Aniline Catalysed Hydrazone Formation Reactions Show a Large Variation in Reaction Rates and Catalytic Effects

Article abstract of DOI:10.1002/adsc.201800342

Hydrazone formation reactions from aldehydes and hydrazides have the remarkable qualities that they proceed in water and the kinetics can be controlled by organocatalysis. For these reasons, this class of reactions finds widespread use in biological as well as material settings. We recently reported a protected aniline catalyst for hydrazone formation that can be activated using a chemical signal. In our search to find a suitable hydrazone formation reaction to investigate the activation of this pro-catalyst, we found a wide variety in reaction rates and response to catalysis. Here we report an overview of hydrazone formation reactions, their reaction rates and response to aniline catalysis, their compatibility for kinetic analysis by UV/Vis spectroscopy, and their compatibility with the reaction environment and with the pro-catalyst pro-aniline. (Figure presented.).

Full text of DOI:10.1002/adsc.201800342

Title: Aniline catalysed hydrazone formation reactions show a large
variation in reaction rates and catalytic effects
Authors: Fanny Trausel, Bowen Fan, Susan van Rossum, Jan van
Esch, and Rienk Eelkema
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201800342
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10.1002/adsc.201800342
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Aniline catalysed hydrazone formation reactions show a large
variation in reaction rates and catalytic effects
Fanny Trausela, Bowen Fana, Susan A. P. van Rossuma, Jan H. van Escha and Rienk
Eelkemaa,*
a
Department of Chemical Engineering, Delft University of Technology, van der Maasweg 9, 2629 HZ Delft, the
Netherlands
Phone: (+31)-15-27-81035; e-mail: r.eelkema@tudelft.nl
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
hydrazone formation and response to catalysis
depends heavily on the type of hydrazide and
aldehyde coupling partners. Overviews reporting
reaction rate constants can thus be useful in allowing
scientists to choose a suitable hydrazone formation
system for their purposes.[2d, 7]
Abstract. Hydrazone formation reactions from aldehydes
and hydrazides have the remarkable qualities that they
proceed in water and the kinetics can be controlled by
organocatalysis. For these reasons, this class of reactions
finds widespread use in biological as well as material
settings. We recently reported a protected aniline catalyst
for hydrazone formation that can be activated using a
chemical signal. In our search to find a suitable hydrazone
formation reaction to investigate the activation of this pro-
catalyst, we found a wide variety in reaction rates and
response to catalysis. Here we report an overview of
hydrazone formation reactions, their reaction rates and
response to aniline catalysis, their compatibility for kinetic
analysis by UV/Vis spectroscopy, and their compatibility
with the reaction environment and with the pro-catalyst
pro-aniline.
Recently we reported a protected aniline catalyst
for hydrazone formation (pro-aniline 2, Scheme 1,
b).[8] Addition of the chemical signal H2O2 leads to
deprotection of pro-aniline 2 and release of aniline 1
which can then catalyse hydrazone formation. We
used 2 to control the formation of hydrogels featuring
hydrazone bonds, introducing signal response in soft
materials.[9] To find a suitable hydrazone formation
reaction to investigate the activation of 2, we
compared a selection of hydrazone formation
reactions. Our goal was to find a hydrazone formation
reaction that shows a detectable conversion within 15
hours when catalysed by 1 at room temperature in
aqueous buffer. To enable a clearly observable signal
response, the reaction should show at least a three-
fold increase in reaction rate when catalysed by 1.
Keywords: Hydrazones; Bioorthogonal chemistry; Click
chemistry; Organocatalysis; UV/vis spectroscopy.
Introduction
Non-biological reactions that proceed in water and
can be accelerated by catalysis are uncommon, but of
high interest for the design of responsive (bio-
H2
N
a)
b)
H
H
N
N
O
)materials
and
for
functionalization
of
H2
N
R'
aniline 1
N
R
R'
N
biomolecules.[1] Hydrazone formation reactions,
between aldehydes and hydrazides, are a convenient
class of bioorthogonal copper-free click reactions as
they proceed in water.[2] Furthermore, because
hydrazone formation reactions proceed at ambient
conditions and are susceptible to catalysis, hydrazone
formation reactions are widely applied in dynamic
combinatorial chemistry.[3] Hydrazone reactions
proceed rapidly at pH 5 or lower, but are
unpractically slow at physiological pH[3a, 4]. Jencks
found that hydrazone formation reactions can be
accelerated by nucleophilic catalysis using the
organocatalyst aniline at physiological pH (Scheme 1,
a).[5] Kool reported alternative organocatalysts for
R
R
- H2O
R
O
H
N
+
H2
N
R'
OH
B
H2
N
H2O2
HO
H
O
N
- CO2, B(OH)3,
quinone methide
aniline 1
O
H
N
R
N
R'
pro-aniline 2
Scheme 1. Catalysis of hydrazone formation. (a)
Hydrazone formation: the reaction between an aldehyde
and a hydrazide catalysed by aniline 1. (b) The pro-catalyst
pro-aniline 2 and the chemical signal H2O2 react to release
the organocatalyst aniline 1 which catalyses hydrazone
formation between an aldehyde and a hydrazide.[8]
hydrazone formation that are more efficient and less
6]
toxic than aniline.[2c,
However, the rate of
1
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10.1002/adsc.201800342
Advanced Synthesis & Catalysis
Furthermore, the reaction mixture should not show
any side reactions with 2 or any other component,
which would complicate analysis.
addition of 1, using 1 mM of aldehyde and 1 mM of
1.[6b] The difference for this response to aniline
catalysis can be due to the amount of DMF as a co-
solvent (Kool used 10% DMF, whereas we used 20%
DMF). When testing cross-reactivity with pro-
catalyst 2, the absorbance of a mixture of hydrazide 3
and pro-aniline 2 changes over time, indicating that
the two compounds react or form a non-covalent
interaction with each other. Therefore, we were
unable to use reactions 1 – 3.
Reaction 4 only shows a 1.1-fold increase in
reaction rate with 1, a value that is barely significant.
Reaction 5, 6 and 7 are not catalysed by 1. The 2nd
order rate constants for reaction 4, 5, 6 and 7 were
also reported by Kool.[6b] He found a very similar
response to aniline catalysis for reaction 5, but more
convincing response to aniline catalysis for reactions
4, 6 and 7: the reaction rate increased between 1.8 –
2.1 fold upon aniline catalysis. Again, this
discrepancy with the results of Kool can be due to the
difference in amount of DMF that was used as a co-
solvent. An explanation for the lack of response to
aniline catalysis can be that hydrazide 7 reacts
already efficiently with aldehydes without catalysis,
and the activation of the aldehydes by aniline in the
form of the imine intermediate does not increase the
reaction rate.
The reaction rate of reaction 8 increases 2.6-fold
when catalysed by 1. For reaction 10, 14 and 16,
there is no detectable change in UV/Vis absorption
over the course of 15 hours during both the catalysed
and uncatalysed reactions. Reaction 11 only shows a
1.2-fold increase in reaction rate upon addition of 1.
Reaction 12, 15 and 17 are promising reactions: they
do not show any conversion within 15 hours without
catalyst and with 1 the reactions have considerable
rate constants of (2.1 ± 0.12) × 10-4 s-1, 5.0 × 10-4 s-1
and 2.5 × 10-4 s-1, respectively. Because the
uncatalysed reactions were found to be immeasurably
slow, we could not reliably calculate the ratio
between the catalysed reaction and uncatalysed
reaction rates. A slight disadvantage of these
reactions is that the change in absorbance during the
reactions is very small, which makes the reactions
less reliable to follow. Besides the coupling partners
of hydrazides with aromatic aldehydes, we also
measured the reaction between hydrazide 14 with the
aliphatic aldehyde propanal. Again, there is no
detectable change in UV/Vis absorption over the
course of 15 hours with or without catalyst 1. It may
be that aliphatic aldehydes are less suited to our
analysis method because of their lack of a
chromophore.
Finally, as we ideally wanted to follow the
progress of the reaction by UV/Vis spectroscopy, the
starting materials, intermediates and products should
be soluble in the reaction medium (aqueous buffer
with 20% dimethylformamide as co-solvent) and
product formation should give a detectable change in
the UV/Vis spectrum above a wavelength of 250 nm.
Here, we disclose our findings on this topic. We
find that the reaction rate constants between different
hydrazone formation reactions may vary by orders of
magnitude, that aniline 1 only catalyses some of the
hydrazone formation reactions that we tested and that
some hydrazides degrade in the solvent system or
react with pro-aniline 2. These findings may help the
reader to choose a suitable hydrazone formation
reaction for his or her experimental purposes.
Results and discussion
Table 1 shows the selection of hydrazone reactions
for which we investigated the response to aniline
catalysis and unwanted reactivity towards 2. The
reaction rates were determined by following the
change in absorbance in UV/vis spectroscopy.
Pseudo-first order rate constants were determined by
using the Guggenheim time lag method.[10] The
graphs were fitted using linear regression. All
reactions were carried out using the same conditions:
0.020 mM hydrazide, 0.5 mM aldehyde, 0.5 mM
aniline 1 or 0.5 mM pro-aniline 2, 20% (v/v) DMF
(dimethylformamide) in 100 mM sodium phosphate
buffer pH 7.4, 25 °C. The concentrations of the
reagents were chosen such that all reactions are in the
right absorbance window to follow the reaction using
UV/vis spectroscopy. We used 20% DMF as a co-
solvent to ensure solubility of all reagents, catalysts
and products. To measure the response on hydrazone
formation rate to catalysis by 1 we determined the
ratio between the reaction rate constant for the
reaction catalysed by 1 and the reaction rate constant
of the uncatalysed reaction. We report the wavelength
at which we followed each reaction (rate analysis
wavelength, Table 1). Full range UV/vis spectra of
the hydrazone reactions at t0 and t = 15 h are shown
in Supplementary Figure 1, graphs of the absorbance
at the rate analysis wavelength over time are shown
in Supplementary Figure 2 and the Guggenheim fits
are shown in Supplementary Figure 3.
Reaction 1 is catalysed by 1 but only shows a 1.7-
fold increase in reaction rate in the presence of 1, the
difference in rate between the catalysed reaction and
the uncatalysed reaction is modest. Reaction 2 and 3
show a more promising response to 1 catalysis: the
reaction rate constant of reaction 2 shows a 3.3-fold
increase in reaction rate and of reaction 3 is 3.7-fold
in the presence of 1: the kinetics of these reactions
can be controlled by aniline catalysis. Kool found an
11-fold increase of reaction rate for reaction 3 upon
Reaction 13 responds well to aniline catalysis: the
reaction rate is increased 24-fold in the presence of 1.
There is a clear change in absorbance during the
reaction, making reaction 13 a promising benchmark
reaction for aniline catalysis.
With a 47-fold increase in reaction rate in the
presence of 1, reaction 9 shows, apart from reactions
12, 15 and 17, by far the largest increase in reaction
rate among the reactions investigated in the current
2
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10.1002/adsc.201800342
Advanced Synthesis & Catalysis
work. Because there is also a clear change in
absorbance during the reaction and as we did not find
any side reactions with 2 (Supplementary Table 2) we
chose this reaction as a benchmark reaction for the
activation of pro-aniline 2 in the 2017 publication.[8]
We also investigated the activity of the catalyst
1,3-phenylenediamine ∙ 2 HCl 15 (Figure 1a, c, d) in
reaction 9.
Table 1. Overview of hydrazone formation reactions tested with aniline 1.[a]
[b]
[c]
[d]
k1, cat
k2 (app)
krel
Rate analysis [e]
wavelength (nm)
Hydrazide
Aldehyde
(s-1)
(M-1 s-1)
(1.8 ± 0.015)
× 10-6
(3.7 ± 0.033)
× 10-3
1.7
500
1
2
3
(5.0 ± 2.0)
× 10-5
(1.0 ± 0.39)
× 10-1
3.3
3.7
500
500
(6.7 ± 1.1)
× 10-6
(1.3 ± 0.21)
× 10-2
H
N
NH2
(2.3 ± 0.016)
× 10-4
(4.6 ± 0.033)
× 10-1
4
5
6
7
8
9
1.1
1.0
1.0
1.0
2.6
47
350
450
350
350
340
330
7
H
N
NH2
(3.2 ± 0.078)
× 10-4
(6.4 ± 0.16)
× 10-1
7
H
N
NH2
(4.3 ± 1.6)
× 10-4
(8.6 ± 3.1)
× 10-1
7
H
N
NH2
(5.4 ± 0.57)
× 10-4
1.1 ± 0.11
7
O
(3.7 ± 0.14)
× 10-4
(7.3 ± 0.28)
× 10-1
HO
HO
NH2
N
H
11
11
O
(3.1 ± 0.20)
× 10-4
(6.2 ± 0.40)
× 10-1
NH2
N
H
H
N
O
O
S
NH2
10
11
N.A.[f]
N.A.
N.A.
1.2
N.A.
340
N
12
H
N
NH2
(5.2 ± 0.065)
× 10-5
(1.0 ± 0.013)
× 10-1
N
13
O
NH2
(2.1 ± 0.12)
× 10-4
(4.2 ± 0.24)
× 10-1
N
H
12
13
N.A.
24
340
340
14
O
NH2
(1.8 ± 0.013)
× 10-4
(4.6 ± 0.033)
× 10-1
N
H
14
11
O
O
O
HO
HO
NH2
N
H
14
15
N.A.
N.A.
1.0
N.A.
N.A.
N.A.
330
OH
16
5.0
NH2
N
H
× 10-4
11
3
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10.1002/adsc.201800342
Advanced Synthesis & Catalysis
Table 1. Overview of hydrazone formation reactions tested with aniline 1.[a]
[b]
[c]
[d]
k1, cat
k2 (app)
krel
Rate analysis [e]
wavelength (nm)
Hydrazide
Aldehyde
(s-1)
(M-1 s-1)
O
O
NH2
N
H
16
17
N.A.
N.A.
N.A.
N.A.
N.A.
330
OH
16
14
O
NH2
2.5
5.0
N
H
× 10-4
× 10-1
14
[a] Reaction conditions: 0.020 mM hydrazide, 0.5 mM aldehyde and 0.5 mM aniline 1 in 20% DMF in 100 mM sodium
phosphate buffer pH 7.4.
[b]
k
is the pseudo-first order rate constant of the aniline catalysed reaction, reported with the standard error of the
1, cat
mean (SEM, n ≥ 2).
[c]
[d]
k2 (app) is de calculated second order rate constant of the aniline catalysed reaction, calculated with k2 (app) = k1,cat
[aldehyde].
/
k
is the ratio of the rate constant of the reaction catalysed by 1 and the rate constant of the uncatalysed reaction (krel
rel
= kcat / kuncat).
[e] We report the wavelengths at which we followed the hydrazone formation reaction using UV/vis spectroscopy.
[f] N.A.: not applicable.
Figure 1. The hydrazone formation reaction 9 and response to aniline 1 and 1,3-phenylenediamine ∙2HCl 15 catalysis.
Reaction conditions: 0.020 mM hydrazide 11, 0.5 mM aldehyde 5, 0.5 mM 1 or 0.5 mM 15 in 20% DMF in 100 mM
sodium phosphate buffer pH 7.4 (a) Reaction 9 between hydrazide 11 and aldehyde 5. (b) Absorbance spectra of the
reaction mixtures for the uncatalysed reaction at t0 (black line) and at t = 15 h (magenta line), for the reaction catalysed by
1 at t0 (green line), at t = 15 h (blue line). (c) Hydrazone formation followed over time for the uncatalysed reaction (black),
for the reaction catalysed by 1 (red) and for the reaction catalysed by 15 (blue). (d) The first-order rate constants were
determined by Guggenheim fits, uncatalysed reaction (black), reaction catalysed by 1 (red), reaction catalysed by 15 (blue).
4
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10.1002/adsc.201800342
Advanced Synthesis & Catalysis
Whereas 1 gives a 47-fold increase in reaction rate
acylhydrazide 11 or 14 and p-nitrobenzaldehyde 5 or
benzaldehyde 8 (reaction 12, 15, 17, 13 and 9) are
significantly accelerated by aniline catalysis without
for reaction 9, catalysis by 15 results in a 74-fold
increase in reaction rate (Supplementary Table 1),
making catalyst 15 1.5-times more active than aniline. observed side reactions, making them useful
This result is in agreement with studies from the
literature: catalyst 15 was reported by Kool as 2.1-
times more active than aniline.[11]
benchmark reactions to test aniline catalysis or in
designing responsive materials where aniline
catalysis plays a role.
We tested each aldehyde and hydrazide
combination for possible side reactions with pro-
aniline 2. None of the aldehydes showed any change
in absorbance in the presence of 2, indicating that the
aldehydes do not react with 2. The absorbance
spectrum of hydrazide 3 changes in the presence of 2,
which indicates that the two compounds react or non-
covalently bind to each other.
We found that the absorbance spectrum of another
nitro-bearing hydrazide, 2,4-dinitrophenylhydrazine
(DNPH), also changes in the presence of 2
(Supplementary Figure 4). This might indicate that
the nitro-group causes this apparent side reaction. A
possible explanation might be that nitro-bearing
hydrazides can coordinate or react with the boronic
acid group on 2.[12]
The side reaction of hydrazide 3 with 2 reduced the
usefulness of hydrazide 3 under our reaction
conditions. However, as long as no compounds
similar to pro-aniline 2 are applied, hydrazide 3 may
still be a good probe to analyse hydrazone formation.
Furthermore, we studied the stability of the
aldehydes and hydrazides in the reaction solvent. The
absorbance spectra of the aldehydes and hydrazides 3,
13 and 14 did not change over a course of 15 h,
indicating that the compounds remain stable. In
contrast, the absorbance spectra of hydrazide 7 and
hydrazide 12 alone changed in the presence of DMF
or DMSO (dimethyl sulfoxide), which suggests that
these compounds react with the solvents or degrade
(Supplementary Figure 5).
Overall it appears that relatively unreactive
hydrazides, such as hydrazide 3, 11, and 14, benefit
from aniline catalysis. Relative reactive hydrazides,
such as hydrazide 7 and 13 react efficiently with the
aldehydes without activation by aniline and do not
seem to benefit from aniline catalysis.
Experimental Section
General procedure to follow a hydrazone reaction in
UV/vis spectroscopy.
The hydrazone reactions were performed in 20% (v/v)
DMF (dimethylformamide) in
a 100 mM sodium
phosphate buffer pH 7.4. The quartz cuvettes contained a
total reaction volume of 2 mL. All reactions were carried
out using the same conditions: 0.020 mM hydrazide, 0.5
mM aldehyde, 0.5 mM aniline 1 or pro-aniline 2, 20%
DMF in 100 mM phosphate buffer pH 7.4, 25 °C. The
stock solutions of the reagents were added as follows:
aldehyde solution (100 µL, 10 mM in DMF), phosphate
buffer, DMF, catalyst solution (100 µL, 10 mM in DMF),
the hydrazide solution (100 µL, 0.4 mM in DMF). Stock
solutions were made fresh for every reaction and used
within 1 h. The cuvettes were closed using Teflon caps and
thoroughly mixed by turning the cuvette upside down 4
times. The spectra of the reaction mixtures at t=0 were
measured (reference measurement using a cuvette with
only solvent as the reference cuvette, 10 nm s-1). The
change in absorbance was followed at the rate analysis
wavelength using a 6-sample holder (standard absorption
measurement, scan every 30 s). At t = 15 h single scans
were measured again using the same settings as for the
starting reaction mixtures. The pseudo-first-order rate
constants were determined using the Guggenheim time lag
fit.[10] The graph was fitted using linear regression to yield
the pseudo-first-order reaction rate constant.
Acknowledgements
This work was supported by the Netherlands Organization for
Scientific Research through a VIDI grant and by the European
Research Council (ERC consolidator grant 726381).
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In summary, the hydrazone formation reactions we
discussed show large variation in reactivity, stability
and response to aniline catalysis. Reactions 2, 3, 13
and especially reaction 12, 15, 17 and 9 show a large
increase in reaction rate in the presence of aniline 1.
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sulfonated benzaldehyde
6
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5
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10.1002/adsc.201800342
Advanced Synthesis & Catalysis
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6
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Advanced Synthesis & Catalysis
UPDATE
Aniline catalysed hydrazone formation reactions
show a large variation in reaction rates and
catalytic effects
Adv. Synth. Catal. Year, Volume, Page – Page
Fanny Trausel, Bowen Fan, Susan A. P. van
Rossum, Jan H. van Esch and Rienk Eelkema*
7
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