Long-Range Substituent Effects

Experimental pK data suggest that eyano substitution can exert substantial long-range effeets on phenol aeidity, but the reason for these effeets is not obvious. If ion-dipole interaetions were to blame, the effeet would fall off with increasing ion (0 ) - dipole (CN) separation. If electron delocalization were responsible, then the effeet would be aeeompanied by eharge transfer between the ionie site (O ) and other atoms in the moleeule. 

Examine atomie eharges and display eleetrostatie potential maps for phenoxide, 3-cyanophenoxide, 4-cyanophenoxide and4-cyanomethylphenoxide anions. Whieh ions eontain the most and the least eleetron-rich oxygen Is the eleetronie eharaeter of oxygen consistent with the trend in pKa s (see table at right) Explain. 

Decide if ion-dipole interactions are responsible for the observed substituent effects. Obtain the charge on carbon and nitrogen in each cyano group. What evidence is there for a polar CN bond Should the ion (O )-dipole (CN) interaction be stabilizing or destabilizing Can these interactions explain the trends in electrostatic potential (Hint Focus on changes in O—CN distance and in orientation of the cyano group.) 

Electrostatic potential map for phenoxide anion shows most negatively-charged regions (in red) and less negatively-charged regions (in blue). 

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Kolb<152 153) has postulated that differences and anomalies seen in opioid activities for compounds with various N-substituents may be accounted for by long-range substituent effects on total molecular conformation. Such molecular distortion is likely to affect overall electron distribution, may influence lone-pair directionality and p K , and would modify opioid-receptor... 

Long-range substituent effects of unknown mechanism influence the esterification of 5-en-3)3-ols by racemic a-phenylbutyric anhydride. Hydrolysis of the resulting esters gave a-phenylbutyric acid with modest optical activity, the sign depending upon the nature of C-17 substitution in the steroid employed. "... 

However, the possibility of obtaining undesired results due to long-range conformational effects as substituents on far removed sites are changed requires careful analysis. 

Some substituents induce remarkably different electronic behaviors on the same aromatic system (8). Let us consider, for example, the actions of substituents on an aromatic electron system. Some substituents have a tendency to enrich their electronic population (acceptors), while others will give away some of it (donors). Traditionaly, quantum chemists used to distinguish between long range (mesomeric) effects, mainly u in nature, and short range (inductive) effects, mainly a. The nonlinear behavior of a monosubstituted molecule can be accounted for in terms of the x electron dipole moment. Examples of donor and acceptor substituents can be seen on figure 1. 

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... 

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