Substrate isotope effects

A SSIMS spectrum, like any other mass spectrum, consists of a series of peaks of dif ferent intensity (i. e. ion current) occurring at certain mass numbers. The masses can be allocated on the basis of atomic or molecular mass-to-charge ratio. Many of the more prominent secondary ions from metal and semiconductor surfaces are singly charged atomic ions, which makes allocation of mass numbers slightly easier. Masses can be identified as arising either from the substrate material itself from deliberately introduced molecular or other species on the surface, or from contaminations and impurities on the surface. Complications in allocation often arise from isotopic effects. Although some elements have only one principal isotope, for many others the natural isotopic abundance can make identification difficult. 

A special type of substituent effect which has proved veiy valuable in the study of reaction mechanisms is the replacement of an atom by one of its isotopes. Isotopic substitution most often involves replacing protium by deuterium (or tritium) but is applicable to nuclei other than hydrogen. The quantitative differences are largest, however, for hydrogen, because its isotopes have the largest relative mass differences. Isotopic substitution usually has no effect on the qualitative chemical reactivity of the substrate, but often has an easily measured effect on the rate at which reaction occurs. Let us consider how this modification of the rate arises. Initially, the discussion will concern primary kinetic isotope effects, those in which a bond to the isotopically substituted atom is broken in the rate-determining step. We will use C—H bonds as the specific topic of discussion, but the same concepts apply for other elements. 

Bromination has been shown not to exhibit a primary kinetic isotope effect in the case of benzene, bromobenzene, toluene, or methoxybenzene. There are several examples of substrates which do show significant isotope effects, including substituted anisoles, JV,iV-dimethylanilines, and 1,3,5-trialkylbenzenes. The observation of isotope effects in highly substituted systems seems to be the result of steric factors that can operate in two ways. There may be resistance to the bromine taking up a position coplanar with adjacent substituents in the aromatization step. This would favor return of the ff-complex to reactants. In addition, the steric bulk of several substituents may hinder solvent or other base from assisting in the proton removal. Either factor would allow deprotonation to become rate-controlling. 

The idea that hydrogen bonding, as a special ortho effect of the substrate, may be involved in the transition state of the reactions with amines was first proposed by Chapman et al. Attempting to test this hypothesis, Hawthorne investigated the hydrogen-isotope effect in the reaction of o- and p-chloronitrobenzene with... 

Much evidence has been obtained in support of the El mechanism. For example, El reactions show first-order kinetics, consistent with a rate-limiting spontaneous dissociation process, l- urthermore, El reactions show- no deuterium isotope effect because rupture of the C—H (or C—D) bond occurs after the rate-limiting step rather than during it. Thus, we can t measure a rate difference between a deuterated and nondeuterated substrate. 

In the El reaction, C-X bond-breaking occurs first. The substrate dissociates to yield a carbocation in the slow rate-limiting step before losing H+ from an adjacent carbon in a second step. The reaction shows first-order kinetics and no deuterium isotope effect and occurs when a tertiary substrate reacts in polar, nonbasic solution. 

Further substrate and solvent isotope effects were measured by Batts and Gold472 for the dedeuteration and detritiation of labelled 1,3,5-trimethoxy-benzene in aqueous protium- and deuterium-containing perchloric acid. Contrary to the observations above, they found the rate coefficients for dedeuteration to detritiation to be independent of the concentration of the catalysing acid (Table 125). Detritiation in the deuterium-containing aqueous perchloric acid media occurred 1.68 times faster than in the protium-containing media. 

RATE COEFFICIENTS, SOLVENT AND SUBSTRATE ISOTOPE EFFECTS FOR REACTION OF... 

CORRELATION OF ISOTOPE EFFECT FOR DEPROTONATION WITH ApJf (SUBSTRATE-... 

The lack of a substrate isotope effect suggests very extensive internal return and is readily explained in terms of the fact that conversion of the hydrocarbon to the anion would require very little structural reorganisation. Since koba = k 1k 2/(kLl+k 2) and k 2 is deduced as > k2, then kobs = Kk 2, the product of the equilibrium constant and the rate of diffusion away of a solvent molecule, neither of the steps having an appreciable isotope effect. If the diffusion rates are the same for reactions of each compound then the derived logarithms of partial rate factors (above) become pAT differences between benzene and fluorobenzene hydrogens in methanol. However, since the logarithms of the partial rate factors were similar to those obtained with lithium cyclohexylamide, a Bronsted cor-... 

Measurements of the solvent isotope effect for different aromatic substrates in a range of sulphuric acid media (Table 196) showed the values to increase as... 

Determination of the solvent and substrate isotope effects in the deacylation of mesitaldehyde yielded the coefficients in Table 222652. The substrate isotope... 

In this, as in many catalysed reactions, the protonated substrate is postulated as an intermediate, and although the proposed reaction scheme in fact accords with all the known experimental facts it perhaps would be instructive to determine the dependence of the rate coefficient on the Hammett acidity function at high acid concentration and also to investigate the solvent isotope effect kD2JkH20. Both these criteria have been used successfully (see Sections 2.2-2.4) to confirm the intermediacy of the protonated substrate in other acid-catalysed aromatic rearrangements. 

Secondly, it has been found that the benzidine rearrangement is subject to a solvent isotope effect d2o/ h2o > 1- If a proton is transferred from the solvent to the substrate in a rate-determining step the substitution of protium by deuterium will lead to a retardation in the rate of reaction (primary isotope effect) whereas if a proton is transferred in a fast equilibrium step preceeding the rate-determining step as in... 

There is one further piece of kinetic evidence which throws light on an aspect of the benzidine rearrangement mechanism, and this is comparison of the rates of reaction of ring-deuterated substrates with the normal H compounds. If the final proton-loss from the benzene rings is in any way rate-determining then substitution of D for H would result in a primary isotope effect with kD < kH. This aspect has been examined in detail42 for two substrates, hydrazobenzene itself where second-order acid dependence is found and l,l -hydrazonaphthalene where the acid dependence is first-order. The results are given in Tables 2 and 3. 

While the A1 mechanism shown above operates in most acetal hydrolyses, it has been shown that at least two other mechanisms can take place with suitable substrates. In one of these mechanisms the second and third of the above steps are concerted, so that the mechanism is Sn2cA (or A2). This has been shown, for example, in the hydrolysis of 1,1-diethoxyethane, by isotope effect studies ... 

Isotope Effects. If the hydrogen ion departs before the arrival of the electrophile (SeI mechanism) or if the arrival and departure are simultaneous, there should be a substantial isotope effect (i.e., deuterated substrates should undergo substitution more slowly than nondeuterated compounds) because, in each case, the C—H bond is broken in the rate-determining step. However, in the arenium ion mechanism, the C—H bond is not broken in the rate-... 

For each catalyst, the mechanism for one direction is the exact reverse of the other, by the principle of microscopic reversibility. As expected from mechanisms in which the C—H bond is broken in the rate-determining step, substrates of the type RCD2COR show deuterium isotope effects (of 5) in both the basic- and the acid -catalyzed processes. 

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 ... 

When reactions were run with substrate deuterated in the ortho position, isotope effects of 1.22 were obtained. It is difficult to account for such high secondary isotope effects in any other way except that an incipient... 

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