Experimental and Theoretical Studies on Tautomerism and Acid-Base Behavior of N-(2-Oxo-2H-chromen-3-yl)acetamide Cemil O ¨ g ˘retir,* ,† Murat Duran, † and Sinem Aydemir ‡ Department of Chemistry and Department of Physics, Faculty of Arts & Sciences, Eskis ¸ehir Osmangazi University, 26480 Eskis ¸ehir, Turkey The structures of all of the chemical species involved in the prototropic tautomerism and acid-base dissociation equilibria of N-(2-oxo-2H-chromen-3-yl)acetamide were determined both experimentally and theoretically. Using the calculated acidity constants, the prototropic equilibrium constants for keto-enol tautomerizm were determined. The enolate and the keto-amino forms were found to be predominant. The gauge including atomic orbital method for calculating 1 H and 13 C NMR nuclear magnetic shielding tensors at both the Hartree-Fock and density functional levels of theory was applied to N-(2-oxo-2H-chromen-3- yl)acetamide. The obtained theoretical data were compared to the experimental data. A satisfactory agreement between the experimental chemical shifts and the theoretical values of shielding constants were obtained. Acceptable correlations were presented between experimental and theoretical results. Introduction The coumarin system is present in a very broad range of natural and non-natural products of biological interest. 1 Cou- marin derivatives are important naturally occurring and synthetic compounds which show several relevant applications. In particular, they exhibit different biological activities, including anticoagulant, spasmolytic, diuretic, anthelmintic, and hypo- glucemic actions. 2-9 In the present study, we focused our attention on N-(2-oxo-2H-chromen-3-yl)acetamide (3-acetami- docoumarin; 3AC) which is a substituted coumarin bearing a relatively volumous substituent at position 3 of the R-pyrone ring. The acidity constant, pK a , of a compound is an important property in both the life sciences and in chemistry. 10 The most important of the parameters are lipohilicity, solubility, perme- ability, and apparent acid dissociaton constants (K a ), because these factors determine the absorption and bioavailability of the molecule. 11-14 The K a value is an important parameter to estimate the extent of ionization of drug molecules at different pH values, which is of fundamental importance in the consid- eration of their interaction with biological membranes and in their synthesis. 15,16 The ability to cross the blood-brain barrier toward the site of action can be characterized by some physicochemical parameters, such as acidity constants, pK a , which can predict the behavior of biologically active compounds in living organisms governing their ionization degree at the physiological pH value. 17 Following our work on drug precursor 2-amino-4-(3 or 4-substituted phenyl)thiazole derivatives, 18 we now report on the acid-base and tautomeric behavior of 3AC (Figure 1). Experimental Section Reagents. The structure of 3AC is depicted in Figure 1. The reagent (98%) was obtained from Sigma-Aldrich and was used without further purification. The other reagents were of analyti- cal grade. Materials and Solutions. The buffer solutions employed were prepared from (a) HCl-KCl, pH 1; (b) KH 2 PO 4 -NaOH, pH 7.0; (c) Borax-HCl, pH 8.0-9.0; (d) Borax-NaOH, pH 9.3-10.7; (e) Na 2 HPO 4 -NaOH, pH 10.9-11.5. 19 The percent- ages of sulfuric acid solution [(1 to 98) % H 2 SO 4 ] were determined by titration with a primary standard substance Na 2 CO 3 using methyl red as an indicator. 20 All of these materials and standard buffer solutions were from Merck and were not further purified. Equipment. The pH values were measured by pH meter (pH/ ion analyzer Orion 720 A+) furnished with a combined glass electrode. It was standardized at 25 °C by using standard buffers and calibrating at three points. To calibrate the pH meter, standard buffer solutions of pH 4.0, 7.0, and 9.0 were used. The UV-vis spectra, were recorded at each pH using a Hitachi 150-20 double beam spectrophotometer controlled by a com- puter and equipped with a 1 cm path length (quartz cells were used). All measurements were carried out at (25 ( 0.1) °C. The theoretical calculations were carried out using the Gaussian 03W program which is implemented in Intel based PCs. * To whom correspondence should be addressed. Tel: +90 222 239 37 50/ 2873. Fax: +90 222 239 35 78. E-mail: cogretir@ogu.edu.tr. † Department of Chemistry. ‡ Department of Physics. Figure 1. Atomic numeration of 3AC. J. Chem. Eng. Data 2010, 55, 5634–5641 5634 10.1021/je100530r  2010 American Chemical Society Published on Web 11/29/2010