CH2208 – Disconnection Theory

Disconnection is an imaginary process, the reverse of a formation reaction, otherwise known as

retrosynthetic analysis – it is the dissection of a molecule in order to arrive at the starting materials.
Retrosynthesis is denoted by a double bodied arrow, => , with the bond being broken shown by a
curved or straight line perpendicular to the bond.
Initial retrosynthesis gives, in most cases, two hypothetical charged species – synthons, the reagent
with which a synthon can be synthesized is called a synthetic equivalent.

E.g.;
(CH3)3C-ǀ-OH => (CH3)3C- + +OH or (CH3)3C++-OH
Here, of the synthons on the right, only the latter pair are sensible. +OH is rarely, if ever, seen, -OH is
easily prepared in situ with NaOH. (CH3)3C+ is also readily available using a halogenated species,
(CH3)3C-Cl, the forward reaction could then occur as an SN1 reaction.
-
OH here is a nucleophile and can be replaced by other similar nucleophiles providing they are easily
prepared, for example –CN can be formed using NaCN, the reaction of this species with an alkyl chain
is an important one as it provides an additional carbon atom to the chain. This can then be
converted into a carboxylic acid moiety by addition of water or reduced down to –CNH2.

Grignard Formation
Grignard reagents are very useful in disconnection theory, they provide simple synthetic equivalents
for many reactions.

A Grignard reagent is formed by;

PhBr+Mg+Et2O→PhMgBr

Addition of a Grignard reagent to a carbonyl will form an alcohol;

H3CC=O+PhMgBr→H3CC(OH)Ph

Added to an ester the alkyl moiety of the Grignard reagent will first substitute with the ester group
and a second equivalent will then react as above to give a tertiary alcohol as the final product;
H3CCOOEt+PhMgBr→ H3CCOPh+PhMgBr→ H3CC(OH)Ph2
If added in a 1:1 ratio a 50:50 mix of starting material and end product will be acquired.

Epoxides
In the above examples the added moiety is added onto the atom directly next to the alcohol,
epoxides can be used to add this moiety one atom away from the alcohol.

-
O O
+
H

-
CH3
Nu Nu CH3

The nucleophile used could be a Grignard reagent as before.

Alkynes and Alkenes
Terminal alkynes can be ‘activated’ by reaction with butyl lithium to give the acetylide anion;

- +
R H R C Li BuH

+-
Li Bu

These will react with an alkyl halide as before, displacing the halogen and replacing it with the alkyne
group. They can also attack carbonyls, pushing the charge through to the oxygen, to give a
substituted alcohol.
The acetylide moiety is useful as it can be converted into many other things. It can be reduced with
H2 over Lindlar’s catalyst (Pd/CaCO3/Pb(OAc)2) to give a cis alkene or reduced with H+ in H2O to give
an enol/carbonyl in equilibrium.

The Wittig Reaction – Formation of an Exocyclic Double Bond

The Wittig reaction is a reaction between a cyclic ketone, MeBr and PPh3.

O Br CH3 H
+- O
+ - Li Bu
PPh3 Br - +
H2C PPh3
Phosphonium salt
:PPh3 Phosphorus ylid

+
CH2 PPh3 PPh3 -
O
O
PPh3 O

An important distinction for Wittig dissociation is that the synthons formed will not be ionic, instead
one side of the bond is redrawn as a cyclic ketone, the other as a halide.

Carbonyl Stabilised Anions/Enolates

A carbonyl group can be used to stabilise a negative charge on a neighbouring carbon atom creating
a nucleophilic carbon centre. This is achieved by using a base (LDA, NaOEt etc.) to remove a
hydrogen from the carbon, the charge is then stabilised through resonance.

-
O O

-
H3C CH2 H3C CH2
To remove the proton in this case requires a strong base, such as LDA, which has its problems since
LDA is pyrophoric. An alternative is to use a species easier to deprotonate and then remove it
afterwards;

O O
-
O O

-
H3C CH O CH3 H3C O CH3

The additional ester group can then be removed with H+(aq) and heat providing the same products as
would be acquired using the basic aldehyde but without having to use potentially dangerous or
difficult reagents.

In cases where the carbonyl group needs to be protected in order to prevent it reacting it can be
converted into an acetal using a diol.

OH
O H+ O
O H2O
HO O
H3C
H3C CH3 CH
CH
CH

Since O- is considerably stable this can be necessary when hoping to deprotonate in another location
(in the example above acetal protection would allow for deprotonation on the alkyne).

Another alternative is to use an enamine.

'
O R'' R
N
'
R'' R
NH
H3C CH3 H3C CH2

Enamines are particularly useful for asymmetric ketones in which it is difficult to control which α-
Carbon is deprotonated, by placing a bulky enamine in place of the carbonyl the deprotonation will
occur much more controllably on the less bulky side of the asymmetric ketone, the lesser product
can then be distilled off to give the desired pure enamine.
The Aldol Reaction
An aldol reaction is a reaction between two carbonyls to form an α-β unsaturated carbonyl.

- + O
O Na
O
H
H3C H H3C
+ -
H Na HO
H3C H3C
O
HO CH3
-hydroxy carbonyl compound

With excess base

O -
O

 unsaturated carbonyl

H3C
H3C

HO CH3

CH3

Claisen-Ester Condensation
The Claisen-Ester condensation is a mechanism for the formation of β-ketoesters from two ester
molecules.

H3C
-
O O
O -
NaOEt O
O
H3C
O CH3 H2C O CH3

H3C O CH3 O
H
CH3

O O
-
OEt
H3C O CH3
-ketoester
The Claisen-Ester condensation can also be intramolecular as the Dieckmann condensation;

O O
-H+
O CH3 O CH3
H3C O NaOEt H C O
3
-
O O

O H3C
O -
O O O

-
OEt
O
CH3 O
CH3

Michael Addition
Michael Addition is a specific mechanism for the formation of 1-5 dicarbonyl compounds.

O -
O
O O
LDA (Deprotonates ketone)

Br CH3 -H+
H3C CH2 H2C
H3C CH3
CH3
H

Unstable, readily eliminates

HBr

-
O O O O

H3C CH3 H3C CH3

+
H
Robinson Annelation
Robinson annelation is a combination of both an aldol reaction and a Michael reaction and can be
used to form molecules in which both a 1-5 dicarbonyl and an α-β unsaturated ketone.

O B-H
H3C
O
H3C O H3C
H -
O
-
B: H3C O
O
H3C CH2
O

O
B: H

- O
O
O
H3C
H3C
O
H2C

O
O
+
H

O O
CH3 CH3
3
-H2O 1
4
2

5

O O

H OH

The Diels-Alder Reaction

The Diels-Alder reaction is a pericylic reaction involving a redistribution in electrons (it is not ionic)
between a diene and a dienophile. If the diene has electron donating groups attached it will react
more readily, similarly if the dienophile has electron withdrawing groups present it will , a Lewis acid
will work in conjunction with a carbonyl on the dienophile will lower the temperature required for
the reaction to occur. Essentially the dienophile must be electron deficient and the diene electron
rich, functionalities that increase these characteristics increase the ease with which the reaction will
occur. The diene must have a favourable cis geometry that isn’t stearically hindered to be readily
reactive, as hindrance increases reactivity decreases.
 H3C
O

H3C
H3C CH2
CH3 O

CH2
H3C CH2

H3C

With asymmetric reagents the preferred position is always ortho or para. If the dienophile is a trans
alkene a trans product will be formed, similarly a cis dienophile will give a cis product.