A Supramolecular Approach to Organic Alloys: Cocrystals and Three‐ and Four‐Component Solid Solutions of 1,4‐Diazabicyclo[2.2.2]octane and 4‐X‐Phenols (X=Cl, CH₃, Br)

Abstract

Herein, we describe the preparation of binary cocrystals and ternary and quaternary solid solutions of 1,4-diazabicyclo-[2.2.2]octane (DABCO) and 4-X-phenols (X = Cl, CH 3 , Br). Multicomponent solids, be they cocrystals or solid solutions, are materials that may exhibit new or superior functionalities relative to the individual components.[1] Though molecular complexes have been studied for a long time, [1][2][3] the design of cocrystals containing more than two different components remains a challenging task.[4] Except for a few notable contributions, [5] most studies on organic cocrystals led only to the formation of binary organic solids.[1] In contrast, metals and inorganic compounds readily form multicomponent solids in the form of solid solutions.[6] Creating multicomponent solid solutions of organic molecules, however, is challenging because these molecules possess intricate shapes and participate in directional intermolecular interactions. [3] Not surprisingly, most molecule-based solid solutions contain only two components. [7] We describe a supramolecular approach for the preparation of solid solutions that contain three or more organic molecules. The principal advantage of solid solutions is that their properties can be modulated by the gradual modification of the relative ratio of the components.[8]Scheme 1 shows our approach to the formation of organic alloys. We begin with a trimolecular motif wherein a central molecule (A) is connected to two peripheral molecules (B or C) through similar intermolecular interactions. If the two peripheral molecules are identical, the binary cocrystals AB 2 or AC 2 are formed. If they are different, a ternary cocrystal BAC or a ternary solid solution A(B n C 1Àn ) 2 (0 < n < 1) can be formed, depending on the similarity of the sizes and shapes of the peripheral molecules. Adding another isosteric component (D) can lead to a quaternary solid solution A(B n C m D p ) 2 (n + m + p = 1, 0 < n, m, p < 1).We use DABCO as the central molecule and 4-X-phenols (X = Cl, CH 3 , Br) as the peripheral molecules (Scheme 2). The chloro, methyl, and bromo substituents of the 4-Xphenols have similar shapes and comparable sizes (20, 24, and 28 3 ), [9] and do not interfere with the O À H···N hydrogen bonding required for the trimolecular assembly. We surmised that the size, shape, and chemical similarity of the 4-Xphenols would enable the formation of solid solutions upon crystallization of DABCO with two or three of the phenols. We call these crystalline materials supramolecular solid solutions because their repeat unit is a trimolecular assembly.[10]Single crystals of binary cocrystals and of ternary and quaternary solid solutions (having equimolar ratios of phenols) suitable for X-ray diffraction were grown from benzene solutions (Table 1; Scheme 2).[11] The binary cocrystals ClCl and MeMe are isostructural; [12] Figure 1 a shows the structure of ClCl. The unit cell of MeMe is larger than that of ClCl, in accordance with the larger size of the methyl groups relative to the chlo...

Probing the Crystal Structure Landscape by Doping: 4‐Bromo, 4‐Chloro, and 4‐Methylcinnamic Acids

“…[9] We have shown in ar ecent report that partial fluoro-substitution, achieved in SS of fluorocinnamic acids,c an serve as af iner probe into the landscape of unsubstituted cinnamic acid than the coarser full fluorosubstitution. [14] However, their very different electronic nature could change this outcome and this is what makes them an attractive test pair in the present context. Thebromine (Br) atom and the methyl (Me) group,with their closeness of volume (24.4 and 24 3 respectively), have the potential to be exchanged in crystal structures without bringing about any deep-seated changes,i fo nly geometrical effects are important.…”

“…Thebromine (Br) atom and the methyl (Me) group,with their closeness of volume (24.4 and 24 3 respectively), have the potential to be exchanged in crystal structures without bringing about any deep-seated changes,i fo nly geometrical effects are important. [14] However, their very different electronic nature could change this outcome and this is what makes them an attractive test pair in the present context. Profiling the landscape of abrominated molecule presents an additional challenge because of the anisotropy and polarizability of the Br atom and the resultant computational difficulties associated with it.…”

Systematic synthesis of a 6-component organic-salt alloy of naftopidil, and pentanary, quaternary and ternary multicomponent crystals

“…Furthermore, this is the first report of six different molecular components for an organic-salt alloy of an active pharmaceutical ingredient solved and refined by singlecrystal X-ray diffraction. Binary, ternary and even quaternary cocrystals have been reported by several research groups during the past three decades (Reddy et al, 1994;Thakur et al, 2010;Sada et al, 2005;Hasell et al, 2012;Tothadi et al, 2017;Dabros et al, 2007;Allu et al, 2017). The bar was raised by Desiraju with the synthesis of 4-and 5-component molecular assemblies in 2016 (Mir et al, 2016;Dubey et al, 2016), and now a 6-component molecular solid (Paul et al, 2018) has been achieved by combining the design strategies of cocrystals and solid solution.…”

Creation of a ternary complex between a crown ether, 4-aminobenzoic acid and 3,5-dinitrobenzoic acid

“…However, it does require the two binding sites of the bridging molecule to be able to distinguish successfully between the two other components and reduce the potential for the formation of a 2:1 composition binary co-crystal. This has been achieved by the use of hydrogen-bond acceptor/ donor sites of differing strengths, and second and third components of differing strengths (Aakerö y et al, 2001(Aakerö y et al, , 2006(Aakerö y et al, , 2007Aakerö y & Salmon, 2005;Bhogala et al, 2005;Tan et al, 2006;Dabros et al, 2007;Bhogala & Nangia, 2008), or by the use of differing but complementary types of interaction such as charge transfer and hydrogen bonding (Thomas et al, 2010;. Examples of the second approach are rarer but the creation of co-crystal frameworks with interchangeable solvent molecules in the lattice has been demonstrated (Friščić et al, 2006).…”