Nucleophilic acyl substitution acid halides

The weakest base in this series, and thus the best leaving group, is halide ion acid halides are the most reactive toward nucleophilic acyl substitution. The strongest base, and hence the poorest leaving group, is amide ion amides are the least reactive toward nucleophilic acyl substitution. Acid halides and acid anhydrides are so reactive that they are not found in nature. Esters and amides, however, are universally present. 

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 Halides into Acids Hydrolysis Acid chlorides react with water to yield carboxylic acids. This hydrolysis reaction is a typical nucleophilic acyl substitution process and is initiated by attack of water on the acid chloride carbonyl group. The tetrahedral intermediate undergoes elimination of Cl and loss of H+ fo give the product carboxylic acid plus HC1. 

Conversion of Acid Halides into Anhydrides Nucleophilic acyl substitution reaction of an acid chloride with a carboxylate anion gives an acid anhydride. Both symmetrical and unsymmetrical acid anhydrides can be prepared in this way. 

We ve already studied the two most general reactions of amines—alkylation and acylation. As we saw earlier in this chapter, primary, secondary, and tertiary amines can be alkylated by reaction with a primary alkyl halide. Alkylations of primary and secondary amines are difficult to control and often give mixtures of products, but tertiary amines are cleanly alkylated to give quaternary ammonium salts. Primary and secondary (but not tertiary) amines can also be acylated by nucleophilic acyl substitution reaction with an acid chloride or an acid anhydride to yield an amide (Sections 21.4 and 21.5). Note that overacylation of the nitrogen does not occur because the amide product is much less nucleophilic and less reactive than the starting amine. 

Many of the reactions of amines are familiar from past chapters. Thus, amines react with alkyl halides in S 2 reactions and with acid chlorides in nucleophilic acyl substitution reactions. Amines also undergo E2 elimination to yield alkenes if they are first qualernized by treatment with iodomethane and then heated with silver oxide, a process called the Hofmann elimination. 

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. 

Displacement of halides by secondary amines and of sulfonyl groups by alkoxides can also take place. Furoxancarboxylic acids are attacked by base to give acyclic products, but their derivatives can undergo nucleophilic acyl substitutions. Likewise nucleophilic addition reactions can be accomplished for ketofuroxans, although ring cleavage is also commonplace. The generation of new heterocyclic systems by reaction with nucleophiles is dealt with in Section 4.22.3.2.5. 

Primary and secondary amines react with acid halides to form amides. This reaction is a nucleophilic acyl substitution the replacement of a leaving group on a carbonyl carbon by a nucleophile. We will study nucleophilic acyl substitution in detail in Chapters 20 and 21. In this case, the amine replaces chloride ion. 

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 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. 

Acid halides, anhydrides, and esters undergo nucleophilic acyl substitution with alcohols (HOR ), the net result being the replacement of each —X, —0C(0)R, or —OR group with the —OR group of the alcohol. 

Acid halides, anhydrides, and esters undergo nucleophilic acyl substitution with ammonia or amines, the net result... 

Amines are nitrogen nucleophiles. They react with the carbonyl group of carboxylic acid derivatives (acyl halides, anhydrides, and esters) by nucleophilic acyl substitution (Sec. 10.11). 

The four carboxylic acid derivatives that are the focus of this chapter have the relative reactivity toward nucleophilic acyl substitution as follows. The differences in this trend are dramatic. For example, at common ambient temperatures and neutral pH, acid halides will react with water within seconds to minutes, while anhydrides will do so over minutes to hours. Esters, however, do not... 

Among the various carboxylic acid derivatives, acyl chlorides are especially useful because they are readily converted to acid anhydrides, esters, and amides by nucleophilic acyl substitution (Table 19.1). Yields are high and the reaction rates are much greater than the corresponding rates of alkyl halides with the same nucleophiles. Benzoyl chloride, for example, is about 1,000 times more reactive than benzyl chloride toward hydrolysis at 25°C. 

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