The structure of pyrazoles in the solid state: A combined CPMAS, NMR, and crystallographic study

Article abstract of DOI:10.1021/jo0609935

The structures of six N-unsubstituted pyrazoles, three already known and three newly synthesized, have been studied by a combination of X-ray crystallography, multinuclear NMR (solution and solid state), and density functional theory (DFT) calculations. I

Full text of DOI:10.1021/jo0609935

The Structure of Pyrazoles in the Solid State: A Combined
CPMAS, NMR, and Crystallographic Study
Rosa M. Claramunt,*,† Pilar Cornago,† Vero´nica Torres,† Elena Pinilla,§ M. Rosario Torres,§
Andre´ Samat,‡ Vladimir Lokshin,‡ Magali Vale´s,‡ and Jose´ Elguero|
Departamento de Qu´ımica Orga´nica y Bio-Orga´nica, Facultad de Ciencias, UNED, Senda del Rey 9,
E-28040 Madrid, Spain, Departamento de Quimica Inorganica, Laboratorio de Difraccio´n de Rayos X,
Facultad de Ciencias Quimicas, UniVersidad Complutense de Madrid, E-28040 Madrid, Spain, Groupe de
Chimie Organique et Mate´riaux Mole´culaires, UniVersite´ de la Me´diterrane´e, Faculte´ des Sciences de
Luminy, Case 901, 13288 Marseille Ce´dex 09, France, and Instituto de Qu´ımica Me´dica (CSIC), Centro
de Qu´ımica Orga´nica ‘Manuel Lora Tamayo’, Juan de la CierVa 3, E-28006 Madrid, Spain
rclaramunt@ccia.uned.es
ReceiVed May 12, 2006
The structures of six N-unsubstituted pyrazoles, three already known and three newly synthesized, have
been studied by a combination of X-ray crystallography, multinuclear NMR (solution and solid state),
and density functional theory (DFT) calculations. In those cases where crystal structure and CPMAS
NMR were available, the agreement was almost perfect, allowing a prediction of the tautomer (with
certitude) and the tetrameric structure (with high probability) in the case of 5-isopropyl-3-phenyl-1H-
pyrazole without knowing the X-ray structure. In the case of the 5-(2-benzylphenyl)-3-trifluoromethyl-
1H-pyrazole above represented, the DFT calculations at the B3LYP/6-31G** level justify the great stability
of this tautomer by the presence of an intramolecular N-H‚‚‚π interaction, present in solution.
Introduction
(Scheme 1, the Etter/Bernstein graph set descriptors are given
for each motif).2,3
Although less relevant biologically than N-unsubstituted
imidazoles, N-unsubstituted pyrazoles are much more interesting
in what concerns the N-H‚‚‚N hydrogen bonds (HBs) network
in their crystals (the HBs of the remaining NH-azoles, 1,2,3-
and 1,2,4-triazoles, tetrazoles, and their benzo derivatives are
all either of the “pyrazole-type” or the “imidazole-type”). The
1,3-disposition of the nitrogen atoms in imidazoles leads
exclusively to the formation of chains, called catemers,1 while
the 1,2-disposition in pyrazoles leads to at least five motifs
The question arises, is there any relationship between the
nature of the C-substituents in the monomer and the hydrogen
bond pattern present in the crystal? In the year 2000, we
published a paper on this problem where two important
conclusions were reached.4 The first and most important one
was that to find a pattern, the structures must be grouped in
(2) (a) Etter, M. C. Acc. Chem. Res. 1990, 23, 120. (b) Etter, M. C.;
MacDonald, J.; Bernstein, J. Acta Crystallogr., Sect. B 1990, B46, 256.
(3) (a) Bernstein, J.; Etter, M. C.; Leiserowitz, L. The Role of Hydrogen
Bonding in Molecular Assemblies. In Structure Correlations; Dunitz, J.
D., Burgi, H.-B., Eds.; VCH: Weinheim, Germany, 1994; Vol. 2, pp 431-
507. (b) Bernstein, J.; Davis, R. E.; Shimoni, L. Chang, N.-L. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 1555.
† UNED.
§ Universidad Complutense de Madrid.
‡ Universite´ de la Me´diterrane´e.
| Instituto de Qu´ımica Me´dica (CSIC).
(1) Cammers, A.; Parkin, S. CrystEngComm 2004, 6, 168.
(4) Foces-Foces, C.; Alkorta, I.; Elguero, J. Acta Crystallogr., Sect. B
2000, B56, 1018.
10.1021/jo0609935 CCC: $33.50 © 2006 American Chemical Society
Published on Web 08/03/2006
J. Org. Chem. 2006, 71, 6881-6891
6881

Claramunt et al.
SCHEME 1. The Motifs Found in NH-Pyrazole Crystals
TABLE 1. Literature Data on Pyrazoles 1, 2, 3, and 5 of Scheme 1
solution
NMR
CPMAS
NMR
pyrazole
mp (°C)
X-ray
PTa
1 (polymorph B)b
114-1259
122.59
8312b
9-11
15
16
9-11
9
16
no (NMR)9
yes (NMR)9
yes (NMR)16
no (X-ray)18
1 (polymorph A)b
tetramer13,14
tetramer16
tetramer18
2
3
5
12217
18
no
9112c
a PT: proton transfer. b In the literature (no polymorph specified) the reported mp is 128.12a
two classes: (i) trimers and catemers and (ii) dimers and
tetramers (hexamers were not known at that time but they belong
to the even class). The second conclusion was that the first
family consists of NH-pyrazoles with small substituents at
positions 3 and 5 (substituents at position 4 were found
irrelevant), whereas the second set corresponds to bulky ones.
The best descriptor for the substituent size was the molar
refractivity, MR (according to the IUPAC, the molar refractivity
is the molar volume corrected by the refractive index; it
represents size and polarizability of a fragment or molecule).5
Four years later, Infantes and Motherwell reexamined this
problem from another crystallographic point of view.6 The two
sets of NH-pyrazoles4,6 differ not only because new structures
have been published but because Infantes and Motherwell
eliminate HB acceptor groups as CO2R. Fayos, Infantes, and
Cano used a neural network for predicting the secondary
structure in NH-pyrazoles.7 More recently, we proposed a mixed
ab initio calculated/experimental crystallography approach.8
To progress in the understanding of the N-H‚‚‚N HBs
formed by the crystallization of NH-pyrazoles, more experi-
mental data are needed. In this paper we will compare the solid-
state properties of the pyrazoles reported in Scheme 2 and
described in Table 1. The new N-methyl derivatives 7 and 8
have been prepared as models to study tautomerism. A priori
we will name a the tautomer with the phenyl (or benzylphenyl)
group at position 3 and b the other one, without any assumption
about their relative stabilities.
The results will be presented in the following order: (1)
Density functional theory (DFT) calculations of the isolated
molecules (energies and dipole moments); (2) crystallographic
results plus differential scanning calorimetry (DSC); (3) solution
multinuclear magnetic resonance (NMR) studies; (4) solid-state
NMR (CPMAS) results; and (5) general conclusions.
We had already identified two polymorphs of 3(5)-methyl-
5(3)-phenyl-1H-pyrazole 1:9 a polymorph B devoided of
dynamic properties (no proton transfer, PT) for which no X-ray
structure could be determined but probably being a tetramer
(9) Elguero, J.; Jagerovic, N.; Foces-Foces, C.; Cano, F. H.; Roux, M.
V.; Aguilar-Parrilla, F.; Limbach, H.-H. J. Heterocycl. Chem. 1995, 32,
451.
(5) Hansch, C.; Leo, A.; Hoekman, D. Exploring QSAR. Hydrophobic,
Electronic, and Steric Constants; American Chemical Society: Washington,
DC, 1995.
(6) Infantes, L.; Motherwell, S. Struct. Chem. 2004, 15, 173.
(7) Fayos, J.; Infantes, L.; Cano, F. H. Cryst. Growth Des. 2005, 5, 191.
(8) Alkorta, I.; Elguero, J.; Foces-Foces, C.; Infantes, L. ARKIVOC 2006,
ii, 15,
(10) Aguilar-Parrilla, F.; Mnnle, F.; Limbach, H. H.; Elguero, J.;
Jagerovic, N. Magn. Reson. Chem. 1994, 32, 699-702.
(11) Claramunt, R. M.; Sanz, D.; Lo´pez, C.; Jimnez, J. A.; Jimeno, M.
L.; Elguero, J.; Fruchier, A. Magn. Reson. Chem. 1997, 35, 35.
(12) Behr, L. C.; Fusco, R.; Jarboe, C. H. Pyrazoles, Pyrazolines,
Pyrazolidines, Indazoles and Condensed Rings; Wiley, R. H., Ed.; Inter-
science, John Wiley: New York, 1967; (a) p 414; (b) p 420; (c) p 421.
6882 J. Org. Chem., Vol. 71, No. 18, 2006

The Structure of Pyrazoles in the Solid State
SCHEME 2. C-Phenyl-1H-pyrazoles 1-6 and N-Methyl Derivatives 7-8
TABLE 2. DFT Calculations (B3LYP/6-31G**) of Pyrazoles 1-6a
pyrazole
tautomer a
tautomer b
µ a
µ b
∆E (a - b)
% at 298.15 K
1
2
3
4
5
6
-496.7779
-535.7052
-794.1501
-574.9935
-727.3917
-1064.4112
-496.7773
-535.7047
-794.1510
-574.9932
-727.3908
-1064.4160
3.01
3.02
0.38
3.03
3.14
0.24
2.14
2.16
5.23
2.15
2.57
5.48
-1.63
-1.31
2.42
-0.79
-2.36
12.63
66% 1a/34% 1b
63% 2a/37% 2b
27% 3a/73% 3b
58% 4a/42% 4b
72% 5a/28% 5b
0.6% 6a/99.4% 6b
a Energies are given in hartree including ZPE correction, dipole moments are in D, and relative energies are in kJ mol-1
.
formed by only one tautomer (the 3-phenyl-5-methyl one 1a)
and presenting three peaks in DSC (after cooling, three peaks
were observed again); and a polymorph A of known X-ray
structure,13,14 presenting PT9 and formed by two 3-phenyl-5-
methyl 1a and two 3-methyl-5-phenyl 1b tautomers. Since these
tetramers have different tautomeric composition they are des-
motropes.
Results and Discussion
1. Theoretical Calculations. We report in Table 2 the results
of the calculations (underlined the most stable tautomer). The
B3LYP/6-31G** level of the calculations is adequate to our
(13) Maslen, E. N.; Cannon, J. R.; White, A. H.; Willis, A. C. J. Chem.
Soc., Perkin Trans. 2 1974, 1298.
(14) Moore, F. H.; White, A. H.; Willis, A. C. J. Chem. Soc., Perkin
Trans. 2 1975, 1068.
(15) Aguilar-Parrilla, F.; Cativiela, C.; Daz de Villegas, M. D.; Elguero,
J.; Foces-Foces, C.; Garc´ıa, J. I.; Cano, F. H.; Limbach, H.-H.; Smith, J.
A. S.; Toiron, C. J. Chem. Soc., Perkin Trans. 2 1992, 1737.
(16) Claramunt, R. M.; Cornago, P.; Santa Mar´ıa, M. D.; Torres, V.;
Pinilla, E.; Torres, M. R.; Elguero, J. Supramol. Chem. 2006, 18, 349.
(17) Nishiwaki, T. Bull. Chem. Soc. Jp. 1969, 42, 3024.
(18) Rasika Dias, H. V.; Goh, T. K. H. H. Polyhedron 2004, 23, 273.
FIGURE 1. The minimum energy conformation of tautomers 6a (left)
and 6b (right, showing the N-H‚‚‚π hydrogen bond).
purpose. There are no problems of optimization for most
compounds; only in the case of 6 has it been necessary to carry
out an exploration of the conformational space to find the
tautomers of minimum energy (Figure 1).
If we make the simplification to consider that the six
pyrazoles have only three different substituents, phenyl (Ph),
J. Org. Chem, Vol. 71, No. 18, 2006 6883

Claramunt et al.
TABLE 3. Summary of the Crystallographic Work
compound
X-ray
tautomer
proton transfer (method)
motif composition
1(B)a
Ph/Me
Ph/Et
Ph/CF3
Ph/i-Pr
Ph/Bn
tetramer13,14
tetramer16
tetramer18
not determined
dimer
2 1a+2 1b
3 2a+1 2b
4 3b
yes (by NMR)9
yes (by NMR)16
no (by X-ray)18
1a1a1b1b/1b1b1a1a
2a2a2a2b/2b2b2b2a
3b3b3b3b
2
3
4
5
6
2 5a
2 6b
no (by X-ray)
no (by X-ray)
5a5a
6b6b
BnPh/CF3
dimer
a B polymorph.
TABLE 4. The HBs Present in the Crystal Structures (Å, deg)
benzylphenyl (BnPh), and trifluoromethyl (CF3), that is, as-
suming that the four alkyl groups (Me, Et, Pr, and Bn) are
equivalent as far as tautomerism and dipole moments (∆µ )
µa - µb) are concerned, then we can establish the following
equations:
i
compd
d(N-H) d(H‚‚‚N) d(N-N)
1.458(4) 1.458(4) 2.913(1) 176.4(4)
1.41(4) 1.44(4) 2.852(2) 178(3)
1.413(4) 1.413(4) 2.824(5) 175(4)
NHN
1a
N1‚‚‚H16‚‚‚N1b
N2‚‚‚H18‚‚‚N3
N4‚‚‚H17‚‚‚N4b
N2b‚‚‚H18b‚‚‚N3b 1.41(4)
1.44(4)
2.852(5) 178(3)
∆E(a - b) (kJ mol-1) ) -(1.5 ( 0.3)Ph +
(3.9 ( 0.7)CF3 + (8.7 ( 1.0)BnPh, n ) 6, r2 ) 0.993 (1)
2c
N1-H1‚‚‚N7
N4-H4‚‚‚N5
N6-H6‚‚‚N2
N8-H8‚‚‚N3
0.86
0.86
0.86
0.86
2.05
2.08
2.07
2.02
2.881(8) 160.9
2.926(9) 167.9
2.921(7) 170.1
2.840(7) 159.6
∆µ(D) ) (0.80 ( 0.08)Ph - (5.65 ( 0.17)CF3 +
(0.41 ( 0.23)BnPh, n ) 6, r2 ) 0.999 (2)
3d
N1-H27‚‚‚N6
N3-H28‚‚‚N8
N5-H26‚‚‚N4
N7-H25‚‚‚N2
0.933
0.929
0.993
0.906
1.962
1.953
1.873
2.005
2.856
2.854
2.844
2.866
159.7
163.0
165.0
158.3
Equation 1 shows that the difference in stability between both
tautomers (a - b, in kJ mol-1) is related to the tendency of
both the phenyl (1.5 kJ mol-1) and trifluoromethyl (3.9 kJ
mol-1) groups to prefer the 3 position (tautomer a in the first
case and b in the second), while the benzylphenyl group has a
strong (8.7 kJ mol-1) and unexpected tendency to occupy the 5
position (6b tautomer). This is accounted for by the existence
of an intramolecular N-H‚‚‚π (phenyl) HB in tautomer 6b (H‚
‚‚Cipso ) 2.404 Å and H‚‚‚Cortho ) 2.631 Å). Although this HB
disappears in the solid state as stronger intermolecular N-H‚
‚‚N HBs are formed, in solution, 6b shows a behavior similar
to the Wilcox’s torsion balance but using tautomerism coupled
with rotation (Scheme 3).19
5
6
N1-H1‚‚‚N4
N3-H3‚‚‚N2
N5-H5‚‚‚N6′e
0.86
0.86
0.86
2.20
2.25
2.26
2.875(7) 135.6
2.917(7) 134.2
2.942(7) 136.7
N1-H1‚‚‚N2′f
0.89(2)
2.21(2)
2.931(3) 138(2)
a In this case the data are in italics to show they correspond to neutron
diffraction results, where the HB is almost lineal and the hydrogen atoms
were located in the middle of the N-H‚‚‚N HB. H16, H17, and H18 are
HA, HB, and HC, described in ref 14. b Binary axis 1 - x, y, -z - 1/2.
c Data taken from ref 16. d Data taken from ref 18. e 1 - x, -y + 2, -z.
f -x + 1, -y + 1, -z + 1.
2. X-ray Structures and DSC Experiments. In Table 3 are
gathered the crystallographic results related to pyrazoles 1-6.
3(5)-Methyl-5(3)-phenyl-1H-pyrazole (1), 3(5)-phenyl-5(3)-1H-
pyrazole (2), and 3(5)-phenyl-5(3)-trifluoromethyl-1H-pyrazole
(3) had previously been solved, and 3(5)-isopropyl-5(3)-phenyl-
1H-pyrazole (4) could not be determined as no quality crystals
were obtained.
SCHEME 3. A Comparison of Wilcox’s Torsion Balance
(top) and Tautomeric Balance of 6
In the 3(5)-benzyl-5(3)-phenyl-1H-pyrazole (5), three inde-
pendent molecules of tautomer 5a were identified in the
structural determination (Figure 2). The three molecules show
some differences between them in the dihedral angles: 15.1°
(pyrazole and phenyl rings), 83.2° (phenyl of the benzyl), 69.1°
(between the two phenyl rings) for the first molecule, 9.2°, 71.3°,
and 63.9° for the second and 13.4°, 88.9°, and 80.1° for the
third one. Two of these independent molecules are linked by
hydrogen bonds, and the third one is bonded through hydrogen
bonds with a centrosymmetric one (Table 4).
These hydrogen bonds led to dimers of two types, which are
sandwiched along the b axis bonded with weak hydrogen bonds,
C44-H44‚‚‚N4 and C12-H12‚‚‚N2, and form one-dimensional
chains between dimers of distinct types (Table 5).
Moreover, a very weak interaction C20-H20‚‚‚C10 between
dimers of different chains led to a thick layer (approximately
12.52 Å) parallel to the (-101) plane (Figure 3).
The crystal structure of 3(5)-(2-benzylphenyl)-5(3)-trifluoro-
methyl-1H-pyrazole (6) shows the presence of molecules 6b
bonded through hydrogen bonds as dimeric species (Figure 4).
The hydrogen lengths and angles of N-H‚‚‚N hydrogen bonds
Concerning the difference in dipole moments between both
tautomers, from tautomer a to tautomer b, in the six pyrazoles
the only important change is that produced by the trifluoromethyl
group.
(19) (a) Paliwal, S.; Geib, S.; Wilcox, C. S. J. Am. Chem. Soc. 1994,
116, 4497. (b) Kim, E.-I.; Paliwal, S.; Wilcox, C. S. J. Am. Chem. Soc.
1998, 120, 11192.
6884 J. Org. Chem., Vol. 71, No. 18, 2006

The Structure of Pyrazoles in the Solid State
FIGURE 2. ORTEP view of the three independent molecules in the asymmetric unit plus the fourth one generated by symmetry of 5-benzyl-3-
phenyl-1H-pyrazole (5a) showing two dimers.
TABLE 5. Secondary Hydrogen Bonds in Compound 5
X-H‚‚‚Y
d(X-H)
d(H‚‚‚Y)
d(X-Y)
XHY
C44-H44‚‚‚N4
C12-H12‚‚‚N2
C20-H20‚‚‚C10
0.97
0.97
0.93
2.80
2.68
2.78
3.48
3.59
3.70
128.2
157.0 (-x, -y + 1, -z)
168.5 (x + 1/2, -y + 3/2, + 1/2)
phenyl groups at position 5 that diminishes the distance in 0.02
Å. With respect to the NHN angle, its value depends on the
compound being a tetramer (about 170°) or a dimer (about
135°).
Concerning annular tautomerism, all the 3(5)-trifluoromethyl
substituted NH-pyrazoles so far described are 3-CF3 derivatives,
for instance, 6, 3, 5-(2-thienyl)-3-trifluoromethyl-1H-pyrazole
(dimer), and 5-tert-butyl-3-trifluoromethyl-1H-pyrazole (tet-
ramer).4 This is consistent with the energy calculations of the
monomers in the gas phase.
Differently to pyrazoles 4 and 5 that correspond to unique
crystalline forms, compound 6 presents polymorphism. The three
polymorphs found for pyrazole 6 melt at 85.1, 108.1, and 70.7
°C; only for the form melting at 85.1 °C were suitable crystals
for X-ray obtained and the structure determined. The problem
was studied by DSC: When compound 6 was crystallized in
acetonitrile/petroleum ether and the solvent slowly evaporated,
crystals melting at 85.1 °C were obtained presenting a unique
endothermic peak. The crystals formed from the same solvent
but by a brusque cooling of the hot solution, show two
endothermic peaks (108.1 and 70.7 °C) with different intensities
depending on the crystalline crops and the DSC heating/freezing
conditions. These polymorphs are metastable forms that evolve
at room temperature to the stable 85.1 °C form but with very
different rates, that of 108.1 °C in 24 h and that of 70.7 °C in
one month. Desmotropy, different tautomers, cannot be excluded
since it has been observed in other pyrazoles,4,20 but it is
improbable owing to the large difference in stability between
6a and 6b.
FIGURE 3. 2D network along b axis of 5-benzyl-3-phenyl-1H-
pyrazole (5a).
are collected in Table 4. These dimeric species are within van
der Waals distances and the packing is presented in Figure 5.
(20) (a) Foces-Foces, C.; Llamas-Saiz, A. L.; Claramunt, R. M.; Lo´pez,
C.; Elguero, J. J. Chem. Soc. Chem. Commun. 1994, 1143. (b) Garc´ıa, M.
A.; Lo´pez, C.; Claramunt, R. M.; Kenz, A.; Pierrot, M.; Elguero, J. HelV.
Chim. Acta 2002, 85, 2763.
The analysis of the data of Table 4 affords the following
information: the reliable d(N-N) distance has an average value
of 2.90 Å, and it is only slightly sensitive to the presence of
J. Org. Chem, Vol. 71, No. 18, 2006 6885

Claramunt et al.
FIGURE 4. ORTEP view of the dimer formed by H-bonding of one independent molecule of 5-(2-benzylphenyl)-3-trifluoromethyl-1H-pyrazole
(6b) with its centrosymmetric counterpart.
FIGURE 5. Packing along b axis of 5-(2-benzylphenyl)-3-trifluoromethyl-1H-pyrazole (6b).
SCHEME 4. 13C NMR and 15N NMR (bold) Chemical Shifts
of Pyrazoles 7 and 8
3. Solution NMR Studies. As a large number of studies
dealing with 1H NMR,21 13C NMR,22 and 15N NMR11 spectros-
copy of pyrazoles have been done, there are seldom assignment
problems. Only in the case of 6 did we find it useful to prepare
the N-methyl derivatives 7 and 8 (for the assignment of other
(21) Elguero, J.; Jacquier, R.; Tien Duc, H. C. N. Bull. Soc. Chim. Fr.
1966, 3727.
(22) Begtrup, M.; Boyer, G.; Cabildo, P.; Cativiela, C.; Claramunt, R.
M.; Elguero, J.; Garcia, J. I.; Toiron, C.; Vedsø, P. Magn. Reson. Chem.
1993, 31, 107.
3(5)-trifluoromethylpyrazoles, see ref 23). Scheme 4 shows the
most relevant data for these two compounds determined in
HMPA-d18.
(23) Martins, M. A. P.; Zanatta, N.; Bonacorso, H. G.; Rosa, F. A.;
Claramunt, R. M.; Garc´ıa, M. A.; Santa Mar´ıa, M. D.; Elguero, J. ArkiVoc
2006, iV, 29.
6886 J. Org. Chem., Vol. 71, No. 18, 2006

The Structure of Pyrazoles in the Solid State
SCHEME 5. 1H-15N Couplings Involving the Protons Marked in Blue
TABLE 6. Selected NMR Data for the Pyrazole Nuclei of Compound 4 at 300 K
1H NMR
13C NMR
C-4
15N NMR
tautomers
percentage
solvent
H-4
H-1
C-3
C-5
N-1
N-2
CDCl3, 0.05 M
DMSO-d6, 0.05 M
average
4a 77
4b 23
4a 82
4b 18
4a
6.38
6.45
6.45
6.41
6.49d
149.6a
99.2
98.3
99.1
97.7
98.6
99.7
154.0b
12.55
12.81
13.46
13.70
149.9
150.8
c
c
HMPA-d18, 0.3 M
150.1
158.3
150.7
151.5
152.3
150.5
142.5
152.3
151.5
150.7
-175.4
-182.5
-87.7
-83.3
CPMAS
-169.7(3)e
-171.6(1)e
-101.5(3)e
-103.7(1)e
a C-Ph. b C-iPr. c Not observed. d Broad. e At 200 K.
The complete 1H NMR, 13C NMR, and 15N NMR results for
pyrazoles 4, 5, and 6 are reported in Tables S1, S2 and S3 in
the Supporting Information. In CDCl3 or CD2Cl2 only average
signals were observed, but in the more polar solvents DMSO-
d6 and HMPA-d18 the existence of two tautomers in the cases
of 3(5)-isopropyl-5(3)-phenyl-1H-pyrazole (4) and 3(5)-benzyl-
5(3)-phenyl-1H-pyrazole (5) was clearly observed. All the
signals that appear at different chemical shift values for both
tautomers in 4 and 5 lead, after integration, to the same
proportions. Particularly useful have been the NH signals in
1H NMR and carbon C-4 in 13C NMR, as well as both nitrogen
chemical shifts in 15N NMR (Tables 6-8). A useful criterium
to confirm the assignment of signals to the minor tautomer,
4b, is that they are broader than those of the major one, 4a.
This is a simple consequence of the fact that the minor tau-
tomer has an activation barrier lower than that of the major
tautomer.
process; this is the most common case and for a new pyrazole
this situation would be predicted to be found experimentally;
(ii) both tautomers are present in the crystal but nothing dynamic
is occurring (no known example); (iii) both tautomers are present
in the crystal and the NH proton is exchanging between the
nitrogen atoms of two adjacent molecules (solid state proton
transfer, SSPT), and that is the case, for instance, of compounds
1 and 2.
3(5)-Isopropyl-5(3)-phenyl-1H-pyrazole (4). This com-
pound, whose crystal structure has not been determined, shows
very well resolved 13C and 15N CPMAS NMR spectra and the
data are gathered in Table 6. In the 13C CPMAS NMR shown
in Figure 6, the fact that eight signals are observed for the two
methyl groups and four signals for the CH (two superimposed)
of the isopropyl substituent points toward 4 being a tetramer,
and the chemical shifts of C-3 and C-5 (about 151.5 ppm) point
to a 4a4a4a4a structure. This guess is completely confirmed,
as explained later on, by the 15N CPMAS NMR.
3(5)-Benzyl-5(3)-phenyl-1H-pyrazole (5). Having deter-
mined by crystallography that pyrazole 5 is a 5a5a dimer, the
only comment about the 13C CPMAS NMR data of Table 7
concerns the multiplicity of signals. Carbon atoms C-3 and C-5
appear as three signals while C-4 and the benzylic CH2 are split
into two signals with the intensities being in a 2:1 ratio. This is
consistent with the existence of three independent molecules
in the crystal.
3(5)-(2-Benzylphenyl)-5(3)-trifluoromethyl-1H-pyrazole (6).
The results shown in Table 8 concerning pyrazole 6 leave no
doubt that there is only one independent molecule and that this
molecule is tautomer 6b (tautomer 6a should resemble 7, see
Scheme 4). Thus, again X-ray and CPMAS NMR are in perfect
agreement.
Noteworthy are the 1H-15N coupling constants measured in
the labeled derivatives (Scheme 5). In the literature, there are
1
some values regarding the J(1H-15N) coupling constant in
pyrazoles,11,24 but the 2J(1H-15N)coupling constant between H-1
and N-2 (7.5 Hz in 6b) has been measured for the first time.
The couplings with H-4 are in the range of those reported for
N-substituted pyrazoles (between 5 and 6 Hz with N-1 and about
1 Hz with N-2 (average 3.5 Hz)). The fact that two different
couplings are observed for 4 in CDCl3 should correspond to an
average of tautomers in a 75% 4a/25% 4b proportion assuming
the couplings of H-4 with N-1 and N-2 in the absence of
prototropy are 5.75 and 1.15 Hz. For 1-benzylpyrazole (com-
pound 156 of ref 21, p 47) it was reported 3J(N1H4) ) 5.8 and
3J(N2H4) ) 1.1 Hz.
4. Solid-State NMR. In the solid state, NH-pyrazoles bearing
different substituents at positions 3 and 5 have three possibili-
ties: (i) to exist in only one tautomer without any dynamic
Solid-state 15N CPMAS NMR chemical shifts are the most
appropriate to study the static and dynamic structure of NH-
pyrazoles. This is mainly because the signals of both nitrogen
atoms are separated by 70-80 ppm. In general, labeling with
15N greatly facilitates these studies, especially if something
dynamic intervenes.
(24) (a) Fruchier, A.; Pellegrin, V.; Claramunt, R. M.; Elguero, J. Org.
Magn. Reson. 1984, 22, 473. (b) Claramunt, R. M.; Sanz, D.; Santa Mar´ıa,
M. D.; Jimenez, J. A.; Jimeno, M. L.; Elguero, J. Heterocycles 1998, 47,
301.
J. Org. Chem, Vol. 71, No. 18, 2006 6887

Claramunt et al.
FIGURE 6. 13C CPMAS NMR spectrum of 3(5)-isopropyl-5(3)-phenyl-1H-pyrazole (4).
TABLE 7. Selected NMR Data for the Pyrazole Nuclei of Compound 5 at 300 K
1H NMR
13C NMR
15N NMR
N-1 N-2
tautomers
percentage
solvent
H-4
H-1
C-3
C-4
C-5
CD2Cl2, 0.14 M
DMSO-d6, 0.04 M
average
5a 55
5b 45
5a 65
5b 35
5a
6.39
6.44
6.44
6.39c
6.39c
10.08
10.08
12.96
13.72c
13.90c
149.7a
150.5
152.2
150.7
151.5
148.5
149.0
149.8
102.1
101.1
101.1
100.5
101.0
102.3(1)
103.5(2)
147.4b
143.1
143.1
143.1
143.3
141.4
142.3
143.3
HMPA-d18, 0.2 M
-172.5
-180.7
-174.5
-87.4
-80.3
-89.7
-90.2
-92.2
-93.3
CPMASd
a C-Ph. b C-Bn. c At 280 K. d At 183 K
TABLE 8. Selected NMR Data for the Pyrazole Nuclei of
Compound 6b at 300 K
DMSO-d6 the N nuclei resonate at -171.2, N-1, and -82.1,
N-2).25 What is noteworthy here is to point out the presence of
exclusively tautomer 3b with a 5-phenyl substituent in the
tetramer.18 Analogously simple is the case of the other triflu-
oromethyl derivative 6. The o-benzyl substituent on the phenyl
ring at position 5 modifies the chemical shifts of the N-2
nitrogen atom from -97.4 (3) to -87.2 (6). Although we have
been unable to grow crystals of the other polymorphs of 6, we
have succeeded in recording a beautiful 15N CPMAS NMR
spectrum of one of them, polymorph B (mp 70.7 °C) shown in
Scheme 6.
The case of the phenyl-benzyl-pyrazole 5 is a little more
complex. The X-ray results show that this compound crystallizes
forming two dimers, one with two independent molecules and
the other with only one. This could explain why four signals
are observed for N-2. What is more surprising is the position
of the signal of the N-2 is observed about -91 ppm. This is
consistent with other 3-phenyl pyrazoles where the N-2 appears
about -102 ppm, because in dimers, compared to tetramers,
the N-2 signal is shifted about 10 ppm.10
We leave to the end the case of the 3(5)-isopropyl-5(3)-
phenyl-1H-pyrazole (4), because lacking the crystallographic
information we have to rely on the solid NMR study to
determine its structure. We have concluded from the 13C
CPMAS NMR study that it is probably a 4a4a4a4a tetramer.
The position of the 15N signals, about -102 and -170 ppm is
consistent with a 5-alkyl-3-phenyl tautomer 4a and, since the
spectrum is independent of the temperature, that no PT occurs.
Two signals are observed for each N atom in a 3:1 ratio but
this is not an indication of a 4a4a4a4b tetramer because the
small signals are not between the larger ones such as in 2. We
conclude that it is a 4a4a4a4a tetramer with two or four
1H NMR
13C NMR
C-4 C-5
15N NMR
N-1 N-2
solvent
H-4 H-1
C-3
CDCl3, 0.05 M
6.53 10.60 143.4 103.9 143.8
DMSO-d6, 0.05 M 6.69 13.79 141.3 103.5 142.9
HMPA-d18, 0.05 M 6.58 14.65 141.7 103.5 143.5 -163.9 -80.3
CPMAS 142.4 104.0 142.4 -177.1 -87.2
We have summarized the situation as far as pyrazoles 1-6
are concerned in Scheme 6 (the data for pyrazole 3 are from
ref 25) which shows the consistency of the chemical shifts for
both kinds of nitrogen atoms. The only compounds showing
proton transfer are 1 (polymorph A) and 2.
In the case of 1, we have reported the spectra at 298 K of
polymorph B (formed exclusively by tautomer 1a and most
probably a tetramer) and that of polymorph A at 263 K.9 The
small splitting in 1B is due to two conformations in a 1:2 ratio
of molecule 1a in the 1a1a1a1a crystal. The large splitting of
1A is due to the suppression of the 1a1a1b1b h 1b1b1a1a
proton transfer at 183 K thus explaining why they are of the
same intensity (50% of 1a and 50% of 1b). On cooling, the
signals of 1a (N-1, 170.4; N-2, 102.0 ppm) and 1b (N-1, 176.3;
N-2, 96.5 ppm) are observed.9 Note that the signals of 1a are
inside those of 1b. The more complex case of 2 (only the low-
temperature spectrum is shown)16 is similar, but the mixture of
2a2a2a2b and 2b2b2b2a is no longer 50:50 but 75:25.16
The case of pyrazole 3 will be discussed in details in a future
publication together with other trifluoromethylpyrazoles (in
(25) Lo´pez, C. Unpublished data.
6888 J. Org. Chem., Vol. 71, No. 18, 2006

The Structure of Pyrazoles in the Solid State
SCHEME 6. 15N CPMAS NMR Chemical Shifts of Pyrazoles 1-6
independent molecules, one of them being more different than
the other three.
C-substituents determine the hydrogen-bonded supramolecular
structure, we have reached the following conclusions:
(1) Density functional calculations at the B3LYP/6-31G**
level allowed us to determine the minimum energies of the
optimized geometries as well as dipole moments, of the two
NH tautomers in six related pyrazoles 1-6 and to predict the
tautomeric composition in the equilibrium at 298.15 K.
(2) The substituents determine the major tautomer in solution
and in the solid state: 5-alkyl-3-phenyl tautomers a are more
stable than 3-alkyl-5-phenyl ones b (1a1a1a1a, 4a4a4a4a,
5a5a), but the differences in energy are small and in some cases
mixtures of a and b are observed in the crystals (1a1a1b1b,
2a2a2a2b). 5-Aryl-3-trifluoromethyl b (3b3b3b3b, 6b6b,
6b6b6b6b) are much more stable than 3-aryl-5-trifluoromethyl
a ones.
(3) The presence of one CF3 substituent prevents proton
transfer (PT) in the solid state as the energies of both states,
6b6b before and 6a6a after the PT, are much different, thus
confirming our previuos results obtained for 1a1a1b1b/
1b1b1a1a and 2a2a2a2b/2b2b2b2a.
(4) With substituents such as those of Scheme 2, empirical
NMR models predict that they should crystallize as dimers or
tetramers.4,6-8
We have published a paper where the differences in 15N
chemical shifts between solid state and solution are related
empirically to the X-ray structure.10 The four main HB motifs
have the following values of ∆δ of, respectively, N-1 and N-2:
catemer 0/-9 ppm; dimer 0/-8 ppm; trimer 1/-2 ppm; tetramer
6/-19 ppm (note the already commented about 10 ppm
difference between dimers and tetramers in what concerns N-2).
For compound 3, a tetramer, the effects are -4/-15 ppm, and
for compound 4 (Table 6) we have found 6/-15 ppm, both
consistent with a tetramer although N-2 seems superior as a
probe. For compound 5 (Table 7) the ∆δ values are 1/-6 ppm,
typical of a dimer, but for dimer 6 (Table 8) the values are
-13/-7 ppm; the effect on N-2 is normal but that on N-1 is
abnormal (-13 ppm). The polymorph represented in Figure 6
has ∆δ values of -7/-19, so the value of N-2 points out toward
a 6b6b6b6b tetramer, but the value for N-1 shows again a
deviation of -13 ppm (from +6 to -7 ppm), probably due to
the N-H‚‚‚π interaction in the Wilcox’s torsion depicted in
Scheme 3.
5. General Conclusions. In the present paper on the
properties of pyrazoles in the solid state and about how the
J. Org. Chem, Vol. 71, No. 18, 2006 6889

Claramunt et al.
hydroxide to liberate the [15N2] hydrazine. Compounds 12 and 12*
(5) 13C and 15N CPMAS NMR are in agreement with the
crystallographic results allowing a determination of dimer or
tetramer motif (1a1a1a1a, 4a4a4a4a, 6b6b6b6b) when no
crystal structure is available, where the chemical shift of N-2
is particularly useful for this purpose.
(6) To the already known case of 1 (1a1a1a1a vs 1a1a1b1b,
desmotropy) we have added a new case of polymorphism, that
of 6b6b dimer versus 6b6b6b6b tetramer.
1
were fully characterized by H, 13C, and 15N NMR spectroscopy
(δ and Js) and the data are supplied in Table S4 of the Supporting
Information.
Transformation of 12 into 6. An amount of 544 mg (1.7 mmol)
of pyrazoline 12 are dissolved in 20 mL of ethanol, and 1 mL of
37% hydrochloric acid is added. The mixture is refluxed 1 h with
stirring. The solvent is evaporated under reduced pressure, 20 mL
of water is added, and the aqueous solution is neutralized with 2.5
M sodium hydroxide. The solution was extracted thrice with ether,
and the ethereal solution was dried over magnesium sulfate, filtered,
and evaporated to dryness. 3(5)-(2-Benzylphenyl)-5(3)-(trifluoro-
methyl)-1H-pyrazole (6) was obtained as a white solid (464 mg,
1.53 mmol, 90%) polymorph with mp 85.1 °C from acetonitrile/
petroleum ether by slow evaporation. m/z (EI) 302 (M+, 100). Anal.
Calcd for C17H13F3N2 (302.29): C, 67.5; H, 4.3; N, 9.3. Found:
C, 67.4; H, 4.5; N, 9.1.
Experimental Section
General Methods. Mass spectra were recorded in a mass
spectrometer coupled with a gas chromatographer (EI 60 eV). For
each sample only the molecular ion and the base peak are reported.
DSC were recorded in a calorimeter using samples of 3-5 mg in
sealed aluminum pans with heating/freezing rates of 5-15 °C
min-1
.
N-Methyl Derivatives 7 and 8. A mixture of 500 mg (1.65
mmol) of pyrazole 6, 235 mg (1.65 mmol) of methyl iodide, and
88.8 mg (1.65 mmol) of sodium methoxide in 50 mL of methanol
were heated at reflux for 4 h. The solvent was evaporated to dryness,
and the residue was dissolved in the minimum amount of water
and neutralized with 50% HCl aq. The solution was extracted three
times with hot chloroform (50 mL), and the chloroform layer was
evaporated. The residue contains starting pyrazole 6 and a 30:70
mixture of pyrazoles 7 and 8 that was not separated and used as
such for NMR studies. Yield 300 mg, 0.95 mmol, 58%.
NMR Spectroscopy. (a) In Solution. The measurements were
Synthesis of â-Diketones. General Procedure. Compounds 9,
10, and 11 were obtained by Claisen condensation between
acetophenone (or 2-benzylacetophenone) and the corresponding
ester.
4-Methyl-1-phenylpentane-1,3-dione (9).26 Yellow-reddish liq-
1
uid, yield 30%. H NMR (CDCl3): δ 1.22 [6H, H-5], 2.62 [1H,
H-4], 6.19 [1H, H-2], 7.47 [3H, 2Hm,1Hp], 7.88 [2H, 2Ho], 15.39
[1H, OH], 100% enol.
1,4-Diphenylbutane-1,3-dione (10). Pale yellow solid, yield
98%, mp 52 °C (lit. 52 °C).27 1H NMR (CDCl3): δ 3.70 [2H, H-4],
6.10 [1H, H-2], 7.10-7.79 [8H, Harom], 7.80 [2H, 2Ho], 15.50 [1H,
OH], 100% enol.
1
carried out on a 9.4 T spectrometer (400.13 MHz for H, 100.62
MHz for 13C, and 40.56 MHz for 15N) using a 5 mm X-H inverse
detection probe provided with a z-gradient coil. The chemical shifts
(δ in ppm) of 1H and 13C are referred to the corresponding
solvents: CDCl3 (7.26), CD2Cl2 (5.32), DMSO-d6 (2.49), HMPA-
d18 (2.52), and CDCl3 (77.0), CD2Cl2 (53.8), DMSO-d6 (39.5),
HMPA-d18 (35.8), respectively. For the 15N NMR spectra, ni-
tromethane (0.00) was used as an external reference. Coupling
constants J are given in Hz.
1-(2-Benzylphenyl)-4,4,4-trifluorobutane-1,3-dione (11).28 Pale
1
orange liquid, yield 93%. H NMR (CDCl3): δ 4.17 [2H, CH2],
6.10 [1H, H-2], 7.00-7.27 [7H, Harom], 7.35 [1H, H-4′], 7.45 [1H,
H-6′], 14.58 [1H, OH], 100% enol.
Synthesis of Pyrazoles. General Procedure. Compounds 4, 5,
and 6 and their [15N2] labeled analogues, 4*, 5*, and 6* were
prepared by reacting the corresponding â-diketones 9, 10, and 11
with 98% hydrazine hydrate (14N) or hydrazine sulfate (15N).
3(5)-Isopropyl-5(3)-phenyl-1H-pyrazole (4). From 380 mg (2
mmol) of 9, a white solid, mp 109.5 °C, was obtained (316 mg,
1.7 mmol, 85%). m/z (EI) 186 [(M+) (64)], 171 (100). Anal. Calcd
for C12H14N2 (186.12): C, 77.4; H, 7.6; N, 15.0. Found: C, 77.1;
H, 7.4; N, 14.7.
Digital resolution was 0.34 Hz/point for 1H NMR, 0.63 Hz/point
for 13C NMR, and 0.44 Hz/point for 15N NMR. Monodimensional
15N NMR spectra were obtained using the inVerse gated sequence.
The 2D (1H-1H) gs-COSY, (1H-13C) gs-HMQC, and (1H-13C)
gs-HMBC spectra were recorded and processed using Bruker
software in a mode nonsensitive to the phase. Gradient selection
was selected by means of a pulse sequence truncated at 5% in the
sinusoid with a 1 ms duration.
(b) In the Solid-State. 13C (100.73 MHz) and 15N (40.60 MHz)
CP/MAS NMR spectra were recorded in a wide-bore 9.4 T
spectrometer provided with a 4 mm DVT probe. The samples were
previously compacted in zirconia rotors with Kel-F caps. The used
rotation frequencies were 12 kHz for the 13C experiments and 6
kHz for the 15N ones. For 1H decoupling, the TPPM sequence was
used. 13C chemical shifts are referred to glycine (176.1 ppm); those
of 15N are referred to 15NH4Cl and converted to nitromethane by
the relationship: δ 15N (CH3NO2 ext.) ) δ 15N [NH4Cl (s)] - 338.1
ppm.
3(5)-Benzyl-5(3)-phenyl-1H-pyrazole (5). From 476 mg (2
mmol) of 10, a yellow-orange solid, mp 88.9 °C [lit. 91 °C],9c was
obtained (346 mg, 1.48 mmol, 74%).
3(5)-(2-Benzylphenyl)-5(3)-trifluoromethyl-1H-pyrazole (6).
Compound 6 was prepared from 11 in two steps. To 612.6 mg (2
mmol) of 11 in 10 mL of ethanol were added dropwise with a gentle
stirring, 3 mmol of 98% hydrazine hydrate (153 mg, 0.15 mL).
The mixture is stirred for 4 h. Half of the ethanol is evaporated
under reduced pressure. The solution, on standing 24 h at room
temperature, affords a white paste of 3-(2-benzylphenyl)-5-triflu-
oromethyl-1H-pyrazolin-5-ol (12), which was purified by column
chromatography over silica gel (70-230 mesh), using as eluent
dichloromethane/ethanol 98:2. Yield 85% (544 mg, 1.7 mmol).
(c) Variable Temperature. In solution and solid-state NMR at
9.4 T, variable temperature (VT) experiments were carried out to
study proton-transfer dynamics in the temperature range of 300-
180 K. A temperature unit was used to control the cooling gas
together with an exchanger to reach low temperatures. To avoid
the 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. In solid NMR measurements zirconia caps
were necessary.
(26) Muir, W. M.; Ritchie, P. D.; Lyman, D. J. J. Org. Chem. 1966, 31,
3790.
(27) Smith, L. I.; Kelly, R. E. J. Am. Chem. Soc. 1952, 74, 3300.
(28) Baxter, A. J. G.; Fuher, J.; Teague, S. J. Synthesis 1994, 2, 207.
The 15N labeled compound 12* was prepared from [15N2]
hydrazine sulfate, that needs previous treatment with 10% sodium
6890 J. Org. Chem., Vol. 71, No. 18, 2006

The Structure of Pyrazoles in the Solid State
TABLE 9. Crystal Data and Structure Refinement for Compounds
5 and 6
hydrogen atoms were refined anisotropically. For 5, all hydrogen
atoms were included in their calculated positions and refined riding
on the respective carbon or nitrogen bonded atoms; for 6 the
hydrogens were located in a difference Fourier synthesis and their
coordinates were refined. Final R (Rw) values were 6.42 (19.8) for
5 and 4.36 (12.4) for 6. Largest peaks and holes in the final
difference map were 0.184 and -0.195 and 0.249 and -0.235 e -3
for 5 and 6, respectively.
Theoretical Calculations. Energy calculations were carried out
at the hybrid Becke B3LYP/6-31G** level with basis sets of
Gaussian-type functions30 within the Windows Titan 1.0.5 package31
and include zero point energy (ZPE) corrections. Starting geometries
for the calculations were the optimized ones obtained at the HF/
6-31G** level, and no symmetry restrictions were imposed. In all
pyrazoles, the final geometries really correspond to the minima as
no imaginary frequencies appear.
crystal data
5
6
empirical formula
fw
C48H42N6 (3 molecules)
702.88
C17H13F3N2
302.29
wavelength (Å)
cryst syst
space group
a (Å)
b (Å)
c (Å)
0.71073
monoclinic
P2(1)/n
14.078(2)
15.693(2)
18.185(2)
106.286(3)
3856.2(8)
4
0.71073
monoclinic
P2(1)/c
12.191(1)
5.1933(5)
23.579(2)
103.880(2)
1449.2(2)
4
â (deg)
V (Å3)
Z
density (calcd)
1.211
1.386
(Mg/m3)
abs coeff (mm-1
)
0.072
0.110
In the case of both tautomers of compound 6, the exploration of
the conformational space was achieved at the same level using a
systematic search. The three angles that define the conformation
of the benzyl-phenyl group were explored using a 2(pyrazole-
C6H4/phenyl) × 3(C6H4/phenyl-CH2) × 3(CH2-C6H5/phenyl).
F(000)
theta range (deg)
index ranges
1488
624
1.63 to 25.0
-16, -18, -19 to
16, 18, 21
19937
6769 [R(int) )
0.2098]
1.72 to 28.85
-14, -6, -29 to
15, 7, 30
8664
3456 [R(int) )
0.0440]
reflns collected
independent reflns
data/restraints/params
6769/0/488
0.0642 (1527 obsd
reflns)
3456/0/238
0.0463 (1901 obsd
reflns)
Acknowledgment. Thanks are given to MCyT of Spain for
economic support (Project Number BQU 2003-00976).
Ra [I > 2σ(I)]
R wFb (all data)
0.198
0.1240
2
2
2
Supporting Information Available: Tables of atom coordinates
and absolute energies to document the computational B3LYP/6-
31G** calculations for tautomers a and b of compounds 1-6 (pages
a ∑||Fo| - |Fc||/∑|Fo|. b {∑[w(Fo - Fc )2]/∑[w(Fo )2]}1/2
.
Crystal Structure Determination. Suitable crystals for X-ray
diffraction experiments were obtained by crystallization of 5 in
chloroform/hexane and 6 from acetonitrile/petroleum ether. Data
collection for both compounds was carried out at room temperature
on a CCD diffractometer using graphite-monochromated Mo KR
radiation () 0.71073) operating at 50 kV and 30 mA. In both cases,
data were collected over a hemisphere of the reciprocal space by
combination of three exposure sets. Each exposure of 30 s covered
0.3 in. The cell parameters were determined and refined by a least-
squares fit of all reflections. The first 50 frames were recollected
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 9.
1
S1-S26) and the complete H NMR, 13C NMR, and 15NMR data
(chemical shifts in ppm and coupling constants J in Hz) of pyrazoles
4, 5, and 6 as well as those of pyrazoline 12 (Tables S1-S4, pages
S27-S40). This material is available free of charge via the Internet
at http://pubs.acs.org.
JO0609935
(29) Sheldrick, G. M. SHELX97, Program for Refinement of Crystal
Structure; University of Go¨ttingen: Go¨ttingen, Germany, 1997.
(30) (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648. (b) Lee, C.; Yang,
W.; Parr, R. G. Phys. ReV. B 1988, 37, 785. (c) Becke, A. D. Phys. ReV. A
1988, 38, 3098. (d) Miehlich, B.; Savin, A.; Stoll, H.; Preuss, H. Chem.
Phys. Lett. 1989, 157, 200.
The structures were solved by direct methods and refined by
full-matrix least-squares procedures on F2 (SHELXL-97).29 All non-
(31) Windows Titan 1.05; Wavefunction Inc.: Irvine, CA .
J. Org. Chem, Vol. 71, No. 18, 2006 6891