Catalyst MPVO

Very recently the Meerwein-Ponndorf-Verley-Oppenauer (MPVO) reaction has been exploited for the racemization of alcohols using inexpensive aluminum-based catalysts. Combination of these complexes with a lipase (CALB) results in an efficient DKR of sec-alcohols at ambient temperature. To increase the reactivity of the aluminum complexes, a bidentate ligand, such as binol, is required. Also, specific acyl donors need to be used for each substrate [31] (Eigure 4.9). 

As an example, Table 20.2 lists the rate of the racemization of 61 via an MPVO procedure utilizing the catalyst neodymium(III) isopropoxide (62) as a function of the solvent. In this case, an equimolar amount of acetone was applied as the oxidant. The best results were obtained with hydrocarbons such as hexane (entry 7) and heptane (entry 8) as solvents, while the reaction rates in dioxane (entry 2) and acetonitrile (entry 1) were much lower due to inactivation of the catalyst by coordination of the solvent to the metallic center (Table 20.2) [84]. 

Lanthanide(III) isopropoxides show higher activities in MPV reductions than Al(OiPr)3, enabling their use in truly catalytic quantities (see Table 20.7 compare entry 2 with entries 3 to 6). Aluminum-catalyzed MPVO reactions can be enhanced by the use of TFA as additive (Table 20.7, entry 11) [87, 88], by utilizing bidentate ligands (Table 20.7, entry 14) [89] or by using binuclear catalysts (Table 20.7, entries 15 and 16) [8, 9]. With bidentate ligands, the aluminum catalyst does not form large clusters as it does in aluminum(III) isopropoxide. This increase in availability per aluminum ion increases the catalytic activity. Lanthanide-catalyzed reactions have been improved by the in-situ preparation of the catalyst the metal is treated with iodide in 2-propanol as the solvent (Table 20.7, entries 17-20) [90]. Lanthanide triflates have also been reported to possess excellent catalytic properties [91]. 

For the reduction of carbonyl groups or the oxidation of alcohols in the presence of C-C double and triple bonds, MPVO catalysts seem to be the best choice with respect to selectivity for the carbonyl group, as reductions with com-... 

Transition-metal catalysts are, in general, more active than the MPVO catalysts in the reduction of ketones via hydrogen transfer. Especially, upon the introduction of a small amount of base into the reaction mixture, TOFs of transition-metal catalysts are typically five- to 10-fold higher than those of MPVO catalysts (see Table 20.7, MPVO catalysts entries 1-20, transition-metal catalysts entries 21-53). The transition-metal catalysts are less sensitive to moisture than MPVO catalysts. Transition metal-catalyzed reactions are frequently carried out in 2-propanol/water mixtures. Successful transition-metal catalysts for transfer hydrogenations are based not only on iridium, rhodium or ruthenium ions but also on nickel [93], rhenium [94] and osmium [95]. It has been reported that... 

As mentioned above, MPVO catalysts are very selective towards carbonyl compounds. Alkenes, alkynes or other heteroatom-containing double bonds are not affected by these catalysts, while they can be reduced by transition-metal catalysts. Examples of the reduction of a,/ -unsaturated ketones and other multifunctional group compounds are compiled in Table 20.3. 

In the MPVO reaction, several side-reactions can occur (Scheme 20.23). For example, an aldol reaction can occur between two molecules of acetone, which then leads to the formation of diacetone alcohol. The latter acts as a good ligand for the metal of the MPVO catalyst, rendering it inactive. Moreover, the aldol product may subsequently eliminate water, which hydrolyzes the catalyst. The aldol reaction can be suppressed by adding zeolite NaA [84, 92]. 

In the presence of an active acyl donor such as isopropenyl acetate, a reductive acetylation of a ketone can be performed in the presence of MPVO catalysts... 

It is important that the catalysts are stable in each other s presence. Typically, kinetic resolution of the reaction is performed with an enzyme, which always will contain traces of water. Hence, MPVO catalysts and water-sensitive transition-metal catalysts cannot be used in these systems. The influence of the amount of the hydrogen acceptor in the reaction mixture during a dynamic kinetic resolution is less pronounced than in a racemization, since the equilibrium of the reaction is shifted towards the alcohol side. 

Table 20.7 A short overview of the reduction of acetophenone with MPVO catalysts and transition metal catalysts developed during the past five years. 

Moreover, MPVO reactions are traditionally performed with stoichiometric amounts of Al(III) alkoxides. Some improvements came from the use of dinuclear AI(III) complexes that can be used in catalytic amount [6, 7]. This is why there has been an ever-increasing interest in catalytic MPVO reactions promoted by lanthanides and transition-metal systems [8]. In these cases, it is believed that reaction proceeds via formation of a metal hydride, in contrast with the mechanism accepted for traditional aluminum alkoxide systems, which involves direct hydrogen transfer by means of a cyclic intermediate [9]. As well as La, Sm, Rh and Ir complexes, Ru complexes have been found to be excellent hydrogen transfer catalysts. The high flexibility of these systems makes them very useful not only for MPVO-type reactions, but also for isomerization processes [10]. 

Significant improvements have also been introduced with the use of heterogeneous catalysts that are less water-sensitive than homogeneous Lewis acids and more convenient because of easier reaction mixture work-up. An important class of MPVO solid catalysts consists of zeolite beta and its metal-containing derivatives, especially Sn-, Zr- and Ti-beta. Several examples are known and the reduction or oxidation can be performed either in the gas phase [11, 12] or in solution [13, 14]. A very recent paper also reports the use of a bifunctional Zr-beta-sup-ported Rh catalyst able to promote both arene and carbonyl reduction [15],... 

The Meerwein-Ponndorf-Verley reduction of carbonyl compounds and the Oppenauer oxidation of alcohols, together denoted as MPVO reactions, are considered to be highly selective reactions. For instance, C=C double bonds are not attacked. In MPV reductions a secondary alcohol is the reductant whereas in Oppenauer oxidations a ketone is the oxidant. It is generally accepted that MPVO reactions proceed via a complex in which both the carbonyl and the alcohol are coordinated to a Lewis acid metal ion after which a hydride transfer from the alcohol to the carbonyl group occurs (Fig. 1) [1]. Usually, metal ec-alkoxides are used as homogeneous catalysts in reductions and metal t-butoxides in oxidations [1]. 

Recently Creyghton et al. [6,7] reported the use of zeolite beta in the MPVO reduction of 4-t-butylcyclohexanone. ITie high selectivity towards the thermodynamically less favoured ds-alcohol is explained by a restricted transition-state around a Lewis-acidic aluminium in the zeolite pores. When using an aluminium-free zeolite, titanium beta, in the epoxidation of olefins, we have shown that Ti-beta has acidic properties when alcoholic solvents were employed [8], This was ascribed to the Lewis-acidic character of titanium in the zeolite framework. As we reported very recently [9], Ti-beta is found to be an excellent catalyst in MPVO reactions with a tolerance for water. Here, results are presented on the high selectivity, stability and low by-product formation of the catalyst, Ti-beta, in both the liquid-phase and gas-phase MPVO reactions. 

Liquid-phase MPVO reactions were performed in 25 ml isopropanol (reductions) or 25 ml 2-butanone (oxidations) at 85 °C using 2.5 mmol of the appropriate substrate 4-r-butylcyclohexanone (4-Bu-ONE), 4-methylcyclohexanone (4-Me-ONE) or 4-t-butylcyclohexanol (4-Bu-OL, cis/trans mixture) 0.5 g zeolite or 0.25 mmol aluminium isopropoxide as the catalyst and 1,3,5-tri-f-butylbenzene as the internal standard. Samples were taken at regular intervals and analyzed by GC on a Carbowax CP-52 column and GC/MS. 

Gas-phase MPVO reactions were performed at 85 to 400 °C in a fixed bed continuous down-flow reactor operated at atmospheric pressure under plug flow conditions. The catalyst, Ti-beta or Al-beta (0.30 g), was diluted with 1.20 g a-quartz powder and processed to pellets then crushed to particles with a diameter of 0.7 - 1.0 mm. Reactant mixtures were pumped into a stream of preheated carrier gas (usually... 

MPVO reduction of cyclohexanones over beta-type catalysts in refluxing isopropanol. 

The most important side reaction in heterogeneously catalysed MPVO reactions is the acid-catalysed aldol condensation. Aldol products are usually observed during the Oppenauer oxidation of alcohols, when a surplus of ketone or aldehyde is used as the oxidizing agent and the solvent. The low amount of by-products formed when Ti-beta was used as the catalyst, demonstrates the advantage of the titanium system over Al-beta. This is probably caused by the much weaker Brpnsted acidity of the solvated titanium site [8] compared with the strong H -acidity of the aluminium site in Al-beta. As we have shown earlier Ti-beta has a high tolerance towards water, which further shows the catalytic potential of Ti-beta in MPVO reactions [9]. 

Another important side reaction for both alcohols was isomerization. It is therefore proposed that the alkene is formed mainly from the cis-alcohol and that at low temperatures the trans-alcohol can only be dehydrated if it is first isomerised to the cis-alcohol via an MPVO transition-state. Comparing the deactivation of the Ti-beta catalyst in the oxidation (Fig. 5) and reduction reactions (Fig. 3) shows that the deactivation is more pronounced during oxidative conditions. This is probably caused by the high amount of ketones present, which easily form aldol condensates which may plug the zeolite chaimels, thus inhibiting access to the micropore system. 

The commonly used MPVO catalysts consist of metal alkoxides, which are easily hydrolysed to inactive oxides in the presence of water. Since the proposed catalytic species for the MPVO reaction also consists of an alkoxide intermediate [6,9] the influence of water and strong Lewis bases on the catalytic activity and selectivity was investigated. As already reported for the liquid-phase reaction [9], Ti-beta has a high tolerance for water due to its hydrophobic interior. As can be seen from Fig. 6a the presence of water is not detrimental to the activity of Ti-beta in the MPV reduction of 4-methylcyclohexanone. The temperature of 110 °C, at which a ketone conversion of 50% is measured, is identical to the temperature required for 50% conversion in the absence of water (Fig. 3), Le. water has no effect whatsoever on the overall MPVO activity of the titanium site. 

Ti-beta is found to be an excellent catalyst in MPVO reactions under both liquid- and gas-phase conditions. Under liquid-phase conditions, a very high selectivity in the reduction of 4-substituted cyclohexanones towards the thermodynamically unfavourable cis-alcohols was observed. By-products were observed only during the oxidation of alcohols using ketone solvents and consisted primarily of aldol condensation products. 

Although the conditions of catalysis have not yet been optimized, the results are interesting in the sense that these heterogeneous molecular catalysts all show properties different from their molecular counterparts, in terms of either activity (epoxidation of olefins, MPVO reactions, silane activation) or selectivities (epoxidation for example). These features need to be further investigated, by varying the number of solid ligands in the coordination sphere of Zr preliminary experiments with epoxidation of olefins show that this parameter is important for the activity of Zr. 

Summary Meerwein-Ponndorf-Verley and Oppenauer reactions (MPVO) are catalysed by metal oxides which possess surface basicity or Lewis acidity. Recent developments include the application of basic alkali or alkaline earth exchanged X-type zeolites and the Lewis-acid zeolites BEA and [Ti]-BEA. The BEA catalysts show high stereoselectivity, as a result of restricted transition state selectivity, in the MPV reduction of substituted alkylcyclohexanones with i-PrOH. 

A major advantage of heterogeneous over homogeneously catalysed MPVO reactions is that the catalysts can easily be separated from the liquid reaction mixture. So far, several examples of heterogeneously catalysed MPVO reactions have been reported. The catalysts comprise (modified) metal oxides which exhibit either Lewis acid or basic properties. The reaction mechanisms involved have in common that the first step consists in the formation of an alkoxide-like species, while the reactions proceed via cyclic six-membered transition states, comparable to those in homogeneous systems. 

This paper presents a comprehensive overview of heterogeneously catalysed MPVO reactions. It includes the recent application of zeolites as new recycleable solid catalysts for the MPVO reaction. The activity of these catalysts is related to their Lewis acid and/or basic properties. Some remarkable examples of shape-selective conversions resulting in high stereoselectivities have recently been found by our group. 

Heterogeneous catalysts which are active for the catalysis of the MPVO reactions include amorphous metal oxides and zeolites. Their activity is related to their surface basicity or Lewis acidity. Zeolites are only recently being developed as catalysts in the MPVO reactions. Their potential is related to the possibility of shape-selectivity as illustrated by an example showing absolute stereoselectivity as a result of restricted transition-state selectivity. In case of alkali or alkaline earth exchanged zeolites with a high aluminium content (X-type) the catalytic activity is most likely related to basic properties. For zeolite BEA (Si/Al=12), however, the dynamic character of those aluminium atoms which are only partially connected to the framework appear to play a role in the catalytic activity. Similarly, the Lewis acid character of the titanium atoms in aluminium free [Ti]-BEA explains its activity in the MPVO reactions. 

Meerwein-Ponndorf-Verley-Oppenauer (MPVO) reactions are usually mediated by metal alkoxides such as Al(0/-Pr)3. The activity of these catalysts is related to their Lewis-acidic character in combination with ligand exchangeability. The mechanism of these homogeneous MPVO reactions proceeds via a cyclic six-membered transition state in which both the reductant and the oxidant are co-ordinated to the metal center of the metal alkoxide catalyst (Scheme 1). The alcohol reactant is co-ordinated as alkoxide. Activation of the carbonyl by co-ordination to Al(III)-alkoxide initiates the hydride-transfer reaction from the alcoho-late to the carbonyl. The alkoxide formed leaves the catalyst via an alcoholysis reaction with another alcohol molecule, usually present in excess [Ij. 

Leyrit et al. reported the synthesis of silica-anchored mononuclear (tris)isopro-poxyzirconium, (=SiO)Zr(Oi-Pr)3, as a true heterogeneous catalyst in MPVO reactions [11,12]. It is worthy of note that dissolved tetraisopropoxyzirconium is not active in MPVO reactions. The solid catalyst was prepared by reacting partially dehydroxylated silica with tetra(neopentyl)zirconium (Zr(Np)4) to form a mono-... 

MgO was found to be the most active catalyst for the hydrogen transfer reaction, then potassium impregnated gamma alumina (y-ALO -K), y-Al203, and CsNaX zeolites. With the zeolites MPVO aetivity decreased with decreasing cesium content. The opposite trend was observed for the acid-catalyzed dehydra-... 

Solid catalysts active in MPVO reactions have surface basicity or Lewis acidity. They include, amongst others, alumina, zirconia, magnesium oxide, and magnesium phosphates. More recent developments include the chemical anchoring of catalytically active co-ordination complexes, and the application of hydrotalcites, mesoporous materials (MCM-41), and zeolites. Anchoring of co-ordination compounds might open the route to true heterogeneous enantioselective MPVO reactions. As a result of their inherent shape-selectivity zeolites uniquely afford remarkable stereoselectivity in MPVO reactions. 

The preliminary experimental work described herein has led us to multiple avenues of research into MPVO reactions using simple and modified aluminum alkoxide catalyst systems. The authors are continuing these various efforts and will publish the detailed results of these investigations elsewhere in the literature. 

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