Inorganic — C–H functionalization
C–H activation via concerted metalation-deprotonation (CMD)
How the C–H activation via concerted metalation-deprotonation (CMD) 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: Pd(OAc)₂ (or PdCl₂ + carboxylate), arene, carboxylate/carbonate base. Conditions: DMA or toluene, 100–140 °C; PivOH additive. Bonds formed: Ar–Pd; O–H (AcOH); bonds broken: Ar–H. Stereochemistry: Site selectivity set by acidity of C–H and directing groups. Rate and selectivity: C–H cleavage is often rate-determining (KIE kH/kD ≈ 2–5).
At a glance
Step 1: Pd(II) acetate meets the arene
A Pd(II) center coordinates an arene; a carboxylate ligand already bound to palladium (often acetate) positions itself near a specific C–H bond on the ring.
Step 2: Concerted metalation–deprotonation
In a single concerted step, the carboxylate's oxygen removes the aromatic proton while the metal simultaneously forms a new bond to that same carbon — acid and base chemistry and bond formation happening together, not sequentially.
Step 3: Aryl–Pd formed from a C–H bond
The result is a new aryl-palladium bond formed directly from a C–H bond, with no need to pre-install a halide or boronic acid — CMD is the key step that makes modern C–H functionalization chemistry possible, bypassing the oxidative-addition-first strategy used throughout classic cross-coupling.
Abbreviations and terms
- Ar
- Aryl group. Any aromatic ring substituent such as phenyl.
- OAc
- Acetoxy. –OC(=O)CH₃, an acetate group.
- DMA
- N,N-Dimethylacetamide. High-boiling polar aprotic solvent.
- AcOH
- Acetic acid. Weak acid and polar protic solvent.
- Pd(OAc)2
- Palladium(II) acetate. Pd(II) pre-catalyst, reduced in situ to Pd(0).
- CMD
- Concerted metalation–deprotonation. C–H activation where a carboxylate shuttles the proton as the C–M bond forms.
- Wheland
- Wheland intermediate (arenium ion). The cyclohexadienyl cation formed when an electrophile adds to a benzene ring.
How it compares with related reactions
| C–H activation via concerted metalation-deprotonation (CMD) | Directed C–H activation via cyclometalation | Iridium-catalyzed C–H borylation | |
|---|---|---|---|
| Reagents | Pd(OAc)₂ (or PdCl₂ + carboxylate), arene, carboxylate/carbonate base | Pd(OAc)₂ (5–10 mol%), directing-group substrate, coupling partner (Ar–I), oxidant/base | [Ir(cod)OMe]₂, dtbpy, B₂pin₂ (or HBpin) |
| Conditions | DMA or toluene, 100–140 °C; PivOH additive | AcOH or toluene, 80–120 °C | THF or hexane, 25–80 °C |
| Stereochemistry | Site selectivity set by acidity of C–H and directing groups | Site-selective ortho functionalisation | Sterically controlled regioselectivity (meta to substituents) |
| Rate / selectivity | C–H cleavage is often rate-determining (KIE kH/kD ≈ 2–5) | C–H cleavage (CMD) is usually rate-limiting | C–H oxidative addition is turnover-limiting |
Test yourself
Try to answer each question before opening it.
Which reagents and conditions are typical for the C–H activation via concerted metalation-deprotonation (CMD)?
Pd(OAc)₂ (or PdCl₂ + carboxylate), arene, carboxylate/carbonate base. Conditions: DMA or toluene, 100–140 °C; PivOH additive.
Which bonds are formed and which are broken?
Formed: Ar–Pd; O–H (AcOH). Broken: Ar–H.
What is the stereochemical outcome?
Site selectivity set by acidity of C–H and directing groups
What controls the rate or the selectivity?
C–H cleavage is often rate-determining (KIE kH/kD ≈ 2–5)
Study guides that help with this reaction
- How to learn reaction mechanisms (without memorising everything)
- How to answer mechanism questions in an exam