STRUCTURE AND DYNAMICS OF AZAPROPAZONE DERIVATIVES STUDIED BY CRYSTALLOGRAPHY AND NUCLEAR-MAGNETIC-RESONANCE

The X-ray crystal structure of a derivative of the nonsteroidal anti-i nflammatory drug, azapropazone, has been determined using a data set o btained from a charge-coupled device (CCD) area detector. Azapropazone itself, -pyrazol[1,2-a][1,2,4]benzotriazine-1,3(2H)-dione, has previo usly been shown to be nonplanar, probably due to steric interactions b etween the pyrazolidine ring and the exocyclic dimethylamino group. Th e derivative studied in this work, 3-dimethylamino-7-methyl- 1,2,4-ben zotriazine, does not have the pyrazolidine ring and is shown here to b e strictly planar. There is also a significant difference in the kinet ics of restricted rotation around the bond joining the dimethylamino g roup to the triazine ring, as measured by NMR. Both the enthalpy and e ntropy of activation are quite different. For the chemical exchange of the two methyl groups in azapropazone, Delta H-double dagger = 36 +/- :0.5 kJ mol(-1), and Delta S-double dagger = -34 +/- 2 J K-1. For the derivative, Delta H-double dagger = 48 +/- 0.4 kJ mol(-1), and Delta S -double dagger = -12 +/-:2 J K-1. This is rationalized by assuming the equilibrium state of the derivative is planar, and this defines the p otential energy curve. The ground state of azapropazone is relatively destabilized, and somewhat disordered, by the steric interaction. Ther efore, azapropazone has a small barrier to surmount, and the entropy o f activation should be negative.