31.6 Intramolecular Olefin Metathesis

Intramolecular Olefin Metathesis

Olefin metathesis rearranges carbon-carbon double bonds by breaking and reforming them with the help of a transition metal catalyst. In its intramolecular form, this reaction is one of the most reliable ways to build rings, especially medium and large ones that are notoriously hard to close by other methods. Understanding how the catalyst works and when to choose intramolecular vs. intermolecular metathesis is central to modern synthetic strategy and polymer design.

Ring-Closing Metathesis in Organic Synthesis

Ring-closing metathesis (RCM) converts an acyclic diene into a cyclic alkene by forming a new C=C bond within the same molecule. It's particularly valuable for building 5- to 7-membered rings (cyclopentenes, cyclohexenes, cycloheptenes), and it really shines for medium and large rings (8–20+ atoms) that are otherwise very difficult to access.

The thermodynamic driving force comes from two sources:

• Loss of a small volatile olefin (usually ethylene) as a byproduct. Because ethylene escapes the reaction mixture as a gas, the equilibrium shifts toward the cyclic product.
• Relief of conformational strain in the starting material, which can provide additional energy payoff when the ring size is favorable.

Mechanism of RCM (step-by-step):

1. The metal-alkylidene catalyst (e.g., Grubbs or Hoveyda-Grubbs) undergoes a [2+2] cycloaddition with one of the two olefins in the substrate, forming a four-membered metallacyclobutane intermediate.
2. The metallacyclobutane breaks apart via retro-[2+2] cycloaddition, releasing ethylene and generating a new metal-alkylidene that is now tethered to the substrate.
3. This tethered metal-alkylidene reacts intramolecularly with the second olefin through another [2+2] cycloaddition, forming a second metallacyclobutane.
4. A final retro-[2+2] cycloaddition releases the cyclic product and regenerates the original metal-alkylidene catalyst, completing the catalytic cycle.

RCM applications span a wide range of synthetic targets:

• Macrocycles: musks, pheromones, and complex natural products like epothilones and ansa-bridged peptides
• Unsaturated heterocycles: dihydrofurans, dihydropyrroles, and dihydrothiophenes, as well as fused ring systems like decalins and indanes
• Cyclic peptides and peptidomimetics with improved metabolic stability and bioavailability compared to their linear counterparts

Ru(II) Complexes as Metathesis Catalysts

Ruthenium(II) complexes are the most widely used catalysts for olefin metathesis because they combine high activity with exceptional functional group tolerance. Unlike earlier molybdenum- and tungsten-based catalysts, Ru(II) complexes tolerate alcohols, amides, esters, and even protic solvents like methanol and water.

The most common families are the Grubbs catalysts (1st, 2nd, and 3rd generation) and the Hoveyda-Grubbs catalysts. Second-generation variants incorporate an N-heterocyclic carbene (NHC) ligand, which donates more electron density to the metal center and dramatically improves both activity and stability.

Structural features:

• A central Ru(II) atom is coordinated to neutral donor ligands (phosphines or NHCs) and anionic ligands (typically chlorides).
• The Ru=CHR (alkylidene) moiety is the active site where metathesis begins.
• Tuning the steric bulk and electron-donating ability of the ligands lets chemists optimize catalyst performance for specific substrates.

How the catalyst enters the cycle:

1. A neutral ligand (usually a phosphine) dissociates from the Ru center, generating a reactive 14-electron species.
2. This active species coordinates to the substrate olefin and proceeds through the [2+2] / retro-[2+2] sequence described above.
3. After product release, the 14-electron species is regenerated and re-enters the cycle.

Advantages of Ru(II) over Mo/W catalysts:

• Much higher functional group tolerance
• Compatible with protic solvents and aqueous conditions
• Reactions often run at or near room temperature with low catalyst loadings (1–5 mol%)
• Far less sensitive to air and moisture, making handling and storage straightforward

Intramolecular vs. Intermolecular Olefin Metathesis

The distinction between these two modes matters most when you think about what product you're building: a ring within one molecule, or a new bond between separate molecules.

Intramolecular metathesis forms cyclic structures from a single substrate molecule.

• RCM is the classic example, producing cycloalkenes and heterocycles from acyclic dienes.
• In polymer chemistry, intramolecular metathesis can introduce cyclic units into an existing linear polymer chain, modifying properties like glass transition temperature ($T_g$) and crystallinity.

Intermolecular metathesis forms new C=C bonds between different molecules and is the basis for two major polymerization methods:

• Acyclic diene metathesis (ADMET) polymerization is a step-growth process that converts $\alpha,\omega$-dienes into unsaturated polymers. ADMET produces polymers with relatively narrow molecular weight distributions ($M_w/M_n < 2$) and controllable molecular weights in the range of $10^3$ to $10^5$ g/mol. Functional groups like esters, ethers, and amides can be built directly into the polymer backbone.
• Ring-opening metathesis polymerization (ROMP) is a chain-growth process that opens strained cyclic olefins (norbornene, cyclopentene, cyclooctene) to produce high-molecular-weight polymers. The ring strain stored in the monomer provides the thermodynamic driving force. ROMP achieves very low polydispersities ($M_w/M_n < 1.1$) and gives access to linear, branched, or cross-linked architectures. Substituted cyclic monomers allow the synthesis of functional polymers such as polyelectrolytes and biomaterials.

Transition Metal Catalysis in Olefin Metathesis

All olefin metathesis reactions depend on a transition metal catalyst to facilitate the breaking and reforming of C=C bonds. The catalyst works by forming a metal-carbene (alkylidene) complex, which is the active species that enters the [2+2] / retro-[2+2] catalytic cycle.

The identity of the metal and its surrounding ligands determines three critical properties:

• Reactivity: how quickly the catalyst turns over and whether it can engage sterically hindered substrates
• Selectivity: whether the catalyst favors ring-closing over oligomerization, or E vs. Z alkene geometry in the product
• Functional group tolerance: which polar or protic groups can be present without poisoning the catalyst

Ruthenium dominates modern practice for the reasons discussed above, but molybdenum-based catalysts (e.g., Schrock catalysts) remain important when very high activity or Z-selectivity is needed, despite their greater sensitivity to air and moisture.