Acid base catalysis electrophilic substitution

Both acid and base catalysis have been used extensively to catalyze exchange in aromatic, and to a lesser extent, heterocyclic molecules. In acid exchange, the most widely used catalysts are sulfuric acid,122,129, 131 phosphoric acid,132 trifluoroacetic acid5133 perchloric acid,134 aluminum chloride,135 and the phosphoric acid-boron trifluoride complex.132 These reactions constitute the simplest electrophilic substitution. The mechanism for such substitution in benzenoid compounds is now comparatively well understood 122 however, the problem of heteroaromatic electrophilic substitution is still being clarified and has led to renewed interest in acid-catalyzed exchange in heterocyclic compounds.122... 

An acid catalyst increases the rate of a reaction by donating a proton to a reactant. In the preceding chapters we have seen many examples of acid catalysis. For example, we saw that an acid provides the electrophile needed for the addition of water or an alcohol to an alkene (Section 6.6). We also saw that an alcohol cannot undergo substitution and elimination reactions unless an acid is present to protonate the OH group, which increases its leaving propensity by making it a weaker base (Section 11.1). 

Among common carbon-carbon bond formation reactions involving carbanionic species, the nucleophilic substitution of alkyl halides with active methylene compounds in the presence of a base, e. g., malonic and acetoacetic ester syntheses, is one of the most well documented important methods in organic synthesis. Ketone enolates and protected ones such as vinyl silyl ethers are also versatile nucleophiles for the reaction with various electrophiles including alkyl halides. On the other hand, for the reaction of aryl halides with such nucleophiles to proceed, photostimulation or addition of transition metal catalysts or promoters is usually required, unless the halides are activated by strong electron-withdrawing substituents [7]. Of the metal species, palladium has proved to be especially useful, while copper may also be used in some reactions [81. Thus, aryl halides can react with a variety of substrates having acidic C-H bonds under palladium catalysis. 

The p/fa for benzimidazole is 12.3 and for indazole, the value is 13.9. The benzimidazolyl and indazolyl anions react straightforwardly on nitrogen with electrophiles, though mixtures of N-1- and N-2-substituted products can result in the latter case. For example, amination with hydroxylamine 0-suIfonic acid gives a 2 1 ratio of 1-amino-l//-indazole and 2-amino-2//-indazole ° or to take another example, the ratio of N-1-to N-2-ethylated products from methyl indazol-3-ylcarboxylate can vary from 1 1 to 18 1 depending on the base and the solvent. The N-arylation of benzimidazoles and indazoles can be achieved with palladium or copper catalysis (See 4.2.10). 

The putative general base catalyst, Glu-43, and electrophilic catalysts, Arg-35 and Arg-87, have been specifically mutated to Asp (9/, 92) and Lys (93) residues, respectively, in the author s laboratory to assess the roles of these amino acid residues in catalysis. Other amino acids were also introduced at these positions, but the present discussion will briefly outline the results obtained with the conservative substitutions. As mentioned previously, the rate acceleration characteristic of the SNase-catalyzed hydrolysis of DNA is approximately 10. The Asp substitution for Glu-43 (E43D) decreased the catalytic efficiency approximately 10, and the Lys substitutions for Arg-35 (R35K) and Arg-87 (R87K) decreased the catalytic efficiency approximately 10 and 10, respectively. While such decreases in catalytic efficiency have been used to describe quantitatively the roles of various active site residues in catalysis, such interpretation is clearly unwarranted in the case of these active site mutants of SNase. The melting temperatures of all three of these mutant enzymes differ significantly... 

Another common reaction is based on the acidity of the a-carbon proton, i.e., the carbon attached to the carbene carbon, a topic that will be discussed in detail in this chapter. The carbanion that results from the deprotonation of the a-carbon can act as a nucleophile and react with a variety of electrophiles, especially in the presence of Lewis acid catalysis, to form many different products (see, e.g., equations 2 or The basicity and nucleophilicity of the carbanion can be enhanced by substituting the MeO group by a Me2N group or replacing a CO ligand with an electron donating one, e.g., R3P. ... 

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