Formation and Out-of-Equilibrium, High/Low State Switching of a Nitroaldol Dynamer in Neutral Aqueous Media

Article abstract of DOI:10.1002/anie.201911706

The nitroaldol reaction is demonstrated as an efficient dynamic covalent reaction in phosphate buffers at neutral pH. Rapid equilibration was recorded with pyridine-based aldehydes, and dynamic oligomerization could be achieved, leading to nitroaldol dynamers of up to 17 repeating units. The dynamers were applied in a coherent stimuli-responsive molecular system in which larger dynamers transiently existed out-of-equilibrium in a neutral aqueous system rich in formaldehyde, controlled by nitromethane.

Full text of DOI:10.1002/anie.201911706

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Accepted Article
Title: Formation and Out-of-Equilibrium, High/Low State Switching of a
Nitroaldol Dynamer in Neutral Aqueous Media
Authors: Antanas Karalius, Yang Zhang, Oleksandr Kravchenko, Ulla
Elofsson, Zoltán Szabó, Mingdi Yan, and Olof Ramström
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201911706
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Formation and Out-of-Equilibrium, High/Low State Switching of a
Nitroaldol Dynamer in Neutral Aqueous Media
Antanas Karalius,[a] Yang Zhang,[a] Oleksandr Kravchenko,[a] Ulla Elofsson,[b] Zoltán Szabó,[a]
Mingdi Yan,*[a, c] and Olof Ramström*[a, c, d]
dynamers based on reversible C-C bonds leading to
Abstract: The nitroaldol reaction is demonstrated as an efficient
stereochemical complexity. Also, in contrast to condensation
dynamic covalent reaction in phosphate buffers at neutral pH. Rapid
reactions, the reaction is essentially self-contained and does not
equilibration was recorded with pyridine-based aldehydes, and
require the product to react with additional molecules to reverse
dynamic oligomerization could be achieved leading to nitroaldol
the bond formation.
dynamers of up to 17 repeating units. The dynamers were applied in
Furthermore,
non-equilibrium
and
dissipative
a coherent stimuli-responsive molecular system, in which larger
dynamers transiently existed out-of-equilibrium in a neutral aqueous
system rich in formaldehyde, controlled by nitromethane.
oligomer/polymer systems are in this context of particular interest
due to their biological relevance and for leading to potential
emergent functions.[7] A prerequisite for the formation of non-
equilibrium systems has been proposed to be kinetic asymmetry,
where fuel is used to cycle the systems into less
thermodynamically favored states.[8] Non-equilibrium states that
exist by means of consumption of energy/fuel become transient if
the fuel is limited.
In this study, we have addressed the challenge of
harnessing the nitroaldol reaction for dynamic covalent systems
in neutral, aqueous media. The dynamic features of nitroaldol-
based dynamic systems in buffered aqueous solutions have been
analyzed, and the formation of main-chain dynamers have been
demonstrated. The dynamers have furthermore been subjected
to size upregulation and disassembly processes to generate
switchable non-equilibrium systems. Through the actions of
nitromethane or formaldehyde, non-equilibrium states could thus
be attained in which the dynamer was transiently formed before
nitromethane was consumed.
The nitroaldol (Henry) reaction remains an important method to
form C-C bonds, leading to β-nitroalcohols with potentially
excellent stereochemical purity in high yields.[1] The stereogenic
reaction is generally reversible and has therefore been applied to
generate dynamic covalent systems, for example coupled with
lipase-mediated resolution processes.[2] Such dynamic covalent
systems have become a powerful tool to explore responsive and
adaptive processes, with the aim to address important problems
in chemistry, biology and materials science.[3] In the nitroaldol
cases, the systems were employed in organic solvents while
typically using amines as mediators/catalysts. However, water is
an especially attractive reaction media in dynamic chemistry
because of its compatibility to selection processes under
physiological conditions. Dynamic nitroaldol systems in aqueous
buffers would thus significantly extend the application scope of
the transformations in dynamic chemistry. Examples of using the
reaction for synthetic purposes in water-rich solutions have been
reported using different catalysts.[4] However, other than in our
preliminary studies,[5] the reaction has not been explored for
dynamic chemistry in aqueous media, nor has it been applied for
the formation of dynamic covalent polymers (dynamers) or
frameworks.
The inherently responsive nature of dynamic covalent
polymers makes them well adapted for a variety of applications,
such as drug delivery, and smart, cyclable materials undergoing
self-assembly or self-healing.[6] The nitroaldol reaction is here of
particular interest, since it enables main-chain or side-chain
Figure 1. Nitroaldol reactions of compounds 1 and 2 vs. reaction time at
different pDs. Lines represent fitted data obtained from non-linear regression
analysis towards a standard kinetics model (cf. Supporting Information).
[a]
A. Karalius, Dr. Y. Zhang, O. Kravchenko, Prof. Dr. Z. Szabó,
Prof. Dr. M. Yan, Prof. Dr. O. Ramström
Department of Chemistry, KTH - Royal Institute of Technology,
Teknikringen 36, S-10044 Stockholm, Sweden;
Dr. U. Elofsson
Bioscience and Materials division, Research Institutes of Sweden,
Box 5607, SE-114 86, Stockholm, Sweden;
Prof. Dr. M. Yan, Prof. Dr. O. Ramström
Department of Chemistry, University of Massachusetts Lowell, One
University Ave., Lowell, MA 01854, USA; Email:
mingdi_yan@uml.edu; olof_ramstrom@uml.edu;
Prof. Dr. O. Ramström
[b]
[c]
The formation and dynamic exchange of β-nitroalkanols in
aqueous media was first evaluated. For this, a model reaction was
devised based on equal amounts of 2-pyridinecarboxaldehyde (1)
and 2-nitroethanol (2), where the reaction was performed in
deuterated phosphate buffers (Figure 1). This reaction was
chosen to ensure high solubilities of the starting materials and
products, as well as incorporating a pendant hydroxyl group in
analogy to the products envisaged with nitromethane (vide infra).
Furthermore, the nitroethanol species did not undergo multiple
[d]
Department of Chemistry and Biomedical Sciences, Linnaeus
University, SE-39182 Kalmar, Sweden
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201911706
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nitroaldol reaction steps, simplifying the analysis. To estimate the
pD-dependence of the reaction, buffers ranging from pD 6.0 to 8.0
were assessed, where the relative amount of nitroaldol product 3
in the system was recorded as a function of the equilibration time
(Figure 1, Table S1).
In all buffers, rapid formation of nitroaldol product 3 was
observed, with a comparatively lower rate at pD 6.0. The resulting,
estimated equilibrium constants amounted to >500 M-1 at all pDs,
polymer (dynamer) in aqueous media was addressed
(Scheme 1). This was accomplished using nitromethane with
bifunctional building block 7 under neutral aqueous conditions.
The polymerization was followed by 1H NMR, resulting in
significantly broadened peaks preventing straightforward
determination of the extent of the reaction (cf. Figure S9).
However, at feed concentrations of 40 mM or higher, gradual
precipitation of the polymeric adduct occurred, and dynamer 8
could be isolated by filtration. Since this threshold molecular
showing
a higher thermodynamic stability of the product
compared to the starting materials. The hydrated aldehyde
species was also observed at a relatively constant level
throughout the reaction. As expected, the relative portion of the
deuterated species, both the starting material and the product,
increased with the basicity of the buffer. Under physiological
conditions (pD = 7.4), the forward rate was approximately 2.9 M-1
min-1 and the time to χ50 (50% equilibration degree/reaction
advancement degree)[9] was ca. 6.4 min. This rate is high
compared to other reversible covalent reactions under similar
conditions, for example, hydrazone/oxime formation.[10] This is
also more rapid than reported in previous studies of the nitroaldol
reaction in organic solvents.[2b, 2d]
Taking both the reaction rate and the equilibrium constant
into account, pD 7.4 was chosen as the optimal pD for the
subsequent reactions involving nitromethane (4). In contrast to
the effects observed for 2-nitroethanol, nitromethane can act as a
bifunctional molecule, leading to multiple equilibria (Figure 2).
The equilibrium formation was thus investigated from either the
substrate- or the intermediate/product sides, starting from
compounds 1 and 4, intermediate 5, or product 6. Lower buffer
concentrations were in these cases used to increase the accuracy
by decreasing the rate and minimize deprotonation of the product
species, and the trace deprotonated species decreased to a
negligible amount. The initial observation of both species
simultaneously can likely be attributed to the nitroalkane
anomaly.[11]
The process was analyzed by 1H NMR and initially several
signals of the different nitroaldol products overlapped, however
becoming resolved once the deuterium exchange of the acidic
nitromethylene protons had occurred (cf. Figure S6). The
resulting equilibrium distributions proved similar between the
complementary pairs of experiments (Figure 2). Interestingly, the
equilibration of equimolar compounds 1 and 4 resulted in a higher
amount of nitroaldol product (K1: 4500 M-1) compared to the result
with 2-nitroethanol (K: 1020 M-1), an effect in part attributable to
the lower steric hindrance of nitromethane in comparison to the
secondary nitrocompound.
Furthermore, the meso-isomers (1R,2r,3S/1R,2s,3S) of
product 6 dominated at equilibrium in aqueous media, while the
non-meso isomers (1R,3R/1S,3S) were exclusively formed in
organic solvent. Preferential syn-stereoselectivity has been
proposed in aqueous media, attributed to a hydrogen-bonded six-
weight represents a dynamer selection pressure, further
concentration increase would in principle lead to higher yields and
easy upscaling without affecting the resulting average size
distribution. Substantial quantities of dynamer 8 could thus be
isolated for characterization and additional testing. Analysis by
MALDI-TOF mass spectrometry (cf. Figure S10) yielded
molecular weights up to 3 kDa. The major peaks in the spectrum
were 196 Da apart, which corresponds to a single unit of the
dialdehyde/nitromethane adduct. Minor peaks appeared at the
same m/z intervals and may be due to different terminal groups,
such as combinations of aldehyde, nitromethylene, and/or
hemiacetal moieties. The highest observed signals correspond to
approximately 15 repeating units at around 3 kDa. Additional
lower-weight signals can be attributed to multiple ionizations and
fragmentation in the ion trap.
Scheme 1. Dynamic polymerization with bifunctional reagents
producing dynamer 8.
7 and 4
Diffusion NMR (DOSY) experiments performed in THF-d8 (Figure
S11) were also used to estimate the molecular weight of the
dynamer using the correlation between the diffusion constants (D)
and the molecular weights (M) (Dpol/Dref = (Mref/Mpol)
1/3; pol and ref
refer to polymer and reference).[12] Dimer 6 was used as external
reference under the same conditions, yielding a diffusion constant
of the oligomer corresponding to approximately 3.3 kDa with an
exponential fit.
This corresponds to a degree of oligomerization of ca. 17.
Since the diffusion constant is estimated for spherical species,
variations in the hypothetical sphere size can depend on the
solubilization and folding of the dynamer. This effect would have
to be accounted for by employing different solvents if larger sizes
were to be investigated. The oligomer was soluble in methanol,
acetonitrile, DMSO, THF and DMF. The stability in most polar
solvents was relatively low, with the exception of THF in which
solvent the polymer was stable over several days. Typically, the
NMR stability experiments showed an increase of single peaks
from the original broad peaks over the course of hours. The nature
of the degradation is unclear, however a depolymerization
pathway could explain the sharp signals emerging from the broad
peaks.
membered transition state involving
a participating water
molecule.[4a] In the present case, this preference would suggest
that the syn,syn-product (1R,2s,3S) forms first, but that
subsequent isomerization of the meso-isomers takes place.
With the bifunctional reactivity of nitromethane established,
the potential of forming a nitroaldol-based dynamic covalent
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Figure 2. Bifunctional nature of nitromethane (4) leading to multiple equilibria (top right). Equilibration (right) and distributions at apparent equilibria (left) of four
systems initiating from aldehyde 1 and nitromethane 2 at 1:1 (A) and 2:1 ratio (C), intermediate 5 (B), and product 6 (D); grey: 1 (incl. hydrate), blue: 5, orange: 6.
Values in percent conversions of aldehyde 1. Note the 50% maximum theoretical conversion of compound 5 in B and C due to the limiting component 4. The split
orange bars indicate the diastereomeric species while the split grey bars indicate the aldehyde and the hydrate. (cf. figures S2-S6).
Scheme 2. Stimuli-responsiveness of dynamic oligomer to both aldehyde and nitro-alkyl compounds. Interaction with corresponding chemical stimuli leads to
depolymerization and reformation of the original building blocks 4 or 7.
It was observed that when the feed concentrations were kept
below 20 mM, no precipitation occurred, and a lower molecular
weight oligomer remained in solution. The solution was stable,
and after ~6 h 3.5% of initial aldehyde signals remained with no
apparent change over several days. This enabled the study of
This difference in rate and product stability between
competing nitroaldol reactions suggested the potential of creating
systems where the oligomer in principle exists out-of-equilibrium
in a reaction network, and this was next evaluated. The processes
were followed by NMR peak broadening, qualitatively indicating
the monomeric/polymeric state of the systems. In a first example
(Figure S16), nitromethane (1 equiv.), dialdehyde 7 (1 equiv.) and
formaldehyde (10 equiv.) were simultaneously added, creating a
harsh environment in which no significant oligomerization
occurred, and the nitromethane was substantially digested by
formaldehyde before forming any larger oligomers. Repetitive
replenishment of both nitromethane and formaldehyde also
yielded the same results.
However, when increasing the nitromethane ratio to 2 equiv.
(Figure 3), significant oligomerization occurred although larger
oligomers would be unattainable in the absence of formaldehyde
due to saturation of the aldehydes (cf. Figure 2). This indicates a
situation where the formation and degradation of the oligomer
operates out-of-equilibrium as long as the ratio is maintained in
the process and the degradation products are inert. This can be
interpreted as an emergent property of the system where a
balance is attained through an interplay between different
processes.
stimuli-responsiveness
where
both
aldehydes
and
nitrocompounds can perturb or reverse an equilibrated dynamer
system (Scheme 2).
To test the stimuli-responsive nature of the dynamer,
formaldehyde was chosen as stimulus. Conspicuously, no
formaldehyde-responsive materials have been reported although
the compound is of biological significance.[13] The reaction
between nitromethane and formaldehyde showed that the
formation of 2-nitroethanol and subsequent formaldehyde
addition products was fairly slow, however resulting in high
conversion (95%) within 8 d. Thus, when an equilibrated system
of dynamic polymer 8 was subjected to the action of 10 equiv. of
formaldehyde (Figure S12), the equilibrium was driven towards
the starting dialdehyde 7, of which 97% emerged over the course
of 4 d. This result shows that formaldehyde can enable recycling
of the dialdehyde component. In the case of using 10 equiv. of 2-
nitroethanol,
a
new equilibrium was established with
approximately 89% conversion to the dinitroaldol product within 4
d, which was stable over the following 4 d.
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Figure 3. Formation and formaldehyde-induced breakdown of dynamer 8. Excess nitromethane allows for successful formation of the oligomer which exists out-of-
equilibrium in a formaldehyde-rich system. Insert (top, left) shows an enlarged snippet of the system at two extremes. Insert (top, left) shows enlarged snippets of
system at high and low molecular weights, established qualitatively via disappearance of sharp signals (starting materials) and emergence of broad, overlapping
oligomer signals. The relative molecular weight diagram (left) qualitatively indicates the appearance of the transient high molecular weight state by simultaneous
addition of upregulating (2 equiv. nitromethane) and downregulating (excess formaldehyde) reagents. The repeated addition of 2 equiv. of bifunctional nitromethane
with replenishment of formaldehyde excess repeats the same systemic effect. Waste build-up is also evident from the increasing signal at 4 ppm.
This was furthermore corroborated by allowing the system to
first equilibrate to higher oligomeric state
control and the extent of the preference would need to be re-
established in the case of the dynamers.
a
(1 equiv. nitromethane, no formaldehyde) and subsequently
adding both nitromethane and formaldehyde (Figure S17). In
this case, the system was noticeably perturbed although
displaying a significant delay before the system moved toward
the lower molecular weight extreme. Thus, the excess
nitromethane acted to protect the high molecular weight-state
of the system.
In this case, the oligomers were formed transiently due
to the discontinuous experimental set-up, with nitromethane
acting as fuel in the formaldehyde-rich system. The difference
observed by changing the starting point in the experiments
In summary, the dynamic features of the reversible
nitroaldol reaction in aqueous buffers have been investigated.
Compared to organic solvents, the nitroaldol-based dynamic
model systems showed rapid equilibration in neutral to basic
aqueous media reaching a 50% equilibration degree (χ50)
within a few minutes. The formed systems also displayed high
stabilities with low degrees of degradation over prolonged
periods of time. Using the bifunctional nature of nitromethane
in combination with dialdehydes, main-chain nitroaldol
dynamers could be straightforwardly made for the first time.
The inherent responsiveness of the dynamers to aldehydes
and nitrocompounds was furthermore evaluated leading to
regulatable dynameric states able to function out-of-
equilibrium. Such adaptable materials can be of use for a
variety of applications involving, e.g., cyclability, turn-on/off
processes, self-healing, and capture/release mechanisms. By
harnessing and controlling the stereochemical complexity of
the structures, hierarchical propagation of the chirality can be
perceived, leading to smart materials operating under
stereocontrol. Extensions for the reported dynamic systems
into different responsive materials and orthogonal systems are
thus under further development.
suggests that
a
steady-state requires an excess of
nitromethane in the system. Reaching this state would entail
the continuous addition of nitromethane, with the addition rate
being a function of the oligomer size as well as the
nitromethane/formaldehyde concentration ratio. Overall, a
higher size-state would require lower concentrations of free
nitromethane, which would, in turn, slow down the digestion
and result in a protecting effect. Furthermore, the time to reach
steady-state would likely depend on the desired dynamer size,
with a longer duration if starting from lower molecular weights.
The stereopreference observed for the model system
may have several consequences. If there is a distinct kinetic
and thermodynamic disparity between the stereoisomers, then
the dissipative systemic state, continuously recycling the
transient larger dynamer, could have an impact on the main
chain stereochemistry, suppressing the thermodynamically
preferred configurations. Furthermore, upregulating the kinetic
effect may allow access to higher stereodiversity by minimizing
both kinetic and thermodynamic traps due to continuous mass
reflux, before all fuel consumption and waste build-up would
eventually lead to the global thermodynamic minimum of the
system. Moreover, the stereopreference may lead to induction
effects whereby the configuration over the oligomer chain can
be controlled in different solvents. However, both the size
Acknowledgements
This study was in part supported by the Swedish Research
council and the European Union’s H2020 framework
programme (under agreement MSCA-ITN-2014-ETN-642192).
YZ thanks the China Scholarship Council for a special
scholarship award. The authors thank Anders Nilsson for
assistance with the MALDI-TOF MS experiments.
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Keywords: dynamic covalent • systems chemistry • nitroaldol
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Entry for the Table of Contents (Please choose one layout)
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The formation and features of a
nitroaldol dynamer is demonstrated.
The dynamer formed spontaneously in
neutral aqueous buffer, displayed
stimuli-responsiveness in the
Antanas Karalius, Yang Zhang,
Oleksandr Kravchenko, Ulla Elofsson,
Zoltán Szabó, Mingdi Yan,* and
Olof Ramström*
Page No. – Page No.
presence of aldehyde and
nitrocompounds, and could be used to
produce systemic, out-of-equilibrium,
high/low molecular weight cycling.
Formation and Out-of-Equilibrium,
High/Low State Switching of a
Nitroaldol Dynamer in Neutral
Aqueous Media
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