. Therefore, attempts were made to the enantioselectivity. Reducing the reaction temperature to
optimize the reaction conditions for reactions catalysed by com- 0 °C (entry 4) reduced the rate of reaction so that a reaction
plex 2 in propylene carbonate by reducing the reaction tempera- time of 18 hours was required to achieve the same conversion
ture to enhance the enantioselectivity and by increasing the as could be achieved in two hours at room temperature
reaction time to optimize the conversion. The results of this (Table 1), but the lower temperature did restore the enantio-
study are shown in Table 2.
selectivity to that observed in dichloromethane at room
Table 2: Optimization of asymmetric cyanohydrin synthesis catalysed by complex 2 in propylene carbonate.
Entry
Aldehyde
T (°C)
Time (h)
2 (mol %)
Conversiona
eeb
1
PhCHO
rt
rt
4
24
2
0.1
0.1
0.2
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
83
92
83
80
85
86
88
82
80
90
81
89
83
61
76
80
75
77
80
2
PhCHO
3
PhCHO
rt
86
4
PhCHO
0
18
24
24
24
18
24
24
24
18
18
18
24
24
24
73
5
4-FC6H4CHO
3-ClC6H4CHO
4-ClC6H4CHO
4-MeC6H4CHO
2-MeC6H4CHO
3-MeC6H4CHO
4-MeC6H4CHO
Me(CH2)7CHO
CyCHO
0
88
6
0
89
7
0
86
8
0
63
9
rt
100
93
10
11
12
13
14
15
16
17
rt
rt
90
0
100
92
0
Me3CCHO
0
100
98
Me(CH2)7CHO
CyCHO
−20
−20
−20
88
Me3CCHO
100
aConversions were determined by 1H NMR spectroscopy; bEnantiomeric excesses were determined by chiral GC analysis of the cyanohydrin
acetates (data presented in Supporting Information File 1). The predominant cyanohydrin derivative always had the (S)-configuration.
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Beilstein J. Org. Chem. 2010, 6, 1043–1055.
temperature. Electron-deficient aromatic aldehydes also gave ysis. The ability of catalyst 2 to function in propylene carbonate
good results at 0 °C (entries 5–7), as did 4-methylbenzaldehyde provided the opportunity to extend this study to a second
(entry 8), although in this case, whilst the enantioselectivity was solvent system with very different polarity to dichloromethane,
higher than that obtained at room temperature in dichloro- and thus offered the potential to obtain a better understanding of
methane, the conversion was not as high. Therefore, to ensure the factors that are important for high catalyst activity.
good conversions, the optimal conditions for electron-rich
aromatic aldehydes were taken as room temperature for 24 Initially, the kinetics of reactions carried out in dichloro-
hours (entries 9–11). The three aliphatic aldehydes studied methane and propylene carbonate were compared. These reac-
(entries 12–14) all gave high conversions at 0 °C, but the tions were carried out at 0 °C with 0.2 mol % of catalyst 2, and
enantioselectivities were not as high as those obtained at room initial concentrations of benzaldehyde and TMSCN of 0.49 M
temperature in dichloromethane. Therefore, for these substrates, and 0.52 M, respectively. Reactions were monitored over a
the reaction temperature was further reduced to −20 °C (entries period of two hours by removing samples at regular intervals
15–17), but this resulted in only a modest improvement in the and monitoring the absorbance of residual benzaldehyde at
enantioselectivity, except when nonanal was used as the sub- 240–260 nm as previously described [28]. The reaction carried
strate.
out in propylene carbonate was found neither to follow zero-
nor first-order kinetics, but gave an excellent fit to second-order
Propylene carbonate has a boiling point of 242 °C and could not kinetics as shown in Figure 2, which shows the kinetic data
be separated from the cyanohydrin trimethylsilyl ethers by dis- obtained in both solvents for comparison. It is apparent from
tillation. Since the cyanohydrin ethers are liquids and are Figure 2 that the reactions in dichloromethane and propylene
unstable during chromatography, it was impossible to purify the carbonate obey the same rate equation, but the reaction in
cyanohydrin trimethylsilyl ethers produced in propylene propylene carbonate has an observed second-order rate constant
carbonate. However, one of the main applications of a factor of four smaller than the reaction in dichloromethane,
nonracemic cyanohydrins is in the synthesis of α-hydroxy acids consistent with the lower conversions observed for reactions
[2,29,30], and (S)-mandelic acid could be obtained in 60% carried out in propylene carbonate (Table 1).
isolated yield simply by refluxing the mixture of propylene
carbonate and mandelonitrile trimethylsilyl ether (81% ee) with
12 N hydrochloric acid for six hours followed by crystallization
from ether/hexane. That no racemization occurred during this
process was demonstrated by conversion of the mandelic acid
into methyl mandelate followed analysis by chiral HPLC (data
presented in Supporting Information File 1), which gave an
enantiomeric excess of 81%.
Kinetic and NMR Studies using benzalde-
hyde
Previous work [28] has shown that the asymmetric addition of
TMSCN to benzaldehyde in dichloromethane catalysed by com-
plex 2 follows overall second-order kinetics, the reaction being
first order in both benzaldehyde and TMSCN. The rate equa-
tion is then represented by Equation 1:
Figure 2: Second-order kinetics plot for the addition of TMSCN to
benzaldehyde at 0 °C catalysed by complex 2 in dichloromethane (red)
and propylene carbonate (blue). The units for the vertical scale are
ln[(B0At)/(BtA0)]/(A0–B0), where A = [PhCHO], B = [Me3SiCN], and the
subscripts 0 and t refer to initial concentrations and concentrations at
time t, respectively.
(1)
To determine the order with respect to catalyst 2 and hence to
investigate if changing the solvent from dichloromethane to
The order with respect to the catalyst (1.2) in Equation 1 propylene carbonate affected the aggregation state of the cata-
provides information on the relative importance of mononu- lyst, reactions were carried out in propylene carbonate at 0 °C
clear and binuclear species in the catalytic cycle [28,47]. A with five different concentrations of catalyst 2 (Table 3). The
value greater than one implies that the catalyst exists in solu- kinetics at each catalyst concentration were determined in tripli-
tion as a mixture of mononuclear and binuclear species, but that cate, using two different batches of propylene carbonate, and
the binuclear species is predominantly responsible for the catal- the average value of the rate constant was calculated from all
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Beilstein J. Org. Chem. 2010, 6, 1043–1055.
Table 3: Second-order rate constants at 0 °C for the addition of TMSCN to benzaldehyde obtained at different concentrations of complex 2.a
Entry
[2] (mol %)
k2obs1 (M−1s−1)
k2obs2 (M−1s−1)
k2obs3 (M−1s−1)
k2obs avg (M−1s−1)
1
2
3
4
5
1.13 mM (0.2)
1.69 mM (0.3)
2.25 mM (0.4)
3.38 mM (0.6)
4.50 mM (0.8)
0.00057
0.00087
0.00100
0.00220
0.00296
0.00099
0.00116
0.00170
0.00205
0.00370
0.00090
0.00127
0.00155
0.00229
0.00296
0.00083 ± 0.00016
0.00110 ± 0.00023
0.00142 ± 0.00042
0.00218 ± 0.00013
0.00321 ± 0.00049
ak2obs1–3 refer to the results of three separate experiments at the specified catalyst concentration (data presented in Supporting Information File 1).
k2obs avg is the average value of the three separate measurements.
three data points for each concentration. As shown in Figure 3, propylene carbonate. This implies that in propylene carbonate,
plots of k2obs against the concentration of catalyst 2 could be the catalyst exists only as mononuclear species and that these
fitted to a straight line, showing that in propylene carbonate the are exclusively responsible for the catalysis. Since it is known
reactions are first order with respect to the concentration of the that catalysis by binuclear complexes formed from catalyst 2 is
catalyst (since k2obs = k2[2]x where x is the order with respect to faster than catalysis by mononuclear complexes [28], this is
the catalyst). This was further supported by a plot of log(k2obs) therefore consistent with the reduction in reaction rate when the
against log([2]), which had a slope of 0.997 (data presented in solvent is changed from dichloromethane to propylene
Supporting Information File 1). Thus, the order with respect to carbonate. The reason for the lack of formation of bimetallic
the catalyst decreases from 1.2 in dichloromethane [28] to 1.0 in complexes in propylene carbonate is probably due to the
polarity of the solvent (dielectric constant 65 [81]), which will
stabilise the highly polar V=O bonds present in the mononu-
clear species.
Having determined the order with respect to catalyst 2 in propy-
lene carbonate, a variable temperature kinetics study was
carried out to determine the activation parameters in propylene
carbonate and to allow these to be compared with those previ-
ously reported for the use of catalyst 2 in dichloromethane [28].
Thus, reactions were carried out at five temperatures between
253 and 293 K. The resulting rate data are presented in Table 4.
The corresponding Eyring plot is shown in Figure 4.
The Eyring equation (Equation 2) relates the rate constant for a
Figure 3: Plot of k2obs against [2], showing that the reactions are first
order with respect to the concentration of catalyst 2 (data presented in
Supporting Information File 1). The red, blue and purple data and best-
reaction to the enthalpy and entropy of activation. Replacing the
actual rate constant in Equation 2 with k2obs (k2obs = k2[2]x) and
fit lines correspond to the three individual data sets given in Table 3.
The black data and best-fit line correspond to the average data.
rearranging gives Equation 3, which, after taking the logarithm
of both sides, gives Equation 4. The enthalpy of activation
Table 4: Second-order rate constants at 253 K to 293 K for the addition of TMSCN to benzaldehyde.a
Temperature (K)
k2obs1 (M−1s−1)
k2obs2 (M−1s−1)
k2obs avg (M−1s−1)
253
263
273
283
293
0.00011
0.00029
0.00057
0.00150
0.00255
0.00006
0.00020
0.00047
0.00172
0.00325
0.00009 ± 0.00003
0.00025 ± 0.00005
0.00052 ± 0.00005
0.00161 ± 0.00011
0.00290 ± 0.00035
a[PhCHO]0 = 0.49 M, [Me3SiCN]0 = 0.49 and [2] = 0.98 mM (data presented in Supporting Information File 1).
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Beilstein J. Org. Chem. 2010, 6, 1043–1055.
explanation for the observed rate reduction is due to differences
in the efficiency with which complex 2 is converted into species
which are involved in the catalytic cycle. If propylene carbonate
inhibits the conversion of complex 2 into catalytically compe-
tent species, then there will be a lower concentration of catalyti-
cally active species present in propylene carbonate than in di-
chloromethane, thus resulting in the observed lower rate of
reaction.
Evidence to support this hypothesis came from 51V NMR
studies of complex 2 (Figure 5). The spectrum of complex 2 in
CDCl3 shows a resonance at −580 ppm (Figure 5a). It is known
from X-ray crystallography that the isothiocyanate unit in com-
plex 2 is directly bound to the vanadium ion through the
nitrogen atom. Thus, the vanadium ion is six-coordinate, and is
bound to three oxygen atoms and three nitrogen atoms. Addi-
tion of benzaldehyde (500 equiv) to this solution results in a
Figure 4: Eyring plot to determine the activation parameters for cata-
lyst 2 in propylene carbonate. The red and blue data and best-fit lines
correspond to the two individual data sets given in Table 4. The black
data and best-fit line correspond to the average data.
(ΔH‡) can then be obtained from the slope of the best-fit line change in the chemical shift of the vanadium ion to −575 ppm
from the data plotted in Figure 4 and was found to be 67.8 (Figure 5b), consistent with the formation of a complex 2/
(±0.2) kJ mol−1. The entropy of activation (ΔS‡) can be benzaldehyde (see complex 4 in Figure 6), in which the vana-
obtained from the y-axis intercept, once the contributions of the dium ion is bound to four oxygen atoms and two nitrogen
fundamental constants and x·ln[2] are subtracted. The latter was atoms. When the 51V NMR spectrum of complex 2 is recorded
only possible as the reaction order with respect to catalyst 2 (x) in propylene carbonate, the 51V NMR signal is observed at
had been determined to be 1.0 as discussed above. This gave a −571 ppm (Figure 5c), again indicative of formation of a
value for ΔS‡ of −54 (±26) J mol−1 K−1. The values for ΔH‡ species, such as 5, in which the vanadium ion is bound to four
and ΔS‡ are very different to those previously determined for oxygen atoms and two nitrogen atoms. The competitive forma-
the asymmetric addition of trimethylsilyl cyanide to benzalde- tion of structure 5 would reduce the amount of complex 4
hyde catalysed by complex 2 in dichloromethane [28] (ΔH‡ = present in solution, thus reducing the concentration of catalyti-
20.4 kJ mol−1 and ΔS‡ = −136 J mol−1 K−1), though the corres-
ponding Gibbs free energies of activation (ΔG‡) at 273 K are
similar at 53.1 and 57.5 kJ mol−1 for reactions carried out in
propylene carbonate and dichloromethane, respectively.
(2)
(3)
(4)
(kB = Boltzmann’s constant, h = Planck’s constant, R = gas
constant)
Figure 5: 51V NMR spectra of complex 2 recorded at 50 °C. a) Spec-
trum in CDCl3; b) spectrum in CDCl3 with 500 equiv of PhCHO added;
c) spectrum in propylene carbonate; d) spectrum in propylene
carbonate with 500 equiv of PhCHO added. All spectra were recorded
with a complex 2 concentration of 24 mM and for spectra b and d, the
concentration of benzaldehyde was 4.8 M.
Since differences in the Gibbs free energy of activation could
not account for the reduction in rate constant between reactions
in dichloromethane and propylene carbonate, the most likely
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Beilstein J. Org. Chem. 2010, 6, 1043–1055.
cally competent species and hence reducing the rate of asym- Hammett analysis
metric cyanohydrin synthesis in propylene carbonate compared It is well established that the asymmetric addition of TMSCN to
to dichloromethane. Addition of benzaldehyde (500 equiv) to aldehydes can be catalysed by both Lewis acids and Lewis
the propylene carbonate spectrum resulted in only a small addi- bases [1]. A Lewis acid catalyst activates the aldehyde by for-
tional change in the chemical shift to −569 ppm (Figure 5d).
mation of an aldehyde-Lewis acid complex (e.g., 4) whilst a
Lewis base catalyst activates the TMSCN through formation of
a hypervalent silicon species [82] or the formation of cyanide
anions. The most effective catalysts possess both Lewis acidity
and Lewis basicity and so can simultaneously activate both the
aldehyde and TMSCN [1].
We have recently shown [52] that a Hammett analysis corre-
lating the rate of reaction of meta- and para-substituted
benzaldehydes with their substituent constants can be used to
investigate the relative importance of Lewis acid and Lewis
base catalysis in a catalysed reaction. This methodology was
developed using the asymmetric addition of TMSCN to alde-
hydes catalysed by complexes including 1, 2 and 6 (Figure 7) in
dichloromethane. A reaction which is predominantly Lewis
base catalysed would be expected to produce a Hammett plot
with a reaction constant (ρ) close to zero, since the aldehyde is
not activated in the catalytic step; so during the rate deter-
mining transition state, the negative charge will largely be
located on silicon as shown in Figure 8a. This was found to be
the case (ρ = +0.4) for asymmetric cyanohydrin synthesis catal-
ysed by bimetallic aluminium(salen) complex 6 in the presence
Figure 6: Structures consistent with the 51V NMR spectra.
The half-widths of the signals recorded in propylene carbonate
(1730 Hz and 1510 Hz for Figure 5c and Figure 5d, respective-
ly) are much greater than the corresponding half-widths of the
signals recorded in dichloromethane (930 Hz and 950 Hz for
Figure 5a and Figure 5b, respectively). This is also indicative of
exchange processes involving species 2, 4 and 5 occurring in
propylene carbonate.
The enthalpy of activation for the asymmetric addition of
trimethylsilyl cyanide to benzaldehyde was found to be much
higher in propylene carbonate than in dichloromethane, which
is consistent with only one of the two reaction components
(benzaldehyde or TMSCN) being activated by the mononuclear,
catalytically active species present in propylene carbonate,
whilst both reaction components are activated and pre-orga-
nized for reaction by the binuclear, catalytically active species
present in dichloromethane [28]. The less negative value for the
entropy of activation in propylene carbonate compared to that
determined in dichloromethane is also consistent with a less
tightly organized transition state, again consistent with only one
of the reaction components interacting with the catalyst. To
investigate this further, a Hammett analysis was undertaken
using a range of substituted benzaldehydes.
Figure 7: Bimetallic aluminium(salen) complex for asymmetric
cyanohydrin synthesis.
Figure 8: Rate determining transition states for asymmetric cyanohy-
drin synthesis: a) when Lewis base catalysis is dominant; and b) when
Lewis acid catalysis is dominant.
1050

Beilstein J. Org. Chem. 2010, 6, 1043–1055.
of triphenylphosphine oxide [83,84], indicating that most of the
catalysis in this case was due to activation of the TMSCN by
the triphenylphosphine oxide rather than activation of the alde-
hyde by the metal(salen) complex. In contrast, reactions catal-
ysed by complex 1 gave a Hammett plot with a reaction
constant of +2.4, indicating that there was a significant increase
in negative charge at the benzylic position of the aldehyde
during the transition state, and hence that complex 1 functioned
predominantly as a Lewis acid catalyst, activating the aldehyde
towards attack by cyanide, and resulting in more charge transfer
to the benzylic position of the aldehyde during the transition
state for formation of the new carbon-carbon bond as shown in
Figure 8b. Asymmetric cyanohydrin synthesis catalysed by
complex 2 in dichloromethane was found to give a Hammett
plot with an intermediate reaction constant of +1.6, indicating
that both Lewis acid and Lewis base catalysis were operative in
Figure 9: Hammett correlations with catalyst 2 at 0 °C. Data in red are
obtained in dichloromethane [52], whilst data in blue are obtained in
propylene carbonate.
this case. Since the kinetic and NMR data suggested that the cyanohydrin acetates derived from 3,4-dichlorobenzalde-
changing the solvent to propylene carbonate was inhibiting the hyde and 3,4-dimethylbenzaldehyde were not separated by
Lewis acidity of complex 2, this should be reflected in a reduc- chiral GC, therefore the enantiomeric excess was determined by
tion in the reaction constant of a Hammett analysis. Therefore, 1H NMR analysis of the free cyanohydrin obtained by hydroly-
the kinetics of the asymmetric addition of TMSCN to 12 meta- sis of the acetate [85], in the presence of (R)-mandelic acid and
and para-substituted benzaldehydes were determined (Table 5) DMAP [86].
and used to construct a Hammett plot (Figure 9).
It is apparent from Figure 9 that the reaction constant for
All of the aldehydes included in Table 5 gave nonracemic cyanohydrin synthesis catalysed by complex 2 does indeed
cyanohydrin trimethylsilyl ethers, confirming that in each case decrease significantly (from +1.6 to +0.4) when the solvent is
the reaction was catalysed by complex 2. In most cases the changed from dichloromethane to propylene carbonate. The
enantiomeric excess of the cyanohydrin trimethylsilyl ether was results obtained in propylene carbonate are almost identical to
determined by chiral GC analysis after conversion to the corres- those previously obtained with complex 6 and triphenylphos-
ponding cyanohydrin acetate [80] as discussed above. However, phine oxide as catalyst [52], and are entirely consistent with a
Table 5: Rate constants used to construct the Hammett plot.a
Entry
Aldehyde
k(a) (M−1s−1)
k(b) (M−1s−1)
k(avg) (M−1s−1)
eeb
1
PhCHO
0.00090
0.00117
0.00093
0.00058
0.00056
0.00104
0.00068
0.00153
0.00089
0.00084
0.00055
0.00078
0.00090
0.00124
0.00099
0.00058
0.00047
0.00100
0.00070
0.00173
0.00076
0.00110
0.00048
0.00090
0.00090
85
40c
74
77
84
72
90
44
70
45
85c
57
2
3,4-Cl2C6H3CHO
4-ClC6H4CHO
4-MeC6H4CHO
4-FC6H4CHO
3-FC6H4CHO
3-MeC6H4CHO
4-F3CC6H4CHO
4-BrC6H4CHO
3,5-F2C6H3CHO
3,4-Me2C6H3CHO
3-ClC6H4CHO
0.00120 ± 0.00004
0.00096 ± 0.00003
0.00058
3
4
5
0.00052 ± 0.00005
0.00102 ± 0.00002
0.00069 ± 0.00001
0.00163 ± 0.00010
0.00083 ± 0.00007
0.00097 ± 0.00013
0.00052 ± 0.00004
0.00084 ± 0.00006
6
7
8
9
10
11
12
aAll reactions were carried out in duplicate (to give k(a) and k(b), respectively) in propylene carbonate at 0 °C with [aldehyde]0 = 0.5 M, [Me3SiCN]0 =
0.55 M and [2] = 1.0 mM. bEnantiomeric excesses were determined by chiral GC analysis of the cyanohydrin acetates (data presented in Supporting
Information File 1) unless stated otherwise. The predominant cyanohydrin derivative always had the (S)-configuration. cDetermined by 1H NMR spec-
troscopy in the presence of (R)-mandelic acid and DMAP.
1051

Beilstein J. Org. Chem. 2010, 6, 1043–1055.
significant reduction in the Lewis acidity of complex 2 in was then added and the reaction mixture stirred for the speci-
propylene carbonate compared to dichloromethane. This is fied time. The solution was then passed through a short silica
manifested as an increase in the relative importance of Lewis plug eluting with CH2Cl2. The eluent was evaporated in vacuo
base catalysis and hence a decrease in the reaction constant. It is to remove the CH2Cl2, and the residue analysed by 1H NMR
important to note however, that complex 2 must still possess spectroscopy to determine the conversion. To determine the
some Lewis acidity in propylene carbonate, otherwise cyanohy- enantiomeric excess, Ac2O (2.0 mmol, 0.15 mL) and Sc(OTf)3
drin synthesis would not occur in the chiral environment around (5 mg, 0.01 mmol) were added to the stirred residue. After
the vanadium ion and racemic cyanohydrin trimethylsilyl ethers 20 min, the reaction mixture was passed through a short silica
would be obtained.
plug eluting with MeCN. The resulting solution was analysed
by chiral GC using a Supelco Gamma DEX 120 fused silica
capillary column (30 m x 0.25 mm) with hydrogen as a carrier
Conclusion
Asymmetric cyanohydrin synthesis catalysed by VO(salen)NCS gas. Details of the analysis of each cyanohydrin acetate are
complex 2 can be carried out in propylene carbonate, thus given in the Supporting Information File 1. When no separation
providing a green, alternative solvent to dichloromethane. Reac- could be achieved by chiral GC, the cyanohydrin acetate
tions in propylene carbonate are slower and less enantioselec- (0.985 mmol) was dissolved in ethanol (3 mL), p-TsOH·H2O
tive than those carried out in dichloromethane; though by opti- (187 mg, 0.985 mmol) was added, and the mixture stirred at
mization of the reaction conditions, high enantioselectivities can room temperature for 2 days. The solvent was evaporated in
still be obtained. A study of the reaction kinetics showed that vacuo and the residue purified by column chromatography
complex 2 is active only as mononuclear species in propylene eluting with a gradient from 1:15 EtOAc/hexane to 1:6 EtOAc/
carbonate. Kinetic and NMR studies also showed that the hexane to give the deprotected cyanohydrin. (R)-Mandelic acid
propylene carbonate can coordinate to the vanadium ion of (2.74 mg, 18 μmol), DMAP (1.73 mg, 18 μmol) and CDCl3
complex 2, thus reducing its Lewis acidity and accounting for (0.6 mL) were mixed in an NMR tube. The cyanohydrin
the decrease in reaction rate observed in propylene carbonate. (18 μmol) was then added and the solution analysed by 1H
The lower Lewis acidity of complex 2 in propylene carbonate NMR spectroscopy.
was confirmed by a Hammett analysis using substituted
benzaldehydes, which gave a reaction constant of only 0.4 in (S)-Mandelic acid
propylene carbonate compared to 1.6 in dichloromethane.
To a solution of mandelonitrile trimethylsilyl ether in propy-
lene carbonate, obtained following the general procedure above,
The lower enantioselectivities observed in propylene carbonate was added 12 N HCl (10 mL). The mixture was heated at reflux
under identical reaction conditions to those used in dichloro- for 6 h, cooled to rt and basified with 10% aqueous NaOH solu-
methane can be explained in two ways. It is possible that in tion. The aqueous solution was extracted with ether (3 x
propylene carbonate, some addition of TMSCN to aldehydes 10 mL), acidified with 12 N HCl and extracted again with ether
occurs exclusively by Lewis base catalysis (using the thio- (3 x 10 mL). The last three ethereal extracts were combined,
cyanate anion as the Lewis base) and hence is independent of dried (Na2CO3) and evaporated in vacuo to give a yellow solid
the chiral VO(salen) unit, thus forming some racemic cyanohy- which was recrystallised at 4 °C from ether/hexane and the
drin trimethylsilyl ether. Alternatively, all of the catalysis may resulting solid washed with hexane to give mandelic acid
occur within the coordination sphere of the VO(salen) unit by (91 mg, 60%) as white crystals. δH (300 MHz, CDCl3) 5.26
cooperative Lewis acid/Lewis base catalysis, but the aldehyde (1H, s, CHO), 7.3–7.5 (5H, m, ArH).
may be less tightly bound to the vanadium ion in the more polar
propylene carbonate than in dichloromethane. This would result (S)-Methyl mandelate
in the aldehyde being further from the chiral salen ligand during Mandelic acid (50 mg, 0.33 mmol) was suspended in toluene
the key transition state and hence less effective transfer of (10 mL), then methanol (2 mL) was added to give a homoge-
chirality from the ligand to the newly formed stereocentre. nous solution. One drop of concentrated H2SO4 was added and
the mixture heated at reflux for 4 h. The reaction mixture was
Experimental
then cooled to room temperature, the solvents were evaporated
in vacuo and the residue was dissolved in water (10 mL). The
aqueous solution was extracted with ether (3 x 5 mL). The ethe-
real extract was dried over anhydrous Na2SO4 and concen-
General procedure for the synthesis and analysis of
cyanohydrin trimethylsilyl ethers in propylene
carbonate
The aldehyde (0.98 mmol) was added to a solution of catalyst 1 trated in vacuo to give methyl mandelate (28 mg, 50%) as a
or 2 (0.98 μmol, 0.1 mol %) in propylene carbonate (1.75 mL) pale yellow solid. δH (300 MHz, CDCl3) 3.77 (3H, s, CH3),
at the specified temperature. Me3SiCN (1.12 mmol, 0.15 mL) 5.20 (1H, s, CHO), 7.3–7.5 (5H, m, ArH).
1052

Beilstein J. Org. Chem. 2010, 6, 1043–1055.
6. Denmark, S. E.; Beutner, G. L. Angew. Chem., Int. Ed. 2008, 47,
1560–1638. doi:10.1002/anie.200604943
General procedure for kinetics experiments in
propylene carbonate
7. Schneider, C. Angew. Chem., Int. Ed. 2009, 48, 2082–2084.
doi:10.1002/anie.200805542
A solution of catalyst 2 (0.2–0.8 mol %) in freshly distilled
propylene carbonate (1.75 mL) was added to a round-bottomed
flask fitted with a magnetic stirrer bar and a SubaSeal stopper.
The reaction temperature was adjusted by a water bath (water/
ice for 0 °С) or cryostat for reactions below 0 °C; temperatures
other than 0 °C were kept within a ±0.5 °С range. A 0.5 μL
aliquot was taken and diluted with dry CH2Cl2 (3.5 mL). This
solution was used for UV-baseline calibration at 240–260 nm.
Freshly distilled aldehyde (0.96 mmol) was then added, and a
t = 0 aliquot was taken and diluted as described for the baseline
calibration sample. Me3SiCN (0.15 mL, 1.125 mmol) was
added, and aliquots of the reaction were taken and diluted at
appropriate intervals for a period of 2 h. After completion of the
kinetics analysis, the reaction mixture was passed through a
short silica plug eluting with CH2Cl2. The solvent was evapo-
rated and the residue converted into mandelonitrile acetate as
described above to allow the enantiomeric excess of the
cyanohydrin to be determined.
8. Shibasaki, M.; Kanai, M.; Matsunaga, S.; Kumagai, N.
Acc. Chem. Res. 2009, 42, 1117–1127. doi:10.1021/ar9000108
9. Nájera, C.; Sansano, J. M.; Saá, J. M. Eur. J. Org. Chem. 2009,
2385–2400. doi:10.1002/ejoc.200801069
10.Breuer, M.; Ditrich, K.; Habicher, T.; Hauer, B.; Keßeler, M.;
Stürmer, R.; Zelinski, T. Angew. Chem., Int. Ed. 2004, 43, 788–824.
doi:10.1002/anie.200300599
11.Belokon, Y. N.; Caveda-Cepas, S.; Green, B.; Ikonnikov, N. S.;
Khrustalev, V. N.; Larichev, V. S.; Moscalenko, M. A.; North, M.;
Orizu, C.; Tararov, V. I.; Tasinazzo, M.; Timofeeva, G. I.;
Yashkina, L. V. J. Am. Chem. Soc. 1999, 121, 3968–3973.
doi:10.1021/ja984197v
12.Belokon, Y. N.; Gutnov, A. V.; Moskalenko, M. A.; Yashkina, L. V.;
Lesovoy, D. E.; Ikonnikov, N. S.; Larichev, V. S.; North, M.
Chem. Commun. 2002, 244–245. doi:10.1039/b110335k
13.Belokon, Y. N.; Carta, P.; Gutnov, A. V.; Maleev, V.;
Moskalenko, M. A.; Yashkina, L. V.; Ikonnikov, N. S.;
Voskoboev, N. V.; Khrustalev, V. N.; North, M. Helv. Chim. Acta 2002,
85, 3301–3312.
doi:10.1002/1522-2675(200210)85:10<3301::AID-HLCA3301>3.0.CO;
2-2
14.Belokon, Y. N.; Carta, P.; North, M. Lett. Org. Chem. 2004, 1, 81–83.
doi:10.2174/1570178043488617
Supporting Information
15.Belokon, Y. N.; Blacker, A. J.; Carta, P.; Clutterbuck, L. A.; North, M.
Tetrahedron 2004, 60, 10433–10447. doi:10.1016/j.tet.2004.07.098
16.Belokon, Y. N.; Blacker, A. J.; Clutterbuck, L. A.; North, M. Org. Lett.
2003, 5, 4505–4507. doi:10.1021/ol035828f
Chiral GC traces for all chiral cyanohydrin acetates and
chiral HPLC data for methyl mandelate. NMR spectra of
cyanohydrins in the presence of mandelic acid.
Additionally, all of the kinetic data used to determine the
catalyst order, the activation parameters and construct the
Hammett plot are given.
17.Belokon, Y. N.; Ishibashi, E.; Nomura, H.; North, M. Chem. Commun.
2006, 1775–1777. doi:10.1039/b602156e
18.Lundgren, S.; Wingstrand, E.; Penhoat, M.; Moberg, C.
J. Am. Chem. Soc. 2005, 127, 11592–11593. doi:10.1021/ja052804q
19.Wingstrand, E.; Lundgren, S.; Penhoat, M.; Moberg, C.
Pure Appl. Chem. 2006, 78, 409–414. doi:10.1351/pac200678020409
20.Belokon, Y. N.; Clegg, W.; Harrington, R. W.; Ishibashi, E.; Nomura, H.;
North, M. Tetrahedron 2007, 63, 9724–9740.
Supporting Information File 1
Analytical data for all chiral compounds.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-6-119-S1.pdf]
doi:10.1016/j.tet.2007.07.016
21.Lundgren, S.; Wingstrand, E.; Moberg, C. Adv. Synth. Catal. 2007,
349, 364–372. doi:10.1002/adsc.200600365
22.Belokon, Y. N.; Green, B.; Ikonnikov, N. S.; North, M.; Tararov, V. I.
Tetrahedron Lett. 1999, 40, 8147–8150.
Acknowledgements
The authors thank the EPSRC physical organic chemistry initia-
doi:10.1016/S0040-4039(99)01677-9
23.Belokon, Y. N.; Green, B.; Ikonnikov, N. S.; North, M.; Parsons, T.;
Tararov, V. I. Tetrahedron 2001, 57, 771–779.
tive for financial support and a studentship (to MOP).
doi:10.1016/S0040-4020(00)01053-X
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