Shielding, secondary steric effects

Secondary steric effects on chemical reactivity can result from the shielding of an active site from the attack of a reagent, from solvation, or both. They may also be due to a steric effect on the reacting conformation of a chemical species that determines its concentration. 

Steric factors play a major role in the acylation of /V-alkyl amino acids during peptide synthesis. It is expected that the increased nucleophilicity of secondary amines, as compared to primary amines, will increase the rate of acylation. However, the opposite is observed acylation of /V-alkyl amino acids (except for Pro) is usually slower than the acylation of primary amines. This is explained by steric hindrance exerted by the /V-alkyl group, which shields the nucleophilic center. The steric effect increases with the size of the /V-alkyl group and is enhanced by bulky side chains and, to a lesser extent, by other remote groups. The relative rate of acylation of various types of /V-alkyl amino acids, as compared to amino acids, is shown in Scheme 35. 

The better the solvent stabilizes the ions, the more probable that the reaction will follow an SN1 pathway (e.g., in polar protic solvents such as water/acetone). The more highly substituted is the incipient carbenium ion, the more probable that the reaction will follow an SN1 pathway. The more unreactive the nucleophile, the more probable it becomes that a reaction with secondary and tertiary electrophiles will follow an SN1 pathway. A weaker nucleophile is not as effective in the backside attack, since this location is sterically shielded, especially in the case of tertiary substrates. Carbenium ions are planar and therefore less sterically hindered, and are naturally more reactive as electrophiles than the uncharged parent compound. 

Several mechanisms, depending on the type of catalyst used, have been proposed to achieve the effective activation of the a-carbon of the carbonyl compound (Scheme 27.1). The use of a chiral primary or secondary amine as organocatalysts led to the formation of a nucleophilic enamine, which then reacts with the electrophilic heteroatom to give the new C-heteroatom bond. Two different types of interactions, steric or electronic, generated by the nature of the substitution at the chiral amine determine the stereochemical outcome of the reaction. Thus, for proUne and their derivatives [3], the approach of the electrophile by the Si-face is forced by the steric shielding of the Re-face of the enamine by the substituent at... 

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