15 16 Massachusetts Institute of Technology 17 Organic Chemistry 5.13 October 16, 18, and 20, 2006 Prof. Timothy F. Jamison Notes for Lectures 15, 16, and 17 Cycloaddition Reactions Molecule of the Day cantharidin O O O Me O Me Cantharidin is a powerful irritant isolated from Cantharis vesicatoria, a.k.a. the "blistering beetle" or "Spanish fly", and is found in the eponymous, alleged aphrodisiac. Several chemistry research groups have prepared cantharidin by total synthesis, and in many of these a Diels-Alder reaction was a key step. Cycloaddition: A pericyclic reaction in which 2 separate conjugated, overlapping arrays of orbitals combine. Cycloadditions proceed by way of a cyclic transition state, and 2 sigma bonds are formed during the course of the reaction. A suprafacial process ("s" in the table below) is one in which the bonds made or broken lie on the same face of the orbital array undergoing reaction. In an antarafacial process ("a"), the newly formed or broken bonds lie on opposite faces of the reacting orbital array. Woodward-Hoffmann Rules for Cycloadditions Stereochemical Course # Electrons Thermal Mode Photochemical Mode 4n + 2 [s + s] [s + a] 4n [s + a] [s + s] 15-2 Coefficients of Frontier Molecular Orbitals FMO Analysis of the "Ortho-Para Rule" and the "Alder Endo Rule" For an in-depth discussion, see I. Fleming, "Frontier Molecular Orbitals and Organic Chemical Reactions," Wiley, 1976, pp. 121-181. OMe OMe CO2Me CO2Me HOMO HOMO OMe LUMO LUMO OMe CO2Me ignoring OMe OMe considering OMe CO2Me considering CO2Me OMe ignoring CO2Me O O OMe OMe etc. resonance hybrid description resonance hybrid description OMe OMe • Regioselectivity? "ortho-para rule" Note: changes to coefficients of anti-bonding orbitals are opposite those seen in bonding orbitals. vs. R overlap maximized R • Diastereoselectivity? "Alder endo rule" etc. OMe OMe consider orbitals of CO2Me vs. O MeO secondary orbital interaction LUMO LUMO OMe