Highly recyclable, imidazolium derived ionic liquids of low antimicrobial and antifungal toxicity: A new strategy for acid catalysis

Article abstract of DOI:10.1039/c003301d

Imidazolium derived ionic liquid catalysts have been developed which are aprotic and of low antimicrobial and antifungal toxicity, yet which can act as efficient Bronsted acidic catalysts in the presence of protic additives. The catalysts can be utilised at low loadings and can be recycled 15 times without any discernible loss of activity. The Royal Society of Chemistry 2010.

Full text of DOI:10.1039/c003301d

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Highly recyclable, imidazolium derived ionic liquids of low antimicrobial
and antifungal toxicity: A new strategy for acid catalysis†
a
b
c
b
a
ˇ
Lauren Myles, Rohitkumar Gore, Marcel Spula´k, Nicholas Gathergood* and Stephen J. Connon*
Received 17th February 2010, Accepted 12th April 2010
First published as an Advance Article on the web 18th May 2010
DOI: 10.1039/c003301d
Imidazolium derived ionic liquid catalysts have been de-
veloped which are aprotic and of low antimicrobial and
antifungal toxicity, yet which can act as efficient Brønsted
acidic catalysts in the presence of protic additives. The
catalysts can be utilised at low loadings and can be recycled
15 times without any discernible loss of activity.
Brønsted-acidic sulfonic acid functionality (1, Fig. 1). These
materials represented a successful (from both catalytic and
operational perspectives) marriage of the excellent solvent
properties and non-volatility of ILs with the convenience and
activity of traditional solid acids such as (for instance) p-TSA.
This seminal report spawned considerable interest in the design
of similarly devised Brønsted acidic based imidazolium-based
IL catalysts and catalytic solvents.10 Two other general strategies
have emerged for the design of organic imidazolium ion based
acidic ILs: the use of protonated imidazolium ion ILs (i.e. 2,
Fig. 1)11 and the installation of an acidic counteranion (3,
Fig. 1).12–14 While these materials can - when appropriately
designed - exhibit excellent catalytic activity and reduce some
of the risks (both practical and environmental) associated with
the use of more volatile liquid acids, they remain in effect
(particularly in the cases of 1 and 3) strong Brønsted acids and
their environmental impact and toxicity have not yet, to the best
of our knowledge, been unambiguously established.
Over the last decade Ionic Liquids (ILs) have been extensively
investigated as potential replacements for volatile organic com-
pounds for use as (inter alia) both tunable reaction media and
catalytic solvents.1 Much of this interest has been focussed on the
development of ionic liquids as alternative, ‘green’ materials with
applications as diverse as ionic compressors, the BASILTM pro-
cess and electroplating.1q Immense interest in the environmental
impact of ILs2 has led to a plethora of papers dealing with
a) their toxicity3 (for example antibacterial and antifungal),4
b) the importance of biodegradation studies5 (something only
recognised since 2002),6 and recently c) bioaccumulation and
metabolite identification studies.7
The design of a ‘green’ compound, whether the role is as
a solvent,1 reagent or catalyst8 should ideally address issues
such as low toxicity and ready biodegradability without the
generation of toxic, persistent metabolites. Of equal importance
is the functional performance of the environmentally benign
material. The decision to replace a ‘toxic’ chemical with a
‘green’ replacement is easier if a performance benefit is also
attained. The role of a green chemist is to make this decision as
easy as possible and avoid the ‘gray area’ where environmental
protection comes at a performance cost.
By utilising the toxicity and ecotoxicity data available for ionic
liquids, in particular imidazolium and pyridinium salts, and
the similarity in structure to analogous heterocyclic reagents
and catalysts we aim to design and prepare effective green
compounds.
In 2002, Forbes and Davis9 introduced imidazolium and
phosphonium ILs equipped with covalently bound strongly
Fig. 1 Imidazolium ion-based acidic ILs: current strategies.
Recently, the somewhat unexpected observation that appro-
priately substituted pyridinium ions were capable of acting
as Brønsted acid catalysts in the presence of protic additives
has been reported.15 It was postulated that the addition of
nucleophiles to these aprotic materials generated catalytically
active Brønsted acidic species in situ (i.e. 5–6, Fig. 2). Later
it was found that the catalytic efficiency of these compounds
was influenced not only by the electronic structure of the cation
but also by the counteranion employed.16 We reasoned that this
general strategy could also be applicable to the design of catalysts
based on imidazolium ions - with potential advantage - as:
a) these species would in all likelihood possess less resonance
stabilisation energy than the corresponding pyridinium ions,17
thus the addition of protic nucleophiles to the heterocyclic core
(leading to increased catalyst efficacy) would be predicted to be
facilitated,
aCentre for Synthesis and Chemical Biology, School of Chemistry,
University of Dublin, Trinity College, Dublin 2, Ireland. Email:
connons@tcd.ie; Fax: +35316712826
bSchool of Chemical Sciences and National Institute for Cellular
Biotechnology, Dublin City University, Glasnevin, Dublin 9, Ireland.
E-mail: Nick.Gathergood@dcu.ie; Fax: +35317005503
cCentre for New Antivirals and Antineoplastics, Department of Inorganic
and Organic Chemistry, Charles University, Faculty of Pharmacy,
Heyrovske´ho 1203, CZ-500 03, Hradec Kra´love´, Czech Republic
b) the presence of the twin nitrogen heteroatoms provides
one with considerably enhanced opportunities (through the
straightforward variation of the substituents at these positions)
to fine tune not only the melting point of the material but
† Electronic Supplementary Information (ESI) available: Synthesis of
all catalysts, general procedures and toxicity screening methods. See
DOI:10.1039/c003301d
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Table 1 Aprotic imidazolium ions: preliminary catalyst evaluation
Fig. 2 Proposed mode of action of catalytic aprotic pyridinium ions.
also its steric, electronic, toxicity and stability to acid catalysed
hydrolysis and biodegradability (vide supra) characteristics and,
c) as our understanding of the structural factors which influ-
ence the environmental impact of imidazolium and pyridinium-
based ILs deepens,4 it should be possible to combine the practical
advantages derived from the physical properties of acidic ILs (i.e.
1–3, Fig. 1) with both the additive-controlled acidity associated
with electrophilic pyridinium ions (Fig. 2) and the inclusion of
the relatively environmentally benign nature of ester or amide4,18
substituted imidazolium ions (vide supra) in a catalytically active
aprotic imidazolium ion-based IL specifically designed to be non-
toxic and (preferably) biodegradable, the acidity of which would be
controllable in an ‘on-off’ fashion using specific protic additives.
It would be our hope that such a compound could potentially
serve as a catalytic material/solvent when required, yet which
would be a safely storable, non-acidic, non-toxic material.
In order to test this hypothesis we synthesised a small,
targeted library of imidazolium-ion based ILs assembled to
allow the contributions of steric hindrance, the biodegradable
side chain and the counterion on catalyst performance.19 In
preliminary experiments we evaluated these catalysts in the
acetalisation of benzaldehyde in methanol (Table 1). In the
absence of catalyst no acetal is detected after 24 hours. We
were pleased to find that each of the imidazolium ions tested
(all of which are equipped with either ester (which we have
shown to greatly facilitate biodegradation),4 or pyrrolidinamide
substituents, (biodegradation studies of amide examples on-
going)) promoted the transformation under conditions under
which the pyridinium species (9) is inactive, which underlines
the inherent superiority of imidazolium over pyridinium ions as
catalysts in these reactions.
It is clear that neither the ester (10–14, entries 2–6) nor
the pyrrolidinamide (15–20, entries 7–12) substituent designed
to facilitate biodegradation influence catalytic activity to any
significant degree. The nature of the alkyl groups at either of
the imidazolium nitrogen atoms (i.e. methyl vs. benzyl) also
seems to be of marginal importance (entries 7–8 vs. 9–10).
This is consistent with a mode of action analogous to that
outlined in Fig. 2 where methanol attacks the catalyst at the
C-2 carbon. A key parameter influencing catalyst efficacy in
these systems proved to be the counteranion–tetrafluoroborate
salt 10 (entry 2) and NTf2 salts 13, 16, 18 and 20 (entries
5, 8, 10 and 12 respectively) are clearly superior to the other
materials evaluated in this study. This is both expected (as the
strength of the putative acid intermediate in these reactions
will be influenced by the counterion) and fortunate, as the
counterion plays a very significant role in determining the
melting point of imidazolium ions–in particular the NTf2 anion
is known to endow imidazolium ions with significantly lower
melting points than many other common counterions. The high
activity conferred by the tetrafluoroborate anion is consistent
Entry
Catalyst
Yield (%)a
1
2
3
4
5
6
7
8
9
9
0
10
11
12
13
14
15
16
17
18
19
20
85
11
33
51
12
13
23
9
10
11
12
29
11
27
a Average of two experiments determined by 1H NMR spectroscopy
using an internal standard.
with previous studies on the strength of added acids in IL
media,20,21 investigations into the effect of the counterion on
the acidity/catalytic activity of both sulfonic acid-substituted
pyridinium ions22 and protic imidazolium ions,10a in addition
to correlating with our own experience concerning the catalytic
activity of aprotic pyridinium ions in acetalisation reactions.15
With an active catalyst in hand we next wished to evaluate
its general utility in the acetalisation of other substrates.
Gratifyingly, it was found that 10 could promote the efficient,
room temperature protection of aromatic aldehydes of variable
steric and electronic characteristics at low catalyst loadings
of 5–10% (Table 2). Activated (irrespective of the substitution
pattern, i.e. acetals 21–23, entries 1–3), hindered (i.e. 24, entry
4) and electron rich deactivated (i.e. 25, entry 5) benzaldehydes
could all be transformed into their corresponding acetals with
good-excellent isolated product yields. Aldehydes incorporating
highly useful (from a synthetic standpoint) heterocyclic and a,b-
unsaturated moieties were also compatible with the methodol-
ogy (26 and 27 respectively, entries 6 and 7), while the saturated
aldehyde 28 underwent near quantitative acetalisation at just
1 mol% catalyst loading inside 1 min reaction time (entry 8).
As expected, the utility of this catalytic strategy is not
confined to methanolysis. The employment of dithiol and diol
nucleophiles 29–31 in only slight excess resulted in the formation
of the synthetically useful dithiolane (a product usually formed
under elevated temperatures), dithiane and dioxane derivatives
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Table 2 Catalytic acetalisation of aldehydes: evaluation of substrate
scope
Table 3 Catalysed dithiolane, dithiane and dioxane syntheses
Entry
1
Nucleophile
Product
Yield (%)a
Entry Product
1
Loading (mol%) Time/h Yield (%)a
92
5
5
5
24
24
24
96
93
95
2
3
65
2
3
86
4
5
10
10
24
24
87
87
a Isolated yield after chromatography.
6
7
10
10
24
24
89
83
Fig. 3 Proposed mode of action of catalytic aprotic imidazolium ions.
In vitro antifungal activities (Table 5) of 10, 11 and 15 were
evaluated on a panel of four ATCC strains (Candida albicans
ATCC 44859, Candida albicans ATCC 90028, Candida parapsilo-
sis ATCC 22019, Candida krusei ATCC 6258) and eight clinical
isolates of yeasts (Candida krusei E28, Candida tropicalis 156,
Candida glabrata 20/I, Candida lusitaniae 2446/I, Trichosporon
beigelii 1188) and filamentous fungi (Aspergillus fumigatus 231,
Absidia corymbifera 272, Trichophyton mentagrophytes 445). An-
tifungal activity was not observed for either 10, 11 and 15 at the
highest concentration screened (2.0 mM). Antimicrobial activity
of imidazolium and pyridinium ionic liquids has been reported
previously, with increasing toxicity observed across a series of
alkyl (C6-C14) substituted methylimidazolium chlorides.4, 24
In vitro antibacterial activities (Table 5) of the compounds
were evaluated on a panel of three ATCC strains (Staphylococcus
aureus ATCC 6538, Escherichia coli ATCC 8739, Pseudomonas
aeruginosa ATCC 9027) and five clinical isolates (Staphylo-
coccus aureus MRSA HK5996/08, Staphylococcus epidermidis
HK6966/08, Enterococcus sp. HK14365/08, Klebsiella pneumo-
niae HK11750/08, Klebsiella pneumoniae ESBL HK14368/08).
Antimicrobial activity was not observed for 10, 11 and 15 at the
highest concentration screened (2.0 mM).
8
1
1 min
97b
a Isolated yield after chromatography. b Determined by H NMR spec-
troscopy using an internal standard due to product decomposition on
chromatography.
1
32–34 in good-excellent yields at room temperature (Table 3,
entries 1–3).
An analysis of the data in Tables 1-3 leads us to propose
that these catalysts operate via an analogous mechanism to that
suggested in Fig. 2. The protic additive (e.g. MeOH) adds to
the C-2 position of the imidazolium ion to generate the acidic
species 35 and 36 in situ (Fig. 3).23
Preliminary screening of the toxicity of 3 ionic liquids was
performed to establish the influence of the ester or amide group
and counter-ion. 10, 11 and 15 were selected as a sample set
based on structure and catalytic activity. A broad spectrum of
organisms was chosen with results relevant to environmental
and medicinal applications of interest.
Gilmore et al.4c recently tested 1-hexyl-3-methylimidazolium
chloride for antimicrobial activity against a number of
pathogens (cocci, rods and fungi) with MIC values of >1.644
mM observed. The data from the screening of 10, 11 and 15 in
Tables 4 and 5 are comparable to Gilmore’s results, although it
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Table 4 Antifungal activity of 10, 11, 15 (MIC [mmol L-1])
Table 6 Catalyst recycling
Organisms
Time/h
10
11
15
Candida albicans
ATCC 44859
Candida albicans
ATCC 90028
Candida parapsilosis
ATCC 22019
Candida krusei
ATCC 6258
Candida krusei
E28
Candida tropicalis
156
Candida glabrata
20/I
Candida lusitaniae
2446/I
Trichosporon beigelii
1188
Aspergillus fumigatus
231
Absidia corymbifera
72
24
48
24
48
24
48
24
48
24
48
24
48
24
48
24
48
24
48
24
48
24
48
72
120
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
Entry
Cycle
Yield (%)a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
92
90
89
91
90
90
91
90
90
90
89
90
90
91
90
a Determined by 1H NMR spectroscopy using an internal standard.
Trichophyton mentagrophytes
445
Table 5 Antibacterial activity of 10, 11, 15 (MIC [mmol L-1])
conditions than those required for the uncatalysed process
is particularly attractive from a ‘green’ perspective, however,
a second, often overlooked advantage is that by definition,
catalysts should be unchanged at the end of the reaction and
thus should in principle be recyclable (if they are sufficiently
robust) indefinitely. To evaluate the recyclability of 10 we carried
out the protection of benzaldehyde as its 1,3-dithiolane 32
catalysed by 10 (Table 6). After 24 h, hexane was added to
precipitate the catalyst and the solution containing the product
was decanted and dried in vacuo to give 32 in excellent yield.
The solid catalyst was dried in vacuo to remove the condensation
water25 and reused in 14 subsequent iterative cycles without any
loss of catalytic activity being observed. It is noteworthy that
the recycling study was terminated at this stage only because no
attenuation of catalyst activity was detected in the 15th cycle. It is
significant that catalyst 10 incorporating the methyl ester group,
susceptible to acid catalysed hydrolysis, gave efficient recycling
and performance. To the best of our knowledge this represents
the most recyclable Brønsted acidic IL catalyst reported to date.
Organisms
Time/h
10
11
15
S. aureus
CCM 4516/08
S. aureus
H 5996/08
S. epidermidis
H 6966/08
Enterococcus sp.
J 14365/08
E. coli
CCM4517
Klebsiella pneumoniae
D 11750/08
Klebsiella pneumoniae
J 14368/08
Pseudomonas aeruginosa
CCM 1961
24
48
24
48
24
48
24
48
24
48
24
48
24
48
24
48
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
>2.0
is noted that different strains of organisms are investigated in
the two studies.
By avoiding the introduction of long lipophilic alkyl chains
into the ionic liquids structure we postulate that undesirable
antimicrobial and antifungal toxicity has been limited. Our data
is limited to ionic liquids 10, 11 and 15 at present - further
toxicity-screening studies are on-going.
Significant is the effect of the anion on antimicrobial and an-
tifungal toxicity. Changing the bromide 11 to the BF4 analogue
10 did not increase the toxicity of the ionic liquid with MIC
values >2.0 mmol L-1 observed. While more lipophilic NTf2
derivatives may have increased antimicrobial and antifungal
toxicity,2,3 examples 13, 16, 18 and 20 gave inferior results in
the preliminary catalyst screening (Table 1). Notwithstanding,
the toxicity of the NTf2 examples herein will be published in due
course.
Conclusions
In conclusion we have designed the first small library of aprotic
ionic liquid catalysts with low antibacterial and antifungal toxic-
ity -specifically designed to beofreduced environmental impact -
which can behave as Brønsted acids in a controlled fashion.
This allows these materials to act as acidic catalysts under
controlled conditions, without requiring the precautions usually
associated with the storage and use of strongly acidic substances.
The systematic variation of the catalyst’s steric and electronic
characteristics (within the framework of using substituents
designed to render these materials more environmentally benign
than archetypal long alkyl chain substituted imidazolium ILs)
revealed that the counterion makes a key contribution to
overall catalyst efficacy. The most active catalyst developed
Finally, the ability of catalysts to accelerate reactions and
generally render them more efficient/selective under milder
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promotes acetalisation and thioacetalisation reactions of a range
of aldehydes at room temperature and low catalyst loadings,
and after the reaction the catalyst can be recovered by simply
adding hexane and decanting the product. The recycled catalyst
can be reused in 15 iterative recycles without any discernible
loss of catalytic activity. Antifungal and antibacterial toxicity
studies demonstrated that the three ionic liquids did not inhibit
the growth of any organism screened at concentrations of >2.0
mM. The inclusion of either an ester or an amide group (as
opposed to an alkyl chain) did not lead to an increase in
toxicity. We were pleased to find that changing the bromide
to the tetrafluoroborate anion also did not lead to significant
increase in toxicity. The most active catalyst (i.e. 10) was also
non-toxic, within the scope of the screening performed. Further
toxicity, ecotoxicity and biodegradation studies are in progress,
to establish the environmental fate of the ionic liquid catalysts
presented herein, and lead to a more informed decision of
performance vs. environmental impact.
5 (a) D. Coleman and N. Gathergood, Chem. Soc. Rev., 2010, 39,
600; (b) S. Morrissey, B. Pegot, D. Coleman, M. T. Garcia, D.
Ferguson, B. Quilty and N. Gathergood, Green Chem., 2009, 11,
475.
6 (a) N. Gathergood and P. J. Scammells, Aust. J. Chem., 2002, 55, 557;
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Green Chem., 2005, 7, 9; (d) N. Gathergood, P. J. Scammells and M.
T Garcia, Green Chem., 2006, 8, 156.
7 Selected examples (a) S. Stolte, S. Abdulkarim, J. Arning, A.
Blomeyer-Nienstedt, U. Bottin-Weber, M. Matzke, J. Ranke, B.
Jastorff and J. Thoeming, Green Chem., 2008, 10, 214; (b) T. P. Pham,
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8 H. Xie, T. Hayes and N. Gathergood, Catalysis of Reactions by Amino
Acids, Amino Acids, Peptides and Proteins in Organic Chemistry:
Andrew B. Hughes (Ed.), Volume 1 - Origins and Synthesis of
Amino Acids, Wiley-VCH Weinheim, Germany, 2009. ISBN: 978-
3-527-32096-7.
9 A. C. Cole, J. L. Jensen, I. Ntai, K. L. T. Tran, K. J. Weaver, D. C.
Forbes and J. H. Davis, J. Am. Chem. Soc., 2002, 124, 5962.
10 For representative recent examples of strategy A see: (a) D. C. Forbes
and K. J. Weaver, J. Mol. Catal. A: Chem., 2004, 214, 129; (b) H.
Xing, T. Wang, Z. Zhou and Y. Dai, Ind. Eng. Chem. Res., 2005, 44,
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Mol. Catal. A: Chem., 2005, 225, 27; (d) D. Liu, J. Gui, X. Zhu, L.
Song and Z. Sun, Synth. Commun., 2007, 37, 759; (e) A. Hubbard,
T. Okazaki and K. K. Laali, Aust. J. Chem., 2007, 60, 923; (f) D. -Q.
Xu, J. Wu, S. -P. Luo, J. -X. Zhang, J. -Y. Wu, X. -H. Du and Z. -Y.
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Xia, Synthesis, 2009, 1969; (h) J. Akbari and A. Heydari, Tetrahedron
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Liu, Z.Z. Li, C. G. Xia and J. J. Peng, Catal. Commun., 2009, 10,
732.
11 For representative recent examples of strategy B see: (a) H. -P. Zhu,
F. Yang, J. Tang and M. -Y. He, Green Chem., 2003, 5, 38; (b) G.
Zhao, T. Jiang, H. Gao, H. B. Han, J. Juang and D. Sun, Green
Chem., 2004, 6, 75; (c) H. -H. Wu, F. Yang, P. Cui, J. Tang and M. -Y.
He, Tetrahedron Lett., 2004, 45, 4963; (d) Y. Du and F. Tian, Synth.
Commun., 2005, 35, 2703; (e) N. B. Darvatkar, A. R. Deorukhkar,
S. V. Bhilare and M. M. Salunkhe, Synth. Commun., 2006, 36, 3043;
(f) A. R. Hajipour, L. Khazdooz and A. E. Ruoho, Catal. Commun.,
2008, 9, 89.
12 For representative recent examples of strategy C see: (a) A. Arfan
and J. P. Bazureau, Org. Process Res. Dev., 2005, 9, 743; (b) Z. Duan,
Y. Gu and Y. Deng, Synth. Commun., 2005, 35, 1939; (c) D. -Q. Xu,
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Org. Chem., 2007, 1007; (d) Z. Duan, Y. Gu and Y. Deng, Synth.
Commun., 2005, 35, 1939.
13 For an example of a catalyst which embodies both strategies A and
C see: Y. Wang, D. Jiang and L. Dai, Catal. Commun., 2008, 9,
2475.
14 For an example of the use of an ionic liquid with a basic anion
in catalysis see: B. C. Ranu and S. Banerjee, Org. Lett., 2005, 7,
3049.
15 B. Procuranti and S. J. Connon, Org. Lett., 2008, 10, 4935.
16 B. Procuranti, L. Myles, N. Gathergood and S. J. Connon, Synthesis,
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17 This assumption is based on the considerably lower resonance
stabilisation energy of imidazole relative to pyridine, see: (a) M. J.
S. Dewar, A. J. Harget and N. Trinajstic´, J. Am. Chem. Soc., 1969,
91, 6321; (b) R. J. Sundberg and R. B. Martin, Chem. Rev., 1974, 74,
471.
18 (a) P. H. Howard, R. S. Boethling, W. Stiteler, W. Meylan and J.
Beauman, Sci. Total Environ., 1991, 635, 109; (b) R. S. Boethling,
Cationic Surfactants, in Surfactant Science Series, Marcel Dekker,
New York, 1994, vol. 53, pp. 95–135.
We are grateful to the Environmental Protection Agency for
their financial support of this work (Project 2008-ET-MS-6).
The antifungal and antibacterial screening was supported by
the Czech Ministry of Education (Project No. 1M0508).
Notes and references
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This journal is
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Green Chem., 2010, 12, 1157–1162 | 1161
©

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<1%).
be
formed
at
low
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1162 | Green Chem., 2010, 12, 1157–1162
This journal is
The Royal Society of Chemistry 2010
©