Study on reactions of long-lived phenoxathiin radical cation with aliphatic alcohols, phenol and phenyl halides in ambient condition by fused-droplet electrospray ionization mass spectrometry

Article abstract of DOI:10.1255/ejms.1136

The reactions of phenoxathiin radical cations with diverse organic compounds in ambient conditions were realized by using fused-droplet electrospray ionization mass spectrometry. In the investigation, the phenoxathiin radical cation was prepared by electrospray ionization. The reactants included aliphatic alcohols, phenol and phenyl halides and the reaction studies showed the unique reactivity the of phenoxathiin radical cation towards neutral organic compounds in ambient conditions, which has not been revealed in previous studies.

Full text of DOI:10.1255/ejms.1136

S.-J. Yao et al., Eur. J. Mass Spectrom. 17, 385–394 (2011)
385
Received: 21 April 2011
n
Revised: 15 August 2011 n Accepted: 16 August 2011 n Publication: 19 August 2011
EuRoPEAN
JouRNAL
oF
MASS
SPECTRoMETRy
Study on reactions of long-lived
phenoxathiin radical cation with aliphatic
alcohols, phenol and phenyl halides
in ambient condition by fused-droplet
electrospray ionization mass spectrometry
Sheng-Jun Yao, Hao-Yang Wang, Li Zhang, Jing Zhang and Yin-Long Guo*
Shanghai Mass Spectrometry center, Shanghai Institute of organic chemistry, chinese Academy of Sciences, 345 Lingling road, Shanghai
200032, Pr china. E-mail: ylguo@mail.sioc.ac.cn
The reactions of phenoxathiin radical cations with diverse organic compounds in ambient conditions were realized by using fused-
droplet electrospray ionization mass spectrometry. In the investigation, the phenoxathiin radical cation was prepared by electrospray
ionization. The reactants included aliphatic alcohols, phenol and phenyl halides and the reaction studies showed the unique reactivity
the of phenoxathiin radical cation towards neutral organic compounds in ambient conditions, which has not been revealed in previous
studies.
Keywords: FD-ESI, phenoxathiin radical cation, reactivity investigation, radical chemistry
Introduction
there has been longstanding interest in understanding
the reactivity of radical cations.1,2 the motivation for these
studies ranges from fundamental interest in organic
Early investigations of 1•+ were carried out in solution. 1•+
could be prepared and stored as phenoxathiin radical cation
−
perchlorate (1•+ clo4 ),9 which was synthesized by perchloric
synthesis3,4 to biological chemistry.5,6 Among the studies, acid oxidation of phenoxathiin solution in anhydrous benzene.7
sulfur-containing radical cations such as the phenoxathiin
radical cation (1•+, Scheme 1)7,8 gained much attention from
chemists. It was found that the radical cation of 1•+ had
an impressive reactivity toward various small molecular
compounds, such as amines,9,10 ketones,11 alkenes,12,13
alkines,14 anisole15,16 and so on.17 Moreover, Everitt and
co-workers18 found that 1•+ can interact with DNA and
showed marked bacteriostatic action on Streptococcus. All
these findings motivated chemists to study the reaction
Scheme 1. General preparation protocol of the phenoxathiin
characteristics of the radical cation 1•+ towards diverse
radical cation 1•+ by chemical synthesis.
organic compounds.
ISSN: 1469-0667
doi: 10.1255/ejms.1136
© IM Publications LLP 2011
All rights reserved

386
Reactions of Phenoxathiin Radical Cations with Diverse Organic Compounds
−
However, the reactant of 1•+ clo4 was extremely hazardous
and explosive when initiated by the friction of transfer, which
restricted the proper studies of 1•+.15 As a consequence, it
is necessary to develop a feasible method to prepare fresh
phenoxathiin radical cations, as well as for the following
studies of its reaction.
was used as the nebulizing gas which was set at 20psi.the
nebulizing gas for the neutral spray tip was also nitrogen with
a pressure of about 15psi.
the fused-droplet electrospray ionization (fD-ESI) source
was constructed on the basis of the ESI-tSQ-MS. As shown in
figure 1, 1mmolL−1 acetonitrile solution of phenoxathiin was
introduced from the electrospray tip, while the neutral reac-
our primary studies showed that phenoxathiin could easily
give its radical cation 1•+ in electrospray ionization conditions, tants (such as methanol, ethanol and so on) or their acetonitrile
which made it possible to perform a study on the reactivity
solutions were fed through the neutral spray tip. collision-
of 1•+. fused-droplet electrospray ionization mass spectrom- induced dissociation (cID) experiments were performed with
etry (fD-ESI/MS),19,20 which was also defined as extractive
electrospray ionization mass spectrometry (EESI-MS),21
based on liquid–liquid extraction between the colliding
microdroplets,20,22 is an important technology for performing
studies on organic reactions in ambient conditions.23–25 the
fD-ESI set-up consists of two independent spray tips: one
is an electrospray to generate the ionic substance, and the
other is a neutral spray to provide neutral reactant. the
present paper describes the application of fD-ESI-tandem
mass spectrometry (MS/MS) for studying the reactivity of 1•+
in ambient conditions with various compounds, including
aliphatic alcohols, phenol and phenyl halides. our studies
showed the unique reactivity of radical cation 1•+ towards
diverse neutral organic compounds in ambient conditions,
which has not been studied previously.
argon at various collision energies (Elab = 0–30eV) and collision
gas pressure of 1.0mtorr.
Computational details
Density functional calculations were performed by using
Becke’s three-parameter hybrid exchange-correlation func-
tional26 containing the non-local gradient correction of Lee,
yang and Parr (B3LyP) within the Gaussian03 program.27 the
basis set used for the remaining atomic species was 6-31G
with the important addition of the polarization functions (d) for
all atoms, including the hydrogen atoms.28
Results and discussions
Formation of 1•+ by electrospray ionization
the experiment for generating 1•+ was achieved by analysis
of acetonitrile solution of 1 (phenoxathiin) with electrospray
ionization mass spectrometry. Generally, the neutral analytes
in ESI are charged by acid/base chemistry or by adduct forma-
tion (such as [M+H]+, [M+Na]+ and so on).29,30 However, those
aromatic compounds31 with low ionization energy can generate
M•+ in the positive ion mode due to single-electron transfer
Experimental
Chemicals and reagents
Phenoxathiin (1) and D5-phenol were purchased from
Sigma (St Louis, Mo, uSA). Phenol (c6H5oH), n-butyl
alcohol (n-c4H9oH), isoamylol ((cH3)2cHcH2cH2oH)
cyclohexanol (c6H11oH), chlorobenzene (c6H5cl), bromo- (SEt) process within the charge-transfer complexation32 or
benzene (c6H5Br) and iodobenzene (c6H5I) were of analytical
grade and purchased from Sinopharm chemical reagent
co. Ltd (Shanghai, china). Methanol (cH3oH, HPLc grade),
acetonitrile (cH3cN, HPLc grade), ethanol (cH3cH2oH, HPLc
grade) and isopropanol [(cH3)2cHoH, HPLc grade] were from
Dima technology Inc. (richmond Hill, VA, uSA). the solution
of 1 for ESI and fD-ESI analysis was prepared by dissolving
0.5mg 1 in 1.0mL solvent. the solution was fed into the ESI
ion source through an infusion syringe pump with a flow
rate at 10 µL min−1. Aliphatic alcohols, phenol D5-phenol,
and phenyl halides (c6H5X, X = cl, Br, I) were dissolved in
acetonitrile.
at the metal–solution interface of the ESI needle.33,34 this
Mass spectrometry experiments
the ESI mass spectrometric experiments were carried out
on a finnigan tSQ (thermo finnigan, Quantum Access) triple
quadrupole mass spectrometer fitted with an ESI source
(ESI-tSQ-MS). the mass spectrometric conditions were used
as follows: ionization voltage at +4.0kV, capillary offset at 37V,
capillary voltage at 10.24V, spray current at 2.44µA and capil-
lary temperature at 275°c. the stainless steel spray needle is
143.5mm (length)×0.10mm (ID) H0.23mm (oD). Nitrogen gas
Figure 1. Diagram of the FD-ESI source set-up used in the
experiments.

S.-J. Yao et al., Eur. J. Mass Spectrom. 17, 385–394 (2011)
387
Figure 2. (a) ESI mass spectrum for 1 in CH3CN, (b) ESI mass spectrum for 1 (stored for 1 week after the first experiment) in CH3CN, (c)
ESI-MS/MS spectrum for CID of the ion 1•+ at m/z 200, (d) ESI-MS/MS spectrum for CID of the ion 2+ at m/z 217.
provides an alternative approach35,36 to generate 1•+ other
than the organic synthesis method.37
the electrospray tip A to give 1•+. Meanwhile, the reactant
of methanol was imported into the ion source through the
neutral spray tip B. Such an experimental set-up allowed the
reaction of 1•+ with methanol under conditions of colliding
the ESI mass spectrum of acetonitrile solution of 1 showed
the clean signal of 1•+ at m/z 200 [figure 2(a)], which allowed
the further investigation on the reactivity of 1•+ by fD-ESI-MS. microdroplets (shown in figure 1). the product ions subse-
Moreover, as phenoxathiin can be easily oxidized to form
phenoxathiin S-oxide,38 the S-hydroxyl phenoxathiinium cation
2+ at m/z 21733 [figure 2(b)] could be detected when we analyzed
the phenoxathiin sample which was stored for about 1 week
after the first experiment. the cID experiment of 1•+ indicates
the losses of S, co and Hco• to form the ions of m/z 168, m/z
172 and m/z 171, respectively [figure 2(c)]. In the MS/MS for
cID of the ion 2+ at m/z 217 [figure 2(d)], 2+ gives the product
ion 1•+ of m/z 200 by the loss of an AoH radical.
quently experienced the desolvation39 and then were further
detected using a mass spectrometer.
figure 3 shows the reaction results of 1•+ with methanol
[figure 3(a)] and ethanol [figure 3(b)]. Besides the ion of m/z
217, the spectra show the S-methoxyl phenoxathiinium cation
(3+ at m/z 231) and the S-ethoxyl phenoxathiinium cation (4+ at
m/z 245) as the major products, respectively. Scheme 2 shows
the possible reaction pathway of 1•+ with neutral aliphatic
alcohols40,41 in ambient conditions.
the MS/MS spectrum of 3+ (m/z 231) gave the major product
ion of 1•+ (m/z 200) and the minor product ion of m/z 216
[figure 4(a)]. the generation of 1•+ at m/z 200 from 3+ at m/z
231 indicated the homolytic cleavage of the sulfur–oxygen
bond15 in 3+ to form 1•+ by loss of an •ocH3 radical. this
phenomenon can be attributed to those weak S–X (X = N, o, c,
Ambient reactions of 1•+ with aliphatic
alcohols
the ambient reactions between 1•+ and aliphatic alcohols were
monitored by fD-ESI-MS. In the fD-ESI-MS experiments, the
solution of 1 in acetonitrile was fed into the ion source through
Figure 3. FD-ESI-MS spectra of droplet reactions of 1•+ with alcohols: (a) methanol, (b) ethanol.

388
Reactions of Phenoxathiin Radical Cations with Diverse Organic Compounds
ROH
O
S
R
O
S
O
S+
+
+
OCH3
S
CH3
R O
O
EESI-MS
O
m/ z 216
O
1+ at m/ z 200
S
3+ at m/ z 231
2+ at m/ z 217
R=H
O
R
O
3+ at m/ z 231
4+ at m/ z 245
R=CH3
S+
1
at m/ z 200
R=CH3CH2
OH
S
O
Scheme 2. Reactions of 1•+ at m/z 200 with water and alcohols
(methanol and ethanol), giving 2+ (m/z 217), 3+ (m/z 231) and 4+
(m/z 245) in the FD-ESI-MS condition.
4+-8+
+
Y
O
2+ at m/ z 217
R=CH3CH2
4+ at m/ z 245
Y=
S) bonds.42 the fragment ion at m/z 216 corresponding to the
S-oxide phenoxathiin radical cation was formed through the
carbon–oxygen bond homolysis of 3+ (Scheme 3) with the loss
5+ at m/ z 259
6+ at m/ z 273
7+ at m/ z 287
8+ at m/ z 299
R=(CH3)2CH
Y=
Y=
R=CH3CH2CH2CH2
R=(CH3)2CHCH2
•
of a cH3 radical. However, the cID mass spectrum [figure
4(b)] of 4+ gave the fragment ion 1•+ of m/z 200 and the frag-
ment ion 2+ of m/z 217. It is interesting that the generation
of m/z 217 from 4+ at m/z 245 suggested a b-H abstraction
process via loss of neutral ethylene, which proved to be one
of the main products in the solution of condensed phase
reactions between 1•+ and aliphatic alcohols43,44 (Scheme
Y=
Y=
R=
Scheme 3. Proposed fragmentation pathways for S-alkoxyl
phenoxathiinium cations 3+–8+.
Figure 4. FD-ESI-MS/MS spectra for CID of S-alkoxyl phenoxathiinium cations (a) 3+ at m/z 231, (b) 4+ at m/z 245, (c) 5+ at m/z 259, (d) 6+
at m/z 273, (e) 7+ at m/z 287, (f) 8+ at m/z 299.

S.-J. Yao et al., Eur. J. Mass Spectrom. 17, 385–394 (2011)
389
Figure 5. Energy-level diagram for the two possible fragmentation pathways of S-ethoxyl phenoxathiinium cation 4+ at m/z 245: (1) b-H
abstraction to 2+ at m/z 217 (right side); (2) C–O band homolysis to ion at m/z 216 (left side).
3). Dft calculations for the two possible gas-phase disso- modynamically favored by 215.6 kJ mol−1 to the pathway of
ciations of 4+ at m/z 245 were shown in figure 5: (1) b-H
abstraction to form 2+ of m/z 217 via the transition state with
an energy barrier of 311.9 kJ mol−1 and the relative energy
of products with 117.6 kJ mol−1; (2) c–o band homolysis to
form ion of m/z 216 via the transition state with an energy
barrier of 343.3kJmol−1 and relative energy of products with
333.2kJmol−1. the calculations indicated that the fragment
pathway of b-H abstraction to form 2+ at m/z 217 is ther-
the carbon–oxygen bond homolysis to the ion at m/z 216.
Meanwhile the energy barrier of b-H abstraction to form 2+
at m/z 217 is lower by 31.4kJmol−1 than the pathway of the
carbon–oxygen bond homolysis to form the ion at m/z 216.
these results supported the proposed dissociation pathway
of 4+ at m/z 245 to form 2+ at m/z 217 by b-H abstraction
process.
Figure 6. (a) FD-ESI-MS spectrum of the reaction between 1•+ and phenol, (b) FD-ESI-MS/MS spectrum of the ion at m/z 293.
Figure 7. (a) FD-ESI-MS spectrum of droplet reaction 1•+ and D5-phenol. (b) FD-ESI-MS/MS spectrum of the ion at m/z 298.

390
Reactions of Phenoxathiin Radical Cations with Diverse Organic Compounds
Scheme 4. Possible products of the reaction between 1•+ and phenol to give isomers 9+ and 10+ with the same m/z at 293 in the FD-ESI-
MS condition.
Meanwhile, similar results were obtained from the reaction
reaction result of 1•+ and c6D5oH, which gives two product
of 1•+ with isopropanol, n-butanol, isopropanol and cyclo- signals at m/z 297 and m/z 298. Based on such results, we
hexanol. they gave the S-alkoxyl phenoxathiinium cations of
deduced that the ion at m/z 297 is isotope peak A of D4–9+
(Scheme 5), generated through the electrophilic substitution of
5+ at m/z 259, 6+ at m/z 273, 7+ at m/z 287 and 8+ at m/z 299
as the major product ions in the ambient reactions with 1•+, 1•+ toward the aromatic ring of the D5-phenol.50–52 According to
respectively. the cID mass spectra of 5+–8+ (figure 4) showed
Scheme 5, the ion at m/z 298 might come from the contribution
that the ion of 1•+ at m/z 200 by homolytic cleavage of sulfur– of D5–10+ (A isotope peak, 12c181H8 D516o232S+, formed through
2
oxygen bond and the ion of 2+ at m/z 217 by loss of olefin Y
(Scheme 3) via b-H abstraction are the major products. these
experimental results clearly demonstrated the reactivity of
1•+ towards alcohols in ambient conditions.45 these results
suggested that the S-alkoxyl phenoxathiinium cations (shown
in Scheme 3) might be the reactive intermediates of solution
reactions of 1•+ with aliphatic alcohols.46–48
the phenolic hydroxylation of 1•+ by phenol), or the contribu-
2
tion of (A+1) isotopic peak of D4–9+ (13c12c171H9 D416o232S+,
formed through the electrophilic substitution of 1•+ toward the
aromatic ring of D5-phenol. the experimental ratio (shown
in table 1) of m/z 200 to m/z 201 obtained from the MS/MS
spectrum of m/z 298 [figure 7(b) and Scheme 6] indicates that
the ion at m/z 298 is a mixture of isotopic peak A of D5–10+
2
(12c181H8 D516o232S+, m/z 298) and isotopic peak (A + 1) of D4–9+
Ambient reaction of 1•+ with phenol
2
(13c12c171H9 D416o232S+, m/z 298). the experimental results
the ambient reaction of 1•+ with phenol49 was performed and
the fD-ESI mass spectrum gave a strong signal at m/z 293
(figure 6). two possible structures, 9+ and 10+, were proposed
for the ion at m/z 293 and they were shown in Scheme 4. to
further confirm the structure of the ion at m/z 293, D5-phenol
(c6D5oH) was employed as the reactant. figure 7(a) shows the
showed the unique reactivity of 1•+ towards phenol in ambient
conditions.
Ambient reactions of 1•+ with phenyl halides
In solution condition at room temperature, 1•+ had been
found not to react with phenyl halides or at least too slowly
OH
D
A of D4-9+
1H92D416O232S+
D
D
m/ z 297
12
C
18
D
S+
A+1 of D4-9+
13C12C171H92D416O232S+
O
m/ z 298
D4-9+ C18H9D4O2S+
S
C6D5OH
D
O
D
D
D
A of D5-10+
12
C
1H82D516O232S+
m/ z 298
m/ z 299
18
O
D
S+
A+1 of D5-10+
13C12C171H82D516O232S+
O
D5-10+ C18H8D5O2S+
Scheme 5. Possible products of the reaction between 1•+ and D5-phenol within FD-ESI-MS.

S.-J. Yao et al., Eur. J. Mass Spectrom. 17, 385–394 (2011)
391
OH
D
D
D
D
13C12C111H816O32
S
m/ z 201
m/ z 200
S
S+
O
O
12
C
1H816O32
S
12
A+1 of D4-9+
13C12C171H92D416O232S+
m/ z 298
D
D
D
D
O
S
D
S+
12
m/ z 200
C
1H816O32
S
12
O
O
A of D5-10+
1H82D516O232S+
12
C
18
Scheme 6. Possible fragmentation pathways for the ion at m/z 298.
Table 1. Calculations for the product ratio of I200 to I201 obtained from m/z 298.
Ratio
theoretical ratio
Precursor ions
A+1 peak of D4-9+ at m/z 298
A of D5-10+ at m/z 298
Signal at m/z 298
Ratio of product ions
I200: I201 ≈ 1:2
theoretical ratio
I200: I201 = 1:0
Experimental ratio
I is the relative abundance of the ion.
I200: I201 ≈ 9:10
to observe.7,53 However, the fD-ESI mass spectra [figures
8(a)–(c)] of the ambient reactions of 1•+ with phenyl halides
phenyl halides directly (Scheme 5) in fD-ESI condition. the
cID experiment of the ion 11+ at m/z 277 [figure 8(d)] indicated
clearly showed a product ion at m/z 277.54–56 the corre- 1•+ at m/z 200 as the major fragment ion, which confirmed the
sponding possible structure of 11+ is shown in Scheme 7. this
experiment indicates that 1•+ has significant reactivity towards
possible structure of 11+.
Conclusions
X
this study showed the reactivity of phenoxathiin radical
cation with alcohols, phenol and phenyl halides in ambient
reactions and these reactions were monitored by an simply
fD-ESI-MS(/MS) experimental set-up. the experimental
results showed that the S-alkoxyl phenoxathiinium cations
are the key intermediates of the reactions between phenox-
athiin radical cation and alcohols. the phenol can react
with phenoxathiin radical cation to produce isomer product
ions in ambient condition. In addition, it has been proved
that phenyl halides react with phenoxathiin radical cations
in ambient conditions. the reaction of phenoxathiin radical
cations with phenyl halides generated electrophilic aromatic
substitution product ions which had not been observed in
the solution before. All these findings not only provided an
alternative approach to studying organic reactions of highly
S
S+
EESI
O
O
X=I, Br, Cl
m/ z 200
m/ z 277
11+
CID
S+
S
O
O
m/ z 200
m/ z 277
11+
1
Scheme 7. Possible structure of 11+ and its possible fragment
pathway.

392
Reactions of Phenoxathiin Radical Cations with Diverse Organic Compounds
Figure 8. FD-ESI-MS spectra of droplet reactions between 1•+ and (a) iodobenzene, (b) bromobenzene, (c) chlorobenzene; (d) FD-ESI-
MS/MS spectrum 11+ at m/z 277.
reactive phenoxathiin radical cations with diverse organic
compounds, but also showed the remarkable convenience
of fD-ESI-MS/MS for probing organic reactions in ambient
reactions.
4. y.S. Park, S.c. Wang, D.J. tantillo and r.D. Little, “A
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the authors acknowledge support from NSfc (20875097, 6. A.B. Whitehill, M. George and M.L. Gross, “reactions
20805056, 20902104 and 21072215), the Ministry of Science
and technology of china (2010IM030900) and cAS (yZ200938,
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