gem-dialkyl effect in the intramolecular Diels-Alder reaction of 2-furfuryl methyl fumarates: The reactive rotamer effect, enthalpic basis for acceleration, and evidence for a polar transition state

Michael E. Jung, Jacquelyn Gervay-Hague

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Investigation of the rates of cyclization of a series of substituted 2-furfuryl methyl fumarates 1a-h has allowed us to determine which of the two explanations for the gem-dialkyl effect is more important. Studies with compounds substituted with small-membered rings showed that the rate acceleration is due primarily to the reactive rotamer effect and not to angle compression ("Thorpe-lngold effect"). For example, the cyclobutyl-substituted compound 1d would experience a reactive rotamer effect similar to that of the dimethyl compound 1e and thus should cyclize relatively rapidly if this effect were dominant. However, due to the small ring, 1d would have a larger "internal" angle than other disubstituted derivatives and thus should cyclize even more slowly than the dihydrido compound 1a if the angle compression effect were dominant. Since the cyclobutyl-substituted compound 1d cyclizes in CD3CN at 25 °C 208 times faster than the dihydrido compound 1a, we have concluded that the reactive rotamer effect outweighs angle compression in determining the rate of cyclization in this system. The activation parameters for the cyclization of 1a-f in CD3CN have been calculated. These data show that the large rate acceleration seen in this system, namely the significant lowering of the ΔG, is due almost entirely to a lowering of the enthalpy of activation (ΔH) and not to a difference in the entropy of activation. For example, on going from the dihydrido 1a to the monomethyl compound 1b, the 1.3 kcal/mol decrease in the ΔG is almost entirely due to the 1.4 kcal/mol decrease in the ΔH. Likewise, comparison of the dihydrido and dimethyl cases shows that the ΔΔG of 4.5 kcal/mol is due very largely to the 4.9 kcal/mol difference in the ΔH with little contribution from the entropy of activation (ΔS). In fact, the entropy of activation is more negative for the more substituted cases (1b vs 1a and 1e vs 1a or 1b) and would, therefore, retard the rate rather than accelerate it, if it were not for the enthalpy change (an isokinetic relationship). The rate enhancements due to the gem-dialkyl effect in this system are much higher than those generally seen in other systems (normally no larger than a factor of 10 for the dimethyl case vs the dihydrido one, but here a ratio of 2100). This discrepancy in rate effects is almost certainly due to the presence of an oxygen atom in the tether of our system next to the affected carbon compared to the all carbon tethers in the other cases. Finally, examination of the effect of solvents on this reaction reveals a strong acceleration of the cycloaddition in polar solvents, with the reaction being slowest in toluene, faster in acetonitrile, and faster again in DMSO. The solvent effect can be quite large in certain cases, with Arel being as large as 3200. The results for the monomethyl compound 1b in a wide variety of solvents indicate a better agreement with the dielectric constant of the solvent rather than other solvent polarity parameters, such as ET. This solvent effect is explained by the rotation of the most stable conformation of the starting material, the s-trans ester conformation 5, about the C-O bond to give the higher energy s-cis conformation 6, which can then cyclize via the transition state 7 to the observed products, the lactones 2. Since the s-cis conformation and the transition state derived from it have a net dipole due to the overlap of the dipoles of the ester, it is more polar than the starting material and thus would be expected to be stabilized by polar solvents. This is not the case for the intermolecular cycloaddition because the s-cis ester conformation is not required in the transition state. As additional evidence for this mechanistic rationale, the analogous tertiary amide 8, which would not have this more polar transition state (relative to the starting material), shows essentially no solvent effect in several solvents under similar conditions.

Original languageEnglish (US)
Pages (from-to)224-232
Number of pages9
JournalJournal of the American Chemical Society
Issue number1
StatePublished - Jan 2 1991

ASJC Scopus subject areas

  • Chemistry(all)


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