Diversifying molecular and topological space via a supramolecular solid-state synthesis: a purely organic mok net sustained by hydrogen bonds

A hydrogen-bond-directed [2+2] photodimerization performed in the solid state is used to generate a head-to-head (HH) cyclobutane photoproduct functionalized with cis-phenolic and cis-pyridyl groups. The photoproduct self-assembles as a pure form in the solid state to form a rare three-dimensional hydrogen-bonded network with a topology that conforms to a mok net. The construction of the HH cyclobutane is achieved using a newly introduced supramolecular protecting-group strategy.


Introduction
Efforts of chemists to develop new avenues to form covalent bonds and generate molecules that diversify chemical space are increasingly important (e.g. materials science, medicine; Dobson, 2004). In this context, chemical reactions performed in organic crystals can be used to synthesize molecules that possess functional groups with stereochemical relationships which are not accessible in solution (Elacqua et al., 2012;Oburn et al., 2017). The stereochemical outcome of a reaction in the crystalline state is generally dictated by topological arrangement or supramolecular organization in a lattice (Biradha & Santra, 2013;Ramamurthy & Sivaguru, 2016;Vittal & Quah, 2017). A well established reaction to proceed in the solid state is the [2+2] photodimerization of alkenes that generates carbon-carbon single (C-C) bonds in the form of cyclobutane rings. The reaction is a mainstay for crystal engineers that seek to form covalent bonds in solids. In recent years, cycloaddition, when controlled by hydrogen bonds (e.g. resorcinol or res templates) and principles of self-assembly, has enabled the synthesis of complex organic molecules based on unique topologies (e.g. ladderanes; Sinnwell et al., 2015;Lange et al., 2017;Gao et al., 2004).
A current goal of crystal engineers, and general efforts of solid-state chemists, is to design molecular building blocks that self-assemble to form extended (i.e. one-, two-and threedimensional) network topologies. Of particular interest are entangled nets, wherein nodes are linked to form intertwined and self-catenated structures. The mok net, which is comprised of tetrahedral nodes linked in three-dimensions -akin to the well known diamondoid net -is one such example ( Fig. 1) (O'Keeffe, 1991;Alexandrov et al., 2012;Bonneau & O'Keeffe, 2015). Self-catenation of the mok net is based on the shortest rings (six-membered rings, blue), with interpenetration of two hexagonal (hcb) subnets of the mok net effectively facilitating the self-catenation. A consequence of the self-catenation is the generation of two additional rings (six-and eight-membered, orange and purple, respectively). Importantly, the mok net has only been observed in assembly processes based on metal-organic components wherein the tetrahedral node is supplied by a metal center (Gong et al., 2011;Zhang et al., 2015;Liang et al., 2013). Moreover, the mok net has been recognized by O'Keeffe as 'likely to be difficult to achieve chemically' in the solid state due to its intricacy. An organic molecule that fulfills the role of the tetrahedral nodes in a mok net has not yet been identified.
With this in mind, we report here the supramolecular solidstate construction of the organic molecule rctt-1,2-bis(4pyridyl)-3,4-bis(4-phenol)cyclobutane (1a), showing it selfassembles in the solid state to form a network that conforms to the mok topology. The synthesis is achieved using a novel supramolecular protecting-group strategy applied to phenols and utilizes 4,6-diiodo-res (diI-res) as a hydrogen-bond donor template (Elacqua et al., 2012). This strategy enables protection of terminal phenolic groups from participating in hydrogen bonds in the solid state and then post-installation of cis-phenolic groups onto a cyclobutane ring system (Fig. 1). We show that the head-to-head (HH) cyclobutane 1a, following removal from the molecular template, self-assembles as a pure form to produce a hydrogen-bonded twofold interpenetrated net of mok topology. Within the network, the cyclobutane ring of 1a acts as a node with the radial phenolic and pyridyl groups serving as hydrogen-bond donor and acceptor linkers, respectively, resulting in the first purely organic mok network (Gong et al., 2011;Liang et al., 2013;Zhang et al., 2015;Li et al., 2017).

Results and discussion
The HH cyclobutane 1a contains cis-4-phenolic and cis-4pyridyl groups. Although cyclobutanes functionalized with cis-4-pyridyl groups have been synthesized in the solid state using hydrogen bonds with res templates, the template-directed synthesis of a cyclobutane lined with phenolic groups has not yet been reported. We note that the synthesis of 1a itself has not been reported in either solution or the solid state, although a photodimerization of protonated 1b (1b = trans-1-(4-phenol)-2-(4-pyridyl)ethylene) in HCl has been shown to yield a mixture of head-to-tail (HT) isomers (Zhang et al., 2000). To us, 1a was attractive as a building block in supramolecular chemistry given the presence of the radial and Post-installation of phenolic groups.
tetrahedrally disposed hydrogen-bond donor (phenol) and acceptor (pyridyl) groups. We expected the groups to equip 1a with a capacity to form 4-connected nets (e.g. diamondoid) (Ermer, 1988;Baburin et al., 2008). Many conformations furnished by the hydrogen-bond donor groups would equip 1a with a capacity to form different 4-connected nets. While 1b has been a subject of numerous studies (e.g. liquid crystals), we were also surprised that the crystal structure of 1b had not been reported. The ability of the symmetrical cyclobutane rctt-tetrakis(4pyridyl)cyclobutane (tpcb) (D 2h symmetry) to serve as a tetrahedral node of extended nets composed of metal and organic building blocks was originally elucidated by Schroder and Champness (Blake et al., 1997). Specifically, tpcb served as a 4-connected node to support a net of composition [Ag(tpcb)]BF 4 (Blake et al., 1997;Liu et al., 2011). We expected the cyclobutane 1a, being of lower symmetry (C s ), to be able to interact with itself, in contrast to tpcb, by way of complementary hydrogen-bond donor and acceptor groups. The presence of the donor and acceptor sites attached to the cyclobutane ring would equip the molecule with a capacity to self-assemble into a net purely organic in composition.

Photostable parent alkene 1b
Plate-like single crystals of 1b were grown by slow evaporation in MeOH/ethyl acetate (1:1, v:v) over a period of 10 d, crystallizing in the orthorhombic space group Pca2 1 . The molecule adopts a planar conformation (twist: 1.63 ) with the hydroxyl and pyridyl groups participating in intermolecular O-HÁ Á ÁN hydrogen bonds [OÁ Á ÁN, O-HÁ Á ÁN: 2.729 (5) Å , 177.8 (2) ] (Fig. 2). The alkene self-assembles to form chains along the a axis that stack HH and edge-to-face. Nearestneighbor C C bonds are separated by 5.65 Å , which is beyond the limit of the work by Schmidt (1971). When subjected to UV-radiation (450 W medium-pressure Hg lamp) for a period of up to 50 h, 1b was determined to be photostable.

Attempts to form cocrystals of 1b
While 1b is photostable, attempts to cocrystallize 1b with diI-res and, in doing so, form a cocrystal with 1b stacked HH, to react to form the cyclobutane 1a were unsuccessful (Fig. 1). Liquid-assisted grinding of 1b with diI-res afforded a mixture of the two solids, as demonstrated by powder X-ray diffraction. Attempts to grow cocrystals from solution were also unsuccessful. The solution crystallization experiments typically produced a powder that was identified as the alkene 1b. We attributed the inability of diI-res to form a cocrystal with 1b to the inability of diI-res to compete with the hydrogen bonding between the phenolic and pyridyl groups present in crystalline 1b [ Fig. 2(a)] (Elacqua et al., 2012).

Supramolecular protecting-group strategy
While 1b is photostable as a pure solid, we determined that the C C bonds of 1b are made photoactive when the protected methyl ester 1c (1c = trans-1-(4-acetoxy)-2-(4pyridyl)ethylene) is cocrystallized with diI-res in a newly designed supramolecular protecting-group strategy (Elacqua et al., 2012). For the strategy, we aimed to develop a method that would allow us to mask the hydrogen bonding ability of the OH group and, at the same time, have minimum steric impact on the requirement of the C C bonds to stack parallel and on the order of 4.2 Å . Given that cinnamates are known to stack and photodimerize in the solid state (Lewis et al., 1984), we targeted the ester linkage. Specifically, we expected acylation of the phenol moiety of 1b to allow the C C bonds of 1b in the form of 1c to stack in the solid state and conform to the topochemical postulate for a photoreaction. Acylation of 1b was thus performed and afforded 1c in high yield (Yin et al., 2011).

Photostable protected alkene 1c
Plate-like single crystals of 1c were generated by slow evaporation in ethyl acetate/ethanol (3:2, v:v) over a period of 2 d. As in the case of 1b, the alkene 1c is photostable [ Fig. 3(a)] and crystallizes in the orthorhombic space group Pbca. The aromatic rings lie approximately coplanar (twist: 4.66 ) with the acetoxy group twisted from coplanarity (twist: 63.9 ). The alkene packs HH and edge-to-face with the nearest C C bonds separated by 4.74 Å , which is also beyond the limit of the work by Schmidt (1971) [Fig. 3(b)]. UV-radiation for up to 50 h revealed 1c to be photostable.
To determine the reactivity of (diI-res)Á2(1c), a finely ground crystalline powder was spread between two glass plates and exposed to broadband UV irradiation. A 1 H NMR spectrum revealed the complete disappearance of alkene signals (7.19 and 7.56 p.p.m.) and the appearance of a cyclobutane signal (4.58 p.p.m.) following 100 h of UV-irradiation (see supporting information).
To determine the stereochemistry of the photoproduct, single crystals as colorless prisms were obtained by recrystallization of the reacted solid from ethanol/ethyl acetate (1:1, v:v) over a period of 3 d. The components of (diI-res)Á(1d) crystallize in the monoclinic space group P2 1 /c with the stereochemistry being confirmed as the rctt isomer 1d (Fig. 4).

Rare organic mok net
The synthesis of the targeted unsymmetrical cyclobutane 1a was next achieved in the deprotection of 1d by treating the photoreacted solid of (diI-res)Á(1d) with NaOH as base (see supporting information). Single crystals of 1a suitable for single-crystal X-ray diffraction were obtained by slow solvent evaporation from solution of aqueous MeOH over a period of 5 d.  The asymmetric unit of 1a consists of two unique cyclobutanes (CB1 and CB2) that crystallize in the monoclinic space group I2/a. The deprotection of 1d with the removal of the acetoxy protecting group confirmed the rctt stereochemistry of the cyclobutane ring of 1a (Fig. 5). A remarkable feature of the crystal structure of 1a is that the cyclobutane self-assembles to generate a three-dimensioanl hydrogenbonded framework of mok topology (point symbol 6 5.8 ). The nodes of the mok are defined by the centroids of the cyclobutane rings of 1a (Fig. 6) (Blatov et al., 2014). The cyclobutanes provide tetrahedrally disposed and cisoid hydrogenbond donor and acceptor sites to form the 4-connected net.
The pattern of hydrogen bonding that defines the mok net of 1a is complex. The complexity arises since the hydroxyl groups of 1a adopt two different conformations -CB1 and CB2 -within the net. Each conformation is based on the relative dispositions of the hydroxyl groups of each molecule (Fig. 5). More specifically, CB1 adopts an anti-gauche conformation wherein the hydroxyl groups are anti and gauche relative to the cis-4-pyridyl groups [ Fig. 5(a)]. The phenyl group related to the gauche orientation of CB1 is disordered [occupancies: site A 0.90 (1); site B 0.10 (1); see supporting information]. CB2 adopts an anti-syn conformation whereby the hydroxyl groups are anti and syn relative to the cis-4-pyridyls [ Fig. 5(b)]. The cyclobutane self-assembles to form the mok network with all OH and N-pyridyl groups participating in O-HÁ Á ÁN hydrogen bonds ( Table 1).
The self-catenation of the mok net arises from interconnection of two twofold interpenetrated hcb layers [blue and green, Fig. 6(a)]. The self-assembly of the cyclobutanes is manifested with CB1 and CB2 alternating as adjacent nodes throughout the net [ Fig. 6(b)]. All rings of the mok network are thus composed of CB1 and CB2 which alternate via the O-HÁ Á ÁN hydrogen bonds.
The compositions of the hydrogen bonds between adjacent cyclobutanes are defined by the orientations (i.e. syn, anti, gauche) of the OH groups of the phenols. Specifically, a primary six-membered ring of the hcb subnet involves nodes with hydrogen bonds of alternating two anti orientations [11.53 Å (CB1), 11.49 Å (CB2)] and one syn orientation (12.15 Å ). The phenol groups in the gauche (11.81 Å ) orientation interconnect the twofold interpenetrated hcb subnets X-ray structure of mok topology of 1a: (a) interpenetration of hexagonal (hcb) sub-nets highlighted in green and blue, (b) building blocks of cyclobutanes as nodes to form hydrogen-bonded hexagons numbered in a clockwise manner (hydrogens removed for clarity), (c) connections of two hcb nets (connection highlighted in orange and hcb nets in blue/green), and (d) twofold interpenetrated mok nets highlighted separately in tan and blue. X-ray structure of 1a: (a) anti-gauche 1a (CB1) and (b) syn-anti 1a (CB2). Note: anti and syn are designated relative to the pyridyl groups.

Figure 7
Hydrogen bonding and rings of mok net 1a: (a) three linkages with CB1 and CB2 (light blue = syn linkage; dark blue = anti linkage; orange = gauche linkage) of a primary six-membered ring, (b) space-filling of primary six-membered ring, (c) primary six-membered ring showing linkages within hcb subnet, (d) two types of linkages of a secondary six-membered ring, (e) space-filling view of secondary six-membered ring, (f) highlighted secondary sixmembered ring within mok net, (g) three types of linkages within an eight-membered ring, (h) stick-view of eight-membered ring with anti-orientation from CB1, and (i) space-filling of eight-membered ring showing two interdigitated hcb subnets (hydrogen atoms omitted for clarity).
secondary six-membered ring is generated from interconnection of the hcb subnets (Fig. 7). The secondary six-membered ring involves nodes with hydrogen bonds of alternating two anti orientations (CB1, CB2) and one gauche orientation. Additionally, eight-membered rings are generated from the interconnection of three hcb subnets, involving nodes of alternating one anti (CB1 or CB2), one gauche and one syn orientation.
The mok framework of 1a also exhibits the overall twofold interpenetration [ Fig. 6(d)]. Highly disordered electron density consistent with MeOH as solvent is located in lacunae ($180 Å 3 ) (Spek, 2015) at the intersection of the interpenetrated hcb and mok subnets and nets, respectively. The mok net of 1a was, before now, an unrealized network in structures of purely organic solids.

A mok net purely organic in origin
The mok net 1a represents a rare family of entanglements that have only been realized in coordination polymers and metal-organic frameworks. For metal-organic materials, the metal centers and organic linkers are nodes and bridges, respectively, Gong et al., 2011;Liang et al., 2013;Zhang et al., 2015). O'Keeffe has pointed out that a single mok net can be considered difficult to achieve chemically given that one distance between two nodes is shorter than the distance between linked nodes. The short distance of a mok net corresponds to two nodes between the interpenetrated hcb layers. For 1a the corresponding distances are 10.1 Å (nonlinked nodes) and 11.5 Å (linked nodes); however, we note that here the twofold interpenetration generates much shorter distances between nodes of two separate nets of the interpenetrated structure (i.e. 6.07, 6.38 Å ).
A major factor that defines how 1a supports the formation of the mok net relates to the different orientations that the cyclobutane assumes to define the nodes and edges of the network. Two copies of the same molecule that are present in two different conformations (i.e. CB1 and CB2) self-assemble to form the network. The conformations support the four different types of linkages (i.e. anti (2), syn, gauche) to create six-and eight-membered rings. In doing so, the cyclobutanes for both the six-and eight-membered rings act as either double hydrogen-bond donors (DD), double hydrogen-bond acceptors (AA) or a donor/acceptor (DA) (Table 2, Fig. 7). The AA linkages involve acceptor pyridyls in the 3,4-position of the cyclobutane ring, whereas the acceptors of the DA linkages are fixed in either the 3-position (3-acceptor) or 4position (4-acceptor) of the ring. The cyclobutane 1a effectively adapts to conform to the topology of the mok net by using chemical information stored at the molecular level (i.e. cyclobutane and conformation) that is then expressed as required at the supramolecular (i.e. hydrogen-bond donor and acceptor capacities) level.

Conclusions
We have reported the first mok network composed of purely organic components. The cyclobutane 1a contains a combi-nation of tetrahedrally disposed (Zhang et al., 2012) hydrogenbond donor and acceptor sites synthesized in the solid state using a newly developed supramolecular protecting-group strategy. Hydroxyl donor sites, which add a second degree of flexibility, are used to achieve the unique topology. We believe our observation of the building block 1a to support different network linkages to form the mok net serves as an important example on how to achieve supramolecular complexity from redundant molecular information. The fact that the solid state can be exploited for such design, particularly given the high degree of control of directionality for covalent bond formation, can be expected to encourage further work in the field.

Funding information
The National Science Foundation (grant No. DMR-1708673 awarded to LRM) is acknowledged for support of the work. RHG gratefully acknowledges financial support from Webster University in the form of Faculty Research Grants. DMP thanks the Universitá degli Studi di Milano for the transition grant PSR2015-1718 and for the grant FFABR2018.