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Multiresponsive Dynamic Covalent Assemblies for Selective Sensing of Both Cu2+ and CN- in Water Daijun Zha, and Lei You ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.5b11552 • Publication Date (Web): 31 Dec 2015 Downloaded from http://pubs.acs.org on January 8, 2016
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Multiresponsive Dynamic Covalent Assemblies for Selective Sensing of Both Cu2+ and CN- in Water Daijun Zha and Lei You* State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou 35002, P. R. China. ABSTRACT: The use of dynamic assembly for molecular sensing is an intensive area of research in supramolecular chemistry. However, the development of self-assembly architectures for the detection of multiple signals remains challenging. Here we present dynamic covalent assemblies with multiresponsive properties, but also showing unique selectivity profiles in water. The receptors were generated in a single step with modularly designed building blocks through acylhydrazone linkages, and their orthogonal assembly with a series of external stimuli was investigated. Notably, the system exhibits responses toward cations, anions, solvents, pH, and amphiphilicity. The discrimination of Cu2+ from other divalent metal ions was achieved by simply changing the solvent and rationalized by Cu2+ induced pKa shift. The selective recognition of CN- in pure aqueous media was also accomplished through cooperative effect in conjunction with Zn2+. Furthermore, the assembly and its response are functional in both solution and solid state. The aggregation feature supports the binding and sensing properties of these dynamic covalent systems. KEYWORDS: supramolecular chemistry, molecular recognition, sensors, dynamic assembly, cooperative binding.
INTRODUCTION The research of dynamic multi-component assembly is one of the frontiers in supramolecular chemistry.1-6 Due to the stimuli-responsiveness of reversible interactions employed for the “bottom-up” construction, dynamic assemblies have found applications in the creation of adaptive or self-healing materials, encapsulation and controlled release, as well as detection and quantitative determination of a variety of substrates.7-13 In addition to the advantages of modular design, molecular recognition can be manipulated through the effects of cooperativity,14-16 multi-valency,17-19 as well as size confinement.20-22 Recently, orthogonal assembly using both supramolecular and dynamic covalent interactions has been generating significant interest within the supramolecular community. For example, Nitschke constructed a series of metal-organic cages through imine formation in conjunction with metal coordination and explored their properties for guest inclusion and supramolecular catalysis.23-25 Using similar reversible bonding forces, Leigh created knot structures, such as pentafoil knot template by anions.26,27 Chirality sensors were developed through orthogonal assembly by Anslyn for the chirality discrimination and enantiomeric excess analysis of mono amines and secondary alcohols.28-30 In a related context, the induction of optically pure helical chirality was reported by Peter Scott.31,32 Despite considerable efforts, dynamic assemblies with responsiveness
and employed for the detection of multiple classes of analytes have been rarely reported. The acylhydrazone functionality provides both reversible covalent characters through the imine-type C=N motif and hydrogen bonding sites through the amide group.33-35 Hydrazone motif has been incorporated to create sensors and switches. For example, salicylhydrazone-based ligands were prepared for the recognition of aluminium and lanthanide ions by Goswami36 and Hooley,37 respectively. Aprahamian developed hydrazone based configurational switches modulated by protonation or metalation.38-40 In another study, Lehn achieved photo-induced acylhydrazone switches and self-sorting systems in conjunction with metal chelation.41,42 Acylhyrazones have also been explored for the identification of receptors through dynamic combinatorial libraries (DCLs).43-46 In one example, Saunders discovered a linear oligomer for binding of dihydrogen phosphate in 96: 4 CH2Cl2/MeOH.47 Greaney constructed protein templated acylhydrazone DCLs which were equilibrated under nucleophilic catalysis.48 Instead of selection and amplification from a DCL, our focus is placed on the direct discovery of molecular sensing systems in aqueous solution through dynamic multi-component assembly. In this study, by combining the strategy of orthogonal assembly and the feature of acylhydrazone unit, we created dy-
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namic covalent assemblies with stimuli-responsive properties as a platform for multiple chemical sensing. Our systems exhibit optical responses toward cations, anions, solvents, pH, and amphiphilicity. Selective and sensitive detection of Cu2+ in water was achieved. Furthermore, selective recognition of CN- was accomplished through cooperative effect with Zn2+. The mechanisms of binding, assembly, and signal transduction were also elucidated in detail.
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O
O
O
N H2NHN
NHNH2 N
O OR RO O HN
N
N
O
RESULTS AND DISCUSSION
NH
Design and Synthesis. In order to realize orthogonal assembly, an appropriate ligand was incorporated to fine tune metal binding properties. Pyridine-2-carboxyaldehyde and its derivatives have been commonly used in imine based assembly. However, their dynamic hydrazone assembly is much less extensively explored. 6,6’-diformyl-3,3’-bipyridine was chosen as the component in an effort to manipulate the selectivity profile (Figure 1). We conceived that the presence of both cation and anion recognition sites could pave the way for the investigation of multi-analyte binding. For the dynamic assemblies to be functional in water, we postulated that amphiphilicity, size, and morphology of the assembly would further affect guest recognition.49-51 Toward this end, the poly(ethylene glycol) or alkyl chain was attached to modulate the amphiphilic behavior of the receptors (Figure 1). Simple hydrazides based on isophthalic acid were employed as the nucleophiles. When dihydrazides were mixed with dialdehydes, polycondensation occurred, and polyacylhydrazone polymers (1 and 2) were formed and precipitated. Taking polymer 1 as an example, 1H NMR signal around 10.0 ppm which was assigned to dialdehyde disappeared while the new acylhydrazone signal at 12.3 ppm emerged, indicating the formation of the polymer. After heating 1 at 110 oC for 24 h in the presence of trifluoroacetic acid in DMSO-d6, the aldehyde signal at 10.0 ppm appeared, confirming the reversibility of the acylhydrazone linkage (Figure S18). These results are in consistence with the literature precedent that strong acids are required for the break of acylhydrazone bonds and validate their stability.52 One control compound (3) was also synthesized. Analyte Binding in DMSO. With the dynamic covalent receptors in hand, their assembly with metal ions was explored. Due to paramagnetic nature of some ions, UV-vis titration of 1 was conducted in DMSO. The solution of polymer 1 was colorless at 10.6 µg/mL, and a yellow color was apparent after addition of Cu2+. A new absorption band appeared at 425 nm, while the peak at 350 nm decreased, resulting in the concomitant formation of an isosbestic point at 384 nm (Figure 2a). The absorption changes at 350 and 425 nm are in agreement with the observed color change. The presence of the isosbestic point suggests that all the binding sites along the polymer backbones coordinate the metal ions in a similar fashion. Comparable color change and titration data were found for Zn2+ (Figure 2b), indicative of the similar mode of molecular recognition and signal transduction as Cu2+.
N
N
1, R = (CH2CH2O) 4 CH3 2, R = (CH2) 11 CH3
O
N
O NH
HN
N
N N
3
b
= dialdehyde = dihydrazide
= cation = anion
Figure 1. (a) Modular design and chemical structures; (b) Illustration of the sensing strategy.
Figure 2. UV-vis spectra of (a) 1 (10.6 µg/mL) upon addition of Cu(OTf)2 (0 to 10 µM) in DMSO and (b) 1 (10.6 µg/mL) upon addition of Zn(OTf)2 (0 to 8.2 µM) in DMSO. Inset: absorbance changes at 425 nm with the addition of corresponding cations.
To evaluate the specificity and sensitivity of 1 toward different anionic analytes, absorption spectra were then recorded in the presence of tetrabutylammonium salts of various anions, such as F-, Cl-, Br-, OAc-, CN-, H2PO4- (Pi), and hydrogen pyrophosphate (PPi). Among these anions, CN- (Figure 3a), OAc- (Figure 3b), F-, and PPi (Figures S21-S22) were able to induce significant changes in absorption spectral pattern, and a yellow color was observed. As the case with Cu2+ and Zn2+, the magnitude of a new peak around 425 nm increased upon addition of anions. OAc- and CN- exhibited better sensitivity, while F- and PPi gave similar binding isotherms. The response of anions with weak basicity is likely due to the deprotonation of the acylhydrazone NH.53-55 The tautomerization of the amide bond leads to enhanced conjugation of the dynamic polymer and hence a bathochromic shift.
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Figure 3. UV-vis spectra of (a) 1 (15 µg/mL) upon addition of Bu4NCN (0 to 115 µM) in DMSO and (b) 1 (15 µg/mL) upon addition of Bu4NOAc (0 to 90 µM) in DMSO. Inset: absorbance changes at 425 nm with the addition of corresponding anions.
NMR Binding Studies. It is notable that almost identical absorbance bands as well as isosbestic points were found upon interaction of 1 with cationic and anionic substrates. We postulated that similar isomerization and signaling were induced by these two classes of analytes. To further validate this hypothesis, the binding mode was studied by 1H NMR with control compound 3 (Figure 4). 3 afforded analogous optical changes in the presence of metal ions (Figures S70 and S71) or anions (Figures S72-S74) as polymer 1, albeit at a shorter wavelength. In addition to the major set, another minor set of signals were found for 3 in DMSO-d6, probably due to cis conformer in respect to amide C(O)-N bond (Figure 5a and S49).56,57 After addition of 1 equiv. of OAc-, the amide NH at 12.2 ppm (He) completely disappeared with the generation of a new broad peak at 13.3 ppm (Figure 4b). As more OAc- was introduced, the new peak became broader and almost disappeared with 4 equiv. of OAc-, confirming the deprotonation pathway (Figure 5b). The downfield shift of Hb and Hc suggests that these two protons form hydrogen bonds with the anion. Moreover, only one set of peaks was apparent, indicative of deprotonation facilitated cis-trans isomerization. When 1 equiv. of Zn(OTf)2 was added to a solution of 3, similar behavior of NH broadening was observed (Figure 4d). There was also a slight downfield shift of the original NH resonance, and the peak further broadened with more Zn2+. We rationalize these changes with the tautomerization of the amide bond (Figure 5c). Different from anion induced deprotonation, the proton migrates from nitrogen to oxygen.58 However, the chemical shift and integral of NH of the minor set remained intact (Figure S75). This is understandable because the metal chelation involving amide unit of the cis isomer is impossible due to the placement of carbonyl oxygen (trans to imine nitrogen), and hence the chemical environment of NH is minimally affected. Discrimination of Cu2+ through Solvent Effects. We next set out to differentiate similar Cu2+ and Zn2+. UV-vis titrations were performed in a mixture of DMSO and water (Figures S26-S51). In 4: 1 DMSO/H2O, a slightly smaller response was detected for Zn2+ than Cu2+ at 425 nm. A much better discrimination between Cu2+ and Zn2+ was observed in 1: 1 DMSO/H2O. When pure water was used as a solvent, the addition of Cu2+ to a solution of 1 afforded similar optical responses as the aforementioned solvent systems (Figure 6a). However, with Zn2+, there was only a tiny increase at 425 nm (Figure 6b). The pH 7.4 PBS buffer gave similar results as pure water.
Figure 4. 1H NMR of 3 (a), 3 with 1 equiv. of Bu4NOAc (b), 3 with 2 equiv. of Bu4NOAc (c), 3 with 1 equiv. of Zn(OTf)2 (d), and 3 with 2 equiv. of Zn(OTf)2 (e) in DMSO-d6. O
a
NH O
N N H
N
N N
cis
tr ans
b O
N N H
N
Bu4NX, DMSO
O
H
c
O
N N H
d
N
O
N N H
N
Bu4N N
M2+, DMSO
Cu2+, H2 O
N
N
H
H X
M
HO N
Cu
O N
N
N
N
N
Figure 5. (a) The equilibrium between trans and cis isomer; (b) Anion binding mode in DMSO; (c) Cation binding mode in DMSO; (d) Cu2+ binding mode in water. Only one acylhydrazone unit is shown.
Moreover, the solution of 1 with other divalent metal ions, such as Mg2+, Ca2+, Co2+, Ni2+, Cd2+, Fe2+, and Mn2+, exhibited very tiny or no absorbance change at 425 nm in aqueous solution. Pb2+ gave similar optical responses as Cu2+ in water (Figure S50), but it can be easily masked by SO42- (Figure S51) or in the pH 7.4 PBS buffer, as evidenced by the color change (Figure 6c). The limit of detection was found to be 6.7 × 10-7 M for Cu2+ in water (Figure S52). One rationalization of this solvent effect comes from perturbation of the tautomerization equilibrium of the amide bond. The carbonyl form is dominating in its free state in water, and the copper ion facilitates the enolization by decreasing the pKa of the resulting OH and stabilizing its conjugate base (enolate) through complex formation (Figure 5d). The shift of pKa upon substrate binding is
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not uncommon, such as metal-catechol adducts and active sites of many enzymes. 59, 60
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limit of detection was in the low µM range. Similar response was observed for CN-, but with better sensitivity. We rationalize this result as enhanced binding of Zn2+ as a result of anion facilitated deprotonation and enolate formation (i.e. cooperative effect, see the equation 1 below). Furthermore, only a tiny increase at 425 nm was detected for cooperative binding with F-, H2PO4- (Pi), and PPi. These results demonstrate the potential for the detection of both Zn2+ and CN- (or OAc-) through cooperative effect and orthogonal assembly. Zn O
N N H
N
Bu4 NX, Zn(OTf)2
O
N N
H
N
H
(1) H
X
Figure 6. (a) UV-vis spectra of 1 (13 µg/mL) upon addition of Cu(OTf)2 (0 to 15.2 µM) in water. Inset: absorbance changes at 425 nm with the addition of of Cu(OTf)2; (b) UV-vis absorption spectra of 1 (13 µg/mL) upon addition of Zn(OTf)2 (0 to 16 µM) in water; (c) Color changes of 1 (38.8 µg/mL) with various metal ions (130 µM) in pH 7.4 PBS buffer. The first vial on the left is the control.
pH Effect. To expand the scope of stimuli-responsiveness and further probe the binding and signaling mechanism, pH effect was studied. UV-vis titrations of 1 were conducted with Cu2+ in PBS buffer at pH 1.5, 4.5, 7.4, 9.2, 11.6, and 13.5, respectively (Figures S54-S59). In weak acidic (pH 4.5) and weak basic (pH 9.2) solution, similar bathochromic shift resulting from Cu2+ was afforded as those at pH 7.4. In the strong acidic solution (pH 1.5), there was no copper binding due to the protonation of the pyridine. A broad peak around 425 nm with a shoulder ranging from 400 to 500 nm was observed for 1 at pH 11.6, indicative of partial deprotonation of acylhydrazone units by OH-. Upon addition of Cu2+, the absorbance at 425 nm gradually increased. With an even higher pH (13.5), there was a bathochromic shift for 1 itself, in agreement with the feature of an acid-base equilibrium. Interestingly, the introduction of Zn2+ also gave rise to a modest increase at 425 nm at pH 9.2, but not at pH 4.5 and 7.4 (Figures S60-S62), further supporting metal binding upon the enolate formation, which was favored in basic solution.61 All these results demonstrate the ability to modulate the binding properties by simply changing pH, and they are also consistent with the proposed binding mode in aqueous solution. Moreover, the reversibility of multiresponsiveness was confirmed by switching of the absorbance peaks at 350 and 425 nm for several cycles of pH change between 1.5 and 7.4 (Figure S63). Anion Sensing in Aqueous Solution. Inspired by the mechanistic insights from pH effect, anion binding was investigated in aqueous solution. Although many anion receptors have been developed in the past decade, the detection of anions in aqueous medium, especially pure water, remains challenging.62-67 Small or no increase at 425 nm was detected for 1 upon the addition of anions in 1: 1 DMSO/H2O. In contrast, there were significant spectral changes of 1 induced by OAcin the presence of Zn(OTf)2 (Figure 7a). The titration isotherm revealed that a broad dynamic range was apparent, though the
Figure 7. Anion detection in aqueous medium: (a) UV-vis spectra of 1 (15 µg/mL) with Zn2+ (18.5 µM) and various anions (430 µM) in 1: 1 DMSO/H2O; (b) UV-vis spectra of 1 (15 µg/mL) with Zn2+ (18.5 µM) and various anions (450 µM) in H2O; (c) Spectral change of 1 (15 µg/mL) with Zn2+ (18.5 µM) and various concentration of CN- (0 to 118 µM) in H2O; (d) color changes of 1 (15 µg/mL) with Zn2+ (18.5 µM) and various anions (450 µM) in H2O. Inset: absorbance changes at 425 nm with the addition of corresponding anions. Zn(OTf)2 was used as the Zn2+ source.
To further fine tune the anion binding, solvent effects were examined. As described previously, solvent effects played a vital role in differentiating between Cu2+ and Zn2+. We postulated that the selectivity profiles for anion recognition could be similarly modulated by simply changing solvents. In water, CN- or Zn2+ itself gave no significant response of 1 at 425 nm. However, a sharp increase was observed with both CN- and Zn2+ present (Figure 7b-7d). The selectivity for CN- in water was demonstrated by the fact that no response was detected for other anions, including OAc-. Titration isotherm revealed that a plateau was reached around 70 µM, indicating that sensitivity was not compromised when the solvent was switched from 1: 1 DMSO/H2O to water. The limit of detection is about 6.5 × 10-6 M for CN- in water (Figure S53). To explore the differential recognition of a series of anions, cooperative effect was further examined in 4: 1 DMSO/H2O. OAc-, F-, H2PO4- , and PPi were all able to induce a spectral change of 1 in the presence of Zn2+, but to a varied extent (Figure S33). Hence, both selective and differential detection of anions in aqueous solution are feasible.
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Aggregation Studies. Finally, the correlation of assembling behavior with molecular recognition was examined. For 2 bearing a dodecyl chain, it exhibited similar responses in DMSO with Cu2+ as 1, but with a larger shoulder peak around 425 nm for the free receptor (Figure S64). The selectivity toward Cu2+ over Zn2+ for 2 has the following trend: DMSO < 4: 1 DMSO/H2O
