Real-time monitoring of a cobalt-mediated one-pot transition metal-catalyzed multicomponent reaction

Article abstract of DOI:10.1016/j.ica.2020.119654

In this paper, pressurized sample infusion electrospray ionization mass spectrometry (PSI-ESI-MS) and FTIR spectroscopy were used to investigate the mechanism of a like-Barbier cobalt-mediated one-pot transition metal-catalyzed multicomponent reaction (MC

Full text of DOI:10.1016/j.ica.2020.119654

InorganicaChimicaActa508(2020)119654
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Inorganica Chimica Acta
journal homepage: www.elsevier.com/locate/ica
Research paper
Real-time monitoring of a cobalt-mediated one-pot transition metal-
catalyzed multicomponent reaction
⁎
Antônio E.M. Crottia,b, , Daniel Previdib, Paulo M. Donateb, J. Scott McIndoea,⁎
a Department of Chemistry, University of Victoria, P. O. Box 3065, Victoria, BC V8W 3V6, Canada
b Departamento de Química, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, CEP 14040-901 Ribeirão Preto, SP, Brazil
A R T I C L E I N F O
A B S T R A C T
Keywords:
In this paper, pressurized sample infusion electrospray ionization mass spectrometry (PSI-ESI-MS) and FTIR
spectroscopy were used to investigate the mechanism of a like-Barbier cobalt-mediated one-pot transition metal-
catalyzed multicomponent reaction (MCR). The use of charge-tagged aryl halides allowed for the detection of
cobalt(II)-promoted hydrodehalogenation products. Although these products were also detected in the off-line
ESI-MS monitoring, the ability of PSI-ESI-MS to track real-time changes in the reaction mixture composition
proved cobalt(II) was responsible for the undesired transformation. The occurrence of cobalt(II)-promoted hy-
drodehalogenation as a side reaction in this MCR had not been considered in previous mechanistic proposals and
represents an important mechanistic consideration.
Charge tagged aryl halides
Hydrodehalogenation
Multicomponent reaction
1. Introduction
reaction vessel. PSI has been successfully employed for real-time ana-
lysis of several catalytic reactions (e.g., palladium and rhodium in al-
Mass spectrometry (MS) has emerged as an additional tool to
spectroscopic (e.g. NMR, IR and UV/vis) and electrochemical techni-
ques for the investigation of reaction mechanisms [1,2]. The develop-
ment of atmospheric pressure ionization (API) techniques, especially
electrospray ionization (ESI), has enabled MS to detect transient species
directly from the reaction vessel, which has furnished valuable in-
formation enabling elucidation and consolidation of the mechanisms
proposed for reactions such as the Mannich-type α-methylenation [3],
Stille reaction [2], Ugi reaction [4], Heck reaction [5,6], Suzuki reac-
tion [6], Sonogashira reaction [7], Morita-Baylis-Hillman reaction
[8,9], Petasis olefination [10], Ziegler-Natta polymerization [11],
Pauson-Khand reaction [12] and hydrodehalogenation [13], among
others.
Electrospray ionization mass spectrometry (ESI-MS) and electro-
spray ionization tandem mass spectrometry (ESI-MS/MS) monitoring of
reaction solutions can be conducted by off-line sampling methods [14]
or by continuous on-line monitoring such as with pressurized sample
infusion (PSI) [15,16]. In PSI-ESI-MS, one of the ends of a PEEK tube is
inserted into the reaction mixture through a rubber septum, whereas
the other end is connected to the ESI source inlet. Continuous sample
introduction into the mass spectrometer occurs thanks to a slight
overpressure of an inert gas (between one and five psi) applied to the
kyne hydrogenation [17] and hydrodehalogenation of aryl iodides
[13]).
The use of charged tags is an elegant and efficient strategy for the
detection of species otherwise invisible to ESIMS [18–22]. The ap-
proach of using charge-tagged compounds in PSI-ESI-MS allows mon-
itoring not only reaction intermediates but also changes in their relative
abundances over the course of the reaction [23] However, homogeneity
of the solution has been reported to play a key role in PSI experiments,
as phase separation or insolubility result in irregularities in the spray,
making the traces very noisy [24]. For these reasons, the use of PSI-ESI-
MS to investigate reaction mechanisms has been largely limited to
homogeneous catalytic systems.
Multicomponent reactions (MCRs) are defined as reactions in which
three or more reactants are added into only one reaction vessel (one-pot
reaction), to yield product molecules containing the essential parts of
the reactant structures. These reactions eliminate the need to isolate
and purify the intermediate products, which saves reactants, solvent,
time, and energy [25,26]. Because MCRs allow the structural blocks of
all the reactants to connect in a single pot, these reactions have become
an attractive alternative to classic multi-step synthesis [27]. Moreover,
by combining reactants with minimal structural differences, a single
MCR can result in a library of compounds [26]. ESI-MS/MS has been
⁎ Corresponding authors at: Departamento de Química, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, Av. Bandeirantes,
3900, Monte Alegre, CEP 14040-901 Ribeirão Preto, SP, Brazil (A.E.M. Crotti).
E-mail addresses: millercrotti@ffclrp.usp.br (A.E.M. Crotti), mcindoe@uvic.ca (J. Scott McIndoe).
https://doi.org/10.1016/j.ica.2020.119654
Received 4 March 2020; Received in revised form 3 April 2020; Accepted 4 April 2020
Availableonline07April2020
0020-1693/©2020ElsevierB.V.Allrightsreserved.

A.E.M. Crotti, et al.
InorganicaChimicaActa508(2020)119654
C7H7Br]+, 32.
Compound
2
(4-bromo-N,N,N-trimethyl-benzeneaminium hexa-
fluorophosphate) was synthesized according to the literature [36] with
some modifications (Scheme 2). To a 250 mL sealed round-bottom
flask, 4-bromo-N,N-dimethyl-aminebenzene (3082 g, 15.4 mmol),
acetone (100 mL), and methyl iodide (2.8 mL, 6.384 g, 44.9 mmol)
were added. The reaction was stirred overnight at 70 °C under a ni-
trogen atmosphere. The reaction mixture was filtered under reduced
pressure and the collected solid washed with ice-cold acetone and dried
under vacuum overnight to afford compound II [4-Br(C4H6)NMe3][I]
(4.616 g, yield 88%) as a white fluffy solid. A salt metathesis was
performed with NaPF6 mixing a saturated aqueous solution of II
(4.052 g, 11.8 mmol) with a saturated aqueous solution of NaPF6 and
stirring for 30 min to give product 2 [4-Br(C6H4)NMe3][PF6] (1.962 g,
yield 46%). 1H NMR (300 MHz, DMSO‑d6): δ (ppm): 7.95 (d, 2H,
J = 8.6 Hz), 7.85 (d, 2H, J = 8.6 Hz), 3.59 (s, 9H). 13C NMR (75 MHz,
DMSO‑d6): δ (ppm): 146.6 (C), 132.7 (CH), 122.8 (CH), 122.0 (C), 56.4
(CH3). LR-ESI-MS/MS (m/z, % rel. int.): 214.2 [M]+, 30; 199.2 [M –
Me]+, 100; 198.3 [M – CH4]+, 80.
Compound 3 (trans-3-(p-benzyl-4-phenyl-3-methoxycarbonyl-γ-bu-
tyrolactone) was synthesized as previously reported by Le Floch and co-
workers (Scheme 2) [33]. Briefly, zinc dust (3.0 g, 46 mmol) was added
to a dried 100-mL round-bottomed flask previously flushed with argon
and charged with acetonitrile (20 mL). Dimethyl itaconate (7.9 g,
50 mmol), benzaldehyde (1.0 mL, 10 mmol), and an aryl bromide
(15 mmol; bromobenzene, 2.35 g, 1.57 mL for compound 3) were
added whilst stirring. Next, cobalt bromide (0.44 g, 2 mmol), tri-
fluoroacetic acid (0.1 mL), and 1,2-dibromoethane (0.2 mL) were added
successively to the mixture, which was heated to 60 °C for 2 h. The
reaction mixture was filtered through Celite, which was exhaustively
washed with diethyl ether. The combined organic fractions were con-
centrated in vacuo. The resulting crude reaction product was purified
by flash column chromatography over silica gel (hexane:ethyl acetate
7:3 v/v) to provide a mixture of stereoisomers of the γ–lactone 3
(1.086 g, 35% yield) as a white powder. 1H NMR (300 MHz, CDCl3): δ
(ppm) 7.45 (2H, m, H-11 and H-17), 7.43 (2H, m, H-16 and H-18), 7.35
(2H, m, H-15 and H-19), 7.23 (2H, m, H-10 and H-12), 6.95 (2H, m, H-9
and H-13), 5.67 (1H, s, H-4), 3.75 (3H, s, H-6), 3.12 (1H, d,
J2b,2a = 17.6, H-2b), 2.86 (1H, d, J7b,7a = 13.9, H-7b), 2.71 (1H, d,
J2a,2b = 17.6, H-2a), 2.17 (1H, d, J7a,7b = 13.9, H-7a); 13C NMR
(75 MHz, CDCl3): δ (ppm) 174.5 (C, C-1), 173.0 (C, C-5), 135.7 (C, C-8),
134.3 (C, C-14), 129.5 (CH, C-9 = C-13), 129.1 (CH, C-11 = C-17),
128.5 (CH, C-16 = C-18), 127.3 (CH, C-10 = C-12), 126.5 (CH, C-
15 = C-19), 85.7 (CH, C-4), 56.3 (C, C-3), 52.9 (CH3, C-6), 39.0 (CH2,
C-7), 35.6 (CH2, C-2); ESI-MS/MS m/z (% rel. int.) 311 [M + H]+, 15;
293 [M + H-H2O]+, 10; 279 [M + H-MeOH]+, 50; 251 [M + H-
MeOH-CO]+, 10; 261 [M + H-H2O-MeOH]+, 80; 233 [M + H-H2O-
C2H4O2]+, 100.
Scheme 1. Mediated-cobalt synthesis of 2,3-di- and 2,2,3-trisubstituted-3-
methoxycarbonyl-γ-lactones [33].
successfully used to characterize the intermediates of several MCRs,
such as the Mannich reaction [28], the Hantzsch reaction [28,29], the
Ugi reaction [4], the Petasis Borono-Mannich reaction [30], the Bigi-
nelli reaction [26,31,32] and the Pauson-Khand reaction [12].
In this paper, the potential of PSI-ESI-MS to investigate MCR me-
chanisms of heterogeneous catalytic systems was explored. For this
purpose, we have chosen as a model the like-Barbier cobalt-mediated
one-pot transition metal-catalyzed MCR (Scheme 1), which was first
reported by Le Floch and co-workers for the synthesis of 2,3-di- and
2,2,3-trisubstituted-3-methoxycarbonyl-γ-lactones and related com-
pounds [33].
2. Experimental section
2.1. Chemicals
Solvents and chemicals were purchased from Sigma-Aldrich. THF
was HPLC grade, previously purified on a Grubbs-type (MBraun SPS-
800) solvent purification system. Acetone was purified by distillation
from potassium carbonate [34]. Acetonitrile was HPLC grade, purified
by distillation from calcium hydride [34]. Triethylamine was purified
by distillation from calcium hydride [34]. Deionized water was ob-
tained from a Millipore Milli-DI water purification system.
2.2. Nuclear magnetic resonance (NMR)
The 1H and 13C NMR spectra were recorded on a Bruker Avance
300 MHz spectrometer as solutions prepared in DMSO‑d6 or CDCl3.
NMR data were processed using Bruker TopSpin 3.6.0 software.
2.3. Synthesis of charge-tagged compounds 1 and 2 and γ-lactone 3
Compound
1
(4-bromo-N,N,N-triethyl-benzenemethanaminium
hexafluorophosphate) was synthesized according to the methodology
proposed by Roiser and co-workers [35] with some modifications
(Scheme 2). To a 250-mL screw-capped round-bottom flask, p-bromo-
benzyl bromide (3.060 g, 12.2 mmol), THF (100 mL), and triethylamine
(4.5 mL, 3.267 g, 32.3 mmol) were added. The resulting solution was
stirred at room temperature for 24 h, during which time the product
precipitated as a white fluffy solid. The mixture was cooled to 0 °C,
filtered under reduced pressure, and the collected solid dried under
vacuum to yield the benzyl ammonium salt I [4-Br(C6H4)CH2NEt3][Br]
(3.67 g, yield 85%) as a white fluffy solid. A salt metathesis was per-
formed with NaPF6 by mixing a saturated aqueous solution of I (3.54 g,
10 mmol) with a saturated aqueous solution of NaPF6 and stirring for
30 min, followed by filtration and dryness under vacuum to produce 1
[4-Br(C6H4)CH2NEt3][PF6] (2.727 g, yield 65%). 1H NMR (300 MHz,
DMSO‑d6): δ (ppm): 7.71 (d, 2H, J = 8.4 Hz), 7.47 (d, 2H, J = 8.4 Hz),
4.48 (br s, 2H), 3.15 (6H, 4, J = 7.4 Hz), 1.28 (9H, t, J = 7.4 Hz). 13C
NMR (75 MHz, DMSO‑d6): δ (ppm): 134.7 (CH), 131.9 (CH), 127.1 (C),
123.9 (C), 66.6 (CH2), 58.6 (CH2), 7.44 (CH3). LR-ESI-MS/MS (m/z, %
rel. int.): 270.3 [M]+, 36; 169.1 [M – NEt3]+, 100; 100.3 [M –
2.4. MCR monitoring by FTIR
Fourier transform-infrared (FTIR) experiments were performed on
Bruker Alpha FTIR in a Harrick demountable transmission flow cell
with BaF2 windows, a 100 μm path length and a 5 μL cell volume. Prior
to the MCR investigation, a series of benzaldehyde and γ-lactone 3
solutions in acetonitrile were prepared by two-fold serial dilution and a
calibration curve was plotted based on absorption bands at 1704 cm−1
and 1791 cm−1, respectively, which corresponding to their carbonyl
stretching. A background spectrum using acetonitrile was recorded
before running the experiments. Next, 100 µL aliquots were sampled
from the reaction mixture every 10 min, 15 min, or 30 min for 6 h. An
initial sample was also collected at 5 min. Acetonitrile was added to
these samples to make them up to 1 mL. The samples were filtered using
a Pasteur pipet with cotton, transferred to 3 mL vials and added to 1 mL
MeCN. Finally, a 10 µL aliquot of this sample was transferred to an
Eppendorf vial, diluted to 1 mL acetonitrile and then introduced onto
2

A.E.M. Crotti, et al.
InorganicaChimicaActa508(2020)119654
Scheme 2. Synthesis of the charge-tagged compounds 1 and 2 and γ-lactone 3.
the IR cell using a 1 mL syringe. Data were processed using a Bruker
Opus Viewer 6.5 software.
benzaldehyde), zinc dust (46 mmol, 3 eq to bromobenzene), and cobalt
bromide (2 mmol, 15 mol% to bromobenzene) go to completion in
about 2 h at 60 °C under conventional heating. Pinato-Botelho and co-
workers employed the same conditions under microwave heating and
obtained a shorter reaction time [38]. Thus, before starting the MCR
monitoring using mass spectrometry, we monitored this reaction by
FTIR under the same experimental conditions reported by Le Floch and
co-workers (Fig. 1). In this study, appearance of the lactone product had
a half-life under normal reaction conditions of approximately 11.4 min.
However, under much more dilute conditions, which are needed for
PSI-ESI-MS experiments to prevent saturation effects [39] and instru-
mental contamination [24], the reaction does not proceed significantly
within 2 h. These results led us to monitor the MCR off-line by ESI-MS.
2.5. MCR monitoring by ESI-MS
The on-line mass spectrometric monitoring of the like-Barbier cobalt
catalyzed MCR was performed using PSI-ESI-MS. Briefly, a flask con-
taining the reaction mixture was placed next to the ESI ion source and
connected to a source of inert gas by means of a small rubber tube [37].
A PEEK tube was inserted into the Schlenk flask through a rubber
septum, with one of the ends immersed into the reaction mixture and
the other connected to the ESI source inlet. A slight overpressure (be-
tween 1 and 4 psi) was applied to facilitate continuous sample in-
troduction through the PEEK tube into the mass spectrometer. To
minimize PEEK or ESI capillary clogging issues, a cotton filter was fitted
to the PEEK tip that was immersed into the reaction mixture. All the
experiments were performed on a Waters Acquity Triple Quadrupole
Detector (TQD). The instrument parameters employed were as follows:
capillary voltage, 3.0 kV, cone voltage, 15 V, extraction voltage, 3.0 V;
source temperature 90 °C, gas flow rate, 100 L/h; desolvation gas flow
rate, 100 L/h. Scan time was 5 s.
3.2. MCR off-line monitoring using ESI-MS and ESI-MS/MS
We monitored the MCR with dimethyl itaconate, benzaldehyde, and
bromobenzene (Scheme 1) under the same conditions as reported in the
For the off-line monitoring experiments, 100 µL aliquots were
sampled from the reaction mixture. Acetonitrile was added to these
samples to make them up to 1 mL. Next, these samples were filtered
using a Pasteur pipet with cotton, then transferred to 3-mL vials and
then added to 1 mL MeCN. Finally, a 10-µL aliquot of this sample was
transferred to an Eppendorf vial, diluted to 1 mL acetonitrile and then
introduced into the ESI source with a 1 mL analytical syringe connected
to PEEK tubing and a syringe pump at a flow rate of 30 μL/min.
Product ion spectra of the selected precursor ions were recorded by
collision-induced dissociation (CID) with argon gas (99.999%) at en-
ergies (Elab) ranging between 5 and 40 V.
3. Results and discussion
3.1. FTIR MCR monitoring
Le Floch and co-workers have reported that the like-Barbier cobalt
catalyzed MCR using benzaldehyde (10 mmol, 1 eq), dimethyl itaconate
(50 mmol, 5 eq to benzaldehyde), bromobenzene (15 mmol, 1.5 eq to
Fig. 1. Changes in the benzaldehyde (1704 cm−1) and γ-lactone 3 (1791 cm−1
concentrations (mmol/L) over time (min), as monitored by FTIR.
)
3

A.E.M. Crotti, et al.
InorganicaChimicaActa508(2020)119654
Fig. 2. ESI-MS spectrum of the MCR mixture sampled at 10 min from two different experiments under literature conditions, added to charge tagged compounds 1 (a)
and 2 (b) as co-reagents. A: [Co(MeCN)3]2+; B: [Co(MeCN)4]2+; C: [Co(MeCN)6]2+; D: [Co(C7H10O4)(MeCN)]2+; E: [C7H10O4 + H]+; F: [ZnBr(MeCN)3]+; G: [Co
(CF3CO2)(MeCN)2]+; H: Co(CF3CO2)(MeCN)3]+
.
literature (stoichiometry, concentrations, the order of addition, and
temperature) [33], except for the addition of charge-tagged aryl halides
1 or 2 (0.2 mmol) as co-reagents. Aliquots were sampled from the re-
action mixture every 5 min, 15 min, or 60 min for 6 h, filtered, diluted,
and then injected directly into the ESI source by a syringe.
Peaks corresponding to the expected charge tagged γ-lactones at m/
z 424 (for charge tagged 1) and m/z 368 (for charge tagged 2) were
observed in the MS spectra from t = 10 min (Fig. 2). Product ion
spectra of m/z 424 and m/z 368 and the formation of their main pro-
duct ions are given in Figs. 3 and 4. Their relative intensities did not
increase in the mass spectra obtained after 10 min, likely due to their
reduced solubilities in acetonitrile. However, the most intense peaks in
the mass spectra were assigned to cobalt and zinc complexes with
acetonitrile, and dimethyl itaconate, which was used in excess. These
peaks were assigned on the basis of their product ion spectrum, isotopic
pattern, and reaction behavior, as will be discussed later. Peaks of m/z
192 and m/z 136 are also intense in the mass spectra (Fig. 2). Analysis
of the product ion spectrum of m/z 192 and m/z 136 revealed that they
are derived from the charge tagged aryl halides 1 and 2, respectively
(Figs. 3 and 4). Peaks corresponding to possible reaction intermediate
were not observed or could not be distinguished from the background.
3.3. MCR on-line monitoring using PSI-ESI-MS
Because there is no previous reports in the literature for the for-
mation of species similar to those of m/z 136 and m/z 192 in this MCR,
we decided to recur to PSI-ESI-MS to track the changes in the reaction
mixture composition in the first 2 h of reaction to better understand the
formation of these ions.
Our initial PSI-ESI-MS experiments were carried out without adding
4

A.E.M. Crotti, et al.
InorganicaChimicaActa508(2020)119654
Fig. 3. Product ion spectrum of m/z 424 (a) and m/z 368 (b) (Ar, Elab = 10 eV) and structure of some their product ions.
charge-tagged aryl halides. To minimize clogging, as well as to avoid
detector saturation issues, the reagents and catalyst amounts used were
fifty times lower as compared to literature [33], as follows: dimethyl
itaconate (1 mmol), aryl halide (0.3 mmol), aromatic aldehyde
(0.2 mmol), zinc dust (0.92 mmol), cobalt bromide (0.04 mmol), TFA
(2 μL), and DBE (4 μL). To ensure good ESI-MS performance, 20 mL
acetonitrile was used. In all the experiments, a Schlenk flask containing
zinc dust was purged with argon and then added to 20 mL of scrupu-
lously dried acetonitrile. Next, the chemicals were added following the
same order of addition as literature (dimethyl itaconate, benzaldehyde,
aryl halide, CoBr2, TFA, and DBE, in this sequence). Most of the re-
agents did not cause any significant increase in the total ion count.
However, a large number of intense new peaks that were not observed
in the off-line monitoring with charge-tagged aryl halides 1 and 2
appeared after cobalt(II) bromide addition. Thus, an experiment was
designed to assign peaks corresponding to cobalt(II) complexation to
acetonitrile and other chemicals. For this purpose, CoBr2 was added to
the Schlenk flask containing acetonitrile only, so that the arising peaks
were assigned to cobalt(II) complexes with acetonitrile. Benzaldehyde
was added followed by dimethyl itaconate. A figure displaying this
strategy and a list of peaks assigned to cobalt(II) complexes on the basis
of this experiment are given in the Supporting Information. Peaks due
to possible intermediates were not evident, likely due to their signal
suppression by the cobalt(II) complex signals. As expected, peaks of m/z
136 or m/z 192 were not observed (charged tagged aryl halides 1 and 2
were not used in these experiments).
Next, to increase the signals of possible MCR intermediate, PSI-ESI-
MS experiments using charge tagged aryl halides 1 (0.3 mmol) and 2
Fig. 4. Product ion spectrum of m/z 192 (a) and m/z 136 (b) (Ar, Elab = 10 eV) and formation of some of their product ions.
5

A.E.M. Crotti, et al.
InorganicaChimicaActa508(2020)119654
(e.g., TFA), added to the fact that these peaks emerged in the mass
spectrum even when TFA was not used.
Le Gall and co-workers have proposed and extensively studied the
cobalt(II)-mediated one-pot transition metal-catalyzed multicomponent
reaction investigated herein. Under like-Barbier conditions, the authors
proposed that an organocobalt (II, Scheme 3) species is a key inter-
mediate in the mechanism of this MCR by favoring the conjugate ad-
dition to dimethyl itaconate (intermediate III) and further aldolization
(intermediates IV and V) and cyclization leading to the formation of the
five-membered lactone ring (product A, Scheme 3). Experimental re-
sults revealed that the reaction can be conducted with reducing agents
others than zinc (e.g., manganese), thus proving that organozinc for-
mation (I, Scheme 3) is not required for the reaction to proceed [33].
The authors also reported the occurrence of side-reactions for the MCR
under study, such as aryl homocoupling (byproduct B) and nucleophilic
addition of the organometallic to the aromatic aldehyde (byproduct C,
Scheme 3). However, although cobalt-promoted dehydrohalogenation
has been previously reported in literature [40], its occurrence as side
reaction in this MCR has not been previously considered. Formation of
the byproduct D may have been overlooked due to the fact that the
hydrodehalogenation products derived from non-charge tagged com-
pounds might have been removed during the isolation process of the γ-
lactones (e.g., benzene derived from bromobenzene can be lost during
sample concentration in
a rotary evaporator). Here, the hydro-
dehalogenation products were detected when charge tagged aryl ha-
lides 1 and 2 were used both in ESI-MS off-line monitoring and PSI-ESI-
MS. The occurrence of hydrodehalogenation as a side reaction in this
MCR reinforce the need of using excess of aryl halide (1.5 eq) to aro-
matic benzaldehyde (1 eq) for obtaining γ-lactones in good yields.
4. Conclusions
This study demonstrated that the PSI-ESI-MS, which has been em-
ployed in many mechanistic studies of homogeneous catalysis can also
be used, albeit with increased practical challenges, for real-time mon-
itoring of heterogeneous catalysis. The use of charge tagged aryl halides
was crucial for the detection of the hydrodehalogenation product.
Although these products were also detected in the ESI-MS off-line
monitoring, the ability of PSI-ESI-MS to track real-time changes in the
reaction mixture composition afforded important pieces of evidence for
the formation of these products only after cobalt(II) addition. The oc-
currence of cobalt(II)-promoted hydrodehalogenation as a side reaction
in this MCR had not been considered in previous mechanistic proposals
and represents an important piece of its global mechanism. On the other
hand, the high signal intensities of the hydrodehalogenation products in
the mass spectrum, as well as the high intensity of cobalt(II) complexes
with acetonitrile and other species in solution, especially in the diluted
conditions needed for PSI-ESI-MS experiments, suppress the signals of
mechanistically important intermediate species and hampered to obtain
a more complete picture of this MCR mechanism.
Fig. 5. Changes in the normalized relative abundances of m/z 270 and 192 (a)
and m/z 214 and 136 (b) over time, as monitored by PSI-ESI-MS.
(0.3 mmol) were performed. In these cases, resolution was a particular
challenging issue; decreased resolution led to detector saturation,
whereas increased resolution reduced the sensitivity and compromised
detection of the lower intensity species. In summary, peaks of possible
reaction intermediate were suppressed by the charge tagged compound
signals and m/z 192 (for charge tagged 1) or m/z 136 (for charged tag
2). Alternatively, under diluted conditions, the intermediates could be
quenched by the solvent, then not forming the expected product.
Because we have used diluted conditions in our PSI-ESI-MS ex-
periments, it was already expected from FTIR results that the reaction
will not go to completion in 2 h. However, analysis of the TIC traces of
the charge tagged compounds 1 (m/z 270) and 2 (m/z 214) revealed
that their relative intensities decreased over 2 h, whereas signals of the
intermediate and the expected charge tagged γ-lactones (m/z 424 and
m/z 368) were not detected. On the other hand, the m/z 192 and m/z
136 peak intensities increased in the same period. We decided to
compare changes in the charge tagged 1 and 2 signal intensities with
those of m/z 192 and m/z 136. As shown in Fig. 5, m/z 270 and m/z 214
signal intensities started decreasing after cobalt(II) addition, whereas
peaks of m/z 192 and m/z 136 arise after cobalt(II) addition to the
reaction mixture. These results revealed that m/z 192 and m/z 136 are
cobalt-promoted hydrodehalogenation products, which are formed
from the charge tagged aryl halides 1 (m/z 270) and 2 (m/z 214), re-
spectively. In addition, these results provided pieces of evidence to
refute the hypothesis that these ions could be due to quenching of the
organometallic species by a proton source from the reaction mixture
CRediT authorship contribution statement
Antônio E.M. Crotti: Conceptualization, Investigation, Writing -
original draft, Writing
Investigation, Writing
Conceptualization, Writing
-
review
original draft. Paulo M. Donate:
original draft. J. Scott McIndoe:
&
editing. Daniel Previdi:
-
-
Conceptualization, Resources, Supervision, Writing - review & editing.
Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influ-
ence the work reported in this paper.
6

A.E.M. Crotti, et al.
InorganicaChimicaActa508(2020)119654
Scheme 3. Overview of the previously reported cobalt(II)-promoted MCR product (A) and byproducts (B and C), added to the hydrodehalogenation side-reaction
(D).
Acknowledgements
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