Electrogenerated N-heterocyclic carbenes in the room temperature parent ionic liquid as an efficient medium for transesterification/acylation reactions

Article abstract of DOI:10.1002/ejoc.201201023

N-Heterocyclic carbenes (NHCs), generated by electrochemical reduction under galvanostatic control of 1,3-dialkylimidazolium-based ionic liquids, were employed as catalysts in transesterification reactions in the parent, room temperature ionic liquids (RTILs) as solvents, without the utilisation of any volatile organic solvent or base. The reaction between isopropenyl or ethyl acetate and an alcohol (not efficient in the absence of catalyst) was induced by the presence of an electrogenerated NHC, which seems to assist the proton transfer from the alcohol to the ester, yielding the corresponding acetate. The reaction also proceeds with methyl nicotinate as starting ester and 2-(diethylamino)ethanol or benzyl alcohol as alcohols and leads to the corresponding biologically active compounds, nicametate and benzyl nicotinate, in good yields. All products were isolated in good to excellent yields and complete recyclability of the ionic liquid as solvent has been demonstrated.

Full text of DOI:10.1002/ejoc.201201023

FULL PAPER
DOI: 10.1002/ejoc.201201023
Electrogenerated N-Heterocyclic Carbenes in the Room Temperature Parent
Ionic Liquid as an Efficient Medium for Transesterification/Acylation
Reactions
Isabella Chiarotto,*[a] Marta Feroci,[a] Giovanni Sotgiu,[b] and Achille Inesi*[a][‡]
Keywords: Synthetic methods / Electrochemistry / Carbenes / Ionic liquids / Acylation / Transesterification
N-Heterocyclic carbenes (NHCs), generated by electrochem- from the alcohol to the ester, yielding the corresponding acet-
ical reduction under galvanostatic control of 1,3-dialkylimid-
azolium-based ionic liquids, were employed as catalysts in
transesterification reactions in the parent, room temperature
ionic liquids (RTILs) as solvents, without the utilisation of any
volatile organic solvent or base. The reaction between iso-
propenyl or ethyl acetate and an alcohol (not efficient in the
ate. The reaction also proceeds with methyl nicotinate as
starting ester and 2-(diethylamino)ethanol or benzyl alcohol
as alcohols and leads to the corresponding biologically active
compounds, nicametate and benzyl nicotinate, in good
yields. All products were isolated in good to excellent yields
and complete recyclability of the ionic liquid as solvent has
absence of catalyst) was induced by the presence of an elec- been demonstrated.
trogenerated NHC, which seems to assist the proton transfer
lated to these catalysts such as low substrate selectivity, for-
Introduction
mation of byproducts, acid- or base-sensitivity of the sub-
strate, toxicity and cost of the catalysts, and high catalyst
loadings. Therefore, remarkable efforts have been made to
discover new catalysts.
The remarkable ubiquity of the ester function in chemis-
try, its utilization as a protecting group and the significant
role of esters as intermediates in organic chemistry have
been frequently emphasised.[1] Usually, esters are synthe-
sised from carboxylic acids and alcohols, either in the pres-
ence of a condensing agent or directly under harsh reaction
conditions. The transesterification reaction (i.e., alkoxy
moiety exchange between an ester and an alcohol) is re-
garded as a more advantageous procedure than ester syn-
thesis from carboxylic acids and alcohols and it could rep-
resent an efficient alternative route. In fact, it should be
borne in mind that some carboxylic acids are not very solu-
ble in organic solvents and/or are labile or difficult to iso-
late. In addition, some esters (particularly methyl or ethyl
esters) are often more readily and commercially available
starting materials than the carboxylic acids.[2]
N-Heterocyclic carbenes (NHCs)[3] have attracted con-
siderable interest as non-toxic and non-pirophoric ligands
(phosphane mimics) in organometallic chemistry[4] as well
as organocatalysts.[5] The NHC-catalyzed transesterifica-
tion reaction has been reported by Nolan and co-workers[6]
and, independently, by Hedrick and co-workers.[7,8] In the
classical procedures of NHC-catalyzed transesterification,
substituted alkyl- and/or aryl-imidazolium-2-ylidenes have
been synthesised in an independent route, following the Ar-
duengo procedure {NaH in THF and catalytic amounts of
dimsyl anion [–CH2S(O)CH3]}.[3d]
Alternatively, N-heterocyclic carbenes have been gener-
ated in situ by deprotonation of their salts in organic sol-
vents containing a suitable strong base, generally KOtBu,
NaH, or an organic base such as 4-(dimethylamino)pyr-
Transesterification reactions catalyzed by acid or base,
organometallic catalysts, as well as by enzymes, have been
the subject of extensive investigations. Nevertheless, some
authors have reported possible limits and complications re-
idine
(DMAP),[9]
1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU),[10] or 1,4-diazabicyclo[2.2.2]octane (DABCO).[11]
However, the use of these bases might be problematic for
[a] Dipartimento di Scienze di Base e Applicate per l’Ingegneria, more sensitive substrates.[2a,12]
Sapienza Università di Roma,
Therefore, the imidazolium salts can be regarded as pre-
Via Castro Laurenziano, 7, 00161 Roma, Italy
Fax: +39-06-49766749
E-mail: isabella.chiarotto@uniroma1.it
catalysts in the transesterification reactions. Following this
idea, an extensive investigation on the reaction conditions
has been performed, focusing on the influence of the nature
of the ester and of the alcohol, on the structure of the pre-
catalyst, and on the effect of base, solvent, and temperature
on the product yields and on the reaction times.[13] Accord-
ingly, other authors have recently reported a new strategy
Homepage: http://w3.uniroma1.it/chiarotto/
[b] Dipartimento di Elettronica Applicata, Università di Roma Tre,
Via Vasca Navale, 84, 00146 Roma, Italy
[‡] Present address: via Antelao, 9, 00141 Rome, Italy
E-mail: achille.inesi@uniroma1.it
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201023.
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N-Heterocyclic Carbenes in Transesterification/Acylation Reactions
aimed at the separation, recovery and reuse of NHC-cata-
lysts in transesterification reactions (benzene as solvent;
ImesHCl, KOtBu as precatalyst; 80 °C).[14]
In this context, many authors have remarked on the need
for an extensive study to establish environmentally friendly
and more sustainable synthetic procedures. Particular tar-
gets in these investigations are the development and use of
benign “green” solvents (instead of the volatile, toxic, or
hazardous chemicals) and catalysts.[15]
Room temperature ionic liquids (RTILs), for example
substituted imidazolium, pyrrolidinium, and thiazolium
salts, owing to their specific properties (chemical and ther-
mal stability, solvating ability, etc.) have been frequently
used as “green” reaction media in clean organic synthetic
procedures as substitutes for conventional, toxic and vola-
tile organic solvents (VOCs).[16] Therefore, the use of an
imidazolium salt as both solvent and as a precursor of an
NHC reagent is possible and could be a valid alternative in
the synthetic procedure.
Figure 1. Ionic liquids and NHC used as solvents, precatalysts and
catalysts.
During the last years, we have generated N-heterocyclic
carbenes by cathodic reduction of suitable ionic liquids in
the absence of bases and organic solvents. The electrolyzed
RTILs have been utilized as solvent/catalyst systems in
some N-heterocyclic carbene catalyzed reactions, including
the benzoin condensation, the Staudinger reaction, γ-
butyrolactone synthesis, and the Stetter reaction.[17]
Herein, we wish to report the results of a subsequent
investigation concerning the possible utilization of an elec-
trogenerated NHC/RTIL system as reaction medium in the
transesterification/acylation reaction.
Scheme 1. General scheme for the reaction.
In preliminary studies, we have used isopropenyl acetate
2a and benzyl alcohol 3a as model substrates. 1-Butyl-3-
methylimidazolium tetrafluoroborate (BMIM-BF4; 1a) was
electrolyzed under galvanostatic control (I = 15 mAcm–2)
in a divided cell (Pt as cathode and anode; T = 60 °C) with
continuous bubbling of N2 (Figure 2); after the consump-
tion of 0.35 Faradays mol–1 of alcohol, the current was
switched off and a mixture of ester 2a and alcohol 3a (mol
ratio 2a/3a ρ = 3:1, see below) was added to the catholyte
(Scheme 2). The resulting solution was stirred at 60 °C for
2.0 h to afford, after subsequent workup, benzyl acetate 4a
(isolated yield 52%). When a solution of nonelectrolyzed
BMIM-BF4 containing a mixture 2a/3a (mol ratio 3:1) was
stirred at 60 °C for 2.0 h, no ester 4a was isolated and 2a
and 3a were completely recovered from the solution.
Results and Discussion
As part of our efforts towards the development of envi-
ronmentally friendly electrochemical methodologies in ionic
liquids, based on the use of imidazolium salts as both sol-
vent and precatalyst,[17] we have investigated the possibility
of obtaining esters by transesterification reaction catalyzed
by electrogenerated NHC. The advantages of this method-
ology lie in the use of a deprotonating reagent, the electron,
which is inexpensive, easy to dose, and does not typically
result in byproducts, in a very polar solvent (the ionic li-
quid), which could stabilize dipolar intermediates and fav-
our the outcome of the reaction. Moreover, the use of a
solvent with virtually null vapour pressure allows its easy
reuse, which can be regarded as an important synthetic
goal.[18]
The intrinsic chemistry of imidazolium-based room tem-
perature ionic liquids, related to the acidity of the C-2 posi-
tion in the imidazolium cation I, can be modified by cath-
odic cleavage of this C–H bond. In fact, the monoelectronic
galvanostatic reduction of an imidazolium salt 1a–c (Fig-
ure 1) at a Pt cathode, in a divided cell, leads to the forma-
tion of the corresponding NHC II and molecular hydrogen
[Scheme 1, Equation (1)].[7,9] The addition of alcohol 3 to
the catholyte, followed by ester 2, gives the corresponding
product 4 [Scheme 1, Equation (2)].
Figure 2. Electrolysis cell.
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I. Chiarotto, M. Feroci, G. Sotgiu, A. Inesi
FULL PAPER
Scheme 2. Electrogenerated NHC in the acetylation reaction.
These results showed the requirement for a catalyst in
the reaction and the ability of electrogenerated NHC, in the
parent BMIM-BF4, to assist the proton transfer from
alcohol to ester.
The yield of ester 4a is affected by many factors such as
RTIL, Faradays per mol of alcohol, and mol ratio ester/
alcohol. Moreover, we should consider that the transesteri-
fication process is an equilibrium so it is advisable to vary
the reaction parameters to shift the equilibrium towards the
desired direction. The initial choice of isopropenyl acetate
2a as acylating agent was targeted to remove the alkoxide
byproduct from the equilibrium; in fact, it is rapidly con-
verted into the low-boiling acetone, shifting the equilibrium
towards the product.[6]
Figure 3. Yield of the isolated product 4a vs. Q (number of Fara-
days per mol of alcohol 3a supplied to the electrodes), in BMIM-
BF4 1a and electrogenerated carbene IIa.
First, we investigated the effect of the mol ratio ester/
alcohol on the equilibrium of transesterification. We veri-
These results emphasise the fact that the NHC-catalyzed
fied that when the concentration of 3a was kept constant, transesterification reaction can be carried out in electro-
a increase in the mol ratio from 1 to 3, promoted an in- lyzed ionic liquids in the absence of classical organic sol-
crease in the yield of isolated 4a, according to the shift of vents and bases. Therefore, the electrogenerated-NHC/
the transesterification equilibrium in the direction of 4a, RTIL system as reaction medium is very efficient in this
respectively from 45 to 92% yield. Further increases caused transesterification reaction.
a significant decrease in the atom economy of the overall
process, but did not noticeably affect the yield of 4a.
In agreement with the mechanism proposed by a number
of authors,[14,21] the NHC-catalysed transesterification can
We then analyzed the effect of the number of Faradays be considered to be a catalytic cycle based on the interac-
per mol of 3a consumed at the electrodes (Q), i.e., of the tion of the N-heterocyclic carbene II and an alcohol form-
amount of NHC. The chemical yield of isolated 4a was ing a hydrogen-bonded complex III. The role of the NHC
found to increase with increasing Q (Figure 3). As regards is to assist the proton transfer from alcohol to the carbonyl
this last matter, we think that the efficiency of the reaction oxygen of the ester (via the hydrogen-bonded carbene-
yielding NHC [Scheme 1, Equation (1)] could be signifi- alcohol complex) forming the tetrahedral intermediate IV,
cantly affected by several factors: (i) the non-Faradaic com- which then evolves into the product (Scheme 3).[21a]
ponent of the whole measured number of Faradays (Q);
The strength and the nature of the hydrogen bond inter-
(ii) the presence, in the RTIL, of cathodically reducible im- action and, consequently, the efficiency of a specific NHC
purities; (iii) the stability of electrogenerated NHC, which to facilitate proton transfer are related to the nature of both
could be removed from the catalytic cycle through forma- alcohol and solvent.[22] Our results suggest a significant
tion of dimers.[19] Considering that the N-heterocyclic carb- ability of N-heterocyclic carbene IIa to assist the proton
ene has been obtained by monoelectronic cathodic re- transfer, from alcohol to ester, particularly when 1a and 1c
duction of 1a, the value of Q (number of Faradays per mol are used as solvents.
of alcohol 3a supplied to the electrode) is, in any case,
A major advantage of the use of an ionic liquid as reac-
greater than the number of mol of electrogenerated NHC tion medium is that the solvent can be recovered and recy-
per mol of alcohol 3a (really present and operating as cata- cled in subsequent runs. The ease of recovery of the ionic
lysts). Nevertheless, the mol ratio carbene IIa/substrate 3a liquid is strongly affected by its nature as well as by the
in any case increases on increasing Q.
synthetic methodology used. In fact, recovery protocols
The optimum for the electrochemical efficiency was esti- should be established for each synthetic procedure. There-
mated to be Q = 0.5 Fmol–1. Therefore, applying the most fore, the possible reuse of the ionic liquid in this system has
suitable experimental conditions (mol ratio 2a/3a of 3:1, been investigated. After ethereal extraction of the catholyte
BMIMBF4 as RTIL and 0.5 Fmol–1 of charge), the yield of (using BMIMBF4, after 0.5 F/mol each time) the catholyte
isolated 4a was 92% [with 0.7 Fmol–1 the yield of 4a was itself was held under vacuum to eliminate diethyl ether
only slightly higher (95%); Figure 3]. Following the de- traces and reused in subsequent electrolyses.
scribed protocol, comparable results were achieved by uti-
lizing ionic liquids 1b and 1c (yield of isolated 4a: 73 and in very high yields, confirming the usefulness of this
93%, respectively).[20]
“green” electrochemical methodology (Figure 4).
Ester 4a was isolated as the only product up to ten times,
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N-Heterocyclic Carbenes in Transesterification/Acylation Reactions
This methodology can also be applied to acylation reac-
tions other than acetylation. In this case, when the acyl part
of the molecule is more valuable, it is advisable to use the
starting ester and alcohol in a 1:1 mol ratio (sacrificing the
yield) or to use an excess of alcohol (instead of ester). So
the reaction between methyl benzoate 2c and benzyl alcohol
3a in a 1:1 mol ratio leads to the formation of benzyl benzo-
ate 4m in 63% yield (Table 1, entry 17), whereas the reac-
tion between methyl nicotinate 2d and benzyl alcohol 3a
leads to the formation of benzyl nicotinate 4n in 62% yield
(mol ratio 2d/3a 1:2, Table 1, entry 18). Using a less reactive
alcohol, for example, 2-(diethylamino)ethanol (3m), the cor-
responding nicametate 4o was obtained in 45% yield by
Table 1. NHC-catalyzed transesterification reaction of esters and
alcohols in BMIMBF4.[a]
Scheme 3. Proposed mechanism for the transesterification.[21a]
Figure 4. Recycling RTIL 1a and the yield of isolated 4a in ten
subsequent runs.
To test the generality of this transformation, the reactiv-
ity of alcohols 3b–l vs. 2a has been investigated; the reaction
was carried out by using the simple protocol described
above. We have verified the considerable efficiency of the
procedure with both benzyl (irrespective of the nature of
the substituent on the aromatic ring; Table 1, entries 1–9)
and aliphatic alcohols (Table 1, entries 10–12). To extend
the applicability of the reaction, we also investigated the
reactivity of ethyl acetate 2b, commonly used as solvent and
readily and commercially available, vs. alcohols 3a–d. Un-
der these conditions the corresponding esters were isolated
in elevated yields (Table 1, entries 13–16).
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I. Chiarotto, M. Feroci, G. Sotgiu, A. Inesi
FULL PAPER
Table 1. (continued)
and volatile organic solvents to be avoided, and enables this
transformation to be carried out under mild conditions, due
to the use of an ionic liquid as solvent and the electron as
reagent.
The system of electrogenerated-NHC/RTIL is able to as-
sist in the proton transfer from alcohol to ester with signifi-
cant efficiency. A recycling protocol has been demonstrated
by reusing the system in ten subsequent runs with no re-
duction in the yield. The simplicity of the system (basic
electrochemical equipment, RTILs as solvent/supporting
electrolyte/precatalysts) make these results of high interest
for electrochemical and organic synthesis. This methodol-
ogy can also be applied to other acylation reactions, leading
to compounds of noticeable pharmaceutical interest.
Experimental Section
General: All reagents are commercially available (Aldrich) and used
as received. Ionic liquids (Iolitec) were used after heating under
vacuum at 45 °C for 2 h. Electrolyses under galvanostatic control
were carried out with an Amel 552 potentiostat equipped with an
Amel 721 integrator. A two-compartment cell was used; the cath-
ode was a Pt spiral (apparent area 1.0 cm2) and the counter elec-
trode a cylindrical platinum gauze (apparent area 0.8 cm2). 1H and
13C NMR spectra were recorded with a Bruker AC 200 spectrome-
ter using CDCl3 as internal standard.
General Procedure for the Transesterification of Esters with
Alcohols: Anolyte (1.0 cm3 of ionic liquid) and catholyte (ca.
2.0 cm3 of ionic liquid) were separated through a G-4 glass septum.
The electrolysis was carried out at 60 °C under a nitrogen atmo-
sphere and at constant current (15 mAcm–2). The electrolysis was
stopped after 49 Coulombs. At the end of the electrolysis, alcohol
(1 mmol) and ester (3 mmol) were added sequentially to the catho-
lyte, the temperature was maintained at 60 °C, and the mixture was
stirred for 2 h. The reaction mixture was then extracted with diethyl
ether (3ϫ10 cm3; stirring with diethyl ether for 15 min each time).
After removal of the solvent from the combined ethereal layers un-
der reduced pressure, the crude reaction mixture was analysed by
1H NMR and TLC. All products were purified by using flash
chromatography [n-hexane/ethyl acetate (95:5); CH2Cl2/ethyl acet-
ate (98:2), respectively, for products 4m and 4n] and identified on
the basis of NMR spectroscopic analysis by comparison with re-
ported data.
[a] Electrolyses of RTIL 1a were carried out in a divided cell (Pt
cathode and anode) under galvanostatic conditions (I
=
15 mAcm–2, T = 60 °C). Number of Faradays per mol of alcohol
supplied to the electrode: Q = 0.5 Fmol–1; alcohol (1 mmol) and
ester (3 mmol) were added to the catholyte at the end of the elec-
trolysis, then the catholyte was stirred for 2.0 h at a controlled tem-
perature of 60 °C. [b] Isolated yield with respect to the starting
alcohol. [c] Alcohol (1 mmol) and ester (1 mmol) were added to
the catholyte at the end of the electrolysis. [d] Alcohol (1 mmol)
and ester (2 mmol) were added to the catholyte at the end of the
electrolysis.
using a 1:1 mol ratio of 2d/3m, however, upon enhancing
this ratio to 1:3, nicametate 4o was obtained in 62% yield
(Table 1, entry 19). Nicotinate esters have important appli-
cations in cosmetic and pharmaceutical industries. Many
publications have reported the pharmacological properties
of various nicotinate esters as A3 adenosine receptor antag-
onists, cholesteryl ester transfer protein inhibitors, blood
circulation promoters and anti-inflammatory agents.[23]
These results suggest that the procedure is widely appli-
cable and that the system comprising electrogenerated-
NHC/RTIL as reaction medium is compatible with a range
of functional groups.
Supporting Information (see footnote on the first page of this arti-
cle): Complete experimental details and spectroscopic data of all
products.
Acknowledgments
The authors thank Mr. Marco Di Pilato for his support in the
experimental part of the paper and the Italian Ministero dell’Univ-
ersità e della Ricerca (MIUR) and Istituto per lo Studio dei Mate-
riali Nanostrutturati (CNR), Rome for financial support.
Conclusions
We have reported the successful application of electrog-
enerated N-heterocyclic carbene/room temperature ionic li-
quid as a catalyst/solvent system for the transesterification
of alcohol to acetate, using isopropenyl or ethyl acetate as
acetyl donor. This protocol allows the use of strong bases
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Published Online: November 12, 2012
Eur. J. Org. Chem. 2013, 326–331
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