Enantioselective hydrogenation of ethyl pyruvate and isophorone over modified Pt and Pd catalysts

Heterogeneous Catalysis and Fine Chemicals IV H.U. Blaser, A. Baiker and R. Prins (editors) © 1997 Elsevier Science B.V. All rights reserved.

157

Enantioselective hydrogenation of ethyl pyruvate and isophorone over modified Pt and Pd catalysts Antal Tungler^ ,Karina Fodor^, Tibor Mathe^, Roger A. Sheldon'' ^Technical University of Budapest, Department of Organic Chemical Technology 1521 Budapest ^Hungarian Academy of Sciences, Res. Group Organic Chemical Technology ''Delft University of Technology, Lab. for Organic Chemistry and Catalysis The present study aimed at revealing the mode of enantiodifferentiation in the asymmetric hydrogenation of ethyl pyruvate and isophorone over platinum and palladium catalysts. The effect of adding the modifier after an initial phase of racemic hydrogenation and the combined use of different vinca and cinchona type modifiers on enantioselectivity and activity were studied. A mechanistic rationale is proposed to account for the experimental observations. 1. INTRODUCTION The most well-known heterogeneous catalysts for enantioselective hydrogenation are Ni modified with tartaric acid for the hydrogenation of P-keto esters [1] and Pt modified with cinchona alkaloids for the hydrogenation of a-keto esters [2]. Premodification of the catalyst prior to the hydrogenation (Ni/tartrate) or in situ modification, i.e. simple addition of the modifier to the reaction mixture (Pt^cinchona), can ensure enantioselectivities up to 95 % under optimised conditions. In recent years new chiral modifiers [3-9] have been found and new prochiral substrates [8-12] have been used in enantioselective heterogeneous catalytic hydrogenations with promising ee's. Several mechanistic proposals have been made to explain the enantiodifferentiating processes. For example, it was proposed that P-keto esters are hydrogenated on chirally modified nickel according to the Langmuir-Hinshelwood mechanism. Competitive reaction on unmodified sites affords racemic product [13]. It was assumed that the interaction between the modifier and the substrate involves hydrogen bonding through hydroxyl and carbonyl groups. In addition to the enantioselective effect, cinchona alkaloids also produce a rate acceleration , i.e. this is an example of ligand accelerated catalysis [14]. The model of a nonclosepacked ordered array of cinchonidine molecules adsorbed on platinum, proposed by Wells and co-workers, was abandoned in their later study [15]. Augustine [16] deduced from the behaviour of this system at low modifier concentrations that the chiral sites are formed at the edge and comer platinum atoms, which involve the adsorbed cinchonidine and a metal adatom. The different authors agreed that the quinoline ring of the modifier is responsible for the adsorption on platinum, the quinuclidine part, through the nitrogen atom, interacts with

158 tbe carbonyl group of the pyruvate, and the product configuration is determined by the C8 and C9 geometry of the modifier molecule. Protonation of the basic nitrogen of the modifier increases the enantiomeric excess. Baiker and co-workers [17] carried out molecular modelling calculations in order to find out the likeliest conformation of the substrate-modifier adduct on the platinum surface. Margitfalvi [18] concludedfiromNMR, kinetic measurements and molecular modelling calculations that the interaction between the modifier and the substrate, which also exists in solution, changes the reactivity of the pyruvate and the conformation of the cinchonidine. The quinoline ring of the latter exerts a shielding effect on the pyruvate determining the direction of the entering of the hydrogen. The emergence of new prochiral substrates and chiral modifiers and new enantioselective reactions have created a need for identifying common mechanistic features in all of these reactions: the structural, reactivity- and affinity characteristics of the effective modifiers, the interactive functional groups of the prochiral substrates and the appropriate catalysts. A vinca-type alkaloid, dihydroapovincaminic acid ethyl ester (dihydrovinpocetine, DHVIN, I) (Fig. 1), proved to be an effective chiral additive in the Pd mediated hydrogenation of C=C and in the Pt mediated reduction of C=0 double bonds [8].

EtOOC

Figure 1. Structure of dihydrocinchonidine and (-)-dihydroapovincaminic acid ethyl ester. The discovery of the new additive afforded the opportunity for the combined use of different chiral modifiers in the asymmetric hydrogenation of ethyl pyruvate and isophorone. The present study aimed at revealing the mode of enantiodifferentiation through the variation of modifiers and catalysts. 2. RESULTS AND DISCUSSION The model reactions were the following:

Pd catalysts H2 MeOH,AcOH modifier

^ o

o

Pt catalysts

H2 ^

\*^i<^^Et

o-^* MeOH,AcOH modifier

^^

Figure 2. Model reactions.

^

159 In both reactions (Fig. 2), different Pd and Pt catalysts (Fig. 3, 4) and the combination of vinca and cinchona modifiers (dihydrocinchonidine (DHCND) and dihydrocinchonine (DHCNN)) were tested (Fig. 5, 6, 7). The effect of hydrogen and product adsorption was investigated; for this reason the hydrogenation was allowed to proceed to 15-30% conversion before addition of the modifier (Table 1, 2). e.e. (%)

(-)-DHVIN DHCND 11 DHCNN

Pd black

Pd/TiOz

Pd/C

Pd/AlgOa

Pd/SiOa Pd powder

Figure 3. Hydrogenation of isophorone with different catalysts and modifiers. Conditions: 0.05 mol isophorone, 0.1 g modifier, 0.5 g acetic acid, 25 ^C, 0.5 g catalyst, 100 ml MeOH, 40 bar. e.e. (%) (-)-DHVIN DHCND DDHCNN

Pt/AlaOa

Pt/C

Adams Pt

Pt/TiOg

Pt/SiOa

Figure 4. Hydrogenation of ethyl pyruvate with different catalysts and modifiers. Conditions: 0.1 mol ethyl pyruvate, O.lg catalyst, O.lg DHCND, 0.1 g DHCNN, 0.2 g (-)-DHVIN + 0.2 g acetic acid, 100 ml MeOH, 250C, 10 bar.

160 The same substrate-modifier-metal systems give different enantiomeric excesses using catalysts on different supports and different preparation methods (Fig. 3, 4). In some cases even the product configuration changed with the catalyst. In the hydrogenation of isophorone, the catalysts of small or moderate dispersion (Pd black, D<0.05, and Pd/Ti02, D<0.1) resulted in the highest enantioselectivities[ll]. In the hydrogenation of ethyl pyruvate the two cinchona alkaloid derivatives (differing in the absolute configuration at C8 and C9) afford the opposite enantiomer in excess. The resulting optical yields are substantially higher than in the hydrogenation of isophorone, where the product configuration depends on the catalyst used (see Fig. 3). Some hydrogenations were carried out in the presence of two modifiers, a vinca type producing, for example, the (S) enantiomer and a cinchona type producing the (R) enantiomer in excess. The catalysts used were Pd black and Pd on titania in the hydrogenation of isophorone, and Pt on carbon, Pt on alumina and Adams Pt in the hydrogenation of ethyl pyruvate. The amount of vinca alkaloid was kept constant, while the amount of the other was increased in each experiment. The results are shown in Figure 5, 6 and 7.

e.e. (%) 20

20 mg (-)-DHVIN and X mg DHCNN 4

10

DHCNN (mg)

Figure 5. Hydrogenation of isophorone over Pd black in the presence of (-)-DHVIN and increasing amount of DHCNN. Conditions: 0.05 mol isophorone, 0.3 g Pd black catalyst, (-)-DHVIN constant 20 mg, 6th bar 0 mg, 50 ml MeOH, 25 ^C, 45 bar. When isophorone was hydrogenated over Pd black, the vinca type alkaloid controlled the enantioselection even if the amounts of the modifiers were equal in the reaction mixture. These results are in good agreement with the considerably higher enantiomeric excesses induced by dihydroapovincaminic acid ethyl ester compared with that of cinchona alkaloids. Using Pd/C catalyst, the cinchona alkaloid dominated with small enantioselectivities, indicating that the combined effect of the modifiers depends also on the catalyst type. In contrast, in the hydrogenation of ethyl pyruvate [19], the cinchona alkaloid controlled the enantiodifferentiation with every platinum catalyst used, as well as inducing much higher optical yields than dihydroapovincaminic acid ethyl ester. In the hydrogenation of ethyl pyruvate using Pt on carbon and Adams Pt, which has a much higher activity, the resulting

161 enantioselectivity significantly decreased with increasing conversion when dihydrocinchonidine was used. The smaller the amount of dihydrocinchonidine, the greater the decrease of the enantiomeric excess. The reason for this behaviour probably is that the quinoline ring of dihydrocinchonidine can be more easily hydrogenated over these catalysts than the indole ring of dihydroapovincaminic acid ethyl ester and as a result, the adsorption ability of molecules and their role in determining the enantioselectivity becomes smaller. e.e. (%)

0.521

1.04

5.21

10.4

DHCND (mmol/l)

Figure 6. Hydrogenation of isophorone over Pd/C in the presence of (-)-DHVIN and increasing amount of DHCND. Conditions: 0.05 mol isophorone, (-)-DHVIN constant 17.4 mmol/l, 0.2 g Pd/C catalyst, 25 ml MeOH, 25 °C, atm. press. e.e. (%) 60 40 (R) 20 0 20 (S) 40

ffll

100 mg (-)-DHVIN and X mg DHCND

20

50

100

100

DHCND (mg)

Figure 7. Enantiomeric excess in the hydrogenation of ethyl pyruvate with (-)-DHVIN and increasing amount of DHCND. Conditions: 0.1 mol ethyl pyruvate, 0.1 g Pt/Al203 thermal-treated (Engelhard), 100 mg (-)DHVIN, 6th bar 0 mg, 0.5 g acetic acid, 100 ml MeOH, 250C, 50 bar.

162 From the results described above, the catalyst-modifier-substrate interaction on and with the catalyst surface seems to be the most important in the enantioselection process. This finding led us to examine the influence of the chiral product molecules and the hydrogen covering the catalyst surface on the asymmetric effect of the chiral modifiers. For this purpose, the modifier was added to the reaction mixture not at the beginning of the hydrogenation, but at 15-30% conversion, thus a racemic mixture of the product molecules was produced in the initial stages of the reaction. The results of these experiments and the ones where the chiral modifier was present from the start of the reaction were compared and are summarised in Table 1 and 2 (ee values were corrected with respect to the modified course of the reactions). The catalysts used were Pd on titania and Pd black in the hydrogenation of isophorone, Pt on carbon and Adams Pt in the hydrogenation of ethyl pyruvate. Table 1. Effect of racemic starting in the hydrogenation of isophorone (e.e. %) Pd black Pd/Ti02 * ** * ** 40 34 19 (-)-DHVIN 40 15 10 5 DHCND 20 <5 5 DHCNN 15 7 * start after modification, ** racemic starting: modification after 15-30% conversion Conditions: 0.05 mol isophorone, catalyst 0.3 g Pd black, 20 mg modifier, 0.5 g acetic acid; or 0.5 g Pd/Ti02 and 100 mg modifier, 50 ml MeOH, 25 *"€, 45 bar. Table 2. Effect of racemic starting in the hydrogenation of ethyl pyruvate ([e.e. %) Adams Pt Pt/C * ** * ** 30 14 12 (-)-DHVIN 10 37 5 25 DHCND 20 15 5 25 DHCNN 12 * start after modification, ** racemic starting: modification after 15-30% conversion Conditions: 0.1 mol ethyl pyruvate, 0.1 g Pt/C catalyst, 100 mg modifier, 0.2 g acetic acid, 10 bar; or 0.05 g Adams Pt and 50 mg modifier, 100 ml MeOH, 25 °C, 50 bar. One general observation is that the chiral effect of both the cinchona and vinca type alkaloids appears to change, in most cases to decrease, if the reaction is started as a racemic hydrogenation compared with the case when the chiral modifier is added at the beginning of the hydrogenation. But no clear conclusion can be made as to whether or not the modifier molecules interact less with the catalyst surface, which is covered by hydrogen and chiral product molecules, and as a result exert less asymmetric effect. 3. CONCLUSION Our results clearly show that the behaviour of the same modifier-substrate system strongly depends on the catalyst used (the same metals on different supports or Adams Pt or Pd black), indicating that the catalyst-modifier-substrate interaction on the catalyst surface is a crucial factor in the process of enantioselection and the observed rate acceleration of pyruvate hydrogenation. On the other hand, it has been shown by CD and NMR measurements that the

163 modifier and the substrate molecules also form a complex or associates in the liquid phase [18, 8]. Nevertheless the formation of the substrate-modifier complex is a necessary but not a sufficient condition for inducing enantioselectivity. We suggest that the modifier-substrate complex is in an equilibrium between the liquid phase and the catalyst surface as well as the "free" substrate and modifier molecules. Whereas it is uncertain that the separately adsorbed substrate and modifier molecules can react on the catalyst surface to give adsorbed substratemodifier complex (Scheme 1). The observed enantioselectivity depends on the equilibrium constants and reaction rates. The differences in the performance of the different catalysts cannot simply depend on the adsorption strength of the modifiers on them, but also on their ability to accommodate the substrate-modifier adduct in an appropriate conformation. To summarise, the most important conditions for enantioselection in precious metal mediated hydrogenations are the following: - condensed aromatic part of the modifier, responsible for the adsorption on the metal, secondary or tertiary nitrogen atom in rather rigid chiral environment to interact with the carbonyl group of the substrate, and protonation of the modifier with a weak acid, - conjugation in the substrate, containing one of the two structural units consisting of two carbonyls or a carbonyl and a C=C double bond: - besides the activity of the metal to saturate the C=0 or C=C double bond, its ability to accommodate the substrate-modifier adduct in an appropriate conformation on its surface. In solution

*- optically active catalyst surface

catalyst surface In adsorbed state

Scheme 1. EXPERIMENTAL The catalysts used were partly commercial products: 5 % Pt/C Merck, 5 % Pd/Al203 Aldrich, 5 % Pd/BaS04 Aldrich, Pd powder Degussa and 10 % Pd/C Selcat of Fine Chemical Co. Budapest. 10 % Pd/Ti02, 10 % Pd/Si02 were prepared as follows. The calculated amount of the catalyst precursor (K2PdCl4) was added to the aqueous suspension of the support. The pH value of the solution was adjusted to 10-11 by addition of KOH. The suspension was boiled for 1 hour then Na(HCOO) was added to the boiling mixture. After half an hour the suspension was cooled, the catalyst was filtered and washed with distilled water.

164 Pd black catalysts were prepared according to the following procedures: 18 mmol (6.0 g) K2PdCl4 was dissolved in 50 ml water and reduced at boiling point with 74 mmol (5.0 g) Na(HCOO) dissolved in 20 ml water. When the reduction was complete, the pH of the suspension was basic (pH 11 ). The catalyst was filtered and washed several times with distilled water. The platinum catalysts used were also partly commercial products: 5% Pt/C Heraeus, Aldrich and Janssen, 5% Pt/Al203 Engelhard, Aldrich, Janssen. Pt02 was the product of Degussa. Pt/Si02, Pt/Ti02 were prepared as follows. The calculated amount of the catalyst precursor ( (NH4)2PtCl5) was added to the aqueous suspension of the support. The pH value of the solution was adjusted to 10-11 by addition of KOH. The suspension was boiled for 1 hour then Na(HCOO) was added to the boiling mixture. After half an hour the suspension was cooled, the catalyst was filtered and washed with distilled water. Some catalyst samples (tt) were heat-treated three hours in hydrogen stream at 400°C in a glass reactor, they were cooled down in nitrogen to room temperature. Ethyl pyruvate, cinchonidine and cinchonine were supplied by Merck. Vinpocetine® was supplied by Richter Gedeon Co. (-)-Dihydrovinpocetine was prepared in our laboratory by catalytic hydrogenation of vinpocetine followed by separation of the epimers[8]. Hydrogenation The hydrogenation of isophorone and ethyl pyruvate was carried out in methanolic solution at 25°C and 1-50 bar hydrogen pressure in a conventional apparatus or in a Biichi BEP 280 autoclave equipped with a magnetically driven turbine stirrer and a gas-flow controlling and measuring unit. Before hydrogenation the reaction mixtures were stirred under nitrogen for 10 minutes in the reaction vessel. During the hydrogenations samples were taken. These samples were analysed with GC on a P-cyclodextrine capillary column (ethyl lactate on 9(fC, dihydroisophorone on llO^'C). The analysis provided base-line separation of the enantiomers. The chromatograms were recorded and the peak areas were calculated with a CWS (chromatography work station). Enantimoric excess values were calculated fi'om the peak areas of the enantiomers with the usual method: [R]-[S]/[R]+[S]. Acknowledgements The authors gratefully acknowledge the financial support of the Commission of European Communities, COST PECO 12382 and the support of the Hungarian OTKA Foundation under No. 6 and 1/3/2239, they are grateful to Gedeon Richter Co. for supplying vinpocetin.

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