In amide hydrolysis

FIGURE 9.5. The potential surface for the 0"C = 0— 0-C-0" step in amide hydrolysis in solution, where the surface is given in terms of the angle 0 and the distance b. The heavy contour lines are spaced by fi (at room temperature) and can be used conveniently in estimating entropic effects. The figure also shows the regions (cross hatched) where the potential is less than for the corresponding reaction in the active site of subtilisin. 

Tetrhedral intermediate, 172 Thermodynamic cycles, 186 Thermolysin, zinc as cofactor for, 204 Thrombin, 170 Torsional potential, 111 Transition states, 41-42,44, 45,46, 88, 90-92 in amide hydrolysis, 219-221 oxyanion hole and, 181 stabilization of, 181,181 carbonium ion, 154,155,156-161, 167-169 for gas-phase reactions, 43... 

Brown, R.S. (2000). Studies in amide hydrolysis the acid, base and water reactions. In The Amide Linkage. Structural Significance in Chemistry, Biochemistry and Materials Science, Greenberg, A., Breneman, C.M. and Liebman, J.F. (eds), p. 85. John Wiley Sons, Inc., New York... 

TIL Fife, Kinetic and Mechanistic Effects of Ease of C-N-Bond Breaking in Amide Hydrolysis, The... 

T.H. Fife, Kinetic and Mechanistic Effects of Ease of C-N-hond Breaking in Amide Hydrolysis, The Mechanisms of Hydrolysis of N-Acylimidazoles and N-Acyl-benzimidazoles, Acc. Chem. Res. 26, 325 (1993). 

By protonation (as in amide hydrolysis, frames 94-97). If PhNH is protonated and eliminated, we just reverse the reaction back to the starting materials, but see what happens if you protonate and eliminate OH. Draw the reaction. 

A reasonably complete discussion of the role of acid in amide hydrolysis requires the inclusion of the Hammett acidity function (//0)l99,200i and the controversial topic of the significance of this function in the determination of mechanism201,202. 

Characterization of HIV-1 protease as a member of the aspartic acid protease family provided the rationale for most of the efforts to design inhibitors (Kohl et al, 1988 Krausslich et al., 1988 Navia et al., 1989 Pearl and Taylor, 1987). Previous efforts to develop therapeutically useful inhibitors of the mechanistically related enzyme renin had demonstrated that potent inhibitors could be prepared by replacing the scissile amide bond of a substrate analogue with a nonhydrolyzable isostere to mimic the tetrahedral intermediate or transition state involved in amide hydrolysis (Greenlee, 1990). Although several dipeptide isosteres have been used to successfully generate highly potent HIV-1 protease inhibitors, a relatively small number have resulted in compounds that reached clinical development. 

Since reactive metal centers were secured, attempts were initiated to achieve substrate selectivity in amide hydrolysis by the metal complexes [50, 51], The active site of... 

The Hofmann and Curtius reactions as applied to both the mono-and diamides and hydrazides have been reported. Marquardt found that a low yield of the amine can be obtained in the Hofmann reaction of l,2,5-thiadiazole-3-carboxamide. The main side reaction was hydrolysis of the electron-deficient amide to the carboxylic acid. Under the same conditions the dicarboxamide (78) formed the amino acid (16b). Attempts to prepare diaminothiadiazole via the Hofmann reaction of the amino amide (16a) resulted only in amide hydrolysis and the formation of the same amino acid. 

On the other hand, the substrate may undergo nucleophilic attack by base, either in the rate-determining step — with or without formation of an intermediate — or in a fast pre-equilibrium step which is followed by rate-determining breakdown of the intermediate. These three possibilities are included in the B2 mechanism according to Ingold s nomenclature [14]. Examples of one-step B2 reactions (SN2 mechanisms) are the alkaline hydrolyses of sulfonic esters [14] and 2,4,6,-tri-f-butylbenzoic esters [18]. Intermediates are formed by carbonyl addition of hydroxide ion in the alkaline hydrolyses of (unhindered) carboxylic esters and amides. Addition of OH is partially or completely rate-determining in ester hydrolysis [4, 15], but probably not in amide hydrolysis [15]. 

Cunningham BA, Schmir GL. Hydroxyl group participation in amide hydrolysis. The influence of catalysts on the partitioning of a tetrahedral intermediate. J. Am. Chem. Soc. 1967 89 917-922. 

Amide nitrogen atoms of ordinary peptide bonds do not coordinate to metal ions since the nitrogen atom contains a partial positive charge due to resonance in the amide bond (F). In a p-lactam, the strained ring prohibits resonance and the nitrogen atom is basic enough to coordinate to a metal ion (G) leading to catalysis in amide hydrolysis (41, 42). 

Data on variations in degradation rates with temperature are reported in Table I. The values of the activation energy for degradation all fall within 60-125 kj/mol. These are values normally observed in amide hydrolysis (12). For the three compounds studied, the activation energy increases as the room temperature stability of the resin solution increases. 

As the rate-limiting steps for the alkaline hydrolysis of amides and p-lactams are different, the relatively small rate enhancement shown by P-lactams indicates that the energy of the transition state for breakdown of the tetrahedral intermediate in amide hydrolysis is not significantly greater than that for formation of the intermediate. 

Compound / rapidly converts in acid to compound ii, which is indefinitely stable. This is a tetrahedral intermediate analogous to those found in amide hydrolysis. The effective molarity of the amine in / is estimated to be 10" to 10 M. The effective molarity is so high that the amine leaving group is e.ssentially permanently attached to the... 

R. Kluger and C. H. Lam (1978), Carboxylic acid participation in amide hydrolysis. External general base catalysis and general acid catalysis in reactions of nor-bornenylanilic acids. J. Amer. Chem. Soc. 100, 2191-2197. 

---