Tautomerization, computational

Free energy perturbation (FEP) theory is now widely used as a tool in computational chemistry and biochemistry [91]. It has been applied to detennine differences in the free energies of solvation of two solutes, free energy differences in confonnational or tautomeric fonns of the same solute by mutating one molecule or fonn into the other. Figure A2.3.20 illustrates this for the mutation of CFt OFl CFt CFt [92]. 

As was pointed out earlier (76AHCS1, p. 217), tautomeric equilibria for substituted isoindole-isoindolenine systems depend critically upon the substituents. Isoindole exists in the o-quinoid form 6. Computational results for the parent systems are given in Table III (99UP1). The results indicate that within the B3LYP functional only large basis sets provide reliable energy differences. 

Hydroxythiophenes 56 have two possible keto tautomers (57 and 58) [for review see (86HC1)]. As has been pointed out earlier (76AHCS1, p. 229), the tautomerism of 5-substituted eompounds was extensively studied by Lawesson and eoworkers (63T1867) and by Hornfeldt (63MI1 68MI1). For 5-alkyl eompounds, only the keto forms were present, whereas with R = phenyl, thienyl and ethoxyearbonyl substantial amounts of the enol forms were deteeted. Computations for the parent system (R = H) showed that the 4 -thiobutenolide of type 57 is most stable (Table VII). 

Many computational studies in heterocyclic chemistry deal with proton transfer reactions between different tautomeric structures. Activation energies of these reactions obtained from quantum chemical calculations need further corrections, since tunneling effects may lower the effective barriers considerably. These effects can either be estimated by simple models or computed more precisely via the determination of the transmission coefficients within the framework of variational transition state calculations [92CPC235, 93JA2408]. 

As is common in heterocyclic chemistry, many studies concern tautomeric equilibria. While quantum chemical calculations are straightforward for the question of the most stable isomer, experiments are sometimes very demanding. Therefore, quantum chemistry can easily provide answers that may require substantial experimental effort. Comparatively few studies concern the investigation of entire reaction paths. This is much more demanding than computing a limited number of tautomers, of course, but usually provides a very detailed picture of the reaction mechanism. In certain cases, it was only possible to judge the nature of a chemical reaction on the basis of quantum chemical calculations. 

The form and shape of a molecule (i.e. its steric and geometric features) derive directly from the molecular genotype , but they cannot be observed without a probe. Furthermore, they vary with the conformational, ionization and tautomeric state of the compound. Thus, the computed molecular volume can vary by around 10% as a function of conformation. The same is true of the molecular surface area, whereas the key (i.e. pharmacophoric) intramolecular distances can vary much more. 

Despite the importance of the oxidative polymerization of 5,6-dihydroxyin-dole, in the biosynthesis of pigments, little experimental data are known on the oxidation chemistry of the oligomers of 1. For such reasons, three major dimers of 1, such as 2-4 (Scheme 2.9), have been computationally investigated at PBEO/ 6-31+G(d,p) level of theory both in gas and in aqueous solution (by PCM solvation model) to clarify the quinone methide/o-quinone tautomeric distribution. 

The tautomeric product distribution has been a prerequisite for a further investigation aimed at predicting absorption properties of the transient semiquinones and quinones generated by pulse radiolytic oxidation of 2-4. The simulation of electronic absorption spectra has been computed using the TD-DFTapproach both in vacuum and in aqueous solution, using the large 6-311 + +G(2d,2p) basis set.19... 

Mentus S, Maroncelli M (1998) Solvation and the excited-state tautomerization of 7-azaindole and 1-azacarbazole computer simulations in water and alcohol solvents. J Phys Chem A 102 3860-3876... 

The tautomerism of furoxan (l,2,5-oxadiazole-2-oxide) has been investigated by different computational methods comprising modern density functions as well as single-reference and multi-reference ab initio methods. The ring-opening process to 1,2-dinitrosoethylene is the most critical step of the reaction and cannot be treated reliably by low-level computations (Scheme 2). The existence of cis-cis-trans- 1,2-dinitrosoethylene as a stable intermediate is advocated by perturbational methods, but high-level coupled-cluster calculations identify this as an artifact <2001JA7326>. 

Whilst this Chapter is primarily concerned with the methods of determining the free energies of tautomeric or ionisation equilibria via computer simulation of free energy differences, many of the issues raised relate also to the determination of other molecular properties upon which behaviour of the molecule within the body may depend, such as the redox potential or the partition coefficient.6 In the next section, we shall give a brief explanation of the methods used to calculate these free energy differences -namely the use of a thermodynamic cycle in conjunction with ab initio and free energy perturbation (FEP) methods. This enables an explicit representation of the solvent environment to be used. In depth descriptions of the various simulation protocols, or the accuracy limiting factors of the simulations and methods of validation, have not been included. These are... 

The present chapter thus provides an overview of the current status of continuum models of solvation. We review available continuum models and computational techniques implementing such models for both electrostatic and non-electrostatic components of the free energy of solvation. We then consider a number of case studies, with particular focus on the prediction of heterocyclic tautomeric equilibria. In the discussion of the latter we center attention on the subtleties of actual chemical systems and some of the dangers of applying continuum models uncritically. We hope the reader will emerge with a balanced appreciation of the power and limitations of these methods. 

Kleinpeter et al. carried out ab initio and semi-empirical (PM3) calculation in order to rationalize the tautomeric equilibria of 7-hydroxy-5-methyl[l,2,4]triazolo[l,5- ]pyrimidine <1995JST(335)273, 1997JST(435)65>. This compound can exist in four tautomeric forms a-d (Figure 1). The authors concluded that the high computational level available can sufficiently reproduce the position of tautomeric equilibria in solution and, thus, can serve as a useful tool instead of time-consuming experimental studies. 

Selected computed structural data on the three tautomeric forms of protonated NNtM, DNNtM and NDNtM are depicted in Figure 33. Only the most stable oxime isomers are presented. As long as only two functional groups are attached to the central methanide carbon, the entire molecule remains planar due to resonance stabilization, whereas introduction of a third group, either NO or NO2, results in rotation of at least one group, preferably the nitro group. Flowever, the CN3 moiety in the nonplanar species remains... 

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