Quinhydrone - the binary cocrystal (BZQ)·(HQ) (where: BZQ = p-benzoquinone and HQ = hydroquinone) - is regarded as the first known cocrystal. The solid was originally reported by Wӧhler in 1844 (Barone et al., 2014; Sakurai, 1965; Wöhler, 1844). (BZQ)·(HQ) is deep green in color and forms upon co-grinding of pale-yellow BZQ and colorless HQ. An X-ray determination of quinhydrone demonstrated the components to assemble by a combination of intermolecular hydrogen bonding and π-π stacking (Sakurai, 1965). Effects of charge transfer have been used to account for the deep green color (Pananusorn et al., 2022; Regeimbal et al., 2003). Quinhydrone has subsequently emerged as a model to evaluate oligomers of biopolymers of melamine and carboxylic equivalents, which have applications in biology, electronics, and related photoelectronic devices (Ariese et al., 2004; Tossell, 2009).

Recent efforts by us have reported an application of co-milling to the orange-red zwitterionic cocrystal (PDA)·(APAP) (where: PDA = 2,4-pyridinedicarboxylic acid, APAP = acetaminophen) (Sander et al., 2010). The milling involved co-grinding of (PDA)·(APAP) with 4,4′-BPE (where: 4,4′-BPE = trans-1,2-bis(4-pyridyl)ethylene) as solid reagents. Dismantling of (PDA)·(APAP) afforded the binary cocrystal (PDA)·(4,4′-BPE) (Ezekiel et al., 2024b). The co-milling involving the orange-red solid resulted in the sample turning colorless. Given that (BZQ)·(HQ) is deep green in color, we turned to apply co-milling to (BZQ)·(HQ).

In contrast to (PDA)·(APAP), (BZQ)·(HQ) is regarded as a neutral cocrystal, meaning that each component is devoid of a formal charge (cf. Zwitterionic PDA). Co-milling is an emerging approach to perform mechanochemical syntheses, being attractive for the design and formation of crystalline phases. Given the shallow landscape of organic solid-state materials, the development of approaches that allow for successful generation of targeted multi-component solids is critical.

Herein, we report application of co-milling to (BZQ)·(HQ). We show co-milling of (BZQ)·(HQ) using either 4,4′-BPE or 4-MA (Scheme 1) to result in dismantling of (BZQ)·(HQ) through cocrystal exchange reactions that generate known (HQ)·(4,4′-BPE) or (HQ)·2(4-MA) (Supplementary Figures S1, S2, Supplementary Material) (Ezekiel et al., 2024a; Siva et al., 2020; Weyna et al., 2009). The exchange reactions are accompanied by discolorations wherein the deep green color of each solid sample changes to light beige or dark brown. Importantly, we show the process of sublimation of BZQ, which involves physical removal of BZQ from the solid sample, to help promote formation and isolation of the targeted co-crystalline solids (Scheme 2). We are unaware of a case wherein sublimation is employed to promote formation and isolation of a cocrystal in a co-milling experiment.

Dark green (BZQ)·(HQ) is stabilized by a combination of O-H···O hydrogen bonds and charge-transfer between the electron donor (HQ) and electron acceptor (BZQ). At the molecular level, applications of (BZQ)·(HQ) to measure hydrogen ion concentration and in potentiometric titrations have been reported while the cocrystal is a promising cathode material for batteries (Choi, 2019; Curtin et al., 1984; Patil et al., 1984; Patil et al., 1986). BZQ itself is used in applications of redox processes (e.g., electron carriers, organic synthesis) (Dandawate et al., 2010). Owing to weak intermolecular interactions in the solid state, BZQ readily sublimes as a pure form (Emel et al., 2017). HQ experiences applications in pharmaceutical and photographic systems (Ghanbarzadeh et al., 2015; Lin et al., 2005; Nordlund et al., 2006), and the molecule readily oxidizes to form BZQ (Brito de Oliveira Moreira et al., 2022).

HQ is reported to form a total of 110 binary cocrystals (Cambridge Structural Database (CSD) version 5.46 November 2024). BZQ forms 47 binary cocrystals. An analysis of the CSD data shows HQ to form cocrystals with N-atom hydrogen-bond-acceptors (94 structures total). The O-H···N hydrogen bond is a resaonably reliable supramolecular synthon in synthesis of multicomponent crystals (Khan et al., 2009). Given our report to develop cocrystals of bipyridines through co-milling (Ezekiel et al., 2024b), we hypothesized (BZQ)·(HQ) could be dismantled by co-milling with the N-atom hydrogen-bond acceptors 4,4′-BPE (Weyna et al., 2009) and 4-MA (Siva et al., 2020) (Figure 1). The acceptors form cocrystals (HQ)·(4,4′-BPE) (light yellow) and (HQ)·2(4-MA) (black) from solution. The co-millings were expected to result in discolorization of dark green (BZQ)·(HQ) to afford samples based on colors of the targeted product cocrystals. The CSD shows HQ to form binary cocrystals of linear chains and a discrete aggregate with 4,4′-BPE and 4-MA, respectively (Figures 1B,C). The co-millings were expected to involve breakage of the O-H···O hydrogen bonds (2 total) of (BZQ)·(HQ) (Table 1) along with formation of O-H···N_pyr hydrogen bonds (2 total) for (HQ)·(4,4′-BPE) and O-H···N_amino (2 total) hydrogen bonds for (HQ)·2(4-MA) (Table 1). Solid BZQ, which does not participate in the formation of appreciably strong hydrogen bonds, was expected to form as side product.

When (BZQ)·(HQ) was subjected to co-milling with 4,4′-BPE by neat grinding (10 min) (Table 2), the dark green color changed to light beige (Figure 2A). Five prominent peaks emerged in the PXRD diffractogram (2θ = 19.3°, 20.2°, 21.3°, 24.4, 28.4°) (Figure 3A). The peaks were consistent with the formation of (HQ)·(4,4′-BPE). The cocrystal (HQ)·(4,4′-BPE) is reported as light-yellow. Peaks attributed to (BZQ)·(HQ) (2θ = 15.8°, 16.5°, 29.4°), BZQ (2θ = 15.5°), 4,4′-BPE (2θ = 28.1°) were also present. A longer co-milling time (60 min) did not result in an appreciable change in color of the solid sample.

When (BZQ)·(HQ) was subjected to co-milling with 4-MA by LAG (10 min, ethanol), the dark green color changed to dark brown (Figure 2B). The PXRD diffractogram showed the emergence of five prominent peaks (2θ = 12.5°, 20.2°, 21.3° 22.1°, 27.8°). The peaks were consistent with the formation of (HQ)·2(4-MA). The color of (HQ)·2(4-MA) is reported as black. Four peaks of reduced intensities (2θ = 15.8, 16.5°, 29.4°) attributed to (BZQ)·(HQ) were also present (Figure 3B). We note that peaks attributed to neither BZQ nor 4-MA were present. A longer milling time (60 min) did not result in a change in color. The generation of (HQ)·2(4-MA) was also realized by neat grinding.

While the PXRD data showed (BZQ)·(HQ) to be dismantled in each co-milling, the amount of BZQ that remained in each sample varied. From ¹H NMR data, over half BZQ (0.75 equivalent) remained upon co-milling with 4,4′-BPE (10 min) (Supplementary Figure S6, Supplementary Material). Significantly less BZQ (0.32 equivalent) remained following co-milling with 4-MA (Figure 4A). For the longer co-milling time (60 min), BZQ that remained was either relatively unchanged or significantly less for 4,4′-BPE (0.75 equivalent) and 4-MA (0.06 equivalent), respectively (Figure 4B). When each co-milled sample was also subjected to moderate vacuum (72 h), BZQ was completely removed in each case (Figure 4C), (Supplementary Figure S6, Supplementary Material). The resulting PXRD diffractograms were consistent with either (HQ)·(4,4′-BPE) or (HQ)·2(4-MA) being present (Figure 5) (Supplementary Table S2, Supplementary Material).

The losses of BZQ in the co-millings can be attributed to effects of sublimation (Acree and Chickos, 2010; Reid et al., 1959; Červinka and Fulem, 2017). BZQ readily sublimes at room temperature, which is reflective of weak intermolecular forces in pure BZQ (Lin et al., 2021). In previous work, Groeneman employed sublimation to remove a halogen-bond-donor coformer to isolate a cyclobutane photoproduct (Grobelny et al., 2017). Mei also used sublimation to remove halogen-bond-donor coformers from a photodimer of vitamin K3 (Zhu et al., 2016). Our group has recently attributed a decrease of a hydrogen-bond-donor coformer in a solid-state photoreaction to sublimation (Oburn et al., 2019). For the current work, sublimation of the hydrogen-bond-acceptor coformer BZQ can be regarded as a means to aide the generation and isolate a cocrystal as a product of a co-milling (Carstens et al., 2020). We are unaware of a case wherein sublimation in co-milling aides and abets the generation of a cocrystal. Similar to (PDA)·(APAP) (Ezekiel et al., 2024b), the cocrystal exchange can be explained on the basis of melting point. The binary cocrystals (HQ)·(4,4′-BPE) (224 °C–225 °C) (Quentin and MacGillivray, 2020), and (HQ)·2(4-MA) (191 °C) (Siva et al., 2020) melt at higher temperatures versus (BZQ)·(HQ) (167 °C–172 °C) (Curtin et al., 1984).

In our report, we demonstrated sublimation to support co-millings involving (BZQ)·(HQ), with the co-millings resulting in discolorations of the solid samples. We are currently expanding applications of co-milling to (BZQ)·(HQ), as well as identifying additional components that sublime and can serve as candidates in co-crystal generation. Understanding mechanisms responsible for dismantling cocrystals with the use of sublimation can be expected to influence conformer selections in the design and manufacturing of multicomponent crystals.