Substituents principal properties

Therefore it is necessary to use methods which allow all variables (substituents) to be investigated simultaneously, i.e. multivariate methods [26], This can be achieved by using design (e.g., factorial design [28] or D-optimal design [29]) in principal properties and evaluating the result by multivariate analysis as shown below. 

Skagerberg, B., Bonelli, D., Clementi, S., Cruciani, G. and Ebert, C. Principal Properties for Aromatic Substituents. A Multivariate Approach for Design in QSAR. QSAR, 1989,8, 32-38. 

To allow for a systematic search of the reaction space it is necessary to quantify the axes . One problem is that discrete variation will change a number of molecular properties. A change of a substituent in the substrate will alter several properties, e.g. electron distribution, steric concestion, lipophilicity, hydrogen bond ability, etc. It is such intrinsic properties of the molecule which determine its chemical behaviour. By the concept of principal properties it is possible to obtain quantitative measures of the intrinsic properties. The principal properties can therefore be used to quantify the axes of the reaction space. 

Principal properties can be calculated for both whole molecules and substituent groups, fragments, amino acids, etc. For example, the ith substituent can be represented by four PPs, each having a different meaning such as PPi = steric, PP2 = lipophilic, PP3 = electrostatic, PP4 = H-bonding properties of the substituent, respectively. 

If it is assumed that the structure of the substrates can be described by the nature of the substituents, it would be possible to use common substituent parameters as descriptors of the substrates. Several studies on substituent parameters by principal components analyses have now been published.[ll] When the experiment described here were carried out, one such study was available.[lla] This study described the variation of the properties of aromatic substituents by a two-component model, and this model was used for the selection of the substrates in the present study. The principal properties of amines and solvents are also described by two-component models. Each axis in the reaction space is therfore two-dimensional, and the whole reaction space is six-dimensional. To span the whole reaction space by selecting test systems from each "comer" would require 2 = 64 different test systems. It would be... 

To characterize the reaction system for the PLS analysis, the principal property score values were used as descriptors. For the ketones, two additional descriptors were used to describe the steric environment of the carbonyl group. The v parameter given by Charton[14] was used to describe the size of the ketone side chain. This parameter is a measure of the van der Waals radius of the substituent, and can be regarded as a measure of how large the side chain appears to be when... 

A large number of substituent descriptors have been reported in the literature. In order to use this information for substituent selection, appropriate statistical methods may be used. Pattern recognition or data reduction techniques, such as PCA or CA are good choices. As explained in Section III.B.3. in more detail, PCA consists of condensing the information in a data table into a few new descriptors made of linear combinations of the original ones. These new descriptors are called PCs or latent variables. This technique has been applied to define new descriptors for amino acids, as well as for aromatic or aliphatic substituents, which are called principal properties (PPs). These PPs can be used in FD methods or as variables in QSAR analysis. ... 

Figure 7. One hundred common organic substituents represented in the space of principal properties. PP, is mainly related with the size of the substituents, while PP2 expresses their electronic properties. The four substituents highlighted with the dark gray circles are possible representatives of the four quadrants of this space. The n-Bu, highlighted in light gray is a possible alternative to OBu when these derivatives are not easily accessible.

Topliss tree and Craig plot Factorial, central composite and D-optimal designs Principal properties of substituents Drug-like properties Combinatorial libraries Virtual screens IV Determining relationships between chemical and biological data A Overview... 

Figure 40 Representation of substituents of Table 2 according to their principal properties. The block represents a two-level factorial design in the three principal components PPj, PP2, and PP3 (reproduced from Figure 1 of ref. [662] with permission from the copyright owner).

It is particularly interesting to consider the influence of the substituents R and Rj in diphenylol alkanes of the type shown in Figure 20.12. Such variations will influence properties because they affect the flexibility of the molecule about the central C-atom, the spatial symmetry of the molecule and also the interchain attraction, the three principal factors determining the physical nature of a high polymer. 

For this reason dual terminology is in use for the aza analogs. The first, derived from the principal pyrimidine and purine derivatives by means of the prefix aza- is used almost exclusively in biochemical papers in organic chemistry is it used together with the systematic names) wherever it is desired to compare the properties of the natural bases and of their aza analogs. The systematic terminology is naturally used in the older literature where no biochemical aspects of the compounds were considered, and in some newer work of strictly chemical nature. Since the numbering of the substituents is in some cases different for the different systems, we shall discuss this in more detail later. ... 

Inamoto and co-workers (97,98) introduced a new inductive parameter i (iota) based on atomic properties of X, namely the effective nuclear charge in the valence shell and the effective principal quantum number, as well as E(X) (97). They thereby established a reasonable correlation between the a-SCSs in substituted methanes and ethanes and the t. parameters for a series of substituents not including X = CN and I (97). 

The need to limit the number of parameters becomes especially evident if molecular shape, which decisively influences the biological properties of chemical compounds, must be considered. Principally, shape can be precisely accounted for by the coordinates of all the atoms in the molecule. Even with rather small molecules (e.g. 20 atoms) one would need a prohibitive amount of parameters (e.g. 60) alone for representation of steric properties. Again, simplifying assumptions are made to reduce the number of parameters. Thus, one can for example assume that only the steric bulk in a certain position determines the biological properties, in which case a one-parameter representation may suffice, e.g. MR or van der Waals volume of the respective substituent. 

Cell membrane lipids are natural surfactants and display most of the properties of synthetic surfactants. The principal difference between these molecules and the surfactants that we discussed above in the chapter is that lipids contain two hydrocarbon tails per molecule. Table 8.5 shows the general structural formula of these cell membrane lipids and the names and formulas for some specific polar head substituents. The alkyl groups in these molecules are usually in the C 6-C24 size range and may be either saturated or unsaturated. 

The principal tautomeric properties of the fundamental biological pyrimidines—cytosine, uracil, and thymine—are due to the presence in these N-heteroaromatic compounds of electron-donor substituents such as NH2 and OH and of SH in some important analogs. The labile hydrogen may remain attached at the exocyclic 0, N, or S atom or migrate to one of the ring nitrogens, giving rise to three principal types of tautomerism (Scheme 1) ... 

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