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,
Mitochondrial accumulation and respiratory inhibition are critical steps in the actions of N-methyl-4-phenylpyridinium ion (MPP+), the toxic metabolite of the parkinsonism-inducing agent, N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. We examined the respiratory characteristics of 2-methylated fi-carbolines (2-MejBCs) and 2-methylated 3,4-dihydro-f3-carbolines (2-MeDHIBCs), which encompass the MPP+ structure. As indoleamine derivatives, they could have endogenous roles in idiopathic parkinsonism. With rat liver mitochondria, the order for inhibition of NAD'-linked 02 consumption (6-min preincubations) was as follows: MPP+ = 2-methylharmine > 2-methylharmol = 2-methylharmaline >> 2-methylharmalol > 2-methylnorharman > 6-OH-2-methyiharmalan >> 2-methylharman. Similar to MPP+, 2-MeDHI3C/2-MePC inhibition was potentiated by tetraphenylboron and reversed by dinitrophenol, consistent with the involvement of cationic forms. However, the participation of neutral forms was indicated by the 2-MeDHfiC/2-MeBC inhibitory time courses, which were unlike MPP+. The neutral forms probably arise via indolic nitrogen deprotonation because the characteristics of a cationic .-carboline that cannot N-deprotonate, 2,9-dimethylnorharman, mirrored MPP+ rather than 2-MeCs. Succinate-supported respiration was also significantly blocked by 2-MeDHI3Cs/2-MefiCs, but results with tetraphenylboron and 2,9-dimethylnorharman indicated that cationic forms were less important than in the inhibition of NAD+-linked respiration. We suggest that the relatively potent inhibition by certain 2-MeDHI3Cs/2-MeIJCs involves neutral forms for passive mitochondrial entry and cationic as well as neutral forms that act at several respiratory sites. Respiratory inhibition could reasonably underlie the reported neurotoxicity of 2-MefiCs.Interest in N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a street drug contaminant that selectively destroys nigrostriatal cells, has stimulated investigations of environmental or endogenous toxins that might be associated with idiopathic parkinsonism (1, 2). An oxidation product of MPTP, N-methyl-4-phenylpyridine (MPP+), is believed to be the species that exerts neurotoxicity by inhibiting the mitochondrial respiratory chain at site I (NADH dehydrogenase) (3,4). Intrigued by the structural overlap between MPP+ and indole-derived p-carboline (,8C) compounds that are methylated (quaternized) on the 2-nitrogen (2-Mef3Cs), we and others (5-9) have hypothesized possible neurotoxic roles for 2-MeBCs in Parkinson disease. Endogenous biosynthetic pathways can be envisioned for 2-MepC formation from indoleamines or even tryptophan (10).Although ,BCs and their hydrogenated derivatives (3,4-dihyro-,BCs; DHPCs) have been studied extensively (see Discussion), little is known about the toxic capabilities of their N-methylated analogs. Hoppel et al. (8) noted that the ,BC, 2-methylharmine, was an effective mitochondrial respiratory inhibitor, and we now present results showing that several 2-MeDHfC/2-Mef3C isomers with 7-oxygenat...
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...
The relative p£a values in Me2SO solution of 13 hydrocarbons that form carbanions with highly dispersed negative charges on deprotonation were found to differ from literature relative ion-pair acidities in cyclohexylamine (CHA) by only ±0.7 unit, or less, when the ion-pair pA"a's were anchored to the pATa of 17.9 for 9-phenylfluorene in Me2SO. The relative p£a's for phenylacetylene, cyclopentadiene, and indene were found to be 2.4, 2.7, and 0.9 units higher, respectively, in Me2SO than in CHA. Higher relative p£a's were also observed for PhCH2S02Ph, PhS02CH3, and PhS02CH2Me, by 1.9, 2.7, and 2.8 units, respectively, and for 2and 1,3-dithiane, by 0.4, 0.65, 0.8, and ~1.9 units, respectively. The apparent higher relative acidities for these compounds in CHA is probably caused by stronger ion pairing or aggregation of the ions derived therefrom than for the hydrocarbon indicator ions with which they are being compared. These perturbations of the equilibria probably arise because of differences in the extent of charge dispersion in the acid and indicator ions. The p£a of 1,3-dithiane itself is estimated from an average of three extrapolations to be 39 ± 2 in Me2SO. Acidities in Me2SO for 1,3-dithianes with electron-withdrawing groups in the 2-position were observed to increase in the following order: 2-C6H5 < 2-p-C6H5phenyl < 2-CONMez < 2-£-PhCH=CH < 2-CH=C-S(-CH2)3-S < 2-COzMe < 2-CN. The order of acidities of 3 alkylthio alkyl sulfoxides was found to be MeSCH2S(0)Me < EtSCH2S(G)Et < Z-BuSCH2S(0)z-Bu.In previous papers we have reported equilibrium acidities in MezSO solution for a large number of hydrocarbons and sulfur-containing hydrocarbons.1 In this paper we turn our attention to a number of types of sulfur compounds that are of particular interest to synthetic organic chemists. The carbanion derived from 1.3-dithiane was the first of several strongly basic ions that were shown to be useful synthetically as acyl anion equivalents since the two sulfur atoms can serve as a masked carbonyl group.2 Reactions of anions derived from 2-substituted 1,3-dithianes with alkylating agents or Michael acceptors have been studied extensively.3 The stereochemistry of these reactions has also received considerable attention following the discovery that 2-lithio-tis-
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