A computational study on azaazulenes

Introduction

Aromatic compounds such as benzene, naphthalene, and anthracene play very important roles in both synthetic and computational organic chemistry. Azulene is an organic molecule that is an isomer of naphthalene. The structures of naphthalene and azulene are isoelectronic in terms of π systems. Both structures possess ten π electrons delocalized in two fused rings. Unlike naphthalene, which is formed by the fusion of two six-membered aromatic rings, azulene is composed of one five- and one seven-membered ionic aromatic ring. The symmetric distribution of electrons through naphthalene makes it nonpolar; however, azulene has a high dipole moment. This polarity can be attributed to azulene being composed of the fused aromatic six π electron cyclopentadienyl anion and aromatic six π electron tropylium cation. To achieve the stable aromatic sextet in both rings, one electron pair from the seven-membered ring is transferred to the five-membered ring [1–3].

Azaazulene compounds can modulate protein kinase (PK) activity and/or act as anticancer agents [4]. PKs are enzymes which catalyze the phosphorylation of specific tyrosine, serine, or threonine residues in cellular proteins. PKs mediate cellular signal transduction in regulating cellular function such as proliferation, differentiation, growth, cell cycle, cell metabolism, cell survival, cell apoptosis, DNA damage repair, cell motility, and response to the microenvironment. Dysregulated PK activity is a frequent cause of diseases such as angiogenesis, cancer, tumor growth, tumor metastasis, atherosclerosis, age-related macular degeneration, diabetic retinopathy, inflammatory diseases, and/or parasitical disease [4].

Aromaticity still continues to be a frequently investigated area of chemistry. The basic criterion for aromatic compounds is that they possess cyclic conjugated π systems containing the proper number of π electrons (i.e., the Hückel rule). Although this criterion is sufficiently strong to predict the aromaticity of a host of neutral and/or charged ring systems, it is not always a good indicator of aromaticity for more complex systems as in the present case.

Aromaticity is expressed by a combination of properties in cyclic delocalized systems. In general, aromaticity is discussed in terms of energetic, structural, and magnetic criteria [5–10]. In 1996, Schleyer and coworkers introduced a simple and efficient probe for aromaticity, namely, nucleus independent chemical shift (NICS) [11], which is the computed value of the negative magnetic shielding at some selected point in space, generally, at a ring or cage center. Negative NICS values denote aromaticity (-11.5 ppm for benzene, -11.4 ppm for naphthalene) and positive NICS values denote antiaromaticity (28.8 ppm for cyclobutadiene), whereas small NICS values indicate nonaromaticity (-2.1 ppm for cyclohexane, -1.1 ppm for adamantane) [11]. NICS may be a useful indicator of aromaticity that usually correlates well with other energetic, structural, and magnetic criteria for aromaticity [12–15]. Resonance energies and magnetic susceptibilities are measures of the overall aromaticity of a polycyclic system, but do not provide information about the individual rings. NICS is an effective probe for local aromaticity of individual rings of polycyclic systems.

The aromatic character of several organic compounds including azulene has been investigated theoretically by Schleyer and coworkers [11]. They applied B3LYP/6-31G(d) and B3LYP/6-31+G(d) methods for the computation of NICS data of the compounds and obtained -8.3 (-7.0) ppm and -21.5 (-19.7) ppm for seven-membered and five-membered rings of azulene, respectively. They reported that NICS values are only somewhat sensitive to the basis set and the use of 6-31+G* (where possible) is recommended [11].

Stanger describes major paradigms in the field of aromaticity and emphasizes the contradictions and paradoxes between these paradigms, and between different measures of aromaticity [16]. The effect of centric perturbation of a heteroatom to the aromatic rings of well-known aromatic compounds have always found application in both theoretical and experimental studies [17–21].

The present article reveals the results of the theoretical investigation on the effect of centric mono, di, tri, tetra, and penta aza substitution on the aromaticity of the parent azulene system. Moreover, the effect of the position of the aza substitution was investigated by the applications of NICS and electronic energy calculations.

Method of calculation

The initial geometry optimizations of all structures leading to energy minima were achieved by using the semi-empirical PM3 self-consistent field molecular orbital (SCF MO) method [22, 23] at the restricted level [24]. Then, geometry optimizations were achieved within the framework of density functional theory (DFT, B3LYP) [25, 26] at the level of 6-31+G(d,p) [24] without any symmetry constrains. The exchange term of B3LYP consists of hybrid Hartree-Fock and local spin density (LSD) exchange functions with Becke’s gradient correlation to LSD exchange [27]. The correlation term of B3LYP consists of the Vosko, Wilk, Nusair (VWN3) local correlation function [28] and the Lee, Yang, Parr (LYP) correlation correction function [29]. The predictions by the B3LYP method are often in qualitative agreement with the experiment [30–32].

The normal mode analysis for the structures yielded no imaginary frequencies for the 3N-6 vibrational degrees of freedom, where N is the number of atoms in the system. This indicates that the optimized structure of each molecule corresponds to at least a local minimum on the potential energy surface.

Absolute nuclear magnetic resonance (NMR) shielding values [33] were calculated using the gauge independent atomic orbital (GIAO) method [34], with the restricted closed shell formalism employing a 6-31+G(d,p) basis set over B3LYP/6-31+G(d,p) optimized geometries. NICS data were obtained by the computation of absolute NMR shielding at the ring centers, NICS(0).

The geometry optimizations and NICS calculations of the present systems were performed by using the Gaussian 03 package program [35].

Results and discussion

All possible aza analogs of azulene, containing from one to three nitrogen atoms in the five-membered ring or from one to five nitrogen atoms in the seven-membered ring were theoretically analyzed by the application of the B3LYP/6-31+G(d,p) level of theory in order to evaluate their stabilities and aromaticities. The mono and/or dicentric perturbations on positions of ring junctions were excluded because they would result in nonaromatic systems.

The molecules were labeled according to the positions of the nitrogens on the system (see Figure 1). The numbering scheme is illustrated for 5-N1 and 7-N1. The abbreviation 5-N1 presents azaazulene structure where aza substitution is at the five-membered ring and at position 1; 7-N1,N3,N5 means that substitution is on the seven-membered ring at positions 1, 3, and 5. Some of the monoaza and diaza derivatives of azulenes have been synthesized by several research groups: 5-N1 [36–38], 7-N1 [39, 40], 7-N2 [41], 5-N1,N2 [42], 5-N1,N3 [43].

Figure 1

The structures under consideration.

Energetics

The zero point corrected total electronic energies of the present systems were obtained by using the B3LYP/6-31+G(d,p) method. For each series of azaazulenes, the electronic energies of the molecules were calculated and relative energies were derived with respect to the most stable compound. Figure 2 shows the calculated relative electronic energies of the mono (black), di (blue), tri (red), and tetra (green) aza substituted azulene derivatives. The lowest energy compounds were found to be the 5-N1, 5-N1,N3, 7-N1,N3,N5, and 7-N1,N2,N3,N5 isomers for mono, di, tri, and tetra aza substituted azulene derivatives, respectively, and the graph was drawn accordingly. The graph of the relative energies indicates that the stability of the structures decreases for adjacent nitrogen atoms. The only exception is 5-N1,N2,N3, which might be due to preservation of aromaticity on both rings (see below). The drastic instability of 7-N1,N2, 7-N2,N3, 7-N1,N2,N3, and 7-N2,N3,N4 compared to the others can be attributed to vicinal positioning of the two nitrogen atoms for the diaza substituted derivatives and the sequential positioning of three nitrogen atoms for the triaza substituted derivatives. This result is consistent with a decrease of aromaticity in these derivatives.

Figure 2

Relative energies of compounds of the four series.

Conclusion

Centrically nitrogen substituted azulene derivatives were theoretically considered by the application of the DFT B3LYP/6-31+G(d,p) method to obtain information about their stabilities and aromaticities. The stabilities of the structures are strongly affected by the position of the aza points. The closer the nitrogens to one another, the less aromatic and thus less stable the system is. When the aza substitution is close to the fusion points for the five-membered ring, the aromaticity of the cyclopentadienyl anion part decreases and the aromaticity of the tropylium cation part increases.