Say you're asked to synthesize this monstrosity from 2-butanone. Or this molecule from propanal.
There are many ways to approach it but in this leah4sci video
we'll focus on grignard reactions with a few key shortcuts to add to your retrosynthesis arsenal.
Let's take a look at what happens when a grignard reacts with formaldehyde,
an aldehyde, a ketone, or a carboxylic acid derivative like an ester. Starting
with formaldehyde, the mechanism between a grignard and a carbonyl is pretty similar
even if the molecule is different as I teach on my website linked below at leah4sci.com/Grignard.
We have a partially positive carbonyl carbon double bound to a partially negative oxygen. The
R-group on grignard acts as a carbanion. And we'll use the electrons that bind carbon to magnesium
to attack the carbonyl carbon. We now have too many bonds on carbon and so the pi bond gets
kicked up onto the oxygen. As a result, the oxygen now has its two original lone pairs along with the
new lone pairs from the collapsed pi bond giving it a negative charge and the former carbonyl
carbon now has a new bond to that grignard R-group in this case a CH3. To get rid of that negative
oxygen we react with a weak acid which we can show as H3O+ so that oxygen reaches for the proton,
the bond between hydrogen and oxygen collapses back onto the oxygen
for a neutral alcohol where the carbonyl used to be. And this is how it looks in line structure.
An aldehyde follows the same mechanism where the grignard carbon attacks the carbonyl
kicking up the pi electrons to give me an O minus and a new bond to the grignard carbon.
Add an acid to protonate and we get an alcohol for the final product.
A ketone will follow the same mechanism where the grignard attacks the carbonyl carbon kicking
up the pi electrons to give me a negative oxygen and a new bond to the grignard carbon
followed by protonation to give me a neutral alcohol. So far so good! Do you notice how
the mechanisms are exactly the same? This changes slightly when we have a carboxylic acid derivative
such as this ester. The reaction starts out the same way where the grignard carbon will attack the
carbonyl breaking the pi bond and collapsing those electrons onto oxygen. This gives me an oxygen
with three lone pairs and a negative charge and a new bond to the grignard's R-group. The difference
here is that unlike the previous reactions where all carbon had was a bond to carbon or hydrogen,
here we have a bond to Oxygen which is a potential leaving group. And the negative oxygen takes full
advantage of that by taking the lone pair collapsing back down to reform the carbonyl
kicking out that OR group. Our resulting molecule has the initial carbon chain with a double bond
to oxygen and the incoming grignard R-group. Off in solution we have an OR minus this time OCH3.
But remember, if we're in a grignard solution we have more molecules of grignard floating around.
And what happens when you have a grignard in the presence of a ketone?
That grignard will attack! It doesn't care that you started with an ester,
all it knows is there's a reactive ketone and it wants to attack. Once again the pi bond collapses
upward to give us an O minus. We have the initial methyl group from the first grignard attack
and a second methyl group from the subsequent grignard attack. And now that Oxygen can't come
back down because there's nothing else to kick out so it'll wait for us to add acid in the next step,
grab a proton and give us a neutral alcohol product. Let's look at the products again
where the formaldehyde gave us a primary alcohol, the aldehyde gave us a secondary alcohol,
the ketone gave us a tertiary alcohol, and the carboxylic acid derivative ester also gave us
a tertiary alcohol. The difference between the Ketone and the Ester is that the ketone only had
one incoming R-group, the ester has two incoming R-groups which looks the same here but if I were
to change the ketone molecule, notice that we can have 3 different R-groups on the tertiary alcohol.
But if I change the ester R-group we have one that can be different and two that are the same
because the same grignard attacked. Once you recognize this, you can very easily understand
the shortcut as follows. Going back to the initial problem, here's the pattern you wanna look for.
Identify the carbon that holds the alcohol, and look for the carbon chain
that we started with and recognize that it used to be a carbonyl. Aldehyde, Ketone, Ester,
doesn't matter, this depends on what we started with. Next, look for the carbons that were added.
In this case, if we had a ketone, numbered as 1, 2, 3, 4, where carbon 2 holds the carbonyl,
that would be here, 1,2,3,4 showing me that the new bond is between this R-group and the Ketone.
And where you broke that bond is where you want to add MgX to give us our grignard. So what did this
reaction look like? For this molecule we simply reacted with a grignard sitting on a benzene ring
for example MgCl. Same thing for the second molecule. Identify carbon holding the Oxygen,
give that a pi bond to form a carbonyl. Identify which carbons were on the carbonyl so that you
know what came in as a grignard. Here we have 1,2,3 where carbon 1 is the carbonyl,
the molecule's symmetrical so I can go to either side, break the molecule between the carbonyl
and the incoming R-group, in this case the ethyl telling me that I reacted with an ethyl grignard.
Are you with me so far? If yes, make sure you give this video a thumbs up and subscribe to my channel
then hit that bell notification icon so you don't miss out on any new videos
and let's take the shortcut to the next level. Let me show you how to identify
exactly what happened. If I have a primary alcohol and that's my carbonyl breaking off the grignard,
it had to come from a formaldehyde because I have no other carbons on this chain. For my secondary
alcohol, I had to start with an aldehyde because I only have one R-group remaining.
For the tertiary Asymmetrical alcohol. I have my carbonyl and any one of these
R-groups could have come from a grignard but only one telling me that it came from a ketone
and a tertiary symmetrical alcohol where I have at least 2 of the same group tells me that I could
have come from a ketone where one of the R-groups attacked, or I could have come from a carboxylic
acid derivative like an ester where both of these came in with a back to back grignard attack.
For even more on grignard reactions, mechanisms, and the reaction cheat sheet visit my website
linked below or go to leah4sci.com/grignard. Again, that’s leah4sci.com/grignard