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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.

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 alpha deuterium and primary leaving group nitrogen KIEs and Hammett ρ values found for the free ion and ion-pair SN2 reactions between benzyldimethylphenylammonium ion and sodium para-substituted thiophenoxides in methanol at 20.000°C show how (i) ion-pairing of the nucleophile, (ii) a change in substituent in the nucleophile, and (iii) a change in solvent alters the structure of a Type II SN2 transition state. Ion-pairing shortens the weaker sulfur - alpha carbon (S—Cα) transition state bond significantly but does not alter the stronger alpha carbon - leaving group (Cα—N) transition state bond as the bond strength hypothesis predicts. However, the effect of ion pairing, i.e., the decrease in the S—Cα bond on ion-pairing, decreases as a more electron-withdrawing substituent is added to the nucleophile, and the S—Cα bond actually increases when the nucleophile is the p-chlorothiophenoxide ion. The identical Hammett ρ values of -0.85 and -0.84 for the free ion and ion-pair reactions, respectively, may be observed because, on average, the S—Cα bonds are identical in the free ion and ion-pair transition states. When a more electron-donating substituent is added to the nucleophile, an earlier transition state is found in both the ion-pair and free ion reactions. However, the substituent effect is smaller in the ion-pair reactions, presumably because the change in the negative charge on the sulfur atom with substituent is greater in the free ion than in the ion-pair. The substituent effect on transition state structure suggested by the KIEs is not predicted by any of the theories that are used to predict substituent effects on SN2 reactions. Both the secondary alpha deuterium and primary leaving group nitrogen KIEs and the Hammett ρ values indicate that the transition state is earlier when the solvent is changed from DMF to methanol as the "solvation rule for SN2 reactions" predicts. This probably occurs because an earlier, more ionic, transition state is more highly solvated (more stable) in methanol.Key words: nucleophilic substitution, SN2, isotope effect, transition state, substituent, ion-pair.

The effect of ion-pairing in an SN2 reaction is very different when the nucleophilic atom is changed from sulfur to oxygen, i.e., changing the nucleophile from thiophenoxide ion to phenoxide ion. When the nucleophile is sodium thiophenoxide, ion-pairing markedly alters the secondary α -deuterium kinetic isotope effect (transition state structure) and the substituent effect found by changing the para substituent on the nucleophile. When the nucleophile is sodium phenoxide, ion-pairing does not significantly affect the secondary α -deuterium or the chlorine leaving group kinetic isotope effects (transition state structure) or the substituent effects found by changing a para substituent on the nucleophile or the substrate. The different effects of ion-pairing may occur because the electron density on the hard oxygen atom of the sodium phenoxide is not affected significantly by ion-pairing.Key words: nucleophilic substitution, SN2, kinetic isotope effect, transition state, substituent effects, ion-pair.

The effects of substituents on the structure of SN2 transition states suggested by kinetic isotope effects and Hammett ρ values are often different and, moreover, often do not agree with substituent effects predicted by current theories whether the change in substituent is made in the nucleophile, in the leaving group, or at the α-carbon. The importance of the strength of the reacting bonds in determining the effects of substituents on transition-state structure is investigated. A bond strength hypothesis that suggests there will be a significant change in the weaker reacting bond but little or no change in the stronger reacting bond in an SN2 transition state when a substituent in the nucleophile, the substrate, or the leaving group is altered in an SN2 reaction, predicts a high percentage of the experimental results.

Fourier transform infrared spectroscopy has been used to investigate the behaviour of HCN and alkali metal and tetraethylammonium cyanides in DMF and aqueous DMF. The cyanide ion exists as free ions and ion pairs in pure DMF but as water-solvated and DMF-solvated ions in aqueous DMF. The aqueous DMF solutions can be treated as a pseudo two-phase system with a distribution coefficient of 0.018 between the aqueous and DMF-rich pseudo phases. A kinetic analysis of the cyanide ion – benzyl chloride reaction in DMF and aqueous DMF has shown that the rate constant for the SN2 reaction is markedly decreased with the addition of as little as 2.5% water. This decrease is primarily due to changes in transition state solvation. The SN2 reactions between cyanide ion and benzylmethyl-4-substituted phenylsulphonium perchlorates in 20% aqueous DMF have also been investigated.

Two research groups have used heavy atom leaving group kinetic isotope effects to determine how the structure of an SN2 transition state is affected by a change in solvent. Two completely different types of behaviour were observed in these studies. In one case, the leaving group kinetic isotope effect, and thus the transition state structure, changed markedly when the solvent was varied over a reasonably narrow range. In the other study, the leaving group kinetic isotope effect (transition state structure) remained constant over a wide range of solvents. A model describing the interaction between solvent molecules and SN2 transition states is developed and a SolvationruleforSN2reactions which rationalizes the different experimental results is explained and justified. Finally, predictions based on the solvation rule are shown to be in agreement with the results of theoretical calculations of solvent effects on SN2 transition states and secondary α deuterium kinetic isotope effect measurements.

Secondary α and β hydrogen–deuterium kinetic isotope effects have been used together to show that the SN reaction between 1-phenylethyldimethylphenylammonium ion and bromide or iodide ion in chloroform occurs by way of an SN2 mechanism within a triple ion in spite of the fact that it reacts faster than the primary substrate, benzyldimethylphenylammonium bromide. The very loose transition state and steric effects in the ground state appear to be responsible for the unusually fast SN2 reactions between 1-phenylethyldimethylphenylammonium ion and halide ions in chloroform.

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.

A kinetic study of the nucleophilic substitution reactions of a series of para-substituted phenylbenzyldimethylammonium nitrates with sodium thiophenoxide at 0 °C in N,N-dimethylformamide containing a large excess of sodium nitrate, has shown the reaction to be a second-order process which is first-order in both the substrate and the nucleophile. A Hammett ρ value of +2.04 for different para-substitutents on the N-phenyl group of the quaternary ammonium salt and a large nitrogen kinetic isotope effect of 1.0200 ± 0.0007 have excluded any mechanism involving a carbonium ion intermediate but are in accord with an SN2 mechanism with a substantial amount of carbon–nitrogen bond rupture in the transition state.

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.

This work demonstrates that organic compounds can be synthesized up to 1240 times faster in sealed Teflon vessels in a microwave oven than by conventional (reflux) techniques. It is shown that all polar molecules absorb microwave energy rapidly and that the rate of energy absorption varies with the dielectric constant. The rates of reaction of polar molecules in nonpolar solvents are not increased appreciably by the microwave method. Also, the homogeneity of the reaction does not affect the rate enhancement. The rate enhancement arises predominantly because the oven superheats the solvent rapidly. Finally, pressure (temperature) measurements have shown that the maximum rate enhancement is achieved when the proper power level and volume of solvent are used. It appears that rate enhancements of approximately 200 are possible for many reactions if the reaction conditions are optimized.

Methyl Z- and E-4-bromo-3-methylbut-2-enoate 13 and 14 react with triethyl phosphite stereospecifically with retention of configuration to give the corresponding Z- and E-phospho-nate esters 8 and 9. The Z- and E-phosphonates react with aldehydes with extensive stereomutation of the double bond. Rapid equilibration to a mixture of one part E-phosphonate to two parts Z-phosphonate occurs when either geometric isomer is treated with base. Despite this, the E-2,E-4 ester 16 is the chief product of the reaction. Methyl E-β-ionylideneacetate 16b is the major product of the reaction of either isomer with β-cyclocitral and with cyclohexene car-boxaldehyde only the E-2,E-4 isomer 16c is formed. Benzaldehyde reacts with the phosphonates to give a mixture of the E-2,E-4 and Z-2,E-4 isomers 16a and 15a in a 4:1 ratio. Although the corresponding Z- and E-phosphonium salts 6 and 7, obtained stereospecifically from the bromo esters, react by the same general mechanism as the phosphonates the main product with benzaldehyde is the Z-2,Z-4 isomer 17a.

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.

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.

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.

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.