Requirements for Terpene Cyclizations inside the Supramolecular Resorcinarene Capsule: Bound Water and Its Protonation Determine the Catalytic Activity

Article abstract of DOI:10.1021/jacs.9b13239

The elucidation of the requirements for efficient catalysis within supramolecular host systems is an important prerequisite for developing novel supramolecular catalysts. The resorcinarene hexamer has recently been shown to be the first supramolecular catalyst to promote the tail-to-head terpene cyclization in a biomimetic fashion. We herein present the synthesis of a number of resorcinarene-based macrocycles composed of different ratios of resorcinol and pyrogallol units capable of self-assembly and compare the corresponding assemblies regarding their catalytic activity in the cyclization of monoterpenes. The assemblies were investigated in detail with respect to a number of properties including the encapsulation of substrate and ion pairs, the structural incorporation of water, and the response to externally added acid (HCl). The results obtained strongly indicate that water incorporated into the hydrogen-bond network of the self-assembled structure plays an integral role for catalysis, effectively acting as a proton shuttle to activate the encapsulated substrate. These findings are also supported by molecular dynamics simulations, providing further insight into the protonation pathway and the relative energies of the intermediates involved.

Full text of DOI:10.1021/jacs.9b13239

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Article
Requirements for Terpene Cyclizations inside the
Supramolecular Resorcinarene Capsule: Bound Water
and its Protonation Determine the Catalytic Activity
Severin Merget, Lorenzo Catti, GiovanniMaria Piccini, and Konrad Tiefenbacher
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b13239 • Publication Date (Web): 07 Feb 2020
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Requirements for Terpene Cyclizations inside the Supramolecular
Resorcinarene Capsule: Bound Water and its Protonation Determine
the Catalytic Activity
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†
‡
#
*,†, §
Severin Merget, Lorenzo Catti, GiovanniMaria Piccini, Konrad Tiefenbacher
†Department of Chemistry, University of Basel, Mattenstrasse 24a, CH-4058 Basel, Switzerland
‡Current address: Laboratory for Chemistry and Life Sciences, Tokyo Institute of Technology, 4259 Nagatsuta, Midori-
ku, Yokohama 226-8503, Japan
#Department of Chemistry and Applied Biosciences, ETH Zurich, c/o USI Campus, Via Giuseppe Buffi 13, CH-6900
Lugano, Switzerland; Facoltàdi Informatica, Istituto di Scienze Computazionali, Universitàdella SvizzeraItaliana (USI),
Via Giuseppe Buffi 13, CH-6900 Lugano, Switzerland
§Department of Biosystems Science and Engineering, ETH Zürich, Mattenstrasse 26, CH-4058 Basel, Switzerland
Supporting Information Placeholder
ABSTRACT: The elucidation of the requirements for efficient catalysis within supramolecular host systems is an important
prerequisite for developing novel supramolecular catalysts. The resorcinarene hexamer has recently been shown to be the first
supramolecular catalyst to promote the tail-to-head terpene cyclization in a biomimetic fashion. We herein present the synthesis of
a number of resorcinarene-based macrocycles composed of different ratios of resorcinol and pyrogallol units capable of self-
assembly, and compare the corresponding assemblies regarding their catalytic activity in the cyclization of monoterpenes. The
assemblies were investigated in detail with respect to a number of properties including the encapsulation of substrate, and ion pairs,
the structural incorporation of water and the response to externally added acid (HCl). The results obtained strongly indicate that
water incorporated into the hydrogen bond network of the self-assembled structure plays an integral role for catalysis, effectively
acting as a proton shuttle to activate the encapsulated substrate. These findings are also supported by molecular dynamics
simulations, providing further insight into the protonation pathway and the relative energies of the intermediates involved.
diversity. Many members exhibit interesting biological activity,
making them suitable lead compounds for drug development.
Introduction
7
Since most compounds in this class require considerable
synthetic effort and are often not available in significant
quantity, an efficient method to access these compounds from
rather simple precursors would provide a powerful tool to the
organic synthetic community. Utilizing capsule I as an aromatic
cavity with some similarities to natural cyclase enzymes, we
The catalytic power and selectivity displayed by natural
enzymes still serves as inspiration and role model for many
1
organic chemists working in the broad field of catalysis.
Chemists successfully mimicked some aspects of enzyme
catalysis utilizing self-assembled supramolecular host
2
, 3
structures.
were able to showcase some first examples: A four-step total
Numerous reactions within different host structures have been
reported, however, their catalytic efficiency and selectivity
usually do not rival their natural counterparts. In order to close
this gap, and to design new, more efficient catalysts, it is
essential to understand the fundamental requirements for
catalytic activity in these artificial systems.
5c
synthesis of isolongifolene, the first total synthesis of
5d

-selinene, as well as a four step synthesis of the complex
8
tricyclic presilphiperfolan-1β-ol, which is difficult to access via
9
other means. Interestingly, the closely related hexamer II,
which is formed from six units of pyrogallolarene 2 (Figure 1b)
has been found to be catalytically inactive in THT cyclizations.
The reason for its inactivity, however, remained unknown. We
previously speculated that either its low intrinsic acidity, or
its inability to bind ion pairs are the cause for this observation.
To clarify this issue, we decided to closely investigate
assemblies I and II, as well as the related macrocycles 3 ‒ 5
(Figure 1d), featuring different ratios of resorcinol and
pyrogallol units. Additionally, the electron-deficient
tetrafluorinated resorcinarene derivative 6 was selected. As
the main test reaction, we chose the THT cyclization of geranyl
acetate (7) to -terpinene (8, Figure 1c, Scheme S1), a reaction
1
0
One of the most frequently applied supramolecular catalyst is
the hexameric capsule I (Figure 1a). It self-assembles from six
units of resorcinarene 1 and eight molecules of water in apolar
1
0
4
media such as chloroform. A number of reactions involving
mainly cationic transition states have been reported using
2
k, 2n, 2q-s
structure I as a catalyst.
A prime example is the
successful catalysis of the tail-to-head terpene (THT)
5
cyclization inside I developed by our group, which utilizes the
supramolecular cavity to enable a reaction that is very difficult
6
to perform in bulk solution. Terpenes form one of the largest
classes of natural products with remarkable structural
5
a
which was shown to undergo a “non-stop” cyclization inside I.
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a)
c) Model reaction: THT Terpene Cyclization
HO
OH
C11H23
C11H23
HO
Assembly
(10 mol%)
OH catalytically
active ()
OAc
HCl
(3 mol%)
HO
C11H23
OH
C11H23
geranyl
acetate (7)
HO
OH
H2O is part of the
H bond network
-terpinene (8)
1
1
6(H2O)8  I ()
OH
R1
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b)
d)
HO
OH
C11H23
HO
OH
C11H23
C11H23
HO
C11H23
HO
This Work:
3 (R = OH, R = H)  III
OH catalytically
inactive ()
OH
1
2-4
2 4a (R1,2
R
= OH, R3,4 = H)  IV
HO
OH
R4
4b (R1,3 = OH, R2,4 = H)  n. a.
5 (R1-3 = OH, R4 = H)  V
HO
C11H23
OH
HO
C11H23
OH
C11H23
OH
C11H23
OH
6 (R1-4
= F)  VI
HO
H2O is not part of the
H bond network
HO
R3
OH
2

26  II ()
insoluble in CDCl3  no self-assembly
Figure 1: a) Self-assembly of I from six units of 1 and eight water molecules, four of which are not fully saturated within the hydrogen
bond network and can function as hydrogen bond donor at the inside of the cavity. b) Self-assembly of II from six units of 2 forming
a fully saturated hydrogen bond network without water. c) Tail-to-head terpene (THT) cyclization of geranyl acetate (7) forming -
terpinene (8). d) Macrocycles 3 ‒ 6 corresponding to assemblies III ‒ VI.
Concerning the prerequisites for catalytic activity, we
considered the following steps in the catalytic cycle as
potentially decisive (Scheme 1): (a) For a successful conversion
inside the molecular capsule, the substrate has to be
encapsulated. Therefore, substrate uptake in the different
assemblies was explored first. (b) The substrate has to be
Results and Discussion
Synthesis of Macrocycles 3 ‒ 6 and Investigation of their Self-
assembling Properties
5b
activated by protonation. Protonation in an apolar solvent
First, it was necessary to develop a reliable route to access the
macrocycles 3 ‒ 6, in pure form on a preparative scale
(Scheme 2). While there has been a report about directly
cyclizing different ratios of resorcinol and pyrogallol with the
corresponding aldehyde to obtain macrocycles 3 ‒ 5 by Atwood
et al., these reactions yielded very complex mixtures that were
like chloroform leads to the formation of ion pairs.
Consequently, we next investigated the ability of the
assemblies to encapsulate ion pairs. (c) Cationic intermediates
and transition states have very likely to be stabilized via cation-
π interactions. Accordingly, we included an electron-deficient
derivative (i.e. 6) featuring four additional fluorine
substituents in the study as it should display reduced cation-
stabilization.
9
d
not separable in our hands. To circumvent these separation
issues, a more controlled route utilizing tetrabromo-derivative
9 was developed (Scheme 2). Compound 9 is accessible via
literature procedures in two steps from resorcinarene 1 on
11
H
decagram scale. It was partially debrominated by treatment
(b) Protonation
with specific amounts of n-butyllithium, and subsequently
methanol. The remaining aryl bromides were then converted
in situ into phenolic moieties using n-butyllithium and
I
H
S
SH
(c) Stabilization of
Cationic
(a) Uptake
H
Intermediates/TS
H
1
2
trimethylborate followed by the addition of NaOH/H
yielded biased mixtures of the octamethylated compounds
0 ‒ 12 which were separable by column chromatography. The
2 2
O . This
S
1
P
tetrafluorinated compound 13 was accessed in a similar way
from 9 using halogen-lithium exchange followed by the
P
Scheme 1: Potentially decisive steps of the catalytic cycle;
S = Substrate, TS = Transition States, P = Products.
addition
of
the
electrophilic
fluorine
reagent
1
3
N-fluorobenzenesulfonimide (NFSI). The removal of the
methyl protecting groups was achieved by stirring in the
presence of boron tribromide at room temperature for several
Here, we report efficient synthetic routes to macrocycles 3 ‒ 6
Figure 1d), their ability to self-assemble to the hexameric
capsules III ‒ VI, and provide evidence that water being
incorporated into the hydrogen bond network of the
corresponding assemblies plays a crucial role for the efficient
catalytic cyclization of monoterpenes.
1
4
(
days, yielding compounds 3 ‒ 6 in moderate to good yields
and in analytically pure form (see SI Chapter 12). The products
were recrystallized and subsequently washed with
O/MeOH mixture in order to remove any acid traces (see SI
for details). Aside from compound 4b, featuring two distal
pyrogallol units, all macrocycles were soluble in chloroform,
and self-assembled to hexameric capsules related to I and II.
a
H
2
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DOSY-NMR experiments15 provided diffusion values for the
new assemblies very close to those of assemblies I and II (see
Table S2). Self-assembly was further corroborated by the fact
that assemblies III ‒ VI show uptake of ammonium salts (i.e.
product, albeit in a lower yield. When employing assembly IV
1
2
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4
5
6
7
8
9
1
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6
(Figure 2c), the conversion of substrate remained significant,
but the overall yield of cyclization products dropped
significantly. We attribute this fact to a side reaction in which
phenolic groups of 4a react with the highly reactive cationic
intermediates of the cyclization reaction. This was also
4
NBu Br (14), Figure S18) indicated by the strong upfield shift
of the guest protons due to the aromatic shielding effect. We,
therefore, concluded that the obtained macrocycles form
assemblies resembling the structures of I and II. However, it
has to be noted that in the case of the assemblies III ‒ V, the
structures are not as symmetric and clearly defined as in I and
II. Due to the lower degree of symmetry of the macrocycles,
5
a
observed for I in an earlier report and confirmed by isolation.
In the current study, these alkylation products were detected
by ESI-MS analysis of the reaction mixtures (see Figures S9 ‒
S14) in the cases of the assemblies I, III and IV. DOSY-NMR
measurements during the reaction indicate that the assemblies
stay largely intact (SI Chapter 7.4). Interestingly, assembly V
(Figure 2d) with three pyrogallol units showed no catalytic
activity in this cyclization reaction. The reaction in the
presence of assembly VI (Figure 2f) featuring subunits with
fluorine substituents proceeded very slowly. Similar results
were obtained when the reaction was conducted with the
intrinsically more reactive nerol (20) as the substrate (see
Figure S3 for the reaction profiles). Assemblies I, III and IV
showed comparable behavior with only small differences in
product selectivity. Initially, mainly α-terpineol (25) is formed,
which is then further converted to eucalyptol (15), the major
product after 72 hours (30 ‒ 38% yield). In the case of the
fluorinated assembly VI, the formation of α-terpineol (25) in
combination with traces of eucalyptol (15) (4% after 72 hours)
indicates a reaction profile similar to the one of assembly I,
with the conversion being, however, again significantly slower.
Assembly II shows no activity, while the closely related
assembly V leads to considerable conversion (60% conversion
after 72h, Table 1, entry 1). At first glance, this seemed
surprising since assembly V showed no conversion with
geranyl acetate (7). In order to understand this observation,
control experiments with assembly V were conducted (Table
different isomers of hexameric capsules are formed. The broad
0
1
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0
1
signals in the H-NMR spectra recorded in CDCl
3
suggest that
there is more than one assembly present and that these are
interconverting. Solid state structures could not be obtained
since crystal formation is hindered by the dynamic nature of
the assemblies, and the long flexible alkyl chains. Besides,
crystal structures do not always correlate with structures
9
d
present in solution as illustrated by macrocycle 5. While we
cannot exclude the presence of the previously reported, X-ray-
9
d
based donut shaped structure, none of the experiments we
carried out hinted at such an assembly in solution. In the case
of assembly VI, the NMR spectrum closely resembles that of the
resorcinarene-based capsule I, indicating a similar structure.
(
see SI for the energy optimized structure)
Evaluation of the Catalytic Activity in the Cyclization of
Monoterpenes
With assemblies I ‒ VI in hand, the cyclization of geranyl
acetate (7, Figure 1c) as the model reaction was investigated
employing the optimized conditions reported previously by
5
b
our group for assembly I. HCl is added as a co-catalyst, which,
1
). No conversion was observed in the absence of V with HCl
unable to catalyze the reaction by itself, works in a synergistic
present (entry 2). Blocking assembly V with tetrabutyl
ammonium bromide (14) did not halt the reaction completely
1
0
fashion with the assembly. As reported by us, no reaction was
observed with assembly II (Figure 2e), while assembly I
(
13%, entry 3), indicating that the reaction is not only taking
(
Figure 2a) catalyzed the formation of α-terpinene (8) from
place within the cavity in that case. This was further
corroborated by substituting assembly V with 4-hexyl
resorcinol (21) which also led to some conversion of nerol (20)
acetate 7 in 30 ‒ 35% yield. The reaction proceeds in good
selectivity with other common cyclization products (Figure 2g)
such as eucalyptol (15), terpinolene (16), limonene (17),
-terpinene (18) and isoterpinolene (19) being only formed in
minor quantities (< 10% yield). Assembly III (Figure 2b),
formed from monomer 3, featuring one additional hydroxyl
group compared to resorcinarene 1, also displayed catalytic
activity and likewise yielded α-terpinene (8) as the main
(
10%, entry 5) after three days. Moreover, the product
distribution of entry 1 indicated that the reaction likely takes
place outside/on the outer surface of the capsule. The main
products are limonene (17) and -terpineol (25), which are
also formed in regular solution experiments under acidic
16
conditions, and in the presence of 4-hexyl resorcinol (21).
Br
R1
R1
MeO
C11H23
OMe
C11H23
MeO
C11H23
OMe
C11H23
HO
C11H23
OH
C11H23
MeO
OMe
MeO
OMe
HO
OH
a) x eq. nBuLi, THF
then MeOH
BBr3, CH2Cl2
Br
Br
R4
R2
R4
R2
b) y eq. nBuLi, THF
then B(OMe)3
then
MeO
C11H23
OMe
C11H23
MeO
OMe
C11H23
HO
11H23
OH
C11H23
C
11H23
C
H2O2, NaOH
MeO
OMe
MeO
OMe
HO
OH
Br
9
R3
R3
10 (R1 = OH, R2-4 = H) (29%)
3 (R1 = OH, R2-4 = H) (68%)
1a (R = OH, R3,4 = H) (5%)
1,2
4a (R1,2 = OH, R3,4 = H) (48%)
1
1
1
1
1b (R = OH, R2,4 = H) (21%)
1,3
4b (R = OH, R2,4 = H) (58%)
1,3
2 (R1 = OH, R4 = H) (32%)
-3
5 (R = OH, R4 = H) (81%)
1-3
4
.5 eq. nBuLi
3 (R1-4 = F) (50%)
1-4
6 (R = F) (50%)
PhO2S
SO2Ph
N
F
Scheme 2: Synthesis of the macrocycles 3 ‒ 6 starting from the literature known compound 9.11
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a)
HO
C11H23
OH
C11H23
b)
c)
OH
1
2
3
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6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
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2
2
2
2
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3
3
3
3
3
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4
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5
5
5
5
5
5
5
6
HO
OH
OH
HO
C11H23
OH
C11H23
HO
C11H23
OH
C11H23
HO
OH
HO
OH
HO
C11H23
OH
C11H23
OH
HO
OH
HO
C11H23
OH
C11H23
HO
C11H23
OH
C11H23
1
/I
HO
OH
HO
OH
3/III
4
a/IV
0
1
2
3
4
5
6
7
8
9
0
1
2
3
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9
0
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0
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9
0
1
2
3
4
5
6
7
8
9
0
d)
e)
f)
OH
F
HO
C11H23
OH
C11H23
OH
HO
OH
HO
C11H23
OH
C11H23
C11H23
HO
C11H23
OH
HO
OH
HO
OH
OH
F
F
HO
OH
HO
C11H23
OH
C11H23
HO
OH
HO
C11H23
OH
C11H23
C
11H23
C11H23
HO
OH
HO
OH
OH
HO
OH
F
5/V
OH
6/VI
2/II
Figure 2 a ‒ f): GC-based reaction profiles of assemblies I, III, IV, V, II and VI with geranyl acetate (7) as substrate (reaction
conditions: 33.3 mmol/L of 7, 10 mol% assembly, 3 mol% HCl, in CDCl at 30 °C). g) Substrate 7 and reaction products. h) Additional
3
substrates and guests.
Table 1: Control experiments for the nerol (20) cyclization with
assembly V under standard reaction conditions. (33.3 mmol/L
of 20, 3 mol% HCl, in CDCl
Additionally, the absence of eucalyptol (15) which is usually
formed to a significant degree when the reaction takes place
within the assembly (i.e. in assembly I) indicates a conversion
outside the assembly. Taken together, these results indicate
that in this case the reaction is taking place mainly outside/on
the outer surface of assembly V presumably via hydrogen
bonding (Table 1, entry 5), due to the higher reactivity of nerol
(20). What causes the difference in capsules II and V? It is likely
3
at 30 °C)
Entry
Catalyst
Additive
(mol%)
Conversion (%) [a]
(72 h)
(
mol%)
1
V (10)
-
-
60
-
9b
that the perfect hydrogen bond network of II prevents
activation of nerol via hydrogen bonds. It should also be noted
that assembly V proved to be an inefficient catalyst in the
cyclization of other substrates (Figure 2h) such as geraniol
-
V (10)
-
2
3
n-Bu NBr (14) (15)
13
-
4
(
22), linalool (23), neryl chloroacetate (24), all of which
4
5
n-Bu NBr (14) (15)
showed less than 15% conversion after 72 hours. In the cases
where traces of product were detected, these correspond again
to limonene (17) and -terpineol (25), indicating that the
conversion is likely taking place in solution rather than inside
V (Figures S5 ‒ S7). In summary, the cyclization studies
revealed that assemblies I, III, IV and VI are active
supramolecular catalysts for the THT cyclization, while II and
V are inactive.
4
HO
OH
-
10
C6H13
(21) (240)
[a]
Determined by GC
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tetrabutylammonium triflate (27). In all cases, the presence of
1
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9
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1
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3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
the assembly causes a shift and broadening of the signal
corresponding to the triflate anion, with the sole exception
being assembly II where no effect on the triflate signal was
Substrate uptake is a prerequisite for catalysis inside the
capsule. In order to elucidate a potential correlation between
catalytic inactivity and inability of substrate uptake, a set of
NMR experiments was performed. For this purpose, the
saturated substrate analogue 26 (Figure 2h), which is not
converted in the presence of assemblies I ‒ VI and HCl, was
employed. Host and guest solutions in chloroform were mixed
in the ratios used for cyclization (1:10) in the presence of HCl
at 0 °C and immediately submitted to NMR spectroscopy. The
observed.
When
employing
tetrabutylammonium
tetrafluoroborate (28), similar results were obtained (Figures
S19, S20). This is in agreement with the ability of all assemblies
beside II to encapsulate ammonium salts such as TBAB (see
also SI Chapter 8.3). Importantly, the catalytically inactive
assembly V is able to bind ion pairs in contrast to the inactive
assembly II. In conclusion, the ability to encapsulate ion pairs
does not correlate with the catalytic activity of assemblies I ‒
VI.
1
samples were then stored at 30 °C and monitored by H-NMR.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
Guest uptake over time was determined via H-NMR analysis
Table 2), by comparison of the respective assembly signals
(
(internal standard) and the signal of ‘free’ 26. The values given
are calculated assuming that directly after addition no
encapsulation is observed. Table 2 shows that the amount of
non-encapsulated substrate 26 is decreasing with time in all
cases, indicating a gradual encapsulation of 26 by all
assemblies to varying degrees (for full details see Tables
S4 ‒ S9). This is further supported by the appearance of small
Assembly I
Assembly III
Assembly IV
1
signals below 0.5 ppm in the respective H-NMR spectra, which
-
78.0
-78.4
-78.8
-79
Assembly V
Assembly II
f1 (ppm)
continued to increase when the samples were monitored over
a longer period of time (see Figures S15, S16). Since all
assemblies investigated, including the catalytically inactive
assemblies II and V, showed some uptake of guest 26, a direct
correlation between catalytic activity and encapsulation of
substrate could not be established.
Assembly VI
NBu OTf (27)
4
-77.8 -78.0 -78.2 -78.4 -78.6 -78.8 -79.0 -79.2 -79.4 -79.6 -79.8 -80.0 -80.2 -80.4
f1 (ppm)
Table 2: Encapsulation of substrate analogue 26 by assemblies
I ‒ VI under reaction conditions. (33.3 mmol/L of 26, 10 mol%
assembly, 3 mol% HCl, in CDCl at 30 °C)
3
Figure 3: 19F-NMR spectra of assemblies I ‒ VI (3.33 mmol/L)
in the presence of 1.0 eq. of NBu OTf (27) in CDCl3.
4
Entry
Assembly
Encapsulation
after 6 h (%)
Encapsulation
after 48 h (%)
Protonation Studies
[a]
[a]
During the cyclization studies, we recognized that some
H-NMR signals of several assemblies changed upon the
addition of HCl as co-catalyst. Therefore, this phenomenon was
investigated in more detail. For this purpose, chloroform
solutions of the assemblies I ‒ VI were titrated with HCl
1
1
2
3
4
5
6
I
1.3
1.0
3.1
1.4
III
IV
V
(
3.33 mmol/L of assemblies I ‒ VI, 0.0 ‒ 1.0 eq. HCl added to the
0.3
0.7
1.5
1.0
2.3
same sample). The results (Figure 4) show that in four cases (I,
III, IV and VI, Figure 4a ‒ c and f) the signals corresponding to
the phenol groups as well as the water signal broaden with
increasing amounts of HCl. We attributed these changes to the
protonation of the assemblies by the external acid. In contrast,
the signals corresponding to the phenol groups of the
assemblies II and V (Figure 4d, e) remain unaffected by the
added acid and also the water signal only broadens to a very
small extent when compared to the other assemblies (Figures
4a ‒ c and f). This indicates that assemblies II and V are not
protonated by the external acid, at least on the H-NMR (500
MHz) time scale. A protonation of the phenolic groups of II
and V in the presence of unbound water seems unlikely
= 0) and protonated
≈ 6). The integrity of the assemblies I ‒ VI in
presence of 1.0 eq. HCl was confirmed by DOSY-NMR
experiments. (see SI Chapter 10 for details). Importantly, the
observed protonation of the host correlates well with the
observed catalytic activity of the respective assemblies in the
cyclization of monoterpenes.
0.5
II
0.6
0.3
VI
[a]
Determined by 1H-NMR Integration
Encapsulation of Ion Pairs
1
After encapsulation, protonation of the substrate with HCl in
the apolar solvent chloroform will form an ion pair. Therefore,
we investigated the ability of the different assemblies to
encapsulate ion pairs. While I readily encapsulates ammonium
salts (e. g. tetrabutylammonium bromide 14) as ion pairs, the
encapsulation of anions in assembly II has been shown to be
1
7
+
18
considering the pK
a
1
values of H
3
O (pK
a
9
phenols (pK
a
1
0
energetically unfavorable. The binding of anions can be easily
1
9
investigated with F-NMR when utilizing fluorine containing
1
9
anions (e.g. triflate). Figure 3 shows the F-NMR spectra of the
assemblies I ‒ VI in the presence of 1.0 equivalent of
5
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Journal of the American Chemical Society
Page 6 of 11
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Assembly I
Assembly III
Assembly IV
a)
b)
c)
1.0 eq HCl
1.0 eq HCl
1.0 eq HCl
0.5 eq
0.5 eq
0.3 eq
0.2 eq
0.1 eq
0.5 eq
0.3 eq
0.2 eq
0.1 eq
0.0 eq
0.3 eq
0.2 eq
0.1 eq
0.0 eq



0.0 eq
1
1.0 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5
f1 (ppm)
11.0 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5
f1 (ppm)
11.0 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5
f1 (ppm)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Assembly V
Assembly II
Assembly VI
d)
e)
f)
1.0 eq HCl
1.0 eq HCl
0.5 eq
0.5 eq
0.3 eq
0.2 eq
0.1 eq
0.3 eq
0
.2 eq
.1 eq
0



0.0 eq
0.0 eq
11.0 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5
f1 (ppm)
11.0 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5
f1 (ppm)
11.0 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5
f1 (ppm)
Figure 4: a ‒ f) NMR titration of the respective assembly (3.33 mmol/L) with HCl (0.0 ‒ 1.0 eq.). Representative signals corresponding
to phenol moieties and water are highlighted (green for catalytically active, red for catalytically inactive). The water signals are
marked with an asterisk ().
shift is associated with the incorporation of water into the
capsular hydrogen bond network. Water being incorporated
into the assembly and ‘free’ water in solution are in fast
20
Water as Integral Part of the Assembly
As mentioned before, the main structural difference between
assemblies I and II is the incorporation of water into the
hydrogen bond network. This can be directly observed in the
H-NMR spectra in CDCl , where the water signal in the
3
presence of I is significantly downfield shifted, while it remains
largely unaffected with II (Figure 4a and e, 0.0 eq. HCl). The
1
exchange on the H-NMR time scale, therefore, only one
averaged water signal is observed. The magnitude of the
downfield shift depends on the total amount of water present
in the solution; with a low water content leading to a stronger
shift. Cohen et al. reported a method based on DOSY-NMR
1
2
0
experiments to determine the water content in I and II.
a)
b)
c)
OH
HO
C11H23
OH
C11H23
HO
C11H23
OH
C11H23
OH
HO
OH
HO
OH
HO
C11H23
OH
C11H23
OH
HO
HO
C11H23
OH
C11H23
HO
C11H23
OH
C11H23
OH
HO
OH
HO
OH
HO
OH
C11H23
1/I
C
11H23
HO
3/III
OH
4a/IV
d)
e)
f)
F
HO
C11H23
OH
OH
C11H23
OH
OH
HO
HO
C11H23
OH
C11H23
HO
C11H23
OH
C11H23
F
F
HO
OH
HO
OH
HO
OH
C11H23
HO
OH
C
11H
OH
23
HO
OH
HO
OH
HO
OH
C11H23
F
C11H23
HO
C11H23
C11H23
HO
6/VI
OH
OH
OH
OH
/V
2/II
5
Figure 5: a ‒ f) Influence of the water content on the diffusion coefficients D of the assemblies (◆) and water (■). Experiments were
performed in CDCl3 solutions of the assemblies (3.33 ‒ 1.67 mmol/L).
6
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Journal of the American Chemical Society
If water is not part of the assembly, like in II, its diffusion value
surrounding phenol groups of the resorcinarene molecules. It
replaces the hydronium ion in the hydrogen bond network of
capsule I
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
is independent of the total water amount in the sample
(e.g. assembly II, Figure 5e). However, if water is an integral
part of the capsule, its diffusion value converges to the value of
the assembly when the total amount of water decreases
a)
(
assembly I, Figure 5a). Varying the water content of
chloroform solutions of the novel catalytically active
assemblies III, IV and VI (Figure 5 b, c, f) indicated that in these
cases water is part of the hydrogen bond network, similar to
structure I (Figure 5a). In contrast, the data obtained for the
inactive assembly V (Figure 5d) implies that water does not
take part in the formation of assembly V; the same observation
as was made for structure II (see SI for a molecular model of
assembly V). It should be noted that in the case of assembly IV,
due to an overlap between the water signal and signals of the
assembly, only a few measurements resulted in reliable data
points concerning the diffusion value of water. However,
considering that the water signal is shifted significantly and
that the diffusion values obtained are significantly lower than
the values observed for the assemblies containing no water, we
concluded that water is part of the hydrogen bond network of
assembly IV.
In conclusion, the incorporation of water into the hydrogen
bond network of the assembly correlates well with the catalytic
activity observed. Interestingly, the assemblies containing
water in the hydrogen bond network also displayed enhanced
protonation in the presence of HCl (see previous section).
These observations indicate a central role of the bound water
molecules for the catalytic activity.
H
Cl
C
H
O
O
H
R
Cl
H
Cl
H
O
H
O
H
H
O
H
O
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
O
R
A
R
O
O
B
b)
C
B
A
Molecular Dynamics Simulations
The results presented in the previous two sections, indicate
that water being part of the hydrogen bond network is essential
in the protonation of the assembly by an external acid; thereby
enabling catalysis within the host structures I, III, IV and VI. In
order to learn more details about the protonation event inside
the capsule, we turned to molecular dynamics (MD)
simulations. Specifically, capsule I containing encapsulated
geranyl acetate (7), and external HCl were submitted to
Figure 6: a) Free energy along the minimum free energy path
(MFEP) showing the three states` (A, B and C) relative
stabilities and free energy barriers separating them. b) Free
energy surface for the geranyl acetate (7) protonation by
means of HCl as co-catalyst for assembly I along the
coordination of the carbonyl-oxygen with the water oxygen
2
1
22
QM/MM (DFT, PBE, +D level ) MD simulations at 300 K using
2
3
the CP2K code. The QM region consisted of six resorcinol
units belonging to three adjacent resorcinarene molecules, one
water molecule, one HCl molecule and geranyl acetate (7),
whereas the rest of assembly I and the chloroform solvent
molecules were treated at the MM level (see SI for
computational details).
atom (CV
with the acidic hydrogen atoms (CV
1
) and the coordination of the water oxygen atoms
). Letters A, B, and C label
2
the minima corresponding to the metastable states referring to
the initial neutral state, the intermediate formation of the
As the proton transfer from HCl to the carbonyl-oxygen of
substrate 7 involves separate, relevant metastable states
separated by high free energy barriers along the reaction path,
standard MD is not suitable. Therefore, the sampling of the
+
-
3
H O /Cl ion pair, and the final protonation of the carbonyl-
+
3
oxygen by H O . The blue line passing through the three states
2
4
represents the MFEP connecting them. The color bar
process was enhanced using Metadynamics
(MetaD)
-1
2
5
represents the energy reported in kJ∙mol .
implemented in the PLUMED2 code. To characterize the
complex free energy landscape describing the proton
migration from HCl throughout the complex hydrogen bond
network, we used the method recently developed by Grifoni et
and shifts the hydronium ion below the inner surface of the
capsule (state B). (iii) Finally, the hydronium ion and the
carbonyl of the geranyl acetate substrate form a very compact
complex, sharing the proton (state C). Similar structures have
been observed in other computational studies focusing on the
2
6
al.
The simulation can be summarized as follows: (i) Energetically,
the most favored pathway involves a direct protonation of the
water at the capsule surface by HCl (Figure 6a, state A → B).
The alternative pathway involving protonation of a phenol
group, followed by rapid proton migration to a water molecule,
is less likely (Figure S23). (ii) The formed chloride of the
27
acid catalyzed ester hydrolysis.
To further analyze the results, we calculated the free energy
surface following the reweighting procedure previously
28
described. . In order to extract useful and chemically
meaningful information on the protonation process, two
+
-
3
H O /Cl ion pair is stabilized by coordination to the
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Journal of the American Chemical Society
Page 8 of 11
collective variables (CV
1
and CV
2
) describing the progressive
Table 3: Comparison of properties of macrocycles 1 ‒ 6 and the
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
protonation reaction of the carbonyl-oxygen have been
selected. To be general in describing the fundamental chemical
features, we used coordination numbers. These functions count
how many atoms of a specific species are found within a cutoff
sphere from the central atom. In the present case, CV
for the proximity of the carbonyl-oxygen and the water oxygen
atoms. At the starting point of the simulation (Figure 6b, state
A), CV is close to zero; after the formation of the final
1
hydronium-carbonyl complex (state C), it will be around one,
as the water molecule gets close to the carbonyl-oxygen. The
corresponding assemblies I ‒ VI indicating a correlation
between water being part of the hydrogen bond network and
catalytic activity in the THT cyclization.
1
accounts
Macrocycle
/Assembly
Catalysis Substrate
Binding
Anion
Binding
Water Proto-
nation
HO
OH
C11H23
HO
C11H23
OH















HO
OH
C11H23
C11H23
second variable (CV
atoms in close proximity to the water-oxygen. At the starting
point of the simulation (state A), CV is two, corresponding to
the number of covalent bonds in the neutral water molecule. As
the proton transfer proceeds, CV increases.
2
) accounts for the number of hydrogen
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
HO
OH
1/I
OH
2
HO
C11H23
OH
C11H23
HO
OH
2
29
The minimum free energy path (MFEP) along the free energy
surface is depicted in Figure 6a. This curve represents the
minimum energy required during the process. It is worth
noticing that state B in which the H
the most stable state. The chloride anion is well stabilized by
the surrounding phenol groups at the surface of the capsule
HO
C11H23
OH
C11H23
HO
OH
3
/III
OH
+
-
3
O /Cl ion pair is formed is
HO
C11H23
OH
C11H23
HO
OH
(
see Figure S24). The estimated energy barrier for the
OH
-1
dissociation process is only approx. 1.5 kJ∙mol , much lower
than the thermal barrier (k
different when we consider the formation of the
carbonyl/hydronium complex of state C. Its formation is
slowed down by a larger barrier of approx. 6 kJ∙mol and state
C is less stable than state B. Again, this result is in line with
previous computational findings.
The calculations, therefore, provide further evidence that
water is indeed essential for the proton transfer process from
the co-catalyst HCl onto the encapsulated substrate.
HO
C11H23
OH
C11H23
-1
B
T ~ 2.5 kJ∙mol ). The picture is
HO
OH
4a/IV
OH
-1
HO
C11H23
OH
C11H23
HO
OH
2
7
n. d.[a]
n. d.[a]
n. d.[a]
n. d.[a] n. d.[a]
HO
C11H23
OH
C11H23
HO
OH
OH
4b
OH
Conclusion
HO
C11H23
OH
C11H23
HO
OH
The experimental results obtained in this study, are
summarized in Table 3. Taken together, these results strongly
indicate that the decisive requirement for catalytic activity in
the context of terpene cyclization is the incorporation of water
molecules into the hydrogen bond network of the assembly.
The crucial water molecule functions as a proton shuttle,
delivering the proton onto the encapsulated substrate. If water
is not incorporated into the assembly, this protonation mode is
prevented, rendering these hosts catalytically inactive. This
holds true even in the case where the host is able to encapsulate
the substrate and stabilize ion pairs (assembly V, Table 3, entry
OH









HO
C11H23
OH
C11H23
HO
OH
OH
5/V
OH
HO
C11H23
OH
C11H23
HO
OH
HO
OH



HO
C11H23
OH
C11H23
HO
OH
OH
5
). This finding has furthermore been validated by calculations,
2/II
which confirm that the proposed intermediary states
constitute the minimum free energy path.
F
HO
C11H23
OH
C11H23
Interestingly, the proposed protonation pathway may also
provide insights into the puzzling observation that the chloride
counter anion of the HCl co-catalyst does not interfere with the
cationic cyclization cascade. Control experiments with HCl, as
well as other Bronsted or Lewis acids
counter anion quenching of cationic intermediates. Since the
chloride anion is bound at the capsule surface (Figure 6a), it is
prevented from quenching cationic intermediates inside the
cavity of the capsule.
HO
OH
F
F



HO
C11H23
OH
C11H23
5a, 6, 30
HO
OH
usually lead to
F
6/VI
[a]
Not determinded due to the insolubility of 4b in CDCl3.
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Summary
Journal of the American Chemical Society
References
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
In summary, we presented the synthesis and characterization
of four new macrocycles 3 ‒ 5 composed of different ratios of
resorcinol and pyrogallol units as well as new
1.
(a) Kirby, A. J. Enzyme Mechanisms, Models, and Mimics.
Angew. Chem. Int. Ed. 1996, 35 (7), 706-724; (b) Motherwell, W. B.;
Bingham, M. J.; Six, Y. Recent progress in the design and synthesis of
artificial enzymes. Tetrahedron 2001, 57 (22), 4663-4686; (c) Garcia-
Viloca, M.; Gao, J.; Karplus, M.; Truhlar, D. G. How Enzymes Work:
Analysis by Modern Rate Theory and Computer Simulations. Science
2004, 303 (5655), 186-195; (d) Zhang, X.; Houk, K. N. Why Enzymes
Are Proficient Catalysts:ꢀ Beyond the Pauling Paradigm. Acc. Chem. Res.
2005, 38 (5), 379-385; (e) Gao, J.; Ma, S.; Major, D. T.; Nam, K.; Pu, J.;
Truhlar, D. G. Mechanisms and Free Energies of Enzymatic Reactions.
Chem. Rev. 2006, 106 (8), 3188-3209; (f) Warshel, A.; Sharma, P. K.;
Kato, M.; Xiang, Y.; Liu, H.; Olsson, M. H. M. Electrostatic Basis for
Enzyme Catalysis. Chem. Rev. 2006, 106 (8), 3210-3235; (g) Ringe, D.;
Petsko, G. A. How Enzymes Work. Science 2008, 320 (5882), 1428-
a
tetrafluorinated resorcinarene derivative 6. With the exception
of compound 4b, all derivatives self-assemble to dynamic,
hexameric hydrogen-bonded assemblies in chloroform
solution. The new assemblies III ‒ VI together with assemblies
I and II, were studied in detail and compared with respect to
their catalytic activity in the monoterpene cyclization, their
ability to encapsulate terpene substrates and ion pairs, their
response to acid additive, and the amount of water
incorporated into the hydrogen bond network. The
experimental results strongly indicate a correlation between
the catalytic activity and water being part of the assembly.
QM/MM molecular dynamics simulations provided insights
into the specific role of the water molecule in the protonation
process of the encapsulated substrate. The incorporated water
molecules likely act as a proton shuttle by transferring the
proton from the acid co-catalyst HCl to the encapsulated
substrate, which initiates the cyclization. Since the chloride
counter anion is replacing one water molecule in the hydrogen
bond network, it is immobilized and does not interfere with the
cationic cyclization cascade reaction.
0
1
2
3
4
5
6
7
8
9
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1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
429; (h) Kamerlin, S. C. L.; Warshel, A. At the dawn of the 21st century:
Is dynamics the missing link for understanding enzyme catalysis?
Proteins 2010, 78 (6), 1339-1375.
2.
For reviews see: (a) Pluth, M. D.; Bergman, R. G.; Raymond,
K. N. Proton-Mediated Chemistry and Catalysis in a Self-Assembled
Supramolecular Host. Acc. Chem. Res. 2009, 42 (10), 1650-1659; (b)
Yoshizawa, M.; Klosterman, J. K.; Fujita, M. Functional Molecular Flasks:
New Properties and Reactions within Discrete, Self-Assembled Hosts.
Angew. Chem. Int. Ed. 2009, 48 (19), 3418-3438; (c) Meeuwissen, J.;
Reek, J. N. Supramolecular catalysis beyond enzyme mimics. Nat. Chem.
2010, 2 (8), 615-21; (d) Wiester, M. J.; Ulmann, P. A.; Mirkin, C. A.
Enzyme Mimics Based Upon Supramolecular Coordination Chemistry.
Angew. Chem. Int. Ed. 2011, 50 (1), 114-137; (e) Marchetti, L.; Levine,
M. Biomimetic Catalysis. ACS Catal. 2011, 1 (9), 1090-1118; (f) Ajami,
D.; Rebek, J. More Chemistry in Small Spaces. Acc. Chem. Res. 2013, 46
(4), 990-999; (g) Raynal, M.; Ballester, P.; Vidal-Ferran, A.; van
Leeuwen, P. W. N. M. Supramolecular catalysis. Part 2: artificial enzyme
mimics. Chem. Soc. Rev. 2014, 43 (5), 1734-1787; (h) Leenders, S. H.;
Gramage-Doria, R.; de Bruin, B.; Reek, J. N. Transition metal catalysis in
confined spaces. Chem Soc Rev 2015, 44 (2), 433-48; (i) Brown, C. J.;
Toste, F. D.; Bergman, R. G.; Raymond, K. N. Supramolecular catalysis in
metal-ligand cluster hosts. Chem. Rev. 2015, 115 (9), 3012-35; (j) Zarra,
S.; Wood, D. M.; Roberts, D. A.; Nitschke, J. R. Molecular containers in
complex chemical systems. Chem. Soc. Rev. 2015, 44 (2), 419-432; (k)
Catti, L.; Zhang, Q.; Tiefenbacher, K. Self-Assembled Supramolecular
Structures as Catalysts for Reactions Involving Cationic Transition
States. Synthesis 2016, 48 (03), 313-328; (l) Levin, M. D.; Kaphan, D. M.;
Hong, C. M.; Bergman, R. G.; Raymond, K. N.; Toste, F. D. Scope and
Mechanism of Cooperativity at the Intersection of Organometallic and
Supramolecular Catalysis. J. Am. Chem. Soc. 2016, 138 (30), 9682-93;
These findings finally reveal the activation mechanism inside
capsule I, and decipher the prerequisites for catalytic activity.
It, therefore, represents an important step towards the rational
design of new supramolecular catalyst systems. We expect this
finding to make a significant impact on future developments in
the field of supramolecular catalysis, since the proposed model
is likely transferable to other types of host systems.
Associated content
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI:
Experimental details and NMR spectra of new compounds
(
PDF)
(
m) Catti, L.; Zhang, Q.; Tiefenbacher, K. Advantages of Catalysis in Self-
Assembled Molecular Capsules. Chem. Eur. J. 2016, 22 (27), 9060-9066;
n) Zhang, Q.; Catti, L.; Tiefenbacher, K. Catalysis inside the Hexameric
Resorcinarene Capsule. Acc. Chem. Res. 2018, 51 (9), 2107-2114; (o)
Mouarrawis, V.; Plessius, R.; van der Vlugt, J. I.; Reek, J. N. H.
Confinement Effects in Catalysis Using Well-Defined Materials and
Cages. Front. Chem. 2018, 6, 623; (p) Hong, C. M.; Bergman, R. G.;
Raymond, K. N.; Toste, F. D. Self-Assembled Tetrahedral Hosts as
Supramolecular Catalysts. Acc. Chem. Res. 2018, 51 (10), 2447-2455;
Author information
(
Corresponding Author
*konrad.tiefenbacher@unibas.ch; tkonrad@ethz.ch
Notes
The authors declare no competing financial interest.
(
q) Zhu, Y.; Rebek Jr, J.; Yu, Y. Cyclizations catalyzed inside a hexameric
Acknowledgements
resorcinarene capsule. Chem. Commun. 2019, 55 (25), 3573-3577; (r)
Gaeta, C.; Talotta, C.; De Rosa, M.; La Manna, P.; Soriente, A.; Neri, P. The
Hexameric Resorcinarene Capsule at Work: Supramolecular Catalysis
in Confined Spaces. Chem. Eur. J. 2019, 25 (19), 4899-4913; (s) Zhang,
Q.; Catti, L.; Syntrivanis, L. D.; Tiefenbacher, K. En route to terpene
natural products utilizing supramolecular cyclase mimetics. Nat. Prod.
Rep. 2019, 36, 1619-1627; (t) Cohen, Y.; Slovak, S.; Avram, L. Hydrogen
Bond Hexameric Capsules: Structures, Host-Guest Interactions, Guest
Affinities, and Catalysis. In Calixarenes and Beyond, Neri, P.; Sessler, J.
L.; Wang, M.-X., Eds. Springer International Publishing: Cham, 2016;
811-842.
This work was supported by funding from the European
Research Council Horizon 2020 Programme (ERC Starting
Grant 714620 – TERPENECAT) and the Swiss National Science
Foundation as part of the NCCR Molecular Systems
Engineering. We thank PD Dr. Daniel Häussinger for assistance
with the DOSY-NMR measurements. L. C. thanks JSPS and the
Alexander von Humboldt Foundation for a postdoctoral
fellowship. GM. P. thanks Prof. Michele Parrinello for fruitful
discussions and Emanuele Grifoni for support and analysis of
metadynamics simulations. All calculations were run on the
ETHZ Euler-IV cluster.
3.
For recent examples see: (a) Wei, J.; Zhao, L.; He, C.; Zheng,
S.; Reek, J. N. H.; Duan, C. Metal-Organic Capsules with NADH Mimics as
Switchable Selectivity Regulators for Photocatalytic Transfer
9
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 10 of 11
Hydrogenation. J. Am. Chem. Soc. 2019, 141 (32), 12707-12716; (b)
Jans, A. C. H.; Caumes, X.; Reek, J. N. H. Gold Catalysis in
Supra)Molecular Cages to Control Reactivity and Selectivity.
ChemCatChem 2019, 11 (1), 287-297; (c) Jongkind, L. J.; Elemans, J.;
Reek, J. N. H. Cofactor Controlled Encapsulation of a Rhodium
Hydroformylation Catalyst. Angew. Chem. Int. Ed. 2019, 58 (9), 2696-
Christianson, D. W. Structural and Chemical Biology of Terpenoid
Cyclases. Chem. Rev. 2017, 117 (17), 11570-11648.
8. Syntrivanis, L.-D.; Levi, S.; Prescimone, A.; Major, D. T.;
Tiefenbacher, K. Four-Step Access to the Sesquiterpene Natural
Product Presilphiperfolan-1β-ol and Unnatural Derivatives via
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
Supramolecular
10.26434/chemrxiv.9891341.v1.
9. (a) Gerkensmeier, T.; Iwanek, W.; Agena, C.; Fröhlich, R.;
Catalysis.
ChemRxiv
2019,
2
699; (d) Bender, T. A.; Bergman, R. G.; Raymond, K. N.; Toste, F. D. A
Supramolecular Strategy for Selective Catalytic Hydrogenation
Independent of Remote Chain Length. J. Am. Chem. Soc. 2019, 141 (30),
11806-11810; (e) Bender, T. A.; Morimoto, M.; Bergman, R. G.;
Raymond, K. N.; Toste, F. D. Supramolecular Host-Selective Activation
of Iodoarenes by Encapsulated Organometallics. J. Am. Chem. Soc. 2019,
Kotila, S.; Näther, C.; Mattay, J. Self-Assembly of 2,8,14,20-
Tetraisobutyl-5,11,17,23-tetrahydroxyresorc[4]arene. Eur. J. Org.
Chem. 1999, 1999 (9), 2257-2262; (b) Atwood, J. L.; Barbour, L. J.; Jerga,
A. Hydrogen-bonded molecular capsules are stable in polar media.
Chem. Commun. 2001, (22), 2376-2377; (c) Shivanyuk, A.; Rebek, J. J.
Hydrogen-bonded capsules in polar, protic solvents. Chem. Commun.
2001, (22), 2374-2375; (d) Atwood, J. L.; Barbour, L. J.; Jerga, A.
Organization of the interior of molecular capsules by hydrogen
bonding. Proc. Natl. Acad. Sci. U.S.A. 2002, 99 (8), 4837-4841; (e)
Avram, L.; Cohen, Y. Discrimination of Guests Encapsulation in Large
Hexameric Molecular Capsules in Solution:ꢀ Pyrogallol[4]arene versus
Resorcin[4]arene Capsules. J. Am. Chem. Soc. 2003, 125 (52), 16180-
16181; (f) Avram, L.; Cohen, Y. Hexameric Capsules of Lipophilic
Pyrogallolarene and Resorcinarene in Solutions as Probed by Diffusion
NMR:ꢀ One Hydroxyl Makes the Difference. Org. Lett. 2003, 5 (18),
3329-3332; (g) Shivanyuk, A.; Friese, J. C.; Döring, S.; Rebek, J. Solvent-
Stabilized Molecular Capsules. J. Org. Chem. 2003, 68 (17), 6489-6496;
(h) Avram, L.; Cohen, Y. Self-Recognition, Structure, Stability, and Guest
Affinity of Pyrogallol[4]arene and Resorcin[4]arene Capsules in
Solution. J. Am. Chem. Soc. 2004, 126 (37), 11556-11563; (i) Guralnik,
V.; Avram, L.; Cohen, Y. Unique Organization of Solvent Molecules
Within the Hexameric Capsules of Pyrogallol[4]arene in Solution. Org.
Lett. 2014, 16 (21), 5592-5595; (j) Avram, L.; Goldbourt, A.; Cohen, Y.
Hexameric Capsules Studied by Magic Angle Spinning Solid-State NMR
Spectroscopy: Identifying Solvent Molecules in Pyrogallol[4]arene
Capsules. Angew. Chem. Int. Ed. 2016, 55 (3), 904-7.
141 (4), 1701-1706; (f) Takezawa, H.; Kanda, T.; Nanjo, H.; Fujita, M.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Site-Selective Functionalization of Linear Diterpenoids through U-
Shaped Folding in a Confined Artificial Cavity. J. Am. Chem. Soc. 2019,
141 (13), 5112-5115; (g) La Manna, P.; De Rosa, M.; Talotta, C.;
Rescifina, A.; Floresta, G.; Soriente, A.; Gaeta, C.; Neri, P. Synergic
Interplay Between Halogen Bonding and Hydrogen Bonding in the
Activation of a Neutral Substrate in a Nanoconfined Space. Angew.
Chem. Int. Ed. 2019, 10.1002/anie.201909865; (h) Gambaro, S.; De Rosa,
M.; Soriente, A.; Talotta, C.; Floresta, G.; Rescifina, A.; Gaeta, C.; Neri, P.
A hexameric resorcinarene capsule as a hydrogen bonding catalyst in
the conjugate addition of pyrroles and indoles to nitroalkenes. Org.
Chem. Front. 2019, 6 (14), 2339-2347; (i) Gambaro, S.; La Manna, P.; De
Rosa, M.; Soriente, A.; Talotta, C.; Gaeta, C.; Neri, P. The Hexameric
Resorcinarene Capsule as a Brønsted Acid Catalyst for the Synthesis of
Bis(heteroaryl)methanes in a Nanoconfined Space. Front. Chem. 2019,
7
(687); (j) Angamuthu, V.; Petroselli, M.; Rahman, F.-U.; Yu, Y.; Rebek,
J. Binding orientation and reactivity of alkyl α,ω-dibromides in water-
soluble cavitands. Org. Biomol. Chem. 2019, 17 (21), 5279-5282; (k)
Köster, J. M.; Häussinger, D.; Tiefenbacher, K. Activation of Primary and
Secondary Benzylic and Tertiary Alkyl (sp3)C-F Bonds Inside a Self-
Assembled Molecular Container. Front. Chem. 2019, 6 (639).
4
.
(a) MacGillivray, L. R.; Atwood, J. L. A chiral spherical
molecular assembly held together by 60 hydrogen bonds. Nature 1997,
89 (6650), 469-472; (b) Avram, L.; Cohen, Y. Spontaneous Formation
10.
Zhang, Q.; Catti, L.; Kaila, V. R. I.; Tiefenbacher, K. To catalyze
3
or not to catalyze: elucidation of the subtle differences between the
hexameric capsules of pyrogallolarene and resorcinarene. Chem Sci
2017, 8 (2), 1653-1657.
of Hexameric Resorcinarene Capsule in Chloroform Solution as
Detected by Diffusion NMR. J. Am. Chem. Soc. 2002, 124 (51), 15148-
1
5149; (c) Avram, L.; Cohen, Y.; Rebek Jr, J. Recent advances in
11.
(a) Elidrisi, I.; Negin, S.; Bhatt, P. V.; Govender, T.; Kruger, H.
hydrogen-bonded hexameric encapsulation complexes. Chem.
Commun. 2011, 47 (19), 5368-5375.
G.; Gokel, G. W.; Maguire, G. E. M. Pore formation in phospholipid
bilayers by amphiphilic cavitands. Org. Biomol. Chem. 2011, 9 (12),
4498-4506; (b) Pietraszkiewicz, M.; Prus, P.; Pietraszkiewicz, O.
Synthesis of novel, boron-containing cavitands derived from
calix[4]resorcinarenes and their molecular recognition of biologically
important polyols in Langmuir films. Tetrahedron 2004, 60 (47),
10747-10752; (c) Tan, S.-D.; Chen, W.-H.; Satake, A.; Wang, B.; Xu, Z.-L.;
Kobuke, Y. Tetracyanoresorcin[4]arene as a pH dependent artificial
acetylcholine receptor. Org. Biomol. Chem. 2004, 2 (19), 2719-2721.
5.
(a) Zhang, Q.; Tiefenbacher, K. Terpene cyclization catalysed
inside a self-assembled cavity. Nat. Chem. 2015, 7 (3), 197-202; (b)
Zhang, Q.; Catti, L.; Pleiss, J.; Tiefenbacher, K. Terpene Cyclizations
inside a Supramolecular Catalyst: Leaving-Group-Controlled Product
Selectivity and Mechanistic Studies. J. Am. Chem. Soc. 2017, 139 (33),
11482-11492; (c) Zhang, Q.; Rinkel, J.; Goldfuss, B.; Dickschat, J. S.;
Tiefenbacher, K. Sesquiterpene Cyclisations Catalysed inside the
Resorcinarene Capsule and Application in the Short Synthesis of
Isolongifolene and Isolongifolenone. Nat. Catal. 2018, 1 (8), 609-615;
12.
(a) Irwin, J. L.; Sherburn, M. S. Practical Synthesis of
Selectively Functionalized Cavitands. J. Org. Chem. 2000, 65 (2), 602-
605; (b) Irwin, J. L.; Sherburn, M. S. Optimized Synthesis of Cavitand
Phenol Bowls. J. Org. Chem. 2000, 65 (18), 5846-5848.
(
d) Zhang, Q.; Tiefenbacher, K. Sesquiterpene Cyclizations inside the
Hexameric Resorcinarene Capsule: Total Synthesis of delta-Selinene
and Mechanistic Studies. Angew. Chem. Int. Ed. 2019, 58 (36), 12688-
13.
Yamada, S.; Gavryushin, A.; Knochel, P. Convenient
1
2695.
Electrophilic Fluorination of Functionalized Aryl and Heteroaryl
Magnesium Reagents. Angew. Chem. Int. Ed. 2010, 49 (12), 2215-2218.
6
.
Pronin, S. V.; Shenvi, R. A. Synthesis of highly strained
terpenes by non-stop tail-to-head polycyclization. Nat. Chem. 2012, 4
11), 915-920.
(a) Croteau, R. Biosynthesis and catabolism of
14.
Deprotection by Boron Tribromide. Org. Lett. 2004, 6 (16), 2777-2779.
15. Avram, L.; Cohen, Y. Diffusion NMR of molecular cages and
capsules. Chem. Soc. Rev. 2015, 44 (2), 586-602.
16. Cori, O.; Chayet, L.; Perez, L. M.; Bunton, C. A.; Hachey, D.
Punna, S.; Meunier, S.; Finn, M. G. A Hierarchy of Aryloxide
(
7
.
monoterpenoids. Chem. Rev. 1987, 87 (5), 929-954; (b) Cane, D. E.
Enzymic formation of sesquiterpenes. Chem. Rev. 1990, 90 (7), 1089-
1103; (c) Christianson, D. W. Structural Biology and Chemistry of the
Terpenoid Cyclases. Chem. Rev. 2006, 106 (8), 3412-3442; (d)
Degenhardt, J.; Köllner, T. G.; Gershenzon, J. Monoterpene and
sesquiterpene synthases and the origin of terpene skeletal diversity in
plants. Phytochemistry 2009, 70 (15), 1621-1637; (e) Dickschat, J. S.
Isoprenoids in three-dimensional space: the stereochemistry of
terpene biosynthesis. Nat. Prod. Rep. 2011, 28 (12), 1917-1936; (f)
Miller, D. J.; Allemann, R. K. Sesquiterpene synthases: passive catalysts
or active players? Nat. Prod. Rep. 2012, 29 (1), 60-71; (g) Dickschat, J.
S. Bacterial terpene cyclases. Nat. Prod. Rep. 2016, 33 (1), 87-110; (h)
Rearrangement of linalool, geraniol, nerol and their derivatives. J. Org.
Chem. 1986, 51 (8), 1310-1316.
17.
(11), 933.
18.
Bryant, R. G. The NMR time scale. J. Chem. Educ. 1983, 60
Silverstein, T. P.; Heller, S. T. pKa Values in the
Undergraduate Curriculum: What Is the Real pKa of Water? J. Chem.
Educ. 2017, 94 (6), 690-695.
19.
Lambrechts, H. J. A.; Cerfontain, H. Solutes in sulfuric acid.
Part IX. Effect of para-substitution on the ionization of the oxonium
ions of phenol and anisole. Recueil des Travaux Chimiques des Pays-Bas
1983, 102 (6), 299-301.
1
0
ACS Paragon Plus Environment

Page 11 of 11
Journal of the American Chemical Society
2
0.
Avram, L.; Cohen, Y. The Role of Water Molecules in a
Resorcinarene Capsule As Probed by NMR Diffusion Measurements.
Org. Lett. 2002, 4 (24), 4365-4368.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
2
1.
Approximation Made Simple. Phys. Rev. Lett. 1996, 77 (18), 3865-3868.
22. Grimme, S.; Antony, J.; Ehrlich, S.; Krieg, H. A consistent and
Perdew, J. P.; Burke, K.; Ernzerhof, M. Generalized Gradient
accurate ab initio parametrization of density functional dispersion
correction (DFT-D) for the 94 elements H-Pu. J. Chem. Phys. 2010, 132
(
15), 154104.
23. Laino, T.; Mohamed, F.; Laio, A.; Parrinello, M. An Efficient
Linear-Scaling Electrostatic Coupling for Treating Periodic Boundary
Conditions in QM/MM Simulations. J. Chem. Theory. Comput. 2006, 2
(
5), 1370-1378.
4. (a) Laio, A.; Parrinello, M. Escaping free-energy minima.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
Proc. Natl. Acad. Sci. U.S.A. 2002, 99 (20), 12562-12566; (b) Barducci,
A.; Bussi, G.; Parrinello, M. Well-Tempered Metadynamics: A Smoothly
Converging and Tunable Free-Energy Method. Phys. Rev. Lett. 2008,
100 (2), 020603.
2
5. Bonomi, M.; Bussi, G.; Camilloni, C.; Tribello, G. A.; Banáš, P.;
Barducci, A.; Bernetti, M.; Bolhuis, P. G.; Bottaro, S.; Branduardi, D.;
Capelli, R.; Carloni, P.; Ceriotti, M.; Cesari, A.; Chen, H.; Chen, W.; Colizzi,
F.; De, S.; De La Pierre, M.; Donadio, D.; Drobot, V.; Ensing, B.; Ferguson,
A. L.; Filizola, M.; Fraser, J. S.; Fu, H.; Gasparotto, P.; Gervasio, F. L.;
Giberti, F.; Gil-Ley, A.; Giorgino, T.; Heller, G. T.; Hocky, G. M.; Iannuzzi,
M.; Invernizzi, M.; Jelfs, K. E.; Jussupow, A.; Kirilin, E.; Laio, A.;
Limongelli, V.; Lindorff-Larsen, K.; Löhr, T.; Marinelli, F.; Martin-Samos,
L.; Masetti, M.; Meyer, R.; Michaelides, A.; Molteni, C.; Morishita, T.;
Nava, M.; Paissoni, C.; Papaleo, E.; Parrinello, M.; Pfaendtner, J.; Piaggi,
P.; Piccini, G.; Pietropaolo, A.; Pietrucci, F.; Pipolo, S.; Provasi, D.;
Quigley, D.; Raiteri, P.; Raniolo, S.; Rydzewski, J.; Salvalaglio, M.; Sosso,
G. C.; Spiwok, V.; Šponer, J.; Swenson, D. W. H.; Tiwary, P.; Valsson, O.;
Vendruscolo, M.; Voth, G. A.; White, A.; The, P. c. Promoting
transparency and reproducibility in enhanced molecular simulations.
Nat. Methods 2019, 16 (8), 670-673.
2
6.
of acid–base equilibrium. Proc. Natl. Acad. Sci. U.S.A. 2019, 116 (10),
054-4057.
27. (a) Gómez-Bombarelli, R.; Calle, E.; Casado, J. Mechanisms of
Lactone Hydrolysis in Acidic Conditions. J. Org. Chem. 2013, 78 (14),
880-6889; (b) Shi, H.; Wang, Y.; Hua, R. Acid-catalyzed carboxylic acid
Grifoni, E.; Piccini, G.; Parrinello, M. Microscopic description
4
6
esterification and ester hydrolysis mechanism: acylium ion as a sharing
active intermediate via a spontaneous trimolecular reaction based on
density functional theory calculation and supported by electrospray
ionization-mass spectrometry. Phys. Chem. Chem. Phys. 2015, 17 (45),
3
0279-30291.
8. Valsson, O.; Tiwary, P.; Parrinello, M. Enhancing Important
2
Fluctuations: Rare Events and Metadynamics from a Conceptual
Viewpoint. Annu. Rev. Phys. Chem. 2016, 67 (1), 159-184.
2
9.
(a) Jonsson, H.; Mills, G.; Jacobsen, K. W. Nudged elastic band
method for finding minimum energy paths of transitions. In Classical
and Quantum Dynamics in Condensed Phase Simulations, 385-404; (b)
Maragliano, L.; Fischer, A.; Vanden-Eijnden, E.; Ciccotti, G. String
method in collective variables: Minimum free energy paths and
isocommittor surfaces. J. Chem. Phys. 2006, 125 (2), 024106.
3
0.
(a) Andersen, N. H.; Syrdal, D. D. Chemical simulation of the
biogenesis of cedrene. Tetrahedron Lett. 1972, 13 (24), 2455-2458; (b)
Yoshimoto, O.; Yoshio, H. Electrophile Induced Cyclization of Farnesol.
Chem. Lett. 1972, 1 (3), 263-266; (c) McCormick, J. P.; Barton, D. L.
Studies in 85% H3PO4—II: On the role of the α-terpinyl cation in cyclic
monoterpene genesis. Tetrahedron 1978, 34 (3), 325-330.
1
1
ACS Paragon Plus Environment