Sulfanilamide anion

The A-oxidation of 3-chloropyridazines increases their reactivity toward methoxide and sulfanilamide anions.The reactivity of 4-chloro- or 4-nitro-quinoline and of chloropyridines toward methoxide ion and piperidine is less than that of the corresponding A-oxides (see Tables II and XI, pp. 270 and 338). The activating effect of the A-oxide moiety in 3-halopyridine A-oxides is greater than that of a nitro group, and in fluoroquinoline A-oxides the activation is transmitted to resonance-activated positions in the adjoining rings. 

An interesting example of the result of conjugation of substituents is the behavior of 3-methoxy-6-methylsulfonylpyridazine studied in our Laboratories. In 6-chloro-3-methoxypyridazine and in 3,6-dimethoxypyridazine, the methoxy groups are unreactive toward sulfanilamide anion, and the chloro group is deactivated relative to... 

It is often advantageous to proceed to a desired product through two nucleophilic displacements rather than directly when one can exploit a difference in the reactivity of two leaving groups. An example is the conversion of 4-chloro-2,6-dimethoxypyrimidine (109) (not satisfactorily reactive with sulfanilamide anion) by means of trimethylamine into the more reactive trimethylammonio derivative 110. Conversion of chloro-quinohnes and -pyrimi-dines into nitriles is best accomplished by conversion (with sulfite) into the sulfonic acids before reaction with cyanide. 

Aryloxy, hydroxy arylsulfonyloxy, and phosphoryloxy. The 4-toluenesulfonyloxy and 4-nitrophenyloxy groups approximate the chloro group in replaceability in benzene derivatives. The former appears to be less reactive than chloro toward hydroxide on quinoline and -phenoxy on pyrimidine is relatively unreactive toward sulfanilamide anion or ammonia. On cinnoline, quinazoline, or quinoline, a 4-phenoxy group is less reactive than a chloro group. 

In work on 6-methoxypyrimidines (130), the 4-methylsulfonyl group was found to be displaced by the sulfanilamide anion more readily than were 4-chloro or trimethylammonio groups. This reactivity may be partly due to the nature of the nucleophile (106, Section II, D, 1). However, high reactivity of alkyl- and aryl-sulfonyl heterocycles with other nucleophiles has been observed. A 2-methylsulfonyl group on pyridine was displaced by methoxide ion with alkaline but not acidic methanol. 3,6-Bis(p-tolylsulfonyl)-pyridazine reacts (100°, 5 hr) with sulfanilamide anion and even the... 

Aqueous acidic or alkaline reactions give equivalent or predominant amounts of 3-substitution (with HO, N2H4, AcO, H2O, or sulfanilamide anion). On the other hand, reactions with hydrazine or ammonia in alcohols or benzene give a great predominance of 6-sub-stitution. 

Direct deactivation by a methoxy group makes 3-chloro-6-methoxy-pyridazine unreactive toward sulfanilamide anion in contrast to its 6-chloro, 6-methyl, and 6-hydrogen analogs. Both direct and indirect deactivation of the two chlorines in 3,6-dichloro-4-methoxy-pyridazine (160) are possible the greater reactivity at the... 

Factor b above is discussed in Sections II, B, 1 II, B, 4 and II, C. A hydrogen-bonded structure such as 221 can account for the facile reaction of 5-bromouracil or for the unique, so-called hydrolyzability of carboxymethylthio-azines (237). The latter may also react via the intramolecular mechanism indicated in 136. The hydrogen-bonded transition state 238 seems a reasonable explanation of the fact that 3,4,6- and 3,4,5-trichloropyridazines react with glacial acetic acid selectively to give 3-pyridazinones while other nucleophiles (alkoxides, hydrazine, ammonia, or sulfanilamide anion) react at the 4- and 5-positions. In this connection, 4-amino-3,5-dichloro-pyridazine in liquid hydrazine gives (95°, 3hr, 60%yield)the isomer-... 

Our results on the reaction of 2,4-dichloropyrimidine with another anion should be pointed out in connection with the fallacy of considering sole product (isolated) to mean absolute selectivity. From the reaction of 2,4-dichloropyrimidine with sulfanilamide anion in molten acetamide (65°, 1 hr), the major product, 2-chloro-4-sulfanilamidopyrimidine, is isolated in good yield paper chromato-... 

The V-oxidation of 3-chloropyridazines increases their reactivity toward methoxide and sulfanilamide anions. The reactivity of... 

Sulfanilamido-6-(p-tolyl8ulfonyl)pyridazine, deactivated by anionization, seems to be about as reactive (150°, 12 hr) toward alkoxide ions as is the 6-chloro analog. In 3-chloro-6-methyl-sulfonylpyridazine the chloro group is preferentially displaced by sulfanilamide anion and by alkylamines and aniline. However, in this substrate as well as in 4-chloro-6-methylsulfonylpyrimidine, the relative reactivity involves their mutual activation as well as their mobilities as leaving groups. 

---