Optical methyl 2-chloropropionate synthesis by decomposition of methyl 2-(chlorocarbonyloxy)propionate with hexaalkylguanidinium chloride hydrochloride

Article abstract of DOI:10.1016/S0040-4020(02)00797-4

The decomposition of methyl S-(-)-2-(chlorocarbonyloxy)propionate in the presence of hexaalkylguanidinium chloride hydrochloride was confirmed to correspond to a nucleophilic substitution of the second order. However, racemization occured by the contact between the catalyst and methyl R-(+)-2-chloropropionate (I). This phenomenon is caused by the exchange between the chloride ion from catalyst and the chlorine atom of (I) according to a SN₂ mechanism as well.

Full text of DOI:10.1016/S0040-4020(02)00797-4

Tetrahedron 58 (2002) 8607–8612
Optical methyl 2-chloropropionate synthesis by decomposition
of methyl 2-(chlorocarbonyloxy)propionate with
hexaalkylguanidinium chloride hydrochloride
a
Frederic Violleau, Sophie Thiebaud-Roux, Elisabeth Borredon and Pierre Le Gars
a
a
b
,
*
´ ´
´
aLaboratoire de Chimie Agro-industrielle, UMR 31010 INRA/INP-ENCIACET, 118 route de Narbonne, 31077 Toulouse Cedex 4, France
bSNPE-Toulouse, Chemin de la loge, 31078 Toulouse Cedex, France
Received 11 February 2002; revised 7 June 2002; accepted 28 June 2002
Abstract—The decomposition of methyl S-(2)-2-(chlorocarbonyloxy)propionate in the presence of hexaalkylguanidinium chloride
hydrochloride was confirmed to correspond to a nucleophilic substitution of the second order. However, racemization occured by the contact
between the catalyst and methyl R-(þ)-2-chloropropionate (I). This phenomenon is caused by the exchange between the chloride ion from
catalyst and the chlorine atom of (I) according to a SN2 mechanism as well. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
nucleophilic substitution (SN1) or to an intramolecular
nucleophilic substitution (SNi)
The alkyl 2-chloropropionates are the subject of many
publications and patents describing their applications. For
example, these compounds are generally used in the
preparation of biological active molecules such as herbi-
cides,1,2 fungicides,3 pesticides4,5 and drugs.6,7
In the SN1 case (Scheme 1), the intermediate carbocation
can be rearranged in a more stable ion by hydrogen
transposition and lead to the formation of a chlorinated
isomer.
Generally, optically active alkyl 2-chloropropionates are
usually synthesized by direct chlorination of the corre-
sponding lactates using chlorinating agents such as hydro-
gen chloride,8 sulphuryl chloride,9 thionyl chloride10,11 and
phosgene.12 They can also be prepared by decomposition of
chlorosulfinates13–17 and chloroformates.18 Among the
latter, chloroformates seem to be more convenient since
their decomposition is accompanied by carbon dioxide
release, which is less toxic than sulphur dioxide.
In the SNi case (Scheme 2), rearrangement occurs inside the
molecule. This mechanism was also described in the
chlorosulphite decomposition.20,21
On the contrary, in the presence of catalyst, the reaction
mechanism described in the literature follows a SN2
reaction. This results in a configuration inversion of the
concerned asymmetrical carbons. For example, with
The chloroformate decomposition follows different mecha-
nisms depending on the presence of catalyst.
Without catalyst, according to Hegarty,19 the chloroformate
thermal decomposition corresponds either to a first order
Scheme 2.
Scheme 1.
Keywords: chloroformates; alkyl 2-chloropropionate; hexaalkylguanidinium chloride; optical; racemization; mechanism.
*
Corresponding author. Tel.: þ33-5-62-88-57-19; fax: þ33-5-62-88-57-30; e-mail: sthiebaud@ensct.fr
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)00797-4

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F. Violleau et al. / Tetrahedron 58 (2002) 8607–8612
Scheme 3.
pyridine,18,19 chloroformate is transformed into pyridinium
chloride (Scheme 3).
Preliminary experiments using the experimental conditions
described in litterature27 were realized. Instead of obtaining
an optical pure compound, we found partially racemised
methyl 2-chloropropionate. The purpose of this work
was to verify the SN2 reaction mechanism. The conversion
rate of methyl S-(2)-2-(chlorocarbonyloxy)propionate
and the enantiomeric composition of the product were
The chloride ion attacks the asymmetrical carbon and
causes the decarboxylation of the salt. Then the alkyl
chloride is obtained with inversion of configuration
(Scheme 4).
Scheme 4.
The same mechanism is followed when QþCl2 compounds
such as pyridine hydrochloride,22,23 ammonium24,25 or
guanidinium chlorides26–28 are used as catalysts. The
chloride ion of catalyst is thus fixed (Scheme 5).
studied. We proposed an explanation to the racemization
phenomenon.
Scheme 5.
We tried to synthesize methyl R-(þ)-2-chloropropionate
by decomposition of methyl S-(2)-2-(chlorocarbonyloxy)-
propionate by using a QþCl2 catalyst, i.e., hexaalkyl-
guanidinium chloride hydrochloride (Scheme 6).
2. Results and discussion
We employed similar experimental conditions than these
described by Foulon’s et al.27 for the decomposition of
(S)-2-octyl chloroformate. According to these authors,
chloroformate is totally decomposed into (R)-2-chloro-
octane with a 96% of enantiomeric excess within 10 h at
808C without solvent, in the presence of 0.5 mol% of
hexabutylguanidinium chloride (HBGC). This catalyst is
considered more efficient than pyridine, tetrabutylphos-
phonium and tetrabutylammonium chlorides.26,27
The decomposition of methyl S-(2)-2-(chlorocarbonyl-
oxy)propionate in the presence of 0.5 mol% of hexabutyl-
guanidinium chloride hydrochloride (HBGC·HCl) with
Scheme 6.
Figure 1. Influence of the temperature on the decomposition of methyl S-(2)-2-(chlorocarbonyloxy)propionate in the presence of 0.5 or 1% of HBGC·HCl.

F. Violleau et al. / Tetrahedron 58 (2002) 8607–8612
8609
Figure 2. Influence of the reaction temperature on the R enantiomeric content of methyl 2-chloropropionate in the presence of 0.5 or 1% of HBGC·HCl.
Foulon’s conditions led to the total conversion into methyl
2-chloropropionate with a 76% of R enantiomer content
after 5 h and 54% after 10 h of reaction.
related to the competition between the mechanisms SN2
(catalytic decomposition) and SN1 or SNi (thermal
decomposition) as described by Foulon27 in her work on
S-(þ)-2-octyl chloroformate at 808C in the presence of 0.5%
of hexabutylguanidinium chloride attributed to the presence
of S-(þ)-2-chlorooctane.
The racemization phenomenon can be probably due to the
nature of the substrate or catalyst which both were different
from Foulon’s experiment. We can however expect the
substrate to be the responsible. Indeed, Bochard26 used
the same catalyst (HBGC) for the decomposition of ethyl
S-(2)-2-(chlorocarbonyloxy)propionate and also observed
the racemization phenomenon.
Scheme 7.
In order to explain the mechanism of racemization, we have
studied the influence of temperature and catalyst concen-
tration on the conversion rate of methyl S-(2)-2-(chloro-
carbonyloxy)propionate (Fig. 1) and on its enantiomeric
composition (Fig. 2).
The phenomenon of racemization (Scheme 8) would rather
occur after the formation of the R isomer and not during the
decomposition of the chloroformate (Scheme 7):
first, there would be the catalytic decomposition of
methyl S-(2)-(2-chlorocarbonyloxy)propionate (Scheme
7) and
According to Fig. 1, the decomposition rate of methyl
S-(2)-2-(chlorocarbonyloxy)propionate decreases with
temperature. Similarly, the racemization phenomenon is
less important at low temperature (Fig. 2). The racemization
of methyl R-(þ)-2-chloropropionate was decreased by
limiting the quantity of catalyst, especially at 808C, but
racemization was not eliminated. At 708C, on the other
hand, decomposition yield is only 50% but the product
obtained was not racemized. The optical purity did not
vary when changing the quantity of catalyst.
Scheme 8.
then the racemization of methyl R-(þ)-2-chloropropio-
nate (Scheme 8)
Such tests did not permit to obtain, at the same time, methyl
R-(þ)-2-chloropropionate with high yield and optical high
purity. We tried to explain this phenomenon by studying the
concerned reaction mechanisms.
In order to determine the exact role played by catalyst
during this racemization and to check more precisely
whether the chlorine atom of the latter plays a role in the
If the decomposition of methyl S-(2)-2-(chlorocarbonyl-
oxy)propionate had followed a SNi mechanism, we mainly
should have obtained methyl S-(2)-2-chloropropionate.
Moreover, the high percentage of R isomer at the beginning
of the decomposition confirms, for that reason, the SN2
mechanism.
This assessment is confirmed by the fact that the thermal
degradation of methyl S-(2)-2-(chlorocarbonyloxy)propio-
nate starts at 1358C as showed by thermogravimetric
analysis. Consequently, in our conditions (70–908C), only
the catalytic degradation of methyl S-(2)-2-(chlorocarbo-
nyloxy)propionate by nucleophilic substitution of SN2
type can take place. The presence of the two enantiomers
R and S at the end of the synthesis does not seem to be
Figure 3. Evolution of the methyl 2-bromopropionate formation from methyl
R-(þ)-2-chloropropionate in the presence of 5% of Br2NþBzEt3 at 908C.

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F. Violleau et al. / Tetrahedron 58 (2002) 8607–8612
Scheme 9.
Figure 4. Evolution of the R-(þ)- and S-(2)-methyl 2-bromopropionate enantiomers content during the contact with 5% of Br2NþBzEt3 and methyl R-(þ)-2-
chloropropionate at 908C.
inversion of configuration, the reaction between methyl
R-(þ)-2-chloropropionate (%R¼94%) with a bromide
onium instead of the chloride onium was made. The
selected catalyst was benzyltriethylammonium bromide
(Br2NþBzEt3). We intentionally added 5 mol% in the
solution of methyl R-(þ)-2-chloropropionate to favor
racemization. After a 30 min contact at 908C, we
detected by GC the presence of 2.5% w/w of methyl
bromopropionate.
The benzyltriethylammonium chloride is formed by reac-
tion of benzyltriethylammonium bromide and methyl
R-(þ)-2-chloropropionate (reaction 3). It is also the
responsible for the methyl S-(2)-2-chloropropionate
presence in the reaction medium (Fig. 5) by reaction
of chloride ion with methyl R-(þ)-2-chloropropionate
according to a SN2 mechanism (reaction 5).
In the same way, the significant reduction in the R
enantiomer content of the methyl 2-chloropropionate (Fig.
5) can be allotted to a reaction between methyl R-(þ)-2-
chloropropionate and benzyltriethylammonium chloride to
give methyl S-(2)-2-chloropropionate according to a
mechanism SN2 (Scheme 11).
This quantity remained stable along the reaction time
(Fig. 3). The presence of this brominated compound
confirmed that the catalyst halide ion was the responsible
for the configuration inversion through a SN2 mechanism.
The brominated compound is then transformed into
benzyltriethylammonium chloride (Scheme 9). At the end
of reaction, it was obtained not only methyl S-(2)-2-
bromopropionate, but also its R isomer (Fig. 4). This means
that the brominated catalyst reacts with the chlorinated
initial derivative but also with the S isomer of the
brominated derivative as well (Scheme 10).
We have thus highlighted that the racemization of the
chlorinated derivative occurred after the formation of the
latter and was related to the attack of catalyst halide ion
according to a mechanism SN2.
In order to increase the enantiomeric excess of methyl
Scheme 10.
Figure 5. Evolution of the R-(þ)- and S-(2)-methyl 2-chloropropionate enantiomers content during the contact with 5% of Br2NþBzEt3 and methyl R-(þ)-2-
chloropropionate at 908C.

F. Violleau et al. / Tetrahedron 58 (2002) 8607–8612
8611
Scheme 11.
Figure 6. Temperature influence on the decomposition of methyl S-(2)-2-(chlorocarbonyloxy)propionate in the presence of 1% of HMGC·HCl.
R-(þ)-2-chloropropionate during the decomposition of
methyl S-(2)-2-(chlorocarbonyloxy)propionate, the hexa-
methylguanidinium chloride hydrochloride (HMGC·HCl)
as catalyst (Figs. 6 and 7) was used. The nucleophilicity
of this chloride ion is less important than that of the
HBGC·HCl. Indeed, the steric hindrance generated by the
methyl substituents over the nitrogen atoms is less important
than that generated by the butyl one. So the distance
between chlorine atom and the cationic center is smaller in
HMGC·HCl than in HBGC·HCl which increases the
interaction between the two ions. The results obtained are
in conformity with our expectations. The racemization
phenomenon is diminished. The decomposition rate of the
chloroformate was decreased as well.
phenomenon observed is due to contact between the catalyst
and the methyl R-(þ)-chloropropionate during the synthesis
by the exchange between chloride ion of the catalyst and
chlorine atom of final molecule according to a SN2
mechanism. In order to limit this racemization with
preservation at the same time of a high yield of
chloroformate decomposition, it will be necessary to isolate
the chlorinated product progressively during its formation.
4. Experimental
4.1. Decomposition of the methyl (2-chlorocarbonyloxy)-
propionate
In a 250 mL reactor equipped with a mechanical stirrer and
a condenser connected to a bubble flask, 40 g of methyl
(2-chlorocarbonyloxy)propionate, prepared by the method
descrided by Kimura and Iwakura,29 are introduced and
heated at the desired temperature (70–908C) with a heating
bath. The desired quantity of catalyst (HBGC·HCl or
HMGC·HCl) solubilized in 10 g of methyl (2-chloro-
carbonyloxy)propionate are introduced in the reactor. The
decomposition rate of methyl S-(2)-2-(chlorocarbonyl-
oxy)propionate and the enantiomer R content of the methyl
2-chloropropionate are calculated after analyses of the
reactional medium by gas chromatography.
3. Conclusion
To obtain a quantity of methyl R-(þ)-2-chloropropionate
with a rate higher or equal to 98%, it is preferable to use the
HMGC·HCl as catalyst and to limit the quantity of the latter
and the temperature of reaction. However, these tendencies
also result in a very slow speed of decomposition of
the choroformate. The study of the reaction of decompo-
sition of methyl S-(2)-2-(chlorocarbonyloxy)propionate
in the presence of hexaalkylguanidinium chloride hydro-
chloride showed that its mechanism follows a nucleophilic
substitution of the second order. The racemization
Figure 7. Temperature influence of reaction on the enantiomer R rate of methyl R-(þ)-2-chloropropionate in the presence of 1% of HMGC·HCl.

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F. Violleau et al. / Tetrahedron 58 (2002) 8607–8612
For the experiment of the mechanism determination of
racemization realized with benzyltriethylammonium bro-
mide, 200 g of methyl S-(2)-2-chloropropionate and 22.2 g
of catalyst (5 mol%) are introduced into a 250 mL reactor
equipped with a mechanical stirrer and a condenser
connected to a bubble flask. The reactional medium is
carried at 908C during 9.3 h.
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Quantification was carried out with an HP 5890 CG
equipped a chiral column DEX 120 (30 m£0.2 mm£
0.25 mm) with the following temperature program: 608C
during 12 min, then increase to 2208C at 308C/min. A 5
minute final time is carried out at 2208C. The injector
temperature is 2208C and the FID detector one was 2508C.
The helium pressure was fixed at 15 psi. Observed retention
times are: methyl S-(2)-2-chloropropionate: 8.4 min;
methyl R-(þ)-2-chloropropionate: 9.0 min; methyl S-
(2)-2-bromopropionate: 12.4 min; methyl R-(þ)-2-bromo-
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following one: 1608C during 12 min. Observed retention
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8.2 min; methyl R-(þ)-2-(chlorocarbonyloxy)propionate:
9.4 min.
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The authors thank SNPE for financial and technical support
of this work.