Esterification in ionic liquids: The influence of solvent basicity

Article abstract of DOI:10.1021/jo8005864

(Chemical Equation Presented) The second-order rate constant (k ₂) for the esterification of methoxyacetic acid with benzyl alcohol is reported in a range of ionic and molecular solvents. The solvent effects on esterification rate are examined by using a linear solvation energy relationship based on the Kamlet-Taft solvent scales (α, β, and π*). It is shown that the hydrogen bond basicity of the solvent is the dominant parameter in determining the esterification rate and that the best rates are achieved in low basicity solvents.

Full text of DOI:10.1021/jo8005864

6
Esterification in Ionic Liquids: The Influence of
Solvent Basicity
mable. Thus, despite concerns over their unknown toxicities,
they are widely proposed as “green solvents”.
Esterification is a fundamental reaction of both academic and
industrial chemistry; the production of polyesters alone exceeds
9 million tons per year and accounts for 55% of synthetic fibres
produced. Consequently the novel synthesis of polyesters is a
subject of much interest. In terms of atom economy, the
stoichiometric condensation of an acid and alcohol, without prior
functionalization, constitutes an efficient process, with water
being the only byproduct. However, due to the unfavorable
position of the esterification equilibrium, reactive acid deriva-
tives, such as acyl chlorides or anhydrides, are commonly
employed and a large excess of one reagent is used to drive the
reaction, thus creating waste.
Thomas P. Wells, Jason P. Hallett, Charlotte K. Williams,*
and Tom Welton*
7
Department of Chemistry, Imperial College London, South
Kensington Campus, London, SW7 2AZ, United Kingdom
8
t.welton@imperial.ac.uk
ReceiVed March 14, 2008
Ionic liquids are useful media for esterification reactions
because they enable vacuum (to remove condensate) and solvent
to be used together, creating an opportunity to drive the
equilibrium. Also, the properties of ILs can be tuned to be both
9
polar and hydrophobic. This points to the intriguing possibility
of being able to dissolve polar solutes in a dehydrating solvent.
For example, ILs have been shown to dissolve a wide range of
carbohydrates, a class of molecules gaining importance as a
1
0–13
chemical feedstock.
Finally, ILs are commonly referred to
2
The second-order rate constant (k ) for the esterification of
as designer solvents. This is because anions and cations can be
changed independently of one another, allowing solvent-solute
interactions to be tuned to purpose.
Recent work by Tanabe et al. and Sakakura et al. has
demonstrated the use of biarylammonium salts as mild catalysts
for the esterification of acids with alcohols. High conversions
were achieved without the removal of water, demonstrating the
potential of salts, in conjunction with hydrophobic solvents, to
catalyze esterification and drive conversion.
methoxyacetic acid with benzyl alcohol is reported in a range
of ionic and molecular solvents. The solvent effects on
esterification rate are examined by using a linear solvation
energy relationship based on the Kamlet-Taft solvent scales
1
4
15
(
R, ꢀ, and π*). It is shown that the hydrogen bond basicity
of the solvent is the dominant parameter in determining the
esterification rate and that the best rates are achieved in low
basicity solvents.
Esterification has already been demonstrated in various ionic
liquids. Davis et al. were the first to report the use of IL tethered
Often, the largest contributor to the environmental footprint
of a chemical process is the solvent used. Solvents have a
significant impact because of the quantity they are used in: for
example, in pharmaceutical production they typically account
for between 80% and 90 % of the mass utilization of a batch
16,17
sulfonic acids to promote Fisher esterification.
of a Bronsted IL being used as an esterification catalyst has
This concept
1
8
subsequently been expanded upon, most recently by Li et al.
1
(
6) Scammells, P. J.; Scott, J. L.; Singer, R. D. Aust. J. Chem. 2005, 58,
55–169.
7) Weissermel, K.; Arpe, H.-J. Industrial Organic Chemistry, 3rd ed.; VCH:
operation. Consequently, replacing conventional solvents, usu-
1
ally volatile organic compounds (VOCs), with more environ-
mentally benign media, or with no solvent at all, is one of the
(
New York, 1997.
2
(8) Williams, C. K. Chem. Soc. ReV. 2007, 36, 1573–1580.
central tenets of Green Chemistry and a subject of significant
(9) Cammarata, L.; Kazarian, S. G.; Salter, P. A.; Welton, T. Phys. Chem.
3
,4
academic and commercial interest.
Chem. Phys. 2001, 3, 5192–5200.
In the search for alternative solvents, ionic liquids (ILs) have
emerged among the front runners due to their unusual and
(10) Zhu, S. D.; Wu, Y. X.; Chen, Q. M.; Yu, Z. N.; Wang, C. W.; Jin,
S. W.; Ding, Y. G.; Wu, G. Green Chem. 2006, 8, 325–327.
(
11) El Seoud, O. A.; Koschella, A.; Fidale, L. C.; Dorn, S.; Heinze, T.
5
interesting properties. First, they exhibit negligible vapor
Biomacromolecules 2007, 8, 2629–2647.
12) Liu, Q. B.; Janssen, M. H. A.; van Rantwijk, F.; Sheldon, R. A. Green
Chem. 2005, 7, 39–42.
13) Ragauskas, A. J.; Williams, C. K.; Davison, B. H.; Britovsek, G.;
(
pressure at standard conditions, negating concern over atmo-
spheric emissions. They also dissolve a wide range of organic
and inorganic materials, have high thermal stability, are liquid
over a wide range of temperatures, and are generally nonflam-
(
Cairney, J.; Eckert, C. A., Jr.; Hallett, J. P.; Leak, D. J.; Liotta, C. L.; Mielenz,
J. R.; Murphy, R.; Templer, R.; Tschaplinski, T. Science 2006, 311, 484–489.
(
14) Funatomi, T.; Wakasugi, K.; Misaki, T.; Tanabe, Y. Green Chem. 2006,
8
, 1022–1027.
(
1) Constable, D. J. C.; Jimenez-Gonzalez, C.; Henderson, R. K. Org. Process
Res. DeV. 2007, 11, 133–137.
2) Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and Practice;
Oxford University Press: Oxford, UK, 1998.
(15) Sakakura, A.; Nakagawa, S.; Ishihara, K. Tetrahedron 2006, 62, 422–
433.
(
(16) Forbes, D. C.; Weaver, K. J. Mol. Catal. A: Chem. 2004, 214, 129–
132.
(17) Cole, A. C.; Jensen, J. L.; Ntai, I.; Tran, K. L. T.; Weaver, K. J.; Forbes,
(3) Tanaka, K.; Toda, F. Chem. ReV. 2000, 100, 1025–1074.
(4) Clark, J. H.; Tavener, S. J. Org. Process Res. DeV. 2007, 11, 149–155.
(5) Welton, T. Chem. ReV. 1999, 99, 2071–2083.
D. C.; Davis, J. H. J. Am. Chem. Soc. 2002, 124, 5962–5963.
(18) Li, X. Z.; Eli, W. J. Mol. Catal. A-chem. 2008, 279, 159–164.
1
0.1021/jo8005864 CCC: $40.75  2008 American Chemical Society
J. Org. Chem. 2008, 73, 5585–5588 5585
Published on Web 06/17/2008

SCHEME 1. Esterification of Benzyl Alcohol with
Methoxyacetic Acid, at Equimolar Concentration
1
9
and Gameshpure et al. Jiang et al. investigated p-TSA-
-
-
catalyzed esterification in imidazolium-based [BF4] and [PF6]
ILs; they observed that the choice of IL had an effect on the
2
0
equilibrium conversion. The use of enzymes in ILs for
21,22
(poly)ester synthesis has also been explored.
To date, it has
remained unclear which properties of ILs, as solvents, are
conducive to rapid esterification kinetics.
We have previously reported kinetic studies of nucleophilic
substitution reactions in ionic liquids, rationalizing solvent
effects with a Kamlet-Taft linear solvation energy relationship
2
3,24
(
LSER).
Recently, LSER methods have also been applied
to ILs in the investigation of chromatography stationary
2
5
26
27
phases, molar volume and gas solubilities. The general
form of an LSER is shown in eq 1, where XYZ represents some
solvent-dependant property (herein, the natural logarithm of the
rate constant). The Kamlet-Taft approach utilizes three solvent
descriptors: R (hydrogen bond acidity), ꢀ (hydrogen bond
basicity), and π* (dipolarity/polarizability) as measured by a
series of solvatochromic dyes. The coefficients a, b, and s are
solute specific and measure the sensitivity of a property (XYZ)
to R, ꢀ, and π*. Multivariant regression can then be used to fit
the three solvent parameters (R, ꢀ, and π*) with the experi-
mentally determined rate constants (ln k2) by varying the sign
and magnitude of the coefficients (a, b, and s).
XYZ ) constant + aR + bꢀ + sπ*
(1)
Here, we report a related approach to rationalize esterification
rates in a range of ionic and molecular solvents. It is proposed
that this will help us to understand which ionic liquids are most
suitable as esterification solvents.
FIGURE 1. (a) Conversion against time for model esterification in
im][N(Tf) ]. (b) Product of the integrated rate equation (eq 2)
[
C
4
C
1
C
1
2
The p-TSA (1 mol %)-catalyzed esterification between
methoxyacetic acid and benzyl alcohol, at 50 °C (Scheme 1),
was studied as a model esterification reaction. Here 1 M
concentrations were used so as to be representative of real
synthetic conditions, as opposed to a classical infinite dilution
kinetic experiment. The reagents were used in approximately,
but not precisely, equimolar amounts; the ratio of initial
against time for the same reaction, up to the point at which the back
reaction became significant.
TABLE 1. The Rate Constants (k2) of Esterification and
Kamlet-Taft Parameters of Different Solvents
k2 (M-1min-1) × 10 σ × 10
4
a
4
R
ꢀ
π*
solvent
toluene
acetonitrile
THF
110
9.4
0.00 0.09 0.46
0.36 0.39 0.82
0.00 0.58 0.62
0.60 0.21 1.01
0.60 0.51 1.03
0.38 0.28 1.03
0.41 0.26 0.97
1
16.6
2.87
52.9
8.60
44.7
55.0
0.36
0.38
4.0
0.71
1.6
concentrations and conversions was determined from H NMR
integrals as discussed in the Supporting Information. The p-TSA
was selected as the Brønsted acid catalyst due to its good
solubility in a wide range of solvents. The reagents were chosen
[
[
C4C1im][N(Tf)2]
C4C1im][OTf]
[C C C im][N(Tf) ]
4
1
1
2
1
because of their suitability for H NMR spectroscopic monitor-
[C4C1py][N(Tf)2]
5.4
1
ing; H NMR resonances of the reagents are clearly distinguish-
a
Rates determined in triplicate.
(
19) Ganeshpure, P. A.; George, G.; Das, J. J. Mol. Catal. A-chem. 2008,
79, 182–186.
20) Jiang, T.; Chang, Y. H.; Zhao, G. Y.; Han, B. X.; Yang, G. Y. Synthetic
Commun. 2004, 34, 225–230.
21) Marcilla, R.; de Geus, M.; Mecerreyes, D.; Duxbury, C. J.; Koning,
C. E.; Heise, A. Eur. Polym. J. 2006, 42, 1215–1221.
22) Lee, S. H.; Dang, D. T.; Ha, S. H.; Chang, W. J.; Koo, Y. M. Biotechnol.
Bioeng. 2008, 99, 1–8.
23) Crowhurst, L.; Falcone, R.; Lancaster, N. L.; Llopis-Mestre, V.; Welton,
T. J. Org. Chem. 2006, 71, 8847–8853.
24) Ranieri, G.; Hallett, J. P.; Welton, T. Ind. Eng. Chem. Res. 2008, 47,
38–644.
25) van Meter, D. S.; Yaqin, S.; Parker, K. M.; Stalcup, A. M. Anal. Bioanal.
2
able from those of the resulting ester and also from those of
most common molecular and ionic solvents. This allowed for
direct measurement of the reaction conversion without the need
for solvent removal.
(
(
(
1
(
In situ H NMR monitoring was not undertaken as ionic
liquids are viscous; therefore the reaction was carried out in
a stirred vessel so that diffusion limited kinetics were avoided
and aliquots were periodically removed for analysis. At 50
(
6
(
Chem. 2008, 390, 897–905.
°
C, the reaction proceeded at an observable rate in all
(
(
26) Kobrak, M. N. Green Chem. 2008, 10, 80–86.
27) Abraham, M. H.; Acree, W. E. Green Chem. 2006, 8, 906–915.
solvents.
5
586 J. Org. Chem. Vol. 73, No. 14, 2008

2 2
FIGURE 3. Predicted values of ln k against experimental ln k values.
FIGURE 2. Linear plot of ln k
σ, 95% confidence limit.
2
against ꢀ values. Error bars denote
2
SCHEME 2. Rate-Limiting Step for AAC2 Esterification
The kinetic measurements were only used until product
concentration was high enough to make the back reaction
significant. The point at which this occurred was dependant on
the solvent’s water miscibility and ranged between 15% and
6
0%. Simultaneously observing the conversion, x, and the initial
1
acid:alcohol ratio, θacid, as experimental ratios of H NMR
integrals enabled the determination of the second-order rate
constant, k2, from a single reaction (eq 2). Figure 1a shows an
example of the conversion data; Figure 1b shows those data
processed by the integrated rate law (eq 2).
Given the observed second-order reaction kinetics and the
likelihood that the mechanism is the same for ionic and
molecular solvents, the most probable mechanism is bimolecular
(
θacid - x)
1
1
k2t )
ln
alcohol] (θacid-1) θacid(1 - x)
(2)
[
0
2
8
acid-catalyzed acyl-oxygen cleavage (AAC2). The rate-
limiting step (RLS) for the proposed mechanism is shown in
Scheme 2. It should be noted that the formation of the activated
complex 2 involves the dispersion of charge. The Hughes-Ingold
approach to nucleophilic substitutions related solvent polarity
to the reaction rate and predicts that a polar solvent would retard
the esterification rate. Kamlet and Taft separated solvent polarity
into three separate components (R, ꢀ, and π*). Therefore, by
analogy with the Hughes-Ingold approach, it is proposed that
a hydrogen bond accepting solvent could preferentially stabilize
[
acid]0
θacid
)
(3)
(4)
[
alcohol]0
[
ester]
alcohol]0
x )
[
The rates of esterification were determined for a range of
solvents, and the corresponding rate constants, their standard
deviations (σ), and experimentally determined Kamlet-Taft
parameters are shown in Table 1. The reaction was also
attempted in DMSO but no reaction was observed in a
reasonable time scale and DMSO was excluded from the study.
Multivariate regression was used to fit the observed ln k2 values
to the Kamlet-Taft LSER. Any coefficients (a, b, or s) with a
p-value of over 0.01 were rejected as statistically insignificant
and assumed to be zero. The analysis was then repeated without
the corresponding parameter (R, ꢀ, or π*, respectively). This
process yielded eq 5, which is shown graphically in Figure 2.
The high degree of confidence in the value of b (-7.25) is
q
the reacting species 1. This stabilization would increase ∆G
and decrease the reaction rate. However, such reasoning fails
to explain why the hydrogen bond basicity is so significant while
the solvent’s acidity and polarizability appear irrelevant. Con-
sequently, this is not thought to be the major effect observed.
Given the relatively high concentrations of acid and alcohol
used, self-association of the species, as a mechanism of
accelerating or decelerating the reaction, cannot be ruled out.
To test this, the k2 of esterification was determined in toluene
at 10× dilution (0.1 M). Toluene was chosen as it has the lowest
values of R, ꢀ, and π* and as such should interact least strongly
with substrates, therefore promoting self-association most
strongly. At 0.1 M concentration of each reagent in toluene, a
-4
demonstrated by a p-value of 1.1 × 10 .
ln k ) 7.25ꢀ - 3.59
(5)
2
This analysis indicates that the ꢀ value of a solvent is the
dominant factor in determining the esterification rate. Therefore,
the hydrogen bond basicity of a solvent determines the esteri-
fication rate and a solvent with low basicity exhibits a high
esterification rate. The predictive strength of this theory is
portrayed in Figure 3, which shows an excellent correlation
between the predicted and experimental values of ln k2.
-4
-1
-1
rate constant of 81.3 × 10
M
min was observed, or 73%
of the original 1.0 M rate. It appears that self-association does
provide a modest acceleration of rate. While a more basic
solvent is likely to reduce the degree of association and thus
(28) Sykes, P. A Guidebook to mechanism in organic chemistry, 6th ed.;
Prentice Hall: Upper Saddle River, NJ, 1986.
J. Org. Chem. Vol. 73, No. 14, 2008 5587

decelerate the reaction, given the small change in rate upon a
0× dilution, it is not considered to be a strong enough effect
to account for the wide range of rates observed between solvents
40×).
The species [HCl2] , [H2Cl3] , and [H3Cl4] are known to
form when Brønsted acids are dissolved in chloride-rich
in the RLS of AAC2, as the major factor behind the observed
solvent dependency. Thus, a low basicity solvent, as show by
its ꢀ value, should be chosen to optimize the esterification rate,
provided that the reagent solubility can be maintained.
1
(
-
-
-
Experimental Section
2
9,30
chloroaluminate ionic liquids.
This suggests that when
Materials and Reagents. All reagents were purchased from
commercial suppliers. Unless otherwise stated, solvents and reagents
were freshly distilled and dried by using standard procedures.
p-TSA dissolves in an ionic solution, the protons will be
associated with the conjugate base, the solvent anions, or both.
The relative prevalence of each association will depend on the
concentration and proton affinity of the species in question. In
the same manner, a “free” proton in molecular solvents will be
associated, to some degree, with its conjugate base and/or the
solvent. The concentration of the conjugate base is constant
across the series of solvents under investigation, so the proton
affinity of the solvent must be responsible for any differences
in the availability of the solvated proton to participate in the
RLS of esterification.
9
Synthesis of Ionic Liquids. As previously reported, except that
ethyl acetate was used in place of toluene in an improved synthesis
of [C
4 1
C im]Cl (see the Supporting Information).
3
1
Kamlet Taft Measurements. As previously reported.
Esterification Kinetics. The procedure was carried out by using
a Carousel 12 Tube stirrer hot plate, with a reflux condenser and
under a nitrogen atmosphere. Three reaction tubes were purged for
3
2
0 min with N . Under a dry atmosphere, p-TSA (0.076 g, 0.400
mmol) was added to a volumetric flask and made up to 10 mL
with diethyl ether. An accurate aliquot of this solution (250 µL)
was added by volumetric syringe to each tube. The tubes were
heated at 50 °C and placed under an aspirator vacuum for 2 h to
Reducing the availability of protons in solution will reduce
the equilibrium concentration of the reacting species (1) and
lower the rate. The proton affinity of a molecule can be described
by its pKa or the Gibbs free energy change for its gas-phase
deprotonation (∆GH). It has been previously shown that, for
ionic liquids, the ∆GH of an anion can be correlated with the ꢀ
remove the diethyl ether. A volumetric flask was purged with N
2
for 30 mins and methoxyacetic acid (0.360 g, 4 mmol) was added
and made up to 2 mL with the solvent under investigation. Accurate
aliquots of this solution (490, 500, and 510 µL, respectively) were
added to each tube by volumetric syringe and allowed time to warm
3
1
value of the corresponding ionic liquid. It follows that a high
value corresponds to a high proton affinity and thereby a low
2
to 50 °C. A volumetric flask was purged with N for 30 min and
ꢀ
benzyl alcohol (0.430 g, 4 mmol) was added and made up to 2 mL
with the solvent under investigation. Accurate aliquots of this
solution (510, 500, and 490 µL, respectively) were added to each
tube by volumetric syringe. The point of injection was deemed to
be t ) 0. Regular samples were taken from each tube and analyzed
proton availability and low rate, as observed. This is evidence
for a degree of solvent leveling of protic acids.
Furthermore, Jiang et al. have demonstrated that the equi-
librium esterification conversion was significantly higher in
-
-
hydrophobic [PF6] -based ILs than in hydrophilic [BF4] -based
1
by H NMR spectroscopy until the reaction reached equilibrium.
2
0
ILs. This is consistent with the hydrogen bond basicity (ꢀ) of
an ionic liquid, controlled by the anion, determining water
miscibility, with a high ꢀ value corresponding to high water
Preparation of NMR Samples. Small volumes of the reaction
1
mixture (ca. 0.05 mL) were dissolved in CDCl (0.5 mL). H NMR
3
spectra were recorded on a 400 MHz spectrometer. A 10 s delay
time was applied to ensure complete relaxation and that accurate
integral values were recorded.
9
miscibility. It follows that a low ꢀ solvent will yield not only
a higher reaction rate but also a greater equilibrium conversion.
In summary, the second-order rate constant (k2) for the
esterification of methoxyacetic acid with benzyl alcohol in a
Acknowledgment. We would like to thank the EPSRC and
the Department of Chemistry at Imperial College London for a
DTA studentship (T.P.W.) and the Marshall-Sherfield Founda-
tion for a research fellowship (J.P.H.). We would also like to
thank Stephen Boyer, London Metropolitan University, for
Elemental Analysis, John Barton, Imperial College London, for
mass spectrometry, and Pete Haycock and Dick Sheppard,
Imperial College London, for NMR support.
1
range of solvents has been determined directly by using H NMR
spectroscopy and the integrated second-order rate law (eq 2). It
has been shown that the ꢀ value of the solvent is the dominant
parameter in the LSER for the ln k2 of esterification. Therefore,
it is concluded that solvent basicity determines the esterification
rate and that the best rates are achieved in low basicity solvents.
This can be rationalized in terms of the solvent’s proton affinity
determining the availability of the catalytic proton to participate
Supporting Information Available: Synthesis and spectro-
scopic characterization of ILs, kinetic data, integrated rate law
derivation, a method of calculating x, θacid, and k2. This material
is available free of charge via the Internet at http://pubs.acs.org.
(
(
29) Trulove, P. C.; Osteryoung, R. A. Inorg. Chem. 1992, 31, 3980–3985.
30) Campbell, J. L.; Johnson, K. E. Electrochem. Soc. 1994, 141, L19–
L21.
(
31) Crowhurst, L.; Mawdsley, P. R.; Perez-Arlandis, J. M.; Salter, P. A.;
Welton, T. Phys. Chem. Chem. Phys. 2003, 5, 2790–2794.
JO8005864
5
588 J. Org. Chem. Vol. 73, No. 14, 2008