A conformationally switchable fluorescent oligophenol foldamer for selective sensing of copper(II) ions

Abstract

A stimuli-responsive hexameric oligophenol host undergoes metal ion-induced co-operative folding from a more fluorescent, more linear structure into less fluorescent, more curved states, enabling easy classification of the bound metal ion guests as well as selective sensing of Cu²⁺ ions.

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Helically or circularly folded aromatic foldamers have continuously attracted considerable interest over the past two decades since the pioneering work using multiple-center H-bonding systems to direct the intramolecular folding of aromatic pyridine-based backbones by Hamilton and co-workers in 1994.¹ Concurrent with the elaboration of their wide-ranging structures, these H-bonded aromatic foldamers² have been demonstrated to perform highly variable functions including reaction catalysis,^3a controllable molecular motion,^3b reactive sieving,^3c–f solvent gelating,^3g,h ion transportation,³ⁱ stabilization of G-quadruplex structures,^3j and selective recognition of both ionic⁴ and neutral⁵ species (e.g., amines,^4i–k water,^5a–c methanol/dichloromethane,^5d,e saccharides,^5f tartaric acid,^5g etc.). Nevertheless, the hitherto developed diverse classes of H-bonded aromatic foldamers mostly lack the structure-switching ability, and so perform their pre-designed functions without significant conformational changes in their molecular backbones. In other words, H-bonded aromatic backbones containing switchable units have been studied comparatively much less,^4e,j,k and no study on the use of metal ions to trigger the conformational change of these H-bonded aromatic foldamers for selectively sensing certain metal ions has been reported. The H-bonded foldamer molecules endowed with “switchable” functions are undoubtedly of great interest in the creation of advanced adaptive bio- and nanomaterials and molecular sensing devices for such as environmental monitoring of toxic molecular species including metal ions. In this communication, we report our very first step toward developing specific sensing of metal ions using a carefully designed and optimized fluorescent folding molecule derived from phenol unit 1a, which can undergo dynamic folding/unfolding processes in response to the external stimuli such as pH and amines,^4j,k,6 and methoxybenzene unit 2 for fine-tuning the curvature of the folding backbone (Fig. 1a).

Fig. 1 (a) Conformational switching between phenol-based amides 1 and 2 can be efficiently induced by primary amines^4j,k or by deprotonation/protonation⁶ of the hydroxyl group; whether or not metal ions can induce the similar conformational switching is the focus of the current work. (b) Structure of a hexameric oligophenol foldamer 3 containing four deprotonable OH groups and its representative anionic oligomers such as 3_a and 3_ab obtained by selectively deprotonating some hydroxyl groups in 3 at positions a–d; for instance, anionic 3_ab refers to the anionic oligomer where the two hydroxyl groups at positions a and b were deprotonated. Do note that mono-anionic oligomers such as 3_a are moderately fluorescent, and di-, tri- or tetra-anionic oligomers are virtually non-fluorescent.^4j,k

As demonstrated recently by us^4j,k and others,⁶ neutral phenol unit 1a makes the phenol-based oligomeric backbone more linear and possibly more planar while both phenolate unit 1b and methoxybenzene unit 2 result in a more curved or even helically folded conformation if the molecular backbone contains five or more repeating units 1b or 2.^4j,k,6,7 Depending on the location and number of units 1a containing an OH group and 2 containing an OMe group, the hybrid foldamer molecules composed of units 1a and 2 in various ratios can thus differ dramatically in their backbone curvature.^4j,k Moreover, these neutral oligophenol molecules as represented by 3 display very interesting conformation-dependent fluorescent properties roughly in line with the relative linearity of the hexameric backbones.^4j The corresponding anionic versions such as 3_a generated from 3 by deprotonating the OH group at position a (Fig. 1b) were also demonstrated to follow the same curvature-dependant fluorescent properties.^4j Therefore, the fluorescent ability decreases in the order of strongly fluorescent linear 3 > moderately fluorescent less linear mono-anionic 3_a, 3_b and 3_c > virtually non-fluorescent more crescent-shaped di-, tri- and tetra-anionic 3_ab, 3_abc, 3_abcd, etc. Since the phenolic OH groups at positions a–d are sensitive to the basicity of the solutions, amines of different types cause the four OH groups to deprotonate in a defined sequence but to varying degrees, leading to a four-step sequential folding of 3 from a more fluorescent linear structure into an essentially non-fluorescent helically folded tetra-anionic state via mono-anionic 3_b, di-anionic 3_bc and tri-anionic 3_abc. Experimentally, it was observed that non-branched primary amines and cyclic secondary amines produce crescent-shaped anionic oligomers to the largest extent, followed by branched primary amines and acyclic secondary amines with both tertiary amines and ammonium ions to the least, making possible the patterned recognition of varying amines and ammonium ions by oligophenol 3.^4j,k

Encouraged by the amine-mediated conformational switching of 3 and the corresponding patterned recognition of amines and ammonium ions by 3, we further envisioned that 3 containing deprotonable phenolic OH groups possibly could be sensitive to the basic metal ions capable of removing the phenolic hydroxyl protons, subsequently forming strong coordination bonds with and stabilizing the resultant phenolate O-atoms. Under this hypothetical scenario, metal ions might be able to induce the folding of linear 3 into crescent-shaped or helically folded anionic oligomers with lessened fluorescence ability (Fig. 1b) to differential extents, possibly allowing an ease detection or classification of metal ions via changes in fluorescence intensity of 3. A selective detection of trace amount of certain metal ions against a background of other competing ions is highly preferred and of great interests given that the heavy metal pollutions are now a worldwide problem that will continue to grow in the future.

To test this hypothesis, a series of titration experiments using 22 metal ions were carried out. In the typical experimental set-up, metal ions were dissolved in water to prepare a stock concentration of 10 mM, followed by addition of 2 μL of the aqueous solution into 1 mL of 3 in THF containing 1% DMSO at 10 μM at room temperature. The resultant solution contains a 3–metal ion molar ratio of 1 : 2, and the corresponding fluorescence spectra/data were obtained with an excitation wavelength at 351 nm. Following this procedure, treatment of 3 with various metal ions indeed gave rise to differential changes in fluorescence intensity of 3 that mostly depend on the nature of the metal ions rather than the charge-neutralizing anionic parts (Fig. 2) or fluorescence-quenching ability of the metal ions.⁸

Fig. 2 Patterned fluorescence quenching of 3 by two equivalents of metal ions of various types. The fluorescence spectra/data were obtained at 10 μM of 3 in THF containing 1% DMSO at room temperature with an excitation wavelength at 351 nm. The values above the columns are the hydrolysis constants (pK_a's) of the respective metal ions.^9a,b The fluorescence intensity of 3 was quenched to the highest extents of 90.1% and 86.6% by Cu(Ac)₂ and CuCl₂, respectively, while Li⁺, Na⁺ and K⁺ ions do not elicit any measurable quenching of 3 within the detection limit of the instrument.

A few points can be noted in terms of correlation between the hydrolysis constant (pK_a)^9a,b of metal ions and fluorescence quenching of 3 by the metal ions: (1) mono- and divalent metal ions with a pK_a value of 8 or larger generally effect a marginal quenching of 18% in the best scenario by Pb(NO₃)₂, (2) divalent metal ions such as Hg²⁺ with a much lower pK_a or trivalent ions such as La³⁺ with a pK_a as high as 8.5 still can produce significant quenching of about 50%, and (3) trivalent metal ions with lower pK_a values quench the fluorescence intensity of 3 by as much as 69% in the case of VCl₃. Similar to the hydrolytic reactions the hydrated metal ions may undergo in aqueous solution, these data strongly suggest that, in the presence of 3 containing deprotonable phenolic OH groups, metal ions might react preferentially with the more reactive phenolic OH groups with a pK_a value of around 10, rather than with the water molecules with a pK_a value of 15.7.^9c Such deprotonation reactions produce phenolate anions that can be further stabilized by metal ions via the formation of coordination bonds, cooperatively enhancing the deprotonation extent of the phenolic OH groups and concurrently inducing very fluorescent linear 3 into its moderately or weakly fluorescent anionic structures of varying types by switching from H-bonding pattern in 1a to that in 1b (Fig. 1a).

Since the hydrolysis constant of the metal ions, pK_a, is a parameter that has taken into consideration of metal ions' ionic radius and valence state, and the stability of metal hydroxide complexes, the fact that the quenching extent by various metal ions does not strictly follow their relative magnitude in pK_a value suggests the ability of the metal ions to stabilize the phenolate anions via the formation of coordination bonds to be another key factor that determines the extent of conformational folding of the linear host into more curved weakly fluorescent anionic structure. Accordingly, the extent of metal ion-induced deprotonation and subsequent conformational switching of 3 is dependent on not only the hydrolysis constant of the metal ions but also the strength of metal–ligand coordination bonds that can more than compensate for the dehydration energy associated with the loss of a few water molecules around metal ions upon their binding to phenolate O-atoms. On these premises, even with similar pK_a values, La³⁺ ions are possibly more able to stabilize the crescent-shaped anionic oligomers, subsequently induce linear 3 into curved anionic structures to higher extents and elicit more significant fluorescence quenching than metal ions such as Pb²⁺ and Zn²⁺. On the same grounds, the highest quenching of about 90% by Cu²⁺ ions can be explained on the basis of its expected highest ability to stabilize the phenolate-based anionic oligomers of certain structures, rather than its hydrolysis constant of as larger as 8.3.

Previously, by titrating 3 stepwise using strong organic base, tetrabutylammonium hydroxide, we have demonstrated that the fluorescence intensity of mono-anionic oligomer is about 40% of that of neutral 3, and di-/tri-/tetra-anionic oligomers are essentially non-fluorescent.^4j The fluorescence quenching of as high as 91% by two equivalents of Cu(Ac)₂ points to a high likelihood of Cu²⁺-assisted generation of di-anionic oligomers such as 3_ab and 3_bc as the predominant anionic forms^10a with co-existence of neutral 3 and its other mono-/di-/tri-/tetra-anionic oligomers in minor forms in solution.^10b In di-anionic 3_ab or 3_bc, a cavity of about 1.5 Å in radius excluding the atomic volume of O-atoms is clearly present that is formed by four O-atoms among which two are from the two immediately adjacent phenolate anions (Fig. 1b). Highly likely, it is the excellent ability of the Cu²⁺ ions to fit into the cavity that leads to surprisingly high quenching effect on 3 exerted by Cu²⁺ ions with respect to all the other metal ions studied in this work.

To support the above notion that the crescent-shaped electron-rich cavity of about 1.5 Å in radius is able to bind electron-deficient metal ions, various efforts to crystallize the metal–ligand complexes formed between metal ions and 3 or other oligomers such as trimer 4 and 5 have been attempted. Eventually, the neutral 4 and anionic 5 in complex with a Na⁺ ion were crystallized with their crystal structures illustrated in Fig. 3. Structural comparison between neutral 4 and anionic 5 once again substantiates our above statement that phenol unit 1a makes the backbone more linear via a six-membered H-bond of O–H⋯O type while phenolate unit 1b causes the backbone to bend more to enclose a sizable hydrophilic cavity in trimer or higher oligomers. The crystal structure of 5·Na⁺ demonstrates the cation-binding ability of the enclosed cavity in 5. Specifically, the Na⁺ ion forms two strong coordination bonds of 2.279 Å and 2.664 Å in length with phenolate and methoxy O-atoms, respectively, and another three bonds with one water molecule and the two amide O-atoms from the two adjacent molecules of 5. Apparently, the two methoxy groups in 5 force Na⁺ ion to stay above or below the near planar trimeric backbone.

Fig. 3 The chemical structures of (a) trimer 4 containing a phenol unit and (b) trimer 5 containing a phenolate unit as well as the corresponding crystal structures of 4 and 5·Na⁺. The large purple balls in (b) refer to Na⁺ ion, and a water molecule coordinated to the Na⁺ ion is also shown.

First principle calculations at the level of B3LYP/6-31G(d,p) using THF as the explicit solvent were then carried out to deduce the possible complexes formed between Cu²⁺ and di-anionic oligomers 3_ab or 3_bc. Our calculations reveal complex 3_ab·Cu²⁺ to be significantly more stable than 3_bc·Cu²⁺ by 6.71 kcal mol⁻¹ (Fig. S1†), leading us to favorably consider 3_ab·Cu²⁺ as the predominant quenching species responsible for the observed quenching of 3 by Cu²⁺ ions. In the computationally determined structure for 3_ab·Cu²⁺, Cu²⁺ ion is stabilized primarily by forming two strong coordination bonds with the two negatively charged phenolate O-atoms with respective bond lengths of 1.89 Å and 1.86 Å, and additionally by interacting with the adjacent amide N-atom (2.48 Å) (Fig. S1a†).

To summarize, the above observations demonstrate that metal ions can be used to induce a conformational change in phenol-based host 3 containing switchable phenolic hydroxyl groups. In most cases studied, such structure-switching ability exhibited by metal ions seems to be in good accord with the metal ions' hydrolysis constants in that metal ions with considerably smaller hydrolysis constants are more able to deprotonate the OH groups in 3 and thus switch 3 from a more linear more fluorescent structure to more curved less fluorescent states. Nevertheless, for La³⁺ and Cu²⁺ ions, the hydrolysis constant appears not to be the sole determining factor. In particular, the abnormally high quenching ability exhibited by Cu²⁺ ions suggests the efficient co-operative interactions between the in situ generated anionic hosts such as 3_ab or 3_bc and Cu²⁺ ions, rather than the metal ion's hydrolysis constants, to be the most influential factor that induces the more linear 3 into more curved anionic structures possibly with 3_ab as the predominant anionic form in solution. In connection with the recently elucidated diverse functions by the H-bonded aromatic foldamers of varying types,² it is quite unusual to note that there has been no use of metal ions to promote the conformational switching of these H-bonded aromatic foldamer molecules for possibly selective sensing of metal ions. The approach described here may promise more selective recognitions of metal ions by other analogous conformationally switchable phenol-based foldamers with elongated backbones and/or with the replacement of methoxy groups by other bulkier groups and the incorporation of electron-donating/withdrawing groups in the aromatic backbone.

Acknowledgements

Financial supports of this work to H.Z. by the Institute of Bioengineering and Nanotechnology (Biomedical Research Council, Agency for Science, Technology and Research, Singapore), the A*STAR Computational Resource Centre through the use of its high performance computing facilities and NRF CRP Grant (NRF-CRP7-2010-03).

Notes and references

1. Y. Hamuro, S. J. Geib and A. D. Hamilton, Angew. Chem., Int. Ed., 1994, 33, 446.
2. (a) S. H. Gellman, Acc. Chem. Res., 1998, 31, 173; (b) G. Guichard and I. Huc, Chem. Commun., 2011, 47, 5933; (c) K. Yamato, M. Kline and B. Gong, Chem. Commun., 2012, 48, 12142; (d) D.-W. Zhang, X. Zhao, J.-L. Hou and Z.-T. Li, Chem. Rev., 2012, 112, 5271; (e) W. Q. Ong and H. Q. Zeng, J. Inclusion Phenom. Macrocyclic Chem., 2013, 76, 1; (f) H. L. Fu, Y. Liu and H. Q. Zeng, Chem. Commun., 2013, 49, 4127.
3. (a) H. Q. Zhao, J. Shen, J. J. Guo, R. J. Ye and H. Q. Zeng, Chem. Commun., 2013, 49, 2323; (b) Q. Gan, Y. Ferrand, C. Bao, B. Kauffmann, A. Grélard, H. Jiang and I. Huc, Science, 2011, 331, 1172; (c) K. Srinivas, B. Kauffmann, C. Dolain, J. M. Leger, L. Ghosez and I. Huc, J. Am. Chem. Soc., 2008, 130, 13210; (d) H.-Y. Hu, J.-F. Xiang, J. Cao and C.-F. Chen, Org. Lett., 2008, 10, 5035; (e) B. Qin, L. Y. Jiang, S. Shen, C. Sun, W. X. Yuan, S. F. Y. Li and H. Q. Zeng, Org. Lett., 2011, 13, 6212; (f) Z. Y. Du, B. Qin, C. Sun, Y. Liu, X. Zheng, K. Zhang, A. H. Conney and H. Q. Zeng, Org. Biomol. Chem., 2012, 10, 4164; (g) W. Cai, G. T. Wang, P. Du, R. X. Wang, X. K. Jiang and Z. T. Li, J. Am. Chem. Soc., 2008, 130, 13450; (h) C. L. Ren, S. Y. Xu, J. Xu, H. Y. Chen and H. Q. Zeng, Org. Lett., 2011, 13, 3840; (i) A. J. Helsel, A. L. Brown, K. Yamato, W. Feng, L. H. Yuan, A. J. Clements, S. V. Harding, G. Szabo, Z. F. Shao and B. Gong, J. Am. Chem. Soc., 2008, 130, 15784; (j) P. S. Shirude, E. R. Gillies, S. Ladame, F. Godde, K. Shin-Ya, I. Huc and S. Balasubramanian, J. Am. Chem. Soc., 2007, 129, 11890.
4. (a) A. Petitjean, L. A. Cuccia, J.-M. Lehn, H. Nierengarten and M. Schmutz, Angew. Chem., Int. Ed., 2002, 41, 1195; (b) A. R. Sanford, L. H. Yuan, W. Feng, K. Y. R. A. Flowersb and B. Gong, Chem. Commun., 2005, 4720; (c) C. Li, S.-F. Ren, J.-L. Hou, H.-P. Yi, S.-Z. Zhu, X.-K. Jiang and Z.-T. Li, Angew. Chem., Int. Ed., 2005, 44, 5725; (d) B. Qin, C. L. Ren, R. J. Ye, C. Sun, K. Chiad, X. Y. Chen, Z. Li, F. Xue, H. B. Su, G. A. Chass and H. Q. Zeng, J. Am. Chem. Soc., 2010, 132, 9564; (e) J.-M. Suk, V. R. Naidu, X. Liu, M. S. Lah and K.-S. Jeong, J. Am. Chem. Soc., 2011, 133, 13938; (f) C. L. Ren, V. Maurizot, H. Q. Zhao, J. Shen, F. Zhou, W. Q. Ong, Z. Y. Du, K. Zhang, H. B. Su and H. Q. Zeng, J. Am. Chem. Soc., 2011, 133, 13930; (g) S. Tashiro, K. Matsuoka, A. Minoda and M. Shionoya, Angew. Chem., Int. Ed., 2012, 51, 13123; (h) L. J. Zhong, L. Chen, W. Feng, S. L. Zou, Y. Y. Yang, N. Liu and L. H. Yuan, J. Inclusion Phenom. Macrocyclic Chem., 2012, 72, 367; (i) W. Q. Ong, H. Q. Zhao, C. Sun, J. E. Wu, Z. C. Wong, S. F. Y. Li, Y. H. Hong and H. Q. Zeng, Chem. Commun., 2012, 48, 6343; (j) C. Sun, C. L. Ren, Y. C. Wei, B. Qin and H. Q. Zeng, Chem. Commun., 2013, 49, 5307; (k) C. Sun, Y. Liu, J. Q. Liu, Y.-J. Lu, L. Yu, K. Zhang and H. Q. Zeng, J. Org. Chem., 2014, 79, 2963; (l) A.-M. Stadler and J.-M. P. Lehn, J. Am. Chem. Soc., 2014, 136, 3400–3409.
5. (a) J. Garric, J.-M. Leger and I. Huc, Angew. Chem., Int. Ed., 2005, 44, 1954; (b) W. Q. Ong, H. Q. Zhao, X. Fang, S. Woen, F. Zhou, W. L. Yap, H. B. Su, S. F. Y. Li and H. Q. Zeng, Org. Lett., 2011, 13, 3194; (c) H. Q. Zhao, W. Q. Ong, X. Fang, F. Zhou, M. N. Hii, S. F. Y. Li, H. B. Su and H. Q. Zeng, Org. Biomol. Chem., 2012, 10, 1172; (d) H. Q. Zhao, W. Q. Ong, F. Zhou, X. Fang, X. Y. Chen, S. F. Y. Li, H. B. Su, N.-J. Cho and H. Q. Zeng, Chem. Sci., 2012, 3, 2042; (e) F. Zhou, H. L. Fu, W. Q. Ong, R. J. Ye, W. X. Yuan, Y.-J. Lu, Y.-P. Huo, K. Zhang, H. B. Su and H. Q. Zeng, Org. Biomol. Chem., 2012, 10, 5525; (f) J. L. Hou, X. B. Shao, G. J. Chen, Y. X. Zhou, X. K. Jiang and Z. T. Li, J. Am. Chem. Soc., 2004, 126, 12386; (g) Y. Ferrand, A. M. Kendhale, B. Kauffmann, A. Grelard, C. Marie, V. Blot, M. Pipelier, D. Dubreuil and I. Huc, J. Am. Chem. Soc., 2010, 132, 7858.
6. D. Kanamori, T. A. Okamura, H. Yamamoto and N. Ueyama, Angew. Chem., Int. Ed., 2005, 44, 969.
7. Y. Yan, B. Qin, Y. Y. Shu, X. Y. Chen, Y. K. Yip, D. W. Zhang, H. B. Su and H. Q. Zeng, Org. Lett., 2009, 11, 1201.
8. The intrinsic fluorescence-quenching ability of transition/lanthanide metal ions should not be the determining factor for the observed differential quenching by the metal ions as compiled in Fig. 2. This can be substrantiated by the demonstrated conformation-dependent fluorescence property of 3 and the facts that (1) moderate quenchers such as Zn²⁺, Mn²⁺, Co²⁺, Ni²⁺ and Cd²⁺ behave similarly with non-quenchers such as Ba²⁺, Sr²⁺, Ca²⁺, Mg²⁺, Li⁺, Na⁺, and K⁺, and they all exhibit insignificant or weak fluorescence quenching of 3, (2) the fluorescence quenching of 3 by strong quenchers such as Hg²⁺, Pb²⁺ and lanthanide ions mostly follows their trend in pK_a values, and (3) Cu²⁺ ions as a moderate quencher nevertheless produce the largest quenching among all the metal ions studied.
9. (a) C. F. Baes and R. E. Messmer, The Hydrolysis of Cations, John Wiley & Sons Inc, New York, 1976; (b) J. Burgess, Metal Ions in Solution, Ellis Horwood Ltd, Chichester, England, 1978, p. 264; (c) It has been observed that Yb³⁺ ions are able to dramatically lower down the pK_a value of the aliphatic OH group from 16 to about 6.4 in water, see: M. Lelli, G. Pintacuda, A. Cuzzola and L. D. Bari1, Chirality, 2005, 17, 201.
10. (a) Di-anionic oligomer 3_ac is unlikely to be produced by Cu²⁺ as the two phenolate units in 3_ac are separated by a phenol group, and as a result, the complex 3_ac·Cu²⁺ is expectedly less stable than complexes 3_ab·Cu²⁺ and 3_bc·Cu²⁺; (b) Although we speculate that it is least likely to produce tri-anioinic oligomers such as 3_abc or tetra-anionic 3_abcd as the dominant anionic forms by two equivalents of Cu²⁺ ions via simultaneous deprotonation of three or four phenolic OH groups in 3, such processes cannot be completely excluded on the basis of data we have.

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Footnotes

† Electronic supplementary information (ESI) available: CCDC 1017708 for trimer 4 and 1017709 for trimer 5. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4ra11706a

‡ These authors contributed equally to this work.

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