Cyclophosphamide and isophosphamide – DFT conformational studies in the gas phase and solution

Cyclophosphamide and isophosphamide have been subjected to comprehensive conformational studies in the vacuum and solution using the SMD solvation model. Vacuum calculations were conducted using the B3LYP, M05-2X, M06-2X and ωB97XD functionals. Natural bond orbital (NBO) analysis has been performed for selected geometries. A preference for a chair conformation with the axial P=O bond is shown (1C4). The 5S0 conformation is 1.25–2.31 kcal/mol and 1.72–2.92 kcal/mol higher in energy than the global minimum conformations of cyclophosphamide and isophosphamide, respectively. In the gas phase, the chair conformation with the equatorial P=O bond (4C1) is of comparable stability or less stable than the skew form, depending on the method used, while it is slightly more favored than the 5S0 conformation in solution. The stereoelectronic effects do not differentiate the ring conformer stability. The steric strains between N(EtCl)1–2 and the C4 and C6 carbon atoms mainly influence the stability of cyclophosphamide and isophosphamide conformers. [Display omitted] •A DFT conformational studies of cyclophosphamide and isophosphamide are presented.•The 1C4 conformers are preferred in the gas phase and solution.•The 4C1 conformers are similarly or less stable than the 5S0 one in the gas phase.•The 4C1 conformation is more favored than the 5S0 conformation in solution.•The steric strains influence the stability of cyclophosphamide and isophosphamide.