Molecular Catalysis 467 (2019) 1–8

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Molecular Catalysis
journal homepage: www.elsevier.com/locate/mcat

Molecular mechanism of heterogeneous supramolecular catalysis of metal- T

free cucurbituril solid for epoxide alcoholysis
Lina Xua, Guoyong Fanga,b, , Yanghong Yua, Yuefan Maa, Zihang Yea, Zhenyu Lib,
⁎ ⁎⁎

a
Key Laboratory of Carbon Materials of Zhejiang Province, College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou 325035, China
b
Hefei National Laboratory of Physical Sciences at the Microscale, School of Chemistry and Materials Sciences, University of Science and Technology of China, Hefei
230026, China

ARTICLE INFO ABSTRACT

Keywords: Heterogeneous and supramolecular catalysis are fundamental processes in chemistry. To understand the sy-
Supramolecular catalysis nergistic role between heterogeneous and supramolecular catalysis, the catalytic mechanism of cucurbituril solid
Heterogeneous catalysis for epoxide alcoholysis was investigated by performing density functional theory (DFT) calculations. The results
Cucurbituril reveal that styrene oxide (StyOx) ethanolysis has an inherent regioselectivity, which results from different
Epoxide alcoholysis
groups linked to the epoxy group. The hydronium ion can catalyze the ring-opening of StyOx ethanolysis and
Density functional theory calculation
lead to the formation of a planar carbenium ion. StyOx can also be hydrolyzed via the homogenous catalysis of
acid to produce 1, 2-diol. Cucurbituril solid can catalyze epoxide alcoholysis because of its acidic property. Its
unique cavity can lead to a favorable frontside-attack of the alcohol on the carbenium ion. The product from the
heterogeneous catalysis of cucurbituril solid is pure β-alkoxy alcohol. The results are important to understand
heterogeneous and supramolecular catalysis and the design of new and effective supramolecular catalysts.

1. Introduction
In the past decade, extensive progress has been made in supramo-
lecular catalysis, which has become a hot topic in the field of chemistry
[1–12]. In principle, supramolecular catalysis is similar to enzyme
catalysis and provides the cavities and catalytic sites for various reac-
tions [13–19]. Because of limitations of experimental and computa-
tional conditions, the molecular mechanism of supramolecular catalysis
is still unclear. To date, only a few supramolecule-catalyzed reactions
exist, such as imine formation, methylation and cycloaddition, which
have been studied in detail by using accurate quantum-chemistry cal-
culations [20–26].
As a well-known supramolecular container, pumpkin-shaped cu-
curbiturils are a family of macrocyclic compounds that comprise gly-
coluril units that are connected by methylene (eCH2e) bridges
[27–33]. Cucurbiturils are written commonly as cucurbit[n]urils, where
n is the number of glycoluril units (]C4H2N4O2]), and they are ab-
breviated as CBn or CB[n] (n = 5 ∼ 10). They can be synthesized by
the condensation of glycoluril and formaldehyde under acidic condi-
tions (Scheme 1). Because of their unique cavity, cucurbiturils can
recognize suitable guest molecules and catalyze many chemical reac-
tions. CBn have been used to control and catalyze various chemical
reactions in the liquid phase, including photochemical and thermal
reactions, such as photodimerization, photolysis, cycloaddition, hy-
drolysis, oxidation, and desilylation [34–50]. Recently, the catalytic
properties of CBn in the gas and solid phases have been investigated
[24,51,52].
To obtain insight into the catalytic mechanism, a few theoretical
calculations have been performed to illustrate the nature of cucurbi-
turil-based supramolecular catalysis [24–26]. The retro-Diels–Alder
reaction inside cucurbiturils in the gas phase has been explored theo-
retically [24]. The enhanced reactivity of 1, 3-dipolar cycloaddition
between an azide and an alkyne inside cucurbiturils in the liquid phase
via homogeneous catalysis has also been addressed [25,26]. However, a
limited understanding exists of the supramolecular catalytic mechanism
and nature of cucurbituril solids that are produced by heterogeneous
catalysis.
Epoxides, which are a type of heterocyclic compound, are used
extensively in organic compounds and as important intermediates in
pharmaceutical synthesis [53–55]. Epoxide ring-opening with alcohols

⁎
Corresponding author at: Key Laboratory of Carbon Materials of Zhejiang Province, College of Chemistry and Materials Engineering, Wenzhou University,
Wenzhou 325035, China.
⁎⁎
Corresponding author at: Hefei National Laboratory of Physical Sciences at the Microscale, School of Chemistry and Materials Sciences, University of Science and
Technology of China, Hefei 230026, China.
E-mail addresses: fanggy@wzu.edu.cn (G. Fang), zyli@ustc.edu.cn (Z. Li).

https://doi.org/10.1016/j.mcat.2019.01.021
Received 11 December 2018; Received in revised form 11 January 2019; Accepted 21 January 2019
Available online 25 January 2019
2468-8231/ © 2019 Elsevier B.V. All rights reserved.
L. Xu et al.
Scheme 1. Synthesis and chemical structure of cucurbit[n]urils.
is an important synthesis technique for β-alkoxy alcohols, which are
useful intermediates and can be used to generate α-alkoxy ketones, α-
alkoxy acids, and many natural products and drugs. We investigated the
catalytic mechanism of metal-free cucurbituril solids for epoxide alco-
holysis. It is expected that insights into the catalytic mechanism of
cucurbituril solid may increase the knowledge of heterogeneous and
supramolecular catalysis.
2. Computational details
All stationary points for the alcoholysis reactions of StyOx without a
catalyst and with an acidic catalyst and cucurbituril solid were opti-
mized fully within the framework of density functional theory (DFT) in
the Gaussian 09 program [56]. The 6–311 G(d,p) basis set and GD3
dispersion-corrected M06-2X functional (M06-2X-GD3) were used for
all calculations, which can describe the noncovalent interaction
[57–61]. All geometry optimizations were performed in ethanol solvent
with a solvation model based on density [62,63]. This solution-phase
optimization method can yield a reasonable free-energy surface of so-
lution reactions [62]. To simulate the condition for heterogeneous
catalysis, all atoms of cucurbituril solid were fixed in geometry opti-
mizations. The Gibbs free energies of all species were calculated at
298.15 K and 1 atm and corrected by 1.9 kcal/mol to convert 1 atm to
1 M standard state [63]. The vibrational frequency and intrinsic reac-
tion coordinate (IRC) calculations were carried out to verify whether a
minimum or a transition state exists [64].
3. Results and discussion
3.1. Alcoholysis of epoxides without catalyst
In general, the ring-opening reactions of epoxide alcoholysis require
catalysts, such as acids, bases, or zeolites [65,66]. For example, etha-
nolysis of StyOx occurs with difficulty without a catalyst, and includes
two possible regioselective pathways (P1 and P2) (Scheme 2). Herein,
alcoholysis of StyOx is used only as a reference reaction and facilitates
the discussion of subsequent mechanisms with acid and cucurbituril
catalysts. To represent the stationary points along all the pathways in a
concise way, we use denotations of intermediates Im1 and Im2, tran-
sition states TS1 and TS2, and products P1 and P2. Superscripts, P1 and
Scheme 2. Two regioselective pathways (P1 and P2) of StyOx ethanolysis.
2
Molecular Catalysis 467 (2019) 1–8
P2, nocat, and H3O+, represent different pathways and catalytic con-
ditions.
Fig. 1 shows the Gibbs free-energy profiles of two reaction pathways
of StyOx and ethanol without a catalyst. The corresponding products
are 2-ethoxy-2-phenylethanol (P1, StyOEt) and 2-ethoxy-1-pheny-
lethanol (P2), respectively. The former is a useful β-alkoxy alcohol. The
difference between the two pathways is that the hydroxyl group of
ethanol can attack different CeO bonds (C1eO3 and C2eO3, shown in
Scheme 2) of the epoxy group of styrene oxide, which results in StyOx
regioselectivity. They can form a concerted four-membered ring (4MR)
transition state (TS) that is composed of epoxy and hydroxyl groups.
Finally, they can be converted into β-ethoxy alcohol products. During
the ring-opening of the first P1 pathway, the old CeO bond of the epoxy
group is lengthened from 1.43 Å (Im1) to 2.23 Å (TS1) and 2.44 Å (P1),
and that of the old OeH bond of the hydroxyl group is lengthened from
0.97 Å (Im1) to 1.03 Å (TS1) and 2.35 Å (P1). The distance of the C and
O atoms of the reaction center is reduced from 3.11 Å (Im1) to 2.64 Å
(TS1) and 1.42 Å (P1). That of the O and H atoms is shortened from
2.02 Å (Im1) to 1.50 Å (TS1) and 0.96 Å (P1). These results indicate
that the epoxy group is opened, the hydroxyl group is broken, and new
CeO and OeH bonds are formed. The second P2 pathway is similar to
the first. From an energy perspective, the two products, P1 and P2, are
almost similarly exergonic by 15.3 and 15.0 kcal/mol, respectively.
However, the two regioselective pathways require high activation free
energies of 45.0 and 59.3 kcal/mol, which indicates that the two
pathways cannot occur in the absence of a catalyst.
3.2. Alcoholysis of StyOx with acid catalyst
It is difficult to react StyOx and ethanol without a catalyst. Aqueous
acid can be used as a catalyst for the ring-opening of epoxides [65,66].
The reaction mechanism of acid-catalyzed ethanolysis of StyOx is
considered further.
Fig. 2 show a possible stepwise mechanism for the reaction of StyOx
and ethanol with an acid (hydronium ion, H3O+) catalyst. H3O+ can
interact with StyOx and ethanol to form a hydrogen-bonding inter-
mediate, Im1P1,H3O+, in which the epoxy group is almost protonated
by H3O+ with a distance of 1.14 Å, which facilitates the ring-opening of
StyOx. It can undergo a transition state of the ring-opening of the epoxy
group, TS1P1,H3O+, in which the proton is transferred entirely to the
epoxy group and the C1-O3 bond is lengthened from 1.47 Å to 1.98 Å.
The reaction can then proceed via an intermediate, Im2P1,H3O+, which
comprises water, ethanol, and carbenium ion, in which the carbenium
ion is planar and is located 3.54 Å from the ethanol hydroxyl group.
Afterwards, the ethanol molecule can attack the planar carbenium ion
via a low-energy transition state, TS2P1,H3O+, and the distance of the C
atom of the carbenium ion and the O atom of ethanol can be reduced to
3.26 Å. Lastly, a new CeO bond and hydrogen-bonding intermediate,
Im3P1,H3O+, is formed and the product, 2-ethoxy-2-phenylethanol
(P1), is deprotonated. The H3O+ is recycled.
Because of its planar property, the carbenium ion is susceptible to
frontside and backside-attacks by ethanol. Two products (P1 and P1’)
of 2-ethoxy-2-phenylethanol are enantiomers and mirror images of each
L. Xu et al. Molecular Catalysis 467 (2019) 1–8

Fig. 1. Two options for the regioselective ring-opening ethanolysis of StyOx. Values represent the distances between two atoms (Å).

other. This property is termed epoxide stereoselectivity. In homo- occur easily.

geneous catalysis, ethanol exists in a free state and can attack the car-
benium ions from the front and the back. So, the stereoselectivity of
StyOx alcoholysis is difficult to control.
The rate-determining step of the entire pathway is a H3O+-cata-
lyzed ring-opening of StyOx with an energy barrier of 9.4 kcal/mol.
Ethanol attack of the planar carbenium ion is almost barrierless and
requires only 1.4 kcal/mol. The energy barrier for product release is
only 8.5 kcal/mol. Therefore, H3O+-catalyzed epoxide alcoholysis can
Fig. 3 shows another regioselective pathway for the reaction of
StyOx and ethanol with a H3O+ catalyst. This pathway is similar to the
P2 pathway without a catalyst and the open C2eO3 bond of the epoxy
group. Because the C2eO3 bond is not linked to the conjugated benzyl
group, this pathway does not undergo an intermediate of the planar
carbenium ion. First, H3O+, StyOx, and ethanol can form a strong hy-
drogen-bonding intermediate, Im1P2,H3O+, in which the ethanol hy-
droxyl group is located on one side of the C2eO3 bond of the epoxy

Fig. 2. Two stereoselective H3O+-catalyzed pathways (H3O+-catalyzed P1 and H3O+-catalyzed P1’) of StyOx ethanolysis via the first regioselective pathway. Values
represent the distances between two atoms (Å).

3
L. Xu et al.
Fig. 3. Another regioselective H3O+-catalyzed pathway (H3O+-catalyzed P2)
of StyOx ethanolysis. Values represent the distances between two atoms (Å).
group. This group undergoes a concerted transition state, TS1P2,H3O+,
in which the epoxy group is opened and a new CeO bond is formed.
The old OeH bond is broken and a new OeH bond is formed via proton
transfer. Finally, a hydrogen-bonding intermediate, Im2P2,H3O+, forms
and the product, 2-ethoxy-1-phenylethanol (P2), is deprotonated.
The energy barrier of the H3O+-catalyzed P2 pathway can be
˜30.0 kcal/mol lower than that of the P2 pathway without a catalyst
and decreased from 59.3 kcal/mol to 29.5 kcal/mol, which indicates
that H3O+ can accelerate the chemical reaction. Compared with the
H3O+-catalyzed P1 pathway, the H3O+-catalyzed P2 pathway does not
produce a planar carbenium ion intermediate and is unfavorable. These
results show that the regioselectivity for β-alkoxy alcohols is an in-
herent character of StyOx ethanolysis and stems from different groups
that are linked to the epoxy group. This finding is also consistent with
the experimental results, where the product is the unique β-alkoxy al-
cohol [52]. In the ensuing studies, only the first regioselective pathway
(P1) is considered.
The H3O+-catalyzed ethanolysis of StyOx is a hypothetical situa-
tion. If H3O+ is present in the ethanolysis, then water (H2O) can par-
ticipate in the chemical reaction. As a nucleophile, H2O can attack the
carbenium ion and compete with the ethanol. The product is a diol, 1-
phenylethane-1, 2-diol (P3, Scheme 3). The reaction is the hydrolysis of
StyOx and the product has no regioselectivity, which differs from the
alcoholysis of StyOx.
Fig. 4 shows the H3O+-catalyzed hydrolysis mechanism of StyOx,
which is similar to the catalyzed ethanolysis mechanism that includes
the ring-opening of the epoxy group, the attack of the hydroxyl group
on the carbenium ion, and the release of the product. Because of the
planar property and stereoselectivity of the carbenium ion, the hydro-
lyzed product of StyOx, 1-phenylethane-1, 2-diol, also includes two
enantiomers (P3 and P3’). As shown by the forward energy barriers (7.9
and 8.1 kcal/mol) of the ring-opening of the epoxy group and the attack
of nucleophiles on the carbenium ion in Figs. 2 and 4, the ethanolysis of
StyOx and H3O+-catalyzed hydrolysis can compete. However, on the
basis of the principle of microscopic reversibility [67], the reverse
4
Molecular Catalysis 467 (2019) 1–8
energy barriers of TS1P1,H3O+ that result in β-alkoxy alcohol (P1 + P1')
and TS1P3,H3O+ that result in 1, 2-diol (P3 + P3') are 7.4 and 5.2 kcal/
mol, respectively. According to the Arrhenius equation [68], this
2.2 kcal/mol energy difference indicates that the reaction under con-
sideration gives β-alkoxy alcohol as the major product with a trace
amount of 1, 2-diol.
3.3. Ethanolysis of StyOx in CB7 solid phase
As well-known supramolecular catalysts, CBn has been used in
heterogeneous catalysis [51,52]. In general, cucurbiturils are synthe-
sized under acidic reaction conditions [28–33]. The crystal structures of
cucurbiturils show that H3O+ is located at the negatively charged
carbonyl portals and the corresponding anion lies at the CBn voids
[69–72]. Based on the shape and size of the host and guest molecules,
we selected one cucurbituril, cucurbit[7]uril (CB7), and investigated
the ethanolysis mechanism of StyOx in CB7 solid. As shown in Fig. 5,
H3O+ and CB7 can form a protonated CB7 (CB7·H3O+) via two strong
hydrogen bonds with a distance of 1.50 Å and 1.51 Å, respectively.
Because of its unique cavity and acidic property, CBn can be used as a
solid acid catalyst to catalyze the ethanolysis of StyOx.
Fig. 5 shows the Gibbs free energy profile of frontside-attack etha-
nolysis of StyOx in protonated CB7. The catalytic mechanism is similar
to the acid-catalyzed mechanism. Two guest molecules, ethanol and
StyOx, enter the host molecule and protonate CB7, which can lead to
the formation of a stable intermediate, Im1P1,CB7·H3O+. In
Im1P1,CB7·H3O+, the epoxy group of StyOx and H3O+ at the carbonyl
portal of CB7 can form a strong 1.47-Å hydrogen bond, which facil-
itates subsequent ring-opening. The ethanol molecule can locate im-
mediately below H3O+ and the epoxy group. Subsequently, the epoxy
group of the StyOx in the protonated CB7 can be opened because of
H3O+ via a transition state, TS1P1,CB7·H3O+, where the epoxy group is
protonated completely and the distance of the CeO bond of the epoxy
group increases from 1.44 Å to 1.94 Å. This can result in the formation
of an intermediate, Im2P1,CB7·H3O+, between the carbenium ion and
ethanol in the CB7 cavity. The ethanol molecule can attack the carbe-
nium ion from the front via a mostly barrierless transition state,
TS2P1,CB7·H3O+, in which the distance of the C atom of the carbenium
ion and the O atom of ethanol decreases from 3.16 Å to 2.24 Å. Lastly,
the intermediate, Im3P1,CB7·H3O+, and β-ethoxy alcohol (P1) in the CB7
cavity is formed and the product is released from the CB7 cavity. The
protonated CB7 (CB7·H3O+) is recycled.
In the frontside-attack pathway in CB7, the barriers of the ring-
opening of the epoxy group of StyOx and the attack of ethanol on the
planar carbenium ion are 11.3 and 1.2 kcal/mol, respectively. Because
of the strong interaction between CB7 and the guest molecules, the free
energies of all the intermediates and transition states are lower than
that of the reactants. The rate-determining step of the CB7-catalyzed
pathway is the release of β-ethoxy alcohol from the solid CB7 and the
barrier is 15.8 kcal/mol. These results indicate that the unique cavity of
CBn and H3O+ at the portal of the solid CB7 can catalyze the epoxide
alcoholysis synergistically.
In the cavity of the solid CB7, ethanol is also located on another side
of H3O+ and the epoxy group of StyOx. Fig. 6 shows the backside-
attack ethanolysis of StyOx in protonated CB7. Frontside or backside-
attack results in H3O+ at the portal of CB7 interacting strongly with the
epoxy group, which can decrease the energy barrier and catalyze the
ring-opening of StyOx significantly. For frontside-attack, the ethanol
molecule and the epoxy group of StyOx are located on one side, as
shown in Im1P1,CB7·H3O+ of Fig. 5. For backside-attack, the ethanol
Scheme 3. Hydrolysis reaction pathway of StyOx.
L. Xu et al. Molecular Catalysis 467 (2019) 1–8

Fig. 4. Two regioselective H3O+-cata-

lyzed pathways (H3O+-catalyzed P3
and H3O+-catalyzed P3’) of StyOx hy-
drolysis. Values represent the distances
between two atoms (Å).

Fig. 5. Frontside-attack ethanolysis of StyOx in solid CB7. Values represent the distances between two atoms (Å).

molecule and the epoxy group of StyOx are located on two sides, as product P1’ of the backside-attack pathway is an enantiomer of the
shown in Im1P1’,CB7·H3O+ of Fig. 6. frontside-attack pathway. From Im3P1’,CB7·H3O+, the energy barrier of
Similar to the frontside-attack pathway, backside-attack ethanolysis the release of the product is up to 24.6 kcal/mol. Furthermore, the
also includes the ring-opening of StyOx, the attack of ethanol on the backside-attack pathway is endergonic by 4.2 kcal/mol, which is
planar carbenium ion, and product release. The entire backside-attack 19.5 kcal/mol higher than that in the frontside-attack pathway. These
pathway passes through Im1P1’,CB7·H3O+, TS1P1’,CB7·H3O+, results indicate that the backside-attack pathway is thermodynamically
Im2P1’,CB7·H3O+, TS2P1’,CB7·H3O+, and Im3P1’,CB7·H3O+. However, the and kinetically unfavorable. The reason for this behavior is that the

5
L. Xu et al. Molecular Catalysis 467 (2019) 1–8

Fig. 6. Backside-attack ethanolysis of StyOx in solid CB7. Values represent the distances between two atoms (Å).

release of the product damages the structure of the initial protonated

CB7 and the catalyst cannot be recovered to the initial CB7·H3O+ state.
In addition, as shown in Fig. 6, after the ring-opening of StyOx, the
H2O molecule, which was converted from H3O+ and had absorbed at
the portal of CB7, may attack the planar carbenium ion, which results
in the formation of 1-phenylethane-1, 2-diol (P3). Subsequently, the
H2O-attacked pathway produces Im2P3,CB7·H3O+, TS2P3,CB7·H3O+, and
Im3P3,CB7·H3O+. The release of product P3 requires a high barrier of
31.9 kcal/mol. Furthermore, this H2O-attacked pathway is endergonic
by 3.7 kcal/mol, which is 19.0 kcal/mol higher than that in the front-
side-attack pathway. Product release in the H2O-attacked pathway also
damages the structure of the initial protonated CB7 and limits catalyst
regeneration. The H2O-attacked pathway in the solid CB7 is thermo-
dynamically and kinetically unfavorable. So, producing the diol (P3) in
the presence of CB7 is very difficult. This finding agrees with the het-
erogeneous experimental result, where the product of StyOx ethanolysis
catalyzed by CB7 solid is unique StyOEt and not the diol [52].
A comparison of Figs. 5 and 6 shows that the frontside-attack
pathway of StyOx ethanolysis in the solid CB7 is the most favorable Fig. 7. Probable catalytic cycle of StyOx ethanolysis by CB7 solid.
pathway (Fig. 7), which is different from the case via free H3O+ cata-
lysis mentioned above. In such a frontside-attack pathway, the epoxy formation of a planar carbenium ion. StyOx can be hydrolyzed via
group of StyOx can be regioselectively ring-opened by the protonated homogenous catalysis of acid to produce 1, 2-diol. The CB7 solid has an
CB7 via a strong hydrogen bonding and then stereoselectively attacked inherent acid property and can catalyze epoxide alcoholysis via het-
by EtOH. These results show that StyOx alcoholysis should have re- erogenous catalysis. The unique cavity of CB7 can lead to a favorable
gioselectivity and stereoselectivity via heterogeneous supramolecular frontside-attack of ethanol to StyOx. The product via heterogeneous
catalysis of the metal-free CB7 solid. Because the reactant, StyOx, has catalysis of CB7 solid is pure β-alkoxy alcohol. These findings on the
two enantiomers and CB7 has two symmetrical portals, it is difficult to selectivity and mechanism of heterogeneous and supramolecular cata-
control the stereoselectivity of StyOx ethanolysis. However, the product lysis of cucurbituril solid may help in the design of new and effective
must be regioselective and pure β-alkoxy alcohol [52]. supramolecular catalysts.

4. Conclusions Acknowledgements

In summary, the uncatalyzed, acid-catalyzed, and cucurbituril-cat-
alyzed mechanisms of epoxide alcoholysis have been investigated by
performing DFT calculations. StyOx ethanolysis has an inherent re-
gioselectivity, which stems from different groups linked to the epoxy
group. H3O+ can catalyze the ring-opening of StyOx, and lead to the
This work was supported by the National Natural Science
Foundation of China (21703158) and the Zhejiang Provincial Natural
Science Foundation of China (LQ15B030001). We thank Professors
Qing Xu and Jun Jiang of Wenzhou University for helpful discussions
and the National Supercomputer Center in Guangzhou and the

6
L. Xu et al.
Supercomputing Center of University of Science and Technology of
China for providing computing resources.
Appendix A. Supplementary data
Supplementary material related to this article can be found, in the
online version, at doi:https://doi.org/10.1016/j.mcat.2019.01.021.
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