Hydroxide Ion-catalyzed Hydrolysis Research Articles

Theoretical Studies of the Transition-State Structures and Free Energy Barriers for Base-Catalyzed Hydrolysis of Amides

The transition-state structures and free energy barriers for the rate-determining step (i.e. the formation of a tetrahedral intermediate) of base-catalyzed hydrolysis of a series of amides in aqueous solution have been studied by performing first-principle electronic structure calculations using a hybrid supermolecule-polarizable continuum approach. The calculated results and a revisit of recently reported experimental proton inventory data reveal that the favorable transition-state structure optimized for the tetrahedral intermediate formation of hydroxide ion-catalyzed hydrolysis of formamide may have three solvating water molecules remaining on the attacking hydroxide oxygen and two additional water molecules attached to the carbonyl oxygen of formamide. The calculated results have also demonstrated interesting substituent effects on the optimized transition-state geometries, on the transition-state stabilization, and on the calculated free energy barriers for the base-catalyzed hydrolysis of amides. When some or all of the hydrogen atoms of formamide are replaced by methyl groups, the total number of water molecules hydrogen-bonding with the attacking hydroxide in the transition state decreases from three for formamide to two for N-methylacetamide, N,N-dimethylformamide (DMF), and N,N-dimethylacetamide (DMA). The larger substituents of the amide hinder the solvent water molecules approaching the attacking hydroxide oxygen in the transition state and, therefore, destabilize the transition-state structure and increase the free energy barrier. By using the optimized most favorable transition-state structures, the calculated free energy barriers, i.e., 21.6 (or 21.7), 22.7, 23.1, and 26.0 kcal/mol for formamide, N-methylacetamide, DMF, and DMA, respectively, are in good agreement with the available experimental free energy barriers, i.e., 21.2, 21.5, 22.6, and 24.1 kcal/mol for formamide, N-methylacetamide, DMF, and DMA, respectively.

Hydrolytic reactions of diribonucleoside 3',5'-(3'-N-phosphoramidates): kinetics and mechanisms for the P-O and P-N bond cleavage of 3'-amino-3'-deoxyuridylyl-3',5'-uridine.

Hydrolytic reactions of 3'-amino-3'-deoxyuridylyl-3',5'-uridine (2a), an analogue of uridylyl-3',5'-uridine having the 3'-bridging oxygen replaced with nitrogen, have been followed by RP HPLC over a wide pH range. The only reaction taking place under alkaline conditions (pH > 9) is hydroxide ion-catalyzed hydrolysis (first-order in [OH(-)]) to a mixture of 3'-amino-3'-deoxyuridine 3'-phosphoramidate (7) and uridine (4). The reaction proceeds without detectable accumulation of any intermediates. At pH 6-8, a pH-independent formation of 3'-amino-3'-deoxyuridine 2'-phosphate (3) competes with the base-catalyzed cleavage. Both 3 and in particular 7 are, however, rather rapidly dephosphorylated under these conditions to 3'-amino-3'-deoxyuridine (5). In all likelihood, both 3 and 7 are formed by an intramolecular nucleophilic attack of the 2'-hydroxy function on the phosphorus atom, giving a phosphorane-like intermediate or transition state. Under moderately acidic conditions (pH 2-6), the predominant reaction is acid-catalyzed cleavage of the P-N3' bond (first-order in [H(+)]) that yields an equimolar mixture of 5 and uridine 5'-phosphate (6). The reaction is proposed to proceed without intramolecular participation of the neighboring 2'-hydroxyl group. Under more acidic conditions (pH < 2), hydrolysis to 3 and 4 starts to compete with the cleavage of the P-N bond, and this reaction is even the fastest one at pH < 1. Formation of 2'-O,3'-N-cyclic phosphoramidate as an intermediate appears probable, although its appearance cannot be experimentally verified. The rate constants for various partial reactions have been determined. The reaction mechanisms and the effect that replacing the 3'-oxygen with nitrogen has on the behavior of the phosphorane intermediate are discussed.

Effects of ionic and non-ionic micelles on rate of hydroxide ion-catalyzed hydrolysis of securinine

The effects of micelles of cetyltrimethylammonium bromide (CTABr), tetradecyltrimethylammonium bromide (TTABr), sodium dodecyl sulfate (SDS) and polyoxyethylene 10 lauryl ether (C12E10) on the rates of alkaline hydrolysis of securinine were studied at a constant [−OH] (0.05 M). An increase in the total concentrations of CTABr, TTABr, SDS and C12E10 from 0.0 to 0.2 M causes a decrease in the observed pseudo-first-order rate constants (kobs) by factors of ca 2.5, 3, 7 and 4, respectively. The observed data are explained in terms of pseudophase and pseudophase ion-exchange (PIE) models of micelle. The binding constants, KS, of securinine with SDS, C12E10, CTABr and TTABr micelles are 32.4, 14.8, 22.1, and 9.1 M−1, respectively. The magnitudes of the second-order rate constants, kM, for the reactions in the micellar pseudophase are negligible compared with the corresponding rate constant, kW, for the reaction occurring in the aqueous pseudophase for CTABr, TTABr, SDS and C12E10. © 1998 John Wiley & Sons, Ltd.

Unusual Rate Enhancement in the Hydroxide Ion-Catalyzed Hydrolysis of N-Phthaloylglycine in the Presence of Anionic Micelles

Pseudo-first-order rate constants (kobs) for hydrolysis of ionized N-phthaloylglycine (NPG) at a constant [NaOH] and 30 °C increase nearly 50% with an increase in the total concentration of sodium dodecyl sulfate ([SDS]T) from 0.0 to 0.2 M. The hydrolysis of NPG involves -OH and anionic NPG as the reactants. The increase in [NaBr] from 0.01 to 0.4 0 M increases kobs by nearly 44% at 0.004 M NaOH and 30 °C. Pseudo-first-order rate constants (kobs ) increase by nearly 50% with an increase in [KCl] from 0.0 to 0.1 M at 0.003 and 0.004 M NaOH and 30 °C. The increase in [SDS]T from 0.0 to 0.3 M decreases kobs for hydrolysis of phthalimide at 0.01 M NaOH and 35 °C by nearly 10%. The attempt is also made to explain pseudo-first-order rate constants in terms of interfacial hyroxide ion concentration calculated from the Boltzmann equation using interfacial electrical potential.

Chemical and biological reactivity of sulfamidopenicillins

A number of semisynthetic penicillins bearing a sulfamido side chain at the 6-position have been prepared and their chemical and biological reactivity examined. The compounds do not show antibiotic activity against Escherichia coli but do show activity against Staphylococcus aureus. The rates of hydroxide-ion catalysed hydrolysis correlate well with the inductive effect of the sulfamido group indicating no pronounced steric effect on the chemical reactivity of the β-lactam ring. Molecular modelling studies show that the sulfamido group does not have an effect on the ‘open’versus‘closed’ conformations of the thiazolidine ring different from that of the benzylamido group. Comparisons with some sulfonamidopenicillins are made.

Large rate enhancement for the hydrolysis of a four-membered ring phosphonamidate

Unlike β-lactams a four-membered cyclic 1,2-azaphosphetidine shows enhanced hydrolytic reactivity compared with an acyclic analogue; the cyclic phosphonamidate 3 undergoes hydroxide-ion catalysed hydrolysis in water with endocyclic P–N fission; a corresponding acyclic derivative hydrolyses with P–O fission in basic solution, the rate difference between the cyclic and acyclic structures for P–N fission is greater than 5 × 108.

ChemInform Abstract: The Effect of the Carboxy Group on the Chemical and β‐Lactamase Reactivity of β‐Lactam Antibiotics

Abstract(I)‐(III).

The effect of the carboxy group on the chemical and β-lactamase reactivity of β-lactam antibiotics

Kinetic parameters are reported for the Bacillus cereusβ-lactamase I and β-lactamase II catalysed hydrolysis of esters and lactones of penicillins and cephalosporins. These are compared with the second-order rate constants for the hydroxide-ion catalysed hydrolysis of the same derivatives. The second-order rate constant, kcat/Km for the hydrolysis of the cephalosporin lactone catalysed by β-lactamase I is 50 times greater than that for an analogous cephalosporin and is 3 × 104 times greater than that for hydroxide-ion catalysed hydrolysis, a ratio similar to that for cephalosporins with a carboxylate group at C-4. The methyl ester of benzyl penicillin, but not the corresponding cephalosporanate, is a substrate for β-lactamase I. All ester derivatives are much poorer substrates for β-lactamase II. The cephalosporin lactone and, to a lesser extent, the methyl ester of benzyl penicillin can obviously bind to β-lactamase I even though they do not possess a formal anionic site at C-4 and C-3 respectively. The esterification of the carboxy group at C-3 in penicillins induces neighbouring-group participation by the C-6 acylamido side chain to give an oxazolinone intermediate. This is attributed to different Brönsted β1g dependency for alkaline hydrolysis and intramolecular acylamido participation, which exhibits rate limiting C–N bond fission of the β-lactam.

The kinetics and mechanism of a highly efficient intramolecular nucleophilic reaction. The cyclization of ethyl N-[o-(N-hydroxycarbamoyl)benzoyl]-carbamate to N-hydroxyphthalimide

The cyclization of ethyl N-[o-(N-hydroxycarbamoyl)benzoyl]carbamate (SH) to N-hydroxyphthalimide (NHPH) has been studied within the pH range 5.18–7.84 at 30 °C. The observed first-order rate constants are linearly dependent on [–OH]. Buffer catalysis could not be detected and the value of the second-order rate constant, kOH, for the specific base-catalysed cyclization reaction is (4.06 ± 0.05)× 104 l mol–1 s–1. The magnitude of kOH is ca. 3 × 105-fold greater than kOH for hydroxide ion-catalysed hydrolysis of methyl benzoate. The suggested mechanism involves the preequilibrium formation of the anionic substrate which cyclizes to produce anionic tetrahedral intermediate followed by its breakdown as the rate-determining step. The cyclized product, NHPH, reacts rapidly and reversibly with hydroxylamine to produce o-(N-hydroxycarbamoyl)benzohydroxamic acid (P). The equilibrium constants for the processes NHPH + NH2OH ⇌ P and PH + H++ NH2OH ⇌ P, where PH is the ionized NHPH, calculated at different pH using authentic NHPH, reveal a non-linear dependence on total hydroxylamine buffer concentrations.

Hydrolysis of 6-alkyl penicillins catalysed by β-lactamase I from Bacillus cereus and by hydroxide ion

Second-order rate constants for the hydroxide ion-catalysed hydrolysis of 6-alkyl penicillins are independent of the length of the alkyl side-chain and replacement of the amido by an amino group decreases the susceptibility to nuclephilic attack on 6-aminopenicillanic acid only three-fold. B. cereusβ-lactamase I catalyses the hydrolysis of 6-alkyl penicillins with values of Kcat/Km which are at least 50-fold greater than that shown by 6-aminopenicillanic acid. For the enzyme-catalysed reaction Kcat/Km increases with increasing chain length, reaching a maximum with hexylpenicillin, and then decreases. The binding energy of the alkyl group is weak, only 1.45 kJ mol–1 per methylene residue. Although there appears to be a recognition site for the amido group there is no specific pocket in β-lactamase I for the recognition of hydrophobic residues in the 6-acylamido side-chain of penicillins.

Prodrugs as drug delivery systems. 68. Chemical and plasma-catalyzed hydrolysis of various esters of benzoic acid: a reference system for designing prodrug esters of carboxylic acid agents

The hydrolysis of a series of esters of benzoic acid including various glycolic acid derivatives was studied in alkaline solution and in human plasma at 37 ° C. For the hydroxide ion-catalyzed hydrolysis a linear free-energy relationship between log kOH and the Taft polar parameter σ ∗ for the substituents in the alcohol portion was derived. The linear correlation equation obtained covered esters with a 100-fold variation in reactivity. All esters hydrolyzed to give benzoic acid except for various benzoylglycolic acid esters which predominantly hydrolyzed to give benzoylglycolic acid. The susceptibility of the ester derivatives to undergo enzyme-catalyzed hydrolysis by human plasma was strongly influenced by the structure of the alcohol moiety and was unrelated to the chemical reactivity of the compounds. Among the alkyl esters the ethyl ester showed the least enzymatic lability whereas the choline, N,N-dimethylaminoethanol and N,N-dimethylglycolamide esters were hydrolyzed extremely rapidly. The benzoylglycolic acid esters were predominantly, although incompletely, cleaved to benzoic acid by plasma enzymes. The results obtained were discussed in relation to design of ester prodrugs of carboxylic acid agents.

ChemInform Abstract: Solvent Effect on Activation Parameters for Intramolecular General Base‐catalysed Hydrolyses of Salicylate Esters and Hydroxide Ion‐catalysed Hydrolysis of Methyl p‐ Hydroxybenzoate

Chemischer InformationsdienstVolume 17, Issue 35 Preparative Organic Chemistry ChemInform Abstract: Solvent Effect on Activation Parameters for Intramolecular General Base-catalysed Hydrolyses of Salicylate Esters and Hydroxide Ion-catalysed Hydrolysis of Methyl p- Hydroxybenzoate M. N. KHAN, M. N. KHANSearch for more papers by this authorI. L. FATOPE, I. L. FATOPESearch for more papers by this authorK. I. ISAAC, K. I. ISAACSearch for more papers by this authorM. O. ZUBAIR, M. O. ZUBAIRSearch for more papers by this author M. N. KHAN, M. N. KHANSearch for more papers by this authorI. L. FATOPE, I. L. FATOPESearch for more papers by this authorK. I. ISAAC, K. I. ISAACSearch for more papers by this authorM. O. ZUBAIR, M. O. ZUBAIRSearch for more papers by this author First published: September 2, 1986 https://doi.org/10.1002/chin.198635108Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume17, Issue35September 2, 1986 RelatedInformation

Solvent effect on activation parameters for intramolecular general base-catalysed hydrolyses of salicylate esters and hydroxide ion-catalysed hydrolysis of methyl p-hydroxybenzoate

The effects of varying concentrations of methyl alcohol, dimethyl sulphoxide, t-butyl alcohol, and acetonitrile on activation parameters for intramolecular general base-catalysed aqueous cleavages of methyl salicylate and alkaline hydrolysis of methyl p-hydroxybenzoate have been studied. The activation parameters for intramolecular general base-catalysed cleavage of phenyl salicylate was studied under varying concentrations of t-butyl alcohol, dimethyl sulphoxide, and acetonitrile. A significant enthalpy–entropy compensation effect is observed in the hydrolyses of these esters with change of t-butyl alcohol content into the reaction medium. The variation of acetonitrile concentration causes an enthalpy–entropy compensation effect only in the alkaline hydrolysis of methyl p-hydroxybenzoate. A significantly larger negative value of ΔS*, observed in the hydrolysis of methyl p-hydroxybenzoate at 90% H2O (v/v), compared with those for hydrolyses of salicylate esters obtained under an essentially similar solvent composition, is attributed to the difference in mechanisms for hydrolysis of these esters.

Prodrugs of 5-fluorouracil. I. Hydrolysis kinetics and physicochemical properties of various N-acyl derivatives of 5-fluorouracil

The kinetics and mechanism of decomposition of nine N 1-acyl, N 3-acyl and N 1, N 3-diacyl derivatives of 5-fluorouracil in aqueous solution and in human plasma at 37°C were studied to assess their suitability as prodrugs for the parent compound. All the derivatives hydrolyzed to yield 5-fluorouracil in quantitative amounts. N 1-Deacylation proceeded much faster than N 3-deacylation and showed a pH-dependence which could be ascribed to water-catalyzed and hydroxide ion-catalyzed reactions. The hydrolysis of the N 1,N 3-diacyl derivatives passed through the corresponding N 3-acyl compound. The pH-rate profiles obtained for the N 3-deacylation were accounted for in terms of spontaneous and hydroxide ion-catalyzed hydrolysis of undissociated N 3-acyl derivative (pK a~7) as well as hydroxide ion-catalyzed hydrolysis of anionic derivative. The rate of N 3-deacylation was accelerated in human plasma, the half-life of hydrolysis in 80% plasma solutions at 37°C being 4.6, 20, 28 and 110 min for the N 3-acetyl, N 3-propionyl, N 3-butyryl and N 3-benzoyl derivatives, respectively. The N 3-acyl derivatives were more lipophilic than 5-fluorouracil as determined by partition experiments in octanol-aqueous buffer systems but their aqueous solubilities were even greater or only slightly reduced as compared with 5-fluorouracil. This behaviour was attributed to a decreased intermolecular hydrogen bonding in the crystal lattice achieved by blocking the 3-NH group by the acylation and manifested in a pronounced melting point decrease. The results suggested that N 3-acylation may be a promising means of obtaining prodrug forms of 5-fluorouracil with the aim of enhancing the delivery characteristics of the drug, e.g. by prodrugs exhibiting increased lipophilicity and/or affording protection against first-pass metabolism.

An investigation of the biphasic kinetics observed during the hydroxide ion-catalyzed hydrolysis of alkyl dithioesters

Kinetic evidence is presented for the establishment of an equilibrium, in dilute aqueous alkaline solutions, between alkyl dithioesters and a species I. The species I is formed cither by the extraction of a proton from, or by the addition of an hydroxide ion to, the dithioester. In the former case I would be an anion (probably an enethiolate) formed by the removal of a proton from the α-carbon atom, and in the latter case I would be a stabilized tetrahedral intermediate formed by the addition of an hydroxide ion to the thiocarbonyl carbon atom. It has not been possible, using kinetic evidence alone, to distinguish conclusively between these two possibilities. However, using the available evidence, arguments are presented in favor of I being an enethiolate anion.

Kinetic study of the degradation of cefotiam dihydrochloride in aqueous solution and of the reaction with aminoglycosides.

The kinetics of the degradation of cefotiam in aqueous solution was studied at 25°C and an ionic strength of 0.6 over the pH range of 2 to 12. The degradation was a pseudo first order reaction in this pH range. The rate-pH profile showed a characteristic maximum near the isoelectric point of cefotiam (pH 5.8). The optimal pH of an aqueous solution of cefotiam dihydrochloride for stability was calculated to be 8.0. The degradation pathways were shown to involve spontaneous hydrolysis of four ion species and hydroxide ion-catalyzed hydrolysis of the monoanion. Aminoglycosides accelerated the degradation of cefotiam by a pseudo second order reaction. From analysis of the rate-pH profile of the second order rate constants of these aminoglycosides, it appeared that the reaction was substantially a third order reaction with regards to cefotiam, aminoglycoside and hydroxide ion. Therefore, the combined use of cefotiam and aminoglycosides should be avoided at alkaline pH and/or at high concentration.

Intramolecular nucleophilic and general acid catalysis in the hydrolysis of an amide

The relative effectiveness of intramolecular nucleophilic and general acid catalysis are compared in the hydroxide-ion catalysed hydrolysis of N-(2-amino-ethyl)-2-endo-hydroxy-6-endo-norbornamide in its amino protonated form; the rate enhancement of ca. 109 is due mainly to nucleophilic catalysis by the neighbouring hydroxy group with only a relatively minor contribution from the protonated amino group acting as a general acid.

In Vitro and In Vivo Hydrolysis of Salicylanilide N-Methylcarbamate and 4-Biphenylyl N-Methylcarbamate

The kinetics of hydrolysis of the carbamoyl group in salicylanilide N-methylcarbamate (I) and 4-biphenylyl N-methyl-carbamate (II) showed that the reaction was first order with respect to both hydroxide ion and carbamate. At 37°, the hydroxideion-catalyzed hydrolysis of I to yield salicylanilide (III) proceeded at a rate over 200 times that for the hydrolysis of II to produce 4-biphenylol (IV). Half-lives of I and II at pH 7.3 were 11 min. and 38.2 hr., respectively. Following oral administration of I to human subjects, only conjugated III, corresponding to 10% of the dose, was detected in urine. In the case of II, urinary excretion products were II (0.40%), IV (1.14%), and conjugated IV (40%). Taken together, these results are consistent with extensive, if not complete, hydrolysis of I in the intestine to yield relatively poorly absorbed III compared to a considerably more efficient absorption of the neutral Compound II foilowed by its nearly complete hydrolysis and conjugation.

Strain effects in acyl transfer reactions. Part I. The kinetics of hydrolysis of some N-aryl-lactams

The hydroxide ion-catalysed hydrolysis of nine N-aryl-β-lactams have been studied at 298 K with [OH–] ranging from 10–2 to 1M. All show first-order dependence on hydroxide ion at high pH. Their reactivity is markedly increased by electron-withdrawing substituents and correlates well with the Hammett σ– function to give ρ–+ 1·225. The relative rates of hydrolysis of N-methyl-p-nitroacetanilide and of N-p-nitrophenyl δ-,γ-, and β-lactams are 1, 1·5, 14, and 110 respectively. It appears from these data that amides are activated in both steps of hydroxide-catalysed hydrolysis, as a result of angular deformation.

Kinetics of Base-Catalyzed Hydrolysis of Trimethadione

An infrared method is reported for determination of intact trimethadione (3,5,5- trimethyl-2,4-oxazolidinedione) in presence of products of hydrolysis. Kinetics have been determined for hydroxide ion-catalyzed hydrolysis of trimethadione and a mechanism is proposed in which there exists a rapid equilibrium between a cyclic and an acyclic structure. The rate of hydrolysis of trimethadione at pH 10 and 30° is 105 to 106 times that for acyclic compounds of similar structure.