G. Martin et al.
presence of different solvents has been widely studied for
the synthesis of flavors, fragrances, additives and phar-
maceuticals [6]. Solvents can lead to variations in the
activity, selectivity and stereoselectivity in hydrogenation
reactions [7]. However, the factors responsible for such
variations could be several, e.g. solubilities of liquid and
gaseous reactants and their adsorption on the catalyst sur-
face, competitive adsorption of solvent molecules, inter-
action between the solvent and the reactant(s) either in the
liquid phase or on the catalyst surface as well as catalyst
deactivation caused by the solvent [8]. Furthermore, com-
plex organic molecules commonly coexist in various con-
formations and the apparent population of different
conformers can vary as a function of the solvent dielectric
constant and thus affect the selectivity [9]. It is for that
reason that the phenomena known as solvent effects are a
combination of several physical and chemical factors
which makes it difficult to predict and rationalize perfor-
mance of solvents in a particular reaction.
the Onsager function [15]. However, the effect of the
reactant conformation in a-ketoesters hydrogenation over
analogous systems is not totally clear.
Quantum chemical methods HF and B3LYP have been
used to study the effect of conformation of 1-phenyl-1,
2-propanedione, and similar results in different media were
obtained. The effect of a polar solvent gave only a slight
decrease in the torsion angle s2 and thus, the dipole
moment of the molecule increased in polar media. In
general, the solvent effect on the reactant conformation can
be considered relatively minor. This was the case also with
ethyl benzoylformate, for which the potential energy sur-
face over s has a similar shape [16].
2
The maximum enantiomeric excess found in the literature
for different substrates is reported in Table 1. Substrates,
such as 1-phenyl-1,2-propanedione, ethyl pyruvate [12],
methyl pyruvate [17], ketopantolactone [18], ethyl ben-
zoylformate [17] and 2,3-butanedione [19] showed inter-
esting differences regarding the influence of the solvent
dielectric coefficient dependence on ee. It became clear that
ketopantolactone, 1-phenyl-1,2-propanedione and ethyl
benzoylformate [16, 20] exhibit pronounced solvent
dependencies (i.e. decline in ee with increasing solvent
dielectric constant), whereas, the others are less solvent
dependent. Therefore, some reactant specific factors (solu-
bility of hydrogen, iterations between the solvent and reac-
tant(s), etc.) should be involved in the explanation of solvent
effects.
The most widely studied model compound in enantio-
selective hydrogenation has been ethyl pyruvate [10, 11].
In contrast to ethyl pyruvate, hydrogenation of ethyl ben-
zoylformate (EBF) has been scarcely studied. Although the
reaction was originally described by Orito et al. [1] at the
time of the discovery of the catalytic enantioselective
hydrogenation of a-ketoesters and these authors achieved
an enantiomeric excess of 84 % for the production of ethyl-
(
R)-mandelate (EM), only few papers have recently been
published on the hydrogenation of EBF. For instance,
Bart o´ k et al. [2] investigated the effect of different alka-
loids (cinchonidine, cinchonine, quinine, quinidine, a-iso-
cinchonine, a-isocinchonidine and d-isoquinidine) in the
hydrogenation of EBF and Sutyinszki et al. [3] found
extremely high ee (98 %) using Pt/Al O as a catalyst
In the present paper, the three-phase hydrogenation of
ethyl benzoylformate in the presence of Pt/Al O and a
2
3
dissolved catalyst modifier (CD) in different solvents is
studied. The reaction scheme for the hydrogenation of EBF
is displayed in Fig. 1. As shown in the Figure, the complete
reaction scheme comprised three components. The reac-
tant, ethyl benzoylformate (A), is hydrogenated on Pt cat-
alyst to produce two enantiomers (R)- and (S)-ethyl
mandelate, (B) and (C), respectively.
2
3
under 25 bar hydrogen pressure. Hydrogenation of EBF
yields very valuable building blocks, ethyl-(R)- and ethyl-
(
S)-mandalate (EM). Indeed, mandelate derivatives are
important synthetic building blocks in preparative organic
chemistry owing to their versatile functional groups, which
may be easily transformed into other functionalities, for
example, diols, halo or amino derivatives and epoxides.
Generally, high enantioselectivities in the hydrogenation
of ethyl and methyl pyruvates can be obtained in solvents
with dielectric constants between 2 and 10 [12]. Conse-
quently, acetic acid [13] and toluene are known to be
among the best solvents. It was proposed that the depen-
dence of the enantioselectivity on the dielectric constant
correlates with the population of the Open(3) conformer of
the modifier (CD) in the liquid phase [14]. This offers a
plausible explanation for the dependence of the enanti-
oselectivity on the dielectric constant. The dependence of
the Open(3) conformer population on the dielectric con-
stant of the solvent is non-linear, resembling the shape of
Typically the enantiomeric excess (ee) is defined as
ee = [C - C ]/[C ? C ]. Hydrogenation of A has been
studied previously both in batch [3] and continuous reac-
B
C
B
C
tors [22]. The highest reported ee has been 98 % (reaction
Table 1 Maximum enantiomeric excess reported for different sub-
strates [21]
Raw material
ee (%)
Methyl pyruvate
Ethyl pyruvate
87
87
84
46
65
91
Ethyl benzoylformate
Butane-2,3-dione
1
-Phenyl-1,2-propanedione
Ketopantolactone
1
23