Versatile Chemistry With Carbenes

When the first isolable carbenes were discovered a quarter-century ago, the reactive chemical species were considered laboratory curiosities. Not anymore, according to carbene specialists at the American Chemical Society national meeting in San Diego last month.

In symposia organized by the Division of Inorganic Chemistry, they described the developing trend to capitalize on the chemistry of persistent carbenes and carbene analogs. No longer are these molecules valued only for catalysis: Chemists are now also using them as reagents to create complex molecules or to incorporate desired properties into functional polymers.

“None of us would have guessed that carbenes would become such powerful tools for chemists,” Guy Bertrand of the University of California, Riverside, and the French National Center for Scientific Research (CNRS) told C&EN. He is credited with creating the first stable carbene.

Persistent carbenes—that is, stable versions that can be bottled and stored on a shelf—are now ubiquitous ligands for transition-metal catalysts and serve as metal-free organocatalysts for a variety of chemical reactions. N-Hetero­cyclic carbenes (NHCs) are the most common type.

“For many years chemists have looked at NHCs and related carbenes as just being good ligands and catalysts,” Bertrand said. “But now we are realizing that we can do much more than that with carbenes.”

Carbenes are unusual molecules because the central carbon atom has two bonds instead of the usual four. The difference is made up by filling one orbital with a lone pair of electrons, but that leaves one orbital empty. This electron deficiency is what gives the carbene carbon atom its spark.

At first, chemists spotted carbenes only as transient intermediates in chemical reactions. They later learned how to use in situ-generated carbenes as reagents in organic synthesis. Despite considerable effort to tame carbenes, chemists conceded by the 1960s that formulating persistent carbenes just wasn’t possible.

But that changed in 1988. That’s when Bertrand, then a CNRS research chemist, reported the first example of an isolable free carbene, in the form of a phosphino­silyl compound, :C[PR₂][Si(CH₃)₃], where R is diisopropylamino. Bertrand’s original carbene had limited applications, he told C&EN, but it heralded the feasibility of persistent carbenes.

The real gem was discovered in 1990, when DuPont research chemist Anthony J. Arduengo III (now at the University of Alabama, Tuscaloosa) found that a cyclic diamine stabilized by bulky adamantyl substituents forms a persistent carbene. This original NHC and derivative versions of it quickly joined cyclopentadiene and tri­phenylphosphine as the ligands of choice for organometallic chemists to stabilize transition-metal catalysts. NHCs were also found to function as metal-free organocatalysts.

Today, carbenes come in many flavors, Bertrand said. These include NHCs with one, two, or three nitrogen atoms in the ring and one or two carbenes per ring, he explained. There are also cyclic carbenes with three- to eight-membered rings and versions with boron, phosphorus, and other heteroatoms in the ring in addition to the core nitrogen and carbon atoms. And they come with a plethora of small and large substituent groups.

Chemists also have made a run on other elements in groups 13 to 16 in the periodic table to make persistent carbene analogs, such as N-heterocyclic phosphinidine and N-heterocyclic silylene. In addition, there are acyclic main-group persistent carbene analogs, such as :GaR and :GeR₂, where R is a bulky aryl substituent. Michael F. Lappert of the University of Sussex, in England, first showed in the 1970s that transient alkyl versions of these acyclic carbene analogs are monomeric in solution but form dimeric olefin analogs as solids.

One of Bertrand’s current interests, which he presented at the ACS meeting, is using cyclic carbenes to stabilize carbene analogs and radicals. He described coordinating a pair of NHCs to a boron atom to make a borylene, :BHR₂, where R is an NHC.

This molecule is the first example of a persistent acyclic boron carbene analog. It’s a neutral molecule that is electronically similar to amines and phosphines, he said. The molecule is unusual, Bertrand pointed out, because boron is in the +1 oxidation state rather than the usual +3, which means it behaves as a Lewis base instead of a Lewis acid. By subsequently oxidizing the borylene, Bertrand’s group created a rare boron radical (Science, DOI: 10.1126/science.1207573).

Bertrand also spoke about work in progress to use carbenes to isolate a persistent nitrene, :NR. Nitrenes are reactive carbene analogs used in chemical reactions and generated in situ from azides and isocyanates. But a stable version has remained elusive, he noted. His dream, Bertrand said, is that borylenes and nitrenes could one day become as chemically useful as NHCs.

Arduengo, Bertrand, and other carbene chemists more recently have been showing that NHCs undergo oxidative addition reactions with small molecules such as H₂, NH₃, CO, P₄, azides, alkenes, and alkynes. These reactions lead to a variety of addition products under mild reaction conditions.

Some of the most versatile of these reactions are taking place in the lab of Christopher W. Bielawski of the University of Texas, Austin. In one set of experiments, Bielawski and graduate student Jonathan P. Moerdyk have shown that diamidocarbenes (DACs), a spin-off of NHCs his group discovered, react with olefins to produce cyclopropanes, with ketones to produce dihydrofurans, and with aldehydes to produce epoxides (Nat. Chem., DOI: 10.1038/nchem.1267). In another set of examples, Bielawski and Moerdyk used DACs in reactions with alkynes, leading to cyclopropene derivatives, and with nitriles, leading to azirine derivatives (J. Am. Chem. Soc., DOI: 10.1021/ja3014105).

These cycloaddition reactions are reversible, Bielawski told C&EN, which indicates DACs may be useful in organic synthesis as protecting groups or in sensing applications. They also could serve as precursors for building complex molecules; for example, hydrolysis of cyclo­propane derivatives leads to ring-opened carboxylic acids. Both of these reversible features could benefit pharmaceutical research and development, he noted.

“Cyclopropanes, epoxides, and azirines are tough to make,” Bielawski said. Chemists traditionally prepare them by generating carbenes in situ from diazo compounds with a strong base or from dihaloalkanes using zinc and copper. “It’s not user-friendly chemistry,” he added.

“The beauty of using DACs is that you mix the carbene and the alkene, alkyne, aldehyde, or nitrile, and you have the addition product, often in a matter of seconds,” Bielawski said. “We simply crack open a bottle, add one reagent to another, and we’re done. Plus, DACs can be prepared and used in multigram quantities. With such simplicity, I believe DACs are poised to streamline many synthetic procedures.”

Developing “onward transformations” with carbenes, like those reported by Bielawski’s group, has also been adopted by Paul J. Ragogna of the University of Western Ontario. “From a structure and bonding perspective, persistent carbenes are fantastic and often display catalytic activity, redox capability, or some interesting photophysical property,” Ragogna observed. “But once we make them, we tend to put them on a shelf and don’t consider what more might be accomplished with them.”

Ragogna’s group is interested in incorporating main-group elements into carbenes and then transferring the modified attributes of carbenes to the macromolecular realm—to move interesting carbene properties into a polymer, for example. “It’s a great idea that more and more chemists are trying,” he told C&EN. “But it’s way harder to do than it is to jot down on a piece of paper.”

In San Diego, Ragogna provided an example of coupling fluorescent carbene analogs by ultraviolet curing to make photo­switchable polymers. Graduate student Jacquelyn T. Price first prepared a phosphorus carbene analog: an N-heterocyclic phosphinidine molecule bearing two thiophene substituents on the heterocyclic ring (Inorg. Chem., DOI: 10.1021/ic201983n). When the molecule is exposed to 350-nm light, the thiophene units undergo ring-closing isomerization, which causes the molecule to switch from colorless to blue.

But when exposed to white light, the molecule fails to undergo ring opening and return to the colorless state as anticipated. The researchers moved ahead with their original plan anyway and coupled a poly­merizable acrylate group to phosphorus to show they could make a processable material. Ragogna thinks that adding this polymerization step is typically overlooked when researchers are considering how to bring offbeat main-group carbene chemistry to the attention of an industrial partner.

“We are trying to blend a complete set of ideas into our research,” Ragogna says. “Unfortunately phosphorus doesn’t yet work out exactly the way we want. We are retooling by switching from phosphorus to boron, for which the reversible switching does work. But we haven’t yet been able to build the boron molecule into a polymer.”

A lot of interesting carbene-based molecules like the boron and phosphorus carbenes are just on the edge of being pushed that one extra step, Ragogna told C&EN. “I hope chemists are willing to keep asking the question: What happens if I try this?”

One such chemist is Philip P. Power of the University of California, Davis. Power’s group is known for developing alkene and alkyne analogs from the heavier group 14 elements silicon, germanium, tin, and lead. These compounds, such as R₂Ge=GeR₂, where R is a bulky aryl substituent, reversibly form monomeric heavy carbene analogs such as :GeR₂. Power’s group and others have discovered that these carbene analogs and multiply bonded compounds react with small molecules, just as NHCs do.

These discoveries have led to a wealth of new structural and bonding insights, Power said. For example, chemists have learned that in carbenes and carbene analogs the central atom’s lone pair of electrons and vacant orbital provide a donor-acceptor capability more typical of transition metals than of lighter main-group elements such as carbon.

In San Diego, Power received the ACS Award in Organometallic Chemistry, in part as a result of his multiple-bonding research. During his award address he reviewed the main-group carbene analog chemistry. He also described some of his team’s latest work. In one example, graduate student Christine A. Caputo carried out cycloaddition reactions of cyclic polyolefins such as norbornene and cyclooctatriene with RGa=GaR, where R is 2,6-(2,6-di­isopropylphenyl)₂phenyl, to form novel multiring structures (J. Am. Chem. Soc., DOI: 10.1021/ja301247h).

The UC Davis researchers found that the digallene carbene analog is more reactive than ethylene, allowing the digallene to undergo reversible catalyst-free cyclization reactions under ambient conditions. That reaction doesn’t happen with unactivated alkenes, Caputo said. Understanding the properties of heavy alkene analogs in these reactions could enable synthesis of compounds with ring architectures that have the potential to be developed into new types of functional materials, she noted.

Another of the Power group’s latest carbene accomplishments is synthesis by graduate student Brian D. Rekken of the first stable acyclic silylene, :Si(SR)₂, where R is 2,6-dimesitylphenyl (J. Am. Chem. Soc., DOI: 10.1021/ja301091v). Until now, stable two-coordinate silicon carbenes were limited to cyclic compounds—that is, N-heterocylic silylenes. But the electron-withdrawing nature of the sulfur atoms stabilizes the acyclic silylene, Power said.

In initial reactivity studies, Power’s team found that this stability inhibits the silylene’s ability to activate H₂. But the molecule does react with CH₃I to make a four-coordinate silicon species, CH₃SiI(SR)₂. Power noted that a team led by Simon Aldridge of the University of Oxford independently prepared an acyclic silylene bearing bulky phenyl and amidoboryl substituents and has shown that it reacts with H₂ and alkyl halides (J. Am. Chem. Soc., DOI: 10.1021/ja301042u).

Power said the key area of focus for carbenes and carbene analogs remains catalysis. But that’s because in the past it wasn’t customary to check the potential reaction chemistry of carbenes and their main-group analogs, he noted. Now that the cat is out of the bag, Power said, using these compounds as reagents “is an exciting prospect, as it will undoubtedly uncover new reaction types as well as new compound classes.”