Energetic and topological approach for characterization of supramolecular clusters in organic crystals

Article abstract of DOI:10.1039/c4ra06040g

In this work, an approach is proposed for understanding the crystal arrangements of organic compounds. The crystals are studied taking into account the stabilization energy and the topological properties like contact surfaces of a molecule (M1) due to the presence of neighboring Mn (cluster). The molecular system models chosen were five heterocycles and one β-enaminone. The cluster of compounds had a Molecular Coordination Number (MCN) of 14, except for one compound that had an MCN of 16. Our study showed that intermolecular interactions can be divided into four main types: type I, with large energy values and a small contact surface; type II, involving a large value for both the energy and the contact surface; type III, with small and medium energy values, and a medium-sized contact surface; and type IV, with small energy values and a relatively large contact surface. Additionally, from this approach we show that only from the supramolecular cluster is it possible to observe the participation of the topological component during the formation of the crystal. This is demonstrated by the fact that the fragility of the electrostatic interaction between M1 and one Mn in the same plane is compensated by a strong interaction of M1 with a molecule in another plane.

Full text of DOI:10.1039/c4ra06040g

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Energetic and topological approach for
characterization of supramolecular clusters in
Cite this: RSC Adv., 2014, 4, 44337
organic crystals†
*
*
Marcos A. P. Martins, Clarissa P. Frizzo, Anna C. L. Martins, Aniele Z. Tier,
Izabelle M. Gindri, Alexandre R. Meyer, Helio G. Bonacorso and Nilo Zanatta
In this work, an approach is proposed for understanding the crystal arrangements of organic compounds.
The crystals are studied taking into account the stabilization energy and the topological properties like
contact surfaces of a molecule (M1) due to the presence of neighboring Mn (cluster). The molecular
system models chosen were five heterocycles and one b-enaminone. The cluster of compounds had a
Molecular Coordination Number (MCN) of 14, except for one compound that had an MCN of 16. Our
study showed that intermolecular interactions can be divided into four main types: type I, with large
energy values and a small contact surface; type II, involving a large value for both the energy and the
contact surface; type III, with small and medium energy values, and a medium-sized contact surface;
and type IV, with small energy values and a relatively large contact surface. Additionally, from this
approach we show that only from the supramolecular cluster is it possible to observe the participation of
the topological component during the formation of the crystal. This is demonstrated by the fact that the
fragility of the electrostatic interaction between M1 and one Mn in the same plane is compensated by a
strong interaction of M1 with a molecule in another plane.
Received 20th June 2014
Accepted 2nd September 2014
DOI: 10.1039/c4ra06040g
www.rsc.org/advances
with these types of interactions, it can be seen that they have a
decisive role in the formation of the crystal. Additionally, there
Introduction
is a lack of adequate support from energetic data, and a lack of
concern for misaligned molecules, which are both strong limi-
tations of the synthon approach.
Supramolecular chemistry is an intrinsically dynamic eld of
chemistry. The crystal design of organic molecules has been
discussed as a supramolecular entity and several researchers
have focused on predicting them by using theoretical data,1 or
basing their results on experimental data from aggregates in
solution.2,3 While experimental results have demonstrated the
existence of dimers, trimers, and even aggregates preserved in
solution, theoretical results have presented a design trend
applicable only to particular crystals. Thus, limited success has
been achieved so far.1
To better understand how interactions are able to determine
crystalline organization, researchers have introduced the
“supramolecular synthon” concept.4–7 Nowadays, this approach
may be insufficient to explain weak interactions, since the
concept seems to be limited to distances predetermined by the
investigator (or soware8) and based on the van der Waals radii.
However, if we pay attention to topological factors associated
Our research group has worked with trihalomethyl hetero-
cycles for more than twenty years and in this time we have
cultivated an interest in understanding and controlling the
crystallization of these compounds, envisioning the develop-
ment of new solid material. In recent works,9–15 we have
described supramolecular synthons in the crystal structure of
trihalomethyl-substituted heterocycles and their precursors.
Remarkably, on these occasions we already observed that the
synthon approach was inadequate for responding to a set of
questions concerning the crystal arrangement of these hetero-
cycles. Thus, we perceived that it is time to consider a percep-
tion based on the energetic and topological data of
intermolecular interactions. In order to better understand this,
we believe that an approach between chemistry and
complexity16 is required. Taking into consideration that both
the parts (the molecules) and the whole (the crystal) have a role
in this process, which by the network of interactions gives rise
to the emergence of structural design, the best path to under-
standing this is via the complex approach. Therefore, the aim of
this work is to use both viewpoints in the study of self-assembly
processes in organic molecules and move towards verifying if
crystal design is something that emerges from intermolecular
´
´
Nucleo de Quımica de Heterocicl1os (NUQUIMHE), Department of Chemistry, Federal
University of Santa Maria, CEP 97105-900, Santa Maria, RS, Brazil. E-mail:
mmartins@base.ufsm.br; clarissa.frizzo@gmail.com; Fax: +55 55 3220 8756; Tel:
+55 55 3220 8756
† Electronic supplementary information (ESI) available. CCDC 993665 (1), 734995
(2), 993666 (3), 914132 (4), 680898 (5) and 993672 (6). For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c4ra06040g
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interactions. For this task we will use the supramolecular completely neutral in terms of information, one can conclude
cluster concept (dened above) and propose a number of useful that the organization emerges from inside the system. Each
surface parameters including topological/geometrical and single molecule is interacting with all its molecule neighbors,
energetics as well as their combinations. To best of our and each molecule neighbor is doing the same with its
knowledge this is the rst attempt to combine surface and respective neighbors, and so on. Taking into consideration that
energetics calculations.
both the parts and the whole have a role in this process gives
rise to the emergence of structural design.
Also, it is worth noting that, currently, the ndings of many
researchers point to the fact that the key to understanding
Background
When individual molecules are gathered together, they form crystal design lies in the comprehension of the emergent
what, in the literature, is called a supramolecular system. As properties involved during the formation process.2,3,16,18
some researchers have already pointed out, the lability of However, to achieve such comprehension, a long journey had to
interactions connecting molecular components enables supra- be undertaken.
molecular entities to exchange their constituents, in order to
The “supramolecular synthon” concept is the beginning of
form a different supramolecular structure. In fact, some the journey. A synthon is dened as a molecular fragment
researchers consider that this process, called self-organization attached by intermolecular interactions that contain a reason-
by design, in striving for total control over the initial explicit able approximation of the organization of the entire crystal.4–7
programming of the molecular or supramolecular entity, The identication of supramolecular synthons arises from
reveals itself to be self-organizing by selection.16 In other words, distances predetermined by the investigator based on the van
while operating on the dynamic constitutional diversity der Waals radii. Thus, it was established that non-covalent
responsible for internal and external factors, this process aims intermolecular interactions, including strong hydrogen bonds,
to achieve what could be compared to a Darwinian selection.17 tend to form robust supramolecular synthons, which, in turn,
As already noted by some researchers, when we consider a self- direct the crystal packing.4 As aforementioned, this approach
organized structure, a startling aspect emerges: the structural may be insufficient to explain interactions weaker than
and functional properties of molecular associations in the hydrogen bonds. In general, these so-called weak interactions,
system do not depend on the properties of the individual sometimes referred to as resulting dispersive forces are
molecules formed.2,3,16,18 Rather, some of these properties, considered to be of minor importance. Additionally, topological
which from now on we will call emergent, seem to be best factors are neglected in the synthon approach, thus inducing
explained as a result of the specic organization of individual the researcher to disregard the molecules which, though
molecules. Such properties cannot be predicted a priori from a present in the crystal, are misaligned with the “appropriate
single component, since they emerge from interactions—they direction” indicated by their respective molecular fragment. In
only begin to appear during the process of self-organization, or other words, this approach focuses only on the molecules that
more precisely, when nucleation aggregates are still in solution. effectively participate in the so-called “robust synthons” to form
Thus, one can conclude that a supramolecule is constructed dimers, chains, layers, or macrocycles.
and dened as a set of interacting molecules. Such a phenom-
enon has only recently been dealt with in publications, given its some paradigms of the synthon approach are currently the
startling characteristics.
subject of review. For example, atom-atom distances less than
The way is being paved for the complex approach, since
The aim of the complex approach is to discover the proper- the sum of van der Waals radii do not imply large stabilization
ties, which emerge from the interactions. As described else- energies. Likewise, distances greater than the sum of atomic
where these properties are characterized by their radii may contain a large amount of stabilization energy.21a The
unpredictability and irreducibility.19,20 In other words, emergent attempt to describe interactions in crystals only in terms of
properties cannot be foreseen from a pre-emergent point of short interatomic contacts as the main structural joining
view; that is, we cannot describe in advance what they will be component is being recognized as a rather simplistic approach,
like if we are to base our description solely on characteristics when, in fact, something far more complex is being dealt with.21
from separate structures—the parts (molecules) or the whole
As an alternative to the synthon approach, we can mention
(crystal)—or on the laws which govern interactions. Rather, we the concept of electrostatic complementarity (already discussed
must turn our attention to the interactions themselves; that is, elsewhere),21b,22,23 in which the intermolecular interaction in the
between the parts and between the parts and the whole. We are crystal formation is the result of an exchange reaction in which
talking about a combination of both point of view parts and interactions with solvent in the unbound state are exchanged
whole with the aim to achieve a complex view. It is an interac- for intermolecular interactions between partners in the bound
tion that will lead to emergence, in a way that the whole pres- complex. In other words, in the crystal, regions of one molecule
ents itself as more (or less) than the sum of all parts. Thus, one with high negative charge density on the surface are closer to
of the key features for the proper characterization of an emer- the regions of another molecule with high positive charge
gent property is its objective unpredictability.
density on the surface. As we insist on searching for a more
It is well known that self-organized systems characterized as complete and satisfactory approach to crystals, it seems that, in
open are able to organize themselves spontaneously when the literature, a systemic point of view regarding the study of
submitted to a given gradient. As the imposed gradient is supramolecular interactions is lacking. In response to this, over
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the last few years we have worked hard in the study of crystalline
structures to introduce an approach that is moving towards
complexity. From the point of view we propose, the crystal must
be considered in terms of all of its parts (the molecules) which
present regions with more or less potential energy. One must
pay attention not only to the so-called robust synthons (appar-
ently the only regions with strong interactions) but also to other
regions. We considered synthons to be parts of the greater
structure, parts named by the observer, which contribute, along
with others, to the composition of the whole. Precisely because
of this, the crystal should be regarded as a complex system, in
which regions of different potential energy from a given mole-
cule are part of the harmony of complementary interactions,
which, together with the neighboring molecules, results in a
stabilizing balance.
Thus, in this article we shall consider two points of view: (i)
the parts (the molecules) are components of a complex system
which contains regions with different electrostatic densities
and topological design that interact with their neighbors in a
complementary manner; and (ii) the whole, in which the cluster
of the rst sphere of coordination of a molecule M1 will
constitute the whole of the system. But one may wonder: why is
it important to study the supramolecular cluster? To answer this
and, subsequently, to understand the purpose of this work, we
must focus on packing rather than interaction, we consider it
appropriate to regard the cluster, as formed by the rst coor-
dination sphere, as the smallest portion of the crystal—a
portion which presents all the necessary information for
understanding the intermolecular interactions of the entire
crystal system. Although the notion of a cluster formed by the
rst coordination sphere has not yet been conceptualized at the
moment we are preparing this paper, it has been used as a
decisive criterion in comparing the molecular packing envi-
ronment between two or more crystal structures, in reports on
the results of a series of blind tests of crystal structure predic-
tion (CSP).1
Fig. 1 Structure of compounds 1–6 selected to support this work.
arrangement in a sandwich-type orientation, which is required
for this packing. Thus, the topology of compound 1 prevents
such an interaction and gives rise to other intermolecular
interactions such as C–H/p.
Compound 2 is a fused heterocycle, 2,7-disubstituted pyr-
azolo[1,5-a]pyrimidine with one methyl group attached at C2
and a trichloromethyl group at C7. Pyrimidine and pyrazole
rings are almost in the same plane (gap of 3.6ꢀ), and one of the
Cl atoms from the trichloromethyl group is in the plane of the
pyrimidine ring (N8C7C71Cl71, 178.1ꢀ). Thus, compound 2 is
planar and contains ten p-electrons, and it does not possess any
polar group able to participate in classical hydrogen bonds.
Compound 3 is a 3,4,5-trisubstituted isoxazole with polar
groups, such as amino and iodine, attached. The planar
topology and the small size of this compound, associated with
the polar groups attached, characterizes it as an interesting
model in which we can visualize the simultaneous topological
and electrostatic interactions governing the crystal packing.
Compound 4 is a 1,4-disubstituted pyrazolo[3,4-d]pyridazin-
7-one, with a tert-butyl group at N1. This compound unites the
topological and electronic properties of compounds 2 and 3. In
other words, it has a fused ring and contains polar and bulky
groups. Pyridazinone and pyrazole rings are almost on the same
plane (gap of 1.7ꢀ), and pyridazinone and phenyl plane rings
have an angle of 41.4ꢀ.
Compound 5 is an enaminone with E-conguration in the
C3C4 double bond, containing an aniline group attached to C4
and three chlorine atoms attached to C1. The carbonyl group is
11.8ꢀ out-of-plane from the enamine system's (C3C4N4) plane,
and presents a chlorine atom in an anti-position in relation to
carbonyl oxygen (Cl1C1C2O2, 171.5ꢀ). The relationship between
the enamine system's (C3C4N4) plane and the phenyl ring's
plane is 29.5ꢀ. Additionally, compound 5 is not a heterocyclic
compound, but rather a longitudinal molecule which contains
highly polar groups with the ability to form strong hydrogen
bonds.
We emphasize that the parts and whole points of view should
not be interpreted as separate or non-correlated, but rather as
complementary approaches, since they are simultaneously
present in the crystal self-assembly. Therefore, the aim of this
work is to use both viewpoints in the study of self-assembly
processes in organic molecules and move towards verifying if
crystal design is something resulting from intermolecular
interactions.
Results and discussion
In order to support the proposal of this work, six compounds
with differentiated structures were selected (Fig. 1). Compound
1 is a 1,3,5-trisubstituted pyrazole, with a bulky tert-butyl group
attached to the N1, and an aryl group attached to the C5. There
is perpendicularity between the aryl group and the pyrazole ring
(angle of 90.0ꢀ). This orthogonality is a consequence of the tert-
butyl group's steric effect which entails particularities in the
crystal's self-assembly. For example, it is common that two
aromatic rings are able to pack via p-stacking; however, the
orthogonality of the pyrazole-aryl rings avoids molecular
Compound 6 is made up of two units of 1-tert-butylpyrazoles
connected to each other in the 5-position through a phenyl
spacer (Fig. 1). The two pyrazole rings are in the same plane,
and, with the benzene ring's plane, form angles of 80.3ꢀ and
99.7ꢀ. Similarly to compound 1, the pyrazole and phenyl rings
are almost perpendicular, which is a consequence of the pres-
ence of a bulky tert-butyl group attached to N1.
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Thus, considering the possible intermolecular interactions, provide a rst coordination sphere that is predominantly
the major difference between compounds 3, 4, 5 and 1, 2, 6 is composed of 14 molecules (>50%), and, secondly, by either 12
the presence of the highly polar N–H functional group which is or 16 molecule.26 Based on these results, Blatov26a justied the
able to establish a strong hydrogen bond with sp2-nitrogen (3) “rule of 14 neighbors”, which establishes that so spherical or
or sp2-oxygen atoms (4, 5).
quasi-spherical groups tend to form the closest packing, in
accordance with the principle of maximum occupancy of
space.
The molecular coordination number and the cluster
Considering the second method mentioned above, we notice
that the Hirshfeld surface is becoming a valuable tool for
analyzing intermolecular interactions, while maintaining a
whole-of-molecule approach. This method allows the determi-
nation of the MCN and the contact area between the molecules
of the cluster from the rst coordination sphere. Spackman
et al.22 have already determined the rst coordination sphere (14
molecules) surrounding a uorobenzene molecule in the
crystal. Shishkin et al.6 showed the MCN and determined the
energy for the dimers of the rst coordination sphere of a
phenanthroline. Additionally, for the determination of a
supramolecular cluster and, consequently, its MCN, it is
important to keep in mind that: (i) the self-organization of
molecules in a crystal includes electrostatic and topological
factors; (ii) the rst coordination sphere around M1 is formed
by all molecules that touch M1, considering the set of interac-
tions of all molecules near this molecule; (iii) a systemic
approach is needed in relation to the whole, and a linear
approach is needed to understand the parts; and (iv) a crystal
possesses supramolecular self-assembly, in other words, a
complex system. Thus, in the crystal of 1–6, if we consider any
M1 molecule in the crystal, the supramolecular cluster will be
formed by all neighboring molecules (M2, M3, M4, ., and Mn),
thus forming the rst coordination sphere of M1 (Fig. 2). The
contact surfaces between the M1 molecule and the Mn molecule
(SM1/Mn) were determined for compounds 1–6 using Hirshfeld
surface analysis27 and VDP.28 Fig. 3 shows the VDP28 and
Hirshfeld surface for compound 3. Both VDP and Hirshfeld
surface analysis lead us to the denition of the rst coordina-
tion sphere of the supramolecular cluster with an MCN of 14
molecules for compound 3, for instance. From the data
obtained using the methods described, the MCN was deter-
mined for compounds 1–6 (Table 1).
With our compound model at hand, and considering that our
proposal is to understand intermolecular interactions by
taking a crystal and designating it as a supramolecular cluster,
it is fundamental to rst dene the coordination spheres and
the Molecular Coordination Number (MCN). Kitaigorodskii24
already proposed the MCN concept for the rst coordination
sphere as being the number of molecules having at least one
contact with a given molecule, which is achieved by applying
the principle of close-packing organic crystals. With this in
mind, there are basically two calculation methods that may
be used to determine contacts: (i) the Voronoi–Dirichlet
Polyhedron (VDP) method; and (ii) the Hirshfeld Surface
method of analysis.
The VDP molecular concept was introduced by Fischer and
Koch25 to nd the number of neighboring molecules that make
contact with a given central molecule. From this, it was
established that the area of a VDP face corresponds to the
contact area between two molecules and reects the strength
of this intermolecular interaction in the crystal. By utilizing
this concept, a Russian research group have shown that the
vast majority of supramolecular clusters of organic molecules
Fig. 2 Cluster of first coordination sphere around M1 is formed by Mn
molecules for a compound with MCN ¼ 14: (a) M1 and six in-plane
molecules; (b) M1 and four above-plane molecules; and (c) M1 and
four below-plane molecules.
Fig. 3 (a) Voronoi–Dirichlet Polyhedron (VDP) for 3 (MCN ¼ 14); and (b) the Hirshfeld surface of M1/Mn (i.e., of the supramolecular cluster).
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ð2SM1 ꢁ SM1$$$Mn
Þ
Interaction energy versus contact
surface
CM1$$$Mn
¼
(1)
(2)
2
CM1/Mn
X
CM1/Mn% ¼
ꢂ100
Now that we have established the contact surface for all the
supramolecular clusters, we shall turn our attention to the
interaction energy between M1 and its molecule neighbours.
According to our proposal, the crystal is formed when molecules
in solution aggregate around a central molecule and such a
process occurs in harmony with the forces responsible for
crystal stability. Thus, the concept of crystal stability necessarily
passes through the determination of the amount of energy for
M1 and each Mn molecule from the rst coordination sphere of
the cluster.
The determination of the intermolecular interaction ener-
gies of M1/Mn dimers was done using the difference between
twice the M1 (alone) energy and the total energy of each of the
M1/Mn dimers (i.e., M1/M2, M1/M3, ., M1/Mn). In eqn
(4), GM1/Mn is the energy resulting from the interaction
between M1 and the Mn molecule; EM1 is the energy of M1 in
the absence of any neighboring molecule; and EM1/Mn is the
total energy of the dimer formed by M1 and Mn. GM1/Mn% is
ðCM1/Mn
Þ
n
X
Ccluster
¼
ðCM1/Mn
Þ
(3)
n
The contact surface
Furthermore, in the process of determining the contact
surfaces, we calculated the contact surface of the central
molecule M1 alone (SM1), as well as the contact surface of M1
and any Mn molecule (SM1/Mn). Thus, the contact surface
between M1 and the Mn molecules (CM1/Mn
) can be
expressed as: SM1/Mn subtracted from two times SM1 and then
dividing this difference by two, since the contact surface
between M1 and Mn is considered twice. We expressed this
relationship in eqn (1); CM1/Mn% is expressed in eqn (2), and
the total contact surface of the cluster (Ccluster) is presented
in eqn (3).
Data from the contact surfaces (CM1/Mn)—which were
obtained using the methods described—for the supramolecular
cluster formed by the rst coordination sphere of compounds
1–6, is presented in Table 1. Although the contact surfaces
obtained from VDP and Hirshfeld surface (CM1/Mn) calcula-
tions are obtained from the same X-ray diffraction data, it is
important to examine the correlation between these data to
conrm the structure of the cluster.
In our analysis, the correlation between VDP contact surfaces
and CM1/Mn showed good linearity, (VDPM1/Mn% ¼ 1.013 ꢂ
CM1/Mn% – 0.091; r ¼ 0.980; N ¼ 86). This result conrms that
both methods are valuable for understanding supramolecular
clusters.
expressed in eqn (5), and the total energy of the cluster (Gcluster
)
is presented in eqn (6). The data presented in Table 1 is for the
interaction energy GM1/Mn of the supramolecular cluster
formed by the rst coordination sphere of compounds 1–6. As
mentioned earlier, a systemic approach is needed to reach the
whole. Thus, when calculating the intermolecular interaction
energies, it is desirable to consider the energetic contribution
that each Mn molecule provides for M1 stabilization—always
having all cluster molecules. However, this kind of calculation,
depending on the number of atoms in each molecule at a
calculation level of ab initio MP2, results in an almost unjusti-
able computational cost. There is (also) the risk of estimating
intermolecular interaction energies from dimers that are
Table 1 Hirshfeld contact surfacea and energy interactionb for dimers of compounds 1–6
Compound
Dimer
1
2
3
4
5
6
GM1/Mn CM1/Mn GM1/Mn CM1/Mn GM1/Mn CM1/Mn GM1/Mn CM1/Mn GM1/Mn CM1/Mn GM1/Mn CM1/Mn
M1/M2
M1/M3
M1/M4
M1/M5
M1$$$M6
M1/M7
M1/M8
M1/M9
M1/M10
M1/M11
M1/M12
M1/M13
M1/M14
M1/M15
M1/M16
M1/M17
ꢁ2.16
ꢁ1.24
ꢁ1.25
ꢁ2.16
ꢁ2.46
ꢁ2.46
ꢁ0.98
ꢁ0.98
ꢁ1.02
ꢁ1.02
ꢁ0.98
ꢁ0.98
ꢁ8.47
ꢁ8.47
0.00
30.65
17.05
17.05
30.65
21.50
21.50
11.28
11.28
10.86
10.86
11.29
11.29
56.13
56.13
4.13
ꢁ0.47
ꢁ1.71
ꢁ2.00
ꢁ0.49
ꢁ2.00
ꢁ1.71
ꢁ2.45
ꢁ2.45
ꢁ0.61
ꢁ0.61
ꢁ2.27
ꢁ2.27
ꢁ6.14
ꢁ6.14
—
9.00
12.63
8.73
9.00
8.73
12.63
19.82
19.82
3.35
3.35
20.03
20.03
39.73
39.73
—
ꢁ8.00
ꢁ1.48
ꢁ0.56
ꢁ0.79
ꢁ1.45
ꢁ0.38
ꢁ0.93
ꢁ0.90
ꢁ1.49
ꢁ1.49
ꢁ0.32
ꢁ0.63
ꢁ3.33
ꢁ3.31
—
8.93
7.94
4.52
15.23
7.94
14.04
6.99
6.99
10.33
10.33
3.41
6.29
26.23
28.76
—
ꢁ4.04
ꢁ2.07
ꢁ2.80
ꢁ7.55
ꢁ2.07
ꢁ0.77
ꢁ5.07
ꢁ5.07
ꢁ3.14
ꢁ0.90
ꢁ3.05
ꢁ3.05
ꢁ3.31
ꢁ0.51
—
29.80
14.64
32.57
11.28
14.64
14.70
37.35
37.35
20.59
11.36
24.88
24.88
21.73
0.89
ꢁ2.22
ꢁ0.80
ꢁ10.76
ꢁ2.22
ꢁ0.79
ꢁ10.76
ꢁ8.50
ꢁ7.38
0.16
ꢁ0.59
ꢁ4.90
ꢁ4.90
0.02
12.94
7.05
30.13
12.94
7.05
30.13
36.47
33.46
0.21
11.03
29.74
29.73
11.74
11.74
—
ꢁ0.43
ꢁ4.36
ꢁ1.26
ꢁ0.43
ꢁ4.31
ꢁ1.15
ꢁ5.46
ꢁ5.45
ꢁ2.22
ꢁ2.27
ꢁ8.65
ꢁ8.65
ꢁ0.52
ꢁ0.51
—
9.20
48.13
9.64
9.20
48.13
9.64
29.24
29.24
18.30
19.00
52.08
52.08
4.62
4.62
—
0.02
—
—
—
—
0.00
4.13
—
—
—
—
—
—
—
—
a
2
b
CM1/Mn, A , Hirshfeld contact surface, eqn (1). GM1/Mn, kcal molꢁ1, energy interaction, eqn (4).
˚
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Table 2 Total energy (Gcluster) and total contact surface (Ccluster) for
the supramolecular clusters
separated from the rest of the cluster: obviously, the energy to
be found from neighboring molecules will not be computed. In
order to nd a solution to this impasse, by using a calculus
approximation at DFT level (wB97X-d/cc-pVTZ-PP), the stabili-
zation energies of all cluster molecules (14 molecules) on M1
were determined for compound 3. Results were compared with
those obtained from the sum of energies of each dimer
considered separately from the rest of the cluster. The differ-
ence between these two parameters was less than 5%. Keeping
such data in mind, and understanding that the idea of a
systemic view of the cluster would not be compromised, we
chose to perform a more robust calculation (MP2), by consid-
ering each dimer without the presence of the other cluster
molecules.
b
Gcluster
Gcluster/Ccluster
Cpd
MCNa
(kcal molꢁ1
)
Ccluster (A )
(kcal molꢁ1
A )
c
2
ꢁ2
˚
˚
1
2
3
4
5
6
16
14
14
14
14
14
ꢁ34.63
ꢁ31.32
ꢁ25.06
ꢁ43.40
ꢁ53.62
ꢁ45.67
317.52
226.58
157.93
296.66
264.36
343.12
ꢁ0.11
ꢁ0.14
ꢁ0.16
ꢁ0.15
ꢁ0.20
ꢁ0.13
a
The MCN is the number of molecules in the supramolecular cluster
formed by the rst coordination sphere. b Eqn (6). c Eqn (3).
It is reasonable to imagine that the magnitude of the stabi-
lization energy of each neighboring molecule on the central
molecule M1 (GM1/Mn) should be proportional to the contact
surface (CM1/Mn) of each dimer M1/Mn.26a In attempting to
apply this statement to our experiment, we made a correlation
between GM1/Mn% and CM1/Mn% for the compounds 1–6
(Fig. 4). As a result, from the data of 86 dimers we achieved a
poor correlation coefficient (r ¼ 0.760). We observed that there
are some outliers which can emerge from dimers that present:
(i) energies much greater than expected when confronted with
the contact surface existing between the molecules considered;
or (ii) contact surfaces larger than expected when considering
the detected energy.
the second case, we can relate this to dimers containing inter-
actions with dispersive forces. Having reached this point in our
examination, it is time to consider why these outliers are
organized in such a way. In other words: why do we not observe
a proper correlation between GM1/Mn% and CM1/Mn%? The
outlier dots seem to be imperfections we see when considering
only the parts, and not the greater whole or the part–part and
part–whole relationships. Thus, the answers we are trying to
achieve depend on a new kind of consideration, as mentioned
above.
The total energy (Gcluster) and the total contact surface
(Ccluster) for 1–6 are listed in Table 2. The Gcluster/Ccluster ratio
shows average stabilization energy distributed over the mole-
cule in a homogeneous manner, which shows how the M1
molecule would appear if it had its interaction energy homo-
geneously distributed on its surface. For example, compound 1
GM1/Mn ¼ 2EM1 ꢁ EM1/Mn
GM1/Mn
(4)
(5)
X
GM1/Mn% ¼
ꢂ100
ðGM1/Mn
Þ
would need to have stabilization energy distributed over the
n
molecule in the proportion of ꢁ0.109 kcal molꢁ1
ꢁ2 (Table 2).
˚
A
X
Polar organic molecules do not show a homogeneous
distribution of stabilization energy over the molecule surface. In
Fig. 5, we take a closer look at inhomogeneous distribution. It
shows part of the supramolecular cluster of compound 3, as well
as the molecules M1 to M7 in the isoxazole ring plane. When we
examine the molecular arrangement, considering the data
inside the sum of the van der Waals radii (using Mercury®
soware), we observe that there are only contacts between
M1/M2, M1/M3, M1/M6, and M1/M7—see Fig. 5(a). For
contacts between M1/M4 and M1/M5, it appears that an
Gcluster
¼
ðGM1/Mn
Þ
(6)
n
Our initial impression is that, in the rst case, this refers to
dimers with strong interactions (e.g., hydrogen bonds); and in
˚
increase of 0.4 A in the sum of the van der Waals radii is
required. These results are conrmed by Fig. 5(b) which shows
the Hirshfeld surface (dnorm, using Crystal Explorer® 3.1) of
molecules M2 to M7, where the close contacts between
M1/M2, M1/M3, M1/M6, and M1/M7 (red regions) and
the distant contacts between M1/M4 and M1/M5 (light blue
regions) can be seen. The electronegativity differences and size
disparities between atoms produce polarized bonds which,
along with n- and p-electron resonances and steric hindrances
in polar molecules, lead to an unequal distribution of charge
density21b creating a positive electrostatic potential zone or a
negative electrostatic potential zone on the molecular surface.
While interacting with its neighboring molecules, the molecule
M1, which already presents inequality in charge density
Fig. 4 Correlation between calculated energy interaction (GM1/Mn%)
and contact surface (CM1/Mn%) in the supramolecular cluster formed
by the first coordination sphere for compounds 1–6 (GM1/Mn% ¼ 1.073
ꢂ CM1/Mn% – 0.506; r ¼ 0.760; N ¼ 84).
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Fig. 5 M1 and M2 to M7 in the isoxazole ring plane of the supramolecular cluster of compound 3: (a) the molecular close contacts inside the sum
of van der Waals radii; (b) the Hirshfeld surface (dnorm) of molecules M2 to M7; and (c) MEP of molecules M1 to M7 (red ¼ ꢁ0.08 au, green ¼ 0, and
blue ¼ 0.08 au) of compound 3. Performed by GaussView (Gaussian 09) program and calculated with an isosurface value of 0.01; MEP were
generated from wave functions obtained from single point calculations using X-ray data and the uB97X-D/cc-pVDZ level of theory.
distribution, has its inequality increased or decreased, in words, each molecule in the rst coordination sphere would
accordance with the induction by its molecular partners, espe- contribute with a 1/MCN fraction of the total stabilization
cially those at the rst coordination sphere. Such distribution of energy (Gcluster). For example, the contribution will be 0.07 for
charge densities in the molecule may be observed with the aid MCN ¼ 14, and 0.06 for MCN ¼ 16. Using the same line of
of Molecular Electrostatic Potential (MEP) calculations, which thought, if the molecules were perfectly spherical, one also
are determined through ab initio calculations (obtained using might expect that each would contribute with 1/MCN of the
Gaussian® 09 (ref. 29 and 30)).
total contact surface of the cluster. But we are well aware that
In Fig. 5(c), regarding the supramolecular cluster of almost all organic molecules do not have the same contact
compound 3, the MEP of M1 and molecules M2 to M7 is pre- surface with every neighboring molecule and do not interact
sented in the isoxazole ring plane. The molecular arrangement with the same energy with all of them. Therefore, in order to
between M1/M2, M1/M3, M1/M6, and M1/M7 can be determine which molecules have the most important interac-
understood if we recall the electrostatic complementarity con- tions for the stabilization of the cluster, we search for a set of
cept.21b,22,23 Considering Fig. 5(a) and (b), we verify that M4 and parameters from the ideal contribution of 1/MCN of the energy
M5 do not develop close contacts in relation to M1.
and 1/MCN of the contact surface.
Looking at the greater context, all dimers (M1/Mn) in the
Given that NGM1/Mn and NCM1/Mn are the normalized
cluster have some amount of interaction energy and so it is energy and normalized surface—eqn (8) and (9), respectively—
reasonable to assume that this energy is due primarily to the in a supramolecular cluster with MCN molecules, the robust-
greater or lesser force of attraction between molecules, which in ness of the interaction between M1 and any Mn molecule can be
turn is a consequence of the difference in electrostatic potential estimated from the contributions of these normalized
between the contact regions of the molecules involved in the parameters.
interaction. On the other hand, it is no less true to consider that
GM1/Mn
NGM1/Mn ¼ MCN ꢂ
NCM1/Mn ¼ MCN ꢂ
(8)
(9)
molecules have regions with nearly neutral electrostatic poten-
tial. These regions generate small forces of attraction between
neighboring molecules, which is the reason why little interac-
tion energy is detected. Fig. 5 presents this situation for the
molecular arrangement between M1/M4 and M1/M5. In this
case, it may be proposed that molecules M4 and M5 are like
puzzle pieces in relation to M1: they t at a supramolecular
level, part of a wholeness controlled by topological com-
plementarity.26a However, a question remains: which dimers
exhibit the most important intermolecular interaction in the
cluster? To answer this question, we must consider the
magnitude of the interaction energies of each dimer. Consid-
ering the total interaction energy of the cluster (Gcluster) to be
1.0, and imagining the interaction energy to be homogeneous
for the whole surface, the interaction energy between M1 and
any of the neighboring molecules would be the same. In other
Gcluster
CM1/Mn
Ccluster
Considering an initial overview of the energy parameter, it
could be seen that: the amount of energy involved in the
interaction of M1/M14 and M1/M15 of 1 was three times
higher than the energy reference (1/MCN); and interaction
M1/M2 of 3 was four times larger than 1/MCN. On the other
hand, the contact surface M1/M14 and M1/M15 of 1 is twice
that of the 1/MCN surface, while for M1/M2 of 3, the contact
surface is smaller than 1/MCN.
The robustness criterion was anchored in the data for
NGM1/Mn dimers of the compounds that have hydrogen bonds:
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Fig. 6 Type of interaction in accordance with the normalized energy (NGM1/Mn) and contact surface (NCM1/Mn).
3, 4, and 5. From these data we believe that a robust amount of both NGM1/Mn and NCM1/Mn; that is, a molecular dimer with
interaction could be considered to take place when NGM1/Mn high interaction energy in a large surface contact. This feature is
>
2.0. The parameter NCM1/Mn can be small, such as for dimers present in all the compounds studied (1–6) and appears in
M1/M2 (3), M1/M5 (4), and M1/M4 and M1/M7 (5); or interactions with an important contribution of p/p and C–H/p
large, such as for M1/M14 and M1/M15 (1, 2) and M1/M12 contacts. Meanwhile, the type III interaction is the one present
and M1/M13 (6)—see Fig. 6. In the compounds 3, 4, and 6, in the largest quantity, and it has small values of NGM1/Mn and
some dimers have a somewhat lower NGM1/Mn; however, NCM1/Mn, with a maximum difference of ꢃ0.5 between the
considering that NGM1/Mn > 1.5, they can be considered to be two parameters. Finally, the type IV interaction has a small
robust. Based on these parameters, it is reasonable to affirm NGM1/Mn parameter and
a relatively higher NCM1/Mn
that dimers with NGM1/Mn > 2.5 may possibly be observed still parameter. This is a type of interaction that appears less
in solution, before forming the crystal; and, in some cases, they frequently. However, it is an interesting kind, as in it the
will govern crystal growth.2,3 However, to understand the crystal topological factor has a more inuential contribution over the
design of compounds 1–6, a closer examination of the energy electrostatic component. These last dimers, along with, which
and surface parameters of each dimer is necessary. Initially, we both present low parameters, conrm what we have said above:
need to dene the main types of interactions that are truly their tting is analogous to that of puzzle pieces and is mainly
present, according to NGM1/Mn and NCM1/Mn data (Table 3 and driven by topological complementarity.
Fig. S27, ESI†). Thus, we dene a type I interaction as one
having large NGM1/Mn values and small NCM1/Mn values; that
Energetic and topological complementarity
is, a molecular dimer with a high interaction energy in a small
As mentioned earlier, compound 3 shows that the dimers M1/M4
surface contact. This feature appears in compounds 3 and 4, in
and M1/M5 have low interaction energy, suggesting that the
which strong hydrogen bonds (N–H/N and N–H/O) are
correlation between M1 and M4 and M5 is due to topological
present. A type II interaction is one involving a large amount of
complementarity.26a The subject raises some doubts: how do
two molecules, with low interaction energy, maintain
themselves as cluster components? What prevents them from
tearing apart? Is topological tting sufficient to justify the
Table 3 Type of interaction in accordance with the normalized energy
permanence of these molecules in their positions? In order to
answer these questions we need to leave the perception of parts
for a moment and go towards a systemic perception of the
cluster, noting that (as mentioned above) the cluster, as formed
by the rst coordination sphere, should be regarded “as the
smallest portion of the crystal—a portion which presents all the
necessary information for understanding intermolecular
interactions of the entire crystal system”.
Thus, in Fig. 6 we schematically represent the interaction
types described here for organic crystal, where the grey circles
represents the contact surface of the molecules and the dashed
lines represent the energy between them. Fig. 7 helps us to
broaden our point of view from parts to system. It shows the
supramolecular cluster of compounds 2 and 3, which can be
seen in perspective at the M1 layer and the upper and lower
layers. The regions of weak interactions and strong interactions
are positioned. It is possible to answer the questions initially
posed by looking at the cluster of 3 shown in Fig. 7 (le). It is
(NGM1/Mn) and contact surface (NCM1/Mn) for the main dimers of
compounds 1–6
Cpd
Dimer
NGM1/Mn
>3.5
NCM1/Mn
>2.5
Inter. type
1
2
3
M1/M14; M1/
M15
M1/M14; M1/
M15
M1/M2; M1/M14
M1/M15; M1/M5
M1/M7; M1/M4
M1/M5
M1/M8; M1/M9
M1/M4
II
II
>2.5
>2.0
>4.0
>1.5
<0.5
>2.0
>1.5
<1.0
>2.8
>1.9
>2.6
<1.0
>2.0
>1.2
<0.5
>1.5
>1.5
>1.6
>1.7
>2.1
I
II
IV
I
II
IV
II
III
II
4
5
6
M1/M4; M1/M7
M1/M8; M1/M9
M1/M12; M1/
M13
M1/M8; M1/M9
M1/M3; M1/M6
>1.6
>1.3
>1.2
>2.0
III
II
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Fig. 7 Clusters of 3 and 2: an overview of strong and weak interactions.
easy to understand why M4 and M5 are placed at the locations
shown if you rationalize that their low stabilization energies in
relation to M1 are compensated by the high stabilization energy
present in the dimers at the upper and lower layers. In the same
gure, a similar rationalization is shown for compound 2
(Fig. 7, right). In conclusion, the fragile bond between the
molecules in some dimers at a given cluster layer is compen-
sated by the strong bond between other molecules in dimers at
the corresponding upper and lower cluster layers. This
perception must be extended to all clusters. It is clear that, if
there is a heterogeneous distribution of electrostatic potential
in the molecule, there will always be dimers with high stabili-
zation energy and, therefore, dimers with low stabilization
energy at the studied cluster. Thus, the arrangement of mole-
cules in the cluster necessarily shows that, for dimers with low
stabilization energy in a given layer, there will be co-existent
dimers with high stabilization energy in a layer immediately
thereaer (Fig. 7). But some doubts still remain: how does the
crystal formation begin? Which intermolecular interactions
govern crystal growth? And, at the convergent process of pre-
crystal formation, which component was more important—the
electrostatic one or the topological one?
Examining compounds 1–6 in light of what has been deter-
mined in this work it is possible to infer that dimers possessing
intermolecular interactions with large energetic content (e.g.,
dimers M1/M2 [3], and M1/M5 [4], or the polymeric frag-
ments of M8/M1/M9 [5]) already exist in concentrate solu-
tions of these compounds as non-protic solvents with low
polarity. Regarding the energetic content of the interactions, we
can conclude that polymeric fragments from molecules M14/
M1/M15 (1, 2, and 3), M8/M1/M9 (4), and M12/M1/M13
(6) also exist in concentrate solutions of these compounds.
Thus, keeping in mind the studies of solutions already pub-
lished in the literature,2,3 which demonstrate that the aggre-
gates observed in solution will generally persist in future crystal,
we verify that the formation of crystals from compounds 1–6
took place in a Darwinian fashion, in which the originated
crystals preserved pre-existing aggregates—those which we
mentioned as “polymeric fragments”. Remarkably, polymeric
fragments possess important components of interactions such
as C–H/p (1 and 6), p/p (2, 3, and 4), and N–H/O hydrogen
bonds (5).
Experimental
Synthesis
The synthesis and complete H and 13C NMR data, mass spec-
trometric data, and elemental analysis of compounds 1, 2, 4, 5,
and 6 is available in the literature.31–35 3-Amino-4-iodo-5-methyl-
isoxazole (3) was synthesized from the iodination, with N-
iodosuccinimide (NIS), of the commercial reagent 3-amino-5-
methylisoxazole. To a solution of 3 (1.0 mmol) in acetic acid (5
mL), NIS (1.0 mmol) was added and stirred for 30 min at room
temperature. Aer the reaction time, the solution was extracted
with chloroform. The solvent was removed in a rotary evapo-
rator and the product 3 was puried by recrystallization from
hexane. Physical and spectrometric data of 3: Mp. 97–99 ꢀC; 1H
NMR, d 2.37 (s, 3H, Me), 4.08 (br s, 2H, NH2); 13C NMR, d 12.7
(Me), 51.2 (C4), 163.2 (C3), 169.6 (C5); MS, 224 (M+, 100), 97 (7),
66 (11), 55 (33). The crystals of 1 were obtained by solubilization
in 6 mL of a mixture of ethanol and dichloromethane at a ratio
of 1 : 1, followed by slow evaporation at 12 ꢀC. The crystals of 2
were obtained by solubilization in 5 mL of a mixture of ethanol
and DMSO at a ratio of 6 : 4, followed by slow evaporation at 25
ꢀC. The crystals of 3 were obtained by solubilization of 5 mL of
heat hexane followed by slow evaporation at 25 ꢀC. The crystals
of 4 were obtained by solubilization in 5 mL of chloroform
followed by slow evaporation at 25 ꢀC. The crystals of 5 were
obtained by solubiꢀlization in 6 mL of ethanol followed by slow
evaporation at 25 C. The crystals of 1 were obtained by solu-
bilization in 6 mL of a mixture of ethanol and chloroform at a
1
ꢀ
ratio of 1 : 1, followed by slow evaporation at 25 C.
X-ray diffraction data
The diffraction measurements were performed using graphite
˚
monochromatized Mo Ka radiation with k ¼ 0.71073 A, on a
Bruker SMART CCD diffractometer.36 The structures were solved
with direct methods using the SHELXS program, and rened on
F2 by full-matrix least-squares with the SHELXL package.37
Absorption correction was performed by the Gaussian
method.38 Anisotropic displacement parameters for non-
hydrogen atoms were applied. The hydrogen atoms were placed
˚
˚
at calculated positions with 0.96 A (methyl CH3), 0.97 A
(methylene CH2), 0.98 A (methyne CH), 0.93 A (aromatic CH),
˚
˚
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˚
and 0.82 A (OH), using a riding model. Hydrogen isotropic
thermal parameters were kept equal to Uiso(H) ¼ xUeq. (carrier
C atom), with x ¼ 1.5 for methyl groups and x ¼ 1.2 for all
others. The valence angles C–C–H and H–C–H of the methyl
groups were set to 109.5ꢀ, and H atoms were allowed to rotate
around the C–C bond. Molecular graphs were prepared using
ORTEP for Windows.39 Data collection and structure renement
for the structures of 1–6 are given in Table 4.
Conclusions
Continuing with the relentless pursuit of researchers to deter-
mine a priori the design of a crystal structure through the use of
experimental and theoretical tools, in this article we gave our
contribution, which proposes considering the crystal as a
complex system. Our experimental and theoretical interpreta-
tion takes into account both a linear interpretation of parts
(molecules), as well as a systemic interpretation of the whole
cluster (represented by the rst coordination sphere of supra-
molecular cluster).
Voronoi–Dirichlet Polyhedron (VDP)
The molecular Voronoi–Dirichlet Polyhedron (VDP) concept was
introduced to nd the number of neighboring molecules that
have contact with a given central molecule.25 It introduced the
idea of the face of the molecular VDP as a set of atomic VDP
faces corresponding to the adjacent contacts between the atoms
of two molecules. From this it was established that the area of
the face of a VDP corresponds to a molecular M1/Mn, and its
contact area is determined by the strength of molecular inter-
action. Such a concept was proposed by Blatov et al.26
Crystal design is an emergent property featuring irreduc-
ibility and unpredictability. The unpredictability of crystal
design has already been shown in the literature, and here we
also contribute to the evidence of this property by showing that
if one is able to estimate the interaction energies between
molecules, one only acquires data about the already-formed
crystal. This information does not guarantee the ability to
predict the structure of the future crystal. The energies obtained
are capable of informing one about the stability of the crystal to
a greater or lesser degree, whereas the distances between
molecules are able to determine which is closer or further—
synthons can inform us about the possibility of interactions
originating at the synthons and which might be repeated in
other similar systems. In our study we showed that molecules
with classical synthons are capable of forming hydrogen bonds
(3, 4, and 5), but, despite having the highest interaction ener-
gies, they are unable to be appointed as responsible for the
design of the crystal, as shown with the possible formation of
dimers (3, 4 and 5). On the other hand, for the irreducibility of
crystal design, it seems quite clear: there is no way to determine
the crystal design from a molecule, because an emergent
property cannot be deduced from a part. The molecule is able to
determine the molecular surface regions with higher or lower
electron density, with a greater or lesser possibility of electro-
static attraction; however, this is not enough for the under-
standing of crystal design. Thus, our study showed that, only
from the supramolecular cluster is it possible to observe the
participation of the topological component during the forma-
tion of the crystal. This is demonstrated by the fact that the
fragility of electrostatic interaction in a particular layer of
molecules is compensated by a strong interaction of molecules
in the layers above and below that given layer. Thus, we may
conclude that our approach is a challenging yet necessary
contribution to further research on the beautiful universe posed
by crystal design.
Hirshfeld surface (HS)
The supramolecular cluster was constructed considering the
central molecule M1 and the Mn molecules of the rst molec-
ular coordination sphere. The clusters were built using Crystal
Explorer® 3.1 soware.27
Computational calculations
The energies of intermolecular interactions in supramolecular
clusters of compounds 1–6 were determined by single point
calculations (without optimization of molecular geometry)
performed with geometries obtained from X-ray diffraction. All
quantum mechanical calculations were performed with the aid
of the Gaussian® 09 soware package.29 To obtain the interac-
tion energy between each M1/Mn dimer, second-order Moller–
Plesset (MP2) perturbation theory was used with a level of theory
of MP2/cc-pVDZ for compounds 2, 4, 5, and 6; and cc-pVDZ-PP
for compounds 1 and 3. The use of the cc-pVDZ-PP basis was
necessary in order to correct the relativistic effects of the iodine
atom. The counterpoise method of Boys and Bernardi30 was
employed to minimize the error of overlapping bases (BSSE).
The MP2 perturbation theory is the method for wave function
theories that is most frequently used in the study of intermo-
lecular interactions, due to the relationship between computa-
tional cost and good performance.30
Some authors have demonstrated that the MP2 method is
highly dependent on the set of basis used.30 Considering the
Acknowledgements
number of atoms in the molecules of compounds 1–6, the The authors are thankful for the nancial support from the
´
complexity of the calculations required, the computational cost, Conselho Nacional de Desenvolvimento Cientıco e Tec-
´
and the quality of results in some preliminary tests, we found nologico (CNPq)—Universal/Proc. 485893/2007-0, Universal/
that the level of calculation used in this study was satisfactory. Proc. 471519/2009-0, and MAPA/Proc. 578426/2008-0; and also
˜
`
Density functional theory (DFT) calculations were performed from the Fundaçao de Amparo a Pesquisa do Estado do Rio
using the Gaussian® 09 soware package29 with a uB97X-d/cc- Grande do Sul (FAPERGS)—PRONEX/Proc. 10/0037-8. The
pVTZ level of theory for compounds 2, 4, 5, and 6; and uB97X-d/ fellowships from CNPq (M.A.P.M., N.Z., H.G.B., I. M. G. and
cc-pVTZ-PP for compounds 1 and 3.
A.R.M.) and CAPES (A.Z.T.) are also acknowledged.
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12 M. A. P. Martins, D. N. Moreira, C. P. Frizzo, P. T. Campos,
K. Longhi, M. R. B. Marzari, N. Zanatta and
H. G. Bonacorso, J. Mol. Struct., 2010, 969, 111–119.
13 C. P. Frizzo, A. R. Meyer, G. S. Caleffi, L. V. Rodrigues,
M. R. B. Marzari, P. T. Campos, D. N. Moreira,
H. G. Bonacorso, N. Zanatta and M. A. P. Martins, J. Mol.
Struct., 2011, 1004, 45–50.
Notes and references
1 (a) G. M. Day, T. G. Cooper, A. J. Cruz-Cabeza, K. E. Hejczyk,
H. L. Ammon, S. X. M. Boerrigter, J. S. Tan, R. G. Della Valle,
E. Venuti, J. Jose, S. R. Gadre, G. R. Desiraju, T. S. Thakur,
B. P. van Eijck, J. C. Facelli, V. E. Bazterra, M. B. Ferraro,
D. W. M. Hofmann, M. A. Neumann, F. J. J. Leusen,
14 P. T. Campos, P. Machado, C. P. Frizzo, D. N. Moreira,
A. R. Meyer, H. G. Bonacorso, N. Zanatta, L. C. Ducati,
R. Rittner, C. F. Tormena and M. A. P. Martins, J. Mol.
Struct., 2011, 1006, 462–468.
J.
Kendrick,
S.
L.
Price,
A.
J.
Misquitta,
P. G. Karamertzanis, G. W. A. Welch, H. A. Scheraga,
Y. A. Arnautova, M. U. Schmidt, J. van de Streek, A. K. Wolf
and B. Schweizerr, Acta Crystallogr., Sect. B: Struct. Sci.,
2009, 65, 107–125 and references therein.
2 (a) R. J. Davey, S. L. M. Schroeder and J. H. Horst, Angew.
Chem., Int. Ed., 2013, 52, 2166–2179; (b) J. H. Harding,
C. L. Freemana and D. M. Duffy, CrystEngComm, 2014, 16,
1430–1438; (c) R. J. Davey, K. Allen, N. Blagden,
W. I. Cross, H. F. Lieberman, M. J. Quayle, S. Righini,
L. Seton and G. J. T. Tiddy, CrystEngComm, 2002, 4, 257–
264; (d) B. A. Grzybowski, C. E. Wilmer, J. Kim,
K. P. Browne and K. J. M. Bishop, So Matter, 2009, 5,
1110–1128.
´
´
´
´
15 J. Berna, M. Alajarın, J. S. Martınez-Espın, L. Buriol,
M. A. P. Martins and R.-A. Orenes, Chem. Commun., 2012,
48, 5677–5679.
16 (a) J.-M. Lehn, Angew. Chem., Int. Ed., 2013, 52, 2836–2850;
(b) J. Vicens and Q. Vicens, J. Inclusion Phenom. Macrocyclic
Chem., 2009, 65, 221–235; (c) J.-M. Lehn, Resonance, 1996,
39–53.
17 (a) A. Kurakin, The universal principles of self-organization
and the unity of Nature and knowledge, in The SOFT, 2007,
pp. 1–34, http://www.alexeikurakin.org/text/theso.pdf; (b)
¨
B. Kuppers, Naturwissenschaen, 1979, 66(5), 228–243.
3 (a) C. A. Hunter, J. F. McCabe and A. Spitaleri,
CrystEngComm, 2012, 14, 7115–7117; (b) A. Spitaleri,
C. A. Hunter, J. F. McCabe, M. J. Packer and S. L. Cockro,
CrystEngComm, 2004, 6, 489–493; (c) C. S. Towler and
L. S. Taylor, Cryst. Growth Des., 2007, 7, 633–638.
4 G. R. Desiraju, Angew. Chem., Int. Ed., 2007, 46, 8342–8356.
5 (a) P. Vishweshwar, A. Nangia and V. M. Lynch, J. Org. Chem.,
2002, 67, 556–565; (b) A. Dey, M. T. Kirchner, V. R. Vangala,
G. R. Desiraju, R. Mondal and J. A. K. Howard, J. Am. Chem.
Soc., 2005, 127, 10545–10559; (c) D. Chopra,
V. Thiruvenkatam, S. G. Manjunath and T. N. G. Row,
Cryst. Growth Des., 2007, 7, 868–874; (d) F. Di Salvo,
18 R. F. Ludlow and S. Otto, Chem. Soc. Rev., 2008, 37, 101–108.
19 E. Morin, La Methode, Du Seuil, Paris, France, 1977–1980,
´
vol. 1–2.
20 N. El-Hani and J. Queiroz, Scientia Studia, 2005, 3, 9–41.
21 (a) A. Gavezzotti, CrystEngComm, 2013, 15, 4027–4035; (b)
J. D. Dunitz and A. Gavezzotti, Chem. Soc. Rev., 2009, 38,
2622–2633.
22 (a) M. A. Spackman, J. J. McKinnon and D. Jayatilaka,
CrystEngComm, 2008, 10, 377–388; (b) M. A. Spackman and
D. Jayatilaka, CrystEngComm, 2009, 11, 19–32.
23 (a) J. P. M. Lommerse, A. J. Stone, R. Taylor and F. H. Allen, J.
Am. Chem. Soc., 1996, 118, 3108–3116; (b) B. Ehresmann,
B. Martin, A. H. C. Horn and T. Clark, J. Mol. Model., 2003,
93, 42–347; (c) J. E. Lennard-Jones, Cohesion, Proc. Phys.
Soc., 1931, 43, 461–482.
˜
B. Camargo, Y. Garcia, F. Teixidor, C. Vinas, J. G. Planas,
M. E. Light and M. B. Hursthouse, CrystEngComm, 2011,
13, 5788–5806; (e) E. Nahua, E. Kolehmainen and
M. Nissinen, CrystEngComm, 2011, 13, 6531; (f)
B. Chattopadhyay, S. Ghosh, S. Mondal, M. Mukherjee and
A. K. Mukherjee, CrystEngComm, 2012, 14, 837–846; (g)
K. Shivakumar, A. Vidyasagar, A. Naidu, R. G. Gonnade and
K. M. Sureshan, CrystEngComm, 2012, 14, 519–524.
6 O. V. Shishkin, V. V. Dyakonenko, A. V. Maleev,
D. Schollmeyer and M. O. Vysotsky, CrystEngComm, 2011,
13, 800–805.
7 J. D. Dunitz and A. Gavezzotti, Cryst. Growth Des., 2012, 12,
5873–5877.
8 Mercury® 3.0, The Cambridge Crystallographic Data Centre,
2012.
9 C. P. Frizzo, E. Scapin, P. T. Campos, D. N. Moreira and
M. A. P. Martins, J. Mol. Struct., 2009, 933, 142–147.
10 C. P. Frizzo, M. A. P. Martins, M. R. B. Marzari, P. T. Campos,
24 A. I. Kitaigorodskii, Molecular Crystals and Molecules,
Academic Press, New York, 1973.
25 W. Fischer and E. Koch, Z. Kristallogr., 1979, 150, 245–
260.
26 (a) V. A. Blatov, Crystallogr. Rev., 2004, 10, 249–318; (b)
T. G. Mitina and V. A. Blatov, Cryst. Growth Des., 2013, 13,
1655–1664; (c) M. R. Singh, P. Verma, H.-H. Tung,
S. Bordawekar and D. Ramkrishna, Cryst. Growth Des.,
2013, 13, 1390–1396; (d) E. V. Peresypkina and V. A. Blatov,
Acta Crystallogr., Sect. B: Struct. Sci., 2000, 56, 501–511; (e)
E. V. Peresypkina and V. A. Blatov, Acta Crystallogr., Sect. B:
Struct. Sci., 2000, 56, 1035–1045; (f) E. V. Peresypkina and
V. A. Blatov, J. Mol. Struct. Theochem., 1999, 498, 225–236;
(g) V. A. Blatov, L. V. Pogildyakova and V. N. Serezhkin, Z.
Kristallogr., 1998, 213, 202–209.
´
R. M. Claramunt, M. A. Garcıa, D. Sanz, I. Alkorta and
27 S. K. Wolff, D. J. Grimwood, J. J. McKinnon, M. J. Turner,
D. Jayatilaka and M. A. Spackman, CRYSTAL EXPLORER®
version 3.0, CrystalExplorer 3.0, University of Western
Australia, Perth, Australia, 2009, http://hirshfeldsurface.net.
J. Elguero, J. Heterocycl. Chem., 2010, 47, 1259–1268.
11 C. P. Frizzo, M. R. B. Marzari, D. N. Moreira, P. T. Campos,
N. Zanatta, H. G. Bonacorso and M. A. P. Martins, J. Mol.
Struct., 2010, 981, 71–79.
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´
28 V. A. Blatov and A. P. Shevchenko, TOPOS® version 4.0
soware, Samara State University, Ac. Pavlov St., 443011
Samara, Russia, http://www.topos.ssu.samara.ru.
29 M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria,
M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone,
J. A. Platts, J. Rezack, P. Hobza and J. G. Hill, J. Phys.
Chem. A, 2012, 116, 4159–4169.
31 M. A. P. Martins, M. R. B. Marzari, C. P. Frizzo, M. Zanatta,
L. Buriol, V. P. Andrade, N. Zanatta and H. G. Bonacorso,
Eur. J. Org. Chem., 2012, 7112–7119.
B. Mennucci, G. A. Petersson, H. Nakatsuji, M. Caricato, 32 M. A. P. Martins, E. Scapin, C. P. Frizzo, F. A. Rosa,
X. Li, H. P. Hratchian, A. F. Izmaylov, J. Bloino, G. Zheng,
J. L. Sonnenberg, M. Hada, M. Ehara, K. Toyota,
H. G. Bonacorso and N. Zanatta, J. Braz. Chem. Soc., 2009,
20, 205–213.
R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, 33 C. P. Frizzo, M. A. Villetti, A. Z. Tier, I. M. Gindri, L. Buriol,
O. Kitao, H. Nakai, T. Vreven, J. A. Montgomery Jr,
J. E. Peralta, F. Ogliaro, M. Bearpark, J. J. Heyd,
F. A. Rosa, D. Sanz, R. M. Claramunt and M. A. P. Martins,
Thermochim. Acta, 2013, 574, 63–72.
E. Brothers, K. N. Kudin, V. N. Staroverov, R. Kobayashi, 34 M. A. P. Martins, E. A. Guarda, C. P. Frizzo, M. R. B. Marzari,
J. Normand, K. Raghavachari, A. Rendell, J. C. Burant,
S. S. Iyengar, J. Tomasi, M. Cossi, N. Rega, J. M. Millam,
D. N. Moreira, N. Zanatta and H. G. Bonacorso, Monatsh.
Chem., 2008, 139, 1321–1327.
M. Klene, J. E. Knox, J. B. Cross, V. Bakken, C. Adamo, 35 D. N. Moreira, K. Longhi, C. P. Frizzo, H. G. Bonacorso,
J. Jaramillo, R. Gomperts, R. E. Stratmann, O. Yazyev,
A. J. Austin, R. Cammi, C. Pomelli, J. W. Ochterski,
N. Zanatta and M. A. P. Martins, Catal. Commun., 2010, 11,
476–479.
R. L. Martin, K. Morokuma, V. G. Zakrzewski, G. A. Voth, 36 Bruker, APEX2 (Version 2.1), COSMO (Version 1.56), BIS
P. Salvador, J. J. Dannenberg, S. Dapprich, A. D. Daniels,
(Version 2.0.1.9) SAINT (Version 7.3A) and SADABS
(Version 2004/1) and XPREP (Version 2005/4), Bruker AXS
Inc., Madison, Wisconsin, USA, 2006.
¨
O. Farkas, J. B. Foresman, J. V. Ortiz, J. Cioslowski and
D. J. Fox, Gaussian® version 09, Revision A.1, Gaussian,
Inc., Wallingford CT, 2009.
37 G. M. Sheldrick, Acta Crystallogr., Sect. A: Found. Crystallogr.,
2008, 64, 112–122.
30 (a) S. F. Boys and F. Bernardi, Mol. Phys., 1970, 19, 553–566;
´
(b) E. K. Riley, M. Pitonak, P. Jurecka and P. Hobza, Chem. 38 P. Coppens, L. Leiserowitz and D. Rabinovich, Acta
Rev., 2010, 110, 5023–5063; (c) E. K. Riley and P. Hobza, J. Crystallogr., 1965, 18, 1035–1038.
Phys. Chem. A, 2007, 111, 8257–8263; (d) K. E. Riley, 39 L. J. Farrugia, J. Appl. Crystallogr., 1997, 30, 565–566.
This journal is © The Royal Society of Chemistry 2014
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