Copper-catalyzed Azide-alkyne Cycloaddition Click Reaction Research Articles

Molecular Diffusivity of Click Reaction Components: The Diffusion Enhancement Question.

Micrometer-sized objects are widely known to exhibit chemically driven motility in systems away from equilibrium. Experimental observation of reaction-induced motility or enhancement in diffusivity at the much shorter length scale of small molecules is, however, still a matter of debate. Here, we investigate the molecular diffusivity of reactants, catalyst, and product of a model reaction, the copper-catalyzed azide–alkyne cycloaddition click reaction, and develop new NMR diffusion approaches that allow the probing of reaction-induced diffusion enhancement in nanosized molecular systems with higher accuracy than the state of the art. Following two different approaches that enable the accounting of time-dependent concentration changes during NMR experiments, we closely monitored the diffusion coefficient of reaction components during the reaction. The reaction components showed distinct changes in the diffusivity: while the two reactants underwent a time-dependent decrease in their diffusivity, the diffusion coefficient of the product gradually increased and the catalyst showed only slight diffusion enhancement within the range expected for reaction-induced sample heating. The decrease in diffusion coefficient of the alkyne, one of the two reactants of click reaction, was not reproduced during its copper coordination when the second reactant, azide, was absent. Our results do not support the catalysis-induced diffusion enhancement of the components of the click reaction and, instead, point to the role of a relatively large intermediate species within the reaction cycle with diffusivity lower than that of both the reactants and product molecule.

Molecules, the Ultimate Nanomotor: Linking Chemical Reaction Intermediates to their Molecular Diffusivity.

The intellectual community focused on nanomotors has recently become interested in extending these concepts to individual molecules. Here, we study a chemical reaction according to whose mechanism some intermediate species should speed up while others slow down in predictable ways, if the nanomotor hypothesis of boosted diffusion holds. Accordingly, we scrutinize the absolute diffusion coefficient (D) during intermediate steps of the catalytic cycle for the CuAAC reaction (copper-catalyzed azide-alkyne cycloaddition click reaction), using proton pulsed field-gradient nuclear magnetic resonance to discriminate between the diffusion of various reaction intermediates. We observe time-dependent diffusion that is enhanced for some intermediate molecular species and depressed for those whose size increases owing to complex formation. These findings point to the failure of the conventional Stokes-Einstein equation to fully explain diffusivity during chemical reaction. Without attempting a firm explanation, this paper highlights aspects of the physics of chemical reactions that are imperfectly understood and presents systematic data that can be used to assess hypotheses.

Synthesis of the Novel AT1 Receptor Tracer [18F]Fluoropyridine-Candesartan via Click Chemistry.

A novel 7-((4-(3-((2-[18F]fluoropyridin-3-yl)oxy)propyl)-1H-1,2,3-triazol-1-yl)methyl)-1H-benzo[d]imidazole derivative of the angiotensin II type-1 receptor (AT1R) blocker candesartan, [18F]fluoropyridine–candesartan, was synthesized via the copper-catalyzed azide–alkyne cycloaddition click reaction between 2-[18F]fluoro-3-(pent-4-yn-1-yloxy)pyridine ([18F]FPyKYNE) and the tetrazole-protected azido-candesartan derivative, followed by acid deprotection. This three-step, two-pot, and two-step purification synthesis was done within 2 h. The use of tris[(1-hydroxypropyl-1H-1,2,3-triazol-4-yl)methyl]amine (THPTA) as a Cu(I) stabilizing agent increased the overall radiochemical yield by 4-fold (10 ± 2%, n = 13) compared to the reaction without THPTA (2.4 ± 0.2%, n = 3; decay-corrected from 18F produced at the end-of-beam). Complete separation of [18F]FPyKYNE from its nitro precursor and [18F]fluoropyridine–candesartan from the deprotected azido-candesartan allowed for high molar activities (>380 GBq/μmol) of the tracer. The use of 0.1% trifluoroacetic acid in water for reformulation and the addition of sodium ascorbate to the final formulation (1.6 ± 0.2 GBq/mL, n = 3) prevented tracer radiolysis with >97% radiochemical purity for a period of up to 10 h after the end-of-synthesis. A significant reduction in the uptake (86 ± 3%, n = 8) of the tracer was observed ex vivo in rats (at 20 min postinjection) in the AT1R-rich kidney cortex following pretreatment with saturating doses of the AT1R antagonist candesartan or losartan. This specific binding to AT1R was confirmed in vitro in the rat renal cortex (autoradiography) by a reduction of 26 ± 5% (n = 12) with losartan coincubation (10 μM). These favorable binding properties support further studies to assess the potential of [18F]fluoropyridine–candesartan as a tracer for the positron emission tomography imaging of renal AT1R.

Synthesis of regioselective chitosan copolymers with β-cyclodextrin and poly(N-isopropyl acrylamide)

This work aimed to design a synthetic route under mild conditions allowing the main chitosan chain to be grafted with β-cyclodextrin (β-CD) and poly(N-isopropyl acrylamide) (PNIPAm), at C2 and C6 positions, respectively. For this reason, the regioselectivity of proposed reactions is an important factor to be considered. β-CD is an oligosaccharide with a cyclic structure capable of forming inclusion complexes with hydrophobic molecules. Grafting β-CD onto the chitosan backbone by reductive N-alkylation at C2 position was carried out. With this purpose, the previous preparation of β-CD monoaldehyde was required. PNIPAm is a thermosensitive polymer with a transition temperature near 33 °C. To regioselectively anchor poly(N-isopropyl acrylamide) chains onto chitosan at C6 position, it was required to attach at the C6 position of chitosan an alkyl group for the subsequent grafting of PNIPAm-N3 by means of copper-catalyzed azide-alkyne cycloaddition click reaction. To guarantee the regioselectivity of the functionalization of chitosan with a C6 terminal alkyne, its oxyalkylation with glycidyl propargyl ether in a solvent composed of LiOH/KOH/urea was used. The structure of all derivatives was confirmed by FT-IR and 1H-NMR spectroscopy.

Photocatalytic copper-catalyzed azide–alkyne cycloaddition click reaction with Cu(ii) coordination polymer

Cu(ii) coordination polymers as photocatalysts for the copper-catalyzed azide–alkyne cycloaddition click reaction under household light irradiation in air.

Continuous metal scavenging and coupling to one-pot copper-catalyzed azide-alkyne cycloaddition click reaction in flow

Increasing usage of catalytic chemistry calls for efficient removal of metal traces. This paper describes the development and optimization of a scavenger-based extraction in flow to remove metal catalysts. It enables liquid–liquid extraction with slug flow and phase separation with a porous fluoropolymer membrane. The use of this unit for copper scavenging of various copper sources from organic solvent was studied. The effects of scavenger type (EDTA, DTPA, EDDS), concentration and pH were also investigated. Such analysis allowed to achieve extraction performance as high as 99% at pH of the scavenger solution adjusted to 9.4 and molar ratio of scavenger to copper of 10. Process integration is achieved by coupling this unit downstream to a flow reaction using homogeneous metal-based catalysis, i.e. presenting a continuous uninterrupted metal scavenging unit. The copper-catalyzed azide-alkyne cycloaddition click reaction is studied in one-pot eliminating the need to isolate and handle potentially explosive azide. The triazole product is attained in flow with high yield of up to 92% with 30min residence time. The level of purity requirement for pharmaceuticals is met in one stage of extraction.

Resin-Supported Catalysts for CuAAC Click Reactions in Aqueous or Organic Solvents

The copper-catalyzed azide-alkyne cycloaddition click reaction is a valuable process for the synthesis of libraries of drug candidates, derivatized polymers and materials, and a wide variety of other functional molecules. In some circumstances, the removal of the copper catalyst is both necessary and inconvenient. We describe here two immobilized forms of a Cu-binding ligand that has been shown to accelerate triazole formation under many different conditions, using different resin supports that are appropriate for aqueous or organic solvents. Copper leaching from these resins was modest, allowing them to be reused in many reaction/filtration cycles without recharging with metal ion. The utility of this catalyst form was demonstrated in the convenient synthesis of 20 N-acetylgalactosamine derivatives for biological testing.