Synthesis of 2-arylbenzimidazoles under mild conditions catalyzed by a heteropolyacid-containing task-specific ionic liquid and catalyst investigation by electrospray (tandem) mass spectrometry

Article abstract of DOI:10.1039/c5ra12044f

A task-specific ionic liquid constituted by a Bronsted acid (1-(3-sulfopropyl)-3-methyl-imidazolium hydrogen sulfate) as the cation, namely MSI, and by [PW₁₂O₄₀]^3- as the triply charged counter-anion, namely PW (a heteropolyacid derivative), was used as an efficient catalyst for the condensation reaction between aldehydes and o-phenylenediamines.

Full text of DOI:10.1039/c5ra12044f

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DOI: 10.1039/C5RA12044F
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Synthesis of 2-arylbenzimidazoles under mild conditions catalyzed
by a heteropolyacid-containing task-specific ionic liquid and
catalyst investigation by electrospray (tandem) mass
spectrometry
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
a
a
b
b
Haline G. O. Alvim, Heibbe C. B. de Oliveira, Giovana A. Bataglion, Marcos N. Eberlin, Luciana
www.rsc.org/
a,c*
a*
M. Ramos, and Wender A. Silva,
A task-specific ionic liquid constituted by a Bronsted acid (1-(3- Environmentally-friend reactions may be achieved by a proper
8
sulfopropyl)-3-methyl-imidazolium hydrogen sulfate as the cation, combination of a catalyst and an IL, with a distinct attention for
3
-
namely MSI, and by [PW12
O
40
]
as the triply charged counter- imidazolium ILs, which proved to be excellent solvents for synthesis
9
-13
anion, namely PW (a heteropolyacid derivative), was used as an and catalysis. Functionalized ILs, also known as task-specific ionic
efficient catalyst for the condensation reaction between liquids (TSILs), with these ideas in mind, we have successfully
aldehydes and o-phenylenediamines.
supported transition metals in imidazolium ILs for an improved
1
4
Biginelli multicomponent reaction. We have also used ionophilic
1
5
There is growing interest in the synthesis of benzimidazole ligands and complexes for iron-catalyzed oxidations in ILs. .More
derivatives mostly because of their potential as antitumoral recently, we evaluated the incorporation of the anionic
1
3-
]
agents. The similarity between purine bases and benzimidazole- heteropolyacid derivative [PW12
O
40
(phosphotungstic acid
based structures renders benzimidazoles the status of “privileged derivative, namely PW) as the counterion for a Bronsted-acid
2
scaffolds”. The interest in benzimidazole derivatives is also based imidazolium-based cation (1-(3-sulfopropyl)-3-methyl-imidazolium
on their vast and frequent therapeutic potential, which includes hydrogen sulfate, namely MSI, Figure 1) applied for
a
1
6
their action as antihypertensive, anti-inflammatory, antimicrobial, multicomponent reaction in imidazolium-based ILs.
antiviral, psychoactive, antioxidant, anticoagulants, and antidiabetic
3
agents. This large spectrum of biological activities shown by a
plethora of benzimidazole-based molecules has boosted the
4
development of several synthetic methodologies. Most of those
methodologies require, however, toxic solvents, high temperatures,
aryl acid chlorides, reagents excesses, large catalysts amounts or
5
other undesired conditions (environmentally maleficent). The
development of new catalytic and green chemistry methodologies
using eco-friendly and sustainable conditions aiming at better
yields, selectivities, and atom economy are therefore highly desired
features.
Figure 1
catalyzed reactions (top). Bronsted-acid task-specific ionic liquid incorporating an
anionic heteropolyacid derivative, namely MSI PW (bottom).
. Imidazolium-based ionic liquids commonly used as supports for
A very promising strategy to overcome these aforementioned
shortcomings is the use of ionic liquids (ILs) as the reaction media,
mostly because they are regarded as “a pathway to environmental
3
6
7
acceptability”, particularly when imidazolium-based ILs are used.
Initially, the condensation reaction to afford 2-arylbenzimidazole
derivatives (Scheme 1) was tested using benzaldehyde and o-
phenylenediamine as the substrates. Upon increasing the
temperature the system was noted to turn dark, especially for
temperatures above 100 °C. Reactions carried out at 60 °C afforded
the desired product in 83% whereas 67% was obtained at 90 °C.
Aiming at more amenable conditions, we tested all reactions close
to room temperature (40 °C) with no reagent excess and using 5
3
mol% of the catalyst MSI PW. The reaction time was set for 10 h in
order to pursue maxima yields. Most reactions were however
completed after 4 h.
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3 2
Scheme 1. Condensation reactions catalyzed by MSI PW (5 mol%) in BMI.NTf
(
0.5 mL) at 40 °C using 1.00 mmol of each reagent for 10 h.
Table 1 summarizes the results for the synthesis of the 2-
arylbenzimidazoles. All products were obtained in excellent
yields under very mild conditions, except for the chlorine-
3
Figure 2. ESI(+)-MS/MS of the catalyst MSI PW acquired from a 50 µM
containing derivative (Table 1, Entry 3), for which the yield of methanolic solution. Note that the fragmentation patter is in accordance with
the proposed structure of the cation MSI.
the isolated product was good (73%).
The ESI(-)-MS of the same solution (Figure 3) detected mainly the
2
-
Table 1. Synthesized 2-arylbenzimidazoles using MSI
3
PW (5 mol%) in BMI.NTf
2
at 40 °C triply charged PW anion of m/z 958. The doubly charged [PW + H]
anion of m/z 1439 could also be detected as the second most
for 10 h.
2
-
abundant ion. A supramolecular assembly [MSI + PW] was also
detected as a doubly charged anion of m/z 1541 (show as the inset
in Figure 3).
Comp.
1
Structure
N
Yield (%)
99
N
H
N
NO
Cl
2
2
3
4
N
91
73
92
H
N
N
H
N
OH
N
H
OCH
3
O
N
N
O
5
6
96
97
H
N
Cl
N
H
N
NO
2
Cl
N
H
7
80
Figure 3. ESI(-)-MS of the catalyst MSI
solution. The inset shows the doubly charged anion [MSI.PW] of m/z 1541
corresponding to the supramolecular assembly of a MSI cation and one triply
3
-
PW acquired from a 50 µ2 M methanolic
3
-
The inherent ionic nature of both the TSIL (catalyst) and the used IL charged PW (PW12
O40 ) anion.
(
BMI.NTf ) and, therefore, their facile transfer from solution to the
2
gas phase by ESI, allowed an investigation on the acid strength Next, the increase of the acidic strength of the catalyst was
behavior of MSI PW in the presence and in the absence of the IL by investigated in the presence of BMI.NTf (Figure 4). Interestingly,
3
2
2
-
ESI-MS(/MS). Indeed, ESI-MS has been shown to be an unsurpassed the ion of m/z 1439 ([PW + H] , also detected in Figure 3) had its
proper tool for the investigation of ILs/TSILs properties, effects and abundance considerably decreased, whereas the abundance of the
17
mechanisms. It is also known that Bronsted acids may behave as triply charged anion PW increased. This trend shows therefore that
1
8,19
superacids when supported (or embedded) in ILs.
the dissociation of the acid was even at a larger extent, in
Initially, a methanolic solution (50 µM) of the catalyst (MSI PW) was accordance with the expected acidic strength increase in the
3
2
0
monitored online by ESI-MS in both the positive (Figure 2) and presence of the IL BMI.NTf
negative (Figure 3) ion modes. The ESI(+)-MS detected a single ion catalyst efficiency in the IL media. When the concentration of
of m/z 205 (attributed to the MSI cation) which had its ESI(+)- BMI.NTf was increased from 50 µM to 100 µM, the supramolecular
MS/MS acquired (Figure 2). The tandem mass spectrum of MSI.PW [BMI(NTf
solution shows that the gaseous cation of the TSIL (MSI, m/z 205) Note that this type of supramolecular aggregate is commonly noted
2
. This feature is directly related with the
2
-
2 2
) ] anion of m/z 698.9 was therefore detected (Figure 4).
21
dissociates to afford fragments in full accordance with the proposed for imidazolium-based ILs. Other interesting ion detected in the
structure (Figure 2).
ESI(-)-MS of Figure 4 is the supramolecular doubly charged anions
2
-
[
BMI + PW] of m/z 1507.5.
2
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Figure 4. ESI(-)-MS of the catalyst MSI PW acquired from a 50 µM methanolic
solution in the presence of BMI.NTf
2
. The supramolecular anion of m/z 698.9 was
) whereas from the 50
detected from a 100
M methanolic solution of BMI.NTf
detected.
µ
M methanolic solution (BMI.NTf
2
only the anion of m/z 279.9 (NTf ) could be
-
µ
2
2
Scheme 2. Plausible catalytic cycle proposed for the synthesis of 2-
3 2
arylbenzimidazole derivatives promoted by MSI PW in BMI.NTf . Note that the
cationic intermediates shown in the catalytic cycle may form ion-pairs with the
Based on the ESI-MS(/MS) data, a plausible catalytic cycle could be
proposed to explain the transformation (Scheme 2). In the presence
-
2
NTf anion therefore with stabilizing effects (ionic liquid effect).
2
of BMI.NTf , the acid strength of the catalyst increases and the
aldehyde is protonated. The amine is protonated as well, but the
equilibrium has been omitted for clarity. The protonated aldehyde
then undergoes the amine addition followed by water elimination.
The processes takes place again in its intramolecular version
releasing the condensation product and restoring the acidic
-
hydrogen. Note that the NTf
2
anion is available to form ion-pairs
with the protonated (cationic) structures therefore stabilizing them
through ion-pairing (ionic liquid effect).
Finally, theoretical calculations were performed to gain insights on
the acid strength increase of the catalyst in the presence of the IL
2
BMI.NTf . We had as the bases the formation of a supramolecular
structure as a consequence of the association between the BMI
cation and PW anion, which allows the cation MSI to be more prone
to promote the reaction. ESI-MS data (from Figures 3 and 4)
2
showed that in the presence of the IL (BMI.NTf ), the cation MSI is
more available (and more acidic) in the reaction medium to catalyze
the reaction as a consequence of the cation exchange. The cation
exchange affords BMI
3
PW structures and releases the MSI cation
(
Scheme 2). All calculations were performed at M062X/6-
3
1G(d,p)/LAN2LDZ//PM6 level of theory and the results are
summarized in Figure 5.
Figure 5. Relative energies profile and stabilizing effects resulting from the BMI
cation association with the triply charged PW anion (0.00 kcal mol-1) affording
the supramolecular structure BMI PW. Calculations performed at M062X/6-
1G(d,p)/LAN2LDZ//PM6 level of theory. Structures have been calculated
considering PW anion (triply charged) with three non-coordinate BMI cations
3
3
2
+
+
followed by consecutive associations affording [PW + BMI] , [PW + 2
.BMI] and
[
PW + 3.BMI], respectively.
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Figure 5 shows that the consecutive associations with BMI cation Olefins in Imidazolium-Based Ionic Liquids. ChemSusChem 2012,
5
1
, 716.
6 Alvim, H. G. O.; de Lima, T. B.; de Oliveira, H. C. B.; Gozzo, F.
greatly improve the stability of the anionic (triply charged)
heteropolyacid derivative therefore in accordance with the
observed IL effect. This high stabilizing effect seems also to explain
C.; de Macedo, J. L.; Abdelnur, P. V.; Silva, W. A.; Neto, B. A. D.
Ionic Liquid Effect over the Biginelli Reaction under
the origin of the superacid behavior observed for Bronsted acids in Homogeneous and Heterogeneous Catalysis. ACS Catal. 2013,
3,
imidazolium-based ILs and the efficiency of the catalytic system 1420.
17 Dupont, J.; Eberlin, M. N. Structure and Physico-Chemical
Properties of Ionic Liquids: What Mass Spectrometry is Telling
described herein.
Us. Curr. Org. Chem. 2013, 17, 257.
1
8 Chiappe, C.; Rajamani, S. Structural Effects on the Physico-
Chemical and Catalytic Properties of Acidic Ionic Liquids: An
Overview. Eur. J. Org. Chem. 2011, 5517.
Conclusions
In summary, we have demonstrated the catalytic ability of
19 Johnson, K. E.; Pagni, R. M.; Bartmess, J. Bronsted acids in
ionic liquids: Fundamentals, organic reactions, and comparisons.
Monatsh. Chem. 2007, 138, 1077.
pointed to the origin of the superacid behavior and the high 20 ESI-MS and ESI-MS/MS measurements were performed in
3
MSI PW in the synthesis of 2-arylbenzimidazole derivatives
22
performed in ILs under mild conditions. ESI-MS monitoring
2
3
both the positive and negative ion modes (m/z 50−2000 range)
on HDMS instrument. This instrument has hybrid
quadrupole/ion mobility/orthogonal acceleration time-of-flight
oa-TOF) geometry and was used in the TOF V+ mode. All
stabilization of the catalyst in ILs. Theoretical calculations
a
a
allowed a better understanding on the superacid behavior of
the catalyst and its efficiency as a consequence of the
pronounced ionic liquid effect.
(
samples were dissolved in methanol to form 50 μM solutions
and were directly infused into the ESI source at a flow rate of 10
μL/min. ESI source conditions were as follows: capillary voltage
3
2
.0 kV, sample cone 20 V, extraction cone 3 V.
1 Gozzo, F. C.; Santos, L. S.; Augusti, R.; Consorti, C. S.; Dupont,
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2
2 A sealed Schlenk tube containing 0.5 mL of BMI.NTf2,1.00
mmol of the aldehyde, 1.00 mmol of the diamine and MSI PW
5 mol %) was allowed to react at 40 °C for 10 h. Substrates were
3
9
(
3
purified by chromatographic column eluted with mixtures of
hexane/ethyl acetate. 2-phenyl-1H-benzo[d]imidazole (1). 1H
NMR (300 MHz, DMSO-d6), δ: 7.55-7.60 (m, 2H), 7.72-7.78 (m,
4
2H), 7.86-7.91 (m, 2H), 8.45-8.51 (m, 2H). 13C NMR (75 MHz,
DMSO-d6), δ: 113.9, 123.1, 125.8, 127.9, 129.5, 131.8, 133.2,
5
1
2
48.5.
3 Aiming to build up the complex of interest, we started from
,
3
6
775.
Petkovic, M.; Seddon, K. R.; Rebelo, L. P. N.; Pereira, C. S.
the crystallographic structure of HPW (with the acidic H
removed) in which we included the three geometric structures
of BMI. During the geometry optimization, the Cartesian
coordinates of the PW triply charged anion were kept frozen and
only the relative positions of the three BMI cations were
optimized using the semiempirical parametric method (PM6).
The optimized geometry were therefore used for the single
point calculation at M06-2X/6-31G(d,p)/LANL2DZ level of theory
Ionic liquids: a pathway to environmental acceptability. Chem.
Soc. Rev. 2011, 40, 1383.
7
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2
8
(
i.e. LANL2DZ pseudo potential for W and the 6-31G(2,p) split-
9
valence basis set for all other atoms). To avoid a basis-set
superposition error (BSSE) the interaction energies were
counter-poise corrected using the standard approach of Boys
and Bernardi. All theoretical calculations were carried out using
Gaussian 09 program suite.
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(
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4
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