An organometallic coupling reagent is one that's going to couple a carbon group covalently
bonded to a metal center or an organoborane, we'll see with the Suzuki, 2A alkyl halide,
in exchange for the halogen so we're coupling two carbon groups and replacing a halogen,
eliminating a metal species in the process.
So these are our coupling reagents that we're going to cover, organolithium, organomagnesium,
organocuprates, boranes and alkenes with the Heck reaction, so organolithium, Grignard,
Gilman, Suzuki, and what are they, are the scope of the reagent here so this is a big
picture look to start with, what do they couple with, what alkyl halide types and then finally
we're going to look at any interfering functional groups that we might have that will be unstable
with each set of our reagents so there's the big picture look if you want to get those
right away let's go and have a few comments about each individual reagent here, so for
our similar types of reagents, organolithiums and Grignard reagents, are going to be very
similar in how we make the reagent, the scope of making the reagent, so we're gonna see
here that for these, with a alkyl type reagents, we're gonna make primary, secondary and tertiary
with these three reagents, so for an organolithium, for example if we wanted to make an isopropyl
type reagent we'd have lithium directly bonded, covalently bonded, remember they act like
they carbanions, like nucleophiles and so they can approximately be thought of as their
anionic counter partner, but really it is still a covalent bond, but we treat it like
it's a nucleophile of that type okay, so again the metals lithium and we're bonded there,
now if it were a Grignard, say a primary Grignard reagent, we might see ethylmagnesium bromide
would look like this, we might also write it like this, again both are approximating
carbon type nucleophiles with those, so alkyl type reagents, we can also use alkenyl substituted
reagents for these like vinyl groups here, so a vinyllithium or a looks like a propylmagnesium
bromide here or assuming a propylmagnesium bromide that we'd have here.
Again, the carbon group that we're attaching would approximate a nucleophile on an SP2
carbon, so directly to that double bond as we've drawn it here.
Organolithiums and organomagnesiums also bond to aryls and heteroaryls so we might see a
phenyllithium or we might see substituted pyridine here a halo-substituted pyridine
that would react with magnesium in ether to make a Grignard reagent out of this heteroaryl
complex so very wide scope on the reagents for these.
So what can we couple with these reagents?
Well we can couple mainly two primary alkyl for organolithiums, most references I checked
said that secondary and tertiary were very difficult reactions for coupling type reactions,
so these primary halides like we see right here.
Alkenyl just no problem exactly as drawn, these halides will not work and aryls and
heteroaryls will not work with the organolithiums directly.
There are catalysts out there that we're not covering in class that are potential ways
of getting these to work, but we're not going to cover those and then with Grignard reagents,
one of the things that we saw is that primaries, yes because of SN2 type reactivity, we get
elimination reactions with secondary halides and tertiary halides, but after doing some
reading, more active Grignard coupling partners are needed and so to get really good reactions
most of of what I saw was benzylic, primary benzylic or anything with an alpha donating
group or the best coupling partners, so what that means is we might see something like
this is a good coupling partner with a Grignard reaction so this benzyl group, there's a CH2
here to make that a primary carbon, but primary benzylic activating primary allylics react,
but we get a lot of rearrangement partners if we're not symmetrical there, so there's
several things that go on side reactions to make those non-ideal and then electron donating
group, such as this species we put an oxygen here, we can actually couple quite nicely
to this position with this electron donating group next door so we have to really activate
those positions, those primary positions for a good coupling with Grignard reagents, and
then again coupling to alkenyl and heteroaryl and aryl do not work with with these two.
So looking at organocuprates, primary organocuprates are best and so we might see something like
an ethylcuprate here.
Steric hindrance prevents the secondary cuprates from forming and so we won't see those.
We might see alkenyl type cuprates again, so two equivalents of halide reacting or lithium
reagent reacts with copper iodide to make these again, another video discusses that
and then aryl/heteroaryl, no problem with the cuprate reagents, we can make those as
readily as we can with the Grignard and with the organolithium reagents.
With the Suzuki, we make organoboranes and primary boranes from out from terminal alkenes
work just fine so we might see a propylborane here, being a reagent that we can make, secondaries
will not work, tertiaries will not work for alkyl substituents, remember we're here in
the alkyl column here and so those will work only for primary.
Now with alkenyl because of the way the borane adds, we'll see that only trans type boranes
will form for the Suzuki reagent that we see here because we're using a borane addition
to an alkyne to make the alkene.
Different reaction makes aryl coupling reagents for the Suzuki, but we can do those, they
perform just fine and so we'll see those be able to couple aryls to other coupling reagents.
Now the Heck reaction will work best for terminal alkenes and so we'll see those reactions reagents
work very well with the palladium catalyst as drawn, however alkyl and aryl and heteroaryl
will not work very well or will not work with the Heck reaction, as we are learning in class.
Now what can these three reagents couple to the Gilman, the Suzuki and the Heck?
Well the cuprates, remember we said they were of this form, they can couple to primary halides
best and so we'll see halides of this form again, primary carbons for the alkyl type
substituents as we're in the first column here.
However, you will see some examples in our textbook of where secondary halides might
couple, one example in particular and these are reported, but they're generally reported
with higher order mixed cuprates and so the standard Gilman I'm kind of skeptical as the
yield in this reaction, but because they're there we'll go with it as far as, as far as
an exam situation, but I if I were doing this in a real synthesis, I would look for higher
order mixed cuprate as what I would want a reagent instead of a pure Gilman in this situation,
we can alkenyl we couple just fine, alkyl halides of alkenyl variety or the aryl and
heteroaryl variety so no problem there.
With the Suzuki, we will not couple to alkyl halides because of competing elimination reactions
that will occur with beta hydrogens in these alkyl substituents and so we don't see this
with the Suzuki and the same thing will happen for Heck so we will want to see those primary,
secondary or tertiary alkyls reacting with these two reagents in basic conditions so
what do we see?
We see great coupling to alkenyl and we actually maintain the stereochemistry, whatever our
for all of these, if their stereochemistry whatever stereochemistry I have with my alkene
I when I couple I retain that stereochemistry in the product noting that the Suzuki reagent
itself, if it's alkenyl will be trans, but when we couple it will maintain the stereochemistry
about that position and again heteroaryl and aryl work just fine for the Suzuki and the
Heck as well and so we see the scope of our reaction, what can we couple together.
What functional groups will interfere with these reagents?
Well, let's look at a couple of rows that I've organized into rows here of interfering
groups and so the first row I'll call row one, acidic groups, so things with pKa is
less than 40, this is where carbon acids tend to hang out, sp2's, sp3's, are going to be
the pKa's greater than 40, so their conjugate bases are ridiculously strong and so these
groups that I've listed here are protic groups that have labile hydrogen's that can pop off
and interact with our reagents, our organometallic reagents that are sensitive to acidic conditions.
In row 2, we see here that we've got some carbonyls, we've got some CN triple bonds,
some O double bonds an so forth so these pi bond acceptors with electronegative elements,
these electrophilic addition groups can undergo addition reactions, such as this Grignard
reaction that we see here where the nucleophile adds to the carbonyl, instead of coupling
to another reagent so in row two, we've got these groups that are addition partners with
some of these organometallic reagents, so row one and row two, let's see what we're
stable to and what we're not stable to.
Organolithium and organomagnesium reagents, the Grignard reagents, they are very polar,
they have a very large degree of negative charge buildup, so they're going to be unstable
to acidic groups and addition groups for lithium's and organomagnesium, so we don't want to have
any of those groups we saw in row one and row two present in the presence of alkyl halides
when we're trying to couple with organolithium and organomagnesium.
For cuprates, they are remarkably stable to both sets of groups, they're stable to the
acidic groups because the copper to carbon bond is a very polar and they're stable to
the addition groups because the mechanistic pathway prefers this the coupling to the halides,
the substitution at the halide carbons and so we're stable to both row one and row two.
Organoboranes and with the Suzuki and the Heck, well we're in the presence of base in
both of these so they're going to have moderate instability to the acidic functional groups,
they could be deprotonated and potentially affect the reaction and slow the catalytic
cycle due to those charge build-ups that we would have from that proton transfer so for
the Suzuki and the Heck we don't want to have those acidic groups present, but we are stable
to the addition groups for the Suzuki and the Heck in the presence of our alkyl halides
which we are coupling to.
If the alkyl halides are there, all bets are off for some of these, but if they are present
will react with those first and couple before we react with the other groups that are present.
Okay so let's look at a few examples of what might happen if there's a ketone present,
for example and we have a Grignard reagent we are going to add to one, two, three, four,
five carbons and then plus one, two from the Grignard, leaving that bromide still in place,
we're going to add to the carbonyl and then that could actually potentially do an intramolecular
SN2, we've created a good nucleophile, we've got a primary carbon, that's SN2 territory
and we end up with a one, two, three, four, five membered cylic either, a furan here,
but tetrahydrofuran derivative, but at that second at that first carbon we have we've
got an ethyl and we've got a methyl coming off in that position and so we're unstable
to that ketone functional group, but if we have a Suzuki we are stable and so we're gonna
couple our ethyl group on in place of the bromine, so one carbon, two carbon then one,
two, three, four, five, one carbon, two carbon, one, two, three, four and five, leaving that
ketone alone and coupling on our new two carbons here in place of the bromine.
For acidic groups which are present, organolithium might react with a thiol to cause a deprotonation
to occur and so we might end up with an S minus isoelectronic with an O minus , that
halide still there, the proton transfer reactions fast, again we would get an intramolecular
SN2, great nucleophile, great leaving group on a primary carbon, one, two, three, four,
five, same thing, but now we've got a sulfur in place with a methyl group on the end here,
bromine's kicked off, but if we do this with a Gilman reagent, we are stable to the acidic
functional group and we end up coupling on our vinyl group to the one, two, three, four,
five carbons, leaving the acidic functional group in place.