Nucleophilic acyl substitution reactions general reaction

Figure21.1 The general mechanisms of nucleophilic addition and nucleophilic acyl substitution reactions. Both reactions begin with addition of a nucleophile to a polar C=0 bond to give a tetrahedral, alkoxide ion intermediate. (a) The intermediate formed from an aldehyde or ketone is protonated to give an alcohol, but (b) the intermediate formed from a carboxylic acid derivative expels a leaving group to give a new carbonyl compound.

The reaction of ammonia and amines with esters follows the same general mech anistic course as other nucleophilic acyl substitution reactions (Figure 20 6) A tetrahe dral intermediate is formed m the first stage of the process and dissociates m the second stage... 

As a general rule, nucleophilic addition reactions are characteristic only of aldehydes and ketones, not of carboxylic acid derivatives. The reason for the difference is structural. As discussed previously in A Preview of Carbonyl Compounds and shown in Figure 19.14, the tetrahedral intermediate produced by addition of a nucleophile to a carboxylic acid derivative can eliminate a leaving group, leading to a net nucleophilic acyl substitution reaction. The tetrahedral intermediate... 

General mechanism of a nucleophilic acyl substitution reaction. 

Both the initial addition step and the subsequent elimination step can affect the overall rate of a nucleophilic acyl substitution reaction, but the addition step is generally the rate-limiting one. Thus, any factor that makes the carbonyl group more reactive toward nucleophiles favors the substitution process. 

We ve now studied three of the four general kinds of carbonyl-group reactions and have seen two general kinds of behavior. In nucleophilic addition and nucleophilic acyl substitution reactions, a carbonyl compound behaves as an electrophile. In -substitution reactions, however, a carbonyl compound behaves as a nucleophile when it is converted into its enol or enolate ion. In the carbonyl condensation reaction that we ll study in this chapter, the carbonyl compound behaves both as an electrophile and as a nucleophile. 

Chapter 22 continues the study of carbonyl compounds with a detailed look at nucleophilic acyl substitution, a key reaction of carboxylic acids and their derivatives. Substitution at sp hybridized carbon atoms was introduced in Chapter 20 with reactions involving carbon and hydrogen nucleophiles. In Chapter 22, we learn that nucleophilic acyl substitution is a general reaction that occurs with a variety of heteroatomic nucleophiles. This reaction allows the conversion of one carboxylic acid derivative into another. Every reaction in Chapter 22 that begins with a carbonyl compound involves nucleophilic substitution. Chapter 22 also discusses the properties and chemical reactions of nitriles, compounds that contain a carbon-nitrogen triple bond. Nitriles are in the same carbon oxidation state as carboxylic acids, and they undergo reactions that form related products. 

The most general method for preparing an acid anhydride is by nucleophilic acyl substitution reaction of an acid chloride with a carboxylate anion. Both symmetrical and unsymmetrical acid anhydrides can be prepared in this way. 

A characteristic reaction of carboxylic acid derivatives is nucleophilic acyl substitution. In this reaction a negative or neutral nucleophile replaces a leaving group to form a substitution product. The leaving groups and nucleophiles are the groups that define the various acid derivatives as a result, the reaction usually involves the conversion of one acid derivative into another. The order of reactivity of acid derivatives is acid chloride > anhydride > acid or ester > amide. In general, reaction of any of these derivatives with water produces acids with alcohols, esters result and with amines, amides are formed. 

PEPTIDE BOND FORMATION Polypeptides are linear polymers composed of amino acids linked together by peptide bonds. Peptide bonds (Figure 5.11) are amide linkages formed when the unshared electron pair of the a-ami no nitrogen atom of one amino acid attacks the a-carboxyl carbon of another in a nucleophilic acyl substitution reaction. A generalized acyl substitution reaction is shown ... 

We can make the following general statement about the reactions of carboxylic acid derivatives A carboxylic acid derivative will undergo a nucleophilic acyl substitution reaction, provided that the newly added group in the tetrahedral intermediate is not a much weaker base than the group that was attached to the acyl group in the reactant. 

Section 17.7 General Mechanism for Nucleophilic Acyl Substitution Reactions... 

The reactions involving 64, 66, and 68 used three different types of nucleophiles, cyanide, an azide, and an alkoxide. The ability to evaluate the relative strength and effectiveness of various nucleophiles is obviously as important for Sn2 reactions as it was for nucleophilic acyl substitution reactions. A general list of nucleophiles in order of their ability to form bonds to sp carbon in a Sn2 reaction is ... 

The carboxylic acid derivatives (RC(O)OX) and carbonic acid derivatives (ROC(O)OX) represent two classes of environmental chemicals that hydrolyze through nucleophilic acyl substitution reactions. The general structural features of representative functional groups in these chemical classes are illustrated in Figure 2.6. 

The net result of this process is substitution of the —OR group of the alcohol for the —OH group of the acid. Hence the reaction is referred to as nucleophilic acyl substitution. But the reaction is not a direct substitution. Instead, it occurs in two steps (1) nucleophilic addition, followed by (2) elimination. We will see in the next and subsequent sections of this chapter that this is a general mechanism for nucleophilic substitutions at the carbonyl carbon atoms of carboxylic acid derivatives. 

There is one additional complicating factor. When an alcohol solvent is used in reactions with thermodynamic conditions, the alcohol solvent should he the same as the alcohol part of the ester. In other words, ethanol is used for an ethyl ester and methanol is used for a methyl ester. In Chapter 20 (Section 20.6.3), transesterification is the displacement of one alcohol unit (the OR group) of an ester by another alcohol unit in a nucleophilic acyl substitution reaction. If a methyl ester reacts with NaOEt in ethanol, the OEt unit displaces OMe to give an ethyl ester in the product. The product may be a mixture of ethyl and methyl esters. In general, make sure the OR portion of the ester matches the OR portion of the alcohol solvent (ROH). 

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