mcat organic chemistry review

8/3/2019 MCAT Organic Chemistry Review

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CARBONYL CONDENSATION

REACTIONS

• Aldol Reaction

• Dehydration of Aldol Products

•

Intramolecular Aldol Reaction• Claisen Condensation Reaction

• Intramolecular Claisen

Condensation

•

Michael Reaction• Stork Enamine Reaction

• Robinson Annulation Reaction



General Mechanism of Carbonyl

Condensation

One carbonyl partnerwith an alpha hydrogen

atom is converted by base

into its enolate ion.

O

CR C

H

OH



CO

C

C O

R

:

..

..

RC

O

C

H2

C

O

:: :

Electrophili

Acceptor

NucleophilicDonor

This enolate ion acts as a

nucleophilic donor andadds to the electrophilic

carbonyl group of the

acceptor partner



Protonation of the tetrahedral alkoxide ion

intermediate gives the neutral condensation

product.

OH2

C

C

C

OH -O

O

+NewC-CBon



ALDOL REACTION

• occurs between two aldehyde or ketonemolecules with a catalytic base

• reaction can occur between two components

that have alpha hydrogens• reversible condensation reaction

• two highlights: enolate formation andnucleophilic attack at a carbonyl carbon

• Aldol products are: alpha-ß-unsaturatedaldehydes/ketones and ß-hydroxyaldehydes/ketones



Mechanism of the Aldol Reaction

HO:

HC

H H

C

O

H

Base removes anacidic alpha hydrogenfrom one aldehydemolecule, yieldinga resonance-stabilized eno-late ion.



C

O

CH3 H

: : OH+2

CH

H

C H

O

..

H3 C

H

O

C

HH H

OC

H

: :..

The enolate ion attacks

a second aldehyde

molecule in a

nucleophilic addition

reaction to give a

tetrahedral alkoxide ion

intermediate.



H O2

O

CHCCHHHH

OH

O3

+-

:

Protonation of the alkoxide ion intermediate yields

neutral aldol product and regenerates the base

catalyst.



Dehydration of Aldol Products:

Synthesis of Enones• ß-hydroxy aldehydes and ß-hydroxy ketones

formed in aldol reactions can be easily dehydrated

to yield conjugated enones• Dehydration is catalyzed by both acid and base

• Reaction conditions for dehydration are only

slightly more severe than for condensation

• Conjugated enones are more stable than

nonconjugated enones



C

O

CH

C

OHOH

Base-catalyzed

C

O

C

C

OH::

-..

Enolate ion

C

O

CC OH

Dehydration of Aldol Products



C

C

CO OH

H

H+

Acid-catalyzed

CC C

OHO

H

2+

Enol

C

O

CC H+

3



Mixed Aldol Reaction

• If two similar aldehydes/ketones react under

aldol conditions, 4 products may be formed

• A single product can be formed from two

different components :

If one carbonyl component has no alpha-

hydrogens or if one carbonyl compound is muchmore acidic than the other.



Intramolecular Aldol Reaction:

• Treatment of certain dicarbonyl compounds

with base can lead to cyclic products

• A mixture of cyclic products may result ,

but the more strain-free ring is usually

formed



Intramolecular Aldol Reaction of 2, 5-

hexanedione yields 3-methyl-2-

cyclopentenone

aC H

H

C

O

HHOC

C

C

C 3

3 2,5- Hexanedionb



CH

HH

C

O

H H

C

C

C

C H H

O

3

-

-OHPath A

CH

HH

C

O

H H

C

C

C

C

H

H

OH

3



C

C

C

C C

C

H H

H

H

H

H

O

H

H

O

HO

3

-:..

..

CH

OH O

3

2+

3-Methyl-2-cyclopentenone

NaOH, H2O



Path b

NaOH, H2O

CH

HH H

C

O

H H O

C

C

C

C3

3

HO-



CH

HHC

O

HC

C

C

C

H

H

O

H

3- CH

HH

C

O

HC

C

C

C

H

H

H

O

3

-

OHH

.. ..



C

H

H

CHO

H

H

OO -:..

..

(2-Methylcyclopropenyl)ethanone(NOT formed)

CH O

CH

H O

3

3+

2



Claisen Condensation Reaction

• Carbonyl condesation that occurs between twoester components and gives a ß-keto ester product

• Reaction is reversible and has a mechanism similar to aldol reaction

• Major difference from aldol condensation is theexpulsion of an alkoxide ion from the tetrahedral

intermediate of the initial Claisen adduct• 1 equivalent of base is needed

to drive the reaction to completion because the

product is often acidic



Mechanism of Claisen Condensation:

• involves nucleophilic acyl substitution of an ester

enolate ion on the carbonyl group of a second

ester molecule• tetrahedral intermediate expels an alkoxide leaving

group to yield an acyl substitution product



Mechanism of the Claisen

Condensation Reaction

CH3COEt

O

- OEt

Ethoxide base abstracts anacidic alpha hydrogen

atom from an ester

molecule, yielding an ester

enolate ion



:CH2

COEt

O

EtOH

CH3C

:O:

OEt

+

Nucleophilic donor

Electrophilicacceptor

In a nucleophilic addition,this ion adds to a secondester molecule, giving atetrahedral intermediate.

CH3

C

:O: -

OEt

CH2

COEt

O..

The tetrahedral intermediateis not stable. It expels ethoxidion to yield the newcarbonylcompound, ethyl acetoacetate.



But ethoxide ion is basic enoughto convert the beta-keto esterproduct into its enolate, thusshifitng the equilibriumand drivinthe reaction to completion.

H3C

O

CH2COEt

O

EtO-+

H3C

O

CHCOEt

O

_ ..

EtO+



H3

C

O

CH2

COEt

O

OH+

Protonation by addition of acidin a separate step yields the finlproduct.

H3O+



Mixed Claisen Condesation

•occurs only when one of the two ester

components has no alpha-hydrogens, and

thus can’t form enolate ion •can also be carried out between esters and

ketones resulting a synthesis of ß-diketones



Example of Mixed Claisen

Condensation

1. NaH/THF

+2. H30

C

O

CH

O

C

H

2 OEt

EtO

Ethyl benzoylacetat

C

O

OEt

Ethyl Benzoate

(Acceptor)

+

CH

O

COEt3Ethyl Acetate

(Donor)



Intramolecular Claisen Condensation:

Dieckmann Cyclization• can be carried out with diesters

• works best on 1, 6-diesters and 1,7-diesters

• 5-membered cyclic ß-ketoesters result from

Dieckmann cyclization of 1,6-diesters

• 6-membered cyclic ß-keto esters result from

cyclization of 1,7-diesters



Examples of Intramolecular

Claisen CondensationO

O

O

C

O

OEt

OEtDiethyl hexanedioate(a1,6-Diester)

1. Na+-OEt, ethanol

2. H3O+ Et

Ethyl 2-oxocyclopentanecarboxylate(82%)

O

O

O

C

O

OEt

OEt

Diethyl heptanediote(a1,7- Diester)

1. Na+-OEt, ethanol

2. H3O+

+

Ethyl-2-oxocyclohexanecarboxylate



Intramolecular Claisen Condensation

Mechanism

H

O

H

OEt

COOEt

+ OEtNa -

Base abstracts an acidic

alpha-proton from the

carbon atom next to one

of the ester groups,

yielding an enolote ion.



Intramolecular nucleophilic addition of the ester enolate

ion to the carbonyl group of the second ester group at the

other end of the chain then gives a cyclic tetrahedral

intermediate.

OH

tEO

COOEt

+ EtO:

..

-



H

O

COO

tEO : :

..

-

Loss of alkoxide ion from the tetrahedral

intermediate forms a cyclic beta-keto ester.



O

H

O

.

H

COOEt

+ tEO :

.

. .

.

-

COOEt-

EtO+

Deprotonation of the

acidic beta-keto ester

gives an enolate

ion…



O

HH O

+H3O

COOEt

+ 2

…which is protonated

by addition of

aqueous acid at theendoth the reaction to

generate the neutral

beta-keto ester

product.



Michael Reaction

• Conjugate addition of a carbon nucleophile to an

alpha, ß-unsaturated acceptor

Best Michael Reactions:• Between unusually acidic donors (ß-ketoesters or ß-

diketones)

• Unhindered alpha,ß-unsaturated acceptors

• Stable enolates are Michael donors, and alpha,ß-

unsaturated compounds are Michael acceptors



The Michael Reaction

EtO

O

C

C

C

O

CH3

HH

Na+ - OEt

The base catalystremoves an acidic alpha

proton from the starting

beta-keto ester to

generate a stabilizedenolate ion nucleophile.



The nucleophile adds

to the alpha,beta-ketounsaturated ketone

electrophile in a

Michael reaction to

generate a new enolate

as product.

EtO

C

O

C

C

O

CH3

H

-

EtOH

C

H

C

C

H3C H

O

C

H3C C

C

H H

C

HHCO

2Et

C

CH3

OO

.. +

..



O

EtOH

H3C

C

C

C

H H

C

C

O

CH3

H HCO

2Et

H

EtO-+

The enolate product

abstracts an acidic

proton, either fromsolvent or from starting

keto ester, to yield the

final addition product.



Some Michael Acceptors and

Michael Donors

2C CHCHO

H2CCHCO

2Et

H2CCHC N

2CCHCOCH

3

2

CCHNO2

H2CCHCONH

2

Propenol

Ethyl Propanoat

Propenenitrile

3-Buten-2-one

Nitroethylene

Propenamide

COCH2COR'

COCH2CO2Et

tO2CCH2CO

2Et

COCH2CN

CH2NO2

Beta-Diketone

Beta-KetoEst

MalonicEster

Beta-Ketonitril

Nitrocompound

Michael Acceptors Michael Donors



Stork Enamine Reaction

• enamine adds to an alpha,ß-unsaturated carbonylacceptor in a Michael- type process

• Overall reaction is a three-step sequence:

Step 1: Enamine formation from a ketoneStep 2: Michael-type addition to an alpha, ß-

unsaturated carbonyl compound

Step 3: Enamine Hydrolysis back to ketone• net effect of Stork Enamine reaction sequence is

the Michael addition of a ketone to an alpha,ß-unsaturated carbonyl compound



Example of Stork Enamine Reaction

ON

H

-H2O

NH2CCHCCH

3

O..

Cyclohexanone Anenamine

NCH

2CHCCH

3

-..O NCH

2CH

2CC

O H2

O

CH2CH2CCH3

O

N

H

+

A1,5-diketone

mcat organic chemistry review

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