Protecting Alcohols from Organometallics - Online Tutor, Practice Problems & Exam Prep

Organometallic compounds, like Grignard reagents, are powerful bases that can react with acidic protons, such as those in alcohols and carboxylic acids, leading to unwanted side reactions. To prevent this, protecting groups, such as t-butyl ethers or silyl ethers, can be employed. These groups shield the alcohol from deprotonation, allowing the Grignard reagent to react with the intended electrophile. Commonly, para-toluenesulfonic acid (TsOH) is used in these protection reactions, facilitating the formation of ethers and ensuring successful nucleophilic substitution without interference from acidic protons.

Use of Protecting Groups

Now that we understand organometallics a little better, hopefully, you're aware of one of the major limitations they have. And that limitation is that they tend to cross-react with acidic hydrogens. So how do you prevent that from happening? Well, let's go ahead and talk about a strategy for that, which is called protecting groups. Organometallics are very powerful bases, so they can react as nucleophiles and attack electrophiles, but they can also act as bases and deprotonate things. They tend to just react with any acidic protons available, and that ruins the reagent. Those acidic protons are usually found in substances like carboxylic acid, which is very acidic, alcohol, which is pretty acidic, and water.

Now, notice this molecule has an alkyl halide on one side and an alcohol on the other. My reagent here is a Grignard reagent, typically drawn as CH3−, indicating a negative charge. Alkyl halides have a partial positive charge, so an SN2 reaction expected. However, we've also got an alcohol on this molecule. With a pKa of 16, that's acidic enough to react with my Grignard. Instead of an SN2, it ends up as an acid-base reaction, resulting in CH4 due to the CH3 gaining an H, while leaving a negative charge on the O. The MgBr⁺ is just a spectator ion associated with O. This scenario is not good because the Grignard can no longer react with the electrophile as intended.

To prevent this, alcohols can be protected. There are strategies used to protect alcohols such as using t-butyl ethers or silyl ethers, both effective ways to protect an alcohol from reaction. When protected, the alcohol won't be deprotonated by the organometallic, being locked up instead in the ether structure. A common acid used for protection is para-toluenesulfonic acid, typically abbreviated as TS-OH or PTSA in literature, a source of H⁺ in the protection reaction. This involves making an ether through the reaction of an acid like H⁺ and a double bond.

I encourage you to try to solve this problem on your own and determine the final product. If you are familiar with protecting groups for alcohol, go ahead and try solving it now. If not, and you need a refresher on protecting groups, I recommend reviewing my previous lessons on the subject to better understand the reaction mechanism.

Provide mechanism and final product of transformation.

All right, guys, so you can see that I have an organometallic here, but I've got an issue. My issue is that this organometallic, if it gets exposed to that alcohol, it's going to react with it, and that's going to be a really bad cross-reaction. It's going to mess up my organometallic. So what can we do? We can use a protecting group. How does a protecting group work? Well, in this case, what I would do is I would take my isobutylene, which is a molecule that looks like this: a double bond on a 4 carbon chain. And what I would do is I would use PTSA, which is a source of H⁺. So what that's going to do is it's going to protonate, and I'm going to wind up getting a carbocation that looks like this. According to this, it would be a Markovnikov addition in case you're familiar with that term. Now that carbocation winds up getting reacted on by the alcohol. The alcohol grabs that carbocation. So what we now get is an alcohol that looks like this, OH, but now it's got a tert-bu

Here’s what students ask on this topic:

What are the common protecting groups used for alcohols in organic chemistry?

In organic chemistry, common protecting groups for alcohols include t-butyl ethers and silyl ethers. T-butyl ethers are formed by reacting the alcohol with isobutylene in the presence of an acid catalyst. Silyl ethers, such as trimethylsilyl (TMS) ethers, are formed by reacting the alcohol with a silyl chloride (e.g., TMSCl) in the presence of a base. These protecting groups prevent the alcohol from reacting with organometallic reagents, allowing the desired reactions to proceed without interference from acidic protons.

Why is it necessary to protect alcohols when using Grignard reagents?

It is necessary to protect alcohols when using Grignard reagents because Grignard reagents are strong bases and nucleophiles. They can deprotonate the acidic hydrogen in alcohols, leading to unwanted side reactions. This deprotonation forms an alkoxide ion and methane, which ruins the Grignard reagent and prevents it from reacting with the intended electrophile. Protecting the alcohol with a group like t-butyl ether or silyl ether prevents this deprotonation, ensuring the Grignard reagent can perform the desired nucleophilic attack.

How does para-toluenesulfonic acid (TsOH) facilitate the protection of alcohols?

Para-toluenesulfonic acid (TsOH) facilitates the protection of alcohols by acting as a strong acid catalyst in the formation of ethers. When used in the protection reaction, TsOH provides H⁺ ions that help in the formation of t-butyl ethers or silyl ethers from alcohols. The acid catalyzes the reaction between the alcohol and the protecting group reagent, such as isobutylene for t-butyl ethers or silyl chloride for silyl ethers, ensuring the alcohol is effectively protected from deprotonation by organometallic reagents.

What is the mechanism of alcohol protection using t-butyl ethers?

The mechanism of alcohol protection using t-butyl ethers involves the reaction of the alcohol with isobutylene in the presence of an acid catalyst like para-toluenesulfonic acid (TsOH). The acid protonates the alcohol, making it a better nucleophile. The alcohol then attacks the double bond of isobutylene, forming a t-butyl ether and water. This t-butyl ether protects the alcohol from deprotonation by organometallic reagents, allowing other reactions to proceed without interference.

What are the advantages of using silyl ethers as protecting groups for alcohols?

Silyl ethers, such as trimethylsilyl (TMS) ethers, offer several advantages as protecting groups for alcohols. They are easy to introduce and remove under mild conditions. Silyl ethers are stable to a wide range of reaction conditions, including strong bases and nucleophiles, making them versatile in multi-step synthesis. Additionally, the removal of silyl ethers can be achieved using fluoride ions, such as from tetrabutylammonium fluoride (TBAF), which selectively cleaves the silyl group without affecting other functional groups.