Electrogenerated N-heterocyclic carbene in ionic liquid: An insight into the mechanism of the oxidative esterification of aromatic aldehydes

Article abstract of DOI:10.1002/adsc.201400163

An N-heterocyclic carbene (NHC), generated by cathodic reduction of BMIm BF₄, mediates the oxidative esterification of aromatic aldehydes with organic bromides in the corresponding ionic liquid as solvent. The product recovery by simple extractive work-up with diethyl ether allowed the ionic liquid to be recycled up to 9 times for subsequent electrolyses, with no significant loss in the product yield. The isolation of an intermediate, whose structure was confirmed by synthesis and transformation into the ester, provided the key for a mechanistic insight into the reaction.

Full text of DOI:10.1002/adsc.201400163

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DOI: 10.1002/adsc.201400163
Electrogenerated N-Heterocyclic Carbene in Ionic Liquid: An
Insight into the Mechanism of the Oxidative Esterification of
Aromatic Aldehydes
Gianpiero Forte,a,* Isabella Chiarotto,a Achille Inesi,b Maria Antonietta Loreto,c
and Marta Ferocia,*
a
Dipartimento di Scienze di Base e Applicate per l’Ingegneria, Sapienza Universitꢀ di Roma, Via del Castro Laurenziano
7, 00161 Roma, Italy
Fax : (+39)-06-49-766-749; e-mail: gianpiero.forte@uniroma1.it or marta.feroci@uniroma1.it
Via Antelao 9, 00141 Roma, Italy
Dipartimento di Chimica, Sapienza Universitꢀ di Roma, P. le Aldo Moro 5, 00185 Roma, Italy
b
c
Received: February 13, 2014; Published online: April 9, 2014
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400163.
Abstract: An N-heterocyclic carbene (NHC), gener- yield. The isolation of an intermediate, whose struc-
ated by cathodic reduction of BMImBF4, mediates ture was confirmed by synthesis and transformation
the oxidative esterification of aromatic aldehydes into the ester, provided the key for a mechanistic in-
with organic bromides in the corresponding ionic sight into the reaction.
liquid as solvent. The product recovery by simple ex-
tractive work-up with diethyl ether allowed the ionic Keywords: aromatic esters; electrochemistry; ionic
liquid to be recycled up to 9 times for subsequent liquids; N-heterocyclic carbenes; oxidative esterifica-
electrolyses, with no significant loss in the product tion
Introduction
in the presence of air or pure oxygen and suggested
that NHCs catalyze the formation of aromatic esters
The manipulation of the aldehyde group is an attrac-
tive approach to the synthesis of esters. Unlike con-
ventional routes, the oxidative esterification of alde-
hydes does not involve the direct activation of a car-
boxylic acid,[1] usually achieved with harsh reaction
conditions or expensive coupling reagents.[2] N-hetero-
cyclic carbenes (NHCs) induce the reaction of alde-
hydes featuring a reducible group with alcohols to
yield the corresponding esters without additional oxi-
dants.[3] Thus, in the presence of NHCs, enals and a-
substituted aldehydes form the Breslow intermediate,
1,[4] which undergoes an internal redox reaction lead-
ing to the electrophilic acyl azolium 2. Instead, the
conversion of aromatic aldehydes under analogous
conditions requires the presence of exogenous oxi-
dants and metal co-catalysts to form the acylating
agent (Scheme 1).[5]
It was in 2010 that Deng and co-workers first ob-
served the formation of benzoates as by-products in
the NHC-promoted synthesis of ketones, starting
from aromatic aldehydes and aryl halides.[6] Subse-
quent investigations pointed out how this unexpected
Scheme 1. Mechanism of NHC-catalyzed oxidative esterifi-
side reaction turns into the major synthetic pathway cation of aldehydes.
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Gianpiero Forte et al.
under mild and metal-free conditions, affording the
products in excellent yields.[7]
Moreover the use of BMImBF4 as solvent in elec-
trochemistry has undeniable advantages: (i) it is
NHCs[8] are generated by deprotonation or cathodic a good current conductor and does not require the
reduction of the corresponding azolium ions and pro- use of supporting electrolytes; (ii) it is immiscible
mote various reactions, acting either as bases or as with diethyl ether, allowing an easy recovery of the
nucleophiles.[9] Some of their precursors belong to the products and the recycling of the IL as solvent for
family of room temperature ionic liquids (ILs), which subsequent electrolyses.
lately have gained much attention as potential alter-
Accordingly, BMImBF4 was subjected to electroly-
natives to the classic volatile organic solvents in sis under galvanostatic conditions at a temperature of
a greener approach to chemical synthesis,[10] even 608C.[13] Subsequently, the carbene solution in the IL
though the high costs and the toxicity for aquatic or- was treated with para-chlorobenzaldehyde and para-
ganisms have prevented to date their wide use in (trifluoromethyl)benzyl bromide, taken as substrates
large-scale processes.[11]
for the optimization of the reaction conditions, in the
Our group has recently focused on the electro- presence of pure oxygen. The addition sequence of
chemical behaviour of 1-butyl-3-methylimidazolium the reagents revealed to be crucial (vide infra) and we
tetrafluoroborate (BMImBF4), demonstrating that obtained the best results with the conditions reported
the corresponding carbene mediates some of the reac- in Scheme 3.
tions promoted by NHCs in classic organic solvents.[12]
The reaction, using 1 F/mol, affords the ester in
In such media, the synthesis of benzoates is a very poor yield, while better results are achieved in-
achieved by reaction of aromatic aldehydes and or- creasing the current over 2 Faradays per mole of alde-
ganic bromides in the presence of oxidants and a stoi- hyde, suggesting a non-catalytic behaviour of the
chiometric amount of the azolium salt, precursor of NHC. Any further increase over 3 equiv. of carbene
the NHC. The active species is formed in situ by using generated did not correspond to a significant en-
an overstoichiometric amount of a base, suggesting hancement in the product yield (Table 1, entries 1–3).
that a deprotonation process may be involved during
A comparison with chemical bases shows the effi-
the conversion of the aldehydic group into the car- ciency of the method. Indeed, when the carbene is
boxylic acid derivative.
generated by deprotonation with a base, the product
is formed in very low yield regardless of the oxidant
employed (Table 1, entries 4–11). Better, yet discour-
aging, results were obtained with a large excess of
MnO2 and combining DBU and Cs2CO3 (Table 1,
Results and Discussion
The direct cathodic reduction of the cation BMIm+ entry 12),[14] rendering the deprotonation of
yields the related carbene 1-butyl-3-methylimidazol-2- BMImBF4 poorly competitive and markedly less eco-
ylidene (Scheme 2), which would act at the same time sustainable than its cathodic reduction.[15]
as catalyst and as base in the above-mentioned reac-
tion, avoiding the use of additional bases.
IL Recycling
Using the reagents and conditions reported in
Table 1, entry 3, the recycling of the solvent was per-
formed (results summarized in Figure 1). Taking ad-
vantage from the negligible vapour pressure of
BMImBF4, and of the ILs in general, the solvent was
dried under vacuum, after the extractive work-up, and
subjected to a new cathodic reduction. The whole
procedure was repeated up to 9 times with excellent
results. Surprisingly, while the average yield stood in
the range 60–70%, an abnormally high yield was ob-
Scheme 2. Formation of 1-butyl-3-methyl imidazol-2-ylidene
by the cathodic reduction of BMIm+ cation.
Scheme 3. Addition sequence of the reagents for the oxidative esterification of aromatic aldehydes in the ionic liquid
BMImBF4 (see Experimental Section).
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Electrogenerated N-Heterocyclic Carbene in Ionic Liquid
Table 1. Oxidative esterification of aromatic aldehydes:
the species 4 were isolated and characterized by
NMR spectroscopy.
screening of different bases and oxidants.[a]
Entry
Deprotonating agent
(equiv.[b])
Oxidant
ACHTUNGTRENNUNG
(equiv.[b])
Ester
[%][c]
U
1
2
3
4
eÀ (1 F/mol)[d]
eÀ (2 F/mol)[d]
eÀ (3 F/mol)[d]
DBU (0.5)
O2
O2
O2
air
14
64
72
4
5
DBU (1.0)
air
7
6
7
DBU (1.5)
DBU (0.5)
air
O2
13
4
8
9
10
11
12
DBU (1.0)
DBU (1.0)
Cs2CO3 (1.5)
AcONa (1.0)
DBU (1.0)+Cs2CO3 (1.5)
O2
12
8
MnO2 (1.0)
air
O2
12[e]
ND[f]
45
MnO2 (5.0)
The structure was further confirmed by the synthe-
sis of 4b (XÀ =IÀ), according to a slight modification
of Miyashitaꢂs method (Scheme 4).[16] To confirm that
the isolated species are actual intermediates in the re-
action, 4a was treated with cesium carbonate and
oxygen in CDCl3 at 508C.[17] Proton NMR spectra, re-
corded at regular time intervals, showed the disap-
pearance of the singlet at d=4.18 and the occurrence
of the singlet at d=5.41 (Figure 2).[18]
[a]
BMImBF4 (2 mL), 608C, 0.5 mmol of para-chlorobenzal-
dehyde followed by the addition of oxidant and of
1.0 mmol of para-(trifluoromethyl)benzyl bromide.
With respect to the starting aldehyde.
Isolated yields, with respect to the starting aldehyde.
Divided cell, galvanostatic conditions. I=20 mA·cmÀ2.
Di-para-(trifluoromethyl)benzyl carbonate was recov-
ered.
[b]
[c]
[d]
[e]
[f]
para-(Trifluoromethyl)benzyl acetate formed.
Figure 1. Recycling of the solvent BMImBF4.
tained in a few cases, with a maximum of 108% in run
#5.
These observations could be explained by assuming
that a charged intermediate, previously postulated
(but not isolated),[6] gathers into the ionic liquid,
being converted into the product in the subsequent
run.
Reaction Mechanism
To shed light on this point, the IL was chromato-
graphed after the synthesis of esters 3a and 3b and
Scheme 4. Synthesis of intermediate 4b.
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Figure 2. Conversion of the isolated intermediate 4a into ester 3a in CDCl3 in the presence of an excess of Cs2CO3 and
1
1
oxygen. Top : H NMR spectrum of pure 3a; bottom: H NMR spectrum of isolated 4a.
On these premises, we formulated two hypotheses
The mechanism B involves the simultaneous forma-
for the mechanism operating in the reaction, relying tion of the ester and the imidazol-2-one 9 from the
on the involvement of 4 (Scheme 5).
degradation of the endoperoxide species 8. According
to the H NMR observation that 9 is present in traces
1
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Electrogenerated N-Heterocyclic Carbene in Ionic Liquid
Scheme 5. Proposed pathways for the mechanism of the NHC-mediated oxidative esterification in BMImBF4.
Scheme 6. Alkylation of 1-butyl-3-methyl imidazol-2-ylidene with benzyl bromide.
at a later stage of the reaction (Figure 2), the occur- bene (Scheme 6),[19] this must quantitatively react
rence of this pathway could be confidently ruled out. with the aldehyde before the treatment with the bro-
The pathway A, instead, does not involve the direct mide. This would also account for the requirement of
formation of imidazolone species, which appear as by- over 2 equivalents of carbene per mole of aldehyde,
product due to the oxidation of the carbene released one equivalent being used to form the adduct and the
at the end of the reaction.
other as a stoichiometric base.[20]
Moreover, the mechanism A would clarify the cru-
Few authors reported that the oxidative esterifica-
cial importance of the addition sequence of the re- tion of enals and aromatic aldehydes in organic sol-
agents. In fact, to minimize the alkylation of the car- vents and in the presence of oxygen may proceed via
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carboxylate species, which react with the bromides to Reaction Scope
afford the esters.[21] When performing the reaction
with electrogenerated NHC in BMImBF4, in the ab- To test the general applicability of the electrochemi-
sence of alkylating agents, no trace of carboxylic acid cally generated NHC to the synthesis of aromatic
was recovered after acidic work-up, excluding the oc- esters in ionic liquids, we used the optimal conditions
currence of such a mechanism in the case under ex- found for the reaction (Table 1, entry 3). The results
amination.
are summarized in Table 2.
Table 2. Synthesis of differently substituted esters: reaction scope.[a]
Entry
1
Ester
Yield [%][b]
72
Entry
13
Ester
Yield [%][b]
70
3a
3b
3c
3m
3n
3o
2
3
75
62
14
15
33
58
4
3d
62
16
3p
43
5
6
7
8
3e
3f
3g
3h
63
65
60
54
17
18
19
20
3q
3r
3s
3t
50
64
71
58
9
3i
3j
68
84
21
22
3u
3v
67
43
10
11
3k
3l
59
39
23
3w
35
12
[a]
Reaction conditions: as reported in Table 1, entry 3.
Isolated yields, with respect to the starting aldehyde.
[b]
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Electrogenerated N-Heterocyclic Carbene in Ionic Liquid
integrator in a two-compartment home-made glass cell,
whose design was already described,[22] at 608C, under a ni-
trogen atmosphere. Anolyte (ca. 0.5 mL BMImBF4) and
catholyte (ca. 2.0 mL BMImBF4) were separated through
a glass frit (porosity 4). The electrode apparent surface area
was 1.0 cm2 for the cathodic Pt spiral (99.9%) and 0.8 cm2
for the anodic Pt spiral (99.9%). The current density was
Benzyl and alkyl bromides react smoothly (Table 2,
entries 1–4) and highly functionalized esters were ob-
tained using substituted 1-bromoacetophenone deriv-
atives bearing either electron-donating or electron-
withdrawing groups on the aromatic ring (Table 2, en-
tries 5–8).
Aromatic and heteroaromatic aldehydes are well
tolerated, but the substituent position should be con-
sidered carefully as the steric hindrance in ortho-sub-
stituted benzaldehydes causes a dramatic decrease in
the reactivity (Table 2, entry 14). Remarkably both di-
bromides and phthalic aldehydes react to give the cor-
responding diesters, opening intriguing perspectives
towards the synthesis of aromatic polyesters.
1
20 mA·cmÀ2. H and 13C NMR spectra were recorded using
a Bruker AC 200 spectrometer with CDCl3 as internal stan-
dard. All ionic liquids and reagents were used as received.
General Procedure
After the consumption of 145 C, the current was switched
off and the aldehyde (0.5 mmol) was added to the catholyte
under stirring. After 10 min, the solution was saturated with
oxygen and treated with the bromide (1.0 mmol). The mix-
ture was kept at 608C under oxygen bubbling for 1 h, and
then at room temperature for 12 h without gas. The catho-
lyte was extracted with diethyl ether and the solvent was re-
moved under reduced pressure. The residue was analyzed
Conclusions
We have reported here that aromatic esters can be
synthesized in BMImBF4, starting from the corre-
sponding aldehydes and organic bromides. The NHC,
electrogenerated from the corresponding ionic liquid,
plays the double role of catalyst and base in the reac-
tion and avoids the use of external bases required
when performing the reaction in organic solvents. A
higher degree of atom economy, compared to analo-
gous procedures reported, is hence achieved, along
with undeniable advantages in the isolation and pu-
rification of the products. To the best of our knowl-
edge, this is the first report of oxidative esterification
of aromatic aldehydes with organic bromides mediat-
ed by NHC in ionic liquids.
In the paper we demonstrated that the ionic liquid,
used also as reaction medium, can be recycled and ef-
fectively reused in subsequent electrolyses. The ab-
normally high yields observed in these cases can be
ascribed to the accumulation of an ionic intermediate,
isolated and characterized for the first time, which
can be converted to the product in subsequent reac-
tions.
Moving from the structural elucidation of the
above-mentioned intermediate, a hypothesis on the
mechanism of the oxidative esterification of alde-
hydes in ionic liquid is provided. Even though the oc-
currence of other pathways cannot be ruled out, such
a mechanism is coherent with all the experimental ob-
servations and provides hints on the non-conventional
behaviour of chemical species in IL with respect to
classic organic solvents.
1
by H NMR and purified by flash chromatography, affording
the corresponding ester in pure form. All known esters gave
spectral data in accordance with those reported in the litera-
ture. When difunctional aldehydes were used, 0.25 mmol
were added to 1.0 mmol of the bromide, while when dibro-
mides were used, 0.25 mmol were added to 0.5 mmol of al-
dehyde.
Recycle of Catholyte
After extraction of the cathodic BMImBF4 and isolation of
3a, the catholyte was kept under vacuum at 608C for 1 h
and then reused in a new electrolysis (the catholyte was
added with a further aliquot of IL, when necessary, while
fresh IL was used as anolyte in each run). The same ionic
liquid was recycled nine times, obtaining 3a in 72, 99, 66, 64,
108, 79, 95, 62, and 62% yields, respectively.
Isolation of 1-Butyl-2-((4-chlorophenyl){[4-
(trifluoromethyl)benzyl]oxy}methyl)-3-methyl-1H-
imidazol-3-ium (4a)XÀ (X=Br or BF4)
Following the general procedure, 4-chlorobenzaldehyde and
4-(trifluoromethyl)benzyl bromide were reacted. After ethe-
real extraction of the catholyte and elimination of residual
diethyl ether under vacuum, the cathodic ionic liquid was
subjected to flash column chromatography (silica gel, ethyl
acetate) to give pure 4aXÀ (X=Br or BF4).
Transformation of 4aXÀ into 3a
4aXÀ was dissolved in CDCl3 in an NMR tube, followed by
the addition of an excess of Cs2CO3. Molecular oxygen was
bubbled into the tube, which was subsequently sealed.
1H NMR spectra were recorded at regular time intervals
(heating to 508C in each interval) until reaction completion
(about 7 days).
Experimental Section
Materials and Methods
Electrolyses under galvanostatic control were carried out
with an Amel 552 potentiostat equipped with an Amel 721
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Gianpiero Forte et al.
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4b iodide was synthesized following a three-step literature
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(5 mL) at À158C, a solution of 1-methylimidazole (5 mmol)
in THF (5 mL) was added dropwise. After 1 h, 4-chloroben-
zaldehyde (5 mmol) in THF (5 mL) was slowly added and
the mixture stirred for 1 h. The reaction was allowed to
warm to room temperature and the solvent was removed
under reduced pressure. Ice was added to the flask and the
crude reaction was allowed to stand overnight. The separat-
ed solid was collected and washed with water and n-hexane
to afford 5 (yield: 66%), which was directly used in the sub-
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Acknowledgements
The authors gratefully acknowledge Mr. Marco Di Pilato for
his support in the experimental work and would like to thank
Prof. Antonella Dalla Cort and Dr. Ilaria Giannicchi for the
HR-MS analyses. This study was funded by Sapienza Univer-
sitꢀ di Roma and MIUR (Ministero dell’Istruzione, dell’Uni-
versitꢀ e della Ricerca).
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Chem. Pharm. Bull. 1994, 42, 1960–1962.
[17] We doubled the same experiment with both the isolat-
ed and the synthesized 4b with DBU instead of
Cs2CO3, obtaining analogous results. The spectra are
reported in the Supporting Information.
[18] The conversion of the intermediate to ester, at least in
deuterated chloroform, is extremely slow and the con-
sumption of 4a and 4b required more than one week to
reach completeness, even with a large excess of Cs2CO3
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Adv. Synth. Catal. 2014, 356, 1773 – 1781
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