Question

How can a Grignard reagent can used to prepare 2-phenyl-2-propanol, 1-phenylethanol, and phenylmethanol?

Answer 1

Before we proceed, here are the structures so we know what we're dealing with:

We should see from all the benzene rings in all three compounds that the Grignard nucleophile is going to be an aryl anion.

One way to determine how to start is to do a retroactive synthesis. Work backwards, in other words. So... let's see.

All of these were attacked via a Grignard nucleophile, meaning that an oxyanion intermediate probably formed. Hence, the first logical backtrack is to that intermediate, and the subsequent removal of the Grignard reagent (e.g. aryl anion).

That implies the step before that involved an attack on a carbonyl carbon. Therefore, we started with either a ketone or an aldehyde on all of these, or perhaps a carboxylic acid.

2-PHENYL-2-PROPANOL

Knowing that we only have to add a proton on the last step, it implies the addition of either water or acid. In this case, adding acid makes it easier to donate the proton since the pKa of hydronium is about `-1.7`, whereas that of the oxyanion is somewhere around `16`.

The large pKa difference is essential to getting substantial protonation.

Then, using our prior knowledge of how carbonyl functional groups have electrophilic carbons due to the higher electronegativity of oxygen (by `~1`), the "reverse" conjugation of `pi` electrons away from the oxygen in this retrosynthesis tells us we had started from acetone.

And of course, we're working with the Grignard reagent in dry ether`""^"*"""`.

1-PHENYLETHANOL

Evidently, the first retrosynthetic step here is the same idea as just mentioned; add acid to protonate a substantial population of the oxyanion intermediates.

Instead of acetone, we started with acetaldehyde, because we should see that there is one less methyl group on this product than on 2-phenyl-2-propanol.

And of course, we're working with the Grignard reagent in dry ether`""^"*"""`.

PHENYLMETHANOL

This third one is a bit of an exception, because I could have suggested using formaldehyde, but it is more dangerous to work with than my proposed alternative, seeing as it is a "known . . . human carcinogen" as of 2011.

The first retrosynthetic step is using lithium aluminum hydride, along with an acid workup as expected, to reduce a carboxylic acid down to an alcohol.

Note that these steps are not both at once, but sequential. Also, if you were to work with this in a lab, do it very carefully and cautiously; it reacts quite violently and is a bi hard to control.

From here, it is standard Grignard reagents plus an acid workup, just as in the two previously-written syntheses above, except we are using carbon dioxide rather than formaldehyde. Not quite as dangerous of an alternative.

And of course, we're working with the Grignard reagent in dry ether`""^"*"""`.

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`""^"*"""` SIDENOTE: The dry ether is so the Grignard reagent doesn't get hydrolyzed and thus deactivated; the anion would have gotten protonated, and there goes your nucleophile...

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CHALLENGE: Can you draw these mechanisms?