Mixed Reactivity of Azanorbornadiene Electrophiles as Fragmentable Linkages

Abstract Azanorbornadiene (ZND) molecules are assembled by Diels–Alder reaction of N-acyl- or N-sulfonyl-pyrroles with electron-deficient alkynes. ZND electrophiles of varying structures were tested for reactivity with protic nucleophiles and subsequent retro-Diels–Alder (rDA) fragmentation to the starting pyrrole, a reaction sequence of interest for drug delivery and degradable materials applications. ZNDs were shown to take on thiols and amines (including heterocyclic and tertiary examples) with similar rates in the range of 10−2–10−4 M−1 s−1. rDA fragmentation was found in most cases to be decelerated in protic solvents relative to chloroform, in contrast to thiol adducts of analogous oxanorbornadienes (ONDs). Furthermore, the presence of a 2-hydroxymethyl group on the N-acylpyrrole moiety gave rise to the release of the free carboxyl fragment by virtue of acyl migration following rDA cleavage, providing a potential method of traceless release of a carboxylic acid cargo molecule. Facile amine reactivity stands in sharp contrast to the thiol-selective reactivity of OND electrophiles. Density functional theory calculations identified electrostatic polarization of the reactive ZND double bond as a potential source of this difference. The reaction patterns identified here mark ZNDs as more complex motifs than ONDs, but also with the potential of a greater variety of uses.