Electrochemical synthesis and characterisation of alternating tripyridyl-dipyrrole molecular strands with multiple nitrogen-based donor-acceptor binding sites

Article abstract of DOI:10.1002/chem.201000859

Synthesis of alternating pyridine-pyrrole molecular strands composed of two electron-rich pyrrole units (donors) sandwiched between three pyridinic cores (acceptors) is described. The envisioned strategy was a smooth electrosynthesis process involving ring contraction of corresponding tripyridyl-dipyridazine precursors. 2,6-Bis[6-(pyridazin-3-yl)]pyridine ligands 2a-c bearing pyridine residues at the terminal positions were prepared in suitable quantities by a Negishi metal cross-coupling procedure. The yields of heterocyclic coupling between 2-pyridyl zinc bromide reagents 12a-c and 2,6-bis(6- trifluoromethanesulfonylpyridazin-3-yl)pyridine increased from 68 to 95% following introduction of electron-donating methyl groups on the metallated halogenopyridine units. Favorable conditions for preparative electrochemical reduction of tripyridyl-dipyridazines 2b,c were established in THF/acetate buffer (pH 4.6)/acetonitrile to give the targeted 2,6-bis[5-(pyridin-2-yl) pyrrol-2-yl]pyridines 1b and 1c in good yields. The absorption behavior of the donor-acceptor tripyridyl-dipyrrole ligands was evaluated and compared to theoretical calculations. Highly fluorescent properties of these chromophores were found (v_em≈2×10⁴ cm^-1 in MeOH and CH₂Cl₂), and both pyrrolic ligands exhibit a remarkable quantum yield in CH₂Cl₂ (φ_f=0.10). Structural studies in the solid state established the preferred cis conformation of the dipyrrolic ligands, which adopting a planar arrangement with an embedded molecule of water having a complexation energy exceeding 10 kcalmol ^-1. The ability of the tripyridyl-dipyrrole to complex two copper(II) ions in a pentacoordinate square was investigated. Electrochemical pyrrole synthesis: Donor-acceptor pyridine-pyrrole molecular strands 1 composed of two electron-rich pyrrole units sandwiched between pyridinic cores were synthesized by electroreduction of alternating tripyridyl-bipyridazine precursors 2 (see picture). The absorption behavior of the tripyridyl-dipyrrole ligands and their structures in the solid state were evaluated and compared to theoretical calculations. C.P.E.=controlled-potential electrolysis.

Full text of DOI:10.1002/chem.201000859

DOI: 10.1002/chem.201000859
Electrochemical Synthesis and Characterisation of Alternating Tripyridyl–
Dipyrrole Molecular Strands with Multiple Nitrogen-Based Donor–Acceptor
Binding Sites
Alexandra Tabatchnik-Rebillon,[a] Christophe Aubꢀ,[a] Hicham Bakkali,[a]
Thierry Delaunay,[a] Gabriel Thia Manh,[a] Virginie Blot,[a] Christine Thobie-Gautier,[a]
Eric Renault,[a] Marine Soulard,[a] Aurꢀlien Planchat,[a] Jean-Yves Le Questel,[a]
Rꢀmy Le Guꢀvel,[b] Christiane Guguen-Guillouzo,[b] Brice Kauffmann,[c] Yann Ferrand,[c]
Ivan Huc,[c] Karꢁne Urgin,[d] Sylvie Condon,[d] Eric Lꢀonel,[d] Michel Evain,[e]
Jacques Lebreton,[a] Denis Jacquemin,[f] Muriel Pipelier,[a] and Didier Dubreuil*[a]
In memory of Gabriel Thia Manh
Abstract: Synthesis of alternating pyri-
dine–pyrrole molecular strands com-
posed of two electron-rich pyrrole
units (donors) sandwiched between
three pyridinic cores (acceptors) is de-
scribed. The envisioned strategy was a
smooth electrosynthesis process involv-
ing ring contraction of corresponding
tripyridyl–dipyridazine precursors. 2,6-
Bis[6-(pyridazin-3-yl)]pyridine ligands
2a–c bearing pyridine residues at the
terminal positions were prepared in
suitable quantities by a Negishi metal
cross-coupling procedure. The yields of
heterocyclic coupling between 2-pyrid-
yl zinc bromide reagents 12a–c and
2,6-bis(6-trifluoromethanesulfonylpyri-
dazin-3-yl)pyridine increased from 68
to 95% following introduction of elec-
tron-donating methyl groups on the
metallated halogenopyridine units. Fa-
vorable conditions for preparative elec-
trochemical reduction of tripyridyl–di-
pyridazines 2b,c were established in
THF/acetate buffer (pH 4.6)/acetoni-
trile to give the targeted 2,6-bis[5-(pyri-
din-2-yl)pyrrol-2-yl]pyridines 1b and
1c in good yields. The absorption be-
havior of the donor–acceptor tripyrid-
yl–dipyrrole ligands was evaluated and
compared to theoretical calculations.
Highly fluorescent properties of these
chromophores were found (nem ꢀ2ꢂ
104 cmꢁ1 in MeOH and CH2Cl2), and
both pyrrolic ligands exhibit a remark-
able quantum yield in CH2Cl2 (ff =
0.10). Structural studies in the solid
state established the preferred cis con-
formation of the dipyrrolic ligands,
which adopting a planar arrangement
with an embedded molecule of water
having a complexation energy exceed-
ing 10 kcalmolꢁ1. The ability of the tri-
pyridyl–dipyrrole to complex two cop-
Keywords: copper · electrochemis-
try · N ligands · nitrogen heterocy-
cles · ring contraction
per(II) ions in
a
pentacoordinate
square was investigated.
[a] Dr. A. Tabatchnik-Rebillon, C. Aubꢀ, H. Bakkali, T. Delaunay,
Dr. G. T. Manh,+ Dr. V. Blot, Dr. C. Thobie-Gautier, Dr. E. Renault,
M. Soulard, A. Planchat, Prof. J.-Y. Le Questel, Prof. J. Lebreton,
Dr. M. Pipelier, Prof. D. Dubreuil
[d] K. Urgin, Dr. S. Condon, Prof. E. Lꢀonel
Institut de Chimie et des Matꢀriaux Paris Est (ICMPE), UMR 7182
Equipe Electrochimie et Synthꢁse Organique (ESO)
CNRS Universitꢀ Paris Est Crꢀteil - Val de Marne
2 rue Henri Dunant, 94320 THIAIS (France)
Laboratoire de Chimie et Interdisciplinaritꢀ: Synthꢁse, Analyse,
Modꢀlisation (CEISAM), UMR 6230
[e] Prof. M. Evain
Universitꢀ de Nantes, UFR des Sciences et des Techniques
2, rue de la Houssiniꢁre, BP 92208, 44322 Nantes Cedex 3 (France)
Fax : (+33)251-12-54-02
Institut des Matꢀriaux Jean Rouxel (IMN), UMR 6502
Universitꢀ de Nantes, UFR des Sciences et des Techniques
2, rue de la Houssiniꢁre, BP 92208, 44322 Nantes Cedex 3 (France)
E-mail: didier.dubreuil@univ-nantes.fr
[f] Dr. D. Jacquemin
[b] Dr. R. Le Guꢀvel, Dr. C. Guguen-Guillouzo
ImPACcell, Inserm U991, Centre Hospitalier Universitaire Pontchail-
lou
Unitꢀ de Chimie-Physique Thꢀorique et Structurale (2742)
Facultꢀs Universitaires Notre-Dame de la Paix
Rue de Bruxelles, 61, 5000 Namur (Belgium)
35033 Rennes Cedex (France)
[+] Deceased on June 20, 2010.
[c] Dr. B. Kauffmann, Dr. Y. Ferrand, Dr. I. Huc
Institut Europꢀen de Chimie et Biologie (IECB), CNRS
UMR5248 et UMS3033
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201000859.
Universitꢀ de Bordeaux
2 rue Robert Escarpit, 33607 Pessac Cedex (France)
11876
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 11876 – 11889

FULL PAPER
Introduction
roles.[11] As an extension of this “green” methodology, we
report here on efficient access to expanded 2,6-bis[5-(pyri-
din-2-yl)pyrrol-2-yl]pyridines 1a–c by electrochemical ring
contraction of the corresponding 2,6-bis[6-(pyridin-2-yl)pyri-
dazin-3-yl]pyridines 2a–c (Scheme 1). These alternating pyr-
rolic sequences flanked by three pyridine units are useful
tools to provide original nitrogen-based donor–acceptor li-
gands of great interest in both photochemistry and biology.
The synthesis of open chain aza donor–acceptor strands con-
stituted by p-conjugated aromatic sequences has been the
focus of intense research in recent years because of their po-
tential in a vast array of fields ranging from medicine to ma-
terials science, including mechanical, electrical, electrochem-
ical and optical devices.[1] In this context, alternating p-con-
jugated polypyrrole strands
with a central or terminal aro-
matic segment are of growing
interest to provide materials for
precise electrochemical conduc-
tivity,[1d,2] light harvesting,[3]
supramolecular
assemblies[4]
and biomedical applications.[5]
In particular, pyridyl–pyrrole
arrays have been used as valua-
ble models to study hydrogen-
bonding interaction in protein
or DNA binding sites involving
the pyrrole NH group, and in-
Scheme 1. Electrochemical retrosynthesis of tripyridyl–dipyrrole derivatives from tripyridyl–dipyridazine pre-
cursors (C.P.E.=controlled-potential electrolysis).
termolecular
excited-state
Results and Discussion
double proton transfer (ESDPT) for photoinduced mutagen-
esis was observed in similar structures.[6] Moreover, polyden-
tate pyrrolic-based ligands have attracted particular interest
in coordination chemistry due to their p-acceptor properties
and their ability to form metal complexes and coordination
polymers with high thermal stability. Specifically, dipyrrolic
architectures with a central pyridyl core have emerged as
potent chromophores, which have recently been found to
display not only high electrical conductivity but also to pro-
vide a unique combination of electroactive, coordinative
and optoelectronic properties. They thus offer an exception-
al prospective as materials for use in chemical power sour-
ces and organic light-emitting diodes (OLEDs).[2a]
The few strategies described to produce 3,4-unsubstituted
bis(pyrrol-2-yl)arylenes currently require the construction of
the heteroaromatic core from a flanked dipyrrole sys-
tem,[5b,7] transition-metal-catalyzed attachment of preformed
pyrrole units to a derivatized aromatic core[2g,8] or tandem
pyrrole synthesis on the aromatic core from a linear precur-
sor.[1d,2a–c,e,9] These approaches have typically given limited
di(pyrrol-2-yl)arylene ring sequences with variable and
almost always low overall yields, even the recent Paal–
Knoor alternative proposed by Hansford et al. affording 2,5-
bis(1H-pyrrol-2-yl)pyridines from homoallylic aryl ketones
in a relatively concise reaction sequence.[1d]
Pyridyl–pyridazine strand synthesis: Our first challenge was
the synthesis of alternating tripyridyl–dipyridazine precur-
sors 2a–c in suitable quantities prior to investigating their
preparative electrochemical ring contraction, which was far
from established. Lehn et al. previously designed the first
and only synthesis of a thirteenfold-alternating S-propyl pyr-
idyl–pyridazine sequence bearing bipyridyl groups at the
end fragments, and reported their winding into helical archi-
tecture 3 (Scheme 2).[12]
The elongation procedure involved construction of the
bridging 4-propylsulfanyl–pyridyl moieties by successive
condensations of the a-oxoketene dithioacetal unit 4, used
as Michael acceptor, with acetylpyridazine cores 5/6 or ace-
tylpyridine 7. Unfortunately, the extended Potts methodolo-
gy used[13] led to variable yields at different key steps of the
reaction sequence and gave dipyridazinic fragments 5 in
quantities too small for electrochemical experiments. We
thus turned to a strategy based on metal-catalyzed cross-
coupling to prepare tripyridyl–dipyridazines 2a–c by two al-
ternative pathways (Scheme 3).
Path A, which involves coupling of stannylpyridazines 9a–
c with commercially available dibromopyridine 8, rapidly
appeared to be ineffective. In accordance with literature
highlighting the difficult metalation of 3-chloropyridazine
derivatives,[14] stannylation of 3-halogeno pyridinyl pyrida-
zines 10a–c[15] did not exceed 9% yield in our hands. We
thus focused on the more promising Path B involving the re-
action of metallopyridines 11a–c or 12a–c with activated di-
pyridazines 13 or 14.
Therefore, the synthesis of the 2,6-di[6-(pyridin-2-yl)pyri-
dazin-3-yl]pyridine derivatives 2a–c was advantageously pur-
sued from 2,6-diacetylpyridine 15 as a common starting ma-
terial (Scheme 4).
We have recently become interested in pursuing the elec-
trochemical synthesis of pyrrole rings from pyridazine pre-
cursors as an elegant alternative to the classic chemical re-
agent based processes (Zn/AcOH) extensively used by
Boger et al. to produce a broad range of pyrrolic derivatives
of biological interest.[10] While the generality of this ap-
proach is not obvious, we have succeeded in effecting the
electroreduction-driven ring contraction of several 3,6-sub-
stituted pyridazines to the corresponding 2,5-substituted pyr-
Chem. Eur. J. 2010, 16, 11876 – 11889
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11877

D. Dubreuil et al.
odipyridazine 13 in 60% yield.
Next, Pd-catalyzed cross-cou-
pling reactions between metal-
lopyridine derivatives 11a–c or
12a–c and dichloropyridazines
13 were evaluated for forma-
tion of dipyridazine targets 2a–
c.
Stille cross-coupling was first
attempted with [PdACTHNUTRGNEUNG(PPh3)4] as
catalyst between chloropyrida-
zine 13 and tributylstannylpyri-
dine 11a,[17] tributylstannyl
methyl pyridine 11b[17] and trib-
utylstannyl dimethyl pyridine
11c[17] in DMF at 1208C
(Table 1, entry 1).[18] Under
these conditions, the formation
of stable Pd complexes in the
reaction mixtures caused diffi-
culties in the purification proce-
dures that resulted in disap-
pointingly poor yields of dipyri-
dazine derivatives 2a–c (6–
19%). Unfortunately, the use of
Scheme 2. Retrosynthesis of an alternating pyridyl–pyridazine strand by using the methodology developed by
Lehn and co-workers.
[Pd
(Table 1, entry 2) instead of
[Pd(PPh3)4] did not solve the
A
as
catalyst
AHCTUNGTRENNUNG
problem and afforded target di-
pyridazines 2a, 2b, and 2c in
modest yields (trace, 21% and
23%, respectively). Conse-
quently, according to a modi-
fied Kasatkin procedure,[19] the
Negishi methodology was fa-
vored to perform the hetero-
cross-coupling reaction of halo-
genopyridazine 13 with appro-
priate pyridyl zinc reagents
12a–c[20] (Table 1, entry 3). The
latter were prepared from the
Scheme 3. Retrosynthetic strategy to tripyridyl–dipyridazine precursors 2a–c.
corresponding
bromopyridi-
nes[17b] by treatment with
1.6 equiv of n-butyllithium in
THF at ꢁ788C for 30 min prior
to the addition of zinc dichlor-
ide (1.6 equiv). The resulting
solutions were stirred from
ꢁ788C to room temperature
over another 30 min, before the
Scheme 4. Synthesis of tripyridyl–dipyridazine precursors 2a–c.
Diacetylpyridine 15 was treated, following a modified
Coates procedure,[16] by condensation with 2.5 equivalents of
glyoxylic acid and 4 equivalents of K2CO3 in water, prior to
addition of an excess of hydrazine in refluxing acetic acid.
Under these conditions, the resulting pyridazinone 17 was
obtained in an improved yield of 91%. Subsequent chlorina-
tion of 17 in refluxing phosphorus oxychloride gave dichlor-
[PdACTHUNGTERNU(NG PPh3)4] catalyst (0.1 equiv) and chloropyridazine 13
(1.0 equiv) were added. The reactions were carried out for
48 h in refluxing THF and the expected dipyridazines 2a, 2b
and 2c were cleanly isolated in 13, 45 and 60% yield, re-
spectively. Finally, we found that the triflate analogue 14
(Table 1, entry 4), easily prepared in good yield from pyrida-
zinone 17 (triflic anhydride and catalytic amount of DMAP
11878
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Chem. Eur. J. 2010, 16, 11876 – 11889

Alternating Tripyridyl–Dipyrrole Molecular Strands
Table 1. Conditions of Pd cross-coupling reactions.
FULL PAPER
The nitrogen-extrusion sequence starts with formation of
dihydropyridazine intermediates (first wave), which evolve
to the pyrrole ring by a second electroreduction step
(second wave, path A) and/or by a dismutation process
(path B). The reduction of the electrogenerated pyrrole de-
rivatives is attributed to the last wave. According to this
postulate, the ring contraction of dipyridazines 2a–c was ex-
pected to follow a similar mechanism requiring a minimum
of eight electrons (Scheme 6). One question to be answered
was which sequence of reduction processes leads to extru-
sion of the two nitrogen atoms: two independent events at
each pyridazine unit or two non-independent consecutive
events? Indeed, it was expected that the sequence of reduc-
tion processes would influence the electrolysis profile and
consequently the yield of dipyrrole formation.
Entry Activated Pyd-M
Pd catalyst
(equiv)
Solvent Pdz (%)
temp.
time
pdz[a]
(2.4 equiv)
N
1
2
3
4
13
11
11
12
12
a
b
c
a
b
c
a
b
c
a
b
c
[Pd
AHCTUNGTRENNUNG
G
DMF
1208C
48 h
2a (<6)
2b (18)
2c (19)
2a (<2)
2b (21)
2c (23)
2a (13)
2b (45)
2c (60)
2a (27)
2b (68)
2c (95)
13
13
14
[Pd
T
1208C
48 h
THF
reflux
48 h
THF
reflux
48 h
[Pd
AHCTUNGTRENNUNG
[Pd
AHCTUNGTRENNUNG
[a] Pdz denotes pyridazine.
in pyridine at room temperature, 69% yield), advantageous-
ly underwent the desired Negishi coupling reaction with pyr-
idylzinc reagents 12a–c, and tripyridyl–dipyridazines 2a–c
were isolated in reproducible yields of 27, 68 and 95%, re-
spectively.
In all the organometallic coupling reactions performed,
treatment with aqueous ammonia solution (33 wt%) over-
night was required to release the pyridazine products
trapped in the resulting amalgam. Of course, the low solubil-
ity of pyridazine 2a (R, R’=H) could explain the poor
yields obtained in this series. In contrast, the presence of ad-
ditional methyl groups led to the expected tripyridyl–dipyri-
dazines 2b and 2c in proportionally increased yields. Having
obtained the dipyridazine precursors in sufficient amounts
to carry out electroreduction experiments, we studied their
ability to produce the desired tripyridyl–dipyrrole ana-
logues.
Scheme 6. Electrosynthesis of tripyridyl–dipyrrole derivatives by ring
contraction of tripyridyl–dipyridazine precursors.
Poor solubility of the polyheterocyclic systems in acetate
buffer/ethanol, previously proven to be an efficient electrol-
ysis medium, could be circumvented by using other buffers.
However, the electroreduction study was restricted to dipyr-
idazines 2b and 2c, as 2a appeared quite insoluble in almost
all electrolysis solvents tested.[21] Prior to attempting prepa-
rative electrolysis experiments, cyclic voltammograms of the
dipyridazines were recorded at a glassy carbon cathode in
acidic aqueous solvents. The electroreduction profile of 2b
was confirmed in a sulfuric acid (0.5molLꢁ1) by the pres-
ence of three irreversible cathodic peaks I, II and III at
Epc =ꢁ0.53, ꢁ0.68 and ꢁ0.85 V, respectively (Figure 1A,
Table 2, entry 1).
Based on the analytical data, the controlled potential elec-
trolysis of 2b was carried out at a mercury-pool cathode in a
two-compartment cell with a glass frit. Electroreduction of
the dipyridazine 2b was initiated at the second reduction
peak potential (EpcII) at Ew =ꢁ0.9 V/SCE (Table 3, entry 1)
and was monitored by cyclic voltammetry measurements in
the cathodic compartment. The shift to the cathodic poten-
tials observed in the cyclic voltammogram (Figure 1B, Epc =
ꢁ0.55, ꢁ0.89 and ꢁ1.16 V), was attributed to the increased
concentration of the substrate used in preparative electroly-
sis (7ꢂ10ꢁ3 molLꢁ1 vs. 10ꢁ3 molLꢁ1 under analytical condi-
tions). A proportionate decrease in the intensity of the two
Electrochemical ring contraction and pyridyl–pyrrole strand
synthesis: In previous studies,[11b–f] we established general fa-
vorable conditions for controlled potential electrolysis of
3,6-dipyridylpyridazine derivatives to give the corresponding
2,5-dipyridylpyrroles in acetate buffer/ethanol medium. The
electroreduction-driven ring contraction process was shown
to be highly sensitive to the nature of the substituents on
the pyridazine rings, yielding the pyrrole derivatives in vari-
able proportions. However, in all cases, cyclic voltammetry
profiles displayed two well-defined irreversible cathodic
peaks and a last wave at a more cathodic potential. These
preliminary results allowed us to propose a mechanism in-
volving consumption of four electrons (Scheme 5).[11a]
Scheme 5. General electroreduction mechanism for transformation of
pyridazine precursors into pyrrole derivatives.
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11879

D. Dubreuil et al.
Table 3. Coulometric data and yield of the electrochemical synthesis of
pyrroles at a mercury-pool cathode.
Entry Pdz
(CmolLꢁ1
Solvent
Ew [V][a]
N
Pyr[b]
[%]
)
[Fmolꢁ1
ACHTUNGTERNNUNG ]
1
2b
(7.0ꢂ10ꢁ3
2b
(2.8ꢂ10ꢁ3
H2SO4
ꢁ0.90
8
1b
N
)
)
(0.5 molLꢁ1
)
(16)[c]
1b
2
DMF/nBu4NBr various
8
E
(0.1 molLꢁ1)/
16 equiv H2SO4
THF/acetate
potentials
ACHTUNGTRENNUNG(trace)
3
4
5
2b
(4.8ꢂ10ꢁ3
ꢁ1.25
ꢁ1.20
ꢁ1.20
8
1b
A
)
)
buffer (pH 4.6)/
CH3CN (5:4:1)
THF/acetate
buffer (pH 4.6)/
CH3CN (5:4:1)
THF/acetate
(71)[d]
2c
(1.6ꢂ10ꢁ3
12
12
1c
E
(93)[d]
2c (1.6ꢂ10ꢁ3
)
1c
buffer pH 4.6)/
CH3CN (5:4:1)
(72)[d,e]
[a] Ew: working potential/SCE. [b] Pyr denotes pyrrole. [c] Purified by
flash chromatography on silica gel. [d] Purified by crystallization from
hexane/chloroform (4:1). [e] Electrolysis was run on a reticulated vitre-
ous carbon cathode.
in CH3CN, DMF was retained as an electrochemically inert
solvent, and in that case the addition of a support electrolyte
(0.10 molLꢁ1 nBu4NBr) to achieve conductivity in the
medium and a new source of protons (16.0 equiv H2SO4)
were required. Under these conditions, the cyclic voltammo-
gram revealed five reduction waves that were difficult to in-
terpret (see the Supporting Information). Several prepara-
tive electrolyses at various reduction potentials until the
consumption of 8 Fmolꢁ1 led to only traces of the expected
pyrrole 1b (Table 3, entry 2). This disappointing result was
difficult to rationalize, as the large excess of nBu4NBr in the
reaction mixture imposed a tedious purification treatment
that prevented convenient isolation of the final product due
to severe loss of material. To solubilize dipyridazine precur-
sor 2b, we then turned to a mixture of an organic solvent
(THF) and an aqueous solution as proton donor, in addition
to a supporting electrolyte (acetate buffer pH 4.6). The re-
sulting biphasic solution was homogenized by adding a
third, miscible cosolvent to the medium. After several
assays, the optimized conditions were defined as THF/ace-
tate buffer (pH 4.6)/acetonitrile in 5:4:1 ratio. Under these
conditions, the cyclic voltammogram of dipyridazine 2b
showed only two well-defined reduction waves, at Epc =
ꢁ0.96 and ꢁ1.19 V (Figure 2A, Table 2, entry 3). In this vol-
tammogram, a third cathodic wave corresponding to reduc-
tion of the pyrrole is also observed but not well enough de-
fined to be measured precisely.
Figure 1. Cyclic voltammograms at
a glassy carbon electrode (v=
0.1 Vsꢁ1) of A) 0.5 molLꢁ1 H2SO4 solution (b) prior to addition of 2b
(c, C=10ꢁ3 molLꢁ1). B) 2b (C=7ꢂ10ꢁ3 molLꢁ1) in 0.5 molLꢁ1 H2SO4
before electrolysis (b), after 5 Fmolꢁ1 (a), and after 8 Fmolꢁ1
(c).
Table 2. Cyclic voltammetry data of compounds 2b, 2c, 1b and 1c (C=
10ꢁ3 molLꢁ1, Ep [V/SCE] and v=0.1 Vsꢁ1).
Entry
Solvent
Compound
EpcI
EpcII
EpcIII
1
2
3
H2SO4
H2SO4
2b
1b
2b
ꢁ0.53
–
ꢁ0.96
ꢁ0.68
–
ꢁ1.19
ꢁ0.85
ꢁ0.98
–
THF/acetate
buffer/CH3CN
THF/acetate
buffer/CH3CN
THF/acetate
buffer/CH3CN
THF/acetate
buffer/CH3CN
4
5
6
1b
2c
1c
–
–
ꢁ1.45
–
ꢁ0.94
ꢁ1.17
–
–
ꢁ1.44
main peaks I and II in favor of the reduction peak III (Epc =
ꢁ1.02 V) highlighted the electroreduction evolution of 2b.
The electrolysis was stopped after total consumption of the
required 8 Fmolꢁ1, and the starting dipyridazine substrate
had disappeared to give the expected tripyridyl–dipyrrole
derivative 1b in an unsatisfactory yield after flash chroma-
tography on silica gel (16%). The electroreduction profile
of purified 1b was controlled to assign the remaining irre-
versible cathodic peaks at Epc =ꢁ0.98 V (Table 2, entry 2).
Alternatively, the preparative electrolysis was then carried
out in an organic solvent. Due to the poor solubility of 2b
Preparative electrolysis of 2b was monitored at Ew =
ꢁ1.25 V/SCE (EpcII, Figure 2B). In the course of electrosyn-
thesis, the appearance of the pyrrole reduction peak was
cleanly observed at Ep =ꢁ1.45 V, in good agreement with
the analytical cyclic voltammogram of the pure dipyrrole 1b
(Table 2, entry 4). This encouraging indication was con-
firmed at the preparative level, since the expected dipyrrole
1b was formed as the sole product of the electroreduction
process after consumption of 8 Fmolꢁ1 (Table 3, entry 3).
11880
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Chem. Eur. J. 2010, 16, 11876 – 11889

Alternating Tripyridyl–Dipyrrole Molecular Strands
FULL PAPER
Epc =ꢁ1.44 V (Table 2, entry 6). The controlled-potential
electrolysis of dipyridazine 2c was alternatively tested with
a reticulated vitreous carbon cathode (Table 3, entry 5), in
the solution described above, avoiding the use of mercury.
Under these “green” conditions, the desired tripyridyl–di-
pyrrole 1c was formed at Ew =ꢁ1.20 V/SCE in an accepta-
ble yield of 72%.
Absorption and fluorescence studies: The absorption char-
acteristics of alternating tripyridyl–dipyridazines 2b and 2c
and their dipyrrole analogues 1b and 1c were tackled. Pre-
vious investigations, through quantum chemistry calculations
(HF, DFT (MPWB1K), LMP2 levels of theory), highlighted
the planar conformational preferences of both strands, and
global energetic minima confirmed the existence of p-elec-
tronic conjugation between the aromatic systems and the oc-
currence of intramolecular H-bonds. Thus, the combination
of N sp2 nitrogen–nitrogen lone-pair repulsion and weak
CH···N sp2 attractive interaction in dipyridazine derivatives
2 results in a preferred anti conformation, whereas, more
surprisingly, the all-cis conformation of tripyridyl–dipyrroles
1 is rationalized by the occurrence of NH···N sp2 H-bonds
involving the central pyridazine core and the two pyrrole
units.[22]
The absorption spectra of dipyridazines 2b and 2c, re-
corded in CH2Cl2 (Figure 3A), show two similar main bands
at 316 and 257 nm for both compounds, that is, additional
methyl groups have no effect on the absorption features.
For 2b, quantum-chemical calculations at the DFT level
yield a perfectly planar C2v structure, and TD-DFT foresees
a strongly allowed transition at 300 nm that obviously corre-
sponds to the experimental band at 316 nm. This 16 nm dis-
crepancy is in line with the expected accuracy of the select-
ed level of theory.[23] At the PCM-CAM-B3LYP level, the
major contribution of this peak corresponds to an electron
promotion from the HOMO to the LUMO+1. As can be
seen in Figure 4, these p and p* orbitals are delocalized
over the full molecule, with the occupied orbital mainly lo-
cated in the five rings, whereas its virtual counterpart dis-
plays a significant contribution on the inter-ring bonds. In
addition, theory predicts significant bands at 287 and
263 nm that are consistent with the shape of the experimen-
tal band, as well as dipole-forbidden excitations at 306 and
312 nm. These latter absorptions, corresponding to n!p*
transitions involving the lone pairs of the pyridazine moiet-
ies, remain unseen experimentally as they are too close ener-
getically to the main p!p* band.
Figure 2. Cyclic voltammograms at
a glassy carbon electrode (v=
0.1 Vsꢁ1). A) THF/acetate buffer (pH 4.6)/CH3CN (5:4:1, b) prior to
addition of 2b (c, C=10ꢁ3 molLꢁ1). B) 2b (C=4ꢂ10ꢁ3 molLꢁ1) in
THF/acetate buffer (pH 4.6)/CH3CN (5:4:1) before electrolysis (b),
after 5 Fmolꢁ1 (a), and after 8 Fmolꢁ1 (c).
Tripyridyl–dipyrrole 1b was isolated in 71% yield by crystal-
lisation from chloroform/hexane (4:1), whereas it was ob-
tained in a lower yield of 45% after flash chromatography
on silica gel. To facilitate a mechanistic interpretation, we
envisaged identifying the intermediates by running the elec-
troreduction at the potentials of the two waves and limiting
the electron source to 4 Fmolꢁ1. Unfortunately, these ex-
periments led to complex mixtures in which dipyrrole and
monopyrrole were identified (see 1H NMR spectra in the
Supporting Information). Inasmuch as no formation of dihy-
dropyridazine was observed along with production of the
pyrrole derivatives and remaining dipyridazine precursor, no
evidence was obtained to elucidate the process.
The optimized electroreduction procedure was then trans-
posed to tripyridyl–dipyridazine 2c in the same ternary
THF/acetate buffer (pH 4.6)/acetonitrile solution (5:4:1)
with the expectation of obtaining the corresponding tripyrid-
yl–dipyrrole 1c. As anticipated from the analytical voltam-
mogram (Table 2, entry 5), the electrolysis of 2c was run at
Ew =ꢁ1.20 V/SCE (EpcII, Table 3, entry 4) to afford 1c in
93% yield after crystallization from chloroform/hexane
(4:1). The electroreduction profile of purified 1c was con-
firmed by the presence of one irreversible cathodic peak at
Both dipyrroles 1b and 1c display a similar absorption
profile (Figure 3B) but the nature of the heterocycle at the
2- and 6-positions of the central pyridine shifts significantly
the electronic absorption maxima to give two main bands at
about 340 and about 380 nm in CH2Cl2 with distinct vibra-
tional structures. For 1b, a twisted C2 ground state is ob-
tained by DFT simulations (see below for discussion). As il-
lustrated in Figure 3C, the two first calculated absorption
maxima are centred at 356 (f=0.6) and 324 nm (f=1.3) in
CH2Cl2.
Chem. Eur. J. 2010, 16, 11876 – 11889
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11881

D. Dubreuil et al.
Figure 4. Relevant molecular orbitals for 2b, computed at the PCM-
(CH2Cl2)-CAM-B3LYP/6-311+GACTHNURTGNEU(GN 2d,p) level and plotted with a contour
threshold of 0.30 a.u.
Table 4. Photophysical properties of dipyrroles 1b and 1c and dipyrida-
zines 2b and 2c in methanol and dichloromethane.
[a]
[a]
ff[b,c]
~
nexc
~
nexc
Entry Solvent Ligand labs
e
[nm] [molꢁ1 Lcmꢁ1
]
A
]
A
]
1
2
3
4
5
6
CH2Cl2 2b
316
257
318
260
380
343
380
341
378
341
378
340
38000
23800
44600
28600
25900
56300
26900
58600
29500
62100
29400
64200
2c
1b
26500 24250 0.12
26500 24200 0.15
26600 23600 0.01
26600 23300 0.01
1c
MeOH 1b
1c
[a] Accuracy ꢂ50 cmꢁ1. [b] Fluorescence quantum yields were calculated
relative to quinine sulfate in 0.5m H2SO4 solution.[24] [c] Measured error
is ꢂ10%.
sponds to a HOMO to LUMO (HOMO to LUMO+1)
transition with
a
smaller HOMOꢁ1 to LUMO+1
(HOMOꢁ1 to LUMO) contribution. These orbitals, sketch-
ed in Figure 5, are basically completely delocalized and no
Figure 3. A) Absorption spectra of dipyridazines 2b (c) and 2c (g)
in dichloromethane. B) Absorption spectra of dipyrroles 1b (g), 1c
(c) in dichloromethane, 1b (a) and 1c (b) in methanol; C) Simu-
lated absorption spectra of 1b. The curves [C2 structure (c), C2v struc-
ture (g), and C2v structure with central water molecule (g)] were
obtained at the PCM-CAM-B3LYP/6-311+GACHTUNGTERN(UNNG 2d,p) level by using a
broadening Gaussian with full width at half-maximum of 0.25 eV. Note
that the two C2v structures are not true minima of the potential-energy
surface and are presented for comparison purposes only.
Though these values are shifted by about 20 nm with re-
spect to their experimental counterparts (Table 4), the
agreement between the two schemes is certainly satisfying.
Indeed, TD-DFT reproduces the gap between the two peaks
(32 nm vs. 37 nm), their relative intensities (0.44 vs. 0.46), as
well as the bathochromic shift with respect to 2b (56 nm vs.
64 nm). The 356 nm (324 nm) absorption mainly corre-
Figure 5. Relevant molecular orbitals for 1b in its optimal geometry,
computed at the PCM-(CH2Cl2)-CAM-B3LYP/6-311+GACHTUNTRGNEU(GN 2d,p) level and
plotted with a contour threshold of 0.30 a.u.
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Chem. Eur. J. 2010, 16, 11876 – 11889

Alternating Tripyridyl–Dipyrrole Molecular Strands
FULL PAPER
strong electronic transfer is associated with the two absorp-
tion bands, though the HOMOꢁ1 to LUMO+1 component
implies a displacement of charge from the terminal pyridine
rings to the central one. For the record, we also computed
the spectra for C2v geometries with or without a central
water molecule (analogous to the crystal structure, see
below), and it can be seen in Figure 3C that all structures
show very similar absorption patterns. The small impact of
the central water molecule may be ascribed to the p symme-
try of the relevant orbitals: they are almost unaffected by
H-bonds between water and the lone pairs of the pyridine
rings.
Changing the concentration of dipyridazines 2b and 2c,
and dipyrroles 1b and 1c, does not modify their absorption
features in CH2Cl2 (data not shown). Moreover, the absorp-
tion peaks in both pyridazine and pyrrole series express a
large molar extinction coefficient on the order of
e
ꢀ104 molꢁ1 Lcmꢁ1 for the two series (Table 4).
The absorption characteristics of dipyrroles were also in-
vestigated in MeOH, while dipyridazines 2b and 2c remain
insoluble in the protic solvents. The absorptions of dipyr-
roles 1b and 1c in MeOH show similar profiles to those in
CH2Cl2 and again are not concentration-dependent (Fig-
ure 3B). This observation indicates that MeOH does not
induce formation of aggregates of the pyrrole species at the
tested concentrations (10ꢁ4–10ꢁ5 molLꢁ1). The absence of a
solvatochromism may result from the constrained conforma-
tion of tripyridyl–dipyrrolic ligands 1b and 1c trapping a
molecule of water, which probably restricts interactions with
protic solvents.
Figure 6. A) Excitation (measured at 24100 cmꢁ1) and emission (excited
at 29400 cmꢁ1) spectra of 1b (b) and 1c (c) in dichloromethane.
All spectra are normalized to the maximum intensity. B) Excitation
(measured at 23800 cmꢁ1) and emission (excited at 29200 cmꢁ1) spectra
of dipyrroles 1b (b) and 1c (c) in methanol.
The fluorescence characteristics of 1b and 1c were also
examined in both protic and aprotic solvents (MeOH and
CH2Cl2), whereas dipyridazines 2b and 2c do not fluoresce
in CH2Cl2. The excitation and emission fluorescence spectra,
the positions of the excitation and emission fluorescence
maxima and the quantum yields are presented in Figure 6
and Table 4. The excitation spectra (Figure 6A for CH2Cl2
and B for MeOH), measured in the region of 40000–
24000 cmꢁ1, coincide with the absorption spectra within ex-
perimental error, that is, the entire emission results from a
common Franck–Condon excited state in each case. The
fluorescence emission behavior of compounds 1b and 1c
Solid-state structures: Single-crystal X-ray diffraction analy-
sis of tripyridyl–dipyrroles 1b and 1c were undertaken to es-
tablish their molecular geometries and intermolecular inter-
actions in the solid state, in anticipation of a potential ability
1
to embed a metal ion. H NMR analysis of 1b and 1c pre-
dicted organization of averaged symmetrical structures sup-
porting the modelling calculations. For example, the termi-
nal methyl proton signals are observed as one singlet (d=
2.64 ppm) for 1b and two singlets (d=2.33 and 2.61 ppm)
for 1c. The free dipyrrole ligands crystallized from dried,
distilled hexane/chloroform (4:1), and both have a coordi-
nated water molecule (Figure 7).
The structures reveal a bent and almost flat conformation
similar to the calculated structures. Thus, both molecules 1a
and 1b have all five pyridyl and pyrrolyl ring endocyclic ni-
trogen atoms oriented towards the cavity and all aryl–aryl
linkages in cis conformation, which is reinforced by intermo-
lecular H-bonds between NHpyr and Owater of the two pyrrole
units and Npyd and Hwater of the two terminal pyridine moiet-
ies (selected bond lengths, distances and angles are given in
Table 5). These H-bonds are both 2.17 ꢅ in length for 1b,
and a weak twist of the conformation is observed between
the pyrrole and the terminal pyridine planes with an angle
(Table 4, nem ꢀ2ꢂ104 cmꢁ1 in MeOH and CH2Cl2) is inde-
~
pendent of the excitation wavelength in both solvents (data
not shown), which indicates adherence to Kashaꢄs rule.[25] In
CH2Cl2, both pyrrole derivatives reveal similar high emis-
sion yields (Table 4; ff =0.15 and 0.12 for 1b and 1c, respec-
tively), but ten times higher than in MeOH (Table 4; ff
ꢀ0.01 for 1b and 1c). Indeed, the effect of solvent on the
de-excitation mode of the pyrrole units could be analyzed to
rationalize the quantum yield in MeOH. As observed by
MacManus-Spencer et al. in 2-(2’-pyridyl)pyrrole structur-
es,[6b] the absence of a red-shifted emission band, which is
one hallmark of an excited-state double proton-transfer pro-
cess, was also found in the emission spectra of dipyrroles 1b
and 1c in MeOH.
Chem. Eur. J. 2010, 16, 11876 – 11889
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11883

D. Dubreuil et al.
groups of 1c are closer together
than those of 1b (Cterm···Cterm
3.772 and 3.825 ꢅ respectively),
while the planar conformation
of 1c is maintained (C6-N2-
C9pyr/C1-N1-C5term pyd
1.88).
However, the distance between
the terminal methyl groups
does not undercut the sum of
the van der Waals distances, in
confirmation of the strained sit-
uation of a square-planar block
conformation.
The dipyrrolic ligands 1 are
arranged in pseudo-helical pil-
lars composed of alternating
opposite orientations of the
monomers (Figure 8A), propa-
Figure 7. Mercury diagrams of dipyrroles 1b (A) and 1c (B) determined by X-ray diffraction.
Table 5. Selected bond lengths [ꢅ], distances [ꢅ], and bond angles [8] for
dipyrrole compounds 1b and 1c and for the dipyrrole dimetal complex of
1b with copper(II).
gation of which along the crystallographic b axis leads to a
solvent channel (Figure 8B).
1b (X=O)
1c (X=O)
1b-Cu2 (X=Cu)
ꢁ
N1 H2
2.17(5)
5.653(4)
2.859(3)
5.133(4)
2.962(3)
4.639(4)
2.747(3)
3.015(3)
3.398(5)
3.94(5)
2.167(3)
–
2.02(4)
–
ꢁ
N1 N1
5.604(3)
2.852(2)
5.120(3)
6.53(1)
2.69(1)
5.21(1)
2.024(9)
5.04(1)
2.92(1)
2.01(1)
3.53(1)
–
ꢁ
N1 N2
ꢁ
N1 N3
ꢁ
N1 X1
2.936ACTHNGUTERNNU(G 2
ꢁ
N2 N2
4.632(7)
2.748(2)
3.021(2)
3.415(3)
3.96(4)
2.112(2)
–
–
–
–
1.381(3)
1.381(3)
1.372(3)
1.391(3)
1.459(3)
1.378(3)
1.399(3)
1.374(3)
1.456(3)
1.393(3)
1.373(3)
3.772(4)
132.23(9)
115.00(9)
–
ꢁ
N2 N3
ꢁ
N2 X1
ꢁ
N3 X1
ꢁ
N3 H2
ꢁ
X1 H1
–
ꢁ
X1 X1
3.082(2)
2.526(3)
1.930(6)
2.00(1)
1.42(2)
1.34(2)
1.39(2)
1.39(1)
1.46(2)
1.45(2)
1.43(2)
1.42(2)
1.50(2)
1.36(2)
1.38(2)
4.79(2)
136.4(5)
119.2(6)
83.7(4)
75.2(1)
106.0(5)
ꢁ
X1 Cl1
–
–
–
ꢁ
X1 O1
Figure 8. Mercury diagrams of the dipyrrole–dipyrroles 1b arrangement
(identical to 1c, see Supporting Information)
ꢁ
X1 O2
ꢁ
C1 C2
1.388(5)
1.378(5)
1.368(5)
1.396(4)
1.450(4)
1.388(4)
1.396(5)
1.383(4)
1.463(4)
1.377(4)
1.376(4)
3.825(5)
132.6(1)
115.2(2)
–
ꢁ
C2 C3
ꢁ
C3 C4
ꢁ
Gas-phase geometry of 1b was optimized at the PBE0/6-
311GACTHUNRTGNEUNG(d,p) level with and without a central water molecule.
C4 C5
ꢁ
C5 C6
ꢁ
C6 C7
For the latter structure, the theory/experiment discrepancies
are relatively small, though the water molecule is not locat-
ed in a perfectly symmetric position as in the solid state.
The performance of PBE0 is illustrated by the relatively ac-
curate estimates for the challenging non-covalent distances,
ꢁ
C7 C8
ꢁ
C8 C9
ꢁ
C9 C10
ꢁ
C10 C11
ꢁ
C11 C12
Cterm···Cterm
N1-N2-N3
N2-N3-N2
N1-X1-N2
X1-Cl1-X1
X1-O1-X1
ꢁ
for example, Cterm···Cterm 3.735 ꢅ (2% error), N1 N1
ꢁ
5.481 ꢅ (3% error) and N2 N2 4.547 ꢅ (2% error). For the
ꢁ
position of the central water molecule, DFT yields an N3
–
–
–
–
ꢁ
O1 distance of 3.490 ꢅ (3% error) and an average H1 O1
separation of 2.067 ꢅ (5% error). For the N1-N2-N2-N1 di-
hedral angle, theory (10.98) and experiment (2.98) provide
diverging estimates, an expected outcome for a parameter
more sensitive to solid-state packing effects. When the cen-
tral water molecule is removed, the predicted twist of the
structure strongly increases with a Cterm···Cterm distance of
4.249 ꢅ and an N1-N2-N2-N1 dihedral angle of 24.28; in
other words, the complexed molecule tends toward a flat-
tened structure, which hints that water has a large impact on
the measured geometrical parameters. From an energetic
of 6.18. The molecule of water positioned in the centre of
the bent conformation deviates from the plane of the central
pyridine ring by 11.48, while the two external pyridine rings
are almost mutually coplanar. Thanks to the electron-donat-
ing effect of an additional para methyl group on each termi-
nal pyridine rings, the H-bond distances vary slightly in 1c
(NHpyr···Owater 2.112 ꢅ and Npyd···Hwater 2.02 ꢅ). The methyl
11884
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Alternating Tripyridyl–Dipyrrole Molecular Strands
FULL PAPER
point of view, the deformation of 1b induced by the central
water molecule is estimated at 2.7 kcalmolꢁ1, whereas the
energy inside the dipyrrole units has been evaluated to be
10.9 kcalmolꢁ1. This relatively large stabilization energy is
consistent with the nearly optimal position of the water mol-
ecule, which interacts with 1b through several H-bonds.
The potential for coordination and molecular distortion of
the tripyridinyl–dipyrrole ligands was addressed by studying
a copper(II) salt. The prediction was confirmed by the X-
ray analysis of a crystal complex of ligand 1b that formed
the two end methyl groups (dCterm···Cterm =3.825 ꢅ for 1b and
d
Cterm···Cterm =4.79 ꢅ for 1b-CuI2I]. The two copper(II) ions are
located only 3.082 ꢅ from each other. More interestingly, to
accommodate the two transition-metal ions, the coordina-
tion preserves a single bridging acetate ion and association
with a molecule of methanol and a chloride ion, which
bridge the two copper(II) cations with Cu1-O1-Cu1 and
Cu1-Cl1-Cu1 angles of 106.0 and 75.28, respectively. Both
the methanol molecule and chloride anion, originating from
the solvents, replaced the acetate counterions of the two
successfully in the presence of Cu
G
copper ions with distances (dCu1ꢁO1 =1.930, dCu1ꢁCl1 =
2.526 ꢅ) similar to those found in other choride-bridged
copper structures. The chloride ion is oriented toward the
inside cavity of the dinuclear complex while the acetate and
methanol ligands point to the convex side.
Conclusion
The synthesis and characterisation of two chromophore
strands in which two electron-rich pyrrole units (donors) are
sandwiched between pyridine cores (acceptors) was ach-
ieved. A smooth, green electrosynthetic approach to alter-
nating pyrrolic–pyridine sequences has been designed. This
strategy required access to alternating tripyridyl–dipyrida-
zine precursors in sufficient quantities to investigate their
electrochemical ring-contraction behavior, which was pro-
vided by a Negishi metal cross-coupling methodology in-
volving 2-pyridyl zinc bromide reagents 12a–c and 2,6-bis-
(6-trifluoromethanesulfonylpyridazin-3-yl)pyridine 14. This
procedure provided the desired tripyridyl–dipyridazines 2a–
c in reproducible yields, which increased further in the pres-
ence of methyl groups on the metallated halogenopyridine
(30–95%). Preparative electrochemical reduction of tripyr-
idyl–dipyridazines 2b and 2c in THF/acetate buffer/acetoni-
trile gave target tripyridyl–dipyrroles 1b and 1c in good
yields of 71 and 93%, respectively. The highly fluorescent
properties of donor–acceptor tripyridyl–dipyrrole ligands 1b
Figure 9. A) Mercury diagrams of CuII complex 1b-Cu2II. B) ORTEP of
dimetallic complex 1b-CuI2I, determined by X-ray diffraction.
chloromethane solution (Figure 9). Two copper atoms are
trapped by one pentadentate single ligand 1b in the bifur-
cated chloro-, acetato-, and methoxyl-bridged 1:2 dicopper-
(II) complex 1b-CuI2I. Both copper(II) atoms are pentacoor-
dinate in a distorted square. Each square involves two nitro-
and 1c were determined (nem ꢀ2ꢂ104 cmꢁ1 in MeOH and
~
gen atoms, one from
a
deprotonated pyrrole moiety
CH2Cl2), and both exhibit a remarkable quantum yield in
CH2Cl2 (ff =0.15 and 0.12 for 1b and 1c, respectively),
which drastically dropped in MeOH (ff ꢀ0.01).
(dN2ꢁCu1 =2.01 ꢅ) and the other from a peripheral pyridine
residue (dN1ꢁCu1 =1.996 ꢅ), while the nitrogen atom of the
central pyridine ring remains too remote to interact
(dN3ꢁCu1 =3.53 ꢅ). To allow the two copper centres to embed
in the ligand cavity, the ligand is slightly distorted from its
otherwise planar conformation (central pyridine vs. pyrrole
6.68; pyrrole vs. terminal pyridine 7.58 and central pyridine
vs. terminal pyridine 13.58; for 1b: 2.7, 6.1 and 2.38, respec-
tively). The Npyr-CuII-Nterm pyd and Nterm pyd-Npyr-Ncentral pyd bond
angles are about 83.7 and 136.48, respectively. Consequently,
the pyridine–pyrrole–pyridine linkages end up twisted, while
all nitrogen atoms of the pentadentate ligand remain point-
ed towards the inner copper atoms in a concave deforma-
tion. This result suggests that the ligand can adapt to various
sizes of metal ions with a variation of ꢂ0.846 ꢅ between the
nitrogen atoms of terminal pyridine units (dN1ꢁN1 =5.653 ꢅ
for 1b and 6.53 ꢅ for 1b-CuI2I) and over ꢂ0.97 ꢅ between
From a structural point of view, the X-ray diffraction anal-
yses of the tripyridyl-dipyrrole sequences in 1b and 1c re-
flect the all-cis conformation in the solid state predicted by
quantum chemical calculations.[22] Additionally, the donor–
acceptor ligands encapsulate a molecule of water, which
contributes to the energetic stability of their planar organi-
sation and may further restrict the rotational freedom,
which generally strongly depends on the extent heterocycle
linkage. Theoretical calculations fully complement and sup-
port the explanations for the experimental observations, by
providing a complexation energy exceeding 10 kcalmolꢁ1
for the central water molecule. The ability of tripyridyl–di-
pyrrole ligand 1b to complex with a metal cation was ex-
plored. In the presence of a copper(II) salt, a bifurcated 1:2
complex in which two copper atoms are trapped by a single
Chem. Eur. J. 2010, 16, 11876 – 11889
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11885

D. Dubreuil et al.
polydentate ligand was isolated in the solid state. The two
copper(II) ions are pentacoordinate in a distorted square in-
volving four nitrogen atoms from both deprotonated pyrrole
rings and the two external pyridine residues. Comparative
X-ray analysis of the ligand 1b and complex 1b-CuI2I empha-
sizes the degree of molecular distortion displayed by such
molecular strands and suggests that versatile formation of
complexes with other geometries may be achieved. This
result sheds light on the structure/property relationship of
the tripyridyl–dipyrrole ligands and provides important in-
formation for future design of complex-based devices ex-
ploiting the high cooperativity potential in dimetallic bind-
ing. Thus, these donor–acceptor pyrrole strands are of inter-
est for the preparation of new bifunctional complexes in-
cluding those with anions or H-bonding with organic bases.
Indeed, alternating dipyrrole ligands are expected to be able
to participate further in the self-assembly of supramolecular
architectures through intermolecular bonds mediated by
metal atoms replacing the central water molecule. Current
work aims at investigating metal-binding properties of such
original donor–acceptor ligands with lanthanides. They also
may be valuable models for study of steric and electronic ef-
fects on associative biological interactions or other H-
bonded molecules. Preliminary in vitro studies were per-
formed to determine whether the new set of pyridazine and
pyrrole derivatives described above can induce cytotoxicity
and/or bioactive effects in living cells from different tissular
origins. Assays were performed by monitoring cell viability
and growth activity of six different tumour cell lines repre-
sentative of the most frequent solid tumours in humans
(liver, colon, prostate, breast and lung) and one normal dip-
loid skin fibroblastic cell line, exposed to increasing concen-
trations of the compounds (from 0.1 to 25 mm) for 1 and 2 d.
Table 6, which lists data for representative compounds, high-
lights that pyridazines 2a and 2b and pyrrole derivatives 1b
and 1c can penetrate cell membranes, and pyrrolic deriva-
tive seem to be effective in inducing cytotoxicity.
Experimental Section
General procedure for the synthesis of 6-tributylstannylpyridines 11a,[26]
11b[26,27] and 11c: nBuLi (2.5 molLꢁ1 in hexanes, 1 equiv) was added to a
solution of 2-bromopyridine (1 equiv) in THF (2 mLmmolꢁ1) at ꢁ788C.
After 30 min, tributylstannyl chloride (1 equiv) was added to the result-
ing dark red solution. Then the solution was stirred for 1 h at ꢁ788C and
an additional 1 h at room temperature. The reaction mixture was
quenched with saturated aqueous NH4Cl solution. The aqueous phase
was extracted with Et2O, and the organic layer washed with brine, dried
over MgSO4 and concentrated to dryness. After purification by distilla-
tion under reduced pressure with a Kugelrohr apparatus, the compounds
were obtained as pale yellow oils.
2,4-Dimethyl-6-(tributylstannyl)pyridine (11c): Following the general
procedure,
a
solution of 2-bromo-4,6-dimethylpyridine (2.0 g,
10.75 mmol), nBuLi (2.5 molLꢁ1 in hexanes, 4.3 mL, 10.75 mmol) and
tributylstannyl chloride (2.9 mL, 10.75 mmol) in THF (20 mL) was stirred
at ꢁ788C for 1 h and an additional 1 h at room temperature. Distillation
of the crude product (2188C, 1.1 mbar) obtained after work-up yielded
3.7 g (86%, overestimated yield due to remaining trace of stannyl re-
1
agent) of 11c as a pale yellow oil. H NMR (300 MHz, CDCl3, 258C): d=
7.03 (s, 1H), 6.81 (s, 1H 2.51 (s, 3H), 2.25 (s, 3H), 1.69–1.53 (m, 6H),
1.41–1.29 (m, 6H), 1.14–1.08 (m, 6H), 0.97–0.88 ppm (m, 9H); 13C NMR
(75.5 MHz, CDCl3, 258C): d=172.5, 158.6, 144.1, 130.8, 122.9, 29.4, 25.0,
21.1, 17.8, 14.0, 10.1 ppm; MS (70 eV): m/z (%): 396 (2) [M]+, 339 (100)
[MꢁBu]+; HRMS: m/z calcd for [M+H]+ (C19H36N116Sn): 394.1886;
found 394.1866.
6,6’-(Pyridine-2,6-diyl)dipyridazin-3ACTHNUGTRNEUNG(2H)-one (17): Glyoxylic acid (2.3 g,
30.67 mmol) was added to a solution of K2CO3 (6.8 g, 49.43 mmol) in
water (40 mL) at 08C. After homogenisation, 2,6-diacetylpyridine 15
(2.0 g, 12.26 mmol) was added and the mixture was stirred at 508C until
total dissolution of the compounds. After cooling at 08C, glacial acetic
acid (10 mL) and then monohydrate hydrazine (5 mL) were added drop-
wise. After 2 h at reflux, the reaction mixture was cooled to 08C and neu-
tralized with K2CO3 (powder then saturated aqueous solution). The re-
sulting precipitate was filtered, washed distilled water and 2-propanol.
Desired compound 17 in a mixture with its tautomer (3.0 g, 91%) was
obtained as a pale yellow powder. M.p. 2848C; 1H NMR (300 MHz,
[D6]DMSO, 258C): d=13.13 (brs, 2H), 8.52 (d, J=9.9 Hz, 2H), 8.11–8.04
(m, 3H), 7.05 ppm (d, J=9.9 Hz, 2H), due to the existence of its tauto-
mer (ca. 5%) most of the signals appear twice; 13C NMR (75 MHz,
[D6]DMSO, 258C): d=160.7, 151.3, 143.1, 138.8, 131.0, 130.0, 119.4 ppm;
MS (70 eV): m/z (%): 267 (100) [M]+, 238 (6) [MꢁN2]+, 211 (32)
[Mꢁ2N2]+.
2,6-Bis(6-chloropyridazin-3-yl)pyridine (13): A solution of dipyridazinone
17 (1.9 g, 6.25 mmol) in POCl3 (15 mL) was heated to reflux for 18 h.
After cooling, the reaction mixture was distilled under reduced pressure
to remove excess POCl3. Then the residue was carefully hydrolyzed by
addition of iced water and neutralized with 1 molLꢁ1 aqueous NaOH so-
lution. The aqueous layer was extracted with CH2Cl2. The combined or-
ganic layers were dried (Na2SO4) and concentrated. Flash chromatogra-
phy on silica gel (AcOEt) gave pure compound 13 (1.1 g, 60%) as a pale
Table 6. Antiproliferative cell activity [mm].
Molecule Huh7[a] Caco2[b] PC3[c]
MDA- NCI[e] Fibroblasts[f]
MB231[d]
2a
2b
2c
1b
1c
15
7
>25
1.2
2.5
3
7
25
5
4
25
15
>25
8
>25
10
>25
5
4
>25
3
>25 >25
1
yellow powder. M.p.>2308C; H NMR (300 MHz, CDCl3, 258C): d=8.77
3
2
3
3
(d, J=7.9 Hz, 2H), 8.62 (d, J=9.0 Hz, 2H), 8.10 (t, J=7.9 Hz, 1H),
7.67 ppm (d, J=9.0 Hz, 2H); 13C NMR (75 MHz, CDCl3, 258C): d=
157.4, 157.2, 152.3, 138.8, 128.7, 126.7, 123.0 ppm; MS (70 eV): m/z (%):
304 (17) [M]+, 240 (100) [MꢁClꢁN2]+, 205 (9) [Mꢁ2ClꢁN2)]+; HRMS:
m/z calcd for [M+Na]+ (C13H7Cl2N5Na): 325.9976; found 325.9950.
5
7
10
[a] Huh7: liver. [b] Caco2: colon. [c] PC3: prostate. [d] MDA-MB231:
breast. [e] NCI: lung. [f] Fibroblasts: reference.
2,6-Bis(6-trifluoromethanesulfonylpyridazin-3-yl)pyridine (14): Triflic an-
hydride (1.9 mL, 11.22 mmol)was added to a cooled (08C) solution of 17
(1.0 g, 3.74 mmol) and 4-dimethylaminopyridine (23 mg, 0.19 mmol) in
pyridine (5 mL). The reaction mixture was allowed to warm to room tem-
perature over 6 h. Water (30 mL) was added and the mixture was extract-
ed with CH2Cl2 (4ꢂ10 mL). The combined organic layers were washed
with brine (30 mL), dried (Na2SO4) and concentrated to dryness. Chro-
matography on silica gel (petroleum ether/CH2Cl2/Et2O, gradient from
100:0:0 to 70:20:10) afforded 14 (1.36 g, 69%) as brown powder. M.p.:
1438C; 1H NMR (300 MHz, [D6]DMSO, 258C): d=9.24 (d, J=9.2 Hz,
The obvious advantages of the developed one-pot electro-
synthetic strategy starting from more easily accessible pyrid-
azine precursors, make our approach attractive for preparing
a number of otherwise inaccessible functionalized molecular
strands in which several pyrrole units are linked by various
heterocyclic spacers. Elaboration of such polyfunctional
metal complexes is currently in progress.
11886
www.chemeurj.org
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 11876 – 11889

Alternating Tripyridyl–Dipyrrole Molecular Strands
FULL PAPER
2H), 8.74 (d, J=7.9 Hz, 2H), 8.34 (t, J=7.9 Hz, 1H), 8.31 ppm (d, J=
9.2 Hz, 2H); 13C NMR (75.5 MHz, [D6]DMSO, 258C): d=160.8, 159.3,
151.6, 139.9, 131.4, 123.2, 122.7, 120.3 ppm; MS (70 eV): m/z (%): 531
(48) [M]+, 370 (51) [MꢁSO2CF3ꢁN2]+, 342 (100) [MꢁSO2CF3ꢁ2N2]+;
HRMS: m/z calcd for [M+Na]+ (C15H7F6N5NaO6S2): 553.9634; found:
553.9628.
ture was stirred at reflux for 48 h. Chromatography on silica gel (CH2Cl2/
Et2O, gradient from 100:0 to 50:50) of the crude product obtained by fol-
lowing the general work-up procedure yielded 306 mg (95%) of pure 2c
as a pale yellow solid. M.p.: 2698C; 1H NMR (300 MHz, CDCl3, 258C):
d=8.86 (d, J=7.8 Hz, 2H), 8.77 and 8.75 (AB system, J=8.9 Hz, 4H),
8.42 (s, 2H), 8.10 (t, J=7.8 Hz, 1H), 7.10 (s, 2H), 2.63 (s, 6H), 2.44 ppm
(s, 6H); 13C NMR (75.5 MHz, CDCl3, 258C): d=158.5, 158.1, 157.7,
153.2, 152.4, 148.6, 138.4, 125.4, 125.3, 124.9, 122.5, 119.9, 24.3, 21.1 ppm;
General procedure for synthesis of dipyridazines 2a, 2b and 2c by Ne-
gishi coupling reaction:
A solution of the requisite bromopyridine
UV/Vis
(CH2Cl2):
l(e)=318
(44600 molꢁ1 m3 cmꢁ1),
260 nm
(1.6 equiv) in THF (3 mLmmolꢁ1 of bromopyridine) at ꢁ788C was treat-
ed with nBuLi (2.5 molLꢁ1 in hexanes, 1.6 equiv). The mixture was
stirred for 30 min, and then a solution of zinc chloride (0.7 molLꢁ1 in
THF, 1.6 equiv) was added by canula at ꢁ788C. At the end of the addi-
tion, the mixture was allowed to warm to room temperature and stirred
for 30 min. Then a solution of tetrakis(triphenylphosphine)palladium
(0.05 equiv) and activated dipyridazine 14 (1.0 equiv) in THF
(6 mLmmolꢁ1 of bromopyridine) was added by a canula at this tempera-
ture. After 48 h at reflux, the mixture was quenched with saturated aque-
ous NaHCO3 (30 mL) and 25 molLꢁ1 aqueous NH4OH (50 mL) solutions,
and the resulting solution was stirred for 24 h. The heterogeneous mix-
ture was filtered through a pad of Celite, which was washed with CH2Cl2
then with 25 molLꢁ1 aqueous NH4OH. The filtrate was extracted with
CH2Cl2 (3ꢂ50 mL). The combined organic layers were dried over
Na2SO4 and the solvents were removed in vacuo to afford the respective
reaction product, which was purified by flash chromatography on silica
gel or crystallization.
(28600 molꢁ1 dm3 cmꢁ1); MS (70 eV): m/z: 445 (36) [M]+, 417 (33)
[MꢁN2]+; HRMS: m/z calcd for C27H23N7: 445.2015; found: 445.2016.
General procedure for the synthesis of dipyrroles 1b and 1c by electro-
chemical ring contraction: Dipyridazine 2b or 2c (70 to 200 mg) was dis-
solved in THF/acetate buffer/CH3CN (5:4:1, 90 mL), and the solution in-
troduced into the cathodic compartment of the electrochemical cell. The
same solvent was put in the anodic compartment. Prior to and during
electrolysis at Ew, the catholyte was deaerated with argon and stirred
magnetically. The course of the reaction was followed by cyclic voltam-
metry in the cathodic compartment, and the electrolysis was stopped
when the consumption of the starting substrate was complete (8 Fmolꢁ1).
Then the solvents were partially evaporated and the resulting precipitate
was collected by filtration. The yellow solid was dissolved in CH2Cl2 and
washed with saturated aqueous NaHCO3 solution and water. The organic
layer was dried (Na2SO4) and concentrated to dryness. After purification
by crystallisation (hexane/chloroform 4:1), dipyrroles 1b and 1c were ob-
tained as yellow powders.
2,6-Bis[6-(pyridin-2-yl)pyridazin-3-yl]pyridine (2a): Following the general
2,6-Bis[5-(6-methylpyridin-2-yl)pyrrol-2ACTHUNTGRENNG(U 1H)-yl]pyridine (1b): A solution
procedure,
a solution of activated dipyridazine–pyridine 14 (1.06 g,
of dipyridazine 2b (150 mg, 0.36 mmol) in THF/acetate buffer/CH3CN
(5:4:1, (100 mL) was reduced at Ew =ꢁ1.25 V/SCE. Then crystallization
(hexane/chloroform 4:1) of the crude product, obtained by following the
general work-up procedure, yielded pure 1b (101 mg, 71%) as a yellow
powder. M.p. 1038C; 1H NMR (300 MHz, CDCl3, 258C): d=11.50 (brs,
2H), 7.60 (t, J=7.8 Hz, 2H), 7.56 (t, J=7.5 Hz, 2H), 7.49 (d, J=7.5 Hz,
2H), 7.35 (d, J=7.8 Hz, 1H), 6.94 (d, J=7.5 Hz, 2H), 6.82–6.76 (m, 4H),
2.66 ppm (s, 6H); 13C NMR (75 MHz, CDCl3, 258C): d=157.4, 150.3,
149.6, 137.0, 136.9, 134.2, 133.0, 120.4, 116.7, 115.5, 110.2, 108.8,
2.0 mmol) and tetrakis(triphenylphosphine)palladium (0.46 g, 0.32 mmol)
in THF (40 mL) was added to the organozinc reagent [prepared from 2-
bromopyridine (1.01 g, 6.4 mmol), nBuli (2.4m in hexanes, 3.0 mL,
7.0 mmol) in THF (20 mL)] and zinc chloride (0.7 molLꢁ1 in THF,
10.0 mL, 7.0 mmol). The reaction mixture was stirred at reflux for 48 h.
Crystallization (AcOEt) of the crude product obtained by following the
general work-up procedure yielded 210 mg (27%) of pure 2a as a pale
yellow solid. M.p. 2588C; 1H NMR (300 MHz, CDCl3, 258C): d=8.87–
8.71 (m, 10H), 8.10 (t, J=8.1 Hz, 1H), 7.89 (dt, J=7.8, 1.8 Hz, 2H),
7.41 ppm (ddd, J=7.5, 4.8, 1.2 Hz, 2H); 13C NMR (75 MHz, CDCl3,
258C): d=158.3, 157.8, 153.3, 153.1, 149.4, 138.5, 137.2, 128.5, 125.1,
124.8, 122.6, 121.7 ppm; UV/Vis (CH2Cl2): l(e)=315 (38200), 290
(33600), 256 nm (29250 molꢁ1 dm3 cmꢁ1); MS (70 eV): m/z (%): 389 (46)
[M]+, 361 (64) [MꢁN2]+, 128 (100) [PyrC4H2]+; HRMS: m/z calcd for
[M+H]+ (C23H16N7): 390.1473; found 390.1467.
24.7 ppm;
UV/Vis
(CH2Cl2):
l(e)=380
(25900),
343 nm
(56300 molꢁ1 dm3 cmꢁ1); UV/Vis (MeOH): l(e)=378 (29500), 341 nm
(62100 molꢁ1 dm3 cmꢁ1); MS (70 eV): m/z (%): 392.1 (100) [M+H]+;
HRMS: m/z calcd for [M+H]+ (C25H22N5): 392.1875; found 392.1869.
2,6-Bis[5-(4,6-dimethylpyridin-2-yl)pyrrol-2ACTHNUTRGNE(UNG 1H)-yl]pyridine (1c): A solu-
tion of dipyridazine 2c (71 mg, 0.16 mmol) in THF/acetate buffer/CH3CN
(5:4:1, 100 mL) was reduced at Ew =ꢁ1.20 V/SCE. Then crystallisation
(hexane/chloroform 4:1) of the crude product, obtained by following the
general work-up procedure, yielded pure 1c (62 mg, 93%) as a yellow
powder. M.p. 2198C; 1H NMR (300 MHz, CDCl3, 258C): d=11.50 (brs,
2H), 7.58 (t, J=7.8 Hz, 1H), 7.35 (d, J=7.8 Hz, 2H), 7.32 (s, 2H), 6.78–
6.75 (m, 6H), 2.61 (s, 6H), 2.33 ppm (s, 6H); 13C NMR (75.5 MHz,
CDCl3, 258C): d=157.0, 150.1, 149.6, 147.9, 136.8, 134.0, 133.0, 121.6,
117.4, 115.3, 109.9, 108.7, 24.4, 21.1 ppm; UV/Vis (CH2Cl2): l(e)=380 nm
(26900 molꢁ1 m3 cmꢁ1), 341 (58600 molꢁ1 m3 cmꢁ1); UV/Vis (MeOH):
l(e)=378 nm (29400 molꢁ1 m3 cmꢁ1), 340 (64200 molꢁ1 m3 cmꢁ1); MS
(70 eV): m/z (%): 419 (100) [M]+, 106 (7) [MePyr]+; HRMS: m/z calcd
for C27H25N5: 419.2110; found: 419.2108; elemental analysis calcd (%) for
2,6-Bis[6-(6-methylpyridin-2-yl)pyridazin-3-yl]pyridine (2b): Following
the general procedure, a solution of activated dipyridazine–pyridine 14
(532 mg, 1.00 mmol) and tetrakis(triphenylphosphine)palladium (231 mg,
0.20 mmol) in THF (20 mL) was added to the organozinc reagent [pre-
pared from 2-bromo-6-methylpyridine (550 mg, 3.20 mmol) and nBuli
(2.5 molLꢁ1 in hexanes, 1.4 mL, 3.50 mmol) in THF (10 mL)] and zinc
chloride (0.7m in THF, 5.0 mL, 3.50 mmol). The reaction mixture was
stirred at reflux for 48 h. Chromatography on silica gel (CH2Cl2/Et2O,
gradient from 100:0 to 50:50) of the crude product obtained by following
the general work-up procedure yielded 284 mg (68%) of pure 2b as a
white solid. M.p. 2598C; 1H NMR (300 MHz, CDCl3, 258C): d=8.88 (d,
J=7.9 Hz, 2H), 8.81 and 8.78 (AB Syst, J=8.9 Hz, 4H), 8.57 (d, J=
7.8 Hz, 2H), 8.12 (t, J=7.9 Hz, 1H), 7.80 (t, J=7.8 Hz, 2H), 7.28 (d, J=
7.8 Hz, 2H), 2.68 ppm (s, 6H); 13C NMR (75 MHz, CDCl3, 258C): d=
158.6, 158.3, 157.8, 153.2, 152.7, 138.4, 137.3, 125.1, 124.9, 124.3, 122.5,
118.7, 24.6 ppm; UV/Vis (CH2Cl2): l(e)=316 (38000), 257 nm
(23800 molꢁ1 dm3 cmꢁ1); MS (70 eV): m/z (%): 417 (100) [M]+, 389 (94)
[MꢁN2]+; HRMS: m/z calcd for [M+Na]+ (C25H19N7Na): 440.1600,
found 440.1599.
.
C27H25N5 1.2H20: C 73.51, H 6.26, N 15.87; found C 73.31, H 6.21, N
15.96.
Synthesis of complex 1b-CuI2II: Cu
ACTHNUTRGNEN(UG OAc)2 (23 mg, 0.12 mmol) was added
to a solution of 2b (10 mg, 0.024 mmol) in THF (5 mL). The mixture was
stirred for 1 h at 608C and the solvent was removed in vacuo. Then the
solid was dissolved in CHCl3 (10 mL). The resulting solution was filtered
through cotton and evaporated to dryness. The powder was again dis-
solved in CHCl3 (1 mL) and dry MeOH was added slowly to form two
distinct layers. After one week at room temperature, the microcrystals
that had formed were collected by filtration and dried under vacuo.
2,6-Bis[6-(4,6-dimethylpyridin-2-yl)pyridazin-3-yl]pyridine (2c): Follow-
ing the general procedure, a solution of activated dipyridazine–pyridine
14 (385 mg, 0.72 mmol) and tetrakis(triphenylphosphine)palladium
(167 mg, 0.14 mmol) in THF (20 mL) was added to the organozinc re-
agent [prepared from 2-bromo-4,6-dimethylpyridine (431 mg, 2.32 mmol)
and nBuli (2.5 molLꢁ1 in hexanes, 1.0 mL, 2.54 mmol) in THF (10 mL)]
and zinc chloride (0.7m in THF, 3.6 mL, 2.54 mmol). The reaction mix-
Chem. Eur. J. 2010, 16, 11876 – 11889
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
11887

D. Dubreuil et al.
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Acknowledgements
This work was supported by an ANR grant (Project # ANR-09-BLAN-
0082-01; financial support and predoctoral fellowship for C.A.). A.T.-R.
thanks the MENRT for a PhD fellowship. T.D. thanks the CNRS for sup-
port as a research fellow engineer, D.D. thanks the CNRS, la Ligue
contre le Cancer association, and the cancꢀropꢆle Grand Ouest for fund-
ing and biological evaluation facilities. D.J. thanks the Belgian National
Fund for Scientific Research for his research associate position. The the-
oretical calculations were partially performed on the Interuniversity Sci-
entific Computing Facility (ISCF), installed at the Facultꢀs Universitaires
Notre-Dame de la Paix (Namur, Belgium), for which D. J. gratefully ac-
knowledges the financial support of the FNRS-FRFC and the Loterie
Nationale for the convention number 2.4578.02 and of the FUNDP.
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Chem. Eur. J. 2010, 16, 11876 – 11889

Alternating Tripyridyl–Dipyrrole Molecular Strands
FULL PAPER
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Received: April 6, 2010
Published online: September 14, 2010
Chem. Eur. J. 2010, 16, 11876 – 11889
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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