Tautomeric equilibria of 3-formylacetylacetone: Low-temperature NMR spectroscopy and ab initio calculations

Article abstract of DOI:10.1021/jo9004475

(Chemical Equation Presented) Keto-enol tautomerization of 3-formylacetylacetone has been studied by NMR spectroscopy, ab initio, and DFT calculations in the gas phase and continuum solvation. By employing very low temperatures in a freonic solvent, tauto

Full text of DOI:10.1021/jo9004475

Tautomeric Equilibria of 3-Formylacetylacetone:
Low-Temperature NMR Spectroscopy and ab
Initio Calculations
Eline M. Bas´ılio Janke,† Sebastian Schlund,‡
Alexander Paasche,‡ Bernd Engels,*,‡ Ru¨diger Dede,|
Ibrar Hussain,§ Peter Langer,*,§ Michael Rettig,| and
Klaus Weisz*,|
Institut fu¨r Chemie, Freie UniVersita¨t Berlin, Takustrasse 3,
D-14195 Berlin, Germany, Institut fu¨r Organische Chemie,
UniVersita¨t Wu¨rzburg, Am Hubland, 97074 Wu¨rzburg, Germany,
Institut fu¨r Chemie, UniVersita¨t Rostock,
Albert-Einstein-Strasse 3a, D-18059 Rostock, Germany, and
Institut fu¨r Biochemie, Ernst-Moritz-Arndt-UniVersita¨t
Greifswald, Felix-Hausdorff-Strasse 4,
D-17489 Greifswald, Germany
weisz@uni-greifswald.de; peter.langer@uni-rostock.de;
bernd@chemie.uni-wuerzburg.de
FIGURE 1. Tautomeric structures of 3-formylacetylacetone with the
backbone numbering scheme indicated for A.
ReceiVed March 2, 2009
synthetic building block, e.g., as a 1,3-dielectrophile in [3+3]
cyclizations.2 It can be regarded as an unsymmetrical analogue
of triacetylmethane and may exist in a tricarbonyl and several
monoenol tautomeric forms as indicated in Figure 1.
Keto-enol equilibria of a large number of carbonyl com-
pounds have been extensively investigated in the past both
experimentally and theoretically. In many cases, a strong
dependence of the tautomerism on the solvent polarity as
exemplified by acetylacetone has been found.3 Surprisingly,
given its role as a parent tricarbonylmethane compound there
are only a few experimental and theoretical studies dealing with
structural aspects of 3-formylacetylacetone.4 In particular, a
rigorous evaluation of formed tautomers and the dependence
of its keto-enol equilibria on the solvent polarity, prerequisite
for a better understanding of its chemical reactivity in various
environments but also of potential significance when evaluating
biological interactions including formation of intra- and inter-
molecular hydrogen bonds, has not been examined so far.
Because keto and enol tautomeric forms of carbonyl com-
pounds have been shown to slowly exchange on the NMR time
scale, NMR spectroscopic techniques have frequently been
employed in their characterization at ambient temperatures.
Keto-enol tautomerization of 3-formylacetylacetone has
been studied by NMR spectroscopy, ab initio, and DFT
calculations in the gas phase and continuum solvation. By
employing very low temperatures in a freonic solvent,
tautomeric and conformational equilibria in the slow ex-
change regime were analyzed in detail. The ꢀ-tricarbonyl
compound always adopts a structure with an enolized keto
group irrespective of an increasing dielectric constant of the
solvent when lowering the temperature of the Freon mixture.
This experimentally observed tautomeric distribution of
3-formylacetylacetone is correctly reproduced by continuum
solvated DFT calculations.
Because of their importance as active methylene synthons in
organic synthesis as well as their occurrence as structural
elements in natural products, the structure of ꢀ-tricarbonyl
derivatives associated with their keto-enol tautomeric equilibria
is of major interest not only to physical chemists but also to
organic and biochemists. As an example, tricarbonylmethane
structural units are found in various antibiotics like tetracyclines
playing an important role in their antibacterial activity and their
binding of metal ions.1 On the other hand, the simple ꢀ-tricar-
bonyl compound 3-formylacetylacetone represents a useful
(1) (a) Matsuo, K.; Kimura, M.; Kinuta, T.; Tarkai, N.; Tanaka, K. Chem.
Pharm. Bull. 1984, 32, 4197–4204. (b) Dos Santos, H. F.; Marcial, B. L.; De
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† Freie Universita¨t Berlin.
‡ Universita¨t Wu¨rzburg.
| Ernst-Moritz-Arndt-Universita¨t Greifswald.
§ Universita¨t Rostock.
4878 J. Org. Chem. 2009, 74, 4878–4881
10.1021/jo9004475 CCC: $40.75  2009 American Chemical Society
Published on Web 06/01/2009

FIGURE 3. BP86/TZVPP optimized tautomeric structures of 3-formy-
lacetylacetone in the gas phase.
Interestingly, 1H and 13C resonances of the pairs of equivalent
CH3 and CO groups in tautomer B split into two signals of equal
intensity below 153 and 173 K, respectively (Figure 2). With a
fast exchange between tautomers B1 and B2, this observation
is only compatible with a frozen rotation about the C3-C6 bond
breaking the molecular symmetry of B. An estimate based on
coalescence temperatures and chemical shift differences yields
a free energy of activation for this bond rotation of about 32 kJ
mol-1, slightly higher compared to the energy barrier of about
20 kJ mol-1 around the C2-C3 bond rotation in butadiene and
in line with a partial C3-C6 double bond character. On the
FIGURE 2. Temperature-dependent 1H NMR (a) and 13C NMR spectra
(b) of 3-formylacetylacetone with signal assignments given for 293 K;
the insets show expanded spectral regions (a) and spectral regions at
133 K (b) with signals marked by asterisks split at low temperatures.
Employing liquified freonic gases (CDF3/CDF2Cl) as solvent
allows NMR measurements to be performed at very low
temperatures below 133 K.5 At such temperatures, many
dynamical processes like hydrogen bond exchange are suf-
ficiently slowed down to enable a more detailed characterization
of molecular and complex geometries. In addition, the dielectric
constant of the freonic mixture exhibits a strong dependence
on temperature and effectively mimics very different solvent
polarities over the temperature range accessible.6 Thus, for a
1:1 mixture of CHF3 and CHF2Cl, the dielectric constant rises
from 14 at 190 K to 34 at 120 K.
3
basis of an observed scalar coupling of J(H6,OH) ) 7.5 Hz,
the C1 tautomer with enolization of the formyl group and being
in fast exchange with C2 even at low temperatures is expected
to be highly populated.
To gain more insight into the relative stabilities of the
individual tautomers, we have performed additional ab initio
and DFT calculations on the keto-enol equilibrium of 3-formy-
lacetylacetone in the gas phase and continuum solvation. As in
related studies,7 we initially applied DFT approaches which are
known for their favorable cost-benefit ratio.8 However, because
in some cases reliable predictions deserve higher level ap-
proaches,9 we also applied perturbational approaches and
coupled cluster methods. The optimized minimum structures
of the keto and enol tautomers are shown in Figure 3 with their
calculated relative electronic energies in the gas phase and
solvent summarized in Table 1. Irrespective of the level of theory
and solvent effects, tautomers B are found to always represent
the energetically most favored structures being >30 kJ mol-1
lower in energy compared to the least favorable keto tautomer
A. As previously described for acetylacetone7c the computed
energy difference between the keto tautomer A and the enol
tautomers B and C strongly depends on the approximation. For
the present problem, however, the keto tautomer A is so high
in energy that it is nonobservable under the experimental
conditions. The energy gaps between the tautomeric forms B
and C are considerably smaller. Note, however, that energy
Temperature-dependent 1H and 13C NMR spectra of 3-formy-
lacetylacetone are shown in Figure 2. Signals at 293 K are
assigned based on intensities and chemical shifts as well as on
additional 1H-13C correlation experiments. They clearly show
a coexistence of tautomeric forms B and C with relative pop-
ulations of about 4:1 and the absence of noticeable amounts of
the tricarbonyl tautomer A. A stronger hydrogen bond in B
compared to C is indicated by its highly deshielded OH proton.
Note that with decreasing temperature further deshielding of
this proton is observed and a chemical shift of 19.3 ppm at 123
K indicates its participation in a very strong intramolecular
hydrogen bond.
Upon lowering the temperature, the B:C molar ratio is found
to increase from 4:1 at ambient temperatures to about 6:1 at
123 K. In contrast to the well-known and significant dependence
on the solvent dielectric constant of the keto-enol equilibrium
in acetylacetone,3 this moderate temperature-dependent shift in
the tautomer equilibrium does not support a major contribution
from polar effects of the solvent on the tautomer populations.
(7) (a) Schlund, S.; Mladenovic, M.; Bas´ılio Janke, E. M.; Engels, B.; Weisz,
K. J. Am Chem. Soc. 2005, 127, 16151–16158. (b) Hupp, T.; Sturm, Ch.; Bas´ılio
Janke, E. M.; Pe´rez Cabre, M.; Weisz, K.; Engels, B. J. Phys. Chem. A 2005,
109, 1703–1712. (c) Schlund, S.; Bas´ılio Janke, E. M.; Weisz, K. Engels, B.
J. Comput. Chem., in press.
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(b) Helten, H.; Schirmeister, T.; Engels, B. J. Org. Chem. 2005, 70, 233–237.
(c) Helten, H.; Schirmeister, T.; Engels, B. J. Phys. Chem. A 2004, 108, 9442–
9452.
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Golubev, N. S.; Denisov, G. S. J. Mol. Struct. 1992, 270, 263–276. (c) Weisz,
K.; Ja¨hnchen, J.; Limbach, H.-H. J. Am. Chem. Soc. 1997, 119, 6436–6437. (d)
Dunger, A.; Limbach, H.-H.; Weisz, K. Chem.sEur. J. 1998, 4, 621–628. (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, 943–949.
(6) (a) Golubev, N. S.; Denisov, G. S.; Smirnov, S. N.; Shchepkin, D. N.;
Limbach, H.-H. Z. Phys. Chem. 1996, 196, 73–84. (b) Shenderovich, I. G.;
Burtsev, A. P.; Denisov, G. S.; Golubev, N. S.; Limbach, H.-H. Magn. Reson.
Chem. 2001, 39, S91-S99.
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B.; Peyerimhoff, S. D. Chem. Phys. Lett. 1991, 176, 407–412.
J. Org. Chem. Vol. 74, No. 13, 2009 4879

TABLE 1. Relative Energies (in kJ mol-1) of Optimized
Structures of 3-Formylacetylacetone Tautomers Calculated in the
Gas Phase or Solvent (COSMO calculations)b
level of theory
(TZVPP basis)
A
B1
B2
C1
C2
BP86
B3LYP
BHLYP
RI-MP2
SCS-MP2a
CCSD(T)a
+63.4
+49.2
+44.8
+42.7
+30.0
+39.4
-1.1
+1.0
+1.2
+0.1
-0.4
+0.1
0.0
0.0
0.0
0.0
0.0
0.0
+5.5
+5.3
+4.3
+4.1
+2.5
+3.0
+5.1
+4.1
+3.9
+4.3
+4.1
+4.0
FIGURE 4. 3-(Aminomethylene)pentane-2,4-dione (left) and 3-(trim-
ethylsilyloxymethylene)pentane-2,4-dione (right).
aldehyde group gives the 3-aza analogue in 74% yield. Likewise,
the reaction of 3-formylacetylacetone with chlorotrimethylsilane
proceeded with similar regioselectivity to give 3-(trimethylsi-
lyloxymethylene)pentane-2,4-dione (Figure 4).2c Regioselec-
tivity may be attributed to the enol OH in tautomers B involved
in a very strong intramolecular hydrogen bond (vide supra).
Inspection of the crystal structure of the amination product
revealed an enaminodiketone tautomeric structure with an
intramolecular N-H· · ·O hydrogen bond as shown in Figure
4.11 The 3-(aminomethylene)pentane-2,4-dione enamine tau-
tomer is also found to form exclusively even under varying
solvent conditions12 and our calculations clearly confirm its
significantly lower energy compared to that of iminoenol and
iminodiketone tautomers (see the Supporting Information).
In summary, our experimental results indicate a preference
of 3-formylacetylacetone to adopt tautomeric structures B and
this preference applies for solvents of both low and high
dielectric constants. Calculated relative energies also predict the
absence of noticeable amounts of the keto tautomer A due to
its unfavorable electronic energy. The very good agreement
between calculations and the experiment may be attributed to
the steric and electronic similarity of the experimentally
observed enolic structures (planarity). It thus can be expected
that the thermodynamic corrections and consequently the errors
in the calculated relative energies stemming from inherent
deficiencies of the continuum models are similar for all enol
forms.
BP86 (ε ) 3)
+58.3
+54.3
+40.4
+37.1
-0.5
-0.1
+0.8
+0.5
0.0
0.0
0.0
0.0
+6.9
+7.7
+4.0
+4.2
+6.2
+6.6
+4.0
+4.7
BP86 (ε ) 40)
BHLYP (ε ) 3)
BHLYP (ε ) 40)
a Single-point calculations with the RI-MP2/TZVPP optimized geom-
etries and zero-point energies. b Values include zero-point energies.
TABLE 2. Dipole Moments (in Debye) of 3-Formylacetylacetone
Tautomers Calculated in the Gas Phase or Solvent (COSMO
Calculations)
A
B1
B2
C1
C2
MP2
BHLYP
BHLYP (ε ) 3)
BHLYP (ε ) 40)
1.33
1.35
1.60
1.96
2.18
2.65
3.25
3.84
1.17
1.07
1.28
1.47
1.80
2.19
2.73
3.28
0.93
0.87
1.02
1.18
differences between B1 and B2 are of the same magnitude as
the available accuracy of the applied methods. Likewise, energy
differences between tautomers C1 and C2 are marginal based
on the accuracy of the calculations.
The NMR experimental analysis at 293 K in Freon gave a
population distribution for B:C of 4:1, which corresponds to a
free energy difference of 3.3 kJ mol-1. By lowering the
temperature to 123 K the ratio slightly increased to 6:1, which
in turn corresponds to a smaller energy difference of 1.8 kJ
mol-1. Note again that B1 and B2 as well as C1 and C2 are
fast exchanging on the NMR time scale and cannot be
distinguished experimentally. Nevertheless, calculations with
BHLYP predict energy differences between B and C tautomers
in solution of about 4 kJ mol-1 in favor of B in very good
agreement with the experiment given the accuracy of the
method.
Overall, solvent polarity does not significantly influence the
relative stabilities of the various tautomers in line with the small
temperature dependence of the experimental data. This can also
be rationalized by the calculated dipole moments (see Table 2)
which exhibit only moderate shifts when going from the gas
phase to solution. The largest changes are observed for the B1
and C1 structures. However, given about equal contributions
from B1/B2 and C1/C2 to the averaged structure, dipole
moments and changes in dipole moments with the solvent
dielectric constant are very similar for the B and C enolic forms.
Also shown in Figure 3 is the transition structure B1*
optimized for a C3-C6 bond rotation in B1. RI-MP2 energy
calculations on B1* reveal a rotation barrier in the gas phase
of about 33 kJ mol-1 in very good agreement with the free
energy of activation as estimated from the experimental data
(vide supra).
Experimental Section
3-Formylacetylacetone was prepared according to the literature
by reaction of acetylacetone with triethyl orthoformate and acetic
anhydride.2a
The deuterated freon mixture CDClF2/CDF3 was prepared as
described13 and handled on a vacuum line that was also used for
the sample preparation. NMR experiments were performed at a
proton resonance frequency of 500 MHz. Temperatures were
adjusted by a Eurotherm Variable Temperature Unit to an accuracy
of (1.0 °C. 1H chemical shifts in a freon mixture were referenced
relative to CHClF2 (δH ) 7.13 ppm).
For the keto form of 3-formylacetylacetone force field based
conformational searches have been performed (MMFF94 force field,
mixed MCMM/LM search algorithm, 5000 steps) employing the
Macromodel V8.0 suite by Schrodinger Inc. The generated con-
formers were subsequently optimized on the DFT level (RI-BP86/
SVP) and the lowest conformer has been used for higher level
calculations.
(11) Gro´f, M.; Milata, V.; Koz´ısek, J. Acta Crystallogr. 2006, E62, o4464-
o4465.
(12) (a) Kozerski, L.; Kamienska-Trela, K.; Kanina, L.; von Philipsborn, W.
HelV. Chim. Acta 1983, 66, 2113–2128. (b) Zhuo, J.-C. Magn. Reson. Chem.
1997, 35, 432–440. (c) Kozerski, L.; Kawecki, R.; Krajewski, P.; Kwiecien´, B.;
Boykin, D. W.; Bolvig, S.; Hansen, P. E. Magn. Reson. Chem. 1998, 36, 921–
928. (d) Kozerski, L.; Kwiecien´, B.; Kawecki, R.; Urban´czyk-Lipkowska, Z.;
Bocian, W.; Bednarek, E.; Sitkowski, J.; Maurin, J.; Pazderski, L.; Hansen, P. E.
New J. Chem. 2004, 28, 1562–1567.
Enolizable ꢀ-triketones are known to be effectively aminated
by the use of hexamethyldisilazane.10 By reaction of the latter
with 3-formylacetylacetone, regioselective amination at its
(13) Golubev, N. S.; Smirnov, S. N.; Gindin, V. A.; Denisov, G. S.; Benedict,
H.; Limbach, H.-H. J. Am. Chem. Soc. 1994, 116, 12055–12056.
(10) Chu, D. T. W.; Huckin, S. N. Can. J. Chem. 1980, 58, 138–142.
4880 J. Org. Chem. Vol. 74, No. 13, 2009

All structure optimizations have been performed with the
Turbomole V5.8 program package and were done on RI-BP86,
B3LYP, BHLYP, and RI-MP2 levels of theory employing a TZVPP
basis set. In the present paper the electrostatic contributions of the
solvent were estimated by using the COSMO approach as imple-
mented in TURBOMOLE with dielectric constants of ε ) 3 and
40 in order to simulate solvents of varying polarity. The nonelec-
trostatic terms of the COSMO approach have been determined by
BP86/6-31++G(d,p) single point calculations employing the
Gaussian03 program package on the BP86/TZVPP optimized
geometries in the respective dielectric. The CCSD(T)/TZVPP and
(SCS)-MP2/TZVPP single-point calculations were performed with
MOLPRO on RI-MP2/TZVPP optimized geometries.
The TS has been checked again by calculating the Hessian
analytically (AOFORCE) on a BHLYP/TZVPP level of theory.
Acknowledgement. We thank the Deutsche Forschungsge-
meinschaft (Bonn-Bad Godesberg) for financial support.
Supporting Information Available: Procedures for synthe-
1
ses; experimental and calculated H chemical shifts, absolute
energies, zero-point energies, and number of imaginary frequen-
cies of 3-formylacetylacetone tautomers; 13C and 1H NMR
spectra of 3-(aminomethylene)pentane-2,4-dione; and relative
and absolute energies, zero-point energies and number of
imaginary frequencies of optimized structures of 3-(aminom-
ethylene)pentane-2,4-dione tautomers. This material is available
free of charge via the Internet at http://pubs.acs.org.
The transition state for C3-C6 bond rotation has been calculated
with STATPT starting from a reasonable initial guess and following
the gradient of negative eigenvalue of the formyl group rotation.
JO9004475
J. Org. Chem. Vol. 74, No. 13, 2009 4881