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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)

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