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The Aldol Reaction
The reaction of an enol or enolate of a carbonyl compound with an
aldehyde or ketone to
form a β-hydroxycarbonyl is known as the aldol reaction. When
the aldol reaction is followed by elimination of the
ß-hydroxyl group (usually as water) to give an α,ß-unsaturated carbonyl, it
is known as the aldol condensation.
The reaction can be acid catalysed (via the enol route) or
base catalysed (via the enolate route), and both
mechanisms are given below.
See reaction notes for further information on this reaction.
1. General Scheme
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Scheme A1: Scheme of aldol condensation
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2. Mechanism [acid catalysed]
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The first
step of the acid catalysed reaction is the formation of the enol by the
protonation of the oxygen atom of the carbonyl. In this case the acid
(H-A, where A- is the conjugate base) will protonate both of
the species' oxygen atoms. |
Scheme A2: Formation of an enol
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The second step is the reaction of species (i) and (I),
whereby the carbanion (i) is attracted to the slightly positive
carbonyl carbon on (I). The oxygen has a lone pair which it uses
to bond the neighbouring hydrogen, and results in the formation of a
carbanion at the α carbon. This carbanion donates its lone pair to form
a double bond with its neighbouring carbon (the ß carbon), which
facilitates the loss of water (note that this water molecule is derived
from a hydrogen from the acid, a hydrogen from one reactant and the
oxygen from the other). The final step is the recapture of the hydrogen by
its conjugate base which leads to the regeneration of the acid catalyst.
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Scheme A3: Addition-elimination reaction to give α,ß-unsaturated
carbonyl species
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3. Mechanism [Base Catalysed] |
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The base catalysed mechanism is slightly easier to follow, as only
one species in the molecule has acidic α-hydrogens that can be removed.
The first step is the formation of the enolate, whereby the base
abstracts an acidic α-proton from the 1,2-difunctional carbonyl. This
sets up enolate resonance, which is identical to the enol resonance with
the exception that the oxygen does not have a hydrogen bonded to it. |
Scheme A4: Enolate formation
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Species (iii) is an effective nucleophile, and will attack the
slightly positive carbon on the carbonyl of the 1,1-difunctional ketone.
This pushes the carbonyl's double bond up into the oxygen which then
abstracts a hydrogen from the conjugate acid of the original base
(H-Base), thus regenerating the catalyst. The next steps are the same as
in the acid catalysed mechanism (although of course the 1,2-difunctional
carbonyl has no hydrogen bonded to its oxygen); the newly protonated
oxygen acquires the neighbouring proton, forcing a negative charge onto
the α-carbon, which then forms a double bond with the ß-carbon with the
elimination of water. Note that this time the water contains the oxygen
from the 1,1-difunctional carbonyl, but both hydrogens come from the
other carbonyl. |
Scheme A5: Reaction of enolate with ketone to give α,ß-unsubstituted
carbonyl species.
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4. Isomeric Considerations
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It is generally understood that high diastereoselectivity of the
ß-hydroxycarbonyl species can be determined from the use of preformed
enolates, whereby (E)-enolates yields the anti- product and
(Z)-enolates
favour the syn-product. This can be rationalised by
considering that the reaction proceeds via a six-membered
chair-like transition state (referred to as the Zimmerman-Traxler
model). Both examples are shown below, using a metal counter ion to
stabilise the oxygen (which would be the case in a base catalysed
reaction with an inorganic base such as NaOH).
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-enolate_syn.gif)
Scheme A6: Zimmerman-Traxler model of the (E)-enolate
-enolate_syn.gif)
Scheme A7: Zimmerman-Traxler model of the (Z)-enolate
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The controlling factor according to this theory is the avoidance of any
1,3-diaxial interaction between the functional groups or metal ligands
with the carbonyl functional group (in the case of simple bases, the
metal itself may be involved in such interactions). By placing a
hydrogen on the plain instead of a functional group, it avoids these
interactions which thus makes the transition state favourable (and more
stable). The example above uses an aldehyde for simplicity, however in
the case of a ketone the functional group that interacts least will end
up located in the plane (giving a"syn-product" with regards
to the least interactive functional group. With a ketone, steric
hindrance may also play a role in the stability of this transition
state.
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5. Reaction Notes
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The aldol reaction can unfortunately occur by self condensation when
using two different ketone based reactants. e.g. in the examples
given in the mechanistic section, the 1,2-difunctional species can in fact
condense with another molecule of itself to form a side product, shown
below (shown next to the self-condensation product is the target
molecule, TM, which was the intended product). To aid visualisation the
new sigma bond is shown in bold in the intermediate.
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Scheme A8: self condensation
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In order to prevent this, careful manipulation of stoichiometry needs to
be maintained at a practical level (e.g. mixing and delivery of
reagents. The strength of the catalyst can aid the control of this
reaction, i.e. the abstraction of acidic protons by a base,
for example, may be only possible on one of the materials using a weak
base). In some cases the self-condensation products are desired and so
the reaction is conducted with only a single reagent, e.g. just
using a 1,2 difunctionalised carbonyl.
Cross condensation can also occur (where reagents
allow) whereby both reagents can harbour a carbanion and both reagents
can attack another carbonyl's slightly positive carbon, and thus mixed
products occur. To prevent this, it is usual to attempt to protect one
of the reagents to prevent enol /enolate formation, or to use conditions
that are only just able to remove the most acid protons on one of the
reagents, and thus render the unreacted reagent the electrophile.
A common solution to this problem is to pre-form the enolate of
one reagent in a separate reaction. Thus, when introducing this
pre-formed reagent to its condensation partner in a second reaction,
there is no acid or base present to react with the other material. An
example of this is the Mukaiyama aldol reaction, whereby silyl enol
ethers are used as a way of protecting a pre-formed enolate, allowing it
to be produced, purified and stored ready to react via the aldol
reaction with another substrate on demand. Scheme A9 shows the formation of
a silyl enol ether. |
Scheme A9: Formation of protected enolate via a silyl enol ether
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Shown in Scheme A10 is a simple Mukaiyama aldol reaction. The
trimethylsilyl protection is removed by the TBAF (tetrabutylammonium
fluoride. This is used as a source of fluoride, which attacks the
silicon and results in the breakage of the silicon-oxygen bond).
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Scheme
A10: Mukaiyama aldol reaction
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The ß-hydroxycarbonyl shown is the sole product of this reaction, and in
batch it is generally seen at near quantitative yields.
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6. Further Reading
The aldol reaction is
exhaustively documented in chemical journals, online resources and
textbooks, however the following sources were useful for the creation of
this resource.
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Clayden, Greeves, Warren and Wothers; Organic Chemistry,
1st edn., 689-720.
(Oxford University Press, 1991)
Sykes;
A Guidebook to Mechanisms in Organic Chemistry, 6th edn., 224-226.
(Longman Scientific & Technical, 1986)
Kürti and
Czakó; Strategic Applications of Named Reactions in Organic
Synthesis. 1st edn., 8-9.
(Elsevier Academic Press 2005)
Carey; Organic Chemistry. 4th edn., 715-721.
(McGraw Hill
Publishing, 2000)
March and Smith; March's Advanced Organic Chemistry,
Reactions, Mechanisms and Structure. 5th edn., 1218-1225.
(John Wiley & Sons, 2001)
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