Hydrogen-Bonding Catalyzed Ring-Closing C?O/C?O Metathesis of Aliphatic Ethers over Ionic Liquid under Metal-Free Conditions

Article abstract of DOI:10.1002/anie.202004002

O-heterocycles have wide applications, and their efficient and green synthesis is very interesting. Herein, we report hydrogen-bonding catalyzed ring-closing metathesis of aliphatic ethers to O-heterocycles over ionic liquid (IL) catalyst under metal- and solvent-free conditions. The IL 1-butylsulfonate-3-methylimidazolium trifluoromethanesulfonate ([SO₃H-BMIm][OTf]) is discovered to show outstanding performance, better than the reported catalysts. An interface effect plays an important role in mediating the reaction rate due to the immiscibility between the products and the IL catalyst, and the products can be spontaneously separated. NMR analysis and DFT calculation suggest that a pair of cation and anion of [SO₃H-BMIm][OTf] could form three strong H-bonds with an ether molecule, which catalyze the ether transformation via a cyclic oxonium intermediate. A series of O-heterocycles including tetrahydrofurans, tetrahydropyrans, morpholines and dioxane can be obtained from their corresponding ethers in excellent yields (e.g., >99 %). This work opens an efficient and metal-free way to produce O-heterocycles from aliphatic ethers.

Full text of DOI:10.1002/anie.202004002

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
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Accepted Article
Title: Hydrogen-Bonding Catalyzed Ring-Closing C-O/C-O Metathesis
of Aliphatic Ethers over Ionic Liquid under Metal-Free Conditions
Authors: Huan Wang, Yanfei Zhao, Fengtao Zhang, Yunyan Wu,
Ruipeng Li, Junfeng Xiang, Zhenpeng Wang, Buxing Han,
and Zhimin Liu
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202004002
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10.1002/anie.202004002
Angewandte Chemie International Edition
COMMUNICATION
Hydrogen-Bonding Catalyzed Ring-Closing C-O/C-O Metathesis
of Aliphatic Ethers over Ionic Liquid under Metal-Free Conditions
Huan Wang,[a,b] Yanfei Zhao,[a] Fengtao Zhang,[a,b] Yunyan Wu,[a,b] Ruipeng Li,[a,b] Junfeng Xiang,[a]
Zhenpeng Wang,[a] Buxing Han[a,b,c] and Zhimin Liu*[a,b,c]
Abstract: O-heterocycles have wide applications, and their efficient
and green synthesis is very interesting. Herein, we report hydrogen-
bonding catalyzed ring-closing metathesis of aliphatic ethers to O-
heterocycles over ionic liquid (IL) catalyst under metal- and solvent-
free conditions. The IL 1-butylsulfonate-3-methylimidazolium
trifluoromethanesulfonate ([SO3H-BMIm][OTf]) is discovered to show
outstanding performance, better than the reported catalysts.
Interface effect plays an important role in mediating the reaction rate
due to the immiscibility between the products and the IL catalyst,
and the products can be spontaneously separated. NMR analysis
and DFT calculation suggest that a pair of cation and anion of
[SO3H-BMIm][OTf] could form three strong H-bonds with an ether
molecule, which catalyze the ether transformation via a cyclic
catalyze oxidative transformation of alcohols into esters without
any other catalysts or additives.[7] In these studies, ILs serve as
both solvents and catalysts, and synergistic effects from cations
and anions are responsible for their performances. However,
separation of products is generally complicated. Biphasic
reaction system that is composed of IL catalyst phase and liquid
product phase may overcome this shortcoming, but it is scarcely
reported.
Tetrahydrofurans, tetrahydropyrans, morpholines and
dioxanes are important O-heterocycles with wide applications in
chemical industry.[8] The ring-closing C-O/C-O bond metathesis
reaction of aliphatic ethers is an efficient approach to access this
kind of chemicals. Lewis acid catalysts such as Fe(OTf)3, AlCl3,
Sc(OTf)3, FeCl3, FeBr3, have been reported to be effective for
this reaction in appropriate solvents.[9] However, they suffer from
low efficiency and separation difficulty. Therefore, it is still highly
desirable to develop simple and green catalytic systems for this
transformation.
oxonium intermediate.
A
series of O-heterocycles including
tetrahydrofurans, tetrahydropyrans, morpholines and dioxane can be
obtained from their corresponding ethers in excellent yields (e.g.,
>99%). This work opens an efficient and metal-free way to produce
O-heterocycles from aliphatic ethers.
Metal-free catalysis is a promising protocol to access
chemicals without metal pollution.[1] H-bond catalysis is an
effective way to realize this approach, but it is heavily reliant on
the systems that can form H-bond.[2] Ionic liquids (ILs) are a kind
of molten salts composed of organic cations and
inorganic/organic anions, which can be devised with unique
properties via precise design of cations and anions.[3] Multiple
interactions including Coulomb force, H-bonding, Van der Waals
force, hydrophilic/hydrophobic interaction, - interaction exist in
the IL systems. Especially, the H-bonding in IL system is very
strong due to the presence of Coulomb force,[4] which makes the
ILs show promising applications in catalysis.[5] For example,
CO2-philic
ILs
could
activate
CO2
via
forming
carbonate/carbamate intermediates and activate substrates via
H-bonding, thus realizing CO2 transformation under metal-free
conditions.[6] Basic IL 1-ethyl-3-methylimidazolium acetate could
Scheme 1. Biphasic reaction system of ring-closing C-O/C-O metathesis of
aliphatic ethers over IL catalyst.
[a]
H. Wang, Dr. Y. Zhao, F. Zhang, Y. Wu, R. Li, Dr. J. Xiang, Dr.Z.
Wang, Prof. B. Han and Prof. Z. Liu
Beijing National Laboratory for Molecular Sciences
Key Laboratory of Colloid and Interface and Thermodynamics, CAS
Research/Education Center for Excellence in Molecular Sciences
Institute of Chemistry, Chinese Academy of Sciences
Zhongguancun North First Street 2, 100190 Beijing (P. R. China)
E-mail: liuzm@iccas.ac.cn
Following our efforts to develop IL-catalyzed metal-free
reactions,[6a, 10] we intend to construct IL-based biphasic system
to realize the reaction and separation simultaneously. Herein,
we report heterogeneously catalytic ring-closing metathesis of
aliphatic ethers to O-heterocycles over SO3H-functionalized
[b]
[c]
H. Wang, F. Zhang, Y. Wu, R. Li, Prof. B. Han and Prof. Z. Liu
University of Chinese Academy of Sciences
imidazolium-based
trifluoromethanesulfonate
([OTf])
ILs
Beijing 100049 (P. R. China)
Prof. B. Han and Prof. Z. Liu
Physical Science Laboratory
Huairou National Comprehensive Science Center
No. 5 Yanqi East Second Street, Beijing 101400 (China)
(Scheme 1). In this approach, interface effect plays an important
role in mediating the reaction rate due to the immiscibility of the
products with IL catalysts, and allows the products to be
collected readily via simple phase separation. It was discovered
that 1-butylsulfonate-3-methylimidazolium trifluoromethanesulfo-
nate ([SO3H-BMIm][OTf]) showed outstanding performance,
better than the best catalyst reported (e.g., Fe(OTf)3)[9]. NMR
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.202004002
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COMMUNICATION
analysis and DFT calculation suggest that a pair of cation and
anion of [SO3H-BMIm][OTf]) could form three strong H-bonds
with an ether molecule, which catalyzes the ether transformation
via cyclic oxonium intermediate. A series of O-heterocycles
including tetrahydrofurans, tetrahydropyrans, morpholines and
dioxane could be obtained in excellent yields, especially in large
scale.
other ILs including [SO3H-BMIm] trifluoroacetate ([TA]), [SO3H-
BMIm][HSO4], [SO3H-BMIm][H2PO4], [SO3H-BMIm][Cl], 1-
carboxymethyl-3-methylimidazolium bis(trifluoromethylsulfonat-
e)imine ([HOOC-MMIm][NTf2]), 1-butyl-3-methylimidazolium
([BMIm]) [OTf] displayed low or no activity (Entries 6-11), while
trifluoromethanesulfonic acid (TfOH) afforded a 2 yield of 28%
(Entry 12). These results indicated that the SO3H-functionalized
imidazolium cation and [OTf]- anion play synergistic roles in
catalyzing the ring-closing reaction of 1 to 2. Notably, these ILs
are immiscible with 2, which allows the product to be
spontaneously separated with high purity, confirmed by GC-MS
and LC-MS analysis (Figures S2-S5). In addition, large scale
production of 2 was achieved using 100 mmol of 1 as the
feedstock, generating 8.3 g of 2 at 120 oC within 36 h (Entry 13).
Table 1. Screening of ionic liquids.[a]
Entry
1
IL
Yield / Isolated Yield of 2[b] [%]
Table 2. Scope of IL-catalyzed metathesis of aliphatic ethers to O-
heterocycles.[a]
[SO3H-BMIm][OTf]
[SO3H-PrMIm][OTf]
[SO3H-BPy][OTf]
[SO3H-BMMIm][OTf]
Fe(OTf)3
94 / 90
90 / 85
92 / 86
80 / 74
-- / 85[9]
5 / 2
2
3
4
5[c]
6
[SO3H-BMIm][TA]
[SO3H-BMIm][HSO4]
[SO3H-BMIm][H2PO4]
[SO3H-BMIm][Cl]
[HOOC-MMIm][NTf2]
[BMIm][OTf]
7
18 / 13
0 / 0
8
9
0 / 0
10
11
12[c, d]
13[e]
0 / 0
0 / 0
TfOH
-- / 28[9]
41[f], >99[g] / 97[g]
[SO3H-BMIm][OTf]
[a] 1 (2 mmol). [b] Yield determined by gas chromatography (GC) / isolated
yield, the data were the average of three replicates with a reproducibility of
±3%, except for 13, where the data were obtained once. [c] Data from
reference [9], 1 (0.2 mmol), Fe(OTf)3 (20 mol%), n-hexane (0.45 M), 100 C,
18 h. [d] Data from reference [9], TfOH (20 mol%) and traces of water. [e] 1
(100 mmol), IL (100 mmol), 120 C, and [f] 2 h, [g] 36 h.
[a] Yields determined by 1H NMR / isolated yields. [b] 20 mol% IL, 24 h. [c] 50
mol% IL, 24 h. [d] 50 mol% IL, 15 h, 2 from 1,5-dipropoxypentane (S12). [e] 50
mol% IL, 15 h, 2 from 1,5-dibutoxypentane (S13). [f] 50 mol% IL, 48 h. [g] 10
mol% IL, 24 h.
Taking 1,5-dimethoxypentane (1) as a model aliphatic ether,
the reaction was performed over various ILs as listed in Table 1
(Figure S1 and Table S1). Brønsted acidic ILs including [SO3H-
BMIm][OTf], 1-propylsulfonate-3-methylimidazolium ([SO3H-
PrMIm]) [OTf], N-butylsulfonate pyridinium ([SO3H-BPy]) [OTf]
and 1-butylsulfonate-2,3-dimethylimidazolium ([SO3H-BMMIm])
[OTf] were found to be effective for the reaction, producing
tetrahydropyran (2) with dimethyether (DME) as the sole
byproduct (Entries 1-4). Especially, [SO3H-BMIm][OTf] showed
the best performance, even better than the best catalyst
Fe(OTf)3 reported (Entries 1&5). Here it is important to
acknowledge that entry 5 pertains to the work of Morandi et al.,[9]
wherein Fe(OTf)3 is employed as a catalyst for the ring-closing
C-O/C-O metathesis of aliphatic ethers under quite different
reaction conditions than those reported herein. In contrast, the
The effects of temperature and molar ratio of IL to 1 on the
reaction were investigated (Figure S6, a-b). As indicated, the
reaction could proceed even at 60 C, and the product yield
increased with temperature, achieving 94% at 120 C within 15 h.
The molar ratios of IL to 1 significantly impact the reaction. With
the molar ratios changing from 1/10 to 3/1, the phases of
reaction system changed from the substrate phase with
dispersed IL to the IL phase with dispersed substrate, and the
reaction was accelerated considerably, achieving a 2 yield of
92% at the ratio of 2.5 within 1 h and a yield of >99% at 1.5 h.
Since the IL is immiscible with 1, the reaction occurs at the
biphasic interface. To explore the effect of the interface on the
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10.1002/anie.202004002
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reaction, the reactions were kinetically investigated under the
conditions with stirring for creating an emulsion with a large
interface area and without stirring so that the interface area is
minimized. As shown in Figure S6c, stirring that can result in
large interface area significantly accelerated the reaction
compared to the cases without stirring, suggesting that the
interface effect plays an important role in promoting reaction.[11]
In addition, [SO3H-BMIm][OTf] could be easily recovered via
phase separation, which could be reused without loss in activity
after five recycles (Figure S6d), suggesting its high stability
ngth of the alkyl substituents, the reactivity of 1,5-dialkyloxypen-
tanes declined, and more IL or longer reaction time was required
for high 2 yield. Interestingly, 1,4-dioxane (12) as well as tosyl-
and nosyl-protected morpholines 13 and 14 that are usually
applied in drug design[13] were obtained in high yields The above
results indicate that [SO3H-BMIm][OTf] is very effective for
catalyzing the ring-closing metathesis of ethers, and the biphasic
reaction system makes the separation easy to access products
in excellent isolated yields. Notably, complete conversion of
every substrate could be achieved accompanied with >99% yield
of the target products via prolonging reaction time or increasing
molar ratio of IL to substrate (Table S2).
Taking the metathesis of 1 over [SO3H-BMIm][OTf]) as an
example, we explored the reaction mechanism. For biphasic on-
water catalysis, the proton transfer mechanism was
accepted.[11a] In this work, [SO3D-BMIm][OTf] was applied in
catalyzing the reaction, which was found to show similar activity
to [SO3H-BMIm][OTf] (Figure S6c). Moreover, both ILs exhibited
the first-order kinetics with a kinetic isotope effect of 1.06
(Figures S9 and S11), which could rule out the proton transfer
mechanism for the reaction.[11a,14] This is also supported by the
fact that no methanol was detected in the reaction process in all
cases.
1
under the experimental conditions. The Hand 19F NMR spectra
of the recovered IL remain unchanged, giving the direct
evidence for its stability[12] (Figures S7 and S8).
Under optimized conditions, [SO3H-BMIm][OTf]) could
effectively catalyze the ring-closing metathesis of various
aliphatic ethers to O-heterocycles (Table 2). Five- and six-
membered O-heterocycles bearing phenyl were acquired in
excellent yields of >99% (e.g., 4-6), and those with electron-rich
and electron-deficient functional group (e.g., methyl and
chloride) substituted aromatic rings were also obtained in high
yields (7, 8). Even the substrate with a gem-dimethyl group at 3-
position was well tolerated, affording product (9) in a yield of
>99%. The five-membered O-heterocycles bearing methyl or
[9]
dimethyl (10 and 11) that could not be obtained over Fe(OTf)3
To gain insight into 1 activation by [SO3H-BMIm][OTf], 1H,
17O and 19F NMR analyses were performed. It was indicated that
the 1H, 17O and 19F NMR spectra of the ether and the IL changed
obviously (Figures 1 and S10), respectively, as they mixed,
suggesting that the ether can be activated by the IL. As known,
electronegative F and O atoms have strong ability to form H-
bond with H atom.[15] Therefore, the changes in the chemical
shifts of IL and ether in the NMR spectra of their mixture should
be ascribed to the H-bond interaction between them.[7] The
resonance band assigning to the H atom of –SO3H in [SO3H-
BMIm][OTf] mixing with 1 shifted to 8.46 ppm from initial 8.39
ppm (Figure 1a), meanwhile the band to the O atoms of 1 shifted
from 18.11 to 18.19 ppm with the signal to the O atoms of [OTf]-
keeping unchanged (Figure 1b). Combining with the fact that
SO3H-functionalized cation is necessary for catalyzing the
reaction, it can be deduced that the O atom in ether forms H-
bond with the H atom from -SO3H in cation.[15d,16] The 19F NMR
spectra of the IL mixing with 1 showed two new peaks
accompanied with obvious downfield shift of the original peak
(Figure 1c), meanwhile the highfield shifts of the H atoms of 1
were observed in 1H NMR spectra of the mixture (Figure 1a).
These results suggest that two F atoms in [OTf]- can form strong
H-bonds with H atoms from -CH3 and/or -CH2- of 1.
were produced in excellent yields in this work. All 1,5-
dialkyloxypentanes with different alkyl substituents (namely
methyl, propyl and butyl) produced the same product 2, but
showing different reactivity. With an increase in carbon-chain le-
Figure 1. NMR spectra of the neat 1, IL and their mixture were recorded at
333.2 K. (a) 1H NMR. (b) 17O NMR. (c) 19F NMR.
Figure 2. Possible interaction structures of 1 with [SO3H-BMIm][OTf] (a) and
with [SO3H-BMIm]+ (b). Black word: atom distance (Å); red word: NBO charges.
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From the NMR analysis, it is obvious that a pair of cation and
anion of [SO3H-BMIm][OTf]) could form three H-bonds with a
molecule of 1. Based on this, we propose a possible structure of
1 interacting with the IL, as displayed in Figure 2a. DFT
calculation (Figure 2) indicated that the estimated H-bond
lengths of OHO (1.421 Å) and CHF (2.481 and 2.879 Å) were
much shorter than the most reported corresponding values, [17]
suggesting the strong H-bonding between the IL and 1. That
means the IL can activate 1. Moreover, the NBO charges of C
To further understand the reaction mechanism, several
control experiments were performed. The ring-closing C-O/C-O
metathesis reaction of the mixture of
1
and 1,5-
dipropyoxypentane (S9) was carried out over [SO3H-BMIm][OTf],
and 2 was obtained with Me-O-Pr as the main byproduct
(Scheme 2a and Figure S14). From these results and those
reported,[9] it can be deduced that cyclic oxonium species 20, 21
and [SO3H-BMIm]-stabilized species 22, 23, as shown in
Scheme 2, maybe exist in the reaction process. To confirm this
hypothesis, oxonium intermediate 24 was synthesized (see SI),
and was used to react with “[SO3H-BMIm]-OMe” 22 that was
generated in-situ by mixing [SO3H-BMIm][OTf] with an equimolar
amount of NaOMe. Consequently, 1 was produced together with
DME in high yield (Scheme 2, b).
In-situ 1H and 13C NMR spectra of the reaction solutions
provide direct evidences for the formation of the above
intermediate species. As shown in Figure 3, two new signals
appeared at δ=8.78 and 3.64 ppm as the reaction proceeded,
which belonged to the H atoms of –SO3H and -OMe in [SO3H-
BMIm]-OMe, respectively. Correspondingly, the resonance band
assigning to the C atom in -OMe of [SO3H-BMIm]-OMe was
observed at δ=49.42 ppm in the 13C NMR and in-situ 13C NMR
spectra (Figures 3b and S15d). Excitingly, chemical shifts with
low intensity at δ = 90.88, 82.22, 28.42 and 17.23 ppm ascribing
to the cyclic oxonium intermediate[9] 20 were also observed in
the in-situ 13C NMR spectra (Figure S16d). In addition, beside
each signal assigning to C-1 and C-2 in 1 appeared a new peak
(δ=72.45 and 57.45 ppm), respectively (Figure 3b), probably
caused by strong H-bonds between the IL and 1. Combining
with the 1H and 19F NMR analysis results, it can be deduced that
two F atoms in [OTf]- can form H-bonds with the H atoms
connected to C-1 and C-2, forming a new species (25) as shown
in Figure 3. Both in-situ 1H and 13C NMR spectra also supported
the increase in 2 amount and decline in 1 amount as reaction
proceeded (Figures S15 and S16).
and
O atoms were estimated to be -0.078 and −0.544,
respectively, as both cation and anion interact with 1 (Figure 2a),
while without anion interaction the difference of NBO charges
between the C and O atoms became smaller (Figure 2b). This
can explain that the cooperation of both cation and anion of
[SO3H-BMIm][OTf]) catalyzes the reaction.6c Notably, DFT
calculation was performed to understand the interaction of a pair
of cation and anion of [SO3H-BMIm][OTf] with an ether molecule
(see SI).
Scheme 2. Control experiments.
Figure 3. In-situ 1H NMR and 13C NMR spectra recorded in 1 transformation process over [SO3H-BMIm][OTf] at 393.2 K.
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COMMUNICATION
Based on the experimental results and previous reports,[9]
a
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possible pathway is proposed as illustrated in Scheme 3. Once
contacting with the IL, the ether is activated via forming H-bond
with the IL. Then, the C atom linked to the activated O atom is
attacked by the other O atom, furnishing cyclic oxonium
intermediate, e.g., 20, together with [SO3H-BMIm]-OMe complex
22. Finally, the oxonium intermediate is demethylated by [SO3H-
BMIm]-OMe, thus generating 2 and DME, meanwhile the IL is
regenerated.
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In conclusion, H-bond catalyzed synthesis of O-
heterocycles from ring-closing metathesis of aliphatic ethers is
realized over [SO3H-BMIm][OTf] under metal-free condition for
the first time, and the efficiency is very high. Mechanistic
investigation indicates that both cation and anion of the IL can
form H-bonds with the substrates, which catalyze the reactions
cooperatively. Moreover, the immiscibility between catalyst and
products making the separation and purification can be easily
achieved. Additionally, the kinetic studies demonstrate that the
reaction rate can be significantly affected by the interface effect.
We believe that this novel route to synthesize O-heterocycles
has very promising applications because of some obvious
advantages. The strategy to catalyze reaction by forming H-
bonds between the IL ions and substrates can be used to
explore other efficient catalytic reactions.
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Acknowledgements
The authors thank the National Natural Science Foundation of
China (21890761, 21533011, 21773266), Chinese Academy of
Sciences (QYZDY-SSW-SLH013-2), and Beijing Municipal
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Conflict of interest
The authors declare no conflict of interest.
Keywords: ionic liquid • hydrogen bond catalysis • ring-closing
metathesis • metal-free • biphasic system
This article is protected by copyright. All rights reserved.

10.1002/anie.202004002
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Hydrogen-bonding catalyzed ring-
closing metathesis of aliphatic ethers
to O-heterocycles is realized over
ionic liquid catalyst via a cyclic
oxonium intermediate under metal-
and solvent-free conditions.
H. Wang, Y. Zhao, F. Zhang, Y. Wu, R.
Li, J. Xiang, Z. Wang, B. Han, Z. Liu*
Page No. – Page No.
Hydrogen-Bonding catalysed Ring-
Closing C-O/C-O Metathesis of
Aliphatic Ethers over Ionic Liquid
under Metal-Free Conditions
This article is protected by copyright. All rights reserved.