The annular tautomerism of the curcuminoid NH-pyrazoles

Article abstract of DOI:10.1039/b812018h

The structures of four NH-pyrazoles, (E)-3,5-bis[β-(4-hydroxy-3- methoxyphenyl)-ethenyl]-1H-pyrazole (3), (E)-3(5)-[β-(4-hydroxy-3- methoxyphenyl)-ethenyl]-5(3)-methyl-1H-pyrazole (4), (E)-3(5)-[β-(4- hydroxy-3-methoxyphenyl)-ethenyl]-4,5(3)-dimethyl-1H-p

Full text of DOI:10.1039/b812018h

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The annular tautomerism of the curcuminoid NH-pyrazolesw
Pilar Cornago,*a Pilar Cabildo,a Rosa M. Claramunt,a Latifa Bouissane,a
b
b
c
´
Elena Pinilla, M. Rosario Torres and Jose Elguero
Received (in Montpellier, France) 16th July 2008, Accepted 10th October 2008
First published as an Advance Article on the web 2nd December 2008
DOI: 10.1039/b812018h
The structures of four NH-pyrazoles, (E)-3,5-bis[b-(4-hydroxy-3-methoxyphenyl)-ethenyl]-1H-
pyrazole (3), (E)-3(5)-[b-(4-hydroxy-3-methoxyphenyl)-ethenyl]-5(3)-methyl-1H-pyrazole (4),
(E)-3(5)-[b-(4-hydroxy-3-methoxyphenyl)-ethenyl]-4,5(3)-dimethyl-1H-pyrazole (5) and (E)-3(5)-
[b-(3,4-dimethoxyphenyl)-ethenyl]-4-methyl-5(3)-phenyl-1H-pyrazole (8), have been determined by
X-ray crystallography. Compounds that have a phenol residue crystallize forming sheets that are
stabilized by a complex pattern of hydrogen bonds between a unique tautomer (4), or by a 2 : 1
mixture of both tautomers (5) (these tautomers being identical in the case of 3). Pyrazole 8, which
lacks OH groups, crystallizes in cyclic dimers that are stabilized by N–Hꢀ ꢀ ꢀN hydrogen bonds.
The tautomerism in solution and in the solid state was determined by 13C and 15N CPMAS NMR
spectroscopy. For compounds 4, 5 and 8, the solid state results agree with those observed by
crystallography; the most abundant tautomer in solution coincides with the tautomer present in
the solid state (4 and 8) or with the most abundant tautomer in the crystal (5).
Introduction
Turmeric is a spice derived from the rhizomes of Curcuma
longa, which is a member of the ginger family.1 The bright
yellow color of turmeric comes mainly from polyphenolic
pigments known as curcuminoids. Curcumin (1) (Scheme 1)
is the principal curcuminoid found in turmeric, and is gen-
Scheme 1 The structure of curcumin (1) and the tautomerism of
erally considered to be its most active constituent. In addition
to its use as a spice and a pigment, turmeric has been used in
India for medicinal purposes for centuries. More recently,
evidence that 1 may have anti-inflammatory and anti-cancer
activities has renewed scientific interest in its potential to
prevent and treat disease. 1 is also an effective scavenger of
reactive oxygen and nitrogen species in vitro. In addition to its
direct antioxidant activity, 1 has been found to inhibit PLA2,
COX-2 and 5-LOX activity in cultured cells. It has also been
found to inhibit NF-kB-dependent gene transcription, and to
inhibit the induction of COX-2 and iNOS in cell culture and
animal studies.2 1 has been found to induce cell cycle arrest
and apoptosis in a variety of cancer cell lines grown in
cultures. The ability of 1 to induce apoptosis in cultured
cancer cells has generated scientific interest in its potential to
prevent some types of cancer. Oral administration of 1 has
been found to inhibit the development of chemically-induced
pyrazoles 2.
cancer in animal models of oral, stomach, liver and colon
cancer.
We have devoted a series of papers to the annular tauto-
merism of NH-pyrazoles 2 (2a vs. 2b),3,4 and decided to study
those derived from 1 and related b-diketones.
Pyrazole 3, which is derived from 1, has been prepared many
times since 1991.5–11 It has been described as a pale yellow
solid that melts at 211–2145 or 2157 1C.
The activity of the curcuminoid pyrazoles covers domains
such as anti-inflammatory (5-lipooxygenase and cyclooxygen-
ase inhibitors)5,8 and anti-tumoral (anti-angiogenic)6–8 agents,
and drugs for the treatment of Alzheimer’s disease (AD;
potent g-secretase inhibitors, potent ligands for fibrillar
Ab42 aggregates, tau aggregation inhibitors and depolymeriz-
ing agents for tau aggregates).10,11 Particularly promising for
treating reduced cognitive functions is 4,40-[(1-phenyl-1H-
pyrazole-3,5-diyl)di-(1E)-2,1-ethenediyl]bis(2-methoxyphenol)
(CNB-001), the product obtained by reacting 1 with phenyl-
hydrazine.12 In the last of these applications, curcumin-
derived pyrazoles were synthesized in order to minimize
the metal chelation properties of 1. The reduced rotational
freedom and the absence of stereoisomers were anticipated
to enhance the inhibition of g-secretase. Accordingly, the
replacement of the 1,3-dicarbonyl moiety by isosteric hetero-
cycles, such as pyrazoles, turned these compounds into very
interesting candidates for AD research.
a
´
´
´
Departamento de Quımica Organica y Bio-Organica, Facultad de
Ciencias, UNED, Senda del Rey 9, E-28040 Madrid, Spain.
E-mail: mcornago@ccia.uned.es; Fax: +34 913988372;
Tel: +34 913987323
b Departamento de Quı´mica Inorga´nica I, Facultad de Ciencias
´
Quımicas, Universidad Complutense de Madrid (UCM), 28040
Madrid, Spain
´ ´
Instituto de Quımica Medica, CSIC, Juan de la Cierva 3, E-28006
Madrid, Spain
c
w CCDC reference numbers 690489–690492. For crystallographic data
in CIF or other electronic format see DOI: 10.1039/b812018h
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The aim of this paper is to determine and discuss the
structure, tautomerism and possible proton transfer in the
solid state (SSPT) of six NH-pyrazoles by using a combination
of X-ray crystallography and 13C/15N NMR spectroscopy.
The nomenclature used in the text and in the experimental is
not in accordance with IUPAC rules. For all of the com-
pounds with phenolic hydroxyl groups, 3–6, the phenol system
has the highest priority; however, using IUPAC nomenclature
here would be at the expense of comparability and clearness.
For instance, compound 4 would be 2-methoxy-4-[(E)-2-
(5-methyl-1H-pyrazol-3-yl)vinyl]phenol under IUPAC rules,
rather than (E)-3(5)-[b-(4-hydroxy-3-methoxyphenyl)ethenyl]-
5(3)-methyl-1H-pyrazole. In order to prioritize comparability
over correct nomenclature, we have named all of the com-
pounds as pyrazole derivatives.
Table 1 The bond lengths (A) and angles (1) for compounds 3, 4, 8
and the three crystallographically-independent molecules of 5
5(1)
5(2)
5(3)
3
4
8
N1–N2
N2–C3
C3–C4
1.354(3) 1.365(3) 1.349(4) 1.352(4) 1.359(3) 1.351(3)
1.347(4) 1.339(3) 1.341(5) 1.348(5) 1.349(5) 1.339(4)
1.399(4) 1.398(4) 1.388(6) 1.410(5) 1.401(6) 1.415(4)
1.373(4) 1.369(3) 1.381(6) 1.366(5) 1.374(6) 1.379(4)
1.353(4) 1.340(3) 1.332(6) 1.346(5) 1.331(5) 1.360(4)
C4–C5
C5–N1
C3–C6
C5–C6
1.445(4) 1.453(3)
—
—
1.446(7)
1.463(5) 1.450(6) 1.377(3)
1.444(4)
—
—
—
C6–C7
C7–C8
1.327(4) 1.325(3) 1.309(1) 1.310(6) 1.304(4) 1.333(4)
1.467(4) 1.472(3) 1.460(1) 1.457(5) 1.475(6) 1.460(4)
C3–C15
C5–C15
C15–C16
C16–C17
C10–O2
O2–C14
C11–O1
C15–O1
C19–O4
O4–C23
C20–O3
—
1.450(4) 1.484(2)
—
1.484(6)
—
—
1.490(5) 1.509(6)
—
—
—
—
—
—
—
1.322(4)
1.463(4)
—
—
—
—
—
—
1.376(4) 1.367(3) 1.359(6) 1.367(4) 1.372(5) 1.372(3)
1.433(4) 1.419(3) 1.424(6) 1.430(5) 1.442(5) 1.416(4)
1.368(4) 1.369(3) 1.372(5) 1.361(5) 1.363(5) 1.371(3)
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
1.418(4)
Results and discussion
1.366(4)
1.416(4)
1.382(4)
—
—
—
Synthesis
N2–N1–C5 112.2(3) 112.7(2) 112.2(4) 111.8(3) 111.6(3) 112.4(2)
N1–N2–C3 105.3(2) 104.4(2) 104.4(3) 105.2(3) 104.7(3) 105.3(2)
All of the compounds discussed in this work (Scheme 2) are
reported in the experimental section. They were prepared by
the reaction of hydrazine with the corresponding b-diketone,
the most common method of synthesizing pyrazoles,13 which
in the case of 3 was 1.14
Crystals of sufficient quality for X-ray diffraction analysis
were obtained for compounds 3 (1 : 1 H2O/EtOH), 4 (1 : 1 : 1
CH2Cl2/hexane/EtOH), 5 (1 : 1 : 1 CH2Cl2/hexane/EtOH) and
8 (1 : 1 : 1 CH2Cl2/hexane/EtOH) from their respective solvent
mixtures. Table 1 shows selected bond lengths and angles for
each of these compounds, and Table 2 shows the distances and
angles of the intermolecular hydrogen bonds.
X-Ray structure determination
The structures of pyrazoles 3 (derived from 1), 4, 5 and 8 have
been determined by X-ray crystallography.
Concerning tautomerism, in the case of 3, tautomers 3a and
3b are identical. In the case of 4, the only tautomer present
is 3-(3-methoxy)-4-hydroxy-styryl-5-methyl-1H-pyrazole (4a).
In the case of 5, there is a 2 : 1 mixture of 3-(3-methoxy)-4-
hydroxy-styryl-4,5-dimethyl-1H-pyrazole (5a) and 3,4-di-
methyl-5-(3-methoxy)-4-hydroxy-styryl-1H-pyrazole (5b). In
the case of 8, the only observed tautomer is 3-phenyl-4-
methyl-5-(3-methoxy)-4-hydroxy-styryl-1H-pyrazole (8b). The
main data are collected in Table 1 and Table 2. A charac-
teristic feature of the geometry of NH-pyrazoles is that the
angle centered at N1 (the atom bearing the NH proton) is
always larger than that centered at N2, about 112 and 1041,
respectively.15
One crystallographically-independent molecule was identi-
fied in the structural determination of 3, where the pyrazole
and phenyl rings were co-planar, with bond distances and
angles within normal ranges (Fig. 1). The intermolecular
hydrogen bonds led to layers parallel to (1 0 1), as shown in
Fig. 2.
Table 2 The bond lengths (A) and angles (1) for the hydrogen bonds
in compounds 3, 4, 5 and 8
Compound D–Hꢀ ꢀ ꢀA
dD–H
dHꢀ ꢀ ꢀA dDꢀ ꢀ ꢀA
+
D–Hꢀ ꢀ ꢀA
3
O3–H3ꢀ ꢀ ꢀO4
1.10
1.06
1.17
1.10
1.98
1.93
1.79
2.26
2.647(4) 115.1
2.864(4) 144.7
2.811(4) 142.7
2.825(4) 108.7
N1–H1Bꢀ ꢀ ꢀO3a
O1–H1Aꢀ ꢀ ꢀN2b
O3–H3ꢀ ꢀ ꢀO1c
4
O1–H1Aꢀ ꢀ ꢀN2d
0.99
1.07
1.86
2.17
2.832(3) 167.5
2.962(3) 128.6
N1–H1Bꢀ ꢀ ꢀO2e
5
O13–H113ꢀ ꢀ ꢀN21 1.16
1.81
1.82
2.03
1.57
2.01
1.93
2.782(5) 137.3
2.914(5) 175.6
2.813(4) 141.3
2.673(4) 159.4
2.951(5) 144.3
2.853(4) 148.6
N12–H12ꢀ ꢀ ꢀN23
1.10
O11–H111ꢀ ꢀ ꢀO13f 0.92
O12–H112ꢀ ꢀ ꢀN22g 1.14
N11–H11ꢀ ꢀ ꢀO11g 1.08
N13–H13ꢀ ꢀ ꢀO12i 1.02
8
N1–H1ꢀ ꢀ ꢀN2j
0.90(4) 2.07(4) 2.872(3) 147(4)
Symmetry transformations used to generate equivalent atoms: a ꢂx +
b
c
d
2, y ꢂ , ꢂz + 12. ꢂx + 1, y + 21, z + 32. x + 1, y, z ꢂ 1. ꢂx + 1,
1
2
e
f
g
ꢂy + 2, ꢂz + 1. x, ꢂy + 32, z ꢂ . ꢂx + 4, y ꢂ , ꢂz + 32. ꢂx +
1
1
2
1
2
h
i
1
2
1
3
1
1, y ꢂ , ꢂz + . ꢂx + 4, y + , ꢂz + . ꢂx + 1, y + , ꢂz +
2
2
2
2
j
1
2
.
ꢂx + 2, ꢂy, ꢂz + 1.
Scheme 2 The structures of the NH-pyrazoles.
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Fig. 1 The X-ray molecular structure of compound 3 (ORTEP plot,
35% probability for the ellipsoids).
Fig. 4 The view along the b axis of 4, showing the formation of layers
due the intermolecular hydrogen bonds.
(N1–H1B–O2) led to layers parallel to (1 0 0), as shown in
Fig. 4.
The asymmetric unit of compound 5 is presented in Fig. 5.
The crystal consists of three crystallographically-independent,
almost planar molecules, held together by hydrogen bonds
that form a trimer, which, through additional hydrogen
bonding, forms layers parallel to (–1 0 3), as shown in Fig. 6.
Fig. 7 shows the non-planar molecule of compound 8, with
a dihedral angle of 15.7(1)1 between the pyrazole and
the phenyl ring at the 3-position, and 36.5(1)1 between the
pyrazole and the phenyl ring of the styryl group at the
5-position. Molecules of 8 are centrosymmetrically linked by
hydrogen bonds (Table 2), giving rise to dimers, and these
species are within van der Waals distances (Fig. 8).
Fig. 2 The view along the a axis of 3, showing the formation of layers
due the intermolecular hydrogen bonds.
The cyclic N–Hꢀ ꢀ ꢀN hydrogen-bonded motifs (cyclamers) of
NH-pyrazoles have been studied on several occasions.4d,16,17
These motifs are characteristic of NH-pyrazoles lacking sub-
stituents that bear hydrogen bonding functional groups, such
as –OH or –CO2H. These groups, as well as solvent molecules
like H2O and ROH, participate in the hydrogen bonding
network that determines the secondary structure of the crys-
tals, destroying the (N–Hꢀ ꢀ ꢀN)n hydrogen bonds.18–20 In three
of the compounds described in the present paper, those
bearing phenol groups (3, 4 and 5) form several hydrogen
bonds involving the OH group: 3 (O–Hꢀ ꢀ ꢀN, N–Hꢀ ꢀ ꢀO,
Fig. 3 shows an ORTEP representation of the asymmetric
unit of compound 4, a non-planar molecule with a dihedral
angle of 19.0(1)1 between the pyrazole and phenyl rings.
Dimers (O1–H1A–N2) linked by hydrogen bonds
O–Hꢀ ꢀ ꢀO),
4
(O–Hꢀ ꢀ ꢀN, N–Hꢀ ꢀ ꢀO) and
5
(O–Hꢀ ꢀ ꢀN,
N–Hꢀ ꢀ ꢀO, O–Hꢀ ꢀ ꢀO, N–Hꢀ ꢀ ꢀN; present as two molecules of
tautomer 5a and one molecule of tautomer 5b). In the case of
8, which lacks phenol groups, the compound crystallizes as a
dimer. This kind of cyclamer is characteristic of NH-pyrazoles
that are substituted with phenyl groups at the 3- and 5-posi-
tions,16 to which compound 8 is clearly related.
Fig. 3 The X-ray molecular structure of compound 4 (ORTEP plot,
35% probability for the ellipsoids).
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Fig. 5 The X-ray molecular structure of compound 5 (ORTEP plot, 40% probability for the ellipsoids).
Fig. 8 The view along the a axis of 8, showing the formation of
dimers.
These data have been collected with the aim of determining the
tautomeric equilibrium constants by simple integration.
1
Although it has been pointed out that only H NMR signal
intensities are reliable for the determination of populations, in
our experience, 13C and 15N signals can also been used in
connection with signals related by tautomerism, i.e. carbon or
nitrogen atoms linked to the same substituents.3c The assign-
ments of the signals were based on standard 2D experiments,
on the values of coupling constants (auto-consistency) and by
comparison with other NH-pyrazoles where tautomerization
is blocked.21
Fig. 6 The view along the a axis of 5, showing the formation of layers
due the intermolecular hydrogen bonds.
We have illustrated with one example the kind of spectra
that we obtained (Fig. 9). The spectrum corresponds to
compound 5 in HMPA-d18, concentration 0.10 M and tem-
perature 268 K (Table 4). The region of the methyl groups
shows two narrow signals corresponding to the most abundant
tautomer, and two broad signals corresponding to the less
abundant one, as expected by simple consideration of the
energy profile.
For compounds whose structure had not been determined
by crystallography, we relied on CPMAS NMR results: 6b and
7b were the only tautomers present in the solid state
(see Table 4 and Table 5). We are aware that solid state
NMR and single crystal X-ray diffraction do not show exactly
the same properties, for instance, static vs. dynamic disorder.3b
To avoid further complications, we used fine powders for
Fig. 7 The X-ray molecular structure of compound 8 (ORTEP plot,
35% probability for the ellipsoids).
NMR study
We have reported the 1H, 13C and 15N NMR results concerning
compounds 3–8 in Table 3, Table 4 and Table 5, respectively.
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Table 4 The 13C NMR chemical shifts (d) and 1H–13C coupling constants (J/Hz) in DMSO-d6 and HMPA-d18 solutions, and under CPMAS
conditionsa
Ca
C4
Cb
C5
Cc
C6
R2
C7
C1
C8
C2
OCH3
C3
R1
Compound R1
R2 R3 Solvent Conc./M T/K
Tautomerism
3
*
H
H
DMSO 0.12
300 151.0 99.3 142.0 — (H)
120.1 128.4 109.5 129.8
147.9
112.9 (C8) 55.6
118.4 (C80)
146.8
115.6
No tautomerism
CPMAS —
300 150.2 95.5 142.8 — (H)
N.o.b 127.1 106.3 129.9
147.4
111.9
145.1
53.5
56.5
114.5
No tautomerism
4
CH3
H
H
DMSO 0.36
HMPA 0.10
300 149.6 101.3 140.5 — (H)
119.9 128.6 109.5 129.0
276 150.9 100.0 142.4 — (H)
119.4 128.4 110.5 128.7
138.4 101.6 148.9 — (H)
119.6 128.4 110.5 129.4
300 151.5 101.1 142.4 — (H)
120.5 129.9 113.2 129.9
115.3
147.9
117.4
148.7
113.2
148.7
119.3
148.8
113.2
146.6
55.6
115.7
11.6 (Me)
115.7
Average
B50% a
B50% b
a
148.6
55.9
10.8 (Me-5)
115.7
146.9
55.9
13.9 (Me-3)
115.3
9.9 (Me-5)
CPMAS —
143.3
55.9
5
CH3 CH3
H
DMSO 0.07
HMPA 0.08
300 141.6 110.4 141.6 8.1 (Me)
119.8 128.8 109.6 127.9
147.9
114.9
149.0
118.7
149.0
112.7
146.6
55.7
115.6
10.6
Average
300 147.5 109.9 135.7 8.4 (Me)
119.6 129.0 111.5 127.7
148.7
56.3
116.1
11.9 (br)
116.1
35% a
HMPA 0.08
HMPA 0.10
HMPA 0.10
CPMAS —
300 138.3 109.9 145.8 8.4 (Me)
119.6 129.0 111.5 128.4
268 147.5 110.0 135.7 8.8 (br, Me) 148.8
148.7
56.3
148.6
55.9
148.6
55.9
146.6
55.3
65% b
35% a
65% b
66% a
34% b
11.9 (br)
115.8
119.5 128.8 110.7 127.6
268 138.3 109.9 145.8 8.4 (Me)
119.5 128.8 110.7 128.3
300 145.9 110.2 138.6 9.8 (Me)
123.4 130.9 105.5 128.9
118.5
148.8
112.4
148.8
117.0
148.8
119.0
9.1 (br)
115.8
12.1
121.8
11.2 (br)
121.8
11.2 (br)
137.5 112.0 146.6 9.8 (Me)
123.4 130.9 105.5 128.9
146.6
55.3
6
C6H5
H
H
DMSO 0.11
DMSO 0.11
300 151.4 100.4 140.3 — (H)
122.1 128.1 109.5 130.1
147.9
118.4
146.6
55.5
115.3
36% a
64% b
132.0 (i)
125.0 (o)
128.7 (m)
127.5 (p)
115.6
133.6 (i)
125.1 (o)
128.7 (m)
127.5 (p)
300 142.6 99.5 151.0 — (H)
120.2 128.1 109.5 130.1
147.9
112.7
147.1
55.6
6b
C6H5
H
H
H
CPMAS —
300 144.0 103.5 152.6 — (H)
116.0 129.0 112.3 129.0
148.3
113.5
116.0
54.0
133.2 (i)
126.4 (o)
129.0 (m)
129.0 (p)
7
C6H5
CH3 DMSO 0.11
300 151.3 99.2 142.8 — (H)
119.4 129.4 108.9 128.9
149.0
113.6
149.0
111.9
40% a
60% b
55.51 (C1) 133.7 (i)
55.45 (C2) 125.0 (o)
128.6 (m)
127.4 (p)
111.9
55.51 (C1) 133.7 (i)
55.45 (C2) 125.0 (o)
128.6 (m)
DMSO 0.11
300 142.4 99.8 150.9 — (H)
119.9 129.4 108.9 129.7
149.0
113.6
149.0
127.4 (p)
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Table 4 (continued )
Ca
C4
Cb
C5
Cc
C6
R2
C7
C1
C8
C2
OCH3
C3
R1
Compound R1
7b C6H5
R2 R3 Solvent Conc./M T/K
Tautomerism
H
CH3 CPMAS —
300 143.1 96.3 149.8 — (H)
120.9 129.1 108.0 129.1
148.8
110.6
148.8
110.6
53.5 (C1*) 132.1 (i)
56.1 (C2*) 125.2 (o)
129.1 (m)
126.2 (p)
8
C6H5 CH3 CH3 DMSO 0.31
300 141.7 110.7 147.1 9.4 (Me)
119.9 130.0 109.1 128.4
149.1
114.5
148.8
111.9
Aver.
Rich in b
55.6 (C1) 133.2 (i)
55.5 (C2) 127.1 (o)
128.5 (m)
127.3 (p)
112.1
55.9 (C1) 135.9 (i)
55.9 (C2) 127.2 (o)
128.6 (m)
HMPA 0.06
268 139.7 110.4 149.5 10.1 (Me)
120.2 130.9 109.1 128.8
149.8
113.2
149.3
b
b
126.9 (p)
112.5
134.6 (i)
128.5 (o)
130.2 (m)
126.7 (p)
CPMAS —
300 140.7 112.5 148.8 9.2 (Me)
124.7 130.2 110.7 130.2
148.8
117.1
148.8
54.7
a
The 1J coupling constants are not reported; their average values are: pyrazole C4–Hb = 175 Hz; phenyl CH = 159 Hz except C4–H and
2
2
C6–H = 156 Hz; olefin C–H = 155 Hz; OCH3 = 144 Hz; C–Me substituents: 126.5 Hz. The other couplings (Hz) are: J = 2.2 (C1), J = 4.5
(C7), 2J = 5.9 (Cb–Me4); 3J = 8.4 (C1), 3J = 7.3 (C2), 3J = 5.8 (C4), 3J = 6.8 (C5), 3J = 6.0 (C6), 3J = 4.5 (C7), 3J = 2.4 (Cb–H).
b
Not observed.
CPMAS NMR, obtained by grinding the same batch of
crystals that we used for X-ray crystallography.
cyclamers, linked by N–Hꢀ ꢀ ꢀN hydrogen bonds. Compound 3
has the same substituent at both positions (tautomer 3a is
identical to tautomer 3b), but crystallizes in a complex
network of hydrogen bonds involving the OH groups. Com-
pound 8 crystallizes as a dimer, but with only one tautomer
present (8a). Thus, none of the compounds of Table 6 display
SSPT. Finally, compound 5 is the only known example of an
NH-pyrazole that crystallizes as a 2 : 1 mixture of two
tautomers (there are examples of 2 : 2 and 3 : 1 mixtures,
but in cyclic tetramers17b,22).
Percentages of tautomers and equilibrium constants
Although some exceptions are known, the assumption of the
identical nature of the most stable tautomer in solution and
the tautomer present in the crystal is one of the most basic
tenets in tautomerism.3b,3c,17b The results in Table 6 confirm
this principle for compounds 4, 5 and 8, and allow us
to conclude that in the solid state, 6 should crystallize as
6b and 7 as 7b, or at least in cyclamers where 6b and 7b are
predominant.
Experimental
Compound 5 exists in the solid state as a 66% 5a/34% 5b
mixture and in HMPA as a 35% 5a/65% 5b mixture, thus
being an exception to the rule of similarity between solution
and solid state. However, the difference in energy at 300 K
The melting points of pyrazoles 3–8 were determined by
differential scanning calorimetry (DSC) on a Seiko DSC
220C connected to a Model SSC5200H Disk Station; for the
other compounds, a hot stage microscope was used. Thermo-
grams (sample size 0.003–0.0010 g) were recorded at a scan-
ning rate of 2.0 1C minꢂ1. Thin-layer chromatography
(TLC) was performed using Merck silica gel (60 F254) and
compounds were detected with a 254 nm UV lamp. Silica gel
(60–320 mesh) was employed for routine column chromato-
graphy separations. Elemental analyses for carbon, hydrogen
and nitrogen were carried out by the Microanalytical Service
of the Universidad Complutense of Madrid on a Perkin-Elmer
240 analyzer.
between the two situations is only of 3.2 kJ molꢂ1
.
Conclusions
The structure, tautomerism and absence of SSPT have been
determined for six NH-pyrazoles by a combination of X-ray
crystallography and 13C/15N NMR spectroscopy. Two of the
conditions required to observe SSPT in NH-pyrazoles are the
identity (or, at least, strong similarity) of the substituents at
the 3- and 5-positions, and the formation of cyclic structures,
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Fig. 9 The methyl group region of the 13C NMR spectrum of 5.
General procedure for the preparation of pyrazole derivatives
(3–8)
Compounds 3–8 were prepared by reacting the corresponding
b-diketones23 (1 mmol) with hydrazine hydrate 98% (1.5 mmol)
in acetic acid (5 mL). After heating at reflux for 2 h, the
reaction mixture was poured into water, and the precipitate
filtered off, washed with water and dried. The solid was
purified by column chromatography using ethyl acetate as
the eluent.
(E)-3,5-Bis[b-(4-hydroxy-3-methoxyphenyl)-ethenyl]-1H-
pyrazole (3)
3 was prepared from purified commercially available 1. The
compound was obtained as a colourless solid after recrystalli-
zation from H2O/EtOH (1 g, 2.74 mmol, 63%). Mp: 217.1 1C,
lit.: 211–214 1C5 or 215 1C.8 Anal. calc. for C21H20N2O4
(364.14): C, 69.22; H, 5.53; N, 7.69; found: C, 68.79; H,
5.53; N, 7.70%.
(E)-3(5)-[b-(4-hydroxy-3-methoxyphenyl)-ethenyl]-5(3)-methyl-
1H-pyrazole (4)
4 was prepared from (E)-6-(4-hydroxy-3-methoxyphenyl)hex-
5-ene-2,4-dione.23 The compound was obtained as a colourless
solid after recrystallization from CH2Cl2/hexane/EtOH
(251 mg, 1.1 mmol, 85%). Mp: 141.6 1C. Anal. calc. for
C13H14N2O2 (230.11): C, 67.26; H, 6.44; N, 12.11; found: C,
67.81; H, 6.13; N, 12.17%.
(E)-3(5)-[b-(4-hydroxy-3-methoxyphenyl)-ethenyl]-4,5(3)-
dimethyl-1H-pyrazole (5)
5 was prepared from (E)-6-(4-hydroxy-3-methoxyphenyl)-3-
methylhex-5-ene-2,4-dione.23 The compound was obtained as
a colourless solid after recrystallization from CH2Cl2/hexane/
EtOH (180 mg, 0.73 mmol, 61%). Mp: 176.1 1C. Anal. calc.
for C14H16N2O2 (244.12): C, 68.46; H, 6.61; N, 11.35; found:
C, 68.83; H, 6.60; N, 11.47%.
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Table 6 The tautomeric composition of 3–8 (Sty: Ar–CHQCH–)a
Compound
Tautomers
X-Ray
CPMAS
DMSO
HMPA
3
4
a, b: 3,5-BisSty
a: 3-Sty-5-Me
b: 3-Me-5-Sty
a: 3-Sty-5-Me
b: 3-Me-5-Sty
a: 3-Sty-5-Ph
b: 3-Ph-5-Sty
a: 3-Sty-5-Ph
b: 3-Ph-5-Sty
a: 3-Sty-5-Ph
b: 3-Ph-5-Sty
3a = 3b
4a
3a = 3b
4a
3a = 3b No PTb
Average rich in 4a
N. M.
B50% 4a
B50% 4b
35% 5a
65% 5b
N. M.
5
6
7
8
66% 5a
34% 5b
N. M.
66% 5a
34% 5b
6b
Average rich in 5b
36% 6a
64% 6b
40% 7a
60% 7b
Average rich in 8b
N. M.
7b
8b
N. M.
8b
8b
a
b
N. M. means not measured. Proton transfer
Table 7 The crystal and structure refinement data for compounds 3, 4, 5 and 8
Crystal data
3
4
5
8
Empirical formula
Formula weight
Crystal system
Space group
Unit cell dimensions
C
364.39
21H20N2O4
C13H14N2O2
230.26
Orthorhombic
Pbca
13.2563(15)
7.6962(9)
22.855(3)
—
2331.7(5)
8
1.312
C14H16N2O2
244.29
Monoclinic
P2(1)/c
8.519(2)
12.964(4)
34.615(10)
94.607(7)
3810.6(19)
12
1.277
0.087
o and j
1560
1.18 to 25.00
C20H20N2O2
320.38
Orthorhombic
Pbca
13.2363(13)
8.2769(8)
30.673(3)
—
3360.4(6)
8
1.267
Monoclinic
P2(1)/c
8.2394(10)
14.0198(17)
16.306(2)
101.060(3)
1848.7(4)
4
1.309
0.092
o and j
768
1.93 to 25.00
a/A
b/A
c/A
b (1)
Volume/A3
Z
Density (calculated)/Mg mꢂ3
Absorption coefficient/mmꢂ1
Scan technique
0.090
0.083
o and j
976
1.78 to 27.00
o and j
1360
1.33 to 25.00
F(000)
Range for data collection (1)
Index ranges
Reflections collected
Independent reflections
ꢂ9, ꢂ16, ꢂ18 to 9, 16, 19 ꢂ13, ꢂ9, ꢂ29 to 16, 9, 29 ꢂ9, ꢂ15, ꢂ41 to 10, 15, 41 ꢂ15, ꢂ9, ꢂ36 to 10, 9, 32
13 998
3244
19 397
2541
28 784
6720
16 484
2954
Observed reflections [I 4 2s(I)] 1418
1248
0.0889
100.0
2541/0/156
1.034
0.0508
0.1768
0.214 and ꢂ0.247
2855
0.0905
100.0
6720/2/497
0.984
0.0769
0.2486
0.950 and ꢂ0.377
1655
0.0708
99.9
2954/0/224
1.074
0.0507
0.1848
0.193 and ꢂ0.192
Rint
0.1198
99.6
3244/0/245
0.912
0.0539
Completeness to y (%)
Data/restraints/parameters
Goodness-of-fit on F2
R1a
wR2b (all data)
Largest differential peak and
hole/eAꢂ3
0.1808
0.232 and ꢂ0.278
P
P
P
P
a
b
2
R1 = ||Fo| ꢂ |Fc||/ |Fo|. wR2 = [w(Fo ꢂ Fc2)2]/ [w(Fo2).
(E)-3(5)-[b-(4-hydroxy-3-methoxyphenyl)-ethenyl]-5(3)-phenyl-
1H-pyrazole (6)
for C19H18N2O2 (306.37): C, 74.48; H, 5.92; N, 9.14; found: C,
74.21; H, 5.82; N, 9.16%.
6 was prepared from (E)-5-(4-hydroxy-3-methoxyphenyl)-1-
phenylpent-4-ene-1,3-dione.23 The compound was obtained as
a colourless solid after recrystallization from CH2Cl2/hexane/
EtOH (228 mg, 0.78 mmol, 77%). Mp: 142.9 1C. Anal. calc.
for C18H16N2O2 (292.12): C, 73.95; H, 5.54; N, 10.11; found:
C, 73.95; H, 5.54; N, 10.11%.
(E)-3(5)-[b-(3,4-dimethoxyphenyl)-ethenyl]-4-methyl-5(3)-
phenyl-1H-pyrazole (8)
8 was prepared from (E)-5-(3,4-dimethoxyphenyl)-2-methyl-1-
phenylpent-4-ene-1,3-dione.23 The compound was obtained as
a colourless solid after recrystallization from CH2Cl2/hexane/
EtOH (170 mg, 0.53 mmol, 58%). Mp: 182.0 1C. Anal. calc.
for C20H20N2O2 (320.39): C, 74.97; H, 6.29; N, 8.74; found: C,
74.28; H, 6.14; N, 8.77%.
(E)-3(5)-[b-(3,4-dimethoxyphenyl)-ethenyl]-5(3)-phenyl-1H-
pyrazole (7)
X-Ray data collection and structure refinement (compounds 3, 4,
5 and 8)
7 was prepared from (E)-5-(3,4-dimethoxyphenyl)-1-phenyl-
pent-4-ene-1,3-dione.23 The compound was obtained as a
colourless solid after recrystallization from CH2Cl2/hexane/
EtOH (196 mg, 1.27 mmol, 51%). Mp: 173.4 1C. Anal. calc.
Data collection for all of the compounds was carried out at
room temperature on a Bruker Smart CCD diffractometer
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using graphite-monochromated Mo-Ka radiation (l
=
In the gs-HMQC experiments, GARP modulation of 13C was
used for decoupling. 15N NMR spectra were acquired using
2D inverse proton detected heteronuclear shift correlation
spectroscopy. Typical parameters for the gs-HMQC
(1H–15N) spectra were: a spectral width of 5787 Hz for 1H
and 12.5 kHz for 15N, a 1024 ꢃ 256 data set, number of
scans = 4, a relaxation delay of 1 s and a 7 ms delay for the
evolution of the 15N–1H coupling. The FIDs were processed
using zero filling in the F1 domain, and a sine-bell window
function in both dimensions was applied prior to Fourier
transformation. A Bruker BVT 3000 temperature unit was
used to control the temperature of the cooling gas stream and
an exchanger was used to achieve low temperatures.
0.71073 A) operating at 50 kV and 30 mA. In all cases, the
data were collected over a hemisphere of the reciprocal space
by the combination of three exposure sets. Each frame ex-
posure time was either 10 or 20 s, covering 0.31 in o. The cell
parameters were determined and refined by a least-squares fit
of all reflections collected. The first 100 frames were re-
collected at the end of the data collection to monitor crystal
decay, and no appreciable decay was observed. A summary of
the fundamental crystal and refinement data is given in
Table 7. The structures of all the compounds were solved by
direct methods and conventional Fourier synthesis, and re-
fined by full matrix least-squares on F2 (SHELXL-97).24 All
non-hydrogen atoms were refined anisotropically.
Solid state. Solid state 13C (100.73 MHz) and 15N (40.60 MHz)
CPMAS NMR spectra were recorded on a Bruker WB 400
spectrometer at 300 K using a 4 mm DVT probe head.
Samples were carefully packed in 4 mm diameter cylindrical
zirconia rotors with Kel-F caps. Operating conditions in-
In all cases, the hydrogen atoms were calculated, included
and refined as riding on their respective carbon-bonded atom
with a common anisotropic displacement. The rest of the
hydrogen atoms, i.e. those bonded to nitrogen or oxygen
atoms, were located in a Fourier difference synthesis, and in
all cases were included and refined as riding on their respective
bonded atoms for 3, 4 and 5, while for 8, its coordinates were
refined and the thermal factors kept constant. The longer O–H
bond distances in some of the hydroxyl groups are due to the
formation of hydrogen bonds.25
1
volved 90 3.2 ms H pulses and a decoupling field strength of
78.1 kHz in a TPPM sequence. The non-quaternary suppres-
sion (NQS) technique to observe only the quaternary carbon
atoms was employed. 13C spectra were initially referenced
to a glycine sample and then the chemical shifts were recalcu-
lated to Me4Si (for the carbonyl atom, dglycine = 176.1).
Similarly, 15N spectra were initially referenced to 15NH4Cl
and then recalculated to nitromethane, using the relationship:
The largest peaks and holes in the final difference map were
0.232 and ꢂ0.278, 0.214 and ꢂ0.247, 0.950 and ꢂ0.377, and
0.193 and ꢂ0.192 eAꢂ3 for 3, 4, 5 and 8, respectively. The final
R1 and wR2 values were 0.0539 and 0.1808, 0.0508 and 0.1768,
0.0769 and 0.2486, and 0.0507 and 0.1848 for 3, 4, 5 and 8,
respectively.
15
15
d
N
= d
N
ꢂ 338.1. Typical acquisition
nitromethane
NH4Cl
parameters for the 13C CPMAS were: a spectral width of
40 kHz, a recycle delay of 15–75 s, an acquisition time of
30 ms, a contact time of 2 ms and a spin rate of 12 kHz.
Typical parameters for the 15N CPMAS were: a spectral width
of 40 kHz, a recycle delay of 15–75 s, an acquisition time of 35
ms, a contact time of 7–8 ms and spin rate of 6 kHz.
NMR spectroscopy
Solution NMR spectra. Solution NMR spectra were re-
corded on a Bruker DRX 400 (9.4 T; 400.13 MHz for 1H,
100.62 MHz for 13C and 40.56 MHz for 15N) spectrometer
fitted with a 5 mm inverse detection H–X probe and equipped
Acknowledgements
1
with a z-gradient coil at 300 K. H and 13C NMR chemical
This work has been financed by the Spanish MEC (CTQ2006-
02586 and CTQ2007-62113).
shifts (d) are referenced to Me4Si; for 15N NMR, nitromethane
(0.00) was used as an external standard. Typical parameters
1
for the H NMR spectra were: a spectral width of 5787 Hz, a
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