Copper-catalyzed azide-alkyne cycloadditions (CuAAC) produce 1,4-disubstituted 1,2,3-triazoles, molecules that have many applications in pharmaceuticals. Click reactions are atom-efficient and produce 1,4-disubstituted triazoles selectively with high yields at room temperature. Byproducts are rarely observed, and the product is easily separated by washing, eliminating the need for purification measures such as column chromatography. We tested various copper complexes for ease of use as homogeneous catalysts at various conditions. The 1,4-disubstituted triazole products were obtained in moderate to excellent yields. The progress of reaction was determined using TLC and IR spectroscopy, and products were characterized by GC-MS and NMR spectroscopy. We found that there is little that changes the outcome of the reaction upon variations in solvent and temperature conditions. However, preliminary results show that the anion of the copper salt used in preparing the copper complexes affects the kinetics of the triazole formation. A significant finding was that copper(II)-catalyzed reactions appear to form product even in the absence of a reducing agent.
more »
« less
New 1,2,3-Triazoles from (R)-Carvone: Synthesis, DFT Mechanistic Study and In Vitro Cytotoxic Evaluation
Aseries of novel 1,4-disubstituted 1,2,3-triazoles were synthesized from an (R)-carvone terminal alkyne derivative via a Cu (I)-catalyzed azide–alkyne cycloaddition reaction using CuSO4,5H2O as the copper (II) source and sodium ascorbate as a reducing agent which reduces Cu (II) into Cu (I). All the newly synthesized 1,2,3-triazoles 9a–h were fully identified on the basis of their HRMS and NMR spectral data and then evaluated for their cell growth inhibition potential by MTS assay against HT-1080 fibrosarcoma, A-549 lung carcinoma, and two breast adenocarcinoma (MCF-7 and MDA-MB-231) cell lines. Compound 9d showed notable cytotoxic effects against the HT-1080 and MCF-7 cells with IC50 values of 25.77 and 27.89 µM, respectively, while compound 9c displayed significant activity against MCF-7 cells with an IC50 value of 25.03 µM. Density functional calculations at the B3LYP/6-31G* level of theory were used to confirm the high reactivity of the terminal alkyne as a dipolarophile. Quantum calculations were also used to investigate the mechanism of both the uncatalyzed and copper (I)-catalyzed azide–alkyne cycloaddition reaction (CuAAC). The catalyzed reaction gives complete regioselectivity via a stepwise mechanism streamlining experimental observations. The calculated free-energy barriers 4.33 kcal/mol and 29.35 kcal/mol for the 1,4- and 1,5-regioisomers, respectively, explain the marked regioselectivity of the CuAAC reaction.
more »
« less
- NSF-PAR ID:
- 10356529
- Date Published:
- Journal Name:
- Molecules
- Volume:
- 27
- Issue:
- 3
- ISSN:
- 1420-3049
- Page Range / eLocation ID:
- 769
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
-
more » « less
Abstract In an alcoholic solvent under the catalysis of Cu(OAc)2⋅H2O, organic azide and terminal alkyne could oxidatively couple to afford 5‐alkynyl‐1,2,3‐triazole (alkynyltriazole) at room temperature under an atmosphere of O2in a few hours. The involvement of 1,5‐diazabicyclo[4.3.0]non‐5‐ene (DBN) is essential, without which the redox neutral coupling instead proceeds to produce 5‐H‐1,2,3‐triazole (protiotriazole) as the major product. Therefore, DBN switches the redox neutral coupling between terminal alkyne and organic azide, the copper‐catalyzed “click” reaction to afford protiotriazole, to an oxidation reaction that results in alkynyltriazole. The organic base DBN is effective in accelerating the copper(II)‐catalyzed oxidation of terminal alkyne or copper(I) acetylide, which is intercepted by an organic azide to produce alkynyltriazole. The proposed mechanistic model suggests that the selectivity between alkynyl‐ and protiotriazole, and other acetylide or triazolide oxidation products is determined by the competition between copper(I)‐catalyzed redox neutral cycloaddition and copper(II)/O2‐mediated acetylide oxidation after the formation of copper(I) acetylide.
-
Since the inception of carbon fiber-reinforced polymers (CFRPs) they have steadily gained in popularity due to their light weight, high tensile strength and modulus, and environmental toughness. However, curing of CFRPs of the thermosetting type generally must be performed within an autoclave, whose fixed, physical dimensions effectively limit the maximum size of the part. Alternative curing chemistries may potentially eliminate the requirement for an autoclave, which would allow creation of much larger panels. This project seeks to develop a thermoset composite matrix that is radiation-curable using the Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) click reaction. Previously, Storey et al.(1,2) reported that the azide-modified epoxy resin, di(3-azido-2-hydroxypropyl) ether of bisphenol-A (DAHP-BPA), could be cured by reaction with polyfunctional alkyne crosslinkers under mild conditions using Cu(I) catalysis. In the absence of reducing agents, Cu(II) compounds are catalytically inactive; however, upon exposure to ultraviolet light, they are reduced to Cu(I), which then catalyzes the reaction, allowing it to progress to a high degree of cure at room temperature. Herein, we report the kinetics of photo-induced CuAAC polymerization of the DAHP-BPA and several polyfunctional propargyl amine based crosslinkers, monitored by real-time FTIR as well as mechanical properties of fully cured materials. Polymerizations were studied as a function of Cu(II) compound type, Cu(II) concentration, UV light (365 nm) intensity, and duration of irradiation.more » « less
-
more » « less
ABSTRACT 1H NMR and SEC analyses are used to investigate the overall efficiency of Copper Catalyzed Azide Alkyne Cycloaddition (CuAAC) “click” coupling reactions between alkyne‐ and azide‐terminated polymers using polystyrene as a model. Quantitative convolution modeling of the entire molecular weight distribution is applied to characterize the outcomes of the functional polymer synthesis reactions (i.e., by atom transfer radical polymerization), as well as the CuAAC coupling reaction. Incomplete functionality of the azide‐terminated polystyrene (∼92%) proves to be the largest factor compromising the efficacy of the CuAAC coupling reaction and is attributed primarily to the loss of terminal bromide functionality during its synthesis. The efficiency of the SN2 reaction converting bromide to azide was found to be about 99%. After taking into account the influence of non‐functional polymer, we find that, under the reaction conditions used, the efficiency of the CuAAC coupling reaction determined from both techniques is about 94%. These inefficiencies compromise the fidelity and potential utility of CuAAC coupling reactions for the synthesis of hierarchically structured polymers. While CuAAC efficiency is expected to depend on the specific reaction conditions used, the framework described for determining reaction efficiency does provide a means for ultimately optimizing the reaction conditions for CuAAC coupling reactions. © 2017 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem.
2018 ,56 , 75–84 -
null (Ed.)As potential high surface area for selective capture in diagnostic or filtration devices, biotin-cellulose nanofiber membranes were fabricated to demonstrate the potential for specific and bio-orthogonal attachment of biomolecules onto nanofiber surfaces. Cellulose acetate was electrospun and substituted with alkyne groups in either a one- or two-step process. The alkyne reaction, confirmed by FTIR and Raman spectroscopy, was dependent on solvent ratio, time, and temperature. The two-step process maximized alkyne substitution in 10/90 volume per volume ratio (v/v) water to isopropanol at 50 °C after 6 h compared to the one-step process in 80/20 (v/v) at 50 °C after 48 h. Azide-biotin conjugate “clicked” with the alkyne-cellulose via copper-catalyzed alkyne-azide cycloaddition (CuAAC). The biotin-cellulose membranes, characterized by FTIR, SEM, Energy Dispersive X-ray spectroscopy (EDX), and XPS, were used in proof-of-concept assays (HABA (4′-hydroxyazobenzene-2-carboxylic acid) colorimetric assay and fluorescently tagged streptavidin assay) where streptavidin selectively bound to the pendant biotin. The click reaction was specific to alkyne-azide coupling and dependent on pH, ratio of ascorbic acid to copper sulfate, and time. Copper (II) reduction to copper (I) was successful without ascorbic acid, increasing the viability of the click conjugation with biomolecules. The surface-available biotin was dependent on storage medium and time: Decreasing with immersion in water and increasing with storage in air.more » « less
- Free Publicly Accessible Full Text
-
Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.3390/molecules27030769
