Inorganic — click chemistry
CuAAC: copper-catalyzed azide-alkyne cycloaddition
How the CuAAC works, in 3 steps. Each step shows the structures and the curved arrows that move the electrons.
In short. A 3-step mechanism. Typical reagents: Terminal alkyne, organic azide, Cu(I) (CuSO₄ + sodium ascorbate, or CuI), base/ligand (TBTA). Conditions: tBuOH/H₂O or DMSO, 25 °C. Bonds formed: C–N; N–N (triazole ring); C–H (C5); bonds broken: alkyne C–H; azide N=N. Stereochemistry: 1,4-regioisomer only (thermal gives 1,4 + 1,5 mixture). Rate and selectivity: 10⁷–10⁸ × faster than uncatalysed Huisgen cycloaddition.
At a glance
Step 1: Copper acetylide forms
Cu(I) coordinates a terminal alkyne and, with the help of a base, forms a copper acetylide — the same first step as the Cu half of Sonogashira coupling.
Step 2: Azide joins at copper: six-membered cuprate ring
The organic azide coordinates to the same copper center, positioning its terminal nitrogen close to the copper-bound alkyne carbon; a stepwise cyclization forms a copper-bound metallacycle rather than a single-step cycloaddition, which is why this reaction is so much faster and more selective than the uncatalyzed thermal Huisgen cycloaddition.
Step 3: Protonation gives the 1,4-triazole
Protonation releases copper and gives a 1,4-disubstituted triazole with complete regioselectivity — this reliability under mild, aqueous, biocompatible conditions is exactly why CuAAC became the prototypical 'click' reaction.
Abbreviations and terms
- R
- R group. Any carbon substituent (alkyl, aryl…) whose identity does not matter for the mechanism.
- L
- Ligand. A Lewis-base group (often a phosphine) bound to a metal centre.
- DMSO
- Dimethyl sulfoxide. Polar aprotic solvent; also the oxidant in Swern/Kornblum-type reactions.
- Et3N
- Triethylamine. Common tertiary-amine base that scavenges HCl.
- H2
- Hydrogen gas. Reductant for catalytic hydrogenation.
- CuI
- Copper(I) iodide. Co-catalyst for Sonogashira, Ullmann and click chemistry.
- CuAAC
- Copper-catalysed azide–alkyne cycloaddition. The copper-catalysed “click” reaction giving 1,4-triazoles.
- pKa
- Acid-dissociation constant (–log). Lower pKa = stronger acid; used to judge which proton a base removes.
How it compares with related reactions
| CuAAC | Associative ligand substitution at a square-planar Pt(II) complex | Dissociative ligand substitution at an octahedral complex | |
|---|---|---|---|
| Reagents | Terminal alkyne, organic azide, Cu(I) (CuSO₄ + sodium ascorbate, or CuI), base/ligand (TBTA) | K₂[PtCl₄] + NH₃ (aq) | [Co(NH₃)₅Cl]²⁺ + H₂O (entering ligand Y) |
| Conditions | tBuOH/H₂O or DMSO, 25 °C | H₂O, 25 °C | Aqueous solution, 25 °C |
| Stereochemistry | 1,4-regioisomer only (thermal gives 1,4 + 1,5 mixture) | Trigonal-bipyramidal intermediate; retention of geometry | Often retention (square-pyramidal intermediate) |
| Rate / selectivity | 10⁷–10⁸ × faster than uncatalysed Huisgen cycloaddition | Rate = k₁[Pt] + k₂[Pt][NH₃] (associative; entering-ligand dependent) | Rate = k[complex]; independent of [Y] (D / Id) |
Test yourself
Try to answer each question before opening it.
Which reagents and conditions are typical for the CuAAC?
Terminal alkyne, organic azide, Cu(I) (CuSO₄ + sodium ascorbate, or CuI), base/ligand (TBTA). Conditions: tBuOH/H₂O or DMSO, 25 °C.
Which bonds are formed and which are broken?
Formed: C–N; N–N (triazole ring); C–H (C5). Broken: alkyne C–H; azide N=N.
What is the stereochemical outcome?
1,4-regioisomer only (thermal gives 1,4 + 1,5 mixture)
What controls the rate or the selectivity?
10⁷–10⁸ × faster than uncatalysed Huisgen cycloaddition
Study guides that help with this reaction
- How to learn reaction mechanisms (without memorising everything)
- How to answer mechanism questions in an exam