Catalytic Gels for a Prebiotically Relevant Asymmetric Aldol Reaction in Water: From Organocatalyst Design to Hydrogel Discovery and Back Again

Article abstract of DOI:10.1021/jacs.9b13156

This paper reports an investigation into organocatalytic hydrogels as prebiotically relevant systems. Gels are interesting prebiotic reaction media, combining heterogeneous and homogeneous characteristics with a structurally organized active solid-like catalyst separated from the surrounding environment, yet in intimate contact with the solution phase and readily accessible via liquid-like diffusion. A simple self-assembling glutamine amide derivative 1 was initially found to catalyze a model aldol reaction between cyclohexanone and 4-nitrobenzaldehyde, but it did not maintain its gel structure during reaction. In this study, it was observed that compound 1 could react directly with the benzaldehyde to form a hydrogel in situ based on Schiff base 2 as a low-molecular-weight gelator (LMWG). This new dynamic gel is a rare example of a two-component self-assembled LMWG hydrogel and was fully characterized. It was demonstrated that glutamine amide 1 could select an optimal aldehyde component and preferentially assemble from mixtures. In the hunt for an organocatalyst, reductive conditions were applied to the Schiff base to yield secondary amine 3, which is also a highly effective hydrogelator at very low loadings with a high degree of nanoscale order. Most importantly, the hydrogel based on 3 catalyzed the prebiotically relevant aldol dimerization of glycolaldehyde to give threose and erythrose. In buffered conditions, this reaction gave excellent conversions, good diastereoselectivity, and some enantioselectivity. Catalysis using the hydrogel of 3 was much better than that using non-assembled 3 - demonstrating a clear benefit of self-assembly. The results suggest that hydrogels offer a potential strategy by which prebiotic reactions can be promoted using simple, prebiotically plausible LMWGs that can selectively self-organize from complex mixtures. Such processes may have been of prebiotic importance.

Full text of DOI:10.1021/jacs.9b13156

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Article
Catalytic Gels for a Prebiotically Relevant Asymmetric Aldol
Reaction in Water: From Organocatalyst Design to Hydrogel
Discovery and Back Again
Kirsten Hawkins, Anna K. Patterson, Paul A. Clarke,* and David K. Smith*
Cite This: J. Am. Chem. Soc. 2020, 142, 4379−4389
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ABSTRACT: This paper reports an investigation into organocatalytic hydrogels as prebiotically relevant systems. Gels are
interesting prebiotic reaction media, combining heterogeneous and homogeneous characteristics with a structurally organized active
“solid-like” catalyst separated from the surrounding environment, yet in intimate contact with the solution phase and readily
accessible via “liquid-like” diffusion. A simple self-assembling glutamine amide derivative 1 was initially found to catalyze a model
aldol reaction between cyclohexanone and 4-nitrobenzaldehyde, but it did not maintain its gel structure during reaction. In this
study, it was observed that compound 1 could react directly with the benzaldehyde to form a hydrogel in situ based on Schiff base 2
as a low-molecular-weight gelator (LMWG). This new dynamic gel is a rare example of a two-component self-assembled LMWG
hydrogel and was fully characterized. It was demonstrated that glutamine amide 1 could select an optimal aldehyde component and
preferentially assemble from mixtures. In the hunt for an organocatalyst, reductive conditions were applied to the Schiff base to yield
secondary amine 3, which is also a highly effective hydrogelator at very low loadings with a high degree of nanoscale order. Most
importantly, the hydrogel based on 3 catalyzed the prebiotically relevant aldol dimerization of glycolaldehyde to give threose and
erythrose. In buffered conditions, this reaction gave excellent conversions, good diastereoselectivity, and some enantioselectivity.
Catalysis using the hydrogel of 3 was much better than that using non-assembled 3demonstrating a clear benefit of self-assembly.
The results suggest that hydrogels offer a potential strategy by which prebiotic reactions can be promoted using simple, prebiotically
plausible LMWGs that can selectively self-organize from complex mixtures. Such processes may have been of prebiotic importance.
gels for applications in catalysis.10 Gels benefit from a
combination of heterogeneous and homogeneous character-
istics, allowing the rapid diffusion of small molecules, like
INTRODUCTION
■
Gels are a colloidal state of matter in which a solid-like
network is dispersed through a continuous liquid-like phase,
leading to solvent immobilization.1 In the case of supra-
reagents and products, through the gel matrix while potentially
immobilizing the catalyst by incorporation into, or interaction
molecular gels, low-molecular-weight gelators (LMWGs) self-
with, the gel nanofibers. Self-assembled organocatalytic gels
assemble via intermolecular non-covalent interactions into a
have been developed,11 with a particular focus on systems in
nanoscale sample-spanning “solid-like” network.2 Hydrogels
which catalysis is enhanced compared with the non-assembled
have wide-ranging potential applications, particularly as
biomaterials3 and in environmental remediation.4 In some
organocatalyst. In landmark work, Escuder, Miravet, and co-
cases, gelation requires two distinct chemical components5
workers demonstrated the potential of gel networks to achieve
a range of catalytic processes, including amino acid-mediated
such “two-component gels” are tunable but relatively rare,
aldol reactions.12 They also developed self-sorted gel networks
especially in the case of hydrogels that self-assemble from
with orthogonal catalytic sites to achieve multi-step reactions
LMWGs in water. Examples include systems in which the two
in one system, demonstrating the potential of gels to act as
components form a non-covalent complex that acts as the
systems for complex processes.13
LMWG,6 or in which they come together to form the LMWG
in a dynamic reaction, such as acylhydrazone formation.7
There are also examples of small molecules that undergo
dynamic reactions, like imine formation, to form polymer
network hydrogels,8 but such gels are more like polymer gels9
than those that self-assemble from LMWGs via non-covalent
interactions. There has been interest in the development of
Received: December 6, 2019
Published: February 5, 2020
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© 2020 American Chemical Society
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Scheme 1. Outline Synthesis of the New Gels Reported Here and Summary of Their Ability to Catalyze Aldol Reactions
Organocatalysis also plays a key role in the field of prebiotic
chemistry, in which researchers aim to demonstrate mecha-
nisms by which simple chemical building blocks, such as those
present on the early Earth, can be converted into the more
complex chemical constituents of life.14 It is hypothesized that
some of the dominant reactions of prebiotic chemistry are
aldol condensations, which can result in the synthesis of sugars
and complex carbohydrates.15 It has been argued that the first
sugars arose from the formose reactionan autocatalytic
reaction of formaldehyde to form glycolaldehyde,16 followed
by aldol homologation of glycoladehyde into higher sugars.
Alternatively, it has been suggested by Sutherland that
glycolaldehyde and higher sugars can be generated from
formaldehyde by iterative Kiliani−Fischer synthesis and
aminooxazoline formation.17
It was first reported that prebiotically relevant amino acids,
such as proline, could catalyze asymmetric aldol cyclizations in
the early 1970s.18 In 2000, Barbas and List studied proline and
other primary and secondary, cyclic and acyclic amino acids as
general aldol catalysts, proposing a six-membered enamine
Zimmerman−Traxler transition state.19 In key work, Pizarello
and Weber showed that the dimerization of glycolaldehyde by
α,α-L-disubstituted amino acids led to the formation of L-
tetroses in 7% enantiomeric excess (ee).20 Similar studies by
Breslow with stoichiometric quantities of amino acids showed
the formation of D-glyceraldehyde with similar ee’s.21
Dipeptides have shown improved reaction selectivity and
tetrose yield,22 and zinc−proline complexes can catalyze an
aqueous aldol reaction in which a cocktail of higher
carbohydrates was produced.23 Barbas demonstrated the
catalysis of aldol reactions on activated nitrobenzaldehydes in
water without the need for co-solvents by using proline
modified with a hydrophobic group. Micellar assembly of the
catalyst mediates the reaction by providing a hydrophobic
environment for the organic reagents.24 This led Janda and co-
workers to critically question what was really meant by
performing organocatalysis “in water”which remains a key
question in the field.25 They also noted that adding an acid to
limit general base catalysis enhanced enantioselectivity. Clarke
and co-workers went on to apply this approach to prebiotically
relevant reactions, reporting the aldol condensation of TIPS-
protected glycolaldehyde in water promoted by amino acid
esters.26 They then reported aldol reactions on unprotected
glycoladehyde to generate threose and erythrose,27 and
demonstrated a plausible prebiotic synthesis in water of 2-
deoxy-D-ribose using amino acid esters and amino nitriles as
organocatalysts.28
Although gels have been studied to some extent in the field
of organocatalysis as described above, only Escuder and co-
workers have performed a prebiotically relevant reaction, using
a tripeptide organogelator to catalyze the reaction between
TIPS-protected glycolaldehyde, yielding TIPS-protected
threose and erythrose derivatives.29 In this research, the
catalysis failed on the unprotected glycolaldehyde. The relative
lack of development of self-assembled prebiotic organocatalytic
gels is surprising, given that such systems can form from
simple, prebiotically plausible molecular-scale building blocks.
Furthermore, gels are known to play vital roles in life itself; for
example, the cytoplasm interior of a cell has a gel-like
structure.30 It has been suggested that gels may have been an
effective medium for organization and compartmentalization
prior to the evolution of protective membranes.31 Gels can, to
some extent, control traffic in and out of themselves, and can
immobilize larger objects, or interactive ones, effectively
separating them from the surrounding environment. We
therefore reason that hydrogels are fascinating potential
prebiotic materialsthe development of gels with prebiotic
catalytic potential may provide insight into how gel assembly
and catalysis can cooperate in the evolution of more complex
yet better organized chemical systems. Indeed, there is
considerable current interest in a “systems chemistry” approach
to prebiotic chemistry, in which holistic systems of multiple
components collaborate in achieving emergent properties32
we suggest self-assembled hydrogels may play an important,
and under-recognized, role in such processes. With this in
mind, we decided to embark on a program of organocatalyst
and hydrogelator discovery with the hope of gaining new
insights relevant to both supramolecular gels and prebiotic
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organocatalysis (Scheme 1). We focus here on self-assembled
gels as catalysts for a specific prebiotic processunprotected
aqueous glycolaldehyde dimerizationa key step in the
pathway leading to sugars.
did not give accurate representation, and each time point was
analyzed across triplicate repeat reactions. After the allotted
time, the reaction mixture was extracted with dichloromethane
(DCM) and solvent removed in vacuo. 1H NMR analysis of the
crude product in deuterated chloroform (CDCl3) was used to
calculate the conversion and diastereomeric ratio (dr) (see SI,
Figures S7 and S8 and Table S1).
RESULTS AND DISCUSSION
■
Glutamine Derivative 1: Gelation. Preliminary research,
in which the behavior of a number of modified amino acids
such as compound 1 had been screened,33 suggested such
compounds had the potential to become involved in aldol
catalysis. Compound 1 was synthesized by coupling dodecyl-
amine and Boc-protected glutamine using 1-ethyl-3-(3-
dimethylaminopropyl)carbodiimide (EDC) and dimethylami-
nopyridine (DMAP), followed by acid-mediated removal of
the Boc-protecting group (Scheme 2). The product was
converted into free base form using NaOH (1 M) for 2−12 h.
The reaction proceeded with excellent conversions, up to
98% after 72 h with an anti:syn ratio of 1.3:1.0. The anti:syn
ratio was higher at shorter reaction times (e.g., 2.1:1.0 at 24 h).
Chiral HPLC was used to determine the enantioselectivity (SI,
Figure S9), with results indicating that the anti product was
obtained with an ee of up to 32%, while the syn product was
obtained with an ee up to 11% (SI, Figures S10−S12 and
Table S2). However, these ee’s varied widely from reaction to
reaction, reflective of the highly heterogeneous nature. The
relatively low diastereo- and enantioselectivities suggest a
relatively poorly organized transition state, as might be
expected given just one amino acid is in the organocatalyst.
Other studies have shown that dipeptides can enhance
selectivity as a result of the introduction of additional non-
covalent interactions,22 although of course, in prebiotic terms,
the catalyst is then more structurally complex, and less likely to
spontaneously emerge from simple building blocks. It is also
worth noting that co-solvents such as DMSO can be added to
homogenize reactions to improve selectivityfor prebiotic
relevance we chose to avoid this approach, but in terms of
basic process optimization we suggest this would be a useful
approach.
Interestingly, on catalysis of the heterogeneous reaction
between cyclohexanone and 4-nitrobenzaldehyde mediated by
compound 1, we consistently observed that a stable sample-
spanning gel was formed during the reaction (see Scheme 1).
We reasoned that this gel was the result of interactions
between the different components in the system, and set out to
understand this in more detail.
Schiff Base 2: Two-Component Gelation. To under-
stand gel formation, we tested compound 1 on its own and
with cyclohexanone and 4-nitrobenzaldehyde individually
under the reaction conditions. Only in the presence of 4-
nitrobenzaldehyde was a hydrogel consistently formed in situ.
Mass spectrometry of the gel and analysis of the dried residue
by 1H NMR spectroscopy indicated quantitative conversion of
catalyst 1 into Schiff base 2 (Scheme 4). There have been
Scheme 2. Synthesis of Glutamine Amide 1
Initially a range of solvents were used to test the gelation of
compound 1 at 3% wt/vol loading using a simple tube
inversion test for gel formation. Partial gels (in which the gel
partially prevented dropping of the sample on inversion) were
formed in acetonitrile, tetrahydrofuran, and toluene, and a full
gel (resistant to tube inversion) was formed in cyclohexane.
Most importantly with regard to this study, a gel was formed in
water. However, this was somewhat irreproducible, which we
attributed to the relatively high solubility of compound 1 in
water. Rather like in crystallization events, this can make the
nucleation of a gel network somewhat temperamental on
application of a heat−cool cycle. We therefore did not
characterize this gel in detail, but decided instead to move
straight on to testing the proficiency of compound 1 as an
organocatalyst.
Glutamine Derivative 1: Organocatalysis. We tested
compound 1 in a standard aldol reaction, which proceeds
effectively and has easy-to-analyze productsthe reaction
between cyclohexanone and 4-nitrobenzaldehyde (Scheme 3).
Scheme 3. Aldol Reaction Investigated Using
Organocatalyst 1
Scheme 4. Reaction between Glutamine Amide 1 and 4-
Nitrobenzaldehyde to Give Compound 2 Which Assembles
into Gels In Situ in Water
Unfortunately, the gel was not reproducible or stable enough
to be used as a catalyst, but to provide some insight into
organocatalysis, we probed the ability of compound 1 to
catalyze this reaction in a heterogeneous “solution” phase.
A solution of 4-nitrobenzaldehyde (1 equiv) in cyclo-
hexanone (10 equiv) was added to a solution of the amide (0.1
equiv) in water (20 mL), and a heterogeneous mixture formed
(see Supporting Information (SI), section 5, for full
experimental details). Reactions were analyzed after 24, 48,
and 72 heach time point was a separate reaction because the
heterogeneous nature of the reaction meant aliquot sampling
previous reports of two-component gels based on dynamic,
reversible imine formation, but in all cases this leads to gels in
organic solvents, whereas here the gel is forming in water.34 As
noted in the Introduction, two-component hydrogels based on
LMWGs that self-assemble through non-covalent interactions
are relatively rare.
Gel formation was accelerated and optimized by use of a
heat−cool cycle to yield highly reproducible gels. These two-
component gels assembled at minimum gel concentrations
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(MGCs) as low as 0.5 mg/mL of glutamine amide 1 and 0.24
mg/mL (1 equiv) of 4-nitrobenzaldehyde, giving a total gelator
loading of 0.074% wt/vol (SI, Table S6). This is remarkable
performance for a two-component LMWG hydrogel, and
allows the system to be categorized as a “supergelator” (i.e.,
gelation at loadings <0.1% wt/vol).35 The maximum gel
concentration was a total gelator loading of 0.74% wt/vol
above this level, solubility problems meant that not all of the
material dissolved prior to gel formation, and consequently, the
resulting gels were not fully homogeneous.
We then characterized these gels in more detail. First, we
used simple tube inversion methodology to gain insight into
the thermal stability of the gel (Tgel value) formed from a 1:1
mixture of components. As expected, on increasing the
concentration, the Tgel increased from 61 °C (0.15% wt/vol)
to 83 °C (0.74% wt/vol) as the sample-spanning network
became more fully established at higher concentration (SI,
Table S7).
Obviously, the reaction to form the Schiff base requires 1:1
stoichiometry, but we were interested to know how much
aldehyde would be required to assemble a gel. Tests of gelation
using 1 mg of glutamine amide 1 indicated that gels would not
form with <0.7 equiv of 4-nitrobenzaldehyde (SI, Table S5).
However, once 0.7 equiv was present, a gel resultedclearly at
this point, sufficient Schiff base is generated to support a
sample-spanning gel-phase network (consistent with the MGC
of the gelator described above). Gels were still formed by the
Schiff base even in the presence of significant excesses of 4-
nitrobenzaldehyde but, once >10 equiv were present the gels
became less stable.
promoting the formation of a sample-spanning network. In this
way, the second component drives gelation. This model of self-
assembly is reminiscent of the widely explored Fmoc-peptide
derivativesin basic conditions the anionic carboxylate
assembles into nanoscale objects (cylindrical micelles), and
only on protonation does the lowering of solubility drive
fibrillar gel network assembly.37
The ability of the isolated and dried Schiff base derivative 2
to form hydrogels directly was also tested. Effective gels could
not be directly formed from 2, probably because the solubility
was too low for heating and/or sonication to fully dissolve the
system and overcome the energy barrier to gelation. Once
again, this is reminiscent of Fmoc peptides, in which the self-
assembling carboxylic acid gelator is difficult to assemble into
gels directly, and is instead generated at a controlled rate in situ
by protonation of the pre-assembled free carboxylate to
assemble effective gels.38 We argue that, for our new two-
component Schiff base gelator 2, the reaction between amine 1
and the aldehyde delivers the LMWG into solution at an
appropriate rate for it to then self-assemble into effective gels in
situ.
The gels were studied by circular dichroism (CD)
spectroscopy to better understand the nanoscale organization
of the gelator. The aldehyde component is achiral and has UV-
active absorption bands associated with the aromatic ring (ca.
280 nm), while the glutamine amide component is chiral, but
only has an absorption band at ca. 220 nm associated with the
chiral amide. The results (Figure 1, top) indicated a small CD
signal associated with each of the chromophores, demonstrat-
ing that, within the gel, both experience a chiral environment;
i.e., the achiral aromatic aldehyde is attached to the chiral
glutamine amide unit, and thus experiences an induced CD
effect.39 The CD signal was thermally responsive, as expected
for a self-assembled system (Figure 1, bottom). On heating
Further analysis of the 1:1 gel was performed using 1H NMR
spectroscopy. In gel-phase NMR, mobile components can be
detected, but the self-assembled “solid-like” network has
broadened peaks and is thus not observed.36 Spiking the gel
with a mobile internal standard allows quantification of any
mobile components in the gel. For the 1:1 gel, we did not
observe Schiff base 2 in the 1H NMR spectrum, indicating it is
indeed assembled into the “solid-like” network (SI, Figure
S34). Neither did we observe any mobile unreacted glutamine
amide 1. However, we did observe ca. 0.3 equiv of mobile
unreacted aldehyde. This suggests, in-line with the observa-
tions above, that ca. 0.7 equiv of aldehyde is sufficient to cause
the system to assemble into a gel. However, the remaining
“excess” unreacted glutamine amide 1 is also probably
assembled within the gel, as it is not observed as mobile in
the NMR.
We then wanted to understand the gelation process. Given
that glutamine derivative 1 shows some ability to assemble in
its own right, and sometimes forms gels, we performed
dynamic light scattering (DLS). It was evident based on light
scattering that compound 1 is indeed self-assembled (SI,
Figure S35). It was not possible to provide an accurate size for
these assemblies, because DLS can only do this for spherical
systems. Interestingly, however, on addition of 4-nitro-
benzaldehyde, the emergence of a new peak in the DLS (SI,
Figure S36) clearly indicated that the self-assembly mode
changes as the two components react with one another,
consistent with the formation of a more effective self-
assembled gel in situ. This suggests that glutamine amide 1
assembles into nanoscale objects, with limited ability to form
an interactive 3D sample-spanning network. However, on
reaction with 4-nitrobenzaldehyde, the solubility changes
decreasing in water; this will enhance fiber−fiber interactions,
Figure 1. (Top) Circular dichroism (CD) spectra at different
temperatures of the gel formed by glutamine amide and 4-
nitrobenzaldehyde (1:1 ratio) at a total loading of 0.15% wt/vol.
(Bottom) Thermal response of the ellipticity of the two-component
gel at 290 nm.
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from 20 to 40 °C, the CD signal, somewhat unusually,
increased in intensitya result of the gel becoming slightly
more transparent (limiting light scattering). On heating further
from 40 to 80 °C, however, the CD band then decreased in
intensity, as would be expected for the thermally induced
disassembly of a chiral gel nanostucture. At 80 °C, the system
shows no CD signal, indicative of complete disassembly into
isolated molecules of 2.
Transmission and scanning electron microscopy (TEM and
SEM) provided further insight into the nanoscale morpholo-
gies of these gels. Although drying effects can be significant in
sample preparation and impact on apparent morphologies,40
EM can still be useful for comparing related samples prepared
in the same way. We used standard methods to image the gel
samples (SI, section 3.1) that avoid any problems associated
with ice crystal formation. For SEM imaging (SI, Fig. S42) we
applied cryo-drying in an attempt to minimize morphological
reorganization during the drying step. The sample with 1 mg/
mL of 1 (total loading ca. 0.15% wt/vol) had a nanofibrillar
morphology as typically observed for self-assembled gels, with
nanofiber dimensions estimated by TEM as 55−110 nm
(Figure 2 left; SI, Figures S41 and S42). However, on
if electron-donating groups were present on the ring, then
gelation did not occur. This preference would reflect the
inherent electrophilicity of the aldehyde, and the ability of the
aromatic ring to self-assemble via π−π interactions, both
preferred in electron-poor systems.
One fascinating property of two-component gels is the
potential for one component to select its ideal partner from a
mixture of possibilities.43 Obviously this has considerable
relevance in a prebiotic setting, as it enables order to
spontaneously emerge from a relatively complex set of inputs.
We therefore tested the assembly of the gel based on glutamine
amide 1 in the presence of benzaldehyde (1 equiv) and 4-
hydroxy-3-methoxybenzaldehyde (vanillin, 1 equiv). Benzalde-
hyde is capable of supporting gelation (Figure 3, left), but
Figure 3. (Left) Photograph of gels formed by (left) 1:1 glutamine
amide:benzaldehyde, (middle) 1:1 glutamine amide:vanillin, and
(right) 1:1:1 glutamine amide:benzaldehyde:vanillin. (Right) Per-
centage of benzaldehyde and vanillin incoporated into the solid-like
gel nanofibers as assessed by 1H NMR on a gel assembled from 1:1:1
glutamine amide:benzaldehyde:vanillin in D2O.
vanillin is not (Figure 3, middle). Interestingly, the 1:1:1
glutamine amide:benzaldehyde:vanillin mixed system still
formed a gel (Figure 3, right), suggesting benzaldehyde can
dominate. We then used 1H NMR analysis43b−d on this mixed
gel to determine how much of each aldehyde was being
incorporated into the “solid-like” gel fibers. This indicated that
the gel network incorporated 75% of the benzaldehyde, but
only 29% of the vanillin (Figure 3; SI, Figures S47 and S48). It
is therefore clear that component selection for the preferred
aldehyde that gives effective gelation. A majority of the vanillin
is left in the solution phase, while a majority of the
benzaldehyde becomes assembled into the gel fibers, clearly
demonstrating that gel assembly can select specific compo-
nents from mixtures to assemble functional materialsa
principle of prebiotic relevance.
In summary, in the hunt for a catalyst for the aldol reaction
between cyclohexanone and 4-nitrobenzaldehyde, we discov-
ered a highly effective two-component hydrogel that forms at
low concentrations and can select preferred components from
mixtures. Clearly there is very considerable scope for tuning
the performance of this class of gels by varying (i) the
aldehyde, (ii) the amino acid, or (iii) the hydrophobic chain.
Full detailed results of these structure−activity relationship
studies will be reported elsewhere.
Figure 2. TEM images of dried samples of (left) 1 mg/mL glutamine
amide 1 and 480 μg of 4-nitrobenzaldehyde (1:1, loading 0.15% wt/
vol) and (right) 5 mg/mL glutamine amide 1 and 2.4 mg of
nitrobenzaldehyde (1:1, loading 0.74% wt/vol). Scale bars = 500 nm.
increasing the loading, the fibers became enlarged, and
additional nodular aggregates also appeared to be present
(Figure 2 right; SI, Figures S43−S45). It seems plausible that
as the loading increases, excess material has a secondary
aggregation mode. Alternatively, the nodules may be associated
with less soluble material as the concentration of gelator is
increased.
Rheological studies (see SI) on the combination of
glutamine amide 1 and 4-nitrobenzaldehyde using parallel
plate geometry indicated that the self-assembled materials
behave as gels with G′ > G′′ (SI, Figures S37−S40).
Interestingly, the gel exhibited self-healing properties, being
broken down by shear during injection and then reforming in
situ on standing (SI, Figure S46 and Table S10). This gives this
family of gelators potential biomaterials applicationsfor
example in drug delivery.41
With our interests in prebiotic chemistry, we then
substituted 4-nitrobenzaldehyde for a simpler aldehyde,
benzaldehyde, which is known to be a prebiotically plausible
building block.42 Pleasingly, benzaldehyde behaved in an
analogous manner to 4-nitrobenzaldehyde, forming gels. In
general, when testing aldehydes (SI, Table S11), we found a
preference for aromatic aldehydes over aliphatic aldehydes, but
Secondary Amine 3: Gelation. Having developed a
highly effective new two-component hydrogel based on simple
building blocks, we then wanted to achieve effective organo-
catalysis. We reasoned that simple reduction of Schiff base 2
would yield a secondary amine that may be an organocatalyst.
Furthermore, given that the perturbation to molecular
structure is relatively small, we believed it may also form a
hydrogel. We opted to use Schiff base 2a, based on
benzaldehyde, rather than the Schiff base based on 4-
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nitrobenzaldehyde, as it is simpler and more prebiotically
relevant.
To synthesize the Schiff base in high yield, we made use of
its gel-forming ability to drive the reaction to completion,
giving us a straightforward reaction in water (Scheme 5). We
Scheme 5. Synthesis of Schiff Base 2a from Benzaldehyde
and Glutamine Amide 1, Using Gelation to Drive the
Reaction to Completion in Water
Figure 4. Benzylglutamine amide 3 hydrogel (loading 0.1% wt/vol)
and SEM image of a dried sample of the gel.
The gel was studied by variable-temperature CD spectros-
copy (Figure 5). The CD signal was very different from that
suggest that gelation may, in the prebiotic world, have
sometimes provided a useful mechanistic driving force for
reactions in this way, giving rise to conversion to products and
assembly of a discrete environment. Indeed, phase change
processes such as crystallization have previously been reported
by other researchers to assist in prebiotic processes.44
Intriguingly, gelation offers the possibility of the phase change
driving the system toward the preferred product, but in a form
retaining high solvent porosity and compatibility, giving
potential for further interaction/reaction of the selected
product with other small molecules.
After drying the gel product 2a, we reduced the imine using
sodium borohydride in methanol to give the desired amine 3 in
good yield (Scheme 6). There has been interest in reductive
Figure 5. Circular dichroism (CD) spectra at different temperatures
of the gel formed by compound 3 (0.1% wt/vol).
Scheme 6. Reduction of Imine with Sodium Borohydride to
Yield Secondary Amine 3
observed for the two-component system, with a much larger
band (50 mdeg) at ca. 215 nm, associated with chiral
organization of the chiral amide. This compares with much
smaller CD bands (ca. 5 mdeg) for the two-component system,
and supports the view that secondary amine 3 is a better
organized, more effective self-assembling hydrogel. The CD
spectrum is thermally responsive; by 70 °C no CD signal is
observed, confirming it can be attributed to LMWG self-
assembly.
1
Analysis of the gel by H NMR spectrosocopy (SI, Figure
amination, specifically to convert α-keto acids into amino
acids, with a number of prebiotically plausible approaches
discussed in the literature.45 As such, we consider this
approach to have some prebiotic potential.
We were delighted to find that compound 3 is a highly
effective hydrogelator (Figure 3)even more so than the two-
component Schiff base. It also formed gels in some organic
solvents (SI, Table S12). A heat/sonication/cool cycle was
used to achieve consistent and fast (ca. 2 h) gel formation, with
the MGC being just 0.03% wt/vol (SI, Figure S49). This is
even lower than the precursor Schiff base, making this a highly
potent LMWG. This suggests that the secondary amine may
enhance non-covalent interactions between LMWGs.
The Tgel value of this new gelator is 50 °C at a concentration
of 0.10% wt/vol. SEM imaging indicates the assembly of a
fibrillar sample-spanning network with diameters of ca. 40 nm
(Figure 4). These fibers are smaller than those found in the
two-component gel, consistent with the formation of a more
stable gel at lower concentrations. It is also consistent with the
fact that the visual appearance of the gel is very different from
those observed for the two-component hydrogel, being much
more optically transparent, as is typical of smaller nanoscale
assemblies, which are less able to scatter the incident light.
S50) indicated 100% incorporation of gelator into the “solid-
like” gel network, with no NMR resonances associated with
free “mobile” gelator being observedagain consistent with
the highly organized assembly of this system.
The rheology of the gel formed by 3 at a loading of 4% wt/
vol (SI, Figures S51 and S52) indicated an effective soft gel,
with G′ > G′′, and a G′ value of ca. 200 Pa. The gel crossover
point is at ca. 3% strain. For detailed comparison, we also
performed rheology on precursor Schiff base gel 2a, formed
from the combination of glutamine amide and benzaldehyde,
under exactly the same conditions (SI, Figures S39 and S40).
In this case, the gel had a G′ value of 780 Pa and a crossover
point at ca. 8% strain. Clearly the precursor gel is somewhat
stiffer than the reduced secondary amine version of the gel.
This is in-line with its more opaque appearance, indicating a
greater degree of crystalline solid-like behavior. Conversely, the
secondary amine gelator 3 gives transparent, more nanoscale
gels that self-assemble at exceptionally low loadings. We were
therefore excited to explore the potential use of these gels in
organocatalysis.
Secondary Amine 3: Organocatalysis. Initially, we
tested the ability of compound 3 to catalyze the model
reaction between cyclohexanone and 4-nitrobenzaldehyde in
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1
the solution phase, to benchmark the organocatalyst against
glutamine amide 1. In water, the conversion was ca. 43% after
72 h, and the anti:syn ratio was ca. 2.0:1, with the anti product
being produced in a typical ee of 15% and the syn product in a
typical ee of 7% (SI, Figures S3 and S13−S22). On performing
the reaction in buffered conditions at pH 7, although the
conversion dropped, the ee’s rose to 55% for the anti product
and 17% for the syn product (SI, Table S4 and Figures S23−
S25). Once again, we suspect better outcomes could have been
achieved by adding a co-solvent, as the system is quite
heterogeneous, but reaction optimization was not the goal of
our research. On testing this reaction on the gel, once the
reagents were applied to the top of the gel, it broke down. We
reasoned that the cyclohexanone acts as an organic solvent,
dissolving compound 3 and thus disrupting the self-assembled
gel network.
In the crude H NMR (SI, Figure S27), the triplet at 6.46
ppm corresponds to the hydrazone proton of glycolaldehyde,
while the doublets at 6.49 and 6.52 ppm correspond to the
hydrazone proton of threose and erythrose, respectively. As
these peaks each integrate to one proton, the integrations can
be simply used to calculate conversion and threose:erythrose
diastereoselectivity. When using deionized water as the solvent
for the hydrogel, the conversion of glycolaldehyde into
erythrose and threose was ca. 10%, with a diastereoselectivity
for threose over erythrose of ca. 2.5:1 (Table 1 and SI, Figures
Table 1. Dimerization of Glycolaldehyde with
Benzylglutamine Amide Data on the Hydrogel over 48 h
conversion
(%)
crude NMR dr
entry solvent
erythrose:threose
HPLC ee%
1
2
3
4
5
6
water
water
water
pH 7
pH 7
pH 7
12
10
7
68
43
76
1.00:2.77
1.00:2.90
1.00:1.38
1.00:2.28
1.00:1.94
1.00:1.95
Ery: 2%; Thr: 2%
Ery: 2%; Thr: 3%
Ery: 2%; Thr: 7%
Ery: 3%; Thr: 7%
Ery: 1%; Thr: 6%
Ery: 4%; Thr: 10%
We therefore decided to probe the ability of this amine to
catalyze a prebiotically relevant aldol reaction that is fully
compatible with aqueous-phase reaction conditionsthe
dimerization of glycolaldehyde (Scheme 7). The gel was
Scheme 7. Dimerization of Glycolaldehyde to Give Threose
and Erythrose
S28−S30). Interestingly, previous work from the Clarke group
using a different catalyst exhibited selectivity for erythrose over
threose in this reaction,27 clearly demonstrating that precise
choice of organocatalyst has a profound influence on reaction
outcome. Chiral HPLC indicated a small enantiomeric excess
for L-threose of ca. 2−7% and for D-erythrose of ca. 3%,
demonstrating that the chiral organocatalyst is intimately
involved in the reaction. Importantly, in the absence of the
catalytic gel, no threose or erythrose products were observed.
The reaction was then performed using pH 7 buffer (0.01 M
phosphate buffered saline, PBS) as solvent to form the gel.
This allows control of pH during the reactionin the
unbuffered reaction, the pH started at ca. 6 and fell slightly
during the course of reaction. Pleasingly, the conversion of
glycolaldehyde to threose and erythrose increased dramatically
to 43−76% (Table 1 and SI, Figures S31−S33). Once again, in
the absence of catalyst, no threose or erythrose was formed. In
addition, there was still significant selectivity for threose over
erythrose (ca. 2:1). Chiral HPLC again indicated a small ee in
favor of L-threose (6.5%), but a change in the favored
enantiomer of erythrose, with small ee in favor of of L-
erythrose (2.5%).
For purposes of comparison, we performed the dimerization
of glycoladehyde reaction using compound 3 as a catalyst in
solution, rather than in the gel phase. To achieve this, we
added the same amount of compound 3 into water but omitted
the heat/cool gel-forming step. Fascinatingly, with conversions
of only ca. 5% either in water or in buffer, and no measurable
ee’s, the reaction was very significantly less successful than
when applying the catalyst in the gel form. This suggests, in-
line with some other literature reports,11,12,29 that the highly
organized nanostructure of the gel plays a key role in helping
achieve a better reaction outcome. We reason that the
nanofibrillar solid-like gel network enhances reactivity and
helps ensure effective contact between the organocatalyst and
the aqueous-phase reagents.
prepared in the standard way (20 mg, 49.6 μmol in 5 mL
solvent), and the dimer of glycolaldehyde (59 mg, 0.49 mmol)
was dissolved in water (200 μL) and then rapidly added (<1
min in total) in small aliquots (20 × 10 μL additions) to the
surface of the gel, ensuring dispersion over the gel surface (SI,
section 6). Under these conditions, the gel was ca. pH 6 during
reaction. The system was monitored for 24 h to see if the gel
remained intact. Initial studies were promising, with the gel
being stable even after 48 h.
To analyze the products, a trapping and analysis method-
ology was developed based on the conversion of the products
to diphenyl hydrazone derivatives. Four individual standards
were prepared from L- and D-threose and L- and D-erythrose by
adding diphenyl hydrazine in methanol with acetic acid and
stirring for 1 h (SI, section 4).33 The products were purified by
column chromatography and analyzed by chiral HPLC. The
four enantiomers could be separated using an IC Chiral-Pak
column with hexane:isopropyl alcohol (90:10) at 40 °C (SI,
Figure S26).
Analysis of the dimerization of glycolaldehyde on the
catalytic hydrogel was then carried out. At the end of each
reaction, the hydrogel was dehydrated in vacuo. To the residue,
diphenyl hydrazine in methanol was added, followed by 1−2
drops of acetic acid, and the mixture left to stir at room
1
temperature for 1 h. The solvent was removed and H NMR
analysis performed on the crude hydrazone product mixture to
determine the conversion of glycolaldehyde to erythrose and
threose (SI, Figure S27). Column chromatography removed
excess diphenyl hydrazine and glycolaldehyde, and chiral
HPLC was performed on the mix of threose and erythrose
hydrazone products (SI, Figure S26).
In summary, hydrogelator 3 is catalytically proficient in a
prebiotically relevant aldol reaction in the gel phase, and can
achieve excellent levels of conversion, along with diastereo-
selectivity and some enantioselectivitythe first time this has
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been demonstrated for a self-assembled LMWG in an
unprotected aqueous-phase prebiotic reaction.
5. Gels can, at least in principle, provide a unique
environment, separated from the bulk yet fully accessible
to small molecules that can diffuse in and outin this
way they can be considered like “reaction vessels” or
even “primitive cells”.
Although the enantioselectivity is relatively low, it is in line
with other reports for this reaction.20−24,26−28 Furthermore,
mechanisms for enantio-enrichment are well-known in the
prebiotic literature.46 A number of these rely on preferential
removal of one enantiomer, which is, at least in principle,
possible in a chiral gel, where one enantiomer may
preferentially interact with the gel network, becoming
effectively isolated from the surroundings and hence
enriched.47 Our reaction workup and characterization method-
ology did not allow such effects to be observed here, but we
suggest it as a potential advantage of gels in prebiotic catalytic
systems that is worth further study.
In future work, we intend to extend the scope of gel-phase
organocatalysts while continuing to explore minimal systems
that are capable of forming self-assembled hydrogels. We hope
in the future to demonstrate advantages of compartmentaliza-
tion within gels. We suggest that self-assembled gels are
previously overlooked materials of potential interest in the
“systems approach”, in which a number of components can
collaborate, in terms of both self-assembly and reactivity, to
achieve outcomes that may have been of prebiotic importance.
CONCLUSIONS AND FUTURE PERSPECTIVES
■
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.9b13156.
■
In summary, this investigation into organocatalytic gels used
simple prebiotically relevant building blocks and reactions. In
this way, we reported a self-assembling glutamine amide
derivative 1, capable of organocatalysis of the reaction between
cyclohexanone and 4-nitrobenzaldehyde in “solution”, but
which could not maintain its gel structure during reaction. In
our studies of this simple reaction, we found that compound 1
could itself, on reaction with benzaldehydes, form an effective
two-component Schiff base hydrogelator 2 in situ. This
versatile, dynamic two-component gel was characterized in
some detail, as two-component hydrogels remain rare.
In the ongoing hunt for an effective organocatalyst, we then
applied reductive conditions to benzaldehyde-modified Schiff
base 2a, to yield secondary amine 3. This minimal perturbation
to the molecular structure yielded a highly effective and well-
organized hydrogelator, active at loadings as low as 0.03% wt/
vol. Most importantly, this new gel was catalytically proficient
for the prebiotically relevant dimerization of glycolaldehyde to
give threose and erythrose. The reaction proceeded with good
diastereoselectivity, some enantioselectivity, and, when the
reaction was performed in buffered conditions, excellent
conversions. The reaction using the gel-phase catalyst was
much more successful that when the catalyst was used in the
solution phase, suggesting that the well-organized nanoscale
environment, bringing the catalytic LMWG into intimate
contact with the solution-phase reagents, is beneficial for
organocatalysis.
sı
Full characterization of novel compounds, materials and
methods, details of analytical techniques, additional
spectroscopic and analytical data, and HPLC traces
(PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Paul A. Clarke − Department of Chemistry, University of York,
York YO10 5DD, U.K.; Email: paul.clarke@york.ac.uk
David K. Smith − Department of Chemistry, University of York,
York YO10 5DD, U.K.; orcid.org/0000-0002-9881-2714;
Email: david.smith@york.ac.uk
Authors
Kirsten Hawkins − Department of Chemistry, University of
York, York YO10 5DD, U.K.
Anna K. Patterson − Department of Chemistry, University of
York, York YO10 5DD, U.K.
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.9b13156
Funding
This research was funded by University of York through an
EPSRC DTA award.
Notes
The authors declare no competing financial interest.
Reference spectroscopic, characterization, reaction, and ana-
lytical data can be found at DOI: 10.15124/fa5a7bed-5fda-
40fc-9bf1-a089136a01e0.
This report combines catalyst design with gelator discovery
(and vice versa) to generate simple new functional gels with
great potential for a range of applications, as well as effective
performance in aqueous-phase unprotected prebiotic reaction
processes.
In terms of the prebiotic relevance of this general approach,
we would highlight the following:
1. LMWGs such as these are based on the self-assembly of
prebiotically plausible small molecules.
2. Gelators are preferentially selected and assembled from
mixtures of components.
3. The gel catalyzes an unprotected, prebiotically relevant
aldol reaction proposed in the synthesis of sugars, in
water, with good yield and with diastereo-/enantiose-
lectivity, results which are comparable with other
studies.
4. Self-assembly into a gel is required in this case for
effective organocatalysis, indicating a potential role for
self-assembly in enhancing activity in mixtures.
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