Gas-phase chemistry of benzyl cations in dissociation of N-Benzylammonium and N-benzyliminium ions studied by mass spectrometry

Article abstract of DOI:10.1007/s13361-012-0344-8

In this study, the fragmentation reactions of various N-benzylammonium and N-benzyliminium ions were investigated by electrospray ionization mass spectrometry. In general, the dissociation of N-benzylated cations generates benzyl cations easily. Formation of ion/neutral complex intermediates consisting of the benzyl cations and the neutral fragments was observed. The intra-complex reactions included electrophilic aromatic substitution, hydride transfer, electron transfer, proton transfer, and nucleophilic aromatic substitution. These five types of reactions almost covered all the potential reactivities of benzyl cations in chemical reactions. Benzyl cations are well-known as Lewis acid and electrophile in reactions, but the present study showed that the gas-phase reactivities of some suitably ring-substituted benzyl cations were far richer. The 4-methylbenzyl cation was found to react as a Bronsted acid, benzyl cations bearing a strong electron-withdrawing group were found to react as electron acceptors, and parahalogen- substituted benzyl cations could react as substrates for nucleophilic attack at the phenyl ring. The reactions of benzyl cations were also related to the neutral counterparts. For example, in electron transfer reaction, the neutral counterpart should have low ionization energy and in nucleophilic aromatic substitution reaction, the neutral counterpart should be piperazine or analogues. This study provided a panoramic view of the reactions of benzyl cations with neutral N-containing species in the gas phase. American Society for Mass Spectrometry, 2012.

Full text of DOI:10.1007/s13361-012-0344-8

B American Society for Mass Spectrometry, 2012
J. Am. Soc. Mass Spectrom. (2012) 23:823Y833
DOI: 10.1007/s13361-012-0344-8
RESEARCH ARTICLE
Gas-Phase Chemistry of Benzyl Cations
in Dissociation of N-Benzylammonium
and N-Benzyliminium Ions Studied by Mass
Spectrometry
Yunfeng Chai, Lin Wang, Hezhi Sun, Cheng Guo, Yuanjiang Pan
Department of Chemistry, Zhejiang University, Hangzhou, Zhejiang, 310027, China
Abstract
In this study, the fragmentation reactions of various N-benzylammonium and N-benzyliminium
ions were investigated by electrospray ionization mass spectrometry. In general, the dissociation
of N-benzylated cations generates benzyl cations easily. Formation of ion/neutral complex
intermediates consisting of the benzyl cations and the neutral fragments was observed. The
intra-complex reactions included electrophilic aromatic substitution, hydride transfer, electron
transfer, proton transfer, and nucleophilic aromatic substitution. These five types of reactions
almost covered all the potential reactivities of benzyl cations in chemical reactions. Benzyl
cations are well-known as Lewis acid and electrophile in reactions, but the present study
showed that the gas-phase reactivities of some suitably ring-substituted benzyl cations were far
richer. The 4-methylbenzyl cation was found to react as a Brønsted acid, benzyl cations bearing
a strong electron-withdrawing group were found to react as electron acceptors, and para-
halogen-substituted benzyl cations could react as substrates for nucleophilic attack at the phenyl
ring. The reactions of benzyl cations were also related to the neutral counterparts. For example,
in electron transfer reaction, the neutral counterpart should have low ionization energy and in
nucleophilic aromatic substitution reaction, the neutral counterpart should be piperazine or
analogues. This study provided a panoramic view of the reactions of benzyl cations with neutral
N-containing species in the gas phase.
Key words: Benzyl cation, Methylene arenium, Ion/neutral complex, Electrophilic aromatic
substitution, Electron transfer, Hydride transfer, Nucleophilic aromatic substitution, Proton
Transfer
are usually short-lived in solution and so it is difficult to
Introduction
characterize their properties in solution. They can be
enzyl cations are highly reactive intermediates in
various chemical and biochemical reactions [1]. They
stabilized only under super-acidic conditions at low temper-
atures [2, 3] or by coordination to a metal center [4, 5].
Studying the structural properties and reactivities of benzyl
cations is a subject of fundamental importance. Experimental
observation supported by theoretical calculations indicates
that two major resonance forms, as shown in Scheme 1,
contribute significantly to the total electronic structure of the
benzyl cation [1–6]. The well-known reactivity of benzyl
B
Electronic supplementary material The online version of this article
(doi:10.1007/s13361-012-0344-8) contains supplementary material, which
is available to authorized users.
Correspondence to: Yuanjiang Pan; e-mail: panyuanjiang@zju.edu.cn
Received: 26 October 2011
Revised: 16 January 2012
Accepted: 20 January 2012
Published online: 25 February 2012

824
Y. Chai et al.: Gas-phase Chemistry of Benzyl Cations
INCs have been found to be ubiquitous in gas-phase ionic
reactions. Based on numerous experiments and theoretical
calculations, the existence and importance of INCs in
unimolecular fragmentation reactions in mass spectrometry
have been well established and reviewed by several authors
[33–38]. In an INC, the ionic and neutral species are bound
together by electrostatic interactions, but still maintain their
individual mobility. The excess energy derived from
ionization or collisional activation and free rotation ability
of an INC permit various interesting chemical reactions to
occur before its final decomposition. Those reactions are
geometrically impossible if the two components are
connected by a covalent bond. Among the INC-mediated
reactions, the well-documented reactions include cation
rearrangement, hydrogen transfer, and small alkyl cation
transfer.
By supposing the intermediacy of INCs, many unusual
observations in the traditional electron ionization mass
spectrometry (EI-MS) have been rationalized [33–38].
Consequently, a need for other examples of INC-mediated
reactions is evident in order to better understand the
fragmentation reactions in the contemporary ESI mass
spectrometry, a method that has become one of the most
popular analytical methods. Thus, renewed interest in studies
on INC-mediated fragmentation reactions has emerged in
recent years [8, 20–25, 39–47].
INCs are also significant for studying the reactivities of
ions in gas phase. The ionic and neutral components of an
INC show reactivities similar to those expected for the
isolated species in the bimolecular reactions. In previous
studies, we found dissociation of protonated N-benzyl
amines gave rise to [benzyl cation/amine] complex and then
nucleophilic aromatic substitution [8], electron transfer [23],
or hydride transfer [24] could occur within the complex in
different cases. In the present study, we systematically
investigated the gas-phase reactions of benzyl cations with
neutral N-containing species through INC intermediates in
collision-induced dissociation of N-benzylated cations in
ESI-MS. With these efforts, we try to figure out a more
integrated landscape of the gas-phase reactivity of benzyl
cations.
Scheme 1. Resonance forms of a benzyl cation
cation is electrophilicity due to the phenylmethyl cation
character. In nearly all reactions of benzyl cations, the
methylene carbon, but not the ring carbon, is the target of
nucleophilic attack by nucleophiles because addition of a
nucleophile at the phenyl ring (ortho or para position)
breaks its aromaticity and, thus, such a reaction is not
favored. The reaction of the ring-charged methylene arenium
ion is unknown, except when it is coordinated to a metal
center in solution [5] or constrained by steric effect in the
gas phase [7]. We recently reported a gas-phase nucleophilic
substitution reaction between piperazine and methylene
arenium ions at the non-restricted state in mass spectrometry
[8].
The rearrangement between benzyl cation and its isomer,
tropylium ion, (Scheme 2) also receives considerable
attraction and is still in debate [9–13]. Although tropylium
is more stable than benzylium, theoretical calculations
suggest that conversion of benzylium to tropylium must
surmount a significant energy barrier which is about 280 kJ
mol−1 [14–16].
Benzyl cations are relatively stable in the gas phase. They
are highly electron-deficient so that they can initiate
electrophilic attack on electron-rich species. The best
investigated reaction is the methylene transfer from the
benzyl cations to the neutral toluene [11, 15, 17, 18]. The
benzyl cation is also an ideal Lewis acid in that it is able to
capture a hydride ion from a saturated hydrocarbon group
but it does not donate a proton—it does not act as a Brønsted
acid [19]. These two kinds of reactions are commonly used
to distinguish benzyl cation from tropylium ion because
tropylium ion is inert towards these reactions.
Benzyl cations can be easily obtained by fragmentation of
the corresponding benzylated cations in mass spectrometry.
In electrospray ionization mass spectrometry (ESI-MS),
fragmentation of benzylated cations prefers to generate
benzyl cations [7, 8, 20–30], though a few exceptions have
been reported that tropylium ion can be co-produced in the
fragmentation of benzylpyridinium ions [18, 31, 32].
Besides the formation of benzyl cations, other interesting
ions resulting from hydride transfer [24, 25] or electrophilic
aromatic substitution reactions [20–22] via the nonconven-
tional ion/neutral complex (INC) can also be generated in
the dissociation of benzylated cations.
Experimental
Mass Spectrometry
All the collision-induced dissociation (CID) experiments
were carried out using a Bruker Esquire 3000plus mass
spectrometer (Bruker-Franzen Analytik GmbH, Bremen,
Germany) equipped with an electrospray ion source and
ion trap analyzer in the positive ion mode. 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. The dry gas temperature
was set at 250°C, and the capillary voltage was set at −4000
V. Solutions were infused to the mass spectrometer with a
syringe pump at a flow rate of 6 μL/min. The CID mass
Scheme 2. Benzylium-tropylium rearrangement

Y. Chai et al.: Gas-phase Chemistry of Benzyl Cations
825
spectra were obtained with helium as the collision gas at an
appropriate collision energy after isolation of the desired
precursor ion. Samples were first dissolved in water (or
methanol), then diluted with methanol. Methanol-d4 was
used as solvent for deuterium labeling experiment to form
[M+D]+ ion.
High-resolution CID mass spectra were measured on
an Apex III (7.0 Tesla) FTICR mass spectrometer
(Bruker, Billerica, MA, USA) equipped with an electro-
spray ion source in the positive ion mode. Sodium
trifluoroacetate was used as an external calibration
compound. Nitrogen was used as the nebulizing gas
and drying gas. Argon was used as the collision gas.
Solutions were infused to the mass spectrometer with a syringe
pump at a flow rate of 3 μL/min. The following parameters
were applied: capillary voltage, −4269 V; end plate, −3803 V;
skimmer 1, 12.00 V; skimmer 2, 6.61 V; offset, 0.98 V; rf
amplitude, 582.5 Hz; drying gas temperature, 150°C.
(m, 12H), 5.24 (s, 4H); 13CNMR (125MHz, D2O): δ (ppm)=
135.4, 133.5, 129.4, 129.4, 128.6, 122.7, 53.0.
N,N'-bis(4-chlorobenzyl)piperazine (15)
4-Chlorobenzyl bromide (2 mmol), anhydrous piperazine
(1 mmol) and potassium carbonate (2.5 mmol) were stirred in
tetrahydrofuran (2 mL) at room temperature. After the
completion of the reaction, the solvent was evaporated under
reduced pressure, water was added, and the mixture was
extracted with ethyl acetate. The combined organic layer was
washed with brine, dried over Na2SO4, and concentrated. The
residue was purified by silica gel chromatography to give the
product. 1HNMR: (500MHz, CDCl3): δ (ppm)=7.23 (m, 8H),
3.43 (s, 4H), 2.42 (br, 8H); 13CNMR (125MHz, CDCl3): δ
(ppm)=136.8, 132.7, 130.5, 128.4, 62.2, 53.1.
N-(4-chlorobenzyl)piperazine (21)
Anhydrous piperazine (6 mmol) and potassium carbonate
(3 mmol) were dissolved in 5 mL tetrahydrofuran and stirred
at room temperature. 4-Chlorobenzyl bromide (2 mmol) in
tetrahydrofuran was added dropwise. After the completion of
the reaction, the solvent was evaporated under reduced pressure,
water was added, and the mixture was extracted with ethyl
acetate. The combined organic layer was washed with brine,
dried over Na2SO4, and concentrated. The residue was purified
General Synthesis
The N-benzyltriethylammonium bromide, N,N'-dibenzylimi-
dazolium bromide, N,N'-dibenzylpiperazine, N-benzyl
amines and their derivatives were synthesized with the
corresponding benzyl bromides and amines. The compounds
after synthesis were purified by extraction and silica gel
flash chromatography. The structures were confirmed by
NMR spectroscopy and mass spectrometry.
1
by silica gel chromatography to give the product. HNMR:
(500MHz, CDCl3): δ (ppm)=7.24-7.29 (m, 4H), 3.44 (s, 2H),
2.88 (t, 4H), 2.40 (br s, 4H), 2.08 (br s, 1H); 13CNMR (125MHz,
CDCl3): δ (ppm)=136.9, 132.9, 130.7, 128.6, 63.1, 54.5, 46.2.
N-(4-methylbenzyl)triethylammonium bromide (9)
4-Methylbenzyl bromide (1.5 mmol) and triethylamine
(2 mL) were stirred at 70°C. After the completion of the
reaction, the excess triethylamine was evaporated under reduced
pressure to afford the product, which was further washed with
Results and Discussion
1
In the present study, the fragmentation reactions of several
representative N-benzylated cations were investigated (data are
shown in the following text). Ion/neutral complexes (INCs)
were proposed as intermediates to rationalize their CID
fragmentation reactions. Dissociation of these N-benzylated
cations first generated INC intermediates consisting of the
benzyl cation (or ring-substituted benzyl cation) and the neutral
component. Five kinds of reactions within the INC intermedi-
ates were observed [i.e., hydride transfer (HT), proton transfer
(PT), electron transfer (ET), nucleophilic aromatic substitution
(NAS), and electrophilic aromatic substitution (EAS)]. Benzyl
cations were also generated by direct fragmentation of the
precursor ions or separation of the INCs, which would be not
further illustrated in the following discussions.
ethyl acetate and dried under vacuum. HNMR: (500MHz,
D2O): δ (ppm)=7.30–7.35 (m, 4H), 4.29 (s, 2H), 3.13 (q, 6H),
2.31 (s, 3H) 1.31 (t, 9H); 13CNMR (125MHz, D2O): δ (ppm)=
141.3, 132.3, 129.8, 124.0, 59.5, 52.0, 20.3, 6.9.
N,N'-dibenzylimidazolium bromide (11)
Benzyl bromide (2 mmol), imidazole (2 mmol) and
potassium carbonate (2.5 mmol) were stirred in acetonitrile
(2 mL) at 70°C. After the completion of the reaction, the
solvent was evaporated under reduced pressure, water was
added, and the mixture was extracted with ethyl acetate. The
combined organic layer was washed with water, dried over
Na2SO4, and concentrated to afford the corresponding 1-
benzylimidazole. Benzyl bromide (1.5 mmol) and 1-benzy-
limidazole (1 mmol) were stirred in acetonitrile (2 mL) at
70°C. After removal of the solvent, the crude product was
washed with ethyl acetate to remove the excess benzyl
bromide and dried under vacuum to afford the product.
1HNMR: (500MHz, D2O): δ (ppm)=8.81 (s, 1H), 7.30-7.34
Proton Transfer
The fragmentation of quaternary ammonium ions (R4N+) has
been reported in previous studies and the formation of INCs
was considered to be involved in the fragmentations [48–51].
Their fragmentation mode was influenced by the nature of their

826
Y. Chai et al.: Gas-phase Chemistry of Benzyl Cations
alkyl chains (R). In this study, the fragmentation reactions of N-
benzyltriethylammonium ions containing different benzyl
groups were studied. For these cations, the benzylic C–N bond
is the most scissile one among the four C–N bonds. Thus, all
the fragmentations were considered to be initiated by heterolytic
cleavage of the benzylic C–N bond. Upon collisional activation,
the N-benzyltriethylammonium ions first dissociate to form
are spatially separated. The two species within an INC can
rotate with respect to each other, which is one of the most
important and well-know features for a true INC [36]. The
precursor INC-1 is first reoriented to the successor INC-2
through rotation. Within INC-2, the 4-methylbenzyl cation
can donate a proton from the methyl group to the triethyl-
amine leading to the formation of protonated triethylamine.
In contrast to many alkyl cations, the benzyl cations were
generally considered not to be proton donors (i.e., Brønsted
acids). A variety of benzyl cations (listed in Table 1) indeed
do not show reactivity towards proton transfer. As an
exception, the acidity of para methyl group of 4-methylbenzyl
cation is dramatically enhanced by the methylene arenium
character. This result is in agreement with similar phenomenon
observed in solution when a methylene arenium molecule is
coordinated to a metal center via the exocyclic double bond [4,
5]. In contrast, the 3-methylbenzyl cation cannot donate proton
because the positive charge cannot reside at meta position and
therefore the meta methyl group cannot react as a proton donor.
+
[RC6H4CH2 /N(C2H5)3] complexes. Intra-complex reactions
between benzyl cation (or ring-substituted benzyl cation) and
triethylamine produce some interesting product ions, as
summarized in Table 1.
Ammonium ions were commonly observed in the
fragmentation of alkylammonium ions through loss of
alkene. However, no protonated triethylamine was produced
in the fragmentation of a series of benzyltriethylammonium
ions except for N-(4-methylbenzyl)triethylammonium ion
(Cation 9). The FTICR/CID spectrum of Cation 9 is shown
in Figure 1. Three main product ions are observed in this
spectrum, that is, iminium ion (m/z 100), protonated
triethylamine (m/z 102), and 4-methylbenzyl cation (m/z
105). The accurate masses of these ions are consistent with
the assigned structures (Table S1 in the online supplemen-
tary material). The mechanism for formation of ion at m/z
102 is proposed in Scheme 3. INC should be the
intermediate in this reaction because the two reactive sites
Hydride transfer and electron transfer
Besides proton transfer, hydride transfer and electron
+
transfer occur within the [RC6H4CH2 /N(C2H5)3] complex
leading to the formation of iminium ion at m/z 100 and
Table 1. Product Ions Generated in ESI-IT/CID Experiments on N-Benzyltriethylammonium Cationsa
aMass spectra are given in the online supplementary material.
bm/z (Relative abundance %)

Y. Chai et al.: Gas-phase Chemistry of Benzyl Cations
827
Electrophilic Aromatic Substitution
Benzyl cation is an excellent electrophile that it can react
with aromatic compounds by electrophilic attack. The attack
at the phenyl ring has been reported in previous studies [20–
22]. A new case that INC-mediated electrophilic aromatic
substitution reaction between benzyl cation and imidazole
derivatives was observed during the fragmentation of N,N'-
dibenzylimidazolium cations (Table 2). The FTICR/CID
spectrum of Cation 12 is shown in Figure 2. The elemental
compositions of product ions are consistent with the
assigned structures (Table S1 in the online supplementary
material). Taking Cation 12 as an example, the EAS reaction
mechanism is proposed in Scheme 5. The parent ion (m/z
263) initially dissociates to form the precursor complex INC-
5, which can be further transformed to two successor
complexes, INC-6 and INC-7. Within INC-6, addition of
the benzyl cation to the imidazole ring by electrophilic
substitution enables the transfer of a proton to either of the
two phenyl rings. The final product ion at m/z 185 is
generated by loss of a benzene molecule. In other pathways,
the benzyl cation can attack the phenyl ring via INC-7
resulting in the formation of product ions including m/z 185,
m/z 181, and m/z 95, which depends on the shift of the
replaced proton. It is noteworthy that electrophilic substitu-
tion by the benzyl cation can occur at different positions of
the aromatic ring, so product ions at m/z 185 and 181 are
probably mixtures of several isomers, which has been
investigated and demonstrated in the studies of other multi-
benzyl-substituted compounds [20–22]. In this study, the
isomerized product ions are no longer discussed in detail.
However, the product ion at m/z 185 (loss of C6H6) can be
formed from electrophilic attack by the benzyl cation either
at the phenyl ring or at the imidazole ring, which can be
distinguished by the deuterium labeling experiment. In the
fragmentation of N,N'-bis(benzyl-d7)-2-methylimidazolium
cation (Cation 12-d14, m/z 277), both product ions at m/z 193
(loss of C6D6) and m/z 194 (loss of C6HD5 or C4H5DN2) are
formed (Figure S27 in the online supplementary material).
The two ions with different elemental compositions both at
m/z 194 can be further distinguished by determining their
accurate masses. In the FTICR/CID mass spectrum
(Figure S28 in the online supplementary material), the
product ion from loss of C6HD5 appears at m/z 194.1641
(error, 1.5 ppm) and the product ion from loss of C4H5DN2
(1-D-2-methylimidazole) appears at m/z 194.1828 (error,
1.5 ppm). Otherwise, the fragmentation of N,N'-bis(benzyl-
d7)imidazolium cation (Cation 11-d14 in Table 2) generates
product ions at m/z 179 (loss of C6D6) and m/z 180 (loss of
C6HD5). This experiment indicates that electrophilic attack
by the benzyl cation at the phenyl ring and at the imidazole
ring both contribute to the loss of benzene. The product ion
at m/z 171 is obtained from hydride transfer through INC-
8 as shown in Scheme 6.
Figure 1. ESI-FTICR/CID spectrum for fragmentation of
Cation 9 (m/z 206)
radical cation at m/z 101, respectively (Scheme 4). Benzyl
cations are electron-deficient that they can accept either a
pair of electrons (i.e., a hydride) or one electron. Electron-
donating groups can stabilize the benzyl cation so that
fragmentation of the N-benzyltriethylammonium cations
bearing such substituents prefers to generate benzyl cations
while the hydride transfer is not favored and the electron
transfer does not take place (Table 1). As the enhancement
of electron-withdrawing effect of the substituent, the benzyl
cation becomes more electron-deficient so that the propor-
tion of electron transfer reaction increases. For benzyl
cations bearing strong electron-withdrawing groups, the
electron transfer dominates over other reactions. The
observable triethylamine radical cation at m/z 101 is not
the major ion because it can further dissociate to form the
dominant product ion at m/z 86 by loss of a methyl radical or
it may also dissociate to form the ion at m/z 100 by loss of a
hydrogen atom. The ionization energies (IEs) obtained from
the NIST Chemistry WebBook for 3-nitrobenzyl radical,
benzyl radical, and triethylamine are 8.6, 7.24, and 7.53 eV,
respectively, which means the electron transfer between 3-
nitrobenzyl cation and triethylamine is exothermic (1.1 eV),
while the electron transfer between benzyl cation and
triethylamine is endothermic (0.3 eV). Similar arguments
hold true for the other cases. Therefore, the electron transfer
reaction is favorable in the cases of Cations 1, 2, and 3, and
the sufficiently exothermic electron transfer within the INC
also favors the subsequent α-cleavage of the triethylamine
radical cation (m/z 101) to form the N,N-diethylmethylenei-
minium ion (m/z 86).
All the ions produced through benzyl cation rear-
rangement here can be considered as analogues of the
Scheme 3. Proposed fragmentation mechanism for Cation
9 to form protonated triethylamine (m/z 102)

828
Y. Chai et al.: Gas-phase Chemistry of Benzyl Cations
Scheme 4. Proposed fragmentation mechanism for N-benzyltriethylammonium cations to form ions at m/z 100 and m/z 101
benzyl cation. Formation of these ions is related to their
energy threshold and the lifetime of the intermediates.
For Cations 12 and 13, when the imidazole ring is
substituted by a methyl group, its electron density is
increased, thus the electrophilic substitution at the
imidazole ring becomes easier. As shown in Table 2,
the relative abundance of ion a when generated from
Cations 12 or 13 is higher than that from Cation 11.
Actually, the relative abundances of all the product ions
except benzyl cation increase because a methyl substit-
uent (electron-donating effect) makes the corresponding
intermediates and product ions more stable.
those unusual reactions, the benzyl cation reacts as a ring-
charged methylene arenium ion, that is, the nucleophilic
attack by nucleophile takes place at the phenyl ring but
not at the methylene carbon. In the present study, the
fragmentation reactions of various protonated N-haloben-
zyl amines were examined, as shown in Table 3. In the
fragmentation of protonated N,N'-bis(4-halobenzyl)pipera-
zines, loss of hydrogen halide (HX) was observed. The
FTICR/CID spectrum of Cation 15 is shown in Figure 3.
The accurate masses of product ions are consistent with
the assigned structures (Table S1 in the online supple-
mentary material). The product ion at m/z 125 is 4-
chlorobenzyl cation and the ion at m/z 209 derives from
hydride transfer. The proposed mechanism for loss of HX
is given in Scheme 7. Fragmentation of the precursor
cation initially forms INC-9, which then is reoriented to
INC-10 through rotation. Within INC-10, the NH group of
piperazine adds as a nucleophile to the halogen-substituted
Nucleophilic Aromatic Substitution
The gas-phase nucleophilic aromatic substitution reactions
of halobenzyl cations with piperazine (or N-methylpiper-
azine) via INC had been reported in a recent work [8]. In
Table 2. Product Ions Generated in ESI-IT/CID Experiments on N,N'-Dibenzylimidazolium Cationsa
aMass spectra are given in the online supplementary material.
bm/z (Relative abundance %)

Y. Chai et al.: Gas-phase Chemistry of Benzyl Cations
829
ring carbon to form a σ complex, which should be the
key step in this reaction. The nature of X affects the rate
of this step because an increase in the electron-withdraw-
ing character of X causes a decrease in the electron
density at the site of attack, resulting in a faster attack by
a nucleophile. Thus, fluoride is the best leaving group
among the halogens in most aromatic nucleophilic
substitutions, which is different from the SN1 and the
SN2 mechanisms, where fluoride is by far the poorest
leaving group of the halogens [52]. In the reaction of 1-
substituted-2,4-dinitrobenzenes with piperidine in metha-
nol, when the substituent was F, the relative rate was
3300 compared with I=1 [53]. The very fact that the
tendency for loss of HX in the fragmentation of
protonated N,N'-bis(4-halobenzyl)piperazines HF 99HCl9
HBr9HI is a good evidence for the nucleophilic aromatic
substitution reaction mechanism. Besides the kinetic
factor, the highly favorable thermochemistry of HF can
Figure 2. ESI-FTICR/CID spectrum for fragmentation of
Cation 12 (m/z 263)
Scheme 5. Proposed mechanism for EAS reactions in the fragmentation of Cation 12

830
Y. Chai et al.: Gas-phase Chemistry of Benzyl Cations
Figure 3. ESI-FTICR/CID spectrum for fragmentation of
Cation 15 (m/z 335)
Only loss of DCl was observed in the fragmentation of
deuterated N,N'-bis(4-chlorobenzyl)piperazine (Cation 19).
These results further proved the nucleophilic aromatic
substitution mechanism for loss of HX in the fragmenta-
tion of protonated N,N'-bis(4-halobenzyl)piperazines.
Scheme 6. Proposed mechanism for formation of ions d
and e in the fragmentation of Cation 12
Furthermore, the nucleophilic aromatic substitution reaction
between different amines and 4-chlorobenzyl cation were
investigated. In the comparison of piperidine, piperazine, N-
methylpiperazine, and morpholine (Table 3), it is quite
interesting and a wonder that only piperazine and N-methyl-
piperazine can be involved in such reactions, but the piperidine
and morpholine cannot react with 4-chlorobenzyl cation to lose
HCl. Experimental and theoretical studies indicate that the
nucleophilicity of piperidine is stronger than that of piperazine
[54, 55], so the nucleophilicity is probably not the reason.
When the amine is diethylamine, diisopropylamine, or pyrro-
lidine, the loss of HCl is not observed as well (Figures S24–S26
in the online supplementary material). The hydride transfer
reaction between these amines and 4-chlorobenzyl cation all
can take place. At present, it seems that only amines
containing piperazine structure can react with halobenzyl
cations to lose hydrogen halide by nucleophilic attack at the
phenyl ring. A proposed mechanism for such a special
reaction is shown in Scheme 8 in which an intermediate Int-
N2 is supposed to be involved between the two INCs (INC-
11 and INC-12). Although the components within an INC
are able to rotate almost freely, the transformation from
INC-11 to INC-12 is unfavorable for N-(4-chlorobenzyl)
amines without piperazine moiety, probably because other
competing reactions are preferred and the lifetime of INC-11
is not long enough for the transformation. The time
constraint is an important factor influencing the INC-
mediated reactions [24]. However, for N-(4-chlorobenzyl)
piperazine and analogues, the formation of INC-12 can be
assisted by the second nitrogen atom (N2) through forming
an intermediate Int-N2. Int-N2 may also be formed from the
precursor ion through 4-chlorobenzyl cation transfer from N1
to N2 (not shown in the scheme). In Int-N2, the N1H group
faces to and interacts with the phenyl ring, but the distance
between it and the chlorine substituent is still long. After
cleavage of the benzylic C–N2 bond, N1H moves closely to
the phenyl ring to form INC-12. This interesting issue is
be another reason for the efficient loss of HF. In the
resonance of a benzyl cation, the positive charge cannot
reside at the meta position of the phenyl ring where,
hence, nucleophilic attack can not occur, so the meta-
chloro-substituted cation (Cation 16) cannot lose HCl.
Table 3 Product Ions Generated in ESI-IT/CID Experiments on Protonated
N-Halobenzyl Aminesa
aMass spectra are given in the online supplementary material.
bm/z (Relative abundance %)
cLoss of DX

Y. Chai et al.: Gas-phase Chemistry of Benzyl Cations
831
Scheme 7. Proposed mechanism for loss of HX in the fragmentation of protonated N,N'-bis(4-halobenzyl)piperazines
worthy of being further studied in the future, and high-level
theoretical calculations may provide useful help.
electron-deficiency character of benzyl cations, especially
those that bear a strong electron-withdrawing group, enables
them to be electron acceptors to obtain an electron from tertiary
amines with low ionization energy.
This study improves and enriches the gas-phase chemis-
try of benzyl cations. The general knowledge on ion/neutral
complex-mediated reactions between benzyl cations and the
neutral counterpart is also useful for understanding the
fragmentation reactions of N-benzylated compounds.
Conclusions
In this study, N-benzylammonium and N-benzyliminium ions
were studied by collisional activation in an ion-trap or Fourier
transform ion cyclotron resonance mass spectrometer. The ion/
neutral complexes consisting of the benzyl cations and the N-
containing counterparts were proposed as intermediates to
rationalize the fragmentation reactions of these ions. Five types
of reactions within the complex, namely proton transfer,
hydride transfer, electron transfer, electrophilic aromatic
substitution, and nucleophilic aromatic substitution, were
observed and comprehensively investigated.
Acknowledgments
The authors gratefully acknowledge financial support from
the National Science Foundation of China (no. 21025207
and no. 20975092).
The positive charge delocalization within the benzyl cation
(or the ring-substituted benzyl cation) contributes to the
diversified reactivities of the benzyl cations. When the charge
is mostly localized at the methylene group, it can react as a
Lewis acid to capture a hydride ion from the neutral amines, or
react as an electrophile to attack the neutral aromatic rings.
When the charge is localized predominantly in the ring, it can
activate the para-methyl group to release a proton as a
Brønsted acid, or act as a substrate for nucleophilic aromatic
substitution at the phenyl ring in which the para-halogen
groups can be replaced by a piperazine or analogues. The high
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