Impact of confinement in multimolecular inclusion compounds of melamine and cyanuric acid

Andre Nicolai Petelski ab, Silvana Carina Pamies a, Agustín Gabriel Sejas a, Nélida María Peruchena *bc and Gladis Laura Sosa *ab
aGrupo de Investigación en Química Teórica y Experimental (QuiTEx), Departamento de Ingeniería Química, Facultad Regional Resistencia, Universidad Tecnológica Nacional, French 414 (H3500CHJ), Resistencia, Chaco, Argentina. E-mail:
bInstituto de Química Básica y Aplicada del Nordeste Argentino, IQUIBA-NEA, UNNE-CONICET, Avenida Libertad 5460, 3400 Corrientes, Argentina
cLaboratorio de Estructura Molecular y Propiedades, Facultad de Ciencias Exactas y Naturales y Agrimensura, Universidad Nacional del Nordeste, Avenida Libertad 5460, 3400 Corrientes, Argentina. E-mail:

Received 17th December 2018 , Accepted 22nd February 2019

First published on 25th February 2019

Supramolecular cavities can be found in clathrates and self-assembling capsules. In these computational experiments, we studied the effect of folding planar hydrogen-bonded supramolecules of melamine (M) and cyanuric acid (CA) into stable cage-like quartets. Based on dispersion-corrected density functional theory calculations at the ωB97XD/6-311++G(d,p) level, we show the flexibility of M and CA molecules to form free confined spaces. Our bonding analysis indicates that only CA can form a cage, which is more stable than its planar systems. We then studied the capacity of the complexes to host ionic and neutral monoatomic species like Na+, Cl and Ar. The encapsulation energies range from −2 to −65 kcal mol−1. A detailed energy decomposition analysis (EDA) supports the fact that the triazine ring of CA is superior to the M one for capturing chloride ions. In addition, the EDA and the topology of the electron density, by means of the Atoms in Molecules (AIM) theory and electrostatic potential maps, reveal the nature of the host–guest interactions in the confined space. The CA cluster appears to be the best multimolecular inclusion compound because it can host the three species and keep its cage structure, and therefore it could also act as a dual receptor of the ionic pair Na+Cl. We think these findings could inspire the design of new heteromolecular inclusion compounds based on triazines and hydrogen bonds.


Extramolecular, exomolecular, or multimolecular inclusion compounds are special cases within host–guest chemistry, in which more than one molecule creates the cavity for the guest complexation.1 In this context, non-covalent interactions play a fundamental role. Firstly, they are responsible for keeping the cavity, and second, they hold the guest inside it. These systems have prompted a great volume of research2,3 due to their promising applications; for instance, sequestration of small molecules, gases and ionic species.

Clathrates are the most well-known multimolecular inclusion compounds found in the crystal state, wherein hydroquinone clathrates are the most representative ones. It has been shown that hydroquinone can form these structures with several molecules and atomic species, like Xe,4 hydrochloric acid,5 carbon dioxide,6 methanol and acetonitrile.7 When clathrates are formed, a special arrangement of the multimolecular host is only stabilized due to the presence of the guest. This process is the result of a balance between attractive and repulsive forces. Takasuke Matsuo indicated that there is cooperative molecular recognition in the formation course,1 and other authors have assumed that there is no specific bond between the host and the guest molecules.6 Nevertheless, M. Ilczyszyn et al.8 have reported hydrogen bonds between the Xe atoms and the –OH groups that form the cavity within the famous Hydroquinone@Xe clathrates, which is a very specific interaction. Although they are classified as van der Waals molecules because they are weakly bound, these types of systems are also hydrogen-bonded complexes.9

While metal–organic cages are widely known2 and have found many applications,10–12 hydrogen-bonded capsules are still in the early stages of research. Rebek and coworkers have obtained perhaps the most prominent multimolecular host–guest complex: the tennis ball.13,14 Among others, they have created several self-assembling capsules, with the ability of capturing small molecules like methane,15 and even dimers.16,17 Atwood18,19 and Whitesides20 have also mastered the supramolecular forces to create hydrogen-bonded capsules with enclosed spaces. In this context, triazine rings, like melamine (M) and cyanuric acid (CA), have been shown to be suitable building blocks for creating supramolecular boxes in solution.21 In the solid state, for instance, Mascal et al.22 have obtained a cylindrophane based on two-faced CA rings that effectively captures fluoride ions, while Frontera et al.23 have crystalized complexes of CA molecules, which were previously covalently modified, with chloride ions.

Confinement using non-covalent interactions is also present in several host–guest systems, in which the host is a simple molecule. By far, calixarenes and cucurbituriles are the smallest molecules that can host atomic species and small molecules. Sashuk et al.24 have obtained a square shaped molecule that can capture a single water molecule or a fluoride anion. Endohedral fullerenes are also a subject of study in this field. Very recently, it has been shown that the confinement of anions within C60 turns it into a big anion.25 Furthermore, the presence of cations was shown to drive the self-assembly of cavitands into multimolecular complexes.26

Chemical species have shown different properties when they are confined. For instance, in catalysis27 and hydrogen-bonded systems.28,29 Therefore, in this work, we investigate the impact of folding planar supramolecules of M and CA into cage-shaped complexes. We focus on the stability of hydrogen bonds and the free confined spaces they hold. We then analyze the capacity of the triazine rings and the chemical spaces to capture monoatomic species like Na+, Cl and Ar. Finally, through our computational experiments, we demonstrate herein that CA is a more robust building block for fabricating supramolecular inclusion compounds.

Computational methods

All computations were performed with dispersion corrected density functional theory (DFT-D) implemented in the Gaussian 03 package,30 by using the ωB97XD hybrid functional from Head Gordon et al.31 with the 6-311++G(d,p) basis set. This method has been proved to show a great performance in similar systems.32–34 The minimum energy nature of the optimized structures was verified using the vibrational frequency analysis.

The bonding energy ΔEbond (eqn (1)) values were obtained at the same level of theory using the approach of Fonseca Guerra et al.,35 calculated as the sum of the interaction energy of the complex ΔEint and the deformation energy ΔEdef.

ΔEbond = ΔEint + ΔEdef(1)

In this equation, the interaction energy ΔEint is the difference between the energy of the complex and the sum of energies of the monomers with the structures that form in the complex. The deformation energy ΔEdef is the energy needed to deform the structure of monomers from their isolated state to that one they acquire in the complex. The ΔEint of the inclusion compounds was further decomposed into encapsulation energy ΔEenc and hydrogen bonding energy ΔEHB according to eqn (2)–(4).

ΔEint = Ecage@A − ΣEmEA(2)
ΔEint = (Ecage@AEcageEA) + (Ecage − ΣEm)(3)
ΔEint = ΔEenc + ΔEHB(4)
Here, Ecage@A is the energy of the multimolecular inclusion compound (with A = Na+, Cl, Ar), Em is the energy of the monomers (either M or CA) and EA is the energy of the host; then, Ecage is the energy of the system without the guest, with the geometry of cage@A. All the interaction energies were corrected for the basis set superposition error (BSSE) within the counterpoise procedure of Boys and Bernardi.36

The non-covalent interactions were analyzed within the framework of the atoms in molecules theory.9 Total electron densities were calculated at the same level of theory. The local properties at the bond critical points were computed using the AIMALL37 and Multiwfn38 programs. Molecular electrostatic potential surfaces were generated by mapping the electrostatic potential V(r) on the electronic density surfaces. We considered an isosurface of ρ(r) = 0.001 a.u., which was suggested by Bader et al.39 and represents the effective molecular volume.

The interactions between the host and the isolated guests were also analyzed with the localized molecular orbital energy decomposition40 (LMOEDA) method at the BLYP-D3/6-311++G(d,p) level of theory, using the GAMESS41 quantum chemistry package. This method partitions the interaction energy into four components, according to eqn (5):

ΔEint = ΔEele + ΔEex–rep + ΔEpol + ΔEdisp(5)
where the term ΔEele describes the classical electrostatic interaction (Coulomb) of the occupied orbitals of one monomer with those of another monomer; ΔEex–rep is the attractive exchange component resulting from the Pauli exclusion principle and the interelectronic repulsion; ΔEpol accounts for polarization and charge transfer components; and ΔEdisp corresponds to the dispersion term.

All images were created with CYLview,42 VMD43 and AIMAll37 software.

Results and discussion

Geometries and relative stabilities

We started from the planar complexes. Then, the cage-like clusters were built by folding the planar ones in order to form cyclic quartets, and keeping the original hydrogen bonds (H-bonds). The structures of the systems are shown in Fig. 1, and the corresponding energies are displayed in Table 1. All the cages assume a C2 symmetry. When folding the planar systems into cyclic quartets, two extra H-bonds are formed (or three in the case of M2CA2). Therefore, one may expect a stronger bonding energy in the latter. However, there is an energy penalty related to the acceptor directionality of the H-bond.44 Although the differences in interaction energies are around 5 kcal mol−1, ΔEbond values show there is no extra stabilization. The only exception is the second cage of CA (CA4-2), which is 4.8 kcal mol−1 more stable than its planar counterpart. The formation of the cages also requires a deformation energy, which is almost zero for CA4-2 and relatively high for M4 and M2CA2.
image file: c8cp07705c-f1.tif
Fig. 1 Optimized geometries at the ωB97XD/6-311++G(d,p) level of theory. Black arrows indicate the folding of the planar systems.
Table 1 Bonding and interaction energies (kcal mol−1) calculated at the ωB97XD/6-311++G(d,p) level of theory
System Type ΔGbond ΔEbond ΔEdef ΔEint
M4 Planar 0.7 −39.6 0.8 −40.4
Cage 6.9 −40.1 4.6 −44.7
CA4-1 Planar −6.9 −40.9 1.2 −42.1
Cage 0.2 −40.6 −0.5 −40.1
CA4-2 Planar −6.4 −41.6 1.0 −42.6
Cage −5.6 −46.4 0.7 −47.1
M2CA2 Planar −21.4 −60.0 4.5 −64.5
Cage −13.3 −60.8 7.4 −68.2

Finally, the Gibbs free energies of bonding show that the planar systems are by far the most stable ones. In the case of CA4-2, the planar and cage systems differ by just 0.8 kcal mol−1. Since this energy difference is very small, we can anticipate that the system will need the help of the guest to favor this cage-like cluster. In the next sections, we will show that the ΔGbond for CA4-2 is notably enhanced due to the presence of ions.

Topology of the cavities

All the cage-shaped quartets form regular cavities with a cup-like shape akin to that of calixarenes. From their molecular electrostatic potential maps shown in Fig. 2(a and b), it can be seen that the inside is more positive than the outside surface. The CA4-1 cage creates the most positive cavity, followed by CA4-2, the mix complex of M2CA2 and M4. In order to gain more information on the cavities, we then obtained sections of the electron density ρ(r), which is also plotted in Fig. 2(c). As shown in Fig. 2, M4, CA4-2 and M2CA2 display a cup-like shape, which is quite similar to some calixarenes.45,46 Furthermore, the CA4-1 complex shows a cage-like cluster with a tubular cavity, alike that observed in the pillar[4]pyridinium molecular box.24 This structure suggests that linear molecules like H2 could fit inside the cavity.
image file: c8cp07705c-f2.tif
Fig. 2 (a) Side views of molecular electrostatic potential (MEP) maps on the 0.001 a.u. electron density isosurfaces. (b) Top views of MEPs. The values of the MEP vary between −31 kcal mol−1 (red) and 56 kcal mol−1 (blue). (c) Contour plots of cage-shaped complexes superimposed onto molecular graphs. The free space is colored in light blue.

Table 2 reports some meaningful topological parameters of H-Bonds. That is, the electron density ρ at the BCPs, which reflects the strength of a bond. The total energy density H = G + V, where G and V are the kinetic and potential energy densities, respectively. Negative values of H are usually associated with a covalent character. Nevertheless, when H is negative, the hydrogen bonds are stronger than those with positive values.34,47,48 The ellipticity ε measures the extent of the electron density within a plane containing the line path. In addition, it is a direct measure of the stability of a given bond, because it takes infinite large values preceding the coalescence of a ring critical point and a BCP.49 The delocalization [δ(A,B)] index is a measure of the number of electrons that are shared or exchanged between A and B. Finally, the repulsive part of the local potential energy density Vrep accounts for electron–electron and nuclear–nuclear repulsion.

Table 2 Values of local topological properties (a.u.) at the bond critical pointsa
Complex Type Atoms ρ H ε δ(H,N/O) V rep
a Due to symmetry reasons, average values are shown. b The sub index up corresponds to the average values of the largest opening. c The sub index down corresponds to the average values of the smallest opening. d Middle corresponds to hydrogen bonds positioned at the middle of the cup-like structure.
M4 Planar H⋯N 0.029 0.001 0.073 0.096 0.888
Cage H⋯N 0.024 0.001 0.093 0.081 0.782
CA4-1 Planar H⋯O 0.031 0.001 0.033 0.087 0.914
Cage H⋯O 0.023 0.002 0.026 0.068 0.777
CA4-2 Planar H⋯O 0.032 0.001 0.032 0.089 0.985
Cage H⋯Oupb 0.022 0.003 0.041 0.064 0.695
H⋯Odownc 0.032 0.001 0.032 0.086 1.088
M2CA2 Planar H⋯O 0.025 0.002 0.051 0.076 0.759
H⋯N 0.045 −0.007 0.065 0.138 1.507
Cage H⋯Oup 0.018 0.002 0.078 0.056 0.533
H⋯Nmiddled 0.033 −0.001 0.096 0.108 1.188
H⋯Odown 0.021 0.002 0.092 0.062 0.744

When going from the planar systems to the cage-like structures, H-bonds undergo an important bending. This deformation has an impact on the acceptor directionality,50 and it is clearly reflected in their topological values (see Table 2). According to ρ, the strength of the bond decreases with the bending along with a decrease in δ(H,N/O). The ellipticity also increases, except in CA4-1. The fact that the cup-like structure of CA4-2 is more stable than the planar form can be undoubtedly understood by looking at the topological parameters. The CA4-2 cup-shaped complex forms 8 H-bonds, four within the largest opening (H⋯Oup) and four below it (H⋯Odown), having different topological properties. As can be seen from Table 2, the bending does not significantly affect the H-bond properties of the smallest opening, if we compare them with the planar system. Therefore, the two extra H-bonds that are formed in the cage complex are enough to compensate the decrease in interaction energy due to the directionality.

Encapsulation effect

As was shown in the previous section, all the cage-shaped complexes form regular cavities that could host atomic species, or even linear molecules. Therefore, we put them to test with ionic and neutral species like sodium, chloride and argon. All the systems were fully optimized, and those who kept their original shapes are reported. Table 3 shows the bonding analysis of the multimolecular inclusion complexes. Gibbs free energies and bonding energies are more stabilized in the presence of the hosts, except for M4@Ar and CA4-1@Ar. Among all the complexes, just CA4-2 can host a sodium cation and keep its original shape, having the greatest encapsulation energy. The other cages (M4, CA4-1 and M2CA2) are fully deformed in the presence of Na+. This is because the coordinating groups of CA4-2 (C[double bond, length as m-dash]O groups) converge to the metal in the complex, similar to guanine quartets.51 Whilst in the other cases, both endocyclic nitrogens and carbonyl groups are not adequately orientated to coordinate the metal. One should also take into account that the triazine rings cannot interact with metals via the π cloud.
Table 3 Bonding analysis (kcal mol−1) of multimolecular inclusion compounds obtained at the ωB97XD/6-311++G(d,p) level of theory
Complex Guest ΔGbond ΔEbond ΔEdef ΔEint ΔEHB ΔEenc
M4 Cl −8.3 −66.6 12.1 −78.7 −44.1 −34.5
Ar 10.3 −44.1 4.3 −48.4 −45.0 −3.4
CA4-1 Cl −40.4 −92.0 2.3 −94.3 −40.3 −54.0
Ar 2.0 −45.0 −1.1 −43.9 −40.1 −3.8
CA4-2 Na+ −51.2 −102.6 6.6 −109.2 −44.8 −64.3
Cl −37.0 −88.3 3.1 −91.3 −45.2 −46.2
Ar −2.6 −49.7 0.2 −49.9 −47.1 −2.8
M2CA2 Cl −39.0 −97.6 10.9 −108.4 −66.8 −41.6
Ar −9.6 −64.9 7.0 −71.9 −68.4 −3.5

Concerning chloride, the greatest ΔEenc is shown for CA4-1, followed by CA4-2, M2CA2 and M4. This trend suggests that the triazine skeleton of CA is better than the melamine one to capture anions, which could be used for synthesizing new heterocalixarenes. In this context, Frontera et al. have already shown experimental evidence of chloride–π interactions in CA crystals.23 The deformation energies are also more favorable for CA complexes. For the sake of comparison, we computed the corrected interaction energy (ωB97XD/6-311++G(d,p)//BP86/TZ2P) for a heterocalixarene–chloride complex recently reported by Caramori et al.52 (see compound 1·Cl). The complex has an encapsulation energy of −31.8 kcal mol−1 (BP86/TZ2P energy52 is −37.6 kcal mol−1), which is very close to those in Table 3, and even smaller. Finally, since the second cage of CA can host both Na+ and Cl, one may think that this system could host both ions at the same time. Indeed, we optimized the CA4-2 system with the NaCl ionic pair and the complex keeps its original shape (see Fig. S1, ESI). ΔEenc is −55.7 kcal mol−1 (value not included in Table 3), and ΔEdef is even lower than for the isolated ions (1.6 kcal mol−1).

When an argon atom is placed within the cavity, the most favorable values are, again, those for CA complexes, as shown in Table 3. That is, high encapsulation energies and low deformation energies.

Confined interactions

Before evaluating the forces that take part in the encapsulation, we must know the nature of the interactions between the atomic species and the isolated triazines. Therefore, we computed a potential energy scan by varying the distance (r) between Cl/Ar and the triazine ring center. The systems were optimized with C3 symmetry, and the r distance was varied from 2.7 Å to 3.4 Å with a 0.05 Å step (15 optimizations). We then decomposed the interaction energy at every step and the profile for chloride is plotted in Fig. 3 (see energy profile for argon in Fig. S2, ESI).
image file: c8cp07705c-f3.tif
Fig. 3 Variation of LMOEDA energy components as a function of r. Chemical structures of the scanned systems are shown, where r is the scanned distance.

At first glance, chloride interacts more strongly with CA than M along the whole scanned distance. At the equilibrium geometry, the interaction energy is −8.7 kcal mol−1 with M and −19.7 kcal mol−1 with CA. Both values are in very good accordance with previous MP2 computations for the same/similar systems. While Berryman et al.53 found a ΔEbond = −8.33 kcal mol−1 for a triazine ring (without –NH2 groups) at the MP2/aug-cc-pVDZ level of theory, Frontera et al.23 obtained a ΔEbond of −22.81 kcal mol−1Ebond = −16.45 kcal mol−1 with BSSE) for the CA@Cl complex at the MP2(full)/6–31++G** level of theory. The profile of the energy components indicates that the electrostatic part is the dominant factor of the interaction energy. In addition, the interaction between Cl and CA has larger charge transfer and dispersion components. These results are in agreement with the trends of encapsulation energies, reaffirming, therefore, the fact that the CA skeleton is a better candidate for synthesizing molecular hosts based on triazines.

Concerning the interactions with argon, the differences in interaction energies are negligible (the energy profiles are shown in the ESI).

When M⋯Cl/Ar and CA⋯Cl/Ar interactions are confined in the cavity, their nature changes drastically. Table 4 collects the LMOEDA analysis of all complexes. In general, the attractive nature of the encapsulation is mostly explained by the charge transfer component. For instance, the interaction of chloride with CA goes from 46% electrostatic in the non-confined state to 5.6% in the CA4-1 complex. The other complexes show repulsive electrostatic interactions, and the trend is shown in Fig. 2 (CA4-2 < M4 < M2CA2). The fact that the M4@Cl cage shows a larger charge transfer contribution is due to the presence of N-H⋯Cl H-bonds that hold the anion. Moreover, the Pauli repulsion is again larger for the systems with M, and the dispersion component is almost the same for all the systems.

Table 4 Energy decomposition analysis (in kcal mol−1) of equilibrium geometries obtained at BLYP-D3/6-311++G(d,p)
Complex Guest ΔEele ΔEex–rep ΔEpol ΔEdisp ΔEint
M Cl −2.90 13.08 −16.12 −2.81 −8.74
Ar 5.69 2.90 −8.62 −1.35 −1.38
CA Cl −21.52 26.98 −19.93 −5.23 −19.71
Ar 6.11 2.94 −9.16 −1.39 −1.51
M4 Cl 5.58 63.46 −93.33 −11.45 −35.45
Ar 48.46 8.94 −58.03 −3.93 −4.55
CA4-1 Cl −4.92 34.76 −75.35 −7.71 −53.22
Ar 44.79 10.1 −55.82 −4.63 −5.56
CA4-2 Cl 0.03 31.73 −70.88 −6.99 −46.11
Ar 42.78 6.49 −50.31 −3.02 −4.05
M2CA2 Cl 7.78 45.53 −86.24 −8.61 −41.46
Ar 51.65 9.40 −61.78 −4.18 −4.91

All of these interaction energy components lead us to think that the CA molecule will be the best choice, not only because of an improved interaction energy with the ions but also because this fact will most likely guide the process to the target system. In the beginning of the assembly, the process will be under the control of the electrostatic energy. When the cage is formed, the ion will be held by stronger orbital interactions than in the free state. Of course, one has to think that all the cages should be equipped with functional groups to improve the stabilization. They can act like “arms”23 or “tweezers”54 in order to assist in holding the guest with extra interactions. In order to pre-induce complexation,20 another approach could be the joint attachment between two or more monomers.22,55

When either chloride or argon approaches the triazine ring, interactions with the π system are expected.52,56 In the framework of QTAIM, a bond path is a line of maximum electron density that links a pair of nuclei57,58 at the equilibrium geometry. When looking at the L(r) function (−∇2ρ) of M and CA (Fig. 4), a nonbonding charge concentration (NCC) over N atoms and a hole over C can be observed. Note that the NCCs correspond to the Lewis model of lone pairs. In the triazine ring of CA, the lone pairs of N appear delocalized. Therefore, BCPs between either Cl or Ar and N atoms would likely be present. Fig. 5 shows the molecular graphs of the complexes M⋯Cl/Ar and CA⋯Cl/Ar, in which BCPs between Cl/Ar and N atoms are observed, and Table 5 reports the average properties of those BCPs. The reported values are characteristic of weak closed-shell interactions: low values of ρ, positive laplacian ∇2ρ and H ≈ 0. Since ρ and δ(A,B) are good indicators of the bond strength, their values are in line with the interaction energies. In addition, Vrep is more repulsive for CA⋯Cl, as was shown in the previous section. Observations regarding Argon indicate that there are no significant differences between M and CA.

image file: c8cp07705c-f4.tif
Fig. 4 Three-dimensional isosurfaces of L(r) = 1.5 a.u. for (a) melamine and (b) cyanuric acid. Circles A and B correspond to L(r) = 1.03 and 3.0, respectively. Bonding (BCC) and nonbonding charge concentrations (NCC) are indicated with arrows.

image file: c8cp07705c-f5.tif
Fig. 5 Molecular graphs of M⋯Cl/Ar and CA⋯Cl/Ar complexes. Small red dots are BCP, yellow dots are ring critical points and green dots are cage critical points.
Table 5 Local topological properties at N⋯Cl/Ar bond critical pointsa (a.u)
Complex Atoms ρ 2ρ H ε δ(A,B) V rep
a Average values of bond critical points.
CA⋯Cl N⋯Cl 0.009 0.029 0.001 2.343 0.064 0.189
CA⋯Ar N⋯Ar 0.003 0.011 0.001 0.370 0.017 0.055
M⋯Cl N⋯Cl 0.006 0.016 0.001 3.416 0.040 0.104
M⋯Ar N⋯Ar 0.003 0.011 0.001 1.216 0.015 0.052

It is worth noting that some meaningful QTAIM parameters (ρ, ESP, Vrep and charge transfer) are directly related to LMOEDA terms (ΔEint, ΔEele, ΔEex–rep, ΔEpol and ΔEdisp), as shown in Fig. S3–S6 in the ESI. These relationships were obtained by computing the local topological properties over the scanned systems, which were discussed above. For instance, among other relationships between EDA components and AIM parameters,59,60 it has been shown that there is a linear relationship between ρ and the interaction energy.48,61 However, we found herein a quadratic relationship between these two parameters. In addition, the sum of the ESPs at the BCPs vs. ΔEele and the charge transfer obtained by QTAIM vs. ΔEpol were found to linearly correlate with both CA⋯Cl and M⋯Cl systems. In the case of Argon, the charge transfer values obtained with QTAIM fail to describe its behavior. Previous studies on Voronoi Deformation Densities have shown that Bader's charges fail to describe some systems.62 Nevertheless, according to these relationships, the topological properties can be used to monitor either the strength, electrostatic or repulsive features of the interactions.

Now that we have identified the nature of the interactions between the atomic species and M and CA isolated rings, we analyze the situations within the cavities. Fig. 6 shows the molecular graphs of the multimolecular inclusion compounds, and the topological properties of the inclusion interactions are reported in Table S1 (ESI). The presence of BCPs between the multimolecular hosts and the guests clearly show the encapsulation effect. They show typical values of weak closed-shell interactions. The values of ρ (BCP) are within the range of 0.004–0.023 a.u. for the systems with chloride and 0.003–0.004 a.u. for the systems with argon. The H-bonds that keep the cavity are also intact, and their topological properties do not change significantly (see Table S2, ESI). When the M⋯Cl/Ar and CA⋯Cl/Ar interactions are confined, their topological properties display a different behavior. These changes are consistent with those observed in the LMOEDA analysis. For example, the interactions with chloride are weaker than those of chloride with the isolated rings. Nevertheless, the presence of multiple bond paths increases the interaction energy. Interestingly, in some cases, the BCPs appear between C atoms and the guests, instead of N (e.g., CA4-2). In the case of M4@Cl, the anion is also held by N–H⋯Cl H-bonds. It is also interesting to point out that in most of the cases, the host–guest N⋯Cl interactions show significantly lower values of ellipticity (ε) when they are compared with the non-confined values. This might indicate that the interactions are more stable within the cage. Furthermore, when comparing CA4-1@Cl and CA4-2@Cl, the sum of ρ and δ(A,B) are in line with the encapsulation energy ΔEenc. The repulsion (∑Vrep) is also greater for the CA4-1@Cl complex, also in agreement with values in Table 4. Even though we cannot form a strong conclusion regarding the character of the interactions, what is evident herein are the differences between the confined and non-confined states. The multimolecular hosts produce a chemical space with an environment that is totally different from the separate triazine rings.

image file: c8cp07705c-f6.tif
Fig. 6 Molecular graphs of multimolecular inclusion compounds.

On the other hand, the CA4-2 cage is the only system that can capture Na+ without losing the original cup structure. The cation is tetracoordinated, and the BCPs show values that are characteristic of closed-shell interactions as well: low values of ρ, and positive values of ∇2ρ and H. According to Bader, this type of interaction cannot be classified as a metal coordination (relatively low values of ρ, small negative values for H with G/ρ ≅ 1 and small positive values for values ∇2ρ).63 It should also be mentioned that barbituric acid and its derivatives have already been used to coordinate metals and cations in supramolecular compounds.64 In some crystals of barbituric acid65 and 5,5-diethylbarbiturato,66 for example, Na+ and K+ ions have been observed to be hexa-(NaO6) and tetra-coordinated (O2–K–O2–K–O2) by the C[double bond, length as m-dash]O groups. Furthermore, the same system (CA4-2@Na+) can simultaneously hold chloride, that is, CA4-2@NaCl. Its molecular graph (Fig. 7) shows a different topology for chloride. In this complex, the anion is pushed down the cavity because of the presence of the cation. Consequently, the anion interacts less with the π cloud of CA. Note that the encapsulation energies for the separate ions Na+ and Cl are −64.3 and −46.2 kcal mol−1, respectively (Table 3). However, the encapsulation energy of the ionic pair is −55.7 kcal mol−1. This suggests that the whole encapsulation energy of NaCl might just come from the coordination of the Na+ counter ion.

image file: c8cp07705c-f7.tif
Fig. 7 Molecular graph of CA cage-shaped cluster acting as a dual receptor of sodium cation and chloride.


In this work, we have conducted a DFT-D analysis over a set of multimolecular inclusion compounds based on M and CA. Our study has shown that these molecules are able to form confined cavities alike calixarenes with the ability to host small atomic species. Whilst the cavity is created by hydrogen bonds, in most of the cases, the guest species are encapsulated due to the interactions with the π systems of melamine and cyanuric acid. Nevertheless, melamine can retain the anion with its amino groups (N–H⋯Cl), while cyanuric acid can coordinate cations with its keto groups (C[double bond, length as m-dash]O⋯Na+).

Our bonding analysis suggests that the cage-shaped supramolecule of CA is more stable than its open structure by ∼5 kcal mol−1. In the other cases, the extra hydrogen bonds, which are created in the cyclic complexes, are not enough to compensate the weakening of the interactions due to the bending. The triazine skeleton of CA was also shown to be more robust in capturing an ionic guest. In addition, our computations suggest that CA could act as a dual receptor of ionic pairs. Therefore, with proper covalent modifications, CA seems to be the most versatile building block for synthesizing supramolecular inclusion compounds via hydrogen bonds. Nevertheless, the other cage-shaped structures could serve as model sets for constructing new heteromolecular hosts.

Conflicts of interest

There are no conflicts to declare.


The authors gratefully acknowledge the financial support from the Secretaría de Ciencia y Tecnología, Universidad Tecnológica Nacional, Facultad Regional Resistencia. A. N. P. thanks the National Scientific and Technical Research Council (CONICET), Argentina, for a doctoral fellowship. N. M. P. is a CONICET career researcher.

Notes and references

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Electronic supplementary information (ESI) available. See DOI: 10.1039/c8cp07705c

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