Carboxylic Acid Derivatives and Nucleophilic Acyl Substitution Reactions

Carboxylic Acid Derivatives and Nucleophilic Acyl Substitution Reactions S43... 

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. 

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.

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... 

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... 

Carboxylic acid derivatives are among the most widespread of all molecules, both in laboratory chemistry and in biological pathways. Thus, a study of them and their primary reaction—nucleophilic acyl substitution—is fundamental to understanding organic chemistry. We ll begin this chapter by first learning about carboxylic acid derivatives, and then we ll explore the chemistry of acyl substitution reactions. 

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. 

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. 

The reactivity of carboxyhc acid derivatives depends on the basicity of the substituent attached to the acyl group. Therefore, the less basic the substituent, the more reactive is the derivative. In other words, strong bases make poor leaving groups. Carboxylic acid derivatives undergo a variety of reactions under both acidic and basic conditions, and almost aU involve the nucleophilic acyl substitution mechanism (see Section 5.5.5). 

A nucleophile is an electron rich species that reacts with an electrophile. The term electrophile literally means electron-loving , and is an electron-deficient species that can accept an electron pair. A number of nucleophilic substitution reactions can occur with alkyl halides, alcohols and epoxides. However, it can also take place with carboxylic acid derivatives, and is called nucleophilic acyl substitution. 

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. 

The combination of addition and elimination reactions has the overall effect of substituting one nucleophile for another in this case, substituting an alcohol for water. The rate of these nucleophilic substitution reactions is determined by the ease with which the elimination step occurs. As a rule, the best leaving groups in nucleophilic substitutions reactions are weak bases. The most reactive of the carboxylic acid derivatives are the acyl chlorides because the leaving group is a chloride ion, which is a very weak base (ATb KT20). 

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. 

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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