Amides, rotational barrier

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... 

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. 

Figure 2-51. a) The rotational barrier in amides can only be explained by VB representation using two resonance structures, b) RAMSES accounts for the (albeit partial) conjugation between the carbonyl double bond and the lone pair on the nitrogen atom. 

Rotational barriers for bonds which have partly double bond character are significantly too low. This is especially a problem for the rotation around the C-N bond in amides, where values of 5-10 kcal/mol are obtained. A purely ad hoc fix has been made for amides by adding a force field rotational term to the C-N bond which raises the value to 20-25 kcal/mol, and brings it in line with experimental data. Similarly, the barrier for rotation around the central bond in butadiene is calculated to be only 0.5-2.0 kcal/mol, in contrast to the experimental value of 5.9 kcal/mol. 

Investigations of hydrogen bonding of several thioamides have been carried out by calculations and spectroscopy. Characterization, hydrolysis and cyclization of thioamides have been discussed by using the results of calculations and spectroscopy. Comparison of amides and thioamides has been investigated.81 86 Rotation barriers for a series of amides and thioamides have been calculated.87 93... 

Table 5.27. Methyl rotation barriers Ai+b for various H-bonded andprotonated acetamide X complexes (cf. Fig. 5.64), with comparison NRT bond orders bco and bcs and bond lengths Rco and Rq n of the amide moiety in each complex...

The intimate connection between methyl torsional stiffening and the variation in amide CO/CN bond orders is illustrated in Fig. 5.65. This plot shows that the methyl rotation barrier A /s,b varies roughly linearly with the difference Ab in CO/CN bond orders,... 

Figure 5.65 The dependence of the acetamide methyl-rotation barrier (AT ) on NRT bond-order differences in the amide group (Ab = bco - cn) for various H-bonded complexes of the pseudo-cA (occH(in) = 0°) rotamer (see Table 5.27).

These results clearly indicate that barriers to all isomerisation processes are at least less than about 8kcalmol 1. In /V-benzyloxy-7V-chlorobenzamide 44 the amide isomerisation was not observable but the anomeric overlap resulted in diastereotopic benzylic hydrogens, which at coalescence afforded a barrier for rotation about the N-OBn bond of around 10.3 kcalmol-1.32 Like its /V-chloro analogue, the amide isomerisation barrier in 43 is too low to be observed by 3H NMR and even though there is definitive X-ray and theoretical evidence for anomeric effects in /V-acyloxy-/Y-alkoxyamidcs, the barrier to isomerisation about the N-OBn bond must be lower than 10.3 kcalmol-1. The n0-CN ci anomeric interaction in 44 is predicted to be stronger than the n0-CN OAc interaction in 43 on purturbation arguments.32... 

In tolnene-rfg, below 217 K, the benzyl aromatic signal resolved into two and the ben-zylic protons became diastereotopic. The exchange process, which was characterized by 217 = 246 s and AG = 10.2 kcalmoU, is a complex process involving both rotation aronnd the O—N bond and inversion at nitrogen, bnt since barriers to the former process are small the barrier best reflects that for rotation away from the anomeric conformation (Fignre 13). The amide isomerization barrier is even lower and both energies are in accordance with theoretical calcnlations (10.7 and 7.7 kcalmoG, respectively, for A—O rotation and amide isomerism in A-chloro-A-methoxyformamide) . 

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. 

The conformational barriers in acyclic radicals are smaller than those in closed-shell acycles, with the barrier to rotation in the ethyl radical on the order of tenths of a kilocalorie per mole. The barriers increase for heteroatom-substituted radicals, such as the hydroxymethyl radical, which has a rotational barrier of 5 kcal/mol. Radicals that are conjugated with a n system, such as allyl, benzyl, and radicals adjacent to a carbonyl group, have barriers to rotation on the order of 10 kcal/mol. Such barriers can lead to rotational rate constants that are smaller than the rate constants of competing radical reactions, as was demonstrated with a-amide radicals, and this type of effect permits acyclic stereocontrol in some cases. "... 

The first synthesized concave bases, the concave pyridine bislactames 3 (Structures 1), possess two amide groups in each molecule. The rotational barrier for a carboxamide bond is ca. 75 kJ/mol [12b, 19]. Therefore at room temperature, E-and Z-forms are observed in the NMR spectra. Because each concave pyridine bislactame 3 contains two amide groups, diastereoisomeric conformers are observable (see Fig. 2). Structures 5 show the ZZ-, EZ- and -conformers for the concave pyridine 3c. 

The rotational barriers of A-nitroso-, A-formyl and A-(A,A-dimethylcarbamoyl)-azetidines, compared with those of analogous acyclic amides, suggest that amide conjugation is weaker when the nitrogen is part of an azetidine ring (87KGS912). 

Separate signals for N-alkyl groups syn or (Z) and anti or ( ) to the carbonyl oxygen are observed for N-N-dialkylamides (Table 4.35) [313-315] due to the amide resonance. But the rotational barrier of the CN partial double bond decreases with increasing size of the carboxylic acid residue R [315]. 

---