Hydrogen-Bonded Dimeric Synthon of Fluoro-SubstitutedPhenylboronic Acids versus Supramolecular Organization in CrystalsIzabela D. Madura,* Karolina Czerwinska, and Dominika Sołdanska

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 offluoro-substituted phenylboronic acids is presented. Interplaybetween the structure of a basic H-bonded dimeric R2

2(8)synthon and a higher-order supramolecular organization ishighlighted. The elucidation of hydrogen bonds formed by theboronic B(OH)2 moiety is supported by energy calculationsbased on a one-dimensional H-bond model as well as byHirshfeld surface analysis. The results revealed that intra-molecular O−H···F hydrogen bonds are insignificant com-pared to O−H···O ones in dimers in controlling the syn−anticonformation of the boronic group. Depending on thestrength of H-bonds in the basic motif, forces constitutingso-called large synthons change from O−H···O hydrogen bonds to stacking interactions. This differentiation entails the twist ofthe boronic group with respect to the phenyl ring. The large synthons serve as main building blocks for three-dimensionalstructures either by their close packing or by the aid of weak secondary interaction such as C−H···π, O−H···F, or C−H···Fhydrogen bonds. The observed isomorphism and polymorphism are discussed in relation to the packing of one-dimensional largesynthons.

■ INTRODUCTION

Supramolecular synthons1 are usually discussed in connectionwith crystal engineering,2,3 but they also have been found to beessential for describing aggregates in solution4 or understandingnucleation processes.5 Very often, the synthons are formed byhydrogen bonds, which seem to be the most vastly and deeplyanalyzed interactions in terms of their nature and energy andthe evidence of their formation.6−8 Hydrogen bonds incombination 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 smallsynthons and crystal growth units.4

In the case of crystals of phenylboronic acids (pba), the mostfrequently observed synthon is a dimer with two O−H···Ohydrogen bonds (Scheme 1).11 It is described by an R2

2(8)graph set12,13 and thus often compared to carboxylic aciddimers.14−17 However, the possibility of forming hydrogenbonds with a second hydroxyl group causes boronic acids tocorrespond more to carboxylic amides, although the latter canform N−H···X bonds.14−16,18 This causes the increasing level ofuse of pba in the field of crystal engineering.14−16,18,19

Noteworthy are examples given by Aakeroy et al.18 signalingthat the flexibility of the B(OH)2 unit resulting in syn−syn, syn−anti, and anti−anti conformers might be a challenge inpredicting the synthons that can be formed during supra-molecular synthesis.19 This flexibility can be attributed to a lowenergy barrier between conformers as demonstrated by high-level ab initio calculations for isolated unsubstituted pba.19,20

These results showed that although a syn−anti conformer isenergetically favored, the remaining anti−anti and syn−synconformers are only 1 and 4 kcal/mol higher in energy,respectively. Nonetheless, conformers other than syn−anticonformers are rare in crystals. The syn−syn conformers aremainly observed in co-crystals in which both hydroxyl groups ofpba act as donors in intermolecular hydrogen bonds,14,15,19,21

whereas the anti−anti conformers are realized provided that inboth ortho positions two strong hydrogen bond acceptors arepresent.22,23 In summary, the conformation of the B(OH)2moiety in crystals of pba seems to be induced by hydrogenbonds, either inter- or intramolecular ones.Hydrogen bonds were also identified as being responsible for

controlling the second factor characteristic for pba molecules incrystals, i.e., a rotation of the B(OH)2 moiety around the B−Cbond.20,24,25 For an isolated molecule of pba, the calculatedrotational barrier did not exceed 4 kcal/mol.20 In crystals, a vast

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

Scheme 1. Hydrogen-Bonded Dimer of Phenylboronic Acid

Article

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range (from 0° to 90°) of dihedral angles between planescontaining the boronic group and the phenyl ring (hereafter atwist angle) was found. For example, in the crystal structure ofunsubstituted pba, two crystallographically independent mole-cules differ significantly in their degrees of rotation. Theobserved values amounted to 6° and 20°. This diversity wasattributed to the presence of weak intermolecular interac-tions.24 In turn, intramolecular hydrogen bonds were found toinfluence the twist angle in a series of ortho-substituted pbaderivatives.25

Continuing our structural research on fluorinated pbaderivatives,26,27 we have chosen a series of crystal structuresof fluorinated acids for this study (Scheme 2). As an objective,

we sought to ascertain whether and how the intra- andintermolecular interactions control the two degrees of freedomof the boronic moiety mentioned above. Besides, we have takeninto account the investigations by Desiraju et al. concerning astructural landscape of benzoic acid.28 They showed that Fsubstitution in benzoic acid reveals crystal structures corre-sponding to high-energy polymorphs of the acid. Thisprompted us to compare crystal data of the fluorinatedderivatives with those of unsubstituted pba24 and to discernsimilarities and differences between them at consecutive levelsof supramolecular organization, including a detection ofLSAMs.10 In general, an isosteric (equivolume) substitutionof hydrogen atoms with fluorine ones does not much changethe molecular size or shape.29 However, because of the highelectronegativity of the fluorine atom, considerable differencescan be observed in the properties of the molecules, includingtheir spatial behavior. In the case of pba compounds, theintroduction of fluorine atoms enhances the Lewis acidity of theboron center. Nevertheless, there is no correlation of aciditywith the number and position of fluorine substituents.30

Systematic investigation of fluorinated boronic acids bymultinuclear nuclear magnetic resonance also revealed thatthe inductive effect plays a minor role compared with that of

steric interactions and hydrogen bond formation.31 Last but notleast, an enhanced biological activity of the fluoro-substitutedderivatives of pba analogues has been identified.32 Therefore,the knowledge of the structural relations coming from thefluorination as well as of the factors controlling the twist angleand B(OH)2 group conformation may help in a design of newcompounds such as pharmaceutical co-crystals.33 From thisindustrial point of view, new polymorphic forms may also bevaluable.34

■ EXPERIMENTAL SECTIONCrystallization. Crystals suitable for experiments were grown by

slow water evaporation from saturated solutions of commerciallypurchased samples or taken directly from these samples. In the case of2,5-difluorophenylboronic acid, the quality of crystals grown from awater solution was very poor; hence, an equimolar amount of L-glutamine was introduced. We expected to obtain either good qualitysingle crystals or co-crystals similar to those described by Cyran ski etal.21 Our crystalline sample contained two types of crystals exhibitingdifferent habits (Figure 1a). Both tapes and blocks were carefully

explored by single-crystal X-ray diffraction (Figure 1b,c), and refinedmodels confirmed different crystal forms, i.e., the presence ofconcomitant polymorphs35,36 of 25Fpba. In this paper, they arenamed 25Fpba_1 (tapes) and 25Fpba_2 (blocks). It is noteworthythat the crystallization experiment was repeated twice and in bothcases the same results were obtained. In addition, crystallization withglycine led to the same results. Systematic studies of this phenomenonare currently underway.

X-ray Crystallographic Studies. Crystal data for all analyzedcrystals, data collection, and details of refinement are listed in Table 1.All single-crystal X-ray experiments were conducted on the Gemini AUltra Diffractometer (Agilent Technologies) equipped with a CCDdetector and using mirror monochromated Cu Kα radiation (λ =1.5418 Å). All crystals were measured at 100(2) K in a stream of coldnitrogen. Data collection and data reduction were performed inCrysAlisPro.37 To solve and refine the structures, the OLEX-2 suite38

with implemented SHELXS97 (direct methods) and SHELXL97 (thefull-matrix least-squares technique) programs39 was used. All non-hydrogen atoms were refined with anisotropic temperature factors.The hydrogen atoms of hydroxyl groups were refined freely, while theremainder were placed in calculated positions with fixed isotropicthermal parameters {Uiso(H) = 1.2[Ueq(C)]} and were included in thestructure factor calculations at the final stage of the refinement. Valuesinvolving hydrogen atoms in the calculated positions are given withoutestimated standard deviations. In the case of 2Fpba, a residual maximaldensity of 0.5 e Å−3 near H6 was found, indicating a “flip-flap”disorder. Nevertheless, the ratio of maximal to minimal residualdensity of only 2.74 did not allow us to refine satisfactorily the model

Scheme 2. Gallery of Studied Compoundsa

aFpba refers to the fluorinated derivative of phenylboronic acid.Associated numbers indicate positions of fluorine atoms in the phenylring with respect to the boronic moiety. The atom numbering schemeis outlined on the 23Fpba derivative. Possible O−H···F hydrogenbonds are denoted as dashed lines.

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

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of the disordered structure. Selected geometric parameters for newlydetermined acids and those deposited in CSD11 are listed in Tables 2and 3, respectively. For the analysis of bond lengths, bond angles, andother geometrical parameters, PLATON40 was used. Molecular andpacking diagrams were generated using DIAMOND41 and ORTEP-3for Windows.42

H-Bond Energy Calculations. To correct for X-ray protonpositioning errors, all O−H bonds were renormalized by setting thedistances to the reference value of 0.94 Å. The O−H···O bondenergies were estimated by the method of Lippincott andSchroeder43,44 using the LSHB program courtesy of the authors.45

The O−H···F bond energy, not parametrized in the original works ofLippincott and Schroeder,43,44 was estimated accordingly by applyingexperimental spectroscopic data for the HF molecule.46 The followingvalues were used for calculation of the O−H···F bond energy (thesame 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, andg = 1.441. We are aware that the estimated standard deviation forLSHBE calculations can exceed 0.1−0.2 kcal/mol. However, we placedthe more precise values in Table 3 in accord with the originalworks.43,44

Hirshfeld Surface Analysis. The molecular Hirshfeld surfaces(HS)47,48 are constructed on the basis of the electron distributioncalculated as the sum of spherical atom electron densities. The di andde parameters, defined for each point on the surface, refer to thedistances from the surface to an atom inside and outside the surface,

respectively.47 Associated HS surface two-dimensional (2D) finger-print plots49,50 show the fraction of points on the surface as a functionof the (di, de) pair. Each point on the 2D graph represents a binformed by discrete intervals of di and de (0.01 Å × 0.01 Å), and thepoints are colored as a function of the fraction of surface points in thatbin, with a range from blue (relatively few points) through green(moderate fraction) to red (highest fraction). The full fingerprint plotfor 24Fpba is presented in Figure 4, while the selected resolved onesare a part of Figure 6. For the decomposed fingerprint plots presentingparticular contacts, the outline of the full fingerprint is colored gray.The normalized contact distance (dnorm)

50 based on both de and di andthe van der Waals (vdW) radii51 (r) of atoms is given by the equationdnorm = (di − ri)/ri + (de − re)/re. In Figure 2 the HS are mapped withdnorm over the range from −0.8 to 1.2 with a red−white−blue coloringscheme (red, shorter than the sum of van der Waals radii, throughwhite to blue, greater than the sum of radii). The van der Waals radiiwere chosen to be equal to those used in CSD.11 A range of fractionsspanning 0.05% of the surface areas was used. The HS were calculatedfrom crystal structure coordinates using CrystalExplorer.52

■ RESULTS AND DISCUSSION

Crystal structure analysis was performed for eight new pbaderivatives (Table 1). The series was supplemented with thedata for pentafluorophenylboronic acid (penFpba) deposited inthe CSD database as entry WAJXEL.53 The gallery of analyzed

Table 1. Crystallographic Data

2Fpba 23Fpba 24Fpba 25Fpba_1 25Fpba_2 26Fpba 234Fpba 246Fpba

molecular formula C6H6BFO2 C6H5BF2O2 C6H5BF2O2 C6H5BF2O2 C6H5BF2O2 C6H5BF2O2 C6H4BF3O2 C6H4BF3O2

molecular weight 139.92 157.91 157.91 157.91 157.91 157.91 175.90 175.90T (K) 100.0(2) 100.0(2) 100.0(2) 100.0(2) 100.0(2) 100.0(2) 100.0(2) 100.0(2)system monoclinic monoclinic monoclinic monoclinic monoclinic monoclinic triclinic monoclinicspace group P21/c P21/n P21/n P21/n P21/c P21/n P1 P21/na (Å) 5.1017(2) 8.9657(2) 3.6793(1) 4.9578(4) 4.1530(1) 5.0272(2) 4.3762(3) 5.0030(1)b (Å) 5.5566(2) 4.9573(1) 12.2868(4) 5.5256(4) 5.1138(1) 5.3942(1) 5.0241(3) 5.3337(1)c (Å) 22.059(1) 29.7170(5) 14.3179(4) 23.484(2) 30.7324(5) 23.2334(7) 15.640(1) 24.2178(4)α (deg) 90 90 90 90 90 90 96.483(6) 90β (deg) 94.731(3) 97.593(2) 93.057(3) 93.974(8) 90.070(1) 91.897(3) 94.143(6) 90.259(2)γ (deg) 90 90 90 90 90 90 92.835(6) 90volume (Å3) 623.19(3) 1309.2(0) 646.34(4) 641.80(8) 652.68(2) 629.69(3) 340.20(4) 646.23(2)Z 4 8 4 4 4 4 2 4Dcalc (mg/m

3) 1.491 1.602 1.623 1.634 1.607 1.666 1.717 1.808R1 [I > 2σ(I)] 0.0343 0.0304 0.0357 0.0466 0.0309 0.0324 0.0309 0.0282wR2 (all data) 0.0930 0.0852 0.0948 0.1398 0.0846 0.0875 0.0878 0.0789

Table 2. Selected Bond Lengths (angstroms), Bond Angles (degrees), and Torsion Angles (degrees) for Studied Compounds

2Fpba 23Fpba A 23Fpba B 24Fpba 25Fpba_1 25Fpba_2 26Fpba 234Fpba 246Fpba penFpbaa

B1−C1 1.572(2) 1.576(2) 1.570(2) 1.572(2) 1.582(3) 1.581(2) 1.585(2) 1.575(2) 1.583(2) 1.579(3)B1−O1 1.367(2) 1.364(2) 1.363(2) 1.371(2) 1.359(3) 1.362(2) 1.361(2) 1.362(2) 1.364(2) 1.362(2)B1−O2 1.358(2) 1.358(2) 1.363(2) 1.349(2) 1.353(3) 1.352(2) 1.353(2) 1.355(2) 1.352(2) 1.355(2)C1−C2 1.387(2) 1.383(2) 1.382(2) 1.385(2) 1.376(3) 1.385(2) 1.390(2) 1.385(2) 1.390(2) 1.385(3)C1−C6 1.405(2) 1.405(2) 1.404(2) 1.401(2) 1.405(3) 1.400(2) 1.391(2) 1.401(2) 1.396(2) 1.390(3)F1−C2 1.365(2) 1.357(2) 1.358(2) 1.371(2) 1.366(2) 1.364(2) 1.359(2) 1.352(2) 1.357(2) 1.349(2)O1−B1−O2 118.2(1) 118.4(1) 117.8(1) 118.9(2) 119.0(2) 119.0(1) 118.3(1) 118.5(1) 118.2(1) 119.6(2)C1−B1−O1 123.9(1) 123.8(1) 124.6(1) 123.9(2) 123.1(2) 123.3(3) 122.3(1) 124.5(1) 121.9(1) 122.2(2)C1−B1−O2 117.9(1) 117.8(1) 117.6(1) 117.2(2) 119.0(2) 119.0(1) 119.4(1) 117.0(1) 119.9(1) 118.2(2)B1−C1−C2 123.8(1) 122.9(1) 122.8(1) 125.1(2) 124.2(2) 124.1(1) 123.2(1) 123.8(1) 123.0(1) 121.9(2)B1−C1−C6 120.9(1) 120.8(1) 120.6(1) 119.6(2) 119.5(2) 119.6(1) 123.7(1) 119.9(1) 124.1(1) 122.7(2)F1−C2−C1 118.4(1) 120.1(1) 120.1(1) 118.4(1) 118.5(2) 118.2(1) 117.8(1) 120.4(1) 118.1(1) 120.1(2)O1−B1−C1−C2 −26.9(2) 25.0(2) 27.4(2) −5.2(3) −22.2(3) −27.0(2) 24.5(2) 27.5(2) 23.1(2) −38.4(3)O2−B1−C1−C2 154.1(1) −155.3(1) −152.3(1) 175.8(2) 158.4(2) 155.5(1) −154.9(1) −154.5(1) −155.9(1) 140.6(2)F1−C2−C1−B1 0.4(2) −1.8(2) 1.5(2) −1.4(2) 1.1(3) −3.6(2) −1.1(2) 1.8(2) −1.6(2) 3.5(3)

aThe atom numbering scheme was changed to be consistent with all discussed molecules.

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compounds in given in Scheme 2. For all the compounds, aconsistent atom numbering scheme was applied (Scheme 2). Itshould be mentioned that the structures of 2,4-difluorophe-nylboronic acid (24Fpba)54 and the di-ortho-fluoro-substitutedderivative (26Fpba)55 were already published but the data weremeasured at 296 K. Hence, an analysis of their structuresdetermined at 100 K is presented here. It should be emphasizedthat in both cases the lowering of the temperature has notaffected significantly the molecular structure or the crystalarrangement. Additionally, for comparison, the crystal data forunsubstituted pba (pba)24 are used.To show the interplay of the observed supramolecular

organization as mentioned in the Introduction between twodegrees of freedom of phenylboronic acids molecules,subsequent levels of molecular aggregation are discussed,starting from a molecule in crystal, through the basicsupramolecular synthon followed by possible large synthonsand ending with a three-dimensional (3D) structure.Molecular Structure. All studied compounds crystallize in

centrosymmetric space groups (Table 1). In all cases but23Fpba, there is only one molecule in an asymmetric part of aunit cell. Selected geometrical parameters are listed in Table 2

and show that differences between molecules A and B in the23Fpba crystal are negligible (within 3σ). The only notable butstill 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, mole-cules in both polymorphs of 25Fpba, and other molecules inthe studied series are very similar (Table 2). The deviations ofcorresponding bond distances and bond angles do not providean unequivocal answer about the influence of fluorinesubstitution on molecular structure. A similar conclusion wasreached in the case of fluorinated diboronic acids20 and fluoro-substituted phenylboronic acid catechol esters26 both in crystalsand in the gas phase.In all acids studied here, the boron atom is three-coordinated

and does not exhibit pyramidalization exceeding 0.01 Å. Thesyn−anti conformation of the boronic moiety is observed;therefore, the formation of one intramolecular O−H···Finteraction with a fluorine atom in the ortho position can beassumed in analyzed series of o-fluorophenylboronic acids(Scheme 2). The observed H···F distances are differentiatedand range from 2.06(2) to 2.53(2) Å (Table 3). The sameapplies to the twist angle that varies from 5.9(1)° to 38.4(3)°

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

compound contact H···A D···A D−H···A LSHBE symmetry

Intramolecular O−H···F2Fpba O1−H1···F1 2.331 2.855(1) 112.48 0.0923dFpba_A O1−H1···F1 2.301 2.846(1) 114.01 0.1123dFpba_B O1a−H1a···F1a 2.462 2.884(1) 105.46 0.0424dFpba O1−H1···F1 2.089 2.807(2) 128.38 0.3725dFpba_1 O1−H1···F1 2.233 2.822(1) 117.21 0.1625dFpba_2 O1−H1···F1 2.331 2.875(1) 114.05 0.0926dFpba O1−H1···F1 2.257 2.781(1) 112.12 0.13234tFpba O1−H1···F1 2.444 2.930(1) 110.03 0.05246tFpba O1−H1···F1 2.195 2.759(1) 115.04 0.19penFpba O1−H1···F1 2.525 2.889(2) 101.67 0.03

O−H···O in Dimer2Fpba O2−H2···O1 1.791 2.766(2) 170.76 3.03 −x, −y, −z23dFpba_A O2−H2···O1a 1.750 2.729(1) 174.22 3.78 1 − x, 2 − y, −z23dFpba_B O2a−H2a···O1 1.788 2.759(1) 168.96 3.08 1 − x, 2 − y, −z24dFpba O2−H2···O1 1.800 2.792(2) 176.42 2.57 2 − x, −y, 2 − z25dFpba_1 O2−H2···O1 1.817 2.799(2) 178.00 2.66 2 − x, 2 − y, −z25dFpba_2 O2−H2···O1 1.773 2.755(2) 176.95 3.34 2 − x, 2 − y, −z26dFpba O2−H2···O1 1.805 2.786(2) 174.84 2.81 2 − x, −1 − y,1 − z234tFpba O2−H2···O1 1.770 2.749(2) 173.85 3.39 −1 − x, 1 − y, −z246tFpba O2−H2···O1 1.810 2.793(1) 178.22 2.75 1 − x, 3 − y, −zpenFpba O2−H2···O1 1.751 2.733(2) 176.69 3.74 −x, −1 − y, −zpba_A O2−H2···O1a 1.743 2.734(2) 175.21 3.70 −1 + x, y, zpba_B O2a−H2a···O1 1.731 2.721(2) 174.95 3.95 1 + x, y, z

Interdimeric O−H···O2Fpba O1−H1···O2 1.967 2.843(1) 147.03 1.16 1 + x, y, z23dFpba_A O1−H1···O2 1.903 2.778(1) 146.83 1.64 x, −1 + y, z23dFpba_B O1a−H1a···O2a 1.848 2.725(1) 146.83 2.18 x, −1 + y, z25dFpba_1 O1−H1···O2 2.023 2.861(1) 141.87 0.86 1 + x, y, z25dFpba_2 O1−H1···O2 1.977 2.851(1) 146.90 1.11 x, −1 + y, z26dFpba O1−H1···O2 1.925 2.819(1) 149.89 1.46 −1 + x, y, z234tFpba O1−H1···O2 1.897 2.777(1) 147.59 1.70 x, −1 + y, z246tFpba O1−H1···O2 1.970 2.843(1) 146.58 1.14 −1 + x, y, zpenFpba O1−H1···O2 1.831 2.765(2) 157.54 2.43 x, −1/2 − y, −1/2 + zpba_A O1−H1···O2 1.752 2.692(2) 156.43 3.48 x, 1 − y, −1/2 + zpba_B O1a−H1a···O2a 1.743 2.709(2) 163.09 3.67 2 − x, y, 1/2 + z

aNormalized O−H distance of 0.983 Å.

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(Table 2). The lowest value is associated with 24Fpba, while inpenFpba, the longest distance and the largest twist areobserved. The other mono-, di-, and tri-F-substitutedderivatives exhibit twists in the narrow range of 20−30° with

severely differentiated H···F distances. As the twist influencesthe intramolecular hydrogen bond angle in such an S(6) motif,instead of H···F distance consideration we have calculated theO−H···F interaction energy based on the one-dimensional H-bond model of Lippincott and Schroeder43,44 (Table 3). Thecalculated energy values point to very weak interactions of <0.5kcal/mol. They are comparable to the data obtained from gasphase calculations at the MP2 level of theory for 2Fpba and26Fpba monomers in which the energy of the O−H···Finteractions was found to be ∼0.7 kcal/mol.20 Moreover, thesecalculations revealed that the planar syn−anti conformation isthe most stable one in the gas phase even though two fluorineatoms are in ortho positions. In conclusion, both conforma-tional degrees of freedom (conformation and the twist) seemnot to be influenced by these admittedly weak intramolecularO−H···F hydrogen bonds. This observation can also besupported by the crystal data concerning a meta fluoro-substituted derivative56 in which the syn−anti conformation isrealized and the twist angle equals 25.9(2)°. Therefore, indiscussed series, consecutive levels of molecular aggregationshould be further analyzed.

Basic Dimeric Synthon. The first level of molecularassembly in the analyzed series of fluoro-substituted pba is azero-dimensional object, a dimer. As mentioned in theIntroduction, the O−H···O hydrogen-bonded dimer with theR2

2(8) graph set is observed for the most pba compounds inthe solid state. Our results are consistent with this trend, alsoincluding compound 23Fpba in which two independentmolecules (A and B) were found. They form two discretemotives, D, associated with different H-bonded bridges, whilethe ring synthon appears at the second level of the graph.13

Like those of intramolecular H-bonds, the energy of the O−H···O bridges in dimers was estimated using the LSHBmethod.43,44 The obtained values vary from 2 to 4 kcal/mol(Table 3). It should be pointed out that ab initio calculationsfor the gas phase for pba dimers at the B3LYP/6−311++(d,p)level of theory revealed a similar value of 3.5 kcal/mol.19

However, the use of lower basis sets or a different method

Figure 2. Molecular Hirshfeld surfaces for dimers mapped with dnorm.A red (fewer contacts than vdW separations)−white (similar numberof contacts and vdW separations)−blue (more contacts than vdWseparations) coloring scheme is used. Red solid arrows indicate O−H···O hydrogen bonds; the black dotted oval shows regions ofstacking interactions, while green dashed lines point to weakintermolecular O−H···F hydrogen bonds.

Figure 3. Versatile association of dimers (solid red rods) through lateral O−H···O hydrogen bonds (dashed blue lines): (a) 1D ladder, (b) 1D tube,and (c) 2D layers.

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(MP2) leads to 2 times24 or 3 times15,20 higher values. Theenergy values calculated with the LSHB method for O−H···Obonds in the noncentrosymmetric dimer in crystals of pbaamounted to 3.6 and 3.9 kcal/mol. They are close to thoseobserved for the strongest dimers in the studied series (Table3). Although in fluorinated derivatives the O−H···O bondenergy does not change much, it is substantially higher than theenergy of intramolecular interactions. However, the presence ofthese weak O−H···F hydrogen bonds is in line with theconsiderations about the hydrogen bond donor−acceptorsaturation rule.57 Outwardly, in such a dimer, both stronghydrogen bond donors are satisfied. However, the ability of theoxygen atom to bind hydrogen atoms is much higher than foran “organic” fluorine atom.58 Therefore, there is still apossibility of the anti OH group acting as a donor and forminglateral interactions of the hydrogen bond type. In addition, theengagement of the syn group in strong H-bonds in the dimermay cause a weakening of the O2−H2 bond. Thus,enhancement of the proton acceptor properties of the O2atom may be assumed. These relations become clear when thenext level of supramolecular organization and the lateral“interdimeric” interactions are analyzed.Large Synthons. An elucidation of interdimeric interaction

was performed with the aid of Hirshfeld surface analysis. Toovercome the influence of evident O−H···O interactionsassociated with dimer formation, the surfaces were calculatedfor the dimers not single molecules (Figure 2). The same scaleof coloring was applied to reliably compare studied compounds.In all cases but 24Fpba, large red spots appear near both

hydroxyl groups (solid arrows in Figure 2). They indicate theirengagement in the formation of interdimeric interactions ofO−H···O hydrogen bond type. The energy of these contactswas calculated and is included in Table 3. The values rangebetween 1 and 3 kcal/mol, and in all cases, they are lower thanthe energy of interactions leading to the dimer. In the case ofpba and penFpba, the energy of both intra- and interdimercontacts is the highest (Table 3). This is consistent with ourrationale concerning the strengthened acceptor properties ofthe syn hydroxyl group while it is engaged in a strong dimericinteraction. In turn, for 24Fpba the H-bond in the dimer is theweakest and no O−H···O interdimeric contacts were detected.Nevertheless, the dimeric synthon can be treated here as a basicstructural unit, and consequently, the lateral interactionsbecome responsible for further supramolecular organization,i.e., formation of large synthons.Figure 3 presents the dimers (solid rods) joined by O−H···O

hydrogen bonds (dashed lines). Assuming that every dimer canact as a double donor (two anti OH groups) and a doubleacceptor (two syn OH groups), we determined that there arefour junctions coming out of one dimer. Therefore, the simplestorganization of such units is a one-dimensional (1D) ladder inwhich the dimer is connected with only two others (related bytranslation) (Figure 3a). The R4

4(8) motif is formed separatingdimeric R2

2(8) rings with the distance between the adjoiningunits being approximately 5 Å. Therefore, the twist on the B−Cbond is required to allow such a supramolecular organizationand to avoid repulsion between phenyl rings. Notably, the 1Dladder is observed in all the cases in which the twist is around20−30°, namely, 2Fpba, 23Fpba, 25Fpba_1, 25Fpba_2,26Fpba, 234Fpba, 246Fpba, and the meta fluoro-substitutedderivative.56 The next two arrangements of the dimeric unitsjoined by O−H···O H-bonds can be derived from the ladder bychanging the R4

4(8) motif into C22(4) chain motif (an

equivalency between the carboxylic acid dimers and catemerscan be noticed). The relation to the simplest arrangement isthat every other dimer in the ladder becomes nearlyperpendicular thereto. Such “damage ladders” with the“perpendicular” dimers can join in two ways to fulfill thefour-node connection: (a) forming a tubular structurecomposed of two “ladders” related by a 2-fold axis (Figure3b) and (b) forming a zigzag layer by joining “damage ladders”related by translation (Figure 3c). In such a layer, the distancebetween crests is smaller than between spans in the simpleladder; therefore, the larger twist is required. Such anarrangement is indeed observed in the case of penFpba. Inthe tube, which is a case of pba, only the small twist is necessaryto accommodate the phenyl rings and to prevent repulsionbetween hydrogen atoms. Thus, the observed differences in thetwist angle observed for two crystallographically independentmolecules in pba crystals24 may be a result of weakerinteractions between the basic O−H···O bond-mediated tubes.In the case of 24Fpba, a close inspection of the Hirshfeld

surface (Figure 2) and fingerprint plots point to a predominantrole of stacking interactions as well as weak O−H···F, C−H···O, and C−H···F hydrogen bonds (Figure 4a). When recent

studies by Desiraju4 are taken into account, the most probablelarge synthon here is a column with stacking dimers separatedby ∼3.5 Å (Figure 4b). The topological similarity to the O−H···O bonded ladder also supports this assumption (seeFigures 3a and 4c). Furthermore, the almost zero twist in the24Fbpa molecule, followed by the flat dimer, seems to favor thestacking interactions, as well.

Crystal Packing. According to Kitaigorodskii’s closepacking principles,59 the 1D objects like chains, rods, columns,or ribbons should be hexagonally packed if no directionalinteractions are present between them. The isotropic dispersionforces should also lead to close packing of 2D layers related bytranslation. Therefore, if the large synthons described above are

Figure 4. (a) Fingerprint plot for the 24Fpba dimer. (b) Largesynthon in 24Fpba composed of stacking dimers. (c) Topology of thelarge synthon with the dimer represented as a solid rod.

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essential, either the close packing of 1D or 2D objects orstructures directed by very weak interactions should beobserved. In the latter, these interactions can be interchanged,for example, during the crystallization process; hence, thepossibility of polymorphism may be observed.In the studied series, the most often observed large synthon

is the ladder composed of dimers related by translation andjoined by medium-strength interdimeric O−H···O hydrogenbonds (Table 3). The symmetry of such an individual is givenby a P1 rod group.60 Thus, except for 234Fpba, it does notpossess all the symmetry elements present in the centrosym-metric space group of the monoclinic system (Table 1). Thecross section of the ladders may be approximated by theellipsoid as schematically shown in Figure 3a. As depicted inFigure 5, two types of arrangements of these 1D large synthonscan be distinguished: a herringbone form (a) and a lamellarform (b). They resemble calamitic (rodlike) liquid-crystallinematerials. It was found that in the smectic C phases the 1Dentities are tilted contrary to hexagonally closely packed smecticA phases. Moreover, there are two types of smectic C phases: anormal phase and an alternating phase.61 They correspond tothose observed in our series of lamellar and herringbonestructures, respectively. In both types, the ladders are tilted

roughly in the same direction in and between “the layers”(Figure 5). The major difference between them resides in therelationship between the tilt directions in successive “layers”. Inthe herringbone type, every other “layer” is rotated by 180°(Figure 5a). The equivalency of these two types of packing isemphasized by an examination of the 3D structure of 25Fpbapolymorphs. In both cases, the molecules of 25Fpba do notdiffer significantly (Table 2) and the energy of the O−H···Ohydrogen bonds is similar; hence, the large synthon is the same.The only notable difference is the packing of laddersrepresenting both possibilities described above (Figure 5).Additionally, the substantial role of such 1D large synthon isrevealed in crystals of monofluoro-substituted (2Fpba),difluoro-substituted (26Fpba), and trifluoro-substituted(246Fpba) derivatives (Figure 5a). All of them crystallize ina herringbone manner forming an isomorphic series despite thedifferent numbers of fluorine atoms. The only variations in thisseries are weak C−H···F hydrogen bonds that play a secondaryrole.In the case of the tubular arrangement (pba) as well as

stacking columns (24Fpba), the hexagonal packing is notobserved either (panels a and b of Figure 6, respectively). Thelarge synthons form a square or a brick arrangement. Thus, the

Figure 5. Packing diagrams of large 1D ladder synthons in fluoro-substituted phenylboronic acids: (a) herringbone and (b) lamellar. Isomorphic andpolymorphic series are indicated. Simplified representation of 1D H-bonded ladders in 25Fpba polymorphs showing the similarity to calamitic liquidcrystals.61

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important directional interactions between 1D entities may beexpected. Moreover, the symmetry of the rod group is only pcc2and P1 in the case of pba and 24Fpba, respectively, indicatingthe lack of some symmetry elements compared to thecorresponding space symmetry groups. The resolved HSfingerprint plots revealed that in pba these are C−H···π whilein 24Fpba these are O−H···F hydrogen bonds (Figure 6d).In the studied series, the 2D large synthon composed of

strong intra- and interdimeric interactions is observed only inthe structure of penFpba. It is noteworthy that the crystalswere not grown from a water solution like the remaining onesbut by slow (14 days) diffusion of hexane into a THF solutionof penFpba.53 The symmetry of this 2D supramolecular entityis given by the P21/b layer group,60 thus comprising allsymmetry elements of the space group. The zigzag layer withpentafluorophenyl rings sticking out on its both sides isperpendicular to the longest unit cell a axis that issimultaneously a measure of its thickness (Figure 6c). Theonly contacts that might occur between these 2D individualsare F···F contacts. Close inspection of a decomposed HSfingerprint plot (Figure 6d) revealed a sharp spike with ashortest distance of 2.758(2) Å, which is 0.18 Å shorter thanthe sum of van der Waals radii of fluorine atoms.51 Although

the pattern formed by the two shortest F···F contacts resemblesa zigzag chain characteristic of halogen bonding of heavieranalogues, the fluorine role in such bonds is still underdiscussion.58,62−66 Moreover, the hydrogen-bonded layers inpenFpba are related by translation; thus additional, directionalinteractions are not needed to form a 3D structure.

■ CONCLUSIONS

Subtle interplay between the structure of the basic dimericsynthon and higher-order supramolecular organization in aseries of fluoro-substituted phenylboronic acid crystals wasfound. Estimations of hydrogen bond energy by the LSHBmethod revealed that the O−H···O bonds in dimers can bedecisive in controlling the syn−anti conformation of theboronic moiety while intramolecular O−H···F hydrogenbonds are insignificant. We have shown that the intermolecularinteractions constituting so-called large synthons depend on thestrength of the interactions in the basic dimeric motif.Relatively strong dimers allow the formation of stronginterdimeric hydrogen bonds; otherwise, the stacking inter-actions become dominant in large synthons. Within the samekind of interdimeric interactions (in this case O−H···Ohydrogen bonds), various large synthons can be formed. This

Figure 6. Packing of large synthons in (a) pba (1D tubes), (b) 24Fpba (1D columns), and (c) penFpba (2D layers). The corresponding resolvedHS fingerprint plots are shown in panel d.

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differentiation entails the twist of the boronic group necessaryfor reducing the repulsion between phenyl rings. The largesynthons may be treated here as the building blocks forconstituting the 3D structures either by isotropic dispersionforces (close packing) or by the aid of weak directionalinteractions such as C−H···π, O−H···F, or C−H···F hydrogenbonds. This balance is very subtle; hence, isomorphism andpolymorphism were detected in the case of 1D large synthons.In the case of closely packed 1D ladders, an analogy tostructures of smectic C phases of calamitic liquid crystals wasnoticed.We believe that further crystallization experiments with

controlled kinetic or/and thermodynamic conditions mightlead to the formation of different polymorphic forms34 of bothunsubstituted pba and its selected analogues. Additionally, thescrutiny of consecutive levels of molecular organization in thiswork may be helpful in theoretical crystal structure predictionsas well as investigations of structural landscapes.

■ ASSOCIATED CONTENT*S Supporting InformationX-ray crystallographic information file (CIF) containing allpresented data. This material is available free of charge via theInternet at http://pubs.acs.org. Crystallographic informationfiles are also available from the Cambridge CrystallographicData Center (CCDC) upon request (http://www.ccdc.cam.ac.uk, CCDC deposition numbers 1015879−1015886).

■ AUTHOR INFORMATIONCorresponding Author*Faculty of Chemistry, Warsaw University of Technology,Noakowskiego 3, 00-664 Warsaw, Poland. E-mail: izabela@ch.pw.edu.pl. Fax: 48 22 628 2741. Telephone: 48 22 234 7272.

NotesThe authors declare no competing financial interest.

■ ACKNOWLEDGMENTSThis work was financed by the National Science Centre ofPoland (Project N N204 135639). K.C. and D.S. acknowledgethe financial support by the Faculty of Chemistry, WarsawUniversity of Technology. We thank Prof. Janusz Zachara andDr. Maciej Dranka for helpful discussions.

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