Energy profiles tetrahedral intermediates

The energy profile for this equilibrium can be studied from either left or right. It is easiest to imagine the tetrahedral intermediate going to the left or to the right depending on the acidity of the solution. 

EPSP synthase catalyzes the synthesis of EPSP by an addition-elimination reaction through the tetrahedral intermediate shown in Fig. 2a. This enzyme is on the shikimate pathway for synthesis of aromatic amino acids and is the target for the important herbicide, glyphosate, which is the active ingredient in Roundup (The Scotts Company EEC, Marysville, OH). Transient-state kinetic studies led to proof of this reaction mechanism by the observation and isolation of the tetrahedral intermediate. Moreover, quantification of the rates of formation and decay of the tetrahedral intermediate established that it was tmly an intermediate species on the pathway between the substrates (S3P and PEP) and products (EPSP and Pi) of the reaction. The chemistry of this reaction is interesting in that the enzyme must first catalyze the formation of the intermediate and then catalyze its breakdown, apparently with different requirements for catalysis. Quantification of the rates of each step of this reaction in the forward and reverse directions has afforded a complete description of the free-energy profile for the reaction and allows... 

When k lk is larger than unity, the rate-determining step is the breakdown of the tetrahedral intermediate and the corresponding kinetic expression is k k jk. It is only in this case that an accumulation of tetrahedral intermediates would be expected to be observed experimentally. The breakdown of the tetrahedral intermediate is rate-determining in alkaline amide hydrolysis however, no reports of the detection of an addition intermediate during hydrolysis have yet appeared in the literature for this or any other system. Figure 8 illustrates the energy-reaction co-ordinate profile for various values of k jk. ... 

The next reaction to be studied in a similar manner was the addition of hydroxide ion to formaldehyde. Ab initio 6-31 -I- G(d) calculations provided the gas-phase energy profile and solute-water potential functions. Conversion of the reactants to the tetrahedral intermediate 3 was computed to be exothermic by 35 kcal/mol. 

The MERP in Cj symmetry has the hydroxide ion coplanar with formaldehyde and on the dipole axis at large separations. A shallow minimum was found at a C-0 separation of 2.75 A (4). This ion-molecule complex is separated from 3 by only a 1.1-kcal/mol barrier, as shown by the solid curve in the bottom half of Fig. 3. Thus the existence of the minimum is uncertain at higher levels of theory. Earlier ab initio studies for addition reactions including hydride ion and OH with formaldehyde and OH with formamide have found the tetrahedral intermediate as the only minimum. However, comparatively small basis sets were used, which exaggerates the overall exothermicity. The viability of the ion-molecule intermediates is anticipated to be enhanced by an increased dipole moment, as we found recently for halide ions with acyl halides. The results are consistent with the ideas of Asubiojo and Brauman, though we find both double-well and triple-well energy profiles in the gas phase. 

Fig. 5.5 Energy profile for epimerization at an acyclic stereogenic centre, showing the transition from a tetrahedrally bonded C atom to a trigonal planar geometry in the intermediate (Eact = activation energy).

Both the acid chloride and alkoxide must therefore be involved in the rate-determining step, which, as you know from Chapter 10, must be the formation of the tetrahedral intermediate. This intermediate is less stable than the starting materials, so the reaction energy profile takes the form shown below, with the highest transition state corresponding to the addition step. 

Numerous kinetic studies have confirmed that this mechanism, with a tetrahedral intermediate, is the normal pathway by which substitution reactions at carbonyl groups take place, as we explained in Chapter 10. You could draw a similar pathway, and a similar energy profile, for all of the reactions shown on p. 215, adjusting the energies of the starting materials, products, and intermediates appropriately, but all of them are second order, with rate-limiting attack on the carbonyl group. 

The tetrahedral intermediate XXVII is, as a rule, more favored thermodynamically than the starting reactants. Most of the calculations made so far support this claim as well as the conclusions drawn in Refs. [91, 92] as to the formation of XXVII in the ion-molecular reaction of Eq. (5.10) without a barrier. The energy profile depicted in Fig. 5.4a is compatible with this character of the reaction. Table 5.4 presents some ab initio and semiempirical calculation data on the energetics of gas-phase reactions of the type of Eq. (5.10). 

Figure 21.2 shows energy profiles for reactions of a nucleophile with an amide and with an acid chloride. The relative energies of transition states and tetrahedral intermediates for the two reactions are about the same because neither intermediate is resonance stabilized. However, because the amide reactant is resonance stabihzed and the acid chloride is not, the reaction of the acid chloride is faster because it is the less stable reactant. 

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