Final 1.0, May 11, 2004
11. Photochemistry of Enones and Dienones
11.1. Introduction
Enones are a general class of compounds that contain both carbonyl and olefin
chromophores in a single molecule. The photochemistry of enones varies depending on the
proximity and interactions of these two chromophores.
When the two chromophores are
separated by more than two carbons, as in α,ω-enones (Scheme 11.1), the photochemistry
resembles that of the individual chromophores. β,γ-Enones, in which the chromophores are
separated by one carbon, and α,β-enones, which lack an intervining carbon exhibit unique
behavior (Scheme 11.1). α , β-Enones are somewhat similar in their photoreactivity to 1,3dienes, and β,γ-enones resemble 1,4-dienes. Carbonyl systems that are substituted with a diene
instead of a monoene unit are called dienones.
In conjugated dienones, the carbonyl
chromophore may occupy either the central or terminal positions.
The former class of
molecules is termed cross conjugated dienones, and the latter is called linearly conjugated
dienones (Scheme 11.1). In this chapter we shall discuss the photochemical behavior of all the
above types of enones and dienones.
1
Final 1.0, May 11, 2004
O
O
O
O
nonconjugated
enones
conjugated
enones
linearly conjugated
dienones
cross-conjugated
dienones
Scheme 11.1
When the two chromophoric units (olefin and carbonyl) are well separated and noninteracting, as in α,ω-enones, the orbitals are localized on the individual chromophores and their
energies remain unperturbed. Under such conditions, the electronic transitions (nπ* and ππ*
carbonyl and ππ* olefin) may be considered to be localized on the carbonyl and olefin
chromophores respectively. The chemistry of these molecules can be predicted on the basis of
the behavior of nπ* and ππ* excited states of the carbonyl and the ππ* excited state of the olefin
chromophores (Chapters 9 and 10).
In this chapter we deal with systems where there is an
interaction between the ‘olefin’ and carbonyl chromophores and therefore their chemistry can’t
be fully defined by that individual chromophores. Yet the known excited state chemistry of the
individual chromophores serve as the starting point.
11.2. β,γ-Enone: Introduction
When the individual chromophores (carbonyl and olefin) of β,γ-enones are not in the
same plane, their π-orbitals overlap resulting in coupling of these orbitals, the extent of coupling
depending on the angle between the chromophore. This results in an alteration of the energy
levels of the π and π* orbitals, and the energies of the nπ* and ππ* transitions are lowered
2
Final 1.0, May 11, 2004
relative to those of the unconjugated enones. The n-orbital of the carbonyl chromophore remains
unaffected in such systems (Figure 11.1).
In the nπ* state, the first excited singlet state of β,γ-enones, a single electron is localized
on the n-orbital of the carbonyl oxygen and the π-system contains five electrons delocalized over
four atoms. The second excited singlet state is ππ* in character. The large energy gap between
S1 and S2 (nπ* and ππ*) in alkanones ensures that the lowest triplet is nπ* in character. On the
other hand, since the energy gap between S1 and S2 (nπ* and ππ*) is smaller in β,γ-enones, the
lowest triplet tends to be ππ* in character. A generalized state diagram for β,γ-enones is shown
in Figure 11.1. Most enones do not phosphoresce and have very poor intersystem crossing
efficiency (crossing from n π * singlet to nπ * triplet).
Thus direct excitation results
predominantly in an nπ* excited singlet state, and triplet sensitization populates the ππ* triplet
state.
π4
π3
S2
ππ*
S1
nπ*
nπ*
ππ*
T2
n
T1
π1
S0
π2
H2C
CH2
H2C
O
H2C
O
H2C
O
Figure 11.1
3
Final 1.0, May 11, 2004
11.3. Reactions that are common with isolated carbonyls and olefins
β,γ-Enones undergo virtually all the known photoreactions of isolated carbonyl and
olefinic chromophores (Figure 11.2). For example, these enones have been observed to undergo
α-cleavage, the hydrogen abstraction, and oxetane formation (addition to an olefin), typical
reactions of isolated carbonyl compounds as well as photoreactions typical of alkenes, such as
geometric isomerization and di-π-methane rearrangement.
Hydrogen atom
transfer
Electron transfer
Addition to C=C bond
(non-concerted)
Olefins
(ππ*)
α-Cleavage
β-Cleavage
Carbonyls
(nπ*)
Geometric Isomerization
Pyramidalization
Proton transfer
Di-π-methane
(Zimmerman) rearrangement
Pericyclic reactions: Sigmatropic shifts
Electrocylisations
Cycloadditions
Figure 11.2
11.4. Photoreactions that are common with carbonyl chromophore (nπ* state)
Direct excitation of a β,γ-enone populates the first excited singlet state, S1, of nπ*
character. This state, as discussed above, in which the n-orbital is unperturbed by the adjacent
4
Final 1.0, May 11, 2004
olefin, would be expected to behave similar to the (n, π*) states of isolated carbonyl compounds.
α-Cleavage in β, γ-enones in which the resulting radical is stabilized by the adjacent C=C bond
(allylic radical vs alkyl radical), is faster than in alkanones and competes favorably with the
intersystem crossing process (S1 to T1). As illustrated with several examples in Scheme 11.2,
α-cleavage of β, γ-enones yields products of all processes expected of an isolated carbonyl
compound, namely decarbonylation, fragmentation (ketene formation), internal hydrogen
abstraction (aldehyde formation), oxacarbene formation and epimerization (Chapter 9).
It
should however be noted that not all processes occur in every case. In addition to these, 1, 3acyl migration also takes place as a consequence of α-cleavage that is discussed in the next
section. The γ-hydrogen abstraction reaction takes place in β,γ-enones in the presence of
easily abstractable hydrogen atoms (Scheme 11.3). The only requirement for this reaction
seems to be the geometric proximity of the allylic γ-hydrogen atom and the carbonyl oxygen.
5
Final 1.0, May 11, 2004
O
hν
O
+
+
O
O
+
O
O
hν
+
CO
CH3
HC(CH2)2CH=CH-CH=C
CH3
O
O
hν
O
O
+
+
O
CH3OH
H
OCH3
O
O
H
OCH 3
Scheme 11.2
O
HO
O
hν
+
O
HO
+
OH
hν
Scheme 11.3
6
Final 1.0, May 11, 2004
In several β,γ enones intramolecular oxetane formation occurs between the carbonyl
group and the C=C bond (Scheme 11.4).
Oxetane formation is likely when the two
chromophores are favorably situated with respect to one another and when the olefin is
electron rich (recall that the singly occupied n-orbital of the nπ* excited carbonyl group is
electrophilic).
hν
O
O
hν
+
O
O
OH
Scheme 11.4
Thus it is clear that nπ* singlet excited β, γ-enones behave very similarly to the nπ*
excited carbonyl compounds (Figure 11.2). All the above reactions compete favorably with
the intersystem crossing process since the rate of intersystem crossing from S1(nπ*) to the
triplet of nπ* character is relatively slow (<108 sec-1).
11.5. Photorearrangements
β, γ-Unsaturated carbonyl compound upon direct excitation gives products resulting
from 1,3-acyl migration (1,3-AM), and upon triplet sensitization yields products of 1,2-acyl
migration (1,2-AM) (Scheme 11.5). Such distinctive behavior allows one to obtain either
one of the two products exclusively by choosing the proper conditions of excitation (there are
7
Final 1.0, May 11, 2004
a few exceptions where both processes may occur upon direct excitation, but this is not
common).
hν
O
O
hν
acetone
O
O
O
hν
acetone
hν
O
O
hν
hν
sensitized
O
O
Scheme 11.5
11.6. α-Cleavage: 1,3-Acyl migration (1,3-AM) from nπ* state
Direct excitation of β,γ-unsaturated ketones as illustrated in Scheme 11.5, results in a
product that can be accounted for by a 1,3-acyl migration. To understand the mechanism of the
rearrangement we need to first answer the question ‘what is the reactive state?’ Molecule A
(Scheme 11.6) upon direct excitation gives two products, B and C, via the 1,3-AM and the γhydrogen abstraction respectively. Acetone sensitization (ET=78 kcal/mole) yields two products,
D and B, via 1,2-acyl migration (ODPMR; see next section) and 1,3-acyl migration respectively.
The absence of γ-hydrogen abstraction product during triplet sensitization is significant. As to be
discussed in the next section, product such as D obtained via the ODPMR results from the T1
(ππ*) state. It is also clear that the γ-hydrogen abstraction product C, which is not formed upon
triplet sensitization, does not arise via a triplet manifold. The product B (1,3-AM), obtained
8
Final 1.0, May 11, 2004
during both direct excitation and triplet sensitization, could arise from a triplet state or from both
triplet and S1 states. From the observation that 2,5-dimethyl-2,4-hexadiene (4M), a triplet
quencher, quenches only the ODPMR product but not the 1,3-AM product, it may be concluded
that the two products are unlikely to be derived from the same reactive state (T1). The possible
choices at this stage are S1 and T2, both of nπ* character. Differential triplet sensitization with
acetone and acetophenone as sensitizers indicates that the reactive state, if triplet, is T2 and not
T1. Scheme 11.6 provides the quantum yields of the products upon sensitization by these two
sensitizers. Acetone, with a triplet energy of 78 kcal/mole, is a better sensitizer of the formation
of D than acetophenone (ET=74 kcal/mole).
This observation, while suggesting the reactive
triplet to be above 74 kcal/mole, does not distinguish between the two options: (a) both S1 and T2
or (b) T2 alone. Temperature-dependent product and fluorescence quantum yield measurements
favor option (a). As the temperature was varied between –14°C and 72°C the quantum yield of
the 1,3-AM product increased from 0.044 to 0.083. While the product quantum yield increased
with temperature, the relative quantum yield of fluorescence decreased. Thus a depletion of S1
with temperature results in an increase of the 1,3-AM product. Assuming that intersystem
crossing to be likely temperature independent, one can conclude that the observed temperature
dependence is due to a barrier present in the S1 surface for the1,3-AM reaction.
Based on
senitization, quenching and temperature dependent emission and product studies it was
concluded that the 1,3-AM reaction occurs from both the S1 and T2 states, both of nπ* character.
Consistent with this conclusion in presence of xenon, a heavy atom perturber, the yield of B
increased and the fluorescence yield decreased. This observation suggests that crossing from S1
(nπ*) to T2 (nπ*) is enhanced by xenon and, once the molecule crosses to T2 reacts to give B.
9
Final 1.0, May 11, 2004
O
hν
hν
+
B
sensitized
O
D
A
T1 specific
Quantum yield of
+
O
B
O
OH
C
S1 specific
D
B
Acetone
0.027
0.102
Acetophenone
0.023
0.052
Scheme 11.6
Accepting the notion that the 1,3-AM is yet another manifestation of the well known αcleavage process (characteristic of the nπ* state), the behavior of the three β,γ-enones shown in
Scheme 11.7 can be rationalized. These three enones undergo 1,3-AM as well as ODPMR. The
photoreactivity of these enones depends on the number of α-methyl groups present. The
unmethylated compound A shows only the ODPMR on both direct and sensitized photolysis.
The dimethylated compound C undergoes only the 1,3-AM on direct photolysis but the ODPM
rearrangement exclusively upon triplet sensitization. The mono methyloctalone C undergoes
both reactions on direct photolysis but only the ODPMR rearrangement on triplet sensitization.
This interesting behavior can be rationalized on the basis that although 1,3-AM occurs from both
S1 and T2 only that from S1 is activated. The activation barrier for the cleavage is expected to
depend on the presence of the methyl group (primary, secondary and tertiary radicals would be
formed from A, B and C respectively). In the absence of a methyl group the barrier in A is too
high and ISC competes favorably with the α-cleavage process. Thus T1 is populated with high
efficiency in A. On the other hand, when there are two methyl groups as in C, the barrier for α10
Final 1.0, May 11, 2004
cleavage is expected to be low, under which conditions the rate of α-cleavage is higher than the
rate of ISC. In such a case only 1,3-AM product is obtained on direct excitation. The mono
methyloctalone B represents an intermediate situation.
H
H
1
nπ*
hν
direct (0.15) or
triplet-sensitized (0.18)
O
Fast
3
ππ∗
O
(0.05)
A
P
CH3
hν
O
direct
CH3
H
1
+
O
Medium
nπ*
3
ππ∗
O
H3C
P1
B
P2
hν
triplet-sensitized
O
H3 C
1
nπ*
hν
Slow
3
ππ∗
CH3
direct
P1
O
CH3 CH3
C
hν
CH3
CH3
triplet-sensitized
O
Scheme 11.7
11
Final 1.0, May 11, 2004
The overall mechanism of 1,3-AM includes the following features: (a) origination from
S1 and T2, both of nπ* character; (b) likely involvement of a diradical intermediate derived from
an α-cleavage process and (c) involvement of a small barrier in the reaction from the S1 state and
its absence in the reaction from the T2 state.
There are evidences to suggest that 1,3−ΑΜ migration from excited singlet state proceeds
via a short lived singlet radical pair. Studies on optically active enones of the type A in Scheme
11.8 suggest that upon direct excitation the 1,3-AM proceed with retention of configuration.
Although this result alone suggests that the reaction could be a concerted process, photo-CIDNP
studies (Scheme 11.8) provide evidence in favor of a radical pair. These obeseravtions suggest
that the 1,3-AM migration involves a short lived radical pair. Similarly the triplet process most
likely involves a triplet radical pair. One could visualize the α-cleavage of β,γ-enoens and the
resulting 1,3-AM by the models shown in Scheme 11.8.
O
O
CD3
(R)-(+)-A
O
hν
CD3
O
D3C
CD3
(S)-(-)
RP
Scheme 11.8
11.7. Photoreactions that are common with olefinic chromophore (ππ* state): The Oxa-diπ-methane rearrangement (1,2-Acyl migration) from ππ* state
12
Final 1.0, May 11, 2004
The 1,2-acyl migration process has been established to occur from the lowest ππ* triplet
state of β, γ-enones, resulting in products (Scheme 11.5) structurally similar to those obtained
via the Zimmerman reaction of 1,4-dienes (Chapter 10). Based on the structural similarities of
the two reactants (β,γ-enones and 1,4-dienes) and the products, 1,2-acyl migration in β,γ-enones
is termed the oxa-di-π-methane rearrangment (ODPMR). Based on the analogy with 1,4-dienes
one would expect the reaction to be initiated at the π* orbital and involve diradical intermediates
as shown in Scheme 11.9.
*
ππ∗ 3
O
O
O
A
O
B
O
O
4
hν
4
2
1
3
O
acetone
1
1
2
2
3
O
3
O
Scheme 11.9
13
Final 1.0, May 11, 2004
Generally, the highest quantum and chemical yields of products from the ODPMR are
obtained with substrates in which the β,γ-enone chromophore is part of a conformationally rigid
molecular assembly that guarantees adequate orbital overlap of the C=C and C=O chromophore
sites. Accordingly, there are a number of examples of bicyclic and bridged β,γ-unsaturated
ketones that undergo the ODPMR (Scheme 11.10). The efficiency of the ODPMR is strongly
coupled to the degree of flexibility of the alkene moiety. When the C=C bond is geometrically
constrained, for example when it is part of a 5-membered ring, the rearrangement proceeds
smoothly (Scheme 11.10). On the other hand, no rearrangement occurs when the vinyl group is
embedded in a 6-or 7-membered or larger ring.
In such systems, geometric isomerization is
believed to occur at a much faster rate than the ODPMR. When the olefin part of the enone is of
styrene type the ODPMR competes with geometric isomerization (Scheme 11.11). In such
sytems, as discussed in Chapter 10, there is a barrier for geometric isomerization in the excited
state. The state diagram provided in Figure 11.3 summarizes the photobehavior of β,γ-enones.
14
Final 1.0, May 11, 2004
O
Sens3
hν
+
O
A
OH
O
Sens3
hν
O
+
O
O
OH
B
Sens3
hν
O
+
O
O
OH
C
Scheme 11.10
Ph
Ph
Sens3
O
Ph
Ph
O
H
H
Ph
Sens3
O
Ph
H
H
Ph
Ph
O
Ph
O
3
Sens
+
O
H
Ph
O
O
+
Scheme 11.11
15
Final 1.0, May 11, 2004
Figure 11.3
The ODPMR is a general process occurring upon triplet sensitization of a large number
of β,γ-enones. The products are obtained in good yield (80-95%), the quantum efficiency is high
(0.5 to 1.0), and based on the mechanism shown in Scheme 11.9, the structures of the products
are predictable. These features have made this process a useful synthetic tool in constructing
complex systems. A few examples are shown in Schemes 11.12 and 11.13.
16
Final 1.0, May 11, 2004
hν
O
O
(acetone)
(+)-modhephene
OR
OR
hν
O
(acetone)
O
O
H
H
(-)-Silphiperfol-6-en-5-one
Scheme 11.12
O
hν
O
O
A
(acetone)
O
H
B
O
A
+
A
H
B
O
HO H
O
C
B
H
H
HO H
H
O
O
O
OH
H
OH
(-)-coriolin
Scheme 11.13
11.8. Geometric isomerization from ππ* state
On the triplet surface, cis-trans-isomerization is very common from the (ππ*)3 excited
states of β, γ-enones. When the carbon-carbon double bond is not geometrically constrained
(i.e. not in a small ring), cis-trans-isomerization can be so efficient for it to be (almost) the
17
Final 1.0, May 11, 2004
only observed triplet process, with no competition from other triplet processes (Scheme
11.14).
D O
D
sens.
+
hν
Φ = 0.02
φ = 0.12
Ph
O
hν
O
D O
O
D
Ph
O
Ph
Ph
Scheme 11.14
11.7 . α,β-Unsaturated Enones: General
The ground state reactions of α,β-unsaturated enones are based on a model in which the π
system is polarized such that the oxygen atom carries a partial negative charge and the β-carbon
atom a partial positive charge. To be able to make predictions concerning the photoreactivity of
enones we need to generate an excited state model for these compounds. A naïve approach
would be to consider α,β-unsaturated enones as polarized 1,3-dienes. In α,β -enones, which are
akin to 1,3-dienes, the π-orbitals of the carbonyl and the olefin chromophores remain extensively
conjugated. As illustrated in Figure 11.4, such a conjugation results in an alteration of the
energy levels of the π and π* orbitals; the energies of the nπ* and ππ* transitions are lowered
compared to those of the individual chromophores. For example, the nπ* and ππ* transitions of
α,β-enones occur at ~300-350 nm and 220-250 nm respectively, while those of a carbonyl
chromophore are at ~290-310 and ~180-220 nm respectively.
18
Final 1.0, May 11, 2004
π4
π3
S2
ππ*
S1
nπ*
n
T2
T1
nπ*
ππ*
π2
π1
H2C
CH2
H2C
O
H 2C
O
S0
Figure 11.4
19
Final 1.0, May 11, 2004
In general, the S1 and S2 states of α,β-unsaturated enones are of nπ* and ππ* character
respectively. The ordering of the corresponding triplet states depends on the structure of the
enone. For example, the lowest excited triplet in cyclohexenones tends to be of ππ* character
while in cyclopentenones it is nπ*. The ordering of the nπ* and ππ* triplet states is subject to
subtle effects such as substitution and the polarity of the medium. An important point to
remember is that when two states are nearby there will be a mix between the two and the two
states can’t considered to be ‘pure’. In the case of enones nπ* and ππ* states both in singlet and
triplet manifold are near one another and therefore lower and upper excited states should be
considered to have both nπ* and ππ* characteristics. In this chapter when we mention nπ* and
ππ* we mean that particular configuration contributes more to the given state.
The electronic configurations of the nπ* and ππ* states of the enone chromophore are
different from those of the individual chromophores that form the enone. The π* orbitals in α,β−
are delocalized over four atoms (three carbon atoms and an oxygen) while those of the individual
chromophores are localized between two atoms. The chemistry that originates from the π*-plane
(of the nπ* and ππ* states) of conjugated enones is therefore expected to be different from the
localized nπ* and ππ* states of the individual chromophores. On the other hand, since the norbital remains localized on the oxygen, the chemistry initiated at this center is expected to be
similar for both the carbonyl and enone chromophores.
A majority of enones have lowest triplet state energies of 68–73 kcal/mole. They rarely
emit from S1 but do, at 77° K, from T1. The intersystem crossing efficiency from the singlet to
the triplet manifold is often near unity. Thus most photochemistry of enones originates from the
triplet manifold.
20
Final 1.0, May 11, 2004
11.8. Photoreactions of enones that are common with carbonyl chromophore (nπ* state)
Enones with nπ*3 as the lowest excited state undergo typical photoreactions of a carbonyl
compound (nπ*3). These include inter and intramolecular hydrogen abstraction, α-cleavage, βcleavage, electron transfer and addition to C=C bond. Examples of the first three reactions are
provided in Schemes 11.15-11.18
Since the mechanism of these reactions are similar to that in
carbonyls systems no further discussion is necessary. No product of hydrogen abstraction from
the S1 (nπ*) state of enones has yet been reported. This is similar to the behavior of aryl alkyl
and diaryl ketones where the nπ* T1 state is the only active state. The rate of intersystem
crosssing from S1 to the triplet manifold in both these systems as well as in enones must be
greater than the rate of photoreactions from S1.
21
Final 1.0, May 11, 2004
hν
O
+
Et2O
HO
HO
OH
HO
H3 CCHOCH2 CH3
OSiMe 3
ClSiMe3
hν
O
OH
H+ or BO
O
HO
X
hν
HO
X
X
X=CH2, O
HO
X
O
X
H
Schemes 11.15 (hydrogen abstraction)
22
Final 1.0, May 11, 2004
O
hν
+ CO
O
C
O
O
COOCH3
CH3 OH
hν
Schemes 11.16 (α-Cleavage)
CH3
CH3
CH3
CH3
hν
O
H
O
O
O
O
O
hν
hν
O
OCOCH3
O
COCH3
O
Schemes 11.17 (β-Cleavage)
23
Final 1.0, May 11, 2004
O
O
O
(H3CH2C)2N
hυ
(CH2CH3)3N/CH3OH
O
OH
(H3CH2C)2N
(CH2CH3)3N
O
O
hυ
SiMe3
SiMe3
CH3CN
N
N
O
OH
SiMe3
N
SiMe3
N
Schemes 11.18 (electron transfer mediated hydrogen abstraction)
24
Final 1.0, May 11, 2004
11.9. Photoreactions that are common with olefinic chromophore (ππ* state): Hydrogen
abstraction
Enones with ππ* 3 as the lowest excited state, similar to olefins, undergo hydrogen
abstraction reaction. In such cases the hydrogen abstraction is done by the β-carbon. Examples
of inter and intramoleculaar hydrogen abstractions are provided in Scheme 11.19 and 11.20.
O
C(CH3 )3
hν
O
C(CH3)3
CH2 C6 H5 +
H
R
Toluene
O
(CH3)3C
C(CH3 )3
O
O
O
O
O
hν
Et2 O
H
Scheme 11.19
O
O
O
hν
O
O
+
+
H
O
O
O
hν
O
+
H
Scheme 11.20
25
Final 1.0, May 11, 2004
In a few cases a higher excited singlet (S2) of ππ* character has been shown to be active
in the reduction process. Examples are provided in Scheme 11.21. It is significant to note that
for a state of ππ* electronic configuration the primary site of hydrogen abstraction is different
for S2 and T1 (compare the products in Schemes x and x). Reduction from the ππ* triplet state is
believed to be initiated at the β-carbon and that from the ππ* singlet state at the α-carbon. One
possible reason for this difference is that ππ* singlet is zwitterionic in nature while the ππ*
triplet is biradical in character.
H2CO
CH3O
π
O
O
π
O
H
H3CO
H
O
H H
π*
H
O
OCH3
π
O
O
π*
H
O H
H
H2CO
OCH3
O
OCH3
π*
O
H
H
O
H
H
Scheme 11.21
26
Final 1.0, May 11, 2004
Since in α, β-enones the nπ* and ππ* states are close, depedning on the system and the
medium, reaction either from both states or from an individual (nπ* or ππ*) state could occur.
As shown in Scheme 11.22, irradiation of phenanthrone A in 2-propanol solution gives four
reduction products in addition to the expected product from Type A rearrangement (for
discussion of this reaction see Section xx). By differential quenching, it has been established
that two different excited states are involved in the formation of products.
Naphthalene
quenches all the reduction products but at different rates suggesting that all products in Scheme
11.22 derive from triplet states. Products B and C were quenched at a different rate from that of
D, E and F. In this study, the Type A product B serves as an ‘internal reporter’. Assuming that
the Type A product derives from the ππ* triplet, the reduction product C, must also comes from
the same state. The other three reduction products (D, E and F) evidently come from a different
state with a different lifetime. This state is presumed to be the nπ* triplet. The mechanism
shown in Scheme 11.23 summarizes the features of hydrogen abstraction from the two different
states. Abstraction by the carbonyl oxygen in the nπ* state and by the olefinic carbon in the ππ*
state to yield a more stable radical pair is consistent with what was learned in earlier chapters on
carbonyl and olefin photochemistry.
hν
O
+
O
O
A
+
+
B
H
O
C
via
D
H
+
2
HO
OH
E
F
3
π,π*
via
3
n,π*
Scheme 11.22
27
Final 1.0, May 11, 2004
O
3π,π*
O
O
H
H
hν
Me2CHOH
O
3n,
π*
+
+
HO
Pinacol
HO
HO
H
Scheme 11.23
11.9. Photoreactions that are common with olefinic chromophore (ππ* state): Geometric
Isomerization
One of the primary photoreactions of ππ∗ excited acyclic enones is the geometric
isomerization of the C=C bond (Scheme 11.24). The mechanism of this reaction is identical to
the one discussed previously in Chapter 10 and will not be elaborated here. Excitation of cyclic
enones of ring size larger than 6, leads primarily to geometric isomerization. For example, 2cycloheptenone and 2-cyclooctenone readily photoisomerize to the corresponding strained trans
isomers. The highly reactive trans isomer of 2-cycloheptenone can react with alcohol, dimerize
or add to a diene (inter or intramoleculary) at room temperature (Scheme 11.24). Trans-2cyclooctenone and trans-2-cycloheptenone have been characterized spectroscopically at room
temperature and at –160°C respectively.
On the other hand, as expected, smaller ring
cycloalkenones such as cyclopropenone, 2-cyclobutenone and 2-cyclopentenone, do not
photoisomerize to the corresponding trans isomers.
28
Final 1.0, May 11, 2004
H
H3C
C
H
C
C
H
hν
CH3
H
O
C
C
CH3
C
CH3
O
H
H
hν
O
O
O
H
CH3OH
O
H
OCH3
O
O
O
H
hν, Pyrex
+
cyclohexane
(69%)
OH
H
H
H
H
Major
+
H
H
H
H
H
H
Minor
Scheme 11.24
29
Final 1.0, May 11, 2004
11.10. Geometric isomerization of 2-cyclohexenones as a special case: Role of trans-2cyclohexenone in type A rearrangement
As illustrated in Scheme 11.25 irradiation of 2-cyclohexenones leads to novel
bicyclo[3.1.0] hexenones. This type of rearrangement, first observed by Gardner et al. during
the irradiation of Δ4-cholesten-3-one, has since been shown to be general. Such rearrangements
are named the lumiketone rearrangement or Type A rearrangement.
hν
t-BuOH
O
O
O
O
6
5
2
4
3
hν
i-PrOH
O
2
4
+
3
Scheme 11.25
The following characteristics typify Type A rearrangements: (a) The reaction originates from a
triplet of ππ* character. (b) Quantum efficiencies are quite low (~0.01). (c) The rearrangement
occurs only when there are two substituents at the C-4 position, one of which is an alkyl group.
For example, neither 2-cyclohexeneone nor 4-methyl-2-cyclohexeneone rearrange while 4,4’dimethyl-2-cyclohexeneone does. (d) The rearrangement fails for enones in which C=C bond
distortion from the planarity is not possible (eg. compare the two enones in Scheme 11.26). (e)
Since the quantum yield of intersystem crossing from S1 to T1 in 2-cyclohexenones is close to
30
Final 1.0, May 11, 2004
one, the rearrangement can be brought about by direct as well as sensitized irradiation of the
enone.
O
hν
hν
O
i-PrOH
O
O
Scheme 11.26
The rearrangement involves disruption of the C5-C4 connection and reconnection of the
C5-C3 atoms (Scheme 11.25).
Given the fact that the reaction occurs from T1, a concerted
process is ruled out. In spite of this limitation, the rearrangement proceeds with stereochemical
integrity at the stereogenic centers: (a) Deuterium-labelled testosterone A derivative
photorearranges to the lumiketone with retention of configuration at C-1 and inversion at C-10
(Scheme 11.27). (b) The photorearrangement of the optically active phenanthrone B proceeds
with inversion at C-10 with no detectable loss of optical purity (Scheme 11.27). (c) Irradiation
of the optically active cyclohexenone C gave two products, both optically pure. The above
observations are consistent with the reaction course illustrated in Scheme 11.28. The reaction is
stereospecific on each face of the 2-cyclohexenone ring, with retention of configuration at C-5
and inversion at C-4, thus leading to diastereomers.
31
Final 1.0, May 11, 2004
OAc
D
H
H
hν
O
D
O
A
hν
t-BuOH
O
O
B
O
O
CH3
hν
t-BuOH
C
CH3
+
O
+
H
CH3
O
Scheme 11.27
• The reaction occurs from T1
(ππ*).
• The reaction is inefficient (Φ =
0.007)
• The reaction does not occur with
rigid cyclohexenones
• The reaction does not occur in
cycloheptenones and
cyclooctenones
• Twisted trans isomer precedes
the rearrangement process.
• The reaction is stereospecific.
Figure 11.5
32
Final 1.0, May 11, 2004
R
R'
R'
R
R' R
O
H
R
R'
hν
O
O
O
H
Twisted trans isomer
H
R
R'
H
O
O
H
R
H
R
R'
O
R'
O
O
CH3
hν
t-BuOH
CH3
+
O
+
H
CH3
O
Scheme 11.28
The following questions need to be addressed: (a) How does the triplet reactant give a
singlet product with no stereochemical loss? (b) How does the 2-cyclohexenone molecule adopt
a twisted geometry shown in Scheme 11.28 so that bond switching can occur easily and
stereospecifically? (c) Why is the reaction inefficient? Answers to all these questions can be
found in Figure 11.5. As shown, the cyclohexenone type A rearrangement involves rapid
intersystem crossing from S1 (nπ*) to T1 (ππ*), which then relaxes by twisting around the C=C
bond as shown in Figure 11.5. The closeness of the ground and the triplet surfaces near a
twisted geometry facilitates the intersystem crossing. The enone, entering the ground surface
33
Final 1.0, May 11, 2004
with a distorted geometry, can either reverse to the cis isomer or rearrange. The potential energy
diagram shown in Figure 11.5 suggests that reversal is preferred and thereby accounts for the
inefficiency of the rearrangement process. According to the mechanism presented in Figure
11.5, geometric isomerization (distortion) is the primary photochemical event and that would
lead one to predict that systems (Scheme 11.26) incapable of isomerization would fail to
undergo Type A rearrangement.
The key intermediate in the above rearrangement is trans-2-cyclohexenone. Although
this intermediate has not been spectroscopically characterized either during the above
rearrangement or during other reactions, indirect evidences in support of trans-2-cyclohexenone
exist.
Highly strained trans isomers of cycloheptenone, 1-phenylcyclohexene and 1-
phenylcycloheptene and cis,trans-1,1’-bicyclohexenyl have been characterized by their
absorption spectra through transient spectroscopic studies.
Trans-cycloalkenes have been
proposed as intermediates in several photoreactions (Scheme 11.29).
For example, 1,1’-
bicyclohexenyl A (Scheme 11.29) upon sensitized irradiation give the valence isomer
cyclobutene in which the ring junction is cis, cis fused. Such a product, at the outset appears to
have been formed via a ‘concerted’ disrotation from the triplet state which is unlikley. However,
this has been accomodated, as shown in Scheme 11.29, via a cis,trans-1,1’-bicyclohexenyl
intermediate (characterized spectroscopically). The true photochemical component of the
transformation is geometric isomerization, the second step, namely cyclization, occurs in the
ground state. Same is true in case of cis,cis-1,3-cyclooctadiene C. This diene upon irradiation
yields the cis, trans isomer D (isolated and characterized) which yields the cyclobutene via
thermally allowed conrotation (Scheme 11.29). Trans-cyclohexene is not new to us, we earlier
invoked this intermediate during the photoaddition of methanol to cyclohexene (Chapter 10).
34
Final 1.0, May 11, 2004
hυ/Sens
A
Thermal
allowed conrotation
Photo
B
Characterized by flash photolysis
hυ/Sens
C
Thermal
allowed conrotation
Photo
D
Isolated
hυ/Sens
+
OCH3
CH3OH
Photo
Thermal
O
Ph
hυ/Sens
CH3
CH3OH
H3 C Ph
O
(–)
(R) (+)
O
Photo
Thermal
Ph
CH3
Scheme 11.29
35
Final 1.0, May 11, 2004
11.11. 1, 2-Aryl and 1,2-vinyl migration in cyclohexenones (Type B rearrangement): A
reaction that is not common with nπ* carbonyl reactivity.
The enones A, B and C with aryl or vinyl substituent at the 4-position, upon excitation
give products through migration of the phenyl or vinyl group. The migration of the phenyl and
the vinyl groups that is obtained from enones A-C in Scheme 11.30 bears similarity to the
Zimmerman rearrangement discussed in Chapter 10. This rearrangement in α,β-enones is
generally known as the type B rearrangement. Based on detailed mechanistic studies on 4methyl-4-phenyl-2-cyclohexenone (A in Scheme 11.30) carried out in various solvents it has
been established that the 1,2-aryl migration occurs from nπ* triplet. The products from A
(Scheme 11.30) were sensitized by the triplet sensitizer acetophenone and quenched by the
triplet quencher naphthalene.
Having found the similarity between the type B and the Zimmerman rearrangement, let us
proceed with the assumption that the same mechanism (Scheme 11.31) would hold good for the
type B rearrangement also.
As per this mechanism, we would expect that if there is a
competition between two aryl groups one that would better stabilize the biradical C would
migrate (Scheme 31). In fact this has been found to be so. In systems such as B in Scheme
11.30 both para-cyanophenyl and para-methoxyphenyl migrate preferentially over phenyl.
36
Final 1.0, May 11, 2004
O
O
Ph
HH
+
O
hν
Ph
Me
Ph
H
Me
A
Me
(Type B)
O
Ph
hν
Ph
H
H
O
Ph
+
Ph
Ph
Ph
Major
B
O
Minor
(Type B)
O
O
H
hν
Me
C
O
Me
+
H
O
+
Me
Minor
Major
Me
(Type B)
Scheme 11.30
37
Final 1.0, May 11, 2004
hυ
A
O
B
O
hυ
O
C
O
D
Scheme 11.31
On direct or triplet-sensitized excitation of 4,4-diphenylcyclohexenone, the major product
is the 6-endo-phenyl bicyclic enone (B in Scheme 11.30). Phenyl migration, besides being endo
selective, is stereospecific as well. For example, a study of the optically pure enone A showed
that both phenyl migration products are formed stereospecifically without any loss of optical
purity (Scheme 11.32). Complete inversion of configuration at C-4 has occurred.
38
Final 1.0, May 11, 2004
O
O
hν
Direct or
Triplet Sensitized
Ph
H3C
A
H
Ph
CH3H
R(+)
electron count: n=4; π =4
O
+
+
type A products
Ph
CH3
H
(–)
(+)
B
C
O
H migration fromC3 to C4
nπ*
1
Oy
5
4
H3C
H3C
3
H
O
y
2
O
yy
Jump from excited to ground
state surface π* electron jumps
to n-orbital
H
H
H
H3C
O
CH3 H
C2–C4 bonding
H
electron count: n=3; π =5
H
Ph
Ph
D
C
Ph
CH3
B
E
electron count: n=3; π =5
electron count: n=4; π =2; σ=2
O
CH3 H
H
O
y
O
O
H
H3C
H
F
electron count: n=3; π =5
H
C
G
CH3 H
+
Ph
CH3
Ph
H
Ph
G
Scheme 11.32
At this point it is fair to ask how a product can be formed stereospecifically from a triplet
precursor (nπ* triplet). The first step of the reaction is the excitation of oxygen n electron to π*
orbital. To keep track of electrons electron count is included in Scheme 11.32. The nπ* excited
state of enone should be viewed to have the structure D in which a radical center is stabilized at
C3. At this stage the adjacent phenyl could migrate to the radical center either in a concerted or
in a stepwise fashion. The former would produce the structure E and the latter F . Both
structures E and F are still in the excited state since the n-orbital is one less and π-face one
excess electron. The triplet diradical most likely enters the ground state surface at this point and
39
Final 1.0, May 11, 2004
further reaction proceeds on a singlet surface. In simple terms the electron jumps from π-face to
n-face with a change in spin.
The diradical E with concerted migration of phenyl and closing of
C2—C4 bond could account for the stereospecific nature of the rearrangement. It is important to
note that in E the back lobes of the p-orbitals on carbons C4 and C2 are favorably situated to
undergo a disrotatory ring closure in concert with phenyl migration from C4 to C3. Such a
synchronous change in geometry will lead exclusively to the endo isomer as has been observed
in a number of cases. The species E on the singlet surface undergoes either H-migration from C3
to C4 (to give C) or bonding between C2 and C4 (to give B), concomitant with cleavage of the C4phenyl bond.
This generalization may not hold good in all cases. As seen in Scheme 11.30
(structures B and C) minor amounts of the exo isomer is formed in some cases, and there is a
likelihood the above rearrangement may not be fully concerted and the open diradical F (Scheme
11.32) may be involved in a few cases.
11.12. Addition to alkenes
The first example of a photochemical addition between an excited α, β-enone and an
alkene is that of carvone to give carvone-camphor reported by Ciamician in 1908 (Scheme
11.33). Since then, as illustrated in Scheme 11.34, this reaction is proven to be general both in
terms of enone and unsaturated system.
Most importantly the cycloaddition has been
synthetically very valuable; syntheses of numerous natural and unnatural products have utilized
this reaction as a key step. In this section we will discuss mechanism of this reaction.
40
Final 1.0, May 11, 2004
O
hν
O
Scheme 11.33
O
O
hν
O
R
hν
O
R
R
R
O
O
CH2
hν
CH2
C
CH2
Scheme 11.34
11.13. Reactive state
α, β-Enone consists of two reactive chromophores, carbonyl and alkene in conjugation.
While in the the nπ* excited state the enone would be expected to react like a carbonyl to form
an oxetane, in the ππ* state it would be expected to react either at the alkene (C3=C4 bond) or at
41
Final 1.0, May 11, 2004
the carbonyl part. In general, enones when react from ππ* state add to the C3=C4 bond to yield
cyclobutanes. An example where addition to both carbonyl and alkene occurs is shown in
Scheme 11.35.
4,4-Dimethylcyclohexenone upon irradiation in presence of 2,3-dimethyl-2-
butene yields four products, one of which is familiar to us already, B, a product of type A
rearrangement derived from nπ* triplet. Based on quenching studies with napthalene it has been
shown that oxetane E also come from nπ* triplet. Formation of the other two cycloadducts, C
and D is quenched at a different rate from that of B and E suggesting that these derive from a
different triplet. The reactive state in these cases is believed to be ππ* triplet. In general, α, βenones react at the C3=C4 bond from the ππ* triplet. Since the intersystem crossing from S1 to T1
is near unity, we need not concern ourselves with reactions from S1. Since addition to alkene
occurs essentially from T1 (ππ*), we will focus only on this state. It should be kept in mind that
in enones T1 (ππ*) and T2 (nπ*) are close-by and interefernce by each other is a possibility.
hν
+
Me
Me
Me
Me
A
B
O
O
O
O
+
O
+
+
Me
Me
C
Me
Me
D
Me
Me
E
Scheme 11.35
11.14. Radical intermediate
42
Final 1.0, May 11, 2004
Cycloaddition and dimerization of acyclic enones do occur but it is less common. In
these cases geometric isomerization effectively competes with the bimolecular addition process.
One example is provided in Scheme 11.36.
Ph
O
Ph
COPh
hν
Ph
Ph
COPh
Ph
COPh
+
PhOC
Ph
Scheme 11.36
Details of photocycloaddition of cyclohexenones and cyclopentenones differ slightly.
We discuss these two examples independently. In this section we discuss the addition of alkenes
to excited cyclopentenones. The addition of an excited cyclopentenones to an alkene involves a
reversible intermediate as evidenced by low quantum yield of the product (~0.3) in spite of fairly
high rate of quenching (>108M-1sec-1). Several experimental observations suggest that this
reversible intermediate is a diradical: (a) Upon irradiation of cyclopentenone with 2methylpropene in addition to cycloadducts, disproportionation products were obtained (Scheme
11.37). These products could be understood on the basis of involvement of diradical
intermediates shown in Scheme 11.38. (b) Intramolecular addition of vinylcyclopropane to
cyclopentenone, in addition to cycloadducts, rearranged products were obtained (Scheme 11.39).
These once again support the involvement of diradical intermediates (Scheme 11.40). (c)
Employing hydrogen selenide as the reagent the diradical intermediate has been trapped
(Scheme 11.41). When the irradiation of cyclopentenone with 2-methylpropene was conducted
in presence of hydrogen selenide no cycloadducts were formed, instead several new products
43
Final 1.0, May 11, 2004
were obtained. The mechanism involving diradicals shown in Scheme 11.42 explain the
formation of these products. (e) Diradical intermediates have been detected through transient
spectroscopy during the dimerization of cyclopentenone. Based on the above observations
addition of ππ* excited α, β-enone to alkene is expected to yield diradical as an intermediate.
O
O
+
hν
O
+
+
+
C6H6
2.9%
69.5%
O
O
9.1%
18.6%
27.7%
72.4%
Scheme 11.37
O
O
O
+
O
+
hν
O
O
O
+
Scheme 11.38
44
Final 1.0, May 11, 2004
Et
O
O
+
hν
O
+
O
O
+
+
Et
Scheme 11.39
O
O
O
hν
+
O
+
O
O
Et
O
+
+
Et
Scheme 11.40
45
Final 1.0, May 11, 2004
O
O
+
hν
O
+
O
O
+
+
O
+
H2Se/C6H6
2.3%
10.0%
15.3%
7.5%
64.5%
35 %
Scheme 11.41
Scheme 11.42
46
Final 1.0, May 11, 2004
11.15. Reversibility of diradical intermediate
Normally interaction of an excited chromophore with an alkene results (refer to addition
of excited carbonyl, alkene and aromatics to unsaturated systems) in an exciplex which yields a
diradical, an ion pair or a stable product. No experimental findings demand an exciplex during
the addition of excited α, β-enone to alkene. The low quantum yield in spite of total trapping
of the excited enone by olefins must be due to the reversibility of the intermediate diradical.
This has been established to be so.
Let us consider the addition of cyclopentenone to 2-methylpropene (Schemes 11.37 and
11.41). The products obtained in the absence of hydrogen selenide are A-D while in the
presence of hydrogen selenide the products are E-I. From the ratios of isolated photoproducts,
the head-tail/head-head selectivity is 72.4/27.7 = 2.6. The yields of hydrogen selenide trapped
products from the head-tail and head-head diradicals are 35% and 65%, respectively. Thus
while the head-tail and head-head diradicals are formed in the ratio of 0.5, they yield products in
the ratio of 2.6. This suggests that head-head diradical more than the head-tail diradical prefers
to reverse to the reactants. From the above examples it is clear that the major cycloadducts do
not come from the biradicals which are formed at the fastest rates; rather, the major products
come from diradicals which show greater propensity to close to products instead of fragmenting
to the ground state enone and alkene.
11.16. Importance of trans-cyclohexenones during addition to olefins
It is important to note that larger cyclic enones such as 2-cyclooctenone and 2cycloheptenone (similar to acyclic enones) do not add to electron rich alkenes. They mainly
47
Final 1.0, May 11, 2004
undergo geometric isomerization. In this context the behavior of cyclohexenones is interesting.
When 2-cyclohexenones adds to alkenes, adducts with trans ring junction is formed as a major
product along with the smaller amounts of more stable cis adduct (Scheme 11.43). Consistent
with the expectation that the trans ring fused adducts would be highly strained, addition to 2cyclopentenones yields only cis ring junction fused products. These observations suggest that
the addition might occur from the relaxed (twisted) rather than from the vertically excited ππ*
state of 2-cyclohexenone. We have seen earlier that additions of alcohols and dienes to twisted
state of 2-cyclohexenone result in trans-addition (see Scheme 11.24). Several thereotical
calculations suggest that α,β-enones prefer a twisted geometry in the ππ* state. Given this
information, it is likley that twisting of C=C bond might preceede the formation of 1,4-diradical
during the addition of cyclohexenones to alkenes. Due to ring strain, isomerization of
cyclopentenones is not expected and the addition occurs from the vertically excited ππ* state of
cyclopentenone.
O
O
O
MeO
hν
MeO
49%
OMe
OMe
21%
OMe
OMe
hν
O
O
O
O
Scheme 11.43
48
Final 1.0, May 11, 2004
11.17. Synthetic applications of photocycloaddition
Although hundreds of enones and alkenes have been irradiated, accurate predictions of
the regiochemistry of cycloadducts still is not possible. Factors contributing to the lack of
predictability are (a) presence of nπ* triplet closer to the reactive ππ* state (b) lack of knowledge
concerning the importance of dipolar attractions between excited enone and ground state alkene
and (c) lack of information on the factors that control the cyclisation and cleavage of the 1,4diradical intermediate. While these are true, there are numerous examples where precise
stereochemical control has been achieved. This in fact is the reason for this reaction being so
popular amongst synthetic chemists (Schemes 44-46).
O
O
O
O
hν
Br
O
O
HOOC
Br
Br
O
Br
Br
cubane
(95%)
O
Scheme 11.44
H
H
hν
+
OH
CO2Me
O
MeOOC
H
O
HO
(+)-calameon
49
Final 1.0, May 11, 2004
Scheme 11.45
Cl
H
O
hυ
O
O
H
Cl
O
O
photocycloaddition
and fragmentation
H
H
H
HO HO
H
COOCH3
OH
OH
Ingenol
Scheme 11.46
11.18. The de Mayo reaction
The photochemical addition of alkenes to enolized 1,2- or 1,3-diketones and their
derivatives is referred to as the de Mayo reaction. The first example reported by de Mayo is the
reaction between acetylacetone and cyclohexene. The reaction proceeds via the excited state of
the enol form of the diketone, and adduct formation effectively competes with cis-trans
isomerization, presumably because the latter process is slowed due to intramolecular hydrogen
bonding between carbonyl and enol (Scheme 11.47). Under the reaction conditions the acyl
cyclobutanol is unstable and undergoes retro-aldol reaction to yield a 1,5-diketone. Another
beautiful example is the photoreaction of cyclohexane-1,3-dione (Scheme 11.48). This reaction
has been utilized for the synthesis of hirsutene (Scheme 11.48). Addition of alkenes to enol
ethers and enol esters of 1,3-diketones is also known as the de Mayo reaction. The first example
50
Final 1.0, May 11, 2004
along with its use in synthesizing two natural products, himachalane and longifolene are shown
in Scheme 11.49.
O
O
O
O
OH
hν
O
H
O
O
Scheme 11.47
O
OH
O
hν
O
O
O
O
O
O
O
HO
OH
O
O
hν
+
AcO
AcO
OAc
O
O
OH
H OAc
H
hirsutene
Scheme 11.48
OAc
OAc
O
hν
OAc
O
O
O
O
O
O
O
OH
β-Himachalene
Scheme 11.49
51
Final 1.0, May 11, 2004
11.18. Diastereo- and enantioselectivity
Since the enone addition to alkenes to yield cyclobutanes is synthetically very useful,
there have been attempts to direct the reaction towards diastereo- and enantio-selective products.
In the absence of any bias the C=C bond of enone will be approached by the incoming alkene by
either enantiotopic face to yield equal amounts of the two enantiomeric cyclobutanes (Scheme
11.50). Strategies have been devised to make the enantiotopic faces of the C=C bond of enone
unequal. When this is achieved, enantioselectivity is expected. The general approach is to
introduce a chiral center so that there is a steric bias for the approaching alkene. The chiral
center could be introduced either on the enone or on the incoming alkene framework. Both
approaches have yielded satisfactory results.
O
O
H2 C CH2
O
+
1:1
O
O
H2 C CH2
O
+
H3 C
H3 C
H3 C
H
H
H
may not be 1:1
Scheme 11.50
Spirocyclic dioxinone A has a chiral center slightly remote from the enone chromophore
(Scheme 11.51).
As seen in the scheme the two faces of the C=C clearly offer different
amounts of steric hindrance to the incoming alkene. When this enone was irradiated in presence
52
Final 1.0, May 11, 2004
of cyclopentene the two diastereomeric products were obtained in the ratio 6:1. As expected
cyclopentene approaches the enone from the less hindered face. Consistent with this model,
when a more hindered cyclopentene B was used a single diastereomer was obtained (Scheme
11.51).
O
O
hν
O
O
O
+
O
O
O
A
O
O
6:1
O
hν
O
O
O
O
OCH2Ph
PhH2CO
PhH2CO
B
OCH2Ph
only
Scheme 11.51
Cyclopentenone adds to the ketene acetal A to yield the expected [2+2] adduct (Scheme
11.52). The reactant olefin has a chiral center with a marginal steric disposition. The
enantiomeric excess (e.e.) obtained after removal of the chiral auxiliary is still significant (33%).
It is important to note the chiral handle can be easily removed and recycled.
53
Final 1.0, May 11, 2004
O
O
O
H
H
hν
+
Me3SiO
O
OSiMe3
*
H
O
OR
H
(33 % de)
A
(33 % ee)
Scheme 11.52
Truly for the above strategy to be a success the chiral auxiliary should be an easily
attachable and removable group (Scheme 11.53). Lactic ester substrate A in Scheme 11.54 gave
head-head (HH) and head-tail (HT) adducts. What is remarkable is that both adducts are formed
as single diastereomer. Removal of the chiral auxiliary gave a single enantiomer in each case
(Scheme 11.54)! This route is highly useful since the inexpensive chiral auxiliary is used as
temporary linker and can easily be removed after photocycloaddition.
O
O
O
O
*
hν
OH + HO
O
O
+
Chiral spacer
O
O
O
Chiral spacer
O
*
*
*
O
O
Chiral spacer
*
O
O
*
OH
OH
+
Chiral spacer
OH
OH
O
OH
OH
Scheme 11.53
54
O
Final 1.0, May 11, 2004
O
O
O
O
O
O
hν
O
O
+
O
2
H
H
O
O
O
O
O
A
O
HT (27%; d.e.: 100%)
O
O
O
O
O
HH (49%; d.e.: 100%)
O
H
H
OH
CO 2Me
e.e. 100%
O
O
e. e.: 100%
Scheme 11.54
11.19. Photocycloaddition reactions of coumarin and psoralen and PUVA treatement
Psoralens have been used in conjunction with UVA irradiation (320-400 nm) as a clinical
treatement, known as PUVA therapy, for dermatological disorders for more than two decades.
More recently, psoralens have been employed in the photoinactivation of lymphocytes and hence
therapy of cutaneous T-cell lymphoma.
The above therapies rely on a basic photoreaction
enones undergo, photocycloaddition to C=C bond. Among the psoralens, 8-methoxypsoralen is
used in the PUVA therapy and therefore we will restrict our discussion only to this molecule and
its parent system coumarin.
55
Final 1.0, May 11, 2004
The lowest excited states of coumarin and psoralen consist of nπ* and ππ* states both in
the singlet and triplet manifolds (Figure 11.6). Upon excitation the main photoreaction
coumarin undergoes is dimerization. The structure of the dimer depends on the reactive state.
For example, from excited singlet state syn-head-head (major) and syn-head-tail and from triplet
state anti-head-head (major) and anti-head-tail cyclobutanes are formed (Scheme 11.55). The
excited state chemistry of coumarin, like most enones, is solvent dependent. While in non-polar
solvents such as benzene the triplet product anti-head-head is obtained, in polar solvents such as
methanol the main adduct formed is syn-head-head (singlet product). The solvent dependence
can be understood on the basis of dependence of rate of intersystem crossing from S1 to T1 on the
solvent.
In non-polar solvents, it is quite likley that nπ*3 state is below ππ*1 (Figure 11.6)
which would enhance the rate of ISC. On the other hand, in polar solvents, the nπ* will be
pushed up and ππ* state lowered in energy placing the nπ*3 state slightly above ππ*1. This
feature would decrease the rate of ISC allowing dimerization to compete with ISC. Thus while
in polar solvents the dimerization comes from ππ* singlet, in non-polar solvents it originates
from ππ* triplet.
56
Final 1.0, May 11, 2004
Figure 11.6
57
Final 1.0, May 11, 2004
O
O
O
O
O
O
O
O
(syn head-head)
*
S1
O
O
O
T1
(anti head-head)
O
O
O
O
O
O
(syn head-tail)
O
(anti head-tail)
Scheme 11.55
8-Methoxypsoralen possesses two reactive C=C bond, C3, C4 double bond of pyrone
ring and C4’, C5’ double bond of furan ring (Scheme 11.56).
Upon excitation 8-
methoxypsoralen, similar to coumarin, undergoes dimerization encaging the C3, C4 double bond
of both monomers. The reaction that is of great interest is the ability of 8-methoxypsoralen to
add to pyrimidine bases thymine and and cytosine.
For example, irradiation of psoralen in
presence of thymine results in four adducts shown in Scheme 11.56. Thus both C3, C4 double
bond of pyrone ring and C4’, C5’ double bond of furan ring of psoralen are reactive towards
pyrimidine bases. This forms the basis of the use of 8-methoxypsoralen in the treatment of
psoriasis and cutaneous T-cell lymphoma.
58
Final 1.0, May 11, 2004
O
O
CH3
+
HN
O
O
4
4'
5'
O
O
3
O
+
CH3
HN
O
N
H
O
O
O
CH3
O
HN
O
N
H
O
hν
N
H
O
H
N
O
O
HN
NH
NH
O
CH3
+
O
O
O
O
O
O
Scheme 11.56
Psoralen photochemotherapy is carried out by topical application or oral administration
of 8-methoxypsoralen (2h before exposure to light) and subsequent localized irradiation of the
patient with UV-A light (320–400 nm). UV radiation is then delivered at progressively
increasing doses to avoid toxic reaction. The technique gives satisfactory results in psoriasis as
well as in less common skin disorders.
Interactions between 8-methoxypsoralen and DNA helices take place in three steps
(Figure 11.7). In the first step, 8-methoxypsoralen molecules form complexes (intercalates) with
hydrogen bonded base pairs of DNA in the dark. The intercalation occurs in such a way that
there is maximum overlap between the base pairs above and below the psoralen ring. Following
irradiation with UVA light, in the second step, 8-methoxypsoralen forms a cycloadduct with
pyrimidine (thymine and cytosine) of DNA double helix. In the third step, on absorption of
second photon of light, 8-methoxypsoralen that is already attached to one strand of the helix
forms a cycloadduct with the second strand thus covalently linking the two strands of the DNA
59
O
Final 1.0, May 11, 2004
double helix. Once the two strands are cross linked, DNA replication and cell multiplication are
prevented. Cross-linking is most important for therapeutic effectiveness of the drug.
The above photochemistry is also used to treat cutaneous T-cell lymphoma (CTCL).
CTCL is a malignancy of white blood cells. With the knowledge that DNA replication can be
arrested with light activated 8-methoxypsoralen, the same treatment is applied to control CTCL.
While full body UV-A exposure effectively controls CTCL, the more advanced target-oriented
approach relies on removing the malignant cells from the body and subjecting them directly to 8methoxypsoralen and light. In this approach 10% of the patients blood (following administring
8-methoxypsoralen) is removed and exposed to UV-A. This process deactiavtes the malignant
white cells, and the purified blood then returned to the patient. Multiple repetition of this process
helps to reduce and eliminate the defective white blood cells. The chemistry of importance that
occurs in this treatment is the same outlined in Figure 11.7 for treatment of psoriasis.
60
Final 1.0, May 11, 2004
•
Intercalation
•
Monofunctional
adduct ( 3, 4 with
pyrimidine base)
•
Bifunctional
crosslinked adduct(3,
4 and 4’, 5’ with
pyrimidine bases)
Figure 11.7
61
Final 1.0, May 11, 2004
11.20. Photocycloaddition reactions of nucleic acid base pairs and skin cancer
The formation of photoproducts in DNA is the fundamental cause of the adverse effects
of UV irradiation including mutagenesis, carcenogenesis and cell death. Thus UV-B radiation
(290-320 nm) is a potent and ubiquitous carcinogen responsible for much of the skin cancer in
the human population today. The basic chemistry that is responsible for DNA damage is [2+2]
photocycloaddition. For, example, UV radiation promotes the formation of a cyclobutyl ring
between adjacent thymine residues on the same DNA strand to form an intrastrand thymine
dimer (Scheme 11.57). Similarly, cytosine and thymine-cytosine dimers also form but less
frequently. Such pyrimidine dimers locally distort DNA base-paired structure, interfering with
transcription and replication. The ability of an organism to survive UV-B radiation is related to
its ability to remove the above dimers from its DNA. Even when damaged DNA can be mended,
the restoration may be imperfect, producing mutation, a heritable alteration of genetic
information.
Importance of photocycloaddition between adjacent thymines in DNA strand justifies a
brief discussion of the photochemistry of thymine. The lowest excited singlet and triplet states
of thymine have ππ* character. In aqueous medium, fast rate of internal conversion from ππ*
singlet to ground state and poor rate of intersystem crossing from ππ* singlet to ππ* triplet
makes the quantum yield of intersystem crossing from S1 to T1 very low (<10-3).
As expected based on the photobehavior of α,β-enone, thymine undergoes [2+2]
dimerization from ππ* singlet state in aqueous medium to yield syn-head-head as the major
dimer with a low quantum yield, (<0.05).
In contrast to singlet chemistry, triplet sensitization
of thymine results in four dimmers, syn-head-head, syn-head-tail, anti-head-head (major) and
anti-head-tail cyclobutanes (similar to coumarin presented in Scheme 11.55). The fact that cis-
62
Final 1.0, May 11, 2004
syn cyclobutane dimer alone is obtained from adjacent thymine residues upon UV-B irradiation
of DNA suggests that excited singlet state is involved during photodamage of DNA. Repair of
the damaged thymine pair also proceeds by a photoactivated process. A photoactivated (>370
nm) enzyme helps to cleave the dimers back to monomers. We will not be discussing this
process.
Scheme 11.57
63
Final 1.0, May 11, 2004
11.21. Photorearrangement of Cross-Conjugated Dienones
Of the many cross-conjugated dienones, cyclohexadienones undergo one of the most
fascinating and complex set of photochemical rearrangements known.
The extreme
propensity of the cyclohexadienone chromophore to undergo light-induced rearrangement
was noted as early as 1830 in connection with studies of the terpene α-santonin. Most of the
rearrangements of cyclohexadienones to be discussed in this section bear direct analogy on
the transformations exhibited by α-santonin, so it is appropriate to begin the section with a
discussion of the photochemistry of α-santonin.
This will be followed by examples
establishing the generality of the process and a discussion of the mechanism and synthetic
value of the rearrangement.
This rearrangement illustrates how mechanistic details were
uncovered during pre-flash photolysis days.
11.22. Santonin
Upon irradiation in neutral media, α-santonin (A) undergoes rapid isomerization to
the cyclopropyl ketone lumisantonin B (Scheme 11.58). This product is photochemically
labile and rearranges further to other products as illustrated in Scheme 11.58. The final
product obtained in the reaction depends not only on the extent of irradiation but also on the
solvent used. For example, in nucleophilic solvents such as alcohol or water, an ester or an
acid E is obtained. In aqueous acidic solvent media the main product is not lumisantonin but
a hydroxy ketone D (Scheme 11.58). Thus through the appropriate choice of solvent and
duration of irradiation α-santonin can be converted to lumisantonin, isophotosantonic
lactone, mazdasantonin C, or photosantonic acid (Scheme 11.58).
64
Final 1.0, May 11, 2004
O
hν
hν
O
O
A
O
O
B
lumisantonin
O
santonin
hν H3+O
O
O
mazdasantonin
hν H2O
OH
H
O
O
O
HOOC
O
C
O
isophotosantonic lactone
O
photosantonic acid
Scheme 11.58
O
O
hν
Me
Me
Me
Me
O
O
hν
H5C 6
C 6H 5
C 6H 5
C 6H 5
C 8H 17
hν
AcO
O
AcO
O
H
Scheme 11.59
65
Final 1.0, May 11, 2004
As illustrated in Scheme 11.59, the rearrangements observed in the case of αsantonin have been established to be general with numerous cyclohexadienones. Only
requirement is that the system must contain a cyclohexadienone chromophore. Employing
simple cyclohexadienones as model systems we will attempt to understand the mechanism of
this process.
11.23. Mechanistic Details: Reactive state
Photoconversion of santonin to lumisantonin as well as to isophotosantonic lactone is
sensitized by triplet sensitizers such as acetophneone and benzophenone and quenched by
triplet quencher cyclohexadiene (along with the formation of the cyclohexadiene dimer)
suggesting that a triplet state is involved. Based on the nature (structured) and lifetime (ms
range) of the phosphorescence emission and reactions of a model cyclohexadienone A
(Scheme 11.60) the reactive state is suggested to be a nπ* triplet. Cyclohexadienone A upon
excitation rearrange to the expected lumiketone B. In presence of an alkene oxetane product
C, and in presence of a hydrogen donor solvents (ethers, secondary alcohols) reduction
product p-cresol D, characteristic products of nπ* state, are obtained at the expense of B.
These suggests that the lumiketone as well as oxetane and p-cresol come from the same
excited state, nπ* triplet.
66
Final 1.0, May 11, 2004
OH
OH
H3C
CCl3
CH3
RH
O
D
O*
hν
O
CH3
CCl3
CCl3
H3C
H3C
CCl3
B
A
H
CH3
H
CH3
CH3
CH3
CH3
O
CH3
CCl3
H3C
C
Scheme 11.60
11.24. Zwitterionic intermediate
A mechanism proposed for the lumiketone rearrangement is outlined in Scheme
11.61. Key intermediate in this process is zwitterion C. What evidences are there for this
intermediate? (a) The oxyallyl zwitterion, generated independently via a Favorskii type
reaction, gave the same lumiketone product in high yield (Scheme 11.62). (b) Direct
evidence in favor of an oxyallyl zwitterion intermediate came from capture of such a species
during the irradiation of cyclohexadienone A (Scheme 11.63). As illustrated in Scheme
11.63 irradiation of A in an alcoholic solvent gave the methyl ether B while in acidic alcohol
gave C. Similar irradiation in the presence of lithium chloride gave the product D. These
products can be rationalized on the basis of nucleophilic (B and D) and electrophilic capture
(C) of the oxyallyl zwitterion. Confirmatory evidence comes from the capture (product E)
67
Final 1.0, May 11, 2004
of the oxyallyl zwitterion by cyclopentadiene via a [3+4] cycloaddition process (Scheme
11.63). An additional point to note is that while the lumiketone rearrangement was quenched
by LiCl in isopropanol, the reduction product p-cresol was not quenched suggesting that the
diradical intermediate (nπ* state) precedes the zwitterionic intermediate. Based on these
results we can be confident that the transformation of a cyclohexadienone to a lumiketone
involves an oxyallyl zwitterion intermediate.
O
O
O
(n)
hυ
Ph
(n)
ISC
(π)
Ph
C3—C5 bond
(π)
Ph
O (n)
Ph
formation
Ph
Ph
A
Ph
Ph
B (triplet)
6π, 2n
7π, 1n
7π, 1n
2 electrons transferred from π orbital to
σ orbital plus nuclear position changed
5π, 1n, 2σ
Electron demotion
from π* to n and ISC
O
ISC
O (n)
O
1,4-sigmatropic
Ph
Ph
Electron demotion
rearrangement
Ph
Ph
from π* to n
C
4π, 2n, 2σ
4π, 2n, 2σ
Ph
Ph
B (singlet)
5π, 1n, 2σ
Scheme 11.61
68
Final 1.0, May 11, 2004
Br
H
t-BuOK
Ph
H
Ph
Ph
O
O
O
Ph
Ph
Ph
H
H
Scheme 11.62
HO
O
ROH
H3C
CCl3
Nucleophilc trapping
OCH3
ROH
H+
H3C
CCl3
O
OH3C
CCl3
ROH
H3C
hυ
Cl
C Cl
C=C
H3C
O-
O-
CCl3
H3C
CCl3
Cl
Cl
O
LiCl
Cl
ROH
Cl
C Cl
H3C
Electrophilc trapping
OCH3
Cl
O *
H3C
O
OR
Cl
Cl
C=C
Cl
H3 C
Cl
O
CH3
CCl3
Electrophilc trapping
CCl3
O
Me
Oxyallyl zwitterion trapping
By [3+4] cycloaddition
Scheme 11.63
69
Final 1.0, May 11, 2004
If one accepts the intermediacy of the oxyallyl zwitterion, absence of lumiketone and
formation other rearranged products under acidic conditions could also be rationalized.
Under aqueous acidic conditions, two types of products are obtained: 5/7 fused hydroxy
ketone and a hydroxy ketone with spiro [4.5] decane ring system (Scheme 11.64). Both
these products can be rationalized on the basis of a common intermediate, hydroxy allyl
cation. A nucleophilic attack by solvent on hydroxy allyl cation at C-10 from the front side
and cleavage of the rear 1-10 cyclopropyl bond gives rise to a spiroproduct (path A in
Scheme 11.65) whereas rear-side attack and cleavage of the front 5-10 cyclopropyl bond
accounts for the formation of a 5/7 fused hydroxy ketone (path B in Scheme 11.65). The
variation of the final product with the position of the methyl group can also be understood on
the basis of the hydroxy allyl cation. The proclivity of the 4-methyl derivatives for
undergoing preferential path B cleavage could be attributed to an inductive effect exerted by
the methyl substitunet, which would cause localization of the positive charge at the more
highly substituted position, or to hyperconjugative stabilization by the methyl group of the
incipient double bond being formed during the cleavage process.
Thus transferring the
methyl group from C-4 to C-2 transfers the point of localization of the positive charge and
hence the cleavage of the cyclopropyl ring from the 5-10 to the 1-10 bond. Thus, in acidic
media the zwitterion is protonated and the resulting hydroxy allyl cation undergoes
rearrangement to a 5/7 fused hydroxy ketone and a spiro ketone where as in non-protic
solvent, the only reaction the oxyallyl zwitterion undergoes is closure to a cyclopropyl ketone
(lumiketone).
Oxy allyl zwitterion model also explains the photobehavior of γ-
hydroxycyclohexadienones (in non-acidic media) shown in Scheme 11.66. In these cases,
70
Final 1.0, May 11, 2004
the γ-hydroxy group serves as the intramolecular nucleophile and the observed products are
the natural result of the expected fate of the oxyallyl zwitterion (Scheme 11.66).
OH
H
10
hν
45% ΑcΟΗ
O
OH
+
O
O
OH
hν
2
45% ΑcΟΗ
O
O
H
O
4
hν
45% AcOH
OH
O
Scheme 11.64
71
Final 1.0, May 11, 2004
R1
hν
O+
H3
O
R2
R1
H3
H
O
OH2
R1
O+
10
10
1
H
HO
5
HO
A
H
R2
R2
R2
OH2
R1
-H +
B
-H +
OH
R1
R1
O
R2
H
OH
O
R2
R 1 = CH 3; R2 = H
R 1 = H; R2 = CH 3
Scheme 11.65
72
Final 1.0, May 11, 2004
O
OH
hν
O
O
CH3
CH3
Me
OH
O
hν
Me
O
O
O
OH
R2
OH
R2
R2 = H
-
O
O
R1
Me
Me
hν
O
O
H
R 1 = Me
O
R1
Me
O
H
O
R1 = H
R 2 = Me
-
O
Me
O
Scheme 11.66
11.25. Transformation of nπ* triplet to the zwitterion intermediate
How does a diradical-like triplet state yield a zwitterionic intermediate?
As
presented above the basic mechanism (Scheme 11.61) of the cyclohexadienone
rearrangement consists of the following steps: (a) excitation and intersystem crossing to the
reactive nπ* triplet state, (b) 3,5-bonding to form the 1,3-triplet diradical (and intersystem
crossing to the 1,3-singlet diradical) (c) electron demotion to give the 1,3-zwitterion (on the
ground state surface) and (d) 1,4-migration to give the final product. The above steps are
graphically illustrated in Scheme 11.67. Light energy promotes an electron from the n-plane
to the π-face. The triplet diradical that results from C3, C5 bonding is still in the excited state
(see Scheme 11.61 for the electron count). At this stage, it is believed that spin inversion
73
Final 1.0, May 11, 2004
and electron demotion of an electron from π-face to the n-orbital take place. Thus one can
visualize an adiabatic transformation of the nπ* triplet to a diradical triplet which is the
excited state of a zwitterion. In all the mechanisms considered thus far we did not encounter
this possibility.
In cyclohexadienone, presence of an adjacent C=C bond stabilizes the
zwitterion relative to the diradical making the diradical to be the excited state of the
zwitterion. Therefore, the last step of the rearrangement, 1,4-migration, takes place on the
ground state surface.
S1
O
T1 (nπ*)
DR1
DR3
Ph
Ph
O
Zwitterion
Ph
Ph
O
Ph
Ph
Scheme 11.67
74
Final 1.0, May 11, 2004
What is the driving force for the bonding of the 3–5 carbons in the nπ* triplet of
cyclohexadienone to generate a high energy intermediate? In Figure 11.8 the two π-MO
(HOMO and LUMO) representations and the n-orbital of a cyclohexadienone are shown.
Clearly there is an increase in the bond order between C3 and C5 upon promotion of an n
electron to π* orbital. Based on this, tendency to form a bond between C-3 and C-5 of
cyclohexadienone in the nπ* excited state is not surprising.
HOMO (n-orbital)
LUMO (π∗-orbital)
O
HOMO -1 (π-orbital)
Figure 11.8
75
Final 1.0, May 11, 2004
11.26. Synthetic Applications
Photochemical rearrangements of cyclohexadienones are stereoselective,
regioselective and most often exo-endo selective with high quantum yields. By employing
the proper excitation wavelength one can avoid secondary photoreactions which are often a
problem. The photorearrangement of dienones has been employed as a key step in the
laboratory synthesis of numerous natural products. A few such examples are listed in
Scheme 11.68.
76
Final 1.0, May 11, 2004
O
O
hν
β-vetivone
O
O
α-vetispirene
AcO
H
H
OH
H
O
H
hν
HO
HO
H
H
OH
H
HO
O
OH
OH
graynotoxin II
HO2C
H
2
4
H
O
hν
O
H
H
H
H
H
O
H
cyclocolorenone
Me
O
Me
O
OH Me
Me
Me
1) hν, dioxane
Me
Me
2) H 2, Pd/C
OH
Me
NC
Me
Me
(–) axisonitrile
Scheme 11.68
11.27. Photochemistry of linearly conjugated cyclohexadienones
Lineraly conjugated cyclohexadienones possess nπ* and ππ* states as the lowest
excited states and their ordering is very much dependent on the substituents on the ring and
77
Final 1.0, May 11, 2004
the medium (Figure 11.9). They undergo two primary photoreactions, α-cleavage from nπ*
state and oxa-di-π-methane type rearrangement from ππ* state (Scheme 11.69). Since the
nature of the reactive state is dependent on the environment, the isolated products could vary
with the system and the medium in which the irradiation is conducted.
The ketene formed
via α-cleavage can be trapped by alcohol and amine present in the medium and in their
absence the ketene generally reverses to the reactant. At 77 K the ketene has been detected
spectroscopically. In general, during irradiation of 2,4-cyclohexadienones in polar medium,
independent of their substituents, ketene formation via α-cleavage from nπ* singlet seems
common.
O
C
O
S2
ππ*
S1
nπ*
HX
X
O
O
nπ* and ππ* are nearby and
the ordering could be
switched with solvents
Figure 11.9
78
Final 1.0, May 11, 2004
O
nπ*
O ππ*
O
C
O
O
O
Scheme 11.69
This process explains the formation of photosantonic acid from lumisantonin
(Scheme 11.58) and photointerconversion of steroidal diastereomers (Scheme 11.70).
During the photoconversion of lumisantonin to photosantonic acid (in aqueous organic
solvent), neither mazdasantonin nor ketene interemediate are detected. The mazdasantonin
(2,4-cyclohexadienone derivative) photoreacts much faster (and more efficiently) than
lumisantonin and the ketene intermediate once formed from mazdasantonin is immediately
trapped by water. Two most elegant applications of the above reactions in synthesis of
natural products are provided in Schemes 11.71 and 11.72.
79
Final 1.0, May 11, 2004
CH3
H3 C
O CH
3
O
H
H
CH3
H
H
hν
H
H
hν
H3 C
O
C
H
H3 C
H
H
Scheme 11.70
OH
OAc
O
PhO2S
OAc
Me
(CH2 )10
OH
H
hν ( > 340 nm) CCl4
OH
N-methylimidazole (1.3 equiv)
OH
SO2Ph
O
Me H O
O
H Me
O
(+)-aspicilin
Scheme 11.71
80
Final 1.0, May 11, 2004
O
O
CH3
hν/ CH3OH
CH3
H3C
H3 CO
CH3
CH3
CH3
CH3
O
OCH3
CH3
O
H3 C
CH3
OCH3
O
O
OCH3
CH3
CH3
Crocetin dimethyl ester
Scheme 11.72
81
Final 1.0, May 11, 2004
11.28. References
(1)
Wilsey, S.; Gonzalez, l.; Robb, M. A.; Houk, K. N. J. Am. chem. Soc. 2000, 122,
5866-5876.
(2)
Stereoselectivity of Photocycloadditions and Photocyclizations; Griesbeck, A. G.;
Fiege, M., Eds.; Marcel Dekker: New York, 2000; Vol. 6, pp 33-100.
(3)
Dorr, H.; Rawal, V. H. J. Am. Chem. Soc. 1999, 121, 10229-10230.
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