Stabilization of the transition state

The suitability of the model reaction chosen by Brown has been criticised. There are many side-chain reactions in which, during reaction, electron deficiencies arise at the site of reaction. The values of the substituent constants obtainable from these reactions would not agree with the values chosen for cr+. At worst, if the solvolysis of substituted benzyl chlorides in 50% aq. acetone had been chosen as the model reaction, crJ-Me would have been —0-82 instead of the adopted value of —0-28. It is difficult to see how the choice of reaction was defended, save by pointing out that the variation in the values of the substituent constants, derivable from different reactions, were not systematically related to the values of the reaction constants such a relationship would have been expected if the importance of the stabilization of the transition-state by direct resonance increased with increasing values of the reaction constant. 

Model building shows that the OH group of Thr in the mutant is too far away to provide such a hydrogen bond. The loss of this feature of the stabilization of the transition state thus reduces the rate by more than a thousandfold. 

Tesmer, J.J.G., et al. Structure of RGS4 bound to AIF4—activated Giai Stabilization of the transition state for GTP hydrolysis. Cell 89 251-261, 1997. 

The soft-nucleophile-soft-electrophile combination is also associated with a late transition state, in which the strength of the newly forming bond contributes significantly to the stability of the transition state. The hard-nucleophile-hffld-elechophile combination inqilies an early transition state with electrostatic attraction being more important than bond formation. The reaction pathway is chosen early on the reaction coordinate and primarily on the basis of charge distributiotL... 

Conjugated substituents at C-2, C-3, C-4, or C-5 accelerate the rearrangement. Donor substituents at C-2 and C-3 have an accelerating effect. The effect of substituents can be rationalized in terms of the stabilization of the transition state by depicting their effect on two interacting allyl systems. 

Markovnikov s rule can be restated by saying that, in the addition of HX to an aikene, the more stable carbocation intermediate is formed. This result is explained by the Hammond postulate, which says that the transition state of an exergonic reaction step structurally resembles the reactant, whereas the transition state of an endergonic reaction step structurally resembles the product. Since an aikene protonation step is endergonic, the stability of the more highly substituted carbocation is reflected in the stability of the transition state leading to its formation. 

Model calculations generally support Felkin s hypothesis35-38. However, an additional controlling factor is the stabilization of the transition state by the approach of the nucleophile antiperiplanar to a vicinal bond35. In the transition state for axial attack (Figure 8), the incipient bond is approximately antiperiplanar to two axial C — H bonds. Flattening of the ring improves this antiperiplanarity and, therefore, the more flattened the cyclic ketone, the more axial attack is preferred. 

As discussed and demonstrated in the previous chapters, the catalytic effect of several classes of enzymes can be attributed to electrostatic stabilization of the transition state by the surrounding active site. Apparently, enzymes can create microenvironments which complement by their electrostatic potential the changes in charges during the corresponding reactions. This provides a simple and effective way of reducing the activation energies in enzymatic reactions. 

Mataka and coworkers reported the studies of the Diels-Alder reactions of [3.3] orthoanthracenophanes 96 and 97, of which anthraceno unit, the potential diene, has two nonequivalent faces, inside and outside. The reactions of 96 with dien-ophiles gave the mixtures of inside and outside adducts with the ratios between 1 1 and 1 1.5. However, the ratio changes drastically, in favor of the inside adducts, when 97 reacts with dienophiles such as maleic anhydride, maleimide and naphto-quinone [55] (Scheme 46). Mataka suggested that the Jt-facial selectivity is controlled by an orbital interaction between the electron-poor dienophiles and the Jt-orbital of the facing aromatics, which would lead to a stabilization of the transition state, while Nishio suggested that the selectivity is due to the attractive k/k or CH/jt interaction [53]. 

The cyclic orbital interaction of p and q with o or with o can significantly occur at the transition state of the ring closure of 1,3-diradicals. The continuous orbital phase for the cyclic orbital interaction with o implies effective stabilization of the transition states when the o bonds are electron acceptors. 

In the brosylate acetolysis sets, conjugative stabilization of the transition state is geometrically excluded in the syn form, but is anticipated in the anti form (13). That is, on structural grounds, is expected to be the parameter of choice for the syn set and for the anti set. The available data (for the OMe, Me, Cl and NO2 substituents) do indeed conform to this expectation ... 

The effect of water molecules on pericyclic reactions can also be compared with the effects of Lewis acids on these reactions. The enhanced polarization of the transition state in these reactions would lead to stronger hydrogen bonds at the polar groups of the reactants, which will result in a substantial stabilization of the transition states in the same way Lewis acids do. A computer-simulation study on the Diels-Alder reaction of cyclopentadiene by Jorgensen indicated that this effect contributes about a factor of 10 to the rates.7... 

Hydrolyses of p-nitrophenyl and 2,4-dinitrophenyl sulfate are accelerated fourfold and eightfold, respectively, by cycloheptaamylose at pH 9.98 and 50.3° (Congdon and Bender, 1972). These accelerations have been attributed to stabilization of the transition state by delocalization of charge in the activated complex and have been interpreted as evidence for the induction of strain into the substrates upon inclusion within the cycloheptaamylose cavity. Alternatively, accelerated rates of hydrolysis of aryl sulfates may be derived from a microsolvent effect. A comparison of the effect of cycloheptaamylose with the effect of mixed 2-propanol-water solvents may be of considerable value in distinguishing between these possibilities. 

As a result of the small, but apparent single bond character of the triafulvene C3/C4 bond and the good stabilization of the transition state of the rotation established earlier, rotation around this bond should be lower in energy in comparison to simple ethylene derivatives183. In fact, 1H-NMR spectra of several types of asymmetrically substituted triafulvenes 219-224 proved to be temperature-dependent and showed reversible coalescence phenomena at definite temperatures diagnostic for internal rotation processes. These were characterized by the free enthalpy of activation AG at the coalescence point of appropriate substituent signals61. ... 

If stabilization of the transition state (TS) is more effective than that of the ground state (GS), this results in enhancement of reactivity as a result of a decrease in the activation energy (Fig. 3.5), because of electrostatic (dipole-dipole type) interactions of polar molecules with the electric field. 

In summary, there now exists a body of data for the reactions of carbocations where the values of kjkp span a range of > 106-fold (Table 1). This requires that variations in the substituents at a cationic center result in a >8 kcal mol-1 differential stabilization of the transition states for nucleophile addition and proton transfer which have not yet been fully rationalized. We discuss in this review the explanations for the large changes in the rate constant ratio for partitioning of carbocations between reaction with Bronsted and Lewis bases that sometimes result from apparently small changes in carbocation structure. 

Fig. 6 Hypothetical free energy reaction coordinate profiles for the interconversion of X-[8]-OH and X-[9] (R = H) and X-[10]-OH and X-[ll] (R = CH3) through the corresponding carbocations. The arrows indicate the proposed eifects of the addition of a pair of ortAo-methyl groups to X-[8]-OH, X-[8+] and X-[9] to give X-[10]-OH, X-[10+] and X-[ll]. A Effect of a pair of or/Ao-methyl groups on the stability of cumyl alcohols. B Effect of a pair of or/Ao-methyl groups on the stability of cumyl carbocations. C Effect of a pair of ortho-methyl groups on the stability of the transition state for nucleophilic addition of water to cumyl carbocations. D Effect of a pair of orf/io-methyl groups on the stability of the transition state for deprotonation of cumyl carbocations.

Substituent effect on the stability of the transition state for solvent addition (C, Figure 6). The difference in the values of ks = 1.4 x 107s 1 for the addition of a solvent of 50/50 (v/v) trifluoroethanol/water to Me-[10+] and ks = 1.0 x 109 s-1 for addition of the same solvent to Me-[8+] (Table 1) reflects the balance between (1) the destabilization of X-[10+] resulting from rotation about the —Ca bond, which results in a less stable carbocation and hence an... 

Substituent effect on the stability of the transition state for deprotonation (D, Figure 6). The addition of two ortho-methyl groups to Me-[8+] to give Me-[10+] results in an increase in kp for proton transfer to solvent from 1.4 x 106 s 1 to 8.3 x 107 s 1 (Table 1). There should be relatively little steric hindrance to the reaction of solvent with the /1-hydrogens of Me-[10+] because these are relatively distant from the ortho-methyl groups. However, the twisting about the CAr-Ca bond that minimizes steric interactions between the methyl... 

Similar results were obtained for analogous complexes of the de-( er -butyl)ated macrocycle (L24)2-. The ter7-butyl substituents do not affect the regiochemistry of this particular Diels-Alder reaction, but they clearly increase its rate. The observed trend is indicative of a small stabilization of the transition-state by hydrophobic effects (AAG 3 kJ/mol k coinpiex/k l) lckgr(nin(i = expiAAG /RT)). This would be consistent with our earlier observation that complexes bearing less polar carboxylate anions have the higher stability constants (see Section III.E). 

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