Amides isomerization barriers

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) . 

These results indicate that barriers to all isomerization processes in A-acyloxy-A-alkoxyamides are likely to be less than about 8 kcalmol. Like that for its A-chloro analogue, the amide isomerization barrier in 100 is too low to be observed by H NMR. While there is dehnihve X-ray and theoretical evidence for anomeric effects in A-acyloxy-A-alkoxyamides, in the case of 100 the barrier to isomerization about the A-OBn bond must be lower than 10.3 kcalmol, the barrier in the corresponding A-chlorohydroxamic ester (Section in.B.2). The no-Oj Q anomeric interaction in A-chloroadducts is predicted to be stronger than the uo-Oj oAcyi interaction on perturbation arguments . 

Anomeric effects are evident from dynamic NMR studies on at least one substrate, N-benzyloxy-Af-chlorobenzamide (2c) ". In acetone-de the benzyl aromatic signal (S 7.85) de-coalesced into two signals (ratio 2 1) close to 200 K, corresponding to a free energy barrier of ca 10-11 kcalmoH Amide isomerization appeared to be faster than N—0 rotation since benzoyl resonances were largely unaffected. 

Shtamburg and coworkers have reported that A,A -dialkoxy-A,A -dicarboalkoxyhydra-zines (219) have lower barriers to amide isomerization and weaker anomeric interactions . They measured a barrier to amide isomerization of only 9.8 kcalmoD. Furthermore, benzylic methylenes in A-benzyloxy systems were isochronous down to at least —90°C. These results are in line with observations for the A,A -diacyl-A,A -dialkoxyhydrazines since, in the carboalkoxy systems, the nitrogen lone pairs are lowered in energy by the additional electron demand, thereby reducing both amide conjugation and anomeric overlap. 

Isomerization of ( /Z) isomers is another important transformation. Isomerization of ( ) and (Z-) conjugated amides is effected photochemically " (photo-isomerization " ). There is a rather high energy barrier for the excited state required for (E/Z) isomerization. Isomerization of the C=C units in dienes is also induced photochemically. " Isomerization of cyclic alkenes is more difficult but cyclooctene is isomerized photochemically. " Conjugated aldehydes have been isomerized... 

Furancarboxamides and furanthiocarboxamides somewhat resemble the oximes in that there are two sources of isomerism. The rotational isomerism about the C(2)—C(O) bond has not been observed, however — only restricted rotation in the amide link. This is easier than in the benzamides since the furan ring is electron-releasing thus reducing the N—C(O) interaction and giving an energy barrier of about 58kJmol 1. There is little difference... 

The pseudo-double bond character of amides is much more pronounced than for esters due to the conjugation of the H-N-C=0 moiety and is correlated to the ability of distorted amides to be hydrolyzed to bases [19]. For this reason, the barrier to interconversion is significantly higher that for the ester series, with AGl typically ranging from 16 to 22 kcal mol-1 [17]. However, the rotational barrier is not solely due to conjugation and also partly arises from the orientation of the nitrogen lone pair which is perpendicular to the amide plane [20]. Therefore, the rates of isomerization are considerably slower than for esters. This means that both isomers can be observed by simple techniques, for example at room temperature by H and 13C NMR spectrometry and UV spectrophotometry [21]. 

Due to competitive conjugation, ureas have barriers to rotation lower than the corresponding amides. Urea isomerization proceeds either via a classical CTI (AHi = 18.5 1.6 kcal mol ) or a whole-body flip (AHi = 15.5 1.2 kcal mol-1), i.e. from trans-trans to cis-cis. 

Excitation of the dominantly trans-secondary amide by a laser pulse in the 206-208 nm range was reported to cause a photochemical trans to cis isomerization which was monitored by resonance Raman spectroscopy. Activation barriers of 13.8 0.8 kcal mob1 and 11.0 0.7 kcal mob1 were obtained for NMA and Gly-Gly 21, respectively. Temperature dependence experiments determined a Gibbs free energy gap between cis and trans conformers of 2.6 0.4 and 3.1 0.5 kcal mob1 for NMA and 21, respectively [2,86]. 

Despite the similarity of cis to trans interconversion rates, secondary amide peptide bonds and imidic peptide bonds differ greatly in their capacity to form the cis isomeric state. This means that the decreased cis population of secondary amide peptide bonds results from higher rates for CTIs. In the case of the Ala-Tyr dipeptide a 250-fold difference for the interconversion rate constants was observed (kc t = 0.6 s-1, kt c = 2.4 x 10-3 s-1, 298 K) [21]. Generally, chain elongation causes destabilization of the cis conformation when located apart from charged termini, and thus leads to a decreased cis population as well as a lowered barrier to rotation in cis to trans direction. 

Oximes and oxime ethers exist as a mixture of E and Z isomers with a relatively low difference of AG° and a moderate energy barrier to isomerization (<10 kcal mol-1) [28]. They show some similarities with imines and may interconvert at room temperature, spontaneously, by an acid- or base-catalyzed isomerization involving a nitronium ion, and photochemically [29,30]. Oxime ethers have been employed as amide surrogates in peptides where they display a marked Z-E isomerism which is mainly controlled by the formation of H-bonds, which stabilize a given isomer. As an example, the structure of pseudopeptide 6 was investigated by Fourier transform infrared spectroscopy (FTIR) and NMR spectroscopy which both showed that Z-6 is folded in a /Mike conformation by a strong bifurcate hydrogen bond whereas the E isomer adopts an extended conformation (Fig. 13.5) [31]. 

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