Quinones hydride transfer

Additionally, it has been noted that Tetralin operates via hydride transfer, at least in its reduction of quinones. Thus it has been shown that Tetralin readily donates hydrogen to electron-poor systems, such as quinones at 50°-160°C. The reaction is accelerated by electron-withdrawing substituents on the H-acceptor and polar solvents, and is unaffected by free radical initiators (6). These observations are consistent with hydride transfer, as is the more recent finding of a tritium isotope effect for the reaction (7). 

Oxidations under Oppenauer conditions are highly selective for alcohols, normally resulting other functionalities sensitive to oxidation unchanged. This happens because the Oppenauer oxidation operates via a mechanism involving a hydride transfer from a metallic alkoxide, which is very specific for alcohols. Over-oxidations have been described only for situations in which very reactive oxidants, such as p-quinone, are employed.14... 

The reactivity of 2- and 3-methoxy-NMAHs towards -acceptors and the cobalt(III) reagent have also been compared (Colter et al., 1984). The 3-methoxy substituent better stabilizes the acridinium ion, while 2-methoxy-NMAH is the better one-electron donor. With a series of quinones in acetonitrile, the 3-methoxy-NMAH is between 4 and 10 times more reactive than its isomer although absolute rates vary by more than 105. With the cobalt(III) oxidant, the 2-methoxy-NMAH is more than 50 times more reactive, suggesting that the quinones react with these acridans uniformly by one-step hydride transfer. 

Entries nos. 1 and 2 deal with a very common type of oxidant in organic chemistry, the so-called high-potential quinones (for a review, see Becker, 1974) which are normally considered to act as hydride-transfer reagents. Entry no. 1 is, however, unique in the sense that all substrates contain aromatic C—H bonds only, the strength of which precludes the operation of a hydride-transfer mechanism. Consequently, we see almost ideal electron-transfer behaviour, provided that E° (DDQH+/DDQH ) in TFA is set equal to 0.87 V. This value is entirely in line with those reported for other media (Becker, 1974). As we go to entry no. 2, where the substrate is difficult to oxidize and has at least one weak C—H bond, electron transfer is not feasible and hydride transfer takes place. The same holds for DDQ oxidation of substituted toluenes (Eberson et al., 1979). 

There are a considerable number of reactions in which the products contain two electrons, more than the starting compounds, and the consecutive two-step one-electron electron transfer process proves to be energetically unfavorable. In such cases, it is presumed that the two-electron process occurs in one elementary two-electron step. An example of a two-electron process is the hydride transfer, when two electrons are transported together with a proton. BH4, hydroquinones and reduced nicotinamides are typical hydrid donors. A specific feature of quinones is the capacity to accept and then to reversibly release electrons one by one or two electrons as a hydride. Therefore, quinones can serve as a molecular device, which can switch consecutive one-electron process to single two-electron process. 

In relatively recent times, a number of biologically novel structures that function as cofactors in redox reactions, some of them as agents of hydride transfer, have been discovered to be present in enzyme or other protein structures. They are often covalently bound and are formed in post-translational reactions from the side-chains of normal, genetically encoded amino-acid residues. The structures are shown in Fig. 4.3, taken from Mure s excellent review [2]. The important chemical functionality of these coenzymes is the quinone ring, an ortho-quinone in most cases, both a para-quinone and an ortho-quinone in TPQ. 

This chapter describes model studies of hydride transfer entirely with respect to nicotinamide coenzymes, flavin coenzymes and quinone coenzymes. Other coenzymes/cofactors may be alluded to but are not reviewed in detail. Some coenzymes involved either in hydride transfer or the transfer of other hydrogen species have been treated elsewhere in these volumes (thiamin diphosphate is treated by Hiibner et al., pyridoxal phosphate by Spies and Toney, folic acid by Benkovic... 

There have been some extraordinarily effective contributions of model-reaction studies, particularly by Klinman and Mure [2], to the understanding of quinone-cofactor chemistry, but there seem to have been no uses of this approach with respect to hydride-transfer reactions. Readers who wish to acquaint themselves with the current situation should consult Davidson s volume of 1993 [64], Klinman and... 

Quinone cofactors are now thought, on the basis of some enzyme structural information, to prefer a hydride-transfer to a proton-transfer mechanism, at least with alcohol substrates. This distinction could benefit greatly from model studies. 

Scheme 2.30. Mechanistic aiternatives of quinone dehydrogenations of hydroaromatic compounds. (1) Hydrogen atom transfer, (2) direct hydride transfer, (3) singie electron transfer, and (4) pericyclic hydrogen transfer.

The dehydrogenation of certain alcohols by quinones (28) is thought to involve a hydride transfer. 

The reaction of alkyl- and halo-substituted phenols with Cr02Cl2 results mainly in the formation of quinones and diphenoquinones. Phenoxyl radicals are involved as intermediates. The mechanism of oxidation of a-hydroxycar-boxylic acids by pyridinium chlorochromate involves a rate-limiting hydride transfer. In the reaction of HOCD2CO2H, a kinetic isotope effect (W d) = 5.80 has been determined. Spectroscopic evidence for Cr(IV) and Cr(V) species has been obtained in the oxidation of alkylaromatics by chromyl acetate in acetic anhydride.Stopped-flow and esr studies show two stages (equations 22, 23) in the reactions of RCH2Ph, with both rates being decreased on deuteration at... 

It was postulated that Ag20 is responsible for generation of o-quinone methide, an efficient hydride acceptor, which upon hydride transfer can form a zwitterionic intermediate capable of subsequent cyclization to furnish the ring-fused oxazine (eq 41). 

These possibilities were followed by the formulation of others. For example Riichardt and co-workers described the possible mechanistic routes for quinone oxidation of hydroarenes with radical pathways (SET/HAT), ionic pathways (direct hydride transfer) and even pericyclic pathways. The conclusions were that initial H-atom transfer appeared more likely than hydride transfer. 

LY311727 is an indole acetic acid based selective inhibitor of human non-pancreatic secretory phospholipase A2 (hnpsPLA2) under development by Lilly as a potential treatment for sepsis. The synthesis of LY311727 involved a Nenitzescu indolization reaction as a key step. The Nenitzescu condensation of quinone 4 with the p-aminoacrylate 39 was carried out in CH3NO2 to provide the desired 5-hydroxylindole 40 in 83% yield. Protection of the 5-hydroxyl moiety in indole 40 was accomplished in H2O under phase transfer conditions in 80% yield. Lithium aluminum hydride mediated reduction of the ester functional group in 41 provided the alcohol 42 in 78% yield. 

Quinones, which become reduced to the corresponding hydroquinones. Two important quinones often used for aromatizations are chloranil (2,3,5,6-tetrachloro-1,4-benzoquinone) and DDQ (2,3-dichloro-5,6-dicyano-l,4-ben-zoquinone). The latter is more reactive and can be used in cases where the substrate is difficult to dehydrogenate. It is likely that the mechanism involves a transfer of hydride to the quinone oxygen, followed by the transfer of a proton to the phenolate ion °... 

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