Monitoring the hydrogen bond net configuration and the dimensionality of aniline and phenyloxamate by adding 1: H -pyrazole and isoxazole as substituents for molecular self-recognition

Article abstract of DOI:10.1039/c9ce00215d

This work describes the synthesis and characterization of a new class of oxamic acid derivatives containing pyrazole and isoxazole as substituents to investigate their ability to form hydrogen bonds aiming at applying them in crystal engineering and molec

Full text of DOI:10.1039/c9ce00215d

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DOI: 10.1039/C9CE00215D
Monitoring the hydrogen bond net configuration and the
dimensionality of aniline and phenyloxamate by adding 1H-pyrazole
and isoxazole as substituents for molecular self-recognition
Willian X. C. Oliveira,† Walace D. do Pim, ‡ Carlos B. Pinheiro,§ Yves Journaux, Miguel
†
Julve|| and Cynthia L. M. Pereira*,
†Departamento de Química, Instituto de Ciências Exatas, Universidade Federal de Minas
Gerais. Av. Pres. Antônio Carlos, 6620, Pampulha, 31270-901 Belo Horizonte, Minas Gerais,
Brazil;
‡Centro Federal de Educação Tecnológica de Minas Gerais, Av. Amazonas, 5253, Nova Suíça,
30421-169 Belo Horizonte, Minas Gerais, Brazil.
§Departamento de Física, Instituto de Ciências Exatas, Universidade Federal de Minas Gerais.
Av. Pres. Antônio Carlos, 6620, Pampulha, 31270-901 Belo Horizonte, Minas Gerais, Brasil;
 Sorbonne Université, CNRS, Institut Parisien de Chimie Moléculaire, IPCM, 75005, Paris,
France.
||Instituto de Ciencia Molecular (ICMol), Universitat de València, C/ Catedrático José Beltrán 2,
46980 Paterna, València, Spain.
*Corresponding author e-mail: cynthialopes@ufmg.br
1

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DOI: 10.1039/C9CE00215D
Abstract
This work describes the synthesis and characterization of a new class of oxamic acid derivatives
containing pyrazole and isoxazole as substituents to investigate their ability to form hydrogens
bonds aiming at applying them in crystal engineering and molecular self-recognition. In this
respect, we report a new synthesis of 2-(4-nitrophenyl)-1,3-propanedial (1) in a high yield using
SOCl2 as chlorinating agent. The new oxamic esters 4-(1H-pyrazol-4-yl)phenylene-N-
(ethyloxamate) (2d) and 4-(1,2-oxazol-4-yl)phenylene-N-(ethyloxamate) (3d) were prepared
from 1. The synthetic route consists of the cyclisation of 1 either with hydrazine to afford the 4-
(-aminophenyl)-1H-pyrazole (2a) or with hydroxylamine to obtain the isozaxole-based molecule
4-(4-nitrophenyl)-1,2-oxazole (3a). The reduction of 2a and 3a was carried out in an acidic/tin
solution to yield 4-(4-ammoniophenyl)-1H-pyrazol-2-ium trichlorostannate(II) chloride
monohydrate (2b) and 4-(4-ammoniophenyl)-1,2-oxazole hexachlorostannate(IV) (3b). Basic
extraction of 3b provided 4-(4-aminophenyl)-1,2-oxazole (3c). The reduction of 2a to 4-(4-
aminophenyl)-1H-pyrazole (2c) was achieved by means of hydrazine associated to supported
palladium on carbon. The condensation of 2c and 3c with ethyl chlorooxoacetate delivers oxamic
esters 2d and 3d. In n-tetrabutylammonium hydroxide solution 2d is fully hydrolyzed, obtaining
the n-tetrabutylammonium salt of 4-(1H-pyrazole-4-yl)phenylene-N-oxamate as hemihydrate
(2e). The low stability of isoxazole molecules in basic solutions was proved by crystallizing the
n-tetrabutylammonium salt of 1-cyano-1-(4-nitrophenyl)-2-oxoethanide (3f) (obtained by
cleavage of 3d with n-Bu4NOH) and preparing its conjugated acid 2-(4-nitrophenyl-3-
oxopropanenitrile (3e). The structures of 2b, 3b, 3d and 2e were solved by single crystal X-ray
diffraction techniques. The analysis of their crystal packing reveals hydrogen bond features
compatible for all compounds as well as some differences depending on the pH of the
crystallization solution and the presence or absence of the oxamate group due to the increase of
hydrogen bond donors and acceptors.
2

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Introduction
The specific interaction of a group, molecule or even an ion with other group in the same molecule
or another one is referred to as molecular recognition.1-3 The specific recognition of molecules
are very relevant as shown by biomolecular chemistry because it rules the living organisms.
Proteins and other receptors have specific interactions in the voids that must be fulfilled in order
to recognize a target molecule.4-6 Among the interactions involved in these processes, we will
focus on the hydrogen bonds since they are in general directional and due to the stability they
afford to the system, they can rule the spatial structure of the molecule, adduct, synthon or even
of the whole crystal packing. The most famous example of hydrogen bond controlling the
structure in biology is the DNA double helix, where the interaction between the nitrogenous bases
links the strands and together with the phosphate-sugar backbone leads to the helicoidal structure
of the macromolecule, which is so strong that only the replication enzymes can break it.4 In this
respect, the molecular recognition for small molecules can be a ruler for the crystal engineering
and it certainly deserves deeper studies and understanding.
In terms of crystal engineering, the molecular recognition allows the user to guide the
self-assembly of the basic units leading to better planning of the supramolecular structures and
consequently, to modulate the properties which are dependent on the specific organization in the
space.7-11 In order to reach the molecular recognition and crystal engineering, one must rely on
supramolecular chemistry, the science field dealing with the study of the interactions among
particles, since all interactions are relevant during the crystallization process, hydrogen bonding
being one of them. One can state that the stronger the interaction, the more relevant for the
7,11
crystallization it is,
and so, the hydrogen bonds may be the focus of crystal engineering.
Finally, a smart way to modulate the crystallization would be the introduction of hydrogen bonds
donors/acceptors in specific parts of the molecule, just as nature has done in DNA.
Given that the 1H-pyrazole groups (a member of the azole family)12,13 (Chart 1) is known
to be hydrogen bond donor and acceptors, its insertion into molecules can turn it capable of
molecular recognition or even self-recognizable.14-25 The pyrazole-nitrogen atoms have double
functions because the protonated one is responsible for recognizing electronegative atoms
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whereas the tertiary one can be recognized by hydrogen bond donor groups. This duality can
culminate in a variety of self-recognition hydrogen bonded nets: discrete supramolecules14-22 or
supramolecular polymers,23-25 as displayed in Chart 2.
1
2
X
N
5
3
4
Chart 1. General structure of the 1,2-azole group: 1H-pyrazole (X = N-H) and isoxazole (X =
O).
H
H
H
H
X
X
N
N
N
N
N
N
N
N
H
(c)
(a)
(b)
N
N
H
N
N
N
N
N
H
H
H
H
H
N
N
N
H
N
N
N
N
N
H
N
(d)
(e)
Chart 2. Common hydrogen bonds and supramolecular motifs in 1H-pyrazole-based assemblies:
recognition of (a) an electronegative group and (b) an electrodeficient hydrogenated group; (c)
discrete dimeric, (d) tetrameric and (e) linear chain self-recognition.
On the other hand, the isoxazole group is formed by placing an oxygen atom at one
position distinct from the nitrogen in the azole ring. This member of the azole family is not capable
of molecular recognition in the same way as the 1H-pyrazole due to the lack of a hydrogen bond
donor. Isoxazole groups in presence of hydrogen donor molecules only interact with them through
their nitrogen atom because the isoxazole-oxygen atom is heavily electronegative and its electron
density is unavailable to interact.13 Then, this group can be used for comparison of the importance
of a protonated group in the self-assembly concerning the pyrazole-based molecules.
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This work describes the synthesis of new class of oxamate based-molecules asDmOoI: l1e0c.1u03la9/rC9CE00215D
recognition agents based on the control of hydrogen bond networks, taking into consideration the
interaction between the pyrazole- and isoxazole substituted molecules and non-substituted aniline
and phenyloxamate molecules.
Experimental Section
All crude materials were purchased from commercial sources and used as received. The solvents
dmf and thf were dried over molecular sieves. Tetra-n-butylammonium hydroxide 40% aqueous
solution was used in the preparations. The synthetic routes of the pyrazole- and isoxazole-
substituted oxamates are shown in Schemes 1 and 2, respectively.
2-(4-nitrophenyl)-1,3-propanedial (1). SOCl2 (3.20 mL, 60.0 mmol) was introduced into a
round flask which was cooled in an ice bath (between 0 and 4 ºC); then, dried dmf (7.30 mL, 100
mmol) was slowly added, under vigorous stirring, in order to maintain the temperature below 4
ºC. After completing the addition of dmf, the solution was kept to react under 30 min when solid
4-nitrophenylacetic acid (3.60 g, 20.0 mmol) was added. The mixture was heated up to 90 ºC,
kept at this temperature for 6 h and allowed to cool down to room temperature. The round flask
was placed again in an ice bath and cold water (below 4 ºC) was added (130 mL) to it followed
by the careful addition a cold aqueous solution of NaOH (30 mL, 10 mol L–1). This mixture was
left overnight under stirring at room temperature, then heated up again at 115 ºC for 4 h and
allowed to cool down at room temperature. The resulting bright red solid which was formed, was
filtered off, dissolved in water (250 mL) and filtered to remove a small amount of black
byproduct. This final mother liquor was acidified with concentrated HCl until pH 1.0 and a pale-
yellow solid was separated. This yellow product was filtered off, washed with water and left to
dry under low pressure for 24 h. Yield: 65% (2.51 g, 13.0 mmol). 1H NMR (dmso-d6, 200 MHz):
7.85 (d, 2H, J = 9.0 Hz, H-ph), 8.21 (d, 2H, J = 9.0 Hz, H-Ph), 8.65 (s, 2H, COCHCO) ppm. 13C
NMR (dmso-d6, 50 MHz): 118.69, 123.16, 130.06, 139.29, 145.78, 181.17 ppm. Elemental
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analysis for C9H7NO4 (1) [Exp. (Calcd.)]: C 56.52 (55.96), H 2.81 (3.05), N 7.00 (7.25)%. Melting
point: 230-232 ºC (followed by decomposition).
H+
N
H
N
Sn
Cl
c
Cl
Cl
Cl
H
N
O
N
O
O
NH+3
OH
H
H
2b
H
N
H
N
N
a
b
H
N
N
N
N+
N+
N+
O-
O
O-
O
O-
O
d
e
f
2a
1
(Bu4N)
.0.5H2O
O
O
NH
O
O
NH
NH2
O-
OEt
2e
2c
2d
Scheme 1. Synthetic pathway of the pyrazole derivatives from 1. (a) SOCl2, dmf, 90 ºC for 6 h;
NaOH, 120 ºC for 3 h; HCl. (b) NH2NH2∙H2O, MeOH, 100 ºC for 3 h. (c) Sn, HCl; EtOH and
slow cooling. (d) NH2NH2∙H2O, Pd/C, MeOH, for 1 h. (e) ClC(O)COOEt, Et3N, thf, 75 ºC for 1h.
(f) n-Bu4NOHaq.
N
O
O
N
O
O
O
N
O
N
O
OH
H
H
Cl
Cl
Cl
Cl
Cl
Sn
Cl
c
a
d
e
b
O
O
NH
N+
N+
N+
NH+3
NH2
O-
O
O-
O
O-
O
2
OEt
3c
3b
1
3a
3d
f
O
O
N
N
C-
H
H
h
g
Bu4N
N+
N+
O-
O
O-
O
3f
3e
Scheme 2. Synthetic pathway of isoxazole derivatives from 2-(4-nitrofenil)-1,3-propanedial (1).
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(a) SOCl2, dmf, 90 ºC for 6 h; NaOH, 120 ºC for 3 h; HCl. (b) NH3OHCl, MeOH, 100 DºCOI:f1o0r.10339h/.C9CE00215D
(c) Sn, HCl; EtOH and slow cooling. (d) NaCO3, extraction with CHCl3. (e) ClC(O)COOEt, Et3N,
thf, 75 ºC for one hour. (f) KOH, CH3OH, 90 ºC for 2 h; HCl 1.0 M. (g) and (h) n-Bu4NOHaq.
4-(4-nitrophenyl)-1H-pyrazole (2a). Hydrazine monohydrate (0.385 mL, 5.28 mmol) and
methanol (20.0 mL) were poured into a round flask containing a solid sample of 1 (1.00 g, 5.28
mmol) and the mixture was allowed to react at 100 ºC for 3 h. Then, water (20.0 mL) was added
and the temperature was kept until complete dissolution. Slow cooling of this solution at room
temperature afforded a crystalline yellowish-orange solid which was filtered off, washed with
water and left to dry under low pressure for 24 hours. Yield: 67% (669 mg, 3.54 mmol). 1H NMR
(dmso-d6, 200 MHz): 7.92 (d, 2H, J = 8.6 Hz, H-Ph), 8.21 (m, 3H, H-Ph + H-pyrazole), 8.49 (s,
1H, H-pyrazole), 13.28 (s, 1H, NH-pyrazole) ppm. 13C NMR (dmso-d6, 50 2a MHz): 119.81,
124.61, 128.88, 137.54, 140.53, 145.36 ppm. Elemental analysis for C9H7N3O2 (2a) [Exp.
(Calcd.)]: C 57.98 (57.14), H 2.84 (3.03), N 22.12 (22.21)%. Melting point: 200-202 ºC.
4-(4-ammoniophenyl)-1H-pyrazole-2-ium trichlorostannate(II) chloride monohydrate (2b).
Granulated tin (200 mg, 1.68 mmol) and concentrated HCl (4.0 mL) were poured into a round
flask containing solid 2a (100 mg, 0.53 mmol) and the whole was kept under continuous stirring
at 130 ºC until a clear colorless solution was reached. After the color change, ethanol (4.0 mL)
was added and the resulting solution was allowed to cool down at room temperature. The white
crystalline solid that separated was collected by filtration, washed with cold ethanol and diethyl
ether and left to dry under ambient conditions for 24 hours. Elemental analysis for
C9H13Cl4N3OSn (2b) [Exp. (Calcd.)]: C 24.02 (23.11), H 2.05 (1.94), N 8.97 (8.98), Sn 26.58
(25.38)%. 1H NMR (dmso-d6, 200 MHz): 7.42 (d, 2H, J = 8.4 Hz, H-Ph), 7.76 (d, 2H, J = 8.4 Hz,
H-Ph), 8.24 (s, 2H, H-pyrazolium), 10.21 (s, 5H, HN–NH-pyrazolium + NH3-anilinium) ppm.
13C NMR (dmso-d6, 50 MHz): 122.07, 125.56, 127.97, 131.20, 132.79, 134.22 ppm.
4-(4-aminophenyl)-1H-pyrazole (2c). Hydrazine monohydrate (0.800 mL, 20.0 mmol),
palladium on carbon (500 mg, 10% w/w) and methanol (40.0 mL) were added to a round flask
containing solid 2a (1.00 g, 5.26 mmol). The mixture was left to react at 100 ºC under continuous
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stirring for 3 h. The resulting suspension was filtered off to remove the carbon and tDhOeI:m10o.1t0h3e9/rC9CE00215D
liquor was evaporated to one fifth of the initial volume for precipitation of a bright white solid.
This product was collected by filtration, washed with cold methanol (1.0 mL) and dried under
low pressure for 24 hours. Yield: 75% (628 mg, 3.94 mmol). 1H NMR (dmso-d6, 200 MHz): 4.99
(s, 2H, NH2), 6.57 (d, 2H, J = 9.6 Hz, H-Ph), 7.26 (d, 2H, J = 10.0 Hz, H-Ph), 7.83 (s, 2H, H-
pyrazole), 12.71 (s, 1H, NH-pyrazole) ppm. 13C NMR (dmso-d6, 50 MHz): 114.62, 121.06,
122.29, 126.33, 135.38, 147.25 ppm. Elemental analysis for C9H9N3O (2c) [Exp. (Calcd.)]: C
67.44 (67.90), H 5.57 (5.70), N 26.27 (26.40)%. Melting point: 232-234 ºC.
4-(1H-pyrazole-4-yl)phenylene-N-(ethyloxamate) (2d). Solid 2c (1.04 g, 6.6 mmol) was
introduced into a round flask containing thf (200 mL) and trimethylamine (0.93 mL, 6.7 mmol).
Ethyl chlorooxoacetate (0.75 mL, 6.6 mL) dissolved in diethyl ether (10.0 mL) was slowly added
to the previous solution under continuous stirring. The final mixture was allowed to react for 1 h
at 75 ºC. Then, the solution was evaporated to one fifth of the initial volume and the further
addition of cold water (200 mL) caused the precipitation of a white polycrystalline solid. This
precipitate was collected by filtration, washed with water and dried at low pressure for 24 h. Yield:
86% (1.47 g, 5.68 mmol). Elemental analysis for C13H13N3O3 (2d) [Exp. (Calcd.)]: C 59.98
(60.22), H 4.88 (5.05), N 16.17 (16.21)%. 1H NMR (dmso-d6, 200 MHz): 1.32 (t, 3H, J = 7.1 Hz,
OCH2CH3), 4.31 (q, 2H, J = 7.1 Hz, OCH2CH3), 7.59 (d, 2H, J = 8.6 Hz, H-Ph), 7.73 (d, 2H, J =
8.7 Hz, H-Ph), 10.78 (s, 2H, NH-oxamate) ppm. 13C NMR (dmso-d6, 50 MHz): 14.22, 62.72,
121.16, 125.69, 129.87, 135.68, 155.66, 161.06 ppm. Melting point: 230-232 ºC.
Tetra-n-buthylammonium 4-(1H-pyrazole-4-yl)phenylene-N-oxamate hemihydrate (2e).
Solid 2d (260 mg, 1.00 mmol), tetra-n-buthylammonium hydroxide (0.655 mL, 1.01 mmol) and
water (10.0 mL) were introduced into to a round flask and the resulting suspension was left to
react under continuous stirring at 80 ºC for one hour. Then, it was allowed to cool down at room
temperature and colorless plates as its characteristic external shape that separated were collected
by filtration washed with water and left to dry on filter paper in the open air for 24 h. Yield: 88%
(417 mg, 0.88 mmol). Elemental analysis C27H45N4O3.5 (2e) [Exp. (Calcd.)]: C 67.21 (67.19), H
1
8.99 (9.19), N 8.78 (8.71)%. H NMR (dmso-d6, 300 MHz): 0.93 (t, 12H, J = 7.3 Hz,
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NCH2CH2CH2CH3), 1.30 (m, 8H, NCH2CH2CH2CH3), 1.56 (m, 8H, NCH2CH2CH2CH3), 3.16
(m, 8H, NCH2CH2CH2CH3), 7.49 (d, 2H, J = 8.5 Hz, H-Ph), 7.70 (d, 2H, J = 8.5 Hz, H-Ph), 7.97
(s, 2H, H-pyrazole), 10.00 (s, 1H, NH-pyrazole), 12.88 (s, 1H, NH-oxamate) ppm. 13C NMR
(dmso-d6, 75 MHz): 13.84, 19.56, 23.42, 57.88, 119.40, 121.46, 125.61, 127.73, 137.61, 162.87,
164.93 ppm. Melting point: 238-239 ºC.
4-(4-nitrophenyl)-1,2-oxazole (3a). Solid 1 (1.00 g, 5.28 mmol) was introduced into a round
flask containing hydroxylamine hydrochloride (400 mg, 2.87 mmol) and methanol (20.0 mL).
This mixture was left to react under continuous stirring at 100 ºC for 3h. Then, water (20.0 mL)
was added and the temperature was kept until the complete dissolution of the solid. Slow cooling
of this solution afforded a crystalline orange solid which was filtered off, washed with water and
left to dry under low pressure for 24 h. Yield: 75% (752 mg, 3.96 mmol). Elemental analysis for
1
C9H6N2O3 (3a) [Exp. (Calcd.)]: C 56.81 (56.85), H 3.22 (3.18), N 14.55 (14.73)%. H NMR
(dmso-d6, 200 MHz): 7.76 (d, 2H, J = 9.0 Hz, H-Ph), 8.19 (d, 2H, J = 8.9 Hz, H-Ph), 8.81 (s, 1H,
H-isoxazole), 9.15 (s, 1H, H-isoxazole) ppm. 13C NMR (dmso-d6, 50 MHz): 120.46, 125.24,
128.02, 136.31, 147.85, 148.61, 156.84 ppm. Melting point: 166-168 ºC.
Bis-4-(4-ammoniophenyl)-1,2-oxazole hexachlorostannate(IV) (3b). Granulated tin (200 mg
1.68 mmol) and concentrated HCl (4.0 mL) were poured into a round flask containing solid 3a
(100 mg; 0.53 mmol). The whole mixture was heated at 130 ºC under continuous stirring until a
clear pale-yellow solution was reached. After the color change, ethanol (4.0 mL) was added and
left the solution to cool down slowly. The yellow crystalline solid which was formed was
collected by filtration, washed with cold ethanol (1.0 mL) and diethyl ether (3.0 mL) and left to
dry under ambient conditions for 24 h. Yield: 65% (225 mg, 0.34 mmol). Elemental analysis for
C18H18Cl6N4O2Sn (3b) [Exp. (Calcd.)]: C 32.28 (32.97), H 2.87 (3.07), N 8.12 (8.54), Sn 18.07
(18.16)%. 1H NMR (dmso-d6, 200 MHz): 7.39 (d, 2H, J = 8.5 Hz, H-Ph), 7.78 (d, 2H, J = 8.7 Hz,
13
H-Ph), 9.17(s, 1H, H-isoxazole), 9.47(s, 1H, H-isoxazole) ppm. C NMR (dmso-d6, 50 MHz):
121.55, 124.93, 129.15, 134.15, 149.90, 157.01 ppm.
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4-(4-aminophenyl)-1,2-oxazole (3c). Solid 3b (1.00 g 1.52 mmol) was added to an
aqueous solution (10.0 mL) of sodium carbonate (0.5 g 4.25 mmol) in a round flask. This mixture
was left to react under continuous stirring for 30 min at room temperature and the title compound
was extracted with two portions of chloroform (20 mL). The organic phases were combined and
evaporated until dryness to afford a yellow solid. Yield: 95% (487 mg, 3.04 mmol). Elemental
analysis for C9H8N2O (3c) [Exp. (Calc.)]: C 67.55 (67.49), H 5.00 (5.03), N 17.22 (17.49)%. 1H
NMR (dmso-d6, 300 MHz): 5.26 (s, 2H, NH2), 6.63 (dd, 2H, J = 8.5 Hz, J’ = 1.9 Hz, H-Ph), 7.36
(dd, 2H, J = 8.5 Hz, J’ = 1.9 Hz, H-Ph), 8.97 (s, 1H, H-isoxazonium), 9,16 (s, 1H, H-isoxazonium)
ppm. 13C NMR (dmso-d6, 75 MHz): 114.49, 115.89, 121.68, 127.46, 148.35 148.86, 152.80 ppm.
Melting point: 311 ºC (decomp.).
4-(1,2-oxazol-4-yl)phenylene-N-(ethyloxamate) (3d). Solid 3c (1.04 g, 6.6 mmol),
trimethylamine (0.93 mL, 6.7 mmol) and thf (200 mL) were introduced into a round flask. Diethyl
ether (10.0 mL) containing ethyl chloroacetate (0.75 mL, 6.6 mL) and was slowly added added
to the resulting solution under continuous stirring and the mixture was allowed to react for one
hour at 75 ºC. Then, the volume was reduced to one fifth and cold water (200 mL) was added to
precipitate a pale-yellow crystalline solid. It was collected by filtration, washed with water and
dried at low pressure for 24 h. Yield: 86% (1.47 g, 5.68 mmol). Elemental analysis for C13H12N2O4
(3d) [Exp. (Calcd.)]: C 60.02 (60.00), H 4.88 (4.65), N 10.58 (10.76)%. 1H NMR (dmso-d6, 300
MHz): 1.32 (t, 3H, J = 7.1 Hz, OCH2CH3), 4.31 (q, 2H, J = 7.1 Hz, OCH2CH3), 7.59 (dd, 2H, J
= 8.7 Hz, J’ = 2.0 Hz, H-ph), 7.73 (dd, 2H, J = 8.8 Hz, J’ = 1.9 Hz, H-ph), 10.78 (s, 2H, NH-
oxamate) ppm. 13C NMR (dmso-d6, 75 MHz): 14.22, 62.72, 121.16, 125.69, 129.87, 135.68,
155.66, 161.06 ppm. Melting point: 210-212 ºC. In order to crystallize this product, 3d (10 mg)
dissolved in dmso (0.5 mL) was deposited at the bottom of a test tube (4.0 mL) and the tube was
filled with a water:dmso solvent mixture (3.0 mL, 50% v/v). The tube was covered with Parafilm®
and pale-yellow plates were grown on standing at room temperature after two weeks. They were
collected by filtration, washed with water and dried at low pressure for 24 hours. Yield: 75% (7.5
mg).
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2-(4-nitrophenyl)-3-oxopropanenitrile (3e). Solid 3a (350 mg, 1.84 mmol) was allowDeOdI:t1o0.r1e0a39c/tC9CE00215D
with an aqueous solution (20 mL) of KOH (400 mg, 8.40 mmol) in a round flask under continuous
stirring for 24 h at room temperature. The solution was filtered to discard any small particle and
concentrated HCl was poured into it until reaching a pH value of 1.0. The yellow solid which was
formed, was filtered off, washed with water and left to dry at low pressure for 72 h. Yield: 58%
(203 mg, 1.06 mmol). Elemental analysis for C9H6N2O3 (3e) [Exp. (Calcd.)]: C 58.02 (56.85), H
3.38 (3.18), N 14.58 (14.73). 1H NMR (CD3CN, 100 MHz): 4.01 (s, 1H, HC(O)CHCN), 7.63 (d,
4H, J = 9.0 Hz, H-Ph), 7.72 (s, 1H, HC(O)CHCN), 7.96 (d, 2H, J = 9.1 Hz, H-Ph), 8.07 (s, 2H,
HC(OH)CCN), 8.22 (m, 6H, H-Ph) ppm. 13C NMR (CD3CN, 100 MHz): 123.77, 124.03, 124.20,
124.79, 127.53, 129.28, 139.27, 159.68, 161.01 ppm. Melting point: 235-238 (dec.) ºC.
Tetra-n-butylammonium 1-cyano-1-(4-nitrophenyl)-2-oxoethanide (3f). Solid 3e (50.0 mg,
0.263 mmol) was added to a mixture of tetra-n-butylammonium hydroxide 40% aqueous solution
(200 µL, 0.307 mmol) and water (5.0 mL) in a beaker. The whole was left to react in an ultrasound
bath to achieve a suspension of a red powder. This powder was filtered off, washed with water
and left to dry at low pressure for 72 hours. Yield: 97% (110 mg, 0.255 mmol). Elemental analysis
1
for C25H41N3O3 (3f) [Exp. (Calc.)]: C 69.49 (69.57), H 9.79 (9.57), N 9.71 (9.74)%. H NMR
+
+
(CDCl3, 400 MHz): 0.98 (t, 12H, N(CH2CH2CH2CH3)4 ), 1.39 (h, 8H, N(CH2CH2CH2CH3)4 ),
+
+
1.57 (m, 8H, N(CH2CH2CH2CH3)4 ), 3.14 (t, 8H, N(CH2CH2CH2CH3)4 )), 8.02 (s, 4H, H-Ph),
8.87 (s, 1H, HC(O)CCN), ppm. 13C NMR (CDCl3, 100 MHz): 13.53, 19.65, 23.81, 58.82, 81.61,
82.66, 119.94, 122.02, 122.86, 123.96, 124.24, 124.48, 126.77, 129.04, 141.10, 141.38. 146.11,
147.18, 176.71 and 177.09 ppm. Melting point: 235-238 ºC. Crystals of 3f suitable for X-ray
diffraction were grown from a dmso/water solution (1:10 v/v) of 3d in the presence of n-Bu4NOH
at room temperature after 45 days.
Physical Techniques. Elemental analysis (C, H and N) were carried out on a Perkin-Elmer 2400
analyzer. Infrared spectra were recorded with Perkin-Elmer FTIR spectrometer as KBr pellets in
the 4000-400 cm-1 region (Supporting Information, SI, Figures S1-S12). NMR spectra was carried
1
in Bruker-200/300/400 NMR spectrometers at 200, 300 or 400 MHz for H nuclei (50, 75 and
100 MHz for 13C) using dmso-d6 or CDCl3/dmso-d6 mixture (1:5 v/v) or CDCl3 with c.a. 20 mg
11

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DOI: 10.1039/C9CE00215D
of material. Tetramethylsilane or residual solvent signals were used as internal standard (SI
Figures S13-S36). X-ray powder diffraction patterns for compounds 2b, 3b, 3d, 2e and 3f were
obtained using a Rigaku/Geirgeflex or PANalytical/Empyrean diffractometer at room
temperature (SI Figures S37-41). The patterns were compared with the calculated ones from the
cif files with the reflection positions based on cell parameters and intensity peaks in both cell
parameters and atom positions using the Mercury® software.26 The observed cell contraction in
compounds 2e and 3f through the analysis of the single crystal data collection at 120 K account
for the major deviation on the reflection positions when compared with the X-ray pattern collected
at room temperature. For a realistic comparison, the cell parameters at room temperature of 2e
and 3f were determined by measuring single crystals at low diffraction limit and compared to the
polycrystalline data through the JANA200627 software matching all diffraction peaks.
Thermogravimetric analysis were carried out for 2b, 2e and 3b. The analysis were performed in
a thermobalance Shimadzu TA-60 using nitrogen flow at rate of 50 mL min–1 and alumina
crucible as sample holder containing 3-6 mg of material (SI Figures S48-S50).
Crystal Data Collection and Refinement. X-ray diffraction data for 2b, 2e, 3b, 3d, and 3f were
performed with an Oxford-Diffraction GEMINI-Ultra diffractometer using Enhance Source Cu-
Kα radiation (λ = 1.5418 Å) or Enhance Source Mo-Kα radiation (λ = 0.71073 Å). Measurements
were performed at different temperatures as shown in Table 1. Data integration and scaling of the
reflections for all compounds were performed with the CRYSALIS suite.28 Final unit cell
parameters were based on the fitting of the positions of all reflections. Analytical absorption
corrections were performed by means of the CRYSALIS suite and the space group identification
was done with XPREP.29 The structures of all compounds were solved by direct methods using
the SUPERFLIP program.30,31 For each compound, the positions of all non-hydrogen atoms could
be unambiguously assigned on consecutive difference Fourier maps. Refinements were
performed using SHELXL-201832 based on F2 through full-matrix least-squares routine. All non-
hydrogen atoms were refined with anisotropic atomic displacement parameters. The hydrogen
atoms were located in difference maps and included as fixed contributions according to the riding
model. Uiso(H) = 1.5 Ueq(O) for water molecules. The values of C–H and N–H of the organic
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moieties were considered equal to 0.97 Å and Uiso(H) = 1.2 Ueq(C or N) for aromaDtiOcI: c10a.r10b3o9n/C9CE00215D
atoms, methylene and amide groups.33 A double split position model was applied to the model
disordered n-Bu4N+ units in 2e. Molecular graphics were prepared with the ORTEP3-2014
software.34 CCDC deposit numbers are 1843194 (2b), 1843195 (2e), 1843196 (3b), 1843197 (3d)
and 1843198 (3f).
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Table 1. Summary of the crystal data and refinement parameters for 2b, 2e, 3b, 3d, and 3f.
Compound
Chemical Formulae
Fw / g mol-1
λ / Å
2b
C9H13N3OCl4Sn
439.71
2e
C54H90N8O7
963.33
3b
3d
3f
C25H41N3O3
431.61
C18H18N4O2Cl6Sn C13H12N2O4
653.75
1.5418
260.25
1.5418
0.71073
0.71073
0.71073
Crystal Size / mm3
Crystal System
Space Group
a / Å
0.40 × 0.11 × 0.01 0.17 × 0.10 × 0.08 0.39 × 0.17 × 0.07 0.16 × 0.14 × 0.13 0.54 × 0.18 × 0.14
Triclinic
푃1
Monoclinic
Orthorhombic
퐶푚푐푒
Monoclinic
Monoclinic
푃21/푐
푃21/푐
푃21/푛
7.006(5)
9.684(5)
11.987(5)
69.910(5)
89.440(5)
84.970(5)
760.7(7)
150(2)
17.8761(15)
20.1749(11)
31.536(3)
90
7.0873(2)
18.2022(6)
20.2832(7)
90
8.4720(11)
20.459(3)
7.1990(16)
90
11.7417(14)
9.6253(15)
22.1211(15)
90
b / Å
c / Å
α / º
β / º
104.661(8)
90
90
96.958(16)
90
99.154(8)
90
γ / º
90
Volume / Å3
T / K
11003.0(15)
120(2)
2616.62(15)
290(2)
1238.6(4)
298(2)
2468.2(5)
120(2)
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Z (Z’)
2 (2)
2 (16)
4 (4)
1288
4 (4)
4 (4)
F(000)
hkl range
428
4208
544
944
–5 ≤ h ≤ 8
–11 ≤ k ≤ 11
–14 ≤ l ≤ 14
1.920
–20 ≤ h ≤ 22
–25 ≤ k ≤ 25
–39 ≤ l ≤ 36
1.163
–24 ≤ h ≤ 24
–10 ≤ h ≤ 10
–24 ≤ k ≤ 25
–8 ≤ l ≤ 8
1.396
–14 ≤ h ≤ 14
–12 ≤ k ≤ 9
–20 ≤ l ≤ 27
1.161
–21 ≤ k ≤ 20
–8 ≤ l ≤ 7
1.660
ρcalc / g cm-3
μ / mm-1
19.772
6229
0.077
13.601
0.105
0.076
Collected reflections
Independent Reflections
Reflections with I ≥ 2σ(I)
Rint
149679
22505
7457
10667
11620
2666
1280
2515
5037
1911
13010
1011
1450
3741
0.122
0.093
0.084
0.078
0.032
Ra; wRb [I ≥ 2(I)]
Ra; wRb (all data)
Goodness-of-fit on F2 (Sc)
Larg. diff. peak and hole/e Å–3
0.074; 0.170
0.076 (0.136)
0.047 (0.118)
0.052 (0.106)
0.048; 0.103
0.108; 0.204
1.060
0.194 (0.232)
1.049
0.063 (0.130)
1.052
0.114 (0.141)
1.058
0.075; 0.119
1.027
+1.84; –1.22
+1.50; –0.41
+1.11; –0.68
+0.22; –0.21
+0.32; –0.28
a R = ∑ ||Fo| – |Fc|| / ∑|Fo|. b wR = [∑w(|Fo|2 – |Fc|2)2 / ∑w|Fo|2]1/2. c S = [∑w(|Fo|2 – |Fc|2)2 / (No – Np)]1/2 where w is proportional to σ–1 whereas No and Np are the
number of observed and refined parameters, respectively.
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Comments on the Synthesis
Several other preparative routes have been proposed to synthetize azole compounds, the
preparation of derivatives followed by the ring close step being easy and common pathways in
the literature for 1H-pyrazoles,35-42 but much less explored for isozaxoles.43-46 The synthesis of
the malonaldehyde requires the presence of the Vilsmeier complex which is achieved by using
dmf with a chlorination compound, originally47 and mostly POCl3.48 However, as described in the
present work, we were able to change the chlorinating reagent in the preparation of 1 without
compromising the yield. The replacement of POCl3 by SOCl2 is interesting from an economic
point of view since the last one is less expensive and wider available than phosphorous(V)
oxychloride and in addition, our synthesis is cleaner due to the release of gaseous SO2 instead of
phosphoric acid which is present at the end of reaction with POCl3.
The ring closing step was carried out without any difficulty, simply reacting 1 either with
hydrazine (2a) or hydroxylamine (3a) sulfate with no need of adding a base (see Schemes 1 and
2). Although the products were prepared as crystals, ensuring high purity, their crystal structures
could not be determined precluding an even deeper investigation of the hydrogen bonds. Thus,
the nitro group reduction was carried out in two ways: (i) by means of tin in a hydrochloric
solution and (ii) by using hydrazine associated with palladium on activated carbon. 2a was
successfully reduced using both methods affording 2b and 2c, respectively; however, 3a did not
yield the desired product when hydrazine was added to it and only the tin/HCl route was used
leading to 3b. This simple observation was the first evidence that the isoxazole group does not
endure basic media and we should carry out the synthesis in acidic or neutral conditions. The use
of 2b to continue the synthetic pathway was found to be tricky. All procedures applied to
deprotonate and isolate the amine from the tin byproducts failed and no pure amine was obtained,
being the reason to focus on the hydrazine-Pd/C as the main reduction agent and therefore, only
2c was used in the synthesis. The deprotonation of 3b and the isolation of 3c revealed to be easier
than in the case of 2b, simply extracting 3c from an aqueous carbonate solution with chloroform
at room temperature in a high yield. 2c and 3c were used to prepare the oxamate-based compounds
2d and 3d by applying the classical procedure of the nucleophilic substitution on carbonyl
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chloride, a widely explored route in the synthesis of this type of compounds.49-52 Compound 2d
View Article Online
DOI: 10.1039/C9CE00215D
was efficiently hydrolyzed upon heating its solution in the presence of tetra-n-butylammonium
hydroxide. The n-tetrabutylammonium salt 2e crystallizes by cooling down the solution. As
previously indicated this does not occur with 3d. The isoxazole group has a quite acid hydrogen
atom and once captured, ring opening occurs.12,53 This parallel reaction competes with the
oxamate hydrolysis and complex mixtures are obtained when the basic hydrolysis was attempted.
To prove its incompatibility of 3d with basic solutions, we reacted it with tetra-n-butylammonium
hydroxide and crystals of 3f were obtained, showcasing the open ring reaction, but the oxamate
was hydrolyzed off and the amine was transformed into the nitro group by oxidation in the open
air. 3f could be also obtained in a larger scale by reacting 3b or 3e (its conjugated acid) with n-
Bu4NOH.
Description of structures.
Compound 2b. The asymmetric unit of 2b consists of diprotonated 4-(4-aminophenyl)-1H-
pyrazole molecules (the aniline and pyrazol free nitrogen atoms being protonated) and the
triclorostannate(II) and chloride anions in a 1:1 molar ratio balancing the positive charges (Fig.
1). One water molecule of crystallization is also present. Both N–C and N–N bonds on the
pyrazolium group are very similar. Thus, no substantial localization of double bonds is observed,
as one can see in Table 2. This fact together with the NMR spectrum corroborate that it is an
aromatic group. Some steric hindrance may be found around C7–H7···H5–C5 and C9–H9···H3–
C3 type interactions, since a torsion angle of 2.8(5)º is observed. Due to the large C8–C4 bond
length [1.512(1) Å], one can conclude that the aromatic systems are not conjugated and further
larger torsion angles can be observed in compounds derived from 2b, since it has very strong
single bond character. Additionally, the protonated aniline nitrogen atom to phenyl ring bond
length [N1–C1 = 1.473(1) Å] is considerably larger than the predicted value for the aromatic
atoms [c.a. 1.39 Å], as a result of its loss of conjugation because of the protonation. Dealing with
the anionic tin(II) unit, the metal atom exhibits a pyramidal geometry being surrounded by three
chloride ligands with Sn-Cl bond lengths and Cl–Sn–Cl bon angles covering the ranges 2.532(3)-
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2.555(4) Å and 88.0(1)-91.5(1)º, respectively. Main geometric parameters for the pyrazolium
group and the [SnCl3]– entity are listed in Table 2.
Figure 1. Asymmetric unit of 2b with the atom numbering. The hydrogen atoms (black circles)
were not labeled for the sake of clarity. Thermal ellipsoids are drawn at the 50% of probability
level.
Table 2. Selected structural data for the triclorostannate(II) complex anion and the pyrazolium
group of 2b
[SnCl3]–
Pyrazolium group
Cl–Sn–Cl / º
Bond lengths / Å
Angle / º
Bond lengths / Å
Sn1–Cl3
2.532 (3)
2.554 (3)
2.555 (4)
Cl3–Sn1–Cl2
88.05 (11)
91.53 (14)
89.64 (13)
N2–N3
1.322 (15)
1.333 (15)
1.409 (16)
1.399 (18)
1.336 (17)
C7–N2–N3
C8–C7–N2
C9–C8–C7
N3–C9–C8
N2–N3–C9
108.3 (9)
Sn1–Cl2
Sn1–Cl4
Cl3–Sn1–Cl4
Cl2–Sn1–Cl4
N2–C7
C7–C8
C8–C9
C9–N3
108.1 (10)
105.2 (10)
106.8 (11)
111.6 (10)
The packing of 2b is mainly ruled by hydrogen bonds (Table 3). The most remarkable
supramolecular structure for this compound is constituted by the free chloride anion and the
organic cation. Each chloride anion interacts with a pyrazolium (N3i) and one anilinium (N1)
nitrogen atoms with a N3i…Cl1…N1 angle of 106.9(3)º, leading to a supramolecular chain that is
extended by translation of the motifs N1∙∙∙Cl1i = 3.242(9) Å and N3∙∙∙Cl1i = 3.184(9) Å [symmetry
code: (i) = x, y, –1+z and (ii) = x, –1+y, z]. This trend is near to inversion center resulting in a
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double chain, with a ladder-like conformation, connected by hydrogen bond between the
anilinium group and a nearest chloride anion in an apical position, as pictured in Figure 2
[N1∙∙∙Cl1iii = 3.206(9) Å; symmetry code: (iii) = 1–x, 2–y, –z].
Figure 2. Ladder-like supramolecular chain of 2b trough N-H∙∙∙Cl hydrogen bonds. All hydrogen
atoms, except those bonded to nitrogen atoms, crystallization water molecule and [SnCl3]– units
were omitted for clarity.
Hydrogen bonds also occur involving the other pyrazolium protonated nitrogen atom
(N2), the water molecule (O1) and trichlorostannate(II) anion (via Cl2, Cl3 and Cl4 atoms). These
groups are responsible for the interconnection of the double chains in the crystallographic bc plane
trough the pyrazolium-water hydrogen bond [N2–H2···O1iv; (iv) = x, y–1, z], followed by the
water–[SnCl3]– interaction [O1–HW2···Cl3] and by the [SnCl3]––anilinium contact [N3–
H3···Cl4] from the subsequent set of chains (see Table 3 and Figures S42 and S43). Finally, the
supramolecular chains are packed along the crystallographic a axis by π–π stacking between the
pyrazolium and phenyl rings, the values of their geometric center separation being 3.67(1) Å
within each double ladder-like chain and 3.97(1) Å between adjacent double chains.
Table 3. Hydrogen bond parameters of 2b*
D–H···A
D–H / Å H···A / Å D···A / Å D–H···A / º
N1–H1B···Cl1i
N1–H1C···Cl1ii
N1–H1A···Cl4iii
0.89
0.89
0.89
2.37
2.38
2.94
3.244 (10)
3.205 (11)
3.231 (10)
166
154
100
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N2–H2···O1iv
N3–H3···Cl4
0.86
0.86
0.86
0.90
0.90
1.84
2.71
2.52
2.57
2.42
2.674 (12)
3.305 (11)
3.189 (10)
3.220 (7)
3.276 (6)
164
128
136
130
160
N3–H3···Cl1iv
O1–HW2···Cl3
O1–HW1···Cl2
*Symmetry codes: (i) = x, y, z–1; (ii) = –x+1, –y+2, -z; (iii) = x, y+1, z-1; iv = x, y–1, z.
Compound 3b. The isoxazole derivative 3b is a salt made up by two 4-(isoxazol-4-yl)anilinium
cations and one hexachlorostannate(IV) anion (Figure 3). It crystallizes in the centrosymmetric
퐶푚푐푒
orthorhombic
space group. Due to the planarity of the cationic organic moiety all its non-
hydrogen atoms are placed over a mirror symmetry element, meanwile the tin atoms occupy the
inversion center positions.
Figure 3. View of asymmetric unit of 3b with the atom numbering. The symmetry operation over
the tin atom was applied to visualize the whole hexachlorostannate(IV) anion in order to get a
better understanding of the structure. The hydrogen atoms (black circles) were not labeled for the
sake of clarity. Thermal ellipsoids are drawn at the 50% of probability level [Symmetry code: (i)
= −x, y, z; (ii) = x, −y, 1−z; (iii) = −x, −y, 1−z]
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The isoxazole group in 3b revealed to be an aromatic system, as confirmed by H NMR
DOI: 10.1039/C9CE00215D
and 13C chemical shifts but differently of 2b, there is a major localization of the double bonds in
3b. The C–O bond length is 1.333(11) Å against 1.297(14) Å for the C–N bond. This difference
is also observed in the C–C bond distances [1.351(14) and 1.408(12) Å for C7–C8 and C8–C9,
respectively]. The organic moiety of this compound is monoprotonated, the aniline part being the
only one to be protonated under our synthetic conditions (pKa of anilinium is 4.7 whereas that of
the isoxazolium is –2.3).54 Just as found in 2b, steric hindrance [C7–H7···H5–C5 and C9–
H9···H3–C3] combined with the high single bond characteristics of the inter-ring link [C4–C8 =
1.469(11) Å] conclude in a torsion angle of aromatic rings of 7(2)º. Somewhat the major
localization of the double bonds in 3b cause the aromatic rings to be more conjugated, since the
C4–C8 bond in this case is shorter than in 2b. The metal center in the hexachlorostannate(IV)
complex anion is in an almost perfect octahedral geometry, as expected for a cation with the
[Xe]5d0 electronic configuration. The Sn–Cl bond lengths and the Cl–Sn–Cl angles cover the
ranges 2.424(1) [Sn1–Cl2] to 2.431(1) Å [Sn1–Cl2] and 89.15(7)-90.85(7)º respectively (see
Table 4 for more details about these parameters).
Table 4. Main structural parameters of the hexachlorostanate(IV) anion and and isoxazole group
in 3b*
[SnCl6]2–
Isoxazole group
Bond lengths / Å Angles / º
Cl–Sn–Cl / º
Bond lengths / Å
Sn1–Cl1
Sn1–Cl2
2.431 (1)
2.424 (1)
Cl1–Sn1–Cl1i
Cl1–Sn1–Cl2
180
N2–O1
N2–C9
O1–C7
C7–C8
C8–C9
1.389 (16)
1.27 (2)
C9–N2–O1
104.7 (11)
90.33 (5)
C7–O1–N2
N2–C9–C8
108.6 (10)
114.1 (13)
Cl1–Sn1–Cl2i
Cl1–Sn1–Cl2ii
Cl1–Sn1–Cl2iii
Cl2–Sn1–Cl2i
Cl2–Sn1–Cl2ii
90.33 (5)
89.67 (5)
1.330 (17)
1.345 (19)
1.412 (18)
C7–C8–C9
O1–C7–C8
101.7 (12)
110.9 (12)
89.67 (5)
90.85 (7)
89.15 (7)
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Cl2–Sn1–Cl2iii
180
*Symmetry codes: (i) = −x, y, z; (ii) = x, −y, 1−z; (iii) = −x, −y, 1−z.
Once more, the crystal packing is dictated by the hydrogen bonds and C–H···O type
interactions. A self-recognition of the cations is observed along the crystallographic b axis. In
these molecules, the isoxazole nitrogen atom is recognized by the anilinium group [N1···N2iv =
2.894(10) Å; (iv) = −x, –1/2+y, 1/2–z]. It repeats indefinably leading to a supramolecular chain
(Figure 4). The isoxazole oxygen atom weakly interacts with one phenyl C–H group [C2···O1iv
= 3.307(10) Å]. The other two anilinium hydrogen atoms also establish weak interactions with
two different [SnCl6]– groups, one above and other below the main plane of this cation,
interconnecting the chains (see Table 5 and Figures S44 and S45). The chains are also packed
down the crystallographic c axis via isoxazole π–π stacking [a separation of 3.57(1) Å between
the centroids of the rings being observed through this interaction].
Figure 4. Supramolecular zigzag chain in 3b with cation-cation anilinium-isoxazol self-
reorganization trough N–H···N hydrogen bonds and C–H···O type interactions (dotted lines).
Atomic color scheme follows that in Figure 3.
Table 5. Intermolecular interactions of 3b*
D–H···A
D–H / Å
0.89
H···A / Å
2.50
D···A / Å
2.894 (10)
D–H···A / º
108
N1—H1B···N2iv
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C2—H2···O1iv
N1—H1C···Cl1v
N1—H1C···Cl2v
N1—H1A···Cl2vi
N1—H1B···Cl2vii
N1—H1B···Cl1vii
N1—H1A···Cl2viii
0.93
0.89
0.89
0.89
0.89
0.89
0.89
2.43
3.307 (10)
3.5445 (2)
3.424 (6)
3.465 (6)
3.424 (6)
3.5445 (2)
3.465 (6)
156
133
123
139
123
133
139
2.88
2.86
2.75
2.86
2.88
2.75
* Symmetry codes: (iv) = –x, –1/2+y, 1/2–z; (v) = 1/2+x, –1/2–y, 1–z; (vi) = 1/2+x, –1/2+y, z;
(vii) = –1/2–x, –1/2–y, 1–z; (viii) = –1/2–x, –1/2+y, z.
Compound 2e. The asymmetric unit of the organic salt 2e is constituted by four
independent anionic oxamic derivatives 4-(1H-pyrazol-4-yl)phenyl-N-oxamate), four tetra-n-
butylamonium cations and two water molecules of crystallization (Figure 5). Although all anions
are chemically identical, the torsion angle of the aromatic rings in the solid state vary together
with the angle of the terminal methyl group of the cations (Figure S46). The pyrazole groups in
2e are deprotonated in contrast with 2b. However, they remain very symmetrical looking at the
C–N bonds, revealing that the asymmetrical presence of the hydrogen atom is not a fundamental
factor to interfere on the aromaticity, and consequently, on the bond lengths. Details of the
geometry of the pyrazole groups and the deviation of the planarity of the rings and the oxamate
planes are shown in Table 6.
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Figure 5. Asymmetric unit of 2e with the atom numbering. The terminal –(CH2)2CH3 and
hydrogen atoms of n-Bu4N cations were omitted for clarity. All remaining carbon atoms (blue
ellipsoids) and hydrogen atoms (black circles) were not labeled. Thermal ellipsoids are drawn at
the 50% of probability level.
The result of this large asymmetric unit is a crystal packing formed by layers of
hydrophobic and hydrophilic interactions very well separated and packed along the
crystallographic c axis (Figure S47). Each hydrophobic layer contains only tetra-n-
butylammonium cations whereas the 4-(1H-pyrazole-4-yl)phenylene-N-oxamate anions and the
crystallization water molecules constitute each hydrophilic layer. The hydrogen bonds are the
main interaction observed within the hydrophilic layer, forming a 2D network as shown in Figure
6. There are three different interaction motifs (black dotted lines in Figure 6): (i) the protonated
pyrazole-nitrogen atom that recognizes the carboxylate part of the oxamate group in the first one;
(ii) the second one concerns the double oxamate amide-to-carboxylate supramolecular dimer; (iii)
and the water molecule that connects the deprotonated pyrazole-nitrogen atom and the
carboxylate groups in the third one. Finally, other very weak C-H…O and C-H…N type interactions
may be pointed out, where aromatic hydrogen atoms are very close to hydrogen bond acceptors.
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In this respect, a dimeric interaction concerning the pyrazole groups where the carbon bonded to
the deprotonated nitrogen atom approaches significantly to the nearest pyrazole nitrogen atom
occurs (golden dotted lines in Figure 6). Also, one of the phenyl hydrogen atoms is very close to
the carboxylate oxygen atom involved in the double oxamate interaction (see the green dotted
lines in Figure 6). This interaction may be responsible for the deviations of the torsion angles,
since it is not observed in all crystallographically independent anions. The supramolecular
interactions in 2e are displayed in Figure 6 and the list of the hydrogen bonds in this compound
is given in Table 7.
Figure 6. View of a fragment of the supramolecular 2D hydrogen network (black dot lines) in 3e
featuring the pyrazole-oxamate and oxamate-oxamate self-reorganization of the anion motifs,
mediated by crystallization water molecule. Additional very weak interactions involving aromatic
carbon atoms as hydrogen donors are displayed interacting with oxygen (lime green dot lines)
and non-protonated pyrazole nitrogen atoms (golden dot lines).
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Table 6. Bond lengths in the pyrazole rings and their torsion angles in relation to the phenyl and
oxamate mean planes for each crystallographically independent HPyox– anion in 2e
Ring A£
Ring B£
Ring C£
Ring D£
Bond Lengths / Å
N2–N3
1.346(3)
N5–N6
1.345(3)
N8–N9
1.353(3)
N11–N12
1.345(3)
1.342(3)
1.371(4)
1.405(4)
1.325(3)
C9–N2
1.327(4)
1.378(4)
1.396(4)
1.326(4)
C20–N5
C20–C21
C21–C22
C22–N6
1.335(3)
1.370(4)
1.400(4)
1.326(3)
C31–N8
C31–C32
C32–C33
C33–N9
1.334(3)
1.371(4)
1.409(4)
1.329(3)
C42–N11
C42–C43
C43–C44
C44–N12
C9–C10
C10–C11
C11–N3
Torsion angle in relation to the phenyl ring
28.5(7)º
1.3(5)º
17.6(7)º
14.2(6)º
24.2(5)º
12.6(3)º
Torsion angle in relation to the oxamate mean plane
5.0(5)º
9.7(4)º
£The ring label is according to the concerned nitrogen atoms: A, B, C and D rings contain the
N2/N3, N5/N6, N8/N9 and N11/N12 pairs, respectively.
Table 7. Summary of the hydrogen bonds in 2e*
D—H···A
D—H
0.93
0.92
1.02
0.97
0.88
0.88
0.88
0.88
0.88
0.88
0.88
0.88
0.88
0.88
0.88
H···A
2.01
2.01
2.03
1.97
1.91
2.48
2.05
1.88
2.11
1.88
2.47
2.27
2.16
1.89
1.89
D···A
D—H···A
160
O14—H14A···N12i
O14—H14B···O8ii
O13—H13B···N9
O13—H13A···O10iii
N8—H8A···O10iii
N8—H8A···O12iii
N1—H1···O5iv
2.900 (3)
2.890 (3)
3.028 (3)
2.815 (3)
2.776 (3)
2.990 (3)
2.881 (3)
2.755 (3)
2.923 (3)
2.745 (3)
2.978 (3)
3.080 (3)
2.982 (3)
2.755 (3)
2.755 (3)
158
164
144
167
117
157
N2—H2···O4v
173
N4—H4A···O1vi
N5—H5A···O2vii
N5—H5A···O3vii
N7—H7A···O7ii
N10—H10···O11viii
N11—H11A···O8viii
N11—H11A···O8viii
152
166
117
152
156
166
166
*Symmetry code: (i) = x+1, y–1, z; (ii) = –x+1, –y, –z; (iii) = –x+1, –y+1, -z; (iv) = –x+1, y+1/2,
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–z+1/2; (v) = x, y+1, z; (vi) = –x+1, y–1/2, –z+1/2; (vii) = x–1, y–1, z; (viii) = –x, –y+1, –z.
Compound 3d. The oxamate derivative of the isoxazole based molecule 4-(1,2-oxazol-
4-yl)phenylene-N-(ethyloxamate) crystallizes in the centrosymmetric monoclinic P21/c space
group. It is a neutral unit with no solvent molecules of crystallization. This compound is built up
by an isozaxole group linked to a phenyl ring which has an oxamate fragment in its para position,
as displayed in Figure 7. Intriguingly, the isoxazole ring in 3d has highly delocalized double
bonds with very close values of the C9–N2 and C7–O1 bonds [1.302(3) and 1.339(3) Å,
respectively], as well as the carbon-carbon bonds with less discrepancy than that observed in the
related compound 3b. Although 3d seems to have the most conjugated rings of all azol
compounds herein, the combination of the aromatic hydrogen steric hindrance [C7–H7···H5–C5
and C9–H9···H3–C3] and van der Waals forces combined lead this compound to have the greatest
torsion angle between the aromatic mean planes [11.1(5)º]. The torsion angle between the
isoxazole ring and the oxamate mean plane [calculated for the N1O2O3O4C10C11 set of atoms]
is equal to 4.7(5)º, and the dihedral angle between the oxamate and phenyl ring is 10.4(5)º.
Figure 7. Asymmetric unit of 3d with the atom numbering. The hydrogen atoms (black circles)
were not labeled for clarity. Thermal ellipsoids are drawn at the 50% probability level.
Hydrogen bonds are occur in the crystal packing of 3d (see Figure 8). The absence of
charges in this compound changes de molecular recognition drastically compared to what was
observed in 2e. The only hydrogen bond donor in 3d (the amide-oxamate group), recognizes the
isoxazole nitrogen atom [N1···N2i = 3.067(3) Å; (i) = x–1, –y+1/2, z–1/2]. This hydrogen bond
net grows along the crystallographic a axis leading to a supramolecular chain. Additional very
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weak C-H O type interactions can be found in this crystal packing involving the aromatic
hydrogen atoms interacting with the carbonyl oxygen atoms [C5–H5···O3ii and C7–H7···O3ii;
(ii) = x+1, –y+1/2, z+1/2] and the isoxazole one [C2–H2···O1i] (lime and orange dotted lines in
Figure 8). They connect the supramolecular chains allowing the growth of the crystal into two
directions. Finally, van der Waals contacts are found dealing with the ester aliphatic part and
phenyl rings, both parallel and perpendicular to the crystallographic ab plane resulting in a 3D
supramolecular network and crystal formation. A summary of the interactions in 3d is shown in
Table 8.
Figure 8. View of a fragment of the supramolecular 2D network in 3d featuring the N–H···N
oxamate-isoxazole self-reorganization of the motifs. Additional very weak C–H···N and C–H···N
type interactions involving aromatic C–H donors interacting with carbonyl groups (lime green
dot lines) and isoxazol oxygen atoms (orange dotted lines) are also displayed. Interactions
between the methyl and aromatic C–H groups are featured as purple dotted lines.
Table 8. Supramolecular interactions in 3d*
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D—H···A
D—H
0.86
0.93
0.93
0.93
0.93
0.93
H···A
2.23
2.63
2.46
2.53
2.39
3.04
D···A
D—H···A
N1—H1···N2i
C2—H2···O1i
C5—H5···O3ii
C7—H7···O3ii
C9—H9···O2iii
C3—H3···C13iv
3.067 (3)
3.506 (3)
3.379(2)
3.085 (3)
3.299 (3)
3.830 (3)
165
158
168
119
167
144
*Symmetry code: (i) = x–1, –y+1/2, z–1/2; (ii) = x+1, –y+1/2, z+1/2; (iii) = –x+3, –y+1, –z+1;
(iv) = –x+2, y–1/2, –z+1/2.
Compound 3f. This compound is the result of the cleavage of the isoxazole derivative in
basic media, the tetra-n-butylammonium cation balancing its negative charge. It crystallizes in
the centrosymmetric monoclinic P21/n space group and the anion is a para disubstituted
nitrobenzene with a carbon atom (C8) bonded to a formyl and a nitrile groups (See Figure 9).
Although the negative charge of the organic anion is mainly located on this C8 atom, it is
somewhat delocalized on the adjacent C4, C7 and C9 carbon atoms. In this respect, whereas the
bond lengths C7–O3 = 1.223(2) Å and C9–N2 = 1.150(2) Å for formyl and nitrile groups, compare
well those of the sp3 carbon in acetaldehyde (c.a. 1.22 Å)56-58 and acetonitrile (1.17 Å)59-61
supporting the no conjugation, the values of the carbon-carbon bonds indicate the opposite, being
shorter than in the model molecules [C7–C8 = 1.412(2) Å, C8–C9 = 1.413(2) Å and C8–C4 =
1.441(2) Å, in comparison with acetaldehyde,55-57 acetonitrile58-60 and toluene58-60 where the bond
lengths are 1.50, 1.46 and 1.55 Å, respectively]. Additionally, the X-ray powder diffraction
patterns proves the bulk material to have the same structure than that of the single crystals,
meanwhile NMR spectra suggests mixture of different contents, which may be due to resonance
structures with enough large lifetimes to be detected separately. The crystal packing is dictated
by van der Waals interactions and the ions form segregated layers of cations and anions along the
crystallographic c axis (see Figure 10).
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