Substituent Effects on Molecular Properties

The study of structure-reactivity relationships by the organic chemist Hammett showed that there is often a quantitative relationship between the two-dimensional structure of organic molecules and their chemical reactivity. Specifically, he correlated the changes in chemical properties of a molecule that result from a small change in its chemical structure that is, the quantitative linear relationship between electron density at a certain part of a molecule and its tendency to undergo reactions of various types at that site. For example, there is a linear relationship between the effea of remote substituents on the equilibrium constant for the ionization of an acid with the effect of these substituents on the rate or equilibrium constant for many other types of chemical reaction. The relative value of Hammett substituent constants describes the similarity of molecules in terms of electronic properties. Taft expanded the method to include the steric hindrance of access of reagents to the reaction site by nearby substituents, a quantitation of three-dimensional similarity. In addition, Charton, Verloop, Austel, and others extended and refined these ideas. Finally, Hansch and Fujita showed that biological activity frequently is also quantitatively correlated with the hydrophobic character of the substituents. They coined the term QSAR, Quantitative Structure-Activity Relationships, for this type of analysis. 

Others have shown a correlation between biological potency and the presence or absence of a variety of substructures such as defined in the search screens described above.  

QSAR is not successful with every set of analogs, presumably because of the lack of explicit attention to shape properties or other factors. However, the success of QSAR in correlating structure with biological aaivity in thousands of series and in forecasting biological activity in more than a hundred examples shows that elearonic and hydrophobic properties must be considered for a complete definition of similarity. 

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III. Some Interpretations of Substituent Effects on Molecular Properties of... 

During the last two decades investigations of substituent effects on molecular properties and chemical reactivities of aromatic (2) and nonaromatic unsaturated (3) systems have been a central concern of physical organic chemistry. The presentations of such topics are an essential part of this series of Progress in Physical Organic Chemistry (2-4). 

With the apparatus outlined in the preceding subsections a consistent treatment of substituent effects on molecular properties of multisubstituted cumulenes is possible. 

For allenes with axially symmetric groups there are fair linear correlations between the magnitudes of their dipole moments /i (D) and those in correspondingly substituted ethylenes and benzenes (9). The directions of the dipole moments in allenes and ethylenes are also very similar. Therefore, for such substituents a discussion of substituent effects on molecular properties may strictly rely on substituent constants transferred from benzenes to allenes (and other cumulenes). 

III. SOME INTERPRETATIONS OF SUBSTITUENT EFFECTS ON MOLECULAR PROPERTIES OF CUMULENES... 

Discussions of substituent effects on molecular properties considered so far have been performed on a quantitative level. In case of molar rotations of allenes, at least allenes with cr-inductive groups, a quantitative interpretation of the substituent constant X(R) is possible. This interpretation is based upon a quantum-theoretical treatment of the molar rotation of (5 )-(+)-l,3-di-methylallene (3a) (164). According to the theory the parameter X(Me) is related to the group anisotropic polarizability Acr(Me) and a factor /c(Me) which reflects the polarity of the C and the ligand carbon atom. 

SYNTHESIS OF SUBSTITUTED OLIGOACENES VIA DIELS-ALDER REACTIONS AND SUBSTITUENT EFFECTS ON MOLECULAR STRUCTURE, PACKING ARRANGEMENT, AND SOLID-STATE OPTICAL PROPERTIES... 

Then, we will model several other compounds in this series using the appropriate model chemistry to examine the substituent effect on this molecular property. 

Pal SK, Itkis ME, Tham PS, Reed RW, Oakley RT, Donnadieu B, Haddon RC (2007) Phenalenyl-based neutral radical molecular conductors substituent effects on solid-state structures and properties. J Am Chem Soc 129 7163-7174... 

While developing a simple model to describe the effect of substituents (X) on the properties of a molecular system (M) has been one of the most earnestly pursued goals by chemists ever since the Hammett equation26 was reported, it was not accomplished until Taft and Topsom13 succeeded in providing a description for the SAG° values of gas-phase acid-base equilibria shown in equation 13,... 

The influence of substituents on the solubility of molecules in water can be due to their effect on the properties of the solid or liquid (for example, on its molecular cohesion) or to the effect of the substituent on its interaction with water molecules. It is not easy to predict what effect a particular substituent will have on crystal properties, but as a guide to the solvent interactions, substituents can be classified as either hydrophobic or hydrophilic, depending on their polarity (see Table 5.4). The position of the substituent on the molecule can influence its effect, however. This can be seen in the aqueous solubilities of o-, m- and p-dihydroxy-benzenes as expected, all are much greater than that of benzene, but they are not the same, being 4, 9 and 0.6 mol dm, respectively. The relatively low solubility of the para compound is due to the greater stability of its crystalline state. The melting points of the derivatives indicate that is so, as they are 105°C, 111°C, and IZO C, respectively. In the case of the ortho... 

A series of /V-salicylidene-2,6-dialky Ian ilines (84a-84e, 85a-85d, 86a-86d, 87a, 87d, 88a, 88b, 88d, 89a, 89d, 90a, 90b and 90d) has been investigated in order to evaluate the alkyl substituent effects on the crystal packing of molecules and, in turn, their photochromic properties in the solid state178. The alkyl groups, particularly the isopropyl group, at the 2,6-positions of the aniline ring can lead to a nonplanar molecular structure, which is effective for the crystals to exhibit photochromism. 

The AMI calculations performed for 2,2 -bis-2//-pyrans 294 were used as approximate MO models of thermo- and piezochromic benzo effects to establish X-substituent effects on solid-state properties. The radicals formed by the 2,2 -homolysis of 294-like molecules have been proposed to be colored species. Molecular orbital calculations have suggested very slight electronic effects but an important steric substituent effect on the C(2)—C(2 ) bond length [92JCS(P2)59]. 

As it is well known for almost a hundred years and what has become a subject of countless reports, substituents may affect significantly chemical reactivity and physicochemical properties of the molecules in question [73,74]. Their effect on molecular geometry became better known since X-ray diffraction techniques of structirre determinations began to be a readily accessible source of molecular geometry and particularly the data bases have become well supplied with precise structural data. 

The study of substituent effects on vector molecular quantities usually refer to electric dipole moments. However, dipole moments of allenes are also intimately related to the discussion of the basis of the geometric model underlying the treatments of scalar and pseudoscalar molecular properties (Section II.A). 

In the subsequent subsections substituent effects on definite molecular properties are interpreted in terms of current concepts of electronic theories that is, the overall observable substituent effects are related to intrinsic properties of the substituents. For this purpose two levels of semiquantitative approaches are used ... 

The Born-Oppenheimer (B.O.) approximation is the cornerstone of most theories dealing with the effect of isotopic substitution on molecular properties. Within the framework of this approximation, the potential energy surface for the vibrational-rotational motions of a molecular system depends on the nuclear charges of the substituent atoms and on the number of electrons in the system but is independent of the masses of the nuclei. Thus isotope effects arise from the fact that nuclei of different mass move differently on the same potential surface. 

The second theme in the MMP analysis literature - and perhaps one of more practical importance - shifts the focus to the statistical analysis ofthe effects of a given molecular transformation on a biological or physicochemical property. Such studies have attempted to identify transformations that consistently lead to the same effect on the property under examination (e.g., favorable, unfavorable, or zero), in the hope that such findings can be distilled into useful guidelines for medicinal chemists. Moreover, these publications have looked at the identification of isosteres, that is, substituents with similar effects on a property. Details on the most important of these studies are given in Table 6.1. 

Increasing attention has been paid to the generation of quantitative stmcture—activity relationships in which the effects of molecular substitution on pharmacologic activity can be interpreted in terms of the physicochemical properties of the substituents. These approaches are based on the extrathermodynamic analysis of substituent effects (36) ... 

Of the various geometric parameters associated with molecular shape, the one most nearly constant from molecule to molecule and most nearly independent of substituent effects is bond length. Bond lengths to carbon depend strongly on the hybridization of the carbon involved but are little influenced by other factors. Table 1.2 lists the interatomic distances for some of the most common bonds in organic molecules. The near constancy of bond lengths from molecule to molecule reflects the fact that the properties of individual bonds are, to a good approximation, independent of the remainder of the molecule. 

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