An nfπ* Interaction in Aspirin: Implications for Structure and Reactivity

Stereoelectronic effects modulate molecular reactivity and conformation. For example, the nucleophilic attack at a carbonyl carbon is preferred along the B€urgi Dunitz trajectory. This orientational preference stems from a stereoelectronic effect arising from the delocalization of an electron pair (n) of a nucleophile into an antibonding orbital (π*) of the carbonyl group. Our experimental and theoretical studies have revealed an analogous stereoelectronic effect that affects the conformation of peptides and proteins. In these systems conformational stability is provided by delocalization of a lone pair of a carbonyl oxygen into the π* orbital of a proximal carbonyl group. In such an interaction, termed the nfπ* interaction, the van der Waals surfaces of the donor oxygen and acceptor carbon interpenetrate. In addition to affecting the conformation of peptides and proteins, an nfπ* interaction has also been implicated in the origin of life by favorably orchestrating the reactivity and stability of prebiotic molecules and in stabilizing conformations of (2S,4S)-4-hydroxyproline, β-alanine, and γ-aminobutyric acid. Herein, we report on the existence of an nfπ* interaction in one of the oldest of drugs and discuss its implications for structure and reactivity. The medicinal benefits of salicylic acid have been known since the time of Hippocrates. Its O-acetylated form, “aspirin”, was first synthesized in 1853 and marketed as an analgesic by the German dyemanufacturer Friedrich Bayer&Company in 1899. This year, daily aspirin was shown to reduce the risk of cancer. The molecular structure and reactivity of aspirin have been studied extensively. Upon examining the crystal structure of aspirin (Figure 1), we observed that a lone pair of its donor oxygen could be poised to interact with theπ* orbital of its ester carbonyl group. Moreover, the key signature of an nfπ* interaction—the pyramidalization of the acceptor carbonyl group—is evident in this crystal structure. This observation motivated us to perform a detailed conformational analysis of acetylsalicylic acid and its conjugate base. The results reveal that electron delocalization via the nfπ* interaction has significant and heretofore unappreciated effects on the physical and chemical properties of aspirin.