Divergent Synthesis of Chiral Covalent Organic Frameworks

Article abstract of DOI:10.1002/anie.201903534

Featuring the simultaneous generation of a library of compounds from a certain intermediate, divergent synthesis has found increasing applications in the construction of natural products and potential medicines. Inspired by this approach, presented herein is a general strategy to introduce functionality, in a divergent manner, into covalent organic frameworks (COFs). This modular protocol includes two stages of covalent assembly, through which functional COFs can be constructed by a three-step transformation of a key platform molecule, such as 4,7-dibromo-2-chloro-1H-benzo[d]imidazole (DBCBI). Constructed herein are four types of chiral COFs (CCOFs) from DBCBI by nucleophilic substitution, Suzuki coupling, and imine formation. The unique array of eight isoframework CCOFs allowed investigation of their catalytic performance and structure–activity relationship in an asymmetric amination reaction.

Full text of DOI:10.1002/anie.201903534

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Accepted Article
Title: Divergent Synthesis of Chiral Covalent Organic Frameworks
Authors: Li-Ke Wang, Jing-Jing Zhou, Yu-Bao Lan, San-Yuan Ding,
Wei Yu, and Wei Wang
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201903534
Angew. Chem. 10.1002/ange.201903534
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10.1002/anie.201903534
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Divergent Synthesis of Chiral Covalent Organic Frameworks
Li-Ke Wang, Jing-Jing Zhou, Yu-Bao Lan, San-Yuan Ding, Wei Yu, and Wei Wang*
ABSTRACT: Featuring the simultaneous generation of a library of
compounds from certain intermediate, divergent synthesis has found
increasing applications in the construction of nature products and
potential medicines. Inspired by this approach, we present herein a
general strategy to introduce functionality, in a divergent manner,
into covalent organic frameworks (COFs). This modular protocol
includes two stages of covalent assembly, through which a number
of functional COFs can be constructed through three-step
transformation of a key platform molecule, such as 4,7-dibromo-2-
chloro-1H-benzo[d]imidazole (DBCBI). We constructed herein four
types of chiral COFs (CCOFs) from DBCBI via nucleophilic
substitution, Suzuki coupling, and imine formation. The unique array
of eight isoframework CCOFs further allowed us to compare their
catalytic performance and study the structure-activity relationship in
many important transformations, such as asymmetric amination
reaction.
combinatorial library makes the further high-throughput
screening and structure-activity investigation impossible.
Because our original synthetic route is only suitable for the
special target,10 we develop herein an updated strategy to
construct a series of CCOFs for parallel evaluation of their
catalytic performance. This effort may present a general protocol
for the bottom-up introducing of designed functionality into COFs.
Inspired with the diversity created by nature, organic chemists
have been using the divergent strategy to improve the synthetic
efficiency of nature products.1 In difference from the target-
oriented synthesis (Figure 1a), the divergent synthesis is
conceptually featured in the designed construction of a series of
compounds from certain intermediate (Figure 1b). This strategy
is extremely advantageous when the follow-up applications
involve high-throughput screening processes2, such as in drug
discovery or catalyst development. Many biomacromolecules,
such as DNA and proteins, are also divergently synthesized
naturally or artificially from limited kinds of nucleotides and
amino acids.3 However, the powerfulness of divergent synthesis
in the field of functional materials4 is yet to be illustrated. We
establish herein a divergent strategy (Figure 1c) to obtain a
combinatorial library of functional covalent organic frameworks
(COFs).
Figure 1. The divergent synthetic strategy to construct functional COFs via
two-stage covalent assembly.
The research area of COFs5 has gained rapid progress in the
past decade. The identity of a crystalline COF involves its
framework topology, the mortise-and-tenon joint, and the
functional moiety. Many novel COFs have been ingeniously
constructed with the diversity in structures or covalent joints.5,6 In
this context, further construction of COFs with embedded
functional moieties7 still remains challenging: the target-oriented
synthesis has to meet all the requirements of crystallinity,
porosity, and functionality. For example, although being
promising in asymmetric catalysis and enantioselective
recognition/separation, only a handful of chiral COFs (CCOFs)
have been successfully synthesized.8-14 In 2016, we targeted at
the direct synthesis of a secondary-amine CCOF with a chiral
pyrrolidine building block.10 However, the lack of its
The key concern for divergent synthesis is that the designed
route should be concise and universally robust so as to prepare
the diversified targets in efficient, simultaneous, and
combinatorial fashion.1 We start with the rational design of a
modular covalent-assembly protocol based on
a suitable
platform molecule. This molecule should be structurally rigid and
symmetric, easily available, and readily installed with (chiral)
functionality and connectivity via reliable transformation. Ideally,
as depicted in Figure 1c, only two stages of covalent assembly
from this platform molecule are necessary. The concise
chemistry we envisioned for this protocol has been exemplified
in Figure 2. As the first attempt, we designed 4,7-dibromo-2-
chloro-1H-benzo[d]imidazole (DBCBI) as the platform molecule,
based on which eight CCOFs (categorized into four different
types) were facilely produced via nucleophilic substitution,
Suzuki coupling, and imine formation.
L. Wang, J. Zhou, Y. Lan, Prof. S. Ding, Prof. W. Yu, Prof. W. Wang
State Key Laboratory of Applied Organic Chemistry,
College of Chemistry and Chemical Engineering,
Lanzhou University, Lanzhou, Gansu 730000, China
E-mail: wang_wei@lzu.edu.cn
Supporting information for this article is given via a link at the end of the
document
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Figure 2. Two-stage divergent strategy to construct multifarious chiral COFs: a) the first stage is the divergent synthesis of chiral monomers via nucleophilic
substitution and Suzuki coupling; b) the second stage is the divergent synthesis of chiral COFs via imine formation. Except for G-CCOF1 (a four-step
transformation), the chiral COFs have been constructed via a three-step transformation from DBCBI.
In difference from the target-oriented route10, the use of
DBCBI as the platform molecule is crucial: (i) DBCBI can be
synthesized in three steps with the total yield of 86% on a large
scale: 500-gram of DBCBI with the chemical purity of 96% can
be routinely obtained without any column purification in our
laboratory. (ii) DBCBI can be facilely installed with various
functional groups via classical transformations. For example, the
monomers (3a-h) with chiral functionality have been obtained via
nucleophilic substitution and Suzuki coupling reactions.
Specifically, the workup of nucleophilic substitution for
introducing functionality is free of solvent and of extraction,
meeting the demands for green chemistry. Meanwhile, the mild
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10.1002/anie.201903534
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conditions for Suzuki coupling reaction guarantee the installation
of terminal connectivity (such as aldehyde or amino groups) with
high functional group tolerance. (iii) The synthesized monomers
3a-h possess the functional diversity, structural symmetry, and
extendable connectivity, all of which are essential for further
construction of CCOFs.
We further applied the divergent strategy to construct a library
of chiral COFs via dynamic covalent assembly between 3a-h
and
a
given structural monomer, such as 1,3,5-tris(4-
aminophenyl)-benzene (TAPB). The optimal solvothermal
condition has been established as: crystallization at 120 °C for
72 h in ethanol/mesitylene (1:1 v/v) as mixed solvents and with
aqueous acetic acid (3 M) as the catalyst. As shown in Figure 2b,
a series of COFs could be made with identical framework
structure but with diverse functionality: MH-CCOF1, MH-CCOF2,
MH-CCOF3, and MH-CCOF4 include multiple hydrogen-bonding
sites; TAH-CCOF1 and TAH-CCOF2 include both tertiary-amine
and hydrogen-bond sites; SAH-CCOF1-Boc contains both
secondary-amine and hydrogen-bonding sites; while G-CCOF1
contains the unique guanidine moieties. Moreover, via this
synthetic design, hydrogen-bond donor, Brønsted acidic and
basic sites have been integrated into each CCOF catalyst, the
catalytic model of which perfectly mimics those of (thio)urea and
squaramide catalysts being frequently used in homogeneous
organocatalysis.15 Meanwhile, by eliminating the uncertain
effects brought from different frameworks, these “isoframework”
CCOFs provide a unique platform for investigation on the
structure-activity relationship involved in heterogeneous
asymmetric catalysis (vide infra). Note that this strategy may
also be extended to construct "isofunctional" COFs when the
structural monomer is changed.
The synthesized CCOFs were thoroughly characterized by
powder X-ray diffraction, Fourier transform infrared spectroscopy,
solid-state 13C magic-angle-spinning (MAS) NMR, nitrogen
adsorption-desorption experiments, thermogravimetric analysis,
scanning electron microscopy, and transmission electron
microscopy (see SI for details). Being isoframework in nature,
these CCOFs possessed very similar PXRD patterns (Figure S1).
Their nitrogen adsorption and desorption curves (Figure S2) all
displayed type-IV isotherms, which are characteristic for
mesoporous materials. The BrunauerEmmettTeller (BET)
surface areas were determined as 215 to 809 m2 g-1. The
nonlocal density functional theory (NLDFT) gave rise to the
pore-size distribution with the average pore width ranging from
2.7 to 2.9 nm (Figure S3). Presented in Figure 3, the 13C cross-
polarization (CP) MAS NMR spectra showed very similar NMR
signals in the low-field region (ca. 110150 ppm), indicating
again the isoframework nature. Notably, the 13C NMR signals in
the high-field region (1080 ppm) are distinct, which directly
reflects the diversity in chiral functionality. The typical
assignments for the 13C NMR signals of the chiral moieties have
been shown in each case and the full assignments have been
provided in the SI.
Figure 3. 13C CP/MAS NMR spectra of CCOFs. The similar signals at
110150 ppm indicate their isoframework nature, while the distinct signals at
1080 ppm reflect the diversity in chiral functionality. The signal at 156157
ppm in each spectrum verifies the successful C=N formation. The signal at
163 ppm in G-CCOF1 case is characteristic for the guanidine carbons. The
asterisks denote the spinning sidebands.
logical activity and potential pharmaceutical applications.16 Our
screening results indicated that, possessing tertiary amine and
hydrogen-bonding sites, TAH-CCOF1 and TAH-CCOF2
displayed better activity and enantioselectivity than other
candidates. Excellent yield (96%) and steric control (99% ee)
have been obtained when the reaction was performed in
dichloromethane (DCM) at 78 °C with TAH-CCOF2 as the
catalyst (entry 6). Note that this performance is superior to those
(entries 9 and 1017) of homogeneous counterparts. We further
investigated the mechanistic reason for this phenomenon.
Comparison of the single-crystal structures of 7 and the model
catalyst of TAH-CCOF2 revealed that the existence of steric
hindrance moieties has weakened the intermolecular hydrogen
bonding by enlarging their distance from 2.073 Å (Figure S103)
to 5.093 Å (Figure S104). Similarly, reticulation of the chiral and
hydrogen-bonding sites into the π-conjugated TAH-CCOF2
framework may further weaken the hydrogen-bonding
interactions and therefore improve18 the steric control and
catalytic activity. Our control experiments have provided
additional evidence to support this conclusion (SI).
With these CCOFs catalysts in hand, we were able to
systematically investigate their structure-activity relationship in
catalyzing many important transformations. The asymmetric
amination reaction of ethyl 2-oxocyclopentane-1-carboxylate (4)
with di-tert-butylazodicarboxilate (5) was first selected.16 Having
never been catalyzed with any CCOF catalysts, this reaction is
however fundamentally important towards the construction of
optically active nitrogen-containing molecules with excellent bio-
Based on this finding, the substrate generality was further
demonstrated by the reactions of other β-keto esters with 5 (SI).
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The desired amination products were obtained in high yields (up
to 98%) with excellent enantioselectivities (up to 91% ee).
Moreover, the TAH-CCOF2 catalyst could be readily recovered
by centrifugation and reused at least for seven times without any
obvious loss of activity and enantioselectivity (Table S11). The
crystallinity and covalent connection for the recycled TAH-
CCOF2 were maintained, as evidenced by the recorded PXRD
(Figure S106) and 13C CP/MAS NMR (Figure S107).
This work was financially supported by the National Natural
Science Foundation of China (Nos. 21425206 and 21871120)
and the Natural Science Foundation of Gansu Province (No.
18JR4RA003). We thank Drs. Chun-An Fan, Xue-Yuan Liu, Yun
Li, Xue-Gong She, Shi-Hui Dong, Xiao-Lei Wang, and Saikat
Das for their insightful discussions.
Keywords: divergent synthesis • covalent organic frameworks •
functionality • chiral • asymmetric catalysis
Table 1. Systematic screening of CCOFs catalysts in asymmetric amination of
β-ketoesters.[a]
[1]
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MH-CCOF1
MH-CCOF2
MH-CCOF3
MH-CCOF4
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SAH-CCOF1-Boc
G-CCOF1
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1
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6
81
72
70
65
94
96
12
8
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reaction was carried out in DCM (2.0 mL) at –78 °C with 4 (0.20 mmol) and 5
(0.24 mmol) as the reactants. [b] Isolated yield. [c] Enantiomeric excess (ee)
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7 (0.01 mmol) for 10 h.
The spirit in classic organic synthesis is the precise and
efficient covalent-assembly.19 For example, the MacMillan group
used the divergent strategy to synthesize six indole alkaloids
(categorized into three families) from the same tetracyclic
intermediate.20 Being a new member of organic family, COFs are
structurally featured as crystalline and porous macromolecules
organized via covalent assembly.5 In light of the divergent
concept, we produced eight CCOFs (categorized into four
different types) via a three-step transformation of a key platform
molecule, DBCBI. This simple and general strategy may not
only fulfil the critical demands for diversity in the COF synthesis,
but also integrate the efficiency and precision of classic organic
synthesis. By realizing the fine-tuning of COF properties at the
atom/molecular level, this approach provides a combinatorial
library of functional COF materials for further high-throughput
screening and structure-activity investigation. This purpose has
also been achieved by screening out TAH-CCOF2 catalyst as
the best candidate reported for the asymmetric amination
reaction. We therefore expect that this contribution set up a
combinatorial procedure to produce diversified functional COFs.
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Li-Ke Wang, Jing-Jing Zhou, Yu-Bao
Lan, San-Yuan Ding, Wei Yu, and Wei
Wang*
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Divergent Synthesis of Chiral
Covalent Organic Frameworks
A divergent strategy has been proposed to construct a combinatorial library of functional covalent
organic frameworks (COFs) from a platform molecule, DBCBI.
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