Secondary Α-deuterium Isotope Effects Research Articles

The nature of the transition state in diarylmethyl cation – nucleophile combination reactions as probed by secondary α-deuterium isotope effects

Transition-state structures for the carbocation–nucleophile combination reactions of (4-substituted-4'- methoxydiphenyl)methyl cations with water, chloride, and bromide ions in acetonitrile–water mixtures have been investigated by measuring the secondary α-deuterium kinetic and equilibrium isotope effects. Rate constants in the combination direction were measured with laser flash photolysis. Equilibrium constants were measured for the water reaction by a comparison method in moderately concentrated sulfuric acid solutions, for the bromide reaction via the observation of reversible combination, and for the chloride reaction from the ratio of the combination rate constant and the rate constant for the ionization of the diarylmethyl chloride product. The fraction of bond making in the transition state has been calculated as the ratio log (kinetic isotope effect):log (equilibrium isotope effect). For the water reaction, there is 50–65% bond making in the transition state; this is also true for cations that are many orders of magnitude less reactive. The same conclusions, 50–65% bond formation in the transition state independent of reactivity, have previously been made in correlations of log kw vs. log KR. Thus, two quite different measures of transition structure provide the same result. The kH:kD values for the halide combinations in 100% acetonitrile are within experimental error of unity. This is consistent with suggestions that these reactions are occurring with diffusional encounter as the rate-limiting step. Addition of water has a dramatic retarding effect on the halide reactions, with rate constants decreasing steadily with increased water content. Small inverse kinetic isotope effects are observed (in 20% acetonitrile:80% water) indicating that carbon—halogen bond formation is rate-limiting. Comparison of the kinetic and equilibrium isotope effects shows ~25 and ~40% bond formation in the transition states for the reactions with bromide and chloride, respectively.Key words: carbocation, isotope effect, transition state, halide.

The nature of the transition state in diarylmethyl cation – nucleophile combination reactions as probed by secondary α-deuterium isotope effects

The nature of the transition state in diarylmethyl cation – nucleophile combination reactions as probed by secondary α-deuterium isotope effects

An unusually large secondary α-deuterium kinetic isotope effect in hydride ion SN2 reactions

Theoretical calculations at the HF/6-31+G* level suggest the secondary α-deuterium kinetic isotope effects for hydride ion SN2 reactions are much larger than expected for the structure of the transition state. The secondary α-deuterium kinetic isotope effects for the SN2 reactions between sodium borohydride (hydride ion) and para-methyl- and para-chlorobenzyl chlorides are much larger than expected as the theoretical calculations suggest. It appears the secondary α-deuterium isotope effects are larger than expected for the structure of the SN2 transition state because the hydride ion is too small to affect the Cα—H(D) out-of-plane bending vibrations in the transition state.Key words: secondary α-deuterium kinetic isotope effects, SN2, nucleophilic substitution, transition state, substituent effects.

The secondary α-deuterium isotope effect at the site of the enzyme-catalyzed cis-trans isomerization of maleylacetone. Mechanistic implications

An equal mixture of monodeuterated isotopomers of maleylacetone, viz., 4-hydroxy-6-oxo-2,4-heptadienoic-2-d1 acid (1) and 4-hydroxy-6-oxo-2,4-heptadienoic-3-d1 acid (2) was synthesized and subjected to catalyzed cis-trans isomerization by the maleylacetoacetate cis-trans isomerase-glutathione system. These studies were designed to probe the detailed mechanism of enzyme-catalyzed cis-trans isomerization about the C-2—C-3 bond of the substrate. In the competitive reaction, 2 accumulates with respect to 1 at high extent of reaction. 1H NMR analysis indicates that 1 reacts 15% faster than 2 in line with a nucleophilic addition mechanism at C-2 rather than a conjugate addition mechanism at C-2 and C-3, to convert the C-2—C-3 double bond to a single bond to allow facile internal rotation.Key words: enzyme-catalyzed cis-trans isomerization, secondary α-deuterium isotope effect, maleylacetoacetate cis-trans isomerase, cis-trans isomerization mechanism.

The secondary α-deuterium isotope effect at the site of the enzyme-catalyzed <i>cis</i>-<i>trans</i> isomerization of maleylacetone. Mechanistic implications

An equal mixture of monodeuterated isotopomers of maleylacetone, viz., 4-hydroxy-6-oxo-2,4-heptadienoic-2-d1 acid (1) and 4-hydroxy-6-oxo-2,4-heptadienoic-3-d1 acid (2) was synthesized and subjected to catalyzed cis-trans isomerization by the maleylacetoacetate cis-trans isomerase-glutathione system. These studies were designed to probe the detailed mechanism of enzyme-catalyzed cis-trans isomerization about the C-2—C-3 bond of the substrate. In the competitive reaction, 2 accumulates with respect to 1 at high extent of reaction. 1H NMR analysis indicates that 1 reacts 15% faster than 2 in line with a nucleophilic addition mechanism at C-2 rather than a conjugate addition mechanism at C-2 and C-3, to convert the C-2—C-3 double bond to a single bond to allow facile internal rotation.Key words: enzyme-catalyzed cis-trans isomerization, secondary α-deuterium isotope effect, maleylacetoacetate cis-trans isomerase, cis-trans isomerization mechanism.

Solvolysis of 3-alkenyl-2-cyclohexenyl estrs

In an attempt to study possible π -participation in allyl derivatives, 3-alkenyl-5,5-dimethyl-2-cyclohexenyl p-nitrobenzoates 4 and 2-alkenyl-3-methyl-2-cyclohexenyl p-nitrobenzoates 5 were solvolyzed in 97 wt % trifluoroethanol and 80 vol % ethanol. Water soluble 1-methyl-3-(3-alkenyl-5,5-dimethyl-2-cyclohexenyl) pyridinium iodides 6 were solvolyzed in water and in aqueous solvents, as well as under micellar conditions. All esters show in each of the solvents normal values of secondary α-deuterium isotope effects ( k H k D = 1.17–1.23). Also in comparison to saturated analogues the investigated esters show a lower solvolytic reactivity. On the basis of these results it was concluded that the solvolysis proceeds via a stepwise mechanism involving a resonance-stabilized cyclohexenyl cation as the reaction intermediate.

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.

Solvolysis of 2-(ω-alkoxyalkyl)-3-methyl-2-cyclohexenyl p-nitrobenzoates : Search for neighboring oxygen participation

The degree of alkoxy group participation in the solvolysis of allylic p-nitrobenzoates with an ω-alkoxyalkyl side-chain at C-2 center was studied. In 80% EtOH the solvolysis rates, secondary α-deuterium isotope effects, and the product composition show that, contrary to π-participation, neighboring oxygen interacts to a certain degree in the ratedetermining step of solvolysis when a six-membered oxygen-containing ring can be formed. In all other cases, and also when 97% CF 3CH 2OH was used as a solvent, no oxygen participation could be detected.

Solvolysis of 2-(2-methoxyethyl)-3-methyl-2-cyclohexenyl p-nitrobenzoate : A case of non-participation of methoxy group

In an attempt to study possible n-participation in allyl derivatives, 2-(2-methoxyethyl)-3-methyl-2-cyclohexenyl p-nitrobenzoate 4 was solvolyzed in various solvents including fluorinated alcohols. Its solvolysis rate is slower than that of the 2-butyl analog 3 . This rate retardation can be explained by an electron-withdrawing inductive effect of methoxy group. The secondary α-deuterium isotope effect of ester 4 is normal in all the solvents investigated. These results show that the methoxy group does not assist the ionization of ester 4.

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.

Model calculations of isotope effects. VIII. Deprotonation of nitroethane

Transition-state models for the base-promoted deprotonation of nitroethane have been designed, and primary and secondary hydrogen-deuterium kinetic isotope effects have been calculated. Comparison of the results with experimental values of the primary isotope effects allows no firm conclusions to be reached concerning probable transition-state structures. However, the secondary α-deuterium isotope effect comparison disqualifies from consideration those transition states in which rehybridization of Cα and delocalization of the partial negative charge by the nitro group keep pace with the extent of deprotonation. Transition-state models wherein Cα is carbanionic and essentially pyramidal yield theoretical isotope effects lying within the experimental range.

Bimolecular nucleophilic substitution on an acetal

Bimolecular nucleophilic substitution at an acetal centre is identified for the first time, and the reaction characterised by a study of the second-order reactions of nucleophiles with methoxymethoxy-2,4-dinitrobenzene. The reaction is restricted to formaldehyde acetals with good (dinitrophenoxide) leaving groups, and shows a strikingly low sensitivity to the reactivity of the nucleophile: acetate is about half as reactive as hydroxide ion, and even the most effective nucleophiles (iodide, thiosulphate) are only a few times more reactive than solvent water. Reactions with nucleophilic anions are subject to positive specific salt effects, and an analysis based on the Setschenow equation has been developed. The results are interpreted in terms of the borderline SN2 mechanism, with weak bonding of both nucleophile and leaving group in the transition state. The consequent build up of positive charge at the acetal centre explains the high secondary α-deuterium isotope effects observed for these reactions (5–16% per deuteron): this isotope effect cannot therefore safely be used to distinguish between concerted and carbonium ion mechanisms for enzyme catalysed glycosyl transfer reactions.

Model calculations of hydrogen–deuterium isotope effects for E2 and E1cB dehydrochlorinations of 1,1-diaryl-2,2-dichlorethanes

A 14-atom transition-state model is employed as the basis for computations of primary β-deuterium and secondary α-deuterium isotope effects for the dehydrochlorination of the substrates Ar2CH·CHCl2 by alkoxide bases. The structure of the transition state is systematically altered by varying the bond orders of O ⋯ H, H ⋯ Cβ,CβCβ and Cα⋯ Cl, with a progressive change in the angular geometry about Cα and Cβ from tetrahedral to trigonal and proportional to the degree of CαCβ double bond character. These changes are translated into force constant changes by means of empirical relations involving bond orders, bond angles, and the associated force constants. The results of changing the way in which the imaginary reaction co-ordinate vibration is formulated are also investigated. Best agreement between experimental values of primary kH/kD isotope effects and computed isotope effects is obtained when proton transfer is allowed to dominate the reaction co-ordinate motion, with the reacting heavy atoms remaining relatively motionless.

Secondary α-deuterium isotope effects on borohydride reductions and on the protonation of benzaldehyde

Secondary α-deuterium isotope effects on borohydride reductions and on the protonation of benzaldehyde

ChemInform Abstract: REEXAMINATION OF THE SECONDARY α‐DEUTERIUM ISOTOPE EFFECT IN THERMOLYSIS OF 1,1′‐DIPHENYLAZOETHANE. MECHANISTIC CONSEQUENCES FOR RELATED COMPOUNDS

Chemischer InformationsdienstVolume 7, Issue 1 Preparative Organic Chemistry ChemInform Abstract: REEXAMINATION OF THE SECONDARY α-DEUTERIUM ISOTOPE EFFECT IN THERMOLYSIS OF 1,1′-DIPHENYLAZOETHANE. MECHANISTIC CONSEQUENCES FOR RELATED COMPOUNDS S. E. SCHEPPELE, S. E. SCHEPPELESearch for more papers by this authorP. L. GRIZZLE, P. L. GRIZZLESearch for more papers by this authorD. W. MILLER, D. W. MILLERSearch for more papers by this author S. E. SCHEPPELE, S. E. SCHEPPELESearch for more papers by this authorP. L. GRIZZLE, P. L. GRIZZLESearch for more papers by this authorD. W. MILLER, D. W. MILLERSearch for more papers by this author First published: January 6, 1976 https://doi.org/10.1002/chin.197601080AboutPDF 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 onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume7, Issue1January 6, 1976 RelatedInformation

Secondary α-deuterium isotope effects on aldehyde hydrate and hemiacetal formation

Secondary α-deuterium isotope effects on aldehyde hydrate and hemiacetal formation

Secondary α-deuterium isotope effects in the diazetidine formation from azodicarboxylates and vinyl ethers

Secondary α-deuterium isotope effects in the diazetidine formation from azodicarboxylates and vinyl ethers

Correlation of isotope effects in substitution reactions with nucleophilicities. Secondary α-deuterium isotope effect in the iodide-131 exchange of methyl-d3 iodide

The secondary α-deuterium isotope effect in iodide-131 exchange of methyl-d3 iodide is kH/kD = 1.05 ± 0.01 in methanol and 1.10 ± 0.04 in water at 20°. A correlation of secondary α-deuterium and 13C effects, in bimolecular nucleophilic substitution reactions, with the difference of E values between nucleophile and leaving group is presented.

Secondary α-Deuterium Isotope Effects and Relative Rates in the Halogen Exchange Reactions of Benzyl and Thenyl Chlorides1

Secondary α-Deuterium Isotope Effects and Relative Rates in the Halogen Exchange Reactions of Benzyl and Thenyl Chlorides¹

The Transition State in Methyl Radical Formation. The Secondary α-Deuterium Isotope Effect

The Transition State in Methyl Radical Formation. The Secondary α-Deuterium Isotope Effect