Ionic liquids: Just molten salts after all?

Article abstract of DOI:10.3390/molecules14072521

While there has been much effort in recent years to characterise ionic liquids in terms of parameters that are well described for molecular solvents, using these to explain reaction outcomes remains problematic. Herein we propose that many reaction outcom

Full text of DOI:10.3390/molecules14072521

Molecules 2009, 14, 2521-2534; doi:10.3390/molecules14072521
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Ionic Liquids: Just Molten Salts After All?
Hon Man Yau 1, Si Jia Chan 1, Stephen R. D. George 1, James M. Hook 2, Anna K. Croft 3,*
and Jason B. Harper 1,*
1
School of Chemistry, University of New South Wales, Sydney, NSW, 2052, Australia
2
Analytical Centre, University of New South Wales, Sydney, NSW, 2052, Australia
3
School of Chemistry, University of Wales Bangor, Bangor, Gwynedd, LL57 2UW, UK
* Authors to whom correspondence should be addressed; E-mails: j.harper@unsw.edu.au (J-B.H.),
a.k.croft@bangor.ac.uk (A-K.C.)
Received: 7 June 2009; in revised form: 6 July 2009 / Accepted: 10 July 2009 /
Published: 13 July 2009
Abstract: While there has been much effort in recent years to characterise ionic liquids in
terms of parameters that are well described for molecular solvents, using these to explain
reaction outcomes remains problematic. Herein we propose that many reaction outcomes in
ionic liquids may be explained by considering the electrostatic interactions present in the
solution; that is, by recognising that ionic liquids are salts. This is supported by evidence in
the literature, along with studies presented here.
Keywords: ionic liquid; molten salt; reaction outcome; electrostatic interactions
1. Introduction
Ionic liquids have been touted as potential alternatives to volatile organic solvents.[1] Arbitrarily
defined as having a melting point of less than 100 ºC [2], they are typically based on bulky organic
cations, generally containing either cationic nitrogen or phosphorus centres, with the charge balanced
by one or more of a variety of organic and inorganic anions [3-7]. Whilst liquid, the electrostatic
interactions between the component ions result in many of the properties widely associated with ionic
liquids, particularly their negligible vapour pressure [3,8]. Modification of either of the ionic
components alters the physical properties [6-11], particularly miscibility with other liquids [6,7],
allowing them to be ‘tuned’ to a given process and thus utilised as versatile ‘designer
solvents’ [12-16].

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A significant hurdle in the widespread application of ionic liquids is the effect that they have on
reaction outcomes. When a reaction is carried out in an ionic liquid, differences in the rates and
selectivities of the process are often observed when compared to the corresponding reaction in
molecular solvents [17]. The variation in outcomes is elegantly demonstrated through treatment of
toluene with nitric acid in a range of ionic liquids [18]. While halogenation, rather than nitration can,
be readily rationalised in the halide based salts, the change in rate and selectivity observed in a
bis(trifluoromethanesulfonyl)imide ionic liquid and the oxidation, rather than nitration, observed in a
mesylate ionic liquid are not so easily explained.
At this stage there are limited reports detailing the origins of such changes [17], which is in marked
contrast to the extensive understanding of the effect on reaction outcome upon changing from one
molecular solvent to another [19]. In addition, these reports focus on using traditional solvent
parameters to describe ionic liquids and, even when limited to considering Diels-Alder processes in
ionic liquids with hydrogen-bonding cations [20-24], the methods give poor correlations, particularly
for rates [24]. Further, the contributing factors vary between different reactions. At the extreme case,
the contributing properties are observed to be markedly different even when the dienophile is changed
in a Diels-Alder reaction [24]. This means that different reactions need to be considered in different
ways, making for a very non-unified or ad hoc approach to explaining reaction outcomes.
Here we propose that an alternative way to understand the effects of moving to ionic liquid solvents
is to consider ionic liquids as originally described in the literature; as molten salts. Being made up of
ions, the principle interactions in such a solvent are electrostatic and the interactions between the
component ions are typically much larger than between the ions and solute molecules. While we have
used such an argument previously to describe the anomalously high solubility of benzenes in ionic
liquids [25,26] and others, particularly Kobrak et al. [27-30], have considered this to describe the
physical properties of ionic liquids, here we extend this idea as a method of rationalising
reaction outcomes.
Some of our earlier work [31,32] has focused on the effect of ionic liquids on the unimolecular
substitution process outlined in Scheme 1. Particularly, the effect of the ionic liquid 1-butyl-3-
methylimidazolium ([Bmim]+) bis(trifluoromethanesulfonyl)imide ([N(CF3SO2)2]-) on this chloride
solvolysis was shown to be a decrease in both the enthalpy and entropy of activation.[32] This was
rationalised through a stabilisation of the incipient charges in the transition state, with an increase in
the ordering of the ionic components of the solution required to achieve this. A key experiment
included in that work was an example where an 'ordinary' salt, in this case lithium
bis(trifluoromethanesulfonyl)imide was added. The effects on the reaction were observed to be
(qualitatively) similar to those obtained with the ionic liquid. This 'salt effect' was used to rationalise
an initial rate increase seen on addition of a small amount of the ionic liquid. However, it also
introduced the possibility that ionic liquids could be considered simply as molten salts in terms of
explaining their observed effects. As such, it serves as a starting point for the work described here.

Molecules 2009, 14
Scheme 1. Nucleophilic substitution of the chloride 1 to give the ether 2, carried out in a
2523
mixture of alcohol and ionic liquid.
R
Cl
O
ROH
[Bmim]
[N(CF3SO2)2]
1
2
2. Results and Discussion
Clearly, given the above observations, it is of interest to determine whether the effects of ionic
liquids on reaction outcomes could be mimicked by salts that are not liquids at room temperature.
Since we have an interest in understanding these reaction processes at the molecular (or ionic!) level,
we are particularly interested in the effect of salts on the kinetics and selectivities of such processes
and have focused on systems for which we have some background. In addition, we discuss a prominent
example from the ionic liquid literature where treating the ionic liquid simply as a salt may provide
some insight along with highlighting the potential of molecular dynamics simulations for these
systems and how such simulations fit well into this argument.
2.1. Bimolecular substitution of a benzyl bromide
The Menschutkin reaction [33] of pyridine and the benzyl bromide 3 (Scheme 2) was considered as
it is related to the unimolecular process described above, however, the extent of charge development is
less than for the unimolecular process. The reaction was carried out in acetonitrile, acetonitrile
containing lithium bis(trifluoromethanesulfonyl)imide (at χ = 0.10) and in [Bmim][N(CF3SO2)2] (at χ
1
= 0.87). Reaction progress was monitored using H-NMR spectrosopy over a range of temperatures
and the activation parameters (Table 1) were calculated using the Eyring equation.[34].
Scheme 2. Menschutkin reaction of the benzyl bromide 3 with pyridine.
N
Br
N
Br
3
4
Table 1. Activation parameters for the reaction outlined in Scheme 2 in the solvent system
specified. Uncertainties quoted are standard deviations.
Solvent
ΔH‡ (kJ mol-1) ΔS‡ (J K-1 mol-1)
Acetonitrile
43.2 ± 1.1
57.1 ± 0.5
48.8 ± 0.9
-219 ± 4
-191 ± 2
-193 ± 3
Acetonitrile containing Li[N(CF3SO2)2]
[Bmim][N(CF3SO2)2]

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The effect of the ionic liquid, in this case, is opposite to that observed previously [32] with an
increase in both the enthalpy and entropy of reaction. While the origin of the changes in the activation
parameters on addition of an ionic liquid are discussed in detail elsewhere [35], these results imply an
increase in stabilisation of, and ordering about, the starting material relative to the transition state on
going from acetonitrile to the systems containing ions. Importantly for the argument presented here,
the effect of the corresponding lithium salt was the same, with only the magnitude of the change in
activation enthalpy being larger. This difference is presumably as a result of the more charge-dense
lithium cation. That is, this case represents a further example where the effect of an ionic liquid is
comparable to an 'ordinary' salt.
2.2. Hydrolysis of benzaldehyde dimethyl acetal (5)
A further reaction we have considered in ionic liquids is the hydrolysis of the acetal 5 to the
corresponding aldehyde 6 (Scheme 3). This reaction was considered as, along with being a markedly
different reaction type to the substitutions described above, it also requires a water-miscible ionic
liquid, in contrast to the systems already studied. As such, the reaction was carried out in mixtures of
acetonitrile/water (10:1), acetonitrile/water containing sodium chloride (at χ = 0.07) and in
acetonitrile/ water containing [Bmim]Cl (at χ = 0.21). Using 17O-NMR spectroscopy, the reaction
progress was followed over a range of temperatures and the activation parameters (Table 2) were
calculated using the Eyring equation [34]. [Bmim]Cl, while often used simply as a precursor to other
ionic liquids, is also an ionic liquid itself and the mole fraction used here corresponds to ca. 50%
by weight.
It is important to note that the reaction does not have a single elementary step; a proton transfer
equilibrium exists prior to the rate determining step. As such, changing the temperature and the solvent
may affect the position of this equilibrium. The linearity of the Eyring plots obtained suggests
otherwise, in this case. Further, a systematic error is introduced in the observed entropies of activation.
No attempt to determine this error is made, as it is difficult to ascertain and the entropies of activation
can only be reported taking note of this deviation (for details, see Supplementary Information). Given
that it is the changes in these parameters, not their absolute values, that are of interest, this systematic
error does not affect the argument presented.
Scheme 3. Acid-catalysed hydrolysis of benzaldehyde dimethyl acetal 5.
OCH
3
+
CHO
H /H O
2
OCH
3
5
6
Table 2. Activation parameters for the reaction outlined in Scheme 3 in the solvent
systems specified. Uncertainties quoted are standard deviations.
Solvent
ΔH‡ (kJ mol-1) ΔS‡ (J K-1 mol-1)
136 ± 5
110 ± 3
71 ± 4
139 ± 17
44 ± 10
-84 ± 13
Acetonitrile/water (10:1)
Acetonitrile/water containing NaCl
Acetonitrile/water containing [Bmim]Cl

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Once again, the effect on the activation parameters of replacing sodium chloride with the ionic
liquid [Bmim]Cl is the same, leading to a reduction in both the enthalpy and entropy of activation
relative to the case when both were absent. This implies that the charge separation involved in the rate
determining step is favoured, presumably by the more 'ionic' environment, but that such stabilisation
requires significant ordering of the components of the solution about the transition state, resulting in a
decrease in the entropy of activation (it is worth highlighting that the effect on the activation
parameters are the reverse of that observed in Section 2.2; this is discussed elsewhere [35]). The
greater effect in the ionic liquid case can be attributed to the larger amount of [Bmim]Cl that can be
dissolved in the reaction mixture when compared to sodium chloride, though the effect remains the
same as the 'typical' salt.
2.3. A nitrile oxide cycloaddition
In addition to considering the effects of ionic liquids on the kinetic parameters of organic processes,
we have examined the effect of these solvents on the regioselectivity of nitrile oxide cycloadditions,
such as that shown in Scheme 4 [36]. These systems have been shown to be versatile synthetic
intermediates due to the high degree of functionality (for a detailed discussion, see [37]). However, for
our purposes it is the mixture of regioisomers produced, which is dependent on both steric and
electronic effects, which is of interest. We have shown that steric contributors to the regioselectivity
are more significant in ionic liquids.[36] Whether 'ordinary' salts have the same effect was examined
by considering the reaction between the nitrile oxide 7 and the cinnamate 8 in acetonitrile, acetonitrile
containing lithium bis(trifluoromethanesulfonyl)imide (at χ = ca. 0.32), acetonitrile containing
tetrabutylammonium tetrafluoroborate (at χ = ca. 0.32) and in [Bmim][N(CF3SO2)2] (at χ = ca. 0.9).
(The ionic liquid is representative of one of a series used; for the others see [36].) The ratio of the
isoxazoles 9a and 9b produced was determined using 1H-NMR spectroscopy (Table 3).
Scheme 4. Nitrile oxide cycloaddition of benzonitrile oxide 7 to ethyl trans-cinnamate 8 to
give the isoxazoles 9a and 9b.
O
N
N
N
O
O
C
CO Et
EtO C
2
2
EtO C
2
7
9b
9a
8
Table 3. Ratios of the isoxazoles 9a and 9b produced in the reaction outlined in Scheme 4
in the solvent systems specified and extents of conversion. Uncertainties quoted are
standard deviations.
Solvent
Acetonitrile
9a : 9b (% conversion)
(6.5 ± 0.4) : 1 (44%)[36]
(4.6 ± 0.3) : 1 (15%)
Acetonitrile containing Li[N(CF3SO2)2]
Acetonitrile containing [NBu4]BF4
[Bmim][N(CF3SO2)2]
(7.5 ± 0.4) : 1 (30%)
(15.2 ± 0.8) : 1 (84%)[36]

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As described previously [36], the effect of ionic liquids on nitrile oxide cycloadditions was to
change the ratio of the isoxazoles produced in favour of the less sterically hindered isomer. This is
seen in the above table with the ratio of the isoxazoles 9a:9b increasing on moving to the ionic liquid.
The addition of salts to this reaction is more complicated than for the substitution reactions described
above as a result of the oxygen atoms in the reagents. In the case of the lithium salt, a reversal of
regioselectivity was observed along with a decrease in the extent of reaction. This is consistent with
the reported effects of addition of lithium ions to nitrile oxide cycloaddition reactions in which both
the dipolarophile and the nitrile oxide can coordinate to the lithium; the resulting chelation favours the
isomer 9b [38]. When the lithium salt is replaced by a tetrabutylammonium salt (a range of salts, each
with a non-coordinating cation, was considered, however, many qualify as ionic liquids; this salt has a
relatively high melting point of 155-161°C [39]) a small but measurable increase in the proportion of
the less sterically hindered isomer 9a is observed with a comparable extent of conversion. That is,
once again the outcome of the reaction when ionic liquid is used might be considered an extension of
that observed when an 'ordinary' salt is added to the reaction mixture with the greater effect accounted
for by the larger mole fraction of ionic liquid present (the limitations of the potential effects of such
salts are demonstrated here by the fact that the saturated ammonium salt solution used is only χ = ca.
0.32 in the salt). Note that given the observed effect of ionic liquids was attributed to the internal
pressure of the ionic liquid system, it is perhaps not surprising that the addition of salts to molecular
solvents has been shown to increase the internal pressure of the mixture [36] (for a discussion on the
increased extent of conversion in the ionic liquid see previous work [36]).
2.4. Results present in the literature
As far as the authors are aware, there are no examples in the literature where the effect of a molten
and a solid salt on the same reaction are compared directly. While it might be of interest to examine a
range of 'unexplained' outcomes in terms of this novel argument, this is beyond the scope of this
article. Rather, it is worth considering one of the most studied processes in ionic liquids, that being the
Diels-Alder reaction [40], on which information on the effect of a molten and a solid salt have been
reported separately.
This reaction is a particularly appropriate case to study is that this reaction has seen much
investigation of the effect of dissolved salts on the outcome [41], with the use of 5 M lithium
perchlorate in diethyl ether (LPDE) being particularly studied. LPDE has been demonstrated to
dramatically increase the rate and stereoselectivity, with an increase in the endo:exo ratio being
observed [42]. This was used to great effect in the synthesis of cantharadin, with reaction in LPDE
being able to be completed under ambient conditions [42], whereas previous syntheses required
ultrahigh pressure to be applied to the reaction mixture [43]. From these observations, it has been
suggested that the effect of LPDE is to act as a medium with high internal pressure [44], with the
effects on the Diels-Alder process being consistent with its negative volume of activation [45-47].
While the Lewis acidity of the lithium cation cannot be overlooked and may catalyse the
cycloaddition, such acidity is moderated by the solvent [48]. The relative importance of each of these
contributing factors (internal pressure and Lewis acid catalysis) is the subject of some debate and is

Molecules 2009, 14
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likely to vary with the reaction considered, both factors contribute to the change in reaction outcomes
of Diels-Alder processes in LPDE [49].
When ionic liquids are used as solvents for Diels-Alder reactions, an increase in the rate and the
endo:exo selectivity is generally observed [50-54]. While, as described in the introduction, correlating
these with reaction outcomes remains problematic [20-24] the effect of the ionic liquid is qualitatively
the same as for the ‘ordinary salt’ system, LPDE. In addition, the hydrogen bonding ability of the
cation was shown to be an important parameter [22,24], which is consistent with the ionic liquid acting
as a Lewis acid. The influence of this on reaction outcomes has been shown to vary with the reagents
considered [24] and there are some systems where hydrogen bonding is not possible, and hence the
Lewis acidity of the ionic liquid greatly decreased, but the outcomes observed are similar (for
example, pyridinium [53]and phosphonium [54] based ionic liquids). The factors contributing to
reaction outcomes in LPDE suggest that the internal pressure of the medium, shown to be larger than
for molecular solvents [55], may also be significant in this case.
This simple case study demonstrates two key points. Firstly, it is a further case where the ionic
liquid can be considered to be acting in the same way as an ‘ordinary’ salt as the outcomes observed
are qualitatively similar. Secondly, it demonstrates a case where an understanding of the effect of the
addition of a simple salt can be used as a starting point to explain the effect of using an ionic
liquid solvent.
2.5. Comparison with molecular dynamics simulations
It is important to note that, in one respect, treating ionic liquids in terms of molten salts to explain
properties is not new. Both we [25,26,56] and many others [57] have used molecular dynamics (MD)
simulations to explain the physical properties of ionic liquids, along with interactions between the
ionic liquid and dissolved solutes, and the application of computational modeling to these problems is
increasing [58]. In MD simulations, components of the ionic liquid are described by the use of
forcefields, which contain parameters relating to the motion of bonded atoms (bending and torsions)
and to non-bonded interactions (electrostatic and dispersion interactions). Several excellent forcefields
exist with broad coverage for ionic liquids, for example those based on the OPLS/AMBER model [59-
63], and information from ab initio studies, and particularly those incorporating dispersion
interactions, is helping to further refine and improve the ionic liquid forcefield descriptions [64-69]. It
should be noted, however, that the bulk of properties and interactions reflect the electrostatic
contributions,[70] particularly for small cations, i.e. those with short to medium alkyl chains. Overall,
these simulations can accurately describe physical and solubility properties of ionic liquid solutions
and suggests that MD simulation is an appropriate way of considering such systems.
Perhaps surprisingly, given the excellent consistency with experimental data, there has been little
reported use of molecular dynamics simulations to account for the effects that ionic liquids have on
reaction outcomes. Partly this may be attributed to the difficulty of simulating reactive intermediates
using classical MD and the computational intensity required for modeling even small timespans and
molecular ensembles with ab initio MD methods. In terms of reactivity, simple electron transfer
processes have been examined using the former [71] and proton transfers with the latter [72]. We have
instead used atomistic classical MD simulations to demonstrate the increased ordering about a fixed

Molecules 2009, 14
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intermediate (and by implication, about the transition state leading to it) to describe a model system for
solvolysis reactions, outlined in Scheme 1 [32]. Of particular note are the significant interactions
between the IL cation and the incipient charge on the chlorine atom, reflecting the importance of the
electrostatic contributions.
The ability of such simulations to elegantly describe changes in reaction entropy and enthalpy on
the molecular level opens up a number of possibilities. Initially, a reaction whose outcome is known in
ionic liquids can be rationalised using molecular dynamics simulations, providing a microscopic
viewpoint that can go hand-in-hand with the macroscopic view of the effect of the ionic liquid as a
salt. Perhaps more excitingly, such an understanding (both at the microscopic and macroscopic levels)
might be gained prior to studying the reaction experimentally. That is, this methodology can be used
as a predictive tool and screening mechanism, catalysing rapid developments in the IL field.
3. Experimental Section
3.1. General
The starting materials 3, 5 and 8 were commercially available, whilst phenylchloroaldoxime was
prepared from commercially available starting materials using literature methods [73].
[Bmim][N(CF3SO2)2] was prepared from [Bmim]Cl, which was in turn prepared by literature methods
from commercially available starting materials, and both were dried to constant weight over
phosphorus pentoxide [7]. Water, where used, refers to deionised water. Pyridine was purified using a
literature method [74] . Other reagents were of analytical grade and were used as received.
3.2. Bimolecular substitution of benzyl bromide
Kinetic analyses of the Menschutkin reaction of the benzyl bromide 3 with pyridine were carried
out in solutions containing the bromide 3 (ca. 0.05 mol L-1) and pyridine (ca. 5-20 equiv.) in either
acetonitrile, acetonitrile (5.91 g, 0.144 mol) containing lithium bis(trifluoromethanesulfonyl)imide
(4.96 g, 17.3 mmol, 1.73 mol.L-1) or [Bmim][N(CF3SO2)2] at temperatures between 278 K and 312 K.
1
In each case the reaction was followed using H-NMR spectroscopy until more than 95% of the
starting material 3 was consumed. Spectra were taken at regular intervals during the reaction and at
least twenty spectra were obtained for each kinetic run. The extent of reaction was deduced through
integration of the signal corresponding to the benzyl protons in the starting material 3 (ca. δ 4.5) and
the products 4 (ca. δ 5.8). From this information, the pseudo-first order rate constants for the reaction
under these conditions was calculated and, consequently, from the concentration dependence of these
values, the second order rate constants at each temperature. The activation parameters were then
determined using the bimolecular Eyring equation [34].
3.3. Hydrolysis of benzaldehyde dimethyl acetal (5)
Benzaldehyde dimethyl acetal (5, 0.6 mL), water (0.3 mL) and pyridinium p-toluenesulfonate (1.5
mg) were added to acetonitrile (3 mL). The reaction mixture was monitored using 17O-NMR
spectroscopy, specifically the disappearance of the signal corresponding to compound 5 at δO 18, at
temperatures between 288 K and 308 K. From these, the first order rate constants at each temperature

Molecules 2009, 14
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were calculated and the activation parameters determined using the unimolecular Eyring equation [34].
17
The process was repeated for mixtures containing the acetal 5 (0.2 mL), O-enriched water (0.1 mL;
the conditions of the experiment necessitated using 0.02% 17O enriched water to ensure sufficient
signal strength given the time constraints of the experiment), pyridinium p-toluenesulfonate (0.5 mg),
[Bmim]Cl (0.45 g) and acetonitrile (0.5 mL) over the temperature range 288 K to 308 K. It was also
repeated for mixtures containing the acetal 5 (0.2 mL), 17O-enriched water (0.1 mL), pyridinium
p-toluenesulfonate (0.5 mg) and acetonitrile (1 mL) which had been saturated with sodium chloride
(ca. 45 mg, χ = 0.07) over the temperature range 308 K – 328 K. In each of these latter cases, the
reaction was followed by observing the appearance of the signal corresponding to the aldehyde 6
at δO 550.
3.4. A nitrile oxide cycloaddition
The reactions were carried out as described previously [36]. Briefly, the nitrile oxide 7 was
produced in situ from the corresponding chloroaldoxime [73], through the addition of triethylamine
(50 μL) to a solution of the chloroaldoxime (25 mg), the cinnamate 8 (52 mg) and either lithium
bis(trifluoromethanesulfonyl)imide (5.14 g) or tetrabutylammonium tetrafluoroborate (5.85 g) in
acetonitrile (2 mL) over 24 h. The regioisomeric ratio of the isoxazoles 9a and 9b produced and the
1
extent of reaction was determined using H-NMR spectroscopy, specifically the integrations of the
signals corresponding to the C-4 and C-5 protons of the products 9a and 9b and the alkene protons of
the residual starting material 8 [36]. The extent of conversion of the cinnamate 8 in these cases was ca.
15% in the case of the lithium salt addition, 30% in the case of the tetrabutylammonium salt addition.
4. Conclusions
The above results demonstrate that, for a range of reaction types, the effect of ionic liquids parallels
that of more 'typical' salts, though care must be taken to recognise that the components of ionic liquids
tend to be comparatively non-coordinating. This is not to suggest that ionic liquids can be replaced by
these salts. The benefits of ionic liquids, particularly the potential to replace volatile organic solvents
and to be highly soluble in such solvents when they are required, remain. However, in terms of
understanding the effects that ionic liquids have on reaction outcomes, this overview demonstrates that
the starting point for proper comprehension of IL interactions is their charged nature. It is clear that, in
these systems, electrostatic interactions are principal and have important application in predicting the
effect of changing reaction solvent from a molecular solvent to an ionic liquid.
Acknowledgements
HMY acknowledges the Australian government for financial support through an Australian
Postgraduate Award. JBH acknowledges the support of the Faculty of Science, University of New
South Wales, through the Faculty Research Grants Programme. AKC acknowledges the support of the
Royal Society in the form of a Travel Grant and Tris Youngs (Queen’s University, Belfast) for
valuable discussions.

Molecules 2009, 14
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Sample Availability: Samples of each of the substrates and the ionic liquids are available from the
authors.
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This article is an open-access article distributed under the terms and conditions of the Creative
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