Thioglycerol matrix interactions in the positive ion fast atom bombardment mass spectrometry of several Hantzsch and Biginelli ester derivatives of boronic acids

Article abstract of DOI:10.1002/rcm.6604

RATIONALE Fast atom bombardment (FAB) ionization is a valuable tool for analyzing non-volatile or thermally labile compounds when harder ionization methods (EI or CI) have been unsuccessful. Unexpected interactions between matrix and analyte may, however, occur in FAB ionization leading to the formation of artifacts whose structures have to be determined. METHODS We used esters synthesized by our research group following green chemistry protocols. Artifacts relating to the target molecules were produced in the solvent cage using positive ion FAB using thioglycerol as the matrix and analyzed by accurate mass measurement. RESULTS Through interactions between thioglycerol and the boron atom, various adducts associated with boron-containing Hantzsch and Biginelli ester derivatives appeared in the FAB mass spectra. These interactions must arise in a solvent cage involving a Lewis acid-base bond. Accurate mass determinations of these adducts confirmed the presence of the target molecules. CONCLUSIONS Interactions between the thioglycerol matrix and the eleven boron-containing Hantzsch and Biginelli ester derivatives in addition to the three reagents were seen in their FAB⁺ spectra. These interactions, together with their accurate mass determinations, allowed us to determine the structures of the new molecules. Copyright 2013 John Wiley & Sons, Ltd. Copyright

Full text of DOI:10.1002/rcm.6604

Research Article
Received: 22 November 2012
Revised: 28 February 2013
Accepted: 19 April 2013
Published online in Wiley Online Library
Rapid Commun. Mass Spectrom. 2013, 27, 1573–1578
(wileyonlinelibrary.com) DOI: 10.1002/rcm.6604
Thioglycerol matrix interactions in the positive ion fast atom
bombardment mass spectrometry of several Hantzsch and
Biginelli ester derivatives of boronic acids
Joel Martínez1, Vida Abarca1, F. Javier Pérez2, Vladimir Carranza3 and René Miranda1
*
1Departamento de Ciencias Químicas, Facultad de Estudios Superiores Cuautitlán-UNAM, Estado de México, 54740 México
2Instituto de Química, Universidad Nacional Autónoma de México, Ciudad Universitaria, Coyoacán, D.F., 04510 México
3Instituto de Ciencias, Benemérita Universidad Autónoma de Puebla, Puebla, 72570 México
RATIONALE: Fast atom bombardment (FAB) ionization is a valuable tool for analyzing non-volatile or thermally labile
compounds when harder ionization methods (EI or CI) have been unsuccessful. Unexpected interactions between
matrix and analyte may, however, occur in FAB ionization leading to the formation of artifacts whose structures have
to be determined.
METHODS: We used esters synthesized by our research group following green chemistry protocols. Artifacts relating to
the target molecules were produced in the solvent cage using positive ion FAB using thioglycerol as the matrix and
analyzed by accurate mass measurement.
RESULTS: Through interactions between thioglycerol and the boron atom, various adducts associated with boron-
containing Hantzsch and Biginelli ester derivatives appeared in the FAB mass spectra. These interactions must arise in
a solvent cage involving a Lewis acid-base bond. Accurate mass determinations of these adducts confirmed the presence
of the target molecules.
CONCLUSIONS: Interactions between the thioglycerol matrix and the eleven boron-containing Hantzsch and Biginelli
ester derivatives in addition to the three reagents were seen in their FAB+ spectra. These interactions, together with their
accurate mass determinations, allowed us to determine the structures of the new molecules. Copyright © 2013 John
Wiley & Sons, Ltd.
Soft mass spectrometry (MS) ionization modes are particularly
useful for analyzing non-volatile or thermolabile compounds.
In the Fast Atom Bombardment (FAB) ionization mode the
sample is suspended in a non-volatile liquid matrix,[1] and, in
positive ion FAB, an [M+H]+ ion is usually produced, allowing
the molecular mass of the target molecule to be determined.
However, anomalous artifact ions sometimes appear in
the FAB spectrum: derived from processes such as solvent
condensation, ligand exchange, dehalogenation, hydride
abstraction, and adducts due to abrupt changes in surface
tension in the region of bombardment, as well as from
convective and diffusive processes.[2,3] The presence of these
artifact ions can lead to confusion in the determination of the
molecular mass of the target molecule.
The increasing importance of boronic acids has led to the
development of new mild and efficient methods for a large
number of boron-containing compounds (BCC). These
molecules have long been used as antiseptics, antibiotics,
cosmetics and insecticides. In addition, BCC have been used
to target biomolecules involved in cancer therapy, including
through non-specific applications (such as boron neutron
capture therapy) and direct selective action on some cancer
targets.[8] As a part of our ongoing research program, we
are interested in developing green chemistry protocols for
the production of novel hybrid heterocyclic molecules with
possible pharmacological activity, mainly in the absence of
solvent and using microwave or infrared irradiation to
activate the reactions.[9–14] These synthesized molecules are
characterized by mass spectrometry.[11,15–19]
The aim of this work was to study the novel thioglycerol
matrix interactions observed during the FAB+ analysis of
various BCC obtained by green chemistry. The BCCs
studied were the reagents o-, m-, and p-boronic acids
(1aÀc), the boronic derivatives of the Hantzsch ester (5aÀc,
6aÀc, and 7bÀc) and the Biginelli ester (9aÀc) (labeled
BCÀHantzsch and BCÀBiginelli, respectively), the syntheses
of which are shown in Schemes 1 and 2. When using
thioglycerol as the FAB matrix, however, we did
not obtain the expected [M+H]+ ions, but several artifact
and other ions were found, and analyzed using
On the other hand, Hantzsch esters (1,4-dihydropyridines)
and Biginelli esters (3,4-dihydropirimidinones) are important
classes of calcium-channel blockers that have emerged as
valuable drugs for treating cardiovascular diseases, including
the reduction of hypertension.[4–7]
* Correspondence to: R. Miranda, Departamento de Ciencias
Químicas, Facultad de Estudios Superiores Cuautitlán-
UNAM, Estado de México, 54740 México.
E-mail: mirruv@yahoo.com.mx
Rapid Commun. Mass Spectrom. 2013, 27, 1573–1578
Copyright © 2013 John Wiley & Sons, Ltd.

J. Martínez et al.
Mass spectrometry
Positive ion FAB and HRMS-FAB spectra were obtained using
a JMS-700 MStation mass spectrometer (JEOL, Japan). The
ꢀ
measurements were performed at 25 C, using a FAB energy
of 6 keV, an emission current of 10 mA, an acceleration voltage
of 10 kV, with Xe as the ionization gas and thioglycerol as the
matrix. The HRMS experiments were carried out with
thioglycerol as the matrix and PEG (poly(ethylene glycol)) ions
from m/z 200 to 800 as internal mass references at 10 000, 20 000,
30 000, and 45 000 resolution. Accurate masses were calculated
as the mean of the data obtained from 5–6 scans, determined
from the top and centroid mass of the ion signals. Elemental
compositions were calculated within a mass range of
Æ10 ppm from the measured mass.
Scheme 1. Synthesis of BC-Hantzsch esters.
Preparation of BC-Hantzsch and BC-Biginelli esters
The studied molecules were obtained,[19] using Schemes 1 and 2,
by green synthesis. These compounds were characterized by
their 1H, 13C and 11B NMR data together with their IR spectra.
RESULTS AND DISCUSSION
The expected molecular or [M+H]+ ions of the target molecules
5a-c, 6a-c, 7b-c and 9a-c were not obtained using electron
ionization, chemical ionization, or FAB+ (with glycerol,
m-nitrobenzyl alcohol, or o-octyloxynitrobenzene matrices).
Therefore, as it is known that the thioglycerol (TG) matrix
affords interesting interactions,[1,3] it was considered that
the sulphur atom, by means of Lewis interaction inside
the matrix with the empty orbital of the target BCC, could
produce FAB adducts related to the target molecules.
Scheme 2. Synthesis of BC-Biginelli esters.
high-resolution mass spectrometry (HRMS). We obtained the
artifact ion accurate masses and, consequently, their unequivocal
elemental compositions.
EXPERIMENTAL
Study of the boron-containing reagents
The boron-containing reagents 1a–c were analyzed using the
same FAB conditions as employed for the analysis of the
target molecules. These all have molecular masses of 150 Da.
An ion was observed at m/z 205 for the ortho-isomer
reagent and it is suggested that this is the oxathiaborinanic
cation, oÀ[MTG]+ (Table 1, Fig. 1(a)), with calculated and
experimental masses of m/z 205.0489 and 205.0495 (À2.5 ppm
error), respectively, corresponding to C10H10O2S111B1. To
validate this structure, the o-[MTGÀ1]+ ion at m/z 204 was also
Chemicals
Formylphenylboronic acids (o-, m- and p-), ethyl and methyl
acetoacetate, 1,3-cyclohexanedione, ammonium acetate and
thioglycerol were purchased from Sigma-Aldrich Chemistry
(St. Louis, MO, USA). Urea was obtained from Merck
(Naucalpan, México) reagent grade ethanol, n-hexane, and
ethyl acetate were acquired from Merck. All of them were
used without further purification.
Table 1. HRMS of the adducts of formylphenylboronic acids and Hantzsch and Biginelli ester derivatives
[MTG–1]+
Reagent
or product
[MTG]+
Mass
[MTG10B]+
Mass
[MTGÀH]+
Mass error
(ppm)
Adduct*
Calc/Exp (m/z) error (ppm) Calc/Exp (m/z) error (ppm) Calc/Exp (m/z)
1a
o-[MTG]+
205.0489/205.0495
223.0595/223.0600
À2.5
+5.2
À0.5
+0.5
+4.6
À4.3
204.0527/204.0531
222.0635/222.0637
415.1349/415.1375
443.1685/443.1688
409.1626/409.1634
394.1487/394.1484
À1.8
À0.6
À6.4
À0.9
À2.0
+0.8
204.0411/204.0416
222.0516/222.0522
415.1255/415.1261
443.1568/443.1574
409.1514/409.1519
394.1364/394.1370
À5.3
À2.3
À6.4
À2.3
À1.3
+7.0
1bÀc
5aÀc
6aÀc
7bÀc
9aÀc
m,p-[MTG]+
o,m,p-[MTG]+ 416.1334/416.1339
o,m,p-[MTG]+ 444.1647/444.1652
m,p-[MTG]+
410.1592/410.1597
o,m,p-[MTG]+ 395.1443/395.1448
*TG = thioglycerol
Calc = calculated; Exp = experimental
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Rapid Commun. Mass Spectrom. 2013, 27, 1573–1578

Molecular masses of boron derivatives obtained by thioglycerol matrix
Figure 1. FAB+ mass spectra and the corresponding [MTG]+ of reagents: ortho
(a) and meta (b).
evaluated, either as the 10B species, o-[MTG10B]+, or as the
ion formed by hydrogen loss, o-[MTGÀH]+, from m/z 205
(see Table 1). The accurate masses for both ions in the doublet
at m/z 204 confirmed the proposed structure, the 10B ion,
C10H10O2S110B1, having a calculated mass of m/z 204.0527 and
an experimental mass of 204.0531 (À1.8 ppm error), and the
C10H9O2S111B1 (hydrogen loss) ion having a calculated mass
of m/z 204.0411 and an experimental mass of 204.0416
(À5.3 ppm error). The base peak at m/z 133 could be formed
by loss of water from the [M+H]+ ion, and its expected formula
was verified as C7H6O211B by HRMS (calculated mass m/z
133.0455, experimental mass 133.0461 (À5.9 ppm error).
experimental mass 223.0600 (+5.2 ppm error). To validate
the structures of m,p-[MTG]+, the respective m,p-[MTGÀ1]+
ions were examined for their isotopic contributions m,
p-[MTG10B]+ and hydrogen losses m,p-[MTGÀH]+ (Table 1).
Both accurate masses were obtained and m,p-[MTG10B]+
was assigned to C10H12O3S110B1 from a calculated mass of
m/z 222.0635 and an experimental mass of 222.0637 (À0.6 ppm
error), with m,p-[MTGÀH]+ assigned to C10H11O3S111B1 from a
calculated mass of m/z 222.0516 and an experimental mass
of 222.0522 (À2.3 ppm error).
BC-Hantzsch esters
The meta- and para-regioisomeric reagent thioglycerol
adducts, m-[MTG]+ and p-[MTG]+, both appeared as peaks at
m/z 223, with relative abundances of 93% and 9%, respectively,
and these were assigned as hydroxyallylborothioate ions
(Table 1, Fig. 1(b)). These assignments were supported by their
elemental compositions, C10H12O3S111B1, determined from
their accurate masses: calculated mass m/z 223.0595,
Target compounds 5aÀc exhibited o,m,p-[MTG]+ FAB+ adducts
at m/z 416, corresponding to a 2-propynylborothioate moiety
(Table 1, Fig. 2(a)), with relative abundances of 17%, 10%, and
7%, for the ortho, meta and para structures, respectively. These
structural assignments were derived from the elemental
composition, C20H2311B1N1O6S1, determined from the HRMS
Rapid Commun. Mass Spectrom. 2013, 27, 1573–1578
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J. Martínez et al.
Figure 2. FAB+ mass spectra of Hantzsch esters and the corresponding [MTG]+: ortho
5a (a), ortho 6a (b), and para 7c (c).
accurate masses for each ion. The ion derived from 5a had a
calculated mass of m/z 416.1334 and a measured mass of
416.1339 (À0.5 ppm error). These proposed structure were
supported by HRMS data obtained for the ions at m/z 415, both
for the isotopic contribution o-[MTG10B]+ and for a hydrogen
atom loss o-[MTGÀH]+ (Table 1), yielding the elemental
compositions C20H2310B1N1O6S1, calculated mass m/z 415.1349
and experimental mass 415.1375 (À6.4 ppm error), and
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Rapid Commun. Mass Spectrom. 2013, 27, 1573–1578

Molecular masses of boron derivatives obtained by thioglycerol matrix
having
C20H2211B1N1O6S1, calculated mass m/z 415.1255, experimental
mass 415.1261 (À6.4 ppm error). Two interesting and
complementary fragment ions from 5a were: m/z 284, which
was assigned to an ortho effect (ii, Fig. 2(a)), and validated
by HRMS (C16H14N1O4, calculated mass m/z 284.0917,
experimental mass 284.0923 (À5.4 ppm error); and the base
peak, m/z 224, which appeared to be formed by loss of the aryl
substituent at position 4 (iii, Fig. 2(a)). This assignment was
validated by HRMS results (C11H14N1O4, calculated mass
m/z 224.0917, experimental mass 224.0917 (À2.6 ppm error)).
Analogous behavior was found for target compounds
6aÀc, and the corresponding o,m,p-[MTG]+ adducts, at
m/z 444 (8%, 12%, and 13%, respectively), were also assigned
to a 2-propynylborothioate moiety (Table 1, Fig. 2(b)), and
validated by HRMS data (C22H2711B1N1O6S1, calculated
mass m/z 444.1647, experimental mass 444.1652 (+0.5 ppm
error)). These assignments were also confirmed by obtaining
accurate masses for the isotopic contribution (C22H2710B1N1O6S1,
calculated mass m/z 443.1685 and experimental mass
443.1688 (À0.9 ppm error)), and for a hydrogen atom loss
(C22H2611B1N1O6S1, calculated mass m/z 443.1568, experimental
mass 443.1574 (À2.3 ppm error)). An ortho effect was also
detected (iv, Fig. 2(b)) in the formation of the ion at m/z 284,
which was again validated by HRMS (C16H14N1O4, calculated
mass m/z 284.0917, experimental mass 284.0923 (+1.5 ppm
error)). The base peak, at m/z 252, was also formed by loss of
the aryl substituent at C-4 (v, Fig. 2(b)), with this assignment
being supported by HRMS data (C13H18N1O4, calculated mass
m/z 252.1230, experimental mass 252.1236 (+0.5 ppm error)).
The FAB+ spectra of compounds 7bÀc (7a was not obtained
because of steric hindrance) exhibited m,p-[MTG]+ adducts at
m/z 410, which were assigned as hydroxyallylborothioate ions
(Table 1, Fig. 2(c)), with relative abundances of 13% for the meta
and 7% for the para isomers. The structural assignments were in
agreement with the elemental composition C22H2511B1N1O4S1,
and the accurate mass data (calculated mass m/z 410.1592,
experimental mass 410.1597 (+4.6 ppm error)) supported this
assignment. The corresponding accurate masses for the
isotopic contribution of 10B and the loss of a hydrogen atom
were also determined to validate these assignments, as in the
previous examples (Table 1). The elemental compositions again
supported the assignments, with the C22H2510B1N1O4S1 ion
a calculated mass of m/z 409.1626 and an
experimental mass of 409.1634 (À2.0 ppm error) and the
C22H2411B1N1O4S1 ion having a calculated mass of m/z
409.1514 and an experimental mass of 409.1519 (+4.3 ppm
error). The base peaks, at m/z 216, corresponded to the loss
of an arylboronic moiety from m/z 410, to provide a 3,4,6,
7-tetrahydroacridine-1,8-dionic cation (vi, Fig. 2(c)). This
structural assignment was based on the elemental
composition, C13H14N1O2, obtained from the experimental
mass of m/z 216.1025, with a calculated mass of m/z
216.1019 (+1.6 ppm error).
BC-Biginelli esters
The FAB+ spectra of compounds 9aÀc contained o,m,p-[MTG]+
adduct peaks at m/z 395, with relative abundances of 1%, 11%,
and 6%, corresponding to dihydroxypropylborothioate ions
(Table 1, Fig. 3). These structural assignments were based
on their accurate masses (calculated mass m/z 395.1443,
experimental mass 395.1448 (À4.3 ppm error)) and fitted the
elemental composition C17H2411B1N2O6S1. Validation of these
assignments was provided by study of the m-[MTGÀ1]+ ions
by HRMS, for the isotopic contribution m-[MTG10B]+ and
hydrogen loss m-[MTGÀH]+ (Table 1). The two ions gave the
formulae C17H2410B1N2O6S1 (calculated mass m/z 394.1487,
experimental mass 394.1484 (+0.8 ppm error)) and
C17H2311B1N2O6S1 (calculated mass m/z 394.1364 experimental
mass 394.1370 (+7.0 ppm error)). Another ion, at m/z 217,
with relative abundances of 2%, 14%, and 9%, for the ortho,
meta, and para species, respectively, was assigned to the
4-cyclobutenyl-3,4,7,8-tetrahydroquinazolinic cation (vii, Fig. 3),
and this was confirmed by the accurate mass data (C12H13N2O2,
calculated mass m/z 217.0971, experimental mass 217.0977
(+3.3 ppm error)).
Finally, a fragment ion at m/z 165, with relative abundances of
3%, 8%, and 9%, for the ortho, meta, and para species,
respectively, was assigned as the 3,4,7,8-tetrahydroquinazolinic
cation (viii, Fig. 3), and this assignment was confirmed
by HRMS which indicated
a formula of C8H9N2O2
(calculated mass m/z 165.0658, experimental mass
165.0664 (+3.1 ppm error)).
Figure 3. FAB+ mass spectrum of Biginelli ester and the corresponding [MTG]+:
meta 9b.
Rapid Commun. Mass Spectrom. 2013, 27, 1573–1578
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J. Martínez et al.
[8] M. A. Soriano-Ursúa, T. Mancilla-Percino, J. Correa-Basurto,
E. Querejeta, J. G. Trujillo-Ferrara. Give boron a chance:
boron containing compounds reach ionotropic and
metabotropic transmembrane receptors. miniRev. Med.
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[9] R. Gómez, E. Ramírez-San Juan, R. Miranda, R. Villalobos-
Molina, F. Delgado, R. Osnaya, J. Trujillo-Ferrara. Vasodilator
effects of bis-dihydropyridines structurally related to
nifedipine. Med. Chem. 2006, 2, 527.
[10] B. Velasco, J. G. Trujillo-Ferrara, L. H. Fabila, R. Miranda,
L. Sánchez-Torres. In vitro apoptotic activity of 2,2-
diphenyl-1,3,2-oxazaborolidin-5-ones in L5178Y cells. Life
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[11] M. O. Noguez, A. García, C. Ibarra, A. Cabrera, J. M. Aceves,
R. Miranda. Green synthesis of bis-Biginelli esters, with
vasodilatory effects, their mass spectrometric and physical
studies. Trends Org. Chem. 2009, 13, 75.
CONCLUSIONS
Interesting interactions between a thioglycerol matrix and
fourteen boron-containing molecules related to Hantzsch
and Biginelli esters were seen in their positive ion FAB
spectra. The reactions seemed to occur in the solvent cage
and involve Lewis acid-base interactions, in which particular
thioglycerol fragment ions acted as chelating agents, through
the sulfur atom, with the boron atom of the target
compounds. In general, the accurate mass determination of
these adducts allowed us to verify the molecular formulae
and confirm the structures of the esters studied.
Acknowledgements
[12] L. Reyes, S. Corona, G. Arroyo, F. Delgado, R. Miranda. Eco-
contribution for the production of N-arylnitrones: solvent-
free and assisted by microwaves. Int. J. Mol. Sci. 2010, 11, 2576.
[13] M. O. Noguez, V. Marcelino, H. Rodríguez, O. Martin,
J. O. Martínez, G. A. Arroyo, F. J. Pérez, M. Suárez, R. Miranda.
Infrared assisted production of 3,4-dihydro-2(1H)-pyridones
in solvent-free conditions. Int. J. Mol. Sci. 2011, 12, 2641.
[14] M. O. Noguez, C. Flores, B. Velasco, G. Arroyo, F. J. Pérez,
V. Carranza, R. Miranda. Comparative study using different
Infrared zones of the solventless activation of organic
reactions. Int. J. Mol. Sci. 2011, 12, 8575.
[15] R. Le Legadec, L. Rubio, L. Velasco, F. J. Pérez, R. Miranda.
Mass spectrometric studies of cyclopentanol derivatives in
the reductive coupling of a,b-unsaturated ketones assisted
by samarium diiodide. Rapid Commun. Mass Spectrom.
2003, 17, 1699, and references cited therein.
The authors appreciate the financial support to UNAM-DGAPA-
PAPIIT IN228010, and also acknowledge CONACyT-México for
the PhD scholarship to Joel Martínez.
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