Positional Isomerism and Conformational Flexibility Directed Structural

Jun 25, 2015 - ... Venkatesvara R. Pedireddi , and Krzysztof Woźniak. Crystal Growth & Design 2017 17 (9), 4918-4931. Abstract | Full Text HTML | PDF...
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Positional isomerism and conformational flexibility directed structural variations in the molecular complexes of dihydroxybenzoic acids Sunil Varughese, Anna A. Hoser, Katarzyna N. Jarzembska, V. R. Pedireddi, and Krzysztof Wozniak Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.5b00471 • Publication Date (Web): 25 Jun 2015 Downloaded from http://pubs.acs.org on July 1, 2015

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Positional isomerism and conformational flexibility directed structural variations in the molecular complexes of dihydroxybenzoic acids Sunil Varughesea*, Anna A. Hoserb*, Katarzyna N. Jarzembskab, V. R. Pedireddic and Krzysztof Woźniakb a

Chemical Science and Technology Division, CSIR-National Institute for Interdisciplinary Science and Technology, Trivandrum 695 019, India b

Chemistry Department, University of Warsaw, Pasteura 1, 02-093, Warsaw, Poland

c

Solid State and Supramolecular Structural Chemistry Laboratory, School of Basic Sciences, Indian Institute of Technology Bhubaneswar, Bhubaneswar 751 007, India E-mail: [email protected]; [email protected]

Mutual disposition and conformational preferences of functional groups can induce variations in the nature and types of interactions and hence the molecular arrangements in the rigid crystal environment. We comprehensively analyzed this effect in a series of 13 (of which 9 are novel)1,2 molecular complexes of positional isomers of dihydroxybenzoic acid with trans-1,2-bis(4-pyridyl)ethene and 1,2-bis(4pyridyl)ethane. Seven of the complexes exist as salts, with an observed carboxyl to pyridine heteroatom proton transfer, which can be explained on the basis of ∆pKa analysis. In all the complexes, carboxyl/carboxylate functionalities interact consistently with pyridine/pyridinium moieties. The –OH groups, in contrast, are more versatile with the formation of diverse interaction types― ‒OH···carboxyl (O‒ H···O), ‒OH···carboxylate (O‒H···O‒), and ‒OH··pyridine (O‒H···N) hydrogen bonds. Hirshfeld surface analysis and computed interaction energy values were utilized to determine the hierarchical ordering of the interactions and further to highlight the significance of weak interactions such as π···π and C‒H···π in structure stabilization. In ionic complexes, these secondary interactions become more expressed, with an enhanced contribution from electrostatic elements. The energetic bias towards the complex formation is evident from the calculated cohesive energies of the complexes vis-à-vis their parent components.

Introduction Non-covalent interactions engaged in molecular recognition and aggregation events are relatively weak and flexible, as compared to the bonds operated in the 1 ACS Paragon Plus Environment

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molecular constructions; this nature makes their decisive utility in crystal engineering a formidable task.3-10 For a better appreciation of the weak interactions and their utility in crystal synthesis, one needs to understand their energetic subtleties and hierarchical ordering.11-15 Structural and statistical evaluation of an extensive collection of related complexes offers a perspective beyond that of the isolated consideration of individual structures and hence is usually adopted as a strategy to draw information on synthon preferences and structural features.16-18 Further, the concurrent presence of competing functional groups, with hydrogen bond donor/acceptor abilities, and their distinct mutual disposition offers an ample opportunity to determine the synthon preferences and their hierarchical ordering.17,18 Such derived information on synthon hierarchy and the modular nature of robust synthons can be employed as essential design elements for the predictable synthesis of cocrystals. The posited relative strength of supramolecular synthons in the order of amides > acids > alcohols is a suggestive example in this context.19,20 Positional isomers, where molecules differ in the spatial distribution of functional groups, offer an effective strategy to study the variations in synthon-types and structural features, with limited number of variables involved. A direct correlation of crystal packing with the degree and pattern of fluorine substitution of the phenyl ring in N-(pyridine-4-yl)-N-phenylurea,21 interchangeability of C‒H and C‒F groups in isomeric fluorinated benzanilides,22,23 viability studies on halogen···nitro interactions in isomeric halo and nitro substituted triaryl compounds24

and

preferences in intermolecular interactions with respect to the bridge orientation in isomeric benzylideneanilines,25,26 are representative examples that highlight the importance of positional isomerism in crystal engineering, derived by collective analysis of a relatively large library of structures. Dihydroxybenzoic acids (DHBs) can exist as six positional isomers (Scheme 1). The mutual disposition of the three substituents (a ‒COOH and two –OH) on the periphery of a rigid, planar platform, and their ability to interact with incoming conformers competently make them an interesting set of compounds. Since some of the DHBs (such as 25DHB (gentisic acid)) are being used in pharmaceutics as FDA approved GRAS coformers, their structural studies as well as their molecular complexes are important.27 For example, in a recent report the cocrystals of different isomers of DHBs with piracetam were investigated to study the effect of the positional isomerism in the formation and physicochemical properties of 2 ACS Paragon Plus Environment

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pharmaceutical cocrystals.28 Further, DHBs and their derivatives are studied for their inhibitory activities,29 metabolism30 and also are explored as fluorescent probes31. Further, each DHB is known to form polymorphs or/and solvates when crystallized (Table S3; Supporting Information) and, therefore, constitute an interesting family of compounds for crystal engineering studies32-36 and crystal structure prediction.37 Interestingly, a statistical report based on CSD38 studies maintains that 21% and 6% of the organic entries comprise of –OH and –COOH, respectively. Further, 33 and 25 of the top 100 prescribed drugs contain these functional groups, correspondingly.18 Evidently, there are attempts to appreciate the predictability and hierarchy in the types of synthons these functional groups establish with various N-donor compounds.2,18 In the present work, we verify the probability to establish the type of synthons and their preferences in the molecular complexes of different isomers of DHBs with the Ndonor

compounds,

trans-1,2-bis(4-pyridyl)ethene

(bpyee)

and

1,2-bis(4-

pyridyl)ethane (bpyea). This work on DHBs was preceded by the structural studies on the molecular complexes of 3,5-dihydroxybenzoic acid and its 4-bromo-derivative with various N-donor compounds2 and also the host-guest complexes of hydrated 3,5dihydroxybenzoic acid39. We have extended these analyses, completing the series and thoroughly investigating the crystal, as well as the intermolecular interaction energetics. The computational results are discussed in the context of Hirshfeld Surface (HS) analysis and experimental pKa values for DHBs.

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2,3-Dihydroxybenzoic acid (23DHB)

2,4-Dihydroxybenzoic acid (24DHB)

2,5-Dihydroxybenzoic acid (25DHB)

2,6-Dihydroxybenzoic acid (26DHB)

3,4-Dihydroxybenzoic acid (34DHB)

3,5-Dihydroxybenzoic acid (35DHB)

trans-1,2-bis(4-pyridyl)ethene (bpyee)

1,2-bis(4-pyridyl)ethane (bpyea)

Scheme 1. Compounds considered for cocrystallization studies. Experimental section X-ray diffraction. Data collection for single crystals of the complexes was carried out at 100 K on κ-axis KM4CCD diffractometer with Mo Kα radiation monochromated by graphite by applying ω-scan technique. Crystals were positioned at a 65mm distance from CCD 1024 × 1024 pix. camera. The 2θ angle range was extended from ca. 2° up to 57°. Computational studies. All the structures were optimized periodically in the CRYSTAL09 program prior to further computational analyses. Cohesive energy values were computed within the supermolecular method using CRYSTAL09, whereas molecular complex interaction energies were estimated employing the counterpoise method available in the Gaussian09 package. In all the cases DFT(B3LYP)/6-31G** level of theory was applied. The energy results were corrected both for BSSE and dispersion (Grimme approach). Detailed information on crystal syntheses, X-ray data collection, crystal structure evaluation method and structural details are provided in the Supporting Information.

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Results and Discussion Isomerism and conformational variations in DHBs At the outset of the discussion on the structural studies, it is worth noting some of the structural intricacies associated with individual components, especially DHBs. Conformational freedom enjoyed by the ‒OH groups in DHBs bears a potential structure-directing role. This in conjunction with the relative disposition of the –OH groups, with respect to the –COOH moiety, provide an infinite number of probable sets of complexes, diverse interactions and three-dimensional structures. The computed conformational energies for different isomers of DHBs40 are provided in Table-S4 (Supporting Information) and the conformations that correspond to the lowest energies are shown in Scheme 2. The syn and anti-conformations, shown in Scheme 2, are described with respect to an arbitrary perpendicular plane cutting through the benzene ring between ‒OH positions. The orientation in which –OH points at the plane is named syn and that the other one as anti. Because the conformers have only small energy differences, robust hydrogen bonds and their associated energetics may be good enough to override these insignificant differences. Thus, in systems with several possibilities of energetically viable conformational arrangements, the conformation observed in a particular crystal structure may not always correspond to that with the lowest energy.

23DHB H

24DHB

H

O

O

O O O

H

H O

O

H

O

O

H H

O

H

O O

O

O

anti,anti

H

O O

H

O

H

syn,syn

O

H

O

O

H O

H

O

H

H

O

anti,anti

syn,anti

H

H

O

O

O

H

H

H O

O

O

H O

H H

H O

26DHB

H O

H O

25DHB O

O

O

O

syn,anti

H

O

H

H

syn,syn

H

H O

O

O

O

O

H O

H

O

O O

O H

syn,syn

syn,anti

anti,anti

syn,syn

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syn,anti

anti,anti

H

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34DHB H

35DHB H

H

O

O

O O

H

H

syn,syn

O O

O H

syn,anti

O

O

H

H

H

H

O

O

O

H

O

anti,anti

O

H O

O

O

O

O

H

H

H

syn,syn

O

O

syn,anti

H

H

O

O

O

H

anti,anti

30 25 20 syn,syn

15 10

syn,anti

5

anti,anti

0

Scheme 2. Different isomers of DHBs, along with the possible conformations and their respective conformational notations adopted in the present report. Statistical evaluation of the preferred conformations in DHBs, based on a CSD search. Crystal structures and molecular arrangements Co-crystallization of various isomers of DHB with N-donor molecules, bpyee and bpyea, (Scheme 1) yielded the corresponding molecular adducts at ambient conditions. Collective analysis of the molecular complexes divulges the similarities and the differences in recognition patterns and three-dimensional architecture in the context of the positional isomerism and conformational pliability of the –OH groups. In all the structures of DHBs with a 2–OH group, the functionality preferentially make an intramolecular hydrogen bond with the carboxyl group, and is in agreement with one of the Etter’s empirical rules.41

(a)

(b) 6 ACS Paragon Plus Environment

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Figure 1. The complex 23EA. (a) The primary recognition unit and the lateral C‒ H···O hydrogen bonds. (b) The corrugated layer structure. In 23EA, obtained by cocrystallizing 23DHB and bpyea, the –OH adopt an anti,anti- conformation and the acid group is deprotonated. The pyridinium/pyridine ends of bpyea unit interacts with 23DHB distinctly― pyridinium end makes N+‒ H···O‒/C‒H··· O‒ cyclic interactions with carboxylate group. The pyridine moiety, however, interact with 3–OH group through O‒H···N hydrogen bond. The resultant infinite tapes interact laterally through C‒H···O hydrogen bonds to form corrugated layer structure (see Figure 1). Depending on the crystallization solvents, two types of crystals were obtained upon cocrystallizing 23DHB and bpyee. Crystallization from a methanol solution yielded colorless plates (23EE_I) and a THF-methanol mixture, red blocks (23EE_II). The complexes are distinct with respect to their composition― 23EE_I has DHB and bpyee in a 1:1 composition, while in 23EE_II the components are in a 2:1 ratio. The molecules in 23EE_I remain as neutral, whereas a proton transfer is observed in 23EE_II, leading to an ionic complex. 23DHB in 23EE_I adopt an anti,anti- conformation. One of the two symmetry independent bpyee units interact with 23DHB entirely through –OH functionality while the interaction with the second pyridine ligand is exclusively through –COOH group. Thus, symmetrically independent bpyee units adopt different recognition with the acid molecules and they stack alternately (Figure 2a). Unlike 23EE_I, the acid in 23EE_II adopt a syn,anti-conformation and consequently the deprotonated acid molecules make a bumpy-layer structure. Individual layers consist of linear chains of 23DHB connected by 3‒OH; 2–OH, remains locked in an intramolecular hydrogen bond (Figure 2b). Neighboring sheets meet at periodic junctions; four acid molecules from adjacent sheets weave through O‒H···O‒ as well as C‒H···O hydrogen bonds to make a tetramer unit. The bpyee molecules protrude through the void space (Figure 2b) and in a unique arrangement each bpyee molecules are in close contact with four 23DHB molecules.

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(a)

(b)

Figure 2. (a) The types of interactions observed in 23EE_I. The O–H···N hydrogen bonds are shown in black while π···π in pink. (b) The corrugated acid layers and the interactions within a unique layer observed in 23EE_II. The interaction between adjacent layers is shown in inset A. The acid-pyridine interactions are represented in inset B. Also shown is the pictorial representation of acid-pyridine arrangement. In the cocrystals of 24DHB with bpyea (24EA) and bpyee (24EE), the acid adopts similar conformation (syn,anti). In both cases two 24DHB interacts with either the bpyea or bpyee molecule, using both –OH and –COOH fragments, to form a threemember entity.1 In 24EA the trimer units extend to make a ladder assembly in 2D, but prominently through C‒H···O hydrogen bonds (Figure 3a). In 24EE also, the primary recognition units extend to make ladder architecture (Figure 3b). In a unique ladder, one side is stabilized by the –COOH group while the interactions of 4‒OH moiety hold the other side.

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(a)

(b)

Figure 3. (a) Ladder-like molecular arrangement in 24EA. (b) In 24EE, π-π (3.7 Å) interactions between the acid molecules and their interaction with bpyee leads to a ladder-like architecture. The primary interaction pattern is provided in the inset. The conformations adopted by 25DHB are distinct and so are their interactions in 25EE and 25EA. In 25EA, the pyridinium ring interacts with the – COO‒ moiety, whereas the neutral pyridyl ring interacts with anti- 5–OH. The resultant one-dimensional chains further propagate to form a stacked corrugated layer structure (Figure 4a). However, the syn-conformation of the 5–OH in 25EE leads to a symmetric acid dimer through O‒H···O‒ hydrogen bonds (Figure 4b). The dimer interact with bpyee through N+‒H···O‒/C‒H···O‒ cyclic interactions to form a stacked-layer structure.

(a)

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(b)

Figure 4. (a) Corrugated layer structure in 25EA. The primary interaction and the formation of 1D chain is represented in the inset. (b) Stacked-layer molecular arrangement in 25EE. The acid dimer and the extension of acid-pyridine synthon are shown in the inset. The complexes 26EA and 26EE contains deprotonated acid and pyridinium moiety involved in N+‒H···O‒/C‒H···O‒ cyclic interactions. Both –OH groups of 26DHB are locked in intramolecular O‒H···O‒ hydrogen bonds. The primary threemolecule supramolecular building block stacks via π···π interactions in the ab-plane, to make a herringbone arrangement (Figure 5a). The near identical nature of 26EA and 26EE is not just confined to similar recognition pattern but is further reflected in their 3D architecture and unit cell dimensions. In consequence, the obtained crystals are isomorphous as evident from an overlay of structures (Figure 5b), as well as with a computed unit cell similarity index, Π = 0.0049.42,43,47

(a)

(b)

Figure 5. (a) The primary three-molecule supramolecular building block (in inset) and a herringbone arrangement, observed in 26EE. (b) Isostructurality in 26EE and 26EA, as demonstrated by an overlay of structures. 10 ACS Paragon Plus Environment

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In 34EA, the acid molecules show significant conformational variations with respect to the relative positions of –OH groups on the aromatic rings, and could be due to a C(aromatic)‒C(COOH) rotation. Thus with respect to one of the 34DHB molecule (red), the –OH groups on the other (green) can be considered on 4- and 5-positions (Figure 6). The conformationally different acid molecules are denoted as A and B, respectively, for an easy representation. In bpyea, the conformational variation is the resultant of the rotational freedom enjoyed by the pyridyl ring about the C(pyridine)‒ C(olefin) bond. One of the bpyea molecules exhibits a twist of ~22o between the two pyridyl rings, whereas the inter-planar angle in the second molecule is ~81o and are denoted as C and D, respectively (Figure 6). In the crystal, two symmetry related acid molecules interact with a bpyea molecule through O‒H···N hydrogen bonds using both ‒OH and ‒COOH groups of the acid molecules. Thus in an individual recognition unit, bpyea of C-type interacts with two acids of A-type while two B-type DHBs interact with a D-type bpyea. The two resultant recognition units are arranged in succession to form a ladder assembly.

Figure 6. Complex 34EA. The conformational differences existing in symmetry independent molecules are represented by the overlay of bpyea and 34DHB molecules. Interactions between DHB and bpyea lead to a ladder-like architecture. In the 1:1 molecular complex 34EE, two molecules each of 34DHB and bpyee constitute the asymmetric part of the unit cell. Two bpyee molecules differ in the

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conformations in terms of rotation of the pyridyl rings about the ethylene bridge. The observed twist between the two pyridyl rings in one of the bpyee molecules is ~33o as against ~19.5o in the other (Figure 7a). The acid molecules differ in the relative orientation of their –OH groups (Figure 7b). In the crystal, molecules arrange to make corrugated sheet structure (Figure 7c). In a unique layer, interactions between two symmetrically independent molecules of the acids and bpyee units lead to the formation of helices with opposite handedness; individual helices arrange in an edgesharing mode to form a cyclic network involving ten molecules (Figure 7d).

(a)

(b)

(c)

(d) Figure 7. An overlay of (a) bpyee and (b) 34DHB molecules, to represent the conformational variations (c) Corrugated sheet structure. (d) Interactions within a unique layer. Helices with opposite handedness are shown on both sides. The structural features of the complexes of 35DHB with bpyee and bpyea were reported in one of our earlier papers.2 The syn,syn and syn,anti-conformations adopted by 35DHB in 35EA and 35EE cocrystals, respectively, are reflected in their recognition patterns and overall molecular arrangements. In 35EE complex, two symmetry independent bpyee units interact with three acid molecules, which in turn make cyclic C‒H···O hydrogen bonds to yield a ladder structure (Figure 8b). In contrast, the interaction of bpyea units with acid molecules extends in one-dimension 12 ACS Paragon Plus Environment

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to form an infinite one-dimensional crinkled tape. In two-dimensional arrangement, the adjacent tapes run in antiparallel mode to yield a ladder-like architecture.

(a) (b) Figure 8. Different packing motifs observed in the molecular complexes (a) 35EA and (b) 35EE. Conformational flexibility and crystal packing As evident from the foregoing section, the conformational preferences of competent hydrogen bonding functionalities become direct and visible in determining the interaction types and crystal packing. For example, the molecular complexes 23EE_I and 23EE_II have the same molecular components but, differ in their interaction characteristics and crystal packing. This difference is rooted from the distinct conformations adopted by the –OH groups (syn,anti vs. anti,anti). Though with a few minor inconsistencies in the secondary interactions established between the neighboring tapes, 23EA and 25EA complexes, in contrast, yielded assemblies with comparable 3D structures. This observed resemblance in the 3D architecture may be attributed to similar orientations of –OH groups (Figure 9), ignoring their relative positions on the aromatic rings. Further, the conformational flexibility of bpyea could also be a driving factor that dictates to override the differences originating from the relative positions of –OH groups. Incidentally, their respective bpyee complexes remain distinct.

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23DHB

25DHB

Figure 9. The conformations of ‒OH groups adopted by the acid molecules in 23EA and 25EA.

Hirshfeld surface analysis Hirshfeld surface (HS) analysis is a valuable tool for the quantitative study of intermolecular interactions in a fast and elegant way.44-46 A correlation of percentage interaction contributions from a given HS with the crystal stabilization energy has been recently proposed.48 Also, the Hirshfeld surface analysis was used as a parameter to rank the stability of cocrystal polymorphs.49 In a recent report some of us demonstrated the utility of HS analysis in establishing the structural equivalence of ethylene and azo bridges in 1,2-bis(4-pyridyl)ethene and 4,4'-azopyridine in the modular design of supramolecular complexes.47 In the present study we used HS analysis to understand the equivalence/variance in the interaction characteristics in isomeric systems and also to highlight the structure stabilization role of weak interactions. The DHB and bpyea/bpyee moieties for each complex were individually studied with the aid of fingerprint plots and percentage contributions of specific contacts to HS area (Supporting Information). 26DHB make isomorphous complexes and an analysis of the percentage contributions of interactions indicate that the isostructurality is mainly driven by the interactions directed by the acid rather than bpyea/bpyee ligands. It is not surprising that bpyee and bpyea differ in the contributions from H···H contacts, with 26EA having 5% excess contributions. Notably, 23EA and 25EA that were considered for structural similarity has similar percentage contributions of interactions both originating from bpyea or the acids, thus corroborating our observation on their structural equivalence. In the case of complexes 23EE_I and 23EE_II, the observed variations in the molecular arrangements are also reflected in the percentage contributions of intermolecular interactions, especially that of weak forces such as H···H, and C···H types. In the context of bpyea and bpyee, dispersive H···H contacts remain the major type with calculated contribution that range between 35-46%. O···H interactions incur large deviation (8-30%) due to the proton transfer observed in some of the complexes. Based on the percentage contribution of O···H interactions to the HS area, the complexes can be classified as ionic (~30%), partially ionic (15-20%) and neutral 14 ACS Paragon Plus Environment

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( 3.75 for possible proton transfer. Although ∆pKa values are usually reliable indicators of salt formation when ∆pKa > 3, the ∆pKa range 0 to 3 is rather ambiguous. Cocrystal formation is expected when ∆pKa < 0, though a salt-cocrystal continuum exist in the range of 0 to 3.67.52

Table 1. pKa value analysis (the pKa values for the studied compounds are taken from CAS Scifinder). The pKa for respective components are given in parentheses.

Component A 26DHB (1.3) 26DHB 23DHB (2.96) 25DHB (3.01) 24DHB (3.32) 23DHB 25DHB 35DHB (3.96) 24DHB 34DHB (4.45)

Component B bpyea(6.13) bpyee(5.41) bpyea bpyea bpyea bpyee bpyee bpyea bpyee bpyea

∆pKa 4.83 4.11 3.17 3.12 2.81 2.45 2.40 2.17 2.09 1.68

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ionic ionic partially ionic partially ionic molecular molecular / ionic ionic molecular molecular molecular

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1.45 0.96

bpyee bpyee

35DHB 34DHB

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molecular molecular

The protonation/deprotonation or species neutrality in the present series of complexes can be explained on the basis of the corresponding ∆pKa values and the aforesaid basic thresholds. There are, however, some exceptions that reflect the above-described uncertainty region of the chosen indicator. The increasing acidity order of the chosen acids is as follows: 34DHB < 35DHB < 24DHB < 25DHB < 23DHB < 26DHB (see Table 1). The pyridyl compound bpyea (pKa = 6.13) has a higher basic character than bpyee (pKa = 5.41). In the present set of 13 complexes the ∆pKa values for the salts are in the range of 2.40 to 4.83 (Table 1). The salt nature of the complexes formed by the most acidic 26DHB with both N-donor compounds is obvious. 23DHB and 25DHB with comparable pKa values make partially ionic complex with bpyea (only one of the pyridyl heteroatoms remains protonated). All of the four complexes are characterized by ∆pKa values >3. On the other hand the neutral complexes 24EE, 24EA, 34EE, 34EA, 35EA and 35EE are described by ∆pKa values < 3. The complexes 23EE_I and 23EE_II are rather intriguing with the formation of both ionic and neutral complexes depending on the crystallization conditions and conformational differences of –OH groups. In fact our observations on the influence of ∆pKa on neutral or salt cocrystal formation are in good agreement with the recent report on carboxylic acid/pyridine complexes by Lemmerer.53 Intermolecular interactions Supramolecular synthon types and their strength is a significant factor in stabilizing molecular units in crystal lattice and hence it is worth analyzing their energy contributions toward the structure formation. In this report, we have depicted all prominent interactions in the structure stabilization and have calculated the corresponding dimer interaction energies. The energy values and the schematic representation are provided in Table 2 and Table S6, respectively. In the complexes, the most stabilizing of all the interactions were found to be those between carboxyl/carboxylate and pyridine/pyridinium moieties. From the interaction energies, the effect of proton transfer from carboxyl to pyridine heteroatom is evident; ionic interactions have enhanced electrostatic contributions over the normal hydrogen bonds. In the neutral systems, interaction energies for acid16 ACS Paragon Plus Environment

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pyridine interactions are in the range of –50 to –60 kJ·mol–1; for partially ionic systems (such as 23EA and 25EA), it amounts to –409 and –420 kJ·mol–1and in ionic systems such as 25EE, 26EA and 26EE the computed energy values are –580, –517 and –543 kJ·mol–1, respectively (Table 2). Second strongest of the synthon types is that formed between hydroxyl group and pyridine moiety with interaction energies in the range of –35 to –50 kJ·mol–1 for non-ionic systems, and ~–160 kJ·mol–1 for two partially ionic systems. Additionally, from the calculated interaction energies, it is evident that π···π stacking interactions also play a significant role in structure stabilization (Table S6). Their effect becomes more visible in ionic systems wherein apart from the dispersive forces there is significant electrostatic contribution, which in turn enhances the interaction energy values. Table 2. Interaction energies in kJ·mol–1 calculated for each complex for interactionstypes (1) carboxyl/carboxylate···pyridine/pyridinium, (2) hydroxyl···pyridine, (3) π..π stacking. 1 23EA 23EE_I 23EE_II 24EA 24EE 25EA 25EE 26EA 26EE 34EA 34EE 35EA 35EE

2

–409 –60 –571 –60 –56 –421 –580 –518 –543 –54 –50 –51 –57 –58 –60 –55

–164 –43 – –49 –39 –168 – – – –42 –36 –42 –37 –46 –47 –43

3 –181 – –483 – –19 – –487 –488 –485 – – –24 – –24 –18 –

Cohesive energy and crystal stability Cohesive energy (Ecoh) quantifies the energy gained by arranging the atoms in crystalline state as compared with the gas state. The computed Ecoh of complexes visà-vis their components highlight the energy bias towards the formation of molecular complexes. Different protonation/deprotonation behaviour and number of molecules in the asymmetric part of the unit cell makes it rather an intricate task to make a comparative analysis of the complexes. It is not surprising that the crystals consisting 17 ACS Paragon Plus Environment

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of ionic moieties exhibit larger cohesive energies than their neutral counterparts. This, however, does not mean that these crystals are far more stable than the ones built of neutral fragments, as the resulting structure is a balance between the molecular energies and the intermolecular interactions, which should provide the most advantageous total energy of the obtained crystal. Further, the final product is also a function of crystallization kinetics and entropic factors. Nevertheless, it is reasonable to compare crystals with similar composition and relate them to the crystals of their pristine components. From the computed Ecoh (Table 3), it is evident that bpyea forms either comparable or more energetically stable crystals than its analogous compound, bpyee. Acids, 34DHB and 35DHB, with no 2‒OH groups, are less acidic and hence make neutral complexes. The 2–OH in the DHBs adds additional resonance structures stabilizing the negative charge on the carboxylate functionality and this leads to its enhanced acidic nature. The complexes of 34DHB and 35DHB in fact are described with the greatest Ecoh among the neutral complexes. This, understandably, results from the absence of any intramolecular hydrogen bonds (that are universal in the complexes of acids with 2–OH, where the ‒OH group is locked in an intramolecular hydrogen bond with the carboxylic moiety), whereby it enables additional intermolecular interactions employing these fragments. The least advantageous Ecoh was obtained for 24EE. Table 3. Cohesive energy values for the complexes (ASU content abbreviations: N = N-donor molecule, A = acid molecule; ‫ܧ‬ୡ୭୦ = cohesive energy).

Structure 23EA 23EE_I 23EE_II 24EA 24EE 25EA 25EE 26EA 26EE 34EA 34EE 35EA 35EE

Crystal type ASU content partially molecular ionic molecular molecular partially Ionic Ionic Ionic molecular molecular molecular molecular

1A + 1N 1A + 1N 1A + 0.5·N 1A + 1N 1A + 1N 1A + 1N 1A + 0.5·N 1A + 0.5·N 1A + 0.5·N 2A + 2N 2A + 2N 2A + 2N 2A + 3N

‫ܧ‬ୡ୭୦ / kJ·mol−1 −737.4 −295.7 −748.0 −294.0 −279.8 −736.2 −756.8 −691.4 −692.2 −624.5 −613.7 −631.7(−315.8) −755.9*

(*) the disorder was removed and crystal symmetry was reduced to P1

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Though isostructural, 26EA and 26EE show observable differences in the interaction energies; the heterosynthon interaction energies are more advantageous for the structure which contains the bpyee moiety. The resulting Ecoh are, however, comparable (Table 3). In the former, intermolecular distances are on average slightly shorter, what is reflected in the shorter interactions between the oppositely charged species. These differences are but compensated by the possible repulsive interactions of the closely located ionic moieties of the same kind. In the structurally equivalent 23EA and 25EA the carboxylate-pyridinium interaction advantage obtained for 25EA is compensated by the enhanced energy contributions from π···π interactions, making their Ecoh comparable (–737.4 and –736.2 kJ·mol–1 for 23EA and 25EA, respectively). 23EE_I and 23EE_II with same components, but distinct crystal packing, differ in their interaction energies and cohesive energies. It is not rather surprising that the observed dissimilarity in Ecoh is the reflection of the variances in their interaction types and the associated energies. In general, the formation of molecular complexes becomes more obvious when the Ecoh of the complexes are more favorable than the sum of the Ecoh of its respective component crystals (Table 4).

Table 4. Cohesive energy values for the mono-component crystals. (ASU content abbreviations: N = N-donor molecule; A = acid molecule and ‫ܧ‬ୡ୭୦ = cohesive energy).

Structure

ASU content

23DHB (CACDAM) 24DHB (ZZZEEU) 25DHB (BESKAL) 26DHB (LEZJAB) 26DHB (LEZJAB01) 34DHB (WUYNUA) 35DHB (WUYPOW) bpyea (ZEXKIW) bpyee (AZSTBB)

2A 1A 1A 1A 1A 3A 3A 1N 1N

‫ܧ‬ୡ୭୦ / kJ·mol−1 −237.1(−118.6) −132.6 −131.0 −129.1 −113.6 −477.5(−159.2) −488.0(−162.7) −105.0 −104.3

Conclusions All the six positional isomers of dihydroxybenzoic acid form molecular complexes with the linear N-donor compounds― trans-1,2-bis(4-pyridyl)ethene and 1,2-bis(4-pyridyl)ethane. The structural features of the resultant complexes were analyzed in the context of the mutual disposition of the three substituents on the 19 ACS Paragon Plus Environment

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periphery of the benzene ring, and also with respect to the conformational preferences of –OH functionality. Among the complexes, seven exist as salts with an observed proton transfer and was accounted on the basis of ∆pKa values, a general predictor of salt/cocrystal

formation.

In

all

the

studied

systems,

carboxyl/carboxylate

functionalities interact with pyridine/pyridinium moieties consistently while –OH groups make diverse interaction types― ‒OH··pyridine (O‒H···N), ‒OH···carboxyl (O‒H···O) or ‒OH···carboxylate (O‒H···O‒). The computed interaction energies confirm the hierarchy in the synthon types; the most stabilizing of the interactions were found to be those between carboxyl/carboxylate and pyridine/pyridinium moieties. With the proton transfer from carboxyl to pyridine heteroatom, the interactions experience enhanced electrostatic contributions. Second in the synthon hierarchy is that formed between –OH and pyridine moiety. The secondary interactions like π···π stacking interactions do play a significant role in structure stabilization and their effect is more visible in ionic systems wherein apart from the dispersive forces there is significant electrostatic contribution, which in turn enhances the interaction energy values. The isostructural complexes 26EA and 26EE show observable differences in the interaction energies, but have comparable cohesive energies. A better close packing in 26EA was inferred to be the compensating factor for the slight disadvantage in interaction energies. Similarly, in the structurally equivalent 23EA and 25EA the carboxylate-pyridinium interaction advantage obtained for 25EA is compensated by an enhanced energy contribution from π···π interactions, making their cohesive energies comparable. The computed crystal cohesive energies vis-à-vis the component energies highlight the energy bias towards the formation of molecular complexes. Thus, an in-depth analysis of interaction and cohesive energies can shed light on various factors that drive the structural equivalence/variance in a related set of complexes.

Acknowledgements S. V. thanks, Department of Science and Technology, New Delhi for a Young Scientist Fellowship and The Director, CSIR-NIIST for the constant support and encouragement. AAH and KNJ gratefully acknowledge the National Science Centre in Poland (grant no. 2011/03/N/ST4/02943) for financial support. Calculations were

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carried out using resources provided by the Wrocław Centre for Networking and Supercomputing (grant no. 285).

Supporting information CCDC1056683, CCDC297520, CCDC615221, CCDC297521, CCDC297522, CCDC297523,

CCDC615222,

CCDC297524,

CCDC297525,

CCDC297526,

CCDC615223, CCDC278692, CCDC278691 entries contain the supplementary crystallographic data for all co-crystals. The data is accessible free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. Experimental procedures, computational details, pKa analysis compilations, Hirshfeld Surface analysis data, crystallographic data for structures, bond distances and angles for structures as well as crystallographic information in CIF format. This material is available free of charge via the Internet at http://pubs.acs.org.

References (1)

Khan, M.; Enkelmann V.; Brunklaus, G. Cryst. Growth Des. 2009, 9, 23542362.

(2)

Varughese, S.; Pedireddi, V. R. Chem. Eur. J. 2006, 12, 1597-1609.

(3)

Metrangolo, P.; Neukirch, H.; Pilati, T.; Resnati, G. Acc. Chem. Res. 2005, 38, 386-395.

(4)

Desiraju, G. R. Angew. Chem. Int. Ed. 1995, 34, 2311-2327.

(5)

Braga, D. Chem. Commun. 2003, 2751-2754.

(6)

Aakeröy, C. B.; Seddon, K. R. Chem. Soc. Rev. 1993, 22, 397-407.

(7)

Nishio, M. CrystEngComm 2004, 6, 130-158.

(8)

Burrows, A. D. Struct. Bond. 2004, 108, 55-96.

(9)

Desiraju, G. R. Angew. Chem. Int. Ed. 2007, 46, 8342-8356.

(10)

Marjo, C. E.; Bishop, R.; Craig, D. C.; Scudder, M. L. Eur. J. Org. Chem. 2001, 863-873.

(11)

Alkorta, I.; Sánchez-Sanz, G.; Elguero, J. CrystEngComm 2013, 15, 31783186.

(12)

Dunitz, J. D.; Gavezzotti, A. Cryst. Growth Des. 2012, 12, 5873-5877.

(13)

Hobza, P.. Acc. Chem. Res. 2012, 45, 663-672.

(14)

Turner, M. J.; Thomas, S. P.; Shi, M. W.; Jayatilaka, D.; Spackman, M. A. Chem. Commun. 2015, 51, 3735-3738. 21 ACS Paragon Plus Environment

Crystal Growth & Design

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

(15)

Yang, L.; Adam, C.; Nichol, G. S.; Cockroft, S. L. Nature Chem. 2013, 5, 1006-1010.

(16)

Aakeröy, C. B.; Baldrighi, M.; Desper, J.; Metrangolo, P; Resnati, G. Chem. Eur. J. 2013, 19, 16240-16247.

(17)

Kavuru, P.; Aboarayes, D.; Arora, K. K.; Clarke, H. D.; Kennedy, A.; Marshall, L.; Ong, T. T.; Perman, J.; Pujari, T.; Wojtas, Ł.; Zaworotko, M. J. Cryst. Growth Des. 2010, 10, 3568-3584.

(18)

Shattock, T. R.; Arora, K. K.; Vishweshwar, P.; Zaworotko, M. J. Cryst. Growth Des. 2008, 8, 4533-4545.

(19)

Infantes, L.; Motherwell, W. D. S. Chem. Commun., 2004, 1166-1167.

(20)

Infantes, L.; Motherwell, W. D. S. Z. Krystallogr., 2005, 220, 333-339.

(21)

Abad, A.; Agullo, C.; Cunat, A. C.; Vilanova, C.; de Arellano, M. C. R. Cryst. Growth Des. 2006, 6, 46-57.

(22)

Chopra, D.; Row, T. N. G. CrystEngComm 2008, 10, 54-67;

(23)

Nayak, S. K.; Reddy, M. K.; Chopra, D.; Row, T. N. G. CrystEngComm 2012, 14, 200-210.

(24)

Ramana, C. V.; Goriya, Y.; Durugkar, K. A.; Chatterjee, S.; Krishnaswamy, S.; Gonnade, R. G., CrystEngComm 2013, 15, 5283-5300.

(25)

Ojala, W. H.; Balidemaj, B.; Johnson, J. A.; Larson, S. N.; Ojala, C. R. CrystEngComm 2014, 16, 7226-7235.

(26)

Ojala, W. H.; Lystad, K. M.; Deal, T. L.; Engebretson, J. E.; Spude, J. M.; Balidemaj, B.; Ojala, C. R. Cryst. Growth Des. 2009, 9, 964-970.

(27)

http://www.fda.gov/Food/IngredientsPackagingLabeling/GRAS/default.htm

(28)

Liao, X. M.; Gautam, M.; Grill, A.; Zhu, H. J. J. J. Pharm. Sci. 2010, 99, 246254.

(29)

Duwel, D.; Metzger, H., J. Med. Chem. 1973, 16, 433-436.

(30)

Grootveld, M.; Halliwell, B., Biochem. Pharmacol. 1988, 37, 271-280.

(31)

Rahmi; Itagaki, H., J.Photopol. Sci. Tech. 2011, 24, 517-521.

(32)

Sarma, B.; Sanphui, P.; Nangia, A. Cryst. Growth Des. 2010, 10, 2388-2399.

(33)

SeethaLekshmi, S.; Row, T. N. G. CrystEngComm 2011, 13, 4886-4894.

(34)

Stilinovic, V.; Kaitner, B. Cryst. Growth Des. 2012, 12, 5763-5772.

(35)

Aitipamula, S.; Chow, P. S.; Tan, R. B. H. CrystEngComm 2009, 11, 18231827.

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Page 22 of 25

Page 23 of 25

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

Crystal Growth & Design

(36)

Aakeroy, C. B.; Epa, K.; Forbes, S.; Schultheiss, N.; Desper, J. Chem. Eur. J. 2013, 19, 14998-15003.

(37)

Braun, D. E.; Karamertzanis, P. G.; Price, S. L. Chem. Commun. 2011, 47, 5443-5445.

(38)

Allen, F. H.; Kennard, O. J. Mol. Graphics 1993, 8, 31-37.

(39)

Varughese, S.; Desiraju, G. R. Cryst. Growth Des. 2010, 10, 4184-4196.

(40)

Yassin, F. H.; Marynick, D. S. Mol. Physics 2005, 103, 183-189.

(41)

Etter, M. C. Acc. Chem. Res. 1990, 23, 120-126.

(42)

Kálmán, A.; Párkányi, L.; Argay, G. Acta Crystallogr. , Sect. B 1993, B49, 1039-1049.

(43)

Fábián, L.; Kálmán, A. Acta Crystallogr. , Sect. B 2011, B55, 1099-1108.

(44)

McKinnon, J. J.; Fabbiani, F. P. A.; Spackman, M. A. Cryst. Growth Des. 2007, 7, 755-769.

(45)

McKinnon, J. J.; Spackman, M. A.; Mitchell, A. S. Acta Crystallogr., Sect. B 2004, 60, 627-668;

(46)

Spackman, M. A.; McKinnon, J. J., CrystEngComm 2002, 4, 378-392.

(47)

Ravat, P.; SeethaLekshmi, S.; Biswas, S. N.; Nandy, P. Varughese, S. Cryst. Growth Des. 2015, 15, 2389-2401.

(48)

Grabowsky, S.; Dean, P. M.; Skelton, B. W.; Sobolev, A. N.; Spackman, M. A.; White, A. H. CrystEngComm 2012, 14, 1083-1093.

(49)

Bolla, G.; Mittapalli, S.; Nangia, A. CrystEngComm 2014, 16, 24-27.

(50)

Childs, S. L.; Stahly, G. P.; Park, A. Mol. Pharmaceutics 2007, 4, 323-338.

(51)

Johnson, S. L.; Rumon, K. A. J. Phys. Chem. 1965, 69, 74-86.

(52)

Hathwar, V. R.; Pal, R.; Row, T. N. G. Cryst. Growth Des. 2010, 10, 33063310.

(53)

Lemmerer, A.; Govindraju, S.; Johnston, M.; Motloung, X.; Savig, K. CrystEngComm 2015, 17, 3591-3595.

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For Table of Contents Use Only Positional isomerism and conformational flexibility directed structural variations in the molecular complexes of dihydroxybenzoic acids Sunil Varughesea*, Anna A. Hoserb*, Katarzyna N. Jarzembskab, V. R. Pedireddic and Krzysztof Woźniakb

Mutual disposition and conformational preferences of functional groups induce variations in the interaction types and crystal

packing

in

the

molecular

complexes of dihydroxybenzoic acids.

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