A Kinetically Stable Macrocycle Self-Assembled in Water - Organic

Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

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A Kinetically Stable Macrocycle Self-Assembled in Water Yang Zhang,†,§ Xujun Zheng,†,‡,§ Ning Cao,† Chuluo Yang,*,‡ and Hao Li*,† †

Department of Chemistry, Zhejiang University, Hangzhou 310027, People’s Republic of China Hubei Collaborative Innovation Center for Advanced Organic Chemical Materials, Department of Chemistry, Hubei Key Lab on Organic and Polymeric Optoelectronic Materials, Wuhan University, Wuhan 430072, People’s Republic of China

‡

S Supporting Information *

ABSTRACT: A macrocycle through a dynamic covalent approach relying on reversible hydrazone formation in acidic aqueous solutions at elevated temperatures is constructed. By decreasing the acidity of the solution and lowering the temperature, the structure becomes kinetically inert. The macrocycle is capable of hosting hydrophobic aromatic guest molecules in water.

n the field of supramolecular chemistry, macrocylic molecular hosts1 in the form of rings2 and cages3 have attracted great attention on account of their ability to provide preorganized cavities or pockets to host a variety of guest molecules. The host−guest binding behaviors enable various tasks to be performed, such as stabilizing labile reaction intermediates,4 catalysis as artificial enzymes,5 and guest separation and detection.6 Traditional syntheses of macrocycles, such as crown ethers2 and the cyclobis(paraquat-pphenylene)7 ring rely on irreversible chemical bond formation. These methods suffer from their low efficiency. That is, ring cyclization is often accompanied by the generation of oligomeric or polymeric byproducts. The advent of dynamic approaches relying on reversible bonds, including coordinative8 or noncovalent bonding interactions such as hydrogen bonds,9 as well as dynamic covalent chemistry (DCC) including imine condensation,10 boronic ester formation,11 and olefin12 or alkyne13 metathesis, efficiently help to avoid the byproduct formation, by allowing the system to undergo error checking and self-correcting. Among these dynamic approaches, imine10 condensation represents one of the most often used dynamic approaches in self-assembly, probably because its starting materials, namely, aldehydes and amines, are both relatively synthetically accessible. However, the labile nature of imine introduces a putative drawback, i.e., the high yields of these selfassembled molecules often come at the expense of their intrinsic stability. In addition, in order to build a connection between the synthesized supramolecular systems with their biological counterparts, it is of importance to realize their functions in water, the medium of life. Unfortunately, imine is considered apt to undergo hydrolysis in water. Using imine reduction14 could solve this problem. However, this approach involves a tedious process of postsynthesis. In addition,

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purification of the reduced products containing amine functions is technically demanding. It is therefore of great interest to develop water-compatible DCC reaction motifs, by taking advantage of a variety of reversible organic reactions that could occur in water, such as the formation of disulfide,15 oxime,16 and hydrazone.17 It has been known that hydrazone is able to progress to almost completion in a reversible manner in water. In addition, the dynamic nature of both hydrazone and disulfide linkages was reported to be switched ON/OFF.18 In terms of the former bond, in the condition of high acidity and elevated temperatures, hydrazone is dynamic, allowing self-correcting. In the condition of low acidity (i.e., higher pH) and/or lower temperatures, the hydrazone linkage is remarkably kinetically inert. By taking advantage of this switchable nature of hydrazone, we obtained a macrocycle by condensing a bisaldehyde and a bishydrazine compound in a [2 + 2] manner in a high yield (i.e., 59%), in acidic aqueous solution. The highyielding self-assembly allows us to separate this macrocycle as a pure compound without the need of chromatographic purification, simply by counteranion exchange. Once isolated, this self-assembled macrocycle is a kinetic robust product, i.e., it did not undergo hydrazone exchange for at least 23 days at room temperature in neutral or weakly acidic aqueous media. This ring could be used to host a few hydrophobic guests in water. Hydrazine derivative 1, as well as a water-soluble aldehyde 22+·2Br− were synthesized from commercially available compounds in one-step procedures (see the Supporting Information (SI)). We combined 22+·2Br− (3.8 mg, 8.0 Received: March 1, 2018

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DOI: 10.1021/acs.orglett.8b00693 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

mixed 34+·4Cl− with 4+·I−, a monoaldehyde analogue of 22+· 2Br−, in D2O. We observed that no appreciable hydrazone exchange occurred between 34+ and 4+ in water for no less than 23 days at room temperature in the condition of no acid (Figure 2C) or a catalytic amount (0.4 μmol) of TFA (Figure

μmol) and 1 (0.72 mg, 8.0 μmol) in D2O solution in the presence of an excess amount of TFA (80 μmol) at 80 °C. After 12 h, its 1H NMR spectrum was recorded (Figure 1A). We

Figure 1. Partial 1H NMR spectra (500 MHz, 1 mL D2O, 298 K) of (A) 1:1 mixture of 22+ and 1 in the presence of TFA after heating the mixture at 80 °C for 12 h, (B) 34+·4Cl−, which was obtained from the sample in panel (A) by means of counteranion exchange, and (C) the bisaldehyde precursor 22+ in its acetal form.

Figure 2. Partial 1H NMR spectra (400 MHz, 1 mL D2O, 298 K) of (A) 34+, (B) 4+, and their mixture when they are mixed in (C) neutral water under room temperature for 23 days, (D) acidic water (add 0.4 umol TFA) under room temperature for 23 days, (E) neutral water solution after being heated at 80 °C for 12 h, and (F) acidic water solution (add 0.4 μmol of TFA) after being heated at 80 °C for 12 h. In D2O, 4+ undergoes hydration and exists as its acetal form.

observed a set of relatively sharp resonances, indicating that a thermodynamically favored product was produced as the major product. By using mass spectrometry, we found that the [2 + 2] condensation product, namely, 34+ (the counteranion could be either Br− or CF3COO−) is the major product. Its yield was calculated to be 59%, by integrating the corresponding peaks in the 1H NMR spectrum. The 59% yield, although not quantitative, is relatively high, considering that four covalent bonds formed simultaneously in one condensation step without the assistance of guest template. The [2 + 2] condensation product 34+·4Cl− could be isolated as a pure compound, by performing counteranion exchange. This was done by the adding NH4+·PF6− into the self-assembled mixture solution, yielding white precipitates containing 34+·4PF6− as the major products. These solids were then dissolved in MeCN, followed by the addition of tetrabutylammonium chloride (TBA+·Cl−), which yielded 34+·4Cl− with relatively high purity as white precipitates. The oligomeric or polymeric byproducts were removed during this two-step counteranion exchange procedure. The molecular structure of 34+·4Cl− was confirmed by 1H (Figure 1B) and 13C NMR spectroscopy (Figure S4), mass spectrometry (Figure S7), and a variety of two-dimensional NMR spectroscopies (Figures S3−S6). In the literature, it has been well-established that using a dynamic bond could efficiently avoid byproduct production and therefore increase the yields of the self-assembled products by allowing self-correcting. However, the reversible forming/ cleaving behaviors of dynamic bonds also jeopardize the stabilities of these products, which represents a long-standing problem in dynamic self-assembly. Hydrazone linkage, however, has a switchable kinetic nature.18 That is, at elevated temperatures and/or higher acidic conditions, it is a reversible bond; while at low temperatures and in the condition of higher pH, it is remarkably kinetically stable. Thus, we investigated the kinetic stability of 34+·4Cl− in water in different conditions. We

2D). However, hydrazone exchange between 34+ and 4+ was observed after heating the mixture solution at 80 °C for 12 h (Figure 2E,F). Hydrazone exchange also occurred at room temperature upon addition of an excess amount (80 μmol) of TFA. In solid state, 34+·4Cl− is remarkably kinetically inert. After the solid state sample of 34+·4Cl− was kept at room temperature for no less than 1 week, we dissolved it in D2O and recorded its 1H NMR spectrum, which indicated that 34+·4Cl− did not undergo an appreciable change during this substantial amount of time. The [2 + 2] cycloaddition product 34+ could function as host to encapsulate a water-soluble guest 5 bearing a hydrophobic naphthalene unit in its pocket. The guest molecule 5 was added into the solution of 34+ in D2O. The 1H NMR spectroscopy (Figure 3D) provided reliable evidence to identify the formation of complex 5⊂34+. Upfield shifts of the resonances of protons x, y, and z in 5 are observed, indicating that the naphthalene unit in 5 experiences a shielded magnetic environment in the aromatic pockets of 34+. The formation of 5⊂34+ was also supported by the corresponding 1H DOSY spectra (Figure S12). The 1:1 binding manner was established by their corresponding job plots (Figures S8 and S9) from 1H NMR spectral analysis. The binding constant (Ka) of the complex 5⊂34+ was measured (Figures S10 and S11) to be around 3900 ± 100 M−1 in D2O at 298 K. We also obtained 34+·4PF6−, an oil-soluble counterpart of 34+·4Cl−, by means of counteranion exchange. In MeCN, 34+·4PF6− does not bind with 5, indicating the major driving force for the formation of 5⊂34+ in water is hydrophobic interactions. In addition, the cationic nature of 34+ affords its ability to accommodate some anionic guests such as 62− in water (see Figures 3B and S13− S18). 1H NMR titration experiment indicates that the binding B

DOI: 10.1021/acs.orglett.8b00693 Org. Lett. XXXX, XXX, XXX−XXX

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is that the macrocycle has to reorganize its conformation to accommodate the guest 62−, which also explains well why the binding constant of the complex 62−⊂34+ is relatively low. An intramolecular hydrogen bond within the urea residues still occurs, which results in a displaced parallel orientation of the other two pyridinium units. The cavity of 34+ is therefore incapable of hosting another 62− guest. Instead, a second 62− guest locates in the peripheral region of the macrocycle, acting as a counteranion. In summary, we demonstrated that a macrocyclic host could be self-assembled in high yields in pure water, by performing reversible hydrazone condensation in acidic aqueous media at elevated temperatures. This macrocycle could be isolated simply by counteranion exchange, without the need for chromatography. In the condition of neutral aqueous media and room temperature, the ring acts as a kinetically inert compound, i.e., it did not undergo hydrazone exchange for no less than 3 weeks. This dynamic approach based on hydrazone condensation thus solves a long-standing problem in selfassembly, i.e., high yields resulting from dynamic bond exchange and kinetic stability cannot be realized simultaneously. The host molecule is capable of hosting hydrophobic or anionic guests within their cavities in water. Further research using these hydrazone-based host molecules as reaction vessels to perform useful tasks such as catalyzing reactions are underway in our laboratory.

Figure 3. Partial 1H NMR spectra (400 MHz, 1 mL D2O, 298 K) of (A) 62−, (B) 1:1 mixture of 34+ and 62−, (C) 34+, (D) 1:1 mixture of 34+ and 5, and (E) 5.

constant (Ka) of the complex 62−⊂34+ was measured to be around 260 ± 30 M−1 in D2O at 298 K. The major driving force for the complex may be ascribed to the Coulombic attraction between these two opposite charges, as well as the hydrophobic interaction between the benzene unit of 62− and the aromatic pockets of 34+. Compared to 5 containing a naphthalene unit, 62− has a smaller phenyl hydrophobic moiety, which accounts for its lower binding constant within the cavity of 34+. A single crystal of 34+·4Cl− was obtained by slow evaporation of the solution of 34+·4Cl− in water, providing unambiguous evidence for the formation of 3 4+ (Figure 4a). The

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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/acs.orglett.8b00693. Details of experimental procedure and characterization data (PDF) Accession Codes

CCDC 1827640−1827641 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

Figure 4. Side view of the core structure of (a) 34+ and (b) 62−⊂34+ obtained from single-crystal X-ray diffraction analysis. Hydrogen atoms, white; carbon, gray; oxygen, red; nitrogen, blue. Counteranions, disordered solvent molecules, and unrelated hydrogen atoms are omitted for the sake of clarity.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected].

conformation of the macrocyclic structure of 34+ in solid state is close to flat. The two phenyl rings in the 22+ residues orientate nearly perpendicularly with respect to the major plane of the macrocycle. In the urea units of 1 residues, the distance between one of the imine nitrogen atoms and one of the amide protons is measured to be 2.3 Å, indicating the occurrence of intramolecular hydrogen bonds. These noncovalent interactions render the macrocycle conformation relatively rigid. The attempts to obtain the single crystal of 5⊂3 4+ were unsuccessful. Fortunately, single crystals of 62−⊂34+ were obtained by slow evaporation of the solution of 62−⊂34+ in D2O and were suitable for X-ray diffraction analysis (Figure 4b). One molecule 62− inserts into the cavity of 34+. Consequently, the conformation of 34+ undergoes remarkable distortion. That is, two pyridinium functional groups in 34+ orientate in a face-to-face manner, in order to create a hydrophobic pocket to encapsulate the guest. The implication

ORCID

Chuluo Yang: 0000-0001-9337-3460 Hao Li: 0000-0002-6959-3233 Author Contributions §

These authors contributed equally. The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Financial support from Zhejiang University, the Chinese “Thousand Youth Talents Plan,” The National Natural Science C

DOI: 10.1021/acs.orglett.8b00693 Org. Lett. XXXX, XXX, XXX−XXX

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(17) (a) Rodriguez-Docampo, Z.; Otto, S. Chem. Commun. 2008, 5301−5303. (b) Li, H.; Zhang, H.; Lammer, A. D.; Wang, M.; Li, X.; Lynch, V. M.; Sessler, J. L. Nat. Chem. 2015, 7, 1003−1008. (18) (a) von Delius, M.; Geertsema, E. M.; Leigh, D. A. Nat. Chem. 2010, 2, 96−101. (b) Kassem, S.; Lee, A. T. L.; Leigh, D. A.; Markevicius, A.; Solà, J. Nat. Chem. 2016, 8, 138−143.

Foundation of China (No. 21772173), and The Natural Science Foundation of Zhejiang Province of China (No. LR18B020001) are gratefully acknowledged.

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DOI: 10.1021/acs.orglett.8b00693 Org. Lett. XXXX, XXX, XXX−XXX