The mechanism of alkene elimination from protonated toluenesulphonamides generated by electrospray ionisation

Article abstract of DOI:10.1255/ejms.1427

The positive ion electrospray mass spectra of a range of sulphonamides of general structure CH₃C₆H₄SO₂NHR¹ [R¹ = C_nH_2n+1 (n = 1-7), C_nH_2n-1 (n = 3, 4), C₆H₅, C₆H₅CH₂ and C₆H₅CH(CH₃)] and CH₃C₆H₄SO₂NR¹R² [R¹, R² = C_nH_2n+1 (n = 1-8)] are reported and discussed. The protonated sulphonamides derived from saturated primary and secondary aliphatic amines generally fragment to only a limited extent unless energised by collision. Two general fragmentations are observed: firstly, elimination of an alkene, C_nH_2n, obtained by hydrogen abstraction from one of the C_nH_2n+1 alkyl groups on nitrogen; secondly, cleavage to form CH₃C₆H₄SO₂⁺. The mechanism by which an alkene is lost has been probed by studying the variation of the intensity of the [M + H - C_nH_2n]⁺ signal with the structure of the alkyl substituent(s) on nitrogen and by monitoring the competition between the loss of different alkenes from protonated unsymmetrical sulphonamides in which two different alkyl groups are attached to nitrogen. This fragmentation is favoured by branching of the alkyl group at the carbon atom directly attached to nitrogen, thus suggesting that it involves a mechanism in which the stability of the cation obtained by stretching the bond connecting the nitrogen atom to the alkyl group is critical. This interpretation also explains the competition between alkene elimination and cleavage to form CH₃C₆H₄SO₂⁺ (and, in some cases, cleavage to form C₆H₅CH₂⁺ or [C₆H₅CHCH₃]⁺).

Full text of DOI:10.1255/ejms.1427

A. Saidykhan et al., Eur. J. Mass Spectrom. 22, 165–173 (2016)
165
Received: 16 June 2016
n
Revised: 12 August 2016 n Accepted: 14 August 2016 n Publication: 14 October 2016
EUROPEAN
JOURNAL
OF
MASS
SPECTROMETRY
The mechanism of alkene elimination
from protonated toluenesulphonamides
generated by electrospray ionisation
a
a
a
b
a,*
Amie Saidykhan, Jenessa Ebert, William H.C. Martin, Richard T. Gallagher and Richard D. Bowen
aSchool of Chemistry and Forensic Sciences, Faculty of Life Sciences, University of Bradford, Bradford, West Yorkshire BD7 1DP, UK.
E-mail: r.d.bowen@bradford.ac.uk
bAstraZeneca, Oncology iMed, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK
1
1
The positive ion electrospray mass spectra of a range of sulphonamides of general structure CH C H SO NHR [R = C H (n = 1–7),
2n+1
3
6
4
2
n
1
2
1
2
C H
(n = 3, 4), C H , C H CH and C H CH(CH )] and CH C H SO NR R [R , R = C H
(n = 1–8)] are reported and discussed. The
n
2n-1
6
5
6
5
2
6
5
3
3
6
4
2
n
2n+1
protonated sulphonamides derived from saturated primary and secondary aliphatic amines generally fragment to only a limited extent
unless energised by collision. Two general fragmentations are observed: firstly, elimination of an alkene, C H2n, obtained by hydrogen
n
+
abstraction from one of the C H
alkyl groups on nitrogen; secondly, cleavage to form CH C H SO . The mechanism by which an alkene
n
2n+1
3
6
4
2
+
is lost has been probed by studying the variation of the intensity of the [M + H – C H2n] signal with the structure of the alkyl substituent(s)
n
on nitrogen and by monitoring the competition between the loss of different alkenes from protonated unsymmetrical sulphonamides in
which two different alkyl groups are attached to nitrogen. This fragmentation is favoured by branching of the alkyl group at the carbon
atom directly attached to nitrogen, thus suggesting that it involves a mechanism in which the stability of the cation obtained by stretching
the bond connecting the nitrogen atom to the alkyl group is critical. This interpretation also explains the competition between alkene
+
+
+
elimination and cleavage to form CH C H SO (and, in some cases, cleavage to form C H CH or [C H CHCH ] ).
3
6
4
2
6
5
2
6
5
3
Keywords: sulphonamides, electrospray, alkene elimination, ion-neutral complex
Introduction
Sulphonamides, particularly those derived from aryl sulphonic
acids, have been utilised in a range of scientific disciplines for
over a century. Early examples of their application include the
characterisation of amines by formation of highly crystalline
tion in medicine.6–8 The first commercial example, Prontosil,
despite being actually a prodrug, offered an effective means
of treating bacterial infections within the body because it was
metabolised to sulphanilamide, 4-H NC H SO NH , which was
2
6
4
2
2
1
sulphonamides with well-defined melting points, the prep- the active component.
aration or purification of secondary amines by preferential
More recently, sulphonamides have been extensively utilised
Moreover, both in vitro
and in vivo studies have established that sulphonamides inhibit
9
–11
monoalkylation of the precursor sulphonamides of the requi- as carbonic anhydrase inhibitors.
2
site primary amines, and their related role as intermediates
in pioneering attempts to synthesise asymmetrical quaternary
ammonium species.3–5
the development of numerous tumour cells, thus indicating
11–13
that they have potential as anticancer agents.
Subsequently, sulphonamide drugs were the first class
In synthetic organic chemistry, the formation of sulphona-
of antibiotics to be used systematically, initiating a revolu- mides has become a principal method for protecting amines
ISSN: 1469-0667
doi: 10.1255/ejms.1427
© IM Publications LLP 2016
All rights reserved

1
66
Mechanism of Alkene Elimination from Protonated Toluenesulphonamides Generated by ESI
Scheme 1. Reagents and conditions: i) LDA, THF, –78°C, N2.
and related nitrogenous functional groups.14,15 Although
sulphonamides are usually considered to be inert towards
basic reagents designed to operate on functional groups
elsewhere in intermediates, the treatment of orthogonally
protected amines with lithium di-isopropylamide (LDA) has
recently been found to induce an interesting rearrangement in
which an acyl (RC=O) or carboalkoxy (ROC=O) group migrates
from the nitrogen atom to the carbon atom in the 2 posi-
Scheme 2. Reagents and conditions: (i) 4-CH C H SO Cl
3
6
4
2
2
2
(
0
0.95equiv.), CH Cl , (C H ) N, 0–10°C; (ii) R Br or R I (0.2–
.25equiv.); (iii) R COCl (0.95equiv.), CH Cl , C H N, 0°C; (iv)
2 2 5 5
2 2 2 5 3
3
LiAlH , (C H ) O or cyclo-C H O; (v) NaOH, H O; (vi) CH NH
4
2
5 2
4
8
2
3
2
(3equiv.), C H OH.
2
5
1
6,17
tion of the aromatic ring, Scheme 1.
When these novel
during 30 minutes to a cold solution of the amine (10mmol)
and triethylamine (12mmol) in dichloromethane (30ml), with
external cooling and/or the attachment of a reflux condenser
in the case of volatile primary amines. The pale-yellow solu-
tion was allowed to stand overnight, during which crystals
4
-CH C H SO N(COR)CH(CH ) and 4-CH C H SO N(CO R)
3
6
4
2
3 2
3
6
4
2
2
CH(CH ) compounds and their precursor sulphonamides
3
2
were characterised by high-resolution mass spectrometry, an
interesting loss of propene was detected from the abundant
+
[
M + H] ions formed under positive ion electrospray ionisa- of amine hydrochloride were usually deposited, and poured
tion (ESI+) conditions. Further investigation of representative
members of other series of sulphonamides confirmed that
alkene loss from the N-alkyl group appeared to be of general
significance. In view of the wide range of contexts in which
sulphonamides are important, and the interest in detecting
onto ice-cold water containing sufficient hydrochloric acid to
render the aqueous phase acidic; the organic phase was sepa-
rated, the aqueous phase was extracted with dichloromethane
(2 × 20ml) and the combined organic extracts were washed
with sodium carbonate solution (10%w/v), dried with magne-
and quantifying their presence in medicinal and agrochem- sium sulphate, filtered and evaporated at reduced pressure to
1
8–20
ical contexts by electrospray mass spectrometry,
further
give the crude 4-toluenesulphonamide, which was recrystal-
lised from aqueous ethanol or light petroleum (boiling point
40–60°C). Analysis by H-NMR, IR and mass spectrometry
investigation of the circumstances in which alkene elimination
occurs is timely in order to establish the analytical value of this
1
fragmentation. Consequently, a range of 4-toluenesulphona- under high-resolution conditions indicated that the products
1
1
mides, R NHTs [R = C H
(n = 1–7), C H
(n = 3, 4), C H , had the assigned structures and molecular formulae. Yields
n
2n+1
n
2n-1 6 5
1
2
C H CH and C H CH(CH ); Ts = SO C H CH ] and R R NTs
R , R = C H
unsymmetrical secondary amines, have been synthesised and
subjected to electrospray mass spectrometry.
after recrystallisation varied from 65% to 90%.
6
1
5
2
6
5
3
2
6
4
3
2
[
(n = 1–8)], derived from primary amines and
The unsymmetrical secondary amines were prepared in
one of two ways. The first method involved treatment of an
excess of one of the parent primary amines (4–6moles) with the
requisite alkyl bromide or iodide. After allowing the mixture to
stand until the reaction was complete (1–10 days), the resultant
mixture of amines and amine hydrohalides was basified, and
the required amine isolated by fractional distillation. Similarly,
n
2n+1
Experimental
Synthesis
4-methylaminoctane was synthesised by treatment of 4-octyl-
The 4-toluenesulphonamides were prepared by condensation
4-toluenesulphonate with excess methylamine in ethanol, as
previously described. The presence of trace quantities of
1
1
2
21
of the requisite primary (R NH ) or secondary (R R NH) amine
2
with 4-toluenesulphonyl chloride in dichloromethane solution
the corresponding tertiary amine would not interfere with the
in the presence of slightly more than one equivalent of trieth- formation of the 4-toluenesulphonamide required in this work
ylamine or pyridine as an acid scavenger, unless the parent
amine was commercially available and inexpensive, in which
because only primary and secondary amines form these deriva-
tives. The second route for synthesising the secondary amines
2
case it was used in excess. In a typical experiment, 4-tolue- involved acylation of the primary amine, followed by reduc-
nesulphonyl chloride (9.5mmol) was added in small portions tion of the resultant amide with lithium aluminium hydride

A. Saidykhan et al., Eur. J. Mass Spectrom. 22, 165–173 (2016)
167
in diethyl ether or tetrahydrofuran, as previously described.21
These routes are summarised in Scheme 2.
from the ion trap to the OrbiTrap for high-resolution mass
measurement. The resolution was 7.5k (full width at half
maximum) for both scan modes. In all the product-ion experi-
ments the collision energy was 35eV and the collision gas
used was helium. The product ion of interest was isolated in a
0.5amu mass window within the ion trap prior to product-ion
data collection. All the product ions of interest formed from a
particular parent ion were transferred from the ion trap to the
Mass spectrometry
Liquid chromatography (LC)–mass spectrometry analysis
2
2
was carried out on a hybrid Linear Ion-Trap-OrbiTrap mass
spectrometer system (LTQ OrbiTrap XL, Thermo Scientific)
fitted with an ultrahigh performance liquid chromatography
(
UHPLC) system consisting of a binary pump, an autosam- OrbiTrap for high-resolution mass measurement, thus giving
pler and a photodiode array detector (Acquity: Binary Solvent
Manager, Sample Manager and PDA Detector, respectively,
Waters Ltd., Elstree, UK). The chromatography system and
mass spectrometer were controlled by the software Xcalibur
v1.4 (Thermo Scientific Ltd., Hemel Hempstead, UK). The
reliable ionic formulae for the product ions.
Results and discussion
1
1
2
LC column was a Waters Acquity UPLC BEH C18, 1.7 µm, All the toluenesulphonamides [R NHTs and R R NTs]
2
.1mm × 100mm. The sample was dissolved in methanol at
studied in this work showed clean ESI+ spectra with few, if
any, fragment ion signals. Tables 1–4 summarise the data for
sulphonamides derived, respectively, from saturated primary
aliphatic amines, secondary saturated aliphatic amines,
aliphatic amines containing a phenyl group and unsaturated
–
1
~
0.01 mg mL concentration and 10 µL of this solution was
injected into the system. The mobile phase flow rate was
0
mobile phase B was acetonitrile. The UHPLC gradient was
–
1
.45 mL min . Mobile phase A was 0.05% aq. formic acid;
T = 0.0 min, A = 95%, B = 5%, T = 9.0 min, A = 20%, B = 80%, primary aliphatic amines.
T = 9.01min, A = 2%, B = 98%, T = 11.0min, A = 2%, B = 98%. With only one exception (the derivative of cyclopropylamine),
At T = 11.01 min the system reverted to the starting condi- strong [M + H] signals, which gave clear confirmation of the
+
tions and was held for four minutes to allow the column to
re-equilibrate. The PDA detector was scanned from 210nm to
molecular formula of each sulphonamide, were observed. In
the case of most toluenesulphonamides derived from simple
+
350nm at 2nm steps during the run. ESI+ was performed with
primary aliphatic amines, the [M + H] ion accounted for the
+
+
an electrospray capillary voltage of +3kV, a sheath gas flow of
base peak in the spectrum. Moreover, [M + Na] and [M + NH ]
4
50 and an auxiliary flow of 20 (arbitrary units) at a source capil- signals were also observed in most cases, especially in the
lary temperature of 250°C. The mass spectrometer collected
data every ~0.25s, alternately recording a mass spectrum over
the mass range 50amu to 500amu and a product ion mass
spectrum from the most abundant ion detected in the normal
mass spectrum. The parent ions of interest were transferred
spectra of the derivatives of primary amines, at 17m/z and
22m/z units above the [M + H] signal, thus giving further confir-
+
mation of the molecular formula of the analyte. The limited
+
amount of fragmentation of the [M + H] ions is typical in ESI+
23
mass spectrometry, which is a very ‘soft’ ionisation method.
Table 1. Significant signals in electrospray spectra of C H2n+1NHTs.
n
[
M + H]+
RIa
[M + NH ]+
[M + Na]+
[MH – C H ]
+
4
n
2n
RIa
c
RIa
m/z
RIa
m/z
c
b
R
n
m/z
m/z
Dm
CH3
1
2
3
3
4
4
4
4
5
5
5
7
186
200
214
214
228
228
228
228
242
242
242
270
100
100
100
100
100
100
100
100
100
100
98
203
217
231
231
245
245
245
245
259
259
259
287
83
51
45
40
40
48
35
48
7
208
222
236
236
250
250
250
250
264
264
264
292
32
37
46
48
60
55
42
53
19
34
71
47
–0.61
–0.36
–0.69
–0.43
–0.46
–0.46
–0.16
–0.38
+0.33
–0.63
–0.66
+0.21
C H
172
172
172
172
172
172
172
172
172
172
172
<<1
<<1
5
2
5
1-C H
3 7
2-C H
3
7
9
1-C H
<1
<1
7
4
(CH ) CHCH
3 2 2
2-C H
4 9
(
(
(
CH ) C
72
3
3
3
C H ) CH
2
5 2
CH ) CH(CH )CH
31
41
40
9
3
2
3
C H (CH ) C
100
9
2
5
3 2
[
(CH ) CH] CH
100
3
2
2
a
b
c
Measured by peak height and normalised to a value of 100 units for the most intense signal.
+
Dm = deviation (in mmu) from the theoretical accurate mass value for the relevant ionic formula for the ion assigned as [M + H] .
Alkene (C H ) loss is not possible from a methyl group.
n
2n

1
68
Mechanism of Alkene Elimination from Protonated Toluenesulphonamides Generated by ESI
alkyl group has a secondary structure. When the alkyl group
+
has a tertiary structure, the RI of [M + H – C H ] increases
n
2n
dramatically (to 72% for n = 4, and becomes the base peak
when n = 5). Figure 1, in which the spectra of the four isomeric
C H NHTs species are compared, illustrates the variation of
4
9
+
+
the [M + H] and [M + H – C H ] signals with the structure of
n
2n
the alkyl group.
This trend, favouring alkene loss when the parent alkyl
group has a more highly branched structure, which corre-
sponds to a more stable structure for the incipient cation that
would be formed by cleavage of the R–N bond, is also found
in the spectra of the less extensive series of sulphonamides,
1
2
R R Ts, derived from secondary amines (Table 2). Thus, when
1
2
1
2
R = CH and R = C H or 1-C H , and when R = R = 1-C H ,
3
2
5
4
9
+
4
9
+
essentially no [M + H – C H ] or [M + H – C H ] signal
was detected. However, when R = CH and R = 4-C H , a
n
2n
m
2m
1
2
3
8
17
moderately strong signal (RI = 15%) was observed for elimina-
+
tion of C H from [M + H] .
8
16
Further support for the proposal that alkene loss from
+
[
M + H] is favoured when the cation that would be formed by
fission of the R–N bond is stable is evident from the RI of signals
+
+
corresponding to [M + H – C H ] or [M + H – C H ] in the
n
2n
m
2m
1
spectra of unsymmetrical sulphonamides. When R = 3-C H
6
13
(
from which a secondary hexyl cation would be formed by
1
2
cleavage of the R –N bond) and R = 1-C H (from which a
7
15
primary heptyl cation would be generated by fission of the
2
+
R –N bond), a significant [M + H – C H ] signal was observed
6
12
Figure 1. Normal ESI+ spectra of (top to bottom)
+
(
RI = 8%), but the corresponding [M + H – C H ] signal was
of negligible intensity (RI < 1%). Similarly, when R = 3-C H
and R = (CH ) CCH , essentially only C H loss from [M + H]
RI = 18%) was observed. The RI of the [M + NH ] signals
7 14
(
(
a) 1-C H NHTs, (b) (CH ) CHCH NHTs, (c) 2-C H NHTs and
1
4
9
3 2
2
4
9
6
12
+
d) (CH ) CNHTs.
3
3
2
3
3
2
6
12
+
(
4
decreases dramatically to 0–4% in the spectra of the sulphon-
amides derived from secondary amines. In contrast, the RI of
the signal corresponding to these adducts typically lies in the
range 35–50% in the spectra of the sulphonamides derived
from primary amines. This abrupt decline may indicate that
It is immediately apparent from the data of Table 1 that
+
+
the relative intensity (RI) of the [M + H] and [M + H – C H ]
n
2n
signals in the spectra of the extensive set of C H2n+1NHTs
n
species shows a systematic dependence on the structure of
the alkyl group. When the alkyl group has a primary structure, the stability of these ammonium adducts is increased by the
essentially no C H alkene loss is observed. In contrast, C H
elimination occurs to a significant extent (3–9%) when the
presence of an N–H entity in the analyte, perhaps because the
ammonium cation is more effectively ‘solvated’ in these cases.
n
2n
n
2n
Table 2. Significant signals in electrospray spectra of C H (C H2m+1)NTs.
n
2n+1
m
M + H]+
[M + NH ]+
[M + Na]+
[MH – C H ]
+
[MH – C H ]+
[
4
RIa
n
2n
RIa
c
m
2m
RIa
R1
n
R2
m
m/z
RIa
m/z
m/z
RIa
m/z
c
m/z
b
Dm
CH3
CH3
CH3
1
1
1
4
6
6
C H
2
4
8
4
7
5
214
242
298
284
354
326
100
100
100
100
100
100
231
259
315
302
371
343
4
~1
<1
~1
<1
<<1
236
264
220
306
376
348
14
14
32
23
28
34
186
186
186
228d
256
256
<<1
<<1
15
–0.06
+1.46
+0.86
+0.15
+1.15
–0.47
2
5
c
c
c
c
1-C H
4
9
4-C H
8
17
1
3
3
-C H
1-C H
228d
270
242
<<1
8
<<1
<<1
<<1
4
9
4
9
-C H
1-C H
6
13
7
15
-C H
(CH ) CCH
2
18
6
13
3 3
a
b
c
d
Measured by peak height and normalised to a value of 100 units for the most intense signal.
Dm = deviation (in mmu) from the theoretical accurate mass value for the relevant molecular formula.
Alkene (C H ) loss is not possible from a methyl group.
n
2n
+
C H loss is possible from either alkyl group in this symmetrical [M + H] species.
4
8

A. Saidykhan et al., Eur. J. Mass Spectrom. 22, 165–173 (2016)
169
Scheme 3
R–N bond is stable. Thus, the ratio of the signals at m/z155
+
and m/z 172 [M + H – C H ] is 100 : 65 in the CID spec-
3
6
+
trum of [M + H] formed from 1-C H NHTs, but it is 32:100
in the corresponding spectrum of [M + H] generated from
-C H NHTs (Figure 2). Parallel trends are found for sulphona-
3
7
+
2
3
7
mides derived from larger primary alkylamines.
Two quite different mechanisms could be proposed for
+
alkene elimination from [M + H] . The first would postulate a
cycloreversion, superficially resembling the retro-Alder ene
2
5
reaction, in which a 1,5-hydrogen shift from the b-carbon
atom of the alkyl group on nitrogen occurs. This process,
which also has common features with the McLafferty rear-
rangement that is an important feature of the fragmenta-
tion of ionised carbonyl compounds containing a g-hydrogen
atom, should be favoured by branching at the b-carbon atom
of the protonated sulphonamide, especially if it were to take
place in two steps, with the hydrogen transfer preceding
cleavage of the N–R bond. It has been known for several
decades that alkene loss via the McLafferty rearrangement
is favoured by branching at the g-carbon atom because
+
Figure 2. CID spectra of [M + H] formed from (top to bottom)
(
a) 1-C H NHTs and (b) 2-C H NHTs.
3 7 3 7
In addition, steric crowding in the sulphonamides derived from
the more heavily substituted secondary amines may discrimi- transfer of a hydrogen from a more substituted position is
2
6,27
nate against formation of the ammonium adducts. This latter
explanation, though rather speculative, appears at first sight
to be supported by the unusually low RI (7%) of the [M + NH4]+
signal in the spectrum of (C H ) CHNHTs; however, this signal
favoured,
particularly when the process occurs in two
2
8
steps via an intermediate distonic ion with the radical site
localised on a secondary or tertiary site, when other frag-
2
9,30
mentations may also occur.
Similar conclusions have
2
5 2
is much stronger (RI = 40%) in the spectrum of the even more
hindered species [(CH ) CH] CHNHTs, thus suggesting that
been reached for alkene expulsion from immonium ions via
an analogous mechanism in which the transfer of a hydride
anion from the g-position produces an open-chain cation
that is stabilised by branching at this carbon atom; the inter-
mediate cation then loses an alkene by undergoing C–C
3
2
2
other factors may influence the RI of these ammonium adduct
signals.
+
Although elimination of C H from [M + H] is not observed
n
2n
3
1–33
from primary C H2n+1 alkyl groups in the normal ESI+ spec- cleavage.
The analogous mechanism for alkene elimina-
n
trum of sulphonamides, it does compete much more effec- tion from protonated sulphonamides is shown in Scheme 3.
+
tively when the parent ions are energised by collision. In
Irrespective of whether the dissociating [M + H] ion is proto-
nated on nitrogen or oxygen, this process should be favoured
by branching at the b-carbon atom, but not by substitution
these collision-induced dissociation (CID) spectra,24 C H
n
2n
loss is often observed in competition with the direct cleavage
+
of the N–S bond to form CH C H SO at m/z 155. However, at the a-carbon atom. In other words, it should occur more
3
6
4
2
4
5
in general, the same trend favouring the loss of an alkene
persists when the incipient cation formed by fission of the
readily if R = H and R = CH or C H , than for the isomeric
3 2 5
4
5
species in which R = CH or C H and R = H.
3
2
5
Scheme 4

1
70
Mechanism of Alkene Elimination from Protonated Toluenesulphonamides Generated by ESI
Table 3. Significant signals in electrospray spectra of C H (C H )NTs.
6
5
p
2p
[
M + H]+
[M + NH ]+
[M + Na]+
[MH – C H C H ]+ CH C H SO
+
C H C H
+
4
RIa
6
5
p
2p-1
RIa
3
6
5
2
RIa
6
5
p
2p
RIa
m/z
m/z
RIa
m/z
m/z
m/z
RIa
b
R
p
m/z
Dm
c
c
Ph
0
1
2
248
262
276
69
51
54
265
279
293
75
66
270
284
298
100
100
81
155
155
155
<1
<1
<1
77
91
<1
57
15
–0.75
+0.73
+0.19
c
c
PhCH2
Ph(CH )CH
100
172
3
105
3
a
b
c
Measured by peak height and normalised to a value of 100 units for the most intense signal.
+
Dm = deviation (in mmu) from the theoretical accurate mass value for the relevant ionic formula for the ion assigned as [M + H] .
Alkene (C H C H ) loss is not possible from a phenyl or benzyl group (p = 0 or 1, respectively).
6
5
p
2p-1
The second general mechanism by which alkene elimination
may occur would involve stretching an N–R bond to produce
the most likely formula of the product ion. Secondly, there is
precedent for the proposed mechanism for the loss of C H
4
8
a species in which TsNH or TsNHR¢ was co-ordinated to an
in the behaviour of a wide range of the related protonated
2
+
incipient cation, R . Hydride transfer from the cationic compo- isomeric butylamines (C H NH ), butyl-N-methylamines
4
9
2
nent to a heteroatom would then result in loss of C H if
(C H NHCH ) and butyl-N,N-dimethylamines [C H N(CH ) ]
n
2n
4 9 3 4 9 3 2
R = C H
(Scheme 4).
generated under chemical ionisation conditions. The compe-
tition at low internal energies between loss of C H from
n
2n+1
This kind of mechanism is known to be important in the
dissociation of low-energy ions of diverse structure and
functionality.
4
8
these protonated amines and the alternative fragmentation
3
4–39
+
In contrast to the mechanism in which
by simple cleavage to give C H and (CH ) NHn+1 (n = 0–2)
4
9
3 2-n
hydrogen transfer precedes or accompanies cleavage of the
N–R bond, this mechanism should be favoured by branching
at the a-carbon atom of R because the developing cation
would have a more stable structure. In other words, it would
shows the same systematic trends as those reported in this
+
work. The RI of the [MH – C H ] signal is greatest when the
4
8
butyl group has a tertiary structure, similar or slightly less
when it has a secondary structure and significantly smaller
4
5
+
occur more readily if R = CH or C H and R = H than for the
when it has a primary structure. In the [C H NH CH ] series,
3
4
2
5
4
9
2
3
5
+
isomeric species in which R = H and R = CH or C H . It is
the RI of [MH – C H ] is 100%, 98%, 74% and 53%, respec-
3
2
5
4 8
clear that the first mechanism (Scheme 3) is inconsistent with
the behaviour of protonated sulphonamides with isomeric
tively, when R = C(CH ) , CH(CH )CH CH , CH CH CH CH and
3 3 3 2 3 2 2 2 3
4
0
CH CH(CH ) .
2
3 2
1
1
2
R groups or with different R and R groups. However, the
second mechanism (Scheme 4), which may be considered to
The behaviour of sulphonamides in which the group
attached to nitrogen contains an aromatic ring is also signifi-
cant (Table 3). As would be expected, the spectra of the tolue-
nesulphonamides derived from aniline or benzylamine do not
show an appreciable signal corresponding to alkene loss from
3
4–39
involve ion-neutral complexes,
is in accord with the trends
induced by branching at the a- or b-carbon atom of the alkyl
group(s) attached to nitrogen in the parent sulphonamides.
Two further points should be made in connection with this
explanation for alkene elimination, as exemplified by C H loss
+
[M + H] (in neither case can a stable alkene be formed by
hydrogen abstraction from the group attached to nitrogen in
4
8
+
+
from [M + H] generated from isomeric C H NHTs species. the parent amine). However, a significant R signal (RI = 57%)
4
9
Firstly, although it may be theoretically possible for expulsion
of C H N to occur by a rearrangement involving the transfer
of a methyl group from the butyl substituent with concomi- PhCH . Moreover, m/z 91 is the base peak in the CID spec-
appears at m/z91 in the spectrum of PhCH NHTs, as would
2
be anticipated given the great stability of the benzyl cation,
3
6
+
2
+
tant removal of any hydrogen atom(s) attached to nitrogen, trum of [M + H] formed from PhCH NHTs. On progressing
2
this alternative explanation is less consistent with the high- to the next homologue, Ph(CH )CHNHTs, alkene elimination
3
+
+
resolution data, which suggested that [M + H – C H ] was
(loss of C H , presumably styrene) occurs from [M + H] in
4
8
8
8
Table 4. Significant signals in electrospray spectra of C H
NHTs.
2n–1
n
[
M + H]+
RIa
[M + NH ]+
[M + Na]+
[MH – C H ]+
n 2n-2
4
RIa
m/z
RIa
m/z
RIa
b
R
n
m/z
m/z
Dm
c
–0.61d
–0.36b
+0.79b
cyclo-C H
3
3
4
212
212
226
229
229
243
100
38
234
234
248
61
39
44
172
172
172
<<1
<<1
9
3
5
CH =CHCH
100
100
2
2
cyclo-C H CH
2
46
3
5
a
b
c
d
Measured by peak height and normalised to a value of 100 units for the most intense signal.
+
Dm = deviation (in mmu) from the theoretical accurate mass value for the relevant ionic formula for the ion assigned as [M + H] .
Signal not observed.
+
Dm = deviation (in mmu) from the theoretical accurate mass value for the relevant ionic formula for the ion assigned as [M + Na] .

A. Saidykhan et al., Eur. J. Mass Spectrom. 22, 165–173 (2016)
171
+
competition with simple cleavage to form C H (presumably
cation. It is highly stabilised by interaction of the strained C–C
ring bonds with the cationic site on the exocyclic methylene
8
9
+
C H CH CH ) to form ions at m/z172 and m/z105 of RI = 3%
6
5
3
4
5,46
and 15%, respectively. The behaviour of this larger protonated
sulphonamide is consistent with that of derivatives of simpler
alkylamines because alkene elimination again appears to be
favoured when the cation produced by N–R cleavage is stable
and may undergo hydride abstraction to generate an alkene.
The spectra of sulphonamides in which the alkyl group
of the original amine contains a unit of unsaturation (a C=C
group.
Consequently, the involvement of this unusually
stable non-classical ‘primary’ cation is consistent with the
general trends found for protonated sulphonamides derived
from simple saturated alkylamines.
Finally, it should be noted that alkene elimination by mecha-
nisms that involve ion-neutral complexes is known to be espe-
3
3–39
cially important for ions with low internal energies.
Indeed,
double bond or a carbocyclic ring) deserve brief consideration. much of the seminal work in this field was performed on
+
When R = cyclo-C H , the [M + H] signal was negligibly weak, metastable ions generated under electron ionisation (formerly
3
5
+
+
but strong [M + NH ] and [M + Na] signals were observed
Table 4). This sulphonamide is unique in those studied in this
work in not forming a stable [M + H] ion. The reason for this
anomaly is probably connected with the unstable nature of the
cyclopropyl cation, as is reflected in the unusual behaviour
known as electron impact) conditions. This point is pertinent
in the current context because ESI+ is a very ‘soft’ ionisa-
tion method, as is attested by the simplicity of the spectra
summarised in Tables 1–4 and by the relatively low degree of
fragmentation that is observed.
4
(
+
+
of incipient C H species with this original structure. The
3
5
cyclopropyl cation is known to undergo facile ring-opening
4
1–43
when generated in the gas phase.
Unfortunately, neither
+
+
Conclusion
the [M + NH ] nor the [M + Na] adducts formed from this
4
sulphonamide under ESI+ conditions eliminate an alkene to a
The elimination of an alkene from protonated sulphonamides
significant extent. This trend is general for the other sulphon- generated under ESI+ conditions is systematically favoured
+
amides and is not unexpected: [M + H] species normally
undergo (much) more extensive fragmentation than their
in cases in which stretching the N–R bond gives access to
a stable incipient cation, R , from which hydride abstraction
can occur to give an alkene. This interpretation is supported
by the influence of branching at the a- and b-carbon atoms
of the alkyl group, both in sets of protonated sulphonamides
containing a single isomeric R group and by competition
+
+
+
[
M + NH ] and [M + Na] counterparts.
4
Since the allyl cation is known to be extensively stabilised
+
by p-conjugation, it might be expected that [M + H] produced
by protonation of CH =CHCH NHTs would readily eliminate an
2
2
alkene via hydride abstraction from the stable incipient cation. experiments involving the loss of a different alkene from one
However, no significant signal at m/z172 corresponding to the
of two different alkyl groups attached to the nitrogen atom.
elimination of C H is observed either in the normal spectrum
3
+
4
or when [M + H] is energised by collision. This finding, which at
first sight appears to be inconsistent with the general mecha-
nism of Scheme 4, may be readily explained by considering the
geometry of the deprotonation step. Abstraction of a proton
from the central carbon atom of the allyl cation would yield
a geometry of allene, C H , in which the developing p-orbital
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