Substituent Effects in Aliphatic Compounds

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. ... 

In the preceding section substituent effects on aliphatic carbon atoms, mostly in monosubstituted molecules, were examined by comparing their, 3C chemical shifts with those of the respective unsubstituted parent compounds. If one proceeds to molecules M bearing two substituents (X, Y Scheme 43) it often happens that SCS(X) (140 — 141) or SCS(Y) (139 — 141) differ considerably from the values expected for the monosubstituted prototypes (138 — 139 and 138 — 140, respectively). 

In aliphatic compounds, reactions of functional groups are often modified very significantly by an adjacent carbonyl group. As would be expected from the discussion in the preceding section, the reactions of certain substituents a and y to pyridine-like nitrogen atoms in azole rings are similarly influenced. Such effects on substituents can be classified into six groups. 

Taft s constants were used as molecular descriptors to correlate with activation energy and kinetic rates, respectively. They were used because they describe the inductive effects of the substituents in aliphatic compounds. Taft s constant showed a poor correlation (r2 = 0.68) for aliphatic compounds however, the correlation between activation energy and Taft s constant was... 

The factor 2.48 puts a on the same scale as Hammett s er, and the k0 values are rate constants for acid and base hydrolysis of acetic acid esters (i.e., R is a methyl group in the reference compound). Usually R is an ethyl or methyl group, but in many cases the rate constants do not depend on the nature of R. Equation 8 is based on the fact that acid hydrolysis rates of substituted benzoic acid esters are only slightly affected by the nature of the substituent, but acid hydrolysis rates of aliphatic esters are strongly affected by substituents. These effects were taken to be caused by steric factors thus log(/c//c0)acid defines s. It is reasonable to assume that steric factors affect base-catalyzed rates in the same way. Substituent effects on base hydrolysis of aliphatic compounds are composed of both polar and steric effects, and subtraction of the latter yields a measure of the former. The parameter a is important because it allows one to evaluate substituent effects on aliphatic reaction rates by a formula analogous to the Hammett equation, or by a bivariate relationship, the Taft-Pavelich equation (Pavelich and Taft, 1957) ... 

The alternatives to mathematical descriptors derived from molecular graphs or molecular geometry are the traditional QSAR (quantitative structure-activity relationship) descriptors and quantum chemically computed parameters. The former include the partition coefficient for oil/water (often octanol/water) (log P), the Hammet sigma value (electronic parameter that measures the electron withdrawal from and the electron release to the aromatic ring by a substituent, the Taft s parameters for the electronic effects of substituents in aliphatic compounds (a ), and a steric parameter for the proximity of substituents on reaction sites (Es)- Also selected molecular properties, such as molar refractivity (MR), polarizability (a), molecular weight (MW), and density (d), have been used. 

In the previous sections the main focus of the discussion of substituent effects was their dependence on structure (especially stereochemistry) and the underlying transmission mechanisms. Admittedly, it would still be veiy difficult to predict 13C chemical shifts in more complicated and highly substituted aliphatic compounds with sufficient precision even if our knowledge about the physical back-... 

Hammett s success in treating the electronic effect of substituents on the equilibria rates of organic reactions led Taft to apply the same principles to steric, inductive, and resonance effects. The Hammett o constants appear to be made up primarily of two electronic vectors field-inductive effect and resonance effect. For substituents on saturated systems, such as aliphatic compounds, the resonance effect is rarely a factor, so the o form the benzoic acid systems is not applicable. Taft extended Hammett s idea to aliphatics by introducing a steric parameter ( .). He assumed that for the hydrolysis of esters, steric and resonance effects will be the same whether the hydrolysis is catalyzed by acid or base. Rate differences would be caused only by the field-inductive effects of R and R in esters of the general formula (XCOOR), where X is the substituent being evaluated and R is held constant. Field effects of substituents X could be determined by measuring the rates of acid and base catalysis of a series XCOOR. From these rate constants, a value a could be determined by Equation (5.9) ... 

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.

In all these structures the Sn-C-C=C angle is close to optimum for g-tc interaction between the C(allyl)-Sn g bond and the n system. In the two crystallographically independent molecules of cyclopenten-2-yl-triphenylstannane 197 and cyclohepten-2-yltriphenylstannane 199, the stannyl substituent takes up a pseudoaxial orientation. Although cyclohex-2-enyltriphenylstannane 198 exists in the solid state with the stannyl substituent in a pseudoequatorial orientation (Sn-C-C=C 120°), it exists in solution predominantly in a pseudoaxial conformation. Analysis of the structural parameters in 198 and 199 provides some tentative structural evidence for the presence of the o-Jt interaction in these compounds the Sn-C(allyl) bond distances, which are 2.189(5) and 2.182(5) A, respectively, are slightly longer than the normal Sn-C(aliphatic) distance, which is typically of the order of 2.13 A, consistent with the expected structural effects of electron donation from the Gc Sn orbital into the n orbital. 

---