Modular Synthesis of Tetraurea and Octaurea Macrocycles Encoded with Specific Monomer Sequences

Abstract

Open AccessCCS ChemistryRESEARCH ARTICLE14 Jul 2022Modular Synthesis of Tetraurea and Octaurea Macrocycles Encoded with Specific Monomer Sequences Guowei Zhao, Si-Qi Chen, Wei Zhao, Boyang Li, Wenyao Zhang, Bo Zheng, Xiao-Juan Yang and Biao Wu Guowei Zhao Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of the Ministry of Education, College of Chemistry and Materials Science, Northwest University, Xi'an 710069 , Si-Qi Chen Key Laboratory of Cluster Science of Ministry of Education, Key Laboratory of Medical Molecule Science and Pharmaceutics Engineering, Ministry of Industry and Information Technology, School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing 102488 , Wei Zhao *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] Key Laboratory of Cluster Science of Ministry of Education, Key Laboratory of Medical Molecule Science and Pharmaceutics Engineering, Ministry of Industry and Information Technology, School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing 102488 , Boyang Li Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of the Ministry of Education, College of Chemistry and Materials Science, Northwest University, Xi'an 710069 , Wenyao Zhang Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of the Ministry of Education, College of Chemistry and Materials Science, Northwest University, Xi'an 710069 , Bo Zheng Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of the Ministry of Education, College of Chemistry and Materials Science, Northwest University, Xi'an 710069 , Xiao-Juan Yang Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of the Ministry of Education, College of Chemistry and Materials Science, Northwest University, Xi'an 710069 and Biao Wu *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of the Ministry of Education, College of Chemistry and Materials Science, Northwest University, Xi'an 710069 Key Laboratory of Cluster Science of Ministry of Education, Key Laboratory of Medical Molecule Science and Pharmaceutics Engineering, Ministry of Industry and Information Technology, School of Chemistry and Chemical Engineering, Beijing Institute of Technology, Beijing 102488 https://doi.org/10.31635/ccschem.021.202101131 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail Intermolecular hydrogen bonding among urea units grants prominent mechanical strength to polyurea elastomer materials. However, such interactions can cause significant solubility problems when synthesizing oligourea macrocycles with a large number of urea units, and it remains unknown for macrocycles containing more than six urea units. Here, we demonstrate a two-step, modular strategy for making a new class of tetraurea and octaurea macrocycles using commercially available building blocks. Intramolecular hydrogen bonding within the fundamental o-phenylene bis(urea) unit is the key to overcoming intermolecular hydrogen bonding to form favorable conformations for ring-closure reactions. The size and monomer sequences can be controlled by varying the flexibility of the spacers. Rigid diphenyl methylene and diphenyl ether linkers selectively afford tetraurea macrocycles, whereas the flexible hexylene linker produces octaurea macrocycles. Macrocycles encoded with two different spacers were also made. All these macrocycles are confirmed by X-ray diffraction structural analysis of the complexed forms with sulfate anions. Interestingly, a unique "figure-eight" structure is observed for the complex of MUH octaurea macrocycle with two encapsulated sulfate anions. Our study shows a paradigm of making large oligourea macrocycles with designer properties in a programable manner with tunable monomer sequences. Download figure Download PowerPoint Introduction The synthesis of macrocycles is a fundamental challenge because of their entropically disfavored nature and competition from side reactions (oligomerization and polymerization) during the ring-closure processes.1 Through elegant molecular designs and synthetic methodologies,2,3 various macrocyclic structures have been made and engineered with specific monomer sequences for the uses of molecular recognition,4–6 chemical storage and separation,7,8 catalysis,9–11 molecular machines,12 assemblies,13–16 and adaptive materials.17–19 Benefitting from the characteristic hydrogen bonding nature (high-rigidity and self-complementarity) of the urea unit,20,21 urea-based macrocycles have attracted great attention in the studies of anion recognition22–26 and hierarchical assembly.27–29 However, compared to the well-established industrialization of polyurea elastomer materials,30 the oligourea macrocycles are far less explored because the intermolecular hydrogen bonding of urea units may induce poor solubility of the desired macrocycles thus inhibiting their syntheses and purifications.31–34 To solve this problem, a ring-closure reaction with minimum competing side-reactions is one of the key factors needed. Efficient ring-closure reactions rely on well-defined conformation of the linear precursor that can be preorganized by binding to a guest molecule or by intramolecular hydrogen bonding.35–37 However, these methodologies have not been well-documented in the preparation of oligourea macrocycles. Pioneer work from Böhmer used relatively flexible xanthenes and diphenyl ether spacers to build triurea,38 tetraurea,39 and hexaurea macrocycles,40–42 in which chloride was used as the template for the formation of hexaurea macrocycles. Similarly, chloride anion can template the formation of shape-persistent tetraurea macrocycles showing unusual columnar assemblies.25 By incorporating exterior intramolecular hydrogen bonding between urea (N–H) and alkyloxy groups, other tetraurea macrocycles were also prepared with carbonyl groups orienting toward the cavity for potassium binding.43,44 For these oligourea macrocycles, besides the geometrical and templating considerations, a flexible backbone or plentiful substitutions, for example, alkyl or fluoride, are also essential to retain fairly good solubility. As a consequence, more steps are required for the ring-closure reaction from commercially available building blocks, further reducing the overall efficiency. Very recently, an alternative approach to the synthesis of tetraurea macrocycles was rationally designed in which dynamic conformation preference helps the macrocyclization using N-tert-butyl substituted amines.45 However, according to a careful literature screening, most oligourea macrocycles consist of only two urea units, with only a few examples of tri-, tetra-, and hexaureas, while macrocycles consisting of more than six urea units remain unknown due to synthetic challenges. In previous studies, it was found that the o-phenylene bis(urea) unit ( U) displays characteristic chelating modes toward chloride, sulfate, and phosphate anions.46–49 Further inspection shows that, in addition to its typical anion binding property (strong positive electrostatic potential, +390 kJ/mol), the bis(urea) unit inclines formation of an anti-conformation with the help of intramolecular hydrogen bonding of N–H...O=C (dN...O = 2.73 Å, Figure 1a). These facts inspired us to develop an efficient strategy for the synthesis of oligourea macrocycles by incorporating the unique bis(urea) unit (instead of a single urea). Studies on bis(urea)-based tetraurea macrocycles have been reported and suggest that the bis(urea) unit may account for decent yield of the final ring-closure macrocyclization.24–26 However, the principles underpinning the synthesis of bis(urea)-based macrocycles are still underdeveloped. To elucidate these, we first hypothesized that strong intramolecular hydrogen bonding of the bis(urea) unit can induce a well-defined, twisted conformation for macrocyclization. Second, complexation of the bis(urea) unit with anions may help to improve the solubility of desired oligourea macrocycles.50 To test these ideas, the o-phenylenediamine was used as the starting material. Satisfyingly, we were able to make macrocyclic tetraureas and octaureas in two steps from commercially available building blocks, where the octaurea macrocycles contain the largest number (8) of urea units. The rigid diphenyl methylene ( M) and diphenyl ether ( E) spacers selectively afford tetraurea macrocycles, while bigger octaurea macrocycles are obtained using a flexible hexylene ( H) linker (Figure 1b and Supporting Information Figures S1 and S2). It is noted that all these macrocycles are made with specific monomer sequences with no template and chromatographic purification. Interestingly, the tetraurea macrocycles are found to bind sulfate in a 1:2 stoichiometry forming artificial sulfate channels in a long-range order in the solid state, while the octaurea macrocycles can encapsulate two sulfate anions in the cavity. A unique figure-eight conformation is observed for the MUH octaurea macrocycle (vide infra) with a diphenyl methylene spacer. Figure 1 | (a) DFT-optimized geometry of o-phenylene bis(urea) moiety showing strong intramolecular hydrogen bonding, and the electrostatic potential map of its planar geometry that is induced by anion binding. (b) The two-step, modular strategy of making tetraurea and octaurea macrocycles (MCs) encoded with specific monomer sequences. The associated letters (U, M, E, H) for the monomer structural sequences are shown at the bottom. All calculations were performed at the B3LYP/6-31+G(d) level of theory. Download figure Download PowerPoint Experimental Methods All the reagents were obtained from commercial suppliers and used as received unless otherwise indicated. Nuclear magnetic resonance (NMR) spectra (1H and 13C) were recorded on Bruker AVANCE III-400 MHz spectrometers (Bruker, Germany) at 298 K. Chemical shifts were referenced to residual solvent peaks. Electrospray ionization (ESI) mass spectroscopy was performed on a Bruker Daltonics micrOTOF-Q II spectrometer (Bruker Daltonics Corp., Bremen, Germany). X-ray diffraction patterns were recorded on a Bruker D8 Venture Photon II diffractometer (Bruker, Germany). Computational analysis was conducted in Spartan′18 (Wavefunction, Inc., United States) using different levels of theory correspondingly. All the experimental details are available in the Supporting Information. Results and Discussion Syntheses and X-ray diffraction structures of tetraurea macrocycles The o-phenylenediamine was selected as the bis(urea) source. We used three spacers of different rigidity, 4,4′-diphenylmethane diisocyanate (MDI), one-step prepared 4,4′-diphenyl ether dicarbamate (EDC) from its corresponding diamine, and hexylene diisocyanate (HDI) for macrocyclizations (Scheme 1 and Supporting Information Scheme S1). These economically feasible reagents are extensively used for making polyurethane and polyurea materials since the 1960s and would allow us to make macrocycles on gram scale. Ultimately, it is surprising to see very different outcomes of the highly efficient, spacer-dependent macrocyclizations. Scheme 1 | Two-step synthesis of tetraurea macrocycles from commercially available building blocks, o-phenylenediamine, MDI, and EDC. TEA, triethylamine. Download figure Download PowerPoint First, one-pot reaction of MDI and o-phenylenediamine in a 1:1 ratio did not produce any macrocycle. Instead, a bis(urea)bis(amine) intermediate, S1, was isolated by precipitation. Modifying the reaction by mixing MDI with 2 equiv of o-phenylenediamine (1:2 ratio) in tetrahydrofuran (THF) under ice-bath produces S1 in 99% yield. Such a selective formation of diamine intermediate S1 is counterintuitive because two monomers with divergent reacting terminal groups are more likely to undergo polymerization or ring-closure reaction instead of forming a dimer. This selectivity is believed to originate from the poor solubility of the diamine intermediate. Next, we conducted macrocyclization of the intermediate S1 with various diisocyanate building blocks. When S1 was mixed with an equivalent amount of MDI in dimethylformamide (DMF) and THF and stirred at 100 °C for 1 h, followed by concentration and addition of acetone, the macrocycle MU was found to precipitate with 92% yield (Scheme 1). Similarly, the low-symmetry macrocycle MUE was obtained in 89% yield using S1 and EDC. These two macrocycles consist of four urea units where two characteristic bis(urea) moieties are bridged by either a diphenyl methylene or a diphenyl ether spacer. The tetraurea MU has a D2h symmetry because the diphenyl methylene spacers and the bis(urea) units are arranged in an alternating sequence (MUMU, see Scheme 1), whereas the tetraurea MUE macrocycle is C2v symmetric. These two reactions suggest that we are able to tune the monomer sequences and symmetries of tetraurea macrocycles by using different diisocyanate or dicarbamate building blocks. Encouraged by the feasible macrocyclization of MU and MUE, we observed similar results for the reaction of o-phenylenediamine with the EDC building block. The intermediate S2 was isolated in 95% yield by precipitation, and further reaction with EDC afforded the tetraurea macrocycle, EU, with a yield of 95%. The EU macrocycle shows similar structure to the MU analogue, where an alternating monomer sequence of diphenyl ether spacer and bis(urea) units is observed. Additionally, macrocyclization of intermediate S2 with MDI afforded the same MUE macrocycle in 85% yield, indicative of high modularity of this two-step strategy. The formation of these tetraurea macrocycles is unambiguously confirmed by crystal structures of the complexed forms with tetraethylammonium sulfate salts (TEA2SO4, Figure 2). Crystals of the tetraurea complex TEA2[ MU.(SO4)2] were obtained by slow vapor diffusion of diethyl ether to an acetonitrile solution at room temperature (Figure 2a). It was found that two sulfate anions coordinate to one macrocycle at opposite sides through hydrogen bonding with the bis(urea) units (4 × N–H...O). Besides these, each sulfate anion forms hydrogen bonding with two water molecules (O...H–O–H), which also interact with the other sulfate anion to form a water-bridged sulfate-sulfate dimer. Accordingly, the tetraurea macrocycle assembles into a linear infinite columnar structure in that solid state that is driven by a combination of macrocycle-sulfate binding and the water-bridged sulfate-sulfate interactions (Figure 2b and Supporting Information Figure S3). Similar assemblies driven by anti-electrostatic hydrogen bonding assisted anion-anion interaction are commonly seen for hydroxyl anions in the solid state.51 Figure 2 | X-ray crystallographic structural analysis. (a) The 1:2 tetraurea:sulfate complex for MU, and (b) the 1D infinite columnar structure driven by a combination of macrocycle-sulfate binding and the water-bridged hydrogen bonding between two sulfate anions. The sulfate complexed structures for tetraureas (c) MUE and (d) EU X-ray crystallographic structure, respectively. Solvents and tetraethylammonium countercations are omitted for the sake of clarity. Download figure Download PowerPoint Similar crystal structures are also observed for the tetraurea macrocycles MUE and EU (Figures 2c and 2d and Supporting Information Table S1 and Figures S4 and S5). In contrast, a cluster of six water molecules are observed to bridge two sulfate anions for MUE and EU macrocycles. Interestingly, each sulfate anion is stabilized by seven hydrogen bonds, akin to the structure of sulfate binding protein.52 All three tetraurea macrocycles can assemble into a one-dimensional chain with water bridged sulfate anions stabilized in their cavities, which is reminiscent of abiotic anion channels.53,54 To understand the principal driving force for the macrocyclization, computational modelling was conducted for the bis(urea) unit and the pre-macrocycle ( S3), the proposed intermediate leading to the final macrocycle product MU (Figure 3). First, the bis(urea) unit is suggested to favor an anti-conformation, where strong intramolecular hydrogen bonding is displayed (dN...O = 2.7–3.0 Å) according to a careful calculation of the torsion angle of C–N bond (Figures 3a and 3b and Supporting Information Figure S9). This result indicates that the bis(urea) unit tends to twist via intramolecular hydrogen bonding, which can facilitate ring-closure reaction.a By performing a conformer analysis of the pre-macrocycle S3 (Figure 3c and Supporting Information Figure S10), we consistently observed that the most favorable conformation shows strong intramolecular hydrogen bonding in the bis(urea) unit and between the isocyanate and remote urea group (N–H...O(NCO)). Density functional theory (DFT)-optimized equilibrium conformation (Figure 3d) also supports that the twisted conformation (closed form, Figure 3e) is favored, where the amine and isocyanate groups are brought into close proximity for macrocyclization. All these results are consistent with our hypothesis and demonstrate that the macrocyclization is promoted by intramolecular hydrogen bonding. Figure 3 | Computational analysis of macrocyclization for the MU tetraurea. (a) Calculated potential energy surface for the bis(urea) unit with varying torsion angle (colored in blue) and (b) corresponding distance changes of O...N showing strong intramolecular hydrogen bonding. (B3LYP/6-31+G(d)) (c) Conformational profile (Merck Molecular Force Field, MMFF) of the pre-macrocycle indicating that the most stable conformer (red circle) is consistent with the close-state conformation. (d) DFT-optimized equilibrium conformation of the pre-macrocycle at the B3LYP/6-31+G(d) level. (e) The chemical structures for the pre-macrocycles S3 showing intramolecular hydrogen bonding promoted macrocyclization. Download figure Download PowerPoint This two-step macrocyclization represents a modular strategy to prepare tetraurea macrocycles from o-phenylenediamine. When compared to typical preparation methods of other macrocycles reported previously, we find the high efficiency of this strategy can be described with the following features: template-free, column-free purifications, and high yielding in two steps. First, the macrocyclization is promoted by intramolecular hydrogen bonding without any template guest, like anions. Second, all three tetraurea macrocycles were precipitated from the reaction mixture and further purified through complexation with sulfate anions ( Supporting Information Section S5). Finally, they are all made using commercially available building blocks with the overall yields ranging from 80% to 91%. Compared to typical conditions for macrocyclization (high dilution, <;5 mM), the macrocyclizations studied here were performed in much higher concentration (20 mM). This unusual phenomenon can be explained by the intramolecular hydrogen bonds helping to facilitate macrocyclization and reduce the propensity of polymerization, which allows these reactions to be performed at high concentrations. To further investigate the modularity of this two-step strategy, we attempted to use a flexible HDI to prepare tetraurea macrocycle. However, the tetraurea macrocycle encoded with hexylene chain cannot be directly prepared from o-phenylenediamine and HDI. Unlike the isolation of S1 and S2, reaction of these two building blocks leads to polymerization instead of dimerization.b This suggests that proper rigidity (such as diphenyl methylene and diphenyl ether) of the spacers may be the key to the formation of intermediates S1 and S2. In contrast, adding HDI into S1 and S2 did not afford tetraurea macrocycle either, but led to larger octaurea macrocycles (vide infra). Nevertheless, the D2h symmetric tetraurea HU can be prepared from 2-nitrophenyl isocyanate in three steps (see the Supporting Information Scheme S2). Syntheses and X-ray diffraction structures of octaurea macrocycles Remarkably, two large, octaurea macrocycles, MUH and EUH, were isolated when HDI was reacted with intermediate S1 or S2, respectively (Figure 4a and Supporting Information Scheme S3). Each of these two octaurea macrocycles consists of three types of monomer units: four bis(urea) motifs, two hexylene spacers, and either two diphenyl methylene or two diphenyl ether spacers. Although we observed the formation of both tetraurea and octaurea based on mass spectrometry of the crude product, recrystallization by adding TEA2SO4 only afforded the octaurea macrocycle as the major product. By slow vapor diffusion of diethyl ether into acetone and DMF solution, crystals of both octaurea macrocycles in sulfate complexed form were produced. The single-crystal X-ray diffraction structures showed unambiguous formation of macrocycles (Figures 4b and 4c and Supporting Information Table S1 and Figures S7 and S8) consisting of the largest number of urea units (8) in a single-macrocyclic structure. Unlike the tetraurea macrocycles, two sulfate anions are encapsulated in the cavities of both octaurea macrocycles. Specifically, these two sulfates are separated with no contact between the other. Each sulfate anion coordinates to four urea units, which is very similar to the geometry of the HU.SO4 complex in the solid state ( Supporting Information Figure S6) and consistent with characteristic bis(urea)-sulfate coordination seen in our previous studies.55 Figure 4 | (a) The [2+2] macrocyclization of the octaureas MUH and EUH from HDI and intermediates S1 and S2, respectively. X-ray crystallographic structures of octaurea macrocycles with two sulfate anions encapsulated in the cavity: (b) twisted "figure-eight" octaurea of MUH and (c) untwisted octaurea of EUH. Tetraethylammonium countercations are omitted for the sake of clarity. Download figure Download PowerPoint In the solid state, the MUH octaurea coordinates to sulfate anions in a helicate "figure-eight" geometry, while the EUH-sulfate complex shows mesocate-like geometry ( Supporting Information Videos S1 and S2). This geometric difference is attributed to one single site difference, CH2 instead of O, where the two extra H atoms may introduce more strain to twist the two phenyl rings. Specifically, the angle between two phenyl spacers is approximately 112° in the former, while 117° and 119° are observed for the diphenyl ether spacer. Very similar centroid-to-centroid distance of the two phenyl rings is illustrated as 4.8 Å in the two complexes. However, an expanded structure is seen for the MUH macrocycle where distance between the two methylenes (CH2) is 8.8 Å. We are surprised that such significant geometric changes are induced by a single atom, which may offer insight into catalyst design and chirality transformation during hierarchical assemblies. A similar "figure-eight" structure has been seen in the study of hexaurea macrocycle complexed with two chloride anions.40 Overall, both octaurea macrocycles display unusual confinement of two sulfate anions inside one macrocycle simultaneously.56,57 For the reaction of HDI and S2, we observed significant conversion from S2 to the EUH macrocycle by monitoring the reaction based on 1H NMR (Figure 5a and Supporting Information Figure S11). First, we saw continuous decrease of amine peak (NH2) at 4.3–4.5 ppm and the urea NH peaks at 8.7–8.8 ppm within 120 min, which are assigned to S2 and the other intermediates that are essential for the ring-closing reaction (Figure 5b and Supporting Information Scheme S5). Second, we saw the formation of a clear set of peaks that are assigned to the octaurea EUH. Compared to the relatively slow formation of other macrocycles in highly diluted solution, this fast (2 h) macrocyclization, believed to benefit from strong intramolecular hydrogen bonding within the bis(urea) unit, is rare. The complexed structures of these octaurea macrocycles with sulfate anions were further confirmed by 1H NMR (Figures 5c and 5d). MUH and EUH macrocycles have very similar spectra because they encapsulate sulfate anions in a 1:2 stoichiometry. All peaks (Ha, Hb, Hc, and Hd) that are assigned to urea units shift downfield significantly compared to free macrocycles, indicating strong hydrogen bonding between urea units and sulfates. Figure 5 | of the [2+2] macrocyclization using 1H (a) 1H NMR spectra of the reaction mixture from to 120 min, and (b) the changes The of EUH and S2 were based on peak at and 8.7–8.8 which are assigned to the NH of macrocycle, S2, and 1H NMR spectra 298 of (c) and (d) complexes. residual Download figure Download PowerPoint By using a two-step, modular synthetic strategy, we are able to make a of tetraurea and octaurea macrocycles from building blocks. These macrocycles consist of specific monomer bis(urea) unit ( ( diphenyl ether ( and hexylene ( H) spacers. This modular synthesis is by isolation of a diamine intermediate and further promoted by intramolecular hydrogen bonding in the bis(urea) The macrocyclization is spacer-dependent where rigid diphenyl methylene and diphenyl ether spacers produce the tetraurea macrocycles, and a flexible hexylene spacer leads to the octaurea macrocycles. These macrocycles display different sulfate coordination properties in the solid The tetraurea macrocycles coordinate to sulfate in a 1:2 stoichiometry driving the formation of columnar assemblies. In contrast, the octaurea macrocycles form unique 1:2 by two sulfate anions in their Overall, we an efficient to prepare oligourea macrocycles in a modular manner with tunable monomer This paradigm a new of making large macrocyclic and with designer properties for hierarchical and a macrocyclization using and were also conducted ( Supporting Information Scheme Although the corresponding intermediate can be prepared by the reaction temperature and we did not the formation of macrocycles. Instead, or were isolated without further analysis. This suggests that unique o-phenylene bis(urea) is for ring-closure reactions where intramolecular is able to may also but we cannot any product in the Supporting Information Supporting Information is available and details for the preparation of macrocyclic synthetic NMR and mass computational and X-ray diffraction of The no competing This work was by the Natural Science of and the of the Beijing Institute of for of of Li Macrocycles for and the of in and with

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