Reactivity in Bicyclic Azines

Kinetic Data and Relation op Rings and Ring-Positions. 

In bicyclic azines, as in the monocyclic azines already discussed, the faster of two nucleophilic substitutions proceeds via the transition state which has the lower free energy (with respect to the reactants) due to the stabilizing effects of resonance, hydrogen bonding, or electrostatic attractions. Different nucleophiles and different leaving 

The relation of the activation by a nitro group to that by an azine-nitrogen in various bicyclic positions provides information in support of that available from studies of azines and forms the basis for certain predictions of azine reactivity. The data tabulated in Section IV, A, 2 also provide a few comparisons of leaving groups, nucleophiles, and deactivating and activating substituents (cf. Sections II, E and III, A, 2). 

Where ortho effects and special entropy factors control the relation of the reaction rates, it seems more appropriate to evaluate relative activation from the energies of activation. 

Summary of Relative Reactivity at Different Ring-Positions. A Proposed Activation-Numbering System. Reactivity Factors 

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Covalent addition of solvent or of nucleophile prior to substitution will alter the reactivity characteristics of the substrate. Covalent addition of nucleophile after substitution will affect the kinetics in a way similar to the formation of 389. Covalent hydration and additions are especially likely to occur in bicyclic azines. (cf. Section IV,B,3,b).ii>i o>i i i4... 

The activation produced by the ring-nitrogens in bicyclic azines is based on the increase in reactivity over that in the corresponding naphthalenes. The difference in reactivity of i- and 2-halo-naphthalenes (Table IX) toward piperidine - is slight the relation of their kinetic parameters is not consistent. At 200°, the... 

In Scheme IV, intranuclejar activation is depicted. Kinetic studies with ionic nucleophiles show a variable relationship between the rates of reaction ortho and para to an azine-nitrogen (348 vs. 353 or 349) or nitro group due to entropy effects the energy of activation is expected on further study to be consistently lower for the para-position. The relative reactivity of 2- and 4-substituted bicyclic azines... 

Chloroquinoline (401) reacts well with potassium fluoride in dimethylsulfone while its monocyclic analog 2-chloropyridine does not. Greater reactivity of derivatives of the bicyclic azine is evident also from the kinetic data (Table X, p. 336). 2-Chloroquinoline is alkoxylated by brief heating with methanolic methoxide or ethano-lic potassium hydroxide and is converted in very high yield into the thioether by trituration with thiocresol (20°, few hrs). It also reacts with active methylene carbanions (45-100% yield). The less reactive 3-halogen can be replaced under vigorous conditions (160°, aqueous ammonia-copper sulfate), as used for 3-bromoquino-line or its iV-oxide. 4-Chloroquinoline (406) is substituted by alcoholic hydrazine hydrate (80°, < 8 hr, 20% yield) and by methanolic methoxide (140°, < 3 hr, > 90% yield). This apparent reversal of the relative reactivity does not appear to be reliable in the face of the kinetic data (Tables X and XI, pp. 336 and 338) and the other qualitative comparisons presented here. 

The alteration of nucleophilic reactivity by the intervention of covalent hydration and analogous nucleophilic additions needs to be borne in mind for many polyazanaphthalenes. Covalent hydration has been observed in several bicyclic azines besides pteridine and quinazoline (Section IV, B) and is related to nucleophilic substitution in activation and in proceeding through the same first stage as 8 Ar2 reactions. The Bucherer interconversion of naphthols and naphthylamines involves exchange of oxygen and nitrogen substituents in a covalent adduct produced by bisulfite ion. ... 

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