Activated Self-Resolution and Error-Correction in Catalytic Reaction Networks**

Article abstract of DOI:10.1002/chem.202100208

Understanding the emergence of function in complex reaction networks is a primary goal of systems chemistry and origin-of-life studies. Especially challenging is to create systems that simultaneously exhibit several emergent functions that can be independently tuned. In this work, a multifunctional complex reaction network of nucleophilic small molecule catalysts for the Morita-Baylis-Hillman (MBH) reaction is demonstrated. The dynamic system exhibited triggered self-resolution, preferentially amplifying a specific catalyst/product set out of a many potential alternatives. By utilizing selective reversibility of the products of the reaction set, systemic thermodynamically driven error-correction could also be introduced. To achieve this, a dynamic covalent MBH reaction based on adducts with internal H-transfer capabilities was developed. By careful tuning of the substituents, rate accelerations of retro-MBH reactions of up to four orders of magnitude could be obtained. This study thus demonstrates how efficient self-sorting of catalytic systems can be achieved through an interplay of several complex emergent functionalities.

Full text of DOI:10.1002/chem.202100208

Full Paper
doi.org/10.1002/chem.202100208
Chemistry—A European Journal
Activated Self-Resolution and Error-Correction in Catalytic
Reaction Networks**
Fredrik Schaufelberger[a] and Olof Ramström*[a, b, c]
Abstract: Understanding the emergence of function in
complex reaction networks is a primary goal of systems
chemistry and origin-of-life studies. Especially challenging is
to create systems that simultaneously exhibit several emer-
gent functions that can be independently tuned. In this work,
a multifunctional complex reaction network of nucleophilic
small molecule catalysts for the Morita-Baylis-Hillman (MBH)
reaction is demonstrated. The dynamic system exhibited
triggered self-resolution, preferentially amplifying a specific
catalyst/product set out of a many potential alternatives. By
utilizing selective reversibility of the products of the reaction
set, systemic thermodynamically driven error-correction could
also be introduced. To achieve this, a dynamic covalent MBH
reaction based on adducts with internal H-transfer capabilities
was developed. By careful tuning of the substituents, rate
accelerations of retro-MBH reactions of up to four orders of
magnitude could be obtained. This study thus demonstrates
how efficient self-sorting of catalytic systems can be achieved
through an interplay of several complex emergent function-
alities.
Introduction
origin-of-life models.[17–21] However, the systems chemistry of
adaptive catalytic molecules is still poorly understood. We have
previously investigated reaction networks of so-called dynamic
covalent catalysts.[22–26] By connecting catalytically active com-
ponents with reversible imine bonds (Figure 1a), catalysts
Biological systems are based on complex networks of inter-
connected chemical interactions and reactions. All these
biochemical processes operate in concert to provide advanced
emergent properties such as replication, regulation and self-
organization.[1] Eventually, when a certain level of connected-
ness in reaction networks is reached, self-conscious living
systems may arise. To understand Nature’s complex machinery
and how it may have emerged, synthetic systems can be used
to mimic biotic reaction networks.[2–4] By studying the systems
chemistry of small molecule models, important insights into
emergence of life-like behavior in prebiotic settings can be
achieved.[5]
Significant advances in the design of synthetic systems
capable
of,
for
example,
self-replication,[2,6–8]
self-
and
organization,[9–11]
self-sorting,[12–14]
compartmentalization,[15,16] have all been made in recent years.
One area of systems chemistry that has received particular
attention is emergent catalytic and autocatalytic behavior, since
catalysis is perceived to be a crucial component in virtually all
[a] Dr. F. Schaufelberger, Prof. Dr. O. Ramström
Department of Chemistry, KTH - Royal Institute of Technology
Teknikringen 36, 10044 Stockholm (Sweden)
[b] Prof. Dr. O. Ramström
Department of Chemistry, University of Massachusetts Lowell
One University Ave., Lowell, MA 01854 (USA)
E-mail: olof_ramstrom@uml.edu
[c] Prof. Dr. O. Ramström
Figure 1. a) Schematic representation and molecular architecture of dynamic
covalent catalyst class used. b) Tertiary amine activation of acrylates for
nucleophilic attack. c) Outline of previous study:[25] a reactant/catalyst set
rearranges to a product/new catalyst set during the course of the catalytic
event. d) Outline of the current study: a dynamic covalent MBH reaction
enables the catalyst system to perform error-correction of the product/
catalyst set.
Department of Chemistry and Biomedical Sciences, Linnaeus University
39182 Kalmar (Sweden)
[**] A previous version of this manuscript has been deposited on a preprint
server (https://doi.org/10.26434/chemrxiv.13604318.v1)
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/chem.202100208
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capable of modifying their own molecular architecture are
accessible.[27] When incorporated into dynamic systems under-
going constitutional exchange, these compounds display self-
resolving behavior. This means that the constituents act on the
system of which they are part, which drives evolution of new
networks of increasing or decreasing complexity.[28–33]
A transformation that has proven highly useful as a model
system in these studies is the Morita-Baylis-Hillman (MBH)
reaction, which is enabled through nucleophilic catalysis (Fig-
ure 1b).[25] By using a dynamic iminoquinuclidine catalyst[34] for
the MBH reaction and tuning the conditions so that self-
resolution was performed under kinetic control, a secondary
function in the form of feedback regulation emerged (Fig-
ure 1c).[25] Since the formation of product and a new catalyst
architecture was coupled, the exchange process always tuned
the catalyst activity as a response to the catalytic event.
incorporated into the product) under complete catalyst control,
and it is known that the reaction show temperature-dependent
reversible character.[38] However, the equilibration rates have
generally been far too low for use in dynamic systems.[48,49]
Herein, we disclose that internal proton transfer within MBH
adducts results in highly accelerated reversible reactions that
make the MBH reaction suitable for use in dynamic covalent
chemistry. Furthermore, these results were used to create
dynamic catalyst systems where multiple emergent function-
alities operate at the same time.[50,51] We thus demonstrate how
the reversible MBH reaction combined with integral catalysis
can be used to create activated reaction networks. These
systems can perform two parallel functions: systemic self-
sorting (distinguishing self from non-self at a systems level) and
programmable error-correction (the ability to reverse formation
a specific compound from the system as a result of operator
input). Finally, we show how all these design elements come
together to form expanded networks where self-sorting from
large systems of constituents into just a single new product can
be observed.
During these studies, some important insights regarding the
complex mechanism of the MBH reaction were gained.[35–43] It
was thus clear that the MBH reaction was under kinetic control
in the time regimes investigated. However, some substrates
showed clear signs of transient product formation of an
“erroneous” MBH product, which subsequently decayed back
into the starting materials during the self-resolution. This led to Results and Discussion
the hypothesis that error-correction behavior can be pro-
grammed into the systems through incorporation of conditional
reversibility in the product. The systems were then envisaged to
initially undergo transformation towards a transient product,
resulting in an MBH adduct/catalyst set imposed by these
conditions (Figure 1d, inner network, red striped zone). Primed
for the retro-reaction, a secondary self-sorting process could
then subsequently traject the components away from this state
towards the most stable MBH adduct/catalyst set (Figure 1d,
outer network, green lined area). A systemic expansion, from an
isolated state towards a complete network, could thus be
unlocked by a single input (addition of acid to turn on imine
exchange).
Key to the realization of this behavior is creation of
conditionally reversible product forming reactions. In this
context, the MBH reaction has long been considered attractive
for use in dynamic covalent chemistry (Figure 2).[44–47] It is a self-
contained transformation (i.e. all atoms in the reactants are
Dynamic covalent MBH reactions
To understand how error-correcting catalytic systems can be
created, a detailed understanding of the reversibility of the
MBH adducts in our previous study was first targeted.[25] It
quickly became clear during preliminary investigations that
salicylaldehydes exhibited unusual MBH equilibration rates
(Table 1).[52,53] This class of compounds rapidly gave rise to MBH
adducts under thermodynamic control, in contrast to almost all
other substrates tested.
To confirm these findings, a range of substituted MBH
adducts were synthesized and subjected to retro-MBH con-
ditions using the general nucleophilic catalyst DABCO.[54] In
order to suppress the cyclization reactions observed by Kaye,[55]
tert-butyl or adamantylacrylates had to be used (Table S1).
Using these, a large acceleration in fragmentation rate with
salicylaldehyde-derived adduct 2b, compared to p-nitro- sub-
stituted reference compound 2a, (Table 1, entries 1–2) was
noticed. The effect was even more pronounced upon substitu-
tion of the tert-butyl moiety for an adamantyl group (Table 1,
entry 3). Both electron-rich and electron-poor o-hydroxy-sub-
stituted MBH adducts 2d and 2e (Table 1, entries 4–5) exhibited
high retro-reaction rates, indicating that electronic effects is not
the primary factor facilitating reversibility. Substrate 2f contains
an amide in the ortho-position of the aromatic ring to the allylic
alcohol (Table 1, entry 6). It was hypothesized that if internal
proton transfer was responsible for the rate acceleration, this
compound should also exhibit enhanced retro-MBH rates
compared to substrate 2a. This was indeed observed, although
to a diminished degree compared to salicylaldehyde-derived
substrates due to the low acidity of the amide group. Further
evidence for the proton transfer hypothesis was obtained with
m-hydroxy-substituted adduct 2g, which did not show any
Figure 2. Outline of irreversible and reversible MBH reactions and their
produced secondary functions within the reaction networks in Figure 1.
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Table 1. Kinetics and thermodynamics of retro-MBH reactions with differ-
ent substitution patterns.[a]
Entry
Substrate
vo
Relative
rate
K
(mM/min)[b]
(M)[c]
1
6.4×10À 4
1.0
0.0033
Figure 3. a) Optimized conformation of compound 2b (DFT, B3LYP/6-31G
(d)). Non H-bonding hydrogens omitted for clarity. b) Potential retro-MBH
rate acceleration via internal proton transfer (six-membered TS).
2
3
4
1.5×10À 1
1.9×10À 1
7.8×10À 2
232
301
123
1.84
1.62
0.96
bonding can contribute to H-bond donor strength by orders of
magnitude,[56,57] potentially activating the acrylate fragment and
accelerating the nucleophilic attack on compound 2b. The
phenolic ortho-substitution pattern may also facilitate the
proton transfer step preceding the elimination of the nucleo-
phile (Figure 3b).
Further insights into the reaction mechanism of the MBH
reaction was obtained by measuring the initial fragmentation
rates of compound 2b in the presence of DABCO over a range
of concentrations (Figure S1). A linear response was observed
for compound 2b, with approximate first order concentration
dependence. For the nucleophilic catalyst, saturation kinetics
with a maximum rate at ca 1.0 equiv. was recorded. Approx-
imate first order dependence was in this case observed at lower
concentrations, indicating that the initial nucleophilic attack is
reversible and not rate-limiting. This corroborates earlier reports
regarding MBH systems with protic additives, which suggested
the proton transfer step to be rate-determining.[40]
[d]
5
6
5.1×10À 2
8.7×10À 3
80
14
–
0.37
0.19
7
8
7.1×10À 4
2.2×10À 4
1.1
[d]
0.35
–
[e]
9
2.2×10À 5
0.034
–
[a] Conditions: MBH adduct (0.1 mmol), DABCO (0.1 mmol), MeCN-d3
(0.50 mL), rt, N2. [b] Initial rate over first 5–12% of reaction conversion as
determined by 1H-NMR spectroscopy (cf. SI). [c] Reaction equilibrium
constant as determined by 1H-NMR spectroscopy. [d] Long-term stability of
aldehyde poor, equilibrium not reached before partial decomposition. [e]
Equilibrium not reached due to slow kinetics.
Taken together, these results provide a clear roadmap for
creating dynamic covalent MBH reactions, where internal H-
transfer is a crucial component to enable rapid equilibration.
acceleration compared to the reference (Table 1, entry 7). This
indicates negligible contributions from intermolecular hydrogen
bonding or intermolecular proton shuttling. Similarly, non- H-
bonding compounds 2h and 2i also showed lower retro-MBH
reaction rates (Table 1, entries 8–9). The rate for o-methoxy-
substituted adduct 2i is especially noteworthy, as substitution
of the phenolic hydrogen for a methyl group led to a 7000-fold
rate deceleration (compare Table 1, entries 2 and 9).
The position of the equilibrium at room temperature could
be recorded for some reactions, for which the time to reach
thermodynamic equilibria varied from 24 h (compounds 2b and
2c) to five months (compound 2g). In line with previous
observations, electron-poor aryl aldehydes favored the MBH
adduct, whereas electron-rich aryl aldehydes preferred the
aldehyde/acrylate side.[26] Dual entry-point analysis with com-
pound 2b was used to confirm the thermodynamic nature of
the equilibrium, and similar product distributions were reached
in 72 h (cf. Scheme S1).
Error-correcting reaction networks
Equipped with an enhanced understanding of the systems, the
H-bond-assisted MBH reaction was next applied to activated
self-sorting catalytic networks, and a system was set up as
shown in Figure 4. Salicylaldehyde-derived MBH adduct 2b was
first mixed with catalyst C1 (Figure 4, orange-shaded Path A, cf.
also Schemes S1 and S3). This led to the fragmentation of
adduct 2b into tert-butyl acrylate and salicylaldehyde 1b,
catalyzed by compound C1, with an equilibrium being estab-
lished within 48 h (Table 1, entry 2).[58]
However, upon addition of a system activator (benzoic
acid), a complex retro-MBH/imine exchange/MBH reaction
cascade was turned-on (Figure 4, green-shaded Path B). In line
with previous observations in Table 1, electron-poor aldehydes
led to more stable MBH adducts than electron-rich. MBH adduct
2a was thus formed along with an equivalent amount of new
catalyst C2, indicating that the system still maintained the
products and catalysts paired in equimolar sets (hydrolysis of
the imine catalysts was not favored under these conditions in
line with previous observations).[25] The increase in catalyst C2
led to gradual downregulation of catalyst C1, concomitant with
To study the origin of the rate acceleration with H-bonding
substrates, the energy-minimized conformation of 2b was
calculated (DFT) showing the presence of a coupled H-bond
system (Figure 3a). This type of polarization-enhanced H-
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As can be seen from Figure 5, an initial buildup of the
kinetic product 2b was observed but the concentration
eventually decreased until the compound essentially disap-
peared from the system (cf. Figure S4). In contrast, the
generation of adduct 2a was initially slow due to the low
amounts of compound 1a available in solution during the early
phase of the reaction. As the imine equilibrium was gradually
established over several days, MBH adduct 2a started to form in
larger amounts (Figure 5, triangles) while adduct 2b was being
consumed via the retro-MBH reaction. The final system
composition was composed of 93% of adduct 2a and 7% of
aldehyde 1b, reached after ca 14 d. From the distinct kinetic
profile, the error-correction regime is evident between 4–10 d.
The evolution of compound 2a reached a plateau after 4 d,
which closely mirrored the point where a maximum concen-
tration of 2b was reached. The delay in evolution of compound
2a between the plateau at 4 d and the gradual disappearance
of compound 2b over days 5 to 9 can be attributed to the rates
of the interconnected imine equilibria that eventually release
aldehyde 1a.
Thus, the system exhibited activated thermodynamically-
driven error-correction with self-sorting towards the MBH
adduct 2a and the connected catalyst C2. The driving force of
the rearrangement appears to be the significantly higher
stability of MBH adduct 2a over compound 2b. The role of the
trigger species (benzoic acid) in the system was also crucial. In
the absence of this catalyst, the expansion of the network was
hindered and only a simple MBH reaction equilibrium was
obtained. This mode of self-resolution provides an additional
systemic mechanism for complexity evolution, providing anoth-
er step on the road towards the grand goal of systems
chemistry to developing dynamic catalytic systems that simu-
lates the functionality of metabolic and regulatory biochemical
pathways.
Figure 4. Activated self-sorting and error-correcting dynamic reaction net-
work. Inner network (orange-shaded): network consisting of catalyst C1 and
MBH adduct 2b. Outer network (green-shaded): Addition of trigger, benzoic
acid, leading to turn-on of imine exchange and formation of catalyst C2 and
aldehyde 1a. This led to downregulation of catalyst C1 and adduct 2b, while
accelerating the formation of MBH adduct 2a. Symbols: ––* catalysis; –┼"
activation.
a decrease in MBH adduct 2b, while accelerating the formation
of adduct 2a. To monitor the process, a system was set up with
catalyst C1 and aldehyde 1b. When benzoic acid and tert-butyl
acrylate were added, compound C1 initially catalyzed the MBH
reaction between the free aldehyde 1b and the acrylate to give
MBH adduct 2b (Figure 5, circles). As the reaction progressed,
imine exchange between the compound pairs C1/1b and C2/
1a occurred producing the more reactive aldehyde 1a and the
more stable MBH adduct 2a.
Expanded self-sorting systems
With an enhanced set of design rules established, the potential
of generating expanded systems capable of activated self-
sorting from larger compound pools was next addressed
(Figure 6). Naturally, the self-sorting efficiency in such scenarios
always decreases due to the lower concentrations of the active
species, and hence it is of great interest to probe the limits of
the self- resolution procedure.
To introduce new aldehyde components to the system
without risking unselective MBH reactions under kinetic control,
the new aldehyde substrates were “masked” as imines with
cyclohexylamine. Initially, kinetic self-sorting along the lines of
Figure 1c was attempted with imines D1 and D2 added to the
systems along with the previously employed electron-rich
aldehyde 1c (Figure 6).[25] Upon addition of acid, these com-
pounds all participated in the dynamic imine system, resulting
in rapidly increased complexity with several new aldehyde and
imine species observed during the reaction.
Figure 5. Self-sorting and error-correction of dynamic reaction system. Graph
showing evolution of MBH adducts with time. Conversion measured by 1H
NMR integration of the key aromatic and alkene signals with internal
standard. Conditions: catalyst C1 (0.1 mmol), aldehyde 1b, (0.1 mmol),
Regardless of the starting position and number of compo-
nents, aldehyde 1a was however always selected as the
°
PhCOOH (0.1 mmol), tert-butyl acrylate (1.0 mmol), MeCN (0.5 mL), 40 C, N2.
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catalysts, providing dynamic catalytic systems capable of error
correction. We have furthermore investigated how internal
proton transfer may activate MBH adducts to achieve high
reversibility, which now enables this attractive, self-contained
CÀ C bond forming reaction to be applied in dynamic covalent
chemistry.
Finally, this chemistry has been applied to activated self-
sorting of dynamic catalysts in both small and expanded
dynamic systems with good efficiencies. These reaction net-
works are unique in that the generation of a product set is
accompanied by the creation of an associated new catalyst, and
the systems furthermore error-correct for the catalyst composi-
tion that leads to its own creation. Hence, through a judicious
choice of parameters, these systems potentially enable pro-
Figure 6. Expanded self-sorting systems under kinetic control. Conditions:
catalyst C1/C4 (0.04 mmol), imine D1/D2 (0.04 mmol), aldehyde 1c,
(0.04 mmol), PhCOOH (0.04 mmol), methyl acrylate (0.4 mmol), MeCN/H2O
(99:1, 0.2 mL), rt, N2.
grammed loops and
a novel autocatalytic and systemic
behavior that is reliant on the error-correction mechanism.
coupling partner from the systems (compare output from Path Acknowledgements
A and B in dashed box, Figure 6).
The MBH reaction networks could also be expanded to up
to twelve potential electrophiles by addition of two new
cyclohexylamine-derived imines D3 and D4 (Table 2). The
system self-sorted efficiently both with the error-correcting
substrate 1b and non-correcting 1c (Table 2). In all cases, the
system showed complete chemoselectivity for aldehydes over
This study was in part supported by the Swedish Research
Council. F.S. thanks KTH for an Excellence Award. Björn
Dahlgren is gratefully acknowledged for assistance with the
DFT calculations.
N-alkyl imines, exclusively selecting the most electron-poor aryl Conflict of Interest
aldehyde 1a as the MBH coupling partner. No side-products or
other MBH adducts were ever observed from the system. The
self-sorting could also reach efficiencies over 90% yield (Table 2,
entry 4), but slowed down considerably with increased number
of compounds (Table 2, entries 5 and 6). Nevertheless, this
strategy clearly enables the construction of more complex and
sophisticated self-sorting systems.
The authors declare no conflict of interest.
Keywords: dynamic covalent chemistry · dynamic systems ·
imine exchange
organocatalysis
·
Morita-Baylis-Hillman reactions
·
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Manuscript received: January 20, 2021
Accepted manuscript online: March 29, 2021
Version of record online: ■■■, ■■■■
Chem. Eur. J. 2021, 27, 1–7
www.chemeurj.org
6
© 2021 Wiley-VCH GmbH
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FULL PAPER
A dynamic covalent Morita-Baylis-
Hillman (MBH) reaction is demon-
strated and applied to the generation
of dynamic catalyst systems. The
systems exhibited triggered self-reso-
lution, preferentially amplifying a
specific catalyst/product set out of a
many potential alternatives, as well as
systemic thermodynamically driven
error-correction.
Dr. F. Schaufelberger, Prof. Dr. O.
Ramström*
1 – 7
Activated Self-Resolution and Error-
Correction in Catalytic Reaction
Networks