Reactivity with Substrate Structure

We shall first consider the effects of varying the structure of the substrate on the stabilities of adducts formed with a given nucleophile. The largest body of data in fact relates to reaction with sodium meth-oxide in methanol though data for some other nucleophiles is available. 

In general the successive equilibria of a parent compound, nucleophile, Hu, to form adducts A, B and C can be written  

Addition of methoxide ion in methanol For reactive substrates, such as 1,3,5-trinitrobenzene, which are converted into complex in dilute solutions of sodium methoxide, the equilibrium constant, Kx, is adequately expressed in terms of concentrations as [A]/[P][OMe-]. However, for less reactive substrates, such as dinitrobenzenes, significant conversion to complex only occurs at fairly high concentrations of sodium methoxide similarly for the higher equilibria of trinitro-substituted benzenes. In these solutions the basicity of the medium cannot be adequately described by the con- 

Equilibrium Constants for Complex Formation with Sodium Methoxide in Methanol at 25°C 

6- trinitrophenetole the nitro-groups at the 2 and 4 positions are twisted by 36° and 61° respectively from the plane of the ring, while in the adducts with base much smaller rotations are found. 

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In the discussion of electrophilic aromatic substitution (Chapter 11) equal attention was paid to the effect of substrate structure on reactivity (activation or deactivation) and on orientation. The question of orientation was important because in a typical substitution there are four or five hydrogens that could serve as leaving groups. This type of question is much less important for aromatic nucleophilic substitution, since in most cases there is only one potential leaving group in a molecule. Therefore attention is largely focused on the reactivity of one molecule compared with another and not on the comparison of the reactivity of different positions within the same molecule. 

Studies of the structures of cuprate species were initiated to elucidate the mechanisms by which they interact with substrates and to understand their special reactivities. In the early days these investigations were restricted to solution studies by spectroscopic techniques. It was not until 1982 that the first example of a cuprate species - [(Cu5Ph6)(Li(THF4))j - was structurally characterized by X-ray crystal structure determination [100] (vide infra). It should be noted that most of these studies, reviewed previously [29, 45, 101], were limited to simple alkyl and aryl derivatives. 

The conditions favoring CH30 -CH30H as the nucleophile-solvent system are most commonly employed for structural studies with substrates of varying reactivities, as described in the following sections. 

A rate factor approach to chemical reactivity assumes that structural effects influence rate constants in an additive way. While this assumption enjoys considerable success, an obvious failure arises when dealing with steric effects. Naturally, agreement between calculated and observed results is best when the reaction conditions applied to a new substrate are similar to those used on model compounds to obtain rate factors. 

In addition to participating in acid-base catalysis, some amino acid side chains may enter into covalent bond formation with substrate molecules, a phenomenon that is often referred to as covalent catalysis.174 When basic groups participate this may be called nucleophilic catalysis. Covalent catalysis occurs frequently with enzymes catalyzing nucleophilic displacement reactions and examples will be considered in Chapter 12. They include the formation of an acyl-enzyme intermediate by chymotrypsin (Fig. 12-11). Several of the coenzymes discussed in Chapters 14 and 15 also participate in covalent catalysis. These coenzymes combine with substrates to form reactive intermediate compounds whose structures allow them to be converted rapidly to the final products. 

As mentioned earlier, Ding et al.15 captured a number of dichlorohetero-cyclic scaffolds where one chloro atom is prone to nucleophilic aromatic substitution onto resin-bound amine nucleophiles (Fig. 1). Even though it was demonstrated that in many cases the second chlorine may be substituted with SNAr reactions, it was pointed out that palladium-catalyzed reactions offer the most versatility in terms of substrate structure. When introducing amino, aryloxy, and aryl groups, Ding et al.15 reported Pd-catalyzed reactions as a way to overcome the lack of reactivity of chlorine at the purine C2 position and poorly reactive halides on other heterocycles (Fig. 10). 

Quantitative structure-activity relationships (QSARs) are important for predicting the oxidation potential of chemicals in Fenton s reaction system. To describe reactivity and physicochemical properties of the chemicals, five different molecular descriptors were applied. The dipole moment represents the polarity of a molecule and its effect on the reaction rates HOMo and LUMO approximate the ionization potential and electron affinities, respectively and the log P coefficient correlates the hydrophobicity, which can be an important factor relative to reactivity of substrates in aqueous media. Finally, the effect of the substituents on the reaction rates could be correlated with Hammett constants by Hammett s equation. 

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