Syntheses, Conformations, and Basicities of Bicyclic Triamines

The multistep syntheses of several bicyclic triamines are described, all of which have an imbedded 1,5,9-triazacyclododecane ring. In 1,5,9-triazabicyclo[7.3.3]pentadecanes 12, 13, 15, and 16, two nitrogens are bridged by three carbons. The monoprotonated forms of these triamines are highly stabilized by a hydrogen-bonded network involving the bridge and both bridgehead nitrogens, producing a difference of more than 8 pK a units in acidities of their monoprotonated and diprotonated forms. The one- and zero-carbon bridges in 1,5,9-triazabicyclo[9.1.1]tridecane (23) and 7-methyl-1,5,9-triazabicyclo[5.5.0]dodecane (39) do not enhance the stabilities of their monoprotonated forms. X-ray crystal structures and computational studies of 12·HI and 16·HI reveal similar, but somewhat weaker, hydrogen-bonded networks, relative to 15·HI. The activation free energies for conformational inversion of 13·HI (14.4 ± 0.2 kcal/mol), 16·HI (15.0 ± 0.1 kcal/mol) and 16 (8.8 ± 0.3 kcal/mol) were measured by variable-temperature 1H and 13C NMR spectroscopy. These experimental barriers give an estimate of 6.2 kcal/mol for the strength of the bifurcated hydrogen bond between the bridge nitrogen and cavity proton in 16·HI. Computational studies support the hypothesis that N-inversion occurs in an open conformation, leading to an estimate of 10.32 kcal/mol for the enthalpy of the bifurcated hydrogen bond in 16·HI in the gas phase.