New Pyrazole- and Benzimidazole-derived Ligand Systems

Article abstract of DOI:10.1002/jhet.3155

A series of N-containing heterocyclic compounds have been synthesized using approaches such as the well-known Knorr synthesis, and a facile N-alkylation method. This series of compounds includes pyrazole derivatives, tris(2-benzimidazolylmethyl)amine derivatives, and “pincer” ligands. Characterization methods include ¹H NMR, FT-IR, CHN analyses, UV-vis spectroscopy, and fluorimetry, while X-ray crystal structures are reported for most of the compounds. The crystallographic results affirm a ¹³C NMR method for isomer assignment of substituted pyrazoles.

Full text of DOI:10.1002/jhet.3155

Month 2018
Mohammad Nozari,
New Pyrazole- and Benzimidazole-derived Ligand Systems
a
a
Anthony W. Addison,
GorDan T. Reeves,b Matthias Zeller,c Jerry P. Jasinski,d
*
*
Manpreet Kaur,d Jayakumar G. Gilbert,e Clifton R. Hamilton,e Jonathan M. Popovitch,a† Lawrence M. Wolf,a†
Lindsay E. Crist,a† and Natalia Bastidaa
aDepartment of Chemistry, Drexel University, 3141 Chestnut Street, Philadelphia, Pennsylvania 19104, USA
bDepartment of Chemistry, Stockton University, 101 Vera King Farris Drive, Galloway, New Jersey 08205, USA
cDepartment of Chemistry, Youngstown State University, One University Plaza, Youngstown, Ohio 44555, USA
dDepartment of Chemistry, Keene State College, 229 Main Street, Keene, New Hampshire 03435, USA
eDepartment of Chemistry, Temple University, 1901 N. 13th St, Philadelphia, Pennsylvania 19122, USA
*
E-mail: mn468@drexel.edu; addisona@drexel.edu
Received August 17, 2017
DOI 10.1002/jhet.3155
Published online 00 Month 2018 in Wiley Online Library (wileyonlinelibrary.com).
†Work performed in partial fulfillment of the requirements for the Drexel University baccalaureate degree.
A series of N-containing heterocyclic compounds have been synthesized using approaches such as the
well-known Knorr synthesis, and a facile N-alkylation method. This series of compounds includes pyrazole
derivatives, tris(2-benzimidazolylmethyl)amine derivatives, and “pincer” ligands. Characterization methods
1
include H NMR, FT-IR, CHN analyses, UV-vis spectroscopy, and fluorimetry, while X-ray crystal struc-
tures are reported for most of the compounds. The crystallographic results affirm a 13C NMR method for iso-
mer assignment of substituted pyrazoles.
J. Heterocyclic Chem., 00, 00 (2018).
INTRODUCTION
antifungal properties [17,18], while benzimidazole and
pyrazole moieties are among the most frequently used
ring systems for small molecule drugs listed by the US
FDA [19].
Transition metal ions play an important role in the
physical and the chemical properties of enzymes [1]. The
structural characterization of such enzymes has provided
insight in understanding the type of donor groups that are
bonded to the transition metal ions [2]. Among these
donor groups, histidine imidazole donors are found in a
wide variety of metalloenzymes [3]. Among other
applications, nitrogen-containing compounds can be used
as sensors for detecting toxic benzene metabolites [4].
One of the important factors in selective structuring of
complexes' architecture is the hydrogen bonding
capability of the ligands. These ligands provide available
hydrogens and are also suitable candidates for selective
complexation [5]. Ligands that incorporate pyridyl,
benzimidazolyl, quinolyl, and indazole groups in their
framework have had frequent applications due to their
relative ease of synthesis and the ready incorporation of
steric constraints [6–11]. Pyrazole derivatives, especially
pyrazoles substituted with N-containing heterocycles,
have been reported to exhibit antitumor [12–16] and
The tridentate ligand tris(2-benzimidazolylmethyl)amine
(NTB) and its alkyl-substituted derivatives tris(N-R-
benzimidazol-2-ylmethyl)amine (R = methyl, Me3NTB;
R = ethyl, Et3NTB; R = propyl, Pr3NTB) can form both
mononuclear and multinuclear complexes, which have
long been studied as models for metalloenzyme active
sites [20–22] and more recently for their role in
water electro-oxidation catalysis (with long-chain N-
substituents) [23], photoluminescence of lanthanide
complexes such as those of Sm3+, Eu3+ and Tb3+, Yb3+
[24,25], and DNA binding properties of Zn and Ni
complexes [26]. A recent study on a ternary Fe(III)
complex has shown that the complex binds to DNA via an
intercalation binding mode [27]. Rhenium(I) complexes of
imidazole derivatives have been used for electrocatalytic
CO2 reduction [28]. Imidazole-copper-based catalysts
have recently been studied for application in lowering
water oxidation overpotentials [29].
© 2018 Wiley Periodicals, Inc.

M. Nozari, A. W. Addison, G. T. Reeves, M. Zeller, J. P. Jasinski, M. Kaur, J. G. Gilbert,
C. R. Hamilton, J. M. Popovitch, L. M. Wolf, L. E. Crist, and N. Bastida
Vol 000
RESULTS AND DISCUSSION
derivatives then attack the second carbonyl group,
resulting in a diimine. Deprotonation of the diimine
delivers the pyrazole compound, while protonation of the
initial carbonyl makes it more susceptible to attack by a
nucleophilic group [30].
To obtain the ligand 1, 2-benzoylcyclohexanone and 2-
hydrazinoquinoline were refluxed in ethanol for 24 h.
Because there are two possible sites for hydrazine
nucleophilic attack with nonsymmetric diketones, we
have to consider two isomer possibilities (Fig. 3). A
Here, we report the synthesis and characterization of a
diverse group of heterocyclic ligands (Figs. 1 and 2). For
ligands 1–4, a Knorr-type reaction is used to convert
heterocyclic hydrazines and 1,3-dicarbonyl derivatives to
substituted pyrazole compounds. The hydrazine
derivatives utilized were 2-hydrazinoquinoline and 2-
hydrazinopyridine. Typical Knorr reactions are initiated
by imine (hydrazone) formation, the hydrazone
Figure 1. Knorr condensation reactions.
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Pyrazole and Benzimidazole-derived Ligands
isomer in the bulk product, as the number of resonances
observed in the spectrum corresponds to the number of
carbon atoms in the product.
The X-ray structure obtained (Fig. 4) confirms the 5-aryl
substituted version’s formation. Crystal and refinement X-
ray data are presented in Tables 1A and 1B.
The ligand-1 molecule is not overall planar, the angles
formed between the phenyl- and quinoline-containing
planes with the pyrazole plane in the molecule are 36.6°
and 38.8°. When the molecule is viewed along the
pyrazole plane with the cyclohexenyl group at the front,
then the enantiomers within the unit cell of 1 may be
distinguished by the twist of the quinolyl group versus
the pyrazole plane: clockwise in one case, anticlockwise
in the other. In 1H NMR, the chemical shifts for
quinoline, phenyl, and cyclohexane protons are well
resolved at (8.46, 8.02), (7.63, 7.18), and (2.83,
1.84) ppm, respectively. Similar results are observed for
our other ligands with analogous structures. The IR
spectrum displayed absorption bands at νmax = 2926,
3061, 1616, and 1598 cmꢀ1 characteristic bands for sp3
CH, sp2 CH, C═N, and C═C vibrations, respectively, the
last three of which are in the range previously reported
for pyrazoles [34].
Figure 2. Heterocyclic ligands via nitrile-based condensations and N-
alkylations.
Ligand 2 (Fig. 5) was synthesized using the same
technique as for 1, but with more extensive reflux and
using dibenzoylmethane as the dicarbonyl compound.
The 1H NMR shows chemical shifts for quinoline,
phenyl, and pyrazole protons at 8.10, (7.84, 7.50, and
7.35), and 6.9 ppm, respectively. Ligand 2 displays an IR
spectrum similar to that of ligand 1.
The quinolyl, pyrazolyl, and 3-phenyl groups form a
bowed plane, the bowing being a contributor to the inter-
Figure 3. Two possible isomers for pyrazoles derived from nonsymmet-
ric diketones.
similar pyrazole isomerism has been investigated, where
the different isomers were isolated and proton and carbon
atoms of the substituent groups were assigned by NMR
[31–33]. It has been reported that 3-aryl substituent
positioning is preferred over 5-aryl substitution [31];
however, exceptions have been observed whereby
internal H-bonding has promoted the 5-aryl substituent
[31]. Singh et al. have reported larger values of δ C4 13C
NMR chemical shift for a 3-aryl substituent than a 5-aryl
substituent (δ C4:103.8, 108.3, respectively) [32], while
in our case, the δ C4 chemical shift is 109.2 (Fig. S15).
In a comparison of chemical shifts for C3 and C5,
Catalan et al. [31] demonstrated that whichever of C3 or
C5 is aryl substituted possesses the larger 13C chemical
shift value, and this further supports our assignment. In
addition, 13C NMR evidences the existence of only one
Figure 4. ORTEP structure of the bidentate quinolyl–tetrahydroindazole
ligand 1. For this and all subsequent ORTEP diagrams, the nonhydrogen
atoms are rendered as 50% probability ellipsoids, and H atoms are ren-
dered as spheres of arbitrary radius. Other structural views of this and
succeeding molecules are in Figures S1–S13. [Color figure can be
viewed at wileyonlinelibrary.com]
Journal of Heterocyclic Chemistry
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M. Nozari, A. W. Addison, G. T. Reeves, M. Zeller, J. P. Jasinski, M. Kaur, J. G. Gilbert,
C. R. Hamilton, J. M. Popovitch, L. M. Wolf, L. E. Crist, and N. Bastida
Vol 000
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DOI 10.1002/jhet

Month 2018
Pyrazole and Benzimidazole-derived Ligands
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M. Nozari, A. W. Addison, G. T. Reeves, M. Zeller, J. P. Jasinski, M. Kaur, J. G. Gilbert,
C. R. Hamilton, J. M. Popovitch, L. M. Wolf, L. E. Crist, and N. Bastida
Vol 000
Figure 5. ORTEP structure of the bidentate quinolyl–pyrazole ligand 2.
[Color figure can be viewed at wileyonlinelibrary.com]
ring angles (16.6° for the phenyl group, 22.7° for the
quinolyl group, vs. the pyrazole ring) (Fig. 5). The
handedness of rotation of the 5-phenyl group (34.5° vs.
the pyrazole) with respect to the bowed plane is
presumably the source of chirality of the unit cells, this
compound being an example of conglomerate
crystallization (spontaneous resolution) [35]. The
molecules are arrayed roughly parallel to the b-direction
(the quinoline rings are tipped by 21° to it). The 5-phenyl
rings of one array are interdigitated between the quinoline
rings of molecules of the adjacent array, with the arraying
and interdigitation alternating in direction, but there is no
π-π stacking.
Figure 6. ORTEP structure of ligand
hydroxypyrazoline. [Color figure can be viewed at wileyonlinelibrary.com]
2
intermediate, the
explored both in solution and in the solid state [36]; for
3-(hydroxymethylene)camphor, the condensation can be
envisioned as proceeding via the diketone to form the
hydrazone and then the pyrazole. This ligand contains
1
CH, CH2, and CH3 groups that are observed in H NMR
at 7.48, 1.92, and 0.96 ppm, respectively. In the IR
spectrum characteristic bands at 3054 cmꢀ1 (ν sp3 CH),
2953 cmꢀ1 (ν sp2 CH), 1611 cmꢀ1, and 1592 cmꢀ1 are
observed. This chiral compound was characterized by X-
ray crystallography (Fig. 7), circular dichroism (CD)
(Fig. 8), and optical rotation. There are four molecules of
equivalent symmetry in the P212121 unit cell, one of the
space groups associated with intrinsically chiral structures.
With shorter refluxing (12 h in EtOH) of the reactants,
dehydration of the diamine is incomplete, leaving a
hydroxyl group on the molecule. This intermediate
pyrazoline has also been isolated and defined by its X-ray
structure (Fig. 6).
The OH group on the central ring in the intermediate
causes the two phenyl rings to twist more toward each
other, the angle between the two phenyl rings being 26.4°
in the final product, while it is 100.0° in the intermediate.
The potential role of the 5-phenyl group’s rotation in
individual
molecule
chirality
is
presumably
overshadowed by the stereochemistry of the pyrazoline
C5 itself. In the intermediate, several interactions are
observed between the OH hydrogen and the quinoline
nitrogen within the same molecule (O─H···N is 2.24 Å),
and oxygen of OH and two hydrogens on the adjacent
quinoline molecule (C─H···O: 2.50, 2.66 Å), these
interactions being attributed to H-bonding. The pyridine
ring planes are aligned parallel to the a-direction.
Formation of ligand 3 was a rather slow reaction at reflux
in EtOH, requiring that 3-(hydroxymethylene)camphor and
2-hydrazinopyridine be refluxed for 2.5 days. The keto-enol
tautomerism of 3-(hydroxymethylene)camphor has been
Figure 7. ORTEP structure of the chiral pyridyl–pyrazole ligand 3.
[Color figure can be viewed at wileyonlinelibrary.com]
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Pyrazole and Benzimidazole-derived Ligands
Figure 9. ORTEP structure of the quinolyl–indazole ligand 4. [Color
figure can be viewed at wileyonlinelibrary.com]
2-hydrazinoquinoline instead of 20-fluoroacetophenone.
1
Ligand 5 has a similar IR spectrum to ligand 4, but in H
NMR, the distinctive chemical shifts are well-resolved for
the quinoline protons at 8.22 (1 H, d), 8.09(1 H, d), 7.90
(1 H, d), 7.80 (1 H, d), 7.68 (1 H, t), 7.48 (1 H, t) ppm,
cyclohexane and methyl protons at 2.76 (4 H, m), 2.52 (2
H, t), 1.82 (5 H, m) ppm.
The X-ray structure of the compound (Fig. 10) reveals
four symmetry-equivalent molecules in the monoclinic
unit cell. The molecule is not planar overall, the
quinoline and pyrazole planes being twisted 15.5° away
from each other. The molecules are arrayed in two
directions in the lattice, at 51° to one another, and
putative stacking is at ca. 4.45 Å, because of the
cyclohexenyl ring’s saturation.
Figure 8. A: UV absorption spectrum of 79 μM ligand 3 in acetonitrile.
B: The UV-CD spectrum of the ligand 3 solution. C: Kuhn anisotropy
spectrum of the compound. [Color figure can be viewed at
wileyonlinelibrary.com]
The pyridine plane is twisted 25.3° away from the pyrazole
plane. The compound has a positive specific rotation [α]
20
= +13.8 deg cmꢀ2 gꢀ1 (0.025 g/100 mL, CH3CN).
D
The UV-CD spectrum of ligand 3 displays a positive
Cotton effect at λmax = 261 nm, with a broad Kuhn
anisotropy of ca. +0.0086–+0.0089 in the longest-
wavelength absorption region, consistent with the optical
rotation’s sign.
Some compounds are less reactive toward condensation
under these conditions. For example, we attempted to
prepare ligand 6 using the aforementioned techniques,
however, after 2 days' reflux in EtOH, the desired product
was not detected and the ring closure was incomplete.
Ligand 4 was prepared by a rather different approach,
using 20-fluoroacetophenone instead of a dicarbonyl.
Initial condensation of the hydrazine NH2 group with the
ketone carbonyl group is followed by nucleophilic attack
of the second nitrogen on the fluorine-bonded carbon, so
that fluoride acts as a leaving group, resulting in
generation of protonated ligand 4. There are four
symmetry-equivalent molecules in the unit cell, (Fig. 9).
The molecules are almost planar, the quinoline and
pyrazole planes being twisted only 6.4° away from
complete coplanarity. The molecules are head-to-tail π-
stacked at 19° to the a-direction, with the quinoline &
indazole rings 3.50 0.12 Å apart.
The structure of the Knorr product pyrazole ligand 5 is
analogous to that of ligand 4 except for the saturated
ring, 2-acetylcyclohexanone being used as reactant with
Figure 10. ORTEP structure of the quinolyl–tetrahydroindazole ligand 5.
[Color figure can be viewed at wileyonlinelibrary.com]
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M. Nozari, A. W. Addison, G. T. Reeves, M. Zeller, J. P. Jasinski, M. Kaur, J. G. Gilbert,
C. R. Hamilton, J. M. Popovitch, L. M. Wolf, L. E. Crist, and N. Bastida
Vol 000
Eventually, ligand 6 was successfully prepared using
2,2,6,6-tetramethyl-3,5-heptanedione and hydrazinoquinoline
by refluxing in ethylene glycol for a period of 24 h. Two
solvomorphs were obtained: crystallization from aqueous
ethanol yielded monoclinic (P21/c) crystals; however, a
better-quality structure (Pca21; Tables 1 and 2; Fig. 11)
was obtained for crystals from methanol, incorporating
solvating MeOH. Some π-π stacking interactions in
the former case are replaced by stronger H-bonding
interactions in this latter solvate.
Figure 12. The two possible isomers for ligand 7.
1.80 Å), and of the N of the pyrazole with H of the water
molecule (O─H···N is 2.86 Å). Two molecules of each
enantiomer are present in the unit cell (Fig. 13), their
individual chirality again arising from ring twists versus
one another. Relative to the pyrazole ring plane, the
phenol and pyridine rings are both rotated clockwise
(phenolic-O “up on left”) in one enantiomer,
anticlockwise (phenolic-O “down on left”) in the other.
The X-ray structure also shows that the pyridyl and
phenol planes are rotated by 53.7° and 56.2° versus the
pyrazole plane, respectively. Alongside the typical
pyrazole IR bands, a broad OH vibration is also observed
at ν = 3400 cmꢀ1 in the IR spectrum. Beside the
distinctive CH and CH3 proton shifts, the phenolic OH
proton is observed as a singlet at 9.32 ppm in the NMR.
In a similar manner, salicyloylacetone reacts with 2-
hydrazinoquinoline to produce ligand 8. The X-ray
structure of the compound (Fig. 14) shows that this
molecule is again not planar overall; the quinoline and
phenol planes are rotated by 49.1° and 47.5° versus the
pyrazole plane, respectively. The individual molecule
solid-state chirality is akin to that in ligand 7, the
nonpyrazole rings being concordantly rotated to be
pseudo-parallel in either of the two directions. Along the
crystallographic c-direction, π-π stacking of the quinoline
rings is observed, with ring separations of 3.63 0.03 Å.
Similarly to ligand 7, there is a water of solvation in the
structure of ligand 8, with interactions observed between O
of the water molecule and H on the hydroxyl group
(O─H···O is 1.76 Å), and also between N of the pyrazole
and the H of the water molecule (O─H···N is 2.90 Å).
The IR spectrum displayed a characteristic broad OH
vibration band at ν = 3350 cmꢀ1, while 8 has a similar
1H NMR pattern to that of ligand 7; the phenolic OH
proton is observed at 9.22 ppm. As in the case of ligand
7, this is the less-suited isomer for chelation, although in
both cases, the compounds may act as anionic ligands via
phenol deprotonation.
Interactions are observed between the alcohol OH and N
on pyrazole, (O─H…N is 2.08 Å), and O of OH and H on
the quinoline (C─H…O is 2.65 Å). The molecule is not
overall planar, with the quinoline and pyrazole planes
turned 51.8° away from coplanarity. In the 1H NMR,
methyl protons are observed as singlets as 1.28 and
1.36 ppm, the C4 pyrazole proton at 6.28 ppm and
quinoline protons at 8.08–7.68 ppm.
Salicyloylacetone
(1-(20-hydroxyphenyl)butane-1,3-
dione) reacts with 2-hydrazinopyridine for 3 days under
reflux in EtOH to yield ligand 7. Unlike the cyclization of
salicyloylacetone by loss of a water molecule and
chromene formation [37], the phenolic OH group does not
participate in the reaction and the carbonyl groups
undergo only a cyclization with hydrazinopyridine. Of the
two possible isomeric products (Fig. 12), the X-ray results
evidence the dominant one as being the “A” isomer
(Fig. 13), which is unsuitable as a tridentate chelating
agent, although (N,N) or (N,O) bidentacy is feasible in a
mononucleating situation. As in ligand 1 and ligand 5,
initial hydrazone formation has occurred at the alkyl-,
rather than the aryl-substituted carbonyl [31]. A solvating
water molecule can be seen in the structure (Fig. 13).
In 7, there are H-bonding interactions between O of the
water molecule and H on the hydroxyl group (O─H···O is
Tridentate 9 (Fig. 15) belongs to what has recently
become known as the “pincer” type class of ligands,
which are effective metal chelators whose coordination
chemistry has long been studied. They have customarily
been prepared by condensation of phthalonitrile with
primary (aromatic) amines, as per Elvidge & Linstead’s
method [38] or Siegl’s variation thereon [39], the latter
Figure 11. ORTEP structure of the quinolyl–pyrazole ligand 6. [Color
figure can be viewed at wileyonlinelibrary.com]
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Pyrazole and Benzimidazole-derived Ligands
Figure 13. ORTEP rendering of the phenolic pyridyl–pyrazole ligand 7 unit cell, approximately along the a-direction; the upper left and lower right
molecules, for instance, are enantiomers. (CrystalMaker 9, inverse stereoview, 75% probability ellipsoids). [Color figure can be viewed at
wileyonlinelibrary.com]
Figure 14. ORTEP structure of the phenolic quinolyl–pyrazole ligand 8.
[Color figure can be viewed at wileyonlinelibrary.com]
Figure 15. ORTEP structure of the phenylpyrazolyl–diiminoisoindoline
ligand 9. [Color figure can be viewed at wileyonlinelibrary.com]
using cationic promoters in an alcohol medium [39].
in loss of ammonia and formation of the product [39].
For preparing ligand 9, phthalonitrile was simply heated
with 3-amino-5-phenylpyrazole. A microwave approach
utilized a small amount of ethylene glycol as a
microwave-absorbing solvent. The thermal solventless
melt method nonetheless showed a higher yield, and was
more reproducible than the microwave technique. The
characteristic isoindoline NH vibration is observed in IR
spectroscopy at ν = 3300 cmꢀ1; NH protons on pyrazole
However, neither solvent nor promoter are necessary, as
fusion of neat reactants is quite effective [6], this
solventless fusion method requiring higher temperature
(160–190°C), but being relatively quick. It is surmised
that primary amine R-NH2 undergoes nucleophilic
addition across a phthalonitrile C─N linkage, leading to
intramolecular cyclization with formation of an
iminoisoindoline. This bears the R-group as the imine’s
N-substituent, and the addition of a second amine results
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M. Nozari, A. W. Addison, G. T. Reeves, M. Zeller, J. P. Jasinski, M. Kaur, J. G. Gilbert,
C. R. Hamilton, J. M. Popovitch, L. M. Wolf, L. E. Crist, and N. Bastida
Vol 000
and isoindoline are observed at δ 13.57 ppm (2H) and
1
6.81 ppm (1H) in the H NMR.
The X-ray structure obtained for ligand 9 displays both
an N-methylpyrrolidinone (NMP) and a water molecule
of solvation, with H-bonding interactions observed
between N of pyrazole and H of the water molecule
(O─H···N is 2.11 Å) and also between O of the water
molecule and H on the pyrazole (N─H···O is 2.85 Å), as
well as between O of NMP and H on the pyrazole
(N─H···O is 1.87 Å; Fig. 15). Indeed, recrystallization of
the product from NMP occurred only after absorption of
atmospheric water by the solution over a long period of
time. None of the molecule’s rings are coplanar. The
terminal benzene planes are twisted 11.3° and 17.4° away
from their adjacent pyrazole planes, which are in turn
twisted 6.3° and 37.8° away from the isoindoline plane,
in the opposite direction. The isoindoline-pyrazole(N1)-
phenyl(C6) ring sets are almost coplanar, with
consecutive but opposite twists of 5.3° and 11.3°. The
solvating NMP appears to displace the N7/C21 arm so
that a C17-N5-C18-C19 torsion of 37° (and like
interplanar angle) twists this other phenylpyrazolyl arm
further away from the isoindoline plane. The
corresponding phenyl versus pyrazolyl twist is 17.4°,
again conrotatory. Nor is the N5─C17 imine bond
completely immune to these influences, being itself
twisted by 5.8°. Nonetheless, a broader view of the
molecule is that there is substantial planarity, although
with one of the phenylpyrazolyl arms twisted away from
the rest of the molecule, so that the two phenyl groups
are at 32.4° to one another. The isoindoline moieties are
stacked alternating head:tail roughly along an ab
Figure 16. ORTEP structure of the methylpyrazolyl–diiminoisoindoline
ligand 10. [Color figure can be viewed at wileyonlinelibrary.com]
occur at each of the two nitriles and the
bis(tetrahydropyrimidine) ligand (11) results. The IR
spectrum displays
a
characteristic NH vibration at
ν = 3255 cmꢀ1. CH, NH, and CH2 protons are observed by
1H NMR at 8.22, 7.90, and 3.42–2.62 ppm, respectively.
This ligand is
a homologue of the corresponding
bis(imidazoline) described by Lever et al. [40].
N-alkylation of NTB, tris(benzimidazol-2-ylmethyl)
amine, to obtain N-substituted derivatives, namely,
Me3NTB, Et3NTB, Pr3NTB, Bu3NTB, Np3NTB, and
An3NTB, utilized sodium metal in dimethyl sulfoxide
(DMSO) for deprotonation of the labile NH units [41,42].
Past syntheses of related ligands have utilized
(commercially available) N-methyl-o-phenylenediamine
(for Me3NTB) or similar N─H deprotonation with
reagents and solvents that could nonetheless entail
solvent reaction (acetone) or equilibrium deprotonation
(KOH, alkoxides). NTB and Na were stirred under
nitrogen with venting of the byproduct H2 pressure, and
after sodium dissolution and concomitant NTB
deprotonation, alkyl halide was added, and the solution
was stirred until any precipitation appeared to be
complete. For isolation, the product was precipitated with
water and filtered off or solvent-extracted (toluene or
benzene) and ultimately recrystallized. However, this N-
alkylation method was not successful with 2° or 3° alkyl
halides, and the DMSO should be dry.
diagonal, with interplanar distances of 3.42
0.02 Å,
while the NMP are stacked against a ligand pyrazole,
with the NMP ring atoms at 3.39
pyrazole mean plane.
0.11 Å from the
The pyrazolyl-isoindoline ligand 10 was also prepared
using the fusion method; the pyrazole used in the
synthesis was 3-amino-5-methyl-1H-pyrazole. Similarly,
to ligand 9, characteristic NH protons are observed at δ
12.50 ppm (2H) and 6.10 ppm in the NMR. The X-ray
structure obtained (Fig. 16) confirms the nature of the
product.
The pyrazole planes are twisted 25.9° and 4.8° away
from coplanarity with the isoindoline plane, in an
antiparallel sense. One of the methyl substituents is
rotationally disordered between two positions. Viewed
along the direction 0.9, 0.1, 2.25 (U, V, W), the molecules
are seen edge-on, stacked in a herringbone pattern in the
lattice. The stacking is again alternating, benzo-“head” to
pyrrole “tail,” with the interplanar distances between the
isoindoline moieties' atoms ranging from 3.24 to 3.27 Å.
In another nitrile-based synthesis essay, the reaction of
phthalonitrile with 1,3-diaminopropane, cyclization reactions
In Np3NTB and Et3NTB, for example, CH2 groups exist
in two different chemical environments, one of them
connecting benzimidazole groups to the central N, and
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Pyrazole and Benzimidazole-derived Ligands
the other connecting the aryl group to the nitrogen. These
protons on different locations are distinctively observable
at 5.65 and 4.32 ppm and shifted to approximately 1 ppm
larger values than typical nonshifted CH2 protons, as
expected. X-ray crystal structures for Bu3NTB and
Np3NTB (the naphthylmethyl derivative) ligands are
illustrated by Figures 17 and 18, while Figure S10 shows
a representation of an Et3NTB structure. In all of these
ligands, the conformation has the three benzimidazole
arms directed “upward,” toward the apex of the central
aliphatic nitrogen’s NC3 trigonal pyramid. Metal
coordination thus necessitates substantial swiveling of the
benzimidazoles about their methylene links to the central
N. The three benzimidazole planes can be envisioned as
three blades of a propeller structure connected to the
central N, as the benzimidazole arms are oriented at
(different) angles of less than 45° versus the NcentralC3
pseudo-threefold axis. For Bu3NTB and Np3NTB, the
individual molecule asymmetry arises in the immediacy
from the tilt directions of the benzimidazole planes
relative to that axis—forming a right-handed “propeller”
in one case, and a left-handed one in the other. The
average angle between the propellers is 67.1° in
Np3NTB, while in the case of Bu3NTB, the propellers
“blades” are oriented all at the same angle of 88.1° from
each other. In the Bu3NTB lattice, there is slightly
Figure 18. ORTEP structure of the naphthyl-derived tripodal benzimid-
azole ligand L17. [Color figure can be viewed at wileyonlinelibrary.com]
naphthyl plane is typically at about 78° versus its
benzimidazole’s plane.
UV absorption and fluorimetry. The optical absorption
spectra of all the ligands were investigated and are
summarized in Tables 2 and 3. The UV spectrum of
ligand 5 (73.1 μM in acetonitrile) is displayed in
Figure 19 as an example.
These pyrazole derivatives contain quinoline, pyrazole,
benzene, and pyridine components, which are observable
in the UV spectra. For instance, ligand 1 contains
quinoline, pyrazole, and benzene motifs, the UV spectra
of the compound displaying peaks with λmax at 207, 241,
268, 285, 321, and 333 nm. Several of the observed
bands can be assigned to π-π* transitions of the pyrazole
(207 nm), benzene (241 nm), and quinoline (268, 285,
333 nm) moieties, respectively, similarly to those
observed in previous studies [43,44].
sideways-slipped
head-to-tail
π-π
stacking
(3.48 0.01 Å) between two benzimidazoles on adjacent
molecules, while in Np3NTB, these are replaced by
naphthyl–naphthyl interactions (at 3.64
0.02 Å). The
Fluorescence characteristics of the ligands were also
investigated. Figure 20 displays the excitation spectrum
of a 1.2 μM solution of ligand 1 in acetonitrile, at
ambient temperature.
With excitation wavelengths of 243 and 283 nm (π-π*)
used for obtaining the emission spectrum, fluorescence
emission by 1 was observed at 342 nm, which we
associate with excitation via the quinoline π-π* transition
at 283 nm (Fig. 21). As the 342 nm emission is also
excited by 243 nm absorption, it is concluded that
internal energy transfer to the quinolyl group from
another locus also occurs. Indeed, ligands 1–8 all
fluoresce except for ligand 3. The observed fluorescence
for ligand 2 at 362 nm (λex 241 nm), for ligand 4 at
365 nm (λex 251 nm), for ligand 5 at 362 nm (λex
285 nm), for ligand 6 at 356 nm (λex 320 nm), and for
Figure 17. ORTEP structure of the n-butylated tripodal benzimidazole li-
gand L16. [Color figure can be viewed at wileyonlinelibrary.com]
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. Nozari, A. W. Addison, G. T. Reeves, M. Zeller, J. P. Jasinski, M. Kaur, J. G. Gilbert,
C. R. Hamilton, J. M. Popovitch, L. M. Wolf, L. E. Crist, and N. Bastida
Vol 000
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Pyrazole and Benzimidazole-derived Ligands
Figure 21. Emission spectrum of the quinolyl–tetrahydroindazole ligand
1 (1.2 μM) in nonpurged acetonitrile at ambient temperature, excited at
240 nm. The feature near 480 nm is a grating ghost. The ordinate units
are arbitrary. [Color figure can be viewed at wileyonlinelibrary.com]
Figure 19. UV spectrum of the quinolyl–tetrahydroindazole ligand 5
(73 μM in acetonitrile). [Color figure can be viewed at
wileyonlinelibrary.com]
Table 4
Maximum absorption (λabs), excitation wavelength (λex), and fluorescence
wavelengths (λem) for ligands in acetonitrile at ambient temperature.
Absorption
maximum
(λabs) nm
Excitation
maximum
(λex) nm
Emission
maximum
(λem) nm
Compound
1
2
4
5
6
7
8
9
12
13
14
15
16
17
18
241
236
248
283
315
256
207
210
222
207
251
257
252
256
255
243
241
251
285
320
256
211
212
226
211
257
263
257
258
250
342
362
365
362
356
332
348
364
303
305
304
302
300
300
415
Figure 20. Excitation spectrum of the quinolyl–tetrahydroindazole ligand
1 (1.2 μM) in nonpurged acetonitrile at ambient temperature, from 200 to
345 nm with emission monitored at 350 nm. The ordinate units are arbi-
trary. [Color figure can be viewed at wileyonlinelibrary.com]
ligand 8 at 364 nm (λex 212 nm) are attributed to quinoline
moiety excitation. Among these fluorescent compounds,
the emission observed at 348 nm (λex 211 nm) for ligand
7 is assigned to excitation of the pyridine π-π* transition,
the large shift to the emission wavelength
notwithstanding [45]. The results are summarized in
Table 4. It is known that extended system conjugation
has a large influence on peak wavelengths and absorption
intensities; for instance, benzene, naphthalene, and
anthracene display peaks at λmax 255, 286, and 375 nm,
respectively. This phenomenon is observed in UV studies
of the substituted NTBs, where Np3NTB and An3NTB
(anthracenylmethyl-NTB) show naphthyl and anthracenyl
motifs' absorptions at λmax 286 and 375 nm, respectively.
These N-alkylated NTB ligands exhibit strong emission
at λmax ~300, 330, and 415 nm corresponding to benzene
(in benzimidazole), naphthalene, and anthracene motifs'
π-π* transitions.
CONCLUSION
Several new metal-chelating compounds with pyrazole,
pyridine, quinoline, isoindoline, and phenol donor
moieties have been prepared. Straightforward methods
such as (a) benzimidazole N-alkylation utilizing sodium
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. Nozari, A. W. Addison, G. T. Reeves, M. Zeller, J. P. Jasinski, M. Kaur, J. G. Gilbert,
C. R. Hamilton, J. M. Popovitch, L. M. Wolf, L. E. Crist, and N. Bastida
Vol 000
metal, (b) addition of arylamines to phthalonitrile, and
especially (c) Knorr pyrazole synthesis via condensation
of arylhydrazine with β-diketone gave successful
outcomes. The great majority of these ligands' structures
and conformations have been elucidated by X-ray
crystallography. The crystallographic approach is
structurally definitive for Knorr condensation products
with unsymmetric β-diketones, and for one of the
compounds described, serves as a strong support for the
previously proposed isomer assignment based on 13C
NMR [31,32]. The UV absorption and fluorescence
spectra have been obtained for the compounds, from
which these ligands will find application in the chemistry
of luminescent metal chelates.
Preparation of compounds. 2-(3-Phenyl-4,5,6,7-tetrahydro-
2H-indazol-2-yl)quinoline (L1).
2-Benzoylcyclohexanone
(12.75 mmole, 2.58 g) and 2-hydrazinoquinoline (12.75
mmole, 2.03 g) were refluxed in 125 mL of ethanol for
24 h. The solvent was evaporated to dryness, leaving an
amber oil. The oil, in a salt-ice bath, was triturated in
the presence of ethanol to yield a brown solid that was
then recrystallized from MeOH (charcoaled); crystals
were obtained suitable for X-ray diffraction; white solid;
yield: 75%; M.p. 94–96°C; 1H NMR 500 (DMSO-d6):
δ 8.46 (2 H, m), 8.02 (3 H, m), 7.63 (3 H, m), 7.18
(3 H, m), 2.83 (2 H, m), 1.83 (6 H, m); IR (cmꢀ1):
3061, 2922, 1616, 1598, 1492, 1395, 1324, 1250,
1102, 1055, 924, 846, 735; FAB-MS: m/z 326.166,
Calcd. for (M
+
1)+, 326.165; Anal. Calcd. for
C22H19N3. 0.5 CH3OH: C, 78.2; H, 6.27; N, 12.2;
EXPERIMENTAL
found: C, 78.2; H, 5.97; N, 12.0.
2-(3,5-Diphenyl-1H-pyrazol-1-yl)quinoline
(L2).
Dibenzoylmethane (3.14 mmole, 0.70 g) and 2-
hydrazinoquinoline (3.14 mmole, 0.50 g) were refluxed
in 125 mL of ethanol for 24 h. The solvent was
evaporated to dryness, leaving a dark orange oil. The oil,
in a salt-ice bath, was triturated in the presence of ethanol
to yield an orange solid that was then recrystallized from
MeOH (charcoaled) crystals were obtained suitable for
X-ray diffraction; white solid; yield: 92%; M.p. 121–
Materials.
Reagents (Alfa Aesar, Aldrich, Frinton
Laboratories, TCI, Strem) were used as received. UV and
luminescence spectra were obtained using PerkinElmer
Lambda 35 and 950 UV-Vis spectrophotometers and a
PerkinElmer LS55 luminescence spectrophotometer,
respectively. FT-IR was obtained on a PerkinElmer
Spectrum One instrument. Proton NMR spectra were
obtained at room temperature using Varian Unity Inova
300 and 500 MHz spectrometers, with samples in CDCl3
or DMSO-d6 and TMS as an internal standard. Elemental
microanalyses were performed by Robertson-Microlit
Laboratories (Ledgewood, NJ) and at the Pisarzhevskii
Institute of the NASU. Optical rotation was measured on
a PerkinElmer 343 digital polarimeter and CD spectra on
a Jasco J-810-150S spectropolarimeter purged with
nitrogen; spectra were recorded between 200 and 400 nm
with a 500 nm/min scan speed, 1 s response time, 0.05
data pitch and a 5 nm bandwidth; the temperature (23°C)
was controlled using a Jasco (J-810) Peltier controller
(model PTC-423S). Samples were in a 100 μm cell from
International Crystal Laboratories. X-ray crystallography
was performed at Youngstown State University, Keene
State College, and Temple University on Bruker AXS
SMART APEX CCD, Rigaku, Oxford diffraction, and
Bruker KAPPA APEX II DUO diffractometers using
CrysAlis PRO 1.171.38.43f (Rigaku), Apex2 v2013.4–1
(Bruker), SAINT V8.30C(Bruker), ShelXT [46],
SHELXL [47], SHELXS97 [48], Olex2 [49], and Olex2.
refine [50] programs. Structures were rendered using
the ORTEP output mode of the CCDC Mercury 3.9
software. EI-, CI-, APCI-, ESI-, FAB-LSIMS-, and
FT-mass spectrometries were performed on Thermo
Finnigan TSQ70, Thermo-Electron LTQ-FT 7T,
VG70SE, and Sciex API3000 mass spectrometers. A
GoldStar MA795W microwave oven was used as
microwave reactor.
1
124°C; H NMR 500 (CDCl3): δ 8.10 (4H, d, J = 8.24),
7.84 (3H, d, J = 8.62), 7.50 (3H, m), 7.35 (6H, m), 6.9 (1
H, s); IR (cmꢀ1): 3062, 2922, 1616, 1600, 1570, 1488,
1407, 1350, 1260, 1125, 1077, 954, 829, 754; FAB-MS:
+
m/z 348.150, Calcd. for (M + 1) , 348.150; Anal. Calcd.
for C24H17N3. 1 H2O: C, 78.9; H, 5.24; N, 11.5: found:
C, 78.6; H, 5.27; N, 11.2.
(4S,7S)-7,8,8-Trimethyl-1-(pyridin-2-yl)-4,5,6,7-tetrahydro-
1H-4,7-methanoindazole (L3).
L3 was prepared by
refluxing 0.721 g (4.0 mmol) of 3-(hydroxymethylene)
camphor and 0.463 g (4 mmol) 2-hydrazinopyridine in
50 mL of ethanol for 2.5 days. The solvent was removed
at the rotary evaporator and the ligand was recrystallized
from chloroform (charcoaled); crystals were obtained
suitable for X-ray diffraction; white solid; yield: 72%; M.
1
p. 160–162°C; H NMR 500 (DMSO-d6) δ 7.72 (m, 1H),
7.48 (m, 2H), 7.38 (m, 1H), 2.18 (m, 1H), 1.92 (m, 1H),
1.24 (m, 3H), 0.96 (m, 6H), 0.72 (m, 3H); IR (cmꢀ1):
3054, 2953, 1611, 1592, 1512, 1436, 1386, 1111, 1020,
985, 910, 761, 688. Anal. Calcd. for C16H19N3, C, 75.8,
H, 7.56, N, 16.6; found, C, 76.0, H, 7.21, N, 16.4; APCI-
MS: m/z 253.158, Calcd. for (M+), 253.157.
2-(3-Methyl-1H-indazol-1-yl)quinoline
(L4).
20-
fluoroacetophenone (21 mmole, 2.90 g) and 2-
hydrazinoquinoline (21 mmole, 3.34 g) were refluxed in
ethylene glycol for 24 h. The solution was cooled and
water was added to precipitate a finely divided brown
solid, which was filtered off and recrystallized from
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Pyrazole and Benzimidazole-derived Ligands
MeOH (charcoaled); crystals were obtained suitable for X-
ray diffraction; brown solid; yield: 55%; M.p. 107–110°C;
1H NMR 500 (DMSO- d6): δ 9.11 (d, 1H, J = 8.45), 8.52
(d, 1H, J = 8.96), 8.25 (d, 1H J = 8.96), 8.09 (d, 1H,
J = 8.20), 8.01 (d, 1H, J = 8.00), 7.89 (d, 1H, J = 7.95),
7.81 (t, 1H, J = 7.64), 7.67 (t, 1H, J = 7.70), 7.58 (t, 1H,
J = 7.45), 7.38 (t, 1H, J = 7.46), 2.62 (s, 3); IR (cmꢀ1):
3051, 2916, 1620, 1599, 1433, 1397, 1339, 1217, 1084,
823, 737; FAB-MS: m/z 260.118, Calcd. for (M + 1)+,
260.118; Anal., calculated for C17H13N3: C, 78.7; H, 5.05;
N, 16.2. Found: C, 78.7; H, 5.42; N, 16.3.
7.12–7.34 (2 H, m), 6.72–6.92 (3 H, m), 6.34 (1 H, m),
2.32 (3 H, m); IR (cmꢀ1): 3400, 3060, 2940, 1594, 1570,
1550, 1465, 1440, 1363, 1210, 1097, 982, 850; CI-MS:
m/z 252.112, Calcd. for (M
+
1)+, 252.113;
C15H13N3O.1H2O: C, 66.9; H, 5.61; N, 15.6. Found: C,
66.6; H, 5.51; N, 15.6.
2-(3-Methyl-1-(quinolin-2-yl)-1H-pyrazol-5-yl)phenol
(L8).
Salicyloylacetone (2.5 mmole, 0.45 g) and 2-
hydrazinoquinoline (2.5 mmole, 0.40 g) were refluxed in
EtOH for 3 days, the solution was cooled down, filtered
off, and recrystallized from MeCN (charcoaled); crystals
were obtained suitable for X-ray diffraction; white solid;
2-(3-Methyl-4,5,6,7-tetrahydro-2H-indazol-2-yl)quinoline
(L5). A sample of 2-acetylcyclohexanone (1.7 mmole,
0.27 g) and 2-hydrazinoquinoline (1.7 mmole, 0.24 g)
1
yield: 63%, M.p. 209–211°C; H NMR 500 (DMSO-d6):
δ 9.22 (1 H, s), 8.42 (1 H, d, J = 8.84), 7.96 (1 H, d,
J = 8.08), 7.86 (1 H, t, J = 7.70), 7.64 (1 H, t, J = 7.65),
7.52 (1 H, t, J = 7.50), 7.32 (1 H, d, J = 8.40), 7.26 (1 H,
d, J = 7.48), 7.18 (1 H, m), 6.88 (1 H, t, J = 7.45), 6.68
(1 H, d, J = 8.11), 6.34 (1 H, s), 2.36 (3 H, s). IR (cmꢀ1):
3350, 3090, 2935, 1598, 1550, 1480, 1447, 1379,
1267, 1184, 1108, 944, 827, 790, 765, 755; APCI-MS: m/z
302.128, Calcd. for (M + 1)+, 302.129; C19H15N3O.1H2O:
C, 71.5; H, 5.37; N, 13.2. Found: C, 71.3; H, 4.98; N, 13.2.
were refluxed in iPrOH, for 2 days, the reaction mixture
rotavapored down to dryness, resulting a brown oil
residue from which a white power was obtained through
recrystallization from MeOH (charcoaled); crystals were
obtained suitable for X-ray diffraction; white solid; yield:
1
65%; M.p. 110–112°C; H NMR 500 (CDCl3): δ 8.22 (1
H, d, J = 8.75), 8.09 (1 H, d, J = 8.59), 7.90 (1 H, d,
J = 7.28), 7.80 (1 H, d, J = 8.25), 7.68 (1 H, t, J = 7.34),
7.48 (1 H, t, J = 6.68), 2.76 (4 H, m), 2.52 (2 H, m), 1.82
(5 H, m); IR (cmꢀ1): 3055, 2921, 1616, 1600, 1502,
1422, 1367, 1049, 954, 829, 756; CI-MS: m/z 263.141,
Calcd. for (M+), 263.142; Anal., calculated for C17H17N3:
C, 77.5; H, 6.51; N, 16.0. Found: C, 77.6; H, 6.54; N, 15.9.
(1Z,3Z)-N1,N3-bis(5-phenyl-1H-pyrazol-3-yl)isoindoline-
1,3-diimine (L9). Pyrazole (0.95 g, 6 mmol) was mixed
with phthalonitrile (0.38 g, 3 mmol) in a test tube, which
was inserted into an aluminum block on a hotplate,
heated to 175°C for 5 h, resulted in deep red mass, which
was then dissolved in hot DMF (N,N-dimethylformamide),
after which water was added to the reaction mixture, until
red crystals were obtained, yield: 81%. In the solventless
melt method, phthalonitrile was thus simply heated with 3-
amino-5-phenylpyrazole, while in the microwave method,
ethylene glycol was added as a microwave absorber.
Single crystals were grown in NMP; M.p. >220°C; IR
(cmꢀ1): 3300, 3060, 1633, 1564, 1482, 1300, 1203, 856,
803, 755. APCI-MS: m/z 430.181, Calcd. for (M + 1)+,
430.180; C26H19N.7 0.5 H2O: C, 71.2; H, 4.60; N, 22.4:
2-(3,5-Di-tert-butyl-1H-pyrazol-1-yl)quinolone (L6).
L6
was prepared by refluxing 1.33 mL (6.37 mmol) of
2,2,6,6-tetramethyl-2,5-heptanedione and 1.01
g
(6.37 mmol) of 2-hydrazinoquinoline in 30 mL of
ethylene glycol for 24 h. The solution was cooled to
room temperature, water was added to the reaction
mixture, until a precipitate was obtained. The crude
ligand recrystallized from MeOH (charcoaled); crystals
were obtained suitable for X-ray diffraction; yellow solid;
1
yield: 86%; M.p. 134–137°C; H NMR 500 (DMSO-d6):
1
δ 8.58 (1 H, d, J = 8.60), 8.09 (1 H, d, J = 8.26), 7.98 (1
H, d, J = 8.48), 7.84 (1 H, t, J = 7.63), 7.76 (1 H, d,
J = 8.65), 7.68 (1 H, t, J = 7.38), 6.28 (1 H, s), 1.36 (9
H, s), 1.28 (9 H, s); IR (cmꢀ1): 3049, 2958, 1618, 1597,
1502, 1440, 1358, 1245, 1015, 994, 835, 762; CI-MS:
m/z 308.213, Cacld. for (M + 1)+, 308.212; Anal. Calcd.
for C20H25N3. 0.25 CH3OH: C, 77.1; H, 8.31; N, 13.3;
found, C, 77.4; H, 7.92; N, 13.5.
2-(3-Methyl-1-(pyridin-2-yl)-1H-pyrazol-5-yl)phenol (L7).
Salicyloylacetone (2.0 mmole, 0.36 g, Frinton) and 2-
hydrazinopyridine (2.0 mmole, 0.22 g) were refluxed in
EtOH for 3 days, after which the product was filtered off
from the cooled solution, and recrystallized from MeCN
(charcoaled); crystals were obtained suitable for X-ray
diffraction; yellow solid; yield: 82%, M.p. 154–156°C;
1H NMR 500 (DMSO-d6): δ 9.32 (1 H, d, J = 6.81), 8.21
(1 H, d, J = 6.22), 7.94 (1 H, t, J = 7.81), 7.64 (1 H, m),
found: C, 71.6; H, 4.25; N, 22.7, H NMR 500 (DMSO-
d6): δ 13.34 (2 H, s), 8.01 (6 H, d, J = 7.42), 7.72 (2 H,
m), 7.50 (6 H, m), 7.32 (2 H, s), 6.81 (1 H, s).
(1Z,3Z)-N1,N3-bis(5-methyl-1H-pyrazol-3-yl)isoindoline-
1,3-diimine (L10). L10 was prepared by the solventless
melt method: 0.38 g (3 mmol) of phthalonitrile fused
with 0.95 g (6 mmol) of 3-amino-5-phenylpyrazole for
3 h, 180–190°C gave 1.25 g red crystals of crude product
when subsequently digested in hot DMF and ppted. with
hot water. Recrystallization from wet DMF (charcoal)
gave 0.50 g (40%) golden-buff microcrystals after drying
in vacuo at 100°C. Crystals suitable for X-ray diffraction
1
were obtained from DMF; M.p. >220°C; H NMR 500
(DMSO-d6): δ 12.50 (2 H, d, J = 6.38), 11.84 (1 H, d,
J = 6.48), 7.98 (2 H, d, J = 5.37), 7.72 (2 H, d, J = 6.52),
6.10 (2 H, d, J = 5.64), 2.32 (6 H, m); IR (cmꢀ1): 3233,
3059, 2985, 1629, 1566, 1213, 1120, 863, 780, 730;
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. Nozari, A. W. Addison, G. T. Reeves, M. Zeller, J. P. Jasinski, M. Kaur, J. G. Gilbert,
C. R. Hamilton, J. M. Popovitch, L. M. Wolf, L. E. Crist, and N. Bastida
Vol 000
FAB-MS: m/z 306.145, Calcd. for (M + 1)+, 306.146;
Anal. Calcd. for C16H15N.7 0.25 H2O: C, 62.0; H, 5.04;
N, 31.6: found: C, 62.2; H, 4.93; N, 32.0.
(DMSO-d6): δ 7.72 (3 H, m), 7.52 (3 H, m), 7.26 (6 H,
m), 4.26 (6 H, m), 3.72 (6 H, m), 1.02–0.88 (9 H, m). IR
(cmꢀ1): 3053, 2974, 1615, 1514, 1165, 1093, 855, 788,
735. FAB-MS: m/z 492.288, Calcd. for (M + 1)+,
492.287; Anal. Calcd. for C30H33N7, C, 73.3; H, 6.77; N,
19.9: found: C, 73.0; H, 6.75; N, 20.0.
Tris(N1-n-propylbenzimidazol-2-ylmethyl)amine (L15).
Pr3NTB: white solid; recrystallized (charcoaled) from 1:3
MeCN:CHCl3; yield: 72%, M.p. >220°C; 1H NMR
(CDCl3): δ 8.87 (6 H, m), 8.37 (6 H, m), 5.35 (6 H, m),
4.52 (6 H, s), 3.85 (6 H, t, J = 6.72), 2.34 (6 H, m), 1.34
(9 H, t, J = 6.88); IR (cmꢀ1): 3054, 2986, 1616, 1590,
1516, 1460, 1416, 1331, 1250, 1160, 1092, 853, 768,
733; APCI-MS: m/z 534.333, Calcd. for (M + 1)+,
534.334; Anal. Calcd. for C33H39N7, C, 74.3; H, 7.37; N,
18.4: found: C, 74.0; H, 7.55; N, 18.0.
For the microwave method: to phthalonitrile (2.56 g,
20 mmol) and 3-amino-5-methylpyrazole (3.90 g,
40 mmol) in a 50 mL Erlenmeyer flask was added 0.5 mL
of ethylene glycol as a microwave absorber. The mixture
was microwaved (ca. 100 W) until it melted, upon which
it was swirled to effect mixing. It was then microwave-
pulsed for 30 s periods (100 W) at intervals of 1.5 min,
until the now greenish-brown melt ceased evolving
ammonia (ca. 12 min). Recrystallization was from DMF
(charcoal) with water added, giving golden-yellow crystals
that were dried in vacuo at 100°C; yield 29%; M.p.
>220°C; FAB-MS, (M + 1)+ m/z 306.146.
1,2-Bis(1,4,5,6-tetrahydropyrimidin-2-yl)benzene (L11).
L11 was prepared by the solventless melt method: 0.38 g
(3 mmol) of phthalonitrile fused with 0.44 g (6 mmol) of
1,3-diaminopropane for 3 h, 180–190°C product was
obtained when digested in hot DMF and ppted. by hot
water addition; yellow solid; yield: 58%; M.p. 118–
Tris(N1-n-butylbenzimidazol-2-ylmethyl)amine (L16).
Bu3NTB; white solid; single crystals were grown from
1
1:3 MeCN:CHCl3; yield: 78%; M.p. >220°C; H NMR
(CDCl3): δ 7.77 (6 H, m), 7.24 (6 H, m), 4.25 (6 H, m),
3.43 (12 H, m), 1.15 (6 H, m), 0.51 (9 H, m). IR (cmꢀ1):
3051, 2968, 1620, 1599, 1509, 1460, 1357, 1320, 1286,
1159, 1086, 991, 872, 735. Anal. Calcd. for C36H45N7: C,
75.1; H, 7.88; N, 17.0: found: C, 74.6; H, 7.64; N, 17.0;
APCI-MS: m/z 576.382, Calcd. for (M + 1)+, 576.381.
1
120°C; H NMR 500 (DMSO-d6): δ 8.22 (4 H, m), 8.12–
7.90 (4 H, m), 3.42 (8 H, m), 2.62 (4 H, m); IR (cmꢀ1):
3255, 3080, 2920, 1640, 1590, 1484, 1394, 1228, 1206,
965, 806, 769, 719; APCI-MS: m/z 243.161, Calcd. for
(M + 1)+, 243.160; Anal. Calcd. for C14H18N4: C, 69.4;
H, 7.49; N, 23.1: found: C, 69.5; H, 7.10; N, 23.1.
Tris(N1-[10-naphthyl]methylbenzimidazol-2-yl)amine
(L17). Np3NTB, cream solid; single crystals were grown
1
Tris(benzimidazol-2-ylmethyl)amine derivatives (L12–18).
Tris(benzimidazol-2-ylmethyl)amine (NTB) L12 and L13
were prepared as previously described [51,52]. Alkylation
of NTB is exemplified by the preparation of Et3NTB to
9.82 g (20 mmol) of NTB in 16 mL of DMSO vented
and under N2 was added 0.95 g (41 mmol) of Na-metal.
The mixture was stirred until the sodium had dissolved
(this may take 6–50 h, depending on the benzimidazole
and the temperature). To the now-homogeneous solution
was added 4.36 g (40 mmol) of bromoethane, and
following an initial mild exothermicity, the reaction
mixture was stirred for several hours, after which reaction
products had precipitated. The mixture was then diluted
with water (20 mL) and benzene (or toluene) (25 mL)
and stirred at length to partition the product into the
nonaqueous layer. This mixture was then filtered to
remove solid impurities; the product was isolated from
the benzene/toluene layer by evaporation of the solvent,
to yield a straw-colored “honey,” which crystallizes if
allowed to stand for a long time. Recrystallization from
decane (charcoal) gave straw-colored crystals. FAB-MS:
m/z 492.288, Calcd. for (M + 1)+, 492.287; Anal. Calcd.
for C30H33N7, C, 73.3; H, 6.77; N, 19.9: found: C, 73.0;
H, 6.75; N, 20.0.
from 1:3 MeCN:CHCl3; yield: 72%; M.p. >220°C; H
NMR 500 (DMSO-d6): δ 7.90 (3 H, d, J = 5.75), 7.72(3
H, d, J = 5.93), 7.63(3 H, d, J = 5.35), 7.50 (3 H, m),
7.44 (3 H, m), 7.28 (3 H, m), 7.02 (3 H, m), 6.96 (6 H,
m), 6.91 (6 H, m), 5.65 (6 H, m), 4.10 (6 H, s). IR
(cmꢀ1): 3053, 2956, 1618, 1540, 1460, 1298, 1223,
1162, 998, 814, 720; APCI-MS: m/z 828.382, Calcd. for
(m + 1)+, 828.381; Anal. Calcd. for C57H45N7. 0.3CHCl3:
C, 79.7; H, 5.29; N, 11.3; found: C, 79.6; H, 5.43; N, 11.4.
Tris(N1-[90-anthracenyl]methylbenzimidazol-2-ylmethyl)
amine (L18).
An3NTB; yellow solid; recrystallized
(charcoaled) from 1:3 MeCN:CHCl3; yield: 65%; M.p.
>220°C; 1H NMR 500 (DMSO-d6): δ 9.18 (3 H, m),
8.59 (6 H, m), 8.45 (3 H, d, J = 6.15), 7.92 (3 H, m),
7.88 (3 H, m), 7.76 (3 H, m), 7.60 (3 H, m), 7.33 (3 H,
m), 6.94 (6 H, m), 6.38 (3 H, m), 6.28 (3 H, s), 5.20 (6
H, m), 3.98 (6 H, s). IR (cmꢀ1): 3051, 2950, 1613, 1521,
1502, 1420, 1303, 1211, 1181, 1020, 954, 820, 725;
APCI-MS: m/z 978.428, Calcd. for (M + 1)+, 978.429;
Anal. Calcd. for C69H51N.71CH3CN.0.6CHCl3: C, 78.8;
H, 5.05; N, 10.2; found: C, 78.7; H, 5.08; N, 10.1.
Acknowledgments. The authors thank Drexel University for
support, D. DiGuiseppi for assistance with CD, Drs. R.J.
Butcher and M.J. Zdilla for assistance with structure files, Dr. D
Martinez Solorio for helpful discussion, and Dr. A.V. Pavlishchuk
for the Art Museum image. J. P. J. and M. K. acknowledge the
NSF–MRI program (grant no. 1039027) for funds to purchase the
Tris(N1-ethylbenzimidazol-2-ylmethyl)amine
(L14).
Et3NTB: white solid; single crystals were grown in
MeCN; yield: 71%; M.p. >220°C; 1H NMR 500
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
Pyrazole and Benzimidazole-derived Ligands
X-ray diffractometer, while M. Z. acknowledges NSF-DMR
(1337296), CHE (0087210), and Ohio Board of Regents (grant
CAP-491) for diffractometer funding.
[26] Wu, H.; Bai, Y.; Wang, X.; Zhang, Y.; Shi, F.; Bai, Y.; Pan, G.;
Kong, J. Transition Met Chem 2013, 38, 553.
[27] Wu, H.; Bai, Y.; Jingkun, Y.; Wang, H.; Pan, G.; Fan, X.;
Kong, J. J Chem Res 2012, 36, 283.
[28] Sinha, S.; Berdichevsky, E. K.; Warren, J. J. Inorg Chim Acta
2017, 460, 63.
[29] Stott, L. A.; Prosser, K. E.; Berdichevsky, E. K.; Walsby, C. J.;
Warren, J. J C Chem Commun 2017, 53, 651.
REFERENCES AND NOTES
[30] Knorr, L. Ber Dtsch Chem Ges 1883, 16, 2597.
[31] Catalan, J.; Fabero, F.; Claramunt, R. M.; Santa Maria, M. D.;
Foces, M. C.; Cano, F. H.; Martinez-Ripoll, M.; Elguro, J.; Sastre, R.
J Am Chem Soc 1992, 114, 5039.
[32] Singh, S. P.; Kumar, D.; Kumar, D. Synth Commun 1996, 26,
3193.
[1] Gray, H. B PNAS 2003, 100, 7, 3563.
[2] Glusker, J. P.; Katz, A. K.; Bock, C. W. The Rigaku Journal 1999,
16, 8.
[3] Seleem, H. S. Chem Cent J 2011, 5, 35.
[4] Chetia, B.; Iyer, P. K. Tetrahedron Lett 2007, 48, 47.
[5] Ghosha, K.; Adhikari, S.; Fröhlich, R. Tetrahedron Lett 2008,
49, 5063.
[6] Addison, A. W.; Burke, P. J. J Heterocyclic Chem 1981, 18, 803.
[7] Addison, A. W.; Rao, T. N.; Wahlgren, C. G. J Heterocyclic Chem
1983, 20, 1481.
[33] Elguero, J.; Martinez, A.; Singh, S. P.; Grover, M.; Tarar, L. S.
J Heterocyclic Chem 1990, 27, 865.
[34] Khan, M. A.; Polya, J. B. J Chem Soc (C) 1970 85.
[35] Bernal, I. Inorg Chim Acta 1985, 96, 99.
[36] Wu, T.; You, X. J Phys Chem A 2012, 116, 8959.
[37] Saeed, A.; Ejaz, S. A.; Shehzad, M.; Hassan, S.; al-Rashida,
M.; Lecka, J.; Sevigny, J.; Iqbal, J. RSC Adv 2016, 25, 21026.
[38] Elvidge, J. A.; Linstead, R. P. J Chem Soc 1952 5000.
[39] Siegl, W. O. J Org Chem 1977, 42, 1872.
[40] Lever, A. B. P.; Ramaswamy, B. S.; Simonse, S. H.;
Thompson, L. K. Can J Chem 1970, 48, 3076.
[8] Wahlgren, C. G.; Addison, A. W. J Heterocyclic Chem 1989,
26, 541.
[9] Gilbert, J. G.; Addison, A. W.; Palaniandavar, M.; Butcher, R.
J. J Heterocyclic Chem 2002, 39, 2, 399.
[10] Dagdigian, J. V.; Reed, C. A Inorg Chem 2623, 1979(18), 9.
[11] Freire, E.; Baggio, S.; Munoz, J. C.; Baggio, R. Acta Crystallogr
2003, C59, o259.
[41] Nozari, M.; Addison, A. W.; Zeller, M. Chem Abstr 2014
1303793.
[12] Amrutkar, S. V.; Sunil, V.; Bhagat, U. D.; Pargharmol, P.;
Kotgire, S. S. Int J Pharm Sci 2010, 2, 84.
[42] Smith, V. I.; Nozari, M.; Zeller, M.; Addison, A. W. Acta
Crystallogr 2017, E73, 127.
[13] Vaidya, S. D.; Kumara, B. V. S.; Kumar, U. N. J Heterocyclic
Chem 2007, 44, 685.
[43] Snyder, R.; Testa, A. C. J Phys Chem 1984, 88, 5948.
[44] Bernarducci, E.; Schwindinger, W. F.; Hughey, J. L. IV;
Jesperson, K. K.; Schugar, H. J. J Am Chem Soc 1981, 103, 1686.
[45] Yamazaki, I.; Sushida, K.; Baba, H. J Chem Phys 1979, 71,
381.
[46] Sheldrick, G. M. Acta Crystallogr 2015, A71, 3.
[47] Sheldrick, G. M. Acta Crystallogr 2015, C71, 3.
[48] Sheldrick, G. M. Acta Crystallogr 2008, A64, 112.
[49] Dolomanov, O. V.; Bourhis, L. J.; Gildea, R. J.; Howard, J. A.
K.; Puschmann, H. J Appl Cryst 2009, 42, 339.
[14] Nassar, E. M.; El-Farargy, A. E.; Abdelrazek, F. M. J Heterocyclic
Chem 2015, 52, 1395.
[15] Starcevic, K.; Kralj, M.; Ester, K.; Sabol, I.; Grce, M.; Pavelic,
K.; Karminski-Zamola, G. Bioorg Med Chem 2007, 15, 4419.
[16] Galal, S. A.; Hageb, K. H.; Kassab, A. S.; Rodriguez, M. L.;
Kerwin, S. M.; El-Khamry, A. A.; El Diwani, H. I. Eur J Med Chem 2009,
44, 1500.
[17] Keller, P.; Müller, C.; Engelhardt, I.; Hiller, E.; Lemuth, K.;
Eickhoff, H.; Wiesmüller, K.-H.; Burger-Kentischer, A.; Bracher, F.;
Rupp, S. Antimicrob Agents Chemother 2015, 59, 6296.
[18] Bai, Y.-B.; Zhang, A.-L.; Tang, J.-J.; Gao, J.-M. J Agric Food
Chem 2013, 61, 2789.
[50] Bourhis, L. J.; Dolomanov, O. V.; Gildea, R. J.; Howard, J. A.
K.; Puschmann, H. Acta Crystallogr 2015, A71, 59.
[51] Thompson, L. K.; Ramaswamy, B. S.; Seymour, E. A. Can J
Chem 1977, 55, 878.
[19] Taylor, R. D.; MacCoss, M.; Lawson, A. D. G. J Med Chem
2014, 57, 5845.
[20] Su, C.-Y.; Kang, B.-S.; Du, C.-X.; Yang, Q.-C.; Mak, T. C. W
Inorg Chem 2000, 39, 4843.
[52] Hendriks, H. M. J.; Birker, P. J. M. W. L.; Verschoor, G. C.;
Reedijk, J. J Chem Soc Dalton Trans 1982 623.
[21] Gregorzik, R.; Hartmann, U.; Vahrenkamp, H. Ber Dtsch Chem
Ges 1994, 127, 2117.
[22] Addison, A. W.; Henriks, H.; Reedijk, J.; Thompson, L. K.
Inorg Chem 1981, 20, 103.
[23] Chen, B.-T.; Morlanés, N.; Adogla, E.; Takanabe, K.; Rodionov,
V. O ACS Catal 2016, 6, 4647.
[24] Yan, C.; Li, K.; Wei, S.-C.; Wang, H.-P.; Fu, L.; Pan, M.; Su,
C.-Y. J Mater Chem 2012, 22, 9846.
SUPPORTING INFORMATION
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in the supporting information tab for this article.
[25] Pan, M.; Lan, M.-H.; Wang, X.-T.; Yan, C.; Liu, Y.; Su, C.-Y.
Inorg Chim Acta 2010, 363, 3757.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet