The role of ion/neutral complexes in the fragmentation of N-benzyl-(alkylpyridinium) ions

Article abstract of DOI:10.1016/j.ijms.2010.10.006

N-Benzylpyridinium ions bearing an alkyl group at the pyridine nucleus were studied as potential precursors of gaseous ion/neutral complexes. The occurrence of I/N complexes [C₆H₅CH₂ ⁺ ? alkylpyridine] was probed by the reactivity of the potential benzylic hydride donor sites present in the ortho-, meta- and para-alkyl groups (R = methyl, ethyl, isopropyl and benzyl). Collision-induced dissociation of the ions, carried out in an electrical ion cage mass spectrometer, revealed that hydride transfer strongly depends both on the energy requirements of the hydride transfer but also on the position of the hydride donor. Hydride transfer, giving rise to the loss of toluene, was found to occur exclusively with those N-benzylpyridinium ions which bear an isopropyl or a benzyl substituent in the ortho position of the pyridine ring, thus reflecting the intermediacy of I/N complexes. All of the putative hydride donor alkyl groups were found to be non-reactive in the meta and para positions, as were methyl and ethyl groups even in the ortho positions. Density functional calculations (B3LYP/6-311+G/3d,2p)//(B3LYP/6-31+G(d)) on the hydride-transfer and simple-cleavage channels were carried out to help rationalizing these observations. The results suggest that the intra-complex hydride abstraction from the 3- and 4-isopropyl- and from the 3- and 4-benzylpyridine neutrals, although being thermodynamically favorable, is suppressed by substantial intra-complex rotational (or reorientation) barriers.

Full text of DOI:10.1016/j.ijms.2010.10.006

International Journal of Mass Spectrometry 306 (2011) 159–166
Contents lists available at ScienceDirect
International Journal of Mass Spectrometry
journal homepage: www.elsevier.com/locate/ijms
The role of ion/neutral complexes in the fragmentation of N-benzyl-
(alkylpyridinium) ions
Dietmar Kuck∗, Hans-Friedrich Grützmacher, Dieter Barth, Sandra Heitkamp, Matthias C. Letzel
Department of Chemistry, Bielefeld University, Universitätsstraße 25, 33615 Bielefeld, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
N-Benzylpyridinium ions bearing an alkyl group at the pyridine nucleus were studied as potential pre-
cursors of gaseous ion/neutral complexes. The occurrence of I/N complexes [C6H5CH2 ··· alkylpyridine]
+
Received 7 September 2010
Received in revised form 6 October 2010
Accepted 7 October 2010
was probed by the reactivity of the potential benzylic hydride donor sites present in the ortho-, meta-
and para-alkyl groups (R = methyl, ethyl, isopropyl and benzyl). Collision-induced dissociation of the
ions, carried out in an electrical ion cage mass spectrometer, revealed that hydride transfer strongly
depends both on the energy requirements of the hydride transfer but also on the position of the hydride
donor. Hydride transfer, giving rise to the loss of toluene, was found to occur exclusively with those
N-benzylpyridinium ions which bear an isopropyl or a benzyl substituent in the ortho position of the
pyridine ring, thus reflecting the intermediacy of I/N complexes. All of the putative hydride donor alkyl
groups were found to be non-reactive in the meta and para positions, as were methyl and ethyl groups
even in the ortho positions. Density functional calculations (B3LYP/6-311+G/3d,2p)//(B3LYP/6-31+G(d))
on the hydride-transfer and simple-cleavage channels were carried out to help rationalizing these obser-
vations. The results suggest that the intra-complex hydride abstraction from the 3- and 4-isopropyl- and
from the 3- and 4-benzylpyridine neutrals, although being thermodynamically favorable, is suppressed
by substantial intra-complex rotational (or reorientation) barriers.
Available online 14 October 2010
Dedicated to Professor Tino Gäumann on
the occasion of his 85th birthday.
Keywords:
Benzylpyridinium ions
Ion/neutral complexes
Reorientation
Hydride ion transfer
Proton transfer
Alkylpyridines
© 2010 Elsevier B.V. All rights reserved.
1. Introduction
as reactive intermediates during mass spectrometric fragmenta-
tion [22–30]. As has been shown, a large number of metastable
N-Benzylpyridinium ions are well known in mass spectrometry
for their role as suitable species to probe the internal energy deposi-
tion on ions generated under various ionization conditions [1–11].
The propensity of such “thermometer ions” to cleanly undergo dis-
sociation of the benzylic C–N bond depends not only on the external
conditions of the ion source but, in particular, on the electronic
properties of the reactant. Therefore, various electron-releasing
and electron-withdrawing substituents have been introduced into
the benzylic moiety of the N-benzylpyridium ion to affect the
energy requirements of the C–N bond cleavage. The readiness to
release the corresponding C7H6X+ ions, which should mostly retain
their (original) benzylic structure but are also believed to partially
rearrange by ring expansion to tropylium ions [9,10], provides a
suitable indicator for the mildness or roughness of the ionization
conditions.
tert-butylbenzenium and related [M+H]+ ions eliminate isobutane,
necessarily formed via an intra-complex hydride transfer, rather
+
than just releasing the tert-C4H9 ion or eliminating isobutene by
intra-complex proton transfer. Similar to the N-benzylpyridinium
ions, even tiny differences in the “electronic” conditions of the reac-
tants strongly affect the relative weight of the hydride transfer
process [24,25,27].
Recently, the fragmentation of various di-, tri- and tetraben-
zylammonium ions was found to occur predominantly via I/N
complexes, reflecting the intra-complex reactivity of benzyl cations
towards the aromatic ␲-systems and benzylic hydride donor sites
of the neutral constituent [31]. A very recent paper reported on the
substituent effects on the fragmentation of N-benzylpiperidinium
and N-benzylpiperazinium ions bearing various electronically
active substituents (X) in the benzylic moiety of the reactants
[32]. Again, hydride transfer leading to the loss of the correspond-
ing toluene derivatives was indicative of I/N complexes, such as
However, gaseous N-benzylpyridinium ions could be ideal
species to study another important probe reaction, namely,
intramolecular hydride transfer. This process has been used exten-
sively to probe the formation of ion/neutral complexes [12–21]
+
[X–C6H4CH2 ···· c-(CH2)5NH], as reactive intermediates during the
fragmentation of such relatively simple cyclic ammonium ions.
In view of all these findings, we raised the question whether
suitable N-benzyl-(alkylpyridinium) ions, bearing alkyl groups as
potential hydride donor sites at the heterocyclic moiety, would
represent useful model ions for probing the intermediacy of I/N
∗
Corresponding author. Tel.: +49 521 106 2060; fax: +49 521 106 6417.
E-mail address: dietmar.kuck@uni-bielefeld.de (D. Kuck).
1387-3806/$ – see front matter © 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.ijms.2010.10.006

160
D. Kuck et al. / International Journal of Mass Spectrometry 306 (2011) 159–166
CHRR'
+
+
CH2
R
C
ESI
CID
N
R'
− Br−
−
N
H
Br
Ion/neutral complex
M+ Br−
(R, R' = alkyl, phenyl)
hydride
transfer
'direct'
cleavage
?
+
CH2
CH3
+
CRR'
CHRR'
+
+
N
N
d (92 u)
a (m/z 91)
c
b
Scheme 1. Fragmentation of N-benzyl-(alkylpyridinium) ions, generated by ESI from the corresponding bromides, via two competing channels under ESI/CID conditions:.
Benzylic cleavage (left) and rearrangement via an I/N complex (right).
complexes during fragmentation (Scheme 1). To the best of our
knowledge, this variant has never been applied to benzylpyri-
dinium thermometer ions. In the present work, we report our
results on the fragmentation of a set of N-benzyl-(alkylpyridinium)
ions (M+) which, after collisional activation in an ion cage mass
spectrometer, should be able to undergo the ‘direct’ dissocia-
(10 mmol) in dichloromethane (15 mL) for 5−6 h. Stirring was con-
tinued overnight. The reaction was monitored by TLC and mostly
driven to completion. Removal of the solvent under reduced pres-
sure gave crystalline products or viscous oils. These crude products
were subjected to the ESI measurements in most cases.
Some of the alkylpyridines were not commercially available. The
2-, 3- and 4-isopropylpyridines were prepared by Grignard reaction
of the respective picolinic acid methyl or ethyl esters with methyl
magnesium iodide. The resulting pyridyl carbinols were reduced
by use of hydroiodic acid and red phosphorous at 150−160 ◦C
[33]. Work-up including kugelrohr distillation (85−90 ◦C, 7 mbar)
gave the corresponding isopropylpyridines in moderate yields
(ortho, 43%; meta 20%; and para, 44%) as colorless liquids. 3-
Benzylpyridine was synthesized by Wolff–Kishner reduction of
3-benzoylpyridine (675 mg, 3.7 mmol) with hydrazine hydrate
(600 ␮L) and powdered potassium hydroxide (800 mg) in diethy-
lene glycol (10 mL). The mixture was heated to reflux (130 ◦C)
for 5 h and then the temperature was slowly increased to 195 ◦C
and kept for 2.5 h. Work-up gave a crude product (650 mg) and
subsequent kugelrohr distillation yielded the product (385 mg,
62%) as a colorless liquid. 1H NMR spectroscopy confirmed the
purity of the compound. The N-[D7]benzyl-2-benzylpyridinium
+
tion reaction giving the (parent) C7H7 ions (a) and the neutral
alkylpyridines b and, in competition, the elimination reaction gen-
erating the corresponding (␣-substituted) azabenzylium ions c and
toluene (d) by intra-complex hydride transfer. In this case, differ-
ent from all the previous studies, the electronic properties of the
alkyl-substituted pyridine moiety as a leaving group and/or as a
hydride donor should govern the course of the fragmentation and,
in particular, the role of the putative ion/neutral complexes.
2. Experimental
2.1. Compounds
The N-benzyl-(alkylpyridinium) bromides (Scheme 2) were syn-
thesised by heating solutions of the appropriate alkylpyridines
(10 mmol) (see below) and freshly distilled benzyl bromide
X
X
3a
3b
3c
4a
4b
4c
X
2-methyl
3-methyl
4-methyl
2-ethyl
2-isopropyl
3-isopropyl
4-isopropyl
2-benzyl
1a
1b
1c
2a
2b
2c
+
+
N
N
D
D
CD2
D
D
3-ethyl
4-ethyl
3-benzyl
4-benzyl
D
[D7]-4a Br−
1a−4c Br−
Scheme 2. Compounds and ions studied.

D. Kuck et al. / International Journal of Mass Spectrometry 306 (2011) 159–166
161
Table 1
Relative reaction enthalpiesa,b, ꢀHdiss and ꢀHelim, for fragmentation of selected N-benzyl-(alkylpyridinium) ions and relative enthalpies of the I/N complexes and the
transition state for the hydride transfer step [/B3LYP/6-311+G(3d,2p)//B3LYP/6-31+G(d)].
Pyridinium ion
Ion/neutral complex ꢀHINC
M+ → a + b ꢀHdiss
TS of H− transfer ꢀHTS
M+ → c + d ꢀHelim
1a
1c
2a
2c
3a
3c
4a
4c
158.4
164.1
157.7
164.0
169.7
167.9
n.d.
202.4
214.2
201.4
215.9
211.3
219.5
206.8
220.1
228.1
258.2
181.6
206.3
173.3
178.0
n.d.
252.4
294.6
178.5
227.1
123.2
164.2
130.0
165.1
n.d.
n.d.
a
Obtained from the total electronic energies (Etotal) and the standard enthalpies (H◦298) relative to those of the respective N-benzyl-(alkylpyridinium) ions.
b
Given in kJ mol−1
.
bromide [D7]-4a Br− was prepared using perdeutero benzyl bro-
mide prepared from commercially available [D8]-toluene (Merck, D
content >99.5%).
culations of the ion/neutral complexes converged very slowly, and
at the end of the optimization procedure the calculation oscillated
between various similar structures which differed in Etotal by less
than 5 kJ mol−1 and were distinguished only by a small rotation of
the methyl groups of the substituent.
2.2. Mass spectrometric measurements
ESI(+)/CID mass spectra were recorded by use of an Esquire 3000
ion trap (ion cage) mass spectrometer (Bruker Daltonik GmbH,
Bremen, Germany) equipped with a standard nanoESI source. Sam-
ples were introduced as dichloromethane solutions by self-made
nanospray needles. Isolation of the ions prior to CID was done
using a small isolation window of about 1 u. Nitrogen, generated
by a Bruker nitrogen generator NGM 11, was used as a drying gas.
Helium served as a cooling gas for the ion trap and as a collision gas
for MS/MS experiments. The spectra shown were recorded with the
Bruker Daltonik Esquire NT 5.2 Esquire Control software by accu-
mulating and averaging several single spectra. DataAnalysisTM 3.4
was used for spectra processing.
3. Results and discussion
3.1. Collision-induced dissociation of N-benzyl-(alkylpyridinium)
ions
A set of twelve N-benzyl-(alkylpyridinium) bromides, 1a Br−
to 4c Br−, and one deuterium-labelled analogue, [D7]-4a Br−
(Scheme 2), were prepared in dichloromethane solutions and
subjected to electrospray ionization in an electrical ion cage.
The collision-induced dissociation of the corresponding free pyri-
dinium ions was determined under similar conditions and found to
be relatively insensitive against variations in the collision potential.
+
As expected, the release of C7H7 ions was found to be ubiquitous
2.3. Computational methods
and dominant in all cases. In fact, and to some extent surprisingly,
all of the methyl- and ethylpyridinium ions 1a–1c and 2a–2c dis-
sociated by exclusive loss of the alkylpyridine neutral; no hydride
transfer or any other fragmentation process occurred. Moreover,
the same holds true for all of the N-benzylpyridinium ions bear-
ing alkyl substitutents of any kind at the meta or para positions
All calculations were performed with the Gaussian 03 package
[34] using the hybrid DFT functionals at the level B3LYP/6-
311+G(2d,3p//B3LYP/6-31G(d)). Wong and Radom have recom-
mended this procedure as a good compromise between reliability
and economy of the computation of large systems [35]. The struc-
tures of the N-benzylpyridinium ions studied here and carrying
the alkyl substituent at the ortho- or para-position, of their rel-
evant fragmentation products and of the reaction intermediates
were optimized using the basis set 6-31+G(d), and harmonic vibra-
tional analysis of the optimized structures were performed at this
level. All calculated species have the correct number of imaginary
frequencies, i.e., zero for stable ions, molecules and ion-neutral
complexes and one for transition states. In the latter case, visu-
alization by the GaussView program was used to ensure that the
imaginary frequency corresponds to the correct movement of
atoms along the respective reaction coordinate. Single point cal-
culations of the optimized structures by B3LYP with the basis set
6-311+G(3d,2p) yielded the total electronic energy, Etotal, which
was converted to the enthalpy H298 at 298 K by correction with the
zero point energy and the thermal enthalpy correction taken from
the harmonic vibrational analysis. The reaction enthalpies ꢀHr rel-
ative to the corresponding parent N-benzylpyridinium ion, which
are presented in Table 1 and which are used in the discussion, were
+
(e.g., 3b–3c and 4b–4c). Again, formation of C7H7 was observed
as the only fragmentation pathway. The latter finding was surpris-
ing since the benzyl substituent, in particular, on the pyridine ring
was expected to provide two amply activated hydride donor C–H
bonds.
However, significant elimination of C7H8 (most probably as
toluene) was found to occur in two cases, viz., the ortho-isopropyl-
(3a) and the ortho-benzylpyridinium (4a) ions. The contrast
between the positional isomers is illustrated for the case of the
two isopropyl analogues 3a and 3c in Fig. 1, and the correspond-
ing CID spectrum of the ortho-benzyl analogue 4a is shown in
Fig. 2. Although the formation of ions [3a−C7H8]+ and [4a−C7H8]+
+
falls far short of that of the C7H7 ions, their relative abundances
are in line with expectation: The ortho-benzyl substituent repre-
sents a slightly better hydride donor than the isopropyl group, as
reflected by the ion abundance ratios {[4a−C7H8]+}:{C7H7 } = 0.17
+
and {[3a−C7H8]+}:{C7H7 } = 0.069. Interestingly, the ortho-benzyl
+
analogue 4a was found to react through a third fragmentation
channel, viz. loss of C6H6. Benzene elimination is known as a charac-
teristic feature of protonated alkylbenzenes and their derivatives
[36–38]; therefore, the observation of ions [4a−C6H6]+ indicates
the formation of substituted benzenium (or arenium ions) [39] as
reactive intermediates in the fragmentation of the ortho-benzyl-
substituted N-benzylpyridinium ions 4a. Since both the loss of
toluene and of benzene from ions 4a should occur via reactive
benzyl cations released into ion/neutral complexes (vide infra), the
calculated from the values of H298
.
It should be mentioned that pre-optimization of the struc-
tures by the semi-empirical method AM1 was used to obtain good
starting structures for the DFT calculations, which ensured fast con-
vergence of the calculations. However, the optimized structures of
transition states and of ion/neutral complexes obtained by AM1 and
by B3LYP, turned out to be very different. Further, the B3LYP cal-

162
D. Kuck et al. / International Journal of Mass Spectrometry 306 (2011) 159–166
Fig. 1. ESI/CID mass spectra of the 2- and 4-isopropyl-substituted N-benzylpyridinium ions 3a (top) and 3c (bottom). The signals at m/z 213 and 214 are due to the mostly
non-activated naturally occurring [13C1]-isotopomers.
latter intermediates are crucial to the formation of a relatively large
amount of fragment ions relative to that of the “normal” C7H7+ ions,
4a involves non-classical transition states instead of non-covalently
bound intermediates, a situation which could be envisioned for the
ortho-substituted species but not in the meta and para isomers.
In this respect, however, the observation of benzene loss from
the benzyl analogue 4a is particularly telling. This fragmenta-
tion necessarily requires the formation of a non-covalently bound
intermediate, in which the benzyl cation released from the nitro-
gen atom can attack the ␲-system of the other benzyl group to
form an ipso-protonated diphenylmethane (benzylbenzenium ion
5, Scheme 3). Such arenium ions are known to undergo both a slow
interannular and a fast intraannular proton transfer (proton ring
walk) prior to the loss of benzene [36–40]. In the present case, the
basic 2-pyridyl group may also interfere in the “proton dance” [41]
but it is obvious that one of the mobile protons is transferred to the
terminal benzene ring of ion 5, giving rise to isomer 6 from which
benzene is lost eventually. (Note that the related ring-protonated
tautomers and other tautomeric arenium ions that may be envi-
sioned in this process are not shown in Scheme 3). Admittedly, the
structure of the final fragment ion [4a−C6H6]+ (m/z 182) depicted
in Scheme 3 is tentative. However, this ion is believed to be the
({[4a−C7H8]+} + {[4a−C6H6]+}):{C7H7 } = 0.48.
+
3.2. Fragmentation via ion/neutral complexes
We assume that the cleavage of the benzylic C–N bond in all
of the N-benzylpyridinium ions generates ion/neutral complexes,
as insinuated in Scheme 3. As shown above, most of these inter-
mediates are non-reactive in that they simply dissociate without
any further intra-complex reaction, giving rise to the exclusive
+
or far predominant formation of C7H7 ions. Only the I/N com-
plexes generated from the ortho-isopropyl and the ortho-benzyl
analogues 3a and 4a, respectively, containing neutral alkylpyri-
dine constituents with strongly activated tertiary or benzylic C–H
bonds as hydride donors, are able to eliminate toluene. It appears
that this specificity reflects the vicinity of the N-benzyl group and
the hydride-donor methyne or methylene groups, respectively, as
a peculiar kind of ortho effect occurring within the ion/molecule
complexes. It might be argued that the loss of toluene from 3a and
Fig. 2. ESI/CID mass spectrum of the 2-benzyl-substituted N-benzylpyridinium ion 4a.

D. Kuck et al. / International Journal of Mass Spectrometry 306 (2011) 159–166
163
X = CH3 and C2H5
X = meta- and para-CH(CH3)2
X = meta- and para-CH2C6H5
simple cleavage
100% Σ
+
+
CH2
CH2
in all cases
X
X
+
X = ortho-CH(CH3)2
X = ortho-CH2C6H5
N
93 %Σ
67% Σ
N
(m/z 91)
I/N complexes
hydride
electropilic
attack
21% Σ
hydride
X =
X =
X =
transfer
transfer
ortho-CH2C6H5
ortho-CH2C6H5
ortho-CH(CH3)2
11% Σ
7% Σ
CH3
CH3
+
+
+
+
N
N
N
+
H
[3a − C7H8]+
(m/z 120)
[4a − C7H8]+
(m/z 168)
5
N
H
+
+
+
N
[4a − C6H6]+
(m/z 182)
6
Scheme 3. Fragmentation of the ion/neutral complexes as both non-reactive and reactive intermediates during the fragmentation of alkyl-substituted N-benzylpyridinium
ions 1a–4c.
+
most stable ionic fragment formed by benzene loss from ions 4a
and its formation via ions 5 and 6 necessarily requires an intra-
complex electrophilic attack of C7H7 ions at the ortho-position of
group (Fig. 3). Besides the expected formation of ions C7D7 (m/z
98) formed by the direct C–N bond cleavage reaction, loss of
[D7]toluene and [D5]benzene were observed, giving rise to the ions
at m/z 168 and m/z 184, respectively. The formation of the latter
ions, in particular, reveals that the original N-benzylic (dideutero)
methylene unit is incorporated into the fragment ion, a typical
feature of the intermolecular methyne-group transfer of benzyl
cations and related electrophiles (X–CH2+) to aromatic partners
[36–39,42]. Interestingly, a minor amount of the ions undergoes
+
the 2-benzylpyridine constituent.
The mechanism proposed above strongly corroborates the
+
intermediacy of ion/neutral complexes [C6H5CH2 ··· alkylpyri-
dine] in general, as depicted in Scheme 3. It is confirmed by
the fragmentation of the isotopomer [D7]-4a, which contains a
fully deuterium-labelled N-benzyl and an unlabelled ortho-benzyl
Fig. 3. ESI/CID mass spectrum of the N-[D7]benzyl-2-benzylpyridinium ion [D7]-4a.

164
D. Kuck et al. / International Journal of Mass Spectrometry 306 (2011) 159–166
+
CH2
a
+
CH3
N
CH(CH3)2
+
CH3
+
a + b
N
CH3
211
TS
INC
173
170
c + d
123
+
CH3
CH3
N
H
3a
0
b
+
CH(CH3)2
CH2
H3C
CH3
+
+
CH3
N
+
a + b
N
220
TS
INC
c + d
178
H
168
164
H3C
CH3
+
N
3c
0
Fig. 4. Energy profiles for the simple C−N bond cleavage (a + b) and the elimination of toluene (c + d) of the N-benzyl-(isopropylpyridinium) ions 3a and 3c, as calculated by
B3LYP/6-311+G(3d,2p)//B3LYP/6-31+G(d) (kJ mol−1).
an intramolecular H/D exchange which, again, is typical for proto-
nated diphenylmethane and its higher homologues [36–38,40,43]
and which, on its own, can be used as a structural probe reaction
1c–4c. The data relevant for the present discussion are collected in
Table 1 as enthalpy differences ꢀH◦
comparing the combined
298
products of fragmentation, the I/N complexes and the transition
states for the hydride transfer relative to the enthalpies of the par-
ent N-benzyl-(alkylpyridinium) cations. (On request, the full details
of the calculations can be obtained from the authors.) The energy
requirements for the dissociation does not depend on the nature
of the alkyl substituent (ꢀHdiss = 206 5 kJ mol−1 was calculated
for the ortho-substituted ions and ꢀHdiss = 217 3 kJ mol−1 for the
para-substituted congeners). In all cases, the I/N complexes were
found to be more stable than the dissociation products (a + b) by
+
[44]. Finally, the formation of C7HD6 ions (m/z 97) along with the
+
expected C7D7 ions (m/z 98) should be noted. Their occurrence
points either to the reversibility of the whole isomerization pro-
+
cess (with the fraction of C7HD6 being eventually released from
the pyridine N atom) or to a competing protonolytic cleavage of
the diphenylmethane moiety in the intermediate ion 5. Notably,
+
the occurrence of the ions C7HD6 should not be considered a hint
to the ring expansion of the benzyl cations released from the “ther-
mometer ions” discussed in the literature [9,10].
ꢀHdiss − ꢀHINC = 46 5 kJ mol−1
.
By contrast to the dissociation reaction, the reaction enthalpy
computed for the elimination of toluene decreases from
ꢀHelim = 252 kJ mol−1 for the ortho-methyl derivative 1a to
ꢀHelim = 123 kJ mol−1 and ꢀHelim = 130 kJ mol−1 for the ortho-
isopropyl and ortho-benzyl congeners, 3a and 4a, respectively.
Clearly, “localized bond activation”, a long-established concept in
organic mass spectrometry [45–47], strongly affects this reaction
channel, as presumed. As a consequence, fragmentation via the
3.3. Computational results
To shed some more light on the fragmentation of the N-benzyl-
(alkylpyridinium) ions, we calculated the energy requirements
for direct dissociation giving the benzyl cation and the alkylpyri-
dine and for the hydride transfer reaction yielding toluene and an
azabenzyl cation for the ortho-isomers 1a–4a and the para-isomers

D. Kuck et al. / International Journal of Mass Spectrometry 306 (2011) 159–166
165
hydride transfer route is energetically more favorable than the
direct dissociation in the case of the ortho-ethyl derivative 2a, both
of the isopropyl derivatives 3a and 3c, and also for both of the
benzyl derivatives 4a and 4c. In fact, the decomposition of the I/N
complexes, which is always endothermic for the direct dissociation
channel, becomes exothermic for the toluene loss from both of the
isopropyl-substituted ions 3a (ꢀHelim − ꢀHINC = − 47 kcal mol−1
)
and 3c (ꢀHelim − ꢀHINC = − 4 kcal mol−1), as illustrated in Fig. 4.
Very likely, this holds also true for the benzyl-substituted ions
4a and 4c. However, while the direct dissociation of the I/N
complexes does not require any additional activation exceeding
the reaction enthalpy, the hydride transfer within the I/N complex
is expected to proceed over an activation barrier. We were able
to locate transition states for this process; their enthalpies, ꢀHTS
,
relative to the parent N-benzyl-(alkylpyridinium) ions are also
collected in Table 1. In the case of ions 1a, 1c and 2c, for which
the elimination of toluene is calculated to be thermodynamically
unfavorable, considerable activation enthalpies, ꢀHTS − ꢀHINC
,
relative to the I/N complexes were obtained (ca. 70, 94 and
42 kJ mol−1, respectively). The corresponding structures represent
transition states, in which the transfer of the migrating hydride
and formation of the toluene molecule is almost complete. By
contrast, in the case of the remaining parent ions 2a, 3a and
3c, the activation barriers for hydride transfer within the I/N
complexes are quite small (ca. 24, 4 and 10 kJ mol−1, respectively)
and the transition states exhibit the expected “normal” structures.
Since the activation enthalpies of the hydride transfer are small
and elimination of toluene is energetically more favorable than
the direct dissociation of the I/N complexes, the computational
results suggest that the toluene elimination route should be
observable for the N-benzyl-(alkylpyridine) ions 2a and 3a–3c, and
likely for all of the N-benzyl-(benzylpyridinium) isomers 4a–4c
as well.
Fig. 5. Minimum structures of the ion/neutral complexes generated from (a)
the N-benzyl-(ortho-isopropylpyridinium) ion 3a and (b) the N-benzyl-(para-
isopropylpyridinium) ion 3c, as calculated by B3LYP/6-311+G(3d,2p)//B3LYP/6-
31+G(d). The dashed lines indicate the shortest atomic distances between the
constituents of the I/N complexes.
Nonetheless, the experiments show that toluene elimination
is only significant for the ortho-substituted ions 3a and 4a. This
contrast between the experimental and computational results dis-
cussed so far is striking. Obviously, an additional effect is operating
which hinders the hydride transfer within the I/N complexes of
the meta- and para-isomers even if this route is energetically sig-
nificantly more favorable than the direct dissociation of the I/N
complexes. We suggest that this is an entropic effect which is due
to fact that direct dissociation of the I/N complexes is possible for all
conformations and all mutual orientations of the two components,
the benzyl cation and the alkylpyridine, within the I/N complex,
while the hydride transfer requires a specific relative orientation
of the components to proceed towards the transition state. Closer
inspection of the optimized structures of the I/N complexes shows
that all these structures are similar and exhibit a rather tight aggre-
gation of the benzyl cation to the nitrogen atom of the neutral
alkylpyridine by two hydrogen bonds between an H atom of the
methylene group and an H atom at the ortho-position of the benzyl
cation. This is shown in Fig. 5 for the I/N complexes arising from
the two isopropyl-substituted ions 3a and 3c. In the case of the
ortho-isomer 3a, the benzyl cation is situated in the neighborhood
of the isopropyl group and the changeover to the transition state of
the hydride transfer requires only a small shift of the benzyl cation.
Obviously, this is a very favorable case for the successful competi-
tion of the toluene elimination with the direct dissociation of the
I/N complex. At variance from the ortho-isomer 3a, the hydride
transfer within the I/N complex formed from the para-isopropyl
isomer 3c requires a complete reorientation of its components to
achieve the transition state structure, which obviously cannot com-
pete with its direct dissociation. In general, it is postulated that the
ionic component of an I/N complex is free to change its orienta-
tion and to move over quite large molecular distances. However,
this may be an oversimplification in particular for I/N complexes
such as those studied here. In fact, the benzyl cation is of similar
size as the neutral component, the alkylpyridine, and the positive
charge is well delocalized. The separation from the N atom, being
the negative end of the dipolar alkylpyridine, may allow the bulky
benzyl cation to leave the sphere where electrostatic attraction
keeps the components of the I/N complex together; as a conse-
quence, the complex dissociates instead of adopting a reoriented
constellation that would allow the hydride transfer to occur. Obvi-
ously, this scenario occurs for the I/N-complexes of both the meta-
and the para-somers.
As mentioned above, it can be argued that the loss of toluene
from the energetically suitable ortho-alkylpyridinium ions may
take place by a concerted process and not involve a reactive I/N
complexes at all. This would mean that the meta- and para-isomers
do not eliminate toluene because such concerted processes are
mechanistically impossible in these cases. However, the finding
that the ortho-benzyl analogue 4a also fragments by elimination
of benzene necessarily requires the interplay of a non-covalently
bound intermediate, as shown in Scheme 3. Of course, the elec-
+
trophilic attack of the C6H5CH2 ion, after its release from the
pyridine nitrogen atom, at the ortho-benzyl group may also happen
within a relatively tight aggregate, and reorientation of its con-
stituents to a more loosely bound I/N complex is intercepted by
the subsequent rearrangement steps [48]. On the whole, however,
and in view of their thermodynamic stability as compared to the
simple C–N bond cleavage, it appears that ion/neutral complexes
+
of the general form [C6H5CH2 ··· alkylpyridine] are involved in the
fragmentation of the N-benzyl-(alkylpyridinium) ions investigated
here.

166
D. Kuck et al. / International Journal of Mass Spectrometry 306 (2011) 159–166
4. Conclusion
[16] P. Longevialle, Mass Spectrom. Rev. 11 (1992) 157.
[17] T.H. Morton, Org. Mass Spectrom. 27 (1992) 353.
[18] D.J. McAdoo, T.H. Morton, Acc. Chem. Res. 26 (1993) 295.
[19] A.G. Harrison, J.Y. Wang, Int. J. Mass Spectrom. Ion Processes 160 (1997) 157.
[20] T.H. Morton, in: P.B. Armentrout (Ed.), Encyclopedia of Mass Spectrometry, vol.
1, Elsevier, Amsterdam, 2003 (Chapter 6, pp. 467–479).
[21] T.H. Morton, in: N.M.M. Nibbering (Ed.), Encyclopedia of Mass Spectrometry,
vol. 4, Elsevier, Amsterdam, 2003 (Chapter 2, pp. 165–173).
[22] D. Kuck, C. Matthias, J. Am. Chem. Soc. 114 (1992) 1901.
[23] C. Matthias, D. Kuck, Org. Mass Spectrom. 28 (1993) 1073.
[24] C. Matthias, K. Weniger, D. Kuck, Eur. Mass Spectrom. 1 (1995) 445.
[25] C. Matthias, S. Anlauf, K. Weniger, D. Kuck, Int. J. Mass Spectrom. 199 (2000)
155.
[26] C. Matthias, D. Kuck, Int. J. Mass Spectrom. 217 (2002) 131.
[27] C. Matthias, A. Cartoni, D. Kuck, Int. J. Mass Spectrom. 255–256 (2006) 195.
[28] C. Matthias, B. Bredenkötter, D. Kuck, Int. J. Mass Spectrom. 228 (2003) 321.
[29] C. Matthias, D. Kuck, Croat. Chem. Acta 82 (2009) 7.
[30] D. Kuck, C. Matthias, D. Barth, M.C. Letzel, Int. J. Mass Spectrom. 306 (2011)
167–174.
N-Benzylpyridinium ions bearing a tertiary alkyl or a ben-
zyl group at the ortho-position of the pyridine nucleus eliminate
toluene by hydride transfer from the ␣-C–H donor site of that
ortho substituent. Our ESI/CID measurements indicate that this
elimination pathway can compete with the simple C–N bond dis-
+
sociation releasing the C7H7 ions because of local C–H bond
activation at the hydride donor site. However, the very same bond
activation does not assist the elimination of toluene from the iso-
meric meta- and para-alkyl-substituted N-benzylpyridinium ions.
Therefore, it appears that the constituents of the ion/neutral com-
+
plexes [C6H5CH2 ··· alkylpyridine] generated from the reactive
ortho-isomers can adopt an intra-complex orientation enabling
the hydride transfer, whereas a suitable reorientation cannot be
adopted in the I/N complexes formed during the fragmentation
of the meta- and para-isomers [49]. The intermediacy of I/N com-
plexes is also supported by the loss of benzene originating from
the N-benzyl group of the N,2-dibenzylpyridinium ions 4a. Fur-
ther studies should shed more light onto the surprising ortho
specificity of the toluene elimination from the isomeric N-benzyl-
(alkylpyridinium) ions.
[31] J. Bialecki, J. Ruzicka, A.B. Attygalle, J. Mass Spectrom. 41 (2006) 1195.
[32] Y. Chai, K. Jiang, Y. Pan, J. Mass Spectrom. 45 (2010) 496.
[33] G.R. Clemo, E. Hoggarth, J. Chem. Soc. (1941) 41.
[34] Gaussian 03, Revision B.04, M.J. Frisch, G.W. Trucks, H.B. Schlegel, G.E. Scuseria,
M.A. Robb, J.R. Cheeseman, V.G. Zakrzewski, J.A. Montgomery, Jr, R.E. Strat-
mann, J.C. Burant, S. Dapprich, J.M. Millam, A.D. Daniels, K.N. Kudin, M.C. Strain,
O. Farkas, J. Tomasi, V. Barone, M. Cossi, R. Cammi, B. Mennucci, C. Pomelli, C.
Adamo, S. Clifford, J. Ochterski, G.A. Petersson, P.Y. Ayala, Q. Cui, K. Morokuma,
D.K. Malick, A.D. Rabuck, K. Raghavachari, J.B. Foresman, J. Cioslowski, J.V. Ortiz,
B.B. Stefanov, G. Liu, A. Liashenko, P. Piskorz, I. Komaromi, R. Gomperts, R.L. Mar-
tin, D.J. Fox, T. Keith, M.A. Al-Laham, C.Y. Peng, A. Nanayakkara, C. Gonzalez, M.
Challacombe, P.M.W. Gill, B. Johnson, W. Chen, M.W. Wong, J.L. Andres, C. Gon-
zalez, M. Head-Gordon, E.S. Replogle, J.A. Pople, Gaussian Inc., Pittsburgh, PA,
1998.
References
[1] D.H. Williams, S. Naylor, J. Chem. Soc., Chem. Commun. (1987) 1408.
[2] A.R. Katritzky, C.H. Watson, Z. Dega-Szafran, J.R. Eyler Jr., J. Am. Chem. Soc. 112
(1990) 2471.
[35] M.W. Wong, L. Radom, J. Phys. Chem. A 102 (1998) 2237.
[36] D. Kuck, Mass Spectrom. Rev. 9 (1990) 583.
[37] D. Kuck, Int. J. Mass Spectrom. 213 (2002) 101.
[3] F. Derwa, E. De Pauw, P. Natalis, Org. Mass Spectrom. 26 (1991) 117.
[4] C. Collette, E. De Pauw, Rapid Commun. Mass Spectrom. 12 (1998) 165.
[5] C. Collette, L. Drahos, E. De Pauw, K. Vekey, Rapid Commun. Mass Spectrom. 12
(1998) 1673.
[6] L. Drahos, R.M.A. Heeren, C. Collette, E. De Pauw, K. Vekey, J. Mass Spectrom.
34 (1999) 1373.
[7] J. Naban-Maillet, D. Lesage, A. Bossée, Y. Gimbert, J. Sztáray, K. Vékey, J.C. Tabet,
J. Mass Spectrom. 40 (2005) 1.
[8] K. Vékey, J. Mass Spectrom. 31 (1996) 445.
[9] E.L. Zins, C. Pepe, D. Rondeau, S. Rochut, N. Galland, J.C. Tabet, J. Mass Spectrom.
44 (2009) 12.
[10] E.L. Zins, D. Rondeau, P. Karoyan, C. Fosse, S. Rochut, C. Pepe, J. Mass Spectrom.
44 (2009) 1668.
[11] K.V. Barylyuk, K. Chingin, R.M. Balabin, R. Zenobi, J. Am. Soc. Mass Spectrom. 21
(2010) 172.
[12] P. Longevialle, R. Botter, J. Chem. Soc., Chem. Commun. (1980) 823.
[13] T.H. Morton, Tetrahedron 38 (1982) 3195.
[38] D. Kuck, J. Label. Comp. Radiopharm 50 (2007) 360.
[39] D. Kuck, in: N.M.M. Nibbering (Ed.), Encyclopedia of Mass Spectrometry, vol. 4,
Elsevier, Amsterdam, 2005 (Chapter 2, pp. 229–242).
[40] D. Kuck, W. Bäther, Org. Mass Spectrom. 21 (1986) 451.
[41] D. Kuck, A. Petersen, U. Fastabend, Int. J. Mass Spectrom. Ion Processes 179–180
(1998) 129.
[42] R.C. Dunbar, J. Shen, E. Melby, G.A. Olah, J. Am. Chem. Soc. 95 (1973) 7200.
[43] D. Kuck, in: N.M.M. Nibbering (Ed.), Encyclopedia of Mass Spectrometry, vol. 4,
Elsevier, Amsterdam, 2005 (Chapter 2, pp. 270–286).
[44] D. Kuck, Int. J. Mass Spectrom. Ion Processes 117 (1992) 441.
[45] S. Meyerson, L.C. Leitch, J. Am. Chem. Soc. 93 (1971) 2244.
[46] D. Kuck, H.F. Grützmacher, Org. Mass Spectrom. 13 (1978) 81.
[47] D. Schröder, H. Florencio, W. Zummack, H. Schwarz, Helv. Chim. Acta 75 (1992)
1792.
[48] D. Kuck, A. Bruder, D.V. Ramana, Int. J. Mass Spectrom. Ion Processes 167–168
(1997) 55.
[49] H. van der Wel, N.M.M. Nibbering, J.C. Sheldon, R.N. Hayes, J.H. Bowie, J. Am.
Chem. Soc. 109 (1987) 5823.
[14] D.J. McAdoo, Mass Spectrom. Rev. 7 (1988) 363.
[15] R.D. Bowen, Acc. Chem. Res. 24 (1991) 364.