Supramolecular construction of a cyclobutane ring system with four different substituents in the solid state

The study addresses the challenge of achieving an intermolecular [2+2] cross-photoreaction (CPR) that forms a cyclobutane ring bearing four different substituents in a quantitative, side-product-free manner. Traditional liquid-phase approaches often require multiple steps and yield mixtures. The authors hypothesize that leveraging face-to-face stacking interactions—specifically perfluorophenyl–phenyl and H–perfluorophenyl–pyridyl interactions—within cocrystals can preorganize unsymmetrical alkenes with parallel C=C bonds at reactive separations, enabling topochemical CPRs in the solid state. The work is important for constructing chiral cyclobutanes and quaternary stereocenters relevant to biologically active molecules and materials.

Background work established that solid-state [2+2] photocycloadditions require alkenes aligned in parallel with C=C separations of about 4.2 Å (Schmidt criteria). Phenyl–perfluorophenyl stacking has been used to promote topochemical photodimerizations and photopolymerizations. Prior CPRs with perfluorophenyl-containing alkenes have afforded cyclobutanes with up to three different substituents, but not four. CPRs can occur in statistical solid solutions; however, a binary cocrystal of two different unsymmetrical alkenes giving a cyclobutane with four different aryl groups quantitatively and cleanly had not been reported. Related advances in crystal engineering and cocrystal synthesis inform the strategy to use complementary electrostatics and stacking to direct olefin alignment.

- Reactants: Symmetrical partially fluorinated alkene 8F (trans-1,2-bis(2,3,5,6-tetrafluorophenyl)ethylene) and unsymmetrical 9F (trans-1-(2,3,5,6-tetrafluorophenyl)-2-(2,3,4,5,6-pentafluorophenyl)ethylene) were synthesized via Wittig reactions. Additional alkenes used: trans-stilbene (SB, symmetrical), trans-4-stilbazole (SBZ, unsymmetrical), and trans-1,2-bis(4-pyridyl)ethylene (BPE, symmetrical). - Computational analysis: DFT calculations provided electrostatic potential maps showing polarized C–F ring carbons (partial positive) and polarized terminal C–H groups (carbon partial negative, hydrogen partial positive), supporting perfluorophenyl–phenyl and H–perfluorophenyl–pyridyl stacking. For 9F, opposite charges at terminal ends indicated propensity for complementary stacking. - Cocrystallization: Equimolar mixtures were dissolved (typically toluene or toluene/ethanol), then slow evaporation (≈2 days) afforded binary cocrystals: SB-8F, BPE-8F, SBZ-8F, SBZ-9F. Single-crystal X-ray diffraction determined structures, showing triclinic P-1 (centrosymmetric) for all four cocrystals. Key preorganization metrics: parallel C=C separations of 3.82 Å (SB-8F), 3.85 Å (BPE-8F), 3.81/3.85 Å (SBZ-8F), and 3.79/3.90 Å (SBZ-9F). Auxiliary interactions included C–H···N hydrogen bonds (≈3.28–3.30 Å) and, in SBZ-9F, intercolumn F···F contacts (2.94 Å). - Solid-state photochemistry: Cocrystals were finely ground, sandwiched between Pyrex plates, and irradiated with a 450 W medium-pressure mercury lamp in 6-h intervals for a total of ≈50 h. Reactions were monitored by 1H NMR (disappearance of alkene resonances and appearance of cyclobutane signals) and confirmed by X-ray diffraction of products. - Product isolation and structure confirmation: Photoproducts formed quantitatively without side products or purification. SB-8F-cb and BPE-8F-cb crystallized from toluene/ethanol and were solved by single-crystal XRD (P-1). SBZ-8F-cb likewise characterized by XRD (P-1). For SBZ-9F-cb (with four different substituents), direct crystallization was challenging; protonation with p-toluenesulfonic acid in dichloromethane/methanol yielded [H-SBZ-9F-cb][p-TsO], crystallizing in monoclinic P21/n, enabling stereochemical assignment. - Instrumentation and materials: Standard reagents (triphenylphosphine, fluorobenzyl bromides, fluorobenzaldehydes, NaH) and solvents (toluene, ethanol, DMF, CH2Cl2, MeOH) were used as received. X-ray crystallographic data were deposited (CCDC 2042036–2042043).

- A solid-state [2+2] cross-photoreaction strategy using binary cocrystals and face-to-face stacking produced cyclobutanes quantitatively (100% yield) without side products or purification across all studied pairs. - Crucially, the unsymmetrical pair SBZ-9F underwent CPR to give SBZ-9F-cb, a chiral cyclobutane bearing four different aryl substituents, in 100% yield. Stereochemistry and substitution pattern were confirmed via X-ray crystallography of the salt [H-SBZ-9F-cb][p-TsO] (space group P21/n). - Other productive CPRs: SB-8F → SB-8F-cb (chiral C2-symmetric) and BPE-8F → BPE-8F-cb (chiral C2-symmetric), and SBZ-8F → SBZ-8F-cb (chiral C1-symmetric), all in 100% yield and confirmed by XRD. - Preorganization metrics satisfying Schmidt criteria were observed: parallel C=C separations of 3.79–3.90 Å in the reactive stacks, supported by perfluorophenyl–phenyl and H–perfluorophenyl–pyridyl interactions, and auxiliary C–H···N hydrogen bonds (~3.28–3.30 Å). - DFT electrostatic maps rationalized stacking preferences, including complementary charge distribution in 9F that promotes directed assembly with SBZ. - The photoproduct SBZ-9F-cb forms chiral carbon scaffolds cleanly in the solid state, addressing a previously elusive target (four different substituents on cyclobutane) without the mixture and multistep issues common in solution-phase methods.

The findings validate the hypothesis that complementary aromatic stacking interactions can be harnessed in cocrystals to preorganize unsymmetrical alkenes for quantitative solid-state cross-[2+2] photocycloadditions. By employing partially fluorinated rings (8F, 9F) to engage both phenyl and pyridyl partners, the authors extend known perfluorophenyl–phenyl stacking concepts and demonstrate mixed stacking modes that align olefins at reactive separations. Achieving a chiral cyclobutane with four distinct aryl substituents (SBZ-9F-cb) shows that binary cocrystals of two different unsymmetrical alkenes can react cleanly and stereospecifically, overcoming prior limitations of statistical solid solutions and product mixtures. The approach simplifies access to chiral cyclobutanes, avoids purification, and underscores the utility of crystal engineering to control reactivity topochemically. These results are relevant for synthesizing complex chiral carbon frameworks important in bioactive molecules and materials.

This work introduces a supramolecular cocrystal-engineering strategy that exploits perfluorophenyl–phenyl and H–perfluorophenyl–pyridyl stacking to direct solid-state [2+2] cross-photoreactions. The method delivers cyclobutanes quantitatively and cleanly, including the key achievement of forming a chiral cyclobutane bearing four different aryl substituents (SBZ-9F-cb). The study demonstrates that partially fluorinated aromatic systems can effectively mediate face-to-face stacking to preorganize unsymmetrical alkenes for topochemical reactions. Future research will expand the substrate scope to create additional chiral carbon scaffolds relevant to biologically important compounds and materials science, and explore broader applications in transiently trapping reactive species and controlling chemical reactivity.

- Crystallization of the neutral four-substituent cyclobutane SBZ-9F-cb was difficult; structural confirmation required formation of a protonated salt [H-SBZ-9F-cb][p-TsO] for X-ray analysis. - The demonstrated scope centers on aryl/perfluoroaryl and pyridyl systems that engage in specific stacking interactions; general applicability to other functional groups or aliphatic alkenes remains to be established. - Reactions required prolonged UV irradiation (~50 hours), which may limit throughput or scalability without optimization.