The effects of solvents and nucleophiles on heteroaromatic SRN1 reactions

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Virginia Polytechnic Institute and State University


This dissertation is concerned with three aspects of the nucleophilic substitution reactions of some heteroaromatic halides.

First, the SRN1 reaction of 2-chloroquinoline with potassioacetone was studied in several solvents. Tetrahydrofuran (THF), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), and dimethoxyethane (DME) were found to be more suitable as solvents for this reaction than were diethylether and benzene. This reaction was stimulated by near UV irradiation. However, substantial reaction occurred in the more polar solvents without photostimulation. The SRN1character of these reactions was substantiated by inhibition studies. The relative rates of this reaction in the solvents generally increased with increased solvent polarity. The SRN1 reactions of 2-chloroquinoline, 2-bromopyridine, and iodobenzene with ketone enolates in THF were found to occur slower than their analogous reactions in liquid arrnnonia.

Second, 4-picoline and acetonitrile anions were employed as nucleophiles for heteroaromatic SRN1 reactions. The photostimulated reaction of 2-chloroquinoline with potassioacetonitrile in liquid ammonia was complicated by 11 polymer 11 formation and by SNAR2 and SN(ANRORC) reactions with equilibrium concentrations of potassium amide. In the absence of photostimulation, 3-cyano-2-methylquinoline was the major product observed and presumably resulted from an interesting SN(ANRORC) reaction involving potassioacetonitrile. Attempts to eliminate the side reactions with amide by employing excess acetonitrile resulted in increased yields of "polymer." The reaction of 4-picoline with 2-bromopyridine was also plagued with a significant competing amination reaction. However, moderate increases in the ratio of 4-picoline to potassium amide employed reduced the yields of 2-aminopyridine. In contrast, the SRN1 reaction of 4-bromopyridine with potassio-4-picoline was accompanied by only trace amounts of 4-aminopyridine.

Lastly, the SRN1 reactions of 2,4-dimethyl-3-pentanone with 2-bromopyridine and iodobenzene were accompanied by a reductive dehalogenation process. That these reactions involved the abstraction of s-hydrogens from the nucleophile was supported by the isolation of 2,4,4,5,5,7-hexamethyloctane-3,6-dione. Spectral characterizations and the independent synthesis of this ketone dimer is described. The search for a similar ketone dimer from the reaction of potassiocyclopentanone with bromobenzene was inconclusive.