Stereochemistry of the C-S bond cleavage in cis-2-methylcyclopentyl phenyl sulfoxide radical cation

Full text of DOI:10.1021/jo802619y

concerning generation, spectral properties, and structure of
aromatic sulfoxide radical cations.5 More recently, we have
studied the C-S bond fragmentation reactions of species
generated by photooxidation sensitized by 3-cyano-N-meth-
ylquinolinium perchlorate (3-CN-NMQ+).6 A conclusion of the
latter study was that with tertiary and secondary benzylic
systems, a fast unimolecular C-S bond cleavage takes place
leading to the formation of the phenylsulfinyl radical C6H5SO•
and the carbocation R1R2R3C+ (eq 1).
Stereochemistry of the C-S Bond Cleavage in
cis-2-Methylcyclopentyl Phenyl Sulfoxide Radical
Cation
Enrico Baciocchi, Osvaldo Lanzalunga,* Andrea Lapi, and
Laura Maggini
Dipartimento di Chimica and Istituto CNR di Metodologie
Chimiche-IMC, Sezione Meccanismi di Reazione c/o
Dipartimento di Chimica, Sapienza UniVersita` di Roma,
P.le A. Moro 5, 00185 Rome, Italy
osValdo.lanzalunga@uniroma1.it
ReceiVed NoVember 26, 2008
However, direct evidence for the formation of a carbocation
was obtained only when R1 ) H and R2 ) R3 ) Ph. In the
other cases the formation of the cation was only inferred by
product and kinetic studies. Moreover, an intriguing result was
obtained with benzyl phenyl sulfoxide radical cation. The
fragmentation rate of this radical cation (1.1 × 106 s-1) was
very close to that of tert-butyl phenyl sulfoxide radical cation
(1.8 × 106 s-1) despite the fact that the C-S bond dissociation
free energy is about 8.5 kcal mol-1 less negative in the former
than in the second radical cation. Among the possible explana-
tions, it was considered that the cleavage of the primary benzylic
system might be nucleophilically assisted (a bimolecular process
with the solvent XH as the nucleophile, eq 2) without involving
the intermediacy of a benzyl carbocation.
The TiO2 photocatalyzed oxidation of cis-2-methylcyclo-
pentyl phenyl sulfoxide in the presence of Ag2SO4 in MeCN/
H2O leads to the formation of 1-methylcyclopentanol,
1-methylcyclopentyl acetamide, and phenyl benzenethiosul-
fonate as the main reaction products. It is suggested that the
C-S heterolysis in the radical cation is an unimolecular
process leading to an ion radical pair. Fast 1,2-hydride shift
in the secondary carbocation leads to 1-methylcyclopentyl
carbocation that forms the observed products by reaction with
H2O and MeCN. Attack of H2O on the ion radical pair may
also occur, but as a minor route (<3%), with formation of
trans-2-methylcyclopentanol.
Indeed, it is well recognized that in the fragmentation
reactions of radical cations a mechanistic dichotomy is possible
between an unimolecular and a bimolecular pathway which,
when cleavage at carbon is concerned, very closely resembles
that between the SN1 and SN2 mechanisms in the nucleophilic
substitutions at carbon.7 Clearly, the fragmentation of an alkyl
sulfoxide radical cation can be usefully seen as a type of
nucleophilic substitution where the leaving group is the sulfinyl
radical.
Since the nucleophilically assisted fragmentation of a radical
cation is expected to occur with inversion of configuration,8
we considered that further interesting information on the possible
role of a bimolecular pathway in the fragmentation of alkyl
phenyl sulfoxide radical cations might be obtained by a study
of the stereochemistry of the fragmentation process of cis-2-
methylcyclopentyl phenyl sulfoxide radical cation (1+•). Ac-
cordingly, in this case the operation of this pathway should lead
to a trans-2-methylcyclopentyl derivative (path a in Scheme
1), whereas, in the case of an unimolecular process (path b in
Sulfoxides are substrates of great interest for their importance
in organic synthesis as well as for their biological activity and
involvement in the general metabolism of many biologically
important sulfides.1 Despite this, few studies are presently
available for sulfoxide radical cations, although these species
should be of interest given their possible role in oxidative
chemical2 and biochemical transformations.3
To cover this gap, the long-standing interest in the chemistry
of radical cations4 has led our group to investigate aspects
(1) Carreno, M. C. Chem. ReV. 1995, 95, 1717–1760. Fernandez, I.; Khiar,
N. Chem. ReV. 2003, 103, 3651–3705. Clarke, M. J.; Zhu, F.; Frasca, D. R.
Chem. ReV. 1999, 99, 2511. Lipponer, K. G.; Vogel, E.; Keppler, B. K. Metal
Based Drugs 1996, 3, 243. Caligaris, M.; Carugo, O. Coord. Chem. ReV. 1996,
153, 83. Shin, J. M.; Cho, Y. M.; Sachs, G. J. Am. Chem. Soc. 2004, 126, 7800–
7811. Legros, J.; Dehli, J. R.; Bolm, C. AdV. Synth. Catal. 2005, 347, 19–31.
Bentley, R. Chem. Soc. ReV. 2005, 34, 609–624.
(2) Adaikalasamy, K.; Venkataramanan, N. S.; Rajagopal, S. Tetrahedron
2003, 59, 3613–3619. Ganesan, M.; Sivasubramanian, V. K.; Rajagopal, S.;
Ramaraj, R. Tetrahedron 2004, 60, 1921–1929.
(3) Watanabe, Y.; Iyanagi, T.; Oae, S. Tetrahedron Lett. 1982, 23, 533–
536.
(4) Baciocchi, E.; Bietti, M.; Lanzalunga, O. Acc. Chem. Res. 2000, 33, 243–
251. Baciocchi, E.; Bietti, M.; Lanzalunga, O. J. Phys. Org. Chem. 2006, 19,
467–478.
(5) Baciocchi, E.; Del Giacco, T.; Gerini, M. F.; Lanzalunga, O. J. Phys.
Chem. A 2006, 110, 9940–9948.
(6) Baciocchi, E.; Del Giacco, T.; Lanzalunga, O.; Mencarelli, P.; Procacci,
B. J. Org. Chem. 2008, 73, 5675–5682.
(7) (a) Baciocchi, E.; Fasella, E.; Lanzalunga, O.; Mattioli, M. Angew. Chem.,
Int. Ed. Engl. 1993, 32, 1071–1073. (b) Shaik, S.; Reddy, A. C.; Ioffe, A.;
Dinnocenzo, J. P.; Danovich, D.; Cho, J. K. J. Am. Chem. Soc. 1995, 117, 3205.
(8) Dinnocenzo, J. P.; Todd, W. P.; Simpson, T. R.; Gould, I. R. J. Am.
Chem. Soc. 1990, 112, 2462. (a) Shaik, S.; Dinnocenzo, J. P. J. Org. Chem.
1990, 55, 3434.
10.1021/jo802619y CCC: $40.75
Published on Web 01/15/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 1805–1808 1805

SCHEME 1
SCHEME 3
TABLE 1. Products and Yields in TiO2 Photosensitized Oxidation
of cis-2-Methylcyclopentyl Phenyl Sulfoxide (1) in N2-Saturated
MeCN in the Presence of Ag2SO4
SCHEME 2
a Yields (%) referred to the starting material. The average error is
(10%
Scheme 1), products deriving from the 2-methylcyclopentyl
carbocation (which can rearrange to the tertiary 1-methylcy-
clopentyl carbocation) should be observed (paths c and e).
It should be noted that in 1+• a secondary, not activated, alkyl
moiety is present with a much smaller tendency to form a
carbocation than that of the systems examined before6 and
therefore with a greater susceptibility to exhibit nucleophilic
assistance in the fragmentation process. The results of this study
are presented in this Note.
In our previous investigation, the alkyl phenyl sulfoxide
radical cations were generated by photooxidation sensitized by
3-CN-NMQ+.6,9 This method, however, could not be applied
to the oxidation of 1 since no products were observed in the
steady-state photolysis experiment carried out by irradiating for
3 h a solution of 1 (0.01 M) in N2-saturated MeCN at around
355 nm in the presence of 3-CN-NMQ+ (0.004 M). This is
probably due to the fact that the fragmentation rate of 1+•
(Scheme 2, path a) is too slow to compete with back electron
transfer from the reduced sensitizer 3-CN-NMQ• to 1+• (Scheme
2, path b).
shown the occurrence of an electron transfer process from aryl
methyl sulfoxides to TiO2(h+).13 A further support to an ET
process is provided by the previous finding that 4-methoxy-
benzyl phenyl sulfoxide undergoes a clean C-S bond cleavage
with formation of benzylic products when the TiO2 sensitized
photolysis of this substrate is carried out in MeCN in the
presence of Ag2SO4.14
The photolysis of 1 (0.01 M) was carried out in deareated
MeCN containing 2.5% or 5% H2O (the addition of H2O assured
the presence of a species with nucleophilic character much
higher than that of MeCN)15 by external irradiation for 30 min
in a photoreactor equipped with 10 lamps with emission centered
at 355 nm in the presence of TiO2 (0.06 M) and Ag2SO4 (0.01
M) at room temperature. After usual workup of the reaction
mixture, significant amounts of fragmentation products of 1+•
(1-methylcyclopentanol, 1-methylcyclopentyl acetamide and
trans-2-methylcyclopentanol) from the alkyl moiety and phenyl
benzenethiosulfonate (PhSO2SPh) accompanied by small amounts
of phenyl benzenethiosulfinate (PhSOSPh), and diphenyl di-
sulfide (PhSSPh), deriving from the phenyl sulfinyl radical,16
were observed. Products were identified and quantitated, after
extraction of the reaction mixtures with dichloromethane, by
Thus, we used another method for the generation of 1+•,
namely, photooxidation sensitized by TiO2, a well-known system
for obtaining the one-electron transfer oxidation of organic
substrates,10 where it is also possible to minimize back electron
transfer by capturing the photogenerated electron by Ag+.11 As
shown in Scheme 3, irradiation of TiO2 leads to charge
separation, TiO2(h+) and TiO2(e-) (eq 3). TiO2(h+) can oxidize
a substrate to the corresponding radical cation (eq 4), which
may then undergo a fragmentation reaction (eq 5), whereas Ag+
(Ag2SO4) captures TiO2(e-) (eq 6).
1
GC-MS, GC, HPLC, and H NMR analysis, by comparison
with authentic specimens. No products were detected without
irradiation or in the absence of TiO2. The alkyl fragmentation
products and the yields referred to the starting material are
reported in Table 1.
It can be immediately noted that 1-methylcyclopentanol and
1-methylcyclopentyl acetamide are by far the largely predomi-
nant reaction products in both 2.5% and 5% aqueous MeCN.
As TiO2(h+) is a strong oxidant (Ered ) 2.4 V vs SCE in
MeCN),12 sulfoxides (Eox ) 2.0 V vs SCE) are suitable
substrates. Accordingly, photoelectrochemical studies have
(13) An increase in the photocurrent has been observed on decreasing the
aryl methyl sulfoxide oxidation potential. Somasundaram, N.; Srinivasan, C. J.
Photochem. Photobiol. A: Chem. 1998, 115, 169–173.
(14) Baciocchi, E.; Del Giacco, T.; Ferrero, M. I.; Rol, C.; Sebastiani, G. V.
J. Org. Chem. 1997, 62, 4015–4017.
(9) The reduction potential of the 3-CN-NMQ+*/3-CN-NMQ• couple is 2.72
V vs SCE, large enough to convert the aromatic sulfoxides into the corresponding
radical cations.
(15) The use of stronger nucleophiles can present problems related to their
possible oxidations by TiO2(h+).
(10) Fox, M. A.; Dulay, M. T. Chem. ReV. 1993, 93, 341–357.
(11) Baciocchi, E.; Rol, C.; Rosato, G. C.; Sebastiani, G. V. J. Chem. Soc.,
Chem. Commun. 1992, 59–60.
(16) The main reaction of the sulfinyl radical is the dimerization to give
phenyl benzenethiosulfonate. Chatgilialoglu, C. In The Chemistry of Sulfones
and Sulfoxides; Patai, S., Rappoport, Z., Stirling, C. J. M., Eds.; John Wiley &
Sons: Chicester, England, 1988; Chapter 24.
(12) Fox, M. A.; Chen, C.-C. J. Am. Chem. Soc. 1981, 203, 6757–6759.
1806 J. Org. Chem. Vol. 74, No. 4, 2009

SCHEME 4
the solvent of the tertiary carbocation ensues. However, we can
also envisage that, as a very minor route, the stronger nucleo-
philic species in the medium (H2O) attacks the ion radical pair
in competition with the hydride shift (Scheme 4, path c). In
this case it is reasonable that, as observed, the inverted trans
alcohol is formed as in the pair the cis face of the cyclopentyl
ring is protected by the sulfinyl radical leaving group.
The step leading to the ion-radical pair should be irreversible,
as it was found that the unreacted substrate maintained the cis
configuration. On the other hand, a substantially irreversible
heterolysis may be predicted for 1+• by the exergonicity of the
process, which can be estimated around 6.9 kcal mol-1 on the
basis of a thermochemical cycle20 and by the additional driving
force provided by the 1,2-hydride shift leading to the more stable
tertiary carbocation.
Interestingly, the mechanism displayed in Scheme 4 is very
close to that suggested by Kim and Brown21 and Imhoff, Shiner,
and co-workers22 for the solvolysis of cis-2-substituted cyclo-
pentyl arenesulfonates, a reaction which, as in our case, led to
products deriving from the tertiary 1-substituted cyclopentyl
carbocation, accompanied by minor amounts of the inverted
product.23
In summary, it seems possible to conclude that the C-S bond
cleavage in cis-2-methylcyclopentyl phenyl sulfoxide radical
cation in aqueous MeCN occurs by an unimolecular process.
The initially formed carbocation radical pair leads to the tertiary
1-methylcyclopentyl carbocation by hydride shift (the largely
dominant path) and to the inverted product (trans-2-methylcy-
clopentanol) by H2O attack.
trans-2-Methylcyclopentanol is also formed but in very small
amounts (<3% of the total yields of alkyl fragmentation
products).17
Clearly, this result indicates that the main pathway of the
fragmentation process involves the formation of a secondary
cyclopentyl carbocation that very rapidly rearranges to the more
stable tertiary carbocation by 1,2-hydride shift (Scheme 1, path
c). Reaction with the solvent (path e in Scheme 1) follows to
produce the tertiary alcohol (from H2O) and the tertiary
acetamide (from MeCN). As expected, the ratio between alcohol
and acetamide increases as the proportion of H2O in the mixed
solvent increases. When the reaction is carried out in the
presence of 2.5% H2O, acetamide and alcohol are formed in
comparable amounts, whereas a larger amount of alcohol is
observed in the presence of 5% H2O. It also appears that no
significant proton loss from the tertiary cyclopentyl carbocation
takes place since the presence of 1-methylciclopentene among
Experimental Section
Oxidation Photosensitized by 3-CN-NMQ+ClO4-. A 5-mL
solution of 3-CN-NMQ+ClO4- (4.0 × 10-3 M) and 1 (1.0 × 10-2
M) in N2-saturated CH3CN plus 5% H2O (v/v) as cosolvent was
placed in a water-cooled jacketed pyrex tube and irradiated at room
temperature for 3 h in a photoreactor equipped with 10 phosphor-
coated fluorescent lamps (15 W each) with emission centered at
1
the products was excluded on the basis of direct H NMR
analysis of the reaction mixture in CD3CN/D2O.18
Thus, the fragmentation reaction of 1+• in slightly aqueous
MeCN is substantially an unimolecular process, and the fact
that this outcome is observed when a secondary nonactivated
alkyl group is involved, as in 1+•, makes it difficult that the
unexpectedly large fragmentation rate of benzyl phenyl sulfoxide
radical cation could be due to the operation of nucleophilic
assistance. Other hypotheses and further investigations appear
necessary to clarify this interesting point.
1
ca. 355 nm. No formation of photoproducts was revealed by H
NMR analysis; the substrate and the sensitizer were quantitatively
recovered.
TiO2 Photocatalyzed Oxidation. Reactions have been carried
out at room temperature by external irradiation (30 min), in a
photoreactor equipped with 10 lamps (355 nm) under magnetic
stirring, of a water-cooled jacketed pyrex tube containing a N2-
degassed solution of cis-2-methylcyclopentyl phenyl sulfoxide (0.05
mmol), TiO2 (25 mg), and Ag2SO4 (0.05 mmol) in 5 mL of
acetonitrile plus 2.5% or 5% H2O (v/v) as cosolvent. After double
paper filtration of TiO2, the reaction mixture was poured into water
and extracted with dichloromethane. GC-MS analysis of the
reaction mixtures indicated the presence of methylcyclopentyl
The secondary cyclopentyl carbocation that rearranges to the
tertiary one, however, cannot be a free species, as in that case
we should have observed both cis- and trans-2-methylcyclo-
pentanol as well as cis- and trans-2-methylcyclopentyl acetamide
(Scheme 1, path d). The fact that only the trans alcohol is
observed leads us to suggest that very likely in the heterolysis
of the radical cation a tight secondary carbocation-radical pair
is first formed (Scheme 4, path a), as previously observed for
the fragmentation of 1-phenylethyl phenyl sulfide radical
cation.7a,19
(19) That in the heterolysis of a radical cation the two fragments can form
a pair in a solvent cage has also been shown by Moiroux, Saveant, and
coworkers. Anne, A.; Frauoa, S.; Moiroux, J.; Saveant, J.-M. J. Am. Chem. Soc.
1996, 118, 3938–3945.
(20) The C-S bond dissociation free energy (BDFE) value for 1+• (-6.9 kcal
mol-1) was estimated by the usual thermochemical cycle (details in Supporting
Information).
For this pair, the largely dominant pathway (path b) involves
a very fast rearrangement of the secondary 2-methylcyclopentyl
carbocation to the tertiary one. Cage escape and reaction with
(21) Kim, C. J.; Brown, H. C. J. Am. Chem. Soc. 1972, 94, 5043–5050.
(22) Imhoff, M. A.; Ragain, M.; Moore, K., Jr. J. Org. Chem. 1991, 56,
3542–3549.
(17) GC analysis of the reaction mixtures carried out before and after
derivatization with the silylating agent N,O-bis(trimethylsilyl)-trifluoroacetamide
(see Experimental Section) showed the absence, even in traces amounts, of cis-
2-methylcyclopentanol and 2-methylcyclopentyl acetamides (comparison with
authentic specimens).
(18) GC analysis of 1-methylcyclopentene is hindered by the coelution of
this compound with the solvent.
(23) In both ref 21 and ref 22 the possibility that hydride migration is
concerted with the departure of the leaving group was dismissed. Thus, we
consider that this possibility is unlikely also in our case. On the other hand, it
should be considered that in the cyclopentane ring substantial energy is required
to obtain the anti periplanar relationship between the C-H bond and the leaving
group, which is thought to be the most convenient one for hydride migration
concerted with leaving group departure.
J. Org. Chem. Vol. 74, No. 4, 2009 1807

acetamides and methylcyclopentanols as alkyl fragmentation prod-
ucts. By comparison with authentic specimens, the only acetamide
identified was 1-methylcylopentyl acetamide. No traces of cis- or
trans-2-methylcyclopentyl acetamides were detected. In order to
identify the structure of methylcyclopentanols it was necessary to
derivatize the reaction mixture with the silylating agent N,O-
bis(trimethylsilyl)trifluoroacetamide. 1-Methylcyclopentyl-trimeth-
ylsilyl ether accompanied by minor amounts of trans-2-methylcy-
clopentyl-trimethylsilyl ether were observed after GC-MS analysis.
Phenyl benzenethiosulfinate (PhSOSPh), diphenyl disulfide (Ph-
SSPh), and phenyl benzenethiosulfonate (PhSO2SPh) were identified
by HPLC analysis by comparison with authentic specimens. By
1H NMR analysis it was found that the unreacted substrate
maintained the cis configuration, no traces of trans-2-methylcy-
clopentyl phenyl sulfoxide24 having been detected. Quantitative
analysis of the alkyl fragmentation products has been carried out
by GC using bibenzyl as internal standard. The amount of unreacted
substrate was determined by H NMR analysis. Material balance
was always >80% versus the amount of starting material.
1
Acknowledgment. Financial support from the Ministero
dell’Istruzione, dell’Universita` e della Ricerca (MIUR) is
acknowledged.
Supporting Information Available: Instrumentation, materi-
als, C-S BDFE for cis-2-methylcyclopentyl phenyl sulfoxide
radical cation. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO802619Y
(24) Ke, B.-W.; Lin, C.-H.; Tsai, Y.-M. Tetrahedron 1997, 53, 7805–7826.
1808 J. Org. Chem. Vol. 74, No. 4, 2009