13.

1A: Keto-enol tautomerization

When we draw a ketone or aldehyde using the Lewis structure convention, we show a double bond between the carbonyl carbon and the oxygen - this
is known as the keto form. It turns out that ketones and aldehydes often exist in rapid equilibrium with a tautomeric form known as an enol.

The alpha-protons of carbonyls, as you recall, are somewhat acidic: the pKa of acetone, for example, is approximately 19. In the formation of an enol, a
base abstracts an a-proton from a carbonyl compound, and that same proton (or a proton on a nearby acid group) is transferred to the carbonyl
oxygen. The result is a new functional group that combines both alkene and alcohol characteristics - hence the term enol. The deprotonated form of
an enol is an enolate.

As a general rule, the keto form of a carbonyl is lower in energy, and thus predominates at equilibrium. Acetone, for example, is present at >99% keto
form at equilibrium.

Example
Exercise 13.1: Draw all of the possible enol forms of the following aldehydes/ketones. There may be more than one possible enol form.

a.
b.
c.
d.

3-pentanone
acetaldehyde (IUPAC name ethaldehyde)
cyclohexanone
2-pentanone
Exercise 13.2: Draw three examples of aldehyde or ketone compounds for which there is no possible enol form.

Solutions

There are a few special cases where the enol form predominates at equilibrium: 2,4-pentane dione exists mostly in its enol form (76%), due to the extra
stability of the conjugated double bonds that are present in the enol form, and due also to a favorable hydrogen bonding interaction.

We saw a good example of an enol to keto tautomerization in the last step of the pyruvate kinase reaction (section 10.2F). The enol served as a
leaving group in this phosphoryl transfer reaction, after which tautomerization occurred to form the ketone group of pyruvate.

13.1B: Imine-enamine tautomerization

Another common tautomeric relationship in biological organic chemistry is the equilibrium between imines (also known as Schiff bases) and enamines,
which are the nitrogen equivalents of enols.

The degradation of serine, for example, involves an enamine to imine tautomerization step, followed by hydrolysis of the imine (section 11.6) to form
pyruvate.

As we shall see in a later section, enamines are key intermediates in a very important type of carbon-carbon bond-forming reaction.

Aldehydes and ketones are somewhat lycanthropic chemical species. Take acetone. It
behaves as a garden-variety polar aprotic solvent, which makes it a useful medium for SN2
reactions; it reacts readily with nucleophiles like enolates, Grignards, and amines; and is
several pKa units less acidic than alcohols (~20 vs. 16). This chemical behavior reflects the
fact that it spends the vast majority of its time as a ketone, with an electrophilic carbonyl
carbon. Its nice and stable. You use it to wash glassware with, or as paint thinner.

But every couple of blue moons (for acetone in water about 1/6600 th of the time at 23 C)
acetone undergoes a transformation to its alter ego, the enol form. [EDIT: equilibrium
constant is 1 x 10^-8 in water) And as its name suggests, the enol form which is an
isomer, not a resonance form has the characteristics of both alkenes and alcohols: it can
involve itself inhydrogen bonding via the OH group, it is acidic at oxygen, and it reacts with
electrophiles (like aldehydes, for example, in the Aldol reaction). In short, the enol form
differs from the keto form in its polarity, acidity, and nucleophilicity just like werewolves differ
from ordinary folks in their copious body hair, nocturnal rambunctiousness, and peculiar
dietary habits.
The reason for the equilibrium lying to the left is due to bond energies. The keto form has a
CH, CC, and C=O bond whereas the enol has a C=C, CO an OH bond. The sum of the
first three is about 359 kcal/mol (1500 kJ/mol) and the second three is 347 kcal/mol (1452
kJ/mol). The keto form is therefore more thermodynamically stable by 12 kcal/mol (48
kJ/mol).
Although the keto form is most stable for aldehydes and ketones in most situations,
there are several factors that will shift the equilibrium toward the enol form. The
same factors that stabilize alkenes or alcohols will also stabilize the enol form. There are
two strong factors and three subtle factors.
Biggies (2):
1. Aromaticity. Phenols can theoretically exist in their keto forms, but the enol form is
greatly favored due to aromatic stabilization.
2. Hydrogen Bonding. Nearby hydrogen bond acceptors stabilize the enol form. When a
Lewis basic group is nearby, the enol form is stabilized by internal hydrogen bonding.

Here are three more subtle effects in keto-enol tautomerism:

3. Solvent. Solvent can also play an important role in the relative stability of the enol form.
For example, in benzene, the enol form of 2,4-pentanedione predominates in a 94:6 ratio
over the keto form, whereas the numbers almost reverse completely in water. Whats going
on? In a polar protic solvent like water, the lone pairs will be involved in hydrogen bonding
with the solvent, making them less available to hydrogen bond with the enol form.
4. Conjugation . systems are a little like Cheerios in milk: given the choice, they want to
connect together than hang out in isolation. So in the molecule depicted, the more
favorable tautomer will be the one on the left, where the double bond is a connected by
conjugation to the phenyl.
5. Substitution. In the absence of steric factors, increasing substitution at carbon will
stabilize the enol form. Enols are alkenes too so any factors that stabilize alkenes, will
stabilize enols as well. All else being equal, double bonds increase in thermodynamic
stability as substitution is increased. So in the above example, the enol on the left should be
the more stable one. As you might suspect, all things being equal sounds like a big
caveat. It is all else is rarely equal. But thats a topic for another day or, more likely,
another course.