Consistency and variability of cocrystals containing positional isomers: the self-assembly evolution mechanism of supramolecular synthons of cresol-piperazine

Abstract

The disposition of functional groups can induce variations in the nature and type of interactions and hence affect the molecular recognition and self-assembly mechanism in cocrystals. To better understand the formation of cocrystals on a molecular level, the effects of disposition of functional groups on the formation of cocrystals were systematically and comprehensively investigated using cresol isomers (o-, m-, p-cresol) as model compounds. Consistency and variability in these cocrystals containing positional isomers were found and analyzed. The structures, molecular recognition and self-assembly mechanism of supramolecular synthons in solution and in their corresponding cocrystals were verified by a combined experimental and theoretical calculation approach. It was found that the heterosynthons (heterotrimer or heterodimer) combined with O-H⋯N hydrogen bonding played a significant role. Hirshfeld surface analysis and computed interaction energy values were used to determine the hierarchical ordering of the weak interactions. The quantitative analyses of charge transfers and molecular electrostatic potential were also applied to reveal and verify the reasons for consistency and variability. Finally, the molecular recognition, self-assembly and evolution process of the supramolecular synthons in solution were investigated. The results confirm that the supramolecular synthon structures formed initially in solution would be carried over to the final cocrystals, and the supramolecular synthon structures are the precursors of cocrystals and the information memory of the cocrystallization process, which is evidence for classical nucleation theory.

Keywords: co-crystals; cocrystal consistency; cocrystal variability; density functional theory; hydrogen bonding; intermolecular interactions; lattice energy; quantum chemistry; supramolecular synthons; theoretical calculations.

Figure 1

The crystal structure, packing model and intermolecular interactions of MC_PP. (a) Unit cell of MC_PP. (b) 3D supramolecular packing model in the supercell with 4 × 1 × 1. (c) LSAM (1D) constructed by amalgamation of Synthon I (supramolecular synthon highlighted in purple interacting via O—H⋯N hydrogen bonds) and Synthon II (supramolecular synthon highlighted in green interacting via N—H⋯π hydrogen bonds). (d) Two-dimensional LSAM structure (highlighted in red) constructed by an arrangement of the LSAMs (1D) along the oac plane. Purple dotted lines and blue dotted lines represent π⋯H and O—H⋯N hydrogen bonding, respectively.

Figure 2

Supramolecular synthons used for the recognition in the cresol isomer cocrystals.

Figure 3

Characteristic absorption peaks corresponding to solid FTIR data (dotted black curve for MC_PP, red for MC and blue for PP), liquid ATR-FTIR data (solid black curve for MC_PP trimer, red for MC, blue for PP in toluene, and gray dotted curve for pure toluene) and the computational results in toluene (light purple vertical line for t(MCPP) in toluene solution and light gray vertical line for the t(PI_MCPP) in toluene solution). Symbols: ν: stretching, δ: in-plane bending; (superscripts) L: ATR-FTIR data; S: FTIR data; cal: computational data; (subscripts) as: antisymmetric.

Figure 4

¹H NMR spectra of MC_PP, MC and PP in toluene-d ₈. ¹H NMR (MC_PP, 500 MHz, toluene-d ₈, 25°C, TMS): δ = 7.07 (t, 2 H; = CH-), 6.63 (ddd, 6 H; = CH-), 4.90 (s, 4 H; OH+NH), 2.31 (s, 8 H; CH₂), 2.18 ppm (s, 6 H; CH₃). ¹H NMR (MC, 500 MHz, toluene-d ₈, 25°C, TMS): δ = 6.94 (dd, 1 H; = CH-), 6.56 (d, 1 H; = CH-), 6.35 (dd, 1 H; = CH-), 6.30 (s, 1 H; = CH-), 4.10 (s, 1 H; OH), 2.06 ppm (s, 3 H; CH₃). ¹H NMR (PP, 500 MHz, toluene-d ₈, 25°C, TMS): δ = 2.54 (m, 4 H; = CH₂-), 0.91 (s, 1 H; NH).

Figure 5

Changing trends of Raman and ATR-FTIR data during the cooling crystallization process of trimer verification experiments for MC_PP. R: Raman data; IR: ATR-FTIR data.

Figure 6

ESP-mapped molecular vdW surface of cresol isomers, a PP molecule and synthons with the ratio of 1:1. (a) MC ESP, (b) MC1PP ESP, (c) OC ESP, (d) OC1PP ESP, (e) PC ESP, (f) PC_PP ESP, (g) PP ESP and (h) deformation of PP molecules in three cocrystals: the PP molecule in PC_PP is green, the PP molecule in MC_PP is yellow, the PP molecule in OC_PP is red and the single free PP molecule is black. Compared with the red, yellow and black structure, the green structure shows more obvious deformation (units: kcal mol⁻¹). Surface local minima and maxima of ESP are represented as cyan and orange spheres, respectively. The global minimum and maximum values are italic.