THE CHEMISTRY OF THE

Professor Tim Donohoe

8 lectures, HT, weeks 1-4, 2006

Handout B

O NC O

CN R R R R

O O

H

OH

You will be able to download copies of the handouts from this course at http://users.ox.ac.uk/%7Emagd1571/finalpage/teaching.html

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4) Enolisation of carbonyl compounds A) keto-enol tautomerism If one looks at the NMR spectrum of dimedone, it contains peaks for TWO different compounds.

O O HO O

The two forms of dimedone are known as the keto and

They are known as TAUTOMERS (isomers that are interchangeable via the transfer of a proton):

and the process of exchange between them is called

However, if we look at the NMR spectra of simple and they have

% enol in neat liquid % enol in neat liquid

O O O

O O O

OEt

If we look at the bond strengths, we can see why Sum (KJMol-1)

Keto (C-H) (C=O)

Enol (C-H) (C=C)

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Clearly, the presence of extra conjugation in the enol form is enough

O O O O

Another factor

There is another way that we can detect the presence of enols in aldehydes and ketones.

When acetone is dissolved in D2O it becomes CD3COCD3 over a long period of time: moreover, this reaction is catalysed by both

This process occurs through

IN

O O

IN ACID

O O

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+ Q. What would happen to CH3CH2COCH2CH2Ph in D2O with cat. H ? Think of a carbonyl compound that exists in 100% enol form?

Remember that th acid (or base) speeds up the rate at which the reaction proceeds ie equilibrium is reached, it does NOT

ENOLATES You have just seen that protons adjacent to a carbonyl are acidic: quantify this property by

O O

Cl OMe

O O

H NMe2

O

Obviously, two carbonyl groups in a 1-3 array activate the protons in between even more. This manifests itself as a much lower pKa.

O O O O

O O

OEt

O O

EtO OEt

For a comprehensive collection of pKa values see: http://www.chem.wisc.edu/areas/reich/pkatable/index.htm

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As well as exchange at the alpha position, another (usually undesirable) consequence of enolisation

O O O O

Ph R H R

The more acidic the protons, the easier

B) enols and enolates as

You should be familiar with the notion of alkenes acting as nucleophiles (using their relatively high energy, polarisable π-bonds-

Enols and enolates are simply electron-rich alkenes and so react rapidly

O O

With the exception of highly reactive, charged, electrophiles,

Simple reactions of enols and enolates

1) alkylation For simple ketones it is best to use a strong base such as LDA at low temp.

BuLi N H

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O (i) LDA (i) LDA (ii)

(ii)

Using an excess of base and alkylating agent it is possible to over-alkylate

O K-H Me-I one-pot

Note: there are problems with the alkylation of enolates derived from aldehydes.

O LDA

H -78°C

But, , acids and can all be alkylated successfully using these conditions.

LDA O -78°C

NMe2

key step in the synthesis of verapamil (angina)

OMe MeO LDA O -78°C OMe

Remember that TWO equivalents of base are required to alkylate carboxylic acids:

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O LDA LDA then R H O -78°C -78°C

It is fair to say that the above conditions are not easy to replicate on a large scale. Remember that if a CH is flanked by TWO carbonyl groups then it is much more acidic: here alkylation doesn’t need such a strong base.

O

KOH, MeOH

MeI O

O O K2CO3, acetone

MeI

With respect to synthesis, the two most important β-dicarbonyl compounds are

O O O O

OEt EtO OEt pKa pKa ethyl acetoacetate diethylmalonate

Both of these are easily alkylated under mild conditions.

Ester and then heating with acid forms CO2 (decarboxylation)

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ethyl acetoacetate diethylmalonate

O O O O

OEt EtO OEt

NaOEt NaOEt EtOH EtOH

OEt EtO OEt

R-X R-X

OEt EtO OEt

NaOH NaOH

O O O O

+ + H3O , ∆ H3O , ∆

O O

Q. Why use NaOEt here: what about NaOMe?

Look at the decarboxylation reaction in more detail.

H O O ∆

X O X X

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Also, there is no reason why we cannot alkylate twice:

O O O O (i) NaOEt then MeI (i) NaOEt then OEt OEt Br benzyl bromide (BnBr)

O O (i) NaOH OEt (ii)

2) Halogenation a) Under basic conditions,

Consider the bromination of acetone with NaOH and Br2

Experimentally, it has been shown that the rate of reaction

But is not related to

Also bromination and iodination proceed at exactly the same rate

The only way to reconcile these observations is with the following mechanism:

O O OH H H C H C 3 slow step 3 (RDS)

rapid reaction with an

Unfortunately, the reaction does not stop here:

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O O O H OH H3C H3C H3C Br Br Br

O O O

H3C H3C H3C Br Br Br

No further deprotonation is possible

the best leaving group is lost

H2O 15.6

HCBr3 9

Known as the bromoform (or iodoform with I2) reaction.

This reaction is unusual because a carbon-carbon bond is broken; the reaction can be used as a test for methyl ketones.

O NaOH, Br2

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b) Under acidic conditions, It is also possible to halogenate ketones under acidic conditions; again, it has been shown that the rate of reaction

But is not related to

So, we need to amend our previous mechanism to accommodate the rate limiting formation of an

Normally, this does not brominate further O O HOAc, Br2

O O

H3C

Clearly, for monobromination of aldehydes and ketones, ACID is superior Compare the bromination of unsymmetrical ketones under the two sets of conditions,

Acid gives monobromination Base gives over-bromination

O O O AcOH, Br2 NaOH, Br2

As for regiochemistry, consider the product determining step in each case:

In base

O

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In acid H O

It is not usually possible to halogenate next to amides, esters and carboxylic acids using this chemistry as these derivatives do not enolise readily.

However, a nice solution is to brominate an acid bromide (much more acidic) and is also made

Known as the Hell-Volhard-Zelinsky reaction.

O O OH PBr3 OH mech?

Br2

Only alpha

Only mono

3) Reaction with carbonyl groups A) reaction with aldehydes and ketones: the

Consider the reaction of an enol or enolate with a carbonyl compound:

With base

O O O O NaOH

H H H H O

H

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With acid

O O O H+ H H H

O

H

O O

H H

In this case the equilibrium favours the product- but this is not always the case and with acetone, for example, the equilibrium favours the starting materials.

If these reactions are forced then elimination follows the aldol to form

Elimination with base

OH O excess base OH

H heat H H

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Elimination with acid O H+

H O

H+

the aldol product

an α,β- unsaturated

Base catalysed aldol reactions can give either the aldol product or the dehydrated product by an

Acid catalysed aldol reactions can give the aldol product but usually give the dehydrated product by an

These are all examples of self condensation, crossed aldol reactions are clearly going to be complicated. For example, reaction of CH3CHO with CH3CH2CHO will result in

In practice, the crossed aldol reaction only works well when one component cannot form an enol/enolate and is more reactive than the other.

CHO O K2CO3 + H H

In fact it is difficult to stop this reaction:

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O O O O H H + H H H H

O O OH O H H OH O H H HO H H OH

Benzaldehyde, PhCHO is also a carbonyl compound that cannot form an enolate; so it is a good partner in the aldol reactions with ketones.

O O NaOH O NaOH + Ph H

We can easily perform crossed aldol reactions with malonates and do not require a strong base to form an enolate.

O O O pyridine, EtO OEt H

EtO OEt EtO OEt EtO OEt

EtO OEt

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Further reading: the enolates of anhydrides are easy to make and condense readily with aldehydes. This is known as the Perkin reaction

B) reactions of esters: the Claisen reaction In essence, this is an equilibrium reaction of an enolate with the ester starting material.

O O O R NaOMe, MeOH R R OMe OMe OMe O R OMe

O O

+ R R H3O OMe OMe

R R

How do we know that deprotonation drives the equilibrium? Try a Claisen with a disubstituted ester.

O O This reaction doesnt NaOMe, MeOH OMe OMe

Just like the aldol, crossed Claisen reactions are only viable if one component is more electrophilic than the other AND

O NaOMe, MeOH R NaOMe, MeOH OMe O O MeO OMe H OMe O + + then H3O then H3O 16

C) further reactions of esters: alpha-halo esters (i) Darzens reaction Aldehydes and ketones condense with alpha-halo esters in the presence of base. This works well for aromatic aldehydes and ketones and for aliphatic ketones.

O O NaOEt Cl + Cl OEt O OEt

irreversible Cl OEt

(ii) Reformatsky reaction of alpha bromo esters

Esters cannot be used in the crossed aldol condensation with aldehydes and ketones because aldehydes and ketones are (I) More (II) More So, the (or ) would simply

One simple way of making ester enolates that can and do react with aldehydes and ketones is

O Zn O Br OEt OEt

O

This zinc enolate is relatively unreactive, so it does not react O + O with the ester H3O OEt OEt

Note: you cannot make zinc enolates from alpha bromo aldehydes and ketones via this chemistry- the carbonyl starting materials

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A modern alternative to this involves making the ester enolate with a very strong base (LDA). This means that self condensation is not a problem. Then, in a separate step, add the aldehyde (or ketone) electrophile. The reaction below was a key step in the laboratory synthesis of the natural product himalchene.

O O then LDA, -78°C OEt OEt

O H

Problems on a large scale

D) α,β-unsaturated carbonyl compounds as electrophiles Earlier, we discussed the fact that delocalisation reduces the electrophilicity of carbonyl groups. By the same token, the alkene is a much worse and indeed becomes

O O

R R R

Enolates are particularly adept at addition to the beta position of α,β-unsaturated carbonyl compounds, this is known as

O

O OMe tBuOK R O

OMe

R + then H

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The reaction works particularly well when the enolate is easily formed with a weaker base, ie

O O O O O MeONa, MeOH + OMe MeO OMe 93% MeO OMe

O

OMe O O O O MeO OMe MeO OMe

An extension of this methodology is the Robinson ring annulation,

O O

base + eg NaOEt O O O O EtOH

O O O

O

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5. Making alkenes from carbonyl compounds: the Wittig reaction

The Wittig reaction consists of three stages. 1) Reaction of an alkyl halide with triphenylphosphine

Ph P Ph Ph

R Br R

2) Treatment of the phosphonium salt with strong base to make an YLID

BuLi or NaH

R P R P

3) Immediate reaction of the ylid with a carbonyl compound to form an alkene

O

R P R P P R

collapse

+ P R

One of the best ways for making alkenes:

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