Pyridines, sterically-hindered, basicity

Methyl- and 2,6-dimethylpyridine as catalysts with sterically hindered a-com-plexes give greater isotope effects (k2n/k2D up to 10.8). Such values are understandable qualitatively, since the basic center of these pyridine derivatives cannot easily approach the C-H group. The possibility of tunneling can be excluded for these reactions, as the ratio of the frequency factors 4h 4d and the difference in activation energies ED—EU (Arrhenius equation) do not have abnormal values. 

Solid-liquid phase systems with no added solvent produce esters in high yield [e.g. 2, 3] and are particularly Useful when using less reactive alkyl halides [e.g. 15], for the preparation of sterically hindered esters [16], or where other basic sites within the molecule are susceptible to alkylation, e.g. anthranilic acid is converted into the esters with minimal A-alkylation and pyridine carboxylic acids do no undergo quat-emization [17]. Excellent yields of the esters in very short reaction times (2-7 minutes) are also obtained when the two-phase system is subjected to microwave irradiation [18]. Direct reaction of the carboxylic acids with 1,2-dichloroethane under reflux yields the chloroethyl ester [19], although generally higher yields of the esters are obtained under microwave conditions [20]. 

The reactions of the 4-halopyridines parallel those of the corresponding 2-isomers, with the exception that 4-halopyridines polymerize much more readily (e.g. to 903) because the pyridine nitrogen atom is not sterically hindered and is more basic (cf. Section 3.2.1.3.4). As expected, the chlorine atom in the 1-position of 1,3-dichloroisoquinoline is more reactive than that in the 3-position, thus, mild treatment with sodium ethoxide gives (904). Halogens in the 9-position of acridine are more reactive, e.g. (906) — (90S), (907). 

The use of less basic and sterically hindered amines [e.g., collidine or 2,6-di-tert-butyl-4-(dimethylamino)pyridine ], the avoidance of preactivation, and the use of less polar solvent systems are additional appropriate strategies for the suppression of racemization. Except for fragment condensations in solution and couplings involving racemization-prone derivatives, the addition of HOXt to the reaction mixture has no pronounced effect on a uronium salt mediated racemization/epimerization, in contrast to the striking effects of HOAt on epimerization caused by PfPyU and haloamidinium salts such as CIP or TFFH (Section 3.8.1.2.1). 

The steric requirements of such a complex would amply account for the low reactivity of axial and other hindered alcohols. The alternative stepwise formation of an alkoxide anion followed by its attack upon the acylating reagent seems unlikely in view of the weakly basic character of pyridine. 

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