Hydrolysis of Naptalam and Structurally Related Amides:  Inhibition by Dissolved Metal Ions and Metal (Hydr)Oxide Surfaces

In metal ion-free solutions, the secondary amide naptalam hydrolyzes more rapidly as the pH is decreased; intramolecular nucleophilic attack by a carboxylate side group is very likely involved. Millimolar levels of dissolved Cu^II and Zn^II inhibit hydrolysis between pH 3.6 and pH 6.5. Metal ion−naptalam complex formation is important since addition of the competitive ligand citrate lessens the inhibitory effect. The metal (hydr)oxide surfaces Al₂O₃ and FeOOH inhibit naptalam hydrolysis to a lesser degree; inhibition is proportional to the extent of naptalam adsorbed. Secondary amides (propanil, salicylanilide, and N-1-naphthylacetamide) and tertiary amides (N-methyl-N-1-naphthylacetamide, furalaxyl, and N,N-diethylsalicylamide) that lack carboxylate side groups do not hydrolyze within 45 days of reaction, even when millimolar Cu^II concentrations are present. Tertiary amides possessing carboxylate side groups (N,N-diethyl-3,6-difluorophthalamic acid and N,N-dimethylsuccinamic acid) do hydrolyze but are insensitive to the presence or absence of Cu^II. The inhibitory effect is believed to occur via metal coordination of (1) the carbonyl group of naptalam, which induces deprotonation of the amide group and makes the substrate less reactive toward nucleophilic attack; (2) the free carboxylate group of naptalam, which blocks intramolecular nucleophilic attack; or (3) a combination of the two. Keywords: Naptalam; amide hydrolysis; metal catalysis; metal inhibition; phthalamic acid derivatives.