Isotope effect and reaction mechanisms

Dependence of kinetic isotope effects on reaction mechanisms and rates... 

Isotope effects on reaction rates have been studied intensively, and will receive the major share of the space in this chapter. This field has been reviewed on a number of previous occasions (Me-lander, 1960 Saunders, 1961 Bigeleisen and Wolfsberg, 1959). The present chapter is not intended to be comprehensive or rigorous its aim is to present qualitatively the theory of isotope effects, and to demonstrate with appropriate examples the use of isotope effects in reaction mechanisms studies. 

Francisco, W.A., Abu-Soud, H.M., DelMonte, A.J., Singleton, D.A., Baldwin, TO., and Raushel, F.M., Deuterium kinetic isotope effects and the mechanism of the bacterial luciferase reaction. 

At this point, attention can be given to specific electrophilic substitution reactions. The kinds of data that have been especially useful for determining mechanistic details include linear ffee-energy relationships, kinetic studies, isotope effects, and selectivity patterns. In general, the basic questions that need to be asked about each mechanism are (1) What is the active electrophile (2) Which step in the general mechanism for electrophilic aromatic substitution is rate-determining (3) What are the orientation and selectivity patterns ... 

A substantial body of data, including reaction kinetics, isotope effects, and structure-reactivity relationships, has permitted a thorough understanding of the steps in aromatic nitration. As anticipated from the general mechanism for electrophilic substitution, there are three distinct steps ... 

When one of the ortho hydrogens is replaced by deuterium, the rate drops from 1.53 X 10 " s to 1.38 X lO s. What is the kinetic isotope effect The product from such a reaction contains 60% of the original deuterium. Give a mechanism for this reaction that is consistent with both the kinetic isotope effect and the deuterium retention data. 

The first step, as we have already seen (12-3), actually consists of two steps. The second step is very similar to the first step in electrophilic addition to double bonds (p. 970). There is a great deal of evidence for this mechanism (1) the rate is first order in substrate (2) bromine does not appear in the rate expression at all, ° a fact consistent with a rate-determining first step (3) the reaction rate is the same for bromination, chlorination, and iodination under the same conditions (4) the reaction shows an isotope effect and (5) the rate of the step 2-step 3 sequence has been independently measured (by starting with the enol) and found to be very fast. With basic catalysts the mechanism may be the same as that given above (since bases also catalyze formation of the enol), or the reaction may go directly through the enolate ion without formation of the enol ... 

Mechanistic studies have been designed to determine if the concerted cyclic TS provides a good representation of the reaction. A systematic study of all the E- and Z-decene isomers with maleic anhydride showed that the stereochemistry of the reaction could be accounted for by a concerted cyclic mechanism.19 The reaction is only moderately sensitive to electronic effects or solvent polarity. The p value for reaction of diethyl oxomalonate with a series of 1-arylcyclopentenes is —1.2, which would indicate that there is little charge development in the TS.20 The reaction shows a primary kinetic isotope effect indicative of C—H bond breaking in the rate-determining step.21 There is good agreement between measured isotope effects and those calculated on the basis of TS structure.22 These observations are consistent with a concerted process. 

In the reaction of the cis-disubstituted olefins 53 (X = S, R = Me) and 53 (X = O, R = D) with DMAZD, only the cis- 1,2-diazetidines are formed.94,95 The observation of this stereospecificity, the isotope effects and lack of solvent dependence would seem to support a concerted mechanism, although the workers prefer to explain the isotope effects by a stepwise mechanism involving a dipolar intermediate, similar to that already described for the reaction of PTAD with indene.95 Other workers claim that the reaction is... 

The mechanism of the spontaneous hydrolysis of aryl cr-disulfones (188) in aqueous dioxan has been studied in some detail (Kice and Kasperek, 1969). The reaction is approximately 104 times slower under a given set of conditions than the very rapid spontaneous hydrolysis of aryl sulfinyl sulfones (135) discussed earlier in Section 5. The large difference in rate arises because AH for the spontaneous hydrolysis of a given cr-disulfone is about 6 kcal mol-1 larger than AH for the spontaneous hydrolysis of the corresponding sulfinyl sulfone. However, despite the large difference in rate and AH, the two spontaneous hydrolyses show a remarkable similarity in (a) Hammett p, (b) increase in rate with increasing water content of the solvent, (c) solvent isotope effect, and (d) AS. ... 

Complications that arise with this simple reaction are twofold. First, because of the low mass of the hydrogen atom its movement frequently exhibits non-classical behavior, in particular quantum-mechanical tunneling, which contributes significantly to the observed kinetic isotope effect, and in fact dominates at low temperature (Section 6.3). Secondly, in reaction 10.2 protium rather than deuterium transfer may occur ... 

An S Ar (nucleophilic substitution at aromatic carbon atom) mechanism has been proposed for these reactions. Both nonenzymatic and enzymatic reactions that proceed via this mechanism typically exhibit inverse solvent kinetic isotope effects. This observation is in agreement with the example above since the thiolate form of glutathione plays the role of the nucleophile role in dehalogenation reactions. Thus values of solvent kinetic isotope effects obtained for the C13S mutant, which catalyzes only the initial steps of these reactions, do not agree with this mechanism. Rather, the observed normal solvent isotope effect supports a mechanism in which step(s) that have either no solvent kinetic isotope effect at all, or an inverse effect, and which occur after the elimination step, are kinetically significant and diminish the observed solvent kinetic isotope effect. 

Kaldor, S.B., Eredenburg, M.E. and Saunders, W.H. (1980). Mechanisms of elimination reactions 32. Tritium isotope effects and tunnel effects in the reaction of 2,2-diphenylethyl-2-t derivatives with various bases. J. Am. Chem. Soc. 102, 6296-6299... 

Miller, S.M. and Khnman, J.P. (1985). Secondary isotope effects and structure-reactivity correlations in the dopamine heta-monooxygenase reaction evidence for a chemical mechanism. Biochemistry 24, 2114-2127... 

Hvistendahl, G. Uggerud, E. Deuterium Isotope Effects and Mechanism of the Gas-Phase Reaction [C3H7] — [C3H3] + H2. Org. Mass Spectrom. 1986, 21, 347-350. 

The mechanisms of permanganate oxidations have been the subject of a fairly intensive study which has now lasted for almost a century. While many of these studies were carried out in aqueous solutions, much of what was learned is also germane to an understanding of the reactions which occur in phase transfer assisted reactions. Although most of these studies are interrelated they can conveniently be discussed under the following headings products, substituent effects, isotope effects, and solvent effects, with the latter being of particular importance to the phase transfer assisted reactions. 

Isotope effects and element effects associated with hydron-transfer steps during methoxide promoted dehydrohalogenation reactions of jo-CF3C6H4C HClCH2X (X=Br, Cl, or F) have also been discussed, with regard to distinction between E2 and multi-step pathways. The Arrhenius behaviour of hydrogen isotope effects was used to calculate the amounts of internal hydrogen return associated with the two-step mechanism. 

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