Amides nucleophilic addition-elimination

Of the acid derivatives that we study in this chapter, acyl chlorides are the most reactive toward nucleophilic addition-elimination, and amides are the least reactive. In general, the ovetall otdet of teactivity is... 

Amides can be prepared in a variety of ways, starting with acyl chlorides, acid anhydrides, esters, carboxylic acids, and carboxylate salts. All of these methods involve nucleophilic addition—elimination reactions by ammonia or an amine at an acyl carbon. As we might expect, acid chlorides are the most reactive and carboxylate anions are the least. 

Because of the low reactivity of the carboxylate ion toward nucleophilic addition-elimination, further reaction does not usually take place in aqueous solution. However, if we evaporate the water and subsequendy heat the dry salt, dehydration produces an amide ... 

The functional groups of acyl substitution reactions all relate to carboxylic acids. They include acyl chlorides, anhydrides, esters, amides, thioesters, carboxylic acids themselves, and others that we shall study in this chapter. In Special Topic C we shall see how acyl substitution reactions are used to synthesize polymers such as nylon and Mylar. In Special Topic E we shall consider the biosynthesis of fatty acids and other biological molecules by acyl substitution reactions. Although many functional groups participate in acyl substitution reactions, their reactions are all readily understandable because of the common mechanistic theme that unites them nucleophilic addition-elimination at an acyl carbon. 

Carboxylic acids can undergo nucleophilic addition-elimination reactions only when they are in their acidic forms. The basic form of a carboxylic acid is not reactive because its negative charge makes it resistant to approach by a nucleophile. Therefore, carhoxylate ions are even less reactive than amides in nucleophilic addition-elimination reactions. 

The relative reactivities toward nucleophilic addition-elimination are acyl chlorides > acid anhydrides > esters carboxylic acids > amides > carboxylate ions. Hydrolysis, alcoholysis, and aminolysis are reactions in which water, alcohols, and amines, respectively, convert one compound into two compounds. 

Nucleophiles react with a,j8-unsaturated carboxylic acid derivatives with reactive carbonyl groups, such as acyl chlorides, at the carbonyl group, forming nucleophilic addition-elimination products. Conjugate addition products are formed from the reaction of nucleophiles with less reactive carbonyl groups, such as esters and amides. 

Biotin reacts with activated bicarbonate in a nucleophilic addition-elimination reaction to form carboxybiotin. Because the nitrogen of an amide is not nucleophilic, the active form of biotin has an enolate ion-like structure. 

The amides are the least reactive of the carboxylic acid derivatives, in part because they are strongly stabilized by delocalization of the nitrogen lone pair (Section 20-1). As a consequence, their nucleophilic addition-eliminations require relatively harsh conditions. For example, hydrolysis to the corresponding carboxylic acid occurs only upon prolonged heating in strong aqueous acid or base by addition-elimination mechanisms. Acid hydrolysis liberates the amine in the form of an ammonium salt. 

Conversion of Amides into Carboxylic Acids Hydrolysis Amides undergo hydrolysis to yield carboxylic acids plus ammonia or an amine on heating in either aqueous acid or aqueous base. The conditions required for amide hydrolysis are more severe than those required for the hydrolysis of add chlorides or esters but the mechanisms are similar. Acidic hydrolysis reaction occurs by nucleophilic addition of water to the protonated amide, followed by transfer of a proton from oxygen to nitrogen to make the nitrogen a better leaving group and subsequent elimination. The steps are reversible, with the equilibrium shifted toward product by protonation of NH3 in the final step. 

Basic hydrolysis occurs by nucleophilic addition of OH- to the amide carbonyl group, followed by elimination of amide ion (-NH2) and subsequent deprotonation of the initially formed carboxylic acid by amide ion. The steps are reversible, with the equilibrium shifted toward product by the final deprotonation of the carboxylic acid. Basic hydrolysis is substantially more difficult than the analogous acid-catalyzed reaction because amide ion is a very poor leaving group, making the elimination step difficult. 

From a chemical point of view, amide and ester bonds have comparable structural and spectroscopic features and are hydrolyzed by the same general mechanism, i.e., a nucleophilic acyl substitution involving an addition-elimination sequence (see Chapt. 3). However, in a given structure, the amide... 

General methods for the preparation of a.jS-unsaturated iron-acyl complexes are deferred to Section D 1.3.4.2.5.1.1. examples of the alkylation of enolates prepared via Michael additions to ii-0 ,/ -unsaturated complexes prepared in situ are included here. Typical reaction conditions for these one-pot processes involve the presence of an excess of alkyllithium or lithium amide which first acts as base to promote elimination of alkoxide from a /f-alkoxy complex to generate the -a,)S-unsaturated complex which then suffers 1,4-nucleophilic addition by another molecule of alkyllithium or lithium amide. The resulting enolate species is then quenched with an electrophile in the usual fashion. The following table details the use of butyllithium and lithium benzylamide for these processes44,46. 

In addition to OH , other nucleophiles such as BH4 ,318 CN-319,320 and N3-321 also add at the nitrile carbon of cobalt(III)-nitrile complexes at rates which are = 104 times those of the corresponding reactions of the free ligands. Catalysis by C032 in the hydration of [(NH3)5RuNCMe]3+,316 and of the acrylonitrile complex [(NH3)5CoNCCH=CH2]3+,322 has been observed. In the latter complex, a direct nucleophilic pathway results in the incorporation of oxygen from C032 into the amide product with elimination of C02. 

Instead of carboxylic acids, other carbonyl compounds can be used acid halides, esters, amides, etc. The commonly accepted general mechanism for these reactions consists of the initial nucleophilic addition of an active hydrogen compound to the electron-poor carbonyl carbon atom of the R COOI I molecule, with the formation of a metastable intermediate that can undergo a subsequent elimination reaction ... 

Treatment of amide 4 with formic acid triggers a nucleophilic addition of the amide NH2 to the protonated ketone, and an elimination of water, to give iminium ion 14. Reduction of 14 then occurs exclusively from the a face, probably via the half-chair transition state shown in Scheme 9.3,... 

Such a charge transfer from the ligated arene can lead to (a) nucleophilic addition or substitution, (b) electron transfer, and (c) proton elimination/transfer, thus revealing the dose relationship between all of these processes. The reactivity of the arene ligands towards nudeophiles in (arene)ML complexes depends on the electrophilidty of the metal fragments [MLn], this increasing in the order [Cr(CO)3] < [Mo(CO)3] [FeCp]+ < [Mn(CO)3]+ [2]. For example, in (arene)FeCp+, which is widely used for synthetic purposes, a chloro or nitro substituent on the arene is readily substituted by such nudeophiles as amides, eno-lates, thiolates, alkoxides, and carbanions [45]. 

Nucleophilic substitution of unactivated benzene derivatives occurs by a mechanism different from the addition-elimination we saw with the nitro-substituted halobenzenes. A clue to the mechanism is provided by the reaction of p-bromotol ucnc with sodium amide. The products are a 50 50 mixture of m- andp-toluidine. 

Ammonia and amines react with acid chlorides to give amides, also through the addition-elimination mechanism of nucleophilic acyl substitution. A carboxylic acid is efficiently converted to an amide by forming the acid chloride, which reacts with an amine to give the amide. A base such as pyridine or NaOH is often added to prevent HC1 from protonating the amine. 

---