Experimental and theoretical study on the reaction of N 3 -phenyl-(pyridin-2-yl)carbohydrazonamide with itaconic anhydride Bo _ zena Modzelewska-Banachiewicz a , Renata Paprocka a , Liliana Mazur b , Jarosław Saczewski c,⇑ , Jolanta Kutkowska d , Dorota K. Ste ˛ pien ´ e , Michał Cyran ´ ski e a Department of Organic Chemistry, Faculty of Pharmacy, Nicolaus Copernicus University, Jurasza 2, 85-089 Bydgoszcz, Poland b Department of General and Coordination Chemistry, Maria Curie-Sklodowska University, M. Curie-Sklodowska Sq. 2, 20-031 Lublin, Poland c Department of Chemical Technology of Drugs, Medical University of Gdansk, Hallera 107, 80-416 Gdansk, Poland d Department of Genetics and Microbiology, Maria Curie-Sklodowska University, Akademicka 19, 20-033 Lublin, Poland e Department of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland highlights " New isomeric 1,2,4-triazole-containing alkenoic acids are obtained. " Mechanisms of base-catalyzed and neutral thermal 1,3-proton shifts are studied theoretically. " The structures are confirmed by 1D and 2D NMR and single crystal X-ray diffraction analysis. " Antimicrobial activity of the 1,2,4-triazole-containing alkenoic acids are investigated. article info Article history: Received 3 March 2012 Received in revised form 24 April 2012 Accepted 25 April 2012 Available online 8 May 2012 Keywords: 1,2,4-Triazole Carbohydrazonamide Itaconic anhydride Alkenoic acids 1,3-Proton shift reaction X-ray diffraction analysis abstract Two new 1,2,4-triazole-containing alkenoic acid derivatives were obtained from the reaction of N-phe- nyl-(pyridin-2-yl)carbohydrazonamide with itaconic anhydride, depending on the reaction conditions. The structures of 2-((4-phenyl-5-(pyridin-2-yl)-4H-1,2,4-triazol-3-yl)methyl)acrylic acid or (E)-2- methyl-3(4-phenyl-5-(pyridine-2-yl)-4H-1,2,4-triazol-3-yl)acrylic acid were confirmed by means of 1D and 2D NMR spectroscopic data as well as by single-crystal X-ray diffraction analysis. The experiential 1 H and 13 C chemical shifts were compared with those calculated with B3LYP, EDF1, and EDF2 density functional theories. The theoretical study of the observed terminal-to-internal alkene isomerization was performed with density functional (DFT) B3LYP/6-31+G / method using SM8 water and DMF solva- tion models. Antimicrobial activities of the newly prepared alkenoic acid derivatives were verified exper- imentally by a broth microdilution method. Ó 2012 Elsevier B.V. All rights reserved. 1. Introduction 1,2,4-Triazole derivatives constitute an important class of het- erocyclic compounds, which gained considerable attention in re- cent years due to a broad spectrum of biological properties, which include: antimicrobial, antiviral, anticancer, antiasthmatic, anticonvulsant, antidepressant, antihypertensive, antiemetic, hyp- notic, sedative, anxiolytic, antithyroid, hypoglycemic and antimi- graine activity [1]. Among them fluconazole and itraconazole belong to the most powerful antimycotic drugs used today in the treatment and prevention of superficial and systemic fungal infec- tions. On the other hand, it is well known that derivatives of vari- ous alkenoic acids [2–4] and cinnamic acid [5] exhibit a pronounced antibacterial and antifungal activities. In view of the above, we expected that by combining the 1,2,4- triazole ring system and the alkenoic acid moiety, a new class of heterocyclic analogues of cinnamic acid with the desired antimi- crobial properties could be obtained. Our research plane aimed at achieving that goal was based on previous investigations of hydra- zonamide chemistry [6–9] and chemical properties of itaconic anhydride [10,11]. The synthetic pathways leading to 2-((4-phe- nyl-5-(pyridin-2-yl)-4H-1,2,4-triazol-3-yl)methyl)acrylic acid (3) and (E)-2-methyl-3(4-phenyl-5-(pyridine-2-yl)-4H-1,2,4-triazol- 3-yl)acrylic acid (4) are presented in Scheme 1. The molecular structures of alkenoic acid derivatives obtained were confirmed 0022-2860/$ - see front matter Ó 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.molstruc.2012.04.087 ⇑ Corresponding author. Tel.: +48 583491953; fax: +48 583491654. E-mail address: js@gumed.edu.pl (J. Saczewski). Journal of Molecular Structure 1022 (2012) 211–219 Contents lists available at SciVerse ScienceDirect Journal of Molecular Structure journal homepage: www.elsevier.com/locate/molstruc