A family of heterocyclic thiosemicarbazone dyes (3a-f and 4) containing furyl groups was synthesized in good yields, characterized and their response in acetonitrile in the presence of selected anions was studied. Acetonitrile solutions of 3a-f and 4 showed absorption bands in the 335-396 nm range which are modulated by the electron donor or acceptor strength of the heterocyclic systems appended to the thiosemicarbazone moiety. Fluoride, chloride, bromide, iodide, dihydrogen phosphate, hydrogen sulphate, nitrate, acetate and cyanide anions were used in recognition studies. From these anions, only sensing features were seen for fluoride, cyanide, acetate and dihydrogen phosphate. Two clearly different chromo-fluorogenic behaviours were observed: (i) a small shift of the absorption band due to the coordination of the anions with the thiourea protons and (ii) the appearance of a new red shifted band due to deprotonation. For the latter effect, a change in the colour of solution from pale yellow to purple was observed. Fluorescence studies were also in agreement with the different effects observed in the UV/Vis titrations. In this case, hydrogen bonding interactions were visible through the enhancement of the emission band, whereas deprotonation induced the appearance of a new red-shifted emission. Logarithms of stability constants for the two processes (complex formation + deprotonation) for receptors 3a-f in the presence of fluoride and acetate anions were determined from spectrophotometric titrations using the HypSpec V1.1.18 program. Semi-empirical calculations to evaluate the hydrogen-donating ability of the receptors and a prospective electrochemical characterization of compound 3b in the presence of fluoride were also performed. © 2012 The Royal Society of Chemistry. We thank the Spanish Government (project MAT2009-14564-C04-01) and the Generalitat Valenciana (project PROMETEO/2009/016) for support. We are also grateful to the Fundacao para a Ciencia e Tecnologia (Portugal) and FEDER-COMPETE for financial support through the Centro de Quimica - Universidade do Minho, Project PEst-C/QUI/UI0686/2011 (F-COMP-01-0124-FEDER-022716) and a Post-doctoral grant to R. M. F. Batista (SFRH/BPD/79333/2011). The NMR spectrometer Bruker Avance III 400 is part of the National NMR Network and was purchased within the framework of the National Program for Scientific Re-equipment, with funds from FCT. The authors are also indebted to the programme "Accoes Integradas Luso-Espanholas/CRUP", for bilateral agreement number E-144/10. Thanks also go to the Fundacion Carolina and UPNFM-Honduras for a doctoral grant to L. E. Santos-Figueroa and the Spanish Ministry of Science and Innovation for an FPU grant to M. E. Moragues. Santos Figueroa, LE.; Moragues Pons, ME.; Raposo, MMM.; Batista, RM.; Costa, SPG.; Ferreira, RCM.; Sancenón Galarza, F.... (2012). Synthesis and evaluation of thiosemicarbazones functionalized with furylmoieties as new chemosensors for anion recognition. Organic and Biomolecular Chemistry. 10(36):7418-7428. https://doi.org/10.1039/c2ob26200b Basabe-Desmonts, L., Reinhoudt, D. N., & Crego-Calama, M. (2007). Design of fluorescent materials for chemical sensing. Chemical Society Reviews, 36(6), 993. doi:10.1039/b609548h Martínez-Máñez, R., Sancenón, F., Hecht, M., Biyikal, M., & Rurack, K. (2010). Nanoscopic optical sensors based on functional supramolecular hybrid materials. Analytical and Bioanalytical Chemistry, 399(1), 55-74. doi:10.1007/s00216-010-4198-2 Karuppannan, S., & Chambron, J.-C. (2011). Supramolecular Chemical Sensors Based on Pyrene Monomer-Excimer Dual Luminescence. Chemistry - An Asian Journal, 6(4), 964-984. doi:10.1002/asia.201000724 Amendola, V., Bonizzoni, M., Esteban-Gómez, D., Fabbrizzi, L., Licchelli, M., Sancenón, F., & Taglietti, A. (2006). Some guidelines for the design of anion receptors. Coordination Chemistry Reviews, 250(11-12), 1451-1470. doi:10.1016/j.ccr.2006.01.006 Suksai, C., & Tuntulani, T. (2003). Chromogenic anion sensors. Chemical Society Reviews, 32(4), 192. doi:10.1039/b209598j Nolan, E. M., & Lippard, S. J. (2008). Tools and Tactics for the Optical Detection of Mercuric Ion. Chemical Reviews, 108(9), 3443-3480. doi:10.1021/cr068000q Formica, M., Fusi, V., Giorgi, L., & Micheloni, M. (2012). New fluorescent chemosensors for metal ions in solution. Coordination Chemistry Reviews, 256(1-2), 170-192. doi:10.1016/j.ccr.2011.09.010 Pallavicini, P., Diaz-Fernandez, Y. A., & Pasotti, L. (2009). Micelles as nanosized containers for the self-assembly of multicomponent fluorescent sensors. Coordination Chemistry Reviews, 253(17-18), 2226-2240. doi:10.1016/j.ccr.2008.11.010 Martínez-Máñez, R., & Sancenón, F. (2003). Fluorogenic and Chromogenic Chemosensors and Reagents for Anions. Chemical Reviews, 103(11), 4419-4476. doi:10.1021/cr010421e Moragues, M. E., Martínez-Máñez, R., & Sancenón, F. (2011). Chromogenic and fluorogenic chemosensors and reagents for anions. A comprehensive review of the year 2009. Chemical Society Reviews, 40(5), 2593. doi:10.1039/c0cs00015a Martínez-Máñez, R., Sancenón, F., Biyikal, M., Hecht, M., & Rurack, K. (2011). Mimicking tricks from nature with sensory organic–inorganic hybrid materials. Journal of Materials Chemistry, 21(34), 12588. doi:10.1039/c1jm11210d Martínez-Máñez, R., & Sancenón, F. (2006). Chemodosimeters and 3D inorganic functionalised hosts for the fluoro-chromogenic sensing of anions. Coordination Chemistry Reviews, 250(23-24), 3081-3093. doi:10.1016/j.ccr.2006.04.016 Davis, A. P. (2006). Anion binding and transport by steroid-based receptors. Coordination Chemistry Reviews, 250(23-24), 2939-2951. doi:10.1016/j.ccr.2006.05.008 García-España, E., Díaz, P., Llinares, J. M., & Bianchi, A. (2006). Anion coordination chemistry in aqueous solution of polyammonium receptors. Coordination Chemistry Reviews, 250(23-24), 2952-2986. doi:10.1016/j.ccr.2006.05.018 Katayev, E. A., Ustynyuk, Y. A., & Sessler, J. L. (2006). Receptors for tetrahedral oxyanions. Coordination Chemistry Reviews, 250(23-24), 3004-3037. doi:10.1016/j.ccr.2006.04.013 Lloris, J. M., Martínez-Máñez, R., Padilla-Tosta, M. E., Pardo, T., Soto, J., Beer, P. D., … Smith, D. K. (1999). Cyclic and open-chain aza–oxa ferrocene-functionalised derivatives as receptors for the selective electrochemical sensing of toxic heavy metal ions in aqueous environments. Journal of the Chemical Society, Dalton Transactions, (14), 2359-2370. doi:10.1039/a902008j García-Acosta, B., Martínez-Máñez, R., Sancenón, F., Soto, J., Rurack, K., Spieles, M., … Gil, L. (2007). Ditopic N-Crowned 4-(p-Aminophenyl)-2,6-diphenylpyridines: Implications of Macrocycle Topology on the Spectroscopic Properties, Cation Complexation, and Differential Anion Responses. Inorganic Chemistry, 46(8), 3123-3135. doi:10.1021/ic062069z Gale, P. A. (2006). Structural and Molecular Recognition Studies with Acyclic Anion Receptors†. Accounts of Chemical Research, 39(7), 465-475. doi:10.1021/ar040237q Yoon, J., Kim, S. K., Singh, N. J., & Kim, K. S. (2006). Imidazolium receptors for the recognition of anions. Chemical Society Reviews, 35(4), 355. doi:10.1039/b513733k Blondeau, P., Segura, M., Pérez-Fernández, R., & de Mendoza, J. (2007). Molecular recognition of oxoanions based on guanidinium receptors. Chem. Soc. Rev., 36(2), 198-210. doi:10.1039/b603089k Li, F., Carvalho, S., Delgado, R., Drew, M. G. B., & Félix, V. (2010). Dimetallic complexes of macrocycles with two rigid dibenzofuran units as receptors for detection of anionic substrates. Dalton Transactions, 39(40), 9579. doi:10.1039/c0dt00340a Lin, Y.-S., Tu, G.-M., Lin, C.-Y., Chang, Y.-T., & Yen, Y.-P. (2009). Colorimetric anion chemosensors based on anthraquinone: naked-eye detection of isomeric dicarboxylate and tricarboxylate anions. New Journal of Chemistry, 33(4), 860. doi:10.1039/b811172c Lin, Y.-S., Zheng, J.-X., Tsui, Y.-K., & Yen, Y.-P. (2011). Colorimetric detection of cyanide with phenyl thiourea derivatives. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, 79(5), 1552-1558. doi:10.1016/j.saa.2011.04.087 Odago, M. O., Colabello, D. M., & Lees, A. J. (2010). A simple thiourea based colorimetric sensor for cyanide anion. Tetrahedron, 66(38), 7465-7471. doi:10.1016/j.tet.2010.07.006 Gale, P. A., García-Garrido, S. E., & Garric, J. (2008). Anion receptors based on organic frameworks: highlights from 2005 and 2006. Chem. Soc. Rev., 37(1), 151-190. doi:10.1039/b715825d Devaraj, S., Saravanakumar, D., & Kandaswamy, M. (2009). Dual responsive chemosensors for anion and cation: Synthesis and studies of selective chemosensor for F− and Cu(II) ions. Sensors and Actuators B: Chemical, 136(1), 13-19. doi:10.1016/j.snb.2008.11.018 Li, Z., Wu, F.-Y., Guo, L., Li, A.-F., & Jiang, Y.-B. (2008). Enhanced Anion Binding ofN-(Anilino)thioureas. Contribution of theN-Anilino −NH Proton Acidity. The Journal of Physical Chemistry B, 112(23), 7071-7079. doi:10.1021/jp801531w Ros-Lis, J. V., Martínez-Máñez, R., Sancenón, F., Soto, J., Rurack, K., & Weißhoff, H. (2007). Signalling Mechanisms in Anion-Responsive Push-Pull Chromophores: The Hydrogen-Bonding, Deprotonation and Anion-Exchange Chemistry of Functionalized Azo Dyes. European Journal of Organic Chemistry, 2007(15), 2449-2458. doi:10.1002/ejoc.200601111 Krishnamurthi, J., Ono, T., Amemori, S., Komatsu, H., Shinkai, S., & Sada, K. (2011). Thiourea-tagged poly(octadecyl acrylate) gels as fluoride and acetate responsive polymer gels through selective complexation. Chem. Commun., 47(5), 1571-1573. doi:10.1039/c0cc03256e Piątek, P. (2011). A selective chromogenic chemosensor for carboxylate salt recognition. Chemical Communications, 47(16), 4745. doi:10.1039/c0cc05537a He, X., Herranz, F., Cheng, E. C.-C., Vilar, R., & Yam, V. W.-W. (2010). Design, Synthesis, Photophysics, and Anion-Binding Studies of Bis(dicyclohexylphosphino)methane-Containing Dinuclear Gold(I) Thiolate Complexes with Urea Receptors. Chemistry - A European Journal, 16(30), 9123-9131. doi:10.1002/chem.201000647 Esteban-Gómez, D., Fabbrizzi, L., & Licchelli, M. (2005). Why, on Interaction of Urea-Based Receptors with Fluoride, Beautiful Colors Develop. The Journal of Organic Chemistry, 70(14), 5717-5720. doi:10.1021/jo050528s Evans, L. S., Gale, P. A., Light, M. E., & Quesada, R. (2006). Pyrrolylamidourea based anion receptors. New Journal of Chemistry, 30(7), 1019. doi:10.1039/b603223k Evans, L. S., Gale, P. A., Light, M. E., & Quesada, R. (2006). Anion binding vs. deprotonation in colorimetric pyrrolylamidothiourea based anion sensors. Chemical Communications, (9), 965. doi:10.1039/b517308f Jakab, G., Tancon, C., Zhang, Z., Lippert, K. M., & Schreiner, P. R. (2012). (Thio)urea Organocatalyst Equilibrium Acidities in DMSO. Organic Letters, 14(7), 1724-1727. doi:10.1021/ol300307c Costa, S. P. G., Batista, R. M. F., Cardoso, P., Belsley, M., & Raposo, M. M. M. (2006). 2-Arylthienyl-Substituted 1,3-Benzothiazoles as New Nonlinear Optical Chromophores. European Journal of Organic Chemistry, 2006(17), 3938-3946. doi:10.1002/ejoc.200600059 Raposo, M. M. M., Castro, M. C. R., Fonseca, A. M. C., Schellenberg, P., & Belsley, M. (2011). Design, synthesis, and characterization of the electrochemical, nonlinear optical properties, and theoretical studies of novel thienylpyrrole azo dyes bearing benzothiazole acceptor groups. Tetrahedron, 67(29), 5189-5198. doi:10.1016/j.tet.2011.05.053 Whitnall, M., Howard, J., Ponka, P., & Richardson, D. R. (2006). A class of iron chelators with a wide spectrum of potent antitumor activity that overcomes resistance to chemotherapeutics. Proceedings of the National Academy of Sciences, 103(40), 14901-14906. doi:10.1073/pnas.0604979103 Zhang, H.-J., Qin, X., Liu, K., Zhu, D.-D., Wang, X.-M., & Zhu, H.-L. (2011). Synthesis, antibacterial activities and molecular docking studies of Schiff bases derived from N-(2/4-benzaldehyde-amino) phenyl-N′-phenyl-thiourea. Bioorganic & Medicinal Chemistry, 19(18), 5708-5715. doi:10.1016/j.bmc.2011.06.077 Tian, Y., Duan, C., Zhao, C., You, X., Mak, T. C. W., & Zhang, Z. (1997). Synthesis, Crystal Structure, and Second-Order Optical Nonlinearity of Bis(2-chlorobenzaldehyde thiosemicarbazone)cadmium Halides (CdL2X2; X = Br, I). Inorganic Chemistry, 36(6), 1247-1252. doi:10.1021/ic9603870 Ramachandran, R., Rani, M., & Kabilan, S. (2009). Design, synthesis and biological evaluation of novel 2-[(2,4-diaryl-3-azabicyclo[3.3.1]nonan-9-ylidene)hydrazono]-1,3-thiazolidin-4-ones as a new class of antimicrobial agents. Bioorganic & Medicinal Chemistry Letters, 19(10), 2819-2823. doi:10.1016/j.bmcl.2009.03.093 Raposo, M. M. M., García-Acosta, B., Ábalos, T., Calero, P., Martínez-Máñez, R., Ros-Lis, J. V., & Soto, J. (2010). Synthesis and Study of the Use of Heterocyclic Thiosemicarbazones As Signaling Scaffolding for the Recognition of Anions. The Journal of Organic Chemistry, 75(9), 2922-2933. doi:10.1021/jo100082k Amendola, V., Boiocchi, M., Fabbrizzi, L., & Mosca, L. (2008). Metal-Controlled Anion-Binding Tendencies of the Thiourea Unit of Thiosemicarbazones. Chemistry - A European Journal, 14(31), 9683-9696. doi:10.1002/chem.200800801 Santos-Figueroa, L. E., Moragues, M. E., Raposo, M. M. M., Batista, R. M. F., Ferreira, R. C. M., Costa, S. P. G., … Ros-Lis, J. V. (2012). Synthesis and evaluation of fluorimetric and colorimetric chemosensors for anions based on (oligo)thienyl-thiosemicarbazones. Tetrahedron, 68(35), 7179-7186. doi:10.1016/j.tet.2012.06.021 Mitsch, A., Wißner, P., Silber, K., Haebel, P., Sattler, I., Klebe, G., & Schlitzer, M. (2004). Non-thiol farnesyltransferase inhibitors: N-(4-tolylacetylamino-3-benzoylphenyl)-3-arylfurylacrylic acid amides. Bioorganic & Medicinal Chemistry, 12(17), 4585-4600. doi:10.1016/j.bmc.2004.07.010 Aldrey, A., Núñez, C., García, V., Bastida, R., Lodeiro, C., & Macías, A. (2010). Anion sensing properties of new colorimetric chemosensors based on macrocyclic ligands bearing three nitrophenylurea groups. Tetrahedron, 66(47), 9223-9230. doi:10.1016/j.tet.2010.09.054 Atta, A. K., Ahn, I.-H., Hong, A.-Y., Heo, J., Kim, C. K., & Cho, D.-G. (2012). Fluoride indicator that functions in mixed aqueous media: hydrogen bonding effects. Tetrahedron Letters, 53(5), 575-578. doi:10.1016/j.tetlet.2011.11.099 Amendola, V., Fabbrizzi, L., Mosca, L., & Schmidtchen, F.-P. (2011). Urea-, Squaramide-, and Sulfonamide-Based Anion Receptors: A Thermodynamic Study. Chemistry - A European Journal, 17(21), 5972-5981. doi:10.1002/chem.201003411 Amendola, V., Bergamaschi, G., Boiocchi, M., Fabbrizzi, L., & Milani, M. (2010). The Squaramide versus Urea Contest for Anion Recognition. Chemistry - A European Journal, 16(14), 4368-4380. doi:10.1002/chem.200903190 Kim, T. H., Choi, M. S., Sohn, B.-H., Park, S.-Y., Lyoo, W. S., & Lee, T. S. (2008). Gelation-induced fluorescence enhancement of benzoxazole-based organogel and its naked-eye fluoride detection. Chemical Communications, (20), 2364. doi:10.1039/b800813b Amendola, V., & Fabbrizzi, L. (2009). Anion receptors that contain metals as structural units. Chem. Commun., (5), 513-531. doi:10.1039/b808264m Caltagirone, C., Mulas, A., Isaia, F., Lippolis, V., Gale, P. A., & Light, M. E. (2009). Metal-induced pre-organisation for anion recognition in a neutral platinum-containing receptor. Chemical Communications, (41), 6279. doi:10.1039/b912942a Pérez-Casas, C., & Yatsimirsky, A. K. (2008). Detailing Hydrogen Bonding and Deprotonation Equilibria between Anions and Urea/Thiourea Derivatives. The Journal of Organic Chemistry, 73(6), 2275-2284. doi:10.1021/jo702458f Dos Santos, C. M. G., McCabe, T., Watson, G. W., Kruger, P. E., & Gunnlaugsson, T. (2008). The Recognition and Sensing of Anions through «Positive Allosteric Effects» Using Simple Urea−Amide Receptors. The Journal of Organic Chemistry, 73(23), 9235-9244. doi:10.1021/jo8014424 Dydio, P., Zieliński, T., & Jurczak, J. (2009). Bishydrazide Derivatives of Isoindoline as Simple Anion Receptors. The Journal of Organic Chemistry, 74(4), 1525-1530. doi:10.1021/jo802288u Xu, Z., Kim, S. K., Han, S. J., Lee, C., Kociok-Kohn, G., James, T. D., & Yoon, J. (2009). Ratiometric Fluorescence Sensing of Fluoride Ions by an Asymmetric Bidentate Receptor Containing a Boronic Acid and Imidazolium Group. European Journal of Organic Chemistry, 2009(18), 3058-3065. doi:10.1002/ejoc.200900120 Amendola, V., Esteban-Gómez, D., Fabbrizzi, L., & Licchelli, M. (2006). What Anions Do to N−H-Containing Receptors. Accounts of Chemical Research, 39(5), 343-353. doi:10.1021/ar050195l Boiocchi, M., Del Boca, L., Gómez, D. E., Fabbrizzi, L., Licchelli, M., & Monzani, E. (2004). Nature of Urea−Fluoride Interaction: Incipient and Definitive Proton Transfer. Journal of the American Chemical Society, 126(50), 16507-16514. doi:10.1021/ja045936c Boiocchi, M., Del Boca, L., Esteban-Gómez, D., Fabbrizzi, L., Licchelli, M., & Monzani, E. (2005). Anion-Induced Urea Deprotonation. Chemistry - A European Journal, 11(10), 3097-3104. doi:10.1002/chem.200401049 Bonizzoni, M., Fabbrizzi, L., Taglietti, A., & Tiengo, F. (2006). (Benzylideneamino)thioureas – Chromogenic Interactions with Anions and N–H Deprotonation. European Journal of Organic Chemistry, 2006(16), 3567-3574. doi:10.1002/ejoc.200600388

Gómez, D. E., Fabbrizzi, L., Licchelli, M., & Monzani, E. (2005). Urea vs. thiourea in anion recognition. Org. Biomol. Chem., 3(8), 1495-1500. doi:10.1039/b500123d

Gómez, D. E., Fabbrizzi, L., LICCHELLI, M., Mr. Monzani, E. (2005). Urea vs. thiourea in anion restoration. ORG. Biomol. Chem., 3 (8), 1495-1500. doi:10.1039/b500123d

Synthesis and evaluation of thiosemicarbazones functionalized with furylmoieties as new chemosensors for anion recognition

Abstract