Protecting Groups

Protecting Groups

professor Dave here, let’s talk about
protecting groups so let’s go ahead and revisit
the SN2 reaction, once again let’s say that we have this substrate and we want
to react with methoxide, let’s say we have it in our heads, methoxide that’s going
to be good for SN2 and we have a leaving group right here so let’s say
that we’re going to do this and this is what we wanna get and so that seems all
well and good, that seems like it’s going to work but actually this is
no good, it’s not going to go SN2 and let’s talk about why, because not only is
this a good nucleophile it’s also a very strong base and so the thing is
because we have a hydroxyl group right here this is just acidic enough that a
strong base is actually it’s just gonna do an acid-base reaction, so this
alkoxide, this methoxide is gonna pick up that proton to form methanol, and then we’re gonna have the alkoxy group there, we’ve ruined our nucleophile we’re not gonna
get any SN2, so everything is terrible. but what we’ve
come to understand is there are ways to manipulate our substrate so that we can
do the SN2 that we planned and the way that we can do that is by protecting the
hydroxyl group, so if we protect that alcohol using a TBDMS group, this is a
tert-butyl dimethyl silyl, because this is a tert-butyl right here a dimethyl and then silyl refers to a
silicon atom, this is actually going to work as a protecting group for that
hydroxyl group so it will temporarily shield it from any unwanted acid-base
chemistry. we can do the SN2 we wanted and then deprotect it and get
it back to normal. so let’s take a look at how this mechanism works so let’s take a look at how this mechanism
works so let’s say we have our substrate that we were looking at before and then
here is our this is called TBDMS-Cl right we’ve got our tert-butyl dimethyl
silyl group there and then the chloro group there, ok so what’s going to happen is
the oxygen atom is more labile than the chlorine atom so this is actually
going to be able to displace the chlorine, the oxygen is more electronegative
so it is actually going to be able to attack the silicon atom and displace the
chlorine so now we have this whole TBDMS group on that substrate so
remember this is TBDMS right so we can actually abbreviate that as TBDMS bound
to the oxygen atom and then the rest of the substrate, now here’s what’s very
interesting about putting this protecting group on the hydroxyl.
remember how before whether it was some base or whatever it was we were worried
about an acid-base reaction with the nucleophile and that hydroxyl proton.
well guess what, there is no longer a hydroxyl proton. this oxygen is not
bound to hydrogen anymore it’s bound to a silicon atom so there is no longer a
proton that is acidic enough to react with whatever base or nucleophile we
might be trying to use to do an SN2 reaction so now there’s no worries, let’s
do an SN2 reaction, let’s say KCN whatever it is doesn’t matter, so here we
go we did our SN2 reaction so the SN2 reaction is now complete without any
interference from the hydroxyl group now that we’ve achieved that we do want to
get a hydroxyl group back so remember how we said that oxygen was more labile
than silicon, so the oxygen the oxygen-silicon bond was able to
replace the silicon-chlorine bond, well now this fluoride is more labile
than even the oxygen so a fluoride can come in here attack the silicon, kick that off, then
that’s going to protonate once it gets a proton from solvent somewhere and then
we’re gonna get our hydroxyl back. so all we did was we used TBDMS-Cl to
protect the hydroxyl group, this is now protected, there is no hydroxyl proton
there to participate in any acid-base reaction we used that protected version
of the substrate to do whatever SN2 we wanted, doesn’t matter what it was, we
achieve the SN2, once we did that we deprotect with TBAF this is
tetrabutylammonium fluoride and that’s because the fluoride can then displace
the silicon-oxygen bond, oxyanion gets protonated from solvent and there we go we
have our deprotected alcohol back to normal and with the SN2 that we wanted to
do achieved. now we looked at protecting groups for hydroxyl groups but there’s
there’s protecting groups for pretty much any functional group you can think
of so let’s look at one more let’s look at a protecting group for an aldehyde or
ketone. so let’s say we want to achieve once again this is always about some
kind of transformation we want to achieve but there’s a different
functional group that’s going to mess it up right so let’s say we have this substrate here and we want to specifically reduce this ester we want to reduce
this ester to the primary alcohol we really want to do that for whatever
synthetic pathway we’re doing who cares why but here’s the problem, we’ve got a
ketone right there, there’s no way we’re gonna get lithium aluminum hydride to
selectively reduce the ester and not the ketone, it’s going to reduce whatever it sees
first so we wouldn’t get this product and this reaction is not gonna work but
here’s the thing, what if we could protect that carbonyl, specifically
the ketone? so what we’re gonna do is we can react in acidic conditions with this
1,2-ethanediol, we have this vicinal diol here, now I’m not gonna write
out the whole mechanism explicitly because this has to do with acetal formation, and you can check out my acetal tutorial to see this very
explicit mechanism but let’s just say that that mechanism occurs and when it ends up happening as
we get this acetal here okay and so the reason that this attacks over here
not over there is because this is a little bit more electrophilic at
the time because this carbonyl carbon is receiving extra
electron density from the lone pairs on that oxygen so this is less
electrophilic than here so this ethane diol will explicitly undergo acetal
formation at this site. now the reason to this is useful is because
this carbon still has two carbon-oxygen bonds so we would still consider it
electrophilic but if you look at the vectors, the dipole on this bond, it
has two carbon oxygen bonds in the same direction so that is why a carbonyl
carbon is very electrophilic because it has two carbon-oxygen bonds it has
its electrons being withdrawn away from it by two bonds and in the same
direction but if we do this then it becomes two vectors that are like this
and so they’re not any longer unidirectional, this greatly reduces the
electrophilicity of that carbon it’s a little bit closer to the electrophilicity of say a hydroxyl carbon which is not not
susceptible to nucleophilic attack by hydride or anything else so we have
effectively protected that ketone carbonyl. now we have lithium aluminum
hydride, it’s not going to mess with that because it has become not electrophilic
enough to to be reduced so instead we’re going to reduce right here, we’re gonna
reduce just the ester that we wanted so we see that there is the reduced, we’ve
got that primary alcohol now a little bit of acidic conditions were gonna be
able to deprotect and get back our ketone and so what we’ve done just the way
we did with hydroxyl we knew that we didn’t want any we didn’t want some unwanted chemistry
here so we protected that area and then we went ahead and did the chemistry that
we wanted to do in the first place and then we deprotected this to get back
over here so now we have methods for protection of hydroxyl groups as well as
ketones and aldehydes. thanks for watching guys subscribe to my channel
for more tutorials and as always feel free to email me

36 Replies to “Protecting Groups”

  1. Thankyou so much for your continued content support, I really hope your videos begin to pick up the recognition they so badly deserve. It is so strange how your video uploads almost fit my lecturers exact model of the course.I'll often have a lecture and come back to find that you have uploaded a video covering that days topics! Thankyou for doing what you do, for doing it so well and for doing it consistently!

  2. Such an awesome channel dude, you make it all so simple to digest! And i'm so impressed you do it all in one take! Wish I had this in first year!!

  3. I'm so upset…

    at myself for not finding these videos until now. I'm literally taking my last ochem final next week. This would have been an amazing supplement for the day before classes. Anyways thanks for making these videos professor Dave. I'll certainly be going back here a few times in the future.

  4. Why is the ester carbon less electrophilic? Wouldn't it be more because there are two more electronegative oxygens pulling electron density away from it as opposed to 1?

  5. Sir, can vicinal glycol be used when we want to protect an aldehyde while reducing a C-C double bond?? or should we use another protecting group?

  6. You are amazing,helpful too
    You videos clear my concept. I m just in grade 12 but I can understand level.
    Thank you for your videos

  7. Will the diol favoure the keton the most in generel. Like if you want reduce a ketone in substance but you also have aldehyd you dont want to be reduced. How will procced to this ?

  8. I have a question: can I use chemoselectivity to protect an aldehyde group in presence of a ketone group in the same structure? (Or the other way around)

  9. Thank you dear professor
    Finally I finish my Orgo study I understand more and more now. I feel so happy thank you a lot😁😁😊🙌🙌

  10. Great video! Is HCl a byproduct when TBDMS replaces the acidic proton? If so, why does the methoxide not preferentially react with the HCl?

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