Resonance effects proton removal

Cephalosporins such as cefixime (5.40) and cefotaxime (5.41) undergo epimerization at C(7) under alkaline conditions without preliminary /3-lactam ring opening. The epimerization is believed to begin with the removal of the acidic H-atom at C(7). The acidity of this proton derives from the resonance effect of the neighboring carbonyl group (Fig. 5.13) enhanced by the presence of electron-withdrawing substituents at C(3 ) [113][114],... 

Tuning of selectivity in the metallation of m-anisic acid has been realized by an appropriate choice of base.67 The results obtained with LTMP have indicated that the regiochemistry of the lithiation of m-anisic acid is thermodynamically controlled. Resonance and inductive effects favour removal of the H(2) proton. In contrast, superbases such as n-BuLi-r-BuOK are not significantly influenced by or//m-directing groups and preferentially attack H(4), the inductively activated aromatic position next to the most electronegative heteroatom and/or the most acidic position available. 

It is known that, at the HORROR condition, homonuclear dipolar couplings between xHs are reintroduced, leading to partial removal of the heteronuclear coupling.28 29 It is worth noting that at 60 and 120 kHz the proton decoupling is insufficient due to the rotary resonance effect. It has been shown theoretically by Emsley and co-workers,19 that the first and second rotary resonances are partially quenched by the presence of homonuclear couplings. 

Because the polarity of carbon-hydrogen bond is very small and exhibits very low acidity, very strong bases are required for such reactions. However, C-H bonds adjacent to substituents such as carbonyl or cyano groups are stabiUzed by resonance/induction and are more acidic. Nitrogen bases have been used effectively in these reactions to minimize the nucleophihc addition that can compete with proton removal when an organometallic compound such as n-butyllithium is used as the base. For example, methyl ketones react with Hthium diisopropylamide (LDA) to form the enolate ion (Eq. (3.4)), and even more sterically hindered amides have been used. The enolate anion is a strong base and a good nucleophile ... 

In summary, the carboxylic acid is stronger if after the removal of the proton, it can form a more stable conjugated base, the carboxylate anion. The anion is stabilized by electron delocalization over the largest possible region of the molecule. The charge delocalization can occur in two ways through the ju-electron system by the resonance effect or through the a-electron network by the inductive effect. The resonance effect has already been explained in the section on alcohols when we discussed the acidity of phenol (vide infra). 

In the Elcb mechanism, the direction of elimination is governed by the ease of removal of the individual (3 protons, which in turn is determined by the polar and resonance effects of nearby substitutents and by the degree of steric hindrance to approach of base to the proton. Alkyl substituents will tend to retard proton abstraction both electronically and sterically. Preferential proton abstraction from less hindered positions leads to the formation of the less substituted alkene. This orientational preference is opposite to that of the El reaction. 

The influence of two meto-interrelated DMGs can be concerted to direct the metalation in between them. LTMP metalates meta-znmc acid 9 in THF at 0°C at the doubly activated position (C2) [62]. The regiochemistry of this lithiation is truly thermodynamically controlled resonance and inductive effects favor removal of the H2 proton. LICKOR deprotonates preferentially the C4 position. To prepare 6-substituted benzoates, one has to (i) protect the C2 site by introducing a trimeth-ylsilyl group with LTMP, (ii) lithiate with s-BuLi/TMEDA, (iii) quench with an electrophile, and (iv) remove the protecting group in C2. 

The base-weakening resonance in aromatic amines (3) was discussed in section II.B. Substituents capable of — / effect increase the proton removal of conjugate acids of aniline more strongly from the nearer position. Groups with +/and +i effects in the ortho and para positions result in an increase in pX values, whereas those groups with —R effects decrease these values. The low pX value of o-NHa relative to ffz-NHa (see Table 7), presumably reflects steric factors impeding... 

The broadening effects of may be removed not only by N substitution but also by proton- N decoupling produced by double resonance techniques. The information concerning 7(N—H) is, however, lost in a decoupling experiment. 

Removal of a proton from Lj gives an anion whose lone pair is orthogonal to the it bond of the carbonyl group by virtue of the rigid geometry of the bicyclic system. Consequently the lone pair cannot overlap with the carbonyl n bond and delocalization via resonance is not possible—it is effectively a localized anion. Removal of a proton from L2 gives rise to a lone pair in a p orbital which can overlap with the carbonyl it bond and thus resonance delocalization is possible. Thus the anion from L2 is resonance stabilized and is thus formed more easily. 

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