Basicity of 3-aminopropionamidine derivatives in water and dimethyl sulphoxide. Implication for a pivotal step in the synthesis of distamycin A analogues

The acid-base properties of eight 3-aminopropionamidine derivatives R1R2N(CH2)2C((DOUBLE BOND)NH)NR3R4 (1, R1 = R2 = R3 = R4 = H; 2, R1 = R3 = R4 = H, R2 = Me; 3, R1 = R2 = R4 = H, R3 = Me; 4, R1 = R2 = H, R3 = R4 = Me; 5, R1 = Tos, R2 = R3 = R4 = H; 6, R1 = Tos, R2 = Me R3 = R4 = H; 7, R1 = Tos, R2 = R4 = H, R3 = Me; 8, R1 = Tos, R2 = H, R3 = R4 = Me; Tos = 4-toluenesulphonyl) related to the antiviral natural product distamycin A were investigated in water and dimethyl sulphoxide (DMSO). The measured pKa values for the ammonium function in 1–4 in water ranged between 7·48 and 7·73, whereas the corresponding values in DMSO were 9·4 ± 0·3. The amidinium moiety of these compounds displayed pKa values in the range 11·4–12·0 and 13·4–13·6 in water and DMSO, respectively. The tosylamide group in compounds 5–8 was deprotonated in the expected pH region and exhibited pKa values between 9·49 and 10·02 in water, but was considerably less acidic in DMSO (14·5 ≤ pKa ≤ 15·7). The behaviour of the amidinium cation of 5–8 in water and DMSO resembled that of 1–4. The measured pKa values are discussed and the solvent-induced pKa shifts are explained in terms of solvent and substituent effects. The observed pKa differences between the ammonium and the amidinium functions in 1–4 render these compounds suitable intermediates in an alternative synthesis of distamycin A.