The elusive endo-product of the archetypal Diels-Alder reaction of furan and maleic anhydride – observed in the solid state at last

Abstract

The [4+2] reaction of furan and maleic anhydride is an archetypal, textbook example of Diels-Alder reactivity, whose role as an early and prominent exception from the Alder endo-rule has made it a model in teaching and focus of continuous research for almost a century. Although the kinetics, thermodynamics and the exo-product of this reaction have been extensively studied, the critically important endo-product has remained almost completely unexplored, generally seen only as a fleeting intermediate in solution. By conducting the reaction without an external solvent, we now discover several solid forms of this historically important system, with the combined use of crystal structure prediction (CSP) and X-ray crystallography enabling the exploration of the structures and supramolecular chemistry of the endo-adduct in solidified reaction mixtures. Depending on the temperature, the endo-isomer appears to preferably form either a single-component solid or a cocrystal with the exo-isomer, which offers an explanation of reproducibility challenges reported 60 years ago and can tentatively be further rationalised through state-of-the-art free energy calculations. The observation and complexity of multiple new solid forms of the endo-, as well as exo-isomer, are surprising, long-missing contributions to this frequently visited Diels-Alder reaction.