Coupling Metaloid-Directed Self-Assembly and Dynamic Covalent

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Cite This: Inorg. Chem. XXXX, XXX, XXX−XXX

Coupling Metaloid-Directed Self-Assembly and Dynamic Covalent Systems as a Route to Large Organic Cages and Cyclophanes Mary S. Collins,† Ngoc-Minh Phan,† Lev N. Zakharov,†,‡ and Darren W. Johnson*,† †

Department of Chemistry & Biochemistry and the Materials Science Institute, University of Oregon, Eugene, Oregon 97403-1253, United States ‡ Center for Advanced Materials Characterization in Oregon (CAMCOR), University of Oregon, Eugene, Oregon 97403-1241, United States S Supporting Information *

ABSTRACT: The synthesis of large cyclic and caged disulfide structures was achieved by pnictogen-assisted iodine oxidation starting from self-assembled pnictogen thiolate complexes. The directing behavior of pnictogen enables rapid and selective syntheses of many discrete disulfide assemblies over competing oligomers/polymers, ranging from structures that are small and strained to those that are large and multifaceted, including 3D cages. Traditional cyclization reactions carried out under kinetic control are generally low-yielding, which often results in the formation of insoluble oligomers and polymers as unwanted side products. The prospect of self-assembling organic structures efficiently under thermodynamic control adds an attractive tool for the synthesis of cyclophanes and other large cage compounds. This method of metaloid-directed self-assembly within a dynamic covalent system allows for the rapid and discriminant self-assembly of disulfide cyclophanes without the consequences sometimes seen in traditional cyclophane syntheses such as poor yields, long reaction times, low ring-closing selectivity, and extensive purifications. The present paper provides an overview of this approach, explores the role of the pnictogen additive and solvent in this reaction, begins to test the limits of this strategy in complex 3D molecule formation, and extends our strategy to include one-pot syntheses that do not require the use of a pnictogen additive. This Viewpoint also includes an extended introduction to serve as a minireview highlighting the utility of a self-assembly approach to create organic cage structures. From a practical standpoint, the cyclophanes isolated from this method can serve as precursors in the production of insulating plastics (e.g., through the widely used parylene polymerization process, which uses derivatives of paracyclophane as monomers) or as potential hosts for molecular separations or capture.

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INTRODUCTION In the field of supramolecular chemistry, the use of both dynamic covalent chemistry (DCC) and metal-directed selfassembly has individually led to a large diversity of sophisticated molecular architectures. Metal-directed self-assembly utilizes metal-mediated synthetic strategies that typically rely on thermodynamic control and thus avoid kinetically controlled pathways that often lead to oligomers and polymers. As such, metal−ligand interactions stabilize the construction of assemblies that are thermodynamically stable through kinetically labile coordination bonding.1−4 Contemporary metal− ligand supramolecular self-assembly strategies have become sophisticated to enable a large variety of hosts tailored for specific applications, including such hallmarks as hosts for the encapsulation of C605−7 or white phosphorus,8 coordination cages that act as reaction vessels for catalysis or reaction templates,9,10 hosts for the crystal growth of otherwise hard-tocrystallize organic small molecules,11 and structural studies that go deeper into interpreting complex self-exchange mechanisms.12−14 DCC, which involves reversible, covalent bond reactivity to allow for free exchange of molecular components, © XXXX American Chemical Society

represents a complementary supramolecular approach to the assembly of complex structures. The formation of products occurs under thermodynamic control, and the product distribution depends on the relative stabilities of the final products. One of the greatest advantages to DCC lies in its ability to modify the distribution of products by simply changing the chemical environment, for example, using temperature, concentration, or additives. Among many achievements, modern DCC includes systems that explore impressive self-replication behavior,15 the interplay between other types of dynamic chemistries with DCC,16,17 and the incorporation of DCC to influence the mechanical properties in dynamic polymeric networks.18 Each with their own advantages and complexities, both supramolecular approaches yield a plethora of fascinating self-assembled systems. Because of the synthetic accessibility to complex molecular architectures from basic Special Issue: Self-Assembled Cages and Macrocycles Received: October 23, 2017

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DOI: 10.1021/acs.inorgchem.7b02716 Inorg. Chem. XXXX, XXX, XXX−XXX

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Inorganic Chemistry

modification reactivity in which anion metathesis of a metal cationic cage framework generates a water-soluble supramolecular complex that otherwise does not form using traditional subcomponent self-assembly methods in water.31 A cubic FeII8L6 (OTf) cage was rendered water-soluble when triflate groups were exchanged with sulfate. In related studies, selective oxidation of the ligand backbones of a self-assembled iron iminopyridine cage has been demonstrated by Hooley and co-workers such that no competitive oxidation at the metal centers was observed.25 The cage impressively yields oxidation only at the ligand sites despite the inherent reversibility of the metal−ligand bonds and its general sensitivity to nucleophiles. In addition, free iron(II) salts were shown to catalytically aid the oxidative transformations of the cages. The generation of new cages through metal-directed assembly under dynamic covalent control does not always require that the reversible metal coordination sites (that keep these supramolecular structures together) remain coordinated and structurally intact during modification. In our research, we recently presented a method in which self-assembled pnictogen thiolate structures afford selective synthesis to disulfide macrocyclic dimers, trimers, and tetramers by oxidation with iodine.32 The use of additives, in our case a pnictogen (Pn), to influence the self-assembly process toward larger structures has long been highlighted as an intriguing synthetic partner in supramolecular systems. Otto et al. have extensively studied the reactive mechanisms within dynamic self-assemblies, specifically on the reversible covalent chemistry of disulfides. Recently, they studied the effect of two different self-assembly pathways (agitation vs no agitation) and show that these modes govern the formation of covalent bonds between macrocycles to give either less-defined aggregates of macrocycles or more welldefined, larger nanoribbons and nanoplatelets.17 The addition of sodium perborate was also hypothesized to behave as a template to influence the formation of these assemblies. Similarly, in our group, we have shown that, in the presence a mild oxidant (iodine), a pnictogen thiolate assembly will rapidly and cleanly oxidize to form discrete, disulfide cyclophane macrocycles because of the assistance of the Pn source (e.g., Figure 1).32 This method has more recently been successful in the synthesis of even larger macrocycles and cage compounds in short reaction times, at high selectivity, and with remarkable resistance against undesirable insoluble byproducts33 (see ref

building blocks, the integration of DCC into nanoscale organic materials yields molecules with tunable structural properties amenable to molecular separations, carbon capture, hybrid nanocomposite fabrication, and nanomedicine.19 Additionally, metal-directed self-assembly has been employed in a variety of disciplines, featuring host−guest capabilities for sensing, catalysis, crystal growth within hosts,11 metal chelation/ remediation, and stabilization of reactive species.20,21 However, the use of self-assembled compounds themselves as precursors/synthons for the synthesis of other larger 3D organic structures has seen far less investigation in comparison.7,22−25 These particular systemswhich contain ligand functionalities that supports both dynamic covalent interactions as well as metal coordinationopen up new avenues to synthesize large compounds that may not be intuitively synthesized via DCC or metal-directed assembly alone. This Viewpoint highlights our own approach to the use of assemblies as synthons and explores some of the key synthetic parameters that influence this type of self-assembly. In the following brief overview, we will concentrate primarily on the solution-based postsynthetic chemistry of metal-directed assemblies in dynamic covalent systems. The concepts discussed in this review should also be applicable and relevant to the postassembly modification of polyoxometalates26,27 and metal−organic framework (MOF)/covalent organic framework systems;28,29 however, these systems are outside the specific focus of this Viewpoint. In both DCC and metal-directed self-assembly, the various interactions between ligands, ligands and metal ions, metal ions and solvent, and ligands and solvent are under dynamic exchange. The use of preassembled structures as precursors allows for a “templated” reaction to occur between the complex and its subsequent reactants, where the synthon’s denticity, orientation of binding groups, and coordination geometry can offset the energetic cost of rearrangement between free components in solution in such a multicomponent selfassembly.30 In the current literature, large self-assembled cages are utilized as precursors for “post-assembly modification” reactions, where chemistry is performed directly on external (or endohedral) ligand functionalities of the cage while conserving the structural integrity of the original assembly. A recent example was showcased by Nitschke and co-workers, where two preassembled dynamic frameworks were used as synthons.22 A tetrazine-based FeII8L12 cube and a maleimidefunctionalized FeII4L6 tetrahedron were exposed to a small organic molecule (norbornadiene), which triggers a reverse Diel−Alder reaction with the tetrazine groups on the cube. This generates a cyclopentadiene side product that then reacts with the maleimide-based tetrahedron. The consequential alkylation of the tetrahedron drives the complex into a nonpolar phase, sorting the initial mixed species into two separate solutions. In this example, two different DCC-based stimuli-responsive chemical systems support a selective reaction with an external, small organic molecule to trigger a post-assembly modification cascade that ultimately can transport a large supramolecular system across a phase boundary. This type of post-assembly modification upon ligands is also represented in further work featuring a FeII4L6 tetrahedral cage that undergoes a Diels− Alder cycloaddition between the anthracene ligand moieties of the cage and tetracyanoethylene. With the addition of tetracyanoethylene, the reaction yields a new ligand functionality that can now facilitate the encapsulation of C60.7 Additionally, Nitschke et al. also demonstrated post-assembly

Figure 1. Oxidation of arsenic cryptand As2L13 with iodine cleanly forms disulfide macrocycles L1 2, L1 3, and L 14 . A wireframe representation of single-crystal X-ray structures of the cryptand and the macrocycles is shown below. B


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Inorganic Chemistry 33 for supplementary crystallographic data in this paper). Furthermore, these disulfide structures can be captured kinetically via sulfur extrusion, providing a direct route to thiacyclophanes (thioethers) in exceptionally high yield. This synthetic strategy might serve as an attractive complement to dynamic combinatorial covalent chemistry, which provides libraries of self-assembling molecules that respond to external stimuli within an equilibrating system.34−43 In this Viewpoint, we comment on a few of the factors influencing the selfassembly in our method and provide a more in-depth investigation of the assembly of the larger-sized macrocycles and cages resulting from our previous reports. We are specifically motivated by (1) an interest in making strained hydrocarbons from these thiacyclophanes (which are known hydrocarbon cyclophane precursors) to serve as precursors to organic materials and (2) a desire to address a bottleneck in classical cyclophane syntheses (the low-yielding, stepwise, and sometimes lengthy syntheses that can be hard to scale). We hope that this Viewpoint also serves as an entry point for others who may wish to pursue applications of such cages or use similar synthetic approaches to find additional utility for supramolecular assemblies as synthons.

Scheme 1. (i) Iodine Oxidation of Dithiol to Disulfide without an Arsenic Cryptand after 5 min, (ii) H2L1 after the Addition of Iodine, and (iii) H2L1 and Iodine after the Addition of Excess N(iPr)2Et

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RESULTS AND DISCUSSION Roll of the Additive. While investigating the reactivity of arsenic thiolate self-assembled complexes, we discovered that in the presence of a mild oxidant (iodine) the reaction cleanly yields discrete disulfide-bridged macrocycles (Figure 1).32 Although the oxidation of thiols with iodine is well-known, we were surprised that oxidation of the arsenic complex (in this case an arsenic cryptand, As2L13; Figure 1) did not lead to the random polymerization commonly observed in typical dithiol oxidations. Driven by this result, we immediately recognized that the Pn additive could be assisting in selective macrocyclization to the discrete disulfide structures. To address the prospect that the arsenic cryptand was playing a templating, or at least organizing, role in discrete disulfide assembly, we performed a series of studies under increasingly dilute conditions. The reactions revealed that selectivity at low cryptand concentrations gives preferential assembly of a dimer (L12), whereas at high concentrations ([As2L13] > 0.25 mM), trimer (L13) is the dominant species. Interestingly, the arsenic cryptand (comprising three dithiol ligands) did not behave as a direct template to give exclusive assembly of the disulfide trimer species at low concentrations.32 The same disulfide macrocycles (L12, L13, and L14) were isolated from control reactions using solely iodine or iodine and a base such as N,N-diisopropylethylamine at low conversion; however, the Pn additive is required for the selectivity and rapid reaction rate and to avoid unwanted polymerization side products (Scheme 1). After reporting these initial studies, we wanted to continue to explore the reactive parameters within Pn-assisted iodine oxidation. In this system, the Pn additive could play several possible roles in this reaction. The oxidation of thiols with iodine is believed to proceed through a mechanism similar to the iodine-facilitated deprotection of tritylthiols.44 Iodine first oxidizes sulfur, which is shortly followed by cleavage of the Pn− S bond. The resulting S−I bond then undergoes insertion into a neighboring As−S bond.45 Arsenic triiodide was isolated as a byproduct for this reaction, suggesting that arsenic does not undergo redox chemistry during the course of the reaction. Also, Pn likely participates in “Pn bonding”, akin to halogen and chalcogen bonding.46−52 In this case, Pn bonding describes

an attractive interaction between the electron-accepting Pn and an electron donor (i.e., thiolate, iodide, or arene π system). The Pn also may serve as a sink or buffer for iodide produced during the reaction, preventing reversible HI formation observed for the direct reaction of thiols with iodine (Scheme 1). Similarly, the Lewis acidic Pn exhibits a supportive stabilizing force between aromatic ring systems known as a Pn···π interaction.53,54 This directing feature has been shown to assist in the self-assembly of Pn coordination complexes and is structurally supported in crystallographic examples where the arsenic lone pair is oriented at a preferred angle relative to the aromatic ring.55−57 Almost certainly, these types of weak interactions play a role in organizing and converging the ligands for discrete self-assembly, and Pn bonding prevents overactive iodine species from producing rapid oxidation toward insoluble disulfide polymers. To better understand the directing role of SbCl3, we performed a quantitative study of Pn-assisted iodine oxidation by varying the amount of SbCl3 with H2L1 and iodine. The results reveal that the rate of consumption of dithiol increases as the concentration of SbCl3 increases from 0 to 70 mol % (NMR was taken directly after Pn addition and mixing). For optimal conditions, complete conversion from free thiol to disulfide macrocycles occurs at 70 mol % SbCl3 after a reaction time of 1 min. We recognize that other factors aid in thiol disulfide exchange such as O2 or intermolecular conversion; however, we have observed, under these specific conditions, that these factors lead to products at a much slower rate (over days) than Pn-assisted iodine oxidation (e.g., control reaction where no Pn is added; Scheme 1 and the Supporting Information, SI). In addition, control NMR exhibits only broad disulfide peaks, suggesting slow, nonselective conversion in comparison to the sharp, defined resonances corresponding to a mixture of discrete disulfides that result in all experiments that contain SbCl3 (see the SI). These experiments also seem to indicate that Pn is not a catalyst but rather a stoichiometric C


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Inorganic Chemistry reagent: the reaction appears to reach a state of equilibrium of free thiol and disulfides and remains almost unchanged after several days (1−2 days); in addition, the optimal 70 mol % SbCl3 aligns with the stoichiometric formation of SbI3 as a product of the reaction. We were curious about whether this reactivity could be replicated using other thiophilic metal centers (i.e., Ag+ or Zn2+) and not soley a Pn additive. To test the scope of the metal-directing reactivity, we performed a reaction of AgOAc or Zn(OAc)2 with 2 equiv of I2 and H2L1. Molar ratios of Ag+ and Zn2+ were calculated based on the generation of AgI and ZnI2 as byproducts. When using AgOAc (1.7 equiv), the 1H NMR spectrum showed the appearance of disulfides in conjunction with the formation of intermediate species. After 24 h, the reaction was not complete. Upon an increase in the concentration of AgOAc (2.1, 2.8, and 4.8 equiv), the reaction still showed traces of starting material and favored the formation of dimer and trimer over tetramer/pentamer species. We conclude that AgOAc is not an ideal substitute for SbCl3 but perhaps assists in the oxidation by a different mechanism. Following this series of experiments, we investigated AgOTf (4.2 equiv). Once again, disulfides formed rapidly, with many intermediates and traces of the starting material still persisting after 24 h. The spectrum using 0.8 equiv of Zn(OAc)2 showed no product formation. Additional studies using BiCl3, Ca(NO3)2, Ca(ClO4)2, Zn(acac)2, and ZnCl2 as potential metal additives were performed as well. Using a free thiol ligand (1 equiv), I2 (2 equiv), and metal salt (2 equiv) in acetone-d6, we monitored the product distribution of each reaction until equilibrium was reached. We found that BiCl3 cleanly converted the ligand into the disulfide species, which once again showed the powerful directing ability of Pn. On the other hand, the other metal salts showed the appearance of both the disulfides and numerous other intermediates or metal−thiol complexes. For example, Ca(ClO4)2 showed a ratio of intermediates to disulfides of 53:47. AgOAc in acetone-d6 showed more disulfide species, yet the intermediates still contributed 26% to the total product distribution (Table S2). Larger Disulfide Macrocycles. We have shown that these discrete disulfide macrocycles can be assembled from preformed arsenic complexes or in a one-pot reaction between the free thiol ligand, the activating Pn (PnCl3), and iodine (Figure 2). The initial studies with metal salts show that group 15 additives are superior to other first-row transition-metal ions and alkali-metal ions. The use of BiCl3 (Table S2) and/or SbCl333 appears to enable the formation of larger disulfide macrocycles, specifically the pentamer and hexamer, the structures of which we have not discussed in detail previously. The disulfide hexamer L16 crystallizes in the P21/c space group and cocrystallizes with chloroform molecules of solvation. This hexameric structure forms stacks along the b axis as a consequence of face-to-face alignment of the macrocycles. Each macrocycle serves as a host for a single chloroform guest within the pores of the macrocyclic stacks, avoiding unfavorable void space formed by the extended pores (ca. 20 Å lengthwise in the solid state; Figure 3A). Similar to the hexamer, the pentamer L15 crystallizes in the P21/c space group and cocrystallizes with chloroform molecules to fill the void within the pores of the macrocycle (Figure 3B). The pentamer adopts an unusual “cinched” conformation in the crystal structure, reducing the symmetry. The centroid distances between two stacked pentamer macrocycles is ca.

Figure 2. Pn-activated iodine oxidation of H2L1 and H2L2 to form disulfide macrocycles (ca. 1 equiv of ligand, 0.5 equiv of SbCl3, and 2 equiv of I2) yielding L1,22 (dimer), L1,23 (trimer), L1,24 (tetramer), L1,25 (pentamer), and L1,26 (hexamer). Overall isolated yields for the selfassembly are 84% and 93% (inset at upper right) respectively for H2L1 and H2L2. The distribution of each disulfide macrocycle formed at ∼2 mM reaction conditions is shown.

5.5 Å, too large for an attractive arene π···π interaction. In addition, overlaying neighboring sulfur atoms between macrocyclic stacks are too far apart (5.5 Å) to suggest S···S contacts. However, the resultant “cinching” motif appears to be part of a short S···H interaction of 2.95 Å that exists between separate channels of macrocycles, suggesting that the alignment of the macrocycles in the solid state is energetically influenced by adjacent columnar stacking (Figure 3B). A shortened S···S contact of 3.82 Å between stacks also reinforces the likelihood that noncovalent intercolumnar stabilizing forces support stacking in the solid state. Again, these weak, but attractive interactions provide the added stabilization required to support the disordered solvent-filled space in the porous packing arrangement. Last, both L16 and L15 feature atypical C−S−S−C disulfide torsion bond angles. The pentamer (L15) exhibits angles at 82.0° and 81.3° that are distorted from the ideal 90°. The larger hexamer (L16) also features a strained torsional disulfide angle of 82.6°. Correspondingly, strain is also even more apparent in smaller disulfide dimers.33 For these reasons, we acknowledge that the use of Pn in thiol disulfide DCC may be a good alternative strategy in cases where at least mild torsional strain makes cyclization difficult to conceive. Solvent Effects in the Disulfide Self-Assembly. Intrigued by the host−guest behavior observed between the macrocycles and solvents of crystallization, we decided to D


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Inorganic Chemistry

Figure 3. Wireframe representations of the crystal packing in L16 (hexamer, A) and L15 (pentamer, B). The pentamer exhibits a “cinched” conformation, stabilized by a S···H contact between a sulfur from a disulfide bond in a stacked macrocycle with a methylene hydrogen from a macrocycle stacked below it in the adjacent columnar stack. Chloroform molecules serve as solvent guests within the pores.

Figure 4. Top: Reaction scheme of Pn-activated iodine oxidation of H3L3 cleanly forming disulfide macrobicycle L32 (dimer, 69%) and tetrahedron L34 (tetramer, 29%) in a combined 98% isolated yield at ∼2 mM concentration (1 equiv of H3L3, 2.5 equiv of SbCl3, and 3 equiv of I2). Middle: Both captured (95%, 1; 94%, 2) by sulfur extrusion with HMPT to provide known trithiacyclophane 1 and new thiatetrahedrophane 2. (A) Wireframe representation of the dimer L32 single-crystal X-ray structure. (B) Wireframe representation of the tetrahedron L34 single-crystal X-ray structure.

the precursor when subjected to iodine.58 Like in the dithiol ligand system (L1,2), concentration studies revealed that the smaller species dominates at low concentrations (favoring primarily L32) and the larger species can dominate at high concentrations ([L34] > [L32]; Figure 4). In more recent kinetic studies, we found that extending the reaction time from minutes to hours or even days also leads to a greater concentration of higher-ordered structures. This time dependence might suggest that the higher-order structure in this case is a more thermodynamically stable product than the dimer; however, the dimer forms first. The promising behavior of our Pn additive within thiol disulfide exchange environments led us to apply dynamic covalent reactivity toward the syntheses of existing and new cyclophanes. Cyclophanes are a venerable class of macrocyclic and/or cage compounds that often feature high strain, unusual conformations, and surprising properties.59 However, the discovery of new and diverse cyclophanes has been slowed by syntheses that are often low-yielding, requiring long reaction times (a representative example of a recent stepwise synthesis

perform experiments to investigate the solvent effects in the formation of the individual cyclic disulfides (Table S1). When Pn-assisted iodine oxidation is performed on ligand H2L1 in acetone, dimer formation is favored over trimer and trimer over tetramer in a 7:3:1 ratio. Conversely, in tetrahydrofuran (THF), the [L12]/[L13]/[L14] ratio is reverse relative to acetone (1:4:7), showing that THF facilitates the conversion to higher ordered structures, whereas acetone favors the dimer. When using halogenated polar organic solvents like chloroform and tetrachloroethane, the ratio [L12]/[L13]/[L14] reveals that the trimer is the dominant product and the ratio remains approximately 1:4:1 for both solvents. Benzene exhibits the same reactivity as chloroform, whereas toluene still favors the trimer but in a 2:4:1 [L12]/[L13]/[L14] ratio. 3-Fold-Symmetric Ligands and Resulting 3D Cages. As previously reported, we applied our Pn-assisted iodine oxidation method to a trisubstituted mercaptomethyl ligand to give the disulfide dimer (L32) and tetrahedron (L34; Figure 4). The self-assembled dimer and tetrahedron were also isolated using an arsenic or a lead macrobicycle (Figure 4; Pn3L32Cl3) as E


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Inorganic Chemistry

Figure 5. Syntheses of 1 and 2 via classical stepwise synthetic cyclophane procedures: (i) NaBH4, CaCl2, THF, EtOH; (ii) PBr3; (iii) (1) thiourea, (2) KOH, H2O; (iv) (1) KOH, EtOH, (2) H3O+; (v) NaBH4, BF3·Et2O; (vi) PBr3; (vii) Cs2CO3, THF; (viii) LiAlH4; (ix) cyanuric chloride, DMF; (x) Na2S, EtOH, CH3CN, room temperature; (xi) Na2S, EtOH, CH3CN reflux.65

to the hexathiother 2 is shown in Figure 5).60−65 We found that by applying our Pn-assisted method we could (1) eliminate some of the very high-temperature steps sometimes used in cyclophane synthesis, (2) avoid low yields that result from the rapid formation of unfavorable insoluble oligomers, and (3) use self-assembly to prepare complex cyclophanes as the major product of the reaction under thermodynamic control. Typically, the synthesis of multibridged, 3D cyclophanes requires stepwise modification and the sequential addition of each bridging unit.66,67 Classical methods such as gas-phase pyrolysis and radical additions can take numerous, often lowyielding steps.68 In our application, these usually low-yielding multistep cyclizations are replaced by a single reaction using Pn-directed self-assembly that occurs under thermodynamic control via DCC to assemble a high-symmetry, discrete (oligo)disulfide. The isolated disulfide macrocycles can then be treated with phosphoramides to remove sulfur atoms, resulting in the kinetic capture of heterocyclophane thioethers (1) or larger species (2). The L34 tetrahedron undergoes sulfur extrusion at each six disulfide sites using stoichiometric amounts of hexamethylphosphoramide (HMPT) to give the hexathioether tetrahedral cage 2 in 94% yield. The sulfur extrusion process occurs rapidly; in the case of L34, the reaction is complete in 4 h at ambient temperature. For the majority of our exploratory experiments, we performed the desulfurization step in chloroform-d to monitor conversion to the desired thiacyclophanes using 1H NMR spectroscopy. We discovered that the solubility of the reactant disulfide in chloroform was not crucial for the success of the reaction. As the sulfur extrusion transpires, the mixture changes from a cloudy white suspension to clear and colorless, signifying that the resultant thiacyclophane is completely soluble in the respective solvent. While we have not observed solvent choice assisting in the driving of the sulfur extrusion process, we found that torsion bond angle strain in the disulfide starting material in fact does. The L32 dimer features strained disulfides (C−S−S−C torsion angles span

107.1−120.0°),33 and HMPT provides trithiacyclophane 1 within 1.5 h at ambient temperature. This heteracyclophane was found by 1H NMR spectroscopy to form in quantitative yield and was isolated in 95% yield with no evidence of ringopened, oligomeric thiother byproducts. Apparently, the sulfur extrusion process relieves the strained disulfide conformation, favoring conversion to the thioether functionality. Again, this reactivity occurs very rapidly without heating, perhaps restricting the formation of oligomers. There are, of course, obvious limits to the sulfur extrusion process. For example, we have observed that large cage systems will “disassemble” with exposure to HMPT and give smaller (more stable) thioether cyclophane structures even if the larger disulfide species itself was isolable. We can mitigate decomposition of the thiacyclophane during sulfur extrusion by (1) utilizing a different phosphoramide (HEPT, PPh3, etc.; Figure 4), (2) changing the solvent, or (3) applying heat. For example, the L12 disulfide paracylophane dimer is unreactive to HMPT in benzene between 25 and 50 °C. When we replace the solvent with THF, we begin to see the presence of intermediates in conjunction with unreacted starting material (25 °C). In chloroform, we observe thiaparacyclophane, but the conversion is low even at elevated temperature (50 °C). We witness the greatest conversion to the thiaparacyclophane product when the reaction is performed in dichloromethane (DCM) at 25 °C. Looking Forward: Testing Functional Group Tolerance and “One-Pot” Reactions. We are currently working on methods to install reactive functional groups, but prior to this work, we explored simple functional groups that could at least test the effects of added steric bulk or minor electronic changes in the aromatic ligand backbone. This preliminary work tested the tolerance to simple functional groups by installing a methoxy group in the 2 and 5 positions of the benzene ring in H2L2 (Figure 2). Iodine oxidation with SbCl3 leads to direct conversion to the L2 dimer, trimer, tetramer, pentamer, and hexamer species. The methoxy group enhances F


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Inorganic Chemistry

Figure 6. (A) Series of trisubstituted ligands used in Pn-assisted iodine oxidation reactions: H3L4, H3L5, H3L6, and H6L7. (B) One-pot Pn-assisted iodine oxidation of dithiol to give trithiacyclophane 3 in 27% overall isolated yield.

the solubility of the resultant disulfide macrocyclic products, effectively improving the overall yield of isolated macrocycles to 93% relative to 84% for nonsubstituted H2L1. Interestingly, the addition of an electron-donating group such as −OMe resulted in slower disulfide macrocyclization. The intermolecular conversion shows greater transformation to larger-sized −OMe macrocycles; however, the reaction takes several days to reach completion. The L23 trimer also successfully undergoes desulfurization (HMPT and DCM) to give the methoxysubstituted trithiacyclophane in 72% isolated yield. We are also testing variants of the 3-fold-symmetric ligand H3L3 by adding groups at the 2, 4, and 6 positions of the benzene core (Figure 6). H3L4 and H3L5 both appear to undergo Pn-assisted iodine oxidation to give discrete disulfides, as noted by the sharp peaks for the mercaptomethylene groups in the 1H NMR spectra (see the SI). H3L5 yields two products after gel permeation chromatography (GPC), suggesting the successful conversion to disulfide dimer and tetrahedron (Figure 7A); however, efforts to crystallize the tetrahedron have proven difficult because the structure decomposes in solution rapidly. We are currently exploring strategies that allow functionalization at these positions without such decreasing stability. Preliminary studies using the ethyl-substituted H3L6 suggest that this ligand system could be a promising target to understand steric gearing using this method. A clear limitation in Pn-assisted iodine oxidation was observed during a study of the reactivity of a highly multisubstituted ligand, H6L7. We were interested in whether we could isolate the disulfide “superphane” dimer,68 yet the resultant species after oxidation revealed a spectrum with only a singlet at ∼4 ppm according to 1H NMR spectroscopy in trichloroethane-d2 (Figure S4). Here intramolecular disulfide formation between neighboring thiol groups competes with intermolecular disulfide bond formation and therefore does not result in a dimer. We are reminded that solvent and concentration effects have played a strong role in the selfassembly reactions presented in this Viewpoint, so perhaps there are conditions that could result in the desired intermolecular reaction. Last, we are eager to accelerate our progress in the isolation of kinetically captured thiacyclophanes produced in one-pot Pn-assisted iodine oxidation/sulfur extrusion reactions. We previously reported 1H NMR spectroscopic evidence of trithiacyclophane dimer 1 in a crude mixture of a one-pot

Figure 7. Putative L54 disulfide tetrahedron (A) and L38 octahedron (B).

reaction using H3L3 with SbCl3, I2, and phosphoramide in CDCl3.33 More recently, we have shown that we can successfully isolate the previously unknown thioether-based cyclophane trimer 3 in a 27.5% yield with H2L1 via a one-pot reaction (Figure 4B).

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EXPERIMENTAL SECTION

One-Pot Synthesis of 2,11,20-Trithia[3.3.3]paracyclophane (3). Under an atmosphere of ambient air, H2L1 (106 mg, 0.624 mmol) was added to CHCl3 (100 mL) in a flask equipped with a stir bar. A second flask was charged with I2 (317 mg, 1.247 mmol) and SbCl3 (142 mg, 0.624 mmol) in 50 mL of CHCl3. The solution of I2 and SbCl3 was then added slowly to the solution of H2L1 with stirring, affording a clear, deep-purple solution. The resulting mixture was then allowed to stir at ambient temperature for 16 h. The solution was then degassed for 1 h before HMPT (1.31 mL, 7.217 mmol) was added to the flask, and the flask was swirled gently to mix. The reaction was allowed to react undisturbed at room temperature for 16 h and then concentrated under reduced pressure. The crude solid was sonicated in G


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Inorganic Chemistry a mixture of 20 mL of saturated sodium sulfite and 20 mL of deionized water. The solid was separated from its aqueous counterpart by centrifugation and washed two more times with fresh deionized water. The solid was then redissolved in CHCl3 and subjected to GPC to yield 23 mg of the thiatrimer (27.5% isolated yield over two steps). Quantitative Study of the Role of SbCl3. A quantitative study of Pn-assisted iodine oxidation was performed. First, stock solutions of H2L1 and I2 were made. In a 20 mL scintillation vial, H2L1 (11.6 mg, 0.068 mmol) was dissolved in 2.5 mL of CDCl3. In a separate 20 mL scintillation vial, I2 (35 mg, 0.136 mmol) was dissolved in 2.5 mL of CDCl3. Each NMR experiment contained 0.5 mL from the H2L1 stock and 0.5 mL from the I2 stock. A stock solution of SbCl3 was then made with 7.7 mg in 2.5 mL of CDCl3. The amount of SbCl3 was varied from 30 to 70 mol %. For each 1 equiv of SbCl3, we recorded the NMR spectra as a function of time: 1 min after all of the reagents were added, 5 min, 15 min, 30 min, 1 h, 3 h, 5 h, overnight, and over 2 days. Quantitative Study for Alternative Thiophilic Metals. We were interested in seeing whether other thiophilic metals, such as Ag+, Zn2+,69 Bi3+,70 or even metals suitable for encapsulation in macrocyclic systems (Ca2+),71 could replicate the reactivity of Sb3+. For AgOAc, AgOTf, and Zn(OAc)2, we ran the oxidation reaction using 1.11 mg (0.0065 mmol) of H2L1 with 3.30 mg (0.0130 mmol) of I2 in (CD3)2SO (CDCl3 for AgOAc). The amount of salt was varied from 1.7 to 4.2 equiv, and none of the reactions went to completion. In order to expand our library of tested salts, we utilized acetone-d6 as our choice of solvent because many of these metal salts exhibited greater solubility in acetone. For each experiment, we used 0.85 mg of H2L1 (0.005 mmol) and 2.54 mg of I2 (0.010 mmol) along with 0.010 mmol of each salt. For example, to study the effects of AgOAc (1.67 mg, 0.010 mmol), the product peaks were integrated via 1H NMR after equilibrium was reached and showed a series of disulfides ranging from dimer to hexamer. Additionally, the intermediates (metal−thiol complex) contributed 26% of the total product, compared to 44% in the case where a metal additive was not added. This indicated that, to a certain extent, Ag+ participated in the oxidation reaction of the thiols. Furthermore, we found that ZnCl2 (1.36 mg, 0.010 mmol) and Zn(acac)2 (2.64 mg, 0.010 mmol) behaved similarly to each other and to AgOAc, indicating that while both metals aided in the synthesis of disulfides, neither showed superior performance, as with a Pn source. In the interest of testing for “metal encapsulation” templating reactivity, we chose Ca2+, specifically, 0.010 mmol of Ca(NO3)2 (1.64 mg) and 0.010 mmol of Ca(ClO4)2 (2.39 mg), which showed behavior similar to that of the control and no immediate templating mechanism. Last, we found that BiCl3 (3.15 mg, 0.010 mmol) proceeded with Pn-assisted iodine oxidation both cleanly and rapidly such that the 1H NMR spectrum gave all of the expected product peaks and no oligomeric/polymeric intermediate resonances after 16 h of reaction. We anticipate that the use of BiCl3 in Pn-assisted iodine oxidation will be a promising alternative for studying ligand systems that require polar protic solvent systems.

serve as excellent precursors to ring-opening polymerizations (e.g., the parylene process)72 or as functional hosts for chemical storage, as demonstrated in the crystallized porous networks of the larger-sized macrocycles. As a last thought, higher-order assemblies beyond tetrahedra can be imagined as targets from this synthetic method. Subtle geometric changes in the ligands or the introduction of steric bulk may enable the assembly of these larger structures. In addition, we have observed intriguing evidence for the assembly of even larger cages, even if their isolation has so far proven elusive (e.g., an L8 octahedron in Figure 7). These higherordered structures appear to form in solution but require additional external stabilizing factors to avoid decomposition in the solid state. We hope to report the synthesis of such structures in the near future. This work on the dynamic reactivity using Pn-assisted iodine oxidation is still in its early stages (and we may find that it will not ultimately require even a Pn additive); we continue to explore its potential to synthesize new and otherwise-hard-to-form cyclophanes.

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.inorgchem.7b02716. Tables showing product distributions from different concentrations and salt additives and NMR spectra (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Darren W. Johnson: 0000-0001-5967-5115 Author Contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. M.S.C., N.-M.P., and D.W.J. conceived and designed the experiments; M.S.C. and N.-M.P. performed the experiments; M.S.C., N.-M.P. and D.W.J. analyzed the data; M.S.C. and D.W.J. cowrote the paper with editorial assistance from N.-M.P.

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Notes

CONCLUSIONS In this Viewpoint, we discussed our approach to synthesizing cyclic and polycyclic disulfide structures that are cleanly and rapidly synthesized from prearranged, self-assembled pnictogen thiolate complexes and iodine. In this method, the usually lowyielding coupling step is replaced by self-assembly performed under thermodynamic control in the presence of a pnictogen trichloride additive. This dynamic covalent technique allows the synthesis of formerly inaccessible, higher-ordered species such as trimers, tetramers, pentamers, hexamers, macrobicycles, and tetrahedra to be isolated in high yield. Current progress indicates that these self-assembly reactions may be tolerant to certain functional groups with prudent ligand design. Because the production of these cyclophanes is synthetically simple and quick, we are mindful of exploring their potential in applications as well. For example, hydrocarbon cyclophanes synthesized from the thioether cyclophanes could

The authors declare no competing financial interest. Biographies

H


Viewpoint

Inorganic Chemistry Mary S. Collins received a B.Sc. in Biochemistry from The University of Texas at Austin in 2010, where she performed undergraduate research under the supervision of Prof. Christopher Bielawski. In 2015, she earned her Ph.D. in Chemistry working with Darren W. Johnson at the University of Oregon, studying the coordination chemistry and reactivity of pnictogen-containing self-assemblies. Currently, Mary is a postdoctoral fellow at the Molecular Foundry at Lawrence Berkeley National Laboratory, where she studies photoluminescent, semiconducting self-assembled nanomaterials.

Darren W. Johnson is a Professor of Chemistry and Associate Director of the Materials Science Institute at the University of Oregon. He obtained his Ph.D. from University of California at Berkeley in 2000 and was an NIH postdoctoral researcher at the Scripps Research Institute from 2001 to 2003. His research draws inspiration from challenges in environmental, supramolecular, and sustainable chemistry, and research in the group uses supramolecular chemistry as a tool to explore a variety of problems in self-assembly, molecule/ion recognition, and inorganic cluster synthesis. He is also cofounder of SupraSensor Technologies (SST). Launched out of the NSF Innovation Corps program, SST seeks to commercialize remote sensors for nutrient management in precision agriculture and was recently acquired by The Climate Corporation. He is a recipient of the University of Oregon’s Research Innovation Commercialization Sustainability Award, the Innovation and Impact Research Award, and the Fund for Faculty Excellence Award. He has coauthored over 115 peer-reviewed publications and is a coinventor on 12 pending and issued patents.

Ngoc-Minh Phan obtained a B.S. in Biochemistry from the University of Dallas in 2016; she completed undergraduate research investigating epigenetic control of gene expressions disorders such as cancer under the supervision of Dr. Elisabeth Martinez (University of Texas Southwestern Medical Center). She then moved to the University of Oregon, where she is now a graduate student in the Department of Chemistry and Biochemistry. In 2017, she joined the Darren W. Johnson laboratory, studying the synthesis of cyclophanes using metaldirected self-assembly and covalent capture.

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ACKNOWLEDGMENTS This material is based upon work supported by the National Science Foundation (NSF) under Grant CHE-1609926. We gratefully acknowledge the use of UO CAMCOR facilities, which have been purchased with a combination of federal and state funding; the NMR facilities in CAMCOR are supported by the NSF (CHE-1427987).

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REFERENCES

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Coupling Metaloid-Directed Self-Assembly and Dynamic Covalent

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