Ring-Closing Metathesis (RCM)

What ring-closing metathesis does

Take an open-chain molecule that has a carbon-carbon double bond at each of its two ends — a diene. Hand it a metathesis catalyst and it swaps partners with itself: the catalyst scrambles the two terminal alkenes, ties the ends together into a ring, and kicks out the leftover carbons as a molecule of ethylene. One floppy chain becomes one clean ring plus a puff of gas.

Metathesis literally means "change places." In alkene metathesis the metal chops both double bonds in half and re-sews the halves in a new combination. When the two alkenes belong to the same molecule, the only way to re-sew them productively is to fold the chain and form a ring — hence ring-closing metathesis. The competing intermolecular version links different molecules and is called cross metathesis; the polymer version that opens strained rings is ROMP.

   CH₂=CH–(chain)–CH=CH₂    ──[Ru]=CHPh──→    (ring, new C=C)   +   CH₂=CH₂↑
      α,ω-diene                                cycloalkene          ethylene

The magic is in what survives. Because the good catalysts are mild, the same flask can carry esters, amides, free alcohols, ketones, even a free carboxylic acid — RCM ignores them and closes the ring anyway. That tolerance is what turned a laboratory curiosity from the 1960s into a reaction now run on thousands of kilograms of drug substance.

The mechanism: Chauvin's metallacyclobutane dance

Yves Chauvin proposed the accepted mechanism in 1971. The key player is a metal carbene (alkylidene), a metal center double-bonded to a carbon: M=CHR. The cycle is a repeating pair of moves — a [2+2] cycloaddition to make a four-membered metallacyclobutane, then a retro-[2+2] that cracks it open the other way.

1. Initiation. The precatalyst (e.g. a Grubbs Ru=CHPh benzylidene) loses a ligand — for second-generation Grubbs, a phosphine dissociates to open a coordination site — giving the active 14-electron carbene.
2. [2+2] cycloaddition. One terminal alkene of the diene coordinates to the metal, then its π bond and the M=C π bond add across each other. The two double bonds become two single bonds arranged in a square: a metallacyclobutane. No free carbocation, no ionic intermediate — the electrons flow in a concerted four-center array.
3. Retro-[2+2] (productive cleavage). The metallacyclobutane breaks apart along the other diagonal. This releases the first product alkene (initially styrene from the benzylidene) and installs a new metal alkylidene — now the metal carries the substrate's own chain end, M=CH–(chain).
4. Intramolecular closure. The metal, now tethered to the substrate, reaches to the second alkene on the same molecule. A second [2+2] folds the chain into a bicyclic metallacyclobutane that spans the forming ring.
5. Retro-[2+2] releases the ring. Cleaving this metallacyclobutane snaps out the cyclic alkene product and regenerates a methylidene, M=CH₂, on the metal.
6. Turnover. The M=CH₂ methylidene reacts with the next substrate's terminal =CH₂, and the two methylene units leave together as ethylene, CH₂=CH₂. The metal is back as a substrate alkylidene, ready for another ring. Each metal atom turns over hundreds to hundreds of thousands of times.

Every C=C in the product traces back to a metallacyclobutane cleaved the "wrong" way relative to how it formed — that diagonal switch is the whole trick. Because the steps are reversible [2+2]/retro-[2+2] equilibria, nothing is thermodynamically downhill on its own; the reaction is pulled to the ring only because ethylene keeps leaving.

   [Ru]=CHR  +  CH₂=CH–R'                 [Ru]──CHR
                             ──[2+2]──→     |     |      ──retro-[2+2]──→   [Ru]=CH–R'  +  CH₂=CHR
                                           CH₂───CHR'
                                       (metallacyclobutane)

Catalyst, conditions, and real specifics

Two families of catalyst dominate, and the choice between them is essentially a trade of reactivity against ruggedness.

• Grubbs 1st generation — RuCl₂(=CHPh)(PCy₃)₂. A ruthenium benzylidene with two tricyclohexylphosphine ligands. Bench-stable, closes most terminal-alkene dienes into common rings. Moderate activity.
• Grubbs 2nd generation — swaps one phosphine for a strongly σ-donating N-heterocyclic carbene (NHC, an H₂IMes ligand). Much more active; closes hindered and trisubstituted alkenes. Still air-tolerant enough to weigh in air.
• Hoveyda-Grubbs 2nd generation — replaces the phosphine with a chelating ortho-isopropoxy benzylidene. Slower to initiate but exceptionally robust and recyclable; the go-to for demanding substrates and industrial use.
• Schrock catalysts — Mo(=CHCMe₂Ph)(=N-Ar)(OR)₂ molybdenum alkylidenes. The most active, capable of electron-poor and very hindered alkenes, but pyrophoric-adjacent: air-, moisture-, and functional-group-sensitive, glovebox required.

Typical conditions: 1–10 mol% catalyst, dichloromethane, toluene, or increasingly a greener solvent, 25–45 °C (reflux for sluggish cases), 1–24 h, under inert atmosphere. Concentration is the critical dial — 0.001–0.05 M for medium and large rings so intramolecular closure beats intermolecular oligomerization; a slow syringe-pump addition of the diene keeps the instantaneous concentration low. Sparging the headspace or applying gentle vacuum sweeps ethylene out and drives the equilibrium. Residual ruthenium is scavenged after the reaction (e.g. with tris(hydroxymethyl)phosphine, silica-supported thiols, or activated charcoal) — critical for pharmaceutical specs at the low-ppm level.

Scope, ring size, and stereochemistry

Ring size is the single biggest predictor of success:

• 5-, 6-, 7-membered rings: form fast and cleanly, often at ordinary (0.1 M) concentrations. This is the sweet spot — dihydrofurans, cyclopentenes, tetrahydropyridines, and dihydropyrans are made routinely.
• 8- to 11-membered (medium) rings: the hard zone. Transannular strain and poor probability of the ends meeting productively make these low-yielding; conformational locks (gem-dimethyl Thorpe-Ingold groups, cis-amide or rigid aryl spacers) are used to bias the chain closed.
• 12-membered and larger macrocycles: close well again under high dilution because the long chain is flexible; RCM is now the premier macrocyclization method.

Geometry: in small rings the double bond is forced cis (Z) because trans would be too strained to exist. In macrocycles standard Grubbs catalysts historically gave E/Z mixtures or a thermodynamic E bias — a real weakness when a natural product needed the Z isomer. That gap was closed by Z-selective catalysts: Grubbs' cyclometalated ruthenium (2011) and the Hoveyda-Schrock stereogenic-at-metal Mo/W complexes, which deliver the cis macrocyclic alkene with high selectivity. Electron-rich, unhindered terminal alkenes react fastest; 1,1-disubstituted and electron-poor alkenes are harder and may need Grubbs 2nd-gen or Schrock catalysts.

RCM vs other ring-forming reactions

	Ring-closing metathesis	Classical macrolactonization	Intramolecular aldol / Dieckmann
Bond formed	C=C (alkene)	C–O ester	C–C to a carbonyl
Catalyst / reagent	Ru or Mo carbene (1–10 mol%)	Activator (Yamaguchi, Mitsunobu, etc.)	Base (alkoxide, LDA)
Byproduct	Ethylene gas (drives equilibrium)	Stoichiometric activator waste	Alcohol / water
Functional-group tolerance	High (Ru): esters, amides, OH, acids survive	Moderate	Low — base-sensitive groups fail
Best ring sizes	5–7 and 12+ (medium rings hard)	Macrolactones, high dilution	5–6 mostly
Stereochemistry of new bond	Ring-size dictated; Z-selective catalysts exist	Sets the tether, not a C=C	New stereocenters, often controllable
Reversible?	Yes — equilibrium pulled by ethylene loss	Effectively irreversible once formed	Aldol reversible; Dieckmann pulled by workup
Signature use	Macrocyclic drug cores, cycloalkenes	Macrolide antibiotics	Cyclopentanones, cyclohexenones

Worked example: closing a five-membered ring, then a drug macrocycle

Textbook case — diethyl diallylmalonate → a cyclopentene. The classic RCM demonstration takes diethyl diallylmalonate (a diene with two allyl arms on a malonate carbon) and closes it to diethyl cyclopent-3-ene-1,1-dicarboxylate.

    (CH₂=CH–CH₂)₂C(CO₂Et)₂
        │  5 mol% Grubbs II, CH₂Cl₂, 40 °C, 1 h
        ▼
    cyclopentene ring with the C(CO₂Et)₂ quaternary center   +   CH₂=CH₂↑

    Yield: typically 90–99%.  The gem-diester is a Thorpe-Ingold group —
    it compresses the C–C–C angle and pre-organizes the two allyl arms
    to meet, which is why this ring closes so readily.

Industrial case — a hepatitis-C macrocycle. The HCV protease inhibitor grazoprevir has an 18-membered macrocyclic ring, and its close cousin simeprevir a 14-membered one; both rings are closed by RCM at manufacturing scale. (Paritaprevir, another macrocyclic HCV protease inhibitor, also has its ring closed by RCM on scale — the reaction runs across this whole drug class.) The metathesis route couples a diene precursor and closes it with a Hoveyda-Grubbs-type ruthenium catalyst under high dilution. These are among the largest metathesis reactions ever operated — carried out on multi-kilogram to multi-tonne scale, with catalyst loadings driven below 0.1 mol% and ruthenium scavenged to single-digit ppm to meet drug-substance purity. The success of these routes is the clearest proof that RCM scaled from flask to factory.

Limitations and side reactions

• Oligomerization / ADMET. If the concentration is too high, the catalyst links dienes together intermolecularly (acyclic diene metathesis, ADMET) into oligomers and polymers instead of rings. Dilution and slow addition are the fix.
• Medium-ring failure. 8–11-membered rings are genuinely hard (see above); no catalyst fully rescues an intrinsically strained target without a conformational bias.
• Alkene isomerization. Ruthenium hydride species formed by catalyst decomposition can walk a double bond along the chain before it closes, giving the wrong ring size or a positional isomer. Additives such as 1,4-benzoquinone or acetic acid suppress the hydride pathway.
• Catalyst-poisoning groups. Basic amines, phosphines, thiols, and nitriles coordinate ruthenium and can shut it down. Amines are often protected (as amides or carbamates) or the substrate is used as an ammonium salt.
• Terminal-alkene requirement bias. RCM works best from terminal (=CH₂) alkenes because they liberate ethylene; internal alkenes give heavier, less volatile byproducts that don't leave as cleanly and can re-enter the equilibrium.
• Residual metal. Ruthenium contamination is colored and toxic at spec levels — pharma routes need dedicated scavenging and analytical control.

Who discovered it, and when

Olefin metathesis was first seen — without anyone understanding it — in the industrial 1950s–60s, when petroleum chemists at DuPont, Standard Oil, and Phillips noticed propylene disproportionating over metal catalysts. The name "olefin metathesis" was coined by Calderon at Goodyear in 1967.

Yves Chauvin (Institut Français du Pétrole) supplied the correct mechanism in 1971, proposing the metal-carbene / metallacyclobutane cycle that everyone doubted at first and everyone now teaches. Turning that insight into a practical reaction required well-defined single-metal catalysts. Richard Schrock (MIT) built the first well-defined, highly active metathesis catalysts — molybdenum and tungsten alkylidenes — through the 1980s and early 1990s. Robert Grubbs (Caltech) developed the ruthenium benzylidene catalysts (Grubbs I in 1995, Grubbs II with the NHC ligand around 1999) whose tolerance of air, water, and functional groups made metathesis usable by any synthetic chemist. Chauvin, Grubbs, and Schrock shared the 2005 Nobel Prize in Chemistry "for the development of the metathesis method in organic synthesis." RCM is the intramolecular application that most changed how chemists build rings.

Industrial and green-chemistry notes

• Atom economy. RCM is close to ideal on paper: the only stoichiometric byproduct is ethylene, and the catalyst is used at low loading. This makes it attractive for green process chemistry versus reagent-heavy alternatives.
• Pharma scale. Beyond the HCV macrocycles, metathesis appears in routes to macrocyclic peptidomimetics and stapled peptides, where two alkene-bearing side chains are joined by RCM to lock a helix.
• Materials via ROMP. The ring-opening sibling (ROMP) of strained cyclic alkenes such as norbornene and dicyclopentadiene makes polynorbornene rubbers and tough polyDCPD thermosets (reaction-injection-molded body panels and pipe) — a multi-hundred-thousand-tonne industry built on the same carbene chemistry.
• Renewables. Cross- and ring-closing metathesis of plant-oil-derived unsaturated esters (e.g. from seed oils) produces specialty diacids, olefins, and fragrance intermediates such as the musk civetone family from long-chain diene precursors.