Catalysis with Supramolecular Carbon-Bonding Interactions

Article abstract of DOI:10.1002/anie.202108973

Herein, we describe a new catalysis platform, supramolecular carbon-bonding catalysis, which exploits the highly directional weak interactions between carbon centers of catalysts and electron donors to drive chemical reactions. To demonstrate this catalys

Full text of DOI:10.1002/anie.202108973

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Accepted Article
Title: Catalysis with Supramolecular Carbon-Bonding Interactions
Authors: Wei Wang, Xinxin Li, Pan-Pan Zhou, and Yao Wang
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Catalysis with Supramolecular Carbon-Bonding Interactions
Wei Wang,[a] Xinxin Li,[a] Pan-Pan Zhou,[c] Yao Wang*[a][b]
[a]
Dr. W. Wang, X. Li, Prof. Dr. Y. Wang
School of Chemistry and Chemical Engineering
Key Laboratory of the Colloid and Interface Chemistry, Ministry of Education
Shandong University, Jinan, 250100, China
E-mail: yaowang@sdu.edu.cn.
[b]
[c]
Prof. Dr. Y. Wang
State Key Laboratory of Crystal Materials
Shandong University, Jinan, 250100, China
Prof. Dr. P.-P. Zhou
Key Laboratory of Advanced Catalysis of Gansu Province, College of Chemistry and Chemical Engineering
Lanzhou University, Lanzhou, 730000, China
Supporting information for this article is given via a link at the end of the document.
Abstract: Herein, we describe
a
new catalysis platform,
specially tailored molecules.[12-17] Despite having a broad prospect,
the introduction of supramolecular carbon-bonding interactions in
catalysis remains unknown. Noncovalent catalysis serves as a
fundamental strategy to solve synthetic problems as evidenced
by fruitful achievements made in hydrogen-bonding as well as -
hole-bonding catalysis.[18-20] The research works from our group
showed that chalcogen-bonding catalysis approach was capable
of facilitating several chemical transformations which otherwise
were problematic by conventional methods with regard to the
reactivity and selectivity issues.[21-23] Considering the universality
of carbon-bonding interactions, the establishment of this
noncovalent force in catalysis would provide a distinct platform for
organic synthesis. In this context, we herein describe
supramolecular carbon-bonding catalysis, which exploits the
highly directional intermolecular interactions between electrophilic
carbons of catalysts and electron donors to promote chemical
reactions (Figure 1).
supramolecular carbon-bonding catalysis, which exploits the highly
directional weak interactions between carbon centres of catalysts and
electron donors to drive chemical reactions. To demonstrate this
catalysis approach, we discovered a class of cyclopropane derivatives
incorporated with carbonyl, ester and cyano groups as catalysts which
showed general catalysis capability in different types of benchmark
reactions. Among these typical examples, a challenging tail-to-head
terpene cyclization can be achieved by supramolecular carbon-
bonding catalysis. The co-crystal structures of catalyst and electron
donors, comparison experiments, and titrations support a catalysis
mode of carbon-bonding activation of Lewis basic reactants.
Chemical reactions that take place at electrophilic carbon centers
constitute a fundamental part of organic synthesis. Upon
imposing
supramolecular
a
crystal environment, the highly directional
carbon-bonding interactions between
electrophilic carbons and electron donors could be observed in a
range of crystal structures.[1] Amongst these electrophilic carbon
donors, three-membered ring molecules represent one of the
most important classes since the ring strain makes them reactive
towards nucleophilic attack. In line with the property of
cyclopropanes, computational studies suggest the formation of
noncovalent interactions between the electrophilic carbons of
cyclopropanes and electron donors is feasible.[2-5] Moreover, the
electrophilic carbons incorporated in unsaturated functional
groups such as carbonyl and cyano also exhibit similar capability
to interact with electron donors as shown in several crystal
structures.[6] For instance, upon installation of carbonyl groups
and electron donors in suitable molecular entities, the seminal
works by Bürgi and Dunitz revealed the presence of
intramolecular interactions between this electrophilic species and
electron donors through analyzing a range of crystal structures.[7-
9] These carbon-bonding interactions were considered as certain
moments of nucleophilic attack processes that have been frozen
in at an initial stage.[7-9] In biological systems, the weak
interactions between the carbonyl groups and the oxygen of a
peptide moiety have been revealed to play a significant role in
modulating conformational preferences of proteins.[10-11]
Figure 1. Supramolecular Carbon-Bonding Catalysis.
To demonstrate the feasibility of supramolecular carbon-
bonding catalysis, the Michael addition of furan derivative 1 with
enone 2 was investigated as a benchmark reaction (Scheme 1A)
while two typical hydrogen-bonding catalysts H1-2 were used as
references (Scheme 1B). In the absence of a catalyst, the reaction
did not take place. The experimental results indicated that these
two hydrogen-bonding catalysts were inactive to promote this
reaction. Then the proof-of-concept study on supramolecular
carbon-bonding catalysis was investigated using this benchmark
Despite the ever-increasing research interest, the translation
of the phenomenon of supramolecular carbon-bonding
interactions into chemical applications remains elusive. Few
works on this topic have been predominantly focused on the
structural analysis and controlling of the conformations of
1
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reaction. It was envisioned that the integration of electrophilic
cyclopropane moiety and unsaturated functional groups into a
single molecular entity would significantly enhance the strength of
carbon-bonding interactions, thus potentially giving rise to
strengthens the carbon-bonding interactions but enables the
formation of double interaction with electron donors (Scheme 1D).
In line with this notion, two extra carbonyl groups were installed
into molecule CB4 to furnish potential catalyst CB7. Indeed, this
catalyst design plan turned out to be successful and molecule
CB7 showed catalytic activity to give product 3 in 41% yield.
Analogously, molecule CB8 displayed promising catalytic activity
to afford 65% yield of 3. Following the same principle of designing
catalyst, the installation of two carbonyl groups into catalyst CB5
gave compound CB9 with ester groups. Molecule CB9 exhibited
good catalytic activity to give product 3 in 75% yield. The trace of
this reaction process by 1H NMR indicated that catalyst CB9 was
stable in this reaction system as no decomposition of CB9 was
observed. Furthermore, CB9-type catalyst is stable in air and the
similar results were obtained regardless of performing the
reaction under an air (73% yield) or an argon atmosphere (75%
yield). Using acrylophenone as a reactant, 85% yield was
obtained (see the Supporting Information). As expected, two
modified catalysts CB10 and CB11 gave comparable catalytic
activity.
catalytic capability. However, the result revealed that
a
tetracarbonyl-appended cyclopropane catalyst CB1 had no
catalytic activity (Scheme 1C). To acquire useful information, a
survey of the Cambridge Structural Database indicated that CB2-
type cyclopropane derivatives bearing a tetracyano moiety could
form noncovalent interactions with Lewis bases.[3-4] Unfortunately,
further investigation revealed that the tetracyano-appended
cyclopropane derivatives CB2-5 still had no catalytic activity. The
further investigation indicated that the variation of the catalyst
scaffold was ineffective. Upon installation of the tetracyano moiety
into a four-membered ring, molecule CB6 was also inactive.
These results suggest a potential catalyst incorporated with a
tetracarbonyl or tetracyano moiety alone was not capable of
activating enone 2 to give rise to catalytic activity.
Scheme 1. Proof-of-Concept Study on Carbon-Bonding Catalysis.
Figure 2. Co-crystal structures of CB9 with acetone, 1,4-dioxane, and
acetonitrile (the hydrogen atoms were omitted for clarity).
To rationally design an effective catalyst, it was further
envisioned that the installation of two additional carbon-based
electron acceptors into the tetracyano-containing molecules
would result in the formation of new host to accommodate the
electron donors along with the generation of more electrophilic
ring carbons of cyclopropane. Therefore, this design not only
To gain some insights into the carbon-bonding behaviour of
catalyst CB9, the co-crystal of catalyst CB9 with acetone was
obtained (Figure 2A).[24] This co-crystal contains two molecules of
2
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CB9 and two molecules of acetone. The crystal structure
indicates that the electrophilic carbons in CB9 could form carbon-
bonding interactions with oxygen atom of acetone. For the ring
carbons of cyclopropane, the C···O interactions were observed
and the distances of C···O ranging from 2.78-2.95 Å, which are
markedly shorter than the sum of their van der Waals radii (3.22
Å) (Figure 2A1). For CB9 itself, the presence of intramolecular
interactions between the oxygen atoms of the ester groups and
the cyano groups (O···CN) was observed (Figure 2A2). Moreover,
the crystal structure also shows the formation of intermolecular
carbon-bonding interactions between the cyano groups and the
oxygen atom of acetone (Figure 2A3). The ester group exhibits
the same capability that enables the formation of interactions with
the oxygen atom of acetone (i.e. O···C=O). The observed N···C
and N···C =O interactions between CB9 itself indicates that the
nitrogen atom is also a suitable electron donor. These N···C
distances are below 3.25 Å, thus indicating the distances between
these two atoms are within the sum of their van der Waals radii.
With regard to the unsaturated functional groups, the favourable
angle for an electron donor to interact with a carbonyl group
follows the Bꢀrgi−Dunitz trajectory which has an approximate 109
± 10° angle of ∠ED···C =O.[7-9] In the co-crystal structure of CB9
with acetone, it was found that the angles for the oxygen or
nitrogen atom to approach the carbonyl and cyano groups are
within the range of 99−114° (i.e. ∠O···CN, O···C=O, N···C=O),
which are in good agreement with the Bꢀrgi−Dunitz trajectory. To
show the generality of the aforementioned observations, the co-
crystals of CB9 with 1,4-dioxane (Figure 2B) and acetonitrile
(Figure 2C) were obtained.[24] The analysis of these crystal
structures reveals the presence of the similar carbon-bonding
interactions as observed in the crystal structure of CB9 with
acetone. In consistence with the design plan, these co-crystal
structures uniformly show this type of catalyst can attract two
molecules of electron donors.
similar structure CB10 was used to investigate the variation of the
ring carbons. As depicted in Figure 3B, the results of 13C NMR
experiments of the mixture of CB10 and enone 2 in CD2Cl2
indicated that the addition of enone 2 led to a marked variation of
the chemical shift of the 13C signals of the ring carbons. To gain
some insights into this carbon-bonding catalysis approach, a
series of control experiments were carried out. In principle, the
addition of an extra Lewis base into the standard reaction system
would lead to a supersession of the reaction process through
competitively binding to the catalyst. In consistence with the
observations from co-crystal structures in Figure 2, the addition of
acetone (40 equiv, 8.0 M) or 1,4-dioxane (50 equiv, 10.0 M) or
acetonitrile (40 equiv, 8.0 M) can outcompete the interaction of
enone 2 with CB9, thus resulting in a substantial suppression of
the reaction process (Figure 3C). The typical binding constants
for a 1:2 binding model of catalyst CB9 and Lewis bases were
obtained by 13C NMR titrations in CD2Cl2 (Table 1, entries 1-4). In
sharp contrast, a much smaller binding constant (0.3 M-1) for
inactive catalyst CB4 and enone 2 was obtained (Table 1, entry
5), which further corroborates the principles for designing
effective catalysts as described in Scheme 1D. These values are
in line with the weak nature of carbon-bonding interactions.
The carbon-bonding interactions were further investigated by
13C NMR experiments (see the Supporting Information). In line
with the observations from the co-crystal structure of CB9 with
acetone, the analysis of the mixture of CB9 and acetone in CD2Cl2
by 13C NMR experiments indicated that the interaction between
CB9 and acetone resulted in the variation of the 13C signals of the
cyano and ester groups as much as 1.82, 0.90 ppm, respectively.
Meanwhile, the 13C signal of the carbonyl group of acetone shifts
down-field up to 0.50 ppm. The NMR titration suggests a higher
concentration of acetone resulted in a more marked change of the
13C signals of the cyano and ester groups. Moreover, a similar
trend of the variation of the chemical shift of the 13C signal of
cyano as well as ester was observed using 1,4-dioxane or
acetonitrile as a Lewis base (LB) (see the Supporting Information).
Figure 3. 13C NMR investigation and inhibition experiments.
Table 1. Typical Binding Constants for Catalysts with Lewis Bases in DCM-d2.[a]
Analysis of the mixture of CB9 and enone 2 in CD2Cl2 by 13
C
NMR indicated that the addition of enone 2 led to a considerable
variation of the chemical shift of the 13C signals of the cyano and
ester groups (Figure 3A). In the presence of 1:3 mixture of CB9
and enone 2 in CD2Cl2, the 13C signal of the carbonyl group of
enone 2 shifts down-field by 0.43 ppm (see the Supporting
Information). In contrast, the analysis of the 1:3 mixture of CB9
and furan derivative 1 in CD2Cl2 by 13C NMR revealed that there
was no observable variation of the 13C signal of CB9 or 1. These
results suggest that the interaction between CB9 and enone 2
gives rise to catalytic activity. As the 13C signal of one of the ring
carbons of CB9 overlap with methyl carbon in CD2Cl2, then a
Entry
Host
Guest
K1 [Mˉ1]
K2 [Mˉ1]
1
2
3
4
5
CB9
CB9
CB9
CB9
CB4
acetone
10.27 ± 0.56
3.28 ± 0.08
5.50 ± 0.47
6.84 ± 0.33
0.30 ± 0.01
0.67 ± 0.04
0.41 ± 0.02
0.36 ± 0.02
0.53 ± 0.03
‒
acetonitrile
1,4-dioxane
enone 2
enone 2
[a] For details, see the Supporting Information.
3
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To uncover the intermolecular interaction between enone 2
and CB9, the complex SCB composed of CB9 and two molecules
of enone 2 was constructed and density functional theory (DFT)
calculations at the M06-2X/6-31g(d,p) level of theory were carried
out (see Figure 4 and the Supporting Information). The optimized
complex SCB has a relative Gibbs free energy of ‒5.5 kcal/mol.
Beyond the observations in the crystal structures, the significant
carbon-bonding interactions that contribute to the formation of
complex SCB were further corroborated by NBO and QTAIM
analyses. The computational results suggest that the specific
carbon-bonding interactions between the oxygen of enone 2 and
the electrophilic carbons of cyclopropane, cyano, and carbonyl of
CB9 play a major role in the formation of complex SCB.
Scheme 2. Supramolecular Carbon-Bonding Catalysis.
To highlight the potential of supramolecular carbon-bonding
catalysis, tail-to-head terpene cyclization was achieved
a
(Scheme 3). Since this type of tail-to-head terpene cyclization
involves unstable carbocations which often lead to a wide range
of product distribution, as a consequence, the major challenge of
this reaction pathway is the controlling of the reactivity of
carbocations to guide the formation of specific product.[28-30] The
talent of terpene synthases lies in the stabilization of the cationic
intermediates in the enzyme pockets, thus directing the
complicated cationic cascade process to give specific terpenes.[29]
Recently, the elegant work by Tiefenbacher indicates the imitation
of terpene synthases using artificial catalysts remains a great
challenge.[30] Using terpene alcohol 12 as a reactant, the use of
several Brønsted acids (HCOOH, CH3COOH, ClCH2COOH,
CF3COOH, TfOH) as catalysts either failed to give cyclization
product or afforded complex mixtures. Inspired by the terpene
synthases catalysis approach, the stabilization of the carbocation
intermediate through carbon-bonding interaction is one of the
solutions to achieving this terpene cyclization reaction. After
optimization of the cooperative catalysis systems, the use of a
cooperative catalysis system involving catalyst CB9 and
chloroacetic acid resulted in an efficient cyclization of terpene
alcohol 12 to give the major diastereomer 13 in 49% yield while
the other catalyst combinations were less productive. The control
experiments indicated that CB9 alone had catalytic activity in this
cyclization process.
Figure 4. Optimized complex of CB9 and two enone 2 molecules.
To demonstrate the generality of carbon-bonding catalysis,
this strategy was applied to a range of benchmark reactions
including the Diels-Alder, oxa-Pictet-Spengler, and Povarov
reactions (Scheme 2A-C).[25-27] In the absence of catalyst CB9, all
of these reactions as depicted in Scheme 2 did not take place,
thus excluding possible background reactions. In contrast, the
reaction of enone 2 with vinyl indole 4 worked smoothly to give
product 5 in 54% yield under catalysis of CB9 (Scheme 2A).
Furthermore, the carbon-bonding catalysis approach could be
applied to the oxa-Pictet-Spengler reaction of tryptophol 6 and
acetal 7, giving the cyclization product 8 in 83% yield (Scheme
2B). Based on the observation of N···C =O and N···CN
interactions in the aforementioned co-crystal structures in Figure
2, the activation of imine with CB9 was examined in the context
of a Povarov reaction. The experimental results demonstrate that
the carbon-bonding interactions could catalyze the reaction of
imine 9 and 2,3-dihydrofuran 10 efficiently, delivering cyclization
product 11 in 68% yield with a 1.3:1 ratio of endo/exo selectivity
(Scheme 2C). For the aromatic moiety, both electron withdrawing
and donating substitutions could be tolerated and the cyclization
products were obtained in 53% (4-FC6H4) and 57% (4-OMeC6H4)
yields, respectively (see the Supporting Information).
Scheme 3. Carbon-Bonding Catalysis of Tail-to-Head Terpene Cyclization.
In summary, supramolecular carbon-bonding catalysis was
established as a new platform for organic synthesis in this study.
A class of versatile carbon-bonding catalysts was discovered
4
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[21] W. Wang, H. Zhu, S. Liu, Z. Zhao, L. Zhang, J. Hao, Y. Wang, J. Am.
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which showed general catalytic capability in different types of
benchmark reactions. The co-crystal structures of catalyst with
distinct Lewis bases and titration experiments suggest the
presence of carbon-bonding interactions between the catalysts
and electron donors. This catalysis strategy shows great potential
and we anticipate a wide application of this concept in chemical
synthesis.
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acetone), CCDC 2088925 (CB9-acetonitrile), CCDC 2088927(CB9-
dioxane) contain the supplementary crystallographic data for this paper.
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We gratefully acknowledge the National Natural Science
Foundation of China (22022105, 21971147, 21772113), the
Natural Science Foundation of Shandong Province (ZR2019JQ08,
ZR2020ZD35). WW acknowledges Postdoctoral Innovation
Talent Support Scheme of Shandong Province (SDBX2020001).
PPZ acknowledges the financial support of the Natural Science
Foundation of Gansu Province, China (No. 20JR5RA289). We
thank Prof. Di Sun and Prof. Pei-Zhou Li at Shandong University
for assistance with the X-ray crystal structure analysis. Technical
support from Shandong University structural constituent and
physical property research facilities was acknowledged.
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Keywords: supramolecular catalysis • carbon-bonding •
noncovalent interactions • catalysts • terpene cyclization
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5
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Entry for the Table of Contents
Supramolecular carbon-bonding catalysis was established as a new platform for organic synthesis. A class of versatile catalysts was
discovered which showed catalytic capability in different benchmark reactions, thus demonstrating the wide potential of this catalysis
strategy.
6
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