Loss of benzene to generate an enolate anion by a site-specific double-hydrogen transfer during CID fragmentation of o-alkyl ethers of ortho-hydroxybenzoic acids

Article abstract of DOI:10.1002/jms.1399

Collision-induced dissociation of anions derived from orffco- alkyloxybenzoic acids provides a facile way of producing gaseous enolate anions. The alkyloxyphenyl anion produced after an initial loss of CO₂ undergoes elimination of a benzene molecule by a double-hydrogen transfer mechanism, unique to the ortho isomer, to form an enolate anion. Deuterium labeling studies confirmed that the two hydrogen atoms transferred in the benzene loss originate from positions 1 and 2 of the alkyl chain. An initial transfer of a hydrogen atom from the C-l position forms a phenyl anion and a carbonyl compound, both of which remain closely associated as an ion/neutral complex. The complex breaks either directly to give the phenyl anion by eliminating the neutral carbonyl compound, or to form an enolate anion by transferring a hydrogen atom from the C-2 position and eliminating a benzene molecule in the process. The pronounced primary kinetic isotope effect observed when a deuterium atom is transferred from the C-l position, compared to the weak effect seen for the transfer from the C-2 position, indicates that the first transfer is the rate determining step. Quantum mechanical calculations showed that the neutral loss of benzene is a thermodynamically favorable process. Under the conditions used, only the spectra from ortho isomers showed peaks at mlz 77 for the phenyl anion and mlz 93 for the phenoxyl anion, in addition to that for the ortho-specific enolate anion. Under high collision energy, the ortho isomers also produce a peak at mlz 137 for an alkene loss. The spectra of meta and para compounds show a peak at mlz 92 for the distonic anion produced by the homolysis of the O-C bond. Moreover, a small peak at mlz 136 for a distonic anion originating from an alkyl radical loss allows the differentiation of para compounds from meta isomers. Copyright

Full text of DOI:10.1002/jms.1399

JOURNAL OF MASS SPECTROMETRY
J. Mass Spectrom. 2008; 43: 1224–1234
Published online 12 March 2008 in Wiley InterScience
(www.interscience.wiley.com) DOI: 10.1002/jms.1399
Loss of benzene to generate an enolate anion by a
site-specific double-hydrogen transfer during CID
fragmentation of o-alkyl ethers of
ortho-hydroxybenzoic acids
Athula B. Attygalle,∗ Jason B. Bialecki, Upul Nishshanka, Carl S. Weisbecker and
Josef Ruzicka
Center for Mass Spectrometry, Department of Chemistry and Chemical Biology, Stevens Institute of Technology, Hoboken, New Jersey 07030, USA
Received 18 December 2007; Accepted 29 January 2008
Collision-induced dissociation of anions derived from ortho-alkyloxybenzoic acids provides a facile way
of producing gaseous enolate anions. The alkyloxyphenyl anion produced after an initial loss of CO2
undergoes elimination of a benzene molecule by a double-hydrogen transfer mechanism, unique to the
ortho isomer, to form an enolate anion. Deuterium labeling studies confirmed that the two hydrogen atoms
transferred in the benzene loss originate from positions 1 and 2 of the alkyl chain. An initial transfer
of a hydrogen atom from the C-1 position forms a phenyl anion and a carbonyl compound, both of
which remain closely associated as an ion/neutral complex. The complex breaks either directly to give the
phenyl anion by eliminating the neutral carbonyl compound, or to form an enolate anion by transferring a
hydrogen atom from the C-2 position and eliminating a benzene molecule in the process. The pronounced
primary kinetic isotope effect observed when a deuterium atom is transferred from the C-1 position,
compared to the weak effect seen for the transfer from the C-2 position, indicates that the first transfer is
the rate determining step. Quantum mechanical calculations showed that the neutral loss of benzene is
a thermodynamically favorable process. Under the conditions used, only the spectra from ortho isomers
showed peaks at m/z 77 for the phenyl anion and m/z 93 for the phenoxyl anion, in addition to that for
the ortho-specific enolate anion. Under high collision energy, the ortho isomers also produce a peak at m/z
137 for an alkene loss. The spectra of meta and para compounds show a peak at m/z 92 for the distonic
anion produced by the homolysis of the O–C bond. Moreover, a small peak at m/z 136 for a distonic anion
originating from an alkyl radical loss allows the differentiation of para compounds from meta isomers.
Copyright  2008 John Wiley & Sons, Ltd.
KEYWORDS: CID; ESI; negative ions; alkyloxybenzoic acid; isotope effect; even-electron ions; fragmentation; ortho effect; ion
neutral complex
approaches offer little help for unambiguous identification
of unknown compounds. Unquestionably, before attempting
to develop successful AI programs for interpretation of EE
spectra,1 the underlying fragmentation pathways must be
thoroughly scrutinized by detailed experimentation.
The interpretation of CID spectra of EE ions becomes
more complicated when double- or multiple-hydrogen
transfers are involved. Double-hydrogen migrations under
electron ionization fragmentation have been noted several
decades ago.3 For example, EI mass spectra of aliphatic
esters show a peak for the protonated acid which origi-
nates by the elimination of an alkenyl radical by a path-
way referred to as a McLafferty rearrangement with a
double-hydrogen transfer (r2H).4 The mechanism has been
widely studied by isotope labeling, which indicates that
the first hydrogen atom is extracted more or less specif-
ically from the ꢀ position, whereas the second hydrogen
INTRODUCTION
Modern mass spectrometric techniques such as electrospray
ionization (ESI) generate predominantly even-electron (EE)
ions. In order to obtain structural information from EE
ions, they are subjected to collision-induced dissociation
(CID). Although CID spectra of EE ions often appear simple,
the interpretation is not always straightforward, especially
when peaks representing both radical and neutral molecule
losses are observed simultaneously. Attempts have been
made to formulate fragmentation rules based on empirical
observations, and use artificial intelligence (AI) to interpret
the CID spectra of EE ions.1,2 In practical terms, such
ŁCorrespondence to: Athula B. Attygalle, Center for Mass
Spectrometry, Department of Chemistry and Chemical Biology,
Stevens Institute of Technology, Hoboken, New Jersey 07030, USA.
E-mail: athula.attygalle@stevens.edu
Copyright  2008 John Wiley & Sons, Ltd.

Benzene loss during CID fragmentation of o-alkoxybenzoic acids
1225
appears to be extracted randomly from several available
positions.4
and filtered through silica gel. Flash chromatographic
purification on silica gel (0–60% Et2O in hexane) gave
a colorless liquid (123 mg, 85%). NMR υC 62.2 (quintet,
J D 21.5), 32.7, 31.9, 29.6, 29.5, 29.4, 29.3, 25.7, 22.6, 14.1;
υH (200 MHz) 1.65–1.48 (m, 2H), 1.48–1.08 (m, 14H), 0.89
(t, J D 6.2, 3H); EI-MS m/z (%) 142 (4), 114 (11), 113 (16), 112
(14), 100 (10), 99 (22), 85 (45), 84 (51), 83 (44), 71 (59), 70 (100),
69 (59), 57 (78), 56 (96), 55 (73), 73 (100), 41 (97).
In our explorations on collision-induced fragmentation
of low-molecular-weight anions,5,6 we noted a site-specific
double-hydrogen migration which enables unequivocal
differentiation of ortho isomers of alkyloxybenzoic acids
from those of meta and para isomers. Moreover, this
unique fragmentation enables facile generation of gaseous
enolate anions which are known to act as intermediates in
photochemical smog cycles, combustion reactions and many
organic syntheses of complex compounds.7
Decane-1,3-diol
LDA (4.5 mmol, 5.63 ml of 1.8 M solution) was stirred in THF
°
(10 ml) at ꢀ78 C and ethyl acetate (0.9 ml, 4.5 mmol) was
EXPERIMENTAL
added, and the mixture was stirred for 45 min.8 Octanal
(5.63 ml, 4.95 mmol) was added, and after 0.5 h the reaction
was quenched with aqueous NH4Cl (5%, 5 ml). The mixture
was extracted with Et2O, and evaporation of the organic
phase gave crude ethyl 3-hydroxydecanoate (1.80 g, 90%).
EI-MS m/z (%) 198 (1), 153 (5), 127 (7), 117 (100), 89 (25),
89 (25), 71 (46), 75 (12), 60 (15), 55 (20), 43 (50). Ethyl 3-
hydroxydecanoate was then reduced with LiAlH4. Crude
product was purified by flash chromatography on silica gel
(0–70% EtOAc in hexane) to give 1,3-decanediol (0.98 g,
70%). NMR υH (200 MHz) 4.00–3.61 (m, 3H), 2.29 (s, 2H),
1.82–1.17 (m, 14H), 0.88 (t, J D 6.7, 3H); EI-MS m/z (%) 129
(4), 127 (13), 111 (6), 110 (7), 100 (4), 95 (5), 84 (12), 82 (10),
81(10), 75 (100), 69 (39), 57 (79), 55 (34), 43 (46), 41 (44).
General
All solvents and reagents were obtained from Aldrich
Chemical Co. (St. Louis, MO) and used as purchased.
All synthetic products were detected as one spot on thin
layer chromatography analysis (precoated 0.25-mm silica gel
plates purchased from Fisher) unless specified. All NMR
spectra were recorded from a Varian INOVA 400, a GE 300,
or a Varian VXR-200 spectrometer using CDCl3 as solvent.
Chemical shifts for 1H NMR are reported in parts per million
(ppm) relative to the internal reference of tetramethyl silane
(TMS). All coupling constants (J values) are reported in
Hertz (Hz). All 13C NMR spectra are decoupled and all
chemical shifts are reported relative to that of CDCl3. EI
Mass spectra were recorded on an HP 5970 series mass
selective detector coupled to a Hewlett Packard 5890 Series
II gas chromatograph.
Synthesis of [2,2-2H2]decan-1-ol and [3,3-2H2]decan-1-ol
Both compounds were synthesized by the general procedure
summarized in Scheme 1.
Chemicals
2-Hydroxybenzoic acid, 3-hydroxybenzoic acid, 4-
hydroxybenzoic acid, 1-bromohexane, 1-hexanol, 1,2-
decanediol, 1,3-decanediol, octanal, lithium diisopropy-
lamide (LDA), tetradhydrofuran (THF), LiAlD4 and D2O
(99.9 atom% D) were obtained from Sigma–Aldrich Chemi-
cal Company (St. Louis, MO).
General method for the synthesis of
1-f[tert-butyl(dimethyl)silyl]oxygdecanols
A solution of tert-butyldimethylsilyl chloride (10.5 mmol)
in CH2Cl2 (5 ml) was added to 1,2-decanediol (1) or
1,3-decanediol (2; 10 mmol), Et3N (11 mmol) and 4-
dimethylaminopyridine (DMAP) (1 mmol) in CH2Cl2 (9 ml)
°
at 0 C under N2. The mixture was stirred for 30 min at
Synthesis of [1,1-2H2]decan-1-ol
°
0 C for 2 h. About 75% of the solvent was evaporated,
hexane (10 ml) was added and the mixture was filtered over
silica gel and Na2SO4. Crude product was purified by flash
chromatography on silica gel (0–30% EtOAc in hexane).
Decanoic acid (158 mg, 0.917 mmol) in Et2O (1 ml) was
°
added to LiAlD4 (46 mg, 1.10 mmol) in Et2O (0.5 ml) at 0 C.
The mixture was stirred for 1 h, treated with H2O ꢁ90 µlꢂ
TBDMS
(CH2)m
(CH2)n
(CH2)m
(CH2)n
CH3
O
CH3
HO
O
OH
(3) n = 1, m = 7
(4) n = 2, m = 6
a) TBDMS-Cl, ET3N, DMAP
b) PDC
(1) n = 1, m = 7
(2) n = 2, m = 6
a) LiAlD4
b) CH3SO2Cl, ET3N
(CH2)m
(CH2)n
HO
CH3
TBDMS
(CH2)m
(CH2)n
CH3
O
D
D
O− SO2CH3
a) LiAlD4
b) p-TsOH, H2O, THF
D
(7) n = 1, m = 7
(8) n = 2, m = 6
(5) n = 1, m = 7
(6) n = 2, m = 6
Scheme 1. Synthesis of deuteriated 1-decanols.
Copyright  2008 John Wiley & Sons, Ltd.
J. Mass Spectrom. 2008; 43: 1224–1234
DOI: 10.1002/jms

1226
A. B. Attygalle et al.
1-f[tert-Butyl(dimethyl)silyl]oxyg-[3-2H]decan-3-ol
Prepared from 1-f[tert-butyl(dimethyl)silyl]oxygdecan-3-one
(4); yield 0.66 g (66%). NMR υH (200 MHz) 3.97–3.75 (m, 2H),
3.45 (br s, 1H), 1.64 (t, J D 5.5, 2H), 1.57–1.20 (m, 12H), 0.90
(s, 9H), 0.88 (t, J D 6.7, 3H), 0.08 (s, 6H); EI-MS m/z (%) 232
(1), 229 (3), 214 (4), 190 (11), 145 (3), 132 (7), 116 (2), 115 (2),
105 (58), 98 (20), 97 (14), 89 (12), 84 (47), 83 (41), 75 (100), 73
(15), 70 (25), 69 (25), 55 (34), 43 (18), 41 (25).
1-f[tert-Butyl(dimethyl)silyl]oxygdecan-2-ol
Prepared from decane-1,2-diol (1); yield 2.78 g (96%). NMR
υH (200 MHz) 3.71–3.55 (m, 2H), 3.38 (dd, J D 8.4 and 10.6,
1H), 2.44 (d, J D 2.4, 1H), 1.50–1.20 (m, 14H), 0.90 (s, 9H),
0.88 (t, J D 7.3, 3H), 0.07 (s, 6H); EI-MS m/z (%) 231 (6), 229
(1), 213 (1), 175 (2), 159 (1), 131 (3), 105 (54), 97 (33), 75 (100),
73 (32), 69 (42), 57 (28), 55 (43), 43 (23), 41 (26).
1-f[tert-Butyl(dimethyl)silyl]oxygdecan-3-ol
Syntheses of
Prepared from decane-1,3-diol (2); yield 1.42 g (90%). NMR
υH 3.98–3.73 (m, 3H), 3.46 (d, J D 2.3, 1H), 1.72–1.58 (m, 2H),
1.58–1.19 (m, 12H), 0.90 (s, 9H), 0.88 (t, J D 6.7, 3H), 0.08 (s,
6H); EI-MS m/z (%) 231 (1), 229 (3), 214 (1), 213 (3), 145 (3),
132 (3), 131 (5), 115 (3), 105 (54), 101(9), 97 (31), 83 (81), 75
(100), 73 (23), 69 (42), 57 (30), 55 (45), 43 (19), 41 (28).
1-f[tert-Butyl(dimethyl)silyl]oxyg-[2H]decyl
methanesulfonates
To a solution of 1-f[tert-butyl(dimethyl)silyl]oxyg-[2-2H]de-
can-2-ol (10 mmol) or 1-f[tert-butyl(dimethyl)silyl]oxyg-[3-
2H]decan-3-ol (10 mmol), and Et3N (28 mmol) in anhydrous
°
CH2Cl2 (10 ml) at 0 C under N2, methanesulfonyl chloride
Syntheses of 1-f[tert-butyl(dimethyl)silyl]oxygdecanones
(13 mmol) was added over a period of 3 min.11 The reaction
mixture was stirred for 3 h. The reaction was quenched
with H2O (10 ml), organic phase separated, and the water
phase was extracted with EtOAc (4 ð 10 ml). Merged organic
fractions were filtered over silica gel and Na2SO4. Crude
product was purified by flash chromatography on silica gel
(0–40% EtOAc in hexane).
To a mixture of pyridinium dichromate (PDC) (13 mmol),
˚
powdered molecular sieves (4 A, 4.2 g) and CH2Cl2 (7 ml)
°
stirred at 4 C, a solution of 1-f[tert-butyl(dimethyl)silyl]oxyg
decan-2-ol (10 mmol), or 1-f[tert-butyl(dimethyl)silyl]oxyg
decan-3-ol (10 mmol), in CH2Cl2 (10 ml) was added and the
mixture was stirred for 5 h.10 The crude product was purified
by flash chromatography on silica gel [0–20% methyl tert-
butyl ether (MTBE) in hexane].
1-f[tert-Butyl(dimethyl)silyl]oxyg-[2-2H]decan-2-yl
methanesulfonate (5)
Prepared from compound 3; yield 1.21 g (95%). NMR υH
(200 MHz) 3.73 (s 1H), 3.72 (s, 1H), 3.05 (s, 3H), 1.59–1.72 (m,
2H), 1.48–1.20 (m, 12H), 0.90 (s, 9H), 0.88 (t, J D 6.7, 3H), 0.08
(s, 3H), 0.07 (s, 3H).
1-f[tert-Butyl(dimethyl)silyl]oxygdecan-2-one (3)
Prepared from 1-f[tert-butyl(dimethyl)silyl]oxygdecan-2-ol;
yield 1.84 g (69%). NMR υH (200 MHz) 4.17 (s, 2H), 2.48 (t,
J D 7.4, 2H), 1.57 (quintet, J D 7.1, 2H), 1.26 (br s, 10H), 0.92
(s, 9H), 0.88 (t, J D 6.7, 3H), 0.09 (s, 6H); EI-MS m/z (%) 271
(4), 253 (1), 229 (100), 219 (1), 199 (1), 143 (13), 131 (8), 129
(11), 117 (52), 105 (21), 95 (36), 75 (68), 73 (62), 69 (23), 55 (26),
43 (40), 41 (53).
1-f[tert-Butyl(dimethyl)silyl]oxyg-[3-2H]decan-3-yl
methanesulfonate (6)
Prepared from compound 4; yield 0.78 g (98%). NMR υH
(200 MHz) 3.71 (t, J D 6.1, 2H), 3.02 (s, 3H), 1.94–1.67 (m,
4H), 1.50–1.19 (m, 10H), 0.89 (s, 9H), 0.88 (t, J D 6.7, 3H), 0.06
(s, 6H).
1-f[tert-Butyl(dimethyl)silyl]oxygdecan-3-one (4)
Prepared from 1-f[tert-butyl(dimethyl)silyl]oxygdecan-3-ol;
yield 1.84 g (69%). NMR υH (200 MHz) 3.88 (t, J D 6.3, 2H),
2.59 (t, J D 6.3, 2H), 2.44 (t, J D 7.3, 2H), 1.56 (quintet, J D 7.3,
2H), 1.27 (br s, 8H), 0.87 (s, 9H), 0.87 (t, J D 6.3, 3H), 0.05 (s,
6H); EI-MS m/z (%) 271 (1), 229 (3), 199 (2), 157 (2), 131 (12),
113 (3), 105 (7), 95 (5), 83 (6), 75 (100), 70 (41), 55 (36), 43 (14),
41 (22).
Synthesis of [2,2-2H2]decan-1-ol (7) and
[3,3-2H2]decan-1-ol (8)
To a suspension of LiAlD4 (30 mmol) in anhydrous Et2O
°
(10 ml)at0 C, asolutionof1-f[tert-butyl(dimethyl)silyl]oxyg-
[2-2H]decan-2-yl methanesulfonate (5) (10 mmol) or 1-f[tert-
butyl(dimethyl)silyl]oxyg-[3-2H]decan-3-yl methanesulfon-
ate (6) in anhydrous Et2O (4 ml) was added, and the reaction
mixture was stirred for 3 h.5 Water was added, the mixture
was filtered, and the precipitate was washed with EtOAc.
Filtrate was refiltered over silica gel and the solvent was
evaporated. Crude product was dissolved in a solution of
p-TsOH (200 mg) in THF (9 ml) and H2O (1.5 ml), and stirred
for 4 h. Then, solvent was partially evaporated, the mixture
was neutralized with aqueous NaHCO3 and extracted with
Et2O ꢁ4 ð 5 mlꢂ. Organic phase was filtered over silica gel,
and crude product was purified by flash chromatography on
silica gel (0–50% Et2O in pentane).
Syntheses of
1-f[tert-butyl(dimethyl)silyl]oxyg-[2H]decanols
1-f[tert-Butyl(dimethyl)silyl]oxygdecanone (10 mmol) was
°
reduced with LiAlD4 (5 mmol) at ꢀ78 C by a procedure
similar to that described for [1,1-2H2]decan-1-ol. Crude
product was purified by flash chromatography on silica
gel (0–30% EtOAc in hexane).
1-f[tert-Butyl(dimethyl)silyl]oxyg-[2-2H]decan-2-ol
Prepared from 1-f[tert-butyl(dimethyl)silyl]oxygdecan-2-one
(3); yield 1.05 g (61%). NMR υH (200 MHz) 3.62 (d, J D 9.9,
1H), 3.38 (d, J D 9.9, 1H), 2.41 (s, 1H), 1.51–1.19 (m, 14H),
0.91 (s, 9H), 0.88 (t, J D 6.8, 3H), 0.07 (s, 6H); EI-MS m/z (%)
232 (5), 214 (2), 176 (1), 147 (1), 146 (1), 140 (1), 132 (2), 131
(2), 118 (2), 105 (42), 98 (21), 89 (10), 84 (49), 75 (100), 73 (31),
69 (23), 55 (27), 44 (18), 41 (23).
[2,2-2H2]Decan-1-ol (7)
Prepared from compound 5; yield 0.42 g (83%). NMR υH
(200 MHz) 3.64 (s, 2H), 1.46–1.11 (m, 14H), 0.88 (t, J D 6.7,
3H); υC 62.8, 31.9 (quintet, J D 19.1), 31.8, 29.6, 29.5, 29.32,
Copyright  2008 John Wiley & Sons, Ltd.
J. Mass Spectrom. 2008; 43: 1224–1234
DOI: 10.1002/jms

Benzene loss during CID fragmentation of o-alkoxybenzoic acids
1227
29.26, 25.5, 22.6, 14.0; EI-MS m/z (%) 142 (3), 114 (6), 113 (11),
112 (13), 111 (4), 99 (16), 98 (11), 97 (12), 86 (12), 85 (33), 84
(43), 83 (35), 71 (50), 70 (98), 69 (45), 57 (75), 56 (98), 55 (60),
43 (100), 42 (56), 41 (74).
Preparation of 2-decyloxybenzoic acid (9),
2-([1,1-2H2]decyloxy)benzoic acid (10),
2-([2,2-2H2]decyloxy)benzoic acid (11),
2-([3,3-2H2]decyloxy)benzoic acid (12)
Each methyl 2-alkyloxybenzoate (¾0.03 g, 0.1 mmol) was
dissolved in methanol (2 ml), treated with 1 M NaOH
(0.15 ml) and stirred for 4 h. The mixture was acidified with
0.1 M HCl, and extracted with diethyl ether (2 ml ð 3). The
extracts were combined, dried over MgSO4 and concentrated
to yield the corresponding 2-alkoxysalicylic acid as a clear
oil. Yield 80% (0.02 g).
[3,3-2H2]Decan-1-ol (8)
Prepared from compound 6; yield 0.28 g (78%). NMR υH
(200 MHz) 3.64 (t, J D 6.7, 2H), 1.55 (t, J D 6.8, 2H), 1.12–1.41
(m, 12 H), 0.88 (t, J D 6.6, 3H); υC 62.9, 32.5, 31.8, 29.5, 29.5,
29.24, 29.15, 24.9 (quintet, J D 19.0), 22.6, 14.0; EI-MS m/z (%)
142 (2), 114 (9), 113 (13), 112 (5), 111 (2), 99 (18), 98 (13), 97
(11), 86 (19), 85 (41), 84 (38), 83 (21), 71 (53), 70 (80), 69 (36),
57 (80), 56 (93), 55 (50), 43 (100), 42 (60), 41 (68).
Mass spectrometry
The purity of each sample was verified to be >99% by GC-MS
analysis on a HP 5989B quadrupole mass spectrometer linked
to a Hewlett Packard 5890 Series II gas chromatograph. The
CID mass spectra were recorded on a Micromass Quat-
tro I mass spectrometer equipped with an electrospray ion
source. Samples were infused as methanol–water–NaOH
(9 : 1 : 10ꢀ5) solutions at a flow rate of 6 µl minꢀ1. The source
Synthesis of hexyl bromide and other n-alkyl
bromides
A mixture of ice-cooled hexan-1-ol (0.05 g, 0.3 mmol) and
PBr3 (0.03g, 0.1 mmol) was allowed to stand at for 4 h. The
mixture was dissolved in Et2O (1.5 ml), washed with water
(1 ml), 1 M NaOH (1 ml) and 1 M HCl (1 ml). The ethereal
layer was separated, dried over MgSO4 and evaporated to
give the desired bromide. Yield 85% (0.06 g). 1-Bromohexane
[EI-MS m/z (%) 164/166 (MCž, 10/10), 135/137 (50), 107/109
(10), 85 (40), 57 (30), 43 (100)]. Other alkyl bromides
and deuteriated decyl bromides (1-bromo[1,1-2H2]decane,
1-bromo[2,2-2H2]decane and 1-bromo[3,3-2H2]decane) were
prepared in a similar way.
°
temperature was held at 80 C. The argon gas pressure in the
collision cell was set to attenuate precursor transmission by
30–50%.
Computational methods
All Quantum Mechanics (QM) calculations were performed
using the Gaussian 03W program package. Computations
were performed using the restricted Hartree–Fock method
as described in the review article by Mercero et al.12 The
6-31GŁ basis set augmented with the addition of polarization
functions on carbon and oxygen atoms was used.13 Struc-
tures depicted in the Results section were energy minimized
to obtain a stationary state.
General synthesis of hexyl and other alkyl ethers
of hydroxybenzoic acids
A mixture of 1-bromohexane (50 µl, 0.356 mmol), 2-, 3-, or 4-
hydroxybenzoic acid methyl ester (54 mg, 0.356 mmol), and
K2CO3 (50 mg) in dimethyl formamide (DMF) (2 ml) was
°
heated at 90 C for 24 h. The reaction was quenched with
RESULTS AND DISCUSSION
2 ml of water, and the product was extracted into the diethyl
ž
ether. Methyl 2-hexoxybenzoate [EI-MS m/z (%) 236 (MC
,
A comparison of product ion spectra of anions derived from
O-alkyl ethers of hydroxybenzoic acids demonstrated that
the spectra of the ortho isomers show several distinctive
peaks that enable the unambiguous identification of the
ortho substitution. To start with, the spectrum of ortho-
ethoxybenzoic acid is very different from those of meta
and para isomers (Fig. 1). For example, the fragmentation
of the m/z 165 ion derived from ortho-ethoxybenzoic acid
produces an intriguing peak at m/z 43 unique to the ortho
isomer. We hypothesized that the m/z 43 peak represents
the vinyloxy anion (Scheme 2). A spectrum recorded by
tandem mass spectrometry of the o-ethoxyphenyl anion
(m/z 121) formed by the initial decarboxylation, showed
peaks at m/z 77 and 43 for two of its product ions (Fig. 2).
These two peaks represented phenyl anion and vinyloxy
anion, respectively. Moreover, the m/z 121 ion from the
ortho isomer required much less collision activation for it to
undergo further fragmentation (see breakdown curves for
m/z 121 in Fig. 3). Of all the spectra recorded from the m/z
165 ion from O-alkyl ethers of hydroxybenzoic acids, only
those of the ortho isomers showed a peak at m/z 77, under
the experimental conditions used (Fig. 1).
10), 205 (8), 152 (50), 120 (100), 92 (20), 55 (10)]. Methyl
3-hexoxybenzoate [EI-MS m/z (%) 236 (MCž, 10), 205 (8),
152 (100), 121 (80), 93 (8), 55 (10)]. Methyl 4-hexoxybenzoate
[EI-MS m/z (%) 236 (MCž, 10), 205 (8), 152 (50), 121 (100), 93
(10), 55 (10)]. The residue obtained by the evaporation of the
°
solvent was hydrolyzed with 1 M NaOH in methanol at 50 C
for 2 h. The sodium salt obtained in this way was acidified
with 1 M HCl. Other n-alkyl ethers of hydroxybenzoic acids
were synthesized in a similar manner.
Preparation of methyl
2-([1,1-2H2]decyloxy)benzoate, methyl
2-([2,2-2H2]decyloxy)benzoate, and methyl
2-([3,3-2H2]decyloxy)benzoate
Each deuterium-labeled bromodecane (¾0.044 g, 0.2 mmol)
was combined with methyl salicylate (0.03 g, 0.2 mmol),
K2CO3 (0.06 g, 0.4 mmol), and DMF (1 ml) and stirred at
°
90 C for 24 h. Water (9 ml) was added and the mixture
was extracted with diethyl ether. The extract was dried over
MgSO4, filtered and evaporated to give the desired products.
Yield 70% (0.05 g).
Copyright  2008 John Wiley & Sons, Ltd.
J. Mass Spectrom. 2008; 43: 1224–1234
DOI: 10.1002/jms

1228
A. B. Attygalle et al.
165
121
93
100 (A)
100
(A)
O
O
COO
121
O
O
O
93
%
%
COO
OH
77
O
43
43
45
77
137
0
0
40
60
60
60
80
100 120 140 160 180 200
m/z
40
60
60
60
80
100 120 140 160 180 200
m/z
121
121
100 (B)
100 (B)
O
165
COO
O
92
O
%
0
%
0
O
O
92
45
40
80
100 120 140 160 180 200
m/z
40
80
100 120 140 160 180 200
m/z
121
165
121
100 (C)
100 (C)
COO
O
O
O
92
%
0
%
0
COO
O
O
92
O
136
77
40
80
100 120 140 160 180 200
m/z
40
80
100 120 140 160 180 200
m/z
Figure 1. Unit–resolution product ion spectrum of m/z 165
([M ꢀ H]ꢀ) ion derived from ortho- (A), meta- (B) and
para-ethoxybenzoic acid (C) at a collision energy settings of
20 eV recorded on a Quattro I mass spectrometer (all the
parameters including collision gas pressure and cone-skimmer
voltage were identical).
Figure 2. Product ion spectrum of m/z 121 ion, which was
produced in source by the fragmentation of the m/z 165
([M ꢀ H]ꢀ) ion derived from ortho- (A), meta- (B) and
para-ethoxybenzoic acid (C).
Corresponding peaks were observed at the expected m/z
values in the spectra of other o-alkyloxy homologues (Fig. 5)
confirming that the fragmentation depicted in Scheme 2 is a
general phenomenon unique to ortho isomers.
For the formation of an enolate anion, a molecule of
benzene must be eliminated from the precursor. In other
The fragmentation proposed in Scheme 2 is in fact
general phenomenon since the spectrum of ortho-
hexyloxybenzoic acid showed an intense peak m/z 77 in
addition to that at m/z 99 for the enolate ion, both of which
were absent in the spectra of meta and para isomers (Fig. 4).
a
(9) X = H, Y = H, Z = H
(10) X = D, Y = H, Z = H
O
O
3
CZ2
1
(11) X = H, Y = D, Z = H
CX2
CH3
2
CY2
O
(CH2)6
(12) X = D, Y = H, Z = D
Copyright  2008 John Wiley & Sons, Ltd.
J. Mass Spectrom. 2008; 43: 1224–1234
DOI: 10.1002/jms

Benzene loss during CID fragmentation of o-alkoxybenzoic acids
1229
221
100 (A)
50
m/z 165
COO
100 (A)
O
O
O
O
93
m/z 93
O
%
m/z 121
0
0
10
20
30
40
50
60
99
Collision Energy (eV)
77
137
177
COO
O
m/z 165
0
100 (B)
50
50
100
150
200
250
221
100 (B)
O
O
m/z 92
O
m/z 121
0
0
10
20
30
40
50
60
%
177
Collision Energy (eV)
O
COO
m/z 165
100 (C)
50
92
O
0
50
100
150
200
250
m/z 92
m/z 121
221
O
O
100 (C)
0
0
10
20
30
40
50
60
O
Collision Energy (eV)
O
O
O
Figure 3. Plot of percentage abundance of ions versus
%
0
laboratory-frame collision energy for m/z 165(- -), 121(-ꢀ-), 93
ž
177
(- -) and 92(-♦-) ions derived from ortho- (A), meta- (B) and
ꢁ
O
para-ethoxybenzoic acid (C).
O
92
136
m/z
COO
+
50
100
150
200
250
O
O
O
m/z 165
m/z 121
m/z 43
Figure 4. Unit–resolution product ion spectrum of m/z 221
[ꢁM ꢀ Hꢂꢀ] from O-hexyl ether of ortho- (A), meta- (B) and
para-hydroxybenzoic acid (C) at a collision energy settings of
20 eV recorded on a Quattro I mass spectrometer (all
parameters including collision gas pressure and cone-skimmer
voltage were identical).
CH3
+
H
O
m/z 77
Scheme 2. Elimination of benzene and acetaldehyde from the
m/z 121 ion derived from o-ethoxybenzoate anion.
A charge-mediated fragmentation of the Ph–O bond of the
anion 16, leads to the formation of an ion–molecule complex
17 between a phenyl anion and an aldehyde (note that all
compounds used in this study were n-alkyloxy derivatives;
a ketone would be eliminated if the C-1 position were
substituted). Presumably, the initial transitional complex 17
either undergoes a direct dissociation to yield a phenyl anion
observed at m/z 77 [which becomes m/z 78 for compound
10, which bears two deuterium atoms at the C-1 position
(Fig. 5(B)); however, for compounds 11 and 12 no shift in
m/z value was observed (Fig. 5(C) and (D))] (Scheme 3,
pathway ‘a’), or endure a spatial rearrangement to reduce
the repulsions between the negative charge on the phenyl
anion and the oxygen atom of the carbonyl group and form an
words, for this fragmentation to occur two hydrogen atoms
must be transferred to the phenyl ring by a very intriguing
mechanism. In order to explore how this fragmentation takes
place, the following deuteriated molecules were synthesized
(10-12) and their spectra were recorded under similar mass
spectrometric conditions (Table 1).
The results demonstrated that one hydrogen atom from
position 1, and another hydrogen atom from position 2 were
specifically transferred to the phenyl ring in the process of
eliminating a benzene molecule. To rationalize the results,
we proposed the fragmentation pathways given in Scheme 3.
After the initial decarboxylation, the o-alkyloxyphenyl anion
that is formed (15) undergoes the first hydrogen transfer
from position 1 of the alkyl chain to give the intermediate 16.
Copyright  2008 John Wiley & Sons, Ltd.
J. Mass Spectrom. 2008; 43: 1224–1234
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1230
A. B. Attygalle et al.
Table 1. Ions observed from anions of some ortho-decyloxybenzoic acids under CID conditions
[M ꢀ H]ꢀ
m/z(%)
[M ꢀ H ꢀ CO2]ꢀ
m/z(%)
Enolate anion
Phenoxide
m/z(%)
Phenyl anion
Compound
m/z(%)
m/z(%)
(9) X D H, Y D H, Z D H
(10) X D D, Y D H, Z D H
(11) X D H, Y D D, Z D H
(12) X D D, Y D H, Z D D
277(100)
279(100)
279(100)
279(100)
233(1)
235(2)
235(2)
235(2)
155(53)
156(20)
156(83)
157(56)
93(99)
77(18)
78(8)
77(51)
77(28)
93(96)/94(5)
93(58)/94(61)
93(93)/94(9)
O
C
O
100
(A)
93
277
O
O
O
155
CO2
77
137
233
0
O
C
100
(B)
93
279
O
CD2
O
D
O
D
D
O
CO2
CO2
CO2
94
156
156
78
137
235
0
O
100
(C)
(D)
279
C
O
O
93
CD2
94
77
O
D
138
O
235
0
O
C
100
93
279
O
CD2
CD2
O
157
94
77
137
235
0
50
100
150
200
250
300
m/z
Figure 5. Product ion spectrum recorded from m/z 277 ([M ꢀ H]ꢀ) ion derived from 2-decyloxybenzoic acid (9) (A), m/z 279
[M ꢀ H]ꢀ) from 2-([1,1-2H2]decyloxy)benzoic acid (10) (B), m/z 279 ([M ꢀ H]ꢀ) from 2-([2,2-2H2]decyloxy)benzoic acid (11) (C), and
m/z 279 ([M ꢀ H]ꢀ) from 2-([3,3-2H2]decyloxy)benzoic acid (12) (D) recorded on a Quattro I mass spectrometer.
intermediate complex 18. The negative charge on the phenyl
ring then removes an acidic ˛-hydrogen (since phenyl anion
is a very strong base) within the complex to form an enolate
anion and eliminate benzene (Scheme 3, pathway ‘b’).
The fragmentation pathways proposed here somewhat
resembles the mechanisms proposed by Chowdhury and
Harrison14 for the fragmentation of enolate ions derived from
acetophenone by negative ion chemical ionization with OHꢀ
as the reagent ion. According to their mechanism, the frag-
mentation of [C6H5COCH2]ꢀ involves an initial formation
of an ion–dipole complex between the phenyl anion and
ketene, which either fragments directly, or undergoes a pro-
ton transfer to produce a ketenyl anion and benzene.
Under collision–activation, the ortho-alkylphenoxide
anions generated by chemical ionization have been observed
previously to undergo ortho-specific fragmentations.15 For
example, o-methyl- and o-ethyl-phenoxide anions have been
observed to lose formaldehyde and acetaldehyde, respec-
tively. It has been proposed that the initial o-ethylphenoxide
anion rearranges to the isomeric ether, which in fact is
Copyright  2008 John Wiley & Sons, Ltd.
J. Mass Spectrom. 2008; 43: 1224–1234
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Benzene loss during CID fragmentation of o-alkoxybenzoic acids
1231
O
O
H
C
(CH2)7
O
- CO2
O
(CH2)7
m/z 233 (15)
m/z 277
(CH2)7
(CH2)7
O
a
(CH2)7
O
+
(16)
O
m/z 77
(17)
H
b
(CH2)7
+
O
(CH2)7
O
m/z 155
(18)
Scheme 3. Formation of an enolate anion by a double-hydrogen migration (pathway ‘b’), and phenyl anion by a single hydrogen
migration (pathway ‘a’).
identical to what is generated by decarboxylation of o-
alkoxybenzoates in the present study. However, for some
unexplained reason o-propylphenoxide anions have not been
observed to undergo a propanal loss.15 In contrast, we have
observed facile losses of aldehydes, as large as decanal. from
our compounds. For example, o-decyloxybenzoate anion at
m/z 233 shows a 156 Da loss to produce the phenyl anion at
m/z 77 (Fig. 5(A)).
To determine the relative energies associated with the
species presented in Scheme 3, a series of QM computations
were carried out by the Hartree–Fock method using a small
basis set called 6-31GŁ. The results are summarized in Fig. 6.
The calculated relative energy of the intermediate 16 formed
by the first hydrogen transfer is about 7 kcal molꢀ1 above that
of the starting anion 15. Moreover, the relative energy of the
five-membered transition state, in which the bond formation
between the negative charge and a hydrogen atom of one of
the C–H bonds at C-1 (this bond is expected to be elongated)
has initiated, is 30.35 kcal molꢀ1 above that of the starting
anion 15. Since this is a significant barrier, compared to that
between the intermediate 16 and the ion/molecule complex
18, the results corroborate the experimental observation that
the first step is the rate determining step. The relative energy
of the transition state between the intermediates 16 and 18
is expected to be low since the conversion involves a direct
bond cleavage. The energy of the ion/molecule complex 18
lies about 3 kcal molꢀ1 below that of the starting anion 15;
consequently, the rearrangement of the intermediate 16 to the
complex 18 is thermodynamically favorable. Since the final
products of the double-rearrangement process lies about
32 kcal molꢀ1 below that of the starting anion, the second
step is even more favorable. Finally, the transitional barrier
between the final products and the ion/molecule complex 18
is very low; therefore the forward reaction should be rapid
as seen by tandem mass spectrometric experiments.
Further support for the proposed mechanisms comes
from the kinetic isotope effects (KIEs) observed from the
deuterium-labeled compounds. For example, the intensities
of the peaks for the monodeuteriated phenyl anion (m/z
78) and the monodeuteriated decyloxy anion (m/z 156)
(Fig. 5(B)) are significantly lower than those recorded for
their nonlabeled counterparts (m/z 77 and 155; Fig. 5(A)).
In fact, the calculated KIE values are 2.3 and 2.7 for the
two respective ions. Despite high margins of error, a KIE
value as large as 2–4 is considered to demonstrate the
participation of H/D atoms in a rate determining step.16
In contrast to the highly pronounced KIE observed for the
deuterium transfer from the C-1 position (m/z 156 Fig. 5(B)),
that from the C-2 position (m/z 156 Fig. 5(C)) is as low as
0.6. This result demonstrates that the transfer of the second
hydrogen atom is not the rate determining step of the two-
step hydrogen migration mechanism proposed in Scheme 3.
Moreover, the low value of 0.9 computed for the KIE effect
for the compound labeled at C-3 position 12 compared to the
nondeuteriated compound 9 indicates the presence of only
a secondary effect, which further supports our mechanism
proposed in Scheme 3.
In addition to the peaks observed for the phenyl
and enolate anions, the spectra also show another ortho-
specific peak at m/z 93, which represents the phenoxide
anion (Fig. 1). However, results from deuterium labeling
Copyright  2008 John Wiley & Sons, Ltd.
J. Mass Spectrom. 2008; 43: 1224–1234
DOI: 10.1002/jms

1232
A. B. Attygalle et al.
40
30
20
10
0
30.35
10.34
7.09
5.87
0.00
-3.09
-
-
-10
[16]
[15]
-
-
[18]
-20
-30
-40
-32.41
o
Figure 6. Relative stabilities of energy-optimized species involved in the double-hydrogen transfer mechanism of o-decyloxyphenyl
anion.
O
O
C
H
O
- CO2
O
m/z 221
m/z 177
O
+
m/z 93
Scheme 4. Fragmentation mechanism of m/z 221 ion derived from O-hexyl ether of ortho-hydroxybenzoic acid.
experiments suggest that the pathways for the formation
of the m/z 93 ion are not as explicit as those observed for
the formation of phenyl and enolate anions. Nonetheless,
the results show that the hydrogen atom required for the
formation of the phenoxide anion originates predominantly
from position 2 of the alkyl group (Fig. 5(C); Scheme 4).
Moreover, deuterium labeling experiments further
showed that the hydrogens on the C-1 make insignifi-
cant contribution to the formation of the phenoxide ion
(Fig. 5(B)). The observation that the spectrum of 2-[20,20-
2H2]decyloxybenzoate (11) showed two peaks at m/z 93 and
94, and that of 2-[30,30-2H2]decyloxybenzoate (12) showed
only a minor peak at m/z 94, indicated that the predominant
mechanism for the formation of m/z 93 is by an elimination
a 1-alkene, mediated by a hydrogen transfer from the C-2
position. However, hydrogen transfers from C-3 and other
positions of the alkyl chain appear possible. The anions
formed by these other mechanisms, attack the C-1 atom to
eliminate a substituted cycloalkane instead of a 1-alkene.
Although not very dramatic, a minor peak, observed at m/z
137, in the spectrum of ortho-ethoxybenzoic acid showed that
an alkene loss by an ortho-specific mechanism is possible
even directly from the parent anion. In fact, an m/z 137 peak
is observed in other ortho isomers as well (Figs 4 and 5).
A product ion spectrum recorded from o-ethoxyphenyl
anion (m/z 121), produced by the initial decarboxylation
Copyright  2008 John Wiley & Sons, Ltd.
J. Mass Spectrom. 2008; 43: 1224–1234
DOI: 10.1002/jms

Benzene loss during CID fragmentation of o-alkoxybenzoic acids
1233
H
is discernible only at about 20 eV. Although the spectra of
meta and para isomers of alkyloxybenzoate anions are more
or less indistinguishable from each other, when the alkoxy
group is relatively small, the spectrum of the para isomer
shows a small peak for the loss of the alkyl radical directly
from the parent anion. For example, Fig. 1 shows a peak at
m/z 136 which is characteristic of the para isomer.
O
O
c
CH2
CH2
+
m/z 121
m/z 93
O
d
+
O
CONCLUSIONS
m/z 45
Although ortho effects are well-established for radical cations
obtained by electron ionization,31,32 only a few examples of
ortho effects have been noted for EE anions.6,15,33–35 The
examples given here not only add to the ortho effects in EE
anions but also mechanistically rationalize the pathway of
a specific double-hydrogen transfer. For the vast number of
double-hydrogen transfers reported previously from radical
cations, the general consensus is that the first hydrogen
atom is extracted more or less specifically from the ꢀ
position, while the second hydrogen is extracted randomly
from other available positions.36,37 However, according to
Kingston et al.4 many interpretations are possible, and there
is no agreement on the ‘correct’ mechanism although a more
specific mechanism has been observed for propylbenzoate.38
In conclusion, the loss of benzene observed here from o-
alkyloxybenzoate anions is one of the clearest examples of a
very specific double-hydrogen transfer.
Scheme 5. Fragmentation mechanism of m/z 121 ion derived
from o-ethoxybenzoic acid.
O
O
C
R
R
- CO2
R
+
O
O
O
R
+
O
m/z 92
Scheme 6. Fragmentation mechanism of anions derived from
O-alkyl ethers of meta-hydroxybenzoic acid (note: the para
isomer fragments by a similar mechanism).
Acknowledgements
This research was supported by funds provided by Stevens Institute
of Technology, NJ.
of o-ethoxybenzoate anion, showed that in addition to the
expected peaks at m/z 93, 77 and 43, a tiny peak is observed
at m/z 45 for ethoxide anion (Fig. 2). Although not very
significant, the o-alkyloxyphenyl anion can fragment by the
mechanisms illustrated in Scheme 5, before it rearranges to
the more energetically favorable ion/molecule complex.
In general all spectra recorded from meta- and para-
alkyloxybenzoic acids were much simpler than those from
ortho compounds (Figs 1 and 4). Moreover, in contrast to
that produced from ortho isomers, the decarboxylated ions
produced from meta and para isomers of alkyloxybenzoic
acids do not undergo the charge-mediated transformations
depicted in Schemes 3 and 4. Instead, they undergo a charge-
remote17–20 homolytic fission to produce a distonic anion
observed at m/z 92 (Scheme 6). Although chemistry of
distonic radical ions is now well-established,21–27 some mass
spectrometry textbooks still advocate that the formation of
ions such as m/z 92 violates the so-called ‘even-electron
rule’.28 On the other hand, numerous violations of this rule
have been documented.29,30
A comparison of energy required for the fragmentation
of the m/z 121 ion derived from ethoxybenzoic acids showed
that less laboratory-frame collisional energy is required for
the ion derived from the ortho isomer to fragment than
those needed for the onset of the homolytic fragmentation
observed for meta and para isomers (Fig. 3). Tandem mass
spectrometric fragmentation experiments performed with
the m/z 121 ion further showed that the m/z 93 ion from
the ortho isomer is visible at about 10 eV collision energy,
whereas the m/z 92 ion from the meta and para isomers
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Copyright  2008 John Wiley & Sons, Ltd.
J. Mass Spectrom. 2008; 43: 1224–1234
DOI: 10.1002/jms