musings on music and life

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.

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1 Comment »

  1. […] 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 […]

    Pingback by Classics in Organic Chemistry, Part VIII | musings on music and life — November 17, 2016 @ 3:46 pm


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