Calix[4]arene sulfonate hosts selectively modified on the upper rim: a study of nicotine binding strength and geometry

ABSTRACT

We present the synthesis and structure-activity relationships of sulfonatocalix[4]arene hosts bearing novel substitutions. The calix[4]arenes are modified on the upper rim at either one or two of the phenolic units, where the dual modifications are introduced regioselectively on neighbouring or opposing phenols. The calix[4]arenes are mono- or di-functionalised with nitro or formyl groups, with the remaining upper-rim sites in all cases occupied by sulphonates. Equilibrium association constants were determined between each host and the guests nicotine, nornicotine, and cotinine. Indicator displacement-based binding studies show that nicotine binds most strongly to the different members of the library followed by nornicotine, whereas cotinine displays weak to no binding. NMR titrations were carried out with nicotine and show different host-guest interaction geometries for the formyl-calix[4]arenes versus the nitro-calix[4]arenes.

Graphical abstract

KEYWORDS:

• Calixarenes
• macrocycles
• host-guest chemistry
• NMR
• drug
• nicotine

Acknowledgments

We thank Allison Selinger and Prof. Peter Bayer for helpful discussions on the data analysis for indicator displacement assays.

Disclosure statement

No potential conflict of interest was reported by the authors.

Supplemental material

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Additional information

Funding

This research was supported by NSERC Discovery Grant RGPIN-2019-04806, Deutsche Forschungsgemeinschaft (BA1624/15-1), and a Canada Research Chair awarded to FH.