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.
There 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.