Mechanistic Study and Ligand Optimization of the Copper(I)-Catalyzed Azide-Alkyne Cycloaddition (CuAAC) Reaction
| dc.contributor.advisor | Cai, Chengzhi | |
| dc.contributor.committeeMember | Daugulis, Olafs | |
| dc.contributor.committeeMember | Thummel, Randolph P. | |
| dc.contributor.committeeMember | Lubchenko, Vassiliy | |
| dc.contributor.committeeMember | Wang, Yuhong | |
| dc.creator | Chen, Haoqing 1989- | |
| dc.creator.orcid | 0000-0002-4290-6092 | |
| dc.date.accessioned | 2019-09-18T19:51:08Z | |
| dc.date.available | 2019-09-18T19:51:08Z | |
| dc.date.created | December 2016 | |
| dc.date.issued | 2016-12 | |
| dc.date.submitted | December 2016 | |
| dc.date.updated | 2019-09-18T19:51:08Z | |
| dc.description.abstract | The copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction is a prime example of “click reaction” that has been widely applied in diverse fields. The mechanism of this reaction has been proposed involving di-copper complexes as the kinetically favored active species, which are difficult to detect due to the multiple fast equilibria between the copper complexes and the instability of copper(I) to disproportionation and aggregation. We first investigated the intermediates in CuAAC reaction with the widely used tris(triazolylmethyl)amine ligand. Using electrospray ionization mass spectrometry (ESI-MS), we detected unprecedented tri-copper(I) acetylide and triazolide intermediates. By linking an alkyne with the ligand, we enriched the di- and tri-copper(I) acetylides in aqueous solutions, and quantitatively analyzed the reactivity under stoichiometric and catalytic conditions. The di-copper(I) reaction mechanism was energetically preferred under stoichiometric conditions, while the tri-copper(I) intermediates are more stable and the reaction can go through both pathways under catalytic conditions. We obtained the single crystal X-ray diffraction structure of the tri-copper(I) acetylide intermediate bearing one tris(triazolylmethyl)amine ligand, which displayed high catalytic activity in CuAAC reaction. Based on the ESI-MS results and the crystal structure, we proposed the tri-copper(I) CuAAC reaction mechanism. Under stoichiometric condition, the tri-copper(I) acetylide directly coordinates with azide and generates an azide-acetylide adduct to form the triazole ring. Under catalytic condition, the reaction could involve an internal copper(I) dissociation from the acetylide to reduce the steric hindrance. The activation energy of the proposed di-copper(I) pathway was calculated 2 kcal/mol lower than the tri-copper(I) pathway. To study the ligand effect on the oxidative side reaction of CuAAC that caused significant damage to biomolecules, we synthesized a series of tripodal amine ligands bearing triazole or phenyl substitution groups, which can coordinate to copper(I) with five- or six-membered chelating arm length. The best copper(I) ligand in CuAAC reaction were screened. In addition, we designed a platform for high throughput screening of copper(I) catalyst exhibiting high CuAAC activity and high stability. The lead catalyst first generating the product upon addition of a low concentration of azide to the library can be identified by ESI-MS. The feasibility of this approach was studied using the tris(triazolylmethyl)amine ligand. | |
| dc.description.department | Chemistry, Department of | |
| dc.format.digitalOrigin | born digital | |
| dc.format.mimetype | application/pdf | |
| dc.identifier.uri | https://hdl.handle.net/10657/4864 | |
| dc.language.iso | eng | |
| dc.rights | The author of this work is the copyright owner. UH Libraries and the Texas Digital Library have their permission to store and provide access to this work. Further transmission, reproduction, or presentation of this work is prohibited except with permission of the author(s). | |
| dc.subject | Click Chemistry | |
| dc.subject | CuAAC Reaction | |
| dc.subject | Intermediate | |
| dc.subject | Mechanism | |
| dc.subject | Ligands | |
| dc.title | Mechanistic Study and Ligand Optimization of the Copper(I)-Catalyzed Azide-Alkyne Cycloaddition (CuAAC) Reaction | |
| dc.type.dcmi | Text | |
| dc.type.genre | Thesis | |
| thesis.degree.college | College of Natural Sciences and Mathematics | |
| thesis.degree.department | Chemistry, Department of | |
| thesis.degree.discipline | Chemistry | |
| thesis.degree.grantor | University of Houston | |
| thesis.degree.level | Doctoral | |
| thesis.degree.name | Doctor of Philosophy |