Indoline Catalyzed Acylhydrazone/Oxime Condensation under Neutral Aqueous Conditions

Article abstract of DOI:10.1021/acs.orglett.0c02128

Acylhydrazones formation has been widely applied in materials science and biolabeling. However, their sluggish condensation rate under neutral conditions limits its application. Herein, indolines with electron-donating groups are reported as a new catalyst scaffold, which can catalyze acylhydrazone, hydrazone, and oxime formation via an iminium ion intermediate. This new type of catalyst showed up to 15-fold rate enhancement over the traditional anilinecatalyzed reaction at neutral conditions. The identified indoline catalyst was successfully applied in hydrogel formation.

Full text of DOI:10.1021/acs.orglett.0c02128

pubs.acs.org/OrgLett
Letter
Indoline Catalyzed Acylhydrazone/Oxime Condensation under
Neutral Aqueous Conditions
Yuntao Zhou, Irene Piergentili, Jennifer Hong, Michelle P. van der Helm, Mariano Macchione, Yao Li,
Rienk Eelkema,* and Sanzhong Luo*
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ABSTRACT: Acylhydrazones formation has been widely applied in materials
science and biolabeling. However, their sluggish condensation rate under neutral
conditions limits its application. Herein, indolines with electron-donating groups
are reported as a new catalyst scaffold, which can catalyze acylhydrazone,
hydrazone, and oxime formation via an iminium ion intermediate. This new type
of catalyst showed up to 15-fold rate enhancement over the traditional aniline-
catalyzed reaction at neutral conditions. The identified indoline catalyst was
successfully applied in hydrogel formation.
he acylhydrazone/hydrazone and oxime formation1 are
fundamental condensation reactions, widely utilized in
effective catalyst, 5-methyl-2-aminobenzenephosphonic acid.10
Recently, Roelfes and co-workers reported an artificial enzyme
featuring p-aminophenylalanine anchoring into the hydro-
phobic pocket as a catalytic residue.11 Compared with aniline,
the designed aniline-enzyme showed a more than 2 orders of
magnitude rate increase for hydrazone and oxime formation.
Despite these prominent advances, most of these catalysts
rely on the primary aniline motif. The secondary amines, which
have been widely employed in asymmetric organocatalysis,12
were generally overlooked for catalysis of acylhydrazone/
hydrazone and oxime formation, although aliphatic secondary
amines have been included for screening, showing only poor
activity.9b We hypothesized that secondary aromatic amine
would serve as an effective catalyst for acylhydrazone/
hydrazone and oxime formation at neutral pH (Figure 1).
Compared with primary aniline, secondary aromatic amines
would condense to form an iminium ion intermediate;
enhanced electrophilicity relative to the typical imine
intermediate with aniline (Figure 1) is anticipated due to its
positively charged nature particularly under neutral pH
conditions. Herein, we report that easily prepared indoline
derivatives with electron-donating groups effectively accelerate
acylhydrazone/hydrazone and oxime formation, enhancing the
reaction rate considerably compared to the traditional aniline-
catalyzed reaction at neutral pH. The new catalysts are active
on a wide substrate scope. 5-Methylindoline successfully
enhanced the rate of supramolecular gel formation at neutral
T
different fields including dynamic combinatorial chemistry,2
bioconjugation,3 polymer chemistry,4 stimuli responsive
materials, and soft materials.5 However, the slow rate of
these condensations under neutral aqueous conditions has
limited their applications in biological contexts. Therefore,
there have been tremendous efforts to improve the reaction
rate.6 In 1960s, Jencks reported aniline as a nucleophilic
catalyst for hydrazone (semicarbazone) formation via trans-
amination of an imine intermediate.7 Later on, this catalysis
was shown to work well under biological conditions (Figure
1).3,8 A number of aniline derivatives with improved catalytic
Figure 1. Acylhydrazone/hydrazone and oxime formation via indoline
catalysis.
ability have been developed. For example, Kool developed
bifunctional anilines with acid/base groups ortho to the amino
group such as 5-methoxyanthranilic acid, 2-aminophenols, and
2-(aminomethyl)benzimidazoles.9 The bifunctional catalysis
was ascribed to the enhanced formation of the imine
intermediate via intramolecular H-bonding, and an up to 7-
fold rate increase over aniline was observed with the most
Received: June 27, 2020
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© XXXX American Chemical Society
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pH, including a particularly challenging formation of
potentially antiviral gel materials.
To obtain more effective catalysts, we investigated the
condensation between 4-nitrobenzaldehyde and benzoylhy-
drazine as a model reaction (Scheme 1). All reactions were
and 19.10 times rate enhancement over aniline (Scheme 1,
entry 9 vs entry 1). We first tested our secondary amine
hypothesis with N-methylaniline. Unfortunately, N-methylani-
line and its derivatives bearing either para-methoxy or ortho-
carboxylic acid displayed negligible catalytic effects. Other
cyclic aromatic secondary amines were examined. To our
delight, we found that indoline (pKa = 5.6)14 showed moderate
catalytic activity for the model reaction, with a 5.0-fold rate
enhancement (entry 10) over that of aniline. In contrast,
1,2,3,4-tetrahydro-quinoline(pKa = 4.7)14 showed poor cata-
lytic activity (not shown). Pyrrolidine (pKa = 11.2) was also
inactive under the present conditions, which may suggest that
the benzene ring decreases the basicity of nitrogen in indoline
and stabilizes the iminium intermediate under aqueous
solution, which pinpoints the importance of aromatic amino-
catalysis.15 All these results confirm the concept that the pKa of
catalysts closest to the neutral buffer solution provide more
rate enhancements for acylhydrazone/hydrazine formatio-
n.3a,10a,16
a
Scheme 1. Screening of Catalysts
Finding the indoline scaffold prompted us to improve its
activity, and indolines with different substitutions were
investigated next. Most substituted indolines are commercially
available or easy to prepare in high yields (for details, see
Supporting Information).17 Inspired by Kool’s work,9,10
indoline derivatives with carboxylic acid groups in the 2- and
7-positions were first explored. Unexpectedly, indoline-2-
carboxylic acid (entry 11) shows the kapp was 0.057 M−1 s−1,
only 1.90 times faster than aniline, while indoline-7-carboxylic
acid was virtually inactive. Compared with indoline, 2-
methylindoline (entry 12) showed a substantial reduction in
catalytic efficiency, likely a result of a steric effect on iminium
formation. However, 7-hydroxyindoline (entry 13) showed
slightly higher activity. 7-aza-Indoline endowed with a fused
pyridinyl ring had no catalytic activity at all.
Next the substitution effects on the benzene ring of indoline
were examined (entries 14−18). Indolines with electron-
donating groups showed enhanced reaction rates. For example,
5-methylindoline (entry 15) showed a 11-fold rate enhance-
ment, and 5-methoxylindoline (entry 14) showed enhance-
ment up to 15.50-fold, comparable to 5-methyl-2-amino-
benzene phosphonic acid (entry 9). With increasing electron-
withdrawing ability, the reaction rate dramatically decreased
(entries 16−18) and 5-nitroindoline (not shown) showed no
activity. A good linear relationship was obtained when the
logarithm of rate constants log kx/kH was plotted against
Hammett substitute constant σ (Figure 2, black line). A large
negative slope (ρ = −1.804) reveals the electron-deficient
nature of the key reaction species in the rate-limiting step,
a
Apparent second-order rate constants, kapp (M−1 s−1), are given as
mean values standard deviations based on triplicate measurements
or more. Conditions: 123 mM NaCl, 2.4 mM KCl, and 10.7 mM
sodium and potassium phosphate (pH 7.4) with 10% DMF as
cosolvent.
performed under pseudo-first-order conditions in phosphate
buffered saline (PBS) at pH 7.4 with 10% DMF as cosolvent.
Apparent second-order rate constant kapp (M−1 s−1) values
were obtained by monitoring UV−vis absorption at 329 nm of
the hydrazone product. To calculate the rate constants we used
nonlinear regression by linear least-squares fits, following the
Guggenheim method (for details, see Supporting Informa-
tion).6b,13 The observed rate increases linearly for both 4-
nitrobenzaldehyde and catalyst under excess concentration,
indicating the reaction is first order for each substrates and
catalyst (see Supporting Information, Figure S1d). Generally,
acylhydrazone formation is more challenging than hydrazone
formation under neutral aqueous conditions. Without catalysis,
the model reaction is too slow to reach equilibrium in pH = 7.4
within 24 h.
Selected screening results are shown in Scheme 1. Aniline
(pKa = 4.6 in H2O)3a,7a was selected as the reference (entry 1).
A range of primary amine catalysts including the well-explored
aniline analogue catalysts were also investigated for compar-
ison.9,10 Among all the primary amine catalysts examined
(Scheme 1, entries 1−9), 5-methyl-2-aminobenzene phos-
phonic acid, previously reported by Kool,10a showed good
catalytic effects, with a 0.573 M−1 s−1 apparent rate constant
Figure 2. Hammett plot of substitution effects of indoline (black) and
benzaldehydes (red).
B
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a
characteristic of an iminium ion species in the current catalysis.
We also explored the electronic effect on benzaldehydes
(Scheme 2). The catalysis seems to be less dependent on the
Scheme 4. Scope of Aldehydes
Scheme 2. Substitution Effects of Benzaldehyde
electronic nature of the substrates (Figure 2, red line), but
slightly favors electron-deficient benzaldehydes, consistent with
their enhanced iminium ion formation and reactivity.
Moreover, the pH effect of the current indoline catalysis was
also examined by increasing the solution pH in phosphate
buffered saline for acylhydrazone formation (see Supporting
Information, Figure S7 and Table S1). Across the pH range
from 4.5 to 7.4, the indoline catalysis was faster than that of
aniline. The acidic condition could enhance the rate of aniline
catalysis; even under this condition (e.g., pH = 5.0), the
catalysis with indoline was still substantially faster (Table S1).
This observation highlights the beneficial secondary amine
motif that is feasible for iminium ion catalysis regardless of pH.
With the optimized catalyst in hand, we next examined its
scope (Scheme 3 and 4). Aliphatic acylhydrazides including
a
Apparent second-order rate constant kapp (M−1 s−1) was measured
under the same conditions as listed in Scheme 1.
a
catalyst, highlighting its applicability and functional group
tolerance. Indoline catalysis was also found to promote
hydrazone and oxime formation effectively (Scheme 3, entries
5 and 6). In oxime formation, the indoline catalysis is 20 times
faster than aniline, representing the most efficient catalysis
examined.18
Scheme 3. Scope of Nucleophiles
The scope of aldehyde substrates was explored with
benzoylhydrazine as a model (Scheme 4). Electron-rich
aldehydes such as 4-methoxyaldehyde and 2-thenaldehyde
are sluggish substrates, and the application of 5-methoxyindo-
line catalysis led to 6-fold and 12-fold enhancement,
respectively (Scheme 4, entries 1 and 2). Aromatic aldehydes
such as picolinaldehyde, quinoline-8-carbaldehyde, and
salicylaldehyde were also used and 5-methoxyindoline and 5-
methyl-2-aminobenzene phosphonic acid demonstrated com-
parable performance (Scheme 4, entries 3−5). Interestingly,
glyoxylic acid showed the highest rates (14.51 M−1 s−1, Scheme
4, entry 6) among all the examined substrates with indoline
catalysis. Aliphatic aldehyde and unactivated ketones have also
been examined; unfortunately indoline did not show effective
catalysis in these cases.
Having discovered substituted indolines as efficient catalysts
for hydrazone formation under neutral conditions, we then
turned our attention to its application in biomedical materials.
In the past, we reported how the formation and the mechanical
properties of low molecular weight (LMW) hydrazone
hydrogelators can be controlled directly by catalytic action
(Figure 3a).5a In those systems, control over the rate of
hydrazone formation is crucial to achieve local gel formation,
control gel object dimensions, and properties.19
The rate of hydrazone formation was mostly controlled
using acid catalysis. When using aniline at neutral pH, the
electron-rich benzaldehyde substrates gave sluggish reactions,
limiting application at neutral pH. Recently, we became
interested in applying these hydrogels as broad spectrum
antiviral materials, inspired by the work of Stellacci, Lembo,
a
Apparent second-order rate constant kapp (M−1 s−1) was measured
under the same conditions as listed in Scheme 1).
bulky ones were compatible with indoline catalysis. Indoline
was 5-fold faster than aniline (Scheme 3, entries 1 and 2), and
the optimal 5-methoxyindoline was 10 times faster. In these
cases, indoline catalysis is comparable but slightly slower than
the best reported aniline phosphonic acid catalyst. The
catalysis also worked well with functionalized arene acylhy-
drazides such as salicylhydrazide or picolinylhydrazide, and up
to 13-fold-rate enhancement over aniline could be achieved
(Scheme 3, entries 3 and 4). In these cases, indoline catalysts
performed much better than the aniline phosphonic acid
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gels with a slight yellow color on account of oxidized indoline
(see Supporting Information, Figure S10).
In summary, we have shown that easily prepared indoline
derivatives bearing a secondary amine in the catalytic center
can act as new efficient catalysts for acylhydrazone/oxime
formation under neutral aqueous conditions. The reaction
rates are faster than the typical primary amine aniline-catalyzed
reactions at neutral pH. Indoline is comparable with the most
effective catalyst reported to date, 5-methyl-2-aminobenzene
phosphonic acid, and shows better reactivity for some
substrates. The benzene ring is crucial for indoline catalysis,
and electron-donating groups increase the catalytic activity by
stabilizing the formation of highly active iminium intermedi-
ates. The new catalysts were investigated for a broad substrate
scope and were successfully used to accelerate hydrogel
formation for challenging biomedical substrates under neutral
pH conditions.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02128.
Figure 3. (a) Catalyzed trishydrazone hydrogelator formation. (b)
The turbidity measurements at 500 nm. (c) Inverted vial method tests
of hydrogelator formation and appearance with or without 5-
methylindoline. For (b) and (c), samples were prepared by mixing
stock solutions of 8 mM acylhydrazide H, 48 mM aldehyde A, with or
without 10 mM catalyst (aniline or 5-methylindoline) in 0.1 M
phosphate buffer at pH 7.0.
Synthesis of indoline derivatives, experimental details,
kinetic fit data analysis, absorbance spectra, pH effect,
NMR spectra, gel formation and rheology test, and
supporting figures (PDF)
AUTHOR INFORMATION
■
and Jones.20 For this purpose, it is crucial that we can generate
gel fibers that have a high density of alkylsulfonate groups,
preferably at neutral pH. These decorated fibers can be made
by reaction and subsequent in situ gelation of a mixture of tris-
hydrazide H, benzaldehyde A, and alkylsulfonate benzaldehyde
AS (Figure 3).21 To investigate the potential of indoline
catalysis, we first looked at gel formation without the sulfonate.
In the reaction between H and A, turbidity measurements were
used to monitor the rate of hydrogel fiber formation. 5-
Methylindoline and aniline were selected as catalysts. All
experiments were performed in 0.1 M phosphate buffer at pH
7.0. As shown in Figure 3b, the turbidity developed much
earlier and at a higher rate when using 5-methylindoline than
when using aniline (for details, see Supporting Information,
Figure S8). The gelation time, as determined by the inverted
vial method, was within 2 h for the 5-methylindoline catalyzed
sample while the uncatalyzed sample remained a liquid
suspension even after 7 h ([H] = 8 mM, Figure 3c).
Rheological measurements showed that 5-methylindoline
catalyzed gelation gives a constant G′ of 6 kPa, 50 min after
starting the reaction. Aniline catalysis leads to G′ = 5 kPa after
110 min, confirming the trends observed in the turbidity
measurements and in the small molecule models (for details,
see Supporting Information, Figure S9). Moreover, when [H]
= 20 mM was used, the uncatalyzed reaction required 8 h to
gel. Using 10 mM aniline, this time is reduced to 3 h, whereas
10 mM 5-methyl indoline further reduces it, providing a gel
within 2 h (for details, see Supporting Information, Table S2).
Next, we used a mixture of A and AS aldehydes (30 mol %
sulfonated aldehyde AS) in the gelation. In the absence of
catalyst, these mixtures require over 6 h to form a gel ([H] =
20 mM). When we used 5-methyl indoline as a catalyst (10
mM), these mixtures gelled in 1.5 h, forming stable and stiff
Corresponding Authors
Sanzhong Luo − Center of Basic Molecular Science (CBMS),
Department of Chemistry, Tsinghua University, Beijing 100084,
China; orcid.org/0000-0001-8714-4047; Email: luosz@
tsinghua.edu.cn
Rienk Eelkema − Department of Chemical Engineering, Delft
University of Technology, 2629HZ Delft, The Netherlands;
orcid.org/0000-0002-2626-6371; Email: R.Eelkema@
tudelft.nl
Authors
Yuntao Zhou − Center of Basic Molecular Science (CBMS),
Department of Chemistry, Tsinghua University, Beijing 100084,
China
Irene Piergentili − Department of Chemical Engineering, Delft
University of Technology, 2629HZ Delft, The Netherlands;
orcid.org/0000-0002-2220-4157
Jennifer Hong − Department of Chemical Engineering, Delft
University of Technology, 2629HZ Delft, The Netherlands
Michelle P. van der Helm − Department of Chemical
Engineering, Delft University of Technology, 2629HZ Delft, The
Netherlands
Mariano Macchione − Department of Chemical Engineering,
Delft University of Technology, 2629HZ Delft, The Netherlands
Yao Li − Center of Basic Molecular Science (CBMS),
Department of Chemistry, Tsinghua University, Beijing 100084,
China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02128
Notes
The authors declare no competing financial interest.
D
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into the Mechanism and Catalysis of Oxime Coupling Chemistry at
Physiological pH. Chem. - Eur. J. 2015, 21, 5980−5985. (i) Wang, S.;
Nawale, G. N.; Kadekar, S.; Oommen, O. P.; Jena, N. K.;
Chakraborty, S.; Hilborn, J.; Varghese, O. P. Saline Accelerates
Oxime Reaction with Aldehyde and Keto Substrates at Physiological
pH. Sci. Rep. 2018, 8, 2193.
ACKNOWLEDGMENTS
■
We thank the Natural Science Foundation of China
(21861132003, 21672217, and 21521002) and Tsinghua
University Initiative Scientific Research Program and The
Netherlands Organization for Scientific Research (NWO-
NSFC joint project) for financial support. S.L. is supported
by the National Program of Top-notch Young Professionals.
We thank the “BT mass spec facility of TU Delft” for the
HRMS measurement.
(7) (a) Cordes, E. H.; Jencks, W. P. Nucleophilic Catalysis of
Semicarbazone Formation by Anilines. J. Am. Chem. Soc. 1962, 84,
826−831. (b) Cordes, E. H.; Jencks, W. P. On the Mechanism of
Schiff Base Formation and Hydrolysis. J. Am. Chem. Soc. 1962, 84,
832−837. (c) Cordes, E. H.; Jencks, W. P. General Acid Catalysis of
Semicarbazone Formation. J. Am. Chem. Soc. 1962, 84, 4319−4328.
(d) Jencks, W. P. Studies on the Mechanism of Oxime and
Semicarbazone Formation. J. Am. Chem. Soc. 1959, 81, 475−481.
(8) (a) van der Helm, M. P.; Klemm, B.; Eelkema, R. Organo-
catalysis in aqueous media. Nat. Rev. Chem. 2019, 3, 491−508.
(b) Rashidian, M.; Mahmoodi, M. M.; Shah, R.; Dozier, J. K.;
Wagner, C. R.; Distefano, M. D. A Highly Efficient Catalyst for Oxime
Ligation and Hydrazone−Oxime Exchange Suitable for Bioconjuga-
tion. Bioconjugate Chem. 2013, 24, 333−342. (c) Mahmoodi, M. M.;
Rashidian, M.; Zhang, Y.; Distefano, M. D. Application of meta- and
para-Phenylenediamine as Enhanced Oxime Ligation Catalysts for
Protein Labeling, PEGylation, Immobilization, and Release. Curr.
Protoc. Protein Sci. 2015, 79, 15.4.1−15.4.28. (d) Wendeler, M.;
Grinberg, L.; Wang, X.; Dawson, P. E.; Baca, M. Enhanced Catalysis
of Oxime-Based Bioconjugations by Substituted Anilines. Bioconjugate
Chem. 2014, 25, 93−101. (e) Yuen, L. H.; Saxena, N. S.; Park, H. S.;
Weinberg, K.; Kool, E. T. Dark Hydrazone Fluorescence Labeling
Agents Enable Imaging of Cellular Aldehydic Load. ACS Chem. Biol.
2016, 11, 2312−2319.
REFERENCES
■
̈
(1) Kolmel, D. K.; Kool, E. T. Oximes and Hydrazones in
Bioconjugation: Mechanism and Catalysis. Chem. Rev. 2017, 117,
10358−10376.
(2) (a) Corbett, P. T.; Leclaire, J.; Vial, L.; West, K. R.; Wietor, J.-L.;
Sanders, J. K. M.; Otto, S. Dynamic Combinatorial Chemistry. Chem.
Rev. 2006, 106, 3652−3711. (b) Vantomme, G.; Jiang, S.; Lehn, J.-M.
Adaptation in Constitutional Dynamic Libraries and Networks,
Switching between Orthogonal Metalloselection and Photoselection
Processes. J. Am. Chem. Soc. 2014, 136, 9509−9518. (c) Ulrich, S.
Growing Prospects of Dynamic Covalent Chemistry in Delivery
Applications. Acc. Chem. Res. 2019, 52, 510−519.
(3) (a) Dirksen, A.; Hackeng, T. M.; Dawson, P. E. Nucleophilic
Catalysis of Oxime Ligation. Angew. Chem., Int. Ed. 2006, 45, 7581−
7584. (b) Dirksen, A.; Dirksen, S.; Hackeng, T. M.; Dawson, P. E.
Nucleophilic Catalysis of Hydrazone Formation and Transimination:
Implications for Dynamic Covalent Chemistry. J. Am. Chem. Soc.
2006, 128, 15602−15603. (c) Bhat, V. T.; Caniard, A. M.; Luksch, T.;
Brenk, R.; Campopiano, D. J.; Greaney, M. F. Nucleophilic catalysis of
acylhydrazone equilibration for protein-directed dynamic covalent
chemistry. Nat. Chem. 2010, 2, 490−497.
(4) (a) Mukherjee, S.; Bapat, A. P.; Hill, M. R.; Sumerlin, B. S.
Oximes as reversible links in polymer chemistry: dynamic macro-
molecular stars. Polym. Chem. 2014, 5, 6923−6931. (b) Folmer-
Andersen, J. F.; Lehn, J.-M. Thermoresponsive Dynamers: Thermally
Induced, Reversible Chain Elongation of Amphiphilic Poly-
(acylhydrazones). J. Am. Chem. Soc. 2011, 133, 10966−10973.
(5) (a) Boekhoven, J.; Poolman, J. M.; Maity, C.; Li, F.; van der
Mee, L.; Minkenberg, C. B.; Mendes, E.; van Esch, J. H.; Eelkema, R.
Catalytic control over supramolecular gel formation. Nat. Chem. 2013,
5, 433−437. (b) Cai, M.; Han, Y.; Zhang, Q.; Luo, S. Aniline Catalysis
in Bioconjugations and Material Synthesis. Youji Huaxue 2018, 38
(1), 10. (c) Ryabchun, A.; Li, Q.; Lancia, F.; Aprahamian, I.; Katsonis,
N. Shape-Persistent Actuators from Hydrazone Photoswitches. J. Am.
Chem. Soc. 2019, 141, 1196−1200. (d) Ono, T.; Fujii, S.; Nobori, T.;
Lehn, J.-M. Optodynamers: Expression of Color and Fluorescence at
the Interface Between Two Films of Different Dynamic Polymers.
Chem. Commun. 2007, 4360−4362.
(6) (a) Wolfenden, R.; Jencks, W. P. The Effect of o-Substituents on
Benzaldehyde Semicarbazone Formation. J. Am. Chem. Soc. 1961, 83,
2763−2768. (b) Kool, E. T.; Park, D.-H.; Crisalli, P. Fast Hydrazone
Reactants: Electronic and Acid/Base Effects Strongly Influence Rate
at Biological pH. J. Am. Chem. Soc. 2013, 135, 17663−17666.
(c) Kool, E. T.; Crisalli, P.; Chan, K. M. Fast Alpha Nucleophiles:
Structures that Undergo Rapid Hydrazone/Oxime Formation at
Neutral pH. Org. Lett. 2014, 16, 1454−1457. (d) Schmidt, P.; Zhou,
L.; Tishinov, K.; Zimmermann, K.; Gillingham, D. Dialdehydes Lead
to Exceptionally Fast Bioconjugations at Neutral pH by Virtue of a
Cyclic Intermediate. Angew. Chem., Int. Ed. 2014, 53, 10928−10931.
(e) Schmidt, P.; Stress, C.; Gillingham, D. Boronic acids facilitate
rapid oxime condensations at neutral pH. Chem. Sci. 2015, 6, 3329−
3333. (f) Wang, X.; Canary, J. W. Rapid Catalyst-Free Hydrazone
Ligation: Protein-Pyridoxal Phosphoramides. Bioconjugate Chem.
2012, 23, 2329−2334. (g) Dilek, O.; Sorrentino, A. M.; Bane, S.
Intramolecular Catalysis of Hydrazone Formation of Aryl-Aldehydes
via ortho-Phosphate Proton Exchange. Synlett 2016, 27, 1335−1338.
(h) Wang, S.; Gurav, D.; Oommen, O. P.; Varghese, O. P. Insights
(9) (a) Crisalli, P.; Kool, E. T. Water-Soluble Organocatalysts for
Hydrazone and Oxime Formation. J. Org. Chem. 2013, 78, 1184−
1189. (b) Larsen, D.; Pittelkow, M.; Karmakar, S.; Kool, E. T. New
Organocatalyst Scaffolds with High Activity in Promoting Hydrazone
and Oxime Formation at Neutral pH. Org. Lett. 2015, 17, 274−277.
(10) (a) Crisalli, P.; Kool, E. T. Importance of ortho Proton Donors
in Catalysis of Hydrazone Formation. Org. Lett. 2013, 15, 1646−
1649. (b) Larsen, D.; Kietrys, A. M.; Clark, S. A.; Park, H. S.;
Ekebergh, A.; Kool, E. T. Exceptionally rapid oxime and hydrazine
formation promoted by catalytic amine buffers with low toxicity.
Chem. Sci. 2018, 9, 5252−5259.
́
(11) (a) Drienovska, I.; Mayer, C.; Dulson, C.; Roelfes, G. A
designer enzyme for hydrazone and oxime formation featuring an
unnatural catalytic aniline residue. Nat. Chem. 2018, 10, 946−952.
(b) Roelfes, G. LmrR: a privileged scaffold for artificial metal-
loenzymes. Acc. Chem. Res. 2019, 52, 545−556.
̈
(12) Erkkila, A.; Majander, I.; Pihko, P. M. Iminium Catalysis. Chem.
Rev. 2007, 107, 5416−5470.
(13) Hemalatha, M. R. K.; Noorbatcha, I. An Undergraduate
Physical Chemistry Experiment on the Analysis of First-Order Kinetic
Data. J. Chem. Educ. 1997, 74, 972−974.
(14) Yang, D.; Zuccarello, G.; Mattes, B. R. Physical Stabilization or
Chemical Degradation of Concentrated Solutions of Polyaniline
Emeraldine Base Containing Secondary Amine Additives. Macro-
molecules 2002, 35, 5304−5313.
(15) Lv, J.; Zhang, Q.; Cai, M.; Han, Y.; Luo, S. Aromatic
Aminocatalysis. Chem. - Asian J. 2018, 13, 740−753.
́
(16) Vargas, E. L.; Velazquez, J. A.; Rodrigo, E.; Reinecke, H.;
́
́
Rodríguez-Hernandez, J.; Fernandez-Mayoralas, A.; Gallardo, A.; Cid,
M. B. pKa Modulation of Pyrrolidine-Based Catalytic Polymers Used
for the Preparation of Glycosyl Hydrazides at Physiological pH and
Temperature. ACS Appl. Bio Mater. 2020, 3, 1955−1967.
(17) Aubry, C.; Wilson, A. J.; Emmerson, D.; Murphy, E.; Chan, Y.
Y.; Dickens, M. P.; García, M. D.; Jenkins, P. R.; Mahale, S.;
Chaudhuri, B. Fascaplysin-inspired diindolyls as selective inhibitors of
CDK4/cyclin D1. Bioorg. Med. Chem. 2009, 17, 6073−6084.
(18) Trausel, F.; Fan, B.; van Rossum, S. A. P.; van Esch, J. H.;
Eelkema, R. Aniline Catalysed Hydrazone Formation Reactions Show
E
https://dx.doi.org/10.1021/acs.orglett.0c02128
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
a Large Variation in Reaction Rates and Catalytic Effects. Adv. Synth.
Catal. 2018, 360, 2571−2576.
(19) (a) Lovrak, M.; Hendriksen, W. E.; Kreutzer, M. T.; van Steijn,
V.; Eelkema, R.; van Esch, J. H. Control over the Formation of
Supramolecular Material Objects Using Reaction-Diffusion. Soft
Matter 2019, 15, 4276−4283. (b) Maity, C.; Hendriksen, W. E.;
van Esch, J. H.; Eelkema, R. Spatial Structuring of a Supramolecular
Hydrogel using a Visible-light Triggered Catalyst. Angew. Chem., Int.
Ed. 2015, 54, 998−1001. (c) Trausel, F.; Versluis, F.; Maity, C.;
Poolman, J. M.; Lovrak, M.; van Esch, J. H.; Eelkema, R. Catalysis of
Supramolecular Hydrogelation. Acc. Chem. Res. 2016, 49, 1440−1447.
(20) (a) Cagno, V.; Andreozzi, P.; D’Alicarnasso, M.; Jacob Silva, P.;
Mueller, M.; Galloux, M.; Le Goffic, R.; Jones, S. T.; Vallino, M.;
̌
Hodek, J.; Weber, J.; Sen, S.; Janecek, E.-R.; Bekdemir, A.; Sanavio,
B.; Martinelli, C.; Donalisio, M.; Rameix Welti, M.-A.; Eleouet, J.-F.;
́
Han, Y.; Kaiser, L.; Vukovic, L.; Tapparel, C.; Kral, P.; Krol, S.;
Lembo, D.; Stellacci, F. Broad-spectrum non-toxic antiviral nano-
particles with a virucidal inhibition mechanism. Nat. Mater. 2018, 17,
̌
195−203. (b) Jones, S. T.; Cagno, V.; Janecek, M.; Ortiz, D.;
Gasilova, N.; Piret, J.; Gasbarri, M.; Constant, D. A.; Han, Y.;
́
́
Vukovic, L.; Kral, P.; Kaiser, L.; Huang, S.; Constant, S.; Kirkegaard,
K.; Boivin, G.; Stellacci, F.; Tapparel, C. Modified cyclodextrins as
broad-spectrum antivirals. Sci. Adv. 2020, 6, eaax9318.
(21) (a) Poolman, J. M.; Maity, C.; Boekhoven, J.; van der Mee, L.;
le Sage, V. A. A.; Groenewold, G. J. M.; van Kasteren, S. I.; Versluis,
F.; van Esch, J. H.; Eelkema, R. A toolbox for controlling the
properties and functionalisation of hydrazone-based supramolecular
hydrogels. J. Mater. Chem. B 2016, 4, 852−858. (b) Wang, Y.; Xu, Z.;
Lovrak, M.; le Sage, V. A. A.; Zhang, K.; Guo, X.; Eelkema, R.;
Mendes, E.; van Esch, J. H. Biomimetic strain-stiffening self-
assembled hydrogels. Angew. Chem., Int. Ed. 2020, 59, 4830−4834.
F
https://dx.doi.org/10.1021/acs.orglett.0c02128
Org. Lett. XXXX, XXX, XXX−XXX