From a Binary to a Quaternary Cocrystal: An Unusual Supramolecular Synthon

Paul, Milova; Desiraju, Gautam R.

doi:10.1002/anie.201904339

Cited by 51 publications

(59 citation statements)

References 48 publications

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“…Finally,w ew ish to comment on the currentt endency for discussing crystal engineering problemsi nt he language of synthetic organic chemistry.S uch at rend is seen in recent papers of Desirajua nd other authors. [1,16,19,20,22,33] To be consistent with this trend, our final conclusion maintains this convention. The processes in ab allm ill, which we showed in Scheme2,r esemble mechanisms well knowni no rganic chemistry.I nt he first variant replacing the "attacking" and "leaving" group takes place in ac oncerted process.…”

Section: Discussionsupporting

confidence: 81%

“…[31,32] In each of the methods described briefly above,t he critical point that determines the successful preparation of ternary or quaternary crystals is knowledge aboutt he tendency for the formationo fb inary systems. [33] If interactions are strongi na binary crystal, then the driving force to form at ernary/quaternary crystal is diminished, andt here might be competition among putative binaries. If the binary interactions are too weak, then only ac onglomerate of single-component crystals might be obtained.…”

Section: Introductionmentioning

confidence: 99%

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Cocrystals “Divorce and Marriage”: When a Binary System Meets an Active Multifunctional Synthon in a Ball Mill

Dudek

Śniechowska

Wróblewska

et al. 2020

Chemistry A European J

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Aw ell-defineda nd stable "AB" binarys ystem in the presence of "C" ac rystalline synthon ground in ab all mill undergoes selective transformation in the solid state according to the equation AB + C!AC + B. When the amount of Ci si ncreased two times then the equation AB + 2C! AC + BC is valid. The other variants are more complex. The pathway BC + Ai sa llowed and leads to the AC andBproducts. The pathway AC + Bi sn ot preferred, and no transformation is observed. These non-obviouscorrelations were observed for cocrystal of barbituric acid (BA):thiobarbituric acid (TBA) recently reported by Shemchuk et al. (Chem. Commun. 2016, 52,1 1815-11818) in the presence of 1-hydroxy-4,5-dimethyl-imidazole 3-oxide (HIMO). This synthon shows high affinity for the BA 0.5 TBA 0.5 cocrystal as well for its individual components,B Aa nd TBA. Single-quantum,d ouble-quantum (SQ-DQ) 2D 1 Hv ery fast MAS NMR with as pinning rate of 60 kHz was employed as ab asic and most diagnostic tool for the study of cocrystals transformations. Analysis of the experimental data was supported by theoretical calculations, including computation of the stabilization energy, E stab ,d efined as the energy difference between the energy of ac ocrystal and the sum of the energies of particular components in the respective stoichiometric ratios. Twom echanisms of synthon replacement have been proposed. Pathway 1a ssumes ac oncerted mechanism of substitution. In this approach, synthon attack is synchronized in time with the departure of one of the components of the binary system.P athway 2i mplies an on-concerted process, with an intermediate stage in whicht hree separate components are present.E vidence suggesting ap reference for Pathway2 is shown.

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Section: Discussionsupporting

confidence: 81%

Section: Introductionmentioning

confidence: 99%

Cocrystals “Divorce and Marriage”: When a Binary System Meets an Active Multifunctional Synthon in a Ball Mill

Dudek

Śniechowska

Wróblewska

et al. 2020

Chemistry A European J

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“…Any synthetic strategy towards higher cocrystals should be of high supramolecular yield and without contamination from by-products such as binaries and pure compounds. A very limited number of stoichiometric quaternaries (less than 20) have been obtained to date (Bhogala & Nangia, 2008;Dandela et al, 2018;Dubey et al, 2016;Mir et al, 2016;Paul et al, 2018;Paul & Desiraju, 2019). All quaternary cocrystals thus far obtained by our group are based on either structural inequivalences or a combinatorial approach.…”

Section: Introductionmentioning

confidence: 99%

Quaternary and quinary molecular solids based on structural inequivalence and combinatorial approaches: 2-nitroresorcinol and 4,6-dichlororesorcinol

Rajkumar

Desiraju

2021

Int Union Crystallogr J

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A synthetic strategy for the formation of stoichiometric quaternary and nonstoichiometric quinary solids is outlined. A series of 2-nitroresorcinol-based quaternary cocrystals were developed from binary precursors in two conceptual stages. In the first stage, ternary solids are synthesized based on the structural inequivalence at two recognition sites in the binary. In the second stage, the ternary is homologated into a stoichiometric quaternary based on the same concept. Any cocrystal without an inequivalence becomes a synthetic dead end. The combinatorial approach involves lower cocrystal systems with different structural environments and preferred synthon selection from a synthon library in solution. Such are the stepping stones for the isolation of higher cocrystals. In addition, a quaternary cocrystal of 4,6-dichlororesorcinol is described wherein an unusual synthon is observed with two resorcinol molecules in a closed loop with two different ditopic bases. The concept of the virtual synthon in binaries with respect to isolated ternaries is validated for the 4,6-dichlororesorcinol system. It is possible that only some binary systems are amenable to homologation into higher cocrystals. The reasons for this could have to do with the existence of preferred synthon modules, in other words, the critical components of the putative higher assembly that cannot be altered. Addition of the third and fourth component might be more flexible, and the choices of these components, possible from a larger pool of chemically related molecules.

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“…However, recent reports of the advantages offered by ionic cocrystals (ICCs) derived from the cocrystallization of APIs with atomic inorganic salts (e.g., NaCl and CaCl 2 ) suggest that the range of practically accessible solid forms for optimizing the properties of APIs continues to widen . This is in the context of recent reports of the synthesis of a quaternary cocrystal and the first reported synthesis of a six‐component molecular solid …”

Section: Introductionmentioning

confidence: 99%

Efficient Screening for Ternary Molecular Ionic Cocrystals Using a Complementary Mechanosynthesis and Computational Structure Prediction Approach

Shunnar

Dhokale

Karothu³

et al. 2020

Chemistry A European J

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The discovery of molecular ionic cocrystals (ICCs) of active pharmaceutical ingredients (APIs) widens the opportunities for optimizing the physicochemical properties of APIs whilst facilitating the delivery of multiple therapeutic agents. However, ICCs are often observed serendipitously in crystallization screens and the factors dictating their crystallization are poorly understood. We demonstrate here that mechanochemical ball milling is a versatile technique for the reproducible synthesis of ternary molecular ICCs in less than 30 min of grinding with or without solvent. Computational crystal structure prediction (CSP) calculations have been performed on ternary molecular ICCs for the first time and the observed crystal structures of all the ICCs were correctly predicted. Periodic dispersion‐corrected DFT calculations revealed that all the ICCs are thermodynamically stable (mean stabilization energy=−2 kJ mol−1) relative to the crystallization of a physical mixture of the binary salt and acid. The results suggest that a combined mechanosynthesis and CSP approach could be used to target the synthesis of higher‐order molecular ICCs with functional properties.

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From a Binary to a Quaternary Cocrystal: An Unusual Supramolecular Synthon

Cited by 51 publications

References 48 publications

Cocrystals “Divorce and Marriage”: When a Binary System Meets an Active Multifunctional Synthon in a Ball Mill

Cocrystals “Divorce and Marriage”: When a Binary System Meets an Active Multifunctional Synthon in a Ball Mill

Quaternary and quinary molecular solids based on structural inequivalence and combinatorial approaches: 2-nitroresorcinol and 4,6-dichlororesorcinol

Efficient Screening for Ternary Molecular Ionic Cocrystals Using a Complementary Mechanosynthesis and Computational Structure Prediction Approach

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