Computational studies tautomerization

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]. 

Magnesium bis(hexamethyldisilazide), Mg(HMDS)2, catalyses the enolization of ketones.287 On addition to propiophenone in toluene at ambient temperature, a ca 3 1 E Z mixture of enolates (103, R=SiMe3) is formed. These enolates, and an initial ketone complex, have been characterized by NMR, X-ray, IR, and UV-visible spectroscopy and computational studies. Kinetics of tautomerization have been measured, with proton transfer confirmed as rate determining ( hAd = 18.9 at 295 K). The significant temperature dependence of the primary isotope effect is indicative of tunnelling. 

The tautomerism between 2-pyridinethione and 2-pyridine thiol has also been examined using variable temperature IR spectroscopy <2002JOC9061>. No evidence for the S-H stretch was observed in a range of solvents and this was determined computationally to be a solvent effect the thiol form is more stable in the gas phase but the thione is more stable in solution. (The effect of phase on the tautomers of 2-hydroxy, 2-amino-, and 2-thiopyridine has also been studied by infrared spectroscopy <2001SAA2659>.) Dimerization is also observed, with the indication that the thione dimer predominates, in contrast with the computational studies described above. 

Pyridinethiol is in equilibrium with 2-pyridinethione and it is been previously thought that the thiol is more stable in nonpolar solvents while the thione is more stable in polar solvents. Recent variable temperature Fourier transform IR experiments and computational studies calculated at the B3LYP/6-311 level of theory indicate that the thione is more thermodynamically stable than the thiol in nonpolar solvents and that tautomerism occurs via the dimer <2002JOC9061> (Equation 82). 

Studies on the tautomerism of heterocycles, including pyrans and derivatives, have been extensively reviewed <2006AHC(91)1>. Computational studies have been used to examine a number of 3-hydroxy-4-pyranones such as maltol 68, ethyl maltol 69, and pyromeconic acid 70, and it has been determined that the 3-hydroxy-4-oxo tautomer is the most stable <2003JMT(639)87>. 

Tautomerism between 4-hydroxycoumarins and 2-hydroxychromones has been investigated extensively by deuterium labeling, 13C NMR, and infrared (IR) spectroscopy <1982JHC385, 1982JHC475>. Computational studies now support the idea that 4-hydroxycoumarins are more stable than 2-hydroxy chromones <1997CJC377>. 

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. 

Another way to study tautomerism is through p/iTa measurements. A comparison of the basic pATa values for 4(5)-nitroimidazole with those of l-methyI-4- (29) and l-methyl-5-nitroimidazole (30) leads one to the conclusion that the 4-nitro tautomer (28) predominates (Scheme 13) in fact the 4-nitro 5-nitro ratio has been computed as about 400 1. In this experiment the methylated compounds serve as fixed models in which the nitro substituent is fixed in each of the two possible orientations. The influence of the methyl group can be shown to be small by comparison of the pATa values for imidazole ( 7.0) and 1-methyl-imidazole ( 7.1), and hence l-methyl-4-nitroimidazoIe resembles the major tautomer. 

Gilli, P., Bertolasi, V., Pretto, L., Antonov, L., and Gilli, G., Variable-temperature X-ray crystallographic and DFT computational study of the N-H- -O/N- H-O tautomeric competition in l-(arylazo)-2-naphthols. Outline of a transition-state hydrogen bond theory, J. Am. Chem. Soc., Ill, 4943-4953 (2005). 

Shchavlev, A.E., Pankratov, A.N., and Shalabay, A.V., DFT computational studies on rotation barriers, tautomerism, intramolecular hydrogen bond and solvent effects in 8-hydroxyquinoline, Int. J. Quantum Chem., 106, 876-886 (2006). 

Unfortunately, the computational studies differ in quantitative detail regarding the importance of the mechanisms that involve either Glu 165 or His 95 as the acid-base catalysts to catalyze interconversion of the tautomeric enediolate intermediates. Friesner and coworkers concluded that the transition state for proton abstraction from DHAP is the highest point on the energy diagram after formation of the enediolate anion intermediate, the calculations predict that the barrier for the criss-cross mechanism catalyzed by Glu 165 is - 3 kcal moU lower than that for classical mechanism involving catalysis of tautomerization of the enediolate intermediates by His 95, so the criss-cross mechanism is predicted to be the favored mechanism. In contrast, Cui and Karplus concluded that transition state energies for tautomerization of the enediolate anion intermediates via an enediol intermediate are isoenergetic for both the classical and criss-cross mechanisms. 

DHFR catalyzes the reduction of 7,8-dihydrofolate (H2F) to 5,6,7,8-tetrahydrofolate (H4F) using nicotinamide adenine dinucleotide phosphate (NADPH) as a cofactor (Fig. 17.1). Specifically, the pro-R hydride of NADPH is transferred stereospecifi-cally to the C6 of the pterin nucleus with concurrent protonation at the N5 position [1]. Structural studies of DHFR bound with substrates or substrate analogs have revealed the location and orientation of H2F, NADPH and the mechanistically important side chains [2]. Proper alignment of H2F and NADPH is crucial in enhancing the rate of the chemical step (hydride transfer). Ab initio, mixed quantum mechanical/molecular mechanical (QM/MM), and molecular dynamics computational studies have modeled the hydride transfer process and have deduced optimal geometries for the reaction [3-6]. The optimal C-C distance between the C4 of NADPH and C6 of H2F was calculated to be 2.7A [5, 6], which is significantly smaller than the initial distance of 3.34 A inferred from X-ray crystallography [2]. One proposed chemical mechanism involves a keto-enol tautomerization (Fig. 

Thiotropocin and TDA exhibit great structural similarity. Recent computational studies showed that both structures represent a pair of tautomers of similar energy that interconvert easily via a 1,5-hydrogen shift (Figure 4.55). Therefore, the structures 109 and 110 must be regarded as two tautomeric forms of the same compound [268]. 

A computational study unravelled two key factors that account for the efficiency of the gold(I)-catalysed hydroamination of alkynes with ammonia, using MeC=CMe as the model system (i) the excess nucleophile, NH3, which assists the proton transfer, and (ii) an unexpected [Au] migration, which allows a feasible enamine-imine tautomerization. ... 

In spite of the higher stability of imidazole-2-ylidenes and their metal complexes, tautomerization of imidazoles to the corresponding NHCs are also scarce processes. The relative stability of imidazole N- or C-metal bound isomers was computationally studied by Crabtree and Einsentein, who found a strong dependence on the nature of the metal fragment. Sundberg et al. published in 1974 the first example of N- to C-tautomerization of an imidazole ligand mediated by a Ru(II) complex (Scheme 29), but an acidic media was needed and very low yields were obtained. 

---