Design and synthesis of novel ditopic ligands with a pyrazole ring in the central unit

Article abstract of DOI:10.1007/s11164-019-04052-3

Four novel ditopic ligands that have a pyrazole ring in their central unit and are useful for the generation of coordination polymers have been synthesized. Two of these ditopic ligands present two carboxylate functions as coordinating groups, while the o

Full text of DOI:10.1007/s11164-019-04052-3

Research on Chemical Intermediates
https://doi.org/10.1007/s11164-019-04052-3
Design and synthesis of novel ditopic ligands
with a pyrazole ring in the central unit
Bogdan‑Ionel Bratanovici1,2 · Alina Nicolescu · Sergiu Shova ·
3
4
1
4
1,5
Ioan‑Andrei Dascălu · Rodinel Ardeleanu · Vasile Lozan
·
4
Gheorghe Roman
Received: 16 August 2019 / Accepted: 27 November 2019
©
Springer Nature B.V. 2019
Abstract
Four novel ditopic ligands that have a pyrazole ring in their central unit and are use-
ful for the generation of coordination polymers have been synthesized. Two of these
ditopic ligands present two carboxylate functions as coordinating groups, while
the other two are hybrid ligands having only one carboxylate function and either
tetrazolate or imidazole as the remaining coordination site. The ligands have been
obtained through a multi-step reaction sequence that begins with the Claisen con-
densation of either 4-acetylbenzonitrile or 4-(1H-imidazol-1-yl)acetophenone with
diethyl oxalate and has the Knorr pyrazole ring closure as its key step. Subsequently,
the tetrazolate in one of the ligands is constructed through a [3+2] cycloaddition
of azide anion to the cyano group, while hydrolysis of the ester and the cyano sub-
stituents generates the carboxylate function(s). The structure of the intermediates
and of the target ligands has been investigated by solution NMR, special attention
being given to keto–enol and pyrazole tautomerism when present. The structure of
two ligands and a key intermediate has also been established by single-crystal X-ray
diꢀraction.
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s1116
4
-019-04052-3) contains supplementary material, which is available to authorized users.
*
Gheorghe Roman
gheorghe.roman@icmpp.ro
1
Centre of Advanced Research in Bionanoconjugates and Biopolymers (IntelCentru), Petru Poni
Institute of Macromolecular Chemistry, 41A Aleea Gr. Ghica Vodă, 700487 Iasi, Romania
2
3
Faculty of Chemistry, Alexandru Ioan Cuza University, 11 Bd. Carol, 700506 Iasi, Romania
Department of Physics of Polymers and Polymeric Materials, Petru Poni Institute
of Macromolecular Chemistry, 41A Aleea Gr. Ghica Vodă, 700487 Iasi, Romania
4
5
Department of Inorganic Polymers, Petru Poni Institute of Macromolecular Chemistry, 41A
Aleea Gr. Ghica Vodă, 700487 Iasi, Romania
Institute of Chemistry of MECR, 3 Academiei Str., 2028 Chişinău, Republic of Moldova
Vol.:(012
1
3456789)
3

B.-I. Bratanovici et al.
Keywords Heterocycle · Pyrazole · Carboxylic acid · Ligand · Crystal structure
Introduction
Polytopic ligands, together with ions of multivalent metals, are the building blocks
of coordination polymers. Because of their signiꢁcant applications [1–4], a par-
ticular type of porous coordination polymers, generically called metal–organic
frameworks (MOFs), has enjoyed the attention of numerous research groups in the
last decades. For the construction of MOFs, the polytopic ligands that are used as
organic linkers should be fairly rigid compounds in order to lead to bi- or tridimen-
sional hollow structures suꢂciently robust to retain the internal voids even after
thermal activation and repeated cycles of gas adsorption–desorption [5]. From a
structural point of view, these rigid organic linkers consist of a central unit (or core),
which is either substituted with various functional groups that are able to coordi-
nate to metal ions (such as carboxylate, sulfonate, or phosphonate), or feature coor-
dinating sites based on nitrogen-containing heterocycles (e.g., pyrazole, imidazole,
triazole, tetrazole, pyridine, etc.). Commercially available, inexpensive terephthalic
and isophthalic acids are frequent dicarboxylate organic linkers in MOFs, while tri-
mesic acid is a well-known example of a broadly used tricarboxylate organic spacer
in metal–organic networks. In fact, most of the organic linkers employed for the gen-
eration of coordination polymers have a central unit based either on a phenyl ring, a
fused aromatic hydrocarbon-based ring system (naphthalene, anthracene, etc.), or an
aromatic hydrocarbon-based ring assembly in whose structure the individual phenyl
rings are joined through a single σ
bond (such as polyphenyl scaꢀolds biphenyl
C–C
or terphenyl, for example). Despite the fact that heterocyclic compounds represent
almost two-thirds of all the known organic compounds, their presence as units in
the make-up of the core of organic linkers used for the synthesis of MOFs is still
limited. Again, commercially available, simple ligands such as thiophene-2,5-di-
carboxylic acid [6, 7], furan-2,5-dicarboxylic acid [8, 9], pyridine-derived dicarbo-
xylic acids [10, 11], or imidazole-4,5-dicarboxylic acid [12, 13] have started to be
employed as organic linkers for MOFs, but the literature on this speciꢁc topic is still
scarce compared to the volume of available information on MOFs based on organic
linkers derived having an aromatic, entirely hydrocarbon-based central unit. As
more research groups have started to design and synthesize their own organic linkers
using conventional organic synthesis, the literature featuring MOFs that incorporate
organic linkers with heterocyclic units in their cores has steadily increased. Design
of organic linkers is critical for the preparation of MOFs with targeted structures
and properties, and the replacement of carbocycles with heterocycles in the core
of these ligands is expected to lead to novel and interesting coordination polymers.
As a part of an ongoing project for the development of novel porous coordination
polymers with organic ligands of variable length for gas storage [14–17], the cur-
rent study outlines the preparation and characterization of several hitherto unknown
ditopic carboxylate and hybrid ligands with a pyrazole ring in the central unit that
are potentially useful for the generation of novel coordination polymers.
1
3

Design and synthesis of novel ditopic ligands with a pyrazole…
Results and discussion
Generally, the series of ligands reported in this paper have been designed by for-
mally replacing a phenyl moiety in the biphenyl central unit of several well-known
ditopic ligands with a pyrazole moiety. For example, starting from [1,1′-biphenyl]-
4
,4′-dicarboxylic acid and employing this simple methodology, the corresponding
ligand to be obtained would have the general structure of 5-(4-carboxyphenyl)-
H-pyrazole-3-carboxylic acid. A valuable synthetic strategy for the generation of
1
pyrazoles having a carboxyl function involves the ring closure of 4-aryl-2,4-dioxob-
utanoic acid esters with hydrazine derivatives [18]. The substituent in the aryl group
in 4-aryl-2,4-dioxobutanoates, which are usually obtained from an aryl alkyl ketone
through a Claisen condensation with ethyl oxalate, should be speciꢁcally chosen
with the view to allow facile access to the second carboxyl function in the designed
pyrazole-containing ligand. After close inspection of commercially available aceto-
phenones, 4-acetylbenzonitrile 1 was selected as a convenient starting material for
the preparation of the previously mentioned ditopic carboxylate ligand. The reaction
sequence leading to the designed ligand is illustrated in Scheme 1.
Various synthetic variants for the Claisen condensation of 4-acetylbenzonitrile
with diethyl oxalate, which usually diꢀer from one another in terms of the combina-
tion solvent/base used in the preparation, reaction temperature or reaction time, are
Scheme 1 Reaction sequence leading to 3(5)-(4-carboxyphenyl)-1H-pyrazole-5(3)-carboxylic acid 5
1
3

B.-I. Bratanovici et al.
available in the literature [19–22]. The procedure employed in this work has been
adapted from Rogez-Florent et al. [22] and was found to reliably aꢀord around 95%
of the crude ethyl 4-(4-cyanophenyl)-2,4-dioxobutanoate (2), which can be conveni-
ently puriꢁed through recrystallization from ethanol. However, this material incor-
porates a small amount of an impurity that is insoluble in ethanol, and attempts to
remove it during the recrystallization stage through ꢁltration of the hot, concentrated
mixture are troublesome, as this operation usually resulted in the separation of the
diketoester 2 on the ꢁlter paper as well. The removal of this impurity is more suit-
ably performed by freely dissolving the diketoester in a small volume of cold chloro-
form, removal of the insoluble impurity through ꢁltration, followed by the removal
of chloroform from the ꢁltrate to give a solid that is subsequently recrystallized from
ethanol.
Although compound 2 appears as an intermediate in the synthesis of pyrazoles in
the previously mentioned publications, its thorough characterization is still absent
in the literature. Its IR spectrum (Fig. 1S in Supplementary Material) exhibits the
−
1
−1
expected ν
band at 2226 cm and ester ν
at 1726 cm , whereas the intense
C≡N
C=O
−1
bands at 1690, 1610 and 1597 cm could be attributed to vibrations of carbonyl
in the keto tautomer and to vibrations of both carbonyl and ethylenic double bonds
in the enol tautomer of compound 2 in solid state. NMR spectroscopy analysis has
shed some light on the contribution of the three possible tautomeric forms to the
structure of compound 2 in solution. In CDCl , the number of signals, their chemi-
3
1
cal shifts values and the ratio of integrals in the H NMR spectrum of 2 (Fig. 2S in
Supplementary Material) suggest the absence of the keto tautomer 2B, while the
sharp singlet at 7.03 ppm and the broad signal centered at approximately 15 ppm
are, however, indicative of an enol form. According to the literature data, the enol
form of β-diketones is generally preferred in solution to the keto form, owing to
the strong intramolecular hydrogen bond which stabilizes the enol form as a six-
membered chelate ring [23, 24]. In these experimental conditions, only one set
of signals was observed in the NMR spectra for the enolic tautomer, presumably
because of the rapid interconversion between enol forms 2A and 2C. As a conse-
quence, the recorded proton and carbon NMR spectra of compound 2 correspond to
the weighted average of the two forms 2A and 2C, in which a single resonance for
each type of nuclei of the non-symmetric enol forms is present. The presence of the
enol form in CDCl is also substantiated by the signals at 98 ppm and 187 ppm in
3
1
3
the C NMR spectrum of 2 (Fig. 3S in Supplementary Material), which are charac-
teristic for enols. The discrimination and exact assignment of the signals for the two
magnetically non-equivalent carbon atoms in the keto–enol fragment of compound
2
were gleaned from the HMBC spectrum (Fig. 4S in Supplementary Material) and
were based on the three-bond correlation between the carbon atom in the carbonyl
adjacent to the phenyl ring and the aromatic protons.
In the next stage, reaction of compound 2 with hydrazine was employed to
construct the pyrazole ring substituted with the ester function (Scheme 1). Ini-
tially, the diketoester was heated in absolute ethanol at reꢃux temperature with a
1
.5-fold excess of hydrazine hydrate for 7 h. NMR analysis of the isolated material
showed that it was a mixture of the hydrazide related to ester 4 and the desired ester
4
(ratio approximately 6 to 1, respectively). A second attempt at obtaining ester 4
1
3

Design and synthesis of novel ditopic ligands with a pyrazole…
was performed under milder conditions and entailed reacting equimolar amounts of
diketoester and hydrazine hydrate in absolute ethanol at room temperature for 48 h.
The isolated material consisted of a mixture of the desired ester 4 and hydroxypyra-
1
zoline 3, according to the H NMR spectrum (Fig. 5S in Supplementary Material).
The existence of hydroxypyrazoline 3 is supported by the presence in this spectrum
of two doublets at 3.14 ppm and 3.52 ppm, characteristic for diastereotopic protons
in the methylene group of the pyrazoline ring. In addition, the existence in the car-
bon spectrum of this mixture of peaks at approximately 43 and 92 ppm that are spe-
ciꢁc to hydroxypyrazoline 3 further substantiates the presence of this intermediate
(
Fig. 6S in Supplementary Material). Formation and even isolation of hydroxypyra-
zolines as intermediates in the cyclocondensation of β-diketones with hydrazine
derivatives have been reported often [25–27]. Two potential hydroxypyrazoline
could arise from the reaction of non-symmetrical diketoester 2 with hydrazine, but
correlation spectroscopy strongly supports for hydroxypyrazoline 3 the particular
structure in which the hydroxyl and ester functions are geminal. Thus, close inspec-
tion of the HMBC spectrum of the mixture of ester 4 and hydroxypyrazoline 3
(
Fig. 7S in Supplementary Material) revealed a three-bond correlation between the
2
sp carbon atom of hydroxypyrazoline (145.60 ppm) and the aromatic protons in the
phenyl moiety.
In order to obtain the fully aromatized pyrazole, the mixture consisting of the
desired ester 4 and hydroxypyrazoline 3 was further reꢃuxed in absolute ethanol,
in the presence of a catalytic amount of concentrated H SO as dehydrating agent,
2
4
for 2 h. The isolated product was practically the pure ester 4, as NMR analysis con-
ꢁ
rmed. Preparation of ester 4 from compound 2 was also examined as a one-pot
reaction under the conditions that have previously been shown to lead to the target
compound in two steps. Therefore, after the mixture of diketoester 2 and hydrazine
had been stirred at room temperature for 48 h, suꢂcient conc. H SO was added in
2
4
order to render it acidic (pH 1–3), and the mixture was then heated at reꢃux tem-
perature for 2 h to aꢀord practically pure ester 4 in 65% yield.
As a non-symmetrically 3,5-disubstituted pyrazole, compound 4 could also be
theoretically conceived as a mixture of two tautomers 4A and 4B (Scheme 1). NMR
analysis of a sample of ester 4 conꢁrmed experimentally the presence of these two
1
tautomers in solution. The sharp signals visible for each tautomer in both H and
1
3
C NMR spectra (Fig. 8S and 9S in Supplementary Material) indicate the exist-
ence of a slow exchange between the two forms, the lifetime of each tautomer being
longer than 1/Δδ (where Δδ represents the chemical shift diꢀerence between the
1
3
corresponding signals of each tautomeric form). In C NMR spectrum, each tau-
tomer has a characteristic signal that allows for their discrimination. Thus, the sig-
nal at 149.57 ppm corresponds to C-3 carbon from the pyrazole ring, in tautomer
4
A, an assignment that is supported by the three-bond correlation signal obtained in
H,C-HMBC spectrum (Fig. 10S in Supplementary Material) between the aromatic
protons H-2′ and the quaternary pyrazole carbon C-3. From the same type of three-
bond correlation, C-5 in tautomer 4B was attributed the signal at 141.74 ppm. Simi-
lar chemical shift values for C-3/C-5 were reported in previous studies of tautomer-
ism of 3(5)-phenyl-1H-pyrazoles [28] and phenylene-bis(pyrazole) derivatives [29]
using both solid NMR and solution NMR. The exact assignment for all the protons
1
3

B.-I. Bratanovici et al.
and carbons in the two tautomeric forms was based on the correlations obtained
from the two-dimensional experiments, such as H,H-COSY, H,C-HSQC, and H,C-
HMBC. The comparison of the integration of the signals corresponding to the same
type of proton in tautomers 4A and 4B yields a ratio of 1 to 0.6 between the respec-
tive tautomers. The IR spectrum of pyrazole 4 (Fig. 11S in Supplementary Material)
−
1
presents the speciꢁc stretching vibration bands ν
at 2228 cm and ester ν
at
C=O
C≡N
−1
1
713 cm .
In the ꢁnal step, compound 4 was converted to diacid 5 through alkaline hydroly-
sis of both cyano and ester functions. Because conversion of a nitrile group to car-
boxylate normally requires harsher conditions than the transformation of an ester
function to carboxylate, compound 4 was heated at reꢃux temperature in water in the
presence of excess NaOH for 48 h with the view to ensure the complete hydrolysis
of the cyano group. The initial suspension gradually turned into a colorless solu-
tion as the ester hydrolysis progressed. Finally, the reaction product was isolated by
bringing the pH of the solution to 5–6 with dilute acetic acid.
From a theoretical point of view, diacid 5 could also be conceived as a pair of
tautomers 5A and 5B (Scheme 1). Nonetheless, NMR analysis of diacid 5 in solu-
tion revealed only one set of signals, which suggests that the slow interconversion
of tautomers identiꢁed for ester 4 does not take place in the case of diacid 5. This
1
dissimilar behavior made the attribution of the signals from the H NMR spectrum
of diacid 5 (Fig. 12S in Supplementary Material) easier than it was for ester 4. How-
ever, several signals corresponding to diꢀerent quaternary carbons were not discern-
1
3
ible in the C NMR, most likely because of a severe line broadening, which is a
characteristic for an intermediate exchange condition [28]. Because it would have
been diꢂcult to conꢁrm the chemical structure of diacid 5 beyond any doubt with-
out the identiꢁcation of all expected signals in the carbon spectrum, an additional
NMR experiment was performed with the same sample. Thus, hoping to disrupt the
interconversion of the tautomers and freeze the molecules of 5 as a single, proto-
nated species, 2 drops of non-deuterated triꢃuoroacetic acid (TFA) were added to
the initial solution of diacid 5 in DMSO-d , and then, the proton and carbon spectra
6
were recorded one more time. The addition of TFA did not chemically modify the
structure of diacid 5 (as proved by the proton spectrum, Fig. 13S in Supplementary
Material), yet it led to sharper signals in carbon spectrum, allowing the identiꢁca-
tion of all of the expected carbon signals (Fig. 14S in Supplementary Material). In-
depth analysis of the solution behavior of the synthesized pyrazole derivatives is
beyond the scope of this work; therefore, no additional NMR experiments, including
(
but not restricted to) measurements at variable temperature or in other NMR sol-
vents, have been performed. The exact assignments, particularly for the peaks in the
1
3
C NMR spectrum, were inferred from HSQC and HMBC experiments, the latter
being especially useful in ascribing the signals for carbon atoms at positions 3 and
of pyrazole ring and in the two carboxylic groups using three-bond correlations.
5
−
1
The IR spectrum of diacid 5 showed a very intense band at 1672 cm , which was
assigned to ν
in the carboxyl function (Fig. 15S in Supplementary Material).
C=O
Because NH-pyrazoles themselves are well-known ligands for the synthe-
sis of complexes and coordination polymers [30–32], ligand 5 could theoretically
act as a tridentate ligand. Therefore, it was considered interesting to synthesize an
1
3

Design and synthesis of novel ditopic ligands with a pyrazole…
1
N -substituted version of ligand 5 as well, with the view to compare the coordination
mode of both ligands. Phenylhydrazine was chosen as the hydrazine derivative for
the Knorr ring closure reaction with diketoester 2 to aꢀord pyrazole 6 (Scheme 2).
The dehydrative cyclocondensation was conducted in reꢃuxing glacial acetic acid
and usually aꢀorded the crude pyrazole in yields greater than 90%. The isolation of
the reaction product by dropwise addition of the reaction mixture onto water and ice
under eꢂcient stirring frequently led to the initial separation of a sticky semisolid
that turned into a solid after had been kept in contact with the liquid medium for up
to 48 h at room temperature, although, in a few occasions, a solid, ꢁnely dispersed
material separated straightforwardly when the reaction mixture was poured onto
ice–water. The NMR analysis of the crude material showed that it contained both
regiosomers that could potentially arise from the reaction of phenylhydrazine with
either of the oxo functions that are present in the structure of diketoester 2, an issue
that has been noticed in similar ring closure reactions [33–35]. It is common knowl-
edge that the proton at C-4 of the pyrazole ring in the 1,5-diaryl isomer resonates
upꢁeld with respect to the corresponding signal of the 1,3-diaryl regioisomer [35].
Based on the ratio of the areas of the singlets corresponding to the proton at C-4 in
both regioisomers in our mixture, the 1,5-diaryl isomer 6 (δ=7.31 ppm) represents
8
5–90% of the mixture, whereas the 1,3-diaryl regioisomer (δ=7.79 ppm) makes
up for the rest. Similar mixtures of regioisomeric pyrazoles have been successfully
separated using column chromatography [35]. However, because we required large
amounts of this key intermediate in the preparation of ligands to be subsequently
employed in the synthesis of coordination polymers, an exploration toward a more
facile approach for the isolation of pure 6 from this mixture seemed reasonable. It
was found out that in our case the 1,3-diaryl isomer could be removed without diꢂ-
culty after two recrystallizations from ethanol, while allowing a good recovery of the
−
1
desired pyrazole 6. The characteristic stretching vibration bands ν
(2230 cm )
C≡N
−1
and ester ν
(1711 cm ) are noticeable in the IR spectrum of intermediate 6
C=O
Scheme 2 Synthesis of intermediate 6 and its conversion into acids 7 and 8
1
3

B.-I. Bratanovici et al.
(
Fig. 16S in Supplementary Material). Structural characterization by NMR spectros-
copy of the pure compound 6 indicated the presence of a single species, character-
ized by sharp and well-deꢁned signals in both proton and carbon spectra (Fig. 17S
and 18S in Supplementary Material). The chemical shifts values for the quaternary
carbons in the pyrazole ring (C-5 at 142.61 ppm and C-3 at 143.67 ppm) serve as
additional proof for the structure of 6 as the 1,5-diaryl isomer.
In order to prove beyond any doubt that the key intermediate 6 is the 1,5-diaryl
isomer, its structure has been also investigated using single-crystal X-ray diꢀraction
technique. Single crystals suitable for diꢀraction were obtained through the slow
evaporation at room temperature of a solution of ester 6 in ethanol. This pyrazole
derivative crystallizes in P-1 space group of triclinic system with one neutral mol-
ecule as the asymmetric part of the unit cell (Fig. 1). No co-crystalized solvate mol-
ecules have been found in the structure. The structure determined by this method
corresponds indeed to the 1,5-diaryl isomer. It is worth mentioning that the structure
of compound 6 is closely related to a previously reported structure of an analogue
having a chloro substituent instead of cyano [36]. In the crystal, the neutral mole-
cules are interacting through C–H···O and C–H···N hydrogen bonding to form a one-
dimensional supramolecular motif running along 101 direction, as shown in Fig. 2.
Alkaline hydrolysis of compound 6 having an ester function and a cyano group in
its structure was conducted under the same conditions previously employed for the
hydrolysis of its analogue 4 (Scheme 2). Thus, good yields of diacid 7 were obtained
by reꢃuxing nitrile–ester 6 for 48 h in an excess of dilute aqueous NaOH. The initial
suspension gradually turned into a homogenous reaction mixture as the ester hydrol-
ysis produced the water-soluble nitrile–acid sodium salt. At the end of the reaction
time, diacid 7 was isolated by treating the cold, ꢁltered reaction mixture with dilute
HCl. The stretching vibration band ν
is no longer present in the IR spectrum of
C≡N
−1
compound 7, while the intense band at 1686 cm could be attributed to ν
in the
C=O
Fig. 1 X-ray molecular structure of pyrazole 6 along with atom labeling scheme and thermal ellipsoids at
0% probability level
5
1
3

Design and synthesis of novel ditopic ligands with a pyrazole…
Fig. 2 A partial view of the 1D supramolecular chain in the crystal structure of 6. H-bonds are shown in
dashed black lines. H-bonds parameters: C11-H···N3 [C11-H 0.93 Å, H···N3 2.50 Å, C11-H···N3(3−x,
1
−y, 2−z) 3.385(2) Å, ∠C11HN3 159.0°]; C15-H···O1 [C15-H 0.93 Å, H···O1 2.55 Å, C15-
H···O1(2−x, 1−y, 1−z) 3.325(2) Å, ∠C15HO1 140.9°]
carboxyl function (Fig. 19S in Supplementary Material). The presence in the oꢀset
1
of the H NMR spectrum of compound 7 of a broad singlet integrating for two pro-
tons (Fig. 20S in Supplementary Material), corroborated with the peaks at 162.89
1
3
and 166.71 ppm in its C NMR spectrum (Fig. 21S in Supplementary Material),
conꢁrmed the complete and successful hydrolysis of both the ester function and the
cyano group.
The long reaction and the relatively harsh conditions used for the alkaline hydrol-
ysis of compound 6 have prompted us to explore a more mild approach toward the
simultaneous transformation of the cyano and ester groups in this compound’s struc-
ture into carboxylate. Thus, a method that has been initially used for the hydrol-
ysis of esters of isoxazole-3-carboxylic acids [37] has been also contemplated for
the hydrolysis of compound 6. While the overnight reaction of nitrile–ester 6 with
LiOH in a mixture of tetrahydrofuran (THF), methanol and water at room temper-
ature proved eꢂcient for the hydrolysis of the ester function at position 3 of the
pyrazole ring, it left the cyano group unaꢀected and aꢀorded the monoacid 8 as
the only product (Scheme 2). IR analysis of this product (Fig. 22S in Supplemen-
−
1
tary Material) showed that the cyano function was still present (ν
=2226 cm ),
C≡N
−
1
while the ester group was converted into carboxyl (ν
=1676 cm ). The course
C=O
of the hydrolysis was also validated by NMR. Compared to diacid 7, the proton
spectrum of monoacid 8 (Fig. 23S in Supplementary Material), presented the same
oꢀset broad singlet, but the signal integrated only for one proton in this instance. In
1
3
the C NMR spectrum of monoacid 8 (Fig. 24S in Supplementary Material), the
single peak with a chemical shift value higher than 160 ppm was associated with the
carbon atom in the pyrazole carboxylate group, while the peak corresponding to the
carbon atom of the cyano group was still noticeable at approximately 118 ppm.
Besides di- or polytopic carboxylic ligands, hybrid ligands containing in their
structure one or several carboxylate functions along with one or more coordinating
sites based on nitrogen-containing heterocycles are often used for the preparation of
coordination polymers [38–42]. Therefore, we were also interested in the develop-
ment of similar hybrid ligands having a pyrazole ring in the central unit. The pres-
ence of a cyano group in the structure of the key intermediate 6 opens the possibility
for the synthesis of such a hybrid tetrazolate–carboxylate ligand using established
1
3

B.-I. Bratanovici et al.
tetrazole chemistry (Scheme 3). Thus, the reaction of nitrile–ester 6 with NaN in
3
N,N-dimethylformamide (DMF) in the presence of NH Cl was employed for the
4
conversion of the cyano into a tetrazole ring, using an adapted version of a method
that previously proved successful for a series of simpler aromatic nitriles [43]. The
[
3+2] cycloaddition of the azide to the cyano group under these harsh reaction con-
ditions is accompanied by the partial conversion of the ester function into carboxy-
late. Thus, in an initial experiment, only about half of the theoretical amount of the
desired tetrazole–ester 9 was isolated as a solid material after the cold reaction mix-
ture had been poured into a large volume of water. When the ꢁltrate from the isola-
tion of compound 9 was brought to pH 2–3 with dilute HCl, a second crop of a solid
1
material was isolated; its analysis by H NMR showed that it was a mixture of tetra-
zole–ester 9 and tetrazole–acid 10, in the approximate ratio of 9 to 1, respectively,
from which the former could be obtained, if desired, through recrystallization from
ethanol. In a subsequent experiment, the suspension obtained after the cold reaction
mixture had been poured onto water was directly treated with dilute HCl until pH
reached 2–3 to aꢀord a solid material which consisted mostly of tetrazole–ester 9
(
90–95% purity) contaminated with tetrazole–acid 10.
The absence of the stretching vibration band associated with the cyano group in
the IR spectrum of compound 9 is indicative for the successful tetrazole ring closure,
while the stretching vibration band of the carbonyl in the ester function is still pre-
1
sent (Fig. 25S in Supplementary Material). The H NMR spectrum of tetrazole–ester 9
(Fig. 26S in Supplementary Material), recorded in DMSO-d , is very similar to that of
6
starting material 6, and only the minor shift upꢁeld of the δ value for the H-3′ protons
and the presence of the tetrazole proton in oꢀset provided an indication for the conver-
sion of compound 6 into the desired tetrazole–ester 9. Despite the potential annular
prototropic tautomerism of the tetrazole ring [44], a single set of signals is present in
the proton spectrum of compound 9. The majority of the signals expected to be found
13
in the C NMR spectrum of 9 (Fig. 27S in Supplementary Material) were sharp, and
Scheme 3 Synthesis of tetrazole–acid 10
1
3

Design and synthesis of novel ditopic ligands with a pyrazole…
their assignment was quite straightforward owing to the resemblance of the carbon
1
3
spectrum of tetrazole–ester 9 to that of starting material 6. Close inspection of the
C
NMR spectrum led, however, to the discovery of a broadening (i.e., a linewidth of
0 Hz, while other quaternary signals had 3–4 Hz) of the signal assigned to the qua-
1
ternary C-4′ of the para-disubstituted benzene ring. In addition, a signiꢁcant broad-
ening of the signal assigned to the carbon atom in the tetrazole ring (C-5‴) was also
identiꢁed. These ꢁndings suggest that an intermediate exchange involving the 1H-tau-
tomer and the 2H-tautomer of tetrazole might occur, which is a process similar to that
hypothesized for the N-1 unsubstituted pyrazole ring in diacid 5. Although the broad-
ening of the C-5‴ peak is so severe that the signal had been initially overlooked in the
analysis of the carbon spectrum of 9, the three-bond correlation between this atom
(δ=155.05 ppm) and H-3′ from the para-disubstituted phenyl moiety (δ=8.00 ppm)
in H,C-HMBC spectrum (Fig. 28S in Supplementary Material) led to its identiꢁcation.
It is worth mentioning that the chemical shift value for C-5‴ in an analog with a simi-
lar structure was 155.1 ppm [45]. The successful assignment of a signal to C-5‴ and
the absence of the peak for the carbon atom of the cyano group in the carbon spectrum
recorded for compound 9 undeniably conꢁrmed the formation of the tetrazole ring.
Both the pure tetrazole–ester 9 and the mixture isolated directly from the cycload-
dition reaction (which contains tetrazole–ester 9 as the major component and the
desired hybrid ligand 10 as a minor component) have been used in the subsequent
alkaline hydrolysis of the ester function to carboxylate. Heating either of these mate-
rials in aqueous NaOH at reꢃux temperature for 10 h (Scheme 3) leads to samples of
tetrazole–acid 10 having practically the same high purity, as proved by NMR analy-
sis. In addition, the milder hydrolysis approach (LiOH in THF–methanol–water at
room temperature) that was successfully used for the hydrolysis of the ester function
in compound 6 was also evaluated for the hydrolysis of tetrazole–ester 9 (Scheme 3)
and found to provide access to ligand 10 with yields and purity that are comparable
to the hydrolysis procedure performed in water at reꢃux temperature. A comparison
between the IR spectra of compounds 9 and 10 shows that in the latter (Fig. 29S in
Supplementary Material) the absorption band associated with the ester function has
disappeared, while a sharp intense band assigned to the stretching vibration band
−
1
of the carbonyl in the carboxyl group is noticeable at 1674 cm . The structure of
tetrazole–acid 10 has been further investigated by NMR spectroscopy. The aromatic
region of the proton spectrum of acid 10 (Fig. 30S in Supplementary Material) is
very similar to that of ester 9, but the lack of signals in the aliphatic region and the
presence of a broad singlet at approximately 13 ppm conꢁrmed the hydrolysis of
ester 9 to acid 10. No peaks were found in the aliphatic region of the carbon spec-
trum of acid 10 as well (Fig. 31S in Supplementary Material), and all of the signals
in the aromatic region of the same spectrum have been accounted for.
A structure in the solid state has been determined for this hybrid ligand through
single-crystal X-ray diꢀraction. X-ray-quality single crystals of tetrazole–acid 10
were obtained by allowing the compound to slowly crystallize from its solution in
DMSO–water (3:1, v/v) that was being kept at 80 °C. According to the data, tetra-
zole–acid 10 crystalizes in the Sohnke P2 2 2 space group of monoclinic system
1
1 1
and exhibits a molecular crystal structure based on neutral entity, as shown in Fig. 3.
No co-crystalized solvate molecules have been found in the structure. The crystal
1
3

B.-I. Bratanovici et al.
Fig. 3 X-ray molecular structure of compound 10 along with atom labeling scheme and thermal ellip-
soids at 50% probability level
packing features N–H···O and O–H···O intermolecular hydrogen bonding, which
determines the formation of a three-dimensional supramolecular architecture, as
depicted in Fig. 4.
Fig. 4 Partial crystal packing diagram in the crystal structure of 10 showing 3D supramolecular network.
Non-relevant H-atoms were omitted for clarity. H-bonds parameters: O2-H···N4 [O2-H 0.82 Å, H···N4
1
.89 Å, O2-H···N4(2+x, y−1, z) 2.708(5) Å, ∠O2HN4 171.2°]; N6-H···O1 [N6-H 0.86 Å, H···O1 2.01
Å, N6-H···O1(−1.5+x, 0.5−y, 1−z) 2.815(5) Å, ∠N6HO1 155.6°]
1
3

Design and synthesis of novel ditopic ligands with a pyrazole…
Hybrid ligand 10 can act as a dianionic ligand in the synthesis of coordination pol-
ymers. In addition, we wanted to develop a hybrid ligand having a neutral N-donor
site and an anionic O-donor coordination site grafted on a central unit containing a
pyrazole ring. If the carboxylate on the pyrazole ring is being preserved as the anionic
O-donor coordination site, this novel hybrid ligand can be formally derived from ligand
10 by replacing the tetrazole ring with an imidazol-1-yl moiety, for example. The key
step in the synthetic strategy toward this ligand would also rely on the construction of
the carboxyl-substituted pyrazole ring from a suitably substituted diketoester, in a man-
ner similar to the approach used for the preparation of ligands 5, 7 or 10. Starting from
commercially available 4-(1H-imidazol-1-yl)acetophenone (11), the reaction sequence
leading to this hybrid ligand is outlined in Scheme 4. The other possible tautomers of
diketoester 12, which are similar to those of diketoester 2 in Scheme 1, have been omit-
ted for clarity.
Ethyl 4-[4-(1H-imidazol-1-yl)phenyl]-2,4-dioxobutanoate (12) required for the
ring closure to pyrazole was conveniently obtained through a typical Claisen con-
densation of 4-(1H-imidazol-1-yl)acetophenone (11) with diethyl oxalate. The
reaction proceeds smoothly to aꢀord the desired compound with good yields. The
crude product is suꢂciently pure to be used directly in the next step. The IR spec-
trum (Fig. 32S in Supplementary Material) has two intense absorption bands at
−
1
−1
1
755 cm (ν
in ester) and 1603 cm (ν
in the keto–enol system). NMR
C=O
C=O
3
investigation of the analytical sample in CDCl (Fig. 33S and 34S in Supplementary
Material) showed that the enol tautomer is the preferred form in solution based on
the signals for the characteristic protons (vinylic CH and enolic OH) and typical
peak for the enolic carbon (δ=97.7 ppm) in the corresponding spectra.
Scheme 4 Preparation of the imidazole-containing hybrid ligand 15
1
3

B.-I. Bratanovici et al.
The key step leading to ligand 15 is the construction of the carboxylate-substi-
tuted pyrazole ring through the reaction of diketoester 12 with phenylhydrazine in
glacial acetic acid. The isolation of reaction product was achieved by bringing the
reaction mixture, which had been previously diluted with ice–water, to pH 8 using
dilute NaOH. Close inspection by NMR showed that this crude material was a
mixture of regioisomers 13 and 14 in an approximate ratio of 9 to 1. The regioi-
somers could be separated by column chromatography to yield pyrazole 14 as the
faster eluting component, followed by pyrazole 13 as the slower eluting compound.
Because of the small diꢀerence between their R values, the separation is not par-
f
ticularly good, leading to fractions which contain both compounds. Consequently,
the cumulate yield of both isomers after separation was only 68%. NMR analysis of
these regioisomers (Fig. 36S–40S in Supplementary Material) conꢁrmed that pyra-
zole 13 is the 1,5-diaryl isomer, while pyrazole 14 is the 1,3-diaryl isomer. Thus, the
chemical shift value for the proton at C-4 in the pyrazole ring in 13 (δ=7.09 ppm)
is upꢁeld from the chemical shift value for the proton at C-4 in the pyrazole ring in
1
4 (δ=7.35 ppm). In addition, the chemical shift values for the quaternary carbon
atoms C-3 and C-5 in the pyrazole ring were examined. For regiosomer 13, these
values are only slightly apart (which is typical for 1,5-diaryl pyrazoles), while in the
case of regioisomer 14 the diꢀerence between these values is 15 ppm. In their IR
spectra (Fig. 35S and 38S in Supplementary Material), both regioisomers have an
−1
intense absorption band close to 1700 cm (ν
in ester).
C=O
The isolation of pure target compound 13 from the mixture of regioisomers obtained
in an identical synthetic experiment was also attempted through recrystallization from
a small volume of 2-propanol. The recovery of pure ester 13 (as shown by the melt-
ing point and proton NMR, which were identical to those of the sample of 13 isolated
through chromatography) was only 10%. Because this method was deemed unsatis-
factory, a diꢀerent approach, based on the property of imidazoles to form salts, was
also examined using the mixture of regioisomers recovered from the recrystallization
attempt. Thus, after 2-propanol was removed under reduced pressure, the mixture of
regioisomers was dissolved in THF, and ethereal HCl was added to the solution until
precipitation of hydrochlorides was complete. Repeated recrystallization of this mix-
ture of hydrochlorides from abs. ethanol with the view to remove the unwanted isomer
ꢁ
nally allowed the isolation of pure 13·HCl, albeit with a modest recovery (30%). NMR
analysis of the hydrochloride (Fig. 41S and 42S in Supplementary Material) conꢁrmed
its purity. Therefore, this method could constitute an alternative to chromatographic
separation toward the isolation of pure intermediate 13.
Hydrolysis of imidazole–ester 13, either as the free base or as the hydrochloride,
aꢀorded the target ligand 15. Based on our previous experience with the hydrolysis
of tetrazole–ester 9, the mild approach employing LiOH as base and taking place
at room temperature was preferred to the procedure using a stronger base at reꢃux
temperature. In the IR spectrum (Fig. 43S in Supplementary Material), the stretch-
−
1
ing vibration band of the carbonyl in the carboxyl group is present at 1690 cm .
The successful conversion of ester 13 into acid 15 is also supported by the presence
in the oꢀset of the proton spectrum of latter compound of a broad signal integrating
for one proton (Fig. 44S in Supplementary Material) and also by the absence of any
1
3

Design and synthesis of novel ditopic ligands with a pyrazole…
Fig. 5 X-ray molecular structure of compound 15 along with atom labeling scheme and thermal ellip-
soids at 50% probability level
Fig. 6 View of 1D supramolecular chain in the crystal structure of imidazole–acid 15. H-bond param-
eters: O2-H···N4 [O2-H 0.87 Å, H···N4 1.71 Å, O2-H···N4(x, y−1, z)
signals in the aliphatic region of the H and 13C spectra of acid 15 (Fig. 45S in Sup-
1
plementary Material).
A single-crystal X-ray diꢀraction study of hybrid ligand 15 has been conducted
in order to gain information on its solid-state structure. Crystals suitable for this
study have been grown in DMSO by slow crystallization. The structure obtained
for imidazole–acid 15 is shown in Fig. 5. This compound crystalizes in Cc space
group of monoclinic system, and its molecular structure comprises neutral units of
1
5 and DMSO as solvate molecules in a 1:2 stoichiometric ratio. The analysis of the
intermolecular hydrogen bonding has revealed the presence of a one-dimensional
chain motif running along crystallographic axis b. A view of this 1D supramolecu-
lar aggregate is shown in Fig. 6. The 1D chain is further involved in intermolecular
1
3

B.-I. Bratanovici et al.
hydrogen bonding interactions with co-crystallized DMSO molecules via formation
of C-H···O contacts.
Conclusions
Our considered synthetic strategy eꢂciently led to the preparation of four hitherto
unknown, structurally diverse, novel ligands with a pyrazole ring in the central unit
to be subsequently used for the generation of coordination polymers. Unlike other
synthetic strategies which rely heavily on palladium-based coupling chemistry for
the preparation of carboxylate ligands, this approach is grounded on the facile Knorr
pyrazole ring closure as the key step in the construction of the carboxylate-substi-
tuted central unit. For three of these target compounds, the investigated methodol-
ogy could aꢀord straightforward access to these ligands on multi-gram scale. NMR
investigations showed that the enolic form is preferred for the two 4-aryl-2,4-oxob-
utanoates employed in these reactions, and demonstrated that hydroxypyrazoline is
an intermediate in the formation of an N-1 unsubstituted pyrazole. For these N-1
unsubstituted pyrazoles, annular prototropic tautomerism could be evidenced in the
case of an ester, but it was no longer noticeable in the case of the corresponding
acid. Formation of 1,5-diarylpyrazoles as major regioisomers in the Knorr reaction
of 4-aryl-2,4-oxobutanoates with phenylhydrazine was proved by NMR and also
using single-crystal X-ray diꢀraction.
Experimental
Materials and instrumentation
All chemicals were purchased from commercial suppliers (Sigma–Aldrich, Stein-
heim, Germany; TCI Europe N.V., Zwijndrecht, Belgium; Merck KGaA, Darmstadt,
Germany) and used without further puriꢁcation. Melting points were taken on a Mel
Temp II apparatus and are uncorrected. Elemental analysis was conducted in-house,
on a PerkinElmer 2400 Series II CHNS/O system. Analytical TLC was run on
Macherey–Nagel (Düren, Germany) aluminum-backed sheets that were precoated
with silica gel 60 (0.20 mm thickness) containing ꢃuorescence indicator UV , and
2
54
the spots were visualized by UV illumination (254 nm). Column chromatography
was performed on silica gel (230–400 mesh ASTM, 60 Å) (Merck, Darmstadt, Ger-
many). A Bruker Vertex 70 spectrometer (Bruker Optik GmbH, Bremen, Germany)
was used for the Fourier transform infrared (FTIR) spectra recording in the atten-
−
1
uated total reꢃection (ATR) conꢁguration. All spectra were collected at a 2 cm
−1
resolution, in the mid-IR range (4000–600 cm ). NMR spectra were recorded on
two Bruker Avance NEO spectrometers (at 400 MHz, with a 5-mm probe for direct
detection of H, C, F, Si, or at 600 MHz, with a 5-mm probe for inverse multinu-
clear detection). The exact signal assignments in both proton and carbon spectra
were based mainly on proton–carbon correlation experiments, such as H,C-HSQC
(
heteronuclear single quantum coherence) and H,C-HMBC (heteronuclear multiple
1
3

Design and synthesis of novel ditopic ligands with a pyrazole…
bond correlation). The residual signals of the deuterated solvents were used as inter-
1
13
nal standard (CDCl : δ=7.26 ppm for H and δ=77.01 ppm for C; DMSO-d :
3
6
1
13
δ=2.51 ppm for H and δ=39.47 ppm for C). The numbering of carbon atoms for
each structure is shown in the corresponding spectra in Supplementary Material.
Synthesis
Claisen condensation of 4‑acetylbenzonitrile (1) with diethyl oxalate
To a solution of sodium ethoxide, obtained by reacting sodium (1.38 g, 60 mmol)
with abs. ethanol (60 mL), 4-acetylbenzonitrile (4.35 g, 30 mmol) and diethyl oxa-
late (8.76 g, 60 mmol) were sequentially added. The mixture was heated at reꢃux
temperature for 2 h; then, it was cooled to room temperature and poured in a mixture
of ice and water (700 g). The solid resulted after the mixture was brought to pH 2–3
by dropwise addition of 10% HCl was ꢁltered, washed thoroughly with water, and
air-dried. The crude compound was dissolved in chloroform (50 mL), and a small
amount of insoluble material was ꢁltered oꢀ. Removal of chloroform under reduced
pressure and recrystallization of the resulting solid from 96% ethanol aꢀorded
1
diketoester 2 as tan crystals (5.51 g, 75%), mp 135–136 °C; H NMR (CDCl ,
3
4
00 MHz): δ 1.41 (3H, t, J=7.2 Hz, CH ), 4.41 (2H, q, J=7.2 Hz, CH ), 7.06 (1H,
3
2
s, vinylic H), 7.80 (2H, d, J=8.0 Hz, H-3), 8.07 (2H, d, J=8.0 Hz, H-2), 14.95
1
3
(
1H, br s, OH); C NMR (CDCl , 100 MHz): δ 14.04 (CH ), 62.89 (CH ), 97.93
3 3 2
(
vinylic CH), 116.72 (C-4), 117.74 (CN), 128.15 (CH-2), 132.62 (CH-3), 138.22
(
C-1), 161.62 (COO), 172.19 (C-3′), 187.29 (C-1′); Anal. Calcd. for C H NO : C,
1
3
11
4
6
3.67; H, 4.52; N, 5.71. Found: C, 63.41; H, 4.41; N, 5.80.
One‑pot synthesis of ethyl 3(5)‑(4‑cyanophenyl)‑1H‑pyrazole‑5(3)‑carboxylate (4)
To a suspension of diketoester 2 (735 mg, 3 mmol) in abs. ethanol (20 mL), hydrazine
hydrate (150 mg, 3 mmol) was added, and the reaction mixture was stirred at room tem-
perature for 48 h. Conc. H SO (3–4 drops) was then added, and the mixture was heated
2
4
at reꢃux temperature for 2 h. After a small amount of insoluble material had been ꢁl-
tered oꢀ, the solvent in the ꢁltrate was removed under reduced pressure to give a solid
material that was triturated with cold 2-propanol (5 mL). The solid was ꢁltered, washed
with water (2×10 mL), and air-dried to yield 470 mg (65%) of practically pure 4. The
material was recrystallized from 96% ethanol to aꢀord the title compound as yellow
1
crystals (360 mg, 50%), mp 214–215 °C; NMR data for the major tautomer: H NMR
(
DMSO-d , 400 MHz): δ 1.34 (3H, t, J=7.2 Hz, CH ), 4.36 (2H, q, J=7.1 Hz, CH ),
6
3
2
7
.51 (1H, d, J=1.5 Hz, H-4), 7.88 (2H, d, J=8.3 Hz, H-3′), 8.09 (2H, d, J=8.3 Hz,
13
H-2′), 14.31 (1H, s, NH); C NMR (DMSO-d , 100 MHz): δ 14.12 (CH ), 60.97 (CH ),
6
3
2
1
06.75 (CH-4), 110.15 (C-4′), 118.85 (CN), 125.84 (CH-2′), 132.75 (CH-3′), 135.14
(
C-5), 137.04 (C-1′), 149.57 (C-3), 158.80 (COO); NMR data for the minor tautomer:
1
H-NMR (DMSO-d , 400 MHz): δ 1.32 (3H, t, J=7.7 Hz, CH ), 4.31 (2H, q, J=7.2 Hz,
6
3
CH ), 7.42 (1H, br s, H-4), 7.96 (2H, d, J=8.3 Hz, H-3′), 8.04 (2H, d, J=8.3 Hz, H-2′),
2
13
1
4.20 (1H, s, NH); C-NMR (DMSO-d , 100 MHz): δ 14.20 (CH ), 60.23 (CH ),
6
3
2
1
3

B.-I. Bratanovici et al.
1
06.60 (CH-4), 110.77 (C-4′), 118.57 (CN), 125.89 (CH-2′), 132.57 (C-1′), 133.06 (CH-
3
′), 141.74 (C-5), 144.36 (C-3), 161.74 (COO); Anal. Calcd. for C H N O : C, 64.72;
1
3 11 3 2
H, 4.60; N, 17.42. Found: C, 64.47; H, 4.68; N, 17.22.
Preparation of 3(5)‑(4‑carboxyphenyl)‑1H‑pyrazole‑5(3)‑carboxylic acid (5)
Ethyl 3(5)-(4-cyanophenyl)-1H-pyrazole-5(3)-carboxylate (4) (241 mg, 1 mmol)
was suspended in a solution of NaOH (120 mg, 3 mmol) in water (20 mL), and
the mixture was heated at reꢃux temperature for 48 h. The slightly turbid liquid
was ꢁltered; then, the resulting solution was treated dropwise under eꢂcient stir-
ring with 5% acetic acid until pH is acidic. The ꢁne precipitate was ꢁltered, washed
thoroughly with water, air-dried, and ꢁnally dried at 40–60 °C under medium
vacuum overnight to aꢀord the diacid 5 as colorless microcrystals (212 mg, 92%),
1
mp>300 °C; H NMR (DMSO-d +TFA, 400 MHz): δ 7.32 (1H, s, H-4), 7.96–8.01
6
(
4H, m, H-2′ and H-3′), 10.7 (3H, br s, OH and NH overlaped with the TFA proton);
1
3
C NMR (DMSO-d +TFA, 100 MHz): δ 106.29 (CH-4), 125.33 (CH-2′), 130.03
6
(
CH-3′), 130.14 (C-4′), 135.67 (C-1′), 139.10 (C-5), 147.82 (C-3), 161.43 (pyrazole
COO), 167.15 (phenyl COO); Anal. Calcd. for C H N O : C, 56.90; H, 3.47; N,
1
1
8
2
4
1
2.06. Found: C, 56.58; H, 3.61; N, 11.93.
Knorr synthesis of ethyl 5‑(4‑cyanophenyl)‑1‑phenyl‑1H‑pyrazole‑3‑carboxylate (6)
To a warm solution of diketoester 2 (4.9 g, 20 mmol) in glacial acetic acid (30 mL),
phenylhydrazine (2.16 g, 20 mmol) was added dropwise under eꢂcient stirring, and
the mixture was heated at reꢃux temperature for 5 h. After it was allowed to reach room
temperature, the mixture was added dropwise, under vigorous stirring, to a mixture of
ice and water (400 g). The resulting solid was ꢁltered and washed with plenty of water.
When the material did not solidify when it was poured onto water, the semisolid was
allowed to turn into a solid in the following one or 2 days, and then, it was ꢁltered
and washed with water. The solid material was recrystallized repeatedly (usually 2 or
3
times) from 96% ethanol until the presence of the minor regioisomer could no longer
1
be detected by proton NMR. Yellowish crystals (3.93 g, 62%), mp 127–128 °C; H
NMR (DMSO-d , 400 MHz): δ 1.33 (3H, t, J=7.1 Hz, CH ), 4.35 (2H, q, J=7.1 Hz,
6
3
CH ), 7.31 (1H, s, H-4), 7.35–7.36 (2H, m, H-2″), 7.46 (2H, d, J=8.4 Hz, H-2′),
2
13
7
.48–7.50 (3H, m, H-3″ and H-4″), 7.85 (2H, d, J=8.4 Hz, H-3′); C NMR (DMSO-
d , 100 MHz): δ 14.18 (CH ), 60.61 (CH ), 110.60 (CH-4), 111.31 (C-4′), 118.29 (CN),
6
3
2
1
25.74 (CH-2″), 129.07 (CH-4″), 129.34, 129.43 (CH-3″ and CH-2′), 132.49 (CH-3′),
1
33.29 (C-1′), 138.82 (C-1″), 142.61 (C-5), 143.67 (C-3), 161.34 (COO); Anal. Calcd.
for C H N O : C, 71.91; H, 4.76; N, 13.24. Found: C, 71.68; H, 4.93; N, 13.47.
19 15 3 2
Preparation of 5‑(4‑carboxyphenyl)‑1‑phenyl‑1H‑pyrazole‑3‑carboxylic acid (7)
Ethyl 5-(4-cyanophenyl)-1-phenyl-1H-pyrazole-3-carboxylate (6) (475 mg,
1
.5 mmol) was suspended in a solution of NaOH (180 mg, 4.5 mmol) in water
(
20 mL), and the mixture was heated at reꢃux temperature for 48 h. The cold reac-
tion mixture was ꢁltered to remove a small amount of solid, and then, the resulting
1
3

Design and synthesis of novel ditopic ligands with a pyrazole…
solution was brought to pH 5–6 by dropwise addition of 5% acetic acid under eꢂ-
cient stirring. The ꢁne precipitate was ꢁltered, washed with plenty of water, air-
dried, and ꢁnally dried at 40–60 °C under medium vacuum overnight to aꢀord com-
1
pound 7 as colorless microcrystals (385 mg, 83%), mp 248–249 °C (dec.); H NMR
(
DMSO-d , 400 MHz): δ 7.19 (1H, s, H-4), 7.33-7.36 (2H, m, H-2″), 7.38 (2H, d,
6
J=8.3 Hz, H-2′), 7.45-7.49 (3H, m, H-3″ and H-4″), 7.90 (2H, d, J=8.3 Hz, H-3′),
1
3
1
3.33 (2H, br s, OH); C NMR (DMSO-d , 100 MHz): δ 110.29 (CH-4), 125.61
6
(
(
CH-2″), 128.75 (CH-2′), 129.33 (CH-3″ and CH-4″), 129.46 (CH-3′), 130.71
C-4′), 133.13 (C-1′), 139.08 (C-1″), 143.21 (C-5), 144.54 (C-3), 162.89 (pyrazole
COO), 166.71 (phenyl COO); Anal. Calcd. for C H N O : C, 66.23; H, 3.92; N,
1
7
12
2
4
9
.09. Found: C, 66.01; H, 4.08; N, 8.95.
Mild hydrolysis of ester 6 to 5‑(4‑cyanophenyl)‑1‑phenyl‑1H‑pyrazole‑3‑carboxylic
acid (8)
Ethyl 5-(4-cyanophenyl)-1-phenyl-1H-pyrazole-3-carboxylate (6) (317 mg, 1 mmol)
and LiOH (48 mg, 2 mmol) in a mixture of THF–methanol–water (5 mL, 3:1:1,
v/v/v) were stirred at room temperature overnight. A small amount of insoluble
material was removed by ꢁltration; then, the solution was diluted with water (45 mL)
and treated dropwise with 10% HCl until pH reached 2–3. The ꢁne precipitate was
ꢁ
ltered, washed thoroughly with water, air-dried, and ꢁnally dried at 40–60 °C
under medium vacuum overnight to aꢀord compound 8 as colorless microcrystals
1
(
270 mg, 93%), mp 215–216 °C (dec.); H NMR (DMSO-d , 400 MHz): δ 7.26 (1H,
6
s, H-4), 7.34–7.37 (2H, m, H-2″), 7.45 (2H, d, J=8.4 Hz, H-2′), 7.48–7.50 (3H,
1
3
m, H-3″ and H-4″), 7.85 (2H, d, J=8.3 Hz, H-3′), 13.10 (1H, br s, OH); C NMR
DMSO-d , 100 MHz): δ 110.71 (CH-4), 111.23 (C-4′), 118.35 (CN), 125.71 (CH-
(
6
2
″), 128.95 (CH-4″), 129.35, 129.42 (CH-3″ and CH-2′), 132.51 (CH-3′), 133.52
C-1′), 138.93 (C-1″), 142.47 (C-5), 144.67 (C-3), 162.84 (COO); Anal. Calcd. for
C H N O : C, 70.58; H, 3.83; N, 14.53. Found: C, 70.39; H, 3.98; N, 14.34.
(
1
7
11
3
2
Tetrazole ring closure—isolation of ethyl 5‑[4‑(1H‑tetrazol‑5‑yl)
phenyl]‑1‑phenyl‑1H‑pyrazole‑3‑carboxylate (9)
A mixture of ethyl 5-(4-cyanophenyl)-1-phenyl-1H-pyrazole-3-carboxylate (6)
(
951 mg, 3 mmol), NaN (683 mg, 10.5 mmol), and NH Cl (402 mg, 7.5 mmol)
3 4
in DMF (10 mL) was heated at 120 °C (oil bath temperature) for 48 h. The cold
reaction mixture was poured slowly, under eꢂcient stirring and in a thin stream in
ice–water (150 g). The precipitate was ꢁltered, washed with water (3×30 mL), and
air-dried to give a colorless solid (575 mg), which was recrystallized from 96% etha-
1
nol to aꢀord ester 9 as oꢀ-white crystals (410 mg), mp 224–225 °C (dec.); H NMR
(
DMSO-d , 400 MHz): δ 1.33 (3H, t, J=7.1 Hz, CH ), 4.36 (2H, q, J=7.1 Hz,
3
6
CH ), 7.27 (1H, s, H-4), 7.38-7.40 (2H, m, H-2″), 7.48-7.51 (5H, m, H-2′, H-3″
2
1
3
and H-4″), 8.00 (2H, d, J=8.4 Hz, H-3′), 16.96 (1H, br s, NH); C NMR (DMSO-
d , 100 MHz): δ 14.18 (CH ), 60.55 (CH ), 110.09 (CH-4), 124.35 (C-4′), 125.70
6
3
2
(
CH-2″), 127.09 (CH-3′), 128.90 (CH-4″), 129.36, and 129.49 (CH-3″ and CH-2′),
1
31.33 (C-1′), 138.99 (C-1″), 143.28 (C-5), 143.60 (C-3), 155.05 (C-5‴), 161.42
1
3

B.-I. Bratanovici et al.
(
COO); Anal. Calcd. for C H N O : C, 63.32; H, 4.48; N, 23.32. Found: C, 63.09;
1
9
16
6
2
H, 4.55; N, 23.51.
When the ꢁltrate from the isolation of the aforementioned colorless solid
was treated with excess 10% acetic acid, a colorless ꢁne solid separated out. The
material was ꢁltered, washed with water (3×30 mL), and air-dried to give a solid
(
385 mg), which was recrystallized from 96% ethanol to aꢀord a second crop of
ester 9 (227 mg), having the same melting point as the ꢁrst crop, the same mixed
melting point, and the same NMR spectra as the ꢁrst crop. The total yield of pure
compound 9 isolated from this experiment was 59%.
Tetrazole ring closure—isolation of a mixture of ester 9 and corresponding acid 10
A mixture of ethyl 5-(4-cyanophenyl)-1-phenyl-1H-pyrazole-3-carboxylate (6)
(
951 mg, 3 mmol), NaN (683 mg, 10.5 mmol), and NH Cl (402 mg, 7.5 mmol) in
3 4
N,N-dimethylformamide (10 mL) was heated at 120 °C (oil bath temperature) for
4
8 h. The cold reaction mixture was poured in ice–water (150 g), and then, the pH
of the mixture was brought to 2–3 by addition of 36% HCl. The precipitate was
washed with water (3×30 mL) and air-dried to give a mixture of ester 9 and acid
1
0 (1025 mg). NMR analysis showed that the ratio between ester 9 and acid 10 is
approximately 12 to 1.
Synthesis of 5‑[4‑(1H‑tetrazol‑5‑yl)phenyl]‑1‑phenyl‑1H‑pyrazole‑3‑carboxylic acid
(10) by hydrolysis of pure ester 9
Ethyl 5-[4-(1H-tetrazol-5-yl)phenyl]-1-phenyl-1H-pyrazole-3-carboxylate (9) (540 mg,
1
.5 mmol) and LiOH (108 mg, 4.5 mmol) were stirred in a mixture of THF–metha-
nol–water (10 mL, 3:1:1, v/v/v) at room temperature overnight. The mixture was then
diluted with water (40 mL) and treated dropwise with 10% HCl until pH reached 2–3.
The precipitate was ꢁltered, washed with water (3×30 mL), air-dried, and ꢁnally
dried at 40–60 °C under medium vacuum overnight to give colorless microcrystals
1
(
490 mg, 98%), mp 269–270 °C (dec.); H NMR (DMSO-d , 400 MHz): δ 7.22 (1H,
6
s, H-4), 7.37–7.39 (2H, m, H-2″), 7.48–7.50 (5H, m, H-2′, H-3″ and H-4″), 8.00 (2H,
13
d, J=8.2 Hz, H-3′), 13.09 (1H, br s, OH), 16.95 (1H, br s, NH); C NMR (DMSO-d ,
6
1
00 MHz): δ 110.22 (CH-4), 124.28 (C-4′), 125.67 (CH-2″), 127.12 (CH-3′), 128.79
(
CH-4″), 129.35 (CH-2′), 129.52 (CH-3″), 131.58 (C-1′), 139.10 (C-1″), 143.15 (C-5),
1
44.53 (C-3), 154.96 (C-5‴), 162.90 (COO); Anal. Calcd. for C H N O : C, 61.44;
17 12 6 2
H, 3.64; N, 25.29. Found: C, 61.22; H, 3.73; N, 25.11.
Preparation of 5‑[4‑(2H‑tetrazol‑5‑yl)phenyl]‑1‑phenyl‑1H‑pyrazole‑3‑carboxylic
acid (10) by hydrolysis of a mixture of ester 9 and acid 10
The previously isolated mixture of ester 9 and acid 10 (1025 mg) was suspended in
a solution of NaOH (360 mg) in water (25 mL) and heated at reꢃux temperature for
1
0 h. The cold reaction mixture was ꢁltered, diluted with water (25 mL), and acid-
iꢁed with 10% HCl. The precipitate was ꢁltered, washed with water (3×30 mL),
air-dried, and ꢁnally dried at 40–60 °C under medium vacuum overnight to give
1
3

Design and synthesis of novel ditopic ligands with a pyrazole…
colorless microcrystals (840 mg, 89%), which had the same melting point as acid 10
obtained through the hydrolysis of pure ester 9, the same mixed melting point, and
the same NMR spectra as the sample obtained from the hydrolysis of pure ester 9.
Claisen condensation of 4‑(1H‑imidazol‑1‑yl)acetophenone (11) with diethyl oxalate
4
-(1H-Imidazol-1-yl)acetophenone (11) (1488 mg, 8 mmol) and diethyl oxalate
(
2336 mg, 16 mmol) were added to a solution of sodium ethoxide, previously obtained
by reacting sodium (368 mg, 16 mmol) with abs. ethanol (60 mL). The reaction mix-
ture was heated at reꢃux temperature for 2 h, and then, it was poured onto a mixture
of ice and water (500 g) and brought to acidic pH by addition of 10% acetic acid. The
solid was ꢁltered, washed thoroughly with water, and air-dried to give diketoester 12
as a yellow solid (1945 mg, 85%) which was deemed pure enough for the next step by
NMR analysis. The analytical sample was recrystallized from ethanol to give yellow
1
crystals, mp 123–124 °C (darkening, dec.); H NMR (CDCl , 400 MHz): δ 1.42 (3H,
3
t, J=7.2 Hz, CH ), 4.41 (2H, q, J=7.1 Hz, CH ), 7.08 (1H, s, H-2′), 7.25 (1H, br s,
3
2
imidazole H-4), 7.37 (1H, br s, imidazole H-5), 7.54 (2H, d, J=8.7 Hz, H-3), 7.97 (1H,
13
br s, imidazole H-2), 8.13 (2H, d, J=8.7 Hz, H-2), 14.87 (1H, br s, OH); C NMR
CDCl , 100 MHz): δ 14.07 (CH ), 62.75 (CH ), 97.77 (vinylic CH), 117.60 (imidazole
(
3
3
2
CH-5), 120.88 (CH-3), 129.89 (CH-2), 131.27 (imidazole CH-4), 133.56 (C-1), 135.32
imidazole CH-2), 141.18 (C-4), 162.01 (COO), 170.14 (C-3′), 188.88 (C-1′); Anal.
Calcd. for C H N O : C, 62.93; H, 4.93; N, 9.79. Found: C, 63.11; H, 4.81; N, 9.91.
(
15 14 2 4
Ethyl 5‑[4‑(1H‑imidazol‑1‑yl)phenyl]‑1‑phenyl‑1H‑pyrazole‑3‑carboxylate (13)
and ethyl 3‑[4‑(1H‑imidazol‑1‑yl)phenyl]‑1‑phenyl‑1H‑pyrazole‑5‑carboxylate (14)
through pyrazole ring formation
A mixture consisting of diketoester 12 (858 mg, 3 mmol) and phenylhydrazine (328 mg,
3
mmol) in glacial acetic acid (10 mL) was heated at reꢃux temperature for 5 h. The
cold mixture was added dropwise to ice–water (150 g), and then, the resulting solution
was brought to pH 8 by addition of 10% NaOH. The brownish semisolid is allowed
to become solid over the weekend; then, the material is ꢁltered, washed with water
(
3×30 mL), and air-dried. Column chromatography (ethyl acetate–n-hexane, 1:1 v/v)
allowed the separation of the minor component 14 (45 mg, 4%) as an oꢀ-white solid,
1
mp 140–141 °C, R 0.11 (ethyl acetate–n-hexane, 1:1 v/v); H NMR (CDCl , 600 MHz):
f
3
δ 1.27 (3H, t, J=7.1 Hz, CH ), 4.27 (2H, q, J=7.1 Hz, CH ), 7.22 (1H, t, J=0.9 Hz,
3
2
imidazole H-4), 7.32 (1H, t, J=1.3 Hz, imidazole H-5), 7.35 (1H, s, H-4), 7.45 (2H,
d, J=8.7 Hz, H-3′), 7.47–7.50 (5H, m, H-2″, H-3″ and H-4″), 7.91 (1H, t, J=0.9 Hz,
13
imidazole H-2), 7.99 (2H, d, J=8.8 Hz, H-2′); C NMR (CDCl , 151 MHz): δ 14.02
3
(
CH ), 61.35 (CH ), 109.38 (CH-4), 118.09 (imidazole CH-5), 121.59 (CH-3′), 126.08
3 2
(
CH-2″), 127.22 (CH-2′), 128.66 (CH-3″), 128.87 (CH-4″), 130.53 (imidazole CH-4),
1
31.55 (C-1′), 135.01 (C-5), 135.49 (imidazole CH-2), 137.15 (C-4′), 140.24 (C-1″),
1
50.13 (C-3), 158.95 (COO); Anal. Calcd. for C H N O : C, 70.38; H, 5.06; N, 15.63.
21 18 4 2
Found: C, 70.62; H, 4.97; N, 15.52.
Further elution with ethyl acetate–n-hexane (1:1 v/v) yielded fractions containing
the major component 13 (685 mg, 64%) as a tan solid, mp 147–148 °C, R 0.06 (ethyl
f
1
3

B.-I. Bratanovici et al.
1
acetate–n-hexane, 1:1 v/v); H NMR (CDCl , 600 MHz): δ 1.42 (3H, t, J=7.1 Hz,
3
CH ), 4.46 (2H, q, J=7.1 Hz, CH ), 7.09 (1H, s, H-4), 7.20 (1H, t, J=1.0 Hz, imida-
3
2
zole H-4), 7.27 (1H, t, J=1.3 Hz, imidazole H-5), 7.31–7.36 (6H, m, H-2′, H-3′ and
13
H-2″), 7.37–7.40 (3H, m, H-3″ and H-4″), 7.86 (1H, t, J=1.0 Hz, imidazole H-2); C
NMR (CDCl , 151 MHz): δ 14.38 (CH ), 61.24 (CH ), 110.10 (CH-4), 117.80 (imida-
3
3
2
zole CH-5), 121.22 (CH-3′), 125.78 (CH-2″), 128.61 (C-1′), 128.69 (CH-4″), 129.19
(
CH-3″), 130.20 (CH-2′), 130.81 (imidazole CH-4), 135.33 (imidazole CH-2), 137.33
C-4′), 139.27 (C-1″), 143.20 (C-5), 144.51 (C-3), 162.23 (COO); Anal. Calcd. for
(
C H N O : C, 70.38; H, 5.06; N, 15.63. Found: C, 70.57; H, 5.14; N, 15.75.
21
18
4
2
The corresponding hydrochloride 13·HCl was obtained as colorless micro-
1
crystals, mp 230–231 °C (dec.); H NMR (DMSO-d , 400 MHz): δ 1.34 (3H, t,
6
J=7.1 Hz, CH ), 4.36 (2H, q, J=7.1 Hz, CH ), 7.30 (1H, s, H-4), 7.40–7.42 (2H,
3
2
m, H-2″), 7.49–7.54 (5H, m, H-2′, H-3″ and H-4″), 7.86 (2H, d, J=8.7 Hz, H-3′),
7
.90 (1H, t, J=1.5 Hz, imidazole H-4), 8.32 (1H, t, J=1.6 Hz, imidazole H-5), 9.76
+
13
(
1H, t, J=1.2 Hz, imidazole H-2), 15.36 (1H, br s, NH ); C NMR (DMSO-d ,
6
1
1
1
00 MHz): δ 14.20 (CH ), 60.58 (CH ), 110.15 (CH-4), 120.38 (imidazole CH-5),
3 2
21.25 (imidazole CH-4), 121.82 (CH-3′), 125.92 (CH-2″), 129.05 (CH-4″),
29.43 (CH-3″), 129.69 (C-1′), 130.09 (CH-2′), 134.58 (imidazole CH-2), 134.95
(
C-4′), 139.01 (C-1″), 142.91 (C-5), 143.55 (C-3), 161.45 (COO); Anal. Calcd. for
C H ClN O : C, 63.88; H, 4.85; N, 14.19. Found: C, 64.16; H, 4.95; N, 14.43.
2
1
19
4
2
Hydrolysis of ester 13 to 5‑[4‑(1H‑imidazol‑1‑yl)
phenyl]‑1‑phenyl‑1H‑pyrazole‑3‑carboxylic acid (15)
Ester 13 (358 mg, 1 mmol) and LiOH (72 mg, 3 mmol) were stirred in a mixture of
THF–methanol–water (10 mL, 3:1:1, v/v/v) at room temperature overnight. After dilu-
tion with water (40 mL), the solution was treated dropwise with 10% acetic acid until
pH 5–6. The ꢁne precipitate was ꢁltered, washed with water (3×30 mL), air-dried, and
ꢁ
nally dried at 40–60 °C under medium vacuum overnight to give colorless microcrys-
1
tals (300 mg, 91%), mp 278–279 °C (dec.); H NMR (DMSO-d , 400 MHz): δ 7.12 (1H,
6
br s, imidazole H-4), 7.17 (1H, s, H-4), 7.38–7.41 (4H, m, H-2′ and H-2″), 7.48-7.50
(
3H, m, H-3″ and H-4″), 7.69 (2H, d, J=8.6 Hz, H-3′), 7.81 (1H, br s, imidazole H-5),
13
8
.33 (1H, br s, imidazole H-2), 13.05 (1H, br s, OH); C NMR (DMSO-d , 100 MHz):
6
δ 109.80 (CH-4), 117.68 (imidazole CH-5), 119.94 (CH-3′), 125.75 (CH-2″), 127.28
(
C-1′), 128.75 (CH-4″), 129.32 (CH-3″), 130.00 (CH-2′), 130.06 (imidazole CH-4),
1
1
6
35.45 (imidazole CH-2), 136.81 (C-4′), 139.23 (C-1″), 143.20 (C-5), 144.41 (C-3),
62.97 (COO); Anal. Calcd. for C H N O : C, 69.08; H, 4.27; N, 16.96. Found: C,
19 14 4 2
8.89; H, 4.41; N, 16.78. The same compound could be obtained in 87% yield by a simi-
lar procedure that used 13·HCl as substrate and 4 equivalents of LiOH.
X‑ray crystallography
X-ray diꢀraction measurements were carried out with an Oxford Diꢀraction XCALI-
BUR E CCD diꢀractometer equipped with graphite-monochromated MoKα radiation.
Single crystals were positioned at 40 mm from the detector, and 369, 215, and 736
1
3

Design and synthesis of novel ditopic ligands with a pyrazole…
frames were measured each for 80, 125, and 5 s over 1° scan width for 6, 10, and 15,
respectively. The unit cell determination and data integration were carried out using the
CrysAlis package of Oxford Diꢀraction [46]. The structures were solved by direct meth-
2
ods using Olex2 [47] and reꢁned by full-matrix least squares on F with SHELXL-97
[
48] using an anisotropic model for non-hydrogen atoms. All H-atoms were placed
in calculated positions (d =0.93 Å) and reꢁned as riding with U (H)=1.2U (C).
CH
iso
iso
The positional parameters of disordered DMSO molecules in 15 were reꢁned using
available tools (PART, DFIX, and SADI) of SHELXL97. The molecular plots were
obtained using the Olex2 program. The crystallographic data and reꢁnement details are
presented in Table 1, while bond lengths and angles are summarized in Table S1 (Sup-
plementary Material). CCDC-1942897 (6), CCDC-1942898 (10), and CCDC-1942903
(
15) contain the supplementary crystallographic data for this contribution. These data
can be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from
Table 1 Crystal data and details of data collection for 6, 10, and 15
Compound
6
10
15
Empirical formula
C H N O
C H N O
C H N O S
4 2
1
9
15
3
2
17 12
6
2
23 26
4
Fw
317.34
332.33
486.60
Space group
a (Å)
b (Å)
c (Å)
α (°)
P-1
P2 2 2
Cc
1
1 1
8.5642(6)
9.3634(6)
11.3812(7)
77.961(6)
69.328(6)
83.693(6)
834.47(10)
2
5.9614(7)
8.8381(10)
28.489(4)
90
90
90
10.3034(3)
14.6606(3)
16.2154(4)
90
96.814(3)
90
β (°)
γ (°)
V (Å )
3
1501.0(3)
4
2432.09(12)
4
Z
λ (Å)
0.71073
1.263
0.71073
1.471
0.71073
1.329
ρcalcd (g cm−3
)
Crystal size (mm)
T (K)
0.35×0.3×0.25
200
0.084
0.40×0.10×0.05
180
0.103
0.35×0.25×0.15
180
0.255
μ (mm−1)
2
Θ range
3.89 to 50.05
5369
5.424 to 50.05
5102
4.856 to 49.426
14,519
Reꢃections collected
Independent reꢃections
2934 [Rint =0.0217]
2934/0/218
0.0453
0.1006
1.048
0.14/−0.23
–
2646 [Rint =0.0501]
2646/0/227
0.0600
0.0827
1.003
0.22/−0.23
–
4148 [Rint =0.0371]
4148/63/318
0.0783
0.2257
1.028
1.01/−0.68
0.01(5)
Data/restraints/parameters
a
R
1
b
wR
2
c
GOF
Largest diꢀ. peak/hole/e Å−
Flack parameter
3
a
R =Σ||F |−|F ||/Σ|F |
1
o
c
2
o
2 2
b
c
2 2 1/2
wR ={Σ[w(F −F ) ]/Σ[w(F ) ]}
2
o
c
o
GOF={Σ[w(F −F ) ]/(n−p)}1/2, where n is the number of reꢃections and p is the total number of
2
2 2
o
c
parameters reꢁned
1
3

B.-I. Bratanovici et al.
the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ,
UK; fax: (+44) 1223-336-033; or deposit@ccdc.ca.ac.uk).
Acknowledgements The ꢁnancial support of European Social Fund for Regional Development, Compet-
itiveness Operational Programme Axis 1—Project “Novel Porous Coordination Polymers with Organic
Ligands of Variable Length for Gas Storage,” POCPOLIG (ID P_37_707, Contract 67/08.09.2016, cod
MySMIS: 104810) is gratefully acknowledged.
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