Anion Recognition

Anion Recognition

We have four main motifs: triazolophane macrocycles, aryl-triazole cages, aryl-triazole foldamers, and cyanostar macrocycles

We have developed a novel shape-persistent macrocycle (see image below) that is easily constructed using click chemistry and displays a high affinity for anions. This is one of the first examples of the weak CH•••anion hydrogen bond (the weakest among Nature's cohort) to be reported and therefore represents an iconoclastic breakthrough in the design of anion receptors. Consequently, the extreme modularity provided by the click chemistry as well as the high affinity (some approaching Ka values of 1,000,000 M–1 in dichloromethane) open up a new and uncharted realm of opportunities. One of our goals are to sequester toxic anions from aqueous environment, deliver them to safe locations and, by using our knowledge of molecular machines, to release them into captivity using a photo-driven light switch – which is where we were able to highlight our use of aryl-triazole foldamers.

New goals include the chelation, sensing, regulation, and transport of chloride and phosphate in biological mileu.

We have leveraged our understanding of receptor design and CH based hydrogen bonding to create a wholly new class of macrocyclic receptors, called cyanostars. We made a couple of exciting discoveries during our initial studies, as outlined in the Nature Chemistry article. First, the macrocycles can be made in one pot with high yields (>80%) and on 10-g scales. Second, we were able to bind anions like PF6 that were originally thought to be non-coordinating and then, after re-evaluation in the 1970's to be "weakly coordinating" – perhaps that idea needs to be completely reformulated because of the extremely high affinities observed with cyanostars showing logK ~ 12. Third, we created a new class of anion-templated rotaxanes using dialkylphosphates. All of these discoveries represent areas for deeper understanding and further exploration.

References for the Triazolophanes and Aryl-triazole Series

158. Parks, F. C.; Sheetz, E. G.; Stutsman, S. R.; Lutolli, A.; Debnath, S.; Raghavachari, K.; Flood, A. H., Revealing the hidden costs of organization in host-guest chemistry using chloride-binding foldamers and their solvent dependence. J. Am. Chem. Soc. 2022, 144, 1274-1287. DOI

157. Lutolli, A.; Flood, A. H., Photoswitchable Ion Receptors, Book Chapter for “Molecular Photoswitches – Synthesis, Properties and Applications,” Ed. Z. Pianowski, Wiley 2022 DOI

156 Sheetz, E. G.; Van Craen, D.; Flood, A. H., Anion recognition and binding constant determination, Book Chapter for “Anion Assisted Catalysis,” Ed. O. Garcia Mancheno, Wiley 2021 DOI

151. Liu, Y.; Parks, F. C.; Sheetz, E. G.; Chen, C.-H.; Flood, A. H. Polarity-Tolerant Chloride Binding in Foldamer Capsules by Programmed Solvent-Exclusion, J. Am. Chem. Soc. 2021, 143, 3191-3204. DOI

144. Castillo, H. D.; Yang, J.; Debnath, S.; Dobscha, J. R.; Trainor, C. Q.; Mortensen, R. D.; Raghavachari, K.; Flood, A. H.; Ortoleva, P. J.; Tait, S. L., Solution-Mediated Annealing Pathways are Critical for Supramolecular Ordering of Complex Macrocycles at Surfaces, J. Phys. Chem. C, 2020 124, 6689-6699. DOI

140. Dobscha, J. R.; Castillo, H.; Li, Y.; Fadler, R.; Taylor, R.; Brown, A.; Trainor, C. Q.; Tait, S. L.; Flood, A. H., Sequence-defined Macrocycles for Understanding and Controlling the Build-up of Hierarchical Order in Self-assembled 2D Arrays, J. Am. Chem. Soc. 2019, 141, 17588-17600. DOI

139. Liu, Y.; Zhao, W.; Chen, C.-H.; Flood, A. H., Chloride capture using a C–H hydrogen bonding cage, Science. 2019, 365, 159-161. (Nominated for Molecule of the Year by Chemical and Engineering News) DOI

135. Parks, F. C.; Liu, Y.; Stutsman, S. R.; Debnath, S.; Raghavachari, K.; Flood, A. H., “Allosteric Control of Photofoldamers for Selecting between Anion Regulation and Double-to-Single Helix Switching, J. Am. Chem. Soc. 2018, 140, 17711-17723. DOI

134. Liu, Y.; Parks, F. C.; Zhao, W.; Flood, A. H., “Sequence-controlled Stimuli-responsive Single-Double Helix Conversion between 1:1 and 2:2 Chloride-Foldamer Complexes” J. Am. Chem. Soc., 2018, 140, 15477-15486. DOI

132. Sengupta, A.; Liu, Y.; Flood, A. H., Raghavachari, Anion-binding Macrocycles Operate Beyond the Electrostatic Regime: Interaction Distances Matter, Chem. Eur. J. 2018, 24, 14409-14417. DOI

127. Dobscha, J. R.; Debnath, S.; Fadler, R. E.; Fatila, E. M.; Pink, M.; Raghavachari, K.; Flood, A. H., Host-host Interactions Control Self-assembly and Switching of Triple and Double Decker Stacks of Tricarbazole Macrocycles Co-assembled with Anti-electrostatic Bisulfate Dimers, Chem. Eur. J.  2018, 24, 9841-9852. DOI

124. Gibb, B. C.; Flood, A. H.; Cremer P. S.; Mobley, D. L., “Collaborative Routes to Clarifying the Murky Waters of Aqueous Supramolecular Chemistry” Nat. Chem. 2018, 10, 8-16. DOI

120. Liu, Y.; Sengupta, A.; Raghavachari, K.; Flood, A. H., Anion binding in solution: Beyond the electrostatic regime, Chem. 2017, 3, 411-427 DOI

116. Dobscha, J. R.; Liu, Y.; Flood, A. H., Shape-persistent Anion Receptors. In Comprehensive Supramolecular Chemistry II; Elsevier, 2016

110. Flood, A. H., Creating molecular macrocycles for anion recognition, Beilstein J. Org. Chem. 2016, 12, 611-627. DOI

108. Lee, S.; Hirsch, B. E.; Liu, Y.; Dobscha, J. R.; Burke, D. W.; Tait, S. L.; Flood, A. H., Multifunctional Tricarbazolo Triazolophane Macrocycles: One-Pot Preparation, Anion Binding, and Hierarchical Self-Organization of Multilayers, Chem. Eur. J. 2016, 22, 560–569. Cover Art DOI

107. Qiao, B.; Sengupta, A.; Liu, Y.; McDonald, K. P.; Pink, M.; Anderson, J.; Raghavachari, K.; Flood, A. H., Electrostatic and Allosteric Cooperativity in Ion-pair Binding: A Quantitative and Coupled Experiment-Theory Study with Aryl-Triazole-Ether Macrocycles, J. Am. Chem. Soc. 2015, 137, 9746-9757. DOI

105. Hirsch, B. E.; McDonald, K. P.; Flood, A. H.; Tait, S. L., Living on the Edge: Tuning Supramolecular Interactions to Design Two-dimensional Organic Crystals near the Boundary of Two Stable Structural Phases, J. Chem. Phys. 2015, 142, 101914. DOI

104. Hirsch, B. E.; McDonald, K. P.; Qiao, B.; Tait, S. L.; Flood, A. H., Crystal Switching and Anion Binding in Surface Monolayers Modulated by Electric Fields from Scanning Probes, ACS Nano, 2014, 8, 10858–10869. DOI

103. Liu, Y.; Flood, A. H., Ch. 9: Synergistic Effects in Double Helical Foldamers, Synergy in Supramolecular Chemistry, Ed. Tatsuya Nabeshima, CRC Press, 2014. (Link 1)

102. McDonald, K. P.; Qiao, B.; Twum, E. B.; Lee, S.; Gamache, P. J.; Chen, C.-H.; Yi, Y.; Flood, A. H., Chloride-binding poly(methyl methacrylate) copolymers bearing aryl-triazole side chains induce changes in polymer size and enhance salt extraction, Chem. Commun., 69, DOI

101. Lee, S.; Hua, Y.; Flood, A. H., Beta Sheet-Like Hydrogen Bonds Interlock the Helical Turns of a Photoswitchable Foldamer to Enhance the Binding and Release of Chloride, J. Org. Chem. 2014, 79. DOI

99. Chen, T.-H.; Lee, S.; Flood, A. H.; Miljanic, O. S., How to print a crystal structure model in 3D, CrystEngComm 2014, 16, 5488–5493. OPEN ACCESS–DOI Cover Art

97. Ramabhadran, R. O.; Liu, Y.; Hua, Y.; Ciardi, M.; Flood, A. H.; Raghavachari, K., An Overlooked yet Ubiquitous Fluoride Congenitor: Binding Bifluoride in Triazolophanes using Computer-Aided Design, J. Am. Chem. Soc. 2014, 136, 5078–5089. DOI

96. Ramabhadran, R. O.; Hua, Y.; Flood, A. H.; Raghavachari, K., C vs N: Which End of the Cyanide Anion is a Better Hydrogen Bond Acceptor?, J. Phys. Chem. 2014,118, 7418–7423. DOI

93. Hua, Y; Liu, Y; Chen, C.-H.; Flood, A. H., Hydrophobic Collapse of Foldamer Capsules Drives Picomolar-Level Chloride Binding in Aqueous Acetonitrile Solutions, J. Am. Chem. Soc. 2013, 135, 14401–14412. DOI

90. Lee, S.; Flood, A. H., Photoresponsive receptors for binding and releasing anions (Mini Review), J. Phys. Org. Chem. 2013 26, 79-86. Cover Art DOI

83 Lee, S.; Flood, A. H., Binding anions in rigid and reconfigurable triazole receptors, Topics Het. Chem. 2012, 28, 85-107. DOI

82 McDonald, K. P.; Hua, Y.; Lee, S.; Flood, A. H., Shape Persistence Delivers Lock-and-Key Chloride Binding in Triazolophanes, Chem. Commun. 2012, 48, 5065-5075. Cover Art DOI

81 Flood, A. H., Profile: Early Excellence in Physical Organic Chemistry J. Phys. Org. Chem. 2011 DOI

80 McDonald, K. P.; Ramabhadran, R. O.; Lee, S.; Raghavachari, K., Flood, A. H., Polarized Naphthalimide CH Donors Enhance Cl Binding Within an Aryl-Triazole Receptor, Org. Lett. 2011, 13, 6260-6263. DOI

78 Ramabhadran, R. O.; Hua, Y.; Flood, A. H.; Raghavachari, K., From Atomic to Molecular Anions: A Neutral Receptor Captures Cyanide using Strong C–H Hydrogen Bonds, Chem. Eur. J. 2011, 17, 9123-9129. DOI

75 Hua, Y.; Ramabhadran, R. O.; Karty, J. A.; Raghavachari, K.; Flood, A. H., Two levels of conformational pre-organization consolidate strong CH hydrogen bonds in chloride-triazolophane complexes, Chem. Commun. 2011, 47, 5979-5981. DOI

74 Zahran, E. M.; Hua, Y.; Lee, S.; Flood, A. H.; Bachas, L. G., Ion-selective electrodes based on a pyridyl-containing triazolophane: Manipulating halide selectivity by mixing dipole-promoted cooperativity with hydrogen bonding, Anal. Chem. 2011, 83, 3455-3461. DOI

73 Hua, Y.; Ramabhadran, R. O.; Uduehi, E. O.; Karty, J. A.; Raghavachari, K.; Flood, A. H., Aromatic and aliphatic CH hydrogen bonds fight for chloride while competing alongside ion pairing within triazolophanes, Chem. Eur. J. 2011, 17, 312-321. DOI.

72 Hua, Y.; Flood, A. H., Flipping the switch on chloride concentrations with a light-active foldamer, J. Am. Chem. Soc. 2010, 132, 12838-12840. DOI.

70 Lee, S.; Hua, Y. Park, H.; Flood, A. H., Intramolecular hydrogen bonds preorganize aryl-triazole receptor into a crescent for chloride binding, Org. Lett. 2010, 12, 2100-2101. DOI

66 Hua, Y.; Flood, A. H., Click chemistry generates priviliged CH hydrogen-bonding triazoles: the latest addition to anion supramolecular chemistry, Chem. Soc. Rev. 2010, 39, 1262-1271. DOI

65 McDonald, K. P.; Hua, Y.; Flood, A. H., 1,2,3-Triazoles and the Expanding Utility of Charge Neutral CH•••Anion Interactions, Anion Receptors Special Issue in Topic in Heterocyclic Chemistry, Springer, 2010. DOI

63 Zahran, E.; Hua, Y.; Li, Y.; Flood, A. H.; Bachas , L. G., Triazolophanes: A new class of halide-selective ionophores for potentiometric sensors, Anal. Chem. 2010,  82, 368-375. DOI

60 Bandyopadhyay, I.; Raghavachari, K.; Flood, A. H., Strong CH•••halide hydrogen bonds from 1,2,3-triazoles quantified using pre-organized and shape-persistent triazolophanes, ChemPhysChem. 2009, 10, 2535-2540. DOI

59 Li, Y.; Vander Griend, D. A.; Flood, A. H., Modelling triazolophane-halide binding equilibria using Sivvu analysis of UV-vis titration data recorded under medium binding conditions, Supramolec. Chem. 2009, 21, 111-117. (Special Issue for the III International Symposium on Macrocyclic and Supramolecular Chemistry, Las Vegas 2008), DOI

55 Li, Y.; Pink, M.; Karty, J. A.; Flood, A. H., Dipole-Promoted and Size-Dependent Cooperativity between Pyridyl-Containing Triazolophanes and Halides Leads to Persistent Sandwich Complexes with Iodide, J. Am. Chem. Soc., 2008, 130, 17293-17295. DOI

53 Li, Y.; Flood, A. H., “Strong, size-selective, and electronically-tunable C–H•••halide binding with steric control over aggregation from synthetically modular, shape-persistent [34]triazolophanes, J. Am. Chem. Soc. 2008, 130, 12111-12122. DOI

52   Li, Y.; Flood, A. H., "Pure CH hydrogen bonding to chloride ions: A pre-organized and rigid macrocyclic receptor," Angew. Chem. Int. Ed. 2008, 47, 2649-2652. DOI

See also the news coverage by: Chem. & Eng. News, • Nature • Chemistry World

References for the Cyanostar Series

166. Dhara, A.; Fadler, R. E.; Chen, Y.; Kottner, L. A.; Van Craen, D.; Carta, V.; Flood, A. H., Orthogonal, modular anion-cation and cation-anion self-assembly using pre-programmed anion binding sites, Chem. Sci. 2023, 14, 2585-2595. DOI

164. Sheetz, E. G., Marogil, A.; Che, M.; Pink, M.; Carta, V.; Raghavachari, K.; Flood, A. H. High-fidelity Recognition of Organotrifluoroborate Anions (R–BF₃^–) as Designer Guest Molecules. Chem. Eur. J. 2022, 28, e202201584. DOI

162. Li, Y.; Saha, A.; Zhao, W.; Neil, J. F.; Chen, Y.; Flood, A. H.; Allen, H. C., Recognition competes with hydration in anion-triggered monolayer formation of cyanostar supra-amphiphiles at aqueous interfaces. Chem. Sci. 2022, 13, 4283-4294. DOI

161. Fadler, R. E.; Flood, A. H., Rigidity and Flexibility in Rotaxanes and Their Relatives On being Stubborn and Easy Going, Frontiers in Chemistry, Special Issue on Advances in Mechanically Bonded Molecules. Front. Chem. 2022, 10, #856173 DOI

160. Benasco, A. R.; Tropp, J.; Kaphle, V.; Chen, Y.; Zhao, W.; Eedugurala, N.; Ng, T. N.; Flood, A. H.; Azoulay, J. D. Receptor Induced Doping of Conjugated Polymer Transistors: A Strategy for Selective and Ultrasensitive Phosphate Detection in Complex Aqueous Environments, Adv. Elect. Mat. 2022, 8, #2101353. DOI

154. Zeynaloo, E.; Zahran, E. M.; Fatila, E. M.; Flood, A. H.; Bachas, L. G., Anion-selective electrode based on a CH-hydrogen bonding bis-macrocyclic ionophore with a clamshell architecture, Anal. Chem. 2021, 93, 5412. DOI

152. Fadler, R. E.; Al Ouahabi, A.; Qiao, B.; Carta, V.; König, N. F.; Gao, X.; Zhao, W.; Zhang, Y.; Lutz, J.-F.; Flood, A. H., Chain Entropy Beats Hydrogen Bonds to Unfold and Thread Dialcohol Phosphates inside Cyanostar Macrocycles to form [3]Pseudorotaxanes. J. Org. Chem. 2021, 86. DOI

148. White, N.; Zhao, W.; Flood, A. H., Recognition and Applications of Anion–Anion Dimers based on Anti-Electrostatic Hydrogen Bonds (AEHBs), Chem. Soc. Rev. 2020, 49, 7893-7906. DOI

147. Dhara, A.; Sadhukhan, T.; Sheetz, E. G.; Raghavachari, K.; Flood A. H., Zero-overlap Fluorophores for Fluorescent Studies at Any Concentration, J. Am. Chem. Soc. 2020 142, 12167-12180. DOI

142. Zhao, W.; Tropp, J.; Qiao, B.; Pink, M.; Azoulay, J. D.; Flood, A. H., Tunable Adhesion from Stoichiometry-controlled and Sequence-defined Supramolecular Polymers Emerges Hierarchically from Cyanostar-stabilized Anion-anion Attractions, J. Am. Chem. Soc., 2020. 142, 2579–2591. DOI

137. Zhao, W.; Qiao, B.; Tropp, J.; Pink, M.; Azoulay, J.; Flood, A. H., Linear Supramolecular Polymers Driven by Anion-Anion Dimerization of Difunctional Phosphonate Monomers inside Cyanostar Macrocycles, J. Am. Chem. Soc. 2019, 141, 4980-4989. DOI

131. Qiao, B.; Leverick, G.; Zhao, W.; Flood, A. H.; Johnson, J; Shao-Horn, Y., Supramolecular Regulation of Anions Enhances Conductivity and Transference Number of Lithium in Liquid Electrolytes, J. Am. Chem. Soc. 2018 140, 10932–10936. DOI

129. Sheetz, E. G.; Qiao, B.; Pink, M.; Flood, A. H., Programmed Negative Allostery with Guest-selected Rotamers Control Anion-anion Complexes of Stackable Macrocycles, J. Am. Chem. Soc., 2018, 7773-7777. DOI

128. Benson, C. R.; Maffeo, C.; Fatila, E. M.; Liu, Y.; Sheetz, E. G.; Aksimentiev, A.; Singharoy, A.; Flood, A. H., “Inchworm movement of two rings switching onto a thread by biased Brownian diffusion: a three-body problem” Proc. Natl. Acad. Sci. USA 2018,38, 9391-9396. DOI

126. Fatila, E. M.; Pink, M.; Twum, E. B.; Karty, J. A.; Flood, A. H., Phosphate-phosphate oligomerization drives higher order co-assemblies with stacks of cyanostar macrocycles, Chem. Sci. 2018, 9, accepted Cover Art. DOI

125. Zahran, E. M.; Fatila, E. M.; Chen, C.-H, Flood, A. H.; Bachas, L. G., Cyanostar: C–H Hydrogen Bonding Neutral Carrier Scaffold for Anion-Selective Sensors, Anal. Chem. 2018, 90, 1925-1933. DOI

121. Zhao, W.; Qiao, B.; Chen, C.-H., Flood, A. H., High Fidelity Multi-state Switching with Anion-Anion and Acid-Anion Dimers of Organophosphates in Cyanostar Complexes, Angew. Chem. Int. Ed. 2017, 56, 13083-13087 DOI

119. Fatila, E. M.; Twum, E. B.; Karty, J. A.; Flood, A. H., Ion-pairing and Co-facial Stacking Drive High-fidelity Bisulfate Assembly with Cyanostar Macrocyclic Hosts, Chem. Eur. J. 2017, 23, Early View DOI

117. Qiao, B.; Hirsch, B. E.; Lee, S.; Pink, M.; Chen, C.-H., Laursen, B. W.; Flood, A. H., Ion-Pair Oligomerization of Chromogenic Triangulenium Cations with Cyanostar-modified Anions That Controls Emission in Hierarchical Materials. J. Am. Chem. Soc. 2017, 139, 6226-6233. DOI

116. Dobscha, J. R.; Liu, Y.; Flood, A. H., Shape-persistent Anion Receptors. In Comprehensive Supramolecular Chemistry II; Elsevier, 2016

115. Qiao, B.; Liu, Y.; Lee, S.; Pink, M.; Flood, A. H., High-yield Synthesis and Acid-base Response of Phosphate-templated [3]Rotaxanes, Chem. Commun. 2016, 52, 13675-13678. DOI

114. Benson, C. R.; Fatila, E. M.; Lee, S.; Marzo, M. G.; Pink, M.; Mills, M. B.; Preuss, K. E.; Flood, A. H., Extreme Stabilization and Redox Switching of Organic Anions and Radical Anions by Large-cavity, CH Hydrogen-Bonding Cyanostar Macrocycles, J. Am. Chem. Soc. 2016, 138, 15057-15065. DOI (See highlight in Cutting Edge Chemistry from the ACS)

113. Fatila, E. M.;Twum, E. B.; Sengupta, A.; Pink, M.; Karty, J. A.; Raghavachari, K.; Flood, A. H., Anions Stabilize Each Other inside Macrocyclic Hosts, Angew. Chem. Int. Ed. 2016, 55, 14057-14062. DOI (See highlghts in C&EN, Quartz, Spectroscopy Now, NSF, and IU Press Release, as well as in the popular press).

112. Qiao, B.; Anderson, J. R.; Pink, P.; Flood, A. H., Size-matched Recognition of Large Anions by Cyanostar Macrocycles is Saved when Solvent-bias is Avoided, Chem. Comm. 2016, 52, accepted. DOI

111. Liu, Y.; Singharoy, A.; Mayne, C. G.; Sengupta, A.; Raghavachari, K.; Shulten, K.; Flood, A. H., Flexibility Coexists with Shape-Persistence in Cyanostar Macrocycles, J. Am. Chem. Soc. 2016, 138, 4843–4851 DOI

106. Singharoy, A.; Venkatakrishnan, B.; Liu, Y.; Mayne, C. G.; Lee, S.; Chen, C-H.; Zlotnick, A.; Shulten, K.; Flood, A. H., Macromolecular Crystallography for Synthetic Abiological Molecules: Combining xMDFF and PHENIX for Structure Determination of Cyanostar Macrocycles, J. Am. Chem. Soc. 2015, 137, 8810-8818. DOI

100. Hirsch, B. E. Lee, S.; Qiao, B.; Chen, C.-H.; McDonald, K. P.; Tait, S. L.; Flood, A. H., Anion-induced dimerization of 5-fold symmetric cyanostars in 3D crystalline solids and 2D self-assembled crystals, Chem. Commun. 2014, 69, 9827–9830. DOI (From themed collection Scanning Probe Studies of Molecular Systems) Cover Art

99. Chen, T.-H.; Lee, S.; Flood, A. H.; Miljanic, O. S., How to print a crystal structure model in 3D, CrystEngComm 2014, 16, 5488–5493. OPEN ACCESS–DOI Cover Art

91. Lee, S.; Chen, C.-H.; Flood, A. H., A pentagonal cyanostar macrocycle with cyanostilbene CH donors binds anions and forms dialkylphosphate [3]rotaxanes, Nature Chem. 2013, 5, 704-710. DOI

See also the news coverage by: Chem. & Eng. News, • NSF • Analytical Scientist