Electron ionization mass spectra of alkylated sulfabenzamides

Article abstract of DOI:10.1002/rcm.4918

Mono-, di- and trialkyl derivatives of 'sulfabenzamide' (N-4-aminophenylsulfonylbenzamide) have been prepared and their electron ionization (EI) mass spectra examined. It is found that the fragmentation of N-alkylsulfabenzamides (alkyl = CH₃ to n-C₅H₁₁) proceeds via a very specific rearrangement process. The proposed mechanism involves an intermediate formation of distonic molecular ions, and the driving force for this process is the formation of stable N-alkylphenylcyanide cations [R-NR⁺ ≡ CC₆H₅]. The findings are confirmed by exact mass measurements, tandem mass spectrometry (MS/MS) experiments and deuterium labeling.

Full text of DOI:10.1002/rcm.4918

Research Article
Received: 22 November 2010
Revised: 27 December 2010
Accepted: 30 December 2010
Published online in Wiley Online Library: 2011
Rapid Commun. Mass Spectrom. 2011, 25, 750–754
(wileyonlinelibrary.com) DOI: 10.1002/rcm.4918
Electron ionization mass spectra of alkylated sulfabenzamidesy
1
1
2
2
*
Nino G. Todua , Kirill V. Tretyakov , Roman S. Borisov , Dmitry I. Zhilyaev ,
Vladimir G. Zaikin2, Stephen E. Stein1 and Anzor I. Mikaia1
1National Institute of Standards and Technology, 100 Bureau Drive, Gaithersburg, MD 20899-8320, USA
2Topchiev Institute of Petrochemical Synthesis RAS, Leninsky Prospekt 29, Moscow 119991, Russia
Mono-, di- and trialkyl derivatives of ’sulfabenzamide’ (N-4-aminophenylsulfonylbenzamide) have been
prepared and their electron ionization (EI) mass spectra examined. It is found that the fragmentation of
N-alkylsulfabenzamides (alkyl ¼ CH3 to n-C5H11) proceeds via a very specific rearrangement process. The proposed
mechanism involves an intermediate formation of distonic molecular ions, and the driving force for this process is the
formation of stable N-alkylphenylcyanide cations [R-NR
CC H ]. The findings are confirmed by exact mass
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measurements, tandem mass spectrometry (MS/MS) experiments and deuterium labeling. Published in 2011 by
John Wiley & Sons, Ltd.
Two major activities of the NIST (Gaithersburg, MD, USA)
Mass Spectrometry Data Center (MSDC) include measure-
ment of electron ionization (EI) mass spectra and gas
chromatographic indices for compounds (a) with low quality
EI spectra present in the 2008 edition of the NIST/NIH/EPA
mass spectral library;[1,2] (b) with poor gas chromatographic
properties; and (c) that are labile chemicals under gas
chromatography/mass spectrometry (GC/MS) conditions.
Metabolites, drugs and environmentally important com-
pounds are on the priority list of the NIST MSDC. In
this study the derivatization of an antimicrobial drug,
sulfabenzamide, is conducted to determine which derivatives
are the best for use in GC/MS analysis.
GC/MS analysis of sulfabenzamide as the compound is labile
under the reaction conditions and mainly derivatives of
degradation products are formed. Alkylation with alkyl
iodides and N,N-dimethylformamide dialkyl acetals is more
successful, and the derivatives (I)–(III) and (IV) are obtained.
EXPERIMENTAL
Chemicals
N-(4-Aminophenylsulfonyl)benzamide (’sulfabenzamide’),
methyl, trideuteromethyl, ethyl, pentadeuteroethyl, n-prop-
yl, n-butyl, n-pentyl iodides, dimethyl and diethyl acetals
of N,N-dimethylformamide are commercially available
(Sigma-Aldrich, St. Louis, MO, USA).
Common derivatization reactions,[3] such as trialkylsilyl-
ation and perfluoroacylation, appear to be unsuitable for
Scheme 1.
* Correspondence to: N. G. Todua, National Institute of Standards
and Technology, 100 Bureau Drive, Stop 8320, Gaithersburg,
MD 20899-8320, USA.
E-mail: nino.todua@nist.gov
This article is a U.S. Government work and is in the public
y
domain in the U.S.A.
Rapid Commun. Mass Spectrom. 2011, 25, 750–754
Published in 2011 by John Wiley & Sons, Ltd.

Electron ionization mass spectra of alkylated sulfabenzamides
Synthesis of derivatives
Instrumentation
Alkylation of ’sulfabenzamide’ is accomplished by heating
(40 8C, 30 min) with alkyl iodides in N,N-dimethylformamide
(DMF) in the presence of NaOH. As a result, the mono-, di-
and trialkyl derivatives (I–III) are obtained (Scheme 1).
The mixed derivatives (IV) were obtained by alkylation
of ’sulfabenzamide’ with N,N-dimethylformamide dialkyl
acetals (DMF, 75 8C, 60 min) (Scheme 2).
The EI mass spectra were recorded on GC/MS systems with
quadrupole (Agilent 6890/5973: Agilent Technologies, Santa
Clara, CA, USA; ionization energy 70 eV; ion source
temperature 230 8C) and magnetic sector analyzers (Finnigan
MAT 95XL: Thermo Scientific, Bremen, Germany; ionization
energy 70 eV, temperature of ionization chamber 220 8C). A
fused quartz capillary column (30 m ꢀ 0.25 mm i.d.) with a
Scheme 2.
Figure 1. EI mass spectra of sulfabenzamide (a), N-methyl-N-(4-aminophenylsulfonyl)- (b), N-methyl-N-(4-methyl-
aminophenylsulfonyl)- (c), N-methyl-N-(4-dimethylaminophenylsulfonyl)- (d), and N-trideuteromethyl-N-(4-di(trideuteromethyl)
aminophenylsulfonyl)benzamides (e).
Rapid Commun. Mass Spectrom. 2011, 25, 750–754 Published in 2011 by John Wiley & Sons, Ltd. wileyonlinelibrary.com/journal/rcm

N. G. Todua et al.
non-polar stationary liquid phase (polydimethylsiloxane,
containing 5% of phenyl groups) was used. The oven
temperature was increased from 60 8C to 200–270 8C at a
rate of 5 8C/min (injection temperature ꢁ250 to 270 8C). Exact
mass determinations and linked-scan experiments (collision-
induced dissociation (CID), helium as a collision gas) were
performed on a GCmate II magnetic sector mass spectrometer
(JEOL, Tokyo, Japan).
known fragmentation rules. It reveals rather weak peaks for
the Mþꢂ and [M–SO2]þꢂ ions and an expected strong peak for
the benzoyl cation at m/z 105. However, the base peak in the
spectrum at m/z 109 is a product of an expected rearrange-
ment process[4] of the Mþꢂ followed by a hydrogen migration
(Scheme 3). Analogs of this radical cation are not present in
the spectra of the alkyl derivatives.
Other peaks in the high-mass region of the spectrum
correspond to ions formed by simple bond cleavages
(Scheme 4). The same set of ions is present in the spectra
of the alkyl derivatives (I)–(IV).
RESULTS AND DISCUSSION
The mass spectra of the mono-, di- and trimethylsulfa-
benzamides (I–III, R ¼ CH3) are depicted in Figs. 1(b)–1(d).
The EI mass spectrum of the initial unsubstituted sulfaben-
zamide (Fig. 1(a)) can be easily interpreted on the basis of
Scheme 3.
Scheme 4.
Figure 2. Product ion spectra recorded for (a) molecular ion (m/z 290) and (b) ion [M–SO2]þꢂ (m/z 226) derived from
N-methyl-N-(4-aminophenylsulfonyl)benzamide (I, R ¼ CH3).
wileyonlinelibrary.com/journal/rcm Published in 2011 by John Wiley & Sons, Ltd. Rapid Commun. Mass Spectrom. 2011, 25, 750–754

Electron ionization mass spectra of alkylated sulfabenzamides
The base peaks at m/z 118 cannot be explained on the basis of
any simple bond cleavage or known fragmentation pathways
for similar compounds. The same mass value (m/z 118) in all
three spectra may point to the benzamide moiety being the
source for the formation of this ion (a). The mass of this
peak in the spectra of the tri-, hexa- and nonadeutero
analogs (Fig. 1(e)) is shifted by 3 m/z units from m/z 118 to
121. All of the above indicate the presence in this ion of the
methyl (trideuteromethyl) group attached to the amide
N-atom, and the absence of the carbonyl oxygen atom. As
a result, C8H8N is the only possible elemental composition
that can be suggested for this ion, and this assignment is
corroborated by exact mass measurements of the ion:
experimental value of 118.0656, and calculated value of
118.0657 (error: ꢃ 0.8 ppm).
ion (a) involves a skeletal rearrangement accompanied with a
migration of either the arylsulfonyl group to the carbonyl
oxygen atom or the carbonyl O-atom to the arylsulfonyl
group. It should be emphasized that the migration of a
carbonyl oxygen atom under EI conditions has not previously
been reported.[5,6]
The homologous type (a) ions exhibit maximum intensity
in the spectra of the derivatization products with higher
N-alkyl groups (I–IV, R ¼ C2H5, C3H7, C4H9, C5H11; Figs. 3(b)
and 4). As expected[6] these ions further eliminate olefin
molecules (R-H) giving rise to an ion of m/z 104 (Scheme 6).
A competing reaction leading to formation of the benzoyl
cation (m/z 105) from the benzamide moiety becomes
significant for compounds with an alkyl group larger than
CH3 at the amide N-atom (Figs. 3(b) and 4); the ions
characterizing the arylsufonyl part of the molecule are also
present: [NH2C6H4]þ (m/z 92), [NH2C6H4SO]þ (m/z 140),
[NH2C6H4SO2]þ (m/z 156) and [NH2C6H4O]þ (m/z 108). The
latter ion is the product of a rearrangement process similar to
that given in Scheme 3. However, this rearrangement
CID experiments indicate that the ion (a) can be derived
from both the molecular and the [M–SO2]þ ion (Fig. 2). The
driving force for the rearrangement process is probably
the formation of a stable immonium cation via a distonic
molecular ion (Scheme 5).The mechanism for the formation of
Scheme 5.
Figure 3. EI mass spectra of N-methyl- (a) and N-ethyl-(4-dimethylaminomethylenaminophenylsulfonyl)benzamides (b).
Rapid Commun. Mass Spectrom. 2011, 25, 750–754 Published in 2011 by John Wiley & Sons, Ltd. wileyonlinelibrary.com/journal/rcm

N. G. Todua et al.
Figure 4. EI mass spectra of N-ethyl- (a), N-propyl- (b), N-butyl- (c), and N-pentyl-N-(4-aminophenylsulfonyl)benzamides (d).
proceeds without a hydrogen migration since the amide
hydrogen atom is substituted by an alkyl group.
Disclaimer
Certain commercial materials are identified in this paper in
order to specify the experimental procedure adequately. Such
identification is not intended to imply recommendation or
endorsement by the National Institute of Standards and
Technology, nor is it intended to imply that the identified
materials are necessarily the best available for the purpose.
CONCLUSIONS
The possibility of obtaining stable and convenient derivatives
of sulfabenzamide for GC/MS analysis has been studied. A
skeletal rearrangement of alkylated sulfabenzamides leading
to the formation of N-alkylphenylcyanide cations via the
intermediate formation of distonic molecular ions is reported.
A loss of a neutral R2NC6H4SO3 fragment can be used for
screening/identification and for quantification of modified
sulfabenzamides.
REFERENCES
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base 1, NIST 08, Standard Reference Data Program, National
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D. V. Tchekhovskoi, O. D. Sparkman, V. Zaikin, D. Zhu. J.
Am. Soc. Mass Spectrom. 1999, 10, 287.
[3] V. Zaikin, J. Halket, A Handbook of Derivatives for Mass Spec-
trometry, IM Publications, Chichester, 2009, p. 517.
[4] H. Budzikiewicz, C. Djerassi, D. H. Williams, Mass Spectrom-
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[5] F. W. MacLafferty, F. Turecek, Interpretation of Mass Spectra,
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[6] N. S. Wulfson, V. G. Zaikin, A. I. Mikaia, Mass Spectrometry of
Organic Compounds, Khimia, Moscow, 1986, p. 312.
Scheme 6.
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