all right let's talk about conjugate addition and alpha beta unsaturated ketones and aldehydes and
a little bit about carboxylic acid derivatives at the end here so situations where that 1,4
conjugate addition is preferred so if we look there are two scenarios we might run into the
first is if we have an anionic nucleophile and so in that case and we add and we're again the
difference between a 1, 2 and a 1,4 product we label the Alpha Beta system 1 to 4 and whether
the nucleophile attacks the 2 position like we talked about in our other lesson or it attacks the
4 position here first determines the outcome the product of the reaction so again we're focusing on
scenarios where the 1,4 addition product is going to be our major product our focus of this lesson
alright so again with an anionic nucleophile what we're gonna see and I'm going to redraw it over
here we're gonna see this attack here occur at the 4 position kick over the PI bond and kick up our
oxygen to a negative charge our PI bond goes up to a negative charge on our carbonyl position what
this does is it creates the backbone here of our 1,4 addition product but we've now got an enolate
okay at this point on the enolate if there's proton available can tautomerize or we can bring
the pH down just enough to neutralize and if we do that we can show this as a hydronium ion in step 2
is available and so that enolate tautomerizes directly back to the ketone here creating
our 1,4 conjugate addition product here okay so our mechanism for anionic nucleophiles is going
to follow this particular method of procedure for the mechanism all right we may need an acidic step
there to work up the reaction if we have a neutral nucleophile then we are looking at a slightly
different mechanism because the nucleophile provides its own proton for capping off the
product at the end again some 1,2 product may be formed we're focusing on when this 1,4 addition
is the major product and so we can take our nucleophile attack position 4 this is also called
beta addition because the alpha and beta carbons can be labeled of one carbon and two carbons
away from the carbonyl they are respectively so we could call it that as well beta addition conjugate
addition or 1,4 addition when that attack occurs we kick over and kick up to an enolate yet again
in some cases you may have already protonated the carbonyl if there's acid present at the beginning
but within the case of sulfides or means we might have a good enough nucleophile to add directly
here without needing any acidic activation just depends on the reaction but if we attack here
count your carbons one two three four one two three four got an extra carbon there let me get
rid of that and there's our nucleophile that has just added and it's got an extra proton okay so
what we can do is we can show a base from solution removing that extra proton from the nucleophile
our enolates still hanging out here and then we can show that protonated base
from solution just like we did before with the acidic proton of hydronium but
we've already got one here we can talk tautomerize directly back to the ketone
and there's our 1, conjugate addition product okay so we'll see examples of both here could
see examples of both because there's anionic bases that are weak there are neutral bases that
are weakened so let's carefully define when conjugate conjugate addition is going to be
favored for alpha beta unsaturated ketones and aldehydes specifically here and that's when we
have soft and nucleophiles so we define those as a good nucleophile and a weak base this is exactly
the same as we would have defined it when we were talking about substitution elimination reactions
good nucleophile we learned a list of them or got we've got them repeated here and the label right
below is here part a weak bases means that their pKa so if this is the acid the pKa or the base
form the pKa of the conjugate acid whether it's protonated with a plus formal charge or neutral
doesn't matter each acids listed in a table with its conjugate acid pKa there and we want that pKa
to be less than 15 more acidic than acid with a pKa of 15 in order to reduce the conjugate base
strength to a point where it's not going to be seeking that 1,2 position as strongly so
weaker base goes for the less polar position that's the soft nucleophile prefers the softer
charge position of the Alpha Beta system that we have here either call it alpha beta call it
the 1 2 3 4 position as we attack ok and if we do attack that beta position with a cyanide ion
just like our mechanism for the formation of a cyanohydrin we would want to use excess cyanide
ion and HCl in order to prevent reversal kicking off of the cyanide ion ultimately here our product
is the beta substituted ketone okay so a remote functional group it's a very powerful reaction so
we just looked at a nitrile before we move off the screen here Gilman reagents are not nearly
as polar as organolithiums and grignard so they tend to add to beta some enolates so we looked
in the other lesson at hard nucleophile enolate some of those add beta it's just hard to predict
with the harder enolates the the more basic conjugate bases of the in of the functional
groups to whether they're gonna add 1,2 or 1,4 but these enolates the beta di functionalized
enolate so we'll have the functional group of the carbonyl okay so any one of our beta diketones
dialdehydes diesters dinitrile there's a whole bunch of them and these bases are stabilized in
three ways we'll look at a resonance contributor of a hybrid of all three in just a moment and so
they are very soft nucleophiles they strongly prefer the beta position so we do have a high
degree of control with those nucleophiles amines in their neutral form primary or secondary ok so
we can do primary or secondary amine sulfides in their neutral form or their anionic form either
one our weak bases and good nucleophiles a cyanide ion we just looked at carboxylates
okay so we can add carboxylates potentially some oxygen nucleophiles are a little more finicky
with these reactions they tend to be highly reversible so there are conditions typically
in actual preps that you have to be careful with halides can also add an an appropriate
solvents when they are good nucleophiles okay so so protic solvents can tend to push those halides
into good beta nucleophiles alright so there are good nucleophiles weak bases just like we
saw them with substitution elimination looked at the cyanide ion the amine here same thing we draw
our alpha beta system just take away the double bond because it goes away there and then we add
our amine to the beta position with our sulfide add it to the beta position neutral nucleophile
providing its own acid as you add so we make a thiol there adds to the beta position HBr that
proton there allows easy tautomerization back from the enolate add the bromide nucleophile to
the beta position gilman reagent same thing we'll see the trend here at our carbon group to that
beta position ketone reforms okay so let's talk a little bit more about enamines so in enamines are
a good alternative to enolate so they're softer nucleophiles and bases than enolates and so we
can carry out this beta addition in high-yield this 1,4 conjugate conjugate conjugate addition
in higher yield and we could with an enolate in much milder conditions so it's safer it's going
to be more selective to the beta addition all good things less reactive with other functional groups
so as we do that just like the enolate we form a CN double bond okay and that alpha carbon attacks
the beta here conjugate addition kicks up to an enolate and the product of this is going to be
a little bit squirrelly to get a hold of so we're going to be very careful in drawing these carbons
that we've connected so they're the four coming from the alpha-beta system and now we need this
alpha carbon of the ene of the enamine to connect here to that beta position and so then we need
one two three four five one two three four five carbons where our enamine was stuck here and so
forming that enamine we required a secondary amine so anytime we're forming an enamine
over this is a ketone um typically ketones work better for this there are ways to make enamines
from aldehydes they involve other reagents like like a like we'd form a grignard reagent almost
magnesium bromide to help stabilize the enamine of the aldehyde we're sticking with ketones and
secondary amines for enamines for this as being the easiest to do other ways to do them of course
but secondary amines always primary amines would make the imine okay so we don't want to
use a primary amine to make an enamine here with our enamine they tend to go toward the kinetics
side so if we form an enamine like an enolate at negative 78 the alkylation tends to occur
the less substituted side presumably due to steric effects and kinetic control okay even though it's
a little less stable it's going to be the position that gets alkylated more alright so we got that
kinetic side when there's a choice there on the on an unsymmetrical ketone back to where we were
we've added to that alpha carbon there it is it's added to the beta position or the four position of
that alpha beta unsaturated system what we're left over with though is an iminium ion that needs to
be hydrolyzed and we've got an enolate that needs to be protonated so we'll follow up that enamine
addition with a final step where we will excuse me where we will protonate with H3O+ it hydrolyzes
the iminium and tautomerizes the enolate and so if we draw our carbon backbone one two three four
five six seven eight nine one two three four five six seven eight nine at the 1,2 position
here we've got our ketone that reforms from it from tautomerization 1 2 3 4 5 6 7 1 2 3 4 5 6
1 2 3 4 5 6 that is where the other ketone forms after the hydrolysis of the iminium ion and so
look you've separated two ketones by by several carbons so very powerful functionalisation here
as far as this goes now you do have potential of some intramolecular stuff here and you will
see that to a certain degree with the Robinson annulation ok so stay tuned and check out the
Robinson annulation annulation mechanism for situations where this is a thermodynamic sink
towards a cyclic product instead and so you'll see that coming up another scenario where you've
got this softer nucleophile is when you have a beta disubstituted system like a beta diketone ok
we need to be able to recognize these functional groups understand that they're pKa's are less than
14 okay so there's a high efficiency of proton transfer between hydroxide whose conjugate acid
pKa is 15.7 and that's so with a pKa of about nine to ten for these beta diketones you've got
a pretty efficient transfer of about you know 10,000:1 or more in difference in peak in equal
in constants so very high degree 99.99% to the product and what is that product it is an enolate
that forms from this acid-base reaction we can show the alpha carbanion we can show the enolate
forming on to one side we show the enolate forming to the other side overall there's a
resonance hybrid that stabilizes this enolate very strongly and so it is a very soft nucleophile and
a weak base when we do the alkylation however we attack the beta position this is called a
michael reaction all of these beta additions are called michael type reactions are more commonly
seen with beta diesters beta diketones to these alpha beta unsaturated ketones and aldehydes
but conjugate addition Michael reaction tend to be synonymous this is more closely related to some of
the original reactions and so as we look at this we've got to keep track of everything again and
so we are going to form an enolate here are four carbons of the Alpha Beta system here is our alpha
carbon here on the disubstituted system the more acidic protons are always in the middle between
the two functional groups not to the outside and so as we connect to that alpha position
we end up with a diketone here and we've got a pretty acidic proton right there so
you would actually get a rearrangement that would eventually put the enolate back into
this position but hydrolysis and acidification excuse me just acidification and tautomerization
will relieve that and we end up with this triketone system there are also equilibrium
products that could result from intramolecular type reactions if the sterics allow it but here
we'd most likely end up with our system because once you put the enolate back here you'd have a
hard time one two three four carbons making a four membered ring from an attack there so we
typically see this michael addition and in this fashion one more topic here just as a
point less active electrophile so electrophiles that are less active than unsaturated ketones
and aldehydes this is from our carboxylic acid derivatives so esters nitriles um and
amides tertiary amides all of these being less active tend to favor conjugate addition okay
so we include them here however in practice the regioselectivity and whether or not the reaction
actually goes is highly specific to conditions and very specific catalysts that are used okay
so we'll assume for our purposes in class that these esters unsaturated nitriles and
saturated nitro groups and so forth nucleophiles are going to need to be stronger and they're going
to prefer to go towards that beta position in these situations where they are possible
we're not going to worry about those specific catalysts and conditions it's beyond the scope
of the class so we just need to know that they do attach to the beta position when they go