The Knoevenagel condensation catalysed by ionic liquids: a mass spectrometric insight into the reaction mechanism

Article abstract of DOI:10.1039/d1nj03594k

The creation of carbon-carbon bonds is still a highly required topic in organic chemistry for the capacity to give a wide variety of new products of industrial value. Accordingly, the Knoevenagel condensation between activated methylene compounds and alde

Full text of DOI:10.1039/d1nj03594k

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The Knoevenagel condensation catalysed by ionic liquids: a mass
spectrometric insight into the reaction mechanism
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Chiara Salvitti, * Martina Bortolami, Isabella Chiarotto, * Anna Troiani, * Giulia de Petris
Received 00th January 20xx,
Accepted 00th January 20xx
The creation of carbon-carbon bonds is still a highly required topic in organic chemistry for the capacity to give a wide variety
of new products of industrial value. Accordingly, the Knoevenagel condensation between activated methylene compounds
and aldehydes is one of the most known carbon coupling reactions. In this work, the catalytic activity of imidazolium-based
DOI: 10.1039/x0xx00000x
ionic
liquids
(1-butyl-3-methylimidazolium
acetate,
1-butyl-3-methylimidazolium
chloride,
1-methyl-3-
carboxymethylimidazolium chloride) was studied under solvent-free conditions and compared with that of sodium salts
(sodium chloride, sodium acetate). Mass spectrometric techniques were used to monitor the formation of the reaction
products and to detect the key intermediates of the process. Based on the catalyst employed different reaction mechanisms
were highlighted, thus laying the foundation for the design of more specific and efficient catalysts.
mechanism,7a assumes that the catalyst combines with the
aldehyde forming a Schiff base; the second one is the base-
catalysed alternative proposed by Hann and Lapworth9
according to which the catalyst removes a proton from the
methylene activated compound giving rise to a carbanion that
easily adds to the aldehyde. Therefore, based on the catalyst
employed, the same condensation product can be obtained
through different intermediates, thus creating new research
opportunities to design specific catalysts.
Introduction
Ionic liquids (ILs) represent a fascinating class of stable
compounds that, contrary to the electrically neutral liquids, are
predominantly made of ions and typically consist of large
organic cations combined with inorganic or organic anions.1,2
The high designability, as well as the opportunity to recycle
them after each reactive cycle, have made ILs efficient catalysts
and green reaction media in the place of common volatile
solvents. Interestingly, the incorporation of a functional
group into either the anion or cation scaffold allowed to
enhance specific properties and favour their task-specific uses
for catalytic applications. Among them, imidazolium-based ILs
are known to be efficient precursors of N-heterocyclic carbenes
NHCs) arising from the chemically or electrochemically induced
C2-H deprotonation. Once generated, NHCs can act as basic or
nucleophilic catalysts in a variety of chemical reactions.6
Gas-phase studies performed by means of mass spectrometry
(MS) offer the unique chance to intercept short-lived species,
3,4
such as the transient intermediates of
a
chemical
transformation. To this end, mass spectrometric techniques are
often coupled with atmospheric pressure ionization sources
(API), such as electrospray ionization (ESI) or atmospheric
pressure chemical ionization (APCI) sources, which gently
transfer ionic species to the gas-phase environment to elucidate
5
(
1
0
their functions at a specific reaction stage. The most relevant
aspect of mass spectrometry consists in investigating intrinsic
properties of charged species, including their structure and
reactivity, in the absence of solvent molecules and counter-
ions, commonly affecting the substrate reactivity. The
possibility to assess ionic compounds in their isolated state or
specifically design a micro-solvated environment provides
energetic, mechanistic, and kinetic information of catalytic
The formation of carbon-carbon bonds is still highly exploited in
synthetic chemistry to obtain a wide variety of new products of
industrial and pharmaceutical value. The Knoevenagel
condensation between activated methylene compounds and
aromatic aldehydes represents an important reaction to obtain
7
this type of bonds. Knoevenagel reactions are typically
performed with nitrogen-based catalysts, categorized as
tertiary, secondary, primary amines, and ammonium salts.
Among those, also imidazole-based ionic liquids are widely used
11
reactions at a strictly molecular level. With this regard, MS
techniques were deeply exploited to investigate fundamental
thermochemical properties of ionic liquids and carbenic
derivatives, such as proton affinity and gas-phase
8
as efficient catalysts.
A flourishing debate is still open on the mechanism of this
reaction since two main reaction pathways have been
proposed. The first one, known as the Knoevenagel
1
2
13
basicity/acidity,
ion-pair evaporation
and clusters
14
speciation. The effective strategy to insert a “silent” charge
tag into the cation scaffold succeeded in “fishing” out from the
solution charged N-heterocyclic carbenes and highlight their
structure, intrinsic reactivity, and catalytic activity. Besides,
the higher sensitivity and selectivity of MS compared to other
spectroscopic methods allows one to monitor the reaction
progress over time by simultaneously sampling from the
reaction mixture a low amount of structurally similar reactants,
a. Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma,
P.le Aldo Moro 5, 00185 Roma, Italy. E-mail: anna.troiani@uniroma1.it;
chiara.salvitti@uniroma1.it
Dipartimento di Scienze di Base e Applicate per l’Ingegneria Sapienza Università
di Roma Via Castro Laurenziano 7, Roma, Italy. E-mail:
1
5
b.
isabella.chiarotto@uniroma1.it
†
Electronic supplementary information (ESI†) available: NMR spectra of
synthesized samples and APCI and ESI mass spectra. See DOI: 10.1039/x0xx00000x
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intermediates, and products without problems of band Table 1. Imidazolium-based ionic liquids and sodiumViseawltAsrticulseeOdnlianes
overlapping. Accordingly, the Knoevenagel condensation was catalysts in the Knoevenagel condensatiDoOn;I: 10B.M10I3m9/:D11N-Jb0u3t5y9l-43K-
first studied by atmospheric pressure ionization MS in 1999 in methylimidazolium; MAI: 1-methyl-3-carboxymethylimidazolium; Ac:
the presence of piperidine catalyst, thus isolating and acetate.
characterizing a Schiff base intermediate consistent with the
1
6
mechanism proposed by Knoevenagel.
Based on our interest in ionic liquids17 and the use of mass
spectrometry to investigate reaction mechanisms in the gas-
phase environment, we have studied the catalytic behaviour
of different imidazolium-based ILs in the Knoevenagel
condensation compared to that of common organic and
inorganic salts showing different basic properties.
Catalyst
BMImAc
BMImCl
MAICl
-R
-(CH
-(CH
X-
CH
Cl
Cl-
2
)
3
CH
CH
3
3
3
COO-
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-
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)
2 3
-CH
2
COOH
Catalyst
NaAc
NaCl
X-
CH
3
COO-
-
Cl
Results and discussion
The mechanistic details of the Knoevenagel condensation were
investigated by mass spectrometry in the presence of different
catalysts, imidazolium-based ILs (1-butyl-3-methylimidazolium
acetate, 1-butyl-3-methylimidazolium chloride, 1-methyl-3-
carboxymethylimidazolium chloride) and sodium salts (NaCl,
always obtained by using 2b (Table 2, entries 6-9) except when
NaCl was used (Table 2, entry 10). On the contrary, only the
ionic liquid BMImAc efficiently catalysed the reaction of p-
anisaldehyde 1 with 2a (Table 2, entry 1) leading to a final yield
of product 3a comparable to that obtained by using 2b and ionic
liquid catalysts or NaAc (Table 2, entries 6-9). The use of MAICl
with the less acidic methylene-activated compound 2a has a
negative effect, being the presence of carboxylic group
detrimental for the catalytic system, and very small amount of
product was observed (Table 2, entry 3).
-
NaAc, Ac = acetate), listed in Table 1. Thus, we have i)
monitored over time the formation of the reaction products, ii)
intercepted the key intermediates of the process and iii)
elucidated the overall reaction mechanism for each catalyst
employed.
The reaction products
T
able 2. Synthetic yields (%) of the Knoevenagel condensation between
p-anisaldehyde (0.5 mmol) and C-H acids 2a-b (0.5 mmol) in the
presence of catalyst (10 mol %) after 24 hours.
p-Anisaldehyde
1 was used as a model substrate with the
1
methylene-activated compounds 2a-b and the reaction mixture
was stirred at room temperature under solvent-free conditions
for 24 hours. The typical products of condensation between
ethyl cyanoacetate 2a and aldehydes or ketones in the presence
of bases, i.e. ammonium acetate, as catalysts are 
-
unsaturated cyanoacetates. Malononitrile 2b is one of the most
reactive compounds in the Knoevenagel condensation as the
reaction can proceed to the product without catalyst, albeit
1
9
very slowly.
The imidazolium-based ionic liquids are probably the most
popular class of ILs and are marked by a complex and intriguing
reactivity related, inter alia, to the scaffold of the cation and the
Entry
1
2
3
4
5
6
7
Catalyst
BMImAc
BMImCl
MAICl
NaAc
2
Yield of 3 (%) Reference
+
nature of the anion. The mutual interactions between BMIM
2a
2a
2a
2a
2a
2b
2b
2b
2b
2b
98
25
1§
25
3
99
94
91
98
43
[8a]
[8a]
This work
[8a]
[8a]
This work
This work
This work
This work
This work
-
20
and X have been analysed. The progress of the Knoevenagel
reaction, the interactions between the catalyst and the
reactants, and the action of the imidazolium ionic liquids
-
-
NaCl
BMImX (X = Cl , Ac ) were compared with those of the sodium
salts NaCl, NaAc, and with the task-specific ionic liquid
1‑methyl-3-carboxymethylimidazolium chloride (MAICl) which
is known to have high thermal stability and nearly universal
solubility. The synthetic yields of the product (3a-b) and their
comparison with the yields obtained in the previous work are
reported in Table 2. A different reactivity was observed in the
presence of ethyl cyanoacetate 2a or malononitrile 2b
depending on the catalyst employed. Excellent yields of 3b were
BMImAc
BMImCl
MAICl
NaAc
8
9
10
2
1
2
2
NaCl
8a
§
very low yield of
3 was also obtained carrying out the reaction with
BMImCl and acetic acid 1:1 molar ratio
2
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In order to follow the progress of the reaction in the presence
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DOI: 10.1039/D1NJ03594K
of the most promising catalysts, the formation of the
condensation product was monitored over time under APCI
mass spectrometric conditions. This approach ensures the
ionization of low-polar compounds such as the products 3a-b
·
-
that were detected as radical molecular anions M (m/z 3a
=
2
31; 3b = 184) resulting from the capture of thermal electrons,
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commonly present in the corona discharge. First of all, the
structure of these species was confirmed by subjecting them to
sequential collision-induced dissociation reactions (MS ). As
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displayed in Scheme S1 (see the ESI†
), the ions at m/z 231 and
1
84 showed the same fragmentation patterns of the
corresponding isolated Knoevenagel products, previously
characterized by NMR-spectroscopy,8a and some diagnostic
daughter ions reported for similar methoxy-functionalized
compounds analysed under negative collision-induced
24
dissociation (CID) conditions.
The variation of the product intensities was then evaluated over
time and reported as a percentage of the total ion current (TIC).
Figure 1a shows that the BMImAc-catalysed condensation
giving rise to the product 3a is complete after only 2 hours since
no further increase of the product intensity was observed after
+
this period of time. When the BMIm was replaced by sodium Figure 2. Plot of the relative intensities versus time for the Knoevenagel
cation, the reaction rate leading to 3a dramatically decreases product 3b in the presence of the most efficient catalysts: a) BMImAc,
(
Figure 1b), according to the low amount of product isolated b) BMImCl, c) MAICl and d) NaAc.
after 24 hours (Table 2, entry 4).
Interestingly, with the malononitrile 2b, the formation of
product 3b occurred in less than 30 minutes by using BMImAc Therefore, BMImAc resulted to be the most efficient catalyst
catalyst (Figure 2a), whereas at least 2 hours were required to leading to a prompt formation of the final products 3a-b and
obtain high yields of product 3b when the acetate was replaced significantly reducing the total reaction time compared to all
by the chloride anion (Figure 2b). A reaction time of ca. 4 hours other catalysts employed.
was instead necessary in the presence of the N-acid substituent
of the MAI cation or by using the NaAc catalyst in which sodium The reaction intermediates
has replaced the BMIm cation of the BMImAc catalyst (Figures
2
c and d). Hence, it clearly appears that a crucial role is played In order to outline the mechanistic picture of the Knoevenagel
by both cation and anion in the catalytic mechanism.
condensation catalysed by ionic liquids and sodium salts, the
key intermediates of the process were intercepted and
characterized by mass spectrometry.
Since no ionic intermediates were detected under APCI
conditions, the reaction mixtures were analysed by ESI mass
spectrometry. In the early stages of the reaction, two negative-
charged ions were regularly detected for all the catalysts
employed except for BMImAc, as shown in Figure 3 in which the
BMImCl system was chosen as a representative example for all
the catalysts employed. The deprotonated reagents 2a or 2b are
listed as ra-b (m/z = 112 and 65) and two ions at m/z = 248 and
2
01 are assigned to the intermediate iIa-b. These species are
consistent with the negative-charged adduct between the
deprotonated C-H acids ra or rb and the p-anisaldehyde
1
.
Interestingly, iIa-b were not detected with the most efficient
BMImAc catalyst. Only in the chloride-based systems (BMImCl,
MAICl, and NaCl) the protonated form of the intermediates iIa-b
named iIIa-b, was intercepted as a Cl adduct (Figure 3, m/z =
84/6 and 237/9), as confirmed by the characteristic isotopic
,
-
2
Figure 1. Plot of the relative intensities versus time for the Knoevenagel pattern of the chlorine atom. Since the ions iIa-b can formally
product 3a in the presence of the most efficient catalysts: a) BMImAc correspond either to a covalent intermediate or to a labile
and b) NaAc
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Figure 3. ESI-(-) mass spectra of a 1:1 a) p-anisaldehyde/2a and b) p-
anisaldehyde/2b reaction mixture stirred for 4 hours and 20 minutes,
respectively, in the presence of 10 mol % of BMImCl catalyst. The ion at Figure 4. ESI-(-) CID mass spectra of the intermediates a)
iIa at m/z 248
m/z 151 (*) corresponds to the acid derivative of the p-anisaldehyde and b) Ib at m/z 201 respectively isolated from a 1:1 p-anisaldehyde/2a
i
resulting from its facile air oxidation.
and a 1:1 p-anisaldehyde/2b reaction mixture in the presence of 10%
BMImCl catalyst.
adduct between the two substrates
1 and 2a-b, CID
experiments were carried out to characterize these charged
species. Accordingly, the main fragmentation channel observed
consists in the loss of a water molecule leading to the daughter
ions at m/z 230 and 183, respectively (Figures 4a and 4b),
whereas the loss of the p-anisaldehyde
counterpart (C ), giving rise to the deprotonated 2a-b at
m/z 112 and 65, only represents a minor channel. This result
points to the formation of a covalent-bonded species that is
prone to dehydrate leading to the condensation product rather
than back-dissociate and release the two reagents.
Likewise, the intermediate iIIb fragments by the loss of a water
molecule giving rise to the chloride-attached Knoevenagel
1 as a neutral
8 8 2
H O
product 3b at m/z 219 (Figure 5b and Scheme S2, ESI†).
Alternatively, the release of an HCl moiety from both
species regenerates the aldol intermediates Ia-b at m/z 248 and
01 (Figure 5a and 5b), the structures of which were probed by
iIIa-b parent
i
2
n
their MS fragmentation patterns (Figures 5a and 5b, insets).
Interestingly, the fragment ion at m/z 169 in Figure 5b was also
reported in the CID mass spectrum of the radical anion at m/z
1
84 (Scheme S1, ESI†), suggesting that
iII can easily rearrange to
form the condensation product. This fragmentation pattern was
3
7
further confirmed by dissociating the corresponding Cl
isotope-containing species (Figure S2, ESI†). For each catalyst Figure 5. ESI-(-) CID mass spectra of the 35Cl isotope-containing
employed, the relative intensities of the diagnostic peaks and intermediates a) IIb at m/z 237 respectively isolated
Ia were compared, highlighting that the intensity ratio (I%) from a 1:1 p-anisaldehyde/2a and a 1:1 p-anisaldehyde/2b reaction
r
a
iIIa at m/z 284 and b) i
i
I
i /r
is much lower when the synthetic yield of the final products 3a mixture in the presence of 10% BMImCl catalyst. In the inset: ESI-(-) CID
is higher (Table 3). Without the intent to provide a quantitative mass spectrum of the daughter ions at a) m/z 248 and b) 201
estimate, the highest i /r ratio (2.67) was found in the presence respectively isolated from the sequence 284 → 248 and 237 → 201,
I
of the least efficient MAICl catalyst (Table 3, entry 5). This result arising from the fragmentation of the intermediate
agrees with the notion that an efficient catalyst acts by driving
i
IIa-b
.
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Table 3. Relative intensity ratios (I%) of the negative-charged
intermediate Ia versus compared to the synthetic yields of product 3a
obtained after 24 hours.
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i
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Entry
Catalyst
time
_
I% iIa/r
_
a
3a (%)
98[8a]
25[8a]
25[8a]
3[8a]
1
2
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BMImAc
NaAc
4 h
4 h
4 h
4 h
0.550
0.838
2.42
2.67
BMImCl
NaCl
MAICl
1
Figure 6. ESI-(+) mass spectra of a 1:1 p-anisaldehyde and 2b reaction
the formation of the final product and preventing the significant
build-up of the intermediate Ia. Accordingly, in the high yield
systems employing malononitrile 2b as a reagent, iIb was
detected only at early reaction times.
When the most efficient catalyst was used, the ionic liquid
BMImAc, the negative-charged intermediate was not found
even at short reaction times (Table 3, entry 1), although the
condensation product was isolated in 95% yield after only 1.5
hours of reaction. It follows that the ionic liquid BMImAc could
efficiently catalyse the Knoevenagel condensation passing
through different intermediates.
Since in the negative ion mode no intermediates were detected,
the catalytic mechanism of the BMImAc was elucidated by
monitoring the reaction between
mixture in the presence of a) BMImAc and b) BMImCl catalyst.
i
anions of imidazolium-based ionic liquids, such as acetate, can
promote the cation-anion proton transfer, speaking in favour of
the spontaneous formation of N-heterocyclic carbenes in ionic
liquids. Nevertheless, the presence of carbenes in imidazolium
acetate ionic liquids have never been directly probed by
spectroscopic techniques, thus pointing to a very low
concentration in solution. In the presence of p-anisaldehyde,
the cation-anion proton transfer equilibrium can be shifted
towards the generation of carbene, therefore allowing the
formation of the transient adduct between aldehyde and
carbene intercepted by MS. This result, as well as the isolation
in the neat BMImAc of a positively charged hydrogen-bonded
adduct between the BMIm cation and the corresponding
carbene (Figure S3, ESI†), provides an indirect mass
spectrometric evidence on this debate, in support of the
spontaneous formation of carbene from imidazolium-based
ionic liquids with basic anions. Accordingly, the ionic
intermediate at m/z 275 was characterized by CID experiments
and the formation of a daughter ion at m/z 201 is consistent
i
I
2
5
8a
2
6
1 and 2a-b in the ESI positive
ion mode. A similar analysis was also performed in the presence
of the BMImCl catalyst which shares with BMImAc the same
organic cation. For the sake of conciseness, we display the data
corresponding to the reaction of malononitrile reagent 2b, as
comparable results were obtained by using the ethyl
cyanoacetate substrate 2a (see Figure S4 in the ESI†). The mass
spectrum of the reaction mixture, reported in Figure 6a, is
dominated by the ionic species at m/z 139, corresponding to the
BMIm cation, also detected when BMImCl was used as a
reaction catalyst (Figure 6b). A second peak at m/z 275 is
instead characteristic of only the BMImAc system since similar
ions were not identified by using BMImCl. Again, this species
can correspond either to a hydrogen-bonded adduct between
with concerted dehydration (-H
2
O) and cleavage of the
imidazolium side chain (-C ), both indicative of a covalent
4 8
H
species (Figure 7a). The dehydration reaction, typically involving
hydroxyl groups, also represents a direct fragmentation channel
leading to the daughter ion at m/z 257 that is structurally
consistent with a carbocation species (inset of Figure 7a and
Scheme S3a, ESI†). This result was confirmed by comparing the
CID mass spectrum of the ion at m/z 275 with that of the
covalent adduct between 1-butyl-3-methyl-imidazolydene and
cyclohexane carboxaldehyde (Figure 7b and Scheme S3b, ESI†),
first isolated and characterized by NMR in 2010. However, the
concomitant presence with the covalent-bonded adduct of a
loosely-bonded ionic population at m/z 275 cannot be excluded,
in the light of the intense daughter ion at m/z 139 which
the aldehyde 1 and the BMIm cation or to a protonated covalent
intermediate, as shown in Figure 6a. The first hypothesis was
excluded since a labile species at m/z 275 should also be
detected in the BMImCl system. Therefore, we considered the
possible formation of a covalent intermediate between the
BMIm-derived carbene and the p-anisaldehyde. Many papers
report the use of the imidazolium acetates in organocatalytic
reactions (i.e., catalysed by NHC), and for this particular
employment they were appointed as "organocatalytic ionic
27
17
liquids”. Thus, it has been postulated that sufficiently basic
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intermediate
i
I
(Table 4). This species can be assigned to the
View Article Online
DOI: 10.1039/D1NJ03594K
negative-charged aldol of the base-catalysed mechanism
9
postulated by Hann and Lapworth. According to this pathway,
chloride or acetate anions can act as a base removing a proton
from the methylene compounds 2a-b to form the resonance-
stabilized anion at m/z 112 or 65 (
adds to the carbonyl group of the aldehyde leading to the
intermediates at m/z 248 and 201, respectively. After that, the
transient species IIa-b can release a water molecule giving rise to
ra-b). The activated reagent
i
Ia-b
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i
the Knoevenagel product and return the catalyst (Scheme 1).
Although the reaction is triggered by the chloride or acetate
anions, the role of the BMIm and MAI cations in the catalysis is
8a
worthy of note. As previously reported, large organic cations
with low charge density, such as BMIm and MAI, show a lower
+
ion-pairing ability than small inorganic cation (e.g. Na ) versus
the chloride anion, rendering it more reactive. Besides, the
BMIm and MAI cations can behave as hydrogen bond donors,
activating the carbonyl moiety of the aldehyde towards the
nucleophilic attack of the C-H acids, once deprotonated by the
Figure 7. ESI-(+) CID mass spectra of the ions at a) m/z 275 and b) m/z ionic liquid counter-anion (Scheme 2).8e
51 isolated from a 1:1 a) p-anisaldehyde/2b and b) cyclohexane This reaction seems to occur through a concerted mechanism
carboxaldehyde/2b reaction mixture in the presence of 10% BMImAc since no positive-charged adduct between BMIm or MAI cation
catalyst. and p-anisaldehyde was intercepted by analysing the
2
1
corresponding reaction mixtures over time. The important role
played by the cation in the catalysis is also confirmed by the
corresponds to the BMIm cation. Nevertheless, it is also synthetic yields of the reaction reported in Table 2. Accordingly,
conceivable that the covalent-bonded population is consumed the yield of 3a switches from 3% when NaCl was employed as a
in the reaction and therefore does not accumulate.
catalyst to 25% when sodium is replaced by BMIm cation (Table
, entries 2 and 5).
Similar results were obtained for product 3b with a synthetic
2
The reaction mechanism
yield that switches from 43% in the presence of NaCl to 94% by
According to the mass spectrometric results collected in this using BMImCl catalyst (Table 2, entries 7 and 10). The different
work, two different reaction mechanisms for the Knoevenagel reaction outcomes found by using ethyl cyanoacetate 2a or
condensation were highlighted, depending on the catalysts malononitrile 2b are predominantly ascribed to the different
employed. As previously described, in the presence of the acidity of the two methylene substrates, depending on the
BMImCl and MAICl ionic liquids and the sodium salts NaAc and chemical features of its electron-withdrawing groups (pKa
2
8
29
2 2 2 2
NaCl, the reaction proceeds through the formation of the CH (CN) = 11 and pKa CH (CN)CO Et = 12 ). Interestingly,
Table 4. Key intermediates and different reaction mechanisms for the Knoevenagel condensation catalysed by ionic liquids and sodium salts.
Catalyst
X-
i
I
i
NHC
X--catalysed
NHC-catalysed
Y= CO Et; CN
2
BMImAc
BMImCl
MAICl
NaAc
CH
Cl-
Cl-
CH
Cl-
3
COO-
COO-
✗
+
+
✓
✗
✗
✗
✗
✓
✓
✓
✓
+
3
+
NaCl
+
6
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Hence, we can conclude that the outcome of the Knoevenagel
View Article Online
DOI: 10.1039/D1NJ03594K
condensation following the base-catalysed mechanism is
affected by i) the basicity of the anionic catalyst, ii) the acidity
of the methylene compound and iii) the chemical features of
the counter-cation of the catalyst. Passing to the BMImAc-
catalysed condensation, four experimental results account for a
reaction mechanism different from that observed for the
chloride-based ionic liquids and the sodium salts: i) the high
yield of the Knoevenagel product 3a comparable to that of
product 3b, obtained from the more reactive C-H acid 2b; ii) the
formation of product 3b occurring in the range of few minutes
only by using BMImAc catalyst; iii) the absence of the negative-
0
1
2
3
4
5
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7
8
9
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0
charged intermediates iIa-b and iv) the interception of a carbene-
aldehyde adduct in the positive ion mode. Based on this
evidence, BMImAc can catalyse the reaction through a
Knoevenagel-like mechanism according to which the catalyst
combines with the aldehyde leading to a positive-charged
3
0
addition intermediate
before the intervention of the
7a
methylene-derived carbanion. In this specific case, the
formation of the final product would be mediated by the 1-
butyl-3-methyl-imidazolydene playing a nucleophilic attack on
the p-anisaldehyde 1 (Scheme 3).
Scheme 1. Base-catalysed mechanism proposed for the formation of
the Knoevenagel product in the reactions catalysed by the ionic liquids
-
-
-
BMImCl, MAICl, and sodium salts NaCl, NaAc. X stands for Cl or Ac .
only the yield of the ethyl cyanoacetate-derived product 3a was
dramatically low in the presence of MAICl catalyst in which the
cation bears an acidic group in the N1- chain (Table 2, entry 3).
The MAICl catalyst, with the acidic function, seems to hinder the
reaction progress, preventing the formation of the product. In
fact, poor yields were obtained by carrying out the reaction with
BMImCl as the catalyst with an equal amount of acetic acid (see
note in Table 2). This result underlines the importance of
designing tailored ionic liquids to improve their effectiveness as
catalysts.
Scheme 2. Schematic representation of the imidazolium cation (R: -
(CH
2
)
3
CH
3
or -CH COOH) activating the p-anisaldehyde by increasing the
2
polarisation of the carbonyl moiety through the formation of a
-
hydrogen bond with the C2-H, and the counter ion Cl deprotonating the
methylene compound (Y: -CO
2
Et or -CN).
Scheme 3. Proposed NHC-mediated mechanism for the Knoevenagel
condensation in the presence of BMImAc catalyst.
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The N-heterocyclic carbenes can indeed act as a nucleophile by putative intermediates, were characterized by colliVsieiownA-rtiinclde uOcnleinde
adding to the carbonyl group of the aldehyde, leading to a dissociation (CID) experiments performDedOI:b1y0.1i0n3c9r/eDa1NsiJn0g35t9h4eK
zwitterionic adduct that rearranges into the so-called Breslow energy of mass-selected ions in the presence of helium as
intermediate. The protonation of these species before the collision gas (pressure of ca. 3 x 10 Torr). Depending on the
Breslow rearrangement forms a transient benzylic alcohol species of interest, normalized collision energies ranging
intermediate that was recognized by different authors in NHC- between 20% and 40% were typically applied, and an activation
3
1
−3
3
2,33
or base-catalysed reactions.
time of 30 ms was used. Ions were isolated with a window of 1
m/z and the Q value was optimized to ensure stable trapping
fields for all the ionic species under investigation.
0
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Experimental
Conclusions
Reagents (p-anisaldehyde 98%, ethyl cyanoacetate ≥98%,
malononitrile ≥99%), catalysts (1-butyl-3-methylimidazolium
acetate ≥98%, 1-butyl-3-methylimidazolium chloride ≥99%, A mass spectrometric study of the Knoevenagel condensation
sodium chloride ≥99%, sodium acetate ≥99%) and all solvents using different catalysts was described. In the presence of
were purchased from Sigma-Aldrich Ltd and used without chloride-based ionic liquids (BMImCl, MAICl) and sodium salts
further purification. The acidic ionic liquid 1-methyl-3- (NaCl, NaAc), the reaction proceeds through a base-catalysed
carboxymethylimidazolium chloride (MAICl) was synthesized pathway, as demonstrated by the isolation of a diagnostic
according to the literature procedure.34 The Knoevenagel negatively charged aldol intermediate. Hence, the insertion of
condensation was carried out at room temperature under an acidic group on the lateral chain of the MAI cation drastically
solvent-free conditions. The detailed synthetic procedure and reduced the yields of the reaction between the aldehyde and
all spectroscopic data are provided in the Supplementary less acidic methylene activated reagents.
Information. H and C NMR spectra were recorded at room On the contrary, in the presence of BMImAc catalyst, the acid-
temperature using a Bruker AC 200 spectrometer with CDCl
internal standard.
The Knoevenagel condensation was monitored over time by triggers the reaction by adding to the aldehydic reagent. The
electrospray ionization and atmospheric pressure chemical reaction then proceeds through a Knoevenagel-like mechanism.
ionization mass spectrometry (ESI-MS and APCI-MS) in positive Excellent yields of the product were thus obtained regardless of
1
13
-
3
as base equilibrium between the BMIm cation and the Ac anion
gives rise to a catalytic amount of the corresponding NHC that
a
and negative ion mode. A mixture of p-anisaldehyde (0.5 mmol), the pK of the methylene substrate. As a result, the request for
activated methylene compound (0.5 mmol) and a 10% amount task-specific catalysts needs precise knowledge of the reaction
of catalyst was stirred at room temperature in a 1.5 mL tube for mechanisms, and such detailed information can be obtained by
2
4 hours under solvent-free conditions. At prefixed time the interception and the characterization of the elusive
intervals, 1.0 μL of the reaction mixture was sampled from the intermediates of the process under investigation. The use of
vessel, diluted to a 1.0 x 10 M concentration with H
-4
2 3
O/CH CN mass spectrometry has again proved to be a promising
(
1:10 V/V), and analysed in an LTQ-XL linear ion-trap (Thermo approach to meet the demands of organic synthesis and
Fisher Scientific). Sample solutions were infused into the ion improve the design of suitable catalytic systems.
source of the instrument and the ionization method was chosen
based on the chemical properties of the compounds we
intended to track. Polar reagents and reaction intermediates
were analysed by ESI, whereas non-polar Knoevenagel products
were detected under APCI conditions.
Typical experimental parameters were as follows: flow rate 10
μL/min, source voltage 2-4 kV, capillary temperature 275°C for
the ESI source; flow rate 20 μL/min, discharge current 3-5 μA,
capillary 275°C and vaporizer temperature 25 °C for the APCI
source. Nitrogen was used in both cases as sheath and auxiliary
gas at a flow rate of 11 and 2 arbitrary units (a. u. ≈ 0.37 L/min),
respectively. Other source parameters, such as capillary and
tube lens voltages, were adjusted in a low range value to ensure
the soft ionization of the species present in the reaction
mixture. Full scan mass spectra were recorded in the range of
Author Contributions
I.C., C.S., A.T. conceived the idea and wrote the manuscript. All
authors have contributed to and approved the manuscript.
Conflicts of interest
There are no conflicts of interest to declare.
Acknowledgements
This research was funded by Sapienza Rome University
Progetti di Ateneo” (Projects n. RM11816428291DFF and
RM120172A8223162) and supported by the project:
Dipartimenti di Eccellenza —L. 232/2016 by Italian Ministry of
Education, Universities and Research -L. 232/2016. C.S. thanks
the Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza
“
5
0-500 m/z by using the Xcalibur 2.0.6 software supplied with
the instrument and the progress of the reaction were evaluated
by correlating the reagent and product ion intensities as a
percentage of the total ion current (TIC) to the reaction time. All
the ionic species involved in the condensation, including the
8
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Phys. 2018, 20, 17132; d) F. Pepi, A. Ricci, S. GarzVoieliw, AAr.tiTclreoOianlninie,
Rome University, for a post-doc position within the project
Dipartimenti di Eccellenza —L. 232/2016.
C. Salvitti, B. Di Rienzo, P. Giacomello, Carbohydr. Res. 2015,
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