Unexpected Anti-Markovnikov Addition to 1-Methoxy-1,3-cyclohexadiene

Abstract

The concepts of carbocation stability and resonance stabilization are central tenets in organic chemistry, and much regiochemistry can be explained in terms of formation of the more stable carbocationic intermediate. Thus Markovnikov addition and the role of carbon substitution on S N 1 and E1 chemistry are promptly taught to first year organic chemistry students.We have noticed an unusual reaction of 1-methoxy-1,3-cyclohexadiene, 1, in methanol with catalytic p-toluenesulfonic acid. 1 Isolation of the major product by gas chromatography and identification by 1-and 2-dimensional NMR spectroscopy and comparison with literature demonstrated that the major product was the dimethyl ketal of cyclohexa-3-enone, 5. 2 The direct formation of this product involves protonation to form the less stable cation 3, followed by capture of the cation by the methanol solvent, Scheme 1. The cationic precursor to 5 is stabilized only through resonance with the ether oxygen, while protonation at carbon 4 of 1 would have generated a carbocation 2 which was stabilized by both the ether oxygen and the adjacent double bond. On the basis of simple resonance theory, the observed product appears to be formed from the less stable cation. We have explored this reaction in further detail to determine the cause of this unexpected regiochemistry.We have investigated the relative stability of the diconjugated cation intermediate 2 and the mono-conjugated intermediate cation 3 by ab initio theory using the Gaussian 98 program. 3 Even at the MP2//6-31G(d) and B3LYP/ 6-31G(d)// B3LYP/6-31G(d) levels of theory, the di-conjugated cation is more stable than the mono-conjugated cation by approximately 14 kcal/mol, Table 1. This energy difference should completely eliminate the formation of product 5 by a direct mechanism.It is conceivable, however, that the reaction proceeds through the more stable cation 2 and then undergoes a rapid rearrangement under the acidic conditions to form the observed product. We have therefore calculated the relative energies of the two ketals 4 and 5, Table 1. Again, several levels of theory predict that the observed ketal is indeed the more stable isomer. This difference, however, is slight: approximately 0.6 kcal/mol. Assuming complete equilibration, one would expect a product ratio of approximately 70:30; however, none of the conjugated ketal 4 is observed. Were the actual energy difference 1.7 kcal/mol (a typical uncertainty for such calculations), the expected product ratio would be 95:5. This obviously does not rule out an equilibrium process.Kinetics and labeling studies are often valuable tools for differentiating between alternative reaction mechanisms. Thus we have followed this reaction by 500 MHz NMR in methanol-d 4 . These experiments demonstrated that any rearrangement from 4 to 5 must occur very rapidly, as no new products or intermediates were observed during the reaction (Scheme 1). More importantly, the position of deuterium incorporation is a strong indication of the pathway for formation of product 5 (Sc...

Superacid-Catalyzed Reactions of Olefinic Pyrazines: an Example of Anti-Markovnikov Addition Involving Superelectrophiles

“…In the addition reaction between 1b and CF 3 SO 3 D with C 6 D 6 (eq 5), there is incomplete deuterium incorporation onto the pyrazine ring, suggesting that the addition reaction is occurring at a faster rate than protonation of the pyrazine ring. This leaves open the possibility of an alternative mechanism involving protosolvation of the olefin group with concominent nucleophilic attack by the arene nucleophile, an Ad E 3-type mechanism (eq 6) . Deuterium incorporation could then occur in a secondary reaction at the pyrazine ring.…”