Tautomerization, computational methods

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>. 

The coordination behavior as well as the tautomerization equilibria of the new pyridone ligands was studied in detail by NMR and computational methods. For all three the data obtained strongly support a pseudo-bidentate hydroxypyridine-pyridone binding mode. 

The use of computational methods in structural chemistry has changed focus in recent years, with less emphasis on the determination of absolute structure and greater emphasis on the application of these methods to explain topics such as conformation, tautomerism, and the source of any preferences for given forms. This change dominates the section below though the computations of some simple structures have been carried out. 

Tautomerism in the benzopyranone 72 has been studied computationally, and tautomer 72 is calculated to be 1.4kcalmol 1 more stable than 73 <1994JCS(P2)2587>. 3-Acetyl-4-hydroxycoumarin has been studied using UV spectroscopy and by computational methods < 1997CJC365, 2000JR0793>. Tautomer 74 is favored in nonpolar solvents such as CCI4 or hexane. In polar solvents, 75 is favored. Computational studies at both semi-empirical and ab initio levels predict 74 and 75 to be of comparable stability, and significantly more stable than all other possible tautomers. 

Quantum-mechanical studies on the tautomerism of heterocyclic compounds involve, in general, two aspects. The first deals with the prediction of physicochemical properties of defined tautomeric forms (e.g., ultraviolet spectra, dipole moments, ionization potentials, etc.). This seems to be easy to handle. Using any semiempirical or nonempirical quantum-mechanical computational method, depending on approximations involved in the method, we are able to calculate properties that, more or less, agree with experimental values. Calculations of this type do not contribute to a direct estimation of the relative stability of the tautomers, however they are particularly important for cases in which a tautomeric form of a compound is so rare that it is not possible to measure it directly. 

The absolute configurations of daphmalenines A (20) and B (21) were determined on X-ray diffraction by using the Flack parameter and computational methods, respectively. Daphnioldhamine A (22) is the first Daphniphyllum alkaloid with transannular effect and is easily tautomerized imder acidic or alkaline conditions (Figure 5). 

The amination of ketenes to produce amides (see Scheme 1) has been subjected to a variety of computational methods, including several treatments of the solvent, with explicit roles for actively participating amine and water molecules. All the results favour a two-step process with initial addition to the C=0 bond, rather than a concerted reaction involving the C=C bond. The former involves a 1-amino-1-hydroxy ene intermediate (6), formally the enol of the amide. Inclusion of a second amine molecule lowers the barrier to the two-step reaction. Replacing the second amine with a water molecule lowers it even further, an effect which should be even greater when water is the bulk solvent. Some experimental evidence is presented for the highly hindered substrates, bis(mesityl)ketene and bis(pentamethylphenyl)ketene. Addition of primary or secondary amines clearly shows, from IR and UV spectra, the build-up and subsequent tautomerization of the intermediate enols. The kinetics of these more hindered substrates are first order in amine this is not inconsistent with the theoretical results, as such hindered ketenes may only react rather slowly with amine dimer, which is also in low concentration under the conditions used. 

About a decade ago, in a review concerning computational methods in heterocyclic chemistry, including tautomerism, several recommendations concerning the... 

Tautomerism of sulfonamides proved an important issue in the development of computational methods for prediction of crystal structures. Molecule VI, 6-amino-2-(pheylsulfonylimino)-l,2-dihydropyiridine (R = phenyl on Scheme... 

It follows that there may be several elementary steps that constitute a tautomerization. But on the other hand, tautomerizations are coupled to a number of other phenomena, in particular hydrogen bond switches, molecular motions, and solvent reorganization. Even tautomerizations may constitute one of many elementary steps of complex molecular reactions, in particular of enzyme reactions. By using combinations of various spectroscopic and computational methods it will be interesting to extend the research area of tautomerism to more and more complex systems. 

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. 

Table VI collects the theoretical quantities appropriate to the description of the tautomeric stability of cytosine, computed by methods including both -n- and cr-electrons. We have added to it the results of a 77-SCF MO approach (including cr-polarization effects) on heats of atomization of different tautomeric forms of cytosine. Bodor et al.liB have related the heat of atomization to the stability of the tautomers, and found that the most stable structure of the molecule is the amine-lactam 2 having the greatest heat of atomization (59.707 eV). They predict on this basis the following order of stability 2 > 3 > 6 > 1.

Quantum-chemical (Gaussian 98W package) calculations have been used, together with spectroscopic (13C, Tl NMR) methods, to investigate the structures and stabilities of the potentially tautomeric 2-phenyl and 3-phenyl benzoxazepinones and their thiolactam analogues. Experimental and computational data indicate the predominance of (thio)lactams 9 in the gas phase and in solution over the imino tautomers 10 (Equation 1) <2004JMT(668)157>. 

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