"Meta elimination," a diagnostic fragmentation in mass spectrometry

Article abstract of DOI:10.1007/s13361-011-0164-2

The diagnostic value of the "ortho effect" for unknown identification by mass spectrometry is well known. Here, we report the existence of a novel "meta effect," which adds to the repertoire of useful mass spectrometric fragmentation mechanisms. For example, the meta-specific elimination pathway described in this report enables unequivocal identification of meta isomers from ortho and para isomers of carboxyanilides. The reaction follows a specific path to eliminate a molecule of meta-benzyne, from the anion produced after the initial decarboxylation of the precursor. Consequently, in the CID spectra of carboxyanilides, a peak for the (R-CO-NH)^- anion is observed only for the meta isomers. For example, the peaks observed at m/z 58, 86, 120, 128, and 170 from acetamido-, butamido-, benzamido, heptamido-, and decanamido-benzoates, respectively, were specific only to the spectra of meta isomers.

Full text of DOI:10.1007/s13361-011-0164-2

B American Society for Mass Spectrometry, 2011
J. Am. Soc. Mass Spectrom. (2011) 22:1515Y1525
DOI: 10.1007/s13361-011-0164-2
RESEARCH ARTICLE
“Meta Elimination,” a Diagnostic Fragmentation
in Mass Spectrometry
Athula B. Attygalle, Upul Nishshanka, Carl S. Weisbecker
Center for Mass Spectrometry, Department of Chemistry, Chemical Biology, and Biomedical Engineering, Stevens Institute of
Technology, Hoboken, NJ 07030, USA
Abstract
The diagnostic value of the “ortho effect” for unknown identification by mass spectrometry is well
known. Here, we report the existence of a novel “meta effect,” which adds to the repertoire of useful
mass spectrometric fragmentation mechanisms. For example, the meta-specific elimination
pathway described in this report enables unequivocal identification of meta isomers from ortho
and para isomers of carboxyanilides. The reaction follows a specific path to eliminate a molecule of
meta-benzyne, from the anion produced after the initial decarboxylation of the precursor.
Consequently, in the CID spectra of carboxyanilides, a peak for the (R-CO-NH)– anion is observed
only for the meta isomers. For example, the peaks observed at m/z 58, 86, 120, 128, and 170 from
acetamido-, butamido-, benzamido, heptamido-, and decanamido-benzoates, respectively, were
specific only to the spectra of meta isomers.
Key words: Ortho effect, Meta effect, Meta elimination, Collision-induced dissociation,
Anthranilic acid, Anilides
Introduction
ion [3–10]. In addition to what is observed directly from odd-
electron molecular ions, this ortho-specific mechanism some-
times applies even to even-electron ions derived from
molecular ions after an initial loss of a radical [11]. Recently,
we reported that the EI spectra of N-formyl, N-acetyl, or
N-benzoyl derivatives of haloanilines also show a dramatic
ortho effect by a different mechanism [12]. For example, the
spectra of derivatives of ortho isomers of chloro-, bromo-, or
iodoanilines show a very prominent peak for the loss of the
halogen atom, instead of an HX molecule usually expected
from a conventional ortho elimination [12].
In contrast to radical ions produced by electron ioniza-
tion, most of the modern desorption ionization methods
produce even-electron gaseous ions. Recent investigations
reveal that collision-induced fragmentation spectra of even-
electron ions of substituted aromatic compounds also show
peaks diagnostic of the ortho-substitution position [13–20].
Anthranilic acid is an important pharmacophore
widely used in drug discovery programs. In our pursuit
of finding intricate details of fragmentation mechanisms
of anions, we recorded spectra of several anilides derived
ons derived from ortho-substituted aromatic compounds
often produce spectra that are different from the spectra of
I
their meta or para isomers [1]. This phenomenon, generally
known as the “ortho effect,” has been recognized as one of
the diagnostically important mass spectral fragmentations.
The mechanism of this process has been widely investigated
for positively charged radical cations. For many radical cations,
this is an outcome of a transfer of a hydrogen atom from a
donor functional group, such as hydroxyl, amino, thiol, or even
alkyl, to a polar functional group attached to the ortho position.
The mechanism, initially presumed to proceed via a six-
membered transition state [2], appears to follow a step-wise
mechanism to eliminate a neutral molecule from the molecular
Electronic supplementary material The online version of this article
(doi:10.1007/s13361-011-0164-2) contains supplementary material, which
is available to authorized users.
Correspondence to: Athula B. Attygalle; e-mail: Athula.Attygalle@stevens.edu
Received: 28 March 2011
Revised: 2 May 2011
Accepted: 5 May 2011
Published online: 3 June 2011

1516
A. B. Attygalle, et al.: “Meta Elimination” a Diagnostic Fragmentation
from anthranilic acid and its ring isomers. Among the
fragmentation pathways investigated, a mechanism spe-
cific to meta isomers was observed. Our conclusions
reported here are supported by ab initio calculations and
deuterium-labeling experiments.
Samples were infused as acetonitrile-water-NH3 (50/50/0.01 %
vol/vol) solutions at a flow rate of 10 μL min–1. The source
temperature was maintained at 100 °C. The argon gas pressure
in the collision cell was adjusted to attenuate precursor ion
transmission by about 30%–50%.
Experimental
Synthesis of N-Acetyl Derivatives of Aminobenzoic
Acids
All chemicals, including 2-aminobenzoic acid, 3-aminobenzoic
acid, and 4-aminobenzoic acid were purchased from Sigma-
Aldrich Chemical Co. (St. Louis, MO, USA). Synthesized
products were characterized using an API 2000 triple quadru-
pole mass spectrometer equipped with an ESI source. The
collision-induced dissociation (CID) mass spectra were
recorded on a Waters (Milford, MA, USA) Quattro Ultima
mass spectrometer equipped with an electrospray ion source.
Each aminobenzoic acid (50 mg, 0.368 mmol) in tetrahy-
drofuran (THF) was mixed with a mixture of acetic
anhydride (1 mL) and pyridine (30 μL, 0.368 mmol), and
the mixture was stirred for 1 h at RT. The reaction mixture
was then acidified with 1% HCl and the final product was
extracted into ethyl acetate.
Figure 1. Unit–resolution product ion mass spectra of m/z 178 [(M – H)–] ion derived from ortho- (a), meta- (b), and para-
carboxyacetanilide (c), and those of m/z 181 ion of ortho- (d), meta- (e), and para-carboxy[2H3]acetanilide (f) at a collision energy
settings of 25 eV recorded on a Quattro Ultima mass spectrometer (all parameters, including collision gas pressure and
skimmer-cone voltages, were kept identical)

A. B. Attygalle, et al.: “Meta Elimination” a Diagnostic Fragmentation
1517
General Synthesis of Other N-Acyl Derivatives
of Aminocarboxylic Acids
23] and 6-31 G(d) basis set for all structures, except the
structures of neutral meta-benzyne and para-benzyne,
which were calculated using the BLYP functional.
Calculated structures were optimized to obtain stationary
states. Frequency analysis of the optimized structures was
used to distinguish energy minima from saddle points.
Transition states were identified as first-order saddle
points with one imaginary frequency. Zero-point energy
corrections were made to the energies of stationary states.
Zero-point energies obtained using the B3LYP functional
were scaled by a factor 0.9804 [24]. Zero-point energies
obtained using the BLYP functional were scaled by a
factor of 1.009 [25].
Each carboxylic acid (50 mg) was dissolved in excess
thionyl chloride (2 mL) and two drops of dimethylforma-
mide (DMF). The mixture was kept 60 °C for 30 min and
excess thionyl chloride was removed by a stream of N2. The
acid chlorides produced in this way were used to synthesize
N-acyl derivatives of aminobenzoic acids.
Computational Methods
All calculations were performed using the Gaussian 03 W
program package [21]. Calculations were performed using
density functional theory using the B3LYP functional [22,
The structures of meta- and para-benzyne have been
extensively investigated, and the ground states of both
Figure 2. Product ion spectra of in-source-generated m/z 134 ion from 2-carboxyacetanilide (a), 3-carboxyacetanilide (b), and
4-carboxyacetanilide (c) recorded at a laboratory frame collision energy setting of 25 eV

1518
A. B. Attygalle, et al.: “Meta Elimination” a Diagnostic Fragmentation
Table 1. Collision-induced Dissociation Mass Spectra of some Carboxyanilides Recorded at a Laboratory-frame Collision Energy Setting of 25 eV
Compound (M)
[M - H]-
[(M
(CO2)]-
m/z (%)
–
H)
–
Ketenyl Amide anion Phenylazanide Aminobenzoate
NXCOR
anion
(or its hydrogen-
shift isomeric
structure)
m/z (%)
m/z (%)
m/z (%)
m/z (%)
m/z (%)
2-acetamidobenzoic acid
178 (90)
178 (65)
178 (70)
134 (55)
41 (8)
58 (0)
92 (100)
136 (5)
NHCOCH3
COOH
X = H
R = CH 3
58 (9)
3-acetamidobenzoic acid
134 (100)
134 (100)
41 (<1)
41 (<1)
92 (12)
92 (15)
136 (<0.5)
136 (<0.5)
NHCOCH3
X = H
COOH
R = CH 3
58 (0)
4-acetamidobenzoic acid
NHCOCH3
X = H
R = CH 3
COOH
2-[2’,2’,2’-
2H3]acetylaminobenzoic acid
181 (98)
181 (55)
137a(80)
42 (8)
61 (0)
93 (95)
137a (?)
137a (?)
NHCOCD3
COOH
X = H
R = CD3
3-[2’,2’,2’-
137a(100)
42 (<1)
61 (9)
93 (100)
2H3]acetylaminobenzoic acid
NHCOCD3
X = H
R = CD3
COOH
4-[2’,2’,2’-
181 (50)
137a(100)
42 (8)
61 (0)
93 (9)
137a (?)
2H3]acetylaminobenzoic acid
NHCOCD3
X = H
R = CD3
COOH
molecules are known to be singlet states [26–28]. The singlet
structure of meta-benzyne determined using B3LYP and
similar hybrid functionals is known to have a short inter-
atomic distance between the C1 and C3 atoms, suggesting a
bicyclic structure with a σ bond between the two carbons [29].
However, the bicyclic structure is not congruent with exper-
imental evidence on the meta-benzyne ground state from IR
spectroscopy. Therefore, the structure of meta-benzyne versus
its isomers is preferably calculated using the BLYP functional,
which produces a more open ring structure with a larger C1–C3
inter-atomic distance. The structures of meta- and para-
benzyne calculated for this paper were optimized using the
restricted BLYP functional with a 6-31 G(d) basis set. The
energies of these optimized molecules were then recalculated at
the B3LYP/6-31 G(d) level for comparison with other
calculated structures in an energy level diagram.

A. B. Attygalle, et al.: “Meta Elimination” a Diagnostic Fragmentation
1519
Table 1. (continued)
Compound (M)
[M - H]-
[(M
(CO2)]-
m/z (%)
–
H)
–
Ketenyl Amide anion
Aminobenzoate
Phenylazanide
(or its hydrogen-
shift isomeric
structure)
NXCOR
anion
m/z (%)
m/z (%)
m/z (%)
m/z (%)
m/z (%)
2-heptamidobenzoic acid
248 (100)
204 (75)
111 (20) 128 (0)
92 (70)
136 (25)
X = H
R =
O
NH
(CH2)5CH3
COOH
3-heptamidobenzoic acid
248 (100)
204 (98)
111 (8)
111 (2)
128 (10)
92 (28)
92 (15)
136 (<1)
O
NH
X = H
R =
COOH
(CH2)5CH3
128 (0)
4-heptamidobenzoic acid
248 (90)
204 (100)
136 (2)
O
NH
X = H
R =
(CH2)5CH3
COOH
2-benzamidobenzoic acid
240 (90)
196 (100)
196 (90)
NA
NA
120 (0)
92 (0)
92 (0)
136 (0)
136 (0)
O
NH
X = H
HOOC
R = (C6H5)
3-benzamidobenzoic acid
240 (100)
120 (20)
O
NH
X = H
R = (C6H5)
COOH
4-benzamidobenzoic acid
240 (100)
290 (100)
196 (50)
246 (55)
NA
120 (0)
92 (0)
136 (0)
O
NH
X = H
R = (C6H5)
COOH
2-decanamidobenzoic acid
153 (26) 170 (0)
92 (55)
136 (35)
O
X = H
R =
NH
COOH
(CH2)8CH3

1520
A. B. Attygalle, et al.: “Meta Elimination” a Diagnostic Fragmentation
Table 1. (continued)
Compound (M)
[M - H]-
[(M
(CO2)]-
m/z (%)
–
H)
–
Ketenyl Amide anion
Aminobenzoate
Phenylazanide
(or its hydrogen-
shift isomeric
structure)
NXCOR
anion
m/z (%)
m/z (%)
m/z (%)
m/z (%)
m/z (%)
3-decanamidobenzoic acid
290 (100)
246 (50)
153 (10) 170 (6)
92 (18)
136 (<1)
X = H
R =
O
NH
(CH2)8CH3
COOH
4-decanamidobenzoic acid
290 (100)
246 (50)
153 (5)
170 (0)
92 (10)
136 (1)
O
NH
X = H
R =
COOH
(CH2)8CH3
100 (18)
3-[(2,2-
220 (75)
176 (100)
NA
92 (2)
136 (<1)
dimethylpropanoyl)amino]-
benzoic acid
X = H
R = C(CH3)3
NH
O
COOH
3-[(2-
206 (55)
162 (100)
69 (0)
86 (18)
92 (8)
136 (<1)
methylpropanoyl)amino]-
benzoic acid
X = H
R =
NH
O
CH(CH3)2
COOH
3-butanamidobenzoic acid
206 (50)
162 (100)
69 (0)
86 (15)
92 (10)
136 (<1)
NH
O
X = H
COOH
R =
(CH2)2CH3
a,b=Composite peaks
carboxyacetanilide are depicted in Figure 1. To our surprise,
the spectrum recorded from meta-carboxyacetanilide (also
known as meta-acetamidobenzoic acid) showed a small but
highly significant peak at m/z 58, unique to the meta isomer
Results and Discussion
Collision-induced dissociation mass spectra recorded from
(M – H)– ions of ortho- meta, and para isomers of

A. B. Attygalle, et al.: “Meta Elimination” a Diagnostic Fragmentation
1521
(Figure 1b). The major fragmentation pathways of anions
derived from ring isomers of carboxyacetanilide can be
attributed to consecutive losses of CO2 and CH2=C=O, or
CH2=C=O and CO2 from the precursor anion of m/z 178
(Figure 1). However, tandem mass spectrometric experi-
ments confirmed that only the ion at m/z 134, formed after
the initial decarboxylation of the meta isomer fragments
further to yield an m/z 58 ion (Figure 2), which in fact
represents the anion of acetamide [H3C – (CO) – NH−]. The
characterization of this ion was supported by the observation
of a peak at m/z 61 in the spectrum of the ion at m/z 181 of
3-[2',2',2'-2H3]acetamidobenzoate (Figure 1e).
Evidently, the formation of an amide anion in this way is a
general phenomenon because the spectra of several other N-acyl
derivatives of meta-aminobenzoic acid also showed analogous
peaks, which were absent in the spectra of corresponding ortho
and para isomers (Table 1). For example, peaks specific for the
meta isomer were observed at m/z 120 and 128 in the spectra of
3-carboxybenzanilide (a.k.a. 3-benzamidobenzoic acid;
Figure 3) and 3-carboxyheptanilide (a.k.a. 3-heptamidoben-
zoic acid; Supplementary Figure S1), respectively. The relative
intensity of the amide peak increased as the collision energy
was increased. For example, see the CID spectrum and the
plots of relative intensities versus laboratory-frame collision
energies given in Figure 4 for 3-decanamidobenzoate.
To the best of our knowledge a peak specific for the meta
isomer has not been previously recognized as a diagnostic
marker in CID spectra. On one rare occasion, however, the
−
formation of an m/z 81 peak for the HSO3 ion, specifically
from the meta isomer has been reported in an investigation
of spectra of sulfobenzoic acids [30].
For the formation of an ion at m/z 58 from meta-
carboxyacetanilide, a molecule of meta-benzyne should be
eliminated from the m/z 134 ion, generated after an initial loss
of a CO2 molecule from the m/z 178 precursor (Scheme 1).
We reiterate that the product ion spectra recorded from the m/z
Figure 3. Product ion spectra generated from m/z 240 ion from 2-carboxybenzanilide (a), 3-carboxybenzanilide (b), and
4-carboxybenzanilide (c) recorded at a laboratory frame collision energy setting of 25 eV

1522
A. B. Attygalle, et al.: “Meta Elimination” a Diagnostic Fragmentation
Figure 4. Unit–resolution product ion spectrum of m/z 290 [(M – H)–] ion derived from 3-decanamidobenzoate at 40 eV
collision energy (a), and a plot of relative intensity versus laboratory-frame collision energy, for ions m/z 290 ( ), 246 ( ), and
170 ( ) generated upon collision-induced dissociation (b)
134 ion from the ortho and para isomers, which are the
hydrogen-shift isomers of that from the meta compound, fail
to show a peak for the m/z 58 ion (Figure 2).
Density functional calculations carried out using 6-31 G
(d) basis set indicated that the phenyl anion 2m formed
after the initial CO2 loss from the meta isomer 1m
generates an intermediate via the transition state TS-2 m-7 m
(Scheme 1). The ion-molecule complex 7 m formed in this way
can further dissociate to eliminate meta-benzyne to form the
ion observed at m/z 58. Calculated relative energies of the
intermediates and transition states are illustrated in Figure 5
(see Supplementary Figure S2 in the Electronic Supplementary
Material for the energy-optimized structures). The structure of
m-benzyne has been the topic of many investigations and much
NH
CH3
NH
CH3
NH
CH3
O
O
O
CO2
C
O
O
2m
m/z 134
TS 2m-7m
1m
m/z 178
NH
O
CH3
NH
CH3
O
8
m/z 58
7m
Scheme 1. Proposed dissociation mechanism of m-carboxyacetanilide anion

A. B. Attygalle, et al.: “Meta Elimination” a Diagnostic Fragmentation
1523
Figure 5. Energy profile for the fragmentation of meta- and para-carboxyacetanilide anions upon collisional activation (relative
energies calculated using B3LYP functional and 6-31 G(d) basis set are given in kcal/mol)
debate [29, 31, 32]. Our results, which indicate that a
m-benzyne is not a regular hexagon but a structure with a
shorter distance between C1 and C3 positions, is congruent
with other recent calculations [33] (Figure S2). In fact, the
image recorded by scanning tunneling microscopy from
chemisorbed m-benzyne on a Cu surface also agrees with the
proposed structure [34].
We also considered an alternative dissociation pathway
involving an initial decarboxylation and a 1,2-hydrogen
transfer that would lead to an expulsion of o-benzyne rather
than m-benzyne. However, the energetic barriers for 1,2-
hydrogen transfers in m- and p-benzynes that have been
calculated by others groups are found to be excessively high
[35]. There is little or no convincing evidence in literature to
support that m- and o-benzynes isomerize via 1,2-hydrogen
shifts. However, another indirect isomerization process
which involves a ring-opening to form an ene-diyne
intermediate has been proposed as more plausible pathway.
Although the para isomer can also fragment by a similar
mechanism (Scheme 2, and Figure S3 in the Supplementary
Information), calculations show that the overall process is more
endothermic than that for the meta isomer (Figure 5). Thus, it is
not surprising that a peak corresponding to an amide anion was
not observed from the para isomers under typical laboratory-
frame collision-energy conditions (10–40 eV). The ortho
isomers also do not show a peak for the amide ions because
ortho isomers have other favorable fragmentational channels,
which are much less endothermic.
Moreover, the amide anions formed in this way can
undergo further fragmentation by eliminating an alkane
molecule (Figure S4 in the Supplementary Information, and
Scheme 3). Indirectly, this fragmentation could also be
NH
CH3
NH
CH3
NH
CH3
O
O
O
O
CO2
O
2p
m/z 134
TS 2p-7p
1p
m/z 178
NH
O
CH3
NH
CH3
O
8
m/z 58
7p
Scheme 2. Proposed dissociation of para-carboxyacetanilide anion [note that the fragmentation of m/z 134 ion given above is
not an energetically favorable process, and a peak of any appreciable intensity is not observed at m/z 58]

1524
A. B. Attygalle, et al.: “Meta Elimination” a Diagnostic Fragmentation
H
N
15. Attygalle, A.B., Bialecki, J.B., Nishshanka, U., Weisbecker, C.S.,
Ruzicka, J.: Loss of Benzene to Generate an Enolate Anion by a Site-
CH2
R
H
CH2 R
+
N
C O
Specific Double-Hydrogen Transfer During CID Fragmentation of o-
Alkyl Ethers of Ortho-Hydroxybenzoic Acids. J. Mass Spectrom. 43,
1224–1234 (2008)
m/z 42
O
16. Nishshanka, U., Attygalle, A.B.: Low-Energy Collision-Induced Frag-
mentation of Negative Ions Derived from Diesters of Aliphatic
Dicarboxylic Acids Made with Hydroxybenzoic acids. J. Mass
Spectrom. 43, 1502–1511 (2008)
Scheme 3. Fragmentation of amide anions derived from
meta-carboxyacetanilide anions to give an m/z 42 product ion
17. Attygalle, A.B., Chan, C.C., Axe, F.U., Bolgar, M.: Generation of Gas-
Phase Sodiated Arenes Such as [(Na3(C6H4)(+)] from Benzene
Dicarboxylate salts. J. Mass Spectrom. 45, 72–81 (2010)
considered a meta-specific pathway due to the fact that
amide anions are formed under conditions described only
from meta-carboxyacetanilides.
18. Jiang, K., Bian, G., Pan, Y., Lai, G.: Recognizing Ortho-, Meta-, or
Para- Positional Isomers of S-Methyl Methoxyphenylmethylenehydra-
zine Dithiocarboxylates by ESI-MS2: The positional effect of the
methoxyl substituent. Int. J. Mass Spectrom. 299, 13–19 (2011)
19. Reddy, P.N., Srikanth, R., Venkateswarlu, N., Rao, R.N., Srinivas, R.:
Electrospray Ionization Tandem Mass Spectrometric Study of Three
Isomeric Substituted Aromatic Sulfonic Acids; Differentiation Via
Ortho Effects. Rapid Commun. Mass Spectrom. 19, 72–76 (2005)
20. Amundson, L.M., Owen, B.C., Gallardo, V.A., Habicht, S.C., Fu,
M., Shea, R.C., Mossmann, A.B., Kenttämaa, H.I.: Differentiation of
Regioisomeric Aromatic Ketocarboxylic Acids by Positive Mode
Atmospheric Pressure Chemical Ionization Collision Activated
Dissociation Tandem Mass Spectrometry in a Linear Quadrupole
Ion Trap Mass Spectrometer. J. Am. Soc. Mass Spectrom. 22, 670–
682 (2011)
Conclusions
The experimental data presented here demonstrate the exis-
tence and utility of a novel “meta elimination,” which enables
unequivocal distinguishing of meta isomers from those of ortho
and para isomers of carboxyanilides. We envisage that this
phenomenon can serve as a diagnostic maker of anions that
bear a good leaving group at the meta position.
21. Frisch, M.J., Trucks, G.W., Schlegel, H.B., Scuseria, G.E., Robb, M.A.,
Cheeseman, J.R., Montgomery, J.A., Vreven Jr., T., Kudin, K.N.,
Burant, J.C., Millam, J.M., Iyengar, S.S., Tomasi, J., Barone, V.,
Mennucci, B., Cossi, M., Scalmani, G., Rega, N., Petersson, G.A.,
Nakatsuji, H., Hada, M., Ehara, M., Toyota, K., Fukuda, R., Hasegawa,
J., Ishida, M., Nakajima, T., Honda, Y., Kitao, O., Nakai, H., Klene, M.,
Li, X., Knox, J.E., Hratchian, H.P., Cross, J.B., Adamo, C., Jaramillo,
J., Gomperts, R., Stratmann, R.E., Yazyev, O., Austin, A.J., Cammi, R.,
Pomelli, C., Ochterski, J.W., Ayala, P.Y., Morokuma, K., Voth, G.A.,
Salvador, P., Dannenberg, J.J., Zakrzewski, V.G., Dapprich, S., Daniels,
A.D., Strain, M.C., Farkas, O., Malick, D.K., Rabuck, A.D., Ragha-
vachari, K., Foresman, J.B., Ortiz, J.V., Cui, Q., Baboul, A.G., Clifford,
S., Cioslowski, J., Stefanov, B.B., Liu, G., Liashenko, A., Piskorz, P.,
Komaromi, I., Martin, R.L., Fox, D.J., Keith, T., Al-Laham, M.A.,
Peng, C.Y., Nanayakkara, A., Challacombe, M., Gill, P.M.W., Johnson,
B., Chen, W., Wong, M.W., Gonzalez, C., Pople, J.A.: Gaussian 03,
Revision C.02. Gaussian Inc., Wallingford (2004)
22. Becke, A.D.: Density-Functional Thermochemistry. 111. The Role of
Exact Exchange. J. Chem. Phys. 98, 5648 (1993)
23. Lee, C., Yang, W., Parr, R.G.: Development of the Colle-Salvetti
Correlation-Enegry Formula into a Functional of the Electron Density.
Phys. Rev. B 37, 785–789 (1988)
24. Foresman, J.B., Frisch, A., Eds.: In: Exploring Chemistry with Electronic
Structure Methods, 2nd ed. Gaussian Inc.: Pittsburgh, PA, p. 64 (1996)
25. Alecu, I.M., Zheng, J., Zhao, Y., Truhlar, D.G.: Computational
Thermochemistry: Scale Factor Databases and Scale Factors for
Vibrational Frequencies Obtained from Electronic Model Chemistries.
J. Chem. Theory Comput. 6, 2872–2887 (2010)
26. Wenthold, P.G., Squires, R.R., Lineberger, W.C.: Negative Ion Photo-
electron Spectroscopy of the o-, m-, and p-Benzyne Negative Ions. The
Electron Affinities and Singlet-Triplet Splittings of o-, m-, and p-
Benzyne. J. Am. Chem. Soc. 120, 5279–5290 (1998)
Acknowledgment
The authors acknowledge support for this research by funds
provided by Stevens Institute of Technology.
References
1. Schwarz, H.: Some Newer Aspects of Mass Spectrometric Ortho
Effects. Top. Curr. Chem. 73, 231–263 (1978)
2. Gross, J.H.: Mass Spectrometry: A Text Book, pp. 304–306. Springer–
Verlag, Berlin (2004)
3. McLafferty, F.W., Golke, R.S.: Mass Spectrometric Analysis of
Aromatic Esters. Anal. Chem. 31, 2076 (1959)
4. Spiteller, G.: The Ortho Effect in the Mass. Spectra of Aromatic
Compounds. Monatsh. Chem. 92, 1147–1154 (1961)
5. Meyerson, S., Drews, H., Field, E.K.: Mass Spectra of Ortho-
Substituted Diaryl- methanes. J. Am. Chem. Soc. 86, 4964–4967 (1964)
6. Lacey, M.J., MacDonald, C.G., Shannon, J.S.: Mass Spectrometry in
Structural and Stereochemical Problems. Org. Mass Spectrom. 5, 1391–
1397 (1971)
7. Martens, J., Praefcke, K., Schwarz, H.Z.: Fragmentation of Organic Ions
and Interpretation of EI Mass Spectra. Z. Naturforsch. B 30, 259–262
(1975)
8. Ramana, D.V., Sundaram, N., George, N.: Concerted and Step-wise
Ejection of SO2 and N2 from N-Arylidene-2-nitrobenzenesulfenamides.
Org. Mass Spectrom. 22, 140–144 (1987)
9. Grützmacher, H.F.: The Loss of Ortho Halo Substituents from
Substituted Thiobenzamide Ions. Org. Mass Spectrom. 16, 448 (1981)
10. Danikiewicz, W.: Ortho Interactions During Fragmentation of N-(2-
Nitrophenyl)methanesulfonamide and Its N-Alkyl Derivatives Upon
Electron Ionization. Eur. Mass Spectrom. 4, 167–179 (1998)
11. Smith, J.G., Wilson, G.L., Miller, J.M.: Spectra of Isopropyl Benzene
Derivatives. A Study of the Ortho Effect. Org. Mass Spectrom. 10, 5–
17 (1975)
27. Winkler, M., Sander, W.: The Structure of m-Benzyne: A Matrix
Isolation and Computational Study. J. Phys. Chem. A 105, 10422–
10432 (2001)
12. Jariwala, F.B., Figus, M., Attygalle, A.B.: Ortho Effect in Electron
Ionization Mass Spectrometry of N-Acylanilines Bearing a Proximal
Halo Substituent. J. Am. Soc. Mass Spectrom. 19, 1114–1118 (2008)
13. Attygalle, A.B., Ruzicka, J., Varughese, D., Sayed, J.: An Unprece-
dented Ortho Effect in Mass Spectrometric Fragmentation of Even-
Electron Negative Ions from Hydroxyphenyl Carbaldehydes and
Ketones. Tetrahedron Lett. 47, 4601–4603 (2006)
14. Attygalle, A.B., Ruzicka, J., Varughese, D., Bialecki, J.B., Sayed, J.:
Low-Energy Collision-Induced Fragmentation of Negative Ions
Derived from Ortho-, Meta-, and Para-Hydroxyphenyl Carbalde-
hydes, Ketones, and Related Compounds. J. Mass Spectrom. 42,
1207–1217 (2007)
28. Price, J.M., Kenttamaa, H.I.: Characterization of Two Chloro-Substi-
tuted m-Benzyne Isomers: Effect of Substitution on Reaction Efficien-
cies and Products. J. Phys. Chem. A 107, 8985–8995 (2003)
29. Wentrup, C.: The Benzyne Story. Aust. J. Chem. 63, 979–986 (2010)
30. Ben-Ari, J., Etinger, A., Weisz, A., Mandelbaum, A.: Hydrogen-Shift
Isomerism: Mass Spectrometry of Isomeric Benzenesulfonate and 2-, 3-,
and 4-Dehydrobenzenesulfonic Acid Anions in the Gas Phase. J. Mass
Spectrom. 40, 1064–1071 (2005)
31. Price, J.M., Nizzi, K.E., Campbell, J.L., Kenttämaa, H.I., Seierstad, M.,
Cramer, C.J.: Experimental and Theoretical Characterization of the 3,5-
Didehydrobenzoate Anion: A Negatively Charged Meta-Benzyne. J.
Am. Chem. Soc. 125, 131–140 (2003)

A. B. Attygalle, et al.: “Meta Elimination” a Diagnostic Fragmentation
1525
32. Wei, H., Hrovat, D.A., Mo, Y., Hoffmann, R., Borden, W.T.: The
Contributions of Through-Bond Interactions to the Singlet-Triplet
Energy Difference in 1,3-Dehydrobenzene. J. Phys. Chem. A 113,
10351–10358 (2009)
33. Winkler, M., Sander, W.: Matrix Isolation and Electronic Structure of
Di- and Tridehydrobenzenes. Aust. J. Chem. 63, 1013–1047 (2010)
34. Simic-Milosevic, V., Bocquet, M.-L., Morgenstern, K.: Adsorption Orienta-
tion and STM Imaging of Meta-Benzyne Resolved by Scanning Tunneling
Microcopy and Ab Initio Calculations. Surf. Sci. 603, 2479–2483 (2009)
35. Blake, M.E., Bartlett, K.L., Jones, M.: A m-Benzyne to o-Benzyne
Conversion Through a 1,2-Shift of a Phenyl Group. J. Am. Chem. Soc.
125, 6485–6490 (2003)