Substituent effects quantitative treatment

Reactions involving monocyclic six-membered heteroaromatic rings have not been studied sufficiently extensively to allow a quantitative treatment of substituent effects. However, comparison with aza-naphthalene reactivities indicates that aza- and polyaza-benzene systems must also be highly selective. 

In considering quantitatively the response of these groups to high electron-demand there are certain caveats. In the first place it must be remembered that amino and related groups are liable to be protonated in the kind of media often used for studying electrophilic aromatic substitution. The observed substituent effect will then be that of the positive pole. Secondly, the straightforward application of the tr+ scale to electron-demanding reactions is not necessarily appropriate. It may well be that some form of multiparameter treatment is needed, perhaps the Yukawa-Tsuno equation (Section II.B). 

Extensive collections of pK values are available in the literature, e.g., [98-101]. It is also possible to predict pK values for a broad range of organic acids and bases using linear free energy relationships based on a systematic treatment of electronic (inductive, electrostatic, etc.) effects of substituents which modify the charge on the acidic and basic center. Quantitative treatment of these effects involves the use of the Hammett Equation which has been a real landmark in mechanistic organic chemistry. A Hammett parameter (a), defined as follows ... 

It is beyond the scope of this chapter to review the numerous attempts to model 8, 2 reactivity. Besides models describing the reaction qualitatively in terms of valence bond configurations and mostly aiming at interpreting substituent effects, anomalous Bronsted slopes and appearance of intermediates on the reaction pathway (see Pross, 1985 8haik, 1985, and references therein), essentially two types of quantitative treatments have been developed. The more rigorous one, based on ab initio quantum chemical calculations (Berthier et al., 1969 Jorgensen, 1988) has reached quantitative... 

The old and lasting problem of heterogeneous catalysis, the mechanism of alkene hydrogenation, has also been approached from the viewpoint of structure effects on rate. In 1925, Lebedev and co-workers (80) had already noted that the velocity of the hydrogenation of the C=C bond decreases with the number of substituents on both carbon atoms. The same conclusion can be drawn from the narrower series of alkenes studied by Schuster (8J) (series 52 in Table IV). Recently authors have tried to analyze this influence of substituents in a more detailed way, in order to find out whether the change in rate is caused by polar or steric effects and whether the substituents affect mostly the adsorptivity of the unsaturated compounds or the reaetivity of the adsorbed species. Linear relationships have been used for quantitative treatment. 

Tphe original objectives of this work were to determine how much the relative reactivity of two hydrocarbons toward alkylperoxy radicals, R02, depends on the substituent R—, and whether there are any important abnormalities in co-oxidations of hydrocarbons other than the retardation effect first described by Russell (30). Two papers by Russell and Williamson (31, 32) have since answered the first objective qualitatively, but their work is unsatisfactory quantitatively. The several papers by Howard, Ingold, and co-workers (20, 21, 23, 24, 29) which appeared since this manuscript was first prepared have culminated (24) in a new and excellent method for a quantitative treatment of the first objective. The present paper has therefore been modified to compare, experimentally and theoretically, the different methods of measuring relative reactivities of hydrocarbons in autoxidations. It shows that large deviations from linear rate relations are unusual in oxidations of mixtures of hydrocarbons. 

The methyl group is the smallest polyhedral substituent which can interact with its neighbors. Its intimate behavior is of primary importance for the quantitative treatment of steric effects, since it is often taken (as a combined atom) as a reference for the size of alkyl groups (Section II). The conformational aspect of the steric size of a methyl and its ability to induce conformational changes was clearly evident in the study of various poly-methylisopropylpyridines or -pyridinium salts 81a-e (83T4209) (Scheme 63). 

For the quantitative treatment of substituent effects in such reactions, Brown proposed (Brown and Okamoto, 1957) a new Hammett-type structure-reactivity relationship, the Brown equation (1), in terms of substituent constant instead of a in the original Hammett equation. 

Usually the activation free energy required for the thermal vinylcyclopropane-cyclopentene rearrangement ranges from 48 to 53kcal mor A quantitative treatment of the substituent effect has been conducted It appears that the trimethyl-... 

This ion as well as its derivatives have played a key role in the development of current concepts and quantitative treatment of substituent effects on organic reactivity. ... 

The energy required to proceed from reactants to products is AG, the free energy of activation, which is the energy at the transition state relative to the reactants. We develop the theoretical foundation for these ideas about reaction rates in Section 3.2. We first focus attention on the methods for evaluating the inherent thermodynamic stability of representative molecules. In Section 3.3, we consider general concepts that interrelate the thermodynamic and kinetic aspects of reactivity. In Section 3.4, we consider how substituents affect the stability of important intermediates, such as carbocations, carbanions, radicals, and carbonyl addition (tetrahedral) intermediates. In Section 3.5, we examine quantitative treatments of substituent effects. In the final sections of the chapter we consider catalysis and the effect of the solvent medium on reaction rates and mechanisms. 

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. 

We have seen numerous examples of substituent effects on rates and equilibria of organic reactions and have developed a qualitative feel for various groups as electron-donating or electron-withdrawing. Beginning in the 1930s, Lewis P. Hammett of Columbia University developed a quantitative treatment of substituent effects represented in the equations ... 

Analysis of the 6-parameter for alkyl substituents in reactivity correlation data suggests its possible utility in quantitative treatment of steric effects in organic reactions (see, for example, the results in Table 15.3). 

Upon treatment with an ethereal solution of methyllithium, both oligocydopropyl-substituted cyclopentadienes 14 and 6 in tetrahydrofuran were quantitatively deprotonated to the corresponding cyclopentadienides 14-Li and 6-Li, respectively, which were characterized by their 1H and 13 C NMR spectra. Treatment of the solutions of 14-Li and 6-Li with solutions of iron(II) chloride in tetrahydrofuran yielded the l,l, 2,2, 3,3, 4,4 -octacydopropylferrocene (16) (74%) and the decacyclopropylferrocene (17) (21%). After crystallization from hexane (for 16) and pentane/dichloromethane (for 17), the structures of both ferrocenes were established by X-ray crystal structure analyses (Scheme 3). The electron-donating effect of the cyclopropyl substituents on these cyclopentadiene systems is manifested in the oxidation potentials of the ferrocenes 16 and 17. While the parent ferrocene has an oxidation potential E1/2 (vs. SCE) = +0.475 V, that of decamethylferrocene is significantly lower with Ei/2 = —0.07 V, and so are those of 16 (Ey2 — —0.01 V) and 17 (f i/2 = —0.13 V) [13]. 

There has been a decisive evolution in the treatment of steric effects in heteroaromatic chemistry. The quantitative estimation of the role of steric strain in reactivity was first made mostly with the help of linear free energy relationships. This method remains easy and helpful, but the basic observation is that the description of a substituent by only one parameter, whatever its empirical or geometrical origin, will describe the total bulk of the substituent and not its conformationally dependent shape. A better knowledge of static and dynamic stereochemistry has helped greatly in understanding not only intramolecular but also intermolecular steric effects associated with rates and equilibria. Quantum and molecular mechanics calculations will certainly be used in the future to a greater extent. 

The recognition of the species which is undergoing reaction, of the quantitative effects of heteroatoms, of interactions between heteroatoms and substituents, and of the importance of hydrogen bonding have made possible, for the first time, a rational, quantitative, overall treatment of heteroaromatic reactivity patterns. 

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