musings on music and life

February 27, 2017

Classics in Organic Chemistry, Part IX

Filed under: Classics in Organic Chemistry — sankirnam @ 10:05 pm

Apologies for the hiatus, I’ve just been busy with getting settled into the routine of work while also juggling everything else going on in my life.

This next paper is one that I feel has not received the attention it deserves – it is incredibly groundbreaking and really should get the author, A. J. Arduengo, a Nobel Prize. Every October, I wait eagerly for the Nobel Committee’s decision in hope that Arduengo’s name comes up, but so far have been disappointed. Oh well… there’s still time for them to redeem themselves.

As students of organic chemistry know, carbon is unique among the elements in terms of the number and variety of stable bonds it can form with itself and other elements. This ability of carbon is central to life and biochemistry; no other element has these properties to the same degree that carbon does. While silicon is also tetravalent like carbon (and has provided inspiration to countless sci-fi writers), it polymerizes through Si-O linkages, forming polysiloxanes. Si forms bonds with itself with great difficulty, in contrast to carbon.

When undergraduate students learn organic chemistry, they are introduced to the concept of “arrow pushing”, which is a formalism that allows one to keep track of electrons – after all, reaction mechanisms are simply the rearrangement of electron pairs (e.g. σ bonds, lone pairs, and π bonds) relative to the nuclei. Most organic mechanisms proceed through carbon intermediates in a variety of oxidation states that students quickly become familiar with. The major ones are carbocations, carbanions, and carbenes.

Prof. G. A. Olah received the Nobel Prize in Chemistry in 1994 for the work he had done studying carbocations over the course of his (now 70-year) career. Prof. Olah’s big breakthrough was the isolation of carbocations – particularly the t-butyl cation, as stable, isolable species that were amenable to spectroscopic characterization (e.g. NMR and IR spectroscopy). This was a big deal at the time of discovery, because prior to that, chemists had proposed the intermediacy of carbocations as intermediates in acid-catalyzed organic reactions and rearrangements, but had not been able to conclusively prove their existence. Regular readers of this blog will know that I had the privilege of working under Prof. Olah and Prof. Surya Prakash, continuing research on new classes of carbocations – but that is not relevant to this discussion.

While carbocations have been isolated, free carbanions still have not been (at least to my knowledge). This also leads into a discussion on solvent effects and solvation. When carbocations are generated in the condensed phase in superacid media, one has to also consider the counterion, which is the conjugate base of the acid (e.g. SbF6). Is the anion also associated with the carbocation, and if so, what is the nature of the ion pair? These questions were studied by Prof. Saul Winstein at UCLA in the early 20th century, and he came up with the concept of the “intimate ion pair” based on solvolytic studies he had carried out in order to probe the the SN1-SN2 continuum.

In organic synthesis, when you want to generate a carbon nucleophile, you don’t actually use a “free” carbanion – instead, you use a pseudo-carbanion, and most common organometallics are exactly that (e.g. Grignard reagents and organolithiums). Grignard reagents and organolithiums are commonly employed as souces of nucleophilic carbon, but the C-Mg or C-Li bond is actually rather covalent. The ionic character increases as you go down the periodic table, and so C-Cs bonds would be expected to be very ionic. I haven’t looked much into organocesium chemistry, but since I have not heard much about it, I can safely assume that it is pretty esoteric – cesium is not the easiest metal to handle, since it ignites spontaneously in air.

Anyway, the main thing is that “free” carbanions have not really been isolated or studied the same way that Prof. Olah was able to study carbocations – perhaps there’s another Nobel Prize up for grabs there?

After carbocations and carbanions, the final carbon intermediate is carbenes. Carbenes are unusual in that they are formally neutral, and have properties of both carbocations and carbanions. They have an empty orbital like a carbocation, and also have a lone pair of electrons. The other complication is that what I just mentioned holds true for one particular spin state of carbenes; the empty orbital allows carbenes to have 2 potential spin states, namely the singlet and triplet states. When the lone electrons are paired, then it is said to be in the singlet state, and when the electrons are unpaired, then it is said to be a triplet species.carbenes

Carbenes are important species because of their utility in a variety of areas – most significantly, the Grubbs 2nd generation catalyst has an NHC (N-heterocyclic carbene) ligand, which confers extra stability compared to phosphines due to its ability to strongly donate electrons as well as engage in π-backbonding.grubbs_catalyst_2nd_generation

With that context, today’s paper is on the isolation of the first stable, crystalline carbene. This was carried out by A. J. Arduengo and coworkers at the DuPont Central Research and Development laboratories in Delaware in 1990. The DuPont laboratories were the place to be in the 20th century for cutting-edge chemistry research – they basically single-handedly revolutionized not just the field of chemistry, but the lives of everyone on the planet. It’s difficult to overstate the impact that DuPont’s research had; here’s a brief list:

  • Wallace Carothers in the 1930’s single-handedly developed the field of polymer chemistry while at DuPont, creating Nylon, Neoprene, and the concept of step-growth polymerization.
  • Roy Plunkett discovered Teflon by accident when he saw that the pressure in a cylinder of tetrafluoroethylene had dropped to zero. Upon sawing the cylinder open, he obtained a white powdery solid that was very chemically inert, had a low surface friction, and had a very high heat resistance. Plunkett became infamous for later developing Freons (fluorochlorocarbons which were extensively used as refrigerants due to their heat capacity, until Prof. Rowland (UCI) discovered that they were responsible for ozone depletion in the upper atmosphere) and tetraethyllead (which was used as an anti-knock additive for gasoline until it was realized how undesirable lead pollution is).
  • Stephanie Kwolek invented Kevlar while at DuPont, and showed that when woven, the strands of aramids were incredibly strong, thus leading to their use in bulletproof vests.
  • Charles J. Pedersen synthesized crown ethers while at DuPont, and showed that 12-C-4 had a high affinity for Li+, 15-C-5 for Na+, and 18-C-6 for K+. Pedersen later received the Nobel Prize in Chemistry for this work, and was one of the few recipients not to have a PhD!
  • Richard Shrock started his research career at DuPont investigating tantalum alkylidenes, which are metallic carbene intermediates in olefin metathesis. Shrock continued these investigations as a professor at MIT, and eventually received the Nobel Prize along with Prof. Robert Grubbs (Caltech) for his work in developing well-defined olefin metathesis catalysts.
  • F. N. Tebbe developed the eponymous Tebbe’s reagent for methylenation of carbonyl compounds. This led to the later development of the Petasis reagent, which I might cover later.
  • Norman Borlaug also worked at DuPont CR&D for 2 years, but did his major Nobel-Prize (and humanitarian) work afterwards. Norman Borlaug’s impact on humanity cannot be overstated; it’s mindboggling to think that just due to three people (himself, Fritz Haber, and Carl Bosch), we have been able to support an estimated extra 3 billion people on the planet!
  • T. V. Rajanbabu (now at OSU) and coworkers did some very elegant work in the 80’s developing a new polymerization method called group-transfer polymerization, and also demonstrated some very nice radical-mediated ring closures using Ti(III) reagents.

Arduengo’s work therefore follows a long line of high-impact research that was conducted by some of the best minds in the world at one of the most productive laboratories in the world! Shrock and Tebbe had done some carbene research at DuPont earlier, so there was a precedent for that. Arduengo generated the first stable persistent carbene by deprotonating the imidazolium species below. arduengo_1Catalytic DMSO is needed, and the actual base is the dimsyl anion, as NaH is basically insoluble in THF. In fact, NaH and THF reminds me of a spectacular gaffe by a research group in China that found its way into JACS in 2009 claiming the discovery of a NaH-mediated oxidation of secondary alcohols to ketones (which turned out to actually be mediated by peroxides in the THF or atmospheric oxygen).

The incredible thing is that the carbene so generated is stable and can be isolated in pure form. It can be recrystallized, and Arduengo was able to get X-ray diffraction data, as well as NMR data. The 13C NMR shows that C2 still has some electrophilic character even though it formally also has a lone pair. Part of the stability enjoyed by the carbene is due to the blocking provided by the very bulky adamantyl groups – in fact, the carbene can be melted and remelted without depression of the melting point!

As Arduengo concludes in the paper:

Carbenes have long been recognized as important reaction intermediates. The aggressive study of carbenes as reactive intermediates has provided much fundamental knowledge for chemical science. Until now there have not been any “bottle-able” carbenes, and we hope that the production of these stable nucleophilic carbenes will allow for convenient study of this class of compounds. We are currently investigating both the electronic structure and chemical reactivity of 1 and related isolable carbenes.

If NHC’s and related compounds are being used as versatile ligands in organometallic chemistry, organic synthesis, and as organocatalysts in their own right, it is all thanks to the seminal work of Prof. A. J. Arduengo. I sincerely hope that one day, he and his work get the recognition that is due.

Addendum: After all this, I hope you will share my disbelief that DuPont gutted the CR&D in 2015-2016.

February 22, 2017

View from the office

Filed under: Photography — sankirnam @ 10:48 pm


Taken with my cellphone (Nexus 5) camera. Effects and filter done automatically by Google Photos.

Create a free website or blog at