3B Chemistry Lecture 16 Tuesday March 17th, 2009
This aldehyde has no alpha hydrogens, so it is not
enolizable. When you react it with hydroxide, you wont
get any aldol products because there are no alpha
hydrogens but it will still make some hydrate. A ketone
with hydroxide will give slow aldols though it will take
place if given enough time. If you take the ketone and
the aldehyde that is not enolizable and throw it in basic
and equilibrium conditions along with heat, we can do
an aldol condensation with very good yields. We need an
enolizable ketone and non enolizable aldehyde under
equilibrium conditions. In this reaction, the ketone and
aldehyde and base must be combined at the same time. It
is an intermolecular cross aldol condensation reaction.
In this next reaction, we will get a major product which
is shown. We have an enolizable ketone and non
enolizable aldehyde again; mainly we can use aromatic
aldehydes or things that are triple branched at the alpha
position . We are limited by the fact that our aldehyde
has to be non enolizable and that limits the system. Can
we ever use enolizable aldehydes in this type of
reaction? No because you will have an enolizable ketone
and enolizable aldehyde. We must do the reaction
differently if we want to use an enolizable aldehyde: for
example we have cyclohexanone and LDA. This is non
equilibrium conditions where we get 100% of the
enolate which means that we can add an aldehyde and
not worry about the aldehyde enolate. Our strong base is
gone; we normally do these reactions at cold
temperatures like -30 degrees. We have an enolate and
an aldehyde: well get a cross aldol reaction where we
got to use an enolizable aldehyde. We have used up all
the strong base in the beginning of the reaction to make
the enolate and now we can react it with an enolizable
aldehyde. Equilibrium= enolate, ketone, enolate ketone
bouncing back and forth. Non equilibrium means that
you went from ketone to enolate and cant go back. We
need to add a source of protons to finish this reaction. To
make an alpha beta unsaturated system, then you can
heat up that species with a base ; we know how to make
aldols and alpha beta unsaturated systems come from
aldols. You can do an acid catalyzed aldol reaction ; but
acid catalyzed means no enolates under those conditions
because enolates are bases. That means you will have to
use something else to do your aldol reaction.
Predict the products with LDA: we have 2 major
stereoisomers. LDA (we had 2 enolizable hydrogens in
this case) went after the least hindered enolizable
hydrogens. Alpha beta unsaturated ketones and ways of
making them: aldol condensation is one way. We have
an alcohol that we just need to oxidize so we can use
PCC or MnO2 which is very selective for allylic or
benzylic alcohols. Another way is using the Wittig
Reagent. Wittig Reagents react with carbonyls though
and in this case we had one react with a molecule with a
carbonyl present in it; these are stable special Wittig
Reagents. You cant use Wittig Reagents that have
carbonyls in them unless the carbonyl is on the carbon
very next to the illid one (with the minus charge). These
Wittig reagents are, hwoever, a good way of making
alpha beta unsaturated systems. One other method has
the product that is an beta gamma unsaturated carbonyl.
You can heat it up with aqeous base and
methoxide/methanol etc you can isomerizes a beta
gamma to an alpha beta. We can make them using PCC
or another chromium reagents because it is a secondary
alcohol and you can make the other species from a
Grignard reagent, and an appropriate aldehyde. Be
careful about R : in allylic systems, you can get 2
separate reactions.
This is the isomerization reaction and weve thrown in
some deuteriums. In the final product, the circled D is
not an enolizable hydrogen because enolizable
hydrogens are hydrogens that form enolates and they
have to be on sp3 hydbridized carbons. (These are not
necessarily alpha hydrogens; they are enolizable
hydrogens). We have aldol, oxidation of an allylic
alcohol, wittig , and isomerization of beta gamma
unsaturated carbonyls and these are all ways of making
alpha beta unsaturated systems. Cycloxheanone plus an
acid catalyst plus the other reagent gives us that product
which we call an enamine. It looks like an enol ; the
mechanism is nothing new. Amine plus a carbonyl
makes an immine (under acid catalyzed conditions) and
we get to the same intermediate as we see in this current
mechanism; something comes and pulls off the proton
and then we get an immine. We cant get rid of the
positive charge on Nitrogen just by pulling off a
hydrogen and it is called an immonium ion. The
immonium chooses whatever happens to be around to
pull off an alpha hydrogen and the mechanism is
identical to isomerizing a ketone to an enol. We dont
use enolates to do aldol like chemistry. The best ways of
making C-C bonds though is by doing aldol like
chemistry however we cant survive under basic
conditions. We need similar types of intermediates based
on enamines to do aldol like chemistry. You can make
enamines from primary and secondary amines.
Enamines exist even if you start with a primary amine.
We have equilibrium between ketone and enol like imine
and enamine.
Predict the product: ketone plus a secondary amine. This
is a standard secondary amine to make enamines. We
have just created an enamine which will furthermore
attack the carbon bearing the Bromine= Sn2 reaction.
We this did with enolates but with enolates we get
overalkylation. Instead of using an enolate, we use an
enamine with no minus charge; they are still
nucleophilic but they arent as nucleophilic or basic as
an enolate. Enamines are nucleophiles and will do
chemistry at the alpha carbon. Step 3 gives us our
carbonyl back. To do these reactions, instead of taking
the ketone and adding LDA and then our electrophile,
we are first making the enamine and then adding the
electrophile to take off the Nitrogen. We can make
enammines because we know how to make an imine.
We can make carbon carbon bonds using the carbonyl,
we can add electrophiles, where R can be lots of
different things. We can add nucleophiles at the alpha
and carbonyl carbon; we can add electrophiles to them
and change the reactivity. Nucleophiles go to the
carbonyl carbon and electrophiles go to the alpha
carbon. We cant do electrophilic chemistry at the alpha
carbon if we dont have enolizable hydrogens. If we
want to add nucleophiles to another position in the
molecule shown, then we have to have an alpha beta
unsaturated carbonyl. We write resonance structures to
help predict where things will react. One of the
resonance structures drawn suggests that something
electron rich will add to the carbonyl carbon due to the
plus charge present. There are, of course, other
resonance structures. We just discovered another site of
reactivity in a carbonyl (but it must be alpha beta
unsaturated).
Lets take a generic nucleophile and make it negatively
charged. We can do a 1,2 addition to a carbonyl. We also
show 1,4 addition. The term 1,4 is a little ify but:
nucleophile adds to position number 1 and the charge
ends up on position number 4. Nucleophile adds to a
beta carbon of an alpha beta unsaturated carbonyl;
nucleophilic addition: nucleophiles add to the carbonyl
and beta position, and electrophiles add to the alpha
position. The 1,2 addition is fast, and the 1,4 is slow.
The electrophile will most quickly go to the carbonyl
carbon. That is because if you look at the resonance
structures, we can see that the 2 resonance structures are
alike even though they dont have an octet. There is less
charge separation in our fast reaction. Less charge
separation= coulombs law. Less of a delta positive on
the carbon means nucleophiles attracted to positive
character are going to go after the most positive
character. We get a lot of 1,4 chemistry though but why
doesnt it all go to 1,2 since its faster? Since its
reversible, we can go to either 1,2 or 1,4. And
thermodynamically, the 1,4 product is more stable due to
resonance. Thermodynamically we prefer the slower
product. what we need in order to get 1,4 addition is
nucleophiles that can go on and come off. Types of
nucleophiles that weve been dealing with: Methyl
magnesium bromide in this alpha beta unsaturated
carbonyl: we have 2 possible positions to react at but the
product only has it at one of those locations. (more
quick). When grignards go to the carbonyl, the reaction
is over. Alkyl aryl anions which typically come in the
form of Grignard reagents; when they add to an alpha
beta unsaturated carbonyl, they only add 1,2 and stop
there. What do we need in order to get 1,4 addition?
Things can add to carbonyls and come back again if their
pka is somewhere around 20 or less of their conjugate
acids. Cyanide.
It can come on and off, creating Cyanohydrins. Adding
cyanide to an alpha beta unsaturated carbonyl and we
have a source of protons present, youll end up with 1,4
addition. Whats the pka of alpha hydrogens of ketones
and aldehydes? Around 20. If we take an enolate and
react it with the alpha beta unsaturated carbonyl, we did
get some 1,2 addition but its reversible. It is an alpha
beta alkoxy carbonyl. It is an aldol product = certainly
reversible back to the 2 carbonyl species. If we do this
under equilibrium conditions: well protonate our
enolate. Lets use a phenyl : we just made a 1,5
dicarbonyl from a ketone and an alpha beta unsaturated
carbonyl. 1)make the enolate even though we dont get a
lot. It is under equilibrium conditions. We have an alpha
beta unsaturated carbonyl and well turn it upside down.
We will do a conjugate addition. We have methanol
present, and we can create the enol.
Another class of enolates: Carboxylic acid chemistry:
these all have 2 carbonyls in a 1,3 relationship. This is a
beta diketone or a 1,3 diketone. This is a keto esther, and
this is a diesther; they all have the same structure. The
pkas respectively for the acidic hydrogens : (pulling off
the one in the middle will create resonance stabilization
over five atoms ) typical alpha hydrogen of a ketone is
20; putting another ketone next door is 9 and that is a
pretty strong acid for a proton on a carbon. These are
then 11, and 13: theyll make excellent enolates and will
come on and off great. The alpha hydrogens are
sandwiched between a couple of carbonyls making them
more acidic.
This predict the product: Its 3 steps . pka of 9 with
methoxide (draw any enolate you want even though
theres 3 possibilites), Kequilibrium will be 10^product
acid (methanol) reactant acid (9) = 10^7. Thats 100%
enolate. Now we can add our ketone and we have our
intermediate product. That hydrogen (even though there
is alkyl group near) will still be 9, or maybe 10. It is an
enolate with a pka of around 20 for the alpha hydrogen.
We have 20-9 = 10^10. This is what will be sitting in
solution waiting to be protonated.