Syn lone pair

This affinity for metals results not only from the structural organization of the new diacids but from stereoelectronic effects at carboxyl oxygen as well. The in-plane lone pairs of a carboxylate 18 differ in basicity by several orders of magnitude 16). Conventional chelating agents17> derived from carboxylic acids such as EDTA, 19a are constrained by their shape to involve the less basic anti lone pairs [Eq. (4)]. The new diacids are permitted the use of the more basic syn lone pairs in contact with the metal 19b. These systems represent a new type of chelate for highly selective recognition of divalent ions. 

Reactions of Phosphoric Acids and Their Derivatives. - Numerous investigations of phosphate ester hydrolysis continue to be reported. The hydrolysis between 1.5 < pH < 4 of five- and six-membered cyclic phosphoramides (71) has been followed by UV and NMR spectroscopy. Small differences in hydrolysis reactivity for n = 5 and n = 6 constitutes evidence for syn lone pair catalysis. The product ratios from the hydrolysis shows that in the five-membered rings the main product is the one produced by endocyclic cleavage meanwhile, in the six- membered cyclic phosphoramide the kinetic product is the one produced by exocyclic cleavage. The syn orientation of two electron pairs on nitrogen stabilizes the transition state of water approach to the phosphoramides by ca. 3 kcal/moN when compared to the orthogonal attack. (Scheme 12). ... 

The lone-pair electrons in a carboxylate group are designated syn or antiy as shown in Fig. 18. The proton on another molecule can approach in either of these directions. In the syn conformation (Z-form) the proton is on the same side of the C-0 bond as the other C-0 bond this is the conformation found when carboxyl groups dimerize by forming two hydrogen bonds. On the other hand, in the anti conformation (E-form) the proton is on the opposite side of the C-0 bond from the other C-0 bond. Ab initio quantum chemical studies of formic acid indicate that the syn (Z) conformation is more stable than the anti (E) conformation by about 4.5 kcal mol" implying that the syn lone pairs are more basic (and therefore bind metal ions more readily) than do the anti lone pairs [55]. Carboxylates in active sites of enzymes generally seem to employ the more basic syn lone pairs for metal chelation [56], and it has been estimated that syn protonation is 10 -fold more favorable than anti protonation (since 1.4 kcal mol corresponds approximately to a tenfold increase in rate). The carboxylate ion is therefore a weaker base when constrained to accept a proton in the anti (E) direction. 

The chelation of small molecules described above may be extended to metal ions. The convergence of the carboxyls within the molecular clefts provides a microenvironment ideal for divalent metals. A special structural feature of the new ligands involves stereoelectronic effects at carboxyl oxygen. Classical chelates such as EDTA present the less anti lone pairs to the metal ion, but the new structures offer the more basic syn lone pairs. Metals such as Ca and Mg are tightly bound and readily transported across liquid membranes (Scheme 6). In addition, the mode of binding within the new ligands is exclusively trans, a feature which is likely to lead to altered reactivity of the bound metal ions as catalysts. 

A unique advantage of the new structures relevant to their significance as enzyme models is the possibility of exploring stereoelectronic effects at carboxyl oxygen. Unlike the situation with acyl carbon, reaction trajectories and lone pair orientation at carboxyl oxygen have been difficult to assess. Candour [19] has pointed out that in most enzymes where the carboxylate appears at the active site, the more basic syn lone pair is involved in catalysis. (Scheme 10). 

In previous models for lysozyme or the serine proteases this orientation effect has been neglected. The Loudon [20] structure 20 involves the less basic anti lone pair for stabilizing the developing carbonium ion, while the Fife [21] case 21 involves both the less basic lone pair and the anti form of the carboxylic acid. The Bruice [22] system 22 is typical of serine protease models. These may be contrasted with the convergent arrangement of the diacids in lysozyme 23, or the involvement of the Asp syn lone pair in the serine proteases 24. 

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