CONFORMATIONS AND ROTATIONAL BARRIERS IN NADH AND NAD(+) ANALOGS - A DYNAMIC NMR AND MOLECULAR MECHANICS INVESTIGATION

The conformational preferences and rotational barriers about both the ring-amide bond and the C-N bond in NADH and NAD(+) analogues have been investigated by dynamic NMR spectroscopy and molecular mechanics calculations with the intention to clarify the stereodynamic situation in these types of cross-conjugated amide. The results can be summarized as follows. (i) The primary amides an thioamides are planar or nearly planar and possess ring-amide barriers (Delta G double dagger approximate to 4-7 kcal mol(-1)) over the 90 degrees twisted state. (ii) The cis conformation is strongly preferred for NADH analogues, but in the indole analogue 6b the two conformations differ by only ca. 0.3 kcal mol(-1). (iii) The tertiary amides are twisted in the ground state and have steric barriers (Delta G double dagger = 6-10 kcal mol(-1)) over the planar state. (iv) The C-N barriers are considerably larger, (Delta G double dagger = 11-17 kcal mol(-1) for amides, and 12-21 kcal mol(-1) for thioamides). (v) The barrier heights are governed by the efficiency of the cross-conjugation in the ground and transition stales, and by the steric interactions in the planar conformations. The exchange process observed in NMR for NADH by Redfield et al, is due to C-N rotation and not to amide group rotation.