Activity, 5.9, 5.11 pure substance

Although it might seem that adrninistration of enantiomericaHy pure substances would always be preferred, the diuretic indacrinone (3), is an example of a dmg for which one enantiomer mediates the harmful effects of the other enantiomer (4). (+)-Indacrinone, the diureticaHy active enantiomer or eutomer causes uric acid retention. Fortunately, the other enantiomer distomer) causes uric acid elimination. Thus, adrninistration of a mixture of the two enantiomers, although not necessarily racemic, may have therapeutic value. 

Hctivity Coefficients. Most activity coefficient property estimation methods are generally appHcable only to pure substances. Methods for properties of multicomponent systems are more complex and parameter fits usually rely on less experimental data. The primary group contribution methods of activity coefficient estimation are ASOG and UNIEAC. Of the two, UNIEAC has been fit to more combinations of groups and therefore can be appHed to a wider variety of compounds. Both methods are restricted to organic compounds and water. 

Compound A can be resolved to given an enantiomerically pure substance, [a]p = —124°. Oxidation gives the pure ketone B, which is optically active, [aJo — —439°. Heating the alcohol A gives partial conversion (an equilibrium is established) to an isomer with [a]p = +22°. Oxidation of this isomer gives the enantiomer of the ketone B. Heating either enantiomer of the. ketone leads to the racemic mixture. Explain the stereochemical relationships between these compounds. 

For the performance of an enantioselective synthesis, it is of advantage when an asymmetric catalyst can be employed instead of a chiral reagent or auxiliary in stoichiometric amounts. The valuable enantiomerically pure substance is then required in small amounts only. For the Fleck reaction, catalytically active asymmetric substances have been developed. An illustrative example is the synthesis of the tricyclic compound 17, which represents a versatile synthetic intermediate for the synthesis of diterpenes. Instead of an aryl halide, a trifluoromethanesul-fonic acid arylester (ArOTf) 16 is used as the starting material. With the use of the / -enantiomer of 2,2 -Z7w-(diphenylphosphino)-l,F-binaphthyl ((R)-BINAP) as catalyst, the Heck reaction becomes regio- and face-selective. The reaction occurs preferentially at the trisubstituted double bond b, leading to the tricyclic product 17 with 95% ee. °... 

The metal M and the salt AB, being pure substances, have an activity of one, while the corrosion product MB and the displaced metal A will in most cases... 

Measurement of the optical rotation of optically active compounds. Polarimetric measurements can likewise be used as a method of identifying pure substances, and can also be employed for quantitative purposes. 

We now have the foundation for applying thermodynamics to chemical processes. We have defined the potential that moves mass in a chemical process and have developed the criteria for spontaneity and for equilibrium in terms of this chemical potential. We have defined fugacity and activity in terms of the chemical potential and have derived the equations for determining the effect of pressure and temperature on the fugacity and activity. Finally, we have introduced the concept of a standard state, have described the usual choices of standard states for pure substances (solids, liquids, or gases) and for components in solution, and have seen how these choices of standard states reduce the activity to pressure in gaseous systems in the limits of low pressure, to concentration (mole fraction or molality) in solutions in the limit of low concentration of solute, and to a value near unity for pure solids or pure liquids at pressures near ambient. 

Chapters 7 to 9 apply the thermodynamic relationships to mixtures, to phase equilibria, and to chemical equilibrium. In Chapter 7, both nonelectrolyte and electrolyte solutions are described, including the properties of ideal mixtures. The Debye-Hiickel theory is developed and applied to the electrolyte solutions. Thermal properties and osmotic pressure are also described. In Chapter 8, the principles of phase equilibria of pure substances and of mixtures are presented. The phase rule, Clapeyron equation, and phase diagrams are used extensively in the description of representative systems. Chapter 9 uses thermodynamics to describe chemical equilibrium. The equilibrium constant and its relationship to pressure, temperature, and activity is developed, as are the basic equations that apply to electrochemical cells. Examples are given that demonstrate the use of thermodynamics in predicting equilibrium conditions and cell voltages. 

In addition to chemical reactions, the isokinetic relationship can be applied to various physical processes accompanied by enthalpy change. Correlations of this kind were found between enthalpies and entropies of solution (20, 83-92), vaporization (86, 91), sublimation (93, 94), desorption (95), and diffusion (96, 97) and between the two parameters characterizing the temperature dependence of thermochromic transitions (98). A kind of isokinetic relationship was claimed even for enthalpy and entropy of pure substances when relative values referred to those at 298° K are used (99). Enthalpies and entropies of intermolecular interaction were correlated for solutions, pure liquids, and crystals (6). Quite generally, for any temperature-dependent physical quantity, the activation parameters can be computed in a formal way, and correlations between them have been observed for dielectric absorption (100) and resistance of semiconductors (101-105) or fluidity (40, 106). On the other hand, the isokinetic relationship seems to hold in reactions of widely different kinds, starting from elementary processes in the gas phase (107) and including recombination reactions in the solid phase (108), polymerization reactions (109), and inorganic complex formation (110-112), up to such biochemical reactions as denaturation of proteins (113) and even such biological processes as hemolysis of erythrocytes (114). 

In the previous sections we have dealt mainly with the catalytic activity of pure substances such as metallic iron, ruthenium, copper, platinum, etc. Real catalyst, however, are often much more complex materials that have been optimized by adding remote amounts of other elements that may have a profound impact on the overall reactivity or selectivity of the catalyst. Here we shall deal with a few prominent examples of such effects. 

In the multimedia models used in this series of volumes, an air-water partition coefficient KAW or Henry s law constant (H) is required and is calculated from the ratio of the pure substance vapor pressure and aqueous solubility. This method is widely used for hydrophobic chemicals but is inappropriate for water-miscible chemicals for which no solubility can be measured. Examples are the lower alcohols, acids, amines and ketones. There are reported calculated or pseudo-solubilities that have been derived from QSPR correlations with molecular descriptors for alcohols, aldehydes and amines (by Leahy 1986 Kamlet et al. 1987, 1988 and Nirmalakhandan and Speece 1988a,b). The obvious option is to input the H or KAW directly. If the chemical s activity coefficient y in water is known, then H can be estimated as vwyP[>where vw is the molar volume of water and Pf is the liquid vapor pressure. Since H can be regarded as P[IC[, where Cjs is the solubility, it is apparent that (l/vwy) is a pseudo-solubility. Correlations and measurements of y are available in the physical-chemical literature. For example, if y is 5.0, the pseudo-solubility is 11100 mol/m3 since the molar volume of water vw is 18 x 10-6 m3/mol or 18 cm3/mol. Chemicals with y less than about 20 are usually miscible in water. If the liquid vapor pressure in this case is 1000 Pa, H will be 1000/11100 or 0.090 Pa m3/mol and KAW will be H/RT or 3.6 x 10 5 at 25°C. Alternatively, if H or KAW is known, C[ can be calculated. It is possible to apply existing models to hydrophilic chemicals if this pseudo-solubility is calculated from the activity coefficient or from a known H (i.e., Cjs, P[/H or P[ or KAW RT). This approach is used here. In the fugacity model illustrations all pseudo-solubilities are so designated and should not be regarded as real, experimentally accessible quantities. 

Thus the free energy of solvation may be calculated from the Henry s law constant or from the vapor pressure of the pure substance and the limiting activity coefficient. Thus, if the deviation of the solution from Raoult s law behavior is known, calculation of the standard state free energy of solvation requires only the vapor pressure of the pure substance (in the standard state... 

All the material world is formed of mixtures, aggregates or more complex combinations of pure substances. For example, it is well known that the bark of the Cinchona tree Cinchona calisaya) shows a remarkable antimalarial activity, which is due, not to the bark as such, but to some "pure substance" which forms an integral part of it. In 1820, the French pharmacists Pelletier and Caventou isolated the active principle of the Cinchona bark, which they called quinine, as a pure, crystalline substance, m.p. 177 °C (dec), -169°, and assigned an elemental... 

It must not be forgotten that the concept of pure substance, referred to earlier, is very rigorous and must take into account, not just the constitution and relative configuration of a molecule, but also the absolute configuration of each chiral center that may present. For example, again in relation to quinine (i), quinidine (2) is also known and the only difference between the two molecules is the disposition in space of the groups bonded to C(8). Nevertheless 2 is a different molecule and shows no antimalarial activity. In addition, only one enantiomer of quinine (1), the laevorotatory, corresponds to the natural compound and manifests the specific physiological properties associated with this substance. 

The aim of this chapter is to give a general overview of the methods available for producing "industrial" quantities -i.e. amounts of at least some kilograms- of enantiomerically pure substances which can be used as "active" materials in commercial preparations (pharmaceuticals, drugs or medicines, pesticides, etc.). 

Pure Substances. In most problems involving pure substances, it is convenient to choose the pure solid or the pure liquid at each temperature and at a pressure of 1 bar (0.1 MPa) as the standard state. According to this convention, the activity of a pure solid or pure liquid at 1 bar is equal to 1 at any temperature. 

Solvent in Solution. We shall use the pure substance at the same temperature as the solution and at its equilibrium vapor pressure as the reference state for the component of a solution designated as the solvent. This choice of standard state is consistent with the limiting law for the activity of solvent given in Equation (16.2), where the limiting process leads to the solvent at its equilibrium vapor pressure. To relate the standard chemical potential of solvent in solution to the state that we defined for the pure liquid solvent, we need to use the relationship... 

Validation parameter Confirmation of the identity of pure substances Determination of identity of unknown substances Amount single pure substance Amount active substance Limit test (semi- quantitiative) Amount impurities/ degradation products (quantitative) Dissolution speed of substances Bioequivalence studies... 

Isolation of the feeding factor for M. sexta was a far more difficult task. Whereas 2-tridecanone is a simple, stable molecule soluble in organic solvents, the feeding factor is water soluble, occurs at trace levels in plant tissue, and is easily hydrolyzed under mild alkaline or acidic conditions with subsequent loss of biological activity. The isolation of such a compound was a formidable obstacle requiring a departure from the more classical approach of hydrolysis or chemical derivatization followed by isolation of the lipophilic product. The necessity that pure substance be isolated with retention of biological activity required some basic research in modem separation techniques to develop a suitably mild isolation strategy. 

The interpretation of the C.E. by a superimposition of reactions occurring at different active surface centers is compatible with the fact that many multicomponent catalysts exhibit a C.E. but no C.E. is found when very pure substances have been subjected to different thermal pretreatments (17). This implies the possibility that many active centers are due to impurities and that their numbers may change with the pretreatment of the catalyst, e.g., by means of aggregation, volatilization, etc. As an illustration, data for the decomposition of N2O on MgO, prepared from synthetic and from natural magnesites, and data for the para-ortho hydrogen conversion on pure metals and on alloys are presented in Tables II and III. 

Self-Activation. Although pure substances do not normally luminesce, zinc sulfide that has been fired in the presence of a halogen luminesces bright blue [5.311], [5.312], The luminescence center is assumed to be a cation vacancy. The charge compensation occurs through exchange of S2- by Cl-. 

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