Gordon B. Barlin

Methylation of aminopyridazines

Quaternisations of mono- and di-aminopyridazines with methyl iodide in methanol have been examined and the products identified. 3- and 4-Aminopyridazine and 3,5-diaminopyridazine gave both 1- and 2-methyl derivatives. 3,4-, 3,6-, and 4,5-Diaminopyridazines each gave a single product, which in the first case was tentatively identified as 3,4-diamino-1-methylpyridazinium iodide. No ammonio-compounds were detected in these reactions. Ionization constants, u.v. and 1H n.m.r. spectra are recorded and discussed.

Kinetics of reactions in heterocycles. Part XV. Reactions of 2-, 6-, or 8-methylthio-1-, -3-, -7-, or -9-methylpurines and related compounds with methoxide ions in methanol

Kinetics have been measured and Arrhenius parameters calculated for the reactions of some 2-, 6-, or 8-methylthio1-, -3-,-7-, or -9-methylpurines, 2-methylthio-1 (and 3)-methyl-1,3,5-triazaindene, and 2-methylsulphonyl-1-methylbenzimidazole with methoxide ions in methanol. The positional order of reactivity in the 1-methylpurines was 6 > 2 > 8 and in the 3-methylpurines 6 > 8.

Kinetics of reactions in heterocycles. Part XIV. Reactions of 2- and 4-amino-, -methylamino-, and -dimethylamino-pyridine methiodides and 2-methylthiopyrimidine methiodide with hydroxide ions in water

The kinetics of the reactions of 2- and 4-amino-, -methylamino-, and -dimethylamino-pyridine methiodides with hydroxide ions in water have been studied. At 20 °C, 2-dimethylaminopyridine methiodide was 8.5 × 103 times more reactive than its 4-isomer, owing mainly to a lower energy of activation (by 6.4 kcal mol–1). The 2- and 4-dimethylaminopyridine methiodides were 2.3 × 10–4 and 3.1 × 10–6 times less reactive than their chloroanalogues. The reaction of 2-methylthiopyridine methiodide with hydroxide ions was found to proceed via a two-step process.

Kinetics of reactions in heterocycles. Part XII. Substituted N-methylquinolinium and N-methylisoquinolinium salts with hydroxide ions

Kinetics of the replacement reactions of chloro-, iodo-, methoxy-, and methylthio-subsittuted N-methylquinolinium and N-methylisoquinolinium iodides with hydroxide ions have been determined. The 2-iodo- and 2-methylthioquinolinium salts at 20° were 1440 and 1490 times more reactive than their 4-isomers respectively, owing to lower energies of activation and higher frequency factors. The reactivity of 1-methylthioisoquinoline methiodide was anomalous, being 530 times greater than that of 2-methylthioquinoline methiodide. N-Methylation of the iodoquinolines and -isoquinolines increased their reactivity towards hydroxide ions at 114·8° by 1·2–3·4 × 107 fold for substituents at the α-position, and 6·1 × 105 fold for substituents at the γ-position of quinoline. U.v. and 1H n.m.r. spectra are recorded and discussed.

Kinetics of reactions in heterocycles. Part XIII. Substituted N-methylpyridinium and N-methylquinolinium salts with piperidine in water and in ethanol

Kinetics of the displacement reactions of some halogeno-N-methylpyridinium and -N-methylquinolinium salts towards half-neutralised piperidine in water, and unneutralised piperidine in ethanol have been determined. These revealed, for reactions in water, smaller differences in reactivity between 2- and 4-isomers than was observed with hydroxide ions. Energies of activation for the reactions with piperidine were 3.7–5.4 kcal mol–1 lower and log A values were lower by 2.9–3.4 and 0.7–1.9 units for pyridinium salts with the substituent at the 2- and 4-position respectively. Displacement reactions with piperidine in ethanol were found to occur 8.0–16.75 times faster than in water. Quaternisation of 4-chloroquinoline by methylation increased its reactivity towards piperidine in ethanol at 100° by 2 × 108 fold.

Kinetics of reactions in heterocycles. Part X. Reactions of substituted N-methylpyridinium salts with hydroxide ions

Kinetics of the reactions of halogeno-, methoxy-, methylthio-, and methylsulphonyl-substituted N-methylpyridinium salts with hydroxide ions have been determined. The salts with the leaving group in the 2-position were the most reactive: e.g. the k2 values for 2-, 3-, and 4-methoxypyridine methiodides at 20° were 2·9 × 10–2, 5·0 × 10–9, and 7·6 × 10–4 l mol–1 s–1, respectively. Quaternisation of 4-methylsulphonylpyridine by methylation increased its reactivity to hydroxide ions by 7·3 × 108-fold at 20°, owing to a decrease in energy of activation of 7·1 kcal mol–1, and an increase in log A 3·5 units.U.v. and 1H n.m.r. spectra are recorded and discussed.

Tautomerism in N-heterocycles. Part 3. 3,4,5-Trimercaptopyridazine

A number of N- and S-methyl derivatives of 3,4,5-trimercaptopyridazine have been prepared, and ionization constants and u.v. spectra determined. These studies reveal that 3,4,5-trimercaptopyridazine exists in an N(2)H tautomeric form. Some oxygen analogues have also been synthesised.

Reactions of 2-, 6-, and 8-monosubstituted 1- and 3-methylpurines with hydroxide ions in water

The reactions of 2-, 6-, and 8-monochloro-(or methylthio-)1-(and 3-)methylpurines towards N-sodium hydroxide have been examined. 1-Methyl-2- and -6-methylthiopurine underwent normal nucleophilic displacement to give the hydroxypurines, but 1-methyl-8-methylthiopurine underwent ring fission to give 5-amino-2-methylthioimid-azole-4-carbaldehyde. 3-Methyl-6-methylthiopurine afforded 5-methylaminoimidazole-4-carbaldehyde predominantly, and some 6-hydroxy-3-methylpurine; and 3-methyl-8-methylthiopurine underwent ring opening like its 1-methyl isomer. 7-(and 9-)Methyl-2-methylthiopurines (for comparison) gave 4-amino-5-methyl-amino- and 5-amino-4-methylamino-2-methylthiopyrimidines, respectively. 6-Chloro-3-methylpurine gave 5-methylaminomidazole-4-carbonitrile and some 6-hydroxy-3-methylpurine; but 8-chloro-3-methylpurine was consumed without forming 8-hydroxy-3-methylpurine.