Nucleophilic Acyl Substitution Mechanisms

Thioesters undergo the same kinds of reactions as esters and by similar mechanisms Nucleophilic acyl substitution of a thioester gives a thiol along with the product of acyl transfer For example... 

Q> j Mechanism 22.1 General Mechanism—Nucleophilic Acyl Substitution... 

Reactions of carboxylic acids can be grouped into the four categories indicated in Figure 15.2. Of the four, we ve already discussed the acidic behavior of carboxylic acids in Sections 15.2 and 15.3, and we mentioned reduction by reaction of the acid with LiAlH4 in Section 13.3. The remaining two categories are examples of fundamental carbonyl-group reaction mechanisms— nucleophilic acyl substitution and a substitution—that will he discussed in detail in Chapters 16 and 17. 

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... 

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 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... 

Hydrazine cleaves amide bonds to form acylhydrazides according to the general mechanism of nucleophilic acyl substitution discussed in Chapter 20... 

The hydrolysis of a carboxylic acid derivative is but one exanple of a nucleophilic acyl substitution. The mechanism of nucleophilic acyl substitution is one of the major... 

Nucleophilic acyl substitutions follow a two-stage mechanism and proceed by way of a tetrahedral intermediate. 

In addition to illustrating the mechanics of translation. Figure 28.12 is important in that it shows the mechanism of peptide bond formation as a straightforward nucleophilic acyl substitution. Both methionine and alanine are attached to their respective tRNAs as esters. The amino group of alanine attacks the methionine carbonyl, displacing methionine from its tRNA and converting the carbonyl group of methionine from an ester to an anide function. 

THF) at room temperature (Scheme 18) (95T8605). The proposed mechanism for this conversion involves the abstraction of H3 by basic attack of NaH to give an enolate anion, which, via ring opening, affords the 2(5//)-furanone 61 by a straightforward intramolecular nucleophilic acyl substitution (Scheme 18) (95T8605). 

Both in the laboratory and in living organisms, the reactions of carbonyl compounds take place by one of four general mechanisms nucleophilic addition, nucleophilic acyl substitution, alpha substitution, and carbonyl condensation. These... 

General mechanism of a nucleophilic acyl substitution reaction. 

The net effect of the addition/elimination sequence is a substitution of the nucleophile for the -Y group originally bonded to the acyl carbon. Thus, the overall reaction is superficially similar to the kind of nucleophilic substitution that occurs during an Sn2 reaction (Section 11.3), but the mechanisms of the two reactions are completely different. An SN2 reaction occurs in a single step by backside displacement of the Leaving group a nucleophilic acyl substitution takes place in two steps and involves a tetrahedral intermediate. 

Show the mechanism of the following nucleophilic acyl substitution reaction, using curved arrows to indicate the electron flow in each step ... 

Mechanism of Fischer esterification. The reaction is an acid-catalyzed, nucleophilic acyl substitution of a carboxylic acid. 

We said in Section 17.4 that carboxylic acids are reduced by L1AIH4 to give primary alcohols, but we deferred a discussion of the reaction mechanism at that time. In fact, the reduction is a nucleophilic acyl substitution reaction in which —H replaces -OH to give an aldehyde, which is further reduced to a primary alcohol by nucleophilic addition. The aldehyde intermediate is much more reactive than the starting acid, so it reacts immediately and is not isolated. 

Acid halides are among the most reactive of carboxylic acid derivatives and can be converted into many other kinds of compounds by nucleophilic acyl substitution mechanisms. The halogen can be replaced by -OH to yield an acid, by —OCOR to yield an anhydride, by -OR to yield an ester, or by -NH2 to yield an amide. In addition, the reduction of an acid halide yields a primary alcohol, and reaction with a Grignard reagent yields a tertiary alcohol. Although the reactions we ll be discussing in this section are illustrated only for acid chlorides, similar processes take place with other acid halides. 

Conversion of Acid Chlorides into Alcohols Reduction Acid chlorides are reduced by LiAJH4 to yield primary alcohols. The reaction is of little practical value, however, because the parent carboxylic acids are generally more readily available and can themselves be reduced by L1AIH4 to yield alcohols. Reduction occurs via a typical nucleophilic acyl substitution mechanism in which a hydride ion (H -) adds to the carbonyl group, yielding a tetrahedral intermediate that expels Cl-. The net effect is a substitution of -Cl by -H to yield an aldehyde, which is then immediately reduced by UAIH4 in a second step to yield the primary alcohol. 

Amide hydrolysis is common in biological chemistry. Just as the hydrolysis of esters is the initial step in the digestion of dietary fats, the hydrolysis of amides is the initial step in the digestion of dietary proteins. The reaction is catalyzed by protease enzymes and occurs by a mechanism almost identical to that we just saw for fat hydrolysis. That is, an initial nucleophilic acyl substitution of an alcohol group in the enzyme on an amide linkage in the protein gives an acyl enzyme intermediate that then undergoes hydrolysis. 

The mechanism of the Dieckmann cyclization, shown in Figure 23.6, is the same as that of the Claisen condensation. One of the two ester groups is converted into an enolate ion, which then carries out a nucleophilic acyl substitution on the second ester group at the other end of the molecule. A cyclic /3-keto ester product results. 

The following reaction involves a hydrolysis followed by an intramolecular nucleophilic acyl substitution reaction. Write both steps, and show their mechanisms. 

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