Fast degenerate double proton transfer in the solid state between two indazolinone tautomers

Article abstract of DOI:10.1039/c0ce00249f

The neutral dimer formed by 4,6-difluoro-1H,2H-indazolin-3-one and 3-hydroxy-4,6-difluoro-1H-indazole linked by two hydrogen bonds presents a very fast intermolecular double proton transfer in the solid state (ISSPT). The combined use of crystallography, solid state NMR and DFT [B3LYP/6-311++G(d,p)] calculations supports this interesting observation and allows us to estimate a barrier of about 20 kJ mol^-1.

Full text of DOI:10.1039/c0ce00249f

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Fast degenerate double proton transfer in the solid state between two
indazolinone tautomers†‡
a
a
a
a
Marta Perez-Torralba, Concepcion Lopez, Carlos Perez-Medina, Rosa M. Claramunt, Elena Pinilla,b
*
*
ꢀ
M. Rosario Torres, Ibon Alkorta and Jose Elguero
ꢀ
ꢀ
ꢀ
b
c
c
ꢀ
Received 31st May 2010, Accepted 14th August 2010
DOI: 10.1039/c0ce00249f
methylpyrazolin-5-one (3).5 But this compound, a catemer 3n, lacks
The neutral dimer formed by 4,6-difluoro-1H,2H-indazolin-3-one
and 3-hydroxy-4,6-difluoro-1H-indazole linked by two hydrogen
bonds presents a very fast intermolecular double proton transfer in
the solid state (ISSPT). The combined use of crystallography, solid
state NMR and DFT [B3LYP/6-311++G(d,p)] calculations
supports this interesting observation and allows us to estimate
a barrier of about 20 kJ molꢀ1.
the sine qua non condition of being a cyclamer (Scheme 2).
Some time ago we started a program aimed at obtaining cyclamers
formed by two different functional tautomers. We selected indazoli-
nones because the two most stable tautomers, 4a (3-oxo-1H,2H-
indazole or 1H,2H-indazolin-3-one) and 4b (3-hydroxy-1H-indazole),
have similar energies (Scheme 3)6 and because 1H-indazoles often
crystallize forming cyclic dimers.7
Several indazolinones bearing different substituents on the benzene
ring were studied by us and in two cases their X-ray structures
determined, indazolin-3-one itself (4)8 and 7-nitroindazolin-3-one
(5).9 A search in the CSD did not show other examples (Table 1).7
Here we present our results on a new compound, the
4,6-difluoroindazolinone (6) whose X-ray structure is shown in
Fig. 1. This molecule forms cyclic dimers containing both tauto-
mers 6a (3-one) and 6b (3-hydroxy) held together by hydrogen
There has been a continuous research interest focused on intermo-
lecular solid state proton transfer (ISSPT), one of the simplest
chemical reactions where covalent bonds are broken and created.
One of the limitations of these reactions, where multiple protons are
transferred, besides being cyclical is that the initial and final states
should be identical or, at least, very similar. This has limited the
examples to pyrazole cyclamers, for instance, trimers 13,1 and to
benzoic acid dimers 22 (Scheme 1).2
bonds.
In the dimeric structure of 6, each molecule is almost planar but
The case of pyrazoles corresponds to what is known as ‘‘annular
tautomerism’’, and for 3,5-dimethyl-1H-pyrazole (1) and benzoic acid
(2) they are examples of ‘‘degenerate tautomerism’’ because both
tautomers are identical. N-Unsubstituted pyrazoles with different
substituents at positions 3 and 5 also show ISSPT if the substituents
are slightly different and the number of types of tautomers remains
unchanged after proton transfer in an even cyclic structure (dimers,
tetramers, and hexamers).3 This is about the only molecules that
present ISSPT, other less common examples are amidine, triazene
and guanidine dimers, aza analogues of 22.4 The proton transfer rate
constants in dimers of carboxylic acids and amidines are in the
nanosecond time scale and in pyrazole cyclamers in the millisecond to
second time scale.
they are situated in different planes. The dimer has a symmetry binary
axis going through the tautomeric OHO bond, with the H2B in
special position at the middle of both N2 atoms and the main
geometrical characteristics are summarized in Scheme 4. The most
obvious explanation for the structure is a mixture of two identical
situations: 6a/6b and 6b/6a, but the X-ray analysis does not allow us
to determine if the disorder is static or dynamic.x
When the 15N CPMAS NMR spectrum of the crystals of the 6a/6b
dimer obtained from methanol was recorded at 300 K and 40.60
MHz, two signals were obtained at ꢀ169.0 and ꢀ240.9 ppm. When
these chemical shift values were compared with the NMR data of two
similar derivatives (Scheme 5),10 4,6-difluoro-7-nitroindazolinone (7)
With functional tautomerism (oxo/hydroxy or imino/amino) no
examples were known because in general both tautomers differ
considerably in stability. Besides, both tautomers must co-crystallize
and this is an even rarer phenomenon, to the point that, to the best of
our knowledge only one example has been reported, 1-phenyl-3-
aDepartamento de Quımica Organica
Ciencias, UNED, Senda del Rey 9, E-28040 Madrid, Spain. E-mail:
ꢀ
ꢀ
ꢀ
y Bio-Organica, Facultad de
Scheme 1 Two classical examples of ISSPT showing the cyclamers held
by hydrogen bonds (HBs).
mtaperez@ccia.uned.es; Fax: +34 913988372; Tel: +34 913988961
b
ꢀ
Departamento de Quımica Inorganica I, CAI de Difraccion de Rayos-X,
Facultad de Ciencias Quꢀımicas, Universidad Complutense de Madrid
ꢀ
ꢀ
(UCM), 28040 Madrid, Spain
c
ꢀ
Instituto de Quımica Medica (CSIC), Juan de la Cierva 3, 28006 Madrid,
ꢀ
Spain
† Electronic supplementary information (ESI) available: X-Ray
crystallographic data, NMR results and computational details. CCDC
reference number 778538. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c0ce00249f
ꢀ
th
‡ Dedicated to Professor Carmen Najera on her 60 anniversary.
Scheme 2 The 1-phenyl-3-methylpyrazolin-5-one (3) catemer.
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Scheme 3 The functional tautomerism of indazolinones.
In order to perform 15N NMR low temperature studies we
prepared the 89% double labeled derivative 6-15N2.{ In solution, this
compound shows two 15N signals at ꢀ224.1/ꢀ121.8 (DMSO-d6, 300
K), ꢀ229.5/ꢀ118.3 (THF-d6, 300 K) and ꢀ227.6/ꢀ119.3 (THF-d6,
193 K), which clearly correspond to the 3-hydroxy tautomer 6b. In
solid state, at 173 K (40.60 and 60.81 MHz) we were not able to slow
down the ISSPT, the chemical shifts resulted in ꢀ169.4 and ꢀ241.8
ppm, proving that the double proton transfer is very fast since not
even line broadening was observed at such temperature. Similar
conclusions concerning the solution and the solid state are reached
using 1H NMR and 13C NMR (see ESI†).
Table 1 Crystal structure of indazolinones
Compd. Tautomer Secondary structure (via HBs)
Ref code7
4
5
4a
5b
Cyclic dimer (two N2–H/O ¼ C3) FADMIG
Cyclic dimer (two N1–H/N2)
—
To estimate the double tautomerization barrier, DG‡, we need to
know the chemical shifts in the absence of prototropy. For such
purpose we carried out theoretical calculations at the B3LYP/6-
311++G(d,p) level. Concerning tautomer stabilities, 6a (indazolin-3-
one) isolated in the gas phase is only 1.6 kJ molꢀ1 less stable than 6b
(3-hydroxyindazole) which corresponds to 66% of 6b at 300 K. The
formation of the 6a/6b dimer supposes a stabilization of 59.6 kJ molꢀ1
with regard to both monomers. To the double transfer process (both
tautomeric protons on the middle, Fig. 3, a transition state TS with
only one imaginary frequency) corresponds a barrier of 40.4 kJ
molꢀ1, that after ZPE correction at the same level lowers to 19.6 kJ
molꢀ1.
Fig. 1 ORTEP plot (30% probability for the ellipsoids) of the 6a/6b
dimer at 296(2) K showing the labelling of the asymmetric unit. Dotted
lines are used to express the alternate situation for the hydrogen on the
N2 atoms.
a 3-hydroxy tautomer 7b and 6,7-difluoroindazolinone (8) a 3-oxo
tautomer 8a, it appears that the signals of 4,6-difluoroindazolinone
(6) are near the middle of those model compounds (average of 7b and
8a, ꢀ172.2 and ꢀ241.1 ppm) (Fig. 2). The NMR data support the
dynamic situation in 6 with a rapid double proton transfer between
6a/6b and the complementary situation 6b/6a.
Moreover, we calculated the absolute shieldings s of monomers 6a
and 6b as well as the 6a/6b dimer (fully optimized, 0 imaginary
frequencies) at the GIAO/B3LYP/6-311++G(d,p) level, and
Scheme 4 ISSPT in 4,6-difluoroindazolinone (6) at 296(2) K.
Scheme 5 The structure of model compounds 7 and 8.
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Fig. 4 15N CPMAS NMR spectrum of 6-15N2 dimer at 60.81 MHz and
173 K (reference NH3).
calculated differences of tautomeric signals between 6a and 6b in the
dimer are 31.1 ppm (1890 Hz) for N1 and 88.0 ppm (5350 Hz) for N2.
Applying the equation for fast processes k ¼ (p/2)(nA ꢀ nB)2/we,13 we
obtain the rates: k ¼ 22 900 sꢀ1 and k ¼ 93 000 sꢀ1 for N1 and N2
respectively.
Using the DG‡ ¼ 19.12T (10.32 + log T/k) equation for T ¼ 173 K,
to these rates correspond barriers of 27.1 for N1 and 25.0 kJ molꢀ1 for
N2. So the energy barrier for the double tautomerization process
should be 25 ꢁ 5 kJ molꢀ1.
Fig.
indazolinone (6), and (c) 8a at 40.60 MHz and 300 K.
2
15N CPMAS NMR spectra of: (a) 7b, (b) 4,6-difluoro-
In conclusion, we have prepared a new indazolinone that consti-
tutes a rare example of cocrystallization between two distinct func-
tional tautomers (oxo 6a and hydroxy 6b) through intermolecular
hydrogen bonding. The existence of a very fast double proton
transfer in the solid state has been proved by combination of several
techniques: X-ray crystallography, solid state NMR (both unlabeled
and 15N-labeled samples) and DFT calculations.
Fig. 3 The calculated structure of the TS.
Acknowledgements
This work was carried out with financial support from the Ministerio
ꢀ
de Ciencia e Innovacion (Projects CTQ 2007-62113 and CTQ2009-
transformed the s15N into chemical shifts by means of the equation
d15N ¼ ꢀ152.0 ꢀ 0.946s15N.11 It results in the following values:
ꢀ
13129-C02-02) and Comunidad Autonoma de Madrid (Project
MADRISOLAR2, reference S-2009/PPQ/1533). Thanks are due to
the CTI (CSIC) for allocation of computer time. We greatly
acknowledged to Bruker for recording the spectra on a Wide-Bore
600 MHz instrument.
dN1/ppm
dN2/ppm
6a monomer
6b monomer
ꢀ276.6
ꢀ239.0
ꢀ235.0
ꢀ120.9
DdN1 ¼ 41.6
ꢀ273.3
DdN2 ¼ 118.1
ꢀ227.1
6a in the dimer
6b in the dimer
ꢀ242.2
ꢀ139.1
Notes and references
DdN1 ¼ 31.1
DdN2 ¼ 88
x Crystal data for the 6a/6b dimer: monoclinic, space group C2/c, Mr ¼
ꢁ
ꢁ
ꢁ
170.12, a ¼ 9.0766(7) A, b ¼ 11.6167(9) A, c ¼ 12.4603(10) A, b ¼
103.471(2) , V ¼ 1277.67(17) A , Z ¼ 8, rc ¼ 1.769 g cmꢀ3, F(000) ¼ 688,
T ¼ 296(2) K, 4493 reflections collected, 1083 unique with [Rint ¼ 0.0380],
R1 [I > 2s(I)] ¼ 0.0363, wR2 ¼ 0.940, final (for all data) R1 ¼ 0.0481,
wR2 ¼ 0.1008, GOF ¼ 1.049.
ꢂ
3
ꢁ
The formation of the HBs modifies some chemical shifts, mainly
those of N2 involved in the HB. The averaged values of the dimer are
ꢀ257.8 for N1 and ꢀ183.1 ppm for N2 to be compared with the
experimental values of Fig. 2b (ꢀ240.9 and ꢀ169.0 ppm) showing
a shift of about 15 ppm due to crystal field effects.12 By applying the
equation d15N ¼ ꢀ152.0 ꢀ 0.84s15N we had proposed in ref. 12a for
solid state CPMAS measurements, we obtained values closer to the
experimental ones: averaged values of the 6a/6b dimer ꢀ245.9 for N1
and ꢀ179.6 ppm for N2.
{ Synthesis of 6 and 6-15N2: 0.51 g (3.9 mmol) of hydrazine sulfate
(normal or double 15N labeled) in 3 mL of water was slowly added to
a solution of sodium bicarbonate (0.77 g, 7.7 mmol) in 3 mL water. The
mixture was stirred 1 h at room temperature. The solution was filtered off
to remove the sodium sulfate and added to a solution of 2,4,6-tri-
fluorobenzoic acid methyl ester10 (0.34 g, 1.8 mmol) in tetrahydrofurane
(THF). The mixture was heated 48 h at 70 ꢂC and then filtered. The solid
was washed with THF. The solution was evaporated under vacuum and
the residue washed with water: yield 260–275 mg of pure compound (85–
90% yield). 6, mp 293.5 ꢂC, and 6-15N2, mp 290.2 ꢂC. Anal. Found: C
49.44, H 2.49, N 16.27. Calcd for C7H4F2N2O: C 49.42, H 2.37, N
16.47%.
These data will serve to estimate the double tautomerization
barrier. For this, we have used the 15N CPMAS NMR spectrum at
60.81 MHz and 173 K (Fig. 4). We have estimated the we (line width)
to be 4 ppm (245 Hz) for N1 and 8 ppm (485 Hz) for N2. The
4054 | CrystEngComm, 2010, 12, 4052–4055
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