Aliphatic substituent constants

Aliphatic substituent constants (improved accuracies by Cohen Takahashi, S., Cohen, L.A., Miller, H.K., and Peake, E.G. (1971) /. Org. Chem., 36, 1205-1209. 

The equation depends on the fact that basic hydrolysis of esters is very sensitive to polar effects and acid hydrolysis is not. Both are sensitive to steric effects, but since the transition states differ from each other by only two hydrogen atoms, as shown in Figure 5.3, steric hindrance would affect both reactions similarly. The difference between the acid and basic terms in Equation (12) therefore eliminates the steric contribution to the substituent constant, leaving only polar and resonance contributions. Further, since the reaction site does not form part of a conjugated system, any resonance effect will be negligible, leaving the polar contribution as the dominant factor. Lists of aliphatic substituent constants (a ) have been published [11]. 

The constants oi were taken equal to a scaled value of the aliphatic polar substituent constants a (which are defined in Section 7.3), and a was set at 3 (or a = in for substituents capable of through resonance). The resulting plots of Eq. (7-32) gave good LEER, which was interpreted to justify the approach. Refinements, - of this treatment showed that a depends upon the reaction, although most values fell ... 

Taft began the LFER attack on steric effects as part of his separation of electronic and steric effects in aliphatic compounds, which is discussed in Section 7.3. For our present purposes we abstract from that treatment the portion relevant to aromatic substrates. Hammett p values for alkaline ester hydrolysis are in the range +2.2 to +2.8, whereas for acid ester hydrolysis p is close to zero (see Table 7-2). Taft, therefore, concluded that electronic effects of substituents are much greater in the alkaline than in the acid series and. in fact, that they are negligible in the acid series. This left the steric effect alone controlling relative reactivity in the acid series. A steric substituent constant was defined [by analogy with the definition of cr in Eq. (7-22)] by Eq. (7-43), where k is the rate constant for acid-catalyzed hydrolysis of an orr/to-substituted benzoate ester and k is the corresponding rate constant for the on/to-methyl ester note that CH3, not H, is the reference substituent. ... 

Table 7-9. Polar Substituent Constants, a, for Aliphatic Substrates X-R...

The Hammett equation is not successful for reactions of aliphatic compounds if the normal cr constants are used. A new scale of substituent constants, labeled cr, was invented to allow the extension of the method to such systems. The difference in the rates of hydrolysis of esters in basic versus acidic solutions is used to define the scale. The transition states are... 

Finally, in this account of multiparameter extensions of the Hammett equation, we comment briefly on the origins of the a, scale. This had its beginning around 1956 in the a scale of Roberts and Moreland for substituents X in the reactions of 4-X-bicyclo[2.2.2]octane-l derivatives. However, at that time few values of o were available. A more practical basis for a scale of inductive substituent constants lay in the o values for XCHj groups derived from Taft s analysis of the reactivities of aliphatic esters into polar, steric and resonance effects . For the few o values available it was shown that o for X was related to o for XCHj by the equation o = 0.45 <7. Thereafter the factor 0.45 was used to calculate c, values of X from o values of XCH2 . ... 

Iwasa, I., Fujita, T., Hansch, C. (1965) Substituent constants for aliphatic functions obtained from partition coefficients. J. Med. Chem. 8, 150-153. 

For the aliphatic compounds the appropriate substituent constant is a, and the first four values in Table 2 correlate well with S if p == 1 "t,... 

If a series of bases obeys a Hammett type of treatment toward a constant acid, the above discussion is applicable to this problem also. Now the transformed base parameter Eb is related to the substituent constant a and Ea is related to g. The appropriate transformation equations result by simply interchanging the subscripts B and A in all of the above equations. It should also be mentioned that the constancy of — R, the requirement for a Hammett-t5q)e equation, is a different requirement than the constancy of the C/E ratio for a one term equation. A limited set of data can obey a one term equation and not be amenable to a Hammett-type of approach. For example, the parameters of all of the alcohols (aliphatic and aromatic) undergoing a hydrogen bonding interaction have a fairly constant C/E ratio and give fair agreement with a one term treatment. 

Many other linear Gibbs energy relationships have been proposed for example, the acid strengths of aliphatic compounds can be correlated using the "Taft polar substituent constants" o. ... 

A common probe of reaction mechanisms used to infer charge distribution in the transition state involves variation of substituent groups near the reaction center. From the variation in reaction rate produced by electron-donating and electron-withdrawing groups or by the steric hindrance of various sized groups, transition state characteristics can be inferred. Two empirical correlations have been proposed and refined which provide a common framework for this process. The Hammett equation is applied to aromatic systems [45]. The Taft correlation is applied to aliphatic systems [45], Definitions of terms, collections of substituent constants (steric and electronic effects for various substituents), and listings of observed reaction response parameters (for typical reaction types) have been collected [45]. 

In the 1950s Taft devised a method of extending linear free-energy relationships to aliphatic systems.16 He suggested that, since the electronic nature of substituents has little effect on the rate of acid-catalyzed hydrolysis of meta- or para-substituted benzoates (p values are near 0, see Table 2.3), the electronic nature of substituents will also have littie effect on acid-catalyzed hydrolysis of aliphatic esters. All rate changes due to substituents in the latter reactions are, therefore, probably due to steric factors.17 Taft defined Es, a steric substituent constant, by Equation 2.16... 

Table 4.5 Examples of the different electronic substitution constants used in QSAR studies. Inductive substituent constants (crO are the contribution the inductive effect makes to Hammett constants and can be used for aliphatic compounds. Taft substitution constants (cr ) refer to aliphatic substituents but use propanoic acid (the 2-methyl derivative of ethanoic acid) as the reference point. The Swain-Lupton constants represent the contributions due to the inductive (.F) and mesomeric or resonance (R) components of Hammett constants. Adapted from An Introduction to the Principles of Drug Design and Action by Smith and Williams 3rd Ed. (1998) Ed. H.J.Smith. Reproduced by permission of Harwood Academic Publishers.

Molecular Weight. Aromatization of hydroaromatic structures, rather than removal of aliphatic substituents, was suggested because the weight per molecule remained approximately constant with increasing temperature up to 900°C. The shift to solid products at 1100°C probably represents a significant increase in molecular weight. 

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