Carbanions and Enolizations

Ionization of CH Bonds

In theory any organic compound such as (1) that contains a CH bond, i.e., nearly all of them
can function as an acid in the classical sense by donating a proton to a suitable base, the
resultant conjugate base (2) being a carbanion:

In considering relative acidity, classically it is only the thermodynamics of the situation that
are of interest in that the pKa value for the acid can be derived from the equilibrium above.
The kinetics of the situation is normally of little significance, as proton transfer from atoms
such as O, N, etc., is extremely rapid in solution. With carbon acids such as (1), however, the
rate at which proton is transferred to the base may well be sufficiently slow as to constitute
the limiting factor: the acidity of (1) is then controlled kinetically rather than
thermodynamically.

Carbanion Formation
The most general method of forming carbanions is by removal of an atom or group X from
carbon, X leaving its bonding electron pair behind:

By far the most common leaving group is X = H where, as above, it is a proton that is
removed, (1)  (2), though other leaving groups are also known, e.g., CO2 from the
decarboxylation of RCO2 (3), or Cl from Ph3CCl to yield the ether soluble salt (4):

Hardly surprisingly the tendency of alkanes to lose proton and form carbanions is not
marked, as they possess no structural features that either promote acidity in their H atoms, or
are calculated to stabilize the carbanion with respect to the undissociated alkane. Thus CH4
has been estimated to have a pKa value of  43, compared with 4ꞏ76 for MeCO2H. The usual

1
methods for determining pKa do not, of course, work so far down the acidity scale as this, and
these estimates have been obtained from measurements on the iodide/organometallic
equilibria:

The assumption is made that the stronger an acid, RH, is the greater will be the proportion of
it in the form RM (e.g., M = Li) rather than as RI. Determination of the equilibrium constant
K allows a measure of the relative acidity of RH and R'H, and by suitable choice of pairs it is
possible to ascend the pKa scale until direct comparison can be made with an RH compound
whose pKa has been determined by other means.

Thus Ph3CH (5) is found to have a pKa value of 33, i.e., it is a very much stronger acid than
CH4, and the carbanion (4) may be obtained from it, preparatively, by the action of sodamide,
i.e., NH2, in liquid ammonia:

Ph3C may also be obtained, as we saw above, by the action of sodium on Ph3CCl (3) in an
inert solvent; the resulting solution of sodium triphenylmethyl is used as a very strong
organic base because of the proton-appropriating ability of the carbanion (4). Alkenes are
slightly stronger acids than the alkanes, CH2=CH2 has a pKa value of 37, but the alkynes are
very much more strongly acidic, and HCCH itself has a pKa value of 25. The carbanion
HCC (or of course RCC) may be generated from the hydrocarbon with NH2 in liquid
ammonia.

Hardly surprisingly, the introduction of electron-withdrawing substituents also increases the

acidity of hydrogen atoms on carbon. Thus we have already seen the formation of a
somewhat unstable carbanion, CCl3 in the action of strong bases on chloroform, and the pKa
values of HCF3 and HC(CF3)3 are found to be  28 and 11, respectively. The effects with
substituents that can delocalize a negative charge, as well as having an electron-withdrawing
inductive effect, are even more marked; thus the pKa values of CH3CN, CH3COCH3 and
CH3NO2 are found to be 25, 20 and 10ꞏ2, respectively. With CH3NO2, the corresponding
carbanion, CH2NO2, may be obtained by the action of OEt in EtOH, or even of OH in
H2O; but small concentrations of carbanion must be developed in aqueous solution even from
the less acidic carbonyl compounds to enable the aldol reaction to take place.

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A table of some pKa values for carbon acids is appended for convenience, before going on to
discuss the factors that can contribute to the relative stabilization of carbanions:

Compound pKa Compound pKa

CH4 43 CH2(CO2Et)2 13.3

CH2=CH2 37 CH2(CN)2 12

C6H6 37 HC(CF3)3 11

PhCH3 37 MeCOCH2CO2Et 10.7

Ph3CH 33 CH3NO2 10.2

CF3H 28 CH2(MeCO)2 8.8

HCCH 25 CH(MeCO)3 6

CH3CN 25 CH2(NO2)2 4

CH3COCH3 20 CH(NO2)3 0

C6H5COCH3 19 CH(CN2)3 0

Stability of Carbanions
There are a number of structural features in RH that promote the removal of H by bases
through making it more acidic, and also features that serve to stabilize the resultant
carbanion, R; in some cases both effects are promoted by the same feature. The main
features that serve to stabilize carbanions are (cf. factors that serve to stabilize carbocations):

(a) Increase in s character at the carbanion carbon;

(b) Electron-withdrawing inductive effects;

(c) Conjugation of the carbanion lone pair with a polarized multiple bond; and

(d) Aromatization.

The operation of (a) is seen in the increasing acidity of the hydrogen atoms in the sequence:
CH3CH3 < CH2=CH2 < HCCH; the increase in acidity being particularly marked on going
from alkene to alkyne. This reflects the increasing s character of the hybrid orbital involved
in the  bond to H, i.e., sp3 < sp2 < sp1. The s orbitals are closer to the nucleus than the
corresponding p orbitals, and they are at a lower energy level; this difference is carried

3
through into the hybrid orbitals resulting from their deployment. The electron pair in an sp1
orbital is thus held closer to, and more tightly by, the carbon atom than an electron pair in an
sp2 or sp3 orbital (effectively, the apparent electronegativity of the carbon atom increases).
This serves not only to make the H atom more easily lost without its electron pair, i.e., more
acidic, but also to stabilize the resultant carbanion.

The operation of (b) is seen in HCF3 (pKa = 28) and HC(CF3)3 (pKa = 11), where the change
from CH4 (pKa = 43) is brought about by the powerful electron-withdrawing inductive effect
of the fluorine atoms making the H atom more acidic, and also stabilizing the resultant
carbanions, CF3 and C(CF3)3 by electron-withdrawal. The effect is naturally more marked
in HC(CF3)3 where nine F atoms are involvedcompared with only three in HCF3despite the
fact that they are not now operating directly on the carbanion carbon atom. We have already
referred to the formation of CC13 from HCC13, where a similar electron-withdrawing
inductive effect must operate. This is likely to be less effective with Cl than with the more
electronegative F, but the deficiency may be overcome to some extent by the delocalization
of the carbanion electron pair into the vacant d orbitals of the second row element chlorine
and this is, of course, not possible with the first row element fluorine. The destabilizing
influence of the electron-donating inductive effect of alkyl groups is seen in the observed
carbanion stability sequence:

CH3 > RCH2 > R2CH > R3C

Hardly surprisingly, it is the exact reverse of the stability sequence for carbocations.

The operation of (c) is by far the most common stabilizing feature, e.g., with CN (6), C=O
(7), NO2 (8), CO2Et (9), etc.:

B: H

H2C C N H2C C N H2C C N + BH pKa = 25

(6) (10a) (10b)

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There is in each case an electron-withdrawing inductive effect increasing the acidity of the H
atoms on the incipient carbanion atom, but the stabilization of the resultant carbanion by
delocalization is likely to be of considerably greater significance. Overall, NO2 is the most
powerful as might have been expected. The marked effect of introducing more than one such
group on to a carbon atom may be seen from the table of pKa values above; thus CH(CN)3
and CH(NO2)3 are as strong acids in water as HCl, HNO3 etc. The question does arise
however, about whether (10ab), (11ab) and (12ab) ought to be described as carbanions: O and
N are more electronegative than C and (10b), (11b) and (12b) are likely to contribute
markedly more to the hybrid anion structure than (10a), (11a) and (12a), respectively.

The carboxylate group, e.g., CO2Et (9), is less effective in carbanion stabilization than the
C=O group in simple aldehydes and ketones, as may be seen from the sequence of pKa
values: CH2(CO2Et)2, 13ꞏ3; MeCOCH2CO2Et, 10ꞏ7; and CH2(COMe)2, 8ꞏ8. This is due to the
electron-donating conjugative ability of the lone pair of electrons on the oxygen atom of the
OEt group:

With second row elements, as we saw above, any inductive effect they exert may be
complemented by delocalization, through use of their empty d orbitals to accommodate the
carbanion carbon atom's lone pair of electrons; this can happen with S in an ArSO2
substituent, and also with P in an R3P substituent.

The operation of (d) is seen in cyclopentadiene (14) which is found to have a pKa value of 16
compared with  37 for a simple alkene. This is due to the resultant carbanion, the
cyclopentadienyl anion (15), being a 6 electron delocalized system, i.e., a 4n + 2 Hückel
system where n = l. The 6 electrons can be accommodated in three stabilised  molecular
orbitals, like benzene, and the anion thus shows quasi-aromatic stabilization; it is stabilised
by aromatization:

5
Its aromaticity cannot, of course, be tested by attempted electrophilic substitution, for attack
by X would merely lead to direct combination with the anion. True aromatic character (e.g.
a Friedel-Crafts reaction) is, however, demonstrable in the remarkable series of extremely
stable, neutral compounds obtainable from (15), and called metallocenes, e.g., ferrocene (16),
in which the metal is held by  bonds in a kind of molecular 'sandwich' between the two
cyclopentadienyl structures:

Enol and Enolate: Tautomerism

Tautomerism, strictly defined, could be used to describe the reversible interconversion of
isomers, in all cases and under all conditions. In practice, the term has increasingly been
restricted to isomers that are fairly readily interconvertible, and that differ from each other
only (a) in electron distribution, and (b) in the position of a relatively mobile atom or group.
The mobile atom is, in the great majority of examples, hydrogen, and the phenomenon is then
referred to as prototropy. Familiar examples are -ketoesters, e.g., ethyl-2-ketobutanoate
(ethyl acetoacetate, 1), and aliphatic nitro compounds, e.g., nitromethane (2):

Such interconversions are catalyzed by both acids and bases.

Mechanism of Interconversion
Prototropic interconversions have been the subject of much detailed study, as they lend
themselves particularly well to investigation by deuterium labelling, both in solvent and
substrate, and by charting the stereochemical fate of optically active substrates having a chiral
center at the site of proton departure. Possible limiting mechanisms are those: (a) in which

6
proton removal and proton acceptance (from the solvent) are separate operations, and a
carbanion intermediate is involved, i.e., an intermolecular pathway; and (b) in which one and
the same proton is transferred intramolecularly:

Many of the compounds that undergo ready base-catalyzed keto↔enol prototropic changes,
e.g., -keto esters, 1,3-(-) diketones, aliphatic nitro compounds, etc., form relatively stable
carbanions, e.g., (3), that can often be isolated. Thus it is possible to obtain carbanions from
the 'keto' forms of the -keto ester (1a) and nitromethane (2a) and, under suitable conditions,
to protonate them so as to obtain the pure enol forms (1b) and (2b), respectively. It thus
seems extremely probable that their interconversion follows the intermolecular pathway (a).
The more acidic the substrate, i.e., the more stable the carbanion to which it gives rise, the
greater the chance that prototropic interconversion will involve the carbanion as an
intermediate.

The mechanism (a) nicely illustrates the difference between tautomerism and mesomerism
that often gives rise to confusion. Thus taking ethyl 2-ketobutanoate (1) as an example, (1a)
and (1b) are tautomers: quite distinct, chemically distinguishable and different species,
readily interconverted but, in this case, actually separately isolable in a pure state.

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The two structures written for the carbanion intermediate (5) are mesomers: they have no real
existence at all; they are merely somewhat inaccurate attempts to represent the electron
distribution in the carbanion, which is a single individual only. It is perhaps better to
represent (5) by a single structure of the form, but this is still not wholly satisfactory in that it
does not convey the important fact that more of the negative charge on the anion is located on
the more electronegative oxygen, rather than on the carbon atom. Indeed, though we have
referred (and will, for convenience, continue to refer) to species such as (5) as carbanions,
they are alsoand perhaps more correctlyreferred to as enolate anions. It is very common to
find a pair of tautomers, such as (1a) and (1b), 'underlain' as it were by a single, stabilised
carbanion/enolate anion such as (5).

Position of Equilibrium and Structure

In this context it is keto/enol systems that have been investigated by far the most closely, and
most of our discussion will center on them. The relative proportion of the two forms was
commonly determined chemically, e.g., by titration of the enol form with bromine under
conditions such that the rate of keto/enol interconversion was very low; it is, however, more
accurate and more convenient to do this spectroscopically, e.g., in the IR for ethyl 3-
ketobutanoate:

In simple carbonyl compounds, e.g., MeCOMe, the proportion of enol at equilibrium is

extremely small; the main structural features that result in its increase may be seen in the
table below. The major feature is a multiple bond, or a  orbital system such as Ph, which can
become conjugated with the C=C double bond in the enol form. C=O is clearly effective in
this respect, with an ordinary carbonyl C=O group being considerably more effective than the
C=O in an ester group, cf. MeCOCH2CO2Et (8%) and CH2(CO2Et)2 (7ꞏ7103%). The added

8
effect of Ph may be seen in comparing MeCOCH2CO2Et (8%) with MeCOCHPhCO2Et
(30%), and MeCOCH2COMe (76ꞏ4%) with PhCOCH2COMe (89ꞏ2%).

Compounds % Enol in liquid

MeCOMe 1.5104

CH2(CO2Et)2 7·7103

NCCH2CO2Et 2.5101

Cyclohexanone 1.2

MeCOCH2CO2Et 8.0

MeCOCHPhCO2Et 30.

MeCOCH2COMe 76.4

PhCOCH2COMe 89.2

Another feature that will serve to stabilise the enol, with respect to the keto, form is the
possibility of strong, intramolecular hydrogen bonding, e.g., in MeCOCH2COMe (6) and
MeCOCH2CO2Et (1).

H H
O O O O

C C C
Me C Me Me C OEt
H H
(6) (1)

Apart from any stabilization effected with respect to the keto form, such intramolecular
hydrogen-bonding will lead to a decrease in the polar character of the enol, and to a more
compact, 'folded-up' conformation of the molecule, compared with the more extended
conformation of the keto form. This has the rather surprising result that where keto and enol
forms can actually be separated, the latter usually has the lower boiling point despite its
hydroxyl group.

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Carbanion Reactions
α-Halogenation of Ketones (SE1 Reaction)
One of the earliest observations relating to the possible occurrence of carbanions as reaction
intermediates was that the bromination of acetone, in the presence of aqueous base, followed
the rate law,
Rate = k[MeCOMe][OH]

i.e., was independent of [Br2]. Subsequently it was shown that, under analogous conditions,
iodination took place at the same rate as bromination; as was to be expected from the above
rate law. Base-induced deuterium exchange (in D2O), and racemization, of the optically
active ketone (1) occur at the same rate, and are subject to a kinetic isotope effect (kH > kD)
when the -H atom is replaced by D, i.e., CH bond-breaking is involved in the slow, rate-
limiting step. All these observations make the involvement of a common carbanion
intermediate, e.g., (2), virtually inescapable:

This intermediate is then attacked in a fast, non rate-limiting step by any one of the series of
electrophilesX2 (Cl2, Br2, I2), H2O, D2O, etc.to yield end-products such as (3), (4), etc.; all
of which will necessarily be produced at the same rate. This process has a formal
resemblance to slow, rate-limiting formation of a carbocationic intermediate, followed by
rapid nucleophilic attack, in the SN1 pathway; it is therefore referred to as an SE1 process.

With ketones such as (5), that have alternative groups of -H atoms to attack, two questions
arise: (a) which group, the CH2 or the CH3, is attacked preferentially, and (b) when one H has
been substituted by halogen, will a second halogen become attached to the same or to the
other -carbon atom. So far as (a) is concerned, it is found that bromination of, for example,
MeCH2COCH3, yields 1- and 3-bromobutanones in virtually equal amount (both these
bromoketones then undergo very rapid further reaction. The inductive effect exerted by a

10
simple alkyl group, R, thus appears to have relatively little effect on the acidity of (2)H, or on
the stability of the resultant carbanion/enolate anion, (7):

So far as (b) is concerned, an introduced halogen substituent, e.g., Br in (8), is found to exert
very considerable influence on the position at which further halogenation occurs:

The powerful electron-withdrawing inductive/field effect exerted by Br makes the -H atoms
of the CH2Br group more acidic than those of the RCH2 group, and may also help stabilize
the resultant carbanion (9), compared with (10). The former will thus be formed
preferentially, and further bromination will thus be expected on CH2Br rather than on RCH2.
Further, because of this electron withdrawal by the Br atom, (9) will be formed more rapidly
than was, for example, (6), i.e., the second bromination will be faster than the first; and the
third bromination of CH3 will be correspondingly faster still. We might thus expect the end-
product of this base-catalyzed halogenation to be RCH2COCX3 (11). Reversible addition of

OH to the C=O group of the ketone can, however, take place at any time, and in CX3 we
now have an excellent leaving group; the result is thus CC bond fission:

CX3 is a good leaving group because of the electron-withdrawing inductive effect of the three
halogen atoms; this activates the carbonyl carbon atom in (11) to nucleophilic attack, and also

11
stabilizes the departing carbanion (12). The end-product, apart from the carboxylate anion
(13), is the haloform (14), and the overall process is known as the haloform reaction.

RCH2COCH3  RCH2CO2 + HCX3

It has been employed as a diagnostic test for methyl ketones, using I2 and aqueous base as the
resultant CHI3 (Iodoform) is yellow, has a highly characteristic smell, and is insoluble in the
reaction medium.

The halogenation of ketones is also catalyzed by acids; the rate law observed is,
Rate = k[ketone][acid]
As with the base-catalyzed reaction, the rates of bromination, iodination, deuterium exchange
and racemization are identical. This time the common intermediate, whose formation is slow
and rate-limiting, is the enol (15):

This then undergoes rapid, non rate-limiting attack by Br2 or any other electrophile present.
To discover which of the groups of -H atoms would be expected to undergo preferential
substitution in RCH2COCH3 requires comparison of the formation of the relevant enols, (16)
and (17):

Of these (16) is likely to be more stable than (17) as it has the more heavily substituted
double bond of the two; the favored bromination product is thus expected to be (18). In fact,
the acid-catalyzed bromination of MeCH2COCH3 is indeed found to yield about three times
as much 3- as 1-bromobutanone.

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Carbanion from Active Hydrogen Compounds to Carbonyl: Knoevenagel
Reaction
Knoevenagel reaction is an organic reaction used to convert an aldehyde or ketone (1) and an
activated methylene (2) to a substituted alkene (3) using an amine base as a catalyst.

The reaction begins by deprotonation of the activated methylene (2) by the base to give a
resonance stabilized enolate (4). The enolate (4) then reacts with aldehyde or ketone (1)
produces another enolate (5), which protonated to yield (6). Subsequent base-induced
elimination from (6) results the final product (3).

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Carbanion from Anhydride to Aromatic Aldehyde: Perkin Reaction
The Perkin reaction is an organic reaction used to convert an aromatic aldehyde and an
anhydride to an αβ-unsaturated carboxylic acid using sodium acetate, a base, and an acid
work-up.

In this reaction the carbanion (4) is obtained by removal of an -H atom from a molecule of
an acid anhydride (2), the anion of the corresponding acid acting as the necessary base; the
carbonyl acceptor is pretty well confined to aromatic aldehydes. The products are αβ-
unsaturated acids, e.g., 3-phenylpropenoic (cinnamic) acid (3) from PhCHO (1) with excess
(CH3CO)2O and CH3COONa at 140 °C. The carbanion (4) attacks the carbonyl carbon of the
aldehyde (1) in the usual way to yield the alkoxide anion (5a). Internal transfer of the acetyl
group in this anion is believed to take place: from the carboxyl oxygen atom (in 5a) to the
alkoxy oxygen atom (in 5b), via the cyclic intermediate (6); thereby forming a more stable
species. Removal of an -H from this anion by CH3COO results in the loss of a good
leaving group CH3COO from the adjacent -position yields the anion (3a) of the -
unsaturated acid. Work up of the reaction mixture with dilute acid leads to the product (3).

Some support for this mechanism is provided by the observation that on reaction with
anhydrides of the form (R2CHCO)2Owhere there would be no -H to remove in the
intermediate corresponding to (5b)it is possible to isolate the analogue of (5b) as the actual
end-product of the reaction.

14
Carbanion (from Aromatic Aldehyde) to Aromatic Aldehyde with the
Involvement of Cyanide Ion: Benzoin Condensation
This reaction of aromatic aldehydes, PhCHO, resembles the Cannizzaro reaction in that the
initial attack is by an anion, CN, on the carbonyl carbon atom of one molecule, the ‘donor’.

But instead of hydride transfer it is now carbanion addition by (5) to the carbonyl carbon
atom of the second molecule of PhCHO, the ‘acceptor’ (1) that occurs. The rate law
commonly observed is, as might be expected,
Rate = k[PhCHO]2[CN]
The reaction is believed to follow the general pathway:

When the reaction is carried out in MeOH neither the step 2, the formation of the carbanion
(5), nor the step 3, addition of this carbanion to the carbonyl carbon of the acceptor molecule
(1), is completely rate-limiting in itself. These steps are followed by rapid proton transfer, (6)
 (7), and, finally, by rapid loss of CN to the product 2-hydroxyketone (2). The product is
called benzoin. The reaction is completely reversible.

CN was for long the only species known to catalyze this reaction. It was thought to owe this
capacity to: (a) its ability as a nucleophile; (b) its ability as a leaving group; and (c) its ability,
through electron-withdrawal, to increase the acidity of the CH bond in (4) and to stabilize
the carbanion (5a  5b) that results from loss of this proton.
15
Enol to Iminium Ion: Mannich Reaction
The Mannich reaction is the aminoalkylation reaction, involving the condensation of an
enolizable carbonyl compound (α-CH acidic compound) with a nonenolizable aldehyde (like
formaldehyde) and ammonia; or a primary or a secondary amine to furnish a β-
aminocarbonyl compound, also known as Mannich base.

 Instead of formaldehyde, other aliphatic or aromatic aldehydes or ketones can be

employed.
 The amine used may be ammonia or 1o or 2o aliphatic amine. Mostly dimethyl amine is
used. The aromatic amines do not undergo Mannich reaction.
 The reaction is usually carried out with the hydrochloride salt of amine. This salt exists in
equilibrium with the free amine and proton. Hence the acidic conditions are maintained in
Mannich reaction.
 The Eschenmoser’s salt, [(CH3)2N=CH2]+I is used as a source of formaldehyde and
dimethyl amine for Mannich reactions.
 The α-CH acidic compounds include carbonyl compounds, nitriles, aliphatic nitro
compounds, alkynes, α-alkyl-pyridines or imines, activated phenyl groups and electron-
rich heterocycles such as furan, pyrrole, thiophene, Indole etc.
 The reactions are usually carried out in aqueous or alcoholic solutions.

Mechanism
Initially an iminium ion is formed due to nucleophilic addition of amine to formaldehyde and
subsequent loss of water molecule.

16
Since the reaction is carried out in acidic conditions, the enolizable carbonyl compound is
converted to enol form, which attacks the iminium ion at positively charged carbon adjacent
to nitrogen to give finally a β-aminocarbonyl compound.

H
H O R"' O H
R"' C C C C

R"" R" R"" R"

Enol

17