Alright let's talk about alkylation of the alpha carbon with enolates being the nucleophile here
and so what alkylation involves is the formation of a new carbon-carbon bond to an alkyl group
okay there are other attacks that we can do like acylation that we'll look at eventually but here
we want to look at alkylation and so the alpha carbon as we identify on our functional groups
with a polar pi bond and no other acidic protons would be right next door to that carbonyl or CN
triple bond whatever happens to be our functional group here we have a tertiary amide with an alpha
carbon so what we're gonna do is we are going to alkylate that alpha carbon with some group
and so if we just put that group on we would be subject to the rules of really an SN2 reaction
where we consider that the nucleophilic enolate that we're going to look at in just a moment is
both a good nucleophile and a strong base so that means that this group would most likely need to be
a primary group whether it's a primary bromide a primary tosylate something that would allow us to
have SN2 be favored over elimination okay and so we're gonna see that those are typically primary
halides there to add on that alkyl group so we've alkylated here but we chose a particular base
LDA lithium diisopropyl amide and so we need to look at why we're using that for this particular
functional group and so when we do alkylations we require an efficient proton transfer because
a lot of bases can act as nucleophiles especially if they're in high concentration even t-butoxide
if it's in high concentration in a solution and so for our more acidic functional groups like
this it can we identify it here it's a beta keto ester, ester is the higher priority the ketone is
in the beta position so beta keto ester has a particularly acidic alpha carbon here because
of the double resonance so we've looked at that already in a separate lesson here and so this is
a pKa less than 14 and what that means is that a base with a basic oxygen like an alkoxide or
hydroxide their conjugate acid has a pKa of about 15.5 to 15.7 for water and so if we're looking at
less than 14 that's at least a hundred to one favors completion of the deprotonation so if
we do this and we add our base and here because we have an ester to prevent transesterification
we want our base to match the ester group if there were no ester we could use hydroxide no
problem like a beta diketone here we want to match up and so when we do that there is an
equilibrium to a certain extent but we greatly favor the formation and again I'm drawing one
form here the alpha carbon on the enolate form it's probably more representative of the true
nature of the solution but we are nucleophilic at the alpha carbon so I'll draw that here and
then we form methanol after the acid-base transfer and so because the pKa here is about 11 or so and
the pKa of our alcohols 15.7 that's a ten to the four is different so you know for ten to the four,
ten thousand to one okay favors the product so we're in great shape for a complete deprotonation
and for hydroxide and and alkoxides yes they're caustic they can they can damage your skin eyes
what not protective equipment is necessary but it's safer to use than LDA which we're gonna look
at next okay so this is a good efficient transfer we can use a milder base okay so this is a milder,
safer base than we're gonna see next here for our less acidic functional groups that
tertiary amide's pKa is about 30 we're gonna need something a little bit stronger a lot a
bit stronger actually and that's our lithium diisopropyl amide that we see here made from
treating diisopropylamine with N-butyl lithium at negative 78 degrees so unless otherwise indicated
we're always gonna react our LDA at negative 78 degrees except when we're looking at thermodynamic
enolates we'll see that in a moment so here our alpha proton there's two of them one of
them will do just like before we'd grab that and create the alpha carbanion or the enolate form
whichever you prefer here and we're gonna get a very efficient transfer of this proton and we're
gonna see that transfer result in the formation of diisopropylamine and our enolate so I could
easily have drawn this instead of the alpha carbon and I could have drawn it as the enolate form is
well okay so either way we're fine here to draw the alpha carbon under the enolate enolate form's
probably more representative because oxygens more electronegative than carbon as we've discussed
previously but here let's point this out about 30 here we're about 35 for LDA so 10 to the 5
difference gives us a very efficient proton transfer so this is almost a hundred percent
completion here of the reaction to settle in on the enolate form okay that's what we need alright
so if we're alkylating an unsymmetrical ketone what we want to see is the formation of either
a kinetic or thermodynamic enolate and so with ketones there are two alpha positions one's here
one's here and there obviously different than one another okay there's a carbon that's a CH3
a carbon that's a CH2 and so when we react these the base we have two different types of enolates
that can form and we need to be able to bias one over the other and so the kinetic enolate
is going to be the less substituted enolate and it's gonna form faster in cold conditions so what
we see again if we're looking at LDA here just to remind us what this looks like we grab the
proton instead of showing the alpha carbanion form I'm going to show the enolate form here
lithium is probably associated here don't have to show that but there it is and we form that enolate
form and diisopropylamine we can abbreviate with DIA they're very efficient transfer again
ketones are a pKa of about 20 remember disopropyl amine is about 35 so at 10 to the 15 difference a
huge advantage to making that enolate so further reactions so this is reaction number one reaction
number two would be to take this enolate and then react it with a primary alkyl group with a leaving
group and we would see the enolate reformed the carbonyl attack the primary halide in an SN2 type
reaction and what have we done we've reformed the carbonyl and we have attached 1-2-3 new carbons to
our alpha carbon so there's our three carbons from the alkyl group here's the alpha carbon that we
see we've alkylated that ketone using the kinetic enolate versus if we take the same ketone and we
carry out the deprotonation in thermodynamic conditions so a little warmer a little warmer
here at zero degrees that's going to favor the more substituted enolate and so when we accomplish
the deprotonation ultimately these two guys these two protons are more likely to be settled
on eventually in the equilibrium because we are in reversible conditions, won't be a hundred percent
excess but it will be in excess so we now have the second alpha carbon as our major player here
in the alkylation so that's step one, step two would then be to turn around and alkylate with our
halide so if we take halide like this so that's 1-2-3-4-5 isopropyl bromide or isopentyl bromide
attack the primary position SN2 style kick off the group and now we've attached this group 1-2-3-4-5
carbons to the more substituted position of the ketone and the other alpha position so there's
the alpha carbon there's the alpha carbon again here so just to follow up with our alkylations
of other functional groups like this amide you know this is a step one we would then follow up
with the alkylation in step two this is just like we saw in the introductory reaction that
enolate reforms the carbonyl and we would attack the primary carbon say of methyl bromide here
to do the alkylation of this tertiary amide and we would add that group on to the alpha
carbon just like we did here so with the ketones. With the ketones though because some of them are
unsymmetrical you have to determine kinetic and thermodynamic conditions with our other
functional groups like amides, esters, and so forth that only have one alpha carbon we
don't have to worry about those conditions and so we would automatically perform this reaction
at negative 78 degrees because that's where we're less likely to catch fire to whatever
it is we're working with LDA or N-butyl lithium so we want to make sure that we're
always using negative 78 unless our goal is the thermodynamic enolate that we see with ketones.