Leaving groups relative ability

The relative leaving-group abilities of R 0 and are strongly correlated with the... 

Dithiocarbamatc 16 has been used to prepare low dispersity PMAA ( Mw 1 Mn-1.2).52 Photopolymerization of S in the presence of dithiocarbamate 16 also displays some living characteristics (molecular weights that increase with conversion, ability to make block copolymer). However, 17 appears to behave as a conventional initiator in S polymerization.53 The difference in behavior was attributed to the relatively poor leaving group ability of the 2-carboxyprop-2-yI radical. This hypothesis is supported by MO calculations. Dithiocarbamatc 17 was used to control polymerizations of MMA,54 HEMA54 and NIPAM.5... 

In contrast to the lability of certain dN adducts formed by the BHT metabolite above, amino acid and protein adducts formed by this metabolite were relatively stable.28,29 The thiol of cysteine reacted most rapidly in accord with its nucleophilic strength and was followed in reactivity by the a-amine common to all amino acids. This type of amine even reacted preferentially over the e-amine of lysine.28 In proteins, however, the e-amine of lysine and thiol of cysteine dominate reaction since the vast majority of a-amino groups are involved in peptide bonds. Other nucleophilic side chains such as the carboxylate of aspartate and glutamate and the imidazole of histidine may react as well, but their adducts are likely to be too labile to detect as suggested by the relative stability of QMs and the leaving group ability of the carboxylate and imidazole groups (see Section 9.2.3). 

Such rate difference as there is for attack on (86) depends on the ability of X, through electron-withdrawal, to influence the relative ease of attack on the substrate by the nucleophile it is in the reverse order of the relative ability of the halide ions as leaving groups. When the same series of halides is reacted with C HsNHMe (in nitrobenzene at 120°), however, the relative rates for X = F, Cl and Br were found to be 1, 15 and 46, e.g. in the order of their relative ability as leaving groups, so that in this latter reaction it would appear that step (2) is now involved, to some extent at least, in the rate-limiting step overall. 

In HO -catalyzed hydrolysis (specific base catalyzed hydrolysis), the tetrahedral intermediate is formed by the addition of a nucleophilic HO ion (Fig. 3.1, Pathway b). This reaction is irreversible for both esters and amides, since the carboxylate ion formed is deprotonated in basic solution and, hence, is not receptive to attack by the nucleophilic alcohol, phenol, or amine. The reactivity of the carboxylic acid derivative toward a particular nucleophile depends on a) the relative electron-donating or -withdrawing power of the substituents on the carbonyl group, and b) the relative ability of the -OR or -NR R" moiety to act as a leaving group. Thus, electronegative substituents accelerate hydrolysis, and esters are more readily hydrolyzed than amides. 

Some cephalosporins can be both substrates and inhibitors of /3-lactamases. The acyl-enzyme intermediate can undergo either rapid deacylation (Fig. 5.4, Pathway a) or elimination of the leaving group at the 3 -position to yield a second acyl-enzyme derivative (Fig. 5.4, Pathway b), which hydrolyzes very slowly [35][53], Thus, cephalosporins inactivate /3-lactamases by a mechanism similar to that described above for class-II inhibitors. It has been hypothesized that differences in the rate of deacylation of the acyl-enzyme intermediates derive from their different abilities to form H-bonds. A H-bond to NH in Fig. 5.4, Pathway a, may be necessary to assure a catalytically essential conformation of the enzyme, whereas the presence of a H-bond acceptor in Fig. 5.4, Pathway b, may drive the enzyme to an unproductive conformation. The ratio between hydrolysis and elimination, and, consequently, the relative importance of substrate and inhibitor behaviors of cephalosporins, is determined by the nature of the leaving group at C(3 ). An appropriate substitution at C(3 ) of cephalosporins may, therefore, increase the /3-lactamase inhibitory properties and yield potentially better antibiotics [53]. 

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