Leaving groups, and amines

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. 

These observations lend some support to the suggestion of Capon and Rees32. It is, however, questionable that an amine or hydroxide ion would supply significant electrophilic assistance for separation of the leaving group, and acetate ion would be effective only in its enolic form, J... 

Because aromatic purines and purine nucleosides and free purines such as hypo-xanthine and guanine 242 are readily silylated-aminated [64] (cf Scheme 4.24), it is obvious that 6-membered hydroxy-N-heterocycles are analogously silylated-aminated, with reactivity in the order given in Scheme 4.25 [73] X=OTf is the best leaving group and X=NHSiMe3 (cf the transamination as discussed in Section 4.2.4) is the weakest. 

Numerous kinetic studies devoted to S/v Ar reactions with amines indicate that the occurrence and efficiency of base catalysis depend on the identity of the amine, the nucleofugue, the base and the solvent. In general, base catalysis is more often observed with secondary than with primary amines, with poor leaving groups and in the less polar solvents one... 

Recently, the same group79 have reported the kinetic study of the reaction of l-pyrrolidino-2,4-dinitrobenzene, l-piperidino-2,4-dinitrobenzene and 1-morpholino-2,4-dinitrobenzene with NaOH in the presence of the amine leaving group and proposed the formation of cr-complexes, which were found to react faster than the original substrates. 

After the initial demonstration of stoichiometric nucleophilic attack on 7i-allyl ligands, catalytic allylic substitution reactions were pursued. In 1970, groups from Union Carbide [3, 4], Shell Oil [5], and Toray Industries [6] published or patented examples of catalytic allylic substitution. All three groups reported allylic amination with palladium catalysts. The Toray Industries report also demonstrated the exchange of aryl ether and ester leaving groups, and the patent from Shell Oil includes catalysts based on rhodium and platinum. 

We saw that reaction of amines with aldehydes or ketones led to imine formation, rather than the simple aminoalcohol addition prodnct (see Section 7.7.1). This was because, in acidic solntion, the protonated aminoalcohol had two possible leaving groups, and water rather than the amine was the better leaving group. Dehydration occurs, leading to the imine. 

This behaviour results from initial formation of an intermediate with two potential leaving groups, an amide anion R2N and the aluminate anion (OAlHs). Aluminate is the better leaving group, and its loss produces an iminium cation that is also subject to further reduction. This gives us the amine product. 

Possibly the most important condensation reaction is that between a carboxylic acid and an amine to give an amide. A great many methods are known by which this formal dehydration process may be carried out, almost all of which involve the two step sequence (i) activation of CO2H COX, where X is a leaving group and (ii) aminolysis of RCOX. Japanese workers have recently advocated the use of 2,2-dichloro-5-(2-phenylethyl)-4-trimethylsilyl-3-furanone (1, "DPTF") for carboxyl activation, and its use for peptide formation is illustrated by the representative conversion 2 —> 3. The byproduct formed from DPTF in these reactions is 5-(2-phenylethyl)-4-trimethylsilylfuran-2,3-dione. 

In aprotic media a l-(acyloxycarbonyl)imidazole such as 16 is formed primarily which reacts to the acylimidazole and carbon dioxide. Imidazole now serves as a good leaving group and so the previously synthesized amine 6 could be added and the desired amide was formed via the usual addition elimination mechanism. One of the advantages of using this more expensive way of activation is the possibility to run the nitro reduction, acid activation and acylation in the same solvent (ethyl acetate) thus all three reactions could be telescoped into a single step during production. 

Sulfonamides also can be metalated at the nitrogen-bound carbon [247] (Scheme 5.27). The sulfonyl group is, however, usually not well suited for the stabilization of a-metalated amines because sulfinate is a good leaving group, and imines... 

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