Effect of Preorganization on the Polymorphism and Cocrystallization of a Squaramide Compound Rafel Prohens,* ,† Anna Portell, † and Xavier Alcobe ́ ‡ † Unitat de Polimorfisme i Calorimetria and ‡ Unitat de Difracció de Raigs X, Centres Científics i Tecnolò gics, Universitat de Barcelona, Baldiri Reixac 10, 08028 Barcelona, Spain * S Supporting Information ABSTRACT: A squaramido-based model compound with the ability to establish an intramolecular hydrogen bond has been designed to study the effect of preorganization on its polymorphism and the cocrystallization with resorcinol. Three out of the four expected supramolecular synthons have been observed in two polymorphs and two cocrystals with resorcinol, whose crystal structures have been solved from X-ray diffraction laboratory data using direct-space strategies. ■ INTRODUCTION The attention that crystal engineering has received in the last years is due mainly to the impact that novel crystalline materials are having in fields such as supramolecular chemistry or pharmaceutical sciences in terms of improved drug properties and intellectual property. 1 The rational design of new crystalline supramolecular structures has been traditionally based on supramolecular synthons, which is a probabilistic model that takes into account only the degree of occurrence of a particular pattern of interaction. 2 Supramolecular synthons can be defined as arrangements of intermolecular noncovalent interactions with a highly occurring frequency in crystal structures. This concept is applied in supramolecular synthesis in such a manner as synthons are in covalent synthesis. 3 Therefore, a deep knowledge of the preference for a particular synthon exhibited by a family of compounds can be used to design new supramolecular crystalline materials. This strategy has been applied successfully in numerous examples. 4 Recently we have experimentally and computationally described the cooperative induction in self-assembled squar- amides to explain the preference of this family of compounds for chains versus ribbons in the solid state. 5 Moreover, this phenomenon explains why this strong homosynthon has resulted to be resistant against double donor H-bonding compounds such as resorcinol. However, it is well-known that the presence of competing H-bond donor/acceptors in the same molecule can affect the resulting synthons in the crystal. In this paper, we decided to study the effect that bringing an intramolecular interaction by introducing an extra H-bond acceptor can have over the resulting intermolecular synthons in a bis squaramide-esther model compound, and in particular to check the feasibility of breaking the omnipresent head-to-tail synthons in squaramides through cocrystallization with H- bonding donors. ■ EXPERIMENTAL SECTION Materials. Diethylsquarate (98%) was purchased from Sigma- Aldrich. Synthesis of 1. Compound 1 was readily prepared from addition of 1,4-bis(3-aminopropyl)piperazine (0.68 g, 3.4 mmol) dissolved in diethyl ether (60 mL) to a solution of diethylsquarate (1.72 g, 10.1 mmol) (Sigma Aldrich) in diethyl ether (10 mL). The amine was added dropwise during 3 h, under argon atmosphere, and it was stirred overnight. A white solid precipitated immediately. The solid was filtered and washed with diethyl ether (3 × 10 mL), and it yielded 87%. 6 1 H-NMR (CDCl 3 , 400 MHz) δ: 8.21 (br, 1H), 8.01 (br, 1H), 7.94 (br, 1H), 7.75 (br, 1H), 4.76 (q, 4H, J = 8 Hz), 3.82 (m, 2H), 3.60 (m, 2H), 2.61 (m, 12H), 1.79 (m, 4H), 1.46 (t, 6H, J = 8 Hz) ppm. 13 C-NMR (CDCl 3 , 400 MHz) δ: 189.8, 182.2, 173.0, 69.6, 57.7, 53.1, 45.7, 25.1, 16.1 ppm. MS (TOF) m/z (%): (M - I + ) 449. X-ray Powder Diffraction. Laboratory X-ray powder diffraction data for the solids obtained were collected at ambient temperature in a Panalytical X’Pert PRO MPD capillary configuration (0.7 mm diameter capillary); focusing elliptic mirror; Cu Kα1,2, λ = 1.5418 Å; 0.01 radians Soller slits; PIXcel detector, active length 3.347°;2θ range, 2°-70°, step size, 0.013°, data collection time, 60 h. After indexing using DICVOL04 7 and space group assignment, the structure was solved using the program FOX, 8 followed by Rietveld refinement using FullProf. 9 Differential Scanning Calorimetry (DSC). Experiments to define the multiphase system were performed in a Mettler-Toledo DSC-822e calorimeter. The samples were placed in aluminum crucibles of 40 μL Received: May 29, 2012 Revised: July 20, 2012 Published: July 23, 2012 Article pubs.acs.org/crystal © 2012 American Chemical Society 4548 dx.doi.org/10.1021/cg300727r | Cryst. Growth Des. 2012, 12, 4548-4553