The Impact of Halogen Substituents on the Synthesis and Structure of Co-Crystals of Pyridine Amides
Strategies for co-crystal synthesis tend to employ either hydrogen- or halogen-bonds between different molecules. However, when both interactions are present, the structural influence that they may exert on the resulting assembly is difficult to predict a priori. To shed some light on this supramole...
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MDPI AG
2021-02-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/26/4/1147 |
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| author | Amila M. Abeysekera Abhijeet S. Sinha Christer B. Aakeroy |
| author_facet | Amila M. Abeysekera Abhijeet S. Sinha Christer B. Aakeroy |
| author_sort | Amila M. Abeysekera |
| collection | DOAJ |
| description | Strategies for co-crystal synthesis tend to employ either hydrogen- or halogen-bonds between different molecules. However, when both interactions are present, the structural influence that they may exert on the resulting assembly is difficult to predict a priori. To shed some light on this supramolecular challenge, we attempted to co-crystallize ten aliphatic dicarboxylic acids (co-formers) with three groups of target molecules; <i>N</i>-(pyridin-2-yl)picolinamides (2Pyr-<i>X</i>), <i>N</i>-(pyridin-2-yl)nicotinamides (3Pyr-<i>X</i>), <i>N</i>-(pyridin-2-yl)isonicotinamides (4Pyr-<i>X</i>); X=Cl/ Br/ I. The structural outcomes were compared with co-crystals prepared from the non-halogenated targets. As expected, none of the reactions with 2Pyr-<i>X</i> produced co-crystals due to the presence of a very stable intramolecular N-H···N hydrogen bond. In the 3Pyr series, all six structures obtained showed the same synthons, –COOH···N(py) and –COOH···N(py)-NH, that were found in the non-halogenated parent 3Pyr and were additionally accompanied by structure directing X···O(OH) interactions (X=Br/I). The co-crystals of the unhalogenated parent 4Pyr co-crystals assembled via intermolecular –COOH···N(py) and –COOH···N(py)-NH synthons. Three of the analogues 4Pyr-X co-crystals displayed only COOH···N(py) and –COOH···N(py)-NH interactions. The three co-crystals of 4Pyr-X with fumaric acid (for which no analogues structures with 4Pyr are known) formed –COOH···N(py)-NH and –NH···O=C hydrogen bonds and showed no structure-directing halogen bonds. In three co-crystals of 4Pyr-I in which –COOH···N(py)-NH hydrogen bond was present, a halogen-bond based –I···N(py) synthon replaced the –COOH···N(py) motif observed in the parent structures. The structural influence of the halogen atoms increased in the order of Cl < Br < I, as the size of σ-holes increased. Finally, it is noteworthy that isostructurality among structures of the homomeric targets was not translated to structural similarities between their respective co-crystals. |
| first_indexed | 2024-03-09T00:41:04Z |
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| last_indexed | 2024-03-09T00:41:04Z |
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| spelling | doaj.art-db16d9a6414d4dc79092a9085418483e2023-12-11T17:53:07ZengMDPI AGMolecules1420-30492021-02-01264114710.3390/molecules26041147The Impact of Halogen Substituents on the Synthesis and Structure of Co-Crystals of Pyridine AmidesAmila M. Abeysekera0Abhijeet S. Sinha1Christer B. Aakeroy2Department of Chemistry, Kansas State University, Manhattan, KS 66506, USADepartment of Chemistry, Kansas State University, Manhattan, KS 66506, USADepartment of Chemistry, Kansas State University, Manhattan, KS 66506, USAStrategies for co-crystal synthesis tend to employ either hydrogen- or halogen-bonds between different molecules. However, when both interactions are present, the structural influence that they may exert on the resulting assembly is difficult to predict a priori. To shed some light on this supramolecular challenge, we attempted to co-crystallize ten aliphatic dicarboxylic acids (co-formers) with three groups of target molecules; <i>N</i>-(pyridin-2-yl)picolinamides (2Pyr-<i>X</i>), <i>N</i>-(pyridin-2-yl)nicotinamides (3Pyr-<i>X</i>), <i>N</i>-(pyridin-2-yl)isonicotinamides (4Pyr-<i>X</i>); X=Cl/ Br/ I. The structural outcomes were compared with co-crystals prepared from the non-halogenated targets. As expected, none of the reactions with 2Pyr-<i>X</i> produced co-crystals due to the presence of a very stable intramolecular N-H···N hydrogen bond. In the 3Pyr series, all six structures obtained showed the same synthons, –COOH···N(py) and –COOH···N(py)-NH, that were found in the non-halogenated parent 3Pyr and were additionally accompanied by structure directing X···O(OH) interactions (X=Br/I). The co-crystals of the unhalogenated parent 4Pyr co-crystals assembled via intermolecular –COOH···N(py) and –COOH···N(py)-NH synthons. Three of the analogues 4Pyr-X co-crystals displayed only COOH···N(py) and –COOH···N(py)-NH interactions. The three co-crystals of 4Pyr-X with fumaric acid (for which no analogues structures with 4Pyr are known) formed –COOH···N(py)-NH and –NH···O=C hydrogen bonds and showed no structure-directing halogen bonds. In three co-crystals of 4Pyr-I in which –COOH···N(py)-NH hydrogen bond was present, a halogen-bond based –I···N(py) synthon replaced the –COOH···N(py) motif observed in the parent structures. The structural influence of the halogen atoms increased in the order of Cl < Br < I, as the size of σ-holes increased. Finally, it is noteworthy that isostructurality among structures of the homomeric targets was not translated to structural similarities between their respective co-crystals.https://www.mdpi.com/1420-3049/26/4/1147hydrogen bondshalogen bondscrystal engineeringmolecular recognition |
| spellingShingle | Amila M. Abeysekera Abhijeet S. Sinha Christer B. Aakeroy The Impact of Halogen Substituents on the Synthesis and Structure of Co-Crystals of Pyridine Amides Molecules hydrogen bonds halogen bonds crystal engineering molecular recognition |
| title | The Impact of Halogen Substituents on the Synthesis and Structure of Co-Crystals of Pyridine Amides |
| title_full | The Impact of Halogen Substituents on the Synthesis and Structure of Co-Crystals of Pyridine Amides |
| title_fullStr | The Impact of Halogen Substituents on the Synthesis and Structure of Co-Crystals of Pyridine Amides |
| title_full_unstemmed | The Impact of Halogen Substituents on the Synthesis and Structure of Co-Crystals of Pyridine Amides |
| title_short | The Impact of Halogen Substituents on the Synthesis and Structure of Co-Crystals of Pyridine Amides |
| title_sort | impact of halogen substituents on the synthesis and structure of co crystals of pyridine amides |
| topic | hydrogen bonds halogen bonds crystal engineering molecular recognition |
| url | https://www.mdpi.com/1420-3049/26/4/1147 |
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