Thomas H. Fife

General acid catalysis in the hydrolysis of 1,3-dioxolanes and 1,3-oxathiolanes. The hydrolysis of acetals and thioacetals of p-(dimethylamino)benzaldehyde

Rate constants have been determined for hydrolysis of acetal and U,S-thioacetal derivatives of p-(dimethylamin0)benzaldehyde in H20. The plots of log kow vs. pH for the di-n-propyl acetal, the 1,3-dioxolane, and the 1,3-oxathiolane are pH independent from pH 1 to 4-5 and linear with a slope of -1.0 at pH >5. General acid catalysis was not observed in the hydrolysis of the di-n-propyl acetal. Consequently, the rate-determining step must be breakdown of the protonated acetal to an oxocarbonium ion. Apparent general acid catalysis was observed in the hydrolysis of the 1,3-dioxolane and the 1,3-oxathiolane. The plots of koW vs. buffer concentration are curved at pH >6 in reactions of the former compound, which indicates that the rate-determining step is changing with increasing buffer concentration to a step with little or no dependence on buffer concentration. The rate-determining step in the reactions of the 1,3-dioxolane and the 1,3-oxathiolane at pH >5 and at low buffer concentrations is attack of a water molecule on the carbonium ion intermediate produced by hydronium ion catalyzed decomposition of the acetal. This must be a consequence of rapid reversal of the ring-opening step. At pH >7.5 attack of OHon the carbonium ion intermediate occurs in hydrolysis of the dioxolane, and the rate-determining step changes to ring opening near pH 8. Rapid attack of a ,&substituent group on an oxocarbonium ion intermediate was demonstrated in ring closure of the oxocarbonium ion produced by C-S cleavage of p(dimethy1amino)benzaldehyde 0-(8-mercaptoethyl) S-(P-hydroxyethyl) thioacetal; the values of kow for hydrolysis of that compound are identical with those of 2-(p-(dimethylamino)phenyl)-1,3-oxathiolane at pH >4. The rate constants for hydrolysis of the 4,4,5,5-tetramethyl-1,3-dioxolane are relatively small, and there is only a 100-fold difference in the second-order rate constants for hydronium ion catalyzed hydrolysis of the neutral and protonated species in contrast with the difference of at least lo4 with the dipropyl acetal and the 1,3-dioxolane. Solvent involvement in the rate-determining step with that compound may be occurring by an A-2 mechanism. Thus, in the hydrolysis of the acetals of p(dimethy1amino)benzaldehyde changes in structure have led to different mechanisms or rate-determining steps. The hydronium ion catalyzed hydrolysis of acetals must proceed Thus, there are three possible via the scheme shown in eq 1.

The metal-ion-promoted water- and hydroxide-ion-catalysed hydrolysis of amides

Rate constants have been determined for the hydrolysis of 8-trifluoroacetamidoquinoline-2-carboxylic acid and N-(6-carboxypicolinyl)-2,4-dinitroaniline in water at 70 °C. The hydrolysis reactions of these amides in the absence of metal ions are OH– catalysed at pH values >7. Divalent metal ions (Co2+, Ni2+, and Zn2+) have a significant catalytic effect on the rates of hydrolysis. Binding of the metal ions to the amides is strong, and saturation occurs at low metal ion concentrations ( <0.01 mol dm–3) At saturating concentrations of the metal ions kobs is pH independent at pH < 7. Thus, the metal-ion-catalysed reactions are water reactions or a kinetic equivalent. Metal-ion-promoted OH– catalysed reactions are not observed. In contrast, the Ni2+ catalysed hydrolysis of the β-lactam, N-(8-quinolyl)azetidin-2-one proceeds through a metal-ion-promoted OH– reaction. A 0.01 mol dm–3 concentration of Ni2+(non-saturating) provides a rate enhancement of 105 over that observed in the absence of metal ion. The type of metal ion catalysis observed in amide hydrolysis, i.e., pH independent or OH– dependent must be determined by the nature of the rate-determining step and the ease of C–N bond breaking. A metal-ion-promoted OH– catalysed reaction will occur at pH values near neutrality when C–N bond breaking is facile and nucleophilic attack is rate determining, whereas when C–N bond breaking is difficult and therefore part of the rate-determining step, the reaction will be pH independent because of the requirement for protonation of the nitrogen leaving group.

Intramolecular general base catalysed alcoholysis of amides

The pH-independent cyclization of 3-amino-2-hydroxymethylbenzamide proceeds with intramolecular general base cataysis at a rate103 times greater than that for the 4-, 5-, and 6-amino, or unsubstituted 2-hydroxymethylbenzamide.

Divalent metal ion catalysis of acetal hydrolysis; effects of oxycarbocation stability and leaving group basicity

Large catalytic effects by low concentrations of Ni2+, Co2+, and Zn2+ were observed in the hydrolysis of 2-(8-quinolyloxy)tetrahydropyran, 6-(8-quinolyloxy)tetrahydropyran-2-carboxylic acid, and ethyl 6-(8-quinolyloxy)tetrahydropyran-2-carboxylate in H2O at 50 °C (µ 0.1M), even though metal ion binding to the acetals is weak. Plots of kobsvs. metal ion concentration are linear even at metal ion concentrations as high as 0.01M. At constant metal ion concentration the reactions are pH-independent at pH >5. The minimum rate enhancement with these compounds at 0.01M-Ni2+ is more than 104 at pH 7.0; Co2+ and Zn2+ are three-fold less effective than Ni2+. The rate constants for oxonium ion catalysis and metal ion catalysis are affected alike by changes in basicity and oxycarbocation stability in 8-quinolyl acetals; these features vary over a wide range (from substituted benzaldehyde methyl 8-quinolyl acetals to 8-quinolyl β-D-glucopyranoside). With each acetal the second-order rate constants for oxonium ion and metal ion catalysis are similar, which indicates that the large rate enhancements observed in the metal-ion-catalysed reactions are due to relative concentration effects of the metal ions in comparison with oxonium ion. Metal ion catalysis was not observed in the hydrolysis of acetals of 2-hydroxymethylpyridine nor in the hydrolysis of m-methoxybenzaldehyde 6-carboxy-2-pyridylmethyl methyl acetal. As in the case of general-acid-catalysed reactions, metal ion catalysis in acetal hydrolysis is highly dependent on leaving group ability; it does not occur when the leaving group is an aliphatic alcohol even in cases where the intermediate oxycarbocation is quite stable (a methoxybenzyl ion) and metal ion binding to the acetal is strong. There are striking mechanistic similarities between intramolecular metal ion catalysis and general acid catalysis in acetal hydrolysis because both reactions involve stabilization of the leaving group in the transition state of the pH-independent C–O bond-breaking reaction.

Carboxy-group participation in acetal hydrolysis. The hydrolysis of benzaldehyde disalicyl acetal

The pH–rate contstant profile for hydrolysis of benzaldehyde disalicyl acetal in either 50% dioxan–H2O (v/v) or in H2O at 25° is bell-shaped and reveals a maximum enhancement of kobs in comparison with the dimethyl ester of 2·7 × 109.