Relative energies estimation

The gas-phase tautomeric equilibrium of the selenium analog, 2,4-diselenouracil 171 (X = Se), was studied at the MP2 level of theory with a basis set of DZP quality. The relative energies, estimated at the MP4(SDQ) level, provided the same order of stability, predicted for 2,4-dithiouracil by the ab initio methods. The di(hydroselenyl) tautomer 171b (X = Se) was found to be less stable than diselenone tautomer 171a by 8.1 kcal/mol (96JST(388)237). 

To obtain a satisfactory evaluation of relative energies, especially for the computation of activation barriers, higher levels of theory than those needed to obtain the underlying geometries are usually required. MP2 is the most economical and popular method of incorporation electron correlation. For a more accurate theoretical estimate, higher-level of correlation treatment such as QCISD(T) or CCSD(T) theory is desirable. 

Fig. 6.12. Block averaging of an FEB or NEW calculation can be used to create a smoothed running profile. This contrasts with the jagged steps of a running average based on the same data. The running steps occur with the relatively rare sampling of events in the tails of the distribution that dominate the relative free energy estimate. The smoothed running curve uses the block procedure described in the text...

Since the linear and related expansion formulas depend on fits to regions of the curve that are statistically less and less reliable, it makes sense to find a measure for extrapolation that depends on the relative accuracy of the relative free energy estimate for all points along the curve. The cumulative integral extrapolation method is one approach to this idea. 

In halogenated solvents the results indicate that return can occur, even for the uncongested stilbenes. Unfortunately, its importance, as measured by the k i/kN ratio (Fig. 10), cannot be estimated. It must be noted that Bellucci s experiments prove only that return is possible, but do not demonstrate conclusively that it occurs in bromination, since reversibility is controlled by the relative energy levels of TS and TSN which can be affected by the reaction conditions. Now, these conditions are not the same for nucleophilic substitution on bromohydrins and for bromine addition in particular, the counter-ions, Br and Br3 respectively, can alter the lifetime of the intermediate and thus control its partitioning between return and nucleophilic attack. 

Figure 1. CADD Flowchart. "E I = enzyme-inhibitor complex. Ascan binding interactions using strategy described in reference 16. T and I are structurally similar, relative energies or estimated relative free energies.

The hybridization parameter X can be estimated at each R by expressions such as (3.1 lb), which in turn are related to visual plots of the s-pz overlap. A procedure for numerically estimating X will be given at the end of this section. For present purposes, we need only recognize from the percentage s characters that the relative energies of the starting atomic hybrids satisfy... 

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