Photoinduced Electron Transfer:
Strategies for Organic Synthesis
D* + Acc = D- + Acc+
MacMillan Group Meeting
Alex Warkentin 2.12.08
Contents
• • • • • • • • • History of photoinduced electron transfer
Basics of electron transfer versus energy transfer
Oxidative PET bond cleavage
Reductive PET bond cleavage
Enabling of macrocyclic ring closures
Intramolecular alpha-amino radical additions
Intermolecular alpha-amino radical additions and applications
Catalytic asymmetric?
Mechanistic verification via spectroscopic analysis
Roth, H. D. Photoinduced Electron Transfer I Springer-Verlag, Heidelberg, 1990. 5.
Griesbeck, A. G.; et. al. Acc. Chem. Res. 2007, 40, 128.
Griesbeck, A. G.; Mattay, J., Eds. Synthetic Organic Photochemistry Marcel-Dekker, New York, 2005.
The First Understandings of Photochemistry
 Priestley was the first to discover photosynthesis, albeit fortuitously
H2O + CO2
hν
O2 + C6H12O6
Discovered accidentally while Priestly was studying the “influence
Of light in the production of ‘dephlogisticated air’ [O2] in water by
Means of a ‘green substance’.”
Priestley, J. Phil. Trans. Roy. Soc. (London) 1772, 62, 147
Joseph Priestley, 1733 - 1804
British chemist
 Ingenhousz developed photosynthesis more rigorously
Ingenhousz, along with Saussure, established the
requirement of light in macroscopic photosynthesis.
But, despite work by Liebig, Baeyer and Willstatter,
electron transfer remained unsolved untill the 20th
century when J. J. Thompson (1897) and Milikan
(1913) convinced the community of the presence
of the electron.
Jan Ingenhousz, 1730 - 1799
Dutch chemist, physicist and physician
Electron Transfer and Actinometry
 Dobereiner foreshadowed photo-redox chemistry with actinometry
O
Fe2O3
(Fe3+)
+
O
O
O
hν
FeO
+
CO2
+
CO2
(Fe2+)
Designed the first actinometer that measures the
power of electromagnetic radiation
J. W. Dobereiner, 1780 - 1849
German Chemist
 The place and usefulness of actinometry was fiercely debated and no other
photo-redox chemistry was studied in-depth in the 19th century
 Furthermore, prior to the advent of NMR, ESR, and CIDNP the presence of
ionic radicals remained highly speculative and their identity often erroneously presumed.
 20th Century PET contributions were made by Bauer and Weiss. The latter enunciated
the basic form of modern PET theory:
“Fluorescence quenching in solution can be
considered as a simple electron transfer process.”
D* + Acc = D- + Acc+
Weiss, J.; Fischgold, H. Z. Physik. Chem. 1936, B32, 135.
Photoinduced Electron Transfer: A Representative Mechanism
 Understanding α-amino radical formation is important for utlizing its reactivity
hν
1 or 3Sens
1 or 3Sens*
PET
E
E
1 or 3Sens*
R
+
N
R
1 or 3Sens
R
+
E
R
+
N
R
Nu
E
+
N
R
R
R
N
R
R
R
R
R
R
Nu
N
Further chemistry
R
R
N
R
R
Basics of Photoinduced Electron Transfer
 More efficient as distance decreases
+
+
 Efficiency dependent on redox potential
1Sens
+
A
1Sens
+
1Sens
+
+
A
 Singlet-excited sensitizer is both a better
oxidant AND reductant. Both processes
quench fluorescence
+
D
1Sens
+
D
 Triplet fluorescence quenching is known
Anslyn, E. V.; Dougherty, D. A. Modern Physical Organic Chemistry University Science Books, Sausalito, CA. 2005, 955 - 958.
Energy Transfer Mechanisms do not Occur Via Polar Intermediates
 Energy Transfer I: Dexter Mechanism
+
3Sens*
+
 Energy Transfer II: Forster Mechanism
+
+
A
Sens
+
3A*
1Sens*
+
+
A
1Sens
+
A*
 Both Energy Transfer Mechanisms Require that E(excited state D) > E(excited state A)
 kee = KJe^(-2rDA/L), so rDA ~ 5 - 10 A
 Primarily triplet sensitization
 Can operate at over 50 A via a dipoledipole (Coulombic) mechanism
(transition dipole coupling)
 Basis for FRET
Anslyn, E. V.; Dougherty, D. A. Modern Physical Organic Chemistry University Science Books, Sausalito, CA. 2005. 955 - 958.
Reductive PET Bond Cleavage
 Reductive cleavage proceeds by electron transfer to benzyl halide or pseudo-halide
Cl
Me
+
Me
O2N
NO2
PET
Na
Me
NO2
ambient light
Me
O2N
Me
Cl
Me
Cl
NO2
Me
Me
+
NO2
O2N
NO2
Me
Me
NO2
O2N
O
N
O
Me
NaN3
Conditions
Yield
Dark
0%
ambient
63%
fluorescent
light (20 W)
100%
Me
N3
O2N
Kornblum, N; et. al. J. Am. Chem. Soc. 1955, 77, 6269; Angew. Chim. Int. Ed. 1975, 14, 734
Reductive PET Reactions and Non-Halide Examples
 NBoc substituents stabilize benzylic radical formation
OMe
OMe
OMe
O
BocHN
O2, Na2S2O3
NaOAc, 4 A MS
DCE, PhMe
OMe
O
Ph
O
hν, NMQPF6
OMe
O
BocHN
O
H
N
OMe
NMQ
O
Me
O
94%, 10 : 1 dr
 OMe groups stabilize benzylic nucleofuges toward tandem epoxide ring openings
O
Ph
hν, NMQPF6
O
O
OEt
OMe
MeO
O
O
H
MeO
O2, Na2S2O3
NaOAc, 4 A MS
DCE, PhMe
O
OH
O
H
H
O
H
OEt
79%
OEt
Me
Floreancig, P. E. Synlett 2007, 191.
Reductive PET Bond Cleavage
 Homobenzylic chlorides also participate in reductive PET chemistry
MeO
Cl
Cl
MeO
PET
MeO
Cl
Cl
MeO
Cl
OAc
MeO
MeO
AgOAc, HOAc
 Besides anti/syn considerations, differences occur between homopara vs. homometa C-X bonds
Cl
MeO
Cl
Cl
MeO
MeO
PET
OAc
Cl
AgOAc, HOAc
70%
Wagner-Meerwein
rearrangement
plus 18% RCl
Cristol, S. J.; et. al. J. Am. Chem. Soc. 1987, 109, 830
Zimmerman, H.; et. al. J. Am. Chem. Soc. 1963, 85, 913; J. org. Chem. 1986, 51, 4681.
Oxidative PET Bond Cleavage
 A representative and early example of oxidative PET bond cleavage
ClO4
N
Me
Ph
PET
N
Me
SiMe3
N
Me
SiMe3
+
+
Ph
Nu
Ph
SiMe3
+
+
+
N
Me
NuSiMe3
Ph
Mariano, P. S.; et. al. J. Am. Chem. Soc. 1982, 104, 617
Oxidative Intramolecular PET Bond Cleavage
 Intramolecular C-C bond formation to form indolizidines
ClO4
Me3Si
N
Me
PET
Me3Si
N
Me
Me
Nu
N
ClO4
90% indolizidine
 Intramolecular organocatalytic Hiyama-type coupling
O
O
PET
Me3Si
N
Bn
CN
N
Bn
CN
Mariano, P. S.; et. al. J. Am. Chem. Soc. 1984, 106, 6439.
 Difficult to perform this chemistry as efficiently with a non-PET approach (polar reagents)
Oxidative PET Bond Cleavage
O
O
Me
PET
Me3Si
Me
MeOH/
MeCN
DCA
N
O
Me
O
Me
Me
Me3Si
Me
N
Me
N
Me
N
90%
 Less polar and aprotic solvents (MeCN alone) afford product retaining silyl group
O
O
Me
Me
H
Me3Si
O
N
Me
O
Me
Me
Si
N
vs
Me
Me
N
Si
N
Mariano, P. S.; et. al. J. Am. Chem. Soc. 1994, 116, 4211.
Application to Macrocyclic RIng Closures
O
O
HO
O
N
O
PET
R1
Ph
O
R1
R2
N
R2
38 - 76%
Hasegawa, T. Tetrahedron, 1998, 54, 12223
O
O
O
S
O
HO
PET
R1
Ph
O
R1
R2
R2
S
35 - 65%
Hu, S.; Neckers, D. C. Tetrahedron 1997, 53, 2751
O
S
N
H
HO
N
N
O H
O
36%
Griesbeck, A. G.; Mattay, J., Eds. Synthetic Organic Photochemistry Marcel-Dekker, New York, 2005. 276.
Application to Poison Frog Therapeutics
 Carbohydrate-mimetic hydroxylated indolizidines
OH
Me
H
 Antidiabetics, antiviral, anticancer,
immunosuppressant, transplantation
medicine
N
Me
(+)-Pumiliotoxin
Dendrobates spp.
 Pyrrolizidines also offer opportunities for synthetic application
OH
HO
O
HO
H
OH
N
O
O
OH
OH
alexine
 Potent glycosidase inhibitor, antiviral,
anti HIV, anticancer
N
riddelliine
 Insect defense agent
Griesbeck, A. G.; et. al. Acc. Chem. Res. 2007, 40, 128.
Intermolecular Non-Silylated, Simple Amino-Alkyl Additions
 Triplet sensitizers have very specific transition energies and can markedly improve reaction efficiency
O
MenthO
O
PET
+
O
RO
H
N
Me
Ph
H
H
NMe
2
O
RO
+
H
O
O
O
NMe
:
1
60%
Ph
O
1
Me
:
1.2
94%
OR
MeO
Me
OMe
Me
OMenth
H
OH
H
N
N
(-)-Isoretronecanol
(+)-Laburnine
OH
Mariano, P. S.; et. al. J. Am. Chem. Soc. 1991, 113, 8847
Proposed Mechanism for Pyrrolidine Addition
 The catalytic cycle may provide more than one opportunity for a product forming step
O
RO
PET
product
N
Me
O
OH
OMe
MeO
MeO
N
Me
N
Me
OMe
MeN
O
O
O
OR
O
NMe
OR
77 - 94%
5 examples
Mariano, P. S.; et. al. J. Am. Chem. Soc. 1991, 113, 8847
O
Further Development of Amine Coupling Partners
 Triethyl amine, piperidone and other amines are a viable coupling partner in PET C-C bond construction
O
O
O
+
TEA
85%, 1:1 dr
350 nm
sensitizer
MenthO
O
O
PET
+
N
Me
350 nm
sensitizer
With
N
2.5 : 1 constitutional
isomeric products
favoring tertiary radical
O
PET
S
EtO
No
EtO
NEt2
RO
H
+
H
H
NMe
:
1
60%
SMe
1
SMe
O
H
NMe
1
S
RO
O
:
~0
48%
Org. Biomol. Chem. 2006, 4, 1202; Zard Angew. Chim. Int. Ed. 1997, 36, 672.
Intramolecular Trapping of Presumed Oxy-allyl Radical
 When trapping oxy-allyl radical acetone was necessary to act as benign oxidant
Me
MenthO
O
O
N
Me
+
RO
PET
H
350 nm
Michler's
ketone
RO
O
H
H
+
Me2N
NMe2
H
O
+
N
N
O
RO
Me
Me
O
O
Without acetone
38%
:
2%
:
18%
With acetone
74%
:
3%
:
0%
Michler's ketone
N
O
O
OR
N
OR
71%, 1 : 1 dr
O
O
Me
N
O
OR
74%, 2 : 1 dr
O
56%, 20 : 1 dr
Bertrand, S.; et. al. J. Org. Chem.2000, 65, 8690; Marinkovic, S.; et. al. J. Org. Chem. 2004, 69, 1646.
Non-Direct Methods for Enantioinduction in PET Reactions
 Cascade cyclization of terpene polyolefins via photoinduced electron transfer
O
O
Me
Perfect diastereoinduction
CO2Me
Me
1) PET, DCTMB
O
Me
BP, MeCN/H2O
-25 oC
2) removal of
(-)-menthone
Me
Me
Me
Me
Me Me
Only 2 of 256 possible
isomers formed and 8
stereocenters set
Me
H
HO
OH
H
H
Shortest steroid route
Remarkably far reaching
asymmetric induction
12%
 Memory of chirality PET study explained by rigidity of amide and aniline bonds toward rotation
O
O
PET, acetone/H2O
N
O
X
N
OH
O
N
X
N
CO2K
O
X = H, 45%, 86% ee
X = Cl, 50%, 79% ee
With ethylene di-ortho linker: 0% ee
Demuth, M. J.; et. al. J. Am. Chem. Soc. 1999, 121, 4894; Griesbeck, A. G.; et. al. Angew. Chem. 2001, 113, 586
Recent Precedent for Catalytic Asymmetric PET Carbon-Carbon Bond Formation
 The Bach example is the only method thus far for a direct, catalytic, asymmetric reaction with chemical
yields above 1%
N
N
hν (λ > 300 nm)
O
30% catalyst
Toluene
N
H
N
N
O
O
H
O
H
N
N
H
N
OH
O
64% yield, 70% ee
single diastereomer
Bauer, A.; Westkamper, F.; Grimme, S.; Bach, T. Nature 2005, 436, 1139
Evidence Supporting the Occurence of Charge Separation
 Why should we trust that charge separation is occuring?
hν
ET
Me
Me
N
H
O
N
NH
O
N
N
Rib
H
N
RN
H
O
Rib
OR
=
H
N
N
1
Rib
OR
OR
R = SiMe2tBu
2
Ka = 38,000 +/- 1300 M-1
 ΔGoCS = -0.41 eV; ΔGoCR = -2.5 eV
 2 Fluoresces upon irradiation and is quenched upon increasing concentration of 1 in solution.
This levels off at 1 molar equivalent of 1.
 Quenching of simple anthracene* fluorescence by adition of aniline only occurs at 2%.
 If masked donor (R = COCHMe2) is used, little quenching occurs.
 Thus, diffusion controlled collisional quenching cannot be responsible for electron transfer.
Sessler, J. L.; et. al. J. Am. Chem. Soc. 2001, 123, 3655.
PET Projects in Total Synthesis
 Selected natural products formed by PET bond-constructive key steps
OH
O
Me
Me
PET
Bn
N
O
SiMe3
60%
HO
O
Me
Me
N
O
Bn
NH
HO
(+)-isofagomine
MeO
OH
O
O
MeO
HO
HO
H
N
berberine analog
N
HO
Me
Me
Me
O
Me
Me
Me
HO
OH
C-furanoside
(+/-)-epilupinine
O
CO2Me
O
Me
O
HN
H
HO
Me Me
H
HO
O
(+/-)-stypoldione
polyterpene cyclization
O
O
H
Me
(+/-)-isoafricanol
HO
OH
(+)-2.7-dideoxypancratistatin
Griesbeck, A. G.; Mattay, J., Eds. Synthetic Organic Photochemistry Marcel-Dekker, New York, 2005. 292.
Conclusions
• Photoinduced electron transfer (PET) utilizing alphaamino radicals was shown to be applicable to
problem solving in organic synthesis.
• Alpha oxo- and alpha thio-radicals are also useful.
• Advantages - unique and/or expedited carbon-carbon
bond construction; vastly underexploited asymmetric
potential for interesting reactivity.
• Disadvantages - Limited substrate scope and/or
specific wavelength for some methods.