The cyclopropyl group as a hypersensitive probe in the singlet oxygen ene reaction mechanism

Article abstract of DOI:10.1021/ol800759u

(Chemical Equation Presented) Cyclopropyl-substituted olefins are employed as mechanistic probes in the singlet oxygen-alkene ene reaction. In MeOH and aprotic solvents [CHCl₃, (CH₃)₂CO, CH ₃CN], only the allylic hydroperoxides bearing an intact cyclopropyl group are detected. The reaction mechanism is independent of solvent polarity. Our findings, to a certain experimental limit, exclude a biradical or dipolar intermediate.

Full text of DOI:10.1021/ol800759u

ORGANIC
LETTERS
2008
Vol. 10, No. 12
2465-2468
The Cyclopropyl Group as a
Hypersensitive Probe in the Singlet
Oxygen Ene Reaction Mechanism
Mariza N. Alberti and Michael Orfanopoulos*
Department of Chemistry, UniVersity of Crete, 71003, Voutes-Heraklion, Crete, Greece
orfanop@chemistry.uoc.gr
Received April 3, 2008
ABSTRACT
Cyclopropyl-substituted olefins are employed as mechanistic probes in the singlet oxygen-alkene ene reaction. In MeOH and aprotic solvents
[CHCl3, (CH3)2CO, CH3CN], only the allylic hydroperoxides bearing an intact cyclopropyl group are detected. The reaction mechanism is
independent of solvent polarity. Our findings, to a certain experimental limit, exclude a biradical or dipolar intermediate.
1
1
The chemistry of singlet oxygen (1O2, ∆g) has received
remarkable attention over the last several years due to its
synthetic utility2 and environmental3 and biomedical sig-
nificance.4 Among the various types of reactions involving
1O2,1,5 the ene or Schenck6 reaction is the most studied
experimentally and computationally. The mechanism of this
reaction is the subject of much current controversy, the main
question being whether the reaction is concerted or involves
intermediates. A concerted mechanism, via a six-membered
ring transition state (a), has been favored by many researchers
(Scheme 1).7 Biradicals (b),8 zwitterions (c),8b,9 perepoxides
(d),10 and a π-complex or exciplex (e)11 have also been
proposed as intermediates. Among these, the formation of a
perepoxide intermediate (d) was the most popular and found
(1) (a) Wasserman, H. H.; Murray, R. W. Singlet Oxygen; Academic
Press: New York, 1979. (b) Frimmer, A. A.; Stephenson, L. M. In Singlet
Oxygen. Reactions, Modes and Products; Frimer, A. A., Ed.: CRC Press:
Boca Raton, FL, 1985. (c) Foote, C. S.; Clennan, E. L. In ActiVe Oxygen
in Chemistry; Foote, C. S., Valentine, J. S., Greenberg, A., Liebman, J. F.,
Eds.; Chapman and Hall: London, 1995; pp 105-140.
(2) (a) Margaros, I.; Montagnon, T.; Tofi, M.; Pavlakos, E.; Vassiliko-
giannakis, G. Tetrahedron 2006, 62, 5308–5317. (b) Hoffmann, N. Chem.
ReV. 2008, 108, 1052–1103, and references cited therein.
(6) Schenck, G. O.; Eggert, H.; Denk, W. Liebigs Ann. Chem. 1953,
584, 177–198.
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525. (b) Foote, C. S. Acc. Chem. Res. 1968, 1, 104–110. (c) Frimer, A. A.;
Roth, D. J. Org. Chem. 1979, 44, 3882–3887. (d) Gorman, A. A. Chem.
Soc. ReV. 1981, 10, 205–231.
(3) (a) Ranby, B.; Rabek, J. F. In Photodegradation, Photooxidation
and Photostabilization of Polymers; Wiley: London, 1975. (b) Abdou,
M. S. A.; Holdcroft, S. Macromolecules 1993, 26, 2954–2962. (c) Scurlock,
R. D.; Wang, B.; Ogilby, P. R.; Sheats, J. R.; Clough, R. L. J. Am. Chem.
Soc. 1995, 117, 10194–10202.
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Radicals in Biology; Academic Press: New York, 1981; pp 379-395.
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Griesbeck, A. G. Ene Reactions with Singlet Oxygen In CRC Handbook of
Organic Photochemistry and Photobiology; Horspool, W. M.; Song, P.-S.,
Eds.; CRC Press: Boca Raton, 1995; pp 301-310.
(9) Jefford, C. W.; Kohmoto, S.; Boukouvalas, J.; Burger, U. J. Am.
Chem. Soc. 1983, 105, 6498–6499
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Res. 1980, 13, 419–425. (b) Yamaguchi, K.; Yabushita, S.; Fueno, T.; Houk,
K. N. J. Am. Chem. Soc. 1981, 103, 5043–5046. (c) Hotokka, M.; Roos,
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10.1021/ol800759u CCC: $40.75
Published on Web 05/20/2008
2008 American Chemical Society

ab initio calculations and experimental kinetic isotope effects,
1
proposed that O2 ene reaction is a concerted two-step no-
1
Scheme 1. Proposed Mechanisms for the O2 Ene Reaction
intermediate mechanism.20 It is useful to note here that in
all of the above computational methods, the influence of the
reaction solvent is neglected. There is no doubt that the
precise mechanism of this reaction remains obscure.
It is obvious that a better experimental approach to probe
the nature of the intermediate in the 1O2 ene reaction requires
designing a more informative substrate. It was this quest that
prompted us to design an alkene that bears the 2,2-
diphenylcyclopropyl group as a mechanistic probe capable
of distinguishing a biradical or dipolar character of the
intermediate.
We have studied the singlet oxygenation of E- and Z-2-
(2′,2′-diphenylcyclopropyl)-2-butene (E-1 and Z-1), prepared
in isomerically pure forms by known chemical reactions
(Scheme 2). From this synthetic scheme it is worth mention-
support through trapping experiments,12 the lack of Mark-
ovnikov effects, stereo-13 and regioselectivities,14 as well as
isotope effect measurements on deuterium-labeled tetra-
methylethylenes10a and 2-butenes.15
Previous theoretical calculations for this mechanism are
notably contradictory.16 A perepoxide intermediate was
favored by semiempirical MINDO/317a as well as SCF
CNDO/2-CI methods.17b However, early ab initio calcula-
tions (GVB-CI) by Harding and Goddard support a biradical
intermediate.8a More recently, evidence in the formation of
biradical intermediates was derived from CASSCF studies
Scheme 2
.
Synthetic Sequence for the Preparation of Olefins
E-1 and Z-1
18
1
on O2-ethylene interaction. In addition, density function
levels of theory support a polar biradical intermediate in the
1
interaction of O2 with propene, excluding an energetically
unfavorable perepoxide intermediate.8b In a recent report by
1
Leach and Houk, the O2 ene reaction with alkenes was
suggested to proceed through a highly asynchronous con-
certed mechanism, involving regions of the potential surface
with both perepoxide and polarized biradical character.19
Subsequently, Singleton and co-workers, based on high level
(11) (a) Clennan, E. L.; Nagraba, K. J. Am. Chem. Soc. 1983, 105, 5932–
5933. (b) Gorman, A. A.; Hamblett, I.; Lambert, C.; Spencer, B; Standen,
M. C J. Am. Chem. Soc. 1988, 110, 8053–8059. (c) Aubry, J-M.; Mandard-
Cazin, B.; Rougee, M.; Bensasson, R. V. J. Am. Chem. Soc. 1995, 117,
9159–9164.
ing that attempts to saponify cyclopropyl ester 4 were
thwarted by the reactivity of the system; only products in
which the cyclopropane ring was ruptured were obtained.
However, transformation of the ethyl ester into a trimeth-
ylsilyl ester with TMSCl/NaI system, followed by hydroly-
sis,21 afforded carboxylic acid 5. Separation of E/Z-1 olefins
was accomplished by flash column chromatography, using
hexane as an eluent. The trans stereochemistry of the newly
formed double bond in E-1 was assigned by nuclear
Overhauser effect difference experiments (DNOE).
(12) (a) Schaap, A. P.; Recher, S. G.; Faler, G. R.; Villasenor, S. R.
J. Am. Chem. Soc. 1983, 105, 1691–1693. (b) Stratakis, M.; Orfanopoulos,
M.; Foote, C. S. Tetrahedron Lett. 1991, 32, 863–866. (c) Poon, T. H. W.;
Pringle, K.; Foote, C. S. J. Am. Chem. Soc. 1995, 117, 7611–7618. (d)
Clennan, E. L.; Chen, M. F.; Xu, G. Tetrahedron Lett. 1996, 37, 2911–
2914.
(13) (a) Prein, M.; Adam, W. Angew. Chem., Int. Ed. Engl. 1996, 35,
477–494. (b) Orfanopoulos, M.; Stephenson, L. M. J. Am. Chem. Soc. 1980,
102, 1417–1418.
(14) (a) Stratakis, M.; Orfanopoulos, M. Tetrahedron 2000, 56, 1595–
1615. (b) Alberti, M. N.; Orfanopoulos, M. Tetrahedron 2006, 62, 10660–
10675.
Similar probes have been used in the past as traps for other
radical intermediates, since they involve the rapid rearrange-
ment of the cyclopropyl carbinyl radical (8a) to the homoallyl
radical (9a) (eq 1).22 In this work, the addition of two phenyl
groups at C2 in the cyclopropyl ring, such as in 8b, results
(15) (a) Orfanopoulos, M.; Foote, C. S. J. Am. Chem. Soc. 1988, 110,
6583–6584. (b) Orfanopoulos, M.; Smonou, I.; Foote, C. S. J. Am. Chem.
Soc. 1990, 112, 3607–3614.
(16) For a recent review of theoretical and computational methods
applied to the oxygen-organic molecule photosystem, see: Paterson, M. J.;
Christiansen, O.; Jensen, F.; Ogilby, P. R. Photochem. Photobiol. 2006,
82, 1136–1160.
(17) (a) Dewar, M. J. S.; Thiel, W. J. Am. Chem. Soc. 1975, 97, 3978–
3986. (b) Inagaki, S.; Fukui, K. J. Am. Chem. Soc. 1975, 97, 7480–7484.
(18) (a) Tonachini, G.; Schlegel, H. B.; Bernardi, F.; Robb, M. A. J. Am.
Chem. Soc. 1990, 112, 483–491. (b) Maranzana, A.; Ghigo, G.; Tonachini,
G. J. Am. Chem. Soc. 2000, 122, 1414–1423.
(20) Singleton, D. A.; Hang, C.; Szymanski, M. J.; Meyer, M. P.; Leach,
A. G.; Kuwata, K. T.; Chen, J. S.; Greer, A.; Foote, C. S.; Houk, K. N.
J. Am. Chem. Soc. 2003, 125, 1319–1328.
(21) For details, see the Supporting Information.
(22) Newcomb, M.; Glenn, A. G. J. Am. Chem. Soc. 1989, 111, 275–
277.
(19) Leach, A. G.; Houk, K. N. Chem. Commun. 2002, 1243–1255.
2466
Org. Lett., Vol. 10, No. 12, 2008

in radicals that ring opens exceedingly fast, with lifetimes
of only a few picoseconds, at ambient temperatures.23
1
Both substrates E-1 and Z-1 react smoothly with O2,
which was generated by 300 W xenon lamp irradiation of
TPP in CHCl3, Rose Bengal in (CH3)2CO and CH3CN, or
Methylene blue in MeOH at 0 °C or rt. In all cases, isomeric
ene allylic hydroperoxides were exclusively formed. Since
the ene adducts contain a new stereogenic center (Scheme
3), the reaction mixture consists of two pairs of diastereo-
Scheme 3
.
Photooxygenation and Subsequent Reduction of
Figure 1.
1H NMR spectral regions from 1 to 6.5 ppm for allylic
alcohols 10a and 10b.
Olefins E-1 and Z-1
previously reported nonbonding large group effect.25 More-
over, in the case of Z-1, the more substituted side of the
double bond was the more reactive (10/11 ) 70:30, in
CHCl3). This product regioselectivity is in agreement with
the well-known site selectiVity or cis effect.26 These trends
in regioselectivity were independent of solvent polarity,
consistent with previous studies on reaction rates.27
The proposed mechanism that could account for these
results is presented in Scheme 4. The O2 ene reaction of
meric hydroperoxides (total of eight isomers). Thus, the 1H
NMR analysis was considerably complicated. Fortunately,
after the reduction of the reaction mixture with PPh3, each
diastereomer of the two pairs 10a,b and 11a,b (Scheme 3)
was separated and well characterized by1H NMR spectros-
copy. In all cases, the 1H NMR spectra show the character-
istic absorptions of the three cyclopropyl protons between
1
alkene E-1 should lead to distinctly different products
depending on the mechanistic path adopted (Scheme 4).
When an intermediate perepoxide is invoked (path I), ene
products with cyclopropyl groups intact may be formed. On
the other hand, an open intermediate (biradical or dipolar)
should result in rearranged products (path II). In particular,
if a biradical intermediate with a lifetime greater than
10-11-10-12 s (rate of 2,2-diphenylcyclopropyl carbinyl
radical ring opening: 5 × 1011 s-1)23b,28 had been formed,
the ring-opened products should have been detected. Interest-
ingly, the exclusive formation of the unrearranged products
10a,b and 11a,b in combination with the observed regiose-
lection, can be rationalized by the intermediacy of a
perepoxide (path I). Subsequently, in transition state TSI
leading to the minor ene products 10a,b, the nonbonding
interactions involving the large diphenylcyclopropyl group,
are expected to be stronger than those in TSII where these
1.1 and 2.5 ppm.21 Representative H NMR spectra of the
1
diastereomeric pair 10a,b are shown in Figure 1.
In nonhydroxylic solvents, the only detected and isolated
products were the ene adducts 10 and 11 with intact
cyclopropyl ring. Even in MeOH, unlike the corresponding
PTAD-cyclopropylalkene ene reaction,24 apart from the ene
adducts 10 and 11, no rearranged methanol-trapping products
were detected. These results also indicate that solvent polarity
1
play an insignificant role in the mechanism of O2 ene
reaction.
1
It is worth mentioning that in the O2 ene reaction with
alkene E-1 there is a substantial preference for hydrogen
abstraction from the methyl group geminal to the 2,2-
diphenylcyclopropyl substituent of the double bond (10/11
) 23:77, in CHCl3). This regioselection can be attributed to
(25) (a) Orfanopoulos, M.; Stratakis, M.; Elemes, Y. J. Am. Chem. Soc.
1990, 112, 6417–6419. (b) Orfanopoulos, M.; Stratakis, M.; Elemes, Y.;
Jensen, F. J. Am. Chem. Soc. 1991, 113, 3180–3181.
(26) (a) Schulte-Elte, K. H.; Muller, B. L.; Rautenstrauch, V. HelV. Chim.
Acta 1978, 61, 2777–2783. (b) Orfanopoulos, M.; Grdina, M. B.; Stephen-
son, L. M. J. Am. Chem. Soc. 1979, 101, 275–276.
(23) (a) Newcomb, M.; Manek, M. B. J. Am. Chem. Soc. 1990, 112,
9662–9663. (b) Newcomb, M.; Johnson, C. C.; Manek, M. B.; Varick, T. R.
J. Am. Chem. Soc. 1992, 114, 10915–10921. (c) Martin-Esker, A. A.;
Johnson, C. C.; Horner, J. H.; Newcomb, M. J. Am. Chem. Soc. 1994, 116,
9174–9181.
(27) (a) Foote, C. S.; Denny, R. W. J. Am. Chem. Soc. 1971, 93, 5168–
5171. (b) Gollnick, K.; Griesbeck, A. Tetrahedron Lett. 1984, 25, 725–
728.
(28) For clocking secondary and tertiary cyclopropyl rearrangements,
see: Engel, P. S.; He, S.sL.; Banks, J. T.; Ingold, K. U.; Lusztyk, J. J.
Org. Chem. 1997, 62, 1210–1214. Choi, S.sY.; Toy, P. H.; Newcomb, M.
(24) (a) Roubelakis, M. M.; Vougioukalakis, G. C.; Angelis, Y. S.;
Orfanopoulos, M. Org. Lett. 2006, 8, 39–42. (b) Acevedo, O.; Squillacote,
M. E. J. Org. Chem. 2008, 73, 912–922.
J. Org. Chem. 1998, 63, 8609–8613
.
Org. Lett., Vol. 10, No. 12, 2008
2467

Scheme 4
.
Proposed Mechanistic Possibilities in the Allylic
Oxygenation of E-1
In all cases, the ene allylic hydroperoxides were exclusively
formed. After the reduction of the complex reaction mixture
with PPh3, we managed to isolate by column chromatography
the mixture of allylic alcohols 14a-d and 15a-d. In these
products, which are presented in Scheme 5, the cyclopropyl
Scheme 5
.
Photooxygenation and Subsequent Reduction of
Olefin E/Z-13
ring remains intact. Even when MeOH was used as a solvent,
no rearranged methanol-trapping derivatives were detected.
The exclusive formation of the unrearranged products 14a-d
and 15a-d can again be better rationalized by the interme-
diacy of a perepoxide. Therefore, the proposed mechanism
that could account for the formation of the allylic alcohols
14a-d and 15a-d, is similar to that already presented in
Scheme 4.
interactions are much less pronounced. A similar mechanism
is also suggested for the photooxygenation of isomer Z-1.
Although the present results can also be rationalized by a
concerted mechanism, previous isotopic studies of tetram-
ethylethylenes-d610a and trapping experiments12 excluded this
mechanistic possibility.
In conclusion, two hypersensitive radical probes were used
1
for the investigation of O2-alkene ene reaction in various
solvents. In all the reaction conditions used herein, no
rearranged products were detected. In light of our findings,
it is difficult to argue for a biradical or dipolar mechanism.
1
In order to further investigate the mechanism of O2 ene
1
In our view, modeling of O2 ene reaction will continue to
reaction, we also used the second-generation hypersensitive
probe (12) which was reported by Newcomb and co-
workers.29 This probe is capable of distinguishing between
biradical and dipolar intermediates. Consequently, in ring
opening of this cyclopropyl carbinyl system, the phenyl group
stabilize an incipient radical more effectively than the
methoxy group; whereas the methoxy group favors an
incipient carbocation. For example, cyclopropyl carbinyl
radical 12 rearranges with regioselectivity 160:1 at ambient
temperature to the benzylic radical; while cyclopropyl
carbinyl cation 12 opens with even more selectivity >1000:1
to oxonium ion.
provide a relevant and challenging problem. Since experi-
mental work seems to have reached its limits, the challenge
now might lead to more accurate computational work for
conclusive mechanistic refinements.
Acknowledgment. This paper is dedicated to the memory
of Prof. Dr. L. M. Stephenson. The project was cofunded
by the European Social Fund and National Resources
(PENED 2001, Pythagoras II 2005). We thank Dr. M. M.
Roubelakis for providing a substrate. We also thank F.
Sweeney for useful discussions.
Supporting Information Available: Detailed experimen-
Specifically, we carried out the photooxygenations of E/Z-
13 in CHCl3, (CH3)2CO, CH3CN, and MeOH at 0 °C or rt.
1
tal procedures, spectral data, and H NMR, DNOE, 13C
NMR, and HMQC spectra. This material is available free
of charge via the Internet at http://pubs.acs.org.
(29) (a) Newcomb, M.; Chestney, D. L. J. Am. Chem. Soc. 1994, 116,
9753–9754. (b) Le Tadic-Biadatti, M.sH.; Newcomb, M J. Chem. Soc.,
Perkin Trans. 2 1996, 1467–1473.
OL800759U
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Org. Lett., Vol. 10, No. 12, 2008