Rotation in amides

The restricted rotation in amide bonds results from the partial double bond character of the C-N bond. 

The time scale of the build-up and decay of the NOE is often such that it can be used to study processes that proceed appreciably more slowly than those aceessible to band-shape studies. This has been used in studies of restricted rotation in amides (205,214) the cis-trans equilibrium of 4-bromo-2-formyl-l-methylpyrrole (215) exchange in water solution of the system l-(T-pyrazolyl)ethanol-acetaldehyde (216) and the cis-trans equilibrium in 4-bromo-2-formylfuran. (217)... 

The example of partial double bond character hindering internal rotation in amides has already been discussed above for dimethylformamide. Other examples of hindered rotation are presented in Table 3.7. 

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. 

Rotation about the carbon-nitrogen bond is slow in amides The methyl groups of NJ dimethylformamide are nonequivalent because one is cis to oxygen the other cis to hydrogen... 

Consider a nucleus that can partition between two magnetically nonequivalent sites. Examples would be protons or carbon atoms involved in cis-trans isomerization, rotation about the carbon—nitrogen atom in amides, proton exchange between solute and solvent or between two conjugate acid-base pairs, or molecular complex formation. In the NMR context the nucleus is said to undergo chemical exchange between the sites. Chemical exchange is a relaxation mechanism, because it is a means by which the nucleus in one site (state) is enabled to leave that state. 

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. 

Caillet, J., P. Claverie, and B. Pullman. 1978. Effect of the Crystalline Environment upon the Rotational Conformation about the N-C and C-C Bonds ( and P) in Amides and Peptides. Theoret. Chim. Acta (Berl.) 47, 17-26. 

Fig. 7.20 Illustration of the additivity of conformational geometry functions for the 41-rotation in (CH3NH)(0=)C-C(CH3)(H)(NHCOCH3) (ALA). During the torsional motion about the C(a)-C bond of ALA, the interactions within the system are the same as those encountered during the C(=0)-C torsion in N-methyl propanamide (NMPA), plus those encountered during the C(ct)-C torsion in N-acetyl N -methyl glycine amide offset by 120° as shown (GLY), minus those encountered during the C-C torsion in N-methyl acetamide (NMA).

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,... 

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. 

The oxidative addition can take place from the top of the molecule (as shown), but it can also take place from the bottom, giving another diastereomeric intermediate that probably does not undergo migration. The two oxidative additions require rotations in opposite directions of the substrate with respect to the rhodium phosphine complex. The rotation required also depends on the geometrical isomer of the rhodium complex to be formed (alkene/amide trans or cis to phosphine here we have chosen an amide cis to both phosphorus atoms). Both the major and the minor diastereomeric substrate complex require such a rotation upon oxidative addition. 

A. T. Hagler, A. Lapicirella, Spatial Electron Distribution and Population Analysis of Amides, Carboxylic Acid, and Peptides, and Their Relation to Empirical Potential Functions , Biopolymers 1976, 1167-1200 A. T. Hagler, L. Leiserowitz, M. Tuval, Experimental and Theoretical Studies of the Barrier to Rotation about the N-C° and Ca-C Bonds ([Pg.369]

Exchange broadening is frequently observed in amides due to restricted rotation about the N-C bond of the amide group. 

The restricted rotation about amide bonds often occurs at a rate that gives rise to observable broadening in NMR spectra. 

In aromatic compounds bearing two rotationally restricted amide groups, diastereoiso-meric atropisomers can arise because of the relative orientation of the amides. Ortholithi-ation can therefore lead to diastereoselectivity if the ortholithiation forms one of the two diastereoisomers selectively. A simple case is 169, whose double lithiation-ethylation leads only to the C2-symmetric diamide 170, indicating the probable preferred conformation of the starting material (Scheme 85) . 

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) . 

Chemical shift differences of O-methylmandelates of four different methylcarbinols have been shown15a to be rather small, varying most in 3,3-dimethyl-2-butanol (4 Hz at 110 °C 13 Hz at — 90 °C). Pirkle and Simmons36 have studied the effect of temperature on ATEA derivatives and found that the configuration about the rotationally hindered amide bond is Z and is quite stable to temperature. 

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. "... 

As discussed in Sect. 3, the structure of concave pyridines 3 (Structures 1) is not uniform. Conformers are present due to the hindered rotation in an amide bond. 

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