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

The consistency and variability as well as self-assembly evolution mechanism of cresol–piperazine cocrystals are investigated by experiments and molecular simulation.

all systems was decreased to the final experimental temperature at a cooling rate of 0.05 °C /min. PAT monitoring will be stopped after these systems reaches stability at the final temperature. Additionally, when sufficient supersaturation is achieved at certain temperature (37.5 °C for MC + PP and 31 °C for OC + PP, respectively), about 0.05g crystal seeds will be added to the crystallizer to induce nucleation, except for the "PC + PP" experiment. During these experiments, Raman and ATR-FTIR spectroscopic analysers were applied in combination to in-situ monitor the formation process of (m-, o-, p-) cresol-piperazine cocrystals. The final products were also analyzed by PXRD, DSC, FTIR, Raman and 1 H NMR.

Figure S2
The experimental conditions for the cocrystallization process monitored by PAT tools.

S3.1.1. Crystal structures and molecular arrangements
In MC_PP cocrystal, obtained by cocrystallizing PP and MC molecules, PP molecules occupy all the eight vertices and all six face-centers of the cuboid cell, while MC molecules fill in the void positions in the unit cell, as shown in Figure 1a). The PP molecules mainly distributes on the XY-plane (or OAB-plane), and two layers of MC molecules (two yellow molecular layers) with opposite stacking direction, such as the filling of sandwich biscuit, are filled between the two opposite PP molecular chains (two green molecular chains), as shown in Figure 1b). Along the z-axis (or oc-axis), two adjacent MC molecules layers interacting with different PP molecules layers are arranged in a herringbone-type fashion (the yellow sticky molecules), while the two MC molecules interacting with the same PP molecule are on two mutually parallel planes, connected by strong hydrogen bonding assemble into corrugated close-packing two-dimension LSAM (LSAM (2D)), as shown in Figure   1d). And the 2D LSAMs are symmetrically inverted V-shape. There is no obvious interaction between the parallel MC molecules (molecules 1 and 1, or molecules 1' and 1'), so is the parallel PP molecules (molecules 2 and 2). As shown in Figure 1c) and d), the three molecular chains consisting of molecules MC (1), molecules MC (1') and molecules PP (2) respectively, are parallel to each other.
Moreover, four MC molecules perfectly surround the PP molecule, preventing the interaction between the second PP molecule with this PP molecule. The types of supramolecular synthons and intermolecular interaction are summarized in Table 1, and all the intermolecular interactions analyzed in this part are also verified by the following Hirshfeld surface (HS) analysis.
In the cocrystal of OC_PP formed by one PP molecule and two OC molecules, the crystal structure, the packing model and supramolecular synthons are almost identical to MC_PP cocrystal, although they belong to different crystal systems (OC_PP cocrystal belonging to monoclinic system and MC_PP cocrystal belonging to orthogonal system, respectively), as shown in Table S2 and Figure   S3. PP molecules occupy all the eight vertices and body-center of the cuboid cell, while OC molecules fill in the void positions in the unit cell, as shown in Figure S3a). There are also two types of vertically arranged supramolecular synthons, composed of one PP molecule and two OC   In OC_PP cocrystal, PP molecules occupy all the eight vertices and body-center of the cuboid cell, while OC molecules fill in the void positions in the unit cell, as shown in Figure S3a). The PP molecules mainly distribute on the XZ-plane (or OAC-plane), and only one layer of OC molecules (one yellow molecular layer), such as the filling of sandwich biscuit, are filled between the two opposite PP molecular chains (one PP molecular chain with green highlighted and one PP molecular chain without thickened and highlighted), as shown in Figure S3b). In adjacent two OC molecules layers along the z-axis (or oc-axis), the molecules in different layers are not arranged in parallel, but arranged with a certain dihedral angle, as shown in Figure S3b). In addition, there are also two types  Figure S3c). The LSAMs (1D) assemble into corrugated close-packing two-dimension LSAM (LSAM (2D)), as shown in Figure S3d), and the 2D LSAMs are in a twisted inverted V-shape. There is no obvious interaction between the parallel OC molecules (molecules 1 and 1, or molecules 1' and 1'), so is the parallel PP molecules (molecules 2 and 2). As shown in Figure S3c) and d), the three molecular chains consisting of molecules OC (1), molecules OC (1') and molecules PP (2) respectively, are parallel to each other. Four OC molecules perfectly surround the PP molecule, preventing the interaction between the second PP molecule with this PP molecule. The types of supramolecular synthons and intermolecular interaction are summarized in Table 1.
In the unit cell of 1:1 PC_PP cocrystal, all the molecules are packed into the cell of the cuboid, and no molecules occupy the feature location, e.g. vertices, body-centers and face-centers, as shown in Figure S4a). The PP molecules mainly distributes on the XY-plane (or OAB-plane), and two layers of PC molecules (one yellow sticky PC layer and one ball-stick PC molecule layer), like the filling of sandwich biscuit, are filled between the two opposite PP molecular chains (two green PP molecular chain with highlighted), as shown in Figure S4b). The PP molecules are connected end to end along the y-axis (or ob-axis), forming a corrugated chain, which runs through the entire crystal, as shown in Figure S4b) and S4d), and the PC molecules are connected at the bend of the zigzag chains, vertical to the PP molecule, as shown in Figure S4c). On the same PP corrugated chain formed by N(1)-H(1)···N(2) between two different PP molecules, one PC molecule (molecule 1) and two mutually parallel but unconnected PP molecules (molecule 2 and 3) interact by hydrogen bonding O(1)-H(1D)···N(1) and N(2)-H(2)···π, respectively, as shown in Figure S4c) and S4d). Nevertheless, there is no apparent and direct weak interaction between two adjacent (molecule 1 and 1') and/or parallel (molecule 1 and 1) PC molecules, as shown in Figure S4c). Two adjacent PP chains has no other strong interaction except for van der Waals interaction. In two adjacent PC molecules layers along the z-axis (or oc-axis), the molecules in different layers between the two PP chains are not arranged in parallel, but arranged with a certain dihedral angle, as shown in Figure S4b). The structural features and conformations of PC_PP cocrystal are apparently different from OC_PP cocrystal and MC_PP cocrystal and so are the interactions. The asymmetric unit of PC_PP cocrystal contains one PP molecule and one PC molecule, as shown in Table S2 and Figure S4. Particularly, it is worth noting that there are three different supramolecular synthon modes in PC_PP cocrystal compared to the MC_PP and OC_PP cocrystals: expect for the two heterosynthons formed by PP and PC molecules interacted with O(1)-H(1D)···N(1) (named as PC_PP, synthon I) and the N(2)-H(2)···π ( named as PI_PC_PP, synthon II), respectively, another homosynthon is also formed by two PP molecules interacted with N(1)-H(1)···N (2), named as PP2 (synthon III), as shown in Table   1 and Figure S4. Another unique feature is that the PP molecules are connected end to end, forming a corrugated chain, which runs through the entire crystal. And no molecules occupy the vertices, facecenter and body-center of the cuboid unit cell.
What is more, different from the MC_PP and OC_PP cocrystals, three types of supramolecular interaction are also summarized in Table 1.

S3.1.2. Hirshfeld surface (HS) analysis and intermolecular interaction modes
Hirshfeld surface (HS) analysis is a useful tool for the quantitative analysis and an unbiased identification for fundamental discussion of the intermolecular interactions of all close contacts. Since the Hirshfeld surface is the electron density isosurface defined by the molecule and the proximity of IUCrJ (2019). 6, doi:10.1107/S2052252519012363 Supporting information, sup-10 its nearest neighbours, it can provide direct insight into intermolecular interactions in crystals (Spackman & Jayatilaka, 2009;Spackman et al., 2008;Ravat et al., 2015). The Hirshfeld surface emerged from an attempt to define the space occupied by a molecule in a crystal for the purpose of partitioning the crystal electron density into molecular fragments (Spackman & Byrom, 1997).
Generally, molecular Hirshfeld surfaces can be constructed by partitioning space in the crystal into regions where the electron distribution of a sum of spherical atoms for the molecule (the promolecule) dominates the corresponding sum over the crystal (the procrystal) (McKinnon et al., 2004). Using the HS analysis, a comparative analysis of intermolecular interaction in clusters and monomers was performed. The results are shown in Figure S5, and Table 1.  is for PC_PP cocrystal, respectively. respectively, as shown in Figure 3. As to OC_PP cocrystal formation, the ATR-FTIR peak at 1174 cm -1 (ν C-O ) was chosen to represent OC, peak at 1137 cm -1 (ν as(C-N) ) was chosen to represent liquid PP and peak at 1252 cm -1 (ν C-O ) was chosen to represent t(OCPP), respectively. And as to PC_PP cocrystal formation, the ATR-FTIR peak at 1602 cm -1 (ν C=C , Ring ) was chosen to represent PC, peak at This effect makes the protons involved in hydrogen bonding more exposed than those which do not are similar to those of MC_PP cocrystal, as shown in Figure S8 and Table S3. Meanwhile, the area of characteristic peaks was normalized to obtain the stoichiometric ratio of the heterosynthons in toluene solution. The results are shown in Table S3.  : Normalized values compared with the standard peak is processed by MestReNova software. In this process, the peak of TMS was selected as the standard peak.

S3.2.1. IR features of various synthons
c : Normalized values at the same concentration compared with the standard peak. (Wang et al., 2017) d : Standard peak, and the normalized value of the standard peak is 1.00.

S3.2.4. Intermolecular interaction energy of synthons.
From Table 2, it can be seen that the interaction energies of all types of supramolecular synthons in the toluene solvent are higher than those of the corresponding synthons in gas-phase, which indicates that the solvation layers formed around a single molecule hinder the formation of hydrogen bonding and are not conducive to the formation of hydrogen bonding between two molecules. When the solvated molecules interact with each other to form dimers or trimers, the repulsive interaction of the solvation layers must be overcome first. In addition, the interaction energies of the heterodimers or

II(MC_PP) ≈ II(OC_PP)
. This is most likely related to the number of interacting cresol molecules with PP molecules and the reasons would be explained later. Meanwhile, the lattice energy of PC_PP cocrystal is also the largest, resulting in the melting point of it higher than the MC_PP cocrystal and OC_PP cocrystal, as shown in Figure S11, and it can also be inferred that the PC and PP molecules in PC_PP cocrystal are more closely packed.
S3.2.5. Verification of evolution path of hetero-dimers and/or trimers during cocrystal formation by PAT tool Figure S9 Changing trends of Raman and ATR-FTIR data during cooling crystallization process of trimer verification experiments for OC_PP cocrystal.
(R: Raman data, IR: ATR-FTIR data) As can be seen from the PAT profiles, when the clarified solutions were cooled down to a certain temperature, the supersaturation of the heterodimers or heterotrimers were accumulated enough to nucleate (from B to C). Hence, the relatively ATR-FTIR intensity of heterodimers or heterotrimers (black solid lines) increased, while those of MC/OC/PC and PP (blue and red solid lines) decreased, as shown in Figure 9, S9 and S10. Then, the cocrystals begins to nucleate and growth. Meanwhile, the concentration of the heterotrimers (t(MCPP) or t(OCPP)) or the heterodimers (d(PCPP)) began to decrease (from C to D). The concentration of the heterodimers or heterotrimers didn't change anymore when the final temperature was reached. And the content of the cocrystals was also balanced