Substitution isotope effects

Deuterium isotope effects have been found even where it is certain that the C—H bond does not break at all in the reaction. Such effects are called secondary isotope effectsf" the term primary isotope effect being reserved for the type discussed previously. Secondary isotope effects can be divided into a and P effects. In a P secondary isotope effect, substitution of deuterium for hydrogen p to the position of bond breaking slows the reaction. An example is solvolysis of isopropyl bromide ... 

If substitution of deuterium for protium in a chemical reaction produces a detectable kinetic isotope effect, substitution of tritium wiU produce an even larger kinetic isotope effect (kii/IcT)) because of the larger mass of tritium and the resultant lower zero-point vibrational energy of a C-T relative to C-D and C-H bond. In a number of chemical and enzymatic reactions, a simple logarithmic proportionahty is observed, known as a SwainSchaad relationship (Swain eta/., 1958) ... 

Others, this is about what would be expected for a substituent effect on the oxygen-centred diradical. Certainly the reaction constant would be very different for a rate-determining step involving C-C bond breakage. Isotope effects -substitution by deuterium - have also been used to support the diradical mechanism [31]. No isotope effect was noted for (3), the conclusion being that rehybridisation at carbon does not occur in the transition state. An inverse... 

Another circumstance which could change the most commonly observed characteristics of the two-stage process of substitution has already been mentioned it is that in which the step in which the proton is lost is retarded because of a low concentration of base. Such an effect has not been observed in aromatic nitration ( 6.2.2), but it is interesting to note that it occurs in A -nitration. The A -nitration of A -methyl-2,4,6-trinitroaniline does not show a deuterium isotope effect in dilute sulphuric acid but does so in more concentrated solutions (> 60 % sulphuric acid kjj/kjj = 4 8). ... 

The occurrence of a hydrogen isotope effect in an electrophilic substitution will certainly render nugatory any attempt to relate the reactivity of the electrophile with the effects of substituents. Such a situation occurs in mercuration in which the large isotope effect = 6) has been attributed to the weakness of the carbon-mercury bond relative to the carbon-hydrogen bond. The following scheme has been formulated for the reaction, and the occurrence of the isotope effect indicates that the magnitudes of A j and are comparable ... 

The azo coupling reaction proceeds by the electrophilic aromatic substitution mechanism. In the case of 4-chlorobenzenediazonium compound with l-naphthol-4-sulfonic acid [84-87-7] the reaction is not base-catalyzed, but that with l-naphthol-3-sulfonic acid and 2-naphthol-8-sulfonic acid [92-40-0] is moderately and strongly base-catalyzed, respectively. The different rates of reaction agree with kinetic studies of hydrogen isotope effects in coupling components. The magnitude of the isotope effect increases with increased steric hindrance at the coupler reaction site. The addition of bases, even if pH is not changed, can affect the reaction rate. In polar aprotic media, reaction rate is different with alkyl-ammonium ions. Cationic, anionic, and nonionic surfactants can also influence the reaction rate (27). 

Isotope Effects on Superconductivity. Substitution of hydrogen by deuterium affects the superconducting transition temperature of palladium hydride [26929-60-2] PdH2 (54,55), palladium silver hydride, Pd Ag H D ( 6), and vanadium—2itconium—hydride, N(57). 

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. 

Fig. 4.9. DifiBoing zero-point energies ofprotium- and deuterium-substituted molecules as the cause of primary kinetic isotope effects.

Secondary isotope effects at the position have been especially thoroughly studied in nucleophilic substitution reactions. When carbocations are involved as intermediates, substantial /9-isotope effects are observed. This is because the hyperconjugative stabliliza-... 

Predict whether normal or inverse isotope effects will be observed for each reaction below. Explain. Indicate any reactions in which you would expect > 2. The isotopically substituted hydrogens are marked with asterisks. 

Stabilization of a carbocation intermediate by benzylic conjugation, as in the 1-phenylethyl system shown in entry 8, leads to substitution with diminished stereosped-ficity. A thorough analysis of stereochemical, kinetic, and isotope effect data on solvolysis reactions of 1-phenylethyl chloride has been carried out. The system has been analyzed in terms of the fate of the intimate ion-pair and solvent-separated ion-pair intermediates. From this analysis, it has been estimated that for every 100 molecules of 1-phenylethyl chloride that undergo ionization to an intimate ion pair (in trifluoroethanol), 80 return to starting material of retained configuration, 7 return to inverted starting material, and 13 go on to the solvent-separated ion pair. 

The second-order rate constants for hydration and the kinetic solvent isotope effect for hydration of several 2-substituted 1,3-butadienes ate given below. Discuss the information these data provide about the hydration mechanism. 

A number of studies of the acid-catalyzed mechanism of enolization have been done. The case of cyclohexanone is illustrative. The reaction is catalyzed by various carboxylic acids and substituted ammonium ions. The effectiveness of these proton donors as catalysts correlates with their pK values. When plotted according to the Bronsted catalysis law (Section 4.8), the value of the slope a is 0.74. When deuterium or tritium is introduced in the a position, there is a marked decrease in the rate of acid-catalyzed enolization h/ d 5. This kinetic isotope effect indicates that the C—H bond cleavage is part of the rate-determining step. The generally accepted mechanism for acid-catalyzed enolization pictures the rate-determining step as deprotonation of the protonated ketone ... 

The distribution of a-bromoketones formed in the reaction of acetylcyclopentane with bromine was studied as a function of deuterium substitution. On the basis of the data given below, calculate the primaiy kinetic isotope effect for enolization of... 

Isotope effects are also useful in providing insight into other aspects of the mechanisms of individual electrophilic aromatic substitution reactions. In particular, because primary isotope effects are expected only when the breakdown of the c-complex to product is rate-determining, the observation of a substantial points to a rate-... 

Table 10.6. Kinetic Isotope Effects in Some Electrophilic Aromatic Substitution Reactions...

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 ... 

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. 

Indicate mechanisms that would account for the formation of each product. Show how the isotopic substitution could cause a change in product composition. Does your mechanism predict that the isotopic substitution would give rise to a primary or secondary deuterium kinetic isotope effect Calculate the magnitude of the kinetic isotope effect from the data given. 

Consider a reactant molecule in which one atom is replaced by its isotope, for example, protium (H) by deuterium (D) or tritium (T), C by C, etc. The only change that has been made is in the mass of the nucleus, so that to a very good approximation the electronic structures of the two molecules are the same. This means that reaction will take place on the same potential energy surface for both molecules. Nevertheless, isotopic substitution can result in a rate change as a consequence of quantum effects. A rate change resulting from an isotopic substitution is called a kinetic isotope effect. Such effects can provide valuable insights into reaction mechanism. 

If the proton is not equidistant between A and B, it will undergo some movement in the symmetric stretching vibration. Isotopic substitution will, therefore, result in a change in transition state vibrational frequency, with the result that there will be a zero-point energy difference in the transition state. This will reduce the kinetic isotope effect below its maximal possible value. For this type of reaction, therefore, should be a maximum when the proton is midway between A and B in the transition state and should decrease as H lies closer to A or to B. 

Kinetic Isotope Effect. The change in reaction rate caused by isotopic substitution. 

The reason for this difference in selectivity of different electrophilic reagents between the 2- and 3-positions must be sought in the finer details of the mechanism of electrophilic aromatic substitution Melander and co-workers are studying this problem by means of isotope effects. 

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