Su bst it ution rea ct ions o f car b on yl co m po un ds at t he α- pos it io n
Carbonyl compounds are acidic at α-C (e.g. CHR2COR ); this is because of the
electrophilic nature of carbonyl C=O bond. The pKa values of simple carbonyl
compounds are generally in between 15-20; loss of an α hydrogen is stabilized
by the C=O dipole.
Thus under basic conditions, bases immediately deprotonate carbonyl
compounds to give an enolate.
O
O
-:B
R
O
R
H
H
H
H
R
H
H
H
resonance-stabilized enolate
How important is the electronegative oxygen atom to the stabilization of the
enolate?
pKa of an α hydrogen of CH3CH=CH2 = 43
pKa of an α hydrogen of CH3CH=O = 16.7
Under acidic conditions, carbonyl compounds are protonated on O first, then
weak base deprotonates at the α-C to give enol.
O
OH
H3O+/H2O
OH
R
H
R
H
H
OH
R
H
H
H
H
R
H
H
H
resonance-stabilized enol
OH
R
H
H
H
In base or in acid, carbonyl compounds that have α-hydrogens are in equilibrium
with their enolate or enol forms.
So, where does the equilibrium lie between the carbonyl compound and its enol
form, and how does it depend on structure?
O
OH
H
Simple aldehydes and ketones are predominantly in their carbonyl forms; e.g.
acetaldehyde and acetone have less than 1% of the enol tautomer present at
equilibrium – the C=O bond is stronger than the C=C bond and dominates (see
section 23 .2 in your textbook).
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More complex carbonyl compounds can be much more enolized; for example,
1,3-dicarbonyls (β-dicarbonyls) exist primarily in their enol forms
H
O
O
H
H
pKa = 9
O
H
O
H
O
O
H
76% enol tautomers
See Ta b le 2 3 .2 for typical pKa values for carbonyl compounds and nitriles.
Reactions of Enols and Enolates
Both enolate and enol are nucleophilic at C (and O).
For example, enolates react in the presence of good electrophiles by undergoing
substitution of the alpha carbon.
The addition of electrophiles to the alpha carbon via the acid- or base-induced
formation of enols or enolates is quite common.
1. Reaction under acidic conditions (i.e. reaction of enols):
1a. Acid-Catalyzed Halogenation of Aldehydes and Ketones
Aldehydes can easily be mono-halogenated at the alpha position by simply
mixing the aldehyde with a halogen (usually Br2 or I2) and a trace of acid.
IMPORTANT NOTE - if there are no alpha hydrogens, this reaction will not take
place!
when various possible enols are formed under equilibrating conditions, usually
the MOST STABLE enol is the one formed in the highest concentration and thus,
is the one that reacts with the halide. For example, methyl cyclohexanone can
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form two different enols - the more highly substituted one is the most stable,
and thus predominates:
There are two major uses for these bromo-ketones and aldehydes. The first is
elimination to form conjugated carbonyl compounds. This is a classic (and
simple) method for preparing such compounds:
1b. The Hell-Volhard-Zelinskii Reaction
The acid-promoted alpha halogenation only works with aldehydes and ketones.
What if you need to brominate a carboxylic acid? That’s where the HVZ reaction
comes in. The reaction basically takes a difficult-to-enolize carboxylic acid, and
first turns it into a much more enolizable acid bromide. Aqueous workup returns
the acid bromide to the carboxylic acid state. Workup with an alcohol would, of
course, produce the ester.
the first step is formation of the acid bromide, which is in equilibrium with its
enol form. Bromination of the enol form gives an isolable α-bromo acid bromide.
O
PBr3
R
OH
H
H
OH
O
Br2
R
R
Br
Br
H
H
acid bromide
H
enol form
O
R
Br
H
Br
The latter reacts like an acid chloride and can be used to generate α-bromo acid,
ester, and amide.
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O
R
H2O
OH
H Br
O
R
H Br
O
HOR
R
Br
NH3
OR
H Br
O
R
NH2
H Br
Please remember that while this reaction can be used to form an ester, it cannot
be used with an ester as starting material – you must start with the carboxylic
acid!
2. Reaction under basic conditions (i.e. Reaction of enolates)
Under sufficiently basic conditions, an enolate ion can be formed:
However, we must generally be careful with our choice of bases – if the base is
also a good nucleophile, then attack at the carbonyl carbon becomes a more
likely pathway. The most common bases used to form enolate ions are sodium
hydride (very basic, non-nucleophilic) and Lithium Diisopropylamide (LDA, very
bulky, thus non nucleophilic). Occasionally, hydroxide ion is used, but this is
usually for very specific reactions (e.g. the haloform reaction).
Dis cuss Ta ble 23 .3
– HO- and RO- bases are more useful for forming enolates from 1,3-dicarbonyl
compounds or in reactions that involve both the enolate and carbonyl starting
material.
The enolate ion has two nonequivalent resonance forms (compare this with both
the allyl anion and the carboxylate anion). The form where the charge is localized
on the oxygen predominates (because of the electronegativity of oxygen), but
the form with the charge localized on carbon is more nucleophilic, and is thus
the form that typically reacts with electrophiles:
There are a few exceptions to this rule; generally acyl and silyl halides (TMS-Cl or
CH3COCl) will react with the oxygen anion, to give silyl enol ethers and enol
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acetates, respectively. As you might expect, alkylation of an enolate is a
powerful tool for the formation of carbon-carbon bonds under relatively mild
conditions.
The Haloform Reaction:
While enolates are great for forming new carbon-carbon bonds, the first reaction
we’ll look at is a method for the destruction of a carbon-carbon bond.
Essentially, the haloform reaction takes a methyl ketone (or a molecule which
can be oxidized to a methyl ketone), and turns it into a carboxylic acid with one
less carbon:
How does it work? As you probably expect, the enolate is formed, and is then
halogenated. The protons on the halogenated compound are even more acidic,
thus facilitating further enolization and halogenation. When the compound is
fully halogenated (in this case, forming a CI3 group), there are no more acidic
protons, so we look for the next possible mechanistic route: nucleophilic attack.
Addition-elimination (as shown) leads to the carboxylate anion and a haloform (in
this case, iodoform):
2b. Alkylation of Enolates
Normal enolates formed by the action of LDA or NaH can generally be alkylated
with alkyl iodides, bromides or tosylates, or benzylic or allylic halides. However,
these reactions can sometimes be difficult to perform in high yield. A few
methods do exist which allow enolate alkylations in high yield, and both take
advantage of highly stabilized enolate anions: The Malonic Ester synthesis, and
the Acetoacetic Ester synthesis. We’ll look at each of these in detail.
The Ma lo n ic Este r S ynt hes is.
Esters of malonic acid (in this case, diethyl malonate) are easily deprotonated to
form the highly stabilized enolate (note sodium ethoxide is used as base – why
not NaOMe?):
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As you can see, the negative charge is delocalized over one carbon and two
oxygens – a very stable anion! The only significantly nucleophilic form is the one
with the negative charge on the carbon, and this is the form that gets alkylated.
You should note that there are two acidic protons on a malonic ester - thus it
can be alkylated twice if desired. If an alkyl compound with two halogens is
added, cyclic compounds can be formed.
But the really cool thing about malonic esters (and acetoacetic esters, which
we’ll see in a minute) is a reaction called decarboxylation. Once a malonic ester is
hydrolyzed, then treated with acid, the two carbonyl groups interact, and
through a 6-membered ring transition state (remember how organic molecules
love to react through 6-membered ring - e.g. think of the Diels Alder reaction!),
one of the carbonyl groups is blown off as CO2:
Note that this is not a common reaction, and only happens with 1,3-dicarbonyl
groups!!!!! Thus, malonic ester chemistry is an ideal way to make substituted
acetic acids (which can then be converted to acid chlorides). Let’s look at an
example:
Acet oa cet ic Est er S ynt hes is
The acetoacetic ester synthesis is almost exactly like the malonic ester synthesis
– invloves a 1,3-dicarbonyl compound that is easily alkylated, and which also
decarboxylates. But instead of making substituted acetic acid derivatives, this
reaction makes substituted acetones.
Just like in the malonic ester synthesis, the protons between the carbonyl
groups are particularly acidic. They can be deprotonated with alkoxide (e.g.
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NaOEt), or sodium hydride, to yield the stabilized anion. Alkylation is also
straightforward. The only difference comes in the decarboxylation step, where
the only carboxyl group is lost to leave a methyl ketone
Some things to note for both the acetoacetic ester and malonic ester synthesis
(all of which are noted for the scheme below):
1) These are highly stabilized anions, and will thus add to conjugated carbonyl
compounds in a 1,4 fashion. Decarboxylation leads to the vinyl-substituted
compound.
2) Saponiofication and decarboxylation can occur in one step - provided the
temperature is high enough (usually, 110 - 120°C will do it).
3) Note that all esters in the molecule are saponified, but only the 1,3dicarbonyl compounds can undergo decarboxylation.
4) As you’ll see in lecture, many different electron withdrawing groups can
stabilize enolate charges, and lead to a large variety of different compounds.
However, you’ll only get decarboxylation if you have at least one group that can
be hydrolyzed to an acid, which is separated from another carbonyl group by
one carbon. For example:
Of course, this same ketone could be alkylated directly:
The product is the same, and there are fewer steps, but the reaction conditions
are much more harsh. Furthermore, if we were not working with a symmetrical
ketone, a mixture of products would result. Sometimes taking a few extra steps
is worth it...
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With simple esters and ketones, however, direct alkylation of the enolate is
usually the way to go:
Notes:
1) These non-stabilized enolated are very basic - alkylation generally won’t
happen with anything other than primary, allylic or benzylic halides. Secondary
and tertiary halides will give elimination products...
2) Again, if there is more than one way to form the enolate, you’ll get a mixture
of products...
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