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Article Cite This: ACS Omega 2019, 4, 3405−3408
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Synthesis of Tetrathia−Oligothiophene Macrocycles David J. Press, Chris Gendy, Samruddhi Pasalkar, Shauna Schechtel, Belinda Heyne,* and Todd C. Sutherland* Department of Chemistry, University of Calgary, 2500 University Drive NW, T2N 1N4 Calgary, Alberta, Canada
ACS Omega 2019.4:3405-3408. Downloaded from pubs.acs.org by 109.94.173.34 on 02/22/19. For personal use only.
S Supporting Information *
ABSTRACT: The synthesis of six tetrathia−oligothiophene macrocycles is described with modest ring-closing yields between 21 and 55%. Single-crystal X-ray studies of four of the macrocycles indicated that encapsulated solvent or guest molecules were possible. A variety of guest molecules were explored for inclusion complexes via NMR, absorption, emission, and X-ray techniques. The solution-phase inclusion complexes were uninformative; yet the solid-state experiments revealed that solvent exchangeable channels exist through the macrocyclic pores.
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INTRODUCTION
Macrocycles are at the foundation of supramolecular chemistry that earned Cram, Lehn, and Pedersen the 1987 Nobel Prize.1−3 The synthesis of novel macrocycles exploded in the literature and common shape-inspired names include crown ethers, spherands, and cryptands. Synthetic strategies in the isolation of macrocycles often employ multistep procedures, which can result in low yields and poor scalability. However, notable exceptions include intramolecular hydrogen bond networks of Zeng,4 dynamic covalent bond formations of MacLachlan,5 or the anion-templated assemblies of Flood.6 The synthetic macrocyclic field was recently reviewed by Stoddart in 2017,7 which highlights the modern trends such as stimuli-responsiveness, 3-D shapes, and rigidification. Recent synthetic macrocycle families include cucurbit[n]urils, pillar[n]arenes, calix[n]arenes, “blue box, exboxes, and excages” by Stoddart et al. and π-conjugated macrocycles such as cycloparaphenylenes. Despite the large number of macrocyclic analogs published, there remains significant chemical space to investigate and we elected to focus on thiophenecontaining thioether macrocycles. Moreover, the use of oligothiophenes as building blocks of the macrocycles provide the host molecules an optical channel to probe potential inclusion interactions with optically silent guests. Independently, thiophene-containing8−12 or thioether11,13 macrocycles are not novel; however, in combination, the macrocycles are largely unexplored as electron-rich large hosts. Figure 1 shows the six thiophene-containing thioether macrocycles investigated.
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Figure 1. Structures of the six macrocycles investigated.
terthiophene (terTh) units that are linked through thioethers and bridging methylenes that vary in length from butyl to hexyl. The six cyclophanes in Figure 1 result in ring sizes that vary from to 24 to 34 atoms with interior dimensions that vary from approximately 7.7 Å by 6.9 Å for C4biTh to 12.1 Å by 4.3 Å for C4terTh in select single-crystal structures. The macrocyclic synthesis is initiated with commercially available bi- and terthiophene, which was dilithiated with 2.2 equiv of n-BuLi and then quenched with elemental sulfur to give bi- and terthiophene polysulfides, as shown in Scheme 1.14 Both polysulfides were then reduced with sodium borohydride, forming their respective bis thiolates, followed by addition of 1,4-bromobutane, 1,5-dibromopentane, or 1,6-dibromohexane, to give BrCnbiTh or BrCnterTh. Isolated yields for the thioether formation were between 40 and 60% over two steps starting from the parent oligothiophene. The terminal alkyl dibromides were then reacted with another equivalent of either bis-thiolate-bithiophene or bis-thiolate-terthiophene to produce the six macrocycles that vary both the thiophene
RESULTS AND DISCUSSION
Received: December 7, 2018 Accepted: February 1, 2019 Published: February 15, 2019
The six macrocycles, or cyclophanes, are divided into two families, based on either the bithiophene (biTh) or © 2019 American Chemical Society
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Scheme 1. Synthesis of CnbiThs and CnterThs Macrocycles; (i) n-BuLi, Then Elemental S; (ii) NaBH4, Then Either 1,4Bromobutane, 1,5-Dibromopentane, or 1,6Dibromohexane; (iii) PolySSbiTh, NaBH4, Then BrCnbiTh; (iv) PolySSterTh, NaBH4, Then BrCnterTh
conjugation length and the alkyl spans of the macrocycles. Crystallization is the preferred purification method for the macrocycles C5biTh, C6biTh, C5terTh, and C6terTh, owing to decomposition by silica gel column chromatography. All of the macrocyclic products were characterized by 1H and 13C NMR spectroscopy and high-resolution mass spectrometry, as described in the Supporting Information. The macrocyclic ring formation conditions resulted in modest yields of ca. 40% for the CnbiThs, which dropped to approximately 20% yields for the larger terthiophenes, CnterThs. The higher yields of the bithiophene macrocycles could be explained by the shorter tether (entropic effect) enabling a U-shaped intermediate that can be more readily ring-closed, given that the ring-closing reaction concentrations were the same. Single crystals of the CnbiTh series of macrocycles are shown in Figure 2 along with the sole terthiophene macrocycle, C4terTh. The remaining terthiophene macrocycles did not form resolvable crystals. The C4biTh and C6biTh macrocycles share similarities in the solid-state structure, such as a nearly 100° C−S−C thioether corners and co-planar bithiophenes. The C5biTh macrocycle deviates from both C4and C6-bithophenes because the two bithiophene moieties are no longer parallel to each other. The C4terTh macrocycle shows the conjugated terthiophenes are co-planar, but the two planes of terthiophenes are perpendicular. Note, the cavity of C4biTh is not empty as shown in Figure 2; rather there is unresolvable solvent within the cavity discussed below. Interestingly, a view down the b-axis of C4biTh reveals a one-dimensional channel filled with disordered solvent, which is absent in the packing of the other macrocycles. The slightly larger cavities of both C5- and C6-bithiophenes co-crystallized with cyclohexane. For C5biTh, steric pressure from the cocrystallized cyclohexane molecule causes the observed out-ofplane twisting of the biothiophene linkers. The cyclohexane in C5biTh is best described as encompassed by two adjacent macrocycles, as can be seen in the Supporting Information Xray data files. Conversely, C6biTh has enough cavity space to
Figure 2. X-ray single-crystal structures of C4biTh to C6biTh and C4terTh. Thermal ellipsoids are drawn at 50% probability.
accommodate completely a single cyclohexane guest. There are limited examples of macrocyclic host complexes that capture cyclohexane.15−17 On the other hand, no solvent molecules were found in the C4terTh structure because the macrocyclic ring collapsed in the solid-state, likely because of the flexible butyl walls. For C4biTh, the intermolecular solid-state interactions are limited to Ar(C−H)···S(Ar) and sulfide(S)···H2C(alkyl). Similar weak intermolecular interactions are shown in the other macrocycles (Supporting Information). In addition, there are no short contacts between the macrocycles and the trapped cyclohexane, which suggests the guest solvent is weakly bound and could be exchangeable. Naturally, the macrocycles were examined for guest inclusion chemistries. Supramolecular assemblies were assessed using NMR, absorption, and fluorescence spectroscopies and powder X-ray techniques. The 1H NMR experiments of all the host macrocycles in a variety of solvents showed no evidence of intermolecular interactions, suggesting the interactions are very weak or the size of the cavity in solution is insufficient. The 1H NMR of C4biTh in a variety of solvents is shown in Figure 3, which clearly displays the chemical shift of both 3406
DOI: 10.1021/acsomega.8b03444 ACS Omega 2019, 4, 3405−3408
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Figure 4. Absorption and emission spectra (λexc = 335 nm) of a 20 μM solution of C4biTh dissolved in ethanol (blue) in the presence of 1000 equiv of adamantine (red), cholesterol (green), camphor(purple), menthol (orange, not visible because of overlap), bisphenol A (brown), butylated hydroxytoluene (black), or dodecanoic acid (pink, not visible because of overlap).
crystal shown in Figure 2 resembles the crystals in either chloroform or nitromethane, suggesting the framework of the channels was preserved, but does not necessarily support or refute solvent exchange. More insight was gained when single crystals of C4biTh were placed in vials and a small volume (∼1 mL) of chloroform or nitromethane was layered on top for 4 days. The single crystals in chloroform slowly dissolved and were not recovered, whereas the single crystals bathed in nitromethane were recovered and remounted on the diffractometer. The solved X-ray structure of C4biTh in nitromethane showed no changes to the macrocycle packing and only disorder in the channels, implying nitromethane exchange in the solid state was inconclusive. Conversely, the acetonitrile solvent exchange experiment shows the appearance of several new peaks in the diffractogram that are not present in the simulated spectrum, consistent with a change in crystal structure and a potential solid-state guest exchange process. Remounting of a single crystal after exposure to acetonitrile for 4 days resulted in a structure that indeed included acetonitrile in the macrocyclic pocket, as shown in Figure 5. The single crystal was observed over several days via microscopy and exhibited no change in crystal shape, suggesting exchange; however, we cannot preclude dissolution and re-deposition on the crystal surface. In addition, a significant re-arrangement of the crystal packing of the macrocycle occurred such that the open one-dimensional channel was closed after acetonitrile inclusion. Crystallographic information of C4biTh-containing bound CH3CN is included in the Supporting Information. The crystal-to-crystal transformation maintains the square shape, but the bithiophene changes from a syn- to anti-arrangement upon encapsulating acetonitrile. The simulated powder diffractogram, shown in the Supporting Information, contains several peaks that align with the acetonitrile-soaked C4biTh powder diffractogram, suggesting efficient guest exchange occurred in the solid-state through the open pores.
Figure 3. 1H NMR peak shifts of the C4biTh macrocycle in five deuterated solvents (dimethyl sulfoxide, pyridine, tetrahydrofuran, chloroform, and benzene).
thiophene β-protons (Ha and Hb) and the methylene protons (Hc and Hd) are solvent-dependent. The remainder of the macrocycles in the 1H NMR study are included in the Supporting Information. As a control, linear n-pentyl chains were appended to both the bi- and terthiophene sulfides to assess the effect of ring closure on the 1H NMR (Supporting Information). The changes in thiophene β-proton chemical shifts in different solvents of the macrocycles are mirrored in the noncyclic control, suggesting the thiophenes of the macrocycle are not affected by the macrocyclic ring constraint. However, the methylene protons did show a change in coupling pattern in the linear versus macrocycle, consistent with constraint. Whereas the 1H NMR peaks do shift in different solvents, titrations of mixed solvent additions, for example cyclohexane in pyridine, did not show any indications of inclusion-induced peak shifts or broadening. At 1H NMR concentrations, no evidence of host−guest binding was observable; thus, a move toward more sensitive optical techniques to assess intermolecular interactions was sought. The bi- and terthiophene macrocycles are spectroscopically active with emissive properties in solution (Supporting Information); consequently, absorption and fluorescence studies were undertaken to probe the electronic effects of different guests in the chromophoric macrocycles. A wide range of guest molecules were investigated with no impact on the electronic properties of the macrocycles, as illustrated for C4biTh in Figure 4. A complete list of all the guest molecules investigated can be found in the Supporting Information. The lack of electronic spectral changes with a variety of guests suggests the macrocycles present too many degrees of freedom in solution, leading to entropic effects that preclude guestbinding. The X-ray structures of the bithiophene series suggested the solvent molecules are weakly bound and might be exchangeable in the solid state. For these experiments, single crystals (formed from a mixture of chloroform, hexanes, and trace ethyl acetate) were collected and placed in vials containing single solvents. The Supporting Information shows powder X-ray diffractograms of these solvent exchange experiments for C4biTh. For C4biTh, chloroform, acetonitrile, and nitromethane were selected as candidate guests based on molecular guest size. The simulated powder pattern from the single
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CONCLUSIONS In summary, six new bi- and terthiophene macrocycles were synthesized and characterized, including single-crystal structures for four. Solution studies to probe inclusion phenomena of small guest molecules were largely unsuccessful, suggesting too much flexibility in the macrocyclic structure to overcome the weak intermolecular interactions. However, upon immersion of the crystals in different solvents the powder X-ray pattern did change, suggesting guest exchange was occurring through the porous cavity, which was confirmed via X-ray 3407
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ACKNOWLEDGMENTS T.C.S. thanks NSERC Discovery Grant RGPIN/04444-2014 and B.H. thanks NSERC Discovery Grant RGPIN/3555482017.
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Figure 5. Single crystal-to-crystal transformation of C4biTh when soaked in acetonitrile, suggesting solvent exchangeable pores.
structure determination for C4biTh in the presence of acetonitrile.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsomega.8b03444. Synthetic details and molecular characterization; 1H and C NMR spectra; absorption and emission spectra. CCDC 1873906-1873909 and 1883143 (PDF) Crystal structures (.cif format) have been combined into a single .zip file (ZIP)
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REFERENCES
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AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected] (B.H.). *E-mail:
[email protected] (T.C.S.). ORCID
Belinda Heyne: 0000-0003-1655-6719 Todd C. Sutherland: 0000-0002-9321-7633 Author Contributions
The article was written through contributions of all the authors and all the authors have given approval to the final version of the article. Notes
The authors declare no competing financial interest. 3408
DOI: 10.1021/acsomega.8b03444 ACS Omega 2019, 4, 3405−3408
