Cyanides involving radicals

Radical formation is a requisite step in cytochrome P450 hydroxylations, and cytochrome P450-mediated hydroxylation proceeds by a stepwise process involving radical substrate intermediates. Metabolism of nitriles to release cyanide involves radical formation on the a-carbon, followed by subsequent hydroxylation to the corresponding cyanohydrin intermediate, which decomposes readily to release cyanide and the corresponding carbonyl-containing co-product. Cytochrome P450-mediated release of cyanide from nitriles is depicted in Scheme 4.4. 

There have been several recent investigations into the mechanism of photo-cyanation of aromatic hydrocarbons. The process with naphthalene, biphenyl, and phenanthrene has been subjected to a kinetic analysis the reactions in dry or aqueous methyl cyanide are shown to involve two transient species, the first of which is an ionic complex formed from a triplet excimer of the arene, or, in the presence of an electron acceptor, from a triplet exciplex. Reaction of the transient complex with the cyanide ion yields the radical ArHCN, and in aqueous methyl cyanide this second transient reacts with itself to produce dihydrocyano- and cyano-compounds. In dry methyl cyanide the radical species is oxidized to the cyano product. 

As a class of compounds, the two main toxicity concerns for nitriles are acute lethality and osteolathyrsm. A comprehensive review of the toxicity of nitriles, including detailed discussion of biochemical mechanisms of toxicity and stmcture-activity relationships, is available (12). Nitriles vary broadly in their abiUty to cause acute lethaUty and subde differences in stmcture can greatly affect toxic potency. The biochemical basis of their acute toxicity is related to their metaboHsm in the body. Following exposure and absorption, nitriles are metabolized by cytochrome p450 enzymes in the Hver. The metaboHsm involves initial hydrogen abstraction resulting in the formation of a carbon radical, followed by hydroxylation of the carbon radical. MetaboHsm at the carbon atom adjacent (alpha) to the cyano group would yield a cyanohydrin metaboHte, which decomposes readily in the body to produce cyanide. Hydroxylation at other carbon positions in the nitrile does not result in cyanide release. 

Most photochemical reactions are not very polar and often involve free radical intermediates. But initiation of a reaction by light is no infallible indication of a radical mechanism, as is clear from the example of the photo-ionization of certain triarylmethyl cyanides.448... 

The primary step in the photolysis of phenyl mercuric cyanide and cyclohexyl mercuric cyanide in methanol at room temperature is mercury-phenyl or mercury-cyclohexyl bond rupture111. The subsequent steps in the mechanism are complex, but do not involve the parent substance. Reactions involving HgCN must be postulated to explain the observed product, so that this radical must have a finite existence. 

In addition to the irritant effects, cyanogen chloride may also cause interference with cellular metabolism via the cyanide radical. Cyanide ion exerts an inhibitory action on certain metabolic enzyme systems, most notably cytochrome oxidase, the enzyme involved in the ultimate transfer of electrons to molecular oxygen. Because cytochrome oxidase is present in practically all cells that function under aerobic conditions, and because the cyanide ion diffuses easily to all parts of the body, cyanide quickly halts practically all cellular respiration. The venous blood of a patient dying of cyanide is bright red and resembles arterial blood because the tissues have not been able to utilize the oxygen brought to them. Cyanide intoxication produces lactic acidosis, probably the result of increased rate of glycolysis and production of lactic acid. ... 

The function of the target molecule may be critical or mncritical. Thus, if the target molecule is an enzyme, this could be involved in a crucial metabolic pathway, such as mitochondrial oxidative phosphorylation. In this case, an adverse interaction with the ultimate toxicant is likely to lead to cell dysfunction and possibly death (e.g., as with cyanide or salicylate). Chemicals such as methimazole and resorcinol, which are activated to free radical intermediates by thyroperoxidase, cause destruction of the enzyme. This then disturbs thyroid hormone synthesis and thyroid function with pathological consequences such as thyroid tumors. 

The most common reactions involving nucleophiles and porphyrin systems take place on the metalloporphyrin 77-cation radical (i.e. the one-electron oxidized species) rather than on the metalloporphyrin itself. One-electron oxidation can be accomplished electrochemi-cally (Section 3.07.2.4.6) or by using oxidants such as iodine, bromine, ammoniumyl salts, etc. Once formed, the 77-cation radicals (61) react with a variety of nucleophiles such as nitrite, pyridine, imidazole, cyanide, triphenylphosphine, thiocyanate, acetate, trifluoroace-tate and azide, to give the correspondingly substituted porphyrins (62) after simple acid catalyzed demetallation (79JA5953). The species produced by two-electron oxidations of metalloporphyrins (77-dications) are also potent electrophiles and react with nucleophiles to yield similar products. 

The commonest reactions involve the displacement of halide by hydroxide or cyanide ion to yield co-ordinated phenols or nitriles. Once again, the metal may play a variety of different functions. The polarisation of the C-Cl bond is the most obvious, but stabilisation of the product may be of equal importance, as could the involvement of a metal coordinated nucleophile. The availability of a one-electron redox inter-conversion between copper(n) and copper(i) also opens up the possibilities of radical mechanisms involving homolytic cleavage of the C-Cl bond. All of these different processes are known to be operative in various reaction conditions. In other cases, organocopper intermediates are thought to be involved. 

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