Mechanisms of ketones

D. C. Wigeield, Stereochemistry and Mechanism of Ketone Reductions by Hydride Reagents, Tetrahedron 35,449 (1979). 

Ketone bodies are formed in the liver mitochondria by the condensation of three acetyl-CoA units. The mechanism of ketone body formation is one of those pathways that doesn t look like a very good way to do things. Two acetyl-CoAs are condensed to form acetoacetyl-CoA. We could have had an enzyme that just hydrolyzed the acetoacetyl-CoA directly to acetoacetate, but no, it s got to be done in a more complicated fashion. The acetoacetyl-CoA is condensed with another acetyl-CoA to give hydroxymethylglutaryl-CoA (HMG-CoA). This is then split by HMG-CoA lyase to acetyl-CoA and acetoacetate. The hydroxybutyrate arises from acetoacetate by reduction. The overall sum of ketone body formation is the generation of acetoacetate (or hydroxybutyrate) and the freeing-up of the 2 CoAs that were trapped as acetyl-CoA. 

Other mechanisms of ketone oxidation are also known and will be discussed in Chapter 8. Peracid, which is formed from aldehyde, oxidizes ketones with lactone formation (Bayer-Villiger reaction). 

Hewitt LA, Palmason C, Masson S, et al. 1990. Evidence for the involvement of organelles in the mechanism of ketone-potentiated chloroform-induced hepatotoxicity. Liver 10 35-48. 

The mechanism of ketone addition has been studied in detail for the reaction of MesAl with benzophenone [50]. With a 1 1 ratio, a coordination complex MeaAl Ph2CO is formed first, and this subsequently rearranges to the adduct, presumably via a 4-centered transition state. With an excess of Me3Al, a path involving two Me3Al units seems to be preferred, and a 6-centered transition state (similar to structure 6 studied theoretically for dinuclear olefin insertion [36, 37]) has been proposed for this alternative path. Studies using more complicated systems also suggest that, if a 6-centered transition state is available, this is preferred over a 4-centered transition state [51]. 

When alkyl halides were used, some elimination occurred to give the corresponding alkene.490 [Pd(CO)(PPh3)2] was again believed to be formed in situ when PPh3 complexes were used as catalysts. The mechanism of ketone formation is shown in Scheme 39. 

Q Use your knowledge of the mechanisms of ketone and aldehyde reactions to propose mechanisms and products of similar reactions you have never seen before. Problems 18-50, 58, 62, 63, 68, and 69... 

The stereoselective enolization of 3-pentanone by LiTMP mixed aggregates with butyl-lithium was studied by Pratt and coworkers. The mixed aggregate resulted in a slightly higher stereoselectivity, which increased with decreasing amount of the lithium base. Semiempirical PM3 calculations were used in an attempt to determine the mechanism of ketone deprotonation by the mixed aggregate. Equations 20 and 21 show two alternative mechanisms for the formation of lithium acetone enolate in thf solution, involving... 

The chemical reactivities of ketones follow the order terf-butyl > ethyl > methyl, which is the stability order for the cations or radicals of these groups. This suggests that the mechanisms of ketone decomposition involve a rate-determining migration of an electrophilic alkyl moiety of the ketone, perhaps leading to the production of acyl and alkoxy radicals from some partially oxidized intermediate. 

The electron transfer/proton transfer mechanism of ketone reduction is under thermodynamic control and not surprisingly leads to the more stable alcohol, usually a trans- alcohol.364b Conjugated ketones react to... 

Figure 10.1. Mechanism of ketone hydrogenation as proposed by Schrock and Osborn. ...

Figure 10.2. Mechanism of ketone reduction in strongly basic media as proposed by Gargano. ...

The mechanism of ketone alkylation was established to proceed via a radical intermediate (19). The following steps were postulated ... 

In view of the complexity of ketone body metabolism, it is not surprising that the mechanism of ketone body production in human diabetes or in pregnant and lactating ruminants is far from understood. Yet the progress of the last decades has permitted the proposals of a number of hypotheses to explain the pathogenesis of ketosis. 

Carbonyl Group Reduction. Brown and Krishnamurthy have published an account of the development of hydride reduction over the past forty years from an interesting research observation to an invaluable synthetic method. Another recent article gives a critical discussion of the stereochemistry and mechanism of ketone reduction by hydride reagents. 

Horn JS, Paul AG, Rapoport H (1978) Biosynthetic conversion of thebaine to codeinone. Mechanism of ketone formation from enol ether in vivo. J Am Chem Soc 100 1895-1898 Kametani T, Ihara M, Honda T (1970) The alkaloids of Corydalis pallida var. tenuis (Yatabe) and the structures of pallidine and kikemanine. J Chem Soc (C) 1060—1064 Kirby GW, Massey SR, Steinreich P (1972) Biosynthesis of unnatural morphine derivatives in Papaver somniferum. J Chem Soc Perkin Trans 1 1642-1647 Kleinschmidt G, Mothes K (1959) Physiology and biosynthesis of alkaloids in Papaver somniferum. Z Naturforsch 14b 52-56... 

Goddard JD, Yamaguchi Y, Schaefer HF III (1992) The decarboxylation and dehydration reactions of monomeric formic acid. J Chem Phys 96 1158-1166 Gonzalez F, Munuera G, Prieto JA (1978) Mechanism of ketonization of acetic acid on anatase Ti02 surfaces. J Chem Soc Faraday Trans 74 1517-1529 Gould ES (1959) Mechanism and structure in organic chemistry. Holt, New York, pp 346-353... 

Vergote T, Gathy T, Nahra E, Riant O, Peeters D, Leyssens T (2012) Mechanism of ketone hydrosilylation using NHC-Cu(I) catalysts a computational study. Theor Chem Acc 131 1253... 

Mechanism of ketone hydrosilylation using NHC-Cu(I) catalysts a computational study... 

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