Researchers have extended a cage-crystal-based structure-determination method to small, low-polarity molecules that it previously could not handle. Adding phenanthrene as a "modulator" to the hollow palladium-based cages let them capture each target molecule while filling the extra space, and this gave X-ray structures for 24 of 30 sesquiterpenoid-type compounds. None of the 30 worked without it. Eleven of these structures were new, including the liquid hydrocarbon longifolene, and a chiral cage gave absolute configurations for selected compounds. Because the host needs no chemical modification, screening other modulators could adapt the method to other compound classes.
Adding phenanthrene as a co-guest let the second-generation crystalline sponge (2G-CS) method determine X-ray structures for 24 of 30 small, low-polarity C15 molecules, mostly sesquiterpenoids. Under standard conditions, none of the 30 gave guest-containing crystals. Eleven of the 24 structures had not been reported before, including that of the liquid hydrocarbon longifolene. A chiral version of the cage gave the absolute configurations of five compounds.
The 2G-CS method determines a molecule's structure without crystallizing the molecule itself. Instead, the molecule is captured inside hollow palladium-based cages that assemble into a crystal. The method often fails for low-polarity molecules with molecular weights of 200-300. The authors attribute this to the cage cavity being too large for such small molecules. The molecules likely have too much freedom of motion and interact only weakly with the host. Such small sesquiterpenoids are important in natural-product research and drug discovery.
The team used a "size-compensation strategy." A flat aromatic "modulator" is encapsulated together with the target molecule, and the pair fills the cavity. The modulator is not meant to be encapsulated alone. The ternary complex preferentially forms when both guests are present. Among six modulators tested, phenanthrene gave the highest inclusion level for (+)-longifolene, about 40% of cages by NMR. The team then applied the same phenanthrene-based strategy to the other 29 compounds without further optimization.
Phenanthrene enabled structure determination for 24 of the 30 compounds (80%), including one analyzed with the chiral cage. The successes spanned hydrocarbons, macrocycles, fused-ring compounds and linear molecules. The modulator's arrangement varied with the guest. Of the 24 successfully determined structures, 11 had not been reported previously, including that of longifolene, a liquid first isolated in 1920. With the standard cage, the complexes crystallized under nearly uniform conditions with very similar lattice parameters. The guest electron density was nonetheless clear enough for assignment. A chiral cage gave the absolute configurations of five selected compounds, including four hydrocarbon natural products. These included the assignment of (+)-longifolene as (1R ,2S ,7S, 9S). The four hydrocarbons matched earlier assignments. The authors believe this is the first crystallographic characterization of these four unmodified parent hydrocarbons.
The modulator approach extends 2G-CS structure determination to small, low-polarity sesquiterpenoids. It does so "without the need for chemical modification of the host," and it keeps the method's operational simplicity, microscale sample use and rapid analysis. Because modulator uptake can be checked by NMR before crystallization, the authors propose that screening other modulators could adapt the same host to other classes of analytes.
