Hybrid macrocycles for selective binding and sensing of fluoride in

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Hybrid macrocycles for selective binding and sensing of fluoride in aqueous solution Aleksandr S Oshchepkov, Tatiana A Shumilova, Siva R Namashivaya, Olga A Fedorova, Pavel V. Dorovatovskii, Victor N. Khrustalev, and Evgeny A. Kataev J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b03077 • Publication Date (Web): 29 Jan 2018 Downloaded from http://pubs.acs.org on February 2, 2018

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The Journal of Organic Chemistry

Hybrid macrocycles for selective binding and sensing of fluoride in aqueous solution Aleksandr S. Oshchepkov,a,b Tatiana A. Shumilova,a Siva R. Namashivaya,a Olga A. Fedorova.b Pavel V. Dorovatovskii,c Viktor N. Khrustalev,d and Evgeny A. Kataeva*

a

Institute of Chemistry, Faculty of Natural Sciences, Technische Universität Chemnitz, 09107 Chemnitz. E-mail: [email protected]

b

A. N. Nesmeyanov Institute of Organoelement compounds of RAS, Vavilova Str., 28, Moscow 119991, Russian Federation

c

National Research Center "Kurchatov Institute", 1 Acad. Kurchatov Sq., Moscow 123182, Russian Federation d

Peoples' Friendship University of Russia (RUDN University), 6 Miklukho-Maklay St., Moscow 117198, Russian Federation

Abstract Synthesis and anion binding properties of hybrid macrocycles containing ammonium and hydrogen bond donor groups are reported. Receptor properties were studied in a 10 mM MES buffer solution at pH 6.2, at which the receptors carry two positive charges at the secondary amine groups. Receptor 1 was found to bind fluoride with the highest affinity (105 M-1) and selectivity among the synthesized receptors. It was the only receptor that demonstrated fluorescence increase upon addition of fluoride. Other titration experiments with halides and oxyanions led to an anion-induced aggregation and fluorescence quenching. The mechanism of the particular turn-on fluorescence for fluoride was explained by the ability of receptor 1 to encapsulate several fluoride anions. Multiple anion coordination resulted in the protonation of the tertiary amine group and subsequent hindering of the PET process. 1H, 19F NMR titrations, single-crystal X-ray structure of chloride complex together with DFT calculation suggest that 1 can perfectly accommodate two fluoride anions in the inner cavity, but only one chloride, keeping the second chloride in the outer coordination sphere. Thus, the importance of size selectivity, which is reflected in a collective behavior of molecules in an aqueous solution, represents a new strategy for the design of highly selective probes for fluoride functioning in an aqueous solution. Introduction Anion recognition and transport in aqueous environment are essential for living organisms. The development of synthetic receptors for anions has attracted much attention in recent years because of their potential broad applications in areas such as sensing, transport and catalysis. Fluoride, as the smallest anion present in the environment, is an important target for anion recognition chemistry. There is a demand to control the concentration of fluoride in food, drinking water and the environment. 1 ACS Paragon Plus Environment

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Fluoride is considered essential in the development and maintenance of healthy teeth. Over the last decade considerable efforts have been made towards the development of fluoride selective receptors. The major obstacle in the design of the receptors is a strong solvation of fluoride by water molecules that prevents interaction of the anion with a receptor. The cryptands, reported by Lehn, BowmanJames, Steed and Inoue can overcome this problem and they are considered among the strongest receptors for fluoride in water ever synthesized.1-6 Recognition and sensing of fluoride in aqueous solution has been recently achieved by various types of receptors, such as lanthanide-7-9 and transition metal complexes,10-12 Lewis acids,13-17 and helix-type organic receptors.18 Kubik and Gale have recently reported on new calixpyrrole-based cryptands that can transport fluoride though a membrane.19 A series of interesting approaches for fluoride sensing in aqueous solution has been also reported by using reactive sensors,20-24 colorimetric array-based assays,25 and functional materials.26-28 In organic solution, fluoride usually facilitates deprotonation of the synthetic receptors bearing hydrogen bond donor sites. This strategy to detect fluoride in organic solution is perhaps the most studied one.29-31 Nevertheless, Rurack and coworkers have demonstrated that strong hydrogen bonding of a neutral receptor with fluoride can be translated to an aqueous solution retaining high selectivity and showing a detection limit of 0.2 ppm.32 The use of fluoride-π interactions,33-35 conformationally restricted biaryls36 and encapsulation of the anion in small cage-like receptors37,38 have been also shown as perspective approaches to bind and sense the anion with the help of organic receptors. In spite of the fact that fluoride has attracted much attention over last decades, there is still a limited number of organic receptors that function in pure aqueous solution and produce an analytical signal upon fluoride recognition. Thus, the challenge of creating a unique selectivity for fluoride remains open. Inspired by the literature known examples of fluoride-selective receptors, we therefore decided to design and study hybrid macrocyclic39 receptors (1-3) with an appropriate cavity size, which contains positively charged ammonium groups and hydrogen bond donor sites. The positively charged groups provide a solubility of the receptors in water and at the same time ensure sufficient affinity for fluoride through electrostatic interactions, similarly as in cryptands. As a reporting unit, we used a naphthalimide dye, which showed excellent fluorescence properties according to our previous investigations.40,41 Herein, we report the synthesis and anion binding properties of three new macrocycles for halide anions. Receptor 1 shows the strongest binding of fluoride with 100-fold selectivity over other anions in aqueous solution. We were surprised to discover that 1 can bind up to three fluoride anions resulting in a visible fluorescence enhancement, which was not observed for other anions. The difference in binding modes of receptors with halide anions were found to be the origin of high fluoride selectivity. Results and discussion Synthesis and solid state analysis Analysis of the crystallographic data of cryptates obtained by Steed and coworkers with different halides revealed that tren (tris(2-aminoethyl)amine) is a unique subunit, which is flexible enough to bind each of the halide anions. According to the reported data, fluoride, chloride, bromide and iodide are found in complexes with average N(tren)-halide distances of 2.6, 3.1, 3.3, 4.6 Å respectively. For the fluoride complex, the average distance between coordinating nitrogen atoms is ca. 4.0 Å. Thus, our idea was to design a macrocycle with an appropriate cavity for fluoride by connecting the tren subunit with a hydrogen bond donor group. In our recent work, we have developed the synthesis of a naphthalimidefunctionalized tren building block (4), which can be used for the preparation of fluorescent receptors for anions.40 This building block was used to prepare target macrocycles 1, 2 and 3 (Figure 1). The structures of the receptors were slightly varied keeping some features common. Two amine groups in the tren 2 ACS Paragon Plus Environment

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subunit are expected to be protonated at neutral pH values in aqueous solution. The tren subunit and the hydrogen bond donor group (pyridine or dipyrrolylmethane) are connected within three carbon atoms: by using a flexible propyl (2) and a rigid methylbenzyl linker (1 and 3). These small variations in the structure of receptors allowed us to understand the influence of the structural flexibility and the cavity size on the binding properties in aqueous solution.

n-Pr

O

O

O n-Pr N

O

N H

n-Pr N O

O

N H

N

HN

NH

N N H

N HN

HN

NH

N NH

NH NH O

NH

HN N O

O

HN

O

N

NH

HN

n-Pr

n-Pr

O

O

2

1

HN

3

Figure 1. Structures of receptors 1-3.

Figure 2. Front and side views of the DFT optimized structure of complex 1H2F+. Only hydrogen atoms that participate in anion coordination are shown. Prior to the synthesis, we optimized the fluoride complex of the diprotonated receptor 1 (1H22+) with the help of DFT calculations (Figure 2). The goal of these calculations was to understand whether there is a good geometrical complementarity in the host-guest complex with fluoride. Analysis of the obtained structure revealed that the flexibility of the methylbenzyl linker is sufficient to adopt the geometry of the receptor for fluoride recognition. As can be seen in Figure 2, the anion is closer to the positively charged tren-fragment. The N-halide (2.5-3.4 Å) and N3-N5 (4.2 Å) distances in the triamine fragment are in a good agreement with those distances observed in Steed’s cryptates. Interestingly, both the NH group in the 4th position of the naphthalimide ring and the adjacent CH group form hydrogen bonds with fluoride. The calculation suggest that the naphthalimide ring and the phenyl ring form stacking interactions. These interactions may stabilize the receptor-anion complex and isolate fluoride from the 3 ACS Paragon Plus Environment


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solvent molecules. Therefore, it was concluded that the designed receptors have appropriate cavity sizes and may have high binding constants with fluoride and other halides. The target receptors were synthesized starting from compound 4 by the reductive amination with either p-nitrobenzaldehyde or Cbz-protected 3-aminopropionaldehyde (Figure 3).42 After introduction of the Boc-group in the product of the reaction between 4 and p-nitrobenzaldehyde, the reduction of the nitro-group yielded diamine 7. Diamine 6 was synthesized by using two protection groups, Cbz and Boc, which allowed us to prepare the target compound with free terminal amines. Diamines 7 and 6 reacted further with derivatives of pyridine-2,6 dicarboxylic acid producing receptors 1 and 2, respectively. Reaction of 7 with pyridine-2,6 dicarboxylic acid chloride resulted in a very good yield of the product (80%), which after stirring in dioxane-HCl solution gave quantitatively receptor 1. In an analogous procedure, the acylation of 7 with dipyrrolylmethan-2,2’-dicarboxylic acid chloride43 resulted after deprotection of the reaction product in receptor 3 with 38% yield. In contrast, diamine 6 reacted with pyridine-2,6 dicarboxylic acid chloride to form polymeric products and traces of 2, even at a high degree of dilution. To solve this problem, we used our strategy of an anion-induced macrocyclization.44 The activated acid was added to 6 under high dilution and in the presence of tetrabutylammonium chloride as a templating reagent. These particular conditions allowed us to perform the reaction at slower reaction rates and obtain the desired macrocycle 2 in a 30% yield. All receptors were obtained as hydrochloride salts, which were further used for the anion binding studies.

Figure 3. Synthesis of target receptors 1-3.

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The first evidence of halide encapsulation by our receptors was obtained from the X-ray structure analysis of the hydrochloride salt of receptor 1 with composition [1H22+Cl-]Cl-·H2O. As can be inferred from Figure 4, one chloride anion is fully encapsulated by the macrocycle, while the other chloride is located outside the receptor cavity. The chloride anion fits ideally to the inner cavity of the receptor. All five NH donor fragments form hydrogen bonds with chloride: amide NHs (N–Cl distances are 3.30 and 3.28 Å) ammonium groups (3.16 and 3.20 Å) and the NH-group in the 4th position of the naphthalimide ring (3.46 Å). This coordination mode resembles the structure obtained by DFT calculations shown in Figure 2, in which naphthalimide NH form a hydrogen bond with the anion. Interestingly, the outside coordinated chloride atoms bridge two receptor molecules with N–Cl distances 3.11-3.13 Å. The chloride anion between the macrocycles and water molecules (not shown) are disordered. Two Cl3 anions have 50% occupancy.

Figure 4. a) Single-crystal X-ray structure of complex [1H22+Cl-]Cl-·H2O; most hydrogen atoms, the outside coordinated chloride and water molecules are omitted for clarity. b) Part of the coordination network in the crystal formed through NH…Cl hydrogen bonds. Anion binding studies and fluorescence properties According to our recent studies on naphthalimide-functionalized tren derivatives, starting compound 4 functions as a pH probe in aqueous solution.40 Compound 4 demonstrates a maximum quantum yield at pH 6 and lower, at which the primary amines are protonated. The fluorescence of 4 at basic pH values is quenched because of the photoinduced electron transfer (PET) process from the free primary amines to the dye. Therefore, a similar pH-dependent fluorescence was expected for receptors 1-3. To verify this, we measured the fluorescence intensity of receptors (0.01 mM) in a 50 mM acetic acid solution adjusted to different pH values with NaOH (Figure S9). Receptors 1 and 2 demonstrated 3- and 6-fold 5 ACS Paragon Plus Environment


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fluorescence decrease by changing the pH from pH 5.5 to pH 7, while for receptor 3 we observed a decrease in fluorescence only at pH values higher than pH 8. These experiments indicate that the secondary amine groups of 1 and 2 are protonated at ca. pH 6. In fact, potentiometric titrations of 1 yielded the following protonation constants for amine groups: pK1 = 7.38, pK2 = 6.82 and pK3 = 4.88 (Figure S10). Thus, for anion binding studies and fluorescence measurements we chose pH 6.2 (10 mM MES buffer) to ensure the protonation of the secondary amines. At this pH value all receptors exist as one major species – a diprotonated form.

Figure 5. a) Photo of solutions of 1 in a 10 mM MES buffer (pH 6.2) in the presence of 50 equiv. of anions and b) the corresponding changes of fluorescence intensities for each solution at 540 nm. c) Binding 6 ACS Paragon Plus Environment

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isotherm and d) fluorescence changes obtained by titration of 1 with NaF in a 10 mM MES buffer (pH 6.2, ex. 440 nm). To test the receptors as visual probes for anions, we added 50 equiv. of different anions as sodium salts (F-, Cl-, Br-, I-, NO3-, SO42-, H2PO4-, C2O42-) to their aqueous solutions (10 mM MES, pH 6.2). Addition of anions in most cases resulted in no visible changes or in the formation of a precipitate. Addition of fluoride to 1 resulted in a fluorescence enhancement, while addition of iodide and oxalate led to an immediate precipitation, apparently due to the formation of insoluble salts (Figure 5a). Fluorescence measurements of the solution before and after addition and an excess of anions are shown in Figure 5b. Addition of anions to receptors 1-3 induced quenching of fluorescence. The only exception is the addition of fluoride to 1, which resulted in a fluorescence enhancement. A separate titration experiment of the parent amine 4 showed negligible changes after addition of a large excess of NaF (Figure S1). This experiment supports the fact that the pyridine-diamide binding site is a key fragment that gives rise to this unique fluoride selectivity. As inferred from the fitting analysis of the fluorescence titration of 1 with fluoride (Figure 5c), the anion forms 1:1, 1:2 and 1:3 complexes with binding constants (logK) 5.50(1), 3.26(4) and 2.63(8), respectively. Coordination of three fluorides can be understood knowing that the receptor can carry up to three positive charges upon protonation. Unfortunately, the titration isotherms for other anions could not be fitted to 1:1 or other binding modes. The reason for this we found in analogous UV-Vis and NMR titrations, which suggested the presence of an anion-induced aggregation. The absorption spectra were broad after addition of an excess of anions other than fluoride. Particular strong broadening of the absorption spectra was observed for oxyanions (Figure S2). A surprisingly strong contrast between binding and aggregation was observed in 1H NMR titrations of 1 (1 mM solution) with fluoride and chloride in a 10 mM MES buffer (pH 6.2, containing 5% DMSO). The spectra of 1 with fluoride and chloride are shown in Figure 6, in which protons were assigned according to the 2D NMR experiments (ESI). Addition of sodium fluoride up to three equivalents induced strong shifts of phenyl (Hc) and naphthalimide (Hg, Hk, Hi) protons, which is indicative of conformational rearrangement of the receptor structure. This fact also supports a 1:3 binding mode for recognition of fluoride. The fitting of the binding isotherm allowed us to calculate precisely only the first 1:1 binding event (logK > 4). The analysis of the solutions of 1 with an excess of NaF with mass spectrometry revealed only the presence of the most stable 1:1 complex with m/z 746.3, which corresponds to 1H2F+ species. NMR titrations with chloride induced a strong shift in the naphthalimides signals and subsequent broadening of all proton signals at high concentrations of the anion. Thus, chloride induced aggregation, likely through intermolecular π-π and electrostatic interactions between naphthalimide dyes. Our calculations discussed above further support this notion. Similar anion-induced aggregation we observed in our recent studies on naphthalimide-based polyammonium receptors.40 To understand the intrinsic selectivity of receptors for halides we carried out 1H NMR titrations in a solution, in which aggregation is absent and all receptors and complexes are soluble. This was achieved by increasing the volume of DMSO in the buffer to 50%. According to our measurements, a high portion of DMSO in the buffer does not considerably change the pH of the solution. For instance, after mixing the MES buffer (pH 6.2) with DMSO the pH meter shows pH 6.5. The changes in the pH of the solution upon titration by anions did not exceed 0.2 pH units. The receptors were titrated under these conditions with NaF, NaCl, NaBr and NaI (Figure S3-S8). The only receptor-anion combinations that showed shifts in NMR spectra were receptors 1 and 2 with fluoride and chloride. To our surprise, receptor 3 was totally silent to all halides. The fitting of binding isotherms was accomplished by using a 1:1 model because the use of higher order models resulted in large fitting errors. Therefore, it was possible to assess only the first binding event. According to the obtained data, receptor 1 can bind fluoride and chloride with 7 ACS Paragon Plus Environment


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binding constants (logK) 3.98(2) and 1.90(5), respectively. Receptor 2 binds these anions weaker with binding constants 2.96(2) and 1.92(6), respectively. In the titration experiments of the receptors with bromide and iodide no shifts in NMR were observed. With the help of these titration experiments, we determined that receptors 1 and 2 have selectivity for fluoride and receptor 3 does not bind halides with detectable affinities.

Figure 6. 1H NMR titrations of receptor 1 with a) fluoride and b) chloride in a 50 mM MES buffer (pH 6.2) containing 5% DMSO. NaF and NaCl is present in the following quantities: a) spectra 1-13 (equiv.): 0, 0.1, 0.4, 0.7, 1, 1.5, 2, 3, 5, 9.5, 18, 38, 59; b) spectra 1-10 (equiv.): 0, 0.5, 1, 2, 4, 7, 10, 20, 49, 99. Next, we attempted to clarify the coordination mode of fluorides in receptor 1 by experimental and theoretical methods. 1H NMR titration of 1 with fluoride did not give any hints about how the second and third fluoride anions can be encapsulated by the receptor. Therefore, we conduced 19F NMR titration in the presence of an external reference – sodium trifluoroacetate (Figure 7). In the spectra, we observed a small signal at -85 ppm and a stronger signal at -120 ppm, which appeared only after addition of ca. 5 equivalents of NaF. Thus, we concluded that up to ca. 5 equivalents, the fluoride anion is mainly coordinated inside the macrocycle producing only one signal in 19F NMR. An excess of NaF resulted in the appearance of a non-coordinating fluoride anion. A longer NMR experiment revealed that there are in sum three signals in the region between -84 and -96 ppm: two overlapping signals at 85 ppm and one signal at -93 ppm (Figure 7a). This observation provides a strong evidence for the 1:3 binding stoichiometry for the recognition of fluoride by 1 in a buffered solution. We looked closer at the fluorescence titration of 1 with NaF because it can also provide a valuable information about the mechanism of the turn-on response. As can be seen in Figure 5c, only addition of 8 ACS Paragon Plus Environment

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more than one equivalent of fluoride induces an increase in fluorescence. A hypsochromic shift is observed during the titrations (Figure 5d), which indicates that naphthalimide-NH proton participates in fluoride coordination as predicted by DFT calculations. As follows from our previous work on PET anion probes, such an increase in fluorescence is an indication of protonation of an amine group. Taking into consideration the pKa values of 1 obtained by potentiometric titrations, we could suggest that the coordination of the second and third fluoride anions induces the protonation of the tertiary amine in the macrocycle. To prove this fact, we carried out potentiometric titrations of 1 (0.25 mM, 30% DMSO – 70% 0.1 M NaClO4 aqueous solution) in the absence and in the presence of an excess of NaF. As can be inferred from Figure 7b, the presence of an excess of fluoride shifts the pKa values of the receptor towards higher values: pK1 = 8.03, pK2 = 7.19 and pK3 = 6.51. As compared to the values without sodium fluoride (pK1 = 7.38, pK2 = 6.82 and pK3 = 4.88), the largest shift is observed exactly for the tertiary amine group (1.63 pH units). The calculation of species distribution using potentiometric data additionally supports that fluoride-induces protonation of this amine group. For instance, at pH 6.2 in the absence of NaF the receptor exists as species 1H22+ (75%) and 1H33+ (35%), while in the presence of NaF species 1H22+ (40%) and 1H33+ (50%) reach almost equal portions. To understand how two and three fluorides can be bound to the macrocycle, we conducted DFT calculations of structures 1H2F2 and 1H3F3. As can be seen in Figure 7c, the size of the macrocycle is sufficient to accommodate two fluorides with a nearly perfect induced-fit with F-F distance of 3.61 Å. Fluorides F1 and F2 are located between pairs of amides and secondary ammonium groups, respectively. The calculations suggest that anions are additionally stabilized from above by naphthalimide C-Hi…F and CHj…F hydrogen bonds. This fact is supported by the shifts of Hi and Hj signals in the 1H NMR titration experiment. In the 1:3 complex (Figure 7d), the distance between F1 and F2 is decreased to 3.16 Å and the triamine subunits forms a separate cavity that accommodates F2. Fluoride F1 is bound to amides and one ammonium fragment, resembling the 1:1 complex depicted in Figure 2. The third anion (F3) forms only one hydrogen bond with the ammonium fragment and is found outside the cavity. Close location of each fluoride anion to positively charge centers in the 1:3 complex is indicative of the dominance of electrostatic interactions holding the overall structure. In spite of the fact that fluoride anions are close to each other, their charge is compensated by the positively charged ammonium groups. As inferred from the calculations, the partial charges on fluorides remain almost the same in 1:1 (-0.26), 1:2 (-0.32, -0.24) and 1:3 (-0.27, -0.22, -0.23) complexes. The earlier reported X-ray structures of halide complexes, fluorides and chloride anions are often bridged by water molecules through hydrogen bonds.5,6,45 This can additionally decrease the repulsion between anions. Therefore, it can be suggested that in reality 1:2 and 1:3 complexes of 1 with fluoride anions contain bridging water molecules between fluoride anions, as in the X-ray structure of the chloride complex reported here.



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Figure 7. a) 19F NMR titration of 1 with NaF in a 10 mM MES buffer (pH 6.2) containing 5% of DMSO. b) Potentiometric titration of 1 in the absence and in the presence of 10 equiv. of NaF. DFT optimized structures of complexes c) 1H2F2 and d) 1H3F3. Conclusions We have designed and synthesized three new hybrid macrocycles bearing the tren subunit and hydrogen bond donor amide groups for recognition of halides in aqueous solution. The macrocycles are equipped with a naphthalimide dye to follow binding events by spectrophotometric measurements. According to the fluorescence and NMR investigations, among the three synthesized macrocycles, receptor 1 demonstrated the highest selectivity and affinity for fluoride in a 10 mM MES buffer (pH 6.2) showing 105 M-1 binding constant and a peculiar turn-on fluorescence response. Addition of other anions induced aggregation accompanied by quenching of fluorescence and subsequent precipitation of anion complexes. 1H NMR titrations conducted in a 1:1 mixture of DMSO and 10 mM MES buffer, in which no aggregation is present, revealed that receptor 2 also binds fluoride selectively but with ca. one order of magnitude lower affinity than that found for receptor 1. Receptor 3 did not show any response 10 ACS Paragon Plus Environment

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towards studied anions, which could originate from larger cavity and strong tendency to aggregation. Analysis of the binding isotherms revealed that up to three fluoride anions can be bound to the receptor. This fact was unambiguously supported by 1H and 19F NMR measurements. The formation of 1:2 and 1:3 complexes resulted in the protonation of the tertiary amine. The protonation leads to a fluorescence increase, which is highly specific for fluoride among other anions. We have also evaluated with the help of DFT calculations how two and three fluorides are bound to the receptors and found high complementarity for the 1:2 complex. Overall, the obtained data suggests that the reason for high selectivity for fluoride is the property of receptor 1 to detect very small difference in sizes of a coordinated anion, e.g. fluoride and chloride. The macrocycle can coordinate only one chloride in the cavity and the second chloride is bound outside the cavity, which in turn leads to the formation of aggregates held through electrostatic interactions. In case of fluoride recognition, the receptor can perfectly accommodate one or two anions in the cavity, which subsequently prevents aggregation. The turn-on fluorescence response for recognition of fluoride represents an opposite situation to aggregation induced emission, efficiently used to detect anions. 46,47 Thus, our results illustrate the importance of size selectivity, which is reflected in a collective behavior of molecules in an aqueous solution. The discovered mechanism of selective recognition may help to design new highly selective probes for fluoride and other anions in aqueous solution. Studies along this line are in progress. Experimental section Compound 5 A solution of 3-[(Benzyloxycarbonyl)amino]propionaldehyde (0.14 g, 0.68 mmol, 2.5 equiv) in 20 mL of dry CH2Cl2 was added dropwise to a solution of amine 4 (0.1 g, 0.26 mmol) in 20 mL of dry CH2Cl2. The reaction mixture was left stirring for 1 h, and after that, NaBH(OAc)3 (0.215 g, 1.01 mmol, 3.9 equiv) was added in small portions under stirring. When the addition was completed, the reaction mixture was left stirring at r. t. for 18 h. Finally, the reaction mixture was washed with water, dried under Na2SO4 and concentrated in vacuo. The crude product was purified by silica gel column chromatography using the mixture CH2Cl2–MeOH–NH3(conc. 25%) 50:5:1 as an eluent. Orange gum, yield 40% (0.08 g). 1H NMR (400 MHz, DMSO-d6): δ 0.89 (t, 3J = 7.4 Hz, 3H), 1.42 (quint, 3J = 6.8 Hz, 4H), 1.57–1.66 (m, 2H), 2.41 (t, 3J = 6.7 Hz, 4H), 2.52–2.57 (m, 8H), 2.76 (t, 3J = 5.9 Hz, 2H), 2.92–2.96 (m, 4H), 3.41–3.46 (m, 2H), 3.95– 3.99 (m, 2H), 4.97 (s, 4H), 6.80 (d, J = 8.6 Hz, 1H), 7.18–7.21 (m, 2H), 7.26–7.35 (m, 10H), 7.66 (t, 3J = 7.8 Hz, 1H), 7.71 (br. s, 1H), 8.26 (d, 3J = 8.5 Hz, 1H), 8.42 (d, 3J = 7.2 Hz, 1H), 8.62 (d, 3J = 8.3 Hz, 1H). 13C NMR (100 MHz, DMSO-d6): δ 163.8, 162.9, 156.0, 150.5, 137.3, 134.2, 130.7, 129.4, 128.3, 127.7, 124.3, 121.9, 120.1, 107.6, 103.9, 65.1, 53.8, 51.9, 47.3, 46.8, 41.0, 40.8, 38.5, 29.7, 21.0, 11.4. HRMS (ESI) m/z: [M + H]+ Calcd for C43H56N7O6 766.4287; Found 766.4299. Compound 8 Amine 5 (0.20 g, 0.26 mmol) was dissolved in CHCl3 (30 mL) and di-tert-butyldicarbonat (Boc2O) (0.23 g, 3.70 mmol) in 10mL of CHCl3 was added. The mixture was stirred 18 h at r.t. Then the solvent was evaporated and the crude product was purified by silica gel column chromatography using the mixture CH2Cl2–MeOH 100:1 as an eluent to give yellowish gum (0.24 g, 94%). 1H NMR (400 MHz, DMSO-d6): δ 0.89 (t, 3J = 7.4 Hz, 3H), 1.33 (s, 18H), 1.56 (br. s, 4H), 1.58–1.64 (m, 2H), 2.64 (br. s, 4H), 2.82 (br. s, 2H), 2.91–2.96 (m, 4H), 3.09–3.20 (m, 8H), 3.44 (br. s, 2H), 3.95–3.99 (m, 2H), 4.98 (s, 4H), 6.83 (br. s, 1H), 7.18–7.22 (m, 2H), 7.26–7.35 (m, 10H), 7.60–7.63 (m, 1H), 7.67 (t, 3J = 7.9 Hz, 1H), 8.27 (d, 3J = 8.5 Hz, 1H), 8.43 (d, 3J = 7.3 Hz, 1H), 8.62 (br. d, 3J = 7.6 Hz, 1H). 13C NMR (100 MHz, DMSO-d6): δ 163.7, 162.9, 156.0, 154.5,137.1, 134.2, 130.7, 129.4, 128.3, 127.7, 124.3, 121.9, 120.1, 107.7, 103.9, 78.5, 65.1, 54.9, 52.1, 45.1, 44.8, 41.2, 40.7, 38.0, 28.0, 21.0, 11.4. HRMS (ESI) m/z: [M + H]+ Calcd for C53H72N7O10 966.5335; Found 966.5322. 11 ACS Paragon Plus Environment


Compound 6 Cbz-protected amine 8 (0.207 g, 0.21 mmol) was dissolved in MeOH (25 mL). To that mixture Pd/C was added by small portions under stirring (0.03 g). The reaction was carried out at r. t. and hydrogen atmosphere. First, H2 was bubbled for 2 h under stirring. Then the reaction mixture was kept overnight under H2 and stirring. The catalyst was filtered off using Celite 545, and the solvent was evaporated. Product was obtained as an orange solid (0.143g, 96% ) and was used in the next reaction without further purification. Mp 66–68 °C (CH2Cl2). 1H NMR (400 MHz, CDCl3): δ 0.98 (t, 3J = 7.4 Hz, 3H), 1.37 (s, 18H), 1.58 (quint, 3J = 6.8 Hz, 4H), 1.69–1.78 (m, 2H), 2.62 (t, 3J = 6.3 Hz, 4H), 2.71 (br. s, 4H), 2.94 (t, J = 5.6 Hz, 2H), 3.06–3.39 (m, 10H), 4.09–4.13 (m, 2H), 6.29–6.50 (m, 1H), 6.65 (d, 3J = 8.5 Hz, 1H), 7.60 (br. s, 1H), 8.22–8.37 (m, 1H), 8.44 (d, 3J = 8.4 Hz, 1H), 8.57 (d, 3J = 7.2 Hz, 1H). 13C NMR (100 MHz, CDCl3, several conformers): δ 167.4, 164.2, 155.6, 149.6, 134.5, 131.1, 129.8, 124.6, 123.0, 120.5, 110.2, 104.4, 79.7, 52.8, 52.3, 45.4, 45.2, 44.7, 41.6, 40.9, 39.3, 32.5, 32.0, 28.4, 21.4, 11.6. HRMS (ESI) m/z: [M + H]+ Calcd for C37H60N7O6 698.4600; Found 698.4614. Compound 9 To a solution of compound 4 (1.524 g, 4.12 mmol) in MeOH (50 mL) 2-nitrobenzaldehyde (1.557 g, 10.3 mmol) in 15 mL of MeOH was added dropwise over 30 min at r. t. After 18 h stirring, NaBH4 (3.113 g, 20.6 mmol) was added to the solution by small portions under stirring. When the addition was complete, the reaction mixture was heated to reflux and stirred for 1 h. The reaction was left overnight at r. t. under stirring. After that, the solvent was removed, and the crude product was purified by gradient column chromatography (CH2Cl2 with 0–5% MeOH). Orange-red gum, yield 62%. 1H NMR (400 MHz, DMSO-d6): δ 0.91 (t, 3J = 7.4 Hz, 3H), 1.58–1.68 (m, 2H), 2.52–2.57 (m, 4H), 2.57–2.62 (m, 4H), 2.75 (t, J = 6.0 Hz, 2H), 3.42–3.46 (m, 2H), 3.81 (s, 4H), 3.94–3.98 (m, 2H), 6.76 (d, 3J = 8.7 Hz, 1H), 7.38–7.44 (m, 2H), 7.47–7.54 (m, 5H), 7.63 (t, J = 5.4 Hz, 1H), 7.85 (d, 3J = 8.0 Hz, 2H), 8.18 (d, 3J = 8.5 Hz, 1H), 8.32 (d, 3J = 7.2 Hz, 1H), 8.51 (d, 3J = 8.4 Hz, 1H) 13C NMR (100 MHz, DMSO-d6): δ 163.7, 162.8, 150.5, 148.5, 135.4, 134.1, 132.9, 130.5, 130.0, 129.3, 128.0, 127.8, 124.1, 121.8, 119.9, 107.6, 103.8, 53.9, 52.1, 49.5, 46.9, 41.0, 40.8, 21.0, 11.4. HRMS (ESI) m/z: [M + H]+ Calcd for C35H40N7O6 654.3035; Found 654.3019. Compound 10 Compound 9 (1.642 g, 2.51 mmol) was dissolved in CHCl3 (20 mL) and Boc2O (1.206 g, 5.23 mmol) in 10 mL of CHCl3 was added. Reaction mixture was stirred 18 h at r. t. Then solvent was removed and the crude product was purified by silica gel column chromatography (CH2Cl2–MeOH 98:2) to give yellow powder (2.058 g, 96%). Alternatively, crude product may be purified by extraction (water/chloroform) and further recrystallization from MeOH. Mp 68–70 °C (MeOH). 1H NMR (400 MHz, DMSO-d6): δ 0.90 (t, 3 J = 7.4 Hz, 3H), 1.12 (br. s, 9H), 1.36 (br. s, 9H), 1.57–1.66 (m, 2H), 2.69 (t, J = 6.6 Hz, 4H), 2.81 (br. s, 2H), 3.19 (br. s, 2H), 3.29 (br. s, 2H), 3.42 (br. s, 2H), 3.94–3.98 (m, 2H), 4.58–4.73 (m, 4H), 6.75 (br. s, 1H), 7.22 (br. s, 1H), 7.29 (br. s, 1H), 7.50 (t, 3J = 7.8 Hz, 2H), 7.55–7.62 (m, 2H), 7.68 (t, 3J = 7.5 Hz, 2H), 7.96–8.04 (m, 2H), 8.19 (br. d, J = 8.0 Hz, 1H), 8.39 (d, 3J = 7.3 Hz, 1H), 8.56 (br. s, 1H). 13C NMR (100 MHz, DMSO-d6, several conformers): δ 163.7, 162.9, 154.9, 154.5, 150.4, 147.8, 134.4, 134.1, 133.8, 133.6, 130.6, 129.4, 128.2, 128.1, 127.8, 127.6, 124.9, 124.6, 124.3, 121.9, 120.0, 107.7, 103.8, 79.4, 79.0, 52.2, 48.4, 47.9, 45.9, 41.3, 40.7, 21.0, 11.4. HRMS (ESI) m/z: [M + H]+ Calcd for C45H56N7O10 854.4084; Found 854.4060. Compound 7 Compound 10 (0.85 g, 1 mmol) was dissolved in EtOH (80 mL). To that mixture Pd/C was added by small portions under stirring. The reaction was carried out at r. t. in hydrogen atmosphere (5 atm) with stirring. After 7 h the catalyst was filtered off, and the solvent was evaporated. The residue was purified by silica gel column chromatography (CH2Cl2–MeOH 100:2). The product was obtained as a gold-colored powder (0.75 g, yield 95%). Mp 112–114 °C (CH2Cl2). 1H NMR (400 MHz, DMSO-d6): δ 0.90 (t, 3J = 7.4 Hz, 12 ACS Paragon Plus Environment

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3H), 1.35 (br. s, 18H), 1.57–1.67 (m, 2H), 2.66–2.74 (m, 2H), 3.06 (br. s, 4H), 3.96–3.99 (m, 2H), 4.22 (br. s, 4H), 4.87–5.14 (m, 4H), 6.37–6.50 (m, 2H), 6.60 (br. d, J = 7.5 Hz, 2H), 6.69–6.76 (m, 1H), 6.84 (br. s, 2H), 6.94 (td, J = 7.8 Hz, J = 7.8 Hz, J = 1.1 Hz), 7.56 (t, J = 5.1 Hz, 1H), 7.66 (t, J = 7.8 Hz, 1H), 8.26 (d, 3J = 8.5 Hz, 1H), 8.43 (d, 3J = 7.2 Hz, 1H), 8.55–8.62 (m, 1H). 13C NMR (100 MHz, DMSO-d6, several conformers): δ 163.8, 163.0, 155.3, 150.4, 150.0, 146.6, 134.2, 130.7, 130.0, 129.6, 129.4, 128.4, 127.8, 124.4, 121.9, 120.1, 119.9, 115.9, 115.5, 114.6, 107.8, 103.9, 79.2, 52.1, 51.7, 47.2, 44.1, 41.2, 40.8, 28.0, 21.0, 11.4. HRMS (ESI) m/z: [M + H]+ Calcd for C45H60N7O6 794.4600; Found 794.4539. Receptor 1 The solution of pyridine-2,6-dicarbonyl dichloride (0.026 g, 0.126 mmol) in 20 mL of dry CH2Cl2 was added dropwise to the mixture of compound 7 (0.100 g, 0.126 mmol) and N,N-diisopropylethylamine (0.036 g, 0.277mmol) in 50 mL of dry CH2Cl2 over 0.5 h at r. t. The reaction mixture was stirred 48 h at r. t. After that 100 ml of water were added, organic layer was collected, and volatiles were evaporated. The product was obtained by silica gel column chromatography (CH2Cl2–MeOH 100:1) as yellow powder (0.093 g, 80%). The obtained product (0.070 g, 0.076 mmol) was dissolved in of 4 mL of 1,4-dioxane. Next, concentrated hydrochloric acid (0.224 g, 2.27 mmol) was added dropwise and the resulting solution stirred for 24 h. The solvent was evaporated and dried in high vacuum at 40 °C for 4 h to give the product as a yellow powder with quantitative yield. Mp 225—227 °C (1,4-dioxane). 1H NMR (400 MHz, DMSO-d6): δ 0.90 (t, 3J = 7.4 Hz, 3H), 1.57–1.67 (m, 2H), 3.04 (br. s, 2H), 3.65 (br. s, 2H), 3.86 (br. s, 8H), 3.96–3.99 (m, 2H), 4.27 (br. s, 4H), 6.80 (d, 3J = 8.2 Hz, 1H), 7.40 (t, 3J = 7.3 Hz, 2H), 7.44–7.52 (m, 4H), 7.63 (t, J = 7.8 Hz, 1H), 7.73 (d, 3J = 7.4 Hz, 2H), 7.88 (br. s, 1H), 8.19 (d, 3J = 8.4 Hz, 1H), 8.30 (t, J = 7.5 Hz, J = 7.8 Hz, 1H), 8.39–8.42 (m, 3H), 8.73 (d, 3J = 8.1 Hz, 1H), 9.65 (br. s, 4H), 11.37 (s, 2H). 13C NMR (100 MHz, DMSO-d6): δ 163.7, 163.0, 162.9, 150.3, 148.6, 139.8, 136.8, 134.2, 131.8, 130.7, 129.8, 129.7, 129.3, 128.8, 128.2, 127.1, 125.6, 124.4, 121.8, 120.2, 103.9, 62.8, 45.8, 40.7, 21.0, 11.4. HRMS (ESI) m/z: [M + H]+ Calcd for C42H45N8O4 725.3559; Found 725.3580. Receptor 2 Diamine 6 (0.15 g, 0.214 mmol) and pyridine-2,6-diylbis((2-thioxothiazolidin-3-yl)methanone) (0.079 g, 0.214 mmol) were mixed in 40 mL of CHCl3 in the presence of tetrabutylammonium chloride (0.297 g, 1.068 mmol) as a template. The reaction mixture was stirred for 12 h at r. t. After complete conversion of starting materials the solvent was removed and the crude product was used for next step (0.060 g, 34%, light yellowish solid). The crude compound (0.060 g, 0.072 mmol) was dissolved in 3 mL of CHCl3 and to this 3 mL of Et2O/HCl solution were added dropwise. Then the reaction mixture was stirred overnight at r. t. Solid was filtered, washed with ether (2x5 mL) and dried. Yellow color solid was obtained (0.040 g, 88%). Mp 186–188 °C (Et2O). 1H NMR (400 MHz, CD3OD): δ 0.98 (t, 3J = 7.4 Hz, 3H), 1.68–1.75 (m, 2H), 1.58 (quint, 3J = 6.3 Hz, 4H), 3.16–3.30 (m, 10H), 3.34–3.41 (m, 4H), 3.62–3.65 (m, 4H), 3.79–3.85 (m, 2H), 4.06–4.09 (m, 2H), ), 6.90 (d, 3J = 8.6 Hz, 1H), 7.65 (dd, 3J = 7.4 Hz, 3J = 7.5 Hz, 1H), 8.15 (dd, 3J = 7.5 Hz, 3J = 7.5 Hz, 1H), 8.28 (d, 3J = 7.7 Hz, 2H), 8.38 (d, 3J = 8.5 Hz, 1H), 8.49 (dd, 3J = 7.3 Hz, 4J = 0.9 Hz, 1H), 8.75 (dd, 3J = 8.4 Hz, 4J = 0.9 Hz, 1H). 13C NMR (100 MHz, DMSO-d6): δ 163.7, 163.03, 162.95, 150.1, 148.6, 139.6, 134.1, 130.8, 129.4, 129.0, 124.5, 124.2, 121.8, 120.4, 108.4, 104.2, 52.3, 45.4, 44.1, 40.8, 35.2, 24.8, 21.0, 11.4. HRMS (ESI) m/z: [M + H]+ Calcd for C34H45N8O4 629.3559; Found 629.3572. Receptor 3 Acid dichloride of the dipyrrolylmethane diacid was prepared as follows: the dipyrrolylmethane diacid (0.20 g, 0.63 mmol) in Schlenk flask was dissolved in 10 mL of freshly distilled dry CH2Cl2 under nitrogen and cooled with ice (0 °C). After that, oxalyl chloride (0.54 mL, 10 equiv) and dimethylformamide (0.05 13 ACS Paragon Plus Environment


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mL) were added. The mixture was stirred under nitrogen 1 h at 0 °C, and additionally 3 h at r. t. Next, the solvents were evaporated at low pressure at elevated temperature (40–45 °C). Finally, freshly distilled dry THF (10 mL) was added. In a separate Schlenk flask under nitrogen the diamine (0.100 g, 0.130 mmol) was dissolved in 160 mL of freshly distilled dry THF. Next, freshly distilled pyridine (1 mL) and the solution of the diacid dichloride in THF (2.4 mL) were added over 20 min. The mixture was stirred overnight at r. t. Conversion was controlled by TLC (CHCl3–MeOH 100:5). When no starting material was observed, the solvent was evaporated. Purification was performed by column chromatography (CHCl3– acetonitrile 100:3). For deprotection, the product (0.070 g, 0.065 mmol) was partially dissolved in 5 mL of CHCl3, and 5 ml of HCl–Et2O mixture were added. At first, the reaction mixture became clear, but after 2–3 h a precipitate was formed. It was filtered, washed with ether and dried. Yellow powder, yield 38%. Mp 214–216 °C (CHCl3). 1H NMR (400 MHz, DMSO-d6): δ 0.90 (t, 3J = 7.4 Hz, 9H), 1.07–1.17 (m, 4H), 1.58–1.67 (m, 2H), 2.19 (br. s, 4H), 3.82 (br. s, 12H), 3.96–4.00 (m, 2H), 4.07 (br. s, 4H), 6.00–6.04 (m, 2H), 6.92 (d, 3J = 8.0 Hz, 1H), 6.98–7.01 (m, 2H), 7.28–7.37(m, 4H), 7.44 (td, 3J = 7.7 Hz, 3J = 7.7 Hz 4J = 1.2 Hz, 2H), 7.65 (t,3J = 7.8 Hz, 1H), 7.75 (d, 3J = 7.7 Hz, 2H), 8.02 (br. s, 1H), 8.29 (d, 3J = 8.5 Hz, 1H), 8.44 (d, 3 J = 7.2 Hz, 1H), 8.87 (d, 3J = 8.4 Hz, 1H), 9.48 (br. s, 4H), 10.10 (s, 2H), 11.24 (s, 2H). 13C{1H} NMR (100 MHz, DMSO-d6): δ. 164.2, 163.4, 160.5, 150.6, 143.0, 137.0, 134.6, 131.4, 131.2, 130.0, 129.8, 129.6, 128.4, 127.7, 126.7, 125.1, 124.9, 122.3, 120.8, 113.4, 106.8, 104.7, 49.4, 47.2, 42.4, 41.2, 36.1, 21.4, 17.1, 14.8, 11.8. HRMS (ESI) m/z: [M + H]+ Calcd for C52H62N9O4 876.4920; Found 876.4929. Computational methods Molecular modeling calculations were performed using the DFT program “PRIRODA”.1 A PBE functional which includes electron density gradient was used. TZ2p-atomic basis sets of grouped Gaussian functions were used to solve the Kohn—Sham equations. The criterion for convergence was a difference below 0.01 kcal/mol/Angstrom in the energy between two sequential structures. The host-guest model structures were generated by combining a preoptimized structure of the receptor with the anion, followed by simultaneous optimization of the proposed structures. Searches for the relevant global minima were performed by calculating different anion-to-receptor coordination modes. Various stationary points on potential energy surface (PES) were determined from analytical calculations of second energy derivatives (Hessian matrixes). Acknowledgement We thank Deutsche Forschungsgemeinschaft (DFG grant 3444/7-1 and 3444/12-1 for E.A.K.) Russian Foundation for Basic Research (RFBR grant 16-53-12042 for O.A.F.), DAAD scholarship for A. S. O. and RUDN University Program “5-100” for V. N. K. for financial support. Supporting Information Electronic supplementary information (ESI) available: computational data, NMR data, titration data and analysis, fluorescence spectra and potentiometric data. Crystallographic data for compound [1H22+Cl-]Cl·H2O].

References

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