DFT calculations indicate that N,N'-dihydroxyamidines (DHBs) have favorable geometries for hydrogen bonding to cytosine and its analogues via the OH groups.  At B3LYP/6-311++G** a DHB and cytosine neutrals have a binding enthalpy about the same as that of a DHB anion and the neutral cytosine, about 50 kJ/mol.  The reported acidities of free DHBs are about pKa=11 for the neutral and pKa=4 for the conjugate acid in solution. Protonation increases the strength of the hydrogen bonds considerably.  Despite the fact that free cytosine is more basic than DHBs, cationic complexes with cytosine contain the N,N'-dihydroxyamidinium ions, with a binding enthalpy of  about 115 kJ/mol.  Although the NHs are the acidic groups in the conjugate acid DHB ions, both OH groups form the hydrogen bonds.  Experimental evidence confirms the theoretical analysis.  

Hydrogen bonding between N,N'-dihydroxyamidines and DNA bases

248th National Meeting (2014)

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