Alkyl cobalamins

In biochemistry, metal hydrides such as NaBH4 have been widely used in synthesis. For example, NaBH4 has been used in the preparation of alkyl cobalamins from cyanocobalamin , and in the synthesis of the chiral [/3,y- 0 7 0, 0]ATPyS from the 5 -aldehyde of adenosine . Lithium triethylborohydride (also known as Su-... 

Vitamin B12s reacts rapidly with alkyl iodides (e.g., methyl iodide or a 5 -chloro derivative of adenosine) via nucleophilic displacement to form the alkyl cobalt forms of vitamin B12 (Eq. 16-31). These reactions provide a convenient way of preparing isotopically labeled alkyl cobalamins, including those selectively... 

A related cleavage by alkaline cyanide can be viewed as a nucleophilic displacement of the deoxy-adenosyl anion by cyanide. The end product is dicyanocobalamin, in which the loosely bound nucleotide containing dimethyl benzimidazole is replaced by a second cyanide ion. Methyl and other simple alkyl cobalamins are stable to alkaline cyanide. A number of other cleavage reactions of alkyl cobalamins are known.392 393... 

The suspected 5-coordinate complexes, Co(saloph)R and base-off al-kylcobalamins, share the behavior that Co—C bond homolysis is less facile than in the counterpart 6-coordinate complexes, LCo(saloph)R and base-on alkyl-cobalamins [93,141,145], Base-off cobalamins (made by adding acid to hy-dronate the benzimidazole ring) and cobinamides (which are derived from cobalamins but lack 5,6-dimethylbenzimidazole) are believed to be 5-coordinate when R is a strong electron donor, but the evidence is primarily spectroscopic [141], However, 5-coordinate species are generally more thermally stable than their 6-coordinate counterparts. 

Thermochemical. Application to the estimation of the enthalpy of a process such as that depicted by Equation 15 requires determination of the heats of formation of LnM—R, R , and LnM . The latter usually is not accessible to measurement although it is in the case of alkyl-cobalamins (where LnM- corresponds to vitamin B12r, a stable and accessible compound). Thus, thermochemical approaches, in principle, are potentially applicable to the estimation of the Co-C bond dissociation energy in coenzyme B12. However, the practical difficulties are considerable and the probable accuracy of the result is questionable. 

The direct extension of similar approaches to other systems, notably alkyl-cobalamins and related alkyl-cobalt compounds, is constrained by the instability of the corresponding hydrides, which are consequently unsuitable as radical traps. Modification of the approach to utilize other radical traps (e.g., 02) potentially is feasible but needs further investigation in view of possible complicating features such as reaction between the trapping agent and the parent metal-alkyl and ambiguities between homolytic dissociation and other (e.g., concerted) mechanisms (26, 27). 

Finally, the apparent thermal stabilities of alkyl-cobalamins, as well as of some of the other transition-metal-alkyl compounds that have been examined in the course of these studies, generally are higher than would correspond to their metal-C bond-dissociation energies. The most probable explanation for this is that, in the absence of effective radical scavengers, homolytic dissociation of metal-alkyl bonds occurs reversibly because of selective recombination of the initially produced radicals and metal complexes. 

Recrystallization from water/acetone (even at a basic pH) causes some hydrolysis of the acetal. (2,2-Diethoxyethyl)cobalamin, like all alkyl cobalamins, is light sensitive in solution in addition, and unlike most other alkylcobalamins, it is add sensitive, decomposing to both (formylmethyl)cobalamin and aqua-cobalamin.2 The formation of other alkylcobalamins and cobaloximes by reaction with enol ethers has been described.2... 

Many short-lived small inorganic radicals and unusual transition metal centers have been generated by photolysis or radiolysis methods in matrices [22], (The matrix can be a glassy frozen solvent or a solid, e.g. zeolite or other oxide). This method is, however, also suitable for investigation of rather complex systems such as alkyl cobalamins and related B12 species [29, 30]. Irradiation with visible light is even sufficient to cleave the crucial Co-Caikyi bond in these macrocyclic compounds to yield Co products and the less persistent alkyl radical intermediates both can be detected by ESR in low-temperature matrices (Eq. 2) [30]. 

Strong bases (pKa > 11) also convert alkyl cobaloximes and alkyl cobalamins into -complexes such as 73. This is usually followed by further decomposition to olefins and alkanes. The stability of complexes such as 73 depends very much upon X and the nature of the axial ligand in the cobalt chelate.98-218-227 230 Strong nucleophiles such as RS or CN can cause decomposition of LCo—R as well.98-231 Under the normal conditions of radical polymerization, Markovnikov organocobaloxime should form whenever the hydride, LCoH, appears in the polymerization mixture. If 1,2-vinylidene monomers are being polymerized, then thermally unstable tert-alkyl-cobaloximes are obtained. These species are expected to undergo homolytic Co—C cleavage to yield tertiary radicals. 

It is claimed that multiple regression analyses, involving Taft s polar substituent constant or and Dubois steric parameter E, can satisfactorily account for the properties of alkyl cobaloximes (R = alkyl) and alkyl cobalamines in terms... 

A series of related reports have appeared on the equilibria between five- and six-coordinate species and possible adduct formation in Co(iii) corrinoids, on the thermodynamic and kinetic properties for what is termed the base-on/ base-off equilibration of alkyl cobalamins, " and on the kinetics and thermodynamics of parallel equilibria of alkyl-13-epicobalamins. In the first report, the pressure dependence of the UV/visible spectra of the five-coordinate (yellow)/six-coordinate (red) equilibrium for both methylcobalamin and vinylcobinamide was obtained. Water is the ligand that converts the five- to a six-coordinate species. The reaction volumes were obtained from the pressure dependence of the equilibrium constant. The values of AF of —12.5 1.2 and —12.5 l.Ocm moF for the methyl and vinyl complexes are close to the values 13cm moF advocated and accepted for the displacement or... 

Another use of cob(I)alamin (40 ) as a tool in toxicology is for the analysis of DNA-phosphate adducts. Utilizing the nucleophilicity of 40", alkyl groups from the phosphotriester configuration in DNA were transferred with the formation of alkyl-cobalamin complexes [251]. 

Surprisingly, the cobalt ion can have the + l(Bi2s), +2(Bi2r)j or +3(Bi2a) oxidation state. Indeed, one of the remarkable properties of alkyl cobalamins is that three routes for cleavage of the Co—C bond are possible ... 

The combination of this radical with the Bi2r species generates a new alkyl cobalamin with the substrate as ligand. We have thus accomplished a transalkylation of the cobalt atom. How does the Co—C bond become activated toward homolytic cleavage It is believed that the presence and proper orientation of the propionamide side chains on the corrin ring are responsible for the ease of the enzymatic system, possibly by some distortion of the corrin (269). Support for this hypothesis comes from the fact that hydrolysis of a side chain to the corresponding acid results in an inactive coenzyme Bi2 molecule. It is not known why nature proceeds by homolytic fission, a unique situation in coenzyme chemistry ... 

---