Structure and tautomerism of 4-bromo substituted 1H-pyrazoles

Article abstract of DOI:10.1016/j.tet.2007.06.007

The tautomerism in the solid state and in solution of five 4-bromo-1H-pyrazoles has been studied by multinuclear magnetic resonance spectroscopy and, for one of them, by X-ray crystallography (3,4-dibromo-5-phenyl-1H-pyrazole). When there is a bromine ato

Full text of DOI:10.1016/j.tet.2007.06.007

Tetrahedron 63 (2007) 8104–8111
Structure and tautomerism of 4-bromo substituted 1H-pyrazoles
Swiatoslav Trofimenko,a,! Glenn P. A. Yap,a Fernando A. Jove,a Rosa M. Claramunt,b,
*
b
M. Angeles Garcıa, M. Dolores Santa Maria, Ibon Alkorta and Jose Elguero
b
c
c
ꢀ
ꢀ
ꢀ
aDepartment of Chemistry and Biochemistry, University of Delaware, Newark, DE 19716, USA
bDepartamento de Quꢀımica Orgaꢀnica y Bioorgaꢀnica, Facultad de Ciencias, UNED, Senda del Rey, 9, E-28050 Madrid, Spain
c
´
Instituto de Quꢀımica Medica, CSIC, Juan de la Cierva, 3, E-28006 Madrid, Spain
Received 13 April 2007; revised 29 May 2007; accepted 2 June 2007
Available online 9 June 2007
Abstract—The tautomerism in the solid state and in solution of five 4-bromo-1H-pyrazoles has been studied by multinuclear magnetic
resonance spectroscopy and, for one of them, by X-ray crystallography (3,4-dibromo-5-phenyl-1H-pyrazole). When there is a bromine
atom at position 3(5), in all cases, the tautomer present in the solid state is the 3-bromo one. In solution, the same tautomer is the major
one. DFT calculations justify the predominance of 3-bromo tautomers over 5-bromo ones and provide some useful chemical shifts obtained
through GIAO calculations.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
described several times, including its X-ray structure (Re-
fcode: LIYGOP).13 It is interesting to briefly summarize
the structure and solid-state properties of 1 since this com-
pound can serve as a model for the remaining four ones.14–17
Compound 1 crystallizes in a tetramer formed by both tau-
tomers in a 1a1b1a1b disposition. The NH protons are
disordered and the situation corresponds to a mixture of
the two situations of Scheme 3. In general, the annular tau-
tomerism of 3(5)-substituted-NH-pyrazoles has been the
subject of many studies,18 but that concerning 3(5)-bromo-
1H-pyrazoles is still unreported and is the object of the pres-
ent paper to explore it.
3(5),4-Dibromopyrazoles unsubstituted at position 1 (NH-
pyrazoles), I, are prepared by the two traditional methods
represented in Scheme 1.1–3 From pyrazolinones II through
3(5)-bromo-1H-pyrazoles III or by perbromination of
pyrazoles IV. The first method we have used to prepare the
3(5)-methyl derivative I (R1¼CH3).4 The second one was
€
discovered by Huttel and co-workers and lead, when
R1¼H, to 3,4,5-tribromo-1H-pyrazole I (R1¼Br).5–9 This
last compound was used to prepare novel scorpionate
ligands devoid of C–H bonds.10
In search of new polybrominated pyrazoles useful in forming
complexes through the corresponding polypyrazolylborates,11
we describe here a series of five 4-bromopyrazoles 1–5
(Scheme 2). The present investigation ontautomerism of these
bromopyrazoles12 will provide general criteria to be used for
the establishment of polypyrazolylborates structure.
2. Results and discussion
2.1. X-ray molecular structure of 3,4-dibromo-5-phenyl-
1H-pyrazole (2a)
This compound crystallizes forming also a tetramer with S4
symmetry (see Fig. 2) as predicted by our model for pyra-
zoles bearing phenyl or bromo substituents at both positions
Of the five compounds in Scheme 2, 4-bromo-3(5)-methyl-
5(3)-phenyl-1H-pyrazole 1 is well known having been
Br
R1
R1
Br
R1
Br
R1
O
Br2
POBr3
Br2
N
N
N
N
N
N
N N
H
H
H
H
III
II
I
IV
Scheme 1. Synthesis of N-unsubstituted dibromopyrazoles.
Keywords: Bromopyrazoles; Tautomerism: X-ray structure; Solid-state NMR; DFT calculations; GIAO calculations.
* Corresponding author. E-mail: rclaramunt@ccia.uned.es
Dr. S. Trofimenko passed away on Monday, February 26, 2007.
!
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.06.007

S. Trofimenko et al. / Tetrahedron 63 (2007) 8104–8111
Br
8105
Br
Br
Br
H3C
Cl
Br
Br
H3C
Br
N
N
N
N
N N
N
N
H
H
H
H
H
2a
1a
3a
4a
Br
Br
Br
1, R1 = C6H5, R2 = CH3
2, R1 = Br, R2 = C6H5
t
R2
R1
R2
R1
Bu
Br
3, R1 = Br, R2 = C6H4CH3(p)
4, R1 = Br, R2 = C6H4Cl(p)
N
N N
N
N
N
H
H
5, R1 = Br, R2 = Bu
t
b
a
5a
Scheme 2. The five pyrazoles of the present study and their tautomerism.
Br
Br
H3C
H3C
N
N
N
N
H
1b
1a
H
H3C
H3C
H
1a
H
1b
N
N
N
N
N
N
N
N
1b
1a
Br
Br
Br
CH3
Br
CH3
H
H
1a
H
H
1b
N
N
N
N
CH3
CH3
Br
Br
Scheme 3. The tautomerism of 4-bromo-3(5)-methyl-5(3)-phenyl-1H-pyrazole 1 in the solid state.
3and5.15,17 Thetautomerpresentis2a(Fig.1). Thisisthesec-
ond example of a 3(5)-bromo-1H-pyrazole whose structure
has been determined. The other example, also a 3-bromo tau-
tomer, has the dimeric azo structure 6 (Refcode: WEJHOI).13
thereby diminishing the accessible surface to the nitrogen
atoms involved in the hydrogen bonds.17 The sum of the mo-
lar refractivities, MR, of the substituents in positions 3 and 5
allows to predict the secondary structure:15 less than 2.6 for
trimers and catemers and larger than 2.6 for dimers and tetra-
mers (taking into account the 4-bromo buttressing effect).17
The data of Scheme 4 are in agreement with this rule.
H
Het
N
N
Br
N
N
Br
N
N
2.2. NMR study in the solid state (CPMAS)
Het
H
6 (WEJHOI)
We have reported in Table 1 the 13C and 15N NMR data con-
cerning compounds 1–5 in solution and in the solid state. We
will first discuss the solid-state results because in crystals
most pyrazoles exist as a single tautomer (100% of a or
A search in the CSD13 for 4-bromo-1H-pyrazoles yields the
structures reported in Scheme 4.
It has been shown that the secondary structure of NH-pyra-
zoles corresponds to two main structural motives: trimers
and catemers for small substituents at positions 3 and 5 and
dimers and tetramers for large substituents at positions 3
and 5.15–17 The substituent at position 4 increases the appar-
ent size of substituents R3 and R5 by a buttressing effect
Figure 1. A view of 3,4-dibromo-5-phenyl-1H-pyrazole (2a).
Figure 2. A view of the tetramer (2a)4.

8106
S. Trofimenko et al. / Tetrahedron 63 (2007) 8104–8111
Br
Br
Br
Br
Br
t
t
1-Ad
Me
Me
Bu
Bu
Ph
N
N
N
N
N
N
N
N
N
N
H
H
H
H
H
8
7
9
10
11
FIWTIP
GOQXOZ
GOQXIT
XAHBUD
PAMTAY
(dimer): 3.90
(catemer): 1.12
(trimer): 0.20
(tetramer): 2.82
(trimer): 2.54
Br
Br
Br
Br
Br
Ph
Me
Ph
CO2Et
CO2Et
Ph
Me
CO2Et
CONH2
N
N
N
N
N
N
N
N
N
N
H
H
H
H
H
16
12
13
15
14
FAQTAS
FAQSUL
FAQTIA
MBCPAZ
(other: CONH2)
LADBEX
(catemer): 2.31
(catemer): 1.75
(tetramer): 4.29
(dimer): 5.08
Br
Br
Br
Ph
Ph
Ph
N
N
N
N
H
H
1
2a
------------
LIYGOP
(tetramer): 3.43
(tetramer): 3.10
Scheme 4. N–H/N hydrogen-bond motifs and sum of molar refractivities (SMR3,5)
15 of 4-bromo-1H-pyrazoles. The presence of a CONH2 substituent gives
rise to a different HB pattern.
100% of b), compound 1 being one of the rare exceptions al-
though there are exactly 50% of a and 50% of b. Assignments
are based on standard 2D techniques in solution (see Section
4) and comparison with other pyrazoles.19,20 Particularly
useful has been a paper of Holzer et al. describing many sim-
ple polybromo-substituted pyrazoles.21
substituent shifted the signal of the carbon where it is bonded
by about 20 ppm and it does not affect the opposite signal.19
We have calculated the expected chemical shifts for tauto-
mers 5a and 5b from those of 21 and 22, and since the effect
of the N-methylation is small,19 there is no doubt that the
tautomer present in the solid state is 5a.
The solid-state 13C NMR chemical shifts of compound 1,
a tetramer 1a1b1a1b, have been already reported.14 Here
we confirm the dynamic nature of the situation depicted in
Scheme 3: the solid-state proton transfer (SSPT) occurs
within the tetramer (the four C3 and C5 carbon atoms appear
at 142.7 ppm). The 15N signals are too far apart (ꢀ176 and
ꢀ98 ppm) for coalescence to occur at 300 K, and only
broadening is observed.
The 15N signals are in the expected range,20 some splittings
are observed (N2 of 4a, N1 and N2 of 5a) probably due to the
proximity of the bromine atoms. N2 atoms resonate at about
ꢀ95 ppm for 3a and 4a and about ꢀ103 ppm for 2a and 5a.
The first ones should be dimers (for 19, also a dimer,15a N2
appears at ꢀ90.5 ppm —Scheme 5) and the second ones tet-
ramers (see the X-ray structure of 2a) according to what we
had already found that in dimers the N2 signal is shifted
about 10 ppm.15b In 2a, 3a, and 4a such conclusions are sup-
ported by the differences in 15N chemical shifts, Dd for N2,
between solid state and solution15b,c the HB motifs have the
following values of Dd for N2: dimers around 8 ppm and tet-
ramers around 19 ppm. However, the Dd in 5a, about 12 ppm
is not so clear.
Since the X-ray structure has been determined and since
there is no polymorphism (we have used the same sample
for crystallography—Fig. 1—and CPMAS NMR) the solid-
state chemical shifts of pyrazole 2 must correspond to
tautomer 2a. To demonstrate that all the other 3(5)-bromo-
1H-pyrazoles are also a tautomers, we need to examine the
data summarized in Scheme 5.
2.3. NMR study in solution and the problem of tauto-
merism of bromo-1H-pyrazoles
The 13C signals of compounds 2–5 are neither splitted (two
tautomers) nor broad (save the carbon atoms linked to
the bromine) thereby excluding an SSPT as found in 1.
Therefore, only one tautomer is present and by internal
comparison, if 2 is a 3-Br tautomer so are the other aryl
derivatives, 3 and 4. A comparison with 4-bromo-3,5-
diphenyl-1H-pyrazole 19 confirms that signals at 137–
140 ppm correspond to a C5-aryl atom. The signal of
C3–Br has not been observed for pyrazoles 2–4, they are ex-
pected at about 127 ppm (see 20 and 22 in Scheme 5) and are
probably under the signals of the 5-aryl substituent. If they
were 5-bromo derivatives, the C–Br signal would appear
near 115 ppm (see 21 and 22 in Scheme 5), a zone devoid
of interferences where nothing was observed. A tert-butyl
Integration in 1H NMR (see Section 4) shows that compound
1 in DMSO-d6 at 300 K is a mixture of 75% 1a–25% 1b while
in THF-d8 at 191 K it is 65% 1a–35% 1b. For the remaining
pyrazoles, only one series of signals is observed in DMSO-d6
at 300 K and in THF-d8 at 200 K. Therefore, only a tautomer
is present in solution or, at least, very predominant. By simple
comparison with the CPMAS data, the conclusion that all
of them are 3-bromo derivatives a prevails. The rule that
the most abundant tautomer in solution coincides with that
found in the crystal is again verified.18,22
Even that from the 13C NMR chemical shifts and the
gs-HMQC and gs-HMBC spectra there is no doubt about

S. Trofimenko et al. / Tetrahedron 63 (2007) 8104–8111
8107
Table 1. 13C and 15N chemical shifts (d, ppm) of pyrazoles 1–5 (THF-d8, DMSO-d6, and CPMAS) and 1J (15N–1H) in hertz
Compd Solv.
Taut. C3
C4–Br C5
Substituent
N(H)1
N2
ꢀ89.6
1
1
1
THF, 191 K
a
C–Ph: 148.4 91.5
C–Me: 139.8 Ph: 134.2 (ipso), 127.9 (ortho), 129.2 ꢀ180.3,
(meta), 130.0 (para); 10.3 (5-Me)
3-Me: 13.0; Ph: 129.7 (ipso), 127.6
(ortho), 128.7 (meta), 130.0 (para)
1J¼ꢀ106.1
b
C–Me: 148.8 92.4
C–Ph: 140.3
ꢀ186.1,
ꢀ87.1
1J¼ꢀ107.7
DMSO, 300 K
CPMAS, 300 K
a
C–Ph: 147.1 90.4
C–Me: 147.2 91.4
C–Me: 138.8 Ph: 132.7 (ipso), 126.9 (ortho), 128.4
(meta), 127.8 (para); 9.8 (5-Me)
C–Ph: 139.0
b
3-Me: 12.2; Ph: 128.4 (ipso), 126.9
(ortho), 128.8 (meta), 128.7 (para)
a
C–Ph: 142.7 83.8
C–Me: 142.7 Ph: 130.5 (ipso), 125.7 (ortho), 127.3 ꢀ176
ꢀ98
(vbr s)
C–Me: 142.7 83.8
(vbr s) (vbr s) (meta), 127.3 (para); 5-Me: 10.5;
3-Me: 11.7; Ph: 130.5 (ipso), 125.7
(ortho), 127.3 (meta), 127.3 (para)
b
C–Ph: 142.7
(vbr s)
(vbr s) (vbr s)
2
2
2
DMSO, 300 K
THF, 219 K
a
a
a
C–Br: nd
93.5
C–Ph: 141.6
C–Ph: 142.5
C–Ph: 140.1
Ph: 127.1 (ipso), 127.1 (ortho), 128.9
(meta), 129.4 (para)
C–Br: 130.6 94.8
Ph: 129.2 (ipso), 128.0 (ortho), 130.1 ꢀ177.7,
ꢀ83.8
(meta), 130.4 (para)
Ph: 126.1 (ipso), 126.1 (ortho), 129.1 ꢀ175.9
(meta), 129.1 (para)
1J¼106.1
CPMAS, 300 K
C–Br: nd
C–Br: nd
93.9
(vbr s)
ꢀ102.0
3
3
3
DMSO, 300 K
THF, 200 K
a
a
a
93.2
C–p-MePh:
141.6
C–p-MePh:
142.4
C–p-MePh:
p-MePh: 125.0 (ipso), 127.0 (ortho),
129.4 (meta), 139.0 (para), Me: 20.8
p-MePh: 126.3 (ipso), 127.9 (ortho), ꢀ179.9,
130.7 (meta), 140.4 (para), Me: 21.6 1J¼104.6
p-MePh: 122.9 (ipso), 124.5 (ortho), ꢀ177.4
129.2 (meta), 138.6 (para), Me: 22.4
C–Br: 130.6 94.4
C–Br: nd 89.6
ꢀ86.5
ꢀ95.0
CPMAS, 300 K
(vbr s) 138.6
4
4
4
4
THF, 300 K
a
a
a
a
C–Br: 130.6 C–Br: C–p-ClPh:
95.2 141.8
C–Br: 130.7 C–Br: C–p-ClPh:
95.2 141.4
C–Br: C–p-ClPh:
p-ClPh: 128.2 (ipso), 129.7 (ortho),
130.1 (meta), 136.0 (para)
p-ClPh: 127.9 (ipso), 129.8 (ortho),
130.3 (meta), 135.9 (para)
p-ClPh: 126.9 (ipso), 128.9 (ortho),
129.0 (meta), 134.1 (para)
p-ClPh: 125.0 (ipso), 129.4 (ortho),
127.2 (meta), 132.7 (para)
THF, 219 K
ꢀ177.3,
ꢀ83.2
1J¼ꢀ105.3
DMSO, 300 K
CPMAS 300 K
C–Br: nd
C–Br: nd
93.9
95.5
140.8
C–p-ClPh:
ꢀ176.2
ꢀ93.4, –95.0
ꢀ89.9
(vbr s) 137.5
5
5
THF, 300 K
THF, 200 K
a
a
C–Br: 130.5 93.3
C–Br: 130.7 93.3
C–t-Bu: 150.7 t-Bu: 33.2 (C), 28.7 (Me)
C–t-Bu: 149.8 t-Bu: 33.0 (C), 28.1 (Me)
ꢀ177.9,
1J¼ꢀ105.2
5
5
DMSO, 300 K
CPMAS, 300 K
a
a
C–Br: nd
C–Br: 124.5 89.1
(vbr s) (vbr s)
91.7
C–t-Bu: 149.8 t-Bu: 32.0 (C), 28.1 (Me)
C–t-Bu: 150.8 t-Bu: 32.9 (C), 27.6, 28.1, 28.4,
29.1 (Me)
ꢀ169.3, ꢀ170.3, ꢀ101.4, ꢀ102.3,
ꢀ171.3, ꢀ172.0 ꢀ102.9, ꢀ103.7
vbr s¼very broad signal; nd¼not detected.
88.0
n.o.
Br
the structure of the most predominant tautomer in each case,
we decided to confirm it by doing some NOESY
experiments. These experiments show a NOE effect
between the NH and the ortho-aryl or the tert-butyl pro-
tons for each studied compound. In Figure 3 we have
Br
107.0
CH3
H3C
138.7
–90.5
128.8
N
N
N
N
N
N
142.3
138.1
148.3
–90.5
145.7
H
H
H
–99.6
–174.7
–174.6
–167.8
19,20
19,20
19,20
19
(Solid state)
18
(Solid state)
17
(Solid state)
(ppm)
NH
7.00
Hmeta
99.3
Br
95.8
131.7
96.1
Br
Br
Hortho
8.00
Br
127.5
Br
127.0
Br
116.6
Br
139.6
115.1
N
N
N
N
N
N
9.00
H3C
H3C
H3C
21
21
21
21
20
22
10.00
11.00
12.00
(CDCl3)
(CDCl3)
(CDCl3)
131.7 +
20 =
~152
t
Br
Br
t
Bu
Bu
Br
127.0
Br
139.6 + 20 = ~160
N
115.1
N
N
N
(ppm)
13.00
12.00
11.00
10.00
9.00
8.00
7.00
H3C
H3C
5b
5a
Figure 3. NOESY spectrum at 300 K of 3(5),4-dibromo-5(3)-p-tolyl-1H-
pyrazole (3).
Scheme 5. 13C and 15N chemical shifts of related pyrazoles.

8108
S. Trofimenko et al. / Tetrahedron 63 (2007) 8104–8111
reproduced the NOESY spectrum of compound 3 as an
example.
4. Experimental
4.1. General
2.4. Computational study
The starting pyrazoles 3(5)-methyl-5(3)-phenyl-1H-pyra-
zole,24,25 3(5)-p-chlorophenyl-1H-pyrazole,26 3(5)-phenyl-
1H-pyrazole,24,27 3(5)-p-tolyl-1H-pyrazole,28 and 3(5)-tert-
butyl-1H-pyrazole27,29,30 were prepared by the literature
methods. Melting points were determined with a Thermo-
Galen hot stage microscope and are given uncorrected.
We have carried DFT calculations at the B3LYP/
6-311++G** level of the energies (Table 2) and absolute
shieldings (Table 3) of a series of simple bromo-1H-
pyrazoles including the effect of DMSO solvent as a contin-
uum (PCM).
4.2. 4-Monobromination of 3-substituted pyrazoles
Table 2. Energetic results, absolute values in hartree and relative values in
kJ molꢀ1
The pyrazole was dissolved in methanol, and few drops of
concentrated hydrochloric acid were added. This was fol-
lowed by the dropwise addition of 1 equiv of bromine. After
the addition was complete, the solution was stirred for 1 h,
and was then poured into a large amount of water with ex-
cess ammonia. The precipitated solid was filtered off, and
extracted with methylene chloride. The extracts were filtered
through a short layer of alumina, and the filtrate was evapo-
rated to dryness. Further purification was via recrystalliza-
tion from toluene/heptane.
Pyrazole
Vacuum
Erel
PCM-DMSO
Erel
17
3-Bromo
5-Bromo
3,4-Dibromo
4,5-Dibromo
3,4,5-Tribromo
ꢀ226.2660
ꢀ2799.8057
ꢀ2799.8040
ꢀ5373.3412
ꢀ5373.3403
ꢀ7946.8773
—
ꢀ226.2785
ꢀ2799.8190
ꢀ2799.8149
ꢀ5373.3542
ꢀ5373.3506
ꢀ7946.8874
—
0.00
10.83
0.00
9.38
—
0.00
4.43
0.00
2.53
—
Table 3. Calculated NMR chemical shifts (d13C¼174.0ꢀ0.941 s13C ꢀ17.6;
4.2.1. 4-Bromo-3(5)-methyl-5(3)-phenyl-1H-pyrazole (1).
Yield 91%, mp 106–108 ꢁC. Lit. mp 97 ꢁC.22 Calcd for
C10H9BrN2: C 50.6; H 3.8; N 11.8%. Found: C 50.3; H
4.0; N 11.6%. NMR (d, ppm): THF-d8 191 K, 1a (65%) 2.30
d
15N¼ꢀ141.7ꢀ0.978 s15N)
Pyrazole
C-3
C-4
C-5
N-1
N-2
3
3
17
3-Bromo
5-Bromo
3,4-Dibromo
4,5-Dibromo
3,4,5-Tribromo
138.2
125.5
140.0
126.6
140.9
128.3
104.5
108.0
108.6
96.6
96.7
98.8
128.1
130.4
112.4
131.7
114.0
116.3
ꢀ173.1
ꢀ173.7
ꢀ168.7
ꢀ174.4
ꢀ168.8
ꢀ170.2
ꢀ79.8
ꢀ79.4
ꢀ72.2
ꢀ76.6
ꢀ71.6
ꢀ72.1
(CH3), 7.92 (ortho, J¼7.4 Hz), 7.42 (meta, J¼7.4 Hz),
7.33 (para, 3J¼7.3 Hz), 12.67 (NH); 1b (35%) 2.22 (CH3),
7.75 (ortho, 3J¼7.5 Hz), 7.53 (meta, 3J¼7.5 Hz), 7.44
(para, 3J¼7.0 Hz), 12.77 (NH); DMSO-d6 300 K, 1a
3
(75%) 2.24 (CH3), 7.77 (ortho, J¼7.4 Hz), 7.43 (meta),
7.35 (para), 13.13 (NH); 1b (25%) 2.18 (CH3), 7.70 (ortho,
3J¼6.5 Hz), 7.48 (meta), 7.41 (para), 13.24 (NH).
It appears that the 3-bromo tautomers are more stable than
the 5-bromo ones and that the predominance increases con-
siderably in DMSO.
4.3. 4,5-Dibromination of 3-substituted pyrazoles
The appropriate pyrazole was dissolved in methanol, con-
taining 3 equiv of sodium hydroxide. Two equivalents of
bromine were slowly added dropwise to this solution. After
completion of the addition, the solution was stirred for
another hour, and was then added slowly to a large amount
water, containing excess hydrochloric acid. The precipitated
product was filtered off, and was partially air-dried. It was
then taken up in ethyl acetate, which allowed for the separa-
tion of the remaining aqueous layer. The organic phase was
passed through a short layer of alumina, and the elute was
evaporated to dryness.
We have calculated (GIAO/B3LYP/6-311++G**) the abso-
lute shieldings of the six NH-pyrazoles in Table 2 both invac-
uum and in DMSO (PCM model). We have transformed these
s into chemical shifts using linear equations and some exper-
imental values from Refs. 19–21. The intercepts should be
similar to the references: for 13C, sTMS¼184.7 ppm and
for 15N, sMeNO2¼ꢀ154.4 ppm at the same level). In the
case of carbon atoms bearing a Br substituent we have had
to include a correction of ꢀ17.6 ppm (statistically calcu-
lated) to fit the experimental values. We have already noted
that calculations at the level used are unable to reproduce
CBr atoms.23
4.3.1. 3(5),4-Dibromo-5(3)-phenyl-1H-pyrazole (2). Yield
83%, mp 130–132 ꢁC. Calcd for C9H6Br2N2: C 35.7; H 1.99;
N 9.27%. Found: C 35.5; H 2.05; N 9.02%. NMR (d, ppm):
DMSO-d6 300 K, 7.72 (ortho, 3J¼7.1 Hz), 7.54 (meta,
The predicted 15N chemical shifts for the 3,4-dibromo deriv-
ative are similar to those found in THF-d8 at low temperature
for 4a (219 K) and 5a (200 K).
3
3J¼7.3 Hz), 7.48 (para, J¼7.2 Hz), 13.94 (NH); THF-d8
3
3
300 K, 7.72 (ortho, J¼6.8 Hz), 7.48 (meta, J¼7.3 Hz),
3
7.42 (para, J¼7.1 Hz), 12.83 (NH); THF-d8 219 K, 7.76
(ortho, 3J¼7.3 Hz), 7.55 (meta, 3J¼7.5 Hz), 7.48 (para,
3. Conclusions
3J¼7.4 Hz), 13.26 (NH).
As a general and useful rule it can be stated that 3(5),4-di-
bromo-1H-pyrazoles crystallize as 3,4-dibromo tautomers,
the same forms that predominate in solution.
4.3.2. 3(5),4-Dibromo-5(3)-p-tolyl-1H-pyrazole (3). Yield
76%, mp 171–173 ꢁC. Calcd for C10H8Br2N2: C 38.0; H
2.53; N 8.86. Found: C 37.7; H 2.71; N 8.67%. NMR (d,

S. Trofimenko et al. / Tetrahedron 63 (2007) 8104–8111
8109
ppm): DMSO-d6 300 K, 7.61 (ortho, 3J¼8.1 Hz), 7.33
40.56 MHz for 15N) spectrometer with a 5-mm inverse-
detection H-X probe equipped with a z-gradient coil. Chem-
ical shifts (d in ppm) are given from internal solvents,
(meta, 3J¼8.1 Hz), 2.36 (CH3), 13.90 (NH); THF-d8
3
3
300 K, 7.61 (ortho, J¼7.8 Hz), 7.30 (meta, J¼7.9 Hz),
3
1
2.38 (CH3), 12.79 (NH); THF-d8 200 K, 7.66 (ortho, J¼
DMSO-d6 2.49 for H and 39.5 for 13C, THF-d8 3.58 for
8.1 Hz), 7.38 (meta, 3J¼8.1 Hz), 2.40 (CH3), 13.27 (NH).
1H and 67.6 for 13C, and for 15N, nitromethane (0.00) was
used as an external reference. Typical parameters for
1H NMR spectra were spectral width 5050–6265 Hz, pulse
width 7.5 ms and resolution 0.31–0.38 Hz per point. Typical
parameters for 13C NMR spectra were spectral width
20,576 Hz, pulse width 10.6 ms and resolution 0.63 Hz per
point; WALTZ-16 was used for broadband proton decou-
pling; the FIDS were multiplied by an exponential weighting
(lb¼1 Hz) before Fourier transformation. NOESY spectra
were acquiredat 300 K in the phase-sensitivemodewith mix-
ing times of 0.9–1.4 s. Inverse proton detected heteronuclear
shift correlation spectra, (1H–13C) gs-HMQC, (1H–13C)
gs-HMBC, and (1H–15N) gs-HMBC, were acquired and
processed using standard Bruker NMR software and in non-
phase-sensitive mode and were carried out to assign the 1H,
13C and 15N signals. Gradient selection was achieved through
a 5% sine truncated shaped pulse gradient of 1 ms. Variable
temperature: a Bruker BVT3000 temperature unit was used
to control thetemperature and an exchanger to reachlow tem-
peratures. To avoid problems at low temperatures caused by
air moisture, pure nitrogen was used as cooling gas stream.
4.3.3. 3(5),4-Dibromo-5(3)-p-chlorophenyl-1H-pyrazole
(4). Yield 85%, mp 200–202 ꢁC. Calcd for C9H5Br2ClN2:
C 32.1; H 1.5; N 8.31. Found: C 31.8; H 1.7; N 8.03%.
NMR (d, ppm): CDCl3 300 K, 7.62 (ortho, 3J¼8.6 Hz,
4
4J¼1.8 Hz), 7.47 (meta, J¼1.8 Hz), 10.85 (NH); THF-d8
300 K, 7.74 (ortho, 3J¼8.6 Hz, 4J¼2.2 Hz), 7.52 (meta,
4J¼2.2 Hz), 12.93 (NH); THF-d8 200 K, 7.80 (ortho,
3
3J¼8.6 Hz), 7.33 (meta, J¼8.1 Hz), 13.90 (NH); DMSO-
3
4
d6 300 K, 7.75 (ortho, J¼8.6 Hz, J¼2.2 Hz), 7.62 (meta,
4J¼2.2 Hz), 14.02 (NH).
4.3.4. 3(5),4-Dibromo-5(3)-tert-butyl-1H-pyrazole (5).
Yield 74%, mp 225–226 ꢁC. Calcd for C7H10Br2N2: C
29.82; H 3.57; N 9.93%. Found: C 29.5; H 3.82; N 9.58%.
NMR (d, ppm): THF-d8 300 K, 1.40 (t-Bu), 12.23 (NH);
THF-d8 200 K, 1.40 (t-Bu), 12.63 (NH); DMSO-d6 300 K,
1.34 (t-Bu), 13.14 (NH).
4.4. X-ray crystallographic analysis
A crystal was selected and mounted on a glass fiber with ep-
oxy cement. Diffraction data were collected on a Bruker-
AXS APEX CCD diffractometer with Mo Ka radiation
4.5.2. Solid state. 13C (100.73 MHz) and 15N (40.60 MHz)
CPMAS NMR spectra were obtained on a Bruker WB 400
spectrometer at 300 K using a 4-mm DVT probehead. Sam-
ples were carefully packed in a 4-mm diameter cylindrical
zirconia rotor with Kel-F end-caps. Operating conditions in-
volved 3.2 ms 90ꢁ 1H pulses and decoupling field strength of
78.1 kHz by TPPM sequence. 13C spectra were originally
referenced to a glycine sample and then the chemical shifts
were recalculated to the Me4Si (for the carbonyl atom d
(glycine)¼176.1 ppm) and 15N spectra to 15NH4Cl and
then converted to nitromethane scale using the relation-
ship: d 15N(nitromethane)¼d 15N(ammonium chloride)—
338.1 ppm. The typical acquisition parameters for 13C
CPMAS were: spectral width, 40 kHz; recycle delay, 5 s
for 5, 35 s for 3, and 60 s for 1, 2, and 4; acquisition time,
30 ms; contact time, 2 ms; and spin rate, 12 kHz. In order
to distinguish protonated and unprotonated carbon atoms,
the NQS (Non-Quaternary Suppression) experiment by con-
ventional cross-polarization was recorded; before the acqui-
sition the decoupler is switched off for a very short time
period of 25 ms. And for 15N CPMAS were: spectral width,
40 kHz; recycle delay, 5 s for 5, 35 s for 3, and 60 s for 1,
2, and 4; acquisition time, 35 ms; contact time, 7 ms; and
spin rate, 6 kHz.
˚
(l¼0.71073 A). The data-set was treated with SADABS
absorption correction Tmin/Tmax¼0.4031. Unit-cell para-
˚
˚
meters, tetragonal, a¼9.6515(10) A, c¼21.725(5) A, V¼
3
˚
2023.8(5) A , were determined by sampling three different
sections of the Ewald sphere. The unit-cell parameters and
systematic absences in the diffraction data were uniquely
consistent for the reported space group P-421c (no. 114).
The structure was solved by direct methods and completed
by difference Fourier synthesis. The absolute structure pa-
rameter refined to nil indicating that the true hand of the
data was determined. All non-hydrogen atoms were refined
with anisotropic displacement parameters. The hydrogen
atom H1 was located from the difference map and refined
with an isotropic parameter constrained as 0.20 Ueq of the
nitrogen atom N1. The phenyl hydrogen atoms were treated
as idealized contributions. Structure factors and anomalous
dispersion coefficients are contained in SHELXTL 6.12 pro-
gram library (G. Sheldrick, 2001; Siemens XRD, Madison,
WI). Selected data: C9H6Br2N2, M¼301.98, T¼298(2) K,
Z¼8, Dcalcd¼1.982 g/cm3, m¼7.964 mmꢀ1, F(000)¼1152,
reflections collected¼22,137, unique reflections¼2455,
Rint¼0.0511, refined parameters¼122, GoF (F2)¼1.040,
R1[I>2s]¼0.0485, wR2 (all data)¼0.1080. The supplemen-
tary crystallographic data for this paper have been deposited
under reference number CCDC 640197. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/conts/
retrieving.html; or from the Cambridge Crystallographic
Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK;
fax: +44 1223 336033; or deposit@ccdc.cam.ac.uk.
4.6. Theoretical calculations
All calculations were carried out using the B3LYP hybrid
functional31 with geometry optimization and frequencies
at the B3LYP/6-31G*32 level and a further optimization at
the B3LYP/6-311++G** level.33 Frequency analyses were
carried out at the same level used in the geometry optimiza-
tions, and the nature of the stationary points was determined
in each case according to the appropriate number of negative
eigenvalues of the Hessian matrix. DMSO solvent effects
were taken into account throughout this study using the
polarized continuum model (PCM)34 as implemented in
4.5. NMR measurements
4.5.1. Solution. The spectra were recorded on a Bruker DRX
1
400 (9.4 T, 400.13 MHz for H, 100.62 MHz for 13C and

8110
S. Trofimenko et al. / Tetrahedron 63 (2007) 8104–8111
Gaussian 03.35 Using the B3LYP/6-311++G** optimized
geometries, we have calculated the GIAO absolute shield-
ings (see Supplementary data).36
ꢀ
Samat, A.; Loshkin, V.; Vales, M.; Elguero, J. J. Org. Chem.
2006, 71, 6881–6891.
16. Fayos, J.; Infantes, L.; Cano, F. H. Cryst. Growth. Des. 2005, 5,
191–200.
17. Alkorta, I.; Elguero, J.; Foces-Foces, C.; Infantes, L. ARKIVOC
2006, ii, 15–30.
Acknowledgements
18. Minkin, V. I.; Garnowskii, A. D.; Elguero, J.; Katritzky, A. R.;
Denisko, O. V. Adv. Heterocycl. Chem. 2000, 76, 157–323.
19. Begtrup, M.; Boyer, G.; Cabildo, P.; Cativiela, C.; Claramunt,
This work was supported by DGES/MEyC (BQU2003-
01251 and CTQ2006-02586 and CTQ2006-14487-C02-01)
of Spain. One of us (M.A.G.) is indebted to MEyC-
UNED-BRUKER ESPANOLA S. A. for a postdoctoral con-
tract.
˜
ꢀ
R. M.; Elguero, J.; Garcıa, J. I.; Toiron, C.; Vedsø, P. Magn.
Reson. Chem. 1993, 31, 107–168.
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Supplementary data
€
21. Holzer, W.; Jager, C.; Slatin, C. Heterocycles 1994, 38,
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Supplementary data associated with this article can be found
in the online version, at doi:10.1016/j.tet.2007.06.007.
22. Trofimenko, S.; Rheingold, A. L.; Liable-Sands, L. M.;
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