Enone Photochemistry: Fundamentals and Applications Initial Discovery Ciamician and Silber were the first to report a 2 + 2 light-induced cycloaddition in 1908: O Italian sunlight, Me Me one year Me O Me carvone camphorcarvone Buchi and Goldman confirmed the structure originally proposed for camphorcarvone in 1957. Ciamician, G.; Silber, P. Ber., 1908, 41, 1928. Buchi, G.; Goldman, I. M. J. Am. Chem. Soc., 1957, 79, 4741. Significance Why should we be interested in enone photochemistry? 1. It is theoretically interesting. 2. For its synthetic utility: i) Efficient cyclobutane synthesis; O ii) Regiochemical control; R6 R1 R2 iii) Predictable stereochemistry at the ring fusion(s); R3 R5 R4 iv) Great method for accessing medium sized rings via fragmentation. Mechanism, Part 1 What happens when an enone is irradiated with UV radiation? If the radiation is of appropriate wavelength (i.e. frequency, energy), excitation will occur. E = hu = (hl) / c p* p* ground state n first excited state n configuation p p 1(p2n2) 1(p2n1p*1) What next? Schuster, D. I. "The Photochemistry of Enones," (p. 629-635) in: Patai, S., Rappoport, Z. The Chemistry of Enones, John Wiley & Sons Ltd., 1989. Mechanism, Part 2 An enone in the first excited state (singlet) can: 1. Return to the singlet ground state (fluorescence); 2. Undergo internal conversion to the ground state via "trickle down" energy loss; 3. Undergo intersystem crossing (ISC; a.k.a. spin flip) to give the lower energy triplet and proceed to the next step of product formation; 4. Skip ISC altogether and proceed to the next step. p* p* first excited n first excited n state (singlet) state (triplet) p p 1(p2n1p*1) 3(p2n1p*1) Schuster, D. I. "The Photochemistry of Enones," (p. 629-635) in: Patai, S., Rappoport, Z. The Chemistry of Enones, John Wiley & Sons Ltd., 1989. Mechanism, Part 3 The excited enone (triplet state) can proceed to the next set of events: 1. Exciplex formation with the alkene. The exciplex has a lifetime of 10 to 100's of ns. In this time it can: 1. Initiate carbon-carbon bond formation at either the a or b carbon of the enone; 2. Revert to starting materials. All intermediates up to the 1, 4 diradical are suceptible to this process. If the diradical survives long enough, it may revert to a singlet state via ISC to give an excited singlet state which can then form the second bond and give the product. Schuster, D. I. "The Photochemistry of Enones," (p. 629-635) in: Patai, S., Rappoport, Z. The Chemistry of Enones, John Wiley & Sons Ltd., 1989. Evidence for Similar Rates of Initial Bond Formation, Part 1 O O O hu, H2Se, O O O + ratio of b to a bonded cyclopentyls is 8.2 to 9.0 Hastings, D. J.; Weedon A. C. J. Am. Chem. Soc., 1991, 113, 8525. Evidence for Similar Rates of Initial Bond Formation, Part 2 O O O OEt OEt OEt 5.7 1.0 O hu, H2Se, OEt O O O OEt EtO EtO 3.2 3.5 Hastings, D. J.; Weedon, A. C. J. Am. Chem. Soc., 1991, 113, 8525. Regioselectivity, Part 1 O O O H hu + + Me Me Me Me 26.5% 6.5% O O hu + MeO OMe OMe OMe 65% O O hu + 55% Corey, E. J.; Bass, J. D.; LeMahieu, R.; Mitra, R. B. J. Am. Chem. Soc. 1964, 86, 5570. Regioselectivity, Part 2 O O Me hu Me Me Me O O Me Me O O CClF2 Me Cl Cl hu CClF2 Me O F F F F O Corey's exciplex model correctly predicts regiochemical outcomes: O EWG d- R d+ O hu, d+ d- EWG R R d+ O d+ d- hu, R d- R EDG R EDG Crimmins, M. T.; Reinhold, T. L. Org. Reactions, 1993, 44, 297. Regioselectivity, Part 3 Other factors that affect regiochemistry: 1. Less polar solvents favor products predicted by the Corey exciplex model; 2. Lower temperatures have the same effect; 3. In general, two to four membered tethers set regiochemistry. Examples: Me Me Me Me O O hu OTBS OTBS O O CO2Me CO Me O Me 2 hu Me O Me Me Crimmins, M. T.; Reinhold, T. L. Org. Reactions, 1993, 44, 297. Stereochemistry, Part 1 General considerations: 1. Cyclopentenones and smaller enones give cis fused products; 2. Cyclohexenones give significant amounts of trans product; 3. Strained enones or strained cyclobutane products preclude trans products 4. trans Fused products are easily epimerized to cis. AcO Me hu + O OAc Me Me O O O Me Me O hu + Bu Me Me Crimmins, M. T.; Reinhold, T. L. Org. Reactions, 1993, 44, 297. Stereochemistry, Part 2 O Me H Me H Me O hu + + 64% H H Me O Me Me Me Me Me 1 : 1 O O H MOMO hu MOMO + 82% Me Me O O H 94:6 facial selectivity CO bornyl Ph Ph 2 Ph hu + MeO C 2 Ph MeO2C CO2bornyl 94% ee Crimmins, M. T.; Reinhold, T. L. Org. Reactions, 1993, 44, 297. Total Synthesis, Part 1 Me O O Me O S H Me hu steps CO Me + H 2 Me O TsCl, py Me O Me Me Me Me Me Me Me Me steps TsCl, py O Me H OH then O HO H MeO O HO O CO2Me O S Me Me Me Me Me MePh3PBr H H O O dl-caryophyllene Corey, E. J.; Mitra, R. B.; Uda, H. J. Am. Chem. Soc. 1964, 86, 485. Total Synthesis, Part 3 O O CO2Et CO2Et hu O many, many steps O 100% TESO tBu TESO tBu O HO O HO H H O O H O H H tBu Me HO O H A dl-ginkgolide B Crimmins, M. T. et al. J. Am. Chem. Soc. 2000, 122, 8453. Total Synthesis, Part 4 Me Me Me Me O O hu O O MeOH, p-TSA O O H H H CO2Me 3 steps smallest known O O inside outside bicycle (1988) H H Winkler, J. D.; Hey, J. P. J. Am. Chem. Soc., 1986, 108, 6425. Total Synthesis, Part 5 R R Me O Me Me Me H Me Me Me hu 4 steps O O O O 16% OTBS O O many steps H Me Me Me O H Me dl-ingenol HO HO HO OH Winkler, J. D. et al. J. Am. Chem. Soc., 2002, 124, 9726. Main Contributors to Enone Photochemistry's Development P. E. Eaton: discovered that cyclopentenone and cyclopentadiene reaction under photochemical conditions; synthesized cubane to exemplify utility. E. J. Corey: established the usual stereochemistry of 2 + 2 photochemical cycloadditions; advanced the notion of an exciplex to explain regioselectivity. P. de Mayo: established that intermolecular 2 + 2 was feasible; invented a method for the preparation of 1, 5 diones by photochemical means, postulated that the first triplet state is the reactive one in enones; found that intermediates could revert to starting materials. D. I. Schuster: determined lifetimes of reactive intermediates thereby disproving Corey's exciplex mechanism; in particular, he determied that rate constants for enones triplet quenching were previously overestimated; proved that enone triplets were reactive intermediates. A. C. Weedon: determined that regioselectivity is goverend by diradical lifetimes. H. E. Zimmerman: explained triplet electronics and reactivity using HMO theory. G. S. Hammond and N. J. Turro: carried out experiments that suggested enone triplets werereactive intermediates..