Photochemistry

and
Applications in Synthesis
Jason M. Rohde
September 1, 2004

Photochemistry
-chemical reactions initiated by light
-energy is absorbed or emitted by matter in discrete
quanta called photons

E = h = hc/
short light corresponds to high energy
-absorption of light leads to an electronic excitation
(ground stateexcited state)
-promote an e- like n or
-most chemistry takes place from S1 and T1 excited
states
S1 have a shorter lifetime
and higher E (10-9 to 10-5)

T1 have a longer lifetime

b/c spin flip req. (10-5 to 10-3)

Photochemistry
-If a molecule absorbs energy, it can undergo a reaction or
undergo loss of energy by two methods:
radiative processes-involve emission of a photon
-phosphorescence-relaxation to a lower state with different
multiplicity, such as T1S0 (spin forbidden)
-fluorescence-relaxation to lower state of same multiplicity,
such as S1S0 (spin allowed)
non-radiative processes-no emission
-internal conversion-involves no spin change, such as S1S0
-intersystem crossing-involves change in spin multiplicity
one way competes with phophorescent decay of the lowest triplet
state to the ground state
another way converts the lowest excited singlet state to the lowest
triplet state (competes with fluorescence and IC)[gives access to
triplet state]
-Excitation by E transfer is Sensitization (deactivation is Quenching)

Geometrical Isomerism
R

h
R

-cis/trans (E / Z) isomerism under photochemical conditions

commonly leads to thermodynamically less stablecis-isomer
-cis-isomer typically absorbs at a lower due to decreased
conjugation b/c of non-bonded interactions
-reactions come to photostationary state unless optical pumping
is performed (irradiation of just 1 isomer to drive the equilibrium)
h

w/o sensitizer photostationary state: E / Z : 8/92

w sensitizer photostationary state: E / Z :50/50

Geometrical Isomerism
h
2-C10H7COMe
5%

95%
Ph

Ph

h
toluene

Ar

Ar

Ar
Ar

-ionone

h, quartz
EtOH
>180nm

6-elec.

-pyran: G. Bchi and N.C. Yang J. Am. Chem. Soc. 1957, 79, 2318.

-pyran

Geometrical Isomerism
h

O
O

h, uranium
DCM, -75C
77%
>340nm

10:1

h, pyrex
cyclohexane
70%
>285nm

H. Dorr, V. Rawal J. Am. Chem. Soc. 1999, 121, 10229

O
H

O
H

5:1

Electrocyclizations

-reactions generate a new -bond between the termini of the

conjugated -system
-concerted process-bond breaking occurs at the same time
as bond formation
-reactions also come to photostationary state based on
absorption coefficient at the of irradiation

Thermal Reactions
-occur via HOMO
4n - conrotatory
4n + 2 - disrotatory

Photochemical Reactions
-occur via LUMO
4n - disrotatory
4n + 2 - conrotatory

4-Electrocyclizations
h
H
H

4-electrocyclizations
occur with disrotatory
ring closure under
photochemical
conditions

254nm
95%
h
O

59%
O

H
O

O
O

Fe(CO)5

Fe
OC

CO
CO

8 and 6-Electrocyclizations
8-electrocyclizations
occur with disrotatory
ring closure under
photochemical
conditions and
6-systems undergo
conrotatory ring
closure

C9H17
C9H17

C9H17
H

h
H
HO

>20C
1,7 H-shift

6
HO

Ergosterol
(provitamin D)

Precalciferol
(previtamin D)

HO

Vitamin D2
(calciferol)

6-Electrocyclization in Synthesis
H
N

O
H

H
O
H H

H
N
H
OH

Ikarugamycin
Wittig Reaction
1. h, -78C, hex.
2. HCl

H
O
H

50%

H
OH

H H

J. Whitesell and M. Minton J. Am. Chem. Soc. 1987, 109, 6403

OH

OH

4:1

H H

OH

retro-6-Electrocyclization

H2
Raney Ni

h
H

O
O

MeOH
-18C
1:1

O
O

E. Corey and A. Hortmann J. Am. Chem. Soc. 1963, 85, 4033

MeOH
-15C

O
O

dihydrocostunolide

Di--methane rearrangement
-Howard E. Zimmerman has studied this reaction extensively
-Reaction takes 1,4-dienes or 3-phenylalkenes to vinyl or phenyl
cyclopropanes

h
61%
barrelene

semibullvalene

h
66%

Oxa-di--methane rearrangement
R2

R2 R3

R2 R3

R1

O
O

R4

R5

R1

R5

R1

R4

R4

h
pyrex
t-BuOH
50%

h
acetone
70%

R3

R5

O
R1

R2

R4

R3
R5

Di--methane rearrangement in Natural Products

OAc

H
O
AcO

OAc

OH

Cl

AcO
O
O

erythrolide B

quartz
PhH
87% conv
in 3 hr
or
5% methanolic
seawater
(glass)
with
sunlight
37% conv
in 8 days

O
AcO

H OH
Cl
AcO

O
O

erythrolide A

S. Look, W. Fenical, D. Van Engen, J. Clardy J. Am. Chem. Soc. 1984, 106, 5026.

Oxa-di--methane vs. 1,3-Acyl Migration

O
O

h
O

254nm
acetone

300nm
hexane
50%

62%

O
OMe

steps

h
pyrex
THF
59%

MeO
O

X = O pinguisone
X = H2 deoxypinguisone

T. Uyehara, Y. Kabasawa, T. Kato Bull. Chem. Soc. Jpn. 1986, 59, 2521

1,3-Acyl Migration in Natural Products

O

h
quartz
PhH
3h

calyculone D back 8.8%

calyculone E 6.2%
O

cembratriene 10.6%

J. Shin, W. Fenical J. Org. Chem. 1991, 56, 1227

calyculone F up 10.6%
calyculone G 15.9%
O

cembratriene 11.5%

[2 + 2] Cycloaddition
-[2+ 2] photocycloadditon is the cyclization of two olefinic units to
provide a cyclobutane (generate 2 new C-C bonds and up to four
new stereocenters)
-1908 Ciamician observed the first [2 + 2] reaction when exposure
to Italian sunlight for 1 year generated carvone camphor from carvone
O

h
O

carvone

carvone
camphor

-photochemical conditions create charge like umpolung

of enone (-carbon is electron rich)
-intermolecular variants also well known, but regioselec.
can be highly dependent on both olefinic partners
-this [2 + 2] follows the "rule of 5" and none of the other
regioisomer is observed

not observed

"Rule of 5"
O

O
H

not
observed

70%
O

h
O

[2 + 2] Cycloaddition in Synthesis
O

H
H

Et2O
72%

2:1

H
O

O
O

O
O
O

0C
CH3CN/
acetone
(9:1)
80%

steps

periplanone B
O

O
O

periplanone: S. Schreiber, C. Santini Tetrahedron Lett. 1981, 22, 4651

saudin: J. Winkler, E. Doherty J. Am Chem. Soc. 1999, 121, 7425

O
O

saudin

de Mayo Reaction

O
CO2Me

CO2Me

retro-aldol

[2 + 2]
OH

CO2Me
OH

-[2 + 2] cycloaddition involving double bond of an enol

and another olefin and the retro-aldol reaction

Paterno-Bchi Reaction
-Paterno and Chieffi observed the first example of a [2 + 2] cycloaddition
between a carbonyl and an olefin to make an oxetane

O*

T1
-many examples of intermolecular reaction, but regioselectivity and
product distributions are highly case dependent
-many synthetic examples of intramolecular variant

h
AcO

acetone
42% AcO

OH

HI
O

AcOH
82%

AcO

vitamin D3 analogs: M. Mihailovic, L. Lorenc, V. Pauolvic, J. Kalvoda Tetrahedron 1977, 33, 441

Paterno-Bchi Reaction in Synthesis

1. i-Pr2NMgI,
2. PDC, DMF

obtained via
Diels-Alder

corex
>250nm
PhH
90%

65%
O

LDBB
THF
-78C
66%
H

NaBH4
TFA
DCM, CH3CN
69%

endo-hirsutene

V. Rawal, A. Fabr, S. Iwasa Tetrahedron Letters 1995, 36, 6851

Furan-Carbonyl Variant of the Paterno-Bchi Reaction

-this variant of the [2 + 2] offers
a photochemical variant of the
aldol reaction through
transformations of the
photoadduct

PhCHO
O

OH

H
Ph

Ph

0.01N HCl
THF

H2
5% Rh/ Al2O3

Ph
O

wet
celite
OH

S. Toki, K. Shima, H. Sakurai Bull. Chem. Soc. Jpn. 1965, 38, 760
K. Shima, H. Sakurai Bull. Chem. Soc. Jpn. 1966, 39, 1806
S. Schreiber, A. Hoyveda, H. Wu J. Am. Chem. Soc. 1983, 105, 660

Ph
OH
O

Furan-Carbonyl Variant of the Paterno-Bchi Reaction

OBn

PhH, Et2O
63%

OH

O
H

establishes 2 sterocenters present in

asteltoxin (architecture used to install
remaining stereocenters in next few steps)

OH

OBn

asteltoxin

S. Schreiber, K. Satake J. Am. Chem. Soc. 1983, 105, 6723

S. Schreiber, K. Satake J. Am. Chem. Soc. 1984, 106, 4186

Arene-Olefin Cycloadditions
-cycloadditions between arenes and an olefin
ortho cycloadditions-[2 + 2]
para cycloadditions-[4 + 2]
meta cycloadditions-[3 + 2]
ORTHO CYCLOADDITIONS
R1

R1

R2

R2

R1 = OMe R2 = CN
R1 = CN R2 = OAc
R2 = CN
R1 = H
O

O
O
O

O
O

Para Cycloadditions

CN
CN

Meta Cycloadditions
Bryce-Smith and Blair dispelled
the long standing myth that arenes
are photochemically inert

In 1966, Wilzbach and Kaplan and Bryce-Smith, Gilber and Orger

codiscovered the meta arene olefin cycloaddition
H
R

Meta Cycloadditions in Synthesis

MeO

h
vycor
pentane
65%

Wender pioneered
the use of [3 + 2]
arene/olefin
cyc loadditions in
synthesis

H OMe

H OMe

1. Br2
2. R3SnH
59%
H2NNH2
KOH
O

200C
H

cedrene

P. Wender, J. Howbert J. Am. Chem. Soc. 1981, 103, 688

Meta Cycloadditions in Synthesis

h
vycor
cyclohexane
85-90%

toluene
230-244C
90%
H2
Pd/C
hexane
98%
isocomene

P. Wender, G. Dreyer Tetrahedron 1981, 37, 4445

Photoinduced Electron Transfer

Acceptor

Donor

A-

D+

chemistry

polar solvents facilitate the generation of radical ions

and subsequent chemical reactions
Witkop Cyclization
O

H
N

CO2H

Cl

HO

N
H

H2O
40%
after
esterification

H
N

CO2H

H
N

CO2H

-HCl

Cl

N
H

O. Yonemitsu, P. Cerutti, B. Witkop J. Am. Chem. Soc. 1966, 88, 3941

N
H

Witkop Cyclization in Synthesis

H
N

H
N
TeocHN

TeocHN

N
H

Br

N
O

CH3CN/
aq. LiOH
72%

NH

h (300nm)

N
O

NH

N
H

OAc

OH

steps
N
O
NH

Li+

(32-40% in initial
synthesis of the
nominal
diazonamides)

H
N

HO

H
N
O

Br

N
H

NH

diazonamide A
A. Burgett, Q. Li, Q. Wei, P. Harran Angew. Chem. Int. Ed. 2003, 42, 4961

Cl
Cl
NH

Additional Photochemical Reactions

-Norrish Type I and II (-cleavage of carbonyl and H-abstraction
and fragmentation)
-nitrogen extrusion (generate carbenes such as the Wolff
rearrangment or to give diradical)
-sigmatropic rearrangements such as (1,3), (1,5), and (1,7)
-1O reactions
-deprotections (such as cleavage of nitroarenes)
-many other PET reactions
isomerizations
rearrangements
fragmentations
arene substitutions and reductions
photooxygenations
and many more reactions

Problem 1 (Were you paying attention to the last slide?)

N2

Br

OTIPS

h
vycor
ClCH2CH2Cl
O
Br

N2

rt then
80C
60-71%

HO

OTIPS

Br

reaction sequence used

in Danheiser's synthesis
of salvilenone
either substrate can be used
to generate the product and
both give essentially the same
yield of tricycle

R. Danheiser, A. Helgason J. Am. Chem. Soc. 1994, 116, 9471

Problem 1 Solution
O

N2

Br

N2

Br

OTIPS

h
vycor
ClCH2CH2Cl

-N2

-N2

OTIPS

Br

rt then
80C
60-71%

Br

Br

HO

6 electro.
(tautomer.)
Wolff rearr.
O

Br

[2 + 2]

O
Br

R. Danheiser, A. Helgason J. Am. Chem. Soc. 1994, 116, 9471

OTIPS

4
electro.

Br

OTIPS

Problem 2

1. h, 87%
2. EtOH, reflux
3. cat. PPTS
EtOH
87% 2 steps

NBoc
N
Boc

Y. Kwak, J. Winkler J. Am. Chem. Soc. 2001, 123, 7429

Problem 2 Solution
1. h, 87%
2. EtOH, reflux
3. cat. PPTS
EtOH
87% 2 steps

NBoc
N
Boc

cat. PPTS
EtOH
Mannich

EtOH, reflux
O

NBoc

retro-Mannich
BocN

Y. Kwak, J. Winkler J. Am. Chem. Soc. 2001, 123, 7429