Reactions of Thiiranium and Sulfonium Ions with Alkenes in the Gas Phase

Article abstract of DOI:10.1021/acs.joc.9b01264

Ion-molecule reactions between thiiranium ion 11 (m/z 213) and cyclohexene and cis-cyclooctene resulted in the formation of addition products 17a and 17b (m/z 295 and m/z 323, respectively) via an electrophilic addition pathway. Associative π-ligand exchange involving direct transfer of the PhS⁺ moiety, which has been observed for analogous seleniranium ions in the gas phase, did not occur despite previous solution experiments suggesting it as a valid pathway. DFT calculations at the M06-2X/def2-TZVP level of theory showed high barriers for the exchange reaction, while the addition pathway was more plausible. Further support for this pathway was provided with Hammett plots showing the rate of reaction to increase as the benzylic position of thiiranium ion derivatives became more electrophilic (ρ = +1.69; R² = 0.974). The more reactive isomeric sulfonium ion 22 was discounted as being responsible for the observed reactivity with infrared spectroscopy and DFT calculations suggesting little possibility for isomerization. To further explore the differences in reactivity, thiiranium ion 25 and sulfonium ion 27 were formed independently, with the latter ion reacting over 260 times faster toward cis-cyclooctene than the thiiranium ion rationalized by calculations suggesting a barrierless pathway for sulfonium ion 27 to react with the cycloalkene.

Full text of DOI:10.1021/acs.joc.9b01264

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Article
Reactions of Thiiranium and Sulphonium
ions with Alkenes in the Gas-phase
Samuel Charles Brydon, Shea Fern Lim, George N. Khairallah, Philippe Maitre,
Estelle Loire, Gabriel da Silva, Richard A. J. O'Hair, and Jonathan M White
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01264 • Publication Date (Web): 22 Jul 2019
Downloaded from pubs.acs.org on July 23, 2019
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Reactions of Thiiranium and Sulphonium Ions with
Alkenes in the Gas-Phase
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Samuel C. Brydona, S. Fern Lima, George N. Khairallaha,b, Philippe Maîtrec, Estelle Loirec, Gabriel
da Silvad, Richard A. J. O’Haira, Jonathan M. Whitea*
a
School of Chemistry and Bio21 Institute, The University of Melbourne, Parkville, Victoria 3010,
Australia.
b Accurate Mass Scientific Pty Ltd, P.O. Box 92, Keilor VIC 3036, Australia
c Laboratoire de Chimie Physique (UMR8000), Université Paris-Sud, CNRS, Université Paris Saclay,
Orsay, 91405, France
d Chemical and Biomolecular Engineering, University of Melbourne, Parkville, Victoria 3010,
Australia.
Email:
whitejm@unimelb.edu.au
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Abstract:
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Ion-molecule reactions between thiiranium ion 11 (m/z 213) and cyclohexene and cis-cyclooctene
resulted in the formation of addition products 17a and 17b (m/z 295 and m/z 323 respectively) via an
electrophilic addition pathway. Associative π-ligand exchange involving direct transfer of the PhS+
moiety, which has been observed for analogous seleniranium ions in the gas-phase, did not occur despite
previous solution experiments suggesting it as a valid pathway. DFT calculations at the M06-2X/def2-
TZVP level of theory showed high barriers for the exchange reaction, whilst the addition pathway was
more plausible. Further support for this pathway was provided with Hammett plots showing the rate of
reactivity to increase as the benzylic position of thiiranium ion derivatives became more electrophilic
(ρ = +1.69; R2 = 0.974). The more reactive isomeric sulphonium ion 22 was discounted as being
responsible for the observed reactivity with infrared spectroscopy and DFT calculations suggesting little
possibility for isomerisation. To further explore the differences in reactivity, thiiranium ion 25 and
sulphonium ion 27 were formed independently with the latter ion reacting over 260 times faster towards
cis-cyclooctene than the thiiranium ion rationalised by calculations suggesting a barrierless pathway for
sulphonium ion 27 to react with the cycloalkene.
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Introduction:
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Thiiranium ions (general structure 1, Scheme 1) have been shown to be important reactive intermediates
in many synthetic transformations, particularly in the stereoselective functionalisation of alkenes.1-16
These intermediates are typically formed by either addition of an electrophilic chalcogen reagent to an
alkene (Path A, Scheme 1) or by the chalcogen lone-pair induced elimination of a suitable β-leaving
group, such as an alcohol following acid treatment or halides in the presence of silver salts (Path B,
Scheme 1).1,3,4,6 Though readily available reagents such as phenylsulphenyl chloride can be used as an
electrophilic sulphur source, more complex species such as trisulphur salts have become popular as they
allow stereoselectivity induction at the sulphur source itself rather than at the alkene.3,8,9,11,17
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R2
R1
R3
R4
R3
R4
R1 SR
RS
R1
RS-X
R2
Path C
R
S+
R4
R3
Path A
R2 Nu
Nu
R1
R2
R4
R3
2'
2
Path D
1
R3
RS
R2
R1
R3
R4
R4
Path B
RS Nu
Path E
R1
R2 LG
3
Scheme 1. Possible pathways for formation and reaction of thiiranium ion 1
Rather than undergoing reactions as conventional n-type reactive intermediates, thiiranium ions follow
two pathways. The first involves nucleophilic attack at the α-carbon yielding products 2 and 2’ (internal
nucleophiles give cyclised products), which are themselves useful synthetic building blocks as
stereochemical integrity is maintained due to anchimeric assistance by the chalcogen atom (Path C,
Scheme 1).1,2,4,18-22 The alternative is nucleophilic attack at the chalcogen centre (Path D, Scheme 1)
to give an alkene and a highly electrophilic sulphur transfer agent 3, which may further undergo π-
ligand exchange.5,8,23-26 This reversible process contributes to the limitations of some chalcogen iranium
ions in synthesis, particularly for the more electrophilic selenium, as stereochemistry of these species
is scrambled.5,7,8,24 Investigations into the effects of varying the R group directly on the chalcogen of
both thiiranium and seleniranium ions in solution have shown that more bulky groups tend to maintain
optical purity, whilst both electron donating and withdrawing groups had minimal impact on the stereo
outcome for sulphur substrates.8,10,27,28 However, electron donating groups such as p-OMe-phenyl on
the selenium of the iranium ion intermediate lead to extensive scrambling compared to electron
withdrawing groups such as o-NO2-phenyl, which maintained stereochemical integrity, a result which
was rationalised by the latter activating the α-carbon of the iranium ion toward nucleophilic attack.29-31
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Associative
R
S+
R
S+
Dissociative
R2
R2
OR
RS+
H
H
H
H
R2
R1
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R1
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Scheme 2. Dissociative and associative transfer mechanisms of RS+ between alkenes
The formal olefin-to-olefin RS+ transfer has previously been thought to be dissociative and involve
nucleophilic assistance with formation of the electrophilic transfer reagent in 3 (RS-Nu, Scheme 1).
However, Denmark et al. have reported transfer of the RS+ moiety (R = Ph only; R = Me showed no
transfer) between olefins to be associative by generating thiiranium ions in the presence of the relatively
-
non-nucleophilic counterion SbF6 in a non-participating solvent, CD2Cl2 (Scheme 2).5,24
H
S
+393
~
~
4
S
H
H S
H S
+46.6
0.0
-25.6
H S
-25.6
H
S
H
S
~
~
-197
Reaction Coordinate
Figure 1. Relative energy diagram for reaction pathways of ethene with thiiranium 4. Calculated at G2
(ZPVE = MP2) level of theory. Electronic energies reported at 0 K in kJ mol-1 with scaled ZPVE.
Adapted from Reference 25.
Though this process was slow even at the higher temperature of 0°C (no transfer was observed at
-20°C), the higher temperatures reflected theoretical calculations by Radom suggesting that direct
transfer of the RS+ group was feasible between ethene molecules with a kinetic barrier of 46.6 kJ mol-1
compared to a thermodynamically preferable insertion product (-197 kJ mol-1) that required a much
higher barrier of 393 kJ mol-1 (Figure 1).25
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Mass spectrometry has grown to be a powerful technique for investigating the reactivity of charged
species in the gas-phase.32-35 This technique removes complications from solvents, counterions and
potential impurities allowing for more accurate insights into reaction mechanisms, such as
differentiating associative vs dissociative π-ligand exchange reactions of chalcogen iranium ions
(Scheme 2). In combination with theoretical calculations, multi-stage mass spectrometry experiments
have been used to probe the olefin-to-olefin RSe+ transfer in the gas-phase.36
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Figure 2. Ion-molecule reaction between seleniranium ion 5 m/z 261 and cyclohexene (at a
concentration of ca 1011 molecules cm-3 for t = 25,000 ms). The mass selected ion is denoted by an
asterisk (the most abundant selenium isotope 80Se was used). Adapted from Reference 36.
The observed seleniranium ion 5 structure was confirmed through a combination of high-resolution
mass spectrometry (HRMS), infra-red multiple photon dissociation spectroscopy (IRMPD), ion-
mobility measurements, and DFT calculations.36 Once mass selected, seleniranium ion 5 was shown to
undergo π-ligand exchange via an associative mechanism in ion-molecule reactions (IMR) with a
variety of cycloalkenes, with increasing rates of reactivity corresponding to an increase in ring strain of
the cycloalkene.37-39 For example, upon exposure to cyclohexene introduced directly into the
spectrometer, there was a loss of parent seleniranium ion intensity m/z 261 and the formation of an ion
at m/z 239 6 reflecting the direct transfer of the PhSe+ moiety from styrene to cyclohexene via a
thermodynamically driven pathway supported by DFT calculations (Figure 2). The transition states for
π-ligand exchange reactions also appear to bear the hallmarks of coarctate transition states with
concomitant bond formation and breakage occurring at the central chalcogen, but this requires further
investigation.40
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m/z 261
m/z 343
m/z 341
Scheme 3. Proposed mechanism for formation of addition/elimination product ions 7 and 8
The appearance of an accompanying smaller peak at m/z 343 was assigned to an electrophilic addition
product 7 following proton transfer from the initial adduct. Apparent ‘spontaneous elimination’ of H2
could plausibly give the product 8 corresponding to the observed peak at m/z 341. However, this was
later shown to be an artefact of a highly reactive impurity in the aged cycloalkenes, possibly a result of
auto-oxidation. The other side-products were attributed to oxidation of the alkene via initial hydride
transfer to the electrophilic iranium ion followed by reactions with water and neutral alkene.36
Though Denmark’s solution experiments showed very high reactivity for seleniranium ions, the results
indicated relatively slow π-ligand exchange for the corresponding thiiranium ions and in some cases no
reaction was observed.24 Given the gas-phase results for the reactivity of seleniranium ions towards
cycloalkenes, particularly the support for an associative π-ligand exchange mechanism, we believed it
would be interesting to investigate the reactivity of thiiranium ions with alkenes under similar
conditions.
Results and Discussion:
Various sulphur substrates were used to generate a range of thiiranium ions allowing for a greater scope
of investigation than the previously explored seleniranium ions. One such variation was the leaving
group with an acetate group employed rather than an amine, allowing for easier syntheses of appropriate
thiiranium ion precursors. The β-thiophenylacetate 9 was introduced as a single regioisomer at a
concentration ca 0.1 mM in acetonitrile with 1% formic acid into the mass spectrometer under
electrospray ionisation (ESI) conditions (Scheme 4).
Ph
Ph
O
SPh
Ph
O
SPh
ESI
S
HO
O
Ph
9
10
11
Not observed
m/z 213
Scheme 4. ESI of acetate precursor 9 to give thiiranium ion 11 (m/z 213)
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Unlike the previously studied β-selenylamines, which gave an ammonium ion upon ESI, the β-
thiophenylacetate 9 did not produce an observable protonated ion, but rather directly produced 11 in
the ESI source (Scheme 4).36 Extensive investigations were undertaken previously with selenium to
provide evidence for the structure of the ion at m/z 261 to be that of the seleniranium ion 5 as discussed.
It was reasonable to assume at this stage that the observed sulphur containing ion at m/z 213 generated
under similar conditions would indeed be that of the corresponding thiiranium ion with HRMS
supporting this assumption (see Supporting Information p S3). The ion 11 in all cases could then be
further isolated (MS2) and allowed to undergo ion-molecule reactions with a variety of volatile alkenes.
Initial investigations into the gas-phase bimolecular reactivity of thiiranium ion 11 involved conducting
IMR with cyclohexene and cis-cyclooctene in the ion-trap of the mass spectrometer as with the previous
studies for seleniranium ion 5. Following isolation, thiiranium ion 11 (m/z 213), produced via ESI of
acetate precursor 9, was independently exposed to a stream of cyclohexene and cis-cyclooctene
introduced at concentrations of ca. 2-3 x 1011 and 6-7 x 1010 molecules cm-3 respectively.
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S
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Figure 3. IMR of thiiranium ion 11 m/z 213 with A) cyclohexene (t = 8000 ms) and B) cis-cyclooctene
(t = 8000 ms) at a concentration of ca 1011 molecules cm-3. The mass selected ion is denoted by an
asterisk (the most abundant sulphur isotope 32S was used in all experiments).
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TS12a-13a
+29.6 (+75.9)
Ph S
Ph S
Ph
+22.4 (+69.1)
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Ph
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14a
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-30.1 (+15.0)
-35.7 (+12.7)
13a
-55.1 (-7.9)
-39.2 (-32.0)
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13b
-73.1 (-29.6)
Reaction Coordinate
B
Ph S
Ph S
Ph S
Ph
Ph
Ph
12a
TS12a-13a
13a
Figure 4. A) Relative energy diagram for π-ligand exchange of cyclohexene (a: n = 1, black) and cis-
cyclooctene (b: n = 3, red) with styrene at the sulphur of thiiranium ion 11. Energies given as ΔH (ΔG)
in kJ mol-1 at M06-2X/def2-TZVP level of theory relative to the total free reactant energies.
B) Gaussview optimised structures of key species 12a, TS12a-13a and 13a with accompanying
Chemdraw diagrams. (Refer to Supporting Information for cis-cyclooctene Gaussview structures).
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Unexpectedly, no π-ligand exchange product (cyclohexene: m/z 191; cis-cyclooctene: m/z 219), which
would be the result of an associative transfer mechanism, was observed during either of these reactions
(Figure 3). Instead, the reactivity between the alkene and the thiiranium ion consisted of an addition
pathway (cyclohexene: m/z 295; cis-cyclooctene: m/z 323),41 previously observed with the seleniranium
ions as a minor pathway.36 Upon further investigation with DFT calculations, however, this result was
less surprising with an enthalpic barrier of approximately +22 and +30 kJ mol-1 to associative π-ligand
exchange for cis-cyclooctene and cyclohexene respectively (TS12a-13a and TS12b-13b, Figure 4).
Note that unlike solution-phase, calculations predict the reaction will happen in the gas-phase when all
species leading towards the product(s) are less than the enthalpy of the free reactants (ΔH < 0), as there
is no solvent present to provide additional energy to overcome endothermic barriers.42 In addition, Dau
et al have highlighted that the relevant thermodynamic parameter to use for low-pressure bimolecular
reactions in the gas-phase is the reaction energy/enthalpy rather than the Gibbs free energy since the
computed entropy of the reactants is not a good measure of the entropy at the entrance channel.43 The
high ΔG‡ of the transition state (cyclohexene: +76 kJ mol-1 ; cis-cyclooctene: +70 kJ mol-1) relative to
the reactants indicates that there is an additional entropic barrier to this reaction occurring in the gas-
phase, most likely a result of the tightly restricted orientation of the alkenes at the chalcogen during the
transition state (Figure 4). Combined, the enthalpic and entropic barriers prevent associative π-ligand
exchange occurring for thiiranium ion 11 under these conditions.
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S
16a
(CH2)n
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-1.4 (+51.1)
Ph
+0.5 (+52.7)
TS16a'-17a
-21.0 (+41.9)
15a
16a'
-22.6 (+37.8)
-12.3 (+37.9)
-28.2 (+13.4)
TS15b-16b
-23.5 (+33.0)
-33.0 (+11.5)
16b
15b
17a
-176 (-114)
-190 (-126)
17b
Reaction Coordinate
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16a
Ph
Ph
Ph
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S
S
S
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17a
Figure 5. A) Relative energy diagram for addition of cyclohexene (a: n = 1, black) and cis-cyclooctene
(b: n = 3, red) to thiiranium ion 11 followed by ring closure to give 17a and 17b respectively. Energies
given as ΔH (ΔG) in kJ mol-1 at M06-2X/def2-TZVP level of theory relative to the combined total of
the free reactant energies. B) Gaussview optimised structures of key species 16a’, TS16’-17a and 17a
with accompanying Chemdraw diagrams. (Refer to Supporting Information for cis-cyclooctene
Gaussview structures).
The most plausible structure for the addition product formed was the bicyclic sulfonium ion 17,
analogous to Radom’s insertion product in Figure 1. DFT calculations were thus performed on the
addition of both cycloalkenes to thiiranium ion 11 to further explore the mechanism. Following an
exothermic ring opening by cyclohexene (TS15a-16a, ΔH‡ = -1.4 kJ mol-1) at the benzylic carbon of
thiiranium ion 11 (the alternative attack at the methylene carbon by cyclohexene gave ΔH‡ = +22.8
kJ mol-1, see Supporting Information p S39 and is not predicted to occur), the addition product 17a
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could be reached via the cyclopropylium ion 16a (ΔH = +0.5 kJ mol-1) with this pathway viable within
the margin of error of the theoretical method (Figure 5).44 The small amount of product 17a formed
under the experimental conditions is also reflective of the large ΔG‡ of +51.1 kJ mol-1 at the RDS
(TS12a-13a, Figure 5), even with a large thermodynamic drive towards formation of -176 kJ mol-1.
The lower energy pathway for addition of cis-cyclooctene to 11, particularly at the C-C bond formation
step (TS12b-13b, ΔH‡ = -12.3 kJ mol-1) and subsequent cyclopropylium ion 16b (ΔH = -23.5 kJ
mol-1), is due to reduced steric interactions between the cycloalkyl and benzyl moieties (Supporting
Information p S45), and greater strain release of the larger cycloalkene.45 The subsequent intermediate
and ring closure transition state were not stable minima at the M06-2X/def2-TZVP level of theory for
cis-cyclooctene, perhaps reflecting rapid capture of the secondary carbocation by the sulphur lone-pair.
Overall, the lower energy RDS predicts a faster rate of reaction for cis-cyclooctene and this is reflected
in the larger amount of product for the same reaction time compared to cyclohexene (Figure 3). The
pathway is also much lower in energy compared to Radom’s concerted mechanism (barrier of +393 kJ
mol-1) as it is step-wise and able to proceed through a discrete secondary carbocation 16’ (compare
Figures 1 and 5).
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Addition by the cycloalkene to a benzylic stabilised carbocation, where the thiiranium ion has
undergone ring opening, was also considered due to strong evidence of this equilibria in solution.46
However, not only was the required open structure found not to be a minima at the M06-2X/def2-TZVP
level of theory in the gas-phase, but the ΔH‡ of a transition state located for the addition of cyclohexene
to the benzylic carbocation was found to be +26.1 kJ mol-1 relative to the free reactants (refer to
Supporting Information p S41). As explained above, the fact that bimolecular IMR with endothermic
barriers will not proceed in the gas-phase, combined with the lower energy pathway calculated for ring
opening of the thiiranium ion, excludes addition by the cycloalkene to an ‘open’ benzylic carbocation.
Ph
Ph
S+
S
Ph
X
S
kRDS
X
X
Scheme 5. Addition of cis-cyclooctene to thiiranium ions with electronic substituents to give bicyclic
addition products via a secondary carbocation intermediate.
Now that the main reaction pathway for thiiranium ions with cycloalkenes had been established in the
parent system 11, we decided to explore electronic effects affecting the observed outcomes and
reactivity. We proposed that by varying the electronic demand at the benzylic carbon, the position
proposed to be involved in the rate-determining step for the addition pathway, the thiiranium ion
electrophilicity could be modulated and the resulting rate of reaction with neutral cycloalkene varied.
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Table 1. Pseudo 1st order reaction rates for ion-molecule reactions of thiiranium ions with varying
electronic substituents and cis-cyclooctene (conc. ca 1011 molecules cm-3)*
6
7
8
X
σ 47
σ+
kobserved* (s-1)
kabsolute
krelative
(kX/kH)
13.9
(cm3 molecules-1 s-1)#
9
10-1
10-2
10-2
10-2
10-3
(4.6
(4.0
(3.3
(2.1
(7.5
1.2)
1.0)
0.8)
0.5)
1.9)
10-12
10-13
10-13
10-13
10-14
18
19
11
20
21
m-NO2
m-OMe
H
0.710
0.115
0
0.674
0.047
0
×
×
×
×
×
±
±
±
±
±
×
×
×
×
×
2.8
2.4
2.1
1.3
4.6
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1.21
1.00
0.64
0.23
p-CH3
p-OMe
-0.170
-0.268
-0.311
-0.778
*determined by monitoring decrease in parent ion intensity #errors given as a conservative
25% of kabsolute
48
±
A variety of sulphur substrates were prepared from the appropriate substituted styrenes by established
methods (see experimental section). Thiiranium ions 18-21, generated directly under ESI conditions
from acetate precursors 33-36 and characterised by HRMS (see Supporting Information p S3-5), were
isolated in the quadrupole ion-trap and then exposed to cis-cyclooctene (Scheme 5). The rates of
consumption of the thiiranium ions were determined under pseudo first order conditions and the results
summarised in Table 1. There is an increase in reactivity with increasing electron-withdrawing
character of the substituent X as determined by the Hammett substituent constant, reflecting the increase
in electrophilicity of the benzylic carbon. The plot of log(krel/kH) vs σ gives a Hammett ρ constant of
+1.69 (R2 = 0.974), whilst log(krel/kH) vs σ+ gives a ρ constant of +1.20 with a lower R2 of 0.947 (see
Supporting Information p S11 for plots), noting the large ρ values are reasonable given the lack of
solvent dampening.49 The reduced correlation moving from σ to σ+ values suggests that through-
conjugation by the electron-donating substituents is not dominant in stabilising the positive charge on
the benzylic carbon compared to the sulphur lone pair. More insight into the resonance demand of this
system could be obtained by analysis with the Yukawa-Tsuno equation, but this requires a much a larger
scope of substituents than presented here.50 In all cases, there was no evidence for the formation of
associative π-ligand exchange products.
Though the lack of exchange product observed for the above thiiranium ions was rationalised with the
aid of calculations (Figure 4), the possibility of the observed addition reactivity being due to the
isomeric sulphonium ions potentially formed via isomerisation during ESI has not been addressed. The
assumption of similarities with the seleniranium ions in terms of structure may not be valid with
suggestions of rapid isomerisation for oxiranium ions to oxonium ions in the gas-phase by Renzi et al.
of concern, and so DFT calculations were performed to determine the barriers to formation of the
potential sulphonium ions.51
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A
+205 (+151)
TS11-23
6
7
8
+106 (+53.6)
TS11-22
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
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30
31
32
33
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36
37
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39
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50
51
52
53
54
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58
59
60
+74.6 (+61.2)
TS10''-22
22
SPh
Ph
AcOH
+28.0 (-24.8)
TS10'-11
+10.2 (+8.1)
+6.1 (-43.3)
Ph
10'
23
0.0
S+
0.0 (-0.1)
AcOH
10''
SPh
Ph
Ph
11
AcOH
-27.6 (-79.9)
Reaction Coordinate
B
Ph
Ph
S
S
Ph
S
Ph
H
H
Ph
H
H
O
Ph
O
H
HO
HO
H
10’
TS10’-11
TS11-23
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H
O
H-
Ph
S
Ph
PhS
H
Ph
H-
Ph
S
H
O
OH
OH
Ph
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
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31
32
33
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47
48
49
50
51
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53
54
55
56
57
58
59
60
10’’
TS10’’-22
TS11-22
Figure 6. A) Relative energy diagram of potential isomerisation pathways from protonated β-sulphur
acetate 10’ to thiiranium ion 11 and sulphonium ions 22 and 23. Energies given as ΔH (ΔG) in kJ
mol-1 calculated at M06-2X/def2-TZVP relative to the protonated ion 10’. Only key transition states
and minima are shown, refer to Supporting Information p S12 for full pathways. B) Gaussview
optimised structures of key species 10’, TS10’-11, TS11-23, 10’’, TS10’’-22, and TS11-22 with
accompanying Chemdraw diagrams.
Thus, we considered pathways for the isomerisation of the precursor 10 to sulphonium ions 22 and 23
(Figure 6). There are likely many conformers accessible for the protonated acetate precursor, but a
manual coordinate search from the transition states identified the relevant minima 10’ and 10’’ (refer
to Supporting Information p S59-S60 for other conformers located). The low barrier of +10 kJ mol-1 for
formation of thiiranium ion 11 from 10’ reflects the lack of observation of the protonated acetate
precursor with the energy from ESI sufficient to induce departure of the leaving group (Figure 6). This
is likely assisted by a large entropic driving force contributing to a Gibbs free energy change of -43 kJ
mol-1 for thiiranium ion formation with accompanying vacuum removal of acetic acid. The calculations
suggest similarly high barriers to isomerisation for sulphur as compared to the previous selenium work
with the change in leaving group to an acetate having minimal impact on these trends.36 Indeed, potential
hydride migration pathways leading to formation of sulphonium ions 22 and 23 involve barriers >70 kJ
mol-1 with those from the thiiranium ion itself +106 kJ mol-1 and +205 kJ mol-1 respectively (Figure 6).
However, a consequence of the lower energy pathway from acetate precursors to thiiranium ion 11 is
formation of 22 or 23 potentially occurring in the presence of solvent during the ESI process. This could
allow for neutral solvent molecules to assist via mechanisms such as proton transport catalysis to allow
for more isomerisation than expected based on the calculations on the isolated molecule.52 This would
particularly impact on the lowest hydride transfer barrier of +74.6 kJ mol-1 which produces the more
reactive sulphonium ion 22 (TS10’’-22, Figure 6).
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+143.6
TS11-23
6
7
8
+88.7
TS10''-22
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
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31
32
33
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53
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59
60
+51.3
TS11-22
TS10'-11
+36.0
22
10'
SPh
Ph
AcOH
AcOH
0.0
-25.6
-41.7
Ph
23
SPh
S+
AcOH
Ph
Ph
11
-65.8
Reaction Coordinate
Figure 7. Relative energy diagram of potential isomerisation pathways from protonated β-sulphur
acetate 10’ to thiiranium ion 11 and sulphonium ions 22 and 23 modelled in solution-phase with the
polarizable continuum model (PCM). Energies given as ΔG in kJ mol-1 calculated at M06-2X/def2-
TZVP relative to the protonated ion 10’.
These barriers are, however, calculated in the gas-phase and given that the formation of thiiranium ion
11 occurs in the ESI source, the same potential isomerisation pathways were recalculated using the
polarizable continuum model (PCM) (Figure 7).53 Examination of the Gibbs free energy differences
(not the enthalpic changes as explained) using this explicit solvent model suggests the same implications
are present as with the gas-phase, even with the change in pathway topography. Despite a slightly higher
barrier of +36.0 kJ mol-1 to form thiiranium ion 11, the ion itself is in a lower energy well at -41.7 kJ
mol-1 relative to the starting protonated acetate than compared with the gas-phase modelling in Figure
6. Hence, though one of the isomerisation barriers, TS11-22, is significantly lower compared to 10’,
the barrier relative to 11 is +93 kJ mol-1 (Figure 7). Overall, the formation of thiiranium ion 11 is still
the lowest energy pathway with high Gibbs free energy barriers in solution-phase and high enthalpic
barriers in the gas-phase to isomerisation.
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59
60
Figure 8. Infrared spectra of the m/z 213 ions. Experimental IRMPD spectra (black) in the 1000-1800
cm-1 range recorded at full laser power generated from ESI of 9, compared to the theoretical IR spectrum
of a) thiiranium ion 11 (red stick spectrum) and b) sulphonium ion 22 (blue stick spectrum) calculated
at the B3LYP/6-311++G(d,p) level of theory with a scaling factor of 0.98 applied to the calculated
frequencies.54 In order to facilitate the comparison, calculated vibrational bands were convoluted by a
Gaussian profile with a 20 cm-1 full width at half maximum. The maximum calculated intensities for
the thiiranium and sulphonium ions are 172 and 92 km.mol-1 respectively.
To provide further evidence for the observed ion at m/z 213 indeed being that of 11, infrared multiple
photon dissociation (IRMPD) spectroscopy was conducted over a range of 1000-1800 cm-1, similar to
that previously performed with the selenium system.36 Experimental IRMPD spectra of the m/z 213 ions
and calculated IR absorption spectra of thiiranium ion 11 and sulphonium ion 22 are given in Figure 8.
Eight bands can be distinguished in the experimental spectrum. Overall there is a better match with the
thiiranium structure, and a tentative assignment is proposed in Table S1. Although the assignment of
bands observed in the 1350-1450 cm-1 is not easy, there is a good quantitative agreement for five bands
which can be considered as diagnostic. The relatively narrow bands observed at 1180, 1245, 1310, 1520
and 1585 cm-1 in particular match the absorption bands of thiiranium predicted at 1189, 1244, 1328,
1507, and 1601 cm-1 respectively (Figure 8).
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SPh
SPh
Ph
S
ESI
HO
O
O
O
8
9
24
25
m/z 137
Not observed
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
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30
31
32
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47
48
49
50
51
52
53
54
55
56
57
58
59
60
Ph
S+
O
SPh
OH SPh
O
ESI
O
26
27
m/z 137
Not observed
Scheme 6. ESI of acetate precursors 24 and 26 to give thiiranium ion 25 (m/z 137) and sulphonium ion
27 (m/z 137) respectively
Though this experimental and computational evidence was convincing, across both the sulphur and
selenium systems studied thus far no chemical precursors to the -onium ions have been independently
synthesised and tested for their resulting structure and reactivity with alkenes. To gain some insight into
the relative reactivities of thiiranium and sulphonium ion intermediates with alkenes, two model
precursors 24 and 26 were synthesised, which would feasibly give thiiranium ion 25 and sulphonium
ion 27 respectively upon ESI (Scheme 6). Evidence for their formation was also attempted via IRMPD
spectroscopy, but the photon dissociation yield was too low to yield good quality spectra. To support
the assumption of the trans-sulphonium ion 27 being formed over the cis (as shown in Scheme 6), DFT
calculations were performed on the acetate precursor and the ions themselves. Though the cis species
was calculated to be only 3 kJ mol-1 less stable than the trans, only two conformers of the starting
acetate precursor were located and both of these would lead to the trans sulphonium ion upon ESI (cis-
precursor was found not to be a minimum at the M06-2X/def2-TZVP level of theory. See Supporting
Information p S84-S87 for these structures). Hence, it is reasonable to assume in further analysis that it
is the trans isomer that is dominant in the sulphonium ion mixture.
What has not been tested thus far was the experimental outcome of an IMR between a sulphonium ion
and a neutral alkene in the gas-phase. However, this could now be investigated and compared between
thiiranium ion 25 and the independently formed sulphonium ion 27, with HRMS of the two ions
supporting their formation (Supporting Information p S5-6). Both were introduced under ESI conditions
as described previously and exposed to cis-cyclooctene with the results summarised in Table 2.
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Table 2. Rates of IMR between cis-cyclooctene and thiiranium ion 25 or sulphonium ion 27
5
6
7
8
kobserved* (s-1)
k
absolute (cm3 molecules-1 s-1)
krelative
1
m/z 137 Ion
2.3
6.0
10-3
10-1
(3.7
(9.8
0.9) x 10-14
2.5) x 10-12
Thiiranium
Sulphonium
×
×
±
±
9
10
11
12
13
14
15
16
17
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21
22
23
24
25
26
27
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51
52
53
54
55
56
57
58
59
60
265
*determined by monitoring decrease in the parent ion intensity
A
27
30
B
32
27
Figure 9. Ion-molecule reactions of cis-cyclooctene with A) thiiranium ion 25 m/z 137 (t = 4000 ms)
and B) sulphonium ion 27 m/z 137 (t = 4000 ms). [cis-cyclooctene] ca 6 x 1010 molecules cm-3.
The sulphonium ion 27 undergoes addition with cis-cyclooctene over 260 times fast than thiiranium ion
25 (Table 2). This is perhaps not surprising since, qualitatively, the weaker π-bond in the sulphonium
ion is much easier to break than the σ-bond in the thiiranium ion. It is also possible, similar to 11, that
a small quantity of reactive sulphonium ion 27 is present from isomerisation of 25, giving rise to the
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observed product following reaction with the cycloalkene (Figure 9A). However, any isomerisation
would have to proceed over higher barriers than those calculated in Figure 6 as any stabilisation afforded
by the benzyl system is absent. Indeed, Broer et al. have calculated the barrier for isomerisation of a
similar small thiiranium ion (S-H instead of S-Ph) to the sulphonium ion to be +129 kJ.mol-1.55 Even if
a small amount of sulphonium ion had formed in the ESI source, the kinetics obtained show that this
species would rapidly be consumed and not be present in any significant amount after a few seconds of
reaction time (Table 2, Figure 9). Given that the thiiranium ion 25 data was obtained from 1 to 15
second reaction time periods (refer to Supporting Information p S13 for the parent ion decay plot), this
is the strongest evidence yet that it is indeed the thiiranium ion undergoing addition and not a
sulphonium ion. To provide further support for this, DFT calculations were performed for addition of
cis-cyclooctene to the two isomeric species (Figure 10).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
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36
37
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39
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43
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46
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53
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57
58
59
60
A
25
Ph
S
TS28-29
+6.2 (+53.3)
0.0
28
29
-26.3 (+10.0)
TS29'-30
-63.1 (-0.3)
-43.2 (+5.1)
29'
-61.4 (-2.2)
30
-213 (-150)
Reaction Coordinate
B
27
Ph
S+
TS31'-32
-38.2 (+16.2)
0.0
31'
31
-38.6 (+17.0)
-44.5 (+1.5)
32
-156 (-93.5)
Reaction Coordinate
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Ph
S
Ph
Ph
S
Ph
S
S
TS28-29
29
TS29’-30
30
S Ph
S
Ph
S Ph
Ph
S
31
31’
TS31’-32
32
Figure 10. Relative energy diagrams for addition of cis-cyclooctene to A) thiiranium ion 25 followed
by ring closure to give 30 and B) sulphonium ion 27 followed by ring closure to give 32. Energies given
as ΔH (ΔG) in kJ mol-1 at M06-2X/def2-TZVP level of theory relative to the combined total of the free
reactant energies. C) Gaussview optimised structures of key species TS28-29, 29, TS29’-30, 30, 31,
31’, TS31’-32, and 32 with accompanying Chemdraw diagrams.
Further examination of these pathways shows a relatively low barrier of +6.2 kJ mol-1 for cis-
cyclooctene addition at thiiranium ion 25 (Figure 10A). Though slightly above the combined reactant
5 kJ mol-1 for transition states and the fact that a
±
energy, the small error in similar DFT methods of
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Boltzmann distribution of ions will be reacting means that it is still plausible for the reaction to
proceed.44 Indeed, the remainder of the pathway to addition product 30 is energetically favourable with
little barrier for S-C bond formation (TS29’-30, Figure 10A). Taken together with a ΔG‡ of +53.3 kJ
mol-1 at the RDS, this explains why the rate of reaction of addition of cis-cyclooctene to thiiranium ion
25 is so slow at ca 10-14 cm3 molecules-1 s-1 (Table 2). Addition by the alkene to sulphonium ion 27 was
found to be barrierless for the C-C bond forming step with a potential energy scan from the
cyclopropylium ion 31’ proceeding smoothly to the separated reactants (see Supporting Information p
S15). This is consistent with the much faster rate of reaction observed at ca 10-12 cm3 molecules-1 s-1 for
addition to 27 as, once the initial complex is formed in the correct orientation, there is relatively
barrierless pathway to form the trans addition product 32 (Figure 10B). Overall, comparison of addition
of cis-cyclooctene to thiiranium ions 11 and 25, and sulphonium ion 27 show good agreement between
the experimental kinetic results (Tables 1 and 2) with the DFT theoretical barrier heights (or lack
thereof) for C-C bond formation.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
CONCLUSIONS
The findings contained in this paper have shown that thiiranium ions react with cyclic alkenes
exclusively via an electrophilic addition pathway to give bicyclic products in the gas-phase. This is in
contradiction with solution experiments that suggest direct transfer of the PhS+ moiety between alkenes
with DFT calculations suggesting high barriers for π-ligand exchange in the gas-phase. Further
modelling showed the rate-determining step for addition to be the initial carbon-carbon bond forming
step and this was supported with Hammett plots showing the rate of reactivity to increase as the benzylic
position of thiiranium ion 11 became more electrophilic. The potential for sulphonium ion presence
contributing to this addition pathway was examined through structural investigations with IRMPD
spectroscopy and DFT calculations, which suggested the potential for a small amount of isomerisation.
However, further studies on an independently isolated sulphonium ion suggested that due to its very
fast reactivity with alkenes, calculated to be barrierless, only the thiiranium ion would be present at
longer reaction times, supporting the fact that the latter exclusively undergoes electrophilic addition
with alkenes in the gas-phase.
EXPERIMENTAL
Reagents: Cyclohexene (99%, Sigma Aldrich) and cis-cyclooctene (95%, Alfa Aesar) were used
without further purification.
Nuclear Magnetic Resonance Spectroscopy: Proton and proton decoupled carbon NMR spectra for 1H
13
and C nuclei respectively were recorded at ambient temperature (25 ºC) as solutions in the stated
solvent using a Varian Inova 400 NMR spectrometer.
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Synthetic Procedures: β-sulphenylacetate precursors 9 and 33-36 were synthesised in one step from
diphenyldisulphide and the corresponding styrene derivative in the presence of diacetoxyiodobenzene
and potassium iodide.56 Most are known compounds and spectroscopic data matched those reported
with the exception of the m-methoxyphenyl derivative (NMR spectra in Supporting Information p S16):
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
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30
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1-(3-Methoxyphenyl)-2-(phenylthio)ethyl acetate 34: 94.8 mg, 62%, yellow oil.
1H NMR (CDCl3, 400 MHz) δ 7.40-7.38 (m, 2H), 7.31-7.21 (m, 4H), 6.93-6.83 (m, 3H), 5.87 (dd, J =
5.3, 8.0 Hz, 1H), 3.81 (s, 3H), 3.40 (dd, J = 8.2, 13.7 Hz, 1H), 3.24 (dd, J = 5.3, 13.9 Hz, 1H), 2.03 (s,
3H,).13C{1H} NMR (CDCl3, 100 MHz) δ 170.0, 159.7, 140.6, 135.6, 130.1, 129.6, 129.0, 126.6, 118.9,
113.6, 112.4, 74.5, 55.3, 40.1, 21.0. HRMS (ESI/OrbiTrap) m/z [M – HOAc]+ Calcd for C15H15OS+
243.0838; Found 243.0836.
The β-sulphenylacetate precursor 24 was obtained by acetylation of the corresponding hydroxyl
derivative obtained from reaction of 2-bromoethanol and thiophenol under basic conditions.57,58 The α-
sulphenylacetate precursor 26 was synthesised via chlorination of ethyl phenyl sulphide with N-
chorosuccinimide with subsequent displacement of the chloride by sodium acetate in DMF.59,60
Mass Spectrometry: Ion-molecule reactions (IMR) were performed by ionising the sample in a mixture
of acetonitrile/formic acid (1% v/v) or a mixture of methanol/formic acid (1% v/v) via ESI into a
Thermo Scientific linear ion trap quadrupole (LTQ) spectrometer, modified to allow introduction of a
volatile neutral into the ion trap with the helium bath gas, as described previously.61,62 It has been
demonstrated that collisions with the helium bas gas quasi-thermalise the ions to room temperature
under IMR conditions.63 ESI solutions were introduced using a syringe pump operating at 5 µL.min-1
and by applying 4.0–4.8 kV to the ESI capillary relative to the heated capillary entrance to the mass
spectrometer (250 °C). The sheath gas and lenses were tuned to optimize the signal of the ion, mass-
selected for the most abundant isotopes of each element (1H, 12C, 14N, 16O, 32S). High-resolution mass
spectrometry (HRMS) characterisation of the generated thiiranium ions was conducted on a Thermo
Scientific direct infusion NanoLC/OrbiTrap mass spectrometer and are available in the Supporting
Information (p S3-6).
Quantum Chemistry Calculations: Standard density functional theory (DFT) calculations were
performed using the Gaussian 16 revision B.01 software package.64 Optimized structures and energies
were obtained with the M06-2X/def2-TZVP level of theory and incorporated zero-point vibrational
energy corrections at 298 K.65,66 The M06-2X method is applicable for main group thermochemistry
and similar hybrid meta-GGA functionals (M05-2X) have been shown to accurately predict the
structure of asymmetric oxiranium ions compared to the high-level couple-clustered CCSD method.67
Vibrational frequency and intrinsic reaction-coordinate analyses were applied to confirm transition state
structures (one imaginary frequency). Cartesian coordinates for all reported structures along with
electronic, enthalpic and Gibbs free energies are provided in the Supporting Information (p S18-87).
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IRMPD Spectroscopy: Infrared spectroscopic experiments were performed using an Esquire 3000+
quadrupole ion trap mass spectrometer (Bruker-Daltonics, Bremen, Germany) equipped with an
ElectroSpray Ionization (ESI) source. As described in details elsewhere, a hole has been drilled in the
ring electrode of the quadrupole ion trap allowing for the irradiation of mass-selected ions with an
infrared beam.68 Infrared activation is performed using the IR beam of the free electron laser (FEL) of
the Centre Laser Infrarouge d’Orsay (CLIO).69 IR FELs deliver highly intense IR pulses and have been
shown to be particularly well suited for fragmenting all kind of molecular ions through an IR multiple
photon dissociation (IRMPD) process.54 The CLIO IR FEL delivers ~8 μs long macropulses of ~40 mJ
at a 25 Hz repetition rate, which corresponds to a mean power of 1W. The bandwidth is ~0.5% of the
central wavenumber. The IR FEL frequency is calibrated using a small fraction of the IR beam which
passes through a polystyrene film. As a result, at each wavelength during the IR FEL scan, polystyrene
absorption, and an MS2 mass spectra are simultaneously recorded. Wavelength corrections can thus be
made during the data treatment. IRMPD spectra of mass-selected ions were recorded in the 1000-1800
cm-1 range using the chromatogram mode of the ion trap instrument. Synchronization of the ion-trap
and IR-FEL control programs allows for a stepwise (~5 cm-1) change of the IR frequency at each step
of the chromatogram. Each MS2 mass spectrum is an average of 10 acquisitions. IRMPD spectra were
acquired multiple times by varying the number of -3dB attenuators.
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CONFLICT OF INTEREST STATEMENT
The authors declare that the research was conducted in the absence of any commercial or financial
relationships that could be construed as a potential conflict of interest.
ACKNOWLEDGEMENTS
We thank the Australian Research Council for financial support for financial support (DP0770565 to
JMW and DP180101187 to RAJO), the Australian Government for a Research Training Program (RTP)
scholarship to S.B, and The University of Melbourne for the Melbourne Research Scholarship (MRS)
to S.F.L. Financial support from the European Community’s Horizon 2020 Programme CALIPSOplus
(grant number 730872) is gratefully acknowledged. The HRMS spectra were acquired at the Mass
Spectrometry and Proteomics Facility (MSPF), Bio21 Institute, The University of Melbourne. The DFT
calculations were performed on the Spartan High Performance Computing (HPC) System hosted by
Research Platform Services at the University of Melbourne.70
SUPPORTING INFORMATION
High-resolution mass spectra of all thiiranium ions. Mass spectra of all ion-molecule reactions and
accompanying time-decay plots of the parent ion. Full isomerisation pathway expanded from Figure 6.
Assignments of the vibrational modes for 11. Potential energy scan for reaction of cis-cyclooctene with
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sulphonium ion 27. H-NMR and C-NMR of m-methoxyphenyl derivative 34. Gaussian cartesian
coordinates and energies for all calculated species.
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