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;

ii) Regiochemical control; O 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.