Ortho substituents substitution mechanics

Halobenzenes undergo nucleophilic aromatic substitution through either of two mechanisms. If the halobenzene has a strongly electron-withdrawing substituent in the ortho or para position, substitution occurs by addition of a nucleophile to the ring, followed by elimination of halide from the intermediate anion. If the halobenzene is not activated by an electron-withdrawing substituent, substitution can occur by elimination of HX to give a benzyne, followed by addition of a nucleophile. 

OH elimination from ortho substituted aldoximes 179 (X = CH2, NH, O) may be at least partially the result of a hydrogen migration/cyclization/elimination process, whereby the heterocycles 182 are formed72 (46). A metastable peak shape analysis, the investigation of 2H-labelled derivatives and the study of positional isomers indicate that in addition to 182 the protonated isocyanide 183 is formed via a mechanism which is not fully understood. However, it is known that the generation of 183 occurs without any detectable interaction with the XH ortho substituent. 

From the understanding, provided by the calculations, of the mechanism by which lb cyclizes, what can be predicted about how the rate of this reaction might be affected by substituents on the benzene ring The substiment effects would, in fact, be expected to be small, except for possible steric effects due to substituents in the ortho positions. If both ortho positions are substimted, one would expect to see a decrease in rate, relative to unsubstituted lb. On the other hand, if only one ortho position is substituted, cyclization should be about as fast as in unsubstituted lb but cyclization should preferentially occur at the unsubstituted ortho carbon. Additional (8/8)CASPT2/6-31G calculations by Bill Kamey in our group and subsequent experiments by the Platz group confirmed these qualitative predictions about the effects of ortho substituents. 

A method of preparing either cis- or trans-aziridine carboxylates (39) from A-diphenylphosphinylimines (37) and the chiral enolate (36) derived from A-bromo-acetyl 25-2,10-camphorsultam (35) has been reported.54 When the arylimine is substituted in the ortho -position, the product is either a mixture of cis- and trans-aziridine or only the trans-isomer. When the ortho-substituent is H or NO2, only a cz s-aziridine is obtained. The suggested mechanism is partially shown in Scheme 18. Both steric and inductive effects of the ortho- substituent affect the stereochemistry of the addition complex (38) and the stereochemistry of the final aziridine. 

Steric hindrance is not nearly as important in electrophilic substitution or in nucleophilic substitution by the addition-elimination mechanism. In both of these reactions, the reagent is attacking the p orbital at right angles to the ring and is some distance from an ortho substituent. 

Extensive studies by Griitzmacher and co-workers94- 96> clearly established that the elimination of ortho substituents X (X = hydrogen, halide) from 88 is not the result of a one step intramolecular substitution reaction. Instead of this, an addition/ dissociation mechanism operates leading to 90 (18). The rate determining step of the reaction sequence is the formation of the a-complex, 89, which itself has the typical characteristics of a reactive intermediate. 

The dissociative loss of a ligand in the first step allows the arene to n complex with the metal. In support of the electrophilic substitution mechanism it has been shown (49) that electron-donating substituents on the ring enhance the rate of ortho substitution. In the above example, this would be consistent with the attack of the electrophile Ru2+ in the n complex to form the a complex which is then stabilized by proton transfer (oxidation) to form the dihydrido species. The essential steps in the reaction sequence are all reasonable and each is more or less documented and hence there is good reason to believe that H—D exchange occurs essentially in the manner shown. 

Only one actual problem in chemistry was solved using molecular mechanics as we use it now, by hand calculations. In a series of studies, Frank Westheimer described the following situation. Ortho-substituted biphenyl molecules are generally not co-planar because of the steric interference of the ortho substituents. A typical example is 2,2 -dibromo-4,4 -dicarboxybiphenyl. Consider the two structures of this molecule shown in Reaction (1) ... 

Intermolecular Reactions Followed by a Polar Ring Closure Reaction In this area, one of the most widely studied approaches to synthesize heterocycles is the Sj j. 1 substitution, followed by a polar ring closure. In this way, aromatic compounds that have an appropriate ortho substituent (Z) to the leaving group (X), such as 32, react with a Nu by the Sj j. 1 mechanism to afford product 33. The ring closure product 34 is achieved by the reaction between the Nu group andZ(Eq. 10.14) ... 

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