Hydrogen-Bonded Dimeric Synthon of Fluoro-Substituted

Article pubs.acs.org/crystal

Hydrogen-Bonded Dimeric Synthon of Fluoro-Substituted Phenylboronic Acids versus Supramolecular Organization in Crystals Izabela D. Madura,* Karolina Czerwińska, and Dominika Sołdańska Faculty of Chemistry, Warsaw University of Technology, Noakowskiego 3, 00-664 Warsaw, Poland S Supporting Information *

ABSTRACT: An analysis of crystal structures of a series of fluoro-substituted phenylboronic acids is presented. Interplay between the structure of a basic H-bonded dimeric R22(8) synthon and a higher-order supramolecular organization is highlighted. The elucidation of hydrogen bonds formed by the boronic B(OH)2 moiety is supported by energy calculations based on a one-dimensional H-bond model as well as by Hirshfeld surface analysis. The results revealed that intramolecular O−H···F hydrogen bonds are insignificant compared to O−H···O ones in dimers in controlling the syn−anti conformation of the boronic group. Depending on the strength of H-bonds in the basic motif, forces constituting so-called large synthons change from O−H···O hydrogen bonds to stacking interactions. This differentiation entails the twist of the boronic group with respect to the phenyl ring. The large synthons serve as main building blocks for three-dimensional structures either by their close packing or by the aid of weak secondary interaction such as C−H···π, O−H···F, or C−H···F hydrogen bonds. The observed isomorphism and polymorphism are discussed in relation to the packing of one-dimensional large synthons.

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Noteworthy are examples given by Aakeröy et al.18 signaling that the flexibility of the B(OH)2 unit resulting in syn−syn, syn− anti, and anti−anti conformers might be a challenge in predicting the synthons that can be formed during supramolecular synthesis.19 This flexibility can be attributed to a low energy barrier between conformers as demonstrated by highlevel ab initio calculations for isolated unsubstituted pba.19,20 These results showed that although a syn−anti conformer is energetically favored, the remaining anti−anti and syn−syn conformers are only 1 and 4 kcal/mol higher in energy, respectively. Nonetheless, conformers other than syn−anti conformers are rare in crystals. The syn−syn conformers are mainly observed in co-crystals in which both hydroxyl groups of pba act as donors in intermolecular hydrogen bonds,14,15,19,21 whereas the anti−anti conformers are realized provided that in both ortho positions two strong hydrogen bond acceptors are present.22,23 In summary, the conformation of the B(OH)2 moiety in crystals of pba seems to be induced by hydrogen bonds, either inter- or intramolecular ones. Hydrogen bonds were also identified as being responsible for controlling the second factor characteristic for pba molecules in crystals, i.e., a rotation of the B(OH)2 moiety around the B−C bond.20,24,25 For an isolated molecule of pba, the calculated rotational barrier did not exceed 4 kcal/mol.20 In crystals, a vast

INTRODUCTION Supramolecular synthons1 are usually discussed in connection with crystal engineering,2,3 but they also have been found to be essential for describing aggregates in solution4 or understanding nucleation processes.5 Very often, the synthons are formed by hydrogen bonds, which seem to be the most vastly and deeply analyzed interactions in terms of their nature and energy and the evidence of their formation.6−8 Hydrogen bonds in combination with other interactions can form large synthons9 or so-called Long Range Synthon Aufbau Modules (LSAMs)10 that were thought to act as intermediates between small synthons and crystal growth units.4 In the case of crystals of phenylboronic acids (pba), the most frequently observed synthon is a dimer with two O−H···O hydrogen bonds (Scheme 1).11 It is described by an R22(8) graph set12,13 and thus often compared to carboxylic acid dimers.14−17 However, the possibility of forming hydrogen bonds with a second hydroxyl group causes boronic acids to correspond more to carboxylic amides, although the latter can form N−H···X bonds.14−16,18 This causes the increasing level of use of pba in the field of crystal engineering.14−16,18,19 Scheme 1. Hydrogen-Bonded Dimer of Phenylboronic Acid

Received: July 28, 2014 Revised: October 7, 2014

© XXXX American Chemical Society

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dx.doi.org/10.1021/cg501132d | Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design

Article

steric interactions and hydrogen bond formation.31 Last but not least, an enhanced biological activity of the fluoro-substituted derivatives of pba analogues has been identified.32 Therefore, the knowledge of the structural relations coming from the fluorination as well as of the factors controlling the twist angle and B(OH)2 group conformation may help in a design of new compounds such as pharmaceutical co-crystals.33 From this industrial point of view, new polymorphic forms may also be valuable.34

range (from 0° to 90°) of dihedral angles between planes containing the boronic group and the phenyl ring (hereafter a twist angle) was found. For example, in the crystal structure of unsubstituted pba, two crystallographically independent molecules differ significantly in their degrees of rotation. The observed values amounted to 6° and 20°. This diversity was attributed to the presence of weak intermolecular interactions.24 In turn, intramolecular hydrogen bonds were found to influence the twist angle in a series of ortho-substituted pba derivatives.25 Continuing our structural research on fluorinated pba derivatives,26,27 we have chosen a series of crystal structures of fluorinated acids for this study (Scheme 2). As an objective,

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EXPERIMENTAL SECTION

Crystallization. Crystals suitable for experiments were grown by slow water evaporation from saturated solutions of commercially purchased samples or taken directly from these samples. In the case of 2,5-difluorophenylboronic acid, the quality of crystals grown from a water solution was very poor; hence, an equimolar amount of Lglutamine was introduced. We expected to obtain either good quality single crystals or co-crystals similar to those described by Cyrański et al.21 Our crystalline sample contained two types of crystals exhibiting different habits (Figure 1a). Both tapes and blocks were carefully

Scheme 2. Gallery of Studied Compoundsa

Figure 1. (a) Sample of crystals of 2,5-difluorophenylboronic acid (25Fpba) indicating the presence of concomitant polymorphs. Single crystals of (b) 25Fpba_1 and (c) 25Fpba_2 used in X-ray experiments.

Fpba refers to the fluorinated derivative of phenylboronic acid. Associated numbers indicate positions of fluorine atoms in the phenyl ring with respect to the boronic moiety. The atom numbering scheme is outlined on the 23Fpba derivative. Possible O−H···F hydrogen bonds are denoted as dashed lines. a

explored by single-crystal X-ray diffraction (Figure 1b,c), and refined models confirmed different crystal forms, i.e., the presence of concomitant polymorphs35,36 of 25Fpba. In this paper, they are named 25Fpba_1 (tapes) and 25Fpba_2 (blocks). It is noteworthy that the crystallization experiment was repeated twice and in both cases the same results were obtained. In addition, crystallization with glycine led to the same results. Systematic studies of this phenomenon are currently underway. X-ray Crystallographic Studies. Crystal data for all analyzed crystals, data collection, and details of refinement are listed in Table 1. All single-crystal X-ray experiments were conducted on the Gemini A Ultra Diffractometer (Agilent Technologies) equipped with a CCD detector and using mirror monochromated Cu Kα radiation (λ = 1.5418 Å). All crystals were measured at 100(2) K in a stream of cold nitrogen. Data collection and data reduction were performed in CrysAlisPro.37 To solve and refine the structures, the OLEX-2 suite38 with implemented SHELXS97 (direct methods) and SHELXL97 (the full-matrix least-squares technique) programs39 was used. All nonhydrogen atoms were refined with anisotropic temperature factors. The hydrogen atoms of hydroxyl groups were refined freely, while the remainder were placed in calculated positions with fixed isotropic thermal parameters {Uiso(H) = 1.2[Ueq(C)]} and were included in the structure factor calculations at the final stage of the refinement. Values involving hydrogen atoms in the calculated positions are given without estimated standard deviations. In the case of 2Fpba, a residual maximal density of 0.5 e Å−3 near H6 was found, indicating a “flip-flap” disorder. Nevertheless, the ratio of maximal to minimal residual density of only 2.74 did not allow us to refine satisfactorily the model

we sought to ascertain whether and how the intra- and intermolecular interactions control the two degrees of freedom of the boronic moiety mentioned above. Besides, we have taken into account the investigations by Desiraju et al. concerning a structural landscape of benzoic acid.28 They showed that F substitution in benzoic acid reveals crystal structures corresponding to high-energy polymorphs of the acid. This prompted us to compare crystal data of the fluorinated derivatives with those of unsubstituted pba24 and to discern similarities and differences between them at consecutive levels of supramolecular organization, including a detection of LSAMs.10 In general, an isosteric (equivolume) substitution of hydrogen atoms with fluorine ones does not much change the molecular size or shape.29 However, because of the high electronegativity of the fluorine atom, considerable differences can be observed in the properties of the molecules, including their spatial behavior. In the case of pba compounds, the introduction of fluorine atoms enhances the Lewis acidity of the boron center. Nevertheless, there is no correlation of acidity with the number and position of fluorine substituents.30 Systematic investigation of fluorinated boronic acids by multinuclear nuclear magnetic resonance also revealed that the inductive effect plays a minor role compared with that of B



Article

Table 1. Crystallographic Data molecular formula molecular weight T (K) system space group a (Å) b (Å) c (Å) α (deg) β (deg) γ (deg) volume (Å3) Z Dcalc (mg/m3) R1 [I > 2σ(I)] wR2 (all data)

2Fpba

23Fpba

24Fpba

25Fpba_1

25Fpba_2

26Fpba

234Fpba

246Fpba

C6H6BFO2 139.92 100.0(2) monoclinic P21/c 5.1017(2) 5.5566(2) 22.059(1) 90 94.731(3) 90 623.19(3) 4 1.491 0.0343 0.0930

C6H5BF2O2 157.91 100.0(2) monoclinic P21/n 8.9657(2) 4.9573(1) 29.7170(5) 90 97.593(2) 90 1309.2(0) 8 1.602 0.0304 0.0852



C6H5BF2O2 157.91 100.0(2) monoclinic P21/c 4.1530(1) 5.1138(1) 30.7324(5) 90 90.070(1) 90 652.68(2) 4 1.607 0.0309 0.0846


C6H4BF3O2 175.90 100.0(2) triclinic P1̅ 4.3762(3) 5.0241(3) 15.640(1) 96.483(6) 94.143(6) 92.835(6) 340.20(4) 2 1.717 0.0309 0.0878


Table 2. Selected Bond Lengths (angstroms), Bond Angles (degrees), and Torsion Angles (degrees) for Studied Compounds B1−C1 B1−O1 B1−O2 C1−C2 C1−C6 F1−C2 O1−B1−O2 C1−B1−O1 C1−B1−O2 B1−C1−C2 B1−C1−C6 F1−C2−C1 O1−B1−C1−C2 O2−B1−C1−C2 F1−C2−C1−B1 a

2Fpba

23Fpba A

23Fpba B

24Fpba

25Fpba_1

25Fpba_2

26Fpba

234Fpba

246Fpba

penFpbaa

1.572(2) 1.367(2) 1.358(2) 1.387(2) 1.405(2) 1.365(2) 118.2(1) 123.9(1) 117.9(1) 123.8(1) 120.9(1) 118.4(1) −26.9(2) 154.1(1) 0.4(2)

1.576(2) 1.364(2) 1.358(2) 1.383(2) 1.405(2) 1.357(2) 118.4(1) 123.8(1) 117.8(1) 122.9(1) 120.8(1) 120.1(1) 25.0(2) −155.3(1) −1.8(2)

1.570(2) 1.363(2) 1.363(2) 1.382(2) 1.404(2) 1.358(2) 117.8(1) 124.6(1) 117.6(1) 122.8(1) 120.6(1) 120.1(1) 27.4(2) −152.3(1) 1.5(2)

1.572(2) 1.371(2) 1.349(2) 1.385(2) 1.401(2) 1.371(2) 118.9(2) 123.9(2) 117.2(2) 125.1(2) 119.6(2) 118.4(1) −5.2(3) 175.8(2) −1.4(2)

1.582(3) 1.359(3) 1.353(3) 1.376(3) 1.405(3) 1.366(2) 119.0(2) 123.1(2) 119.0(2) 124.2(2) 119.5(2) 118.5(2) −22.2(3) 158.4(2) 1.1(3)

1.581(2) 1.362(2) 1.352(2) 1.385(2) 1.400(2) 1.364(2) 119.0(1) 123.3(3) 119.0(1) 124.1(1) 119.6(1) 118.2(1) −27.0(2) 155.5(1) −3.6(2)

1.585(2) 1.361(2) 1.353(2) 1.390(2) 1.391(2) 1.359(2) 118.3(1) 122.3(1) 119.4(1) 123.2(1) 123.7(1) 117.8(1) 24.5(2) −154.9(1) −1.1(2)

1.575(2) 1.362(2) 1.355(2) 1.385(2) 1.401(2) 1.352(2) 118.5(1) 124.5(1) 117.0(1) 123.8(1) 119.9(1) 120.4(1) 27.5(2) −154.5(1) 1.8(2)

1.583(2) 1.364(2) 1.352(2) 1.390(2) 1.396(2) 1.357(2) 118.2(1) 121.9(1) 119.9(1) 123.0(1) 124.1(1) 118.1(1) 23.1(2) −155.9(1) −1.6(2)

1.579(3) 1.362(2) 1.355(2) 1.385(3) 1.390(3) 1.349(2) 119.6(2) 122.2(2) 118.2(2) 121.9(2) 122.7(2) 120.1(2) −38.4(3) 140.6(2) 3.5(3)

The atom numbering scheme was changed to be consistent with all discussed molecules. respectively.47 Associated HS surface two-dimensional (2D) fingerprint plots49,50 show the fraction of points on the surface as a function of the (di, de) pair. Each point on the 2D graph represents a bin formed by discrete intervals of di and de (0.01 Å × 0.01 Å), and the points are colored as a function of the fraction of surface points in that bin, with a range from blue (relatively few points) through green (moderate fraction) to red (highest fraction). The full fingerprint plot for 24Fpba is presented in Figure 4, while the selected resolved ones are a part of Figure 6. For the decomposed fingerprint plots presenting particular contacts, the outline of the full fingerprint is colored gray. The normalized contact distance (dnorm)50 based on both de and di and the van der Waals (vdW) radii51 (r) of atoms is given by the equation dnorm = (di − ri)/ri + (de − re)/re. In Figure 2 the HS are mapped with dnorm over the range from −0.8 to 1.2 with a red−white−blue coloring scheme (red, shorter than the sum of van der Waals radii, through white to blue, greater than the sum of radii). The van der Waals radii were chosen to be equal to those used in CSD.11 A range of fractions spanning 0.05% of the surface areas was used. The HS were calculated from crystal structure coordinates using CrystalExplorer.52

of the disordered structure. Selected geometric parameters for newly determined acids and those deposited in CSD11 are listed in Tables 2 and 3, respectively. For the analysis of bond lengths, bond angles, and other geometrical parameters, PLATON40 was used. Molecular and packing diagrams were generated using DIAMOND41 and ORTEP-3 for Windows.42 H-Bond Energy Calculations. To correct for X-ray proton positioning errors, all O−H bonds were renormalized by setting the distances to the reference value of 0.94 Å. The O−H···O bond energies were estimated by the method of Lippincott and Schroeder43,44 using the LSHB program courtesy of the authors.45 The O−H···F bond energy, not parametrized in the original works of Lippincott and Schroeder,43,44 was estimated accordingly by applying experimental spectroscopic data for the HF molecule.46 The following values were used for calculation of the O−H···F bond energy (the same units and naming as in original paper43): n0 = 9.30 × 10−8 cm−1, n* = 13.40 × 10−8 cm−1, r0* = 0.917 Å, k0* = 9.67 × 10−5 dyn/cm, and g = 1.441. We are aware that the estimated standard deviation for LSHBE calculations can exceed 0.1−0.2 kcal/mol. However, we placed the more precise values in Table 3 in accord with the original works.43,44 Hirshfeld Surface Analysis. The molecular Hirshfeld surfaces (HS)47,48 are constructed on the basis of the electron distribution calculated as the sum of spherical atom electron densities. The di and de parameters, defined for each point on the surface, refer to the distances from the surface to an atom inside and outside the surface,

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RESULTS AND DISCUSSION

Crystal structure analysis was performed for eight new pba derivatives (Table 1). The series was supplemented with the data for pentafluorophenylboronic acid (penFpba) deposited in the CSD database as entry WAJXEL.53 The gallery of analyzed C



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Table 3. Geometry of Hydrogen Bondsa (angstroms and degrees) and LSHB Energies (kilocalories per mole) compound

a

contact

H···A

2Fpba 23dFpba_A 23dFpba_B 24dFpba 25dFpba_1 25dFpba_2 26dFpba 234tFpba 246tFpba penFpba

O1−H1···F1 O1−H1···F1 O1a−H1a···F1a O1−H1···F1 O1−H1···F1 O1−H1···F1 O1−H1···F1 O1−H1···F1 O1−H1···F1 O1−H1···F1

2.331 2.301 2.462 2.089 2.233 2.331 2.257 2.444 2.195 2.525

2Fpba 23dFpba_A 23dFpba_B 24dFpba 25dFpba_1 25dFpba_2 26dFpba 234tFpba 246tFpba penFpba pba_A pba_B

O2−H2···O1 O2−H2···O1a O2a−H2a···O1 O2−H2···O1 O2−H2···O1 O2−H2···O1 O2−H2···O1 O2−H2···O1 O2−H2···O1 O2−H2···O1 O2−H2···O1a O2a−H2a···O1

1.791 1.750 1.788 1.800 1.817 1.773 1.805 1.770 1.810 1.751 1.743 1.731

2Fpba 23dFpba_A 23dFpba_B 25dFpba_1 25dFpba_2 26dFpba 234tFpba 246tFpba penFpba pba_A pba_B

O1−H1···O2 O1−H1···O2 O1a−H1a···O2a O1−H1···O2 O1−H1···O2 O1−H1···O2 O1−H1···O2 O1−H1···O2 O1−H1···O2 O1−H1···O2 O1a−H1a···O2a

1.967 1.903 1.848 2.023 1.977 1.925 1.897 1.970 1.831 1.752 1.743

D···A Intramolecular O−H···F 2.855(1) 2.846(1) 2.884(1) 2.807(2) 2.822(1) 2.875(1) 2.781(1) 2.930(1) 2.759(1) 2.889(2) O−H···O in Dimer 2.766(2) 2.729(1) 2.759(1) 2.792(2) 2.799(2) 2.755(2) 2.786(2) 2.749(2) 2.793(1) 2.733(2) 2.734(2) 2.721(2) Interdimeric O−H···O 2.843(1) 2.778(1) 2.725(1) 2.861(1) 2.851(1) 2.819(1) 2.777(1) 2.843(1) 2.765(2) 2.692(2) 2.709(2)

D−H···A

LSHBE

symmetry

112.48 114.01 105.46 128.38 117.21 114.05 112.12 110.03 115.04 101.67

0.09 0.11 0.04 0.37 0.16 0.09 0.13 0.05 0.19 0.03

170.76 174.22 168.96 176.42 178.00 176.95 174.84 173.85 178.22 176.69 175.21 174.95

3.03 3.78 3.08 2.57 2.66 3.34 2.81 3.39 2.75 3.74 3.70 3.95

−x, −y, −z 1 − x, 2 − y, −z 1 − x, 2 − y, −z 2 − x, −y, 2 − z 2 − x, 2 − y, −z 2 − x, 2 − y, −z 2 − x, −1 − y,1 − z −1 − x, 1 − y, −z 1 − x, 3 − y, −z −x, −1 − y, −z −1 + x, y, z 1 + x, y, z

147.03 146.83 146.83 141.87 146.90 149.89 147.59 146.58 157.54 156.43 163.09

1.16 1.64 2.18 0.86 1.11 1.46 1.70 1.14 2.43 3.48 3.67

1 + x, y, z x, −1 + y, z x, −1 + y, z 1 + x, y, z x, −1 + y, z −1 + x, y, z x, −1 + y, z −1 + x, y, z x, −1/2 − y, −1/2 + z x, 1 − y, −1/2 + z 2 − x, y, 1/2 + z

Normalized O−H distance of 0.983 Å.

compounds in given in Scheme 2. For all the compounds, a consistent atom numbering scheme was applied (Scheme 2). It should be mentioned that the structures of 2,4-difluorophenylboronic acid (24Fpba)54 and the di-ortho-fluoro-substituted derivative (26Fpba)55 were already published but the data were measured at 296 K. Hence, an analysis of their structures determined at 100 K is presented here. It should be emphasized that in both cases the lowering of the temperature has not affected significantly the molecular structure or the crystal arrangement. Additionally, for comparison, the crystal data for unsubstituted pba (pba)24 are used. To show the interplay of the observed supramolecular organization as mentioned in the Introduction between two degrees of freedom of phenylboronic acids molecules, subsequent levels of molecular aggregation are discussed, starting from a molecule in crystal, through the basic supramolecular synthon followed by possible large synthons and ending with a three-dimensional (3D) structure. Molecular Structure. All studied compounds crystallize in centrosymmetric space groups (Table 1). In all cases but 23Fpba, there is only one molecule in an asymmetric part of a unit cell. Selected geometrical parameters are listed in Table 2

and show that differences between molecules A and B in the 23Fpba crystal are negligible (within 3σ). The only notable but still subtle change is observed in the twist angles being 25.0(2)° and 27.4(2)° for molecules A and B, respectively. Likewise, crystallographically independent molecules of 23Fpba, molecules in both polymorphs of 25Fpba, and other molecules in the studied series are very similar (Table 2). The deviations of corresponding bond distances and bond angles do not provide an unequivocal answer about the influence of fluorine substitution on molecular structure. A similar conclusion was reached in the case of fluorinated diboronic acids20 and fluorosubstituted phenylboronic acid catechol esters26 both in crystals and in the gas phase. In all acids studied here, the boron atom is three-coordinated and does not exhibit pyramidalization exceeding 0.01 Å. The syn−anti conformation of the boronic moiety is observed; therefore, the formation of one intramolecular O−H···F interaction with a fluorine atom in the ortho position can be assumed in analyzed series of o-fluorophenylboronic acids (Scheme 2). The observed H···F distances are differentiated and range from 2.06(2) to 2.53(2) Å (Table 3). The same applies to the twist angle that varies from 5.9(1)° to 38.4(3)° D



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severely differentiated H···F distances. As the twist influences the intramolecular hydrogen bond angle in such an S(6) motif, instead of H···F distance consideration we have calculated the O−H···F interaction energy based on the one-dimensional Hbond model of Lippincott and Schroeder43,44 (Table 3). The calculated energy values point to very weak interactions of

Hydrogen-Bonded Dimeric Synthon of Fluoro-Substituted

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