A molecular balance to measure the strength of N-H?π hydrogen bonds?based on the tautomeric equilibria of C-benzylphenyl substituted NH-pyrazoles

Article abstract of DOI:10.1016/j.tet.2008.02.026

A theoretical (B3LYP/6-31G^**) study of 30 pyrazoles, most of them existing in two tautomeric forms, has been carried out. 3(5)-(2-Benzylphenyl)-5(3)-methyl-1H-pyrazole (11) and 3(5)-(2-benzylbenzylphenyl)-5(3)-phenyl-1H-pyrazole (20) were synth

Full text of DOI:10.1016/j.tet.2008.02.026

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Tetrahedron 64 (2008) 3667e3673
www.elsevier.com/locate/tet
A molecular balance to measure the strength of NeH/p hydrogen
bonds based on the tautomeric equilibria of C-benzylphenyl
substituted NH-pyrazoles
a
a
b,
Pilar Cornago a, , Rosa M. Claramunt , Latifa Bouissane , Jose Elguero
*
*
´
a Departamento de Qu´ımica Orga´nica y Bio-Orga´nica, Facultad de Ciencias, UNED, Senda del Rey 9, E-28040 Madrid, Spain
b Instituto de Qu´ımica Me´dica, CSIC, Juan de la Cierva 3, E-28006 Madrid, Spain
Received 2 January 2008; accepted 8 February 2008
Available online 12 February 2008
Abstract
A theoretical (B3LYP/6-31G**) study of 30 pyrazoles, most of them existing in two tautomeric forms, has been carried out. 3(5)-(2-
Benzylphenyl)-5(3)-methyl-1H-pyrazole (11) and 3(5)-(2-benzylbenzylphenyl)-5(3)-phenyl-1H-pyrazole (20) were synthesized from 2-benzoyl-
acetophenone, and their annular tautomeric equilibrium determined. The substituent effects were statistically analyzed and discussed with the
help of Hammett substituent constants. In the case of the 5-(2-benzylphenyl) groups, the strength of the NeH/p hydrogen bond depends on the
electronic effect of the substituent at position 3.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Pyrazoles; Tautomerism; B3LYP/6-31G** calculations; Hydrogen bonds
1. Introduction
NeH/p hydrogen bonds are of great importance in protein
folding. Thus in some proteins, Phe, Tyr, Trp, aminoacids have
p rings that show N/pm and H/pm distances less than or
We will report in this paper a DFT study of 30 3,5-disubsti-
tuted (including proton as a substituent) NH-pyrazoles 1e30
aimed at understanding the effect of substituents on the tauto-
meric equilibrium constant KT and to provide further insight
into a statement that we made in 2006. At that time, we proposed
that NH-pyrazoles bearing a 3(5)-benzylphenyl group (Scheme
1)1 should behave in a similar way to Wilcox torsion balance.2
Wilcox balance 31 measures the strength of C(sp3)eH/p
hydrogen bonds (HBs) present in 31a and absent in 31b. We
proposed that our balance should measure N(sp2)eH/p
HBs although it was built up on only one example, the trifluoro-
methyl derivative 24 represented in Scheme 1. We have now
decided to verify this assumption studying theoretically a large
series of tautomeric pyrazoles and determining the equilibrium
constant for two of them.
˚
equal to 4.3 and 3.5 A (pm represent the mid point of the
ring).3,4 NeH/p hydrogen bonds also are important for the
determination of crystal structures as Malone,5 Desiraju ,and
Steiner6 as well as Page and Rzepa have pointed out.7 There
have been a number of theoretical studies on NeH/p interac-
tions, including those of the preceding authors.7 For instance,
ammoniaebenzene complex was studied at MP2/CCSD(T)
level8,9 and N-methyl-formamide-benzene complex was stud-
ied as a prototypical peptide NeH/p hydrogen-bonded sys-
tem at the DFT and MP2 levels.10
2. Results and discussion
2.1. Synthesis
We have synthesized two benzylphenyl pyrazoles 11 and 20
following the procedure described in Scheme 2. b-Diketones
34 and 35 were obtained by Claisen condensation between
2-benzyl-acetophenone (33) (prepared from commercial 32)
* Corresponding authors. Tel.: þ34 913987323; fax: þ34 913988372 (P.C.);
tel.: þ34 914110874; fax: þ34 915644853 (J.E.).
E-mail addresses: mcornago@ccia.uned.es (P. Cornago), iqmbe17@iqm.
csic.es (J. Elguero).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.02.026

3668
P. Cornago et al. / Tetrahedron 64 (2008) 3667e3673
protons and the ortho protons H200 of the phenyl substituent,
F3C
F3C
respectively. For 3(5)-(2-benzylbenzylphenyl)-5(3)-phenyl-
1H-pyrazole (20), we have noted that increasing the concen-
tration from 10 to 30 mg in 0.5 mL of DMSO-d6 produces
an increase of the broadening and then a coalescence of the
signals indicating that the tautomerization barrier decreases
significantly.12
N
N
H
K
N
H
N
24b
O
24a
O
O
CH3
H3C
H3C
O
CH3
CH3
2.3. DFT calculation of the a/b equilibrium
K
CH3
In all we have determined the differences in energy (zero
point energy, ZPE, corrected) for 30 pyrazoles. When the sub-
stituents at positions 3 and 5 are identical (1, 8, 14, 19, 23, 26,
and 28) the difference in energy is 0.00 by definition and only
one tautomer has been calculated. The results in kJ molꢀ1 are
N
N
N
N
X
X
31b
31a
Scheme 1. Comparison of both balances.
R
R
3
5
4
4
O
O
O
O
1
6'
3'
2
6'
3'
N
1
H
6'
3'
N
2
H
1'
5'
4'
N
5'
4'
5
R
N
CO2H
CH3
3
5'
4'
c
b
2'
a
ipso
o
o
o
m
m
m
p
p
p
b
a
32
34, R = CH3
35, R = C6H5
33
11, R = CH3; 20, R = C6H5
Scheme 2. Reagents and conditions: (a) MeLi/Et2O; (b) RCO2Et, NaH, THF; (c) NH2NH2$H2O, EtOH.
and the corresponding ester. Finally, 3(5)-(2-benzylphenyl)-
5(3)-methyl-1H-pyrazole (11) and 3(5)-(2-benzylbenzylphenyl)-
5(3)-phenyl-1H-pyrazole (20) were formed by reacting 34 and
35 with 98% hydrazine hydrate.
reported in Scheme 3, the absolute values are given in the Sup-
plementary data.
In order to get the effect of the substituents on DH, we have
built up a matrix of presence/absence (also called Free-Wilson
matrix)13e15 containing all the principal terms (R3 and R5
effects) and all the product terms (R3*R5) (the matrix is in
the Supplementary data). The matrix is complete for the
six substituents CH3, CH2C6H5, C6H5, C6H4CH2C6H5, CF3,
and NO2 and corresponds to the following equation: DH¼
a1x1þa2x2þ.þa6x6þa11x1x1þa12x1x2þ.þa66x6x6. For the
Nþ2 derivatives, 29 and 30, only two equilibria were calculated,
but the fact that DH¼0 for 3,5-didiazoniumpyrazole was
included.
2.2. Determination of the a/b equilibrium in solution by NMR
We have reported in Table 1 the NMR results that we
obtained for pyrazoles 11, 20, and 24.1
The assignments were based on previous work on 1H,
13C, and 15N NMR studies of pyrazoles,11 as well as on 2D
experiments. Particularly useful to achieve such task have
been the correlations encountered between the C signals at
positions 3 and 5 of pyrazoles 11 and 20 with the methyl
A multiple regression (R2¼1.000) affords the coefficients
of Table 2.
Table 1
Tautomer percentages and 1H, 13C, and 15N NMR selected data of benzylphenyl pyrazoles
Pyrazole
Percentages
Solvent
H-4
H-1
C-3
C-4
C-5
143.3 (CMe)
N-1
N-2
11
a
CD2Cl2
6.11
6.14
6.01
6.91
6.80
6.53
6.69
6.58
11.69
13.70
13.74
13.48
13.15
10.60
13.79
14.65
149.6 (CPhBn)
105.8
103.7
104.6
102.5
102.5
103.9
103.5
103.5
c
90% of 11a
10% of 11b
52% of 20a
48% of 20b
>98% of 24a
>98% of 24a
>98% of 24a
HMPA-d18
HMPA-d18
DMSO-d6
DMSO-d6
CDCl3
151.2 (CPhBn)
146.8 (CMe)
151.6 (CPhBn)
150.6 (CPh)
143.4
138.4 (CMe)
141.8 (CPhBn)
143.2 (CPh)
143.2 (CPhBn)
143.8
ꢀ175.1
a
ꢀ171.4
ꢀ82.4
c
c
20
b
c
c
241
b
DMSO-d6
HMPA-d18
141.3
141.7
142.9
143.5
ꢀ163.9
ꢀ80.3
a
263 K.
300 K.
Not detected.
b
c

P. Cornago et al. / Tetrahedron 64 (2008) 3667e3673
3669
PhH2C
C6H5
H3C
N
N
N
N
N
N
N
N
CH3
C6H5
CH2Ph
N
H
N
H
N
H
N
H
N
H
N
H
N
H
N
H
4a
1a
2b
3a
1b
4b
2a
3b
0.00
0.00
0.37
0.20
0.00
1.26
0.00
0.00
PhH2CC6H4
N
F3C
O2N
N
N
N
N
N
C6H4CH2Ph
CF3
NO2
N
H
5b
N
H
6b
N
H
7b
N
H
N
H
N
H
7a
6a
5a
0.00
5.70
0.00
2.51
2.48
0.00
H3C
H3C
PhH2C
N
H3C
C6H5
N
H3C
N
N
N
N
CH3
CH3
CH3
CH2Ph
CH3
C6H5
N
H
N
H
N
H
N
H
N
N
H
H
10a
8b
8a
9a
9b
10b
0.00
0.00
0.22
0.00
1.63
0.00
O2N
PhH2CC6H4
N
F3C
H3C
H3C
H3C
N
N
N
N
N
CH3
NO2
CH3
CH3
C6H4CH2Ph
CF3
N
H
13a
N
H
N
H
N
H
N
H
N
H
12a
11a
13b
11b
12b
0.00
2.00
5.54
0.00
0.00
2.46
PhH2C
PhH2C
C6H5
N
PhH2C
PhH2CC6H4
PhH2C
N
N
N
N
N
CH2Ph
CH2Ph
CH2Ph
C6H5
CH2Ph
C6H4CH2Ph
N
H
N
H
N
H
N
H
N
N
H
H
16a
14a
15a
16b
14b
15b
0.00
2.36
5.60
0.00
0.00
0.00
PhH2C
C6H5
C6H5
N
F3C
O2N
PhH2C
N
N
N
N
N
NO2
C6H5
C6H5
CH2Ph
CH2Ph
CF3
N
H
N
H
N
H
N
H
N
H
N
H
17a
19a
18a
18b
19b
17b
0.00
PhH2CC6H4
0.00
0.00
5.21
0.00
4.82
C6H5
O2N
C6H5
N
C
C6H5
F3
N
N
N
N
N
CF3
C6H5
C6H4CH2Ph
C6H5
C6H5
NO2
N
H
N
H
N
H
N
H
N
H
N
H
21b
22a
20a
20b
21a
22b
2.42
2.68
6.71
0.00
0.00
0.00
PhH2CC6H4
PhH2CC6H4
O2N
PhH2CC6H4
F3C
PhH2CC6H4
N
N
N
N
N
N
CF3
C6H4CH2Ph
C6H4CH2Ph
C6H4CH2Ph
C6H4CH2Ph
NO2
N
H
N
H
N
H
N
H
N
H
N
H
25a
23a
24b
23b
24a
25b
0.00
12.63
0.00
0.00
0.00
8.81
F3C
F3C
N
O2N
N
F3C
O2N
O2N
N
N
N
N
N
N
N
H
26a
CF3
NO2
NO2
CF3
CF3
NO2
N
H
N
H
N
H
H
H
27a
26b
27b
28a
28b
4.95
0.00
0.00
0.00
0.00
0.00
+N2
N
PhH2CC6H4
N
+N2
N
+
N
+
N2
N2
C6H4CH2Ph
N
H
N
N
H
N
H
H
29a
29b
30a
30b
0.00
42.40
0.00
64.62
Scheme 3. The 30 studied pyrazoles.

3670
P. Cornago et al. / Tetrahedron 64 (2008) 3667e3673
Table 2
Contributions of the different terms (in kJ molꢀ1
Table 3
Interaction terms with the 5-phenylbenzyl substituent (in kJ molꢀ1
)
)
3-Me
5-Bn
0.37 5-Me
0.20 3-Ph
ꢀ0.37 3-Bn
ꢀ0.20
ꢀ1.18
2.51
Subs. Term
sp
Subs. Term
sp
Subs. Term sp
1.22 5-Ph
5.66 3-CF3
H
0.00
0.00 Me
ꢀ0.53 ꢀ0.12
Bn
0.10
4.42
ꢀ0.06
3-PhBn
5-CF3
3-Nþ2
3-Me/5-Me
ꢀ5.62 5-PhBn
ꢀ2.51 3-NO2
42.40 5-Nþ2
Ph
NO2
a
ꢀ0.25 ꢀ0.03 PhBn ꢀ0.08 ꢀ0.07a CF3
0.54
ꢀ2.48 5-NO2
0.00
2.48
5.59
0.78 Nþ2
16.52
1.91b
sp of p-tolyl.
sp value determined only once.16
0.00 3-Me/5-Bn
ꢀ0.35 3-Me/5-Ph
ꢀ0.32 3-Me/5-NO2
0.00 3-Bn/5-Ph
ꢀ2.11 3-Bn/5-NO2
ꢀ3.29 3-Ph/5-Ph
ꢀ1.17 3-Ph/5-NO2
2.44
ꢀ0.85
3.21
b
3-Me/5-PhBn ꢀ0.53 3-Me/5-CF3
3-Bn/5-Me
3-Bn/5-PhBn
3-Ph/5-Me
0.35 3-Bn/5-Bn
0.10 3-Bn/5-CF3
ꢀ2.52 3-Ph/5-Bn
ꢀ0.25 3-Ph/5-CF3
0.45 3-PhBn/5-Bn
2.3.1. Analysis of the eight principal effects
2.93
ꢀ0.08
ꢀ1.06
The principal effects should be identical or statistically very
similar for the positions 3 and 5 in order to have DH¼
0 kJ molꢀ1 when they are the same. This is what happens in
Table 2, so they can be averaged: H¼0.00, Me¼0.37, Bn¼
ꢀ0.20, Ph¼1.22, PhBn¼ꢀ5.62, CF3¼2.51, NO2¼ꢀ2.48,
3-Ph/5-PhBn
3-PhBn/5-Me
ꢀ0.18 3-PhBn/5-PhBn ꢀ0.08
3-PhBn/5-CF3 ꢀ4.50 3-PhBn/5-NO2
ꢀ5.67 3-CF3/5-Me
1.09 3-CF3/5-PhBn
ꢀ0.04 3-NO2/5-Me
0.98 3-NO2/5-PhBn
0.00 3-Nþ2 /5-PhBn
ꢀ42.40
0.32
4.42
0.85
5.59
3-CF3/5-Bn
3-CF3/5-CF3
3-NO2/5-Bn
3-NO2/5-CF3
5-Nþ2 /3-PhBn
2.11 3-CF3/5-Ph
0.00 3-CF3/5-NO2
ꢀ2.93 3-NO2/5-Ph
0.04 3-NO2/5-NO2
5.62 3-Nþ2 /5-Nþ2 /
and Nþ2 ¼42.40 kJ molꢀ1
.
16.52
When the principal effects are plotted against sp (Fig. 1),
the NO2 group is the one that deviates most. May be when
˚
there is an NeH/ONO HB at position 5 (dNO¼2.478 A),
this HB perturbates the effect (see Fig. 2).
The percentages of three compounds experimentally stud-
ied (Table 1) transformed into DG at 298.15 K are: 11 (90%
50
40
30
20
10
0
11a/10% 11b) 5.6 kJ molꢀ1
; 20 (52% 20a/48% 20b)
N2+
0.2 kJ molꢀ1; 24 (99% 24b; 1% 24a) ꢀ12.6 kJ molꢀ1. The cal-
culated (no temperature correction, Scheme 3) are: 11
5.54 kJ molꢀ1; 20 6.71 kJ molꢀ1 and 24 þ12.63 kJ molꢀ1
.
The relationship is DGexp.¼0.73DHcalcd, R2¼0.82, with a mod-
erate correlation coefficient that is certainly due to the differ-
ent conditions (solution in DMSO or HMPA at 263 or 300 K
vs gas phase at 0 K).
2.3.2. Analysis of the interaction terms: the 5-phenylbenzyl
group
We have reported the italicized values of Table 2 in Table 3
together with the corresponding Hammett sp values.16
CF3
NO2
PhBn
0.25 0.5 0.75
2.5
-10
-0.25
0
1 1.25 1.5 1.75
sigma p
2
2.25 2.5
2.25
2
Without NO2: Principal effects = –0.80 + 18.4* sigma p; R^2 = 0.95
With NO2: Principal effects = –2.28 + 17.1* sigma p; R^2 = 0.82
N2+
1.75
1.5
Figure 1. Plot of principal effects versus sp.
1.25
1
0.75
NO2
0.5
0.25
0
CF3
Me
-0.25
-2
0
2
4
6
8
10
Interaction terms with 5-PhBn
12
14
16
18
Figure 3. The line corresponds to sp¼(0.136ꢁ0.003) interaction term, n¼8,
r2¼0.997 (the reciprocal equation is interaction term¼(7.34ꢁ0.14)sp, n¼8,
r2¼0.997).
Figure 2. Structure of the minimum of 7b showing the NeH/ONO HB of
˚
2.478 A.

P. Cornago et al. / Tetrahedron 64 (2008) 3667e3673
3671
4.2. Synthesis
4.2.1. 2-Benzylacetophenone (33)
MeLi (1.6 M, 6.3 mL, 10 mmol) in 200 mL of anhydrous
Et2O was slowly added, under argon atmosphere, to a stirring
suspension of 2-benzylbenzoic acid (32) (870 mg, 4 mmol) in
200 mL of anhydrous Et2O cooled at 0 ꢂC. The mixture was
stirred for 16 h. Water (200 mL) was added and the organic
layer was extracted, washed, respectively, with 200 mL of
saturated Na2CO3 and saturated NaCl solutions. The ethereal
extract was dried (anhydrous MgSO4) and evaporated to
give the crude product. 2-Benzylacetophenone was obtained
by column chromatography (hexane/ethyl acetate 9/1) as a col-
orless solid (640 mg, 3.05 mmol, 76%). Mp¼38e40 ꢂC (lit.
colorless liquid18). 1H NMR (400 MHz; CDCl3) d (ppm):
3
2.46 (s, 3H, CH3), 4.29 (s, 2H, CH2), 7.13 (d, 2H, J¼7.6 Hz,
3
3
Ho), 7.16 (t, 1H, J¼7.2 Hz, Hp), 7.23 (dd, 1H, J¼7.5 Hz,
Figure 4. Structure of the minimum of 5b showing an NeH/p HB of
˚
2.395 A.
3
3
4
4J¼1.2 Hz, H30), 7.29 (ddd, 1H, J¼7.7 Hz, J¼7.5 Hz, J¼
1.2 Hz, H50), 7.30 (m, 2H, Hm), 7.40 (ddd, 1H, J¼3J¼7.5 Hz,
3
4J¼1.4 Hz, H40), 7.64 (dd, 1H, J¼7.7 Hz, J¼1.4 Hz, H60).
3
4
There is a linear relationship between the interaction terms
and sp. For Nþ2 , the fitted value for sp is 2.25 instead of 1.91
(Fig. 3).16 See Figure 4 for an example of NeH/p
interaction.
4.2.2. General procedure for the preparation of b-diketones
34 and 35
Under argon atmosphere, 12.5 mmol of ester in 5 mL of an-
hydrous THF was added to a suspension of 20 mmol of NaH
in 5 mL of anhydrous THF. The mixture was heated at reflux
for 10 min. Then, a suspension of 2-benzylacetophenone (33)
in anhydrous THF was carefully added for 30 min. The
mixture was heated at reflux for 6 h. After cooling, the reac-
tion crude was poured into ice and acidified by a solution of
10% HCl until pH 3e4. The aqueous solution was extracted
three times with CH2Cl2. The organic extract was washed
with saturated aqueous NaHCO3 (40 mL, two times), then
with saturated aqueous NaCl (20 mL, two times), dried
(MgSO4), and the solvent was evaporated. Chromatography
on silica gel eluting with hexane/ethyl acetate mixture (9/1)
gave the corresponding b-diketones.
2.3.3. Analysis of other interaction terms
There are other interaction terms between the substituent at
position 3 and that at position 5, some of them important, in
Table 2, none of them showing linear relationships with Ham-
mett s constants. Their origin is probably electronic as in meta
and para disubstituted benzenes.17
3. Concluding remarks
Having calculated the annular equilibrium constant for the
complete series of 3,5-disubstituted pyrazoles bearing methyl,
benzyl, phenyl, 2-phenylbenzyl, trifluoromethyl, and nitro
substituents (the diazonium group was used as a test), has al-
lowed to solve the problem of determining their effect on KT.
The calculation of interaction terms (non-additivity of 3 and 5
substituent effects) in the case of the 2-phenylbenzyl group has
supported our idea that the study of the tautomerism of
NH-pyrazoles bearing this substituent can be used as a molec-
ular balance to determine the electronic effects of substituents
at position 3 through modifying the strength of the intramole-
cular NeH/p hydrogen bond.
4.2.2.1. 1-(2-Benzylphenyl)-1,3-butanedione (34). The com-
pound was prepared using ethyl acetate (1.30 mL, 12.5 mmol)
1
as ester to give a colorless oil (2.1 g, 8.33 mmol, 67%). H
NMR (400 MHz, CDCl3) d (ppm): 2.11 (s, 3H, CH3), 4.24 (s,
2H, CH2), 5.75 (s, 1H, eCH]CeOH), 7.14 (m, 2H, Ho),
7.19 (t, 1H, 3J¼7.4 Hz, Hp), 7.20 (dd, 1H, 3J¼7.6 Hz,
4J¼1.2 Hz, H30), 7.25e7.29 (m, 3H, H50 and Hm), 7.36 (ddd,
4
1H, 3J¼3J¼7.6 Hz, J¼1.3 Hz, H40), 7.45 (dd, 1H, 3J¼
7.7 Hz, 4J¼1.3 Hz, H60), 15.88 (s, 1H, OH).
4. Experimental
4.2.2.2. 1-(2-Benzylphenyl)-3-phenyl-1,3-butanedione (35). The
compound was prepared using ethyl benzoate (1.80 mL,
12.5 mmol) as ester to give a colorless oil (2.7 g, 8.59 mmol,
70%). 1H NMR (400 MHz, CDCl3) d (ppm): 4.31 (s, 2H,
4.1 . General
3
Melting points were determined on a hot-stage microscope
and are uncorrected. Thin-layer chromatography (TLC) was
performed with Merck silica gel (60 F254). Compounds were
detected with a 254-nm UV lamp. Silica gel (60e320 mesh)
was employed for routine column chromatography separations.
CH2), 6.42 (s, 1H, eCH]CeOH), 7.19 (d, 2H, J¼7.8 Hz,
Ho), 7.27 (t, 1H, 3J¼6.9 Hz, Hp), 7.33 (ddd, 1H, 3J¼3J¼7.5 Hz,
4J¼0.8 Hz, H50), 7.40e7.46 (m, 4H), 7.51e7.60 (m, 3H), 7.80
(d, 1H, 3J¼8.6 Hz), 8.06 (dd, 2H, 3J¼7.1 Hz, 4J¼1.6 Hz),
16.56 (s, 1H, OH).

3672
P. Cornago et al. / Tetrahedron 64 (2008) 3667e3673
3
1
4.2.3. General procedure for the preparation of pyrazoles
11 and 20
(m, J¼3J¼2J¼2J¼2J¼6.2 Hz, C20), 131.6 (m, J¼158.3 Hz,
3J¼3J¼3J¼5.8 Hz, C30), 129.3 (m, J¼160.2 Hz, J¼7.4 Hz,
1
3
3
A mixture of 1,3-butanedione 34 or 35 (0.02 mmol) and 98%
hydrazine monohydrate (0.03 mmol) in EtOH (10 mL) was
heated at reflux for 4 h and then stirred for additional 12 h at
room temperature. The solvent was then removed under reduced
pressure and the remaining residue was chromatographed on sil-
ica gel eluting with hexane/ethyl acetate 9/1 to furnish the desired
pyrazole.
C40), 127.2 (m, 1J¼162.8 Hz, J¼7.8 Hz, C50), 130.3 (m,
1J¼161.5 Hz, J¼7.6 Hz, C60), 129.2 (m, 1J¼160.6 Hz,
3
3J¼3J¼7.2 Hz, Co), 129.1 (m, J¼160.6 Hz, J¼7.6 Hz, Cm),
126.6 (m, 1J¼160.4 Hz, 3J¼3J¼7.4 Hz, Cp), 141.8 (m,
3J¼3J¼2J¼2J¼6.4 Hz, Cipso), 132.7 (m, 3J¼3J¼7.4 Hz,
1
3
C100), 126.1 (m, 1J¼158.6 Hz, J¼3J¼6.9 Hz, C200), 129.3
3
1
3
1
(m, J¼160.2 Hz, J¼7.4 Hz, C300), 128.6 (m, J¼161.1 Hz,
3J¼3J¼7.7 Hz, C400). H NMR (400 MHz, DMSO-d6, 300 K)
1
4.2.3.1. 3(5)-(2-Benzylphenyl)-5(3)-methyl-1H-pyrazole (11).
From 34 (1 g, 3.96 mmol) it was obtained as a yellow oil
(hexane/ethyl ether) (521 mg, 2.10 mmol, 53%). 1H NMR
(400 MHz, CD2Cl2, 300 K) d (ppm): 2.08 (s, Me), 4.19 (s,
d (ppm): 4.15 (48%) and 4.34 (52%) (s, CH2), 6.80 (48%)
and 6.91 (52%) (s, H4), 7.22 (m, H30), 7.32 (m, H40), 7.32
(m, H50), 7.58 (m, H60), 7.05 (m, Ho), 7.23 (m, Hm), 7.14
(m, Hp), 7.80 (m, H200), 7.44 (m, H300), 7.32 (m, H400), 13.15
(48%) and 13.48 (52%) (s, NH). 13C NMR (100 MHz,
4
CH2), 6.11 (s, H4), 7.21 (dd, 3J¼7.9 Hz, J¼1.6 Hz, H30),
3
3
7.30 (ddd, J¼7.9 Hz, J¼7.5 Hz, 4J¼1.6 Hz, H40), 7.25 (ddd,
DMSO-d6, 300 K)
d
(ppm): 38.5 (td, 1J¼127.8 Hz,
3J¼7.5 Hz, J¼7.5 Hz, J¼1.6 Hz, H50), 7.49 (dd, J¼7.5 Hz,
4J¼1.6 Hz, H60), 7.08 (m, Ho), 7.23 (m, Hm), 7.17 (tt,
3J¼7.3 Hz, 4J¼1.7 Hz, Hp), 11.69 (s, NH). 13C NMR
3J¼3.6 Hz, CH2), 102.5 (d, 1J¼174.6 Hz, C4), 150.6 and
143.2 (br s, CPh), 151.6 and 143.2 (br s, CPhBn), 128.8 (s,
C10), 138.7 (m, C20), 130.6 (m, C30), 128.0 (m, C40), 126.3
(m, C50), 129.5 (m, C60), 128.7 (m, Co), 128.3 (m, Cm),
125.8 (m, Cp), 140.8 and 141.5 (m, Cipso), 133.4 and 133.7
(m, C100), 125.1 (m, C200), 128.8 (m, C300), 127.7 (m, C400).
3
4
3
1
(100 MHz, CD2Cl2, 300 K) d (ppm): 11.6 (q, J¼128.0 Hz,
Me), 39.6 (td, 1J¼127.6 Hz, 3J¼4.0 Hz, CH2), 105.8 (m,
1J¼173.6 Hz, 3J¼3J¼3J¼3.0 Hz, C4), 143.3 (br s, CMe),
149.6 (br s, CPhBn), 133.5 (s, C10), 139.8 (m, 3J¼
3J¼2J¼2J¼6.4 Hz, C20), 131.1 (m, 1J¼157.9 Hz, 3J¼
3J¼3J¼6.0 Hz, C30), 128.9 (m, 1J¼163.6 Hz, 3J¼8.2 Hz, C40),
126.8 (m, 1J¼163.0 Hz, 3J¼7.8 Hz, C50), 130.5 (m,
4.3. NMR experiments
4.3.1. Solution
The spectra were recorded on a Bruker DRX 400 (9.4 T,
1J¼162.3 Hz, J¼6.8 Hz, C60), 129.4 (m, J¼163.4 Hz, J¼
3
1
3
3J¼3J¼3J¼5.8 Hz, Co), 128.7 (m, J¼160.0 Hz, J¼7.5 Hz,
400.13 MHz for H, 100.62 MHz for 13C, and 40.56 MHz for
1
3
1
Cm), 126.4 (m, J¼160.1 Hz, J¼3J¼7.5 Hz, Cp), 142.1 (m,
3J¼3J¼2J¼2J¼7.0 Hz, Cipso). 1H NMR (400 MHz, HMPA-
d18, 263 K) d (ppm): 2.19 (10%) and 2.32 (90%) (s, Me), 4.19
(10%) and 4.37 (90%) (s, CH2), 6.01 (10%) and 6.14 (90%) (s,
H4), 7.09 (m, H30), 7.19 (m, H40), 7.24 (m, H50), 7.55 (m,
H60), 7.20 (m, Ho), 7.25 (m, Hm), 7.16 (m, Hp), 13.70 (90%)
and 13.74 (10%) (s, NH). 13C NMR (100 MHz, HMPA-d18,
263 K) d (ppm): 10.7 (90%) and 13.9 (10%) (q, Me), 39.2 (td,
CH2), 103.7 (90%) and 104.6 (10%) (d, C4), 138.4 (90%) and
146.8 (10%) (br s, CMe), 151.2 (90%) and 141.8 (10%) (br s,
CPhBn), 134.9 (s, C10), 138.9 (m, C20), 130.8 (m, C30), 127.2
(m, C40), 126.1 (m, C50), 129.7 (m, C60), 129.4 (m, Co), 128.5
(m, Cm), 126.0 (m, Cp), 142.5 (m, Cipso). 15N NMR (100 MHz,
15N) spectrometer with a 5-mm inverse detection HeX probe
equipped with a z-gradient coil at 300 K. Chemical shifts (d in
1
3
1
ppm) are given from internal solvent, for H, CDCl3 (7.26),
CD2Cl2 (5.32), DMSO-d6 (2.49), HMPA-d18 (2.52), for 13C,
CDCl3 (77.0), CD2Cl2 (53.8), DMSO-d6 (39.5), HMPA-d18
(35.8). For 15N, nitromethane (0.00) was used as external refer-
1
ences. Typical parameters for H NMR spectra were spectral
width 3100e3900 Hz, pulse width 7.5 ms, and resolution
0.19e0.24 Hz per point. Typical parameters for 13C NMR spec-
tra were spectral width 13,800e20,600 Hz, pulse width 10.6 ms,
and resolution 0.42e0.63 Hz per point; WALTZ-16 was used for
broadband proton decoupling; the FIDS were multiplied by an
exponentialweighting (lb¼1 Hz) before Fouriertransformation.
1D 15N NMR was acquired using inverse gated decoupling and
typical parameters were spectral width 14.368 Hz, pulse width
28.5 ms, relaxation delay 30 s, and resolution 0.44 Hz per point;
WALTZ-16 was used for proton decoupling; the FIDS were mul-
tiplied by an exponential weighting (lb¼2 Hz) before Fourier
transformation. 2D (1He1H) gs-COSY and inverse proton
detected heteronuclear shift correlation spectra, (1He13C) gs-
HMQC, and (1He13C) gs-HMBC were acquired and processed
using standard Bruker NMR software and in non-phase-sensi-
tive mode, and the NOESYexperiment was acquired with a mix-
ing time of 1100 ms. Gradient selection was achieved through
a 5% sine truncated shaped pulse gradient of 1 ms.
1
HMPA-d18, 300 K) d (ppm): ꢀ171.4 (90%) (d, J¼106.8 Hz,
N1), and ꢀ175.1 (10%) (N1), ꢀ82.4 (N2).
4.2.3.2. 3(5)-(2-Benzylbenzylphenyl)-5(3)-phenyl-1H-pyrazole
(20). From 35 (1 g, 3.18 mmol) it was obtained as a white
oil (641 mg, 2.06 mmol, 65%); all attempts to crystallize the
oil by treating it with hexane/ethyl ether gave rise to a gel.
1H NMR (400 MHz, CD2Cl2, 300 K) d (ppm): 4.18 (s, CH2),
6.60 (s, H4), 7.28 (m, H30), 7.36 (ddd, 3J¼7.5 Hz,
4
3J¼7.5 Hz, J¼1.5 Hz, H40), 7.32 (m, H50), 7.50 (dd,
4
3J¼7.5 Hz, J¼1.5 Hz, H60), 7.08 (m, Ho), 7.25 (m, Hm),
3
7.18 (dd, J¼3J¼7.3 Hz, Hp), 7.73 (m, H200), 7.40 (m, H300),
4
7.33 (tt, 3J¼7.5 Hz, J¼1.6 Hz, H400), 9.89 (s, NH). 13C
NMR (100 MHz, CD2Cl2, 300 K) d (ppm): 39.8 (td,
4.3.2. Variable temperature (VT)
VT experiments were carried out to study proton-transfer
dynamics in the temperature range of 300e180 K. A
3
1
1J¼127.6 Hz, J¼3.7 Hz, CH2), 103.6 (d, J¼175.1 Hz, C4),
150.0 (br s, CPh), 147.0 (br s, CPhBn), 131.6 (s, C10), 139.6

P. Cornago et al. / Tetrahedron 64 (2008) 3667e3673
3673
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problems due to air humidity at low temperatures, we used
pure nitrogen obtained by evaporation of liquid nitrogen as
the bearing, driving, and cooling gas.
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Energy calculations were carried out at the hybrid Becke
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Supplementary data
Contains a table with the calculations (energies, ZPE
correction, dipole moment) and the Free-Wilson matrix. Sup-
plementary data associated with this article can be found in the
online version, at doi:10.1016/j.tet.2008.02.026.
´
J. J. Phys. Chem. A 1998, 102, 9278e9285; (f) Jimenez, J. A.; Claramunt,
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Alkorta, I.; Rozas, I.; Elguero, J. J. Phys. Chem. A 2001, 105, 743e
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~
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