Molecular size and shape

Studies on the 2-, 3-, and 4-isomers of aminobiphenyl have shown good correlations among the mutagenic or carcinogenic activities, the capability of N-hydroxylation (first metabolic activation step), and the planarity of the molecules. 

In general, chemicals that are highly hydrophilic are poorly absorbed by the oral or dermal routes and, if absorbed, are readily excreted. Thus, the introduction of hydrophilic groups (e.g., sulfonyl, carboxyl, hydroxyl, glucuronyl) into an otherwise 

Therefore a continued interest exists in the role of in oral absorption, which often is related to its effect on lipophilicity and solubility. Medicinal chemists can modulate these properties through structural modifications [47]. Various methods to measure pK values have been developed [47-50] and considerable databases are now available. 

The difference between the log P of a given compound in its neutral form (log P ) and its fully ionized form (log P ) has been termed dialog P ) and contains series-specific information, and expresses the influence of ionization on the intermolecular forces and intramolecular interactions of a solute [44, 51, 52]. 

A number of approaches to predict ionization based on structure have been published (for a review, see [53]) and some of these are commercially available. Predictions tend to be good for structures with already known and measured functional groups. However, predictions can be poor for new innovative structures. Nevertheless, pfCa predictions can still be used to drive a project in the desired direction and the rank order of the compounds is often correct. More recently training algorithms have also become available which use in-house data to improve the predictions. This is obviously the way forward. 

Molecular size can be a further limiting factor in oral absorption [54]. The Lipinski Rule-of-5 proposes an upper limit of molecular weight (MW) of500 as acceptable for orally absorbed compounds [25]. High-MW compounds tend to undergo biliary excretion. Size and shape parameters are generally not measured, but rather calculated. A measured property is the so-called cross-sectional area, which is obtained from surface activity measurements [55]. 

Various ways a charged compound may cross a membrane by a passive mechanism have been described [40]. These include ion (trans- and/or paracellular), ion pair, or protein-assisted transport (using the outer surface of a protein spanning a membrane). 

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The relationship between molecular stmcture and sensory properties is very unclear for compounds with odor. It seems likely that there is a set of odors that could be called primaries, but a widely accepted Hst of such primary odor quahties has not been devised. Molecular size and shape have been used to... 

The behavior of binary hqnid solutions is clearly displayed by plots of M, AM, and In % vs. X at constant T and P. The vohime change of mixing (or excess vohime) is the most easily measured of these quantities and is normally small. However, as illustrated by Fig. 4-1, it is subject to individiiahstic behavior, being sensitive to the effects of molecular size and shape and to differences in the nature and magnitude of intermoleciilar forces. 

The UNIQUAC equation treats g G /RT as comprised of two additive parts, a combinatorial term g, accounting for molecular size and shape differences, and a residual term g (not a residual property), accounting for molecular interactions ... 

Deviations from Raonlt s law in solution behavior have been attributed to many charac teristics such as molecular size and shape, but the strongest deviations appear to be due to hydrogen bonding and electron donor-acceptor interac tions. Robbins [Chem. Eng. Prog., 76(10), 58 (1980)] presented a table of these interactions. Table 15-4, that provides a qualitative guide to solvent selection for hqnid-hqnid extraction, extractive distillation, azeotropic distillation, or even solvent crystallization. The ac tivity coefficient in the liquid phase is common to all these separation processes. 

One needs then to compute 5 based on differences in molecular size and shape. 

To these may be added Blicke and Kaplan s conclusion, that the nature of the basic nucleus and the relative positions of the phenyl and hydroxyl groups in the esterifying acid are of prime importance. These conclusions do not provide a full explanation of the results of these investigations. It seems clear that chemical structure alone provides an insufficient basis and that molecular size and shape and other physical properties of the substance play a considerable part in determining the pharmacological action. 

The complex interplay of physicochemical and biological charactenstics that regulate the all important rate at which fluorocarbons may migrate within and finally leave the body, through the lungs and the skin, is not yet completely understood Certainly, variables are involved, such as vapor pressure, solubility m body tissues, molecular size and shape, lipid solubility, electron configuration, and critical soluQon temperatures [16, 17]... 

Electron Density Surfaces. An alternative technique for portraying molecular size and shape relies on the molecule s own electron cloud. Atoms and molecules are made up of positively-charged nuclei surrounded by a negatively-charged electron cloud, and it is the size and shape of the electron cloud that defines the size and shape of an atom or molecule. Quantum mechanics provides the mathematical recipe for determining the size and shape of the electron cloud, and computer programs can carry out the necessary calculations. 

Electron density surface for hydrogen fluoride depicts overall molecular size and shape. 

Sulfur is made up of S8 molecules each molecule has a cyclic (crown) structure. Phosphorus contains P< molecules each molecule has a tetrahedral structure. On the basis of molecular size and shape, which would you expect to have the higher melting point ... 

Figure 4.3. Relative diffusion rates in HZSM5. The shaded areas are the pore walls, the unshaded parts the vertical pore system from Figure 4.1. As can be seen, the rate of diffusion varies enormously with only very small changes in molecular size and shape. This allows the zeolite to discriminate almost completely between the three molecules shown, a situation which is unprecedented in traditional, homogeneous chemistry.

Molecular sizes and shapes play key roles in determining chemical and physical properties. The immense variety of chemical and physical properties displayed by substances in the natural world mirrors an equally immense variety of different types of molecules. However, variety need not come from a large number of different elements. The molecules that make up a cup of coffee are made up almost entirely of atoms of just five elements hydrogen, carbon, oxygen, nitrogen, and sulfur. Carbon, in particular, is capable of combining in many different ways, generating molecules with elaborate stractures. 

G., Folkers, G., Chretien, J. R., Raevsky, 0. A. Estimation of blood-brain barrier crossing of drugs using molecular size and shape, and H-bonding descriptors. f Drug Target. 1998, 2,151-165. 

Molecular size and shape Vapor pressure and velocity Velocity Particle size... 

Thus, for a hydrophobic solute is determined by quantifying the probability po of successfully inserting a hard-core solute of the same size and shape into equilibrium configurations of water, as illustrated in Figure 4. A virtue of this approach is that the thermodynamics of hydrophobic hydration characterized by is determined from the properties of pure water alone. The solute enters only through its molecular size and shape (see Fig. 4). 

The molecular descriptors refer to the molecular size and shape, to the size and shape of hydrophilic and hydrophobic regions, and to the balance between them. Hydrogen bonding, amphiphilic moments, critical packing parameters are other useful descriptors. The VolSurf descriptors have been presented and explained in detail elsewhere [8]. The VolSurf descriptors encode physico-chemical properties and, therefore, allow both for a design in the physico-chemical property space in order to rationally modulate pharmacokinetic properties, and for establishing quantitative structure-property relationships (QSPR). 

A high diffusion coefficient increases the rate of diffusion, all else being the same. The diffusion coefficient is determined in part by molecular size and shape. Small molecules tend to have high diffusion coefficients, which is one reason why formaldehyde penetrates faster than glutaraldehyde. In addition, interactions between the chemical and its environment will influence the diffusion coefficient. Thus, if the chemical hydrogen bonds to the water around it, the diffusion coefficient will be lower and the rate of diffusion will be reduced. 

Separation of materials according to molecular size and shape by passage of a solution through a column or across a surface consisting of a polymeric gel. 

Molecular sieves are synthetic zeolites that can be manufactured with extremely close control of pore size. Therefore, they can be tailored to suit specific applications. In addition to gas drying applications, molecular sieves are used for the separation of gases and vapors on the basis of molecular size and shape. Surface areas range from 350 to 1000 ft2/ft3. 

The separation of substituted benzene derivatives on a reversed-phase C-18 column has been examined [78]. The correlations between the logarithm of the capacity factor and several descriptors for the molecular size and shape and the physical properties of a solute were determined. The results indicated that hydrophobicity is the dominant factor to control the retention of substituted benzenes. Their retention in reversed-phase HPLC can be predicted with the help of the equations derived by multicombination of the parameters. 

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