Α-deuterium Kinetic Isotope Effects Research Articles

α-Deuterium kinetic isotope effects in reactions of methyllithium: is better aggregation the cause of lower reactivity?

The values k H/ k D for α-deuterium kinetic isotope effects for the reaction of methyllithium and methylmagnesium iodide with a series of substrates are consistently ca. 10–15% higher for the lithium reagent than for the Grignard reagent. This may indicate a pre-equilibrium between an aggregate and a reactive monomer, with a better fit of the trideuterio monomer in the aggregate. An attempt has been made to compare the equilibrium constants for the aggregation of deuterio and protio methyllithium by studying the metal-halogen equilibrium between methyllithium and methyl iodide.

Theoretical investigation of the origin of secondary α-deuterium kinetic isotope effects

Although the secondary α-deuterium kinetic isotope effect upon the degenerate SN2 reaction of chloromethane with chloride anion arises from changes in α-CH stretching force constants, α-substitution by methyl and/or methoxy groups shows this inverse inductive contribution to be approximately constant and reveals that the trend in the isotope effect (calculated by semiempirical molecular orbital theory) is determined by changes in bending force constants, in accord with the conventional view.

High secondary α-deuterium kinetic isotope effect in the acetolysis and formolysis of dideuterioferrocenylmethyl benzoate

Acetolysis and formolysis of dideuterioferrocenylmethyl benzoate exhibit large secondary α-deuterium kinetic isotope effects and an abnormal temperature dependence. In the presence of LiClO4(ca. 0.1 mol dm–3), which prevents the reversion from solvent-separated to contact ion-pairs, kH/kD at 25 °C amount to 1.53 ± 0.02 (acetolysis) and 1.48 ± 0.03 (formolysis). In the presence of LiClO4 the ratios of Arrhenius pre-exponential factors, AH/AD, are significantly less than unity and amount to 0.49 ± 0.01 (acetolysis) and 0.38 ± 0.04 (formolysis). In the absence of LiClO4 the AH/AD ratios are much smaller (0.02 both in acetolysis and formolysis). We suggest that these surprisingly low values result from a change in rate-determining step over the temperature range, from formation of the solvent-separated ion-pair at low temperatures to reaction of the dissociated carbocation with solvent at the highest temperatures. Whether tunnelling plays any role in these solvolyses is discussed.

Silicon Effects. II. Structure and Stability of 1-Phenyl-2-(trimethylsilyl)ethyl Cation in Solution

Abstract Solvolysis rates have been measured in various solvents at 25°C for 1-(substituted phenyl)-2-(trimethyl-silyl)ethyl trifluoroacetates (1a–1g; R=H, 4-Me, 4-Cl, 4-Br, 3-Cl, 3,4-Cl2, and 3,5-Cl2, respectively) and structurally related compounds, 1-phenylethyl-, 3,3-dimethyl-1-phenylbutyl-, and 1-(4-methylphenyl)ethyl trifluoroacetates (3a, 4, and 5). In dioxane/water mixtures 1g solvolyzes with the same sensitivity to the change in solvent ionizing power as that for a kc substrate 5. The solvolyses of 1e and 5 exhibit almost identical α-deuterium kinetic isotope effects (kH⁄kD) of 1.18–1.19 in aq dioxane. Substituent effect on the solvolysis of 1 in 90% aq dioxane is expressed by an LArSR equation: logkX⁄kH=−3.05 (σ°+1.05Δ\barσR+) (R=0.9997). These findings are consistent with kc mechanism for the solvolysis of 1. Relative rates for the solvolysis of 1a, 3a, and 4 in 30% aq dioxane are 2.99×105 : 2.84 : 1.0 indicating solvolytic generation of α-(trimethylsilylmethyl)benzyl cation to be about 7 kcal mol−1 energetically more favorable than that of the corresponding α-alkylbenzyl cations.

Isotope effects in nucleophilic substitution reactions. VIII. The effect of the form of the reacting nucleophile on the transition state structure of an SN2 reaction

A spectroscopic investigation indicated that lithium thiophenoxide exists as a contact ion pair complex in dry diglyme whereas the other alkali metal thiophenoxides exist as a solvent-separated ion pair complex in diglyme. The addition of small amounts of water converts the lithium thiophenoxide contact ion pair complex into a solvent-separated ion pair complex. A smaller secondary α-deuterium kinetic isotope effect and a larger Hammett p value are observed when the nucleophile is the contact ion pair complex in the SN2 reaction between n-butyl chloride and thiophenoxide ion in diglyme. This indicates that the transition state for the contact ion pair complex reaction is tighter with a shorter nucleophile–α-carbon bond than the transition state for the solvent-separated ion pair complex reaction. The secondary α-deuterium kinetic isotope effects for the free ion and the solvent-separated ion pair complex reactions between sodium thiophenoxide and n-butyl chloride in DMF suggest that the loosest transition state is found when the nucleophile is the free ion. Key words: transition state, SN2, isotope, deuterium, Hammett ρ.

Acetolysis of ferrocenylmethyl benzoate. High secondary α-deuterium kinetic isotope effect for primary carbon-oxygen cleavage

Secondary α-deuterium kinetic isotope effect ( KIE) in acetolysis of ferrocenyl-1,1-dideuteriomethyl benzoate was determined at 298 K as kH/ kD = 1.50 (22.5% per D). This appears to be one of the largest KIE observed for carbon-oxygen cleavage. The solvolysis exhibits a ‘special salt effect’, and a common ion rate depression effect, indicating the presence of solvent-separated ion pairs and the return to tight pairs. The high value of KIE in acetolysis strongly suggests that the acetolysis is a limiting dissociative process with the carbonium ion transition state, stabilized mainly by conjugation with the π-system. The entropy of activation (−30 J K −1 mol −1) is very similar to those values we previously determined in ethanolyses of ferrocenylmethyl acetate and benzoate (−22 and −25 J K −1 mol −1), where the KIE was only 11.4% per D. In the latter reactions the stabilization of the transition state probably involves some Fe-C exo bond formation. It appears that the mode of stabilization of the ferrocenylmethyl cation depends on the type of solvolysis and on the nature of the media: high KIE is observed in solvents of high ionizing power. Entropies of activation cannot help in distinguishing between the two possible modes of stabilization.

Secondary α-deuterium kinetic isotope effects for addition of phenyl radical to benzyl isocyanides: An evidence of concerted mechanism.

Addition of phenyl radical to benzyl isocyanides gives benzonitrile and benzyl radicals, exhibiting positive Hammett γ = 0.26 and notable secondary α-deuterium kinetic isotope effects. These can be rationalized by concerted bond formation/cleavage occurring with polar transition states(TS).

Kinetic isotope effects involving deuteriated aniline nucleophiles

Primary and secondary α-deuterium kinetic isotope effects are observed with deuteriated aniline nucleophiles in the SN2 reactions of 1-phenylethyl and benzyl benzenesulphonates, providing evidence in support of the four centre transition state mechanism for the former reaction.

Solvent effects on SN2 transition state structure. II: The effect of ion pairing on the solvent effect on transition state structure

Identical secondary α-deuterium kinetic isotope effects (transition state structures) in the SN2 reaction between n-butyl chloride and a free thiophenoxide ion in aprotic and protic solvents confirm the validity of the Solvation Rule for SN2 Reactions. These isotope effects also suggest that hydrogen bonding from the solvent to the developing chloride ion in the SN2 transition state does not have a marked effect on the magnitude of the chlorine (leaving group) kinetic isotope effects. Unlike the free ion reactions, the secondary α-deuterium kinetic isotope effect (transition state structure) for the SN2 reaction between n-butyl chloride and the solvent-separated sodium thiophenoxide ion pair complex is strongly solvent dependent. These completely different responses to a change in solvent are rationalized by an extension to the Solvation Rule for SN2 Reactions. Finally, the loosest transition state in the reactions with the solvent-separated ion pair complex is found in the solvent with the smallest dielectric constant. Keywords: ion pairs, transition state, solvent effects, nucleophilic substitution, isotope effects.

Isotope effects in nucleophilic substitution reactions. VII. The effect of ion pairing on the substituent effects on SN2 transition state structure

The secondary α-deuterium kinetic isotope effects and substituent effect found in the SN2 reactions between a series of para-substituted sodium thiophenoxides and benzyldimethylphenylammonium ion are significantly larger when the reacting nucleophile is a free ion than when it is a solvent-separated ion pair complex. Tighter transition states are found when a poorer nucleophile is used in both the free ion and ion pair reactions. Also, the transition states for all but one substituent are tighter for the reactions with the solvent-separated ion pair complex than with the free ion. Hammett ρ values found by changing the substituent on the nucleophile do not appear to be useful for determining the length of the sulphur–α-carbon bond in the ion pair and free ion transition states. Keywords: Isotope effects, ion pairing, nucleophilic substitution, SN2 reactions, transition states.

Isotope effects in nucleophilic substitution reactions. VI. The effect of ion pairing on the transition state structure of SN2 reactions

Spectroscopic and conductivity studies of sodium thiophenoxide solutions in four different solvents and the secondary α-deuterium kinetic isotope effects found in the presence of 15-crown-5 ether demonstrate that the secondary α-deuterium kinetic isotope effect and transition state structure for the SN2 reaction between sodium thiophenoxide and n-butyl chloride are significantly different, depending on whether the ionic reactant is a solvent-separated ion-pair complex or a free ion. In all three solvents in which the form of the ionic reactant changes, a smaller isotope effect and tighter transition state are found for the reaction with the ion-pair complex.

Secondary α hydrogen–deuterium kinetic isotope effects in the syn-elimination reaction of 2-phenylethyldimethylamine oxide

The secondary α-deuterium kinetic isotope effect has been measured for the thermal reaction of 2-phenylethyldimethylamine oxide in 90 mol% DMSO–H2O at 60.0 °C. A large secondary α-deuterium isotope effect of 1.158 per α-D was found, which indicates significant [Formula: see text] bond rupture and very little double bond formation at the transition state for this concerted syn-elimination process. The observed large normal value for (kH/kD)α is discussed in terms of the use of secondary α-D isotope effects for the determination of stereochemistry for a concerted elimination process. Various isotope effects found for the syn elimination of the above amine oxide and those for the anti elimination of 2-arylethyltrimethylammonium salts with ethoxide are considered with respect to the relative transition state structures for syn- and anti-elimination reactions.

Secondary α-deuterium kinetic isotope effects for the E2 reaction of the 2-phenylethyl halides with tert-butoxide ion in tert-butyl alcohol

Secondary α-deuterium kinetic isotope effects have been determined for the elimination reactions of 2-phenylethyl halides with tert-butoxide in tert-butyl alcohol at 40 °C in the presence and absence of the crown ether 18C6. The second-order rate constant k2 and the normal (kH/kD)α effect remained constant when the tert-butoxide concentration was varied for reaction of the iodo and bromo compounds. However, both the magnitude of k2 and the secondary α-deuterium isotope effect were significantly dependent on [t-BuO−] when chlorine and fluorine are the leaving groups. It is noteworthy that (kH/kD)α is inverse for the reaction of both the chloro and fluoro compounds at "low" base concentrations and normal at "high" base concentrations. These results are discussed in terms of both syn- and anti-elimination pathways promoted by various associated and dissociated base species. It is suggested that the (kH/kD)α effect may be useful as a criterion for determining the stereochemistry of E2 elimination reactions.

Isotope effects in nucleophilic substitution reactions. IV. The effect of changing a substituent at the α carbon on the structure of SN2 transition states

Kinetic studies, secondary α-deuterium kinetic isotope effects, primary chlorine kinetic isotope effects (1), Hammett ρ values determined by changing the substituent in the nucleophile, and activation parameters have been used to determine the detailed (relative) structures of the transition states for the SN2 reactions between para-substituted benzyl chlorides and thiophenoxide ion. A rationale for the U-shaped Hammett ρ plots observed when para-substituted benzyl compounds react with negatively charged nucleophiles is also presented.

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.

Secondary deuterium kinetic isotope effects in the solvolysis of 4-t-butylcyclohexyl and bicyclo[3.2.1]octan-3-yl toluene-p-sulphonates. New results using 50% aqueous ethanol, acetic acid, and 97% aqueous hexafluoropropan-2-ol

Secondary α-deuterium kinetic isotope effects for the solvolysis of cis- and trans-4-t-butylcyclohexyl toluene-p-sulphonates in 50% aqueous ethanol (1.200 ∓ 0.007 and 1.16 ∓ 0.01 respectively, 44.8°), acetic acid (1.172 ∓ 0.004 and 1.13 ∓ 0.01 respectively, 79.6°), and 97% aqueous hexafluoropropan-2-ol (1.232 ∓ 0.013, 40.0° and 1.175 ∓ 0.010, 56.2°, respectively) and for the solvolysis of endo- and exo-bicyclo[3.2.1]octan-3-yl toluene-p-sulphonates in 97% aqueous hexafluoropropan-2-ol (1.246 ∓ 0.009 and 1.234 ∓ 0.004 respectively, 25.2°) have been measured. Mechanisms for these reactions which involve ion-pair intermediates are proposed. Even in 97% aqueous hexafluropropan-2-ol, intimate ion-pairs from trans-4-t-butylcyclohexyl toluene-p-sulphonate undergo further reaction more rapidly than internal return. The other three compounds investigated in this highly ionizing solvent of low nucleophilicity are believed to react, as anticipated, through reversibly formed intimate ion-pairs.

Isotope effects in nucleophilic substitution reactions. III. The effect of changing the leaving group on transition state structure in SN2 reactions

The nucleophilic substitution reactions of a series of 4-substituted phenylbenzyldimethyl-ammonium ions with thiophenoxide ions at 0 °C in N,N-dimethylformamide have been used to demonstrate how a change in the leaving group alters the structure of the SN2 transition state. Heavy atom (nitrogen) kinetic isotope effects, secondary α-deuterium kinetic isotope effects and Hammett ρ values provide qualitative descriptions of both the nucleophile–α-carbon and α-carbon–leaving group bonds in the transition states of these reactions. The results indicate that changing to a better leaving group causes the bond between the α-carbon and the nucleophile to be much more fully formed while the bond to the leaving group is essentially unchanged. The results are discussed in the light of current theories of substituent effects on SN2 reactions and a possible explanation for the surprising results (i) that the greatest effect is in the bond more remote from the point of structural change and (ii) that more nucleophilic assistance is required to displace a better leaving group is given.

Isotope effects in nucleophilic substitution reactions. II. Secondary α-deuterium kinetic isotope effects: a criterion of mechanism?

A very large secondary α-deuterium kinetic isotope effect of 1.179 ± 0.007 (1.086 ± 0.003 per α-deuterium) has been observed for the SN2 reaction of thiophenoxide ion with benzyldimethylphenylammonium ion in DMF at 0°C. This large isotope effect which is far outside the range reported for SN2 reactions, is attributed to the fact that the extraordinarily large steric crowding around the Cα—H bonds in the substrate is reduced in the SN2 transition state. The structure of the transition state is shown to be consistent with this hypothesis.

Participation of the ferrocenyl group in the solvolysis of ferrocenylmethyltrimethylammonium ion[1

The α-deuterium kinetic isotope effect in the solvolysis of ferrocenyl-1,1-dideuteriomethyltrimethylammonium iodide in aqueous solution has been measured. The isotope effect, k H / k D , is 1.06 ± 0.04 at 80°C (about 3% per deuterium atom). This effect is only a small fraction of the limiting α-deuterium isotope effect for a nitrogen leaving group, which is estimated to be about 20% per deuterium atom at 80°C. The small isotope effect supports the transition state model involving participation of the electrons localized on the iron atom. The activation parameters for the solvolysis reaction in the temperature range 70–90°C are: ΔH ≠ = 132.6 ± 3.8 kJ mol −1 and ΔS ≠ = 54.0 ± 20.1 JK −1 mol −1.

Solvolysis of endo- and exo-bicyclo[3.2.1]octan-3-yl toluene-p-sulphonates. Part 2. Rates and deuterium kinetic isotope effects

Rates and secondary deuterium kinetic isotope effects for the solvolysis of endo-and exo-bicyclo[3.2.1]octan-3-yl toluene-p-sulphonates [(4a and c) and (5a and c)] have been measured. Rate constants, rate ratios, and apparent m values, when compared with results for model compounds, suggest that the solvolyses of (4a) and (5a) are close to the limiting (SN1) extreme in all solvents. The α-deuterium kinetic isotope effects are high (ca. 1.19—1.20 at 25 °C) for (5c) in formic and acetic acids, aqueous 50, 80, and 98% ethanol, and aqueous 97% 2,2,2-trifluoroethanol, and for (4c) in all these solvents except aqueous 98% ethanol (1.141 at 60.4 °C). The β-2H4 kinetic isotope effects are also high for both (4a) and (5a). The results are interpreted in terms of a principal mechanism involving rate-determining formation of intimate ion-pair intermediates. For the solvolysis of (4a) in aqueous 98% ethanol some direct SN2 reaction of solvent with covalent tosylate is also invoked. Mechanisms of solvolysis generally are discussed including the roles of intimate and solvent-separated ion-pairs, and solvent-induced SN2.