Fluorescence of some tri- and tetra-dentate pyrazol-derived stable ligands

Article abstract of DOI:10.1007/s11164-012-0809-1

A new class of tripodal N-ligands have been prepared under mild conditions by reaction of N-hydroxymethyl-3,5-dimethylpyrazole with 2-furylmethylamine; 2-pyridylmethylamine; 4-nitrobenzaldehyde hydrazone and (E)-1-((anthracen-9-yl) methylene)hydrazine in a double equimolar ratio (2:1). The tripodal ligands were characterized by IR, ¹H-, and ¹³C-NMR, microanalysis, and mass spectrometry. The fluorescence properties of the ligands were analyzed. Graphical abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s11164-012-0809-1

Res Chem Intermed (2013) 39:2963–2969
DOI 10.1007/s11164-012-0809-1
Fluorescence of some tri- and tetra-dentate
pyrazol-derived stable ligands
•
Taibi Ben Hadda Abdelali Kerbal
•
•
Oumaima Touimi Benjelloun Abdeljalil El Fatmi
•
•
Maria Daoudi Najib Ben Larbi Ismail Warad
•
Received: 11 July 2012 / Accepted: 7 September 2012 / Published online: 26 September 2012
Ó Springer Science+Business Media B.V. 2012
Abstract A new class of tripodal N-ligands have been prepared under mild conditions
by reaction of N-hydroxymethyl-3,5-dimethylpyrazole with 2-furylmethylamine;
2-pyridylmethylamine; 4-nitrobenzaldehyde hydrazone and (E)-1-((anthracen-9-yl)methy-
lene)hydrazine in a double equimolar ratio (2:1). The tripodal ligands were characterized
by IR, 1H-, and 13C-NMR, microanalysis, and mass spectrometry. The fluorescence
properties of the ligands were analyzed.
Keywords Tripodal N-ligands Á Substituted hydrazones Á Pyrazol Á Fluorescence
Introduction
Metal complexes with suitable fluorescent ligands are useful models for various
medicinal applications, i.e., analysis, imaging and detection. Interest in designing
and using chelators as anti-tumor agents has grown with the evidence that cancer
cells generally require more copper and iron for their growth and metabolism than
normal resting cells [1–3]. Studies on desferrioxamine (DFO), a hexadentate
chelator, have recognized its potential for the treatment of iron overload and, in turn,
for retarding tumor growth [2]. However, its short plasma half-life and poor oral
activity limits its usefulness and has led to the exploration of new chelators. Several
T. Ben Hadda (&)
Laboratoire de Chimie des Materiaux, Faculte des Sciences,
´
Universite Mohammed Premier, 60000 Oujda, Morocco
´
´
e-mail: taibi.ben.hadda@gmail.com
A. Kerbal Á O. Touimi Benjelloun Á A. El Fatmi Á M. Daoudi Á N. Ben Larbi
´
Laboratoire de Chimie Organique, Faculte des Sciences Dhar Mehraz, 30000 Fez, Morocco
I. Warad
Department of Chemistry, Science College, King Saud University, P. O. Box 2455,
Riyadh 11451, Saudi Arabia
123

2964
T. Ben Hadda et al.
H3C
CH3
H3C
O
CH3
O-
N+
N
N
N
N
N
N
O
N+
O-
N
O
N
O
1c
1a
N
H2
N
NH
N
N
2
H3C
CH3
H3C
CH3
H3C
CH3
3
5
N
N
H3C
CH3
H3C
N
CH3
H
O
NH
2
N
N
N
N
N
2
N
1b
H
N
N
N
N
2
1d
N
N
N
N
H3C
CH3
H3C
CH3
6
4
Scheme 1 Synthesis of armed tripodal N-ligands 3–6
classes of promising bi- and tridentate molecules have been developed, including
desferrithicin derivatives, O-trensox, thiosemicarbazones, hydroxypyridinones, and
bis-hydroxyphenyltriazoles [4]. Tridentate chelators in general have been more
effective than bidentate chelators due to their higher metal binding affinity [5].
A major problem lies with the toxicity of many of the compounds.
Polydentate pyrazol compounds are well-known ligands for transition metal ions
in the building of polynuclear complexes as models for bioinorganic systems [6, 7]
as well as for the discovery of new catalyst precursors [8]. We are currently
studying the synthesis and coordination of tridentate nitrogen ligands, such as N,N-
bis-[(3,5-dimethyl-1-pyrazolyl)methyl]alkylamines [9, 10]. There is now current
interest to gain insight into the coordination behavior of larger ligand systems
containing multiple pyrazol nitrogen-coordinating sites and a delocalized p-
conjugated spacer such as an aryldiammine.
In continuation of our previous study [9, 11], we report in the present study on
the synthesis of a class of polydentate ligands containing two pyrazol rings leading a
functionalized chelating group or a fluorophore with the general topology shown in
Scheme 1. We therefore describe here for the first time two new fluorescent
tridentate compounds.
Results and discussion
On the basis of our initial study for the synthesis of tripodal N-ligands [9, 11], the new
polydentate ligands 3–6 were prepared by reaction of (3,5-dimethyl-1H-pyrazol-1-
yl)methanol 2 with 2-tetrahydrofurylmethylamine 1a or 2-pyridylmethylamine 1b,
4-nitrobenzaldehyde hydrazone 1c and (E)-1-(anthracen-9-yl)methylene)hydrazone
123

Fluorescence of tri and tetra-dentate pyrazol
2965
160
16
12
8
120
Cyclohexane
Acetonitrile
Hexane
Ether
Hexane
Ether
80
40
0
Acetonitrile
Ethanol
EtOH
4
0
305 355 405 455 505 555
355 405 455 505 555 605
Wavelength / nm
Wavelength / nm
Compound 5
Compound 6
Fig. 1 Fluorescence spectra of compound (5 and 6) (10-5 M) in the presence of various solvents with an
excitation of 250 and 350 nm, respectively
1d, respectively, under mild conditions (room temperature), using anhydrous
acetonitrile as solvent (Scheme 1).
The initial reaction of aldehyde precursor with hydrazine in CH2Cl2/ethanol
mixture at room temperature produced hydrazone derivatives 1c and 1d. The
compounds 3–6 were isolated after 5 days of stirring at room temperature in good
yield. The condensation reaction is very slow but very selective at room
temperature, and, after 4–5 days of stirring at room temperature, the derivatives
3–6 were isolated.
Compounds 5 and 6, containing an extended delocalized p-system, are able to
exhibit fluorescence properties. In contrast, the fluorescence is inhibited in 3 and 4
when the central aromatic part is replaced by a tetrahydrofuran-2-yl-methyl or
2-pyridin-methyl group, respectively. Representative emission spectra for 5 and 6
are reported in Fig. 1.
The two compounds exhibit the same absorption profile: intense and structured
bands between 400 and 500 nm. The molecular absorption coefficients are quite
large and the bathochromic shift is consistent with a better delocalization in the
p-conjugated system of 5 as compared to 6. Luminescence is observed for both
compounds; modification of the substituents (anthracenyl vs. 4-nitrophenyl) only
induces a modulation of the quantum yield efficiency. Thus, the two tridentate
ligands 5 and 6, better described by their hydrazinium limit, form similar extended
p-conjugated systems as they present similar absorption and fluorescence properties
(Fig. 2).
Conclusion
The synthesis of new fluorescent tridentate compounds 5 and 6 is relatively flexible
and clean. Their synthesis from aromatic aldehydes could certainly be generalized
for the access of a variety of p-conjugated aromatic amines and hydrazones.
123

2966
T. Ben Hadda et al.
H3C
CH3
H3C
CH3
O-
O-
N+
O-
N
N
N
N
N
N+
N+
N
O
N
..
N
N
H3C
CH3
H3C
CH3
5
5
(Hydrazone form)
(Diazonium form)
H3C
CH3
H3C
CH3
N
N
N
N
N
..
N+
N
N
N
N
-
C
N
N
H3C
CH3
H3C
CH3
6
6
(Hydrazone form)
(Diazonium form)
Fig. 2 Delocalized pi-system in the case of ligands 5 and 6
Experimental
General methods
Infrared spectra were recorded on a PYE Unicam SP3-300 spectrometer as KBr
1
pellets. The H and 13C NMR spectra were recorded on a Bruker spectrometer
(250 MHz) using TMS as internal standard. Chemical shifts are reported downfield
from the standard in ppm. The FAB mass spectra were obtained on a NERMANG
R10-LOC instrument. For the chemical ionization (DCI/NH3/CH3), the compounds
were dissolved in DMSO or MeOH and dispersed in a matrix solution, currently
3-nitrobenzyl (MNBA) or glycerol (GLY). Elemental analyses were performed by
the Service Central d’Analyse du CNRS LCC (Toulouse). Fluorescence experi-
ments were performed in dilute organic solvents (ca. 10-5 mol l-1) using a PTI
spectrometer. Fluorescence quantum yields were measured on non-degassed
samples at room temperature. A solution of quinine sulfate in H2SO4 was used as
the standard for the quantum yield measurement (/ = 0.546 for k = 365 nm).
Refraction index has been performed.
123

Fluorescence of tri and tetra-dentate pyrazol
2967
Synthesis of compounds (1a–1d)
Chemicals were purchased from commercial sources and used as received with the
exception of MeCN, which was distilled over CaH2. Starting compounds 1c and 1d
were prepared according to routine literature procedures. Reactions were monitored
by thin-layer chromatography, using aluminum sheets coated with silica.
4-Nitrobenzaldehyde hydrazone (1c)
p-Nitobenzaldehyde 1 (4.1 g, 82 mmol) dissolved in a mixture of solvents (50 mL
of dichloromethane and 20 mL of ethanol) was added dropwise to hydrazine (NH2–
NH2) (4.1 g, 26 mmol) in ethanol (25 mL) at room temperature. The mixture was
stirred at room temperature for 4 days. The solvent was removed under reduced
pressure. The recrystallization in hexane/dichloromethane (1/3) of the residue
afforded a yellow product of 1c (4 g) in good yield (91 %).
Melting point: 120–122 °C. TLC: Rf = 0.21 (Silica; dichloromethane/hexane,
1/2). IR (KBr) cm-1: 3,423, 3,301, 3,066, 1,629, 1,594, 1,576, 1,502, 1,401, 1,317,
1,236, 1,171. 1H NMR (250 MHz, CDCl3) d ppm: 8.5–7.5 (2 dd, 5H, Ph ? CH=N);
5.9 (s, 2H, NH2). 13C NMR (250 MHz, CDCl3) d ppm: 147.37, 141.57, 139.01,
130.73, 129.42, 128.71, 126.36, 124.02, 111.66. MS (m/z): 165 ([M]?., 100 %).
Elemental analysis: calculated for C7H7N3O2: C, 50.91 %; H, 4.27 %; N, 25.44 %.
Found: C, 50.71 %; H, 4.32 %; N, 25.37 %.
(E)-1-((anthracen-9-yl)methylene)hydrazine (1d)
Anthracene-9-carbaldehyde 5 (1 g, 4.85 mmol) was dissolved in a mixture of
solvents (20 mL of dichloromethane and 10 mL of ethanol) and then hydrazine
(NH2–NH2) (1 g, 20 mmol) was added dropwise at room temperature. The mixture
was stirred for 24 h at room temperature. The solvent was removed under reduced
pressure. The recrystallization in hexane/dichloromethane (1/3) of the residue
offered a yellow product in good yield (0.80 g, 80 %).
Melting point: 122–124 °C. TLC: Rf = 0.31 (Silica; ether/hexane, 3/2). IR (KBr,
1
t cm-1): 3,368 (NH), 1,640, 1,520, 1,440, 900, 700, 650. H NMR (250 MHz,
CDCl3) d ppm: 8.5–7.8 (m, 10 H, anthracenyl ? CH=N); 5.6 (s, 2H, NH2). 13C
NMR (300 MHz, CDCl3) d = 140.92, 138.90, 131.69, 129.99, 129.14, 128.94,
128.83, 128.29, 128.17, 126.74, 126.27, 125.70, 125.35, 125.31, 125.17. MS (m/z):
220.1 ([M]?); 204.3 ([M–NH2]?); 203 ([A9–CN]?); 177 ([A9]?); 176 [M–HCN]?).
Elemental analysis: calculated for C15H12N2: C, 81.79 %; H, 5.49 %; N, 12.72 %.
Found: C, 81.86 %; H, 5.38 %; N, 12.64 %.
General procedure for the synthesis of compounds 3 and 4
The products were prepared by the addition of appropriate amine 2-C4H7O–CH2–
NH2 (1a), and 2-C5H5N–CH2–NH2 (1b) to 1-(hydroxymethyl)-3,5-dimethyl pyra-
zole (1). Then, a solution of the substituted 1 (1.01 g, 8 mmol) in acetonitrile
(30 mL) was added to the desired amine (4.5 mmol) and the mixture continued to
123

2968
T. Ben Hadda et al.
be stirred at room temperature for 4–5 days. The formed compound was precipitated
by addition of cold water to acetonitrile solution, washed with hexane and dried
under vacuum. Compounds 3 and 4 were obtained as white solids (65–91 % yield).
N,N-bis[(3,5-dimethyl-1H-pyrazol-1-yl)methyl](tetrahydro-2-furanyl)methanamine
(3) Yellow oil. Yield (75 %). Melting point and TLC: Rf (not determined). IR
1
(KBr, m cm-1): 2,921, 2,866, 1,555, 1,457, 1,421, 1,377. H NMR: (CDCl3; 300 -
MHz) (d ppm): 5.65 (s. 2H, pyrazol); 4.80 (s, 4H, 2NCH2N); 3.60 (m, 2H, CHC-
H2N); 2.60 (s, 6H, 2CH3); 2.15 (s, 6H, 2CH3); 1.60 (m, 2H, C4H7O–); 1.15 (m, 2H,
C4H7O–). 13C NMR (CDCl3; 250 MHz) d ppm: 9.11, 11.81, 23.69, 27.52, 50.87,
64.43, 66.29, 76.27, 104.00, 138.22, 145.56. SM (IC): [M]? = 317, 302, 258, 246,
222, 205, 179, 150, 138, 125, 109 (100 %), 96.
N,N-bis[(3,5-dimethyl-1H-pyrazol-1-yl)methyl](2-pyridinyl)methanamine (4) Yield
(63 %). Melting point: 60–62 °C. IR (KBr, m cm-1): 3,464, 3,114, 2,920, 1,665,
1,590, 1,570, 1,551, 1,473, 1,451. 1HNMR: (CDCl3; 250 MHz) d ppm: 8.50 (m, 1H,
C5H4N); 7.51 (m, 2H, C5H4N–); 7.25 (m, 1H, C5H4N–); 5.75 (s. 2H, pyrazol); 4.95
(s, 4H, 2NCH2N); 3.85 (s, 2H, C5H4N–CH2N); 2.60 (s, 6H, 2CH3); 2.15 (s, 6H,
2CH3). SM: (M)? = 324, 277, 258, 246, 228, 133, 121, 109 (100 %), 93, 80. 13C
NMR (CDCl3; 250 MHz) d (ppm): 158.59, 148.81, 147.61, 139.93, 136.43, 123.10,
122.07, 105.70, 64.99, 54.60, 13.47, 10.6 0. SM (IC): [M]? = 324, 109 (100 %).
Elemental analysis: calculated for C18H24N6: C, 66.64 %; H, 7.46 %; N, 25.90 %.
Found: C, 65.16 %; H, 7.25 %; N, 23.94 %.
General procedure for the synthesis of 5 and 6
The products 5 and 6 were prepared by the addition of appropriate hydrazone
4-nitro-C6H4–CH=N–NH2 (1c), or 9-C14H9–CH=N–NH2 (1d) to N-hydroxymethyl-
3,5-dimethyl-pyrazole 1. To a solution of the substituted 1 (3.1 g, 25 mmol) in
acetonitrile (60 mL) was added the desired hydrazone (4.5 mmol) and the mixture
continued to be stirred at room temperature for 36 h. The formed compound was
precipitated by addition of cold water to acetonitrile solution, washed with hexane
and dried under vacuum. Compounds 5 and 6 were obtained as white solids
(64–76 % yield).
4-nitrobenzaldehyde bis[(3,5-dimethyl-1H-pyrazol-1-yl)methyl]hydrazone (5) Yield
(64 %). Melting point: 160–163 °C. TLC: Rf = 0.20 (silica; ether/hexane, 2/3). IR
(KBr) t cm-1: 2,923, 1,597, 1,557, 1,516, 1,462, 1,421, 1,380, 1,337, 1,309, 1,249,
1
1,179. H NMR (250 MHz, CDCl3) d: 8.5–7.8 (m, 5 H, Ph ? CH=N); 5.9 (s, 2 H,
2(=CH) of pyrazol); 5.7 (s, 4H, 2CH2–); 2.4 (s, 6H, 2CH3); 2.2 (s, 6H, 2CH3). 13C
NMR (250 MHz, CDCl3) d ppm: 148.4, 147.1, 142.3,140,135.42, 126.40, 123.92,
106.44, 65.96, 13.50, 11.25. MS (m/z): 381 ([M]?); 286 ([M-Pz]?); 272 ([M-H2C–
Py]?); 232 [(Pz-CH2)2–N]?); 147 [O2N–Ph–CH=N–H2]?); 122 ([O2N–Ph]?); 176
([A9–H2]?); 96 ([Pz]?). Elemental analysis: calculated for C19H23N7O2: C, 59.83 %;
H, 6.08 %; N, 25.71 %. Found: C, 59.72 %; H, 6.17 %; N, 25.64 %.
123

Fluorescence of tri and tetra-dentate pyrazol
2969
1,4-dihydro-9-anthracenecarbaldehyde-bis[(3,5-dimethyl-1H-pyrazol-1-yl)meth-y-
l]hydrazone (6) Yield (76 %). Melting point: 156–158 °C. TLC: Rf = 0.30 (Sil-
ica; dichloromethane/hexane, 3/2). IR (KBr, t cm-1): 3,048, 2,955, 2,917, 1,677,
1
1,623, 1,591, 1,553, 1,520, 1,457, 1,419, 1,384, 1,369, 1,330. H NMR (300 MHz,
CDCl3) d: 9.3 (s, 1H,–CH=N); 7.8–8.5 (m, 9H, Aromatic proton); 5.9 (s, 2 H,
2(=CH) pyrazol); 5.8 (s, 4 H, 2 NCH2–N); 2.4 (s, 6 H, 2CH3); 2.3 (s, 6 H, 2CH3).
13C NMR (300 MHz, CDCl3) d: 148.32 (C=N); 140.21, 138.36, 131.5, 129.94,
128.56, 128.28, 127.82, 125.88, 125.69, 125.08, 106.12, 77.49, 77.07, 76.64, 66.38,
13.60, 11.40. MS (m/z): 460.5 ([MH?Na]?., 30 %); 459.5 ([M?Na]?., 100 %);
341.5 ([M-Pz]?); 109.0 ([Pz–CH2]?). Elemental analysis: calculated for C27H28N6:
C, 74.28 %; H, 6.46 %; N, 19.25 %. Found: C, 74.12 %; H, 6.48 %; N, 19.34 %.
Acknowledgment This study was generously financed by CNRST of Morocco.
References
1. J. Easman, Exp. Opin. Ther. Pat. 12, 789 (2002)
2. J.L. Buss, F.M. Torti, S.V. Torti, Curr. Med. Chem. 10, 1021 (2003)
3. H. Nick, P. Acklin, R. Lattmann, P. Buehlmayer, S. Hauffe, J. Schupp, D. Alberti, Curr. Med. Chem.
10, 1065 (2003)
4. D.Y. Liu, Z.D. Liu, R.C. Hider, Best Pract. Res. Clin. Haemotol. 15, 369 (2002)
5. F. Aouad, A. Florence, Y. Zhang, F. Collins, C. Henry, R.J. Ward, R.R. Crichton, Inorg. Chim. Acta
339, 470 (2002)
6. W.L. Driessen, R.A.G. Graaff, F.J. Parlevliet, J. Reedijk, R.M. Vos, Inorg. Chim. Acta 216, 43
(1994)
7. S.C. Sheu, M.J. Tien, M.C. Cheng, T.I. Ho, S.M. Peng, Y.C. Lin, J. Chem. Soc. Dalton Trans. 3503
(1995)
8. A. Togni, L.M. Venanzi, Angew. Chem. Int. Ed. Engl. 33, 497 (1994)
9. R. Touzani, A. Ramdani, T.B. Hadda, S. El Kadiri, O. Maury, H. Le Bozec, P.H. Dixneuf, Synth.
Commun. 31, 1315 (2001)
10. M. Dauodi, N.B. Larbi, D. Benjelloun, A. Kerbal, J.P. Launay, J. Bonvoisin, J. Jaud, M. Mimouni,
T.B. Hadda, Molecules 8, 269 (2003)
11. T.B. Hadda, A.T. Kotchevar, M. Daoudi, B. Bennani, N.B. Larbi, A. Kerbal, Lett. Drug Des. Discov.
2, 584 (2005)
123