Electronic effects isosterism

Although fluorine does not have the same valency as hydrogen, it is often considered an isostere of that atom since it is virtually the same size. Replacement of a hydrogen atom with a fluorine atom will therefore have little steric effect, but since the fluorine is strongly electronegative, the electronic effect may be dramatic. 

It was necessary, therefore, to make the side-chain electron withdrawing rather than electron donating. This can be done by inserting an electronegative aom into the side-chain—preferably one which has a minimum disturbance on the rest of the molecule. In other words, an isostere for a methylene group is required—one which has an electronic effect, but which has approximately the same size and properties as the methylene group. 

For example, substitution of the vinyl sulfone 13 by primary, secondary, and teriary amines (equation 3) obeys a single equation (equation 4) (56), where 2a is the sum of the inductive effects of the amine substituents, and En is an isosteric parameter where the steric effect of an amine R1R2NH is taken as similar to Es of CHR 2. Twenty-two amines obeyed the equation with p = —4.8 and 8 = 1.70 where p and 8 are the sensitivity parameters to the inductive and steric effects, respectively. As a demonstration of the electronic effects, fccyciohexyUmin Aniline 10 in sPite of their similar size, whereas steric effects are reflected in the Et2NH i-Pr2NH °f approximately 3000 in spite of the similar basicities. Similar LFERs were observed in other reactions (Table IX) (29). 

The infrared (IR) data quoted for 5-hydroxythieno[2,3-6]pyridinel (the isostere of 3-hydroxyisoquinoline) implies no contribution from the keto tautomer, and in numerous reports on studies of pyridoxine-type analogs,69, 11-73,92-94 which contain a 7-hydroxy-thieno[3,4-c]pyridine system, the oxygen function /3 to the nitrogen is invariably represented as a normal hydroxy group. In a paper devoted to ketoenol equilibria in l,3-dihydro-5-hydroxythieno[3,2-6 pyridine derivatives42 (72-73), it was reported that the keto farms were exclusively present in the solid state, but in dioxane the ratios 72 73 and 74 75 were 0.43 1 and 1.09 1, respectively. These facts were interpreted in terms of steric and electronic effects. 

One of the most common monovalent isosteric replacements is the substitution of hydrogen with fluorine [7]. These atoms have similar van der Waals radii but different electronic effects, fluorine being the most electronegative element in the periodic table. Due to the high strength of the C—F bond, fluorine is often introduced to achieve metabolic stability. Moreover, due to its high electronegativity, fluorine can be introduced to reduce basicity of proximal amines or increase acidity of proximal adds and also to introduce a conformational bias in molecules. 

The enthalpies of reaction for nucleophilic carbencs depend on the stereoelec-tronic properties of the ligands affecting the availability of the carbene lone pair. An example of electronic influence is the 3.5 kcal/mol enthalpy difference between the isosteric pair IMes and IMesCI that shows the electron-withdrawing nature of Cl compared to H. This trend again is in line with electron donor/withdrawing ability of arene substituents. The effect in this la.st case is a long range electronic... 

Benzacridine tetrahydroepoxides and did epoxides. The isosteric molecules BA, benz[a]acridine (BaAcr) and benz[c]acridine (BcAcr) and their derivatives provide excellent probes for studying the effect of electronic changes upon biological properties. The... 

In cyclophilin inhibition assays (Table 1), a comparison of the fluoroolefin and olefin isosteres illustrated the subtle differences between the two closely related isosteres and thereby presumably the importance of the added electrostatic and electronic interactions derived from fluorination. Note in particular that the c/s 1 (H) disastereomer was a more potent inhibitor than the cis 1 (F) and that similarly trans 2 (F) was more effective than trans 2 (H). 

Heats of adsorption measurements do not lead to very specific interpretation since the isosteric heat of adsorption (AH) arises from both nonspecific interactions, which occur in all cases of adsorption, and from specific interactions with the hydroxy groups nevertheless, valuable conclusions about the binding forces can be deduced. Saturated hydrocarbons, e.g., n-pentane, have a value of — AH of 8.0 kcal/mole, while saturated ethers have values of around 16 kcal/mole.14 Probably dispersion forces only are involved in the former case and additional specific interaction with the silanol-OH occurs in the second case. On graphite, where there is no specific interaction, the heats of adsorption of hydrocarbons and ethers are very similar.17 The heat of adsorption of furan (11 kcal/mole) is 5 kcal/mole less than that of tetrahydrofuran this again indicates the effect that delocalization of electrons by the double bonds has on the binding forces.14... 

This base, MAL, lies as a hybrid of two other compounds, AL and CPM. It is an olefin (as is AL) which means that it has a place of unsaturation in its structure. And it is an isostere of CPM which means that the carbon atoms are all in the same location, but just the connecting electrons (called the chemical bonds) are in different places. Actually there is yet a third compound in this same picture, called PROPYNYL. And yet, although all of them have extremely close structural similarities, there are such great differences in action that one does not dare to generalize. CPM leads largely to fantasy, MAL largely to visual imagery, AL is twice as potent as either of these but it doesn t show either effect, and PROPYNYL is almost without any action at all. 

For the characterization of the electronic and steric effects of substituents on the catalytic properties of tertiary aliphatic amines, Bogatkov et al. 71,72) proposed a correlation between the steric hindrance of R1R2R3N amines by means of the En(En) constants which are identical with steric constants ES(E9) according to Taft for isosteric hydrocarbon substrates R1 R2R3C. On this basis, they proposed the following linear correlation for the nucleophilic activity of amines ... 

The Vilsmeier-Haack reaction (herein, Vilsmeier reaction ) provides an effective method for the formylation of aromatic systems. The combination of phosphoryl chloride with V-methylaniline or dimethylformamide generates an iminium phosphorus derivative or chloro-iminium cation that is the active electrophile in an electrophilic substitution reaction. The resulting substitution product is an iminium salt 1, which is hydrolyzed on workup with alkali to give the carbaldehyde product 2 (Scheme l).1,2 The method is particularly useful with activated arenes or electron-rich heterocycles, such as pyrroles, furans, thiophenes, and indoles. We had a special interest in the preparation of indole-7-carbal-dehydes, namely, their properties as isosteres of salicylaldehyde. Thus, we became involved in a wide-ranging investigation of 4,6-dimethoxy-... 

Halogens (particularly chlorine) can be replaced by other electron-attracting functions snch as trifluoromethyl or cyano groups. In the antibiotic chloramphenicol, both the chlorine atoms of the dichloroacetic moiety and of the para-nitro-phenyl group yielded productive isosteric replacements (Table 15.6). Many other examples of univalent atoms or groups replacements are found in the chapter dealing with substituent effects (Chapter 20) and with quantitative structure-activity relationships (Chapter 23). 

---