2
A. A. Choliq et al. / Tetrahedron: Asymmetry xxx (2016) xxx–xxx
on tartaric acid-modified sites and rE/(rE + rN) is a contribution of
tartaric acid-modified sites in the total hydrogenation (rE: reaction
rate over the modified sites and rN: reaction rate over non-modified
or non-selective sites).8,9 In our previous study, it was suggested
that the relatively low %ee in the enantioselective hydrogenation
of 1 (52%ee) over tartaric acid-modified Raney nickel, compared
to that of methyl acetoacetate (86%ee), resulted from two factors;
a relatively lower [factor i] and a relatively lower rE/(rE + rN) ratio.15
Recently, we showed with the enantioselective hydrogenation of
methyl acetoacetate over tartaric acid-, malic acid-, and succinic
acid-modified Raney nickel catalysts that molecular interactions
between the chiral surface acids and the substrate determined both
the enantioselectivity and the reaction rate.20 It has been proposed
that hydrogen bond(s) interactions between the surface chiral car-
boxylate and methyl acetoacetate induce stronger adsorption of
methyl acetoacetate and thereby an enhanced reaction rate (ligand
acceleration) as well as an increased enantioselectivity.
Experimental techniques of the competitive hydrogenation of
more than one substrate provide important information on the
reaction mechanism in enantioselective hydrogenations: the rela-
tive rates of each substrate indicate the relative adsorption
strength in a dynamic adsorption equilibrium21 and relative contri-
bution of the catalysis on modified sites.14 In a previous study, we
briefly studied the competitive hydrogenation of 1 or 2 and methyl
acetoacetate over tartaric acid-modified Raney nickel, which sug-
gested that with 1, the contribution of the catalysis on modified
sites was lower than that with methyl acetoacetate, while with
2, it was similar.15 In the present study, we have extended previous
study to obtain further insight into the catalytic behaviors of the
enantioselective hydrogenations of aromatic b-ketoesters, repre-
sented by 1 and 2 (Scheme 1), through competitive hydrogenations
with methyl acetoacetate as a reference substrate over tartaric
acid- and malic acid-modified Raney nickel catalysts.
over tartaric acid-modified Raney nickel catalysts. These ee values
are consistent with our best ee values for these enantioselective
hydrogenations.8,15 With the hydrogenation over malic acid-modi-
fied Raney nickel, the products were almost racemic for 1 and 2. A
considerable decrease in the enantioselectivity to 60%ee was also
observed for the hydrogenation of methyl acetoacetate over malic
acid-modified Raney nickel in our previous study.20 This can be
rationally accounted for in terms of the hydrogen bond interaction
modes between the hydroxyl groups of the modifier and the car-
bonyl groups of methyl acetoacetate: A two-point interaction mode
between the surface bitartrate (possibly monosodium bitartrate
surface species8,9 in the presence of NaBr) and methyl acetoacetate
for tartaric acid-modified Raney nickel to result in a high enantio-
differentiation, while a single point interaction between adsorbed
bimalate and methyl acetoacetate for malic acid-modified Raney
nickel to result in less selective hydrogenation. The significant
decreases in the hydrogenation selectivity of 1 and 2 over malic
acid-modified Raney nickel compared with tartaric acid-modified
Raney nickel lead us to conclude that the enantioselective hydro-
genation of the aromatic b-ketoesters is also controlled by the
hydrogen bond interaction modes with the surface modifier: two-
point interaction modes with surface bitartrate species are much
more favorable for enantio-differentiation than single point interac-
tions with bimalate counterparts. It was found that the hydrogena-
tion rate of methyl acetoacetate was also affected by the
interactions with the surface modifier.20 When unmodified Raney
nickel (modified with NaBr but without the organic acid modifier)
was modified with succinic acid, the hydrogenation rate of methyl
acetoacetate was greatly reduced and racemic products were
obtained, thus indicating that the surface modifier species poisoned
Raney nickel by covering the Ni metal surface.20 On the other hand,
the hydrogenation rate of methyl acetoacetate was increased by
replacing succinic acid with malic acid in spite of the same coverage
of the surface modifier. The reaction rate was further increased by
replacing malic acid with tartaric acid. On the basis of the analysis
of the kinetic behaviors of the enantioselective hydrogenation of
methyl acetoacetate, it was suggested that such profound ligand
acceleration effects were induced by the increase in the adsorption
strength of methyl acetoacetate through hydrogen bond interac-
tions with the hydroxyl groups of the modifier.20 A two-point
hydrogen bond interaction model for methyl acetoacetate over tar-
taric acid-modified Raney nickel is illustrated in Figure 1.8
O
O
OH
O
(R,R)-tartaric acid-modified Raney nickel
R
OMe
R
OMe
H2
1: R = Ph
2
: R = p-CH3O-Ph
methyl acetoacetate: R = CH3
Scheme 1. Enantioselective hydrogenations of aromatic b-ketoesters 1 and 2.
Figure 2a–c show the conversions of the substrates to the prod-
ucts [(S)- and (R)-enantiomers] as a function of reaction time in the
competitive hydrogenations of 1 and methyl acetoacetate over
unmodified Raney nickel, malic acid-modified Raney nickel, and
2. Results and discussion
Since reproducible and precise kinetic information was rela-
tively difficult to obtain by using a usual reactor with a magnetic
stirrer because of diffusion limitations, enantioselective hydro-
genation reactions over the tartaric acid- or malic acid-modified
Raney nickel catalysts were conducted at an elevated H2-pressure
(10 MPa) under reciprocation shaking (the strongest agitation
technique available to our group).13–15 Herein, a certain amount
of the reaction sample was periodically withdrawn from the reac-
tor while keeping the hydrogen pressure high and the conversion
analysis of each sample was conducted by NMR. The sizes of the
reaction solution and sampling, however, limited the numbers of
the sampling and analysis (in the present study, 4 times sampling
for each run). In the present study we adopted a technique of com-
petitive hydrogenation of 1 or 2 and methyl acetoacetate, a stan-
dard substrate, to facilitate a direct comparison of the catalytic
behavior of 1 or 2 with that of methyl acetoacetate under the iden-
tical reaction conditions. Equimolar amounts of methyl acetoac-
tartaric acid-modified Raney nickel, respectively. Table
1
etate and
1 or 2 were used in the present competitive
hydrogenation for the sake of simplicity.
The enantioselectivities of methyl acetoacetate, 1, and 2 were 86,
52, and 72%ee, respectively, in separate hydrogenation reactions
Figure 1. Two-points hydrogen bond interaction model for methyl acetoacetate-
surface tartrate modifier.