The n,π* States of Heteroaromatics: When are They the Lowest Excited States and in What Way Can They Be Aromatic or Antiaromatic?

Heteroaromatic molecules are found in areas ranging from biochemistry to photovoltaics. We analyze the n,π* excited states of 6π-electron heteroaromatics with in-plane lone pairs (nσ, herein n) and use qualitative theory and quantum chemical computations, starting at Mandado's 2n + 1 rule for aromaticity of separate spins. After excitation of an electron from n to π*, a (4n + 2)π-electron species has 2n + 2 πα-electrons and 2n + 1 πß-electrons (or vice versa) and becomes πα-antiaromatic and πß-aromatic. Yet, the antiaromatic πα- and aromatic πß-components seldom cancel, leading to residuals with aromatic or antiaromatic character. We explore vertically excited triplet n,π* states (3n,π*), which are most readily analyzed, but also singlet n,π* states (1n,π*), and explain which compounds have n,π* states with aromatic residuals as their lowest excited states (e.g., pyrazine and the phenyl anion). If the πß-electron population becomes more (less) uniformly distributed upon excitation, the system will have an (anti)aromatic residual. Among isomers, the one that has the most aromatic residual in 3n,π* is often of the lowest energy in this state. Five-membered ring heteroaromatics with one or two N, O, and/or S atoms never have n,π* states as their first excited states (T1 and S1), while this is nearly always the case for six-membered ring heteroaromatics with electropositive heteroatoms and/or highly symmetric (D2h) diheteroaromatics. For the complete compound set, there is a modest correlation between the (anti)aromatic character of the n,π* state and the energy gap between the lowest n,π* and π,π* states (R2 = 0.42), while it is stronger for monosubstituted pyrazines (R2 = 0.84).

On the Unusual Global Aromaticity of Two Cyclopenta-ring-fused Oligo(m-phenylenes).

Some years ago, Jishan Wu reported the synthesis of 8MC and 10MC, two homologues of the cyclopenta-ring-fused oligo(m-phenylene) macrocycles mMC, each behaving as an annulene-within-an-annulene (AWA). This was a surprising result as the AWA behavior is rare. Both molecules have a partial polyradical character, enforced by the quest for restoring some aromatic character of benzene rings. However, that restoration brings back some coupling between the two annulenes. Indeed, we found that the geometry and the magnetically induced currents indicate that, while 8MC does have an AWA character, this is not the case of the larger 10MC. Limitations of the design strategy of AWA molecules should be taken into account in future attempts to prepare novel large coronenes.

3,4-Dimethylenecyclobutene: A Building Block for Design of Macrocycles with Excited State Aromatic Low-Lying High-Spin States.

3,4-Dimethylenecyclobutene (DMCB) is an unusual isomer of benzene. Motivated by recent synthetic progress to substituted derivatives of this scaffold, we carried out a theoretical and computational analysis with a particular focus on the extent of (anti)aromatic character in the lowest excited states of different multiplicities. We found that the parent DMCB is non-aromatic in its singlet ground state (S0), lowest triplet state (T1), and lowest singlet excited state (S1), while it is aromatic in its lowest quintet state (Q1) as this state is represented by a triplet multiplicity cyclobutadiene (CBD) ring and two uncoupled same-spin methylene radicals. Interestingly, the Q1 state, despite having four unpaired electrons, is placed merely 4.8 eV above S0, and there is a corresponding singlet tetraradical 0.16 eV above. The DMCB is potentially a highly useful structural motif for the design of larger molecular entities with interesting optoelectronic properties. Here, we designed macrocycles composed of fused DMCB units, and according to our computations, two of these have low-lying nonet states (i. e., octaradical states) at energies merely 2.40 and 0.37 eV above their S0 states as a result of local Hückel- and Baird-aromatic character of individual 6π- and 4π-electron monocycles.

Effect of Benzo-Annelation on Triplet State Energies in Polycyclic Conjugated Hydrocarbons.

In a series of earlier studies, the effect of benzo-annelation was found to be a useful tool for tuning the aromaticity in polycyclic conjugated compounds to desired level. In this work we studied the (anti)aromaticity of benzo-annelated derivatives of three conjugated hydrocarbons (anthracene, fluoranthene and biphenylene) in their lowest lying singlet (S0) and triplet (T1) states by means of the energy effect (ef), harmonic oscillator model of aromaticity (HOMA), multicentre delocalization indices (MCI), magnetically induced current densities (MICDs) and nucleus independent chemical shifts (NICS). We showed that benzo-annelation is a topology-based effect which can be used to modify the T1 state excitation energies (E(T1)). A quantitative model was established being able to accurately predict the E(T1) based only on the numbers of angularly, linearly and geminally annelated benzene rings. In addition, it was demonstrated that the E(T1) can be directly related to the (anti)aromatic character of the central ring in the studied molecules in their S0 state.

Aromaticity of Osmaacenes in Their Lowest-Lying Singlet and Triplet States.

The aromatic character of a series of osmaacenes in their lowest-lying singlet and triplet states was thoroughly examined by means of the magnetically induced current densities and multicentre delocalization indices (MCIs). Both employed approaches agree that the osmabenzene molecule (OsB) in the S0 state exhibits dominant π-Hückel-type aromatic character, with a small but nonnegligible amount of π-Craig-Möbius aromaticity. Contrary to benzene, which is antiaromatic in the T1 state, OsB preserves some of its aromaticity in the T1 state. In higher members of the osmaacene series in the S0 and T1 states, the central Os-containing ring becomes nonaromatic, acting as a barrier between the two side polyacenic units which, on the other hand, exhibit a significant extent of π-electron delocalization.

Dichotomy of Delocalization/Localization and Charge-Shift Bonding in Germanazene and its Heavier Group 14 Analogues: a Valence Bond Study.

We present here a valence bond analysis of structure and π-delocalization in Ge3 (NH)3 , which models germanazene that was prepared by Power et al. To get a broader perspective, we explore the entire E3 (NH)3 series (E=C, Si, Ge, Sn, Pb). Thus, while (4n+2)π systems of carbon rings are aromatic with cyclic π-delocalization, the E3 (NH)3 rings are dominated by a nonbonded structure, wherein π-lone pairs are localized on the N atoms. Nevertheless, these molecules enjoy large covalent-ionic resonance energies of 153.0, 86.6, 74.2, 61.2, and 58.9 kcal/mol, respectively, for E=C, Si, Ge, Sn, Pb. The covalent-ionic mixing in E3 (NH)3 creates π-systems, which are stabilized by charge-shift bonding. Thus, unlike in benzene, in Ge3 (NH)3 delocalization of π-electron pairs of the N atoms is primarily confined to the domains of their adjacent Ge atoms. These features carry over to the substituted germanazene, Ge3 (NAr)3 (Ar=Ph).

Curcumin and Diclofenac Therapeutic Efficacy Enhancement Applying Transdermal Hydrogel Polymer Films, Based on Carrageenan, Alginate and Poloxamer.

Films based on carrageenan, alginate and poloxamer 407 have been formulated with the main aim to apply prepared formulations in wound healing process. The formulated films were loaded with diclofenac, an anti-inflammatory drug, as well as diclofenac and curcumin, as multipurpose drug, in order to enhance encapsulation and achieve controlled release of these low-bioavailability compounds. The obtained data demonstrated improved drug bioavailability (encapsulation efficiency higher than 90%), with high, cumulative in vitro release percentages (90.10% for diclofenac, 89.85% for curcumin and 95.61% for diclofenac in mixture-incorporated films). The results obtained using theoretical models suggested that curcumin establishes stronger, primarily dispersion interactions with carrier, in comparison with diclofenac. Curcumin and diclofenac-loaded films showed great antibacterial activity against Gram-positive bacteria strains (Bacillus subtilis and Staphylococcus aureus, inhibition zone 16.67 and 13.67 mm, respectively), and in vitro and in vivo studies indicated that curcumin- and diclofenac-incorporated polymer films have great potential, as a new transdermal dressing, to heal wounds, because diclofenac can target the inflammatory phase and reduce pain, whereas curcumin can enhance and promote the wound healing process.

Aromaticity of Singlet and Triplet Boron Disk-like Clusters: A Test for Electron Counting Aromaticity Rules.

Boron clusters are polyhedral boron-containing structures that have unique features and properties. The disk-like boron clusters are among the most fascinating boron cluster forms. These clusters have a molecular orbital (MO) distribution similar to the one derived from the simple particle-on-a-disk model. In this model, the MOs come in pairs except for m = 0. Disk-like boron clusters in their singlet ground state are aromatic when they reach a closed-shell structure. One could expect that disk-like aromatic boron clusters in the singlet state, when acquiring or releasing two electrons, may also be aromatic in the lowest-lying triplet state. We use magnetically induced current densities and bond current strengths to analyze the aromatic character of a series of disk-like boron clusters. Our results show that, with the exception of triplet 3B19-, the disk-like boron clusters follow Hückel and Baird's rules if one considers the different MOs grouped by their symmetry. We also found that if the lowest-lying triplet state in disk-like boron clusters is aromatic, this triplet state is the ground state for this species.

Tuning the Structure and Properties of N-doped Positively Charged Polycyclic Aromatic Hydrocarbons.

A detailed study of the geometry, aromatic character, electronic and magnetic properties for a series of positively charged N-doped polycyclic aromatic hydrocarbons (PAHs) was performed. Magnetic properties of the examined molecules were analyzed by means of the magnetically induced current density calculated using the diamagnetic-zero version of the continuous transformation of origin of current density (CTOCD-DZ) method. The comparative study of the local aromaticity of the studied molecules was performed using several different indices: energy effect (ef), harmonic oscillator model of aromaticity (HOMA) index, six centre delocalization index (SCI) and nucleus independent chemical shifts (NICS). The presence of N-atoms in the inner rings was found to cause a planarity distortion in the studied N-doped systems. The geometric changes and charged nature of the studied N-doped systems do not significantly influence the current density and the local aromaticity distribution in comparison with the corresponding parent benzenoid hydrocarbons. The present study demonstrates how quantum chemical calculations can be used for rational design of novel PAHs and for fine tuning of their properties.

Electronic structure, stability, and aromaticity of M2B6 (M = Mg, Ca, Sr, and Ba): an interplay between spin pairing and electron delocalization.

It has been shown in previous studies that the Be2B6 complex exhibits a triplet ground state with double aromaticity. In this work, the stability, electronic structure, and aromaticity of the homologous series M2B6 (M = Mg, Ca, Sr and Ba) were examined and compared to those of Be2B6. At the CCSD(T)/def2-TZVP//B3LYP/def2-TZVP level of theory, the target molecules were found to be more stable in the singlet than in the triplet spin state. Magnetically induced current densities and multicentre delocalization index (MCI) were employed to assess the aromatic character of the studied complexes. Both employed methods agree that M2B6 (M = Mg, Ca, Sr and Ba) are π aromatic and σ nonaromatic in the singlet ground state, and double aromatic in the triplet state. It was demonstrated that the electron counting rules of aromaticity cannot be used to correctly predict the aromaticity and relative stability of the examined molecules in different spin states.

Spatial and Electronic Structures of BeB8 and MgB8 : How far Does the Analogy Go?

Doping boron clusters with Be and its heavier alkaline-earth congener, Mg, usually leads to complexes of different geometry and electronic structure. In this work we show that both neutral BeB8 and MgB8 exhibit a singlet ground state umbrella-like form. In addition, the stability, electronic structure, and aromaticity of the target molecules are compared. The magnetically induced current densities show that BeB8 and MgB8 are double aromatic systems: π and σ electrons induce strong diatropic currents. The current densities induced in the studied complexes are of very similar intensity, but with a different spatial distribution. The differences in the current density patterns observed for BeB8 and MgB8 arise from the very nature of the bonding interactions between the M atom and B8 fragment, as demonstrated through the energy decomposition analysis.

On the Nature of the Bonding in Coinage Metal Halides.

This article analyzes the nature of the chemical bond in coinage metal halides using high-level ab initio Valence Bond (VB) theory. It is shown that these bonds display a large Charge-Shift Bonding character, which is traced back to the large Pauli pressure arising from the interaction between the bond pair with the filled semicore d shell of the metal. The gold-halide bonds turn out to be pure Charge-Shift Bonds (CSBs), while the copper halides are polar-covalent bonds and silver halides borderline cases. Among the different halogens, the largest CSB character is found for fluorine, which experiences the largest Pauli pressure from its σ lone pair. Additionally, all these bonds display a secondary but non-negligible π bonding character, which is also quantified in the VB calculations.

Relating nucleus independent chemical shifts with integrated current density strengths.

Indices based on the nucleus independent chemical shift (NICS) are the most frequently used in analysis of magnetic aromaticity. The magnetically induced current density, on the other hand, is a key concept in defining magnetic aromaticity. The integrated current strength (current strength susceptibility) was found to be a very useful tool in aromaticity studies. There is widely accepted notion that the properly chosen NICS-based index can provide information on the current density strength and direction in a molecule of interest. In this work, a detailed numerical testing of the relationship between the integrated bond current strength and the most employed NICS indices was performed for a set of 43 monocyclic aromatic molecules. Based on the statistical data analysis, the relationship between the bond current strength and its π and σ electron components, on one side, and the isotropic NICS (NICSiso and NICSπ,iso) and zz-component of the NICS tensor (NICSzz and NICSπ,zz), on the other side, was examined. It was found that between the NICSπ,zz(1) and π-electron bond current strenghts there is very good linear correlation. Quite surprisingly, it was revealed that the NICSiso(1) and NICSzz(1) are not correlated with the π electron bond current strengths. On the other hand, a reasonably good linear correlation was found between the NICSzz(1) and total bond current strengths.

Na⋠⋠⋠B Bond in NaBH3 - : Solving the Conundrum.

Bonding in the recently synthesized NaBH3 - cluster is investigated using the high level Valence Bond BOVB method. Contrary to earlier conclusions, the Na-B bond is found to be neither a genuine dative bond, nor a standard polar-covalent bond at equilibrium. It is rather revealed as a split and polarized weakly coupled electron-pair, which allows this cluster to be more effectively stabilized by a combination of (major) dipole-dipole electrostatic interaction and (secondary) resonant one-electron bonding mechanism. Our analysis of this unprecedented bonding situation extends to similar clusters, and the VB model unifies and articulates the previously published variegated views on this exotic "bond".

Heteroatom effects on aromaticity of five-membered rings in acenaphthylene analogs.

The pattern of cyclic conjugation was thoroughly studied in the series of N- and P-acenaphthylene derivatives using several different aromaticity indices: the energy effect (ef), multicenter delocalization index (MCI), harmonic oscillator model of aromaticity (HOMA) index, and nucleus independent chemical shifts (NICS). The Kekulé-structure-based reasoning predicts that there would be no cyclic conjugation in the "empty" five-membered heteroatom-containing rings in the studied molecules. It was found that according to the ef, MCI, and HOMA values, the extent of cyclic conjugation in the pentagonal rings is strongly influenced by the number and mutual arrangement of the hexagonal rings. In addition, it was revealed that in some of the examined molecules, the intensity of cyclic conjugation in the "empty" pentagons is even stronger than that of some hexagonal rings within the same molecule. The obtained results refute what one would expect based on "chemical intuition," which is usually strongly rooted to the Kekulé structures.Graphical abstract.

Magnetically Induced Current Density in Nonplanar Fully Benzenoid Hydrocarbons.

In our recent paper, the effects of molecular planarity on the local aromaticity in several series of increasingly planar fully benzenoid hydrocarbons were examined. It was found that the Clar formulas can provide correct information on the local aromaticity distribution even in nonplanar fully benzenoid systems. In the present work, the influence of molecular planarity on the ab initio magnetically induced current densities was examined for the same sets of molecules. The planarity effects were rationalized by examining the origins of the induced current density through the virtual transitions between occupied and unoccupied molecular orbitals.

Magnetically induced current density in triple-layered beryllium-boron clusters.

Magnetically induced current densities were used to examine the aromatic character of two charged Be-B clusters, Be6B102- (1) and Be6B11- (2). The current densities were computed by means of the diamagnetic-zero variant of the continuous transformation of the origin of the current density (CTOCD-DZ) method. It has been shown in previous studies that 1 and 2 have a triple-layered structure in which a B10/B11 central ring is sandwiched between two Be3 rings. The current density calculations for the examined Be-B clusters revealed their double aromatic nature, which arises from the presence of two orthogonal, cyclically delocalized electronic subsystems within these molecules. The pattern of the current density distribution in the triple-layered Be-B clusters was found to be analogous to the one in the monocyclic C10 cluster, which is a prototypical double aromatic system. The present study demonstrated that the current-density-based analysis provides much more information about the aromatic nature of the studied molecules than that based on the nucleus independent chemical shifts (NICS) index.

Assessing the Extent of π-Electron Delocalization in Naphtho-Annelated Fluoranthenes by Means of Topological Ring-Currents.

The extent of π-electron delocalization in the five-membered rings of 14 naphtho-annelated fluoranthenes has recently been assessed by means of several approaches, including application of the following indices: the energy effect (ef), bond resonance-energy (BRE), multicenter delocalization-energies (MCI), the index arising from the harmonic-oscillator model of aromaticity (HOMA), and nucleus-independent chemical shifts (NICS). The calculated Hückel-London-Pople-McWeeny (HLPM) ("topological") ring-current intensities (TRC) for the five-membered rings of these same structures are here compared with the above-named indices in order to assess how well TRC parallels these other criteria. The indices ef and BRE are the ones that correlate best with TRC, and it is suggested that this is because all three approaches are founded on the Hückel model. TRC does not, however, confirm the proposal that cyclic delocalization in the five-membered rings can be greater than in any of the six-membered rings in this series of conjugated systems. Certain ostensible shortcomings of the NICS approach are discussed, and some doubts are emphasized regarding the legitimacy of associating "ring currents" with "aromaticity".

Mononuclear gold(III) complexes with phenanthroline ligands as efficient inhibitors of angiogenesis: A comparative study with auranofin and sunitinib.

Gold(III) complexes with 1,7- and 4,7-phenanthroline ligands, [AuCl3(1,7-phen-κN7)] (1) and [AuCl3(4,7-phen-κN4)] (2) were synthesized and structurally characterized by spectroscopic (NMR, IR and UV-vis) and single-crystal X-ray diffraction techniques. In these complexes, 1,7- and 4,7-phenanthrolines are monodentatedly coordinated to the Au(III) ion through the N7 and N4 nitrogen atoms, respectively. In comparison to the clinically relevant anti-angiogenic compounds auranofin and sunitinib, gold(III)-phenanthroline complexes showed from 1.5- to 20-fold higher anti-angiogenic potential, and 13- and 118-fold lower toxicity. Among the tested compounds, complex 1 was the most potent and may be an excellent anti-angiogenic drug candidate, since it showed strong anti-angiogenic activity in zebrafish embryos achieving IC50 value (concentration resulting in an anti-angiogenic phenotype at 50% of embryos) of 2.89µM, while had low toxicity with LC50 value (the concentration inducing the lethal effect of 50% embryos) of 128µM. Molecular docking study revealed that both complexes and ligands could suppress angiogenesis targeting the multiple major regulators of angiogenesis, such as the vascular endothelial growth factor receptor (VEGFR-2), the matrix metalloproteases (MMP-2 and MMP-9), and thioredoxin reductase (TrxR1), where the complexes showed higher binding affinity in comparison to ligands, and particularly to auranofin, but comparable to sunitinib, an anti-angiogenic drug of clinical relevance.

Aromaticity of Nonplanar Fully Benzenoid Hydrocarbons.

The Clar aromatic sextet theory can provide a qualitative description of the dominant modes of cyclic π-electron conjugation in benzenoid molecules and of the relative stability among a series of isomeric benzenoid systems. In a series of nonplanar fully benzenoid hydrocarbons, the predictions of the Clar theory were tested by means of several different theoretical approaches: topological resonance energy (TRE), energy effect (ef), harmonic oscillator model of aromaticity (HOMA) index, six center delocalization index (SCI), and nucleus-independent chemical shifts (NICS). To assess deviations from planarity in the examined molecules, four different planarity descriptors were employed. It was shown how the planarity indices can be used to quantify the effect of nonplanarity on the local and global aromaticity of the studied systems.