Introduction

Recent years have witnessed efforts to perform organic syntheses that are efficient, atom economical, and sustainable1. In this context, the ability to achieve an intermolecular [2 + 2] cross-photoreaction (CPR) to form a four-membered cyclobutane ring system with four different substituents—vis a vis a stereogenic carbon atom2—that occurs quantitatively and without side products represents an important and fundamental synthetic challenge (Fig. 1)3,4,5. In such a reaction, two unsymmetrical carbon–carbon double (C=C) bonds on two different molecules are expected to be assembled and preorganized parallel and in close proximity to photoreact.

Fig. 1: Cross-photoreactions involving different substituents to afford chiral cyclobutanes.
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Unsymmetric olefins can provide access to cyclobutanes bearing four different substituents.

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Alkenes functionalized with perfluorophenyl (i.e., fully fluorinated) groups, along with phenyl-, and/or carboxylic acid groups, are known to undergo rare CPRs in the solid state6 upon cocrystallization7,8,9,10,11,12. For a photocycloaddition to occur in the solid state, two alkenes are expected to crystallize in a parallel arrangement with the C=C bonds separated on the order of 4.2 Å13. While the CPRs involving the perfluorophenyl groups6 have generated aryl-substituted cyclobutanes with up to three different substituents6,12, the formation of a cyclobutane ring with four different substituents has remained elusive. CPRs also occur in the solid state in statistical mixtures of solid solutions14,15,16, although an example of two different unsymmetrical alkenes assembling in a cocrystal that react in a CPR to form a cyclobutane with four different aryl groups quantitatively and without side products has not been reported.

Our solution to the aforementioned problem is to use four different functional groups that support two different face-to-face stacking interactions; namely, perfluorophenyl-phenyl and H-perfluorophenyl-pyridyl stacking to direct the assembly of C=C bonds to react (Fig. 2)13. We hypothesized that the partially fluorinated phenyl groups present in the symmetrical alkene trans-1,2-bis(2,3,5,6-tetrafluorophenyl)ethylene (8F) would have a capacity to participate in face-to-face stacking with phenyl groups, akin to a fully fluorinated analog17. Density functional theory (DFT) calculations demonstrated bond polarization and significant partial positive charges on the ring C-atoms of the C–F bonds of 8F (Fig. 3). Such polarization supports stacking of fully fluorinated groups via perfluorophenyl-phenyl forces, and we expected the idea could be applied to the partially fluorinated analog 8F18. DFT calculations also showed the end C–H groups to be polarized, having—in contrast—partial negative and positive charges on the C- and H-atoms, respectively. The fluorophenyl-bearing alkenes symmetrical 8F and unsymmetrical trans-1-(2,3,5,6-tetrafluorophenyl)-2-(2,3,4,5,6-pentafluorophenyl)ethylene (9F) were, thus, used. Symmetrical trans-stilbene (SB) and unsymmetrical trans-4-stilbazole (SBZ) were used as the phenyl-bearing alkenes. Symmetrical trans-1,2-bis(4-pyridyl)ethylene (BPE) was also a reactant.

Fig. 2: Cross-photoreactions studied to generate a cyclobutane with up to four different substituents.
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Perfluorophenyl-phenyl and H-perfluorophenyl-pyridyl stacking directs the assembly of C=C bonds.

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Fig. 3: DFT calculated electrostatic map for functionalized alkenes (blue = positive electrostatic charge, red = negative electrostatic charge).
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Note terminal ends of 9F to exhibit opposite charges.

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Results and discussion

The symmetrical and partially fluorinated alkene 8F was prepared by a Wittig reaction. When 8F (25 mg, 0.077 mmol) in toluene (2.0 mL) was cocrystallized with SB (14 mg 0.077 mmol) in toluene (2.0 mL), colorless plate-shaped single crystals of the binary cocrystal SB·8F formed upon slow evaporation after a period of 2 days. The components of SB·8F crystallize in the centrosymmetric triclinic space group P ī (Table 1, Fig. 4) (Supplementary Data 1). The two alkenes participate in offset face-to-face π-stacking to form stacked columns, with 8F of adjacent columns aligned end-to-end and interaction by means of C–H···F forces (Fig. 4a). Within each column, SB and 8F stack in an alternating fashion and in registry17. The C=C bonds of the stacked molecules lie parallel and separated by 3.82 Å (centroid···centroid), which conforms to the criteria of Schmidt. When the cocrystal SB·8F was exposed to UV-radiation (medium-pressure Hg lamp) for a period of 50 h, the two alkenes reacted in an intermolecular CPR to form SB-8F-cb (chiral C2 symmetric) in quantitative yield. Cyclobutane formation was evidenced by the disappearance and appearance of the multiplets at 7.94 and 7.61 ppm, respectively.

Table 1 Crystallographic parameters for cocrystals that undergo CPRs.
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Fig. 4: Cross-photoreaction showing X-ray structures.
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a SBˑ8F (inset: representation of packing type). b SB-8F-cb with solid-state photoreaction highlighted.

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The stereochemistry of SB-8F-cb was confirmed by single-crystal X-ray diffraction (Fig. 4b) (Supplementary Data 2). When the as-photoreacted powder was dissolved in toluene (1.0 mL) and ethanol (1.0 mL), colorless block crystals formed, upon slow evaporation. The cyclobutane product SB-8F-cb crystallizes in the triclinic space group P ī to form a layered structure within the crystallographic ab-plane. The centrosymmetric space group is consistent with the photodimerization affording a mixture of two enantiomers in equal amounts from the reacting solid. The cyclobutane exhibits a tongue-in-groove fit sustained by offset face-to-face H-perfluorophenyl-phenyl forces (3.88 Å).

A CPR of 8F was also achieved with the symmetrical bipyridine BPE. When 8F (25 mg, 0.077 mmol) in toluene (2.0 mL) was cocrystallized with BPE (14 mg, 0.077 mmol) in toluene (1.0 mL) and ethanol (1.0 mL), colorless plate-shaped single crystals of BPE·8F formed upon slow evaporation after a period of 2 days. The components of BPE·8F also crystallize in the centrosymmetric triclinic space group P ī (Table 1, Fig. 5) with the alkenes in offset face-to-face π-stacking geometries (Supplementary Data 3). The C=C bonds of the stacked molecules are parallel and separated by 3.85 Å (Fig. 5a). Both end pyridyl N-atoms of BPE also participate in rare C–H···N type hydrogen bonds (3.30 Å) with 8F to afford one-dimensional (1D) arrays. Thus, in contrast to SB·8F, the 1D columns are offset. The 1D arrays assemble such that the alkenes are also engaged in alternating face-to-face stacks. When the cocrystal BPE·8F was exposed to UV-radiation for a period of 50 h, BPE-8F-cb (chiral C2 symmetric) formed in quantitative yield as evidenced by the disappearance and appearance of the multiplets at 7.94 and 7.61 ppm, respectively. The stereochemistry of BPE-8F-cb was also confirmed by single-crystal X-ray diffraction with the cyclobutane crystallizing in the centrosymmetric space group P ī (Fig. 5b) (Supplementary Data 4).

Fig. 5: Cross-photoreaction showing X-ray structures.
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a BPEˑ8F (inset: representation of packing type), b BPE-8F-cb with solid-state photoreaction highlighted.

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The method also generates a cyclobutane ring with three different substituents. When symmetrical 8F (25 mg, 0.077 mmol) was cocrystallized with unsymmetrical SBZ (14 mg, 0.077 mmol) in toluene (1.0 mL) and ethanol (1.0 mL), colorless rectangular-shaped single crystals of the binary cocrystal SBZ·8F formed upon slow evaporation after a period of 2 days. The components of SBZ·8F crystallize in the centrosymmetric triclinic space group P ī with the alkenes face-to-face (Table 1, Fig. 6) (Supplementary Data 5). The C=C bonds lie parallel, and separated by two unique distances of 3.81 and 3.85 Å (Fig. 6a). The olefins stack with the aromatic rings engaged in a combination of H-fluorophenyl-phenyl and H-fluorophenyl-pyridyl forces. The pyridyl N-atoms of SBZ also participate in C–H···N type hydrogen bonds (3.28 Å) with 8F to define a two-component complex of offset columns. When SBZ·8F was exposed to UV-radiation for a period of 50 h, SBZ-8F-cb (chiral C1 symmetric) formed in quantitative yield. The stereochemistry of SBZ-8F-cb was confirmed by single-crystal X-ray diffraction with the cyclobutane crystallizing in the centrosymmetric triclinic space group P ī (Fig. 6b) (Supplementary Data 6).

Fig. 6: Cross-photoreaction showing X-ray structures.
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a SBZˑ8F (inset: representation of packing type), b SBZ-8F-cb with solid-state photoreaction highlighted.

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Whereas stacking of fully fluorinated aromatic rings with phenyl groups is known, we are unaware of an example that uses partially fluorinated rings to achieve such face-to-face stacking in a cocrystal. Moreover, that the rings of 8F participate in stacks with both a phenyl- and a pyridyl-group prompted us to turn to form a cyclobutane ring with four different substituents. We expected that cocrystallization of the unsymmetrical alkenes 9F and SBZ would generate a binary cocrystal wherein the two alkenes assemble in a face-to-face stacked geometry. While two orientations of the stacked alkenes would be possible, perfluorophenyl-phenyl stacking was expected to be favored based on complementary electrostatics19. A cocrystallization of 9F and SBZ would, thus, afford a binary cocrystal with the olefins stacked face-to-face (Fig. 2). A topochemical [2 + 2] photodimerization would generate the chiral cyclobutane SBZ-9F-cb (chiral C1 symmetric) that bears four chemically different substituents.

The unsymmetrical alkene 9F was prepared by a Wittig reaction. When 9F (25 mg, 0.073 mmol) in toluene (2.0 mL) was cocrystallized with unsymmetrical SBZ (13 mg, 0.073 mmol) in toluene (1.0 mL) and ethanol (1.0 mL), colorless plate-shaped single crystals of the binary cocrystal SBZ·9F formed upon slow evaporation after a period of 2 days. The components of SBZ·9F crystallize in the centrosymmetric triclinic space group P ī (Tables 1 and 2, Fig. 7) with the alkenes in offset face-to-face π-stacked geometries (Supplementary Data 7). The C=C bonds lie parallel and separated by two unique distances of 3.79 and 3.90 Å. The olefins stack with the aromatic rings engaged in a combination of perfluorophenyl-phenyl and H-perfluorophenyl-pyridyl forces. The end pyridyl N-atoms of SBZ, as in BPE·8F, participate in C–H···N hydrogen bonds (3.30 Å) to form two-component complexes of offset columns (Fig. 7a). The perfluoronated rings of 9F also interact between columns by F···F forces (2.94 Å). When SBZ·9F was exposed to UV-radiation for a period of 50 h, the cyclobutane with four different aryl substituents SBZ-9F-cb (chiral C1 symmetric) formed in quantitative yield. The formation of SBZ-9F-cb was evidenced by the disappearance and appearance of the alkene and cyclobutane resonances, respectively (Fig. 8).

Table 2 Selected parameters of photoreactive cocrystals and cyclobutanes of CPRs.
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Fig. 7: Cross-photoreaction showing X-ray structures.
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a SBZˑ9F (inset: representation of packing type), b [H-SBZ-9F-cb][p-TsO] with solid-state photoreaction and isolation as salt highlighted. Note four different groups present on cyclobutane ring system.

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Fig. 8: NMR spectroscopy.
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1H NMR spectrum of photoreacted solid showing cross-photoreaction of SBZ·9F that generates cyclobutane SBZ-9F-cb with four different substituents (100% yield, no purification).

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The stereochemistry of SBZ-9F-cb was confirmed by single-crystal X-ray diffraction (Fig. 7b) (Supplementary Data 8). Specifically, while SBZ-9F-cb resisted crystallization from a number of different organic solvents, reaction of SBZ-9F-cb with p-toluenesulfonic acid in dichloromethane-methanol (2 mL, 1:1, v:v) afforded single crystals of the salt [H-SBZ-9F-cb][p-TsO]. The components crystallize in the centrosymmetric monoclinic space group P21/n. The X-ray data confirm attachment of the four different substituents and stereochemistry of the cyclobutane ring system of SBZ-9F-cb. The components assemble to form a channel-type solid with the cyclobutanes forming ribbons along the crystallographic a-axis.

In this report, we have demonstrated how principles of crystal engineering and supramolecular chemistry can be used to construct a cyclobutane with four different substituents. The cyclobutane photoproduct, along with other generated chiral cyclobutanes, forms quantitatively, without side products, and without a need for purification. The process is remarkable, given the facile manner in which all products form compared to liquid phase approaches. In experiments to further widen the scope, we expect the process to be useful to generate additional carbon scaffolds that are relevant to biologically important compounds and materials science. These ideas are also important to further efforts that focus to transiently trap compounds and control chemical reactivity 20.

Methods

Chemicals

Triphenylphosphine (Strem) 2,3,5,6-tetrafluorobenzyl bromide (Oakwood), 2,3,4,5,6-pentafluorobenzyl bromide (Oakwood), 2,3,5,6-tetrafluorobenzaldehyde (Oakwood), 2,3,4,5,6-pentafluorobenzaldehyde (Oakwood), sodium hydride (dry, Sigma-Aldrich), BPE (Sigma-Aldrich), SB (ACROS), and solvents (toluene, chloroform, ethanol, dimethylformamide) (Fisher) were commercially available and used as received.

Photoreactions

All photochemical reactions were conducted using UV-radiation from a 450 W medium-pressure mercury lamp in an ACE Glass photochemistry cabinet. All cocrystals were finely ground using a mortar and pestle, and then placed between a pair of Pyrex glass plates. Samples were irradiated in 6-h intervals.

Syntheses

For the syntheses and characterizations of triphenyl-(2,3,5,6-tetrafluorobenzyl)phosphonium bromide, 8F, SBZ, and 9F, as well as all cocrystals and products of photoreactions and CCDC codes (2042036-2042043), see Supplementary Methods.