predicting the tautomeric equilibrium of acetylacetone in solution. i. the right answer for the...
TRANSCRIPT
Predicting the Tautomeric Equilibrium of Acetylacetone
in Solution. I. The Right Answer for the Wrong Reason?
SEBASTIAN SCHLUND,1 ELINE M. BASILIO JANKE,2 KLAUS WEISZ,3 BERND ENGELS1
1Institute for Organic Chemistry, University of Wurzburg, Am Hubland,97074 Wurzburg, Germany
2Institute for Chemistry, Free University of Berlin, Takustr. 3, 14195 Berlin, Germany3Institute for Biochemistry, Ernst-Moritz-Arndt University of Greifswald, Felix-Hausdorff-Str. 4,
17489 Greifwald, Germany
Received 14 February 2009; Revised 14 May 2009; Accepted 19 May 2009DOI 10.1002/jcc.21354
Published online 25 June 2009 in Wiley InterScience (www.interscience.wiley.com).
Abstract: This study investigates how the various components (method, basis set, and treatment of solvent effects)
of a theoretical approach influence the relative energies between keto and enol forms of acetylacetone, which is an
important model system to study the solvent effects on chemical equilibria from experiment and theory. The compu-
tations show that the most popular density functional theory (DFT) approaches, such as B3LYP overestimate the sta-
bility of the enol form with respect to the keto form by �10 kJ mol21, whereas the very promising SCS-MP2
approach is underestimating it. MP2 calculations indicate that in particular the basis set size is crucial. The Dunning
Huzinaga double f basis (D95z(d,p)) used in previous studies overestimates the stability of the keto form consider-
ably as does the popular split-valence plus polarization (SVP) basis. Bulk properties of the solvent included by con-
tinuum approaches strongly stabilize the keto form, but they are not sufficient to reproduce the reversal in stabilities
measured by low-temperature nuclear magnetic resonance experiments in freonic solvents. Enthalpic and entropic
effects further stabilize the keto form, however, the reversal is only obtained if also molecular effects are taken into
account. Such molecular effects seem to influence only the energy difference between the keto and the enol forms.
Trends arising due to variation in the dielectric constant of the solvent result from bulk properties of the solvent,
i.e., are already nicely described by continuum approaches. As such this study delivers a deep insight into the abil-
ities of various approaches to describe solvent effects on chemical equilibria.
q 2009 Wiley Periodicals, Inc. J Comput Chem 31: 665–670, 2010
Key words: keto-enol equilibrium; solvent effects; method dependency
Introduction
The influence of the surrounding medium on both the reaction
pathway (thermodynamics) and reaction rate (kinetics) is one of
the major challenges in chemistry as nearly all reactions take
place in solvent.1 Several studies show that not only the bulk
properties but also the molecular structure of the solvent can be
of great significance.2 Hence, the development of theoretical
methods which allow for solvent effects has become an impor-
tant field of research.
For electronic structure calculations the continuum models
approximating a homogeneous bulk of solvent molecules have
gained large popularity in the recent past.3 Hereby, the polariza-
tion effect of a continuum on the electronic structure of the sol-
ute is taken into account. Often used solvent models are the
polarizable continuum model (PCM) method developed by Tom-
asi or the conductor-like screening model (COSMO) by Klamt
and Schuurmann.4 The molecular nature of the solvent environ-
ment can be treated explicitly by the combined quantum
mechanics/molecular mechanics simulation method.5 The solute
is calculated within a QM framework, whereas the solvent mole-
cules are described by a classical force field. The interaction
potentials between solvent and solute are included either by an
electrostatic or polarized embedding approach.6 However, due to
the large computational costs, this approach is only feasible with
a semiempirical or density functional based treatment of the QM
part.
A well-studied example of solvent effect is the keto-enol tau-
tomerism of acetylacetone: either the keto or the enol form is
favored depending on the surrounding solvent. Experiments have
Additional Supporting Information may be found in the online version of
this article.
Correspondence to: B. Engels; e-mail: [email protected]
Contract/grant sponsor: Deutsche Forschungsgemeinschaft; contract/grant
numbers: EN1971/10, SFB 630
q 2009 Wiley Periodicals, Inc.
shown that in gas phase and media of low polarity the enol form
is more stable than the keto form, whereas the keto form domi-
nates in more polar environments.2,7 The large effects result
from the intramolecular stabilization of the enol form that is
strongly reduced by competing intermolecular interactions with
the solvent shell (Fig. 1).
With the availability of new nuclear magnetic resonance
(NMR) experiments using the liquefied freonic gases (CDF3/
CDF2Cl), we were able to investigate the keto-enol tautomeric
equilibrium of acetylacetone in solvent with different dielectric
constants. The NMR measurements were performed at tempera-
tures as low as 123 K.8 Because the dielectric constant of the
freonic mixture depends strongly on temperature, it effectively
mimics very different solvent polarities if measurements are per-
formed over a large temperature range (from e 5 14 at 190 K to
e 5 34 at 120 K).9 Thus, unusually strong temperature effects
on the acetylacetone keto-enol equilibrium were experimentally
observed on lowering the temperature (see Supp. Info.). An enol
tautomeric preference typical for the presence of a nonpolar sol-
vent is observed at higher temperatures. The corresponding sig-
nal intensities show a enol:keto molar ratio of about 4:1 at T �173 K. With decreasing temperature, however, the keto tautomer
becomes increasingly populated and at 123 K the enol:keto
molar ratio has completely reversed (1:4).
To model these new NMR experiments, we have performed
state-of-the-art electronic structure calculations taking bulk
effects of the solvent into account. However, by using a contin-
uum approach for modeling the solvent shell, we were not able
to reproduce the experimentally observed shift in the keto-enol
ratio of acetylacetone upon increasing the solvent polarity.
This was curious since previous theoretical works seemed to
describe this reversal with less sophisticated approaches. Previ-
ous computations showed10,11 that the keto tautomer undergoes
a geometric change as the solvent polarity increases making its
dipole moment larger compared to the enol form.12,13 Finally,
Ishida et al.13 correctly reproduced the experimentally observed
enol ? keto transition in polar solvents by means of electronic
structure calculations on MP2/D95z(d,p) level of theory. The
solvent effects were taken into account by the reference site
interaction model self-consistent field (RISM-SCF) method.
The RISM-SCF by Kato and coworkers14 represents an inte-
gral equation method based on statistical mechanics of molecu-
lar liquids coupled with Hartree-Fock equations. Hence, the mo-
lecular effects of the solvent molecules are only described by
potential functions and do not explicitly include hydrogen bond-
ing from the solvent molecules to the solute. Therefore, the suc-
cess of this approach suggests that the shift from the enol form
to the keto form derives primarily from the bulk properties of
the solvent, whereas the molecular nature of the solvent is of
smaller relevance (Sakaki et al.15 have recently extended the
RISM-SCF model using a more realistic Coulomb interaction
between solvent and solute by introducing a spatial electron den-
sity distribution instead of using a set of grid points).
Because our improved computations were not able to reproduce
the experimentally observed shift, we reinvestigated the problem
to reveal possible error cancellations. Our calculations clearly
show that the good agreement of former theoretical studies with
corresponding experimental results indeed result from an error
compensation due to two opposite trends. The present results also
give a deeper insight into the accuracy of various ab initio meth-
ods in the description of keto-enol equilibria and indicate that the
molecular nature of the solvent plays an important role.
Theoretical Details
As in related studies,16 we first applied DFT approaches, which
are known for their favorable cost-benefit ratio.17 However, in
some cases, reliable predictions deserve higher level
approaches,18 we also applied perturbational approaches and
coupled cluster methods. All structure optimizations have been
performed with the Turbomole program package (V5.8-V5.10)19
and were done at RI-BP86, B3LYP, BHLYP, HF, and RI-MP2
level of theory using a TZVPP (valence triple zeta plus two sets
of polarization functions) basis set. Furthermore, MP2 single-
point calculations with D95v(d,p), SV(P), SVP, and TZVPP ba-
sis sets have been performed on HF/TZVPP optimized struc-
tures. The electrostatic contributions of the solvent were esti-
mated using the COSMO approach with dielectric constants
from e 5 3 to e 5 78 to simulate solvents of varying polarity.4
The CCSD(T)/TZVPP and (SCS)-MP2/TZVPP single-point cal-
culations were performed with MOLPRO on RI-MP2/TZVPP
optimized geometries.20
The frequencies and thermodynamic corrections in gas phase
were calculated analytically on DFT (BHLYP) level with the Tur-
bomole program package. Hereby, the geometries have been reopti-
mized using a Valence triple zeta plus two sets of polarization
functions (TZVPP) basis set because the analytical gradient was
not available for g-functions. Frequencies of the continuum sol-
vated molecules have been calculated numerically on a RI-
BHLYP/TZVPP level of theory as calculations of numerical deriv-
atives with COSMO were only possible using the RI approxima-
tion. All wave numbers were scaled by a factor of 0.9 and the
enthalpic and entropic contributions were determined at 273 and
123 K. The nonelectrostatic contributions to the free energy of sol-
vation have been determined with the COSMO approach as imple-
mented in Gaussian-03 (C-PCM with standard parameters). We
performed BHLYP/TZVP single-point calculations on the BHLYP/
TZVPP optimized geometries in the respective dielectric.21
For the explicitly solvated structures of acetylacetone, force
field-based conformational searches have been performed
(MMFF94 force field, Mixed MCMM/LM search algorithm,
5000 steps) using the Macromodel V8.0 suite by Schrodinger
(Portland, OR). The generated conformers were subsequently
optimized on DFT level (RI-BP86/SVP), and the lowest con-
formers have been reoptimized on BHLYP/TZVPP level to
locate the global minima on the PES.
Figure 1. Tautomeric structures of acetylacetone.
666 Schlund et al. • Vol. 31, No. 4 • Journal of Computational Chemistry
Journal of Computational Chemistry DOI 10.1002/jcc
Results
The optimized structures of the keto and enol tautomers of ace-
tylacetone are depicted in Figure 2. The respective electronic
energies in gas phase and solvent for the various levels of theory
are given in Table 1. Regarding first the gas phase values one
can see a discrepancy in the relative energies between pure
GGA functionals (BP86, BLYP) and hybrid functionals
(B3LYP, BHLYP). In comparison with the most accurate
CCSD(T) result, the energy difference between the keto and
enol forms is strongly overestimated if pure GGA functionals
(BP86, BLYP) are used. If an increasing amount of exact
exchange is included, the computed energy difference
approaches the CCSD(T) value. The BHLYP value deviates by
about 4 kJ mol21, which is of similar accuracy than the RI-MP2
results. Moreover, density functionals with less exact exchange
were not able to locate the second local minimum K2 on the
energy hypersurface which becomes more stable in continuum
solvation with large dielectrics than K1.
The gas phase energies obtained by Møller-Plesset perturba-
tion theory second order calculated with a triple-f-basis set with
additional polarization functions are generally in good agreement
with coupled-cluster results. Only the spin-component scaled
MP2 method describes the relative energies of the keto forms
K1 and K2 systematically as too stable. It seems that the
decreased ‘‘triplet’’ contribution of the SCS-MP2 method is
underestimating the intramolecularly hydrogen bonded enol form
E. A much stronger underestimation of the energy difference is
obtained if a double-f-basis is employed as it was done in the
study of Dannenberg and Rios.11 The relative energy of the K1
tautomer lies only 4 kJ mol21 higher than for the enol tautomer
if the D95** basis set by Dunning and Huzinaga is used.
The influence of bulk effects of a polar solvent was estimated
on BHLYP/TZVPP level. Going from gas phase to solution, two
effects can be observed: (1) with increasing dielectric constant
of the solvent, the keto forms are stabilized with respect to the
enol form and (2) the keto form K2 becomes more stable than
K1 for e values larger than 3. This behavior is reflected in a
larger increase of the dipole moment (Table 2) of K2 indicating
a stronger stabilization of this tautomer in polar solvents. The
measured dihedral angles between both carbonyl groups in K2
are in excellent agreement with previously published studies that
predicted a geometrical change of the keto tautomer on solva-
tion.12,13 However, by using a simple continuum model the trend
reversal in the stability of keto/enol tautomers as observed
experimentally is not found. BHLYP/TZVPP predicts K2 to be
about 6 kJ mol21 less stable than E. For gas phase, BHLYP
deviates from the more accurate CCSD(T) by 4 kJ mol21.
Transferring this difference to solvent, K2 is still less stable
than E by about 2 kJ mol21, even in a continuum simulating an
aqueous surrounding (e 5 78).
To estimate the influence of enthalpic and entropic contribu-
tions on the tautomeric equilibrium of acetylacetone, the thermo-
dynamic corrections have been calculated both for gas phase
and solution on DFT level with varying dielectric constants and
temperatures (Table 3).
In all cases enthalpic (DHcorr) and entropic effects (2TDScorr)stabilize the keto form relative to the enol form. The entropic
effect results from the more disordered state of the keto form.
The enthalpic effect is mainly connected with the zero-point
Figure 2. Tautomeric structures of acetylacetone in gas phase (RI-MP2/TZVPP).
Table 1. Relative Energies (in kJ mol21) of Optimized Structures of
Acetylacetone Tautomers Calculated in Gas Phase or for Continuum
Solvation (COSMO) With a TZVPP Basis Set (Exception: MP2/D95**).
Level of theory
Enol Keto
E K1 K2
CCSD(T)a 0.0 118 122
BP86 0.0 138 2BLYP 0.0 128 2B3LYP 0.0 127 2BHLYP 0.0 122 125
MP2a 0.0 122 128
RI-MP2 0.0 120 125
SCS-MP2a 0.0 111 121
MP2/D95**b 0.0 14 2BHLYP (e 5 3) 0.0 115 115
BHLYP (e 5 10) 0.0 112 19
BHLYP (e 5 40) 0.0 110 16
BHLYP (e 5 78) 0.0 110 16
aSingle-point calculations on RI-MP2/TZVPP optimized geometries.bThese recalculated energies employing Gaussian-03 are in excellent
agreement with the energies published by Dannenberg et al.11
Table 2. Dipole Moments in Debye of Acetylacetone Tautomers
Calculated in Gas Phase or Solvent (COSMO Calculations).
E K1 K2
MP2 2.98 1.50 3.80
BHLYP 3.15 1.65 3.77
BHLYP (e 5 3) 3.73 1.96 4.98
BHLYP (e 5 40) 4.36 2.29 6.45
667Predicting the Tautomeric Equilibrium of Acetylacetone in Solution
Journal of Computational Chemistry DOI 10.1002/jcc
energy. Because the varying bonding situation the zero-point
energy of the enol form is somewhat greater than that of the
keto form. Hence, the difference between both forms decreases
if one goes from DE to DH. The nonelectrostatic part of the sol-
vation free energy DEn.e. is composed of cavitation energy, dis-
persion energy, and repulsion energy terms. The keto forms
show a slightly larger cavity that is created within the polariz-
able continuum (�127 A3 vs. 125 A3). The larger volume of the
keto forms results in an increased contribution to the cavitation
and dispersion energy, whereas the repulsion energy remains
nearly unchanged. In total, the nonelectrostatic contributions to
the solvation free energy favor the enol form.
The Gibbs free energies show an energy difference of 111
kJ mol21 between the keto form K2 and the enol form at 273 K
in a dielectric continuum with e 5 3. The NMR experiment
measured a keto:enol ratio of about 1:4 for temperatures higher
than 173 K resulting in a free energy difference of about 13 kJ
mol21. At 123 K and with e 5 40 the keto form K2 is still pre-
dicted to be less stable than E, but the value decreases to 6 kJ
mol21. The experiment, however, clearly shows a trend reversal
at 123 K making the K2 tautomer more stable than the enol
form E (22 kJ mol21). The presented approach, thus, underesti-
mates the keto form in both cases by 8 kJ mol21.
The gas phase values in Table 1 indicate that the BHLYP
relative electronic energies of E are in general overestimated by
3–4 kJ mol21. Taking this into account, we estimated the K2
tautomer to be 7 kJ mol21 (273 K, e 5 3) and 2 kJ mol21 (123
K, e 5 40) less stable than E. This means that the stability of
the enol form in solvent is overestimated by 4 kJ mol21 for
both temperatures resp. dielectrics. In contrast for the relative
stability of the keto tautomer with respect to the enol form
(about 5 kJ mol21) experiment and theory agree very well.
Ishida et al.13 reproduced the experimentally found shift from
the enol form to the keto form. However, on the basis of our
gas phase findings, we suspected that the agreement results by
chance from the deficiency of the small double f basis set
{(9s5p1d/4s1p)/[3s2p1d/2s1p]} used in this study. To investigate
this assumption, the correlation energies for both gas phase and
solvation of the keto form K2 and the enol form E have been
determined by MP2 single-point calculations on HF/TZVPP
optimized structures using different basis sets of double f and
triple f size with varying amount of polarization. The valence
double f basis D95v(d,p) basis set is very similar to that used by
Ishida et al.
Table 4 reveals that the energies of the MP2/TZVPP single-
point calculations are already in very good agreement to the val-
ues obtained by full structure optimizations on MP2 and BHLYP
level of theory (Table 1). This clearly shows that the structural
parameters are alike for all methods. However, the relative HF
energy DE(K2-E) is very sensitive with respect to the quality of
the basis set. Table 4 indicates that the inclusion of polarization
on hydrogen atoms seems to be very crucial as the enol form is
stabilized stronger in gas phase by increasing p-function admix-
ture from SV(P) (216 kJ mol21) to TZVPP (14 kJ mol21). The
SVP basis set seems to overestimate the HF energy of the enol
form, which also holds for all solvated structures. Moreover, for
gas phase conditions, the inclusion of correlation effects strongly
favors the enol form. This effect is more than twice as strong
for a triple f basis as for a double f basis. For TZVPP this
amounts to 19 kJ mol21, whereas both SVP and D95v(d,p) give
a correlation energy of only 9 kJ mol21.
In solution, the same trends as in gas phase can be observed,
however, the relative energies are all shifted toward a stabiliza-
tion of the keto form K2. As is clearly seen, the trend reversal
that has been observed experimentally can only be obtained for
the D95v(d,p) basis set. Only for this basis the keto form
Table 3. Relative Thermodynamic Corrections (in kJ mol21) of
Optimized Structures of Acetylacetone Tautomers Calculated in Gas
Phase (Analytically) or in Solvent (Numerically) on a BHLYP/TZVP
(Gas Phase) and a RI-BHLYP/TZVPP (Solvent) Level of Theory. The
Nonelectrostatic Terms (DEn.e.) Have Been Determined by BHLYP/
TZVP Calculations.
DEne DEeleca ZPVE T [K] DHcorr b 2TDScorr b DG
e 5 0 D(K1-E) – 118 13 273 22 24 112
123 22 21 114
D(K2-E) – 122 14 273 22 25 115
123 23 22 117
e 5 3 D(K1-E) 14 115 14 273 22 25 113
123 23 22 115
D(K2-E) 13 115 15 273 23 25 111
123 24 21 114
e 5 40 D(K1-E) 14 110 13 273 22 24 19
123 23 21 111
D(K2-E) 14 16 14 273 23 24 14
123 23 21 16
aGas phase: CCSD(T) value on BHLYP optimized structure.bMinus-sign indicates that the difference becomes smaller, i.e., the keto
form is more stabilizied than the enol form.
Table 4. Relative Energies DE(K2-E) (in kJ mol21) of Hartree-Fock (HF) Optimized Structures of
Acetylacetone Tautomers Calculated in Gas Phase and Continuum Solvation (COSMO) as a Function of the
Basis Set Size.
HF MP2
SV(P) D95v(d,p) SVP TZVPP1 SV(P) D95v(d,p) SVP TZVPPa
Gas phase 216 11 17 14 27 110 114 123
e 5 40 233 219 212 216 219 25 11 18
e 5 78 233 219 212 217 219 25 11 17
aRI approximation (frozen-core).
668 Schlund et al. • Vol. 31, No. 4 • Journal of Computational Chemistry
Journal of Computational Chemistry DOI 10.1002/jcc
becomes more stable in a polar continuum than the enol form,
which indeed is in agreement with the experimental findings, but
for the wrong reasons. The SVP basis that is often used as a
compromise between costs and accuracy gives a better descrip-
tion. Nevertheless, it still overestimates the stability of the keto
form by 6–9 kJ mol21. The SV(P) basis (standard basis in the
Turbomole package) is describing the enol form already in gas
phase as being less stable than the keto form due to the lack of
polarization functions on the hydrogen atoms.
Molecular Solvent Effects on Acetylacetone
Tautomerism
The conductor-like screening model (COSMO) used in the pres-
ent approach can only give information about the polarization
effect of the continuum on the electronic structure of the solute,
but the molecular nature of the solvent is not explicitly taken
into account. Because both acetylacetone tautomers E and K2
possess two hydrogen bonding acceptor sites, it is very likely
that directed hydrogen bonds to a protic surrounding are formed
(we cannot exclude that different continuum approaches may
lead to different trends. One possibility would be approaches
with terms which take directed interaction more accurately into
account. Other effects may also result from differences in the
treatment of nonelectrostatic effects as mentioned in ref. 22).
The remaining differences between experiment and theory indi-
cate that differences in the strength of these hydrogen bonds
lead to the trend reversal that is found experimentally. This may
happen since the intramolecular hydrogen bond has to compete
with the intermolecular interactions between solvent and solute.
To estimate the influence of such hydrogen bonds on the relative
energies, we computed clusters in which the tautomers of acetyl-
acetone are explicitly solvated with up to six water molecules.
The rest of the solvation shell is approximated by a regular con-
tinuum model (COSMO) of either low (e 5 3) or high (e 5 40)
polarity. The conformational distribution of the water molecules
has been investigated on force field level and the most promis-
ing structures were fully optimized on a DFT level (BHLYP/
TZVPP/COSMO). Exemplary structures for tautomers sur-
rounded by six extra water molecules are shown in Figure 3.
Such cluster approaches can only provide trends because a com-
putations of free energies need to take all low lying minima into
account. In addition, more explicit water molecules would be
needed. Hence, we only concentrated on the shifts in the relative
energies.
Figure 4 shows the computed relative energies DE (K2-E) as
a function of the number of water molecules. The relative ener-
gies of the keto form show a significant decrease from initially
16 kJ mol21 (no water molecule) to 11 kJ mol21 (six water
molecules) surrounded by a continuum environment (e 5 40),
but even more water molecules are necessary for shift in the tau-
tomeric equilibrium which is found experimentally. An extrapo-
lation of Figure 4 indicates that at least eight surrounding water
molecules are necessary, but we would like to point out that
entropic effects which are not included may also be important.
A similar behavior is expected for other hydrogen donating sol-
vents like CHClF2/CHF3 (Freon).
Conclusion
Using state-of-the-art ab initio methods, this work investigates
how the keto-enol equilibrium of acetylacetone is influenced by
a varying polarity of the solvent. Unlike previous calculations,
the experimentally observed trend reversal for acetylacetone is
not found by using a continuum solvation model (COSMO). In
our opinion, this is due to two important reasons:
A basis set of double f size as used in various studies before
leads to an underestimation of the hydrogen bond strength of the
enol form, which erroneously results in the expected change in
the keto:enol molar ratio on solvation in a polar solvent (which
in turn further stabilizes the keto form due to its large dipole
moment).
Interactions arising from the molecular nature of the solvent,
which are not included in most continuum models such as
COSMO, are responsible for an overestimation of the hydrogen
bond in solvent. We could show that the inclusion of several
explicit solvent molecules (‘‘supermolecular ansatz’’) leads to a
lowering of the energy gap between keto and enol forms. By
extrapolation of the calculated energies, we expect a trend rever-
Figure 3. Examples for optimized structures of acetylacetone tauto-
mers E and K2 in continuum solvation (e 5 40) with additional
explicit six water molecules (BHLYP/TZVPP/COSMO).
Figure 4. Relative energies DE (K2-E) in kilojoules per mole of
optimized structures of acetylacetone in continuum solvation with
additional explicit water molecules calculated on a BHLYP/TZVPP/
COSMO level of theory.
669Predicting the Tautomeric Equilibrium of Acetylacetone in Solution
Journal of Computational Chemistry DOI 10.1002/jcc
sal for a solvation shell that comprises at least eight protic sol-
vent molecules.
In summary, the trend reversal in the equilibrium of keto-
enol tautomers of acetylacetone is footed on shifts in relative
stabilities of the keto and enol forms. Standard quantum chemi-
cal approaches in combination with continuum solvation models
are not able to predict this reversal. However, if the dielectric
constant is increased from e 5 3 to e 5 40, the relative shift in
the energy difference between the keto and enol tautomer is
reproduced very well (5 kJ mol21). This indicates that trends are
already covered by bulk effects, but absolute values of the keto-
enol energy difference are systematically overestimated by about
4 kJ mol21. This indicates that the change in tautomeric popula-
tion for different solvation conditions result from molecular sol-
vent effects that further destabilize the enol form. In order to
describe the shift correctly, it is necessary to calculate the vari-
ous tautomers within an explicit solvent shell by means of quan-
tum chemical methods that are known for treating hydrogen
bonding interactions and correlation effects correctly.
References
1. Reichardt, C. Solvents and Solvent Effects in Organic Chemistry,
3rd ed.; Wiley-VCH: Weinheim, 2003.
2. (a) Cook, G.; Feltman, P. M. J Chem Educ 2007, 84, 1827; (b)
Mills, S. G.; Beak, P. J Org Chem 1985, 50, 1216; (c) Emsley, J.;
Freeman, N. J. J Mol Struct 1987, 161, 193.
3. (a) Tomasi, J.; Persico, M.; Chem Rev 1994, 94, 2027; (b) Tomasi,
J.; Mennucci, B.; Cammi, R. Chem Rev 2005, 105, 2999.
4. (a) Miertus, S.; Scrocco, E.; Tomasi, J. Chem Phys 1981, 55, 117; (b)
Klamt, A.; Schuurmann, G. J Chem Soc Perkin Trans 2, 1993, 5, 799.
5. (a) Warshel, A.; Levitt, M. J Mol Biol 1976, 103, 227; (b) Cramer, C.
J. Essentials of Computational Chemistry; Wiley: Chichester, 2002.
6. Bakowies, D.; Thiel, W. J Phys Chem 1996, 100, 10580.
7. (a) Spencer, J. N.; Holmboe, E. S.; Kirshenbaum, M. R.; Firth, D.
W.; Pinto, P. B. Can J Chem 1982, 60, 1178; (b) Hibbert, F.; Ems-
ley, J. Hydrogen Bonding and Chemical Reactivity, Vol. 26; Aca-
demic Press: Amsterdam, 1990; p 256; (c) S. L. Wallen, C. R.
Yonker, C. L. Phelps, C. M. Wai, J. Chem. Soc., Faraday Trans.
1997, 93, 2391; (d) Moriyasu, M. Kato, A. Hashimoto, Y. J Chem
Soc, Faraday Trans 2 1986, 82, 515.
8. (a) Siegel, J. S.; Anet, F. A. L. J Org Chem 1988, 53, 2629; (b) Golu-
bev, N. S.; Denisov, G. S. J Mol Struct 1992, 270, 263; (c) Weisz, K.;
Jahnchen, J. Limbach, H.-H. J Am Chem Soc 1997, 119, 6436; (d)
Dunger, A.; Limbach, H.-H.; Weisz, K. Chem Eur J 1998, 4, 621; (e)
Smirnov, S. N.; Benedict, H.; Golubev, N. S.; Denisov, G. S.; Kreevoy,
M. M.; Schowen, R. L.; Limbach, H.-H. Can J Chem 1999, 77, 943.
9. (a) Golubev, N. S.; Denisov, G. S.; Smirnov, S. N.; Shchepkin, D.
N.; Limbach, H.-H. Z Phys Chem 1996, 196, 73; (b) Shenderovich,
I. G.; Burtsev, A. P.; Denisov, G. S.; Golubev, N. S.; Limbach, H.-
H. Magn Reson Chem 2001, 39, S91–S99.
10. (a) Buemi, G.; Gandolfo, C. J Chem Soc Faraday Trans 2 1989, 85,
215; (b) Rios, M.; Rodriguez, J. J Mol Struct (Theochem) 1990, 204,
137; (c) Karelson, M. Maran, U. Tetrahedron 1996, 34, 11325; (d)
Bauer, S. H.; Wilcox, C. F. Chem Phys Lett 1997, 279, 122; (e) Buemi,
G.; Zuccarello, F.; Electron J Theor Chem 1997, 2, 302; (f) Sliznev, V.
V.; Lapshina, S. B.; Girichev, G. V. J Struct Chem 2006, 47, 220.
11. Dannenberg, J. J.; Rios, R. J Phys Chem 1994, 98, 6714.
12. Cramer, C. J.; Truhlar, D. G. Solvent Effects and Chemical Reactiv-
ity; Tapia, O.; Bertran, J., Eds.; Kluwer: Dordrecht, 1996.
13. Ishida, T.; Hirata, F.; Kato, S. J Chem Phys 1999, 110, 3938.
14. (a) Ten-no, S.; Hirata, F.; Kato, S. Chem Phys Lett 1993, 214, 391;
(b) Ten-no, S.; Hirata, F.; Kato, S. J Chem Phys 1994, 100, 7443;
(c) Sato, H.; Hirata, F.; Kato, S. J Chem Phys 1996, 105, 1546; (d)
Yokogawa, D.; Sato, H.; Sakaki, S. J Chem Phys 2007, 126,
244504; (e) Yamazaki, T.; Sato, H.; Hirata, F. J Chem Phys 2001,
115, 8949; (f) Sato, H.; Hirata, F. J Chem Phys 1999, 115, 8545; (g)
Sato, H.; Hirata, F. J Chem Phys 2001, 115, 8949; (g) Yamazaki,
T.; Sato, H.; Hirata, F. Chem Phys Lett 2000, 325, 668.
15. Yokagawa, D.; Sato, H.; Imai, T.; Sakaki, S. J Chem Phys 2009,
130, 064111.
16. (a) Schlund, S.; Mladenovic, M.; Basılio Janke, E. M.; Engels, B.;
Weisz, K. J Am Chem Soc 2005, 127, 16151; (b) Hupp, T.; Sturm,
Ch.; Basılio Janke, E. M.; Perez Cabre, M.; Weisz, K.; Engels, B. J
Phys Chem A, 2005, 109, 1703; (c) Baslio Janke, E. I.; Schlund, S.;
Paasche, A.; Engels, B.; Dede, R.; Hussain, I.; Langer, P.; Rettig,
M.; Weisz, K. J Org Chem DOI: 10.1021/jo9004475; (d) Schlund,
S.; Schmuck, C.; Engels, B. J Am Chem Soc, 2005, 127, 11115; (e)
Schlund, S.; Muller, C.; Graßmann, C.; Engels, B. J Comput Chem
2008, 29, 407; (f) Schlund, S.; Schmuck. C.; Engels, B. Chemistry
2007, 13, 6644.
17. (a) Musch, P. W.; Engels, B. J Am Chem Soc 2005, 123, 5557; (b) Hel-
ten, H.; Schirmeister, T.; Engels, B. J Org Chem 2005, 70, 233; (c) Hel-
ten, H.; Schirmeister, T.; Engels, B. J Phys ChemA 2004, 108, 9442.
18. (a) Engels, B.; Peyerimhoff, S. D. J Phys Chem 1989, 93, 4462; (b)
Engels, B. J Chem Phys 1994, 100, 1380; (c) Bundgen, P.; Engels,
B.; Peyerimhoff, S. D. Chem Phys Lett 1991, 176, 407.
19. (a) Ahlrichs, R.; Bar, M.; Haser, M.; Horn, H. Kolmel, C. Chem Phys
Lett 1998, 162, 165; (b) Haser, M.; Ahlrichs, R. J Comput Chem 1989,
10, 104; (c) Haase, F.; Ahlrichs, R. J Comput Chem 1993, 14, 907; (d)
Treutler, O.; Ahlrichs, R. J Chem Phys 1995, 102, 346; (e) Deglmann,
P.; May, K.; Furche, F.; Ahlrichs, R. Chem Phys Lett 2004, 384, 103;
(f) Weigend, F.; Haser, M. Theor Chem Acc 1997, 97, 331; (g) Degl-
mann, P.; Furche, F.; Ahlrichs. R. Chem Phys Lett 2002, 362, 511; (h)
Deglmann, P.; Furche, F. J Chem Phys 2002, 117, 9535; (i) Schafer,
A.; Huber, C; Ahlrichs, R. J Chem Phys 1994, 100, 5829; (j) Vahtras,
O.; Almlof, J.; Feyereisen, M. W. Chem PhysLett 1993, 213, 514; (k)
Eichkorn, K.; Treutler, O.; Ohm, H.; Haser, M.; Ahlrichs, R. Chem
Phys Lett 1995, 242, 652; (l) Schafer, A.; Klamt, A.; Sattel, D.; Loh-
renz, J. C. W.; Eckert, F. Phys Chem Chem Phys 2000, 2, 2187.
20. Werner, H.-J.; Knowles, P. J.; Lindh, R.; Manby, F. R.; Schutz, M.;
Celani, P.; Korona, T.; Rauhut, G.; Amos, R. D.; Bernhardsson, A.;
Berning, A.; Cooper, D. L.; Deegan, M. J. O.; Dobbyn, A. J.; Eckert,
F.; Hampel C.; Hetzer, G.; Lloyd, A. W.; McNicholas, S. J.; Meyer,
W.; Mura, M. E.; Nicklass, A.; Palmieri, P.; Pitzer, R.; Schumann, U.;
Stoll, H.; Stone, A. J.; Tarroni, R.; Thorsteinsson, T.MOLPRO, Ver-
sion 2006.1, a Package of ab Initio Programs.
21. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M.
A.; Cheeseman, J. R.; Montgomery, J. A., Jr; Vreven, T.; Kudin, K. N.;
Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Men-
nucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji,
H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida,
M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.;
Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.; Jara-
millo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.;
Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.;
Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich,
S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A.
D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A.
G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.;
Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham,
M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.;
Johnson, B.; Chen, W.; Wong, M.W.; Gonzalez, C.; Pople, J. A. Gaussian
03, Revision C. 02; Gaussian, Inc.: Wallingford, CT, 2004.
22. Cramer, C. J.;, Truhlar, D. G. Acc Chem Res 2008, 41, 760.
670 Schlund et al. • Vol. 31, No. 4 • Journal of Computational Chemistry
Journal of Computational Chemistry DOI 10.1002/jcc