Benzyl anion transfer in the fragmentation of N-(phenylsulfonyl)-benzeneacetamides: a gas-phase intramolecular SNAr reaction

Article abstract of DOI:10.1039/c5ob01582k

In this study, we report a gas-phase benzyl anion transfer via intramolecular aromatic nucleophilic substitution (S_NAr) during the course of tandem mass spectrometry of deprotonated N-(phenylsulfonyl)-benzeneacetamide. Upon collisional activati

Full text of DOI:10.1039/c5ob01582k

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Biomolecular Chemistry
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Benzyl anion transfer in the fragmentation of
N-(phenylsulfonyl)-benzeneacetamides:
a gas-phase intramolecular SNAr reaction†
Cite this: Org. Biomol. Chem., 2015,
13, 10205
Shanshan Shen,a Yunfeng Chai,b Yaqin Liu,a Chang Lib and Yuanjiang Pan*a
In this study, we report a gas-phase benzyl anion transfer via intramolecular aromatic nucleophilic substi-
tution (SNAr) during the course of tandem mass spectrometry of deprotonated N-(phenylsulfonyl)-
benzeneacetamide. Upon collisional activation, the formation of the initial ion/neutral complex
([C6H5CH2−/C6H5SO2NCO]), which was generated by heterolytic cleavage of the CH2–CO bond, is pro-
posed as the key step. Subsequently, the anionic counterpart, benzyl anion, is transferred to conduct the
intra-complex SNAr reaction. After losing neutral HNCO, the intermediate gives rise to product ion B at
m/z 231, whose structure is confirmed by comparing the multistage spectra with those of deprotonated
2-benzylbenzenesulfinic acid and (benzylsulfonyl)benzene. In addition, intra-complex proton transfer is
also observed within the complex [C6H5CH2−/C6H5SO2NCO] to generate product ion C at m/z 182. The
INC-mediated mechanism was corroborated by theoretical calculations, isotope experiments, breakdown
curve, substituent experiments, etc. This work may provide further understanding of the physicochemical
properties of the gaseous benzyl anion.
Received 30th July 2015,
Accepted 18th August 2015
DOI: 10.1039/c5ob01582k
www.rsc.org/obc
ionic fragment and a neutral counterpart which bind together
through electrostatic attraction but still maintain its individual
Introduction
Carbanions are highly-reactive intermediates in numerous mobility. In such a temporary system, various intriguing
chemical processes and widely employed in organic solution chemical reactions occur prior to final separation of the INC
reactions.1 In the condensed phase, they are usually paired partners. Among them, the most common INC-mediated
with the corresponding metal counterions to form organo- process is proton transfer.13 Several other transfer reactions
metallics. Evaluation of their intrinsic reactivity is quite a big were also observed including transacylation,15 hydride
challenge because they are quite sensitive to temperature, transfer,16–19 electron transfer,20,21 benzyl cation transfer
additives and solvent.2,3 Therefore, it is of great importance (BCT),22–24 etc. Particularly, research on intramolecular BCT
and general interest to gain insight into the essential behavior has been well-documented and has received considerable
of monomeric carbanions in the gas phase.
interest. In contrast, quite a few studies were focused on the
Mass spectrometry (MS) has become an indispensable tool transfer of carbanions, as the occurrence of such reactions
in conducting fundamental studies of gas-phase ion requires a suitable carbanion donor and acceptor. In many
chemistry.4–7 In gaseous ionic reactions, ion-neutral complex cases, however, most compounds analyzed by negative-ion MS
(INC) intermediates are extensively invoked to rationalize the contain one or several basic sites which can easily capture a
generation of some special product ions.8–12 Previously, carbocation, and thus, carbanion transfer is usually inhibited
numerous theoretical and experimental studies have been by other competing reactions.
reported on the existence and importance of INC in unimole-
The benzyl anion, the simplest aromatic negative ion con-
cular dissociation reactions in MS.13,14 An INC consists of an taining an exocyclic carbon atom and a highly-reactive inter-
mediate in various chemical and biochemical reactions,25–27 is
less fragile than alkyl types of carbanions due to resonance
stabilization.28 Efforts have been made to obtain its crystal
structure under low temperature and strictly anhydrous con-
ditions, but failed due to its rapid decomposition.29 By con-
trast, the benzyl anion is relatively stable in the gas phase, and
thus can be obtained in the collision induced dissociation
(CID) process of some specific precursor ions in MS. The
aDepartment of Chemistry, Zhejiang University, Hangzhou 310027, China.
E-mail: panyuanjiang@zju.edu.cn; Fax: +86-571-87951629; Tel: +86-571-87951264
bCollege of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
†Electronic supplementary information (ESI) available: NMR spectra of model
compounds, Cartesian coordinates, total energies, zero point energy corrections
and the number of imaginary frequencies of the structures discussed in the text.
See DOI: 10.1039/c5ob01582k
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25 psi; and ion source gas (GS1 and GS2) at 40 psi. The col-
lision energy (CE) was 40 eV, and the collision energy spread
(CES) was 15 eV in the MS/MS experiments.
Scheme 1 Gas-phase generation of the ion/neutral complex contain-
ing the reactants through the collision-induced dissociation (CID)
method.
Theoretical calculation
Theoretical calculations were carried out using the Gaussian
03 package of programs.31 All structures were optimized at the
B3LYP/6-31++G(d, p) level of density functional theory (DFT),
and were identified as the true minima by the absence of ima-
ginary frequencies. Transition states were identified by the
presence of only one imaginary frequency. The minima con-
nected by a given transition structure were confirmed by intrin-
sic reaction coordinate (IRC) calculations. The energies
discussed here are the sum of electronic and thermal energies.
benzyl anion is so highly electron-rich that it can act as an
electron donor to undergo a single electron transfer reaction.20
It is also an ideal Brønsted base as it is able to capture a
proton from an aromatic ring.30 In view of its well-known
nucleophilicity, here we question if it could undergo intra-
molecular transfer to achieve gas-phase nucleophilic substi-
tution reactions.
Sample synthesis and preparation
The motivation of the present investigation is to delve into
the gas-phase benzyl anion transfer (BAT) reaction via INC,
which is not only essentially important for gas-phase ionic
reactions, but also crucial in expanding our understanding on
the chemical nature of the benzyl anion. Therefore, we
selected N-(phenylsulfonyl)-benzeneacetamides as the model.
Presumably, the deprotonated model compounds can simul-
taneously in situ generate both the nucleophile (benzyl anion)
and the electrophilic species (benzenesulfonyl isocyanate
moiety) (Scheme 1) in tandem mass spectrometry.
The N-(phenylsulfonyl)-benzeneacetamide derivatives (1–8)
were synthesized from the corresponding phenylacetic acids
and benzenesulfonamide in the presence of EDCI and
DMAP.32 Compounds 9–11 were prepared using the corres-
ponding sulfonyl chlorides and 2-phenylacetamide.33 Deutera-
tion (8) and 2-benzylbenzenesulfinic acid (12) were obtained
following the reported procedures.34,35 Experimental details,
high-resolution mass spectrometry (Table S1†) and 1H NMR
data are available in the ESI.† The structure of the representa-
tive model compound (1) was confirmed by NMR spectroscopy.
N-(Phenylsulfonyl)-benzeneacetamide (1), 1H NMR (600 MHz,
DMSO-d6): δ (ppm) 7.95 (d, 2H), 7.68 (t, 1H), 7.60 (t, 2H),
7.29–7.17 (m, 5H), 3.59 (s, 2H); 13C NMR (150 MHz, DMSO-d6):
δ (ppm) 172.6, 142.3, 137.0, 136.7, 132.3, 132.2, 131.4, 130.6,
130.0, 45.2 (ESI Fig. S4†).
Experimental
Mass spectrometry
The samples were analyzed with negative ion ESI-MS on a
Bruker Esquire 3000plus ion trap mass spectrometer (Bruker-
Franzen Analytik GmbH, Bremen, Germany), with data acqui-
sition using the Esquire 5.0 software. The compounds were
dissolved in methanol, and then the solutions were infused
into the source chamber at a flow rate of 3 μL min−1. Nitrogen
was used as the nebulizing gas at a pressure of 10 psi, and the
drying gas at a flow rate of 5 L min−1. The capillary voltage was
set at 4000 V, and the ion source temperature was set at
250 °C. CID mass spectra were obtained with helium as the col-
lision gas, and the collision energy was set at appropriate
collision energies to give energy for dissociation of all samples.
High-resolution mass spectrometry experiments were con-
ducted by using a TripleTOF4600 system with a DuoSpray™
ion source operating in the positive ESI mode (AB SCIEX, CA,
USA). The APCI probe of the source was used for fully auto-
matic mass calibration using a Calibrant Delivery System. CDS
injects a calibration solution matching the polarity of ioniza-
tion and calibrates the mass axis of the TripleTOF system in all
scan functions used (MS or MS/MS). Data acquisition and pro-
cessing were carried out using Analyst TF 1.6 and PeakView
(AB SCIEX, Foster City, CA) software version 1.2 with the XIC
Manager. Solutions were infused from the ESI source at 10 µL
min−1 with the following parameters applied: ion spray voltage
The samples except for compound 8 were dissolved in
methanol first, and then diluted with methanol–water (1 : 1,
v/v) containing 0.1% ammonia before being introduced into
mass spectrometers. Compound 8 was dissolved in methanol-
d4 first, and then diluted with methanol-d4 before being intro-
duced into the mass spectrometer.
Results and discussion
The gas-phase BAT reaction was explored by investigating the
fragmentation pattern of the deprotonated N-(phenylsulfonyl)-
benzeneacetamides (compounds 1–7, Fig. 1). Generally, these
analogues produced similar fragment ions in the negative
floating (ISVF), 5500 V; temperature, 550 °C; curtain gas, Fig. 1 Compounds for gas-phase benzyl anion transfer studies.
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total energy of the isomer A-1 is 21.8 kcal mol−1 lower than
that of A-2. As for the two mesomeric structures of A-1, they
are likely to share similar proportions because calculational
results reveal close charge distributions of nitrogen (−0.407)
and oxygen (−0.461) (Fig. S2†). The most abundant ion at m/z
156 is attributed to the (phenylsulfonyl)amide anion, originat-
ing from the heterolytic cleavage of the acylamide bond of A-2.
The fragment ion at m/z 93 is assigned as the phenolate anion,
derived from Smiles rearrangement from A-1 via the stepwise
loss of SO2 and C6H5CH2CN. Such cases are not unusual in
the gas-phase anionic fragmentations.38–40 Several other
common fragmentations were also observed, such as the ion at
m/z 256 that results from the loss of H2O, and the benzyl
anion at m/z 91 that results from the direct decomposition of
A-1. Herein, the other two product ions, m/z 182 (C) and m/z
231 (B), drew our interest on their generation pathways since
they can’t be explained by conventional mechanisms.
Fig. 2 CID spectra (a) deprotonated compound 1 and (b) dedeuterated
compound (8). Signal peaks marked with rhombus correspond to the
parent ions.
Table 1 CID mass spectral data of the deprotonated N-(phenylsulfo-
nyl)-benzeneacetamide derivatives (fragmentation amplitude, 0.8 volts)a
[M − H]−
m/z
RC6H4CH2 C6H4SO2NCO− [(M−H)-43]−
D
C
B
−
No.
R
1
2
3
4
5
6
7
–H
274
304
288
292
308
352
91 (0.42)b 182 (0.67)
121 (0.081) 182 (2.8)
231 (2.0)
261 (3.9)
245 (2.6)
249 (3.0)
265 (8.7)
309 (7.0)
289 (1.1)
Benzyl anion transfer within INC
–OCH3
–CH3
–F
105 (0.12)
109 (0.37)
125 (8.8)
169 (9.8)
149 (100)
182 (1.4)
182 (0.94)
182 (1.4)
182 (1.2)
N. D.c
The recognizable product ion B (m/z 231) of interest is formed
by elimination of 43 Da (Fig. 2a). The accurate mass of the
fragment ion, 231.0482, corresponding to C13H11O2S (calcu-
lated mass = 231.0485), indicates that the expelled neutral is
CHON, likely isocyanic acid. Although such a loss appears
trivial, the mechanism is not straightforward since the depro-
tonated molecule should undergo a complicated skeletal
rearrangement to eliminate HNCO.
–
–
35Cl
79Br
–COOCH3 332
a For other ions, see the CID spectra in Fig. S1 (ESI). b m/z (Relative
abundance %, related to the base peak). c N. D.: not detected.
The structure of B was confirmed by multistage mass spec-
trometry (Fig. 3). Two comparative ions with definite structures
ESI-MS/MS experiments but in different relative abundances. A
typical CID spectrum for the [M − H]− ion of compound 1 is
shown in Fig. 2a; partial CID MS data are summarized in
Table 1.
For clarification, compound 1 was picked up to exemplify
the characteristic fragmentations. On the basis of exhaustive
investigations of gaseous negative ions,36,37 we propose the
fragmentation routes of some selected product ions generated
from deprotonated compound 1 as depicted in Scheme 2.
After deprotonation, the [M − H]− ion may form different
isomers, as the methylene proton may undergo migration.
Among these, A-1 should possess higher population, which
can be confirmed by theoretical calculation results that the
of C6H5CH2C6H4SO2 or C6H5(CH−)SO2C6H5 were generated
−
from deprotonated 2-benzylbenzenesulfinic acid (12, Fig. 1)
and (benzylsulfonyl)benzene (13) respectively, and sub-
sequently subjected to collisional dissociation. The fragmenta-
tion pattern of ion
B is almost the same as that of
Fig. 3 CID spectra of the ion at m/z 231 derived from (a) deprotonated
2-benzylbenzenesulfinic acid (12), (b) deprotonated (benzylsulfonyl)-
benzene (13), and (c) the loss of HNCO from deprotonated 1. Signal
peaks marked with rhombus correspond to the parent ions.
Scheme 2 Proposed MS/MS fragmentation mechanisms for the
selected product ions from deprotonated compound 1.
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−
Fig. 4 DFT energy diagram for the SNAr reaction between C6H5CH2
Scheme 3 Gas-phase fragmentation reaction mechanisms proposed
for the INC-involved product ions from deprotonated compound 1;
ortho-position selected as an example for clear illustration; the italic
suffix represents the reaction position of the phenyl ring.
(D) and C6H5SO2NCO. All structures were optimized at the B3LYP/6-
31++G(d,p) level of theory in kcal mol−1 (in parentheses).
compound 8 (Fig. 2b), the product ion at m/z 233 was observed
rather than m/z 232, which experimentally corroborates the
possibility of the INC-pathway.
deprotonated 12 but differs from that of deprotonated 13,
which gives us a vital clue to its generation mechanism.
As aforementioned, the anticipative way to commence this
investigation is to consider the widespread INC mechanistic
scenario as the route exhibited in Scheme 3. Given the fact
that the benzyl anion is electron-rich while the neutral aro-
matic moiety is highly electron-deficient, the nucleophilic
attack of benzyl carbanion at the phenyl ring can easily occur
to form an anionic σ-complex.41 This marked BAT achieves the
SNAr reaction between the benzyl anion and the phenyl ring,
and successively activates the corresponding ring hydrogen to
become mobile. Once the hydrogen is attached on the disso-
ciative isocyanic nitrogen, the elimination of isocyanic acid
occurs to give rise to ion B.o.
Another plausible reaction pathway (Path 2) for the loss of
HNCO was proposed via a three-step process (Scheme 4): inci-
pient cyclisation through the nucleophilic attack of the
benzylic anion at the phenyl ring forms a six-membered ring,
and subsequent HNCO loss gives rise to the product ion. At
first glance, Path 2 is of faint chance because it is confor-
mationally unfavourable for a saturated carbon to adopt an
extra hydrogen in the hydrogen transfer step.
To verify the foregoing speculation, compound 8 was syn-
thesized to check the possibility of the two proposed pathways
since they will generate two different product ions with
different m/z values. Specifically, if the reaction underwent the
cyclisation channel (Path 2), a loss of DNCO would be expected
to give the product ion at m/z 232; on the contrary, if BAT takes
place (INC-pathway), the loss of HNCO from the intermediate
will generate a product ion at m/z 233. Consequently, the two
mechanisms can be readily distinguished from one another.
According to the ESI-MS/MS spectrum of the [M − D]− ion of
What’s more, DFT calculations were conducted at the
B3LYP/6-31++G(d, p) level of theory to further confirm the
mechanism of the present INC-mediated BAT reaction. Com-
pound 1 is used as a representative example. An energy
diagram was created as illustrated in Fig. 4, and full details of
the structures and energies of involved species are given in the
ESI.† The INC (INC-1), formed by dissociation of the parent
ion (A-1), is located 14.6 kcal mol−1 below the separated
−
C6H5CH2 (D) and C6H5SO2NCO. Within INC-1, the benzyl
anion undergoes aromatic nucleophilic attack at the ortho site
of C6H5SO2NCO to form
a much more stable anionic
σ-complex, E.o, in which the calculated Caryl–C bond length is
1.58 Å. The conversion of INC-1 to E.o is almost barrierless
with a relatively low energy barrier (INC-TS) being only 2.3 kcal
mol−1 higher than that of INC-1 (see ESI Fig. S4† for more
details). The subsequent loss of HNCO is thermodynamically
favourable since the total energy of the products is 37.8 kcal
mol−1 lower than that of E.o, with a not very high energy
barrier (TS.o) to be surmounted. It should be noted that the
last step might be triggered by the dissociative isocyanate
anion on account of the overwhelming tendency towards the
cleavage of the scissile S–N bond (1.94 Å). The theoretical cal-
culations provide reasonable and reliable evidence for the
−
SNAr reaction between C6H5CH2 and C6H5SO2NCO involving
a multistep addition–elimination pathway through an anionic
σ-complex intermediate.
Proton transfer within INC
The other interesting product ion C (m/z 182), corresponding
to the elimination of toluene, is derived from intra-complex
proton transfer (PT) attributing to the Brønsted basicity of the
benzyl anion. As proposed in the upper reaction route in
Scheme 3, within INC-1, the benzyl anion captures an ortho
proton from the neutral counterpart leading to the formation
of C.o. This route is similar to that discussed by Lu et al.30 On
the other hand, calculations show that the product ion C.o,
resulting from the ortho-channel, stabilizes the negative charge
by cyclization (as shown in parentheses), whereby it is placed
in an extremely deep potential well compared with the meta-
Scheme 4 Plausible MS/MS fragmentation mechanism for the loss of
HNCO from the cyclization reaction.
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or para-channel (ESI Fig. S3†). Previous gas-phase kinetic
studies have explained the reason why the product ion exhibi-
ted such a low intensity signal. That is, proton transfer to
charge-delocalized anions proceeds with low efficiency even
when energetically favorable.42
Breakdown curve
Supporting evidence for the existence of INC is obtained from
CID experiments at varying energies. The breakdown graph for
deprotonated 1, shown in Fig. 5, indicates that, with increasing
collision energy, the sum of the abundance of the INC-involved
product ions, C and B, keeps decreasing after reaching the
maximum at 0.82 volts; a steady increase is observed for one of
their rival ions, D (m/z 91). This is the behavior one would
expect43,44 for an INC-mediated reaction since the stability of
an INC is quite susceptible to collision energy.
Fig. 6 Competition between benzyl anion formation (ion D) and INC-
mediated PT & BAT (ion C + ion B) from the [M − H]− ions of N-(phenyl-
sulfonyl)-benzeneacetamides with different substituents.
− 48
constant σp
.
The results can strongly support our proposed
INC-mediated mechanism.
Substituent effect
Substituent effects are very helpful in probing different reac-
tion mechanisms.45–47 As shown in Scheme 3, the INC can
generate three product ions, B, C and D. The relative abun-
dances of these competing ions highly depend on the presence
of substituents on the benzyl ring which alter either the stabi-
lity of the product ions or the reactivity of the intermediates.
Specifically, an electron-withdrawing substituent (EWS) is able
to stabilize the benzyl anion (D) by spreading the negative
charge. In contrast, an electron-donating substituent (EDS)
increases both the Brønsted basicity and nucleophilicity of the
benzylic anion, resulting in stronger reactivity towards the PT
route or the SNAr route, respectively. In a word, the former is
expected to promote the formation of product ion D, while the
latter is expected to prefer the generation of B and C.
A series of compounds bearing different substituents at the
para-site of the phenylacetyl moiety (Fig. 1) were studied sys-
tematically to further understand the reaction mechanism. All
the compounds exhibit similar fragmentation patterns as
stated above, whereas the relative intensities of the three com-
petitive INC-product ions (B, C and D) vary significantly as the
substituent changes (Table 1). As depicted in Fig. 6, the inten-
sity ratio of these three product ions (D over (B + C)) generally
follows a linear relationship with the Hammett substituent
Blocking experiments
It is well known that SNAr is accelerated by electron-withdraw-
ing groups, especially at positions ortho and para to the
leaving group. Last but not least, CID spectra of deprotonated
2-phenyl-N-tosylacetamide (9), N-((2,6-dichlorophenyl)sulfo-
nyl)-2-phenylacetamide (10) and N-(mesitylsulfonyl)-2-phenyl-
acetamide (11) were studied (Fig. 7), confirming the reaction
position of BAT where the signal peak assigned to the loss of
HNCO is what we focus on.
As shown in Fig. 7, the results turned out to be in good
accordance with the criterion. When the two ortho sites
(Fig. 7b) or both the ortho and para sites (Fig. 7c) are occupied,
no signal peak corresponding to the loss of HNCO is observed;
whereas, in the case of the para-blocked one, the abundance
of the target peak (m/z 245, Fig. 7a) decreases (RA, 0.93%) com-
Fig. 7 CID mass spectra of deprotonated (a) 2-phenyl-N-tosylaceta-
mide (9), (b) N-((2,6-dichlorophenyl)sulfonyl)-2-phenylacetamide (10)
and (c) N-(mesitylsulfonyl)-2-phenylacetamide (11). The signal peak
corresponding to HNCO loss is marked with asterisks for clarity.
Fig. 5 Breakdown graph for the selected product ions of deproto-
nated 1.
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Conclusions
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−
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