KINETICS OF THE CYCLIZATION OF PHENACYL ANTHRANILATE UNDER VARIOUS CONDITIONS

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1 ACTA UNIERSITATIS PALACKIANAE LMUCENSIS FACULTAS RERUM NATURALIUM 999 CHEMICA 38 KINETICS F THE CYCLIZATIN F PHENACYL ANTHRANILATE UNDER ARIUS CNDITINS Hradil Pavel. a, Hlaváč Jan. b, Krejčí Petr. b, Lemr Karel. c a b c Farmak a.s., Na lčinci 3, 77 7 lomouc, Czech Republic Department of rganic Chemistry, Palacký University, lomouc; Czech Republic Department of Analytic Chemistry, Palacký University, lomouc; Czech Republic Abstract Kinetics of the cyclization of substituted phenacyl anthranilates by spectro-photomethric method were measured. Phosphoric acid at 00 C and boiling N-methylpyrrolidone were used as a solvent. The rate constants were calculated. Key Words: Kinetic, phenacyl anthranilate, 3-hydroxy--phenylquinolin-4(H)-one The preparation of 3-hydroxy--arylquinolin-4(H)-ones () by the cyclization of substituted phenacyl anthranilates () was described in our previous works, (Scheme ). The kinetics of the reaction has not been studied yet. DEF D E F DEF D E F 6FKHPH 7

2 We suppose that the reaction starts by nucleophilic attack on the carbonyl group and unstable intermediate 3 is formed. This seven-membered ring is then transformed in to six membered one. The possible course to be drawn is illustrated (Scheme ). d - d 6FKHPH Kinetics of the reaction has been studied in two different solvents in phosphoric acid 8% at 00 C and in N-methylpyrrolidone under the reflux of the reaction mixture. The reaction rate of the cyclization of the derivative b in phosphoric acid is lower than in the case of anthranilate (a). This result did not comply with our expectation. We supposed that the amino group at the phenacyl part of the molecule was protonized and the partial positive charge on the carbon atom of the carbonyl group was enlarged by mesomeric effect and as a result of the reaction the rate would be higher. We obtained a different result in contradiction to expectation also for the cyclization of the compound c. This reaction rate was the lowest one. Reaction rates of the cyclization increased for all compounds in N-methylpyrrolidone. The rate was approximately five times faster for the derivatives a and b as well and fourteen times for the compound c. The cyclization of anthranilate a was 8

3 the most rapid. The rate constant for the cyclization of the nitro derivative c is higher than the one for the compound b. We interpret these unexpected differences in reaction rates by the formation of the enol form (Scheme 3), which can be supported under acid conditions. This effect could decrease the reaction rate. Nitro group in the derivative c can stabilized this enol form, and phosphoric acid can also support it. The same effect might be expected in cyclization of the compound b in phosphoric acid. Scheme 3 )LJ The partial positive charge on the carbonyl group is decreased for the compound b and the reaction rate is lower in comparison with the compound a for cyclization in N-methylpyrrolidone. For the cyclization of the compound c an influence of the medium is not applied, but only stabilization of the enol form by the nitro group in this solvent. Measured absorbance for each compound and the reaction medium are in Tables to 6. Rate constants are calculated from measured figures by Excel and are shown in the Graphs. Calculated rate constants are summarised in Table 7. Experimental The spectra were measured in methanol on spectrophotometr UNICAM HELIS a Analytical procedure Method A A Sample of the measured starting compound (0. mmol) was dissolved in phosphoric acid ( ml). Reaction mixture was heated to 00 C in thermostat. The reaction mixture was sampled (0. ml) in appropriate time intervals of time. These samples were diluted by methanol to ml to give concentration c = 6. 0 mol/l. The periods of time are described bellow. 9

4 Method B The starting phenacyl anthranilate a, b or c (0.94 g) was dissolved in N-methylpyrrolidine (. ml). The solution was refluxed (temperature 0 C). At suitable intervals of time the sample of approx. 0 mg was withdrawn and diluted by methanol to ml to give concentration c = 6. 0 mol/l. The periods of time are described bellow. The spectra were measured in range nm. Actual concentration of the starting compound and product as well was calculated from the spectra at two wave numbers. Primary concentration of the starting compound was calculated as a sum of both concentrations. For each measurement two pairs of wave numbers were chosen. Average concentration in the appropriate time was used for the calculation. Molar absorption coefficients for each starting compound and product were determined from the calibration curve. Table Reaction of the compound a in phosphoric acid received absorbance for time and wavelength e Table Reaction of the compound a in N-methylpyrrolidine received absorbance for time and wavelength e 0

5 Table 3 Reaction of the compound b in phosphoric acid received absorbance for time and wavelength l (P $ERUEDFH e Table 4 Reaction of the compound b in N-methylpyrrolidine received absorbance for time and wavelength e Table Reaction of the compound c in phosphoric acid received absorbance for time and wavelength l (P $ERUEDFH e

6 Table 6 Reaction of the compound c in N-methylpyrrolidine received absorbance for time and wavelength e *UDSKRIGHSHGHFHRIRWLPHIRUUHDFWLR RIFL03 \ [ *UDSKRIGHSHGHFHRIRWLPHIRUUHDFWLRRID L03 \ [ *UDSKRIGHSHGHFHRIRWLPHIRU UHDFWLRRIELSKRSKRULFDFLG *UDSKRIGHSHGHFHRIRWLPHIRUUHDFWLR RIEL03 \ [ \ [ *UDSKRIGHSHGHFHRIRWLPHIRU UHDFWLRRIFLSKRSKRULFDFLG *UDSKRIGHSHGHFHRIRWLPHIRUUHDFWLRRI FL03 \ [ \ [

7 Table 7 Rate constants of the cyclization RPS DWHFRW DWHUDWLR DWHFRW DWHUDWLR DWHUDWLR XPEHU SKRSKDFLG LSKRSKDFLG 03 L03 03SKRSDFLG D E F Legend: Cs actual concentration of starting compound Cp actual concentration of product C primary concentration of starting compound NMP N-methlypyrrolidone l (nm) wavelength e s molar absorption coefficient of starting compound e p molar absorption coefficient of product References. Hradil P., Jirman J.: Collect. Czech. Chem. Commun. 99, 60, 37.. Hradil P., aněček J., Hlaváč J., Ševčík J.: Collect. Czech. Chem. Commun. 999, 64, 7. 3