Collect. Czech. Chem. Commun. 2008, 73, 1-18

New Hydrophobicity Constants of Substituents in Pyrazine Rings Derived from RP-HPLC Study

Marta Kučerová-Chlupáčováa, Veronika Opletalováa,*, Josef Jampílekb, Jan Doležela, Jiří Dohnalb, Milan Pourc, Jiří Kunešc and Viktor Voříšekd

a Department of Pharmaceutical Chemistry and Drug Control, Faculty of Pharmacy, Charles University, Heyrovského 1203, CZ-500 05 Hradec Králové, Czech Republic
b Zentiva a.s., U kabelovny 130, CZ-102 37 Prague 10, Czech Republic
c Department of Inorganic and Organic Chemistry, Faculty of Pharmacy, Charles University, Heyrovského 1203, CZ-500 05 Hradec Králové, Czech Republic
d Institute of Clinical Biochemistry and Diagnostics, University Hospital, Sokolská 581, CZ-500 05 Hradec Králové, Czech Republic


Pyrazine derivatives show a wide range of biological activities. 1-Pyrazin-2-ylethan-1-ones have served as food flavourants, and together with pyrazine-2-carbonitriles have been widely used as intermediates in the synthesis of various heterocyclic compounds. In our laboratory, substituted pyrazine-2-carbonitriles and 1-pyrazin-2-ylethan-1-ones have been used as intermediates for the preparation of potential antifungal and antimycobacterial drugs. Using established methods, a library of pyrazine derivatives was synthesized. Homolytic alkylation of commercially available pyrazine-2-carbonitrile yielded a series of 5-alkylpyrazine-2-carbonitriles which were converted into the corresponding 1-(5-alkylpyrazin-2-yl)ethan-1-ones (5-alkyl-2-acetylpyrazines) via the Grignard reaction. Homolytic acetylation of pyrazine-2-carbonitrile yielded 5-acetylpyrazine-2-carbonitrile. Using the same procedure, 3-acetyl-5-tert-butylpyrazine-2-carbonitrile was obtained with 5-tert-butylpyrazine-2-carbonitrile as a starting material. The hydrophobicity of the compounds was determined both experimentally (RP-HPLC) and by computation (CS ChemOffice Ultra version 9.0, ACD/LogP version 1.0 and ACD/LogP version 9.04), and both the approaches were compared. New hydrophobicity constants π based on experimental results were derived. These constants are markedly different from tabulated constants π valid for benzene rings, and can be widely used in estimating physicochemical properties of new biologically active pyrazines.

Keywords: Lipophilicity; Pyrazinecarbonitrile; Acetylpyrazine; Homolytic alkylation; Homolytic acetylation; Hydrophobicity; Chromatography; Pyrazines.

References: 85 live references.