The Lone-Pair Bond Weakening Effect

ELECTRON-DEFICIENT MOLECULES, GIANT MOLECULES, AND CONNECTIVITY 

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Valence Bond Analysis of the Lone Pair Bond Weakening Effect for the X—H Bonds in the Series XH = CH4, NH3, OH2, FH. 

Scheme 7 Lone-pair bond-weakening effect (LPBWE) in the ionic structure for halogen (X) transfer reactions in (a) and the lack of LPBWE in the ionic structure of H transfer reactions in (h). Adapted from [9] with permission of Wiley-VCH...

The chemical shift of the methine proton in orthoamide 223 is 2.3 ppm. It is therefore at a much higher field than that of orthoamide 122. This remarkable difference of 2.7 ppm can be ascribed to a dramatic stereoelectronic effect. The origin of the unusual spectroscopic properties of orthoamide 123 presumably is the antiperiplanar relationship of the central C-H bond to the three lone pairs. This arrangement permits mixing of the lone pair orbital with the antibonding orbital of the central C-H bond (a ). As a result, the electron density at the methine hydrogen increases and the central C-H bond is weakened. Indeed, this hydrogen has a notably small chemical shift. 

The effect is naturally more pronounced if the substituent is charged. The best known example is the so-called anionic oxy-Cope reaction,54 where an O- at position 3 induces a rate acceleration of 1010-1017-fold, a result generally attributed to the 3-4 bond weakening.47 55 The lone pairs of HN" lie at even higher energies than those of O-. The 3-4 bond breaking then becomes so easy that the anionic amino-Cope reaction occurs by a stepwise mechanism.56... 

As indicated in Scheme VII/32, cyclononanone (VII/165) is transformed into hydroperoxide hemiacetal, VII/167, which is isolated as a mixture of stereoisomers. The addition of Fe(II)S04 to a solution of VII/167 in methanol saturated with Cu(OAc)2 gave ( )-recifeiolide (VII/171) in quantitative yield. No isomeric olefins were detected. In the first step of the proposed mechanism, an electron from Fe2+ is transferred to the peroxide to form the oxy radical VII/168. The central C,C-bond is weakened by antiperiplanar overlap with the lone pair on the ether oxygen. Cleavage of this bond leads to the secondary carbon radical VII/169, which yields, by an oxidative coupling with Cu(OAc)2, the alkyl copper intermediate VII/170. If we assume that the alkyl copper intermediate, VII/170, exists (a) as a (Z)-ester, stabilized by n (ether O) —> <7 (C=0) overlap (anomeric effect), and (b) is internally coordinated by the ester to form a pseudo-six-membered ring, then only one of the four -hydrogens is available for a syn-//-elimination. [111]. This reaction principle has been used in other macrolide syntheses, too [112] [113]. 

Finally, transition states for hydroxide attack and methoxide departure, corresponding to each of the rotameric TBP intermediates [56]-[58] were partially geometry-optimized. Population analysis of these putative penta-coordinate transition states does indeed demonstrate that the bond-weakening effects observed in the intermediate and ground state are accentuated in the transition state . The percentage decreases in overlap population in P—O bonds subject to an app lone-pair interaction in the ground, intermediate and transition states are 4-5%, 6-8% and 7-12% respectively. 

This anomeric (n->CT ) interpretation, employing an electron-delocalization model, is the basis of the phosphorus app lone-pair hypothesis (PAPH). This hypothesis is completed by integration of two observations from the theoretical calculations discussed above (I) bond-weakening effects are calculated to be greater for apical than equatorial P—O bonds and (2) effects on conformational energy and electron distribution are amplified in pentacoordinate transition-state structures. 

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