Revisiting Homochiral versus Heterochiral Interactions through a Long Detective Story of a Useful Azobis-Nitrile and Puzzling Racemate

This paper documents and reinvestigates the solid-stateand crystalstructures of 4,4 & PRIME;-azobis-4-cyanopentanoic acid (ACPA), a water-solubleazobis-nitrile of immense utility as a radical initiator in livingpolymerizations and a labile mechanophore that can be embedded withinlong polymer chains to undergo selective scission under mechanicalactivation. Surprisingly, for such applications, both the commerciallyavailable reagent and their derivatives are used as singleinitiators when this azonitrile is actually a mixture of stereoisomers.Although the racemate and meso compounds were identifiedmore than half a century ago and their enantiomers were separatedby classical resolution, there have been confusing narratives dealingwith their characterization, the existence of a conglomeratic phase,and fractional crystallization. Our results report on the X-ray crystalstructures of all stereoisomers for the first time, along with furtherdetails on enantiodiscrimination and the always intriguing argumentsaccounting for the stability of homochiral versus heterochiral crystal aggregates. To this end, metadynamic (MTD)simulations on stereoisomer molecular aggregates were performed tocapture the incipient nucleation events at the picosecond time scale.This analysis sheds light on the driving homochiral aggregation ofACPA enantiomers. Thesolid-state behavior and crystal structures of all stereoisomersof ACPA, a useful azobis-nitrile-based radical initiator, have beendescribed and discussed in depth. The investigation sheds light oncomplex and often confusing structural data collected so far and providesfurther reasoning on homochiral versus heterochiralaggregation of Pasteurian-type racemates.

Automated summary

This paper documents and reinvestigates the solid-state and crystal structures of 4,4'-azobis-4-cyanopentanoic acid (ACPA), a water-soluble azobis-nitrile of immense utility as a radical initiator in living polymerizations and a labile mechanophore that can be embedded within long polymer chains to undergo selective scission under mechanical activation. The X-ray crystal structures of all stereoisomers of ACPA have been reported for the first time, along with further details on enantiodiscrimination and the aggregation behavior of ACPA enantiomers.