Unprecedented Packing Polymorphism of Oxindole: An Exploration Inspired by Crystal Structure Prediction.

Crystal polymorphism, characterized by different packing arrangements of the same compound, strongly ties to the physical properties of a molecule. Determining the polymorphic landscape is complex and time-consuming, with the number of experimentally observed polymorphs varying widely from molecule to molecule. Furthermore, disappearing polymorphs, the phenomenon whereby experimentally observed forms cannot be reproduced, pose a significant challenge for the pharmaceutical industry. Herein, we focused on oxindole (OX), a small rigid molecule with four known polymorphs, including a reported disappearing form. Using crystal structure prediction (CSP), we assessed OX solid-state landscape and thermodynamic stability by comparing predicted structures with experimentally known forms. We then performed melt and solution crystallization in bulk and nanoconfinement to validate our predictions. These experiments successfully reproduced the known forms and led to the discovery of four novel polymorphs. Our approach provided insights into reconstructing disappearing polymorphs and building more comprehensive polymorph landscapes. These results also establish a new record of packing polymorphism for rigid molecules.

"Click"-Like η6 -Metalation/Demetalation of Aryl Iodides as a Means of Turning "ON/OFF" Halogen Bond Donor Functionality.

η6 -Metalated aryl halides are recognized as a class of halogen bond (XB) donors. Click-like η6 -metalation/demetalation of aryl iodides by cyclopentadienylruthenium(II) ([CpRuII ]+ ) is shown to turn ON/OFF (amplify/suppress) XB donor functionality. [CpRu(MeCN)3 ][PF6 ] is shown to react quantitatively with iodobenzenes (ArIn , n=1,2) to yield [CpRu(η6 -ArIn )][PF6 ] compounds. Photochemical demetalation (405 nm) quantitatively reverts these compounds to ArIn and [CpRu(MeCN)3 ][PF6 ]. Crystal structures of [CpRu(ArXn )]+ salts show that the [CpRu(ArIn )]+ cations are strong, charge-assisted XB donors analogous to iodopyridinium cations. XB-induced association of [CpRu(C6 H5 I)]+ with diazobicyclo[2.2.2]octane (DABCO) is established by NMR spectroscopy. [CpRu(C6 H5 I)][BPh4 ] and [CpRu(1,4-C6 H4 I2 )][BPh4 ] co-crystallize with DABCO and the structure of [CpRu(1,4-C6 H4 I2 )][BPh4 ]⋅DABCO⋅Et2 O is reported. DFT calculations support amplification of the XBing capabilities of aryl iodides upon [CpRu]+ -metalation.