Synthesis, structural, conformational and DFT studies of N-3 and O-4 alkylated regioisomers of 5-(hydroxypropyl)pyrimidine

•Syntheses of N-3 acyclic and O-4 acyclic pyrimidine derivatives are presented.•Regioisomers were distinguished based on their NMR and FT-IR analyses.•DFT global chemical reactivity descriptors were calculated for the regioisomers.•Descriptors were used to predict and describe stability and reactivity.

Because of the great pharmacological potential of the pyrimidine motif, novel C-5 substituted N-3 acyclic and O-4 acyclic pyrimidine derivatives were prepared as an interesting class of compounds for biological evaluation. Introduction of the 2,3-dihydroxypropyl (DHP) and penciclovir (PCV)-like side chains to 2-methoxypyrimidin-4-one (2) afforded a mixture of N- and O-acyclic pyrimidine nucleosides in the ratio of 54: 29 (3:4) and 57:21 (5:6) with N-3 isomer being dominant. Distinction between N- and O-alkylated pyrimidine moiety was deduced from extensive experimental FT-IR, HPLC-MS and 1D (1H, 13C) and 2D (COSY, HMQC and HMBC) NMR analyses. The N-, O-regioisomers were also examined by computational method at density functional theory (DFT) RB3LYP/6-31G(d), 6-31G∗∗ and 6-31+G∗ levels. DFT global chemical reactivity descriptors (total energy, chemical hardness, electronic chemical potential and electrophilicity) were calculated for the isomers and used to predict and describe their relative stability and reactivity. The chemical reactivity indices were related to the C2N3C4 bond angle. Theoretical predictions can be used to compare chemical reactivity and stability with future biological evaluation and behaviour of these compounds.

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