Kinetic isotope effects intramolecular reactions

Song and Beak161 have used intramolecular and intermolecular hydrogen-deuterium kinetic isotope effects to investigate the mechanism of the tin tetrachloride catalysed ene-carbonyl enophile addition reaction between diethyloxomalonate and methylenecy-clohexane (equation 105). These ene reactions with carbonyl enophiles can occur by a concerted (equation 106) or a stepwise mechanism (equation 107), where the formation of the intermediate is either fast and reversible and the second step is slow k- > k-i), or where the formation of the intermediate (the k step) is rate-determining. 

Song and Beak found intramolecular and intermolecular hydrogen-deuterium kinetic isotope effects of 1.1 0.2 and 1.2 0.1, respectively, for the tin tetrachloride catalysed ene reaction. Since significant intramolecular and intermolecular primary deuterium kinetic isotope effects of between two and three have been found for other concerted ene addition reactions161, the tin-catalysed reaction must proceed by the stepwise pathway with the k rate determining step (equation 107). 

Kelley and co-workers [70, 71] measured the dynamics of the excited-state intramolecular proton transfer in 3-hydroxyflavone and a series of its derivatives as a function of solvent (Scheme 2.9). The energy changes associated with the processes examined are of the order of 3 kcal/mol or less. The model they employed in the analysis of the reaction dynamics was based upon a tunneling reaction path. Interestingly, they find little or no deuterium kinetic isotope effect, which would appear to be inconsistent with tunneling theories. For 3-hydroxy-flavone, they suggest the lack of an isotope effect is due to a very large... 

In the aldol-Tishchenko reaction, a lithium enolate reacts with 2 mol of aldehyde, ultimately giving, via an intramolecular hydride transfer, a hydroxy ester (51) with up to three chiral centres (R, derived from rYhIO). The kinetics of the reaction of the lithium enolate of p-(phenylsulfonyl)isobutyrophenone with benzaldehyde have been measured in THF. ° A kinetic isotope effect of fee/ o = 2.0 was found, using benzaldehyde-fil. The results and proposed mechanism, with hydride transfer rate limiting, are supported by ab initio MO calculations. 

The effect of ring substituents on the rate constants, deuterium kinetic isotope effects and Arrhenius parameters for ene-additions of acetone to 1,1-diphenylsilane have been explained in terms of a mechanism involving fast, reversible formation of a zwitterionic silene-ketone complex, followed by a rate-limiting proton transfer between the a-carbonyl and silenic carbon. A study of the thermal and Lewis acid-catalysed intramolecular ene reactions of allenylsilanes with a variety of... 

OTHER EXAMPLES OF KINETIC ISOTOPE EFFECTS. The power of kinetic isotope effects in enzymol-ogy is well illustrated in the work of Rose ° and Knowles deahng with hydrogen effects in proton transfer to and from carbon. Abstraction of a proton from a tetrahedral carbon is a fundamental step in many enzyme-catalyzed reactions. Intramolecular proton transfer as well as partial loss (wash-out) migrating protons have provided important clues in mechanistic investigations. Enol and enediolate formation constitute several... 

The intramolecular kinetic isotope effect determined in reaction of BTNO with p-MeO-C6H4CH(D)0H gave a h/ d ratio of 5.6 in MeCN , consistent with a rate-determining H-abstraction step. Additional determinations gave a h/ d of 7 with PhCH(D)OH, and 12 for the intermolecular competition of fluorene vs. 9,9-dideuteriofluorene. The latter value supports the contribution of tunnelling already commented on for reaction of PINO with various C—H donors ( h/ d values in the 11-27 range) . ... 

Enthalpies of activation, transition-state geometries, and primary semi-classical (without tunneling) kinetic isotope effects (KIEs) have been calculated for 11 bimolecu-lar identity proton-transfer reactions, four intramolecular proton transfers, four nonidentity proton-transfer reactions, 11 identity hydride transfers, and two 1,2-intramole-cular hydride shifts at the HF/6-311+G, MP2/6-311+G, and B3LYP/6-311+-1-G levels.134 It has been found that the KIEs are systematically smaller for hydride transfers than for proton transfers. The differences between proton and hydride transfers have been rationalized by modeling the central C H- C- unit of a proton-transfer transition state as a four-electron, three-centre (4-e 3-c) system and the same unit of a hydride-transfer transition state as a 2-e 3-c system. 

With thermal systems either in the gas phase or in solution, it is in ter -molecular isotope effects which are more commonly studied. Intramolecular isotope effects involve distinguishing and measuring two, or more, chemically identical but isotopically different products produced in the same reaction vessel from the same reactant. The situation is different in mass spectrometry. Intramolecular isotope effects are conveniently studied, because the chemically identical products are naturally separated according to their masses. Intermolecular isotope effects on ion abundances are also easily measured, but, as regards kinetics and mechanism of reaction, their value is limited. Whereas an intramolecular isotope effect (on ion abundances) reflects kinetic isotope effects, an intermolecular isotope effect (on ion abundances) reflects kinetic isotope effects, isotope effects on the internal energy distribution, P(E), and other factors as well and the effects cannot be easily separated (vide infra). 

Measurements of product ion abundances or rates of decomposition can, as has been discussed, provide reliable, even if not precise, information on intramolecular kinetic isotope effects. These isotope effects constitute a powerful probe of reaction mechanism. 

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