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 T1 have a longer lifetime
and higher E (10-9 to 10-5) 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

R 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)

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 h Ph

toluene

h Ar
Ar Ar

Ar

O
h, quartz

EtOH 6-elec.
O O
>180nm -pyran
-ionone

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

h O h O

O O

O O
O H H
h, uranium
DCM, -75C
77% H H H H H H
>340nm 10:1

O O
O H H
h, pyrex
O O
O cyclohexane
70% H 5:1 H
H H
>285nm

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

 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 Photochemical Reactions

-occur via HOMO -occur via LUMO
4n - conrotatory 4n - disrotatory
4n + 2 - disrotatory 4n + 2 - conrotatory
 4-Electrocyclizations

h
H
H

h
4-electrocyclizations
254nm
occur with disrotatory
ring closure under 95%
photochemical
h
conditions O
O
59%
H
O h H h
Fe
O O Fe(CO)5 OC CO
O CO
 8 and 6-Electrocyclizations

8-electrocyclizations
h
occur with disrotatory
ring closure under
photochemical
conditions and
6-systems undergo h
conrotatory ring
closure
C9H17

C9H17 C9H17

h H
>20C

6 1,7 H-shift
H
HO HO
Ergosterol Precalciferol
(provitamin D) (previtamin D) HO
Vitamin D2
(calciferol)
 6-Electrocyclization in Synthesis
H
O N
H H H
O N
H

H H OH
H
O
Ikarugamycin

Wittig Reaction
H 1. h, -78C, hex. H H
2. HCl
O OH OH
50%
H H H H
H O H OH H OH
4:1

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

 retro-6-Electrocyclization

H2
h Raney Ni

H MeOH O
MeOH O
O -18C -15C
O O
O 1:1
dihydrocostunolide

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

 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
O O
h
66%
 Oxa-di--methane rearrangement
R2
R2 R3 R2 R3 R3 R2
O O R3
R1 h
O
O R5 R1 R1
R1 R5
R4 R5 R4 R5 R4
R4

O pyrex
t-BuOH O
50%

O
h
acetone
70% O
 Di--methane rearrangement in Natural Products

OAc OAc

H h O H OH
OH
O Cl Cl
AcO quartz AcO
AcO AcO O
O PhH
87% conv
O in 3 hr O

erythrolide B or erythrolide A
5% methanolic
seawater
(glass)
with
sunlight
37% conv
in 8 days

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 O
h h

254nm 300nm
O
acetone hexane
62% 50%

O X
OMe steps
h
pyrex O
MeO
THF
O
59%
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 O

h calyculone D back 8.8% calyculone F up 10.6%

calyculone E 6.2% calyculone G 15.9%
quartz
PhH
3h O O

cembratriene 10.6% cembratriene 11.5%

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

 [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

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 O
-this [2 + 2] follows the "rule of 5" and none of the other
regioisomer is observed not observed
 "Rule of 5"

O O O
H
h not
observed
70%
O O
O
O

O O O
 [2 + 2] Cycloaddition in Synthesis
O O O
H h
H H H

H Et2O
H 2:1
72% H H

O
O

O O O
O O
O O
O H H
h steps
O periplanone B
0C O
O O CH3CN/ O O O
acetone O
O O O
O (9:1) O O
80% saudin

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

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

O
O O
CO2Me CO2Me retro-aldol
h
[2 + 2] CO2Me
OH OH
O

-[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*
O h O O

T1

-many examples of intermolecular reaction, but regioselectivity and

product distributions are highly case dependent
-many synthetic examples of intramolecular variant

OH
h HI
acetone O AcOH
AcO 42% AcO 82% AcO
O

vitamin D3 analogs: M. Mihailovic, L. Lorenc, V. Pauolvic, J. Kalvoda Tetrahedron 1977, 33, 441
 Paterno-Bchi Reaction in Synthesis

1. i-Pr2NMgI,
h 2. PDC, DMF

corex 65%
>250nm
O
PhH O
O 90%
obtained via
Diels-Alder LDBB
THF
-78C
66%

H H NaBH4 O H H
TFA

DCM, CH3CN
H 69% H

endo-hirsutene

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

 Furan-Carbonyl Variant of the Paterno-Bchi Reaction

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

OH H Ph
H2 H Ph
0.01N HCl 5% Rh/ Al2O3
Ph
O O
O THF O O
O

wet
celite
S. Toki, K. Shima, H. Sakurai Bull. Chem. Soc. Jpn. 1965, 38, 760 OH
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
H OBn h
O PhH, Et2O O
O
O
63% H

establishes 2 sterocenters present in

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

O O O
H O

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 h R2 R1 = OMe R2 = CN
R1 = CN R2 = OAc
R1 = H R2 = CN

O O O

h
O O O
O

O O O

O
Para Cycloadditions

CN
CN h
 Meta Cycloadditions

Bryce-Smith and Blair dispelled h

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 H H
R
h
R
R
H R

R
R
 Meta Cycloadditions in Synthesis

MeO

h
vycor
pentane H OMe H OMe
65%
Wender pioneered
1. Br2
the use of [3 + 2]
arene/olefin 2. R3SnH
cyc loadditions in 59%
synthesis
H2NNH2
KOH
O
200C
H 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

h
Acceptor Donor A- D+ chemistry

polar solvents facilitate the generation of radical ions

and subsequent chemical reactions

Witkop Cyclization

O H O H
N CO2H HO H N CO2H
N CO2H
Cl h Cl -HCl
H2O
40%
N N
H after N H
esterification H

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

 Witkop Cyclization in Synthesis
H
H N
N
TeocHN
TeocHN O
O N
N O N
O N h (300nm)
O
O CH3CN/
NH aq. LiOH
O N NH
O N Br 72% H
H
OAc
OH
steps
N
H
N
H
O N
HO O
(32-40% in initial O
N
O N
Li+ NH synthesis of the Cl
nominal O
diazonamides) Cl
O
O N NH
Br H

NH
diazonamide A

A. Burgett, Q. Li, Q. Wei, P. Harran Angew. Chem. Int. Ed. 2003, 42, 4961
 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
O
Br OTIPS
h
vycor HO OTIPS
ClCH2CH2Cl
Br
rt then
O 80C
N2
Br
60-71%

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
N2 O
Br Br
OTIPS
h
vycor HO OTIPS
ClCH2CH2Cl
-N2 -N2 Br
rt then
O 80C
O 60-71%
Br Br

6 electro.
(tautomer.)

Wolff rearr.
O
OTIPS
4
O

Br [2 + 2] O OTIPS electro. Br
Br

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

 Problem 2

1. h, 87%
2. EtOH, reflux
3. cat. PPTS
O
EtOH
87% 2 steps
NBoc
N
Boc
O

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

 Problem 2 Solution

1. h, 87%
2. EtOH, reflux
3. cat. PPTS
O
EtOH
87% 2 steps
NBoc
N
Boc
O

cat. PPTS
h EtOH
Mannich

O
EtOH, reflux
O
NBoc retro-Mannich
BocN

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