Structural and Stability Studies of a Series of para-Phenylenediboronic

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Structural and stability studies of a series of para-phenylenediboronic and para-hydroxyphenylboronic acid cocrystals with selected aromatic N-oxides Sylwia E. Kutyla, Dorota K. Stepien, Katarzyna N. Jarzembska, Rados#aw Kami#ski, Lukasz Dobrzycki, Arkadiusz Ciesielski, Roland Boese, Jacek Mlochowski, and Michal K. Cyranski Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.6b01250 • Publication Date (Web): 13 Oct 2016 Downloaded from http://pubs.acs.org on October 14, 2016

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Crystal Growth & Design

Structural and stability studies of a series of para-phenylenediboronic and para-hydroxyphenylboronic acid cocrystals with selected aromatic N-oxides Sylwia E. Kutyła,a Dorota K. Stępień,a,* Katarzyna N. Jarzembska,b,* Radosław Kamiński,b Łukasz Dobrzycki,a Arkadiusz Ciesielski,a Roland Boese,a Jacek Młochowski,c Michał K. Cyrańskia,*

a

Advanced Crystal Engineering Laboratory, Department of Chemistry, University of Warsaw, Żwirki i Wigury 101, 02-089 Warsaw, Poland

b

Department of Chemistry, University of Warsaw, Żwirki i Wigury 101, 02-089, Warsaw, Poland

c

Department of Chemistry, Wrocław University of Technology, Wybrzeże Wyspiańskiego

27, 50-370 Wrocław, Poland

* Corresponding authors: Dorota Stępień ([email protected]), Katarzyna N. Jarzembska ([email protected]) Michał K. Cyrański ([email protected])

Dedicated to Professor Tadeusz Marek Krygowski on the occasion of his 80 th birthday.

Abstract:

Nine

new

cocrystals

of

para-phenylenediboronic

or

para-

hydroxyphenylboronic acids with a series of aromatic N-oxides are reported. All of the complexes form centrosymmetric crystal structures. They are stabilised by an extended net of hydrogen bonds further supported by effective π-stacking interactions. In the studied structures four main synthons were distinguished. Only in the 3,10phenanthroline-3-N-oxide and 3,10-N,N-dioxide cocrystals from the series, an acid-acid dimeric motif characteristic for arylboronic acid crystals was observed. The majority of the obtained cocrystals exhibit layered architectures, where the N-oxide molecules are separated by boronic acid slabs. Furthermore, most of the cocrystals form hydrates, where water molecules play role of a ‘molecular glue’. Water contribution to the lattice stability is significant and the energy gain per water molecule ranges from −66.8 to

ACS Paragon Plus Environment


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117.6 kJ·mol−1. The cocrystal cohesive energies seem to be more favourable when compared to the corresponding values for crystals of their components. However, the presence of various ASU contents and numerous hydrated crystal structures indicate that the crystallization process and the final products are highly dependent on kinetic and entropy factors. Finally, the calculated energetic features are confronted with the experimental TGA-DSC results obtained for selected cocrystals. Synopsis:

Nine

new

cocrystals

of


and

para-

hydroxyphenylboronic acids with a series of aromatic N-oxides are reported and comprehensively characterized both structurally and computationally. Energetic features of the studied crystal structures are confronted with the experimental TGA-DSC results for selected cases.

Keywords: cocrystals, arylboronic acids, aromatic N-oxides, periodic computations

TOC Graphic


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1. Introduction In order to design and produce new materials with desirable physicochemical properties, it is indispensable to understand the nature of intermolecular interactions and then the interrelations between structure, energy and both micro- and macroscopic features.1 Crystal engineering is among scientific fields which contribute to our knowledge about the crystalline state, crystal structure prediction and the structureproperty relationships.2 Cocrystallization is a common method used in crystal engineering to tune the physicochemical properties of a given substance.3 Such approach is most often applied to improve the activity of pharmacologically important substances.4,

5

So as to succeed in cocrystallization, one needs to combine

complementary molecular units, which may form effective interactions in the solid state, such as, hydrogen bonds.6 Certainly organoboron compounds constitute here very interesting building blocks, being simultaneously hydrogen bond acceptors and donors. They have already found vast applications in synthetic organic chemistry (Suzuki coupling reaction), supramolecular chemistry, biology, medicine (enzyme inhibitors, saccharide, sensing agents, boron neutron capture therapy agents).7 Furthermore, a number of boronic acids exhibit extremely low toxicity when compared to many other organic compounds. Thus, they are eagerly used as components of pharmaceuticals. As we have already some experience with mono-8-12 and multifunctional13-15 arylboronic acids, this group of compounds was a natural choice. In turn, aromatic N-oxides and N,N-dioxides were selected as cocrystal co-formers. This class of compounds is known for its biological activity,16-21 crystal engineering applications,22-26 complexation properties,27-32 and is used in organic synthesis as protective groups, auxiliary agents, oxidants, or catalysts.33, 34 Importantly, an aromatic N-oxide being a nucleophile can interact with a boronic acid at the electron deficient boron centre, whereas employing its hydrogen bond acceptor and/or donor centres, it can cocrystallize with various molecules exhibiting similar properties, what makes it a promising cocrystal component. In general, boronic groups, have propensity to form hydrogen-bonded dimeric motifs characteristic for carboxylic acids. The −BOH fragments may adopt several conformations, i.e., syn-anti, syn-syn, anti-anti, what may lead to different types of hydrogen bond network.14,

35, 36

For the purpose of our studies two arylboronic acids



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have

been

chosen:


Page 4 of 31

acid

(pdba)

and

para-

hydroxyphenylboronic acid (phba). There is no literature-reported structure of phba, whereas in the case of pdba up to now its two solid-state forms are known.14, 37, 38 It crystallizes either as an anhydrous crystal structure, or with four water molecules per acid moiety in the asymmetric part of the unit cell. As expected, in the anhydrous form the characteristic hydrogen-bonded tape motifs are created by the mentioned boronic acid dimers (Figure 1a). Such pattern is common for all known anhydrous structures of boronic acids.39-42 The same happens in the pdba hydrate. However, in the latter case the acid molecules create also lateral hydrogen bonds with water molecules which fasten the adjacent chain motifs together. Additionally, water species interact one with another via hydrogen bonding yielding 6-membered ring motifs linked further into the water tapes (Figure 1b).

(a)

(b)

Figure 1. (a) Motif in the anhydrous pdba crystal form. (b) H-bond motif in the pdba crystal hydrate.

Similarly, all of the literature-reported aromatic N-oxides easily bind water, and thus crystallize as hydrates.

16, 43-45

They form ladder-like 1D motifs, where water

species fasten together N-oxide molecules via hydrogen bonds directed to the nitroso groups (Figure 2).


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(a)

(b)

Figure 2. Examples of structural motifs present in selected crystal structures of Noxides: (a) 4,10-phenanthroline-4-N-oxide (NO6)43 and (b) 3,10-phenanthroline-3,10N,N-dioxide (NO3’).43

Cocrystals of aromatic N-donor compounds, such as, phenantroline, phenazine, bipyridine, etc., and boronic acids, especially pdba, are widely represented in the literature.46-48 In many cases similar cocrystals of phba are also successfully synthesized and are often used for comparison purposes.46,

49

Nevertheless, a few

interesting examples of pdba cocrystals with aromatic N-oxides can also be found. Among them, Sarma & Baruah50 published a series of cocrystals of pdba and pyridine-, quinoline- and isoquinoline-N-oxides, and 4,4-bipyridine-N,N-dioxide, which are close to the scope of our current study. Interestingly, none of them contain water molecules. Moreover, similar cocrystals with phba are not available. Hence, the aim of this paper was to investigate the cocrystal formation between the two above-mentioned classes of compounds, i.e. phenyl/phenyleneboronic acids and aromatic N-oxides, and get the insight into the structural features of the obtained cocrystals. The very important aspect of this contribution was also to analyse the role of water in the crystal formation and lattice stabilisation. Therefore, nine new cocrystals with pdba and phba and seven various N-oxides (Scheme 1) were synthesized. These are cocrystals of pdba and acridine-N-oxide (pdba+NO1), phenantridine-N-oxide (pdba+NO2), 3,10-phenanthroline-3-N-oxide (pdba+NO3), 1,10-phenantroline-Noxide

(pdba+NO4),

3,10-phenanthroline-N,N-dioxide

phenanthroline-N,N–dioxide

(pdba+NO5’),

and

(pdba+NO3’),

4,7-

4,10-phenanthroline-N,N-dioxide

(pdba+NO6’), and two cocrystals of phba with NO1 and NO3 (phba+NO1 and phba+NO3, respectively). The X-ray diffraction studies were supplemented by the



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comprehensive computational characterization of crystal cohesive energies, indicating to some extent the relative stabilities of the studied systems, and of intermolecular interactions describing molecular motifs. The computational findings were then confronted with the results of TGA-DSC analyses when applicable.

NO1

NO2

NO3

NO3’

NO4

NO5’

NO6’

pdba

phba

Scheme 1. Schematic representation of the used cocrystal components (prime means doubly oxidised aromatic species; pdba = para-phenylenediboronic, phba = parahydroxyphenylbornic acid).

2. Experimental section 2.1. Materials and crystallization. para-phenylenediboronic (pdba) and parahydroxyphenylboronic (phba) acids were purchased from Sigma-Aldrich Co., whereas the aromatic N-oxides were synthesized according to literature procedures for the purpose of this study.51,

52

Equimolar quantities of a given N-oxide and boronic acid

were dissolved in various solvents, or solvent mixtures, such as, ethanol/water, methanol/water, acetone/water, or 1,4-dioxane, and the respective solutions were


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subsequently mixed together. Crystals were grown by slow solvent evaporation method. More detailed information about the cocrystal syntheses is available from the Supporting Information. 2.2. X-ray structure determination. All crystal structure determinations were carried out through the X-ray diffraction method. In all the cases measurements were conducted at 100 K, and the subsequent data treatment and reduction were done according procedures described in references53, 54 and.55-58 Structures were solved by direct methods, as implemented in the SHELXS package.59 Further structure refinements were performed using the SHELXL59 program within the independent atom model (IAM). Scattering factors, in their analytical form, were taken from the International Tables for Crystallography.60 Crystal data and structure refinement parameters for the obtained crystals are collected in Table 1. All details about the X-ray data collection and structure refinement together with thermal ellipsoid plots and packing diagrams prepared in Diamond 3.261 and Mercury 3.7 software62 are available from the Supporting Information. All crystal structures have been deposited in the Cambridge Crystallographic Database63 (CSD) (for deposition codes see Table 1). 2.3. Computational details. Crystal cohesive energies of the obtained cocrystals and interaction energy stabilizing selected intermolecular motifs were calculated using the CRYSTAL program (CRYSTAL09 version).64,

65

Prior to energy computations

structures were optimized at the DFT level of theory using B3LYP functional66, 67 and 631G** basis set.68 Cell parameters were kept fixed during the optimization procedure, whereas atom positions were varied. Such obtained geometries were used for subsequent cohesive energy computations.69, 70 The DFT(B3LYP)/6-31G** results were corrected for dispersion71-73 and basis set superposition error (BSSE).74 Ghost atoms used for the BSSE estimation were selected up to 5 Å distance from the considered molecule in a crystal lattice. Finally, intermolecular interaction energies were calculated using the CRYSTAL-optimised geometries. In this case the DFT(B3LYP)/pVTZ75 method was used with Grimme dispersion correction and correction for BSSE. All input files were prepared with the CLUSTERGEN program.76 2.4. TGA-DSC experiments. Thermal stabilities of the studied cocrystals were examined by the TGA/DSC method using a Netzsch STA 449 F1 Jupiter differential scanning calorimeter. Powdered samples of about 1−4 mg were heated in a corundum crucible between 30−210°C in a helium gas flow with a heating rate of 10°C∙min−1. The



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results were supplemented with the melting point temperature measurements of the studied crystals. 3. Results and discussion 3.1. General structural remarks. All of the studied compounds cocrystallize forming centrosymmetric crystal structures, belonging either to triclinic 1 (6 cocrystals: pdba+NO2, pdba+NO3, pdba+NO4, pdba+NO6’, phba+NO1, phba+NO3), monoclinic 2 / or 2 / (2 cocrystals: pdba+NO1, pdba+NO3’), and orthorhombic

(pdba+NO5’) space groups. Basic crystal structure and refinement parameters are summarized in Table 1. The structures are characterized by an extended net of hydrogen bonds further stabilized by π⋯π contacts. Cocrystals of pdba and phba with a series of aromatic N-oxides have a tendency to crystallize as hydrates. Among several systems obtained in this study, only two cocrystals, namely pdba+NO3’ and pdba+NO6’, do not contain water. The remaining synthesized cocrystals contain at least one water molecule per asymmetric unit (ASU). The highest number of water molecules per ASU is incorporated in the cocrystals formed with the NO3 species, i.e., four water molecules in the case of pdba+NO3. This structure is in fact contaminated by a small amount of 3,10-phenanthroline-N,N-dioxide, which leads to substitutional disorder, where both N-oxides share the phenantroline skeleton. The composition of this particular cocrystal can be described as pdba+(83%-NO3/17%-NO3’). Crystallization of such a structure resulted probably from some contamination of the used N-oxide. Nevertheless, similar effect was not observed in the case of the phba+NO3 cocrystal – another example of a system containing quite high number of water molecules (two and a half per ASU) among the analysed group. Interestingly this structure is also disordered with alternative positions of one of the water molecules imposing positional disorder of all water and hydroxyl H atoms. Importantly, in all hydrated systems water molecules play role of ‘molecular glue’77,

78

mediating the interactions between the acid and N-

oxide moieties.

Table 1. Structural parameters characterising the studied cocrystals. Crystal structure

pdba+NO1

pdba+NO2

ASU content a Empirical formula Mx / g mol-1 T/K

A+2N+W C16H15BNO4 296.10 100(2)

Space group

P21/c

½A+N+W C16H15BNO4 296.10 100(2) 1

pdba+(83% NO3/ 17% NO3’) ½A+N+4W C21H28B3N2O11.17 519.57 100(2) 1


pdba+NO3’

pdba+NO4

A+N C18H17B2N2O6 377.95 100(2)

½A+N+W C15H14BN2O4 297.09 100(2) 1

P21/n

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a/Å b/Å c/Å α/° β/° γ/° V / Å3, Z dx / g·cm−3 µ / mm−1 Crystal size / mm θmin-θmax, completeness Reflections collected/ independent Data / restraints / parameters GooF R indices [I>2σ(I)] R indices (all data) ρmax, ρmin / eÅ-3 CCDC code a

10.408(2) 18.367(4) 7.4198(14) 90.0 93.719(5) 90.0 1415.4(5), 4 1.390 0.099 0.417×0.066×0.030 1.96-27.50°, 100% 18142 / 3246 Rint=0.0365 3246 / 0 / 259 1.034 R1=0.0374 wR2=0.0927 R1=0.0544 wR2=0.1042 0.414, -0.215 CCDC 1453916

7.548(4) 9.332(5) 10.515(5) 81.949(11) 82.301(11) 77.098(11) 710.7(6), 1.384 0.098 0.251×0.093×0.056 1.93-27.50°, 100% 18355 / 3262 Rint=0.1188 3262/ 0 / 254 1.030 R1=0.0630 wR2=0.1442 R1=0.1436 wR2=0.1971 0.313, -0.314 CCDC 1453917

7.1168(5) 10.8265(7) 16.6766(11) 100.782(5) 92.619(5) 102.490(5) 1227.39(14), 2 1.406 0.111 0.380×0.280×0.120 3.09-26.50°, 99.8% 25041 / 5065 Rint=0.0637 5065 / 12 / 438 0.697 R1=0.0354 wR2=0.0562 R1=0.0929 wR2=0.0616 0.273, -0.226 CCDC 1453918

6.8214(2) 35.0555(12) 7.2064(3) 90.0 104.5493(14) 90.0 1667.99(10), 4 1.505 0.931 0.015×0.205×0.393 2.52-67.49°, 97.5% 13678 / 2935 Rint=0.0336 2935 / 0 / 270 1.032 R1=0.0377 wR2=0.0918 R1=0.0507 wR2=0.0997 0.281, -1.189 CCDC 1453914

ASU – asymmetric unit; A = boronic acid, N = N-oxide, W = water.

Crystal structure

pdba+NO5’

pdba+NO6’

phba+NO1

phba+NO3

ASU content a Empirical formula Mx / g mol-1 T/K

½A+½N+W C18H20B2N2O8 413.98 100

Space group

Pnma

A+N C15H12BN2O4 295.08 100 1

1½A+N+4W C32H27BN2O6 546.36 100(2) 1

A+N+2½W C36H40B2N4O13 758.34 100(2) 1

a/Å b/Å c/Å α/° β/° γ/° V / Å3, Z dx / g·cm−3 µ / mm−1 Crystal size θmin-θmax, completeness Reflections collected/ independent Data / restraints / parameters GooF

12.8136(15) 19.463(2) 7.3394(8) 90.0 90.0 90.0 1830.4(4), 4 1.502 0.116 0.070×0.071×0.144 2.97-27.50°, 99.9% 32063 / 2167 Rint=0.0918 2167 / 0 / 152 1.035 R1=0.0437 wR2=0.1035 R1=0.0681 wR2=0.1188 0.422, -0.276 CCDC 1453913

6.7726(8) 7.8417(9) 13.1175(15) 99.639(3) 99.614(3) 104.401(3) 649.16(13), 2 1.510 0.110 0.075×0.140×0.407 2.75-27.52°, 99.7% 13907 / 2952 Rint= 0.0629 2952 / 0 / 208 1.102 R1=0.0626 wR2=0.1417 R1=0.0841 wR2=0.1541 0.420, -0.334 CCDC 1453915

7.6501(7) 9.7400(9) 19.1250(17) 80.812(2) 89.518(2) 69.334(2) 1314.5(2), 2 1.380 0.095 0.327×0.083×0.040 2.16-25.05°, 100% 28059 / 4644 Rint=0.0406 4644 / 0 / 478 1.020 R1=0.0323 wR2=0.0736 R1=0.0526 wR2=0.0856 0.182, -0.185 CCDC 1453921

6.7746(14) 10.377(2) 13.336(2) 73.150(16) 79.733(16) 82.498(16) 879.9(3), 1 1.431 0.108 0.250×0.120×0.090 3.07-26.00°, 99.9% 5863 / 3463 R(int) = 0.0577 3463 / 0 / 260 1.016 R1=0.0711 wR2=0.1173 R1 = 0.1610 wR2 = 0.1469 0.308, -0.307 CCDC 1453920

R indices [I>2σ(I)] R indices (all data) ρmax, ρmin / eÅ-3 CCDC code a

7.8100(10) 8.9651(11) 10.6234(14) 74.662(3) 82.284(3) 82.528(3) 707.35(16), 2 1.395 0.101 0.05×0.146×0.272 2.00-28.00°, 100% 19709 / 3421 Rint=0.0348 3421 / 0 / 215 1.030 R1=0.0421 wR2=0.1146 R1=0.0532 wR2=0.1236 0.425, -0.235 CCDC 1453919

ASU – asymmetric unit; A = boronic acid, N = N-oxide, W = water.

3.2. Hirshfeld surface analysis. A simple Hirshfeld surface approach79-83 and related fingerprint plots79, 80, 84 constitute a good tool to illustrate and, to some extent, quantify main intermolecular contact types encountered in a given crystal lattice. In the



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present case, such analysis shows that in every structure the O⋯H contacts are shortest, and thus visible as spikes in the fingerprint plots (Figure 4 and Supporting Information). The percentage contribution of such contacts to Hirhsfeld surfaces of both acid and Noxide molecules are also significant and range from 13% to 34%. These two observations reflect hydrogen bond interactions formed in the studied crystal networks and their importance in the crystal structure stabilisation. In turn, the C⋯C, C⋯H, N⋯O, and C⋯O contacts, widely represented in the studied crystals, show notable contributions of other weak interactions, such as dispersive forces and π-stacking. πstacking is rather frequent in the examined series due to the presence of fused aromatic rings of the investigated N-oxides, as well as, the aromatic fragments of the complementary acid molecules. The most significant contribution of C⋯C contacts was calculated for pdba+NO1 and pdba+NO4 regarding the Hirshfeld surface generated for the N-oxide species (Figure 3). These contacts reflect antiparallel arrangement of Noxide molecules in the crystal lattice. The neglidgible contribution of the C⋯C contacts is observed only for the phba molecule in phba+NO1, which instead interacts via the C⋯H contacts. In the case of anhydrous cocrystals, we can additionally detect some important lateral N⋯H bonding patterns (Figure 3). As expected for molecular crystals, most common are the H⋯H contacts. In general they either support the mentioned major interactions, or constitute inevitable contacts between the close-packed organic moieties.

(a) pdba+NO1


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(b) pdba+NO3'

Figure 3. Fingerprint plots generated for the acid (left panels) and N-oxide (right panels) molecules of exemplary hydrated and anhydrous cocrystals, i.e. pdba+NO1 (a) and pdba+NO3’ (b), respectively.

(a)

(b)

Figure 4. Percentage contributions of intermolecular interactions/contacts to the Hirshfeld surface area generated for acid (a, left panel) and N-oxide (b, right panel) molecules based on the Hirshfeld fingerprint plots. Structural motifs. Detecting motifs and structural patterns most commonly created by molecules in crystals is a very important part of crystal engineering investigations. This is because such molecular assemblies can be further used to predict unknown crystal structures. Small molecular building blocks or structural units, which can be formed via hydrogen bonds, or other intermolecular interactions, are known as synthons.6 For the purpose of the current discussion we have defined four synthons most often formed in the studied cocrystals (Scheme 2).

(a) R 8


(b) R 12


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(d) R 12

(c) R 22

Scheme 2. Main structural motifs present in the studied cocrystals: (a) motif A, (b) motif B, (c) motif C and (d) motif D.

Among the series, the acid:acid A motif, which is, as mentioned before, very characteristic for arylboronic acid crystal structures, is observed only in the case of NO3/NO3’-oxide-containing

cocrystals,

namely:

pdba+NO3,

pdba+NO3’

and

phba+NO3. The two acid molecules are bound together via two relatively strong directional hydrogen bonds between boronic groups revealing syn-anti conformations. The average intermolecular interaction energy of such a dimer reaches about −44 kJ·mol−1 (Table 3). Nevertheless, such boronic dimers are not further connected together yielding boronic acid tapes, which was the case in the pdba crystals. In pdba+NO3’ we can observe arrangements of three hydrogen-bonded boronic acid species, which then interact with water, or laterally with N-oxides. In the anhydrous pdba+NO3’ crystal structure such pdba dimers are involved in the hydrogen bond interactions with N-oxide species via the remaining boronic groups. Finally, in the case of phba+NO3 free hydroxyl groups of each acid moiety form hydrogen bonds with water molecules, however, it should be note that such a hydrogen bond network is disordered (see Figure 1S in the Supporting Information).


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Table 3. Selected interactions between boronic acid molecules (motif A) in the studied cocrystals.

Interaction

/ Å

⋯ / Å

⋯ / Å

/ kJ·mol−1

pdba+NO3

O60−H60⋯O20#1

0.84(2)

1.88(2)

2.71(2)

−42.4

phba+NO3

O20−H10⋯O10#2

0.86(3)

1.94(4)

2.78(3)

−48.9

pdba+NO3’

O4−H40⋯O3#3

0.90(3)

1.88(3)

2.77(2)

−44.4

Crystal structure

Symmetry transformations: (#1) , !, "; (#2) # , 1 # !, 1 # "; (#3) 1− , −!, −".

In turn, in the pdba+NO1 and phba+NO1 cocrystals the above described dimeric motif is substituted by a similar cyclic synthon, i.e., motif B, in which two molecules of boronic acid are connected together via hydrogen bonding interactions mediated by two water molecules. Typical energy of a hydrogen bond between acid and water molecules in the motif B ranges from −14 to −24.5 kJ·mol−1 (Table 4). It appears that the overall stabilisation energy of this motif (including four hydrogen bonds between pdba/phba and water species) is significantly greater, i.e., by about 30 kJ·mol−1, for phba+NO1 than pdba+NO1. Interactions of two diboronic acid molecules are also bridged by water molecules in the case of pdba+NO2 (Figure 5a). However, here only one OH function from the boronic group is involved in the interactions with water and further with another acid species, the other hydroxyl function forms hydrogen bond with the N-oxide group.

(a)

(b)



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(c)

Page 14 of 31

(d)

Figure 5. Main structural motifs observed in the selected cocrystals: (a) structural Blike motif in the pdba+NO2 crystal structure, (b) a typical interaction between boronic acid and N-oxide molecule illustrated for pdba+NO1, (c) D-like motif in the pdba+NO4 cocrystal, (d) ladder-like motif in the pdba+NO6’ cocrystal.

Table 4. Selected interactions between boronic acid and water molecules (motif B) in the studied cocrystals.

Crystal structure pdba+NO1

pdba+NO2

phba+NO3

Interaction

/ Å

⋯ / Å

⋯ / Å

/ kJ·mol−1

O1W−H1W⋯O10#1

0.89(2)

1.91(2)

2.79(2)

−14.2

O20−H20⋯O1W#1

0.88(2)

1.82(2)

2.69(2)

−18.5

O1W−H1W⋯O10#1

0.81(4)

1.98(4)

2.77(3)

−14.5

O10−H10⋯O1W#2

0.95(4)

1.68(4)

2.62(4)

−18.0

O1W−H3W⋯O4#1

0.90

1.86(2)

2.76(4)

−24.8

Symmetry transformations: (#1) , !, "; (#2) − +1, −!+2, −"; (#3) − +1, −!, −"+2;

As expected, the latter interaction, namely the hydrogen bond between N-oxide and the acid molecule via the NO group and the –OH species from the boronic function, constitutes the most common interaction among all the studied cocrystal structures (Figure 5b). The interaction energy characterising the respective heterodimers ranges from −34 to −62 kJ·mol−1 and reflects also the strength of the supporting contacts, which depend on the mutual orientation of the two molecules (Table 5). The strongest interaction of this kind is observed for cocrystals of pdba+NO4, where the energy


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reaches −62.1 kJ·mol−1. In this case the N1A−O1A⋯H10−O10 hydrogen bond is additionally supported mainly by more distant O20−H20⋯N11A contact. In turn, significant interaction energy value for pdba+NO1 is the result of a superposition of the strength of hydrogen bond and the effective C−H⋯π interactions. In the case of pdba+NO3 and pdba+NO5’ the interaction energy is less advantageous (around −35 kJ·mol−1) and reflects almost exclusively the N−O⋯H−O contact. It is worth mentioning that solely in the phba+NO1 cocrystal the N−O⋯H−O interaction is realised via the para-hydroxyl group of the phba acid molecule instead of the boronic species.

Table 5. Selected strongest interactions between N-oxide and boronic acid molecules in the studied cocrystals.

Interaction

/ Å

⋯ / Å

⋯ / Å

/ kJ·mol−1

pdba+NO1

O10−H10⋯O1A#1

0.90(2)

1.74(2)

2.64(2)

−52.2

pdba+NO2

O20−H20⋯O1A#1

0.81(4)

1.90(4)

2.70(3)

−40.4

pdba+NO3

O50−H5O⋯O1A#1

0.90(2)

1.81(2)

2.70(2)

−36.6

pdba+NO4

O20−H20⋯O1A#1

0.83(2)

1.95(2)

2.77(1)

−62.1

pdba+NO5'

O2−H20⋯O1A#2

0.84(3)

1.92(3)

2.75(2)

−34.4

pdba+NO6'

O10−H10⋯O1A#3

0.84(5)

1.95(3)

2.77(3)

−43.7

O20−H20⋯O1A#1

0.89(4)

1.91(4)

2.75(3)

−34.8

phba+NO1

O20−H20⋯O1A#1

0.88(2)

1.79(2)

2.66(2)

−47.1

phba+NO3

O10−H10⋯O1A#1

0.77(4)

1.96(4)

2.72(3)

−45.2

Crystal structure

Symmetry transformations: (#1) , !, "; (#2) , 1,5 # !, "; (#3) # , 1 # !, 1 # ";

Hydrogen-bonded N-oxide and boronic acid molecules may further interact both directly and bridged via water species forming cyclic motifs C and D, respectively (Scheme 2). Motif C is encountered in the anhydrous pdba+NO6’ cocrystal. Interestingly, in the case of the remaining anhydrous system, i.e. pdba_NO3’, a similar, but more complex, motif is formed. It consists of two A motifs linked together via hydrogen bonds with the N-oxide groups. In turn, the water-glued molecular arrangement, i.e. motif D, is more common and it is present in the pdba+NO1, phba+NO1 and pdba+NO2 cocrystals. In the case of pdba+NO1 water binds stronger with N-oxide (Table 6) than with boronic acid, whereas it is opposite for pdba+NO2. Nevertheless, the energy of these interactions differ by no more than 6 − 8 kJ·mol−1 on



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average. A similar motif can be found also in the pdba+NO4 crystal structure (Figure 5c). This motif is characterized by the strongest interaction between the molecule of water and N-oxide, which exceeds −30 kJ·mol−1. It is worth mentioning here that for acid-to-N-oxide 1:2 ratios (which stands for one boronic group per one N-oxide group), similar molecular motifs are preferred, namely B and D. Therefore, such synthons coexist in pdba+NO1, phba+NO1 and pdba+NO2. On the other hand, the same number of boronic and N-oxide groups for pdba+NO3’, pdba+NO5’ and pdba+NO6’ does not indicate similar synthons formation in the corresponding crystal structures. In this case either motifs A, B or C are created, respectively (see Supporting Information). Consequently, it is difficult to find a general rule governing molecular motifs in the examined series of cocrystals. Such observation results from different water contents and mutual arrangement of the N,O-groups in the N-oxide molecules, which affect considerably the preferred intermolecular interactions and molecular orientations.

Table 6. Selected strongest interactions between N-oxide and water molecules in the studied cocrystals.

Interaction

/ Å

⋯ / Å

⋯ / Å

/ kJ·mol−1

pdba+NO1

O1W−H2W⋯O1A#1

0.89(2)

1.86(2)

2.74(2)

−21.7

pdba+NO2

O1W−H2W⋯O1A#2

0.94(4)

1.72(4)

2.66(3)

−18.0

pdba+NO4

O1W−H1W⋯O1A#3

0.98(2)

2.04(2)

2.83(2)

−31.2

O1W−H2W⋯O1A#1

0.85(2)

1.94(2)

2.79(1)

−34.3

O1W−H12W⋯O1A#1

0.90(2)

1.78(2)

2.67(2)

−23.0

Crystal structure

phba+NO1

Symmetry transformations: (#1) , !, "; (#2) −1 + , !, "; (#3) 1− , −!, 1−";

The above-mentioned molecular synthons are usually connected further via hydrogen bonds leading to 1-3D hydrogen bonded patterns. Many of such motifs are also supported by effective π-stacking interactions, which is well visible from the Hirshfeld surface analysis. A good example of the 1D sub-structure is a ladder pattern propagating along the '010) direction (Figure 5d) in the anhydrous pdba+NO6' crystal structure. One molecule of pdba fastens here together four N,N-dioxide moieties, whereas each N-oxide group is hydrogen-bonded with two different pdba moieties. Additionally, N-oxides are parallel-oriented one to another, thus enabling effective π-


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stacking interactions (−37.0 kJ·mol−1, Table 7) between the two adjacent ladder motifs stabilizing further the crystal network. This polymeric motif resembles those observed for aromatic N-oxide crystals, where the N-oxide species are glued together by water instead of diboronic acid molecules, resulting in the ladder-like patterns (Figure 2). In the case of pdba+NO6’ such parallel oriented molecular ladders yield the 3D structure consisting of N-oxide layers separated by the pdba domains.

Table 7. Most significant energies calculated for the π⋯π interacting N-oxide molecules in the studied crystal structures.

Crystal

structure

/ kJ·mol−1

pdba+NO1

−42.7

pdba+NO2

−47.9

pdba+NO4

−43.7

pdba+NO6’

−37.0

phba+NO1

−44.4

phba+NO3

−52.1

Some kind of the ladder-like motif is also present in the pdba+NO1 and pdba+NO2 cocrystal structures. In both cases, the central part of the pattern is occupied by hydrogen-bonded pdba and water molecules, which fasten together parallel oriented Noxide species forming an extended ribbon. The boronic acid ribbons interact further via hydrogen bonds leading to 2D acid-water layer motifs. In consequence, N-oxide layers are separated by boronic acids and water molecules (Figure 6). Within the N-oxide layers molecules interact through π-stacking. Pdba+NO4 constitutes another structure where one can observe separated layers of N-oxide and acid-water species. In the three above cases the stacking interactions between N-oxide molecules are effective and the respective dimers are characterized by the interaction energies exceeding −40 kJ·mol−1 (Table 7).



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Figure 6. Layered structure of the pdba+NO1 cocrystal (view along * axis).

A bit more complex, but still similar, crystal structure is represented by pdba+NO3. First of all, there is the mentioned substitutional disorder of NO3/NO3’ N-oxide associated with the positional disorder of one of the water molecules. Secondly, this structure contains the highest number of water species in the asymmetric unit. Nevertheless, again the parallel oriented N-oxide moieties form layers separated by pdba species, whereas water moieties fill the empty spaces and saturate hydrogen bond donor and acceptor centres. Interestingly, in the anhydrous cocrystal of pdba and doubly oxidized NO3’ we can observe a different hydrogen-bonded network, when compared both to pdba+NO3 and the other anhydrous crystal structure among the series − pdba+NO6’. Here, herringbone-like patterns of the N-oxide and pdba are further interacting via hydrogen bonds with the adjacent pdba molecules yielding a 3D-hydrogen bonded network. The basic motif where two N-oxides are fastened together by a pdba dimer (motif A, Figure 7a) resembles the molecular arrangements present in the literature-reported anhydrous cocrystal structure of 4,4-bipyridine N,N-dioxide and pdba (Figure 7b).50 In contrast to the former described cocrystals, in the case of pdba+NO3’ the π···π interactions are formed between the acid and N-oxide molecules (Figure 7c). The respective interaction energy amounts to −27.2 kJ·mol−1.


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(a)

(b)

(c)

Figure 7. (a) NO3’ molecules linked together by the A motif. (b) Literature-reported example of 4,4-bipyridine N,N-dioxide molecules connected by pdba molecules. (c) Wavy layer motifs linked via hydrogen bonds formed in the pdba+NO3’ cocrystals (view along + direction).

Pdba+NO5’ constitutes another interesting crystal structure. Similarly to pdba+NO3’ π-stacking interactions are formed here between acid and N-oxide molecules characterized by comparable interaction energy of −27.8 kJ·mol−1.



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Page 20 of 31

Surprisingly, motif A is not created. Instead, there are hydrogen bonds from boronic groups to either N,N-dioxide or water molecules. Water molecules stample acid and N,N-dioxide species. High symmetry of the structure manifests in the formation of regular layered crystal architecture (Figure 8).

(a)

(b)

Figure 8. (a) π-stacking interactions between the pdba and NO5’ molecules being additionally clipped together by water. (b) Hirshfeld surface generated for the NO5’ molecule interacting with pdba.

In the remaining structures, i.e. phba+NO1 and phba+NO3, again the separated Noxide and phba layers are encountered. Phba+NO1 looks more regular, whereas the phba+NO3 architecture seems more complex. In the former case, phba+NO1, motif B expands further into the phba-water tapes propagating along the '100) direction. Noxide molecules are attached to such constructed acid-water motifs via boronic groups and water moieties, and additionally through phba hydroxyl groups sticking outwards. These patterns are further dispersively interacting with the adjacent motifs of this kind. In the latter case, phba+NO3, both N and N−O centres of the N-oxide molecule are involved in hydrogen bonds with water species and with one acid molecule. Water molecules, all with disordered H atoms, link acid and N-oxides together and due to their high number per asymmetric unit hydrogen bonded network expands in 3D. The only ordered H atoms engaged in hydrogen bonds are those from the B(OH)2 group (see Figure 1S in the Supporting Information). Furthermore, parallel oriented N-oxide species interact effectively via π-stacking, with the energy of −52.0 kJ·mol−1. The role of water molecules in crystal structure stabilisation constitutes another interesting aspect of the study. Naturally, water as a solvent is very important for many


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chemical reactions and most life processes. Water molecule exhibits great flexibility and capability of forming hydrogen bonds (energy gain during hydration), which are fundamental factors in determining chemical processes. In the obtained cocrystals water plays a very important role of a molecular glue, biding boronic acid and N-oxide molecules together. Among the studied systems the most interesting water motifs are formed in the cocrystals with the greatest water content (Tables 1 & 7), what enables efficient water⋯water interactions. In the pdba+NO3 cocrystal structure, water molecules form cyclic hexagonal motifs, which are further connected via H-bonds one with another resulting in the infinite water tapes. Water chains are also encountered in phba+NO3. In this case they consist of fragments based on four molecules of water, again connected via hydrogen bonds. A typical water⋯water hydrogen bond energy amounts to about 20−23 kJ·mol−1 (Figure 9).

(a)

(b)

Figure 9. The comparison of water motifs present in the (a) pdba+NO3 and (b) phba+NO3 crystal structures (note the disorder was removed for clarity).



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3.4. Relative crystal stability: computational

analysis and TGA-DSC

investigations. The analysis of relative crystal stabilities is a very complex task. A number of factors and conditions should be here taken into account. In the case of this study our considerations were limited to cohesive energy elucidation and TGA-DSC analyses supplemented by the melting point temperature measurements. It is worth mentioning here that the TGA-DSC data were meaningful only in selected cases due to significant heterogeneity of the samples. Additionally, the examined series of cocrystals cannot be straightforwardly compared due to the different crystal contents. Various percentage of water incorporated in the crystal structure also affects the final results. Theoretical periodic calculations were performed for both the nominal crystal structures and the structures with excluded water molecules (Table 8), so as to estimate the water contribution to crystal stability. To supplement the computational data, also cohesive energies for structures of the related monocomponent crystals were evaluated.

Table 8. Cohesive energy values calculated for studied cocrystals, their selected components and water-free hypothetic structures (water energy contribution: 21 , water energy contribution per 1 water molecule: - = ∆- /- ). ∆- = /01 # /01

Compound

ASU content

21 /01

/01 /

kJ·mol−1

/

kJ·mol−1

∆/

kJ·mol−1

/ kJ·mol−1

pdba1 a

A

−88.8

−88.8

−c

−c

pdba2 b

A+4W

−420.4

−91.0

−329.4

−82.6

NO1

N+2W

−259.3

−80.1

−89.6

−44.8

NO3’

N+W

−214.1

−117.0

−97.1

−97.1

NO6’

N+2W

−284.3

−133.1

−75.6

−37.8

phba+NO1

A+2N+W

−504.3

−437.5

−66.8

−66.8

phba+NO3

A+N+2½W

−455.9

−223.0

−232.9

−93.2

pdba+NO1

½A+N+W

−283.4

−201.8

−81.6

−81.6

pdba+NO4

½A+N+W

−316.5

−198.8

−117.6

−117.6

pdba+NO2

½A+N+W

−290.5

−180.5

−110.1

−110.1

pdba+NO3

1½A+N+4W

−694.5

−276.5

−418.0

−104.5

pdba+NO3’

A+N

−322.5

−322.5

−c

−c

pdba+NO5’

½A+½N+W

−236.9

−124.3

−112.6

−112.6

pdba+NO6’ a

A+N

−235.3

−235.3

−

c

−c

Anhydrous pdba structure.37 b pdba structure with water molecules.38


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Water mass percentage contribution does not exceed 13% and is highest for the pdba+NO3 crystal structure, which contains four water molecules per ASU (Supporting Information). As indicated by the TGA-DSC curves for pdba+NO1, pdba+NO4, pdba+NO5’ and phba+NO1, dehydration may start prior to, or may proceed simultaneously with the sample melting (Figure 10). TGA signal shows mass loss corresponding to water content usually around 110−130°C. In the case of pdba+NO1 the TGA signal is disturbed most probably due to the degree of purity of this sample. Nevertheless, the peaks for the corresponding endothermic processes are sharp and well visible. Water contribution to the crystal cohesive energy for all hydrates is high and ranges from −66.8 kJ·mol−1 to −117.6 kJ·mol−1 per water molecule for pdba+NO1 and pdba+NO4, respectively. If there is one water molecule in ASU it usually forms three hydrogen bonds with the other crystal components. In the case of pdba+NO3, we observe 6 such interactions per 4 water molecules, whereas for phba+NO3 there are 4 H-bonds per 2½ water species.

Figure 10. TGA-DSC results for the cocrystals of phba+NO1 (black), pdba+NO1 (red), pdba+NO4 (blue), pdba+NO5’ (green). The DSC signal is represented with solid lines and TGA with dotted curves.



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The structures of pdba+NO1, pdba+NO2, pdba+NO4 are characterized by identical ASU contents, thus can be relatively easily compared. As mentioned earlier, the strongest interaction with water among the group is observed for pdba+NO4. It contributes significantly to its highest energetic stability in respect to the other two cocrystals, −316.5 kJ·mol−1. This is the effect of the additional nitrogen atom in the aromatic ring supplementing the N-oxide group present for all the three N-oxide moieties. In the case of pdba+NO4 the TGA-DSC curves indicate that both dehydration and sample melting processes happen simultaneously, which is reflected in a wide single endothermic signal. This could be a result of the mentioned strong bonding of water in the crystal structure. In turn, pdba+NO1 is described by very similar cohesive energy to pdba+NO4 for the structure with the excluded water content (around −200 kJ·mol−1). However, the pdba+NO1 crystals exhibit two separated peaks in the DSC curve, for dehydration and melting processes. Thus, it seems that the weaker-bound water content in the latter case may be released easier and less affecting the remaining structure when compared to pdba+NO4. Finally, the pdba+NO5’ cocrystals exhibit very similar TGA-DSC signal to pdba+NO4, where sample melting and dehydration take place at the same time. The cohesive energy values cannot be directly compared here due to the different ASU contents, however, both structures contain one water molecule per ASU which contributes to the overall crystal cohesive energy in a comparably high degree. It should be also noted here that both melting temperature and the respective transition enthalpy cannot be directly related to the cohesive energy values, which correspond to the sublimation enthalpies. The comparison of the cocrystal cohesive energies with the respective values for crystals of their components is no straightforward. It seems that cocrystal cohesive energies are more favourable. However, since the water incorporation in the crystal lattice in most cases is crucial, the crystallization process and the final products are presumably highly dependent on crystallization kinetics and entropy factors.

4. Conclusions In this contribution nine new cocrystals were synthesized and structurally and computationally characterized in the context of the related component crystals. The synthesis of cocrystals of p-phenylenedibrononic acid with aromatic N-oxides containing only one N−O group occurred to be most problematic. All of the cocrystal


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form centrosymmetric crystal structures. The structures are characterized by an extended net of hydrogen bonds further stabilized by π-stacking contacts. Most of these cocrystals form separate layers of boronic acid species alternated with those composed of N-oxides molecules. Additionally, only NO3-oxides allow for formation of the acid:acid motif A, which is characteristic for boronic acid crystals. The vast majority of cocrystals presented in this paper exist as hydrates. Water links together the molecules of acids and N-oxides. Solely pdba+NO3’ and pdba+NO6’ containing N,N-dioxide molecules form anhydrous structures. Water contributes very significantly to the stability of the structures. Its average contribution to the cohesive energy ranges −66.8 kJ·mol−1 to −117.6 kJ·mol−1 per water molecule. For all examined hydrates water molecules are released prior, but close, to the sample melting point temperatures. The cohesive energy values for the studied cocrystals seem to be more favourable than those of the monocomponent crystals. However, due to the lack of data (not all of the Noxide were structurally determined, different ASU contents encountered – cannot be straightforwardly compared) and regarding the water content, one may conclude that entropic and kinetic factors are crucial in the crystallization process and govern the final product.

Acknowledgements The X-ray structures were determined in the Czochralski Laboratory of Advanced Crystal Engineering (Department of Chemistry, University of Warsaw) established thanks to the generous support from the Polish Ministry of Science and Higher Education (614/FNiTP/115/2011), at the Department of Chemistry, University of Duisburg-Essen (Essen, Germany) and in the Crystallochemistry Laboratory at the Chemistry Department of the University of Warsaw. The research was funded by the OPUS grant from the National Science Centre in Poland (2011/03/B/ST4/02591) and the IUVENTUS PLUS IP2010 007370 grant supported by the Ministry for Polish Science. All computations were carried out using the resources provided by the Wroclaw Centre for Networking and Supercomputing (grant No. 285).

Associated content

Supporting Information



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

The Supporting Information is available free of charge on the ACS Publications website at DOI:

Supporting materials contain experimental details regarding cocrystallization procedures, single crystal X-ray diffraction studies, Hirshfeld surface analyses, water contribution information, structural motif interaction energy values, sample melting temperature estimation.

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Structural and stability studies of a series of para-phenylenediboronic and para-hydroxyphenylboronic acid cocrystals with selected aromatic N-oxides Sylwia E. Kutyła,a Dorota K. Stępień,a,* Katarzyna N. Jarzembska,b,* Radosław Kamiński,b Łukasz Dobrzycki,a Arkadiusz Ciesielski,a Roland Boese,a Jacek Młochowski,c Michał K. Cyrańskia,*

a

Advanced Crystal Engineering Laboratory, Department of Chemistry, University of Warsaw, Żwirki i Wigury 101, 02-089 Warsaw, Poland

b

Department of Chemistry, University of Warsaw, Żwirki i Wigury 101, 02-089, Warsaw, Poland

c

Department of Chemistry, Wrocław University of Technology, Wybrzeże Wyspiańskiego

27, 50-370 Wrocław, Poland

* Corresponding authors: Dorota Stępień ([email protected]), Katarzyna N. Jarzembska ([email protected]) Michał K. Cyrański ([email protected])

Dedicated to Professor Tadeusz Marek Krygowski on the occasion of his 80 th birthday.

TOC Graphic


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Synopsis:

Nine

new

cocrystals

of


and

para-

hydroxyphenylboronic acids with a series of aromatic N-oxides are reported and comprehensively characterized both structurally and computationally. Energetic features of the studied crystal structures are confronted with the experimental TGA-DSC results for selected cases.


Structural and Stability Studies of a Series of para-Phenylenediboronic

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