THE strength of an acid, HA, in water is expressed quantitatively by its pK (= -log K ) value, where K = (H+)(A-)/(HA) the parentheses denoting activities. Often, when experimental results are not available, useful estimates of the approximate thermodynamic pK values of organic acids in water can be made, either from consideration of substituent effects or by analogy with substances of known pK. The present Review shows how such treatments, that have already been discussed for organic bases,l can be applied to organic acids. Except where stated, all experimental pK values are from reference 2. In almost all cases they refer to temperatures within the range 18-25' (usually 25").For convenience, acids are considered under the headings: (1) Aromatic acids ; (a) carboxylic acids, (b) phenols, naphthols, and tropolones, (c) thiophenols, (d) other acids; (2) Aliphatic and alicyclic acids; (a) carboxylic acids, (b) alcohols and aldehydes, (c) thio-acids and -alcohols ; (3) Heterocyclic acids ; (a) carboxylic acids, (b) substituted azoles, (c) hydroxy-compounds.Other types, such as amides, imides, /3-ketones (enolic and ketonic forms), hydroxynaphthaquinones, and aromatic thio-acids, are also dealt with in the Discussion.Representative pK values are given in Table 1, in which the acids are arranged in order of decreasing strength.Qualitatively, the same factors' govern the strengths of acids and bases. At any given temperature, the pK, value of an acid or a base is directly proportional to the free energy change in the ionisation reaction, so that the effect of substituents on pK values can be discussed in terms of factors affecting free energies. These factors are mainly polar, resonance, and steric interacti0ns.l Of these, polar effects are approximately constant for any substituent and cumulative when more than one group is involved, so long as two or more highly polar groups are not attached to the same atom.Resonance contributions often roughly parallel polar effects, whereas steric factors usually vary from one class of reaction to another. Carboxylic acid and phenolic groups are able, both in their ions and in their neutral molecules, to exhibit resonance interaction with the remainder of the molecule. In an amine, on the other hand, the lone pair of electrons on the

other solvents (see ref. 6). p. 51. 1943.

Methylations of heterocyclic systems, such as benzimidazole, naphth[2,3-c]imidazole, imidazo[4,5-c]-pyridine, purine, pyridine, pyrimidine, pyridazine and s-triazolo[4,3-b]pyridazine, which bore SH, NH and/or OH groups, were carried out with dimethylformamide dimethyl acetal to give the corresponding S-, N- and/or O-methyl derivatives in high yields. Selective methylation of some compounds containing both SH and NH groups took place to give first the S-methyl and subsequently the S,N-dimethyl derivatives. No side reactions, such as C-methylation, were observed.

We have compared the ex vivo antimalarial activity of 12 new quinoline di-Mannich base compounds containing the 7-dichloroquinoline or 7-trifluoromethylquinoline nucleus with amodiaquine, chloroquine, and pyronaridine using the Saimiri-bioassay model. Each compound was administered orally (30 mg/kg of body weight) to three or more noninfected Saimiri sciureus monkeys, and serum samples were collected at various times after drug administration and serially diluted with drug-free (control) serum. In vitro activity against the multidrug-resistant K1 isolate of Plasmodium falciparum was determined in serum samples by measuring the maximum inhibitory dilution at which the treated monkey serum inhibited schizont maturation in vitro. Of the 12 Mannich bases tested, 8 were associated with levels of ex vivo antimalarial activity in serum greater than those of amodiaquine, chloroquine, or pyronaridine 1 to 7 days after drug administration. Further studies were carried out with four of these compounds, and the results showed that the areas under the serum drug concentration-time curves for the four compounds were between 7- and 26-fold greater than that obtained for pyronaridine. Activity against four multidrug-resistant strains of P. falciparum was also much greater in serum samples collected from monkeys after administration of these four compounds than in serum samples collected after administration of pyronaridine or chloroquine. These findings suggest that these four quinoline Mannich base compounds possess a very marked and prolonged antimalarial activity and that further studies should be performed to determine their value as antimalarial drugs.

The proton magnetic resonance spectra of various charged species from thirty-three azoles have been measured.In N-methvl-imidazoles and -1.2.4-triazoles the sites of protonation have been determined, and the cations appear to be stabilised by amidinium type resonance.THE proton magnetic resonance (p.m.r.) spectra of imidazole, pyrazole, 1,2,3-and 1,2,4-triazole, tetrazole, and certain of their derivatives have been described 1-7 but no systematic study of the spectra of these ring systems has been reported. We here discuss the spectra of neutral molecules, cations, and where possible anions, of thirty-three compounds from these series.Chemical shift data for the compounds studied, measured as neutral molecules in deuteriochloroform, as cations in trifluoroacetic acid, or as anions in 2~-sodium deuteroxide,8 are in Table 1. Assignment of peaks to specific protons in the parent compounds is readily accomplished by inspection, and for the N-methyl derivatives is made simpler by the small substituent