2-Chloropyrazine kinetics

Quinoxalinyl, 4-cinnolinyl, and 1-phthalazinyl derivatives, which are all activated by a combination of induction and resonance, have very similar kinetic characteristics (Table XV, p. 352) in ethoxylation and piperidination, but 2-chloroquinoxaline is stated (no data) to be more slowly phenoxylated. In nucleophilic substitution of methoxy groups with ethoxy or isopropoxy groups, the quinoxaline compound is less reactive than the cinnoline and phthalazine derivatives and more reactive than the quinoline and isoquinoline analogs. 2-Chloroquinoxaline is more reactive than its monocyclic analog, 2-chloropyrazine, with thiourea or with piperidine (Scheme VI, p. 350). 

An investigation has been made of the reactions of p-nitrophenoxide ion in methanol with equimolar quantities of chloropyrazine and (other monochloro-diazabenzenes) in the presence of a tenfold excess of p-nitrophenol (908). The second-order rate coefficient for 2-chloropyrazine at 80° was determined as 9.57 X 10 1/mol sec and as 23.4kcal/mol and logiofias 10.5 and its reactivity (at 50°) compared to that of chlorobenzene was 4.1 x 10, whereas the estimated value for 2-chloropyridine (relative to chlorobenzene) was 2.7 x 10 (908). Kinetics have also been measured for the reaction of 2-chloropyrazine with piperidine in toluene and the energy of activation and entropy of activation determined as 13.2 and 46.2 (909) the corresponding values for 2-chloropyridine are 17.1 and 42.2, respectively. 

Kinetics have been measured for the reactions of p-nitrophenoxide ion in methanol with equimolar quantities (0.01-0.024/) of 2-chloropyrazine, 3- and 4-chloropyridazines, and 2-, 4-, and 5-chloropyrimidines in the presence of a tenfold excess (0.1-0.24/) of p-nitriphenol (908). There was evidence for mild acid catalysis by the p-nitrophenol added to prevent concurrent methanolysis. The reactivity order observed was 2-chloropyrimidine>4-chloropyrimidine>4-chloropyridazine — 3-chloropyridazine — 2-chloropyrazine > 5-chloropyrimidine, and corresponded with the theoretical order as modified by mild acid catalysis, more effective in the order ortho > meta > para to the point of substitution, and including the inverted order, 2- > 4-chloropyrimidine, whereas the usual reactivity order with anionic reagents was 4- > 2-chloropyrimidine (908). 

The reactivity of 2-fluoropyrazine with aqueous sodium hydroxide to give 2-hydroxypyrazine has been investigated (882, 884). In 1.07N sodium hydroxide at 26° the reaction followed pseudo-first-order kinetics with a half-life of 43 minutes, whereas under the same conditions 2-chloropyrazine had a half-life of 18 days, and 2-iodopyrazine and 2-fluoropyridine remained unchanged (882, 884). Thus, under the above conditions, 2-fluoropyrazine was 640 times more reactive than 2-chloropyrazine (882). Hydrolysis of 2-fluoropyrazine in 61V hydrochloric acid proceeded at a much slower rate with a half-life of 4 days at room temperature (884). Some literature preparations of hydroxypyrazines by hydrolysis of halogenopyrazines (chloropyrazines with aqueous sodium or potassium hydroxide unless otherwise specified) are as follows 2-hydroxy (150°) (818) 2-hydroxy-3-methyl (reflux) (680) 2-hydroxy-3,5-dimethyl (reflux) (978) 3-hydroxy-2,5-dimethyl (reflux) (98, 312, 680, 740) [at 120° (978)] 3-hydroxy-2,5-di- -butyl (powdered potassium... 

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