Acid Derivatives and Nucleophilic Acyl Substitution Reactions

Closely related to the carboxylic acids discussed in the previous chapter are carboxylic acid derivatives, compounds in which the acyl group is bonded to an electronegative atom or substituent -Y that can act as a leaving group in a substitution reaction. Many kinds of acid derivatives are known, but 

CHAPTER 21 Carboxylic Acid Derivatives and Nucleophilic Acyi Substitutiom 

The chemistry of all acid derivatives is similar and is dominated by single reaction—the nucleophilic acyl substitution reaction that saw briefly in A Preview of Carbonyl Compounds  

Let s first learn more about acid derivatives and then explore the chemistry of acyl substitution reactions. 

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In contrast, the carbonyl group of an aldehyde or a ketone is attached to a group that is too strong a base (H or R ) to be eliminated under normal conditions, so it cannot be replaced by another group. Consequently, aldehydes and ketones react with nucleophiles to form addition products, not substitution products. Thus, aldehydes and ketones undergo nucleophilic addition reactions, whereas carboxylic acid derivatives undergo nucleophilic acyl substitution reactions. 

The characteristic reaction of carboxylic acid derivatives is nucleophilic acyl substitution. This is a general reaction that occurs with hoth negatively charged nucleophiles (Nu ) and neutral nucleophiles (HNu ). 

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. 

The conjugate base of an alkyne is an alkyne anion (older literature refers to them as acetylides), and it is generated by reaction with a strong base and is a carbanion. It funetions as a nucleophile (a source of nucleophilic carbon) in Sn2 reactions with halides and sulfonate esters. Acetylides react with ketones, with aldehydes via nucleophilic acyl addition and with acid derivatives via nucleophilic acyl substitution. Acetylides are, therefore, important carbanion synthons for the creation of new carbon-carbon bonds. Some of the chemistry presented in this section will deal with the synthesis of alkynes and properly belongs in Chapter 2. It is presented here, however, to give some continuity to the discussion of acetylides. 

When a nucleophile attacks a carboxylic acid derivative, a nucleophilic acyl substitution can occur in which the nucleophile replaces the leaving group. The mechanism of this reaction involves two core steps and often utilizes several proton transfer steps as well (especially in acidic conditions). 

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.

Amides are the least reactive carboxylic acid derivative, and the only nucleophilic acyl substitution reaction they undergo is hydrolysis. Amides are fairly stable in water, but the amide bond is cleaved on heating in the presence of strong acids or bases. Nominally, this cleavage produces an amine and a car boxylic acid. 

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... 

A nucleophilic acyl substitution reaction involves the substitution of a nucleophile for a leaving group in a carboxylic acid derivative. Identify the leaving group (Cl- in the case of an acid chloride) and the nucleophile (an alcohol in this case), and replace one by the other. The product is isopropyl benzoate. 

Amides, like esters, are abundant in all living organisms—proteins, nucleic acids, and many pharmaceuticals have amide functional groups. The reason for this abundance of amides, of course, is that they are stable to the conditions found in living organisms. Amides are the least reactive of the common acid derivatives and undergo relatively few nucleophilic acyl substitution reactions. 

Amino groups are often protected as their tert-butoxycarbonvl amide, or Boc, derivatives. The Boc protecting group is introduced by reaction of the amino acid with di-fert-butyl dicarbonate in a nucleophilic acyl substitution reaction and is removed by brief treatment with a strong organic acid such as trifluoro-acetic acid, CF3C02H. 

Carboxylic acid and its derivatives undergo nucleophilic acyl substitution, where one nucleophile replaces another on the acyl carbon. Nucleophilic acyl substitution can interconvert all carboxylic acid derivatives, and the reaction mechanism varies depending on acidic or basic conditions. Nucleophiles can either be negatively charged anion (Nu ) or neutral (Nu ) molecules. 

An acid-base reaction (Reaction [1]) occurs with OH, NH3, and amines, all common nucleophiles used in nucleophilic acyl substitution reactions. Nonetheless, carboxyhc acids can be converted to a variety of other acyl derivatives using special reagents, with acid catalysis, or sometimes, by using rather forcing reaction conditions. These reactions are summarized in Figure 22.2 and detailed in Sections 22.10A—22.10D. 

Carboxylic acid derivatives such as esters and amides undergo nucleophilic acyl substitution reactions with the ketone dianion derived fiom benzophenone, providing modest yields of the corresponding carbonyl products (equations 102 and 103). Benzhydrol is a significant by-product in these reactions. 

Nucleophilic acyl substitution reactions take place in living organisms just as they take place in the chemical laboratory. The same principles apply in both cases. Nature, however, often uses a thiol ester, RCOSR, as the add derivative because it is intermediate in reactivity between an acid anhydride and an ester. Thiol esters aren t as reactive as anhydrides, yet they re more reactive than typical esters toward nucleophilic attack. 

Carboxylic acids and carboxylic acid derivatives can also be prepared by methods other than nucleophilic acyl substitution reactions. A summary of the methods used to synthesize these compounds is given in Appendix IV. 

A carboxyhc 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. The weaker the base attached to the acyl group, the easier it is for both steps of the nucleophilic acyl substitution reaction to take place. The relative reactivities toward nucleo-phihc acyl substitution acyl halides > acid anhydrides > carboxylic acids and esters > amides > carboxylate ions. 

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. 

Aldehydes and ketones undergo nucleophilic acyl substitution reactions, while derivatives of carboxylic acids undergo nucleophilic addition reactions. (14.2)... 

There is one last reaction to consider. Remember the reaction of a carboxylic acid such as butanoic acid with a base such as NaOH or NaOCHg described in Chapter 6 (Section 6.2). Sodium methoxide is a good base (Chapter 12, Section 12.1), but as seen in Chapter 11 (Section 11.3.2), methoxide is also a good nucleophile. What happens when butanoic acid reacts with sodium methoxide in ether The answer is that the acid-base reaction dominates indeed, the acid-base reaction is much faster than the acyl substitution reaction. Therefore, sodium methoxide reacts with butanoic acid to give the sodium salt of butanoic acid (76, the conjugate base) and methanol (the conjugate acid). If a potential nucleophile is a potent base, the acid-base reaction will dominate with carboxylic acids. Nucleophilic acyl substitution reactions dominate with acid derivatives, with some exceptions that are discussed in Chapter 22. 

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