The use of distribution coefficients (log D) for the analysis of structure-activity relationships of ionizable compounds is described. (D is the ratio of the equilibrium concentration of compound in an organic phase to the total concentration of un-ionized and ionized species in the aqueous phase at a given pH.) Simpler equations, often with improved correlations, have resulted. This method has the advantage that the influence of pKa or equivalent electronic factors on distribution can be distinguished from electronic effects related to mechanism of action. Several absorption studies are reanalyzed as well as studies on membrane conductance and uncoupling of oxidative phosphorylation.
The knowledge base of factors influencing ion pair partitioning is very sparse, primarily because of the difficulty in determining accurate log PI values of desirable low molecular weight (MW) reference compounds. We have developed a potentiometric titration procedure in KCl/water-saturated octanol that provides a link to log PI through the thermodynamic cycle of ionization and partitioning. These titrations have the advantage of being independent of the magnitude of log P, while maintaining a reproducibility of a few hundredths of a log P in the calculated difference between log P neutral and log P ion pair (diff (log PN − I)). Simple model compounds can be used. The titration procedure is described in detail, along with a program for calculating pKa′′ values incorporating the ionization of water in octanol. Hydrogen bonding and steric factors have a greater influence on ion pairs than they do on neutral species, yet these factors are missing from current programs used to calculate log PI and log D. In contrast to the common assumption that diff (log PN − I) is the same for all amines, they can actually vary more than 3 log units, as in our examples. A major factor affecting log PI is the ability of water and the counterion to approach the charge center. Bulky substituents near the charge center have a negative influence on log PI. On the other hand, hydrogen bonding groups near the charge center have the opposite effect by lowering the free energy of the ion pair. The use of this titration method to determine substituent ion pair stabilization values (IPS) should bring about more accurate log D calculations and encourage species-specific QSAR involving log DN and log DI. This work also brings attention to the fascinating world of nature’s highly stabilized ion pairs.
Diphenyliodonium-2-carboxylate (DPIC) reacts readily in copper ion catalyzed condensations with a variety of nucleophiles to give ortho-substituted substituted benzoic acids. These reactions occur at temperatures (80-100 °C) below those at which benzyne formation and other side reactions become important. The nature of the Cu(II) catalysis appears to be different from the more common Cu(I) catalysis of diaryliodonium reactions in that high specificity in the displacement reaction is retained. Products obtained directly from DPIC condensations include jV-[2,6-dichloro-3-(dimethylsulfamoyl)phenyl]anthranilic acid (5b), A-methyl-N-phenylanthranilic acid (5c), 7V-mesyl-jV-(2,3-dimethylphenyl)anthranilic acid (5d), jV-(3-chloro-2-methylphenyl)-jV-tosylanthranilic acid (5e), and o-(2,3-dimethylphenoxy)benzoic acid (5f). Compound 5d has been cyclized to jV-(2,3-dimethylphenyl)líf-2,l-benzothiazin-4(3H)-one 2,2-dioxide (6).We wish to describe details of our work on nucleophilic displacement reactions of diphenyliodonium-2-carboxylate (DPI®. We find DPIC is an excellent reagent for the preparation of ortho-substituted benzoic acids under mild conditions. This reaction is very unusual for a diaryliodonium salt in two respects. First, it is highly specific for nucleophilic attack on the carboxylate-bearing ring. Second, this selective reaction is copper(II) catalyzed, whereas Ar2I+ reactions are usually catalyzed by copper® and in a way which reduces selectivity (via reduction to the radical species Ar2I•).2 3"4 DPIC is known primarily for its usefulness as a precursor to benzyne5"9 (Scheme I, path A). While the decomposition is reported to be catalyzed by CuS04, AgOAc, and iodine,6 catalysts are usually not used to generate benzyne. At temperatures in the range of 130-150 °C the predominant decomposition course is to phenyl o-iodobenzoate7 8(Scheme I, path B), presumably occurring by an intramolecular displacement by the carboxylate ion on the adjacent ring.This work describes a third reaction course which is available at temperatures below 130 °C (generally 80-100 °C; Scheme I, path C). The nucleophilic displacement reactions illustrated in path C cover reactants with a range of nucleophilicity and steric hindrance. The products obtained are characteristically tar free. Brief descriptions of the reaction of DPIC with anilines have appeared.10 11"12Results and Discussion Reaction with Anilines. 2,3-Dimethylaniline reacts slowly with DPIC in 2-propanol at reflux (80 °C) to give a 2.5% yield of N-(2,3-dimethylphenyl)anthranilic acid (5a) after 3 h (Table I, expt 1). The addition of 3.6 mol % of cupric acetate, however, has a very beneficial effect,
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