Amides rotation

Wiberg, K.B. (2000). Origin of the amide rotational barrier. In The Amide Linkage. Structural Significance in Chemistry, Biochemistry and Materials Science, Greenberg, A., Breneman, C.M. and Liebman, J.F. (eds), p. 33. John Wiley Sons, Inc., New York... 

Amides possess planar or almost planar structures (1 and 2). Their rotational ground state is stabilized because the amino group is a strongly electron-donating group and the carbonyl function is strongly electron accepting. Excellent reviews on this topic have been published (28,29,30), and should be consulted by readers interested in amide rotation. 

Saturated centers in the corresponding dihydro and tetrahydro derivatives interrupt cycloconjugation and rotation of the amide becomes more difficult (A/7 for amide rotations 17kcalmol in both) <1992JA4307>. 

Conformational effects are clearly important in the cyclization of alkyl amides. It was observed60 that the proportion of products 16/17 + 18 from the cyclization of amide 15 did not change with changing electronic demands of the catalyst. Apparently, rhodium-catalyzed cyclization is faster than amide rotation. 

The barrier to amide rotation is about 16 kcal/mol. It was later demonstrated53 that aryl amides, such as 19, with a somewhat lower barrier to rotation, do rotate more rapidly than they cyclize. Selectivity, then, is governed by electronic and steric factors. 

A number of azabicyclic derivatives have also been investigated (7 ICC 1104) as model compounds to study the effect of increasing the nitrogen inversion barrier upon the amide rotational barrier. From the experimental results and simplified MO pictures of the inversion and rotational mechanism, the authors (71CC1104) conclude that changes in the amide rotational barrier do not necessarily correspond to enhancement of the nitrogen inversion barrier. 

Optical Rotatory Dispersion in the Carbohydrate Group. Part VI. The Amide Rotation Rule, T. L. Harris, E. L. Hirst, and C. E. Wood, /. Chem. Soc., 1658 (1935). 

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... 

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). 

Now, if we take amide rotation in N,N-dimethylacetamide as an example, we can assume that = 0.05 sec", which is the observed rate constant at neutral pH. Knowing that at pH 1.8 = 6.7 see allows us... 

To probe the transition state structure for these reactions further, the effect of para substituents on amide rotation rates was measured for a series of N,Af-dimethylbenzamides (Berarek, 1973). When the data are correlated with cTp (Ritchie and Sager, 1964), a p value of —1.14 0.06 is obtained (see Fig. 2). The negative p value indicates that electron-donating substituents accelerate the reaction. This can rationalized in the context of Scheme III, where resonance forms for these substrates are shown. The rotational barrier about the C—N bond is decreased as resonance forms I and III predominate. If R is electron donating, these resonance forms will contribute more to the structure of the amide than will II and C-N rotation will therefore be accelerated. 

The single most revealing mechanistic parameter for prolyl isomerization and amide rotation is the secondary deuterium isotope effect. In general for such studies, the hydrogens on the carbon that is bonded to the carbonyl carbon of the amide or imide (the /3-hydrogens ) are substituted with deuterium and reaction rate constants are measured for... 

Fig. 2. Linear free energy correlation for amide rotation in Af,Af-dimethylbenzamides. Rate constants were taken from the work of Berarek (1973) and correlated with values (Ritchie and Sager, 1964) to obtain a p value of -1.14 0.06 (r = 0.986).

In more general terms, amide rotation is a simple example of an equilibrium reaction. If we replace rotation about the C-N bond with extent of reaction we have a picture of a typical reaction in which reagents and products are in equilibrium. 

Atropisomerism was demonstrated in 379. It arose from aryl-C=0 and amide rotations. The rotation about the N-p5u-azolyl-aryl bond was not blocked (09BMCL1767). 

Similarly, photolysis of the complex TpW( = CH Bu)Cl(NPh) induces rotational isomerism of the alkylidene ligand and proton transfer to generate TpW( = C Bu)Cl(NHPh). The syn orientation of the amido substituent and the alkylidyne ligand positions the amide proton distal to the alkylidyne ligand, disfavouring the reverse tautomerisation reaction without prior amide rotation or catalysis. 

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