8.9 Addition of Carbenes to Alkenes: Cyclopropane Synthesis

Carbene Addition to Alkenes

Carbene reactions with alkenes

Carbenes are highly reactive, neutral species containing a divalent carbon with two nonbonding electrons. That divalent carbon has only six electrons in its valence shell, which is why carbenes are so electron-deficient and reactive.

These nonbonding electrons can be either paired or unpaired, giving rise to two distinct electronic states:

• Singlet carbenes have both nonbonding electrons paired in one orbital, with an empty $p$ orbital remaining. This is the form most relevant to stereospecific additions.
• Triplet carbenes have two unpaired electrons in separate orbitals. They behave more like diradicals and do not add in a concerted fashion.

The key reaction here is the concerted, single-step addition of a singlet carbene to an alkene, forming two new $\sigma$ bonds simultaneously with no intermediates. The product is a cyclopropane ring, a strained three-membered ring of carbon atoms.

Because the addition is concerted, the stereochemistry of the alkene is fully retained in the product:

• A cis alkene gives a cis-substituted cyclopropane
• A trans alkene gives a trans-substituted cyclopropane

This stereospecificity is one of the most testable points in this topic. If you see a question asking you to predict the stereochemistry of a cyclopropane product, look at the geometry of the starting alkene.

Methods of carbene generation

There are several ways to generate carbenes in the lab. Each method produces a slightly different carbene, so pay attention to which one gives you $\ce{:CH2}$ versus $\ce{:CCl2}$.

1. Decomposition of diazo compounds

Diazo compounds contain an $\ce{R-C=N=N+}$ group. When heated or exposed to UV light (photolysis), they lose $\ce{N2}$ gas, leaving behind a carbene. The most common example:

• Diazomethane $(\ce{CH2N2})$ decomposes to give methylene $(\ce{:CH2})$ plus $\ce{N2}$

The driving force is the formation of the very stable $\ce{N2}$ molecule. Note that diazomethane is toxic and explosive, which limits its practical use.

2. $\alpha$-Elimination of haloforms

Haloforms are trihalomethanes like $\ce{CHCl3}$ or $\ce{CHBr3}$. Treatment with a strong base ($\ce{NaOH}$, $\ce{KOtBu}$, or sodium methoxide) removes the acidic proton in an $\alpha$-elimination, generating a dihalocarbene:

• $\ce{CHCl3}$ + strong base → $\ce{:CCl2}$ (dichlorocarbene)

This is a two-step process: the base first deprotonates to form a trihalomethyl carbanion, which then loses a halide ion to give the carbene.

3. Thermal decomposition of sodium trichloroacetate

Heating $\ce{NaO2CCCl3}$ causes loss of $\ce{NaCl}$ and $\ce{CO2}$, yielding $\ce{:CCl2}$. This is a milder way to generate dichlorocarbene without needing a strong base.

Simmons-Smith reaction

The Simmons-Smith reaction is the most practical method for cyclopropane synthesis in complex molecules. Instead of generating a free carbene, it uses a carbenoid, a species that reacts like a carbene but is never actually a free divalent carbon.

Reagents: Diiodomethane $(\ce{CH2I2})$ reacts with a zinc-copper couple $(\ce{Zn(Cu)})$ to form the organozinc carbenoid $\ce{ICH2ZnI}$. This carbenoid then delivers a $\ce{CH2}$ unit to the alkene in a concerted, stereospecific addition.

The stereochemistry rules are the same as for free carbene additions: cis alkenes give cis cyclopropanes, and trans alkenes give trans cyclopropanes.

Why use Simmons-Smith over free carbenes?

1. Safer. No explosive diazo compounds or highly reactive free carbenes are involved.
2. More selective. The organozinc carbenoid is less reactive than a free carbene, so it preferentially reacts with alkenes and tolerates other functional groups (esters, alcohols, ethers) in the molecule.
3. Milder conditions. The reaction runs under relatively gentle conditions, making it compatible with complex substrates.

If a nearby hydroxyl group is present, the zinc can coordinate to the oxygen, directing the cyclopropanation to occur on the same face as the $\ce{OH}$. This is a useful stereochemical handle in synthesis.

Carbene Addition Mechanism and Properties

Carbene addition to an alkene is classified as a $[1+2]$ cycloaddition. The carbene contributes one carbon, and the alkene contributes two, forming the three-membered ring.

For a singlet carbene, the mechanism is a single concerted step: both new $\ce{C-C}$ bonds form at the same time, on the same face of the alkene. This is why stereochemistry is preserved.

Triplet carbenes, by contrast, add in a stepwise (non-concerted) fashion through a diradical intermediate. Because bond rotation can occur at the intermediate stage, triplet carbene additions are not stereospecific. For most problems in this course, you'll be dealing with singlet carbenes or the Simmons-Smith carbenoid, both of which are stereospecific.

The chemoselective nature of carbenoid reagents (especially Simmons-Smith) makes cyclopropanation a powerful tool in synthesis. You can target an alkene for ring formation even when other reactive groups are present in the molecule.