Development of Copper(II)-Mediated Azide-Alkyne Cycloaddition Reactions Using Chelating Azides
Brotherton, Wendy S. (author)
Zhu, Lei (professor directing dissertation)
Chase, P. Bryant (university representative)
Dudley, Gregory B. (committee member)
Alabugin, Igor V. (committee member)
Roper, Michael G. (committee member)
Department of Chemistry and Biochemistry (degree granting department)
Florida State University (degree granting institution)
This dissertation describes the development of copper(II)-mediated azide-alkyne cycloaddition reactions using chelating azides. The first chapter provides an introduction to the copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) through describing the history of the CuAAC reaction, its current mechanistic understanding, and selected applications of this widely used reaction. Within the second chapter, the development of copper(II)-accelerated azide-alkyne cycloaddition (AAC) is presented. Therein, 1,4-disubstituted-1,2,3-triazoles were synthesized via the azide-alkyne cycloaddition in good to excellent yields using copper(II) salts in alcoholic solvents. The developed procedures avoided the need for an added reducing agent. Two pathways could be operational to generate copper(I) under these conditions: oxidation of alcoholic solvent or oxidative homocoupling of the alkyne. 2-Picolylazide behaved as a superior substrate under these conditions due to its chelating ability to copper that facilitates the cycloaddition. Preliminary spectroscopic results (EPR, UV-Vis spectroscopy) provided evidence that copper(I) was generated after an induction period. Within the third chapter, the reactivity of other chelating azides and their products as assisting ligands regarding the Cu(OAc)2-accelerated AAC reaction are briefly discussed. This data, combined with the results from the initial study, allowed us to study the mechanism. Results pertaining to solvent screening and alkyne screening are discussed in detail. In regards to solvent, the reaction can proceed in aprotic organic solvents but required longer reaction times than reactions in protic solvents. The Cu(OAc)2-accelerated AAC reactions were also observed to proceed fairly rapidly in aqueous solvents. The alkyne screening results under preparative, heterogeneous conditions show no clear trend between the structure of the alkyne and efficiency of the reaction. However, under homogeneous conditions used for the kinetics studies, a clear trend was observed where electron-withdrawing substituents on the para-position of phenylacetylene show shorter induction periods and react very rapidly. During the solvent and alkyne screening, a discontinuous reaction profile was observed suggesting the structure evolution of the catalyst, therefore lowering the catalytic activity. Application of the developed Cu(OAc)2-accelerated AAC reaction for the facile and rapid synthesis of tridentate 2,6-bis(1,2,3-triazol-1-ylmethyl)pyridine ligands is described in Chapter 4. Upon coordination with transition metal ions, the pyridyl nitrogen as well as the less Lewis basic N2 nitrogen of the 1,2,3-triazole ring were found to participate in binding. The ligands created in this study complement other well-studied tridentate ligands such as the triazolyl-based terpy motif and the 2,6-bis(pyrazol-1-ylmethyl)pyridine systems. Additionally, a ligand was designed to include two bidentate binding sites at both the N3 and N2 positions forming a five- and six-membered chelation ring, respectively. Its coordination was studied and showed that metals prefer the 5-membered planar chelation pocket over the puckered 6-membered pocket that contains the N2 nitrogen of the 1,2,3-triazole. Stable copper(II)/organic azide complexes from chelating azides were also observed and their features described. All copper(II)/azide complexes exhibit the alkylated nitrogen atom (Nα) of the azido group coordinating to the copper(II) ion. Analysis of the bond lengths show that copper(II) coordination at Nα enhances the electrophilicity of the terminal Nγ, accelerating the CuAAC reaction. The information gained from this study enhances our knowledge and understanding of the coordination chemistry of 1,4-substituted-1,2,3-triazole molecules, particularly in regards to the N2 atom of the 1,2,3-triazole. Chapter five describes the synthesis of 5-iodo-1,2,3-triazoles. These compounds were synthesized with the intention of functionalizing the 5-position with an electron donating group to enhance the electron density at the N2 position and enhance binding affinity. Unlike previous reports, 5-iodo-1,4-disubstituted-1,2,3-triazoles were generated from 2-picolylazide and iodoalkynes without the need of an assisting ligand. Moderate to good yields of the 5-iodotriazole products were obtained from a small set of iodoalkynes screened. Wanting to circumvent the synthesis of iodoalkynes, a one-pot method was created where copper(II) salts are reduced by NaI. This in situ method generates the necessary copper(I) catalyst as well as the iodinating source. The reaction requires an equivalent of base and was able to proceed in a variety of solvents. The reaction performed well with a variety of alkynes and azides, however, the reaction is sensitive to excess base and those with tertiary amines exhibited lower yields due to the formation of protonated triazole. The in situ generating conditions are more reactive than that of the direct addition of CuI and I2. Use of another electrophile, allyl iodide, under these conditions gave the 5-allyl-1,4-disubstituted-1,2,3-triazole in a multicomponent, one-pot reaction. 1,4,5-trisubstituted-1,2,3-triazoles were obtained through palladium cross-coupling reactions, such as the Sonogashira or the Suzuki reactions. However, minor amounts of the dehalogenated triazole by-product complicates purification of these compounds. Further study of 1,4,5-trisubstituted-1,2,3-triazoles is underway in our laboratory.
1, 2, 3-triazoles, 5-iodo-1, 2, 3-triazoles, Azide-alkyne cycloaddition, Chelating azides, Copper(II)-mediated, CuAAC
December 8, 2011.
A Dissertation submitted to the Department of Chemistry and Biochemistry in partial fulfillment of the requirements for the degree of Doctor of Philosophy.
Includes bibliographical references.
Lei Zhu, Professor Directing Dissertation; P. Bryant Chase, University Representative; Gregory B. Dudley, Committee Member; Igor V. Alabugin, Committee Member; Michael G. Roper, Committee Member.
Florida State University
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