{'fraction_non_alphanumeric': 0.04256010396361273, 'fraction_numerical': 0.03256985055230669, 'mean_word_length': 5.2281234193222055, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 1, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Hydroxy-Substituted Azacalix[4]Pyridines: Synthesis, Structure, and Construction of Functional Architectures

A number of hydroxyl-substituted azacalix[4]pyridines were synthesized using Pd-catalyzed macrocyclic “2+2” and “3+1” coupling methods and the protection–deprotection strategy of hydroxyl group. While the conformation of the these hydroxyl-substituted azacalix[4]pyridines is fluxional in solution, in the solid state, they adopted shape-persistent 1,3-alternate conformations. Besides, X-ray analysis revealed that the existence of hydroxy groups on the para-position of pyridine facilitated the formation of solvent-bridged intermolecular hydrogen bonding for mono-hydroxyl-substituted while partial tautomerization for four-hydroxyl-substituted macrocycles, respectively. Taking the hydroxyl-substituted azacalix[4]pyridines as molecular platforms, multi-macrocycle-containing architectures and functional building blocks were constructed. The self-assembly behavior of the resulting building blocks was investigated in crystalline state.


INTRODUCTION
Design of ingenious macrocyclic molecules has been one of the driving forces to promote the major advances of supramolecular chemistry, which has been manifested by examples of crownether, cyclodextrin, calixarene, resorcinarene, cucurbituril, calixpyrrole, pillarenes, etc. (Lehn et al., 1996). Indeed, macrocyclic compounds provide unique models in the study of non-covalent interactions, and they have been serving as building blocks in the construction of high-level supramolecular architectures. Typical examples such as by anchoring derivative groups on the macrocycles, versatile building blocks, have been prepared and widely applied to the fabrication of molecular devices and smart materials (Chen and Liu, 2010;Guo and Liu, 2014;Ma and Tian, 2014;Strutt et al., 2014;Caricato et al., 2015;Le Poul et al., 2015;Parisi et al., 2016;Murray et al., 2017;Pazos et al., 2018;Wang, 2018;Ogoshi et al., 2019).
Heteracalixaromatics, or heteroatom-bridged calix(het)arenes, are a new type of macrocyclic host molecules (König and Fonseca, 2000;Lhoták, 2004;Morohashi et al., 2006;Maes and Dehaen, 2008;Wang, 2008Wang, , 2012Thomas et al., 2012;Ma and Chen, 2014;Chen and Han, 2018). In comparison with the classical calix[n]arenes in which the phenol moieties are linked by methylene units, heteracalixaromatics enjoy much richer molecular diversity and complexity as the different combinations of various heteroatoms and heteroaromatic rings afford almost limitless macrocyclic compounds. Because of the electronic nature of heteroatoms are different from that of carbon and they are able to conjugate differently with their adjacent aromatics, the incorporation of heteroatoms into the bridging positions and aromatic rings endows heteracalixaromatics unique conformational structures and versatile recognition properties. In particular, heteracalixaromatics show unique association property toward ionic species including cations (Gong et al., 2006a;Ma et al., 2009;Zhang et al., 2009;Fang et al., 2012;Wu et al., 2012Wu et al., , 2013, metal clusters (Gao et al., 2011, Gao et al., 2012Zhang and Zhao, 2018), anions (Wang et al., , 2010Wang and Wang, 2013;Luo et al., 2018), and neutral molecules (Wang et al., 2004;Gong et al., 2007;Hu and Chen, 2010). Despite the powerful ability as host molecules, surprisingly, the application of heteracalixaromatics as functional building blocks is obviously underexplored. Herein, we report the facile synthesis and structure of a number of hydroxy-substituted azacalix[4]pyridines. These functionalized macrocycles as molecular platform to construct high-level architectures and functional building blocks were also demonstrated.
For the synthesis of hydroxyl-substituted azacalix[4]pyridines 10-14, the Pb/C-catalyzed hydrogenation reactions were performed on the different protected macrocycles. As shown in Scheme 2, all the reactions proceeded with high efficiency to afford the desired products in the yields ranging from 95 to 99%.

Structure
The characterization of 10-14 was established on spectroscopic data and elemental analysis. In solution, all the macrocyclic compounds gave one set of 1 H and 13 C NMR signals, indicating that they are very fluxional at room temperature and the various conformational structures most probably interconvert rapidly relative to the NMR time scale (Figures S2, S3). Under decreased temperatures (from 298 to 178 K), the conformational interconversion became slow and coexistence of different conformations was clearly observed at 178 K ( Figure S4). To probe the structure in solid state, single crystals were cultivated and analyzed by X-ray diffraction method. Pleasantly  Table S2 respectively. In the case of 10, the molecule shows a similar 1,3-alternate conformation with other azacalix[4]pyridines ( Figures 1A,B). While the existence of hydroxyl group on the para-position of one pyridine does not affect the conformation of the macrocyclic backbone; it leads to interesting hydrogen-bonded packing. For example, each hydroxyl group as hydrogen bond donor interacts with the oxygen of DMSO; an infinite DMSO-separated layer structure is then produced ( Figure 1C).
Surprisingly, the structure crystallized from 14 might not be this compound itself. Representative parameters such as two of the C-O distances (d C8−O2 = 1.291 Å) is shorter than the other pair (d C3−O1 = 1.349 Å). The former distance is typical of C = O double bond, while the latter is C-O single bond as expected (Figure 2). Besides, a dimer structure linked by an O2-O1-O3-O2 hydrogen bonding network could be observed. Here, O2 serves as a hydrogen bond acceptor while the hydroxyl group (O1) or a water molecule (O3) serves as a hydrogen bond donor ( Figure 2B). The function of O2 in the hydrogen bonding network is consistent with the nature of carbonyl oxygen. These structural features therefore indicate that the obtained structure is a partially tautomerized compound 14 ′ , i.e., two of the 4hydroxyl pyridine of 14 turn to pyridine-4-one moieties. As in solution, 14 gives one set of NMR signals, and the partial tautomerization product is most probably facilitated in solid state (Scheme 3). SCHEME 1 | Synthesis of mono-PMB-protected macrocycle 3.
a Isolated yields.

Application of the Hydroxyl-Substituted Azacalix[4]pyridines
We took the mono-and tetrahydroxy-substituted azacalix[4]pyridines as representative molecular platforms and tested the possibility to construct high-level architectures and functional building blocks. As illustrated in Scheme 4, treatment of 10 with 1,3-bis(bromomethyl)benzene 15 in the presence of NaH in DMF proceeded smoothly to afford a di-cavity compound 16 in 80% yield. When a linker compound 1,3,5-tris(bromomethyl)benzene 17 was applied under the same reaction condition, the tri-cavity compound 18 was obtained in 46% yield (Scheme 4).
On the other hand, we applied 14 as the starting materials to react with pyridine-2-acylchloride hydrochloride 19 and pyridine-4-acylchloride hydrochloride 20, respectively. The reactions in the presence of trimethylammonium in CH 2 Cl 2 resulted in two pyridine-contained functional building blocks 21 and 22 in 64 and 52% yields, respectively (Scheme 5).
The introduction of the pyridine substituents on azacalix[4]pyridine provides diverse binding sites to facilitate intermolecular self-assembly. To demonstrate the application of the functional building blocks, the self-assembly of 21 and 22 in crystalline state was investigated (Table S3). It is worth addressing that the different pyridine substituents caused significant changes in the conformations. In the case of 21, the azacalix[4]pyridine backbone maintains the typical 1,3-alternate conformation, i.e., two of the pyridines tend to be edge-to-edge flattened while the other two pyridines tend to be face-to-face paralleled ( Figure 3A). For 22, the molecule exhibits a non-typical orthorhombic 1,3-alternate conformation ( Figure 4A). Moreover, due to the different shapes of the building block and different position of nitrogen SCHEME 2 | Synthesis of hydroxyl-substituted azacalix[4]pyridines 10-14. forms hydrogen bond with the aryl hydrogen of pyridine on the backbone, which produces network with rhombic porosity (Figure 4B).

CONCLUSION
In summary, we have synthesized hydroxyl-substituted azacalix[4]pyridines using an efficient protection-deprotection strategy and Pd-catalyzed macrocyclic "2+2" and "3+1" coupling methods. The unique structure and tautomerization of the macrocycle in solid state were revealed by X-ray analysis. This work demonstrated that the synthesized macrocycles could be useful molecular platforms for highly efficient construction of multi-macrocycle-containing architectures and functional building blocks. The high-level architectures and the functional building blocks could find the potential application in Frontiers in Chemistry | www.frontiersin.org SCHEME 4 | Synthesis of di-and tri-cavity architectures 17 and 18.
fabricating supramolecular or metal-organic porous framework in the future.

EXPERIMENTAL General Information
Chemical shifts are reported in parts per million vs. tetramethylsilane with either tetramethylsilane or the residual solvent resonance used as an internal standard. Melting points are uncorrected. Elemental analyses, mass spectrometry, and Xray crystallography were performed at the Analytical Laboratory of the Institute. All solvents were dried according to standard procedures prior to use. All other major chemicals were obtained from commercial sources and used without further purification.
General Procedure for the Synthesis of (4-methoxybenzyl)Oxy-substituted Macrocycles 3, 6-9 Under argon protection, a mixture of di-methylaminopyridine fragment (2 mmol) and di-bromopyridine fragment (2.2 mmol), Pd 2 (dba) 3 (184 mg, 0.2 mmol), dppp (164 mg, 0.2 mmol), and sodium tert-butoxide (576 mg, 3 mmol) in anhydrous toluene (400 ml) was heated at reflux for 5 h. The reaction mixture was cooled down to room temperature and filtered through a Celite pad. The filtrate was concentrated under vacuum to remove toluene and the residue was dissolved in dichloromethane (50 ml) and washed with brine (3 × 15 ml). The aqueous phase was re-extracted with dichloromethane (3 × 20 ml), and the combined organic phase was dried over anhydrous Na 2 SO 4 . After removal of solvent, the residue was SCHEME 5 | Construction of functional building blocks 21 and 22.   Under nitrogen protection, Pd/C (150 mg, 10 wt%) was added rapidly in a 100-ml round bottom flask with a mixture of PMBprotected macrocycles (2 mmol), THF (20 ml), and methanol (20 ml). The flask was switched three times with hydrogen balloon. The reaction was stopped after reacting at room temperature for 24 h. The reaction mixture was worked up in two ways. Method A: After filtration of the catalyst and removal of the solvent, the residue was chromatographed on a silica gel column (100-200) with a mixture of dichloromethane and methanol as the mobile phase to give the product. Method B: Before filtration of catalyst, the concentrated aqueous ammonia solution was added to the reaction mixture to dissolve the precipitated product. After filtration of the catalyst and removal of the solvent, acetone was added to slurry the residue. The solid was filtered out and washed with a small amount of acetone and dried to give the product.

Preparation of Functional Building Block 21
To a solution of 14 (98 mg, 0.2 mmol) in dry dicholormethane (20 ml) at room temperature was added pyridine-2-acylchloride hydrochloride 19 (156 mg, 0.88 mmol) and triethylamine (0.55 ml). After reacting for 24 h, the reaction mixture was washed by saturated Na 2 CO 3 solution (10 ml) and saturated brine (3 × 20 ml) and then dried over anhydrous Na 2 SO 4 . After removal of solvent, the residue was crystallized by dichloromethane and ethyl acetate to give pure 21 as a light yellow solid (

DATA AVAILABILITY
The raw data supporting the conclusions of this manuscript will be made available by the authors, without undue reservation, to any qualified researcher.

AUTHOR CONTRIBUTIONS
E-XZ performed the experiments and participated in manuscript preparation. D-XW and M-XW prepared the manuscript.