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N. Gyo˝rffy, A. Tungler / Journal of Molecular Catalysis A: Chemical 336 (2011) 72–77
The results of hydrogenation of TMCH + Pro are collected in
−
35
30
25
20
15
10
5
Tables 1 and 3, second line. Beyond the reactions with acidic and
basic additives, a non-doped reaction is also presented for compar-
ison. Beside conversion and ee, the yields of the TMCH enantiomers
and the alkylated proline, and reaction rate values for the two
periods of the process were given. In all hydrogenations with dif-
ferent additives there are two sections with respect to reaction
rate. Initially it is faster approximately until 30–40% conversion,
this period is followed by a significantly slower one. The reaction
rate and stereoselectivity of reductive alkylation of Pro, namely the
kinetic resolution of TMCH, significantly changed with the proper-
ties of additives. Both acidic additives and TEA, in 0.5 and 1.0 ratio
increased the reaction rate, while NaOMe decreased it significantly.
The values of the consumed S enantiomer in excess vs. time and vs.
ee are shown in Fig. 1a and b.
TFAA
AA
NaM
TEA
0
0
20
40
60
80
100
Reactions in the presence of basic additives, with higher selectivity
appear below this line. NaOMe influenced slightly and TEA signifi-
cantly the selectivity, with less consumed S enantiomer in excess.
be seen also in Fig. 2, where the influence of additives on selectivity
at a given ee is compared.
conversion (%)
Fig. 4. The amount of missing ketones minus S ee vs. conversion in the reaction
carried out at 10 bar hydrogen pressure.
AA 2 bar
30
AA
The increase of the molar ratio of AA did not, but that of TEA
changed the selectivity (Table 1). In the case of the latter this can
be due to its strong adsorption on Pd. The selectivity change can be
attributed rather to the surface change of the catalyst than to the
change of ratio of the two condensation product diastereoisomers
upon adding the acidic and basic additives.
2 bar
20
The effect of acidic additives on the activity can also be explained
by the sequence of the strengths of the added acids.
10
TEA acts not only as a base but as a catalyst modifier, which
increases both activity and selectivity, due to its strong adsorp-
tion on Pd. TEA is the best additive, at almost 100% ee the amount
of missing TMCH S enantiomer is only 13%, which is less by 10%
than that of the non-doped reaction. The optimum ratio of TEA
is 1:1 mole, both less and more added modifier is less benefi-
cial.
0
0
20
40
60
80
100
-10
conversion (%)
3.2. Hydrogenation of IP in the presence of Pro
Fig. 5. The amount of missing ketones minus S ee vs. conversion in the reactions
carried out at 2 and 10 bar hydrogen pressure with and without AA additive.
On the basis of the results of TMCH + Pro hydrogenation and of
the asymmetric reduction of benzylidene benzosuberone [8] our
expectation was that basic additives will improve enantioselectiv-
ity in the hydrogenation of IP, too. But according to the results in
Table 2, the additives with the exception of TEA all increased the
reaction rate (conversion rate and reaction time until 50% conver-
sion (t50)), but decreased the enantioselectivity (yields and values
of missing S isomer). The majority of the ee values in Fig. 3 are
located below the curve of the non-doped reaction (continuous
thick line), meaning that the additives deteriorate enantioselec-
tivity. This is surprising in the light of the results of TMCH + Pro
hydrogenation, where both basic additives improved the yield of
kinetic resolution. The reason of enantioselectivity decrease can
genation of the C C bond.
result compared with those measured at 10 bar and 2 bar with and
without the same additive (Fig. 5). The values of missing ketones
minus S ee for the doped reactions were positive at both pres-
sures, this indicated that the direct C C hydrogenation could not
be confirmed.
The suggested explanation is that both basic and acidic addi-
and diastereoselective hydrogenation of the condensation product
of IP and Pro (see Schemes 1 and 2 in [6]). The neutral reaction mix-
ture seems to be beneficial for the condensation product of IP and
Pro being not only a spectator molecule [3], but to be hydrogenated
at the C C bond through the asymmetric reaction route.
Beside the trend in enantioselectivity and rate (Table 3) upon
tionable whether direct asymmetric C C hydrogenation could be
verified in the doped reactions. Data of Table 3, third line and Fig. 4
indicates that the answer is no, all missing ketones minus S ee val-
In previous investigations [6] significant negative values could be
detected with Pd catalysts on basic supports (BaCO3, MgO) and with
Pd/C catalyst in hydrogenation at 2 bar pressure. Therefore hydro-
genation with Pd/C and AA additive (the other additives decreased
ee significantly, see Table 2) was carried out at 2 bar pressure and its
4. Conclusions
Basic (TEA, NaOMe) and acidic (AA, TFAA) additives were tested
in the asymmetric hydrogenation of TMCH + Pro and IP + Pro. In the
kinetic resolution of TMCH with Pro the effect of these additives
can be summarized in the following (Table 3, second line):
1. Basic additives increased, acidic ones decreased selectivity.
2. Acidic additives increased the reaction rate.