Nucleophilic addition-elimination amines

A number of compounds of the general type H2NZ react with aldehydes and ketones m a manner analogous to that of primary amines The carbonyl group (C=0) IS converted to C=NZ and a molecule of water is formed Table 17 4 presents exam pies of some of these reactions The mechanism by which each proceeds is similar to the nucleophilic addition-elimination mechanism described for the reaction of primary amines with aldehydes and ketones... 

Fluoride ion produced from the nucleophilic addition-elimination reactions of fluoroolefins can cataly7e isomerizations and rearrangements The reaction of per fluoro-3-methyl-l-butene with dimethylamine gives as products 1-/V,/Vdimeth-ylamino-1,1,2,2,4,4,4-heptafluoro-3-trifluoromethylbutane, N,W-dimetliyl-2,2,4,4,4-pentafluoro 3 trifluoromethylbutyramide, and approximately 3% of an unidentified olefin [10] The butylamide results from hydrolysis of the observed tertiary amine, and thus they share a common intermediate, l-Al,A -dimethylamino-l,l 24 44-hexafluoro-3-trifluoromethyl-2-butene, the product from the initial addition-elimination reaction (equation 4) The expected product from simple addition was not found... 

Formation of C—Nu The second mode of nucleophilic addition, which often occurs with amine nucleophiles, involves elimination of oxygen and formation of a C=Nu bond. For example, aldehydes and ketones react with primary amines, RNH2, to form imines, R2C=NR. These reactions proceed through exactly the same kind of tetrahedral intermediate as that formed during hydride reduction and Grignard reaction, but the initially formed alkoxide ion is not isolated. Instead, it is protonated and then loses water to form an imine, as shown in Figure 3. 

In contrast, the addition of amines results in nucleophilic addition/elimination at the opposite a-position, resulting in substitution of the a-oxygen substituent, a reaction consistent with the Fischer carbene character embedded into this architecture (Equation 2) <2004JOM2000>. This regioselectivity difference almost certainly arises from the reversible nature of addition reactions using such weakly nucleophilic reagents. 

Overall, the addition of a nitrogen nucleophile to an aldehyde or a ketone is a nucleophilic addition-elimination reaction nucleophilic addition of an amine to form an unstable tetrahedral intermediate, followed by elimination of water. The tetrahedral intermediates are unstable because the newly formed sp carbon is bonded to an oxygen and to a nitrogen—another electronegative atom. Water is eliminated, and loss of a proton from the resulting protonated imine forms a stable imine. 

Because of the lone pair on the nitrogen, amines are both bases and nucleophiles. Amines react as nucleophiles in nucleophilic substitution reactions, in nucleophilic acyl substitution reactions, in nucleophilic addition-elimination reactions, and in conjugate addition reactions. 

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. 

Acyl chlorides also react with tertiary amines by a nucleophilic addition—elimination reaction. The acylammonium ion that forms, however, is not stable in the presence of water or any hydroxylic solvent ... 

Esters undergo nucleophilic addition—elimination at their acyl carbon atoms when they are treated with ammonia (called ammonolysis) or with primary and secondary amines. These reactions take place much more slowly than those of acyl chlorides and anhydrides, but they can still be synthetically useful ... 

The aromatic amine undergoes a nucleophilic addition-elimination reaction at the sulfonyl group, with loss of chloride this generates a sulfonamide. The basic conditions of this reaction gives a carboxylate product, which is reprotonated on acidic work-up. 

Carboxylic acids do not undergo nucleophilic addition-elimination reactions with amines. A carboxylic acid is an acid and an amine is a base, so the carboxylic acid... 

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. 

Overall, the addition of an amine to an aldehyde or a ketone is a nucleophilic addition-elimination reaction nucleophilic addition of an amine to form a tetrahedral intermediate, followed by elimination of water. 

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. 

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