Versatile Dynamic Covalent Assemblies for Probing π-Stacking and Chirality Induction from Homotopic Faces

Article abstract of DOI:10.1002/chem.201606040

Herein we report for the first time the use of dynamic covalent reactions (DCRs) for building a π-stacking model system and further quantifying its substituent effects (SEs), which remain a topic of debate despite the rich history of stacking. A general DCR between 10-methylacridinium ion and primary amines was discovered, in which π-stacking played a stabilizing role. Facile quantification of SEs with in situ competing π-stacking systems was next achieved in the form of amine exchange exhibiting structural diversity by simply varying components. The linear correlation with σ_m in Hammett plots indicates the dominance of purely electrostatic SEs, and the additivity of SEs is in line with the direct interaction model. With α-chiral amines π-stacking within the adduct enabled chirality transfer from homotopic faces. The strategy of dynamic covalent assembly should be appealing to future research of probing weak interactions and manipulating chirality.

Full text of DOI:10.1002/chem.201606040

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
A Journal of
Accepted Article
Title: Versatile Dynamic Covalent Assemblies for Probing π-Stacking
and Chirality Induction from Homotopic Faces
Authors: Hebo Ye, Yu Hai, Yulong Ren, and Lei You
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.201606040
Link to VoR: http://dx.doi.org/10.1002/chem.201606040
Supported by

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
10.1002/chem.201606040
Chemistry - A European Journal
COMMUNICATION
Versatile Dynamic Covalent Assemblies for Probing π-Stacking
and Chirality Induction from Homotopic Faces
Hebo Ye,+ Yu Hai,+ Yulong Ren, and Lei You*
Abstract: Herein we report for the first time the use of dynamic
covalent reactions (DCRs) for building a π-stacking model system
and further quantifying its substituent effects (SEs), which remain a
topic of debate despite the rich history of stacking. A general DCR
between 10-methylacridinium ion and primary amines was
discovered, in which π-stacking played a stabilizing role. Facile
quantification of SEs with in situ competing π-stacking systems was
next achieved in the form of amine exchange exhibiting structural
diversity by simply varying components. The linear correlation with
σm in Hammett plots indicates the dominance of purely electrostatic
SEs, and the additivity of SEs is in line with the direct interaction
model. With α-chiral amines π-stacking within the adduct enabled
chirality transfer from homotopic faces. The strategy of dynamic
covalent assembly should be appealing to future research of probing
weak interactions and manipulating chirality.
early developed polarization model (Hunter-Sanders model),[14]
which proposed the modulation of the electrostatic energy
through changing electron density of the π system by the
substituent, also plays a minor role. However, few experimental
systems to probe such SEs exist.[15] Shimizu established double
mutant cycles[16] from molecular torsional balances[17] to explore
the mechanism of SEs for π-stacking (Scheme 1a).[18] By
utilizing hydrogen bonding based rigid models,[19] Diederich
showed that both electron-donating and electron-withdrawing
groups had a stabilizing effect on π-stacking (Scheme 1b).[20]
Although insightful, these elegant systems are not quite
synthetically versatile considering stepwise reaction sequences
required for various substitution patterns. We envisioned a
strategy of bridging together the research of dynamic covalent
chemistry and weak interactions as a means of developing
simple, general, and versatile systems for the regulation of π-
stacking through cooperative orthogonal assembly (Scheme 1c).
Dynamic covalent reactions (DCRs), which are the
cornerstone of the continuingly growing field of reversible
covalent chemistry, can lead to in situ generated molecular
diversity as well as complexity and have found applications in
many aspects, such as chemical sensing, gas storage, and
catalysis.[1] Dynamic interactions that do not interfere with each
other in one vessel are called orthogonal,[2] and recently the use
of both non-covalent and dynamic covalent bonds or multiple
DCRs for orthogonal assembly has been blossoming.[3] In one
latest study, Anslyn accomplished four simultaneous yet
orthogonal DCRs within one flask.[4] Sanders,[5] Otto,[6]
Nitschke,[7] and Matile[8] constructed complex dynamic covalent
architectures controlled by π-stacking. Waters created dynamic
combinatorial libraries, in which CH-π interactions contributed to
the stabilization.[9] Asensio designed a combinatorial approach
for the study of carbohydrates CH-π interactions.[10] In this work,
we demonstrate the development of dynamic covalent
assemblies for modulating and quantifying π-stacking and also
show its application in chirality induction.
Scheme 1. The comparison of previous work (a and b) and our strategy of
dynamic covalent assemblies (c) for the study of π-stacking based on the
general DCR of 1 with amines. Reversible covalent bonds were marked in red.
The perchlorate counteranion was not shown in Schemes and Figures.
π-stacking is central to a variety of chemistry pursuits,
including crystal engineering, organocatalysis, and photoelectric
materials.[11] Despite its prevalence and importance, the nature
of π-stacking, especially its substituent effects (SEs), is pretty
complicated.[11] Recent computational studies[12] reveal that the
origin of this SE is mainly from local and direct interaction
between the substituent itself and the unsubstituted ring (the
direct interaction model, or Wheeler-Houk model),[13] though the
Recently we reported a dynamic Michael reaction between 10-
methylacridinium perchlorate (1) and monothiols, leading to the
release of protons.[21] Due to their high nucleophilicity, the
reversible covalent binding of monoamines to 1 would be
plausible with excess amine as the proton scavenger (Scheme
1c). Moreover, we postulated that π-stacking between aromatic
shelves of adduct 2 and the sidechain of amines would further
stabilize the assembly. Therefore, the dynamic assembly could
in turn function as a potential probe for π-stacking (Scheme 1c).
A dynamic covalent system would allow us to gain access to
structural diversity by simply changing amine components, thus
minimizing the work of synthesis and isolation. More importantly,
such an approach would have the luxury of obviating the need
[*]
Hebo Ye, Yu Hai, Yulong Ren, Prof. Dr. Lei You
State Key Laboratory of Structural Chemistry, Fujian Institute of
Research on the Structure of Matter, Chinese Academy of Sciences
Fuzhou 350002 (China)
E-mail: lyou@fjirsm.ac.cn
Yu Hai
College of Material Science and Engineering, Fujian Normal
University
for
a control, as the interference from background and
Fuzhou 350007 (China)
These authors contributed equally.
secondary interactions would be comparable and thereby offset
between in situ competing stacking systems with the same
scaffold, thus enabling facile quantification of the relative
strength of π-stacking through the equilibrium of amine
[+]
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
10.1002/chem.201606040
Chemistry - A European Journal
COMMUNICATION
Table 1: The equilibrium constant (K) of amine exchange and its logarithmic
value.
exchange (Scheme 1c). In essence, the proposed DCRs would
provide us a platform to readily set up and measure equilibrium
between competing stacking systems in one vessel.
With the concept in mind, we set out to investigate the DCRs
of 1 with monoamines. A broad set of primary aliphatic amines
with varied structural features were chosen: linear alkyl (1-
butylamine), branched alkyl (2-propylamine and isobutylamine),
R1NH2
R2NH2
K
log K
1.84
0.265
aromatic
(benzylamine),
branched
aromatic
(α-
1.27
1.29
1.35
2.62
4.10
7.50
0.104
0.110
0.130
0.418
0.613
0.875
methylbenzylamine), and cyclic aliphatic (cyclohexylamine).
Each amine (3.0 equiv.) was stirred together with 1 (1.0 equiv.)
in DMSO-d6, and 1H NMR revealed the formation of 2 in an
almost quantitative yield (Figures S1-S18). Taking benzylamine
as an example, the reaction was rapidly complete within 3 min
(Figure S8). The peaks from 1 (Figure 1a) disappeared, and the
emergence of new resonances at 4.7 (Ha) and 3.4 (Hb) ppm
suggests the creation of 2 (Figure 1b).
[a] α-methylpentafluorobenzylamine.
To validate the impact of π interaction and to shed light on its
structural basis, further evidence was gathered. First, DFT
computation
was
performed.
For
α-
methylpentafluorobenzylamine derived adduct there is π-
stacking adopting approximately a parallel-offset orientation
(centroid distance 3.40 Å; dihedral angle 11.2o) (Figure 2a). With
benzylamine and α-methylbenzylamine an analogous structure
exhibiting π-stacking was also revealed, respectively (Table S7).
NOESY experiments further confirmed π-stacking. For example,
cross peaks between aromatic protons from 1 and the fluorines
from the bound amine were detected for
2
from α-
methylpentafluorobenzylamine, thus suggesting the proximity of
two arene planes (Figures 2b). NOE correlations were also
found for other adducts (Figures S19-S31).
Figure 1. 1H NMR spectra of 1 (23 mM, a), the DCR of 1 with benzylamine (b),
or isobutylamine (c), and the component exchange between two amines (d) in
DMSO-d6.
To prove the reversibility of the Michael reaction and to
simultaneously quantify the relative binding affinity, component
exchange was next conducted. The reaction was first performed
with isobutylamine (Figure 1c), followed by the addition of
1
benzylamine, which has a similar skeleton as isobutylamine. H
NMR indicated that benzylamine derived adduct appeared with a
concomitant decrease in the amount of
2 incorporating
Figure 2. (a) The calculated structure of α-methylpentafluorobenzylamine
derived assembly and (b) its partial 19F, 1H-HOESY spectrum. NOE
correlations were marked in red.
isobutylamine (Figure 1d). This observation demonstrates that
the amine exchange was occurring. The dynamic nature of the
system was further validated by amine exchange irrespective of
the sequence of amine addition (Figure S34). It is notable that
the reaction is reversible even though the DCR is quantitative.
An equilibrium constant (K) of 1.84 was found (for detailed
deduction of K, see SI), thus favoring 2 from benzylamine (Table
1). We reasoned that such a finding would imply that π-stacking
could have a stabilizing effect on the assembly. To verify this
rationalization, the component exchange was also run with linear
1-butylamine and 2-methoxyethylamine. The K value was 1.27
and 1.29 for 1-butylamine and 2-methoxyethylamine,
respectively, also preferring benzylamine (Table 1). Exchange
between α-branched amines, such as α-methylbenzylamine and
α-methylpentafluorobenzylamine, and 2-propylamine, again
favors the amine with the aromatic unit (Table 1). These results
support our postulation of the stabilization of the adduct through
potential π interactions.
Having developed a new DCR between 10-methylacrinidium
ion and monoamines and having unraveled the role of π-
stacking, its SEs were systematically examined. Dynamic
component exchange of benzylamine derived adduct 2 with a
series of para-substituted benzylamines was hence performed.
Such a library of amines with the same scaffold will serve as a
barometer for the nucleophilicity and π interaction. A rather
small window of K values (0.958-1.12) was apparent even
though a broad range of substituents were used (Table S5 and
Figure 3a). Nevertheless, the reproducibility was excellent, as
revealed by independent experiments (Table S4). Gratifyingly,
the amines incorporating electron-withdrawing groups (EWGs)
afforded an increase in the K value compared to benzylamine,
This article is protected by copyright. All rights reserved.

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
10.1002/chem.201606040
Chemistry - A European Journal
COMMUNICATION
while electron-donating Me showed opposite result. These
findings confirm that π-stacking, not nucleophilicity, dictates the
variation of equilibrium constants, since the introduction of
EWGs leads to the enhancement of π-stacking but has the
opposite effect on nucleophilicity.
binding affinity between
1
and a pair of amines, its
corresponding ΔG would in turn be indicative of the energy
difference for π-stacking (see details in SI), and the ΔG from di-
substituted benzyl amines, including m,m- and m,p-, was
compared with that from mono-substituted amines (Figure 4a).
All ΔG values (Table S6) match pretty well with the data
calculated based on the sum of individual ΔG values of mono-
substituted amines. Moreover, an excellent linear correlation of
measured ΔG versus predicted ΔG was afforded (Figure 4b),
with the slope near unity (0.981) and the y-intercept close to the
origin (0.0009). The additivity of SEs was further supported by
the amine exchange with α-methylpentafluorobenzylamine,
which gave the largest K value among all α-methylbenzylamine
analogs studied (Tables 1 and S5). These results provide strong
evidence for the direct interaction model on π-stacking.
Figure 3. (a) Hammett plot for amine exchange with para- or meta-substituted
benzylamine; (b) Hammett plot for amine exchange with para-substituted
benzylamine or α-methylbenzylamine.
The data was next subjected to linear free energy relationship
(LFER) based Hammett analysis[22] to provide deep insights for
π-stacking. The use of LFER parameters for model building is
gaining popularity in supramolecular and dynamic covalent
chemistry, including examining weak interactions.[23] Correlation
with σp values gave a scattered plot (Figure S35), but a plot of
log K versus σm values was linear (slope = 0.120, Figure 3a).
This is because that σm closely represents purely electrostatic
SEs through induction while σp reflects both inductive and
resonance effects. In particular, the role of OMe, which is a π
donor (negative σp), but an σ acceptor (positive σm), was
successfully modeled. These results are consistent with the
direct interaction model of SEs for π-stacking. Furthermore,
meta-substituted benzylamines exhibited different K values for
exchange reactions (Table S5) and afforded a Hammett plot with
a sensitivity factor of only 0.027 (Figure 3a). This positional
dependence of SEs further falls in line with the direct SE model.
It is worthwhile to mention that the same trend of p-Me and m-
Me relative to H is in contrast to the system in Scheme 1a, in
which the effect of p-Me and m-Me is opposite.[18]
Our next goal was to expand the substrate scope as a means
of regulating π-stacking. Amine exchange of 2-propylamine
derived assembly with α-substituted primary amines (i.e., α-
methylbenzylamine derivatives) was thus conducted (Table S5).
A linear relationship of log K versus σm values was again
obtained (slope = 0.442, red line in Figure 3b), in agreement with
non-branched benzylamine series (black line in Figure 3b) and
thereby confirming the modulation mechanism of π interactions.
More importantly, the enhanced sensitivity toward arene
substitution for α-branched amines (0.442) relative to linear
amines (0.059) echoes the larger K values for the former
(Tables 1 and S5). We rationalized these findings with more
dominance of π-stacking for α-substituted amines due to
restricted bond rotation and thus increased structural rigidity
imposed by the bulkier methyl group. These results also
showcased the versatility of our dynamic covalent system.
Figure 4. (a) The design of amine exchange for examining additive SEs; (b)
the linear fitting of measured ΔG versus calculated ΔG.
Finally, π-stacking within our system was employed for the
control of chirality, which is vital to many chemistry endeavors,
such as asymmetric catalysis[24] and molecular motors.[25] The
faces of 1 are homotopic, and hence, π-stacking between the
arenes on two ends of 1 and the arene unit in amine will afford a
pair of diastereomers for the reaction of
1
with an
enantiomerically pure chiral amine (Figures 5a and S83).
Although these structures can interconvert through the rotation
along the newly formed C-N bond, the two stacking arene
planes will lead to the preference of one isomer due to restricted
conformation (i.e., conformational chirality), and the proximity of
two chromophores will hence afford an induced circular
dichroism (CD) signal.[5b, 26] 1 is CD inactive, and free amines
exhibited no or tiny CD signals above 220 nm (Figure 5b), and
therefore, any strong signals above this wavelength are
indicative of 2 and thus reflect the induced chirality. The
solutions of α-methylbenzylamine and α-(1-naphthyl)ethylamine
Figure 5. (a) The illustration of chirality induction from (R)-α-chiral amine; (b)
CD spectra of (R)-α-chiral amine derived adduct 2 (0.169 mM in CH3CN, solid
line). The spectra of free amines were in dashed line.
To further test SEs of π-stacking, the additivity of SEs was
probed. As the K value of amine exchange reflects relative
This article is protected by copyright. All rights reserved.