Kinetics and mechanism of base catalysed ethyl cyanoformate addition to aldehydes Dedicated to the memory of Professor Sandy McKillop

Article abstract of DOI:10.1016/j.tet.2014.02.009

The mechanism by which tertiary amines catalyse the formation of cyanohydrin carbonates from aldehydes and alkyl cyanoformates is investigated by means of a kinetic study. The reaction rate shows a second order dependence on amine concentration unless the

Full text of DOI:10.1016/j.tet.2014.02.009

Tetrahedron xxx (2014) 1e6
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Kinetics and mechanism of base catalysed ethyl cyanoformate
addition to aldehydes
Michael North ,*, Stephanie Urwin b
a,b
a
Green Chemistry Centre of Excellence, Department of Chemistry, The University of York, Heslington, York YO10 5DD, UK
School of Chemistry, Newcastle University, Newcastle upon Tyne NE1 7RU, UK
b
a r t i c l e i n f o
a b s t r a c t
Article history:
The mechanism by which tertiary amines catalyse the formation of cyanohydrin carbonates from alde-
hydes and alkyl cyanoformates is investigated by means of a kinetic study. The reaction rate shows
a second order dependence on amine concentration unless the amine is sterically hindered, when the
rate has a first order dependence on amine concentration. The catalytic activity of the amine correlated
with its pKaH. On the basis of these results, a mechanism is proposed in which the amine acts as a base to
activate a water molecule, which reacts with the ethyl cyanoformate generating cyanide in situ.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 2 January 2014
Received in revised form 2 February 2014
Accepted 4 February 2014
Available online xxx
Dedicated to the memory of Professor Sandy
McKillop
Keywords:
Cyanohydrin
Ethyl cyanoformate
Base
Catalysis
Kinetics
1. Introduction
and Denmark and Chung had studied the use of various amines
and phosphines as Lewis base catalysts for the reaction between
6
The base catalysed addition of cyanide to aldehydes to form
a cyanohydrin was one of the first reactions to be mechanistically
studied1 and is still an important carbonecarbon bond forming
aldehydes and trimethylsilyl cyanide. Therefore, we initiated
a project to investigate the mechanism of cyanohydrin formation
using various cyanide sources and have previously reported our
results on the Lewis base catalysed addition of trimethylsilyl cya-
2
reaction for organic synthesis. Although cyanide salts are still used
3
15
in cyanohydrin synthesis, other cyanide sources such as trime-
nide to aldehydes.
4
e7
7,8
thylsilyl cyanide,
ethyl cyanoformate, diethyl cyanophospho-
Cyanoformates such as ethyl cyanoformate 1 are also good
cyanating agents and react with aldehydes and ketones to form
cyanohydrin carbonates (Scheme 1). This reaction does not occur
spontaneously, but has been shown to be catalysed by homoge-
neous catalysts including: triethylamine 2,
amines, triarylphosphines, DMSO, N-heterocyclic carbenes,
nates and acyl cyanides7,10 are now often preferred to avoid side
reactions,11 render cyanohydrin synthesis irreversible and directly
produce protected cyanohydrins. Another advantage of these cya-
nide sources is that they permit the asymmetric synthesis of cya-
nohydrin derivatives.1 We have previously developed metal(salen)
complexes as highly effective catalysts for asymmetric cyanohydrin
synthesis13 and have also studied the mechanism of asymmetric
cyanohydrin synthesis using trimethylsilyl cyanide as the cyanide
source.14 During this work, we realised that very little work had
been reported on the mechanism of racemic cyanohydrin synthesis
using cyanide sources other than alkali metal cyanides. Thus,
Umani-Ronchi and co-workers had studied the indium tribromide
7,9
16,17
8e,f
DMAP, secondary
2
18
4k
19
20
8
d
8a
ionic liquids, 1-methoxy-2-methyl-1-(trimethylsiloxy)propene
10c
ꢀ
8b,c
and tributyltin cyanide.
Heterogeneous catalysts including 4 A
21
molecular sieves and silica-alumina supported tertiary amines
have also been used. These compounds are, or are sources of, Lewis
basic, nucleophilic catalysts, and therefore, where the authors have
8
bef,19,20
proposed a mechanism for the reaction
in the absence of
any mechanistic evidence, this has generally been of the form
shown in Scheme 2. In this mechanism, the nucleophilic catalyst
reacts with the cyanoformate to form a cyanide ion. The cyanide
then reacts with the carbonyl compound to form a cyanohydrin
alkoxide, which reacts with the nucleophileeformate adduct to
form the cyanohydrin carbonate and regenerate the nucleophile.
5
catalysed reactions between ketones and trimethylsilyl cyanide,
*
Corresponding author. Tel.: þ44 1904 324 545; fax: þ44 1904 322 705; e-mail
address: michael.north@york.ac.uk (M. North).
0
040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.02.009
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M. North, S. Urwin / Tetrahedron xxx (2014) 1e6
Scheme 1. Synthesis of cyanohydrin ethyl carbonates.
Scheme 4. Reaction used for kinetic studies.
This result is consistent with either mechanism shown in
Schemes 2 and 3 since although thiocyanate is a very good nucle-
ophile, it is a very soft nucleophile and so will not readily react with
a hard electrophile such as a carbonyl group as required by the
mechanism shown in Scheme 2. In addition, thiocyanic acid (HSCN)
2
3
has a pK
would not deprotonate hydrogen cyanide (pK
required by the mechanism shown in Scheme 3.
a
(in water) of ꢁ1.1, so thiocyanate is a very weak base and
24
a
9.0 in water ) as
It was also not possible to monitor reactions catalysed by tet-
rabutylammonium cyanide 4. Reactions carried out with 5 mol % or
Scheme 2. Lewis-base catalysed mechanism proposed for cyanohydrin carbonate
synthesis.
1
mol % of catalyst 4 proceeded very rapidly and were complete in
The one exception is Najera et al.17 who on the basis of DFT calcu-
less than 1 min when [5] ¼0.45 M and [1] ¼0.49 M. In contrast,
0
0
2
2
lations on a related asymmetric process proposed the mechanism
shown in Scheme 3 for the triethylamine catalysed addition of
cyanoformates to carbonyl compounds. In this mechanism, the
triethylamine acts as a Brønsted-base catalyst for the addition of
hydrogen cyanide to the carbonyl compound. It is proposed that
reactions carried out with 0.75 mol % or 0.5 mol % of catalyst 4 were
very slow and did not give reliable kinetic data. It was noticed that
a solution of tetrabutylammonium cyanide in dichloromethane was
not stable, changing from a colourless to brown colour over a period
of 24 h. This may explain why the reactions with less than 1 mol % of
catalyst 4 gave poor kinetic data. It is not surprising that higher
concentrations of tetrabutylammonium cyanide gave extremely
fast kinetics as the mechanisms shown in both Schemes 2 and 3 rely
upon the in situ formation of cyanide to attack the aldehyde and
catalyst 4 provides a higher concentration of this nucleophile.
In contrast to the systems catalysed by tetrabutylammonium
salts, reactions catalysed by triethylamine 2 were kinetically well-
behaved and could be analysed by UV spectrophotometry, moni-
17
traces of hydrogen cyanide are present in the cyanating agent and
that subsequent reaction of the initially formed cyanohydrin with
the cyanoformate forms the cyanohydrin carbonate and re-
generates the hydrogen cyanide. In view of the lack of experimental
evidence as to the mechanism of base catalysed cyanohydrin car-
bonate synthesis we decided to carry out a kinetic study of the
reaction to distinguish between the proposed mechanisms and in
this paper we report the results of this study.
toring the disappearance of the benzaldehyde carbonyl absorption
ꢀ
at 246 nm. A reaction carried out at 0 C with [5]
0
¼0.45 M,
[1]
0
¼0.49 M and using 5 mol % of triethylamine went to completion
in 2.5 h. It was observed that reactions catalysed by triethylamine
had an induction period of about 20 min as shown in Fig. 1. Once
this induction period was over, the reaction showed a good fit to
first order kinetics (Fig. 2).
Scheme 3. Brønsted-base catalysed mechanism proposed for cyanohydrin carbonate
synthesis.
2
. Results and discussion
Initially, we selected triethylamine 2, tetrabutylammonium
thiocyanate 3 and tetrabutylammonium cyanide 4 as catalysts for
ꢀ
the addition of ethyl cyanoformate 1 to benzaldehyde 5 at 0 C in
dichloromethane (Scheme 4) as these catalysts, aldehyde and sol-
vent were used in our previous work on the mechanism of trime-
thylsilyl cyanide addition to aldehydes.15 Tetrabutylammonium
thiocyanate 3 was the most effective catalyst for the addition of
trimethylsilyl cyanide to benzaldehyde, so this catalyst was studied
Fig. 1. Reaction profile versus time plot for the conversion of benzaldehyde and ethyl
cyanoformate into 6 catalysed by Et N.
3
first. However, when 0.5 mol
%
of
3
was employed with
To determine the order with respect to substrates 1 and 5, re-
actions were carried out at three concentrations of each substrate
whilst keeping all other reactant concentrations constant. The re-
sults shown in Figs. 3 and 4 clearly show that the reaction rate does
not depend on benzaldehyde concentration (Fig. 3), but does in-
crease as the initial concentration of ethyl cyanoformate increases
(Fig. 4). Thus, the reaction follows a rate equation of the form:
rate¼kobs[EtOCOCN].
[
0
5]
0
¼0.45 M and [1]
0
¼0.49 M, no reaction occurred after 2.5 h at
ꢀ
C or even after 18 h at room temperature. Even when the catalyst
loading was increased to 5 mol %, only 8% conversion of benzal-
dehyde into cyanohydrin ethyl carbonate 6 was observed after
ꢀ
a reaction time of 2.5 h at 0 C. Thus it was apparent that tetra-
butylammonium thiocyanate was not an effective catalyst for the
addition of ethyl cyanoformates to benzaldehyde.
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M. North, S. Urwin / Tetrahedron xxx (2014) 1e6
3
Fig. 5. Plot of log(kobs) versus log[Et
benzaldehyde. [1]
¼0.54 M; [5]
5.0 mM.
3
N] for the addition of ethyl cyanoformate to
¼0.49 M; [2]¼11.2 mM, 22.5 mM, 33.8 mM and
Fig. 2. First order kinetics plot for the conversion of benzaldehyde and ethyl-
cyanoformate into 6 catalysed by Et N. The best fit line is based only on the filled data
points. Empty data points correspond to the induction period.
0
0
3
4
(Fig. 6), which gave a linear correlation with a best fit line passing
through the origin. Thus, the triethylamine catalysed addition of
ethyl cyanoformate to benzaldehyde was found to follow the rate
2
equation: rate¼0.5[Et
3
N] [EtOCOCN].
Fig. 3. Dependence of reaction rate on [PhCHO]
0
. [1]
0
¼0.54 M; [2]¼24.5 mM. Empty
triangles [5] ¼0.49 M, empty squares [5]
0
¼0.25 M, filled diamonds [5]
0
0
¼0.98 M.
Fig. 6. Plot of kobs versus [Et
hyde. [1] ¼0.49 M; [2]¼11.2 mM, 22.5 mM, 33.8 mM and 45.0 mM.
¼0.54 M; [5]
N]2 for the addition of ethyl cyanoformate to benzalde-
3
0
0
The second order dependence of the reaction rate on triethyl-
amine concentration implies that two triethylamine molecules are
involved in the catalytic cycle before or during the rate determining
step of the mechanism. This is not consistent with the mechanism
shown in Scheme 2 or Scheme 3. Second order catalysis involving
2
5
amine bases is well established and usually implies that the base
is acting as a general base rather than a specific base catalyst, i.e.,
2
6
that the reaction mechanism involves proton transfer.
In order to investigate the relative importance of Brønsted and
Lewis base catalysis, three other tertiary amines 7e9 were used as
catalysts. The four tertiary amine bases (2, 7e9) differ in both the
steric hindrance around the nitrogen lone pair (9<7<2<8) and in
their pKaH values (9 (10.12)<8 (10.50)<7 (10.54)<2 (10.71)). Re-
actions catalysed by amines 7e9 were all kinetically well-behaved
and followed overall first order kinetics after an induction period.
Fig. 7 compares the rates of reactions carried out using 5 mol % of
each amine catalyst.
Fig. 4. Dependence of reaction rate on [EtOCOCN]
0
. [5]
0
¼0.49 M; [2]¼24.5 mM. Empty
¼1.08 M.
triangles [1] ¼0.54 M, empty squares [1]
0
¼0.27 M, filled diamonds [1]
0
0
2
7
The concentration of triethylamine does not change during the
reactions and its influence on the reaction rate is incorporated
x
within the observed rate constant (kobs¼k[Et
3
N] so log(kobs)¼
log(k)þx log[Et
3
N]). Therefore, to determine the order with respect
to triethylamine concentration, reactions were carried out at four
It is apparent from Fig. 7 that the rates of reactions catalysed by
bases 2, 7e9 are not determined by the steric nature of the amine.
Thus, triethylamine gives the fastest reaction rates even though
amines 7 and 9 are both less hindered. Indeed, the least hindered
amine, ethyldimethylamine 9 gives the slowest reaction rate, two
orders of magnitude slower than reactions catalysed by triethyl-
amine. In addition, Hunigs base (ethyldiisopropylamine, 8), which
different triethylamine concentrations and log(kobs) plotted against
log[Et N]. These reactions were all carried out in duplicate with the
3
average of the two observed rate constants being used to provide
the data point and the individual experiments being used to pro-
vide error bars. The resulting log/log plot is shown in Fig. 5 and the
best fit line through the data points had a slope of 1.75ꢂ0.13,
suggesting that the reaction might have a fractional or second order
dependence on triethylamine concentration. The latter (i.e., that
2
8
is known to have low nucleophilicity gives the second fastest
reaction rate. In contrast, there is a good correlation between the
pKaH of the base and its effectiveness as a catalyst. Thus,
2
2
k
obs¼k[Et
3 3
N] ) was confirmed by a plot of kobs versus [Et N]
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4
M. North, S. Urwin / Tetrahedron xxx (2014) 1e6
Fig. 7. First order kinetic plot comparing the use of tertiary amines 2, 7e9 as catalysts
ꢀ
for the addition of ethyl cyanoformate to benzaldehyde at 0 C in CH
2
Cl
2
. [1]
0
¼0.54 M;
[
5]
0
¼0.49 M; [7e9]¼24.5 mM. Filled circles¼9, empty triangles¼7, filled diamonds¼8,
Fig. 9. Plot of kobs versus [8] for the addition of ethyl cyanoformate to benzaldehyde.
[1] ¼0.49 M; [8]¼22.5 mM, 45.0 mM, 67.5 mM and 90.0 mM.
¼0.54 M; [5]
empty squares¼2.
0
0
triethylamine has the highest pKaH and is the most effective cata-
lyst, whilst ethyldimethylamine is the least effective catalyst and
has the lowest pKaH. The other two bases (7 and 8) have virtually
identical pKaH values and catalyse the reaction with virtually
identical rates. This correlation between the pKaH of the base and its
catalytic activity is consistent with the mechanism shown in
Scheme 3, but not with that shown in Scheme 2.
To further investigate the influence of the tertiary amine
structure on the catalytic activity of the base, the order with respect
to catalyst was determined for each of amines 7e9 by carrying out
reactions in duplicate at four different concentrations of the amine.
mechanism are invisible to kinetics, but the in situ generated cya-
nide can react with benzaldehyde 5 to form a cyanohydrin alkoxide,
which would be rapidly protonated by the ammonium ion to form
a free cyanohydrin 10. The cyanohydrin then reacts with ethyl
cyanoformate (or an equivalent ethyl formate source generated
in situ from ethyl cyanoformate) to form cyanohydrin ethyl
carbonate 6.
In the case of diethylmethylamine 7, the resulting plot of log(kobs
)
2
against log[7] had a slope of 1.8 and a plot of kobs versus [7] (Fig. 8)
confirmed that the reaction was again second order in base con-
centration. However, for diisopropylethylamine 8, the plot of log(-
kobs) against log[8] had a slope of 0.9 suggesting that the reaction
was first order in catalyst concentration and this was confirmed by
a plot of kobs against [8] (Fig. 9). It was not possible to determine the
order with respect to catalyst for reactions catalysed by dimethy-
lethylamine 9 as the reactions were so slow (Fig. 7) that the con-
version of aldehyde 5 into cyanohydrin derivative 6 was too low to
give meaningful kinetic profiles when using 5e25 mol % of 9.
Scheme 5. Catalytic cycle consistent with the kinetic results.
This mechanism is essentially an amalgamation of the pre-
viously proposed mechanisms in Schemes 2 and 3. Thus it follows
the catalytic cycle shown in Scheme 2 with amine activated water
as the nucleophile except that it is the cyanohydrin rather than the
cyanohydrin alkoxide, which reacts with ethyl cyanoformate as
proposed in Scheme 3. The importance of the tertiary amine acting
as a Brønsted-base in the rate determining step explains the rela-
tive catalytic activity of amines 2, 7e9 (Fig. 7). The very low cata-
lytic activity associated with the use of tetrabutylammonium
thiocyanate 3 and very rapid catalysis found when using tetrabu-
tylammonium cyanide 4 are also consistent with the mechanism
shown in Scheme 5.
Fig. 8. Plot of kobs versus [7]2 for the addition of ethyl cyanoformate to benzaldehyde.
[
1]
0
¼0.54 M; [5] ¼0.49 M; [7]¼22.5 mM, 45.0 mM, 67.5 mM and 90 mM.
0
The above data suggest that the addition of ethyl cyanoformate
to benzaldehyde 5 catalysed by amines 2, 7e9 follows the
1
mechanism shown in Scheme 5. Thus, ethyl cyanoformate is first
hydrolysed by adventitious water to generate cyanide. The role of
the amine is to act as a Brønsted-base, hydrogen bonding to the
water to increase its nucleophilicity. For small bases, two amines
are involved in activating the water, but for sterically hindered
Hunigs base only one amine is involved in the water activation. The
kinetics suggest that this is the rate determining step of the
mechanism as it involves ethyl cyanoformate and either one or two
amines, but not the aldehyde. All subsequent steps of the
3. Conclusions
The mechanism by which tertiary amines catalyse the addition
of alkyl cyanoformate to aldehydes is more complex than pre-
viously suggested and involves the amine acting as a Brønsted-base
to activate water to undergo nucleophilic attack on the alkyl cya-
noformate. This results in a correlation between the pKaH of the
amine and its catalytic activity. Either one or two molecules of
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M. North, S. Urwin / Tetrahedron xxx (2014) 1e6
5
amine may be involved in activating the water depending on how
sterically hindered the amine is. Thus, the search for more highly
active catalysts for this reaction should focus on those tertiary
amines and related species such as amidines and guanines, which
have high pKaH values.
according to the estimated rate of reaction, and quenched into
CH Cl (3.5 mL) and the UV absorbance at 246 nm was measured to
determine the amount of PhCHO remaining in the reaction. A re-
action mixture, which had gone to completion (2 mol % Bu NCN as
catalyst) was worked up to allow compound 6 to be isolated. The
reaction mixture was transferred to a separating funnel and
washed with water (10 mL). The organic layer was extracted with
2
2
4
The mechanistic results obtained in this study for racemic cya-
nohydrin carbonate synthesis may also be relevant to the ongoing
development of catalysts for the asymmetric addition of cyano-
additional CH
2 2 2 4
Cl , dried (Na SO ) and the solvent removed in vacuo
12
formates to aldehydes and ketones. This reaction is known to be
to leave compound 6 as a yellow oil whose spectroscopic data were
1
2
12,29
8
catalysed by Lewis acids, bases
and bifunctional compounds
consistent with those reported in the literature.
CDC1 ) 1.36 (3H, t J 7.2 Hz, CH ), 4.26e4.36 (2H, m, CH
CH), 7.47e7.57 (5H, m, ArH); (75 MHz CDC1 ); 14.0, 65.5, 66.5,
d
H
(300 MHz
), 6.29 (1H, s,
12
possessing both Lewis acidic and basic sites. If the mechanism
3
3
d
2
2
2
shown in Scheme 5 holds true for asymmetric reactions, then it is
significant that the asymmetry forming step involves the addition
of free cyanide to the carbonyl compound and does not directly
involve the (protonated) chiral amine. For Lewis acid catalysed
reactions, coordination of the carbonyl compound to the Lewis acid
provides an asymmetric environment for this reaction and it is
C
3
115.6, 127.7, 129.2, 130.4, 131.6, 153.41.
References and notes
3
0
known that alkali metal cyanides act as cocatalysts in this case.
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1
2
The role of the cyanide cocatalyst is simply to provide an alterna-
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2
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cemic cyanohydrin.2
2,29
Our results suggest, however, that the
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4
. Experimental section
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4
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B 1
mL microsyringes. UV measurements were performed on a Bio-
1
chrom Libra S12 spectrometer using 10 mm quartz cuvettes. H and
13
C NMR spectra were recorded on a Bruker Avance 300 spec-
trometer at 300 and 75 MHz, respectively. All spectra were recor-
ded at room temperature, referenced to TMS and chemical-shift (
5
6
d)
values, expressed in parts per million (ppm), are reported down-
1
field of TMS. The multiplicity of H NMR signals is reported as
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singlet (s), triplet (t) or multiplet (m).
8
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4
.2. General method for kinetic experiments on the synthesis
of O-ethoxycarbonyl-2-hydroxy-2-phenylacetonitrile 6
All kinetic experiments were carried out in duplicate. A stock
solution of each catalyst (2e4, 7e9) in CH
which 1.8 mL of the solution contained 0.9 mmol of catalyst. A
0 mL round bottom flask was fitted with a stirrer bar and sealed
2 2
Cl was prepared in
9
1
990, 607e610; (b) Yoneda, R.; Harusawa, S.; Kurihara, T. J. Org. Chem. 1991, 56,
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ꢀ
with a subaseal, then cooled to 0 C. The appropriate amount of
catalyst stock solution and additional CH Cl were added via a sy-
ringe to give a volume of 1.8 mL. A sample (0.5 L) was then taken
and quenched into CH Cl (3.5 mL) to give a reference sample for
UV measurements. PhCHO (0.1 mL, 95 mg, 0.90 mmol) was then
added to the solution and another sample (0.5 L) taken and
quenched into CH Cl (3.5 mL) to provide an initial concentration
2
2
1
0. (a) Marvel, C. S.; Brace, N. O.; Miller, F. A.; Johnson, A. R. J. Am. Chem. Soc. 1949,
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2. (a) North, M.; Usanov, D. L.; Young, C. Chem. Rev. 2008, 108, 5146e5226; (b)
m
2
2
2
1
measurement. EtOCOCN (0.1 mL, 98 mg, 0.99 mmol) was then
added so that the total reaction volume was 2.0 mL and a timer
Khan, N. H.; Kureshy, R. I.; Abdi, S. H. R.; Agrawal, S.; Jasra, R. V. Coord. Chem.
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started. Aliquots (0.5
mL) were taken at appropriate intervals
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6
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Please cite this article in press as: North, M.; Urwin, S., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.02.009