CuAAC click reaction template

Accepted dinuclear mechanism of the Cu(I)-catalysed azide–alkyne cycloaddition (Fokin): a σ,π-bis(copper) acetylide binds the azide, the first C–N bond closes a six-membered copper metallacycle, ring contraction gives the copper triazolide and protonation releases the 1,4-disubstituted 1,2,3-triazole; key step: protonolysis of the Cu–C bond.

What the template shows

• Copper(I)-catalysed azide–alkyne cycloaddition: a terminal alkyne and an azide give only the 1,4-triazole
• Overall: R¹–C≡CH + R²–N₃ → 1-R²-4-R¹-1,2,3-triazole (cat. CuSO₄ + sodium ascorbate, H₂O/tBuOH, rt)
• Cu(I) ×2 (π-bound Cu not drawn)
• Azide complex
• 6-membered; first C–N bond
• accepted mechanism
• (Worrell, Malik & Fokin)
• Cu(I) speeds the reaction about 10⁷-fold and gives only the 1,4-isomer; the thermal Huisgen reaction needs heat and gives 1,4/1,5 mixtures.
• Rate is second order in Cu; ⁶³Cu-labelling showed that two copper atoms become equivalent in the metallacycle (accepted dinuclear mechanism).
• Only terminal alkynes work (a C–H is needed to form the acetylide); Cu(I) is made in situ from CuSO₄ and sodium ascorbate, in water.
• Ruthenium (Cp*RuCl catalysts, RuAAC) gives the 1,5-triazole instead, and also works with internal alkynes.
• Key step: protonolysis releases the triazole
• The C5–Cu bond electrons take the proton from the ammonium ion (or from the next alkyne); copper leaves as Cu⁺ and re-enters the cycle. C5–H of the product comes from this proton, C4 carries R¹ and N1 carries R².
• Ligands on Cu are not drawn; the formal oxidation state of Cu in the metallacycle (Cu(III) in the DFT model) is debated · every part of this figure is editable

Drawn with 60 atoms, 8 arrows, 99 shapes – every one editable in MolDraw.

Sources

• Smith, March's Advanced Organic Chemistry, 8th ed., Wiley 2020, ch. 15 Textbook
• Clayden, Greeves & Warren, Organic Chemistry, 2nd ed., OUP 2012, ch. 34 Textbook