In this Leah4sci video we'll look at the TMS Alcohol Protecting group including the reaction
and mechanism. Say you’re looking to carry out this chain elongation with an alkyne in
the product. Or this elongation where we also turn the aldehyde into an alcohol. It seems
straightforward enough. For the first reaction, we simply add this alkynide for an SN2 reaction
and here we just add a grignard followed by acid.
Right? not quite! These reagents would work if we didn't have the alcohol present.
The problem is that alcohol is acidic because of the polar covalent bond between
Oxygen and Hydrogen. Oxygen is partially negative and Hydrogen is partially positive.
And therefore in the presence of a strong base like the alkynide or the grignard, the base is
going to attack the hydrogen rather than anything else on the molecule deprotonating the alcohol,
destroying the reagent and making sure that our reaction does not proceed the way we want.
So how do you carry out this reaction? Very simple! If alcohol’s proton is the distraction,
get rid of the proton, make it unreactive, then the base is forced to attack the other portion
of the molecule to give us the reaction we want. As an example, I love browsing instagram. And even
though my phone is always silent, if I see the notification I want to click it! So what do I do?
I just cover my phone. Can't see the notification? Not distracted. And then,
when I want to browse instagram, I uncover my phone, I see the notifications
and I'm good to browse. We said that alcohol is a distraction because the partially negative oxygen
is bound to a partially positive hydrogen and the base will attack the hydrogen. But if we
look at an ether which is very similar, we have the R group bound to a partially negative Oxygen,
but the oxygen doesn't have a hydrogen, it has another R group. And even though the
oxygen is partially negative, this R group is not positive enough to be attacked by a strong base
and therefore not distracting enough to derail a reaction. In fact, haven't we already seen
an ether protecting group when we looked at acetal formation with carbonyl reactions?
In this reaction we're going to create a Silyl ether which instead of R-O-R using carbon, we'll
have an oxygen bound to a silicon atom. Silicon is bigger, it's a more effective protecting group
and it's easily removed with a fluoride ion or an acid. The two reagents to know are TMS
Trimethyl Silyl in this case chloride which looks like this. A silicon atom in the middle, the
trimethyl, 3 methyl groups around it, and chlorine as a leaving group to initiate the reaction.
And so in reactions you'll see it written as TMS-Cl. And the second reagent TBAF or Tetrabutyl
Ammonium Fluoride is a source of Fluoride Ions with a counter cation. This molecule has a
central Nitrogen with four butyl groups giving it a positive charge and a counter anion F- . You'll
also see this written as Bu4 for the butyls, N+ F- . Ready to see it in action? Let's go back
to our grignard reaction and recognize that the first thing we have to do is protect the alcohol.
Forget the grignard for a moment and let's first react it with TMS-Cl. The mechanism isn't clearly
known for this but it's presumed to follow an SN2 Style reaction where the alcohol attacks
the silicon, yes it's tertiary which wouldn't happen with carbon. Silicon is a bigger atom and
it's presumed to happen one step at a time where after this is attacked, chlorine gets kicked out.
This gives us our starting molecule which still has the hydrogen atom with one lone pair and a
positive charge because the other electrons are now bound to the silicon which still has the 3
methyl groups. This reaction takes place in a weak base like Et3N which is going to come in
and grab that proton off of the oxygen giving it back its electrons and making it neutral.
For a molecule that no longer looks like an alcohol because we have this funky ether going on.
Now that there is no proton to distract, we can finally bring in the grignard which will attack
the carbonyl carbon kicking those pi electrons up to the oxygen to give us an O-, that is step 1.
In step 2 we protonate so that O- becomes an OH. It's okay to form the OH here because the grignard
is done. This gives us an OH where the carbonyl used to be and the new bond between the carbonyl
carbon and the incoming grignard carbon atoms. Now what we have to do is remove that protecting
group which is very simple, we bring in our TBAF which is the source of Fluoride Ions, a mechanism
that you very likely don't have to know and simply recognize that fluoride will kick this group out
and reform the alcohol finally giving us the product that we expected from the beginning.
If your professor requires you to know and draw every single molecule, this is what you have
to do. Most professors however, will let you show a simplified version as follows; you have
your starting molecule and you know you need to protect the alcohol. Simply react it with TMS-Cl
this right here is our trimethyl silyl group with a chlorine. Show the oxygen attacking TMS
and kicking out the Cl. In fact you can take it a step further by showing that it reacts in Et3N,
put minus H+ over here to show that the H+ was removed and you can go right to the protected
ether showing Oxygen bound to TMS for the O-TMS group. Now, you're free to carry out
your reactions so bring in your grignard for step 1, and show that step 2 you protonate the O- with
water, the grignard attacks the carbonyl, you kick out those electrons, that O- ultimately
reaches for an H+ which you may or may not have to show, make sure you know what your professor
is looking for to give us the following; the carbonyl oxygen is now a hydroxy group
and we have a new bond to those two incoming grignard carbons. Finally in the last step,
you simply write TBAF to show that we're using the tertbutyl ammonium Fluoride to remove the
TMS to give you your final product with the alcohol reformed and the incoming grignard
exactly where you want it to be with no side reactions. Regardless of which method you follow,
I want you to recognize the pattern here of a 1,2,3 reaction. Step 1 we protect the alcohol,
step 2, we react the rest of the molecule, and step 3, we de-protect to reform the alcohol.
Are you ready to apply this to the other example? If yes, first, make sure you give this video a
thumbs up, subscribe to my channel and hit that bell icon so you don't miss out on any new videos,
then pause this video, give it a try and see if we came up with the same answer.
Is this what you got? For even more on alcohols, from physical properties to
reactions and mechanism, a practice quiz and cheat sheet, see the link below or
visit my website leah4sci.com/Alcohol, again, that's leah4sci.com/alcohol.