Leaving groups, amino

The differences in the rates of alkaline hydrolysis of /3-lactams have been shown to depend primarily on the basicity of the amino leaving group [76]. The rate of alkaline hydrolysis increases as the pKa of the leaving group increases. Several structural features affecting the pKa of the leaving amino group are summarized in Table 5.4, the details of which follow. 

The rate of hydrolysis in monocyclic /1-lactams can also be predicted from the basicity of the amino leaving group Table 5.4,H) [90]. 

Aziridines can be readily prepared utilizing 1,2-amino leaving groups as precursors. Traditionally an amine lone pair or an amide anion facilitates an intramolecular nucleophilic displacement to generate the aziridine ring. Utilization of enantiomerically pure 1,2-amino leaving groups renders the possibility of enantiopure aziridines via asymmetric synthesis. 

Figure 12.9 Proposed catalytic mechanism for carboxypeptidase A. The C-terminal residue, R represent a bulky, hydrophobic side chain. Carboxypeptidase (EC3.3.4.17.-) promotes the polarization of the scissile carbonyl group by hydrogen bonding to Argl27, the activation of water molecule by Zn and its deprotonation by Glu270. The zinc-hydroxide ion attack on the carbonyl carbon forms the tetrahedral oxyanion transition state. The formation of products requires protonation of the amino leaving group presumably by Glu270...

Additionally, aziridines can be prepared via a 1,2-amino-leaving group motif generated either in situ or as part of the starting material. For example, an atom economic, direct conversion of epoxides into N-aryl aziridines was reported via the employment of N-arylphosphoramidate anions (14TL5890). Shown below... 

In the anthraquinone series, apart from the special case of the amination of leucoquinizarin, sulfonic acid and nitro are the preferred leaving groups. 1-Aminoanthraquinone is manufactured from anthraquinone-l-sulfonic acid or 1-nitroanthraquinone, and 2-amino anthraquinone (betamine) from anthraquinone-2-sulfonic acid. 

In the second major method of peptide synthesis the carboxyl group is activated by converting it to an active ester, usually a p-nitrophenyl ester. Recall from Section 20.12 that esters react with ammonia and amines to give fflnides. p-Nitrophenyl esters are much more reactive than methyl and ethyl esters in these reactions because p-nitrophenoxide is a better (less basic) leaving group than methoxide and ethoxide. Simply allowing the active ester and a C-protected amino acid to stand in a suitable solvent is sufficient to bring about peptide bond formation by nucleophilic acyl substitution. 

Peptide bond resonance has several important consequences. First, it restricts free rotation around the peptide bond and leaves the peptide backbone with only two degrees of freedom per amino acid group rotation around... 

Some substituents such as the acylamino group are readily decomposed by many nucleophiles to give a poorer leaving group (e.g., amino). Others, such as nitroamino and sulfonylamino, are less reactive when they are anionized by the nucleophile. 3-Nitroamino-pyridazine (117) and its 6-methyl derivative are readily aminated with benzylamine (130°, short time ). 4,6-Dimethyl- and 6-methyl-2-nitroaminopyrimidine undergo 2-substitution on warming a few minutes with hydroxylamine, hydrazine, primary or secondary alkylamines, or anilines. 

The activation in cinnolines is sufficient to enable nucleophilic substitution of poor leaving groups such as amino and phenoxy... 

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