Conjugate addition and nucleophilic aromatic substitution

Regioselectivity ch24 Conjugate addition of enolates ch26 Reactions of heterocyclic aromatic compounds ch29 ch30 

This chapter is also the last chapter in the second cycle of chapters within this book, with which we complete our survey of the important elementary types of organic reactions. We follow it with two review chapters, where we bring together aspects of selectivity, before looking in more detail at enolate chemistry and how to make molecules. 

To start this chapter, let us take you back to one of the first reactions we introduced nucleophilic addition to carbonyl groups. Here are two examples, both of which give products which you should fully expect. We ve included details of the IR spectra of the products to confirm firstly that the product has no carbonyl group and secondly that the alkene is still there. 

Now let s tweak the conditions we repeat the first reaction at a higher temperature, and we add to the second a small amount of a copper salt. Now the products are different  

Both products A and B have kept their carbonyl group (IR peak at 1710-1715 cm i) but have lost the C=C. Yet A, at least, is unquestionably an addition product because it contains a C=N peak at 2250 cm h 

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Problems for Chapter 22 - Conjugate addition and nucleophilic aromatic substitution 89... 

CHAPTER 22 CONJUGATE ADDITION AND NUCLEOPHILIC AROMATIC SUBSTITUTION... 

A wide variety of other heterocyclic ring systems can conceivably serve as the conjugated backbone in nonlinear organic molecules. We will give examples from preliminary work on two of these, the thiazole and pyrimidine heterocycle derivatives 65-72 in Table VIII. These two heterocycles were chosen because the appropriate haloderivatives are commercially available as starting materials for nucleophilic aromatic substitution. The pyrimidine derivatives are of particular interest since their absorption edges ( 400 nm) are shifted hypsochromically an additional 30 nm relative even to the pyridines. 

The nitro and nitrile functional groups can also accept and delocalize electron density (remember the effect of nitro groups in nucleophilic aromatic substitution), so alkenes bearing these functional groups can also undergo conjugate addition (Figure 17.60). 

Tomioka documented the use of organolithium reagents in enantioselec-tive conjugate additions to conjugated imines (Equation 31) [136]. The readily available chiral diether 173 served to mediate such additions with high asymmetric induction for example, the addition of PhLi to 172 furnished aldehyde 174 in 94% ee after hydrolysis of the imine adduct. In subsequent developments, Tomioka reported the enantioselective preparation of biaryls in which a naphthyllithium participates in a nucleophilic aromatic substitution catalyzed by only 5mol% of 173 (see insert on the left) and delivers the product in 82% ee [137]. 

Heterocycles with conjugated jr-systems have a propensity to react by substitution, similarly to saturated hydrocarbons, rather than by addition, which is characteristic of most unsaturated hydrocarbons. This reflects the strong tendency to return to the initial electronic structure after a reaction. Electrophilic substitutions of heteroaromatic systems are the most common qualitative expression of their aromaticity. However, the presence of one or more electronegative heteroatoms disturbs the symmetry of aromatic rings pyridine-like heteroatoms (=N—, =N+R—, =0+—, and =S+—) decrease the availability of jr-electrons and the tendency toward electrophilic substitution, allowing for addition and/or nucleophilic substitution in yr-deficient heteroatoms , as classified by Albert.63 By contrast, pyrrole-like heteroatoms (—NR—, —O—, and — S—) in the jr-excessive heteroatoms induce the tendency toward electrophilic substitution (see Scheme 19). The quantitative expression of aromaticity in terms of chemical reactivity is difficult and is especially complicated by the interplay of thermodynamic and kinetic factors. Nevertheless, a number of chemical techniques have been applied which are discussed elsewhere.66... 

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