Amides steric hindrance

If the reactions occurred merely statistically, we should expect twice as much ortho as para product because there are two ortho positions. However, we should also expect more steric hindrance in ortho substitution since the new substituent must sit closely beside the one already there. With large substituents, such as the amide, steric hindrance will be significant and it is not surprising that we get more para product. 

Acylation of 6-APA by the naphthoic acid, 13, again affords an agent with considerable steric hindrance about the amide function. There is thus obtained the antibiotic nafcillin (14). a compound with good resistance to penicillinases. 

Both methods of nitrile synthesis—SN2 displacement by CN- on an alkyl halide and amide dehydration—are useful, but the synthesis from amides is more general because it is not limited by steric hindrance. 

The selectivity decreases with increasing amide size. This may be due to steric hindrance which prevents the chiral ligand from approaching the reaction site or may reflect a change in the reaction mechanism going from an SN1 reaction (A-acylimine 2 as intermediate) to an SN2 displacement of benzotriazole11. 

Molecules that contain two or three bulky aryl groups. An example is 2,2-dimesitylethenol (112). In this case, the keto content at equilibrium is only In cases such as this steric hindrance (p. 189) destabilizes the keto form. In 112 the two aryl groups are 120° apart, but in 113 they must move closer together (w 109.5°). Such compounds are often called Fuson-type enols ° There is one example of an amide with a bulky aryl group, A-methyl l w(2,4,6-triisopropylphenyl)acetamide, that has a measurable enol content, in sharp contrast to most amides. 

This reaction to bicyclic compounds containing the aziridine group was also observed for other amides, viz., 44c-f, when treated with a catalytic amount of f-BuOK in THF or MeONa in methanol. LDA treatment of the tosyl-activated substrate 44 a gave the five-membered ring product albeit in a low yield (31 %). Remarkably, the carboxamide derived from the cz5-aziridine failed to react with base, probably due to steric hindrance. 

Steric effects on both the amide and the acyloxyl side chain are similar. Tert-butyl and adamantyl groups on the amide side chain in 29v, 29x, 29c, and 29e (Table 2 entries 53 and 54, 63 and 65) result in lower stretch frequencies that, on average, are only 40 cm-1 higher than their precurser hydroxamic esters. Streck and coworkers have suggested that such changes in dialkyl ketones can be ascribed to destabilisation of resonance form II through steric hindrance to solvation which, in the case of tert-butyl counteracts the inductive stabilisation.127... 

Alkoxycarbonylation of 2,3-dichloro-5-(methoxymethyl)pyridine (78) took place regioselectively at C(2) to give ester 79 [79], Aminocarbonylation of 2,5-dibromo-3-methylpyridine also proceeded preferentially at C(2) to give amide 80 despite the steric hindrance of the 3-methyl group [80]. 

Methylation in both ortho-positions on the aniline ring appears to impede hydrolysis of the amide bond. Thus, 2,4,6-trimethylacetanilide (4.105) was not hydrolyzed by rat liver homogenates, perhaps due to steric hindrance by the 2- and 6-Me groups [71]. Similarly, the amide bond of the hypocholes-terolemic agent 2,2-dimelhyl-A-(2,4,6-trimethoxypheiiyl )dodccanamidc... 

Niclosamide (4.158), which carries the three substituents, was hydrolyzed by neither mammalian liver nor helminth tissue preparations. The resistance of niclosamide to enzymatic hydrolysis was explained by steric hindrance caused by the two substituents adjacent to the amide bond [102], But, since monosubstitution also considerably reduced hydrolysis, one can postulate that H-bonding and electronic effects also contributed to the hydrolytic stability of niclosamide. 

After oral administration of ameltolide (4.143, Fig. 4.6) to rats, no hydrolytic products were detected in biological fluids [103], One could argue that the two o-Me groups afforded steric protection to the amide bond. However, steric hindrance may not be the main reason for the absence of metabolic cleavage in this compound, since, for lidocaine (4.12, Fig. 4.5), cleavage of the amide bond represents a major metabolic route in mammals. The apparent absence of hydrolysis in the metabolism of ameltolide may be caused by the predominance of major alternative pathways, namely A-acetylation and hydroxylation. Furthermore, the small fraction of unidentified polar metabolites may contain some products of hydrolysis. 

The salicylimides (4.169) were found to be markedly more resistant to chemical hydrolysis than 4.166. These compounds were hydrolyzed exclusively at the distal amide bond, meaning that hydrolysis produced only sali-cylamide (4.170) and not salicylic acid. This behavior has been ascribed to steric hindrance by the 2-OH group. An intramolecular general base catalysis does not seem to be involved since, as stated, the salicylamides were less reactive than the corresponding benzamides. The rate of plasma-catalyzed hydrolysis of the A-acylsalicylamides was also dependent on the nature of... 

As with the O-Mannich bases discussed above, the rate of nonenzymatic hydrolysis of N-Mannich bases depends on factors such as steric hindrance and electrophilicity of the sp3 C-atom. A rather large number of studies have been published on the value and properties of N-Mannich bases as potential prodrugs for amines, amides, and imides [80] [82] [88] [89], Here, we first review available reactivity data and then discuss selected examples of medicinal relevance. 

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