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Chloride capture using a C–H hydrogen-bonding cage

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Science  12 Jul 2019:
Vol. 365, Issue 6449, pp. 159-161
DOI: 10.1126/science.aaw5145

A C–H bonding trap for chloride

Part of the reason salt dissolves so well in water is that the polarized O–H bonds attract the negatively charged chloride ions. It has therefore been common to include O–H or N–H bonds in molecular receptors designed to capture anions such as chloride. Liu et al. report the surprising finding that sufficiently polarized C–H bonds can work even better (see the Perspective by Bowman-James). They designed a cage with triazole rings that directed C–H bonds inward to encapsulate chloride with a remarkable attomolar affinity in dichloromethane.

Science, this issue p. 159; see also p. 124

Abstract

Tight binding and high selectivity are hallmarks of biomolecular recognition. Achieving these behaviors with synthetic receptors has usually been associated with OH and NH hydrogen bonding. Contrary to this conventional wisdom, we designed a chloride-selective receptor in the form of a cryptand-like cage using only CH hydrogen bonding. Crystallography showed chloride stabilized by six short 2.7-angstrom hydrogen bonds originating from the cage’s six 1,2,3-triazoles. Attomolar affinity (1017 M–1) was determined using liquid-liquid extractions of chloride from water into nonpolar dichloromethane solvents. Controls verified the additional role of triazoles in rigidifying the three-dimensional structure to effect recognition affinity and selectivity: Cl > Br > NO3 > I. This cage shows anti-Hofmeister salt extraction and corrosion inhibition.

Hydrogen bonding is an essential noncovalent interaction used in the design of synthetic receptors for selective molecular recognition. Hydroxyl (OH) and amino (NH) groups are commonly used for this purpose, and they are widely represented in biomolecular and chemical recognition. A recent reclassification of hydrogen bonding by the International Union for Pure and Applied Chemistry (1), however, assigns hydrogen bond donors more broadly by using differences in Pauling electronegativities (Δχ). OH and NH donors have high differences (Δχ = 1.24 and 0.84, respectively), whereas even a CH group with a difference of 0.35 should support hydrogen bonding. Consistently, increasing examples of receptors relying on CH hydrogen bonding have emerged (27) to expand the toolkit available for receptor design. Nonetheless, CH hydrogen bonds are usually relegated to the role of secondary contacts during the conception of receptors designed for high-affinity recognition. We challenge this conventional wisdom by designing a CH hydrogen-bonding cage (Fig. 1) that displays high affinity and selective binding of chloride ions.

Fig. 1 Synthesis and structure of the chloride-binding cage.

(A) One-pot synthesis of triazolo cage 1. NaAsc, sodium ascorbate; TBTA, tris[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine. (B) Crystal structure of cage 1⋅NaCl. (C) Chemical structure of 2D triazolophane macrocycle 2.

Interest in chloride has risen with intensive and extensive water usage increasing the salinity of terrestrial waters. Such lowered water quality is anticipated to have negative impacts across a range of industries including the food, energy, and water sectors (8). Therefore, the creation of high-affinity synthetic receptors for Cl has the potential to inspire new strategies for effective management of chloride salts, such as in the extraction of ions from water (9).

Synthetic receptors capable of ion extraction need affinities high enough to overcome the associated hydration energies, which are substantially larger for anions than for cations. The transfer of Cl from water (ε = 80) to 1,2-dichloroethane (DCE; ε = 10.4), a typical solvent used in liquid-liquid extraction (9), costs +52 kJ mol–1, whereas the Na+ cation can be transferred at a cost of just +25 kJ mol–1 (10). The high free energy of Cl transfer demands that a synthetic receptor has an affinity constant exceeding 1 billion (ΔG of +52 kJ mol–1Ka ~109 M–1). Furthermore, the larger size of Cl (diameter = 3.8 Å) relative to Na+ (2.3 Å) necessitates a larger binding cavity, which in turn lowers charge density and therefore affinity. Only a handful of receptors display affinities exceeding the free-energy penalty of transferring Cl from water to typical nonpolar extraction solvents: Sindelar’s fluorinated bambus[6]uril (1010 M–1) measured in acetonitrile (7), Maeda’s pyrrole macrocycle (1010 M–1) measured in dichloromethane (CH2Cl2) (11), as well as Davis’s steroidal tris-thiourea (1011 M–1) (12) and steroidal squaramide (1014 M–1) (13) measured in wet chloroform. Surprisingly, these affinities are achieved using charge-neutral receptors, which circumvent the pH sensitivity typical of ionizable receptors and avoid the introduction of additional anions stemming from the ion exchange when using charged receptors (9).

High size selectivity is needed to enable selective extraction of smaller anions such as Cl over larger anions such as iodide, I. Large anions are less hydrated and are easier to remove using liquid-liquid extractions according to the Hofmeister bias (14). One approach to size selectivity is to use cryptands (15). These receptors have a three-dimensional (3D) binding pocket and have demonstrated improvements in size-selective cation binding: When the 2D pocket of a crown ether is converted into a 3D pocket in a cryptand, the selectivity toward the size-matched K+ over the larger Cs+ cation increases from a factor of 10 to a factor of 2500 (16). This design principle has been used in NH hydrogen-bonding anion receptors including Lehn’s cationic aza-cryptands (17), Sessler’s neutral pyrrolo cryptands (18), and Bowman-James’s polyamide cryptands, which are selective for fluoride (19) and have been used by Cummins and Nocera to stabilize peroxide (20).

We have pioneered the use of nontraditional CH donors originating from 1,2,3-triazoles in planar triazolophane macrocycles (Fig. 1C) (3). They display an alternating sequence of aryl and triazole units to define a size-selective cavity for Cl and stabilization by CH⋅⋅⋅Cl hydrogen bonds. The triazoles’ CH donors are polarized (3) by the cluster of three electronegative nitrogen atoms. The Cl affinity of triazolophane macrocycles is –38 kJ mol–1 in dichloromethane (21). Although this affinity is relatively high, it is still insufficient to overcome the water-DCE phase-transfer free energy of chloride.

We designed a cryptand-like triazolo cage 1 (Fig. 1A) bearing only CH donors. The cavity size is identical to Bowman-James’s NH hydrogen-bonding cryptand (19) but with triazoles in the place of amides. This replacement increases rigidity (fig. S3) by restricting rotation about two bonds instead of just one bond in amides. Overall, we hypothesized that the affinity and selectivity shown by the rigidly preorganized aryl-triazole macrocycles (3) would be enhanced further by the cryptand effect (22). Our results agree with these ideas, but the performance surpassed expectations: An attomolar (1017 M–1) affinity was found in dichloromethane (ε = 8.9), whereas a nanomolar affinity (108 M–1) was found in the more polar dimethylsulfoxide (DMSO, ε = 46.8). This decreased affinity with an increased dielectric constant is consistent with our previous finding on the 1/ε solvent dependence of rigid triazolophanes (21).

Triazolo cage 1 was designed such that each opening retained the same 24-membered chelation site (Fig. 1B) as the 2D triazolophane macrocycle (Fig. 1C). A one-pot synthesis (15% yield) was achieved using copper(I)-catalyzed alkyne-azide cycloaddition (23) to combine a 2:3 stoichiometric mixture of the commercially available C3-symmetric building block tripropargylamine and the readily prepared C2-symmetric bisazide (24). A crystal structure of the cage verified its geometry (Fig. 1B and fig. S27). The Cl is stabilized by six short CH⋅⋅⋅Cl hydrogen bonds from the triazoles (dH⋅⋅⋅Cl = 2.7 Å) and three from the phenylenes (dH⋅⋅⋅Cl = 2.9 Å), all below the 3.0 Å van der Waals contact distance.

The 1⋅NaCl complex was consistently obtained after column chromatography, providing an early hint of the high Cl affinity. The NaCl was not intentionally added and was thought to have been scavenged (11, 25) from the silica used in the chromatographic purification of the cage. Most of the salt could be removed after six extractions with deionized water (fig. S4). By contrast, the 2D triazolophanes completely released chloride with just two extractions. Use of nitromethane (ε = 35.9) as a more polar solvent to weaken ion binding (21) offered no improvement (26). Precipitation of AgCl by addition of AgNO3 was too rapid and led to irreversible loss of the cage (fig. S5). All subsequent experiments were performed on a 90 mol % salt-free batch of the cage.

Affinities were initially determined in DMSO (24). The high dielectric constant helps weaken binding (21) relative to less polar media, thereby allowing quantitative determination of affinity by nuclear magnetic resonance (NMR) spectroscopy. Addition of Cl as the tetra-n-butylammonium (TBA+) salt to 1 in DMSO led to large downfield shifts of triazole (Ha, 1.6 ppm) and phenylene (Hb, 0.8 ppm) resonances in the 1H NMR spectra, indicating strong CH hydrogen bonding. Despite use of the polar solvent to weaken binding, the high affinity precludes direct measurement of the Cl affinity.

Competition titrations were used to sequentially measure anion affinities. The cage’s NO3 affinity was measured (~104 M–1; fig. S6) by direct titration and then fitting the shifts of CH donor proton peaks to a 1:1 binding isotherm (fig. S7). The Br affinity (~105 M–1; fig. S8) was quantified using a competition titration of complex 1⋅NO3 with Br. The equilibrium constant for the conversion of 1⋅NO3 to 1⋅Br was determined from relative peak integrations (table S3). Finally, the nanomolar affinity of Cl (~108 M–1; Fig. 2A and fig. S9) was determined using the same method by monitoring conversion from 1⋅Br to 1⋅Cl (table S4). This chloride affinity exceeds that of the 2D triazolophane (Fig. 2B) and Bowman-James’s polyamide cryptand (19) by four orders of magnitude. Slow anion exchange on the NMR time scale matches the behavior seen for cryptands binding to alkali cations (22), which suggests that substantial structural reorganization of the cage is needed to engage or release anions.

Fig. 2 Quantifying and understanding chloride affinity and selectivity.

(A) 1H NMR spectra of cage 1 upon titration with Br and then by competitive exchange with Cl ([1]0 = 0.5 mM, 298 K, 500 MHz, DMSO-d6). Peaks associated with free triazolo cage 1 are colored in red, 1⋅Br in magenta, and 1⋅Cl in blue. (B) Anion affinities (K1) determined in DMSO-d6 for Cl, Br, NO3, and I as TBA+ salts. Colored lines are drawn to guide the eye. Errors were determined by root-mean-square deviations from the nonlinear fitting (peak shifts) or by averaging multiple data points (peak integral ratios). See figs. S6 to S24 for more details. (C) Chemical structure of 3D flexible receptor 3.

The superior affinity suggested that the cage would display elevated selectivities. Cl was favored over the larger iodide, I, by a factor of 1 million in DMSO (Fig. 2B). The 2D triazolophane macrocycle showed only a factor of 500 difference between Cl and I. We synthesized a second receptor as a control, triazolo tripod 3 (Fig. 2C). The cavity of 3 has the same spatial arrangement of CH donors as the cage but with more flexibility, and it only displayed a selectivity factor of 10. Thus, both higher dimensionality and rigidity contribute to the cage’s selectivity. Weaker solvation of the cage’s cavity is also expected to lower the cost of its desolvation to enhance complexation (27).

We investigated the liquid-liquid extraction of Cl of various salts (24). On the basis of the 1/ε solvent dependence of Cl binding seen with the 2D triazolophane (21), we estimated that the affinity in dichloromethane would increase and would far exceed the cost of aqueous extraction. Extractions conducted at 1 mM on small scales (2 ml) were quantified by 1H NMR spectroscopy, and the results were verified using ionic conductivity measurements on larger scales (80 ml). Extraction of Cl was first tested using the tetraethylammonium (TEA+) salt. This cation contributes a minor penalty to extraction (+8.4 kJ mol–1) (28). Without the cage, extraction of the TEACl salt from aqueous solution into dichloromethane was minimal (~2%), whereas with the cage present it was quantitative (Fig. 3A and figs. S29 and S32). The cage overcomes the accumulated phase-transfer penalty of the TEACl salt of +60 kJ mol–1. When we changed to the more lipophilic TBA+ cation to favor extraction by –13 kJ mol–1 (28), we saw complete removal and complexation of various anions, including bromide, iodide, nitrite, and nitrate (Fig. 3A and fig. S29).

Fig. 3 Use of the cage for extraction of salts and as an anticorrosion agent.

(A) Extraction efficiencies for salts as ammonium cations (black) and when assisted by triazolo cage 1 (red). [1]0 = 0.2 mM, [X]0 = 0.24 mM. See figs. S28 and S29. Extraction efficiency is defined as the amount of salts extracted relative to the total salts (direct extractions) or total cage (limiting reagent in the assisted extractions). (B) Extraction efficiencies for salts as alkali cations (black) and when assisted by the cage 1 (red). [1]0 = 0.1 mM, [X]0 = 0.5 mM. See fig. S30. (C) A thin film of the triazolo cage can protect mild steel from corrosion in brine solution (5.6 M NaCl).

The high anion affinity of the cage also facilitated the more difficult task of extracting alkali metal salts (Fig. 3B) from water into dichloromethane. The difficulty stems from the transfer free energy of Na+ (+25 kJ mol–1) being higher than that of TEA+ by a factor of 3 (27). To our satisfaction, extraction efficiency using the cage was highest for NaCl (18%), which was enhanced over solvent alone by a factor of at least 108. Extraction efficiencies correlated with the cage’s binding selectivity, where Br extraction efficiency was 8%, and there was no observable extraction of NaI (Fig. 3B and fig. S31). The latter manifested despite iodide’s substantially smaller phase-transfer penalty (+21 kJ mol–1). The extraction using the triazolo cage thus displays anti-Hofmeister selectivity, reversing the normal trends dictated by anion size (8, 14).

The Na+ salt showed higher extraction efficiency than other alkali cations (K+, Cs+). Presumably, Na+ forms ion pairs with complex 1⋅Cl. The 1H NMR signals of 1⋅NaCl (fig. S33) were used to determine the diffusion coefficient before and after NaCl complexation and showed minimal change (fig. S34), confirming that 1⋅NaCl is nonaggregated. The addition of 1 equivalent of 18-crown-6 (18-C-6) helped overcome the last portion of the penalty of coextraction of Na+ (fig. S32) to effect quantitative extraction of salt from water for NaCl at a concentration as low as 5 μM. The low concentration shifts ion partitioning toward the aqueous phase (29), allowing us to explore the limit of this dual-host strategy (9).

The measured equilibrium constant (KWO = 108.5 M–1) for extraction of TEACl from water to the organic phase (fig. S38) was used to evaluate the Cl affinity (K1) in dichloromethane at 1 μM. Extraction can be described as overcoming the penalty of transferring the cation and anion (Kt+Kt = 10–8.5) from water to dichloromethane by forming 1⋅Cl complexes (K1). Ion-pairing (Kipc = 104.6 M–1) between the TEA+ counter cation and 1⋅Cl is negligible at 1 μM in dichloromethane. The following equation relates the observables to the Cl affinity (K1):Kwo=[CageCl]o[TEA+]o[Cage]o[Cl]w[TEA+]w=K1Kt+Kt(1)Using this equation, the cage’s Cl affinity (K1) was estimated to be attomolar (1017 M–1) in wet CH2Cl2. This high affinity explains the challenges encountered when trying to remove Cl from the cage and the facile extraction of NaCl from its surroundings.

We next investigated whether the high-affinity sequestration of Cl could confer anticorrosion properties. Cl is classified as an aggressive ion that enhances the corrosion of iron by promoting pitting (30). Consequently, we hypothesized that cage 1 would be able to inhibit corrosion by making Cl inaccessible. This concept has been explored previously using layered double hydroxide coatings (31). We deposited a small patch (~1 cm2) of the cage (20 mg) on a test sample of mild steel (0.1% carbon). The sample was submerged in saturated brine (5.6 M) for 2 weeks. The smooth film of the cage, which had formed upon solvent-vapor annealing, remained adhered and was found by visual inspection to inhibit the corrosion seen in the uncoated steel (Fig. 3C).

The modularity of the cage lends itself to further customization and incorporation into technologies for selective Cl extraction as well as protection of materials interfaced with water that carries dissolved Cl.

Supplementary Materials

science.sciencemag.org/content/365/6449/159/suppl/DC1

Materials and Methods

Supplementary Text

Tables S1 to S8

Figs. S1 to S39

References (3245)

References and Notes

  1. See supplementary materials.
  2. We also refuted the hypothesis that the incomplete removal of salt from the cage resulted from the exchange of complexed Cl with OH ions from the aqueous washing layer (fig. S6).
Acknowledgments: Y.L. thanks J. Fu for the inspirational discussion that led to the conception of this project. Funding: Supported by the Chemical Sciences, Geosciences and Biosciences Division, Office of Basic Energy Sciences, Office of Science, U.S. Department of Energy (DE-FG02-09ER16068). A.H.F. was supported by a Waterman Professorship. Author contributions: Y.L. conceived the project under the supervision of A.H.F.; Y.L. conducted experiments with assistance from W.Z.; W.Z. duplicated attomolar affinity determination and NaCl extraction experiments; C.-H.C. performed x-ray single crystal structural analysis; Y.L. and A.H.F. analyzed the data and wrote the manuscript with input from all coauthors. Competing interests: Indiana University has filed a patent application (PCT/US62/675572) on the work described for inventors A.H.F., Y.L., and W.Z. Data and materials availability: Crystallographic data are available free of charge from the Cambridge Crystallographic Data Centre under reference CCDC No. 1533500. All other data supporting the findings of this study are available in the manuscript or supplementary materials.
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