Βlg Values Research Articles

Reactivity and Mechanism in the Hydrolysis of β-Sultams

β-Sultams show extraordinary rate enhancements of 109- and 107-fold, respectively, compared with the acid- and base-catalyzed hydrolysis of corresponding acyclic sulfonamides. They are about 103-fold more reactive than analogous β-lactams. The alkaline hydrolysis of some β-sultams shows a rate term that is second-order in hydroxide ion concentration, which is indicative of a stepwise mechanism involving a trigonal bipyramidal intermediate (TBPI). The Brønsted βlg value for the alkaline hydrolysis of N-aryl-β-sultams is −0.58 and the kinetic solvent isotope effect / is 0.60, compatible with rate-limiting formation of the TBPI. Conversely, / for N-alkyl-β-sultams is 1.55, indicative of rate-limiting breakdown of the TBPI. The acid-catalyzed hydrolysis of β-sultams is strongly retarded by electron-withdrawing groups α to the sulfonyl group, and it is suggested that the mechanism may involve unimolecular ring opening to generate a sulfonylium ion. The Brønsted βlg value for the acid-catalyzed hydrolysis of N-benzyl-β-sultams is 0.32. The general-acid-catalyzed hydrolysis of N-benzyl-β-sultam by carboxylic acids shows a Brønsted α value of 0.67 and is attributed to a specific acid−nucleophilic mechanism with the formation of a mixed-anhydride intermediate.

Effects of mixed H2O?CH3CN solvents on the Br�nsted coefficient for the intramolecular general base-catalyzed cleavage of ionized phenyl salicylate in the presence of primary and secondary amines

Nucleophilic second-order rate constants, knms, for the reactions of several primary and secondary amines with ionized phenyl salicylate (PS−) show a nonlinear decrease with the increase in the content of CH3CN from 2 to ≤50% v/v in mixed aqueous solvent. The values of knms remain almost unchanged with the change in the content of CH3CN at >50% v/v. The nucleophilic reactivity of primary and secondary amines toward PS− reveal Brønsted plots of different Brønsted coefficients, βnuc, at a constant content of CH3CN in mixed aqueous solvents. The values of βnuc decrease from 0.4 to nearly 0 for primary amines and from 0.22 to 0.12 for secondary amines with the increase in CH3CN content from 2 to 70% v/v. The values of knms/kMeOHms (where kMeOHms represents the nucleophilic second-order rate constant for the reaction of MeOH with PS− in H2OCH3CN solvents), obtained within 2–50%v/v CH3CN, fit to an empirical equation: log (knms/kMeOHms) = θ + λX where X is the % v/v content of CH3CN, and θ and λ are empirical constants. It has been shown empirically that both θ and λ are the function of Brønsted coefficient βlg. The values of λ are used to calculate βlg and these βlg values for all amines except Tris lie within −0.32 to −0.46. The effects of mixed water–acetonitrile solvents on pKa of leaving the group, phenol, and conjugate acid of amine nucleophile have been concluded to be the major source for the observed solvent effects on knms. The βlg for Tris is unusually very close to zero. © 2000 John Wiley & Sons, Inc. Int J Chem Kinet 32: 153–164, 2000

The mechanism of the metal ion promoted cleavage of RNA phosphodiester bonds involves a general acid catalysis by the metal aquo ion on the departure of the leaving group

A series of uridine 3′-alkyl phosphates and 3′-aryl phosphates were synthesised and their cleavage was studied in the presence of Zn2+ aquo ions. A βlg value was determined for the Zn2+ promoted cleavage of both types of compounds. Comparison of the results obtained to those reported previously for the cleavage of the same substrates in the absence of metal ion catalysts suggests that the alkyl leaving group departs as an alcohol in the presence of metal ion catalysts. Furthermore, metal ion catalysts seem to enhance the departure. The aryl leaving group, in contrast, departs as an oxyanion.

Hydrolysis and intramolecular transesterification of ribonucleoside 3′-phosphotriesters: comparison of structural effects in the reactions of asymmetric and symmetric dialkyl esters of 5′-O-pivaloyl-3′-uridylic acid

β rg Values (rg = remnant group) for the O2′⇆O3′ isomerization of asymmetric dialkyl esters of 5′-O-pivaloyluridine 3′-phosphate and βlg values (lg = leaving group) for the cleavage of the more electronegative alkoxy group from these triesters under various conditions have been determined. The reactions studied included hydronium ion, hydroxide ion, general acid and general base, and pH- and buffer-independent cleavage. The results are compared with the corresponding values obtained earlier with the symmetric 3′-triesters and the catalysis mechanisms are discussed.

PH- and buffer-independent cleavage and mutual isomerization of uridine 2′- and 3′-alkyl phosphodiesters: implications for the buffer catalyzed cleavage of RNA

Concurrent isomerization of the ethyl, 2-ethoxyethyl, 2,2-dichloroethyl and 2,2,2-trichloroethyl esters of uridine 3′-phosphate to their 2′-counterparts and cleavage to uridine 2′,3′-cyclic phosphate have been studied over a wide pH-range (H0 = –0.2 to pH 9) at 363.2 K. The buffer-independent pH-rate profiles obtained show involvement of four distinct kinetic terms in the cleavage reaction, viz. dependence of rate on [H+][SH], [SH], [S–] and [S–][H+]–1 (S– denotes the diester monoanion). The βlg values (lg = leaving group) for the partial reactions are –0.04 ± 0.04, –0.19 ± 0.12, –0.59 ± 0.12 and –1.10 ± 0.05, respectively. The isomerization, in turn, shows dependence of rate on [H+][SH], [SH] and [S–], the βrg values (rg = remnant group) being –0.23 ± 0.04, –0.23 ± 0.11 and –0.03 ± 0.01. The mechanisms of various partial reactions are evaluated by comparing these values with those of specific and buffer catalyzed reactions of the corresponding 3′-phosphotriesters, regarded as mimetics of the neutral ionic form of diesters. Furthermore, the mechanistic significance of the dissimilar competition between the cleavage and isomerization with diesters and triesters is discussed.

Hydrolysis and intramolecular transesterification of ribonucleoside 3′-phosphotriesters: the effect of alkyl groups on the general and specific acid–base-catalyzed reactions of 5′-O-pivaloyluridin-3′-yl dialkyl phosphates

Diisopropyl, diethyl, bis(2-methoxyethyl) and isopropyl 2-methoxyethyl esters of 5′-pivaloyl-2′-(tetrahydropyran-2-yl)uridin-3′-yl phosphate have been prepared. The 2′-protecting group has been removed under acidic conditions, and the isomerization of the resulting ribonucleoside 3′-phosphotriester to its 2′-counterpart and the cleavage of the isomeric mixture to 2′- and 3′-phosphodiesters and a 2′,3′-cyclic phosphate has been followed by reverse phase HPLC in aqueous hydrogen chloride and several buffer solutions over a wide acidity range from H0 – 1.5 to pH 8. The βlg values of the buffer-independent partial reactions, and the βlg and Brønsted α and β values of the buffer catalyzed reactions have been determined. The mechanisms of various partial reactions are discussed on the basis of the structural effects observed.

Structure‐reactivity correlation in the reactions of pyrrolidine with O‐ethyl S‐aryl dithiocarbonates in aqueous ethanol

The reactions of pyrrolidine with O-ethyl S-(X-phenyl) dithiocarbonates (X = 4-methyl, 4-methoxy, H, 4-chloro, 4-nitro, 2,4-dinitro, and 2,4,6-trinitro) are subjected to a kinetic study in 44 wt% aqueous ethanol, 25.0°C, and ionic strength 0.2 M (maintained with KCl). Pseudo-first-order kinetics are found under amine excess. Linear plots of the pseudo-first-order rate coefficient against concentration of free-base pyrrolidine are obtained for all the reactions, the nucleophilic rate coefficient (kN) being the slope of such plots. The Bronsted-type plot (log kN vs. pKa for the leaving group) is linear with slope βlg = − 0.2, which is consistent with a mechanism through a tetrahedral intermediate (T±) where its formation is rate determining. The βlg value is very similar to that found in the same reactions in water. There is a great difference in the mechanism of the reactions of O-ethyl S-phenyl dithiocarbonate with pyrrolidine (order one in amine) and piperidine (complex order in amine) in aqueous ethanol, and this is attributed to a greater nucleofugality from T± of piperidine rather than pyrrolidine. © 1997 John Wiley & Sons, Inc.

Structure-reactivity correlation in the reactions of pyrrolidine with O-ethyl S-aryl dithiocarbonates in aqueous ethanol

The reactions of pyrrolidine with O-ethyl S-(X-phenyl) dithiocarbonates (X = 4-methyl, 4-methoxy, H, 4-chloro, 4-nitro, 2,4-dinitro, and 2,4,6-trinitro) are subjected to a kinetic study in 44 wt% aqueous ethanol, 25.0°C, and ionic strength 0.2 M (maintained with KCl). Pseudo-first-order kinetics are found under amine excess. Linear plots of the pseudo-first-order rate coefficient against concentration of free-base pyrrolidine are obtained for all the reactions, the nucleophilic rate coefficient (kN) being the slope of such plots. The Bronsted-type plot (log kN vs. pKa for the leaving group) is linear with slope βlg = − 0.2, which is consistent with a mechanism through a tetrahedral intermediate (T±) where its formation is rate determining. The βlg value is very similar to that found in the same reactions in water. There is a great difference in the mechanism of the reactions of O-ethyl S-phenyl dithiocarbonate with pyrrolidine (order one in amine) and piperidine (complex order in amine) in aqueous ethanol, and this is attributed to a greater nucleofugality from T± of piperidine rather than pyrrolidine. © 1997 John Wiley & Sons, Inc.

Kinetics of breakdown of aryl hemiacetals of α-bromoacetophenone. Effect of phenol leaving groups on the lifetimes of tetrahedral intermediates

The kinetics of breakdown of seven aryl hemiacetals of α-bromoacetophenone (TOH) have been examined, with aryl substituents 4-MeO, 4-Me, 3-Me, H, 3-MeO, 4-Cl, 3-Cl. The hemiacetals were generated as intermediates in the aqueous bromination of α-aryloxystyrenes, where the breakdown of the hemiacetal is the rate-limiting stage in the overall reaction. Base catalysis of the breakdown shows large Brønsted β values (0.8–1.0) and similarly large βlg values (−0.8 to −1.0). These are argued to arise because of a preassociation mechanism in which the hydrogen-bonded intermediate [Formula: see text] loses aryloxide faster than diffusional separation of the acid–base pair. This mechanism is enforced by lifetimes of the deprotonated hemiacetals TO− in the 1010–1012 s−1 range. Such lifetimes were estimated in two independent ways, by extrapolation of data previously obtained for alkyl hemiacetals of α-bromoacetophenone, and through a calculation based upon the experimental catalytic coefficients, and estimates of the acidity constants for TOH and the equilibrium constants for formation of hydrogen-bonded complexes. The pH-independent breakdown has βlg = −1.03, and the point lies near the Brønsted line for the carboxylate catalysts. This, therefore, also occurs by a preassociation mechanism with water as the catalyst forming the intermediate [Formula: see text], which loses aryloxide faster than diffusional separation. Catalysis by hydroxide ion occurs with rate constants of 8 × 109 M−1 s−1 independent of aryl substituent. This represents rate-limiting diffusional encounter of the hemiacetal and hydroxide ion, the hydrogen-bonded intermediate [Formula: see text] rapidly proceeding on to products. Acid catalysis of the hemiacetal breakdown occurs by a class "n" mechanism in which the acid assists departure of the substitued phenol. Alkyl hemiacetals of α-bromoacetophenone break down by a class "e" mechanism where the leaving group is fully protonated before bond cleavage. The class "e" mechanism can be excluded for the aryl derivatives, since rate constants much greater then diffusion are required to explain the observed catalytic coefficients. The different mechanism is followed in order to avoid the fully protonated hemiacetal, which, being of an O-protonated anisole structure, is of very high energy. Key words: hemiacetal kinetics, preassociation, intermediate lifetime.

Failure of the antiperiplanar lone pair hypothesis in glycoside hydrolysis. Synthesis, conformation, and hydrolysis of α-D-xylopyranosyl-and α-D-glucopyranosyl-pyridinium salts

(1) Two series of crystalline α-D-xylopyranosyl-and α-D-glucopyranosyl-pyridinium bromides have been made, by reaction of the acetylated α-bromides with the pyridines in an aprotic solvent in the presence of bromide ion, followed by deacetylation with aqueous HBr at room temperature. (2) 200 MHz 1H N.m.r. spectra in D2O of representatives of each series show the xylo-compounds to adopt the 1C4 conformation, and the gluco-compounds the 1S3 conformation. (3) The hydrolyses of α-D-xylopyranosyl- and α-D-glucopyranosyl-3-bromopyridinium ions in 1.0M-NaCIO4 at 25.0 °C are described by kobs/s–1=4.7 × 10–8+1.4 × 10–18/[H+] and kobs/s–1=2 × 10–7+1.4 × 10–17/[H+], respectively. (4) The products of pH-independent hydrolysis of the foregoing ions are the sugars and 3-bromopyridine, whereas at pH 12, 10% of both reactions proceed by attack on the pyridine ring: attack on the sugar yields glucose and 1,6-anhydroglucopyranose, but no xylose. (5) The pH-independent hydrolyses display strongly positive entropies of activation: at 25.0 °C, those of five xylo-compounds give a βlg value of –1.27 ± 0.06, and those of four gluco-compounds one of –1.06 ± 0.12. (6) Arguments are presented, in the light of the low α:β rate ratios for both xylo and gluco pyridinium salts (8–23 and 80, respectively, at 25 °C), that departure of a pyridine from C(1) of an aldopyranose ring does not require a conformation in which the leaving group is antiperiplanar to a lone pair of electrons on O(5). (7) The antiperiplanar lone pair hypothesis is shown to be a special case of the principle of least nuclear motion, which is known not to apply to reactions with very product-(or reactant-) like transition states.

Catalysis by β-glucosidase A3of Aspergillus wentii

(1)α-Deuterium kinetic isotope effects on Vmax. for hydrolysis of both β-D-glucopyranosylpyridinium ions and aryl β-D-glucopyranosides are in the range kH/kD 1.08–1.14, indicating that bond-breaking limits the rate of hydrolysis of both sets of substrates. The variation of kcat with aglycone acidity, expressed by log kcat=A+βlgpKa, is governed by a βlg value of –0.96 ± 0.19 for the N-glycosides and –0.05 ± 0.05 for the O-glycosides. The latter, low value of |βlg| is evidence for extensive proton donation to the oxygen at the transition state, even for the departure of acidic aglycones. The dependence of rate on protonation of a group of pKa < 6 required by this idea is indeed observed. (2) Comparison of log kcat values with spontaneous hydrolysis rates indicates that nucleophilic and non-covalent interactions accelerate C–N bond cleavage in the ES complex by a factor of 10(8 + 0.3[pka]N) for glucosyl pyridinium salts where [pKa]N is the pKa of the pyridine. On the assumption that these interactions are similar for O-glucosides, proton donation to the aglycone oxygen atom can be estimated to contribute a rate-enhancement of 10(0.1 + 0.7[pKa]O), where [pKa]O is that of the free phenol. (3)D-Glucono-δ-lactone and 5-amino-5-deoxy-D-gluconolactam are bound 102.8 and 102.2 times, respectively, more tightly than β-D-glucopyranose, because of their analogy to a transition state in which α-deuterium kinetic isotope effects have shown the anomeric carbon atom to have substantial sp2 character. (4) Cationic inhibitors are bound 102.5–103.5 times more tightly than directly comparable neutral ones, if the positive charge resides on the equatorial substituent at C-1, but protonated 2-amino-2-deoxyglucose is bound no more tightly than glucose. This indicates the presence of a negative charge in the El complex near C-1 on the α face of the pyranose ring (an aspartate residue previously identified by covalent labelling) which is partly compensated by a positive charge near C-2.