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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.
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
- +
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.
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.
-
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).
'
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
O -
O
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
-
O O O O
+
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
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.