{"title":"有机酸碱复合物晶体在压缩条件下违背 ΔpKa 规则","authors":"Shovan Das, Saied Md Pratik, Ayan Datta","doi":"10.1021/acs.jpcc.4c05301","DOIUrl":null,"url":null,"abstract":"Crystals of organic acid–base adducts are major components in active pharmaceutical ingredients. These 1:1 adducts either form a cocrystal with a hydrogen-bonded motif or a salt by transfer of a proton from the acid to the base. As a <i>rule of thumb</i>, if the difference in p<i>K</i><sub><i>a</i></sub> between the protonated base and the acid (Δp<i>K</i><sub><i>a</i></sub>) is < −1, a cocrystal is expected, while Δp<i>K</i><sub><i>a</i></sub> > 4 leads to a salt, and in the intermediate zone (−1 ≤ Δp<i>K</i><sub><i>a</i></sub> ≤ 4) both cocrystal and salt are observed. The preferred crystalline form for 1:1 adducts of pyridine, pyridazine, pyrazine, and furan with formic acid is elucidated using genetic algorithm-assisted <i>first-principles</i> crystal structure predictions. In agreement with the Δp<i>K</i><sub><i>a</i></sub> rule, all the adducts stabilize as H-bonded cocrystals under ambient pressure. However, under isotropic pressure, formic acid transfers the protons to the three nitrogenous bases, forming salts of pyridinium formate, pyridazinium formate, and pyrazinium formate. External pressure is found to dictate the cocrystal–salt equilibrium. Critical pressure (<i>P</i><sub><i>c</i></sub>) required to induce cocrystal → salt conversion for formic acid··· pyridine/pyridazine/pyrazine is 3, 5, and 15 GPa, respectively. Compression is shown to enhance the electrostatic interactions between the molecules, leading to additional stabilization of the ionic configurations, namely, N<sup>+</sup>-H···O<sup>–</sup> in salts vis-à-vis the neutral N–H···O motifs in the cocrystals. Violating the Δp<i>K</i><sub><i>a</i></sub> rule, <i>P</i><sub><i>c</i></sub> overcomes the free energy required for the proton transfer (Δ<i>G</i><sub>PT</sub>) to stabilize the salts. The very high Δ<i>G</i><sub>PT</sub> = 177.9 kcal/mol for the furan···formic acid adduct prevents salt formation even at 30 GPa. Apart from thermodynamic and kinetic control during crystallization, <i>pressure</i> acts as a key control for organic acid–base adducts.","PeriodicalId":61,"journal":{"name":"The Journal of Physical Chemistry C","volume":null,"pages":null},"PeriodicalIF":3.3000,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Crystals of Organic Acid–Base Complexes Defy the ΔpKa Rule Under Compression\",\"authors\":\"Shovan Das, Saied Md Pratik, Ayan Datta\",\"doi\":\"10.1021/acs.jpcc.4c05301\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Crystals of organic acid–base adducts are major components in active pharmaceutical ingredients. These 1:1 adducts either form a cocrystal with a hydrogen-bonded motif or a salt by transfer of a proton from the acid to the base. As a <i>rule of thumb</i>, if the difference in p<i>K</i><sub><i>a</i></sub> between the protonated base and the acid (Δp<i>K</i><sub><i>a</i></sub>) is < −1, a cocrystal is expected, while Δp<i>K</i><sub><i>a</i></sub> > 4 leads to a salt, and in the intermediate zone (−1 ≤ Δp<i>K</i><sub><i>a</i></sub> ≤ 4) both cocrystal and salt are observed. The preferred crystalline form for 1:1 adducts of pyridine, pyridazine, pyrazine, and furan with formic acid is elucidated using genetic algorithm-assisted <i>first-principles</i> crystal structure predictions. In agreement with the Δp<i>K</i><sub><i>a</i></sub> rule, all the adducts stabilize as H-bonded cocrystals under ambient pressure. However, under isotropic pressure, formic acid transfers the protons to the three nitrogenous bases, forming salts of pyridinium formate, pyridazinium formate, and pyrazinium formate. External pressure is found to dictate the cocrystal–salt equilibrium. Critical pressure (<i>P</i><sub><i>c</i></sub>) required to induce cocrystal → salt conversion for formic acid··· pyridine/pyridazine/pyrazine is 3, 5, and 15 GPa, respectively. Compression is shown to enhance the electrostatic interactions between the molecules, leading to additional stabilization of the ionic configurations, namely, N<sup>+</sup>-H···O<sup>–</sup> in salts vis-à-vis the neutral N–H···O motifs in the cocrystals. Violating the Δp<i>K</i><sub><i>a</i></sub> rule, <i>P</i><sub><i>c</i></sub> overcomes the free energy required for the proton transfer (Δ<i>G</i><sub>PT</sub>) to stabilize the salts. The very high Δ<i>G</i><sub>PT</sub> = 177.9 kcal/mol for the furan···formic acid adduct prevents salt formation even at 30 GPa. Apart from thermodynamic and kinetic control during crystallization, <i>pressure</i> acts as a key control for organic acid–base adducts.\",\"PeriodicalId\":61,\"journal\":{\"name\":\"The Journal of Physical Chemistry C\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":3.3000,\"publicationDate\":\"2024-09-27\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"The Journal of Physical Chemistry C\",\"FirstCategoryId\":\"1\",\"ListUrlMain\":\"https://doi.org/10.1021/acs.jpcc.4c05301\",\"RegionNum\":3,\"RegionCategory\":\"化学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"CHEMISTRY, PHYSICAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"The Journal of Physical Chemistry C","FirstCategoryId":"1","ListUrlMain":"https://doi.org/10.1021/acs.jpcc.4c05301","RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, PHYSICAL","Score":null,"Total":0}
Crystals of Organic Acid–Base Complexes Defy the ΔpKa Rule Under Compression
Crystals of organic acid–base adducts are major components in active pharmaceutical ingredients. These 1:1 adducts either form a cocrystal with a hydrogen-bonded motif or a salt by transfer of a proton from the acid to the base. As a rule of thumb, if the difference in pKa between the protonated base and the acid (ΔpKa) is < −1, a cocrystal is expected, while ΔpKa > 4 leads to a salt, and in the intermediate zone (−1 ≤ ΔpKa ≤ 4) both cocrystal and salt are observed. The preferred crystalline form for 1:1 adducts of pyridine, pyridazine, pyrazine, and furan with formic acid is elucidated using genetic algorithm-assisted first-principles crystal structure predictions. In agreement with the ΔpKa rule, all the adducts stabilize as H-bonded cocrystals under ambient pressure. However, under isotropic pressure, formic acid transfers the protons to the three nitrogenous bases, forming salts of pyridinium formate, pyridazinium formate, and pyrazinium formate. External pressure is found to dictate the cocrystal–salt equilibrium. Critical pressure (Pc) required to induce cocrystal → salt conversion for formic acid··· pyridine/pyridazine/pyrazine is 3, 5, and 15 GPa, respectively. Compression is shown to enhance the electrostatic interactions between the molecules, leading to additional stabilization of the ionic configurations, namely, N+-H···O– in salts vis-à-vis the neutral N–H···O motifs in the cocrystals. Violating the ΔpKa rule, Pc overcomes the free energy required for the proton transfer (ΔGPT) to stabilize the salts. The very high ΔGPT = 177.9 kcal/mol for the furan···formic acid adduct prevents salt formation even at 30 GPa. Apart from thermodynamic and kinetic control during crystallization, pressure acts as a key control for organic acid–base adducts.
期刊介绍:
The Journal of Physical Chemistry A/B/C is devoted to reporting new and original experimental and theoretical basic research of interest to physical chemists, biophysical chemists, and chemical physicists.