Superdelocalizabilities electrophilic

The drug designer must consider the susceptibility to, and consequences of, the principal Phase 1 metabolic reactions hydrolysis, reduction and oxidation. Susceptibility to oxidation can be calculated using semi-empirical molecular orbital theory. Ease of oxidation is reflected by the energy of the HOMO, and the probable site of oxidation can be predicted from calculation of the electrophilic superdelocalizability. Likewise, ease of reduction is related to LUMO energy, and probable site to nucleophilic superdelocalizability (Loew and Burt, 1990). 

An electronic parameter that often correlates with metabolic rates is the electrophilic (or nucleophilic) superdelocalizability. This quantity is a reactivity index formulated by Fukui and colleagues as an orbital-weighted electron density.145 The total electrophilic superdelocalizability, 2SE, summed over all atoms in a molecule, exhibits a parallelism with the hydrophobic parameter, log P, in several series of compounds such as PAHs and aliphatic amines, where it is probably approximating molecular volume. 

The superdelocalizability of an atom in a molecule provides another measure of the tendency of the molecule to be attacked by an electrophile or nucleophile. It is related to electron density on that atom. The electrophilic superdelocalizability for a given atom k in the molecule may be defined as a sum over occupied MOs (index i) and valence AOs (index r), Eq. [14]. 

It is a measure of the availability of electrons in the flth atom. If the transition states are mainly controlled by the frontier orbital, the electrophilic superdelocalizability is calculated on the highest occupied molecular orbital (HOMO). 

The maximum electrophilic superdelocalizability among all the atoms in a molecule is a molecular descriptor defined as ... 

The total electrophilic superdelocalizahiiity is the sum over all of the atoms of the electrophilic superdelocalizability, i.e. 

The average electrophilic superdelocaiizability is derived from the total electrophilic superdelocalizability as ... 

In another study, the electrophilic superdelocalizability at the 6-position of purine derivatives, Sf, was established as the main factor determining the activity of these compounds against murine solid adenocarcinoma CA 755. The respective QSAR equation [97] ... 

In practice, this Hansch equation is usually simplified. Some of its parameters are considered as empirical ones, the others being obtained from quantum chemical estimates. A similar correlation with the atomic electrophilic superdelocalizability S, (E) is given for phenyl derivatives ... 

An example of a QSERR study is by Carotti [39]. It involves the resolution of sulfoxides, 20, on a it-acid CSP containing (S,S)-N,N -(3,5-dinitrobenzoyl)-frans-1,2-diaminocyclohexane (DACH-DNB), 19a. After establishing capacity factors, k s and k R for the first and second eluted enantiomers, respectively, as well as determining the separation factors, a, the authors began their computational studies. They used a variety of electronic descriptors for the analytes including electrophilic superdelocalizabilities (S omo) and nucleophilic superdelocalizabilities of various key analyte atoms... 

Protein binding and several other SAR s of phenols are correlated by summed electrophilic superdelocalizabilities [ZS (E)] and the electron density of the hydroxyl oxygen atom divided by MW (q /MW) (142). Descriptor estimations are based on HMO calculations. The involvement of molecular electrophilic character with specific in-volvment of phenolic OH suggests general dipolar binding with probable H-bond formation. As in the previous case, the same conclusions would likely be reached with classical descriptors, though it is rare for quantum chemists to cross-validate in this way. 

Tehan et al. [213] used the AMI [211] semiempirical method and parameters from frontier electron theory [214] to model the pK s of 55 anilines, Using the electrophilic superdelocalizability SE, of the nitrogen atom they obtained the relation... 

Historically, multiple theoretical descriptor-based approaches to H-bond strength ranking were proposed. That includes approaches based on group contribution method [46], electrostatic potentials [47], electrophilic superdelocalizability and self-atom polarizability [48], Quantum Theory of Atoms In Molecules (QTAIM) descriptors [49-51], the two-center shared electron number a and the product of ionization potential [45, 52], and local quantum mechanical molecular parameters, which quantify electrostatic, polarizability, and charge transfer contributions to H-bonding [53, 54],... 

Another problem which is frequently encountered in the distribution of data is the presence of outliers. Consider the data shown in Table 3.1 where calculated values of electrophilic superdelocalizability (ESDLIO) are given for a set of analogues of antimycin Al, compounds which kill human parasitic worms, Dipetalonema vitae. The mean and standard deviation of this variable give no clues as to how well it is distributed and the skewness and kurtosis values of —3.15 and 10.65 respectively might not suggest that it deviates too seriously from normal. A frequency distribution for this variable, however, reveals the presence of a single extreme value (compound 14) as shown in Fig. 3.5. This data was analysed by multiple linear regression (discussed further in Chapter 6), which is a parametric method based on the normal distribution. The presence of this outlier had quite profound effects on the analysis, which could have been avoided if the data distribution had been checked at the outset (particularly by the present author). Outliers can be very informative and should not simply be discarded as so frequently happens. If an outlier is found in one of the descriptor variables (physicochemical data), then it may show... 

Correlation with the electrophilic superdelocalizability on the oxygen atom was poor (r = 0.324), as was that with the difference in values between the carbon and oxygen atoms (r = 0.022). 

Site-specific reactivity indices are arrived at by considering electronic information at specific locations in the molecule. The electrophilic and nucleophilic superdelocalizabilities at atom i are energy-weighted atomic electron densities. The electrophilic superdelocalizability roughly measures the availability of electrons at atom i nucleophilic superdelocalizability measures the availability of room on atom i for additional electron density. While these indices are atomic in nature, they may be classified as whole molecule descriptors if atom i is a fixed position in a series of congeners, or if the maximum superdelocalizability among all the atoms is chosen. 

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