An integrated high-throughput strategy enables the discovery of multifunctional ionic liquids for sustainable chemical processes

Article abstract of DOI:10.1039/c8gc03119c

Development of new chemical processes with simplified reaction systems and work-up procedures is a challenging task. Although ionic liquids are a class of potential multifunctional compounds to simplify traditional chemical processes, their rational design is difficult due to complex interactions. In this work, a proof-of-concept strategy has been proposed to achieve an integration of high-throughput preparation of ionic liquids and in situ screening of their reaction-promoting performance in 96-well plates. The integrated approach then enables a facile identification of optimal ionic liquids from a 400-ionic liquid candidate pool to act as the solvent, the catalyst and the separating assistant, simultaneously, for carbonyl-azide cycloaddition reactions. Merits of the ionic liquids-based processes have been demonstrated not only in the convenient and efficient synthesis of 1,2,3-triazolyl compounds but also in the discovery of a new reaction for the chemical post-modification of free peptides.

Full text of DOI:10.1039/c8gc03119c

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An integrated high-throughput strategy enables
the discovery of multifunctional ionic liquids for
sustainable chemical processes†
Cite this: DOI: 10.1039/c8gc03119c
Anlian Zhu,a Lingjun Li, *a Chi Zhang,a Yutan Shen,a Mingjie Tang,a Lili Bai,a
Chunyan Du,a Suojiang Zhang b and Jianji Wang*a
Development of new chemical processes with simplified reaction systems and work-up procedures is a
challenging task. Although ionic liquids are a class of potential multifunctional compounds to simplify tra-
ditional chemical processes, their rational design is difficult due to complex interactions. In this work, a
proof-of-concept strategy has been proposed to achieve an integration of high-throughput preparation
of ionic liquids and in situ screening of their reaction-promoting performance in 96-well plates. The inte-
grated approach then enables a facile identification of optimal ionic liquids from a 400-ionic liquid candi-
date pool to act as the solvent, the catalyst and the separating assistant, simultaneously, for carbonyl-
azide cycloaddition reactions. Merits of the ionic liquids-based processes have been demonstrated not
only in the convenient and efficient synthesis of 1,2,3-triazolyl compounds but also in the discovery of a
new reaction for the chemical post-modification of free peptides.
Received 6th October 2018,
Accepted 30th November 2018
DOI: 10.1039/c8gc03119c
rsc.li/greenchem
as clean solvents,4 organocatalysts,5 catalyst ligands6 and sep-
aration assistants.7,8 Intriguingly, the easy combination of
Introduction
Typical chemical reactions usually require the use of solvents, cations and anions leads to a number of ionic liquids up to
catalysts and additives, such as acids, bases, catalyst ligands 1018.9 This huge number and their functional diversity make it
etc. The synergetic effect of these components are crucial for possible to discover multifunctional ionic liquids that can
efficient chemical transformations. However, time and labor replace traditional solvents, catalysts, additives and even separ-
consuming procedures have to be used to optimize different ating materials, simultaneously. In this way, new, simple and
reaction variables and to search for the optimal separation efficient chemical processes can be developed only through
strategy for target compounds. At the same time, the chemical the elaborate combination of the cation and the anion.
reaction, product separation and catalyst recovery are often However, there exist abundant interactions in ILs, such as
considered as separate unit operations, which significantly electrostatic, hydrogen bond, van der Waals, π–π stacking and
add to the economic cost and the environmental impact of the hydrophobic–hydrophilic interactions.9 These complex inter-
process. Therefore, development of new chemical processes actions imply that it is very difficult to anticipate the relation-
with simplified reaction systems and work-up procedures has ship between the structure and properties of ionic liquids,
been a long-term challenging task in academic researches and thus, the rational design of multifunctional ILs for a specific
industrial applications.1–3
chemical process is a great challenge.
Ionic liquids (ILs) are composed of cations and anions and
High-throughput strategies have been recently used as an
have been successfully applied in various chemical processes efficient tool to optimize the reaction conditions of known
reactions and even to discover new chemical reactions.10–15
The advances in the simplification of screening methods11
aCollaborative Innovation Center of Henan Province for Green Manufacturing of
and the miniaturization of screening substrates12 greatly
Fine Chemicals, Key Laboratory of Green Chemical Media and Reactions, Ministry of
promote their practical applications in ordinary chemical
Education, Henan Key Laboratory of Organic Functional Molecule and
laboratories. These strategies may offer a novel pathway to
manipulate the multifunctional effects of ILs in the utilization
of new chemical processes if the screening method is correct.
In this work, we designed a fluorescence enhancing probe
reaction for the high-throughput screening of ILs. With the
assistance of this new screening method, it is possible to
Drug Innovation, School of Chemistry and Chemical Engineering Henan Normal
University, Xinxiang, Henan 453007, P. R. China. E-mail: lingjunlee@htu.cn,
jwang@htu.cn
bChinese Acad Sci, Inst Proc Engn, CAS Key Lab Green Proc & Engn, Beijing Key Lab
Ion Liquids Clean Proc, Beijing 100190, P. R. China
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c8gc03119c
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visualize the promoting performance of ILs for the reaction, were shaken in a water bath for 48 h. The solvents were evapor-
identify the optimal ionic liquid candidates from a readily ated under reduced pressure after the completion of the reac-
accessible plate reader and realize the integration of all high- tions. Considering the possible volatilization of acids and
throughput experiments on a 96-well plate.
bases used for the building of the ILs pool, the samples were
dried under reduced pressure at 50 °C for 12 h for ILs with
non-volatile components or at 25 °C for 24 h for ILs with vola-
tile components (Table S1 in the ESI†). The 1 : 1 stoichiometry
of cations to anions in dried ILs was checked from 1H NMR
Results and discussion
One-plate integration of high-throughput preparation and
1
(the copies of H NMR spectra are given in pages 36–90 in the
ESI†). In addition, the water contents in ILs after drying were
screening of ILs
The intrinsic combinational properties of ILs imply the feasi- measured to be less than 0.5% (Table S5 in the ESI†). This
bility of generating m × n ILs by mixing a set of n cation pre- level of water content did not affect the discovery of catalysts
cursors and
a set of m anion precursors (Fig. 1A). for carbonyl-azide cycloaddition reactions by high throughput
Neutralization reaction of amines and acids is a desirable screening (Scheme S2 in the ESI†).
means for the parallel synthesis of protic ILs.16 Aprotic ILs,
At present, although several multi-channel methods have
like choline-based liquid salts, can also be synthesized directly been reported for the determination of chemical and physical
from the equivalent mixing of choline hydroxide and acids. properties of ILs,16–19 high-throughput screening for the reac-
According to the parallel orthotropic rules, 400 ILs have been tion-promoting performance of ILs is inherently difficult since
prepared rapidly from 20 bases and 20 acids (Fig. 1B) posses- its assessment requires the unambiguous detection of target
sing variant geometric shapes, acidities, sizes, and electronic products from a mixture of reactants, products and ILs. Mass
and steric effects. In a typical procedure, equal stoichiometric spectrometry is usually used as a powerful tool for high-
amounts of acids and bases were added orderly into 400 mL × throughput screening of catalysts; however, the existence of
1.5 mL Eppendorf tubes containing methanol as the solvent in lots of cations and anions in ILs interferes with the ionization
ice bath; then, the 96-well plates bearing reaction mixtures of products. Therefore, at this stage, development of a practical
Fig. 1 (A) Combinational preparation of the ILs library in 96-well plates. (B) The anions and cations used in the building of the ILs pool. (C)
Fluorescence-enhancing probe reaction used in the present work. (D) Fluorescence intensities of compounds 2a and 3a under fluorescence exci-
tation (Ex = 340 nm). (E) Conversion extents expressed by fluorescence yields (calculated from the standard curve) and isolated yields.
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high-throughput detection strategy is vital for the successful current catalysts to organic bases and/or alkoxides. In
application of high-throughput tools in the screening of reac- addition, the harsh basic condition and the high reaction
tion-promoting performance of multifunctional ILs. temperature make the carbonyl-azide [3 + 2] cycloaddition less
Fluorescence-enhancing probes have the advantages of quanti- competitive in applications compared to other click reac-
tative and in situ detection of targets from complex surround- tions.29,30 Thus, we desired to find mild and effective ILs to
ing environments,20 which suggest that the possibility of direct promote a metal-free carbonyl-azide click reaction and demon-
detection of products in ILs involved systems by fluorescence- strate the use of our integrated high-throughput method to
enhancing probe reactions. Following this clue, 5-N3-1,8- accelerate this discovery process.
naphthalimide 2a was found to have weak fluorescence by
The experiments were performed by the following pro-
itself, but its potential cycloaddition product, 5-triazolyl-1,8- cedures. The probe reactants (400 nmol 2a in 400 μL of diace-
naphthalimide exhibited strong fluorescence due to the tone) were directly loaded into each of the 400 Eppendorf
chromophore effect of 1,2,3-triazole moieties in this kind of tubes containing freshly prepared ILs (20 μmol), and the reac-
compounds. By using 1,8-diazabicyclo[5.4.0]undec-7-ene tion was then incubated in a shaking bath for 2 h at 50 °C.
(DBU) as the catalyst, we found for the first time that the The resultant reaction mixtures were in situ detected by a plate
donor of organic azide 2a could react with diacetone 1a to reader, and all the data for 400 samples could be collected
produce 3a, and the fluorescence intensity of 3a was about 300 within 1.5 h. False positive results due to the existence of poss-
times higher than that of 2a at its maximum excitation wave- ible insoluble ILs and the reflection of UV light by them were
length (Fig. 1C & D). This finding means that it is appropriate removed by repeating the reactions. All the samples were
to use the reaction between 1a and 2a as a probe for the in situ tested and recorded in triplicate, and the result was an average
detection of their [3 + 2] cycloaddition products only through of three determinations (Fig. 2A and Fig.S4–S23 in the ESI†).
the measurements of fluorescence intensity, without the need Distribution analysis of the acquired data is given in Fig. 2B. It
of any isolation and purification procedures.
was found that there were 55 kinds of ILs that could promote
Before the utilization of high throughput strategy, we evalu- the reaction with the yields over 50%, which covered 5 cations
ated the accuracy of the probe reaction by a panel of basic ILs and 15 anions. Interestingly, cations paired with different
bearing guanidinium cations (IL1–IL10 in Table S1 in ESI†). anions gave the optimal ILs for metal-free click reaction
Guanidinium ILs were chosen here because they exhibited between 1a and 2a. For example, IL A1–B16 with the combi-
some catalytic performance in enamine/enolate mediated reac- nation of guanidinium and 2-methylpentanoate could give the
tions.21 In the blank control, a mixture of diacetone 1a and product with an 87% yield, IL A13–B2 consisting of 1,8-diaza-
compound 2a without an IL was incubated at 50 °C for bicyclo[5.4.0]-7-undecenium and the acetate anion afforded a
2 hours. No fluorescence enhancement was detected, which 95% yield, while IL A6–B6 composed of cholinium and 2,2,2-
was in agreement with the result (no produce of 3a) indicated trichloroacetate gave a 91% yield. These results indicate that
by TLC. Then, ten ILs were used to test the model. Towards the effect of an IL on a given reaction came from the synergis-
this end, 10 mg of azide 2a, 1.0 equivalent of diacetone 1a and tic actions of cations and anions as a whole, but not from the
0.5 mL of an ionic liquid were mixed and incubated at 50 °C simple sum of the effects of the separated cation and anion.
for 2 h. Subsequently, the diluted samples of reaction mixtures The huge number of ILs in this strategy was therefore prefer-
were analyzed by a plate reader. The products in reaction mix- able because this could avoid missing some useful combi-
tures could also be isolated and purified by a silica gel column nations owing to subjective bias. Indeed, in the three optimal
(Table S1 in ESI†). As shown in Fig. 1E, most of the conversion ILs, B16 and B6 anions were not frequently used in the existing
extents in this assay showed a high correlation to those from task-specific ILs. In this context, the high-throughput method
fluorescence yields, with an error in the range of 7% (Fig. S2 for the discovery of multifunctional ILs would be greatly valu-
in the ESI†).
able in the cases where the reaction mechanisms are not clear,
and the relationship between the structure and activity of ILs
is hardly predicted in advance.
Facile discovery of ILs to promote carbonyl-azide [3 + 2]
cycloaddition reactions
After the optimal ILs were obtained for the effective pro-
The one-plate integrated high throughput strategy was next motion of probe reaction, we turned our attention to study the
applied in the discovery of multifunctional catalytic ILs from generality of ILs for a wider scope of substrates (Fig. 3). Taking
400-IL candidates to promote the reactions between azides and 1-aryl-4-carbonyl-1,2,3-triazole scaffold as an example, we
carbonyls. The [3 + 2] cycloaddition reaction of azides with car- exhibited a series of merits of ILs-promoted chemical pro-
bonyls is known to be effective for the synthesis of 1,2,3-tri- cesses in Fig. 4. 1-Aryl-4-carbonyl-1,2,3-triazole moieties high-
azoles under metal-free conditions. Since the pioneering work lighted in Fig. 4A represent a useful scaffold with a wide scope
in 1980s, a number of organic and/or inorganic bases, such as of biological activities.31,32 Using IL A6–B6 as an all-in-one
triethylamine,22 NaOEt,23 K2CO3,24 Et2NH,25 1-butyl-3-methyl- catalyst, structurally diverse modifications on three parts of
imidazolium hydroxide ([Bmim]OH)26 and DBU27,28 have been the scaffold, including aryl, carbonyl and triazolyl moieties
actively investigated in the last 30 years. However, all the cata- could be accomplished smoothly from readily accessible start-
lytic systems for carbonyl-azide cycloaddition reactions were ing materials. Much higher reaction efficiencies were achieved
found via trial-and-error experiments, which limited the in the syntheses of 4-carbonyl-1,2,3-triazoles from azides-
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Fig. 2 (A) The identified ILs for the efficient promotion of [3 + 2] cycloaddition reactions between azides and carbonyls. (B) Analysis of the distri-
bution of cations and anions for the fluorescence-enhancing reaction with yields >50%. (C) Three optimal ILs for the efficient promotion of carbo-
nyl-azide [3 + 2] cycloaddition reactions.
yields of target triazoles could be obtained in the A6–B6
system within 3 hours, while less than 32% yields were given
in the ethylenediamine/DMSO system within the same reac-
tion time. More intriguingly, the products of the ILs-promoted
chemical processes could be separated automatically from the
IL phase after the reaction. Through the extraction of cloudy
reaction mixtures with ethyl acetate, clear ILs could be recov-
ered (Fig. 4C). After the simple separation process, the recov-
ered ILs were ready to be reused for the next run. All the recov-
ered ILs, including A6–B6, A6–B10 and A13–B2 could be
reused at least five times without additional activation
(Fig. S24 in the ESI†). No decrease in catalytic efficiency was
found during repeated cycles, and the IR spectra of the recov-
ered ILs also indicated no significant differences from the
fresh ILs (Fig. S25 in the ESI†). Therefore, this homogeneous
reaction followed by the heterogeneous separation process had
significant superiority in efficiency and energetic economy.
On the basis of our experimental results and previous
reports in literature,5,25 a possible reaction mechanism is pro-
posed in Scheme 1. First, the IL would activate the alpha-H
and the carbonyl of the acetoacetic ester through the for-
Fig. 3 (A) Azides used as the reactant in this work. (B) Dicarbonyls used
as the reactant in this work.
mation of H-bonds (intermediate 4), which can simultaneously
increase the nucleophilicity of the alpha-carbon and the elec-
bearing MeO– groups (3i, 3j, 3k in Fig. 4). We compared A6–B6 trophilicity of the carbonyl-carbon. The activated alpha-carbon
and ethylenediamine/DMSO systems25 in three reactions of then attacks the gamma-nitrogen of azide, while the alpha-
o-MeO-aryl, m-MeO-aryl and p-MeO-aryl with acetoacetic ester nitrogen of azide attacks the carbonyl-carbon to complete a
to prepare compounds 3i, 3j and 3k (Fig. 4B). More than 93% dipolar cycloaddition for the formation of intermediate 6.
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Fig. 4 (A) 1-Aryl-4-carbonyl-1,2,3-triazole parent core in bioactive molecules. (B) Structurally diverse 1-aryl-4-carbonyl-1,2,3-triazole compounds
prepared by the ILs-promoted click reaction. (C) Simple recovery and the reuse of ILs and the purification of products.
desirable for the direct modification of biomolecules.30 In this
regard, we determined the pH values of the aqueous solutions
of the optimal ILs (1 M) obtained by the high throughput
screening. The ILs, A6–B6, A6–B10 and A13–B2 (Fig. 2B)
showed the pH values of 7.2, 7.3 and 7.8 in aqueous solutions,
respectively. In addition, the unique solvent structures of ILs
may stabilize the biomacromolecules.35 We were thus inspired
to apply our all-in-one ILs for the chemical post-modification
of free peptides. From the screening, the peptide-I was found
to effectively react with the β-carbonyl amide of the IL A13–B2
at 50 °C, producing modified peptide-II in a 76% yield
(Scheme 2). Furthermore, this IL-promoted metal-free click
Scheme 1 Plausible reaction mechanism (BH+ is the cation of ILs).
Furthermore, another activation by the formation of H-bonds
between the cations and the hydroxyl of intermediate 6 can
promote the subsequent dehydration reaction. Finally, the
1,2,3-triazole product is given. The existence of H-bond acti-
vation of the ILs on the dicarbonyls was suggested by the ana-
lysis of 1H NMR spectra of the mixture of ILs (A13–B2 and
A1–B16) and the acetoacetic ester, where the unambiguous
broad peaks for the alpha-carbon of dicarbonyl could be
observed (Fig. S26 in the ESI†).
Application in the chemical modification of free peptides
Chemical modification of free peptides is of great importance
in the synthesis of antibody drugs and bio-materials.33,34
However, it is usually difficult to modify free peptides due to
their structural complexity, unique solubility and binding
ability to some metal ions. Thus, high selectivity, insensitivity
to water and mild reaction conditions are required for candi-
date reactions. It is known that the reactions that can proceed
smoothly under neutral or closed to neutral conditions
Scheme 2 Application of ILs-promoted chemical processes in the
without the addition of metal catalysts and ligands are highly modification of free peptides.
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reaction demonstrated good tolerance to water and air. In the
system of IL–water (5 : 1 mol mol−1), the cycloaddition of
peptide-I and the β-carbonyl amide kept the same level of iso-
lated yield (75%) after 24 hours. However, a higher content of
water (e.g. IL–water (1 : 1 mol mol−1)) would result in a dra-
matic decrease of the reaction yield. The discovery that IL A13–
B2 could promote the cycloaddition of free peptides might be
intriguing to develop new bioconjugation reactions on
complex biomolecules.
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Conclusion
In this work, we report an integrated high-throughput strategy
to discover multifunctional ILs toward the development of
new, simple and effective chemical processes. By using this
integrated high-throughput strategy, a facile discovery of multi-
functional catalytic ILs for cycloaddition reactions between
dicarbonyls and azides (a kind of metal-free click reaction)
could be achieved directly from a 400-IL pool containing
simple and inexpensive cations and anions. Then, the ionic
liquids-based processes have been demonstrated not only in the
more convenient and efficient synthesis of small molecular 1,2,3-
triazolyl compounds but also in the discovery of a new method
for the post-modification of free peptides. In all these processes,
ILs played the roles of the solvent, the catalyst and the additives;
thus, these systems are particularly simple, and only the reactants
and an IL are required for each system without any other chemi-
cals. The pool of potential ILs is huge and contains plenty of
structurally and functionally diverse candidates. Therefore, probe
reactions can be designed based on different chemical trans-
formations, and the equipment involved in this strategy are com-
monly available in a chemistry laboratory. Together with the
other intrinsic advantages of ILs, the high-throughput methods
developed in this work would provide a general platform to dis-
cover various new chemical processes associated with simplified
reaction systems and work-up procedures.
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