Hydrogenation of ethyl pyruvate

A typical probe molecule for enantioselective hydrogenation reactions (ethyl pym-vate) was chosen to test the performance of the chiral organometalUc catalysts prepared by SOMC/M techniques. 

CMK = cyclohexyl methyl ketone, CHE = 1-cyclohexylethanol, EB = ethylbenzene and ECH = ethylcyclohexane). 

Reaction conditions 250 ing catalyst, 2.65 mmol ethyl pyruvate, 60mL 2-propanol, 353 K, lOatm H2. 

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An attractive alternative to these novel aminoalcohol type modifiers is the use of 1-(1-naphthyl)ethylamine (NEA, Fig. 5) and derivatives thereof as chiral modifiers [45-47]. Trace quantities of (R)- or (S)-l-(l-naphthyl)ethylamine induce up to 82% ee in the hydrogenation of ethyl pyruvate over Pt/alumina. Note that naphthylethylamine is only a precursor of the actual modifier, which is formed in situ by reductive alkylation of NEA with the reactant ethyl pyruvate. This transformation (Fig. 5), which proceeds via imine formation and subsequent reduction of the C=N bond, is highly diastereoselective (d.e. >95%). Reductive alkylation of NEA with different aldehydes or ketones provides easy access to a variety of related modifiers [47]. The enantioselection occurring with the modifiers derived from NEA could be rationalized with the same strategy of molecular modelling as demonstrated for the Pt-cinchona system. 

Not so long ago, the general opinion was that high enantioselectivity can only be achieved with natural, structurally unique, complex modifiers as the cinchona alkaloids. Our results obtained with simple chiral aminoalcohols and amines demonstrate the contrary. With enantiomeric excesses exceeding 80%, commercially available naphthylethylamine is the most effective chiral modifier for low-pressure hydrogenation of ethyl pyruvate reported to... 

Hydrogenation of ethyl pyruvate in the presence of cinchonidine. In our previous studies [3, 4,14] variety of experimental data were obtained, which could not be explained by existing models [1,2] proposed earlier. These results are as follows [3,4,12] (i) the monotonic increase type behaviour of the optical yield - conversion dependencies, (ii) the complexity of the reaction kinetics, (iii) side reactions catalyzed by CD. It was also demonstrated that the enantio-differentiation can be induced if the modifier is injected into the reactor during racemic hydrogenation. 

One of the most interesting side reactions taking place during the enantioselective hydrogenation is the transesterification of the substrate or the reaction product. If the enantioselective hydrogenation of ethyl pyruvate was performed in methanol as a solvent the formation of methyl pyruvate and methyl lactate was observed. CD appeared to be an effective catalyst for the above transesterification reaction. 

Pt/Al2C>3-cinchona alkaloid catalyst system is widely used for enantioselective hydrogenation of different prochiral substrates, such as a-ketoesters [1-2], a,p-diketones, etc. [3-5], It has been shown that in the enantioselective hydrogenation of ethyl pyruvate (Etpy) under certain reaction conditions (low cinchonidine concentration, using toluene as a solvent) achiral tertiary amines (ATAs triethylamine, quinuclidine (Q) and DABCO) as additives increase not only the reaction rate, but the enantioselectivity [6], This observation has been explained by a virtual increase of chiral modifier concentration as a result of the shift in cinchonidine monomer - dimer equilibrium by ATAs [7],... 

New modifiers have traditionally been discovered by the trial-and-error method. Many naturally occurring chiral compounds (the chiral pool38) have been screened as possible modifiers. Thus, the hydrogenation product of the synthetic drug vinpocetine was discovered to be a moderately effective modifier of Pt and Pd for the enantioselective hydrogenation of ethyl pyruvate and isophorone.39 Likewise, ephedrine, emetine, strychnine, brucine, sparteine, various amino acids and hydroxy acids, have been identified as chiral modifiers of heterogeneous catalysts.38... 

Torok B, Karoly F, Gerda S, Mihaly B (1997) Sonochemical enantioselective hydrogenation of ethyl pyruvate over platinum catalysts. Ultrason Sonochem 4(4) 301-304... 

Scheme 9.11 Enantioselective hydrogenation of ethyl pyruvate with platinum colloids stabilized by protonated-dihydrocinchonidine.

Recently, platinum nanoparticles protected by N,N-dimethyl-N-cetyl-N-(2-hydro-xyethyl)ammonium chloride salt and modified with cinchonidine were investigated in the enantiomeric hydrogenation of ethyl pyruvate in pure biphasic liquid-liquid (water/substrate) media at room temperature [139]. For the first time, the aqueous phase containing Pt(0) nanocatalysts with an average size of 2.5 nm could be reused for successive hydrogenations, and with a total conversion of activity and enantioselectivity in (R)-(+)-ethyl lactate up to 55% (Scheme 9.12). 

Scheme 9.12 Reusable aqueous suspension of Pt nanoparticles for enantioselective hydrogenation of ethyl pyruvate.

The colloidal catalysts have been prepared in different particle sizes by the reduction of platinum tetrachloride with formic acid in the presence of different amounts of alkaloid. Optical yields of 75-80% ee were obtained in the hydrogenation of ethyl pyruvate with chirally modified Pt sols (Equation 3.7). The catalysts were demonstrated to be structure-insensitive since turnover frequencies (ca. 1 sec-1) and enantiomeric excess are independent of the particle size. 

Kohler, J.U. and Bradley, J.S., Enantio selective hydrogenation of ethyl pyruvate with colloidal platinum catalysts the effect of acidity on rate, Catal. Lett., 45, 203,1997. 

In catalysis, adsorbed CO may retard some reactions such as olefin hydrogenation, fuel cell conversion, and enantioselective hydrogenation. For instance, Lercher and coworkers observed the deactivation of Pt/Si02 in the liquid-phase hydrogenation of crotonaldehyde, and ascribed this deactivation to the decomposition of crotonaldehyde on platinum surface to adsorbed CO [138]. Blaser and coworkers found that the addition of a small amount of formic acid decreases the rate of liquid-phase hydrogenation of ethyl pyruvate on cinchonidine-modified Pt/Al203 catalyst, which they explained as the decomposition of formic acid on the catalyst to adsorbed CO. Interestingly, the addition of acetic acid does not decrease the reaction rate, but whether acetic acid decomposes on the catalyst as formic acid does was not mentioned [139]. 

Figure 6.18 Enantioselective hydrogenation of ethyl pyruvate on heterogeneous chiral catalysts. Activity as a function of time for the following catalysts ( ) Pt/(-)-MenSnBu3, ( ) Rh/ (-)-MenSnBu3 and (A) Ni/(-)-MenSnBu3. (Reproduced from Reference [45].)...

Table 6.12 Enantiomeric excess (e.e.) obtained in the hydrogenation of ethyl pyruvate with the chiral catalysts M-MenSnBu3 (M = Pt, Rh, Ni). (Reproduced from Reference [109].)...

Collier, P. J., Iggo, J. A. and Whyman, R. 1999. Preparation and characterization of solvent-stabilised nanoparticulate platinum and palladium and their catalytic behaviour towards the enentioselective hydrogenation of ethyl pyruvate. Journal of Molecular Catalysis A-Chemical, 146 149-157. 

The equipment depicted in Fig. 17 also allows monitoring of species adsorbed on a solid catalyst. For this application, the ZnSe IRE is coated with a layer of the catalyst before assembly of the cell and the start of the reaction. This approach was chosen for investigation, for example, of the interaction of the reactant with the catalyst during the asymmetric hydrogenation of ethyl pyruvate catalyzed by cinc-honidine (CD)-modified Pt/Al2O3 in the presence of supercritical ethane (79). 

In the hydrogenation of ethyl pyruvate in the presence of Pt-Al203 modified by 10,11-dihydrocinchonidine, alkaloid adsorption leads to a marked increase in reaction rate (44). The actual hydrogenation involves two kinds of reactive sites, chirally modified Pt (Ptm) and unmodified metal (Pt ). Accordingly, the reaction is analyzed in terms of a general two-cycle mechanism (Scheme 18). The first cycle is ligand-... 

Fig. 10. Interdependence of rate and enandoselectivity for the hydrogenation of ethyl pyruvate with Pt/Al203 catalysts, a) For varying HCd concentrations (results from Fig. 9) — ee versus 1/rate and —ee versus rate b) For different Pt/AljOj catalysts modified with cinchonidine [59].

Recently, the enantioselective hydrogenation of ethyl pyruvate catalyzed by cinchona modified Pt/Al203 (ref. 1) was shown to be a ligand accelerated reaction (ref. 2). The rate of reaction for the fully modified system is more than 10 times faster than the racemic hydrogenation using unmodified catalyst. Under certain reaction conditions, this liquid phase hydrogenation exhibits a turn-over frequency of up to 50 s 1 (3.4 mol/kg-cat s). Emphasis until now has been directed at empirically increasing optical yields (ref. 3,4). 

We have identified reaction conditions where intrinsic kinetics can be obtained for the very fast enantioselective hydrogenation of ethyl pyruvate using a commercially available Pt/Al203 powder catalyst, modified with dihydrocinchonidine. We conclude that this is in pan due to i) the egg-shell structure of the catalyst, ii) the high turbulence achieved in the reactor and iii) the density and/or the viscosity of the solvent used. In solvents like ethyl pyruvate, liquid-solid transpon problems can arise. 

Methylation of the hydroxyl group of CD in OMeCD does not affect all reactions in the same way. In the hydrogenation of ethyl pyruvate 9 the influence is only marginal, independent of the solvent used. A similar small effect was observed in the hydrogenation of 4 in apolar solvent, while the ee increased by 20 % in acetic acid, using OMeCD instead of CD. On the contrary, O-methylation of CD led to a remarkable drop in ee in the hydrogenation of 1 in apolar solvents such as 1,2-dichlorobenzene. In the latter reaction, acetic acid is a poor solvent, affording low ee s with both CD and OMeCD. 

Later studies by Blaser et al. revealed that the enantioselectivities as well as the rates of hydrogenation for a-keto esters are increased by hydrogenation in acetic acid. In the hydrogenation of ethyl pyruvate the best results (93-95% ee) were obtained in ace-... 

Minder et al. studied various modifiers containing a nitrogen base for the enantioselective hydrogenation of ethyl pyruvate.223,224 Up to 82% ee with (R)-l-(l-naphthyl)ethylamine and up to 75% ee with (/ )-2-( 1 -pyrrolidinyl)-1 -(1 -naphthyl)-ethanol as modifiers were achieved in the hydrogenation of ethyl pyruvate to (R)-ethyl lactate over Pt-Al203 in acetic acid. 

The Pt-catalyzed enantioselective hydrogenation of ethyl pyruvate to (/ )-ethyl lactate was considerably faster (by a factor of 3-3.5) in supercritical ethane than in the conventional apolar solvent toluene, whereas the enantioselectivity was unaffected. Complete catalyst deactivation was observed in C02, which was shown by FTIR to be due to the reduction of C02 to CO via reverse water gas shift reaction. The catalyst could be regenerated by exposing it to ambient air, while hydrogen treatment was less efficient. This is the first evidence to the limitation of catalytic hydrogenations over Pt metals in supercritical C02. 

Enantioselective hydrogenation of ethyl pyruvate in supercritical and conventional solvents... 

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