IP Library › Granted Patent US 12,692,272
Granted Patent B2
US 12,692,272 · App. 18/104,469 · Granted Jul 28, 2026

Scalable anion capture macrocycles

Inventors: Amar Hugh Flood (Bloomington, IN); James Robert Dobscha (Bloomington, IN)
Assignee: INDIANA UNIVERSITY RESEARCH AND TECHNOLOGY CORPORATION
C07D487/22C02F1/683C02F2101/12
View Patent ↗
Loading inventors, assignments & file history…
Monitor This Case
Get email alerts when status or documents change.
Order Certified Copies
Most orders are placed with the USPTO same day — all within 24 business hours.
Order via The Patent Place →
Pre-filled with this patent's details
Quick Facts
Patent No.
US 12,692,272
App. No.
18/104,469
Filed
Feb 1, 2023
Granted
Jul 28, 2026
Kind
B2
Art Unit
1779
USPC
210/749
Abstract

The present disclosure concerns scalable single-pot synthesis, anion binding features, liquid-liquid extraction of salts of the triazolophane macrocycle of Formula (I): wherein the substituents R are independently selected from the group consisting of a linear and branched alkyl, a linear and branched alkyl substituted with an ionizable functional group such as an amine or carboxylic acid, a linear and branched alkoxy (R=—OR), an alkyl comprising —O(CH 2 CH 2 O) n CH 3 , where n is 1-20, an amide —CO—NR 1 R 2 , where R 1 is any alkyl, organic substituent, R 2 is any alkyl, organic substituent, wherein R 1 and R 2 may be identical or different, —OCO—R, wherein R is any alkyl, organic substituent, an aromatic ring and their substituted analogues, any length and sequence of natural and unnatural amino acids that make up a peptide chain, and —C≡C—R where R is any alkyl, organic substituent.

Claims (32)

1 . A triazolophane macrocycle of Formula (I) comprising:

wherein the substituents R are independently selected from the group consisting of a linear and branched alkyl, a linear and branched alkyl substituted with an ionizable functional group such as an amine or carboxylic acid, a linear and branched alkoxy —OR 3 , where R 3 is any alkyl, an alkyl comprising —O(CH 2 CH 2 O) n CH 3 , where n is 1-20, an amide —CO—NR 1 R 2 , where R 1 is any alkyl, R 2 is any alkyl, wherein R 1 and R 2 may be identical or different, —OCO—R 4 , wherein R 4 is any alkyl, an aromatic ring or their substituted analogues, any length and sequence of natural and unnatural amino acids that make up a peptide chain, and —C≡C—R 5 where R 5 is any alkyl.

2 . The triazolophane macrocycle of Formula (I) according to claim 1 , wherein the substituents R are identical.

3 . The triazolophane macrocycle of Formula (I) according to claim 1 , wherein the triazolophane macrocycle of Formula (I) consists of Formula (IA):

4 . A method of synthesizing a triazolophane macrocycle of Formula (I) according to claim 1 , the method comprising:

converting

in a single-pot synthesis according to Scheme (I):

5 . The method of synthesizing the triazolophane macrocycle of Formula (I) according to claim 4 , wherein the substituents R are identical.

6 . The method of synthesizing the triazolophane macrocycle of Formula (I) according to claim 4 , wherein the triazolophane macrocycle of Formula (I) consists of Formula (IA):

wherein the method comprises converting

in a single-pot synthesis according to Scheme (IA):

7 . A method of increasing the yield and scale of the single-pot synthesis of triazolophane macrocycle of Formula (I) according to claim 1 , the method comprising reacting

in the presence of a halide salt as a template according to Scheme (X):

8 . The method of increasing the yield and scale of the single-pot synthesis of the triazolophane macrocycle of Formula (I) according to claim 7 , wherein the substituents R are identical.

9 . The method of increasing the yield and scale of the single-pot synthesis of the triazolophane macrocycle of Formula (I) according to claim 7 , the method comprising reacting

in the presence of the halide salt as a template according to Scheme (Y):

10 . The method of claim 7 , wherein the halide salt comprises an anion selected from the group consisting of chloride, fluoride and iodide.

11 . The method of claim 7 , wherein the halide salt is a chloride salt.

12 . The method of claim 11 , wherein the chloride salt is tetrabutylammonium chloride.

13 . A complex comprising:

(a) an anion; and

(b) a triazolophane macrocycle of Formula (I) according to claim 1 .

14 . The complex according to claim 13 , wherein the triazolophane macrocycle of Formula (I) has identical substituents R.

15 . The complex according to claim 13 , wherein the triazolophane macrocycle of Formula (I) consists of Formula (IA):

16 . The complex of claim 13 , wherein the anion is selected from the group consisting of chloride, fluoride, iodide, bromide, hydroxide, sulfide, hydrogen sulfide, cyanide, azide, organosulfides, alkoxides, bifluoride, borohydride, tetrafluoroborate, hydride, bisulfide, selenide, hydrogen selenide, superoxide, peroxide, and hypochlorite.

17 . The complex of claim 13 , wherein a ratio of the complex comprising the triazolophane macrocycle of Formula (I):anion is selected from the group consisting of 1:1 (macrocycle:anion), 2:1 (macrocycle:anion), and 3:2 (macrocycle:anion).

18 . A method of removing an anion from a solution containing the anion, wherein the method comprises:

(a) contacting the solution with a triazolophane macrocycle of Formula (I) according to claim 1 ;

(b) forming a complex, said complex comprising the anion and the triazolophane macrocycle of Formula (I); and

(c) removing the complex from the solution.

19 . The method of removing an anion from a solution containing the anion according to claim 18 , wherein the triazolophane macrocycle of Formula (I) has identical substituents R.

20 . The method of removing an anion from a solution containing the anion according to claim 18 , wherein the triazolophane macrocycle of Formula (I) consists of Formula (IA):

Assignments (2)
CONFIRMATORY LICENSE Recorded Aug 1, 2023
From: INDIANA UNIVERSITY
To: UNITED STATES DEPARTMENT OF ENERGY
Reel/Frame 064451/0680 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 2, 2023
From: FLOOD, AMAR HUGH; DOBSCHA, JAMES ROBERT
To: INDIANA UNIVERSITY RESEARCH AND TECHNOLOGY CORPORATION
Reel/Frame 062568/0481 →
Continuity (2)
Provisional Application 63090826 · Oct 13, 2020
Related Publication 20240262839A1 · Aug 8, 2024
References Cited (68)
US 9701621B2 · Flood et al. · 2017 [cited by applicant]
US 10077233B2 · Flood et al. · 2018 [cited by applicant]
US 10202395B2 · Flood et al. · 2019 [cited by applicant]
US 11939336B2 · Flood · 2024 [cited by examiner]
“Gauthier-Jaques et al.”, “Synergy of Macrocycles and Macromolecular Topologies: An Efficient [34] Triazolophane-Based Synthesis of Cage-Shaped Polymers”, ACS Macro Lett., 9, pp. 700-705, 2020. (Year: 2020). [cited by examiner]
Li et al., “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., 130, 12111-121… [cited by examiner]
Stephenson, A.; Argent, S. P.; Riis-Johannessen, T.; Tidmarsh, I. S.; Ward, M. D., Structures and Dynamic Behavior of Large Polyhedral Coordination Cages: An Unusual Cage-to-Cage Interconversion. J. Am. Chem. Soc. 2011,… [cited by applicant]
Thompson, M. C.; Busch, D. H., Reactions of Coordinated Ligands. IX. Utilization of the Template Hypothesis to Synthesize Macrocyclic Ligands in Situ. J. Am. Chem. Soc. 1964, 86, 3651-3656. [cited by applicant]
Vander Griend, D. A.; Bediako, D. K.; DeVries, M. J.; DeJong, N. A.; Heeringa, L. P., Detailed Spectroscopic, Thermodynamic, and Kinetic Characterization of Nickel(II) Complexes with 2,2′-Bipyridine and 1,10-Phenanthrol… [cited by applicant]
Wagner, P.; Rominger, F.; Mastalerz, M., Switching the Statistical C3/C1 Ratio in the Threefold Aromatic Substitution of Tribenzotriquinacenes towards the C3 Isomer. Angew. Chem. Int. Ed. 2018, 57, 11321-11324. [cited by applicant]
Wang, Q.; Zhong, Y.; Miller, D. P.; Lu, X.; Tang, Q.; Lu, Z.-L.; Zurek, E.; Liu, R.; Gong, B., Self-Assembly and Molecular Recognition in Water: Tubular Stacking and Guest-Templated Discrete Assembly of Water-Soluble, S… [cited by applicant]
Yin, J.; Hu, Y.; Zhang, D.; Li, X.; Jin, W., Synthesis and characterization of symmetrical sulfur-fused polycyclic aromatic hydrocarbons with controlled shapes. Tetrahedron 2017, 73, 5794-5799. [cited by applicant]
Zhang, C.; Yu, C.; Long, H.; Denman, R. J.; Jin, Y.; Zhang, W., Synthesis of Phenylene Vinylene Macrocycles through Acyclic Diene Metathesis Macrocyclization and Their Aggregation Behavior. Chem. Eur. J. 2015, 21, 16935… [cited by applicant]
Zhang, J.; Pesak, D. J.; Ludwick, J. L.; Moore, J. S., Geometrically-Controlled and Site-Specifically-Functionalized Phenylacetylene Macrocycles. J. Am. Chem. Soc. 1994, 116, 4227-4239. [cited by applicant]
Zhang, W.; Moore, J. S., Shape-Persistent Macrocycles: Structures and Synthetic Approaches from Arylene and Ethynylene Building Blocks. Angew. Chem. Int. Ed. 2006, 45, 4416-4439. [cited by applicant]
Zhao, D.; Moore, J. S., Shape-persistent arylene ethynylene macrocycles: syntheses and supramolecular chemistry. Chem. Commun. 2003, 807-818. [cited by applicant]
Zhou, X.-P.; Liu, J.; Zhan, S.-Z.; Yang, J.-R.; Li, D.; Ng, K.-M.; Sun, R. W.-Y.; Che, C.-M., A High-Symmetry Coordination Cage from 38- or 62-Component Self-Assembly. J. Am. Chem. Soc. 2012, 134, 8042-8045. [cited by applicant]
Duan Qunpeng et al., “Two new triazolophanes: synthesis, structures, self-assembling and anion complexation properties”, Tetrahedron Letters, Elsevier, Amsterdam, NL, vol. 56, No. 26, Jun. 24, 2015, pp. 4002-4006. [cited by applicant]
European Patent Office, International Search Report and Written Opinion for corrsponding International Application No. PCT/US2021/054689, mailed Apr. 21, 2022. [cited by applicant]
Argent, S.P.; Jackson, F. C.; Chan, H. M.; Meyrick, S.; Taylor, C. G. P.; Ronson, T. K.; Rourke, J. P.; Ward, M. D., A family of diastereomeric dodecanuclear coordination cages based on inversion of chirality of individ… [cited by applicant]
Balakrishnan, K.; Datar, A.; Zhang, W.; Yang, X.; Naddo, T.; Huang, J.; Zuo, J.; Yen, M.; Moore, J. S.; Zang, L., Nanofibril Self-Assembly of an Arylene Ethynylene Macrocycle. J. Am. Chem. Soc. 2006, 128, 6576-6577. [cited by applicant]
Brooks, S. J.; García-Garrido, S. E.; Light, M. E.; Cole, P. A.; Gale, P. A., Conformational Control of Selectivity and Stability in Hybrid Amide/Urea Macrocycles. Chem. Eur. J. 2007, 13, 3320-3329. [cited by applicant]
Busch, D. H., First considerations: Principles, classification, and history of templates. Top. Curr. Chem. 2005, 249, 1-65. [cited by applicant]
Busch, D. H., The significance of complexes of macrocyclic ligands and their synthesis by ligand reactions. Record Chem. Progr. 1964, 25, 107-26. [cited by applicant]
Chang, K.-J.; Moon, D.; Lah, M. S.; Jeong, K.-S., Indole-Based Macrocycles as a Class of Receptors for Anions. Angew. Chem. Int. Ed. 2005, 44, 7926-7929. [cited by applicant]
Chen, L.; Chen, Q.; Wu, M.; Jiang, F.; Hong, M., Controllable Coordination-Driven Self-Assembly: From Discrete Metallocages to Infinite Cage-Based Frameworks. Acc. Chem. Res. 2015, 48, 201-210. [cited by applicant]
Choi, K.; Hamilton, A. D., A Dual Channel Fluorescence Chemosensor for Anions Involving Intermolecular Excited State Proton Transfer. Angew. Chem. Int. Ed. 2001, 40, 3912-3915. [cited by applicant]
Choi, K.; Hamilton, A. D., Rigid Macrocyclic Triamides as Anion Receptors: Anion-Dependent Binding Stoichiometries and 1H Chemical Shift Changes. J. Am. Chem. Soc. 2003, 125, 10241-10249. [cited by applicant]
Choi, K.; Hamilton, A. D., Selective Anion Binding by a Macrocycle with Convergent Hydrogen Bonding Functionality. J. Am. Chem. Soc. 2001, 123, 2456-2457. [cited by applicant]
Dalvie, D. K.; Kalgutkar, A. S.; Khojasteh-Bakht, S. C.; Obach, R. S.; O'Donnell, J. P., Biotransformation Reactions of Five-Membered Aromatic Heterocyclic Rings. Chem. Res. Toxicol. 2002, 15, 269-299. [cited by applicant]
Dobscha, J. R.; Castillo, H. D.; Li, Y.; Fadler, R. E.; Taylor, R. D.; Brown, A. A.; Trainor, C. Q.; Tait, S. L.; Flood, A. H., Sequence-Defined Macrocycles for Understanding and Controlling the Build-up of Hierarchical… [cited by applicant]
Du, Z.; Ren, C.; Ye, R.; Shen, J.; Maurizot, V.; Lu, Y.; Wang, J.; Zeng, H., BOPmediated one-pot synthesis of C5-symmetric macrocyclic pyridone pentamers. Chem. Commun. 2011, 47, 12488-12490. [cited by applicant]
Eller, L. R.; Stpień, M.; Fowler, C. J.; Lee, J. T.; Sessler, J. L.; Moyer, B. A., Octamethyl-octaundecylcyclo[8 pyrrole: A Promising Sulfate Anion Extractant. J. Am. Chem. Soc. 2007, 129, 11020-11021. [cited by applicant]
Feng, W.; Yamato, K.; Yang, L.; Ferguson, J. S.; Zhong, L.; Zou, S.; Yuan, L.; Zeng, X. C.; Gong, B., Efficient Kinetic Macrocyclization. J. Am. Chem. Soc. 2009, 131, 2629-2637. [cited by applicant]
Finke, A. D.; Gross, D. E.; Han, A.; Moore, J. S., Engineering Solid-State Morphologies in Carbazole-Ethynylene Macrocycles. J. Am. Chem. Soc. 2011, 133, 14063-14070. [cited by applicant]
Fu, H.; Chang, H.; Shen, J.; Yu, L.; Qin, B.; Zhang, K.; Zeng, H., An unusual macrocyclization reagent for highly selective one-pot synthesis of strained macrocyclic aromatic hexamers. Chem. Commun. 2014, 50, 3582-3584. [cited by applicant]
Gallant, A. J.; Hui, J. K. H.; Zahariev, F. E.; Wang, Y. A.; MacLachlan, M. J., Synthesis, Structure, and Computational Studies of Soluble Conjugated Multidentate Macrocycles. J. Org. Chem. 2005, 70, 7936-7946. [cited by applicant]
Gauthier-Jaques, M.; Theato, P., Synergy of Macrocycles and Macromolecular Topologies: An Efficient [34] Triazolophane-Based Synthesis of Cage-Shaped Polymers. ACS Macro Lett. 2020, 9, 700-705. [cited by applicant]
Gong, B., Hollow Crescents, Helices, and Macrocycles from Enforced Folding and Folding-Assisted Macrocyclization. Acc. Chem. Res. 2008, 41, 1376-1386. [cited by applicant]
Guieu, S.; Crane, A. K.; MacLachlan, M. J., Campestarenes: novel shape-persistent Schiff base macrocycles with 5-fold symmetry. Chem. Commun. 2011, 47, 1169-1171. [cited by applicant]
Haketa, Y.; Maeda, H., From Helix to Macrocycle: Anion-Driven Conformation Control of π-Conjugated Acyclic Oligopyrroles. Chem. Eur. J. 2011, 17, 1485-1492. [cited by applicant]
Jin, Y.; Zhang, A.; Huang, Y.; Zhang, W., Shape-persistent arylenevinylene macrocycles (AVMs) prepared via acyclic diene metathesis macrocyclization (ADMAC). Chem. Commun. 2010, 46, 8258-8260. [cited by applicant]
Kim, N.-K.; Chang, K.-J.; Moon, D.; Lah, M. S.; Jeong, K.-S., Two distinct anionbinding modes and their relative stabilities. Chem. Commun. 2007, 3401-3403. [cited by applicant]
Krygowski, T. M.; Szatylowicz, H.; Stasyuk, O. A.; Dominikowska, J.; Palusiak, M., Aromaticity from the Viewpoint of Molecular Geometry: Application to Planar Systems. Chem. Rev. 2014, 114, 6383-6422. [cited by applicant]
Lee, S.; Chen, C.-H.; Flood, A. H., A pentagonal cyanostar macrocycle with cyanostilbene CH donors binds anions and forms dialkylphosphate [3]rotaxanes. Nat. Chem. 2013, 5, 704-710. [cited by applicant]
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… [cited by applicant]
Li, Y.; Flood, A. H., Pure C. H Hydrogen Bonding to Chloride lons: A Preorganized and Rigid Macrocyclic Receptor. Angew. Chem. Int. Ed. 2008, 47, 2649-2652. [cited by applicant]
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… [cited by applicant]
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 lodide. J. Am. Chem. Soc.… [cited by applicant]
Liu, Y.; Shen, J.; Sun, C.; Ren, C.; Zeng, H., Intramolecularly Hydrogen-Bonded Aromatic Pentamers as Modularly Tunable Macrocyclic Receptors for Selective Recognition of Metal lons. J. Am. Chem. Soc. 2015, 137, 12055-1… [cited by applicant]
Ma, C.; Lo, A.; Abdolmaleki, A.; MacLachlan, M. J., Synthesis and Metalation of Novel Fluorescent Conjugated Macrocycles. Org. Lett. 2004, 6, 3841-3844. [cited by applicant]
Meisel, J. W.; Hu, C. T.; Hamilton, A. D., Heterofunctionalized Cavitands by Macrocyclization of Sequence-Defined Foldamers. Org. Lett. 2019, 21, 7763-7767. [cited by applicant]
Mingos, D. M. P.; Rohl, A. L., Size and shape characteristics of inorganic molecules and ions and their relevance to molecular packing problems. Dalton Trans. 1991, 3419-3425. [cited by applicant]
Okochi, K. D.; Han, G. S.; Aldridge, I. M.; Liu, Y.; Zhang, W., Covalent Assembly of Heterosequenced Macrocycles and Molecular Cages through Orthogonal Dynamic Covalent Chemistry (ODCC). Org. Lett. 2013, 15, 4296-4299. [cited by applicant]
Okochi, K. D.; Jin, Y.; Zhang, W., Highly efficient one-pot synthesis of hetero-sequenced shape-persistent macrocycles through orthogonal dynamic covalent chemistry (ODCC). Chem. Commun. 2013, 49, 4418-4420. [cited by applicant]
Pruchyathamkorn, J.; Kendrick, W. J.; Frawley, A. T.; Mattioni, A.; Caycedo-Soler, F.; Huelga, S. F.; Plenio, M. B.; Anderson, H. L., A Complex Comprising a Cyanine Dye Rotaxane and a Porphyrin Nanoring as a Model Light… [cited by applicant]
Qiao, B.; Anderson, J. R.; Pink, M.; Flood, A. H., Size-matched recognition of large anions by cyanostar macrocycles is saved when solvent-bias is avoided. Chem. Commun. 2016, 52, 8683-8686. [cited by applicant]
Qin, B.; Jiang, L.; Shen, S.; Sun, C.; Yuan, W.; Li, S. F. Y.; Zeng, H., Folding-Promoted TBACI-Mediated Chemo- and Regioselective Demethylations of Methoxybenzene-Based Macrocyclic Pentamers. Org. Lett. 2011, 13, 6212-… [cited by applicant]
Qin, B.; Shen, S.; Sun, C.; Du, Z.; Zhang, K.; Zeng, H., One-Pot Multimolecular Macrocyclization for the Expedient Synthesis of Macrocyclic Aromatic Pentamers by a Chain Growth Mechanism. Chem. Asian J. 2011, 6, 3298-33… [cited by applicant]
Ren, C.; Shen, J.; Zeng, H., One-Pot Synthesis of Strained Macrocyclic Pyridone Hexamers and Their High Selectivity toward Cu2+ Recognition. Org. Lett. 2015, 17, 5946-5949. [cited by applicant]
Ren, C.; Xu, S.; Xu, J.; Chen, H.; Zeng, H., Planar Macrocyclic Fluoropentamers as Supramolecular Organogelators. Org. Lett. 2011, 13, 3840-3843. [cited by applicant]
Rickhaus, M.; Jirasek, M.; Tejerina, L.; Gotfredsen, H.; Peeks, M. D.; Haver, R.; Jiang, H.-W.; Claridge, T. D. W.; Anderson, H. L., Global aromaticity at the nanoscale. Nat. Chem. 2020, 12, 236-241. [cited by applicant]
Rickhaus, M.; Vargas Jentzsch, A.; Tejerina, L.; Grubner, I.; Jirasek, M.; Claridge, T. D. W.; Anderson, H. L., Single- Acetylene Linked Porphyrin Nanorings. J. Am. Chem. Soc. 2017, 139, 16502-16505. [cited by applicant]
Roobottom, H. K.; Jenkins, H. D. B.; Passmore, J.; Glasser, L., Thermochemical Radii of Complex lons. J. Chem. Educ. 1999, 76, 1570. [cited by applicant]
Sanford, A. R.; Yamato, K.; Yang, X.; Yuan, L.; Han, Y.; Gong, B., Well-defined secondary structures. Euro. J. Biochem. 2004, 271, 1416-1425. [cited by applicant]
Seidel, D.; Lynch, V.; Sessler, J. L., Cyclo[8]pyrrole: A Simple-to-Make Expanded Porphyrin with No. Meso Bridges. Angew. Chem. Int. Ed. 2002, 41, 1422-1425. [cited by applicant]
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, 140, 7773-7777. [cited by applicant]
Shopsowitz, K. E.; Edwards, D.; Gallant, A. J.; MacLachlan, M. J., Highly substituted Schiff base macrocycles via hexasubstituted benzene: a convenient double Duff formylation of catechol derivatives. Tetrahedron 2009, … [cited by applicant]