Substituent Effect on the Aromaticity of 1,3-Azole Systems

Substituent effect on the aromaticity of 1,3-azole systems

Sel ç uk G ü m ü s¸ 1, * and Lemi T ü rker2 shift (NICS) (Schleyer et al. , 1996 ), which is the computed 1 Department of Chemistry , Faculty of Sciences, value of the negative magnetic shielding at some selected Yuzuncu Yil University, 65080, Kamp ü s, Van , Turkey points in space, generally, in a ring or a cage center. Negative 2 Department of Chemistry , Faculty of Arts and Sciences, NICS values denote aromaticity (-11.5 for benzene, -11.4 for Middle East Technical University, 06531, Ankara , Turkey naphthalene) and positive NICS values denote antiaromaticity (28.8 for cyclobutadiene), whereas small NICS values indi- * Corresponding author cate non-aromaticity (-3.1 for 1,3-cyclopentadiene). NICS e-mail: [email protected] may be a useful indicator of aromaticity that usually corre- lates well with the other energetic, structural and magnetic criteria for aromaticity (Jiao and Schleyer , 1998 ; Schleyer Abstract et al., 2000; Patchkovskii and Thiel, 2002; Quinonero et al., 2002 ). Resonance energies and magnetic susceptibilities are The effects of substituent type and position on the aromaticity measures of the overall aromaticity of a polycyclic molecule, of certain derivatives of oxazole, imidazole and thiazole have but do not provide information about the individual rings. been theoretically investigated by using density functional However, NICS is an effective probe for local aromaticity of theory at the levels of B3LYP/6-31G(d,p) and B3LYP/6- individual rings of polycyclic systems. ++ 31 G(d,p) methods. The second heteroatom substitution Furan, pyrrole and thiophene are the most common fi ve- decreases aromaticity of furan, pyrrole and thiophene. The membered aromatic heterocycles. They show aromatic decreased aromaticity is gained back to some extent by the delocalization involving the unshared electrons located on substitution of strong electron withdrawing groups or atoms respective heteroatom of the ring system. The nitrogen atom of (NO and F). Nucleus-independent chemical shift (NICS) 2 pyrrole is of ideal size to permit extension of the conjugation data have been considered to determine the aromaticity of the around the entire ring leading the maximum aromatic char- systems. The most effective substitution to enhance the aro- acter among the three (Cordell and Boggs , 1981 ). Through maticity has been calculated to be at position 4. The variation the same argument of size alterations, furan and thiophene of the bond lengths of the main skeleton supports the fi ndings become less aromatic than pyrrole. through NICS calculations. The frontier molecular orbital Introduction of a second heteroatom, nitrogen in the pres- energies have also been reported to draw a general correlation ent case, creates azoles. By means of centric perturbation between these energies and the aromaticity of the system. at position 3, oxazole, imidazole and thiazole (1,3-azoles) are structurally obtained from furan, pyrrole and thiophene, Keywords: aromaticity; imidazole; nucleus-independent respectively. It is expected that the introduction of a second chemical shift (NICS); oxazole; thiazole. heteroatom (nitrogen) will reduce the aromaticity of the parent heterocyclic structures due to less effective ring current because of some electron localization arising from electrone- Introduction gativity of the nitrogen atom at the perturbed site. The aim of the present article was to investigate the substituent effect on Aromaticity continues to be an actively investigated area of the aromaticity of 1,3-azoles. The effects of type and the posi- chemistry of cyclic structures. It has been shown to be a useful tion of certain substituents on these systems have been theo- quantity in the rationalization of structure, stability and reac- retically studied by means of density functional theory (DFT) tivity of many molecules. The simplest criterion for aromatic calculations focusing a particular interest on NICS values. compounds is that they possess cyclic conjugated π -systems containing the proper number of π -electrons. Although this criterion is robust enough to predict the aromaticity of a host Method of calculation of neutral and charged ring systems, it is not always a clear indicator of aromaticity for more complex systems (Garrat, The geometry optimizations of all the structures were achieved 1986 ; Proft and Geerlings , 2001 ). within the framework of DFT (B3LYP) (Kohn and Sham , Aromaticity is expressed by a set of combinations of prop- 1965 ; Parr and Yang , 1989 ). The exchange term of B3LYP erties in cyclic delocalized systems. In general, aromaticity is consists of hybrid Hartree-Fock and local spin density (LSD) discussed in terms of energetic, structural and magnetic crite- exchange functions with Becke’ s gradient correlation to LSD ria (Minkin et al., 1994; Schleyer and Jiao, 1996; Glukhovtsev, exchange (Becke, 1988). The correlation term of B3LYP 1997 ; Krygowski et al. , 2000 ; Schleyer , 2001 ; Cyranski et al. , consists of the Vosko, Wilk, Nusair (VWN3) local correla- 2002 ). In 1996, Schleyer et al. introduced a simple and effi - tion functional (Vosko et al., 1980) and Lee, Yang, Parr (LYP) cient probe for aromaticity: nucleus-independent chemical correlation correction functional (Lee et al., 1988). The BLYP 12 S. G üm ü s¸ and L. T ürker

method gives a better improvement over the SCF-HF results. ring current. This might be valid for fi ve-membered one het- Its predictions are in qualitative agreement with experiments eroatom containing systems. By contrast, if the heteroatom (Scuseria, 1992; Sosa and Lee, 1993; Wilson et al., 2000). has already caused some electron population localization on 6-31G(d,p) and 6-31 + +G(d,p) basis sets were used for geom- itself, thus affecting proper ring current destructively, then etry optimizations. the electron withdrawing substituent may counter balance The normal mode analysis for each structure yielded no this localization effect to restore the ring current. Hence, imaginary frequencies for the 3 N-6 vibrational degrees of positional effects of substituents arise. Similar type of argu- freedom, where N is the number of atoms in the system. This ments could be asserted for electron donating substituents indicates that the structure of each molecule corresponds to at which may restore the already disturbed ring current pres- least a local minimum on the potential energy surface. ent in the parent ring system. The most stable isomer for Absolute nuclear magnetic resonance (NMR) shielding each series depends on the type of the substituent and there values (Pulay et al., 1993) were calculated using the Gauge- is no general trend for nitro (NO2 ) and fl uoro (F) deriva- Independent Atomic Orbital method (Hehre et al. , 1986 ) with tives. However, substitution on position 2 creates the most the restricted closed shell formalism employing 6-31G(d,p) stable derivatives in the case of amino (NH2 ) substituted and 6-31 + +G(d,p) basis sets over B3LYP/6-31G(d,p) and heterocyclic systems, which can be attributed to the electron B3LYP/6-31 + + G(d,p) optimized geometries, respectively. donating ability of NH2 into the expectedly most electron NICS values were obtained by calculating absolute NMR defi cient point of the structures. For the NH2 substituted sys- shielding at the ring centers, NICS(0). tems, the stability order is 2 > 4 > 5 in terms of position of the The geometry optimizations and NICS calculations of substitution (Table 1 ). the present systems have been performed by the use of the Gaussian 03 package program (Frisch et al. , 2004 ). NICS

The delocalization of a certain number of π -electrons freely Results and discussion in a ring accounts for the aromaticity in that ring which results in better stability. NICS is a measure of aromatic- General ity related to the magnetic properties of the ring under consideration. The effects of centric perturbation of a heteroatom to the cen- The most well-known aromatic compound is benzene tral ring and/or substitution of a heteroatom or a heterocy- where a perfect delocalization of six π-electrons exists. clic group with the hydrogen atoms of well-known aromatic Therefore, in an aromatic ring substitution of a heteroatom compounds have always found application in both theoreti- decreases the aromaticity of the system to some extent due cal and experimental studies. In the present study, 1,3-azoles to the electronegativity difference between carbon and other (oxazole, imidazole and thiazole) and their substituted (NO , 2 atoms. The aromaticity of that ring even decreases more with F, NH ) counterparts have been theoretically investigated 2 the substitution of a second heteroatom, as in the present by performing DFT calculations at the levels of B3LYP/6- case. However, this diminished aromaticity can be restored 31G(d,p) and B3LYP/6-31+ +G(d,p) to determine their sta- back, up to a certain extent, by the substitution of one of the bilities and aromaticities. hydrogen atoms of the system by certain atoms or groups, The structures and numbering of the compounds are given thus improving cyclic delocalization of the ring electrons, in Figure 1 . as explained above in the energetics section. In our case, the effects of substitution of the electronegative nitro group and Energetics the fl uorine atom, as well as the electron donating amino The zero point corrected total electronic energies of the group, have been investigated by obtaining the NICS data at present systems have been obtained by the aforementioned the ring centers [NICS(0)], and the results are presented in methods and the results are given in Table 1 . At fi rst glance, Table 2 . The NICS values for the unsubstituted parent (1,3- one may think that either inductively and/or mesomerically azoles) and grandparent heterocycles (pyrrole, furan and thi- electron attracting groups decrease the aromatic stability ophen) have also been calculated at the same level to observe of the parent as well as its aza-substituted derivatives, 1,3- the change on the aromaticity, via both centric substitution azoles, by pulling some of the electron density out of the of C with N to form azoles and substitution of H with NO2 , F and NH2 . Pyrrole possesses better aromaticity than furan and thiophene as already reported in the literature (Cordell and Boggs, 4 3 3 3 N 4 N 4 N 1981). The very high electronegativity of oxygen disturbs the perfect delocalization of π -electrons over the periphery 5 2 5 2 5 2 of furan ring forming the least aromatic structure among the O N 1 S 1 H 1 three one-heteroatom-containing fi ve-membered molecules. Oxazole Imidazole Thiazole The NICS calculations successfully reproduce the expected decrease of the aromatic character after the second hetero- Figure 1 1,3-Azoles under consideration. atom substitution into the ring. Aromaticity of 1,3-azole systems 13

Table 1 Zero point energy corrected total electronic energies of the present structures.

System Substituent Energy (au) 245

Oxazole NO 2 -450.5568215 -450.565123 -450.5623468 -450.5768101 -450.584911 -450.5818323 Imidazole -430.718622 -430.7203484 -430.7214935 -430.738362 -430.7401607 -430.7409923 Thiazole -773.5398071 -773.5437326 -773.5408173 -773.5605968 -773.5643882 -773.5615828 Oxazole F -345.3034534 -345.3011643 -345.2983534 -345.3212699 -345.3199787 -345.3178564 Imidazole -325.4524601 -325.4520865 -325.4450461 -325.4725835 -325.4722104 -325.4651658 Thiazole -668.2791475 -668.2811163 -668.268907 -668.2981787 -668.3002487 -668.288019

Oxazole NH2 -301.4391176 -301.4335142 -301.4303801 -301.4569133 -301.4505452 -301.4475125 Imidazole -281.5839305 -281.5805658 -281.5770517 -281.6005069 -281.5969648 -281.5931504 Thiazole -624.4140277 -624.4118814 -624.4040885 -624.4340042 -624.4313909 -624.4233297 The ﬁ rst and second energy value in each cell was obtained from 6-31G(d,p) and 6-31+ + G(d,p) basis sets, respectively.

Going through the NICS data for different positions of the Table 2 Calculated NICS data for the present systems together substituents, the results reveal that substitution to the position with unsubstituted parent systems.

4 becomes more effective to enhance the aromaticity for NO2 - and F-substituted cases. The strongly electron withdrawing System Substituent NICS

NO2 group and electronegative F atom pulls the electrons 245 located on the nitrogen atom at position 3 into the ring result- Furan Unsubstituted -13.58 ing in greater (absolutely) NICS values than in the parent -13.03 azole. However, the decrease of the aromaticity when sub- Pyrrole -16.06 stitution exists on position 5 can be attributed to withdrawal -15.76 of the electrons on the double bond. The two unpaired elec- Thiophene -14.34 trons on the fi rst heteroatom (O, NH and S) which complete -13.87 the aromatic sextet can also be targeted by the electron-poor Oxazole Unsubstituted -12.56 -11.98 substituents. As published previously (T ü rker et al., 2009), Imidazole -14.94 NICS data differ with the applied method although the trend -14.54 of aromaticity is conserved. Thiazole -13.84 Figure 2 gives the 3D electrostatic potential maps of some -13.12 of the derivatives considered herein together with the parent Oxazole NO2 -12.00 -12.83 -11.47 imidazole. Red, green and blue represent strongly negative, -11.58 -12.44 -11.91 slightly positive and strongly positive values, respectively. Imidazole -14.54 -15.22 -13.08 Location of the negative charge is clearly observed on posi- -14.07 -14.93 -12.66 Thiazole -13.00 -13.96 -12.54 tion 3 of parent imidazole. The carbon between the two -12.76 -13.45 -12.19 nitrogen atoms of the main skeleton is more positive than Oxazole F -11.49 -13.59 -11.70 the other two. Substitution of the NO2 group on position 2 -11.00 -13.04 -11.24 results in a much more positively charged point 2 carbon, Imidazole -14.54 -15.80 -14.91 thus a much worse electron distribution for the enhance- -14.21 -15.39 -14.42 ment of the aromaticity. When this group is attached to Thiazole -12.85 -13.91 -12.46 position 5, it is so far to the nitrogen atom that the electrons -12.30 -13.43 -11.98 Oxazole NH2 -10.42 -12.37 -11.83 localized on this nitrogen cannot be pulled into the ring. -10.01 -11.88 -11.25 In other words, the aromaticity of the imidazole skeleton Imidazole -13.43 -14.36 -14.22 is maximized when the nitro group is located at position -12.89 -13.91 -14.01 4. The inductive effect of the amino-substituted position 4 Thiazole -11.54 -12.69 -11.75 makes carbons on position 4 more positive, hence the elec- -11.17 -12.14 -11.27 tron poor main ring becomes even more electron-defi cient The fi rst and second NICS value in each cell was obtained from and less aromatic. 6-31G(d,p) and 6-31+ + G(d,p) basis sets, respectively. 14 S. G üm ü s¸ and L. T ürker

Imidazole

2-Nitroimidazole 4-Nitroimidazole 5-Nitroimidazole

4-Aminoimidazole

Figure 2 3D electrostatic potential maps of some selected 1,3-azole derivatives.

Bond lengths the substituent has been found to be highly effective on the bond lengths in the systems. The shortening of the 3,4 bond Table 3 presents the bond lengths of the main skeleton for NO2 and F derivatives indicates the pulling of electrons obtained after the geometry optimizations. The position of from the nitrogen at point 3. By contrast, the same bond

Table 3 The effect of substitution on the bond lengths ( Å ).

Substituent Bond Oxazole Imidazole Thiazole 245245245

Unsubstituted 1,2 1.358 1.367 1.750 2,3 1.294 1.315 1.300 3,4 1.392 1.378 1.378 4,5 1.356 1.372 1.365 5,1 1.371 1.380 1.733

NO2 1,2 1.347 1.367 1.353 1.362 1.375 1.356 1.741 1.757 1.741 2,3 1.293 1.292 1.301 1.312 1.312 1.326 1.294 1.298 1.308 3,4 1.383 1.375 1.380 1.367 1.363 1.364 1.369 1.363 1.367 4,5 1.363 1.360 1.362 1.384 1.376 1.379 1.373 1.367 1.370 5,1 1.365 1.358 1.360 1.367 1.368 1.374 1.728 1.721 1.735 F 1,2 1.341 1.352 1.372 1.359 1.362 1.375 1.752 1.745 1.760 2,3 1.285 1.298 1.291 1.296 1.321 1.312 1.283 1.303 1.297 3,4 1.398 1.369 1.395 1.388 1.354 1.383 1.384 1.360 1.378 4,5 1.353 1.357 1.353 1.368 1.371 1.365 1.361 1.364 1.360 5,1 1.386 1.376 1.353 1.391 1.386 1.372 1.746 1.733 1.745

NH 2 1,2 1.356 1.345 1.380 1.368 1.358 1.367 1.775 1.740 1.764 2,3 1.303 1.297 1.287 1.315 1.319 1.315 1.304 1.301 1.294 3,4 1.395 1.390 1.395 1.385 1.376 1.379 1.380 1.381 1.377 4,5 1.350 1.364 1.367 1.367 1.379 1.376 1.358 1.374 1.372 5,1 1.393 1.385 1.364 1.391 1.390 1.383 1.755 1.738 1.753 Aromaticity of 1,3-azole systems 15

Table 4 Frontier molecular orbital energies of the systems (eV).

System Position 2 4 5 Substituent HOMO LUMOΔ ε HOMO LUMO Δ ε HOMO LUMO Δ ε

Oxazole -7.95 -2.94 5.01 -7.99 -2.57 5.42 -8.08 -2.93 5.15

Imidazole NO 2 -7.29 -2.58 4.71 -7.30 -2.02 5.28 -7.45 -2.59 4.86 Thiazole -7.78 -3.03 4.75 -7.88 -2.56 5.33 -7.94 -3.01 4.93 Oxazole -6.93 -0.02 6.92 -6.88 -0.38 6.50 -6.83 -0.13 6.69 Imidazole F -6.22 0.88 7.10 -6.16 0.51 6.68 -6.17 0.77 6.94 Thiazole -6.87 -0.73 6.14 -6.83 -1.07 5.76 -6.85 -0.87 5.98 Oxazole -5.46 0.95 6.41 -5.60 0.24 5.84 -5.25 0.75 6.00

Imidazole NH2 -5.35 1.23 6.58 -5.02 1.03 6.05 -5.66 1.04 6.71 Thiazole -5.49 0.17 5.66 -5.55 -0.49 5.06 -5.72 -0.32 5.40 length remains unchanged or slightly shortened in the case By contrast, position-wise inspection of substituent effects of the amino derivatives. The effect of substitution on the on the interfrontier molecular orbital energy gaps reveals that other centers has a very small effect on the shortening of in the cases of nitro and ﬂ uoro substitutions, Δ ε values follow this bond. the order of 4 > 5 > 2 and 4 < 5 < 2, respectively. Whereas, the When the substitution takes place at position 5, the 5,1 amino substitution exhibits the order of 4 < 5 < 2 for oxazole bond also becomes shorter, which may be an implication of and thiazole but 4 < 2 < 5 for imidazole. the shift of unshared π -electrons towards the substituent on this position. In the case of the amino-substituted derivatives, the 5,1 bond is lengthened, therefore the system ends up with Conclusion a less aromatic character. The effect of substitution on the aromaticity of dou- The HOMO-LUMO gap ble heteroatom containing 1,3-azole heterocycles has been theoretically investigated via NICS calculations at Haddon and Fukunaga showed that a direct relationship exists B3LYP/6-31G(d,p) level of theory. The decreased aroma- between the resonance energies and the HOMO-LUMO ticity by the introduction of the nitrogen heteroatom into energy gaps in [4n + 2] annulenes (Haddon and Fukunaga , the ring is gained back by the substitution of the strongly 1980). The HOMO-LUMO energy gap is an approxima- electron withdrawing groups or atoms. Aromaticity is tion to the global hardness of the system measuring stability enhanced mostly when the substitution takes place at posi- (Proft and Geerlings, 2001). Thus, the hardness and aro- tion 4 where the substituent is closest to the pyridine-like maticity show some relationship. A small HOMO-LUMO nitrogen. Generally, the frontier molecular orbital energies energy gap has been associated with antiaromaticity (Cava (HOMO and LUMO) are smaller for the structures with and Mitchell, 1967; Dewar, 1971; Willner and Rabinowitz, greater aromatic character. 1980). However, Fowler has pointed out that the HOMO- LUMO separation cannot be considered as a general criterion for the aromaticity or kinetic stability of polycyclic References aromatic hydrocarbons, as this energy gap generally tends Becke, A. D. Density-functional exchange-energy approxima- to be smaller for the larger hydrocarbons whether they are tion with correct asymptotic behavior. Phys. Rev. A 1988 , 38 , kinetically stable (Fowler , 1991 ). However, in the present 3098 – 3100. study it can be used to understand the positional effects of Cava, M. P.; Mitchell, M. J. Cyclobutadiene and Related Compounds ; substituents on the aromaticity of the ring as long as the ring Academic Press: New York, 1967. system is the same. Cordell, F. R.; Boggs, J. E. Structure and degree of aromatic char- Table 4 presents the calculated HOMO and LUMO ener- acter in furan, pyrrole, and thiophene. J. Mol. Struct. 1981 , 85 , gies together with the interfrontier molecular orbital energy 163 – 178. gaps. The nitro derivatives, which are generally more aro- Cyranski, M. K.; Krygowski, T. M.; Katritzky, A. R.; Schleyer, P. R. matic structures, possess lower HOMO and LUMO values. To what extent can aromaticity be deﬁ ned uniquely ? J. Org. Their HOMO-LUMO energy gaps are narrower than the Chem . 2002 , 67 , 1333 – 1338. systems having other substituents, F and NH , with a few Dewar, M. J. S. Aromatizitat und pericyclische reaktionen. Angew. 2 Chem. 1971 , 83 , 859 – 875. exceptions. Although the correlation is not that strong, the Fowler, P. Aromaticity revisited. Nature 1991 , 350 , 20 – 21. following conclusion can be drawn between these energies Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, and the aromaticities of the systems such that, the more aro- M. A.; Chesseman, J. R.; Montgomery, J. A. Jr.; Vreven, T.; matic the system is the lower HOMO and LUMO energies Kudin, K. N.; Burant, J. C.; et al. Gaussian 03, Revision D.01 ; or the more aromatic the system the narrower the HOMO- Gaussian Inc.: Wallingford, CT, 2004. LUMO gap. Garrat, P. J. Aromaticity. Wiley: New York, 1986. 16 S. G üm ü s¸ and L. T ürker

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