& Carboxylate Receptors Towards the Discrimination of Carboxylates by Hydrogen-Bond Donor Anion Receptors Sandip A. Kadam, [a] Kerli Martin, [a] Kristjan Haav, [a] Lauri Toom, [b] Charly Mayeux, [a] Astrid Pung, [a] Philip A. Gale, [c] Jennifer R. Hiscock, [c] Simon J. Brooks, [c] Isabelle L. Kirby, [c] Nathalie Busschaert, [c] and Ivo Leito* [a] Abstract: The binding constants (log K ass ) of small synthetic receptor molecules based on indolocarbazole, carbazole, indole, urea and some others, as well as their combinations were measured for small carboxylate anions of different ba- sicity, hydrophilicity and steric demands, that is, trimethyla- cetate, acetate, benzoate and lactate, in 0.5 % H 2 O/[D 6 ]DMSO by using the relative NMR-based measurement method. As a result, four separate binding affinity scales (ladders) includ- ing thirty-eight receptors were obtained with the scales anchored to indolocarbazole. The results indicate that the binding strength is largely, but not fully, determined by the strength of the primary hydrogen-bonding interaction. The latter in turn is largely determined by the basicity of the anion. The higher is the basicity of the anion the stronger in general is the binding, leading to the approximate order of increasing binding strength, lactate < benzoate < acetate  trimethylacetate, which holds with all investigated receptors. Nevertheless, there are a number of occasions when the binding order changes with changing of the carboxylate anion, sometimes quite substantially. Principal component analysis (PCA) reveals that this is primarily connected to pref- erential binding of trimethylacetate, supposedly caused by an additional hydrophobic/solvophobic interaction. These findings enable making better predictions, which receptor framework or cavity is best suited for carboxylate anions in receptor design. Introduction Carboxylates are among the most important anions in nature and in technology. [1] Smaller carboxylates are important metab- olites whereas carboxylic acids with long aliphatic chains are crucial in the formation of fats. Amino acids are the key com- ponents in the formation of peptides and proteins and many widely used anti-inflammatory drugs such as aspirin and ibu- profen are carboxylic acids. [2] Between pH 7 and 8, that is, under physiological conditions, carboxylic acids exist predomi- nantly in their anionic form. For these reasons the synthesis of receptors capable of binding carboxylates in analytical applica- tions [3] (e.g., sensors) or acting as anion transporters [4] in mem- branes is attracting intense current interest. Carboxylate anions have a distinct geometry with equal CO bond lengths (1.26  in acetate) [5] and bond angles between the CO bonds (close to 1208 in acetate) [5] and a distance be- tween the oxygen atoms around 2.2 . [6] The negative charge of carboxylate ions is largely distributed between the two oxygen atoms making these ions strongly solvated in hydro- gen-bond-donating solvents, especially in water. [7] Because car- boxylic acids are quite strong acids in aqueous media [8] they are deprotonated quite readily, although the respective car- boxylates are not protonated so easily. The geometry of car- boxylates enables formation of hydrogen-bonded complexes with chelating receptors of suitable geometry in 1:1 stoichiom- etry. The alkyl or aryl moiety (often with substituents) of a car- boxylate ion significantly modifies its properties (e.g., size, ba- sicity and hydrophilicity) and forms the basis of differentiating between different carboxylates. Numerous synthetic receptor molecules have been pro- posed for binding carboxylates. In 2005, Gale and co-workers reported the anion-binding ability of acyclic receptors contain- ing ortho-phenylenediamine-based bis-urea units. [9, 10] The four NH urea protons stabilise hydrogen-bond interactions with the negatively charged oxygen atoms of the carboxylate, produc- ing a complex through four hydrogen bonds with functional- ised systems offering additional amide hydrogen-bond donors. [9, 10] Other similar structures have been reported, for ex- ample, receptors based on 1,8-diaminocarbazole [11] and 1,2-dia- [a] S. A. Kadam, K. Martin, K. Haav, Dr. C. Mayeux, A. Pung, Prof. I. Leito University of Tartu, Institute of Chemistry Ravila 14a, 50411 Tartu (Estonia) Phone: + 372-51-84-176 E-mail : ivo.leito@ut.ee [b] Dr. L. Toom University of Tartu, Institute of Technology Nooruse 1, 50411 Tartu (Estonia) [c] Prof. P. A. Gale, Dr. J. R. Hiscock, Dr. S. J. Brooks, Dr. I. L. Kirby, Dr. N. Busschaert Chemistry, University of Southampton Southampton, SO17 1BJ (UK) Supporting information (containing the relative binding measurement spec- tra ( 1 H NMR and UV/Vis spectrophotometric), additional compound charac- terisation data ( 1 H, 13 C and 15 N NMR spectra, IR and HR MS data) of the synthesised compounds) for this article is available on the WWW under http ://dx.doi.org/10.1002/chem.201405858. Chem. Eur. J. 2015, 21, 5145 – 5160 # 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 5145 Full Paper DOI: 10.1002/chem.201405858