Crystal engineering rescues a solution organic synthesis in a cocrystallization that confirms the configuration of a molecular ladder

Abstract

Treatment of an achiral molecular ladder of C 2h symmetry composed of five edge-sharing cyclobutane rings, or a [5]-ladderane, with acid results in cis-to trans-isomerization of end pyridyl groups. Solution NMR spectroscopy and quantum chemical calculations support the isomerization to generate two diastereomers. The NMR data, however, could not lead to unambiguous configurational assignments of the two isomers. Single-crystal X-ray diffraction was employed to determine each configuration. One isomer readily crystallized as a pure form and X-ray diffraction revealed the molecule as being achiral based on C i symmetry. The second isomer resisted crystallization under a variety of conditions. Consequently, a strategy based on a cocrystallization was developed to generate single crystals of the second isomer. Cocrystallization of the isomer with a carboxylic acid readily afforded single crystals that confirmed a chiral ladderane based on C 2 symmetry. The chiral ladderane and acid self-assembled to generate a five-component hydrogen-bonded complex that packs to form large solvent-filled homochiral channels of nanometer-scale dimensions. Whereas cocrystallizations are frequently applied to structure determinations of proteins, our study represents the first application of a cocrystallization to confirm the relative configuration of a small-molecule diastereomer generated in a solution-phase organic synthesis. supramolecular synthesis | solid-state reactivity | hydrogen bonding

Hydrogen-bonded frameworks for molecular structure determination

“…crystalline sponges) 16,17 . Co-crystallization explicitly for determination of the molecular structure of compounds that otherwise cannot be crystallized relies on specific interactions, and it is limited by an absence of universal co-crystallizing agents 18,19 . The crystalline sponge approach has been used for absolute configuration determination for natural products, synthetic molecules, and reaction intermediates 20–24 .…”

Naphthocrown‐Strapped Calix[4]pyrroles: Formation of Self‐Assembled Structures by Ion‐Pair Recognition

“…[7][8][9][10][11][12][13] To date, molecularbased self-assembled structures have relied on such classic weak interactions as hydrogen bonding, electrostatics, hydrophobic effects, Van der Waals forces, and p-p interactions. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17] Halogen bonding interactions between halogen atoms and electron-rich donors have also been utilized for the construction of self-assembled materials. [18][19][20] Metal cations have likewise been widely exploited as constituents in molecular self-assembly and are a critical feature of a very large and immensely important class of self-assembled materials, commonly referred to as metal-organic frameworks (MOFs).…”

“…This interest is attributable to the fact that self‐assembled materials could see application in various fields, including chemical sensing, drug delivery, and catalysis, as well as the construction of liquid crystals, micelles, supramolecular polymers, and molecular machines; appropriately designed solids are also of interest as semiconductors and as storage materials for small molecules 7–13. To date, molecular‐based self‐assembled structures have relied on such classic weak interactions as hydrogen bonding, electrostatics, hydrophobic effects, Van der Waals forces, and π–π interactions 1–17. Halogen bonding interactions between halogen atoms and electron‐rich donors have also been utilized for the construction of self‐assembled materials 18–20.…”

Functional diversity in templated solid state reactions

“…33 The MacGillivray group has since shown that the ladderane motif can also be synthesized through the photocycloaddition of pyridine decorated trienes ( Figure 18). [34][35] This templated reaction proceeds quantitatively in 72h of UV irradiation and gives an isolated yield of 85%. The generation of ladderanes in the solid state not only optimized the synthesis compared to Corey's solution phase procedure and introduced trienes into solid state reactivity, but further demonstrated the many benefits of solid state reactivity versus solution phase synthesis.…”

“…The crystal data can be found in the Appendix (Tables A3-A6) Figure 49). 22,23,30,31,34,35 Photoreactions of each of these molecules have been successfully demonstrated in the solid state using resorcinol derived templates. With this in mind then, we proposed also cocrystallizing 4,4'PTC with organic templates to investigate the possible formation of photoactive assemblies.…”