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.
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