Unidirectional triple hydrogen rearrangement in the radical cations of electron-rich 3-aryl-1-propanols: Further evidence and limitation

Article abstract of DOI:10.1255/ejms.1239

The unidirectional triple-hydrogen (3H) rearrangement of the radical cations of 3-aryl-1-propanols bearing an electron-rich substitutent in the para-position was investigated for the diastereomeric 2-(4-dimethylamino) benzylcyclohexanols and 2-(4-dimethyl

Full text of DOI:10.1255/ejms.1239

D. Kuck et al., Eur. J. Mass Spectrom. 20, 51–61 (2014)
51
Received: 23 August 2013
n
Revised: 30 October 2013 n Accepted: 30 October 2013 n Publication: 31 October 2013
EUROPEAN
JOURNAL
OF
MASS
SPECTROMETRY
Special Issue dedicated to Professor Michael Linscheid on the Occasion of his 65th Birthday
Unidirectional triple hydrogen
rearrangement in the radical cations of
electron-rich 3-aryl-1-propanols: further
evidence and limitation
Dietmar Kuck,* Linda C. Salameh, Kenneth I. Onwuka and Matthias C. Letzel
Department of Chemistry, Bielefeld University, Universitätsstraße 25, 33615 Bielefeld, Germany. E-mail: dietmar.kuck@uni-bielefeld.de
The unidirectional triple-hydrogen (3H) rearrangement of the radical cations of 3-aryl-1-propanols bearing an electron-rich substitutent
in the para-position was investigated for the diastereomeric 2-(4-dimethylamino)benzylcyclohexanols and 2-(4-dimethylamino)-
benzylcyclopentanols and confirmed to be a highly stereospecific feature. Whereas the standard electron ionization (EI) (70 eV)
mass spectra of the trans-isomers exhibit very minor (~2%−3%) albeit stereospecific peaks for the relevant C8H13N•+ ions (m/z 123),
the metastable ion [mass-analyzed ion kinetic energy (MIKE)] spectra show these peaks with significant relative intensity (8%−17%).
The respective cis-isomers do not undergo the 3H rearrangement, be it under standard or under metastable-ion conditions. The
stereospecific 3H rearrangement is suppressed in the radical cations of cis- and trans-3-(4-dimethylamino)phenylcyclohexanol, the
mass and MIKE spectra of which are governed by cleavage processes of the cyclohexane ring, which impedes the stereochemical
assignment of the isomers by mass spectrometry. A multistep mechanism for the unidirectional 3H rearrangement is discussed in view
of the present and previous experimental data.
Keywords: hydrogen rearrangement “triple”, hydrogen rearrangement “unidirectional”, proton transfer, distonic ions, ion/neutral complexes,
radical cations, metastable ions, multistep reactions, stereochemistry, stereospecific fragmentation, anilines, cycloalkanols
Introduction
non-mass spectrometrists may become interested in the
Mass spectrometric fragmentation processes remain an
ever-lasting source of chemical surprise. Although a wealth
of insight into the chemistry of unimolecular dissociation of
gaseous ions has been accumulated in the past decades,1−5
the possibility of encountering unexpected mass spectral
origin and chemical logics behind them. If their abundance is
low or minute, then such peaks will probably be interpreted as
the result of impurities or—no less “irritating”—attributed to
the fact that the high-energy conditions of mass spectrometric
fragmentation processes are known to give rise to untypical
phenomena—sometimes addressed as “irritating” peaks— side reactions. The occurrence of side reactions, however, is
has remained remarkably high.6,7 If the underlying fragment
ions are abundant, it is hard to ignore their formation and
the very rule for chemical processes carried out in synthesis.
However, just as an undesired side reaction may lead to
new chemical insights, new methodology, or even novel
compounds with unusual structural motifs,8,9 an unexpected
fragmentation reaction in mass spectrometry may yield novel
significance for use as an analytical feature. As a consequence,
Dedicated, in friendship, to Professor Michael W. Linscheid on the
occasion of his 65th birthday
ISSN: 1469-0667
doi: 10.1255/ejms.1239
© IM Publications LLP 2014
All rights reserved

52
Unidirectional 3H Rearrangement in Radical Cations
any observation of unusual fragment ion peaks in whatever
type of mass spectrum should be taken seriously, and this
holds true even more since the advent of modern ionization
techniques which have brought us so many and formerly
ca 25% abundance relative to the base peak (m/z 134 for the
Me2NC6H4CH2+ ion) and the mass-analyzed ion kinetic energy
(MIKE) spectrum of the metastable ions 1•+ even displays
the m/z 123 signal as the base peak [Scheme 1(c)]. Extensive
unimaginable sorts of ions, be it positive and negative ions, deuterium labeling in that case revealed that the three
doubly or multiply charged ions, or adduct ions of any kind.
In this contribution, we will present and discuss a rather
peculiar fragmentation reaction of a particular group of
“conventional” organic molecular radical cations formed under
electron ionization conditions. It concerns the dissociation
of 3‑aryl-1-propanols bearing a strongly electron-donating
substituent in the para-position of the aryl residue with
concomitant rearrangement of three hydrogens from the
alcohol moiety to the arene moiety [Scheme 1(a)].10 Such
a unidirectional triple-hydrogen (3H) rearrangement is
extremely rare in organic ions11−17 and is beyond the quite
large variety of unidirectional 2H rearrangements.18,19 The
most consequent simplification of the structural prerequisites
required for this process to occur—be it in inferior rates or as
an efficiently competing reaction channel—may be illustrated
by formula A [Scheme 1(b)]. The unique 3H rearrangement
involved in this process implies a redox reaction between the
alcohol moiety of the radical cation and the arene unit prior to
fragmentation, giving what is believed to be an unconventional
(distonic) Type B fragment ion and a conjugated enone, C, as
the neutral fragment. Specifically, the most prominent case
of the unidirectional 3H rearrangement was encountered in
the 70 eV electron ionization (EI) mass spectrum of trans-
2-(4-dimethylamino)benzyl-1-indanol (1).10 The standard EI
mass spectrum of this isomer exhibits a peak at m/z 123 of
migrating hydrogen atoms originate with high specificity from
the carbinol position (C1), the hydroxyl group (OH), and the
position b to the carbinol group (C2).10 Therefore, the formation
of an enone as the neutral fragment has been inferred. The
structure of the m/z 123 ion is speculative, still, but it appears
reasonable to assume a dimethylammonium species attached
to a cyclohexadienyl ring [a, Scheme 1(c)]. Further striking
features, in the case of the benzylindanol 1, showed that neither
the molecular ions of the corresponding cis-stereoisomer nor
those of the respective meta-dimethylamino constitutional
isomer undergo the 3H rearrangement.
Here, we disclose some more evidence of the occurrence
of the unidirectional 3H migration and also of the limitation of
this peculiar fragmentation route. In a cursory exploration, we
synthesized a number of related cycloalkanols bearing either
para-(dimethylamino)benzyl or para N,N-dimethylanilino
residues. Both standard EI mass spectra and EI-MIKE
spectra were recorded to check for the occurrence of the 3H
rearrangement under high- and low-energy conditions.
Results and discussion
The set of cycloalkanols studied is displayed in Scheme
2. The mixture of the racemic cis-2-(4-dimethylamino)-
Scheme 1. The unidirectional 3H migration: (a) the generalized process with the migrating hydrogens highlighted, (b) the simplest
structural preconditions and (c) the specific and most prominent case.

D. Kuck et al., Eur. J. Mass Spectrom. 20, 51–61 (2014)
53
benzylcyclohexanol (cis-2) and the racemic trans- trans-3, whereas this method fails in the case of the
isomer (trans-2) was synthesized by a conventional
three-step sequence starting from cyclohexanone
and para-dimethylaminobenzaldehyde. The diastereomers
were obtained in pure form after chromatography of
the cis/trans-2 mixture. Similarly, the corresponding
racemates of cis-2-(4-dimethylamino) benzylcyclopentanol
(cis-3) and the respective trans-isomer (trans-3) were
prepared, starting from cyclopentanone. Furthermore, the
3-(4-dimethylamino)- phenylcyclohexanols cis-4 and trans-4
were synthesized by copper(I)-mediated Michael addition
3-phenylcycloalkanols 4 and 5.
The standard (70 eV) EI mass spectra of the benzylcyclo-
hexanols cis-2 and trans-2 are reproduced in Figure 1.
Not surprisingly, the peak due to the ionic fragment of
+
the benzylic cleavage, Me2NC6H4CH2 (m/z 134), domi-
nates in both cases. It appears that this process is much
more favorable than elimination of water which, remark-
ably, is almost absent in both cases (rel. abundance 2−3%).
Considering the fact that the molecular ions (m/z 237) and
also the other fragment ions (m/z 118) have very similar
of para-dimethylaminophenyllithium to cyclohexen-3-one, relative abundances in both spectra, it appears as if the
subsequent reduction with lithium aluminium hydride and diastereomers cis-2 and trans-2 were indistinguishable by
chromatographic separation of the diastereomeric alcohols. EI mass spectrometry. However, the peak at m/z 123 due to
Finally, a mixture of 3-(4-dimethylamino)phenylcyclopentanols, the unidirectional 3H rearrangement does make a signifi-
cis/trans-5, was synthesized by the same sequence
starting from cyclopenten-3-one without accomplishing
chromatographic separation.
cant difference. While being absent in the spectrum of the
cis-isomer, this signal amounts to ∼ 2% in the spectrum
of the trans-isomer. In fact, considering the peak groups
m/z 118−123 in both spectra, the peak intensity at m/z 123
makes the only significant difference. Hence, again, forma-
tion of the underlying C8H13N•+ ions (m/z 123) is a charac-
teristic, albeit rather inconspicuous, feature of the trans-
stereoisomer, trans‑2.
Very similar findings were obtained with the EI mass spectra
of the diastereomeric benzylcyclopentanols cis-3 and trans-3
(Figure 2). Again, the two spectra are almost indistinguish-
able (for example, water loss ≤ 1% in both cases), but the
peak corresponding to the unidirectional 3H rearrangement
(m/z 123) appears exclusively in the case of the trans-isomer,
trans-3, with minor relative abundance (~2%).
The stereochemical purity of the diastereomers cis-2 to
1
trans-4 was determined by H nuclear magnetic resonance
(NMR) spectroscopy. Whereas the stereochemical
assignment of the arylcyclohexanols cis-4 and trans-4 was
straightforward, that of some of the benzylcycloalkanols was
not. As will be shown, the unidirectional 3H rearrangement
observed by EI mass spectrometry turned out to be
useful as a complementary tool for the identification of
the diastereoisomeric 2-benzylcycloalkanols cis-2 to
Considering the fact that the migration of three hydrogen
atoms (possibly including the migration of a proton, see
below) should be entropically disfavored compared to the
simple benzylic cleavage giving the dominant C9H12N+ ions
(m/z 134), the fragmentation of long-lived, metastable ions
was expected to give enhanced relative abundances of the m/z
123 ions. In fact, the MIKE spectra of the trans-cycloalkanols,
trans-2 and trans-3, were found to exhibit relatively
pronounced peaks for the 3H rearrangement at m/z 123, as
well as the still predominating peaks at m/z 134 indicating
the simple benzylic cleavage (Figure 3). The C8H13N•+ ions
(m/z 123) amount to ∼7.5% of the total fragmentation of the
metastable molecular ions, trans-2•+, of the cyclohexanol
derivative. In the case of the cyclopentanol homolog, the
relative abundance of the C8H13N•+ ions is increased
to even ∼ 17% of the total fragmentation of the trans-3•+
ions. In contrast, the metastable ions of the corresponding
cis-isomers both exclusively undergo benzylic cleavage
giving the C9H12N•+ ions (m/z 134) (the minute contribution at
m/z 123 in the spectrum of cis-2 is attributed to an impurity
of trans-2). It is also noteworthy that, similar to the standard
EI mass spectra, elimination of water is a negligibly minor
process for the metastable ions in all cases.
The EI mass spectra of the three-(dimethylamino)
phenylcyclohexanols, cis-4 and trans‑4, reveal quite different
fragmentation behaviour (Table 1). In both cases, a number
Chart 1.

54
Unidirectional 3H Rearrangement in Radical Cations
%B
100
134
Me2N
OH
m/z 118
m/z 120
cis-2 (MW 233)
50
233
118
50
100
150
200
250
m/z
%B
100
134
Me2N
OH
m/z 118
m/z 120
trans-2 (MW 233)
m/z 123
50
233
118
50
100
150
200
250
m/z
Figure 1. EI (70eV) mass spectra of the diastereoisomeric para-(dimethylamino)benzylcyclohexanols cis-2 (top) and trans-2 (bottom).
%B
134
100
Me2N
OH
m/z 118
cis-3 (MW 219)
m/z 120
50
219
118
50
100
150
200
250
m/z
%B
100
134
Me2N
OH
m/z 118
m/z 120
trans-3 (MW 219)
m/z 123
50
219
118
50
100
150
200
250
m/z
Figure 2. EI (70eV) mass spectra of the diastereoisomeric para-(dimethylamino)benzylcyclopentanols cis-3 (top) and trans-3 (bottom).

D. Kuck et al., Eur. J. Mass Spectrom. 20, 51–61 (2014)
55
m/z 134
m/z 134
Me2N
OH
trans-3+ (m/z 219)
trans-2+ (m/z 233)
m/z 123
m/z 123
m/z 134
m/z 215
Me2N
m/z 134
Me2N
OH
OH
cis-3+ (m/z 219)
cis-2+ (m/z 233)
m/z 215
m/z 215
Figure 2. Metastable ion mass spectra (EI-MIKE spectra, 70eV) of the trans-para-(dimethylamino)benzylcycloalkanols, trans-2 and
trans-3 (top), and the corresponding cis-isomers, cis-2 and cis-3 (bottom). The peaks of the precursor molecular ions at m/z233 and
m/z219, respectively, have been suppressed.
of competing fragmentation channels are accessible even
in the EI spectra of both diastereomers. This also holds
for the metastable ions, including that for the elimina- true for the corresponding MIKE spectra, which exhibit
•
tion of water (m/z 201) and the loss of C3H7 (m/z 176), a
the peaks for most of the various fragmentation channels
discussed above but are void of the m/z 123 signal. As a
typical multistep fragmentation of cyclohexane derivatives.4
In the latter case, particularly stable 1-arylallyl cations, result, and in contrast to the 2-benzylcycloalkanols cis-2
p-Me2NC6H4CHCHCH+OH, are formed.
to trans-3, the EI and EI-MIKE spectra of diastereomeric
2-arylcycloalkanols, such as cis-4 and trans-4, cannot be
used for stereodifferentiation.
Similarly, losses of C3H7O•, C4H8O and C5H9O•, probably
all triggered by particularly favorable benzylic cleavage
+
steps, give rise to very stable ions p‑Me2NC6H4CHCHCH2
The multifaceted fragmentation behaviour found for the
•+
(m/z 160), p‑Me2NC6H4CHCH2 (m/z 147) and, here again, 2-(4-dimethylamino)phenylcyclohexanols cis-4 and trans-4
p‑Me2NC6H4CH2+ (m/z 134), respectively. The efficient compe- was also encountered in the case of the cyclopentanol homo-
tition of most of these fragmentation channels is certainly
due to the prevailing cleavage of the cyclohexanol ring of
ions cis-4•+ and trans-4•+ in the primary dissociation step, in
contrast to the highly selective exocyclic benzylic cleavage
in the cases of the N,N-dimethylaminobenzyl-substituted
logue, cis/trans-5, which, however, was analysed as a mixture
of diastereomers only (Table 2). Again, besides water elimina-
tion, the losses of radicals as well as the expulsion of C3H6O,
all being triggered by facile benzylic cleavage of the cyclo-
pentane ring, compete in this case. This holds also true for
cycloalkanol ions cis-2•+ to trans-3•+. Noteworthy, however, the metastable ions. Remarkably, the MIKE spectrum of the
is the finding that particularly facile endocyclic ring cleavage
molecular ions, cis/trans-5•+, does exhibit a minor signal at
m/z 123, suggesting the occurrence of the unidirectional 3H
of the (N,N-dimethylamino)-phenylcyclohexanol ions cis-4•+
and trans-4•+ also suppresses the unidirectional 3H migra- rearrangement in the case of the trans-isomer. Unfortunately,
tion. In fact, the peak expected for the formation of the
stereochemical assignment in this case was impeded by
experimental restrictions.
characteristic C8H13N•+ ions (m/z 123) is completely absent

56
Unidirectional 3H Rearrangement in Radical Cations
Table 1. Fragmentation of the diastereomeric 2-(4-dimethylamino)phenyl-cyclohexanols, cis-4 and trans-4, under EI (70eV) and EI-MIKES
(70eV) conditions.
cis-4
trans-4
Fragment ion
(tentative)b,c
Neutral
fragment
m/z
Rel. abundance
Rel. abundance
EI
(EI-MIKES)a
EI
(EI-MIKES)a
219
201
176
160
147
146
134
123
122
121
120
118
91
100
7
100
9
(28)
(33)
(3)
(35)
(32)
(3)
[M–H2O]•+
H2O
•
36
27
25
22
97
≤1
5
33
24
26
21
86
≤1
5
Ar–CHCHCH+OH
C3H7
C3H7O•
+
Ar–CHCHCH2
•+
Ar–CHCH2
C4H8O
+
(100)
(100)
Ar–CH2
C5H9O•
(≤2)
(8)
(≤2)
(11)
12
8
14
7
8
5
5
5
77
7
6
aRelative abundances in the MIKE spectrum derived from peak intensities.
b”Ar” denotes the para-(dimethylamino)phenyl residue.
cStructural assignment based on the accepted fragmentation mechanisms of cyclohexane derivatives under EI conditions (Reference 4).
It is obvious that the fragmentation of the molecular ions of
Mechanistic aspects
the trans-2-(4-dimethylamino)benzylcycloalkanols, trans-2•+
and trans-3•+, starts with the same stereospecific g-H atom
transfer (Scheme 2). Compared to the case of the indanol-
derived ions 1•+, the lack of benzylic activation (“localized bond
activation”)28,29 leads to an attenuated relative fragmentation
rate with respect to the simple benzylic cleavage giving ions
C9H12N•+ (m/z 134). It can be envisioned that the comparably
flat cyclopentane ring in ions trans-3•+ is a favorable
factor for the initial g-H atom transfer compared to the
A mechanistic interpretation of the unidirectional 3H
rearrangement was given previously on the basis of the
trans-stereospecificityoftheprocess, theclearcutelectronic
influence of substituents both at the benzyl residue and
the carbinol center and, in particular, on the basis of
extended deuterium labeling.10 The latter technique was
applied to the radical cations of trans-2-(4-dimethylamino)
benzyl-1-indanol, 1•+, for which the 3H rearrangement was
found to be most prominent [Scheme 1(c)].10 In addition, cyclohexane homolog, trans-2•+, in which conformational
kinetic isotope effects shed some light on the mechanistic
interpretation. It is our understanding that this unusual
and complicated process involves both highly specific steps
via distonic ion intermediates20 but, necessarily, also ion/
neutral complexes21,22 as crucial intermediates. There is no
doubt that the successive transfer of three hydrogen atoms
(or protons) from the indanol moiety to the dimethylaniline
moiety of ions 1•+ starts with the stereospecific transfer of
the carbinol H atom, which is oriented cis with respect to
the electron-rich benzyl group. Most importantly, and at
variance from the usual migration of such a g-positioned
H atom to one of the ortho-positions of the benzyl group—a
path crucial to the well-known McLafferty reaction of higher
effects may slow down this step. In any case, the distonic
ion b generated by the g-H atom transfer to the ipso-carbon
atom of the N,N-dimethylanilino residue should be by far
the most stable among the ring-protonated tautomeric
intermediates.27 Heterolysis of the Ca−Cipso bond in ion b
corresponds to the well-known proton-induced cleavage of
alkylbenzenium ions giving the respective alkyl cation and
the neutral benzene derivative.30−32 However, it is also known
that concomitant transfer of a hydrogen atom (formally as
H+) can compete efficiently if the arene moiety is sufficiently
basic.27,32 This channel gives rise to formation of an alkene
and the protonated benzene derivative. In the present case,
it appears that the Hb atom takes on this role, migrating
alkylbenzenes, including 2-benzylindanes23−25—the para- from the tertiary C2 position at the cycloalkane ring to the
dimethylamino substituent navigates the migrating carbinol
g-H atom to the ipso-position of the benzyl residue, giving
rise to a particularly stable para-protonated benzenium
ion.26,27
dimethylaniline fragment being released. It also appears
reasonable to assume that there is a concerted mechanism
via ion c, possibly as a transition state. In this way, the first
two hydrogen transfer steps are believed to generate the

D. Kuck et al., Eur. J. Mass Spectrom. 20, 51–61 (2014)
57
Table 2. Fragmentation of the 2-(4-dimethylamino) phenylcyclopentanols cis/trans-5 (mixture of diastereomers) under EI (70eV) and EI-
MIKES (70eV) conditions.
m/z
cis/trans-5
Fragment ion
(tentative)b,c
Neutral
fragment
Rel. Abundance
EI
100
8
(EI-MIKES)a
205
187
186
176
160
147
146
134
123
(100)
[M −H2O]•+
H2O
9
•
14
41
27
19
53
1
(46)
(81)
(12)
Ar–CHCHCH+OH
C2H5
+
Ar–CHCHCH2
C2H5O•
•+
Ar–CHCH2
C3H6O
+
(46)
(7)
Ar–CH2
C4H7O•
122
121
120
118
117
91
4
7
6
5
6
5
(~3)
(∼1)
aRelative abundances in the MIKE spectra derived from peak intensities.
b“Ar” denotes the para-(dimethylamino)phenyl residue.
cStructural assignment based on the accepted fragmentation mechanisms of cycloalkane derivatives (Reference 4) and alkylbenzenes (References 1, 2 and
5) under EI conditions.
Scheme 2. Suggested mechanism for the unidirectional 3H migration (see discussion).

58
Unidirectional 3H Rearrangement in Radical Cations
Mass spectrometry
first ion/neutral complex, intermediate d, consisting of para-
protonated dimethylaniline, a particularly stable arenium
Mass spectra were obtained by using a double-focusing
ion,27 and a rather stable cyclic 1-hydroxyallyl radical. Intra- AutoSpec X mass spectrometer34 of EBE geometry. Standard
complex charge transfer and internal rotation may lead to
¼ ¼
H N
hydrogen bond (cf. ion f) should facilitate the final transfer of
a proton to the nitrogen atom. According to this mechanistic
view, the a-distonic20 radical cation a is formed along with
the corresponding methylenecycloalkanone.
Admittedly, this mechanism is tentative, still, and extended
theoretical calculations may be required to substantiate
this model. However, the model is based on previous
experimental findings. The present experimental findings
made with the 2-(4-dimethylamino)benzylcycloalkanols
cis-2 to trans-3 further demonstrate that the unidirectional
3H rearrangement does represent a stereospecific
fragmentation route under EI conditions of cycloalkanols
EI mass spectra were recorded at 70 eV electron energy
and with an acceleration voltage of 8 kV, at an ion source
temperature of 200°C, and by using the direct inlet probe.
MIKE spectra of the molecular ions generated at 70eV were
obtained by focusing the ions the 3rd field free region (FFR)
between the magnet and the 2nd electrostatic analyzer (ESA)
and then scanning the deflection voltage of the 2nd ESA. The
spectra recorded by a multiplier were processed using the
Origin 8 program.35
the electromeric33 I/N complex e, in which a strong O
Cis- and trans-2-(4-dimethylaminobenzyl)
cyclohexanols (cis-2 and trans-2)
(1) Cyclohexanone (10.0 g, 102 mmol) and para-N,N-dimeth-
ylaminobenzaldehyde (5.01 g, 33.5 mmol) were reacted in
bearing an electron-rich benzyl residue at the position C2. a solution of potassium hydroxide (2.1 g) in water (45 mL)
However, this process is easily suppressed if energetically
and entropically more favorable fragmentation reactions
compete. Hence, as shown in this work for the case of
the 3-(4-dimethylamino)phenylcycloalkanols cis-4 and
trans-4, structural preconditions for the unidirectional 3H
rearrangement are quite delicate.
under reflux for 20 h. Work-up and recrystallization of the
precipitated product gave 2-(4-dimethylaminobenzylidene)
cyclohexanone as yellow crystals (2.89 g, 38%). H NMR
(CDCl3, 500MHz): d 7.52 (s, 1H), 7.37 (d, J=8.9Hz, 2H), 6.66
(d, J =8.9Hz, 2H), 2.98 (s, 6H), 2.84 (t, J=4.6Hz, 2H), 2.47 (t,
J = 6.6 Hz, 2H), 1.87 (m, 2H), 1.74 (m, 2H). 13C NMR (CDCl3,
126 MHz): d 201.2 (C), 150.4 (C), 137.1 (CH), 132.6 (C), 131.6
(CH), 123.4 (C), 111.5 (CH), 40.0 (CH3), 39.9 (CH2), 29.0 (CH2),
23.8 (CH2), 23.1 (CH2).
1
Conclusion
(2) The benzylidenecyclohexanone (780 mg, 3.4 mmol) was
hydrogenated in 1,4-dioxane solution (90mL) in the presence of
The unidirectional rearrangement of three hydrogen
atoms within the molecular radical cations of 3-aryl-1- Pd/C catalyst (100mg, 10% Pd) at 25°C (H2 take-up 1.0 equiv.).
propanols, bearing suitably activating substituents at the
para-position of the arene moiety, has been shown to
operate stereospecifically in the cases of the trans-isomers J=8.5Hz, 2H), 6.67 (d, J=8.5Hz, 2H), 3.11 (m, 2H), 2.86 (s, 6H),
Work-up gave 2-(4-dimethylaminobenzyl)cyclohexanone as a
yellow oil (360mg, 46%). H NMR (CDCl3, 500MHz): d 7.00 (d,
1
of 2-(4-dimetylamino)benzylcyclohexanol, trans-2, and
2-(4-dimetylamino)benzylcyclopentanol, trans-3. Although
being of minor (or even minute) relative abundance under
1.74−2.39 (m, 9H).
(3) The benzylcyclohexanone (360 mg, 1.6 mmol) was
reduced in anhydrous tetrahydrofuran (3.5 mL) with lithium
standard (70 eV) EI conditions, the relevant fragment ions, aluminium hydride (70 mg, 1.75 mmol) by heating the
C8H13N•+ (m/z 123), give rise to valuable analytical information. suspension under reflux for 2 h. Careful hydrolysis and
This holds particularly true for the low-energy, long-lived
metastable ions, trans-2•+ and trans-3•+, which undergo the
3H rearrangement with a significant relative abundances. The
related 3-(4-dimethylamino)phenylcyclohexanols do not show
work-up gave a mixture of the 2-(4-dimethylaminobenzyl)
cyclohexanols, which were separated by column chroma-
tography (silica).—The first fraction was assigned to be
the cis-isomer, cis-2a. H NMR (CDCl3, 500 MHz): d 7.08 (d,
1
this process. The mechanism of the unique 3H rearrangement J = 8.6 Hz, 2H), 6.71 (d, J = 8.5 Hz, 2H), 3.81 (s, 1H), 2.92 (s, 6H),
appears to be very complicated, still, and there is no doubt
that theoretical modeling of this multistep process will be a
challenging task.
2.55 (m, 2H), 1.42−1.76 (m, 10H). 13C NMR (CDCl3, 126 MHz):
d 148.6 (C), 129.6 (CH), 129.0 (C), 112.8 (CH), 68.5 (CH), 43.6
(CH2), 40.8 (CH3), 37.5 (CH2), 33.1 (CH), 26.3 (CH2), 25.2 (CH2),
20.3 (CH2). EI-MS (70 eV): m/z (%) 234 (4, 13C1–M•+), 233
(21, M•+), 135 (10) , 134 (100), 120 (2), 118 (6), 91 (3).—The
second fraction was assigned to be the trans-isomer, trans-
Experimental
1
2a. H NMR (CDCl3, 500 MHz): d 7.06 (d, J = 8.5 Hz, 2H), 6.66
Syntheses (General)
(d, J = 8.6 Hz, 2H), 3.82 (s, 1H), 2.90 (s, 6H), 2.30 (m, 2H),
0.88−1.70 (m, 10H). 13C NMR (CDCl3, 126 MHz): d 149.0 (C),
129.9 (CH), 128.7 (C), 112.8 (CH), 74.6 (CH), 47.1 (CH2), 40.9
(CH3), 38.0 (CH2), 35.6 (CH), 30.1 (CH2), 25.5 (CH2), 24.9 (CH2).
EI-MS (70 eV): m/z (%) 234 (5, 13C1–M•+), 233 (30, M•+), 135
(12), 134 (100), 123(2), 120 (3), 118 (7), 91 (4).
Melting points (uncorrected): Electrothermal melting point
apparatus. TLC: silica (Kieselgel 60) on aluminum foil with
1
fluorescence indicator F254, thickness 0.2 mm (Merck). H
NMR spectra (300MHz) and 13C NMR spectra (75.4MHz) were
measured on a Bruker AM 300 instrument (CDCl3/TMS).

D. Kuck et al., Eur. J. Mass Spectrom. 20, 51–61 (2014)
59
Cis- and trans-2-(4-dimethylaminobenzyl)
cyclopentanols (cis-3 and trans-3)
the concentrated to dryness under reduced pressure. The
dark oily product was subjected to column chromatography
(1) Cyclopentanone (8.6 g, 102 mmol) and para-N,N-dimeth- (Chx/EtOAc 70:30) and recrystallized from n-pentane to give
ylaminobenzaldehyde (5.02 g, 33.5 mmol) were reacted in a
solution of potassium hydroxide (2.1g) in water (45mL) under
reflux for 20h. Work-up and recrystallization of the precipitated
product gave 2-(4-dimethylaminobenzylidene)cyclopentanone
2-(4-dimethylaminophenyl)cyclohexanone as a colorless solid
1
(600mg, 8%), mp 65−66°C. H NMR (CDCl3, 250MHz): d 7.10
(d, J=8.6Hz, 2H), 6.74 (d, J=8.7Hz, 2H), 2.93 (s, 6H), 2.85−3.01
(m, 1H), 2.45−2.55 (m, 2H), 2.31−2.43 (m, 2H), 2.02−2.17 (m, 2H),
1.70−1.87 (m, 2H). 13C NMR (CDCl3, 126MHz): d 211.3 (C), 149.2
(C), 132.8 (C), 127.1 (CH), 113.0 (CH), 49.2 (CH2), 43.9 (CH3), 41.2
1
as orange crystals (4.55g, 63%). H NMR (CDCl3, 500MHz): d
7.44 (d, J=8.1Hz, 2H), 7.33 (s, 1H), 6.68 (d, J=7.8Hz, 2H), 2.99
(s, 6H), 2.92 (t, J=7.1Hz, 2H), 2.35 (t, J=7.8Hz, 2H), 1.97 (m, (CH2), 40.8 (CH), 33.0 (CH2), 25.5 (CH2).
2H). 13C NMR (CDCl3, 126MHz): d 208.1 (C), 150.9 (C), 133.3
(2) The arylcyclohexanone (350mg, 1.60mmol) was reduced
(CH), 132.4 (C), 131.0 (CH), 123.2 (C), 111.7 (CH), 40.0 (CH3), in anhydrous diethyl ether (40mL total volume) with lithium
37.7 (CH2), 29.3 (CH2), 20.1 (CH2).
(2) The benzylidenecyclopentanone (1.05 g, 4.86 mmol) was
hydrogenated in 1,4-dioxane solution (130mL) in the presence
aluminium hydride (17mg, 450µmol) by heating the suspen-
sion under reflux for 1 h. Careful hydrolysis at 0°C and
work-up gave a mixture of the 2-(4-dimethylaminophenyl)
of Pd/C catalyst (130mg, 10% Pd) at 25°C (H2 take-up 1.0 equiv). cyclohexanols cis-4 and trans-4 as a brownish oil. Separation
Work-up gave 2-(4-dimethylaminobenzyl)cyclopentanone as a
by column chromatography (silica, Chxn/EtOAc 70:30) gave
1
yellow oil (740mg, 70%). H NMR (CDCl3, 500MHz): d 7.01 (d, the trans-isomer, trans-4, as the first-eluting fraction (10mg,
J=8.6Hz, 2H), 6.65 (d, J=8.7Hz, 2H), 2.89 (s, 6H), 1.21−1.76
(m, 9H).
3%) and the cis-isomer, cis-4, as the second fraction (140mg,
40%). Cis-4: Colorless solid, mp 71−73°C (from cyclohexane).
1H NMR (CDCl3, 250 MHz): d 7.10 (d, J = 8.6 Hz, 2H), 6.74 (d,
(3) The benzylcyclopentanone (739 mg, 3.4 mmol) was
reduced in anhydrous tetrahydrofuran (7.0 mL) with lithium J=8.8Hz, 2H), 3.65−3.76 (m, 1H), 2.92 (s, 6H), 2.44−2.54 (m, 1H),
aluminium hydride (130 mg, 3.50 mmol) by heating the
suspension under reflux for 2 h. Careful hydrolysis and
2.09−2.19 (m, 1H), 2.01−2.08 (m, 1H), 1.81−1.93 (m, 1H), 1.78
(br s, 1H, OH), 1.42−1.47 (m, 1H), 1.36−1.41 (m, 1H), 1.29−1.35
work-up gave a mixture of the two-(4-dimethylaminobenzyl)- (m, 1H), 1.20−1.27 (m, 1H). 13C NMR (CDCl3, 126MHz): d 149.0
cyclohexanols, which were separated by column chromatog- (C), 134.9 (C), 127.3 (CH), 113.1 (CH), 71.0 (CH), 43.5 (CH2), 41.6
raphy (silica).—The first fraction was assigned to be the cis- (CH), 40.9 (CH3), 35.3 (CH2), 33.6 (CH2), 24.5 (CH2).
isomer, cis-3a. 1H NMR (CDCl3, 500MHz): d 7.13 (d, J=6.1Hz, Trans-4: Color-less solid, mp < 71°C (from cyclohexane).
2H), 6.72 (d, J=6.1Hz, 2H), 4.11 (s, 1H), 2.94 (s, 6H), 2.69 (m, 1H NMR (CDCl3, 250 MHz): d 7.12 (d, J = 8.5 Hz, 2H), 6.79 (d,
2H), 1.27−2.01 (m, 8H). EI-MS (70 eV): m/z (%) 220 (4, 13C1– J=8.5Hz, 2H), 4.21 (quin, J=2.9Hz), 2.93 (s, 6H), 2.84−2.99 (m,
M•+), 219 (26, M•+), 135 (12), 134 (100), 118 (8), 91 (4).—The
1H), 1.81−1.91 (m, 2H), 1.71−1.81 (m, 2H), 1.59−1.70 (m, 2H),
second fraction was assigned to be the trans-isomer, trans- 1.42−1.55 (m, 2H).
3a. H NMR (CDCl3, 500MHz): d 7.10 (d, J=8.1Hz, 2H), 6.72 (d,
2-(4-dimethylaminophenyl)cyclopentanol
J=8.1Hz, 2H), 3.92 (s, 1H), 2.94 (s, 6H), 2.58 (m, 2H), 1.29−3.03
(m, 8H). EI-MS (70eV): m/z (%) 220 (3, 13C1–M•+), 219 (21, M•+),
135 (10), 134 (100), 123 (2), 120 (3), 118 (6), 91(3).
(mixture of cis/trans-5)
(1) A solution of 4-bromo-N,N-dimethylaniline (3.40 g,
17 mmol) in anhydrous tetrahydrofuran (50mL) was stirred
and cooled to −78°C under argon and tert-butyllithium (1.09g,
12 mL, 17.0 mmol) were added quickly through a septum.
Cis- and trans-2-(4-dimethylaminophenyl)
cyclohexanols (cis-4 and trans-4)
(1) A solution of 4-bromo-N,N-dimethylaniline (6.80 g, After stirring for 1h, the viscous colorless solution formed
17 mmol) in anhydrous tetrahydrofuran (50mL) was stirred was diluted with THF and a solution of copper(I) iodide (1.30g,
and cooled to −78°C under argon and tert-butyllithium (2.18g, 7.0 mmol) in the same solvent (15 mL) was added at 0°C.
23mL, 34.0mmol) were added quickly through a septum. After The color of the solution first turned dark and then yellow–
stirring for 1 h, the viscous colorless solution formed was
diluted with THF and a solution of copper(I) iodide (2.60 g, to −78°C again and a solution of cyclopenten-3-one (560mg,
14.0mmol) in the same solvent (15mL) was added at 0°C. The 7.0mmol) in anhydrous THF (10mL) was added through the
color of the solution first turned dark and then slightly yellow– septum. The reaction mixture was allowed to warm to 0°C
green. After stirring at 0°C for 2 h, the mixture was cooled and stirred under GC-MS monitoring. After 18h, the mixture
to −78°C again and a solution of cyclohexen-3-one (1.30mg, was hydrolyzed by the addition of saturated aqueous ammo-
green. After stirring at 0°C for 2 h, the mixture was cooled
14.0mmol) in anhydrous THF (10mL) was added through the
septum. The reaction mixture was allowed to warm to 0°C and
stirred under GC-MS monitoring. After 18h, the mixture was
hydrolyzed by the addition of saturated aqueous ammonium
chloride (pH≈7). The product was extracted with diethyl ether
(3 × 100 mL) and the combined extracts were washed with
water and then brine, dried over magnesium sulphate and
nium chloride (pH≈7). The product was extracted with diethyl
ether (3 × 100 mL) and the combined extracts were washed
with water and then brine, dried over magnesium sulfate
and concentrated to dryness under reduced pressure. The
dark oily product was subjected to column chromatography
(Chx/EtOAc 70:30) and recrystallized from n-pentane to give
2-(4-dimethylaminophenyl)cyclopentanone, an orange solid

60
Unidirectional 3H Rearrangement in Radical Cations
(480mg, 20%), mp 72°C. 1H NMR (CDCl3, 250MHz): d 7.12 (d,
J=8.5Hz, 2H), 6.72 (d, J=8.7Hz, 2H), 3.26−3.40 (m, 1H), 2.94
of g-arylalkanols”, Org. Mass Spectrom. 23(9), 643 (1988).
doi: 10.1002/oms.1210230904
(s, 6H), 2.57−2.67 (m, 1H), 2.09−2.46 (m, 4H), 1.86−2.02 (m, 11. S. Meyerson, I. Puskas and E.K. Fields “Organic ions
1H). 13C NMR (CDCl3, 126MHz): d 218.8 (C), 149.3 (C), 131.3
(C), 127.3 (CH), 113.1 (CH), 46.0 (CH2), 41.3 (CH), 40.8 (CH3),
38.9 (CH2), 31.4 (CH2).
(2) The arylcyclopentanone (400mg, 1.97mmol) was reduced
in anhydrous diethyl ether (40mL total volume) with lithium
aluminium hydride (20mg, 540µmol) by heating the suspen-
sion under reflux for 1 h. Careful hydrolysis at 0°C and
in the gas phase. XXVII. Long-range intramolecular
interactions in 4-n-alkyl trimellitic esters”, J. Am. Chem.
Soc. 95(18), 6056 (1973). doi: 10.1021/ja00799a037
12. S. Meyerson, I. Puskas and E. K. Fields, “Triple-
hydrogen migration in 4-N-alkyl esters of trimellitic
anhydride under electron impact”, Chem. Ind. (London)
52, 1845 (1968).
work-up gave a mixture of the 2-(4-dimethylaminophenyl)- 13. S. Meyerson, I. Puskas and E. K. Fields, “Long-range
cyclopentanols cis/trans-5 (370 mg, 92%). Separation by
column chromatography (silica) was unsuccessful.
Intramolecular Interactions in 4-n-Alkyl Trimellitic
Esters”, Adv. Mass Spectrom. 6, 17 (1974).
14. M. Katoh and C. Djerassi, “Mass spectrometry in
structural and stereochemical problems. CXC. Electron
impact induced triple hydrogen migration in vinyl alkyl
ethers, J. Am. Chem. Soc. 92, 731 (1970). doi: 10.1021/
ja00706a067
15. J. Cable and C. Djerassi, “Mass spectrometry in
structural and stereochemical problems. CCIII. The
course of a triple hydrogen migration in esters of
trimellitic anhydride”, J. Am. Chem. Soc. 93, 3905 (1971).
doi: 10.1021/ja00745a014
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