Acylation substitution

CARBOXYLIC ACID DERIVATIVES NUCLEOPHILIC ACYL SUBSTITUTION... 

Carboxylic Acid Derivatives Nucleophilic Acyl Substitution... 

Both stages involve more than one step and these steps differ in detail among the various carboxylic acid derivatives and for different reaction conditions This chapter is organized to place the various nucleophilic acyl substitutions into a common mechanis tic framework and to point out the ways m which individual classes differ from the rest... 

IS general for nucleophilic acyl substitution and well worth remembering The range of reactivities is quite large a factor of about 10 m relative rate separates acyl chlorides from amides... 

The features that complicate the mechanism of nucleophilic acyl substitution are almost entirely related to acid-base chemistry We try to keep track as best we can of the form m which the various species—reactants intermediates and prod nets—exist under the reaction conditions... 

Each one of these can proceed to the product of nucleophilic acyl substitution Dissociation of TI—H ... 

Mechanisms for a number of nucleophilic acyl substitutions will appear m the sec tions that follow It is better to look for the important ways m which they are similar than to search for details m which they differ... 

The sp hybridized carbon of an acyl chloride is less sterically hindered than the sp hybridized carbon of an alkyl chloride making an acyl chloride more open toward nude ophilic attack Also unlike the 8 2 transition state or a carbocation intermediate m an Stvfl reaction the tetrahedral intermediate m nucleophilic acyl substitution has a stable arrangement of bonds and can be formed via a lower energy transition state... 

Conversions of acid anhydrides to other carboxylic acid derivatives are illustrated m Table 20 2 Because a more highly stabilized carbonyl group must result m order for nucleophilic acyl substitution to be effective acid anhydrides are readily converted to carboxylic acids esters and amides but not to acyl chlorides... 

Nucleophilic acyl substitutions at the ester carbonyl group are summarized m Table 20 5 on page 849 Esters are less reactive than acyl chlorides and acid anhydrides Nude ophilic acyl substitution m esters especially ester hydrolysis has been extensively mves tigated from a mechanistic perspective Indeed much of what we know concerning the general topic of nucleophilic acyl substitution comes from studies carried out on esters The following sections describe those mechanistic studies... 

From acyl chlorides (Sections 15 8 and 20 4) Alcohols react with acyl chlorides by nucleo philic acyl substitution to yield esters These reactions are typi cally performed in the presence of a weak base such as pyri dine... 

The mechanism of acid catalyzed ester hydrolysis is presented m Figure 20 4 It IS precisely the reverse of the mechanism given for acid catalyzed ester formation m Section 19 14 Like other nucleophilic acyl substitutions it proceeds m two stages A... 

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