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Enol/Enolate Alkylations.

Enolization:

R

O

H2C

!+ !

-

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

+ H2O

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

OHH

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

HR

OH

H H

R

OH

H

HR In the presence of good electrophiles, a nucleophilic attack occurs, leading to substitution

of the alphacarbon (the carbon next to the carbonyl group).

O

H H

R

O

H

HR

E+ E

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The addition of electrophiles to the alphacarbon via the acid or base-induced formation of enols

(or enolates) forms the bulk of the material of this chapter. Lets 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 alphaposition by simply mixing the aldehyde with a halogen (usually Br2orI2) and a trace of acid. IMPORTANT NOTE - if there are no alphahydrogens, this reaction will

not take place!

O

H

H H

H+/ Br2

OH

H

H H

H O

H

O

H

H

H

Br

Br

O

H

H Br

H

H2O

H

O

H

O

H

H Br

O

H2O / Br2/ HBr

O

Br H2O / Br2/ 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:

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O

H2O / Br2/ 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 pyridineO

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

Br1) KOH

O

OH

2) H3O+

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? Thats where the HVZreaction

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

alphabromination 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) PBr3/ Br2

2) H2O (or R'OH)R

O

OHR

Br

(or OR')

Please remember that while this reaction can be used to formand ester, it cannot be used with an

ester as starting material you must start with the carboxylic acid!O

OH 1) PBr3/ Br2

2) MeOH

O

OMe

Br

Hot Pyridine

O

OMe

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Reactions of Enolates (i.e. basic conditions)

Under sufficiently basic conditions, an enolate ion can be formed:

O

C

B:H

HH

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 OE

O

E

There are a few exceptions to this rule; generally acyl and silyl halides (TMS-Cl or CH3COCl)

will react with the oxygenanion, 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. Lets explore this reaction a bit further.

The Haloform Reaction:

While enolates are great for forming new carbon-carbon bonds, the first reaction well

look at is a method for the destructionof a carbon-carbon bond. Essentially, the haloformreaction 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

I2/ NaOH

O

R O

+ HCI3

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 CI3group),

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):

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O

R

O

R O

O

R C

HOH

H

H

I IO

R C

I

H

H

O

R C

I

I

I

No more acidicprotons...

HO

R C

I

I

I

HO O

H

+CI3

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. Well 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

ONaOEt

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 chargeon the carbon, and this is the form that gets alkylated. You should note that there are twoacidic

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)2C1) NaH

2)R-Br

H

H

(EtOOC)2C

R

H

1) NaH

2)R'-Br(EtOOC)2C

R

R'

O

EtO OEt

O

H H

1) 2 NaOEt

Br Cl2)

O

EtO OEt

O

But the really cool thing about malonic esters (and acetoacetic esters, which well 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

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(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 CO2:

O

EtO OEt

O

NaOH

O

O OH

OH

HO OH O OH

+ CO2

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!). Lets just look at another example:

O

EtO OEt

O

H H

1) NaOEt

Br2)

O

EtO OEt

O

H

1) NaOEt

Br2)

O

EtO OEt

O

1) NaOH

2) HCl / H2O

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) CH3I

O

OEt

O

H

HCl / H2O

120C

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

OH

O

OEtC

H

O

EtO

O

O

OEt H

O

EtO

O

O

EtO

HCl / H2O120C 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 - 120C will do it).

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3) Note that all esters in the molecule are saponified, but only the 1,3-dicarbonyl

compounds can undergo decarboxylation.

4) As youll see in lecture, many different electron withdrawing groups can stabilize

enolate charges, and lead to a large variety of different compounds. However, youll 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 / H2O

heat

O

Br

Of course, this same ketone could be alkylated directly:

O

1) LDA

2) BrBr

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 / H2O

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 wont 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, youll get a mixture of

products...