Carbenes : Cyclopropanation, C-H Insertion, and the Bamford-Stevens Reaction

The general formula for a carbene is R2C, where R can be alkyl or hydrogen, such as with the methylene carbene, although in some cases it can represent other substituents. After learning a bit about the geometry of carbenes and other properties, it’s time to talk about what we can do with them. One of the most important applications of carbenes, which we alluded to in the previous tutorial, is cyclopropane synthesis, or cyclopropanation. Cyclopropane is a three-membered ring which is subject to a lot of ring strain, with the 60 degree bond angles deviating significantly from the 109.5 degree angles that sp3 hybridized carbons prefer.

Given the instability of these compounds, they are difficult to synthesize. But carbenes offer a relatively simple method of doing so, by reacting them with alkenes or cycloalkenes. Take for example the reaction of the methylene carbene with cis-2-butene. The carbene is prepared in situ, in this case from diazomethane just as we have learned, simply in the presence of light, and this will be the slow step of the reaction, since carbenes are highly reactive once formed. The carbene will then insert itself into the pi bond to generate the three-membered ring, and in doing so the stereochemistry of the alkene is retained. We can observe the same reaction with trans-2-butene and see that again the stereochemistry is retained.

We could do the same thing with halogenated carbenes instead of the methylene carbene if it was deemed desirable to have halogen functionality on the product for one reason or another, such as this reaction of cyclohexene with chloroform in the presence of potassium hydroxide. We should note that singlet and triplet carbenes react in different ways. Because singlet carbenes have a lone pair and an empty p orbital, they can act as traditional nucleophiles or electrophiles, though more typically the latter, and cyclopropanation with a singlet carbene is a concerted reaction. But triplet carbenes do not have a lone pair, they are diradicals, meaning they have two unpaired electrons. As such, they participate in stepwise radical additions, in stark contrast with the concerted reactions of singlet carbenes. First, one bond forms between two electrons of opposite spin, but then the other two electrons have the same spin, and therefore cannot pair directly.

The system must wait until one of them flips to the opposite spin, either via radiative emission, also known as phosphorescence, by spin-orbit coupling, or some other process. This is typically rather slow, and only once this has occurred may the second bond form. Because of this, there is also a discrepancy in stereochemistry. Singlet carbenes react in stereospecific fashion, as we just saw with the alkenes. Because the reaction is concerted, the stereochemistry of the alkene will necessarily be conserved. By contrast, triplet carbenes can exhibit some stereoselectivity, but will tend to give mixtures of isomeric products. As we said, in order to form the second bond, one of the electrons must first flip its spin. In the time it takes for this to happen, any carbon-carbon bond in the molecule may have rotated millions of times, thus scrambling any stereochemistry that was inherent in the substrate, resulting in a mixture of cis and trans cyclopropanes. This distinction allows us to determine the identity of a carbene by reaction if its status is unknown. The next major application of carbenes is insertion.

Carbenes have the ability to insert themselves into existing sigma bonds, which are most frequently carbon-hydrogen bonds. This type of chemistry is often employed to promote intramolecular cyclization reactions, such as the following, which produces a five-membered ring. As we can imagine, this involves carbene formation when nitrogen gas evolves, and then the carbene coordinates to this other carbon, while a hydride shifts over to this first carbon as well, giving us our product. Here is another example, involving the following substrate and the butyl lithium tert-butoxide superbase. This reagent is so basic that we can deprotonate at this location to get a carbanion, after which chloride will leave to produce a carbene.

This will perform C-H insertion with one of these methyl groups, producing this three-membered ring. So as we can see, this is an interesting technique with wide application. Now these examples we have mentioned have something in common. They all involve carbenes with no alpha hydrogens, meaning no hydrogens on any carbons next door. Let’s now examine the case where alpha hydrogens are present so that we can discuss another important reaction called the Bamford-Stevens reaction. This is a method of converting ketones into alkenes which utilizes carbene chemistry. Consider the following ketone, which we will treat with N-tosylhydrazine, where as we recall, a hydrazine is a functional group that involves two adjacent nitrogen atoms.

Nitrogen will attack the carbonyl just as an amine would to generate an imine through dehydrative condensation, meaning the carbonyl oxygen is lost as water, except that since this is a hydrazine, we will end up with this N-tosylhydrazone. This N-H bond is now somewhat acidic due to all the potential for resonance if deprotonated, so we can treat with strong base and get the anion. Now elimination can occur, where a lone pair on this nitrogen can generate a pi bond with the other, kicking off the whole tosyl group. At this point things should look quite familiar, and this diazoalkane can evolve nitrogen gas to produce the following carbene. Notice that this does have two alpha hydrogens on the carbon next door, and this is what allows for this species to proceed differently from the examples outlined thus far.

What happens next is technically an insertion into the vicinal C-H bond, which we can just think of as the lone pair on the carbene going to form a carbon-carbon pi bond, while a hydride performs a 1,2-shift to make it to the other carbon. We have thereby produced an alkene, although there is not much stereochemical control, so a mixture of E and Z alkenes can be expected. For this reason, this reaction is useful only in a limited number of cases, but it can be employed with very particular cyclic substrates, such as the following. Here, there are only alpha hydrogens on one side of the carbonyl, and the cyclic nature of the compound produces torsional constraints that require the formation of exclusively Z-alkenes. In such a case, the Bamford-Stevens reaction is synthetically useful. And with that, we’ve learned a few things we can do with carbenes.

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