Bromine Atom Interactions in Biologically Active Acrylamide

Article pubs.acs.org/crystal

Bromine Atom Interactions in Biologically Active Acrylamide Derivatives Maura Malińska,† Izabela Fokt,‡ Waldemar Priebe,*,‡ and Krzysztof Woźniak*,† Biological and Chemical Research Centre, Chemistry Department, University of Warsaw, Ż wirki i Wigury 101, 02-089 Warszawa, Poland ‡ The University of Texas, MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit Number: 422, Houston, Texas 77030, United States †

S Supporting Information *

ABSTRACT: Halogen bond interactions, C−Br···NC−, have been found in a crystal structure of an important drug compound WP1066. In order to characterize the nature of these interactions, experimental charge density distribution has been accomplished for a single crystal of WP1066. The energetic study of the halogen bond proved that this is one of the weakest interactions in the crystal structure and in energetic terms is close to the energy of the Br···H hydrogen bond type close contacts. Experimental charge density studies revealed a charge redistribution between molecules connected by halogen and hydrogen bonds enhancing electrostatic interaction energy. Using structural, charge density, and computational studies for WP1066 and two analogs, WP1130 and WP1220, we showed determining factors for the formation of the crystal structure, i.e. the presence of a bulky side chain next to the donor and acceptor of the hydrogen bond resulting in a change in conformation and electrostatic potential of molecules.

1. INTRODUCTION Oncogenic transcription factors were shown to drive malignant potential in a wide variety of human cancers, and many studies have already indicated their importance as unique therapeutic targets. Development of small effective drugable inhibitors of transcriptional factors still remains a challenge. Signal transducer and activator of transcription 3 (STAT3) is one such factor, and its constitutive activation has been observed in a wide range of human cancers and is usually considered an indicator of poor prognosis. STAT3 mediates cytokines and growth factor signaling in tumor cells, and in response to such extracellular stimulation, STAT3 is phosphorylated at Tyr705 leading to dimerization and translocation to the nucleus, where it induces the transcription of key genes responsible for increased proliferation, survival, and metastasis of tumor cells and decreased immune response. A new family of drug candidates structurally related to a natural component of propolis potently inhibiting activation of STAT3 has been developed by Priebe et al.1−3 The lead compound, (S,E)-3-(6-bromopyridin-2-yl)-2-cyano-N-(1phenylethyl)-acrylamide (WP1066, Scheme 1), is a small molecule with drug-like properties (based on pharmacokinetics, stability, tissue and organ distribution, oral bioavailability), and its derivatives, WP1130 ((S,E)-3-(6-bromopyridin-2-yl)-2cyano-N-(1-phenylbutyl)acrylamide) and WP1220 ((S,E)-3(8-bromopyridin-2-propyl)-2-cyano-N-(1-phenylethyl)acrylamide), have been identified (Scheme 1) and studied. All of them represent a novel class of drugs and are in active © 2015 American Chemical Society

Scheme 1. Chemical Diagram of WP1066 (a), WP1130 (b), and WP1220 (c)

preclinical development; therefore, their chemistry and biology, including mechanism of action, are extensively analyzed. Here, we present successful crystallization and X-ray studies on the three compounds WP1066, WP1130, and WP1220. The details of the data collection and crystallographic statistics can be found in Table 1. Recently, halogen bonding (XB) has been exploited to control crystallization of organic compounds in the design of Received: October 29, 2014 Revised: May 4, 2015 Published: May 11, 2015 2632

DOI: 10.1021/cg501598h Cryst. Growth Des. 2015, 15, 2632−2642

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Crystal Growth & Design Table 1. Experimental Details for WP1066, WP1130, and WP1220 Data Collection Parameters Crystal data chemical formula Mr crystal system, space group temperature (K) a, b, c (Å) α, β, γ (deg) V (Å3) Z Z′ radiation type Tmin, Tmax μ (mm−1) crystal size (mm) Data collection diffractmeter detector detector to sample distance (mm) exposure time (s) absorption correction Sin θ/λ (Å−1) no. of measured, independent, observed [I > 2σ(I)] reflections Rint IAM refinement R[F2 > 2σ(F2)], wR(F2), S no. of reflections no. of parameters no. of restraints largest residual density peak and hole absolute structure Flack parameter Multipole refinement no. of reflections [I > 3σ(I)]/parameters R1/wR1 (for I > 3σ(I)) R2/wR2 (for I > 3σ(I)) GOOF (for I > 3σ(I)) largest residual density peak and hole

WP1066

WP1130

WP1220

C17H14BrN3O 356.22 monoclinic, P21 90(2) 9.8223(5), 13.2699(6), 12.2716(6) 90, 99.696(2), 90 1576.64(13) 4 2 Mo Kα 0.774, 0.943 2.61 0.22 × 0.11 × 0.08

C19H18BrN3O 384.27 orthorhombic, P212121 90(2) 5.5865(2), 14.0802(5), 21.6239(8) 90, 90, 90 1700.92(11) 4 1 Mo Kα 0.642, 0.793 2.43 0.20 × 0.10 × 0.10

C19H16BrN3O 382.26 triclinic, P1 100(2) 4.9664(8), 12.703(1), 14.149(2) 82.03(1), 86.26(1), 89.918(9) 882.2(2) 2 2 Mo Kα 0.800, 0.892 2.34 0.10 × 0.05 × 0.05

Bruker Kappa Apex II Ultra Apex II 45 10−60 multiscan 1.02 184 147, 25 757, 23 143

KUMA4 CCD Opal 62 5 multiscan 0.83 53 240, 8210, 7580

KUMA4 CCD Opal 62 30 multiscan 0.61 11 155, 6634, 4142

0.04

0.04

0.06

0.023, 0.063, 1.04 0.022, 0.070, 1.16 25757 8210 407 218 3 0 1.06, −0.69 0.51, −0.33 Flack H D (1983), ActaCryst. A39, 876−881 −0.005 (2) 0.004(4)

0.106, 0.291, 1.05 6634 483 159 1.51, −0.50 −0.01 (2)

23143/802 = 28 0.016/0.017 0.022/0.025 0.93 0.605, −0.338

new functional materials and supramolecular assemblies in crystal engineering.4−6 The XB also appeared to be effective in driving the formation of a multitude of supramolecular architectures with different useful properties.7,8 The protein and nucleic acid structures reveal halogen and hydrogen bonds as potentially stabilizing inter- and intramolecular interactions that can affect the ligand binding and molecular folding; for example, see protein kinase complexes with halogenated ligands.9,10 The XB is a directional interaction between the positive electrostatic potential region in a halogen atom and a Lewis base located in the closest proximity in space. The polarizable halogens exhibit electrophilic (δ+) character along the axis of the C−X bond and nucleophilic (δ−) character perpendicular to the C−X bond.11,12 This type of bond is attributed to the anisotropic distribution of the charge density at the halogen atom resulting in the formation of a positive cap (called the σhole) centered on the C−X axis.13,14 A linear connection is needed for the formation of halogen bonding. The directionality of the halogen···oxygen and halogen···nitrogen contacts is primarily the result of the anisotropic distribution of the

electron density around the halogen nucleus. The charge density studies of crystal structures with halogen bonds are found in literature.15,16 A number of studies have shown that many properties of the halogen bond are analogous to those of the hydrogen bond.10,17,18 The recently established definition of halogen bond interaction highlights that it should have an attractive nature.19 A hydrogen bond is a noncovalent (van der Waals) attractive interaction caused mainly by the electrostatic attraction of a hydrogen atom with a lone electron pair of another atom. The hydrogen bond donor must have a sufficiently large δ+ charge caused by bonding to a highly electronegative element (O, N, or F; or in uncommon cases by strong electron-withdrawing inductive effects). Halogen and hydrogen bonds have some common properties; for example, the driving force to form these interactions is electrostatic in nature. However, for XB, polarizations, charge-transfer, and dispersion contributions all play an important role in the interpenetration of van der Waals spheres of the interacting atoms.20−23 Structural data from the Cambridge Structural Database show that electronegative atoms in various hybridization states clearly prefer to form 2633


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Crystal Growth & Design

Figure 1. Molecular structure of WP1066 and atomic labeling. Brown dashed lines indicate the halogen bonds. Thermal displacement ellipsoids are drawn at the 50% probability level. The multipole refinement against experimental structure factors of WP1066 based on the Hansen and Coppens formalism28 has been accomplished using the XD program suite.29 Atomic positions and mean-square displacement parameters of the non-H atoms were refined using the high order X-ray diffraction data (sin θ/λ > 0.75 Å−1). Atomic coordinates x, y, z and anisotropic displacement parameters (ADPs) were fixed after high order refinement. The C− H bond distances were fixed at the averaged distances for similar groups taken from single crystal neutron diffraction data.30 The hydrogen thermal displacement parameters were estimated using the SHADE231,32 program and then fixed. For the bromine and oxygen atoms, multipoles up to the hexadecapole level were refined in multipole refinements and up to the octupole level for the rest of the non-H atoms. For the H atoms, only monopoles, bond directed dipoles, and bond directed quadrupoles were used. For oxygen atom, the mm2 symmetry restriction was applied for the multipole parameters, and for the N(1), N(3), N(4), and N(6) nitrogen atoms, the m symmetry was used. The κ and κ′ parameters were refined alone for the non-H atoms after the multipoles population refinement. The κ and κ′ parameters for hydrogen atoms were fixed to the values obtained from the WP1066teo model. The kappa parameters were restricted to be the same for the equivalent atoms in both molecules, and other restrictions were applied (for details see the Supporting Information (Table 1S)). After these steps, the κ values were fixed for all the non-H atoms, and the full matrix refinement for position, ADPs for the non-H atoms, and population of multipoles was refined. Each refinement cycle was considered fully converged at the point at which the maximum shift/s.u. (standard uncertainty) ratio was less than 10−5. The Hirshfeld’s rigid-bond test33 was applied after each step. The DMSDA (Differences of Mean-Squares Displacement Amplitudes) values are less than 0.0010 Å2. 2.4. Atoms in Molecules (AIM) Integrated Atomic Charges. All calculations of the integrated properties were performed using the TOPXD program, a part of the XD package.29 The error in the atomic lagrangian measures the accuracy of the numerical integration, and it was less than 10−3−10−4. 2.5. Computations. The geometry of WP1066 for theoretical calculation was taken directly from the final multipole refinement cycles. The geometry of WP1220 and WP1130 were taken from X-ray refinement, and then only the positions of hydrogen atoms were changed to fit the average neutron data.30 Supermolecular calculations were performed with the basis set superposition error (BSSE) in the Gaussian0934 program using the B97D35,36 method and 6-311+ +G(2d,2p) basis set for the selected dimers for WP1066, WP1130, and WP1220. An Energy scan for the WP1066 molecule was done for the C(25)C(24)C(26)O(2) torsion angle with a 10° step change. After

short contacts to Cl, Br, and I (rarely F) in the direction of the extended C−X bond axis.24 The aim of this work is to investigate the bromine atom interaction in a series of related molecules, WP1066, WP1130, and WP1220. We try to investigate why the XD is present in only one of these closely related molecules. The quantitative experimental charge density of WP1066 is used to identify similarities and differences in detail of the charge density distribution and interaction energies for the halogen and hydrogen bonds present in the crystal lattice of this biologically active compound.

2. EXPERIMENTAL SECTION 2.1. Synthesis. WP1066, WP1130, and WP1220 were synthesized in the Waldemar Priebe’s laboratory. Crystals of WP1066, WP1130, and WP1220 were obtained by slow evaporation from a methanol/ ethanol solution at 278 K. 2.2. Data Collection. Single-crystal X-ray data collection of the scattered intensities of reflections for WP1066 was performed using the Bruker AXS KAPPA-APEX II ULTRA diffractometer. Indexing and integration were performed with the original Bruker Apex software. The multiscan absorption correction was applied in the scaling procedure using the SORTAV Program.25 Conventional spherical atom refinement was carried out using SHELX9726 with the full-matrix least-squares on the F2 method for all data sets (Table 1). The least-squares multipolar refinement applied for WP1066 was based on F2 with resolution limited to 0.49 Å to gain 100% data completeness. Measurement of the diffraction data for WP1130 and WP1220 was performed on a Kuma KM4CCD-axis diffractometer with graphitemonochromated MoKα radiation and equipped with an Oxford Cryosystems nitrogen gas-flow apparatus. The crystal was positioned 62 mm from the KM4CCD camera. The data were corrected for Lorentz and polarization effects. The multiscan absorption correction was applied. Data reduction and analysis were carried out with the Oxford Diffraction Ltd. suite of programs. The lattice parameters and the final R-indices obtained are shown in Table 1. 2.3. Multipole Refinement of WP1066. The first step was obtaining a multipolar model of WP1066 based on theoretical structure factors (WP1066teo) obtained from the CRYSTAL09 program.27 The modeling was performed in the XD program to get a reference model and the starting values for κ and κ′ parameters for all atoms. 2634


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Crystal Growth & Design each step full geometry optimization was performed. Electrostatic interaction energy (Ees) calculations were carried out using the experimental (EPMM method in XD program29) and theoretical charge densities (EP method implemented in the SPDF program37). Periodic calculations for WP1066 were performed using the CRYSTAL0927 with experimentally observed crystal geometry as input. The calculations were carried out at the B3LYP 6-31G(d,p) level of theory. Theoretical structure factors were derived at the resolution 1.2 Å−1. The multipolar refinements (based on F) against the theoretical structure factors were carried out using XD2006. Multipolar refinements of theoretical structure factor were performed to the same multipole levels as described for experimental charge density modeling. κ and κ′ of the H atom were allowed to refine during the multipolar refinements, and all of them were used as a starting point in the refinement of experimental data.

found in similar compounds with the same chemical groups. The molecules represent two conformations with a different orientation of the nitrile group and amide bond. The WP1066 and WP1220 have the “cis” conformation where carbonyl and cyano groups point toward the same direction. It is defined by the C(25)C(24)C(26)O(2) torsion angle in WP1066 (Figure 1) equal to −18.8(2)°. The WP1130 has the “trans” orientation with the corresponding torsion angle equal to −163.1(1)°. Ab initio calculations for the WP1066 isolated molecule showed that the rotation barrier is 26 kJ mol−1 for the torsion angle, and the “trans” conformation is energetically favorable. A comprehensive structural analysis supplemented with Hirshfeld surfaces analysis was carried out to see the interactions responsible for formation of these crystal structures. The fingerprint plots clearly differ even though the molecular structures are similar. Characteristic interactions for the crystals are pinpointed on Hirshfield surface fingerprint plots (Figure 4). The two independent molecules in the asymmetric unit of WP1066 form a dimer connected by two halogen bonds between the bromine and nitrogen atoms in the nitrile groups. The length of this contact is 3.180(1) Å for Br(1)...N(5) and 3.011(2) Å for Br(2)...N(2) (Figure 5, D1). These halogen bonds are directional and linear interactions with the C(1)Br(1)N(5) and C(18)Br(2)N(2) angles equal to 173.90(9)° and 173.41(9)°, respectively. Two dimers interact with each other by hydrogen bonds. The amide group is a donor and acceptor of the following hydrogen bonds; N(4)− H(2N)...O(1)#2 (Figure 5, D2) and N(1)−H(1N)...O(2)#1 (Figure 5, D3). The distance between N(1) and O(2) is 2.936(2) Å and the N(1)H(1N)O(2)#1 angle is 157.9°, and for the second hydrogen bond N(4)−H(2N)...O(1)#2, the corresponding values are 2.850(2) Å and 161.6°. Hydrogen bonds form characteristic sharp spikes on the fingerplot for WP1066 (Figure 4). Along the X direction, the molecules are packed into blocks with hydrogen bonds connecting the amide groups thus forming infinite chains. Such an arrangement of molecules is also associated with other weak interactions; weak

3. RESULTS AND DISCUSSION 3.1. X-ray Structure and Hirshfeld Surface Analysis. All three molecules crystallize in chiral space groups: P21, P1, and P212121 with two, one, and two molecules in the asymmetric unit for WP1066 (Figure 1), WP1130 (Figure 2), and WP1220

Figure 2. Molecular structure of WP1130 and atomic labeling. Thermal displacement ellipsoids are drawn at the 50% probability level.

(Figure 3), respectively. The geometrical parameters in terms of bond lengths and valence angles are similar to the ones

Figure 3. Molecular structure of WP1220 and atomic labeling. Thermal displacement ellipsoids are drawn at the 50% probability level. 2635


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Figure 4. Hirshfeld surface fingerprint plots for the studied acrylamide derivatives (a) WP1066, (b) WP1130, and (c) WP1220.

Figure 5. Selected dimers from WP1066 molecules studied with pinpointed major interactions.

C−H···O hydrogen bonds (O(1)...H(23)#3 (Figure 5, D2), with the O(1)...C(23) distance equal to 3.128(2) Å and C−H··· N (N(5)...H(19)#2, Figure 5, D7, where N(5)...C(19) is 3.389(4) Å. The aromatic pyridine rings also interact by π···π stacking (the C(1)...C(20) separations 3.234(4) Å, D6).

Bromine atoms form interactions with hydrogen atoms that are perpendicular to the plane formed by halogen bonds (Figure 5, D4 and D5). The crystal packing of WP1130 molecules is governed by weak hydrogen bonds: the C−H···O, C−H···π interactions and 2636


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has enough space to slightly rotate, which can explain the disorder present in the crystal lattice. XB interactions are only present in the WP1066 crystal structure. The closest contacts formed by the bromine atom are to the hydrogen atoms in the WP1220 and WP1130 crystal structures; however they are shorter than the sum of the van der Waals radii only in WP1220. There is a clear difference for Br···H contacts visualized on the fingerprint plots. To further investigate the halogen interaction, QTAIM analysis of the WP1066 experimental charge density has been performed. The charge density studies and the following topological analysis can explain the formation of interactions such as hydrogen bonds, halogen bonds, molecular stacking, etc. Additionally, it gives quantitative information about the interaction strengths. 3.2. Charge Density Studies of WP1066. The details of the refinement strategy of the multipolar model against high resolution data are in the Experimental Section. The largest peaks close to the bromine atoms are 0.6 eÅ−3 and −0.33 eÅ−3. High values of residual density can be explained by disorder in bromine atom positions shown also in the elongated ADPs for the bromine atoms and C, N atoms forming the cyano group. The deformation density of WP1066teo and experimental model are visualized in Figure 8. The difference in distribution of bromine and the cyano group between models is significant; however, both models also have similar features. The bromine atoms have an anisotropic distribution with negative charge density pointing toward the cyano group from the second molecule. 3.2.1. Hydrogen Bonds. The BCP (bond critical point) properties obtained in the topological analysis of the experimental charge density for the hydrogen bonds can be found in Table 2. Three types of hydrogen bonds were found in WP1066, which included two strong ones connecting amide groups and forming the H(2N)...O(1)#1 and H(1N)...O(2)#1 hydrogen bonds. The second and third hydrogen atoms are formed by hydrogen atoms with smaller positive charge O(1)...H(23) and N(5)...H(19) resulting in smaller values of charge density and Laplacian at the BCP. The value of density for the BCP of O(1)...H(23)−C(23)#3 is 0.12(4) eÅ−3, and the Laplacian value is equal to 1.2(1) eÅ−5. The corresponding values for the N(5)...H(19)#2 hydrogen bond are smaller and equal to 0.09(5) eÅ−3 and 0.6(1) eÅ−5, respectively. The empirical formula proposed by Espinosa and Lecomte showed that the C−H···O and C−H···N are two and three times weaker, respectively, than the classic hydrogen bonds in WP1066. 3.2.2. Halogen Bonds and Bromine Atom Contacts. The deformation density of the bromine atoms shows an anisotropic distribution of the charge density resulting in the formation of a positive cap (called the σ-hole) centered on the A−X axis (Figure 8b). The bromine atom can therefore interact with nucleophiles such as N, O, X, etc. atoms along the A−X bond (D1) and with electrophiles, e.g., H atoms, in the directions perpendicular to the A−X bond (D4, D5). The halogen bond is formed between the bromine atoms connected to the carbon atoms from the pyridine rings and the nitrogen atoms as a part of the cyano groups: C(1)− Br(1)...N(5)C(25) and C(18)−Br(2)...N(2)C(8). The values of ρ(r) and ▽2ρ(r) at BCPs of the C−Br bonds are 0.97(4) eÅ−3, 1.83(5) eÅ−5 for Br(1)C(1) and 0.80(6) eÅ−3, 3.27(5) eÅ−5 for Br(2)−C(18). A slightly positive Laplacian value is indicative of the closed-shell interaction character for the C−Br bond. The bond paths and BCPs have been found

molecular stacking. The molecules form zigzag chains by the stacking contact C(6)...N(2)#7 (3.079(2) Å, Figure 6, D1′).

Figure 6. Selected dimers from WP1130 molecules studied with pinpointed major interactions.

The aforementioned chains are connected with each other by the O(1)...H(2)−C(H) contacts and C−H···π with the distance between heavy atoms equal to 3.225(2) Å and 3.642(2) Å (Figure 6, D2′). The fingerprint plot for WP1130 shows the shorter spikes for N···H and O···H due to the presence of weak hydrogen bonds O···H−C and N···H−C (Figure 6, D3′). The fingerprint plot for WP1220 also suggests a different packing. The molecules form planes linked by the N(4)H(4A)...N(5)#6 hydrogen bonds (long spikes in Figure 4) and much weaker C(4)−H(4)...O(3)#6 contacts (Figure 7, D1″). The contact lengths between the non-H atoms are 3.135(2) Å and 3.396(2) Å, respectively. The C(13)− H(13C)...Br(2) and stacking contact (C(27)...C(31)#8 holds the planes together (Figure 7, D2″−D4″). The phenyl group

Figure 7. Selected dimers from WP1220 molecules studied with pinpointed major interactions. 2637


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Figure 8. 3D static deformation density map for the Br(1)N(5) and Br(2)N(2) halogen bonds; D1 from charge density modeling on theoretical structure factors from CRYSTAL09 (a) and experimental charge density modeling of WP1066 (b). The positive blue and negative red isosurfaces drawn at ±0.1 eÅ−3.

Table 2. Selected Interactions from the WP1066 Crystal Structure Together with the Interaction Lengths Rij [Å] and the Corresponding Values of Charge Density ρ(r) [eÅ−3] and Its Laplacian ▽2ρ(r) [eÅ−5] at BCPsa,b WP1066

Interaction

ρ(r)

▽2ρ(r)

Rij [Å]

EHB

D1

BR(1)...N(5) BR(2)...N(2) H(2N)...O(1)#2 O(1)...H(23)#3 H(1N)...O(2)#1 BR(1)...H(32)#5 BR(2)...H(31)#5 C(1)...C(20)#5 N5···H(19)#2

0.060(9) 0.082(2) 0.21(6) 0.12(4) 0.19(4) 0.05(1) 0.03(1) 0.04(1) 0.09(5)

0.75(3) 0.99(4) 1.3(1) 1.2(1) 1.45(6) 0.6(1) 0.5(1) 0.4(1) 0.6(1)

3.180(1) 3.011(2) 1.87 2.10 1.96 2.79 2.95 3.234(4) 2.34

−7 −10 −29 −14 −26 −5 −4 −3 −7

D2 D3 D4 D5 D6 D7

a EHB [kJ mol−1] stands for the interaction energy calculated using the empirical formula proposed by Espinosa and Lecomte.38 bSymmetry code definition is as follows: #1: −x, −1/2 + y, 1 − z; #2: 1 − x, 1/2 + y, 1 − z; #3: 1 − x, −1/2 + y, 1 − z; #4: 1 + x, y, −1 + z; #5: 1 + x, y, z; #6: −1 + x, y, z; #7: 2 − x, 1/2 + y, 1/2 − z; #8: 1 − x, y, z.

N(4) has −1.01e charge. The charge is redistributed from N(1) again involved in a shorter interaction. Both halogen and hydrogen bonds act in the same direction, and charge is transferred from molecule 1 (with Br(1) atom) to molecule 2. The charges of hydrogen atoms involved in hydrogen bonding are significantly greater than the charges of noninteracting H atoms. For weaker C(23)−H(23)#3···O(1) and C(19)− H(19)...N(5) hydrogen bonds, the trend is opposite. It was previously shown for hydrogen atoms of methyl groups in DMAN molecules.40 Although moieties 1 and 2 have similar geometrical properties, there are some differences in electron density distribution for both molecules due to the properties of interactions joining them together into the crystal lattice. 3.3. Interaction Energy. In order to compare the relative strengths of halogen and hydrogen bond interactions in selected dimers (Figures 5−7) we used charge density topological parameters and DFT calculations. The simplest approach, proposed by Espinosa and Lecomte,38 indicate that the strongest interactions in WP1066 structure are the H(1N)...O(2)#1 and H(2N)...O(1)#2 hydrogen bonds (−26 and −29 kJ mol−1, Table 2), whereas the halogen bonds are three times weaker (−7 and −10 kJ·mol−1), which is even weaker than typical C−H···O interactions (−14 kcal·mol−1). The analogues’ value of interaction energy to the halogen bond was found for the N···H−C interaction holding the D7. However, it should be noted that Espinosa’s approach is an

for the XBs. The values of ρ(r) and ▽2ρ(r) at BCPs of the halogen bonds are 0.060(9) eÅ −3 , 0.75(3) eÅ −5 for Br(1)...N(5) and 0.082(2) eÅ −3 , 0.99(4) eÅ −5 for Br(2)...N(2). It is worth noting that the similar values were found at the BCP of Br(1)...H(32)#5 and Br(2)...H(31)#5 (Table 2). 3.2.3. Atomic Charges in WP1066. To further explore the possible involvement of charge transfer in the character of the interactions, the atomic charges have been obtained by integration of the electron density over the topological atomic basins.39 The sum of charge integrated over the atomic basins in both molecules is 0.00 e. The molecular charges obtained for the investigated structures are 0.37 e and −0.37 e, while the individual atomic contributions are given in the Supporting Information (Table 2S). The bromine atoms have charges of −0.08 and −0.07 for Br(1) and Br(2), respectively. The charges of the N(2) and N(5) nitrogen atoms involved in the halogen bonds are −0.74 and −1.06, respectively. The charge is transferred from N(2), which is involved in a shorter halogen bond. The hydrogen atoms involved in the N−H···O hydrogen bonds have charges of 0.41 for H(1N) and 0.45 for H(2N), whereas the corresponding charges of the oxygen atoms are −1.20 and −1.22 for O(2) and O(1) respectively. The difference is shown in a charge of the donor of hydrogen bonds, nitrogen atoms, for which N(1) has −0.83e, whereas 2638


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This can suggest that some polarization effect is visible in experimental charge density. However, electrostatic is not always an attractive force. The weak N5···H(19)#2 hydrogen bond probably has a positive contribution to the interaction energy, but the total Ees for D7 is repulsive. Additionally charge redistribution in this case has an unfavorable effect, and the experimental Ees is 17 kJ mol−1 greater than the theoretical one. A halogen bonded dimer (D1) interacts with a strength of −20 kJ·mol−1, the result obtained by using both theoretical and experimental Ees. However, the bromine atoms also form different contacts in WP1066. The Br atom is also involved in the C−H···Br interaction. In terms of electrostatic forces the D4 dimer exhibits similar strength to the halogen bonded dimer (−22 kJ mol−1). A smaller value was found for D5 with the Ees equal to −10 kJ mol−1, due to the less favorable geometry of the interaction. The C−H···Br valence angle is significantly greater than the optimal 90°. Currently, it is impossible to estimate total interaction energies from experimental densities. Therefore, to check how electrostatic energy relates to the total interaction energy for these particular dimers, quantum mechanical calculations were carried out for molecular dimers in the gas phase (Table 3). The interaction energy for the halogen bonds is −6 kJ·mol−1 for the D1 dimer. The result obtained for the H(2N)...O(1)#2 hydrogen bond is −59 kJ·mol−1 (D2), whereas for the second H(1N)...O(2)#1 hydrogen bond it is −55 kJ·mol−1 (D3). The hydrogen bonds predominantly have electrostatic character with a small difference between Ees and the total energy. Bromine interactions in the crystal lattice with a favorable Ees contribution are significantly smaller when all contributions to the total energy are taken into account. The negative impact is probably caused by the repulsion energy between atoms due to the large size of the bromine atom. The opposite effect is seen for D6 and D7, where the different contributions to the total energy enhance the strength of the interactions. The D6 dimer connected by π···π stacking has a small negative Ees; however, the total energy is as low as −43 kcal mol−1. For stacking, interaction dispersion has an important contribution. Probably for D7, dispersion also shows a positive impact and the total energy is smaller. As mentioned before the WP series showed two different configurations with the trans configuration as the favorable one. It was found only in the WP1130 crystal structure. The penalty for the cis configuration can be paid by formation of more energetically favorable interactions. For example only the cis configuration allows for the formation of hydrogen bonds

empirical formula obtained for standard and weak hydrogen bonds.38 In a more global approach to intermolecular interactions, the interaction energy is computed on the basis of the charge density of the whole molecule, not from local descriptors such as properties of BCPs. Therefore, some dimers were selected from the WP1066, WP1130, and WP1220 crystal structures for further energetic consideration (Figures 5−7). The EPMM approach41 takes into account contributions not only from hydrogen/halogen bonding but also from long-range electrostatic interactions present between any molecular charge densities. Attractive electrostatic interactions are naturally found in dimers linked together via well-oriented and relatively strong hydrogen bonds, such as D2 and D3 (Table 3). The significant Table 3. Electrostatic Interaction Energy (Ees) and Total Interaction Energy (E) [kJ mol−1] Obtained for Selected Dimers Extracted from the WP1066, WP1130, and WP1220 Crystal Structures WP1066 Ees D1 D2 D3 D4 D5 D6 D7

a

−20 −126 −87 −22 −10 −8 37

Ees

WP1130 b

−20 −78 −58 −18 −4 −3 20

E

c

−6 −59 −55 −17 −5 −43 18

E D1′ D2′ D3′ D4′

WP1220 c

−57 −44 −37 −8

Ec D1″ D2″ D3″ D4″

−60 −39 −40 −17

a

Ees obtained with the EPMM method41 between two molecular charge distributions within the Hansen−Coppens model28 refined against experimental data. bEes obtained with the Exact Potential37 from monomer charge distributions expressed in terms of Gaussiantype basis functions (wave functions calculated in Gaussian0934). c Interaction energy obtained by supermolecular method with BSSE correction42,43 for gas phase dimers (calculations performed in Gaussian0934).

difference between the Ees values calculated on the basis of experimental and theoretical charge densities can be explained by the aforementioned charge redistribution (0.37 e) between molecules in the dimer. The theoretical calculation was carried out with zero charge on both molecules. The Ees values for D2 and D3 formed by neutral molecules are −78 kJ·mol−1 and −58 kJ·mol−1, respectively, whereas the Ees values with charge redistribution amount to −126 kJ·mol−1 and −78 kJ·mol−1.

Figure 9. Illustration of the electrostatic potential of two molecules from asymmetric unit of the WP1066 mapped on isosurface of charge density obtained from experimental multipolar modeling for (a) molecule 1 and (b) molecule 2. Charge density isosurface drawn at 0.067 eA−3. ESP color scale from −0.25 eÅ−1 (red) up to 0.25 eÅ−1 (purple). 2639


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Figure 10. Electrostatic potential mapped onto the Hirshfeld surface: (a) D1 and D2 dimer interactions in WP1066; (b) D1′ and D2′ dimer interactions in WP1130; (c) D1″ and D2″ dimer interactions in WP1220.

The hydrogen bond mainly has an electrostatic nature, clearly seen in the comparison of the total and electrostatic interaction energy for WP1066 in Table 3. In the case of D1 in WP1066, the halogen bonded dimer, the ESP has an adverse effect. However, the positive cap of ESP at the bromine atom contributes positively and the electrostatic interaction energy for D1 is still negative. In the case of strongly bound dimers in WP1130, and also D1′ and D2′, interacting by weak interaction as C−H···O or π···π stacking also exhibits complementarity of ESP. The presented results can suggest that the complementarity of positive and negative ESP regions might be considered as a driving force in the crystal formation. It is however worth noting that the change of conformation lead to a change of electrostatic potential and in consequence to the formation of crystal structures with or without classic hydrogen bonds.

between amide groups. The butyl side chain in WP1130 would block formation of short contact between amide groups; therefore, molecules form the net of weaker interactions: C− H···O, Br···π, and π···π stacking (D1′). The interaction energy for the D1′ dimer is −57 kJ mol−1, and the strength of these contacts is comparable with the hydrogen bonded dimers: D2, D3, and D1″. A similar example was found for different interactions; e.g., π···π stacked dimers (D6 and D3″) are formed in crystals with cis molecules, not found in the WP1130. D6 and D3″ joined by the same interaction have a similar total interaction energy. The remaining dimers in WP1130 are connected by weak hydrogen bond C−H···O and C−H···π interactions (D2′ and D3′). Nonetheless all of them are represented by very close energy values around −40 kJ mol−1. The weaker interactions in D4′ and D4″ have smaller contribution to the lattice energy; however, both are attractive in nature. These dimers are connected by long C−H···π and Br···π contacts. 3.4. Electrostatic Potential. The electrostatic potential (ESP) derived on the basis of experimental charge density shows a clear difference between two molecules in the asymmetric unit of WP1066 (Figure 9 and Figure 5S in the Supporting Information). A larger area of negative ESP on molecule 2 was expected due to the negative charge found for this molecule. It is a well-known phenomenon that the electrostatic potential around halogen atoms mapped on a charge density isosurface has a positive cap at elongation of the C−Br bond and is negative in the perpendicular direction (Figure 9). Experimental data show that charge redistribution between molecules also influences this cap. The Br(2) atom involved in the shorter halogen bond has a smaller positive cap due to the strong connection with the nitrogen atom from the cyano group. The electrostatic potential mapped onto the Hirshfeld surface44−46 proved to be a useful tool in the analysis of weak interactions in molecular crystals.47 The change of conformation of the C(25)C(24)C(26)O(2) torsion angle (numbering from the WP1066) causes the change of the ESP of molecules (Figure 10). In the case of the WP1066 and WP1220 structures, the hydrogen bonded dimers (D2 and D1″ dimers, respectively) exhibit complementary regions of negative and positive ESP.

4. CONCLUSIONS The study provides a detailed charge density distribution analysis together with comprehensive energetic investigations for different interactions formed by a bromine atom in acrylamide derivatives. Our work covers an experimental charge density study of the WP1066 crystal structures and analysis of the X-ray data for two analogs, WP1130 and WP1220. These experimental data enable the analysis of weak interactions with respect to energetic features in the crystalline state, and an attempt to generalize the energy of interactions formed by bromine atom. Experimental charge density combined with theoretical studies indicate that the halogen bond (Br···N) interaction is one of the weakest in crystal structure and in energetic terms is similar to Br···H contacts. It is even weaker than the C−H···O hydrogen bonds. However, experimental charge density studies revealed a charge redistribution between molecules in the asymmetric unit due to the properties of the halogen and hydrogen bonds. Both interactions are driven by electrostatic forces; however, in case of halogen interaction a repulsive term of total energy is an important factor. The Hirshfeld surface analysis allowed us to determine bonding patterns in analyzed crystal structures. This served as a starting point for the evaluation of energetic features, with the special emphasis on dimer interactions. The presence of a different conformation has an impact on the electrostatic 2640


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potential of molecules. This influences the weak interaction preferences of the studied compounds within the crystal lattice. Therefore, the observed crystal packing motifs are considerably different in the case of WP1066, WP1220 (trans), and WP1130 (cis). WP1066 forms two strongly bound hydrogen-bond dimeric motifs (D2 and D3) and one weak halogen bond dimeric motif (D1). Here only one strong interaction is present joining molecules into dimers. The WP1220 molecules form a slightly weaker N···H−N hydrogen bond, compensating for the energetic difference by formation of two C−H···O interactions. The bulky side chain next to the amide group in WP1130 disables the chance of formation of hydrogen bonds. Therefore, molecules adopt the more favorable conformation and forms a crystal structure with weaker interactions when considered individually. Nonetheless the resulting interaction energy for these dimers is still very similar. A similar result was found for weaker π···π interactions, present only in the WP1066 and WP1220 crystal structure.

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ASSOCIATED CONTENT

S Supporting Information *

Residual density maps, normal probability plots, scale plots, integrated atomic charges, figures with ESP mapped onto Hirshfeld surfaces. The cif file containing the WP1066, WP1130, and WP1220 crystal structure data has been deposited at the Cambridge Crystallographic Data Centre and allocated the deposition number CCDC 909489, 1028438, and 1028439, respectively. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/cg501598h.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: (W.P.) [email protected]. *E-mail: (K.W.) [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS M.M. thanks the National Science Centre for financial support within Grant UMO-2011/01/N/ST4/03616 and UMO-2013/ 08/T/ST4/00494. The authors gratefully acknowledge the Interdisciplinary Centre for Mathematical and Computational Modelling in Warsaw (Grant No. G33-14) for providing computer facilities on which most of the calculations were done. K.W. acknowledges the Polish NCN MAESTRO grant, Decision Number DEC-2012/04/A/ST5/00609. Also, support from the Viragh Fundation is gratefully acknowledged (W.P.).

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REFERENCES

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Bromine Atom Interactions in Biologically Active Acrylamide

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