Theoretical study of molecular structure, reactivity, lipophilicity, and solubility of N-hydroxyurea, N-hydroxythiourea, and N-hydroxysilaurea

Ab initio molecular orbital methods at the CBS-QB3 level of theory have been used to study the structure and gas-phase stability of various tautomers and rotamers of N-hydroxyurea, N-hydroxythiourea, and N-hydroxysilaurea, their anions and protonated forms. The geometries of N-hydroxyurea, N-hydroxythiourea, and N-hydroxysilaurea, their anions and cations were optimized at the Becke3LYP/CBSB7 level of theory. For all compounds studied, the amidic form is computed to be substantially more stable than the iminolic tautomer. N-Hydroxyurea and its thio and sila derivatives are computed to behave as N acids in the gas phase. These compounds are in gas-phase weak acids with a calculated acidity of about 1425 to 1355 kJ-mol(-1). Basicities increase in the order: N-hydroxyurea < N-hydroxythiourea < N-hydroxysilaurea. The most stable protonated structures are represented by several isomers with almost equal stability. Thus, in the N-hydroxyurea, N-hydroxythiourea, and N-hydroxysilaurea, both protonation at the double bonded (C=O, C=S and Si=O) oxygen and sulfur atoms, as well as the protonation at the N( H) OH nitrogen basic center is equally probable. The experimental pK(a) value (10.6) of N-hydroxyurea and the computed value (9.7) for its monohydrated complex with the specifically hydrogen-bonded water molecule to the ionizable OH group are in a good agreement. The experimental partition coefficient of N-hydroxyurea is best reproduced by the Alog P-s method. The formation of nitroxide radical in the reaction of N-hydroxyurea and its sulfur and silicon substituted derivatives with the phenol radical is an exothermic process. Thus, the-N(H)OH moiety of these compounds may quench the structurally related tyrosyl radicals in the active site of ribonucleotide reductase.