Amide bond rotation

Coldham and coworkers have shown that the asymmetric deprotonation protocol can be used to regioselectively alkylate the 5-position of imidazolidines (Scheme 35). The process is used as part of a sequence that results in asymmetric alkylation of 1,2-diamines with high stereoselectivity. The yields are limited, in this case, by the barrier to rotation around the carbamate C—N bond. Thus, only the amide rotamer having the carbonyl group syn to C-5 of the heterocycle is deprotonated. There are several examples in this review where this limitation is possible whether it is a factor or not may depend on the temperature at which amide bond rotation occurs versus the stability of the organolithium compound. In this case, the barrier to amide bond rotation was determined as 16.6 kcalmoD at 60 °C. 

In this context, the solvent influence on the C—N rotational barrier in N,N-dimethylformamide, Mc2N—CH=0 <-> Me2N+=CH—0 , is noteworthy [280]. For this rotation, the Gibbs free energy of activation in the gas phase AG =81 kJ/mol) is much smaller than in polar HBD solvents such as water AG = 92 kJ/mol). Thus, the rate of amide bond rotation decreases as the polarity and the HBD ability of the solvent increases. This can be attributed to the change in dipole moment on rotation, whereby a polar solvent stabilizes the ground state with the higher dipole moment fi = 3.8 D) in preference to the less dipolar activated complex [280]. 

Otani, Y, Nagae, O., Naruse, Y. et al. (2003) An evaluation of amide group planarity in 7-azabicyclo[2.2.1]heptane amides. Low amide, bond rotation barrier in solution. Journal of the American Chemical Society, 125,15191 15199. 

The necessary molecular rigidity of polybenzamide undoubtedly results from the hindered bond rotation within the planar amide group. 

A nitrogen atom at X results in a variable downfield shift of the a carbons, depending in its extent on what else is attached to the nitrogen. In piperidine (45 X = NH) the a carbon signal is shifted by about 20 p.p.m., to ca. S 47.7, while in A-methylpiperidine (45 X = Me) it appears at S 56.7. Quaternization at nitrogen produces further effects similar to replacement of NH by A-alkyl, but simple protonation has only a small effect. A-Acylpiperidines show two distinct a carbon atoms, because of restricted rotation about the amide bond. The chemical shift separation is about 6 p.p.m., and the mean shift is close to that of the unsubstituted amine (45 X=NH). The nitroso compound (45 X = N—NO) is similar, but the shift separation of the two a carbons is somewhat greater (ca. 12 p.p.m.). The (3 and y carbon atoms of piperidines. A- acylpiperidines and piperidinium salts are all upfield of the cyclohexane resonance, by 0-7 p.p.m. 

C—N bond and restricts rotation around it. The amide bond is therefore planar, and the N—H is oriented 180° to the C=0. 

Certain types of bond, whilst nominally being considered as single , have in fact, sufficient double bond character , to render rotation about their axis, restricted . The one you are most likely to encounter, is the amide bond. Partial double bond character exists between the carbonyl, and the nitrogen, and may be represented as in Structure 6.12 ... 

Secondary amides, on the other hand, generally do not exhibit two rotametric forms (that is not to say that rotation about the amide bond in secondary amides doesn t occur at all - just that secondary amides spend most of their time with the two large groups, R and R2, trans to each other (Structure 6.13). 

In the case of the molecule in Structure 6.14, only the protons of the piperidone ring would be affected by restricted rotation about the amide bond. As far as the aromatic protons are concerned, there is no anisotropic difference in the environment they experience, because the piperidone has a plane of symmetry through it. 

Peptides and proteins are composed of amino acids polymerized together through the formation of peptide (amide) bonds. The peptide bonded polymer that forms the backbone of polypeptide structure is called the a-chain. The peptide bonds of the a-chain are rigid planar units formed by the reaction of the oc-amino group of one amino acid with the a-carboxyl group of another (Figure 1.1). The peptide bond possesses no rotational freedom due to the partial double bond character of the carbonyl-amino amide bond. The bonds around the oc-carbon atom, however, are true single bonds with considerable freedom of movement. 

The characteristic properties of peptides result from the presence of a chain of several or many amide bonds. A first problem is that of numbering, and here Fig. 6.1 taken from the IUPAC-IUB rules may help. A second and major aspect of the structure of peptides is their conformational behavior. Three torsion angles exist in the backbone (Fig. 6.2). The dihedral angle co (omega) describes rotation about C-N,

rotation about N-C , and ip (psi) describes rotation about C -C. Fig. 6.2 represents a peptide in a fully extended conformation where these angles have a value of 180°. 

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

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

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