organic photochemistry and pericyclic reactions (cy50003) 3-0-0
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Organic photochemistry and pericyclic reactions (CY50003)
3-0-0
O
OSunlight (h)
One Year
Carvone Carvonecamphor
Course contentPrinciples of photochemical reactions; Excited states and their properties; experimental set up for photochemical reactions(1); Several useful photochemical reactions and their applications in organic synthesis (isomerization, Patterno-Buchi reaction (1), Norrish type I and II reaction(1), Photoreduction, Rearrangements: di-π-methane, oxa di-π- and aza di-π-methane rearrangements(2), Photocycloaddition (2), Photochemical aromatic substitution reaction (1), Reactions with singlet oxygen (1), Photochemical methods for protection and deprotection(2). Photochemistry of biological systems (photosensitized reactions of DNA/RNA, DNA damage and repair-1).
Books
• CRC Handbook of Photochemistry and Photobiology. Eds by. William M. Horspool and Pill-Soon Song. 1994. CRC Press. ISBN: 0-8493-8634-9
• Synthetic organic photochemistry. Eds by. William M. Horspool, Plenum press. 1984. ISBN: 0-306-41449-X
OrganicCompound
Ground electronic stateThermalactivation
Thermally activated state(change in vibrational, rotational andtranstational energy levels which is governedby Boltzman distribution law)
Formation of new chemical entity
E = hExcited electronic states(selective excitation)
photochemical reactions
Photo products
# two pathways are entirely different hence the reaction outcome
Questions need to be asked during the analysis of photochemical reaction
1. What are the products of the photo reaction
2. what are the electronic characters of the reactive state
3. what are the spin characters of the reactive state
4. what intermediates are involved in the reaction
5. what orbitals are involved and how do they react
6. what are the various chemical and physical processes and what are their rates with which a reaction of interest competes
R P
h
R R* I P
R 1R* 3R* 3I 1I PISCh
h
Relative energies of atomic and molecular orbitals
E
Bonding orbital (, )
E1
Atomic orbital
Antibonding orbital (*, *)
E2 E2>E1
Relative energies of , and n MOs
Enon bonding (n)
*
*
Bonding
Anti bonding
Most common transition module
n *(E1) * (E2)
n-* (E3)
E2>E3>E1
Absorption maxima for few molecules and functional groups
Molecule Transition max (nm) E (Kcal/mol)
Iodobutane n-* 224 127.7Ethylene 165 173.3Ethyne 173 165.3Acetone 150 190.7 n- 188 152.1 n-* 279 102.5Butadiene * 217 131.8Acrolein 210 136.2 n-* 315 90.8
Functional group
RCH = CHR 165 173.3 193 148.2Alkyne 173 165.3Ketones 188 152.1 279 102.5Aldehydes 290 98.6Carboxylic acids <205 <137.5
E
Bonding
Excited states
S0 S1 T1
Antibonding (SOMO)
S0 : Ground state (spin paired, Pauli exclusion principle)S1: Excited singlet stateT1: Excited triplet state (spin inversion)
S0 S1T1
X
# T1 is more stable than S1 ( parallel spin, lesser inter-electronic repulsion)
LIGHT ABSORPTION AND FATE OF EXCITATION ENERGY: Franck-Condon Principle
Ground state (E0) and two excited states (E1, E2) of a molecule (vibrational and rotational levels are not shown).
Modes of Dissipation of Energy
(S0)
(S1)10-8s
(S2)10-11s
(T1)10-3s-1s
S2 : The higher vibrational level of the excited singlet state S1
IC: Internal conversion; RD: Radiative deactivationF: Fluorescence (spin consevation); ISC: Inter system crossingP: Phosphorescence (Spin inversion).
h
IC
RD F
ISC
P RD
(Jablonski diagram)
Deactivation
no radiative
IC
ISC (Spin inversion)
radiative
F
P
S1
T1+ +
+
photosensitization
O
CHO O O
S0
S1
n-*74 Kcal/mole
*100 Kcal/mole
S2
1012/s
1011/sT2 ( *)
T1 (n-*)69 Kcal/mole
1.8X 102/s
106/s
pyrene aldehyde2-acetonaphthone fluorenone
lowest triplet state is *
Energy transfer through photosensitization
D 1Dh
1D 3DISC
A + 3D D + 3A
3A Products
D = DonorA = Acceptor1 = Singlet3 = Triplet
S0
S1
74 Kcal.mole-1 69 Kcal/mole
T1
ISC
120 Kcal/mole
S0
T1
S1
60 Kcal/mole
Energy transfer
Benzophenone Butadiene
Ph2COh
1[Ph2CO]ISC 3[Ph2CO]
+ Ph2CO3
Dimeric products
Criteria of an ideal sensitizer
• It must be excited by the irradiation to be used, small singlet triplet splitting. High ISC yield.
• It must be present in sufficient concentration to absorb more strongly than the other reactants under the condition.
• It must be able to transfer energy to the desired reactant, low chemical reactivity in Triplet state.
Experimental set up for photochemical reactions
Synthetic organic chemist (high intensity
light source, easy to handle, various
Flask size, specially designed systems)
Physical chemist or physical-organic
Chemist (mechanistic study)
Basic equipments for photochemical reactions
Mercury vapor lamps (200-750 nm, 599 kj/mol-159 kj/mol)
1. Low pressure or resonance lamps (0.005-0.1 torr, operates at RT)Emission at 253.7 and 184.9 nm
Hg (3P1) Hg (1S0) + h
Hg (1P1) Hg (1S0) + h
2. Medium pressure lamp (1-10 atm, and relatively high T)Requires little time to warm up, more of direct irradiation lamp
3. High pressure lamp (200 atm and very high T)
Ideal lamp characteristic : Need of spectral overlap between the lamp and the absorption spectrum of the compound to be irradiated.
Lamps in conjugation with filters
# A greater degree of selectivity is required if irradiation into one ofthe absorption bands of the molecule is required.# Or if the product of the irradiation is sensitive to a wavelength differentfrom the one used to excite the starting molecule.
Problems
Solution
# Monochromatic source of light (Lamp and a diffraction grating)# In conjugation with filters (solution or glass)
Wavelength of cutoff (nm) Chemical composition
Below 250 Na2WO4
Below 305 SnCl2 in HCl (0.1 M)
Below 330 2M Na3VO4
Below 355 BiCl3 in HCl
Below 400 KH phthalate + KNO2 (in glycol at
pH = 11)
Below 460 0.1 M K2CrO4 (NH4OH-NH4Cl at pH = 10)
Above 360 1 M NiSO4 + 1M CuSO4 (in 5% H2SO4)
Above 450 CoSO4 + CuSO4
Short and Long cutoff filter solutions
Immersion Well ReactorsComponents# Lamps# Immersion wells# Reaction flasks# Standard flasks# Gas inlet flasks# Flow-through flasks# Larger capacity standard flasks
Non-Rotating AnnularPhotochemical Reactor
# Large Quartz immersion well.# 400 watt medium pressure mercury lamp.# Reactor base and carousel assembly (non rotating), including support rod and immersion well adjustable clamp.# set of sample tube support rings for eight 25mm sample tubes# Only the inner or the outer tubes may be irradiated effectively at one time# UV Screen:- consisting of three black coated consisting of three black coated aluminum sections. A light tight lid, a removable front and back section, that are joined by means of a light tight seal
Semi-Micro ReactorThe semi-micro is a low cost, easy-to-use device for irradiating a standard 1 cm cuvette (or small tube) with either 254nm or 350nm radiation for any preset time between 1 and 70 minutes. This reactor is ideal for preliminary studies of small volumes of solution.
# The multilamp reactors consist of a base, lid, six or three lamp modules. Each module contains two lamps.# The base is hexagonal and provided with a centrally located fan# A number of modules up to six or three may be operated.# Switches are provided to control the fan and lamp modules.# Supports from the lid hold samples inside the reactors. Magnetic strips are used to eliminate light leaks between the lamp modules.
Multilamp Reactors: Six and Three Modules
Complete photochemical reactor comprising:
* Multilamp reactor base with cooling fan and control switches* Three twin lamp modules* Six lamps of customers choice* Magnetic light sealing strips
One set of attachments for supporting the reaction flask comprising :* Reaction flask support base* Flask support rod holder* Support rod hinged lid
Purity of solvent and gases
• Dilution (suppression of side reaction e.g., polymerization and dimerization.)
• Spectral transmission of solvent ( solvents devoid of low-lying excited states are best)
• Purity of solvent (Oxygen free, impurities free)
Solvent 10% Transmission (nm) 100% Transmission (nm)
Acetone 329 366
Acetonitrile 190 313
Benzene 280 366
Carbon Tetrachloride 265 313
Cyclohexane 205 254
Diethyl ether 215 313
Dimethyl sulfoxide 262 366
Ethanol 205 313
Hexane 195 254
Propan-2-ol 205 313
Tetrahydrofuran 233 366
Transmission characteristics of various solvents
Measured for a 1cm path length of pure solvent
O O*
C O
O O* O
CF3
O*
CF3
Electronic configuration of Reactive states
n-*
carbonyl chromophore
h~
Dipolar species
2.9 D1665 cm-1
2.1 D1225 cm-1
1696 cm-1 1326 cm-1
O
CHO O O
S0
S1
n-*74 Kcal/mole
*100 Kcal/mole
S2
1012/s
1011/s
T2 ( *)
T1 (n-*)69 Kcal/mole
1.8X 102/s
106/s
pyrene aldehyde2-acetonaphthone fluorenone
lowest triplet state is *
O O
MeO
O
Me
O
F
Triplet lifetime depends on the nature of lowest excited states
= 0.0064 s, 77oKn-*
= 0.45 s, 77oK *
= 0.13 s, 77oKn-* & *
= 0.039 s, 77oKn-* & *
# Electron donating substituents such as Me and -OMe stabilize * state# Electron withdrawing substituents such as CF3 and CN stabilize n-* state
A
B
D
E
A
B
E
D
Cis-Trans isomerization of alkenes
3S**3
h
tripletdonor
h
H
H
h
185 nm
sens
heath
h
Ph Ph
Ph
Ph Ph
H
h
Max = 380 nm
= 9 s
Dimer
4+2 [1, 3] H
Trapping of a trans cyclohexene
h
sens
h
sens
ORH
H
O2N
HOR
H
O2N
N NN N
NH N
H
h
R = H, Me
heat
heat
h
h
N
H OH
Ph
N
H
Ph OH
HNH
O
Ph
O
NH2Ph
NOH
H
NH
OH
NH
H O
h orh-sens
*
oxaaziridine
h orh-sens
N+
O
CN N+
O CN
O
N
CN
h or
h-sens
hh
R1
NH R2 N
H
R1 R2
N
NN
HH R
N
N
H
N
H
R
h
h
N NR
RN N
R R
h
R = Me R = CHMe
R = R =
R = R =
NN
N N
N NN N
C C
h
h (405nm)
h(436nm)/heat
h (313nm)-N2
h (313nm)-N2
OH
R
OH
R
OH
R
OH
R
R
OH
Ergosterol
h 1,7-H
Vitamin D
R =
Vitamin D2
R =
Vitamin D3
previtamin D
previtamin D
h
tachysterol
Photochemical synthesis of oxetans
Paternò-Büchi Reaction
O
O
O
EtO
OEt
CO2HO N
N
OOH
OH
N
N
NH2
O
O
NH2
NH
NH2
O
O
O
OO
O
OAc
OR
HOBz
OOAc OH
+
Paterno and Chieffi (1909), Buchi in 1954 mechanistic analysis
Insecticidal activity
Thromboxane A2 Oxetanocine
Bradyoxetin
Merrilactone A
Palitaxel
CHO
C O
H
O
C C
O
C C
OO
Reaction mechanism
h[PhCHO] S1
ISC[PhCHO] T1
(n-*)
Kisc aromatic >> Kisc aliphatic (>>1010/s)responsible
+
electrophile nucleophile
+
Major Minor
Biradical intermediate
OO O
O
O
tBuO
O
tBu
O
O
O
O
tBu
O
Ph PhO
O
C O
O
C
Ph
Ph O
OO
Ph
Ph
Intermediacy of biradical
+h
+
1 1.6
+h
1 atm O2
h, 11 atm O2
+
lifetime = 1.6 ns
h
O
H
O
O
O
H
X
O
R X
O
X
O
Me X
O
X
OMe
Substrate spectrum of Paterno-Buchi Reaction
Aromatic ketones and aldehydes
+
54%
+ R = H, X = S, 46%R = Ph, X = O, 27%R = Ph, X = S, 76%
+ + + [4+2]
X = O 8% 33% 0%
X = S 11% 10% 38%
h
h
h
OMe
O
H
O H
H
O
Ph
O
Ph OMe O
O
OPh
OMeH
Ph
OMe
O
OO OAc
Ph
O
OPh
MeOO
OPh
OMeH
C OH
Ph OMe OCH2.
OH
PhOMe
O
O
O
Ph O
O
Ph
H
O
O
Ph
Carboxylic acid derivatives and nitriles
+
33% 34%
+
h
h [2+2] H2O
1,7 sigmatropic
17
+
-MeOH 1, 3 Bz shift 1,3 H shift
CNN
N
Ph
CN O
O
CN
O
O
O
OO
Me
COMe
O
CN O
OO
R
CN
+
66%
+
h
-55oC R = Ph, endo/exo = 5.3:1
h
h
h
X O* T1 X O* T1
C
XO
C
X
C
O XO
O
Ph PhN
N C
N
N
O
C Ph
PhC
N
NO
C
Ph
Ph
O N
NPh
Ph
H
H
N
N
OH
PhPh
Oxetane formation: addition to heterocycles
+
+.
+
h
hand
more stable
OCO2Me *T1 O
PhPh OO
Ph
Ph
CO2Me
SR R2
R1
R3
O
R4 SO
R1
R2
R4
R3
R SO
R1
R2
R3
R4
R
SeR2 R
R1 O
Ph PhSe
O
R1
RR2
Ph
Ph
+h
+ +
+
R1 = R2 = H, R = MeR = R2 = H, R1 = MeR1 = H, R = R2 = Me
h
h
Methyl coumarilate
SiMe Me
PhPh
O
Ph Ph Si
O
Me MePh Ph
Ph
Ph SiO
Me MePh Ph
Ph
Ph
N
COR
O
Ph Ph N
COR
O
Ph
Ph
N
COMeO
Ph Ph
NO
COMe
Ph
Ph
+ h, 436 nm
MeCN
+
18% 51%
+h
h
O O O
O
Me CCl3 Me CCl3
OO
O
Me Me
F
O
F
O
F
O
Me Me
Cl
O
Cl
O
Cl
Enones and Ynones
+ +
42% 47%
+ +Low T
3% oxetane
+ +
10% 9 0%
+ +
90% 10%
O O O
O OO
OO
C C
+ +
14% 86
h
+h
+
..
OAc OAc
O
OTMS
O
OTMS
OAc
OAc
O
O
O
OEtEtO
OOO
O
O
CO2Et
EtO2C
O OO
O
H
H
Alkenes substituted with electron donor
h
+ZnCl2
+
h
h
O
PhPh SiMe3
O
SiMe3
Ph
Ph
O
Ph
Ph
SiMe3
O
PhPh OTMS
O
OTMS
Ph
Ph
O
Ph
Ph
OTMS
O
PhPhH SMe
HO
H
Ph
Ph
SMe
O
H
Ph
Ph
SMe
+h
+
24 1
+
h +
94 6
+
h+
100 0
OO
H
O
O
PhPh O
PhPh
O
PhPh
O
RPh
O
C C
R
PhO
R
Ph
O
C
R
Ph
C
O
R
Ph
O
O
OAc
CHO
O
O
O
OAc
O
OH
O CO2Me
OH
Miscelleneous Paterno-Buchi Reaction
+h
+
COM
+
300oC
+
+h
h
h
O OEtO
OEtO
OEt
O
OEtH
OH O
OOR
R
R'
R H
OH OR'
R"MgX R R"
OH OHR'
OO
R
R'
O
OO OAc OAc
O
O O
O O
OAc
OAcCH2OH
CHO
H
OHH
CH2OH
O
O O
OO
The Paterno-Buchi reaction as a photochemical aldol equivalent
+h/70%
+
3 : 7
+
H2O
H2O, RT
h
+h
OH-/H2O
NaBH4
H+
R
R
O R
R*
Ob
b'
a
a'
c
d
a
bA B
enantiotopic faces a,a' and b,b' diastereotopic faces a,b and c,d
non prostereogenic carbonyl prostereogenic carbonyl
Parallel approach
# Nucleophilic attack of carbonyl (half filled *)towards the alkene empty *
# Electron defficient alkenes favored this approach
Perpendicular approach
#Nucleophilic attack of alkene toward carbonyl half filled n orbital
# Electron rich alkenes favored this approach
# Carbon-oxygen 1,4 biradical
O
R
R'
O
R
R'
O-.
R
R'C+.
C O
C
R'R
C O
C
R
R'H
H
Regioselectivity a closer look (Perpendicular approach)
(nucleophilic)Exciplex
Radical ion pair
+
# nucleophilic attack of the filled -orbitalof the olefin to the excited carbonyl oxygen (n-orbital) to form an exciplex
# the attack results either in full or partial electorn transfer to generate a radical ion pair
# the ion pair or exciplex combines to form a C-O bond resulting a diradical intermediate
# the diradical if triplet lives long and undergoes other reactions before ISC
# finally the singlet diradical closes to yield the oxetane
O
R
R'
O
R
R'
O-.
R
R'C+.
O C R
R'
O C R'
R
Regioselectivity a closer look (parallel approach)
(electrophilic)Exciplex
Radical ion pair
+
# nucleophilic attack of the carbonyl by its half filled * to alkene *
# the attack results either in full or partial electorn transfer to generate a radical ion pair
# the ion pair or exciplex combines to form a C-C bond resulting a diradical intermediate
# the diradical if triplet lives long and undergoes other reactions before ISC
# finally the singlet diradical closes to yield the oxetane
A
A
AO
D
D
D
AD
HOMO
LUMO
electron deficient alkeneA = electron acceptor
n*
LUMO
*
HOMO
n
HOMO
* LUMO
electronrich alkeneD = Donor
n
Parallel approach perpendicular approach
O
CN
NC OEtEtO
O
O
O O
OOR
OR
O
CN
NC
O
OR
OR
O
CN
NC
Fluorescence quenching of 2-norbornanone singlets by trans-DCE and cis-DEE
5.11.2
1.0 1.5
0.48 <0.03
parallel approach(-orbital attack)
perpendicular approach(n-orbital attack)
"edges"(n-orbital attack)
"faces"(-orbital attack)
Fast Slow
SlowSlow
OR CHO
O
OHR
H O
ORH
H
X
O
H
R
HX
O
R
H
H
Intermediacy of diradical explains certain facts
+h
benzene +
Endo ExoR endo:exo
Me 45:55ethyl 58:42isobutyl 67:33phenyl 88:12o-tolyl 93:7mesityl >98:2
Perpendicular approach
3A
ISC
1Aendo
ISC
3B
1B exo
CO2R*
O
Ph O
OO
CO2R*
OO Ph
H
HO O
OPh
H
H
O
O
O
Ph
Pri
OMe
O
O
Ph
O
O
H
H CO2R*
Ph
Enantiocontrol and diastereocontrol inPaterno-Buchi Reaction
+h
+
R* = (-) 8-phenyl menthyl; de>96%R* = (-) menthyl; de 57%
one face of carbonyl blocked by the menthyl group
R*O2C
NROO
O
OHC
NH
O
NROO
O
O
NH
O
NROO
O
O
NH
O
NHOO
O
O
H
NH
ONRO
OO
O
H
NH
O
h
+
R = H acetonitrile 1:1 benzene 83:17 toluene 95:5R = Me, benzene 1:1
R
O R
O
R
R
O
R
R
Me
OH
H
O
O
O
O
O
O
O O
O O
O
O
O
O OO
H
Intramolecular oxetane formation
R = H, Me
h
+
+
Me2CO
h
hh
h
h
O
Ph O
O
O
OO
Ph O
O
Ph
OMe
O
O O
O
O
HH
OH
H
AcOO
O
AcO AcO
OH
h Silica gel
Pd
heat
azulene
LAH
HI
intermediate for 1 -hydroxy-vitamin D3
h
h
hh
O O
CHO O OH
O O R
O
OO
R
O
O
O
R
OH
OMe
O
OMOM
CHO
O O
H
OMOM
H
O OH
H
OMOM
OH
h
LAH
MeOH
C6H6
H3O+
h
h
h
O
H
O
OO
H HPh
Me
OMeO
OH
Ph
OO
H HPh Me
OHMeO
OH
Ph
O
H
O
H
H
O
H
H
O OH
OO
R
OOH+
RH
O
OH
R
+h .01N HCl
THF
H2, 5% Rh/Al2O3
wet celite
+
Fruit fly attractant
h
R = Me, Ph, CO2nBu
H+
Science, 1985, 227, 857JACS, 1984, 106, 7200ibid, 1984, 106, 4186
R1R2
R3 R4O
R
R4
R3
R1
R2
OXR4
R3
CHRYR1
R2
O
PhR
OTMS OHR OTMS
Ph OHR OH
Ph
O
OPh O
OH
Ph
+ R CHOh XY
Carboxydroxylation strategy by reductive cleavage of oxetanes
H2
H2
N
OH
Ph
H
O
Ph N
PG
N
PG
O
Ph N
PG
OH
Ph
N
CO2Me
R
N
CO2Me
R
O
H
H
Ph NR
OH
Me
Ph
N
CO2Me
N
CO2Me
O
Ph N
OH
Ph
Total synthesis of (+)-Preussin
+
Carbohydroxylation strategy fo N-containing unsaturated heterocycles
PhCHO/h
MeCN
H2, Pd(OH)2/C
LAH/THF
endo
MeCN
17%
H2, Pd(OH)2/C
LAH/THF
Chem.Eur.J, 2000, 6, 3838-48
PhCHO/h
N
CO2Me
RN
R
HMeO2C
H2
H1 N
H
RMeO2C
H2
H1
N
R
HMeO2C
H2
H1
OH
Ph
N
R
HMeO2C
H2
H1
O
H
Ph
4 3
2
A 1,3 StrainPseudoaxial orientation of R
Si
ReFavored
Possible explanation for the facial diastereoselectivity
COMeO O
O+
AlEt3
C OAlEt3
OH
+ h
PB
Et3Al
LDBB
1-e reduction of C-O bond
Angularly fused triquinane
JOC, 1998, 63, 5302TL, 1995, 38, 6851
N Ph
O
ON
O
Ph
ON
O
Ph
NH2 PhN Ph
O
O
NAcPh
Ph
O
NAcPh
Ph
N
O
H
Me
Ph
N
O
H H
Me
PhH
N
O
Me
H
Ph
N
O
H HMe
H
Ph
Chiral enamides and diastereoselective PB reaction
MeCHO
Ac2O, TEA
PhCHO/h+
2 1
GS conformations of parent enamides
ON
O
Ph
ON
O
Ph
ONH
O
Ph
ON
O
Ph N
O
O
Ph O
Ph
N
O
O
Ph O
Ph
N
O
OHPh
OPh
NH2
OHPh
Chiral enamides and diastereoselective PB reaction
MeCH(OEt)2
CSA
PhCHO/ h+
H2, Pd/C
Li, NH3
O
NH
Ph
O
HNHMe
Ph
OH
O
Ph NBnBoc
R1 O NBn
O
R1
OH
PhO
Ph R1
NBnBoc O NBn
O
R1Ph
OH
O
NBn
O OtBu
PhR1
O+
NBn
O OtBu
Ph
H
R1 OC
+NBn
OtBu
OH
R1
Ph
O NBn
OH
R1
Ph
O
LAH/ THF
Ring opening of cis-aminooxetanes obtained by PB photocycloaddition
TFA TFA
H+ -tBu+
Tet.Lett, 1997, 38, 3707-10Inversion occurs at this center
NMeBoc
CHO
O
NMeBocPhO NMe
O
Ph OTs
O NMe
O
Ph OTs
Ph
OH
NMe2
Ph
OH
NHMe
+h TFA
TsCl/py
LAH/THF
NaBH4, KOH/EtOH, water
+orthopara
meta
1
2
3
45
61
2
1
4
1
3
Possible modes of addition in the arene-alkene photocycloaddition reactions
C C
C
C
C
C
C
C
C* C*
C*
*
+
1
23
4
5
6
Exciplex
ortho cycloaddition
meta cycloaddition
para cycloaddition
prefulvene
Mechanistic proposal for the arene-alkene photocycloaddition reaction
(3C + 2C)
(4C + 2C)
(2C + 2C)
6
2
1
6
23
+
-
CN CN CN
C C C C
O
O
zz
O
O
O
O
z
O
O
z
+h
+
5 2
z = OMe z = CONH2, CN, Me
R
RR
R
C
R
R
C
C C
R
R
C C
C R
R
+a
b
c
-a
-b
-ac
Possible mode of cleavage of the cyclophotoadduct
R
R
HH
R
+
endo exciplex
h
O
O
O
O
O
OO
OO
O
OO
O
*
+h
exo adduct
+
secondary orbital intercation is not favoreddue to presence of non bonded "O" electron
h+
endo exo
5 1
C C
C C
Br
O O
Br
12
3
4
7
8
12
4
38
3
21
7
4
h
Favored
Disfavored
+Li, CuI
+Li
Li, NH3
56
10
11
3
21
7
456
10
11
Isocomene
56
56
Tetrahedron, 1981, 37, 4445
OMeOMe
H OMe
OMe
OMe
Br
OMe
O
OMe
vs.
endoexo
disfavoredfavored
h
+Li, Et2O
Li, NH3
Me
Me
Me
H
Me
Me
Me
HMe
H
Me
HO
Me
HO
OH Me
HOH
Me
HMe
H
vs
disfavored favored
Allylic stereocontrol: for the synthesis of silphiperfolene
h, CH3CHO
PhNO2SeCNBu3PH2O2
Silphiperfolene
Li, NH3(l)
h
Tet. Lett, 1985, 26, 5987
OAc
OAc
H
H
CO2H
H
O
O
O
O
OOH
H
H
O
O
HO2C
O
OOHOH
h
12 3
49
10
1156
7
83
4
2
5
1
9
11
Modhephene
-cedrene hirsuteneretigeranic acid
isoiridomyrmecin coriolin3-oxosilphinene subergorgic acid
rudmollin
JACS, 103, 688, 1981Tet.Lett, 23, 3983, 1982ibid, 31, 2517, 1990ibid, 24, 4543, 1983ibid, 24, 5325, 1983ibid, 31, 5429, 1990ibid, 27, 1986, 1857.
Br
O
C*
C*
C
C
+Li, Et2O
NH3
h
Li, NH3
Silphene
OAc C
C
OAc
OAc O
O
Me
OR
Me
Me
OR
MeMe
OR
Me
Me Me
O
O
OMe
Me
O
O
+h LAH
MnO2
LDA, -780C
MeI
Me2CuLi, THF
(Me2N)2POCl+
H2, PtO2
O3, MeOH
NaBH4
NaBH3CN
Iso iridomyrmecin
NH3+
CO2-
CHO
CHO
CHO
OH
O
OTs
O
OTs
Br O O
O O
I
O O O O O OH
O
O
P
O
NMe2
NMe2
P
O
NMe2
Me2N
+
O3, DMS
Zn(BH4)2
TsCl, PCC NBS, AIBN KOHH2, Pt
LDA, DMPUh
Li, MeNH2
KHMDS(Me2N)2POCl
Li, EtNH2
Laurenene
C*
C*
C
C
H2NOC
R2NOCR2NOC
HO2C
O
CO2H
H2NOC
OHC
CO2H
h h
HCONH2
4 + 2
Retigeranic acid
(-)-Carvone
(Ph3P)3RhCl, H2
Br2, AcOHKOH
Ph3P+CH3Br-,
nBuLi
+
Br CHO
OHO
O
O
O
O
O
C
C
O
O
NC
O
O
O
O
O
O
O
OH
O
Cl
O
OH
O
HO2C
Li, Et2O PCC
EGC/CSA
h, 3C + 2C
(PhCO)2O, h
CH3CN
K, 18-C-6
mCPBA LICA, THF SOCl2
NaClO2
Subergorgic acid
OH
OMe
OTBS
OTBS
H OMe
OTBS
H
OHO
OTBS
H
OOR
OTBS
H
OHOR
OTBS
OTBS
H
OTBS
OBn
H
OBnO
CO2H
H
OBnO
O
O
H
OHOH
O
O
H
OHOH
O
O
h, 3C+ 2C Hg(OAc)2
THF, H2O
NaBH4
MnO2,H2
(PhCO)2O
KHMDS, allyl-I
Tet. Lett, 1986, 27, 1857
MsCl, Pyr
LAH, Heat
Seven membered ring synthesis based on arene-olefin cycloaddition
Rudmollin
OMe
OTBS
OAc
C*
C*
OMe
OTBS
OAc
C C
OMe
OTBS
OAc
OAc
OTBSOMe
OTBS
H
OCl
Cl
OAc
OTBS
H
OO
OTBS
OAc
OTBS
H
O
OTBS
OO
OH
H
OH
OHOH
OH
OAcH
OTBSOMe OAcOTBS
HOMe
h
PhSeCl
KOH
Grayanotoxin
Disfavored Favored
R
COX R R
R
COX
R
R
ClOC
R
R
O
COCHN2
O
R
R
h
X = OMe, R = Me
Fenestrane derivative
Tetrahedron, 1985, 41, 5697
OMe
XX
C OMe
C
X
OMe
.
.
O* *
O
X
OMe
OMe
X
OMe
X OMe
X
OOO OH O OOEt
OH
OH OH O OHO O
+
Si-face of olefin in exo-adduct(Re-face in endo-adduct)
Re-face of olefin in exo-adduct(Si-face in endo-adduct)
Introductionof PD tether
6-substituted 7-substituted
Hg(OAc)2
+
O O
O O
O
O
Rn
OO
Rn
O O
O O
O
O
OO
Rn
Rn
C
C O
OC
C O
O
C
C O
O
+ +
Si- face attack to the olefin
Re-face
Stereochemistry at 2- position is important
Re-face
Abolished stereochemistry at C-4
Abolished stereochemistry at C-2
2R 2S
Re- face attack to the olefin
MgBr
OMe
OH
MeO
OTBS
MeO
H
O OTBS
MeO
OTBS
MeO
OTBS
OMeMeO
OH
OTBS
MeO
MeO
OH
HOH
OH
OH
H
OH
O
CuCN
Cy-hex-2-enoneMeLi, allyl-IL-selectride
9-BBN
DMP
endo (favored)exo ( disfavored)
aphidicolin stemodinone
Norish Type I Processes of Ketones Basic Concepts
R
OC O
C h
+
O O O
O OO
O
OMe
O
O
2 X 106 3 X 1071 X 108
2 X 108 2 X 107
1 X 107
7 X 105not measured
>109
# Norish type I reaction is much faster for n-* compared to * excited states
# n-* reactivity is due to the weakening of the -bond by overlap of this bond with the halfvaccant n-orbital of oxygen.
# This overlap is not possible for * excited states
# Electron releasing group at para position lead to stabilization of * excited states hence decrease in reactivity
R
R1
R
R1 .
O C C
C C
C C
n
O O O
O* O*O*
K3.3 x 107/s 4.7 x 108/s 1.8 X 109/S
Rate of cleavage increasing ring strain
< <
O
C C O O
MeNO
O
C C
O
C C
O O
h NO
h
-780C
acyl-alkyl diradical
Intermediate trapping experiment
O
MeH
Ph
C O
C MeH
Ph
C O
C HMe
Ph
O
MeH
Ph
O
HH H
HPh
h
retention
racemization
disproportionation
O
C C O
C C O O
O
C C O
C C O O
h
h
O
C O
C
O
C C (CH2)n-1CH3
(CH2)n-1CH3
O
H
(CH2)n-1
O
n
O
OR
n
OC
O
OR
(CH2)n
h
(CH2)n
recombination
(CH2)n
decarbonylation
(CH2)n (CH2)n
+
disproportionation
enal
ROH
ketene
ring expansion
(CH2)n
ROH
oxacarbene(CH2)n
OC
C OC
C
O
C C O
C O C
OO
h
-cleavage
ring opening
cyclization
ring opening and cyclization
(CH2)n
O
(CH2)n
OC
(CH2)n
O
(CH2)n
OOR
O
C C O O
H
OC
O
OMe
O
O
O
O
O
C OO
O O
OO
O
OEt
ROH
h
MeOH
EtOHh
h
O O*
C C
O*
O ..
O OR
C
C
O
h
S1 (n-*)
ROH
Ring expansion
Oxa carbene
+ CO
cycloelimination
+
O
O
O
O
.. O
O
O
R2
R1
OH
CN
O
R2
R1OH
CN
.. OO
R1
R2 CN
H
H
Si OPhPh
SiO
PhPh
..
E
ESi
O
PhPh
E
E
h
h
h
OO
O O
S
S
h
MeOHROH
tBuOH
h
hROH
h
h
MeOH
OTBS COCl
Cl Cl OCl
Me
OTBS
O Me
OTBS
O Me
OTBS
O
OTBS
OMe O
OTBS
CN O
OTBS
CN
O
OTBS
NH2
O
OTBS
NH2
O
OH
N+Me3I-
O
OH
N+Me3I-
+Zn Zn/Cu
NH4Cl+
3 1
h/ MeOHTMSCN
+
1 1
BH3:SMe2BH3:SMe2
MeI
Muscarine
allo-muscarineTet.Lett, 1988, 29, 159
ClCl
O
O
O OH
O OTBS O OTBS
MeO2C
OMeO2C OiPr
OTBS
OO
OTBS
SiMe3
OMeO
OTBS
OR
OMe O
OTBS
OR
O
OMe
O
OTBS
OR
OH
OMe
OOMe
BzO
OBz
OMe
NaOH O2, h
Rose bengal+
NaOAC/EtOH
H2, Pd-C
TBSCl
h
iPrOH
LAH
PTSA
BF3:OEt2
TBS-Cl
OsO4, NaIO4
LiAlH(OtBu)3 NaH, MeI F-
H2
PhCOCl
Pederol dibenzoateJ. Org. Chem. 1987, 52, 2335
OH
O
OH
OC O
O
O
R
OH
O
OH
OH
R ROH
OH
R'
OH
CO2H
OC C
OOH
O
H
R
OHO
H
ROTHP
h
Wittig
R = R' =
+
R =
h
h
OTBS
O
Bu
HH
OTBS
Bu
HH
O
O
OTBS
Bu
H
O
O
OTBS
Bu
H
O
O
Me
OTBS
Bu
H
O
OH
MeCO2- Ph3P+
OTBS
Bu
H
OP
Me
CO2H
Bu
H
OP
Me
O
CO2Me
C C Bu
H
OP
Me
O
CO2Me
O Bu
(CH2)6CO2Me
OP
..O Bu
(CH2)6CO2Me
OH
MeO
MeCO3HLDA, PhSeCl
H2O2
Me2CuLi
DIBAL-H+
CH2N2
HF, MeCNPCCH2, Pt/C
h, MeOH
Thromboxane analogue
• Norish type II photoelimination of ketones: Cleavage of 1,4-biradicals formed by γ-hydrogen abstraction
RR'
O
RR'
1O*
RR'
1O*
R
R'OH
n
R
OH R'
RR'
O
RR'
1O*
RR'
1O*
RR'
3O*
RR'
O
RR'
3O*
R
R'OH
n
R
OH R'
R'OH
R
RR'
O
h
1KHa
1Kd
Kisc3Kd
3KH
O
Ph
H
C O
Ph
C H
C O
Ph
C H
O
Ph
OH
Ph
O
Ph
H
optically active
S1 (n-*) T1 (n, *)
racemic
# Yang cyclization
# cleavage
# hydrgen reversal
C
OHC
R R'
Ph
O
R R'
H
Ph
C
C
R R'
Ph
OH
Solvent
O
R
R'
O
Solvent effect
racemizationsolvent
X
+
valerophenone
# racemization is suppressed in H-bonding solventsuch as t-BuOH
# With H-bonding solvent conformational change of bi-radical occurs hence influence the decay process.
O*
O
OMe
O
O*
OMe
O
O
O O
MeO
107 108
2X107
1X105
n-*
*
O O
O PhPh
OH
O
Ph
Conformational effects
trans-4-tert butyl-2,2-di-n-propyl cyclohexanone
h +
h
no -further reaction
PhCHOh
h
O Ph
O
Ph
O* PhH
PhOH
O*
Ph C C O
CHO
105/s
h
KH = 1.7 x 108/s
105/s K cleavage = 2.5 x 107/s
+
+
h
OH
OH
O PhH
1.3 x 108 6 X 108 7 X 109
# Restriction of conformational freedom plays important role
#The mobility of parcipating molecules (carbonyl compound and hydrogen donor) is severely restricted at the TS during intermolecular hydrogen abstraction process.
# the more freezing in bond rotation is higher the rate of H abstraction
KH
O
H
R
OHR
OH
R
OH
R
OH
.
.
R
HO
+
1,4 diradicals as intermediates in -hydrogen abstraction
R
OR2
X
R1
H
RC OH C R2
X
R1
R C
O C R2
R1
R
O
R1
R2
O
OMs
H
Ph
O
Ph
O
OTs
Ph
H O
Ph
h
ISC
-HX
Spin center shift
X = OAc, OTs, OMs, ONO2
h
h
R
O
H
R
OH
CH3
R
O
R
OH
CO2Me
CO2Me
CO2Me
CO2Me
R OHR
CO2Me
CO2Me
H-Transfer
spin-inversion
+
Photoenolization
R
O
Ph
R
O*
Ph
H
OH
H
R
Ph
OH
H
R
Ph
OD
H
R
Ph
R
O
Ph
D
R'OD
O
Ph
.
C OH
Ph
Me
.
C
Me
OH
OH
PhOH
Ph
OHPhO
Ph
h
O
OAc
OAc
O
OO
OAc
OAc
O
O
OAc
OAc
CHO
O O
O
O
O
N
N
O
O
Synthetic applications
h
h
h
O OH O
O
O O
OMe
OMe
MeO
O O
CO2Et O
O OH
OMe
OMe
MeO
O O
CO2Et
O
O
OMe
OMe
MeO
O O
OHCO2Et
h
Norish II, Cleavage
(-)Ephidrine
EnantioselectiveH-transfer
h
Photoenolization
4+2
Podophyllotoxin derivative
O
O
C C OH
OH
C C OH
OH
O
O
n Ph
PhO
C
C
OH
n Ph
Ph
n
OOH
PhPh
Norish type II process involving 1,6 and greater H transfer reactions
S1
T11, 5 H abstraction1, 7 H abstraction
Photocyclization of cyclodecanones
h
n = 0, 1
photocyclization of -[o-(benzoyl) phenyl ] acetophenone
h
O O O
OH
C
C O O
H
C
C O O
H
n
R
O
O
Ph
C C
ROH
Ph
R
OH
Ph
O
O O
OR
OO
OHOR
O
O
OH
OR
h
photocyclization of o-methylphenyl 1,3-diketone
photocyclization of o-benzyl substituted ketones
h
h
O
O
O
O
PhX X
O
O
O
OH
Ph
C
O
O
O
C
O
Ph
X
H OC O
O
C
O
Ph
H
XX
O
Ph O
O
Men
OH
(CH2)y(CH2)x
O
O
Ph
Me
Long distance H abstraction
h
1, 5 H
1, 9 H
X = H or D
X
n = 12-18
Remote oxidation of unactivated methylene groups
h
h
O
OR
O
OHR
OO
Ph
O
OHPh
h R = H, Me
h
Photochemical synthesis of tetrahydropyran-3-ols and benzopyranols
O
O
(CH2)n
O
O
O
(CH2)n
OH
O
O
(CH2)n
OH
O
O
(CH2)n
OH
h
n = 1
hn = 2
Remote oxidation and photocyclization of steroids
PhPh
PhPh
PhPh
O
PhPh
Tol OPh
PhTol
The -cyclopropane rearrangement
h
h
PhPh
PhPh
PhPhC
C Ph
Ph Ph
PhPh
Ph
PhPh
Ph
..Ph
PhPh
h
h
The basic reaction mechanism; singlet mechanism
R1Ph
R2
R1Ph
R2
C
C R2
Ph R1
R1Ph
R2
R1Ph
R2
..R1
PhR2
h
h
Ph
Ph
Ph
Ph
Tol
C
C
Ph
Ph
Ph
C
PhPh
Ph
.
PhPh
Ph
C
C Tol
Ph
C
MePh
Tol
.
Tol
Ph
Tol
Me
Ph
h
h
sens
a
b
a
ba
b
The triplet rearrangement
Tol
Ph
MeC
C
Me
Ph
Tol
C
MeTol
Ph
.
MeTol
Ph
TolPh
h
sens
a
b
The triplet rearrangement of 3-phenyl regioisomer
a
b
Tol
Me
PhC
C Me
Tol Ph
C
Tol
Me
Ph
.
Tol
Me
Ph
TolMe
Ph
h
sens
a
b
The triplet rearrangement of 3-methyl regioisomer
a
b
Tol NN
Ph
Tol
Ph C
.
Tol
Ph
TolPh
Proof of cyclobutenylcarbinyl diradical as an intermediate
h
-N2
a
b
a
b
Tol
O
Ph Ph
C
Tol O
Ph Ph
Tol O
Ph Ph
.
OTol
Ph Ph
Me
O
Tol Ph
Ph
The acylcyclopropene triplet rearrangement
h
sensb
a
ab
C C
C
C
C C
C
C Ph Ph
The Di- Methane Rearrangement
h
h
h
Barrelene Semibullvalene
Chem.Rev; 1996, 96, 3065-3112
PhPh
C C Ph
Ph
A BC
C
Ph
Ph
PhPh
C
C
Ph
Ph
PhPh
Reaction regioselectivity
h
BA
MajorMinor
# Stabilty of benzyhydryl biradical
# More available electron density for ring opening
PhPh
C
C Ph
PhC C
PhPh
C
C
Ph
Ph
Ph
Ph
C
C
Ph
Ph
Ph
Ph
X
PhPh CN
PhPh
NC
PhPh
NC
PhPh OMe
Ph
Ph
OMe
Ph
Ph
MeO
h
direct+
h
direct+
# there is a strong tendency for electron donors to appear on the residual - bond of the photoproduct
# and for electron withdrawing groups to be found on the product three membered ring
Electronic factor on regiochemical outcome
PhPh
CN
CN
Ph
Ph
CN
CN
PhPh
OMe
OMeOMeMeO
Ph
Ph
Reaction regioselectivity
PhPh
CO2MeCO2Me
PhPh
C C
PhPh
Ph
Ph CO2Me
CO2Me
C
C
PhPh
Ph
Ph CO2Me
CO2Me
C
C
CO2Me
CO2Me
Ph
Ph
PhPh
PhPh
Ph
Ph
CO2MeMeO2C
Ph Ph
PhPh
CO2Me
CO2Me
s ts t
Multiplicity control of regioselectivity
2K2K
T1
S1
T1
S1
E
Large K vs. small K control of excited state selectivity
PhPh
Ph
Ph
PhPh
h, Direct
h, sensFree rotor effect
h, sens
2,3-naphthobarrelene
Effect of excited state multiplicity on reaction outcome
# di--methane triplets which have double bonds not incorporated in a ring structure or not inhibitited from free rotationin some other manner are commonly unreactive.
# In contrast cyclic di-enes tend to be perfectly reactive as triplets, and this can be ascribed to their inability to undergofree rotation in the excited state.
# If rate of radiationless conversion of the triplet reactant is slower than the rate of reaction, despite in the presence of free rotor group, triplet reactivity in an acyclic system was observed. Generally in this case free rotation is inhibited by effectssuch as steric hindrance, so that the triplet may be reactive.
PhPh
PhPh
Ph
Ph
Ph Ph
h, sens
# The original generalization is that cyclic molecules are more likely to react successfully from the tripletexcited state via sensitization while acyclic molecule tend to perform better as singlets (obviously in the case of triplet reactivity absence or presence of free rotor is important).
h, sens
h, Direct
# For many cyclic molecules, direct irradiation with formation of the singlet excited state does not lead to asuccessful di-p-methane rearrangement. This behaviour arises not because the singlet excited state is incapableof a di-p-methane rearrangement but rather because many cyclic systems have potentially available facile alternativepericyclic process which competes all too successfully.
MeO
MeO
MeO
NC
NC
h
MajorMinor
h
h
JACS, 1977, 99, 3723-33
Ph
Ph O
Ph
HPh H
HO
Ph
Ph
Ph
Ph
OO C O
C
C
O
C
O
O
The Oxa-di--methane rearrangement
h
OPDM
X
OCD3
O
OAc
OCD3
OAc
O
OCD3
OAc
O
OPh O
Ph
h, Direct+
h
Chrysene/sens.
racemization
O O
O O
Chrysene Sens.
h
Chrysene Sens.
h
Retention of Configuration
CH2CO2H
O
O
CH2CO2HH
O
HO
tBu
tBu
But
H
H
OO
tBu
H
tBu
tBu
H
R1O
Me
R3
R2
R2
O
R1
R3
Inversion of conviguration
h
acetone snes.
Direct
acetone snes.
h
h
Mechanism I
OD
O OMe O O
OMe O
MeO
MeO
Me
Ph
OMe
Me
OMe
Me
OPh
Ph
O
MeOH
O
MeOEt
O
O
OPh
Ph
OPh
Ph O
OPh
Me
PhO
Ph
Me
The OPDM rearrangement of acyclic -unsaturated ketones
Key structural features favoring OPDM
# Conjugation of the alkene moiety with phenyl, vinyl or oxo groups (efficient triplet energy transfer, biradical stabilization) # disubstitution or alternatively, monosubstitution by bulky groups at the central carbon
Unreactive towards OPDM
OPh
OPh
OPh
OPh
Ph
OPh
Ph
PhO
O
O
O
O
OPh
Ph
# The cental methylene carbon is di-substituted or having bulky mono substitution# Conjugation with vinyl, phenyl or carbonyl groups
On
O
n
On
O
O
The OPDM Rearrangement of cycloalkenyl -unsaturated ketones
n = 1, 2 n = 1, 2
n = 1, 2, 3
X
h
h
O
O
O
O
O
O
OO O O
The OPDM rearrangement s of monocyclic and condensed polycyclic -unsaturated ketones
O CO2MeO CO2Me
O
O
O
O O
+
O
R1
R2
O
R
OO
O O
The OPDM rearrangement of Bridged cyclic -unsaturated ketones
h, sens
R1 = Me, R2 = HR1 = H, R2 = MeR1 = R2 = H
h, sens
h, sens
O
Me HOMEM
OMEM
O
OMEM
O
HH
O
Synthetic application of OPDM rearrangement
h/ sens
7 steps
(-)-Silphiperfol-6-en-5-one
O
MeO2C
MeO2C
O
H
CO2MeCO2Me
OO
OH
h
Sens
Cedrol
Tetrahedron, 1981, 37, 4401-10
O
H
CO2MeCO2Me
OO
O
H
CO2MeCO2Me
O
H
CO2Me
H
CO2Me
OH
H
CO2Me
OAc
COMe
H
CO2Me
COMe
ClNCO
O
+
h/ sens
(racemic)-modhephene
OOPiv
OPiv OPivOPiv
O
H
OAc
O
H
O
H
OHC
O
H
OMeO
H
OMeO
OTf
H
O
CO2Me
O
H
O
CO2Me
O
h/sensLi/NH3
Ac2O, DMAP/TEA
Swern
Pentalenolactone P methylester
JACS, 1992, 114,7387-95
OH
OH
O
O
OH
OH OP
O
O
OP
H
H
+
hacetone
(-) Hirsutene
PT (1), 2002, 2439
OH
O
OOH OH
R
OMeOO
O
R
H
R = CH2CH2OMe
O
R
HO
C
R
HO
OC
R
HO
OH
h
sens
(Me3Sn)2
3-OH-Peristylane
h
Acetone/iPrOH
H Donor
- Me
O
O
O
O
O
OO
OO
OH
OOH
O
OH
O
O
O
h
(-) Coriolin
a
b
O O
O O
h
Competition between all-carbon DPM and OPDM rearrangement
ab
a = benzo vinylb = keto vinyl
h
O
O
O
OMeO2C
MeO2C
O
O
H
MeO2C CO2Me
O
O
HMeO2C
MeO2C
O
O
DPM
vinyl-vinyl > keto-vinyl > benzo-vinyl
Not observed
ODPM
DPMODPM
R
O
X
O
O
X
O
OO
R
R
O
C
X
O
O
.R
O
C
X
O
O
DPM
Benzo-vinyl > keto vinyl
Stable biradical
O
OAcH
H
O
OCHO
O
OH
O
O
H
PhPh
Ph
PhCHO
O
H
PhH
PhCHO
H
H
The OPDM rearrangement of -unsaturated aldehydes
h
Direct or sens + +
h, sens
h, sens
CHOCHO
CHO
CHO
CHO
Phn
Ph
H CHO
h, sens
n = 1, 90%n = 2, 25%n = 3, 25%
h, sens
h, sens
CHO
Ph
Ph
Ph
CHO
CHO
Ph
CHO
CHO
CHO
CHO O
OO
R
h
Direct
Sens+
R = H, BioallethrinR = vinyl, pyrethrin
h
NPh
Ph PhN
Ph
Ph
PhO
Ph
Ph
NRPhPh N
RPhPh
N C
RPh
Ph
NR
PhPh
C
C N R
Ph
Ph
NR
Ph
Ph
The Aza-di--methane (ADPM) Rearrangement
h, sens H3O+
h, sens
*T1
X
NRPhPh
N RPhPh
NRPhPh
-.
C N R
Ph
Ph
NR
Ph
Ph
NArPhPh
NPhPh Ar
SET
+.
Ar = PhAr = 4-OMeAr = 4 ClAr = 3 MeAr = 4 CN
Ar = PhAr = 4 MeAr = 4 ClAr = 3 FAr = 4 CF3
NOHPhPh
NPhPh OMe
NOAcPhPh N
OAc
Ph
Phh, acetophenone sens
SET from "N" lone pair to the alkene moiety is restricted due to low IP of oxime and oxime ether
IP of the oxime can be raised by incorporating Ac group
NOAc
NOAc
NOAc
NOAc
NOAc
N OAc
NOAc
NOAc
NOAcn
N OAc
H
n
n = 1, 2, 3
O
R R
O
RR
O
OAc
O
OAc
O
Ph Ph
O
Ph
Ph
O
H
Ph
Ph
O
Me
O
Me
O
Me
Photorearrangement of cyclohexenones
2
3
4
5
2
35
4
h/ tBuOH
Type A
h
+
+Type Bh
h
OR1
R2
O
HH
R1R2R1
R2
O
O
R2
R1 H
H
OR2
R1
H
H
O
R1R2
Mechanism and stereochemistry of Type A rearrangement
23
4
5
O
Me
O
Me
O
Me nPr
O
MenPr
O
nPrMe
Inversion occurs at C-4
hn
+
Inversion occurs at C-4
# Cleavage of the bond between C4 and C5 of the enone is concerted with dformation of bondbetween C3 and C5 and C2-C4.
# In a formal sense the reaction occurs with inversion at C4 and retention at C5
# In a fuse ketone the rearrangement occurs on only one face of the enonebcause of steric constraints(i.e, the necessary of cis-fusion of the cyclopropaneto both five and six membered ring), hence yielding one product.
O
R R
O
R R
O
R = MeR = H
h
Twisted ( around C=C bond) relaxed excited triplet state of ketone
No reaction
O
C+
O O
C+
O
OAc
O
Competiting reactions
h
AcOH
O
PhPh
O
HPh
Ph
H
O
Ph
H
Ph
H
Ph C
O
PhH
Ph
Mechanism and stereochemistry of Type B rearrangement:Aryl and vinyl migration
hdirect
h-sens+
Major (endo) Minor (exo)
O
Me Ph
O Me
H
O
H MePh
OH
Me
Ph
C O MeH
Ph
O
H
Me
Ph
h
X
PhPh
RR RR
Ph
Ph
C+
PhPh
C
R
R
C+
Ph
C
R
R
h
O O
Photochemical cycloaddition reaction(enone olefin cycloaddition)
+h
enone
1(enone)*
ISC3(enone)*
alkene3(enone-alkene)*
Exciplex
biradical
cycloadduct
h
Chem.Rev; 1988,88, 1453-73
O
n
O
n
O
n
X
Y
W
z
O
n XY
W z
O
n
O
n
O
n
O
n
O
n
hn
ISC
Exciplex
+
ISC
+
Reversion
O
H
C
C
CHO
CHO
CHOO
O
h
fission
closure
abstraction
furopelargone
O OEtCN O
OEt
OCN
O O
OEt OEtO
OEt
CN N O
CN
Regiochemistry of enone cycloaddition
-
h
reversal of polarity
head to tail
head to head
-
-
O
OMe
OMe
O
O
nBu
OAc
nBu
O
OAc
nBu
nBu
O
OEtEtO
CO2Et
O
CO2Et
OEt
OEt
OOEt
OEt
CO2Et
O
SiMe3
OSiMe3
OSiMe3
O
OAc
OO OO
OAc
O
O OOAc
O
O
OAc
O
OAc
O O O98%
+
+
only
+
82.5 17.5
+1 1
+
95 5
96%
81 19
X
O
OO
O
O
CO2Et
EtO OEt
O
OEt
OEt
CO2EtO
CO2Et
OEtOEt
O
CO2Et
EtO OEt
O
OEt
OEt
CO2EtO
CO2Et
OEtOEt
O
CO2Et
EtO OEt
O
OEt
OEt
CO2EtO
CO2Et
OEtOEt
X = Ohead to tail
head to head
+
RT 82.5 17.5-40OC 94 6
+
RT 83.5 16.5-40OC 91.5 8.5
+
RT 71 29-40OC 100 0
O O O
OAc
OAcO
OAc
O
OO
OOO
nBu nBu
O
nBu nBu
O
nBu
nBu
O
nHex nHex
O
nBu nHex
O
nHex
nBu
h
K+
K+
Micelle core
Aqueous phase
cyclohexane 51: 49micelle 78: 22
cyclohexane 53: 47micelle 88 : 12
h
O
Y
YX
O
Y
YX
O
X
z
O
X
z
O OO OO
O
O
Y
Y
O
Y
Y
O
R
Y
Y
O
Y
YR
H
Stereochemistry of enone cycloaddition
+ +
1. ring junction stereochemistry2. exo or endo (Y)3. cis or trans with respect to each other (y)4. effect of remote substituents X
1. ring fusion stereochemistry2. stereochemistry of a wrt b or vice versa3. Remote substituents effect (X and Z)
a b
always cis ring fusion
+ or or or
always cis ring fusion
+
can be cis or transcis is favored
+
rigid cyclohexenones(presnce of heteroatoms, fused ring)
always cis fused ring junction
O
OH
H
OH
H
OH
H
OH
H
always cis
always cis
C
C
C
C
C
C
Regiochemistry of the intramolecular [2+2] photocycloaddition of 1,4; 1,5 and 1,6 dienes "Rule of FIVE"
h
h
h
O
OMe
OOMe
O O
O
O
O
O
O O
Me
O
OMe
O
OMe
O*
R
C C
O
R
Intramolecular enone cycloadditions
h
HH : HT = 0 : 100
HH : HT = 26 : 74
HH : HT = 70 : 30
HH : HT = 87 : 13
HH : HT = 100 : 0
d+
d-
d-
d+
h
h
h
h
OO
H
HO
OMe
H
O O
O OH
H
H H
H
H OH
OH
O OO
enone cycloadditions in organic synthesis
hMeOH
hirsutene
Ph3P=CH2 TsOH
isocumene
+MeLi H+
-caryophyllene alcohol
vinyl chloride, hCO protect
Na/ NH3, H+
TsOH
modhepheneCargill rearrangement
h
h
OH
H
O
H
H
O
H
H
MgBr
H
HOH
O
H H
HO
OO
O
O
+h
+
KH
18-C-6
thermal ring opening
periplanone B
Tet. Lett, 1981, 22, 4651
N
O
O
N
O
O
N
O
O
O
MeO2C
O
MeO2CMeO2C
HH
OH
H
CN
H
OH
h
+
MeOH/H+
(-) Grandisol
JACS, 1986, 108, 306-307
SnMe3
OOP
OP
OOP
OPOAc
O
OP
OP
OOP
OPX
OOP
OP
OOH
CHO
AcO
+-allyl Stille cross coupling
Intramolecular 2+2photocycloaddition
Fragmentation
enolate trapping
elimination
Guanacastepenes
Guanacastepene A
h
JACS, 2006, 128, 7025-35
O
O
H
ONOR
CO2Me CN
NH
O
H
N
O
O
H
H
Dendrobine
O O
Cl
OH Cl
H
OH
H
OH
H
Me
O
H
Me
P
O OEt
OEt
TBHP, SeO2
NCS, DCM
h
Li, NH3LTMP, MeI
LDA, ClPO(OEt)2Li, NH3
Acoradiene
HCA, 1983, 66, 522
(CH2)n
O
(CH2)n
O
H
(CH2)n
O
H
O
CO2Et O O
O
N2
CO2Me
n = 1, 2
MVK, Pyrrolidineh
[6,6,5,4] Fenestrane
NaH, HCO2Et
TSN3, TEA
[5,5,4,4] Fenestrane ester
h
h
Tet. Lett, 1982, 23, 711
O
SiMe3
O
CO2Me
O
CO2Me
O
CO2Et
O
CO2Et
O
h
LAH, Swern
Ph3P=CHCO2Et
Li, NH3
H2, Pd/C
Laurenene
JACS, 1987, 109, 6199
O
OHOH
O
O
O
OTBDPSO
O
OTBDPS
O
OTBDPS
O
R1
R2 H OH
CHOMeO2C R1
R2OH
CO2Me
CHO
O
OH
R1
R2
CO2Me
De Mayo Reaction
+
h
TiCl3
aq. HF
Azulene intermediate
+
methyl diformylacetatetetrahydrocoumalate
h
h
OH H
CO2MeOHC
OAc OAc
H
H
OH
OHC
OMeO
OOAc
OH
CO2Me
OH H
CO2MeOHC
O
MeO
H
H
OH
OHC
OMeO
O
OMe
O O
OH
CO2Me
OMe
O O
CO2Me
O
+h
loganin aglucone acetate
+
Sarracenin
h
O O OH O
O
OH
OAc O O
OAc
O
O
O
O
O
OAc
Cl
Cl
O
Cl
ClOAc
HO
OH
O
O
Cl
Cl
h
base
cis fused
trans fused
acid or base
+ base
h
h
O
OAc
CO2Me
Cl CO2Me
O
Cl
CO2Me
CO2MeO
OH
MeO2C CO2Me
OH
O
OAc
OO
O O O
OAc
O O
OAc
OH
O O
OH
H
OOOO
OAc
O
OAc
O O O
OAcOAc
+h
+
-himachalene
h
h
O
OAc
OOAc OH
CO
MeO
O
CO2Me
O
OH CO2Me
O
OO
O
OH CO2Me
O
OO
OHC
OHC
CO2Me
O
OAc
OO
CO
OH O
CO2Me
O
+base
Pb(OAc)4
+h
methyl isomarasmate
+base
Pb(OAc)4
acorenone
h
h
O O
Ph
OH O
Ph
O OH
Ph
O
CH3
O O
CH3
OHOH
CH3
O
O O
CO2Me
O OH
CO2Me
OH O
CO2Me
CHOOHC
CO2MeOH OMe
CHOOHCOH
OHC
CO2Me
O
CHO
OH
CHOO OH
Non symmetrical -diketones
major
O
O
O
O
O
NOH
OH
NCCHOO
OH
O
O
O
O
O
O
O O
CHO
OH
CHO
+
h+
+DIBAL-H
+X
h
h
h
OBn
OAc O
O
O
OBn
OAc
O
OBn
OAc
O
O
O
OBn
OAc
O
OH
OMe
OH
CHO
CO2Me
NMe
NMe
O
ON
N
O
O
CHO
CO2Me
OH
CO2Me
OH
CO2Me
+
genipic acid
h
+ X
h
h
OH
O
OH
O
O
CHO
O
OH
O
O
CHO
O
+h
valerane isovalerane
+h
O
X(CH2)n
O
OR
(CH2)n
OR
O
(CH2)n
O
O
O
(CH2)n
O
OR(CH2)n
1,3 -dicarbonyl compounds (intramolecular De-Mayo reaction)
X = O, NR
Different templates
O
OH
O OTBS
HO2C
O
O
O
O
OTBS
O
O
O OH
HOTBS
O
O OH
HMeOOBn
O
OH
H
HMeOOBn
H
HOBn
OH
H
+DCC h, MeCN
Stoechospermol
Tet.Lett, 1985, 26, 3035
O
O
O
O
OO
OH
OO
OH
OO
O
OO
O
O
HO
O
OO
H
CO2Me
OO
O
H
CO2Me
O
O
H
CO2Me
O
O
O
h
JOC, 1988, 53, 227
Methyl ester of Pentalenolactone G
COCl N
O
O
O
O
O
OPh
OCO2Ph
O
O
O
O
OAcOAc
O
OAc
OH
O
OMs
O
+
OH-
Longifolene JACS, 1978, 100, 2583.
Intramolecular De-Mayo reaction
-bulnesene
h
h
O
O
O
OTBS OTBS
OH
O Me
Me
Me
Me
Me
Me Me
Me
TBS-Cl, h/Pyrex Me3CuLi2
HF, THF, H2O Ph3P=CH2
RhCl3, 3H2O
BF3:OEt2
Pentalene
O
O
OAc
O
O
OAc
OAc
OO
OAcO
OO
O
O
OH
OTs
OH
OO
Ac2O
+
+
L-selectride
Ts-Cl
KTB
h
O
O
O
(CH2)n
O
O
O
(CH2)n(CH2)n
O
CO2Me
O
O
O
OTBS
O
O
O
OTBS
O
OTBS CHO
O O
OH
OTBS O O
OOTBS
H
Dioxolenones as -keto ester equivalents
h, acetone PTSA/MeOH
hPTSA, MeOH
DIBAL-H
cis:trans = 4:1
CisTrans
OO
O
OO
O
O
CO2Me
H
H
O
H
H
h PTSA/MeOH
Smallest known inside-outside bicycloalkane
OO
O
O OMe
OO
O
OO
O
O
CO2H
O
LDA, MeOPhOCOCN Ac2O, TFA
Acetone
h KOH, MeOH
Ingenane skeleton
O
OO
O
O
NH
O
MeO2C
O
ONH
O O
MeO2C
O
ONH
OH O
MeO2C
NH
O
O
CO2Me
O
NH
OH
h, MeCN
NaBH4
NaH
Perhydrohistrionicotoxin
O
O
OH
O
O
O
O
O
O
O
O
O CO2H
+h
RuO4 KOH/H2O
synthesis of Taxane sceleton (Chem. Lett, 1985, 323)
O
O O
OH
O
OH
O
OH
nPr
O
OTMS
nPr
O
O
nPr
h
TMSOTf HCl, H2O
O
O
O
O
OH
OH OH
O O O O
HO2C
OH
O O O OH
OH
O
O
HO2C
h
MeLi
grandisol
fragrantol
h
h
O
OAc
OOAc
O
OAc
OOOAc OO
OAc
OOAc
OSiMe3OAc
OAcO
O
CO2Me OHO
O
OH OHCHO
OH
n
O
O
h
+ +
+
2278
MeMgI
lineatin
OCO2R
O
H
CO2R
H
CO2R
H
OHOH
H
O P
O
OEt
OEt
OHOH
O
OMeMeO
O
OMe
OMe
O
OMe
C+
OMe
OH
CO
OMeO
OMe OHC
CHO
O
+
epijunenol
+ heatH+
helminthosporal sativine
h
h
Copper (I) catalyzed intra and intermolecular photocycloaddition of alkenes
M + S M-S
hM + P
4s (-acceptor)
3d (-donor)
*
copper orbitals molecularorbitals
olefin orbitals
Schematic energy level diagram for copper (I)-olefin coordination
LMCT
MLCT
Cu+
Cu
Cu+
h, LMCT
Cu++
.-
Cu+
.
.
+ Cu+
h, MLCT
Cu.
+
Cu+
+
Cu+
+
-
+
-
C+
Cu
C+
Cu
CuOTf, h
trans fused
CuOTf, h
trans fused
+
CuOTfh
CuOTftrans fused
1,3 H shift - Cu+
O O
OH OH
O
H
O
H
O O
O
CuOTf, h
exo pdt
The observed selectivity is assumed to arise froma preferential formation of the less sterically crowdedcopper (I)-diene complex, leading to exo pdt.
NaIO4/RuO4
CuOTf, h
CuOTf, h
OH
OH
H
H
OH H
H
OH
HO
HOH
OH OH
Cu+
Cu+
endo (favored)exo
Cu+
Cu+
endo exo (favored)
OH OH
OH OH
OH OH
OH OH
OH
H
CuOTf, h
-panasinsene -panasinsene
grandisol
CuOTf, h
CuOTf, h
CuOTf, h
OH
OMe
OMe
MeO OMe
OMe
MeO
OH
O
H
OH
OH
CHOOHC
CuOTf, h
Robustadial A; H = Robustadial B; H = JACS, 1986, 108, 1311.
OO
Meo
O
O
Photoreduction: Addition to a C-H bond
# Photochemical reduction of carbonyl compounds is a useful complimentary method to the numerous thermal methods
OPh
PhPh2CHOH C
OH
PhPh Ph
Ph
Ph
PhOH
OH
OPh
Ph
Me
C OH
PhPh
CH2.
Ph
Ph
Ph
PhOH
OH
PhPh
OPh
PhCH3OH C
OH
PhPh.CH2OH
Ph
Ph
Ph
PhOH
OH OHH
CH2OH PH
Ph
Ph
OH
OH
H
H
CH2OH
O
Ph
+h
+ + +
+ + +
h
h
OPh
PhMe2CHOH C
OH
PhPh
Ph
Ph
Ph
PhOH
OH
C OH
MeMe
OPh
Ph
C OH
PhPhO
OPh
PhN
Ph C OPh
PhN
+ Ph
C OH
PhPhN
Ph
Ph
Ph
Ph
PhOH
OH
+h
+
+
+h +
O
OH
C OH
OHOH
OH
OH
OHO
h2
coupling
disproportionation
H -transfer
+
+
# which pathway is preferred depends on the radical pair
# nature of H donor and the conditions used for irradiation
O
C OH
OH
O
Ph
C OH
Ph
OH
O
C OH
OH
O
Me
C OH
Me
OH
O
Me
Me
C OH
Me
Me
OH
Photoreduction of the carbonyl * state via hydrogen abstraction
Kr M -1s-1
2 x 106
1 X 103
1.6 X 106
1.6 X 105
3.2 X 104
H
HOMO
C. O.
*
n
* LUMO * LUMO
H
HOMO
First excited state (n*)
X
H
In plane approachPerpendicular approach
XH
C. O.
*
n
* LUMO
H
HOMO
First excited state (*)
X
H
In plane approach
O
O.
H
X
C. O
H .X
H
E1
E2
OR
OR
O
Ph
O OH
Ph
O
OH
Ph
O
PhOH
Ph
O
O
O
Ph O
O
OHPh
O
O
Ph
Ph
O
OHHPh Ph
h
h
h
h
h
Intramolecular photoreduction
O PhPhC
OH PhPh OHPh
Ph
O
NMe2Ph
OH
H
NMe2
Ph
OH H
Ph NMe2
C O NMe2
Ph C C O NMe2
Ph
N
O
Ph
Ph
CO2Me
z
OH
N
CO2Me
z
PhPh
NOH
z
CO2Me
Ph
Ph
h
+
+h
h
Ar2C=O*(T1) RCH2NR'2
Ar2C=O RCH2NR'2 Ar2C.OH RC.HNR'2
ArNR'2
Ar
OHR
Ar
Ar
OHOH
Ar
Ar
Photoreduction of carbonyl (n*) state via electron and charge transfer
+ Ar2C.-O- RCH2N.+R'2
back electron transfer
+
Kh
Proton transfer
+Disproportionation/back H transfer
+
OON
H H
H
O N+
H H
H
n
n
n
n*
O
O
N O
O
Competition between H-abstraction and charge transfer
XAN(n*) AZAX(*)
Tol m-Xyl Mes Dur
Quencher
# the rate constants for photoreduction by CT are higher than those expected forH abstraction# The quantum yields are solvent-polarity dependent# Direct spectroscopin evidence proved it
COMe CH3
COMe CD3
COCF3CH3
COCF3CD3
Deuterium isotope effects quenching constants (H abstaction or ekectron transfer)
Kq
1 X 105
0.2 X 105
7.5 X 106
7.5 X 106
H-abstraction
Electrontransfer
NH
N
O
O
R
R'
N
N
NH2
O
R
N
N N
N
NH2
R
NH
N N
N
R
O
NH2
DNA photochemistry
Ura R ' = H R = HUrd R ' = H R = riboseUMP R ' = H R = ribose phosphate
Thy R ' = Me R = HThd R ' = Me R = deoxyriboseTMP R ' = Me R = deoxyribose phosphate
Cyt R = HCyd R = riboseCMP R = ribose phosphate
PYRIMIDINES
Ade R = HAdo R = riboseAMP R = ribose phosphate
Gua R = HGuo R = riboseGMP R = ribose phosphate
PURINES
260 nm ( *)270 nm ( *)
N
NH
N
N
O
OH
NH2
O
O P
O
O
O
O
OH
O
O
N
NH
N
N
O
OH
NH2
O
O P
O
O
O
O
OH
O
O
H
HH
O
N
NH
N
N
O
OH
NH2
O
O P
O
O
OO
OHO
N
NH
N
NH
O
OH
O
O P
O
O
O
O
OH
O
O
H
HH
O
O
N
N
N
N
O
OH
NH2
O
O P
O
O
O
OHO
OH
h
heat
Possible photoreaction at dipyrimidine sequences (CT); cyclobutane and oxetane formation
h
N
NH
N
N
O
OH
NH2
O
O P
O
O
O
O
OH
O
O N
NH
N
N
O
OH
O
O P
O
O
O
O
OH
O
O
NH2
H
OH
H
H
O
N
N
N
N
O
OH
NH2
O
O P
O
O
O
OHO
OH
O
N
N
N
N
O
OH
NH2
O
O P
O
O
O
OHO
OH
O
N
N
N
NH
O
OH
O
O P
O
O
O
OHO
OHO
N
NH
N
NH
O
OH
O
O P
O
O
O
O
OH
O
O
OH
H
OH
H
h heat
hheat
N
N
N
NH
O
OH
O
O P
O
O
O
O
OH
O
N
N
NH2
O
N
NH
O
OH
O
O P
O
O
O
O
N
NNH2
NN
OH
N
N
N
N
O
OH O P
O
O
O
O
OH
N
N
NH2
N
N
NH2
N
N
O
O
O
PO O
O
OH
N
N
N
N
NN
NH2
NH2
h
Cycloadditions involving adenine; Cyclobutane and azetidine dimer formation
h
N
N
O
O
N
N
O
O
H
OH
HN
N
O
O
OH
N
N
O
O
H
H
NH
NHN
N
O
O
H
H
O
OH
H
N
NH
O
OH
OHO
O
NH2 NH
CO2H
O
NH
O
NHO
OH
OH
NH
N
O
O
NH2
CO2H
O NH2OH
OH
h
EtOH+
h
Thy
h
Lysine
heat+
radical and nucleophilic photochemical addition reaction of thymidine derivatives
N
NO
NH
NO
H
X
X
NH
N
O
O
OH
HN
N O
N
N
NN N
NH
O
O
NH2
N
NO
NH2H
H
H
OH
NH
NO
OH
H
OH
Me NH
NO
OOH
H
OH
Me
Structures of the major photoproducts induced by UVR
Cyclobutyl pyrimidine dimer Dewar pyrimidinone
Adenine-thymine heterodimer
Cytosine photohydrate
Thymine phohydrates
N
N N
N
O
O
O
O
R2
R3
R2
R3R1 R1
H H
N
N N
N
O
O
O
O
R2
R3
R2
R3R1 R1
H H
N
NN
N
O
O
R2
R3 R1 R1
H HO
O
R3
R2
N
NN
N
O
O
R2
R3 R1 R1
H HO
O
R3
R2
N
NH
OHO
O
Cl
ClCl
Cl
N
N
NH
N
O
O N
NH
N
O
ON
NH
N
O
O
(CHOH)3
OH
DNA repair: photochemistry
Cis-syn trans-syn Cis-anti trans-anti
structures of the pyrimidine dimers and abbreviations
c-s[TT]; c-s[DMTD] c-s[DMTD]; c-s[DMUD] c-s[DMTD]; t-s[DMTD]; c-a[DMTD]
c-s[TT] c-s[TT]c-s[TT]
Dimer splitting sensitizers
N
NO
N
NO
O
O R
N
N
O
O
N
N
O
O
R
NH N
H
MeO
NH
H
OMe
OMe
h
+
Dimer splitting by covalently linked sensitizers
R =
X
N
NH
N
O
ONH
NH
NH
NH
O
O
O
O
X
N
C NH
N
O
ONH
N NH
NH
O
O
O
O
NH
N
O
O
NH
NH
O
O
NH
NH
O
O
X = N, CH
+ Complex
h
1 flavin----------Thymine dimer
3 flavin----------Thymine dimer
electron transfer+
radical pair
+1 e from
flavin
2
Possible mechanism for flavin as sensitizers for dimer photomonomerization
N
N
N
O
N
N
O
OO
HO2C
NH
O
NH
N
O
OOH
CH2
Intramolecularly photosensitized dimer splitting by a deazaflavin (irr = 436 nm)
NNR2
NH
N
N
NN
N
O
O
O
OBu
Bu
HH
NH
N
CONCOR1
CO
CO
N COCOR1
R2
NH N
H
MeO
Dimer Splitting by noncovalently bound chromophores
R1 =
N N
NHMe
OH
O
O
CH2
CHOH
CHOH
CHOH
O POH
O
OR
N N
NHMe
OH
O
O
N
N
O
OHOH
N
N
NH2
Photo reactivating enzyme (PRE) or photolyase (EC : 4.1.99.3)
1
3
5
8-hydroxy-5-deaza-isoalloxazine
Reduction
e- 1
3
5
8-OH-5-deaza-isoalloxazine H2
+ Dimer splitting
Scenedesmus acutus (green alga)
Bioluminescence
Artistic rendering of bioluminescent Antarctic krill
Fireflies
Firefly luciferin
N
SOH
N
S
OHOxyluciferin
Image of bioluminescent red tide event of 2005 at a beach in Carlsbad California showing brilliantly glowing crashing waves containing billions of Lingulodinium polyedrum dinoflagellates
CHO NH+
P
NH+
P
N
P
CHO
CHO
Chemistry of vision
Cys-NH2 h
Rhodopsin
Bathorhodopsin (contains all trans retinal)
H+
Metarhodopsin II
11-cis retinal
Opsin
H3O+
Opsinall trans retinal
retinal isomerase
11-cis retinal
OHNH
O
NH
OOOH
NH
OHNH
O
N
OOHOH
NH
N
N
OH
O
O
OHNH
N+
N
OH
O
O
OHNH
H
Nature's Fluorophore (GFP)
-H2O
O2
Fluorophore (absorb = 397nm, emit = 509 nm)
Aequorea victoria (Pacific jellyfish)
Ser-65
Tyr-66 Gly-67
Photochemical aromatic substitution reaction
Electron rich
SE is more common than SN reaction
# Majority of SE reaction is of SEAr type
# Arenium ion or -complex is the intermediate
# SE1 mechanism follows (leaving group departs before electrophile arrives)
SNAr type reaction
# Meisenheimer complex
# Electron withdrawing group favored the reaction
# SN2 mechanism follows
L
EWG
L
EWG
L Nu
-EWG
Nu
EWG
hn
ex
Nu- - L-
# Fomation of exciplex (usually triplet state)
# Formation of -type complex
# the rate determining step is addition of nucleophile to the leaving group bearing carbon atom
L : Leaving group; EWG : Electron withdrawing group; Nu: nucleophile
Mechanism of SN2Ar* reaction
NO2
OPO3=
18 OH-
NO2
O18-
HPo4=
NO2
OPO3=
MeNH2
NO2
NHCH3
HPo4=
NO2
OMe
OH-
NO2
O
MeOH
h
H2O+
+
+H2O
+
+H2O
+h
h
OMe
OMe
NO2
OH
OMe
NO2
OMe
OH
NO2
X
NH2 NH2
NO2 X
NMe2
NO2
NMe2
OH-
H2O/THF
heat
h
h, NO2-
MeOH
X = Cl, Br, I
h, NO2-
MeOH
NH2
SO2X
NH2
Nu
R
Cl
R
SO3Na
h/Nu-
X = NH2, Me, CF3
Nu = CN-, NO2-, SCN-, MeO-
h/Na2SO3
R = NH2, NMe2, OH
OMe OMe
CN
OMe
CN
OMe
OMe
OMe
CN
OMe
OMe
OMe
CN
h, CN-
MeOH+
tBUOH
MeOH
h, CN-
h, CN-
NO2CN
NO2 CN
CN
CN
h, CN-
MeCN/H2O
tBuOH/H2O
tBuOH/H2O
tBuOH/H2O
h, CN-
h, CN-
h, CN-
L
EWG
L
EWG
-.
L
EWG
L Nu
-EWG
Nu
EWG
Alternate mechanism SN(ET)Ar
h Nu-Nu.
-L-
OMeOMe
NO2
NHhexOMe
NO2
OMeNHhex
NO2
NO2
OMe
NHhexO2N
GlyEtMeO
NH2CH2CO2Et
n-HexNH2
SN(ET)Ar*
SN2Ar
+ n-HexNH2
SN(ET)Ar*
SN2Ar
L
EDG
L
EDG
.+
L
EDG
L Nu
.EDG
Nu
EDG
.+
Nu
EDG
h Nu-
-L-
SR+N1Ar* mechanism
-e-
ArL
L : Leaving group; EDG : Electron donating group; Nu: nucleophile: ArL: ground-state substrate
CN
OMe OMe
CN
OMe OMe
CN
NO2 OMe
Synthetic applications
h, KCN
Bu4N+CN-/ MeCN
h, CN-
tBuOH/H2O
h, CN-
tBuOH/H2O
h, NaOMe
MeOH
NO2
OMe
NO2
OMe
N O
NO2
OMe
NH2
OMe
OMe
NO2
OH
OMe
NO2
OMe
OMeO2NOHO2N
OMe
h, OCN-
H2O, O2
H2O
h, OH-
MeCN/H2O
h, OH-
MeCN/H2O
Photochemical reactions with singlet Oxygen
1O2
1O2O2h
?
The fate of singlet oxygen
# deactivated by chemical acceptor
# physical quenching is possible by solvent and sensitizer
# 2+2, 4+2 cycloaddition and ene reaction are the probable reactions
# Nonpolar solvents (halogenated or fluorinated hydrocarbons) suppress electron transferreaction hence increase the lifetime of singlet Oxygen
# Weak electron acceptors TPP, metaloporphyrins, with low triplet energies should used as sensitizers. RB is possible (in polar solvents) in some cases, use of MB should be avoided.
# Regio and stereoselectivity for certain transformation should be determined directly at the peroxide stage. In many cases further transformation (reduction, rearrangement and cleavage) clearlychange the regio as well as stereochemistry of the products.
OH OHOH OH
(+)-Limonene
MeOH/RB
O2, h/redn+ + +
31% 11% 25% 21%
CH3
CH3
CH3
X
Y
O X
O Y
CH3
CH3
OMe
CH3
CO2R
CH3CH3
SOR
CH3
CH3 CH3
tBu
CH3 CH3
tBu
General effects controlling the regioselectivity of allylic oxidations of C-C double bond
(53) (40)
(7)
1O2
(>98)
(<2)
Cis effect
(<2) (>98) (<2) (>98)
Geminal effect
(34) (66) (17) (83)
Large group effect
Me
HD
PhPri
D
Ph
Me
OOH
PriH
Ph
OOH
Me
Pri
Me
H
OSiRMe2Me
CN
OSiRMe2
Me
OOH
MeNC
Me OOH
H
OSiRMe2
CN
Acyclic substrates
Acetone/ R.B
R.T/ O2/ h+
CCl4, TPP
h, O2
+
CO2MeCO2Me
OOH
CO2Me
OOH
-unsaturated carbonyl compounds
CHCl3/TPP
0oC/ O2/ h+
E dr = 90:10Z dr = 65:35
OH
OH
OH
OH
OMeCO2H
Cycloalkenes with excocyclic C-C double bond
MeOH, RB/ RTO2/ h
Na2SO3
+ +
35 12 23
OH
OMeCO2H
H
OH
OMeCO2H
OOH
H
OH
OMeCO2H
H
MeOOOH
H
O
O
O
O
H
HH
H
DCM/ MBRT/ O2/ h
MeOH/ RB
-78oC/ O2/ h
HCO2H/ DCM
qinghaosu
OSiMe3 O
OOSiMe3
O
OSiMe3
R
R'
OOHOH
H
OO
OH
HHOOH OOH
CCl4/ TPP
O2/ h
Ph3P
O2/ h
R' = H, R = OHR', R ; = O
EtOH/MB/O2/h +
Major
Ph
Ph
Ph
Ph
O
OPh
Ph
Ph
Ph
O
OPh
Ph
Ph
Ph
O
O
O
O
O
O
O
O O
O
O
OO
O O
O
O
O
Photooxygenation of 1,3-dienes
1O2
+
1O2 1O2
+
1O21O2
H
H' H
H'
H
H'H
H'
tBu O O
tBu
O O
1O2
62%
1O2
23%
n
(CH2)n
OO
X O
O
X
1O2
1O2
X = CH2, (CH2)2, CH=CH
O OOO
Ph
OO
OO
Ph
1O2
1O2
O
O
OO
OO
O
O
OO
OH
OMe
OOH H
S
S
OO
S
OO
1O2 heat
+
MeOH
Ph3P
1O2 HN=NH
(CH2)n O
O
(CH2)n
Chemoselectivity in photooxygenations of 1,3 dienes
3 factors controlling the reactivity
# the amount of s-cis conformer in the equlibrium necessary for 4+2
# the relative reactivity difference of the C-C double bonds
# the appropriate alignment of allylic H for ene reaction
1O2
+ ene products
n = 1 16 84n = 2 20 80n = 3 22 78n = 4 50 50n = 5 67 33
MeOH/DCMRB
O
O
OOH
Me
H
H
H
Me
H
1O2
1O2
OMe
OMeO
O
OMe
OMe
OMe
OMeO
O
OMe
OMe
OMe
CHO
OMe
OMe
OO
1O2
1O2
+
O
O
OOH
OO
OOH
OOH
OOH
OO
OtBu
OMe O
O
OtBu
OMe
OtBu
OMe
1O2
MeOH+ + +
1O2
+
1O2
-Myrcene
-Myrcene
1O2
+
Ar OO
Ar
H
OO
H
Ar
OH
OH
ArN
NH Cl
h/O2 +
epibatidine
OH
OH
OTBS
OTBS
OTBS
OTBS
O O
OH
OH
O
OH
OH
OH
OH
OH
MeO
1O2
Pinitol
h
O
O
OH
OH O
O
OH
OH
O
O
O
O
O
O
OOH O
+
ab
c
d
e
fg
a, b, c; Reductiond, e; Thermolysisf; Deoxygenationg; Acid/base Catalyzed reactions
Photo removable protecting groups
R S
O
O
OR' R S
O
O
OR' R .SO2OR
R H
SO2.OR
R OH
OTs RSO2O OTs
O
OHOTs
OO
OH
O
O
O
OR
O
O
O
OTs
O
O
O
O
O
O
OTs
O
h
H abstraction fromsolvent
proposed mechanism for photochemical reaction of sulfonates
R = Ts
O
OTsO
O
OCHPh OMe
O
O
O
OCHPh OMe
O
OHO
O
OCHPh OMe
OTs
O
OTs
O
O
O
O
O
OSO2CF3O
O
O
O
H
H
X
h/MeOH
hNo deprotection observed
h/ (Me2N)3PO
H2O
h/MeOH
CH2OR
NO2
NO
CHO
CH.OR
N+
O
OH
CHOR
N+
OH
O
NO
H
OR
OH
O+
N H
H
OR
O
hROH +
proposed mechanism for the photochemical cleavage of o-nitrobenzyloxy compounds
Acinitro intermediate
n-
O
O
O2N
OH
OH
OHO
O
O2N
OHOH
OH
Me
O ONO2
RR
OH
OH
OH
OH
O ONO2
ROBn
OBn
BnO
OBn
MeO
OB
OR O
NO2
OH
R = H, OMe
N
N
OO P
O
O
O P
O
O
O P
O
O
O
OHOH
H
N
N
NH2
NO2
OH O
O
NH2
O CO2-NO2
O O
NN
CO2- CO2- CO2- CO2-
NO2
N
N
OO
OH
N
N
NH2
O
PO
O
NO2
O-Nitrobenzyl group known as Caged group
Caged ATP Caged glutamic acid, neurotransmitter
Photocaged Ca2+
Photolysis release Ca2+Caged cAMP
Ca+2
O
X
X
NH
O
NHO
NO2
OH
X
X
NH
O
NHO
h
365nm
X = H, TyrosineX = D, [D2] Tyrosine
Photodeprotection of o-nitrobenzyl adducts to yield natural amino acids
RO NO2RO. .NO2 R OH
O
O
O
O
O
R1
R2
O
O
O
O
O
ONO2
O
O H NO2
O
OOH
NO
O
OOH
NO2
radical quencher
photochemical removal of nitrate group
R 1 = H; R2 = ONO2, 100%
R1 = ONO2; R2 = H, 92 %
h/ MeOH TFA
h
O
OCH2OH
NO2
O OMe
O O
NO2
AcOO OMe
O O
NO2
AcO
OMe
O
OAc
OO
O2N OMe
O
OAc
OAc
O
O
NO2
OMe
O
O
O
NO2
OMeO
O
O
NO2
O
C O
N+
O
OH
N+
O
O
O
OH
NO
O
OOH
NO
O
O OH
OO
NOH+
O
Proposed mechanism for the photochemical rearrangement of o-nitrobenzylidine acetals to o-nitroso benzoates
NO2
O
O
OR
N O
OH
C O
O
OR
H
N
O
OH
O
O
OR
O
O
OR
NO
OH
NO
CHO
CO2 ROH
O
O
OR
NO2 N
O
OH
O
O
OR
NO2CO2 ROH
o-nitrobenzyloxycarbonyl (NBOC)
+ +
2-(o-nitrophenyl)-ethoxycarbonyl [NPEOC]
+ +
S
O
N
NH
O
O
O
O
OH
NO2
O
O
S
O
NO2
CO2
N
NH
O
OH
OH
O
O
1. light absorption andintersystem crossing
Covalent linkage
2. Energytransfer
3. H- Transfer
4. -elimination and fragmentation
+ +
Intramolecular sensitized photocleavage of a protecting group of NPPOC type
O
O
OR
NO2
S
O
O
O
OR
NO2
O
O
OR
NO2
S
O
O
O
OR
NO2
S
O
S
O
O
OR
O
NO2
S
O
O
OR
NO2
O
S O
O
O
O
OR
NO2
O
NPPOC Protecting group
Overview of different covalent linker attached with NPPOC group
Angew. Chem. Int. Ed. Engl, 2006, 45, 2975-78
OO
O
OO
NO2
O
OO
NO2
OH
OO
NO2
O
O
Cl
OOH B
OHO
O
NO2
O
O
ClOO B
OH
O
O
OO
NO2
OO B
O
O
O
OO
NO2
PO
O
OMe
CN
OO
O
OOH B
O
PO
O
OMe
CN
MeNPOC [(-methyl-2-nitropiperonyl)-oxy] carbonyl
COCl2, THF
+Pyridine
h+ + CO2
JACS, 1997, 119, 5081
R O
O
ArR
C O
Ar O
ArOH RCO2H
RH CO
OH
COR
OCOR
R1 OCOR2
NH2
HO2C
O oNB
NH
O
NH
CO2Et
O
OtBu
O oNB
S-H
+
or
+
Proposed mechanism for the photochemical cleavage and rearrangement of aryloxy esters
R = Ph, Me, CCl3, CPh3, 9-Fluorenyl
Photo fries rearrangement
h
OH
OH
NO2
R1 R2
O
NO2
O
O R1
R2
O
O
NOH+
O
R1
R2
N+
O
O R1
R2
O
OH
O
O R1
R2
NO
OH
OH
O
NOR1 R2
O
photochemical deprotection of ketones protected as ketals of 1-(o-nitrobenzyl)-1,2-ethane diol
+h
+
R1
O
NO2
O
R2O
NO2
O
R2
O2N
NH
O
R
NO2O
NH
(P)
Photochemical deprotection of carboxylic acids and amides protected as o-nitrobenzyl ester and amide derivatives
R1 = H, R2 = PhR1 = ph = R2R1 = Ph, R2 = (CH2)14 MeR1 = Ph, R2 = Bn
R2 = Ph, Bn, CH2-naphthyl, -Boc Ala, Boc-Phe
R = Boc-GlyR = Boc-ValR = protected decapeptide
O
OCOR'
R"
R
OR
R
R'CO2H
OMe
OAc
C
O
O
OAc
HOMe
MeOC
O
OAc
O
OAc
OMe
O
MeO
H
O
MeO
Carboxylic acid
h/ C6H6
+
R = OMe, R " = H
SOCOR
NO2
NO2 N+
S+ O
O
R
O
O
NO2
S+
NO2
NO2
RCO2-
S
NO2
NO2
RCO2H
h+
C6H6
+
proposed mechanism for the photochemical cleavage of dinitro phenylthio derivatives of carboxylic acids
R1 S
O
O
NR2
R3
R1. S O
O
NR2
R3
SH
S
O
O
NR2
R3H N
R2
R3H
SO2. N R2
R3
h
-SO2
SH
Proposed mechanism for photochemical reaction of sulphonamides
O P
O
O
O
NO2
OH
NO2
O P
O
O
O
O P
O
OH
OBn
O2N
O2N
OO P
O
O
O
O O
N
N
N
N
NH2
NO2O2N
h/MeOH+
photochemical deprotection of phenol phosphates
S
NH
SS
NS
O
R
S
NS
O R
R OR'
O S
NH
S
S
NS
O
H
R'R
S
NC SH
O
C
R'
R
R
R'O
R
R'O
OR2
RCOCl/ NaH
h/ R'OH
+
Photolysis of N-acyl-2-thionothiazolidines
h
R2OH
Photochemical activation in N-Acyl-2-thionothiazolidine
S
S H HO
SS
R2
R1R3
R2
R1R3
O
h
Photolytic dethioacetalization
h
ONOH
O H
NOC O
H
NO
OHON
OHN H
OHOHN
+N
+ OHO
O
Remote functionalization by Nitrites: The Barton Reaction
h+ +
+
heat
ONO O H
C
OH
C
OH
OHNO
six membered cyclic TS for hydrogen abstraction
+ NO.+ NO.
O
OH
OOAc
H
H HO
O
OOAc
H
H H
NO
O
O
OOAc
H
H H
H
O
OH C O
OAc
H
H H
O
OH
OOAc
H
H H
ON
O
OH
OOAc
H
H H
N
OH
O
OAc
H
H H
OO
OH
NOCl/ Pyrh, PhMe
H atom abstractionNO
tautomerization
HNO2
Aldosterone 21-acetate
OH O N O
OH
N
OH
O
OH
OH
H
NOCl
Pyr, 0oC
h, n-hexane, RT
iPrOH, reflux
Grandisol
Magnus et.al, 1976, JACS, 98, 4594
O
OH
OHOH
OH
OH
OAc OAc OAc
O
OAc
O
OAc
OHC
OH
-cleavage
Norrish type-I
H
H
O
H
ONO
H
H
O
H
O
C H
H
O
H
O
H
H
O
H
NOHO
h
ONO O
N
OH
O
N
H
OH
R
R
ONO(CH2)n R
(CH2)n
R
NO
O
h
benzene
X
CS2
h
H
ONO
H
H
O
H
C
H
O
H
H
H
H
O
C
H
H
OH
H
H
OH
N OH
h
benzene+ .NO
H
OHR2R1
H
OR2R1
S
X
H
OHR2R1
H
OHR2R1
H
OHR2R1
NN
H
OHR2R1
Barton-McCombie reaction [R1R2CHOH to R1R2CH2]
2,4,6-Cl3C6H2OC(S)Cl, Pyr[X = 2,4,6-Cl3C6H2O]
NaH, CS2, MeI
[X = SMe]
C6F5OC(S)Cl, Pyr[X = C6F5O]
Im2CS, THF
X = PhOC(S)Cl, Pyr[X = PhO]
H
OR2R1
S
X
H
OR2R1
S
X
.Sn-nBu3
H
OR2R1
C S
X
Sn-nBu3
R1
C R2 H
S
XO
Sn-nBu3H
HR2
R1.Sn-nBu3
H
OR2R1
S
X
nBu3SnH, h
+nBu3SnH
+
R Cl
O
N
SO-Na+
R ON
O
S
R ON
O
S
.R
R ON
O
C
S R
N
SR
CO2.R
Barton's thiohydroxamate ester chemistry: synthesis of alkyl pyridyl sulfides
+ N-Hydroxypyridine-2-thione sodium salt
DMF or POCl3
thiohydroxamate ester
h
++
N
SO
R
R-Cl
R-BrR-I
R-SPh
R-H
CCl4
BrCCl3
PhSeSePhRSePh
CHI3
PhS-SPh
nBu3SnH O2
R-OH
Barton's Thiohydroxamate ester chemistry: Use of neutral molecule radical traps
O
ON
S
S
O
ON
S
S
O
ON
C S
S
C
SS
NC
C
h
-CO2
+5-exo-trig
A K
B
Organocatalytic enantioselective photoreactions (OCEP)
A
A-K
Bh (S)
B*
AB
K
The photochemical excitation and the enantioselective key step are decoupled
# Reactants A & B do not react with each other (or if they do so very slowly in GS or ES)
# One of the reactants B is, through sensitization (S), converted into excited state B*
# While A forms a complex A-K with the chiral catalyst (not necessarliy covalent)
# The complex A-K now reacts with B* because of its changed electronic properties to give B-A-K
# Complex B-A-K dissociates into product A-B, releases K and the cycle continues.
R1
O
R2
R3NH
R4
CO2H
R1
R2
NR3
R4
CO2H
R3N
R1
R2
COO-
R4
OOH
R1
O
R2
OOHR1
O
R2
OH
1O2
3O2
h, TPP
J. Am. Chem. Soc, 2004, 126, 8914Angew. Chem. Intl. Ed. Eng. 2004, 43, 6532
SK*
A B
SK
A* B A B
SKh
SK*
A + B
PET
#The central role is played by a chiral complexing reagent SK
# Which at the same time acts as a sensitizer and transfers th energy to the substrate
# After the excitation of SK, a complex with A and B is formed, in which the excitation energy is transferred
# the enantioselective key step then occurs, and SK is released again
# The important points of this approach are high facial differentiation in the complex SK-AB and the exclusion of intermolecular sensitization
CO2HCO2HCO2H
NH
O ON
NH
O ON
O
Ph
NO
H
N O
H
Kemp's triacid
X
NH
O
OMe
R
R
H
O
OMe
R
H
O
OMe
R
H
O
OMe
R
H
O
OMe
NONO
HNH
O
OMe
ONNO
H
h
R = CH2CH2CH2OHR = CH2OAcR = OAcR = PhR = CO2Me
endo
exo
JACS, 2000, 112, 11525
NH
O
O
NH
H
O
OH
NONO
H
NH
O
OMe
ONN
O
H
NH
O
O
NH
O
OH
h
h
93% ee
> 90% ee
JACS, 2002, 124, 7982
NH
O
N
ON
O
Ph
NOH
NH O
N
ON
C O
Ph
NOH
NH O
N+.
ON
C OH
Ph
NOH
NH O
N
C
ON
O
Ph
NOH
NH O
N
NH
O
N
PET
h
ISC
-H+
70% ee
Nature, 2005, 436, 1139
N
NH NH
OR
R
Me
OO
COPh
NH
O
O
NH
O
O
N
NH NH
OR
R
Me
OO
NH
ON
NH NH
OR
R
Me
OO
O
NH
O
O
Facial differentiation or complexation is key to enantiocontrol
R =
CDCl3
h
19% ee J.Org. Chem, 2003, 68, 15
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