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April 9, 2017

Classics in Organic Chemistry, Part X

Filed under: Classics in Organic Chemistry — sankirnam @ 8:14 pm

It’s been over a month since Prof. Olah passed away, and I haven’t made a post here since then, so this one can also be dedicated to some of the work that he did.

Prof. Olah may have been best known for carbocation and superacid chemistry, but his research covered a very broad swath of organic chemistry, including novel synthetic methods, nitration, Friedel-Crafts chemistry, onium ion chemistry, fluorine chemistry, polymer chemistry (carbocationic polymerization), and physical organic chemistry. This post will be about work that I did during my PhD (2008-2014), and was in full force during the time Prof. Olah received the Nobel Prize (1994).

This topic is called superelectrophilic activation and can be thought of as a way to rationally design new electrophiles for Friedel-Crafts chemistry, as well as develop new types of Friedel-Crafts reactions. But first, some background is required.

In the 1970’s, Prof. Olah’s group (then at Case Western Reserve University, Cleveland), as well as Brouwer and Kiffen at Shell Amsterdam, had noted that acetylium salts could carry out hydride abstraction from tertiary alkanes. Prof. Olah noted the solvent dependence of this reaction – it took place in superacid media (e.g. HF-BF3 or FSO3H), but not in aprotic solvents. A similar phenomenon was observed with the nitronium ion (NO2+ salts); in superacid solution, the nitronium ion was capable of reacting with methane, forming nitromethane (although the yields are low and this is not preparatively useful, it is in stark contrast to the usual scenario of no reaction).


Slides are from my PhD Defense, University of Southern California, 2014.

Around the same time, Prof. Koichi Shudo (University of Tokyo), was doing independent but related research in a similar area. Prof. Shudo had just come back to Japan after doing a postdoc with Prof. Paul G. Gassman (University of Minnesota). Gassman’s influence is evident in Prof. Shudo’s research in Physical Organic Chemistry, as he was doing research at the time on nitrenium ion chemistry. Prof. Shudo was a brilliant chemist and bought a lot of rigor to his investigations on superelectrophiles. I never met him, but I did meet his junior colleague, Prof. Tomohiko Ohwada, at Prof. Olah’s 85th birthday at USC a few years ago.

In any case, Prof. Shudo and his colleagues observed that when N-phenylhydroxylamine or nitrosobenzene was mixed with benzene and TFA (trifluoroacetic acid), N-arylation was observed, yielding diphenylamines. On the other hand, when TFSA (triflic or trifluoromethanesulfonic acid) was substituted for the acid, completely different products were obtained – the reaction yields aminobiphenyls, indicating attack on carbon rather than nitrogen. One thing to keep in mind is that triflic acid has a Hammett acidity of -14.1, while TFA’s is -2.7; triflic acid is therefore about 1012 times more acidic than TFA! In addition, most people would expect that simply increasing the acidity would just affect the reaction kinetics, and that this would be subject to general acid catalysis. However, since the products and product distribution is completely different, a different reaction or mechanism is now involved.


Prof. Olah’s insight was to propose that in a superacidic medium, positively charged cations (or “onium” ions) could undergo further interaction with the solvent to yield even more electron-deficient species. The nature of this interaction can vary anywhere from a hydrogen-bonding interaction to a complete protonation yielding dications or dicationic species in the limiting case. This is still an area of research, and it is quite possible that the observed effects could also be due to dielectric or field effects alone, with no contribution from protonation (since superacids are a high-dielectric medium). Prof. Olah dubbed this interaction of the superacid medium with onium ions protosolvation, and this general concept came to be called superelectrophilic activation.

superelectrophile_slide_3There are a couple of things to keep in mind here. The resulting species are known as superelectrophiles and are transient, short-lived, high-energy intermediates. Prof. Olah and his coworkers put a lot of effort into trying to characterize the protonitronium dication (HNO22+) by NMR and other methods, but these were largely unsuccessful. But just because an intermediate cannot be characterized, it doesn’t mean that it doesn’t exist at all; we now know that stability and reactivity are opposing properties, and that just because a particular species is amenable to isolation and characterization, it may not be the true reactive intermediate in the reaction coordinate.

The real proof of the existence of superelectrophiles comes from kinetic studies done with varying acidities. The rationale behind these studies is as follows: if the monoprotonated species is the key intermediate in the rate-determining step of the reaction, then the rate should level off once the acidity required for complete monoprotonation of the substrate has been achieved. If on the other hand, the reaction rate continues to increase with increasing acidity, then it is not the monoprotonated species that is involved in the reaction, but a diprotonated (or protosolvated) species.

The slide above shows some examples of this; the Friedel-Crafts hydroxyalkylation of benzaldehyde with benzene is particularly illustrative. The rate of the reaction increases dramatically with increasing acidity! Although the superelectrophile has not been characterized, one can use this kinetic data as support for its intermediacy. The nature of the superelectrophile is also up for debate; experimental data suggests that the O,O-diprotonated species is involved, while theoretical data suggests an O,C-diprotonated species.

This concept can therefore be used for the design of new electrophiles in Friedel-Crafts chemistry. Protonated moieties, substituents than can become positively charged (by protonation or ionization), or other highly electron-withdrawing groups can be used to activate carbenium ions nearby in the substrate towards reaction. N-halosuccinimides can be activated in superacid media and do halogen (“X+“) transfer to arenes; this reaction was investigated by Prof. Olah and can be carried out in BF3-H2O. BF3-H2O is a particularly interesting superacid; it was first discovered by Hans Meerwein and is probably the cheapest superacid available today (apart from anhydrous HF). It can be prepared by bubbling one equivalent of BF3 into ice-cooled water, and can be stored as a frozen solid and thawed when needed. In related chemistry, the nitronium ion can be activated in superacid in order to carry out nitrations of challenging substrates, such as nitrobenzene other nitrated aromatics (which are used in explosives and synthetic musks). Benzoyl esters can also be activated in superacid, giving protoacyl dications or diprotonated esters which can undergo condensation with arenes to conveniently yield benzophenones.


Currently, Prof. Douglas Klumpp (Northern Illinois University) is doing research in this area; he started as a postdoctoral fellow with Prof. Olah at the time he received the Nobel Prize. Prof. Klumpp has extended Prof. Olah’s concept to design new types of electrophiles and superelectrophiles, including novel condensations and domino reactions.


R. R. Naredla, C. Zheng, S. O. N. Lill, D. A. Klumpp, J. Am. Chem. Soc., 2011

Once these multiply-charged species are generated, new types of reactions can be designed based on charge-charge repulsion; this enables regioselectivity at a different position, such as an aryl carbon, similar to what Shudo did earlier with N-phenylhydroxylamine in TFSA.

This should serve as a brief introduction to this fascinating topic, and if you’re interested in reading further, there are several excellent manuscripts and reviews available, including a book Superelectrophiles and their Chemistry*.

*I’m not condoning the use of illegitimate PDFs – this was the first hit when I searched for “Superelectrophiles and their Chemistry”, so its not like nobody else would have found it anyway.


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.

November 17, 2016

Classics in Organic Chemistry, Part VIII

Filed under: Classics in Organic Chemistry — sankirnam @ 3:46 pm

This paper was further down on my list, but I’ve decided to bump it up and cover it today.

Modern practitioners of organic synthesis or medicinal chemistry will no doubt be aware of how hot fluorine chemistry is now; every issue of JACS, JOC, Organic Letters, Angewandte Chemie, or Chemical Science has at least one paper on the development of new fluorination methodologies. But this was not always the case. Fluorine chemistry used to be considered very esoteric, primarily because of the reagents required (F2, HF, SF4, among others), which also necessitated special reaction conditions and apparatus. This limited the accessibility of fluorinated compounds, and research in this area was primarily done by groups in academia (such as Olah, Seppelt, Christe, Bartlett, Rozen, Haszeldine, Barton) or industry (DuPont, 3M) that had the infrastructure in place to carry out this chemistry.

One of the long-standing challenges in organofluorine chemistry was the development of a mild, effective method to introduce the trifluoromethyl (-CF3) group into organic molecules. I had briefly discussed the challenges in isolating the trifluoromethide anion earlier; this is why the development of nucleophilic trifluoromethylation methods only came about recently. It is necessary to use reagents that act as “pseudo-anions”, and can do a transfer of the -CF3 group under certain conditions.

Prakash and Olah were motivated by their desire to study carbocations that had an electron-withdrawing group α to the cation, such as the ones below:coc_8_1

The synthesis of the precursors for these cations is rather interesting – each involves a different type of chemistry. The α-nitro cation above is prepared by ionizing the gem-dinitro compound (which was synthesized from benzophenone oxime and N2O4), while the α-fluoro cation is prepared from gem-difluorodiphenylmethane, which can be prepared from benzophenone and SF4. The α-cyano cation is prepared by ionizing benzophenone cyanohydrin, which can be easily prepared using a procedure developed by Prof. Paul Gassman with TMSCN and ZnI2.

The α-CF3 cation can be prepared from 2,2,2-triphenylacetophenone and phenylmagnesium bromide, but substituted derivatives are more challenging to prepare; you’ll need substituted derivates of 2,2,2,-triphenylacetophenone which are either challenging to synthesize, of limited commercial availability, or expensive. The easier route would be to start from benzophenone and add a -CF3 to the carbonyl. This was elegantly solved by Prakash, Olah, and Krishnamurti in 1989. They demonstrated that the compound TMSCF3 could undergo nucleophilic trifluoromethyl transfer to carbonyls very readily, under fluoride-ion catalysis. TMSCF3 had first been prepared by Prof. Ingo Ruppert (Germany) a few years earlier, but he had not demonstrated any potential reactions with it.


This is the proposed mechanism; interestingly, fluoride is not necessarily the only catalyst that can initiate this reaction – Dr. Prakash later showed that carbonates and amine-N-oxides can also act as catalysts. I’m not sure if DMF/imidazole can also initiate this reaction (as they do Corey’s TBS protection), but I’m sure that should also work. One big challenge that still has not been solved is to do this transfer asymmetrically; in other words, a facially-selective trifluoromethyl transfer to carbonyls is still lacking.

This has led to a whole slew of developments which are simply too numerous to list here, leading to TMSCF3 being called the “Ruppert-Prakash reagent”, after the chemists who first synthesized it (Ruppert) and demonstrated its synthetic utility (Prakash). The commercial availability of TMSCF3 also opened up trifluoromethylation to all organic chemists (the original synthesis (adapted from Ruppert’s work) uses CF3Br, which is now banned under the Montreal Protocol). Recently, a postdoc in Prakash’s group (who used to work next to me) came up with an improved synthesis of TMSCF3 from CF3H, which is a byproduct of Teflon manufacturing, and therefore much cheaper and more readily available than CF3Br.

Many, many other types of trifluoromethyl transfer reagents have been developed, and almost all of these use TMSCF3 in their synthesis. The electrophilic trifluoromethylating reagent developed by Togni is illustrative of this. Melanie Sanford has also conducted very nice work in organometallic chemistry studying the reductive elimination of -CF3 from Pd(IV); I particularly remember a very interesting set of papers she had published that showed that “F+” reagents were the only compounds capable of oxidizing the Pd(II) to Pd(IV) and selectively inducing the reductive elimination of the -CF3, because the energy of reductive elimination of -F was greater than that of -CF3. It’s not much though; I think it was 5 kcal or less! Of course, all of these trifluoromethylated metal complexes were synthesized with TMSCF3 as the -CF3 source.

Stephen Buchwald (MIT) also published a couple of papers using TMSCF3 and Pd/Cu complexes for doing -CF3 transfer to a variety of systems.

CuCF3 and AgCF3 are also receiving increased interest now; I talked about CuCF3 earlier. Both of these complexes can be generated in situ from TMSCF3 and appropriate metal salts, and can be used for a variety of transformations, including Sandmeyer-type reactions. I remember that I and my labmates had tried to implement this reaction without much success, and when we saw Goossen’s paper, it seems that the copper counterion is very significant; the reaction only works with CuSCN, which we did not have on hand.

As mentioned earlier, the challenge with developing organometallic reagents for nucleophilic -CF3 transfer (such as LiCF3 or CF3MgBr) is that the CF3 anion is kinetically unstable and tends to undergo fast α-defluorination to yield difluorocarbene. This can be a nuisance, but depending on your needs, can also be synthetically useful. Difluorocarbene can also undergo the usual carbene reactions, such as 2+1 additions to olefins to give gem-difluorocyclopropa(e)nes, as well as insertions into weak bonds, such as S-H or Sn-H. Some friends of mine in Prakash’s group were able to use this to develop useful chemistry – one nice example is the insertion of CF2 carbene so generated into the Sn-H bond of Bu3SnH to make Bu3SnCF2H, which proved to be a useful reagent for -CF2H transfer.


There was a paper published a couple of years ago by a group in Russia describing the synthesis of TMSCF2H from TMSCF3 by a simple reduction using sodium borohydride. This allows improved access to TMSCF2H (which was otherwise difficult to prepare) and related analogues (such as TMSCF2D, TMSCF2Cl, and others). The challenge with TMSCF2H is that it is more difficult to activate compared to TMSCF3 (it is speculated that the reactive species that does the actual -CF3 transfer is a pentavalent siliconate), accounting for the limited substrate scope (with ketones) in this paper by Jinbo Hu.

Anyway, this is a brief overview of trifluoromethylation chemistry, and I hope the huge impact that Dr. Prakash’s initial paper had is evident – TMSCF3 is now the major source of -CF3 in organic chemistry; most research chemists will not think about how it is produced! This is by no means exhaustive, and numerous reviews (such as this one) are being published about this area of chemistry all the time; check those out if you want more details.

October 12, 2016

Classics in Organic Chemistry, Part VII

Filed under: Classics in Organic Chemistry — sankirnam @ 6:04 pm

Ok, let’s keep the train rolling here…

This next topic is related to an ill-defined project I worked on early in my PhD, where I was investigating synthetic reactions related to isocyanide synthesis using TMSCN. One of the first places my advisor told me to look was at an intriguing 1982 JACS communication by Prof. Paul Gassman. To preface, it is well-established that the cyanide ion is ambident and can react from either the or the C position; the conditions employed can influence whether a nitrile or isonitrile will be obtained as the product. Gassman’s paper revisited this topic using epoxides as the electrophile, and he demonstrated that by intelligently choosing the right Lewis Acid (ZnI2 in this case), one can obtain β-isocyano alcohols as the product upon ring-opening with TMSCN (followed by desilylation with KF).


Now that I reflect about the background for this paper, it is actually not as serendipitous as I had used to think as a first/second year grad student. Gassman had previously published a few papers, including an Organic Syntheses procedure, for converting ketones to cyanohydrins; the conditions employed in the above reaction are pretty much identical, save for switching out the ketone for an epoxide.

The utility of this reaction lies in the fact that isocyanides are extremely valuable synthons – there are a family of extremely useful multicomponent reactions based on isocyanides, including the Ugi Reaction and the Passerini Reaction. These reactions succeed because the isocyanide is a rare example of a (1,1)-amphoteric molecule; the same atom (the R-carbon) establishes a connection with both the nucleophile (carboxylic acid) and electrophile (aldehyde or imine). The Ugi reaction was developed by Prof. Ivar Ugi (no surprise), and I discovered a cool fact about him when I happened to check out his book Isonitrile Chemistry from the library, and I saw that it said “Prof. Ivar Ugi, University of Southern California”. Apparently he was a faculty member at USC for a short time (around a year or two) in the early 70’s, before Prof. Olah came to USC.

In any case, the next question is, how does this isocyanation work? In my mind, the mechanism is pretty straightforward; it’s simply a variant of the Ritter reaction with TMSCN, avoiding the use of aqueous acids to prevent hydration of the intermediate nitrilium ion or isocyanide to an amide. This reaction has seen a slow stream of contributions – you can see the references for a list of papers that describe the conversion of various types of compounds to isocyanides or amides. Recently, Ryan Shenvi (Scripps) revisited this chemistry and somehow got a paper in Nature; I don’t understand why this was selected for publication, because as you can see here, there’s nothing truly original about it, and the conditions are not really practical:

A solution of trifluoroacetate 13 (32.0mg, 0.1 mmol) in TMSCN(0.1ml) was cooled to 0 ℃ and treated with a solution of anhydrous Sc(OTf)3 (1.5 mg, 0.003 mmol) in TMSCN (0.1 ml). […]”

The reaction is carried out neatusing TMSCN as the solvent! Not really scalable, and only for the truly desperate.

If you ask me, the cyanation reactions are more intriguing, because the mechanism is more unclear. Prof. Weber (who used to be at USC) demonstrated a complementary reaction to Gassman’s reaction above; when Et2AlCl is used as the Lewis acid instead of ZnI2nitriles are obtained instead. The mechanism invoked by Prof. Weber involves a little more hand-waving, however:


The first step involves the interconversion of TMSCN with its isocyano isomer. It’s not far-fetched on paper, and you can certainly defend this using the Curtin-Hammett principle. However, the literature support for this is rather weak; detailed spectroscopic studies of triorganosilyl cyanides gave no evidence for the presence of the isocyano form. However, another Japanese group studied this set of reactions with more Lewis Acids, and what seems apparent to me is that soft Lewis acids seem to promote formation of the isocyanide, whereas hard Lewis acids promote formation of the cyanide. Thus, two different mechanisms are at play depending on the Lewis acid involved. With reactions involving cyanide, the nitrogen preferentially attacks hard electrophiles (i.e. carbocations, giving the Ritter reactions, as well as other electron-deficient species). My proposal is that the first step would be a nitrilium ion formed from TMSCN attacking the aluminum atom; this species would be the active cyanating agent. If anyone is up for it, it may be possible to characterize this species; Melanie Sanford recently wrote about rapid-injection (RI)-NMR being used to characterize transient Cu(III) intermediates, and the same technique could possibly be used here. In contrast, other Lewis acids (ZnI2, Pd salts, etc.) activate the epoxide for nucleophilic ring-opening by attack of the nitrogen in TMSCN, which is drawn to the nascent carbocation by Coulombic forces.

do have some ideas for new synthetic reactions based on this chemistry, but that will have to be explored once I can get back in a lab.


  1. Gassman, P. G.; Guggenheim, T. L. J. Am. Chem. Soc. 1982104, 5849 
  2. Spessard, G. O.; Ritter, A. R.; Johnson, D. M.; Montgomery, A. M. Tetrahedron Lett. 198324, 655 (This paper was published independently and at the same time as Gassman’s paper above, and describes the same results)
  3. Gassman, P. G.; Talley, J. J. Org. Synth. 198160, 14  (Gassman’s 1981 prep for converting aldehydes/ketones to cyanohydrins with TMSCN)
  4. Okada, I.; Kitano, Y. Synthesis 201124, 3997 (Refs. 3-9 cover converting various functional groups to isocyanides)
  5. Kitano, Y; Chiba, K.; Tada, M. Tetrahedron Lett. 199839, 1911
  6. Kitano, Y.; Chiba, K. Tada, M. Synthesis20013, 437
  7. Kitano, Y.; Chiba, K. Tada, M. Synlett19993, 288
  8. Kitano, Y.; Manoda, T.; Miura, T.; Chiba, K.; Tada, M. Synthesis 20063, 405
  9. Pronin, S. V.; Reiher, C. A.; Shenvi, R. A. Nature 2013501, 195
  10. Mullis, J. C.; Weber, W. P. J. Org. Chem. 1982 47, 2873 (Weber’s conditions for the ring-opening of epoxides and oxetanes with TMSCN + Et2AlCl)
  11. Seckar, J. A.; Thayer, J. S. Inorg. Chem. 1976 15, 501 (Detailed spectroscopic study on the interconversion of the iso- and normal forms of triorganosilyl cyanides)
  12. Hickman, A. J.; Sanford, M. S. Nature2012484, 177 (Review in which various methods for characterizing transient high-valent metal intermediates are discussed, including RI-NMR)

This is by no means an exhaustive list; I have many more papers with me on this topic. If you want them, let me know.

Finally, I have to include this link to Prof. Andrei Yudin’s blog, which got this whole discussion started in my mind.

September 11, 2016

Classics in Organic Chemistry, Part VI

Filed under: Classics in Organic Chemistry — sankirnam @ 8:31 pm

Sorry for the hiatus – back to our regularly scheduled programming!

In this post, we transition from the “classical” methods of organic chemistry, and move to modern material. The “classical” reactions are those generally taught in undergraduate organic chemistry, and while reactions such as oxymercuration, alkynylation with acetylide anions, and PCC oxidation are no doubt useful, they are not used that much anymore. Reactions dealing with mercury and superstoichiometric amounts of chromium are no longer palatable in today’s environmentally conscious era.

One of the holdovers from classical organic chemistry is the necessity of conducting reactions with as little water as possible. Water is generally thought of as a “bad” solvent, one that will rapidly quench any reactive species present and bring everything to a grinding halt. This thought process is not unfounded; after all, when working in the lab, frequently you will quench a reaction with water before working it up in order to extract any products formed. However, given the recent interest in Green chemistry from the chemical research and manufacturing sector, there is now a lot of interest in developing water-tolerant reactions. These reactions also have the added benefit of being milder, but the caveat is that one has to put more thought into extracting and purifying the organic material afterwards.

The papers covered in today’s post are on Shu Kobayashi’s work on water-tolerant Lewis Acids and their application in organic synthesis. This paper really marks a distinct gap between “classical” and modern organic chemistry, because when most people think of Lewis Acids, they will think of Friedel-Crafts promoters such as AlCl3, FeCl3, Al2Br6, BrF3, and others. These are very strong Lewis Acids and are also notoriously water-sensitive; they all react with water or undergo hydrolysis. One of Kobayashi’s early papers from 1998 demonstrated the possibility of doing a Lewis Acid-catalyzed Mukaiyama aldol reaction with water-tolerant Lewis acids – this is a big step from the previous versions of the Mukaiyama aldol reaction, which commonly used TiCl4 as the Lewis acid. Even this Evans’ asymmetric aldol reaction makes use of some very water sensitive reagents – namely, n-butyllithium and dibutylboron triflate.

Kobayashi’s main insight was that both the hydrolysis constant and water exchange rate constant (WERC) were critical features for determining if a metal salt would be a good Lewis acid in aqueous media. Basically, if you can choose a metal cation that has a low enough affinity for water (as determined by the hydrolysis constant), but yet can exchange it’s ligands with water at a fast enough rate, you have a good aqueous Lewis acid. This can be seen from the figure below – all the lanthanide cations are good Lewis acids because they have WERC values and hydrolysis constants right in that sweet spot. It’s like Goldilocks – not too low, not too high.


This simple observation then opens the door to a whole plethora of possibilities. The next question is – are asymmetric reactions possible in aqueous media? The answer is… yes.


The ligand in the figure above is a chiral bis-pyridino-18-crown-6 derivative, but the point is yes, asymmetric reactions are possible in aqueous media! I mean, this should be no surprise – all biochemistry is asymmetric, and it occurs in aqueous media too.

Friedel-Crafts reactions are also possible with these lanthanide triflates in aqueous media, but the issue here is reactivity. A traditional Friedel-Crafts reaction with benzene generates a benzenium ion as the intermediate, which will immediately quench itself with any adventitious water present. Therefore, one can only do aqueous Friedel-Crafts reactions involving less reactive (or more reactive depending on how you look at it) species, such as indoles.


So now you’re familiar with one of the most important advances of modern organic chemistry – water-tolerant Lewis Acids!


  1. Kobayashi, S.; Nagayama, S.; Busujima, T. J. Am. Chem. Soc. 1998120, 8287 (link)
  2. Kobayashi, S.; Sugiura, M.; Kitagawa, H.; Lam, W. W.-L. Chem. Rev. 2002102, 2227 (link)
  3. Kobayashi, S.; Manabe, K. Acc. Chem. Res. 200235, 209 (link)

June 1, 2016

Classics in Organic Chemistry, Part V

Filed under: Classics in Organic Chemistry — sankirnam @ 3:59 pm

Wow, we’re on our fifth post in this series!

This next paper is a classic by E. J. Corey that all serious students of organic chemistry should have read at least once. It’s not terribly complicated, but at the same time is iconic enough that it is worth mentioning in this context.

A key concept when doing total synthesis (or almost any type of organic synthesis) is “functional group protection”. During the course of a synthesis, you may want to conduct a reaction to change one part of the molecule, but the reaction conditions employed for that transformation may affect other sensitive groups in other parts of the molecule. Thus, you will need to “protect” the vulnerable functional group(s) in the molecule so that they are not unnecessarily changed by the reaction.

When I was younger, I used to joke that a lot of total synthesis was basically “protection, coupling, deprotection”, making it like sex. If you do use this dirty chemistry joke later, remember to credit me (or not…do I really want to be associated with such hopeless humor?).

Anyway, a particularly sensitive functional group in organic chemistry is the hydroxyl (-OH) group. The hydroxyl group is what makes compounds alcohols. Ethanol, the alcohol we all know and love, is simply an ethyl group with an -OH.

Alcohols can also be thought of as organic derivatives of water. Water’s formula is H2O, and so alcohols can be thought of as water molecules with one of the hydrogen atoms replaced by an organic group (giving rise to the generic formula R-OH, where R represents any organic structure). Alcohols also undergo reactions on their own, and as such, are sensitive to acidic and basic reaction conditions. In basic media, the hydroxyl can be deprotonated, making it a stronger nucleophile (R-O vs. R-OH), and in acidic media, E1 and E2 eliminations are possible, depending on the structure of the carbon backbone. Therefore, if you want to do a reaction on a molecule containing hydroxyl groups, you have to be aware of the reaction conditions, and if the alcohol proves to be reactive, it may be necessary to temporarily “protect” it or “mask” it. A common way of doing so is by converting it to an ether, such as a THP (tetrahydropyranyl) ether.

Another alternative is the use of a silyl ether (-OSiR3) as a protecting group. Silyl ethers are easily synthesized by adding a chlorosilane and a weak base (to mop up the HCl produced) to an alcohol. As with everything in chemistry, while the concept is simple, the situation is much more nuanced than might seem on the surface. Standard TMS (trimethylsilyl) ethers are not useful, because as mentioned in Corey’s paper, “Trimethylsilyl ethers are too susceptible to solvolysis in protic media (either in the presence of acid or base) to be broadly useful in synthesis“. One solution is to increase the steric bulk of the groups attached to the silicon atom. Replacing one of the methyl groups with an isopropyl, while promising, still did not give the stability desired, especially in “Grignard reagent formation, Wittig reaction, or Jones (CrO3) oxidation”. Thus, Corey decided to increase the steric bulk further, opting for a tert-butyl group on the silicon. This is called the “t-butyl dimethylsilyl” group, and is abbreviated -TBS or -TBDMS.

However, another roadblock ensued – TBSCl proved to be too unreactive with most alcohols under conventional or even forcing conditions, “for example, with excess silyl chloride, excess dry pyridine in tetrahydrofuran at temperatures from 20 to 60° for many hours”. This was solved by the discovery that the use of TBSCl with catalytic imidazole in DMF turned out to be appropriate conditions for the activation of TBSCl. These conditions quickly became known as Corey’s classic conditions for TBS protection. Even though a detailed experimental section is not included in this communication, Corey demonstrates the versatility of this method in the total synthesis of several prostaglandins. The TBS group is much more stable to hydrolysis than less bulky silyl ethers, and as such became widely used in synthesis. Like all silyl groups, it can be quantitatively removed by the use of fluoride (either a solution of KF or TBAF (tetra n-butyl ammonium fluoride)).

This begs the question – how does this method of activation work? My guess is that imidazole is able to initially bond to the silicon, forming a hypervalent pentavalent species, which is then transferred to the hydroxyl oxygen atom. Unfortunately, I cannot find the source right now, but imidazole is known to be able to activate silicon groups too, although not as strongly as fluoride does. DMF is also known to be able to activate silicon compounds such as TMSCN and TMSCF3.

More in the next. I need to get some coffee!

EDIT (7/28/2016): Prof. Andrei Yudin has a very nice discussion about this reaction on his blog.

May 16, 2016

Classics in Organic Chemistry, Part IV

Filed under: Classics in Organic Chemistry — sankirnam @ 12:41 pm

And now for our next topic, Sir D. H. R. Barton’s Gif Chemistry.

Derek Barton was another one of the “rockstars of organic chemistry” along with esteemed individuals such as R. B. Woodward, E. J. Corey, Professor G. A. Olah, Prof. K. B. Sharpless, and others. Like Einstein, Ernst Rutherford, and a few others, Derek Barton was particularly famous because his most famous work was not what he received the Nobel Prize for! Derek Barton contributed to an extremely wide range of research areas, including radical chemistry, hypervalent bismuth and selenium chemistry, fluorine chemistry, and of course, his last work involved the oxidation of saturated hydrocarbons under mild conditions – a class of reactions dubbed “Gif chemistry”.

The name is derived from the place where this type of chemistry was first studied, Gif-sur-Yvette in France. At the time, the functionalization of saturated hydrocarbons (alkanes) was a hot topic in the organic chemistry community; it still is today, although it has taken on the sexier name of “C-H activation”. I initially learned about this class of reactions when I was reading Iron Catalysis in Organic Chemistry: Reactions and Applications during the course of my PhD. Iron catalysis remains a topic of personal interest, as it focuses on one aspect of the question “can we substitute 3d metals for the precious 4d metals (Ru, Rh, Pd) as catalysts in organic synthesis?”.

In any case, the overall premise of the Gif reactions is the oxidation of saturated alkanes (by air or other oxidants) using iron as the catalyst. In all cases, adamantane was chosen as the substrate for “its non-volatility, which would make good mass balances feasible, and its symmetry, which simplifies the problem of product identification. In addition, adamantane is a nice mechanistic probe. It has 12 equivalent secondary C-H bonds and four equivalent tertiary C-H bonds”.


Conceptually, this is not terribly difficult to understand; the terminal oxidant in both reactions above is O2 from the air, and the solvents involved are pyridine, acetic acid, and water (in the GifII reaction). Pyridine is necessary because you need an organic solvent to dissolve something as nonpolar as adamantane (or any alkane), and acetic acid is employed as an anion once the iron is also in solution. The surprising observation is that this alkane oxidation takes place in the presence of hydrogen sulfide, which is much easier to oxidize than any alkane; in fact, it turned out that the presence of a sulfide (or phosphine) was necessary for the oxidation to proceed.

Historically, oxidative chemistry using Fe is well known in the literature, and the earliest example is probably Fenton’s reagent, which is well over 100 years old. That being said, there is still a lot of uncertainty regarding the mechanism of the Gif reactions, and unfortunately interest in these investigations waned with Derek Barton’s demise in 1998. The main question was whether this reaction proceeded via radical intermediates (like the Fenton system), or did it involve the intermediacy of a high-valent Fe(IV) or Fe(V) species? One of the arguments against the involvement of radicals is the observation that the reaction proceeds in the presence of hydrogen sulfide; the S-H bond is known to quench carbon radicals readily by HAT (hydrogen atom transfer). Another is the regioselectivity of the reaction; since tertiary radicals are more stable than secondary radicals, one would expect the tertiary product (1-adamantanol) to dominate if radicals were really involved. But, as one can see from the figure above, the secondary products are obtained in greater yield.

Barton and his coworkers were able to isolate a soluble black crystalline complex from the dissolution of iron powder in acetic acid and pyridine; it was found that when this complex was employed in the reaction instead of iron powder, better yields and selectivities could be obtained. Barton’s theory was that a high-valent Fe(V) or Fe(IV)-oxo or -hydroxo species was responsible for the oxidation, as that would also account for the selectivity to secondary positions based on steric arguments. There is some precedence for this, as it is believed that high-valent Fe(V)/Fe(IV) is involved in biological oxidations using cytochrome P450.Barton_gif_2

This catalyst or cluster would be considered “primitive” by today’s standards, as the synthesis is pretty trivial, and the ligands are extremely simple. And yet, it is able to do some pretty impressive transformations!

Barton had this to say about how the reactions work:

“The only way that we can explain these results is by a hypothesis that the reagent that oxidizes the hydrocarbon is present in a dormant form (Sleeping Beauty) until it collides with the saturated hydrocarbon (the Prince) and reacts with a saturated C-H bond (the kiss) to form the real reagent, which immediately gives the iron-carbon bond […]. So, the hydrocarbon on contact with the iron species activates and reacts with the activated iron species without separation. The hydrocarbon should be inducing in the (formally) FeV=O species a change that makes possible such an unusual reaction. There is evidence in the literature for this sort of agostic interaction between nonactivated carbon-hydrogen bonds and organometallic species”.

Funnily enough, this chemistry has been rediscovered recently by Prof. M. Christina White (UIUC). I remember reading her papers and wondering in confusion why it was being published in top journals when there was a distinct lack of originality…all she was doing is repackaging the work Barton had done with Gif chemistry! For instance, in this paper, she has almost the same complex that Barton has described above, except that the ligands have been tweaked a little. Instead of using simple pyridine, she is using PDP (2-({(S)-2-[(S)-1-(pyridin-2-ylmethyl)pyrrolidin-2-yl]pyrrolidin-1-yl}methyl)pyridine). Of course you’re going to improve the selectivity, lifetime, and TOF of the catalyst by making it better defined, but you’re not inventing a new reaction paradigm here. It should be no surprise that the catalyst therefore has an even greater preference for primary or secondary sites over tertiary sites than Barton’s original systems. I would not consider this work Science-worthy by any means, but hey, what do I know?



For those interested, you can read more on these topics in the references below:

  1. “The Selective Functionaliztion of Saturated Hydrocarbons: Gif Chemistry” Barton, D. H. R.; Doller, D. Acc. Chem. Res. 199225, 504
  2. Barton, D. H. R. Tetrahedron 199854, 5805
  3. Barton, D. H. R.; Doller, D. Pure & Appl. Chem. 199163, 1567
  4. Barton, D. H. R.; Boivin, J.; Gastiger, M.; Morzycki, J.; Hay-Motherwell, R. S.; Motherwell, W. B.; Ozbalik, N.; Schwartzentruber, K. M. J. Chem. Soc. Perkin Trans. I 1986, 947
  5. Barton, D. H. R.; Chabot, B. M. Tetrahedron 199753, 487

April 26, 2016

Classics in Organic Chemistry, Part III

Filed under: Classics in Organic Chemistry — sankirnam @ 1:59 pm

The next paper in this series is by Prof. Andrew Myers. I followed his work closely during my PhD out of sheer interest; Myers’ research, while focused on total synthesis, is very broad, and he and his coworkers have had many important discoveries and achievements over the years. Off the top of my head, some of the major ones include his work on the tunicamycin and dynemycin classes of antibiotics, which also led to important discoveries regarding a class of cyclizations now known as the Myers-Saito reaction (which is a variant of the Bergman cyclization). Andy Myers also published interesting work on the use of pseudoephedrine as a chiral auxiliary in organic synthesis, and the use of silacyclobutane enolates in aldol chemistry (these are particularly interesting when you notice the amazing rate enhancements due to the effects of the strain in the 4-membered ring). Myers was also the first to publish a variant of the Heck reaction in which you can use benzoic acids as one of the coupling partners; in essence, decarboxylative palladation. This is now an active area of research and decarboxylative coupling reactions are being studied by several research groups, in particular that of Lucas Gooßen. Andrew Myers’ lab also carried out some very nice, complex synthetic work on the development of new classes of tetracycline antibiotics, which ended up getting spun off into a company, Tetraphase Pharmaceuticals. This is an important area of research, as the number of antibiotic-resistant bacteria is growing every day; without effective antibiotics, it would be very difficult to prevent infections, and a simple open wound can end up being fatal. On a side note, Myers was sued by his former PhD student over the royalties stemming from this work, but I’m not sure what happened to the case.

Some of Andy Myers’ early papers are gems of physical organic chemistry, and this one is particularly interesting. It details the synthesis and characterization of 1,6-didehydro[10]annulene, which had been a challenge for physical organic chemists for over 40 years. The parent compound C10H10 (or [10]annulene) should be aromatic as per Huckel’s rule, but it is not due to angular and steric strain. 1,6-didehydro[10]annulene is also a 10π system, but the geometry is planar and so the compound should display aromaticity.


The synthesis of the precursor for 1 is not trivial, but it uses some very interesting reactions. It is mentioned that the final ring closure could not be accomplished with standard methods involving metal acetylides, and so a variant of the Takai olefination had to be employed. The synthesis also involves a Sonogashira coupling and “Wittig reaction of [a] ylide with (trimethylsilyl)propionaldehyde”; this type of Wittig reaction is better known as a Peterson olefination. The late-stage oxidation of an alcohol to an aldehyde is done with the Dess-Martin periodinane, and the final cyclization, as mentioned above, is a variant of the Takai Olefination carried out with chromium doped with a small amount of nickel, conditions reminiscent of the Nozaki-Hiyama-Kishi reaction. What’s interesting is the final statement in the paragraph describing the synthesis: “Due to the extreme sensitivity of 6 [the precursor to 1] toward adventitious decomposition when neat, this product was typically handled in solution in the presence of a free radical inhibitor”. Since this compound (6) was isolated by flash column chromatography, I’m guessing that the column was probably done on a small scale with deuterated solvents (!), since the characterization (coming up) was done by NMR.

1,6-didehydro[10]annulene (1) was generated in an NMR tube in CD2Cl2/THF-d8 solution at -90 ℃, using triflic anhydride and triethylamine. At temperatures above -75 ℃, 1 slowly cyclized to naphthalene, and deuterium incorporation was observed at the indicated carbon-centered radicals.


The NMR spectra (13C (insert) and 1H) are shown below.


The downfield shifts of the signals in both spectra is evidence for an aromatic species, due to a diamagnetic ring current. The 13C spectrum is suspiciously clean, however; if stoichiometric triflic anhydride was used to generate 1, then the 13C peaks for the CF3 group should appear in that range, as reported here. Yet the 13C spectrum in the paper (above) does not have those signals! Odd indeed…

In any case, Myers and Finney were able to measure the kinetic parameters for the cyclization by NMR. In spite of a fairly high activation energy of 16 kcal/mol, the cycloaromatization to naphthalene is fairly quick (25 min at -51 ℃). The quantification of these parameters is important due to this same type of cycloaromatization mechanism being operative in the enediyne class of antibiotics.

In any case, this is a very nice piece of work in pure physical organic chemistry. A lot of work in physical organic chemistry, including what I did for my PhD, concerns the isolation or characterization of unstable species or reaction intermediates, and this falls squarely in that category.

April 13, 2016

Classics in Organic Chemistry, Part II

Filed under: Classics in Organic Chemistry — sankirnam @ 4:04 pm

The next post in this series is about a reaction known as the “Shi Epoxidation”. This was first reported in 1997 by Prof. Yian Shi at Colorado State University, and has since been refined many times and is now an important component of the synthetic chemist’s toolkit. As mentioned in the paper, this method complements the other asymmetric epoxidation methods in the literature nicely. The Sharpless AE (asymmetric epoxidation), which was one of the first truly robust and reproducible asymmetric synthetic methods to be reported, works best with allylic alcohols, and while there are several ways to asymmetrically epoxidize cis-olefins, trans-olefins remained a major challenge until the development of the Shi epoxidation.

When broken down into its constituent conceptual components, this reaction is very simple to understand.shi_epoxidation_1The terminal oxidant is Oxone, a triple salt containing potassium peroxysulfate (KHSO5), and the species 1 is the catalyst that actually does the epoxidation. When mixed with Oxone, the ketone functionality in 1 is converted to a dioxirane, which is the species that does the actual epoxidation. And since 1 is chiral, it will also do a facially selective epoxidation, in essence, an asymmetric epoxidation!shi_epoxidation_2Oxidation with dioxiranes is well-established in the chemical literature. DMDO (dimethyldioxirane) is readily generated from mixtures of acetone and Oxone, and the chemistry of this was explored by Prof. Waldemar Adam. The breakthrough here is that instead of using a simple symmetric ketone like acetone and making DMDO in situ, one can use a chiral ketone and make a chiral dioxirane. The nice thing about the ketone 1 is that it can be made relatively easily and is derived from D-fructose (which is inexpensive and readily available) by ketalization (acetone, HClO4, 0 °C, 53%) and oxidation (PCC, rt, 93%). The enantiomer is also accessible from L-sorbose, although that requires more synthetic steps.shi_epoxidation_3So that’s the broad picture of this reaction, and one can readily see why this gained popularity. It is an asymmetric synthetic method that complements others in the literature, and the chiral ketone catalyst can be readily prepared from inexpensive starting materials. In fact, it is commercially available. This is also one of the early instances of organocatalysis, and it is unfortunate that Shi did not use the term in any of his early papers – he could have gotten credit as one of the pioneers of this field of chemistry. Shi only started using the term “organocatalytic” in his papers much later, after the field of organocatalysis had been kickstarted by MacMillan, Barbas, and List.

One of the drawbacks with the Shi epoxidation is that it does not work very well with cis-olefins, but that is why this is complementary to other methods – this works very well with trans-olefins, and there are other methods that work just fine for cis-olefins. There are more details and nuances that can be discussed here as well. The first is that in the initial publication, the epoxidation is not catalytic with respect to chiral ketone 1. Shi had to use 3 equivalents of the ketone, as he and his coworkers observed that it decomposed very rapidly under the reaction conditions (pH 7-8). Those were initially chosen to minimize the background reaction (oxidation of the olefin by Oxone, giving a racemic product). It was also proposed that the ketone catalyst 1 was decomposing under the oxidative conditions through a Baeyer-Villiger reaction. It was then found that increasing the pH to 10.5 by using a K2CO3 buffer allowed the ketone catalyst to become longer-lived, thus enabling a catalytic process by slowing down the Baeyer-Villiger oxidation and improving the nucleophilicity of Oxone in the reaction medium. The implication is that the pH needs to be carefully controlled during this reaction, necessitating the use of syringe pumps to slowly add buffer or base in order to maintain the pH. Shi has also done a lot more work in this area, trying to improve the lifetime, scope, and generality of the reaction, as well as trying to asymmetrically epoxidize trisubstituted olefins, which is still a long-standing challenge.

Further information can be found in the links above, or in the references below:

  1. Shi Epoxidation – Organic Chemistry Portal
  2. Shi epoxidation – Wikipedia
  3. Oxidations with Dioxirane
  4. Murray, R. W.; Singh, M. Org. Synth. 199774, 91 (Example of a procedure for doing epoxidation with DMDO)
  5. Adam, W.; Curci, R.; Edwards, J. O. Acc. Chem. Res. 198922, 205 (Review on dioxiranes)
  6. Murray, R. W. Chem. Rev. 198989, 1187 (Review on dioxiranes)
  7. Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.; Shi, Y. J. Am. Chem. Soc. 1997119, 11224 (First full article by Shi)
  8. Wong, O. A.; Shi, Y. Chem. Rev. 2008108, 3958 (Review on organocatalytic asymmetric epoxidation methods, including an in-depth discussion on the applications of Shi’s method)

April 6, 2016

Classics in Organic Chemistry, Part I

Filed under: Classics in Organic Chemistry — Tags: — sankirnam @ 1:07 pm

I’ve decided to start a new series of posts where I discuss classic old papers from the organic chemistry literature. Of course, my focus will be on Physical Organic Chemistry, but anything that I deem important will be discussed.

I’ve decided to start this series with a paper by Prof. J. C. Martin from 1979. I gave a brief overview of his work earlier; I remember coming across it when I was studying for my qualifying exams and got instantly hooked. The nature of his work is fascinating and unorthodox, and led to developments in “elemento-organic” chemistry; that is, organo-iodine, organo-sulfur, organo-selenium, organo-tellurium, organo-bromine, organo-bismuth, and many other new types of chemistry. These were all developed around a growing understanding of the nature of “hypervalent” bonding. Previously, VSEPR theory invoked the use of s,p, and d orbitals in order to generate trigonal bipyramid and octahedral geometries. However, this was slowly coming under attack, and the “hypervalent” bond, which is the apical-apical bond in trigonal bipyramid and octahedral complexes, came to best be described as a “3-center 4 electron” system stabilized by electronegative ligands. Our knowledge of this type of bonding is still being refined by theoreticians today.

The significance of this manuscript is that it describes the characterization of the first 5-coordinate compound of carbon! This is distinct from the “onium” ions such as CH5+, that are best described as “5-center 8-electron systems”. In this case, you’re actually trying to cram extra electron density onto the central carbon so that it has 5 formal bonds (although one should recall that in the perfect SN2 transition state, the total number of bonds is still 4, as the bond-forming and bond-breaking events are synchronous).


The synthesis of this compound is a few steps from the starting 1,8-dichloroanthraquinone, which is commercially available. Previous studies with similar model compounds had shown they underwent a “bell-clapper” rearrangement; the result being that the central carbon underwent reversible binding with the apical atoms, and the resulting compounds had a fluxional structure with a moderate activation enthalpy (10 kcal/mol) for rearrangement. In this case, the asymmetric structures and the p-quiniodal dicationic structures are ruled out on the basis of 1H-NMR shift assignments.

However, more concrete evidence in favor of this structure is lacking. As Prof. Martin mentions in the communication, they were unable to grow X-ray crystals in order to provide conclusive proof of structure. This is consistent with my experience; growing X-ray crystals of charged substances is incredibly difficult, as these tend to be more sensitive to handle. 13C NMR evidence was also lacking, and was only published much later; the follow-up articles to this communication were only published in 1993! The 13C NMR peak of the central carbon is δ 109.3, which is in the range for an sp2 carbon, but at the same time not shifted quite as dramatically as one would expect for an extremely electron-rich carbon (remember, it now has 10 electrons instead of 8)! Theoretical studies would serve as a very useful complement to this extremely nice experimental work. For instance, it would give a useful handle on the activation energy to desymmetrization, as well as what orbitals are actually involved in bonding. J. C. Martin also published some follow-up electrochemical studies on this compound as further proof of the hypervalent nature of the central carbon atom. Further work in this area is being continued by Prof. Kin-Ya Akiba in Japan; I remember seeing some nice experimental work published by him over the years attempting to isolate different types of “hypervalent” boron and carbon compounds.

In any case, this is a really nice piece of work, and all serious students of organic chemistry should be aware of this. I think that is probably my main motivation for this series of posts – I’ll be writing about papers that all students of organic chemistry should be aware of at any level (whether it is high school, bachelors, masters, PhD, postdoc, or professional). Of course, this will be biased towards what I am aware of and what I feel is important, so bear with me!

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