Noncovalent Interactions in Succinic and Maleic Anhydride

Dec 20, 2017 - Herein, we present a study of the short contacts that several heterocycles of the same family, namely, succinic and maleic anhydrides, ...
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Article Cite This: Cryst. Growth Des. XXXX, XXX, XXX−XXX

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Noncovalent Interactions in Succinic and Maleic Anhydride Derivatives Jorge Echeverría* Departament de Química Inorgànica i Orgànica (Secció Inorgànica) and Institut de Química Teòrica i Computacional IQTC-UB, Universitat de Barcelona, Martí i Franquès 1-11, 08028 Barcelona, Spain S Supporting Information *

ABSTRACT: Herein, we present a study of the short contacts that several heterocycles of the same family, namely, succinic and maleic anhydrides, maleimide, and succinimide establish in their condensed phases. DFT calculations on model systems in the gas phase have allowed us to calibrate the strength of such interactions, obtaining associated energies up to 2 kcal/ mol. We have performed MEP and EDA analysis to unveil their nature, which is mainly electrostatic with some London dispersion contribution. Furthermore, the origin of the interaction is the existence of a charge depletion region (a π-hole) in the inner part of the rings. This hole interacts with a Lewis base in a precise topological way, with the contacts showing a high directionality as revealed by the analysis of hundreds of crystal structures. We believe that the description for the first time of these interactions, along with their abundance, can assist their use as a tool in crystal design.



INTRODUCTION Noncovalent interactions have attracted much attention in recent years due to their central importance in numerous chemical and biological processes.1,2 In particular, electrostatically driven interactions based on electron density “holes” have been widely studied from a theoretical point of view and also experimentally identified in several families of compounds.3 Hole interactions occur between an electron rich species (the Lewis base) and a molecule containing a region of electron density depletion (the Lewis acid).4 Such regions are associated with different types of empty orbitals. For instance, group 13 tricoordinated species contain two π-holes coincident with two p-antibonding orbitals perpendicular to the molecular plane.5,6 Group 14 tetracoordinated molecules have σ-holes in the regions opposite to the four covalent bonds.7,8 In CH3F, for example, the polarization of the C−F bonds leads to an enhanced σ-hole between the three H atoms that can be easily confirmed by measuring the molecular electrostatic potential (MEP). Also, group 15 element-containing compounds can participate in hole interactions as electron deficient species.9,10 Many studies have explored the presence of σ/π-holes in other families of compounds.11−17 Seminal work by Bürgi and Dunitz investigated experimental data from crystal structures to prove the capability of carbonyls to act as electrophiles in nucleophilic attack reactions.18−20 More recently, it has been seen that carbonyl-containing species can act as electron acceptors in πhole interactions, as in the case of carbon dioxide21 and naphthalene derivatives.22 Cyclic molecules, from organic hexafluorobenzene23 and cycloalkanes24 to inorganic borazine,25,26 have been studied as species with electron-deficient regions able to participate in σ-hole and π-hole interactions. In © XXXX American Chemical Society

general, those studies are important because identifying and rationalizing these interactions allow their use in crystal engineering, materials design, and biochemical processes. Maleic anhydride (MA) is a derivative of maleic acid that has been widely used in polymer science, as, for example, in the functionalization of polypropylene27,28 or in the development of new advanced biomaterials.29 In particular, MA copolymers are important in multiple research fields such as biomedicine,30 composites,31 or metal protection.32,33 The nitrogen analogous, maleimide (MI), in which the central oxygen atom has been substituted by NH, is utilized for technological and biotechnological purposes.34,35 Hydrogenation of the double bond of MA and MI cycles leads to the formation of succinic anhydride (SA) and succinimide (SI), respectively. SA is also a well-know molecule with several applications. For instance, it has been reported that SA-modified celluloses can be easily utilized for the removal of heavy metals from aqueous solutions.36 A derivative, n-octenyl-SA, is commonly used as food starch modifier.37 On the other hand, succinimide (SI) is extensively used in organic synthesis and drug design.38−40 Here, our goal is to investigate the capability of MA, MI, SA, SI, and their derivatives to participate in hole-interactions. We believe that the abundance and extensive use of such species make them an appealing subject of research. Moreover, the presence of heteroatoms can facilitate the formation of different regions of charge concentration and depletion necessary for the establishment of hole-interactions. Accordingly, we have Received: October 30, 2017 Revised: November 23, 2017

A

DOI: 10.1021/acs.cgd.7b01511 Cryst. Growth Des. XXXX, XXX, XXX−XXX

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Article

Figure 1. Molecular electrostatic potential (MEP) maps on the 0.002 au isosurface of (a) succinic anhydride, (b) succinimide, (c) N-methylsuccinimide, (d) N-phenyl-succinimide, (e) maleic anhydride, (f) maleimide, (g) N-methyl-maleimide, and (h) N-phenyl-maleimide. Energy values are given in kcal/mol.

Table 1. Geometrical Parameters and Interaction Energies for the Adducts Formed by MA, MI, SA, SI (and Derivatives) Interacting with N2 as the Lewis Base, Calculated at the M06-2X/aug-cc-pVTZ Level of Theorya compound

dC1 (Å)

dC2 (Å)

dcent (Å)

α (deg)

β (deg)

ΔE (kcal/mol)

ΔECP (kcal/mol)

MA MI MI-CH3 MI-C6H5 SA SI SI-CH3 SI-C6H5

3.244 3.365 3.075 3.234 3.148 3.237 3.177 3.055

3.236 3.346 3.497 3.267 3.104 3.237 3.116 3.252

3.100 3.196 3.164 3.125 2.925 3.007 2.945 2.965

85.6/86.0 86.3/87.3 74.7/95.5 84.1/85.7 86.7/88.9 89.1/89.1 86.1/89.1 82.2/91.9

169.3 175.2 128.2 134.7 156.7 147.3 130.6 133.4

−1.49 −1.12 −1.50 −1.83 −2.22 −1.76 −2.08 −2.35

−1.28 −0.92 −1.25 −1.50 −1.96 −1.51 −1.77 −2.00

a ΔECP is the Counterpoise-corrected interaction energy. dC1 and dC2 are the distances between the donor and the two carbonyl carbon atoms, respectively; dcent is the intermolecular distance between N2 and the centroid of the ring. Angles α are defined as C1-centroid-N(N2) and C2centroid-N(N2), whereas angle β is defined as centroid···N−N.

carbon atoms opposite to the heteroatom is accompanied by an increase of the Vs.max value (+44.7 and +31.3 kcal/mol for SA and SI, respectively; and +34.8 and +22.5 kcal/mol for the insaturated analogous MA and MI, respectively). There are other regions with positive MEP in some molecules, as, for example, H atom in SI and MI (Figure 1b and f), but these unsubstituted species are not abundant in crystal structures. Therefore, MA and SA derivatives present a region of electron density depletion in the inner part of the ring that can allow them to engage in hole-like interactions with Lewis bases, as previously observed for other cyclic compounds.41,42 Interaction Strength. Next, we have calibrated the strength of the interaction of MA, MI, SA, SI, MI-CH3, SICH3, MI-C6H5, and SI-C6H5 (as the Lewis acids) with a molecule of N2 (as the Lewis base). We have selected the latter as the electron-rich species because of its small size and neutral nature. The corresponding interaction energies and key geometrical parameters are shown in Table 1. After full optimization of all dimers, we observed that the N2 molecule is located above the heterocycle at distances between 2.95 and 3.30 Å (distance defined between ring centroid and the closest N of N2). The angles and the distances between N2 and the two carbonyl carbon atoms (dC1 and dC2) give an idea of how centered is N2 with respect to the ring. Both the two angles and dC1 and dC2 are very similar for MA, MI, SA, and SI. More differences, however, are found for MI-CH3 and SI-CH3. While for the latter the N2 molecule is above the center of the ring, for

analyzed the molecular electrostatic potential (MEP) maps of several molecules and evaluated their interactions with a Lewis base. An energy decomposition analysis has also been carried out to understand the physical nature of the interactions. Furthermore, we have comprehensively inspected the structural databases in order to find experimental evidence that can corroborate our computational predictions and hypotheses.



RESULTS AND DISCUSSION MEP Analysis. We have first mapped the MEPs of maleic and succinic anhydrides and several of their derivatives, namely, succinimide, N-methyl-succinimide (SI-CH3), N-phenyl-succinimide (SI−C6H5), maleimide, N-methyl-maleimide (MICH3), and N-phenyl-maleimide (MI-C6H5). The results are presented in Figure 1. All molecules present regions of electron density depletion in the inner part of the ring. The calculated values for the MEP range from +20.7 to +44.7 kcal/mol in MICH3 and SA, respectively. It is worth noting that whereas in SA, SI, SI-CH3, and SI−C6H5 (Figure 1a, b, c, and d), the region with most positive MEP value, i.e., Vs,max, is located at approximately the centroid of the ring, in MA, MI, MI-CH3, and MI-C6H5 (Figure 1e, f, g, and h), Vs.max is displaced toward the carboxylic C atom. The difference with the ring centroid, which also shows positive MEP, is only 0.3 kcal/mol in MA, becoming more marked for MI-C6H5 (2.9 kcal/mol). The origin of these π-holes seems to be associated with the presence of the two carbonyl groups. Moreover, the saturation of the two B

DOI: 10.1021/acs.cgd.7b01511 Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design

Article

Table 2. Energy Decomposition Analysis (EDA) Results for Several Dimers of Succinic and Maleic Anhydrides Derivatives Interacting with N2 as the Lewis Base at the M06-2X/aug-cc-pVTZ Level of Theorya compound

ΔEPauli

MA MI MI-CH3 MI- C6H5 SA SI SI-CH3 SI−C6H5

5.04 4.16 6.51 6.73 6.97 6.10 7.50 10.40

ΔEElec −3.98 −3.11 −4.36 −4.62 −5.30 −4.39 −5.15 −5.79

(63) (61) (56) (56) (59) (58) (56) (56)

ΔEDisp −1.85 −1.66 −2.75 −2.95 −2.67 −2.52 −3.26 −3.63

ΔEPol

(29) (33) (36) (36) (30) (33) (35) (35)

−0.31 −0.18 −0.32 −0.38 −0.62 −0.41 −0.47 −0.56

(5) (4) (4) (5) (7) (5) (6) (5)

ΔECT −0.16 −0.12 −0.32 −0.27 −0.33 −0.29 −0.39 −0.42

(3) (2) (4) (3) (4) (4) (4) (4)

ΔEint −1.27 −0.92 −1.24 −1.49 −1.95 −1.51 −1.77 −2.00

a

Pauli (ΔEPauli), electrostatic (ΔEElec), dispersion (ΔEDisp), polarization (ΔEPol), charge transfer (ΔECT), and total energies (ΔEInt) are given in kcal/ mol. The values in parentheses are the contribution in percentage (%) of each component to the total energy.

the former the values of the two angles (and also of dC1 and dC2) are significantly different indicating a displacement of the N2 molecule toward one of the CO groups. Note that this is in very good agreement with the position of Vs.max in those two molecules (see previous section). Concerning the energetic analysis, the interaction energies are in general larger for SA, SI, and their derivatives than for their insaturated analogues (i.e., MA, MI, and derivatives). Again, this fact is in good agreement with the calculated values of Vs,max. The strongest interactions are found for SA and SI−C6H5, with interaction energies of 2 kcal/mol after correction of the BSSE. These values are within the range of other previously described σ and π-hole interactions.41−43 Energy Decomposition Analysis. To try to understand the physical nature of the interactions under study, we have performed an energy decomposition analysis (EDA, see Computational Methods for further details) of the dimers of Table 1. The complete results are detailed in Table 2. It can be seen that the interaction energies obtained by means of the EDA are practically identical to those obtained by means of the supermolecular approach in the previous section. The first observation is that the Pauli energy component is large and positive, indicating a strong repulsion between the monomers. This term is compensated in part by a considerably large electrostatic attraction (ΔEElec) that represents more than 55% of the total attractive interaction energy in all cases. The intermolecular dispersion term (ΔEDisp) is not negligible and represents 30−36% of the interaction energy and is larger for the bulkier methyl and phenyl-subtituted species. Finally, the polarization (ΔEPol) and charge transfer (ΔECT) energy terms contribute 4−7% to the total energy, probably due to the relatively long distances between the N2 and the ring atoms (3.0−3.5 Å). The fact that the electrostatic term is the largest among all attractive energy contributions indicates that the formation of the adducts is stabilized by electrostatic interactions between the two molecules. This stabilization is enhanced by London dispersion with only a small contribution of induced electrostatics and orbital interactions. It must be noted that different EDA methods can lead to significantly different results and, thus, they must be taken with caution. Moreover, although dominated by electrostatics, it is not completely clear what the contribution of charge transfer and polarization terms is to π/σ-hole bonds.44,45 NBO Analysis. We have performed and NBO analysis of the SA···N2 adduct to understand which orbitals are involved in the donor−acceptor interactions that, according to the previous EDA analysis, also contribute to some extent to the overall stability of the systems. The most relevant interaction is

associated with a charge transfer from the lone pair of the nitrogen atom to two empty π orbitals of the carbonyls (nN → π*C−O), with an associated NBO energy of 0.9 kcal/mol. Moreover, the N lone pair is also able to interact with two σ* orbitals localized at the C−H bonds involving the sp3 carbons (ENBO = 0.4 kcal/mol). This interaction pattern involving carbonyl groups, which has been named the n → π* interaction, has been observed in many biochemical systems contributing to biomolecular structure and function.46 Structural Evidence. We have searched the Cambridge Structural Database47 (CSD) to try to find experimental examples that confirm our computational predictions. We have found numerous examples of Lewis bases interacting with maleic and succinic anhydride derivatives. Perhaps one of the clearest pictures is found for the dimer of maleic anhydride48 (MLEICA01, Figure 2). There, one of the carbonyl oxygen

Figure 2. Examples of experimental structures of MA and MI derivatives with short ring-donor atom distances (CSD refcodes are indicated). Distances are given in Å.

atoms of one molecule points to the inner region of a neighboring molecule, with the donor atoms slightly displaced from the ring centroid toward a carbonyl carbon (dC···O = 2.93 Å; ΣrvdW = 3.27 Å). Another interesting example is the dimer found in the crystal structure of bicyclo(2.2.2)octa-2,5-diene2,3-dicarboxylic anhydride49 (GIQRAZ, Figure 2), in which there are two short O···C contacts at 2.96 and 3.18 Å (ΣrvdW = C

DOI: 10.1021/acs.cgd.7b01511 Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design

Article

the other, are significantly different, as can be appreciated in the colors distribution of Figure 4a and b. While the maximum is clearly located at 90° for SA and SI, it is displaced toward 70− 80°, without a clear peak of abundance, in the case of MA and MI. It seems thus that the presence of a single C−C bond in the heterocycle favors the establishment of shorter and more directional donor−acceptor contacts. This is in excellent agreement with our calculated structures, which showed shorter and stronger interactions for SA and SI derivatives than for the MA and MI ones.

3.27 Å). Those contacts support two C−H···O contacts at distances (2.87 and 3.02 Å) longer than the sum of the corresponding van der Waals radii (ΣrvdW = 2.70 Å). Among the N-containing heterocycles, we found the dimer of ethyl 4(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)benzoate50 (ELIGEL, Figure 2), with two O···C short contacts at 3.15 Å (ΣrvdW = 3.27 Å) (and a distance from the donor O to the ring centroid of 2.99 Å. We also searched for short contacts between derivatives of SA and SI. For this type of compound, in general, the donor atom is located over the centroid of the ring. Two examples are given in Figure 3. In the crystal structure of 2-(1,1,2,2-



CONCLUSIONS We have carried out, by means of a combined computational and structural analysis, a systematic investigation of the short contacts that maleic and succinic anhydride derivatives can establish with neighboring molecules. DFT calculations at the M06-2X/aug-cc-pVTZ level have shown that the interaction of those cyclic species with an electron-rich species can play a role in the formation of their crystalline phases as evidenced by the computed interaction energies, which can be as large as 2 kcal/ mol for the dimer of N-phenylsuccinimide···N2. An energy decomposition analysis has proven that the interaction is electrostatic in nature and enhanced by London dispersion. The molecular electrostatic potential maps of maleic and succinic anhydrides and their derivatives have exposed the presence of charge depletion regions in the inner part of the rings that facilitate the interaction with an electron-rich species. Our computational model predictions regarding the existence of a π-hole interaction have been confirmed by a comprehensive structural analysis of experimental crystal structures. We also have observed that the interaction is highly directional for succinic anhydride and succinimide derivatives. This fact and their considerable strength open the possibility of using these interactions in organic synthesis and crystal design.

Figure 3. Examples of experimental structures of SI and SA derivatives with short ring-donor atom distances (CSD refcodes are indicated). Distances are given in Å.

tetrachloroethylsulfanyl)-3a,4,7,7a-tetrahydro-1H-isoindole1,3(2H)-dione (HANDUW, Figure 3) the distance from the donor O atom to the ring centroid is 2.79 Å and the two angles C-centroid-O are 88.1° and 91.4°. In this case there are also two CO···H−C short contacts at 2.66 and 2.79 Å (ΣrvdW = 2.70 Å). Another interesting interaction occurs between a SI derivative and an acetonitrile molecule found in the same crystal structure (NIXPAL, Figure 3). In this case, the centroid····N distance is 2.87 Å (all other distances from N to the C atoms of the ring are between 3.09 and 3.17 Å; ΣrvdW = 3.43 Å), and the two angles 89.1° and 89.3°, respectively. Moreover, there is no possibility here of C−H···O interactions since the two sp3 C atoms of the ring are substituted with CN groups with no H atoms. It has been recently reported that 1,1,2,2-tetracyanocyclopropane, which resembles the interacting moiety of NIXPAL, can act as electron acceptor in tetrel bonding interactions via a region of charge depletion located in between the two substituted carbon atoms.51 We have also found several examples of derivatives of fused norbornadienesuccinic anhydride with centroid···donor distances around 2.90 Å and angles close to 90° (see examples in Figure S1).52,53 To further test the directionality of the interactions we have systematically searched the CSD for short contacts (