The creation of efficient, atom-economical, and sustainable organic syntheses is a significant area of ongoing research. A key challenge in this field is achieving a quantitative intermolecular [2+2] cross-photoreaction (CPR) to form a cyclobutane ring system with four different substituents, resulting in a stereogenic carbon atom. Such reactions typically involve multiple steps, occur in the liquid phase, and produce mixtures of products. Previous research has shown that alkenes functionalized with perfluorophenyl groups, along with phenyl and/or carboxylic acid groups, can undergo rare solid-state CPRs upon cocrystallization. For a solid-state photocycloaddition, two alkenes must crystallize in a parallel arrangement with C=C bonds separated by approximately 4.2 Å. While previous studies have produced aryl-substituted cyclobutanes with up to three different substituents, the formation of a cyclobutane with four distinct substituents remained elusive. This study aims to address this challenge by using four different functional groups to promote face-to-face stacking interactions, specifically perfluorophenyl-phenyl and H-perfluorophenyl-pyridyl stacking, to precisely direct the assembly of the C=C bonds for reaction.

The literature extensively covers efforts towards efficient and sustainable organic synthesis, with a particular focus on the challenges involved in creating cyclobutane rings with diverse substituents. Several studies highlight the use of perfluorophenyl groups and the significance of solid-state reactions for achieving controlled photocycloadditions. Previous work demonstrated the formation of cyclobutanes with up to three different substituents through solid-state CPRs utilizing specific stacking interactions. However, forming a cyclobutane ring with four distinct substituents has remained a significant synthetic hurdle, primarily due to the challenges associated with precise pre-organization of the reactant molecules in the solid state. This study builds upon these prior efforts, investigating the potential of specific intermolecular interactions to facilitate the desired reaction.

The researchers synthesized several alkenes: the symmetrical trans-1,2-bis(2,3,5,6-tetrafluorophenyl)ethylene (8F), and the unsymmetrical trans-1-(2,3,5,6-tetrafluorophenyl)-2-(2,3,4,5,6-pentafluorophenyl)ethylene (9F). They also employed symmetrical trans-stilbene (SB) and unsymmetrical trans-4-stilbazole (SBZ) as phenyl-bearing alkenes, along with symmetrical trans-1,2-bis(4-pyridyl)ethylene (BPE). Density functional theory (DFT) calculations were performed to predict the electrostatic properties of these alkenes, guiding the selection of combinations for cocrystallization. Cocrystals were prepared by slow evaporation from toluene and/or ethanol solutions. The resulting cocrystals were then subjected to UV-irradiation from a 450 W medium-pressure mercury lamp. The reactions were monitored, and the products were characterized using single-crystal X-ray diffraction and NMR spectroscopy. Specific cocrystals studied include SB-8F, BPE-8F, SBZ-8F, and SBZ-9F. The crystal structures revealed parallel stacking of the olefins, with specific distances between C=C bonds and various intermolecular interactions (e.g., C-H···F, C-H···N, and F···F forces) contributing to the reaction's success. In the case of SBZ-9F, the cyclobutane product required further processing with p-toluenesulfonic acid to obtain crystals suitable for X-ray diffraction analysis. The authors detailed the synthesis of all compounds involved (8F, 9F, SBZ) and provided complete crystallographic data (CCDC deposition numbers 2042036-2042043).

The study successfully generated cyclobutane rings with up to four different aryl substituents using solid-state [2+2] cross-photoreactions (CPRs). The key to this achievement was the precise control over the arrangement of reactant molecules within cocrystals. Through careful selection of alkenes (based on DFT calculations predicting electrostatic properties) and cocrystallization, the authors obtained face-to-face stacking geometries that favored the CPR. Specifically, the following results were obtained: * **SB-8F cocrystal:** Upon UV irradiation, this cocrystal quantitatively yielded a chiral C₂-symmetric cyclobutane (SB-8F-cb). The C=C bonds were parallel and separated by 3.82 Å. * **BPE-8F cocrystal:** Similar to SB-8F, this cocrystal underwent quantitative conversion to a chiral C₂-symmetric cyclobutane (BPE-8F-cb) upon UV exposure. The C=C bond distance was 3.85 Å. Additional C-H···N hydrogen bonds were observed in this system. * **SBZ-8F cocrystal:** This yielded a chiral C₁-symmetric cyclobutane (SBZ-8F-cb) with three different substituents. The C=C bond distances were 3.81 and 3.85 Å. * **SBZ-9F cocrystal:** This represents the key achievement of the paper—the quantitative formation of a chiral C₁-symmetric cyclobutane (SBZ-9F-cb) with four chemically distinct substituents. The C=C bond distances were 3.79 and 3.90 Å. The cyclobutane product SBZ-9F-cb required derivatization with p-toluenesulfonic acid for single-crystal X-ray diffraction analysis, confirming the presence of four different substituents and the stereochemistry of the cyclobutane ring system. The NMR spectrum of the photoreacted SBZ-9F solid showed 100% yield with no purification required. In all cases, the reactions were quantitative, produced no side products, and required no purification, highlighting the efficiency and selectivity of the solid-state approach. The crystallographic data for all cocrystals and cyclobutane products were provided, supporting the findings. The success of the method relies on the carefully engineered face-to-face stacking interactions between partially fluorinated and phenyl/pyridyl groups, enabling precise alignment of the reactive C=C bonds.

This research successfully addresses the long-standing challenge of generating cyclobutane rings with four different substituents via [2+2] cross-photodimerization. The use of solid-state cocrystallization, coupled with the strategic design of reactant molecules and the exploitation of specific intermolecular interactions, proved crucial for achieving high yields and selectivity. The quantitative nature of the reactions and the absence of side products demonstrates a significant advancement over traditional solution-phase methods. The ability to create chiral cyclobutanes with four different substituents opens new possibilities in organic synthesis and provides access to complex molecular frameworks relevant to various applications. The precise control over molecular arrangement within the crystal lattice underscores the importance of crystal engineering in directing chemical reactivity. The findings highlight the potential of leveraging partially fluorinated phenyl groups to achieve controlled face-to-face stacking interactions. The successful generation of the four-substituted cyclobutane demonstrates the effective use of complementary electrostatic interactions to drive the desired transformation. This approach offers a new toolset for stereoselective synthesis of complex molecules.

This study presents a significant advancement in the field of organic synthesis by demonstrating the quantitative and highly selective formation of cyclobutanes with four different substituents. The strategic use of solid-state cocrystallization and specific intermolecular interactions led to highly efficient and clean reactions, requiring no purification. This approach offers promising avenues for the synthesis of complex chiral molecules relevant to biological and materials science applications. Further research could explore the scope of this method by investigating different combinations of functional groups and their ability to promote the desired stacking interactions. This approach could also be applied to other solid-state reactions, offering a powerful tool for controlling reactivity and selectivity in crystal engineering.

While the current study demonstrates the successful synthesis of cyclobutanes with four different substituents, the scope of applicable functional groups needs further exploration. The method's reliance on specific intermolecular interactions to achieve the desired molecular orientation may limit its generality. The synthesis of the four-substituted cyclobutane necessitated derivatization with p-toluenesulfonic acid to obtain suitable crystals for structural analysis, suggesting that other products might require similar post-reaction processing.