C O OMe X O C X O Me a X = SMe b X = SOMe c X = SO2Me d X = H 1 a X = SMe b X = SOMe c X = SO2Me d X = H 2 406 J. CHEM. RESEARCH (S), 1997 J. Chem. Research (S), 1997, 406–407† Reactions of Carbonyl Compounds in Basic Solutions. Part 31.1 The Effect of 2-Methylsulfonyl, 2-Methylsulfinyl and 2-Methylsulfanyl Substituents on the Alkaline Hydrolysis of Methyl Benzoate and Phenyl Acetate† Keith Bowden* and Saima Rehman Department of Biological and Chemical Sciences, Central Campus, University of Essex, Wivenhoe Park, Colchester, Essex CO4 3SQ, UK Rate coefficients have been measured for the alkaline hydrolysis of methyl 2-methylsulfonyl-, 2-methylsulfinyl- and 2-methylsulfanyl-benzoates and 2-methylsulfonyl-, 2-methylsulfinyl- and 2-methylsulfanyl-phenyl acetates, as well as of the parent esters, in 30% (v/v) 1,4-dioxane–water at several temperatures: the relative rates of hydrolysis and the activation parameters indicate the importance of both polar and steric effects.Esters are commonly designed as prodrugs of drugs having carboxy or hydroxy functions.2 Such prodrugs can regenerate the drugs by hydrolysis either enzymatically or nonenzymatically. 3 Oxidative metabolism of the methylsulfanyl group to methylsulfinyl and, subsequently, methylsulfonyl is known to occur,4 and has been employed in the design of aspirin prodrugs, methylsulfanylmethyl, methylsulfinylmethyl and methylsulfonylmethyl aspirin.5 The alkaline hydrolysis of ortho-substituted alkyl benzoates6 and phenyl acetates7 has been investigated in some detail; but the methylsulfanyl, methylsulfinyl and methylsulfonyl groups have not been included.ortho-Substituents can exert both polar and steric effects,8 as well as being involved in neighbouring group participation where the capacity exists, cf. ref. 9. As model prodrug esters we have prepared methyl 2-methylsulfanyl-, 2-methylsulfinyl- and 2-methylsulfonylbenzoates, 1a–c, and 2-methylsulfanyl-, 2-methylsulfinyl- and 2-methylsulfonyl-phenyl acetates, 2a–c, and studied their alkaline hydrolysis.Results The alkaline hydrolysis of both the methyl benzoates and phenyl acetates is of first-order in both ester and hydroxide anion. Rate coefficients for the alkaline hydrolysis of the methyl 2-substituted-benzoates and 2-substituted-phenyl acetates at 30.0, 45.0 and 60.0 °C in 30% (v/v) 1,4-dioxane– water are shown in Table 1. The activation parameters are shown in Table 2.Discussion Both polar (electronic) and steric effects will control the reactivity of ortho-substituted systems.6–8 The para-s values of SMe, SOMe and SO2Me are 0.0, 0.49 and 0.73, respectively.10 The Hammett r constants for the alkaline hydrolysis of phenyl acetates in 3% aqueous ethanol at 25 °C, of ethyl benzoates in 3% aqueous ethanol at 25 °C and of methyl benzoates in 40% aqueous 1,4-dioxane at 20 °C are 1.17, 1.33 and 2.07,6,7,11 respectively. Reliable estimates12 can be made for kpara-X/kH in 30% aqueous 1,4-dioxane at 30 °C for SMe, SOMe and SO2Me of 1.0, 7.6 and 21, for the methyl benzoates, and 1.0, 5.4 and 12, for the phenyl acetates.Steric effects are more difficult to estimate for these substituents.8,10 However, estimates of kortho-X/kH in 30% aqueous 1,4-dioxane at 30 °C for SMe, SOMe and SO2Me as 0.4, 0.8 and 0.2, for the methyl benzoates, and as 0.84, 3.8 and 4.8, for the phenyl acetates, can be made. Comparison with the observed values for SMe, SOMe and SO2Me of 0.25, 14 and 0.44, for the methyl benzoates, and of 0.80, 10 and 6.4, for the phenyl acetates, shows reasonable agreement, with the exception of that of methyl 2-methylsulfinylbenzoate. The rate enhancement of ca. 18 for the latter ester could arise from intramolecular catalysis as observed for 2-acylbenzoates9 or, more *To receive any correspondence (e-mail: keithb@essex.ac.uk). †This is a Short Paper as defined in the Instructions for Authors, Section 5.0 [see J.Chem. Research (S), 1997, Issue 1]; there is therefore no corresponding material in J. Chem. Research (M). Table 1 Rate coefficients (k2) for the alkaline hydrolysis of methyl 2-substituted benzoates and 2-substituted phenyl acetates in 30% (v/v) 1,4-dioxane–watera 102k2/dm3 molµ1 sµ1 2-Substituent At 30.0 °C At 45.0 °C At 60.0 °C l/nmb Methyl benzoates H SO2Me SOMe SMe 3.28 1.45 45.0 0.813 8.00 4.00 109 2.43 21.1 10.2 216 5.71 230 283 290 323 Phenyl acetates H SO2Me SOMe SMe 120 770 1200 95.5 313 1990 2540 232 700 4500 5070 538 292 319 312 308 aRate coefficients were reproducible to �3%.bWavelength used to monitor alkaline hydrolysis. Table 2 Activation parameters for the alkaline hydrolysis of methyl 2-substituted benzoates and 2-substituted phenyl acetates in 30% (v/v) 1,4-dioxane–water at 30.0 °Ca 2-Substituent DH‡/kcal molµ1 b DS‡/cal molµ1 Kµ1 b Methyl benzoates H SO2Me SOMe SMe 11.8 12.5 9.8 12.4 µ26 µ26 µ27 µ27 Phenyl acetates H SO2Me SOMe SMe 11.3 11.0 9.1 11.0 µ21 µ18 µ24 µ22 aValues of DH‡ and DS‡ are considered accurate to within �500 cal molµ1 and �2 cal molµ1 Kµ1, respectively. b1 cal= 4.184 J.J.CHEM. RESEARCH (S), 1997 407 likely, from a favourable conformation enhancing the electrostatic field effect. The latter would be similar to the finding in the alkaline hydrolysis of the toluene-p-sulfonate salt of methyl 2-dimethylsulfoniophenylacetate.13 The activation parameters, shown in Table 2, are those expected for a bimolecular ester hydrolysis of this type.The significantly reduced enthalpies of activation for the 2-methylsulfinyl substituted esters confirm the facilitation of ester hydrolysis by this group arising from the above effect. Thus, prodrugs employing activation of ester hydrolysis following oxidative metabolism of 2-methylsulfanyl groups have been shown to be possible in model systems; but without the great facility and tuneability of 2-acyl substituents.14 Experimental Benzoic acid, methyl benzoate, phenol, phenyl acetate and thiosalicylic acid were obtained pure commercially. 2-Methylsulfanylbenzoic acid was obtained by methylation of thiosalicyclic acid by methyl iodide in base,15 which gave the corresponding methyl ester by refluxing with methanol–concentrated sulfuric acid.15 Oxidation of the latter acid or methyl ester gave the corresponding methylsul- finyl derivatives, with 1 mol.equivalent of m-chloroperbenzoic acid,5,16 or methylsulfonyl derivatives, with 30% hydrogen peroxide. 17 Phenol reacted with dimethyl disulfide–aluminium trichloride to give 2-methylsulfanylphenol,18 which was acetylated with acetic anhydride–triethylamine to give 2-methylsulfanylphenyl acetate.19 Oxidation of the latter phenol or phenyl acetate gave either the corresponding methylsulfinyl or methylsulfonyl derivatives, with either 1 or 2 mol. equivalents of m-chloroperbenzoic acid, respectively.5,16 The purities of the acids, phenols and esters were monitored by 1H and 13C NMR and IR spectroscopy, as well as by mass spectrometry.The mps of the compounds, after repeated recrystallization and drying under reduced pressure (P2O5), or the bps of the compounds were in agreement with literature values,15,16,18–22 except for those shown below. Methyl 2-methylsulfonylbenzoate, mp 60–61 °C [colourless needles from chloroform–light petroleum (bp 40–60 °C)] (Found: C, 50.3; H, 4.7; S, 14.8.C9H10O4S requires C, 50.5; H, 4.7; S, 15.0%). 2-Methylsulfonylphenyl acetate, mp 102–103 °C [colourless crystalline solid from diethyl ether–light petroleum (bp 40–60 °C)] (Found: C, 54.2; H, 5.1; S, 16.4. C9H10O3S requires C, 54.5; H, 5.1; S, 16.2%). 2-Methylsulfinylphenyl acetate, mp 79–80 °C (colourless crystalline solid from toluene) (Found: C, 50.5; H, 4.6; S, 14.7. C9H10O4S requires C, 50.5; H, 4.7; S, 15.0%). The solvents were purified as described previously.11 Measurements.·Rate coefficients for the alkaline hydrolysis of the esters were determined spectrophotometrically by use of a Perkin-Elmer Lambda 16 UV&ndasspectrophotometer.The reactions were followed at the wavelengths shown in Table 1. The procedure used was that described previously.23 The substrate concentrations were ca. 1Å10µ4 mol dmµ3 and those of hydroxide anion were 2Å10µ3 to 6Å10µ2 mol dmµ3. The products of the reactions were found to be the anion of either the substituted benzoic acids or phenols in quantitative yield and were further confirmed spectrophotometrically by comparison of the spectrum of the acid or phenol in base with that of the reaction product.Received, 19th May 1997; Accepted, 18th August 1997 Paper E/7/03419I References 1 Part 30, K. Bowden, J. Izadi and S. L. Powell, J. Chem. Res. (S), preceding paper. 2 H. Bundgaard, in Design of Prodrugs, ed. H. Bundgaard, Elsevier, Amsterdam, 1985, ch. 1. 3 N. M. Nielsen and H.Bundgaard, J. Med. Chem., 1989, 32, 727. 4 J. Caldwell and S. C. Mitchell, in Comprehensive Medicinal Chemistry, vol. 5, ed. J. B. Taylor, Pergamon, Oxford, 1990, ch. 23.5. 5 T. Loftsson, J. J. Kaminski and N. Bodor, J. Pharm. Sci., 1981, 70, 743; T. Loftsson and N. Bodor, J. Pharm. Sci., 1981, 70, 750, 756. 6 N. B. Chapman, J. Shorter and J. H. P. Utley, J. Chem. Soc., 1963, 1291; Y. Iskander, R. Tewfik and S. Wasif, J. Chem. Soc. B, 1966, 424; M. Hojo, M. Utaka and Z.Yoshida, Tetrahedron Lett., 1966, 19, 25. 7 T. Nishioka, T. Fujita, K. Kitamura and M. Nakajima, J. Org. Chem., 1975, 40, 2520. 8 R. W. Taft, in Steric Effects in Organic Chemistry, ed. M. S. Newman, Wiley, New York, 1956, ch. 13. 9 K. Bowden, Adv. Phys. Org. Chem., 1993, 28, 171; K. Bowden, Chem. Soc. Rev., 1995, 24, 431. 10 C. Hansch, A. Leo and D. Hoekman, Exploring QSAR Hydrophobic, Electronic and Steric Constants, American Chemical Society, Washington, 1995. 11 K. Bowden and M. J. Price, J. Chem. Soc. B, 1971, 1784. 12 K. Bowden, Org. React. (Tartu), 1995, 29, 19. 13 J. Casanova, N. D. Werner and H. R. Kiefer, J. Am. Chem. Soc., 1967, 89, 2411. 14 K. Bowden, A. P. Huntington and S. L. Powell, Eur. J. Med. Chem., in the press; K. Bowden and J. Izadi, Eur. J. Med. Chem., in the press. 15 G. Swarzenbach and E. Rudin, Helv. Chim. Acta, 1939, 22, 360. 16 R. Benassi, U. Folli, D. Iarossi, A. Mucci, L. Schenetti and F. Taddei, J. Chem. Soc., Perkin Trans. 2, 1989, 517. 17 F. G. Bordwell and P. J. Bouton, J. Am. Chem. Soc., 1957, 79, 717. 18 P. F. Ranken and B. G. McKinnie, Synthesis, 1984, 117. 19 D. M. McKinnon, Can. J. Chem., 1980, 58, 2761. 20 T. Durst, K.-C. Tin and M. J. V. Marcil, Can. J. Chem., 1973, 51, 1704. 21 P. Stoss and G. Satzinger, Angew. Chem., Int. Ed. Engl., 1971, 10, 76. 22 K. Andersen, S. Chumpradit and D. J. McIntyre, J. Org. Chem., 1988, 53, 4667. 23 K. Bowden and A. M. Last, J. Chem. Soc., Perkin Trans. 2, 1973, 345.