Nucleophilic Attack on the Carbon - Nitrogen Double Bond Leading to Tetrahedral Intermediates with Conformationally Restricted Stereochemistry

Methoxide ion substitution on 4-chloro-1H-2,3-benzoxazine 4 has been investigated. The rates of cyclization have been measured for (Z)- and (E)-O-(2-hydroxyethyl)benzohydroximoyl halides (PhC(X)=NOCH2CH2OH; X = Cl or Br) using potassium t-butoxide to generate alkoxide ions from the alcohols. The element effect for the Z and E isomers are kZBr/kZCl = 3.08 and kEBr/kECl = 2.38. The Z-to-E rate ratios are 0.25 (chlorides) and 0.33 (bromides). These reactions are proceeding by rate-determining nucleophilic attack by the alkoxide ion on the carbon–nitrogen double bond (AN# + DN). The restricted stereochemistry of the tetrahedral intermediates suggests that the E-hydroximoyl bromide and chloride may be undergoing unassisted ionization to form a zwitterionic intermediate that leads to product. Alternatively, the chair conformation of the tetrahedral intermediate may be undergoing a ring flip to a boat conformation in which there are antiperiplanar electron pairs that assist in the ionization of the bromide or chloride ion.