Biocompatible ionic liquid [Betaine][H2PO4] as a reusable catalyst for the substitution of xanthen-9-ol under solvent-free conditions

Article abstract of DOI:10.1039/d0ra05374k

An ionic liquid, namely [Betaine][H2PO4], was found to be an efficient catalyst for the direct substitution reaction of xanthen-9-ol with different nucleophiles under solvent-free conditions. This catalytic system is easy to be operated and the following work-up procedure is simple, with the ionic liquid catalyst reusable for at least five cycles at a high catalytic activity level. In addition, the ionic liquid is easy to prepare and its raw materials are inexpensive and have good biocompatibility. Therefore, our study presents an intriguing and sustainable protocol for the direct substitution of alcohol. This journal is

Full text of DOI:10.1039/d0ra05374k

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Biocompatible ionic liquid [Betaine][H2PO4] as
a reusable catalyst for the substitution of xanthen-
9-ol under solvent-free conditions†
Cite this: RSC Adv., 2020, 10, 31662
*
*
and Lingjun Li
Anlian Zhu,
Tong Wang,
Wanlu Feng, Jianji Wang
An ionic liquid, namely [Betaine][H2PO4], was found to be an efficient catalyst for the direct substitution
reaction of xanthen-9-ol with different nucleophiles under solvent-free conditions. This catalytic system
is easy to be operated and the following work-up procedure is simple, with the ionic liquid catalyst
reusable for at least five cycles at a high catalytic activity level. In addition, the ionic liquid is easy to
prepare and its raw materials are inexpensive and have good biocompatibility. Therefore, our study
presents an intriguing and sustainable protocol for the direct substitution of alcohol.
Received 19th June 2020
Accepted 8th August 2020
DOI: 10.1039/d0ra05374k
rsc.li/rsc-advances
efficiency. Therefore, the development of the direct substitution
of alcohols has fallen into the aspects of green chemistry.30 The
Introduction
direct substitutions of xanthen-9-ol with different nucleophiles
have been realized via the catalysis of numerous Lewis acidic
catalysts such as BF3$OEt2 in CH2Cl2,31 1,3-dichloro-tetra-n-
butyl-distannoxane in CH2Cl2,32 and Ceric ammonium nitrate
in anhydrous methanol.33 These reaction systems benet from
high reactivity, but due to their sensitivities to moisture, the
anhydrous reaction conditions are compulsory. Indium Tris(-
dodecyl sulfonate), which is compatible with water can promote
this reaction in aqueous solutions,34 still suffers from the
potential metal residual in the product. The aqueous solution of
Brønsted acids such as acetic acid,35 TFA,36 d odecylbenzene-
sulfonic acid37 and gluconid acid38 have also been utilized for
this transformation. The limited number of reports on the
reutilization of this type of catalysts revel that these systems
suffer from catalytic activity decrease from 99% to 89% aer ve
cycles. Alternatively, Cozzi et al.39,40 found an “on-water”
catalyst-free nucleophilic substitution method, but excess
nucleophilic reagents and long reaction times are necessary. Li
et al.41 reported an ionic liquid-promoted substitution method
for xanthen-9-ol with [Bmim][BF4] as solvent and catalyst. As
they have stated in their manuscript, the ionic liquid [Bmim]
[BF4] is unstable in moisture and produces strongly acidic HF,
which may be the main active species for the substitution
reactions. Therefore, efficient catalysis systems for the direct
substitution of xanthen-9-ol with mild and easy-prepared cata-
lysts under moderate conditions are still needed.
As novel functional materials, ionic liquids have been widely
utilized in organic synthesis and catalysis,1–8 extraction and
separation,9,10 biomass conversion11,12 and electrochemistry13,14
among others. In catalysis, the functions of ionic liquids include
being a solvent, catalysts or co-catalysts, ligand for metal cata-
lysts, and even separation assistants.15,16 The cations and anions
of ionic liquids have shown signicant synergetic effects in
different organic syntheses,5,17,18 particularly the hydrogen bonds
in functional ionic liquids, which have been proven to be able to
simultaneously activate the electrophiles and nucleophiles in
reactions and promote the related reactions under moderate
conditions.2,19,20 Due to the excellent biocompatibility, easy
preparation procedure, and low cost, choline and betaine-based
ionic liquids have been utilized in Aldol reactions,21,22 Knoeve-
nagel reactions,23,24 enzymatic reactions,25,26 and in the utilization
of CO2.27–29 The inherent tunable properties of the ionic liquids
such as acidity/basicity, solubility, and others make them
intriguing in numerous kinds of reactions.
Alcohols are ideal substrates to construct C–C and C–X
bonds as carbocation resources, which produce water as the
sole by-product. However, alcohols traditionally have to be pre-
converted to corresponding halides, sulfonates or related
compounds with easy leaving groups due to the weak leaving
ability of the hydroxyl group. This greatly increases the
complexity of the overall processes and decreases the atom
As our ongoing work on the utilization of ionic liquids in
organic syntheses,19,24,27,28,42–44 here, we investigated the catalytic
effects of a series of functional ionic liquids on the direct
substitution of xanthen-9-ol with different nucleophiles. The
results showed that both of the cations and anions of the ionic
liquids have signicant effects on their catalytic activity for the
target reactions, and the ionic liquid betainium dihydrogen
School of Chemistry and Chemical Engineering, Key Laboratory of Green Chemical
Media and Reactions, Ministry of Education, Collaborative Innovation Center of
Henan Province for Green Manufacturing of Fine Chemicals, Henan Normal
University, Xinxiang, Henan 453007, P. R. China. E-mail: alzhuchem@126.com;
lingjunlee@htu.cn
† Electronic supplementary information (ESI) available. See DOI:
10.1039/d0ra05374k
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Table 2 The effect of the amount of ionic liquid on the reaction
phosphate([Betaine][H2PO4]) showed excellent catalytic activity
under solvent-free conditions. Numerous nucleophiles such as
indoles with different substituted groups, dicarbonyl
compounds, malononitrile, pyrrole, pyridine-2-thiol, methima-
zole or azidotrimethylsilane were able to react with xanthen-9-ol
under the catalysis of [Betaine][H2PO4] smoothly, leading to the
target substitution products with high product yields. This
catalytic system benets from moderate and solvent-free reac-
tion conditions, the simple operation and work-up procedures,
and the reusability of the ionic liquid catalyst for at least ve
iterations. In addition, the preparation of the ionic liquid
catalyst is very simple and its raw materials are biocompatible
and inexpensive. All of these aforementioned properties make
this catalytic system intriguing for the green chemistry
applications.
Entrya
Ratio
Time (h)
Yieldb (%)
1
2
3
4
0.01
0.05
0.1
0.2
1.0
0.1
0.1
0.1
2
2
2
2
2
4
7
4
80
85
93
93
93
98
87
90
5
6
7c
8d
a
Reaction conditions: xanthen-9-ol (0.5 mmol), indoles (0.5 mmol),
b
c
d
50 ꢀC. Isolated yields. The reaction under room temperature. The
reaction at 40 ꢀC.
acids in methanol. Typically, a certain amount of betaine was
added into a round bottom ask using anhydrous methanol as
the solvent. Under magnetic stirring, an equal amount of acid
dissolved in anhydrous methanol was dropwise added to the
mixture of betaine and methanol in an ice bath. The reaction
was then stirred at 40 ꢀC for 24 h. Aer the reaction was
Experimental section
The synthesis of ionic liquids
The protic ionic liquids were synthesized simply by the
neutralization of corresponding amines with equal amount of
Scheme 1 The structures of ionic liquids.
Table 1 Catalytic performances of different ionic liquids on the substitution reaction of xanthen-9-ol and indole
Entrya
IL
Yieldb (%)
Entrya
IL
Yieldb (%)
1
2
3
4
5
6
[Betaine][Ac]
90
86
88
98
51
88
7
8
9
10
11
[Choline][H2PO4]
[DMEOA][H2PO4]
[DEEOA][H2PO4]
[DEA][H2PO4]
85
88
87
86
90
[Betaine][Pro]
[Betaine][Lac]
[Betaine][H2PO4]
[Betaine][HSO4]
[DMEA][H2PO4]
[TEOA][H2PO4]
a
b
Reaction conditions: xanthen-9-ol (0.5 mmol), indoles (0.5 mmol), IL (0.1 eq.), 50 ꢀC, 4 h. Isolated yields.
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Table 3 Extension of reaction substrate
M.P./ꢀC
Found
Entrya
Nucleophiles
Product
Yieldb (%)
Report (Lit)
1
98
140–142
142–143 (ref. 37)
2
88
158–160
134–135 (ref. 29)
3
91
189–191
176–178
154–155
187–189 (ref. 29)
4
98
183–191 (ref. 37)
5
88
142–145 (ref. 37)
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Table 3 (Contd.)
M.P./ꢀC
Found
Entrya
Nucleophiles
Product
Yieldb (%)
Report (Lit)
6
90
168–169
184–186 (ref. 37)
7
93
151–153
145–147 (ref. 37)
8
93
169–172
155–158 (ref. 37)
9
95
158–160
—
10
92
193–195
186–187 (ref. 29)
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Table 3 (Contd.)
M.P./ꢀC
Found
Entrya
Nucleophiles
Product
Yieldb (%)
Report (Lit)
11
91
193–194
176–178 (ref. 37)
12
88
110–112
113–119 (ref. 36)
13
14
91
90
136–138
184–186
139–141 (ref. 37)
—
15
92
74–76
77–80 (ref. 31)
16
95
189–191
192 ꢀC (ref. 36)
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Table 3 (Contd.)
M.P./ꢀC
Found
Entrya
Nucleophiles
Product
Yieldb (%)
Report (Lit)
White oil36
17
Me3SiN3
90
White oil
a
b
Reaction conditions: xanthen-9-ol (0.5 mmol), indoles (0.5 mmol), ionic liquid (0.1 eq.), 50 ꢀC, 4 h. Isolated yields.
completed, the solvent was removed by rotary evaporation, and conditions within 4 h. Recently, it has been reported by
sufficiently dried in a vacuum oven at 40 C to obtain betaine- Harper et al.45 that the increase of the hydrogen bond donor
ꢀ
based ionic liquids.
ability of the ionic liquids is benecial to the direct substitution
reactions of xanthen-9-ol. Accordingly, the highest catalytic
activity of [Betaine][H2PO4] may be due to the presence of
carboxyl group on the cation, which has the potential to
increase the hydrogen bond donor ability of the ionic liquid.
The typical procedure for the substitution reaction between
xanthen-9-ol and nucleophiles
In a 10 mL round bottom ask, the required amount of xanthen-
9-ol (0.5 mmol), indoles (0.5 mmol), and ionic liquid (0.05
mmol) were sequentially added. The reaction was conducted at
50 ꢀC for corresponding time under solvent-free conditions. The
whole reaction was monitored by TLC. Upon completion, the
reaction system was cooled to room temperature, and then
extracted with ethyl acetate and water. The product was dis-
solved in an organic phase and the ionic liquid was dissolved in
an aqueous phase. The crude products could be obtained
through the removal of ethyl acetate, and the column chroma-
tography method was used to purify the products. The ionic
liquid dissolved in water can be used for the next reaction run
directly aer it is fully dried in a vacuum drying oven.
The inuences of the dosage of ionic liquid and reaction
temperature
Using the optimized ionic liquid, the inuences of the dosage of
ionic liquid and reaction temperature on the model reaction
were investigated, and the results are shown in Table 2. It can be
seen that the increase in the ionic liquid dosage from 0.01 to 0.1
equivalent is benecial to the target reaction, but further
Results and discussion
The catalytic performances of different ionic liquids
A series of ionic liquids with different cations and anions (their
structures are illustrated in Scheme 1) were synthesized and
their catalytic performances for the direct substitutions of
xanthen-9-ol were investigated using the reaction between
xanthen-9-ol and indole as the model reaction. The results
shown in Table 1 suggest that both of the cations and the
anions have signicant effects on their catalytic activities for the
substitution reactions, and when the ionic liquid [Betaine]
[H2PO4] was used as the catalyst, the target substitution product
gave almost quantitative isolated yields under the solvent-free Fig. 1 Recyclability of the IL catalyst.
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results showed in Fig. 1 indicated that the catalytic activity of
ionic liquid remained very high aer ve cycles. The further FT-
IR spectra of the fresh and reutilized ionic liquid [Betaine]
[H2PO4] aer ve cycles shown in Fig. 2 suggested that there was
no signicant difference between the fresh and the recycled
ionic liquid.
Conclusion
In this study, we have found an inexpensive and easily prepared
ionic liquid, namely [Betaine][H2PO4], which can efficiently
catalyze the direct substitution reaction of xanthen-9-ol with
different nucleophiles under solvent-free conditions, leading to
the target products with excellent product yields. This catalytic
system is easy to be operated and the following work-up
procedure is very simple. The ionic liquid catalyst [Betaine]
[H2PO4] can be conveniently recycled and reutilized for at least
ve cycles without noticeable decrease in activity. The above-
mentioned benets, in addition to the inherent superiority of
the direct substitution reactions of alcohol and the biocom-
patibility of raw materials for the preparation of the ionic liquid
suggest that this reaction system is greatly sustainable and
promising for the further utilization in the direct substitution of
xanthen-9-ol with various nucleophiles. The nding that the
presence of the carboxyl group on the Betaine cation is the main
reason for the high catalytic activity of [Betaine][H2PO4] may
give constructive indications for the further design of ionic
liquid according to this type of reactions.
Fig. 2 FT-IR spectra of the fresh and recycled ionic liquid [Betaine]
[H2PO4].
increase in the dosage has no signicant inuence within 2 h
(entries 1–5, Table 2), and the prolonged reaction time to 4 h
leads to the completion of the reaction (entry 6, Table 2). The
lowered reaction temperature is not benecial to the reaction
(entries 7–8, Table 2).
Direct substitution reactions of xanthen-9-ol with different
nucleophiles
Using the optimized catalytic system, the direct substitution
reactions of xanthen-9-ol with different nucleophiles were
investigated and the results are summarized in Table 3. The
results showed that indoles with various substitution groups at
different positions (entries 2–11, Table 3) could all react with
xanthen-9-ol smoothly to obtain the target compounds with
excellent isolated yields, whether the substituents were
electron-withdrawing or electron-donating groups. The other
nucleophiles such as pyrrole, acetylacetone, malononitrile,
pyridine-2-thiol, methimazole and azidotrimethylsilane (entries
12–17, Table 3) could also be easily converted to the target
products under the optimized reaction conditions with excel-
lent product yields. Owing to the potential biological activities
of compounds bearing xanthen-9-yl groups,46–48 the current
efficient catalytic methods for the preparation of variant
xanthen-9-yl derivatives would be valuable.
Conflicts of interest
There are no conicts of interest to declare.
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (21373079 and 21733011) and S&T
Research Foundation of Education Department of Henan
Province (No. 20A150022).
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