Communication pubs.acs.org/crystal
Revealing the Polarizability of Organic Fluorine in the Trifluoromethyl Group: Implications in Supramolecular Chemistry Venkatesha R. Hathwar,† Deepak Chopra,*,‡ Piyush Panini,‡ and T. N. Guru Row§ †
Center for Materials Crystallography, Department of Chemistry & iNano, Aarhus University, Langelandsgade 140, Aarhus C, DK-8000, Denmark ‡ Crystallography and Crystal Chemistry Laboratory, Department of Chemistry, IISER Bhopal 462066, India § SSCU, IISc, Bangalore 560012, India S Supporting Information *
ABSTRACT: The experimental evidence for the polarization of the electron density on the fluorine atom of the trifluoromethyl group in the crystal results in the formation of an electron deficient region. This facilitates F···F halogen bond formation along with the subsequent presence of “short” C−H···F intermolecular contacts (rare geometry) which are a significant electronic and structural feature. This study proves that such an interaction has a substantial “electrostatic contribution”. It breaks the long-accepted lore that “organic fluorine is not polarizable”.
H
ydrogen bonding is an important structural feature present in nature, and its significance has already been realized in chemistry and biology.1−3 In recent years, IUPAC has defined the term “halogen bonding”.4 It is of significance to know that only “electrophilic” halogen can form a halogen bond.4 The group of Resnati and Metrangolo have contributed toward the understanding of the halogen bond.5 With respect to halogens, the participation of organic fluorine in intermolecular interactions has remained an attractive area of interest.6 It has always been debated that the C−F bond is a weak acceptor of electrophilic species (due to the very weak polarizability of the lp’s on fluorine), and hence, the formation of hydrogen bonds with the C−H donor, wherein the H···F distance is short, is scarce. The C−H···F structure, being weak, soft, and flexible, exhibits the propensity to participate in many interactions, and hence this structural feature reflects in the formation of altered packing motifs, thereby making the exercise of prediction of crystal structures difficult.7 Although still speculative, the recent literature highlights8−11 the significant role of these weak interactions in crystal packing. Furthermore, X···X contacts involving organic fluorine, connected to a sp2 hybridized phenyl carbon atom, have been characterized using electron density (ED) studies.12 In this study we present the unequivocal experimental evidence for the existence of polarization of the fluorine atoms (of the trifluoromethyl group) connected to an sp3 hybridized carbon atom. In addition, we also highlight the electronic features associated with the presence of short contacts to organic fluorine in terms of their energetic stability toward the crystal packing. The two molecules of interest which are considered for our study are N-(2-(trifluoromethyl)phenyl)benzamide (A) and 4fluoro-N-(3-(trifluoromethyl)phenyl)benzamide (B) (Figure 1). Molecule A crystallizes as a “chiral crystal” in the tetragonal, © 2014 American Chemical Society
Figure 1. Nomenclature scheme for compound A and B.
non-centrosymmetric space group P43, whereas B crystallized in the centrosymmetric P21/c. There is no disorder associated with the CF3 group or in any related portion of the molecule for both A and B. The molecular conformation in the solid state is nonplanar for both A and B. It is of interest to compare the electronic features associated with the fluorine atoms in different chemical environment (one attached to sp2 carbon and the other to sp3 carbon for the trifluoromethyl group). Furthermore, the molecules containing the trifluoromethyl group are known to participate in the formation of intermolecular contacts with hydrogen forming different supramolecular motifs.10 This group is strongly electron withdrawing in nature, resulting in the adjacent hydrogens being acidic in nature.10 In particular, it has been observed that there exists a “short, linear” C−H···F−C (sp3) contact in the crystal lattice of A. Molecule B shows the presence of short geometrical C−H···F−C (sp2) contact to organic fluorine belonging to a different electronic environment. Thus, this depicts the capability of organic fluorine to participate in Hbond formation. The notable feature is the presence of such Received: August 20, 2014 Revised: September 23, 2014 Published: September 29, 2014 5366
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Table 1. Topological Values and Interaction Energies in the Crystala interaction [angle (deg)]
Rij (Å)
ρb (e/Å3)
O(1)···H(1) [169]
1.8066 1.8065 2.3954 2.3428 2.3629 2.3645 2.6787 2.6383
0.150 0.222 0.060 0.057 0.044 0.056 0.031 0.019
2.2205 2.5448 2.5257 2.6622
0.083 0.020 0.026 0.022
∇2ρb (e/Å5)
Ees(mult) (kJ/mol)
IEb (kJ/mol)
2.690 1.823 0.863 0.949 0.726 0.592 0.404 0.496
−89.5 −82.7 −34.7 −11.6 −22.7 −14.1 −19.2 −6.0
−25.6 −33.8 −6.8 −7.0 −5.0 −5.3 −2.8 −2.7
0.935 0.541 0.575 0.337
−22.5 −16.9 −13.6 −14.0
−9.2 −2.9 −3.3 −2.1
A
O(1)···H(9) [132] F(1)···H(3) [169] F(1)···H(12) [117]
B F(4)···H(9) [174] F(4)···H(2) [131] F(2)···H(6) [126] F(3)···H(12) [137]
a Values in italics are obtained from theory. bCalculated from EML approach.12 Dissociation energy (DE) = −0.5 Vb; Vb is local potential energy density at the bond critical points (BCP). Interaction energy (IE) = −DE.
contacts in the presence of strong N−H···OC H-bonds in a conformationally flexible molecule. Hence a detailed investigation of the electron density features associated with the molecule in the crystal was performed via experimental electron density analysis (multipolar modeling using the program XD13−16 in A and compared with the theoretical estimates (periodic calculations from theoretical structure factors in CRYSTAL 09).17 In B, in the absence of high quality crystals, a theoretical ED evaluation was done. The residual density maps, static deformation densities (DD), Laplacian maps for the electronically significant regions (Figures S1−S3, S7−S9), and topological properties (intramolecular bond critical points (BCP’s)) were evaluated from both experiment (for molecule A) and theory (molecule A and B) (Table S1) and are included in the Supporting Information. All the obtained critical points are characterized by positive values of the Laplacian indicating the closed-shell nature of the participating interactions. Table 1 depicts the most important intermolecular (3, −1) BCP’s along with the associated topological properties observed in the experimental crystal for molecule A and compared with those obtained from periodic DFT calculations (both A and B). The static DD, Laplacian maps, and bond paths for all the significant interactions are given in the Supporting Information (Figures S4−S6, S10−S12). Another important electronic feature is the electrostatic potential (ESP) of the molecule extracted from the crystal environment as determined from experiment and theory (Figures S13−S14). The analysis of the ED features of the trifluoromethyl group presents interesting electronic features. From chemical considerations, the concept of “group electronegativity” is well known, with the important property being that “Groups are superatoms capable of absorbing a large amount of positive or negative charge”.18 This electronic feature is quantitatively revealed from ED analysis. The presence of three fluorine atoms makes carbon electron deficient [red represents the charge depletion (CD) region]. This positive region intramolecularly polarizes the lone pair ED on all the fluorine atoms, resulting in the anisotropy of the ED distribution on fluorine. This results in a CD region on the fluorine atom (σ-hole) (Figure 2) and this effect operates on all the fluorine atoms in the molecule inside the crystal. This feature has been visualized over the theoretically calculated ESP with the B3PW91/631G(d,p) procedure for molecules wherein the fluorine atom is
Figure 2. 3D-deformation density map showing the presence of CD regions (σ-holes in red) and CC regions on the fluorine atoms of the trifluoromethyl group in A obtained from (a) experiment and (b) theory. The isosurfaces are drawn at 0.15 eÅ−3.
connected to an electron withdrawing group.19,20 This electronic distortion increases the charge carrying capacity of this functional group and hence justifies the property of “group electronegativity”. This also has ramifications in the crystal packing because the anisotropic distribution of the ED now influences the interaction of the fluorine atom with other fluorine atoms via the principle of electrostatic complementarity promoting the formation of a rarely observed near “Type-II” C(sp3)−F···F−C(sp3) contact (153°, 106°, Rij = 2.9255 Å), the topological values being ρb = 0.030 and ∇2ρb = 0.633, respectively. Such contacts and their topological characterization have also been performed (obtained from theoretical calculations).21−24 In addition the “torus” of ED perpendicular to the plane of the C−F bond also facilitates the formation of C−H···F intermolecular interactions resulting in increased propensity to form “short, near linear” contacts in the crystal. Figure 3a reveals the 3D-deformation density (DD) maps highlighting the interaction of H3 with F1 (recognition of the CD region with the charge concentration (CC) region), (Rij = 2.3629 Å), as obtained from experiment and theory. In addition, another interaction between H12 and F1 (Rij = 2.6787 Å) is also present in the crystal structure (Figure 3b). These electronic features were further supported with inputs from NCI analysis using the program NCImilano,25 which is another powerful method to visualize the nature of weak supramolecular interactions.26 Figure 4a,b highlights the discshaped RDG (reduced density gradient)-isosurfaces (yellow and brown color) depicting the attractive nature of the C−H··· 5367
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Figure 3. 3D deformation density maps highlighting the C−H···F− C(sp3) interaction region [obtained from experiment (left side) and theory (right side)] (Blue regions depict CC and red regions depict CD) for (a) C3−H3···F1 and (b) C12−H12···F1 in A. The isosurfaces are drawn at 0.15 eÅ−3.
Figure 5. 3D static deformation density plots depicting (a) F1···F3 (type II), (b) C9−H9···F4 and C2−H2···F4, (c) C6−H6···F2, and (d) C12−H12···F3 interaction regions from theoretical charge density for B. The iso-surface value is ±0.15 eÅ−3.
Figure 4. RDG-based NCI isosurfaces obtained from experimental (above) and theoretical charge (below) density models for (a) C3− H3···F1 and (b) C12−H12···F1 interaction in A. NCI surfaces corresponding to interactions are highlighted by blue square boxes. NCI surfaces correspond to s(r) = 0.6 au and the color scale is −0.04 < ρ < 0.05 au.
Figure 6. RDG-based NCI isosurfaces from theoretical charge density model for B (a) for F1···F3 (type II), (b) C9−H9···F4 and C2−H2··· F4, (c) C6−H6···F2, and (d) C12−H12···F3 interactions.
F interactions in molecule A (obtained from experiment and theory). Figure 5a highlights the formation of an F∂+···F∂‑ halogen bond in the crystal structure of B, a real depiction of the role of electrostatics, involving the fluorine atom. Surprisingly, “short and linear” C−H···F−C(sp2) interactions were observed in molecule B involving an electronically different fluorine atom. This also has a σ-hole, and the CC regions interact with hydrogen atoms H2 and H9 resulting in the formation of bifurcated H-bonds to fluorine (Figure 5b). Figure 5c,d depicts the DD maps for the supporting C−H···F−C(sp3) interactions involving the trifluoromethyl group. The attractive nature of these interactions was confirmed by the presence of disc-shaped RDG isosurfaces (Figure 6). The electrostatic contribution of the intermolecular interaction energy, for a given interaction, between two symmetry equivalent molecules in the crystal via the atom-centered multipole expansion) was evaluated using the module XDINTERN in XD. The method used for the evaluation of Ees(mult) values (Table 1) is the Exact Potential and Multipole Model Method (EP/MM) which is a numerical quadrature integration method using pseudoatom electron
densities derived from accurate experimental X-ray data and in principle includes the effect of polarization (intermolecular interactions), charge transfer, and electron correlation in the crystal. This combines an exact evaluation of the electrostatic energy of interaction (EP) for the short-range pseudoatom− pseudoatom interactions with the Buckingham-type multipole approximation (MM) for the abundant long-range interactions, assuming nonoverlapping charge densities.27,28 These values are compared with those obtained via the EML approach.29 It is of interest to note that the Ees(mult) values are higher in comparison to those obtained from theoretical charge densities of isolated molecules, dimers, or trimers.30−32 In the case of compound A, the magnitude is ∼90 kJ/mol (both from experiment and theory) for a strong N−H···OC H-bond compared to −35 kJ/mol for a relatively weaker C− H···OC H-bond. For a C−H···F−C (involving H3 and F1) H-bond, the electrostatic contribution is approximately −23 kJ/ mol, which is 26% of the strongest H-bond in the crystal. This is a substantial stabilizing contribution (in terms of electrostatics) for an interaction involving the fluorine atom with a hydrogen atom. Similarly in the case of B, the C−H···F−C 5368
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(12) Pavan, M. S.; Prasad, K. D.; Guru Row, T. N. Chem. Commun. 2013, 49, 7558−7560. (13) Volkov, A.; Macchi, P.; Farrugia, L. J.; Gatti, C.; Mallinson, P. R.; Richter, T.; Koritsanszky, T. S. XD 2006; University at Buffalo, State University of New York, New York. (14) Hansen, N. K.; Coppens, P. Acta Crystallogr. 1978, A34, 909− 921. (15) Macchi, P.; Coppens, P. Acta Crystallogr. 2001, A57, 656−662. (16) Su, Z.; Coppens, P. Acta Crystallogr. 1998, A54, 357. (17) Dovesi, R.; Orlando, R.; Civalleri, B.; Roetti, C.; Saunders, V. R.; Zicivich-Wilson, C. M. Kristallografiya 2005, 220, 571−573. (18) Huheey, J. E.; Keiter, E. A.; Keiter, R. L. Inorganic Chemistry: Principles of structure and reactivity, 4th ed.; HarperCollins: New York, 1993; pp 196−199. (19) Metrangolo, P.; Murray, J. S.; Pilati, T.; Politzer, P.; Resnati, G.; Terraneo, G. CrystEngComm 2011, 13, 6593−6596. (20) Metrangolo, P.; Murray, J. S.; Pilati, T.; Politzer, P.; Resnati, G.; Terraneo, G. Cryst. Growth Des. 2011, 11, 4238−4246. (21) Matta, C. F.; Castillo, N.; Boyd, R. J. J. Phys. Chem. A 2005, 109, 3669−3681. (22) Castillo, N.; Matta, C. F.; Boyd, R. J. Phys. Chem. A 2005, 409, 265−269. (23) Chopra, D.; Cameron, T. S.; Ferrara, R. D.; Guru Row, T. N. J. Phys. Chem. A 2006, 110, 10465−10477. (24) Hathwar, V. R.; Guru Row, T. N. Cryst. Growth Des. 2011, 11, 1338−1346. (25) Saleh, G.; Presti, L. L.; Gatti, C.; Ceresoli, D. J. Appl. Crystallogr. 2013, 46, 1513−1517. (26) Johnson, E. R.; Keinan, S.; Mori-Sánchez, P.; Contreras-García, J.; Cohen, A. J.; Yang, W. J. Am. Chem. Soc. 2010, 132, 6498−6506. (27) Volkov, A.; Koritsanszky, T.; Coppens, P. Chem. Phys. Lett. 2004, 391, 170−175. (28) Volkov, A.; Coppens, P. J. Comput. Chem. 2004, 25, 921−934. (29) Espinosa, E.; Molins, E.; Lecomte, C. Chem. Phys. Lett. 1998, 285, 170−173. (30) Vargas, R.; Garza, J.; Freisner, R. A.; Stern, H.; Hay, B. P.; Dixon, D. A. J. Phys. Chem. A 2001, 105, 4963−4968. (31) Vargas, R.; Garza, J.; Freisner, R. A.; Stern, H.; Hay, B. P.; Dixon, D. A. J. Phys. Chem. A 2005, 109, 6991−6992. (32) Dixon, D. A.; Garza, J.; Hay, B. P.; Vargas, R. J. Am. Chem. Soc. 2000, 122, 4750−4755.
(involving H9 and F4) H-bond was also observed to contribute similar stabilization in addition to another short C−H···F−C (involving H2 and F4) H-bond, the electrostatic contribution being −17 kJ/mol. Furthermore, it is noteworthy that the remaining interactions involving fluorine do contribute toward the crystal stability in case of A and B; the energies are in the range of −10 to −20 kJ/mol (from experiment). Thus, short contacts to fluorine are “true” H-bonds, an aspect of crystal engineering which can influence molecular recognition events in liquids and solids (including proteins). In conclusion, it is noteworthy that organic fluorine is indeed polarizable in different chemical and electronic environments. Future studies are aimed at increasing the extent of polarization and the observation of H-bonds to fluorine with changes in hybridization of the atom at the donor end.
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ASSOCIATED CONTENT
S Supporting Information *
Geometrical and multipolar information, data collection, experimental and theoretical modeling, residual, DD, Laplacian maps for both intra- and intermolecular regions, crystal data, topological properties for all the bonds, and crystallographic information files. This material is available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Fax: 91-0755-6692392. Tel: 910755-6692370. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS D.C. thanks DST-Fast Track Scheme for research funding. P.P. thanks UGC-India for research scholarship. We acknowledge IISER Bhopal for research facilities and infrastructure. We thank the CCD facility at IISc, Bangalore under the IRHPADST Scheme for charge density data collection.
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NOTE ADDED AFTER ASAP PUBLICATION This paper was published ASAP on October 7, 2014. The updated version contains three additional CIF files in the Supporting Information. This paper was reposted on October 15, 2014.
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