Amide rotation organic solvent effects

Two types of solvent effects have been determined for prolyl isomerization and amide rotation (1) the effect of solvent deuterium on reaction rate and (2) the effect of organic solvents on reaction rate. Solvent deuterium isotope effects are useful tools in probing the role of proton transfer... 

To supplement the data on prolyl isomerization, I will draw on the literature describing rotation about the C-N bond in secondary amides. Early studies in this field were described by Stewart and Siddall in an excellent 1970 review. As we will see, these reactions are related to prolyl isomerization and support the mechanism to be proposed for prolyl isomerization. The mechanism is based on results from a variety of experimental approaches. In all cases, experiments employing kinetic-based probes will be used to obtain an accurate picture of the activated complex in the rate-limiting transition state. The experiments that will be described include thermodynamics, in which activation parameters (i.e., AG, AHt, and ASt) will be described solvent effects, in which the influence of organic solvents and deuterium oxide will be reviewed acid-base catalysis substituent effects and secondary deuterium isotope effects. 

The effect of organic solvents on the rate constant for amide rotation in Af,A -dimethylacetamide (DMA) has also been investigated (Drakenberg et ai, 1972). As the solvent is changed from water to acetone to cyclohexane, first-order rate constants for rotation increase from 0.025 to 0.33 to 1.5 sec . This observation that nonpolar solvents increase reaction rates indicates that the transition state for amide rotation is nonpolar relative to the reactant state and, thus, is stabilized in nonpolar solvents. This transition state is presumably characterized by partial rotation about the amide bond. In this transition state, polar resonance structures for the amide bond no longer exist and, thus, the transition state is less polar than the reactant state. The 60-fold rate acceleration that accompanies transfer of DMA from water to cyclohexane will provide an important clue in understanding enzymatic prolyl isomerization (see below). 

The chromophores are closely related to those in peptides. Dissymetric perturbations of the amide chromophores of the main chain arise solely from side chain effects the aliphatic polyisocyanate has enhanced rotational strength as compared to its model compound (5 )-(-)-A,A -diacetyl-2-methylbutylamine. In the aliphatic polymer, the main chain has inherently symmetric chromophores which acquire optical activity from dissymetric perturbation of their environment by the side chain. In the aromatic polymer an additional Cotton effect also arises from interactions among the aromatic side chains. This enhancement may be explained by a conformational preference resulting from favored spatial arrangements of the asymmetric side chain but the study was complicated by the fact that the polymer is insoluble in most organic solvents except in chloroforms and by the specific interactions between this solvent and the urea-like main chain (XIXc). 

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