Leah here from leah4sci.com and in this video we're going to look at the reaction mechanism
for a cyclic acetal protecting group.
In video 1 of this series, we looked at how a diol like ethylene glycol can be used as
a carbonyl protecting group.
And in video 2 we looked at the detailed mechanism for an acetal formation.
In this video we're going to look at the detailed mechanism performing this cyclic acetal protecting
group.
I'm going to be moving fast assuming that you already understand the basics of mechanism.
If you don't go back to the beginning of this series which you can find on the link below
or visiting my website leah4sci.com/acetal.
Why do we need an acetal protecting group?
Say you have a molecule with both a carbonyl like an aldehyde or ketone and something else
like an ester and you wanna reduce the molecule so that the carbonyl remains intact.
But the ester is turned in into an alcohol which then you can turn into whatever else.
The problem is a reducing agent that would attack the ester for example lithium aluminum
hydride will also attack the carbonyl so that instead of a ketone and an alcohol, your product
would be an alcohol for the reduced` ester but another alcohol for the reduced ketone.
If you specifically want this product, what you have to do is first turn that ketone into
something else.
Give it a gas mask protect it from the lithium aluminum hydride, then you can reduce your
ester, then you can remove the gas mask.
If you react this with something like ethylene glycol which is a diol that can form an acetal
with an aldehyde or ketone but will not react with the ester, you're going to get a protected
molecule and look how happy it is, but the ester is still intact.
Then you can react this with lithium aluminum hydride`which reduces just the ester to an
alcohol because acetals are not reactive in base.
And finally you remove the gas mask, you remove that acetal to help protecting group by reacting
this in an acidic solution.
Since acetal formation is a reversible reaction in acidic conditions, the acid catalyst will
reverse reaction, remove the protecting group and reform the ketone.
One final note before we go into the mechanism, we're calling this an acetal protecting group,
technically this is a ketal because the carbonyl was a ketone but as we said in the first video
acetal sometimes refers to both.
As we're working through the mechanism, I want you to think about what's going to happen
next.
Try to see if you can predict the next step as a test to see how well you understand this
mechanism.
We’ll use simple molecules for the purpose of this reaction but remember it can get complex,
you can have rings and your diol can be bigger than something as simple as ethylene glycol.
Your acid catalyst will typically come from something like HCl, toluenesulfonic acid but
we'll just show it as an H+ in solution.
Pay attention to the colors of the electrons so that you'll understand what is happening,
why it's happening and where the electrons and atoms are going.
As we showed in the last video this reaction starts out by activating the carbonyl.
This happens when the lone pair of electrons on the carbonyl oxygen reaches for a proton
in solution.
The activated carbonyl now has an oxygen with a hydrogen for a total of 3 bonds, 1 lone
pair, and a formal charge of plus 1.
Oxygen is positive but it pulls on the electron density between itself and carbon making that
carbon very partially positive and susceptible to attack.
In this case the attack will come from one of the alcohol on the diol, in this case ethylene
glycol.
When Oxygen attacks, carbon would have 5 bonds which can't happen so we collapse the pi bond
between carbon and oxygen onto the Oxygen giving us an intermediate that now has the
purple oxygen with just one bond, one hydrogen, two lone pairs, and no charge and the incoming
oxygen now has three bonds, one lone pair, and a positive charge.
What's most positive?
The partial positive hydrogen.
What's most negative?
an Oxygen in solution.
We can show 2 separate steps where another ethylene glycol from solution grabs the proton
or we can show an internal proton transfer where the OH grabs that Hydrogen.
Some professors will allow it, some will not, so make sure you find out before you start
showing this on your exam.
This will collapse the hydrogen electrons onto the Oxygen giving it back its lone pair
and making it neutral again.
Our intermediate now has a purple oxygen with 2 hydrogen atoms, one from the activation,
one from the ethylene glycol, with one lone pair and a positive charge.
And this oxygen now has just 2 lone pairs and no charge.
Water is a good leaving group but it won't leave by itself, we have to kick it out by
showing the greedy oxygen taking its lone electron pair, collapsing down attacking the
carbon.
This would form too many bonds on carbon which is how we kick out that water molecule.
The oxygen atom now has just one lone pair because the second lone pair of electrons
are now sitting as pi bond between itself and carbon giving oxygen a formal charge of
plus 1.
We also have the water molecule floating around somewhere in solution.
The next step gets a little tricky so what I would recommend is if you know the molecule's
going to twist in a certain way, don't try to envision it, redraw the molecules so that
you can very easily see the next step.
We know that the next step is going to be an alcohol attacking the activated carbonyl
carbon, but because this is a diol that alcohol would be the second oxygen on the molecule
that is already attached.
So instead` of trying to figure out where this thing is going, I like to redraw.
I know it takes extra time but the sanity and clarity that comes from visualizing the
next step is going to save you so much down the line.
And this redraw is not a mechanism so it's not a forward or reverse arrow, it's just
a sanity step and we want to draw it exactly how we expect this product to be.
We know that ultimately we have two oxygens bound like this so let's show the second oxygen
right here.
And then as we see it, the oxygen on the left had a double bond, one lone pair, and two
carbons bound to the second oxygen.
Again, it's the same molecule.
We have oxygen with a lone pair and a positive charge attached to two carbon atoms, two carbon
atoms with another alcohol on carbon 2.
This step makes it too easy to visualize that the oxygen with the two lone pairs that is
still flailing around is ultimately going to attack that carbonyl carbon and break the
pi bond between carbon and oxygen onto the left oxygen.
No crazy imagination required to figure out the next step just redraw it exactly as you
see it.
Oxygen on the left now has just one bond to carbon.
The initial green lone pair and now the second green lone pair that came from the pi-electrons
collapsing.
We have the two carbon atoms bound to that second oxygen that just attacked which we
should with blue electrons.
So we have a blue bond between carbon and oxygen, a blue lone pair but we still have
that hydrogen atom.
This means oxygen on the right has one lone pair, three bonds, and a formal charge of
plus one.
We're already starting to see that gas mask, it's starting to look like the protecting
group but we have one final step to remove that extra proton.
You can show anything basic in solution.
I like to show another diol molecule because if this is the solvent it's most abundant
in solution.
Some professors will show the conjugate base from your acid catalyst or the water molecule
that came off earlier.
Whatever base you use, use this lone pair of electrons to grab that hydrogen and give
the electrons back to oxygen.
This gives us a final product where the oxygen on the right now has that second lone pair
of electrons from the hydrogen bond breaking on onto the oxygen.
We also have a protonated molecule in solution which is the regeneration of our acid catalyst.
If we had our acid catalyst as an H+ you can show it just as an H+ floating around, or
you can justify the way we draw the final product by having shown another ethylene glycol
in solution grabbing that hydrogen and the carbonyl oxygen instead of grabbing a proton
out of solution which typically doesn't exist by itself showing that oxygen grabbing a proton
off a molecule that look like this which is why we regenerated that acid catalyst.
Now that you have this mechanism, make sure to try the acetal practice quiz.
First give this video a thumbs up then see the link in the description or visit my website
leah4sci.com/acetal to find the quiz and the entire acetal video series.
Again, that's leah4sci.com/acetal.