An accurate spectrophotometric method of determining relative equilibrium acidities of carbon acids in DMSO has been developed. The pK scale in DMSO has been anchored by comparisons of values obtained by the spectrophotometric method with those obtained potentiometrically in the 8 to 11 pK range. As a result, the pK of fluorene, formerly arbitrarily taken as 20.5, has been raised to an absolute value of 22.6. The pA"s of other carbon acids previously reported, including nitromethane, acetophenone, acetone, phenylacetylene, dimethyl sulfone, acetonitrile, and the corresponding indicator pX's must also be raised. The pK's have been found to be correlated with heats of deprotonation in DMSO by potassium dimsyl, and evidence is presented to show that pK measurements in DMSO are free from ion association effects. Data are presented which indicate a pK of 35.1 for DMSO. In the methane carbon acids, CHyEWG, the order of acidities is NO2 » CH3CO > CN, CH3SO2. The differences amount to 12.2 and 6.8 kcal/mol, respectively, which are believed to be of a comparable magnitude to gas-phase substituent effects. Carbon acids wherein the charge on the anion resides mainly on oxygen, such as ketones and nitroalkanes, are found to be weaker acids in DMSO than in water by 5.5 to 9.6 pK units. On the other hand, carbon acids wherein the charge on the anion is delocalized over a large hydrocarbon matrix, such as in the anion derived from 9-cyanofluorene, are stronger acids in DMSO than in water. Factors that may contribute to this reversal are discussed. The scale of pX's for 9-substituted fluorenes in DMSO is shown to be expanded when compared to the earlier pK scale determined by the Hmethod. A rationale is presented. The apparent relative acidities of fluorenes and phenylacetylene differ by 6 and 11 pK units, respectively, for cyclohexylamine (CHA) vs. DMSO solvents and benzene vs. DMSO solvents. Similarly, in benzene, acetophenone is a stronger acid than fluorene by ca. 6 pK units, whereas in DMSO acetophenone is a weaker acid by 3.2 pK units. These differences result from ion association effects that occur in solvents of low dielectric constant (benzene, ether, CHA, etc.) causing relative acidities to be dependent on the reference base, as well as the solvent. This is not true in strongly dissociating solvents of high dielectric constant, such as DMSO. A list of 13 indicators covering the pAT range 8.3 to 30.6 in DMSO is presented. Equilibrium acidities of weak (i.e., pX ^15) carbon acids have been measured by a variety of methods3 in a variety of solvents including ether,4a benzene,4b diglyme,5 cyclohexylamine (CHA),6 mixtures of dimethyl sulfoxide (DMSO) with ethanol, methanol, or water,7•8•9 and pure DMSO.10 We have chosen DMSO for our studies because it allows accurate measurements to be made spectrophotometrically for many different types of carbon acids over a wide range of pK (ca. 30 pK units) with apparently little or no interference from ion association effects.1 Furthermore,
Results of the replacement of one or two hydrogen atoms in CH3EWG carbon acids (EWG = CHZSO, CN, PhS02, CH&O, F:jCS02, and the like) by phenyl on equilibrium acidities in Mens0 are reported. The progressive decrease in phenyl acidifying effects with a progressive increase in acidity of the CHzEWG parent acids is interpreted as a resonance saturation effect. The acidifying effects of phenyl on PhCHZEWG, 9,10-dihydroanthracene, and xanthene are found to be severely attenuated by steric inhibition of resonance. Similar effects were observed on substitution of a second Ph group into PhCHzEWG to give PhZCHEWG. The ratios of resonance to polar contributions to the acidifying effect of P h were estimated by (a) removing the resonance contribution through steric inhibition of resonance and (b) by using the MeZN+ group as a model for polar effects. The first method indicated a ratio of 4:l. the second a ratio of 4.61 to 6.6:l depending on the nature of EWG. The resonance to polar ratio for phenyl was found to be larger than that for PhCO (or CH&O), which, in turn, is much larger than that for NOe, CN, or PhSOz.
and NMR was obtained. All attempts at crystallization were unsuccessful: IR (CHClg) 3700-3300 (br), 2950-2800 (br), 1725 cm"1; NMR (CDClg), composite of Table I and Table II; EIMS m/e (relative intensity) 317 (M+, 0.6), 148 (10), 139 (15), 138 (89), 135 (22), 105 (17), 94 (42), 93 (100), 80 (24), 77 (17), 57 (44); CIMS m/e (relative intensity) 318 (M+ + 1,83), 138 (100); high-resolution MS, molecular ion m/e 317.1524, caled, for CyHggNCh 317.1628. 9-0-[(±)-2-Hydroxy-2-phenylbutyryl]retronecine . To a solution of 0.974 g (3.07 mmol) of 2 in 3.75 mL of ethanol was added 1.0 mL of 30% hydrogen peroxide. This mixture was kept at 4 °C in a refrigerator for 2 days. The excess peroxide was destroyed by the addition of Mn02. The solution was then filtered and the solvent removed in vacuo, leaving a colorless viscous oil. The presence of N-oxide was determined by using a Mattocks test.18 TLC on silica gel with 10% methanol/CHClg as the solvent showed a single spot at R¡ 0.47 as compared to Rf 0.59 for the free alkaloid. This difference in R¡ of 0.1 is typical for pyrrolizidine alkaloid iV-oxides:1 NMR (CDClg) characteristic peaks 0.85 (br t, 3 H, J = 5.0 Hz), 4.69 (br s, 2 H), 5.51 (br s, 1 H), 7.29 (br m, 3 H), 7.47 (br m, 2 H); EIMS m/e (relative intensity) 165 (1), 155 (4), 138 (22), 136 (22), 135 (100), 117 (23), 106 (12), 105 (49), 104 (12); CIMS m/e (relative intensity) 318 ( + 1, 36), 300 (11), 163 (16), 139 (13), 138 (100), 136 (14), 135 (20). 9-0-[(S)-(+)-2-Hydroxy-2-phenylbutyryl]retronecine (5).A solution of 1,1 '-carbonyldiimidazole (0.218 g, 1.35 mmol) and (+) -2-hydroxy-2-phenylbutyric acid (0.212 g, 1.29 mmol) in 15 mL of dry CHClg under an argon atmosphere was stirred for 15 (18) Mattocks, A. R. Anal. Chem. 1967, 39, 443. min to allow for the complete evolution of C02. To this was then added retronecine (0.2058 g, 1.33 mmol), and the solution was stirred for 20 h at room temperature. The CHClg was washed with 10 mL of saturated NaHCOg. The aqueous layer was extracted with 10 mL of CHClg, and the combined CHC13 extracts were dried (MgSOJ, filtered, and reduced in vacuo, leaving 0.3844 g (94%) of a colorless viscous oil: NMR (CDClg) see Table I; IR (CHClg) 3650-3400, 3100-2800,1725 cm"1; [ ]20^+ 4.6°(c 2.19, MeOH); EIMS m/e (relative intensity) 317 (M+, 2), 139 (18), 138 (95), 136 (14), 135 (32), 105 (11), 94 (41), 93 (100), 80 (26);CIMS m/e (relative intensity) 318 (M+ + 1,44), 300 (11), 139 (13), 138 (100), 136 (16), 135 (20); high-resolution MS, molecular ion m/e 317.1588, caled, for Ci8H23N04 317.1628. 9-0-[(JZ)-(-)-2-Hydroxy-2-phenylbutyryl]retronecine (6). The reaction was carried out exactly as described for 5 except that (-)-2-hydroxy-2-phenylbutyric acid was used: NMR (CDClg) see Table II; [a]20^+ 6.0°(c 3.16, MeOH); EIMS exactly the same as for 5; high-resolution MS, molecular ion m/e 317.1660, caled, for C18H23N04 317.1628.Registry No. (±)-2a, 81340-07-0; 3, 480-85-3; 4, 315-22-0; (+)-(S)-5,81340-08-1; (-)-fi-6, 81370-87-8; (+)-2-hydroxy-2-phenylbutyric acid, 24256-91-5; (-)-2-hydroxy-2-phe...
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