INDEX substituent effects

Recent research by Kornilov et al. (91ZOR144) on the aromaticity of 6-nitro-TPs substituted at C-2 revealed that the experimentally detected values (by reversible covalent hydration) proved more sensitive to substituent effects than the modified aromaticity index ANs of Pozharskii did. 

Chemical reactivity and NMR spectroscopy suggested that the tria-zolopyrimidines with bridgehead nitrogens are planar and possess a high degree of aromatic character (80PAC1611). The aromaticity of 6-nitrotriazolopyrimidines was found to be more sensitive to substituent effects than the ANs index (91ZOR144). The tautomeric equilibrium of the... 

Gaining maximum potency is only half the problem in drug design. The other half is to minimize unwanted side effects. Therefore, for the ultimate in maximization of the therapeutic index, regression analysis must also be applied to relate substituent effects to the various kinds of serious toxicity as these become evident. 

The polarizability effect index is based on the stabilizing energy Ex caused by the polarizability effect for a substituent X interacting with a point charge q. For alkanes and aliphatic alcohol substituents, the PEI values were defined by the following ... 

Kier, L.B. (1987d). The Substituent Steric Effect Index Based on the Molecular Graph. Quant Struct.-ActRelat, 6,117-122. 

Theoretical models provide interesting alternatives to evaluate intrinsic electronic substituent effects. This can be done for instance by means of the response functions defined as global or local reactivity indices. The variations of a reactivity index for a set of functional groups attached to a common molecular frame may also be taken as a measure of the influence that the different substituents may have on the reactivity pattern of molecules. 

For this study, we selected 42 representative FGs from a list of more than 500 substituents compiled by Hansch et a/.128 The electrophilicity index co for the whole series of ethylene derivatives, together with the experimental electronic substituent effects from the reactivity index co was as follows we first compared the computed co values with the experimental crp (see Figure 8). The analysis revealed a poor linear correlation between both quantities, with a regression coefficient R2 = 0.53. A better correlation was found when all the 42 points were fitted to a logarithm curve (.R2 = 0.84, see Figure 8). 

In summary, the calculated electrophilicity index, to, for a series of substituted ethylenes may be used to make reliable estimates of the intrinsic electronic contributions to the <7p constants of Hammett equation for a series including 42 functional groups commonly present in organic compounds. The computed trjto) parameters account for the intrinsic electronic substituent effects, which are contained in the experimental values of the <7p substituent constants. This useful predictive tool to assess the reactivity pattern of gas-phase reactions or those reactions that take place in solvents of very low polarity. 

Taking each ith carbon atom of an alkane molecule as the beginning one in the action of the probe, a P EI (X ) value can be calculated in the same way as P EI (X) for the substituent X then, the Molecular Polarizability Effect Index (MPEI) is derived as [Cao and Li, 1998] ... 

The Topological Steric Effect Index (TSEI) was proposed to describe the steric effects of substituents in terms ofthe relative specific volume ofthe reaction center screened by the atoms... 

Then, the topological steric effect index TSEI for an alkyl substituent, ignoring hydrogen atoms, is defined as... 

The topological steric effect index TSEIx for a substituent containing any heteroatom X is analogously calculated as... 

Kier, L.B. (1987d) The substituent steric effect index based on the molecular graph. Quant, Struct, -Act, Relat., 6, 117-122. 

Fuiidamental studies on the aromatic properties of the azoles was r orted during period. In a study of the role of zwitterions in the tautomerism of hydroxy anr mercaptoheterocycles, the introduced aromaticity index (1 ) for the l,z,3-triazoK thiolates (5, 5 ) was 99.8 and 99, respectively. These values are higher than the predictei value of 90 which indicates considerably more aromaticity than expected for this syster (94H(37)249]. The substituent effects of the trifluorometnyl group on the structure anc basicity of the 1,2,4-triazole nucleus was determined from studies with the mono- an<... 

Chermahini et al. (2007JMST(822)33) also studied substituent effects on the aromaticity (expressed by HOMA and NICS indices) of anionic and protonated forms of C5-X tetrazole derivatives (with X = NH2, OH, OMe, SMes, H, Me, F, Cl, BH2, CF3, CN, NO, and NO2). They have shown that the stability order of protonated forms is related to the nature of the substituent. For electron-withdrawing substituents, the stability follows the sequence 1,3-H > 1,4-H > 2,3-H > 1,2-H, but in the case of electron-donating groups the order of the stabihty changes to 1,4-H > 1,3-H > 1,2-H > 2,3-H. NICS(O) values suggest that the anionic forms of tetrazoles are less aromatic than IH- tautomers, whereas the obtained NICS(l) and HOMA values indicate that the aromaticity of anionic forms lies between those found for IH- and 2H- tautomeric forms. In the case of protonated tetrazole derivatives, the most aromatic are the 2,3-H forms, whereas 1,4-H tautomers are the least aromatic. Based on the HOMA index analysis the authors concluded that the aromaticity of protonated systems can be related to the nature of the substituent. However, a closer look on their results suggests that the Tt-electron delocalization of all the studied protonated systems hardly depends on the nature of the substituent at the position C5. 

A comparison of the substituent effects in monosubstituted tetrazole systems and benzene derivatives has been presented (2011T(67)6316). For this purpose the pEDA index (2009JPOC(22)769), defined as the sum of the occupation of 2p orbitals at aU atoms of the ring minus 6, has been used as a substituent descriptor. In aU three cases (substituted benzenes, IH- and 2H-tetrazole derivatives) the pEDA index, which ilLustrates the Tc-electron transfer from the substituent to the ring or vice versa, is weU correlated with constants. A more detailed analysis revealed that the dependence of 2pj, occupancies at the carbon atoms of benzene in either ortho- or para-positions on pEDA values are represented by linear trends with cc= 0.971 and 0.968, respectively. In contrast, the same correlation for the carbon atom in the meta-position is worse cc= —0.791) and with a small... 

Second, the substituent effect on the stabiHty and the aromaticity of substituted aza analogs of naphthalene should be considered. Different mono- and disubstituted derivatives of aza- and diazanaphthalenes (with F, Cl, OH, OCH3, and CN substituents) have been studied theoretically (2010JPOC(23)440, 2011CTC(963)263). Electronic (para-delocalization index (PDl), ATI, and FLU), magnetic (NICS), and structural (HOMA) aromaticity indices have been used to describe the local Tt-electron delocalization. It has been pointed out that the decrease of the aromaticity of dia-zanaphthalene can be compensated by the introduction of an... 

Continued investigations by Sawyer et al. (18-22) showed specific interactions affecting retention, thermodynamics and separation efficiencies, and correlations of aromatic substituent effects. These studies led to a thermodynamic gas chromatographic retention index for organic molecules. 

The hydrophobicity index is also suitable for correlating the cM values of various substituted sodium alkane 1-sulfonates [68]. The perfluoroalkyl substituent, e.g., 8 17 has a pronounced hydrophobic effect (/ = 1.66 at 75°C, sodium salt), whereas the hydrophilic disulfonates have values distinctly below 1 (for a-disulfonates, / = 0.75 was derived [70]). Further, it was somewhat surprisingly shown that substituents like 1-hydroxymethyl, 3-hydroxyethoxy, or even the hydroxyethoxyethoxy groups have hydrophobic effects. 

The susceptibility or mixing coefficients, pj and pj , depend upon the position of the substituent (indicated by the index, /) with respect to the reaction (or detector) center, the nature of the measurement at this center, and the conditions of solvent and temperature. It has been held that the p/scale of polar effects has wide general applicability (4), holding for substituents bonded to an sp or sp carbon atom (5) and, perhaps, to other elements (6). The or scale, however, has been thought to be more narrowly defined (7), holding with precision only for systems of analogous pi electronic frameworks (i.e., having a dependence on reaction type and conditions, as well as on position of substitution). 

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