Conformational studies on some nitrogen containing compounds.

Abstract

Some N.M.R. techniques used in conformational analysis, the principal factors peculiar to heterocyclic conformational analysis, and the background to conformational effects in alkyl substituted hydroxylamines are reviewed. The synthesis of N-carbethoxy- and N-methyl-tetrahydro-1,2- oxazines is discussed. The mechanism of formation of N-carbethoxytetrahydro-1,2-oxazines from the condensation of 1,4 dibromo-alkanes with N-hydroxyurethan under basic conditions is found to proceed by initial attack of the oxy-anion tautomer, formed from N-hydroxyurethane, on the more reactive bromo-substituted carbon. The preferred conformations of several N-methyl-tetrahydro1,2-oxazines are deduced from their N.M.R. spectra, and a measure of the free energy difference between the equatorial and axial positions for a methyl group substituted on any one of the four ring carbon atoms is estimated. A qualitative rationalisation of the variation in free energy difference with the point of substitution is given. The N-methyl group is found to strongly prefer the equatorial position. The stereochemistry of the B/C ring junction of the alkaloid geneserine is deduced from its N.M.R. spectra, and is found to be cis. The conformational equilibrium at nitrogen in some N,N-dimethyl-hexahydropyrimidines is studied by N.M.R. For N,N-dimethyl hexahydropyrimidine and l,3,5-trimethyl-hexahydropyrimidine a free energy difference between an equatorial and axial N-methyl group of ca. 0.5 kcal./mol. is found. A new method of measuring rate constants by N.M.R. using a small digital computer is tested by studying the barriers to internal rotation in the N,N-dimethyl amides of the three pyridine carboxylic acids. The method is found to be satisfactory, and the free energies of activation for the rotational process at 25°C are 17.9 kcal./mol. for N ,N-dimethyl picolinamide, 15,9 kcal./mol. for N,N-dimethyl nicotinamide, and 16.6 kcal./mol. for N,N-dimethyl isonicotinamide. The error on these values is considered to be less than 0.1 kcal./mol.