EM and transition state structure

One of the major objectives of physical organic chemistry is the detailed description of transition states in terms of nuclear positions, charge distributions, and solvation requirements. A considerable aid to this task is provided for many reaction series by the existence of extrathermodynamic relationships, whose mathematical simplicity largely arises from extensive cancellation of the contribution to the free-energy change from the part of the molecule outside the reaction zone. 

For intramolecular reactions the situation is different. Here the free-energy contribution from the non-reacting part of the molecule can be, and quite often is, most significant. Moreover, steric restrictions due to the intervening chain can significantly alter the way in which the end-groups interact in the 

In the common parlance of physical organic chemists such phrases as product-like or reactant-like transition states are common. The degree of resemblance of transition states to either reactants or products is usually assessed for reaction series obeying the linear-free-energy principle on the basis of suitable reaction constants, such as Bronsted a- and p-values, and Hammett reaction constants p. The question is inherently more complex for cyclisation reactions, since they are not expected to follow the linear-free-energy principle. 

Another idea, which was originally put forward by Ruzicka (1935) and has ever since provided a common basis for many discussions of reactivity in intramolecular reactions, is that the ring-shaped transition state should be affected by a significant fraction of the strain-energy of the ring being formed. The simplest way to express this idea is by use of (62), where the weighting 

Let EM and EM be the kinetic and equilibrium EM s, respectively, for the individual members of the same cyclisation reaction, and 0AG and flAG the corresponding free energy quantities. The latter can be expressed as in (63) and (64), combination of which with (61) and (62) gives (65) or (66). 

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Although we can make some sense of EM ratios by discussing them in terms of varying transition state structure, the data so far available do not require this approach which must be considered only tentative at this stage. Equilibrium and kinetic EM s for many more reactions are required before it will be possible to decide whether they contain useful information about transition-state structure. It is to be hoped that it will rapidly become normal practice to attempt an estimate of the effective molarity as part of any quantitative work on intramolecular reactions. 

A point which emerges very clearly from the above discussion of structural effects on SN2 ring-closure reactions, is that there is a special effect, namely, a substantial reduction of non-bonded interactions in the transition states for closing of the smallest rings. This effect is held responsible for remarkably high kinetic EM s for the 3- and 4-membered rings in spite of their extremely low equilibrium EM s, and unusually high rate ratios of 5- vs 6-membered... 

Few relevant data are available. Both equilibrium and rate constants have been measured for very few reaction series in solution, but comparisons are possible for lactone and thiolactone formation, and for a few anhydrideforming reactions (Tables 4 and 5). For lactone formation (Table 4) the EM for the rate process is of the same order of magnitude as that derived from the equilibrium constant data, and in some cases actually exceeds it (though only in one case by an amount clearly greater than the estimated uncertainty which is nominally a factor of 4 for these ratios). Lactonization generally involves rate-limiting breakdown of the tetrahedral intermediate, and the transition state is expected to be late and thus close in structure to the conjugate acid of the lactone. 

Neutral sulphur and oxygen nucleophiles of similar structure react with carbonyl groups at similar rates (Jensen and Jencks, 1979) the position of the transition state for thiolactonization is therefore expected to be similar. The comparisons of EM possible for three compounds in Table 4 show that the EMk/EMeq ratios are somewhat smaller for thiolactonization, by factors of 3 and 9 for the two compounds where all four EM s can be estimated. 

EM data are plotted in Figure 8.3 together with available data related to the basic ethanolysis catalyzed by dinuclear complexes 14-Ba2 and 15-Ba2. The superiority of both 14-Ba2 and 15-Ba2 to the structurally related 24-Zu2 and 25-Zu2 indicates a lower adaptability of the zinc(n) complexes to the altered substrates in the transition state, which is believed to arise from more stringent requirements of the coordinative interactions of a d-block metal ion compared with an x-block metal ion. 

Diels-Alder reaction, catalyzes the cycloaddition between terachlorothiophene dioxide and iV-ethylmaleimide. This reaction occurs via a bridged sulfone intermediate forming tetrachlorophthalimide through sulfone elimination and spontaneously oxidative aromatization (Fig. 3B). This catalyst displays an effective molarity (EM=kca/ku cat) of 1000 M, which is extremely efficient for a bimolecular reaction catalyzed by an antibody. The hapten used to elicit this antibody is a derivative of endo hexachloronor-bomene. which is a shape mimic of the transition state. Because it has less structural similarity to the aromatic product, product inhibition in the lE9-catalyzed reaction is avoided. 

Table 5.10. Calculated EM transition energies (meV (cm-1 in parentheses)) from the Is state to the first np quasi-hydrogenic donor levels of five compounds with the sphalerite structure. Enp is. R ood/n2. For InSb, GaAs, and InP, es at low temperature is taken as 17, 12.4, and 12.2, respectively, and rnn/rne is taken from Table 3.6. Experimental Is — 2p transition energies are given in Table 6.37...

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