NMR studies of chemical exchange amongst five conformers of a ten-membered ring compound containing two amide bonds and a disulfide†

Abstract

This paper presents experimental measurements which provide a very detailed picture of the free energy surface of a molecule. The compound, N,N′-dimethyl-N,N′-(2,2′-dithiobisacetyl)ethylenediamine (a diamino–disulfide, DADS, chelate), is a symmetrical ten-membered ring compound. Five conformers with significant populations are observed in dimethylformamide solution at 300 K. The ring consists of a pair of methylene groups at the top, each of which is bonded to the nitrogen of an N-methylamide linkage. The amides are then connected, through a methylene group, to a disulfide linkage, which forms the bottom of the ring. The conformations can be classified according to the stereochemistry of the amide bond. The lowest energy conformer, C, has one amide in the Z geometry and one in the E geometry. Conformer B, 0.9 kJ mol^–1 above C, has both amides Z. Two other Z,E conformations, labelled A and E, lie 3.1 and 3.5 kJ mol^–1, respectively, above C. Finally, there is a Z,Z conformer, labelled D, which is 5.6 kJ mol^–1 above C. NMR lineshape and selective-inversion measurements have permitted estimates of some of the barriers to interconversion amongst these conformers. The barrier from C to A, which involves an inversion of the disulfide, has a barrier (ΔG ^‡ at 300 K) of 72 kJ mol^–1, and the barrier from C to D (an amide rotation) is 80 kJ mol^–1. The barrier from A to B, also an amide rotation, is 78 kJ mol^–1. Finally, the barrier to conversion of A to E, which is a ring flip process, is 70 kJ mol^–1. Although the disulfide can invert when one amide is Z and the other is E (this process converts conformer C to A), the barrier to this process when both amides are Z is too high to be measured accurately. Selective-inversion NMR experiments allowed extension of the lineshape exchange measurements to lower temperatures, so that the Gibbs’ free energies above could be separated into entropy and enthalpy contributions. For the C to A process, ΔH ^‡ = 72 ± 1 kJ mol^–1 and ΔS ^‡ = 0 within experimental error. For the C to D process, ΔH ^‡ = 86 ± 1.5 kJ mol^–1 and ΔS ^‡ = 19 ± 4 J K^–1. For the A to B process, ΔH ^‡ = 84 ± 1.2 kJ mol^–1 and ΔS ^‡ = 22 ± 4 J K^–1. For the A to E process, ΔH ^‡ = 74 ± 1 kJ mol^–1 and ΔS ^‡ = 11 ± 3 J K^–1.