molecules
Article

Synthesis, X-ray Characterization and Density
Functional Theory (DFT) Studies of Two Polymorphs
of the α,α,α,α, Isomer of Tetra-p-Iodophenyl
Tetramethyl Calix[4]pyrrole: On the Importance of
Halogen Bonds
Dragos Dăbuleanu 1,2 , Antonio Bauzá 3 , Joaquín Ortega-Castro 3 ,
,
Eduardo C. Escudero-Adán 1 , Pablo Ballester 1,4, * and Antonio Frontera 3, *
1

2
3
4

*

Institute of Chemical Research of Catalonia (ICIQ), The Barcelona Institute of Science and Technology (BIST),
Avinguda Països Catalans, 16, 43007 Tarragona, Spain; ddabuleanu@iciq.es (D.D.);
eescudero@iciq.es (E.C.E.-A.)
Departament de Química Analítica i Química Orgànica, Universitat Rovira i Virgili,
carrer Marcel•li Domingo, 1, 43007 Tarragona, Spain
Departament de Química, Universitat de les Illes Balears, Crta. de Valldemossa km 7.5,
07122 Palma de Mallorca (Baleares), Spain; antonio.bauza@uib.es (A.B.); joaquin.castro@uib.es (J.O.-C.)
Catalan Institution of Research and Advanced Studies (ICREA), Passeig Lluís Companys, 23,
08018 Barcelona, Spain
Correspondence: pballester@iciq.es (P.B.); toni.frontera@uib.es (A.F.)

Received: 16 December 2019; Accepted: 8 January 2020; Published: 10 January 2020

Abstract: This manuscript reports the improved synthesis of the α,α,α,α isomer of tetra-p-iodophenyl
tetra-methyl calix[4]pyrrole and the X-ray characterization of two solvate polymorphs. In the solid
state, the calix[4]pyrrole receptor adopts the cone conformation, including one acetonitrile molecule
in its aromatic cavity by establishing four convergent hydrogen bonds between its nitrogen atom
and the four pyrrole NHs of the former. The inclusion complexes pack into rods, displaying a
unidirectional orientation. In turn, the rods form flat 2D-layers by alternating the orientation of
their p-iodo substituents. The 2D layers stack on top of another, resulting in a head-to-head and
tail-to-tail orientation of the complexes or their exclusive arrangement in a head-to-tail geometry.
The dissimilar stacking of the layers yields two solvate polymorphs that are simultaneously present
in the structures of the single crystals. The ratio of the two polymorph phases is regulated by the
amount of acetonitrile added to the chloroform solutions from which the crystals grow. Halogen
bonding interactions are highly relevant in the crystal lattices of the two polymorphs. We analyzed
and characterized these interactions by means of density functional theory (DFT) calculations and
several computational tools. Remarkably, single crystals of a solvate containing two acetonitrile
molecules per calix[4]pyrrole were obtained from pure acetonitrile solution.
Keywords: polymorphs; halogen bonds; supramolecular chemistry; lattice energies; Density
Functional Theory (DFT) calculations

1. Introduction
Calix[4]pyrroles are well-known receptors for the binding of a variety of guests ranging from
neutral Lewis bases to different anions and ion pairs [1–3]. In fact, calix[4]pyrroles were used as chloride
transporters in liposomal models and cells [4]. Ballester’s group utilized “two-wall” α,α-aryl-extended
and “four-wall” α,α,α,α-aryl-extended calix[4]pyrroles for the study and evaluation of anion-π
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interactions [5] and as synthetic anion transporters demonstrating that the “four-wall” calix[4]pyrroles
are better carriers than the “two-wall” counterparts [6].
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Polymorphism studies of calix[4]pyrrole compounds are scarce in the literature.
Lynch et al. interactions monoclinicsynthetictemperature) and triclinic (low-temperature) phases of
anion-π reported [5] and as (room anion transporters demonstrating that the “four-wall”
meso-octa-methylcalix[4]pyrrole complexed to dimethyl sulfoxide [7]. Moreover, Panda’s group
calix[4]pyrroles are better carriers than the “two-wall” counterparts [6].
Polymorphism studies of calix[4]pyrrole compounds are scarce calix[4]pyrrole Lynch et al.
reported two polymorphic forms of the trans isomer of meso-diacylated in the literature.[8]. More recently,
reported monoclinic (room temperature) and ion-pair receptors based phases of meso-octaSessler’s group reported two polymorphic forms oftriclinic (low-temperature)on hemispherand-strapped
methylcalix[4]pyrrole complexed to dimethyl sulfoxide [7]. Moreover, Panda’s group reported two
calix[4]pyrrole derivatives [9].
polymorphic forms (XB) trans isomer of meso-diacylated noncovalent interaction that Sessler’s
Halogen bonding of theis currently a well-establishedcalix[4]pyrrole [8]. More recently,is similar to a
group reported two polymorphic forms of ion-pair receptors based on hemispherand-strapped
hydrogen bond (HB). However, a relevant difference is the higher directionality of XB that stems from
calix[4]pyrrole derivatives [9].
the σ-hole (small area of positive potential) of the halogen being surrounded by a belt of high electron
Halogen bonding (XB) is currently a well-established noncovalent interaction that is similar to a
density [10]. Therefore, a However, a relevant difference is the higheratom or groups of atoms opposite
hydrogen bond (HB). linear approximation of the electron rich directionality of XB that stems
to the C–X bond is required. Halogen bonding has beenhalogen being surrounded by a belt of high
from the σ-hole (small area of positive potential) of the successfully used in supramolecular crystal
engineering [11], conducting and magnetic materials [12,13] and catalysisatom or groups of atoms
electron density [10]. Therefore, a linear approximation of the electron rich [14].
opposite to report the is required. synthesis of the tetra-α isomer of a calix[4]pyrrole bearing
Herein wethe C–X bond improved Halogen bonding has been successfully used in supramolecular
crystal engineering [11], conducting and each four of its [12,13] and catalysis Scheme 1a). We also
p-iodophenyl and methyl substituents inmagnetic materials meso-carbons (see [14].
describedHerein we report single crystals of the compound from CHCl3a calix[4]pyrrole bearing pthe isolation of the improved synthesis of the tetra-α isomer of :acetonitrile solvent mixtures.
iodophenyl and of the crystals revealed thefour of its meso-carbons (seetwo solvate polymorphic
The X-ray structure methyl substituents in each simultaneous presence of Scheme 1a). We also
described the isolation of single crystals of the compound from CHCl3:acetonitrile solvent mixtures.
phases. Both phases crystallize in the triclinic P-1 symmetry group. However, they provide a
The X-ray structure of the crystals revealed the simultaneous presence of two solvate polymorphic
significantly different structural arrangement of the receptor in the crystals. The importance of Type I
phases. Both phases crystallize in the triclinic P-1 symmetry group. However, they provide a
(see Scheme 1b) halogen···halogenarrangement of the receptor iniodide atoms inimportance of Type of
significantly different structural interactions involving the the crystals. The the crystal packing
one of (see Scheme 1b) halogen···halogen interactions involving the iodide atoms in the crystal packing of
I the polymorphs is studied and rationalized using density functional theory (DFT) calculations,
molecular electrostatic potential (MEP) surfaces and noncovalent interaction plot index (NCIPLOT)
one of the polymorphs is studied and rationalized using density functional theory (DFT) calculations,
molecular tools. The single (MEP) surfaces and noncovalent interaction plot index of the receptor
computationalelectrostatic potentialcrystals that grew from pure acetonitrile solution (NCIPLOT)
computational tools. incorporation of that grew from molecules in their structure.
featured the unexpected The single crystalstwo acetonitrile pure acetonitrile solution of the receptor
featured the unexpected incorporation of two acetonitrile molecules in their structure.

Scheme 1. (a) Chemical structure of the α,α,α,α-isomer of tetra-p-iodophenyl tetramethyl calix[4]pyrrole.
Scheme 1. (a) Chemical structure of the α,α,α,α-isomer of tetra-p-iodophenyl tetramethyl
(b) Schematic representation of Type I and Typeof Type I and Type II halogen bonding “like–like” red
calix[4]pyrrole. (b) Schematic representation II halogen bonding “like–like” interactions in the
negative, the blue positive and thethe blueneutral regions of electron density. of electron density.
interactions in the red negative, green positive and the green neutral regions

2. Results andand Discussion
2. Results Discussion
2.1. Synthesis
2.1. Synthesis
A few years ago, we reported the synthesis of the α,α,α,α isomer of tetra-p-iodopheny tetraA few years ago, we reported the synthesis of the α,α,α,α isomer of tetra-p-iodopheny tetra-methyl
methyl calix[4]pyrrole in an overall yield of 16% [15]. Owing to the versatile and easy synthetic
calix[4]pyrrole in an overall yield of 16% [15]. Owing to the versatile and easy synthetic transformation
transformation of this molecular scaffold into a extended calix[4]pyrrole derivatives [16,17],
of this molecular scaffold into a variety of super-arylvariety of super-aryl extended calix[4]pyrrole we
derivatives [16,17], we sought to optimize its preparation in a multigram optimization procedures,
sought to optimize its preparation in a multigram scale. After numerous scale. After numerous
optimization procedures, we describe herein its synthesis in batches of more than 4 g, using high
we describe herein its synthesis in batches of more than 4 g, using high dilution conditions for
dilution conditions for the acid catalyzed condensation of the 4′-iodoacetophenone and pyrrole. We
the acid catalyzed condensation of the 4 -iodoacetophenone and pyrrole. We placed 500 mL of a
placed 500 mL of a dichloromethane (DCM) solution (0.08 M) of 4′-iodoacetophenone (10 g, 40.6
dichloromethane (DCM) solution (0.08 M) Next,-iodoacetophenone (10 g, 40.6 (36%, 40.6 mmol)
mmol) in a 1000-mL round bottom flask. of 4 5 mL of aqueous chloridric acid mmol) in a 1000-mL

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round bottom flask. Next, 5 mL of aqueous chloridric acid (36%, 40.6 mmol) were added dropwise to
the above solution. With the assistance of an automatic injector pump syringe, we added a solution of
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100 mL of dichloromethane containing 2.82 mL of pyrrole (40.6 mmol) to the above reaction mixture
over werecourse of 24 h. Thethe above flask was protected from light using aluminum foil and the
the added dropwise to reaction solution. With the assistance of an automatic injector pump
syringe, we added a solution of for 48 of dichloromethane containing 2.82 mL of pyrrole (40.6 mmol)
reaction mixture was left stirring 100 mL h at room temperature. A solid precipitate appeared during
to the above solid was filtered and washed with 300 mL of methanol. The filtered and washing
the reaction. Thereaction mixture over the course of 24 h. The reaction flask was protected from light
using aluminum foil and the reaction mixture was left reduced pressure to afford a brown solid
organic layers were combined and concentrated under stirring for 48 h at room temperature. Asolid. The
precipitate was obtained the brownish solid was filtered and washed with 300 mL of methanol.
α,α,α,α isomerappeared duringas areaction. Thesolid (4.55 g, 36%) after silica column chromatography
The filtered and washing organic layers were combined and concentrated under reduced pressure to
purification of the reaction crude using a 40:60 mixture of DCM:hexanes as the mobile phase.
afford a brown solid. The α,α,α,α isomer was obtained as a brownish solid (4.55 g, 36%) after silica
Analytical samples of the α,α,α,α, tetra-p-iodophenyl tetramethyl calix[4]pyrrole were obtained
column chromatography purification of the reaction crude using a 40:60 mixture of DCM:hexanes as
by crystallization from solvent mixture containing CHCl3 and acetonitrile in different proportions. The
the mobile phase.
single crystals that samples of the α,α,α,α, tetra-p-iodophenyl tetramethyl calix[4]pyrrole were obtained the
Analytical grew from the solutions were analyzed by X-ray diffraction. The solution of
diffracted data revealed the presence of the compound as3 two solvate polymorphic phases including
by crystallization from solvent mixture containing CHCl and acetonitrile in different proportions.
only The single crystals molecule.from the solutions were analyzed by X-ray diffraction. The solution of
one acetonitrile that grew Remarkably, the crystals obtained from pure acetonitrile solution
the diffracted data revealed the presence of the compound as two solvate polymorphic phases
displayed the incorporation of two acetonitrile molecules in the packing of the lattice.
including only one acetonitrile molecule. Remarkably, the crystals obtained from pure acetonitrile
solution displayed the incorporation in the Single Crystals
2.2. Structural Description of the Packingof two acetonitrile molecules in the packing of the lattice.

Figure 1 depicts the asymmetric units of the crystal structures of the solvates of polymorph A
2.2. Structural Description of the Packing in the Single Crystals
(left panel) and polymorph B (right panel). Both polymorphs crystalize in the triclinic P ¯ symmetry
ı
Figure 1 depicts the asymmetric units of the crystal structures of the solvates of polymorph A
group. In both cases, the calix[4]pyrrole adopts the cone conformation and includes one acetonitrile
(left panel) and polymorph B (right panel). Both polymorphs crystalize in the triclinic P ī symmetry
molecule inIn both cases, the calix[4]pyrrole the establishment of four H-bonds with the pyrrole rings.
group. its aromatic cavity through adopts the cone conformation and includes one acetonitrile
The average CH3 CN···N(pyrrole) distancesestablishmentidentical in both polymorphs rings. The in A
molecule in its aromatic cavity through the are almost of four H-bonds with the pyrrole (3.209 Å
and 3.205 Å CHB). Nevertheless, there is a almost identical in both polymorphs (3.209 Å in A and of
average in 3CN···N(pyrrole) distances are subtle difference in the size of the aromatic cavities
3.205 Å in B). Nevertheless, in the a subtle difference The size of the aromatic cavities of the tetrathe tetra-iodo calix[4]pyrroles there is two polymorphs.in the zenithal view of the inclusion complexes
iodo bottom) includes the I···I distances measured view of the inclusion In short, the inclusion
(Figure 1,calix[4]pyrroles in the two polymorphs. The zenithalfor the polymorphs.complexes (Figure 1,
bottom) includes the I···I distances measured for the polymorphs. In short, the and two slightly longer
complex in polymorph A has two I···I distances slightly shorter (horizontal) inclusion complex in
polymorph A has polymorph B. Most likely, these small geometric differences are consequence
(vertical) than those intwo I···I distances slightly shorter (horizontal) and two slightly longera(vertical)
than those in polymorph B. Most likely, these small geometric differences are a consequence of the
of the dissimilar packing of the crystal lattice (vide infra).
dissimilar packing of the crystal lattice (vide infra).

Figure 1. Perspective (top) and zenithal (bottom) views of the X-ray asymmetric units of polymorphs
Figure 1. Perspective (top) and zenithal (bottom) views of the X-ray asymmetric units of polymorphs
A (a) A (a)B (b). Distances in Å. Thermal ellipsoids forfor N and I atoms setset 50% probability; HH
and and B (b). Distances in Å. Thermal ellipsoids C, C, N and I atoms at at 50% probability; atoms
are shown as spheres of 0.20 Å diameter. The bound acetonitrile (ACN) molecule is shown as a
space-filling model.

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atoms are 285
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4
a space-filling model.

polymorphs, the
3
In both polymorphs, the CH3CN@calix[4]pyrrole inclusion complex packs side-by-side into rods
the p-iodo-substituents.
layers with
displaying an identical orientation of the p-iodo-substituents. In turn, the rods form 2D layers with
views of size-selected
alternating orientation of p-iodo substituents. Figure 2 displays side and top views of size-selected
packing (3 ×
the crystal lattices of the two polymorphs
packing (3 × 3 complexes) of the 2D layers present in the crystal lattices of the two polymorphs
highlighting their structural similarities.
highlighting their structural similarities.

Figure 2. Top and side views ofof restricted packing thethe latticespolymorphs A (a) and B (b).BThe rods
Figure 2. Top and side views restricted packing of of lattices in in polymorphs A (a) and (b). The
(columns) formed by CH3by CH3CN@calix[4]pyrrole inclusion complexes unidirectional orientation
rods (columns) formed CN@calix[4]pyrrole inclusion complexes display a display a unidirectional
of p-iodo substituents. In turn, the In turn, the rods pack in almost identical 2D layers with having an
orientation of p-iodo substituents. rods pack in almost identical 2D layers with having an alternating
orientation of inclusion complexes (antiparallel).(antiparallel). The calix[4]pyrrolesstick shown in stick
alternating orientation of inclusion complexes The calix[4]pyrroles are shown in are representation
and the included acetonitrile molecules as Corey-Pauling-Koltun (CPK) models. (CPK) models.
representation and the included acetonitrile molecules as Corey-Pauling-Koltun

The significant structural difference between the two polymorphs is found in the arrangement in
The significant structural difference between the two polymorphs is found in the arrangement
which the 2D layers of CH3 CN@calix[4]pyrrole inclusion complexes stack on top of another (Figure 3).
in which the 2D layers of CH3CN@calix[4]pyrrole inclusion complexes stack on top of another
In the case of polymorph A, the staking of the layers produces a columnar arrangement of inclusion
(Figure 3). In the case of polymorph A, the staking of the layers produces a columnar arrangement of
complexes exclusively featuring a head-to-tail orientation. On the other hand, in polymorph B, the stack
inclusion complexes exclusively featuring a head-to-tail orientation. On the other hand, in polymorph
of 2D layers results in alternative head-to-head and tail-to-tail arrangement of inclusion complexes.
B, the stack of 2D layers results in alternative head-to-head and tail-to-tail arrangement of inclusion
In short, where calix[4]pyrrole units are out-of-register in polymorph A, producing alternating columnar
complexes. In short, where calix[4]pyrrole units are out-of-register in polymorph A, producing
stacks of unidirectional oriented molecular units. They are in register in the packing of polymorph B,
alternating columnar stacks of unidirectional oriented molecular units. They are in register in the
yielding columnar stacks of dimeric capsules stabilized by four halogen-bonding interactions.
packing of polymorph B, yielding columnar stacks of dimeric capsules stabilized by four halogenbonding interactions.

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Figure 3. Cubes (3 × 3) of 2D layers stacks of CH3 CN@calix[4]pyrrole inclusion complexes forming the
Figure 3. Cubes (3 × 3) of 2D layers stacks of CH3CN@calix[4]pyrrole inclusion complexes forming
3D crystal lattices of polymorphs A (a) and B (b) viewed from two adjacent faces (90◦ rotation). The
the 3D crystal lattices of polymorphs A (a) and B (b) viewed from two adjacent faces (90° rotation).
calix[4]pyrroles are shown in stick representation and the included acetonitrile as CPK models. In the
The calix[4]pyrroles are shown in stick representation and the included acetonitrile as CPK models.
top panel, halogen-bonding interactions are denoted with dashed black lines.
In the top panel, halogen-bonding interactions are denoted with dashed black lines.

The head-to-tail or parallel orientation of inclusion complexes present in polymorph A leads to
The head-to-tail or parallel orientation of inclusion complexes present in polymorph A leads to
halogen bonds in which the acceptors unit (XB acceptor) is the electron-donor π-system of the pyrrole
halogen bonds in which the acceptors unit (XB acceptor) is the electron-donor π-system of the pyrrole
rings. In contrast, the p-iodine substituents of two CH3 CN@calix[4]pyrrole inclusion complexes located
rings. In contrast, the p-iodine substituents of two CH3CN@calix[4]pyrrole inclusion complexes
in head-to-head (antiparallel arrangement) present in polymorph B are involved in Type I, C–I···I–C
located in head-to-head (antiparallel arrangement) present in polymorph B are involved in Type I,
“like–like” halogen bonding interactions (See Scheme 1). The geometric and energetic details of both
C–I···I–C “like–like” halogen bonding interactions (See Scheme 1). The geometric and energetic
halogen-bonding interactions that are present in the two different dimeric aggregates mentioned above
details of both halogen-bonding interactions that are present in the two different dimeric aggregates
were further investigated using DFT calculations and the obtained results are described in detail in the
mentioned above were further investigated using DFT calculations and the obtained results are
next section.
described in detail in the next section.
Remarkably, the X-ray results showed that the two polymorphs were present simultaneously as
Remarkably, the X-ray results showed that the two polymorphs were present simultaneously as
different phases in single crystals. Moreover, the ratio of the two phases varied as a function of the
different phases in single crystals. Moreover, the ratio of the two phases varied as a function of the
content of acetonitrile in the solvent mixture used to grow crystals. Thus, at high concentrations of
content of acetonitrile in the solvent mixture used to grow crystals. Thus, at high concentrations of
chloroform, the single crystals contained polymorph A as the major component. Conversely, as the
chloroform, the single crystals contained polymorph A as the major component. Conversely, as the
composition of the solvent mixture increased in acetonitrile percentage, the obtained single crystals
composition of the solvent mixture increased in acetonitrile percentage, the obtained single crystals
largely displayed polymorph B. In short, the reduction in CHCl3 content in the solutions used to
largely displayed polymorph B. In short, the reduction in CHCl3 content in the solutions used to grow
grow the crystals favored the establishment of halogen bonding interactions between the iodine atoms
the crystals favored the establishment of halogen bonding interactions between the iodine atoms of
of the calix[4]pyrrole units in the solid-state. The ratios of the two polymorphic phases displayed
the calix[4]pyrrole units in the solid-state. The ratios of the two polymorphic phases displayed by the
by the crystals were quantified using single crystal X-ray diffraction data. Table 1 lists the accurate
crystals were quantified using single crystal X-ray diffraction data. Table 1 lists the accurate obtained
obtained values.
values.

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Finally, the complete removal of CHCl3 from the solution used to grow crystals of the
calix[4]pyrrole produced a new solvate, C, incorporating two acetonitrile molecules. In solvate C, the
tetraiodo-calix[4]pyrrole receptor also adopts the cone conformation by including one hydrogen-bonded
acetonitrile molecule in its aromatic cavity. Remarkably, the CH3 CN@calix[4]pyrrole inclusion complex
in the solid state of solvate C features two I···I distances (horizontal) that are quite similar, however
the other two (vertical) are significantly dissimilar (Figure 4a). In solvates A and B, the I···I distances
either in the horizontal or vertical pairs were almost identical. We assign these differences to the
packing effects of the lattice. Also, in contrast to solvates A and B, displaying only the included
acetonitrile molecule in the receptor’s scaffold, the asymmetric unit of solvate C reveals the presence of
an additional molecule of acetonitrile (Figure 4a,b colored in yellow). This second acetonitrile molecule
is bound in the shallow and electron-rich aromatic cavity defined by the four-pyrrole rings of the
CH3 CN@calix[4]pyrrole inclusion complex in cone conformation. This aromatic cavity possesses a
suitable size for the inclusion of the methyl group of the acetonitrile molecule and establishes multiple
CH-pi interactions between the methyl hydrogen atoms and the electron-rich pyrrole rings. The
CH3 CN@calix[4]pyrrole inclusion complex and its externally bound acetonitrile pack into rods having
the iodo-substituents oriented in the same directions. In addition, the externally bound acetonitrile
molecule is sandwiched between two twisted CH3 CN@calix[4]pyrrole inclusion complexes of an
adjacent rod. The packing of the unidirectional-oriented rods of solvated inclusion complexes form
extended layers (Figure 4c). The stack of two extended layers, stabilized mainly through side-to-side
C–H···π interaction of inclusion complexes, forms a dimeric layered block in which the tetra-iodo
substituents of the complexes are oriented in opposite direction in order to cancel their dipoles. Finally,
the dimeric-layered blocks stack on top of another also by alternating the orientation of their tetra-iodo
substituents, but with a slightly shifted side-by-side arrangement of inclusion complexes. This results
in the observation of stair-like 2D-layers of the CH3 CN@calix[4]pyrrole inclusion complexes when the
lattice is viewed from the b axis.

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Figure 4. Side (a) and top (b) views of of the X-ray asymmetric unitsolvate C. Distances in Å; in
Figure 4. Side (a) and top (b) views the X-ray asymmetric unit of of solvate C. Distances (c)
Å; (c) Restricted packingthe the layer formed by thepilling of rods of unidirectional-oriented
Restricted packing of of layer formed by the pilling of
of unidirectional-oriented
CH3 CN@calix[4]pyrrole inclusion complexes mediated by sandwiched ACN molecules; (d) 90◦
CH3CN@calix[4]pyrrole inclusion complexes mediated by sandwiched ACN molecules; (d) 90°
rotated view of (c) showing the packing of two adjacent layers with the CH3 CN@calix[4]pyrrole
rotated view of (c) showing the packing of two adjacent layers with the CH3CN@calix[4]pyrrole
oriented in opposite directions (see text for details); (e) Restricted packing of the acetonitrile solvate,
oriented in opposite directions (see text for details); (e) Restricted packing of the acetonitrile solvate,
C. The stair-like 2D layers formed by the CH3 CN@calix[4]pyrroles when viewed from the bbaxis is
C. The stair-like 2D layers formed by the CH3CN@calix[4]pyrroles when viewed from the axis is
highlighted between solid lines. Rectangles are used to define the blocks of perfectly aligned dimeric
highlighted between solid lines. Rectangles are used to define the blocks of perfectly aligned dimeric
layers depicted in (d). The calix[4]pyrroles are shown in stick representation. The two bound ACN
layers depicted in (d). The calix[4]pyrroles are shown in stick representation. The two bound ACN
molecules are shown as space fill models with the externally bound ACN in yellow color. Thermal
molecules are shown as space fill models with the externally bound ACN in yellow color. Thermal
ellipsoids for C,C, and I atoms set at 50% probability; H atoms are shown as spheres of 0.20 Å diameter.
ellipsoids for N N and I atoms set at 50% probability; H atoms are shown as spheres of 0.20 Å
diameter.

2.3. Theoretical Study

2.3. Lattice Energies
2.3.1.Theoretical Study
First, the lattice
2.3.1. Lattice Energies energies for both polymorphs A and B were estimated by using a
supercell of two molecules and periodic boundary conditions at the Generalized Gradient
First, the lattice energies for both polymorphs A and B were estimated by using a supercell of
Approximation/Perdew-Burke-Ernzerhof (GGA/PBE) level of theory by means of the DMOL3 software.
two molecules and periodic boundary conditions at the Generalized Gradient
Approximation/Perdew-Burke-Ernzerhof (GGA/PBE) level of theory by means of the DMOL3

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software. The computed values were calculated using the formula Elattice = E as recommended
The computed values were calculated using the formula Elattice = Ecrystal /n − Emolecule crystal/n−Emolecule as
recommended [18].the literature lattice The resulting are similar for both polymorphs, that for both
in the literature in The resulting [18]. energy values lattice energy values are similar is Elattice
polymorphs, that is Elattice = - 74.4 and - 71.5 kcal/mol for A relaxed coordinates When the relaxed
= −74.4 and −71.5 kcal/mol for A and B, respectively. When the and B, respectively. are used instead of
coordinatesX-ray crystals for thethose of the X-ray crystals for the calculations, the computed lattice
those of the are used instead of calculations, the computed lattice energies become almost identical
energies become −71.0 identical (Elattice = -71.9 and -71.0 kcal/mol for A and B, respectively).
(Elattice = −71.9 andalmost kcal/mol for A and B, respectively). Experimentally polymorph B features
Experimentally polymorph B features the largest density.
the largest density.
2.3.2. MEP Surface Analysis
2.3.2. MEP Surface Analysis
Figure 5 shows the molecular electrostatic (MEP) surface computed for the calix[4]pyrrole
Figure 5 shows the molecular electrostatic potentialpotential (MEP) surface computed for the
calix[4]pyrrole receptorB, as a model of the a model ofin both of them.both of them. The MEP surface
receptor in polymorph in polymorph B, as molecule the molecule in The MEP surface is useful to
is useful to rationalize donor–acceptor interactions since it identifies identifies the electron rich and
rationalize and predictand predict donor–acceptor interactions since it the electron rich and electron
electron poor regions of the In Figure 5, we depict two zenithal zenithal views of the one with one
poor regions of the molecule.molecule. In Figure 5, we depict twoviews of the receptor, receptor, the
with the C–I bonds pointing towards the viewer (Figure 5a) and another with the C–I bonds pointing
C–I bonds pointing towards the viewer (Figure 5a) and another with the C–I bonds pointing opposite
opposite to the viewer (Figure 5b). The most positive region is located in the interior of the cavity
to the viewer (Figure 5b). The most positive region is located in the interior of the cavity where the
where the four N–H bonds converge. The is very large (+ 69 kcal/mol) kcal/mol) and explains of
four N–H bonds converge. The MEP valueMEP value is very large (+ 69 and explains the abilitythe
ability of this type of to incorporate electron electron rich guests. surface also evidences that the
this type of moleculesmolecules to incorporaterich guests. The MEPThe MEP surface also evidences
that the energy value at the σ-holes of σ-holes of the I-atoms are positive and moderately strong (+
potential potential energy value at thethe I-atoms are positive and moderately strong (+ 16.8 kcal/mol),
16.8 kcal/mol), therefore suitable with electron-rich electron-rich atoms or groups of atoms. Finally,
therefore suitable for interacting for interacting withatoms or groups of atoms. Finally, the MEP at
the MEP at the surface of the aromatic H-atoms is also positive (+ 15.0 kcal/mol). This is similar is
the surface of the aromatic H-atoms is also positive (+ 15.0 kcal/mol). This MEP valueMEP valueto
similar to the one assigned to of σ–hole of I. Consequently, H-bonding interactions these H-atoms
the one assigned to the σ–holethe I. Consequently, H-bonding interactions involving involving these
H-atoms could compete with the formation of halogen bonds. The MEP values in regions of the
could compete with the formation of halogen bonds. The MEP values in the equatorial the equatorial
regions of the I-atoms reaches a minimum of In these equatorial region, the van der Waals van der
I-atoms reaches a minimum of –16.0 kcal/mol. –16.0 kcal/mol. In these equatorial region, thesurfaces
Waals surfaces of the closest I-atoms overlap. Finally, the the π-system in the pyrrole in the pyrrole
of the closest I-atoms overlap. Finally, the MEP values of MEP values of the π-system rings are also
rings are also kcal/mol). 18.8 kcal/mol). Taking the account that the interior of the cavity is
negative (− 18.8negative (− Taking into account that into interior of the cavity is unreachable by the
unreachable by the π-system most favorable ring, the most a purely interaction from a purely
π-system of the pyrrole ring, the of the pyrrole interaction from favorableelectrostatic point of view is
electrostatic point of view is the formation of halogen bonds betweenof the pyrrole rings. This type
the formation of halogen bonds between the I-atoms and the π-system the I-atoms and the π-system
of the pyrrole rings. This type of interaction is exclusively observed Moreover, in A solid-state, 3a).
of interaction is exclusively observed in polymorph A (see Figure 3a). in polymorphthe (see Figure the
Moreover, in cavity already accommodates one acetonitrile molecule.
calix[4]pyrrole the solid-state, the calix[4]pyrrole cavity already accommodates one acetonitrile
molecule.

Figure 5. MEP surface of the p-iodophenyl meso-substituted calix[4]pyrrole (polymorph B) in two
Figure 5. MEP surface of the p-iodophenyl meso-substituted calix[4]pyrrole (polymorph B) in two
zenithal orientations, C–I bonds pointing towards the viewer (a) and opposite to the viewer (b). The
zenithal orientations, C–I bonds pointing towards the viewer (a) and opposite to the viewer (b). The
energies at selected points of the MEP surface are indicated in kcal/mol.
energies at selected points of the MEP surface are indicated in kcal/mol.

2.3.3. Energetic and Noncovalent Interaction Plot (NCIPLOT) Index Analyses
2.3.3. Energetic and Noncovalent Interaction Plot (NCIPLOT) Index Analyses
Several dimeric aggregates present in the crystal lattices of polymorphs A and B were selected in
orderSeveral dimeric aggregates present in the crystal lattices of polymorphs A and B were selected
to compare their dimerization energies and correlate them with the existence of both polymorphs.
in order to compare their dimerization energies and correlate them with the existence of both
polymorphs. Moreover, the influence of the bound acetonitrile molecule on the interaction energies

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Moreover, the influence of the bound acetonitrile molecule on the interaction energies was also analyzed.
For polymorph B, we selected the two types of dimers shown in Figure 5. These dimers are responsible
was also analyzed. For polymorph B, we selected the two types of dimers shown in Figure 5. These
for the crystal growth by the packing of the 2D layers. The interactions in the growing of the 2D
dimers are responsible for the crystal growth by the packing of the 2D layers. The interactions in the
layers are almost identical in both polymorphs (vide supra) and were not analyzed in detail. In dimer 1
growing of the 2D layers are almost identical in both polymorphs (vide supra) and were not analyzed
(Figure 6a), the I···I distances are significantly longer than the sum of the van der Waals radii (3.96 Å),
in detail. In dimer 1 (Figure 6a), the I···I distances are significantly longer than the sum of the van der
thus explaining the moderate binding energy ∆E1 = − 9.3 kcal/mol (for six long contacts). In this type
Waals radii (3.96 Å), thus explaining the moderate binding energy ΔE1 = − 9.3 kcal/mol (for six long
of halogen bonding (Type I), the van der Waals regions of both halogen-atoms with negligible MEP
contacts). In this type of halogen bonding (Type I), the van der Waals regions of both halogen-atoms
values interact (see Scheme 1a). Therefore, dispersion and polarization effects dominate this type of
with negligible MEP values interact (see Scheme 1a). Therefore, dispersion and polarization effects
“like–like” halogen bonding [10]. It is interesting to note that the interaction of the dimer weakens in
dominate this type of “like–like” halogen bonding [10]. It is interesting to note that the interaction of
the absence of the bound guest acetonitrile molecules. This is likely due to the fact that the H-atoms of
the dimer weakens in the absence of the bound guest acetonitrile molecules. This is likely due to the
the methyl group of the acetonitrile interact with the negative belt of the I-atoms, thus influencing the
fact that the H-atoms of the methyl group of the acetonitrile interact with the negative belt of the Inature and strength of the I···I interactions. The interaction energy of dimer 2 (Figure 6b) is stronger
atoms, thus influencing the nature and strength of the I···I interactions. The interaction energy of
(∆E3 = − 22.7 kcal/mol) because it is electrostatically more favored than dimer 1, as can be deduced
dimer 2 (Figure 6b) is stronger (ΔE3 = − 22.7 kcal/mol) because it is electrostatically more favored than
from the MEP surface plot shown in Figure 4. The positive H-atoms point to the negative π-cloud of
dimer 1, as can be deduced from the MEP surface plot shown in Figure 4. The positive H-atoms point
the pyrrole rings. In this case, the bound acetonitrile molecule does not affect the interaction energy to
to the negative π-cloud of the pyrrole rings. In this case, the bound acetonitrile molecule does not
a major extend since the calculations show that the dimer stabilization only weakens 0.2 kcal/mol upon
affect the interaction energy to a major extend since the calculations show that the dimer stabilization
elimination of the acetonitrile molecules.
only weakens 0.2 kcal/mol upon elimination of the acetonitrile molecules.

Figure 6. Two supramolecular dimers retrieved from the X-ray structure of polymorph B. Distances in
Figure 6. Two supramolecular dimers retrieved from the X-ray structure of polymorph B. Distances
Å (a) dimer 1; (b) dimer 2.
in Å.

For the two dimers of polymorph B, the noncovalent interaction (NCI) plot index analysis has
been carried out to characterize the typeB, C–I···I–C halogeninteraction the C–H···π index analysis has
For the two dimers of polymorph I the noncovalent bond and (NCI) plot interactions. The
NCIPLOT index is acharacterize the type I C–I···I–C halogen bond and the C–H···π interactions.and
been carried out to convenient computational tool that allows for the efficient visualization The
identification of noncovalent interactions [19]. Its foundation resides on the fact thatvisualization and
NCIPLOT index is a convenient computational tool that allows for the efficient the noncovalent
contacts are easily identified with the peaks that emerge in the RDGon the factdensity gradient) at
identification of noncovalent interactions [19]. Its foundation resides (reduced that the noncovalent
low densities easily identified a more comprehensive treatment). RDG (reduced density gradient) at
contacts are (see ref. [20] for with the peaks that emerge in the These are plotted in real space by
mapping an isosurface of s (s = |a ρ|/ρ4/3 ) for a low value treatment). These are plotted supramolecular
low densities (see ref. [20] for more comprehensive of RDG. Upon formation of a in real space by
dimer, thean isosurface ofat(s = |∇ρ|/ρ4/3pointslow value of the monomers due to of a annihilation of
mapping RDG changes s the critical ) for a in between RDG. Upon formation the supramolecular
the density RDG changes at the critical points inthe NCIPLOT index allows visualizing the extent the
dimer, the gradient at these points. Therefore, between the monomers due to the annihilation of to
which NCIs stabilizethese points. Therefore, the NCIPLOT index allows visualizing the extent to which
density gradient at a supramolecular assembly. The information that the NCIPLOT index provides is
qualitative revealing which molecular regions interact. The color scheme is a red-yellow-green-blue
NCIs stabilize a supramolecular assembly. The information that the NCIPLOT index provides is
scale with red for repulsive (ρ+ cut ) and blue for attractiveThecut ). Weak repulsive and weak attractive
qualitative revealing which molecular regions interact. (ρ− color scheme is a red-yellow-green-blue
forces with red for repulsive (ρ+cut) and blue for attractive (ρ−cut). Weak repulsive and weak attractive
scale are represented by yellow and green surfaces, respectively.
forces are represented by yellow and green surfaces, respectively.
The representations of the NCIPLOT index surfaces of the two dimers of polymorph B are shown
in Figure 7. Form the two plots, it is established that the included acetonitrile molecules interact with

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The representations of the NCIPLOT index surfaces of the two dimers of polymorph B are shown
in Figure 7. Form the two REVIEW is established that the included acetonitrile molecules interact with
Molecules 2019, 24, x FOR PEER plots, it
10 of 15
the aromatic walls of the receptor. This is demonstrated by the presence of several green extended
the aromatic walls of the receptor. This is demonstrated by the presence of several green extended
isosurfaces located between the acetonitrile atoms and the aromatic rings. Moreover, the interaction
isosurfaces located between the acetonitrile atoms and the the I-atoms is also evidenced in the plot
of the methyl H-atoms of the included acetonitrile with aromatic rings. Moreover, the interaction
of the methyl Figure 7b). the included acetonitrile with of I-atoms is also the existence the plot
(exemplified inH-atoms of More importantly, the NCIPLOT thedimer 1 confirms evidenced in of the six
(exemplified in Figure 7b). the long distances between the two atoms (longer than the van der Waals
I···I interactions in spite of More importantly, the NCIPLOT of dimer 1 confirms the existence of the
six I···I Six symmetrically distributed globular isosurfaces are distributed between thanI-atoms. The
radii). interactions in spite of the long distances between the two atoms (longer the the van der
Waals radii). Six also confirms the C–H···π interactions in dimer 2, in addition tobetween the I-atoms.
NCIPLOT index symmetrically distributed globular isosurfaces are distributed other van der Waals
The NCIPLOT the close proximity of the two molecules. The extension2, in addition to other van der
contacts due to index also confirms the C–H···π interactions in dimer of the isosurfaces in this dimer
Waals contacts due to the close proximity of of shape, size and functionality. Thisthe isosurfaces in
suggests a strong complementarity in terms the two molecules. The extension of result is in quite
this dimer suggests a strong complementarity in terms of shape, size and functionality. This result is
good agreement with its large computed interaction energy.
in quite good agreement with its large computed interaction energy.

Figure 7. NCIPLOTs of dimer 1 (a) and dimer (b) retrieved from the X-ray structure polymorph B.
Figure 7. NCIPLOTs of dimer 1 (a) and dimer 22(b) retrieved from the X-ray structure ofof polymorph
The gradient cut-off is s = 0.35 au, and the color scale is − 0.04 < ρ < 0.04 au.
B. The gradient cut-off is s = 0.35 au, and the color scale is − 0.04 < ρ < 0.04 au.

For polymorph A, we computed the interaction energy of a dimer extracted from its crystal lattice
For polymorph A, we computed the interaction energy of a dimer extracted from its crystal
(Figure 8a). The interaction energy of this dimer when the acetonitrile molecules are included in the
lattice (Figure 8a). The interaction energy of this dimer when the acetonitrile molecules are included
calculation is ∆E5 = − 15.5 kcal/mol. On the other hand, removing the acetonitrile molecules reduced
in the calculation is ΔE5 = − 15.5 kcal/mol. On the other hand, removing the acetonitrile molecules
the interaction energy of the dimer to ∆E6 = − 13.7 kcal/mol. This finding suggests that the existence of
reduced the interaction energy of the dimer to ΔE6 = − 13.7 kcal/mol. This finding suggests that the
C–H···I interactions reinforce the halogen bonds (C–I···π) stabilizing the dimer, which are established
existence of C–H···I interactions reinforce the halogen bonds (C–I···π) stabilizing the dimer, which are
between the host and the included acetonitrile. A likely explanation is that the electron transfer from
established between the host and the included acetonitrile. A likely explanation is that the electron
the negative belts of the I-atoms to the acidic H-atoms of acetonitrile methyl group increases the positive
transfer from the negative belts of the I-atoms to the acidic H-atoms of acetonitrile methyl group
MEP value at the I σ-holes, thus strengthening the halogen bond. It is also interesting to note that twice
increases the positive MEP value at the I σ-holes, thus strengthening the halogen bond. It is also
the binding energy of the dimer (head-to-tail) present in polymorph A (2 × ∆E5 = −31.0 kcal/mol) is
interesting to note that twice the binding energy of the dimer (head-to-tail) present in polymorph A
approximately equal to the sum of the energies of the two type of dimers (head-to-head and tail-to
(2 × ΔE5 = −31.0 kcal/mol) is approximately equal to the sum of the energies of the two type of dimers
tail) that are present in polymorph B (∆E1 + ∆E3 = − 32.0 kcal/mol). Keeping in mind that many
(head-to-head and tail-to tail) that are present in polymorph B (ΔE1 + ΔE3 = − 32.0 kcal/mol). Keeping
other packing effects could be involved in the crystallization and final solid state architecture of the
in mind that many other packing effects could be involved in the crystallization and final solid state
polymorphs, the similar energy values computed for the dimers detected in polymorphs A and B
architecture of the polymorphs, the similar energy values computed for the dimers detected in
suggest that their crystal lattices are similarly favored, as observed by experiment. The analogous
polymorphs A and B suggest that their crystal lattices are similarly favored, as observed by
lattice energies calculated for both polymorphs also support this conclusion (see Section 2.3.1).
experiment. The analogous lattice energies calculated for both polymorphs also support this
conclusion (see Section 2.3.1).
Finally, the NCIPLOT of the dimer of polymorph A is represented in Figure 8b that confirms the
existence and relevance of the C–H···I interactions between the host and the included acetonitrile and
also the C–I···π interactions involving the π-system of two pyrrole rings as donors. Both C–H···I and
C–I···π interactions are characterized by green isosurfaces located between the C–I bonds and either
the H-atoms of acetonitrile (C–H···I ) or the π-system of pyrrole (C–I···π).

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Figure 8. (a) Supramolecular dimer retrieved from the X-ray structure of polymorph A. Distances in Å
Figure 8. (a) Supramolecular dimer retrieved from the X-ray structure of polymorph A. Distances in
(b) NCIPLOT of theof the dimer retrieved from the X-ray structureof polymorphA. The gradient cut-off
dimer retrieved from the X-ray structure of polymorph A. The gradient cut-off is
Å (b) NCIPLOT
s = 0.35 au, and the colorcolor scale is − 0.04 ρ < < 0.04au.
is s = 0.35 au, and the scale is − 0.04 < < ρ 0.04 au.

Finally, the and Methods the dimer of polymorph A is represented in Figure 8b that confirms the
3. Materials NCIPLOT of
existence and relevance of the C–H···I interactions between the host and the included acetonitrile and
3.1. Materials and Techniques
also the C–I···π interactions involving the π-system of two pyrrole rings as donors. Both C–H···I and
C–I···π interactions are characterized by green isosurfaces located between the C–I bonds and either
The tetra-α isomer of the tetra-p-iodophenyl calix[4]pyrrole was synthesized using a modified
the H-atoms offrom the on reported in or the π-system of pyrrole (C–I···π).
procedure acetonitrile (C–H···I) literature [15]. The new synthetic procedure is described in detail
in the synthesis section of this paper and in the Supplementary Information, which also contains the

3. Materials data of the compound.
spectral and Methods
The IR spectrum of the calix[4]pyrrole was recorded on a Bruker Optics FT-IR Alpha

3.1. Materials and (Madrid, Spain) equipped with a deuterated triglycine sulfate (DTGS) detector , KBr
spectrometer Techniques
beamsplitter isomer resolution using a one-bounce attenuated total reflection (ATR) accessory modified
The tetra-α at 4 cm of the tetra-p-iodophenyl calix[4]pyrrole was synthesized using a with
diamond windows. Routine 1H-NMR and 13C-NMR spectra were recorded on a Bruker Advance 400
procedure from the on reported in literature [15]. The new synthetic procedure is described in detail
(400 MHz for 1H-NMR) (Madrid, Spain) or a Bruker Advance 500 (500 MHz for 1H-NMR) (Madrid,
in the synthesis section of this paper and in the Supplementary Information, which also contains the
Spain) ultrashield spectrometer. Deuterated solvents were purchased from Aldrich.
spectral data of the compound.
TheCrystalization of Polymorphs A and B was recorded on a Bruker Optics FT-IR Alpha spectrometer
3.2. IR spectrum of the calix[4]pyrrole
(Madrid, Spain) equipped with a deuterated triglycine sulfate (DTGS) detector, KBr beamsplitter
The polymorphs were present as two crystallographic phases in single crystals that grew from
at 4 cm−1 resolution using a one-bounceof acetonitrile total reflection (ATR) (CHCl3). Anwith diamond
solutions containing different mixtures attenuated (ACN) and chloroform accessory aliquot of
windows. Routine 1 H-NMR and 13 C-NMR spectra were recorded on a Bruker Advancecrude wasMHz
the calix[4]pyrrole isolated from the column chromatography purification of the reaction 400 (400
1
for 1 H-NMR) in the corresponding solvent mixture at room temperature (rt). The solution (Madrid, Spain)
dissolved (Madrid, Spain) or a Bruker Advance 500 (500 MHz for H-NMR) was filtered
and left to evaporate Deuterated solvents open. Single crystals obtained from the three solvent
ultrashield spectrometer.at rt by leaving the vialwere purchased from Aldrich.
−1

mixtures were subjected to single crystal X-ray diffraction. The solution of the diffracted data

3.2. Crystalization of Polymorphs A and B
revealed the structures of the two crystallographic phases of the calix[4]pyrrole (polymorphs A and
B) and the ratio in which they were present in the crystal sample. Table 1 lists the polymorphic

The polymorphs were present as two crystallographic phases in single crystals that grew from
solutions containing different mixtures of acetonitrile (ACN) and chloroform (CHCl3 ). An aliquot of
the calix[4]pyrrole isolated from the column chromatography purification of the reaction crude was
dissolved in the corresponding solvent mixture at room temperature (rt). The solution was filtered

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and left to evaporate at rt by leaving the vial open. Single crystals obtained from the three solvent
mixtures were subjected to single crystal X-ray diffraction. The solution of the diffracted data revealed
the structures of the two crystallographic phases of the calix[4]pyrrole (polymorphs A and B) and the
ratio in which they were present in the crystal sample. Table 1 lists the polymorphic composition of the
crystals that grew from the series of solvent mixtures. The crystals that grew from pure acetonitrile
solutions corresponded to a solvate of the calix[4]pyrrole containing two molecules of acetonitrile
per molecule of the receptor. The packing of the lattice of this latter solvate resembles that of the
polymorph solvates. However, its 2D layers show a stair-like arrangement with acetonitrile molecules
intercalated between them.
Table 1. Polymorphs’ percentage present in single crystals grown for different solution mixtures of
ACN and CHCl3 . The reported values were determined by means of single crystal X-ray diffraction.
Percentage ACN in chloroform

Polymorph A (%)

Polymorph B (%)

0.7%
1%
1.3%

88
35
0

12
65
100

3.3. Crystallographic Data Collection and Refinements
CrysAlisPro 1.171.40.53a (Rigaku OD, Neu-Isenburg, Germany, 2018) was used for the unit cell
determination, data reduction and absorption correction. Structure solution was obtained with the
program SIR2019 through the vive la difference (VLD) algorithm. Structure refinement was done
with ShelXL using the ShelXLe interface. The details of the crystal parameters are summarized in
Table 2. Cambridge Crystallographic Data Centre CCDC: 1971260, 1971261 and 1971262 contain
the crystallographic data for A, B and C, respectively. Copy of the data can be obtained free of
charge from CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (Fax: +44-1223-336-033; E-Mail:
deposit@ccdc.cam.ac.uk).
Table 2. Selected crystallographic and refinement data for polymorphs, A and B, and crystal structure
C.
Crystal

A

B

C

Empirical Formula
Formula weight
Crystal system
Space group
a/Å
b/Å
c/Å
α/◦
β/◦
γ/◦
V/Å3
Z
Radiation type
µ/mm−1
Temperature/K
Crystal size/mm
Dcalc /g·cm−3
Reflections collected
Independent Reflections
Completeness to theta = 25.242◦
F(000)
Data/restraints/parameters
Goodness-of-fit
Final R indices [I < 2d(I)]
R indices (all data)
Largest diff. peak and hole/e·Å−3
CCDC nº

C50 H43 I4 N5
1221.49
Triclinic
P¯
ı
10.66587(19)
11.1800(2)
19. 7496(3)
76.8217(14)
88. 7021(14)
80.1011(15)
2258.53(27)
2
Mo Kα
2.800
100(2)
0.10 × 0.05 × 0.05
1.796
64,252
11,647 [R(int) = 0.0637]
99.9 %
1180
11,647/0/537
1.013
R1 = 0.0385, wR2 = 0.1066
R1 = 0.0448, wR2 = 0.1107
1.828 and −1.097
1971260

C50 H43 I4 N5
1221.49
Triclinic
P¯
ı
10.95660(10)
14.07090(10)
15.34390(10)
85.1190(10)
89.8210(10)
71.2270(10)
2230.85(3)
2
Mo Kα
2.877
100(2)
0.20 × 0.20 × 0.12
1.818
113,257
12,126 [R(int) = 0.0241]
99.5 %
1180
12,126/0/537
1.396
R1 = 0.0212, wR2 = 0.0503
R1 = 0.0242, wR2 = 0.0513
0.872 and −0.645
1971261

C52 H46 I4 N6
1262.55
Monoclinic
P21 /c
21.4451(9)
10.8483(4)
21.8771(6)
90
98.339(3)
90
5035.8(3)
4
Mo Kα
2.515
100(2)
0.11 × 0.05 × 0.04
1.665
76,454
10,380 [R(int) = 0.0503]
99.9 %
2448
10,838/0/537
1.396
R1 = 0.0439, wR2 = 0.1222
R1 = 0.0540, wR2 = 0.1259
1.217 and −1.483
1971262

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3.4. Computational Details
We used the X-ray geometries in the energetic characterizations of the supramolecular aggregates
i.e., dimers. The level of theory used in this work was the PBE0 functional [21] in combination with
the D3 Grimme’s dispersion correction [22] and the def2-TZVP basis set [23,24] by means of the
Turbomole 7.2 [25] program. The molecular electrostatic potential (MEP) surfaces were obtained
using Gaussian-16 [26] at the PBE1PBE/def2-TZVP level and using the 0.001 a.u. isosurface. The
NCIPLOT [19,20] index has been performed using the PBE1PBE/def2-TZVP wave function.
Lattice energies (Elattice ) were evaluated using the DMol3 software in Materials Studio 2016 [27],
where all atoms were relaxed with the experimental unit cell parameters fixed. We used a double
numerical with polarization (DNP) basis set as implemented in material studio [28,29]. For the
solid-state calculations, PBE functional into GGA approximation [30] was utilized together with
Grimme’s long-range dispersion correction [31]. Computations were carried out with the maximum
number of numerical integration mesh points available and the density matrix convergence threshold
being set to 10−5 Ha.
4. Conclusions
We report the improved synthesis of the α,α,α,α steroisomer of a calix[4]pyrrole framework
bearing a p-iodophenyl and a methyl substituent in its four meso-carbons. We characterize the
compound using X-ray single crystal diffraction methods and discovered the simultaneous presence
of the compound as two polymorphic phases. Remarkably, the crystal lattice of polymorph A is
dominated by conventional C–I···π halogen bonds. Conversely, polymorph B displays a crystal lattice
dominated by type I halogen bonds and C–H···π interactions. The ratio of the two polymorphs present
in single crystals depends on the solvent mixtures (ACN:CHCl3 ) used to grow them. Both polymorphs
are solvates incorporating one ACN bound in the aromatic cavity of the calix. In contrast, the use of
pure acetonitrile solutions produces single crystals of a new calix[4]pyrrole solvate with two ACN
molecules per calix. The energetic features of the dimeric supramolecular assemblies observed in
the crystal lattices of the two polymorphs are almost isoenergetic on the basis of DFT calculation
results. The intermolecular interactions present in the dimers were characterized using MEP and
NCIPLOT computational tools. The obtained results confirm the relevance of two different types
of halogen bonds in the solid-state structure of the polymorphs. Finally, we believe that the results
reported herein further support the functional relevance of halogen bonds in crystal engineering and
supramolecular chemistry.
Supplementary Materials: The Supplementary Materials are available online.
Author Contributions: D.D. prepared the compound. D.D. and P.B. designed the experiments. D.D. obtained the
single crystal. E.C.E.-A. performed the data collection and the resolution of the crystal structure. A.B. and J.O.-C.
performed the DFT study and lattice energy calculations. P.B. and A.F. designed the concept. P.B. and A.F. wrote
and revised the manuscript. All authors have read and agreed to the published version of the manuscript.
Funding: This research was funded by MICIU/AEI from Spain, project numbers CTQ2017-84319-P,
RED2018-102331-T and CTQ2017-85821-R, FEDER funds. P.B. also thanks the CERCA Programme/Generalitat de
Catalunya and AGAUR 2017 SGR 1123 for financial support. D.D. thanks La Caixa for an Infinit Fellowship.
Acknowledgments: We thank the CTI (Centre de Tecnologies de la Informació) at the UIB (Universitat de les Illes
Balears) for computational facilities.
Conflicts of Interest: The authors declare no conflict of interest.

References
1.
2.
3.

Shah, H.; Bhatt, K.D. Review on Calix[4]Pyrrole: A versatile receptor. Adv. Org. Chem. Lett. 2019, 6, 1–12.
Kim, D.S.; Sessler, J.L. Calix[4]pyrroles: Versatile molecular containers with ion transport, recognition, and
molecular switching functions. Chem. Soc. Rev. 2015, 44, 532–546. [CrossRef] [PubMed]
Park, I.W.; Yoo, J.; Adhikari, S.; Park, J.S.; Sessler, J.L.; Lee, C.-H. Calix[4]pyrrole-Based heteroditopic Ion-Pair
receptor that displays Anion-Modulated, Cation-Binding behavior. Chem. Eur. J. 2012, 47, 15073–15078.

Molecules 2020, 25, 285

4.

5.

6.

7.

8.
9.

10.
11.
12.

13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.

24.
25.
26.

14 of 15

Martinez-Crespo, L.; Sun-Wang, J.L.; Ferreira, P.; Mirabella, C.F.M.; Aragay, G.; Ballester, P. Influence of the
insertion method of aryl-extended Calix[4]pyrroles into liposomal membranes on their properties as anion
carriers. Chem. Eur. J. 2019, 25, 4775–4781. [CrossRef] [PubMed]
Adriaenssens, L.; Gil-Ramírez, G.; Frontera, A.; Quiñonero, D.; Eduardo, C.; Escudero-Adán, C.; Ballester, P.
Thermodynamic characterization of Halide−π interactions in solution using “Two-Wall” aryl extended
Calix[4]pyrroles as model system. J. Am. Chem. Soc. 2014, 136, 3208–3218. [CrossRef]
Adriaenssens, L.; Estarellas, C.; Vargas-Jentzsch, A.; Martinez Belmonte, M.; Matile, S.; Ballester, P.
Quantification of Nitrate−π Interactions and Selective Transport of Nitrate Using Calix[4]pyrroles with Two
Aromatic Walls. J. Am. Chem. Soc. 2013, 135, 8324–8330.
Lynch, V.M.; Gale, P.A.; Sessler, J.L.; Madeiros, D. Room-temperature monoclinic and low-temperature
triclinic phase-transition structures of meso-octa-methylcalix[4]pyrrole±dimethyl sulfoxide (1/1). Acta Cryst.
2001, C57, 1426–1428.
Mahanta, S.P.; Kumara, B.S.; Panda, P.K. Meso-diacylated calix[4]pyrrole: Structural diversities and enhanced
binding towards dihydrogenphosphate ion. Chem. Commun. 2011, 47, 4496–4498. [CrossRef]
He, Q.; Zhang, Z.; Brewster, J.T.; Lynch, V.M.; Kim, S.K.; Sessler, J.L. Hemispherand-Strapped Calix[4]pyrrole:
An Ion-pair Receptor for the Recognition and Extraction of Lithium Nitrite. J. Am. Chem. Soc. 2016, 138,
9779–9782. [CrossRef]
Cavallo, G.; Metrangolo, P.; Milani, R.; Pilati, T.; Priimagi, A.; Resnati, G.; Terraneo, G. The Halogen Bond.
Chem. Rev. 2016, 116, 2478–2601.
Metrangolo, P.; Meyer, F.; Pilati, T.; Proserpio, D.M.; Resnati, G. Dendrimeric Tectons in Halogen
Bonding-Based Crystal Engineering. Cryst. Growth Des. 2008, 8, 654–659. [CrossRef]
Yamamoto, H.M.; Maeda, R.; Yamaura, J.-I.; Kato, R. Structural and Physical Properties of Conducting Cation
Radical Salts Containing Supramolecular Assemblies Based on p-Bis(iodoethynyl)benzene Derivatives.
Annu. Rev. Synth. Met. 2001, 11, 101–102.
Pang, X.; Zhao, X.R.; Wang, H.; Sun, H.L.; Jin, W.J. Modulating Crystal Packing and Magnetic Properties of
Nitroxide Free Radicals by Halogen Bonding. Cryst. Growth Des. 2013, 13, 3739–3745. [CrossRef]
He, W.; Ge, Y.C.; Tan, C.H. Halogen-Bonding-Induced Hydrogen Transfer to C=N Bond with Hantzsch Ester.
Org. Lett. 2014, 16, 3244–3247. [CrossRef] [PubMed]
Galan, A.; Aragay, G.; Ballester, P. A chiral “Siamese-Twin” calix[4]pyrrole tetramer. Chem. Sci. 2016, 7,
5976–5982. [CrossRef]
Escobar, L.; Aragay, G.; Ballester, P. Super Aryl-Extended Calix[4]pyrroles: Synthesis, Binding Studies, and
Attempts To Gain Water Solubility. Chem. Eur. J. 2016, 22, 13682–13689. [CrossRef]
Escobar, L.; Villaron, D.; Escudero-Adan, E.C.; Ballester, P. A mono-metallic Pd(II)-cage featuring two
different polar binding sites. Chem. Commun. 2019, 55, 604–607. [CrossRef]
Perger, W.F.; Pandey, R.; Blanco, M.A.; Zhao, J.J. First-principles intermolecular binding energies in organic
molecular crystals. Chem. Phys. Lett. 2004, 388, 175–180. [CrossRef]
Johnson, E.R.; Keinan, S.; Mori-Sanchez, P.; Contreras-Garcia, J.; Cohen, A.J.; Yang, W. Revealing Noncovalent
Interactions. J. Am. Chem. Soc. 2010, 132, 6498–6506. [CrossRef]
Contreras-García, J.; Johnson, E.R.; Keinan, S.; Chaudret, R.; Piquemal, J.P.; Beratan, D.N.; Yang, W. NCIPLOT:
A program for plotting non-covalent interaction regions. J. Chem. Theor. Comp. 2011, 7, 625–632. [CrossRef]
Adamo, C.; Barone, V. Toward reliable density functional methods without adjustable parameters: The PBE0
model. J. Chem. Phys. 1999, 110, 6158–6169. [CrossRef]
Grimme, S.; Antony, J.; Ehrlich, S.; Krieg, H. A dispersion correction for density functionals, Hartree-Fock and
semi-empirical quantum chemical methods DFT-D3. J. Chem. Phys. 2010, 132, 154104. [CrossRef] [PubMed]
Weigend, F.; Ahlrichs, R. Balanced basis sets of split valence, triple zeta valence and quadruple zeta valence
quality for H to Rn: Design and assessment of accuracy. Phys. Chem. Chem. Phys. 2005, 7, 3297–3305.
[CrossRef] [PubMed]
Weigend, F. Accurate Coulomb-fitting basis sets for H to Rn. Phys. Chem. Chem. Phys. 2006, 8, 1057–1065.
[CrossRef] [PubMed]
Ahlrichs, R.; Bär, M.; Hacer, M.; Horn, H.; Kömel, C. Electronic structure calculations on workstation
computers: The program system turbomole. Chem. Phys. Lett. 1989, 162, 165–169. [CrossRef]
Frisch, M.J.; Trucks, G.W.; Schlegel, H.B.; Scuseria, G.E.; Robb, M.A.; Cheeseman, J.R.; Scalmani, G.; Barone, V.;
Petersson, G.A.; Nakatsuji, H.; et al. Gaussian 16, Revision, A.03; Gaussian, Inc.: Wallingford, CT, USA, 2016.

Molecules 2020, 25, 285

27.
28.
29.
30.
31.

15 of 15

Grillo, M.E.; Andzelm, J.W.; Govind, N.; Fitzgerald, G.; Stark, K.B. Computational materials science with
materials studio: Applications in catalysis. Lect. Notes Phys. 2004, 642, 214–220.
Delley, B. An all-electron numerical method for solving the local density functional for polyatomic molecules.
J. Chem. Phys. 1990, 92, 508–517. [CrossRef]
Delley, B. From molecules to solids with the DMol3 approach. J. Chem. Phys. 2000, 113, 7756–7764. [CrossRef]
Perdew, J.P.; Burke, K.; Ernzerhof, M. Generalized gradient approximation made simple. Phys. Rev. Lett.
1996, 77, 3865–3868. [CrossRef]
Grimme, S. Semiempirical GGA-type density functional constructed with a long-range dispersion correction.
J. Comput. Chem. 2006, 27, 1787–1799. [CrossRef]

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