Ionization and tautomerization of 2-nitrocyclohexanone in aqueous solution

Article abstract of DOI:10.1021/jo0700629

(Chemical Equation Presented) The keto-enol tautomerism of 2-nitrocyclohexanone (2-NCH) was studied in aqueous solution under different experimental conditions. Ketonization rate constants were measured spectrophotometrically at 25°C at an ionic strength of 0.4 mol dm ^-3 (NaCl) in diluted hydrochloric acid, in diluted sodium hydroxide, and in several buffers by using NaHSO₃ as the scavenger of the keto form. A value of pK_a^EH = 4.78 for the enol form was obtained from the rate-pH profile of the reaction. A value of pK _a^KH = 5.97 for the keto form was directly obtained from the UV-vis spectra of 2-NCH recorded at different pHs. The equilibrium constant for the keto-enol tautomerism, pK_T = -log([enol]/[ketone]) = 1.19, was obtained by combining the two pK_a values (pK_T = pK_a^KH - pK_a^EH). A comparison of these results with the corresponding values (Keefe, J. R.; Kresge, A. J. In The Chemistry of Enols; Rappoport, Z., Ed.; Wiley & Sons: New York, 1990; pp 399-480) for cyclohexanone shows the dramatic effects of an α-nitro substituent on the keto-enol acidities and the tautomerization constant of alicyclic ketones. Rates and equilibria were discussed in the light of the Bronsted equation, the principle of nonperfect synchronization, and the Marcus theory. It turns out that, on passing from nitroalkanes to nitroketones, the resonance contribution to pK_a and deprotonation rate decreases, being overwhelmed by steric and inductive effects.

Full text of DOI:10.1021/jo0700629

Ionization and Tautomerization of 2-Nitrocyclohexanone in
Aqueous Solution
†
†
†
‡
Guido Angelini, Paolo De Maria, Antonella Fontana, Marco Pierini, and
,
†
Gabriella Siani*
Dipartimento di Scienze del Farmaco, UniVersit a` “G. d’Annunzio”, Via dei Vestini 31, Chieti, Italy, and
Dipartimento di Studi di Chimica e Tecnologia delle Sostanze Biologicamente AttiVe,
UniVersit a` “La Sapienza”, P.le Aldo Moro 5, Roma, Italy
siani@unich.it
ReceiVed January 11, 2007
The keto-enol tautomerism of 2-nitrocyclohexanone (2-NCH) was studied in aqueous solution under
different experimental conditions. Ketonization rate constants were measured spectrophotometrically at
3
2
5 °C at an ionic strength of 0.4 mol dm- (NaCl) in diluted hydrochloric acid, in diluted sodium hydroxide,
EH
and in several buffers by using NaHSO
the enol form was obtained from the rate-pH profile of the reaction. A value of pK
keto form was directly obtained from the UV-vis spectra of 2-NCH recorded at different pHs. The
equilibrium constant for the keto-enol tautomerism, pK ) -log([enol]/[ketone]) ) 1.19, was obtained
3
as the scavenger of the keto form. A value of pK
a
) 4.78 for
KH
a
) 5.97 for the
T
KH
EH
by combining the two pK
corresponding values (Keefe, J. R.; Kresge, A. J. In The Chemistry of Enols; Rappoport, Z., Ed.; Wiley
Sons: New York, 1990; pp 399-480) for cyclohexanone shows the dramatic effects of an R-nitro
a
values (pK
T
) pK
a
- pK
a
). A comparison of these results with the
&
substituent on the keto-enol acidities and the tautomerization constant of alicyclic ketones. Rates and
equilibria were discussed in the light of the Brønsted equation, the principle of nonperfect synchronization,
and the Marcus theory. It turns out that, on passing from nitroalkanes to nitroketones, the resonance
contribution to pK
a
and deprotonation rate decreases, being overwhelmed by steric and inductive effects.
Introduction
is available for R-nitroketones.7,8 The enol of 3-nitrobutanone
8
(
3-NB) displays an unusual stability (pKT ) 2.34) as compared
In the past 20 years, many studies on rates and equilibria for
keto-enol tautomerism have been performed for a wide variety
of carbonyl compounds.1 In sharp contrast, very little work
9
to that of the enol of butanone (pKT ) 7.50). It was also found
that both tautomers of 3-nitrobutanone are considerably acidic,
-6
(
5) Fontana, A.; More O’Ferrall, R. A. J. Chem. Soc., Perkin Trans. 2
†
Universit a` “G. d’Annunzio”.
Universit a` “La Sapienza”.
1994, 2453-2459.
‡
(6) De Maria, P.; Fontana, A.; Cerichelli, G. J. Chem. Soc., Perkin Trans.
2 1997, 2329-2334.
(
1) Keefe, J. R.; Kresge, A. J. In The Chemistry of Enols; Rappoport,
Z., Ed.; Wiley & Sons: New York, 1990; pp 399-480.
2) Toullec, J. In The Chemistry of Enols; Rappoport, Z., Ed.; Wiley &
(7) Bell, R. P.; Robinson, R. R. Proc. R. Soc. London, Ser. A 1962, 270,
411-416.
(
Sons: New York, 1990; pp 323-398.
(
(
(8) Fontana, A.; De Maria, P.; Siani, G.; Pierini, M.; Cerritelli, S.; Ballini,
R. Eur. J. Org. Chem. 2000, 1641-1646.
(9) Keeffe, J. R.; Kresge, A. J.; Schepp, N. P. J. Am. Chem. Soc. 1990,
112, 4862-4868.
3) Kresge, A. J. Acc. Chem. Res. 1990, 23, 43-48.
4) Capon, B.; Guo, B.-Z.; Kwok, F. C.; Siddharta, A. P.; Zucco, C.
Acc. Chem. Res. 1988, 21, 135-140.
1
0.1021/jo0700629 CCC: $37.00 © 2007 American Chemical Society
Published on Web 04/24/2007
J. Org. Chem. 2007, 72, 4039-4047
4039

Angelini et al.
TABLE 1. Intercepts (k0) and Slopes (kB) Obtained from the Plots of the Experimental Pseudo-First-Order Rate Constants (ke/s-1) for the
Ketonization of the Enol/Enolate of 2-NCH against the Concentrations of the Buffer Base B in Aqueous Solution at 25 °C and Ionic Strength
-
3
EH
0
.4 mol dm (NaCl) (Rate Constants kB Refer to the Enol as the Reactant)
[
B]/10-
2
k0
(s
kB
kB
EH
-1
(mol-1 dm3 s-1
(mol-1 dm3s-1
)
base
r
(mol dm-3)
pHa
)
)
chloroacetate
1
3
5
0.5
1
3
0.5
1
3
5
1-8
3.13
3.28
3.32
3.23
3.60
3.92
4.08
4.27
4.76
4.91
4.96
5.53
0.049 ((0.002)
0.048 ((0.002)
0.056 ((0.003)
0.058 ((0.004)
0.076 ((0.004)
0.079 ((0.005)
0.110 ((0.009)
0.156 ((0.008)
0.348 ((0.048)
0.499 ((0.015)
0.527 ((0.013)
0.655 ((0.025)
0.639 ((0.037)
0.477 ((0.040)
0.302 ((0.062)
1.59 ((0.08)
1.69 ((0.09)
1.93 ((0.11)
4.55 ((0.18)
4.69 ((0.22)
1.85 ((0.15)
1.34 ((0.05)
1.11 ((0.05)
1.29 ((0.07)
0.56 ((0.12)
0.8-8
0.8-8
1-8
cyanoacetate
glycolate
0.30 ((0.06)
1.74 ((0.18)
1-8
1-8
acetate
0.8-8
0.6-6
5-50
10-50
5-40
2-5
4.97 ((0.61)
1
0
1
phosphate
a
Potentiometrically determined soon before and after each experiment.
being the microscopic ionization constants pKaKH ) 5.15 and
EH
pKa ) 2.81. As a consequence, at moderate pHs in aqueous
solution, the dominant equilibrium is that between the keto form
and the enolate anion.
1
0
It is known that R-substituents which are π-electron
acceptors and σ-electron acceptors, such as the -NO2 group,
destabilize the keto and stabilize the enol tautomer by allowing
extensive delocalization in the latter tautomer. A contribution
to the stability of the enol might also arise from intramolecular
1
1
hydrogen bonding. Furthermore, the relative instability of the
1
2
keto tautomers of R-nitroketones has been attributed to steric
hindrance and repulsive electrostatic interactions between the
adjacent nitro and carbonyl groups.
With the present work, we have studied the ionization and
keto-enol tautomerism of 2-nitrocyclohexanone (2-NCH) as a
representative of the class of alicyclic R-nitroketones. The aci-
form of 2-NCH has been ignored in the investigated equilibria
8
due to its well-known high acidity in aqueous solutions.
FIGURE 1. Absorption spectra of an aqueous 2 × 10 mol dm-3
-4
solution of 2-NCH, registered at different times, showing the decrease
of the absorption band at 336 nm due to the ketonization reaction of
the enol (enolate) form.
Results
Keto-Enol/Enolate Equilibria. It is now well-established1
that for simple ketones the enol tautomer is favored in aprotic
solvents while the keto tautomer, which has a higher dipole
moment, is favored in polar solvents. Accordingly, the UV-
3-15
Kinetics of the Ketonization Reaction. The rate of keton-
ization of the enol/enolate of 2-NCH has been measured
spectrophotometrically in cyanoacetate, chloroacetate, acetate,
glycolate, and phosphate buffers at different buffer ratios, r )
-
4
-3
vis spectrum of a 2 × 10 mol dm aqueous solution of
2
-NCH, recorded soon after the addition of the appropriate
[
B]/[A], by following the decrease of the absorbance of the
-2
-3
volume of a dioxane 2.5 × 10 mol dm stock solution, shows
an absorption band with a maximum at 336 nm which decreases
steadily with time (within 45 min) due to the progressive
conversion of the enol (or enolate) to the keto form (Figure 1).
The initial absorption at 336 nm of the solution is higher at
higher pHs and is lower at lower pHs, suggesting that the band
at 336 nm is mainly due to the enolate of 2-NCH. The absence
of one isosbestic point in Figure 1 is understandable if one
considers that the spectra at the different times are not corrected
for the concurrent hydration of the keto form.
enolate at λmax ) 336 nm. In most experiments, the concentra-
tion of the conjugate base B of the buffer acid A, at constant r,
was varied over a range of ca. a factor of 10 (see Table 1).
Sodium bisulfite was used as the scavenger of the keto form
8,16,17
following a previously reported procedure.
The concentra-
-2
tion of NaHSO3 was varied over the range of 0.5-50 × 10
-3
mol dm . The observed pseudo-first-order rate constant, ke,
increases upon increasing [NaHSO3] at relatively low concentra-
tions of NaHSO3, but levels off to a limiting value at higher
bisulfite concentrations (see a typical example in Figure 2).
The reaction is zero order, with respect to NaHSO3, at
(
(
(
10) Bouma, W. J.; Radom, L. Aust. J. Chem. 1978, 31, 1649-1660.
11) Feuer, K. H.; Piwaver, P. M. J. Org. Chem. 1966, 31, 3152-3158.
12) Simmons, T.; Love, R. F.; Kreuz, K. L. J. Org. Chem. 1966, 31,
-
3
[
NaHSO3] g 0.1 mol dm , where the ketonization step
becomes rate determining. Under this condition, the ketonization
reaction is irreversible and the potentially competitive hydration
2
2
400-2401.
(
(
13) Emsley, J.; Freeman, N. J. J. Mol. Struct. 1987, 161, 193-204.
14) Reichardt, C. SolVents and SolVent Effects in Organic Chemistry,
nd ed.; Verlag Chemie: Weinheim, Germany, 1988.
(16) Harcourt, M. P.; More O’Ferrall, R. A. Bull. Soc. Chim. Fr. 1988,
(
15) Angelini, G.; Chiappe, C.; De Maria, P.; Fontana, A.; Gasparrini,
F.; Pieraccini, D.; Pierini, M.; Siani, G. J. Org. Chem. 2005, 70, 8193-
196.
407-414.
(17) Harcourt, M. P.; More O’Ferrall, R. A. J. Chem. Soc., Perkin Trans.
2 1995, 1415-1425.
8
4040 J. Org. Chem., Vol. 72, No. 11, 2007

Ionization and Tautomerization of 2-Nitrocyclohexanone
FIGURE 2. Plot of the observed rate constants for the ketonization
-
1
FIGURE 3. Rate-pH profile for the ketonization reaction of the enol
of 2-NCH.
e 3
reaction of 2-NCH, k /s , against [NaHSO ] in glycolate buffer with
-
3
-3
-3
r ) 5, [B] ) 0.06 mol dm , initial [2-NCH] ) 1 × 10 mol dm
,
-
3
λ ) 336 nm, ionic strength ) 0.4 mol dm (NaCl).
TABLE 2. Pseudo-First-Order Rate Constants (ke/s-1) for the
Ketonization of the Enol/Enolate of 2-NCH in HCl and NaOH at 25
-
3
°
C and an Ionic Strength 0.4 mol dm (NaCl)
ke/s-
1
pH
ke/s-1
pH
1
.30
.54
.02
.89
.14
0.030 ((0.001)
0.026 ((0.001)
0.027 ((0.001)
0.035 ((0.002)
0.042 ((0.002)
3.27
3.40
3.55
6.00
6.60
0.052 ((0.002)
0.053 ((0.003)
0.059 ((0.002)
0.649 ((0.018)
0.655 ((0.022)
1
2
2
3
reaction is suppressed as the keto tautomer is instantaneously
trapped by the scavenger as it forms. The ke is linearly related
to [B] according to eq 1:
FIGURE 4. Plot of the absorbance, Abs, at λ ) 336 nm against pH
-3
-3
of a 1 × 10 mol dm solution of 2-NCH.
ketonization reaction can be obtained by plotting log k0 and
log ke values from Tables 1 and 2 (reported as “log k” in
Figure 3) against the corresponding experimental pHs.
The data fit eq 3:
k ) k + k [B]
(1)
e
0
B
where k0 and kB represent the pseudo-first-order rate constant
-
(
including the contribution of [OH ]) for the buffer independent
ketonization and the second-order rate constant for general base
catalysis, respectively. On the other hand, a contribution of acid
catalysis was not detected (see Table 2). The values of kB for
the different buffer bases, B, can be obtained from the slopes
of the plots of ke against [B].
E
EH
+
EH
EH
+
k ) {kW Ka /[H ] + k
}/{1 + Ka /[H ]}
(3)
W
where kWE and kWEH are the rate constants for the “water”
reaction for the enolate, E, and the enol, EH, respectively.
A value of pKa ) 4.78((0.03) can be obtained from eq 3,
while a value of k
OH -catalyzed ketonization of the enol can be obtained from
eq 4, where KW is the ionic product of water.
EH
EH
9
-1
3
-1
The pH values of the acetate buffer solutions are close to the
) 1.08 × 10 mol dm s for the
OH
EH
-
pKa of the enol, and rate constants, kB, are related to pH by
EH
eq 2, where kB is the corresponding rate constant for the
ketonization of the enol.5
,6,18
EH
E
EH
kOH ) kW Ka /KW
(4)
EH
EH
+
kB ) kB /(1 + Ka /[H ])
(2)
Determination of the Ionization Constant, pKaKH, of the
Keto Tautomer. The apparent acid dissociation constant, Ka
of 2-NCH in aqueous solution, that is, the experimental acid
ionization constant for the deprotonation of the mixture of the
two tautomers, was measured spectrophotometrically by moni-
app
,
A best fit of eq 2 by using KaEH obtained from the pH profile
(
see the following section) gave for acetate catalysis a value of
EH
3
-1 -1
kB ) 4.97((0.61) dm mol s . An analogous treatment in
terms of eq 2 for the other buffers of Table 1 was not attempted
due to the paucity of experimental data, and the values of kB
toring the absorbance at λmax ) 336 nm of a 1 × 10 mol/dm3
solution of 2-NCH after equilibrium had been established at
each pH. The pHs of the different solutions were set by using
glycolate, acetate, cacodilate, phosphate, and borate buffers at
appropriate buffer ratios. The experimental results are reported
in Figure 4.
-3
EH
for chloroacetate and glycolate buffers have been calculated by
averaging the kB values obtained at different r.
The ketonization reaction was similarly followed in dilute
HCl and NaOH solutions. The obtained pseudo-first-order rate
constants (ke) are reported in Table 2.
The total absorbance, Abs, of the solution is given by eq 5:
Rate-pH Profile and Determination of the Ionization
EH
Constant, pKa , of the Enol. A rate-pH profile for the
Abs ) ꢀKH[KH] + ꢀ [EH] + ꢀ [E]
(5)
EH
E
Taking into account that [2-NCH] ) [KH] + [EH] + [E], and
that the keto form does not absorb at 336 nm, eq 5 reduces to
(
18) Carey, A. R. E.; Fukata, G.; More O’Ferrall, R. A.; Murphy, M. G.
J. Chem. Soc., Perkin Trans. 2 1985, 1711-1722.
J. Org. Chem, Vol. 72, No. 11, 2007 4041

Angelini et al.
SCHEME 1
TABLE 3. Dissociation and Rate Constants for the Ionization by
-
OH in Water at 25 °C of the Monocarbonyl Compounds of Scheme
2
(The Data in Bold Have Been Used for the Brønsted Plot of
Figure 6b)
intrinsic
log(kOHKH/p) barriers
compound pKaKH -log(K/p) log(kOHKH/p)
calcda
(kcal/mol)
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
25.60
21.48
21.00
20.33
19.30
19.27
18.90
18.41
18.30
18.27
18.26
16.70
16.60
15.91
15.76
15.49
13.27
13.10
12.20
11.00
10.40
5.97
10.3
5.74
-3.40
-2.98
-2.18
-2.43
-1.46
-1.14
-1.83
-1.17
-1.08
-1.13
-2.62
-0.41
-0.85
0.20
0.25
-0.85
1.91
1.00
2.05
3.24
2.40
7.84
7.51
-2.55
16.8
5.74
4.59
4.04
4.01
3.64
3.15
3.04
3.01
2.52
1.44
1.34
0.47
0.32
-0.25
-2.17
-2.34
-3.24
-4.74
-5.34
-9.77
-10.6
-1.91
-1.61
-1.60
-1.40
16.9
17.0
17.0
17.0
0
1
2
3
4
5
-1.06
17.0
-0.19
0.25
0.33
17.0
16.9
16.9
eq 6:
+
app
app
+
Abs ) (Absmin[H ] + AbsmaxKa )/(Ka + [H ]) (6)
16
1
1
1
2
21
2
3
7
8
9
0
1.55
16.6
where Absmin (0.055) and Absmax (1.295) are the limiting
2.06
2.75
16.4
16.1
absorbances at the lowest and the highest pHs, respectively. A
app
pKa
) 6.00((0.02) could be obtained from a best fit of
-NCH
-NB
4.89
5.22
14.4
14.0
experimental data to eq 6.
5.15
The ionization constant of the keto tautomer, KaKH, can be
calculated from eq 7:
a
Calculated according to the Marcus equation.
app
+
1
/Ka ) {[EH] + [KH]}/{[E][H ]} )
TABLE 4. Dissociation and Rate Constants for the Ionization by
H2O at 25 °C of the Monocarbonyl Compounds of Scheme 2 (The
Data in Bold Have Been Used for the Brønsted Plot of Figure 7b)
EH
KH
1
/Ka + 1/Ka (7)
compound
log(K′/p)
log(kWKH/p)
by using the above pKaapp and the pKaEH ) 4.78 from the rate-
KH
pH profile of Figure 3. A value of pKa ) 5.97 was obtained.
6
9
1
1
-21.5
-20.5
-20.0
-18.9
-17.8
-17.5
-15.3
-14.9
-12.8
-7.71
-6.90
-9.82
-9.21
-9.78
-8.10
-7.36
-7.56
-5.85
-6.33
-6.36
-2.74
-3.19
app
KH
We conclude that the values of Ka and Ka are equal
within the experimental error.
1
2
Determination of the Tautomeric Constant, pKT. The
15
16
17
EH
KH
values of pKa and of pKa can be combined to obtain the
KH
tautomeric constant pKT) -log([enol]/[ketone]) ) pKa
pKa ) 1.19 in aqueous solution at 25 °C according to the
thermodynamic cycle of Scheme 1.
-
1
2
8
0
EH
2-NCH
-NB
3
The rate constants for the ionization of the keto form of
KH
KH
2
-NCH by hydroxide, kOH , and water, kW , can be calculated
EH
EH
by fitting kOH and kW to eqs 8 and 9, respectively.
KH
EH
kOH ) kOH KT
(8)
(9)
KH
EH
kW ) kW KT
The obtained values are reported in Tables 3 and 4.
Brønsted Plots. The rate constants, kBKH, for the ionization
of 2-NCH by the buffer bases, B, of Table 1 can be calculated
EH
by fitting kB of Table 1 to eq 10:
KH
EH
kB ) kB KT
(10)
Figure 5 is a Brønsted plot of kBKH, kOHKH, and kWKH against
the corresponding pKa values. Rate constants and acid dissocia-
tion constants have been statistically corrected for the number
p of acidic proton and for the number q of basic sites. From
the obtained straight line, a Brønsted â of 0.63((0.02) can be
calculated.
1
9
FIGURE 5. Brønsted plot for the ionization reaction of 2-NCH.
The values of kOHKH for 2-NCH and a number of simple
1
monocarbonyl compounds (Scheme 2) have been used for the
Brønsted plots of Figure 6, where abscissa values, pK, refer to
(19) Bell, R. P.; Evans, P. G. Proc. R. Soc. London, Ser. A 1966, 291,
2
97-323.
the equilibrium of Scheme 3.
4042 J. Org. Chem., Vol. 72, No. 11, 2007

Ionization and Tautomerization of 2-Nitrocyclohexanone
FIGURE 6. Brønsted plots for the ionization by OH- (a) of all the monocarbonyl compounds of Table 3 and (b) of only the ketones of Table 3
(for the dotted line of Figure 6b, see the text under the Discussion section).
FIGURE 7. Brønsted plots for the ionization by H
2
O (a) of all the monocarbonyl compounds of Table 4 and (b) of only the ketones of Table 4.
SCHEME 2
SCHEME 3
SCHEME 4
Molecular Modeling.20 An exhaustive conformational analy-
sis has been carried out by molecular mechanic calculations
with the MM2* force field in order to obtain the geometries of
lowest energy for the two tautomeric forms as well as the enolate
anion of 2-NCH. Each geometry has been further minimized
by semiempirical calculations with the AM1 Hamiltonian as
well as the Hartree-Fock ab initio method at the SCF level,
employing the 6-31G* basis set. For the selected conformations,
the corresponding hydration energies, based on the SM5,4 model
of Cramer and Truhlar, were estimated. For sake of comparison,
(
20) Conformational searches were carried out by Batchmin and Mac-
The Brønsted plots of kWKH for 2-NCH and the same
monocarbonyl compounds (Scheme 2) against pK′ of
Scheme 4 are reported in Figure 7.
Rate and equilibrium constant values used for the Brønsted
plots of Figures 6 and 7 are reported in Tables 3 and 4,
respectively.
romodel version 4.5 (Columbia University, NY) using the following
options: MM2* force field, Monte Carlo stochastic algorithm with 3000
generated structures, minimization by PR conjugate gradient. All of the
rotatable bonds were explored. The aqueous solvation energies by the SM5,4
model and all of the semiempirical calculations were performed by using
the computer program SPARTAN ’02, Wavefunction Inc., 18401 Von
Karman Avenue, Suite 370 Irvine, CA 92612.
J. Org. Chem, Vol. 72, No. 11, 2007 4043

Angelini et al.
TABLE 5. Estimated Hydration Energies, Values of +δ(H), and Steric Entropy Contributions for the Selected Conformations of NP, 3-NB,
and 2-NCH
Ab initio calculations
Semiempirical calculations
dihedral
energy of
species X
hydration
energy
dipole
moment
(debye)
dihedral
angle of
OdCsC-H
conformations
of species X
steric entropy
(eu)
+δ(H)
(AM1)
pKa
angle of
in vacuum (au)
(kcal/mol)
(calcd)
OdCsC-NO2
NP
1KH
-395.424757
-395.423126
-434.464325
-434.463475
-434.461599
-434.449888
-434.426606
-434.437298
-434.436839
-433.886893
-433.902280
-511.371880
-511.371440
-511.364827
-511.343648
-510.800207
-4.641
-8.655
-3.543
-4.235
-7.358
-4.548
-11.181
-6.522
-8.921
-60.743
-55.53
-7.172
-4.724
-4.185
-9.484
-59.312
1.03
6.30
2.01
1.44
4.82
4.54
7.42
4.56
5.64
9.85
2.98
6.83
4.27
4.63
7.28
12.05
0.77
0.55
0.167
0.157
0.166
0.164
0.147
0.272
0.226
0.233
0.234
-
3.7
6.2
3.9
4.4
8.7
3.0
9.4
8.4
8.3
-169
-8.06
-146
-116
38.4
-
-48.0
112
-30.1
-1.38
153
-
2KH
3
-NB
1KH
2
3
1
2
3
4
1
2
KH
KH
EHZ
EHZ
EHE
0.00
0.25
0.01
0.11
0.00
0.00
-
-
-
-
EHE
-
-
-
E
E
Z
-
-
-
E
-
-
-
2
-NCH
1KH
0.155
0.161
0.272
0.224
-
6.7
5.2
3.0
9.6
-2.24
-105
-
113
10.5
-
2
1
2
1
KH
EHZ
EHZ
-
-
-
-
-
E
Z
SCHEME 5
step which is then consumed in the second step. Accordingly,
the rate of the process should be independent of hydronium ion
+
concentration. In fact, H3O catalysis for the ketonization
reaction of the undissociated enol is detectable1 only for
relatively basic ketones, and it is not surprising that it is not
8
detectable for nitroketones. The positive limb (in the range
3
.0 e pH e 4.9) probably represents the water ketonization of
E
increasing amounts of enolate upon increasing the pH, kW ,
rather than the kinetically indistinguishable OH -catalyzed
ketonization of the enol, kOH . The plateau at higher pH values
-
the same search was performed for 3-nitrobutanone, 3-NB, and
the keto form of nitropropanone, NP. The semiempirical atomic
charges on the R-hydrogens, +δ(H), have been used as the
descriptors of their acidity in order to predict pKa values
EH
corresponds to the reaction after full conversion to the enolate
E
-1
anion, kW ) 0.652((0.003) s . The point of inflection
EH
EH
corresponds to the pKa of the enol, and a value of pKa
.78((0.03) can be obtained from a best fit of experimental
data to eq 3.
(
Table 5) of the corresponding conformations, according to the
4
+
procedure of ref 8. The δ(H) values have been considered as
a function of the OdC-C-H and OdC-C-NO2 torsional
angles shown in Scheme 5, within each keto conformation. Ab
initio energies of the different conformations together with the
corresponding hydration energies are reported in Table 5. The
steric entropy contributions, S, were evaluated by eq 11where
The effectiveness of acids and bases as catalysts in proton-
22
transfer reactions is generally related linearly to their acid or
basic strengths. However, if a sufficiently large range of pKa
values is investigated, a curvature is often observed in the plot
of log k against pKa. This curvature is usually in the direction
22
of a smaller slope (R or â) at higher velocities. An interpreta-
X
X
X
S ) -Rp ln p
(11)
23
i
i
tion of such a curvature is offered by the Marcus theory in
terms of constant intrinsic barriers. In the case of the enolization
reaction, the intrinsic barrier for a given catalyst (e.g., OH or
R is the gas constant and pi is the Boltzmann population of each
conformation of species X (where X ) KH, EH, or E) obtained
-
H2O) depends only of the type of carbonyl compound (e.g.,
EH
from the total energy of X, including the hydration energy. S
21,23,24
monocarbonyl, dicarbonyl, etc.).
Nevertheless a good
for the enol of 3-NB was evaluated assuming that free E/Z
interconversion is unattainable. The data obtained are collected
in Table 5.
linear Brønsted plot, extending over 14 pK units and 5 log k
25
units, was evidenced by Amyes and Richard for the proton
-
abstraction by OH from a number of monocarbonyl com-
pounds. The authors explained this extended linearity in terms
2
5
Discussion
of non-constant intrinsic barriers. An interesting occasion for
8
testing this explanation is offered by the present and previous
results on 2-NCH and 3-NB. The Brønsted plots of log kOH
The rate-pH profile of Figure 3 shows a region, at interme-
diate pHs, for apparent OH catalysis and two regions where
KH
-
the reaction is pH-independent. The plateau at lower pH values
21
(22) (a) Bell, R. P. In The Proton in Chemistry, 2nd ed.;Cornell University
Press: Ithaca, NY, 1973; Chapter 10. (b) Bronsted, J. N.; Pedersen, K. Z.
Phys. Chem. 1924, 108, 185-285.
(
1.3 e pH e 3) corresponds to the “water” ketonization of
EH
-1
the enol, kW ) 0.028((0.002) s . The mechanism of this
reaction involves ionization of the enol to the enolate ion
followed by the rate-determining protonation of the enolate by
hydronium ion. Thus a hydronium ion is produced in the first
(23) Marcus, R. A. J. Phys. Chem. 1968, 72, 891-899.
(
24) (a) Guthrie, J. P. Can. J. Chem. 1979, 57, 1177-1185. (b) Guthrie,
J. P. J. Am. Chem. Soc. 1991, 113, 7249-7255. (c) Pruszynski, P.; Chiang,
Y.; Kresge, A. J.; Schepp, N. P.; Walsh, P. A. J. Phys. Chem. 1986, 90,
3
760-3766.
(
21) Chiang, Y.; Kresge, A. J.; Santaballa, J. A.; Wirz, J. J. Am. Chem.
(25) Amyes, T. L.; Richard, J. P. J. Am. Chem. Soc. 1996, 118, 3129-
Soc. 1988, 110, 5506-5510.
3141.
4044 J. Org. Chem., Vol. 72, No. 11, 2007

Ionization and Tautomerization of 2-Nitrocyclohexanone
Table 3) and log kWKH (Table 4) against pK (Figure 6a) and
TABLE 6. Correlation Analysis for the Rates [log(kOHKH/p)] and
Equilibria [-log(K/p)] of Ionization of Some Ketones (compounds 6,
(
pK′ (Figure 7a) are linear over 20 and 16 pK units, respectively.
14, 15, 17, 20, and 3-NB of Scheme 2) with Selected Substituent
2
The correlation coefficient, R , of the plot of
2
Parameters (R ) Correlation Coefficient)
Figure 6a increases up to 0.98 if only the ketones of Table 3
are considered (Figure 6b). The Brønsted plot of Figure 6b
extends to 16 pK units with an R of 0.64, a value considerably
parameters
R2 log(kOHEH/p)
R2 - log(K/p)
Es
σI
σR
σm
0.886
0.491
0.109
0.626
0.948
0.573
0.053
0.697
2
5
higher than that (R ) 0.38) found by Amyes and Richard. It
should be noticed, however, that the reported25 R value refers
also to aldehydes, esters, and thioesters and refers to a lower
number of considered structures.25 The unusual linearity of the
correlation of Figure 6b is apparently against the prediction of
the Marcus theory. For the ketones of Table 3, a constant
A similar conclusion can be arrived at by the use of ∆ ) R
â as a measure of the imbalance at the transition state,2
6d
-
-
1
where R is the Brønsted coefficient determined by varying the
substituent in the ionization reaction of a series of selected
carbon acids by a given base, and â is the Brønsted coefficient
determined by varying the substituent in the protonation reaction
of a series of bases by a given carbon acid. Several ∆ values
have been calculated by using the R value (0.64) of the plot of
Figure 6b and the â values for the deprotonation of acetone
intrinsic barrier Λ ) 16.8 kcal mol can be calculated by a
linear interpolation of the data to pK ) 0. This Λ value can be
inserted into the Marcus equation (eq 12 derived at 298 K
25
without the inclusion of a work term, wr ) 0) in order to obtain
KH
a set of “calculated” log kOH
.
KH
log kOH ) 1/1.36{17.44 - w -
r
2
9
21
24c
2
(0.72), acetophenone (0.68), isobutirophenone (0.63), 2-
Λ[1 + (1.36pK - w )/(4Λ)] } (12)
r
30
and 3-acetylthiophenes (0.53), and 2-NCH (â ) 0.63, see
The calculated values of log kOHKH have then been plotted
against pK, and as expected, a curve is obtained (dotted line in
Figure 6b).
Results) by different bases. In all cases, ∆ values are small
(-0.08 e ∆ e +0.11), suggesting that the imbalance in the
TS is either low or absent. This conclusion is also supported
by a comparison of the R value (0.64) of Figure 6b with that
Individual intrinsic barriers, Λ′, can vice versa be calculated
KH
31
-
from the experimental values of log kOH by using eq 12. We
(1.54) for the ionization of arylnitroalkanes by OH , a reaction
2
6d,32
note that the obtained values (Table 3) are lower for more
reactive compounds, in agreement with the “reactivity-selectiv-
ity principle”.
with a strongly imbalanced transition state.
Further evidence of a minor contribution by resonance as the
product-stabilizing effect in the ionization of nitroketones by
-
Departure from Brønsted linearity has also been interpreted
OH may come from the application to 2-NCH and 3-NB of a
26
26d
in terms of the principle of nonperfect synchronization (PNS).
treatment previously proposed by Bernasconi in terms of
An elementary reaction generally involves more than one
concurrent and unequally developing molecular processes at the
imbalanced transition state. According to the PNS,26 “a product
eq 13
δ log K ) δ log k /(ân - â)
(13)
R
R
(
reagent)-stabilizing factor whose development at the transition
ref
where δ log KR ()log KR - log K ) and δ log kR ()log kR -
state is late lowers (enhances) the rate constant, whereas a
product (reagent)-stabilizing factor whose development at the
transition state is early enhances (lowers) the rate constant”.
ref
log k ) represent the change in the equilibrium constant and in
the rate constant, respectively, induced by the resonance effect,
with reference to a proton-transfer reaction (log K and log
k ) unaffected by resonance. Taking into account that the
overall effect of the nitro group on the acidity of an R hydrogen
of a ketone can be taken as 14.9 pK units from the ∆pKa of
ref
Product-stabilizing factors that typically develop late and hence
ref
26d
lower the rate constant are2
6a,b,27
resonance, solvation, intramo-
lecular hydrogen bonding, and specific electrostatic effects.
Resonance effects are considered particularly important in
enhancing the intrinsic barrier of reactions wherein the depro-
tonation of a carbon acid is activated by a π-acceptor substituent,
3
3
propanone and nitropropanone, the resonance contribution to
this effect can be estimated as 3.0 (20%) pK units for 2-NCH
and 3.9 (26%) pK units for 3-NB (if n ) 3 and â ) 0.63).
Thus, it appears that the resonance contribution to the overall
acidifying effect of the nitro group of R-nitroketones is smaller
as the nitro or the phenyl groups.2
5,26d
Therefore, the absence
of significant departures from the linearity of the Brønsted plot
of Figure 6b could mean that resonance does not play a major
role as a product-stabilizing factor in the ionization reaction of
the investigated ketones. We have tested this possibility by
2
6d
than that found for nitroalkanes (53%).
A possible reason for the unexpectedly overwhelming role
played by steric and inductive effects on the deprotonation of
nitroketones comes also from our molecular modeling study.
From the conformational search, several representative geom-
etries were found (Figure 8) for the keto form of 2-NCH (two
KH
means of a correlation analysis of log K or log kOH for some
2
8
R-substituted ketones with different substituent parameters
σm,σI,σR,Es). The results of Table 6 clearly show that steric
(
effects play the major role both for the equilibrium and for the
kinetic deprotonation processes, whereas resonance effect plays
a minor role.
(
29) Shelly, K. P.; Nagarajan, K.; Ross, S. Can J. Chem. 1987, 65, 1734-
738.
30) De Maria, P.; Fontana, A.; Spinelli, D. J. Chem. Soc., Perkin Trans.
1
(
(
26) (a) Bernasconi, C. F. Acc. Chem. Res. 1987, 20, 301-308. (b)
2 1991, 1067-1070.
Bernasconi, C. F. AdV. Phys. Org. Chem. 1992, 27, 119-238. (c)
Bernasconi, C. F. Tetrahedron 1985, 41, 3219-3234. (d) Bernasconi, C.
F. Acc. Chem. Res. 1992, 25, 9-16.
(31) Bordwell, F. G.; Boyle, W. J., Jr. J. Am. Chem. Soc. 1972, 94, 3907-
3911.
(32) However, it should be recalled that the anomalous R value for the
ionization reaction of arylnitroalkanes has been alternatively attributed by
Cox to a solvent effect: Cox, B. G.; Gibson, A. J. Chem. Soc., Chem.
Commun. 1974, 638-639.
(33) Chiang, Y.; Kresge, A. J.; Schepp, N. P. J. Am. Chem. Soc. 1989,
111, 3977-3980.
(
27) Bernasconi, C. F. AdV. Chem. Ser. 1987, 215, 115-133.
(28) (a) Unger, S. H.; Hansch, C. Prog. Phys. Org. Chem. 1976, 12,
9
1-118. (b) Hansch, C.; Leo, A.; Unger, S. H.; Kim, K. H.; Nikaitani, D.;
Lien, E. J. J. Med. Chem. 1973, 16, 1207-1216. (c) Ehrenson, S.; Brownlee,
R. T. C.; Taft, W. Phys. Org. Chem. 1973, 10, 1-80.
J. Org. Chem, Vol. 72, No. 11, 2007 4045

Angelini et al.
FIGURE 8. Conformations of the keto, enol, and enolate form of 3-NB and 2-NCH and conformations of the keto form of NP obtained by
molecular modeling study.
conformations), 3-NB (three conformations), and NP (two confor-
mations), whose energies are reported in Table 5. Considering
the charge value [estimated by semiempirical calculations on
CdO and C-NO2 dipoles assume the most favorable alignment
for the polarization of the C-H bond.
To very similar +δ(H)max values for 3-NB and NP (0.166
+
the acidic hydrogen, δ(H)], the tendency of each geometry of
and 0.167, respectively) correspond very similar experimental
8
KH
the keto form to act as an acid can be evaluated, as it is known
pKa values (5.15 and 5.1, respectively). The calculated pKa
+
KH
that δ(H) is a meaningful descriptor of acidity. By analyzing
the variations of δ(H) as a function of the rotation about the
values are 3.9 and 3.7, respectively. These pKa values are
+
+
considerably lower than that of 2-NCH [ δ(H)
max
) 0.161;
KH
OC-CNO2 bond (see Scheme 5), it turns out that there is a
clear dependence of the polarity of the C-H bond on the
reciprocal disposition of the CdO and C-NO2 dipoles. Thus,
pKa ) 5.97 (exp), 5.2 (calcd)] where the ring decreases the
degrees of freedom and does not allow the OdC-C-NO2
dihedral angle to be greater than 112°. Since the most acidic
conformations of the three considered nitroketones display the
lowest molecular dipoles, for those conformations, a less
favorable hydration is expected (see values in Table 5). Thus,
+
the highest charge value [ δ(H)max] is attained when the Od
C-C-NO2 dihedral angle approaches to 150° and the OdC-
C-H dihedral angle is about 30° inmodule, that is, when the
4046 J. Org. Chem., Vol. 72, No. 11, 2007

Ionization and Tautomerization of 2-Nitrocyclohexanone
3
5
the more populated and less acidic conformations of 2-NCH,
for 2-NCH and 0.14 for 2-acetylcyclohexanone ). A comparison
between open chain and alicyclic R-nitroketones highlights that
the enol content at equilibrium is higher for 2-NCH than for
3-NB, and NP have to interconvert to the more acidic and more
reactive ones in order to react with a base. If this is the case,
the relevant role played by steric and inductive effects of the
nitro group on the thermodynamics and kinetics of the enoliza-
tion process can be easily understood. The smaller acidity
observed for the enol of 2-NCH than that of the enol of 3-NB
may be rationalized by considering that the internal energy
difference between the enolate ion and the enol is more positive
for 2-NCH than for 3-NB (see Table 5). On the contrary, the
steric entropy does not play a relevant role (∆SE-EH ) 0.00
u.e. for 2-NCH and 0.01 u.e. for 3-NB).
8
3-NB (pKT ) 2.34). This result can be understood by
remembering that alicyclic R-nitroketones can be better stabi-
1
0
lized by intramolecular hydrogen bonds.
Experimental Section
Materials. 2-Nitrocyclohexanone, inorganic salts (NaCl, NaH-
SO , KH PO , Na HPO ), and acids (CNCH COOH, ClCH COOH,
HOCH COOH, CH COOH) were commercial samples of AnalaR
3
2
4
2
4
2
2
2
3
grade and were used without further purification. Aqueous solutions
were prepared using deionized water.
Instruments. The kinetic experiments were carried out with a
UV/vis spectrophotometer equipped with a rapid kinetic accessory
for the faster reactions. The spectrophotometer was provided with
a thermostated cell holder.
Conclusions
13
It has been shown that 2-NCH is 5 × 10 times more acidic
1
7
than cyclohexanone, while the enol of 2-NCH is about 10
1
times more acidic than that of cyclohexanone. This remarkable
acidity of 2-NCH is attributable to the dramatic effect of the
R-nitro group. The value of pKT ) 1.19, for 2-NCH, is in sharp
Kinetic Measurements. The ketonization reaction of the enolate
of 2-NCH was followed spectrophotometrically by using NaHSO
3
as the scavenger of the ketone.8,16,17 The decrease of the absor-
contrast with the values for simple ketones such as acetone (pKT
banceat λ ) 336 nm of the enolate was followed at 25.0 ( 0.1 °C
)
8.33),33 acetophenone (pKT ) 7.96), and cyclohexanone
34
and at a constant ionic strength of 0.4 mol dm (NaCl). A small
-3
1
aliquot of a stock solution of 2-NCH in anhydrous dioxane was
added to the cuvette immediately before each kinetic run, in order
to minimize the hydration of the carbonyl group. The initial
(
pKT ) 6.39) for which the keto-enol equilibrium is largely
in favor of the more stable keto form. The keto-enol equilibria
and acidities of 2-NCH could more closely resemble those of
-
3
-3
concentration of 2-NCH was ca. 1 × 10 mol dm in all
3
5
1
,3-dicarbonyl compounds such as 2-acetylcyclohexanone.
experiments. The pH of the solution was tested before and after
However, the two systems appear quite different in terms of
each
experi-
both acidity of KH (pKa ) 5.94 for 2-NCH and 9.62 for
ment.
35
2-acetylcyclohexanone ) and tautomeric constants (pKT ) 1.19
Acknowledgment. We thank MIUR-Rome for financial
support (PRIN 2006: protocol number 2006035502).
(
34) Keeffe, J. R.; Kresge, A. J.; Toullec, J. Can. J. Chem. 1986, 64,
224-1227.
35) Iglesias, E. J. Org. Chem. 2003, 68, 2680-2688.
1
(
JO0700629
J. Org. Chem, Vol. 72, No. 11, 2007 4047