Change In Transition-state Structure Research Articles

ChemInform Abstract: Synthesis of Aryl 3-O-β-Cellobiosyl-β-D-glucopyranosides for Reactivity Studies of 1,3-1,4-β-Glucanases.

Abstract A series of substituted aryl β -glycosides derived from 3- O - β -cellobiosyl- d -glucopyranose with different phenol-leaving group abilities as measured by the pK a of the free phenol group upon enzymatic hydrolysis has been synthesised. Aryl β -glycosides with a pK a of the free phenol leaving group>5 were prepared by phase-transfer glycosidation of the per- O -acetylated α -glycosyl bromide with the corresponding phenol, whereas the 2,4-dinitrophenyl β -glycoside was obtained by condensation of 1-fluoro-2,4-dinitrobenzene with the partially acetylated trisaccharide followed by acid de- O -acetylation. The aryl β -glycosides have been used for reactivity studies of the wild-type Bacillus licheniformis 1,3-1,4- β - d -glucan 4-glucanohydrolase. The Hammett plot log k cat versus pK a is biphasic with an upward curvature at low pK a values suggesting a change in transition-state structure depending on the aglycon.

Single-Molecule Force Spectroscopy Measurements of Bond Elongation during a Bimolecular Reaction

It is experimentally challenging to directly obtain structural information of the transition state (TS), the high-energy bottleneck en route from reactants to products, for solution-phase reactions. Here, we use single-molecule experiments as well as high-level quantum chemical calculations to probe the TS of disulfide bond reduction, a bimolecular nucleophilic substitution (S N2) reaction. We use an atomic force microscope in force-clamp mode to apply mechanical forces to a protein disulfide bond and obtain force-dependent rate constants of the disulfide bond reduction initiated by a variety of nucleophiles. We measure distances to the TS or bond elongation (Delta x), along a 1-D reaction coordinate imposed by mechanical force, of 0.31 +/- 0.05 and 0.44 +/- 0.03 A for thiol-initiated and phosphine-initiated disulfide bond reductions, respectively. These results are in agreement with quantum chemical calculations, which show that the disulfide bond at the TS is longer in phosphine-initiated reduction than in thiol-initiated reduction. We also investigate the effect of solvent environment on the TS geometry by incorporating glycerol into the aqueous solution. In this case, the Delta x value for the phosphine-initiated reduction is decreased to 0.28 +/- 0.04 A whereas it remains unchanged for thiol-initiated reduction, providing a direct test of theoretical calculations of the role of solvent molecules in the reduction TS of an S N2 reaction. These results demonstrate that single-molecule force spectroscopy represents a novel experimental tool to study mechanochemistry and directly probe the sub-ångström changes in TS structure of solution-phase reactions. Furthermore, this single-molecule method opens new doors to gain molecular level understanding of chemical reactivity when combined with quantum chemical calculations.

Altered Thermodynamics from Remote Mutations Altering Human toward Bovine Purine Nucleoside Phosphorylase

Human (HsPNP) and bovine (BtPNP) purine nucleoside phosphorylases are homotrimers with the catalytic sites located near the subunit-subunit interfaces. Despite the high amino acid sequence similarity (87% identical) and the fully conserved catalytic site contacts between BtPNP and HsPNP, crystal structures reveal that the subunits interact differently and isotope effect studies indicate distinct transition-state structures. The subunit interfaces and crystallographic packing properties of BtPNP differ from HsPNP. Hypothetically, mutating HsPNP toward BtPNP might alter the dynamic, catalytic and subunit packing properties of HsPNP to become more similar to BtPNP. Amino acids Lys22 and His104 in HsPNP were target candidates based on crystal packing contacts and were replaced with their BtPNP counterparts to give Lys22Glu:His104Arg (E:R-PNP). The kinetic properties (steady and pre-steady state), inhibition constants, and thermodynamic properties of E:R-PNP were compared to HsPNP and BtPNP. The E:R-PNP is similar to HsPNP in steady-state kinetic properties. However HsPNP and E:R-PNP show remarkable ratios for (Km guanosine)/(Ki* DADMe-ImmG) of 2.8 x 10(70 and 4.7 x 10(7) respectively, suggesting that DADMe-ImmG is an excellent mimic of the transition states for both HsPNP and E:R-PNP with a preference for E:R-PNP. Thermodynamic parameters obtained from the temperature dependence studies of the chemical step establish E:R-PNP to be catalytically more efficient than the parent enzyme and reveal differences in the entropic component of catalysis. The two companion manuscripts (Luo, M., Li, L. and Schramm, V. L. (2008) Biochemistry 47, 2565-2576; Li, L., Luo, M., Ghanem, M., Taylor, E. A., and Schramm, V. L. (2008) Biochemistry 47, 2577-2583) report changes in transition-state structure as a consequence of mutations remote from the catalytic sites of both HsPNP and BtPNP.

The Effect of Solvent on the Structure of the Transition State for the SN2 Reaction between Cyanide Ion and Ethyl Chloride in DMSO and THF Probed with Six Different Kinetic Isotope Effects

The secondary alpha- and beta-deuterium, the alpha-carbon, the nucleophile carbon, the nucleophile nitrogen, and the chlorine leaving group kinetic isotope effects for the S(N)2 reaction between cyanide ion and ethyl chloride were determined in the very slightly polar solvent THF at 30 degrees C. A comparison of these KIEs with those reported earlier for the same reaction in the polar solvent DMSO shows that the transition state in THF is only slightly tighter with very slightly shorter NC-C(alpha) and C(alpha)-Cl bonds. This minor change in transition state structure does not account for the different transition structures that were earlier suggested by interpreting the experimental KIEs and the gas-phase calculations, respectively. It therefore seems unlikely that the different transition states suggested by the two methods are due to the lack of appropriate solvent modeling in the theoretical calculations. Previously it was predicted that the transition state of S(N)2 reactions where the nucleophile and the leaving group have the same charge would be unaffected by a change in solvent. The experimental KIEs support this view.

The effect of inert salts on the structure of the transition state in the SN2 reaction between thiophenoxide ion and butyl chloride.

The effect of inert salts on the structure of the transition state has been determined by measuring the secondary alpha deuterium and the chlorine leaving group kinetic isotope effects for the S(N)2 reaction between n-butyl chloride and thiophenoxide ion in both methanol and DMSO. The smaller secondary alpha deuterium isotope effects and very slightly larger chlorine isotope effects found in both solvents when the inert salt is present suggests that the S(N)2 transition state is tighter and more product-like, with a shorter S-C(alpha) and very a slightly longer C(alpha)-Cl bond when the added salt is present. The salt effect on the reaction in methanol where the reacting nucleophile is the solvent-separated ion-pair complex is much greater than the salt effect on the reaction in DMSO where the reacting nucleophile is the free ion. This greater change in transition-state structure found when the inert salt is present in methanol is consistent with the solvation rule for S(N)2 reactions. The greater change in the S-C(alpha) bond is predicted by the bond strength hypothesis. A rationale for the changes found in transition-state structure when the inert salt is present is suggested for both the free-ion and the ion-pair reactions.

Mechanism of catalysis of the hydrolysis of a formamidinium compound

The hydrolysis of a fluoroformamidinium ion to give a urea is subject to general base catalysis, where the addition of water is catalyzed by carboxylate monoanions (pKa 2.22–5.52) with a Bronsted coefficient of β = 0.80 through a class n mechanism. The Bronsted coefficient and small solvent isotope effect of kH/kD = 1.2 ± 0.2 for catalysis by acetate anion are consistent with significant movement of a hydron towards the catalyst in a late asymmetric transition state. A concerted mechanism is proposed that is enforced by proton transfer within a hydrogen-bonded intermediate species, in which the difference in pKa between the catalyst and the intermediate is ∼16 units. Hydroxide and carbonate deviate below an extrapolation through a series of carboxylate anions, suggesting that over a wider range of pKa the Bronsted plot displays downward curvature, possibly due to a ‘Hammond effect’ on the proton transfer component of the reaction, that results in a change in transition-state structure with increasing pKa of the base catalyst. A 30-fold positive deviation of the uncatalyzed reaction from the limiting Bronsted line through the carboxylates suggests that the uncatalyzed reaction occurs via a different mechanism. The solvent isotope effect of kH/kD = 1.7 ± 0.1 and Bronsted type coefficients (for donating nitrogen substituents) of βdgArN = −0.3 and βdgRN = −0.4 for the uncatalyzed reaction are consistent with either a stepwise mechanism of addition and proton transfer, or a cyclic transition state containing two hydrogen bonded water molecules.

Using secondary alpha deuterium kinetic isotope effects to determine the stereochemistry of an E2 reaction; the stereochemistry of the E2 reaction of 1-chloro-2-phenylethane with potassium tert-butoxide in tert-butyl alcohol

Isotopic labelling studies have shown that the E2 reaction of 1-chloro-2-phenylethane with potassium tert-butoxide in tert-butyl alcohol occurs via an anti-periplanar stereochemistry. This demonstrates that the different secondary alpha deuterium kinetic isotope effects found for the high and low base concentrations and in the presence of 18-crown-6 ether are because of changes in transition state structure that occur when the form of the reacting base changes rather than to a change in the stereochemistry of the reaction.Key words: E2 reaction, stereochemistry, secondary alpha deuterium kinetic isotope effects, transition state.

Synthesis of aryl 3- O- β-cellobiosyl- β- d-glucopyranosides for reactivity studies of 1,3-1,4- β-glucanases

A series of substituted aryl β-glycosides derived from 3- O- β-cellobiosyl- d-glucopyranose with different phenol-leaving group abilities as measured by the pK a of the free phenol group upon enzymatic hydrolysis has been synthesised. Aryl β-glycosides with a pK a of the free phenol leaving group>5 were prepared by phase-transfer glycosidation of the per- O-acetylated α-glycosyl bromide with the corresponding phenol, whereas the 2,4-dinitrophenyl β-glycoside was obtained by condensation of 1-fluoro-2,4-dinitrobenzene with the partially acetylated trisaccharide followed by acid de- O-acetylation. The aryl β-glycosides have been used for reactivity studies of the wild-type Bacillus licheniformis 1,3-1,4- β- d-glucan 4-glucanohydrolase. The Hammett plot log k cat versus pK a is biphasic with an upward curvature at low pK a values suggesting a change in transition-state structure depending on the aglycon.

Using 11C/14C Incoming Group and Secondary α-Deuterium KIEs To Determine How a Change in Leaving Group Alters the Structure of the Transition State of the SN2 Reactions between m-Chlorobenzyl para-Substituted Benzenesulfonates and Cyanide Ion

The 11C/14C incoming group and secondary α-deuterium KIEs and Hammett ρ value found by changing the substituent in the leaving group of the SN2 reactions between meta-chlorobenzyl para-substituted benzenesulfonates and cyanide ion in 0.5% aqueous acetonitrile at 0 °C suggest that these reactions occur via an unsymmetrical, product-like transition state. Changing to a better leaving group leads to a transition state with a slightly shorter nucleophile−α-carbon bond and a longer α-carbon−leaving group bond. The changes in transition state structure are consistent with the Bond Strength Hypothesis.

Transition-state structural variation and mechanistic change

An important link between theoretical and experimental views of organic reactivity is provided by More O'Ferrall-Jencks diagrams, which are commonly used in empirical discussions of reaction mechanisms and of changes in transition-state structure. We have performed semiempirical AM1 molecular-orbital calculations for SN2 displacements on α-substituted alkyl substrates and for general acid-catalysed hydride reduction of a carbonyl group which demonstrate transition-state structural variations in accord with the predictions of these diagrams. We provide an example of a possible danger associated with the use of these diagrams in considerations of mechanistic change. We have examined the changeover in mechanism from SN2 to SN1 occuring in the degenerate reaction H2O + CHR′R″OH+2→+H2OCHR′R″+ OH2 as the α-substituents R′ and R″ are altered. The methyl (R′= R″= H) and ethyl (R′= H, R″= Me) substrates react by the SN2 mechanism, whereas the isopropyl (R′= R″= Me), methoxymethyl (R′= H, R″= OMe) and methoxyethyl (R′= Me, R″= OMe) substrates follow the SN1 mechanism. The mechanisms merge according to the classical model of Doering and Zeiss, with the SN1 intermediate appearing with essentially the same structure and energy as the disappearing SN2 transition state.

Retrograde aldol-type reactions involving thiamin in aqueous solution: Evidence for changes in transition-state structure

Cleavage of racemic 2-(1-hydroxyethyl)- and 2-(1-hydroxyaryl)-3-R-4-methylthiazolium ions to the corresponding aldehyde and thiazolium ion in aqueous solution is catalyzed by oxygen-containing and amine buffer bases at 40°C and ionic strength 1.0 m (KCl). The buffer base-catalyzed reactions are formulated as general acid catalysis of the departure of thiazolium ion from the alcoholate anion of the substrate (general base catalysis of thiazolium ion attack on the aldehyde in the reverse direction). Brønsted α values decrease from 0.38 to 0.21 for general acid catalysis of the cleavage of (2-1-hydroxyethyl)-R-4-methylthiazolium ions (R = C 6F 5CH 2, 4-aminopyrimidinyl, Bzl). The decrease in α with decreasing p K a of C(2)-H in the leaving thiazolium ion is described by a positive interaction coefficient p xy′ = ∂α ∂ pK lg = 0.3 ± 0.1 . Brønsted α values increase from 0.39 (R′ = Ph) to 0.48 (R′ = 4-CF 3-Ph) for the corresponding reactions with 2-(HOCH(R′))thiamin. The increase in α as the carbon electrophile becomes less stable is described by a positive interaction coefficient p xy = sol∂α ∂σ para = 0.2 ± 0.1 . These positive interaction coefficients support a nonenforced concerted reaction mechanism with an important component of proton transfer in the transition state. Mechanistic implications for thiamin diphosphate-dependent enzymes are discussed.

Kinetics of deprotonation of triphenyl(2‐substituted‐9‐fluorenyl)phosphonium ions in 50% dimethyl sulfoxide–50% water. Intrinsic rate constants, imbalances and evidence for changes in transition state structure

AbstractRate constants (kB1 and kBH−1) for the reversible deprotonation of triphenyl(2‐Z‐9‐fluorenyl)phosphonium ions (Z = H, Br, NO2) by piperidine, morpholine, n‐butylamine, 2‐methoxyethylamine, glycine ethyl ester, cyanomethylamine, OH− and water were determined in 50% Me2SO–50% (v/v) water at 20°C. Brønsted αCH (variation of carbon acid) and β values (variation of amine), and intrinsic rate constants [log k0 = log kB1/q when pKBHa ‐ pKCHa + log(p/q) = 0] were obtained. αCH decreases with increasing basicity of the amine whereas βB decreases with increasing acidity of the carbon acid. These trends, which imply changes in the transition‐state structure with reactivity, can be described by the interaction coefficient pxy = ∂βB/∂pKCHa = ∂αCH/ ‐ ∂pKBHa = 0.03 (primary amines) and 0.01 (piperidine/morpholine). αCH is smaller than βB, indicating an imbalance due to a lag in the delocalization of the negative charge into the fluorenyl moiety at the transition state. The influence of the Ph3P+ group on the intrinsic rate constant is analyzed in terms of possible contributions by inductive/field (I), resonance (R), polarizability (P) and steric (S) effects. Using 9‐carbomethoxyfluorene as a reference, it is shown that the stronger electron‐withdrawing I effect of the Ph3P+ group relative to the COOMe group enhances log k0 substantially; the fact that the R effect of Ph3P+ is weaker than that of COOMe also contributes to an increase in k0, and so does the P effect of the phosphorus. All these increases are virtually completely offset by the rate‐retarding S effect of the bulky Ph3P+ group. A similar analysis for the Me2S+ derivative studied by Murray and Jencks [J. Am. Chem. Soc. 112, 1880 (1990)] leads to similar conclusions except that the still smaller R effect is probably one of the main reasons why k0 for the Me2S+ derivative is more than ten times higher than for the Ph3P+ derivative; another potential reason is a difference in the steric effect.

Proton abstraction from dimethyl(2-substituted 9-fluorenyl)sulfonium ions. Evidence for changes in transition-state structure

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTProton abstraction from dimethyl(2-substituted 9-fluorenyl)sulfonium ions. Evidence for changes in transition-state structureChristopher J. Murray and William P. JencksCite this: J. Am. Chem. Soc. 1990, 112, 5, 1880–1889Publication Date (Print):February 1, 1990Publication History Published online1 May 2002Published inissue 1 February 1990https://doi.org/10.1021/ja00161a036RIGHTS & PERMISSIONSArticle Views143Altmetric-Citations20LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (1 MB) Get e-AlertsSupporting Info (1)»Supporting Information Supporting Information Get e-Alerts

Nucleophiles of high reactivity in phosphoryl transfer reactions: .alpha.-effect compounds and fluoride ion

The second-order rate constants for reactions of hydrogen peroxide, acetohydroxamate, and fluoride anions with phosphorylated pyridine monoanions (H20, 25 OC, ionic strength 1.5) are larger than those of oxygen nucleophiles of the same pK, by factors of 600-, 160-, and 30-fold, respectively. The values of {-&} = 0.70 and 0.86 for reactions of phosphorylated pyridines with hydrogen peroxide and fluoride anions are smaller than predicted by a plot of {-&} against the pK, of normal oxygen nucleophiles; however, they fit a plot of (-g Le., the rate enhancements for these nucleophiles may reflect an enhanced thermodynamic affinity for the phosphoryl group that influences the stability and structure of the transition state. The observed changes in transition-state structure are not predicted for rate enhancements from hydrogen bonding in the transition state or from weak solvation of the a-effect nucleophile.

On the magnitude of primary isotope effects for proton abstraction from carbon

Primary deuterium isotope effects have been measured for the loss of an ..cap alpha.. proton from 4-(4-nitrophenoxy)-2-butanone. The isotope effect data showed that no significant change in transition-state structure occurred in the same region of oxyanion catalyst pK/sub a/ range that does exhibit a large change in ..beta.. value. This conclusion confirms the previous assertion that the dramatic curvature in the Broensted plot for proton abstraction by oxyanions from carbon is due to solvation. The effect upon k/sub H/ / k/sub D/ of varying the identity of the atom acting as the proton acceptor was examined. Catalysts having oxygen, nitrogen, carbon, and sulfur as the acceptor atom were included. An inverse correlation was found between the magnitude of the isotope effect for proton abstraction by X/sup -/ and the energy change upon conversion of HX to DX. With use of the Marcus equation as a basis, an equation was derived for predicting values of k/sub H/ / k/sub D/ which not only relies on the ..delta..pK/sub a/ value but also incorporates the zero-point energy difference of both the reactants and the products as measured by infrared stretching frequency shifts upon deuteration. This equation demonstrates improved correlation between calculated and experimentalmore » values of k/sub H/ / k/sub D/ taken from the literature. 48 references.« less

.alpha.-Deuterium isotope effects in benzyl halides. 2. Reaction of nucleophiles with substituted benzyl bromides. Evidence for a change in transition-state structure with electron-donating substituents

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXT.alpha.-Deuterium isotope effects in benzyl halides. 2. Reaction of nucleophiles with substituted benzyl bromides. Evidence for a change in transition-state structure with electron-donating substituentsV. P. Vitullo, J. Grabowski, and S. SridharanCite this: J. Am. Chem. Soc. 1980, 102, 21, 6463–6465Publication Date (Print):October 8, 1980Publication History Published online1 May 2002Published inissue 8 October 1980https://doi.org/10.1021/ja00541a014RIGHTS & PERMISSIONSArticle Views362Altmetric-Citations23LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (375 KB) Get e-Alerts Get e-Alerts

Kinetics and mechanism of electrophilic bromination of acetylenes

The rates of addition of molecular bromine in acetic acid to a number of acetylenes have been found to follow the general equation[Formula: see text]In the absence of bromide ion and at low bromine concentrations (< 2 × 10−4 M), only the k2 process is observable. These k2 values for a series of ring-substituted phenylacetylenes are correlated well with σ+ values and give a ρ value of −5.17 which is interpreted in terms of a transition state leading to a vinyl cation intermediate. As expected from this intermediate, both cis and trans dibromide products are formed and the bromoacetates are only of the Markownikoff type (1-acetoxy-1-phenylethylene derivatives). An ion pair scheme has been presented to account for the variation in product composition with substrate structure.In contrast to these results for phenylacetylenes, a cyclic bromonium ion intermediate is postulated for alkyl acetylenes on the basis of only trans dibromide formation for 3-hexyne and 1-hexyne.The kBr− values have also been obtained for the ring-substituted phenylacetylenes as well as 3-hexyne. For all the substrates studied, this kBr− process represents a bromide ion catalyzed attack of molecular bromine in an AdE3 mechanism. Thus only trans dibromide products are formed from this rate process. The non-linear σ+ plot for these values has been interpreted in terms of change in transition state structure with substituent.