Fei Wang

Christophe Bucher

Qing He
email: heqing85@hnu.edu.cn

Atanu Jana
email: atanu.j78@gmail.com

Jonathan L Sessler
email: sessler@411cm.utexas.edu

; Zhang

Oligopyrrolic Cages: From Classic Molecular Constructs to Chemically Responsive Polytopic Receptors

CONSPECTUS: "Functional molecular systems", discrete and self-assembled constructs where control over molecular recognition, structure, bonding, transport, release, catalytic activity, etc., is readily achieved, are a topic of current interest. Within this broad paradigm, oligopyrrolic cages have garnered attention due to their responsive recognition features. Due to the presence of slightly polar pyrrole subunits which can also behave as hydrogen-bonding donors, these oligopyrrolic cages are potential receptors for various polarized species. In this Account, we summarize recent advances involving the syntheses and study of (1) covalent oligopyrrolic macrobicyclic cages, (2) oligopyrrolic metallacages, and (3) oligopyrrolic noncovalently linked cages. Considered in concert, these molecular constructs have allowed advances in applied supramolecular chemistry; to date, they have been exploited for selective guest encapsulation studies, anion binding and ion-channel formation, and gas absorption, among other applications. While key findings from others will be noted, in this Account will focus on our own contributions to the chemistry of discrete oligopyrrolic macrocycles and their use in supramolecular host-guest chemistry and sensing applications. In terms of specifics, we will detail how oligopyrrole cages with well-defined molecular geometries permit reversible guest binding under ambient conditions and how the incorporation of pyrrole subunits within larger superstructures allows effective control over anion/conjugate acid binding activity under ambient conditions. We will also provide examples that show how derivatization of these rudimentary macrocyclic cores with various sterically congested β-substituted oligopyrroles can provide entry into more complex supramolecular architectures. In addition, we will detail how hybrid systems that include heterocycles other than pyrrole, such as pyridine and naphthyridine, can be used to create self-assembled materials that show promise as gas-absorbing materials and colorimetric reversible sensors. Studies involving oligopyrrolic polymetallic cages and oligopyrrolic supramolecular cages will also be reviewed. First, we will discuss all-carbon-linked oligopyrrolic bicycles and continue on to present systems linked via amines and imines linkages. Finally, we will summarize recent work on pyrrolic cages created through the use of metal centers or various noncovalent interactions. We hope that this Account will provide researchers with an initial foundation for understanding oligopyrrolic cage chemistry, thereby allowing for further advances in the area. It is expected that the fundamental design and recognition principles made in the area of oligopyrrole cages, as exemplified by our contributions, will be of general use to researchers targeting the design of functional molecular systems. As such, we have structured this Account so as to summarize the past while setting the stage for the future.

Chem. Commun. 2019, 55, 6185-6188. 3 This paper showcases the use of dynamic covalent chemistry (DCC) to produce symmetric three-dimensional (3D) oligopyrrolic cryptands for potential applications in the area of gas adsorption. This latter application had not previously been explored with pyrrolic cage systems.

• Wang, F.; Sen, S.; Chen, C.; Baḧring, S.; Lei, C.; Duan, Z.; Zhang, Z.; Sessler, J. L.; Jana, A. Self-Assembled Cage-Like Receptor that Binds Biologically Relevant Dicarboxylic Acids via Proton-Coupled Anion Recognition. J. Am. Chem. Soc. 2020Soc. , 142, 1987Soc. -1994. 4 . 4 This report is significant because it demonstrated the reversible "capture" and "release" of dicarboxylic acid guests using a fully organic self-assembled cage-like pyrrolic receptor.

Both the supramolecular recognition and the corresponding assembly and disassembly processes were reflected in visible color changes.

■ INTRODUCTION

This Account is concerned with the chemistry of pyrrolic cage systems. Cages of this general class have been the focus of increasing attention since the late 1990s. However, in many respects the antecedents for work in this area can be traced to the revolutionary report of laterally symmetric macrobicyclic "cryptands" 5 and "cryptates" 6 by Lehn et al. in 1969 as well as the 1968 report of Simmons and Park of anion binding within a bicyclic diammonium construct. 7 A spotlight was shown on the cryptands with the awarding of a share of the 1987 Nobel Prize in Chemistry to Lehn, who codified "supramolecular chemistry" as the chemistry beyond the molecule. 8 To date, more than 2000 papers have detailed the synthesis, derivatization, and application of cryptands and their supramolecular complexes to problems running the gamut from fundamental to applied. This activity reflects in large measure the fact that these macrobicyclic hosts can act as artificial synthetic organic (or metal-organic hybrid) receptors for a wide variety of ionic inferred from X-ray crystallographic analyses, one CH 2 Cl 2 solvent and three water molecules are located within the three external clefts of 1 via cooperative hydrogen-bonding, halogenbonding, and CH•••π interactions (Figure 1d). In an effort to test the ability of cage 1 to act as an anion receptor, its interactions with a range of anions, e.g., F -, Cl -, Br -, NO 3 -, H 2 PO 4 -, and SCN -, were screened. A significant downfield chemical shift was seen in the pyrrolic NH protons when cage 1 in CD 2 Cl 2 was subject to 1 H NMR spectroscopic titrations with various tetra-nbutylammonium (TBA) anion salts. In the representative case of NO 3 -, a fast equilibrium process and an overall Δδ = 1.1 ppm Accounts of Chemical Research 144 differences were ascribed to the combined effect of size 145 complementary, steric, and electronic interactions.

146 Chemical oxidation of cage 1 by 5,6-dichloro-2,3-dicyano-p-147 benzoquinone (DDQ) was found to produce an unprecedented f2 148 sp 2 -hybridized carbon bridgehead calixphyrin (4) (Figure 2). 12 149 Compound 4, as a prototypical three-dimensional (3D) 150 calixphyrin, belongs to a class of hybrid molecular systems that 151 bear structural and chemical analogy to both calixpyrroles and 152 porphyrins owing to the presence of both sp 2 -and sp 3 -153 hybridized meso-like bridging carbon atoms. Distinctive broad 154 absorption maxima (λ max ) at 421 and 474 nm were taken as 155 evidence for the generation of partially oxidized species in 156 solution where the characteristic "porphyrin-like" features (e.g., 157 an absorption spectrum containing both a sharp Soret band and 158 weaker "Q" bands) are absent. In contrast to what was observed 159 in the X-ray structure of 1 where the two bridging apical -CH 160 hydrogen atoms were seen to point inward (endo-endo 161 orientation), the sp 2 -hybridized bridging carbon atom produces 162 a degree of local planarity. The net result is that cage 4 possesses 163 a more open cavity (cf. Figure 2, inset) that was expected to 164 facilitate the "inside binding" of guests.

165 While this Account is mainly focused on our own 166 contributions, we would like to make clear that subsequent to 167 our initial report of bicycle 1, many elegant oligopyrrolic cages 168 were reported by other research groups. For instance, in 2008, Dynamic covalent chemistry (DCC) has emerged as an attractive and efficient means for preparing intricate molecular constructs, including macrocycles, [START_REF] Kovarícěk | Merging Constitutional and Motional Covalent Dynamics in Reversible Imine Formation and Exchange Processes[END_REF] cages, [START_REF] Jin | Dynamic Covalent Chemistry Approaches Towards Macrocycles, Molecular Cages, and Polymers[END_REF][START_REF] Zhang | Stimuli-Responsive Host-Guest Systems Based on the Recognition of Cryptands by Organic Guests[END_REF][START_REF] Granzhan | Connection of Metallamacrocycles via Dynamic Covalent Chemistry: A Versatile Method for the Synthesis of Molecular Cages[END_REF][22] and covalent organic frameworks (COFs), [START_REF] Powers-Riggs | Electron Hopping and Charge Separation within a Naphthalene-1,4:5,8-bis-dicarboximide) Chiral Covalent Organic Cage[END_REF][START_REF] Zhu | 3D Cage COFs: A Dynamic Three-Dimensional Covalent Organic Frameworks with High-Connectivity Organic Cage Nodes[END_REF] and has yielded a number of systems with potential applications. [START_REF] Rao | Conjugated Covalent Organic Frameworks via Michael Addition-Elimination[END_REF][START_REF] Shan | Dynamic Transformation between Covalent Organic Frameworks and Discrete Organic Cages[END_REF][START_REF] Cacciapaglia | Metathesis Reaction of Formaldehyde Acetals: An Easy Entry into the Dynamic Covalent Chemistry of Cyclophane Formation[END_REF][START_REF] Ulrich | Growing Prospects of Dynamic Covalent Chemistry in Delivery Applications[END_REF] Not surprisingly, DCC has been exploited to access discrete oligopyrrolic cages. Taking advantage of this approach, we designed and synthesized the Schiff-base macrobicyclic cage 18 [START_REF] Oh | Synthesis and Anion Recognition Features of a Molecular Cage Containing Both Hydrogen Bond Donors and Acceptors[END_REF] starting from a suitably s3 functionalized pyrrolic precursor (15) as shown in Scheme 3. Here, it was postulated that the amidic and pyrrolic protons 206 could act as hydrogen-bond donors to the oxygen atom, whereas 207 one or more imine nitrogen atoms could serve as hydrogen-208 bond acceptors for the OH protons present in H 2 PO 4 -. As 209 inferred from single-crystal X-ray diffraction analysis, the 210 H 2 PO 4 -anion was found to be nestled within the cavity of 211 cage 18 and apparently was stabilized by such interactions f4 212 (Figure 4b).

A similar [1 + 1] Schiff-base condensation reaction between the phenyl-bridgehead trialdehyde (20) and the triamine (16) allowed the macrobicyclic imine cage 21 to be synthesized s4 (Scheme 4a). [START_REF] Han | Small Triiminopyrrolic Molecular Cage with High Affinity and Selectivity for Fluoride[END_REF] reported [START_REF] Francesconi | A Self-Assembled Pyrrolic Cage Receptor Specifically Recognizes β-Glucopyranosides[END_REF][START_REF] Francesconi | Synthetic Tripodal Receptors for Catbohydrates. Pyrrole, a Hydrogen Bonding Partner for Saccharidic Hydroxyls[END_REF][START_REF] Francesconi | XXXX, XXX, XXX-XXX L pyrrolic Cage Receptor for β-Glucopyranosides Reveals the Essentials for Effective Recognition[END_REF] a series of self-assembled polypyrrolic benzene-c2 bridgehead cryptand receptors (22-24) (Chart 2). Among this series of receptors, cage 22 was found to recognize βglucopyranosides with high specificity. This cryptand receptor provides six primary amino groups for complementary hydrogen-bonding interactions with this particular carbohydrate, as inferred from 1 H NMR spectroscopic analyses (CDCl 3 , 298 K).

Consistent with this rationale, replacement of the pyrrole subunits in 22 by pyridines and benzenes to produce the isostructural cages 23 and 24 was found to give rise to a reduced level of guest recognition. [START_REF] Francesconi | Synthetic Tripodal Receptors for Catbohydrates. Pyrrole, a Hydrogen Bonding Partner for Saccharidic Hydroxyls[END_REF][START_REF] Francesconi | XXXX, XXX, XXX-XXX L pyrrolic Cage Receptor for β-Glucopyranosides Reveals the Essentials for Effective Recognition[END_REF] Porous organic cages (POCs) have garnered attention as examples of self-assembled architectures. They often display unique guest binding properties, such as the capture of substrates within infinite channels. This has made them of potential interest in the context of many applications, including gas storage, [START_REF] Jin | Highly CO 2 -Selective Organic Molecular Cages: What Determines the CO 2 Selectivity[END_REF][START_REF] Culshaw | Dodecaamide Cages: Organic 12-Arm Building Blocks for Supramolecular Chemistry[END_REF][START_REF] Jiang | Covalent Chemistry beyond Molecules[END_REF][START_REF] Mastalerz | Porous Shape-Persistent Organic Cage Compounds of Different Size, Geometry, and Function[END_REF] catalyses, [START_REF] Ajami | More Chemistry in Small Space[END_REF][START_REF] Sun | Toward Homogenization of Heterogeneous Metal Nanoparticle Catalysts with Enhanced Catalytic Performance: Soluble Porous Organic Cage as a Stabilizer and Homogenizer[END_REF][START_REF] Liu | Elucidating Heterogeneous Photocatalytic Superiority of Microporous Porphyrin Organic Cage[END_REF] and guest separation [START_REF] Hasell | Porous Organic Cages for Sulfur Hexafluoride Separation[END_REF][START_REF] Shi | Selective Extraction of C 70 by a Tetragonal Prismatic Porphyrin Cage[END_REF][START_REF] Wang | Soft Porous Crystal Based upon Organic Cages That Exhibit Guest-Induced Breathing and Selective Gas Separation[END_REF][START_REF] Su | Efficient Ethylene Purification by a Robust Ethane-Trapping Porous Organic Cage[END_REF][START_REF] Yang | Ethylene/Ethane Separation in a Stable hydrogen-bonded Organic Framework through a Gating Mechanism[END_REF] to name a few. In many instances, dynamic covalent chemistry has been used to access POCs. This is true in the case of pyrrole- 5a). In the case of cryptand 29, the pyridine nitrogen atoms "point" toward the inner core. This results in a compressed molecular geometry (cf. Figure 5b). However, in case of cryptand 30, the naphthyridine nitrogen atoms face out from what is a relatively elongated molecular cage (cf. Figure 5c).

Inspired by Atwood, Cooper, and Mastalerz, who reported independently the gas adsorption features of porous amorphous noria and imine cages, [START_REF] Tian | Amorphous Molecular Organic Solids for Gas Adsorption[END_REF][START_REF] Tozawa | Porous Organic Cages[END_REF][START_REF] Schneider | A Shape-Persistent exo-Functionalized [4 + 6Imine Cage Compound with a very High Specific Surface Area[END_REF][START_REF] Schneider | Post-Modification of the Interior of Porous Shape-Persistent Organic Cage Compounds[END_REF][START_REF] Schneider | Exo-Functionalized Shape-Persistent [2 + 3] Cage Compounds: Influence of Molecular Rigidity on Formation and Permanent Porosity[END_REF] the pyrrolic bicycles 27-31 were = acetate) were tested in combination with an inherently nonlinear pyridine-fused oligopyrrolic dicarboxylic acid linker (32). Reaction of this chelate ligand 32 with Zn(acac) 2 followed by crystallization from methanol/dimethylformamide (DMF) was found to give an octametallic cage, 33, that consists of f7 discrete hydroxide-bridged Zn(II) dimers (see Figure 7a and7b). In contrast, when Zn(OAc) 2 was used as the zinc(II) cation source, an abacus type of fluorescent "cage polymer" (34) was obtained, as inferred from single-crystal X-ray crystallographic analyses (cf. Figure 7c). The underlying chemistry is shown in s6 Scheme 6. This work stands as a case study in how the choice of counteranion can serve to dictate the overall geometry of the

OLIGOPYRROLIC NONCOVALENTLY LINKED

305

CAGES 306 Currently, a number of organic cages 53-56 prepared using 307 covalent bonds including, inter alia, dynamic covalent 308 bonds [START_REF] Kovarícěk | Merging Constitutional and Motional Covalent Dynamics in Reversible Imine Formation and Exchange Processes[END_REF][START_REF] Jin | Dynamic Covalent Chemistry Approaches Towards Macrocycles, Molecular Cages, and Polymers[END_REF][START_REF] Zhang | Stimuli-Responsive Host-Guest Systems Based on the Recognition of Cryptands by Organic Guests[END_REF][START_REF] Granzhan | Connection of Metallamacrocycles via Dynamic Covalent Chemistry: A Versatile Method for the Synthesis of Molecular Cages[END_REF][22][START_REF] Powers-Riggs | Electron Hopping and Charge Separation within a Naphthalene-1,4:5,8-bis-dicarboximide) Chiral Covalent Organic Cage[END_REF][START_REF] Zhu | 3D Cage COFs: A Dynamic Three-Dimensional Covalent Organic Frameworks with High-Connectivity Organic Cage Nodes[END_REF][START_REF] Rao | Conjugated Covalent Organic Frameworks via Michael Addition-Elimination[END_REF][START_REF] Shan | Dynamic Transformation between Covalent Organic Frameworks and Discrete Organic Cages[END_REF][57][58][59][60] are known. These impressive contributions 309 have provided a springboard for the no less challenging task of 310 creating cage-or capsule-like systems based on noncovalent 311 interactions. [61][62][63][64][65][66][67][START_REF] Gibb | Well-Defined, Organic Nanoenviron-735 ments in Water: The Hydrophobic Effect Drives a Capsular Assembly[END_REF] Several of the authors of this Account have 312 contributed to the development of the latter theme; they 313 reported 4,69 the all-organic self-assembled dimeric cage-like s7 314 receptors (41) 2 and ( 42) 2 (cf. Scheme 7). These supramolecular 315 systems, constructed from the acyclic pyridyl-/naphthyridyl-316 polypyrrolic molecular building blocks 41 and 42, respectively, 317 are stabilized via quadruple hydrogen-bonding interactions 318 between individual "U"-shaped acyclic units (41 or 42). 319 Notably, both (41) 2 and (42) 2 are stable in the solid state in 320 CHCl 3 , tetrahydrofuran (THF), and dimethyl sulfoxide 321 (DMSO) solution and even in the gas phase as evidenced 322 from various spectroscopic analyses and single-crystal X-ray f8 323 diffraction studies (Figure 8). Depending on the pK a values of 324 the acid guests in question as determined in aqueous solution, 325 these self-assembled cages act as potential acid receptors. In 326 THF solution, receptor (41) 2 was found to bind effectively only 327 strong acids having pK a values of below ca. -1.92 (e.g., 328 methanesulfonic acid (MSA), p-toluenesulfonic acid (PTSA), HNO 3 , H 2 SO 4 , and HCl). In contrast, receptor (42) 2 proved to be an excellent receptor for biologically relevant organic dicarboxylic acids with pK a < 2.8 in water (e.g., oxalic acid, maleic acid, and to a lesser extent malonic acid). It was also found to bind the same strong organic and mineral test acids that were recognized by receptor (41) 2 .

It was speculated that the acids protonate the pyridyl or naphthyridyl moieties first, which creates a positively charged environment within the cavity of receptors (41) 2 and (42) 2 suitable for counteranion recognition. However, weaker acids (e.g., acids having pK a > 2.8 in water) were deemed unlikely to induce this protonation even in the case of the more basic cage, (42) 2 ; therefore, these acids do not interact with the receptor.

On this basis, the acid capture seen in organic media was termed "proton-coupled anion recognition". Consistent with this suggestion, washing the receptor-acid complexes produced from (41) 2 and (42) 2 with water was found to regenerate the corresponding pristine cage with a visible color change. This capture and release could be repeated several times without any degradation of the constituent receptor units.

Further studies of the pyridine-containing tetrapyrrolic monomer 41 revealed subtleties associated with its selfassembly. The discrete self-assembled cage form (41) 2 used for the acid capture experiments was obtained by allowing precursor 41 to crystallize from the relatively noncoordinating solvent CHCl 3 . However, when this same building block was crystallized from more polar and presumably better coordinating solvents, such as tetrahydrofuran (THF) or DMF, an infinite s8 "zig-zag" hydrogen-bonded network (41) n was obtained (cf.

  Scheme 1. Synthesis of the Oligopyrrolic Calix-Cryptand 1

  134 downfield shift was seen. These spectral changes were ascribed 135 to the formation of a 1:2 host-guest complex characterized by 136 association constants of K 1 = 1740 M -1 and K 2 = 420 M -1 , 137 respectively. In contrast to what is seen in the case of NO 3 -, F - 138 was found to form a 1:1 complex with 1 as inferred from a 139 corresponding 1 H NMR spectroscopic titration. In the case of 140 Cl -, an overall association constant on the order of 10 6 M -2 in 141 CD 2 Cl 2 was recorded at 298 K. Very slow exchange was seen in 142 the cases of H 2 PO 4 -and SCN -(as their TBA salts) under 143 otherwise identical experimental conditions. Overall, these

Figure 2 .

 2 Figure 2. Synthesis of cage 4 via the partial oxidation of 1 by DDQ. (Inset) Space-filling view of the structure of cage 4 deduced from single-crystal Xray crystallographic analysis. Neutral guest molecules, specifically H 2 O, EtOH, and EtOAc, are omitted for clarity. Data from ref 12. Scheme 2. Synthetic Scheme of Pyrrole-Pyridine-Pyrrole-Based Cryptand 8

  Setsune et al. reported a highly symmetric pyrrole-cryptand (8) constructed by three dipyrrylpyridine (pyrrole-pyridinepyrrole hybrid system) side arms. 9 The receptor was obtained via an acid-catalyzed condensation of precursors 6 and 7 as s2 shown in Scheme 2. Starting in 2011, Mani et al. reported a series of cages, c1 compounds 9-14 given in Chart 1, 13-17 which were seen capable of binding a number of representative anions (e.g., F -, Cl -, Br -, NO 3 -, H 2 PO 4 -, and HSO 4 -) in organic media such as CDCl 3 , DMSO-d 6 , and (CD 3 ) 2 CO under ambient conditions. A few representative X-ray structures of the resulting anion-bound f3 cryptates are shown in Figure 3. In the case of cages 9 and 11a, the F -and PO 4 3-anions were found to be bound within the cryptand cavity (cf. Figure 3a and 3d); however, most of the other anions give rise to exo complexes (cf. Figure 3b, 3c, and 3e).

Figure 3 .

 3 Figure 3. Single-crystal X-ray structures of representative anion-bound cryptates. (a) Fluoride complex of receptor 9, and (b) corresponding nitrate complex. (c) Bromide complex of receptor 10. (d) Phosphate complex of receptor 11a. (e) Chloride complex of receptor 12. Solvent molecules are omitted for clarity. Data from refs 13-17.

  In contrast to what was observed in the case of cage 18, the alkyl-imine-linked system 21 was characterized by selectivity for the fluoride anion, as evidenced by K a values of 1.01 × 10 7 M -1 for TBAF for cage 21 vs 1.57 × 10 6 M -1 for amide-imine cage 18 determined by the absorption spectroscopic titration method at 298 K. This selectivity was ascribed to the rigidity and comparatively smaller cavity size of cage 21 as compared to 18. When cage 21 was exposed to F -and various competing anions, e.g., Cl -, Br -, I -, HCO 3 -only F -produced an appreciable chemical shift in the 1 H NMR spectrum in CDCl 3 at 298 K. Unexpectedly, cage 21 was able to retain the trapped fluoride anion within its cavity even after deprotonation of one or two of the receptor pyrrolic NH protons as evidenced by the 1 H and 19 F NMR spectroscopic analyses conducted in DMSO-d 6 at 298 K. The proposed fluoride-binding modes expected to pertain within the cavity of cryptand 21 upon the incremental addition, e.g., >1.66 equiv) of TBAF are shown in Scheme 4b. Prior to our own contributions, but likewise based on the concept of dynamic imine chemistry, Roelens et al.

Figure 4 .

 4 Figure 4. X-ray diffraction structure of the dihydrogen phosphate complex of receptor 18 obtained using single crystals grown by allowing hexanes to diffuse slowly into a chloroform solution of cage 18 in the presence of excess TBAH 2 PO 4 . (a) Space-filling representation of receptor 18 with the bound H 2 PO 4 -removed to highlight the spherical void volume of the cage that would be expected to pertain in the absence of an anionic guest. (b) Side view of the H 2 PO 4 --inclusion complex of receptor 18 showing the 1:1 host-guest binding stoichiometry. Note: tetrabutylammonium countercation is denoted by a ball-and-stick model. Solvent molecules are omitted for clarity. Data from ref .

Scheme 4 .

 4 Scheme 4. Synthetic Route to Cage 21 and Its Proposed F -Binding Mode

Chart 2 .FFigure 5 .

 25 Scheme 5. Preparation of Various Oligopyrrolic Schiff-Base Cryptands 27-31 via [3 + 2] Condensation Reactions

Figure 6 .

 6 Figure 6. (a-e) Comparative sorption isotherms for the pyrrolic imine cages 27-31. Note: N 2 , H 2 , and O 2 isotherms were recorded at 77 K; CH 4 and CO 2 isotherms were recorded at 196 K. Reproduced with permission from refs 3 and 46. Copyright 2019 and 2020 Royal Society of Chemistry and World Scientific.

Figure 7 .

 7 Figure 7. Single-crystal X-ray structures of the two structurally characterized products obtained when precursor 32 was allowed to react with ostensibly similar zinc(II) salts. (a and b) Different views of the discrete oligopyrrolic metallacage (33) obtained from the reaction of 32 with Zn(acac) 2 . (c) View of the abacus-type infinite oligopyrrolic metallacage (34) obtained from 32 and Zn(OAc) 2 . Data from refs 2 and 52. Scheme 6. Synthesis of Oligopyrrolic Metallacages Controlled by Choice of Zinc Salts

Scheme 7 .

 7 Scheme 7. Synthesis of Acyclic Pyrrolic Precursors 41 and 42 Used To Prepare the Cage-Like Supramolecular Receptors (41) 2 and (42) 2 Accounts of Chemical Research

Figure 8 .

 8 Figure 8. (a and b) Solid-state structures of receptors (41) 2 and (42) 2 as determined by single-crystal X-ray structural analyses. (c-f) Single-crystal Xray structures of discrete supramolecular complexes with empirical chemical formula [(42H) 2 2+ ⊂(counteranion -) 2 ] formed between receptor (42) 2 and various biologically relevant small organic dicarboxylic acids (oxalic acid, maleic acid, malonic acid) and a mineral acid (H 2 SO 4 ). Note: Solvent molecules inside the cavity are omitted for clarity. (Inset) Comparative "space-filling" models of pyridine-and naphthyridine-based supramolecular cage-like structures formed by quadruple hydrogen bonding showing the void volumes for the guest-free forms. Data from refs 4 and 69. Scheme 8. Schematic Representation of the Solvent-Dependent Self-Assembled Macrocyclization Process Leading to Dimer (41) 2 and the Corresponding Oligomeric Product (41) n

  194 This phenyl-bridgehead oligopyrrolic cryptand cage contains 195 both imine (hydrogen-bonding acceptor) and amide (hydro-196 gen-bonding donor) functionalities within its side arms. The 197 latter receptor and its analogues were explored as potential 198 supramolecular hosts for specific anions. It was found that cage 199 18 exhibits specificity toward tetrahedral oxyanions, e.g.,

	200 H 2 PO 4 -, HP 2 O 7 3-, SO 4	2-, and HSO 4 -, in the noncompetitive
	201 solvent chloroform at 298 K. This selectivity is reflected in the 202 calculated K a values of 1.56 × 10 4 M -1 for TBAH 2 PO 4 , 1.76 × 203 10 6 M -1 for (TBA) 3 HP 2 O 7 , 2.66 × 10 6 M -1 for (TBA) 2 SO 4 , and 204 4.53 × 10 6 M -1 for TBAHSO 4 , respectively.
	205

Scheme 3. Synthesis of Benzene Bridgehead Oligopyrrolic Cage 18

Accounts of Chemical Research D

https://doi.org/10.1021/acs.accounts.2c00120Acc. Chem. Res. XXXX, XXX, XXX-XXX B

https://doi.org/10.1021/acs.accounts.2c00120Acc. Chem. Res. XXXX, XXX, XXX-XXX

Wang, F.; Liang, K.; Larsen, M. C.; Bähring, S.; Ishida, M.;

Furuta, H.; Jana, A. Solvent-Controlled Self-Assembled Oligopyrrolic


Yandi Lan

Christel Causserand

Laurie Barthe

Practical insights into ultrasound-assisted heterogeneous Fenton membrane reactors for water treatment

Keywords: Ultrasound, Microfiltration, Cavitation damage, Ultrasonic fouling control, Heterogeneous Sono-Fenton oxidation

Cavitation damage to membranes is a major barrier for developing an ultrasound (US)assisted membrane water treatment process. In this study, US was integrated to a heterogeneous Fenton membrane reactor for the treatment of pharmaceutical-containing water with the aims of i) fouling control, ii) enhancement of heterogeneous Fenton oxidation. In order to prevent membrane damages due to cavitation, the stable and violent cavitation regions were identified by quantification and analysis of the cavitation activity axial along the ultrasound transducer via hydrophone measurements. Results showed the cavitation activities occur in both regions with US on, while the cavitation damage to membrane materials was only observed when membranes were placed in the violent cavitation region. On one hand, cracking and physical erosion of the surface were observed on membrane samples when exposed to violent cavitation.

On the other hand, no such erosion occurred in stable cavitation regions, and membranes kept their mechanical, chemical and morphological properties, confirming that cavitation damage was controlled by placing membranes in the identified stable cavitation region. Based on these results, a heterogeneous Sono-Fenton membrane reactor was designed by placing a scalable hollow-fibre membrane module in the stable cavitation region. Within this reactor, the experiments confirmed that the oxidation of organics was enhanced thanks to the US assistance in the novel designed heterogeneous Sono-Fenton membrane reactor. However, this study also showed that US accelerated membrane ageing and zeolite-catalysts erosion, leading to more severe fouling. Overall, this paper introduces a method to control the cavitation damage to membranes and discusses the issues in US-assisted membrane systems with practical insights.

Introduction

The production and demand of pharmaceuticals has dramatically increased for high economic growth and better human health [START_REF]Treatment of wastewater containing pharmaceuticals: biological treatment[END_REF]. However, the discharge of pharmaceuticals contained wastewater, from all kind of sources such as the pharmaceutical industry and hospital effluents, has become a major challenge to the sustainability of the aquatic system: most pharmaceuticals are partially-or non-biodegradable and resistant to the conventional activated sludge process of a wastewater treatment plant (WWTP), releasing into the environment [START_REF] Rodriguez-Mozaz | Occurrence of antibiotics and antibiotic resistance genes in hospital and urban wastewaters and their impact on the receiving river[END_REF].

These refractory pharmaceuticals accumulate in the aquatic ecosystems and pose significant threats to the ecosystem's sustainability and drinking-water safety [START_REF] Li | Occurrence, sources, and fate of pharmaceuticals in aquatic environment and soil[END_REF][START_REF] Bruce | Toxicological Relevance of Pharmaceuticals in Drinking Water[END_REF]. It is therefore crucial to develop new and advanced treatment systems. In particular, integrated treatment systems combining several techniques have recently become a very interesting approach, providing additional options for treatments of harsh wastewater or high discharge standard [START_REF] Zhang | A new reactor coupling heterogeneous Fenton-like catalytic oxidation with membrane separation for degradation of organic pollutants[END_REF][START_REF] Arefi-Oskoui | A review on the applications of ultrasonic technology in membrane bioreactors[END_REF][START_REF] Lan | An experimental and modelling study of the electrochemical oxidation of pharmaceuticals using a boron-doped diamond anode[END_REF][START_REF] Gągol | Wastewater treatment by means of advanced oxidation processes based on cavitation -A review[END_REF][START_REF] Ince | Ultrasound-assisted advanced oxidation processes for water decontamination[END_REF][START_REF] Ritesh | Understanding of ultrasound enhanced electrochemical oxidation of persistent organic pollutants[END_REF].

Membrane-based oxidation processes are increasingly attracting attention for water treatment as the integration of membrane filtration and advanced oxidation processes efficiently remove and eliminate refractory pollutants [START_REF] Zhang | A new reactor coupling heterogeneous Fenton-like catalytic oxidation with membrane separation for degradation of organic pollutants[END_REF][START_REF] Lan | An experimental and modelling study of the electrochemical oxidation of pharmaceuticals using a boron-doped diamond anode[END_REF][START_REF] Perez | Electro-oxidation of reverse osmosis concentrates generated in tertiary water treatment[END_REF][START_REF] Lan | On the role of salts for the treatment of wastewaters containing pharmaceuticals by electrochemical oxidation using a boron doped diamond anode[END_REF][START_REF] Rostam | Advanced oxidation processes integrated by membrane reactors and bioreactors for various wastewater treatments: A critical review[END_REF][START_REF] Lan | Feasibility of a heterogeneous Fenton membrane reactor containing a Fe-ZSM5 catalyst for pharmaceuticals degradation: Membrane fouling control and long-term stability[END_REF]. In these processes, the role of membranes can be applied to separate and concentrate pollutants [START_REF] Lan | An experimental and modelling study of the electrochemical oxidation of pharmaceuticals using a boron-doped diamond anode[END_REF][START_REF] Perez | Electro-oxidation of reverse osmosis concentrates generated in tertiary water treatment[END_REF][START_REF] Lan | On the role of salts for the treatment of wastewaters containing pharmaceuticals by electrochemical oxidation using a boron doped diamond anode[END_REF] or complete an oxidation reactor by retention and reuse of the catalysts [START_REF] Zhang | A new reactor coupling heterogeneous Fenton-like catalytic oxidation with membrane separation for degradation of organic pollutants[END_REF][START_REF] Lan | Feasibility of a heterogeneous Fenton membrane reactor containing a Fe-ZSM5 catalyst for pharmaceuticals degradation: Membrane fouling control and long-term stability[END_REF]. However, the process efficiency is limited by the membrane fouling induced by the components in wastewater matrix or catalysts in oxidation reactors. To tackle fouling issues, the integration of ultrasound (US) with membrane filtration has been widely studied during the last two decades [START_REF] Borea | Wastewater treatment by membrane ultrafiltration enhanced with ultrasound: Effect of membrane flux and ultrasonic frequency[END_REF][START_REF] Lee | Dewatering of activated sludge by forward osmosis (FO) with ultrasound for fouling control[END_REF][START_REF] Kyllönen | Experimental aspects of ultrasonically enhanced cross-flow membrane filtration of industrial wastewater[END_REF][START_REF] Juang | Flux recovery in the ultrafiltration of suspended solutions with ultrasound[END_REF][START_REF] Lamminen | Mechanisms and factors influencing the ultrasonic cleaning of particle-fouled ceramic membranes[END_REF][START_REF] Ahmad | Membrane Antifouling Methods and Alternatives: Ultrasound Approach[END_REF]. US enables to detach or loosen deposits/particles from membrane surfaces by cavitation mechanism (i.e., microjets) and transport foulants away from the surface by acoustic streaming [START_REF] Lamminen | Mechanisms and factors influencing the ultrasonic cleaning of particle-fouled ceramic membranes[END_REF]. Indeed, US enables to promote both physical and chemical processes [START_REF]Introduction to Applied Ultrasonics[END_REF][START_REF] Latt | Ultrasound-membrane hybrid processes for enhancement of filtration properties[END_REF]. Besides fouling control, US furthermore promisingly improves oxidation efficiency in a membrane-based oxidation process [START_REF] Ritesh | Understanding of ultrasound enhanced electrochemical oxidation of persistent organic pollutants[END_REF][START_REF] Zhu | Strategies for enhancing the heterogeneous Fenton catalytic reactivity: A review[END_REF], for example, US enhanced heterogeneous Fenton oxidation (Sono-Fenton) in multiple functions [START_REF] Gągol | Wastewater treatment by means of advanced oxidation processes based on cavitation -A review[END_REF][START_REF] Tekin | Use of Fenton oxidation to improve the biodegradability of a pharmaceutical wastewater[END_REF][START_REF] Rodríguez | Heterogeneous Fenton Catalyst Supports Screening for Mono Azo Dye Degradation in Contaminated Wastewaters[END_REF][START_REF] Shin | Polymer-encapsulated iron oxide nanoparticles as highly efficient Fenton catalysts[END_REF]. US improving Fe 2+ regeneration and subsequent formation of radicals in the heterogeneous Fenton reactor has been proven. Moreover, US assisted the mineralization of organic pollutants. It was found that the mineralization degree of phenol by heterogeneous Fenton oxidation was significantly enhanced with up to 90% of TOC removal after US irradiation [START_REF] Segura | Enhancement of the advanced Fenton process (Fe0/H2O2) by ultrasound for the mineralization of phenol[END_REF]. This enhancement of the mineralization of organic pollutants can be associated to US preventing from the catalyst deactivation, the formation of other reactive oxidant species, and/or thermal cleavage of volatile compounds, contributing to the acoustic cavitation which gives rise to extreme conditions inside and around the collapsing bubble -up to 5000 K and 500 bar. The cavitation also contributes to the increase of accessible surface of catalysts by its mechanical effects.

The cavitation activities induced by US irradiation in the water potentially benefits both membrane fouling control and oxidation efficiency. However, the cavitation damage to membrane materials is a major concern for the integration of US into membrane-based processes. It was widely reported that cavitation and bubble implosion may induce physical and chemical erosion of membrane materials [START_REF] Aktij | A critical review on ultrasonic-assisted fouling control and cleaning of fouled membranes[END_REF][START_REF] Masselin | Effect of sonication on polymeric membranes[END_REF][START_REF] Kyllönen | Membrane filtration enhanced by ultrasound: a review[END_REF][START_REF] Lamminen | Cleaning of particle-fouled membranes during cross-flow filtration using an embedded ultrasonic transducer system[END_REF]. Indeed the damaging effects of US are highly related to the cavitation type and intensity [START_REF] Reuter | Membrane cleaning with ultrasonically driven bubbles[END_REF]. During acoustic cavitation, gas bubbles appear due to acoustic waves. Depending on the bubble size and local acoustic pressure, the oscillation of a bubble is variable. Schematically, some bubbles violently collapse (transient cavitation), generating a very strong shock wave, followed by the production of •OH radicals responsible for mechanical and chemical damage to materials. Other types of bubbles slightly oscillate and are more stable with a relatively long lifetime (stable cavitation) [START_REF] Leighton | The Acoustic Bubble[END_REF]. This latter type of cavitation is less active and so less destructive to materials. Therefore, the cavitation damage to membranes can be potentially controlled by identifying the cavitation intensity and minimising the effects of violent cavitation activity.

To promote US assisted membranes and advanced oxidation processes for water treatment, the present study integrated sonication with the heterogeneous Fenton membrane reactor which was investigated in our previous study [START_REF] Lan | Feasibility of a heterogeneous Fenton membrane reactor containing a Fe-ZSM5 catalyst for pharmaceuticals degradation: Membrane fouling control and long-term stability[END_REF]. A heterogeneous Sono-Fenton membrane reactor (HSoFM) was then developed for the degradation of pharmaceuticals in an aqueous solution.

The oxidation ability of this process is attributed to highly reactive hydroxyl radicals (•OH) generated from Fenton-like reactions involving hydrogen peroxide as the oxidant and ironcontaining micro-sized zeolites as catalysts [START_REF] Mirzaei | Removal of pharmaceuticals from water by homo/heterogonous Fenton-type processes -A review[END_REF]. The role of membrane filtration in the HSoFM reactor is to retain the zeolite catalysts in the effluent compartment during the continuous water treatment, overcoming the issue of difficult iron recovery in the Fenton oxidation process [START_REF] Khatri | Recent strategies for the removal of iron from water: A review[END_REF].

The further integration of the sonication in this process is of great interest to control membrane fouling induced by the zeolite catalysts and to enhance the degradation of pharmaceuticals.

In this present paper, the practical aspects of the coupling of US with membranes and advanced oxidation processes for water treatment have been discussed. Firstly, a stable cavitation strategy for controlling cavitation damage to membrane materials was investigated.

Secondly, the violent and stable cavitation regions were identified by quantification and analysis of the cavitation activity axial along with an ultrasound transducer via hydrophone measurements. The control of cavitation damage to membranes in the stable cavitation region was then verified, following the analysis of the role of US on membrane ageing in a Sono-Fenton aggressive media. Moreover, since the chemical effects of ultrasound on membrane are rarely investigated in the literature [START_REF] Naji | Ultrasound-assisted membrane technologies for fouling control and performance improvement: A review[END_REF], the impact of both the chemical and physical effects will be discussed in this study. The model system, a bench-scale HSoFM reactor with a scalable hollow-fibre membrane module, was then designed by placing the membrane module in a stable cavitation region. Two potential benefits of US in water treatment processes, fouling control and oxidation enhancement, were then evaluated in the HSoFM reactor.

Materials and methods

Chemicals and membrane

All aqueous solutions were prepared using deionized (DI) water generated by a PURELAB maxima system (ELGA labwater's, UK). Ibuprofen (IBP, C13H18O2, purity 99.99%) was purchased from BASF Corporation and used as received. Hydrogen peroxide (H2O2, 30% w/w), sulphuric acid (1 mol/L), titanium tetrachloride solution (0.09 mol/L in 20% HCl) for H2O2 concentration analysis, monopotassium phosphate (KH2PO4) and sodium phosphate dibasic dehydrate (Na2HPO4,2H2O) for preparing the buffer solution were purchased from Sigma-Aldrich. A commercial iron-containing zeolite of ZSM-5 structure (provided by Clariant TM ) was used as Fenton's reagents. This zeolite exhibited a Si/Al ratio of 13 and an iron content of 3.5 wt%. The average particle size of this catalyst is approximately 8 μm [START_REF] Khatri | Recent strategies for the removal of iron from water: A review[END_REF].

MF0808XS Polysulfone/Polyvinylpyrrolidone (PSU/PVP) hollow-fibre membrane module (provided by Polymem TM ) was tested. PVP was blended (5%, w/w) into the PSU matrix to increase the hydrophilicity of the membranes. The membrane pore size was 0.1 μm (microfiltration membrane). In this study, membrane filtration was only intended to maintain the catalyst (approximately 8 μm) in the oxidation reactor during the continuous treatment rather than to selectively reject the pharmaceutical and by-products. The membrane module for the HSoFM reactor contained 200 fibres. Its total active membrane surface was approximately 0.07 m 2 .

Cavitation activity analysis method

Cavitation activity and acoustic pressure

The aim of cavitation activity analysis was to estimate the intensity of axial cavitation activity along the US transducer. In the region where the major group of cavitation bubbles was transient, the cavitation activity was intensive and violent. The violent collapse of (transient) cavitation bubbles most likely led to membrane erosion. Conversely, where the dominate cavitation bubbles was relatively stable (or long lifetime), the cavitation activity was considered stable and expectedly less destructive to membrane materials.

The intensity of cavitation activity can be related to the spectral components of the acoustic wave. The US spectrum includes a ray at the fundamental frequency f (emitted by the ultrasonic generator), possibly harmonics of this fundamental frequency (k.f), sub-harmonics (f/n) and ultra-harmonics (kf/n). Between all the rays there is a broadband noise. It was proposed that the fundamental frequency is associated with violent collapses of cavitation bubbles (potentially transient cavitation) that lead to mechanical and chemical damage to membranes. Conversely, harmonics induce a relatively long lifetime of the cavitation bubble.

Indeed, the intensity of the cavitation activities is highly dependent on the acoustic pressure [START_REF] Gu | Harmonic responses and cavitation activity of encapsulated microbubbles coupled with magnetic nanoparticles[END_REF]. For this reason, the cavitation activity can be estimated by measuring the acoustic pressure by means of a hydrophone (section 2.2.2). The hydrophone determines the frequency band for the majority of the signal power [START_REF] Grosjean | Axial acoustic field along a solidliquid fluidized bed under power ultrasound[END_REF].

Therefore, by analysing the acoustic pressure axial along US transducer, the acoustic cavitation, due to the fundamental frequency, can be identified from the total US power. A stable cavitation region is identified where the majority of the cavitation bubbles are relatively stable. Conversely, in a violent cavitation region, the cavitation activities are violent and intense. In the stable cavitation region, the cavitation activities expectedly remain but intensive cavitation due to the fundamental frequency is minimized.

Acoustic pressure measurements with hydrophone and data analysis

The acoustic pressure measurements were performed using a hydrophone (model 8103) provided by Brüel & Kjᴂr. The piezoelectric ceramic was encapsulated in a rubber cylinder 3 cm long and 0.7 cm in diameter. It was calibrated by the manufacturer who provided the evolution of the sensitivity in volts versus the acoustic frequency. This calibration curve relates the amplitude of the acoustic pressure to which the sensor is subjected to the resulting electric charge.

The measurement system then comprises three devices provided by Brüel & Kjᴂr: an amplifier (model 1704) intended to simulate an infinite input impedance and whose gain is set to the unit value, a signal converter (model 2647 A) connected upstream of the amplifier 1704, and finally a load attenuator (model WB0779) connected to the hydrophone to remain in the voltage range compatible with the amplifier 1704 and thus avoid saturation at very high acoustic pressures. At 20 kHz, this setup has a resulting sensitivity of 0.896 V/bar. It should be noted that this configuration had a cutoff frequency located at 50 kHz.

For data acquisition, the measurement system was connected to a digital oscilloscope (Pico Technology). This device makes it possible to measure and digitize the output voltage of the measuring device so a computer can register it. The whole measurement system involved in this study is represented in Figure 1.

The signal is processed with MATLAB software. After pretreatment of the signal, a spectral analysis was performed by Discrete Fourier Transform (DFT). The data processing is already detailed in a previous article [START_REF] Grosjean | Axial acoustic field along a solidliquid fluidized bed under power ultrasound[END_REF]. Thus, a spectrum was obtained which determines the frequency bands where there is the majority of the power contained in the signal. It is then possible to determine the contribution to the total US power of the different elements of the spectrum (fundamental frequency, harmonics and broadband noise) by calculating the RMS (Root Mean Square value) pressure. According to the discussion in section 2.1, the RMS acoustic pressure contributions to the total US power and to the fundamental frequency were determined and analyzed to estimate the stable and violent cavitation regions axial along the ultrasonic probe.

Experimental set-up and protocol

Ultrasound generator and identification of the stable cavitation region

The ultrasound generator (SinapTec NexTgen Inside 500), connected with a Cup-Horn type transducer, was used for both the membrane stability tests set-up and HSoFM reactors.

The operating ultrasound frequency is 20 kHz, which is commonly used for the integration of membrane-based processes since lower frequencies had higher cleaning efficiencies than higher frequencies [START_REF] Lamminen | Mechanisms and factors influencing the ultrasonic cleaning of particle-fouled ceramic membranes[END_REF]. The US power is fixed at 50 W because previous studies determined that membrane erosion was insignificant for US power less than 60 W [START_REF] Lamminen | Cleaning of particle-fouled membranes during cross-flow filtration using an embedded ultrasonic transducer system[END_REF].

To analyse cavitation activity axial along the US transducer, the acoustic pressure (section 2.2) was measured every 0.5 cm along US transducer using the hydrophone in a waterfilled glassware. The stable and violent cavitation regions were estimated by quantification and analysis of acoustic pressure due to fundamental frequency of the total US power.

Membrane stability and ageing tests under US

The membrane stability under US was measured in a 1L jacketed thermostat glassware shown in Figure 2. The US transducer was located at the bottom of the glass reactor and membranes were fixed in a frame. By moving this frame up or down, the distance between membranes and the US transducer could be adjusted from 1.5 to 4 cm. This axial distance between membranes and the transducer tip is referred to as tip height. By adjusting the tip height, membranes can be exposed to identified stable or violent cavitation region.

For US exposure, the PSU/PVP membranes were immersed in DI water in the glassware.

The tests were conducted for 10 hours under continuous 50 W US power by placing membranes in both stable and violent cavitation regions. Then the membranes were sampled and characterized.

Furthermore, to understand the effect of US on membrane ageing while exposed to oxidative media, PSU/PVP membranes were immersed into a heterogeneous Fenton reactive suspension containing 4.8 g L -1 of ZSM-5 zeolite and 6.4 mM H2O2 under stable cavitation.

The concentration of catalysts and H2O2 was chosen according to selected conditions in a previous study on the heterogeneous Fenton membrane reactor [START_REF] Lan | Feasibility of a heterogeneous Fenton membrane reactor containing a Fe-ZSM5 catalyst for pharmaceuticals degradation: Membrane fouling control and long-term stability[END_REF]. The H2O2 concentration in the suspension was maintained at 6.4mM by continuous H2O2 injection using a syringe pump (Harvard PHD 2000). The US power was maintained at 50 W. For comparison, other groups of PSU/PVP membranes were submerged into Fenton reactive suspension with the same concentration of ZSM-5 zeolite catalyst and H2O2 under silent conditions. All the soaking tests were conducted for 30 hours. Membrane samples were taken periodically during the experiment for analysis.

Heterogeneous Sono-Fenton hollow-fibre membrane reactor

The HSoFM reactor was designed by placing the membrane module in the identified stable cavitation region for the control of cavitation damage (Figure S1 in supplementary information). The experimental solution was introduced in a 6.5 L thermo-regulated glass reactor. The membrane module reactor retains the catalyst in the glass reactor. The filtrations were performed in the outside-in filtration mode. The permeate was recycled back into the reactor to simulate a continuous process from a hydrodynamic point of view. The US transducer was located on the side wall of the reactor within the designed distance to the membrane module with on and off options.

The water treatment performance of HSoFM reactor was assessed by the degradation of the pharmaceutical solution. Ibuprofen (IBP), a widely used drug, was selected as the target pollutant for the reactor assessment, because it was found in effluents from various wastewater treatment plants and groundwater up to 95 µg/L [START_REF] Adityosulindro | Sonolysis and sono-Fenton oxidation for removal of ibuprofen in (waste)water[END_REF]. IBP was dissolved in deionized water with an initial concentration of 20 mg L -1 . The stoichiometric amount of H2O2 (6.4 mM) was applied twice to avoid extensive scavenging of hydroxyl radicals. For effective production of hydroxyl radicals, the [H2O2]/[Fe] molar ratio was maintained at 10, and the catalyst concentration at 4.8 g/L. The concentration of H2O2 was maintained at 6.4mM due to its continuous injection using a syringe pump (Harvard PHD 2000) during oxidation. The water treatment experiments were conducted at a controlled temperature of 25 ± 2 °C. The rotation rate of the stirrer inside the reactor was 300 rpm.

In this preliminary test of HSoFM reactor, the objective was to understand the membrane fouling phenomenon and Fenton oxidation under sonication. Therefore, the water treatment process was conducted in two stages.

Stage one with US off. Filtration flux was maintained at 30 L h -1 m -2 for fouling development with US off and the variation of transmembrane pressure was monitored during the process. The filtration was performed at 30 L h -1 m -2 because this flux value was above the critical flux value (flux below which a decline of flux over time, due to irreversible fouling, does not occur, and above which irreversible fouling is observed [START_REF] Lan | Feasibility of a heterogeneous Fenton membrane reactor containing a Fe-ZSM5 catalyst for pharmaceuticals degradation: Membrane fouling control and long-term stability[END_REF]). Oxidation was started by injecting H2O2, when the adsorption of IBP by catalysts and membranes had reached equilibrium.

Stage two with US on. Filtration and oxidation were conducted following the same protocol as in stage one whilst US was switched on in this stage.

Since the HSoFM reactor is a constant permeate flux system, the development of fouling causes the increase in transmembrane pressure (TMP). In these two stages, transmembrane pressure was monitored to investigate fouling development. Solution samples were taken at regular intervals in the reactor for analysis and immediately treated by phosphate buffer (a mixture of KH2PO4 0.05M and Na2HPO4•2H2O 0.05 M) to reach a neutral pH after the removal of catalysts using a 0.45 μm RC syringe filter to stop the oxidation reaction.

Analysis

Solution analysis

To evaluate the water treatment efficiency, the total organic carbon (TOC) of solution samples from the reactor was analysed. The TOC value was calculated from the difference between Total Carbon (TC) and Inorganic Carbon (IC), measured by a TOC-L analyser (Shimadzu). The TC of all samples was measured three times and the coefficient of variation was less than 2 %. Calibration curves were established using commercially available standard solutions (Shimadzu).

Membrane characterization

SEM-EDX Scanning electron microscope with energy-dispersive X-ray spectroscopy.

Morphology and elemental information on the membrane surface were examined with a SEM (Hitachi Tabletop Microscope TM-1000) interfaced with an EDX spectroscopy system (Thermo-Fisher). Samples were coated with a thin layer of gold before SEM analysis for better contrast. EDX analyses were carried out at the same time. EDX measurements were performed at different locations of the membrane surface to obtain a comprehensive elemental composition.

ATR-FTIR Attenuated Total Reflection-Fourier Transform InfraRed spectroscopy was obtained with a Thermo-Nicolet Nexus 670 apparatus (USA). The sample was placed on diamond crystal substrates and the analytical depth was approximately 2 μm. Membrane samples after soaking in the reactive medium were firstly dried at 40 °C for 48 h. Then they were examined using ATR-FTIR spectra to identify chemical membrane changes. All the recorded PSU/PVP IR spectra were corrected by adjusting the 1587 cm -1 band to an arbitrary chosen absorbance value of 1. This band corresponds to an aromatic in-plane ring bend stretching vibration of the PSU and considered to be invariable during membrane degradation [START_REF] Lan | Feasibility of a heterogeneous Fenton membrane reactor containing a Fe-ZSM5 catalyst for pharmaceuticals degradation: Membrane fouling control and long-term stability[END_REF]. The corrected absorbance is mentioned as relative absorbance. To facilitate the reader's understanding, when monitoring changes of specific IR bands upon degradation, normalization by dividing the relative absorbance by the one of the pristine membranes was performed.

Tensile testing Tensile tests were performed to obtain the stress-strain curve, reflexing membrane's mechanical property. The measurements were performed on wet membranes using an INSTRON 4281 series tensile apparatus. Tailor-made grips for the hollow-fibre geometry were fitted to the device to avoid stress concentration. The initial distance between grips was fixed at 50mm and samples were extended at a constant elongation rate of 100 mm/min. Ultimate elongation at breakpoint was calculated from the experimental stress-strain curves. A set of five samples were analysed and averaged for each tested condition.

Results and discussion

Determination of the stable cavitation region

This section aims to determine a stable cavitation region where the cavitation bubbles are relatively stable (or long lifetime) and less violent to membrane materials. As discussed in section 2.2.1, the fundamental frequency is usually associated with violent collapses of cavitation bubbles, while harmonics induce the relatively long lifetime cavitation bubble [START_REF] Grosjean | Axial acoustic field along a solidliquid fluidized bed under power ultrasound[END_REF].

Therefore, by means of a hydrophone (section 2.2), the fundamental frequency from the ultrasonic spectrum was identified and its associated cavitation activity characterized by the RMS acoustic pressure was determined. The stable cavitation region was identified. In this region, cavitation activities (by RMS acoustic pressure) remain, but RMS acoustic pressure associated to the fundamental frequency are minimized.

To identify the frequencies of the ultrasonic wave, the time-frequency signal was measured by a hydrophone, followed by a Fourier transform spectral analysis. The spectrum obtained from the signal measurement at 1.5 cm tip height is presented in Figure 3a. The frequencies were identified by indicating their amplitude. Two peaks were detected in Figure 3a, corresponding to the fundamental frequency (20 kHz) and the first harmonic (40 kHz) with the 50 kHz frequency cut-off of the measuring system.

Figure 3b shows the RMS acoustic pressure of fundamental frequency (20 kHz) and total power as a function of the axial distance to the transducer tip (referred to as tip height).

Each value in the graph is obtained from an average of 32 spectra. One can observe that the RMS acoustic pressure of fundamental frequency dramatically decreased from 0.2 bar with the increase in tip height until reached the lowest value (0.02 bar) at 3.5 cm. On the other hand, RMS acoustic pressure of total power was 0.28 bar at the initial point (1.5 cm tip height). After approximately 50% decline, its value relatively stabilized at around 0.15 bar from 2 cm to 4 cm tip height. Figure 3c highlights the ratio of RMS acoustic pressure of fundamental frequency to total power. It was found that the percentage of RMS acoustic pressure of fundamental frequency decreases from 1.5 cm to 3.5 cm tip heigh then increases.

The estimation of the intensity of cavitation activity depends on both the magnitude of RMS acoustic pressure induced by the fundamental frequency as well as its percentage in the RMS acoustic pressure of total US power. Therefore, for a tip height of 1.5 cm, the RMS acoustic pressure induced by the fundamental frequency is high (0.2 bar) and accounts for 73% of the RMS acoustic pressure of total power. The violent collapse of the cavitation bubbles associated with fundamental frequency likely occurred there, thus this region was referred as 'violent cavitation'. In contrast, at 3.5 cm tip height, the RMS acoustic pressure of the fundamental frequency is much lower (0.02 bar, 10 % of that at 1.5 cm) and only takes account for the 23% of RMS acoustic pressure of total power. Considering the remaining 0.12 bar (~40 % of that at 1.5 cm) of the RMS acoustic pressure induced by total power, this region remains the cavitation activity, whilst most of the cavitation bubbles induced by the harmonics should be less violent to membranes. This region was referred to as a "stable cavitation", where membrane rupture by US expectedly was minimized whist the cavitation-cleaning capacity of US remains.

Membrane stability in water under violent and stable cavitation

In this section, membrane stability was compared in the determined stable cavitation region and in the violent cavitation region (3.5 cm and 1.5 cm to transducer tip, respectively).

In this comparison objective, membranes were placed in the test system (section 2.3.2) filled with water. The surface morphology, as well as mechanical and chemical properties of membranes were monitored.

Cracks were observed on the membranes exposed to violent cavitation for 10 h. From SEM images in Figure 4b, irregular-section cracks were found. The surface of the membranes was eroded (Figure 4d), as demonstrated by the disappearance of the membrane selective skin by comparing to the surface of the pristine membrane (Figure 4a). On the other hand, no such crack and no significant changes in membrane micro-surface morphology were found on the membranes exposed to stable cavitation (Figure 4c). Moreover, the stress-strain curve obtained by tensile tests on membrane samples subjected to stable cavitation is presented in Figure S2 in supplementary information. The curve shapes of these membranes remain the same as that of pristine membranes, indicating that membranes mechanical strength is maintained.

The chemical changes of membranes in stable and violent cavitation regions were analysed by EDX and FTIR. It's worth noting that the PSU/PVP membranes used in this study were made from PSU blended with 5% PVP. The fraction of PVP on the membrane material can be monitored by the N/S atomic ratio, because repeat units of PSU and PVP carry only one sulphur atom (S) and one nitrogen atom (N), respectively. From the EDX analysis, the N/S atomic ratio of membranes submitted to stable cavitation maintained the same value of the pristine membrane N/S atomic ration (4.53 ± 0.6), whilst the ratio decreased from 4.53 ± 0.6 to 1.88 ± 0.4 upon exposure to violent cavitation. Moreover, according to FTIR analysis (Figure S3 in supplementary information) of membranes exposed to both violent and stable cavitations, no new absorbance band appears in their FTIR spectra comparing to that of the pristine membrane. The band at 1674 cm -1 corresponding to the stretching vibration of the amide unit of the PVP, and the one at 1145 cm -1 associated with symmetric SO2 stretching vibration of PSU [START_REF] Tang | Effect of membrane chemistry and coating layer on physiochemical properties of thin film composite polyamide RO and NF membranes: I. FTIR and XPS characterization of polyamide and coating layer chemistry[END_REF] were analysed. The ratio of these two absorbance's (-N-of PVP / SO2 of PSU) on membranes submitted to violent cavitation is around 0.08, which is below the ratio obtained for pristine membranes (0.18), and for membranes exposed to stable cavitation (0.16). These results are in accordance with the EDX analysis. They enable the conclusion that, under violent cavitation, the PVP fraction on the membrane material decreases mainly by PVP dislodgement from the membrane rather than by its chemical degradation (no new band observed by FTIR). This is in accordance with MEB observations: the membranes exposed to violent cavitation dominantly suffered from physical erosion under 50 W ultrasonic irradiation when this erosion is negligible for membranes submitted to stable cavitation These results confirmed that the exposure of membranes to stable cavitation effectively controls their cavitation damage. In these conditions, membranes maintained their mechanical and chemical properties as well as their surface structure. Exposing membranes to violent cavitation, although with a relatively low US power of 50W, led to severe damage, or even cracking.

Role of US on membrane ageing during exposure to oxidative media

Membrane ageing, the degradation of the membrane over time, was evaluated during exposure to oxidative media, resulting in performance decline or complete membrane failure [START_REF] Causserand | Ageing of polysulfone membranes in contact with bleach solution: Role of radical oxidation and of some dissolved metal ions[END_REF][START_REF] Antony | Impact of membrane ageing on reverse osmosis performance -Implications on validation protocol[END_REF]. Therefore, besides the control of cavitation damage to membranes, it is important to understand the membrane ageing process in the heterogeneous Sono-Fenton reactor. With this aim, PSU/PVP hollow-fibre membranes were placed under stable cavitation and submerged in Fenton reactive medium (4.8 g L -1 catalyst and 6.4 mM H2O2). To identify the role of US on membrane ageing, another group of membranes was soaked in a Fenton reactive medium under silent conditions (US off). Changes in mechanical and chemical properties of the membrane material were then monitored.

Mechanical properties of membranes in Sono-Fenton and Fenton media were monitored as a macroscale view of changes in material performances. By comparing the stress-strain curves of membranes sampling at different exposure times, it was found that the shapes of the elastic domain and early stages of the plastic domain were generally unchanged (results not shown), while the ultimate elongation value (at break) appeared to be affected. The ultimate elongation, therefore, was the most sensitive parameter compared, for example, to Young's Modulus. For this reason, the ultimate elongation was presented to demonstrate the change in mechanical properties of the membranes. The variation of ultimate elongation of membranes over exposure time is shown in Figure 5a. One can observe that, without US, ultimate elongation of membranes remained constant. On the other hand, when membranes were submitted to US, their ultimate elongation slightly decreased, before reaching a plateau at around 80% of the initial value after a 20-hour exposure. At the same time, SEM images of these last membrane samples after a 30-hour exposure presented a similar surface to that of the pristine membrane, indicating no significant change in membrane surface morphology (Figure S4 in supplementary information).

The change in chemical properties of 30h-aged membranes was then investigated by FTIR and EDX analysis. FTIR spectra of PSU/PVP membranes after 30-hour exposure to Fenton (US off) and Sono-Fenton (under stable cavitation) were presented in Figure 5c. The major distinction among the spectra appeared from 1700 to 1630 cm -1 . The intensity of the IR band at 1674 cm -1 characteristic of PVP, decreased in samples submitted to Sono-Fenton medium compared to the pristine membranes. At the same time, a sharp absorbance peak appeared at 1735cm -1 , associated with the formation of non-cyclic imide groups, characteristic of degradation products of PVP resulting from hydroxyl radical attack [START_REF] Prulho | Ageing of polyethersulfone/polyvinylpyrrolidone blends in contact with bleach water[END_REF]. On one hand, these results revealed that the chain scission of PVP occurred when membranes are submitted to Sono-Fenton conditions. Furthermore, the absorbance intensity at 1735 cm -1 increased with exposure time and then stabilized after a 20-hour exposure to Sono-Fenton conditions (panel of Figure 5c). It is likely that the PVP chain scission developed more quickly at the early stage of exposure, then stabilised. On the other hand, previous studies [START_REF] Lan | Feasibility of a heterogeneous Fenton membrane reactor containing a Fe-ZSM5 catalyst for pharmaceuticals degradation: Membrane fouling control and long-term stability[END_REF] showed that the chain scission of PSU evidenced with absorbance peaks at 1638 cm -1 , caused a dramatic decrease in membrane mechanical properties. Herein, no such peaks were observed in the FTIR spectra of aged membranes. These results show that US induced chain scission of the PVP additive when the PSU is not oxidated. The chemical properties stabilization after a 20-hour exposure (stabilized PVP chain scission and absence of PSU chain scission) is in accordance with the behaviour in mechanical properties: decrease in ultimate elongation of aged membranes, followed by stabilisation after a 20-hour exposure (Figure 5a).

As discussed in section 3.2, the N/S atomic ratio from the EDX analysis represents the fraction of PVP on the membrane surface. Figure 5b compares the N/S atomic ratio of pristine membrane and samples exposed to Fenton (US off, 10, 30-hour exposure) and Sono-Fenton media (5, 10, 20, 30-hour exposure). One can find after a 5-hour exposure to Sono-Fenton, the N/S atomic ratio on the surface of membranes decreases to 75% of the pristine value. This ratio was then maintained until the end of the experimental period (30-hour exposure). That is to say, the release of PVP additive from the membranes mainly occurred at the early stage of exposure. Combining the FTIR analysis (spectra shown in Figure 5c), it was found that the membrane ageing in Sono-Fenton began with the release of a certain amount (~25%) of PVP additive at the early stage (<5-hour exposure). After, the further membrane ageing involved the chain scission of PVP (chemical properties change) until reaching stabilisation after a 20hour exposure.

By comparing the FTIR spectra and N/S atomic ratio of aged membranes in Fenton medium (US off), no significant change in IR absorbance was observed and the N/S atomic ratio kept 90% of that of pristine membranes. These results indicated that membrane ageing was accelerated under US radiation. Although the acceleration of membrane ageing by US radiation is likely to a controllable degree: membranes properties stabilisation and no significant degradation of backbone material, one can suggest the application of a pulsed mode ultrasound, reducing the US exposure time, in a US-assisted membrane process for a sustainable system.

HSoFM reactor design and preliminary test for water treatment

Placement of membranes in a stable cavitation region is evident in order to prevent cavitation damage of membranes while keeping the cavitation-cleaning capacity of US.

According to the study in section 3.1, a 6.5L bench-scale HSoFM reactor (Figure S1 in supplementary information) was designed, where a scalable hollow-fibre membrane module was placed in a stable cavitation region (~3.5 cm to the transducer tip). In this preliminary test of HSoFM reactor, the objective was to evaluate over time the oxidation of organic pollutants and the evolution of membrane fouling when US are applied. Therefore, the heterogeneous Fenton oxidation was conducted in the reactor in two stages (section 2.3.3): stage one under silent conditions (with US off) to preform fouling induced by zeolite catalysts; stage two with US on for treatment of membrane fouling.

The HSoFM reactor was filled with 4.8 g L -1 zeolite catalysts. The oxidation of ibuprofen in water was started by continuous injection of H2O2. Figure 6a shows that the TOC of the solution in the reactor decreased from the beginning of oxidation and reached a plateau from 180 min at stage one (US off). No significant decrease of TOC was found from 180 min to 300 min of oxidation time. These results indicate that the heterogeneous Fenton oxidation (US off) contributed little to oxidate organic pollutants until total mineralisation, which is in accordance with other studies [START_REF] Makhotkina | Catalytic detoxification of 1,1dimethylhydrazine aqueous solutions in heterogeneous Fenton system[END_REF][START_REF] Velichkova | Heterogeneous Fenton oxidation of paracetamol using iron oxide (nano)particles[END_REF]. Since the FeZSM-5 catalysts are stable over several sequential uses in oxidation reactions [START_REF] Makhotkina | Catalytic detoxification of 1,1dimethylhydrazine aqueous solutions in heterogeneous Fenton system[END_REF], the plateau of TOC from 180 min oxidation is likely due to the formation of refractory oxidation intermediates. With US on (Sono-Fenton oxidation, stage two), the TOC value of the solution in the reactor decreased again in 40 min with statistical significance (p<0.05), confirming that US integration enhanced the Fenton oxidation in the HSoFM reactor. According to previous studies [START_REF] Gągol | Wastewater treatment by means of advanced oxidation processes based on cavitation -A review[END_REF][START_REF] Segura | Enhancement of the advanced Fenton process (Fe0/H2O2) by ultrasound for the mineralization of phenol[END_REF], the enhancement of mineralization degree by US (TOC decrease) is probably attributed to 1) additional powerful oxidants, •OH radicals, generated by water sonolysis (US on), 2) US improving Fe 2+ regeneration and subsequent formation of radicals.

For the fouling control aspect, since the HSoFM reactor is a constant permeate flux system, the development of fouling causes an increase in transmembrane pressure (TMP). A higher increase rate of TMP reflected a faster fouling rate. Figure 6b presents the evolution of TMP and the permeate flux from the beginning of oxidation treatment. At stage one (US off), the operating flux is constant at 30 L h -1 m -2 . According to the value of critical flux for irreversible fouling in the HSoFM reactor (23 L h -1 m -2 ), the operating flux is above this threshold value [START_REF] Lan | Feasibility of a heterogeneous Fenton membrane reactor containing a Fe-ZSM5 catalyst for pharmaceuticals degradation: Membrane fouling control and long-term stability[END_REF]. The fouling induced by the catalysts is then expected to be irreversible, which means the foulants persisted on the membrane even if the TMP decreases [START_REF] Lan | Feasibility of a heterogeneous Fenton membrane reactor containing a Fe-ZSM5 catalyst for pharmaceuticals degradation: Membrane fouling control and long-term stability[END_REF]. From Figure 6b, the TMP increased due to the fouling occurrence. During a 3-hour filtration (US off), the irreversible fouling was further developed with an average rate of 8.7×10 -5 bar min -1 .

Thereafter, the experiment turned into stage two with US on. The TMP unexpectedly increased faster than for stage one with an average rate of 2.3×10 -4 bar min -1 . Rather than mitigating fouling, applying US likely led to a more rapid formation of fouling. To understand this phenomenon, membrane samples were taken from the module and SEM analysis were performed. From the SEM images in Figure 6c, one can observe that many fine catalyst fragments were firmly adhesive to the membrane surface, blocking the membrane pores. The reduction of catalyst size under US was confirmed by particle-size distribution test (Figure S5 in supplementary information). The size decreases from D90=13.5 µm for initial zeolite catalysts to D90=11.4 µm and 6.51 µm for catalysts after 10 and 30-hour exposure to US respectively. Hence, it appears that the catalysts were eroded under US, the fine catalyst fragments leading to severe membrane fouling. Similar phenomena were reported in a study using US control of fouling by sludge flocs. US radiation cracking the sludge flocs caused the deterioration of membrane fouling condition [START_REF] Lee | Dewatering of activated sludge by forward osmosis (FO) with ultrasound for fouling control[END_REF]. In their study, the performance of US for fouling control was improved by optimising the radiation length and by integrating a flush of the membrane in the process. Therefore, applying the pulse-mode US (reducing the US exposure time), and/or integrating backwashing could be some solutions to this issue. It's worth noting that the pulse-mode US also benefits membrane stability under US as discussed before.

For these reasons it can be suggested that pulse-mode radiation be used in a US-assisted membrane and oxidation process and optimize the HSoFM reactor with a pulse-mode US in further study.

Conclusion

This study discussed the practical aspects of the integration of ultrasound with membrane and advanced oxidation process for water treatment. A model system integrating ultrasound with heterogeneous Fenton membrane reactor was designed for pharmaceutical oxidation where a scalable hollow-fibre membrane module was applied. US was integrated in the system to potentially enhance heterogeneous Fenton oxidation and control fouling induced by zeolite catalysts.

A stable cavitation strategy was first investigated for the control of cavitation damage to membranes, a major concern for US-assisted membrane-based processes. The intensity of cavitation activity axial along ultrasound transducer was quantified by hydrophone measurements and spectrally analysed. The Stable cavitation located at 3.5 cm to the transducer tips was identified, where cavitation activities were in a minority generated by harmonics and so less violent to membrane materials. After tests of membrane stability in both stable and violent cavitation regions confirmed that membranes placed in a stable cavitation region kept their mechanical and chemical properties and surface morphology. Exposing membranes to the violent cavitation region, albeit with a relatively low US power of 50W, led to severe physical damage of the membranes and even cracking.

Considering the sustainable aspect of the US-membrane system, the role of US on membrane ageing was then studied in a stable cavitation region. US radiation was found to accelerate membrane ageing in the oxidative Sono-Fenton medium, but likely in a controllable degree. On one hand, the membrane ageing involved the decrease in PVP additive content (5% in the virgin membrane material) partly by dislodgment from the membrane structure, and partly by chain scission. However, this PVP degradation reached a stable state under the experimental period. On the other hand, absence of degradation of the backbone material (PSU) of membranes was observed.

A heterogeneous Sono-Fenton membrane (HSoFM) reactor was designed by placing a hollow-fibre membrane module in a stable cavitation region for bench-scale testing. The preliminary tests confirmed that US integration enhanced the heterogeneous Fenton oxidation of organic pollutants in the HSoFM reactor: TOC reduction by Fenton oxidation in the reactor reached a plateau, but, when US applied, TOC value decreased again. However, US unexpectedly eroded the catalysts and the fine catalyst fragments caused severe fouling. A pulsed mode US was proposed for further optimisation of HSoFM reactor and control of the membrane ageing under US.

Figure 3 :

 3 Figure 3: Analysis of cavitation intensity: (a) ultrasonic wave spectrum at 1.5 cm tip height (axial distance to the transducer tip); (b) RMS acoustic pressure of fundamental frequency (20 kHz) and total power as function of tip height; (c) the ratio of RMS acoustic pressure of fundamental frequency to total power.

Figure 4 :

 4 Figure 4: SEM images of (a) pristine membrane surface (×5000), and of membranes exposed to 10-hour continuous 50 W ultrasonic irradiation: (b) membrane crack section under violent cavitation (×200), (d) membrane surface under violent cavitation (×5000), (c) membrane surface under stable cavitation (×5000).

Figure 5 :

 5 Figure 5: Characterization of pristine and aged membranes in Fenton and Sono-Fenton (stable cavitation region) conditions: (a) Ultimate elongation of membranes versus exposure time, (b) N/S elemental ratio, (c) FTIR spectrum and normalized relative FTIR absorbance at 1735 cm -1 (characteristic of non-cyclic imide groups, PVP chain scission products) against exposure time.

Acknowledgment

This work was supported by ANR (French National Research Agency) through ANR project "SOFENcoMEM" (ANR 14 CE04 0006).

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