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Me
Me N
N
NH
N O
O
R
Flavins: A Bio-Inspired Approach to Photocatalysis
Group Meeting: 3/02/2017
Steven Bloom
MacMillan Group
-
Flavins: A Bio-Inspired Approach to Photocatalysis
Outline
Photophysical properties of Flavins
Flavins in organic synthesis: PhotoredoxOxidationHalogenation
Introduction to Flavins: A Brief HistoryRole of Flavins in Biolgy and Basic Mechanisms
Energy transferSubstitution reactions
-
Flavins: A Bio-Inspired Approach to Photocatalysis
Riboflavin Biosynthesis
O
OH OH
NPPP OH2C
N
N
NH
O
NH2 O
OH OH
HNP OH2C
H2N
N
NH
O
NH2 O
OH OH
HNP OH2C
H2N
NH
NH
O
O
bacteria
H2CHN
H2N
NH
NH
O
O
HCHCHCCH2O
OHOHOH
P
H2CHN
H2N
NH
NH
O
O
HCHCHCCH2OH
OHOHOH
H3C
OCH2O
OH
P
CH2
N
NH
O
O
HCHCHCCH2OH
OHOHOH
N
N
Me
MeCH2
N
NH
O
O
HCHCHCCH2OH
OHOHOH
N
N
Me
Me
Riboflavin
GTP
H2O
GTPcyclohydrolase II deamination
condensationriboflavin synthase
Bachner,A.;Eberhardt,S.;Fischer,M.;Kis,K.;Richter,G.Annu.Rev.Nutr.2000,20,153-167.
-
Flavins: A Bio-Inspired Approach to Photocatalysis
Riboflavin Biosynthesis
CH2
N
NH
O
O
HCHCHC
CH2OH
OHOHOH
N
N
Me
Me
Riboflavin( vitamin B2)
post-modification
CH2
N
NH
O
O
HCHCHC
CH2O
OHOHOH
N
N
Me
Me
PO3H2
flavin mononucleotide(FMN)
CH2
N
NH
O
O
HCHCHC
CH2O
OHOHOH
N
N
Me
Me
PO2
O
O2P O O NN
HOOH
N
NNH2
flavin adenine dinucleotide(FAD)
CH3
N
NH
O
O
N
N
Me
Me
Lumiflavin(LF)
Bachner,A.;Eberhardt,S.;Fischer,M.;Kis,K.;Richter,G.Annu.Rev.Nutr.2000,20,153-167.
-
Flavins: A Bio-Inspired Approach to Photocatalysis
Flavoproteins
flavodoxin old yellow enzyme yeast FMO EpiD
90 Flavoproteins found in the human genome
84% contain FAD and 16% FMNlocated in the mitochondria90% perform redox reactions, 10% are transferases, lyases, isomerases, and ligases
FAD first isolated in 1879 from bovine milkFAD structure determined in 1934
Ghisla,S.;Massey,V.J.Biochem.1986,239,1-12.Fraaije,M.W.;Mattevi,A.TrendsBiochem.Sci.2000,25,126-132.
-
Flavins: A Bio-Inspired Approach to Photocatalysis
Conference19th International Symposium on Flavins and Flavoproteins
Organised by RUGDate Sun 2 July 2017 until Thu 6 July 2017
Venue Groningen
Newly discovered flavoproteinsFlavin-based chemistry
Flavoenzyme mechanisms & structuresFlavoenzyme engineering
Flavoproteins & lightFlavoenzymes & health
Flavoenzymes & industrial applications
-
Flavins: A Bio-Inspired Approach to Photocatalysis
Riboflavin Biochemistry
CH2
N
NH
O
O
HCHCHC
CH2OH
OHOHOH
N
N
Me
Me
Riboflavin
metabolism
( vitamin B2)
antioxidant
drug processing
- break down fats and carbohydrates-provides electrons for electrontransport chain
-neutralizes reactive oxygen speciesdirectly-activates glutathione reductase
-activates Cyt P450 for drugmetabolism
photochemical processes
-circadian rhythms-phototropism-phototaxis
Hemmerich,P.;Nagelschneider,G.F.E.B.S.Lett.1970,8,69-83.
-
Flavins: A Bio-Inspired Approach to Photocatalysis
Riboflavin Biochemistry
CH2
N
NH
O
O
HCHCHC
CH2OH
OHOHOH
N
N
Me
Me
Riboflavin
metabolism
( vitamin B2)
antioxidant
drug processing
- break down fats and carbohydrates-provides electrons for electrontransport chain
-neutralizes reactive oxygen speciesdirectly-activates glutathione reductase
-activates Cyt P450 for drugmetabolism
photochemical processes
-circadian rhythms-phototropism-phototaxis
Hemmerich,P.;Nagelschneider,G.F.E.B.S.Lett.1970,8,69-83.
-
Flavins: A Bio-Inspired Approach to Photocatalysis
Riboflavin Biochemistry
CH2
N
NH
O
O
HCHCHC
CH2OH
OHOHOH
N
N
Me
Me
Riboflavin
metabolism
( vitamin B2)
antioxidant
drug processing
- break down fats and carbohydrates-provides electrons for electrontransport chain
-neutralizes reactive oxygen speciesdirectly-activates glutathione reductase
-activates Cyt P450 for drugmetabolism
photochemical processes
-circadian rhythms-phototropism-phototaxis
Hemmerich,P.;Nagelschneider,G.F.E.B.S.Lett.1970,8,69-83.
-
Flavins: A Bio-Inspired Approach to Photocatalysis
Riboflavin Biochemistry
CH2
N
NH
O
O
HCHCHC
CH2OH
OHOHOH
N
N
Me
Me
Riboflavin
metabolism
( vitamin B2)
antioxidant
drug processing
- break down fats and carbohydrates-provides electrons for electrontransport chain
-neutralizes reactive oxygen speciesdirectly-activates glutathione reductase
-activates Cyt P450 for drugmetabolism
photochemical processes
-circadian rhythms-phototropism-phototaxis
Hemmerich,P.;Nagelschneider,G.F.E.B.S.Lett.1970,8,69-83.
-
Flavins: A Bio-Inspired Approach to Photocatalysis
Riboflavin Biochemistry
CH2
N
NH
O
O
HCHCHC
CH2OH
OHOHOH
N
N
Me
Me
Riboflavin
metabolism
( vitamin B2)
antioxidant
drug processing
- break down fats and carbohydrates-provides electrons for electrontransport chain
-neutralizes reactive oxygen speciesdirectly-activates glutathione reductase
-activates Cyt P450 for drugmetabolism
photochemical processes
-circadian rhythms-phototropism-phototaxis
Hemmerich,P.;Nagelschneider,G.F.E.B.S.Lett.1970,8,69-83.
-
Flavins: A Bio-Inspired Approach to Photocatalysis
Riboflavin Biochemistry
CH2
N
NH
O
O
HCHCHC
CH2OH
OHOHOH
N
N
Me
Me
Riboflavin
metabolism
( vitamin B2)
antioxidant
- break down fats and carbohydrates-provides electrons for electrontransport chain
-neutralizes reactive oxygen speciesdirectly-activates glutathione reductase
Conrad,K.S.;Manahan,C.C.;Crane,B.R.Nat.Chem.Bio.2014,10,801-809.
-
Conrad,K.S.;Manahan,C.C.;Crane,B.R.Nat.Chem.Bio.2014,10,801-809.
Flavins: A Bio-Inspired Approach to Photocatalysis
Riboflavin Biochemistry
CH2
N
NH
O
O
HCHCHC
CH2OH
OHOHOH
N
N
Me
Me
Riboflavin
metabolism
( vitamin B2)
antioxidant
- break down fats and carbohydrates-provides electrons for electrontransport chain
-neutralizes reactive oxygen speciesdirectly-activates glutathione reductase
-
Flavins: A Bio-Inspired Approach to Photocatalysis
Riboflavin Biochemistry
oxidative catalysis
reductive catalysis
Conrad,K.S.;Manahan,C.C.;Crane,B.R.Nat.Chem.Bio.2014,10,801-809.
-
Flavins: A Bio-Inspired Approach to Photocatalysis
Riboflavin Photochemistry
CH2
N
NH
O
O
HCHCHC
CH2OH
OHOHOH
N
N
Me
Me
Riboflavin( vitamin B2)
N
NH
O
O
N
N
Me
MeR
Halwer,M.J.Am.Chem.Soc.1951,73,4870-4874.
-
Flavins: A Bio-Inspired Approach to Photocatalysis
Riboflavin Photochemistry
CH2
N
NH
O
O
HCHCHC
CH2OH
OHOHOH
N
N
Me
Me
Riboflavin( vitamin B2)
1Riboflavin*0.67
3Riboflavin*
N
NH
O
O
N
N
Me
MeR
OISC
3RF*= 15 µs
Halwer,M.J.Am.Chem.Soc.1951,73,4870-4874.
-
Flavins: A Bio-Inspired Approach to Photocatalysis
Riboflavin Photochemistry
CH2
N
NH
O
O
HCHCHC
CH2OH
OHOHOH
N
N
Me
Me
Riboflavin( vitamin B2)
1Riboflavin*0.67
OISC
3Riboflavin*
pka of RF = 8.3
N
NH
O
O
N
N
Me
MeR
N
NH
O
O
N
N
Me
MeR
N
NH
O
O
N
N
Me
MeR
440 nmSET, H+
or
PCET
OISC
N
NH
O
O
HN
N
Me
MeR
*
3RF*/RFH = 1.5 V RFH/RF = -0.5 V
N
NH
O
O
N
N
Me
MeR
- e- H+
3RF*= 15 µs
-
Korvinson,K.A.;Hargenrader,G.N.;Stevanovic,J.;Xie,Y.;Joseph,J.Maslak,V.;Hadad,C.M.;Glusca,K.J.Phys.Chem.2016,120,7294-7300.
Flavins: A Bio-Inspired Approach to Photocatalysis
Riboflavin Photochemistry
CH2
N
NH
O
O
HCHCHC
CH2OH
OHOHOH
N
N
Me
Me
Riboflavin( vitamin B2)
N
NH
O
O
N
N
Me
Me
R
N
NH
O
O
N
N
Me
Me
SET to S1 (unproductive, ~ 50 ps)
SET to T1 (productive, ~ 15 µs)
heavy element substitutuion inreasesS1 to T1 ISC by spin-orbit coupling (100 x faster)
increases oxidation potential
RF = 1.5 V (ISC = ns), 3RF* = 15.0 µs
IRF = 1.65 V (ISC = ps), 3RF* = 5.8 µs
I
OH
OHHO
OH
H
intramolecular HAT from T1 competeswith SET
HAT from OH is 2x faster than α-C-H
N
NH
O
O
N
N
Me
Me
OR
ORRO
OR
H
R = OAc = OBu
acylation prevents HATand increases T1 lifetimes
-
Flavins: A Bio-Inspired Approach to Photocatalysis
Riboflavin Mechanisms
Monoamine oxidase (MAO)
Me
SEnz
N
N
NH
N
O
OR
R NH2
HMe
SEnz
NH
N
NH
N
O
OR
NH2
R
Me
SEnz
NH
N
NH
HN
O
OR
R NH2
Glucose oxidase
O
OH
HO
HO OH
OH O
OH
HO
HO OH
O
+
Conrad,K.S.;Manahan,C.C.;Crane,B.R.Nat.Chem.Bio.2014,10,801-809.
-
Flavins: A Bio-Inspired Approach to Photocatalysis
Riboflavin Mechanisms
Glutathione reductase
Me
GR
N
N
NH
N
O
OR
Me
GR
NH
N
NH
N
O
OR
S
Me
GR
NH
N
NH
N
O
OR
NR
HH
NH2
O
NADH
NAD+
SSBH
SH
Me
GR
N
N
NH
N
O
OR
S
flavin-thiolatecharge-transfer
complex
Conrad,K.S.;Manahan,C.C.;Crane,B.R.Nat.Chem.Bio.2014,10,801-809.
-
Conrad,K.S.;Manahan,C.C.;Crane,B.R.Nat.Chem.Bio.2014,10,801-809.
Flavins: A Bio-Inspired Approach to Photocatalysis
Riboflavin Mechanisms
p-Hydroxybenzoate
Me
GR
N
N
NH
N
O
OR
Me
GR
NH
N
NH
N
O
OR
OOH
3,4-hidroxybenzoate
H2O2
OHHO2C Base
Me
GR
NH
N
NH
N
O
OR
OH
OHHO2C
OH
-H2O
-
Flavins: A Bio-Inspired Approach to Photocatalysis
Riboflavin Mechanisms
Me
Me
NH
N
NH
N
O
OR
OOH
O
O
NMe
RS
R RR
O
NOMe
RR
O
Last 50 years of research
many have now been demonstratedasymmetrically by H-bonding catalysis
RS
R
O
O
O
N-oxidation
epoxidation
lactonization
sulfoxidation
Massey,V.J.Biol.Chem.1994,269,22462-22462.
-
Nicewicz,D.A.;Nguyen,T.M.ACSCatal.2014,4,355-360.
Flavins: A Bio-Inspired Approach to Photocatalysis
RFRF*
RF
RF
oxidation
Ar NH2Ar OH
Ar SO
Me
Ar OAr O
Ar SO2
Me
O2
H2O2
reduction
flow of 2e- and 2H+
blue light
RF
RFHOH
oxidation
Ar NH2Ar OH
Ar SO
Me
Ar OAr O
Ar SO2
Me
-H2O
SLOW REACTION
Me
Me
NH
N
NH
N
O
OR
OOH
H2O2
RFOOH
reduction
RFflow of 1e- and 1H+
λmax = 440 nm
FAST REACTION
Me
Me
N
N
NH
N
O
OR
-
RFRF*
RFH2
oxidation
Ar NH2Ar OH
Ar SO
Me
Ar OAr O
Ar SO2
Me
O2
H2O2
reduction
blue lightRF
flow of 1e- and 1H+λmax = 440 nm
FAST REACTION
Me
Me
N
N
NH
N
O
OR
Flavins: A Bio-Inspired Approach to Photocatalysis
Direct Benzylic oxidation
benzylic oxidationMe Me
Odirect
- first oxidation is difficult ( > 1.8 V)- catalyst deactivation by O2- competing O2 sensitization
air
simple benzylic oxidized product
Nicewicz,D.A.;Nguyen,T.M.ACSCatal.2014,4,355-360.
-
Flavins: A Bio-Inspired Approach to Photocatalysis
Direct Benzylic oxidation
benzylic oxidationMe Me
Odirect
Me
Me N
N
NH
N O
O
R
RFλmax = 440 nm
air
simple benzylic oxidized product
E0V vs SCE
1.67
2.06
2.25
2.45
3RF*
RFhυ
RF-Mg2+
RF-Yb3+
RF-Sc3+
p-OMe-toluene
p-Me-toluene
toluene
Sc3+
Sc3+
hυ
3RF*
Lewis acid coordination increasesreduction potential
Wolf,R.;Muhldorf,B.Chem.Commun.2015,51,8425-8428.
-
Flavins: A Bio-Inspired Approach to Photocatalysis
Direct Benzylic oxidation
Me
O
MeCN, airsimple benzylic oxidized product
MeRiboflavin (10 mol%)
Sc(OTf)3 (20 mol%)
440 nm
CHO
no Sc, with Sc
0%, 71% 3%, 60%
Me
O
4%, 93%
Ph
OCHO
0%, 29%NC
CHO
0%, 15%MeO2C
0%, 49%MeO2C
Me
O
deactivated arenes
Wolf,R.;Muhldorf,B.Chem.Commun.2015,51,8425-8428.
-
Flavins: A Bio-Inspired Approach to Photocatalysis
Direct Benzylic oxidation
Me
O
MeCN, airsimple benzylic oxidized product
MeRiboflavin (10 mol%)
Sc(OTf)3 (20 mol%)
440 nm
mechanistic proposal
Me RF-2Sc3+
PCETMe
O2 Me
OO
Me
Ohυ
RF-2Sc3+O2
SLOWRF-2Sc3+ + H2O2
Wolf,R.;Muhldorf,B.Chem.Commun.2015,51,8425-8428.
-
Flavins: A Bio-Inspired Approach to Photocatalysis
Direct Benzylic oxidation
Me
O
MeCN, airsimple benzylic oxidized product
MeRiboflavin (10 mol%)
Sc(OTf)3 (20 mol%)
440 nm Me
Me N
N
NH
N O
O
AcO
AcOOAc
OAc
Me
O
MeCN, H2O airsimple benzylic oxidized product
MeRiboflavin (10 mol%)
[Fe(TPA)(MeCN)2](ClO4)2
440 nm
N NN
NFe
LL
Fe(TPA)L2
Flavin catalyst
*disproportions H2O2 byproductWolf,R.;Muhldorf,B.Agnew.Chem.Int.Ed.2016,55,427-430.
-
Flavins: A Bio-Inspired Approach to Photocatalysis
Direct Benzylic oxidation
Me
O
MeCN, H2O airsimple benzylic oxidized product
MeRiboflavin (10 mol%)
[Fe(TPA)(MeCN)2](ClO4)2 (2 mol%)
440 nm
OH
O
60%
overoxidation
Me
O
74% 70%
O
70%
O
66%
O
O
96%O
O
Wolf,R.;Muhldorf,B.Agnew.Chem.Int.Ed.2016,55,427-430.
-
Flavins: A Bio-Inspired Approach to Photocatalysis
Direct Benzylic oxidation
Me
O
MeCN, H2O airsimple benzylic oxidized product
MeRiboflavin (10 mol%)
[Fe(TPA)(MeCN)2](ClO4)2 (2 mol%)
440 nm
mechanistic proposal
Me RF-Fe(TPA)PCET
MeO2 Me
OO
Me
Ohυ
RF-Fe(TPA)O2
SLOWRF-Fe(TPA) + H2O2
Fe(TPA)
disproportionationN N
N
NFe
OOH
active for C-H oxidationWolf,R.;Muhldorf,B.Agnew.Chem.Int.Ed.2016,55,427-430.
-
Flavins: A Bio-Inspired Approach to Photocatalysis
HN
RHal
HN
RHal
Me
Me
hydroperoxyflavin
NH
N
NH
N O
O
R
OHO
Cl or Br
HOCl or HOBr
Wu,X.;Meng,C.;Yuan,X.;Jia,X.;Qian,X.;Ye,J.Chem.Commun.2015,51,11864-11867.
-
Flavins: A Bio-Inspired Approach to Photocatalysis
Decarboxylative Fluorination
SelectfluorCs2CO3
MeCN/H2O23 W CFL, rt
NTs
CO2H
NTs
F
photocatalyst
photocatalyst yield
Mes-Acr ClO4RiboflavinEosin Y
Rhodamine B
58%55%tracetrace
HN
RHal
HN
RHal
Me
Me
hydroperoxyflavin
NH
N
NH
N O
O
R
OHO
Wu,X.;Meng,C.;Yuan,X.;Jia,X.;Qian,X.;Ye,J.Chem.Commun.2015,51,11864-11867.
-
Flavins: A Bio-Inspired Approach to Photocatalysis
Selectfluor
Decarboxylative Fluorination
Cs2CO3MeCN/H2O23 W CFL, rt
NTs
CO2H
NTs
F
photocatalyst
photocatalyst yield
Mes-Acr ClO4RiboflavinEosin Y
Rhodamine B
58%55%tracetrace
NTs
F
71%
NTs
F
36%
R
O FN
O
OF
n n = 2, 35%n = 3, 40%n = 4, 39%n = 5, 42%
R = Ph, 73%R = tBu, 76%R = Br, 45%
Wu,X.;Meng,C.;Yuan,X.;Jia,X.;Qian,X.;Ye,J.Chem.Commun.2015,51,11864-11867.
-
Flavins: A Bio-Inspired Approach to Photocatalysis
Selectfluor
Decarboxylative Fluorination
Cs2CO3MeCN/H2O23 W CFL, rt
NTs
CO2H
NTs
F
photocatalyst
photocatalyst yield
Mes-Acr ClO4RiboflavinEosin Y
Rhodamine B
58%55%tracetrace
NN
F
Cl
R COO
-CO2
R+ R F
NN
Cl
NN
Cl
RFRF*
RF
Wu,X.;Meng,C.;Yuan,X.;Jia,X.;Qian,X.;Ye,J.Chem.Commun.2015,51,11864-11867.
-
Flavins: A Bio-Inspired Approach to Photocatalysis
Energy Transfer [2+2] cycloaddition
400 nm LED
photocatalyst
O
Me
MeAr
MeCN O
H H
Ar MeMe
N
N
N
NMeO
MeOO
O
Me
ET = 59 kcal/mol-1
O
CH3
ET = 63 kcal/mol-1
photocatalyst λmaxRiboflavin (OH)4Riboflavin (OAc)4
450 nm450 nm
ET
50 kcal/mol-1 N
N
N
N
O
O
Bu
Me
alloxazine Me4
E0-0 = 69 kcal/mol-1
57 kcal/mol-1
yield
0%0%
Me
MeMe
Me
Alloxazine Me4 350 nm 59 kcal/mol-1 traceAlloxazine OMe2 400 nm 69 kcal/mol-1 87% (10 min)
E0-0 = 59 kcal/mol-1
Mojr,V.;Svobodova,Strakova,K.;Nevesely,T.;Chudoba,J.;Dvorakova,H.;Cibulka,R.Chem.Commun.2015,51,12036-12039.
-
Ir(ppy)3
Ir(ppy)2 4,4'-(MeO)2bpy
Ir(ppy)2 4,4'-Me2bpy
Ir(ppy)2 bpy
photocatalyst
Ru(bpy)3Ir(ppy)2 4,4'-(CO2Me)2bpy
47.7
47.6
46.3
ET (kcal)
45.4
39.7
53.6
Flavins: A Bio-Inspired Approach to Photocatalysis
Energy Transfer [2+2] cycloaddition
400 nm LED
photocatalyst
X
Me
MeAr
x = CH2, OMeCN X
H H
Ar MeMe
x = CH2, O
Me
ET = 59 kcal/mol-1
O
CH3
ET = 62 kcal/mol-1
Riboflavin (OH)4 50.0
Alloxazine OMe2 69.0
N
N
N
NMeO
MeO O
O
Bu
Me
Alloxazine OMe2
Ir[dFCF3ppy)]2dttbpy 61.0
Mojr,V.;Svobodova,Strakova,K.;Nevesely,T.;Chudoba,J.;Dvorakova,H.;Cibulka,R.Chem.Commun.2015,51,12036-12039.
-
Benzoquinone
Mesityl AcridiniumFluorenone
Riboflavin (OH)4
photocatalyst
FluoresceinEosin Y
55.053.050.0
ET (kcal)
47.045.0
69.0
Flavins: A Bio-Inspired Approach to Photocatalysis
Energy Transfer [2+2] cycloaddition
400 nm LED
photocatalyst
X
Me
MeAr
x = CH2, OMeCN X
H H
Ar MeMe
x = CH2, O
Me
ET = 59 kcal/mol-1
O
CH3
ET = 62 kcal/mol-1
Naphthalene 61.0
Acetophenone 74.0
N
N
N
NMeO
MeO O
O
Bu
Me
Alloxazine OMe2
Alloxazine OMe2 69.0
Anthracene 43.0Rose bengal 41.0
Mojr,V.;Svobodova,Strakova,K.;Nevesely,T.;Chudoba,J.;Dvorakova,H.;Cibulka,R.Chem.Commun.2015,51,12036-12039.
-
Mojr,V.;Svobodova,Strakova,K.;Nevesely,T.;Chudoba,J.;Dvorakova,H.;Cibulka,R.Chem.Commun.2015,51,12036-12039.
Flavins: A Bio-Inspired Approach to Photocatalysis
Energy Transfer [2+2] cycloaddition
400 nm LED
photocatalyst
O
Me
MeAr
MeCN O
H H
Ar MeMe
N
N
N
NMeO
MeOO
OBu
Me
E0-0 = 69 kcal/mol-1
O
H H
MeMe
R
R = OMe, 82% (>10:1)R = H, 87% (>10:1)R = Br, 76% (>10:1)R = CF3, 81% (>10:1)
H H
Ph
42% (7:1) 80%
H H
ArOC COAr
Ar = Ph, 70% (5:1)Ar = 4-OMePh, 67% (4:1)Ar = 4-CF3Ph, 58% (1:1)
-
Flavins: A Bio-Inspired Approach to Photocatalysis
Energy Transfer [2+2] cycloaddition
400 nm LED
photocatalyst
O
Me
MeAr
MeCN O
H H
Ar MeMe
N
N
N
NMeO
MeOO
OBu
Me
E0-0 = 69 kcal/mol-1
O
H H
MeMe
R
R = OMe, 82% (>10:1)R = H, 87% (>10:1)R = Br, 76% (>10:1)R = CF3, 81% (>10:1)
H H
Ph
42% (7:1) 80%
H H
ArOC COAr
Ar = Ph, 70% (5:1)Ar = 4-OMePh, 67% (4:1)Ar = 4-CF3Ph, 58% (1:1)
Mojr,V.;Svobodova,Strakova,K.;Nevesely,T.;Chudoba,J.;Dvorakova,H.;Cibulka,R.Chem.Commun.2015,51,12036-12039.
-
Mojr,V.;Svobodova,Strakova,K.;Nevesely,T.;Chudoba,J.;Dvorakova,H.;Cibulka,R.Chem.Commun.2015,51,12036-12039.
Flavins: A Bio-Inspired Approach to Photocatalysis
Energy Transfer [2+2] cycloaddition
400 nm LED
photocatalyst
O
Me
MeAr
MeCN O
H H
Ar MeMe
N
N
N
NMeO
MeOO
OBu
Me
E0-0 = 69 kcal/mol-1
O
Me
MeAr Energy Transfer
N
N
N
NMeO
MeOO
OBu
Me
*O
Me
MeAr *
O
H H
Ar MeMe[2+2]
Z
-
Metternich,J.B.;Gilmour,R.J.Am.Chem.Soc.2015,137,11254-11257.
Flavins: A Bio-Inspired Approach to Photocatalysis
(E) to (Z) Isomerization
(-)-riboflavinhνO
HMeMe
Me
(E)
MeMe
Me
(Z)
Me
OH
Me Me
Me
Nature 1967, 215, 1483.retinal
the squalene conundrum
Me
Me
Me
Me
Me
Me
Me
Me
selective functionalization of polyenes
Scott Miller, Yale
-
Flavins: A Bio-Inspired Approach to Photocatalysis
(E) to (Z) Isomerization
(-)-riboflavinhνO
HMeMe
Me
(E)
MeMe
Me
(Z)
Me
OH
Me Me
Me
Nature 1967, 215, 1483retinal
O
OR(-)-riboflavin (5 mol%)
402 nmMeCN, rt
R R
ORO
Metternich,J.B.;Gilmour,R.J.Am.Chem.Soc.2015,137,11254-11257.
-
Flavins: A Bio-Inspired Approach to Photocatalysis
(E) to (Z) Isomerization
O
OR(-)-riboflavin (5 mol%)
402 nmMeCN, rt
R R
ORO
Me
OEtO
Z/E
quant., 99:1
Et
OEtO
quant., 95:5
OEtO
99%, 59:41
H
OEtO
quant., 95:5
Me
H3C OEtO
quant., 97:3
H
F3C
Metternich,J.B.;Gilmour,R.J.Am.Chem.Soc.2015,137,11254-11257.
-
Flavins: A Bio-Inspired Approach to Photocatalysis
(E) to (Z) Isomerization
O
OR(-)-riboflavin (5 mol%)
402 nmMeCN, rt
R R
ORO
N
Me
OEtO
Z/E
88%, 95:5
Me
OEtO
quant., 83:17
HO
quant., 87:13
Et
NO
quant, 96:4
Et
H3C OHO
24%, 99:1
Et
OMe
Me
Metternich,J.B.;Gilmour,R.J.Am.Chem.Soc.2015,137,11254-11257.
-
Metternich,J.B.;Gilmour,R.J.Am.Chem.Soc.2015,137,11254-11257.
Flavins: A Bio-Inspired Approach to Photocatalysis
(E) to (Z) Isomerization
O
OR(-)-riboflavin (5 mol%)
402 nmMeCN, rt
R R
ORO
Z/E
Et
(-)-riboflavin (5 mol%)
402 nmMeCN, rt
OHO
24%, 99:1
Et
OH
O
O O
Et
57%
+
-
Metternich,J.B.;Gilmour,R.J.Am.Chem.Soc.2015,137,11254-11257.
Flavins: A Bio-Inspired Approach to Photocatalysis
(E) to (Z) Isomerization
(-)-riboflavin (5 mol%)
402 nmMeCN, MeOH (1:1) rt
R
OH
O
O O
RO2
O O
R
R = H, 79%
O O
R
R = Alkyl, 60-90%
O O
Me
R = OMe, 65%R = CF3, 48%R = Me, 60%
RO OMeO
herniarinhepatoprotectent
-
Flavins: A Bio-Inspired Approach to Photocatalysis
(E) to (Z) Isomerization
(-)-riboflavin (5 mol%)
402 nmMeCN, MeOH (1:1) rt
R
OH
O
O O
RO2
R
OH
O
mechanistic proposal
(E) to (Z)isomerization
(-)-riboflavin (RF) R
OHO
PCETR
OO
R
OO
RFH
RF
RFH2
PCET
O O
R
O2 RF
Merger of energy transfer and SET catalysis
ET
(E)-cinnamic acid coumarin
Metternich,J.B.;Gilmour,R.J.Am.Chem.Soc.2015,137,11254-11257.
-
Metternich,J.B.;Gilmour,R.J.Am.Chem.Soc.2015,137,11254-11257.
Flavins: A Bio-Inspired Approach to Photocatalysis
(E) to (Z) Isomerization
O
OR(-)-riboflavin (5 mol%)
402 nmMeCN, rt
R R
ORO
Z/E
R
RO
R
R
O
mechanistic hypothesis
(-)-riboflavinhυ
R
R
O
(-)-riboflavinhυ
E ZisomerizationX
conjugated deconjugated(Z)
-
Metternich,J.B.;Gilmour,R.J.Am.Chem.Soc.2015,137,11254-11257.
Flavins: A Bio-Inspired Approach to Photocatalysis
(E) to (Z) Isomerization
O
OR(-)-riboflavin (5 mol%)
402 nmMeCN, rt
R R
ORO
Z/E
R
RO
R
R
O
mechanistic hypothesis
E Z
1:1competition study
(-)-riboflavin (5 mol%)
402 nmMeCN, rt RO
R
Z -(E) quenches 10x faster than (Z)
Stern Volmer quenching study
-
Metternich,J.B.;Gilmour,R.J.Am.Chem.Soc.2015,137,11254-11257.
Flavins: A Bio-Inspired Approach to Photocatalysis
(E) to (Z) Isomerization
O
OR(-)-riboflavin (5 mol%)
402 nmMeCN, rt
R R
ORO
Z/E
R
R
O
mechanistic hypothesis
Etriplet sensitizer
RO
R
ZRiboflavinET = 50 kcal/mol-1
(E)ET ~ 34 kcal/mol (Z)ET ~ 60 kcal/mol-1
34 < ET < 60 kcal/mol-1
60 < ET < 74 kcal/mol-1
consistent with triplet energy transfer (ET) mechanism
X
-
Metternich,J.B.;Gilmour,R.J.Am.Chem.Soc.2015,137,11254-11257.
Flavins: A Bio-Inspired Approach to Photocatalysis
(E) to (Z) Isomerization
O
OR(-)-riboflavin (5 mol%)
402 nmMeCN, rt
R R
ORO
Z/E
mechanistic hypothesis
R
R
O
isomerizationTol OEt
O
PhPh standardconditions
Tol
PhPh
OEtO
Tol
PhPh
OEtO
52%60:40
* No reaction without photocatalyst
scrambled
-
Flavins: A Bio-Inspired Approach to Photocatalysis
(E) to (Z) Isomerization
O
OR(-)-riboflavin (5 mol%)
402 nmMeCN, rt
R R
ORO
Z/E
mechanistic hypothesis
R
R
O
isomerization
standardconditions
52%60:40
Ar
O
R
R H F Me Et Pr
increasing Z/E ratio
consistent with radical stabilityMetternich,J.B.;Gilmour,R.J.Am.Chem.Soc.2015,137,11254-11257.
-
Metternich,J.B.;Gilmour,R.J.Am.Chem.Soc.2015,137,11254-11257.
Flavins: A Bio-Inspired Approach to Photocatalysis
(E) to (Z) Isomerization
O
OR(-)-riboflavin (5 mol%)
402 nmMeCN, rt
R R
ORO
Z/E
R
RO
R
R
O
mechanistic hypothesis
E Zvsdeconjugation induces selective excitation
(-)-riboflavin (5 mol%)
402 nmMeCN, rt OEtO
Me
OOEtO
Me
S
reduced A 1,3 strain in (Z)-products(E) and (Z) are conjugated and planar
94%, 27:73 quant, 41:59
-
Metternich,J.B.;Gilmour,R.J.Am.Chem.Soc.2015,137,11254-11257.
Flavins: A Bio-Inspired Approach to Photocatalysis
(E) to (Z) Isomerization
O
OR(-)-riboflavin (5 mol%)
402 nmMeCN, rt
R R
ORO
Z/E
R
RO
R
R
O
mechanistic hypothesis
E Zvs
deconjugation induces selective excitation
(-)-riboflavin (5 mol%)
402 nmMeCN, rt OEtO
Me
introduction of allylic strain by ortho-fluoro
quant, 81:19
F
-
Marz,M.;Chudoba,J.;Kohout,M.;Cibulka,R.Org.Biomol.Chem.2017.
Flavins: A Bio-Inspired Approach to Photocatalysis
catalytic esterification
CO2H O
O
MeCN, O2 1 atmsimple carboxylic acidsand alcohols
ester
Riboflavin (10 mol%)
PPh3 (2 equiv)
440 nm
R OHR
EtO2CHN
NH
CO2Et(10 mol%)
Mitsunobu conditions-typically performed with
stoichiometric azodicarboxylate
O2N O
O
R
R = H, 53%R = Me, 54%R = NO2, 60%R = OMe, 70%
O2N O
OPh
n = 1, 80%n = 7, 61%
nO p-Cl-Ph
32%
MeMe
O
O
58%
O
p-Cl-Ph
-
Marz,M.;Chudoba,J.;Kohout,M.;Cibulka,R.Org.Biomol.Chem.2017.
Flavins: A Bio-Inspired Approach to Photocatalysis
catalytic esterification
CO2H O
O
MeCN, O2 1 atmsimple carboxylic acidsand alcohols
ester
Riboflavin (10 mol%)
PPh3 (2 equiv)
440 nm
R OHR
EtO2CHN
NH
CO2Et(10 mol%)
Mitsunobu conditions-typically performed with
stoichiometric azodicarboxylate
65% 99:1 er
NO2
O
O
Ph
Me
59%, 99:1 er
NO2
O
O
Ph
Me
50%, 98:2 er
NO2
O
O
CO2Et
MeO2N
48%, 98:2 er
NO2
O
O
CO2Et
MeO2N
-
Marz,M.;Chudoba,J.;Kohout,M.;Cibulka,R.Org.Biomol.Chem.2017.
O2
Flavins: A Bio-Inspired Approach to Photocatalysis
catalytic esterification
CO2H O
O
MeCN, O2 1 atmsimple carboxylic acidsand alcohols
ester
Riboflavin (10 mol%)
PPh3 (2 equiv)
440 nm
R OHR
EtO2CHN
NH
CO2Et(10 mol%)
Mitsunobu conditions-typically performed with
stoichiometric azodicarboxylate
mechanistic proposal
EtO2CHN
NH
CO2Et
(1.62 V vs SCE)RFH2
EtO2CN
NCO2Et
PPh3EtO2C
NNH
CO2EtPPh3
R OH
R OPPh3
R COOOPPh3R
O
O
R+
RF 1.67 V vs SCE
-
Flavins: A Bio-Inspired Approach to Photocatalysis
Concluding Remarks
Flavin photoredoxcatalysis is still under-ultized in synthetic organic chemistry
Flavin photocatalysis is an emerging field
Flavins serve an essential role in biochemistryThe unique photoredox properties of Flavins make them interesting photocatalyst
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