Glacial acetic acid as a resolution solvent for growing enantiopure crystals from racemic mixtures

Abstract

Chirality is pervasive in nature, yet chiral separation continues to be a real challenge. Herein we report the synthesis and structure of [Pd₄S₂(dppm)₃(CN^tBu)₂][H(OAc)₂]₂ (abbre. Pd₄S₂, HOAc = acetic acid), with an intrinsically chiral Pd–S core. The as-prepared clusters are racemates crystallized in the centric space group P2₁/n or as twins of acentric space groups P4₃2₁2 and P4₁2₁2, both with co-crystallized acetic acid molecules. Surprisingly, when re-crystallized from glacial acetic acid, optically pure enantiomeric crystals of P4₃2₁2 or P4₁2₁2 were obtained simultaneously, with the same amount in one pot. In this regard, glacial acetic acid functions both as a recrystallization solvent and as a resolution agent. It also effectively eliminates twinning. This unexpected finding suggests an easy and economical way to separate a racemic mixture into enantiomers which may find applications in chiral separation technologies.

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Introduction

Chirality (or handedness) is ubiquitous in nature.^1,2 The chirality of matter has dramatic consequences in both living and non-living systems, ranging from biology, medicine to materials science and beyond.³ While many protocols for the synthesis of chiral molecules using chiral precursors^4–18 or catalysts¹⁹ and the separation of racemic chiral molecules^20–28 have been developed, it is still a challenge to separate enantiomers without the influence of exogenous chiral factors such as chiral counterions.²⁹ Since Louis Pasteur³⁰ discovered the spontaneous resolution of racemic sodium ammonium tartrate tetrahydrate in 1848, the potential of using spontaneous resolution to separate enantiomers has been well recognized. It has the advantages of easy operation, cost-effectiveness, and simple conditions.³¹ However, only about 10% of racemic crystals exhibit spontaneous resolution behavior,³² which prevents its widespread industrial application.³³

Although predicting and controlling the spontaneous resolution behavior of racemic crystals has long been considered a formidable task,^33–35 there are nevertheless two controversial rules of thumb: (1) Wallach's rule: racemic crystals are denser than their chiral counterparts^36,37 and (2) chiral salts have a higher propensity of spontaneous resolution than their neutral counterparts.³⁸ In this regard, “counterion engineering” may be an effective means of inducing spontaneous resolution of racemic chiral charged molecules.

In this work, we discovered that spontaneous resolution of the as-prepared title clusters can be achieved simply by recrystallization from glacial acetic acid. We further demonstrate that a unique solvent such as glacial acetic acid could be used, simultaneously as a recrystallization medium (purification process) and as a resolution agent (enantiomeric separation) for racemic nanoclusters.^39,40 In addition, glacial acetic acid can effectively eliminate twinning. This 3-in-1 attribute of glacial acetic acid is unmatched by any other solvent which may find applications in chiral separation technologies of importance ranging from pharmaceutics to materials sciences.

Results and discussion

Synthesis, characterization, and structure analysis

The title cluster, [Pd₄S₂(dppm)₃(CN^tBu)₂]²⁺ (abbre. as Pd₄S₂), as the [H(OAc)₂]⁻ salt, was synthesized by adding, consecutively, t-butylisonitrile (CN^tBu), bis(diphenylphosphino)methane (dppm), and (Me₃Si)₂S to a solution of Pd₄(OAc)₄(CO)₄ in CH₂Cl₂ (cf. synthesis in the ESI†). The ligand CN^tBu, with a stronger σ-donation power than that of CO,⁴¹ and the chelating ligand (diphenylphosphino)methane (dppm) were chosen to replace CO and PR₃, respectively, to overcome the well-known intrinsic instability of Pd NCs⁴² co-protected by the latter ligands. In addition, hexamethyldisilathiane (Me₃Si)₂S was introduced as the S²⁻ source to further enhance the stability. As a result, the title cluster is extremely stable, even surviving in harsh solvents such as glacial acetic acid.

Crystals suitable for X-ray diffraction were obtained by diffusing diethyl ether into the reaction mixture. Pd₄S₂ can be obtained in a high yield (62.5%) when the ratio of the reactants, viz., CN^tBu, dppm and (Me₃Si)₂S, is 3 : 1 : 1 (relative to Pd). Pd₄S₂ crystallizes in three different space groups P4₃2₁2 and P4₁2₁2, and P2₁/n (trace amount), respectively (Fig. 1). P4₃2₁2 and P4₁2₁2 constitute a pair of enantiomorphic space groups while P2₁/n is achiral. Two acetates and two acetic acids per Pd₄S₂ cluster (Fig. 2) were found in crystals with the P4₃2₁2 and P4₁2₁2 space groups ([Pd₄S₂(dppm)₃(CN^tBu)₂][H(OAc)₂]₂, hereafter abbreviated as Pd₄S₂-P4₃2₁2 and Pd₄S₂-P4₁2₁2). However, due to the serious disorder, only one acetate and one acetic acid per Pd₄S₂ cluster (Fig. 3a) were found in the P2₁/n crystal (hereafter abbreviated as Pd₄S₂-P2₁/n). The co-existence of acetic acid and acetate was also confirmed by FT-IR (Fig. S1†). Subsequent discussions will be based on the crystal structure of Pd₄S₂-P4₁2₁2.

Fig. 1 Schematic illustration of the synthesis and spontaneous resolution of Pd₄S₂. Color legend: deep sky-blue, Pd; yellow, S; orange, P; light purple, N; and grey, C. All hydrogen atoms, solvents and counterions are omitted for clarity.

Fig. 2 Enantiomer pair (R and S) of Pd₄S₂ (top), along with HOAc/OAc⁻ aggregates A (middle) and B (bottom) were derived from the crystal structures of Pd₄S₂-P4₁2₁2 and Pd₄S₂-P4₃2₁2, respectively. Color legend: deep sky-blue, Pd; yellow, S; orange, P; red, O; light purple, N; grey, C; and white, H.

Fig. 3 Different structures of HOAc/OAc⁻ aggregates were observed in different crystal structures of space groups: (a) Pd₄S₂-P2₁/n and (b and c) Pd₄S₂-P4₁2₁2. Mirror images of (b) and (c) were observed in Pd₄S₂-P4₃2₁2. Color legend: red, O; grey, C; and white, H.

Pd₄S₂ displays a twisted planar metal core with four Pd–Pd bonds. The dihedral angle formed by Pd(1)–Pd(1)′–Pd(2) and Pd(1)′–Pd(2)–Pd(2)′ is 126.21° (Fig. 4a). The shortest Pd(1)–Pd(1)′ bond length is 2.5875(9) Å, shorter than the 2.75 Å in palladium metal,⁴³ indicating a strong Pd–Pd interaction. The longest Pd(2)–Pd(2)′ bond length is 3.0375(9) Å, which is ligated by two μ₃-S atoms from above and below the twisted Pd₄ plane (Fig. 4a). Two more Pd–S bonds exist between these two S atoms and the other two Pd atoms (Pd(1)–S(1) and Pd(1)′–S(1)′). All Pd–Pd bonds are bridged by dppm except the longest one (Fig. 4b), which is terminally coordinated by two CN^tBu ligands (Fig. 4c). There is a two-fold axis passing through the midpoints of the longest and shortest Pd–Pd bonds and the methylene carbon of the middle dppm (Fig. 4c). As a result, the entire Pd₄S₂ cluster conforms to the crystallographically imposed symmetry of C₂.

Fig. 4 (a) Arrangement of S atoms on Pd₄S₂. (b) Arrangement of dppm ligands on Pd₄S₂. (c) The crystallographic C₂ symmetry axis and the arrangement of CN^tBu ligands on Pd₄S₂. Color legend: deep sky-blue, Pd; yellow, S; orange, P; light purple, N; and grey, C.

The UV/Vis absorption spectrum of Pd₄S₂ in a methanol solution displays two peaks at 323 and 415 nm. Additionally, the UV/Vis spectra indicate that Pd₄S₂ remains stable, with no noticeable decomposition under ambient conditions for at least 3 days (Fig. S2†). As shown in Fig. S3,† there is a prominent peak at m/z = 904.0408, which corresponds to the dication [Pd₄S₂(dppm)₃(CN^tBu)₂]²⁺. There is a perfect match between the simulated isotopic patterns and experimental data. The absence of other impurity peaks indicates the high purity of Pd₄S₂. Since Pd₄S₂ is a dication, and there are two S²⁻ in Pd₄S₂, the four palladium atoms carry six positive charges. In this context, due to the rather short bond length, Pd(1)–Pd(1)′ can be considered as a bona fide Pd(I) dimer with a strong Pd–Pd bond, while Pd(2)–Pd(2)′ is a nonbonded Pd(II) dimer. Here I and II represent the formal oxidation states of +1 and +2 of Pd atoms, respectively. XPS analysis also confirmed the coexistence of Pd(I) and Pd(II)⁴⁴ (Fig. S4†). The two dimers are connected by Pd(1)–Pd(2) and Pd(1)′–Pd(2)′ bonds of length 2.9659(7) Å (Fig. 4a). The two dimers are twisted by 40.48° about the crystallographic C₂ axis, thereby lowering the symmetry of Pd₄S₂ from D_4h (hypothetical intermediate structure, vide infra) to C₂, turning it into a chiral nanocluster (Fig. 7c).

Spontaneous resolution induced by glacial acetic acid

The as-grown crystals from dichloromethane belong to either the P4₁2₁2 or P4₃2₁2 chiral space group, but with a Flack parameter of 0.5, along with a trace amount of achiral crystals of the space group P2₁/n (as proved by PXRD, Fig. S5†). The Flack parameter of 0.5 of the chiral crystals indicates that they are inversion twins.⁴⁵ They are in fact identical and will be hereafter labeled as Pd₄S₂-P4₁2₁2-twin and Pd₄S₂-P4₃2₁2-twin. To our surprise, by adding increasing amounts of acetic acid to the dichloromethane solution, equal proportions of optically pure chiral crystals of space groups P4₁2₁2 and P4₃2₁2, both with a Flack parameter of zero (0), could be obtained. They will be referred to as Pd₄S₂-P4₁2₁2 and Pd₄S₂-P4₃2₁2 (see Tables S3 and S4†). The relative yields of different crystals depend on the ratio of the reactants as well as the acetic acid : CH₂Cl₂ solvent mixture. Subsequently, glacial acetic acid was used as the sole solvent in the recrystallization process and optically pure enantiomeric crystals of space groups P4₁2₁2 or P4₃2₁2, both with a Flack parameter of zero (0), were obtained (Table S10†). The electronic circular dichroism (ECD) spectrum also confirmed the spontaneous resolution of Pd₄S₂ clusters (Fig. S6†). On the other hand, recrystallization from methanol yielded achiral crystals of the space group P2₁/n as the sole product.

Obviously, the solvent plays a crucial role in determining whether chiral or achiral crystals are formed. However, the underlying mechanisms driving the spontaneous resolution of racemic mixtures are far more intricate. Many factors can influence the spontaneous resolution of racemic mixtures, including but not limited to space filling (Wallach's rule³⁶), hydrogen bonding,³ symmetry,⁴⁶ stacking,⁴⁷ coulombic interactions,³⁸etc. In fact, these factors are difficult to completely distinguish because they are not mutually independent.

From the perspective of space filling, homochiral stacking is less efficient (Wallach's rule), suggesting that voids in homochiral stacking are larger than voids in heterochiral stacking. How to fill these larger voids becomes the key in inducing homochiral stacking. Consistent with this notion, in our case, acentric space groups have larger voids to accommodate the anions and solvent molecules, as reflected in the (unit cell volume)/Z listed in Table S11.† Crystallographically, for spontaneously resolved chiral Pd₄S₂ crystals (Flack = 0), each Pd₄S₂ cluster has four acetic acids and four acetates with an occupancy of 0.5. They form two independent sets of HOAc/OAc⁻ aggregates labeled as A and B depicted in Fig. 3b and c. This is also the case in the twin crystals (Flack = 0.5). However, only one molecule of acetic acid was found in the crystals of Pd₄S₂-P2₁/n. Furthermore, recrystallization of the as-grown Pd₄S₂ crystals in methanol leads to the replacement of one acetic acid by two methanols per cluster (Fig. S8†), as confirmed by SC-XRD, giving rise to the formula [Pd₄S₂(dppm)₃(CN^tBu)₂](OAc)₂ (MeOH)₂ (labeled as Pd₄S₂-P2₁/n-MeOH, one of the two OAc⁻ anions was not found due to the serious disorder). This reflects smaller voids in the achiral crystals (cf. Table S11†). To rule out the influence of disorder, we performed liquid-state NMR tests (Fig. S13–16†) on crystals with different space groups. The results once again demonstrated that the chiral space group contains more acetic acid molecules compared to the achiral space group (Table S13,† entries 1–3). Therefore, we believe the larger voids in the chiral crystals accommodate the extra acetic acid molecule, helping to stabilize the chiral crystals.

Non-covalent interactions have been considered to play a crucial role in the spontaneous resolution of enantiomers.^3,35,39,40 In our case, a manifold of hydrogen bonds, π⋯π, or C–H⋯π interactions was observed, as tabulated in Table S12.† Particularly worth noting is the H⋯O distances of 2.148 Å between the methylene groups of the wingtip dppm ligands and HOAc/OAc⁻ aggregate B, as portrayed in Fig. 5. The latter represents significant hydrogen bonding. Considering the disordered nature of aggregate B (related by two-fold rotation axes), it appears that aggregate B keeps switching between two positions. In this way, aggregate B may function as a “linker”, connecting two adjacent Pd₄S₂ clusters of the same chirality to form a homochiral “chain” (Fig. S7†).

Fig. 5 The weak but significant hydrogen bonding interaction between the carbonyl oxygen atom of acetic acid in aggregate B and one hydrogen atom of the methylene group of the dppm ligand in Pd₄S₂-P4₁2₁2. Color legend: deep sky-blue, Pd; yellow, S; orange, P; red, O; light purple, N; grey, C; and white, H.

Remarkably, the symmetry of the counterions also seems to affect the spontaneous resolution of Pd₄S₂. As shown in Fig. 3, the HOAc/OAc⁻ aggregates in Pd₄S₂-P2₁/n have a noncrystallographic mirror plane passing through them. In contrast, the aggregates A and B in Pd₄S₂-P4₁2₁2 or Pd₄S₂-P4₃2₁2 have their planes moved to one side, making the anions chiral as well. Consistent with this observation, the introduction of PF₆⁻ as the counteranions, with a smaller volume and spherical symmetry, also led to the centric space group P2₁/n (see Fig. S9 and Table S7†). Therefore, we believe the symmetry of these chiral anions also contributes to the spontaneous resolution of the racemates to form the respective enantiomers (vide infra).

Finally, it is also interesting to note that glacial acetic acid can effectively eliminate crystal twinning. We note that there are no structural differences between Pd₄S₂-P4₁2₁2/P4₃2₁2 and Pd₄S₂-P4₁2₁2/P4₃2₁2-twin except for the Flack parameters (zero (0) for the former and 0.5 for the latter twin). In this regard, glacial acetic acid can eliminate twinning. Rasmuson⁴⁸et al. studied the crystal aggregation of paracetamol crystallized in different solvents and found that the aggregation of crystallites can be reduced by using highly polar solvents. They believed that there were strong interactions between highly polar solvents and the crystal surface, thus reducing “crystalline bridging”, thereby promoting the formation of single crystals rather than the twin crystals. We believed that the same effect or a similar effect may be operational here.

Enantioseparation of Pd₄S₂ by chiral anions

In order to illustrate the importance of the symmetry factor in the spontaneous resolution process, we also performed enantioseparation of Pd₄S₂ by using chiral counteranions. Here (S)-1,1′-binaphthyl-2,2′-diyl hydrogen phosphate or (R)-1,1′-binaphthyl-2,2′-diyl hydrogen phosphate (abbre. as S-Phos and R-Phos, Fig. S10†) were used in separate experiments to grow the respective enantiomers. The resulting SC-XRD structure determination confirmed that chiral phosphates were successfully introduced into the crystal lattice (see S-Phos&R-Pd₄S₂ and R-Phos&S-Pd₄S₂ in Fig. 6 and Tables S14, S15†). Additionally, we also identified the crystal structures of S-Phos&S-Pd₄S₂ and R-Phos&R-Pd₄S₂ (Tables S8, S9 and Fig. S18†), although these were only minor (ca. 10%) products. In addition to the ECD peaks at 325 nm (and the accompanying shoulders) of the chiral anions, there are additional peaks at 444 nm and 396 nm due to the chiral Pd₄S₂ clusters (Fig. 7a). Subsequently, a circular dichroism spectrometer was used to study the racemization of Pd₄S₂. As can be seen in Fig. S11 and Fig. S12,† the CD signal decreased with increasing temperature and the racemization activation energy obtained from weighted linear fit of the Arrhenius plot (Fig. 7b) was determined to be 31.55 ± 0.82 kcal mol⁻¹.

Fig. 6 Enantiomer pair of R-Phos&S-Pd₄S₂ and S-Phos&R-Pd₄S₂. Color legend: deep sky-blue, Pd; yellow, S; orange, P; light purple, N; red, O; and grey, C. All hydrogen atoms are omitted for clarity.

Fig. 7 (a) The ECD spectra of methanol solutions of the enantiomeric pairs S-Phos&R-Pd₄S₂ and R-Phos&S-Pd₄S₂, S-Phos and R-Phos and racemic Pd₄S₂. (b) Arrhenius plot ln(k) vs. 1/T for the racemization of S-Phos&R-Pd₄S₂ at 353, 358, 363, and 368 K. (c) The origin of chirality of the two enantiomers of Pd₄S₂. Middle figure: hypothetical intermediate structure (D_4h symmetry) consisting of four Pd atoms and two μ₄ sulfur atoms. Left and right figures: the clockwise rotation of the Pd(1)–Pd(1)′ bond about the crystallographic C₂ axis by 2 × 40.48° relative to the Pd(2)–Pd(2)′ bond results in the conversion of R to S enantiomers, respectively. Color legend: deep sky-blue, Pd and yellow, S.

Finally, we wish to propose a plausible racemization mechanism with an octahedral Pd₄S₂ structure as the intermediate, as follows. First, it occurs to us that the observed Pd₄S₂ framework may be described as a distorted trigonal prism (tp) with an additional Pd(2)–Pd(2)′ bond across the diagonal of the distorted square face (formed by Pd(2), Pd(2)′, S(1), and S(1)′ as shown in Fig. 7c, left). A clockwise rotation of 40.48° about the two-fold symmetry axis of the enantiomer R-Pd₄S₂ (Fig. 7c, left) produces two additional Pd–S bonds (Pd(1)–S(1)′ and Pd(1)′–S(1)), making the four Pd atoms coplanar and the S atoms quadruply bridging (μ₄-S). The Pd₄S₂ structure then becomes a distorted octahedron of D_4h symmetry (Fig. 7c, middle). Further clockwise rotation of 40.48° gives rise to the enantiomer S-Pd₄S₂ (Fig. 7c, right), completing the racemization process.

Conclusions

In conclusion, the title cluster [Pd₄S₂(dppm)₃(CN^tBu)₂]²⁺ was synthesized and fully characterized. It has a peculiar structure rendering it chiral and crystallizes either as a racemate in a centric space group (P2₁/n) or as twin crystals of acentric space groups (P4₁2₁2/P4₃2₁2). When recrystallized from glacial acetic acid, optically pure crystals of P4₁2₁2 or P4₃2₁2 can be obtained. We believe that, in addition to preventing the formation of twin crystals, the number and structural characteristics of the anionic acetic acid/acetate (HOAc/OAc⁻) aggregates formed in glacial acetic acid may have contributed, in a significant way, to the formation of the optically pure chiral crystals. The use of glacial acetic acid, both as a recrystallization solvent and a resolution agent, as demonstrated in this work, represents an easy and economical route in separating racemic mixtures. This unexpected finding may find applications in chiral separation technologies ranging from pharmaceutics to materials sciences.

Author contributions

Hongwen Deng: conceptualization, data curation, formal analysis, investigation, methodology, validation, visualization, writing – original draft, and writing – review & editing; Peng Yuan: methodology; Kejie Lao: data curation; Qijun Fu: data curation; Boon K. Teo: conceptualization, data analysis, experiment supervision, and writing – review & editing; Nanfeng Zheng: conceptualization, data analysis, funding acquisition, resources, supervision, and writing – review & editing.

Data availability

Crystallographic data: Pd₄S₂-P4₁2₁2-twin (CCDC 2343119), Pd₄S₂-P4₃2₁2-twin (CCDC 2343114), Pd₄S₂-P4₁2₁2 (CCDC 2343112), Pd₄S₂-P4₃2₁2 (CCDC 2343113), Pd₄S₂-P2₁/n (CCDC 2343120), Pd₄S₂-P2₁/n-MeOH (CCDC 2343115), Pd₄S₂-P2₁/n-PF₆⁻ (CCDC 2343116), S-Phos&S-Pd₄S₂ (CCDC 2343118), R-Phos&R-Pd₄S₂ (CCDC 2343117), S-Phos&R-Pd₄S₂ (CCDC 2382579) and R-Phos&S-Pd₄S₂ (CCDC 2382580).†

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We acknowledge the financial support from the National Natural Science Foundation of China (grant no. 92261207, and NSFC Center for Single-Atom Catalysis under grant no. 22388102) and the New Cornerstone Science Foundation. Boon K. Teo acknowledges the support from the State Key Laboratory for Physical Chemistry of Solid Surfaces (PCOSS).

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Footnote

† Electronic supplementary information (ESI) available: Experimental section, physical measurements, additional characterization data, and detailed crystal structure analysis. CCDC 2343112–2343120, 2382579-2382580. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d4qi01944j

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