Grignard Reactions And Synthesis (2)

More Grignard Practice Problems, This Time Incorporating Oxidation

Here’s the summary for today’s post on synthesis incorporating Grignard reagents and oxidants.

Converting an aldehyde into a tertiary alcohol can be performed if we start with a Grignard reaction, oxidize the resulting secondary alcohol, and then perform a second Grignard reaction. As we’ll see, the key to planning these syntheses is thinking backwards.

Table of Contents

1. Solving a Common Synthesis Problem On Exams
2. The Missing Link: Oxidation
3. Working Backwards From the Final Product
4. Summary: Grignard Practice Problems Incorporating Oxidation
5. Notes (Including Bonus Problems)

1. Solving A Common Synthesis Problem On Exams

In the last post we saw how to approach some fairly straightforward synthesis problems using Grignard reagents. We learned how to think backwards from our final products (alcohols) to appropriate precursors for a Grignard reaction (aldehydes, ketones, or esters).

In this post we’ll take it one step further by incorporating a reaction you’ve probably seen before, but not in this context.

For instance: here’s a fairly common type of exam problem using Grignard reagents.

Given the aldehyde shown, how would you build it up to the tertiary alcohol on the right incorporating Grignard reactions in your synthesis?

While you ponder that, one thing should be clear. It can’t be done in one step. After all, we’ve seen that we can convert aldehydes into secondary alcohols via the Grignard reaction, and likewise ketones into tertiary alcohols, but connecting aldehydes to tertiary alcohols requires an intermediate step missing from the scheme below.

Do you see what rung of the ladder is missing?

We need a way to convert a secondary alcohol to a ketone! If we can find a reaction that does this, then we’ll have a chain of 3 reactions that can deliver a tertiary alcohol from an aldehyde.

2. The Missing Link: Oxidation

Let’s look at that secondary alcohol –> ketone transformation more closely. It should seem familiar. Note how we’re breaking C-H and forming C-O on the same carbon (if you’re having trouble seeing this, don’t forget that there’s a “hidden” or
“implied” C-H bond on the carbon bearing OH ).

Anytime we form a C-O bond at the expense of a C-H bond we’re looking at an oxidation reaction.

Now, practically, how do we bring this transformation about? Most textbooks will show the use of the reagent pyridinium chlorochromate (PCC) or, increasingly, Dess-Martin Periodinane or the Swern oxidation. We covered these in a previous article on  oxidation. 

Add this step to our synthesis and now we have a ketone that’s ready to be treated with another Grignard reagent to form the desired tertiary alcohol!

[To the chemistry majors out there – these reagents are truly the tip of the iceberg. The list of reagents that will transform a secondary alcohol to a ketone is staggeringly long].

3. Working Backwards From The Final Product

With this piece of the puzzle completed, let’s now work backwards from our final product (this is called “retrosynthetic analysis” – for some specific examples with Grignard reactions, see the last post again) to come up with a plan for building that tertiary alcohol from our starting aldehyde. Note: this is not the only way to do it. Synthesis has a  “choose your own adventure” aspect to it, a feature students alternately find frustrating and inspiring.

[note that the choice of halides on the Mg is completely arbitrary here. You can pick anything except fluoride (F) and I suppose Astatine, as it’s ridiculously ephemeral]

Let’s put in the exact conditions so that it’s clear what this synthesis would look like in the forward direction. Omitting solvent here, although you can write “ether” or THF below the Grignard reagent if you want to provide more detail.

[Bonus Q: can you come up with at least one other plan for this molecule that involves a Grignard reaction?]

4. Summary: Grignard Practice Problems Incorporating Oxidation

To summarize: we can devise three-step syntheses of most tertiary alcohols from appropriate aldehydes and Grignard reagents by incorporating an intermediate oxidation step. This is a very common type of exam problem. 

In the next post, we’ll move from Grignard reagents to a second important type of organometallic, although not one based on Mg but on copper. These reagents, called Gilman reagents, have very special properties and uses in organic chemistry. Until next time!

Next Post: Gilman Reagents (Organocuprates): How They’re Made

Notes

Note 1. Bonus questions: try doing these problems!

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