The geometry of N-hydroxymethyl compounds. Part 5. Studies on ground-state geometry and reactions of N-(hydroxymethyl)pentamethylmelamine and related compounds using MNDO calculations

Abstract

MNDO and PM3 calculations of the most favoured conformations of antitumour N-hydroxymethylmelamines including N-(hydroxymethyl)pentamethylmelamine (2) and trimelamol indicate that the O–H group is orientated towards the closest ring nitrogen but is too distant for hydrogen bonding. Modelling of decomposition pathways of 2 using MNDO predicts that concerted loss of formaldehyde is not favoured. Loss of [H₂COH]⁺ from oxygen-protonated 2 is also a high energy process, but loss of formaldehyde from deprotonated 2 is exothermic with a low activation barrier; this is the most likely decomposition mechanism under basic or neutral conditions. Under acidic conditions loss of water from protonated 2 to give an iminium ion is exothermic from O-protonated 2, but the initial O-protonation is disfavoured over protonation on nitrogen, particularly ring nitrogens. Reaction of 2 with nucleophiles is difficult by S_N2 routes but proceeds exothermically with low activation energies by the S_N1 mechanism from protonated 2 to give products of similar thermodynamic stability to ring-protonated 2. Reaction of O-protonated 2 with amines gives aminals that may decompose with low activation energies to pentamethylmelamine and a methylene iminium ion.