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Can Melting Point Trends Help Us Develop New Tools to Control the Crystal Packing of Weakly Interacting Ions? Manish Kumar Mishra, Steven P. Kelley, Julia Leonidovna Shamshina, Hemant Choudhary, and Robin D. Rogers Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.7b01680 • Publication Date (Web): 10 Jan 2018 Downloaded from http://pubs.acs.org on January 11, 2018

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Crystal Growth & Design

Can Melting Point Trends Help Us Develop New Tools to Control the Crystal Packing of Weakly Interacting Ions? Manish Kumar Mishra,a,b Steven P. Kelley,a,b,† Julia Leonidovna Shamshina,a,‡ Hemant Choudharya,b and Robin D. Rogersa,b,c* a

Department of Chemistry, McGill University, 801 Sherbrooke St. West, Montreal, QC H3A

0B8, Canada. b c

Department of Chemistry, The University of Alabama, Tuscaloosa, AL 35487, USA

525 Solutions, Inc., P.O. Box 2206, Tuscaloosa, AL 35403, USA

Abstract: Ionic liquid forms of biologically active molecules (e.g., active pharmaceutical ingredients or herbicides) are often designed by using weakly interacting, conformationally flexible ions. However, crystalline forms of these molecules involve strong interactions and efficient packing. The salts of biologically active molecules may completely lack the directional supramolecular synthons typically used in crystal engineering, and thus new tools must be developed to control the crystal packing without strong directional interactions and predict their structure-property relationships in advance. The crystal structures of tetrabutylammonium and phosphonium salts of two structurally related, biologically active ions, salicylate and dicamba, show systematic differences from their free acids and metal salts, which are dominated by strong directional interactions. Molecular conformation and the structure of oligomeric ions of acids and their conjugate bases are conserved across multiple structures. The use of flexible, weakly coordinating cations to make salts of high melting biologically active acids can dramatically change melting points based on the size and shape complementarity of the ions and the ability of the cations to enhance anion-anion repulsion.

The pure forms of biologically active compounds (such as active pharmaceutical ingredients) are frequently solids with poor water solubility, creating problems with their purification, storage, and use.1 In crystal engineering, the physical properties of such compounds are improved by designing new solid forms, taking advantage of reproducible supramolecular synthons to control the packing or promote the inclusion of other molecules or ions.2 An even more recent approach explores eliminating the solid state and its disadvantages altogether by 1 ACS Paragon Plus Environment

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making liquid salt forms of biologically active ions.3 These latter compounds are known as ionic liquids (ILs) and, if designed properly, may have melting points or glass transitions below human body temperature (for pharmaceuticals) or ambient temperature (for environmental applications).4 The design of ILs involves “anti-crystal engineering,” where the ability to link any two ions through ionic bonding is exploited to pair two species which are not likely to interact and form a stable crystal structure.5 In general, certain groups of low symmetry, charge-delocalized ions reduce the possibility of hydrogen bonding and other strong interactions while interfering with efficient packing and thus lead to ILs.6 The problem with this strategy is that small changes to either ion often lead to unexpected changes in melting point, and thus IL design remains largely empirical. The reliance on conformationally flexible, weakly interacting ions, raises a fundamental challenge in their design: Without strong, directional interactions to control packing, what tools are left? Among the so-called “weakly coordinating” ions, tetraalkylammonium and phosphonium cations are frequently used in ILs to make low melting salts with high thermal and chemical stability,7 and are recognized for their antimicrobial properties.8 The large size and conformational flexibility of these ions are considered to be the source of their ability to form low melting salts, yet these same traits also give these ions the ability to engage in large numbers of weak, yet cumulatively highly stabilizing, interactions. For example, we recently showed that the N-butyl-N-methylpyrrolidinium cation can adopt multiple conformations which separately stabilize different tautomers of the [B9H14]- anion in the same crystal structure.9 However, despite the fact that a vast range of ILs with such cations have been structurally characterized, there are surprisingly few sets of related structures which could be used to precisely identify structural consequences of using tetraalkylammonium and phosphonium cations.10 Here, we have selected two structurally similar, biologically active anions both derived from benzoic acids (Scheme 1), dicamba ([Dic]-) and salicylate ([Sal]-) which have been incorporated in a number of ILs.11-14 [Dic]- is the conjugate base of 3,6-dichloro-2-methoxybenzoic acid and one of the most widely used agrochemicals, which researchers worldwide including our group have incorporated into ILs to improve uptake into plants and reduce environmental drift.13,15,16 [Sal]- is a key active ingredient of the non-steroidal anti-inflammatory drug (NSAID) family and its crystalline salts have been used as model APIs for IL synthesis.11,14 Some ILs of dicamba and 2 ACS Paragon Plus Environment

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salicylic acid have also been reported with dimeric anions (anion and neutral molecule sharing a proton).11,16 Here, we compare the crystal structures and melting points of tetrabutylammonium and tetrabutylphosphonium salts of dicamba and salicylic acid, some of whose syntheses were reported earlier.13,14

[P4444]+

[N4444]+

[Sal]-

[Dic]-

Cations Scheme

1.

The

ions

Anions investigated

in

this

study:

tetraalkylammonium

[N4444]+,

tetraalkylphosphonium [P4444]+, dicamba [Dic]-, and salicylate [Sal]-. A comparison of the available physical property data for the tetrabutylammonium and tetrabutylphosphonium salts of dicamba and salicylate illustrates the apparent unpredictability of their melting points (Table 1). Making [N4444]+ salts of [Sal]- and [Dic]- has opposite effects on their melting points when compared to the free acids. Similarly, adding an additional equivalent of salicylic acid or dicamba free acid to [P4444][Sal] or [P4444][Dic], respectively, also has opposite effects on the melting points of their respective salts. Table 1. Melting points and Kitaigorodskii packing indices (KPI)a Compound

Melting point, Tm (°C)

KPI (%)

Reference

Salicylic acid

158.2

72.1

11

[N4444][Sal]

92

67.9

11

[P4444][Sal]

57

67.8

11

[P4444][H(Sal)2]

-45.6 (Glass transition temperature, Tg)

-

11

Dicamba

114.3

66.5

13

[N4444][Dic]

126.2

68.1

13

[P4444][Dic]

64

66.6

13

[P4444][H(Dic)2]

112

66.6

This work 3

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a

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KPIs, the ratios of volume occupied by molecules to unit cell volume.20

For our study, we determined the single crystal structures of [N4444][Sal], [N4444][Dic], [P4444][Dic], and [P4444][H(Dic)2], to investigate the molecular-level origins of the physical property trends observed for these salts. Together with available literature data for the free acids and inorganic salts of these two anions, and the known structure of [P4444][Sal],17 the IL compounds show unique crystal packing supported by the flexibility of the weakly interacting cations. Before analyzing the salts, it is instructive to understand how neutral dicamba18 and salicylic acid19 crystallize, to establish similarities and differences between how these molecules assemble into a lattice. Both crystal structures contain molecular dimers held together by strong carboxyl dimer C=O···HO hydrogen bonds, but differ in how these dimers assemble (Figure 1). For salicylic acid, the intramolecular hydrogen bond between the –OH and –COOH groups makes the molecule and the resulting dimer rigorously planar, leading to infinite columns of dimers stacked through π···π interactions along a which efficiently pack with each other. For dicamba, the steric bulk imposed by the chlorine atoms forces the methoxy group and the carboxylate group to be oriented out of the plane of the ring. As a result, the hydrogen bonded dimers are not flat, and this structure forms weakly hydrogen bonded layers which stack inefficiently. The effect of molecular planarity can be seen by comparing the Kitaigorodskii packing indices (KPIs, the ratios of volume occupied by molecules to unit cell volume).20 Salicylic acid (mp 158.2 °C), which stacks much more efficiently than dicamba (mp 114.3 °C), has a much higher KPI which is consistent with its higher melting point (Table 1). Thus, while both structures are dominated by the same strong interactions, the differences in molecular conformation lead to major differences in packing and physical properties.

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(a)

(b)

Figure 1. Intermolecular interactions in (a) dicamba and (b) salicylic acid. The figures were drawn from data in references 18 and 19.

Pairing pharmaceutical molecules, particularly carboxylic acids, with inorganic counterions is a common approach for increasing the water solubility of these molecules,21 and these typically high melting inorganic salts are also discussed briefly. Metal carboxylates possess incredible structural diversity due to the possibility for different stoichiometries, ancillary ligands, lattice solvent molecules, and other structural variables, and all their structural trends cannot be summarized here. However, a few specific dominating features are noted by comparing the known salts of [Dic]- with structurally similar [Sal]- salts. For [Dic]-, the crystallographically characterized salts include Ca(Dic)2(OH2)222 and M(Dic)2(OH2)3·2H2O (M = Mn2+, Co2+, or Zn2+).18 The crystallographically characterized [Sal]- analogs of these are Ca(Sal)2(OH2)2 and Zn(Sal)2(OH2)2.23,24 These four structures differ from each other in a number of ways; for instance, the Ca2+ salts of [Dic]- and [Sal]- are structurally very similar and have related unit cells while the Zn2+ salts differ extremely in connectivity, metal coordination environment, and overall structure. Nevertheless, there are some broad similarities that show how inorganic salts behave. Because these are divalent metal ions, they join at least two carboxylate groups close to each other through coordination to a common metal ion. Also, in all these cases reported earlier, it can be noted that there are noncovalent short contacts between [Dic]- or [Sal]- ligands bonded to different metal ions. Next, we consider the crystal structures of four salts which have been previously synthesized and characterized in the form of ionic liquids by our group,11,13,14 but were not crystallographically characterized: [N4444][Sal], [N4444][Dic], [P4444][Dic], and [P4444][H(Dic)2] 5 ACS Paragon Plus Environment


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(see Supporting Information (SI) for experimental details). We will first examine in depth the structures of [N4444][Sal] and [N4444][Dic] to understand the reason for the opposite melting point trends, as well as systematic differences in packing between the organic salts and free acid or inorganic forms. Both [N4444][Sal] and [N4444][Dic] crystallize in the space group P21/n with Z’ = 1 (Figure 2). In both cases, the entire anion is disordered over two positions (related by approximate 2-fold symmetry). This is consistent with the fact that there are no individual strong, directing interactions giving these ions a preferential orientation. It is also notable that unlike the free acids and inorganic salts, where are there are a number of homomolecular interactions such as weak hydrogen bonding and π···π interactions, [N4444][Sal] has no anion-anion short contacts (atoms in different molecules at distances less than the sum van der Waals radii) and [N4444][Dic] has only one weak anion-anion hydrogen bond). The overall packing is a charge-ordered arrangement of alternating cations and anions, where the larger size of the cation appears to generate cavities too large for the anion which leads to disorder (Figure 3).

(a)

(b)

Figure 2. ORTEP diagram (50% probability ellipsoids) of (a) [N4444][Dic] and (b) [N4444][Sal] with the anion disorder omitted for clarity.


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(a)

(b)

Figure 3. Molecular packing of (a) [N4444][Dic] down the a axis and (b) [N4444][Sal] down the b axis (green = cations, blue = anions and red= disordered anions).

The crystal structures of [N4444][Sal] (mp 92 °C) and [N4444][Dic] (mp 126.2 °C) offer insight into their different melting points relative to the free acids i.e., salicylic acid (mp 158.2 °C) and dicamba (mp 114.3 °C). In [N4444][Sal], the [N4444]+ cation is playing its designed role as a structure destabilizer. The homomolecular interactions in salicylic acid are disrupted by deprotonating it, and the size mismatch between [N4444]+ and [Sal]- gives rise to a structure with a much lower KPI. For [Dic]-, however, the conformational flexibility of the [N4444]+ cation allows it to accommodate its nonplanar conformation better than in dicamba free acid, giving rise to a slightly improved KPI. Despite the fact that strong hydrogen bonding has been eliminated, the weak interlayer interactions in free dicamba have been replaced with a large number of interionic interactions which are cumulatively stabilizing. This is interesting as it shows how the size and conformational flexibility of [N4444]+ gives rise to completely opposite effects on two structurally similar ions, triggered by a small but important difference in molecular conformation between the two. The crystal structure of [P4444][Dic] was also determined and found to be isomorphous with [N4444][Dic], however, the previously reported [P4444][Sal] is not isomorphous with its [N4444]+ analog (see SI).17 Despite being isomorphous with [N4444][Dic] (mp 126.2 °C), [P4444][Dic] (mp 64 °C) actually has a much lower melting point than the free acid (mp 114.3 °C). In this case, there is a weakening of cation-anion interactions upon going from [N4444]+ to the more delocalized [P4444]+ on the nearest connected carbons due to the lower electronegativity, as well as higher polarizability of phosphorus vs. nitrogen, but no corresponding weakening of the 7 ACS Paragon Plus Environment


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anion-anion repulsion.25 Such an observation reinforces the fact that the [N4444]+-[Dic]interactions have a significant stabilizing contribution. We have previously made [Sal]--containing ILs by adding salicylic acid to 1:1 [Sal]- salts, including the room temperature liquid [P4444][H(Sal)2]. This lowering of the melting point is presumably a result of the formation of hydrogen-bonded oligomeric anions inducing a fast proton exchange between anion and corresponding acid.11,14 By contrast, crystals of [P4444][H(Dic)2] (mp 112 °C) form spontaneously from the melt and have a melting point that is nearly as high as the free acid (mp 114.3 °C). [P4444][H(Dic)2] crystallized in the orthorhombic space group Pbcn with Z’ = 1/2. Two crystallographically equivalent [Dic]- ions are related by a center of inversion which is occupied by the acidic proton, indicating that the negative charge is either fully delocalized or disordered across both molecules. The [P4444]+ counterion sits on a crystallographic glide plane which passes through the phosphorous atom. One of the crystallographically unique butyl groups is fully ordered while the other is disordered. It can be seen from a view of the full formula unit (Figure 4a) that the cation is roughly as wide as the anion and overlaps heavily with it. Furthermore, there are additional anion-anion hydrogen bonds between benzene C-H groups and carboxylates which are not present in any of the 1:1 salts, and these lead to formation of infinite layers which pack by alternating with layers of cations (Figure 4b). The apparent better size match of [P4444]+ and [H(Dic)2]- and additional anion-anion interactions are likely the cause of the increase in melting point relative to [P4444][Dic].


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(a)

(b)

Figure 4. (a) ORTEP diagram (50% probability ellipsoids) of [P4444][H(Dic)2] and (b) its packing down the b axis (green = cations, blue = anions and red = disordered cation). While there is no crystal of [P4444][H(Sal)2],11 which is liquid at room temperature, the 1,2,3trimethylimidazolium salt of [H(Sal)2]- has been reported.26 Notably, this salt contains a low symmetry oligomeric ion where the two [Sal]- moieties have clearly distinct intermolecular environments, which was considered evidence for unsymmetric charge distribution. The complexity of the shape of [H(Sal)2]- and its packing intuitively explain why oligomeric ions of [Sal]- have lower melting points, and they contrast dramatically with the inversion-symmetric [H(Dic)2]- oligomeric anion. It is not immediately apparent why the geometries of the two oligomeric anions differ, but it nevertheless shows that increasing the size-to-charge ratio of an ion by oligomerization is not as fundamentally destabilizing to an ionic lattice as one might assume. In conclusion, direct insight into the complicated melting point trends of two families of biologically active benzoic acid-based ILs is obtained from examining their crystal structures. Organic salts show recurring features such as whole-molecule disorder and an absence of homomolecular interactions which distinguish them from both free acid forms and inorganic salts of [Sal]- or [Dic]-. The large size and conformational flexibility of quaternary ammonium and phosphonium cations leads to an important stabilizing effect for [Dic]- and [H(Dic)2]-. These effects are triggered by minor differences in the conformations of the molecules which might be difficult to predict or control. Interestingly though, the nonplanar conformation of [Dic]- is



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conserved across its structures. The crystal structure of a related imidazolium salt of [H(Sal)2]offers insight into the behavior of liquid compounds such as [P4444][H(Sal)2]. This study suggests that flexible, weakly coordinating cations are an effective tool which can dramatically change the melting points of salts of high melting biologically active acids based on an understanding of the size and shape complementarity of the ions and on the ability of these cations to enhance the repulsion between the anions. These suggest that gas phase optimized structures of biologically active molecules might be useful in predicting whether weakly interacting counterions are likely to stabilize or destabilize their crystal structures. Ultimately, the influence of even weakly interacting counterions cannot be excluded and, indeed, may prove to be a tool to access new types of structures.

ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.cgd.xxxxxxx. Experimental details on the synthesis and characterization of [P4444][Dic], [N4444][Dic], [N4444][Sal], and [P4444][H(Dic)2], differential scanning calorimetry data, ORTEP diagrams, and additional structural figures reported in the paper. Accession Codes CCDC 1588705-1588708 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

AUTHOR INFORMATION Corresponding Authors *E-mail: [email protected] ORCID Manish Kumar Mishra: 0000-0002-8193-3499 Steven P. Kelley: 0000-0001-6755-4495 Julia Leonidovna Shamshina: 0000-0003-0708-764X 10 ACS Paragon Plus Environment

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Hemant Choudhary: 0000-0003-2847-3080 Robin D. Rogers: 0000-0001-9843-7494 Present Address †

S.P.K.: Department of Chemistry, University of Missouri, Columbia, MO 65211, USA

‡

J.L.S.: Mari Signum, Ltd., 3204 Tower Oaks Boulevard, Rockville, MD 20852, USA

Notes The authors declare no competing financial interest.

ACKNOWLEDGEMENTS We thank the Natural Sciences and Engineering Research Council of Canada (NSERC) for financial support through Discovery Grant RGPIN-2016-04944. This research was undertaken, in part, thanks to funding from the Canada Excellence Research Chairs Program.

REFERENCES 1. 2. 3. 4.

Hann, M. M. Med. Chem. Commun. 2011, 2, 349-355. Desiraju, G. Angew. Chem. Int. Ed. 1995, 34, 2311-2327. Shamshina, J. L.; Kelley, S. P.; Gurau, G.; Rogers, R. D. Nature 2015, 528, 188-189. Hough, W. L.; Smiglak, M.; Rodríguez, H.; Swatloski, R. P.; Spear, S. K.; Daly, D. T.; Pernak, J.; Grisel, J. E.; Carliss, R. D.; Soutullo, M. D.; Davis, J. H., Jr.; Rogers, R. D. New J. Chem. 2007, 31, 1429-1436. 5. Dean, P. M.; Turanjanin, J.; Yoshizawa-Fujita, M.; MacFarlane, D. R.; Scott, J. L. Cryst. Growth Des. 2009, 9, 1137-1145. 6. Wilkes, J. S.; Zaworotko, M. J. Chem. Commun. 1992, 965-967. 7. Subbiah, S.; Srinivasadesikan, V.; Tseng, M. -C.; Chu, Y. -H. Molecules 2009, 14, 37803813. 8. Cieniecka-Rosłonkiewicz, A.; Pernak, J.; Kubis-Feder, J.; Ramani, A.; Robertson, A. J.; Seddon, K. R. Green Chem. 2005, 7, 855–862. 9. Kelley, S. P.; McCrary, P. D.; Flores, L. A.; Garner, E. B., III; Dixon, D. A.; Rogers, R. D. ChemPlusChem 2016, 81, 922-925. 10. Winterton, N. “Crystallography of Ionic Liquids.” In Ionic Liquids Completely unCOILed: Critical Expert Overviews, Plechkova, N. V.; Seddon, K. R., Eds.; Wiley: Hoboken, 2015, pp. 231-534. 11. Bica, K.; Rogers, R. D. Chem. Commun. 2010,46,1215-1217. 12. Choudhary, H.; Pernak, J.; Shamshina, J. L.; Niemczak, M.; Giszter, R.; Chrzanowski, Ł.; Praczyk, T.; Marcinkowska, K.; Cojocaru, O. A.; Rogers, R. D. ACS Sustainable Chem. Eng. 2017, 5, 6261-6273. 13. Cojocaru, O. A.; Shamshina, J. L.; Gurau, G.; Syguda, A.; Praczyk, T.; Pernak, J.; Rogers, R. D. Green Chem. 2013, 15, 2110-2120.



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14. Bica, K.; Rijksen, C.; Nieuwenhuyzena, M.; Rogers, R. D. Phys. Chem. Chem. Phys. 2010, 12, 2011-2017. 15. Kramer, V. J.; Ouse, D. G.; Pearson, N. R.; Tank, H.; Zettler, M.W. US2008/0207452A1. 16. Ławniczak, Ł.; Syguda, A.; Borkowski, A.; Cyplik, P.; Marcinkowska, K.; Wolko, Ł.; Praczyk, T.; Chrzanowski, Ł.; Pernak, J. Sci. Total Environ. 2016, 563-564, 247-255. 17. Ando, T.; Kohno, Y.; Nakamura, N.; Ohno, H. Chem. Commun. 2013, 49, 10248-10250. 18. Smith, G.; O'Reilly, E. J.; Kennard, C. H. L. Aust. J. Chem. 1983, 36, 2175-2183. 19. Montis, R.; Hursthouse, M. B. CrystEngComm 2012, 14, 5242-5254. 20. Kitaigorodskii, A. I. Molecular Crystals and Molecules; Academic Press: New York, 1973; pp. 18-21. 21. Stahl, P. H.; Wermuth, C. G. In Handbook of Pharmaceutical Salts; Stahl, P. H., Wermuth, C. G., Eds.; Verlay Helvetica Chimica Acta & Wiley-VCH: Zurich, 2008. 22. Kennard, C. H. L.; Kerr, B.; O’Reilly, E. J.; Smith, G. Aust. J. Chem. 1984, 37, 1757-1761. 23. Debuyst, R.; Dejehet, F.; Dekandelaer, M. -C.; Declercq, J. -P.; Meerssche, M. V. J. Chim. Phys. Phys. Chim. Biol. 1979, 76, 1117-1124. 24. Klug, H. P.; Alexander, L. E.; Sumner, G. G. Acta Cryst. 1958, 11, 41-46. 25. Dean, P. M.; Pringle, J. F.; MacFarlane, D. R. Phys. Chem. Chem. Phys., 2010, 12, 91449153. 26. Kelley, S. P.; Narita, A.; Holbrey, J. D.; Green, K. D.; Reichert, W. M.; Rogers, R. D. Cryst. Growth Des. 2013, 13, 965-975.


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For Table of Contents Use Only

Can Melting Point Trends Help Us Develop New Tools to Control the Crystal Packing of Weakly Interacting Ions? Manish Kumar Mishra,a,b Steven P. Kelley,a,b,† Julia Leonidovna Shamshina,a,‡ Hemant Choudharya,b and Robin D. Rogersa,b,c* a

Department of Chemistry, McGill University, 801 Sherbrooke St. West, Montreal, QC H3A

0B8, Canada. b c

Department of Chemistry, The University of Alabama, Tuscaloosa, AL 35487, USA

525 Solutions, Inc., P.O. Box 2206, Tuscaloosa, AL 35403, USA

Present Address †

S.P.K.: Department of Chemistry, University of Missouri, Columbia, MO 65211, USA

‡

J.L.S.: Mari Signum, Ltd., 3204 Tower Oaks Boulevard, Rockville, MD 20852, USA

*E-mail: [email protected]

Synopsis: Analysis of the crystal structures of biologically active free acids and their salts of flexible, weakly interacting cations allow the rationalization of melting point trends.


Can Melting Point Trends Help Us Develop New ... - ACS Publications

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