Stereodynamics of 1,3,5-trialkyl-1,3,5-triazacyclohexanes: H-1 and C-13 dynamic NMR studies. Solvent effects. Ab initio and molecular mechanics calculations

The H-1 NMR signal due to the ring methylene protons of 1,3,5-trimethyl-1,3 ,5-triazacyclohexane (TMTAC), 1,3,5-triethyl-1,3,5-triazacyclohexane (TETAC ), 1,3,5-tri-isopropyl-1,3,5-triazacyclohexane (TPTAC), and 1,3,5-tri-(tert -butyl)-1,3,5-triazacyclohexane (TBTAC) decoalesces over the temperature ra nge from 330 down to 190 K due to the slowing of chair-to-chair interconver sion. Free energies of activation (Delta G(not equal) = 12.8-10.3 kcal/mol) decrease with increasing steric bulk of the alkyl substituents. At tempera tures below 200 K. in solvents that do not hydrogen-bond to nitrogen, the H -1 and C-13{H-1} NMR spectra show a second decoalescence due to slowing inv ersion at nitrogen. Under conditions of slow chemical exchange, the spectra of all four compounds show a strong preference for three equivalent monoax ial conformations. No other conformations are detected. Free energies of ac tivation for interconversion among monoaxial conformations via sequential i nversions at nitrogen (Delta G(not equal) = 7.3-5.7 kcal/mol) decrease with increasing steric bulk of the alkyl substituents. For TBTAC, this work con stitutes a rare, unequivocally documented case of a preferred axial tert-bu tyl group unconstrained by any counterpoised substituent on the chair confo rmation of a saturated six-membered ring. The data also establish a strong preference for the monoaxial conformations in TETAC and TPTAC. In a solvent that can hydrogen-bond to nitrogen (CHF2Cl), TMTAC and TETAC show a strong preference for the monoaxial conformations, but they also show about 1% of the triequatorial conformation at 120-130 K, providing evidence for mitiga tion of the anomeric effect by hydrogen-bonding. TPTAC shows only monoaxial conformations in CHF2Cl; the triequatorial conformation is not detected. I n a dramatic reversal of conformational preference, TBTAC in CHF2Cl shows o nly the triequatorial conformation at 112 K. Barriers to conformational int erconversion, via nitrogen inversion, increase in CHF2Cl, consistent with h ydrogen-bonding to nitrogen. Attempts to calculate the energies of 1,3,5-tr ialkyl-1,3,5-triazacyclohexane equilibrium conformations using available mo lecular mechanics force fields were unsuccessful. Changes in three torsiona l constants in the MMX (PCMODEL) force field give significantly improved ag reement with experiment and with ab initio (HF/6-31G*) calculations. The mo dified MMX (PCMODEL) force field was also used to study the effect of hydro gen-bonding by methanol on the conformational energies of the 1,3,5-trialky l-1,3,5-triazacyclohexanes. These calculations are in remarkably good agree ment with the experimental NMR data in CHF2Cl, including the reversal of co nformational preference in TBTAC, providing additional support for mitigati on of the anomeric effect by hydrogen-bonding.