Rekker method

Method of Nys and Rekker The Nys and Rekker method [53,54] has been developed for mono- and di-substituted benzenes. The substituents considered are halogen atoms and hydroxyl, ether, amino, nitro, and carboxyl groups, for which contributions have been calculated by multiple regression analysis (s = 0.106, r = 0.994, F = 1405). Rekker discusses the extension of his approach to other compound classes, such as PAHs, pyridines, quinolines, and isoquinolines. 

Table 5. Log P calculation of DDT (2) comparison of the Leo/Hansch and the Rekker method (reproduced from ref. [259] with permission from the copyright owner)...

A modified version of the Rekker method, which has to be further evaluated, was recently published [56]. Some other atom-, bond- and group-based calculation procedures e.g. [264—271]) have been developed most of them are reviewed and critically commented in ref. [173]. The calculation of hydrophobic fields from lipophilicity contributions is discussed in chapter 9.2. 

Fiirst Sandor utca 5 H-1136 Budapest, Hungary Tel. 36-1-112-4874, fax 36-1-132-2574 Prediction of metabolic products based on a library of known transformations. HARZARDEXPERT for prediction of toxicity. MOLIDEA for molecular modeling, molecular mechanics CNDO/2 and CNDO/S calculations. DRUGIDEA for QSAR. LABSWARE for general computations and statistics. PRO-LOGP for lipophilicity calculation using R. F. Rekker method. PC. 

The ProLogP (1992) software estimates partition coefficients based on the Rekker method. 

Log P (Rekker method) and log D (PROLOGP and pKalc) calculation software. 

The obvious drawback of this method is that the parent solute, at least, has to be available or must be synthesized, and its log P value has to be determined experimentally. Nys and Rekker therefore developed a method known as the fragmental constant approach, which is based on the additivity of fragment contributions to the molecular lipophilidty [7] (see Eq. (9), where a( is the inddence of fragment i, fi the lipophilic fragment constant, Ci a corredion factor, and the frequency of Cm). 

Fig. 14.1 LogP calculation for quinidine with the fragmental method according to Rekker and Mannhold. Calculation starts with the gross formula C20H24N2O2 definition of...

The difficulties and low-throughput nature of the experimental dual determination, especially in alkane-water systems, the development of other techniques more amenable to automation, as well as more refined computational approaches for octanol-water systems, aU have contributed to Umit the use of the alkane-water system as a second bulk-phase system. However, efforts have been devoted to the development of log (alkane) computational prediction methods by Rekker et al. [13] as well as Caron and Ermondi [14]. 

The presenee of intramoleeular interaetions ean be eheeked by eomparing calculated and experimental log P values. Sueh identifieation ean yet only be obtained for the water-OCT system, sinee eomputed lipophilieity values have only been derived for this solvent pair. Due to its simplicity and its easy adaptation to eomplex structures, Rekker s calculation method is often appreciated, but more sophistieated approaches like that evaluating log P using the molecular lipophilicity potential (MLP) has also been employed. 

As mentioned before, the hydrophobicity and the partition coefficient can be related to the solubility of the solutes in water (also see Section 15.8.4). The partition coefficient (P) between octanol and water can be described as the 7r-constant of Hansch or the logP values of Rekker. The logP values calculated from the fragmental constant are then used for the optimization of RPLC. However, this method is not adequate to develop an optimization system for the mixtures of different types of compounds [71]. 

The measurement of the solubility of drugs in polar and non-polar media is very important in the pharmaceutical field. One method proposed to describe this solubility is the partition coefficient between octanol and water. The mathematical calculation of an octanol-water partition coefficient from values for functional groups was first proposed by Hansch et al. as Hansch s n constants,1 and was later developed by Rekker as hydrophobic fragmental constants (logP).2 This method was further improved by the use of molecular connectivities.17 The prediction of logP values can be performed by either a computer program or by manual calculation. For example, approximate partition coefficients (log P) have been calculated by Rekker s method ... 

It seemed possible to correlate the elution order in reversed-phase liquid chromatography with the octanol-water partition coefficient, logP. For example, the partition coefficients calculated by Rekker s method showed a... 

Every component of an organic compound has a defined lipophilicity and calculation of partition coefficient can be performed from a designated structure. Likewise, the effect on log P of the introduction of a substituent group into a compound can be predicted by a number of methods as pioneered by Hansch [5-8] (k values), Rekker [9-10] (fvalues) and Leo/Hansch [5-7, 11-12] (f values). 

Zf Method This method developed by Rekker and Mannhold [36] uses fragmental hydrophobicity coefficients and correction factors obtained via a reductionist approach, deriving the constants for each fragment from Free-Wilson type... 

ClogP This method developed by Leo and Hansch presents some similarities with the method of Rekker, since the log P of a molecule is calculated by adding lipophUicity values attributed to multiatomic fragments and numerous corrections factors which take into account not only geometrical and topological effects but also electronic and steric effects (Equation 5.3) [39-41]. 

Doucette and Andren [4] have compared six methods to estimate Kow for highly hydrophobic aromatic compounds such as halogenated benzenes, biphenyls, diben-zofurans, and dibenzo-p-dioxins with log Kow values ranging from 2.13 to 8.58. The comparison includes the GCM of Hansch and Leo, the GCM of Nys and Rekker, and correlations based on the following molecular descriptors HPLC retention times, M, TSA, and MCIs. The method using MCIs had the smallest average percent error. The method is... 

Solution. The octanol-water partition coefLcient of methyl paraben is estimated using a fragmental method as described by the following equation (Rekker, 1977) ... 

Nys and Rekker (Nys, 1973) were the first to publish a method of calculating log Poctby the addition of fragment values, and this procedure has been improved over time (Rekker, 1992). The designers determine what constitutes a valid fragment and verify the selection using a large database of measured values. 

The octanol-water partition coefficient is an additive chemical property that lends itself very well to calculation. Since the work of Rekker (1977) and Hansch and Leo (1979) a large number of methods (possibly in excess of 50) for the calculation of log Kow have been published. Many of the published methods have been computerized and are available as commercial software and shareware, or may be used over the Internet. A number of the better recognized software packages are summarized in Table 3.1. 

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