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REVIEW

Cite this: DOI: 10.1039/d0ob01761b

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Molecular recognition and sensing of dicarboxylates and dicarboxylic acids Stephen M. Butler

a

and Katrina A. Jolliffe

*a,b

The recognition and detection of dicarboxylic acids and dicarboxylates is of significance for a wide variety of applications, including medical diagnosis, monitoring of health and of environmental contaminants, and in Received 25th August 2020, Accepted 22nd September 2020

industry. Hence small molecule receptors and sensors for dicarboxylic acids and dicarboxylates have great

DOI: 10.1039/d0ob01761b

potential for applications in these fields. This review outlines the challenges faced in the recognition and detection of these species, strategies that have been used to obtain effective and observable interactions

rsc.li/obc

with dicarboxylic acids and dicarboxylates, and progress made in this field in the period from 2014 to 2020.

Introduction Dicarboxylic acids Dicarboxylic acids and dicarboxylates play many roles in industry and in biological systems. Many simple dicarboxylic acids, such as the amino acids aspartic acid, glutamic acid, and succinic acid, are intermediates in the biosynthesis of more complex biological molecules.1,2 These dicarboxylic acids and

a School of Chemistry, The University of Sydney, NSW 2006, Australia. E-mail: kate.jolliff[email protected] b The University of Sydney Nano Institute (Sydney Nano), The University of Sydney, NSW 2006, Australia

Stephen M. Butler

Stephen M. Butler completed his undergraduate (2015) and PhD (2020) studies with Prof. Jonathan Morris at UNSW Sydney, investigating the development of small molecule probes for biologically-relevant kinases and phosphatases. He is currently employed in a postgraduate appointment working with Prof. Kate Jolliffe at the University of Sydney, investigating macrocycles for the detection of anions. He is the second of his name to work with Prof. Jolliffe!

This journal is © The Royal Society of Chemistry 2020

others are also active participants in biological signaling and feedback pathways, and hence the concentration of dicarboxylic acids may have significant consequences for cellular homeostasis and overall health. Indeed, excessive consumption or production, or insufficient clearance of the simplest dicarboxylic acid, oxalic acid, may cause a multitude of health problems including nephropathy, recurrent kidney stone formation, and liver disease.3 Hence, tools to monitor oxalate concentrations in urine and blood may be valuable for diagnosis, medical investigation and management. Similarly, there are medical applications for the monitoring of dicarboxylates including glutamate,4 itaconate,5 α-ketoglutarate,6 and succinate.7 Industrially, salts of dicarboxylic acids such as tartaric

Katrina (Kate) Jolliffe received her BSc (1993) and PhD (1997) from the University of New South Wales. She held positions at Twente University, The Netherlands; the University of Nottingham, UK and the Australian National University before moving to the University of Sydney in 2002, where her current position is Payne-Scott Professor. She is a Fellow of the Australian Academy of Science Katrina A. Jolliffe and has been awarded the Beckwith (2004), Biota (2006), Birch (2017) and H. G. Smith (2018) medals of the Royal Australian Chemical Institute. Her research interests focus on the design and synthesis of functional molecules, including molecular sensors capable of detecting anions in biological environments.

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Review acid and maleic acid are commonly used in the formulation of drugs and food products,8–10 while phthalates are commonly used in plastics production and have emerged as environmental contaminants of concern.11 Dicarboxylates have risen to prominence as common components in the construction of metal–organic frameworks: hence it is expected that functional materials based on dicarboxylate building blocks may be an important part of future technologies.12 Consequently, the recognition and detection of dicarboxylic acids and dicarboxylates is of considerable interest for applications in medicine, environmental management, and in industrial processing and development. Previous reviews by Fitzmaurice, Kyne, Douheret and Kilburn13 (2002) and by Curiel, Más-Montoya and Sánchez14 (2015) have covered advances in the field of polyand di-carboxylic acid recognition and sensing up to early 2014. Consequently, this review will focus on notable developments and publications in the field from mid-2014 until early 2020. An overview of the common dicarboxylic acids encountered in this review is provided in Table 1. Challenges in dicarboxylic acid recognition and detection In the most recent review on dicarboxylic acid recognition and detection, Curiel, Mas-Montoya and Sanchez noted that despite numerous developments over the past 35 years, significant challenges persist in the field. In particular, the development of sensors that are effective in a biological context—that is, in aqueous environments and in the presence of competing analytes—remains a formidable obstacle. At biologically relevant pH levels (∼7.32–7.42), the majority of dicarboxylic acids predominate as dicarboxylates (see pKa values below). Consequently, many of the challenges associated with the recognition and detection of dicarboxylic acids are shared with those for anion recognition more broadly. One of the most significant challenges for dicarboxylate recognition is the ability to form high affinity interactions between receptor and analyte. Carboxylate groups possess a diffuse negative charge, which presents a challenge for high-affinity binding. Furthermore, the hydration energies of carboxylate groups lie in the order of ∼−400 kJ mol−1.15 Hence, binding of a receptor to dicarboxylate species in aqueous media relevant to realworld applications incurs a significant desolvation penalty that must be overcome for effective binding to occur. Another major challenge in the field is selective recognition of the dicarboxylic acid/dicarboxylate of interest. Many dicarboxylates share a common carbon skeleton, while others possess a flexible carbon chain that links the carboxylate groups. As may be noted from the data presented in Table 1, the acid/base properties of many dicarboxylic acids are similar. Consequently, effective discrimination between related dicarboxylic acids and dicarboxylates poses a significant challenge. Outlined in this review are recent advances in the development of high-affinity and selective molecular recognition of dicarboxylic acids and dicarboxylates. This includes the exploitation of the unique functionality and behavior of selected dicarboxylates, the development of increasingly complex mole-

Org. Biomol. Chem.

Organic & Biomolecular Chemistry cular architectures matched to the target dicarboxylate, and the utilization of strong, directional interactions. Progress in the development of array-based systems and receptors that display non-specific binding but target-specific responses, for the effective identification and quantification of dicarboxylates, will also be discussed. While the majority of dicarboxylic acids form complexes with divalent metal cations in aqueous solution with log Ka values between 2 and 4, the dicarboxylates oxalate and dipicolinate, and the tricarboxylate citrate, are able to form metal complexes with sufficiently high stabilities (log Ka values between 4 and 7) that they may be readily detected in aqueous media, even in the presence of competing anions.18 Consequently, chemosensors for these analytes based on the displacement of a lower-affinity ligand or formation of a stable metal complex are common and will not be covered in detail in this review. The reader is directed to recent examples of the detection of oxalate,19–22 malate,23 citrate,24–28 and dipicolinic acid29–42 for further information on this class of anion sensor. Receptors that are reliant on functionality that is in addition to the carboxylate groups for effective binding, such as those found in malate43,44 and α-ketoglutarate,45 were also excluded from the scope of the discussion in this review. Although the exploitation of high-affinity metal coordination or extraneous functionality is useful for the molecular recognition of a subset of dicarboxylates, the design of effective sensors for the remaining dicarboxylates must rely on additional or alternative interactions with the carboxylate or carboxylic acid group. Due to the competition between solvation of dicarboxylates and interaction with the receptors, as well as competitive binding with solvent and alternative ligands, binding of simple dicarboxylates in water is not an insignificant challenge. Early successes, typified by the efforts of Lehn and others,46–48 generally involved the construction of polycyclic cage-like structures with multiple recognition elements. Such structures provide a highly organized, high affinity binding pocket for dicarboxylate targets. The structured nature of these receptors, such as Lehn’s cryptand 1,46 allows dicarboxylate binding affinities of up to 1010 M−1 in water, and may favour selectivity for those dicarboxylates that best match the length and shape of the binding pocket. Recent work on the development of linear and macrocyclic receptors has led to improvements in binding affinities for simple dicarboxylates and a greater understanding of the requirements for effective binding.


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Organic & Biomolecular Chemistry Table 1

Common dicarboxylic acids and their properties

Acid


Review

Structure

Formula

Lengtha (A)

pKa1 (H2O)

pKa2 (H2O)

Ref. (pKa values)

Oxalic acid

C2H2O4

1.6

1.23

4.19

16

Malonic acid

C3H4O4

2.6

2.83

5.69

16

Succinic acid

C4H6O4

3.9

4.19

5.48

16

Glutaric acid

C5H8O4

5.1

4.34

5.42

16

Adipic acid

C6H10O4

6.4

4.42

5.41

16

Pimelic acid

C7H12O4

7.6

4.48

5.42

16

Suberic acid

C8H14O4

9.0

4.52

5.40

16

Azelaic acid

C9H16O4

10.2

4.55

5.41

16

Sebacic acid

C10H18O4

11.5

Maleic acid

C4H4O4

3.3

1.92

6.23

16

Fumaric acid

C4H4O4

3.9

3.03

4.54

16

Malic acid

C4H6O5

3.8

3.40

5.2

17

Tartaric acid

C4H6O6

3.8

2.89

4.40

17

Aspartic acid

C4H7NO4

3.9

2.09

3.86

17

Glutamic acid

C5H9NO4

5.0

2.19

4.25

17

Phthalic acid

C8H6O4

3.0

2.98

5.28

16

Isophthalic acid

C8H6O4

5.0

3.46

4.46

16

Terephthalic acid

C8H6O4

5.8

3.51

4.82

16

a

Length determined between carbonyl carbon atoms for extended structure, using publicly available crystal structures from Crystallography Open Database (http://www.crystallography.net/cod/index.php)

A growing frontier in dicarboxylate binding with linear and macrocyclic receptors is the use of C–H hydrogen bonding and halogen bonding. Both bonding interaction types are increasingly emerging as a powerful tool for the development of receptors with high affinity and selective binding.


The following sections will outline recent advances in the design and application of dicarboxylate binding, building up from simple linear receptors through to macrocycles and more complex polycyclic cage structures. Receptors that highlight the use of C–H hydrogen bonding and halogen bonding will be emphasized.

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Review

‘Simple’ receptors


Ionic interactions Some of the simplest possible dicarboxylate recognition units have been outlined by Kusukawa and co-workers.49–53 Receptors 2–6 feature simple naphthalene, anthracene and tetraphenylethylene fluorophores, functionalized with amidine or guanidine groups, which interact with dicarboxylates via hydrogen bonding and ionic interactions. These receptors are not sufficiently soluble in water to be functional in this solvent. However, it was observed that some selectivity may be obtained between long and short chain aliphatic dicarboxylic acids in less competitive solvents (DMSO, MeCN). Short chain dicarboxylic acids (oxalic acid, malonic acid, and succinic acid) protonate the receptors but do not bind, whereas longer chain dicarboxylic acids protonate the receptors and may simultaneously bind both amidinium or guanidinium groups.

Organic & Biomolecular Chemistry ist used in the mobilization and collection of stem cells from bone marrow.55 Fabbrizzi and co-workers evaluated the unusual bicyclam structure of Mozobil as a dicarboxylate binder.56 In its pentaprotonated form, Mozobil binds diphenyl-4,4′-dicarboxylate in aqueous solution with an impressive association constant of over 1010 M−1. The strength of interaction is strongly dependent on the distance between carboxylate groups and appears to be supported by π–π interactions. Terephthalate and citrate were reported to bind to Mozobil in water with association constants in excess of 106 M−1. However, due to the need for protonation of Mozobil for effective anion binding, affinity towards dicarboxylates was found to drop off significantly above pH 7. Electrochemical sensor 10 was developed by Kim and coworkers, and exhibits discrimination between isomers of phthalic acid.57 In the absence of phthalic acid, differential pulse voltammogram (DPV) spectra of the sensor showed two anodic waves that correspond to sequential oxidation of the secondary amine and ferrocene groups. However, in the presence of phthalic acid, the first anodic peak was suppressed: complete suppression of this peak was observed with the addition of 1.5 molar equivalents of phthalic acid. Addition of isophthalic or terephthalic acids was found to cause a positive shift in the peak potential of the first anodic wave, without a reduction in peak current as observed for phthalic acid. Molecular modelling of the three isomers of phthalic acid with sensor 10 revealed that phthalic acid is predicted to display the strongest hydrogen-bonding interactions between the secondary amine and carboxylic acid groups: interactions between these groups are thought to lead to the electrochemical response of the sensor. Addition of the base DBU rendered sensor 10 insensitive to phthalic acid, however this response could be reversed by the addition of a small excess of phthalic acid.

In a 2019 report of diguanidium receptor 7, Sessler, Thordarson and Gong sought to replicate the strong hydrogen bonding interactions observed between DNA base pairs in water with a guanidinium-carboxylate duplex.54 The combination of a rigid diguanidinium with four accessible hydrogen bond donors and a similarly rigid dicarboxylate (8) resulted in the formation of robust heterodimers, with an association constant in the order of 105 M−1 in water. Although this example involved the use of a custom-designed rigid dicarboxylate binding partner, it marks a promising step in the development of simple dicarboxylate receptors with high-affinity in water.

Another simple linear system with impressive dicarboxylate binding in water is the drug Mozobil (9): a CXCR4 antagon-

Org. Biomol. Chem.

An aggregation induced emission (AIE) sensor based on the formation of extended supramolecular structures has been developed by Noguchi, Shinkai and coworkers.58 The structure


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Organic & Biomolecular Chemistry of aggregates of probe 11 were found to vary depending on the dicarboxylates present in solution. Isomers fumarate and maleate could be distinguished from each other based on the fluorescence response observed: a greater emission intensity was observed for fumarate, which self assembles with 11 to form supramolecular fibres. Smaller aggregates and a weaker fluorescence response were noted for maleate. H-Bonding interactions In contrast to the high affinities observed for linear dicarboxylate receptors that rely on a combination of hydrogen bonding and ionic interactions, simple neutral linear receptors with hydrogen bond donors typically display weaker binding, but are less dependent on pH. The majority of reported neutral linear hydrogen bonding receptors rely on rigid scaffolds. Such rigidity serves dual roles of reducing the entropic penalty of binding by receptor preorganization, and of supporting selectivity by fixing the position of hydrogen bond donors. Wang and co-workers explored the importance of receptor shape on selectivity with the azobenzene dithiourea receptor 12.59 Although dicarboxylate affinities were modest, isomerization of the azobenzene group was found to have an impact on selectivity towards the binding of α,ω-dicarboxylates. In comparison to the trans-isomer of the receptor, the cis-isomer displayed small increases in binding affinity with dicarboxylates longer than glutarate, and small decreases in binding affinity towards malonate and acetate. Compounds 13 and 14, developed by Trivedi and Madhuprasad, act as colorimetric sensors for maleate, with selectivity over fumarate.60 Maleate was found to bind to receptor 14 in anhydrous DMSO with an affinity of 2.88 × 104 M−1. The presence of maleate, acetate, or fluoride was found to induce a colour change in the sensors from colourless to orange-red due to hydrogen bonding interactions with the hydrazide moieties. Large concentrations of fluoride led to deprotonation of the sensor.

Pfeffer and co-workers have extensively studied the dicarboxylate binding properties of a series of polynorbornane scaffolds.61–64 These receptors consist of a rigid polynorbornane backbone with flexible thiourea groups appended. Building on work first reported in 2012, the binding of isophthalate and terephthalate to norbornanes 15–17 was


Review recently investigated.63 Remarkably, despite significant flexibility of the urea “arms” of the structure, a difference in binding affinity for these two dicarboxylates of nearly two orders of magnitude was observed in DMSO, favouring binding of isophthalate. This was attributed to a significantly larger energetic penalty for conformational adjustment of the host to match terephthalate than for isophthalate, as indicated by molecular modelling. In a reversal of typical trends, Pfeffer also demonstrated selectivity for flexible dicarboxylates over rigid dicarboxylates with the extended polynorbornane 18.61 The inclusion of a blocking group between the urea binding groups hindered the binding of aromatic dicarboxylates 4,4′-biphenylate and 2,6-naphthalate, without impairing binding of alkyl dicarboxylates azelate and dodecandioate. Central functionality has also been explored as a potential method to improve the binding of rigid dicarboxylates through additional interactions.62 However, significant improvements in binding have not yet been achieved by this method.

Ghosh and Majumdar developed chiral amide receptor 19, which was found to give a ratiometric fluorescence response to L- and D-tartrate in acetonitrile.65 Compound 19 gave differing responses to the two enantiomers of tartrate and in the presence of 20 equiv. of anion the ability to discriminate between the enantiomers was reduced. Modest enantioselectivity was observed in the presence of 4 equivalents of tartrate. Changes in fluorescence intensity in response to mandelate were much lower. Similarly, Liu and co-workers reported chiral hydrogen bonding amide receptor 20 for tartrate, which displayed limited enantioselectivity (KD/KL = 0.60).66

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Review

In 2016, Curiel reported the rigid carbazole-based dicarboxylate receptor 21.67 Screening of the receptor for its affinity with succinate, glutarate, and adipate in DMSO revealed a preference for glutarate, with reduced binding observed for the longer and shorter dicarboxylates. A limit of detection of 5.2 µM for glutarate was determined—a sensitivity that is appropriate for the diagnosis of glutaric aciduria.68 However, the chemosensor was not evaluated in aqueous solution, and the ratiometric fluorescent response does not distinguish between glutarate and competing analytes. Work by Felix, Moiteiro, and co-workers expanded on previously developed azacalixarene-based dicarboxylate receptors with the bisurea compound 22.69 Although the azacalixarene ring is conformationally restricted, the urea groups, which are involved in binding to dicarboxylates, are flexible.

Org. Biomol. Chem.

Organic & Biomolecular Chemistry Consequently, selectivity between dicarboxylate species was generally modest. Succinate and fumarate, which have a similar distance between carboxylate groups (in an extended conformation) were found to differ in binding affinity by a factor of four, with fumarate displaying the highest affinity (Ka = 4007 M−1, CDCl3). This difference may be attributed to the reduced conformational flexibility of fumarate relative to succinate. Maleate, the geometrical isomer of fumarate, binds poorly to the receptor, with an association constant of 481 M−1 (CDCl3). Interaction of dicarboxylic acids through hydrogenbonding interactions with the pyrazole groups of Miljanic’s tripodal receptor 23 was found to induce dimerization and turn-on fluorescence by AIE in DMF solution.70 The strongest responses were observed for ortho-phthalic acid maleic acid and short α,ω-dicarboxylic acids, e.g. oxalic and malonic acids. The turn-on fluorescence response to these dicarboxylic acids results from dimer formation with the dicarboxylic acids bridging between two receptor molecules. Dimerization required the correct geometric orientation of the two carboxylic acid groups. The rotational motions of stacked receptor molecules are restricted in the dimers, leading to an increase in receptor fluorescence. The fluorescence response was found to increase until ∼12 equivalents of dicarboxylic acid were added, then decrease again as the pyrazole binding groups became saturated and monomers of the receptor became more favoured. Longer dicarboxylic acids and the geometric isomers of phthalic acid, which do not bring the receptors into close proximity with each other, had little or no effect on the receptor fluorescence, and monocarboxylic acids had no effect. Sensing was ineffective in water due to precipitation of the receptor. In 2020, Bahring, Lei, Zhang, Sessler and co-workers reported sensor 24 which also dimerizes in the presence of dicarboxylic acids.71 Binding of dicarboxylic acids and formation of a self-assembled cage-like dimer was found to be specific to dicarboxylic acids with a pKa below ∼2.8. Oxalic acid, maleic acid, and malonic acid were found to singly proto-


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Organic & Biomolecular Chemistry nate the naphthyridine group of the sensor and bind between the naphthyridine and pyrrole groups, leading to formation of sensor dimers in dichloromethane and THF. A ratiometric absorption response was observed. Dimers were not formed with strong monocarboxylic acids, but were observed upon addition of sulfonic acids with pKa values 4-fold improvement in binding affinity observed for fumarate. The chiral nature of the receptor also facilitated selective binding between the enantiomers of glutamate, with an almost 6-fold binding affinity preference for the (S)-isomer (KS/KR = 5.66). Cages and cryptands As noted above for the progression from linear receptors to macrocyclic receptors, building further complexity into dicarboxylate receptors to form cage-like structures may result in

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Review

increased selectivity and binding affinity. The legacy of Lehn’s work on the development of polyamine cryptands is particularly prominent, as are later contributions by Nelson, and recent work by Delgado.46,105–108 Bandaru, English, and MacElroy undertook a computational study of the dinuclear Zn(II) and Cu(II) complexes of Nelson’s cryptate 59,107 and proposed that such complexes may be suitable for the separation of isomeric dicarboxylates.109 The cryptate was predicted to show preferential binding for fumarate over its diasteroisomer maleate and selectivity between cis/trans 1,2-cyclopropane dicarboxylates. To the best of our knowledge this complex has not been tested experimentally for dicarboxylate binding, although it has previously been noted to bind several other anions, including carbonate.110 A similar strategy was employed by Mateus, Delgado, Andre, and Duarte,111 utilising the dinuclear Cu(II) complex of azacryptand 1, which was first described by Lehn in 1991.46 In Lehn’s original work,46 the free cryptand was found to bind dicarboxylates in mildly acidic aqueous solution with affinities of up to 2.5 × 104 M−1 (terephthalate).46 By comparison, dinuclear Cu(II) complex 60 was found to bind dianionic terephthalate with a binding constant of approximately 1010 M−1 in water.111 As well as displaying higher affinities for dicarboxylates than the free azacryptand, binding to the copper complex was also found to be less dependent on pH, as it is not reliant on protonation of the amine groups for optimal binding affinity. As may be expected for such a highly constrained structure, the binding affinities of dicarboxylates were highly dependent on the length of the dicarboxylate and its fit inside the cage. Binding affinity was highest for adipate among the aliphatic dicarboxylates; for monocarboxylates and dicarboxylates of shorter or longer lengths binding affinity was reduced by at least one order of magnitude. Hirshfeld analysis of the binding cleft revealed a snug fit for terephthalate and adipate, with little exposure of the dicarboxylates to the solvent environment. Similar work by Delgado and co-workers in 2016 112 involved revisiting Nelson’s azacryptand 61.106 The dinuclear copper complex, 62, has been previously described and investigated for the recognition of azide and cyanide anions.107

Org. Biomol. Chem.

Organic & Biomolecular Chemistry

Succinate formed the expected high affinity complex in which the dicarboxylate bridged between the two copper(II) centres.112 However, oxalate and malonate were found to form an unexpected trinuclear copper(II) complex in the absence of excess copper. The third Cu(II) cation—which displays square planar geometry—bridged between the existing copper centres via hydroxy ligands, and bound oxalate or malonate.

In another variation on this theme, Amendola and co-workers investigated the binding affinities of substituted terephthalates to the azacryptand 63 ( previously described by Taglietti47,48


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Organic & Biomolecular Chemistry and a known receptor for terephthalate).113 Disubstituted terephthalates with alkyl and polyethyleneglycol chains were found to form pseudorotaxane structures threaded into the cryptand, albeit with reduced binding affinities compared to terephthalate itself. Anthracene-strapped cages 64 and 65, developed by Kataev and co-workers, were found to be high affinity sensors for aqueous oxalate.114 The inclusion of an anthracene unit within the cage structure facilitated monitoring of binding via fluorescence titrations. The strength of binding was found to be highly dependent on pH, with a difference in binding affinity of four orders of magnitude between pH 3.6 and pH 6.2 for oxalate. At low pH the cages were highly selective for oxalate over other oxyanions and azide. Pyridine-containing cage 65 displayed slightly lower binding affinities, presumably due to increased solvation or the presence of competing intramolecular hydrogen bonds in the cage pocket. More recent work from Kataev described the amido-anthracene cage receptor 66, which was determined to be a mixture of the tri- and tetra-protonated species at pH 7.2 and bound oxalate, fumarate, maleate, and malonate with little or no selectively over common oxoanions.115 However, the greatest fluorescence response was noted for oxalate. This response was attributed to enhanced protonation (i.e. an increase in the tetra-protonated form) of the receptor upon oxalate binding. In an attempt to improve the dicarboxylate binding properties of azacryptands developed in 2012108 across a broader pH range, Delgado and co-workers developed triamide cage 67.116 Binding affinities were found to be less dependent on pH than the previously reported polyamine cages, such as cryptand 68, with notable improvements at higher pH. However, binding affinities for the triamide cage were typically lower than those for the polyamine cages at low pH, and a less competitive solvent was used (DMSO/H2O, 1 : 1, cf. H2O).


Review Compromises between binding affinity, solubility, and effectiveness across a broad pH range are common for these amidebased cages: a similar reduction in binding affinity was noted for Kataev’s diamide cage 66.115

Selective responses to dicarboxylic acids An exciting prospect for the field of dicarboxylate recognition, and indeed for anion sensing in general, is the idea of nonselective chemosensors that display similar binding affinities against a range of dicarboxylate guests but give a response that is selective to the guest. The ideal chemosensor would be capable of indicating which analytes are present in a complex mixture, as well as the concentration of one or several analytes of interest. One of the most versatile solutions to this challenge is the use of sensing arrays, pioneered by Anslyn,117,118 and recently reviewed by Jolliffe, New, and co-workers.119 This technique involves the use of multiple complementary chemosensors. Although each individual sensor may be insufficiently selective to distinguish between multiple competing analytes in a mixture, analysis of the responses of multiple receptors may be used to determine the identity and concentration of each analyte. Sensing arrays Tripodal sensors 69 and 70, prepared by Anzenbacher and coworkers, bind to di- and tricarboxylates through hydrogen bonding interactions in acetonitrile, but do not bind to acetate, benzoate, or chloride.120 The pendant dimethylaminonaphthalene groups provide a fluorescent response upon binding. Although neither sensor is selective for a particular di- or tricarboxylate, and both sensors 69 and 70 are insoluble in water, 100% classification of a variety of analytes in water was achieved. Each tripodal sensor was doped into a polyether-urethane matrix on a microarray chip: the matrix swells in water, leading to desolvation of the analytes, binding to the doped sensor, and a measurable fluorescence response.121 Linear discriminate analysis was used to correctly distinguish between acetate, benzoate, oxalate, maleate, malonate, citrate, glutarate, and tricarballylate in aqueous solution.120 Using this system, quantitative determination of citrate concentration at micromolar levels in urine, and within an error of 2.4%, was achieved. Further investigations of dicarboxylate binding were undertaken by Anzenbacher with the series of calixpyrrole sensors 71–75.122 These sensors differed only in the size of the macrocyclic ring system used, and in the pendant fluorophore. Once again, the sensors were doped into a polymer matrix in a microarray. The sensors were non-selective towards dicarboxylates among a screen of 18 analytes, but 100% classification of the analytes was possible following linear discriminant analysis of the results from all five sensors. Quantitative analyses of aqueous solutions of oxalate, malonate, glutamate, aspar-

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Review

Organic & Biomolecular Chemistry

tate, and phthalate were demonstrated, with an error of less than 1%. Xu and Bonizzoni extensively explored the responses of arrays based on an ensemble of polycationic amino-terminated poly(amidoamine) (PANAM) dendrimer with the polycarboxylate dye calcein (76).123 Calcein and PANAM generation 5 dendrimer were deposited on a variety of solid supports, including commercially-available printer paper. Addition of solutions of carboxylic acids led to displacement of calcein from the dendrimer, and the resulting fluorescence response could be read on a plate reader. Linear discriminant analysis of the results obtained from both wet and dried samples led to the successful discrimination of a range of carboxylates, including citrate, isocitrate, malate, and oxaloacetate. Sensors with a selective response An alternative to the use of sensing arrays is the development of a single sensor that may give a response that is selective to the analyte. Beer’s series of C–H hydrogen bonding, halogen bonding, and chalcogen bonding receptors 35–37,81 which were noted previously in this review to display small changes in emission wavelength and fluorescence intensity in response to different dicarboxylic acids, mark a step towards such a sensor. In the following section, the design of sensors that give analyte-selective responses will be discussed, with particular focus on systems that give an output that corresponds to the length of a dicarboxylic acid. In work that bridges the gap between sensing arrays and a single, multi-responsive sensor, Zonta and co-workers have investigated dynamic covalent chemistry (DCC) to produce dicarboxylate-templated cages of the form of 77.124–127 The assembly of zinc tris(2-pyridylmethyl)amine (ZnTMPA) cages constructed from aldehyde and diamine building blocks was

Org. Biomol. Chem.

investigated in the presence and absence of a range of α,ω-dicarboxylic acids.124 The binding affinities of α,ω-dicarboxylic acids to a cage constructed with ethylenediamine (R, R′, R″ = –CH2CH2–) in acetonitrile were found to be dependent on the length of the dicarboxylic acid alkyl chain. C6 and C8 dicarboxylic acids were found to be the optimal length, with reduced binding affinities observed for pimelic acid (C7) and for shorter and longer dicarboxylic acids. Furthermore, the rate of cage assembly followed a similar trend, with the fastest rates of assembly noted when synthesis was templated with even chain length dicarboxylic acids adipic (C6), suberic (C8), and sebacic (C10) acids. Disassembly was fastest for longer dicarboxylic acids, which must coil to fit inside the cage, and slowest for shorter dicarboxylic acids. The preferred binding profiles of cages composed of various diamine linkers have been characterized by both 1H


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Organic & Biomolecular Chemistry NMR and by ESI mass spectrometry, and a “fingerprint” for each α,ω-dicarboxylic acid (C5–C14) has been developed by Zonta and co-workers.125 Combination of an unknown α,ω-dicarboxylic acid with a mixture of cage building blocks, including multiple different diamines, led to the formation of a mixture of cages of varying composition. Principal component analysis of raw ESI-MS data or selected 1H NMR data was used to correctly classify α,ω-dicarboxylic acids based on their influence on cage formation.126 Further work with chiral diamine building blocks facilitated determination of α,ω-dicarboxylic acid length by circular dichroism measurements.127 Long dicarboxylic acids form cages where substituents on the chiral diamine unit are twisted into an antiperiplanar arrangement, whereas this arrangement is gauche for short dicarboxylic acids. Consequently, chiroptical measurements may be transcribed into molecular length using this system. Binaphthalene receptor 78 developed by Kondo, Nakadai, and Unno bound dicarboxylic acids with affinities of the order of 105 M−1 in aqueous acetonitrile, and also provided a small differential response in the presence of α,ω-dicarboxylic acids of varying lengths.128 Changes in the dihedral angle between the naphthyl groups were found to correlate with changes in binding affinity and absorption spectra. In an effect similar to that noted by Zonta, an even–odd relationship between α,ω-dicarboxylic acid length and binding affinity was observed: dicarboxylic acids with an even number of carbons displayed higher binding affinities than their odd chain length neighbours.

The most sophisticated examples to date of chemosensors with an output corresponding to α,ω-dicarboxylic acid length involve use of 9,14-dihydrodibenzo[a,c]phenazine (DPAC) fluorophores. This scaffold was first reported in 2015 to display changes in fluorescence wavelength depending on the degree of planarity of the system.129 In 2019, Stang and coworkers prepared a series of DPAC-based bimetallic platinium complexes of the form of 79, with bridging aromatic dicarboxylate ligands bridging between two platinum centres.130 Subtle changes in the dicarboxylate length, and hence the planarity of the DPAC system, were reported to lead to significant changes in the absorption and emission spectra of the bimetallic complexes. Indeed, in situ reduction of a bridging fumarate ligand to succinate resulted in a shift in the emission maximum from 502 nm to 533 nm: a difference that is observable by the naked eye. These complexes were found to be sen-


Review

sitive to chloride, which displaced the dicarboxylate ligands, and hence are unsuitable as practical sensors for real-world applications. However, this work acted as a valuable proof of concept for sensors with a conveniently analysed and selective response to molecular length. Soon after the publication of Stang’s work, Sessler, Tian and co-workers disclosed the development of DPAC-based dicarboxylate sensor 80.131 Two calix[4]pyrrole units appended to the DPAC unit each recognize one end of a dicarboxylate guest. In acetonitrile, binding of long dicarboxylates (up to C12) resulted in fluorescent properties similar to the free receptor, but the emission wavelength underwent a hypsochromic shift as the distance between carboxylate units decreased (see Fig. 3). The sensor was completely non-responsive to monocarboxylates, and complete differentiation of dicarboxylate species of varying length was possible by analysis of emis-

Fig. 3 Fluorescence images of sensor 80 with and without α,ω-dicarboxylates of various lengths. Images recorded in MeCN upon irradiation with 365 nm UV light. Reprinted with permission from W. Chen, C. Guo, Q. He, X. Chi, V. M. Lynch, Z. Zhang, J. Su, H. Tian and J. L. Sessler, J. Am. Chem. Soc., 2019, 141, 14798–14806. Copyright 2019 American Chemical Society.

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Review


sion spectra. Furthermore, the ratiometric response to dicarboxylates facilitated the quantitative determination of dicarboxylate concentration in acetonitrile with nanomolar limits of detection.

Conclusions There has been significant progress in the development of sensors and receptors for dicarboxylic acids over the past five years. New receptor scaffolds and an increased understanding of existing scaffolds have led to improvements in dicarboxylate recognition in competitive solvents and in selectivity between related analytes. Exploration of simple amidinium and guanidinium receptors has yielded important insights into the affinities that may be achieved in competitive solvents when receptor and host are ideally matched. Previous contributions by pioneers of the field continue to be valuable sources of inspiration for receptor design and discovery. This is particularly evident in the area of polyaza-cryptands: an area in which early work by Lehn and others remains a source of investigation and discovery. Although many of the recognition elements of dicarboxylate sensors have remained constant over the years, this time period (2014–2020) has seen the incorporation of C–H hydrogen, halogen, and chalcogen bonding motifs into dicarboxylate sensors, and these have brought advantages for stability across extended pH ranges, high directionality, and reduced receptor solvation. Receptors based on these interactions have been shown to be the equal of previously utilized interaction tropes and are an exciting prospect for the future. Many of the challenges identified by Curiel, Más-Montoya, and Sánchez in 2015 have been tackled, although perhaps not in the manner envisioned by the authors. Previous efforts in enantioselective binding and discrimination of chiral substrates have not been surpassed, however the use of circular dichroism measurements of supramolecular assemblies has facilitated the accurate determination of enantiomeric excess of chiral substrates. Rather than increasing the solubility and affinity of receptors in aqueous environments, advances in polymer technology have made possible the use of insoluble and low-affinity sensors for the analysis of aqueous samples. Selective binding between flexible dicarboxylates, especially between those that differ by a single methylene unit, remains a challenge for single receptors. However, the advent of sensing arrays has facilitated the classification of a variety of dicarboxylate substrates using non-selective receptors. The combination of sensing arrays with other advances such as sensor-doped polymer matrices greatly improves the utility of existing sensors, and is an exciting prospect for the application of dicarboxylate sensors in medicine and industry. Similarly, the development of sensors that display non-selective binding, but provide a selective response to various dicarboxylates is a powerful advance for the field. Despite these advances, several key challenges remain. Curiel, Más-Montoya, and Sánchez noted in 2015 that although molecular modelling has been used extensively for

Org. Biomol. Chem.

Organic & Biomolecular Chemistry the post hoc analysis of dicarboxylate receptors and sensors, this technology has rarely been utilized for de novo design or structural optimisation and this remains the case. Second, with the exception of systems for the sensing of dipicolinic acid, the majority of dicarboxylate sensors are homogeneous. The development of heterogenous receptors that are reusable or incorporated into in-line detection is an exciting prospect that is yet to be realised. Third, the majority of dicarboxylate sensors are not functional in water. Although systems such as the polymer matrices developed by Anzenbacher may facilitate the use of such sensors for aqueous samples, this solution is limited to the analysis of environmental samples or physiological fluids. Real-time analysis within cells is not currently possible for the majority of dicarboxylate species of interest in biomedical research. Finally, the selectivity of many receptors for dicarboxylate species has been insufficiently characterized to determine their suitability for use as effective sensors. For example, metal-based systems are often prone to the binding of phosphate species. This potential cross-reactivity is particularly pertinent for applications involving biological systems, in which phosphate species are likely to be common. In summary, while considerable progress has been made in the development of receptors and sensors for dicarboxylates and dicarboxylic acids, numerous challenges still need to be addressed to facilitate the use of these systems in real world applications.

Conflicts of interest There are no conflicts to declare.

Acknowledgements This work was supported by the Australian Research Council (DP170100118 to K. A. J.).

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What's in a title--Mr or Dr?

Writing style: what's in a title?

[Funktionsoberarzt. Pseudo-title or meaningful position?].

Futurist Art: Motion and Aesthetics As a Function of Title.

The anatomy of an article: title, abstract, and introduction.

"The chronic patient": in search of a title.

Citations-be sure to have a good title.

World title boxing: from early beginnings to the first bell.

Peer bids for protection of title 'veterinary nurse'.

Barriers to effective outreach in Title VII nutrition programs.

Article title misstates the role of pavement sealers.

Title and Abstract Screening and Evaluation in Systematic Reviews (TASER): a pilot randomised controlled trial of title and abstract screening by medical students.

No title

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