Tetrahedron 61 (2005) 6665–6691

Tetrahedron report number 723

Advances in singlet oxygen chemistry

Edward L. Clennana,* and Andrea Paceb
a
Department of Chemistry, University of Wyoming, Laramie, WY 82071, USA
b
Dipartimento di Chimica Organica ‘E. Paternò’, Università degli Studi di Palermo, Viale delle Scienze, Parco d’Orleans II,
90128 Palermo, Italy
Received 27 January 2005

Available online 23 May 2005

Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6666
2. Fundamental reaction types . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6666
2.1. Ene, [2C2] and [4C2] cycloadditions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6666
2.1.1. Historical perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6666
2.1.2. Recent advances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6667
2.2. Heteroatom oxidations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6669
2.2.1. Historical perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6669
2.2.2. Recent advances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6670
2.2.2.1. Organosulfur compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6670
2.2.2.2. Organophosphorus compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6672
2.2.2.3. Organometallic complexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6673
2.2.2.4. Amines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6674
3. Heterocyclic photooxygenations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6674
3.1. Five-membered rings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6674
3.1.1. Furans and benzofurans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6674
3.1.1.1. Historical perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6674
3.1.1.2. Recent advances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6675
3.1.2. Pyrroles and indoles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6678
3.1.2.1. Historical perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6678
3.1.2.2. Recent advances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6678
3.1.3. Thiophenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6681
3.1.4. Oxazoles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6681
3.1.4.1. Historical perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6681
3.1.4.2. Recent advances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6681
3.1.5. Imidazoles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6682
3.1.5.1. Historical perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6682
3.1.5.2. Recent advances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6682
3.1.6. Thiazoles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6683
4. Formation and reactions of singlet oxygen in heterogeneous media . . . . . . . . . . . . . . . . . . . . . . . . . 6684
4.1. Zeolites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6684
4.2. Micelles and vesicles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6685
5. Conclusion and future prospects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6686
References and notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6686

Keywords: Photooxygenation; Singlet oxygen; Heteroatom oxidation.

* Corresponding author. Tel.: C1 307 766 6667; fax: C1 307 766 2807; e-mail: [email protected]

0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.04.017
6666 E. L. Clennan, A. Pace / Tetrahedron 61 (2005) 6665–6691

1. Introduction powerful protocols for the addition of molecular oxygen to

organic substrates. The ene reaction generates allylic
Oxygen is ubiquitous. It comprises nearly 50% of the hydroperoxides which can be converted to synthetically
Earth’s crust and is an essential component in metabolic valuable allylic alcohols (Scheme 1).9 The [2C2] cyclo-
pathways in all higher organisms.1 It was first identified by addition is observed with electron rich alkenes, and with
Carl Wilhelm Scheele and by Joseph Priestly in the late 18th alkenes devoid of, or those containing only geometrically
century. Its unpaired electronic structure and the possibility inaccessible, allylic hydrogens.10 The dioxetane products
of a spin-paired electronic state was first predicted by Lewis (Scheme 1) are often sensitive molecules that thermally
in 1924. These seminal contributions, along with the decompose in a fascinating chemiluminescent process to
Mulliken molecular orbital prediction of two low-lying carbonyl compounds.10 The [4C2] cycloaddition leads to
oxygen excited states (1Dg and 1SC g ), and the demonstration formation of endoperoxides (Scheme 1).11 These endo-
by Katusky2–4 of a metastable intermediate species in peroxides are versatile intermediates that can be trans-
photooxygenation reactions in the 1930s, laid the foun- formed via a variety of synthetic procedures to specifically
dation for the following 50 years of singlet oxygen research. oxygenated products.12,13 Despite the inherent geometric
These years, between 1940 and 1990, were characterized by control present in each of these fundamental reactions, the
delineation of the physical5 and chemical6 pathways of control of reaction regio- and stereochemistry remains a
singlet oxygen formation and deactivation. The physical challenge as a result of the small size of the singlet oxygen
studies, with the aid of technological advances that have molecule.
taken advantage of the luminescence of both the 1Dg and
1 C
Sg states, have demonstrated that only 1Dg (approximately 2.1.1. Historical perspective. The ene,14 and [4C2]
22.5 kcal/mol above the ground state triplet) has a sufficient cycloaddition15 reactions have been recognized for more
lifetime to allow it to play a role in chemical reactions in than 50 years while the [2C2] cycloaddition16 leading to
solution. The chemical studies have identified the funda- isolable dioxetanes is a more recent addition to the arsenal
mental [2C2], [4C2], ene, and heteroatom oxidation of synthetic procedures. The mechanistic foundations that
reactions of 1Dg (referred to as singlet oxygen or 1O2 allow rational synthetic use of these reactions are well
throughout this review) and have established their basic established.
mechanistic details. In a review published in 2000 we
outlined the efforts initiated in the 1990s to influence the The generally accepted mechanism6,17,18 for the singlet
regio- and stereoselectivity of singlet oxygen reactions.6 In oxygen ene reaction is depicted in Scheme 2. The
this review we discuss the advances made in both stereochemical and regiochemical outcome of a singlet
mechanistic and synthetic aspects of the fundamental oxygen ene reaction can often be determined by evaluation
reactions discussed in our previous review.6 In addition, of the conformational, steric, electronic, and hydrogen
we have also expanded the discussion to include new bonding interactions in the perepoxide traversed on the
developments in heteroatom and heterocyclic photo- potential energy surface. The key features of the reaction
oxygenations. We have made no attempt to be exhaustive include: (1) singlet oxygen functions as the electrophilic and
in our treatment of the singlet oxygen literature. In the alkene as the nucleophilic component of the reaction, (2)
particular, advances in the photophysical and biological it is a suprafacial process involving addition of oxygen and
aspects of singlet oxygen chemistry, although briefly removal of hydrogen from the same face of the alkene, (3)
mentioned, are not discussed in detail. Recent excellent only those hydrogens properly aligned to maximize overlap
reviews should be consulted for more information on these in the developing alkene linkage are subject to abstraction,
aspects of singlet oxygen chemistry.5,7,8 (4) hydrogen abstraction occurs preferentially on the more
crowded side of the alkene; a phenomenon known as the cis
effect, (5) Markovnikov directing effects play little or no
2. Fundamental reaction types role in determining the end of the alkene from which
hydrogen abstraction occurs, and (6) hydrogen bonding,
electronic, and steric interactions with the trailing
2.1. Ene, [2C2] and [4C2] cycloadditions pendant oxygen in the perepoxide can be used to dictate
the diastereoselectivity (facial and side selectivity) of
The ene, [2C2], and [4C2] reactions (Scheme 1) represent perepoxide and subsequent product formation.

Scheme 2.

The majority of singlet oxygen [4C2] cycloadditions are

considered to be concerted Diels–Alder like processes.11,19
This assertion is supported by the suprafacial stereo-
chemistry of the reaction20,21 and by substituent effects.22
Nevertheless, several non-stereospecific singlet oxygen
Scheme 1. [4C2] cycloadditions 23–25 as well as competitive
 E. L. Clennan, A. Pace / Tetrahedron 61 (2005) 6665–6691 6667

formations of ene and [2C2] cycloaddition products26–28 product ratio. However, it has recently been argued that
have been reported. These processes appear to be most non-statistical dynamic behavior does not occur near the
important in 1,3-dienes which cannot readily attain the s-cis valley-ridge inflection and that variational transition state
conformation. For example, force field calculations29 theory can be used to calculate partitioning ratios.45
indicate that 3,3 0 ,4,4 0 -tetrahydro-1,1 0 -binaphthalene, 1, Consequently, generation of massive numbers of dynamical
prefers to exist overwhelmingly in a perpendicular (dihedral trajectories can be circumvented in order to obtain
angle w898) conformation and it reacts with singlet oxygen statistically interpretable results. Regardless of whether
to give both the anti- and syn-cycloadducts (Scheme 3).25 statistical or non-statistical behavior is observed, it is clear
The [2C2] cycloadditions are also promoted in 1,3-dienes that the two transition states are spatially isolated on the
bearing electron rich substituents such as alkoxy groups.30–34 potential energy surface to a sufficient degree that it is
possible to selectively influence one but not the other. As a
result, minor perturbations, such as isotopic substitution in
the Stephenson isotope effect experiment makes it appear
that this concerted process proceeds via two kinetically
distinguishable steps.

Ongoing synthetic efforts have focused on improving the

p-facial diastereoselectivity of singlet oxygen addition to
olefinic linkages; several examples are given in Scheme 5.
In example I, high diastereoselectivity from the Re face was
Scheme 3.
observed.46 This stereochemical outcome was attributed to
the steric and electronic features of the sultam functional
A myriad of experimental studies have suggested that group. The carbonyl group is electrostatically repelled by
singlet oxygen [2C2] cycloadditions occur via the mecha- the sultam sulfonyl group dictating a geometry in which it
nism depicted in Scheme 4.35 For example, (1) both points away from the sultam SO2 group. This electronic
stereospecific16 and non-stereospecific34 dioxetane forma- effect coupled with steric shielding of the Si face in the
tions have been observed, (2) when ene and [2C2] adduct preferred rotamer is responsible for diastereoselectivity in
formation compete increasing solvent polarity favors excess of 80% even when RZMe. In general, however,
dioxetane formation,36 and (3) methanol trapping products chiral auxiliary approaches relying exclusively on steric
are formed under conditions where the dioxetane product is effects fail as a result of the small size of singlet oxygen. On
stable arguing for interception of either an exciplex or the other hand, chiral auxiliaries that rely on hydrogen
zwitterion precursor.36 bonding as a directing element are spectacularly successful.
For example, steric repulsion between singlet oxygen and
2.1.2. Recent advances. Advances in both mechanistic the RZOtBu group in complex A (interaction X example II;
understanding and synthetic applications of the fundamental Scheme 5) leads to a modest diastereoselectivity of
reactions have been made in the past 5 years. On the 75:25 for the RS-ene product.47 When RZNHPh, however,
mechanistic front, high-level computational results37–39 hydrogen bonding to the trailing oxygen in the perepoxide-
suggest that the perepoxide in the singlet oxygen ene like complex A completely reverses the diastereoselectivity
reaction is a transition state rather than an intermediate to 6:94 for the SS-ene product and dramatically suppresses
as implicated by experimental evidence such as the the formation of regioisomer C. The efficacy of the chiral
Stephenson isotope effect test.40–42 Recently, Singleton auxiliary was reduced in acetone consistent with its
and co-workers43,44 have provided both experimental and hydrogen bonding origin.
computational results which attempt to reconcile the
conflicting evidence for a perepoxide intermediate. They Example III illustrates preferential p-facial formation of a
have suggested that the singlet oxygen ene reaction helimeric mixture of (M)-2/(P)-2-(K)-isocolchicine endo-
proceeds via two transition states without an intervening peroxide with a diastereoselectivity of 1:7 from the anti
intermediate. This topographical arrangement is made direction.48 In this case, electrostatic repulsion between the
possible because these two maxima on the reaction pathway amide functionality and the incoming singlet oxygen
are saddle points on a three-dimensional energy surface. appears to protect the syn face.
The first transition state does not involve hydrogen
abstraction by the trailing oxygen but leads to the second Turro, Adam, and co-workers49 have recently introduced
perepoxide-like transition state. This second transition state the use of enecarbamates as chiral auxiliaries. The isopropyl
lies near a valley-ridge inflection where a bifurcation to the substituent in enecarbamate 3Z (Scheme 6) effectively
isomeric allylic hydroperoxides occurs. Consequently, shields the bottom face of the alkene and directs
dynamic effects (i.e., the momentum of atoms) dictate the singlet oxygen to the top face to exclusively form the

Scheme 4.
6668 E. L. Clennan, A. Pace / Tetrahedron 61 (2005) 6665–6691

Scheme 5.

S,S-dioxetane.50 The chirality at the phenethyl group (C-5) temperature switching of stereoselectivity is evidence for a
does not influence the p-facial selectivity but does influence reversibly formed exciplex preceding collapse to the
the rate of reaction.51 The 1R,5R substrate reacts more dioxetane. Despite the attractive features of this chiral
rapidly than the 1R,5S diastereomer to give 33% enantio- auxiliary its usefulness is diminished by the fact that it
meric excess (ee) of the (R)-methyldesoxybenzoin (MDB) effectively physically quenches singlet oxygen and as a
dioxetane decomposition product at less than 30% conver- result enecarbamate 3Z produces product with a quantum
sion. The enhanced reactivity of the 1R,5R in comparison yield of less than 0.1.53
to the 1R,5S substrate was attributed to the preferred
population of the conformation which places the smaller The ene carbamate group can also be used to switch reaction
methyl group in the 1R,5R, but the larger phenyl group in selectivity from the [2C2] to the ene reaction as illustrated
the 1R,5S, on the same face as the approaching singlet by enecarbamate substrate, 4 (Scheme 6). In the E isomer,
oxygen. The E isomer of 3 shows a remarkable temperature the enecarbamate auxiliary and the methyl group are on the
effect on the enantioselectivity of MDB formation.52 same side of the double bond and overwhelming ene
In CD3CN 3E gives (S)-MDB in 64% ee at 50 8C and reactivity is observed. On the other hand, in the Z isomer in
(R)-MDB in 58% ee at K40 8C. It was suggested that this which the phenyl group is on the same side of the double
 E. L. Clennan, A. Pace / Tetrahedron 61 (2005) 6665–6691 6669

Scheme 6.

bond as the enecarbamate group [2C2] reactivity dom- heteroatom oxidation. The key mechanistic features of this
inates. Orbital interaction between the HOMO of the reaction were delineated by Foote and co-workers in the
enecarbamate and the LUMO of singlet oxygen directs 1970s and early 1980s and are depicted in Scheme 7. The
reaction to the side of the alkene bearing the nitrogen atom. unique feature of the mechanism is the presence of two
In the Z alkene, that has no allylic hydrogen cis to the intermediates X and Y. Decomposition of the first
enecarbamate group, only [2C2] cycloaddition can intermediate, X, to sulfide and triplet oxygen is responsible
occur.54,55 The ene product exhibits a preference for for the inefficiency of the reaction (typically the quantum
formation of the (S)-allylic hydroperoxide (71% in the E yield for sulfoxide formation F!0.05). The sulfide
isomer and 85% in the Z isomer) consistent with the substrate reacts with the second intermediate, Y, to give
previously illustrated facial shielding. the sulfoxide product. On the other hand, the sulfoxide
product, as well as exogenous reagents such as phos-
2.2. Heteroatom oxidations phites57–59 and selenoxides,60 trap the first intermediate to
generate phosphates, selenones, and sulfones, respectively.
Singlet oxygen by virtue of its potent electrophilic character This observation along with studies designed to probe the
reacts readily at electron pair bearing heteroatom centers. electronic character of the reaction suggests that the first
Consequently, singlet oxygen is known to interact with intermediate is a nucleophilic and the second intermediate
sulfur, selenium, phosphorus, and nitrogen compounds, and an electrophilic oxygen donor. Consequently, the prevailing
with some iridium and rhodium transition metal complexes. opinion was that X was best represented as a persulfoxide, 5,
The interaction is often dominated by physical quenching, and Y as a thiadioxirane, 6. In polar protic solvents such as
kq, but can be accompanied by chemical quenching, kr, methanol only a single intermediate is kinetically required
leading to formation of covalent adducts involving transfer and speculation has resulted in its assignment as a hydrogen
of one or two oxygen atoms to the heteroatom center. bonded persulfoxide, 7, or as a hydroperoxy sulfurane, 8.
Compelling experimental evidence for this mechanistic
2.2.1. Historical perspectives. Sulfide photooxidation, suggestion has been difficult to generate since all attempts to
reported by Schenck56 in the early 1960s, represents one spectroscopically identify intermediates in either protic or
of the earliest and most thoroughly studied examples of aprotic solvents have failed.

Scheme 7.
6670 E. L. Clennan, A. Pace / Tetrahedron 61 (2005) 6665–6691

from a hydroperoxy sulfonium ylide intermediate (Scheme

8).65 Finally, the extremely reluctant oxidations of sulfides
devoid of a-hydrogens can also be explained within the
framework of this mechanistic suggestion.66 Parenthetic-
ally, the singlet oxygen inaccessible thiadioxirane has
recently been implicated as an intermediate in electron
transfer initiated molecular oxygenations of sulfides.67

Hydroperoxy sulfonium ylides have previously been

implicated in sulfone formation, as shown in Scheme 9,68
and as key intermediates in sulfur carbon bond cleavages69
during photooxygenations of benzylic and five-membered
ring sulfides.70,71 Evidence for the intermediacy of the
hydroperoxy sulfonium ylide included the observations that
Scheme 8. the two oxygen atoms in the sulfone product were derived
from the same oxygen molecule and that isotopic exchange
2.2.2. Recent advances. at the a-position accompanied sulfone formation. A
2.2.2.1. Organosulfur compounds. Recent studies of subsequent report72 that singlet oxygen induced double
sulfide photooxidations have focused on the question of the migration during reaction of singlet oxygen with a
structural identities of the reactive intermediates. In 1992, homoallylic sulfide, 13 (Scheme 9) also provides experi-
Jensen published an extensive ab initio study of the mental verification of the intermediacy of 9 during sulfone
reactions of singlet oxygen with organic sulfides.61,62 He formation. Alternatively, sulfone formation can occur by
pointed out that the computed barrier separating the adventitious trapping of the persulfoxide, X in Scheme 7, by
persulfoxide, 5, and thiadioxirane, 6, intermediates the sulfoxide product. This latter pathway requires an
was nearly 20 kcal/mol and incompatible with the exper- incubation period for formation of the sulfoxide product
imentally observed rapid interconversion of X and Y (trapping agent) and can be easily distinguished from the
(Scheme 7). In 1998, Jensen and co-workers63 suggested a hydroperoxy sulfonium ylide route.
revised mechanism of sulfide photooxidation that invoked
hydroperoxy sulfonium ylide, 9, rather than thiadioxirane, In a detailed study of the effect of radical and anion
6, as intermediate Y. The computed barrier separating 5 and stabilizing groups, R 0 in Scheme 10A, Toutchkine and
9 is a more palatable 6 kcal/mol given the experimental ease co-workers73,74 suggested that there are both diradical, B 0 ,
of interconversion.
and zwitterionic, B, isomers of the hydroperoxy sulfonium
ylide, whose populations dictate partitioning between
Pummerer, step a, sulfoxide, step b, and sulfone, step c,
formation (Scheme 10A). The lack of an internal hydrogen
bond in B 0 in particular appears to enhance Pummerer
rearrangement. Albini and co-workers75,76 have also noted
during examinations of substitutent and isotope effects on
Compelling experimental evidence supporting the ab initio C–S cleavages in benzyl sulfides that the a-hydrogen
assignment of 9 as intermediate Y has been reported. In abstraction is best characterized as a homolytic rather than
particular, reactions of singlet oxygen with 1,3-dithianes, 10 heterolytic process. Isolation of trace amounts of bibenzyl
and 11, and their 2-deuterated isotopomers, which react from photooxygenations of benzyl sulfides also provides
exclusively to give a single sulfoxide product, exhibited support for the radical character of the Pummerer rearrange-
substantial isotope effects indicative of a-proton abstrac- ment.76 The product of the Pummerer rearrangement, the
tion.64 In addition, the formation of ethyl vinyl sulfide a-hydroperoxy sulfide (C, Scheme 10) is normally not
during photooxidation of 2-chloroethyl ethyl sulfide, 12, can isolated but decomposes by both inter- and intramolecular
most easily be rationalized by invoking a b-elimination pathways to the sulfur–carbon bond cleavage products.73,74

Scheme 9.
 E. L. Clennan, A. Pace / Tetrahedron 61 (2005) 6665–6691 6671

Scheme 10.

Sulfides exhibit distinctly different behavior in polar aprotic The reactions of singlet oxygen with a variety of other sulfur
solvents. Rapid conversion of the persulfoxide to either a containing compounds including disulfides, sulfena-
hydrogen bonded persulfoxide 8 or to a hydroperoxy mides,83–85 and sulfenate esters86 have also been investi-
sulfurane 9 (Scheme 7), as the only kinetically detected gated. In each case, with the possible exception of some
intermediate, competively inhibits both hydroperoxy sulfo- disulfides, the persulfinate appears to be the initially formed
nium ylide formation and physical quenching. The viability intermediate whose fate is a sensitive function of the
of hydroperoxy sulfurane formation was compellingly identity of the sulfur containing functional group and of
demonstrated by formation of unusual oxidative elimination the experimental conditions. For example, as anticipated, a
products during photooxygenations of a series of hydroxy kinetic study of the reaction of sulfenate ester, 14, does not
tethered sulfides in aprotic solvents (Scheme 11).77,78 require a second intermediate because of the absence of an
However, their formations did not completely inhibit a-hydrogen.86 On the other hand, it also reacts with 100%
physical quenching as is the case in methanol as a solvent.79 efficiency to give the sulfinate ester as the exclusive product.
On the other hand, Albini and co-workers75,80–82 in a series This unusual behavior was attributed to inhibition of
of manuscripts demonstrated that the rate constants for physical quenching by the unique ability of the sulfenate
chemical reaction linearly correlate with the acid strengths ester to act as an electrophilic trapping agent for the per-
of protic additives thereby providing a strong argument that sulfinate and its thermodynamic stabilization via resonance
it is formation of the hydrogen bonded persulfoxide, and not form A in Scheme 12.86 A similar resonance stabilization of
the hydroperoxy sulfurane, which is responsible for the the intermediate formed during photooxygenation of the
unique behavior observed in polar protic solvents. sulfenamide, 4-morpholinyl benzyl sulfide (PhCH2SN

Scheme 11.
6672 E. L. Clennan, A. Pace / Tetrahedron 61 (2005) 6665–6691

Scheme 12.

(CH2CH2)2O) is perhaps also responsible for its inability to experimental studies to determine the mechanism of
physically quench singlet oxygen.83 However, in this case it reaction were not undertaken until the 1990s101,102 and
is possible that the competitive abstraction of the benzylic have lagged far behind the effort in organosulfur chemistry.
hydrogens also contribute to inhibition of physical quench- Sawaki and co-workers102 examined sulfoxide trapping of
ing since 45–55% physical quenching is still observed with the intermediates formed in the reaction of singlet oxygen
4-morpholinyl tert-butyl sulfide (t-C4H9SN(CH2CH2)2O) with tri-n-butylphosphite and triphenylphosphine. They
which lacks these activated a-hydrogens. It has also been concluded that an electrophilic intermediate was involved
reported that photoxygenation of N-alkyl sulfenamides with in both reactions and that in the triphenylphosphine reaction
labile N–H groups leads to iminopersulfinic acids, 15, it collapsed to produce both triphenylphosphine oxide
(isoelectronic to the hydroperoxy sulfonium ylide) capable (Ph3PO) and diphenylphosphinate (Ph2PO2Ph). They also
of epoxidizing norbornene (Scheme 12).84,85 demonstrated that both oxygen atoms in the phosphinate had
their origin in the same singlet oxygen molecule. Ando and
The biologically relevant disulfides (RSSR) exhibit several co-workers101,103 also established the electrophilic nature of
unique features.87,88 These include: (1) a preference in the intermediate and demonstrated that it was capable of
aprotic solvents for thiosulfonate (RS(O)2SR) rather than epoxidizing norbornene. Both research groups speculated,
thiosulfinate (RS(O)SR) formation and a dramatic solvent based on their results that the intermediate was a three-
dependent product ratio, (2) a decrease in efficiency of membered ring phosphadioxirane. This suggestion was
singlet oxygen quenching in comparison to sulfides, and supported by a computational study at several levels of
(3) a remarkable dependence of quenching rate, kT, on theory which easily located the phosphadioxirane, O2PH3,
ionization potential, IP, rather than on steric effects as as the only intermediate on the phosphine/singlet oxygen
observed with simple dialkyl sulfides.89 These phenomena reaction surface.104 The absence of an open intermediate
have been attributed to predominant physical quenching of isoelectronic to the persulfoxide, 5, was attributed to the fact
singlet oxygen by a charge transfer mechanism. Only those that the terminal oxygen is always anti to a P–H (or a P–R)
disulfides with small alkyl groups, MeSSMe, or with bond allowing it to readily collapse to the trigonal
exposed disulfide linkages (QC–S–S–C!308 or smaller) can bipyrimidal phosphadioxirane. The persulfoxide, however,
form a persulfinate at a reasonable rate which can either go adopts a conformation that places the terminal oxygen anti
on to chemically react or decompose in a physical to the lone pair on sulfur that could only collapse to the
quenching process to give triplet oxygen and the disulfide energetically unfavorable trigonal bipyrimidal sulfurane
substrate.90–94 with an apical lone pair. On the other hand, rotation of the
terminal oxygen anti to the SH (or S–R) bond resulted in
Several examples of organometallic complexes bearing spontaneous formation of the thiadioxirane, O2SH3.
thiolate ligands have recently been demonstrated to react
with singlet oxygen at sulfur.95–98 The mechanistic details Selke and co-workers105 have recently examined reactions
of these reactions are still not clear, however, the intriguing of singlet oxygen with tris(o-methoxyphenyl)phosphine, 16,
suggestion that a long lived transient (t1/2O1 ms) observed tris(m-methoxyphenyl)phosphine, 17, and tris(p-methoxy-
during photooxidation of a platinum(II) diamine dithiolate phenyl)phosphine, 18. They report that all three phosphines
complex might be the long sought after and elusive react to produce the corresponding phosphine oxide but that
persulfoxide,97 and reports of oxidative damage to sulfur only 16 produces the rearranged phosphinate, 19 (Scheme
rich metalloenzymes,99 are likely to provide the impetus for 13). They suggest that the ortho-methoxy groups in 16
further studies in this area. sterically shield the peroxy linkage in a phosphadioxirane
intermediate from bimolecular conversion to the phosphine
2.2.2.2. Organophosphorus compounds. The ability of oxide allowing unimolecular phosphonate formation to
singlet oxygen to oxidize organophosphorus compounds compete (Scheme 13). Indeed, a detailed kinetic study
was established in the early 1970s, 100 however, revealed that 19 and the phosphine oxide are formed from
 E. L. Clennan, A. Pace / Tetrahedron 61 (2005) 6665–6691 6673

Scheme 13.

the same intermediate, that no detectable physical quench- and triplet oxygen with 20 to give 21 is 109. This remarkable
ing of singlet oxygen is observed, and that these phosphines rate enhancement was attributed to the 22 kcal/mol
are two to three orders of magnitude better quenchers of excitation energy of singlet oxygen. These workers also
singlet oxygen than P(OCH3)3 (i.e., kT (MK1 sK1) in demonstrated that peroxo complex 21 photochemically
benzene) 16—(5.0G0.2)!10 6; 17—(9.2G0.3)!10 6; regenerates 20 and releases oxygen as a triplet, although
18—(3.31G0.43)!107; P(OCH3)357—4.7!104. To ration- formation of a small amount of singlet oxygen cannot be
alize all of these results they suggested the mechanism completely ruled out (Scheme 14).115
shown in Scheme 13. Direct observation of the phospha-
dioxirane at K80 8C by low temperature NMR, its ability to
epoxidize alkenes, and its reaction with methanol all
provide compelling support for this mechanistic sugges-
tion.106 These workers also report that at K80 8C formation
of phosphine oxide and rearrangement of the phosphinate
are sufficiently suppressed to allow decomposition of the
Scheme 14.
phosphadioxirane to triplet oxygen (physical quenching) to
compete.
Since the initial Selke and Foote communication114 a
2.2.2.3. Organometallic complexes. Organometallic variety of other iridium and rhodium organometallic
complexes are known to react both physically and complexes have been reported to react with singlet oxygen
chemically with singlet oxygen and the chemical reactivity to give the peroxo complexes as shown in Scheme 15. For
can either be ligand or metal centered. The ability to example, the bromide and fluoride analogues of Vaska’s
physically quench singlet oxygen107–111 has been estab-
lished for many years and an excellent complication of the
quenching rates is available.112 On the other hand, metal and
ligand centered chemical reactions of singlet oxygen have
only recently attracted attention (vide supra).

Ligand centered reactions have been investigated for both

their mechanistic interest and their synthetic potential.
Studies of the reactions of singlet oxygen with platinum II
dithiolates has provided valuable mechanistic information
on the photooxidative destruction of thiolate ligands (vide
supra).97 The ability of tricarbonyl iron to function as a
protecting group and suppress reaction at the site of
complexation has been exploited synthetically in order to
direct oxidation to a remote site in the ligand.113

The first report of a metal centered reaction was that of

Selke and Foote114 who reported that Vaska’s complex, 20,
reacted to produce metal–dioxygen complex, 21. However,
a detailed kinetic study revealed that physical deactivation
of singlet oxygen by 20 is about an order of magnitude more
important than its chemical reactivity. Nevertheless, the
ratio of the chemical rate constants for reaction of singlet Scheme 15.
6674 E. L. Clennan, A. Pace / Tetrahedron 61 (2005) 6665–6691

complex, 22, and both Ir(I), 23, and Rh(I), 24, complexes116 3. Heterocyclic photooxygenations
bearing the weakly bound acetonitrile ligand react with
singlet oxygen to give isolable peroxo complexes. 3.1. Five-membered rings
Especially noteworthy is Rh(I) complex, 25, which does
not react with triplet but does react with singlet oxygen to A significant number of articles regarding the reactions of
give the peroxo complex 26.117 The rhodium complexes are singlet oxygen with heterocyclic systems have been
in general less stable than the iridium analogues and require published. The definition of heterocyclic system itself
low temperature irradiation for successful isolation. In embraces a very wide class of organic compounds and as
addition, the singlet oxygen physical quenching rate constant a consequence it is difficult to classify and summarize all the
for the iridium complex 20 (2.4G0.3!108 MK1 sK1) is reported reactions in an organized manner. In fact, at the
nearly identical to that observed for the rhodium complex 25 beginning of the preparation of this manuscript no recent
(1.9G0.7!108 MK1 sK1) ruling out a spin–orbit coupling comprehensive review on this topic was available.129
quenching mechanism which should be more important for Wasserman and Lipshutz in 1979130 published a well-
iridium with its much higher atomic number. In contrast to organized review on the reaction of singlet oxygen with
the successful photooxygenations shown in Scheme 15, several heterocyclic systems such as furans, pyrroles,
Crabtree’s catalyst, [Ir(PPh3)2(1,5-cyclooctadiene)], was indoles, imidazoles, purines, oxazoles, thiazoles and
thiophenes. During the same period, George and Bhat131
surprisingly unreactive towards singlet oxygen.
reviewed the photooxygenations of nitrogen heterocycles
that also included examples involving singlet oxygen. In
Ir(I) and Rh(I) thiolate complexes, 27 and 28, respectively,
addition, studies that compare the singlet oxygen reactivity
react at the metal rather than at the sulfur ligand in sharp
of different five-membered heterocycles have occasionally
contrast to exclusive thiolate oxidation observed in appeared in the literature.132 We adopt the same approach as
Ni(II),118 Pd(II),96 Pt(II),95,97 and Co(III)98 thiolates these previously published reviews and concentrate on
(vide supra). On the other hand, even though the Pt(II) reactions of five-membered rings which reflects the
complex PtHCl(PEt3)2 does not chemically react it does importance of this ring system in biological and hetero-
physically quench singlet oxygen with a rate constant of cyclic chemistry.
1.9!107 MK1 sK1.119 It is possible that a Pt(IV) dioxygen
complex could be an intermediate in this quenching process, 3.1.1. Furans and benzofurans. The unabated intense
however, attempts to directly observe it at temperatures as interest in the reactions of furans with singlet oxygen
low as K79 8C were unsuccessful (Scheme 16). reflects: (1) the widespread occurrence of this functionality
both in biologically important substrates133 and in pharma-
ceuticals;134,135 (2) their use as probes for the presence of
singlet oxygen both in aqueous136,137 and microhetero-
genous media;138 and, (3) the value of the singlet oxygen
furan reaction in organic synthesis.139

3.1.1.1. Historical perspective. Reactions of singlet

Scheme 16. oxygen with furans typically occur by formation of a
2,5-endoperoxide (II in Scheme 18) that evolves into the
final products. In the absence of stabilizing substituents
2.2.2.4. Amines. The ability of amines to both chemi-
the endoperoxide is generally very reactive (sometimes
cally and physically quench singlet oxygen has been well
explosively) and its isolation can only be achieved at low
established.120,121 A considerable amount of data implicates
temperatures under carefully controlled conditions.140 For
a charge transfer complex between singlet oxygen and
example, the parent system, 2,3,7-trioxabicyclo[2.2.1]hept-
amines as a key component of these processes.122–125 5-ene, has been prepared at K78 8C and its structure
Berstein and Foote126 recently reported compelling evi- verified by microwave spectroscopy.141 The endoperoxides
dence that singlet oxygen mediates a novel cycloaddition of can also be trapped in situ by reduction to the corresponding
an amine and C60 (Scheme 17). Gan and co-workers127 have 2,3,7-trioxabicylco[2.2.1]heptanes (bicyclic ozonides) with
extended this very useful reaction to cycloadditions of diimide.142
maleimides. Exclusive formation of pyrrolidine, 29, with Cs
symmetry led these workers to suggest the mechanism The heterocyclic endoperoxide intermediates are formed via
shown in Scheme 17.128 Addition of singlet oxygen to a mechanism reminiscent of the hydrocarbon analogues.13
methyl-iminodiacetate generates a N-peroxide, A, which Symmetrically substituted furans react by a synchronous
collapses to a hydroperoxy anion iminium ion pair, B, which and asymmetrically substituted furans by an asynchronous
subsequently partitions to a-hydroperoxyamine, C, via a concerted [4C2] cycloaddition of singlet oxygen across the
Pummerer-like rearrangment, and to syn-azomethine ylide, 2,5-positions of the furan.143–145 The reactions are entropy
D, which adds to the maleimide to give the 1,3-cis isomer. controlled146 and, in the case of 1,3-diphenylisobenzofuran,
The use of a polar solvent such as pyridine allows excellent evidence has been collected to suggest the
isomerization of the ylide to the anti-configuration intervention of an exciplex intermediate.147,148
and competitive formation of the 1,3-trans isomer. The
a-amidoester, 30, is a minor product except in the absence Previously recognized reactions and rearrangements of
of any, or in the presence of an electron rich, 1,3-dipolaro- these endoperoxide intermediates are summarized in
phile such as cyclohexene. Scheme 18. Reduction (path a) occurs by cleavage of the
 E. L. Clennan, A. Pace / Tetrahedron 61 (2005) 6665–6691 6675

Scheme 17.

O–O bond and loss of oxygen. Solvolysis (path b), as endoperoxide formation (XVIII/XIX) dominate their
exemplified by reaction with methanol (Scheme 18), can singlet oxygen chemistry (Scheme 19). The sensitive
lead to a variety of products. Attack at C-1 or C-4 leads to 2,3-dioxetane products formed in the 1,2-cycloaddition
formation of methanol addition product IV and further can either cleave thermally to form XVI or be reduced to the
substitution to the bis-methanol adduct V. Loss of alcohol corresponding diol XVII.
from IV leads to the cyclic lactone VI, or loss of hydrogen
peroxide and addition of water, to the alkoxy-alcohol The reactivity, or lack of reactivity, of benzofurans is a
VII which can cleave with loss of methanol to the sensitive function of the identity of substituents and the
a,b-unsaturated carbonyl compound III. Baeyer–Villiger substitution pattern. Electron-donating groups increase
like rearrangements (path c) are initiated by O–O cleavage reactivity while electron-withdrawing substituents decrease
and migration of one of the bonds to the bridgehead carbons reactivity and may even render the substrate inert to
to give ester VIII or IX. This reaction can be made photooxidation. This effect is less important when the
regioselective by incorporation of a trimethylsilyl group at substituent is attached to the benzene ring. 2-Arylbenzo-
either R1 or R4 leading to preferential formation of the furans are less reactive than their 3-aryl-isomers presumably
trimethylsilyl ester.149 This regioselective approach has as a result of greater planarity in the 2-position leading to
been widely used for the synthesis of the butenolide [2(5H)- enhanced conjugative removal of electron density from the
furanone] moiety.150 Epoxide XII formation (path d), which benzofuran nucleus.151
can be initiated by decomposition of endoperoxide II or
presumably by direct formation of zwitterion X from the 3.1.1.2. Recent advances. An exciplex intermediate has
furan, occurs by oxygen donation from carbonyl oxide recently been implicated in the [4C2] cycloadditions of
intermediate XI. On the other hand, bisepoxide formation singlet oxygen to a series of furans by a study of pressure
(path e) can occur by heterolytic cleavage of endoperoxide effects on the reactions.152 In addition, a detailed kinetic
II or less likely by intermolecular epoxidation of the furan. study has demonstrated that the interaction of singlet
oxygen is completely chemical in nature with no physical
Endoperoxide formation across the 2,5-positions of benzo- quenching component.153
furans (XIV; Scheme 19) would lead to loss of a significant
amount of aromatic resonance energy. As a consequence, On the product studies front, Gollnick and Griesbeck have
1,2-cycloaddition or, if appropriately substituted, exocyclic reported the isolation of a series of ozonides as the primary
6676 E. L. Clennan, A. Pace / Tetrahedron 61 (2005) 6665–6691

Scheme 18.

furan/singlet oxygen photoproducts and a detailed study of bridgehead substituents is hydrogen a 1,2-hydrogen shift
their subsequent reactions under a variety of conditions.154 can occur to give an epoxylactone, D. (3) Polar protic
Their principal observations are summarized in Scheme 20 solvents can react as nucleophiles, acids or bases with furan
and include: (1) the primary unimolecular decomposition endoperoxides. For example, formations of cis-alkoxy
route in non-polar aprotic solvents involves homolytic hydroperoxides, E, occur with the protic solvent functioning
cleavage of the O–O bond to give a bis-alkoxy radical, A. as both an acid to assist in the cleavage of the peroxy bridge
(2) The fate of the bis-alkoxy radical is a sensitive function and as a nucleophile adding with retention of stereo-
of reaction conditions and the identities of the bridgehead chemistry to the bridgehead carbon. Consistent with this
substitutents. For example, when R 0 ZRZCH3 at tempera- mechanistic formulation is the fact that the protic solvent
tures between 50 and 60 8C dimer formation, B, is the adds to the bridgehead carbon best able to accommodate the
predominant process. At higher temperatures, however, bis- developing positive charge. Formations of 5-hydroxy-
epoxide, C, formation is observed. When one of the 2(5H)-furanones (4-hydroxybutenolides), F, can occur by
 E. L. Clennan, A. Pace / Tetrahedron 61 (2005) 6665–6691 6677

A significant amount of work has been devoted to

controlling the regio- and stereochemistry of 4-hydroxy-
butenolide, F, formation as a result of the widespread
occurrence of this functional group in natural products. Two
very different approaches have been taken. In the first
approach substituents have been used to direct the
regiochemistry of the Baeyer–Villiger-like rearrangement
(Scheme 20) In particular, Lee and co-workers155 have
developed the trialkylsilyl and 1-hydroxyalkyl groups in
order to dictate the site of oxidation in the furan nucleus
(Scheme 21a and b, respectively). In the second approach
the site of oxidation is determined by the use of hindered
bases that promote hydrogen abstraction from the sterically
most accessible bridgehead in the furan endoperoxide
intermediate (Scheme 21c).156 These strategies have
subsequently been implemented in an impressive array of
natural product syntheses.157–162 A particularly interesting
natural product strategy uses protected hydroxy groups
Scheme 19.
tethered to the furan nucleus that can be unmasked after
oxidation of the furan for Michael addition to the butenolide
the protic solvent acting as a base to remove the bridgehead and formation of oxacycles.163,164
hydrogen or as a nucleophile to attack a bridgehead
aldehyde which ultimately undergoes C–C cleavage to The reduction of furan endoperoxides with sulfides or
generate the butenolide, or alternatively (vide infra) via a phosphines to generate 2,3-unsaturated-1,4-dicarbonyl
Baeyer–Villiger like rearrangement. compounds has also attracted synthetic attention.165 In a

Scheme 20.

Scheme 21.
6678 E. L. Clennan, A. Pace / Tetrahedron 61 (2005) 6665–6691

has often been suggested, however, the initial formation of a

zwitterion that serves as a common precursor to all these
intermediates is also possible (Scheme 23). In striking
contrast to the reactions of furan derivatives, the pyrrole ring
does not generally open by N(1)–C(2) or N(1)–C(5) bond
cleavage (Scheme 23). Homolytic cleavages of the oxygen-
Scheme 22. oxygen bond in the endoperoxide preferentially produce
maleimides or g-hydroxy-a,b-unsaturated lactams. The
dioxetane can either decompose with cleavage of the
very interesting application Feringa166 reported a novel C(2)–C(3) bond or rearrange to an epoxide.130,131
tandem photooxidation–intramolecular Diels–Alder reac-
tion that takes advantage of the selectivity of singlet Indoles, reminiscent of benzofurans, do not give the [4C2]
oxygen for the most electron rich furan in a tethered dyad cycloaddition products because of the concomitant loss of
(Scheme 22). aromatic resonance energy and instead the site of attack is at
the C2–C3 double bond. Only in the case of 3-vinyl indoles
3.1.2. Pyrroles and indoles. The interest in the reactions of are [4C2] cycloadditions observed170 (Scheme 24). The
singlet oxygen with pyrroles and indoles has been driven by reactions at the C2–C3 bond occurs predominantly at C3
developments in phototherapeutic methods to treat neonatal to give a zwitterionic intermediate146,171 which is suscep-
jaundice167 and in the hope that these reactions might serve tible to nucleophilic attack (from an external or internal
as models for oxidations of important biological molecules nucleophile) at C2 leading to subsequent rearrangements
such as tryptophan. (Scheme 24).130,131,171

3.1.2.1. Historical perspective. The first photochemical 3.1.2.2. Recent advances. In 1991, both Wasserman172
oxidation of the parent heterocycle pyrrole was reported in and Boger173 discovered that attenuation of the reactivity of
1912 by Ciamician and Silber.168 Early studies report the the pyrrole nucleus with a combination of electron donating
formation of tarry products169 which, unless carefully and withdrawing groups allowed controlled synthetically
controlled, render pyrrole photooxidations useless for useful singlet oxygenations (Scheme 25). Pyrrole 31 reacted
preparative purposes. Reactions conditions such as solvent, with singlet oxygen to give a 45, 35, and 10% yield of 32,
dilution, and temperature, and the substitution pattern on the 33, and 34, respectively.172 Addition of 10% pyridine
pyrrole ring, play a significant role in determining the nature resulted in an increase in the yield of 32 to 80% consistent
of the isolated products. with its formation via base catalyzed decomposition of an
endoperoxide intermediate. Concomitantly, the yields of
Endoperoxide, dioxetane, and hydroperoxide intermediates both 32 and 34 decreased, which were formed by base
have all been implicated in reactions of pyrroles with singlet independent decomposition of a dioxetane and deoxygena-
oxygen. A [4C2] cycloaddition to form the endoperoxide tion of a perepoxide intermediate, respectively. Pyrrole 35

Scheme 23.
 E. L. Clennan, A. Pace / Tetrahedron 61 (2005) 6665–6691 6679

Scheme 24.

reacted via a novel oxidative decomposition, also via an is undoubtedly responsible for the high molecular weight
endoperoxide intermediate to give 36.173 Both of these products formed in the singlet oxygen reactions of many
oxidations have subsequently been used in total syntheses of pyrroles and the often-noted influence of substrate concen-
d,l- and meso-isochrysohermidin.174–176 tration on product distribution. This unique behavior has
been elegantly utilized to synthesize the A and B rings of
Pyrroles without the N-alkyl group take a different reac- the potent antimicrobial and cytotoxic prodigiosin180
tion pathway to produce hydroperoxides such as 37.177 (Scheme 26). When the C-5 position is blocked nucleophilic
(Scheme 26) This hydroperoxide is electrophilic and will attack is impeded and alternative reactivity is observed. For
react with a wide variety of nitrogen and carbon centered example, pyrrole 38, reacts via cleavage of the 2,3-bond to
nucleophiles, including pyrroles at C-5.178,179 This behavior give imidazoline, 39, in 69% yield (Scheme 26).

Scheme 25.
6680 E. L. Clennan, A. Pace / Tetrahedron 61 (2005) 6665–6691

Scheme 26.

The dioxetane precursor for the oxidative ring opening of 38 stable dioxetane and a small amount of cleavage product.181
was not directly observed, however, dioxetanes have been In methanol, formation of the dioxetane is enhanced and
isolated during photooxygenations of acylated indoles.181–185 even 40 gives 53% of the dioxetane accompanied by 37% of
(Scheme 27). In chlorinated solvents, indole 40 gives the ene and 10% of the cleavage product.182
exclusively the ene product, however, 41, which cannot
undergo an ene reaction at the 3-position, give a remarkably Indolizines, such as 42, are isoelectronic to indole and also

Scheme 27.

Scheme 28.
 E. L. Clennan, A. Pace / Tetrahedron 61 (2005) 6665–6691 6681

Scheme 29.

react with singlet oxygen.186,187 These reactions primarily Most recent physical organic studies have focused on
result in cleavage of the N–C3 bond (Scheme 28). development of polythiophenes as singlet oxygen sensi-
Zwitterion 43, is a likely key intermediate in these reactions tizers193 and little is known about the detailed mechanistic
and can partition to give the various products as a function pathways for formation of sulfine (e.g., 47) and a,b-unsa-
of reaction/solvent conditions. turated 1,4-dicarbonyl compounds (e.g., 48) in these
reactions.
The high reactivity of electron rich pyrroles also makes
them attractive for use in detection systems for singlet 3.1.4. Oxazoles.
oxygen. Compounds such as tert-butyl-3,4,5-trimethyl- 3.1.4.1. Historical perspective. Oxazoles are highly
pyrrolecarboxylate (BTMPC) and N-benzyl-3-methoxy-2- reactive singlet oxygen substrates that are converted in high
tert-carboxylate (BMPC) have been employed as post- yields to endoperoxides194 which react by sequential
column mobile phase additives to detect elution of singlet Baeyer–Villiger like rearrangement and O- to N-acyl
oxygen sensitizers in HPLC.188 In addition, the chemi- transposition to give triamides.130,131 Consequently, oxa-
luminescence of indole singlet oxygen products provides a zoles represent acyl synthons since the imide group is an
convenient tool to monitor their reactions.189 activated leaving group (Scheme 30). In substrates that
geometrically prevent the O- to N-acyl transposition the
3.1.3. Thiophenes. In comparison to furans and pyrroles, imino anhydride, 49, can be isolated. In addition when a
thiophene and monosubstituted thiophenes exhibit substan- carboxylic acid group is tethered to the oxazole the
tially reduced reactivity towards singlet oxygen. For endoperoxide can be diverted to form a spiro-hydroperoxy
example, cis- or trans-3-styrylthiophenes, 44, (Scheme 29) lactone195 (Scheme 30).
do not react with singlet oxygen even after 10 h of
irradiation.190 However, a [4C2] cycloaddition involving 3.1.4.2. Recent advances. Recent studies of oxazole
the furan nucleus is responsible for the major product in the photooxygenation have focused on modulation of the
photooxygenation of 45 (Scheme 29).191 Dialkyl substi- reactivities of the three carbonyls in the triamide product
tution at the 2,5-positions increases the reactivity of the by manipulation of the substituents on the oxazole substrate.
thiophene nucleus as illustrated by the recently reported In an elegant demonstration of this strategy Wasserman and
reaction of the C-60 appended thiophene 46 (Scheme 29).192 co-workers196 showed that when two of the substituents are

Scheme 30.
6682 E. L. Clennan, A. Pace / Tetrahedron 61 (2005) 6665–6691

Scheme 31.

aryl and one alkyl nucleophilic addition to the triamide was chemiluminescence, first reported by Radziszewski130 in
regioselective for the acyl rather than the aroyl group. 1877 during reaction of 2,4,5-triphenylimidazole (lophine)
Intramolecular addition leading to ring formation is also with singlet oxygen, is emitted during decomposition of the
possible when a nucleophile is appended to one of the dioxetane precursor of the diacylamidine product. Methoxy-
substituents. Wasserman and co-workers used this strategy imidazolones have been observed by addition of methanol
in the synthesis of Antimycin A3197 (Scheme 31) and of to the endoperoxides primarily by the process shown in
Pyrenolide C.198,199 Oxazole photooxygenation has also Scheme 32. Interestingly, when R2, R4, and R5 are good
been utilized to synthesize novel [60]fullerenes in a self- leaving groups such as halogen parabanic acid derivatives,
sensitization process (Scheme 31).200 C, are observed.202

3.1.5. Imidazoles. The reactions of imidazoles with singlet

oxygen are of limited synthetic value but are of great 3.1.5.2. Recent advances. In recent years, imidazole
mechanistic interest because of their prevalence in nucleic photooxygenation has been investigated from both theo-
acids and proteins. retical203 and experimental perspectives. For example, in
developing synthetic strategies towards biologically active
3.1.5.1. Historical perspective. In the 1960s and 70s, trifluoromethylated compounds, Li et al. have recently
Wasserman and co-worker extensively investigated the exploited the photooxidative ring opening-ring closure of
photooxidations of a wide range of alkyl and aryl substituted imidazoles to obtain 4,4 0 -bis(trifluoromethyl)-imidazo-
imidazoles.130 The endoperoxide is the key intermediate lines.204 In a mechanistic study the formation of two
formed in these reactions and can be directly observed by imidazolinone isomers during photooxygenation of 2,4-
low temperature NMR.201 The decomposition of the disubstituted imidazoles has been attributed to nucleophilic
endoperoxide is a sensitive function of the substitution attack by the solvent on both an endoperoxide and a
pattern (Scheme 32). When RN is hydrogen lone-pair dioxetane intermediate (Scheme 33).205
assisted opening of the endoperoxide to give either
hydroperoxides A or B can be observed. If the R group Kang and Foote206 have reported the previously unobserved
geminal to the –OOH group is hydrogen loss of water from formation of CO2 during photooxygenation of 4,5-di-
these hydroperoxides produces the corresponding amide or phenylimidazole. They also examined this reaction using
urea, respectively. Hydroperoxide A has also been impli- low temperature NMR with a series of isotopically labeled
cated in formation of diacylamidines. Presumably the (13C and 15N) isomers. They were able to spectroscopically

Scheme 32.
 E. L. Clennan, A. Pace / Tetrahedron 61 (2005) 6665–6691 6683

Scheme 33.

observe the time resolved formations of intermediates A–E examined under physiological conditions and have been
(Scheme 34). shown to generate dimeric products (Scheme 35).212 The
proposed mechanism provides an elegant explanation
Several model studies to understand the photooxidative for the photosensitized crosslinking of proteins observed
behavior of the imidazole containing nucleic acid base, during the photodynamic therapy (PDT) of tumors and
guanine, have been reported.207,208 This intense interest in other diseases213 and during premature UV-induced skin
guanine reflects the often-observed selective decomposition aging.214
of this residue during photodynamic action. The most
informative model studies have used soluble derivatives and 3.1.6. Thiazoles. Photooxygenations of thiazoles have
low temperatures to prevent decomposition of primary rarely been used synthetically despite the fact that they
photoproducts thereby circumventing the major obstacles have been reported to undergo reactions similar to
that have prevented a detailed understanding of the oxazoles.130 Nevertheless, Wasylyk and co-workers215
mechanism of guanosine photooxygenation.209–211 These have reported [4C2] cycloaddition of singlet oxygen to a
studies have unambiguously demonstrated that the imida- thiazole moiety in a novel cyclic peptide and the
zole ring is the site of oxidative damage to guanosine and decomposition of the thioozonide to an amide. The lack of
that [4C2] cycloaddition to form an endoperoxide is the synthetic interest has in part been a result of the impractical
initiating event in the singlet oxygen reaction. The and troublesome work up encountered in these reactions.
photooxygenations of N-benzoyl-histidine have been On the other hand, interest in this reaction persists as a result

Scheme 34.

Scheme 35.
6684 E. L. Clennan, A. Pace / Tetrahedron 61 (2005) 6665–6691

of concern about the environmental impact of thiazole substrates via tetrahedrally arranged 7.4 Å windows. The
containing drugs216 and of changes in biological activity cations present in the interior, needed to balance the
due to modifications caused by such reactions.217 negative charge on the tetravalent aluminum atoms, create
a highly charged electrostatic and unique reaction
environment.
4. Formation and reactions of singlet oxygen in
heterogeneous media Dramatic changes in the regiochemistry of the singlet
oxygen ene reaction have been realized in the intrazeolite
Photooxygenations in heterogeneous media have attracted medium by the Ramamurthy group and others.220–223
considerable attention because of their relevance to Several examples of the contrasting solution/zeolite beha-
biological and environmental oxidations and to the vior and a mechanistic model that provides a rationale for
expectation that constrained environments could enhance these changes are depicted in Scheme 36.224 The unique
regio- and stereochemistry of these synthetically useful features of these reactions which must be explained by any
reactions.218 successful mechanistic model include: (1) the ‘cis effect’,
the propensity for hydrogen abstraction from the most
4.1. Zeolites substituted side of an alkene, which has been attributed to a
secondary orbital interaction between the pendant oxygen
The first report of an intrazeolite singlet oxygen reaction on the persulfoxide and the allylic C–H orbitals, is
was made by Li and Ramamurthy in 1996.219 In this seminal dramatically diminished in the zeolite in comparison to
contribution these authors utilized thiazine exchanged solution (e.g., from 99 to 89% in A; from 81 to 43% in B;
zeolite Y as a reaction medium. Zeolite Y (e.g., NaY) is from 93 to 48% in C; and from 92 to 67% in D). (2)
an aluminosilicate composed of catenated [SiO4]4K and Markovnikov directing effects, the propensity for hydrogen
[AlO4]5K tetrahedra connected to generate a honeycomb abstraction from the most highly substituted end of the
network of supercages that provide access to organic alkene, is enhanced in the zeolite (e.g., from 50 to 68% in A;

Scheme 36.
 E. L. Clennan, A. Pace / Tetrahedron 61 (2005) 6665–6691 6685

from 37 to 65% in B; from 45 to 79% in C; and from 56 to binding of the sodium to remote oxygen functionality and
94% in D). (3) Replacement of each of the unique methyl the perepoxide (Scheme 37).
groups in C by an ethyl group decreases the extent of
hydrogen abstraction at that position by a greater amount in The report that allylic hydroperoxides are not stable to
the zeolite than in solution (e.g., intrazeolite hydrogen extended irradiation times reduces the synthetic potential of
abstraction from the ethyl group is 11% in A, 9% in B, 6% in this intrazeolitic reaction.232 On the other hand, introduction
D, and 43, 36, and 21%, respectively, from the methyl of a new experimental procedure that allows large scale
groups in the analogous position in C) and, (4) reaction rates reactions,233 and the often observed reduced reaction
are dramatically faster in the zeolite than in solution. Ene times225,234 and simplified reaction mixtures225 suggests
reactions that require several hours of irradiation in solution that the full potential of this reaction has not been realized.
have been reported to go to completion within 5 min in In particular, only a few enantioselective235,236 and
zeolite Y.225 diastereoselective229,237 intrazeolite singlet oxygen reac-
tions have been reported.
The sodium ion has a profound influence on the potential
energy surface for the intrazeolite singlet oxygen ene 4.2. Micelles and vesicles
reaction and is invoked as an integral part of the mechanistic
model depicted in Scheme 36.6 In this model sodium ion Photooxygenation reactions in micelles and vesicles have
complexation to the alkene226,227 sterically force allylic been examined extensively as models for the more complex
substituents rather than allylic hydrogens (e.g., methyl in A, microheterogeneous cellular environment, and to a lesser
B, and D, Scheme 36) to occupy the face accessible to extent as a result of the expectation that these restrictive
singlet oxygen thereby precluding hydrogen abstraction at environments might influence reaction diastereoselectivity.
these sites. As the singlet oxygen approaches the sodium ion The intense interest in photodynamic based therapies has
moves preferentially to the least substituted side of the provided the impetus for many of the cellular photooxy-
alkene to provide stabilization to the incipient perepoxide. genation model studies. Singlet oxygen, a well-established
This sterically constrained movement of the sodium ion and oxidant in these photodynamic processes, has an average
stabilization of the perepoxide provides an explanation for diffusion length of approximately 780 and 2500 nm in H2O
the diminished importance of the cis effect and for the and D2O, respectively, suggesting that cellular targets
counterintuitive observation of intrazeolite enhanced reac- considerably removed from its loci of generation are
tivity. In addition, the electropositive sodium ion pulls susceptible to oxidative damage.238 Indeed, inter-vesicle
electron density away from the perepoxide increasing migration of singlet oxygen has been shown to occur with
hydrogen abstraction from the allylic sites on the end of either neutral sensitizers like DCA or TPP that are located in
the bilayer region of the vesicle or with charge sensitizers
the alkene bearing the bulk of the cation-induced positive
like methylene blue that are localized in the vesicle enclosed
charge density. This model is supported by intrazeolite
water pool.239 The kinetic behavior of these model systems
photooxidation of Z-2,3-dimethyl-1,1,1,2,2,2-hexadeutero-
can be very complex since it is also well established that the
2-butene which exhibited an intramolecular isotope effect quantum yield of singlet oxygen formation is a sensitive
of 1.04G0.02 which is consistent with a perepoxide but function of the sensitizers microheterogenous environ-
completely inconsistent with a zwitterion. In addition, ment.240 A detailed discussion of the complex kinetic
dramatic substitutent effects on the regiochemistries of the treatments of photooxygenations in micelles and vesicles is
singlet oxygen ene reactions of a series of aryl substituted beyond the scope of this manuscript, however, a recent
trimethylstyrenes in the interior of NaY but not in solution expertly written review can be consulted for more details.241
are consistent with significant build up of positive charge on
the carbon framework of the perepoxide. Tung and co-workers242,243 took advantage of the ability of
vesicles to compartmentalize reagents and substrates to
The mechanistic model given in Scheme 36 is not valid for influence product distributions in photooxygenation reac-
substrates for which cation binding is electronically tions. Three examples using 9,10-dicyanoanthracene (DCA)
precluded228 or for those in which alternative binding as a sensitizer and vesicles composed of a 1:1 mixture of
modes are facilitated.226,229,230 For example, Stratakis and octyltrimethylammonium bromide and sodium laurate are
co-workers231 report that photooxidations of a series of shown in Scheme 38. DCA suffers from the feature that it
cyclohexenes lead to an intrazeolite increase in hydrogen acts both as a singlet oxygen and electron transfer sensitizer
abstraction from the least substituted end of the alkene and consequently can produce very complicated product
linkage (Scheme 37). This is consistent with simultaneous mixtures as shown for all three substrates in CH3CN and

Scheme 37.
6686 E. L. Clennan, A. Pace / Tetrahedron 61 (2005) 6665–6691

Scheme 38.

CH2Cl2. When the substrate and DCA are placed in the 5. Conclusion and future prospects
same vesicle formation of electron transfer products is
preferred as a result of close contact of the sensitizer and Efforts to understand the impact of the oxidative destruction
substrate. On the other hand, when the substrate and of natural and manmade materials will continue to drive
sensitizer are placed in separate vesicles electron transfer interest in singlet oxygen chemistry. In addition, increased
products are completely suppressed in favor of the singlet emphasis on environmental and economic concerns will
oxygen products. This result is consistent with the fact that also generate significant synthetic interest in this readily
under the reaction conditions singlet oxygen has a sufficient available and green reagent to make novel natural products
lifetime to allow inter-vesicle migration while both the such as the litseaverticillols.244 In particular, new methods
sensitizer and substrate are confined to their separate to direct the stereo- and regiochemistry of singlet oxygen
vesicles. In the case of substrate A, only product A-1 is addition to organic and inorganic substrates are needed and
derived from singlet oxygen and it is the exclusive product the study of reactions in supramolecular systems will be at
when DCA and the substrate are physically separated but is the forefront of this effort.
completely suppressed when they are cosolubilized in the
same vesicle. In the case of substrate B, products B-2, B-3,
B-4, and B-5 are derived from electron transfer and Acknowledgements
endoperoxide, B-6, from singlet oxygen, while B-1 and
B-2 are formed in both electron transfer and singlet oxygen We thank the National Science foundation and the Italian
reactions. The absence of endoperoxide, B-3, even when MIUR for their generous support of this research.
DCA and B are in separate vesicles was attributed to the
confined intra-vesicle environment which precluded popu-
lation of the s-cis conformer needed for 4C2 cycloaddition References and notes
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 E. L. Clennan, A. Pace / Tetrahedron 61 (2005) 6665–6691 6691

Biographical sketch

Edward L. Clennan was born in 1951 in St. Paul Minnesota. He received Andrea Pace was born in 1970 in Palermo, Italy. He received his BS
his BS degree in chemistry and mathematics from the University of degree in chemistry from the University of Palermo. He spent two years at
Wisconsin at River Falls and his PhD from the University of Wisconsin at the Naval Academy of Livorno working as a teaching officer for the
Madison. Prior to joining the faculty at the University of Wyoming he spent General Chemistry course. He worked in the laboratory of Professor R.
two years at Texas Christian University working as a postdoctoral fellow in Noto as a graduate student. In 1997 he became a member of the Faculty of
the laboratory of Professor P. D. Bartlett. In addition, in recent years he Science at the University of Palermo as an assistant professor of Organic
spent a year at the National Science Foundation as a program officer and Chemistry joining the research group of Professor N. Vivona. In addition, in
three years as Head of the Department of Chemistry at the University of recent years he spent two years at the University of Wyoming working
Wyoming where he is currently a Professor of Chemistry. His research with Professor E. L. Clennan. His research interests are in the area of
interests are in the area of oxidation chemistry in homogeneous and heterocyclic chemistry, photochemistry and fluorinated compounds.
heterogeneous media. Current projects include the study of singlet oxygen Current projects include the photooxidation of natural products, the
reactions in zeolites and the development of new mechanistic tools to study synthesis of fluorinated macromolecules and the study of heterocyclic
organic reactions in homogeneous and heterogeneous media. chemistry in zeolites.