Mechanisms of Singlet Oxygen Reactions

Matt Winston Stoltz Research Group σ * z December 1, 2008

πy* πx* 2p HO O O πy πx

OH σz

σs* H 2s (+)-zerumin B

σs Molecular Orbital Theory Treatment of Dinitrogen

σz*

π * π * y x N N 2p

πy πx

N 2 σz y σs* z N N + N N 2s x σz πy + πx

σs Low HOMOs, high LUMOs --> Stability Bond order = 3 - 0 = 3 Molecular Orbital Theory Treatment of Dioxygen

-Spin S = (1/2) + (1/2) = 1 --> Paramagnetic

-Two electrons in two orthogonal, antibonding orbitals.

-Significant radical character on both oxygens contributes to reactivity of triplet oxygen. σz*

πy* πx* 2p y z O O O O π x πy x πy* πx* O 2 σz

* σs O O 2s

σs

Bond order = 3 -1 = 2

3O O 3 A Brief Overview of O2 Chemistry

-Radical reactions a result of triplet ground state (S = 1).

-Reactions with metals: 2- Mn + O2 Mn+1 + O -Autoxidation of organics: σz* initator RH R π * π * 3O y x R 2 ROO 2p RH + ROO ROOH + R πy πx

σ -Stabilized carbanions may be radicalized: z

σs* 2s O

base Ar 3O2 Ar σs O + O O - superoxide O2

Ar Ar OOH

OOH

Sosnovsky, G.; Zaret, E.H., Dwern, D. Organic Peroxides, Vol. 1, Wiley, NY 1970, pp. 517-560. 3 O2 in Biological Systems

Aerobic oxidation: O2 as an electron sink. 3 O2 in Biological Systems O O H Flavin N N adenosine NH NH diphosphate FADH N N O N N O 2 H FAD OH OH

OH OH HO HO R = adenosine diphosphate R R H O 2 2 2H+, 2H+, 2 e- 2 e-

σz* σz* σz* O2 2 x H2O

πy* πx* πy* πx* πy* πx*

πy πx πy πx πy πx

σz σz σz Essential in establishing the chemiosmotic gradient that drives ATP production from ADP phosphorylation. 3 O2 in Biological Systems (Hemoglobin) O x2-y2 O 2 z 3 Irreversible iron oxidation and O2 Nporph Nporph formation of a m-oxo dimer in non- Fe biological systems. xz, yz Nporph Nporph dimerize O xy FeII O II 2 Fe FeII N O Fe(II) d6 hist high spin square pyramidal

FeIII O FeIII FeIII O

= Nporph FeNporph Nporph Nporph Prevented by steric bulk and along distal edges of heme porphyrin and rigidity of hemoglobin protein backbone.

Maton, A.; Hopkins,J.; McLaughlin, C.W.; Johnson, S.; Warner, M.Q.; LaHart, D.; Wright, J.D. Human Biology and Health. Englewood Cliffs, New Jersey, USA: Prentice Hall (1993). Early Discoveries and Mechanistic Proposals 1 of O2-Mediated Reactions hv, O 2 Fritzsche, M. Compt. Rend., 64, 1035 (1867). 1867: O O Δ

1900: + dye + light cell death Raab, O. Z. Biol., 39, 524 (1900). paramecium

+ dye + light + O cell death Jodlbauer, A.; von Tappeiner, H. Deut. 1905: 2 Arch. Klin Med., 82, 520 (1905). paramecium

1924: Ground-state O2 is a triplet diradical species. Lewis, G.N. Chem. Rev., 1924, 231 (1924).

1 + 37 Σg 1928: fast excited singlet state Mulliken, R.S. Nature, 122, 505 (1928). Energy 1Δ (kcal/mol) 22 g slow

3 - 0 Σg ground state triplet Early Discoveries and Mechanistic Proposals 1 of O2-Mediated Reactions

hv Sens 1Sens

1Sens 3Sens

3 3 Sens + 1O 3 3 Sens + O2 2 Sens + O2 Sens-O-O

1 AO Sens-O-O + A AO + Sens O2 + A 2 2

Kautsky, H.; de Bruijn, H. Naturwiss., 19, 1043 (1931). Gaffron, H. J. Am. Chem. Soc. 287, 130 (1936). Early Discoveries and Mechanistic Proposals 1 of O2-Mediated Reactions 1931: Leucomalachite and trypaflavine adsorbed to SiO2 beads, mixed, and irradiated at trypaflavine excitation wavelength in dry conditions under O2 to yield oxygenated products. 1. Immobilized starting materials cannot physically interact with one another. 2. Dry conditions suggests that oxygenation cannot originate from water. 3. Trypaflavine luminscence dependent upon oxygen pressure.

trypaflavine adsorbed to SiO hv, O2 O OH 2 leucomalachite

Me2N NMe2 Me2N NMe2

SiO2 bead

hv (trypaflavine O excitation) H3N N NH2 + O Me2N Me N NMe 2 2 NMe2 trypflavine

trypaflavine

Reaction-prohobitive distance Kautsky, H.; deBruijn, H. Naturwiss., 19, 1043 (1931). Early Discoveries and Mechanistic Proposals 1 of O2-Mediated Reactions 1. Excitation of mobile, ground-state triplet oxygen to mobile, excited-state singlet oxygen.

* 3 hv O2 1 O2 1 (assumed to be Σg+) H2N N NH2 H2N N NH2

2. Reaction of mobile, excited-state singlet oxygen with oxidized leucomalachite.

1 O2* O

O O Me2N O NMe Me2N NMe2 Me2N NMe2 2

1 Suggestive of a diffusable reactive intermediate such as O2. Early Discoveries and Mechanistic Proposals 1 of O2-Mediated Reactions

iPr H 1. H2N N

S H N H N N H 2 O + CH2O N N hv, O2 S H 1 + N 37 Σg HO2C OH 820 nm Energy22 1 O O (kcal/mol) Δg 2 (35 kcal/mol) 2

HO C 3 - 2 0 Σg emits at 820 nm --> 35 kcal/mol

1 Δg energy not fully characerized, so existence of singlet oxygen in this mechanism disputed.

2. Different kinetic behavior of active intermediate when formed with anthracene and diphenylanthracene as sensitizer.

Livingston, R.; Subba Rao, V. J. Phys. Chem., 63, 794 (1959). Early Discoveries and Mechanistic Proposals 1 of O2-Mediated Reactions

phenanthrine sensitizer and substrate O O 3 hv O2 O bimolecular O

intramolecular

O O

Kinetics suggest intramolecular reaction.

Schenk, G.O. Naturwiss, 41, 452 (1954). 1 Support for O2-Mediated Photosensitized Autoxidations

30% H2O2 1 1. NaOCl red-orange chemiluminescence (1960) 20oC

1 2 2. Chemiluminescence of O2 detected in NaOCl-H2O2 solutions (1964)

3. Same products and similar yields observed for substrate oxidations under NaOCl-H2O2 and photosensitized autoxidation conditions (1964)3a,b O OOH NaOCl/H2O2 84% O O O OCH CH3OH O 3 (photoautoxidation: 74%)

OOH 63% NaOCl/H2O2 (photoautoxidation: 54%)

O O 50% Ph Ph Ph O NaOCl/H2O2 O (photoautoxidation: Ph O Ph 65%) Ph Ph O Ph Ph Ph Ph CO Ph

4. Rates of photooxidation independent of sensitizer (1965)4 1. Seliger, H. Anal. Biochem. 1, 60 (1960). 2. Khan, A.U.; Kasha, M. Nature 204, 241 (1964). 5 3a. Foote, C.S.; Wexler, S. J. Am. Chem. Soc., 86, 3879 (1964). 5. No steric influence by sensitizers (1965) 3b. Corey, E.J.; Taylor, W.C. J. Am. Chem. Soc., 86, 3881 (1964). 6. No effect by radical scavengers (1965)5 4. Kopecky, K.R.; Reich, H.J. Can. J. Chem. 43, 2265 (1965). 5. Foote, C.S.; Wexler, S.; Ando, W. Tetrahdron Lett. 46, 4111 (1965). 1 Direct Spectroscopic Evidence of O2 in Photosensitized Autoxidations

1 1. EPR absorption of Δg state detected.

a. Kearns, D.R.; Khan, A.U.; Duncan, C.K.; Maki, A.H. J. Am. Chem. Soc. 91, 1039 (1969). b. Wasserman, E.; Kuck, V.J.; Delavan, W.M.; Yager, W.A. J. Am. Chem. Soc. 91, 1040-1041 (1969).

1 3 2. 1268-nm emission of the Δg--> Σg transition of molecular oxygen in liquid solution at room temperature is reported in multiple cases.

a. Snelling, D.R. Chem. Phys. Lett. 2, 346 (1968). b. Krasnovsky, A.A. Biophys. USSR 2, 748 (1976). c. Krasnovsky, A.A. Photochem. Photobiol. 29, 29 (1979). d. Khan, A.U.; Kasha, M. Proc. Natl. Acad. Sci. USA 76, 6047 (1979).

hv Sens 1Sens

1Sens 3Sens 3 3 1 Sens + O2 Sens + O2 1 3 O2 Relaxation to O2

-Intersystem crossing from singlet to triplet state:

1 + 37 Σg

1 - Energy 22 (kcal/mol) Δg 1280 nm vibrational energy 3 - 0 Σg

-Relaxation time is highly solvent dependent (solvent vibrational frequencies.)

Solvent Lifetime (ms)

H2O 3.8 D2O 62.0 CH OH 10.0 3 Solvents with larger vibrational frequencies are CHCl3 264.0 easier to excite, and are more efficient quenchers of CDCl3 740.0 1 (CH3)2C=O 50 O2. (CD3)2C=O 723 C6H6 30 C6D6 630 Freon-113 15,800

-1 -H2O vibrational frequency = 3600 cm -Organics ~ 3000 cm-1 -Freon-113 (no O-H/C-H bonds)

Clennan, E.L.; Pace, A. Tetrahedron 61, 6665 (2001). 1 Preparation of O2 via Sensitized Irradiation

S S (1 -) 1 1 - 1 Δg S1 ( Δg ) 2 T1 hv (violation of spin conservation) 1 3 T (3 -) 3 - 0 Σg Solution S0 T0 ( Σg )

O2 Photosensitizer O2

Direct excitation of O2 from triplet to singlet state is spin-forbidden. 1 = Absorption/excitation 2 = Intersystem crossing 3 = Allowed energy transfer I I O O O

I I Me2N S NMe2

Cl CO2 N Cl Cl Cl

rose bengal methylene blue 1 Preparation of O2 via Chemical Processes

1 Peroxide/bleach H2O2 + NaOCl O2 + H2O + NaCl

Phosphite ozonide O O O o O O O o -78 C -15 C OR 1 (RO)3P + O3 OR RO P (RO)3P=O + O2 (RO)3P O O P OR OR OR O

Ph Ph

Δ 1 Aromatic endoperoxides O + O2 O PhH retro [4+2] Ph Ph Heterocycle/ozone adducts 1,3-diphenyl- Ph dil. O3 O O O Ph O isobenzofuran, Ph O CH2Cl2 Ph Ph Ph o Ph then warm to rt O Ph N O C N O3 + N Ph Ph Ph

Clennan, E.L.; Pace, A. Tetrahedron 61, 6665 (2001). 1 Preparation of O2 via Chemical Processes

1 2H2O2 +MoO4- 2H2O + O2 Proceeds in very polar environments (water, aqueous methanol/ethanol)1

aqueous phase in microemulsion

2H2O2 + MoO4- 1 Generation of O2 in aqueous phase, followed by diffusion organic phase into organic phase solvating 1 the substrate. O2 SO2 S

"Microemulsion was prepared at room temperature by adding dropwise [aq. NaMoO4] to a sturred slurry of sodium dodecylsulfate (SDS - surfactant), n- butanol, and methylene chloride." Add 9,10-diphenylanthracene and 1.0 mmol of 50% H2O2. Stir at room temperature for 13 minutes.2

1. Aubry, J.M.; J. Am. Chem. Soc. 107, 5844 (1985). 2. Aubry, J.M.; Bouttemy, S. J. Am. Chem. Soc. 119, 5286 (1997). 1 O2 Ene Reactions

1 O2 OOH

Me iPr H H iPr D 1 Me Me O2 + iPr H OOH D OOD H

-Olefin shifts to allylic position. -Syn formation of C-O bond and breakage of C-H/D bond.

Me D H iPr H HO O H Exciplex Formation in the Ene Reaction

-1 -1 Olefin ΔH (kcal/mol) ΔS (eu) kr (M s ) 1.6 -35 4.8x104

0.3 -45 7.2x103

2.0 -34 3.9x104

0.4 -42 7.7x103

-Small or slightly negative activation enthalpies and highly negative activation entropies. -Electron rich olefins react with 1O2 at rates 103 less than diffusion control.

1 O2 Electrophilic dioxygen stabilized by association with alkene, but entropic penalty of association. O2 exciplex

Hurst, J.R.; Wilson, S.L.; Schuster, G.B. Tetrahedron, 41, 2191 (1985). Gorman, A.A.; Hamblett, I.; Lambert, C.; Spencer, B.; Standen, MC. J. Am. Chem. Soc. 110, 8053 (1988). Identifying Intermediates in the Ene Reaction

Ph Ph Ph Ph

D3C CD3

kH/kD = 1.08 intermolecular kinetic isotope effect

D3C CD3

D3C CD3

kH/kD = 1.11

1 CD3 O2 CD CD 3 3 intramolecular kinetic isotope effect OOH OOD D C 3 D3C D2C

kH/kD = 1.4

Stephenson, L.M.; Grdina, M.J.; Orfanopoulos, M. Acc. Chem. Res. 13, 419 (1980). Identifying Intermediates in the Ene Reaction

intermolecular KIE ≠ intramolecular KIE

Rate-determining and product-determining steps must be distinct.

1 O2

O HOO O2 O

O CD3 1O O 2 H CD3 CD3 D3C D OOH OOD D3C D3C D2C 1.4 1.0

kH/kD = 1.4

Stephenson, L.M.; Grdina, M.J.; Orfanopoulos, M. Acc. Chem. Res. 13, 419 (1980). Identifying Intermediates in the Ene Reaction

kH/kD = 1.0

D3C CD3

O O D3C CD3 H k OOH 1 D3C H D3C 1.0 kH/kD = 1.0 O D C CD O CD3 3 3 D k OOH 2 D D2C 1.0

-Perepoxide formation does not involve breaking C-isotope bond, so k1/k2 = 1. -Perepoxide formation is irreversible.

Stephenson, L.M.; Grdina, M.J.; Orfanopoulos, M. Acc. Chem. Res. 13, 419 (1980). Regiochemical Issues

1 MeO O2 MeO

HOO

100%

MeO 1O MeO MeO 2 +

HOO HOO 72% 28%

OOH 1O 2 + HOO 48% 52%

H Relative rate A(%) B(%) Ph H Ph H Ph 1O Me Me 2 Me + 8 80 20 HOO HOO CO Me CO2Me CO2Me 2

H Ph H Ph Me 1 Me 1 65 35 O2 Me + Ph CO2Me H HOO HOO CO Me CO2Me 2 A B Rousseau, G.; LePerchec, P.; Conia, J.M. Tetrahedron Lett. 2517 (1977). Lerdal, D.; Foote, C.S. Tetrahedron Lett. 3227 (1978). Regiochemical Issues

1 MeO O2 MeO

HOO Preference for "cis abstraction" overrides unfavorability of an olefin exocyclic to the 100% cyclopropane ring.

MeO 1O MeO MeO 2 +

HOO HOO 72% 28%

OOH 1O 2 + HOO 48% 52%

H Relative rate A(%) B(%) Ph H Ph H Ph 1O Me Me 2 Me + 8 80 20 HOO HOO CO Me CO2Me CO2Me 2

H Ph H Ph Me 1 Me 1 65 35 O2 Me + Ph CO2Me H HOO HOO CO Me CO2Me 2 A B Rousseau, G.; LePerchec, P.; Conia, J.M. Tetrahedron Lett. 2517 (1977). Lerdal, D.; Foote, C.S. Tetrahedron Lett. 3227 (1978). Secondary Orbital Overlap

1 O2 (π*)

H H

-1 -1 Olefin ΔH ΔS (eu) kr (M s ) (kcal/mol) Less structural reorganization required upon forming 1.6 -35 4.8x104 perepoxide, since rotational barriers of cis vinyl substituents already exist.

0.3 -45 7.2x103 H 2.0 -34 3.9x104 R R H H H H 0.4 -42 7.7x103 H

Stephenson, L.M. Tetrahedron Lett. 21, 1005 (1980). Houk, K.N.; Williams Jr., J.C.; Mitchell, P.A.; Yamaguchi, K. J. Am. Chem. Soc. 103, 949 (1981). Secondary Orbital Overlap

1 O2 (π*)

H H

-1 -1 Olefin ΔH ΔS (eu) kr (M s ) (kcal/mol) 1.6 -35 4.8x104

0.3 -45 7.2x103

2.0 -34 3.9x104

0.4 -42 7.7x103

Stephenson, L.M. Tetrahedron Lett. 21, 1005 (1980). Houk, K.N.; Williams Jr., J.C.; Mitchell, P.A.; Yamaguchi, K. J. Am. Chem. Soc. 103, 949 (1981). Effects of Secondary Orbital Overlap

OMe OMe

1 O2 OOH

Presumably more 100% favorable to break OOH aromaticity in a [4+2] 1 OMe O2 cycloaddition reaction than to OMe OMe undergo ene reaction 1 O O2 O in the absence of H secondary orbital 100% 0% overlap??

H Relative rate A(%) B(%) Ph H Ph H Ph 1O Me Me 2 Me + 8 80 20 HOO HOO CO Me CO2Me CO2Me 2

H Ph H Ph Me 1 Me 1 65 35 O2 Me + Ph CO2Me H HOO HOO CO Me CO2Me 2 A B

Lerdal, D.; Foote, C.S. Tetrahedron Lett. 3227 (1978). 1 Substituent Effects in the O2 Ene Reaction

These range from the obvious....

H OOH H 1 O2 O O O steric effects O H by methyl group H

O2

OOH 1 O2 O O O O2

Facial steric encumberance

Lin, H.-S.; Paquette, L.A. Synth. Commun. 16, 1275 (1986). 1 Substituent Effects in the O2 Ene Reaction

... to subtle...

O O O 1 O O2 VS. L L L A B -Steric interactions between pendant O and L to favor structure B.

-Interactions between the perepoxide and L can lengthen the (L)C-O+ bond and encourage hydrogen abstraction from the geminal alkyl group. 1 Substituent Effects in the O2 Ene Reaction

... to subtle...

O O O 1 O O2 VS. L L L A B -Steric interactions between pendant O and L to favor structure B.

-Interactions between the perepoxide and L can lengthen the (L)C-O+ bond and encourage hydrogen abstraction from the geminal alkyl group.

...to the more subtle... -Increasing energy of C-L bond will increase antibonding character of interaction and weaken the C-O bond. O O Ol.p.

L C-L σ

Fristad, W.E.; Bailey, T.R.; Paquette, L.A.; Gleiter, R.; Bohm, M.C. J. Am. Chem. Soc. 101, 4420 (1979). Stereoelectronic Effects Governing Regiochemistry

H N SO2Ph O N SiMe 1. 1O SiMe H2NNHSO2Ph 2 MeLi, 3 2 3 TsOH then TMSCl 2. NaBH4 OH TBAF OH

oxygenation β to Si, and abstraction 25% on geminal methyl

Fristad, W.E.; Bailey, T.R.; Paquette, L.A. J. Am. Chem. Soc. 101, 4420 (1979). Interesting Regiochemical Effects

Ph Ph Minimizing A[1,2] strain, the proton remains H psuedoequatorial and cannot be abstracted by the H perepoxide complex. (Me)3Si 1 O2 (Me)3Si

no reaction

Me Si Me3Si HO 3 OH O2, Despite the reactivity of the benzylic hydrogen, rose bengal + abstraction still occurs at the geminal methyl, MeOH, hv presumably due to the stereoelectronic effect mentioned earlier. then NaBH4

76% 24%

Steric and stereoelectronic effects work hand-in-hand. SiMe3 SnMe3 C-Sn, C-Si bonds are longest, and should mitigate steric effects, but electron rich C-Sn/Si bond strengthens stereoelectronic effect. (34) (66) (100) (11) (89)

(x) = percent abstraction

Fristad, W.E.; Bailey, T.R.; Paquette, L.A. J. Am. Chem. Soc. 101, 4420 (1979). Allylic Strain As a Determining Factor

(10) (7)

(43) (22) (50) (68)

O O O O H HCH CH3 H C 3 H3C 3 H CH3 H H3C A[1,2] strain A[1,3] strain

OOH

major

Adam, W.; Richter, M.J. J. Org. Chem. 59, 3335 (1994). Allylic Strain As a Determining Factor

(10) (7)

(43) (22) (50) (68)

O O O O O O H3C H HCH HH CH3 H C 3 H C H3C 3 3 H CH CH3 3 H H3C H A[1,2] strain A[1,3] strain

OOH OOH

major major

Adam, W.; Richter, M.J. J. Org. Chem. 59, 3335 (1994). Electronic Effects

SiMe3 HOO 1 HOO SiMe O2 + 3 SiMe3 H H SiMe3 22% 78% O2

1. Hyperconjugation of C-Si bond into π bond forces C-Si bond perpendicular to the plane containing the olefin.

2. O2 approaches olefin face anti to the silyl group. Electronic Effects

SiMe3 HOO 1 HOO SiMe O2 + 3 SiMe3 H H SiMe3 22% 78% O2

1. Hyperconjugation of C-Si bond into π bond forces C-Si bond perpendicular to the plane containing the olefin.

2. O2 approaches olefin face anti to the silyl group.

H 1 HOO O2 tBu H tBu tBu 100% O2

A[1,3] minimized

Laporterie, A.; Dubac, J.; Mazerolles, P.; Loughmane, H. J. Organometal. Chem. 216, 321 (1981). Electronic Effects

1 1. O2 HO 2. Me2S

anchimeric assistance 76%

OMe Cl F

Cl F

MeO Cl Cl F F

anti=79 anti=80 anti=48 anti=46 syn=21 syn=20 syn=52 syn=54 -1 -1 4 -1 -1 4 k(M-1s-1) = 4.28x106 k(M-1s-1) = 1.36x105 k(M s ) = 9.63x10 k(M s ) = 5.24x10

Okada, K.; Mukai, T. J. Am. Chem. Soc. 100, 6509 (1978). Hertel, L.W.; Paquette, L.A. J. Am. Chem. Soc. 101, 7620 (1979). Hydrogen Bonding Effects -A[1,3] minimization OH H H H Me -OH perpendicular to plane of olefin. 1 O2 O H O O H

OH OH OH HOO HOO OH

OOH OOH 93 : 7

96% 4% Hydrogen Bonding Effects -A[1,3] minimization OH H H H Me -OH perpendicular to plane of olefin. 1 O2 O H O O H

OH OH OH HOO HOO OH

OOH OOH 93 : 7

96% 4% OAc O 1O H H Me OAc H H 2 O + O H H H HAcO Me O

OH OH OH HOO HOO OH + + OOH OOH 32% 7% 50% 11% Adam, W.; Nestler, B. J. Am. Chem. Soc. 115, 5041 (1993). Hydrogen Bonding Effects -A[1,3] minimization OH H H H Me -OH perpendicular to plane of olefin. 1 Me O2 O H O O H

OH OH OH HOO HOO OH

OOH OOH 93 : 7

96% 4%

O OH OH OH 1O HOO HOO 2 + + OOH 54 : 46

>96% <4%

No A[1,3] strain to direct preference of one conformation over the other. Perepoxide can hydrogen bond to -OH or participate in cis effect with anti methyl.

Adam, W.; Nestler, B. J. Am. Chem. Soc. 115, 5041 (1993). Hydrogen Bonding Effects -A[1,3] minimization OH H H H Me -OH perpendicular to plane of olefin. 1 Me O2 O H O O H

OH OH OH HOO HOO OH

OOH OOH 93 : 7

96% 4%

OH OH OH H H H Me 1O HOO HOO 2 + Me O H O O H 93 : 7

A[1,2] strain does not influence the diastereoselectivity of this reaction.

Adam, W.; Nestler, B. J. Am. Chem. Soc. 115, 5041 (1993). 1 Chiral Auxiliaries in the O2 Ene Reaction

Me CMe2Np Me

1 OOH O2 OOH Me O CH2Cl2 O O -60oC O O O CMe2Np CMe2Np

re attack 82 : 18 si attack

O O

O O

Dussault, P.H.; Woller, K.R., Hillier, M.C. Tetrahedron 50, 8929 (1994). A Two-Step, No-Intermediate Ene Reaction?

-At 24, we see the reaction heading towards a perepoxide intermediate. -Structure 25 is not an intermediate, but a transition state! -At 25, the reaction path can bifurcate toward one of two products.

O O H H

-Not a concerted reaction, because there are two kinetically distinguishable steps that can be influenced through isotopic substitution. -"Two-step, no-intermediate mechanism."

Houk et al. J. Am. Chem. Soc. 125, 1319 (2003). 1 O2 [4+2] Cycloadditions

O2, hv O O

-At least a formal [4+2] reaction, but is it concerted or stepwise? 1 - O2 is a superdienophile by virtue of its dipole.

X

O O X X X X Y O O O or O O O O O X Y Y O Y Y O

Y 1 Quantum Chemical Treatment of the [4+2] Cycloaddition of O2

-Path of least energy to the endoperoxide involves a singlet diradical intermediate, followed by ring closure.

O O O O O O 21 kcal/mol 11-12 kcal/mol

-calculation includes rotational barrier

Bobrowski, M.; Liwo, A.; Odziej, S.; Jeziorek, D.; Ossowki, T. J. Am. Chem. Soc. 122, 8112 (2000). 1 Quantum Chemical Treatment of the [4+2] Cycloaddition of O2

-A concerted mechanism prevails with aromatics. -A diradical intermediate at 26.7 kcal/mol could not be linked to the reactants via a transition state.

Bobrowski, M.; Liwo, A.; Odziej, S.; Jeziorek, D.; Ossowki, T. J. Am. Chem. Soc. 122, 8112 (2000). Experimental Evidence for Stepwise Mechanism

o CD2Cl2/TPP, -78 C O2/hv O O + O O

E,E 74 7 E,Z 46 12 Z,Z 42 10 O O 1 O2 O O O O

rotation = 5 kcal/mol

O O O O 1 O2

-Isomerization leads to most stable diene, which can undergo oxygenation.

O'Shea, K.E.; Foote, C.S. J. Am. Chem. Soc. 110, 7167 (1988). 1 Guiding Effects in the [4+2] Cycloaddition of O2

O O 1 O2

O O O O O O O O 78 22

1O 2 O O O O O O O O O O O O O 14 86

1 O O2 O O O O O O O O O O O O O O O

0 100

Mehta, G.; Uma, R. J. Org. Chem. 65, 1685 (2000). 1 Guiding Effects in the [4+2] Cycloaddition of O2

O O 1 O2

O O O O O O O O 78 22

1O 2 O O O O O O O O O O O O O 14 86

1O 2 O O S S S S O S O O O O S 0 100

C-thioacetal bond is more electron rich than cyclobutane bonds. S 1 Cieplak model predicts O2 addition from opposite face to minimize dipole. O S

Mehta, G.; Uma, R. J. Org. Chem. 65, 1685 (2000). Heterocycles as Cycloaddition Substrates

Furans:

4 1 4 R R R 4 O O R O O O O 1 1O Reduction R 2 R1 3 R 3 3 2 2 R R R R R2

Solvolysis

4 OR 4 OMe R ROH 4 OOH R4 OMe R OR O OMe R OMe O OOH ROH O -H O O 1 1 2 2 1 R R R1 R -H2O2 3 3 R 3 3 R R R 2 2 2 R R R2 R

[1,2] shift [1,2] shift

OMe O R4 O OMe O O R1 R3 R3 Gollnick, K.; Griesbeck, A. Tetrahedron, R2 R2 41, 2057 (1985). Heterocycles as Cycloaddition Substrates

Furans: O O O2 O O rose bengal Δ, >-10 oC hv explosion 2:2:1 MeOH-EtOH-Acetone o O2 -90 C rose bengal, hv PPh3, MeOH O MeOH o ether, O -70 C O O rt -30 C

O O O O OMe

1. peroxide dimer 2. epoxidzied products

Gollnick, K.; Griesbeck, A. Tetrahedron, 41, 2057 (1985). Koch, E.; Schenck, G.O. Chem. Ber. 99, 1984 (1966). Heterocycles as Cycloaddition Substrates

Furans:

4 R 4 O R2 R3 O R O O 1 1O Baeyer-Villiger R 2 R1 1 4 3 R OR R 3 2 R R R2 O O

R2 R3 4 O R O O R4 1 R R1 O R3 O O R2 Heterocycles as Cycloaddition Substrates

Furans:

4 R 4 O R2 R3 O R O O 1 1O Baeyer-Villiger R 2 R1 1 4 3 R OR R 3 2 R R R2 O O

R2 R3 4 O R O O R4 1 R R1 O R3 O O R2

O2, rose bengal O hv Me O tBuOH, CH Cl O CCl , -90oC Me O O 2 2 4 -78oC Me Me O

O

Gollnick, K.; Griesbeck, A. Tetrahedron, 41, 2057 (1985). Adam, W.; Rodriguez, A. Tetrahedron Lett, 22, 3509 (1981). Manipulating Ozonide Cleavage

HO O O O O 1 O O2 OH +

OH OH OH R R R

O O O TIPS

2,6-lutidine, nBuLi, TIPSOTf HMPA O2, methylene blue, hv OH OTIPS OH 91% 90%

H H H HO O HO O O O O OTIPS O Silica gel, H2O OH 83% of both OH OH epimers

H H H (+)-zerumin B

Margaros, I; Vassilikogiannakis, G. J. Org. Chem. 73, 2021 (2008). 1 O2 [4+2] Cycloadditions in Natural Product Synthesis

1. O2, methylene blue hv, MeOH O O O -40OC, then 25OC 2. NaBH , MeOH, 25OC O 4 O O + O H H H O O O O ricciocarpin A ricciocarpin B 46% O

O

O H OH O

Held, C; Frohlich, R.; Metz, P. Angew. Chem. Int. Ed. 40, 1058 (2001).

CO Me MeO CO2Me dilute O3 MeO 2 MeO CH2Cl2 MeO OH o NMe O C, 5 min HO NMe isochrysohermidin MeO C MeO2C 2

MeN CO2H MeN O CO2H O + meso

Wasserman, H.H.; Rotello, V.M.; Frechette, R.; DiSimone, R.B.; Yoo, J.U.; Baldino, C.M. Tetrahedron. 53, 8731 (1997). 1 O2 [4+2] Cycloadditions in Natural Product Synthesis

1. O2, methylene blue hv, MeOH O O O -40OC, then 25OC 2. NaBH , MeOH, 25OC O 4 O O + O H H H O O O O ricciocarpin A ricciocarpin B 46% O

O

O H OH O

Held, C; Frohlich, R.; Metz, P. Angew. Chem. Int. Ed. 40, 1058 (2001).

MeO O R O MeO2C MeN O O H

Wasserman, H.H.; Rotello, V.M.; Frechette, R.; DiSimone, R.B.; Yoo, J.U.; Baldino, C.M. Tetrahedron. 53, 8731 (1997). 1 Steric Effects in the O2 [4+2] Cycloaddition Reaction O2 O TPP, hv o O CCl4, -5 C, 12 h EtO O EtO O racemic

O O O O2 TPP, hv N o N O O CCl4, -5 C, 12 h N O O O O O Ph Ph Ph >95 : 5 Adam, W.; Gthlein, M.; Peters, E.M.; Peters, K.; Wirth, T. J. Am. Chem. Soc. 120, 4091 (1998).

O2, methylene blue H K2OsO4 CCl4 H citric acid -40oC H NMO O 66% AcO O H H H AcO H H H H H2, Pd/C MeOH Biologically active terpenoid O 95% AcO from E. fortunei AcO O OHH H HO OH OH HO HO Valente, P.; Avery, T.D.; Taylor, D.K.; Tiekink, E.R.T. J. Org. Chem. ASAP doi: 10.1021/jo8020506 Directing Effects by Hydrogen Bonds in [4+2] Reactions

-Hydrogen-bond directed [4+2] cycloadditions have been known to occur, but they are infrequent due to the reactivity of singlet oxygen as a dienophile.

OH OH OH H CH3 H CH3 H CH3 1 O2

O O O O

85 : 15

H CH3 O 1 O2 H

Adam, W.; Prein, M. J. Am. Chem. Soc. 115, 3766 (1993). Adam, W; Peters, E.M.; Peters, K.; Prein, M.; von Schnering, H.G. J. Am. Chem. Soc. 117, 6686 (1995). Adam, W.; Prein, M. Acc. Chem. Res. 29, 275 (1996). 1 O2 [2+2] Cycloadditions

R2 1 2 R R R 1 1 O2 O O 3 R3 R4 R R4

1. Not necessarily stereospecific. 1 2. Increasing solvent polarity favors dioxetane formation when other O2 reaction pathways exist. 3. Pathway more favorable with electron-rich olefins.

H O 1O O O O 2 O O O O O O H 1 O2 [2+2] Cycloadditions

R2 1 2 R R R 1 1 O2 O O 3 R3 R4 R R4

1. Not necessarily stereospecific. 1 2. Increasing solvent polarity favors dioxetane formation when other O2 reaction pathways exist. 3. Pathway more favorable with electron-rich olefins.

H O 1O O O O 2 O O O O O O H

H O O A O O 1O O O O 2 H A/B increases with solvent polarity. 58-fold more A than B in acetonitrile compared to B benzene. O OOH O O

Kearns, D.R.; Fenical, W.; Radlick, P. Ann. N. Y. Acad. Sci., 171, 32 (1970). Bartlett, P.D.; Mendenhall, G.D.; Schaap, A.P. Ann. N. Y. Acad. Sci., 171, 79 (1970). Fenical, W.; Kearns, D.R.; Radlick, P. J. Am. Chem. Soc. 91, 3396 (1969). 1 Substrates for O2 [2+2] Cycloadditions OMe EtO OEt N

O Ph

O Ph

OMe MeO OMe OMe

O

Ph Ph

Fenical, W.; Kearns, D.R.; Radlick, P. J. Am. Chem. Soc. 91, 3396 (1969). Foote, C.S.; Lin, J.W.-P. Tetrahedron Lett., 3267 (1968). McCapra, F.; Hann, R.A. Chem. Commun., 442 (1969). Richardson, W.H.; Hodge, V. J. Org. Chem. 35, 1216 (1970). Schultz, A.G.; Schlessinger, R.H. Tetrahedron Lett., 2731 (1970). Evans-Based Chiral Auxiliary Toward 1O [2+2] Cycloaddition Reactions 2 1 O2

O O O O O H O O2, TPFPP iPr N O N H H CDCl , -35oC Ph N 3 Ph H iPr TsOH Ph iPr PhCH3 Ph reflux, 48 h quantitative Ph

O O O O O O O O N iPr N iPr N iPr iPr N + + Ph + Ph Ph O Ph O O O O O O O

Ph Ph Ph Ph

>95:05 >95:05 Evans-Based Chiral Auxiliary Toward 1O [2+2] Cycloaddition Reactions 2 1 O2

O O O O O H O O2, TPFPP iPr N O N H H CDCl , -35oC Ph N 3 Ph H iPr TsOH Ph iPr PhCH3 Ph reflux, 48 h quantitative Ph

O O O O O O O O N iPr N iPr N iPr iPr N + + Ph + Ph Ph O Ph O O O O O O O

Ph Ph Ph Ph

L-methionine, >95:05 o >95:05 MeCN, H2O, 0 C O O NaBH4, DBU Ph N THF, H2O (4:1) OH iPr OH Ph OH OH Ph Adam, W.; Bosio, S.G.; Turro, N.J. J. Am. Chem. Soc. 124, 8814 (2002). Ph Hydrogen Bonding Effects in [2+2] Reactions

OOH

O O OX O OX O OX OX

A (β-attack) B (α-attack) C

O X Solvent A:B [2+2]:ene O HO H CDCl3 >95:5 47:53 Me H H CD3OD/ 89:11 >95:5 CCl4 conformation of allylic alcohol CDCl N/A <5:95 prevents H-abstraction to the OAc 3 ene product OAc CD3OD N/A <5:95 Hydrogen Bonding Effects in [2+2] Reactions

OOH

O O OX O OX O OX OX

A (β-attack) B (α-attack) C

O X Solvent A:B [2+2]:ene O HO H CDCl3 >95:5 47:53 Me H H CD3OD/ 89:11 >95:5 CCl4 conformation of allylic alcohol CDCl N/A <5:95 prevents H-abstraction to the OAc 3 ene product OAc CD3OD N/A <5:95

-Increasing solvent polarity favors more polar transition state of [2+2] cycloaddition.

O O OOH H

Me OAc OX

Adam, W.; Saha, Moller, C.R.; Schambony, S.B. J. Am. Chem. Soc. 121, 1834 (1999). Matsumoto, M.; Kobayashi, H.; Matsubara, J.; Watanabe, N.; Yamashita, S.; Oguma D.; Kitano, Y.; Ikawa, H. Tetrahedron Lett. 37, 397 (1996). Other Modes of Reactivity of Dioxetanes

1 O2 EtOD/CHCl3 solvolysis

O N O N H O H O

O N O N H OEt H OEt OOH O Other Modes of Reactivity of Dioxetanes

1 O2 EtOD/CHCl3 solvolysis

O N O N H O H O

O N O N H OEt H OEt OOH O

tBu tBu tBu O HO 1 O O2 O

OMe OMe OMe

OH tBu O tBu O HO HO mCPBA O

OMe OMe O O

Abeilo, F.; Bois, J.; Gomez, J.; Morell, J. Bonet, J.J. Helv. Chim. Acta. 58, 2549 (1975). Wasserman, H.H.; Terao, S. Tetrahedron Lett., 1735 (1975). 1 O2 Effects on DNA O O O N 1 N N HN O2 HN HN OH H N N N H N N N O N 2 2 O H2N N dr dr dr

1 O2

O O N HN N O O HN O OH N H2N N N OH HN H N N N dr 2 O O dr HN N N dr

solvolysis retro [2+2]

Ravanat, J.-L.; Martinez, G.R.; Medeiros, M.H.G.; di Mascio, P.; Cadet, J. Tetrahedron, 62, 10709 (2006).