Low-energy collision-induced dissociation mass spectra of protonated p-toluenesulfonamides derived from aliphatic amines

Article abstract of DOI:10.1007/s13361-014-0865-4

Collision-induced fragmentation of protonated N-alkyl-p-toluenesulfonamides primarily undergo either an elimination of the amine to form CH ₃-(C₆H₄)-SO₂ ⁺ cation (m/z 155) or an alkene to form a cation for the protonated p-toluenesulfonamide (m/z 172). To comprehend the fragmentation pathways, several deuterated analogs of N-decyl-p-toluenesulfonamides were prepared and evaluated. Hypothetically, two mechanisms, both of which involve ion-neutral complexes, can be envisaged. In one mechanism, the S-N bond fragments to produce an intermediate [sulfonyl cation/amine] complex, which dissociates to afford the m/z 155 cation (Pathway A). In the other mechanism, the C-N bond dissociates to produce a different intermediate complex. The fragmentation of this [p-toluenesulfonamide/ carbocation] complex eliminates p-toluenesulfonamide and releases the carbocation (Pathway B). Computations carried out by the Hartree-Fock method suggested that the Pathway B is more favorable. However, a peak for the carbocation is observed only when the carbocation formed is relatively stable. For example, the spectrum of N-phenylethyl-p-toluenesulfonamide is dominated by the peak at m/z 105 for the incipient phenylethyl cation, which rapidly isomerizes to the remarkably stable methylbenzyl cation. The peaks for the carbocations are weak or absent in the spectra of most of N-alkyl-p- toluenesulfonamides because alkyl carbocations, such as the decyl cation, rearrange to more stable secondary cations by 1,2-hydride and alkyl shifts. The energy freed is not dissipated, but gets internalized, causing the carbocation to dissociate either by transferring a proton to the sulfonamide or by releasing smaller alkenes to form smaller carbocations. The loss of the positional integrity in this way was proven by deuterium labeling experiments. [Figure not available: see fulltext.]

Full text of DOI:10.1007/s13361-014-0865-4

B American Society for Mass Spectrometry, 2014
J. Am. Soc. Mass Spectrom. (2014) 25:1068Y1078
DOI: 10.1007/s13361-014-0865-4
RESEARCH ARTICLE
Low-Energy Collision-Induced Dissociation Mass Spectra
of Protonated p-Toluenesulfonamides Derived from
Aliphatic Amines
Jason B. Bialecki, Carl S. Weisbecker, Athula B. Attygalle
Center for Mass Spectrometry, Department of Chemistry, Chemical Biology and Biomedical Engineering, Stevens Institute of
Technology, Hoboken, NJ 07307, USA
Abstract. Collision-induced fragmentation of protonated N-alkyl-p-
toluenesulfonamides primarily undergo either an elimination of the amine to form
CH3-(C6H4)-SO2+ cation (m/z 155) or an alkene to form a cation for the protonated
p-toluenesulfonamide (m/z 172). To comprehend the fragmentation pathways,
several deuterated analogs of N-decyl-p-toluenesulfonamides were prepared and
evaluated. Hypothetically, two mechanisms, both of which involve ion-neutral
complexes, can be envisaged. In one mechanism, the S–N bond fragments to
produce an intermediate [sulfonyl cation/amine] complex, which dissociates to
afford the m/z 155 cation (Pathway A). In the other mechanism, the C–N bond
dissociates to produce a different intermediate complex. The fragmentation of this
[p-toluenesulfonamide/carbocation] complex eliminates p-toluenesulfonamide and releases the carbocation
(Pathway B). Computations carried out by the Hartree-Fock method suggested that the Pathway B is more
favorable. However, a peak for the carbocation is observed only when the carbocation formed is relatively
stable. For example, the spectrum of N-phenylethyl-p-toluenesulfonamide is dominated by the peak at m/z
105 for the incipient phenylethyl cation, which rapidly isomerizes to the remarkably stable methylbenzyl
cation. The peaks for the carbocations are weak or absent in the spectra of most of N-alkyl-p-
toluenesulfonamides because alkyl carbocations, such as the decyl cation, rearrange to more stable
secondary cations by 1,2-hydride and alkyl shifts. The energy freed is not dissipated, but gets internalized,
causing the carbocation to dissociate either by transferring a proton to the sulfonamide or by releasing
smaller alkenes to form smaller carbocations. The loss of the positional integrity in this way was proven by
deuterium labeling experiments.
Key words: Collision-induced fragmentation, Sulfonamides, Fragmentation, Ion neutral complex
Received: 2 October 2013/Revised: 15 February 2014/Accepted: 18 February 2014/Published Online: 28 March 2014
Introduction
[3]. Electrospray and atmospheric-pressure chemical ioniza-
tion mass spectrometry in conjunction with liquid chroma-
tography provides ideal analytical procedures for
characterization and quantification of sulfonamides and their
metabolites [4, 5]. However, to facilitate unknown metabo-
lites identification by mass spectrometry, their fragmentation
mechanisms must be well understood.
Mass spectrometric fragmentation of protonated and
deprotonated sulfonamides have been extensively investi-
gated [6–10]. However, most sulfonamides that have been
investigated are those of aniline-based aromatics [6, 7, 11–
13] or cyclic [14] and secondary amines [8]. Some
protonated sulfonamides afford a unique loss of SO2 by an
intramolecular rearrangement [8]. Protonated
benzenesulfonamides of anilines, on the other hand, frag-
romatic sulfonamides are widely deployed as
pharmacophores for drug industry. Several pharmaceu-
A
ticals on the market, such as Sildenafil, Celecoxib,
Aprenavir, and many others are sulfonamides [1]. LFI, one
of the effective compounds known to reduce tissue damage
associated with anthrax is also a sulfonamide [2]. In fact,
sulfonamides are extensively used as antimicrobial agents in
animal husbandry. Consequently, sulfonamide metabolic
residues are commonly found in dairy products and meat
Electronic supplementary material The online version of this article
(doi:10.1007/s13361-014-0865-4) contains supplementary material, which
is available to authorized users.
Correspondence to:Athula Attygalle; e-mail: athula.attygalle@stevens.edu

Bialecki et al.: Spectra of Protonated p-Toluenesulfonamides
1069
ment to produce radical cations [7]. The fragmentation
mechanism described by Hu et al. for this fragmentation is
of particular interest because it violates the so-called “even-
electron” rule [6]. According to the proposed mechanism,
the S–N bond of the sulfonamide dissociates spontaneously
upon protonation of the molecule to produce an ion-neutral
complex. A subsequent charge transfer between the two
partners of the complex gives rise to ionized anilines [6]. In
an investigation of fragmentation mechanisms of the
benzenesulfonamides synthesized from aliphatic primary
amines, we found that they undergo neither the SO2
elimination nor the formation of radical cations. Our results
from a number of derivatives enable several generalizations
useful for interpreting CID spectra of protonated sulfon-
amides of open-chain aliphatic amines.
lithium aluminum deuteride, to generate amines. Amines
were derivatized with p-toluenesulfonyl chloride to obtain
sulfonamide. All sulfonamide products were detected as one
spot upon thin-layer chromatographic analysis (precoated
0.25 mm silica gel plates from Fisher Scientific, Hampton,
NH, USA). All products were detected as a single peak on
gas-chromatographic analysis, except those for the oximes,
which gave a double peak representing the E and Z isomers.
EI mass spectra were recorded on a HP 5970 series Mass
Selective Detector coupled to a Hewlett Packard 5890 Series
II gas chromatograph.
Mass Spectrometry
The collision-induced dissociation (CID) mass spectra were
recorded on a Micromass Quattro I tandem mass spectrom-
eter equipped with an electrospray ion source. Samples were
introduced to the source as acetonitrile-water-formic acid
(9:1:10−2) solutions, at a flow rate of 320 μL h–1, for
positive-ion MS analysis. The source temperature was held
constant at 80°C. The capillary voltage was held at 4000 V.
The argon gas pressure in the collision cell was set to
attenuate precursor ion transmission by 30%–50%. For
experiments performed in deuterated solvents D2O (99.8
atom % D; Aldrich), and CD3COOD (99 atom % D;
Cambridge Isotope Lab., MA, USA) were used.
Experimental
Materials
All solvents and reagents were obtained from commercial
suppliers (Aldrich Chemical Co., St. Louis, MO, USA) and
used as purchased. The synthesis of [1,1-2H2]decanol, [2,2-
2H2]decanol, [3,3-2H2]decanol, [4,4-2H2]decanol and [5,5-
2H2]decanol was described previously [15, 16]. These
alcohols were converted to corresponding aldehydes by
oxidation with pyridiniumchlorochromate (see
Supplementary Data for synthetic details). The aldehydes,
decanal, [1-2H]decanal, [2,2-2H2]decanal, [3,3-2H2]decanal,
[4,4-2H2]decanal, and [5,5-2H2]decanal were converted to
oximes by allowing them to react with NH2OH, and then
reducing the products with lithium aluminum hydride, or
Computational Methods
All calculations were performed using the Gaussian 03 W
program package [17]. Calculations were performed using
the Hartree-Fock method. Calculated structures were opti-
Figure 1. Product ion spectra of m/z 312 and 314 ions derived from N-decyl-p-toluenesulfonamide and N-decyl-p-[N-
2H2]toluenesulfonamide by positive-ion electrospray ionization from respective CH3CN/H2O (a), or CH3CN/D2O (b) solutions
(collision energy setting, 15 eV)

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Bialecki et al.: Spectra of Protonated p-Toluenesulfonamides
mized to obtain stationary states using a 6-31G(d) split-
valence basis set. Electronic energies of the structures were
then recalculated using density functional theory with the
B3LYP exchange-correlation functional [18, 19] and a 6-
31+G(d) basis set. Frequency analysis of optimized struc-
tures was used to distinguish energy minima from saddle
points. Zero-point energy corrections were made to the
energies of stationary states, and the corrections were scaled
by a factor of 0.9135 [20].
Results and Discussion
The CID mass spectrum recorded from the m/z 312 ion for
protonated N-decyl-p-toluenesulfonamide (1) is depicted in
Figure 1. To start with this spectrum is very different from
those previously reported from other protonated sulfonamides
because of the absence of a peak for a SO2 loss [8, 13], or peaks
that represent radical cations [7]. In contrast, the CID spectrum
of protonated N-decyl-p-toluenesulfonamide showed an in-
Figure 2. Product ion spectra of m/z 314 ions derived from N-[1-2H2]decyl-p-toluenesulfonamide (a), N-[2-2H2]decyl-p-
toluenesulfonamide (b), N-[3-2H2]decyl-p-toluenesulfonamide (c), N-[4-2H2]decyl-p-toluenesulfonamide (d), and N-[5-2H2]decyl-
p-toluenesulfonamide (e) by electrospray ionization from CH3CN/H2O/H+ solutions (collision energy setting, 15 eV)

Bialecki et al.: Spectra of Protonated p-Toluenesulfonamides
1071
tense peak at m/z 172 for the formation of protonated p-
toluenesulfonamide by an elimination of a decene molecule
(Figure 1). For the formation of the m/z-172 ion, the C–N bond
must be cleaved and a hydrogen atom from the decyl group
must be transferred to the p-toluenesulfonamide moiety.
Hydrogen transfers that occur to eliminate an alkene under
CID conditions sometimes follow a specific pathway [21]. For
example, upon collision-induced activation, the anion derived
from 1-decyl sulfate anion undergoes fragmentation by
transferring a proton specifically from the beta position of the
decyl group to the sulfate group by a charge-driven mechanism
to eliminate a decene molecule [21]. In contrast, the hydride
transfer required for the loss of an alkene from “onium”
cations, such as immonium, oxonium, and sulfonium, follows a
less specific multistep pathway that involves ion-neutral-
complex intermediates [22]. Before an ion-neutral-complex
dissociates, the less stable cationic species within the complex
undergoes rapid rearrangements by 1,2-hydride and alkyl shifts
to more stable carbenium ions or proton-bridged complexes
[22, 23]. Consequently, the positional integrity of hydrogen
atoms in a carbenium ion is rapidly lost. Similar observations
have been reported from protonated dibenzylamine, which
eliminates ammonia upon activation [24]. Although the proton
necessary for the loss of ammonia came from the aromatic ring,
it did not originate from any specific position in the aromatic
ring. The reasoning was that the ion-neutral complex formed
from protonated dibenzylamine dissociated first to form an
arenium ion, which allowed the deuterium atoms on the
aromatic ring to scramble [25].
To determine if a specific hydrogen-atom transfer occurs
during the loss of decene from protonated N-alkyl-p-
toluenesulfonamides, several deuteriated N-decyl-p-
toluenesulfonamides were synthesized and their CID spectra
were recorded. The results obtained from N-decyl-p-[N-
2H2]toluenesulfonamide cation (m/z 314) showed that the
positional integrity of the protons is not lost when they are
on the nitrogen atom (Figure 1b) because the spectrum
showed a peak at m/z 174 without any adjacent peaks for
any isotopologs. In contrast, the m/z 172 peak in all spectra
recorded from several other isotopomers of N-[2H2]decyl-p-
toluenesulfonamide (with the deuterium substitution on the
alkyl chain) showed a small peak at m/z 173 indicating that
the hydrogen atom that is transferred did not originate from
any specific position of the decyl chain (Figure 2).
We envisaged that protonated p-toluenesulfonamides
derived from aliphatic amines fragment upon activation by
two different pathways (Scheme 1). A direct elongation and
a heterolytic cleavage of the S–N bond could lead to the
formation of the ion/neutral Complex A, which could then
dissociate to form the m/z 155 ion (Pathway A, Scheme 1).
Alternatively, a direct cleavage of the N–C bond could
generate the ion/neutral Complex B (Pathway B, Scheme 1).
(1)
HF/6-31(G)//B3LYP/6-31+G(d)
B
A
(1A)
(1B)
29.6 kcal/mol
30.5 kcal/mol
Scheme 1. Hypothetical pathways of formation and computed relative energies based on HF/6-31(G)//B3LYP/6-31+G(d) level
of theory, of ion/neutral complexes formed upon collisional activation of protonated N-alkyl-p-toluenesulfonamides

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Bialecki et al.: Spectra of Protonated p-Toluenesulfonamides
Computations carried out by the Hartree-Fock method
spiro[2.5]octa-5,7-dien-4-ylium cation (ethylenebenzenium
cation) (Supplementary Figures 1 and 2). The stability of
this ethylenebenzenium cation drives the fragmentation of
protonated N-phenylethyl-p-toluenesulfonamide primarily
by the Pathway B (Scheme 2).
suggest that the Complex 1B (25.0 kcal/mol) is more
favorable than Complex 1A (40.0 kcal/mol), although
recalculated energies at the B3LYP/6-31+G(d) level predict
Complex B (29.6 kcal/mol) and Complex A (30.5 kcal/mol)
to be similar in energy. A peak for the incipient carbenium
ion in the spectra of N-alkyl-p-toluenesulfonamides is
generally weak or absent unless it is tertiary carbenium or
any other relatively stable ion (Figure 3). For example, a
prominent peak is observed at m/z 57 in the spectrum of
protonated N-(t-butyl)-p-toluenesulfonamide (Figure 3a) but
an analogous peak for a decyl cation is absent at m/z 141 in
the spectrum of protonated N-decyl-p-toluenesulfonamides
(Figure 1a). In other words, the intensity of the peak for the
incipient carbenium ion depends on the relatively stability of
carbenium ions. For example, the fragmentation spectrum of
N-phenylethyl-p-toluenesulfonamide is entirely dominated
by a peak at m/z 105 because the carbenium generated is
particularly stable (Figure 4).
In addition to the direct dissociation of Complex B, a
proton transfer from the alkyl group to the amino group can
also occur (Scheme 1). In this way, an alkene is eliminated
and a protonated p-toluenesulfonamide (m/z 172) is pro-
duced. As mentioned previously, the single hydrogen atom
that is necessary for the formation of the m/z 172 ion does
not originate from any specific position of the decyl chain.
This is evident because none of the spectra recorded from an
array of N-[2H2]decyl-p-toluenesulfonamides showed a
dominant peak specifically at m/z 173. Instead, the spectra
showed a prominent peak at m/z 172 accompanied by a
small peak at m/z 173 for the corresponding monodeuterio
isotopolog (Figure 2).
In practice, a peak for the initial carbenium ion is rarely
observed in the spectra of protonated sulfonamides derived
from long-chain primary aliphatic amines (the same can be
said for the ammonia loss from protonated aliphatic primary
amines; unpublished observations). For example, a peak at
m/z 141 is not observed for the decyl cation in the spectrum
of N-decyl-p-toluenesulfonamides (Figure 1). The primary
carbocations, such as the decyl cation, apparently rearrange
Within an ion/neutral complex, the two participants are
held together only by Coulombic attractive forces
(Scheme 1B). It is known that the carbenium ions isomerize
within the complex to more stable forms by 1,2-hydride
shifts [26]. Even the phenylethyl cation has been reported to
isomerize to the more stable methylbenzyl cation [27, 28].
Our computations indicate the structure of the m/z 105 to be
Figure 3. Product ion spectra of m/z 228, 242, and 284 ions generated by electrospray ionization from protonated N-(t-butyl)-
p-toluenesulfonamide (a), N-pentyl-p-toluenesulfonamide (b), and N-(2-octyl)-p-toluenesulfonamide (c), respectively (collision
energy setting, 15 eV)

Bialecki et al.: Spectra of Protonated p-Toluenesulfonamides
1073
Figure 4. Product ion spectrum of m/z 276 ions of protonated N-phenylethyl-p-toluenesulfonamide (a) (collision energy setting,
15 eV); (b) represents a vertical expansion of 100 times to highlight the minor peaks
very rapidly to more stable secondary cations by 1,2-hydride
shifts. By this process, which is generally referred to as
“scrambling,” the positional integrity of hydrogen atoms in
the carbon chain is lost [25]. Consequently, the protonated
p-toluenesulfonamide (m/z 172) formed by the alkene
elimination acquired only a fraction of the deuterium
labeling from any of the double-deuterium labeled alkyl
groups in the sulfonamides used in this study. If the
carbocation underwent total scrambling before the proton
transfer occurs, the ratio of the intensities of the m/z 172 and
173 peaks should be the same for all the [1H2]-isotopologs.
However, Figure 2 shows that the intensity of the m/z 173
peak is significantly higher in the spectra of sulfonamides of
[3,3-2H2]decylamine and [4,4-2H2] decylamine (Figure 2c
and d), which indicate that the proton transfer rate is higher
than the scrambling rate.
The energy freed by the rearrangement of the initial
primary carbenium ion to a more stable secondary
carbocation, however, is not dissipated to the surroundings.
Instead, the energy gets internalized to vibrational modes
2
m/z 276
HF/6-31(G)//B3LYP/6-31+G(d)
A
B
(2A)
(2B)
+ 31.2 kcal/mol
+ 14.8 kcal/mol
Scheme 2. Proposed formation of m/z 105 ion upon collisional activation of protonated N phenylethyl-p-toluenesulfonamide
via ion-neutral Complex 2B. Relative energies presented are based on HF/6-31(G)//B3LYP/6-31+G(d) level of theory

1074
Bialecki et al.: Spectra of Protonated p-Toluenesulfonamides
and increases the internal energy of the ion providing
impetus for the carbenium ion to undergo immediate
fragmentation to smaller and more stable carbenium ions,
usually by eliminating an alkene molecule. For example, the
spectrum from N-decyl-p-toluenesulfonamide does not show
a peak at m/z 141 for the decyl cation itself, but it shows a
series of peaks at m/z 43, 57, 71, 85, and 99 for smaller
carbocations (Figure 1). In the spectra of N-[2H2]decyl-p-
toluenesulfonamides, all peaks for these smaller
carbocations appeared as multiplets, indicating that “scram-
bling” has taken place in the initial precursor carbocation as
(Scheme 3). The m/z 155 ion can then lose SO2 to form the
of m/z 91 ion. The low intensity peak at m/z 156 drew our
attention because it represents an iminium ion. The
formation of the m/z 156 ion should occur via a specific
hydride transfer mechanism because deuterium-labeling
studies showed a specific peak shift to m/z 157 for N-[1-
2H2]decyl-p-toluenesulfonamide (Figure 2). The spectra of
sulfonamides with 2H2-labeling at 2-, 3-, or 4-position of the
amino moiety showed the corresponding peak at m/z 158.
This result established that the hydrogen transfer takes place
explicitly from the position 1 of the carbon chain. Thus, the
envisaged by the proposed mechanism (Scheme 3; Figure 2).
The other significant peaks in the spectrum of protonated
N-decyl-p-toluenesulfonamide are found at m/z 155, 156
(small), and 91. The formation of the m/z 155 ion can be
rationalized by an ammonia loss from the m/z 172 ion
formation of the m/z 156 should not involve an unbound
carbocation such that given in Pathway B because it would
lead to deuterium scrambling. The fragmentation should
occur via the ion/neutral Complex A, in which the amine
participates as a neutral molecule (Scheme 4). The low
Ion/Neutral Complex B
O
S
NH2
CH2
m/z 312
O
hydride shifts
O
loss of decene
S
NH3
H
O
S
O
m/z 172
NH2
m/z 312
loss of
NH3
O
O
S
loss of
O
O
m/z 155
S
NH2
loss of
heptene
O
C3H7
m/z 43
or
or
loss of
hexene
C4H9
m/z 57
loss of
pentene
C5H11
m/z 71
or
loss of
butene
C6H13
m/z 85
Scheme 3. Fragmentation of the m/z 312 ion for protonated N-decyl-p-toluenesulfonamide by Pathway B (note that only a few
arbitrarily selected cations are illustrated here; many others are possible)

Bialecki et al.: Spectra of Protonated p-Toluenesulfonamides
1075
O
S
NH2
O
m/z 312
A
O
S
loss of
decylamine
O
S
NH2
O
O
m/z 155
Ion/Neutral Complex A
m/z 312
loss of
SO2
O
S
O
m/z 91
H
H2N
SO2H
H2N
m/z 156
Scheme 4. Further fragmentation of protonated N-decyl-p-toluenesulfonamide (m/z 312) via Pathway A
intensity of the peaks is understandable because this is not
an energetically favored pathway.
with a relative intensity ratio of about 2:1. This ratio
indicated that the fragmentation via Complex B is somewhat
more favorable than the pathway involving Complex A. In
contrast, protonated N-(2-octyl)-p-toluenesulfonamide (m/z
284) underwent more severe fragmentation, even at a
laboratory-frame collisional energy as low as 4 eV. The m/
z 284 ion dissociated to furnish an intense peak at m/z 172,
and the intensity ratio of the m/z 172 to 155 peaks was about
30:1. This difference in ratios indicated that the replacement
of the primary alkyl group with a secondary alkyl group
significantly favors the formation of Complex B over
Complex A. Apparently, the secondary alkyl group seems
to lower the activation energy required for the formation of
Complex B more than for the Complex A.
When the collision energy was increased above 8 eV, the
peak intensity ratio between m/z 172 and m/z 155 began to
drop for both compounds. This was expected because at
higher collisions energies the m/z 172 ion starts to lose a
molecule of ammonia by a secondary process to form the ion
at m/z 155. In fact, at a collision energy setting of 11–14 eV,
the peak intensity of m/z 155 becomes greater than that of
the peak at m/z 172 for both compounds, indicating that at
higher collision energies the m/z 155 ion originates more by
the secondary fragmentation of the m/z 172 ion. This
observation highlights the usefulness of the breakdown
From the spectra of numerous sulfonamides that were
investigated, it was evident that the relative ratios of the m/z
155 and 172 peaks were different for different compounds.
According to the proposed pathways, both these ions could
originate via ion-neutral Complexes A and B. To explore the
feasibility whether these intensity differences could be
correlated to the relative contributions of the two pathways
to the fragmentation of the precursor ion, we recorded
intensity profiles of the product ions generated upon
collisional activation. Although it appeared challenging
because to some extent m/z 155 ion could originate also
from the m/z 172 ions by an ammonia loss, the breakdown
profiles that were constructed for protonated N-pentyl-p-
toluenesulfonamide and N-(2-octyl)-p-toluenesulfonamide
revealed that the intensities of the m/z 155 and 172 peaks,
obtained at low collision energies, are useful to determine
the relative contribution of each pathway. Protonated N-
pentyl-p-toluenesulfonamide is more defiant to fragmenta-
tion than that of the N-(2-octyl)-p-toluenesulfonamide,
although the former is the smaller ion (Figure 5). At a
laboratory-frame collisional energy of 4 eV, protonated N-
pentyl-p-toluene sulfonamide (m/z 242) underwent only a
little fragmentation to produce peaks at m/z 172 and m/z 155

1076
Bialecki et al.: Spectra of Protonated p-Toluenesulfonamides
100
90
80
70
60
50
40
30
20
10
0
graphs to determine the fragmentation pathways. In other
words, only results from low collision energies should be
deployed to estimate which ion-neutral complex is energet-
ically preferred.
The iminium ion that represents the peak at m/z 156 in the
spectrum of protonated N-decyl-p-toluenesulfonamide is
generated via Complex A (Scheme 4). Only a very small
portion of the precursor ions follow this reaction channel via
Complex A. Low intensity peaks for the iminium ions are
observable for 2-octyl or tert-butyl derivatives, which
indicate that only a minute percentage of the Complex A
dissociates to form iminium ions.
The spectrum of protonated N-phenylethyl-p-
toluenesulfonamide (m/z 276) shows a weak but significant
peak at m/z 259 for an ammonia loss (Figure 4). Because the
relative intensity of the m/z 259 peak is only about 0.5%, the
vertical scale had to be multiplied by 100 to make it visible
(Figure 4b). In a previous publication, we reported that
protonated dibenzylamines, upon collision-induced activa-
tion, loses ammonia [24]. Tandem mass spectrometric
experiments conducted with appropriate deuterium-labeled
dibenzylamines confirmed that the additional proton re-
quired for this enigmatic ammonia loss originated from the
ortho positions of the phenyl rings and not from the benzylic
methylene groups. Thus, we envisaged that the ammonia
loss observed from protonated N-phenylethyl-p-
toluenesulfonamide would follow an analogous pathway
m/z 242
(a)
(b)
m/z 155
m/z 91
m/z 172
4
6
8
10
12
14
16
Laboratory-Frame Collision Energy (eV)
100
90
80
70
60
50
40
30
20
10
0
m/z 172
m/z 284
m/z 155
m/z 91
4
6
8
10
12
14
16
Laboratory-Frame Collision Energy (eV)
Figure 5. Plot of percentage relative intensities of peaks
versus laboratory-frame collision energy for m/z 242 (-♦-), 172
(-■-), 155 (-▲-), and 91 (-●-) ions derived from N-pentyl-p-
toluenesulfonamide (a), and m/z 284 (-♦-), 172 (-■-), 155 (-▲-),
and 91 (-●-) ions derived from N-(2-octyl)-p-
toluenesulfonamide (b), respectively
O
S
H
N
H
m/z 276
O
O
S
SO2
NH2
H
NH2
O
H3C
H3C
O
S
SO2
NH3
O
NH3
H3C
H3C
m/z 259
Scheme 5. Proposed fragmentation of the m/z 276 ion for protonated N-phenylethyl-p-toluenesulfonamide by Pathway A

Bialecki et al.: Spectra of Protonated p-Toluenesulfonamides
1077
spectrometry analyses to the characterization of novel glyburide
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(Scheme 5). The methylbenzyl cation could initiate an
electrophilic attack on the phenyl group by removing a pair
of electrons from the aromatic sextet yielding an arenium ion
(Scheme 5). The highly reactive arenium ion then stabilizes
itself by regenerating the aromatic ring by donating a ring
proton to the amino group, thereby generating a protonated
amine intermediate (Scheme 5), which then undergoes a
charge-driven heterolytic cleavage to eliminate ammonia.
Conclusions
Protonated N-alkyl-p-toluenesulfonamides primarily under-
go fragmentation by two pathways. One pathway (Pathway
A) generates predominantly the p-toluenesulfonyl cation
(m/z 155). The second pathway (Pathway B) generates
protonated p-toluenesulfonamide (m/z 172) by eliminating
an alkene, or
a carbocation by eliminating p-
toluenesulfonamide as a neutral molecule. The relative
intensities of the peaks at m/z 155 and 172 indicate which
fragmentation mechanism takes precedence. When the initial
fragmentation produces a remarkably stable carbocation,
such as the methybenzyl cation, the fragmentation follows
overwhelmingly the Pathway B, and the spectra are virtually
dominated by the peak for the carbocation, whereas the
peaks at m/z 155 and 172 are negligibly small. On the other
hand, when the fragmentation leads to a relatively unstable
incipient carbocation, such as the decyl cation, Pathway A
takes precedence. In general, the CID spectra of p-
toluenesulfonamides derived from aliphatic amines are very
different from those of aromatic amines. The positive ion
CID spectra of aromatic amine derivatives are dominated by
the peaks for SO2 loss and radical cations derived from the
amine moiety. Analogous peaks are not observed in the CID
spectra of p-toluenesulfonamides derived from aliphatic
amines.
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Acknowledgments
The authors gratefully acknowledge Bristol-Myers Squibb
Pharmaceutical Company (New Brunswick, NJ) for the
donation of the Waters Quattro mass spectrometer.
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