Car b on yl Co nd ensa tion Rea ct ions (C o nj ug ate Add ition )
If we look at resonance structures for conjugated carbonyl compounds (often
called α,β-unsaturated compounds), we’ll see that there are TWO sites for
nucleophilic attack. Thus, we’ll find that the alpha carbon is often quite
nucleophilic and the β carbon is electrophilic.
Addition of a nucleophile to the double bond to form an enolate, which
tautomerizes to the ketone, is called conjugate addition.
When carbonyl addition or conjugate addition will occur? In other words, when
will a nucleophile add to the carbonyl, or the double bond of a conjugated
carbonyl compound?
We have seen that “hard” nucleophiles, such as present in RMgBr and RLi
reagents, add to the carbonyl. A way to force only conjugate addition with an
organometallic reagent is to form the copper salt - in this case, a dialkylcuprate.
We’ve already seen these are used to prepare ketones from acid chlorides –
formation of copper salts is a great way to “soften” a hard nucleophile.
Thus, “soft” nucleophiles favor conjugate addition to α,β-unsaturated
compounds. Hence non-carbon nucleophiles like nitrogen (amines) and oxygen
(alcohols) will always add in a conjugate fashion, particularly if the reaction is
carried out under neutral conditions. Some examples:
Enolates are also “soft” nucleophiles and hence add to conjugated carbonyls in
conjugate fashion.
Ald ol Rea ct ion
Two molecules of an aldehyde or ketone react with each other in the presence
of base to form a β-hydroxy carbonyl compound:
1
O
HO–, H2O
O
2
H
H
+ HO–
HO
O
O
O
H
H
H
O
O
H
H
OH
In this reaction, an enolate is the nuclophile; one aldehyde molecule becomes the
enolate while the other molecule serves as the electrophile.
With aldehydes, the equilibrium usually favors the aldol products. But with
ketones, the equilibrium usually favors starting materials. Of course, there are
ways to derive the equilibrium towards products in either case. You should also
note that an y carbonyl compound with alpha hydrogens can undergo the aldol
reaction (i.e. esters, acids, etc.).
How can we tell whether a molecule is going to undergo an aldol-like reaction, or
an enolate-like reaction? There are a couple of clues:
1) STRONG base. If bases like LDA are being used, and a decent electrophile is
present, then you’re likely looking at an e no late type reaction.
2) GOOD electrophiles. If there’s another strong electrophile around, such as a
halogen molecule (Br2, for example), or something like iodomethane (CH3I),
you’re looking at an en ola te type of reaction.
3) Catalytic amounts of a weak base. If t he r e are no ot he r e le ctr op hiles
adde d, then the use of a “weaker” base, such as sodium ethoxide (NaOEt) or
hydroxide (HO-) is usually a clue that an a ld o l-type reaction will be taking
place.
Ald ol C on den sat io n
β-Hydroxy carbonyl compounds formed in the aldol reaction dehydrate more
readily than other alcohols. In fact, under basic conditions, the β-hydroxy
carbonyl compound is often not isolated; it loses elements of H2O from the α
and β carbons to form an α,β-unsaturated compound. For example,
2
As you see, the ene-al is simply the aldol product minus the elements of water a condensation reaction. In fact, e lim inatio n o f wate r is sp on tan eo us a nd
the β- h yd rox y car bo n yl co mp o un d is n o t is ola ted when the α,βunsaturated product is further conjugated with a C=C or a benzene ring:
O
O
HO–,
O
H 2O
Ph
2
Ph
CH3
H3C
HO
HO–
Ph
-H2O
Ph
H3C
Ph
NOT ISOLATED
So, one more time . . . the aldol condensation takes a carbonyl compound
(usually an aldehyde, ketone or ester) and joins two of them together to form a
conjugated carbonyl compound.
Generally, with aldol condensations you are combining two of the same molecule
to form a dimer. However, in a few cases it is possible to combine two different
molecules to form the aldol product. There are two MAJOR restrictions: (1) One
of the pair must not have any enolizable (i.e. alpha) protons (for example, aryl
aldehydes & ketones like benzaldehyde or benzophenone).
H
OEt
O
OR (2) One of the pair must form an enol MUCH more easily than the other
Cla ise n Co nd ensa tion
But what about the enolates of other carbonyl compounds, such as esters? Do
they undergo these “self-condensation” reactions as well? Of course they do!
However, the thing to note is that esters have essentially a “leaving group”
attached to the carbonyl carbon. Thus, the products of the condensation
reaction are slightly different. In essence, the product of an aldol-type reaction
between two esters is almost always a 1,3-dicarbonyl compound. In its simplest
form:
3
(note - why do we use NaOEt, and not NaOH?).
Again, this is a fairly general reaction – just about any ester can undergo this
type of self-condensation. The “driving force” of this reaction is not dehydration,
however – it is the formation of the stable enolate anion (i.e. the one between
the two carbonyl groups) that makes the final step irreversible. Is it possible to
do “mixed” Claisen reactions? Of course, provided the same rules are followed as
for the mixed aldol. One component must either have no enolizable protons, or
must be enolized VERY rapidly.
Mechanism Practice!!! Draw the mechanism for the reaction above.
M ichea l Add ition
The nature of the electrophile is also worth considering. What if we have a
conjugated carbonyl compound? Recall that we then add a stabilized nucleophile
to the alkene portion – a 1,4 addition. Malonates and keto-esters are particularly
good at this type of reaction, called a Michael addition:
4
If a large excess of the conjugated compound is used, it is of course possible to
get a double-Michael (dialkylated) product:
5