hey it's professor Dave let's talk about nucleophilic aromatic substitution so
we've gone through a number of tutorials regarding electrophilic aromatic
substitution just to quickly review let's say we've got benzene we're gonna
react with some molecule that has an electrophilic portion right so we're
gonna get that electrophile there that's gonna leave a carbocation on there and
this is gonna have a few resonance structures for the intermediates so we
can get this one or that will leave the positive charge there or we can get this
one which will leave the positive charge here so that is the slow step right the
creation of that arenium ion intermediate is not very energetically
favorable and then we the fast step will be when some base usually the other
portion of that initial molecule will grab a proton and we're going to restore
aromaticity so we've got our the electrophilic portion on there so we
went through a bunch of different reactions we saw all of our
friedel-crafts chemistry we saw how two halogenate all these different things
that utilize this chemistry electrophilic aromatic substitution but
now we want to learn something else let's say we do some EAS reaction let's
say we throw a halogen on there so imagine we've got a halogen on there we
can now do another completely different type of reaction called nucleophilic
aromatic substitution and as you might guess this involves this molecule
reacting with a nucleophile so now a nucleophile is going to attack instead
of benzene attacking electrophile so this is going to be very similar as
you'd expect a nucleophile is going to attack here and now remember this bond
is polarized because of the because of the halogen so that's the most partially
positive site on the molecule and now we've got again some intermediates here
but now notice that each of these resonance structures has a negative
charge on there instead of a positive charge like with EAS
so again we've got some resonance so this can move over here right we can get
this negative charge down there and that will pop this pi bond up there to give
us this one and then again we can move this right here
which will pop this bond over there put the negative charge over there so these
are the intermediates and then so as you would expect again that is the slow step
the generation of this intermediate is the energetically unfavorable step and
then this can go ahead and kick this off we're gonna kick off the leaving group
so that is gonna leave some other nucleophile so this is a group that
would have been difficult to get on to a benzene ring initially because right
we're used to putting electrophiles on benzene so now we're figuring out a way
to put nucleophiles on there as well but we were able to do it because of this
halogen there so this is a type of nucleophilic substitution but it's quite
a bit different than any other type of nucleophilic substitution that we've
seen so remember if we go back we know about SN2
but with SN2 as well as SN1 we're dealing with with sp3 centers so for SN2
we've got the nucleophile coming in and the leaving group leaving all at the
same time that's a concerted reaction then with SN1 we saw a leaving group
leave and then we had an intermediate and then in a separate step the
nucleophile attacks well now we have a different situation where a nucleophile
is attacking an sp2 center and now it is the reverse situation where we have a
nucleophile attacking then we have an intermediate and then in a second step
the leaving group leaves so that leaves us this here and so this is a completely
new type of nucleophilic substitution which is abbreviated this way SNAr so
the thing that it has in common without luck with electrophilic substitution is
that the first step is the slow step right we've got a stable molecule and
then we're generating a relatively unstable intermediate so we need to
understand some ways that we can promote this first reaction we want to if we
want to do this reaction we want to make it a little more energetically favorable
and the way we do that is by putting electron withdrawing groups on the on
the benzene ring so let's say we're trying to do some nucleophilic aromatic
substitution and on this molecule there was a nitro group so we know that nitro
groups are electron withdrawing by resonance because of the the positive
charge on that nitrogen so let's say this is a
this is our intermediate what we want to notice that's interesting about the
resonance here is that we can do this we can push this over here and then we can
push this all the way up to that oxygen there so that's going to give us this
intermediate so we know that anytime we we distribute electron density along a
greater portion of the molecule that's a stabilizing effect and so hats why
having electron withdrawing groups on on the molecule is going to stabilize that
intermediate just the same way that electron donating groups were able to
stabilize the intermediate for for electrophilic aromatic substitution
because we had a positively charged intermediate so more electron density
was stabilizing that here we've got a negatively charged intermediate so
anything that withdraws some of that negative charge into some substituent is
going to stabilize that intermediate so typically when we are going to be doing
nucleophilic aromatic substitution you're gonna see nitro groups and some
other electron withdrawing groups on those molecules in order to get them to
go and we know that this is true because if we put several nitro groups if we sit
say three nitro groups on there we can actually isolate that intermediate it's
called a meisenheimer adduct so we're able to crystallize that and isolate it
and so that is very firm empirical evidence of this mechanism so now that
we understand the basics about an about the mechanism for nucleophilic aromatic
substitution let's go ahead and take a look at some examples so in order to do
nucleophilic aromatic substitution we know that we need to have a leaving
group on the substrate and so we want to notice something that's a little bit
interesting about leaving group trend usually when we're looking at other
other situations where we see leaving groups we're looking at the halide ions
usually it's the iodo group is the best leaving group and then it gets worse as
they get smaller because they're less stable but for this it's actually
different we see that the fluoro group is the best leaving group in this
context and the reason is that the nucleophile has to attack the carbon
where the leaving group is and so the more polarized that bond is the more the
more readily it will attack that carbon because that's the slow step
so anything that maximizes the energetic favorability of the nucleophile
attacking that carbon is going to help the reaction go and so because fluorine
is the most electronegative that's the most polarized carbon halogen bond and
so fluorine is actually going to be the best to get these to go so here's an
example we see a floral group on their para to this Nitro group and then we're
gonna do nucleophilic aromatic substitution with this amine so we're
gonna go ahead and pop the amine on there and that's how we get that product
so this is a this is a classic example we can get amines on there in this way
and so that's pretty common example now let's talk about one other aspect of
regiochemistry because what we've looked at so far is we've had the we've
had the electron withdrawing group that's helping the reaction go in a
situation where it's para to the leaving group and this will also work just as
well if it's ortho so ortho or para that works well for the resonance but what if
we have a situation where the leaving group and the electron withdrawing group
like a nitro group are meta to one another so this is a little bit
different because let's say we have a nucleophile that's trying to attack now
it's not so clear where it's going to go it's true that this is the most
partially positive carbon right that that is what we might expect for in
terms of where the nucleophile is going to go but the resonance won't work out
if it attacks there the resonance can't get over to get pushed up into this
nitro group which is the feature that stabilizes the intermediate in the first
place so actually it's true that that in often cases nothing is going to happen
it's just not going to work out but there are situations where it will
attack and it will attack some other location so let's say it attacks here
right and we can that way we can push these pi electrons all the way up into
that nitro group so remember if we attack there right that the polarization
of that bond is a factor but this is a bigger factor where we want to be able
to push the electrons by resonance all the way up to the nitro group so we have
this intermediate here now this is actually quite basic so we could
protonate from solvent it could grab a proton off you know whatever solvent is
in there so let's go ahead and protonate that
we'll push this all the way up here and we'll protonate there and then the the
conjugate base of whatever whatever offer that proton can go ahead and
eliminate HCl so let's grab that and let's put that there and let's kick off
the chlorine okay so all we've done is we had the nucleophile attack but we had
the nucleophile attack here in a different position one away from the
chlorine and so then we just protonated and then did our elimination so here is
our product but this is called the cine product so we just did seen a
substitution and we call it that because the nucleophile the incoming nucleophile
is one away right we say it's one away from where the where the leaving group
initially was so we had the we had the leaving group there but the nucleophile
came in there so that's the cine product okay now we can also see something else
we can see the nucleophile attacking here and the the the the mechanism is
essentially the same sort won't draw it all again but if we do that we get the
tele product so this is tele substitution and it's the tele product
because the the leaving group was here and now the incoming nucleophile is para
with respect to that's on the opposite side of the ring so this is the spatial
orientation or the regiochemistry that produces the tele product or tele substitution
so now we understand a little bit more about the differing
regiochemistry depending on where the electron withdrawing group is with
respect to the leaving group and the sites where the incoming nucleophile
will attack depending on that regiochemistry and so we actually see
cine and tele substitution quite a lot in the literature so a real-life
example from the literature is shown here the authors tried to replace one
of the chloro groups in 2,6-dichloro pyridazine with a dithiane anion but instead
they got a tele substitution product and so we can see that these these
substitutions are pretty common in the literature especially among heterocyclic
compounds
so let's go over one other very important example we can see that
sometimes we can do nucleophilic aromatic substitution even when there is
not a special electron withdrawing group to stabilize the intermediate and that
can be done when we have extremely basic nucleophiles so NH2- we know that's a
super duper strong base it's such a strong base that its conjugate acid
ammonia is a base so super strong base and what we see here is this is going to
go ahead and grab a proton and that'll leave that there and so we've got this
intermediate this is a little bit strange we typically do not see this
kind of a situation we have a formal negative charge on that benzene ring
again that's just because this base is so exceptionally strong and now this is
the this is the rate determining step so this can go ahead and do this pop off
that leading group and this is going to produce something that will seem
extremely strange if you've never seen this before this is called benzyne so
that is a triple bond right there so this is an extremely strained alkyne we
know that alkynes like to be linear those are sp hybridized they want 180
degree bond angles so to be to have to fit into this cyclic structure
it's very strained and this is the rate determining step so for that reason this
returns to the normal leaving group trend that we would expect so the more
stable the halide ion once it's left the more the better the leaving group it was
so this is benzyne again a little bit weird but this is the intermediate that
we're looking at and we can use benzene's to do nucleophilic aromatic
substitution because now we still have some NH2 minus in there can act as a
base can also act as a nucleophile so this can go ahead an attack let's say
this attacks right there and pops this pi bond up onto that carbon we're gonna
get this guy right here it can also attack at the other position so this is
totally symmetrical the benzene has lost any memory of where the leaving group
was right so this is completely symmetrical this can just as well attack
here and pop that pi bond up there so we can also get this and then from here the
we'll just get protonated in solvent and we're gonna get these two products and
be it is true that these are exactly the same molecule but we want to be aware
that we would refer to them slightly differently if we had other substituents
or something on there the type of substitution that's going on and we've
discovered this through isotopic labeling studies so if we labeled this
carbon right here so that even though the chlorine is gone because that's
carbon 14 we would know which carbon it was and we know that if we get if we
have the incoming nucleophile next to that carbon we would call that ortho
substitution and if we have that incoming nucleophile on the same carbon
we would call that if so substitution so even though we've the benzene has lost
the memory of where the leaving group was isotopic studies have told us this
and so this is important terminology to know the difference when using benzene
between ortho substitution and if so substitution so we're gonna talk a lot
more about benzene later so this is gonna come back this is a very important
intermediate that we're gonna look at some more later but for now hopefully
that will help you understand a little bit about nucleophilic aromatic substitution.
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