Communication pubs.acs.org/crystal
Significant Expansion of the Solid State Landscape of Salicylic Acid Based on Charge-Assisted Hydrogen Bonding Interactions Published as part of the Crystal Growth & Design virtual special issue IYCr 2014 - Celebrating the International Year of Crystallography Benyong Lou,#,†,‡ Sathyanarayana R. Perumalla,#,† and Changquan Calvin Sun*,† †
Department of Pharmaceutics, University of Minnesota, 308 Harvard Street S.E., Minneapolis, Minnesota 55455, United States Department of Chemistry and Chemical Engineering, Minjiang University, Fuzhou, Fujian 350108, China
‡
S Supporting Information *
ABSTRACT: Successful cocrystallization between a salicylate salt with salicylic acid and chemically distinct carboxylic acids suggests the robustness of the carboxylic acidcarboxylate supramolecular synthon. This type of robust synthon involving charge-assisted hydrogen bonding interactions has the potential to significantly expand the solid-state landscape of ionizable molecules.
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serendipity,13 their systematic design has historically lagged. Recently, we have made systematic efforts to cocrystallize conjugate acid−base (CAB) pairs of organic molecules based on charge-assisted short strong hydrogen-bonds, which may be termed CAB synthons.14 There have been many known examples of CAB cocrystals that were mostly synthesized by serendipity. A search of the CSD database returned at least 115 unique CAB cocrystals (see Table S1, Supporting Information). Such CAB synthons are robust because of the exceptional strength of charge-assisted hydrogen bonds formed between a CAB pair, e.g., −COO−···HOOC- or NH+···N.15 Compared to conventional salts of some common molecules, CAB cocrystals exhibit improved material properties, such as chemical stability, physical phase stability, hygroscopicity, and improved purification efficiency.14b,c Although promising, the design of new CAB cocrystals for fine-tuning crystal properties is limited by the prerequisite of two species structurally differing only by one proton, which restricts chemical diversity in cocrystal formation. To overcome this limitation, we hypothesize that, provided the chargeassisted hydrogen bonding is sufficiently strong, it is possible to maintain the CAB synthon while allowing chemical diversity in the cocrystal former. Such a synthon may be called a pseudo CAB synthon. Using the pseudo CAB synthon approach, we
he design and synthesis of new crystal forms for improving materials properties is an important area of research with applications ranging from functional materials to drug delivery.1 Crystal engineering is an effective means for fine-tuning crystal properties through systematic variations in crystal structures, and the range of accessible crystal properties directly depends on the number of available solid forms. Therefore, any new crystal engineering strategy to expand the solid state landscape of a molecule will have a great impact in materials research. A versatile and common strategy for obtaining new solid forms of a given molecule involves the formation of new molecular complexes, such as salts and cocrystals.2−5 Salt formation has remained the primary choice for easily ionizable acids and bases. Cocrystallization represents an emerging crystal engineering approach for modifying structures and properties of molecular solids. In the past few decades, a variety of cocrystals have been designed by exploiting various hydrogen-bonded supramolecular synthons.6−9 In principle, salt formation involves proton transfer between an acid and a base but cocrystallization does not. However, a clear distinction between organic salt and cocrystal is difficult to make when the neutral and ionic molecules cocrystallize to form a class of materials known as ionic cocrystals or salt cocrystals. Examples of ionic cocrystals include those between organic amine hydrochloride salts and neutral carboxylic acids,10 simple inorganic salts and neutral organic molecules,11 as well as an organic molecule and its own salts.12 Although ionic cocrystals have existed for a long time and have often been discovered by © XXXX American Chemical Society
Received: October 8, 2014 Revised: November 10, 2014
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dx.doi.org/10.1021/cg501496a | Cryst. Growth Des. XXXX, XXX, XXX−XXX
Crystal Growth & Design
Communication
hydrogen-bonding with the carboxylate (2.5055(13) Å, 154.3(18)°). The two molecules interact mainly through a strong N+−H···O- hydrogen-bond (2.6612(13) Å, 179.9(19)°) and stabilized by an auxiliary C−H···O − interactions (3.2482(15) Å, 127.8°) between Sac− carboxylate and Dmap pyridyl ring to form a R22(7) hydrogen bonding synthon. This makes DmapH+ and Sac− roughly coplanar (Figure 1).
can significantly increase the number of accessible crystalline phases of a given acid or base (Scheme 1). In this strategy, salts Scheme 1. Strategies To Expand Solid State Landscape of Moleculesa
Figure 1. Basic building unit of salt 1.
In 2, a similar DmapH+-Sac− unit with a strong N+−H···O− hydrogen-bond (2.7292(14) Å, 172.8(17)°) exists. However, the C−H···O− interactions between DmapH+ and Sac− is replaced with a strong O−H···O− hydrogen bond (2.5453(13) Å, 169(2)°) between Sac− and the second SacH. DmapH+ is oriented nearly perpendicular to Sac−, instead of being coplanar as in 1. Thus, 2 (DmapH+-Sac−-SacH) is a CAB cocrystal (Figure 2). In 3, the DmapH+-Sac− unit with strong N+−H···O− hydrogen-bond (2.7785(16) Å, 152(2)°) also exists along with the strong hydrogen-bond (2.5482(14) Å, 174(3)°) between −COO− of Sac− and −COOH of BzH (pseudo CAB synthon) (Figure 2). The crystal structure of 4 (not shown) is closely similar to that of 3, where −COO− of Sac− and −COOH of ClBzH similarly interact through a pseudo CAB synthon (2.5140(13) Å, 173(2)°) without significantly disturbing the DmapH+-Sac− interaction in 3 (Figure 2). The hydroxyl group on the aromatic ring of 4-hydroxybenzoic acid is a strong hydrogen bond donor and therefore can be used to further probe the stability and robustness of the O−H···O− pseudo CAB synthon. In the basic unit of crystal 5, a pseudo CAB synthon (2.5449(12) Å, 172.5(18)°) between the −COOH of OHBzH and −COO− of Sac− is observed (Figure 2). The hydroxyl group on OHBzH is satisfied through forming a hydrogen bond (2.6717(13) Å, 171.1(18) °) with the carboxylic groups of OHBzH in an adjacent basic unit, resulting in a one-dimensional (1D) hydrogen-bonded chain which stacks to form a packing structure stabilized by C−H···O weak interactions. The relative orientations of the three components in the basic three-member building unit of crystals 2−4 are similar, but the hydrogen bonding patterns slightly differ (Figure 2). In 2, SacH is hydrogen-bonded to the carboxylate O of Sac−, participating in an intramolecular hydrogen-bond with a hydroxyl group. However, BzH and ClBzH in 3 and 4 interact with the carboxylate O of Sac− that does not form an intramolecular hydrogen bond (Figure 2). In 2, the Dmap pyridyl ring in the basic building unit undergoes complementary C−H···O interaction (3.1607(16) Å, 142.3°) with carboxylic O of SacH in an adjacent basic unit to form a bricklike six-component structural unit (Figure 3a). The other C− H···O hydrogen bonds result in a packing structure based on a 2D layer in which all hexamer units have the same orientations (Figure 3b).
a
Pseudo CAB cocrystals significantly expand available crystalline phase of a given molecule over conventional salts and CAB cocrystals.
of an organic molecule cocrystallize with structurally related but chemically distinct neutral molecules through charge-assisted strong hydrogen bonding interactions. A search of CSD for structures containing carboxylic acid, carboxylate, and N−H yielded only one serendipitous structure that contains the pseudo CAB synthon.16 Although other pseudo CAB cocrystals possibly exist, a clear design strategy as mentioned above has not been published to our knowledge. To illustrate this new cocrystal design strategy based on the pseudo CAB synthon, we have chosen salicylic acid (SacH), an aromatic monocarboxylic acid (pKa = 2.98). For SacH, a salt with 4-dimethylamino pyridine (Dmap, pKa = 9.58), 1 (DmapH+-Sac−), a CAB cocrystal, 2 (DmapH+-Sac−-SacH), are expected because of the large difference in pKa (ΔpKa = 6.6). A Dmap salt of nitrofurantoin has been recently described.17 When the ΔpKa is much smaller (e.g.,
