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Questa è la versione dell’autore dell’opera:
[Organic Preparations and Procedures International, 44, 2012, DOI:
10.1080/00304948.2012.657568]
ovvero [E. Calcio Gaudino, G. Cravotto, D. Garella, S. Tagliapietra, W. Bonrath, 44,
Taylor & Francis, 2012, pagg.175-179]
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Esterification of Terpene Alcohols Catalyzed by
Acidic Brønsted Ionic Liquids
E. Calcio Gaudino,1 G. Cravotto,1 D. Garella,1 S. Tagliapietra,1 and W. Bonrath2
1Dipartimento
di Scienza e Tecnologia del Farmaco, Universita` degli Studi di Torino, Via P.
Giuria 9, 10235 Torino, Italy
2DSM Nutritional Products, Research and Development, NRD/CC, Building-214/071, P. O. Box
3255, CH 4002-Basel, Switzerland
Submitted August 12, 2011. Addrress correspondence to G. Cravotto, Dipartimento di Scienza
e Tecnologia del Farmaco, Universita` degli Studi di Torino, Via P. Giuria 9, 10235 Torino,
Italy. E-mail: [email protected]
The Fisher esterification is an equilibrium reaction and generally requires the removal of
water and/or use of excess amounts of the reactants if satisfactory conversion rates are to be
obtained.1 The major drawbacks of these common methods are the final neutralization of the
homogeneous acid catalyst and/or the separation of a metal catalyst on a solid support.
Moreover, the removal of adsorbed products from the catalyst can be difficult and often
requires a large excess of organic solvents.2 These issues make this process environmentally
questionable. The esterification of primary terpene alcohols is a more difficult task as they are
rather prone to isomerization and other untoward reactions under normal acidic conditions.
Acidic reagents may promote ring formation, as reported for cyclogeraniol, or allyl
rearrangements that isomerize geraniol and nerol.
The use of ionic liquids (ILs) as solvents and catalysts in chemical reactions3 offers many
advantages from an environmental point of view.4–8 These solvents are non-flammable,
thermally stable and exhibit negligible vapor pressure; moreover their physico-chemical
properties can be easily tuned.9 For these reasons, the replacement of current esterification
protocols with environmentally more benign processes involving the use of ILs is an area
worthy of investigation. Deng et al. reported the esterification of carboxylic acids with
alcohols in acidic chloroaluminate ILs10 and Cole synthesized acidic Brønsted functionalized
ILs and used them as solvent-catalysts in the synthesis of ethyl acetate.11 Since then, many
Brønsted acidic ILs, including SO3H-functionalized derivatives, including ILs with an acidic
counter-anion and protonated N-alkylimidazolium ILs have been used in esterification
reactions.12–19 We now report a mild and eco-friendly synthetic procedure to prepare terpene
esters using acidic Brønsted ionic liquids (ILs)20 both as catalysts and solvents.
Preliminary efforts were directed towards the formation of neryl, geranyl and farnesyl
acetate, starting from the respective alcohols and acetic acid using 1-ethyl-3methylimidazolium methanesulfonate (EMImMeSO3) as both solvent and acidic catalyst
(Scheme 1). At first, the reactions were performed using a 1:2:1 millimolar ratio (alcohol,
acetic acid and EMImMeSO3). The influence of time and temperature was investigated first.
Good yields were obtained for farnesol, nerol and geraniol acetates in 12 h at 50°C, 79 and 82
and 85% respectively.
Scheme 1.
No ester were detected at 100°C due to degradation of the alcohol; the same reaction carried
out in toluene failed. This IL is miscible with all reagents but immiscible with the products,
which were recovered using separatory funnel. EMImMeSO3 is miscible with the water
generated during the esterification, thus favoring reaction rates and equilibrium. The
influence of the molar ratio of acetic acid was also studied by varying it from 1:1 to 1:4
(alcohol:acetic acid). Best results were achieved using two equivalents of acetic acid.
Various imidazolium salts with different anions were screened in the synthesis of neryl
acetate, taken as a model alcohol, in order to study the influence of nature of the anion on the
catalytic activity of the ILs. Formulas, names and acronyms of all these ILs are listed in Figure
1. The highest yield of neryl acetate (89%) was obtained in BMImMeSO3, while negligible or
no conversion were observed using BMImAcOH, BMImPF6 and OMImBF4.
Figure 1.
These results confirm the higher catalytic activity of ILs with stronger Brønsted acidity. It is
important to note that all ILs tested exhibited different types of biphasic behavior when
mixed with the produced esters. The immiscibility of BMImMeSO3 and EMImMeSO3 with the
final product favorably influenced the equilibrium. Of all the ILs used, BMImMeSO3 showed
the best catalytic activity in the esterification of both geraniol and nerol (86% and 89% yield,
respectively). Finally the mole ratio effects of alcohol and BMImMeSO3 were studied with the
aim of decreasing the IL amount used. When the amount of the IL was reduced from 1:1 to
1:0.5 (alcohol:IL), the yields in neryl acetate decreased from 89% to 50%. No significant
change in yield was found when the alcohol: IL mole ratio was further reduced from 1:0.5 to
1:0.25 (47%). Best results were then achieved with one equivalent of IL.
Applicability and sustainability of the ILs-catalyzed esterification in larger scale, is mainly
dependent on the molar ratio IL:reagents (alcohol and carboxylic acid) and the recyclability of
the IL. Although ILs can be easily separated and recycled, a small loss in these processes still
cannot be overlooked in view of a possible industrial scale up. So far, only a few studies have
focused on the optimal catalyst ratio IL:reagents, usually 10–30% with respect to the reagent
present in the lowest quantity. A series of experiments were conducted to investigate the
recycling of ILs. As mentioned above, the ILs used and the ester were immiscible so the ILs
were easily recovered by simple decantation using separatory funnel. The unreacted acetic
acid and the water formed during the esterification were distilled off from the corresponding
IL which was reused without further purification for the next reaction. Five experiments
conducted in order to investigate the possibility of recycling of the two Brønsted acid ILs used
in the synthesis of neryl acetate, showed that the catalytic activity decreased slightly only
after EMImMeSO3 and BMImMeSO3 had been used four times. Fairly good yields could still be
obtained even in the 5th recycle. This indicates that these ILs were sufficiently stable to be
recycled as catalysts for esterification. A further improvement was achieved under
microwave-assisted conditions. The esterification of nerol with acetic acid in BMImMeSO3 was
conducted under conventional and microwave (MW) heating at the same temperature (50°C).
The reaction under MW irradiation reached 90% yield after 30 min, with little further
improvement after 60 min (96%) compared only 21% yield obtained under conventional
heating in the same reaction time.
A series of Brønsted acid ILs have been used as solvent-catalysts for the esterification of some
terpene alcohols with acetic acid. Sulfonic acid (SO3H)-functionalized imidazolium ILs showed
the highest catalytic activity. All the products are easily separated from the reaction mixture
and isolated in good yields (>75%) and purity. The IL can be recycled after removal of water,
with only moderate loss in activity. Reaction rates were further improved under MW
irradiation. In conclusion, BMImMeSO3 and similar ILs could be the solvent/catalyst of choice
for the esterification of terpene alcohols. This green protocol avoids unwanted isomerization
and side-reactions, and in term of efficiency and costs is suitable for industrial scale up.
Acetates of primary and secondary aliphatic alcohols can be easily prepared with this
procedure in almost quantitative yield, while sugars are only partially esterified even after
longer reaction times (10 h). Work is in progress to extend the procedure to other carboxylic
acids. Although each substrate requires specific reaction conditions, we can confirm that the
MW-assisted esterification catalyzed by Brønsted acidic ILs is a promising method with a
fairly good range of applicability.
Experimental Section
Commercially available reagents were used without further purification. For MW irradiation,
a professional multimode oven (Microsynth-Milestone, BG, Italy) was used. IR spectra were
recorded on a Shimadzu FT-IR8001 spectrophotometer; 1H- and 13C-NMR spectra were
obtained on a Bruker Avance 300 spectrometer, at 300 and 75 MHz respectively (25°C).
Chemical shifts were calibrated to the CDCl3 residual peak (δ = 7.27 for 1H- and δ = 77.16 for
13C-NMR).
Conventional and MW-assisted General Procedures
In 50 mL four-necked flask equipped with a magnetic stir bar, thermometer and a condenser,
geraniol (7.71 g, 50 mmol) in a mixture of 1-ethyl-3-methylimidazolium methanesulfonate
(10 g, 48.5 mmol) and glacial acetic acid (6.05 g, 100 mmol), was stirred and heated at 50°C
(oil bath) for 24 h.
For the MW-assisted reaction, the same reacting mixture was stirred in 50 mL two-necked
flask equipped with an optic-fibre thermometer, a magnetic stir bar, and a condenser, and
irradiated with MW for 60 min at 50°C (30 W, mean power).
In both methods, the mixture was cooled to room temperature and cyclohexane (50 mL) and
water (50 mL) were added to the reaction mixture. After phase separation (separatory
funnel), the organic phase was dried (MgSO4) and evaporated under vacuum. The brown oil
was purified by flash chromatography (hexane/EtOAc 95:5, Combi Flash Rf , Teledyne ISCO)
and analyzed by GC. The IL was reused after the removal of water under vacuum (0.02 mbar)
at 70°C for 1 h. The use of conventional heating led to the formation of 8.35 g of geraniol
acetate (85%) while the MW-assisted reaction gave 9.42 g (96%) of the ester.
All products were analyzed by 1H- and 13C-NMR and IR spectroscopy thereby confirming their
structures in accordance with the literature and a satisfactory degree of purity.
Acknowledgements
Financial support from MIUR (PRIN 2008 “A Green Approach to Process Intensification in
Organic Synthesis”) is gratefully acknowledged.
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