SISTEMA DE JUSTICIA PENAL ACUSATORIO Y ORAL

In 1979, Orito and co-workers first observed the enantioselective hydrogenation of a prochiral activated ketone to the corresponding alcohol catalysed by platinum with added chiral modifier.257 Specifically, they used the chiral alkaloid cinchonidine (CD) to modify a carbon supported platinum catalyst to convert methyl pyruvate (MP, dissolved in dichloromethane) to R-methyl lactate (ML) to a high ee (Figure 1.13). It was also shown that, when using cinchonine (CN, an epimer of CD) as the modifier, S-ML was obtained with similar enantioselectivity. The structures of CD and CN are shown in Figure 1.14. Both can be divided into three parts. The aromatic quinoline (Q) ring system is considered to be responsible for anchoring the alkaloid to the metallic surface. Meanwhile, the quinuclidine (QN) ring is a system containing a tertiary nitrogen which facilitates complexation with the reactant. The last section is the chiral centre determining the chirality of the product.

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Figure 1.14 Structures of the cinchona alkaloids used in the Orito reaction. The functional group X is a hydrogen for CD and CN and a methoxy group for quinine and quinidine respectively.

In the Orito reaction, the carbonyl group to be hydrogenated is usually activated by an electron withdrawing group in the alpha position.257 As shown in Figure 1.13, the ester group is the electron withdrawing group in MP. Hence, the stability of the ketone towards hydrogenation is reduced. When MP reacts with hydrogen, a chiral alcohol will be formed. Ethyl pyruvate (EP) has a similar structure to MP except for the difference of one carbon in the length of the ester alkyl chain. Both MP and EP give a high reaction performance in terms of rate and final ee.258 Therefore, in order to understand the mechanism of the Orito reaction, it is essential to study how hydrogen, CD and MP/EP interact with the surface of the platinum catalyst. Although enantiopure methyl and ethyl lactate are rarely used commercially, the racemate is used in products such as electronics, adhesives, printing, paints, textile, and polar solvent in cleaners.259 However, as one of the first examples of a heterogeneously catalysed enantioselective reaction discovered, it provides a bench mark by which many other enantioselective reactions can be understood.

Until recently, information concerning the orientation of EP on Pt was scarce. Hence, much reliance was placed upon previous surface science studies of simpler carbonyl compounds such as acetone. Using Electron Energy Loss Spectroscopy (EELS), acetone adsorbed on

N H HO N Quinuclidine Quinoline Chiral centre N H OH N Cinchonidine Cinchonine 4' _4' 9 8 8 9 R R S S X X

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Pt{111} suggested two possible adsorption modes, both involving ζ-bonding with the surface. One is an η1

lone pair bond between the oxygen of the carbonyl group and the Pt surface, which is an end-on mode as shown in Figure 1.15a. The other, called η2-mode, involves both oxygen and carbon from the keto carbonyl bonding with the metal surface (Figure 1.15b).260, 261

Figure 1.15 EP adsorption modes; (a) η1, (b) η2, (c) π-bonded, and (d) enediolate. Reprinted from reference 165.

Later, X-ray Absorption Near Edge Structure (XANES) was utilised to explore EP adsorption on Pt{111}.262 It was discovered that only the η1-mode was formed on the surface with an oxygen lone pair bond. There was no evidence of η2

-type configuration. However, as shown in Figure 1.15c, a new orientation of EP with the molecular plane lying parallel to the surface plane was suggested. This absorption mode indicates the π-orbitals of the two carbonyl groups interacting with the Pt surface. Although both of these modes may co-exist on the metal surface, an introduction of hydrogen gas could cause a tilt of the molecular plane of the η1

-mode closer to the surface plane. Hence, the η1-mode was proposed to be a precursor of the flat configuration mode, which corresponded to previous studies concerning the mechanism of catalytic hydrogenation.263 Later, the same authors also explored the binding energy of core shell and valence shell electrons using X-ray Photoelectron Spectroscopy

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(XPS) and Ultra-Violet Photoelectron Spectroscopy (UPS).264 A stabilisation of the highest occupied molecular orbital (HOMO) upon adsorption was observed. This lone-pair orbital is associated with both C=O groups on EP. Hence, the keto carbonyl was definitely involved in the chemisorption to the surface according to these workers but the possible involvement of ester carbonyl could not be ruled out. Angle-resolved measurements suggested an upright or tilted surface configuration for EP under UHV conditions at low temperature in accordance with results for similar molecules.262

However, a study of MP adsorption on Pt{111} using Density Functional Theory (DFT) suggested that the most energetically stable mode was the η2

-, not the η1- mode.265 Since the π-bond of the carbonyl was believed to rehybridise upon adsorption in the η2

-mode, it would now present a more ζ-bond like feature which was supported by the observation of an extension in the C-O bond length in the η2-configuration compared to the η1-mode. This was suggested as a possibly reason for the increasing rate of the hydrogenation reaction on platinum because the carbonyl bond was strongly activated and that the real rate may actually depend on the ratio of the η1

- and η2-modes at the surface. It should be noted that the rate acceleration over and above the intrinsic hydrogenation rate facilitated by CD/CN is due to quite a different effect (see later).266

Reflection-Absorption Infra-Red Spectroscopy (RAIRS) also confirmed the presence of the η1

- and η2- configurations of MP adsorbed on a Pt surface as a function of temperature.267 Furthermore, another adsorption mode with both the keto and ester carbonyl oxygen lone pairs bonding to the surface were identified (Figure 1.15d). This so-called enediolate configuration possesses a delocalised π system across the O-C-C-O framework.267 Nevertheless, it only survives at very low temperatures (110 K).

In order to discover alternatives to platinum for the catalytic hydrogenation reaction, UHV studies of MP adsorption on copper{111}268 and nickel{111}269 have also been carried out. Although it was shown that a η2

- configuration was dominant in the adsorption of EP on Cu{111}, copper does not dissociate hydrogen as readily as platinum. Hence, it is not a potential candidate as a hydrogenation catalyst. Meanwhile, nickel{111} was found to stabilise a cis-bidentate adsorption type of MP, which is similar to the enediolate configuration on Pt but with no delocalisation.269 Theoretical investigations based on a single nickel atom (not a plane) suggested the existence of an η1

-mode of adsorption.270 However, since nickel is known to be inactive in the hydrogenation of α-ketoesters and may yield

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different fragments due to decomposition, the relevance of EP studies on nickel in relation to the Orito reaction is doubtful.271, 272

Although enantiopure EL is not a commercially valuable compounds, other analogous alcohols with optical feature may be quite useful organic synthons.273 R-pantolactone is one of the alcohols which is usually used in the synthesis of vitamin B5 and co-enzyme.274 Its ketone precursor, ketopantolactone (KPL), has a cyclic ring structure. Therefore, the degree of enantioselectivity of the reaction is affected slightly, with 79% ee compared to >95% for EP under optimal conditions.275 However, since Pt/Al2O3 catalysts modified by CD caused an excess of R-pantolactone to form, the sense of enantioselectivity remains unchanged compared to EP and hence, a similar chiral induction mechanism was suggested.274, 275