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Enol/Enolate Alkylations.

Enolization:

R
O
H
2
C
!
+ !
-
R'

You should remember this picture from previous notes. The slight positive charge which
develops on the carbonyl carbon does more than make it a good electrophile - it also “acidifies”
the protons on the carbon next to it. In essence, it turns the pair of electrons in the !-bond into a
good “leaving group” – even moderately weak bases can effect this transformation (sort of like
an elimination):
O
H
H
R
H
!
+
!
-
OH
O
H
H
R
+ H
2
O

The product of this reaction is an enolate. Enols can form under acidic conditions, but because
the carbonyl form is more thermodynamically stable, the enol is only present in tiny amounts:
O
H
H
R
H
H
+
O
H
H
R
H
H
O
H H
OH
H
H
R

Enolates are stabilized by a mechanism similar to that of carboxylates - the negative
charge is stabilized over two different atoms – in this case, both a carbon and an oxygen atom.
This method of stabilization is present in both enols and enolates:
O
H
H
R
O
H
H R
OH
H
H
R
OH
H
H R

In the presence of good electrophiles, a nucleophilic attack occurs, leading to substitution
of the alpha carbon (the carbon next to the carbonyl group).
O
H
H
R
O
H
H
R
E
+
E

The addition of electrophiles to the alpha carbon via the acid or base-induced formation of enols
(or enolates) forms the bulk of the material of this chapter. Let’s begin with our first example.
Reactions of Enols (i.e. Acidic conditions)
Acid-Catalyzed Halogenation of Aldehydes and Ketones
Our first example works under mild acidic conditions. Aldehydes can easily be mono-
halogenated at the alpha position by simply mixing the aldehyde with a halogen (usually Br
2
or
I
2
) and a trace of acid. IMPORTANT NOTE - if there are no alpha hydrogens, this reaction will
not take place!
O
H
H H
H
+
/ Br
2
OH
H
H H
H
O
H
O
H
H
H
Br
Br
O
H
H Br
H
H
2
O
H
O
H
O
H
H Br



O
H
2
O / Br
2
/ HBr
O
Br
H
2
O / Br
2
/ HBr
O
NO
REACTION!!!


Because the various enols possible are under equilibrating conditions, usually the MOST
STABLE enol is the one formed in the highest consentration - and thus the one which reacts with
the halide. For example, methyl cyclohexanone can form two different enols - the more highly
substituted one is the most stable, and thus predominates:

O
H
2
O / Br
2
/ HBr
OH
OH
more stable
less stable
O
Br


There are two major uses for these bromo-ketones and aldehydes. The first is elimination
to form conjugated carbonyl compounds. This is a classic (and simple) method for preparing
such compounds:
O
H
H Br
warm pyridine
O
H

With cyclic ketones, these halogenated compounds can undergo what is called the
Favorskii reaction. This is in essence a ring-contracting reaction, and usually proceeds in good
yield. Time permitting, we will discuss this mechanism in class:
O
Br
1) KOH
O
OH
2) H
3
O
+


The Hell-Volhard-Zelinskii Reaction
As stated above, the acid-promoted alpha halogenation only works with aldehydes and
ketones. What if you need to brominate a carboxylic acid? That’s where the HVZ reaction
comes in. The reaction basically takes a difficult-to-enolize carboxylic acid, and first turns it
into a much more enolizable acid bromide. This reaction produces HBr, which then assists in the
alpha bromination of this acid bromide. Aqueous workup returns the acid bromide to the
carboxylic acid state. Workup with an alcohol would, of course, produce the ester.
O
OH
1) PBr
3
/ Br
2
2) H
2
O (or R'OH)
R
O
OH
R
Br
(or OR')

Please remember that while this reaction can be used to form and ester, it cannot be used with an
ester as starting material – you must start with the carboxylic acid!
O
OH
1) PBr
3
/ Br
2
2) MeOH
O
OMe
Br
Hot Pyridine
O
OMe


Reactions of Enolates (i.e. basic conditions)
Under sufficiently basic conditions, an enolate ion can be formed:
O
C
B:
H
H
H
O
+ BH

However, we must generally be careful with our choice of bases – if the base is also a good
nucleophile, then attack at the carbonyl carbon becomes a more likely pathway. The most
common bases used to form enolate ions are sodium hydride (very basic, non-nucleophilic) and
Lithium Diisopropylamide (LDA, very bulky, thus non nucleophilic). Occasionally, hydroxide
ion is used, but this is usually for very specific reactions (e.g. the haloform reaction).
The enolate ion has two nonequivalent resonance forms (compare this with both the allyl
anion and the carboxylate anion). The form where the charge is localized on the oxygen
predominates (because of the electronegativity of oxygen), but the form with the charge localized
on carbon is more nucleophilic, and is thus the form that typically reacts with electrophiles:
O O
E
O
E


There are a few exceptions to this rule; generally acyl and silyl halides (TMS-Cl or CH
3
COCl)
will react with the oxygen anion, to give silyl enol ethers and enol acetates, respectively.
As you can see, alkylation of an enolate is a powerful tool for the formation of carbon-
carbon bonds under relatively mild conditions. Let’s explore this reaction a bit further.
The Haloform Reaction:
While enolates are great for forming new carbon-carbon bonds, the first reaction we’ll
look at is a method for the destruction of a carbon-carbon bond. Essentially, the haloform
reaction takes a methyl ketone (or a molecule which can be oxidized to a methyl ketone), and
turns it into a carboxylic acid with one less carbon:
O
R
I
2
/ NaOH
O
R O
+ HCI
3

How does it work? As you probably expect, the enolate is formed, and is then halogenated. The
protons on the halogenated compound are even more acidic, thus facilitating further enolization
and halogenation. When the compound is fully halogenated (in this case, forming a CI
3
group),
there are no more acidic protons, so we look for the next possible mechanistic route: nucleophilic
attack. Addition-elimination as shown leads to the carboxylate anion and a haloform (in this
case, iodoform):
O
R
O
R O
O
R C
HO
H
H
H
I I
O
R C
I
H
H
O
R C
I
I
I
No more acidic
protons...
HO
R C
I
I
I
HO O
H
+
CI
3

Alkylation of Enolates:
Normal enolates formed by the action of LDA or NaH can generally be alkylated with
alkyl iodides, bromides or tosylates, or benzylic or allylic halides. However, these reactions can
sometimes be difficult to perform in high yield. A few methods do exist which allow enolate
alkylations in high yield, and both take advantage of highly stabilized enolate anions: The
Malonic Ester synthesis, and the Acetoacetic Ester synthesis. We’ll look at each of these in
detail.
The Malonic Ester Synthesis.
Esters of malonic acid (in this case, diethyl malonate) are easily deprotonated to form the
highly stabilized enolate (note sodium ethoxide is used as base – why not NaOMe?):
O
EtO OEt
O
NaOEt
O
EtO OEt
O O
EtO OEt
O O
EtO OEt
O
H H
OEt

As you can see, the negative charge is delocalized over one carbon and two oxygens - a
very stable anion! The only significantly nucleophilic form is the one with the negative charge
on the carbon, and this is the form that gets alkylated. You should note that there are two acidic
protons on a malonic ester - thus it can be alkylated twice if desired. If an alkyl compound with
two halogens is added, cyclic compounds can be formed.

(EtOOC)
2
C
1) NaH
2)R-Br
H
H
(EtOOC)
2
C
R
H
1) NaH
2)R'-Br
(EtOOC)
2
C
R
R'
O
EtO OEt
O
H H
1) 2 NaOEt
Br Cl
2)
O
EtO OEt
O

But the really cool thing about malonic esters (and acetoacetic esters, which we’ll see in a
minute) is a reaction called decarboxylation. Once a malonic ester is hydrolyzed, then treated
with acid, the two carbonyl groups interact, and through a 6-membered ring transition state
(remember how organic molecules love to react through 6-membered ring - e.g. think of the
Diels Alder reaction!), one of the carbonyl groups is blown off as CO
2
:
O
EtO OEt
O
NaOH
O
O OH
O
H
HO OH
O OH
+ CO
2

Note that this is not a common reaction, and only happens with 1,3-dicarbonyl groups!!!!!
Thus, malonic ester chemistry is an ideal way to make substituted acetic acids (which can
then be converted to acid chlorides, and you should know all the types of reactions we can do
with acid chlorides!). Let’s just look at another example:
O
EtO OEt
O
H H
1) NaOEt
Br
2)
O
EtO OEt
O
H
1) NaOEt
Br
2)
O
EtO OEt
O
1) NaOH
2) HCl / H
2
O
O
OH

Acetoacetic Ester Synthesis
The acetoacetic synthesis is almost exactly like the malonic ester synthesis – a 1,3-
dicarbonyl compound that is easily alkylated, and which also decarboxylates. But instead of
making substituted acetic acid derivatives, this reaction makes substituted acetones.
Just like in the malonic ester synthesis, the protons between the carbonyl groups are
particularly acidic. They can be deprotonated with alkoxide (e.g. NaOEt), or sodium hydride, to
yield the stabilized anion. Alkylation is also straightforward. The only difference comes in the
decarboxylation step, where the only carboxyl group is lost to leave a methyl ketone:

O
OEt
O
H H
1) NaOEt
2) CH
3
I
O
OEt
O
H
HCl / H
2
O
120°C
O

Some things to note for both the acetoacetic ester and malonic ester synthesis (all of
which are noted for the scheme below):
O
OEt
O
H
O
OEt
C
H
O
EtO
O
O
OEt H
O
EtO
O
O
EtO
HCl / H
2
O
120°C H
O
O
HO
H


1) These are highly stabilized anions, and will thus add to conjugated carbonyl
compounds in a 1,4 fashion. Decarboxylation leads to the vinyl-substituted compound.
2) Saponiofication and decarboxylation can occur in one step - provided the temperature
is high enough (usually, 110 - 120°C will do it).
3) Note that all esters in the molecule are saponified, but only the 1,3-dicarbonyl
compounds can undergo decarboxylation.
4) As you’ll see in lecture, many different electron withdrawing groups can stabilize
enolate charges, and lead to a large variety of different compounds. However, you’ll only get
decarboxylation if you have at least one group that can be hydrolyzed to an acid, which is
separated from another carbonyl group by one carbon. For example:
O
O
OEt
1) NaH
2)
Br
Br
O
O
OEt
Br
HCl / H
2
O
heat
O
Br

Of course, this same ketone could be alkylated directly:
O
1) LDA
2)
Br
Br
O
Br

The product is the same, and there are fewer steps, but the reaction conditions are much more
harsh. Furthermore, if we were not working with a symmetrical ketone, a mixture of products
would result. Sometimes taking a few extra steps is worth it...
O
1) LDA
2)
Br
O
O
O
OEt
1) NaH
2)
Br
O
O
OEt
HCl / H
2
O
heat
O
+
O

With simple esters and ketones, however, direct alkylation of the enolate is usually the way to
go:
O
OEt
1) LDA
2)
I
O
OEt
O
1) LDA
2)
Br
O

Notes:
1) These non-stabilized enolated are very basic - alkylation generally won’t happen with
anything other than primary, allylic or benzylic halides. Secondary and tertiary halides will give
elimination products...
2) Again, if there is more than one way to form the enolate, you’ll get a mixture of
products...