Simultaneous Formation of a Fully Organic Triply Dynamic Combinatorial Library

Article abstract of DOI:10.1021/acs.orglett.1c01042

Here we report the simultaneous formation of doubly and triply dynamic libraries as a result of exchange reactions between functionalized organic building blocks. A combination of three different reversible covalent linkages involving a boronate ester transesterification along with an imine and disulfide exchange was employed to generate a new type of fully organic triply dynamic molecular assembly.

Full text of DOI:10.1021/acs.orglett.1c01042

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Letter
Simultaneous Formation of a Fully Organic Triply Dynamic
Combinatorial Library
̇
̇
Wojciech Drozdz, Anna Walczak, and Artur R. Stefankiewicz*
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ABSTRACT: Here we report the simultaneous formation of
doubly and triply dynamic libraries as a result of exchange
reactions between functionalized organic building blocks. A
combination of three different reversible covalent linkages
involving a boronate ester transesterification along with an imine
and disulfide exchange was employed to generate a new type of
fully organic triply dynamic molecular assembly.
of three orthogonal bonds (disulfide, hydrazone, and boronate
ultidynamic systems capable of constitutional inter-
Mconversions are of increasing interest, as they efficiently ester) was presented.5,11 Furlan, on the other hand,
investigated DCLs composed of disulfides, thioesters, and
hydrazones under conditions ensuring the efficient exchange of
the latter, leaving the sulfur moieties intact2 and vice versa.12
Bonifazi examined multiple-reaction systems based on a
disulfide exchange along with boronate and acylhydrazone
formations to generate chromophore-supported multicompo-
nent architectures.13 Noteworthy is the work of Leclaire, where
an appropriate design and the combination of simple building
blocks enable the formation of a highly interesting class of
compounds capable of capturing CO2.14 More recently, Anslyn
and co-workers reported reversible exchange processes
involving four independent linkages, namely, boronic ester,
disulfide, hydrazone, and coordination bonds.15 Although such
examples define the essence of multidynamic systems, those
operating simultaneously under the same conditions are still
very rare.14,16 The examples of multidynamic molecules
presented above, although very interesting and sophisticated,
contain a hydrazone bond in their structure. The imine group,
the reactivity and stability of which is significantly different
from the former, is clearly omitted. This may be due to the
greater lability of this bond, often resulting in the formation of
kinetic products, as opposed to the more stable, thermody-
namic hydrazone products.17 This prompted us to combine the
above-mentioned set of linkages, reliably investigated in terms
implement chemical diversity and lead to “informed” dynamics
with applications in the medical and pharmaceutical industries
including drug delivery.1 Thus, the simultaneous use of several
reversible covalent linkages is essential to the expansion of the
range of constituents expressed in a Dynamic Combinatorial
Library (DCL).2 Those most extensively used in combinatorial
systems currently are disulfide,3 boronate ester,4 hydrazone,5
and imine6 bonds. The combination of more than one
reversible bond, within a single library, can lead to a significant
increase in both the number of possible products formed and
factors that can effect the features of the products such as self-
healing, degradability, recyclability, or even shape memory.
It has been reported7 that structural diversity within a DCL
is increased by using thioester and disulfide exchange
processes, generating a doubly dynamic library formed either
competitively or orthogonally. In other instances, such DCLs
have been obtained using different combinations of disulfide,
hydrazone, imines, and boronate ester exchange reactions.8 An
interesting achievement was the use two of the above-
mentioned covalent linkages in the formation of linear small-
molecular motors.9 Another extraordinary example comes from
the Otto group involving an antiparallel dynamic system where
two chemistries, thiol−disulfide and thio-Michael exchange,
operate simultaneously.10
The use of three or more reversible bonds within a dynamic
library is quite a challenge due to the complexity of the
resulting systems. However, the benefits of a multitude of labile
bonds make such architectures more and more popular among
scientists. On the one hand, one of the pioneering works on
complex orthogonal libraries was presented by Matile, in which
the optimized conditions enabling the independent exchange
Received: March 26, 2021
Published: April 27, 2021
© 2021 The Authors. Published
byAmerican Chemical Society
https://doi.org/10.1021/acs.orglett.1c01042
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Scheme 1. Schematic Formation of Triply Dynamic System Via Two Separate Synthetic Routescontinuous Expansion of the
Dynamic Library (Stepwise, from Left to Right) or Simultaneous Formation (One Pot, Right)
of reversibility, to generate a fully organic multicomponent
combinatorial system.
mM of the individual substrate concentration, (2) temperature
adjusted to 50 °C, (3) deuterated dimethyl sulfoxide (DMSO-
d6) was used as the reaction medium and also as a mild oxidant
(thiol to disulfide oxidation).18 Unless otherwise mentioned,
reactions were performed for 24 h or until thermodynamic
equilibrium was obtained.
In this work we report the first example of a solely organic
triply dynamic library based on disulfide, boronic ester, and
imine bonds operating simultaneously under the same
conditions. Although all three distinct linkages are known to
exhibit reversibility, they have not been studied within a single
reaction system in terms of dynamic combinatorial chemistry
(DCC). Thus, all three reversible bonds have been employed
for the preparation of covalently assembled triple-level
dynamic combinatorial libraries consisting of the following
components: p-formylphenylboronic acid 1, two aliphatic
dialcohols: ethylene glycol 2 and neopentyl glycol 3, two
aromatic amines: aniline 4 and p-hydroxyaniline 5, and two
aromatic thiols: p-aminothiophenol 6 and p-bromothiophenol
7 (Scheme 1).
Initially, the reversibility and exchange reactions of each of
the dynamic bonds were examined separately under the above
conditions. The aim of these studies was to evaluate the
effectiveness of a specific dynamic bond formation under the
condition applied, but it also allowed a comparison of the
relative reactivity of the chosen molecular components. First,
we investigated the formation of boronic esters from 1 and the
two aliphatic diols differing in that the hydroxyl groups were in
1,2 (2) or 1,3 (3) positions, so that esters formed contained
either a five- or a six-membered ring, 8 or 9, respectively
(Figure 1a). Although both ester products were formed, only
30% of 8 was generated, while the formation of 9 occurred in
almost quantitative yield (92%), confirming its greater
thermodynamic stability.19 Preferential formation of a specific
boronic ester product was also observed in the two subsequent
reactions performed for this system, that is, self-selection and
exchange processes, in which molecule 9 was obtained in 81%
and 72% yields, respectively (Figure 1a,b). The remaining
material consisted of ester 8 (10% and 6% yields, respectively)
and unreacted substrates. The second reversible reaction
investigated was that of imine formation between aldehyde 1
and aniline 4 and its p-hydroxy substituted analogue 5. After 24
To fully investigate the equilibration and final composition
of the generated dynamic libraries, all experiments were
1
monitored and analyzed via H NMR spectroscopy. At least
two exchange pathways are possible for each investigated
reaction: boronate ester exchange might occur through either
hydrolysis/re-esterification (dissociative exchange) or trans-
esterification (associative exchange) mechanisms; imine
exchange could proceed through an amine addition to give
an aminal intermediate, which then undergoes elimination, or
it could involve a metathesis reaction between two imines
(unobservable in the present systems, where a single aldehyde
was involved), while disulfide exchange could occur through a
reaction with a thiol/thiolate or through a metathesis reaction.
While for the formation of dynamic systems it is important that
the reactions proceed and equilibrate reasonably quickly,
regardless of their mechanisms, note that we have found mild
reaction conditions so that all three above-mentioned
reversible processes could proceed essentially simultaneously.
It is also worth emphasizing that all library components
employed in this study had good solubility under the
conditions used. Thus, the following reaction conditions
were employed in all experiments described below: (1) 5
1
h, the library was analyzed by H NMR spectroscopy and
indicated the generation of the corresponding imine products
10 and 11 in ∼77% and 89% yields, respectively (Figures S5a
and S6 in the Supporting Information). As with the boronic
esters, self-sorting and exchange reactions were also conducted,
clearly showing a preferential formation of 11 compared to 10
(ratios of 76/24 and 69/31, respectively, Figures S5 and S7 in
the Supporting Information). This may be due to the greater
nucleophilicity of the amine 5 containing an electron-donating
OH group in the para position.
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62 and 72, each at 5 mM), thus confirming the thermodynamic
nature of the investigated equilibria.
Following this characterization of the single-level dynamic
libraries, we moved toward a more complex system, where the
simultaneous formation and exchange processes within double-
level dynamic systems were investigated. These experiments
were intended to provide compounds containing both boronic
ester and imine dynamic linkages within a single molecular
component. For this purpose, two separate DCLs were
prepared that, depending on the type of the studied exchange
reaction (imine exchange and/or boronic transesterification),
differed in the composition of the components used. The first
doubly dynamic library was obtained using a stoichiometric
mixture of boronic acid 1, diol 3, and two different amines, 4
1
and 5. The generated DCL was analyzed after 24 h by H
NMR spectroscopy and revealed the presence of two doubly
dynamic compounds 13 (marked blue) and 14 (marked red)
in the ratio 24/76 along with unreacted substrate (Figure S11
in the Supporting Information). A similar library composition
was observed upon the addition of amine 5 to the solution of
preformed molecule 13, which induced the imine exchange
reaction, yet left the ester bond intact.
Figure 1. Schematic representation of the experiments performed to
establish the thermodynamic equilibrium of boronic esters 8 and 9
formation through (a) self-sorting of starting materials and (b)
components exchange between isolated ester 8 and diol 3 (the
unreacted materials constituted 22% of the postreaction mixture).
The same procedure was exploited in the second DCL,
involving a transesterification in the vicinity of the imine bond.
Analogously to the previous experiment, diols 2 and 3 were
1
mixed with boronic acid 1 and p-hydroxyaniline 5. The H
NMR spectrum showed a strong preference toward the
formation of product 14 possessing the more stable six-
membered boronate ester ring (88% of the products library)
compared to its structural analogue 15 (12% of the products
library, Figure S12 in the Supporting Information). Sub-
sequently, a transesterification between 3 and isolated 15 was
found to give a DCL with the same distribution. These
observations highlight again the influence of the structural
features of the molecular building blocks on the ultimate
constitution of the generated DCLs. The dynamic processes in
the second system proceeded orthogonally without the
decomposition of a reversible bond not involved in the
exchange reaction.
The final step of the present work involved the investigation
of a triply dynamic library within the same reaction flask.
Although the formation of disulfide, boronate ester, and
hydrazone exchange has been previously established for
multicomponent surface architectures,5,11 a reaction set
consisting of the first two linkages and an imine has not
been studied. Two approaches were used to evaluate the
possibility of simultaneous formation of the three dynamic
bonds under the conditions applied. First, the “one pot”
approach was performed, where building blocks 1−6 (each at 5
mM) were combined together in an equimolar ratio in DMSO-
d6 at a temperature adjusted to 50 °C. After 24 h, the resulting
mixture was analyzed by 1H NMR spectroscopy (Figure S13 in
the Supporting Information), which confirmed the presence of
a complex dynamic library of structurally distinct compounds,
among which the desired triply dynamic compound 16 was
found in trace amounts. In an attempt to reduce the library
complexity, which would in turn allow for an easier isolation
and a full characterization of 16, a stepwise approach was
performed using only those components that constitute the
desired molecule, that is, 1, 3, and 6 (each at 5 mM). Although
the DCL generated from these building blocks remained
complex in solution (Figure S14 in the Supporting
Information), it allowed the isolation of 16, which precipitated
The last linkage studied within a single-level dynamic library
was that of the disulfide bond. Unlike the two previously
discussed reversible bonds, a symmetrical disulfide formation
may result from the autoxidation of an individual reaction
component. Thus, the rate of the autoxidation process was
monitored by 1H NMR spectroscopy, separately for each thiol
building block (6 and 7), which differ in the type of substituent
in the para position. While the signal from the p-
bromothiophenol 7 disappeared within 9 h as a result of 72
formation, component 6 (p-aminothiophenol) required 28 h
for the complete oxidation to homodimer 62, indicating a
major influence of the thiol structural features on the rate of
disulfide formation. (Figures S8−S10 in the Supporting
Information). To assess that the disulfide exchange operates
under thermodynamic control, two distinct pathways for
generating the DCL were explored. In the first, the DCL was
engendered by mixing equimolar amounts of thiol components
6 and 7, while in the second pathway the preoxidized disulfides
62 and 72 were mixed together (Figure S15). In the case of a
thermodynamically controlled system, the composition of the
generated DCL (a mixture consisting of heterodimer (12) and
two homodimers (62 + 72) was expected) should be identical,
regardless of the pathway used. The first DCL was prepared by
dissolving 6 and 7 (each at 5 mM concentration) in DMSO-d6
at a temperature adjusted to 50 °C. The library was stirred for
24 h in air in a capped NMR tube to allow oxidation of the
1
thiol building blocks. An analysis of the H NMR spectrum of
the reaction mixture (Figure S15b, top) revealed a fully
oxidized library with several sets of doublets corresponding to
the aromatic protons of homodimeric products 62 (marked
red) and 72 (marked blue), respectively (each accounted for
30% of the library material). The remaining set of peaks was
assigned to the heterodimeric disulfide compound 12 (marked
green), the predominant species in the mixture (40% of the
library material). An essentially identical product distribution
(Figure S15b, bottom) was observed in the DCL generated by
the alternative pathway (starting from preformed homodimers
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out of the reaction mixture in the form of a yellow powder, in
15% yield.
state, providing the first example of the crystal structure of a
molecular compound containing three distinct dynamic
linkages. The developed methodology and an analytical
protocol put forward in this paper is straightforward and
should be widely applicable in the generation of other
multidynamic functional architectures possessing more com-
plex topologies such as cages, knots, or polymers. The
physicochemical properties and potential functions of such
architectures, for instance, in catalysis, to prevent product
inhibition or in medicine, to release a drug at a specific site,
could then be controlled by a strategic application of a
precisely selected exchange chemical reaction.
Given its apparently low solubility, one obvious way to
promote the formation of this species at the expense of other,
more soluble coproducts, is to increase the concentration of
DCL components. To our delight, the isolated yield of 16 was
significantly enhanced (to 57%) by a 10-fold increase of the
initial building block concentration (50 mM). When
components 1, 3, and 6 were combined under these
conditions, a gradual precipitation of a yellow, crystalline
solid was observed, which, after filtration and washing with
Et2O, could be isolated in quantities sufficient for its full
characterization. Confirmation of the expected structure of
triply dynamic molecule 16 was provided by solution NMR
measurements (Figure 2 for 1H and Figure S2 in the
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01042.
Experimental procedures, characterization data, and
copies of the NMR spectra, crystallographic data
(PDF)
Accession Codes
CCDC 2057952 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
Figure 2. 1H NMR (300 MHz, CDCl3) spectrum of the isolated triply
dynamic molecule 16 and (inset) its crystal structure.
■
Artur R. Stefankiewicz − Faculty of Chemistry, Adam
́
Mickiewicz University, 61-614 Poznan, Poland; Center for
Supporting Information for 13C), mass spectrometry (MS)
(Figure S3), and elemental analysis (see Synthetic procedure
in the Supporting Information). The 1H NMR spectrum shows
a well-resolved set of signals with a characteristic imine proton
peak at 8.45 ppm (H5) and two sharp singlets from −CH2
(H2) and −CH3 (H1) moieties, at 3.79 and 1.04 ppm,
respectively (Figure 2). The mass spectrum showed an [M +
H]+ ion, m/z = 649.2489 and confirmed the expected
composition.
The final structural confirmation for 16 was provided by a
single-crystal X-ray crystallographic analysis. The molecules are
linked by weak CH···π interactions between a methylene
hydrogen atom and the aromatic six-membered ring
(CH···πPh 2.712(1) Å, Figure S16 in the Supporting
Information), and S···CHPh (2.903(1) Å, Figure S17 in the
Supporting Information) along the a-axis, forming a two-
dimensional network.
In conclusion, we have described the first multicomponent
reaction system operating simultaneously in a DMSO solution
at a slightly elevated temperature and consisting of three
distinct reversible linkages, that is, disulfide, boronate, and
imine. The gradual increase of the system complexity has
ultimately led to the generation of a unique example of a fully
organic triply dynamic molecular compound formed in a one-
pot reaction between six components via three independent
reversible reactions. Such a combination of covalent bonds has
never been employed in the formation of a multidynamic
molecule. Interestingly, we successfully isolated and fully
characterized the final product both in solution and in the solid
Advanced Technologies, Adam Mickiewicz University, 61-614
́
Poznan, Poland; orcid.org/0000-0002-6177-358X;
Email: ars@amu.edu.pl
Authors
Wojciech Drozd
University, 61-614 Poznan, Poland; Center for Advanced
z − Faculty of Chemistry, Adam Mickiewicz
̇ ̇
́
́
Technologies, Adam Mickiewicz University, 61-614 Poznan,
Poland
Anna Walczak − Faculty of Chemistry, Adam Mickiewicz
́
University, 61-614 Poznan, Poland; Center for Advanced
́
Technologies, Adam Mickiewicz University, 61-614 Poznan,
Poland
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01042
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The work was supported by the National Science Centre of
Poland (Grant No. SONATINA UMO-2019/32/C/ST4/
00565).
DEDICATION
■
Dedicated to Prof. Janusz Jurczak on the occasion of his 80th
birthday.
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