A theoretical study of the conformation and dynamic properties of 1,5-benzodiazepines and their derivatives Rosa M. Claramunt a , Ibon Alkorta b,⇑ , José Elguero b a Departamento de Química Orgánica y Bio-Orgánica, Facultad de Ciencias, Universidad Nacional de Educación a Distancia (UNED), Senda del Rey 9, E-28040 Madrid, Spain b Instituto de Química Médica, Centro de Química Orgánica ‘‘Manuel Lora-Tamayo’’, CSIC, Juan de la Cierva, 3, E-28006 Madrid, Spain article info Article history: Received 20 May 2013 Received in revised form 1 July 2013 Accepted 1 July 2013 Available online 9 July 2013 Keywords: 1,5-Benzodiazepines Conformation Ring inversion Quasi-aromaticity DFT abstract The geometries of eighteen 1,5-benzodiazepines including their oxo and thioxo derivatives have been cal- culated and compared with experimental geometries determined by X-ray crystallography using as prop- erty the methylene flip angle. Protonation of 3H-1,5-benzodiazepine lead to a planar quasi-aromatic cation. For the non-planar structures we have calculated ring inversion barriers that are well correlated with ten experimental values determined by Dynamic NMR allowing the establishment of an empirical equation for predicting new values. Ó 2013 Elsevier B.V. All rights reserved. 1. Introduction 1,5-Benzodiazepines (see Fig. 1), although of much lesser important than 1,4-benzodiazepines [1–4], have found their place in medicinal chemistry. The most important is Clobazam (a 2,4-dione derivative) to the point that several analogs have been developed. But there are much more, some of them being represented in Fig. 1. Their main field of application is in Central Nervous System (CNS) pathologies but 1,5-benzodiazepines have found applications in other fields, the most promising being as Cholecystokinin (CCK) antagonists with possible utility as analge- sics and for the treatment of Alzheimer’s disease [5]. Concerning 1,5-benzodiazepinones an excellent summary can be found in the paper by Okovytyy et al. [6]. Several of the different kinds of 1,5-benzodiazepines are struc- turally characterized by a conformational process that, in a first approximation, can be described as a flip involving position 3. It is similar to the equilibrium of cycloheptatriene (Fig. 2) [7]. Lloyd and Marshall introduced in 1971 the principle of quasi- aromaticity to describe the properties of diazepinium cations [8]. In what concerns their benzene analogs, such as 4 (see later on, Fig. 6), Lloyd and McNab have reviewed their properties, in partic- ular, their basicity and the intense change in color upon proton- ation [9]. Since we will start a research program to study the synthesis, spectroscopic and biological properties of 1,5-benzodiazepines as well as they theoretically calculated parameters, we decided to carry out a theoretical study of their geometries (in comparison with those determined by X-ray crystallography), their energies (related to their tautomerism) and one very characteristic property of many 1,5-benzodiazepines, their inversion barriers. This will allow testing the accuracy of our computational approach. The last section will deal with the old problem of the quasiaromaticity of benzo-1,5-diazepinium cations. 2. Computational details The geometry of the molecules has been fully optimized with the hybrid HF/DFT B3LYP [10–12] computational method at the B3LYP/6-311++G(d,p) level [13,14]. Frequency calculations have been carried out at the same computational level to verify that the structures obtained correspond to energetic minima (0) or to true transition states (1). NICS values [15] have been calculated at the GIAO [16]/6-311++G(d,p) level on the optimized geometry. All the calculations have been carried out with the Gaussian-09 package [17]. The chemical shifts (d, ppm) of compound 4 (R@H) and 4 0 (R@CH 3 ) were calculated from the GIAO absolute shieldings (r, ppm) and a set of empirical equations relating d to r [18,19]. Only 1 H chemical shifts were available (determined at 60 MHz) for these compounds [20–22]. 2210-271X/$ - see front matter Ó 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.comptc.2013.07.002 ⇑ Corresponding author. E-mail address: ibon@iqm.csic.es (I. Alkorta). Computational and Theoretical Chemistry 1019 (2013) 108–115 Contents lists available at SciVerse ScienceDirect Computational and Theoretical Chemistry journal homepage: www.elsevier.com/locate/comptc