Solvent effects on the rate of the keto-enol interconversion of 2-nitrocyclohexanone

Article abstract of DOI:10.1039/b813011f

The rates of tautomerization of 2-nitrocyclohexanone (2-NCH) have been measured spectrophotometrically at 25.0 ± 0.1 °C in several organic aprotic solvents and their binary mixtures. In cyclohexane the reaction is effectively catalyzed by bases and inhibi

Full text of DOI:10.1039/b813011f

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Solvent effects on the rate of the keto–enol interconversion of
2
-nitrocyclohexanone†
a
a
a
a
b
Gabriella Siani,* Guido Angelini, Paolo De Maria, Antonella Fontana and Marco Pierini
Received 28th July 2008, Accepted 26th August 2008
First published as an Advance Article on the web 10th October 2008
DOI: 10.1039/b813011f
The rates of tautomerization of 2-nitrocyclohexanone (2-NCH) have been measured
◦
spectrophotometrically at 25.0 ± 0.1 C in several organic aprotic solvents and their binary mixtures. In
cyclohexane the reaction is effectively catalyzed by bases and inhibited by acids while the so-called
“
spontaneous reaction” appears essentially due to autocatalysis. Apparent second order rate constants
B
(
k
app ) for the reaction catalyzed by triethylamine (TEA) and pyridine (Pyr) have been obtained. From
B
B
B
the experimental kapp values rate constants for the enolization (k
1
) and ketonization (k-1 ) reactions
have been calculated. A Kamlet–Taft type linear solvation energy relationship (LSER) adequately
accounts for the observed solvent effects. Activation parameters for both reactions show that solvent
effects are mainly entropic in origin and that there is a shift of the transition state from a ketone-like to
an enol-like structure on passing from less to more polar solvents.
Introduction
CD
3
OD and CD
3
OD–CH
3
CN) correlates well with the E (30)
T
parameter of the solvent.
The keto–enol interconversion of carbonyl compounds is one of
the most investigated organic reactions in aqueous solution.
10
In a previous work some of us obtained kinetic data (k,
1–4
#
#
#
DG , DH and DS ) for the enantiomer interconversion of some
linear a-nitroketones by means of dynamic high-resolution gas
chromatography using a b-cyclodextrin derivative chiral stationary
2,5
In particular the less studied a-nitroketones represent an
interesting class of derivatives due to their high acidity and
relatively high enol content. They are, in principle, an equilibrium
mixture of three tautomers: the keto form, the enol form and the
nitronic acid form (aci form). However the aci form in most cases
#
phase. The highly negative values of DS obtained, suggest a
transition state with large charge separation in agreement with
a general acid–base catalyzed mechanism for the enolization
reaction.
In this work we have measured spectrophotometrically the rate
constants of tautomerization of 2-NCH following the change in
3,6
can be neglected in aqueous solutions due to its high acidity
and it is also hardly detectable in a number of aprotic organic
3,7
solvents. The values of the tautomeric equilibrium constants of
7
2
-nitrocyclohexanone (2-NCH) have been recently measured in
◦
absorbance of the enol form at 25.0 ± 0.1 C in some organic
organic solvents and ionic liquids and the solvent effects have been
discussed in terms of multiparameter equations.
On the other hand the available data on the kinetics of keto–
enol tautomerism for carbonyl compounds in aprotic solvents
aprotic solvents. DFT calculations have also been performed to
ascertain if the keto–enol interconversion can possibly occur with
a one-step mechanism through the formation of a four-membered
transition state.
Solvent effects have been discussed in terms of multiparameter
equations that take into account non specific and specific solute–
solvent interactions.
8
are very scarce. In a recent study the solvent effect on the
base-catalyzed tautomerization of 2-acetylcyclohexanone and 2-
acetyl-1-tetralone was studied in dimethylsulfoxide (DMSO)–
water mixtures of different composition. The reaction rate strongly
increases at high percentages of DMSO and the author interpreted
this effect in terms of solvent polarity and the molecular structure
The separate activation parameters of enolization and ke-
#
#
#
tonization, DG , DH and DS , have been derived from
rate-measurement at different temperatures in chloroform,
dichloromethane and acetonitrile.
8
9
of the solvent molecules. Furthermore a LC-NMR study of the
ketonization of the ethyl butylryl acetate enol has shown that
the rate constant in three binary mixtures (D
2
O–CH
3
CN, D O–
2
Results and discussion
Kinetics of the keto–enol interconversion of 2-NCH in cyclohexane
a
Dipartimento di Scienze del Farmaco, Universit a` “G. d’Annunzio” Via dei
Vestini 31, Chieti, Italy. E-mail: siani@unich.it; Fax: 39 0871 3554461;
Tel: 39 0871 3554784
The rate of the keto–enol interconversion of 2-NCH has been
◦
measured in cyclohexane by UV–vis spectroscopy at 25.0 ±0.1 C,
b
Dipartimento di Studi di Chimica e Tecnologia delle Sostanze Biologica-
following the appearance of the band of the enol from a solution
containing an excess of the keto form in the absence and in the
presence of trifluoroacetic acid (TFA) or triethylamine (TEA).
The plot of Fig. 1 shows that the tautomerization reaction of 2-
NCH is catalyzed by bases and hampered by acids. It is somewhat
unexpected that the “spontaneous” tautomerization is detectable
mente Attive, Universit a` “La Sapienza” P.le Aldo Moro 5, Roma, Italy
†
Electronic supplementary information (ESI) available: UV-determined
tautomeric constants, K , of 2-NCH in several organic solvents and
their binary mixtures and selected descriptors of solvent polarity; second
T
B
B
B
order rate constants, kapp , k
interconversion of 2-NCH in aprotic solvents at different temperatures.
See DOI: 10.1039/b813011f
1
and k-1 for the base catalyzed keto–enol
4
236 | Org. Biomol. Chem., 2008, 6, 4236–4241
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Fig. 1 Kinetic profiles for the tautomerization of 2-NCH in cyclohexane
in the presence of TEA (solid line), TFA (dotted line) and in the absence
of the catalyst (dashed line).
Fig. 2 Energy diagram for the keto–enol–aci interconversions of 2-NCH
via intramolecular proton transfer. The energy values reported in the
diagram are in kcal mol- and refer to calculations performed in a vacuum
in an aprotic solvent such as cyclohexane. In this solvent the
tautomerization reaction can only occur either by intramolecular
proton transfer in a one-step mechanism through the formation of
a four-membered transition state or by an intermolecular stepwise
mechanism of autocatalysis. The two possibilities are separately
analyzed as follows.
1
(
out of parentheses) and in cyclohexane (within parentheses).
Intermolecular proton transfer
An energetically more favorable mechanism may occur if a second
molecule with basic functionalities can assist the proton transfer
in one concerted step, as depicted in Scheme 1a, or in two steps
through the formation of a more or less intimate (depending upon
the particular solvent) ion paired intermediate, as depicted in
Scheme 1b.
Intramolecular proton transfer
Some DFT calculations (non local density functional model BP
with a 6–31G** basis set) have been performed on the most stable
geometries, obtained by conformational search, of the keto form
(
2
KH), the enol form (EH) and the nitronic acid form (ACI) of
-NCH to test if an intramolecular proton transfer mechanism is
a plausible mechanism. Structures and energies of the transition
states (TS) have also been optimized for the enol–aci, keto–aci and
keto–enol intramolecular interconversions.
It is noteworthy that the present calculations point to a very
easy interconversion between the enol and the aci form and that
the enol is the most stable tautomer in the gas phase (K
as well as in apolar solvents (see Table 1).
T
= 19.4)
The results are shown in Fig. 2, in the form of an energy diagram.
The energy values obtained in the gas phase and in a highly
apolar solvent like cyclohexane (e = 2.0), as expected, are very
similar.
The DE values for the different forms of 2-NCH reported in
Fig. 2 are too high to support a mechanism of interconversion via
Scheme 1
#
The former mechanism is more likely in less polar solvents, while
the latter mechanism should be prevalent in more polar solvents.
In Scheme 1, B can be a molecule of an external general base
(triethylamine or pyridine) or a second molecule of 2-NCH. The
presence of TFA, which can reduce the basicity of 2-NCH, makes
intramolecular proton transfer. This conclusion is in agreement
11
with that previously advanced for simple carbonyl compounds
and some linear a-nitroketones.
10
TEA
TEA
TEA
Table 1 Second order rate constants, kapp , k
1
and k-1
for the base catalyzed keto–enol interconversion of 2-NCH in some aprotic solvents
TEA
/M-1s-1
TEA
/M-1s-1
TEA
/M-1s-1
a
EH
Solvent
k
app
k
1
k
-1
K
T
l
max
Cyclohexane
0.194 (±0.005)
2.50 (±0.16)
32.7 (±0.2)
74.4 (±0.8)
522 (±21)
0.168
2.14
21.5
32.6
55.9
0.026
0.359
11.2
41.8
466
6.46
5.97
1.92
0.78
0.12
319
323
330
330
330
CCl
CHCl
4
3
CH
CH
2
Cl
CN
2
3
a
Values determined by UV–vis spectroscopy from ref. 7.
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the process much slower (Fig. 1). The mechanism of autocatalysis
is also supported by some experiments carried out in cyclohexane
carefully purified through chromatographic columns containing
basic and acid aluminium oxide to remove possible acidic and/or
rate = kapp [2-NCH]
(1)
The obtained values of kapp were linearly related to [B] according
to eqn 2
0
basic impurities. The “spontaneous” rate constant, kapp , increased
0
B
k
app = kapp + kapp [B]
(2)
-
5
-4 -1
from 6.38 ¥ 10 to 1.51 ¥ 10
s as the concentration of 2-NCH
-
5
-4
-3
increased from 2.0 ¥ 10 to 1.0 ¥ 10 mol dm .
B
where B is Pyr or TEA. The second order rate constants, kapp , can
be calculated from the slopes of the plots of kapp against [B] (see a
typical example in Fig. 5).
Docking experiments between 2-NCH molecules in their keto
form have been performed, taking into account both homochiral
(
R-KH : R-KH) and heterochiral (R-KH : S-KH) associations.
The most stable and most populated homo and hetero chiral
adducts have at least one of the basic functionalities of a molecule
of 2-NCH facing the acidic hydrogen of the other molecule (see
Fig. 3). This result suggests transition states in which one molecule
of 2-NCH assists the transfer of the acidic hydrogen from the other
molecule.
Fig. 3 Hetero and homo KH : KH adducts obtained by docking
procedures based on molecular mechanics calculations.
Fig. 5 Plot of the pseudo-first order rate constant, kapp, vs. [Pyr] in
CH
2
Cl
2
. The slope corresponds to the second order rate constant for the
Pyr
Pyr-catalyzed keto–enol interconversion, kapp
.
General base catalysis
0
As expected the contribution of kapp is not detectable in the
presence of Pyr or TEA.
The rate of the base-catalyzed tautomerization of 2-NCH has
been measured in different solvents, following the increase (in
cyclohexane and carbon tetrachloride) or the decrease (in the more
polar solvents where the keto tautomer is more stable than the enol
tautomer) of the absorbance at the lmax of the enol form (see typical
examples in Fig. 4).
Triethylamine, TEA, or pyridine, Pyr, have been used as the
catalysts. In most solvents the concentration of the catalyst was
varied over a range of a factor of ten. Under the adopted
experimental conditions, all the kinetic profiles were consistent
with a pseudo-first order process according to eqn 1.
Since the tautomerization reaction is a reversible reaction
B
(
k
Scheme 1), kapp includes both contributions from the enolization,
B
B
B
B
1
, and the ketonization, k-1 , reaction. k
1
and k-1 have been
calculated in the five aprotic solvents from eqn 3 and 4 by using
7
previously determined K
T
= [EH]/[KH] values.
B
B
k
1
= kapp [K
T
/(K
T
+ 1)]
(3)
(4)
B
B
B
k
-1 = kapp - k
1
Fig. 4 Kinetic profiles for the keto–enol interconversion of 2-NCH catalyzed by pyridine (a) in cyclohexane and (b) in acetonitrile.
238 | Org. Biomol. Chem., 2008, 6, 4236–4241
4
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Pyr
Pyr
Pyr
Table 2 Second order rate constants, kapp , k
1
and k-1 for the base catalyzed keto–enol interconversion of 2-NCH in some aprotic solvents and
binary mixtures, listed in order of increasing permittivity, e
10-
2
k
appPyr/M-1s-1
10-2
k
1
Pyr/M-1s-1
10-2
k
-1Pyr/M-1s-1
K
a
e
Solvent
T
b
b
b
b
Cyclohexane
0.0256 (±0.0010)
0.0643 (±0.0013)
1.30 (±0.01)
1.89 (±0.01)
3.88 (±0.16)
6.43 (±0.10)
8.82 (±0.10)
8.98 (±0.11)
9.60 (±0.16)
0.0222
0.0551
0.855
0.828
1.08
1.16
1.06
0.00342
0.00923
0.445
1.062
2.80
5.27
7.76
6.46
5.97
1.92
0.78
0.39
0.22
0.14
0.14
0.12
2.0
2.2
4.8
8.9
13.7
21.7
28.8
30.7
35.9
CCl
CHCl
4
3
CH
CH
CH
CH
CH
CH
2
3
3
3
3
3
Cl
2
CN–CH
CN–CH
CN–CHCl
CN–CH
CN
2
2
Cl
Cl
2
(20 : 80)
(50 : 50)
(80 : 20)
(80 : 20)
2
3
2
Cl
2
1.08
1.03
7.90
8.57
b
a
b
Values determined by UV–vis spectroscopy as in ref. 7. From ref. 7.
Values of K
T
in CH
3
CN–CH
2
Cl
2
and CH
3
CN–CHCl
3
binary
where D
i
represents the i selected descriptors of solvent polarity, f
i
mixtures of various composition have been determined by follow-
ing the previously described procedure.
the corresponding regression coefficients and C is the regression
constant.
7
Comparison of the rate constants for TEA (pK
a
in water =
The best correlations were obtained from the equation that uses
12
13
2
7
1
0.8 ) and Pyr (pK
solvents, collected in Tables 1 and 2, clearly shows that the stronger
base acts as the most efficient catalyst.
a
in water = 5.17 ) catalysis in the different
the cohesive pressure, d , the previously described normalized
16–18
polarity index, T
N
(analogous to the well known
indexes p*,
p*azo and E
T
) and the Kirkwood’s function, F(e) = (e - 1)/(2e + 1)
Tables 1 and 2 show that rate constants increase on passing from
apolar to polar solvents. To evaluate the solvent effect on the rate of
tautomerization a correlation analysis was performed as follows.
(eqn 6). These parameters express different and complementary
properties of the solvent, namely the electrostatic shielding of
2
partial or full charges [F(e)], the cavitational energy (d ) and
B
A good correlation was found simply by plotting kapp against
the aspecific as well as donor–acceptor and hydrogen bonding
2
solvent permittivity, e, both for TEA (R = 0.996) and Pyr catalysis
interactions (T ).
N
2
(
R = 0.990; Fig. 6—solid line). In the case of binary mixtures the
Pyr
2
14
lnk = C + aF(e) + bd + cTN
(6)
values of e were calculated as previously reported. An analogous
satisfactory correlation was obtained for the ketonization rate
For binary mixtures the values of d were calculated from eqn 7:
B
2
2
constant k-1 both for TEA (R = 0.993) and Pyr catalysis (R =
0
.990; Fig. 6—dotted line), while the correlation for the enolization
d = [(%)V/V1
d
1
+ (%)V/V2
d
2
]/100
(7)
B
rate constant k
1
was not linear (Fig. 6—dashed line) and it seems
scarcely affected by the solvent permittivity.
where 1 and 2 refer to the two different solvents. The results are
collected in Table 3.
Poorer correlations were observed for LSERs that use other clas-
sical solvent parameters (the results are available upon request).
Pyr
The values of lnk calculated from eqn 6 have been plotted
against the corresponding experimental values. Fig. 7 shows, as an
example, the good validation of the correlation of eqn 6 applied
Pyr
2
to kapp values (R = 0.998).
The relative contributions of the solvent parameters of eqn 6
to the different rate constants have been calculated, on a
percentage basis, from the absolute values of the regression
coefficients (see Table 3). It turns out that total specific and non-
specific electrostatic interactions prevail over cavitational energy
interactions in each solvent investigated (see Fig. 8). As expected,
while the contribution of the former interactions increases in
solvents with an e value lower than about 8, the contribution of the
latter interactions decreases in the same range of e values. This is
Fig. 6 Plots of kapp (●—solid line), k
ꢀ—dotted line) against solvent permittivity, e, for the Pyr catalyzed
tautomerization of 2-NCH.
1
(▲—dashed line) and k-1
Table 3 LSER of eqn. 6 applied to the different rate constants of the
(
Pyr-catalyzed tautomerization of 2-NCH
Kinetic
constant (k )
B
2
R
LSER
15
A multiparameter treatment of the data obtained for Pyr
catalysis was performed according to the Kamlet–Taft type eqn 5:
Pyr
Pyr
2
k
k
k
app
0.997
0.997
0.998
lnkapp = -11.7 + 9.36F(e) + 0.021d + 3.05T
N
Pyr
Pyr
2
1
lnk
1
= -9.26 + 4.62F(e) - 0.004d + 4.60T
N
Pyr
Pyr
2
ꢀ
-1
lnk-1 = -15.3 + 17.4F(e) + 0.021d + 2.53T
N
B
lnk = C +
I
f
i
D
i
(5)
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#
#
The contribution of the term TDS to DG , for both reactions, is
#
higher than that of DH , particularly in CHCl
being the Pyr-catalyzed reaction in CH CN. This fact suggests
that the solvent effect on the rate of tautomerization is mainly
3
, the only exception
3
#
#
entropic in origin and that there is a tendency for DH and DS to
compensate each other. The entropy decrease (DS < 0) observed
#
in the investigated solvents depends on the combination of two
different molecules (substrate and catalyst) to form one unstable
geometry (transition state) with loss of six (roto-translational)
degrees of freedom.
Pyr
Fig. 7 Plot of experimental lnkapp values against values calculated from
eqn 6.
Conclusions
(
i) The tautomerization reaction of 2-NCH occurs in aprotic
consistent with the more efficient solvation of a charge-separated
transition state by more polar solvents (Scheme 1).
◦
solvents at 25.0 C. The reaction is effectively catalyzed by bases
and inhibited by acids, while the so-called “spontaneous” reaction
is probably due to autocatalysis.
#
#
#
Determination of the activation parameters DG , DH and DS ,
(
ii) The rate of proton transfer is faster when the basic strength of
for the enolization and ketonization reactions
the catalyst is higher.
The kinetics of the tautomerization reaction of 2-NCH have been
(iii) The overall solvent effect can be accounted for by a Kamlet–
Taft type multiparameter equation.
(iv) The ketonization reaction of the enol is faster in the more polar
solvents and the solvent effect appears to be prevalently entropic
in origin.
(v) According to the Hammond postulate there is a shift from
a ketone-like to an enol-like structure of the transition state on
passing from less polar to more polar solvents.
also investigated in the temperature range 283.15–323.15 K in
#
CHCl
3
, CH
2
Cl
2
and CH
3
CN. DG values for the enolization and
B
B
ketonization reactions have been calculated from k
1
and k-1
values at different temperatures (see ESI†) according to the Eyring
eqn 8
#
B
DG (T) = RT(lnT/k + lnk
B
/h)
(8)
where R is the gas constant, T is temperature, h is the Planck
#
constant and k
B
is the Boltzmann constant. The values of DH
Experimental
#
and -DS can be determined as the slope and the intercept of
a plot of DG /T vs. 1/T. The obtained results are collected in
#
Materials
Table 4.
The organic solvents (cyclohexane, carbon tetrachloride,
dichloromethane, chloroform and acetonitrile), 2-nitrocy-
clohexanone and trifluoroacetic acid were commercial samples
of AnalaR grade and were used without further purification.
Triethylamine and pyridine were distilled in the presence of NaOH
before each experiment.
#
The data of Table 4 show that DG values of enolization and
ketonization, for a given catalyst, significantly decrease on passing
from the less polar (cyclohexane) to the more polar (CH CN)
solvent. This effect is due to a more efficient stabilization, by
more polar solvents, of the polar transition state where the acidic
proton of the reactant is somewhat transferred to the neutral base
3
#
#
catalyst. The relative values of DG
1
and DG-1 suggest that there is
Instruments
a shift from a ketone-like to an enol-like structure of the TS of the
tautomerization reaction (according to the Hammond postulate)
on passing from the less to the more polar solvents.
The kinetic runs were carried out with a UV–vis spectrophotome-
◦
ter provided with a thermostatted (±0.1 C) cell holder.
Fig. 8 Percent contribution of electrostatic (ꢀ) and cavitational energy interactions (▲) on the enolization (a) and ketonization (b) reaction of 2-NCH
in solvents of different permittivity, e.
4
240 | Org. Biomol. Chem., 2008, 6, 4236–4241
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#
-1
#
-1
#
Table 4 Activation parameters, DG (kcal mol at 298.15 K), DH (kcal mol ) and DS (e.u.), for the enolization and ketonization reactions of 2-NCH
in CHCl
3
, CH
2
Cl
2
3
and CH CN
Enolization
Ketonization
#
#
#
#
#
#
#
#
DG
1
DH
1
DS
1
-TDS
1
DG-1
DH--1
DS-1
-TDS-1
Catalysis by TEA
Cyclohexane
18.5
17.0
15.6
15.3
15.1
—
—
2.54
5.17
7.00
—
—
-44
-40
-27
—
—
13.1
11.9
8.05
19.6
18.1
16.0
15.2
13.8
—
—
4.20
5.53
5.88
—
—
-40
-32
-27
—
—
11.8
9.59
8.05
CCl
CHCl
4
3
CH
CH
2
Cl
CN
2
3
Catalysis by Pyr
Cyclohexane
22.4
21.9
20.3
20.3
20.1
20.1
20.1
20.1
20.2
—
—
7.29
8.82
—
—
—
—
10.4
—
—
-43
-38
—
—
—
—
—
12.8
11.3
—
—
—
—
9.82
23.5
23.0
20.7
20.1
19.6
19.2
19.0
19.0
18.9
—
—
9.02
9.19
—
—
—
—
9.32
—
—
-39
-37
—
—
—
—
—
11.6
11.0
—
—
—
—
9.54
CCl
CHCl
4
3
CH
CH
CH
CH
CH
CH
2
3
3
3
3
3
Cl
2
CN–CH
CN–CH
CN–CHCl
CN–CH
CN
2
2
Cl
Cl
2
20 : 80
50 : 50
80 : 20
80 : 20
2
3
2
Cl
2
—
-33
—
-32
Kinetic measurements
procedure was repeated after inverting the configuration of one of
the two molecules. All the adducts obtained were finally optimized,
relaxing all their degrees of freedom by the molecular mechanics
method based on the mm2* force field, as implemented in the
computer program MacroModel v.4.0.
The keto–enol interconversion of 2-NCH was followed spec-
trophotometrically by monitoring the variation of the absorbance
EH
at lmax of the enol form of 2-NCH at different temperatures.
A small aliquot of a stock solution of 2-NCH in CCl was
4
added immediately before each kinetic run to a cuvette containing
Pyr or TEA dissolved in the appropriate organic solvent. The
initial concentration of 2-NCH was ca. 1 ¥ 10 mol dm in all
Acknowledgements
-
3
-3
We thank MIUR-Rome for financial support (PRIN 2006:
protocol number 2006034372).
experiments.
Computational methods
References
Optimized geometries of the tautomeric forms of 2-NCH were
obtained by performing molecular modeling calculations with the
computer program SPARTAN 04 (Wavefunction Inc. 18401 Von
Karman Avenue, Suite 370 Irvine, CA 92612) running on a PC
equipped with Intel Pentium 4, CPU 3.40 GHz, 2 GB of RAM and
OS Windows 2000 Professional. As the first step, conformational
searches on the keto, enol and aci forms of 2-NCH were carried out
by setting the options as follow: MMFF force field; search by the
Montecarlo stochastic algorithm (all rotatable bonds explored);
maximum number of conformers = 100; window energy cut =
1
2
R. P. Bell, The Proton in Chemistry, Chapman and Hall, London 1973.
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G. Angelini, C. Chiappe, P. De Maria, A. Fontana, F. Gasparrini, D.
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6
7
-
1
8 E. Iglesias, New J. Chem., 2005, 29, 625.
9
0 F. Gasparrini, M. Pierini, C. Villani, P. De Maria, A. Fontana and R.
5
kcal mol . As the second step, the most stable conformer
Chun C. Zhou and D. R. Hill, Magn. Reson. Chem., 2007, 45, 128.
obtained of each tautomeric form was further optimized at the
SCF level by the non local density functional model BP with the
1
Ballini, J. Org. Chem., 2003, 68, 3173.
6
–31G** basis set. Transition state geometries for the enol–aci,
11 D. Lee, C. K. Kim, B. S. Lee and I. Lee, J. Comput. Chem., 1997, 18,
5
6.
keto–aci and keto–enol intramolecular interconversions were also
achieved by the same quantistic model, again optimized at the SCF
level. The solvation energies of the tautomers and the transition
states of 2-NCH in cyclohexane were obtained by performing
single-point calculations on the BP optimized geometries by the
conductor like screening model (COSMO), as implemented in the
Amsterdam density functional (ADF) package v. 2007.01.
1
1
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1
1
A rigid docking experiment between the most stable conforma-
tions of 2-NCH within the (R) configuration was performed by the
19
home made computer program MolInE, carrying out molecular
mechanics calculations based on the mm2* force field. The same
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