Stereospecific fragmentation of 3-dimethylaminocyclohexanols upon electron impact ionization

Article abstract of DOI:10.1002/(SICI)1096-9888(199707)32:7<750::AID-JMS527>3.0.CO;2-Y

Stereoisomeric cis- and trans-1-butyl-3-dimethylaminocyclohexanols have been previously reported to exhibit different electron impact (EI) mass spectra. The m/z 100 [C₆H₁₄N]⁺ ion is obtained only from the cis-isomer. The results of a collision-induced dissociation study are inconsistent with the previously proposed protonated dimethylaminocyclobutane structure (ion a) and suggest the N,N-dimethyl-1-butaneimmonium (CH₃CH₂CH₂CH=N⁺(CH₃)₂) structure (ion b) for this ion. The mechanistic pathway proposed for this highly stereospecific process involves initial hydrogen migration from the hydroxy group to the radical site at the charged amino group as the stereospecific step, this being possible only for the cis-amino alcohol. The EI mass spectra of the corresponding stereoisomeric methyl ethers exhibit preferential elimination of formaldehyde from the cis-isomer, which is explained by initial hydrogen migration from the methoxy group to the N atom. The unsubstituted cis- and trans-1-methoxy-3-dimethylaminocyclohexanes do not show any stereospecificity in their behavior under EI.

Full text of DOI:10.1002/(SICI)1096-9888(199707)32:7<750::AID-JMS527>3.0.CO;2-Y

JOURNAL OF MASS SPECTROMETRY, VOL. 32, 750È754 (1997)
StereospeciÐc Fragmentation of
3-Dimethylaminocyclohexanols upon Electron
Impact Ionization
V. Vais and A. Mandelbaum*
Department of Chemistry, TechnionÈIsrael Institute of Technology, Haifa, Israel
Stereoisomeric cis- and trans-1-butyl-3-dimethylaminocyclohexanols have been previously reported to exhibit dif-
ferent electron impact (EI) mass spectra. The m/z 100 [C H N]` ion is obtained only from the cis-isomer. The
6
14
results of a collision-induced dissociation study are inconsistent with the previously proposed protonated di-
methylaminocyclobutane structure (ion a) and suggest the N,N-dimethyl-1-butaneimmonium
(CH CH CH CHxN`(CH ) ) structure (ion b) for this ion. The mechanistic pathway proposed for this highly
3
2
2
3 2
stereospeciÐc process involves initial hydrogen migration from the hydroxy group to the radical site at the charged
amino group as the stereospeciÐc step, this being possible only for the cis-amino alcohol. The EI mass spectra of the
corresponding stereoisomeric methyl ethers exhibit preferential elimination of formaldehyde from the cis-isomer,
which is explained by initial hydrogen migration from the methoxy group to the N atom. The unsubstituted cis- and
trans-1-methoxy-3-dimethylaminocyclohexanes do not show any stereospeciÐcity in their behavior under EI.
( 1997 by John Wiley & Sons, Ltd.
J. Mass Spectrom. 32, 750È754 (1997)
No. of Figs: 10 No. of Tables: 0 No. of Refs: 11
KEYWORDS: fragmentation mechanism; stereochemical e†ects; hydrogen transfer; collision-induced dissociation; amino
alcohols
but no mechanistic pathway was suggested that would
INTRODUCTION
account for the high stereospeciÐcity of its formation.
A similar stereospeciÐc behavior has been reported
by the same group in cis- and trans-3-alkyl-N-(3-
hydroxycyclohexyl)piperidines.5 The EI mass spectra of
the cis-isomers exhibited m/z 140 and 85 ions, which
were of much lower abundance in the spectra of the
trans counterparts. Here again a cyclobutylamine struc-
ture (protonated N-cyclobutylpiperidine) was proposed
for the characteristic m/z 140 ion,5 but the origin of the
stereospeciÐc behavior of the cis- and trans-isomers was
not dealt with.
Stereochemical e†ects in the chemistry of gas-phase ions
have been one of the major objectives in the research
activities of this laboratory.1h3 Such e†ects have been
applied in structural and mechanistic studies of ions in
the gas phase and in conÐgurational assignments of
organic compounds in the condensed phase. In this
context, our attention was caught by a report on the
highly stereospeciÐc fragmentation behavior of stereo-
isomeric 1-alkyl-3-dimethylaminocyclohexanols (1, R \
CH , C H , n-C H , n-C H , t-C H , n-C H , i-
The primary objective of this work was to investigate
3
2 5
3 7
4 9
4 9
5 11
the structure of the m/z 100 [C H N]` ion obtained
C H ) under electron impact ionization (EI).4 The cis-
6 14
5 11
from cis-3-dimethylaminocyclohexanols (1) under EI
isomers gave rise to m/z 100 [C H N]` and m/z 45
6 14
[C H N]`Õ cations, which were absent in the EI mass
2 7
spectra of the trans-analogs. The elemental composi-
tions of the two ions have been conÐrmed by high-
resolution measurements, and deuterium labeling
experiment indicated the presence of the hydroxylic
hydrogen in the m/z 100 ion. The structure of proto-
nated dimethylaminocyclobutane (ion a) was proposed
for the m/z 100 ion in the paper cited (see Scheme 1),4
* Correspondence to: A. Mandelbaum, Department of Chemistry,
TechnionÈIsrael Institute of Technology, Haifa, Israel.
Contract grant sponsor: Fund for Promotion of Research at the
Technion.
Scheme 1
CCC 1076È5174/97/070750È05 $17.50
( 1997 by John Wiley & Sons, Ltd.
Received 24 February 1997
Accepted 1 April 1997

STEREOSPECIFIC FRAGMENTATION OF 3-DIMETHYLAMINOCYCLOHEXANOLS
751
and to propose a mechanism for its stereospeciÐc for-
mation.
RESULTS AND DISCUSSION
The
cis-
and
trans-1-butyl-3-dimethylamino-
cyclohexanols cis-1 and trans-1 (R \ n-C H ) were syn-
4 9
thesized by the reported route.4 The EI mass spectral
measurements reproduced the stereospeciÐc formation
of the m/z 100 ion from the cis-isomer cis-1 (12% rela-
tive abundance). Collision-induced dissociation (CID)
measurements on this ion and on the m/z 100 N,N-
dimethylcyclobutylammonium ion a, obtained upon
isobutane chemical ionization (CI) from dimethyl-
aminocyclobutane, were performed in order to investi-
gate its structure. The two CID spectra shown in Fig. 1
are entirely di†erent, indicating di†erent structures for
these ions. The abundant m/z 55 ion in the CID spec-
trum of protonated dimethylaminocyclobutane, which
presumably has the elemental composition [C H ]`, is
4 7
consistent with the structure of ion a. The absence of
the m/z 55 ion in the CID spectrum of the m/z 100 ion
obtained in Fig. 1(c) suggests the absence of the cyclo-
butyl moiety in its structure.
The CID spectrum of the m/z 100 ion obtained from
cis-1 was found to be similar to the CID spectrum of
N,N-dimethyl-1-butaneimmonium cation (ion b) formed
from 4-dimethylaminoheptane (2) upon EI [Scheme 2
and Fig. 1(c)] (the tandem mass spectrometric behavior
of immonium ions has been described in two recent
papers6). This Ðnding suggests the structure of ion b for
the product of the stereospeciÐc fragmentation of cis-1.
Scheme 2
A plausible mechanism for the formation of ion b
from cis-1 is proposed in Scheme 3. The initial hydro-
gen migration from the hydroxy group to the radical
site at the charged amino group is the stereospeciÐc
step, this being possible only for the cis-isomer cis-1.
As expected, based on the above mechanism, the EI
mass spectra of cis- and trans-1-butyl-1-methoxy-3-
dimethylaminocyclohexanes cis- and trans-3 (R \
C H ) (shown in Fig. 2) do not exhibit the analogous
4 9
m/z 114 ion (Scheme 4). The formation of such an ion
would require migration of a methyl group from the
oxygen to the nitrogen atom. A signiÐcant di†erence in
the behavior of these two stereoisomeric amino ethers 3
appears in the relative abundances of the m/z 182 and
183 [M [ CH O]` and [M [ CH O]`Õ ions. The pref-
3
2
erential elimination of formaldehyde observed in cis-3
suggests the occurrence of a hydrogen transfer from the
methoxy group to the cation radical site at the N atom,
which is possible only in the cis-isomer, unless ring
cleavage is involved in this process. A mechanistic
pathway for this fragmentation is proposed in Scheme
5.
In contrast to cis-1 and trans-1, the unsubstituted cis-
and trans-3-dimethylaminocyclohexanols cis- and
trans-4 give rise to similar EI mass spectra (Fig. 3).
Figure 1. CID spectra of m/z 100 ions: (a) obtained from cis-1-
butyl-3-dimethylaminocyclohexanol (cis-1, R ¼C H ) under 70
eV EI conditions; (b) protonated (isobutane CI) dimethyl-
aminocyclobutane (ion a); (c) CID spectrum of m/z 100 ion b
obtained from 4-dimethylaminoheptane (2) upon EI.
4
9
( 1997 by John Wiley & Sons, Ltd.
JOURNAL OF MASS SPECTROMETRY VOL. 32, 750È754 (1997)

752
V. VAIS AND A. MANDELBAUM
Scheme 3
High-resolution mass spectral measurement of the
mixture of cis- and trans-4 shows the presence of two
m/z 100 ions. The major [C H NO]` ion (m/z
5 10
100.0755, calculated 100.0762, most abundant in the
mass spectrum) is formed presumably by the standard
fragmentation process7 shown in Scheme 6. The minor
[C H N]` ion (m/z 100.1128, calculated 100.1126,
Scheme 4
6 14
Figure 2. EI mass spectra of stereoisomeric 1-butyl-1-methoxy-3-dimethylaminocyclohexanes cis- and trans-3 (R ¼C H ).
4
9
( 1997 by John Wiley & Sons, Ltd.
JOURNAL OF MASS SPECTROMETRY, VOL. 32, 750È754 (1997)

STEREOSPECIFIC FRAGMENTATION OF 3-DIMETHYLAMINOCYCLOHEXANOLS
753
Scheme 5
10% relative abundance), corresponding to ion b, is pre-
sumably formed from cis-4 via a route similar to that
shown in Scheme 3. This presumably di†erent behavior
of the unsubstituted cis- and trans-3-dimethyl-
aminocyclohexanols cis- and trans-4 is hidden in their
low-resolution EI mass spectra.
The unsubstituted cis- and trans-1-methoxy-3-
dimethylaminocyclohexanes cis- and trans-5 a†ord
indistinguishable EI mass spectra (shown in Fig. 4). In
Figure 3. EI mass spectra of stereoisomeric unsubstituted 3-
dimethylaminocyclohexanes cis- and trans-4.
Figure 4. EI mass spectra of stereoisomeric 1-methoxy-3-
dimethylaminocyclohexanes cis- and trans-5.
Scheme 6
( 1997 by John Wiley & Sons, Ltd.
JOURNAL OF MASS SPECTROMETRY VOL. 32, 750È754 (1997)

754
V. VAIS AND A. MANDELBAUM
contrast to the 1-alkyl-substituted amino ethers 3, none
of the stereoisomers cis- and trans-5 exhibits elimination
of formaldehyde.
Materials
1-Butyl-3-dimethylaminocyclohexanols (1). A mixture of cis-
and trans-1 (R \ n-C H ) was synthesized from 3-
4 9
dimethylaminocyclohexanone and n-butyllithium by the
CONCLUSION
literature procedure.4
It has been shown a long time ago that stereoisomeric
3- and 4-arylcyclohexylamines give rise to identical EI
mass spectra.1,8 This non-stereospeciÐc behavior has
been ascribed to the low energy required for the ring
cleavage in cycloalkylamines (a-cleavage of the C(1)È
C(2) bond), which results in identical structures of the
fragmenting M`Õ ions of the cis- and trans-isomers.1,8,9
The results of this investigation show that the addi-
tional hydroxy and methoxy groups at position 3
induce additional fragmentation channels initiated by a
hydrogen transfer between the oxygen and nitrogen
functions. These additional fragmentation processes
occur preferentially in the cis-isomers, where the dis-
tance between the two interacting functions is small.
1-Butyl-1-methoxy-3-dimethylaminocyclohexane (3). A mix-
ture of cis- and trans-1 (R \ C H ) (0.2 g, 1 mmol) was
4 9
added to a suspension of NaH (0.03 g, 12 mmol) in 2 ml
of dry tetrahydrofuran (THF). After stirring for 20 min
at 40 ¡C, iodomethane (0.4 g, 3 mmol) was added, and
the mixture was stirred for 4 h. Addition of water (3 ml)
followed by evaporation of THF and methylene chlo-
ride extraction yielded a mixture of cis- and trans-3
(R \ C H ) (70%).
4 9
4-Dimethylaminoheptane (2). 4-Aminoheptane was pre-
pared by lithium aluminum hydride reduction of
heptan-4-one oxime.10 EschweilerÈClarke methyl-
ation11 with formaldehyde and formic acid gave 2 (yield
65%).
EXPERIMENTAL
Dimethylaminocyclobutane. This
was
obtained
by
EschweilerÈClarke methylation11 of aminocyclobutane
Mass spectrometry
(Aldrich).
Gas chromatographic/mass spectrometric analyses and
CID measurements were carried out on a Finnigan
TSQ-70B triple-stage quadrupole mass spectrometer.
The stereoisomeric pairs were introduced as mixtures,
and separations were performed on a DB-5 (0.25 km
Ðlm thickness) 30 m ] 0.25 mm i.d. capillary column.
The column temperature was programmed from 60 to
260 ¡C at 15 ¡C min~1. The scan rate was 1 scan s~1.
EI measurements were performed at a 150 ¡C ion
source temperature and 70 eV electron energy. CID
measurements were performed with argon as the target
gas (0.3 mTorr, indicated (1 Torr \ 133.3 Pa)) at 40 eV
collision energy (indicated) in order to ensure reliable
comparisons.
3-Dimethylaminocyclohexanols (4). A mixture of cis- and
trans-4 was prepared by sodium borohydride reduction
of 3-dimethylaminocyclohexanone.
1-Methoxy-3-dimethylaminocyclohexanes (5). A mixture of
cis- and trans-5 was obtained from 4 by the procedure
described above for the preparation of 3.
Acknowledgement
This work was supported by the Fund for Promotion of Research at
the Technion.
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JOURNAL OF MASS SPECTROMETRY, VOL. 32, 750È754 (1997)