Differentiation of isomeric haloanilines by tosylation in combination with electrospray ionization mass spectrometry

Article abstract of DOI:10.1177/1469066718757587

Differentiation of the isomeric haloanilines still remains a challenging and?necessary?analytic task due to their identical retention time in chromatography and similar mass spectra. In this work, p-tosylation of haloanilines by reaction of haloanilines with p-toluenesulfonyl chloride resulted in the corresponding N-tosyl haloanilines. Fragmentation of protonated N-tosyl haloanilines in electrospray ionization tandem mass spectrometry (ESI-MS/MS) mainly resulted in tosyl cation, haloaniline radical cation, and halohydroxyaniline radical cation. The MS/MS of the three group isomeric derivatives showed significant difference in abundance distribution of these product ions, respectively. Theoretical calculations showed that the stability of the ion-neutral complex (INC) is a key factor influencing the relative intensity of the product ions. The three group isomeric derivatives were also separated by high performance liquid chromatograph (HPLC) at conventional conditions. p-Tosylation combined tandem MS (or HPLC) technique were carried out to realize the differentiation of isomeric haloanilines.

Full text of DOI:10.1177/1469066718757587

Original research paper
European Journal of Mass Spectrometry
(00) 1–7
The Author(s) 2018
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Differentiation of isomeric haloanilines
by tosylation in combination with
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DOI: 10.1177/1469066718757587
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electrospray ionization mass spectrometry
1,2
1
2
2
Shanshan Wang , Yuanyuan Cheng , Mengmeng Chen and Kezhi Jiang
Abstract
Differentiation of the isomeric haloanilines still remains a challenging and necessary analytic task due to their identical
retention time in chromatography and similar mass spectra. In this work, p-tosylation of haloanilines by reaction of
haloanilines with p-toluenesulfonyl chloride resulted in the corresponding N-tosyl haloanilines. Fragmentation of proto-
nated N-tosyl haloanilines in electrospray ionization tandem mass spectrometry (ESI-MS/MS) mainly resulted in tosyl cation,
haloaniline radical cation, and halohydroxyaniline radical cation. The MS/MS of the three group isomeric derivatives showed
significant difference in abundance distribution of these product ions, respectively. Theoretical calculations showed that the
stability of the ion-neutral complex (INC) is a key factor influencing the relative intensity of the product ions. The three group
isomeric derivatives were also separated by high performance liquid chromatograph (HPLC) at conventional conditions. p-
Tosylation combined tandem MS (or HPLC) technique were carried out to realize the differentiation of isomeric haloanilines.
Keywords
Haloanilines, isomeric differentiation, tosylation, ESI-MS/MS, INC, HPLC
Received 25 December 2017; accepted 15 January 2018
strategy for many analytical problems. Appropriate
chemical transformation can give rise to derivatives
Introduction
Haloanilines have been extensively applied in the manu- with improved physico-chemical properties, thus
facture of azo-dyes, agrochemicals, pharmaceuticals, improving the chromatographic peak shapes and sep-
1
10–15
rubber, and many other industrial chemicals.
However, they are toxic compounds with nephrotoxic analysis and quantitative determination,
aration,
enhance sensitivity and selectivity in trace
1
4–18
and pro-
vide additional structural information in the tandem
2
3
potential
Haloanilines represent a family of isomers, and accord- MS analysis.
and suspected human carcinogens.
1
9–21
Amidation of the amino group to
ing to Directive 2002/72/EC and Directive 2002/61/ N-formyl, N-acetyl, or N-benzoyl derivatives allowed
4
5
EC, p-chloroaniline, rather than o-chloroaniline and for differentiation of the ortho isomer from the meta
m-chloroaniline, is one of the prohibited primary aro- and para ones of haloanilines, but failed to differentiate
2
1
matic amines associated with polyurethane products or meta from para isomers. Interestingly, our previous
azo-colours. Unfortunately, the ortho, meta, and para work has demonstrated that the three isomeric N-tosyl
isomers of haloanilines possess the virtually identical methylanilines can be differentiated by ESI-MS/MS,
electron ionization mass spectra (EI-MS, see the supple-
mentary Figure S1), and only the ortho-isomer can be
1
State Key Laboratory Breeding Base for Zhejiang Sustainable Pest and
differenced from the meta and the para ones by tandem
mass spectrometry analysis (APCI-MS/MS, see the sup-
Disease Control, Key Laboratory for Pesticide Residue Detection of Ministry
of Agriculture, Institute of Quality and Standard for Agro-products,
plementary Figure S2). What’s worse, not all of these
isomers can easily be separated by the common gas chro-
matography (GC) or HPLC column. Thus, it is very
important and challenging to differentiate isomeric
haloanilines so as to quantitatively analyze any isomer.
Derivatization is a classic pre-treatment method in
Zhejiang Academy of Agricultural Sciences, Hangzhou, China
2
Key Laboratory of Organosilicon Chemistry and Material Technology,
6
–9
Hangzhou Normal University, Hangzhou, China
Corresponding author:
Kezhi Jiang, Key Laboratory of Organosilicon Chemistry and Material
Technology, Hangzhou Normal University, Hangzhou 311121, China.
analytical chemistry, which has provided a promising Email: jiangkezhi@hznu.edu.cn

2
European Journal of Mass Spectrometry 0(00)
indicating the promising potential of tosylation in data acquisition using the Xcalibur software (Version
2
isomer differentiation. In this work, we try to develop 1.4). Diluted solutions were dissolved in a mixed solv-
2
an effective method to differentiate isomeric haloani- ent of methanol and water (V:V ¼ 70:30) at a concen-
lines by tosylation.
tration of about 10 mg/mL, which was introduced into
the source chamber at a flow rate of 5 mL/min. The
sheath gas (N , 99.99%) was set at 25 arbitrary units
(a.u.), the spray voltage at ꢂ4.5 kV, and the heated ion
2
Experimental
ꢀ
transfer tube (250 C) at þ55 V. Pure helium (99.999%)
Reagents and sample preparation
was used for the trapping and collision activation of the
HPLC-grade methanol was purchased from Sigma- selected ions. The collision induced dissociation mass
Aldrich (St Louis, MO, USA), and HPLC-grade spectrometry (CID-MS) spectra of the protonated mol-
water was generated using Milli-Q system (Millipore, ecules were obtained by isolation and activation of the
Bedford, MA, USA). The analytical reagents of precursor ions, and the normalized collision energy was
haloanilines, p-toluenesulfonyl chloride, pyridine, and held at 18%. Each mass spectrum was the average of
dichloromethane were purchased from Aladdin over 50 scans.
(
Shanghai, China).
Theoretical calculations
Derivatization
Theoretical calculations were performed using the
2
Tosylation of haloanilines was carried out by the clas- Gaussian 03 program. The equilibrium geometries
4
2
3
sical method (Scheme 1). Each haloaniline was mixed of the target species were optimized using the density
with p-toluenesulfonyl chloride in dichloromethane in functional theory (DFT) method at the B3LYP/6-
the presence of pyridine, and the resulting mixture was 311þG(d,p) level, and frequency calculations were
ꢀ
kept at 40 C for 60 min. The solvent was removed carried out at the same basis set. The optimized struc-
by reduced pressure distillation, and the residue was tures for the precursor ions, intermediates and products
purified by silica gel chromatography. The purity of were identified as a true minimum in energy by
the corresponding derivative products was determined the absence of imaginary frequencies. Transition
by HPLC (see the supplementary Figure S3).
states, on the other hand, were identified by the pres-
ence of one single imaginary vibration frequency with
the normal vibrational mode, and further confirmed
by the intrinsic reaction coordinates (IRC) analysis.
HPLC analysis
HPLC separation was performed on a Surveyor system The electron excitation energy of a target species was
ThermoFisher Scientific Inc., USA), equipped with a obtained by the Configuration Interaction approach
(
high-pressure gradient pump and a column heater. (CI-Singles). The optimized structures were shown by
The haloanilines and their derivatives were separated Gauss View (Version 3.09) software to give higher qual-
on a Dikma C18 column (250 mm ꢁ 4.6 mm, 5 mm) ity images of these structures. The energies discussed
ꢀ
(
Dikma Company, China) at 25 C. Optimum of separ- here were the sum of electronic and thermal free
ation was achieved using a common isocratic elution of energy. The optimized geometry data of the relevant
the methanol-water system (V:V ¼ 70:30) at the flow species were available in the supplementary data.
rate of 0.8 mL/min. The sample volume injected was
1
0 mL. The wavelength of UV scan was set at 254 nm.
Results and discussion
Mass spectrometry analysis
HPLC analysis
The ESI-MS/MS experiments were performed on Complete separation in chromatography is essential for
an LCQ quadrupole ion trap mass spectrometer quantitation of the isomeric haloanilines (Scheme 1),
(
Thermo-Finnigan
LCQ
Advantage
MAX, since none of them possesses a unique product ion.
ThermoFisher Scientific Inc., USA), equipped with an What’s worse, not all of these isomeric haloanilines
ESI ion source in the positive ionization mode, with can easily be separated by a common GC or HPLC
6
–9
method.
The three groups of isomeric haloanilines
appear as one peak on a routine C18 column (supple-
mentary Figure S4). Interestingly, the three groups of
N-tosyl haloanilines isomers (Mo-Cl, Mm-Cl, and Mp-Cl
in Scheme 1) can be easily separated by HPLC under
the same conditions (Figure 1). Tosylation of haloani-
lines increases the substituent size in the derivatives,
which increases the hydrophobicity of the haloanilines
and enlarges the mild difference in the physicochemical
properties among the original isomers, and thus the
Scheme 1. N-tosyl derivatives of o-, m-, and p-haloanilines
isomers.

Wang et al.
3
Figure 1. HPLC of the isomeric N-tosyl fluoroanilines (a), N-tosyl chlororoanilines (b), and N-tosyl bromoanilines (c) on Dikma C18
ꢀ
column (250ꢁ4.6 mm, 5 mm) at 25 C, isocratic elution of the methanol-water system (V:V ¼ 70:30) at the flow rate of 0.8 mL/min, and the
wavelength of UV scan was set at 254 nm.
isomeric derivative products could be separated suc- subsequent electron transfer, and gives an amino
cessfully by HPLC. Thereby, tosylation provides a pro- phenol radical cation at m/z 143 (P3Cl).
mising solution for simultaneous quantitation of the
Interestingly, the three isomeric derivatives display
isomeric haloanilines, and these isomeric derivatives significant difference in the tandem MS spectra
can also be easily differentiated by ESI-MS/MS as (Figure 2), indicating that they can be differentiated
described in the following sections.
by ESI-MS/MS analysis. As shown in Figure 2, tosyl
cation at m/z 155 (P1) is the base peak ion in the MS/
MS of Mo-Cl and Mm-Cl, implying that tosyl cation
Tandem mass spectrometry analysis
rather than chloroaniline radical cation is more feasibly
þ
Figure 2 shows the ESI-MS/MS spectra of protonated formed in fragmentation of [M þH] or [M
o-Cl
m-
þ
þ
N-tosyl chloroanilines (Mo-Cl, Mm-Cl, and Mp-Cl), and
þH] . Whereas fragmentation of [M þH] shows
Cl
p-Cl
the corresponding CID-MS data are summarized in the opposite result in the MS/MS, in which the relative
Table 1. Fragmentation of the protonated isomers abundance of P1 decreases sharply to 18.2%, and the
mainly yields three product ions at m/z 155 (P1), m/z chloroaniline radical cation (P2p-Cl, m/z 127) appeared
127 (P2 ), and m/z 143 (P3 ), and the potential reac- as the base peak ion. In addition, the relative intensity
Cl Cl
tion pathways are proposed in Scheme 2 according to (21.7%) of P2o-Cl is apparently higher than that of
2
2,25
þ
the previous works.
Dissociation of [M þH]
(6.5%) of P3o-Cl in the MS/MS of Mo-Cl, indicating
Cl
leads to an INC of [tosyl cation / chloroaniline] (INC- a relative more feasible reaction channel to generate
1Cl), which undergoes direct separation to give tosyl P2o-Cl, while Mm-Cl displays the opposite result in
cation (P1) at m/z 155. Electron transfer between the the MS/MS (2.4% for P2m-Cl, and 10.0% for P3m-Cl).
two species of INC-1Cl finally gives rise to the chloroa- The above results have been further consolidated by
niline radical cation at m/z 127 (P2 ). Alternatively, analysis of the corresponding energy-resolved plots at
Cl
coupling of tosyl oxygen with chloroaniline in INC- various collisional energies (Figure 3). Thus, the three
1Cl results in formation of an intermediate of sulfonic isomeric chloroanilines can be easily differentiated by
acid ester (IM ), which subsequently undergoes dis- tosylation in combination with tandem MS analysis.
Cl
sociation to give another INC of [ p-toluenesulfonic Analogously, fragmentation of protonated N-tosyl
acid cation / amino phenol] (INC-2 ) by breakage of fluoroaniline at m/z 266 mainly gives rise to tosyl
the S–O bond. Similarly, INC-2Cl undergoes the cation (P1, m/z 155), fluoroaniline radical cation
Cl

4
European Journal of Mass Spectrometry 0(00)
Figure 2. CID-MS spectra of (a) [Mo-Cl+H]+, (b) [Mm-Cl+H]+, and (c) [Mp-Cl+H]+.
Table 1. Main product ions observed in the ESI-MS/MS of the
The effect of the [tosyl cation / haloaniline] INC
protonated title compounds, at the relative CID energy of 18%.
Formation of P1 and P2 are the two predominant com-
peting reaction channels in the CID-MS experiments.
P2/IP1 The remarkable difference in the relative abundance of
the product ions, used for isomer differentiation, is
Product ions m/z (%)
þ
[
Comp. m/z (%)
MþH]
P1
P2
P3
I
o-F
266 (74.9) 155 (100.0) 111(8.9)
266 (71.9) 155 (100.0) 111 (1.1)
127 (2.3) 0.089
127 (6.5) 0.011
viewed as a result of the different reactivity in dissoci-
ation of the precursor ions. The gas-phase dissociation
chemistry of their analogs, N-phenyl p-toluenesulfona-
mides, has been investigated in detail in previous
m-F
p-F
266 (66.6) 155 (33.2) 111 (100.0) 127 (1.8) 3.012
282 (91.2) 155 (100.0) 127 (21.7) 143 (6.5) 0.217
o-Cl
m-Cl
p-Cl
o-Br
2
1,23
282 (69.5) 155 (100.0) 127 (2.4)
143 (10.0) 0.024
works.
Herein, DFT calculations at the B3LYP/6-
282 (43.6) 155 (18.2) 127 (100.0) 143 (1.1) 5.495
326 (87.1) 155 (100.0) 171 (47.0) 187 (12.1) 0.470
31þG(2d,p) level were carried out to further investigate
the mechanism of the positional effect on the two main
dissociation reactions in detail.
m-Br 326 (77.7) 155 (100.0) 171 (5.6)
187 (14.8) 0.056
As shown in Scheme 2, P1 is formed by direct
separation of INC-1, while P2 originates from the
intra-complex electron transfer and the subsequent
p-Br 326 (56.2) 155 (10.1) 171 (100.0) 187 (0.9) 9.901
(
(
P2 , m/z 111), and amino fluorophenol radical cation decomposition of INC-1. Thus, INC-1 is a key inter-
F
P3 , m/z 127) (supplementary Figure S5). Dissociation mediate in the dissociation reactions, and the details
F
of protonated N-tosyl bromoanilines at m/z 326 mainly structures of the corresponding species are available
generates tosyl cation (P1, m/z 155), bromoaniline rad- as Figure 4 and the supplementary Figure S9. The rele-
ical cation (P2 , m/z 171), and amino bromophenol vant calculated energies are summarized in Table 2.
Br
radical cation (P3 , m/z 187) (supplementary Figure
Br
Every INC-1 from the protonated N-halophenyl
S6). The two groups of isomers also display distinctive p-toluenesulfonamides has its triplet states, INC-1-T.
difference in the tandem mass spectrometry (Table 1), As shown in Figure 4, the two species are bounded
and similar reactivity of the corresponding fragmenta- more tightly in the triplet INC-1-TCl than that in
þ
tion channels has been obtained (supplementary the corresponding singlet INC-1 . Take [M þH]
Cl
p-Cl
Figures S7 and S8). In short, apparently different prod- as an example. The two species of INC-1
uct ion distribution has been obtained in the MS/MS of are combined each other with two intermolecular
p-Cl
˚
(2.222 A
isomeric N-tosyl fluoroanilines or N-tosyl bromoani- N–H. . .O
˚
hydrogen
lines, and thus the isomeric fluoroanilines and bromoa- 2.221 A), which decrease to 2.143 A and 2.069 A in
bonds
and
˚
˚
nilines also can be also differentiated by tosylation in INC-1-Tp-Cl, respectively. The free energy of INC-1p-Cl
combination with tandem MS analysis.
is calculated to be 69.0 kJ/mol, which is higher than

Wang et al.
5
Scheme 2. The proposed fragmentation pathways for protonated N-tosyl haloanilines.
Figure 3. Breakdown curves of selected ions in MS2 of (a) [Mo-Cl+H]+, (b) [Mm-Cl+H]+, and (c) [Mp-Cl+H]+ at different collision energies.

6
European Journal of Mass Spectrometry 0(00)
Figure 4. The optimized structures of the three isomeric INC-1Cl at theb3lyp/6-311+ g(d,p) level.
Table 2. Relative free energy (kJ/mol) of the key species in dissociation of protonated N-tosyl haloa-
niline derivatives.
Comp.
[MþH]þ
INC-1
(P1þN1)
INC-1-T
(P2þN2)
(P1þN1)- INC-1
o-F
ꢂ2.8
0.0
70.7
70.6
70.6
70.2
73.7
69.0
70.9
88.6
70.2
72.3
68.8
75.2
70.5
70.9
73.1
71.7
72.4
74.0
19.3
18.5
6.8
57.1
60.1
46.1
52.8
58.8
42.8
51.7
57.9
41.0
1.6
ꢂ1.8
4.6
a
m-F
p-F
ꢂ1.9
ꢂ3.2
0.0
o-Cl
26.0
28.8
11.1
27.9
21.6
7.5
0.3
a
m-Cl
ꢂ2.8
4.1
p-Cl
ꢂ0.3
ꢂ0.8
0.0
o-Br
0.8
a
m-Br
ꢂ16.2
3.8
p-Br
2.5
a
Relative free energy (kJ/mol) of the meta isomers was set at zero, respectively.
˚
that of INC-1-Tp-Cl by 57.9 kJ/mol. Similarly, INC-1 of incompact, with the distance of 2.653 A, and calcula-
any title N-halophenyl p-toluenesulfonamide is located tions show that it is located above it fragments
above the corresponding INC-1-T in free energy (Table (P1þN1)
by 2.8 kJ/mol, indicating an unstable
), indicating a thermodynamically more stable struc- structure of the INC. Thus, INC-1m-Cl is prone to
m-Cl
2
ture of the triplet INC.
undergo direct decomposition to give P1 (base peak),
In addition, the total free energy of (P2p-Cl þN2), rather than to generate P2 (relative abundance of 2.4%
originating from decomposition of INC-1-Tp-Cl, is in Figure 2(b)). The order of the stability follows:
3
(
1
0.3 kJ/mol lower than that of the corresponding INC-1p-Cl (4.1 kJ/mol) > INC-1o-Cl (0.3 kJ/mol) > INC-
P1þN1p-Cl), originating from separation of INC- 1m-Cl (ꢂ2.8 kJ/mol), indicating that the abundance
p-Cl. Analysis of Table 2 also indicated that the total ratio of P2 to P1 (I /I ) obeys the same order,
P2 P1
free energy of (P2þN2) is lower than that of the cor- which is in a good agreement with the experimental
responding (P1þN1). Thus, the reaction channel to results (Table 1).
afford P2 is thermodynamically much more favorable
than that to P1 in dissociation of [M þH] .
Similar calculation results have been obtained for
the isomeric [M þH] and [M þH] . As shown in
þ
þ
þ
F
Br
However, to generate P2, it is essential for INC-1 to Table 1, both INC-1
and INC-1
, originating
þ
m-F
m-Br
undergo the intra-complex electron transfer prior to its from dissociation of the corresponding [M þH]
m-F
þ
decomposition. Thereby, the stability of INC-1 is a key or [Mm-BrþH] , predominantly undergoes the direct
factor affecting the relative abundance of P2. INC-1p-Cl separation to afford the ion P1 (m/z 155). However,
þ
þ
possesses the stabilization energy of 4.1 kJ/mol because fragmentation of [Mp-FþH] (or [Mp-BrþH] ) leads to
of the two intermolecular N–H. . .O hydrogen bonds, INC-1p-F (or INC-1p-Br), which is inclined to undergo
and thereby it is inclined to undergo an intra-complex intra-complex electron transfer and mainly generates
electron transfer to generate P2p-Cl (the base peak ion in the radical product ion P2 (base peak ion in Figure
Figure 2(c)). Whereas INC-1m-Cl is distinctively more 2), due to the relative stable structure of INC.

Wang et al.
7
Conclusion
8
9
. Narvekar MS and Srivastava AK. Separation of isomers
of aromatic amines on HPTLC plates impregnated with
In this work, tosylation combined tandem MS tech-
nique were carried out to investigate the differentiation
on isomeric haloanilines. The para-isomers were more
favorable to undergo the ion-neutral complex mediated
electron transfer to haloaniline radical cation, whereas
the ortho and the meta isomers were more preferred to
afford tosyl cation. Significant difference in the abun-
dance distribution of product ion has been obtained for
every group of the isomeric N-tosyl haloanilines.
Theoretical calculations showed that the stability of
the INC is a key factor influencing the relative intensity
of the product ions. Additionally, the three groups iso-
meric derivatives were also separated one another on
a common C18 column at conventional conditions.
The above results provided a promising solution for
simultaneous quantitation of isomeric haloanilines,
and further works in this field will be carried out.
1
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Declaration of conflicting interests
2
015; 7: 2557.
The author(s) declared no potential conflicts of interest with
respect to the research, authorship, and/or publication of this
article.
5. Baghdady YZ and Schug KA. Review of in situ deriva-
tization techniques for enhanced bioanalysis using liquid
chromatography with mass spectrometry. J Sep Sci 2016;
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9: 102–114.
Funding
16. Sun CR, Sun HZ, Lai YQ, et al. Liquid chromatog-
raphy/mass spectrometry method for determination of
perfluorooctane sulfonyl fluoride upon derivatization
with benzylamine. Anal Chem 2011; 83: 5822.
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(
LY15B050007), and Analysis and Detection Foundation of
Science and Technology Department in Zhejiang Province
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