A mechanistic study of the alkaline hydrolysis of diaryl sulfate diesters

Nearly all of the reported studies of reactions of sulfate diesters are for dialkyl or alkyl aryl diesters, which undergo reaction by carbon-oxygen bond fission. Sulfuryl transfer reactions of sulfate diesters (RO-SO(2)-OR') proceeding by attack at sulfur have been little explored. When both ester groups are aryl groups the hydrolysis reaction (sulfuryl transfer to water) occurs by way of attack at sulfur. The alkaline hydrolysis of diaryl sulfate diesters was shown to obey first-order kinetics with respect to [(-)OH] and proceed through S-O bond fission, in a mechanism that is most likely concerted. Activation parameters for 4-chloro-3-nitrophenyl phenyl sulfate and 4-nitrophenyl phenyl sulfate gave the following respective values: Delta H(++) = 88.0 +/- 0.1 and 84.83 +/- 0.06 kJ mol(-)(1) and Delta S(++) = -37 +/- 1 and -50.2 +/- 0.5 J mol(-)(1) deg(-)(1). The dependence of the second-order rate constant for hydrolysis on leaving group pK(a) was analyzed giving a beta(lg) slope of -0.7 +/- 0.2 and a Leffler alpha parameter value of 0.36. A (15)k kinetic isotope effect (KIE) for the hydroxide attack on 4-nitrophenyl phenyl sulfate of 1.0000 +/-0.0005 and an (18)k(lg) KIE value of 1.003+/-0.002 were obtained.     

Transition-state variation in the nucleophilic substitution reactions of aryl bis(4-methoxyphenyl) phosphates with pyridines in acetonitrile

The kinetics and mechanism of the reactions of Z-aryl bis(4-methoxyphenyl) phosphates, (4-MeOC(6)H(4)O)(2)P(=O)OC(6)H(4)Z, with pyridines (XC(5)H(4)N) are investigated in acetonitrile at 55.0 degrees C. In the case of more basic phenolate leaving groups (Z = 4-Cl, 3-CN), the magnitudes of beta(X) (beta(nuc)) and beta(Z) (beta(lg)) indicate that mechanism changes from a concerted process (beta(X) = 0.22-0.36, beta(Z) = -0.42 to -0.56) for the weakly basic pyridines (X = 3-Cl, 4-CN) to a stepwise process with rate-limiting formation of a trigonal bipyramidal pentacoordinate (TBP-5C) intermediate (beta(X) = 0.09-0.14, beta(Z) = -0.08 to -0.28) for the more basic pyridines (X = 4-NH(2), 3-CH(3)). This proposal is supported by a large negative cross-interaction constant (rho(XZ) = -1.98) for the former and a positive rho(XZ) (+0.97) for the latter processes. In the case of less basic phenolate leaving groups (Z = 3-CN, 4-NO(2)), the unusually small magnitude of beta(Z) values is indicative of a direct backside attack TBP-5C TS in which the two apical sites are occupied by the nucleophile and leaving group, ap(NX)-ap(LZ). The instability of the putative TBP-5C intermediate leading to a concerted displacement is considered to result from relatively strong proximate charge transfer interactions between the pi-lone pairs on the directly bonded equatorial oxygen atoms and the apical bond (n(O)(eq) - sigma(ap)). These are supported by the results of natural bond orbital (NBO) analyses at the NBO-HF/6-311+G//B3LYP/6-311+G level of theory.     

Application of Brønsted-type LFER in the study of the phospholipase C mechanism

Phosphatidylinositol-specific phospholipase C cleaves the phosphodiester bond of phosphatidylinositol to form inositol 1,2-cyclic phosphate and diacylglycerol. This enzyme also accepts a variety of alkyl and aryl inositol phosphates as substrates, making it a suitable model enzyme for studying mechanism of phosphoryl transfer by probing the linear free-energy relationship (LFER). In this work, we conducted a study of Br?nsted-type relationship (log k = beta(lg) pK(a) + C) to compare mechanisms of enzymatic and nonenzymatic reactions, confirm the earlier proposed mechanism, and assess further the role of hydrophobicity in the leaving group as a general acid-enabling factor. The observation of the high negative Br?nsted coefficients for both nonenzymatic (beta(lg) = -0.65 to -0.73) and enzymatic cleavage of aryl and nonhydrophobic alkyl inositol phosphates (beta(lg) = -0.58) indicates that these reactions involve only weak general acid catalysis. In contrast, the enzymatic cleavage of hydrophobic alkyl inositol phosphates showed low negative Br?nsted coefficient (beta(lg) = -0.12), indicating a small amount of the negative charge on the leaving group and efficient general acid catalysis. Overall, our results firmly support the previously postulated mechanism where hydrophobic interactions between the enzyme and remote parts of the leaving group induce an unprecedented negative-charge stabilization on the leaving group in the transition state.     

Kinetics and mechanism of the aminolysis of aryl ethyl chloro and chlorothio phosphates with anilines

The reactions of ethyl Y-phenyl chloro (1) and chlorothio (2) phosphates with X-anilines in acetonitrile at 55.0 degrees C are studied kinetically and theoretically. Kinetic results yield the primary kinetic isotope effects (k(H)/k(D) = 1.07-1.80 and 1.06-1.27 for 1 and 2, respectively) with deuterated aniline (XC(6)H(4)ND(2)) nucleophiles, and the cross-interaction constants rho(XY) = -0.60 and -0.28 for and , respectively. A concerted mechanism involving a partial frontside attack through a hydrogen-bonded, four-center-type transition state is proposed. The large rho(X) (rho(nuc) = -3.1 to -3.4) and beta(X) (beta(nuc) = 1.1-1.2) values seem to be characteristic of the anilinolysis of phosphates and thiophosphates with the Cl leaving group. Because of the relatively large size of the aniline nucleophile, the degree of steric hindrance could be the decisive factor that determines the direction of the nucleophilic attack to the phosphate and thiophosphate substrates with the relatively small-sized Cl leaving group.     

Reactions of [aryloxy(phenyl)carbene]pentacarbonylchromium(0) complexes with thiolate ions. Decreasing reactivity with increasing basicity of the nucleophile

A kinetic study of the reactions of thiolate ions with three Fischer-type [aryloxy(phenyl)carbene]pentacarbonyl chromium(0) complexes in 50% MeCN-50% water (v/v) is reported. Br?nsted plots of the second-order rate constants are biphasic with an initial steep rise for weakly basic thiolate ions (beta(nuc) approximately equal to 1.0) followed by a slightly descending leg with a negative slope (beta(nuc) approximately equal to -0.2) for strongly basic thiolate ions. This indicates a change from rate-limiting leaving group departure at low pK(RSH)(a) to rate-limiting nucleophilic attachment at high pK(RSH)(a). The negative beta(nuc) values result from a combination of minimal progress of C-S bond formation at the transition state and the requirement for partial desolvation of the nucleophile before it enters the transition state. Possible factors that may affect the degree of bond formation in reactions of Fischer carbene complexes as well as reactions of other unsaturated electrophiles with thiolate ions are discussed.     

Transition state differences in hydrolysis reactions of alkyl versus aryl phosphate monoester monoanions

Although aryl phosphates have been the subject of numerous experimental studies, far less data bearing on the mechanism and transition states for alkyl phosphate reactions have been presented. Except for esters with very good leaving groups such as 2,4-dinitrophenol, the monoanion of phosphate esters is more reactive than the dianion. Several mechanisms have been proposed for the hydrolysis of the monoanion species. (18)O kinetic isotope effects in the nonbridging oxygen atoms and in the P-O(R) ester bond, and solvent deuterium isotope effects, have been measured for the hydrolysis of m-nitrobenzyl phosphate. The results rule out a proposed mechanism in which the phosphoryl group deprotonates water and then undergoes attack by hydroxide. The results are most consistent with a preequilibrium proton transfer from the phosphoryl group to the ester oxygen atom, followed by rate-limiting P-O bond fission, as originally proposed by Kirby and co-workers in 1967. The transition state for m-nitrobenzyl phosphate (leaving group pK(a) 14.9) exhibits much less P-O bond fission than the reaction of the more labile p-nitrophenyl phosphate (leaving group pK(a) = 7.14). This seemingly anti-Hammond behavior results from weakening of the P-O(R) ester bond resulting from protonation, an effect which calculations have shown is much more pronounced for aryl phosphates than for alkyl ones.     

An altered mechanism of hydrolysis for a metal-complexed phosphate diester

Isotope effects in the nucleophile and in the leaving group were measured to gain information about the mechanism and transition state of the hydrolysis of methyl p-nitrophenyl phosphate complexed to a dinuclear cobalt complex. The complexed diester undergoes hydrolysis about 1011 times faster than the corresponding uncomplexed diester. The kinetic isotope effects indicate that this rate acceleration is accompanied by a change in mechanism. A large inverse 18O isotope effect in the bridging hydroxide nucleophile (0.937 +/- 0.002) suggests that nucleophilic attack occurs before the rate-determining step. Large isotope effects in the nitrophenyl leaving group (18Olg = 1.029 +/- 0.002, 15N = 1.0026 +/- 0.0002) indicate significant fission of the P-O ester bond in the transition state of the rate-determining step. The data indicate that in contrast to uncomplexed diesters, which undergo hydrolysis by a concerted mechanism, the reaction of the complexed diester likely proceeds via an addition-elimination mechanism. The rate-limiting step is expulsion of the p-nitrophenyl leaving group from the intermediate, which proceeds by a late transition state with extensive bond fission to the leaving group. This represents a substantial change in mechanism from the hydrolysis of uncomplexed aryl phosphate diesters.     

Concerted mechanisms of the reactions of methyl aryl carbonates with substituted phenoxide ions

The reactions of 4-nitrophenyl, 2,4-dinitrophenyl, and 2,4,6-trinitrophenyl methyl carbonates (NPC, DNPC, and TNPC, respectively) with substituted phenoxide ions are subjected to a kinetic study in water at 25.0 degrees C, ionic strength 0.2 M (KCl). Production of the leaving groups (the nitro derivatives) is followed spectrophotometrically. Under excess of the phenoxide ions pseudo-first-order rate coefficients (k(obsd)) are found throughout. Plots of k(obsd) vs substituted phenoxide concentration at constant pH are linear, with the slope (k(N)) independent of pH. The Br?nsted-type plots (log k(N) vs pK(a) of the phenols) are linear with slopes beta = 0.67, 0.48, and 0.52 for the phenolysis of NPC, DNPC, and TNPC, respectively. The magnitudes of these Br?nsted slopes are consistent with a concerted mechanism. In the particular case of the phenolysis of NPC the expected hypothetical curvature center of the Br?nsted plot for a stepwise mechanism should be pK(a)(0) = 7.1 (the pK(a) of 4-nitrophenol). This curvature does not appear within the pK(a) range of the substituted phenols studied (5.3--10.3), indicating that these reactions are concerted. The phenolysis of DNPC and TNPC should also be concerted in view of the even more unstable tetrahedral intermediates that would be formed if the reactions were stepwise. The reactions of the same substrates with pyridines are stepwise, which means that substitution of a pyridine moiety in a tetrahedral intermediate by a phenoxy group destabilizes the intermediate perhaps to the point of nonexistence. The k(N) values for the title reactions are larger than those for the concerted phenolysis of the corresponding ethyl S-aryl thiolcarbonates. The k(N) values found in the present reactions are subjected to a dual regression analysis as a function of the pK(a), of both the nucleophile and leaving group, the coefficients being beta(N) = 0.5 and beta(lg) = -0.3, respectively. These coefficients are consistent with a concerted mechanism.     

Aminolysis of Y-substituted phenyl diphenylphosphinates and benzoates: effect of modification of electrophilic center from C=O to P=O

The effect of modification of the electrophilic center from C=O to P=O on reactivity and reaction mechanism has been investigated for aminolysis of Y-substituted phenyl diphenylphosphinates (1a-j) and benzoates (2a-i). The phosphinates 1a-j are less reactive than the benzoates 2a-i. The reactions of 2,4-dinitrophenyl diphenylphosphinate (1a) with alicyclic secondary amines resulted in a linear Br?nsted-type plot with a beta(nuc) value of 0.38, while the corresponding reactions of 2,4-dinitrophenyl benzoate (2a) yielded a curved Br?nsted-type plot. Similarly, a linear Br?nsted-type plot with a beta(lg) value of -0.66 was obtained for the reactions of 1a-j with piperidine, while the corresponding reactions of 2a-i gave a curved Br?nsted-type plot. The linear Br?nsted-type plots for the reactions of 1a-j have been taken as evidence for a concerted mechanism, while the curved Br?nsted-type plots for the reactions of 2a-i have been suggested to indicate a change in the rate-determining step of a stepwise mechanism. The Hammett plot for the reactions of 1b-j exhibited a poor correlation with sigma(-) constants (R(2) = 0.962) but slightly better correlation with sigma(o) (R(2) = 0.986). However, the Yukawa-Tsuno plot for the same reactions resulted in an excellent correlation (R(2) = 0.9993) with an r value of 0.30. The aminolysis of 1a-j has been suggested to proceed through a concerted mechanism with an early transition state on the basis of the small beta(nuc) and small r values.     

Kinetics and mechanism of the aminolysis of aryl N-ethyl thiocarbamates in acetonitrile

The aminolysis of aryl N-ethyl thiocarbamates (EtNHC(=O)SC(6)H(4)Z) with benzylamines (XC(6)H(4)CN(2)NH(2)) in acetonitrile at 30.0 degrees C is investigated. The rates are faster than the corresponding values for aryl N-phenyl thiocarbamates (PhNHC(=O)SC(6)H(4)Z), reflecting a stronger push to expel the leaving group by EtNH than the PhNH nonleaving group in a concerted process. The negative rho(XZ) (-0.86) and failure of the reactivity-selectivity principle found are consistent with the concerted mechanism. The kinetic isotope effects involving deuterated nucleophiles (k(H)/k(D) = 1.5-1.7) and low Delta H(++) with large negative Delta S(++) values suggest a hydrogen bond cyclic transition state.     

Elimination reactions of (E)-2,4-dinitrobenzaldehyde O-benzoyloximes promoted by R2NH/R2NH2(+) in 70 mol % MeCN(aq). Change of reaction mechanism

Elimination reactions of (E)-2,4-(NO(2))(2)C(6)H(3)CHNOC(O)C(6)H(4)X (1) promoted by R(2)NH/R(2)NH(2)(+) in 70 mol % MeCN(aq) have been studied kinetically. The reactions are second-order and exhibit Bronsted beta = 0.27-0.32 and |beta(lg)| = 0.28-0.32. The result can be described by a negligible p(xy) interaction coefficient, p(xy) = partial differential beta/partial differential pK(lg) = partial differential beta(lg)/partial differential pK(BH) approximately = 0, which describes the interaction between the base catalyst and the leaving group. The negligible p(xy) coefficients are consistent with the (E1cb)(irr) mechanism.     

Catalysis of hydrolysis and nucleophilic substitution at the P-N bond of phosphoimidazolide-activated nucleotides in phosphate buffers

Phosphoimidazolide-activated derivatives of guanosine and cytidine 5'-monophosphates, henceforth called ImpN's, exhibit enhanced rates of degradation in the presence of aqueous inorganic phosphate in the range 4.0 < or = pH < or = 8.6. This degradation is been attributed to (i) nucleophilic substitution of the imidazolide and (ii) catalysis of the P-N bond hydrolysis by phosphate. The first reaction results in the formation of nucleoside 5'-diphosphate and the second in nucleoside 5'-monophosphate. Analysis of the observed rates as well as the product ratios as a function of pH and phosphate concentration allow distinction between various mechanistic possibilities. The results show that both H2PO4- and HPO4(2-) participate in both hydrolysis and nucleophilic substitution. Statistically corrected biomolecular rate constants indicate that the dianion is 4 times more effective as a general base than the monoanion, and 8 times more effective as nucleophile. The low Bronsted value beta = 0.15 calculated for these phosphate species, presumed to act as general bases in facilitating water attack, is consistent with the fact that catalysis of the hydrolysis of the P-N bond in ImpN's has not been detected before. The beta nuc = 0.35 calculated for water, H2PO4-, HPO4(2-), and hydroxide acting as nucleophiles indicates a more associative transition state for nucleotidyl (O2POR- with R = nucleoside) transfers than that observed for phosphoryl (PO3(2-)) transfers (beta nuc = 0.25). With respect to the stability/reactivity of ImpN's under prebiotic conditions, our study shows that these materials would not suffer additional degradation due to inorganic phosphate, assuming the concentrations of phosphate, Pi, on prebiotic Earth were similar to those in the present oceans ([Pi] approximately 2.25 micromoles).     

Kinetics and mechanism of the phenolysis of asymmetric diaryl carbonates

The reactions 4-methylphenyl 4-nitrophenyl carbonate (MPNPC), 4-chlorophenyl 4-nitrophenyl carbonate (CIPNPC), 4-methylphenyl 2,4-dinitrophenyl carbonate (MPDNPC), and 4-chlorophenyl 2,4-dinitrophenyl carbonate (CIPDNPC) with a homogeneous series of phenoxide anions are subjected to a kinetic investigation in aqueous solution (25.0 degrees C, ionic strength 0.2 M (KCI)). Under an excess of phenoxide with respect to the substrate, all of these reactions obey pseudo-first-order kinetics and are first order in phenoxide. The Br?nsted-type plots for the nucleophilic rate constants (k(N)) are linear, with slopes beta = 0.48 (MPNPC), 0.67 (ClPNPC), 0.41 (MPDNPC), and 0.32 (ClPDNPC). The magnitude of these slopes and the absence of a curvature in the Br?nsted plot at pK(a) = 7.1 for the CIPNPC reactions are consistent with concerted mechanisms (one step). The carbonates MPDNPC and ClPDNPC are more reactive than MPNPC and CIPNPC, respectively, toward phenoxide nucleophiles. This can be explained by the presence of a second nitro group in the nucleofuge of the dinitro derivatives, which (i) leaves their carbonyl carbon more positively charged, making them better electrophiles, and (ii) makes 2,4-dinitrophenoxide a better leaving group than 4-nitrophenoxide. The 4-chloro derivatives are more reactive than the corresponding 4-methyl derivatives. This should be due to the greater electron withdrawal of 4-chloro than 4-methyl, which makes the former carbonyl more electrophilic. Comparison of the concerted phenolysis of MPNPC with the stepwise reactions of secondary alicyclic amines with the same substrate indicates that substitution of a secondary alicyclic amine group in a zwitterionic tetrahedral intermediate by a phenoxy group greatly destabilizes the intermediate. An equation is deduced for log k(N) in terms of the basicity of the nucleophile, the nonleaving moiety, and the leaving group. This equation shows that for these reactions, the sensitivity of log k(N) to the basicity of the nonleaving moiety (beta(nlg) = -0.27) is very similar to that of the nucleofuge (beta(lg) = -0.25).     

Aminolysis of aryl chlorothionoformates with anilines in acetonitrile: effects of amine nature and solvent on the mechanism

The aminolysis of aryl chlorothionoformates (7, YC(6)H(4)OC(=S)Cl) with anilines (XC(6)H(4)NH(2)) in acetonitrile at 5.0 degrees C has been investigated. The rates are slower than those for the corresponding reactions of aryl chloroformates (6, YC(6)H(4)OC(=O)Cl). This rate sequence is a reverse of that for alkyl chloroformates (1-4) in water, for which rate-limiting formation of a tetrahedral intermediate, T(+/-), is predicted. On the basis of the large negative cross-interaction constant, rho(XY) = -0.77, failure of the reactivity-selectivity principle, normal k(H)/k(D) values involving deuterated nucleophiles (XC(6)H(4)ND(2)), and low DeltaH(not equal) with large negative DeltaS(not equal) values, a concerted mechanism with a four-membered hydrogen bonded cyclic transition state (11) is proposed for the title reaction series. It has been shown that the solvent change from water to acetonitrile for the aminolysis of 6 and 7 causes a mechanistic change from stepwise to concerted.     

General base and general acid catalyzed intramolecular aminolysis of esters. Cyclization of esters of 2-aminomethylbenzoic acid to phthalimidine

Plots of log k(0) vs pH for the cyclization of trifluoroethyl and phenyl 2-aminomethylbenzoate to phthalimidine at 30 degrees C in H(2)O are linear with slopes of 1.0 at pH >3. The values of the second-order rate constants k(OH) for apparent OH(-) catalysis in the cyclization reactions are 1.7 x 10(5) and 5.7 x 10(7) M(-)(1) s(-)(1), respectively. These rate constants are 10(5)- and 10(7)-fold greater than for alkaline hydrolysis of trifluoroethyl and phenyl benzoate. The k(OH) for cyclization of the methyl ester is 7.2 x 10(3) M(-)(1) s(-)(1). Bimolecular general base catalysis occurs in the intramolecular nucleophilic reactions of the neutral species. The value of the Bronsted coefficient beta for the trifluoroethyl ester is 0.7. The rate-limiting step in the general base catalyzed reaction involves proton transfer in concert with leaving group departure. The mechanism involving rate-determining proton transfer exemplified by the methyl ester in this series (beta = 1.0) can then be considered a limiting case of the concerted mechanism. General acid catalysis of the neutral species reaction or a kinetic equivalent also occurs when the leaving group is good (pK(a) 相似文献   

Kinetics and mechanism of the pyridinolysis of aryl furan-2-carbodithioates in acetonitrile

Kinetic studies on the pyridinolysis of aryl furan-2-carbodithioates 1 are carried out at 60.0 degrees C in acetonitrile. The biphasic rate dependence on the pyridine basicity with a breakpoint at pK(a) degrees = 5.2 is interpreted to indicate a change of the rate-limiting step from breakdown (beta(X) = 0.7-0.8) to formation (beta(X) = 0.2) of the tetrahedral intermediate, T(+/-), at the breakpoint as the basicity of the pyridine nucleophile is increased. Observation of the breakpoint is possible with pyridines since the expulsion rate of the pyridine (k(-)(a)) from T(+/-) is sufficiently low, with the low k(-)(a)/k(b) ratio leading to a low breakpoint, pK(a) degrees. The clear-cut change in the cross-interaction constants, rho(XZ), from a positive (rho(XZ) = +0.86) to a small negative (rho(XZ) = -0.11) value at the breakpoint supports the mechanistic change proposed. The magnitudes of rho(Z) and activation parameters are also consistent with the proposed mechanism.     

Mechanistic study of protein phosphatase-1 (PP1), a catalytically promiscuous enzyme

The reaction catalyzed by the protein phosphatase-1 (PP1) has been examined by linear free energy relationships and kinetic isotope effects. With the substrate 4-nitrophenyl phosphate (4NPP), the reaction exhibits a bell-shaped pH-rate profile for kcat/KM indicative of catalysis by both acidic and basic residues, with kinetic pKa values of 6.0 and 7.2. The enzymatic hydrolysis of a series of aryl monoester substrates yields a Br?nsted beta(lg) of -0.32, considerably less negative than that of the uncatalyzed hydrolysis of monoester dianions (-1.23). Kinetic isotope effects in the leaving group with the substrate 4NPP are (18)(V/K) bridge = 1.0170 and (15)(V/K) = 1.0010, which, compared against other enzymatic KIEs with and without general acid catalysis, are consistent with a loose transition state with partial neutralization of the leaving group. PP1 also efficiently catalyzes the hydrolysis of 4-nitrophenyl methylphosphonate (4NPMP). The enzymatic hydrolysis of a series of aryl methylphosphonate substrates yields a Br?nsted beta(lg) of -0.30, smaller than the alkaline hydrolysis (-0.69) and similar to the beta(lg) measured for monoester substrates, indicative of similar transition states. The KIEs and the beta(lg) data point to a transition state for the alkaline hydrolysis of 4NPMP that is similar to that of diesters with the same leaving group. For the enzymatic reaction of 4NPMP, the KIEs are indicative of a transition state that is somewhat looser than the alkaline hydrolysis reaction and similar to the PP1-catalyzed monoester reaction. The data cumulatively point to enzymatic transition states for aryl phosphate monoester and aryl methylphosphonate hydrolysis reactions that are much more similar to one another than the nonenzymatic hydrolysis reactions of the two substrates.     

Different transition-state structures for the reactions of beta-lactams and analogous beta-sultams with serine beta-lactamases

Beta-sultams are the sulfonyl analogues of beta-lactams, and N-acyl beta-sultams are novel inactivators of the class C beta-lactamase of Enterobacter cloacae P99. They sulfonylate the active site serine residue to form a sulfonate ester which subsequently undergoes C-O bond fission and formation of a dehydroalanine residue by elimination of the sulfonate anion as shown by electrospray ionization mass spectroscopy. The analogous N-acyl beta-lactams are substrates for beta-lactamase and undergo enzyme-catalyzed hydrolysis presumably by the normal acylation-deacylation process. The rates of acylation of the enzyme by the beta-lactams, measured by the second-order rate constant for hydrolysis, kcat/K(m), and those of sulfonylation by the beta-sultams, measured by the second-order rate constant for inactivation, k(i), both show a similar pH dependence to that exhibited by the beta-lactamase-catalyzed hydrolysis of beta-lactam antibiotics. Electron-withdrawing groups in the aryl residue of the leaving group of N-aroyl beta-lactams increase the rate of alkaline hydrolysis and give a Bronsted beta(lg) of -0.55, indicative of a late transition state for rate-limiting formation of the tetrahedral intermediate. Interestingly, the corresponding Bronsted beta(lg) for the beta-lactamase-catalyzed hydrolysis of the same substrates is -0.06, indicative of an earlier transition state for the enzyme-catalyzed reaction. By contrast, although the Bronsted beta(lg) for the alkaline hydrolysis of N-aroyl beta-sultams is -0.73, similar to that for the beta-lactams, that for the sulfonylation of beta-lactamase by these compounds is -1.46, compatible with significant amide anion expulsion/S-N fission in the transition state. In this case, the enzyme reaction displays a later transition state compared with hydroxide-ion-catalyzed hydrolysis of the beta-sultam.     

Combined dual substituent constant and activation parameter analysis assigns a concerted mechanism to alkaline ethanolysis at phosphorus of Y-substituted phenyl diphenylphosphinates

Second-order rate constants have been measured for reactions of Y-substituted phenyl diphenylphosphinates (1a-h) with EtO(-)K(+) in anhydrous ethanol. A linear Br?nsted-type plot is obtained with beta(Lg) = -0.54, a typical beta(Lg) value for reactions which proceed through a concerted mechanism. The Hammett plots correlated with sigma(o) and sigma(-) constants are linear but exhibit many scattered points, while the corresponding Yukawa-Tsuno plot results in excellent linear correlation with r = 0.41. The r value of 0.41 indicates that the leaving group departs at the rate-determining step (RDS) whether the reactions proceed through either a concerted or a stepwise mechanism. However, a stepwise mechanism in which departure of the leaving group occurs at the RDS is excluded since the incoming EtO(-) ion is much more basic and a poorer leaving group than the leaving aryloxide. The DeltaH(++) values determined in the current reactions are strongly dependent on the nature of the substituent Y, while the DeltaS(double dagger) values remain constant on changing the substituent Y in the leaving group, i.e., from Y = H to Y = 4-NO(2) and Y = 3,4-(NO(2))(2). These DeltaH(++) and DeltaS(++) trends also support a concerted mechanism.     

Kinetics and mechanism of the pyridinolysis of S-2,4-dinitrophenyl 4-substituted thiobenzoates

[reaction: see text] The reactions of S-2,4-dinitrophenyl 4-methyl (1), S-2,4-dinitrophenyl 4-H (2), S-2,4-dinitrophenyl 4-chloro (3), and S-2,4-dinitrophenyl 4-nitro (4) thiobenzoates with a structurally homogeneous series of pyridines are subjected to a kinetic investigation in 44 wt % ethanol-water, at 25.0 degrees C and an ionic strength of 0.2 M (KCl). The reactions are studied spectrophotometrically (420 nm) by monitoring the appearance of 2,4-dinitrobenzenethiolate anion. Pseudo-first-order rate coefficients (k(obsd)) are obtained for all the reactions, employing excess of amine. The plots of k(obsd) vs [free pyridine] at constant pH are linear with the slopes (k(N)) independent of pH. The Br?nsted-type plots (log k(N) vs pK(a) of the conjugate acid of the pyridines) are curved for all the reactions. The Br?nsted curves are in accordance with stepwise mechanisms, through a zwitterionic tetrahedral intermediate (T(+/-)), and a change in the rate-limiting step. An equation based on this hypothesis accounts well for the experimental points. The Br?nsted lines were calculated with the following parameters: Reactions of thiolbenzoate 1: beta(1) 0.33 (slope at high pK(a)), beta(2) 0.95 (slope at low pK(a)), and pK(a)(0) = 8.5 (pK(a) at the curvature center); thiolbenzoate 2: beta(1) 0.30, beta(2) 0.88, and pK(a)(0) = 8.9; thiolbenzoate 3: beta(1) 0.33, beta(2) 0.89, and pK(a)(0) = 9.5; thiolbenzoate 4: beta(1) 0.21, beta(2) 0.97, and pK(a)(0) = 9.9. The increase of the pK(a)(0) value with the increase of the electron-withdrawing effect of the acyl substituent is explained by the argument that the rate of pyridine expulsion from T(+/-) (k(-)(1)) is favored over that of 2,4-dinitrobenzenethiolate leaving (k(2)), i.e., k(-)(1)/k(2) increases, as the acyl group becomes more electron withdrawing. The pK(a)(0) values for the title reactions are smaller than those for the reactions of the corresponding 4-nitrophenyl 4-substituted thiolbenzoates with the same pyridine series. This is explained by the larger k(2) value for 2,4-dinitrobenzenethiolate leaving from T(+/-) compared with 4-nitrobenzenethiolate, which results in lower k(-)(1)/k(2) ratios for the dinitro derivatives. The pK(a)(0) value obtained for the pyridinolysis of thiolbenzoate 2 (pK(a)(0) = 8.9) is smaller than that found for the same aminolysis of 2,4-dinitrophenyl benzoate (pK(a)(0) = 9.5). This is attributed to the greater nucleofugality from T(+/-) of 2,4-dinitrobenzenethiolate (pK(a) of conjugate acid 3.4) relative to 2,4-dinitrophenoxide (pK(a) of conjugate acid 4.1). The title reactions are also compared with the aminolysis of similar esters to assess the effect of the amine nature and leaving and acyl groups on the kinetics and mechanism.