Mechanisms of alkoxide substitution reactions at the carbon-nitrogen double bond. Stereoelectronic control during nucleophilic substitution

Abstract

The stereochemistry and mechanisms of the alkoxide substitution reactions of O-methylbenzohydroximoyl chlorides (1 and 2) and alkyl O-methylbenzohydroximates (3 and 4) have been investigated. The reactions of the (Z)-hydroximoyl chlorides 1 with alkoxides in 10% methanol-90 % Me2SO proceed with >95% retention of configuration to give the (Z)-hydroximates 3. The alkoxide reactions of the (£)-hydroximoyl chlorides 2 are usually less stereoepecific and give >77% of the substitution product (4), corresponding to retention of configuration. The reactions of the hydroximoyl chlorides la and 2a with methoxide ion follow second-order kinetics and have approximately the same rate constants. The reaction of the hydroximoyl bromide lh with methoxide is only 2.2 times faster than that of the chloride la. The methoxide substitution rates of five (Z)-hydroximoyl chlorides (la, ld-g) give a Hammett correlation with with a p value of 1.90. These observations are consistent with a mechanism in which a hydroximoyl chloride (1) undergoes rate-determining nucleophilic attack by methoxide to form a tetrahedral intermediate which rapidly loses chloride ion to give the hydroximate 3. The (Z)-hydroximate 3e undergoes a methoxide substitution reaction to give 4e but at a considerably slower rate than the (Z)-hydroximoyl chloride la (fe(la)/fc(3e) = 53). The second-order rate constant for the reaction of the (Z)-hydroximate 3e with methoxide is about 300 times greater than the rate constant for the reaction of the (E)-hydroximate 4e with methoxide. The reaction of methoxide with the (E)-hydroximate 4e initially produces mainly the Z product 3a, but the product distribution changes with time, and eventually the E isomer 4a predominates. The change in product distribution during the course of this reaction is due to a methoxide-catalyzed isomerization of 3a to 4a. The stereochemistry and relative rates of the reactions of 1-4 with methoxide ion are interpreted in terms of Deslongchamp's theory of stereoelectronic control. It is suggested that stereoelectronically controlled loss of chloride ion from the tetrahedral intermediate 12 (from the reaction of la with methoxide ion) is faster than either loss of methoxide ion to give starting material or stereomutation. In the tetrahedral intermediate 13 (from 2a), stereomutation to 12 and 14 and stereoelectronically controlled loss of chloride ion from 12 and 14 are faster processes than loss of methoxide ion from 13. The tetrahedral intermediate 15 (from 3e) undergoes stereoelectronically controlled loss of methoxide or ethoxide ion faster than it undergoes stereomutation. In the case of the intermediate 17 (from 4e), stereoelectronically controlled loss of methoxide ion to give starting material is faster than stereomutation.In 1973 we communicated the first examples of stereospecific nucleophilic substitution at the carbon-nitrogen double bond.3 The reaction of methoxide ion with the Z and E isomers of O-methylbenzohydroximoyl chlorides

2-Azabuta-1,3-diene-4-carbonitriles: stereoselective synthesis and nucleophilic substitution at the carbon–nitrogen double bond

“…Methylation of adducts 9-11 with diazomethane occurs stereoselectively, affording (E)-1-methoxy-1-phenyl-2-azabuta-l,3-dienes [12][13][14].…”

“…There are several studies (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17) on nucleophilic substitutions at the C-N double bond. A nucleophilic additionelimination mechanism or a pathway involving a nitrilium ion intermediate has been suggested.…”

A new method for introducing iodo and bromo fluorides into organic molecules using elemental fluorine

“…A cold (-75 °C) CHC13 solution of 15 mmol of citronellal (5) was added to the IF suspension and allowed to react for 1-2 min. After the usual workup and after chromatography using 10% EtOAc in petroleum ether as eluent, 6 was obtained in 50% yield as an oil: IR (neat) 1720 cm'1; NMR 9.5 (CHO, 1 H, t), 4.30 (CHI, 1 H, m), 1.45 (CH3CF, 3 H, d, s/Hf = 22 Hz), 1.40 (CH3CF, 3 H, d, JHF = 22 Hz), 0.87 (CH3, 3 H, d, JHH = 6 Hz); 19F NMR -134 ppm (m). Compound 6 decomposes slowly in the air due to both oxidation and dehydrofluorination.…”

“…It was obtained in 64% yield as an oil with the same physical and spectral properties as reported in the literature. 6,7 transl-Fluoro-2-iodomenthane (10). A cold CHC13 solution of 1.38 g of 9 was allowed to react with IF for 5 min and then worked up as usual.…”

“…Despite its high reactivity, an aldehyde CH3(CH2)"CH=CH2 CH3(CH2)nCHFCH2I function may be present, since unlike IF3 and IF5, IF itself is not a strong oxidizer. Thus citronellal (5) forms only one regiospecific adduct, 3,7-dimethyl-7-fluoro-6-iodo-loctanal (6) in good yield.…”