Computational chemistry substrates

Today a good understanding of transition state structure can be obtained through a combination of experimental measurements of kinetic isotope effects (KIE) and computational chemistry methods (Schramm, 1998). The basis for the KIE approach is that incorporation of a heavy isotope, at a specific atom in a substrate molecule, will affect the enzymatic reaction rate to an extent that is correlated with the change in bond vibrational environment for that atom, in going from the ground state to the... 

Since the first use of catalyzed hydrogen transfer, speculations about, and studies on, the mechanism(s) involved have been extensively published. Especially in recent years, several investigations have been conducted to elucidate the reaction pathways, and with better analytical methods and computational chemistry the catalytic cycles of many systems have now been clarified. The mechanism of transfer hydrogenations depends on the metal used and on the substrate. Here, attention is focused on the mechanisms of hydrogen transfer reactions with the most frequently used catalysts. Two main mechanisms can be distinguished (i) a direct transfer mechanism by which a hydride is transferred directly from the donor to the acceptor molecule and (ii) an indirect mechanism by which the hydride is transferred from the donor to the acceptor molecule via a metal hydride intermediate (Scheme 20.3). 

Finally, one has to concede that gas-phase calculations are not the ideal way to model a reaction taking place on a catalyst surface. Computational chemistry developments in this area have been continuing but they are a long way from providing completely realistic models. For example, the overall kinetics for dehydrocyclizations are likely to be rate-limited by the binding of the alkane substrate to catalytically active sites. 

Docking a molecule into the active site of an enzyme to see how it fits is an extremely important application of computational chemistry. One manipulates the substrate with a mouse or a kind ofjoystick and tries to fit it (dock it) into the active site (automated... 

Docking by Monte Carlo rninimization with a solvation correction application to an FKBP-substrate complex. Journal of Computational Chemistry, 18, 723—743. 

Verras, A., Kuntz, I.D, Ortiz de MonteUano, P.R. Cytochrome P450 enzymes computational approaches to substrate prediction, in SpeUmeyer, D.C., editor. Annual reports in Computational Chemistry. Amsterdam Elsevier 2006, p. 171-95. Ref. Type Serial (Book, Monograph). 

Three pathways for the ruthenium-catalyzed hydrogenations of ketones, aldehydes, and a,(3-unsaturated aldehydes with several catalyst systems were studied the direct insertion, the migratory insertion, and the concerted hydrogen transfer highlighting the catalyst/substrate configurations that lead to stereoselective differentiation. The contribution of computational chemistry were essential to differentiate these mechanisms of ruthenium-catalyzed reactions and to rationalize the experimentally observed stereochemical outcome. 

As for the computer chemistry of cyclometalation reactions, the reaction with the most representative substrate, A,A-dimethylbenzylamine in a palladium compound, was studied. This reaction proceeds very easily, and its intermediate state, or agostic interaction, is therefore not actually isolated. As shown in Scheme 6.3, however, the activation energy for the agostic interaction is only 13 kcal/mol. It may be pointed out that the acyl group assists the formation of the agostic interaction in the reaction, as exhibited by the agostic intermediate 6.6 shown in Scheme 6.3 [24]. 

Nakayama, T., Kamachi, T., Jitsumori, K., et al., 2012. Substrate specificity of fluoroacetate dehalogenase an insight from crystallographic analysis, fluorescence spectroscopy, and theoretical computations. Chemistry 18 (27), 8392-8402. 

Finally, the proton transfer reactions of multiply-charged anions recently have been reported in mass spectrometric studies. These systems are of great interest, particularly in the analysis of complex substrates such as peptides, and computational chemistry can play an important role in the interpretation of experimental results. Special considerations... 

Penzotti, J.E., Lamb, M.L., Evensen, E. and Grootenhuis, P.D.J. (2002) A computational ensemble pharmacophore model for identifying substrates of P-glycoprotein. Journal of Medicinal Chemistry, 45, 1737—... 

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