Open Journal of Physical Chemistry, 2013, 3, 138-149
Published Online November 2013 (http://www.scirp.org/journal/ojpc)
http://dx.doi.org/10.4236/ojpc.2013.34017
Open Access OJPC
Substituent, Temperature and Solvent Effects on the
Keto-Enol EQUILIBRIUM in
 -Ketoamides: A Nuclear
Magnetic Resonance Study
Sergio L. Laurella, Manuel González Sierra, Jorge J. P. Furlong, Patricia E. Allegretti*
Laboratorio LADECOR, División Química Orgánica, Departamento de Química, Facultad de Ciencias Exactas,
Universidad Nacional de La Plata (UNLP), La Plata, Argentina
Received August 2, 2013; revised September 1, 2013; accepted September 9, 2013
Copyright © 2013 Sergio L. Laurella et al. This is an open access article distributed under the Creative Commons Attribution Li-
cense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ABSTRACT
Substituent, temperature and solvent effects on tautomeric equilibria in several β-ketoamides have been investigated by
means of nuclear magnetic resonance spectroscopy (NMR). Keto-enol equilibrium predominates over the amide-imidol
one. The relative stability of the individual tautomers and the corresponding equilibrium shifts are explained consider-
ing electronic and steric effects and tautomer stabilization via internal hydrogen bonds. In solution, these compounds
exist mainly as ketoamide and Z-enolamide tautomers, both presenting intramolecular hydrogen bonds.
Keywords: β-Ketoamides; Keto-Enol Equilibrium; Nuclear Magnetic Resonance Spectroscopy
1. Introduction
Keto-enol tautomerism in β-ketoesters, β-diketones and
β-ketonitriles is a topic that has been extensively studied
from several points of view and by means of a variety of
experimental methods [1-3]. However, the occurrence of
this phenomenon in β-ketoamides has not been studied
deeply, with exception of a few previous works [4,5]. It
is usual to describe them only as keto forms [6], although
some of them have been demonstrated to exist as a tau-
tomeric mixture where the enol form is the major tauto-
mer.
The importance of studying β-ketoamides arises from
their versatility as intermediates in the synthesis of sev-
eral heterocycles: 3-acyltetramic acids [7] (used in the
total synthesis of tirandamycin and other related natural
antibiotics [8]), pyrans [9], alkaloids [10], lactams and
spirolactams [11], azetidin-2-ones [12], as well as several
3-hydroxyisothiazol bioisosteres of glutamic acid and
analogs of the AMPA receptor agonist [13]. Moreover,
some β-ketoamides have been converted into γ-ketoa-
mides, a class of compounds related with a wide variety
of biologically relevant systems [14].
The reactivity of β-ketoamides is related to their
structure and their tautomeric equilibria; that is why it
should be useful to determine their spectral behaviour in
different conditions in order to study their tautomeric
distribution. Hence, it is of practical and theoretical im-
portance to investigate tautomeric equilibria in such sys-
tems.
Keto-enol tautomerism has attracted much interest
during the last few decades. The fact that the equilibrium
involved is sufficiently slow to permit keto and enol
tautomeric forms to be detected by nuclear magnetic
resonance (NMR) spectroscopy has allowed many inves-
tigations on these processes [15].
The tautomeric equilibria of some β-ketobutanamides
in solution were investigated by means of 1HNMR and
13CNMR. Their chemical shifts were compared with
those of related β-hydroxybutanamides. Equilibrium po-
pulations of the keto and enol forms were measured.
Substituent effects on the chemical shifts and the equilib-
rium populations were discussed [16].
Intramolecular hydrogen bonding is the main factor
that governs the kinetics and influences the structure of
keto-enol tautomerism in solution. Regarding β-ke-
toamides, internal hydrogen bonding is possible to be
established in several tautomeric forms. This point has
been studied for a series of 3-oxo-2-phenylbutanamides
[17].
*Corresponding author.

S. L. LAURELLA ET AL. 139
In the present work, effects of substituents, solvents
and temperature on the equilibria among different tauto-
meric forms in eleven β-ketoamides have been studied.
Differential solvation effects, electron donor and accep-
tor substituents and temperature variations should shift
the protomeric tautomerism.
2. Experimental
2.1. Synthesis of β-Ketoamides
β-ketoamides were synthesized and purified according to
literature procedures or their modified versions [18]. The
compounds under study were identified by 1HNMR and
13CNMR in DMSO-d6, in which the peaks corresponding
to the enol forms are depleted (Table 1).
2.2. NMR Measurements
1HNMR spectra in CDCl3 and DMSO-d6 were recorded
with a Bruker 300 spectrometer, 300.13 MHz, grad Z and
temperature control. The typical spectral conditions were
as follows: spectral width 4000 Hz, acquisition time 2 s
and 8 - 16 scans per spectrum. Digital resolution was
0.39 Hz per point, TMS was used as internal standard.
Sample concentrations were 0.05 M. Spectra were taken
at 25˚C, 35˚C and 45˚C. The content of long-lived
tautomeric forms was calculated from the integrated peak
intensities of hydoxyl and methine proton signals.
13C proton decoupled and gated decoupled spectra
were recorded with a Varian Mercury Plus 200 spec-
trometer operating at 4.5 T from DMSO-d6 solutions at
25˚C. The spectral conditions were the following: spec-
tral width 10,559 Hz, acquisition times 1.303 s and 512 -
1000 scans per spectrum.
3. Results and Discussion
Schemes 1 and 2 show the possible tautomeric structures
for β-ketoamides I-III and IV-XI respectively.
Each NMR spectrum is the result of the superposition
of the spectra of the individual tautomers, since they are
altogether in equilibrium. The only two tautomeric forms
that could be identified in each spectrum were ketoamide
and Z-enolamide (Scheme 3). The rest of the tautomeric
forms could not be detected, and this fact indicates that
they are absent or in very low concentration. The as-
signment of the peaks to their corresponding protons was
made keeping in mind the theoretical displacements.
As an example, Figure 1 shows the 1HNMR spectrum
of I (3-oxo-2-phenylbutanamide) in CDCl3 at 25˚C. Val-
ues at the top correspond to the chemical shifts and the
ones at the bottom, to the integration of each peak.
In order to assign the 1HNMR signals to the corre-
sponding tautomers, the peaks can be separated into to
groups whose integration values show simple ratios.
Peaks A, B, C and D appear to be in 3:1:1:1 ratio, while
peaks X, Y and Z show 3:2:1 ratio.
Table 2 shows the expected number of non-aromatic
signals and their respective integration for each tautomer,
considering that in some of them internal hydrogen bond
is possible to be established.
Thus, peaks X, Y ans Z can be assigned to the Z-
enolamide hydrogens (CH3, NH2 and OH respectively),
whereas peaks A, B, C and D can assigned to the ke-
toamide hydrogens (CH3, CH, NH and NH respectively).
The possibility of the latter to belong to ketoimidol or
2-enolimidol tautomers is discarded regarding previous
studies which include theoretical calculations on these
compounds [19].
Intramolecular hydrogen bonding is the main factor
that governs the kinetics and influences the structure of
keto-enol tautomerism in solution. In the case of keto-
amides, the two tautomers of major concentration are
capable of establishing internal hydrogen bonds (see
Scheme 3). This stabilizing factor explains the following
observations:
1) The high relative concentration of the involved
tautomers,
2) The high value of δ observed for the hydroxyl pro-
ton in the enolamide form (peak Z, Figure 1),
3) The two different δ values of the hydrogen atoms
bonded to nitrogen in the ketoamide form (peaks C and
D, Figure 1).
Table 3 shows the 1H chemical shifts of the studied
compounds in CDCl3 and DMSO-d6. In many cases, hy-
drogens attached to N were observed as very broad and
low peaks in DMSO-d6 (due to the fact that they estab-
lish hydrogen bonds with the solvent causing a signify-
cant broadening of the corresponding signals), so their
chemical shift could not be stablished properly. Atom
numbering is shown in Scheme 3.
Table 4 shows the enol content present in each com-
pound for both solvents. The integrated spectra made
possible to calculate the enol ratio considering the peaks
of H linked to C-2 (ketoamide tautomer) and the OH
(Z-enolamide tautomer). Thus, enolic contents were cal-
culated as follows:
% enol = (OH integration)/(C-2 integration) Com-
pounds I-VIII
% enol = (OH integration)/((C-2 integration)/2) Com-
pounds IX-XI
Then the equilibrium constant (Keq = [enol]/[keto])
and the corresponding free energy differences at 25˚C
(ΔG0 = −RT lnKeq) for the keto-enol equilibrium were
determined (Table 3).
The relative stability of individual tautomers and the
corresponding equilibrium shifts are explained consider-
ing several factors, such as electronic effects on the car-
onyl group, stabilization by conjugation of the enol b
Open Access OJPC

S. L. LAURELLA ET AL.
Open Access OJPC
140
Table 1. 1HNMR and 13CNMR data for the selected -ketoamides (200MHz, DMSO-d6).
COMPOUND 1H NMR  (ppm)
13C NMR 
(ppm) COMPOUND 1H NMR  (ppm)
13C NMR 
(ppm)
O
NH2
O
1
2
3
4
56
7
8
6
7
3-oxo-2-phenylbutanamide (I)
2.13 (s, 3H, 4)
4.58 (s, 1H, 2)
7.2-7.4 (m,5H, 6-7-8)
27.3 (4)
65.3 (2)
127.1 (8)
127.8 (6)
128.8 (7)
138.8 (5)
172.7 (1)
206.0 (3)
O
NH2
O
1
2
3
4
56
7
8
6
7
OCH3
9
2-(4-methoxyphenyl)-3-oxobutanam
ide (II)
2.10 (s,3H, 4)
3.85 (s,3H 9)
4.51 (s,1H, 2)
6.87 (d,2H, 7)
7.12 (d,2H, 6)
27.1 (4)
56.5 (9)
62.1 (2)
114.4 (7)
130.1 (6)
131.1 (5)
159.1 (8)
171.0 (1)
205.5 (3)
O
NH2
O
1
2
3
4
56
7
8
6
7
Cl
2-(4-chlorophenyl)-3-oxobutanami
de (III)
2.16 (s, 3H, 4)
4.65 (s, 1H, 2)
7.17 (d, 2H, 6)
7.37 (d, 2H, 7)
27.8 (4)
66.3 (2)
128.9 (7)
130.5 (6)
132.7 (8)
136.9 (5)
173.1 (1)
206.2 (3)
O
1
2
3
4
5
6
76
55´
6´
7´
4´
5´
6´
NH2
O
3-oxo-2,3-diphenylpropanamide
(IV)
5.75 (s, 1H, 2)
7.2-7.9 (m, 10H,
5-5´-6-6´-7-7´)
60.3 (2)
127.5 (7´)
129.4 (6´)
128.0 (5´)
141.0 (4´)
128.2 (6)
128.9 (5)
132.7 (7)
172.1 (1)
195.6 (3)
O
1
2
3
4
5
6
7
6
55´
6´
7´
4´
5´
6´
H3CO
8
NH 2
O
3-(4-methoxyphenyl)-3-oxo-2-phe
nylpropanamide (V)
3.83 (s, 3H, 8)
5.69 (s, 1H, 2)
7.1-7.9 (m, 10H,
5-5´-6-6´-7-7´)
60.9 (2)
55.6 (8)
114.3 (6)
127.2 (7´)
128.4 (5´)
129.0 (4)
129.3 (6´)
129.8 (5)
140.4 (4´)
165.2 (7)
172.5 (1)
194.1 (3)
O
1
2
3
4
5
6
7
6
55´
6´
7´
4´ 5´
6´
Cl
NH2
O
3-(4-chlorophenyl)-3-oxo-2-phenylp
ropanamide (VI)
5.74 (s, 1H, 2)
7.2-8.0 (m, 10H,
5-5´-6-6´-7-7´)
61.5 (2)
127.5 (7´)
128.1 (5´)
128.7 (6)
129.2 (6´)
130.4 (5)
135.0 (4)
138.3 (7)
140.5 (4´)
173.2 (1)
195.3 (3)
O
1
2
3
4
5
6
7
6
55´
6´
7´
4´ 5´
6´
OCH3
8
NH2
O
2-(4-methoxyphenyl)-3-oxo-3-phe
nylpropanamide (VII)
3.73 (s, 3H, 8)
5.68 (s, 1H, 2)
7.1-7.9 (m, 10H,
5-5´-6-6´-7-7´)
60.5 (2)
55.3 (8)
114.8 (6´)
128.4 (6)
128.8 (5)
130.6 (5´)
132.7 (4´)
133.1 (7)
136.7 (4)
159.5 (7´)
171.1 (1)
193.2 (3)
O
1
2
3
4
5
6
7
6
Cl
55´
6´
7´
4´ 5´
6´
NH2
O
2-(4-chlorophenyl)-3-oxo-3-phenylp
ropanamide (VIII)
5.79 (s, 1H, 2)
7.3-7.9 (m, 10H,
5-5´-6-6´-7-7´)
61.7 (2)
128.2 (6)
128.7 (5)
129.3 (6´)
131.0 (5´)
133.0 (7´)
133.5 (7)
136.9 (4)
138.5 (4´)
173.0 (1)
195.3 (3)
O
1
2
3
4
5
6
7
6
5
NH 2
O
3-oxo-3-phenylbutanamide (IX)
3.44 (s, 2H, 2)
7.16 (s, 2H, N)
7.5-7.9 (m, 5H, 5-6-7)
45.3 (2)
128.9 (5)
128.5 (6)
133.1 (7)
136.7 (4)
171.3 (1)
194.2 (3)
O
1
2
3
4
5
6
7
6
5
H3CO
8
NH2
O
3-(4-methoxyphenyl)-3-oxopropana
mide (X)
3.41 (s, 2H, 2)
3.83 (s, 3H, 8)
7.02 (s, 2H, N)
7.21 (d, 2H, 6)
7.83 (d, 2H, 5)
44.8 (2)
55.8 (8)
114.2 (6)
129.0 (4)
129.8 (5)
165.0 (7)
171.2 (1)
193.5 (3)
O
1
2
3
4
5
6
7
6
5
Cl
NH2
O
3-(4-chlorophenyl)-3-oxopropanam
ide (XI)
3.55 (s, 2H, 2)
7.20 (s, 2H, N)
7.60 (d, 2H, 6)
7.88 (d, 2H, 5)
46.2 (2)
128.7 (6)
130.2 (5)
134.8 (4)
138.7 (7)
171.8 (1)
195.1 (3)

S. L. LAURELLA ET AL. 141
Scheme 1. Possible tautomeric structures for compounds I-III.
Scheme 2. Possible tautomeric structures for compounds IV-XI.
Scheme 3. Internal hydrogen bonds occurring in Z-enolamide and ketoamide tautomers.
Table 2. Expected signal integration for non-aromatic hydrogens in compund I tautomers.
Tautomer ketoamide 2-enolamide 3-enolamide ketoimidol 2-enolimidol 3-enolimidol
Expected signal integration 3:1:1:1 3:2:1 2:1:1:1:1 3:1:1:1 3:1:1:1 1:1:1:1:1:1
double bond, steric effects introduced by bulky groups
and tautomer stabilization via internal hydrogen bonds.
Steric effects: The structure of Z-enolamide tautomers
of compounds presenting two phenyl groups (compounds
IV-VIII) exhibit greater steric repulsion than compounds
having a phenyl and a methyl groups (compounds I-III),
reducing the enol content in the former ones. In the case
of ketoamide tautomer, this steric repulsion is reduced
because of the rotation in the C-2 - C-3 bond, letting the
two phenyl groups to get further from each other.
On the other hand, bulky phenyl groups in C-2 posi-
tion increase the enolic content (compare compounds
IX-XI with I-III and IV-VIII). This fact is in concor-
ance with previous studies [20,21]. d
Open Access OJPC

S. L. LAURELLA ET AL.
142
Figure 1. 1HNMR spectrum of compound I in CDCl3 at 25˚C.
Substituent effects: The substituents may push or pull
electrons inductively or by resonance. The effects of an
electron releasing methoxy group and an electron with-
drawing chlorine atom attached at the para-position of
phenyl rings are opposite to each other: chlorine atoms
(compounds III, VI, VIII and XI) increase the enol con-
tent, whereas methoxy groups (compounds II, V, VII
and X) shift the equilibrium towards the keto tautomer.
These effects are more pronounced if the substituent is in
C-3 (compare V-VII/VI-VIII).
These observations could be explained taking into ac-
count the influence of the substituents on the internal
hydrogen bonds established in each tautomer:
An electron donor in C-2 position (compounds II,
2-(4-methoxyphenyl)-3-oxobutanamide, and VII, 2-(4-
methoxyphenyl)-3-oxo-3-phenylpropanamide) weakens
the enol hydrogen bond destabilizing it, and, at the same
time, stabilizes the keto form. These facts decrease the
enolic content.
An electron acceptor in C-2 position (compounds III,
2-(4-chlorophenyl)-3-oxobutanamide, and VIII, 2-(4-
chlorophenyl)-3-oxo-3-phenylpropanamide) strengthens
the enol hydrogen bond stabilizing it, and, at the same
time, destabilizes the keto form. These facts increase the
enolic content.
An electron donor in C-3 position (compounds V,
3-(4-methoxyphenyl)-3-oxo-2-phenylpropanamide, and
X, 3-(4-methoxyphenyl)-3-oxopropanamide) strengthens
the enol hydrogen bond stabilizing it, but it stabilizes the
keto form even more. These facts decrease the enolic
content.
An electron acceptor in C-3 position (compounds VI,
3-(4-chlorophenyl)-3-oxo-2-phenylpropanamide, and XI,
3-(4-chlorophenyl)-3-oxopropanamide) strengthens the
enol hydrogen bond stabilizing it, and, at the same time,
destabilizes the keto form. These facts increase the eno-
lic content.
In C-2 position, the stabilizing effects in keto and enol
form would be, ultimately, inductive. That is why in this
position the effects are weaker than in C-3, were induc-
tive and mesomeric effects are affecting the keto and
enol form. These assumptions are supported by previous
works in the gas phase [19] (where the same behaviour
was observed and supported by theoretical calculations)
and the analysis of the dependence of δ with temperature
in the next section.
Temperature effects: Enol contents and equilibrium
onstants Keq were determined for compounds I-XI in c
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S. L. LAURELLA ET AL. 143
Table 3. 1H chemical shifts (δ, ppm) for compounds I-XI (atom numbering depicted in Scheme 3).
Compound Solvent δH
CDCl3 1.80 (C-4 enol); 2.26 (C-4 keto); 4.68 (C-2 keto); 5.10/5.16 (NH2 enol); 5.60/6.88 (NH2 keto); 7.2 - 7.5
(aromatics); 14.68 (OH enol).
I
DMSO-d6 1.66 (C-4 enol); 2.13 (C-4 keto); 4.58 (C-2 keto); 7.2 - 7.4 (aromatics); 15.7 (OH enol).
CDCl3 1.79 (C-4 enol); 2.24 (C-4 keto); 3.82 (OCH3 keto); 3.84 (OCH3 enol); 4.61 (C-2 keto);
5.10/5.31 (NH2 enol); 5.73/6.81 (NH2 keto); 6.9 - 7.4 (aromatics); 14.63 (OH enol).
II
DMSO-d6 1.71 (C-4 enol); 2.10 (C-4 keto); 3.85 (OCH3 keto); 3.89 (OCH3 enol);
4.51 (C-2 keto); 6.8 - 7.2 (aromatics) 15.67 (OH enol).
CDCl3 1.80 (C-4 enol); 2.26 (C-4 keto); 4.63 (C-2 keto); 5.02/5.21 (NH2 enol);
5.63/6.89 (NH2 keto); 7.2 - 7.5 (aromatics); 14.72 (OH enol).
III
DMSO-d6 1.66 (C-4 enol); 2.16 (C-4 keto); 4.65 (C-2 keto); 7.2 - 7.5 (aromatics); 15.79 (OH enol).
CDCl3 5.30 (NH2 enol); 5.61 (C-2 keto); 5.53/6.98 (NH2 keto); 7.1 - 8.0 (aromatics); 15.25 (OH enol).
IV
DMSO-d6 5.75 (C-2 keto); 7.2 - 7.9 (aromatics)
CDCl3 3.90 (OCH3 keto); 3.93 (OCH3 enol); 5.31 (NH2 enol); 5.49 (C-2 keto);
5.63/7.18 (NH2 keto); 6.9 - 8.0 (aromatics); 14.31 (OH enol).
V
DMSO-d6 3.83 (OCH3 keto); 5.69 (C-2 keto); 7.1 - 7.9 (aromatics)
CDCl3 5.37/5.46 (NH2 enol); 5.54 (C-2 keto); 5.72/6.93 (NH2 keto); 7.0 - 8.0 (aromatics); 15.30 (OH enol).
VI
DMSO-d6 5.74 (C-2 keto); 7.2 - 8.0 (aromatics)
CDCl3 3.76 (OCH3 keto); 3.76 (OCH3 enol); 5.38 (NH2 enol); 5.54 (C-2 keto); 5.66/6.91 (NH2 keto); 6.8 - 8.0
(aromatics); 15.22 (OH enol).
VII
DMSO-d6 3.73 (OCH3 keto); 5.68 (C-2 keto); 7.1 - 7.9 (aromatics)
CDCl3 5.33 (NH2 enol); 5.58 (C-2 keto); 5.62/7.21 (NH2 keto); 7.0 - 8.0 (aromatics); 15.32 (OH enol).
VIII
DMSO-d6 5.79 (C-2 keto); 7.3 - 7.9 (aromatics)
CDCl3 3.99 (C-2 keto); 5.26 (NH2 enol); 5.57 (C-2 enol); 5.55/7.02 (NH2 keto);
7.2 - 8.1 (aromatics); 14.22 (OH enol).
IX
DMSO-d6 3.90 (C-2 keto); 7.15 (NH2 enol); 5.78 (C-2 enol); 7.36 (NH2 keto); 7.4 - 8.1 (aromatics); 15.31 (OH enol).
CDCl3 3.86 (OCH3 enol); 3.90 (OCH3 keto); 3.93 (C-2 keto); 5.49 (C-2 enol);
5.64/7.21 (NH2 keto); 6.9 - 8.0 (aromatics); 14.31 (OH enol).
X
DMSO-d6 3.78 (C-2 keto); 3.80 (OCH3 enol); 3.84 (OCH3 keto);
5.63 (C-2 enol); 7.0 - 8.0 (aromatics); 15.27 (OH enol).
CDCl3 3.96 (C-2 keto); 5.34 (NH2 enol); 5.54 (C-2 enol);
5.68/7.00 (NH2 keto); 7.2 - 8.0 (aromatics); 14.28 (OH enol).
XI
DMSO-d6 3.86 (C-2 keto); 5.74 (C-2 enol); 7.1 - 8.0 (aromatics); 15.31 (OH enol).
1In compounds VII, VIII and X, the peak corresponding to the ketoamide NH2 overlaps the aromatic signals and its value could not be determined precisely.
CDCl3 and DMSO-d6 at five different temperatures be-
tween 25˚C and 45˚C. Equation 1 provides a simple
method to determine ΔH and ΔS in keto-enol tautomeri-
zation for the studied compounds.



enol 1
ln ln
keto
GH
kRTR TR
  




S
(1)
Figures 2 and 3 show the lnK vs 1/T plot for β-ke-
toamides I-XI in both solvents. The calculated slopes and
y-intercepts from these graphics can be used to determine
the enthalpy and entropy changes. Results are shown in
Table 5.
As it is expected, compounds bearing an electron re-
leasing group (compounds II, V, VII and X), which have
lower enolic contents (Table 3), show higher values of
ΔH. Compounds attached to electron withdrawing groups
(compounds III, VI, VIII and XI) have higher enolic
contents and lower ΔH values.
Solvent effects: Differential solvatation effects should
shift the protomeric tautomerism. Data from Table 4
clearly demonstrate that an increase in the solvent polar-
ity increases the proportions of keto forms for com-
pounds I-VIII. In the case of compounds IX-XI, the ef-
fect is the opposite. This effect can be explained consid-
ering the values of ΔH and ΔS of each compound.
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S. L. LAURELLA ET AL.
144
Table 4. Keto-enol content, equilibrium constant (Keq) and ΔG0 in CDCl3 and DMSO-d6 at 25˚C for compounds I-XI.
Compound Solvent % enol % keto Keq ΔG0 (kcal·mol−1)
CDCl3 79.2 20.8 3.82 −0.79 ± 0.06
I
X = H DMSO-d6 17.3 82.7 0.210 0.97 ± 0.06
CDCl3 75.5 24.5 3.09 −0.67 ± 0.06
II
X = OCH3 DMSO-d6 16.5 83.5 0.198 0.96 ± 0.06
CDCl3 79.5 20.5 3.88 −0.80 ± 0.06
H3C
O
NH2
O
X
III
X = Cl DMSO-d6 18.0 82.0 0.220 0.90 ± 0.06
CDCl3 28.0 72.0 0.389 0.56 ± 0.06
IV
X = Y = H DMSO-d6 0.0 100.0 0.0 -
CDCl3 9.0 91.0 0.099 1.79 ± 0.06
V
X = H/Y = OCH3 DMSO-d6 0.0 100.0 0.0 -
CDCl3 40.6 59.4 0.684 0.22 ± 0.06
VI
X = H/Y = Cl DMSO-d6 0.0 100.0 0.0 -
CDCl3 25.0 75.0 0.333 0.65 ± 0.06
VII
X = OCH3/Y = H DMSO-d6 0.0 100.0 0.0 -
CDCl3 28.8 71.2 0.404 0.54 ± 0.06
O
NH2
O
X
Y
VIII
X = Cl/Y = H DMSO-d6 0.0 100.0 0.0 -
CDCl3 12.2 87.8 0.139 1.17 ± 0.06
IX
Y = H DMSO-d6 29.1 70.9 0.411 0.53 ± 0.06
CDCl3 3.8 96.2 0.0393 1.94 ± 0.06
X
Y = OCH3 DMSO-d6 14.7 85.3 0.173 1.58 ± 0.06
CDCl3 16.7 83.3 0.200 0.95 ± 0.06
O
NH2
O
Y
XI
Y = Cl DMSO-d6 39.4 60.6 0.650 0.26 ± 0.06
Figure 2. lnK vs 1/T plot for compounds I-XI in CDCl3.
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S. L. LAURELLA ET AL. 145
Figure 3. lnK vs 1/T plot for compounds I-III and IX-XI in DMSO-d6.
Table 5. Thermodinamic parameters in CDCl3 and in DMSO-d6 for compounds I-XI.
CDCl3 DMSO-d6
Compound ΔH
(kcal·mol−1)
ΔS
(cal·mol·K−1)
ΔH
(kcal·mol−1)
ΔS
(cal·mol·K−1)
I
X = H −3.0 ± 0.2 −7.4 ± 0.7 −3.6 ± 0.8 −15 ± 3
II
X = OCH3 −1.6 ± 0.2 −3.0 ± 0.7 −2.0 ± 0.2 −10.0 ± 0.5
H3C
O
NH2
O
X
III
X = Cl −3.1 ± 0.1 −7.6 ± 0.3 −5 ± 1 −18 ± 4
IV
X = Y = H −0.40 ± 0.02 −3.20 ± 0.05 - -
V
X = H/Y = OCH3 −0.23 ± 0.08 −6.7 ± 0.3 - -
VI
X = H/Y = Cl −1.0 ± 0.3 −4 ± 1 - -
VII
X = OCH3/Y = H −0.32 ± 0.07 −3.3 ± 0.3 - -
O
NH2
O
X
Y
VIII
X = Cl/Y = H −0.58 ± 0.08 −3.7 ± 0.5 - -
IX
Y = H −0.92 ± 0.01 −7.02 ± 0.04 −3.6 ± 0.9 −14 ± 3
X
Y = OCH3 +0.5 ± 0.3 −4.9 ± 0.9 −2.7 ± 0.2 −14.4 ± 0.5
O
NH2
O
Y XI
Y = Cl −1.1 ± 0.3 −7 ± 1 −4 ± 1 −14 ± 4
As it can be seen from Tables 4 and 5, the values of
ΔH are more negative in DMSO-d6, indicating that the
enol form would be favored in this solvent. This effect
can be explained considering that the enolamide form is
capable of establishing two intermolecular hydrogen
bonds per molecule, while in the ketoamide tautomer
only one intermolecular hydrogen bond is possible
(Scheme 4).
On the other hand, ΔS values are more negative in this
solvent, what would shift the equilibrium towards the
keto tautomer. This can be explained from the different
molecular arrangements that are set when the tautomers
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S. L. LAURELLA ET AL.
146
establish hydrogen bonds with DMSO-d6, with different
degrees of molecular coordination order (Scheme 4).
The result of these two contrary effects is explained by
experimental determinations, and the overall equilibrium
shift (which depends ultimately on ΔG, Table 4) indi-
cates that in compounds I-VIII the entropic effect pre-
dominates over the enthalpic effect. On the other hand, in
compounds IX-XI the entropic effect is the one that rules
the situation.
The difference between these two opposite behaviors
can be explained considering that in compounds I-VIII
(in which R1 = Ar) the solvation of one NH hydrogen is
sterically hindered by the phenyl group in C-2 position.
In the case of compounds IX-XI (in which R1 = H) both
NH hydrogens are easily solvated. These assumptions are
supported by the different decrease in ΔH in DMSO-d6
respecting to CDCl3 (approximately a decrease of 1 Kcal/
mol in compounds I-VIII and 3 Kcal/mol in compounds
IX-XI).
Data obtained from these experiments suggest an en-
thalpy-entropy compensation (since ΔH and ΔS seem to
be lineally correlated ΔH = a·ΔS + b), but, at first sight,
this correlation would not be strictly valid since ΔS and
ΔH values were obtained from the same experiment [22].
However, linearity between lnK at two different tem-
peratures (25˚C and 45˚C) is observed, as shown in Fig-
ure 4. From the equation lnK(45˚C) = m·lnK(25˚C) + n,
a simple deduction can be made to obtain ∆H = a·∆S + b
(i.e. an enthalpy-entropy compensation), as follows:
21
ln ln
K
mKn




22 11
GRTmGRT n




21
+
H
RTSRmHRT mSRn




122112 21
1
H
m TTmTT SnRTTmTT 
H
aSb


where T1 = 25˚C (298 K), T2 = 45˚C (318 K), K1 and K2
are the equilibrium constants at T1 and T2 respectively,
and ΔH and ΔS are supposed to be constant within the
Scheme 4. Tautomer-solvent interactions via hydrogen bond in DMSO-d6.
Figure 4. lnK (45˚C) vs lnK (25˚C) plot for compounds I-XI in CDCl3.
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S. L. LAURELLA ET AL. 147
temperature interval. This enthalpy-entropy compensa-
tion suggests a common mechanism underlying all of the
studied equilibria [22].
In order to correlate enol contents and thermodynami-
cal functions (ΔH and ΔS) with the stability of the in-
tramolecular hydrogen bonds, the dependence of δ of OH
and NH hydrogens with temperature were studied for
compounds I-III and IX-XI in CDCl3. Previous works
have established that Δδ/ΔT values can be correlated with
the stability of hydrogen bonds (the lower the value of
Δδ/ΔT, the greater the stability of the bond) [23,24]. The
data are presented in Tables 6 and 7.
This analysis was not made for compounds IV-VIII,
since the signals corresponding to NH hydrogen are
overlapped with the aromatic ones, not allowing a precise
determination of their δ.
Table 6. Temperature dependence of δ for compounds I-III in CDCl3.
Tautomeric form Compound Temp. δ (ppm) Δδ/ΔT (ppb·K−1)
I
X = H
25˚C
35˚C
45˚C
14.665
14.650
14.632
−1.6 ± 0.1
II
X = OCH3
25˚C
35˚C
45˚C
14.612
14.597
14.577
−1.8 ± 0.2
C
CC NH2
O
H3C
OH
X
enolamide Z
III
X = Cl
25˚C
35˚C
45˚C
14.700
14.689
14.675
−1.2 ± 0.1
I
X = H
25˚C
35˚C
45˚C
6.867
6.798
6.731
−6.80 ± 0.06
II
X = OCH3
25˚C
35˚C
45˚C
6.805
6.750
6.675
−6.5 ± 0.6
H
C
CCO
NH
H3C
OH
X
ketamide
III
X = Cl
25˚C
35˚C
45˚C
6.860
6.773
6.715
−7.3 ± 0.8
Table 7. Temperature dependence of δ for compounds IX-XI in CDCl3.
Tautomeric form Compound Temp. δ (ppm) Δδ/ΔT (ppb·K−1)
IX
X = H
25˚C
35˚C
45˚C
14.223
14.208
14.192
−1.7 ± 0.2
X
X = OCH3
25˚C
35˚C
45˚C
14.228
14.205
14.198
−1.5 ± 0.5
H
C
CC NH2
OO H
X
enolamide Z
XI
X = Cl
25˚C
35˚C
45˚C
14.260
14.248
24.237
−1.15 ± 0.03
IX
X = H
25˚C
35˚C
45˚C
7.152
7.095
7.043
−5.80 ± 0.06
X
X = OCH3
25˚C
35˚C
45˚C
7.116
7.051
7.012
−5.2 ± 0.8
CH2
CC O
NHOH
X
ketoamide
XI
X = Cl
25˚C
35˚C
45˚C
6.976
6.925
6.856
−6.0 ± 0.6
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S. L. LAURELLA ET AL.
148
The calculated Δδ/ΔT values agree with the ones ob-
tained in previous works for similar compounds (Δδ/ΔT
< 4 ppb·K−1 for O―H•••O and Δδ/ΔT < 9 ppb·K−1 for
N―H•••O) [23,24], corroborating that the hydrogen
bonds are, indeed, intramolecular.
Taking into account data from Tables 6 and 7, it can
be concluded that they are consistent with the previous
assumption regarding the effect of the internal hydrogen
bonds on the stability of the tautomers. In other words,
compounds showing lower values of Δδ/ΔTOH enol and
higher values of Δδ/ΔTNH keto are also the ones that have
higher enolic content and vice versa.
4. Conclusions
It has been demonstrated that keto-enol tautomerism in
β-ketoamides (studied by NMR spectroscopy, a very
useful technique for the determination of tautomeric spe-
cies in solution) is strongly dependent on the solvents,
temperature and substituents. Intramolecular hydrogen
bond seems to be the main factor in stabilizing the dif-
ferent tautomeric forms.
In solution, these compounds exist mainly as ke-
toamide and Z-enolamide tautomers, both presenting
internal hydrogen bonds. The rest of the possible
tautomers (ketoimidol, E-enolamide, 3-enolamide, eno-
limidol) show very low concentration (at least lower than
the detection limit) or probably do not exist in neutral
solution.
In all cases, the equilibrium is shifted to the Z-enola-
mide form by several factors:
1) Electron withdrawing substituents attached to aro-
matic rings (e.g. chlorine).
2) A temperature decrease, since the equilibria are
exothermic (except for compound X).
3) Bulky groups in C-2 position. This effect is less
important when two phenyl groups in C-2 and C-3 posi-
tions are present, because of the steric hindrance.
4) The presence of hydrogen bond acceptor solvents
(e.g. DMSO), but only when there are no bulky groups in
C-2. Otherwise, hydrogen bond acceptor solvents de-
crease the enol content.
All these factors increase the enolamide content ap-
parently by stabilizing the Z-enolamide tautomers (streng-
thening the internal O―H•••O = C hydrogen bond) and/or
destabilizing the ketoamide tautomer (weakening the
internal C = O•••H―N hydrogen bond).
5. Acknowledgements
We are indebted to the Facultad de Ciencias Exactas,
Universidad Nacional de La Plata for financial support,
to Agencia Nacional de Promoción Científica y Tecno-
lógica, República Argentina and the Consejo Nacional de
Investigaciones Científicas y Tecnológicas (CONICET).
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