Halogen-Bond Mediated [2+2] Photodimerizations: À la Carte Access to Unsymmetrical Cyclobutanes in the Solid State

The ditopic halogen-bond (X-bond) donors 1,2-, 1,3-, and 1,4-diiodotetrafluorobenzene (1,2-, 1,3-, and 1,4-di-I-tFb, respectively) form binary cocrystals with the unsymmetrical ditopic X-bond acceptor trans-1-(2-pyridyl)-2-(4-pyridyl)ethylene (2,4-bpe). The components of each cocrystal (1,2-di-I-tFb)·(2,4-bpe), (1,3-di-I-tFb)·(2,4-bpe), and (1,4-di-I-tFb)·(2,4-bpe) assemble via N···I X-bonds. For (1,2-di-I-tFb)·(2,4-bpe) and (1,3-di-I-tFb)·(2,4-bpe), the X-bond donor supports the C=C bonds of 2,4-bpe to undergo a topochemical [2+2] photodimerization in the solid state: UV-irradiation of each solid resulted in stereospecific, regiospecific, and quantitative photodimerization of 2,4-bpe to the corresponding head-to-tail (ht) or head-to-head (hh) cyclobutane photoproduct, respectively.


Introduction
Cyclobutane rings appended with n-pyridyl (n = 2, 3 or 4) (pyr) groups are useful building blocks to construct metal-organic assemblies and materials [1][2][3][4]. Many such molecules have been accessed via template-directed, topochemical [2+2] photodimerizations of alkenes within cocrystals. These transformations are conducted in the organic solid state and consequently, due to the highly ordered environment characteristic of crystalline reaction media, often proceed stereospecifically and quantitatively. Of particular and recent interest to our group have been cyclobutanes derived from photodimerization of unsymmetrical alkenes. These photoproducts are appended with two pairs of differently substituted pyr groups. Head-to-head (hh) and head-to-tail (ht) regioisomers are possible from photodimerizations of unsymmetrical alkenes [5]. Given that covalent-bond-forming reactions performed in the solid state are extremely sensitive to molecular packing, it is imperative to identify diverse and robust classes of template molecules capable of directing photodimerizations in crystals.

Results and Discussion
Work by our group has demonstrated that the unsymmetrical cyclobutanes rctt-bis(npyridyl)-bis(n -pyridyl)cyclobutanes (n = n , n = 2 or 4, n = 2 or 4) can be constructed in the solid state by way of hydrogen-bond (H-bond) mediated self-assembly. The photoproducts were generated using ditopic H-bond donor coformers in binary cocrystals. Cyclobutanes with the pyr substituents in both ht- [13] and hh-regiochemistries [14] were obtained via infinite and discrete H-bonded assemblies, respectively. While H-and X-bonds often display similar structural effects in the solid state (i.e., strength, directionality), the donor moieties (e.g., hydroxyl versus halogen) exhibit very different chemical properties, which can impact processes that follow the solid-state reactions (e.g., separations of photoproducts) [15].

Structural Considerations
The unsymmetrical nature of 2,4-bpe provides two different pyr N-atoms (i.e., 2-pyr versus 4-pyr) to participate in X-bonding. We note that in virtually all cases, the N···I X-bond lengths involving I-atoms of the X-bond donors 1,n-di-I-tFb to N-atoms of the X-bond acceptors 2,4-bpe, ht-2,4-tpcb, and hh-2,4-tpcb are shorter for 4-pyr versus 2-pyr ( Table 3). The average percent relative shortening (prs) values for N···I X-bonds to 2-pyr versus 4-pyr N atoms were 15.7% and 19.5%, respectively ( Table 3). Given that pK a values for similar 4-pyr and 2-pyr analogs are comparable [31], we attribute the observation to greater steric crowding between the lone pair on the N-atom of 2-pyr versus 4-pyr rings. Crowding would presumably preclude maximal orbital overlap (i.e., strongest X-bond formation) between the N-atom lone pair and the σ-hole of the relatively large I-atoms relative to an appreciably less congested 4-pyr N-atom.

General Experimental
All reagents and solvents (synthesis grade) were purchased from commercial sources and used as received unless otherwise stated. 1,2-diiodotetrafluorobenzene (1,2-di-I-tFb; 99%), trans-1-(2-pyridyl)-2-(4-pyridyl)ethylene (2,4-bpe; 97%), and 1,4-diiodotetrafluorobenzene (1,4-di-I-tFb, 98%) were purchased from Aldrich © . 1,3-diiodotetrafluorobenzene (1,3-di-I-tFb; 97%) was purchased from Apollo Scientific © (Bredbury, UK). Chloroform (CHCl 3 ; certified ACS grade, ≥99.8%, approximately 0.75% EtOH as preservative) was purchased from Fisher Chemical © (Hampton, NH, USA). All cocrystal syntheses were conducted in screw-cap glass scintillation vials. For cocrystal syntheses, "thermal dissolution" refers to the process of: (1) combining both cocrystal components in the same screw-cap glass vial; (2) adding solvent portion-wise while maintaining a saturated mixture at rt; and (3) tightly capping the vial and heating the mixture on a hotplate until all solids dissolve to afford a homogeneous solution in the minimum necessary volume of solvent. Compositions of all single crystals were shown to be representative of the bulk material by matching experimental pXRD patterns with those simulated from scXRD data. Photoreactions were conducted in an ACE ® photo cabinet equipped with a water-cooled ACE ® quartz, 450 W, broadband (λ = 1367.3-222.4 nm), medium pressure, Hg-vapor lamp (of the total energy emitted by the broadband lamp, approximately 40-48% is in the ultraviolet portion of the spectrum, 40-43% in the visible, and the balance in the infrared). Photoreactions were conducted by: (1) grinding single crystals of the cocrystal to a fine powder with an agate mortar and pestle; (2) smearing the powder between two UV-transparent Pyrex ® plates to create the thinnest layer possible; and (3) irradiating the powder in 10 h intervals, taking care to ensure uniform irradiation. Uniform irradiation of the powdered cocrystals was accomplished by: (1) occasionally (between every other irradiation interval) scraping (razor blade) the irradiated powder from both plates of the plate assembly; (2) combining the powder from both plates; (3) homogenizing the combined, bulk powder via thorough grinding (agate mortar and pestle); and (4) redistributing the homogenized powder between both plates. The plate assembly was also flipped between irradiation intervals to ensure equal irradiation of both faces of the plate assembly.

H NMR Spectroscopy
Proton nuclear magnetic resonance ( 1 H NMR) spectra were recorded at room temperature on a Bruker ® AVANCE NEO-400 spectrometer (Bruker Corp., Billerica, MA, USA) operating at 400 MHz using a liquid-N 2 -cooled double-resonance broadband Prodigy TM cryoprobe. 1 H NMR data are reported as follows: chemical shift (δ, ppm), multiplicity (d = doublet, dd = doublet of doublets, ddd = doublet of doublet of doublets, app td = apparent triplet of doublets, m = multiplet), coupling constant(s) (J, Hz), and integration. Chemical shift values were calibrated relative to residual solvent resonance (central peak of DMSO: δ H = 2.50 ppm) as the internal standard. All 1 H NMR data were collected and plotted within the Bruker ® TopSpin TM v3.6.1 software suite.

Powder X-ray Diffraction (pXRD)
Powder X-ray diffraction (pXRD) data were collected at room temperature on a Bruker ® D8 Advance X-ray diffractometer (Bruker Corp., Billerica, MA, USA) on samples mounted on glass slides. Each sample was finely ground using an agate mortar and pestle prior to mounting. Instrument parameters: radiation wavelength, CuKα (λ = 1.5418 Å); scan type, coupled TwoTheta/Theta; scan mode, continuous PSD fast; scan range, 5-40 • two-theta; step size, 0.02 • ; voltage, 40 kV; current, 30 mA. Background subtractions were applied to all experimentally collected data within the Bruker ® DIFFRAC.EVA v3.1 software suite. All data were plotted in the Microsoft ® Excel 2016 software suite. Simulated pXRD patterns were calculated from scXRD data within the CCDC Mercury [32] software suite.

Single-Crystal X-ray Diffraction (scXRD)
Single-crystal X-ray diffraction data were collected on a Bruker ® D8 VENTURE ® (DUO) CCD diffractometer (Bruker Corp., Billerica, MA, USA) equipped with a Bruker ® PHOTON III ® photon counting detector and an Oxford Cryostream ® 800 series cold N 2 gas stream cooling system (Oxford Cryosystems, Oxford, UK). Data were collected at a low temperature (150(2) K) using graphite-monochromated MoKα radiation (λ = 0.71073 Å). Crystals were mounted in Paratone ® oil on a MiTeGen © magnetic mount. Data collection strategies for ensuring maximum data redundancy and completeness were calculated using the Bruker ® Apex II TM software suite. Data collection, initial indexing, frame integration, Lorentz-polarization corrections and final cell parameter calculations were likewise accomplished using the Apex II software suite. Multi-scan absorption corrections were performed using SADABS [33]. Structure solution and refinement were accomplished using SHELXT [34] and SHELXL [35], respectively, within the Olex2 [36] v1.2 graphical user interface. Space groups were unambiguously verified using the PLATON © [37] executable. All non-hydrogen atoms were refined anisotropically. All hydrogen atoms were attached via a riding model at calculated positions using suitable HFIX commands. The occupancies of the major and minor positions for the disordered alkene C=C core within (1,3-di-I-tFb)·(2,4-bpe) converged to their respective ratios after each was identified in the difference map and freely refined. Figures of all structures were rendered in the CCDC Mercury [32] software suite.

Conclusions
N···I X-bonds have been used to support topochemical [2+2] photodimerizations of an unsymmetrical alkene to generate either of two regioisomeric cyclobutane photoproducts in the organic solid state. The transformations proceeded stereospecifically, regiospecifically, and quantitatively to generate ht-or hh-2,4-tpcb. Our contribution, thus, can be considered to afford à la carte access to either regioisomer. The formation of each product is achieved from the same alkene substrate, 2,4'-bpe, using commercially available X-bond donor cocrystal formers. Our future efforts will aim to expand the scope of the supramolecular methodology described herein to other unsymmetrical alkenes to afford access to additional unsymmetrical cyclobutane photoproducts.