Ground-state destabilization

FIGURE 6.3. The strain hypothesis for the catalytic reaction of lysozyme. The enzyme is assumed to destabilize the chair geometry by pushing the ground state substrate toward the sofa configuration. This ground-state destabilization effect is supposed to reduce Ag M. 

Some quinone methides with two MeS groups or one MeS and one Me2N group as donors (47b, 48 to 50) show quite low barriers (49). In the naphthoquinone methides a ground state destabilizing peri effect must be at work, but... 

Is there any ground-state destabilization of the substrate by bond-angle strain or binding in a high-energy conformation ... 

For electrophiles such as Me3SiCH2X strong ground-state destabilization has been observed for X = 4-nitrobenzoate[130]. For X= halide, on the other hand, this ground-state destabilization is significantly smaller, and it may therefore be advisable to choose carboxylates or sulfonates as leaving groups when alkylations with a-silyl-substituted electrophiles are to be performed. 

Table 2 summarizes the racemization barriers in unsubstituted chiral alkenes 23 with different bridging moieties in their upper and lower halves. As is evident from these data, the tetrahydrophenanthrene-type upper part is large enough to prevent fast racemization by movement of the aromatic moieties of upper and lower halves through the mean plane of the molecule. On the other hand, there is enough conformational flexibility in the molecules to prevent excessive distortion of the central olefmic bond (leading to ground state destabilization), which would lower the racemization barrier. 

Theoretical studies on 12 4-substituted phenyl acetates concluded that, in contrast to the proposed interpretation based on 13C NMR chemical shifts and ground-state destabilization calculations, the electrophilicity of the C=0 group increases due to the effect promoted by the electron-withdrawing groups in these systems.11 A DFT investigation of the alkaline hydrolysis of 4-nitrophenyl acetate has shown that a model including seven water molecules proceeds via a concerted transition state.12... 

Stepwise decarboxylation and C6-protonation via ground state destabilization 204... 

STEPWISE DECARBOXYLATION AND C6-PROTONATION VIA GROUND STATE DESTABILIZATION ... 

This proposal of a ground state destabilization mechanism for ODCase (this type of mechanism was referred to earlier by Fersht as electrostatic stress 81 and by Jencks as the Circe effect ) sparked considerable controversy. In some circles it was seen as a prime example of the catalytic power of ground state destabilization,83 but several groups immediately questioned its validity on the basis of theoretical objections and apparent inconsistencies with biochemical experiments.23 26... 

The enzyme mechanism, however, remains elusive. Quantum mechanical models generally disfavor C6-protonation, but 02, 04, and C5-protonation mechanisms remain possibilities. Free energy computations also appear to indicate that C5-protonation is a feasible mechanism, as is direct decarboxylation without preprotonation O-protonation mechanisms have yet to be explored with these methods. Controversy remains, however, as to the roles of ground state destabilization, transition state stabilization, and dynamic effects. Because free energy models do take into account the entire enzyme active site, a comprehensive study of the relative energetics of pre-protonation and concerted protonation-decarboxylation at 02, 04, and C5 should be undertaken with such methods. In addition, quantum mechanical isotope effects are also likely to figure prominently in the ultimate identification of the operative ODCase mechanism. 

Carbenes and carbynes can exert both a strong trans influence and trans effect. A trans influence is a ground-state destabilization (thermodynamic) of the trans M-L bond. The trans effect is a kinetic phenomenon wherein the lability of the trans ligand is increased either by ground-state destabilization or transition-state stabilization. 

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