Catalytic alcoholysis of epoxides using metal-free cucurbituril-based solids

Article abstract of DOI:10.1039/c6ob00512h

Metal-free cucurbit[7]uril (CB7) solid-state assemblies promote acid-catalysed alcoholysis of aliphatic and aromatic epoxides under mild conditions to give β-alkoxy alcohols, which are important intermediates for the synthesis of a vast range of compounds such as bioactive pharmaceuticals. The catalytic process is heterogeneous and the catalyst can be reused in consecutive runs without any reactivation treatment. The acid species responsible for the catalytic activity of CB7 may be entrapped hydronium ions.

Full text of DOI:10.1039/c6ob00512h

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Catalytic alcoholysis of epoxides using metal-free
cucurbituril-based solids†
Cite this: DOI: 10.1039/c6ob00512h
Sofia M. Bruno,a Ana C. Gomes,a Tânia S. M. Oliveira,b Margarida M. Antunes,a
Received 7th March 2016,
Accepted 22nd March 2016
André D. Lopes,b Anabela A. Valente,*a Isabel S. Gonçalvesa and Martyn Pillinger*a
DOI: 10.1039/c6ob00512h
www.rsc.org/obc
Metal-free cucurbit[7]uril (CB7) solid-state assemblies promote porosity may comprise interstitial voids in amorphous solids4a
acid-catalysed alcoholysis of aliphatic and aromatic epoxides or channels in crystalline materials.4b–e In addition to water
under mild conditions to give β-alkoxy alcohols, which are impor- molecules, the channels or voids may be filled with acid mole-
tant intermediates for the synthesis of a vast range of compounds cules, which has led to studies of proton conductivity and to
such as bioactive pharmaceuticals. The catalytic process is hetero- the suggestion that CB materials could have potential as acid
geneous and the catalyst can be reused in consecutive runs catalysts.5 However, to the best of our knowledge, the use of
without any reactivation treatment. The acid species responsible CB assemblies as acid catalysts has hardly been explored.
for the catalytic activity of CB7 may be entrapped hydronium ions.
Herein, we report that the unfunctionalised CB7, used in its
as-prepared form, is a highly efficient metal-free catalyst for
the heterogeneous alcoholysis of styrene oxide (StyOx) under
mild conditions (Table 1). The acid-catalysed opening of epox-
ides with alcohols is an important transformation in the syn-
thesis of β-alkoxy alcohols, which are useful intermediates for
the synthesis of α-alkoxy ketones, α-alkoxy acids, enol ethers,
and a range of bioactive natural and synthetic products.6 In
the production of drugs, high product purity is a crucial
requirement for commercialisation, and the use of mild
Cucurbit[n]urils (CBn, n = 5–8, 10, 14) are a family of macro-
cyclic compounds comprising n glycoluril units linked by
methylene bridges.1 CBn can be readily prepared on a large
scale by one-pot synthesis from cheap starting materials, glycol-
uril and formaldehyde. The unique properties of CBs, notably
their rigid structure, two highly polar carbonyl-lined portals,
a hydrophobic non-polarisable inner cavity, and high binding
affinities, have prompted numerous studies within the fields
of host–guest chemistry,2a supramolecular catalysis,1c,2b drug
delivery,2c molecular machines and electronics, amongst
others.1d Catalytic applications are still waiting to be exten-
sively explored. Although CB-mediated catalysis has made
important contributions to organic synthesis, the virtual lack
of solubility of CBs in common organic solvents has restricted
the reaction scope to transformations involving aqueous solu-
tions, e.g. acid hydrolysis,3a,b oxidation of alcohols,3c desilyla-
tion,3d and photodimerisation.3e One exception is the use of
an oxovanadium(IV)–CB6 complex as a heterogeneous catalyst
for hydrocarbon oxidation.3f
Table 1 Catalytic performance of CB7 in StyOx alcoholysisa
Cat. load
T
Conversion
(%)
Solvent
EtOH
(gcat L−1
)
(°C) t (min)
An interesting feature of CBn assemblies in the solid-state
is the existence of both intrinsic (from the cavity) and extrinsic
(from inefficient molecular packing) porosities. The extrinsic
10
35
35
55
55
55
55
35
35
1/10/30/60
17/61/94/100
13/63/97/100
39/96/100
40/100
EtOH (CT/35)b 10
1/10/30/60
1/10/30
1/10
EtOH
10
EtOH (CT/55)b 10
EtOH
BuOH
EtOHc
EtOHd
5
10
10
10
1/10/30
13/67/100
aDepartment of Chemistry, CICECO – Aveiro Institute of Materials, University of
Aveiro, Campus Universitário de Santiago, 3810-193 Aveiro, Portugal.
E-mail: atav@ua.pt, mpillinger@ua.pt
1/30/60/120/240 0/23/44/69/100
1/10/30/60
240/360
18/54/92/100
40/95
bFaculty of Science and Technology, CIQA, University of the Algarve, Campus de
a The only product was the corresponding 2-alkoxy-2-phenylethanol
(100% selectivity). b Catalytic runs using the solids recovered from the
contact tests at 35 (CT/35) or 55 °C (CT/55). c In-house synthesized CB6
was used instead of CB7. d A commercial CB7 sample (Sigma-Aldrich)
was used instead of in-house synthesized CB7.
Gambelas, 8005-136 Faro, Portugal
†Electronic supplementary information (ESI) available: Synthetic protocol and
characterisation data for CB6 and CB7, and experimental details for the alcoho-
lysis reactions. See DOI: 10.1039/c6ob00512h
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synthesis conditions helps to avoid the decomposition of rela-
tively unstable polyfunctionalised products. Hence, the use of
metal-free catalysts capable of promoting the chemical reac-
tions with excellent selectivity, under mild conditions, is
highly desirable. To date, most of the homogeneous and
heterogeneous catalysts that have been investigated for the
alcoholysis of epoxides contain metals and/or metalloids. Only
a few examples of metal-free heterogeneous acid catalysts have
been reported, e.g. graphene oxide,7a mesoporous carbon,7b
and the commercial ion-exchange resin Amberlyst™-15.7c
In the ethanolysis of StyOx, the alcohol serves as both a
solvent and a reactant. As a catalyst, CB7 was highly active and
selective, giving 2-ethoxy-2-phenylethanol (StyOEt) with 100%
selectivity at 100% conversion, which was reached within 1 h
of reaction at approximately room temperature (35 °C,
Table 1). Increasing the reaction temperature from 35 to 55 °C
led to an extremely fast alcoholysis reaction (96% conversion
at 10 min) without affecting product selectivity (100%). At this
reaction temperature, the catalyst loading could be reduced
from 10 to 5 gcat L−1 while still maintaining very good results
(100% conversion within 30 min, Table 1). The catalytic role of
CB7 was confirmed by the fact that the reaction of StyOx was
negligible in the absence of cucurbituril (e.g., conversion was
only 1% after 4 h of reaction at 55 °C).
Fig. 1 FT-IR spectra of (a) CB7 and (b) CB7-reused.
The use of n-butanol as a reacting solvent instead of
ethanol led to excellent selectivity towards the corresponding
β-alkoxy alcohol product: 100% 2-butoxy-2-phenylethanol
(StyOBu) yield at 4 h reaction (Table 1). The slower kinetics
with n-butanol than with ethanol may be partly due to more
important steric effects in the former case.
To check whether the catalytic reaction occurred in the
homogeneous or heterogeneous phase, two tests were per-
formed for CB7 (as described in detail in the ESI†): (i) contact
test (CT), in which CB7 was treated with ethanol, followed
by separation and use of the liquid phase for the reaction of
StyOx, and (ii) filtration test (FT), in which the catalytic reac-
tion was interrupted at an initial stage by separating (at the
reaction temperature) the solid from the reaction solution,
which was then allowed to react further. The solution obtained
from the CT led to less than 5% StyOx conversion after 4 h at
55 °C, which is negligible compared to that observed for a
typical catalytic batch run with CB7. Similarly, for the CT and
FT at 35 °C, the liquid phases led to no catalytic reaction.
Hence, the catalytic reaction occurred in the heterogeneous
phase.
The solids obtained from the CTs at 35 and 55 °C (denoted
CT/35 and CT/55, respectively) were tested in the reaction of
StyOx, and led to comparable catalytic results to those
observed for the original catalyst, under similar reaction con-
ditions (Table 1). Hence, CB7 seems to be fairly stable. The
catalyst stability was further studied in terms of recyclability by
carrying out three consecutive batch runs at 35 °C; between
runs, the solid catalyst was separated from the reaction
mixture, washed and dried. StyOx conversion reached 100% at
1 h for the three runs, and StyOEt selectivity was always 100%.
The FT-IR spectrum of the reused catalyst was similar to that
Fig. 2 SEM and the corresponding EDS Cl mapping images of CB7 (a,
b) and CB7-reused (c, d).
of the original catalyst (Fig. 1), and SEM indicated no signifi-
cant morphological changes (Fig. 2), suggesting that the
physico-chemical integrity of CB7 was essentially preserved
during the catalytic process.
Acid–base titration for the fresh and used catalysts (per-
formed with ethanol as the solvent) indicated a similar acid
content of ca. 34 μeq H+ gsolid for the two solids. A value of
−1
−1
ca. 63 μeq H+ gsolid was obtained when the titrations were
performed in water. Similar chloride contents (corresponding
to HCl) of ca. 74 μeq H+ gsolid were determined by ion
−1
chromatography (IC) for the fresh and used catalysts. Accord-
ingly, EDS elemental mapping for Cl indicated that no signifi-
cant depletion of Cl had occurred during the catalytic reaction
(Fig. 2). These results are consistent with the fairly good
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Table 2 Literature data for catalytic alcoholysis of StyOx performed in
the presence of metal-free heterogeneous catalysts
Cat. load [StyOx]0
T
(°C)
t
Conv.
Catalyst
(gcat L−1
)
(M)
(min) (%)
Ref.
CB7
Amberlyst™-15
Amberlyst™-15
Mesoporous carbon 32
Graphene oxide 0.45
10
10
20
0.40
0.40
0.20
0.47
0.80
35
35
60
30
100a
100a
100c
99e
t.w.b
t.w.b
7c
7b
7a
Scheme 1 StyOx reaction mechanism in the presence of CB7.
24–28 30
a.t.d
a.t.d
30
60
99 f
a StyOEt was formed with 100% selectivity. b This work. c Isolated
StyOEt yield was 95%. d Ambient temperature. e StyOEt was formed
with 97% selectivity. f StyOMe was formed with 93% selectivity.
100% conversion at 1 h (no reaction occurred with NaOH and
without CB7 up to 24 h). In another test, a commercially avail-
able CB7 sample (Sigma-Aldrich) led to 40%/95% StyOx con-
versions at 4 h/6 h and 35 °C, which are lower than those
observed for the as-prepared (in-house) CB7, under similar
reaction conditions (Table 1). The lower activity for the com-
mercial sample correlates with its lower acid content of
catalyst stability results discussed above. The initial catalytic
activities (or turnover frequencies) expressed per mass of cata-
lyst (or per eqH+, based on the titration results in ethanol) are
−1
ca. 14 µeq H+ gsolid determined by acid–base titration in
0.41 mol gcat h−1 (12 000 mol molH+ h−1) at 35 °C, and
0.94 mol gcat−1 h−1 (27 500 mol molH+−1 h−1) at 55 °C.
−1
−1
ethanol. The activity of the in-house synthesised CB7 was
found to be comparable with that of a CB6 sample (isolated
from the same synthesis batch used to obtain CB7) possessing
a similar acid content of ca. 38 μeq H+ gsolid−1, under identical
The catalytic performance of CB7 was compared to that of
HCl, chosen as a liquid acid catalyst and used in an amount
equivalent to the acid content for 10 gCB7 L−1, at 35 °C. The
ethanolysis of StyOx in the presence of HCl was much slower
(<10% conversion at 24 h reaction) than for CB7. In a second
comparison, the commercially available sulfonic acid ion-
exchange resin AmberlystTM-15 (which possesses a much
higher acid content of 4300 µeq H+ gsolid−1) was chosen as a
benchmark solid acid catalyst (the mass of the solid
reaction conditions (10 gsolid L
−1, 35 °C), i.e., similar kinetic
results (Table 1) correlate with similar acid contents of the two
catalysts. Overall, the catalytic reaction seems to be essentially
governed by hydronium ions. The StyOx reaction mechanism
may involve protonation of the oxygen atom of the oxirane
ring, thereby favouring the nucleophilic attack of the alcohol
reagent at the more substituted carbon atom of the epoxide
group, leading selectively to the β-alkoxy alcohol product
(Scheme 1).8
As mentioned above, water, hydronium ions and anions
such as chloride play an important role in the assembly and
packing patterns of CB molecules in the solid state. Extensive
hydrogen-bonding networks are present both within voids or
channels and between neighbouring CB molecules. Strong
interactions between hydronium ions and the carbonyl groups
located at the CB7 portals have been studied by DFT calcu-
lations9 and proposed to be the driving force for the unusual
hydrogel formation observed under acidic conditions.4c On the
basis of these structural studies and the results of the catalytic
tests performed in the present work, we propose that the etha-
nolysis of StyOx is promoted by hydronium species that are
directly interacting with CB7 molecules and/or located in the
void spaces of the solid-state structure; the relative contri-
butions of the differently located acid species may depend on
their accessibility towards the reactants.
The catalytic performance of CB7 was further investigated
for the ethanolysis of aliphatic epoxides, namely cyclohexene
oxide (Cy6Ox), cyclooctene oxide (Cy8Ox) and cyclododecene
oxide (Cy12Ox), at 35 °C (Table 3). The reaction of Cy6Ox was
fast, giving 2-ethoxycyclohexanol in 93% yield at 96% conver-
sion (6 h reaction; cyclohexane-1,2-diol was formed as a by-
product in 3% yield). The reaction of Cy8Ox was very sluggish
(7% conversion at 96 h), and that of Cy12Ox did not occur. For
the three aliphatic cyclic epoxide substrates, using HCl (in an
amount equivalent to the acid content for 10 gCB7 L−1) instead
catalyst was the same for the different catalysts). AmberlystTM
-
15 led to 100% conversion at 30 min reaction and 100%
StyOEt selectivity (Table 2), and initial catalytic activity was
1.52 mol gcat−1 h−1 (353 mol molH+−1 h−1). While, for the same
mass of the catalyst, the ion-exchange resin led to a faster reac-
tion, the intrinsic activity of the acid sites was higher for CB7.
Hence, CB7 seems to possess distinct acid properties. The
catalytic performance of CB7 compares favourably with
the limited literature data available for metal-free solid acid
catalysts tested in the same reaction (Table 2).7
CBs such as CB7 have been shown to promote acid hydro-
lysis of amides, carbamates and oximes under homogeneous
conditions.3a The CBs were proposed to serve as unconven-
tional “acid substitutes” by virtue of complexation-induced
pKa shifts, thereby facilitating the protonation of the sub-
strates. Similar effects are difficult to investigate for hetero-
geneous catalytic processes which, besides chemical reactions,
involve physical phenomena (e.g. adsorption, internal
diffusion) that do not apply for homogeneous catalysts.
The acid sites responsible for the catalytic activity of
CB7 may be stabilised by hydronium ions associated with the
co-crystallised acid molecules, which are very difficult to
remove.4e The results of various tests supported this hypo-
−1
thesis. In one test performed at 35 °C with 10 g
L , Brønsted
CB7
acid species in the CB7 sample were neutralised by the initial
addition of NaOH (in an amount equivalent to 34 μmol
gCB7−1). The subsequent reaction led to 21% conversion at 2 h,
whereas a typical batch run with the as-prepared CB7 gave
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Table 3 Reaction of different epoxides in the presence of CB7
Substrate
Conv. (%)
100
t (h)
Alkoxy alcohol product yields (%)
1
87
6
96
7
6
96
96
95
24
24
Reaction conditions: [substrate]0 = 0.40 M, 10 gCB7 L−1, 35 °C.
of CB7 led to negligible conversion, which parallels that vinyl-cyclohexane formed in 25% yield (26% selectivity), and
observed for StyOx as a substrate. The trend in the reaction 7% yield (7% selectivity) of vinyl cyclohexane-1,2-diol. The
rate for the substrates with increasing ring dimension may be ethanolysis of LimOx led to 95% conversion at 24 h, giving
partly due to steric hindrance and/or reduced accessibility to 73% total yield (77% total selectivity) of alkoxy alcohol
active sites.
isomers, namely 2-ethoxy-2-methyl-5-(prop-1-en-2-yl)cyclohexa-
and 2-ethoxy-1-methyl-4-(prop-1-en-2-yl)cyclohexanol
The CB7 catalyst was further investigated for the ethanolysis nol
of substituted aliphatic and aromatic C6-membered ring sub- (Table 3); 1-methyl-4-(prop-1-en-2-yl)-cyclohexane-1,2-diol was
strates, namely (1R,2R)-phenylpropylene oxide (Me-StyOx), formed with 10% yield (11% selectivity). The slower conversion
4-vinylcyclohexene oxide (vinyl-Cy6Ox) and the renewable of the more substituted substrate Me-StyOx when compared
epoxide R-limonene oxide (LimOx). With Me-StyOx as a sub- with that for StyOx (and also for vinyl-Cy6Ox and LimOx vs.
strate, 87% conversion was reached at 6 h and 1-ethoxy-1- Cy6Ox) may be partly due to steric hindrance.
phenyl-2-propanol was the only product (100% selectivity).
In summary, cucurbit[7]uril has been demonstrated to be
With vinyl-Cy6Ox as a substrate, 96% conversion was reached an efficient heterogeneous metal-free catalyst for the alcoho-
at 24 h to give a 62% total yield (65% total selectivity) of the lysis of aliphatic and aromatic epoxides under mild conditions.
cis/trans alkoxy alcohols; other products were 1,2-diethoxy-3- The catalytic potential of CBs may be extended to different
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acid-catalysed reactions in future studies, and advanced solid-
state molecular-level characterisation may help gain deeper
insights into structure–activity relationships.
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CICECO-Aveiro Institute of
Materials, POCI-01-0145- 4 (a) J. Tian, S. Ma, P. K. Thallapally, D. Fowler, B. P. McGrail
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