Solvent effect nitroimidazoles

The solvent effects on the relative stabilities of 4-nitroimidazole and 5-nitroimidazole exhibit interesting patterns81. In the excited state the 5-nitro isomer is more stable than the 4-nitro isomer in aprotic solvents, while the stability order is reversed in the ground state. 

Nitroimidazole in solution (amphiprotic medium) is stabilized as the 5-nitro isomer due to formation of hydrogen bond with an aprotic protophilic solvent [1124], The medium favors displacement of the tautomeric equilibrium toward the 4-nitro isomer via formation of a solvate complex at the same time 4-nitroimi-dazole acts as hydrogen-bond acceptor. The specific solvatochromic effect in the UV spectrum of 4-nitroimidazole is caused by the electronic configuration of the excited jr,ji -state [1124],... 

It is not always necessary to use a large quantity of solvent to have a low concentration of dissolved substrate. Using a solvent in which the reactant is only partially dissolved will have the same effect. The nitroimidazole, 12, was selectively hydrogenated only in concentrated ammonia, a solvent in which the concentration of dissolved reactant was low enough that the amount of the intermediate nitroso compound in solution was minimized and condensation with... 

The tautomeric character of the imidazole system is involved in the synthesis of the related dmg dimetridazole (9.52, 1,2-dimethyl-5-nitroimidazole), which is an effective agent against trichomonal infections in veterinary medicine (Scheme 9.28). The synthesis involves the nitration of 2-methylimidazole to form 2-methyl-5-nitroimidazole (9.50), followed by N-methylation. However, compound 9.50 is involved in tautomeric equilibrium with compound 9.51 (2-methyl-4-nitroimidazole), which would give an isomer (9.53) on methylation. This can be avoided by the proper choice of solvent. Using a nonpolar solvent for methylation with dimethyl sulfate, the desired 9.52 is the predominant product. Tautomerism is a complicating factor in imidazole chemistry where an NH unit is present, and N-alkyl derivatives are more commonly encountered. We will see this factor again with the purines. 

Sun and DiMagno demonstrated the rapid generation of Af-methyl-5-fluoro-4-nitroimidazole from the corresponding chloride using anhydrous TBAF that was generated in situ from KF by fluoride relay (Scheme 60) [75]. hi fluoride relay, the reaction of KF with 2,6-dicyano-tetrachlorobenzene transfers the fluoride to the arene that finally produces the activated anhydrous tetrabutylammonium fluoride (TBAF) upon the addition of tetrabutylammonium cyanide (>60 % yield from KF). Other polar aprotic solvents, such as THF and acetonitrile, are also effective for this SnAt fluorination reaction. 

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