Recent Advances in Supramolecular Analytical Chemistry Using

Review pubs.acs.org/CR

Recent Advances in Supramolecular Analytical Chemistry Using Optical Sensing Lei You,*,† Daijun Zha,† and Eric V. Anslyn*,‡ †

State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou, 35002, People’s Republic of China ‡ Department of Chemistry, The University of Texas at Austin, Austin, Texas 78712, United States 5.2. Direct Sensing 5.2.1. Synthetic Receptors 5.2.2. Self-Assembled Receptors 6. Conclusions and Future Perspectives Author Information Corresponding Authors Notes Biographies Acknowledgments List of Abbreviations References

CONTENTS 1. Introduction: Definition of Supramolecular Analytical Chemistry 1.1. Analytical Chemistry and Sensors 1.2. Dynamic Interactions and Molecular Recognition 2. General Principles of Sensor Design 2.1. Direct Sensing vs Indicator Displacement Assay 2.1.1. Direct Sensing 2.1.2. Indicator Displacement Assay 2.2. Single Analyte Sensing vs Differential Sensing 2.2.1. Single Analyte Sensing 2.2.2. Differential Sensing 2.3. Types of Sensors 2.3.1. Detection Method 2.3.2. Origin 2.3.3. Structure 3. Single Analyte Sensing 3.1. Synthetic Receptors for Sensing 3.1.1. Direct Sensing 3.1.2. Indicator Displacement Assay 3.2. Dynamic Assembly for Sensing 3.2.1. Ion Pairing Interaction 3.2.2. π−π Interaction 3.2.3. Amphiphilic Interaction 3.2.4. Reversible Covalent Interaction 4. Differential Sensing 4.1. Cations 4.2. Anions 4.3. Small Neutral Molecules 4.4. Proteins, Cells, and Bacteria 5. Chirality Sensing 5.1. Enantioselective IDA

© XXXX American Chemical Society

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1. INTRODUCTION: DEFINITION OF SUPRAMOLECULAR ANALYTICAL CHEMISTRY The field of supramolecular chemistry has been flourishing since J.-M. Lehn, D. J. Cram, and C. J. Pedersen were awarded the 1987 Nobel Prize in Chemistry. By Prof. Lehn’s definition,1 “supramolecular chemistry” refers to the domain of chemistry beyond that of molecules. In other words, it focuses on molecular assemblies built upon intermolecular interactions. Nowadays, supramolecular chemistry is a highly interdisciplinary field of chemical, biological, and material sciences. In particular, supramolecular chemistry has been making a significant impact on the development of analytical sciences in the past two decades. The integration of analytical and supramolecular chemistry promotes the birth of a new research area: “supramolecular analytical chemistry”, first termed by Prof. Eric Anslyn.2 In Prof. Anslyn’s original definition, the field involves analytical chemistry applications of synthetic chemical structures that undergo molecular recognition and selfassembly. In detail, “supramolecular analytical chemistry” exploits the dynamic exchange of synthetic chemical structures that create assemblies which result in signal modulations upon addition of analytes. In this review, we will detail this perfect “marriage” as well as its latest embodiments.

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1.1. Analytical Chemistry and Sensors

Analytical chemistry, including chemical analysis as well as instrumental analysis, is one of the four traditional fields of chemical science. In essence, it mainly focuses on the creation and application of sensors. From the perspective of analytical chemists, a sensor is defined as a device that makes a measurement. For example, in a fluorescence measurement, the Special Issue: 2015 Supramolecular Chemistry Received: September 29, 2014

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DOI: 10.1021/cr5005524 Chem. Rev. XXXX, XXX, XXX−XXX

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fluorimeter is the sensor. Obviously, a signal, which can be optical, electronic, mechanical, etc., must be created first in order to be measured by a sensor. In the work flow of an analytical experiment, there are generally three steps: generation, detection, and processing of a signal. The generation of a signal is normally dependent on chemical interactions and equilibriums and the detection of a signal is achieved by instrumentation, while the processing of signals can be facilitated by chemometric techniques, which are extensively used in analytical chemistry. These techniques advance the state of the art of the analytical paradigm, instrumentation, and methodology. For example, in a redox titration, the signal of electrochemical potential is created by quantitative redox reactions, and detected by redox indicators or electrodes. In supramolecular chemistry, the sensor is generally viewed as a receptor (host) that interacts with an analyte (guest), producing a detectable change in a signal. In other words, the signal is modulated upon the binding of an analyte to a receptor. For example, in an acid−base titration, the sensors are normally pH indicators. 1.2. Dynamic Interactions and Molecular Recognition

When is a chemical interaction dynamic? What is the difference between dynamic and supramolecular interactions? In Prof. Lehn’s original definition, supramolecular interactions refer to intermolecular noncovalent interactions, such as hydrogen bonds, salt bridges, π−π stacking, van der Waals forces, hydrophobic interactions, etc. (Figure 1). Many textbooks and reviews3−5 also list metal coordination as supramolecular interactions, and this is worth debating since the coordination bond could be electrostatic or covalent, depending on the electron distribution. For example, in de Silva’s pioneering work of crown ether based sensors for alkaline metal ions,6 there are ion−dipole interactions, while the bonds in transition metal complexes have more covalent bond character. Over the past decade a new field, “dynamic covalent chemistry”, has been growing rapidly, in which the formation and exchange of reversible covalent bonds are employed to construct assemblies.7 Common dynamic covalent interactions include imine formation and exchange, 8 acylhydrazone formation and exchange,9 disulfide exchange,10 olefin metathesis,11 Diels−Alder reactions,12 acetal13 and hemiacetal14 formation and exchange, etc. For example, the reversible formation of cyclic boronate esters is essential for many carbohydrate sensors.15 To achieve orthogonal dynamic covalent chemistry in a functional system, James, Bull, and co-workers developed an NMR shift reagent based on imines and boronic esters for the differentiation of chiral primary amines.16,17 Moreover, elegant multicomponent dynamic assemblies have been created by orthogonal supramolcular and dynamic covalent interactions recently, such as those reported by Nitschke,18 Leigh,19 Anslyn,20 and Matile.21 As a result, it is important to avoid ambiguity as well as to consider and contrast the latest developments in the research of supramolecular and dynamic covalent chemistry. Although the bonding strength is different, with covalent bonds generally more stable than noncovalent bonds, there are similarities between supramolecular and dynamic covalent interactions. First, from the kinetic and thermodynamic points of view, both are reversible processes and can undergo component exchange. Second, the equilibrium should be reached quickly, and the time scale normally ranges from seconds to a few minutes, or at

Figure 1. Representative examples of supramolecular (noncovalent) and dynamic covalent interactions.

most several days. Because covalent bonding generally reverses less slowly than supramolecular interactions, catalytic acceleration is needed in many occasions. Hence, we will use the term “dynamic interaction” in this review, and define it as “reversible interactions that can undergo component exchange within a reasonable time scale.” Obviously, dynamic interactions include both supramolecular and reversible covalent bonding. Having expanded the scope of traditional supramolecular interactions, we now define “molecular recognition” as “the specific interaction between two or more molecules through dynamic bonding.” The building blocks for molecular recognition include inorganic species, small organic molecules, macromolecules, and biomolecules. Therefore, it follows that supramolecular analytical chemistry is a f ield that explores the molecular recognition and self-assembly of chemical structures using dynamic interactions that create ensembles which result in signal modulations upon addition of analytes. Below the strategies and methodologies of three aspects of supramolecular analytical chemistry will be presented in detail: single analyte sensing, differential sensing, and chirality sensing. In this review, we will mainly concentrate on optical sensing. It is also important to note that this review does not focus on fluorescent probes and cellular imaging,22−24 such as photoswitchable probes develB


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oped by Tian,25,26 reaction based probes developed by Chang,27−29 and enzyme activated probes.30

2. GENERAL PRINCIPLES OF SENSOR DESIGN 2.1. Direct Sensing vs Indicator Displacement Assay

2.1.1. Direct Sensing. In the paradigm of direct sensing, the analyte is directly bound to the receptor to lead to a signal change. For the extensively used receptor−spacer−reporter approach, a reporter (indicator, i.e., the signaling unit) is covalently tethered to a receptor (i.e., the binding unit) through a spacer (Figure 2). The binding of an analyte will induce a

Figure 3. Electron transfer process of PET (a) and fluorescence (b).

pH indicators are commercially available, and they have the advantage of covering a broad color range. Moreover, a lot of pH indicators are metal chelators, such as catechol based dyes, resulting in different protonation states upon metal coordination and thereby a color change. A variety of synthetic organic dyes have been developed, such as BODIPY36 and FURA.37 Recently, novel organic dyes based on aggregation induced emission (AIE)38,39 as well as inorganic and organometallic dyes, such as lanthanide complexes,40 lanthanide doped nanoparticles,41 and quantum dots,42 have been reported and gained popularity. Because of page limitation, this review will not discuss dyes in detail, instead focusing on the supramolecular aspect of molecular sensing. 2.1.2. Indicator Displacement Assay. Competitive binding, in which a series of guests compete for a host (receptor), is a well-established approach in supramolecular chemistry. Due to the reversible nature of the molecular recognition process, the differentiation of equilibrium between the host and multiple guests will be achieved, leading to binding selectivity. The exploitation of competitive binding for sensing applications has a long history, and the so-called competitive binding assay is extensively used in biochemistry, such as competitive binding immunoassays, competitive enzyme inhibition, and DNA intercalation assays, to name a few. However, the use of synthetic receptors with competitive binding assays has gained popularity within the past two decades, and the so-called “indicator displacement assay”43 or IDA, has become a standard strategy for molecular sensing, complementary to the approach of direct sensing discussed above. IDA is based on the competition between an indicator and an analyte for the binding of a receptor. In a typical IDA experiment, an indicator is bound to a receptor first, creating the sensing ensemble. An analyte is then introduced, and the indicator is displaced from the sensing ensemble. Generally, the free and bound indicators have different optical (colorimetric or fluorescent) properties, resulting in a signal change (Figure 4). The most common indicators are pH indicators, and their

Figure 2. Illustration of the receptor−spacer−reporter approach of molecular sensing.

signal change, and vice versa, signal measurements can be employed to explore guest binding. Elegant design and optimization as well as multistep synthesis are generally required for the purpose of selective sensing. Actually, direct sensing can trace its origin to the “lock and key principle”, first postulated in 1894 by Emil Fischer. The active site of an enzyme has a unique geometric shape that is complementary to the shape of a substrate, which means that enzymes specifically react with only one or a very few similar compounds. However, it is much more challenging to achieve selectivity using synthetic receptors. Indeed, the development of selective sensors is still one of the frontiers in supramolecular analytical chemistry. In addition to complementarity, the concepts developed by supramolecular chemists, such as molecular self-assembly, cooperative binding and multivalency, dynamic combinatorial library, etc., have been having a significant impact on designing selective receptors. Besides selective binding, signal engineering is crucial for sensor development. In other words, some mechanism must be incorporated to translate analyte binding into signal modulation of the reporter. For optical sensing, the photoinduced electron transfer (PET) mechanism is the most popular, and has been harnessed to create a variety of “turn-on” fluorescent sensors.31,32 PET based electron donor−acceptor systems can be explained from the perspective of frontier molecular orbital theory (Figure 3). In the absence of the analyte, the HOMO of the donor lies higher in energy than that of the acceptor, and as a result, an electron transfers to the acceptor’s HOMO after excitation and before emission, thereby quenching the fluorescence. After the analyte is bound to the receptor, the energy level of the donor HOMO is lowered, diminishing the ability to transfer an electron to the acceptor HOMO, and resulting in fluorescence recovery. Pioneering work by Czarnik, de Silva, and Shinkai for phosphate related anions,33 alkaline metal ions,3 and carbohydrates,34 respectively, paved the way for the future development of PET based chemosensors. The third aspect is the reporter motif itself. Design of novel dyes with desirable photophysical properties is important for optical sensor development, especially those intended for imaging.35 The pH indicators are the oldest and among the most used reporters in analytical applications. Many classes of

Figure 4. Illustration of the indicator displacement assay. C


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selectivity can be achieved by the design of elegant receptors, and other factors, such as solvents, are used complementarily to optimize the selectivity. From the practical point of view, one must take into consideration the possibly overwhelming synthetic work when designing selective receptors. Despite tremendous successes, single analyte sensing has several drawbacks that limit its applications. First, it remains very challenging to design selective receptors for structurally similar analytes. For example, the only difference between glutamate and aspartate is a methylene group in the side chain, and it is highly likely that the receptor designed for one would interact with the other. Second, the rational design of receptors is almost impossible for analytes whose structure is unknown, such as many biomolecules. Finally, it is impractical to use lock and key receptors to analyze complex mixtures, such as perfume and wine, in which there are many components with subtle structural differences. 2.2.2. Differential Sensing. In order to solve the aforementioned challenges, the approach of differential sensing, which mimics the mammalian nose and tongue for the sense of smell and taste, have been developed.45 Rather than sensing an analyte by its strong affinity for one particular receptor, recognition is achieved by the composite response of the analyte to the entire array of receptors (Figure 5), and in this regard, differential sensing is also called “array sensing”. Each receptor within the array may bind to multiple analytes, but recognize each of them to varied extents. The resulting fingerprint provides characteristic patterns for the individual analyte or complex mixtures comprised of multiple analytes. As a result, the receptors are differential instead of highly specific for a single analyte. Actually, “lousy” receptors with low selectivity may be beneficial for differential sensing, because cross-reactivity is enhanced, and hence, more information could be extracted. Moreover, this approach allows the discrimination and identification of analytes and complex mixtures whose structure or components are unknown. Although both the direct sensing and IDA approaches can be used, IDA is more compatible with differential sensing, because an array can be easily constructed by the combination of multiple receptors and multiple indicators without additional synthetic efforts. Similar to single analyte sensing, a measurable signal is generated upon the introduction of analytes to a sensor array. The signals collected are then analyzed by chemometric methods. Pattern recognition protocols, such as principal component analysis (PCA) and linear discriminant analysis (LDA), are extensively used.46 Both PCA and LDA produce score plots for the analytes tested, and the score plots are displayed in a two, three, or higher dimensional coordinate system to best discriminate the analytes. Both PCA and LDA create score plots by decomposing the raw data by a matrix technique, in which the eigenvectors of the matrix produce axes in the coordinate system and the eigenvalues give a measure of the level of discrimination that exists in the data. Although the mathematics of PCA and LDA might be complicated, chemists can simply judge the discrimination by inspecting the score plots. In a good plot, both close clustering between repetitions of the same analyte class and good separation between different analyte classes are present. PCA reduces the dimensionality of a data set, with the magnitudes of the eigenvalues representing the variances in the data, which are displayed in the score plot with principal component (PC) axes with the first principal component axis expressing the most variance in the data. LDA is a supervised

protonation state is modulated upon binding. In order to have an IDA with desirable sensitivity, the binding constant of the analyte to the receptor should be comparable to that of the indicator to the receptor. There are several similarities between the receptor−spacer− reporter approach and IDA. First, the interaction between the analyte (or the indicator) and the receptor can be either covalent or noncovalent. All dynamic forces can be employed for either method. Second, the sensitivity of the chemosensor is primarily controlled by the binding affinity of the analyte to the receptor. Third, the sensing system can be fine-tuned by changing the solvent, pH, and temperature, or by adding chemical stimuli. IDAs also display many advantages. First, because the indicator is reversibly bound to the receptor, the synthetic efforts to incorporate the reporter motif is avoided, making the receptor more available. Second, a variety of receptors and “on the bench” indicators can be screened to modulate the sensitivity and selectivity of the assay. For the assay development, the host is generally designed and synthesized, and indicators are then screened to optimize the system. Third, because of the almost infinite combination of the receptor and the indicator, IDA is much more adaptable to the increasingly popular array sensing, in which diversity and cross-reactivity of the system are desired. One major disadvantage of IDA is that it is not suitable for imaging applications, because the free indicator can interfere with the desired signal. 2.2. Single Analyte Sensing vs Differential Sensing

2.2.1. Single Analyte Sensing. In traditional molecular sensing, one receptor is designed and optimized for a particular analyte based on the “lock and key” principle (Figure 5).44 As a result, it is vital to increase selectivity among multiple analytes. The single analyte sensing is crucial for imaging analysis, where both selectivity and sensitivity are required. From the inspirations of specific molecular recognition in biological systems, especially enzymes and antibodies, many synthetic receptors have been developed for single analyte sensing. The

Figure 5. Illustration of single analyte sensing (a), differential sensing using one receptor (b), and differential sensing using multiple receptors. D


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ular sensing. For example, Rotello explored the usage of the gold nanoparticles for cancer cell screening.53

protocol used for the classification of data as well as the assignment of unknown analytes to their appropriate classes. The data from the array and the analyte classes are used as inputs (training set), and discriminant functions are then calculated with the goals of maximizing separation between classes and minimizing separation within classes. An analyte of unknown identity will be assigned to one of the classes after comparing its response to those in the training set. In addition to score plots, loading plots can be generated to determine the contribution of receptors in the array to each axis, thereby revealing the cross-reactivity and differential nature of the array. For example, if only two receptors in a five-sensor array are found to be mainly responsible for the discrimination, the other three would be unnecessary.

3. SINGLE ANALYTE SENSING Single analyte sensing is one of the most explored areas in analytical sciences and can trace its origin all the way back to the lock and key principle proposed by Emil Fischer at the end of the 19th century. As described in the previous sections, how to enhance selectivity is crucial for the single analyte sensing. Because of its importance and relatively long history, there are a variety of extensive reviews26,54,55,56 covering this topic, and hence, this review will concentrate on dynamic interaction and assembly involved in the sensing process, instead of detailed examples of each class of receptors and analytes.

2.3. Types of Sensors

3.1. Synthetic Receptors for Sensing

2.3.1. Detection Method. There are different types of chemosensors. Depending on the detection method, sensors can be classified as optical, electrochemical, mechanical, etc., and this review focuses on optical sensing. Optical sensors can be colorimetric, fluorescent, or circular dichroism based.47 Fluorescence polarization and time-resolved fluorescence are also commonly used, especially in biological detection and screening. For array sensing, a multimode plate reader is extremely powerful because different detection methods can be easily switched. 2.3.2. Origin. The receptors can be either natural or synthetic. Most sensors are based on synthetic receptors, which have the advantage of structural design with principles of organic and supramolecular chemistry. A variety of hosts has been developed for a broad range of analytes, including cations, anions, and neutral molecules. For natural receptors, enzyme− substrate, protein−ligand, and antibody−antigen interactions are employed for selective recognition due to their high specificities.48 It is noteworthy that antibodies and antigens have been incorporated into many biological sensors to enhance the selectivity.49 Another class of natural receptors is serum albumin,50 which binds metal ions, fatty acids, hormones, etc. The nonspecific interaction of albumins with many substrates makes them a perfect platform for differential sensing. 2.3.3. Structure. The receptors can also be classified by their structures. The traditional small molecule based chemosensors are either organic or inorganic, and the major difference is whether metal coordination is used for recognition. Since array sensing is becoming more popular, synthetic biomolecules, such as peptides and nucleic acid aptamers, have been extensively explored as differential receptors because their libraries can be readily prepared via solid-phase synthesis to enhance diversity and cross-reactivity.51 Moreover, construction and modulation of dynamic multicomponent assemblies is at the forefront of current supramolecular chemistry research, and the application of molecular assemblies as receptors for sensing have been generating considerable interest. Self-assembled architectures from metals, small organic molecules, and macromolecules have all been employed to create molecular sensors. One notable example is the assembly and amplification of receptors within dynamic combinatorial libraries, where the analyte is used as a template. Another approach takes advantage of the cavity of the assembly. For example, Wang’s group recently achieved the recognition of dichromate by a metal−organic framework.52 Moreover, assembled nanomaterials have been functionalized for molec-

3.1.1. Direct Sensing. Numerous synthetic receptors for cations, including metal and ammonium ions, have been reported since the discovery of crown ethers. In many scenarios, binding of cations is achieved through multiple coordination sites within the macrocyclic or acyclic structures. In essence, design of ligands is the key. Lippard and co-workers recently reported the successful phosphorescent sensor ZIrF (1) for biological mobile zinc ions.57 The di(2-picolyl)amine (DPA) motif was incorporated for zinc binding, while an Ir(III) complex bearing two blue-phosphorescent 2-(2,4difluorophenyl)pyridine (dfppy) ligands and a yellow-phosphorescent 1,10-phenanthroline (phen) ligand was utilized as a signaling unit. In its free state the sensor shows dual emission in the blue (461 nm) and yellow (528 nm) regions from dfppy and phen ligands, respectively. Upon the coordination of zinc, the yellow band is significantly enhanced, leading to a ratiometric response. The photophysical mechanism studies using molecular modeling, electrochemical measurements, and steady-state and femtosecond spectroscopies suggested a combined effect of common PET modulation and perturbation of charge-transfer transition. The sensor is able to detect zinc ions selectively and reversibly with Kd = 11 nM (1:1 binding mode confirmed by a Job’s plot) and pKa = 4.16 at pH 7.0. Free zinc detection was also demonstrated in live A549 cells by confocal laser scanning microscopy, and an increase in photoluminescence lifetime for the zinc-treated A549 cells was observed. Using a similar phosphorescent Ru(II) complex (2) with two phen ligands and one bipyridine ligand carrying two benzothiazoleamide units, quantification of Hg2+ and Ag+ was achieved at two different wavelengths by Schmittel and Khatua,58 although the receptor exhibits higher selectivity toward Hg2+ over Ag+ when both are present. The usage of polymers for sensing, such as conjugated polyelectrolytes (CPEs), is generating significant interest among analytical chemists. Woo, Shim, and co-workers developed a highly selective and sensitive detection system for potassium ion even with excess sodium ions in aqueous solution by taking advantage of the interaction between the Gquadruplex forming molecular beacon aptamer (MBA) and cationic CPE (3).59 The aptamer sequence in MBA was appropriately designed to display selectivity for K+. In the absence of K+, the hairpin-type MBA labeled with a fluorophore and quencher at both termini adopts an open-chain conformation by binding to CPEs through electrostatic interaction, resulting in amplified fluorescence resonance energy transfer (FRET) based fluorescence signal (on state) (Figure 6). In the presence of K+, the formation of GE


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Lamy and co-workers discovered a novel sodium probe by encapsulating an azocrown based sodium dye into a PAMAM dendrimer nanocontainer. The sensor exhibits high selectivity and sensitivity toward Na+, good biocompatibility, as well as strong stability, and is suitable for prolonged detecting and imaging of intracellular Na+, such as those in neutrons.60 Ceroni, Gingras, and co-workers developed a magnesium and fluoride responsive sensing system based on the creation and dissociation of a supramolecular polymer.61 A hexathiobenzene scaffold with six multivalent terpyridine (tpy) ligands at the end (4) was designed to modulate aggregation induced emission (AIE). With divalent Mg2+ present, a dendrimer-like supramolecular polymer is formed in THF, and phosphorescence of the hexathiobenzene unit is turned on at 545 nm (Figure 7).

Figure 7. Mechanism for Mg2+ and F− detection. Reprinted from ref 61. Copyright 2014 American Chemical Society.

The signal enhancement is due to radiative deactivation of the luminescent excited state by limiting rotations and motions of the fluorophore. The system performs as a very efficient lightharvesting antenna with >90% efficiency of sensitization and an emission quantum yield of 10%. The supramolecular architecture is disassembled upon addition of fluoride anions, and hence, the luminescence is turned off, enabling the detection of F−. The size of the polymer was also characterized by dynamic light scattering (DLS), and the average diameter is 60 nm. Similar phosphorescence was detected for Ca2+, Zn2+, and Cd2+, but with a lower quantum yield than Mg2+. No response was apparent for Fe2+, Co2+, Ni2+, and Cu2+ because of their involvement in electron transfer processes. This example provides valuable insights for future design of luminescent sensors because its signal results from a self-assembled supramolecule, rather than a ligand itself. The recognition and sensing of anions is more challenging than that of cations in water due to their high solvation energy. Many binding units have been incorporated into anion receptors, including organic motifs, such as ureas, amides, ammoniums, guanidiniums, hydrazones, pyrroles, imidazoliums, triazoles, and electron-deficient arenes.62−65 Belfield and coworkers reported a novel fluorescent fluoride sensor bearing one fluorene and two triazolium units (5).66 The sensor exhibits highly specific turn-on fluorescent response at 498 nm toward F− in DMSO (quantum yield 0.66), and 1H NMR studies revealed deprotonation of triazolium C−H bond induced by F−. Test strips were prepared and utilized to detect

Figure 6. Strategy for the detection of K+. Reprinted from ref 59. Copyright 2012 American Chemical Society.

quadruplex leads to the almost complete quenching of the fluorophore emission (off state). A detection limit of ∼1.5 nM was determined for K+ even with 100 mM Na+ present, and is the lowest among those reported. The approach should be applicable to other G-rich aptamer binding analytes.

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dimethylaminophenyl unit was attached to the terpyridine ligand to modulate the optical signal. Although a bathochromic shift (∼30 nM) was observed upon the addition of PPi and other nucleotide triphosphates (ATP, GTP, and CTP), only PPi induces significant fluorescence change at 591 nm. The receptor exhibits an unprecedented ∼500-fold increase in fluorescent signal and remarkable sensitivity toward PPi with the lowest limit of detection (LOD) around 0.8 nM. A Job’s plot revealed a 1:3 binding stoichiometry between the sensor and PPi, which may account for the high sensitivity. Moreover, the zinc complex was successfully used to stain HeLa cells and create self-assembled hydrogels to coat paper strips for easy detection of PPi. Schäferling and co-workers prepared a series of pyridyl-based multidentate europium complexes (9 and 10) and explored their luminescence responses toward various phosphates and other oxyanions, such as citrate and malate.73 It was shown that both the sensitivity and selectivity of the luminescence signal change of sensitized europium complexes toward anions are dependent on the number of free coordination sites at the metal center. A model lanthanide probe was also employed to monitor the activity of ATPases and apyrases that consume ATP during their respective enzymatic reactions. Further, Yoon, Park, and co-workers developed a near-infrared fluorescent Cu2+ complex (11) for selective recognition of cyanide in aqueous solution.74

F− in aqueous solution at concentrations as low as 1.9 ppm. Although 1,3-triazole and triazolium have been employed for anion recognition through C−H−anion hydrogen bonding, anion receptors based on the deprotonation of a C−H bond are rare. Based on a similar strategy, Bielawski, Sessler, and coworkers developed F− activated tetrapropyl benzobisimidazolium salts (TBBI, 6) for fluorescent and colorimetric detection of carbon dioxide through an incipient NHC intermediate without the addition of external bases.67 The sensor displays decent selectivity toward F−. Different from C−H deprotonation, deprotonation of N−H in urea/thiourea is commonly used for anion sensing. Gunnlaugsson and co-workers recently prepared thiourea-functionalized Tröger’s base receptor (7) for colorimetric detection of F−.68

Organic boranes and borates have also been used for anion sensing.75 Introduction of cationic groups provides an electrostatic driving force for the capture of the anion by the Lewis acidic boron center, and affinity and selectivity can be modulated by the linker between the anion binding site and the positively charged unit. Jäkle and co-workers synthesized several luminescent triarylborane homo and block copolymers through controlled free radical polymerization of a highly electron-deficient borane monomer.76 The fluoride binding properties of these polymers were extensively explored by UV− vis and fluorescent spectroscopies (Figure 8). Both the homo and block copolymers exhibit F− induced fluorescence quenching in THF. A PNIPAM based amphiphilic block copolymer (12) behaves as a dual-responsive F− sensor. Selfassembly of this copolymer creates micelles in 99:1 DMF/THF, while disassembly leads to a decrease in particle size (from 93

In addition to organic receptors, another important class of anion receptors is metal complexes, especially those used for biologically relevant phosphate related anions. Zn2+ and Cu2+ complexes of DPA and terpyridine ligands are among the most explored. For example, Tian, Zhu, and co-workers developed DPA or iminodiacetate receptors bearing dicyanomethylene4H-chromene fluorophore for the detection of pyrophosphate in both solution and film.69−71 In a very recent example, Rissanen and co-workers designed a simple terpyridine−Zn2+ complex (8) for sensitive and selective sensing of nanomolar pyrophosphate (PPi) in water at physiological pH.72 A 4-N,NG


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based chemosensors have been successfully developed for anionic substrates, such as citrate,78 tartrate,79 glucose-6phosphate,80 inositol-1,4,5-trisphosphate (IP3),81 gallate,82 and heparin83 as well as carboxy and phospho sugars84 by Anslyn and co-workers with their trademark 1,3,5-trisubstituted-2,4,6-triethylbenzene scaffold. We will not present these examples in detail since they are the topic of several extensive reviews. Recently, Anslyn, Ariga, and co-workers introduced a mechanically controlled indicator displacement assay (MCIDA) at the air−water interface.85 An amphiphilic dilysine peptide host (14) was designed to contain three important motifs: a phenylboronic acid for the reversible covalent binding of carbohydrates, a cholesterol group to modulate the hydrophobicity, and a carboxyfluorescein dye serving as a FRET acceptor for coumarin based indicators, such as 4methylesculetin (ML). The monolayer of the host/indicator complex acts as a mechanically controllable signal-emission unit, and external compression and expansion of monolayers in lateral directions lead to molecular conformation change, thereby switching on and off the FRET between ML and fluorescein (Figure 9). Displacement of the ML indicator by Dglucose turned off the FRET, and the system was employed for sensitive detection of glucose.

Figure 8. (a) Spectra of PNIPAM-b-P(BM-ran-4VPMeOTf) (13) upon titration with TBAF in 9/1 (w/w) DMF/water. (b) Spectra of PNIPAM-b-PBM (12) upon titration with TBAF in 9/1 (w/w) DMF/ water. Reprinted from ref 76. Copyright 2013 American Chemical Society.

to 10 nm) upon F− binding, and simultaneous fluorescence quenching enables naked-eye detection. Incorporation of cationic pyridinium units into the copolymer (13) enhances F− binding affinity, and the sensor is functional in 9:1 DMF/ water. The modulation of Lewis acidity of the boron center also plays an important role in aryl borate based chemosensors for carbohydrates.77

Figure 9. Illustration of the mechanically controlled indicator displacement assay (MC-IDA). The FRET between the host and indicator was switched on by compression, and the guest displaced the indicator, switching off the FRET. Reprinted with permission from ref 85. Copyright 2012 Wiley-VCH Verlag GmbH & Co. KGaA.

Ghosh and co-workers developed a pyridinium amide based receptor (15) for selective and effective sensing of hydrogen pyrophosphate in both CH3CN and CH3CN/H2O (4:1, pH 6.5).86 The solution of the uranine dye (fluorescein) becomes colorless upon the addition of 15, and the yellow color (525 nm) is restored after dye replacement with PPi, enabling nakedeye detection. Ion paring, hydrogen bonding, and the shape and dimension of the cleft were thought to dictate selectivity in the binding process. To demonstrate the practicality, the sensor bead was prepared and employed to measure PPi in blood serum. Metal complexes have also been widely incorporated into indicator displacement assays (M-IDA). The diversity resulting from metal−ligand interaction significantly expands the scope of M-IDA. Moreover, a color change is induced upon coordination of a transition metal ion to an indicator. Many M-IDAs for amino acids as well as phosphate related anion species have been reported by Anslyn, Fabbrizzi, Reymond, Kim, and others.87 Jolliffe and co-workers prepared a library of

3.1.2. Indicator Displacement Assay. Anslyn’s group has revitalized indicator displacement assays (IDAs) as a sensing paradigm in supramolecular analytical chemistry. The majority of IDAs have been developed for anions to date. By using ionpairing interaction, hydrogen bonding, as well as reversible covalent reactions between boronic acids and 1,2-diols, IDA H


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Figure 10. Reaction of 17 and CEES to create receptor 18 which was used for IDAs.

0.2 mM is relatively high, the assay is sensitive enough to detect agent levels that pose a health risk. Amine-containing molecules play important roles in many biological processes, such as neurotransmitters in signal transduction and products of biodegradation and metabolism. Amines are protonated at physiological pH, and the resulted ammonium cations can form inclusion complexes with macrocyclic hosts, such as calixarene and cucurbituril. Nau and co-workers developed a series of IDAs for detection of cationic biological species (Figure 11).90,91 For example, a competition assay has been created to monitor cationic products of amino acid decarboxylase catalyzed reactions.92 Cucurbit[7]uril (CB7) and p-sulfonatocalix[4]arene (CX4) interact with two fluorescent indicators, Dapoxyl (DAP) and aminomethyl-substituted 2,3-diazabicyclo[2.2.2]oct-2-ene (DBO), respectively. The two reporter pairs display opposite fluorescence modulation properties. For Dapoxyl, its fluorescence is enhanced 200-fold upon binding to CB7, and the signal is turned off after displacement by ammonium products. However, there is an enhancement in fluorescence once DBO is displaced from CX4−DBO complex. Both CB7 and CX4 have higher affinities for the cationic alkylammonium products than amino acids, and therefore, the addition of amino acids did not interfere with the assay. Based on these IDAs, label-free and real-time monitoring of amino acid decarboxylase activity was achieved. In a collaborative effort with Urbach, Nau and co-workers also developed a method for the continuous monitoring of protease activity based on similar label-free supramolecular tandem enzyme assays (Figure 12).93 The reporter pair of CB7 and the fluorescent dye acridine orange (AO) was employed. CB7 selectively recognizes the cleavage products that bear an N-terminal phenylalanine residue. The ability of this assay to quantify protease inhibition was validated using a known inhibitor. CX4 or CB7 and a fluorescent indicator (lucigenin or berberine) were also trapped inside liposomes for real-time fluorescence monitoring of membrane transport.94 In the aforementioned IDAs an analyte and an indicator compete for binding to the same recognition site of the host.

linear peptides bearing two Zn2+−DPA units (16) using solid phase synthesis and screened their anion sensing abilities in water with IDAs.88 High selectivity and affinity toward PPi over ATP and ADP are achieved using receptors with hydrophobic and aromatic side chains. Very recently, Anslyn and Kumar reported a selective turn-on fluorescent sensor for sulfur mustard simulants in water using an M-IDA.89 By taking advantage of the rapid reaction between a dithiol (17) and a sulfur mustard simulant 2-chloroethyl ethyl sulfide (CEES) through a three-membered cationic sulfonium heterocyclic ring, they created podand 18, which exhibits high affinity to Cd2+ and hence displaces an indicator (4-methylesculetin) from a Cd2+−indicator complex, leading to fluorescence enhancement at 460 nm (Figure 10). Due to the unique reaction mechanism, interference from other electrophiles, such as the oxygen analogue of the mustard gas, was not observed. The concentration of CEES on surfaces and in soil samples was also successfully determined. Although the detection limit of I


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ylates in water was explored using a fluorescent indicator, HPTS.95 The signal transduction mechanism of donor− acceptor interaction between HPTS and viologen (Figure 14a) was confirmed by a charge transfer complex in the solid state by X-ray crystallography and in solution by UV−vis spectroscopy as well as fluorescence quenching studies. The fluorescence intensity increases upon binding of analytes. The selectivity for glucose over fructose and galactose is fine-tuned by changing the nitrogen position around the bipyridyl rings and the boronic acid position in the phenyl rings to afford a 1:1 receptor/substrate stoichiometry through cooperative diboronic acid binding. All receptors can bind tartrate and malate, although one exhibits an 8-fold preference for tartrate over malate. Schiller and co-workers recently reported an AIDA for the selective detection of the cyanogenic glycoside amygdalin in water based on similar boronic acid appended bis(viologen) receptors.96 The released cyanide from β-glucosidase catalyzed degration of the cyanogenic glycoside amygdalin binds selectively at the allosteric site (i.e., boronic acid) and modulates the affinity of bound HPTS dye at the other side of the receptor (Figure 14b). A 1:1 binding stoichiometry of the boronic acid and cyanide is preferred. 3.2. Dynamic Assembly for Sensing

Self-assembly is one of the most fundamental concepts in supramolecular chemistry, and its associated methodologies are powerful tools for constructing molecular aggregates, complex nanostructures, and functional materials. Recently, this “bottom-up” strategy has becoming increasingly popular for the development of novel molecular sensing systems. Since the assembly is created from relatively small building blocks through dynamic intermolecular interactions, it can minimize synthetic efforts and also have almost unparalleled diversity. Moreover, the properties of assembled structures can be modulated by chemical stimuli, providing exciting opportunities for sensing. Although a case can be made that the sensing ensemble in IDAs is formed by the assembly of a receptor and an indicator, we do not include synthetic receptor based IDAs in this category. Similarly, the elegant approach of templateassisted self-organized chemosensors developed by Tonellato, Tecilla, and others, in which a receptor and a dye are organized on a template, such as surfactant aggregates, monolayers, glass surfaces, and nanoparticles, will not be covered here.97 Below the assembly will be classified by intermolecular binding forces. 3.2.1. Ion Pairing Interaction. Many biological molecules, including amino acids, nucleic acids, and fatty acids, have an anionic motif, paving the way for molecular sensing through ion pairing interaction. Yu and co-workers reported a highly sensitive label-free turn-on fluorescence sensing system for single-stranded DNA (ssDNA).98 A perylene probe bearing two negative carboxylates (20) was prepared, and its emission spectrum exhibits a peak maximum at 545 nm and a shoulder at 588 nm. The fluorescence intensity is both concentration and pH dependent, indicative of signal modulation through aggregation and deaggregation. Upon binding of the probe with polycations through electrostatic interaction, the induced aggregation leads to quenching of the monomer fluorescence (Figure 15). When polyanionic ssDNA is added, its assembly with the polycationic polymer leads to the release of monomer and hence the recovery of fluorescence. A limit of detection of 2 pM ssDNA was determined. Moreover, an assay was developed for convenient and sensitive detection of alkaline

Figure 11. (a) Structures of macrocyclic hosts as synthetic receptors. (b) Mode of signal transduction by IDAs. Reprinted from ref 90. Copyright 2014 American Chemical Society.

Alternatively, the indicator can be displaced as a result of an allosteric interaction of an analyte with a receptor in the socalled allosteric indicator displacement assay (AIDA, Figure 13). Singaram and co-workers designed a series of diboronic acid substituted bipyridinium salts (BBV, 19), and their recognition of monosaccharides as well as α-hydroxycarboxJ


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Figure 12. Product selective fluorescence switch-off supramolecular tandem assay using CB7 and AO as a reporter pair. Reprinted from ref 93. Copyright 2011 American Chemical Society.

phosphatase (ALP) that removes the 5′-phosphate functional group of DNA. Wang and co-workers developed water-soluble cationic copolythiophenes (CPT1, 21−23) for colorimetric and fluorometric sensing of lipopolysaccharide (LPS).99 The sensing system displays great selectivity as well as extremely high sensitivity at the picomolar level and also allows for nakedeye detection (Figure 16). TEM and AFM studies revealed that

Figure 13. Illustration of an allosteric IDA.

Figure 14. AIDA scheme for glucose (a) and amygdalin (b) detection. K


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by achieving the detection of explosives, such as TNT (trinitrotoluene) and RDX (Research Department Explosive, cyclotrimethylenetrinitramine), using conjugated polymers.100,101 In a recent example, Ajayaghosh and co-workers achieved attogram sensing of TNT with a self-assembled fluorescent organogelator.102 The perfluoroarene-based gelator (OPVPF, 24) forms stable gels in hexane and exhibits a color change (green to yellow). The yellow color then changes to orange-red when a hot solution of the gel is dip-coated on filter paper. The color change is thermally reversible, and micrometer-sized fibers from self-assembly of OPVPF were confirmed by SEM. Although not efficient in solution, the gelator molecule can detect TNT in the gel form with a detection limit of 0.23 ppq after coating on a paper strip (Figure 17). Using a similar strategy, fluorescent supramolecular aggregates based on a pentacenequinone derivative (25) were employed by Bhalla and co-workers for the detection of picric acid (PA).103 Zhang and co-workers reported 4-amino-3-hydroxynaphthalene-1-sulfonic acid (26) as a simple fluorescent sensor for cyanide ion.104 The self-assembly mechanism was confirmed by

Figure 15. Illustration of binding and signal transduction for ssDNA detection.

Figure 16. (a) Absorbance titration spectra of CPT1-C upon addition of LPS. (b) Fluorescence titration spectra of CPT1-C upon addition of LPS with an excitation at 460 nm. The insets show the corresponding color change. Reprinted from ref 99. Copyright 2012 American Chemical Society.

CPT1 assembles to a quasi-sphere structure in aqueous solution. Upon LPS binding, cooperative electrostatic and hydrophobic interactions induce a conformational change of CPT1, resulting in a signal amplification. The sensor CPT1-C is also capable of discriminating Gram-negative bacteria from Gram-positive ones. 3.2.2. π−π Interaction. Self-assembled architectures of πconjugated molecules have captured the attention of supramolecular chemists for use in chemosensor development. These π-conjugated molecules also show unique photophysical properties, and their assembly can modulate the optical signal change. Swager and co-workers significantly advanced the field

Figure 17. (a) Photograph of the fluorescence quenching of OPVPF coated test strips by nitroaromatics on contact mode when viewed under 365 nm UV illumination. (b) Emission spectral change (excitation at 450 nm) of the test strips upon addition of TNT. Reprinted from ref 102. Copyright 2012 American Chemical Society. L


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aggregation. The cationic receptor becomes zwitterionic at high pH due to the interaction of boronic acid and a hydroxide ion. More ordered aggregates are assembled upon glucose introduction because of 1:2 binding stoichiometry of glucose and boronic acid, leading to a more hydrophobic unit, shorter distance between pyrene motifs, and hence turn-on of excimer fluorescence. However, one fructose molecule can only interact with one boronic acid unit, and the higher hydrophilicity destabilizes the aggregates, resulting in a pyrene monomer band. The selectivity for glucose over fructose was further improved by “knock-out” binding (mask) of fructose by adding phenylboronic acid to the sensing ensemble (Figure 19). This aggregation strategy and the concept of “knock-out” of the fructose offer valuable insight for future design of glucose receptors.

Figure 19. Cartoon illustrating glucose induced aggregation and the knock-out binding of fructose by an excess of phenylboronic acid. Reprinted from ref 106. Copyright 2013 American Chemical Society.

X-ray, ESI-MS, and NMR analyses. The π−π stacking between the naphthalenes and electrostatic interaction between ammonium and sulfonate as a result of intramolecular proton transfer lead to a strong fluorescence emission at 452 nm, and CN− destroys the assembly and therefore turns off the signal (Figure 18). This sensing system shows good selectivity toward CN− over F−, Cl−, Br−, I−, AcO−, H2PO4 −, HSO4 −, and ClO4 − due to the high basicity of CN−.

With a similar self-assembly approach, Wang, Lee, and coworkers designed amphiphilic N,N-dimethyl-N-(pyrenyl-1methyl) dodecan-1-ammonium (28) for ratiometric and sensitive detection of LPS with a low detection limit of 100 nM in 1:6 MeOH/HEPES buffer.107 Schmuck and co-workers developed cationic polydiacetylene (PDA) liposomes as a turnon fluorescent sensor for LPS in 1:4 DMSO/TBS buffer.108 The liposomes are composed of two lipids in a ratio of 9:1 (29/ 30). In one lipid (30), a pentalysine oligopeptide bearing a naphthalic acid reporter on one lysine side chain is attached to 10,12-tricosadiyonic acid, while the other lipid (29) has a histidine connected to the tricosadiyonic acid. The diacetylene units within cationic liposomes polymerized to form conjugated cross-linked polydiacetylene fluorophore upon irradiation with UV light. Fluorescence resonance energy transfer from the naphthalic acid reporter to PDA led to quenching, and the signal was recovered upon interaction with LPS. The spherical self-assembled liposomes were confirmed by DLS and AFM studies, and the binding of LPS increased the size of aggregates. This sensing system exhibits selectivity for LPS over other anionic biological relevant species, such as nucleotides. Fluorescence staining of the membrane of E. coli bacteria was also performed. Hamachi and co-workers recently reported a series of selfassembling fluorescent nanoprobes (31, Figure 20) consisting

Figure 18. Proposed sensing mechanism for CN−.

3.2.3. Amphiphilic Interaction. Amphiphiles are basic building blocks in colloidal and biomimic chemistry, and their assembly and modulation are essential for drug and gene delivery as well as biological sensing.105 James, Jiang, and coworkers recently reported a highly selective and sensitive ratiometric fluorescent sensor for glucose in aqueous solution.106 The amphiphilic receptor (27) has a cationic pyridinium unit as well as a monoboronic acid. A hydrophobic pyrene group was also incorporated to fine-tune the amphiphilic properties of the sensing system and allows ratiometric sensing with its emissive excimer band. Only monomer fluorescence at 390 nm is present for the receptor itself, and the binding of glucose increases the excimer emission at 510 nm while there is only a slight change in the monomer emission at pH 10.0. Frutose exhibits opposite effects with a modest increase in the monomer band and no excimer peak. The signaling mechanism was rationalized with amphiphilic M


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Figure 20. Illustration of mechanism of self-assembling probes (a) and related structures (b).

imine condensation of di- and triamines with a metallamacrocycle bearing three aldehyde units,113 Severin and co-workers recently reported a new cylindrical, imine-based cage (33, Figure 22) as a host for alkali metal ions.114 The cage was created from two Ru metallamacrocycles and contains six (pcymene)Ru fragments. The molecular recognition properties were studied by NMR and X-ray crystallography (Figure 23). The smaller Li+, Na+, and K+ occupy the binding site outside the cage and are coordinated with oxygen atoms and their counteranion. In contrast, the larger Rb+ and Cs+ are bound inside the cage through cation−π interactions with CN, instead of direct binding with the lone pair of nitrogen. The receptor displays good selectivity for Li+ and Cs+ at the external and internal binding sites, respectively. Moreover, the recognition of Cs+ induces a color change. Nitschke and co-workers constructed a series of metal− organic cages through subcomponent assembly of pyridine-2carboxyaldehyde derivatives, primary amines, and metal ions, such as Fe2+,115 Zn2+,116 and Cd2+.117 Both imine bonds (C N) and metal coordination bonds (N−M) are created, resulting in great molecular complexity in a single reaction step. The host−guest behavior of the cages was investigated, and both neutral and anionic substrates can be bound.118 Very recently, they developed a strategy of reduction and demetalation of a preformed cage (34) for a new functional cage (35) that is challenging to construct (Figure 24), and the host exhibits

of a hydrophilic protein ligand (biotin, benzamidine, or benzenesulfonamide) and a hydrophobic BODIPY fluorophore.109 The fluorescence is quenched in the aggregates, but disassembly upon binding of the receptor to the corresponding protein turned on the signal. The design of ligand-tethered probes is modular. For example, by changing the ligand, similar probes were developed for the specific detection of human carbonic anhydrase I (hCA, Figure 21), avidin, and trypsin. Moreover, a hydrophobic linker was introduced to modulate the aggregation behavior of the sensor (32), allowing the use of more hydrophilic probes, such as fluorescein or rhodamine. Using their respective ligands, selective imaging of cell surface protein biomarkers, such as dihydrofolate reductase (DHFR), was also achieved.110 Very recently, Tian, Wu, Zou and coworkers developed a peptide probe for the detection of neurokinin-1 receptor using disaggregation induced enhancement of fluorescence as well as magnetic resonance signals.111 This recognition-driven disassembly of ligand−linker−reporter nanoprobes could be applicable to other biological targets. 3.2.4. Reversible Covalent Interaction. The field of dynamic covalent chemistry has been burgeoning in the past decade, and the formation of reversible covalent bonds has been increasingly employed for creating complex architectures through self-assembly or poststructure modification.112 Building upon their construction of supramolecular cages through N


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Figure 23. X-ray cystal structures of the Cs+ (left) and the bis-LiCl (right) adducts of cage 33. Reprinted with permission from ref 114. Copyright 2013 Wiley-VCH Verlag GmbH & Co. KGaA.

Figure 21. (a) UV−vis absorption spectra of hCA-specific probe alone: 0.5 (red) and 25 μM (blue). (b) UV−vis titration (25 μM probe) upon addition of hCA (0−75 μM). (c) Fluorescence titration (25 μM probe, excitation at 468 nm) upon addition of hCA (0−75 μM). The inset shows the fluorescence titration isotherm at 580 nm. (d) DLS analysis of the particle size distribution of self-assembled probe (25 μM). Reprinted from ref 109. Copyright 2010 American Chemical Society.

Figure 24. Construction of cage 35 and HPTS dye used for the binding assay.

Another important strategy for receptor creation is the construction of dynamic combinatorial libraries (DCLs). Lehn120 and Sanders121 made pioneering contributions to the development of dynamic combinatorial chemistry. In a DCL, a series of receptors is assembled, and they are in equilibrium due to the dynamic nature of the process. Upon introduction of an analyte (template), the molecular recognition leads to a redistribution, thereby amplifying the desired receptor. A series of reviews have been published,122−124 and hence, only several representative examples are shown here. Sanders and coworkers identified a new linear hydrazone receptor that binds multiple dihydrogen phosphate ions.125 A DCL of macrocyles and linear oligomers was created and equilibrated by a di(valine hydrazide) on a ferrocene motif (V), 4-methylbenzhydrazide (H), and isophthalaldehyde (I) in 96:4 CHCl3/MeOH after 10 days. The addition of tetrabutylammonium dihydrogen phosphate induced an increase in concentrations of oligomers with a concomitant decrease of the macrocycle (VI)2 (Figure

Figure 22. Construction of cage 33.

strong affinity toward aromatics with anionic substituents and could be used in IDAs.119 Particularly, nanomolar affinity for HPTS was achieved. In addition to molecular cages, dynamic covalent assemblies with other structures and topologies should further propel their applications in molecular sensing. O


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25). The amplification and selection of long and complex linear isomers at the expense of competing macrocycles is

Figure 25. HPLC chromatogram (290 nm) of DCLs formed from V, I, and H in 96:4 CHCl3/MeOH in the absence (dashed black curve) and presence (solid red curve) of Bu4NH2PO4. Reprinted from ref 125. Copyright 2011 American Chemical Society.

unprecedented. The linear pentamer HIVIH (36) binds two molecules of H2PO4− cooperatively through hydrogen bonding with K1K2 = 800 000 M−2. The preorganization by intramolecular hydrogen bonding and flexibility to adapt its conformation contribute to the strong cooperative ditopic binding of linear receptor 36 (Figure 26).

Figure 27. Creation of 37 (a) and structures of related amino acids (b).

substrates with different sizes, shapes, and charge states in aqueous solution.127

4. DIFFERENTIAL SENSING Differential sensing has become a standard strategy, complementary to single analyte sensing over the past decade. All dynamic bonding forces as well as supramolecular concepts and techniques can be employed in these two approaches. However, cross-reactivity is desired for differential sensing while a premium is placed on enhancing affinity and selectivity in single analyte sensing. Due to this key difference, the design, synthesis, and optimization of differential receptors are not as demanding as for specific sensors. This method also allows the discrimination of analytes and mixtures whose structure or component is unknown. The differential recognition of analytes based on different mechanisms with a single receptor (for example, a receptor reported by Sykes and co-workers for sensing of Cu2+ and Zn2+)128 will not be covered here. The groups of Suslick,129 Anslyn,38 Anzenbacher,130,131 Severin,126 and Rotello132 have made important contributions to the development of this field. We will present detailed examples of each analyte class: cations (section 4.1), anions (section 4.2), small neutral molecules (section 4.3), and bioanalytes (section 4.4).

Figure 26. Creation of 36 and its binding of H2PO4−.

Waters and co-workers recently discovered the first small molecule synthetic receptor for selective recognition of asymmetric dimethyl arginine (aRMe2) over the isomeric symmetric dimethyl arginine (sRMe2) using dynamic combinatorial chemistry.126 The DCLs were built from aromatic thiols bearing anionic groups using disulfide exchange (Figure 27). The receptor A2D (37) has binding affinities for aRMe2 containing peptides in the low micromolar level and exhibits selectivity toward aRMe2 over other basic amino acids. Detailed structural studies revealed that cation−π interactions are the main driving force for binding, similar to nature protein receptors. Similarly, but using only two aromatic dithiols as building blocks, Otto and co-workers developed a DCL based general receptor platform for a series of amine and ammonium

4.1. Cations

As the case in single analyte sensing, metal ions are among the earliest targets subjected to differential sensing. This is understandable considering that the availability of numerous ligands provides an excellent opportunity for creating sensor arrays. Anzenbacher and co-workers reported rational design of a fluorescent sensor array for detection of metal ions.133,134 One common ligand, 8-hydroxyquinoline (8-HQ), was attached to a series of conjugated fluorophores (38−43). The fluorescence is partially quenched in the free form, and the coordination of metal ions induces a signal change (Figure 28). The sensor array is highly cross-reactive as varied binding affinity, extent of conjugation, and fluorescence modulation P


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Figure 28. Fluorescence change upon metal coordination by the 8hydroxyquinoline unit.

scheme lead to a characteristic pattern for each receptor−metal complex. The information from three emission channels (blue, green, and yellow) could be used in both qualitative and quantitative analyses. PCA and LDA protocols were employed to evaluate the contributions of individual sensors within and the differentiation power of the array (Figure 29). The analysis was conducted with arrays containing various numbers of sensors for identification of 10 metal ions (Ca2+, Mg2+, Cd2+, Hg2+, Co2+, Zn2+, Cu2+, Ni2+, Al3+, and Ga3+), and a two member array was able to discriminate all 11 analytes (10 cations and one control) with 100% accuracy. Moreover, the two best receptors were found to identify the analytes with 99 and 96% accuracy, respectively. As a demonstration of realworld applications, the sensor array was used for identification of complex mixtures, such as enhanced water samples, based on levels of Ca2+, Mg2+, and Zn2+. The approach of receptor selection for creating minimal size sensor arrays should be applicable to other classes of analytes.

Instead of using a single binding motif, Anzenbacher and coworkers also constructed a sensor array with nine sensing elements (41, 44−51) based on different kinds of coordination chemistries for the discrimination of 10 metal ions.135 The selectivity and cross-reactivity as a result of metal−ligand interactions gave rise to unique fingerprints. Qualitative tests can be achieved with over 96% accuracy in a concentration

Figure 29. Discriminatory ability of three arrays containing various numbers of sensors. (a) PCA for the complete set of sensors (S1−S6) indicates that the main contributors for the dispersion were S4, S2, and S5 on the PCs with statistical significance (numbers in yellow); (b) PCA analysis after S1, S3, and S6 were excluded from the data set shows that the main contributors were S2 and S4; (c) PCA analysis after S5 was excluded from the data set. The PCA score plot for the final set of two sensors (S2 and S4) shows clustering of the data without any evident overlap between different samples. LDA analysis shows 100% accurate classification for all three arrays. Reprinted from ref 134. Copyright 2008 American Chemical Society. Q


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range of 5−5000 μM, and quantitative measurements can be conducted with over 90% accuracy in the concentration range between 10 and 5000 μM using LDA analysis. They also developed a facile method for fabrication of ultrasmall fluorescent probes as a means of developing wearable sensors for metal ions.136 The probes (such as 52−54) were created in situ by three amines (such as tetraethylene pentamine) and three reactive fluorescent dyes (fluorescamine, dansyl chloride, and 7-chloro-4-nitrobenz-2-oxa-1,3-diazole), and the signal can be modulated by simply changing the probe concentration in each attoreactor. The sensor array could also be deposited on various devices. In a recent report, Bunz and co-workers synthesized several water-soluble bis-triazolyl benzochalcogendiazoles (55−57) and explored their metal binding properties.137 The optical signal as well as the affinity for metal ions is dependent on the chalcogen heteroatom (O, S, or Se). The metal coordination within the binding pocket of chalcogendiazole and triazole resulted in fluorescence quenching. Discrimination of Cu2+, Ni2+, and Ag+ and classification of unknowns were achieved using LDA analysis.

In an effort to increase the dynamic range of the signal responses and achieve better differentiation of fluorescencequenching metal ions, Kool and co-workers incorporated metal ligands and fluorophores on a DNA backbone to construct oligodeoxyfluoroside (ODF) type chemosensors.138 The interaction of nearby ligands and fluophores could afford different properties from monomers. Three deoxyribosides bearing hydrophobic fluorophores and three deoxyribosides with nonselective metal-binding fluorescent ligands were chosen as building blocks for modular design and synthesis. Upon metal coordination, the modulation of interfluorophore electronic interactions leads to distinct signals for individual metal ions. The phosphodiester linkages also increase the water solubility of the receptors. A library of tetrameric fluorophores and ligands on modified PEG−polystyrene beads was rapidly prepared by the split-and-pool method on a DNA synthesizer, and abasic spacer nucleotide monomers (58) were attached on both ends of the ODF to increase water solubility and prevent aggregation. The beads were screened with eight quenching metal ions (Co2+, Ni2+, Cu2+, Hg2+, Pb2+, Ag+, Cr3+, and Fe3+), and six receptors with strong fluorescence responses were identified and resynthesized for further analysis (Figure 30). A

Figure 30. RGB color representation of the changes in fluorescence response of six oligomer sensors to each of the eight metal ions. The three wavelengths selected to represent RGB are 650, 550, and 450 nm, respectively. The fluorescence change values for each of the wavelengths were transformed into a 0−255 scale with 127 set as the value for no change. References A, B, and C represent RGB values of 0, 0, 0; 127, 127, 127; and 255, 255, 255. Reprinted from ref 138. Copyright 2011 American Chemical Society.

wide variety of responses to quenching metal ions, including both fluorescence peaks and intensities, were discovered, allowing successful discrimination of these eight metal ions with only two sensors using pattern recognition. Moreover, identification of unknown metal ion solutions was also achieved.

The differential sensing of organic cations, such as basic amino acids, has also been reported. They are protonated at R


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neutral pH and hence recognized as charged species. Generally, the same IDA strategy was employed as the previously discussed Nau’s systems, but in an array format. Hof and coworkers developed antibody-free detection of the histone code using chemical sensor arrays.139 The histone code is the complex network of post-translational modifications present mainly on the N-terminal tails of the DNA-packaging proteins called “histones”, and is related to a variety of human diseases. The sensor arrays constructed from readily available dyes and calixarene hosts were able to produce characteristic fingerprints for and thereby discriminate a series of cationic amino acids and peptides (Figures 31 and 32). For example, this mix and match

Figure 32. Fluorescence response (F − F0) (a) and LDA plot (b) for analysis of amino acids by a sensor array in which the host and dye remain the same but pH and solvent composition vary (S1, S2, and S3). Reprinted from ref 139. Copyright 2012 American Chemical Society.

Figure 31. (a) Receptors and fluorescent dyes used in the construction of the sensor arrays. (b) Illustration of pattern generation by sensor arrays to identify and quantify analytes. Reprinted from ref 139. Copyright 2012 American Chemical Society.

tool kit can identify unmethylated and mono-, di-, and trimethylated lysines on a single histone tail sequence, varied modifications and combinations of modifications on a single histone tail sequence, a single modification type in several different sequence contexts, and isomeric dimethylarginine modifications. Moreover, the sensor array was employed to detect the concentrations and identities of histone modifications simultaneously. Based on their previously reported turn-on fluorescent cucurbit[n]uril (CB[n]) sensor (65) for diamines,140 Anzenbacher, Isaacs, and co-workers reported a sensor array for recognition and quantification of cancer-associated nitrosamines with the addition of a complementary acyclic CB[n]type probe (66, Figure 33).141 Nitrosamines are less basic than aliphatic amines and are challenging to detect. Due to the naphthalene moieties, both probes are fluorescent, but their fluorescence was partially quenched upon coordination of metal ions, such as Eu3+, Yb3+, Zn2+, Ba2+, and Hg2+, with different binding profiles. After the addition of the amine analytes at pH 3, the metal ion was displaced, leading to a signal change. The varied competition among the probe, metal, and analyte generates a signal with high information density, allowing the differentiation of structurally similar analytes. This two probe array is able to identify 13 amine guests with 100% correct

Figure 33. Structures of analytes and sensors used. Reprinted from ref 141. Copyright 2012 American Chemical Society.

classification. Moreover, there was a dose dependence of the fluorescence response, enabling semiquantitative and quantitative determination (Figure 34). The concentrations of tobaccospecific N-nitrosamines NNN and NNK in their mixtures were successfully predicted based on the corresponding calibration data set in the presence of excess of nicotine (50 μM), with the limits of detection of 0.05 and 0.27 ppm for NNN and NNK, respectively. These values are comparable with or within the requirements in food safety applications. With the same two probes and competition approach, the differential recognition and quantification of drug related amines,142 as well as discrimination of basic amino acids,143 were also achieved. S


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Figure 35. Intramolecular partial charge transfer (IPCT) leads to anion-induced changes in absorbance or fluorescence.

chemosensors in polyurethane hydrogel allow the use of previously reported sensors that are poorly functional in aqueous solution because the cooperative effects between the hydrogel in solid state and sensors facilitate extraction of the anionic analytes from the solution phase. Moreover, the anion affinity and selectivity profiles in organic solvents help the rational design of arrays with predictable analytical properties for a target analyte. The eight-sensor array composed of sensing elements selective for fluoride and pyrophosphate, but exhibiting significant cross-reactivity for other anions, was able to differentiate between 10 inorganic anions, including F−, Cl−, Br−, AcO−, BzO−, NO3−, HSO4−, H2PO4−, PPi, and HS− (Figure 36). The quantitative tests revealed that the sensor array can function in a wide concentration range from picomolar to millimolar scale for target anions. The complex mixtures in several toothpaste brands were also successfully discriminated with the fluoride content as the main differentiating factor.

Figure 34. (a) LDA plot of the semiquantitative assay of NNN and NNK. (b) Results of the support vector machine (SVM) regression for quantitative analysis of NNN mixtures in the presence of interfering nicotine. The values of the root-mean-square errors (RMSEs) of calibration (C), cross-validation (CV), and prediction (P) (shown as insets) confirmed the high quality of the model and prediction. Reprinted from ref 141. Copyright 2012 American Chemical Society.

4.2. Anions

The recognition and sensing of anions is of significant importance due to their biological relevance. Although a variety of synthetic receptors have been developed for inorganic, organic, and biological anionic analytes, the selective detection of structurally similar substrates, such as amino acids, peptides, and nucleotides, remains challenging. Yet differential sensing takes advantage of low-selective and cross-reactive sensor arrays and can exhibit powerful discriminatory ability. Both sensing strategies (direct sensing and IDA) as well as all anion binding units can be employed for the creation of sensor arrays. Because most biological molecules have an anionic motif, this section will only cover inorganic anions and small organic anions, and the sensing of proteins will be presented in section 4.4. Based on their efforts of discovering new macrocyclic hosts for selective anion sensing,144,145 Anzenbacher and co-workers reported an eight-member sensor array for multianion detection in aqueous solution.146 Pyrrole based hydrogen bonding anion receptors were used: one N-confused calix[4]pyrrole (67), six regular calix[4]pyrroles (68−73), and 2,3di(pyrrol-2-yl)quinoxaline (74). An intramolecular partial charge transfer (IPCT) results in a color change in the presence of anions, and different chromophores were also incorporated to manipulate the optical signal (Figure 35). Two key features were found to significantly enhance the discriminatory ability of sensor arrays utilizing pattern recognition protocols. The arrays constructed by embedding

In a recent report, Anzenbacher and co-workers extensively investigated the effect of polymeric matrices on the performance of anion sensor arrays.147 The arrays prepared by embedding a single ratiometric calix[4]pyrrole probe (74) in different poly(ether−urethane)s (PEUs, 75), with varying comonomer proportions, were able to differentiate and classify eight different anions and eight urine samples.

T


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Figure 36. (a) Array responses to aqueous solutions of anions. (b) PCA score plot of the first three PCs for 100 samples (10 anions, 10 trials each). (c) Hierarchical clustering analysis (HCA) dendrogram obtained using Ward linkage shows the Euclidean distance between the trials. Reprinted from ref 146. Copyright 2007 American Chemical Society.

Anzenbacher and co-workers also developed a fluorescent turn-on sensor array for anions, including phosphate species, using simple sensors embedded in a polyurethane hydrogel matrix.148 Eight tripodal receptors based on 1,3,5-triaminomethyl-2,4,6-triethylbenzene (76−79, 81−84) can form an anion binding pocket with six hydrogen-bond donors. The fluorescence is turned on upon anion coordination in aqueous solution, with dihydrogen phosphate and pyrophosphate showing the strongest binding affinity. Various phosphate ions, including AMP and ATP, were successfully differentiated even in human blood serum. Similar fluorescent tripodal anion receptors (77, 80, 82, 84, and 85) were also employed to detect and discriminate hydrolysis products of the nerve gas sarin, isopropyl methylphosphonate (IMP), and methylphosphonate (MP) (Figures 37 and 38).149

Figure 37. Hydrolysis of sarin to generate IMP and MP.

Very recently, Anzenbacher and co-workers achieved efficient sensing of carboxylate drugs in water or urine with a supramolecular sensor array embedded in polyurethane films.150 The calix[4]pyrrole unit was incorporated into seven sensors (72−74, 86−89) with different chromophores, while the eighth (82) was based on the aforementioned tripodal scaffold to further modulate the binding and signaling properties. Using PCA and LDA analysis, the eight-member array was found to detect 14 carboxylates in water with 100% classification accuracy. The performance of the array was further validated by successful and accurate identification of carboxylate drugs in human urine (Figure 39). Moreover, the differentiation of and simultaneous semiquantitative analysis for six nonsteroidal anti-inflammatory drugs (NSAIDs) were conducted in the concentration range of 0.5−100 ppm, demonstrating the potential for real life applications. In the latest report, Anzenbacher, Ema, and co-workers prepared amide or sulfonamide based chiral macrocycles (90−92) for colorimetric and fluorescent detection of anions.151 Discrimination of seven phosphate anions (AMP, ADP, ATP, CMP, GMP, Pi, and PPi) was achieved using two or four receptors in an array in 1:9 water/DMSO with 100% classification accuracy. Pinet, Sojic, and co-workers developed a guanidinium 3,3′functionalized bipyridylruthenium(II) complex (93) for differential sensing of anions with two detection channels.152 Two

Figure 38. LDA score plots using a five-member (a) or two-member (b, 82 and 84) sensor array. Reprinted with permission from ref 149. Copyright 2013 Royal Society of Chemistry.

guanidinium arms serve as the anion recognition motif, and the resulting photoluminescence (PL) and electrochemiluminescence (ECL) of the Ru3+ complex were monitored. In the PL sensing scheme, better sensitivity and selectivity were found for L-glutamate over dihydrogen phosphate, while only dihydrogen phosphate was able to induce a change in the ECL intensity with L-glutamate irreversibly oxidized at the very anodic potential required for the ECL generation. Acetate, iodide, and chloride exhibited no response in both PL and ECL. Based on cross-correlation of two luminescence detection modes, multianion analysis was also conducted in competitive assays. This multichannel approach for better discrimination could be applicable to other sensing systems. Tomapatanaget and co-workers achieved the differentiation of nucleotides with a single fluorescent chemosensor (94) under solvent-dependent conditions.153 The receptor was based U


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Figure 39. (a) PCA score plot for 150 samples (14 carboxylates in water plus a control, 10 trials each) produced by an eight-member sensor array. (b) LDA score plot for the response of an eight-member sensor array to 14 carboxylates in urine. Reprinted from ref 150. Copyright 2013 American Chemical Society.

adenosine portion of ATP and the pyrene unit apparent. Ten nucleotides were successfully discriminated with high accuracy in two solvent systems using PCA analysis. Moreover, the sensor was employed for quantitative prediction of the PPi and ATP ratios for the reaction of ATP hydrolysis. In addition to direct sensing, Anslyn and Severin advanced the field by developing IDA based differential sensing. Building on IDAs for a series of anionic analytes using both organic and organometallic receptors, Anslyn and co-workers successfully transitioned them into sensor arrays. In an early example, two differential receptors were employed for the simultaneous detection of structurally similar tartrate and malate using a

on a Zn−DPA complex with an attached methylpyrene unit. The sensor shows excellent selectivity for PPi over other anions in an aqueous solution with a log K value of 10.2, but favors nucleotide polyphosphates, such as ATP and UTP, with a large fluorescence enhancement in 9:1 DMSO/HEPES buffer. Detailed structural analysis and molecular modeling revealed that zinc complexation of the phosphate moiety of ATP is the dominating binding force with no interaction between the V


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and nine indicators were screened initially using a simplified receptor without peptide arms and phosphoserine. Three metal ions (Co2+, Ni2+, and Cu2+) and three indicators (pyrocatechol violet, celestine blue, and gallocyanine) were selected and subjected to prescreening with resin-bound receptors to determine the peptide sequences. Five peptide receptors were resynthesized and employed for pattern recognition. As many as 45 IDAs were created on a sensor array by multiple combinations of metal ions, indicators, and tripeptide functionalized receptors. The capability of discriminating peptide phosphorylation was demonstrated by identification of six model peptides (MPS, MPSp, PSE, PSpE, SEE, and SpEE) with 100% classification using LDA analysis. multicomponent indicator displacement assay.154 Two tripodal structures were chosen, with one bearing two guanidinium units and one boronic acid (95) and the other with one guanidinium motif and two boronic acids (96). The guest binding was achieved thorough dynamic boronic ester formation in conjunction with hydrogen bonded salt bridges. Pyrocatechol violet (PV) and bromopyrogallol red (BR) were used as colorimetric indicators to modulate the magnitude and wavelength ranges due to their varied binding strengths and optical responses. All species were mixed and the absorbance spectra of this four-component sensing ensemble were recorded. A training set for multilayer perceptron artificial neural networks (MLP-ANN) was generated with the same respective concentrations of receptors and indicators but varied amounts of two analytes. The unknown samples were then tested, and their concentrations were predicted with an error as low as 2%. It is worthwhile to mention that this is among the earliest examples of using ANN for supramolecular detection. With three organic receptors (95−97) and three indicators (PV, BR, and AC), they also achieved pattern recognition based discrimination of organic acids and red wine varietals.155 In their effort to enhance diversity and cross-reactivity in a simple and modular way, Anslyn and co-workers took advantage of solid phase combinatorial synthesis for the creation of differential peptide receptors156 for phosphate related anions157 and tripeptides.158 In a more recent example, an array sensing scheme was developed to pattern peptide phosphorylation.159 The receptors (98) were based on their previously reported C3v symmetric copper binding tris(2pyridylmethyl)amine motif with appended guanidinium groups designed for complementing tetrahedral oxyanions of phosphate.80,160 Tripeptide arms were attached to create the sensor array. A library of hosts was prepared using split-and-pool methods starting from a tripodal precursor. Eight metal cations

Severin and co-workers developed a series of IDA sensor arrays using simple metal complexes as nonselective receptors (Figure 40).161 They achieved colorimetric identification of structurally similar, nonfunctionalized amino acids with a commercially available, air-stable and water-soluble organometallic rhodium complex (99) that exhibits relatively fast exchange kinetics.162 Three indicators (gallocyanine, xylenol orange, and calcein blue) were employed to create the array, and pH change was used complementarily to enhance the

Figure 40. Metal complexing IDAs for the construction of sensor arrays. W


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differentiation. All 20 natural amino acids were distinguishable, including closely related leucine and isoleucine. Excellent predictive ability was revealed using LDA analysis, and the clustering of the data was also detected in a PCA score plot (Figure 41).

Figure 42. LDA score plot for the discrimination of eight different hexanucleotides and a blank sample without any analyte. Reprinted with permission from ref 164. Copyright 2010 Royal Society of Chemistry.

Figure 41. PCA score plot for the identification of the amino acids. Reprinted from ref 162. Copyright 2005 American Chemical Society.

In a recent report, Prins, Severin, and co-workers developed an IDA based sensing system using metal complex functionalized gold nanoparticles (monolayer protected gold clusters, Au MPCs) as a template (Figure 43).166 Although the array was prepared with a self-assembly strategy and was able to discriminate eight nucleotides, the IDA took place on the metal center, similar to other sensor arrays discussed above. Discrimination of inorganic anions was also achieved using simple metal complexes based IDA arrays by Guan, Feng, and co-workers.167 In the previous examples, only one receptor, such as a metal complex, was used in each sample on the arrays (Figure 44). By contrast, Severin and co-workers took a page from dynamic combinatorial chemistry for the utilization of DCLs to create differential sensing systems. The key was to transduce DCL composition into an optical signal output for quick and costeffective analysis. Built upon the foundation of their metal

In another example, Severin and co-workers utilized a multicomponent indicator displacement assay for the identification and quantification of low millimolar concentrations of nucleotides and PPi in water at pH 7.4.163 The array was created from the same Rh complex and three dyes (Mordant yellow, gallocyanine, and Evans blue), and was able to discriminate PPi, ATP, GTP, ADP, AMP, and cAMP. The measurements were performed in 50 mM phosphate buffer due to the sensor’s selectivity for PPi and nucleotides over phosphate. Moreover, the simultaneous determination of the concentrations of ATP and cAMP/PPi with a single colorimetric reading was successfully conducted using standard MLP-ANN. The IDA array was also expanded to other metal complexes, such as Ru2+ (100) and Pd2+ (101 and 102), for the detection of short oligodeoxynucleotides (Figure 42)164 and dipeptides.165 X


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Figure 43. (a) Schematic representation of the displacement of multiple fluorescent indicators from the surface of Au MPCs upon the addition of an analyte. (b) Molecular structure of the monolayer and fluorescence indicators. Reprinted with permission from ref 166. Copyright 2013 Royal Society of Chemistry.

Figure 44. Two approaches for creating sensor arrays: (a) a sensor array based on the combination of different metal complexes with different dyes and (b) a sensor based on a dynamic combinatorial library of metal−dye complexes. Reprinted from ref 170. Copyright 2010 American Chemical Society.

complexing IDAs, DCLs of metal−dye complexes were created from two metal ions (Cu2+ and Ni2+) and three indicators (Arsenazo I, methylcalcein blue, and glycine cresol red) (Figure 45a).168 Each library member has a characteristic absorbance spectrum, and the disturbance of the equilibrium would lead to a color change, allowing the identification of analytes. This adaptive system was able to discriminate dipeptides, even the steroisomers Phe-Ala and D-Phe-Ala. Similarly, a dynamic mixture of Fe2+ complexes with dipicolylamine (DPA), the functionalized bipyridyl ligand N-(6-aminohexyl)-4′-methyl2,2′-bipyridine-4-carboxamide (103), and the indicator Evans blue (Figure 45b) was used for colorimetric identification of different sulfated glycosaminoglycans.169 In a separate study, Severin and co-workers compared two different approaches for pattern recognition of short peptides using two metal salts (CuCl2 and NiCl2) and three dyes (methylcalcein blue, Arsenazo I, and xylenol orange): sensors based on DCLs with all metal ions and dyes in one pot and sensor arrays constructed from six separate metal−dye combinations (Figure 44).170 Upon the introduction of an analyte, the optical changes were detected at six selected wavelengths for the DCLs, while only one wavelength was used for six individual sensors in the array. The DCL based sensors afforded better differentiation of 13 di- and tripeptides than the standard sensor array in most cases, although DCLs of intermediate complexity were the best. As a modification of the standard IDA approach, Rurack, ́ Martinez-Má ñ ez, and co-workers developed a quencher displacement assay (QDA) for the differential recognition of anions with a hybrid organic−inorganic sensing ensemble.171 Rather than competing for one binding site between an indicator and an analyte, a sulforhodamine B indicator (I) and a terpyridine receptor (R) were attached separately on the

Figure 45. Dynamic mixtures of metal complexes for the detection of dipeptides (a) and glycosaminoglycans (b).

surface of silica nanoparticles (TNSP). A quenching metal ion (Q) can bind the receptor as well as the anionic analyte, thus serving as a mediator (Figure 46). Upon binding of metal ions to the terpyridine units, the fluorescence of the neighboring fluorophores was quenched. Coordination of the target anions Y


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Figure 46. Illustration of the quencher displacement assay (QDA) involving terpyridine/sulforhodamine-functionalized nanoparticles (TSNP) and metal ion quenchers (Q).

to the metal ions resulted in the recovery of the signal. A delicate balance between the binding affinity of the metal center with the terpyridine receptor and the anionic substrate allows differentiation of inorganic anions. The easy functionalization of silica surfaces with various molecular recognition and signaling units provides ample opportunities for developing sensors for other analytes. 4.3. Small Neutral Molecules

Due to the diverse nature of small neutral molecules, a large number of receptors, dyes, and substrate supports upon which the sensing ensemble are placed have been employed for constructing sensor arrays. For example, acid/base indicators, redox indicators, metal complex indicators, solvatochromic and vapochromic dyes, and aggregative chromogens have all been utilized (Figure 47). Suslick’s group made significant contributions to the field of differential sensing by developing a large variety of sensor arrays for organic gases and vapors. They recently published a comprehensive review of optical sensor arrays based on chemoresponsive colorant probes in both the gas and liquid phases,172 and hence, only selected examples will be presented in this review. In Suslick’s pioneering work of metalloporphyrin based colorimetric sensor array, coordination of analytes to the metal center resulted in color changes, and a broad range of volatile organic compounds (VOCs), including alcohols, amines, ethers, phosphines, thiols, arenes, and ketones, were identified.173 With a 24 dye array composed of metalated tetraphenylporphyrins, bis-pocketed Zn porphyrins, pH indicators, and solvatochromic dyes spotted onto a reverse-phase silica gel plate to differentiate analytes based on metal coordination, the size and shape, Brønsted basicity, and polarity of the analytes, respectively, discrimination of closely related amines was achieved with sensitivities well below 1 ppmv (Figure 48).174 Distinction between isomeric amines, such as dipropylamine and diisopropylamine, was also possible. Moreover, due to the hydrophobic nature of the indicators and analytes, changes in humidity did not interfere with the response of the array to analyte vapors. With an array of 36 colorimetric sensors, a library of 100 VOCs were discriminated, including amines, alcohols,

Figure 47. Several classes of indicators for sensing of small neutral molecules.

Figure 48. Color-difference maps for 12 amines (24 dyes). Maps were generated from the absolute values of the differences of the red, green, and blue values of each dye spot before and after equilibration with the analyte vapor. Reprinted with permission from ref 174. Copyright 2005 Wiley-VCH Verlag GmbH & Co. KGaA.

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aldehydes, arenes, carboxylic acids, esters, hydrocarbons, ketones, phosphines, and thiols.175 Selective responses were modulated through a wide range of intermolecular interactions, such as acid−base interaction, metal ion coordination, hydrogen bonding, and dipole−dipole interaction. The array was more sensitive toward strongly coordinating vapors, such as amines, carboxylic acids, thiols, and phosphines, than weakly coordinating vapors, such as esters, ketones, alcohols, arenes, and hydrocarbons. Recently, Suslick and co-workers developed a preoxidation technique that dramatically improves the detection and identification of less-reactive VOCs (Figure 49).176 The array

It was found that the porous matrix also serves as a preconcentrator and hence improves the overall sensitivity. In one example, the pattern of color changes within 2 min of exposure of TICs afforded a characteristic fingerprint, and 19 different TICs were successfully differentiated (Figure 51). The detection of TICs was also achieved with low detection limits, generally below the permissible exposure limits (PELs). In addition to using inexpensive flatbed scanners for imaging in the research laboratory, a fully functional prototype handheld device was also demonstrated as a potential wearable device for the portable monitoring of ambient toxic gases. Moreover, Suslick and co-workers developed a new method for sensitive detection of the vapor phase of the primary explosive triacetone triperoxide (TATP) with limits of detection (LOD) below 2 ppb.183 A sensor array of redox active nanoporous pigments was used to detect the resulting H2O2 vapor after decomposition of TATP by a solid acid catalyst (Figure 52). Discrimination of TATP from other chemical oxidants was also achieved using PCA analysis. Detection of structurally similar aliphatic amines184 as well as complex mixtures, such as coffee aromas,185 was also reported with arrays of nanoporous pigments. Besides detection and identification of vapors and gases, Suslick and co-workers reported a colorimetric sensor array printed on a hydrophobic surface for sensing of organics in water.186 The array was composed of 36 dyes (Lewis acid dyes, pH indicators, and solvatochromic dyes), and showed unique responses for dissolved organic compounds with various functional groups, such as carboxylic acids, aromatic amines, and aliphatic amines. The color change was so intense that a different class of analytes was distinguished by naked-eye detection. Moreover, the sensitivity was dependent on the analytes, and amines gave the lowest detection limits (100−1 μM). The enormous discriminatory capability of the array was also validated by hierarchical cluster analysis (HCA) and PCA analysis (Figure 53). Suslick and co-workers also achieved discrimination of complex mixtures using similar colorimetric sensor arrays. For example, 18 commercial beers were successfully identified in both liquid and gas phases with identification error rates less than 3%,187 and 14 commercial soft drinks were easily differentiated with identification error rates less than 2% (Figure 54).188 These results demonstrate the potential of those sensor arrays for quality control applications of foods and

Figure 49. Schematic illustration of the preoxidation technique. A Teflon tube was packed with chromic acid to pretreat the gas flow containing a VOC before it was passed over the colorimetric sensor array. Reprinted from ref 176. Copyright 2011 American Chemical Society.

sensing after passing the analyte stream through an oxidation tube packed with chromic acid on silica improved the sensitivity by ∼300-fold. The creation of more reactive species allowed discrimination of 20 commonly found indoor VOC pollutants over a wide range of concentrations. Suslick, Carey, and coworkers also achieved rapid identification of both species and specific strains of human pathogenic bacteria based on the produced volatiles with similar colorimetric sensor arrays.177 Suslick and co-workers also developed colorimetric sensor arrays of cross-responsive nanoporous pigments for the sensitive detection and discrimination of toxic industrial chemicals (TICs).178−181 The chemical interactions are similar to those described for VOCs, and four classes of indicators were utilized to target the chemical reactivity of the analytes: dyes containing metal ions (e.g., metalloporphyrins), pH indicators, vapochromic or solvatochromic dyes, and metal salts that participate in redox reactions. Thirty-six dyes were immobilized with nanoporous sol−gel matrices to provide both stability and analyte access to the chromophores (Figure 50).182

Figure 50. Colorimetric sensor array consisting of 36 different chemically responsive pigments printed directly on a polyethylene terephthalate film. (a) Image of the array with different pigment classes labeled. (b) Structures of examples from each dye class. Reprinted with permission from ref 182. Copyright 2009 Nature Publishing Group. AA


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Figure 51. Color change profiles of representative TICs at their IDLH concentrations (in ppm) after 2 min of exposure. RH = relative humidity. Reprinted with permission from ref 182. Copyright 2009 Nature Publishing Group.

Figure 52. Reactions for the detection of TATP.

Figure 54. PCA plot using the three most important principal components based on the data for the analysis of soft drinks. Abbreviations: A&W RB, A&W Root Beer; CD TW, Canada Dry Tonic Water; CD CS, Canada Dry Club Soda; LC SW, LaCroix Sparkling Water. Reprinted from ref 188. Copyright 2007 American Chemical Society.

Figure 53. HCA of organics using the color change profiles. The dendrogram shows quantitatively pattern similarities of the color change profiles. Reprinted from ref 186. Copyright 2005 American Chemical Society.

beverages. Analogous analysis has also been conducted with disposable colorimetric sensor arrays of nanoporous pigments by Suslick and co-workers. For example, 15 mono- and AB


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disaccharides as well as artificial sweeteners were discriminated without error in 80 trials after the array was exposed to the analyte in buffered arylboronic acid solutions (Figure 55).189,190 3-Nitrophenylboronic acid was chosen to modulate the pH and thereby color change of pH indicators due to its reversible covalent binding of 1,2-diols.

In a recent report, Anslyn and co-workers described sensor arrays that can fingerprint selected flavonoid metabolites and wines.194 The individual supramolecular sensing ensemble is composed of a metal ion, a colorimetric indicator, and a histidine-rich peptide of random sequence or previously known sequences (Figure 56). Upon introduction of a flavonoid or

Figure 56. Indicator displacement by flavonoids from peptide/metal ion/indicator complexes.

wine, the indicator is displaced, leading to a color change. Both flavonoids and red wines (Figure 57) were differentiated, even Figure 55. Change of pH upon dynamic covalent binding of carbohydrates with phenylboronic acid.

In addition to cross-reactive peptide sensor arrays for anionic analytes, Anslyn and co-workers developed boronic acid based peptide receptors for pattern recognition of saccharides in aqueous solution at physiological pH.191 Pentapeptidic receptors bearing boronic acids (106) were prepared using solid phase synthesis and tested in a taste-chip platform. The binding of a series of saccharides to peptide receptors was examined using a competitive indicator uptake protocol with bromopyrogallol red. The rate of indicator uptake after addition of saccharides generated characteristic patterns by following absorbance change, and the discriminatory capability of the array was evaluated with LDA analysis. It was found that monosaccharides and disaccharides were successfully classified, and compounds within each saccharide group were also differentiated. The array was able to discriminate structurally similar saccharide derivatives, such as sucrose, maltose, sucralose, and maltitol. Moreover, the LDA data set was utilized as a training set for the identification of a specific saccharide in a complex beverage sample. Using reversible covalent interaction of boronic acids and 1,2 or 1,3-diols, Lavigne and co-workers developed boronic acid functionalized peptidic synthetic lectins (SLs) for the discrimination of cancer associated glycans and glycoproteins.192,193

Figure 57. LDA plot of the response from different wine varietals Beaujolais (blue ○), Pinot Noir (blue ◇), Shiraz (●), Merlot (■), Cabernet Sauvignon (▲), and different brands of Zinfandel wines BS (red ◇), BT (□), C (△), R (∗), and SV (red ○). Reprinted with permission from ref 194. Copyright 2011 Royal Society of Chemistry.

though the exact structures and concentrations of the flavonoids in wines were not known. Such an approach of sensor arrays can be extended for the analysis of other complex mixtures.

With simple bis-boronic acids as differential receptors, Anslyn and co-workers achieved pattern recognition based detection of ginsenosides and ginsengs using multicomponent indicator displacement sensor arrays.195 Ginsenosides are a class of complex natural products, and their selective sensing is challenging. Two o-aminomethylphenylboronic acid units were AC


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incorporated into receptors for simultaneous binding of saccharides on two ends of ginsenosides, while various linkers between the two boronic acids were employed to target the hydrophobic steroids. After screening of three indicators Alizarin red S (ARS), 4-methylesculetin (ML), and pyrocatechol violet (PV), the pairing of indicators was found to afford greater signal modulation. The sensing array constructed from dynamic three-component sensing ensembles (host−ML−PV, host−ARS−PV) allowed discrimination of both ginsenosides and ginsengs with 100% correct classification, and the crossreactivity of these simple receptors was demonstrated by the corresponding loading plots (Figure 58). Using the same suit of

Figure 58. LDA plot from spectroscopic data of sensing arrays for five ginsenosides at 440 nm (a) and the corresponding loading plot (b). Points on the loading plot are individual members of arrays, represented by each sensing ensemble. C1 and C2 are the combinations of ML−PV and ARS−PV, respectively. Reprinted with permission from ref 193. Copyright 2012 Wiley-VCH Verlag GmbH & Co. KGaA.

receptors, they also reported differentiation of vicinal-diolcontaining flavonoids and black teas.196 The analytes were successfully classified with both two and three-dimensional LDA analysis. Anslyn and co-workers also designed a sensor array for the discrimination of a series of thiols and metal ions with a single squaraine dye (SQ, 120) as both a receptor and an indicator (Figure 59).197 The thiols reacted with SQ via a conjugation addition mechanism in DMSO, and the fluorescence at 680 nm was turned off. Upon addition of Pd2+ and Hg2+ into SQ/thiol

Figure 59. Squaraine/thiol/metal ion interaction as well as metal ions and thiols used in the array creation.

complexes, the fluorescence was recovered. The modulation of optical signal by thiols and metal ions allows pattern AD


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recognition of these analytes. Five metal ions (Pd2+, Hg2+, Cu2+, Fe2+, and Ni2+) were successfully differentiated using SQ and five thiols: propanethiol (PT), 3-mercaptopropionic acid (MPA), naphthalene-2-thiol (NT), 2,3-dimercaptopropanol (DMP), and 2-acetylamino-3-mercaptopropionic acid methyl ester (ACM). Similarly, these five thiols were discriminated with SQ and the five metal ions. SQ in combination with ACM gave the best differentiation of metal ions, while Hg2+ was the most effective for the discrimination of thiols. These results demonstrate the capability of a single receptor/sensor system in conjunction with pattern recognition protocols. Hydrophobic substances are challenging targets in aqueous solution due to their relatively few molecular recognition contacts. Anslyn and co-workers introduced the use of natural proteins, serum albumins (SAs), as low-selectivity receptors for differential sensing of terpenes (Figure 60).198 SA can bind a

Figure 60. Schematic illustration of the sensing mechanism of serum albumin proteins.

broad range of guests, including metal ions and hydrophobic molecules, such as fatty acids and steroids. To enhance diversity, bovine serum albumin (BSA), human serum albumin (HSA), and rabbit serum albumin (RSA) were utilized as hosts. The sensing ensemble is composed of SA and the indicator 6propionyl-2-dimethylaminonaphthalene (PRODAN). A blue shift in fluorescence emission was observed when SAs were added to a solution of PRODAN, and the binding of five terpenes (linalool, nerol, geraniol, citronellol, and α-terpineol) afforded varied extent of signal modulation. The terpene induced fluorescence changes was likely due to allosteric changes in the binding site of PRODAN together with some degree of dye displacement. The sensor array was able to discriminate the aforementioned five terpenes, but most discrimination took place along one axis of the LDA plot (Figure 61). The addition of one hydrophobic additive, such as deoxycholate, increased the discrimination along the second axis. As a real-world application, terpenes in complex mixtures, such as perfumes, were also successfully identified. Using a similar approach, they also achieved pattern recognition based detection of fatty acids and oils199 as well as plasticizers and plastic explosives.200 Bunz and co-workers developed a series of cruciform (XF) fluorophores (121−130)201 based on dialkylamino- and/or pyridine-substituted 1,4-distyryl-2,5-bis(ethynylaryl)benzenes, and extensively investigated their photophysical properties in organic solvents.202,203 The frontier molecular orbitals (FMOs) of these chromophores are dependent on the substitution pattern, and the location of HOMO and LUMO is either congruent or disjoint. The spatially separated FMOs allow the independent modulation of HOMO and LUMO through guest binding, resulting in a hypsochromic or a bathochromic shift in emission. Upon addition of an excess of trifluoroacetic acid or metal ions, such as Mg2+, Ca2+, Mn2+, and Zn2+, similar optical changes were observed, indicative of the same binding mode of protons and metal ions through free electron pairs of

Figure 61. (a) LDA response patterns for five terpenes. (b) LDA response patterns with deoxycholate additions. (c) LDA response patterns for terpenes with deoxycholate and Masaki ̈ perfume additions. Reprinted from ref 198. Copyright 2009 American Chemical Society.

dialkylaniline and pyridine nitrogens, though dialkylanilines are bound first due to their high basicity (Figure 62). WaterAE


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photographic analysis of color changes of three pyridine substituted cruciform fluorophores (122, 129, and 130) with 12 structurally related carboxylic acid analytes.206 A facile process of optimized photographical data acquisition, processing, and statistical workup was developed, paving the way for future array sensing using digital photography.

Besides detection of carboxylic acids, Bunz and co-workers also prepared two water-soluble aldehyde appended distyrylbenzenes (DSBs) for amine sensing in water.207 One receptor (134) has two reactive sites, while the other (135) only has one. Branched oligo(ethylene)glycol side chains were incorporated to achieve water solubility and increase the quantum yield of fluorophores in aqueous media. Upon addition of primary amines to the receptors, either imine or cyclic aminal was generated depending on the structure of the amine analytes, leading to a blue shift as well as an increase in fluorescence intensity. The dialdehyde was able to discriminate and identify 12 different amines in distilled water by digital photography.

soluble cruciform analogues (131−133) have also been created and explored.204 More recently, Bunz and co-workers achieved discrimination of organic acids using cruciform based sensor arrays.205 The array was constructed from three reactive cruciform fluorophores (124, 127, and 128) in six different solvents (dichloromethane, ethyl acetate, acetonitrile, methanol, 2propanol, and DMF). The protonation induced differential fluorescence response recorded by digital photography was able to discern 10 different aromatic carboxylic acids, even though some acids have very similar pKa values (Figure 63). In a very recent report, they analyzed in detail factors that define the

Figure 62. Protonation of or coordination of metal ions with cruciforms, leading to a signal change. AF


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Based on their work of detection of biogenic amines in micellar aqueous solutions with a coumarin derivative,210 Severin and co-workers achieved pattern recognition of peptides and aminoglycosides in the micromolar concentration range with a single molecular probe.211 Two bifunctional coumarin-based probes (140 and 141) were prepared, and they react with primary amines by condensation with their aldehyde and/or the enol function to generate different covalent adducts, resulting in distinct color changes (Figure 64). The reaction was conducted in the presence of the surfactant sodium dodecyl sulfate (SDS) to solubilize the dyes and to facilitate the condensation reactions. Dye 141 afforded more complex UV− vis spectra than dye 140 after the reaction, and was utilized for differential sensing. Structurally related analytes, including six

Figure 63. (a) Photograph of an array formed by exposing XF1−XF3 (124, 127, and 128) in six solvents (1 = DCM, 2 = EtOAc, 3 = MeCN, 4 = DMF, 5 = iPrOH, 6 = MeOH) to 10 different carboxylic acids (excitation at 366 nm). (b) Three-dimensional plot for XF1 (124) and XF3 (128) with acid analytes (B−K) in three solvents. A = reference; B = 4-hydroxybenzoic acid; C = 4-hydroxyphenylacetic acid; D = ibuprofen; E = aspirin; F = phenylacetic acid; G = 4chlorophenylacetic acid; H = benzoic acid; I = 3,5-dihydroxybenzoic acid; J = 2,4-dichlorobenzoic acid; K = 5-iodosalicylic acid. Reprinted from ref 205. Copyright 2011 American Chemical Society.

The sensors are also functional in basic buffers, but unreactive at pH 7 or below due to the formation of ammonium salts. Moreover, amino acids with an additional SH or NH2 group, such as cysteine, arginine, and lysine, afforded color responses. In a related study, Bunz and co-workers investigated three different DSB and XF-based water-soluble aldehydes (134, 136, and 137) as reactive amine sensors.208 The fluorescence was turned on with primary amines and particularly diamines in basic solution. Manipulation of the pH of the solution allows discrimination of the amine analytes. The rate of the response as well as the detection limit was also examined. Moreover, they synthesized two nonconjugated distyrylbenzene polymers bearing aldehdye reactive sites (138 and 139).209 The solutions of polymers and monomers were sprayed onto silica gel or alox TLC plates to create strip-shaped sensor arrays. The strips were then used to differentiate vapors of primary, secondary, and 1,ndiamines. It was found that a neutral silica gel support gave better discrimination of amines than alox TLC plates and analysis in solution.

Figure 64. Formation of different covalent adducts by probes 140 and 141 with amines. AG


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Figure 65. Sensing scheme for fragrance by pattern generation in fluorogenic vesicles. Hydrophobic analytes (odorants O1−O30) are incubated with hydrophilic hydrazide based reactive counterions (A1H1−A1H3, G1H1−G1H3) to give amphiphilic acylhydrazone counterions (A1H1O5− A1H3O5, G1H1O5−G1H3O5) that activate polyions (ctDNA) in lipid bilayer membranes. Reprinted with permission from ref 213. Copyright 2011 Royal Society of Chemistry.

different aminoglycosides and 11 different peptides, were successfully discriminated and classified. Matile and co-workers developed a synthetic differential sensing system that operates in lipid bilayer membranes.212,213 They have extensively explored the sensing platforms based on polyion−counterion transport systems.214 In order to cross a lipid membrane, polyions need to exchange their hydrophilic counterions by the amphiphilic counterion activators, and the charged fluorescent probes trapped inside the liposomes are picked up and transported across the membrane by active polyion−counterion complexes, leading to a fluorescence response. Due to the varied interaction between polyions and different counterion activators, a characteristic fingerprint pattern would be generated. In order to target hydrophobic aldehyde/ketone odorants, cationic hydrazides were employed to react in situ with analytes to create hydrazone based cationic dynamic covalent amphiphilic activators for polyanionic transporters (Figure 65). To enhance cross-reactivity, a suite of six peptides bearing one positively charged unit and one to three hydrazide reactive sites were synthesized. At least 21 closely related odorants were discriminated in a single score plot with PCA and HCA analysis (Figure 66). Differentiation of subtle structural differences, such as cis−trans isomers and enantiomers, was also achieved, demonstrating the discriminatory power of the system. The approach could be expanded to other classes of analytes in biomembranes. Similarly, Matile and co-workers reported pattern recognition of odorants using anionic activators.215 More recently, they developed an easy methodology for the screening of single component siRNA

Figure 66. PCA score plot for 21 odorants. Reprinted with permission from ref 213. Copyright 2011 Royal Society of Chemistry.

transfecting agents with controlled libraries of dynamic hydrazone amphiphiles.216 4.4. Proteins, Cells, and Bacteria

The discrimination and quantification of proteins, cells, and other biological targets in complex mixtures, such as plasma, is important for the diagnosis of diseases. Traditional approaches for biomarker detection, such as time-resolved fluorescence and chemluminescence, are highly sensitive, but generally rely on specific enzymatic or antibody/antigen interaction, thereby limiting the scope of the analytes. Recently, differential sensor AH


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hydrogen-bonding units were incorporated into the terminus to further modulate NP−polymer and NP−protein interactions. Upon binding of charge complementary indicators to the NPs, the fluorescence was quenched. The protein analyte displaced the polymer indicator from the NP−polymer conjugate, leading to the recovery of the fluorescence. A sensor array containing these noncovalent gold nanoparticle− fluorescent polymer complexes was able to generate repeatable and distinct responses for individual proteins at nanomolar concentrations. The identification and quantitative differentiation of seven proteins with diverse structural features were achieved by LDA analysis (Figure 68). Moreover, 52

arrays have been gaining increasing popularity for distinguishing a broad range of bioanalytes. Among them nanoparticle (NP)-based arrays are particularly intriguing.217 The diverse composition, structure, and morphology of NPs as well as the facile and tunable functionalization through self-assembly or conjugation on the surface of NPs make them a unique platform for sensing applications. Rotello’s group developed nanoparticle/fluorescent polymer complexes for the differentiation of bioanalytes, including proteins, bacteria, and mammalian cells. In their approach, competition binding (IDA) affords varied signal output and therefore characteristic fingerprints for pattern recognition. Several reviews have been published over their work,132,218,219 and hence, only representative examples will be presented here. In one of their early examples, six structurally related cationic gold nanoparticles (NP1−NP6) were fabricated to create protein sensors (Figure 67).220 These NPs act as both molecular recognition sites and quenchers for the highly fluorescent anionic poly(p-phenyleneethynylene) (PPE) derivative, PPE-CO2. Additional hydrophobic, aromatic or

Figure 68. Array sensing of protein analytes with an identical absorbance at 280 nm. (a) Fluorescence response patterns of the NP− PPE sensor array. (b) LDA score plot obtained with NP−PPE arrays against proteins with identical absorption values of A = 0.005 at 280 nm. [BSA] = 110 nM; [cytochrome c] = 215 nM; [β-galactosidase] = 4 nM; [lipase] = 90 nM; [acid phosphatase] = 20 nM; [alkaline phosphatase] = 80 nM; [Subtilisin A] = 190 nM. Reprinted with permission from ref 220. Copyright 2007 Nature Publishing Group.

unknown protein samples from these seven different proteins were identified with an accuracy of 94.2% based on a training set generated at protein concentrations of an identical absorbance at 280 nm. More recently, Rotello and co-workers conducted a structure−activity relationship analysis of both the polymer probes and gold NPs for the detection of 12 proteins with pattern recognition.221 They also achieved differentiation of 11 glycosaminoglycans (GAGs) using similar gold NP−PPE dye conjugates.222 In a collaborative work of Rotello and Bunz, a PPE-based sensor array composed of six conjugated poly-

Figure 67. Displacement protein sensor array. (a) Displacement of quenched fluorescent polymer (dark green strips, fluorescence off; light green strips, fluorescence on) from cationic gold nanoparticles (NPs) by protein analytes (in blue) with concomitant restoration of fluorescence. (b) Fluorescence pattern generation through differential release of the polymer indicator from NPs. (c) Chemical structures of NP1−NP6 and anionic fluorescent polymer PPE-CO2. Reprinted with permission from ref 220. Copyright 2007 Nature Publishing Group. AI


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electrolytes was employed for the discrimination of 17 protein analytes.223 Instead of using fluorescent conjugate polymers, Rotello and co-workers developed enzyme-amplified array sensing (EAAS) with NPs to dramatically increase the sensitivity toward protein analytes.224 Each sensing ensemble is composed of three components: gold NPs as the differential receptors, βgalactosidase (β-Gal) as the enzyme, and 4-methylumbelliferyl-β-D-galactopyranoside (MUG) as an enzymatic substrate and activatable fluorescent probe to provide “turn-on” signaling (Figure 69a). In detail, cationic gold NPs bind the anionic β-

Figure 70. (a) Illustration of Fe3O4 NP enzyme mimetic amplified colorimetric sensing of proteins. (b) Structures of Dop−Fe3O4 NP and TMA−Fe3O4 NP. Reprinted with permission from ref 225. Copyright 2010 Wiley-VCH Verlag GmbH & Co. KGaA.

Figure 69. (a) Schematic illustration of enzyme-amplified array sensing: release of β-galactosidase (β-Gal) from β-Gal/AuNP complex upon displacement by protein analytes restores the catalytic activity of β-Gal toward probe 4-methylumbelliferyl-β-D-galactopyranoside, resulting in an amplified signal for detection. (b) LDA plot of the first three factors of fluorescence response patterns obtained through βGal/AuNP sensor array against nine protein analytes at 1 nM concentration. Reprinted from ref 224. Copyright 2010 American Chemical Society.

Figure 71. Schematic illustration of the cell detection assay and the interactions between polymers and different cell types. Reprinted from ref 228. Copyright 2010 American Chemical Society.

69b). Moreover, similar sensitivity was obtained when the proteins were spiked into the complex matrix provided by desalted human urine, demonstrating the potential of arraybased protein sensors for real-world diagnostic applications. Rotello and co-workers also achieved colorimetric detection of proteins with catalytically active NPs used for both recognition and signal transduction/amplification (Figure 70).225 Dopamine (Dop) or trimethylammonium (TMA) functionalized Fe3O4 NPs were employed as enzyme mimics

Gal through electrostatic interaction, inhibiting enzyme activity. Upon addition of a protein target, β-Gal is displaced, restoring its activity and generating an amplified fluorescent readout after enzyme catalyzed hydrolysis of MUG. With six NPs in the array, nine proteins at concentrations of 1 nM in phosphate buffer were successfully discriminated and identified (Figure AJ


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metastatic murine epithelial cell lines. Using a series of both cationic and anionic PPE based fluorescent conjugated polymers (142−149), several cancer cell types as well as isogenic healthy, cancerous, and metastatic cells that possess the same genetic background were distinguished with LDA analysis (Figure 71).228 Rotello and co-workers also developed gold nanoparticle− green fluorescent protein (NP−GFP) based sensor arrays for the identification of mammalian cell types and cancer states.229,230 GFP is negatively charged at physiological pH and can bind to positively charged gold NPs. A 4-fold enhancement of sensitivity was observed compared to gold NP−PPE conjugates. With either gold NP−conjugated polymer conjugates231 or gold NP−enzyme complexes (for enzyme amplified sensing),232 fluorescent or colorimetric detection and discrimination of bacteria were also reported (Figure 72). Dravid, Chou, and De developed nanoscale graphene oxide (nGO) as artificial receptors for array based protein detection.233 Different from conventional GOs, size inconsistencies of which affect the performance of the sensing system, the near uniform lateral dimension (∼20 nm) of nGO sheet leads to enhanced supramolecular response. Size-enabled supramolecular properties of nGOs were further exploited for differential sensing applications. The arrays were constructed by assembling nGOs and conventional GOs with fluorescent indicators, respectively (Figure 73). Five fluorophores, including acridine orange, rhodamine B, pyronine Y (PY), rhodamine 6G (R6G), and His-tagged emerald green fluorescent protein (eGFP), were screened, with the last three affording greatest signal responses. They were bound to nGOs through π−π stacking and electrostatic interactions. Histag was attached to GFP to modulate hydrophobic interactions on the GO surface. Analogous to gold NPs, GO serves as both a recognition element and a fluorescence quencher, and the displacement of indicators from the GO surface by protein targets turns on the signal. Eight different proteins were

Figure 72. LDA score plot for fluorescence response patterns of individual bacteria. Reprinted with permission from ref 231. Copyright 2008 Wiley-VCH Verlag GmbH & Co. KGaA.

to catalyze the oxidation of colorless 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) to a green product in the presence of hydrogen peroxide. Differential binding of proteins to Fe3O4 NPs modulated the accessibility of reaction substrates to the NP surface and hence affecting the catalytic efficiency, resulting in varied absorbance change. The array was able to differentiate 10 proteins at a concentration of 50 nM. With analogous gold NP/fluorescent indicator assembly, Rotello and co-workers created sensor arrays for rapid and effective differentiation of cell states.226 Similar IDA based multivalent binding and signal transduction as protein sensors were utilized to target subtle changes in different cell surfaces and induce varied signal change. In one example, only three quaternary ammonium modified gold NPs and one dye PPECO2 were employed to construct the array.227 The discriminatory capability was demonstrated by full differentiation of different cell types, normal, cancerous, and metastatic human breast cells, as well as isogenic normal, cancerous, and

Figure 73. Design and preparation of GO-based sensor array. (a) Mechanism of the fluorescence displacement assay. (b) LDA patterns from a three sensor array (c) Structures of fluorescent indicators used. Reprinted from ref 233. Copyright 2012 American Chemical Society. AK


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Figure 74. Identification of cells (a) and bacteria (b) with nGO− ENSaptamer sensing platform. Reprinted from ref 234. Copyright 2012 American Chemical Society.

1,3,5-triacryloylhexahydro-1,3,5-triazine (150) was chosen as a Michael acceptor for 1,4-addition of thiols. Bis-Zn(DPA) motif was employed as phosphate binding site, and two peptides with known affinities to MAP kinases were synthesized to impart cross-reactivity. Moreover, dithiothreitol (DTT) was used as a linker to generate complexity because of oligomerization to afford dimers, trimers, or even larger receptors. Through the different combinations of three nucleophilic components with the conjugate acceptor in the individual wells, a unique set of receptors was afforded. The signaling was achieved with an IDA protocol. When the coumarin indicator was bound to a model receptor, the fluorescence was quenched, and the displacement of the dye with a phosphorylated peptide resulted in an increase in the fluorescence intensity. The sensor array in conjunction with chemometrics was able to fingerprint and identify different classes of MAP kinases and cell lysates in vitro with high accuracy (Figure 76).

successfully discriminated at 100 and 10 nM protein concentrations, and nGO arrays exhibited much better separation of clusters than conventional GO in the LDA score plot. Moreover, identification of 48 unknowns was achieved with a >95% success rate. The size dependence of the supramolecular behavior of GOs is beneficial for future sensor design. In a separate work, Fan, Hu, and co-workers employed the combination of fluorescently labeled adaptive “ensemble aptamers” (ENSaptamers) and nGOs for high-precision identification of a wide range of bioanalytes, including proteins, cells, and bacteria (Figure 74).234 The sensing platforms took advantage of differential supramolecular interactions between rationally designed, nonspecific DNA sequences and large, flat, and relatively homogeneous nGO surfaces. Zhang and coworkers developed a sensor array based on nanomaterialassisted thermochemluminescence (TCL) for protein and cell discrimination.235 Distinct TCL response patterns generated by the catalytic oxidation of analytes with nanomaterials provides the basis for sensing. Protein kinases play key roles in many cellular processes, and their malfunction leads to many human diseases. As a result, detection of kinases bears significant potential for diagnostic applications. Anslyn, Dalby, and co-workers recently reported an array sensing approach for the detection and differentiation of mitogen-activated protein (MAP) kinases and their phosphorylation states.236 Different from their previously reported synthetic peptide receptors,237 a general method was developed for the creation of a suite of differential receptors simply by mixing components in situ (Figure 75). The scaffold

5. CHIRALITY SENSING Chirality is one of the most fundamental concepts in chemistry. Most biologically relevant molecules, including both natural and synthetic, are chiral, and enantiomeric compounds usually show different pharmaceutical activity due to varied interactions with protein receptors, which themselves are made of L-amino acids. Considering the significant importance of chiral compounds, the development of asymmetric reactions and catalysts for chirality induction is one of the major research areas in modern organic chemistry.238,239 The 2001 Nobel Prize in Chemistry was awarded to W. S. Knowles, R. Noyori, and K. B. Sharpless for their work on asymmetric catalysis. As a result, AL


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Figure 76. LDA score plots of the response from the sensor array showing in vitro differentiation of active and inactive MAP kinases. (a) LDA score plot of phosphorylated MAP kinases (ERK-1, ERK-2, JNK3, and p38γ) with 100% jack-knife analysis. (b) LDA score plot of phosphorylated (○) and nonphosphorylated (△) kinases (ERK-1, ERK-2, JNK-3, and p38γ) with 93.5% jack-knife analysis. Reprinted from ref 236. Copyright 2013 American Chemical Society.

are based on derivatization, and there is a signal change (for example, melting point or NMR chemical shift) upon tethering of a reporter to an analyte. In order to avoid additional synthesis and isolation, an in situ derivatization would be desirable, and dynamic interaction (both supramolecular and reversible covalent bonding) and assembly have been explored for chirality sensing in the past decade. For colorimetric and fluorescence methods, the key is to differentially interact with R or S enantiomers of a chiral analyte to induce different signal changes. For CD based methods, a CD active chromophore must be introduced or created through the dynamic recognition of the chiral analyte. As the case in single analyte sensing, both the receptor− spacer−reporter approach and indicator displacement assay have been employed for chirality analysis. In addition, differential sensing methods can be used to discriminate the absolute configuration as well as the chemical identity of the chiral analytes. Several recent reviews have been published that cover chirality sensing from different perspectives. Yoon and Corradini reviewed the latest development of chiral fluorescent and colorimetric sensors,240−242 while Wolf summarized the mechanisms and results of CD based chirality analysis.243 Anslyn reviewed the optical methods for the rapid determination of enantiomeric excesses (ee) and their applications in asymmetric reaction discovery.244 As a result, our review mainly focuses on the supramolecular aspects (recognition and assembly) of chirality sensing.

Figure 75. (a) IDA with assembled receptors for kinase sensing. (b) Conjugate addition and related components for array creation.

rapid determination of enantiomeric purities of chiral substances is in growing demand. The most employed techniques for chirality analysis are chromatographic methods, such as HPLC and GC. These approaches are very reliable, but usually time-consuming and expensive due to the large amounts of solvents and sophisticated instrumentation required. Moreover, they are not readily adaptable to high-throughput screening (HTS) of enantiomeric content. Hence, chirality sensing by optical methods (UV−vis, fluorescence, circular dichroism, etc.) is currently of great interest in the field of organic analysis. Optical methods are simple, fast, sensitive, and cost-effective and, importantly, can be easily implemented into HTS. For example, naked-eye detection in colorimetric assay would be quite useful for quick qualitative analysis of enantiomeric composition. Most chiral organic molecules are only optically active in the far-UV region, and hence, a reporter unit (a chromophore or fluorophore) must be incorporated into the sensor or created upon analyte binding. Many classic organic analysis methods

5.1. Enantioselective IDA

In an enantioselective indicator displacement assay, two diastereomeric dynamic complexes are created upon the interaction of R or S enantiomer of a chiral analyte with an AM


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Figure 77. Enantioselective indicator displacement assays for α-amino acids based on displacement of CAS from the copper complex.

optically pure chiral receptor. The difference in thermodynamic stability (i.e., binding constants) between two diastereomers leads to different extent of indicator displacement and hence difference in optical signal change (absorbance or fluorescence). With an achiral receptor, the total concentration of the chiral analyte can be measured via a standard IDA, and therefore, both the concentration and enantiomeric composition can be determined in a single plate. Anslyn’s group has pioneered the development of enantioselective IDAs.245 KR

H*:I + GR ⇌ H*:GR + I KS

H*:I + GS ⇌ H*:GS + I

With copper complexes as receptors,246,247 chirality recognition and ee sensing of α-amino acids were achieved using eIDA.248,249 Two C2 symmetric chiral 1,2-diamines (152 and 153) were chosen as ligands and chrome azurol S (CAS) was utilized as a colorimetric indicator. Coordination of CAS to copper resulted in a color change from yellow (429 nm) to intense blue (602 nm) in aqueous solution, and the color change was reversed after the replacement of CAS from the complex by α-amino acids. The difference in steric interactions between the side chain of R or S α-amino acids and the chiral receptor leads to differential binding, and therefore, a different extent of CAS displacement is expected (Figure 77). Chiral recognition of 13 of the 17 studied α-amino acids was observed (Ala, Arg, Asn, Asp, His, Ile, Leu, Met, Pro, Ser, Thr, Trp, Val). Calibration curves were created, and ee of the unknown samples was determined with an average error less than 14%. Moreover, the chemical identity of α-amino acids was discriminated using PCA analysis. The eIDA assay was also developed for chiral αhydroxycarboxylates250,251 and vicinal diols252,253 using chiral arylboronic acids as receptors (155 and 156). The dynamic covalent interaction between boronic acid and α-hydroxycarboxylates or diols to form cyclic boronic esters that has been described in the previous section was utilized to modulate the signal change (Figure 78). The chiral centers near B−N dative bond or solvent inserted B−solvent−N bridge in the receptor would induce enantioselectivity for the binding between the

Figure 78. Enantioselective indicator displacement assay using a chiral host for chiral diols with pyrocatechol violet (PV) as the indicator. Reprinted with permission from ref 253. Copyright 2009 National Academy of Sciences.

receptor and two enantiomers of the analyte. Several achiral and chiral phenylboronic acids were designed and synthesized, and colorimetric indicators pyrocatechol violet (PV), bromopyrogallol red (BR), and 4-methylesculetin (MS) provide a relatively broad dynamic range. The average error on ee determinations is within 10% after optimization. The eIDAs for α-hydroxycarboxylates, diols, and α-amino acids have been successfully transitioned into high throughput analysis using AN


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array sensing protocol and employed for asymmetric reaction screening, such as Sharpless dihydroxylation.

Figure 79. (a) Three independent measurements of the fluorescence enhancement of (S)-157 at 374 nm at various MA concentrations (excitation at 290 nm). (b) Three independent measurements of the fluorescence enhancement of (R)-158 at 330 nm at various MA concentrations (excitation at 290 nm). Reprinted from ref 258. Copyright 2010 American Chemical Society.

5.2. Direct Sensing

For direct sensing of a chiral analyte, absorbance, fluorescence, and CD can be used as the signal output, but a key difference exists between these optical methods as a consequence of different signaling mechanisms. An optically pure receptor is required to create diastereomers to discriminate R or S enantiomers and result in different signal changes in colorimetric and fluorescent chirality analysis. In a CD based assay, two enantiomers can be differentiated through opposite Cotton effects, and the primary focus would be to create a preferential chiral twist of chromophores induced by R or S enantiomers. Several classes of representative examples of both synthetic and self-assembled receptors are discussed in sections 5.2.1 and 5.2.2. However, elegant examples of chiral foldamers as well as their design and amplification254,255 are beyond the scope of this review and will not be described in detail here. 5.2.1. Synthetic Receptors. Chiral ligands play a vital role in asymmetric catalysis, and by taking a page from organic synthesis, supramolecular chemists extensively utilize those ligands for the creation of chiral sensors. 1,1′-Binaphthyl compounds, such as 1,1′-bi-2-naphthol (BINOL) derivatives are among the most explored. Binaphthyl compounds show a series of characteristic properties, such as C2 axial chirality, relatively rigid structures, hydrogen bond donors, and acceptors. Moreover, they are versatile fluorophores. By taking advantage of those, Pu and co-workers developed a class of novel monomeric binaphthyl fluorescent chiral sensors.256 With two chiral amino alcohol arms attached with three phenyl substituents in the positions 2 and 2′, respectively, the sensor (S)-157257 exhibits outstanding enantioselectivity for a series of α-hydroxycarboxylic acids. The R enantiomer of the acid greatly enhances the monomer emission while the S enantiomer quenches it, with extraordinarily high ratios of the fluorescence intensities for the monomer emission IR/IS for phenyllactic acid (11.2), hexahydrophenyllactic acid (22.8), and hexahydromandelic acid (25.8). Hydrogenated analogue (R)-158258 was prepared and used as a pseudoenantiomeric partner with (S)157. In methylene chloride, (R)-mandelic acid (MA) greatly enhances the emission of (S)-157 at 374 nm, and (S)-mandelic acid greatly enhances the emission of (R)-158 at 330 nm, enabling simultaneous measurement of the concentration and the enantiomeric excess of MA using a 1:1 mixture of (S)-157 and (R)-158 (Figure 79). Detailed modeling studies revealed structural rigidity through an array of multiple hydrogen bonds in a 1:1 complex. In addition to chirality recognition by hydrogen bonding, Pu and co-workers designed a chiral sensor (S)-159 with two

trifluoroacetyl units that can bind trans-1,2-diaminocyclohexane through dynamic hemiaminal/imine/aminal formation (Figure 80).259 (S)-159 shows very different fluorescence responses at

Figure 80. Proposed mechanism for the reaction of (S)-159 with trans-1,2-diaminocyclohexane.

370 and 438 nm, one with high sensitivity and one with high enantioselectivity. It was demonstrated for the first time that both the concentration and enantiomeric composition of a chiral analyte can be determined simultaneously by one fluorescence test using only one fluorescent sensor, although the substrate scope of chiral diamines was not explored in this report. For the development of a CD-based chirality sensing system, asymmetric induction upon dynamic binding of a chiral analyte to a chromophoric, CD-silent probe that is achiral or exists as a racemic mixture of rapidly interconverting enantiomers can lead to strong Cotton effects in the UV or visible region, which correlates with the absolute configuration as well as enantiomeric purity of the substrate. Wolf and co-workers recently reported several stereodynamic probes based on the AO


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aforementioned mechanism of induced circular dichroism (ICD) for amino-containing substrates, including amines, diamimes, amino alcohols, and amino acids. They designed and prepared the 1,8-diarylnaphthalene derivative 1,8-bis(3′formyl-4′-hydroxyphenyl)naphthalene 160 (Figure 81) with

Figure 82. (a) CD spectra of the imine derived from 161 and samples of 1-phenyl-2-hydroxy-2-phenylethylamine with various ee values in CHCl3 and the corresponding ee calibration plots at 260 (blue), 290 (red), and 340 nm (green). (b) Fluorescence change of 161 upon titration with 1-phenyl-2-hydroxy-2-phenylethylamine (excitation 340 nm) and plot of the fluorescence intensity at 515 nm vs ratio [amine]/ [161]. Spectra collected in the presence of substoichiometric or equimolar amounts and excess of amine are shown in blue and red, respectively. Reprinted from ref 261. Copyright 2013 American Chemical Society.

diimines from [1 + 2] condensation of 162 and monoamines or amino alcohols also exhibit characteristic Cotton effects even though no rigid cyclic conformation is available. Chirality sensing of citronellal was also achieved using an analogous sensor with terminal anilines (163).264 In a very recent example, Kim and co-workers developed a very simple stereodynamic probe (2,2′-dihydroxybenzil, 164) for CD based determination of the absolute chirality and ee of primary monoamines.265 The formed diimine exhibits P or M axial chirality which is dictated by the steric hindrance with moderate (1.4:1) to good (4.7:1) stereoselectivity (Figure 83). Borhan and co-workers prepared a receptor MAPOL (165) based on a biphenol core with two bulky porphyrin units at positions 2 and 2′, respectively, and the diastereomeric complex favoring either P or M helicity is created upon binding of chiral monoamines within the cavity of the host via hydrogen bonding, leading to a CD signal (Figure 84).266

Figure 81. Stereodynamic probes based on imine formation.

two cofacial salicylaldehyde rings.260 The enantiomeric C2symmetric anti-isomers rapidly interconvert via the thermodynamically less stable meso syn-isomer, and hence 160 is CD inactive. The imine condensation between 160 and amino alcohols proceeds rapidly probably due to intramolecular acid catalysis by the neighboring hydroxyl group, and the resulting adducts exhibit strong CD signals above 345 nm. Extensive structural studies suggested that (S)-amino alcohols favor the diimine products with (P, P) conformation and show a positive first Cotton effect at 410 nm, while (R)-enantiomers create the (M, M)-conformer and afford the mirror image of CD spectra of their S counterparts. The locked conformation is dictated by two intramolecular hydrogen bonds and minimizes steric interaction between the receptor and the analyte. Linear ee calibration lines were obtained, and the average error is less than 6%. By replacing one salicylaldehyde ring with a pyridyl N-oxide fluorophore (161), in situ determination of enantiomeric composition and concentration of amino alcohols was achieved by CD and fluorescence readouts, respectively (Figure 82).261 Moreover, Wolf and Iwaniuk developed a chirality probe for amines, 1,2-diamines, and amino alcohols based on a stereodynamic arylacetylene framework with two terminal benzaldehyde units (162).262,263 For diamines, cyclic adducts from [1 + 1] condensation afford strong Cotton effects, but

Another important class of receptors for chirality recognition is metal complexes. The design and optimization are facilitated by structural diversity resulting from numerous combinations of metals and ligands. The pioneering work of metalloporphyrin based sensors developed by Nakanishi,267 Berova,268 and Inoue269 significantly advanced the field. Exciton-coupled circular dichroism (ECCD) is present for tweezer-like metalloporphyrins, allowing the determination of the absolute AP


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configuration of a variety of chiral compounds, although derivatization is generally required to enhance binding affinity except for the case of diamines. In order to achieve dynamic recognition of the substrate, Borhan and co-workers incorporated three electron-withdrawing pentafluorophenyl units into porphyrin tweezers (166 and 167)270−272 to enhance Lewis acidity of zinc centers. These receptors have been used successfully for the direct determination of the absolute configuration of diamines, amino alcohols, diols (Figure 85), and epoxy alcohols.

Figure 83. (a) Generation of axial chirality upon the reaction of 164 and (R)-3,3-dimethyl-2-butylamine. (b) Calculated structure (left) of M-RR isomer from (R)-3,3-dimethyl-2-butylamine (DFT B3LYP/631G(d,p)) and its crystal structure (right, 50% ellipsoid probability). All hydrogens except for phenols and chirality carbon centers are omitted for clarity. Reprinted from ref 265. Copyright 2014 American Chemical Society.

Figure 85. Proposed side-on binding of tweezer 166 with diols. P1 and P2 approach the hydroxyls anti to the R groups and sterically differentiate between the smaller H and the larger alkyl chain, leading to the observed helicity. Reprinted from ref 272. Copyright 2012 American Chemical Society.

In addition to metalloporphyrin tweezers, simple metal complex based chirality probes have been developed for bidentate analytes (Figure 86). Metal−ligand charge transfer circular dichroism (MLCT-CD) was employed by Anslyn and co-workers for chirality sensing of 1,2-diamines using simple BINAP complexes of Cu+ or Pd2+ (168−171).273 The ligands are CD silent above 300 nm, but a strong CD band arises after

Figure 84. Proposed model for assigning the absolute stereochemistry of chiral amines. Binding of (S)-cyclohexyl ethyl amine with 165 is illustrated with both M and P helicity of the host molecule. The P-(S) complex is disfavored due to steric interactions. The negative ECCD spectrum correlates well with the predicted assignment. Reprinted from ref 266. Copyright 2014 American Chemical Society.

Figure 86. Metal complex based chirality sensors for bidentate analytes. AQ


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including Et2Zn and B(OMe)3, could limit the practicability of this system. They also achieved detection of both the concentration and ee of 1,2-diamines and β-amino alcohols with Pd2+ complexes of tropos ligand (176).279

coordination with the analytes. By using a chiral BINAP, the chirality and identity of both meso and mer diamines were successfully discriminated (Figure 87). Moreover, racemic

The recent work of chirality recognition and sensing using metal−organic framework (MOF) reported by Lin is very intriguing.280 The chiral porous and fluorescent MOF was constructed from a chiral tetracarboxylate bridging ligand derived from BINOL (177) and cadmium (Figure 89). Figure 87. LDA based discrimination of diamine analytes using (R)168 as the receptor. Reprinted from ref 273. Copyright 2008 American Chemical Society.

complexes were utilized for chirality sensing.274 They also expanded the analyte scope to monoamines,275 cyclohexanones,276 and aldehydes.277 These analytes were converted into bidentate ligands after their reaction with pyridine-2carboxaldehyde (172, for monoamines) and 1-methyl-1-(2pyridyl) hydrazine (173, for carbonyls), respectively (Figure 88).

Figure 89. Structures of ligand 177 and chiral amino alcohols.

Enantioselective fluorescence quenching by chiral amino alcohols via hydrogen bonding with a BINOL unit is highly sensitive, with Stern−Volmer constants as high as 31 200 M−1 due to the preconcentration effect by which the substrates are absorbed and concentrated inside the MOF cavities. A significant enantiomeric quenching ratio [KSV(S)/KSV(R)] of 3.12 was observed for 2-amino-3-methyl-1-butanol (AA4), presumably due to steric confinement by the MOF cavity. However, enantioselectivities for other three analytes are modest with KSV(S)/KSV(R) values less than 1.5. Similarly, Wang demonstrated the potential of metal clusters for chirality sensing.281 Chirality is transferred from the chiral monoamine to the gold−silver cluster by postclustering modification through dynamic covalent imine formation, and the resulting CD signals allow for chiral recognition and ee determination (Figure 90). The strategy of preformed metal−organic architectures with recognition sites provides ample inspiration for future design. 5.2.2. Self-Assembled Receptors. For examples presented above, elegant synthetic receptors are required. To enhance practicality for HTS applications, Anslyn and coworkers proposed the concept of facile dynamic multicomponent assemblies to create CD active probes in situ. Anslyn and You discovered a dynamic covalent reaction of pyridine-2-carboxaldehyde, di(2-picolyl)amine, an alcohol, and zinc triflate via an activated iminium intermediate (Figure 91). The high binding affinity for monoalcohols is driven by metal

Figure 88. Derivatization reactions for monoamines (top) and carbonyls (bottom).

Very recently, stereolabile binaphtholate boron and zinc complexes (174 and 175) were reported as universal CD probes for chiral amines, diamines, amino alcohols, amino acids, and α-hydroxylcarboxylic acids by Wolf and co-workers.278 The mechanism is based on asymmetric transformation of complexes that undergo chiral amplification upon binding of a chiral substrate. However, the use of sensitive reagents, AR


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Figure 90. (a) Schematic illustration of chirality control. (b) CD spectra of two enantiomers (blue and red traces), and UV−vis spectrum (dotted line) in dichloromethane. Reprinted from ref 281. Copyright 2013 American Chemical Society.

Figure 92. (a) CD spectra of assemblies derived from alcohols in Figure 91c. (b) LDA plot for six enantiomeric pairs of chiral alcohols. Reprinted from ref 283. Copyright 2012 American Chemical Society.

Figure 93. Dynamic multicomponent assembly reactions with monoamines.

complex formation.282 With a chiral secondary alcohol, diastereomers are created, and the resulting tripodal tris(pyridylmethyl)amine (TPA)-like complex exhibits M or P helical twist.283 Detailed structural and modeling studies revealed that the direction of the twist is dictated by the newly formed stereocenter of hemiaminal ether, which in turn is governed by the handedness of alcohol α-carbon. (R)-1Phenylethanol (PEO) favors formation of the (S)-hemiaminal ether and a P helical twist, which shows a negative first Cotton effect at 268 nm, while (S)-1-phenylethanol affords opposite

Figure 91. (a) Dynamic multicomponent covalent assembly reactions with monoalcohols. (b) Newman projection of M and P isomers. (c) Chiral secondary alcohols studied (only R isomer is listed).

AS


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Figure 94. Twenty-four possible stereoisomers that can form upon mixing of enantiomers of the chiral imines with Fe2+. The red dotted lines trace out the “faces” and “meridians” defined by the three imine nitrogens for the fac and mer isomers, respectively. Reprinted from ref 285. Copyright 2012 American Chemical Society.

with 5-hydroxy-pyridine-2-carboxaldehyde (178) within 10 s in acetonitrile, followed by formation of a series of diastereomeric octahedral iron complexes (Figure 94) that show strong CD bands in both the UV and visible regions. The CD signal in UV region results from exciton coupling (i.e., ECCD), and allows for the determination of absolute configuration of the amine αcarbon, while the signal in the visible region arises from MLCT bands, and can be used to determine the enantiomeric composition of chiral amines. In addition, a statistical analysis of the distribution of stereoisomers accurately modeled the Sshaped ee calibration curves (Figure 95). The preference of the Δ-fac isomer was further confirmed by NMR and X-ray studies. In a collaborative work with James and Bull,16,17 Anslyn and

results (Figure 92). The identity and absolute configuration of a broad range of secondary alcohols were differentiated by LDA analysis, and the ee value of three representative alcohols was determined with an average error of 3%. Moreover, the mathematical relationship between CD magnitude and diastereoselectivity was derived, and a quantitative model was established to correlate diastereoselectivity with Charton steric parameters, paving the way for quick ee prediction.284 This selfassembly system is one of the very few chirality sensing platforms for monoalcohols. The approach of multicomponent assembly was also exploited by Anslyn and Dragna for chirality sensing of monoamines (Figure 93).285 The imines were created in situ AT


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protocols for pattern recognition based quantitative determination of a broad range of analytes and mixtures must be established for real-life applications. For chirality sensing, most receptors to date target strongly coordinating bidentate analytes, such as amino acids, diamines, and diols, as well as strongly nucleophilic monodentate guests, such as monoamines. Few systems have been reported for weakly coordinating and poorly nucleophilic alcohols and carboxylic acids, which are among the most common functionalities. To solve these problems, we believe that more effort should be placed on dynamic self-assembling systems in future sensor design. Another goal in this field is to discover new mechanisms of analyte binding and signal modulation. As a consequence, it is important to incorporate newly emerging dynamic bonds, such as halogen bond and anion−π interaction, into sensors. Moreover, the development of efficient in situ derivatization through dynamic covalent assembly is promising for chirality sensing applications. Finally, it is very appealing to employ novel nanomaterials for sensor construction. Inorganic, organic, and hybrid nanomaterials can be used as a template, a binding motif, or a signaling unit, hence providing a versatile platform for many classes of analytes, especially bioanalytes.

Figure 95. Overlays of ee calibration curves for MBI (imine of MBA): uncorrected calculated data (×), corrected calculated data (+), and experimental data (□). Reprinted from ref 285. Copyright 2012 American Chemical Society.

Metola also developed a dynamic three-component assembly of chiral BINIOL, 2-formylphenylboronic acid (179), and a primary amine for the chirality recognition and differentiation of α chiral amines.286

6. CONCLUSIONS AND FUTURE PERSPECTIVES In summary, the development of sensors is a central task of analytical sciences, and as a perfect combination of analytical chemistry and supramolecular chemistry, the field of supramolecular analytical chemistry has been rapidly growing in the past decade. This review has summarized the latest advances of three aspects of this promising field: single analyte sensing, differential sensing, and chirality sensing. In order to get functional sensors, a measurable signal must be generated upon the addition of an analyte, and hence, molecular recognition (i.e., binding) of the analyte and the mechanism of associated signal transduction must be taken into consideration for sensor design. Both direct sensing based on the receptor−spacer− reporter strategy and indicator displacement assays were discussed for a variety of analytes, including cations, anions, small neutral molecules and bioanalytes, with both synthetic and natural receptors. For single analyte sensing, it is crucial to increase sensitivity and selectivity. Representative examples of synthetic receptors and dynamic assemblies were presented, with the latter being particularly intriguing. For differential sensing, cross-reactive receptors are designed and employed to construct the sensor array, and the differential responses are exploited to generate fingerprints in conjunction with chemometric techniques, such as PCA and LDA. Discrimination of pure analytes, complex mixtures, and unknowns was discussed. For chirality sensing, differentiation of R and S enantiomers is the key. With colorimetric and fluorescent sensors, the creation of diastereomers with different stabilities leads to chirality discrimination, while a preferential chiral twist must be induced for circular dichroism based probes. Although a large number of elegant receptors and systems have been reported, many challenges remain in the field of supramolecular analytical chemistry. It generally requires dedicate design and optimization to achieve sensitivity and selectivity, and as a result, many specific receptors have complicated structures and require multistep synthesis, thereby limiting their availability and practicality. Many differential sensing systems mainly focus on qualitative identification and discrimination of analytes and model samples. General

AUTHOR INFORMATION Corresponding Authors

*L.Y.: Tel.: 86-591-83256723. Fax: 86-591-83256723. E-mail: [email protected]. *E.V.A.: Tel.: 512-471-0068. Fax: 512-471-7791. E-mail: [email protected]. Notes

The authors declare no competing financial interest. Biographies

Lei You was born in Shannxi, People’s Republic of China, in 1980. He received his B.S. degree from Fudan University in 2003 and obtained his Ph.D. degree in Chemistry with Dr. George W. Gokel from Washington University in St. Louis in 2008. He then joined Dr. Eric V. Anslyn’s group as a postdoctoral fellow at The University of Texas at Austin. In 2013, he began his independent career as a professor at Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences. His research interests are highly interdisciplinary and include investigations of dynamic interactions, molecular assemblies, and their applications in sensing, labeling, and catalysis. AU


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AO ARS BINOL BODIPY BR BSA CAS CB[n] CD CEES CPE CX4 DAP DBO DCL DHFR DLS DMF DMSO Dop DPA DSB DTT EAAS ECCD ECL eIDA FMO FRET GAG GFP hCA HCA HOMO HPTS

acridine orange Alizarin red S 1,1′-bi-2-naphthol boron dipyrromethene difluoride bromopyrogallol red bovine serum albumin chrome azurol S cucurbit[n]urils circular dichroism 2-chloroethyl ethyl sulfide conjugated polyelectrolyte p-sulfonatocalix[4]arene Dapoxyl 2,3-diazabicyclo[2.2.2]oct-2-ene dynamic combinatorial library dihydrofolate reductase dynamic light scattering N,N-dimethylformamide dimethyl sulfoxide dopamine di(2-picolyl)amine distyrylbenzene dithiothreitol enzyme-amplified array sensing exciton-coupled circular dichroism electrochemiluminescence enantioselective indicator displacement assay frontier molecular orbital fluorescence resonance energy transfer glycosaminoglycan green fluorescent protein human carbonic anhydrase hierarchical clustering analysis highest occupied molecular orbital 8-hydroxypyrene-1,3,6-trisulfonic acid, trisodium salt HSA human serum albumin HTS high-throughput screening ICD induced circular dichroism IDA indicator displacement assay IMP isopropyl methylphosphonate IPCT intramolecular partial charge transfer LDA linear discriminant analysis LOD limit of detection LPS lipopolysaccharide LUMO lowest unoccupied molecular orbital MA mandelic acid MAP mitogen-activated protein MBA molecular beacon aptamer MC-IDA mechanically controlled indicator displacement assay ML 4-methylesculetin MLCT metal−ligand charge transfer MLP-ANN multilayer perceptron artificial neural network MOF metal−organic framework MP methylphosphonate nGO nanoscale grapheme oxide NP nanoparticle NSAID nonsteroidal anti-inflammatory drug ODF oligodeoxyfluoroside PA picric acid PC principal component PCA principal component analysis

Daijun Zha was born in China in 1983 and received his B.S. degree in Chemistry from the Nanchang University in 2005. He earned his Ph.D. under the supervision of Dr. Yiwang Chen at Nanchang University in 2013. After his doctoral studies, he joined Dr. Lei You’s group as a research assistant at Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences. His current research interests focus on design, construction, and application of stimuli responsive dynamic multicomponent assemblies.

Eric V. Anslyn is the Welch Regents Chair of Chemistry and a University Distinguished Teaching Professor at the University of Texas at Austin. He attended the California State University Northridge to receive his B.S. degree in Chemistry. After that he performed doctoral research at the California Institute of Technology under the direction of Dr. Robert Grubbs, and received his Ph.D. in Organic Chemistry in 1987. Prof. Anslyn’s research involves the use of physical organic chemistry principles in the development of synthetic receptors and chemical sensors.

ACKNOWLEDGMENTS L.Y. thanks The Recruitment Program of Global Youth Experts and Fujian Institute of Research on the Structure of Matter for start-up funding. L.Y. also thanks The CAS/SAFEA International Partnership Program for Creative Research Teams. LIST OF ABBREVIATIONS 8-HQ 8-hydroxyquinoline ABTS 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) AC Alizarin complexone AFM atomic force microscope AIDA allosteric indicator displacement assay AIE aggregation induced emission ALP alkaline phosphatase AV


Chemical Reviews PDA PEL PET PEU PL PPE PRODAN PV PY QDA R6G RDX RSA SA SDS SEM TATP TCL TEM THF TIC TNT TPA VOC XF

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polydiacetylene permissible exposure limit photoinduced electron transfer poly(ether−urethane) photoluminescence poly(p-phenyleneethynylene) 6-propionyl-2-dimethylaminonaphthalene pyrocatechol violet pyronine Y quencher displacement assay rhodamine 6G Research Department explosive rabbit serum albumin serum albumins sodium dodecyl sulfate scanning electron microscope triacetone triperoxide thermochemluminescence transmission electron microscope tetrahydrofuran toxic industrial chemical trinitrotoluene tris(pyridylmethyl)amine volatile organic compound cruciform

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