Kinetic Selectivity and Thermodynamic Features of Competitive Imine Formation in Dynamic Covalent Chemistry

Article abstract of DOI:10.1002/chem.201702088

The kinetic and thermodynamic selectivities of imine formation have been investigated for several dynamic covalent libraries of aldehydes and amines. Two systems were examined, involving the reaction of different types of primary amino groups (aliphatic amines, alkoxy-amines, hydrazides and hydrazines) with two types of aldehydes, sulfobenzaldehyde and pyridoxal phosphate in aqueous solution at different pD (5.0, 8.5, 11.4) on one hand, 2-pyridinecarboxaldehyde and salicylaldehyde in organic solvents on the other hand. The reactions were performed separately for given amine/aldehyde pairs as well as in competitive conditions between an aldehyde and a mixture of amines. In the latter case, the time evolution of the dynamic covalent libraries generated was followed, taking into consideration the operation of both kinetic and thermodynamic selectivities. The results showed that, in aqueous solution, the imine of the aliphatic amine was not stable, but oxime and hydrazone formed well in a pH dependent way. On the other hand, in organic solvents, the kinetic product was the imine derived from an aliphatic amine and the thermodynamic products were oxime and hydrazone. The insights gained from these experiments provide a basis for the implementation of imine formation in selective derivatization of mono-amines in mixtures as well as of polyfunctional compounds presenting different types of amino groups. They may in principle be extended to other dynamic covalent chemistry systems.

Full text of DOI:10.1002/chem.201702088

A Journal of
Accepted Article
Title: Kinetic Selectivity and Thermodynamic Features of Competitive
Imine Formation in Dynamic Covalent Chemistry
Authors: Jean-Marie Lehn, Sirinan Kulchat, and Manuel N Chaur
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10.1002/chem.201702088
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Kinetic Selectivity and Thermodynamic Features of Competitive
Imine Formation in Dynamic Covalent Chemistry
Sirinan Kulchat,[a,b] Manuel N. Chaur,[a,c] and Jean-Marie Lehn*[a]
compounds[6-10] has been actively investigated to develop the core
Abstract: The kinetic and thermodynamic selectivities of imine
formation have been investigated for several dynamic covalent
libraries of aldehydes and amines. Two systems were examined,
involving the reaction of different types of primary amino groups
(aliphatic amines, alkoxy-amines, hydrazides and hydrazines) with
two types of aldehydes, sulfobenzaldehyde and pyridoxal phosphate
of DCC in view of their dynamic features as well as for their use
for generating conjugates in chemistry and biology. Nucleophiles
such as hydrazine and hydroxylamine where the amino group has
an alpha-substituent bearing a lone pair have long been known to
act as stronger nucleophiles than normal primary amines[11] and
their low basicity allows the formation of more stable imine
products[12]. In recent times, imine formation from these alpha-
in aqueous solution at different pD (5.0, 8.5, 11.4) on one hand,
2-
pyridinecarboxaldehyde and salicylaldehyde in organic solvents on
the other hand. The reactions were performed separately for given
amine/aldehyde pairs as well as in competitive conditions between an
aldehyde and a mixture of amines. In the latter case, the time
evolution of the dynamic covalent libraries generated was followed,
taking into consideration the operation of both kinetic and
thermodynamic selectivities. The results showed that, in aqueous
solution, the imine of the aliphatic amine was not stable, but oxime
and hydrazone formed well in a pH dependent way. On the other
hand, in organic solvents, the kinetic product was the imine derived
from an aliphatic amine and the thermodynamic products were oxime
and hydrazone. The insights gained from these experiments provide
a basis for the implementation of imine formation in selective
derivatization of mono-amines in mixtures as well as of polyfunctional
compounds presenting different types of amino groups. They may in
principle be extended to other dynamic covalent chemistry systems.
[13-
nucleophiles has received much attention in chemical biology
[19-
15], polymer chemistry[16-18], dynamic combinatorial chemistry
23], and reaction development[24]. Attention has been mainly paid
to the thermodynamic features of the constituents of DCLs based
on the formation of C=N connections. However, the kinetics of the
condensation reactions are also of basic interest and have
received increasing attention[25-31], as they may be expected to
affect the composition of a dynamic C=N library as a function of
time in the course of its generation from carbonyl and amino
components. We have examined earlier the effect of structural
features on imine formation for a variety of aldehydes and primary
amines[32] as well as the rates of the reactions for hydrazine and
hydroxylamine derivatives[27]. We have also investigated the
complex behaviour of a dynamic covalent library of four imines
displaying protonic and temperature modulation of constituent
expression by component selection[33,34]
.
Introduction
We now extend these studies to the kinetics and
thermodynamics of imine formation from different aldehydes and
various types of amino derivatives (including primary amine,
hydrazine, hydrazide and oxyamine compounds)[27]. Beyond
simple two component reactions, we also considered the
condensation of aldehydes with a mixture of different amino
derivatives. Such competitive processes generate mixed DCLs,
containing different types of C=N compounds, which undergo
variations in imine product distribution as a function of time,
depending on the relative reaction rates and imine stabilities.
Such experiments also allow for the exploration of selectivity in
derivatization and dynamic protection of molecules possessing
different amino groups in order to select different products based
Dynamic covalent chemistry (DCC) is based on the operation
of reversible reactions between complementary functional groups
and the resulting generation of dynamic covalent libraries (DCLs)
of molecular constituents by component exchange. Among
reversible reactions, the formation of imine-type C=N connections
by condensation between carbonyl and amino groups plays a
prominent role in view of its importance in both chemistry and
biology. Imines, together with the related compounds,
acylhydrazones, hydrazones and oximes, have been extensively
used in the application of DCC towards the search for bioactive
molecules, the generation of dynamic polymers in materials
science as well as the exploration of adaptive chemistry. Thus,
many DCC processes based on imine formation, exchange and
hydrolysis have been widely implemented[1-5]. The formation of
reversible C=N connections from reaction of primary amines,
hydrazide, hydrazine and hydroxylamine derivatives with carbonyl
on either kinetic or thermodynamic features[35]
.
Considering the two features characterizing the C=N bond
forming processes, reactivity and stability, the rates of conversion
lead to the kinetic products and the conversion equilibria
correspond to the thermodynamic products. When multiple such
reactions are performed in parallel with mixtures of aldehydes and
amino compounds, thus generating a mixture of different imine
constituents, the evolution of the composition of the DCL as a
function of time and the final composition of the mixture can in
principle be considered to represent respectively the kinetic
[a]
[b]
Dr. S. Kulchat, Dr. M. N. Chaur, Prof. Dr. J.-M. Lehn
Laboratoire de Chimie Supramoléculaire, Institut de Science et
d’Ingénierie Supramoléculaires (ISIS), Université de Strasbourg,
8 allée Gaspard Monge, BP 70028, F-67000 Strasbourg Cedex
E-mail: lehn@unistra.fr
Dr. S. Kulchat
selectivity and the thermodynamic selectivity of the system[33]
.
Materials Chemistry Research Unit, Department of Chemistry and
Center of Excellence for Innovation in Chemistry,
Faculty of Science, Khon Kaen University, Nai Muang, Muang,
Khon Kaen, 40002, Thailand.
However, if the reaction rates are very slow and/or very different
(when operating with mixtures of reagents in competition), it
becomes difficult to determine whether or not equilibrium has
been reached, and thus to ascertain thermodynamic selectivity.
Email: sirikul@kku.ac.th
[c]
Dr. M. N. Chaur
The present investigation was based on two groups of
aldehydes (Scheme 1): 1) the water-soluble aldehydes sodium 5-
formyl-2-methoxybenzene sulfonate 1 and pyridoxal phosphate 2
Departamento de Química, Universidad del Valle, Cali, Colombia.
Email: manuel.chaur@correounivalle.edu.co
Supporting information for this article is given via a link at the end of
the document.
used in aqueous solution studies; 2)
pyridinecarboxaldehyde and salicylaldehyde
2-
3
4
used for
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10.1002/chem.201702088
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experimentation in organic solvents. The different primary amino-
compounds chosen are shown in Scheme 2; they comprise of
pentylamine A, O-methoxyamine B, methylhydrazine C, O-
benzylhydroxylamine D, benzhydrazide E, and phenylhydrazine
F. Experiments were conducted in aqueous solution (under pD
control) as well as in organic solvents (CD3OD or CD3CN). No
hydrazide was used in aqueous solution as hydrazides are
susceptible to hydrolysis (for instance the water soluble
acetylhydrazide). Both the rates and amount of product formation
of the reactions investigated were monitored by 1H-NMR
spectroscopy, determining the fractions of different compounds
by signal integration with respect to the signal of 1,4-dioxane as
an internal standard. Especially for the very slow reactions, it was
not possible to confirm that equilibrium had been reached and
only percentages of the products at a given time could be
determined. In some cases it was observed that relative fractions
of constituents evolved over long times, showing even changes in
relative amounts. Over the initial stages of the reaction (i.e. when
reverse reaction of the C=N products may be ignored), the time
dependence of the concentrations provided a good fit to simple
second-order kinetics (for details, see supporting information),
thus providing the rate constants given herein. For easy
comparison of initial rates, we provide the t10 values, the time for
10% completion of the reactions.
(“sulfonate aldehyde”) (1) and pyridoxal phosphate (2)
with different primary amino derivatives (A, B, C) both
separately and as mixtures in aqueous solution
[6-
Imine formation reactions have been extensively studied
10,32], however in water it is limited by low equilibrium constants,
due to competition of hydration of the aldehyde to a greater or
lesser extent depending on the electronic properties of the amine
or aldehyde[27, 32, 36]. Thus, imine formation is much more efficient
when performed in organic solvents not only to avoid hydration of
aldehyde but also to shift the equilibrium toward the condensation
products by favouring elimination of water from carbinolamine
intermediates. DCC of imine compounds has been investigated in
organic solvents[37], aqueous-organic mixtures,[38] and aqueous
20,
solutions[27,
39-43]. The objective here was to extend these
studies to assess the reactivity of a given aldehyde towards not
only a single primary amine compound, but in competition
reactions involving several different amines in order to determine
the kinetic features of the time dependent generation of a DCL as
well as to obtain, when feasible, an estimation of the relative
thermodynamics of the constituents. The reactions of the
aldehydes sodium 5-formyl-2-methoxybenzene
sulfonate
(“sulfonate aldehyde”) (1) and pyridoxal phosphate (2) with
different primary amino derivatives (A, B, C) were performed both
with the individual amines and with mixtures of the amines. The
kinetic features are given as the reaction time t10 [h] for 10%
completion of the reaction and as the rate constant k calculated
from a fit to a second-order reaction over the first 10% of the
reaction. In aqueous solution, the reverse reaction of C=N
hydrolysis takes place with the bulk water as soon as the product
forms; it is thus pseudo-first order. Comparative thermodynamic
features may be estimated from the fractions (%) of the C=N
constituents formed at a given time, noting however that
equilibrium may not have been reached in view of very slow
exchange reactions. Relative amounts of products can be found
from the reaction curves given in the Figures and the Tables
below.
As stressed above, in view of the fact that some reaction rates are
very slow, it is not feasible to determine whether thermodynamic
equilibrium has been reached and thus to quantify the exact
thermodynamic selectivity, in particular in experiments involving
competition in mixtures. In this respect, the Figures and Tables
show the results for the longest times of data collection. As a
consequence, only the relative order in the product distribution at
the time of last data collection has significance, not their exact
fractions. Only in the case of the reactions involving the sulfo-
benzaldehyde 1 is it probable that equilibrium has indeed been
reached.
a) Imine formation from sulfonate aldehyde 1 and amino
compounds A-E separately and as mixtures in aqueous
solution
As it is well known that both the rates and equilibria of imine
formation in general are pH-dependent[44-48], experiments were
performed under controlled pD conditions (pD = 5.0, 8.5, and
11.4; the pD value was calculated employing pD = pH + 0.4 where
“pH” is the apparent pH value indicated by the conventional glass
Scheme 1. Structures of the aldehydes 1-4 used in this study.
electrode[36,49]
NaH2PO4/Na2HPO4) mixtures.
)
using
phosphate
buffers
(160
mM
Firstly, the formation of 1A, 1B, and 1C was studied separately
in order to determine the kinetic and thermodynamic parameters
of the individual reactions using initial reactant concentrations of
20 mM in all three buffers at 25oC (Table 1; Figures S2-S13). The
results showed that 1A did not form at pD 5.0. At pD 8.5 and 11.4,
it formed rapidly after mixing but the % of product was very low.
The oxime 1B formed faster at pD 5.0 than at higher pD values,
showing that acidic media are preferable for oxime formation. The
pKa of O-methoxyamine being 4.6[50], at pD 5.0 (pH = 4.6),
approximately half of it should still be present as neutral
methoxylamine for nucleophilic condensation with the aldehyde
and further free amino groups would be liberated as the reaction
proceeded. Finally, the hydrazone 1C formation was nearly
insensitive to solution pD but formed slightly more slowly at pD
Scheme 2. Structures of the different primary amino derivatives A-F
used in this study.
Results and Discussion
1. Imine formation in aqueous solution from reaction of
sodium 5-formyl-2-methoxybenzene sulfonate
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11.4, despite the fact that, given the pKa value of 7.87 for C[51], it
would have been presented predominantly in its protonated form
at pD 5.0 but largely in its neutral form at pD 8.5 and 11.4. These
results provide a good illustration of the complexity of the pH
dependence of imine formation from different types of amino
compounds[36]
.
Figure 1. Kinetic traces for imine formation from the reactions of aldehyde 1
with a mixture of the amine components A, B, and C in D2O phosphate buffers
a) pD = 5.0, b) pD = 8.5, and c) pD 11.4. The concentrations of reactants were
20 mM in all cases. Error in 1H-NMR integration: 5%.
Table 2 Distribution of imines 1A, 1B, and 1C and time (t) after full consumtion
of sulfonate aldehyde 1 in DCLs generated by reaction of the sulfonate aldehyde
1 with a mixture of the amino derivatives A, B, and C in D2O (in phosphate
buffers of pD 5.0, 8.5 and 11.4), using an initial concentration of 20 mM for all
reactants at 25oC.
Table 1. Time for 10% conversion t10 and second order rate constants k for
imine formation from sulfonate aldehyde (1) and several amino derivatives (A,
B, C) in separate runs. Reactions were performed in D2O in phosphate buffer at
pD 5.0, 8.5, and 11.4. Solutions were equimolar (20 mM) in each reactant.
K[b]
Compound distribution [%][b]
Entry
pD
5.0
8.5
11.4
t[h][a]
1.0
11.2
1.2
1A
1B
90
37
15
1C
10
63
85
Entry
1
pD
5.0
Product
t10 [h][a]
[x10-3 M-1 s-1]
n.d.[d]
[c]
1
2
3
-
[c]
[c]
1A
1B
1C
1A
1B
1C
1A
1B
1C
-
-
[c]
<2 min
0.5
194.3
3.74
-
[a] Time when sulfonate aldehyde 1 is fully consumed. [b] Error in 1H-NMR
determination: 5%.[c] Compound not formed.
2
3
8.5
0.03[e]
0.7
n.d.[d]
6.71
0.4
5.21
DCLs from sulfonate aldehyde 1 and a mixture of the amino
derivatives A, B, and C were generated similarly in the three
buffers (Scheme 3) at 25oC. The results showed that the reactions
gave the compound distribution 1B (90%), and 1C (10%) after one
hour (Fig. 1a, Table 2). 1A was not formed as expected from its
pKa, indicating that pentylamine was protonated and did not react
with 1. 1B was kinetically favoured, in agreement with the first set
of results on the individual rates of formation of imines 1A, 1B, 1C
(Table 1, Entry 1) which showed that 1B was formed fastest and
1C slowest. It was also obtained in the largest amount, indicating
that at this weakly acidic pD it may well be also the
thermodynamically favoured product.
11.4
0.03[e]
2
n.d.[d,e]
0.504
3.39
0.7
[a] Time for 10% completion of the reaction. [b] Rate constant calculated
from a fit to a second-order reaction over the first 10% of the reaction, except
over 30% for 1B at pD 5.0, reached when the first spectrum recorded. [c]
Product not observed. [d] Not determined. [e] Reaction very fast, reached
equilibrium within the time of mixing (less than about 2 min according to the
first NMR measurement) giving about 5 and 40 % 1A at pD 8.5 and 11.4
respectively. Error in 1H-NMR integration: 5%
a)
Scheme 3. Dynamic covalent library (DCL) formed by a mixture of the 5
components 1, A, B, C and the three possible imine products 1A, 1B, 1C to be
analyzed in different buffers (pD = 5.0, 8.5, and 11.4). The study was performed
at 25oC using an initial solution concentration of 20 mM for each reactant in D2O.
b)
a)
b)
Figure 2. Distribution of different imines at pD values of 5.0 (blue), 8.5 (red),
and 11.4 (green) after full consumption of the respective aldehyde 1 or 2. (Top)
1A-1C in the DCL generated from a mixture of the sulfonate aldehyde 1 with a
mixture of the amino derivatives A, B, C (see also Table S1). (Bottom) 2A-2C
in the DCL generated from a mixture of pyridoxal phosphate 2 and various
c)
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amino compounds (see also Table S3). All reagents 20 mM at 25°C. Error in
1H-NMR integration: 5%.
Thereafter, a DCL was generated from a mixture of pyridoxal
phosphate 2 with the three amino derivatives A, B, and C
(20
mM each; Scheme 4) and analyzed in the same way as with
aldehyde 1. All the competitive reactions (DCLs) at the three pD
values reached equilibrium within approximately 2-3 min (Table 4
and Fig. 2b). In all cases, only oxime 2B and hydrazone 2C were
detected in significant concentrations. At pD 5.0 and 8.5, 2B was
favored over 2C, as shown by the distributions of products 2B
(85%) and 2C (15%) at pD 5.0 and 2B (60%) and 2C (40%) at pD
8.5. At pD 11.4, 2C dominated. LC-MS confirmed imine formation
at pD 8.5 and 11.4 by the observed peaks at m/z 298.87 ([2B +
K+]) and at m/z 277.16 ([2B + H3O+]). These results showed that
in the DCLs generated from an equimolar mixture of 2, A, B, and
C at different pD values, the oxime 2B and the hydrazone 2C were
the dominant species. At low pD, 2B had the highest %-product
while, at high pD 2C dominated, in line with the respective pKa
values.
The DCL of an equimolar mixture of 1, A, B, and C (20 mM
each) was next examined at pD 8.5. The results showed that the
reaction was slower than at pD 5.0, (Fig. 1b and Table 2 Entry 2)
and that only two imine compounds 1B (37%) and 1C (63%) were
formed while 1A was not detected. At this pD, 1C was now more
abundant than 1B. Finally, the DCL of the same mixture was
established at pD 11.4 (Fig. 1c, Table 2 Entry 3). The reactions
gave a compound distribution of 1B (15%) and 1C (85%) after
about 1 h with again no evidence of 1A. In summary, DCLs of the
mixture of 1, A, B, and C in acidic conditions were dominated by
the formation of oxime 1B whereas, in basic solution, the
hydrazone 1C was favoured. Meanwhile, in slightly basic
solutions (pD 8.5), the reaction progressed relatively slowly,
compared to either acidic or more basic conditions. These results
show that the acidity of the medium is an effective tool for
controlling the relative rates of formation and the fractions of
imines in a DCL in aqueous solution. It is known that oxime
formation occurs preferentially in acidic solution and hydrazine
Table 3. Percent product formed at time after full consumption of pyridoxal
phosphate 2 for imine formation between pyridoxal phosphate (2) and several
amino derivatives (B, C, D, E) in separate runs in D2O (in phosphate buffers of
pD 5.0, 8.5 and 11.4), using an initial concentration of 20 mM for all reactants
at 25oC.
formation in basic medium[53]
.
b) Imine formation from pyridoxal phosphate 2 and amino
compounds A-C separately and as mixtures in aqueous
solution
Compound
Entry
1
pD
5.0
Product
t [min][b]
[%][a]
[c]
[c]
2A
2B
2C
2A
2B
2C
2A
2B
2C
-
-
99
99
5
Pyridoxal phosphate (2) was chosen as aldehyde reactant in
view of its role as coenzyme for a wide range of different
reactions[52, 54-56], involving amino acids and other biological
processes[57-58]. It has also been used in dynamic covalent
systems[58]. Firstly, imine formation between pyridoxal phosphate
2 and the different amino derivatives (A, B, C) was monitored
separately at different pD values (pD = 5.0, 8.5, and 11.4) under
the same conditions as used with the sulfonated aldehyde 1
(Table S2). Imine formation from pyridoxal phosphate 2 and
pentylamine A was not observed at any pD due to the dominance
120
[c]
[c]
2
3
8.5
-
-
99
99
5
120
[c]
[c]
11.4
-
-
99
70
5
5
[a] Error in 1H-NMR integration: 5%. [b] Time when pyridoxal phosphate
2 is fully consumed
[c] Product not formed.
Table 4 Distribution of imines 2A, 2B, and 2C in DCLs generated by reaction of
pyridoxal phosphate 2 with a mixture of the amino derivatives A, B, and C at
pD values of 5.0, 8.5 and 11.4 at 25oC in D2O (in phosphate buffers of pD 5.0,
8.5 and 11.4), using an initial concentration of 20 mM for all reactants at 25oC.
All reactions were terminated within < 3 min.
1
of the hydrated form of the aldehyde (as detected by H-NMR).
2B formed quickly at all pD values, reaching equilibrium in about
5 min without any residual hydrated form of 2 being detectable.
The hydrazone 2C was obtained in quantitative amounts at both
pD 5.0 and 8.5 while at pD 11.4 the reaction was faster but with
only 70% conversion after 5 min. As all reactions were fast, being
finished right after mixing and when measuring the 1H-NMR
spectrum, no quantitative data are given here (for some indication
see Table 3). One may note that the aldehyde group of pyridoxal
phosphate is activated by being located in position 4 of the
pyridine ring and that in addition the resulting imines are likely to
be stabilized by formation of a hydrogen bond between the imine
=N- site and the neighbouring hydroxyl group.
Compound distribution [%][a]
Entry
pD
2A
2B
85
60
45
2C
15
40
55
[b]
1
2
3
5.0
8.5
11.4
-
[b]
-
[b]
-
[a] Error in 1H-NMR integration: 5%. [b] Product not formed after 2 h.
2) Imine formation from 2-pyridyl aldehyde (3) and various
amino derivatives (A, D, E and F) in organic solvent
a) Imine formation from pyridine-2-aldehyde (3) with
individual amines
Pyridine-2-aldehyde (3) is known to react efficiently with amino
compounds. It contains an sp2 nitrogen atom that can be used as
a binding site for metal ions, thus offering other means of
modifying its properties[59-60]. Furthermore, this pyridine-N can act
as
a site for intramolecular H-bonding in appropriately
functionalized imines, thus serving, for example, to stabilize the Z
isomer of hydrazones and acylhydrazones susceptible to
photochemical interconversion between E and Z forms[60-62]
.
A
study of the competitive imine formation in a mixture of a primary
amine and hydrazine with pyridine-2-aldehyde and its
derivatives in CD3CN showed that the kinetic product was the
imine derived from the primary amine while the thermodynamic
product was the hydrazone[62]. The DCC of the imines derived
a
Scheme 4. DCL of the 5 components 2, A, B, C and the three possible imine
products 2A, 2B, 2C studied in phosphate buffers in D2O at different pD values
(5.0, 8.5, and 11.4) at 25oC.
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from aldehyde 3 has been widely investigated[60,63-65]. Here we
extended these studies to determine the kinetic features for imine
formation from the reaction of aldehyde 3 with different amino
compounds both separately and in mixtures.
Firstly, imine formation between 3 and the four different amino
derivatives A and D-F separately (20 mM each) was evaluated in
CD3OD at 25°C (see structures in Scheme 5). The formation of
imine 3A reached about 90% conversion after 2 h with no further
observable change. On the other hand 3D, 3E, and 3F were
formed more slowly taking each about ca.18 h for about 90%
conversion. The hemiaminal intermediate (about 10%) was
observed in all the reactions[66]. The measurements of imine
formation here were just meant to provide a rough guide as to the
differences between the reactions. Given that there was no
control of acidity and various intermediates were detectable, a
kinetic analysis was not conducted in this case.
Figure 3. Kinetic traces for imine formation from the reactions between a) 3 +
A + D, b) 3 + A + E, and c) 3 + A + F, d) 3 + D + E, e) 3 + D + F. in CD3OD in
at 25oC. Initial reactant concentration were all 20 mM. Error in 1H-NMR
integration: 5%.
Table 5. Time-dependence of component distributions for competitive reactions
of pairs of amino derivatives with a 2-pyridyl aldehyde (3).
Compound distribution [%][b]
Time
b) Competitive reactions of two amino compounds with
pyridine-2-aldehyde (3)
Entry
1
Reaction
[h][a]
0.03
4.5
3A
34
45
15
23
13
28
57
3D
-
55
85
3E
3F
[c]
3 + A + D
n.d.[d]
n.d.[d]
n.d.[d]
6
n.d.[d]
n.d.[d]
n.d.[d]
n.d.[d]
n.d.[d]
In order to study kinetic selectivities, competitive reactions
between pyridine-2-aldehyde 3 and equimolar amounts of two
amines were considered first. The time dependence of imine
formation for the different cases is shown in Fig. 3. Quantitative
data are given for each case in Table 5.
27.2
0.03
3.5
0.03
0.3
2
3
3 + A + E
3 + A + F
n.d.[d]
n.d.[d]
n.d.[d]
n.d.[d]
n.d.[d]
67
87
n.d.[d]
n.d.[d]
n.d.[d]
9
-
[c]
18
73
4.9
27
Following the reaction of 3 with pentylamine A and O-benzyl
hydroxylamine D in CD3OD at 25oC (Fig. 3a, Table 5, Entry 1),
only imine 3A (34%) was detected immediately after mixing, along
with the hemiaminal intermediate. Subsequently, the
concentrations of 3A and 3D increased with time but at different
rates such that after about 50 min, the concentration of 3A began
to decrease and 3D became the predominant species. In parallel,
the hemiaminal disappeared. The reaction was followed up to 27
h, at which point the product conversions were 3A (15%) and 3D
(85%) and did not change any more.
4
5
3 + D + E
3 + D + F
0.03
0.18
0.03
3.9
n.d.[d]
n.d.[d]
n.d.[d]
n.d.[d]
n.d.[d]
n.d.[d]
15
87
2
30
13
n.d.[d]
n.d.[d]
68
[a] Reaction times indicate the time at which data were collected [b] Error in
1H-NMR integration: 5%. [c] Compound not formed. [d] n.d.; not
determined.
As a third case, for an equimolar mixture of 3 with A and F
in the same conditions (Fig. 3c, Table 5, Entry 3), only 3A (28%)
was observed immediately after mixing all the components
together. Subsequently, the concentration of 3A first increased
rapidly until reaching 57% after about 18 min, when it began to
decrease slowly. 3F started to appear after 5 min and slowly
increased in concentration with time, leading to a crossing of the
two formation curves. The reaction was followed up to 5 h, giving
then 3F (73%) as a major product and 3A (27%) as a minor
product.
Next, for an equimolar mixture of the two amino derivatives A
and the hydrazide E with aldehyde 3 (Fig. 3b, Table 5, Entry 2),
initially aldehyde 3 reacted rapidly with both of them (somewhat
faster with 3A), giving about 20% of imine 3A and acylhydrazone
3E after about 2 min, again in presence of detectable amounts of
the hemiaminals. Later, 3A disappeared, to be replaced by more
3E that became then the major product with 13% 3A and 87% 3E
after 3.5h.
These results show that oxime 3D, acylhydrazone 3E, and
hydrazone 3F are favoured over imine 3A as expected.
Pentylamine A has a higher basicity than the other amino
a)
b)
compounds (for comparison, the pKa of pentylamine is 10.63[67]
,
while the pKa 3.0 for benzhydrazide[68] 4.23 for O-benzyl
hydroxylamine[69] and 5.21 for phenylhydrazine[70]). Thus, imine
3A formed faster than 3D, 3E, and 3F, being therefore the kinetic
product, whereas the more stable 3D, 3E, and 3F were the
thermodynamically more stable products, as expected for
–
CH=N-X ( X = O or N) compounds[12,71]
.
c)
d)
The reaction of 3, D, and E (Fig. 3d, Table 5, Entry 4) showed
a rapid formation of both 3D and 3E upon mixing to 67% and 9%,
respectively, after about 10 min, with however much faster
increase in the oxime 3D. After about 20 min, the composition was
87% 3D and 13% 3E. Finally, a mixture of 3, D, and F
(Fig. 3e)
gave 3D (2%) and 3F (15%) after mixing and 30% 3D and 68%
3F after about 4 h. On this basis, the relative thermodynamic
stability of the condensation products would lie in the order 3F >
3D > 3E.
e)
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b) Competitive reactions of three and four amino
compounds with pyridine-2-aldehyde (3)
We thereafter investigated more complex mixtures involving
competition between three and four amino compounds (Scheme
5). For the reaction of an equimolar mixture of 3, A, E and F, (20
mM each in CD3OD at 25oC) (Fig. 4a, Table 6, Entry 1), only imine
3A (23%) and acylhydrazone 3E (7%) were detectable
immediately after mixing. About 15 min later, 3A started to
decrease in concentration and completely disappeared as 3E and
3F increased to 79% and 21% respectively after 2h. Interestingly,
for this system, 3E was formed more efficiently than 3F.
c)
Figure 4. Kinetic traces for imine formation in CD3OD in the reaction mixtures
of: a) 3 + A + E + F; b) 3 + E + D + F; c) 3 + A + D + E + F (20 mM each in
CD3OD at 25°C); the last data points correspond to the fractions of the imines
at 238h. Error in 1H-NMR integration: 5%.
Table 6. Time-dependence of the DCL distributions in the competitive reactions
between mixtures of amino derivatives and 2-pyridyl aldehyde (3) in CD3OD.
Compound distribution [%][d]
Time
Entry
1a)
Reaction
[h][c]
0.03
0.99
2.00
0.03
0.42
1.6
3A
23
9
3D
3E
7
74
79
-b)
2
3F
-e)
18
21
11
56
71
3 + A + E + F
n.d.[f]
n.d.[f]
n.d.[f]
1
[e]
-
2a)
3a)
3 + D + E + F
n.d.[f]
n.d.[f]
n.d.[f]
15
10
20
-
3
3
[e]
[e]
3 + A + D + E +
F
0.05
-
Scheme 5. DCL of the 5 components 3, A, D, E, F and the four possible imine
products 3A, 3D, 3E and 3F studied in CD3OD at 25oC.
0.48
2.63
21.8
0.05
28
<1
-
5
54
64
53
3
13
26
32
0
10
16
0
[e]
4b)
3 + A + D + E +
F
11
Next, examining an equimolar mixture of 3, D, E, and F, only
3D (1%) and 3F (11%) were detectable immediately after mixing
(Fig. 4b, Table 6, Entry 2). The reaction gave 3D (20%), 3E (3%),
3F (71%) after 1.6h. One notes that in the reactions without
pentylamine A, 3E is strongly diminished compared to when
pentylamine is present. The increased formation of 3E as
observed in presence of A (Fig. 4a) may result, at least in part,
from the stabilization of 3E by hydrogen bonding between A and
the N-H site, which is more acidic in the acylhydrazone 3E
compared to the hydrazone 3F. In absence of such H-bonding, 3F
becomes preferred over 3E.
[e]
2
4
6
23
28
47
73
317
-
8
55
46
43
25
25
21
21
10
37
45
45
54
53
50
45
38
[e]
-
10
12
21
22
29
34
52
[e]
-
[e]
-
[e]
-
[e]
-
[e]
-
[e]
-
[a] The reaction was performed at 25oC. [b] The reaction was performed at
60oC. [c] Reaction times indicate the time at which data were collected.
)
d
Error in 1H-NMR integration: 5%. [e] Compound not formed. [f] n.d.; not
determined. The Z forms of 3G and 3H were formed in very small amount
(2-3 %).
The behaviour of the DCL generated by the reaction of
aldehyde 3 with an equimolar mixture of the four different amino
derivatives A, D, E, and F was studied under the same conditions
(Fig. 4c, Table 6, Entry 3). Only 3A (15%) and 3E (3%) were
detectable immediately after mixing. A large amount (together
about 82%) of the hemiaminal derivatives was also observed in
the 1H-NMR spectra (signals in the 6-7 ppm range). These
species disappeared progressively in about 30 min. At that
reaction time, the compound distribution had changed to 3A
(28%), 3D (5%), 3E (54%), and 3F (13%). Thereafter, 3A
Following the previous experiments, the DCL formed by the
equimolar mixture of aldehyde 3 and four different amines (A, D,
E, F) was also studied at 60oC (Table 6, Entry 4). Again, only 3A
(11%) and 3E (3%) were detectable immediately after mixing
while the hemiaminal species were also observed (86%). After
about 2 h, the compound distribution had changed to 3D (8%), 3E
(55%), and 3F (37%) whereas 3A had totally disappeared. The
reaction was left for 73 h, giving 3D (34%), 3E (21%), and 3F
(45%). After about 317 h (about 13 days), the concentration of 3E
had decreased to 10% while those of 3D and 3F had increased to
52% and 38%, in agreement with the previous results above. The
exchange reaction of 3E with 3D and 3F was very slow even at
this higher temperature, so that equilibrium was not reached even
after 10 days at either 25oC or 60oC.
In summary, for the study of imine formation between pyridine-
2-aldehyde 3 and different amino derivatives (A, D, E, and F) in
CD3OD at 25oC, the most reactive amino compound was always
pentylamine A and 3A was the kinetic product (kinetic selectivity).
In contrast, the imines ultimately present in the DCL were 3D, 3E,
and 3F as thermodynamic products (thermodynamic selectivity).
Furthermore, in the presence of pentylamine A, 3E was formed in
higher amount than 3D and 3F at the beginning of the reaction
(after 2 or 3 h) displaying kinetic selectivity.
decreased progressively and completely disappeared after
2.6
h, while the concentrations of the other imines increased with
time, giving 3D (10%), 3E (64%), and 3F (26%). Interestingly, the
concentration of 3E decreased slightly after 2.6 h whereas that of
3D and 3F slightly increased, giving 3D (16%), 3E (53%), and 3F
(32%) after 22 h and indicating that the mixture had still not
reached equilibrium. After about 238 h, the concentration of 3E
had now decreased to 29% while those of 3D and 3F had
increased to 32% and 39%, again in agreement with the stability
sequence above.
b)
a)
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decreased, the relative amounts being now 4F (29%), 4E (9%),
and 4F (63%), and after 21h only 4F (65%) and 4D (35%) were
detectable. Thus, again kinetic selection favored the imine 4A
whereas thermodynamic selection favored the hydrazone 4F. The
same DCL was then monitored in pure CD3CN rather than CD3OD
(Fig. S2), again at 25oC. Only the imine 4A was detectable
immediately upon mixing and after 1 h, it began to be slowly
consumed in favor of the other three imines 4D, 4E, and 4F. Thus,
similar DCL characteristics were observed in CD3CN as in
CD3OD, but as the reactions were much slower they were not
followed further.
3) Imine formation from salicylaldehyde (4) and various
amino derivatives (A, D, E, and F) in organic solvents
Salicylaldehyde 4 has displayed remarkable imine formation
efficiency[72-74] as well as exchange properties in DCC studies[5,73-
77]. It provides internal hydrogen bonding between the imine
nitrogen and the nearby hydroxyl group thus favoring imine
formation. We investigated the kinetic and thermodynamic
selectivity of aldehyde 4 toward different amino derivatives
(pentylamine A, O-benzylhydroxylamine D, benzhydrazide E, and
phenylhydrazine F). First, the individual reactions forming imines
4A, 4D, 4E, and 4F were monitored (20 mM each, in CD3OD at
25oC) (Table 2). The corresponding rate constants estimated from
observation of the initial 10% product formation were in the order
4A > 4F > 4D > 4E, indicating that again pentylamine A reacted
faster than the alpha-substituted nucleophiles towards 4.
Amongst the alpha nucleophiles, phenylhydrazine F, was the
most reactive.
Table 7. DCL composition and second order reaction rate constant for imine
formation between salicylaldehyde 4 and several amino derivatives in CD3OD
at 25oC. The initial solution was equimolar (20 mM) in all the reactants.
Scheme 6. DCL of the 5 components 4, A, D, E, F and the four possible imine
products 4A, 4D, 4E and 4F studied in CD3OD at 25oC.
Entry
Product
4A
4D
4E
4F
Product [%][a]
Time [h][b]
1.5
4.8
4.6
k [x 10-3 M-1 s-1][c]
1
2
3
4
90
76
10
75
40.37
8.17
0.423
17.5
4.6
[a] Error in 1H-NMR integration: 5%. [b] The reaction time indicates the time
at which there was no change anymore and the % shown was determined.
[c] Rate constants were calculated from a fit to initial rates (about 10 %
completion) of a unidirectional second-order reaction.
The competitive reaction between aldehyde 4 and the amino
compounds, A, E, F (20 mM each) was followed at 25oC
(Fig.
Figure 5. Kinetic traces for imine formation in a mixture of a) 4 + A + E + F, b)
5a, Table 8, Entry 1). Three imines were detected immediately
after mixing, 4A (44%), 4E (6%), and 4F (32%). The concentration
of 4A then decreased as a function of time to 2% after about 1h.
In contrast, the concentrations of both 4E and 4F increased to 4E
(18%), 4F (81 %) after about 3h. They may not yet have reached
equilibrium as interconversion between 4E and 4F is expected to
be very slow, as indicated above for the corresponding imine
derivatives of aldehyde 3 where 3F finally had overtaken 3E after
a very long time (over 10 days). Thus, 4A was again the kinetic
product and 4E and 4F were the thermodynamically favored
products. The reaction of aldehyde 4 with amines D, E, F was
followed similarly (Fig. 5b, Table 8, Entry 2). 4D and 4F were
detectable immediately after mixing (2% and 14% respectively)
and reached 18% and 81% after 4 h. In contrast, 4E barely
formed, representing only 1% of the reaction mixture. Thus, the
hydrazone 4F was clearly the dominant constituent of this DCL.
4 + D + E + F (20 mM each, in CD3OD at 25oC). Error in 1H-NMR integration: 
5%.
Figure 6. Kinetic traces for imine formation in a mixture of 4 + A + D + E + F (20
mM each, in CD3OD at 25oC). The last data points correspond to the fractions
of the imines at 21h. Error in 1H-NMR integration: 5%.
Finally, salicylaldehyde 4 was reacted with a mixture of the four
different amino derivatives A, D, E, and F (20 mM each) in the
same conditions (Scheme 6, Fig. 6, and Table 8, Entry 3). All of
the corresponding imine compounds were found to be present
immediately after mixing in relative amounts of 4A (42%), 4D
(6%), 4E (4%), and 4F (23%). As the reaction progressed, 4A was
gradually lost and replaced by the other imines in the mixture,
being undetectable after 0.6 h. Compounds 4D, 4E, and 4F rose
in concentration over time, attaining 4D (27%), 4E (16%), and 4F
(58%), respectively, after 1.4 h. After 3.5 h, the % of 4E had
Table 8. Time-dependence of the distribution of DCL constituents in the
competitive reaction of salicylaldehyde 4 with a mixture of amino derivatives
Compound distribution [%][b]
Time
Entry
1
Reaction
[h][a]
0.05
0.74
2.54
0.05
0.8
4A
44
2
2
n.d.[c]
n.d.[c]
4D
4E
6
4F
32
74
81
14
66
4 + A + E + F
n.d.[c]
n.d.[c]
n.d.[c]
2
24
18
[d]
2
4 + D + E + F
-
12
1
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4.0
0.03
n.d.[c]
42
18
6
1
4
81
23
equilibrium states with slow exchange leading progressively
towards equilibrium. The knowledge gained here is a first step
towards implementation of kinetics in more complex DCC
systems for achieving i) kinetic control over the composition of a
DCL; ii) functional selective reaction in mixtures of various amino
and carbonyl derivatives (in particular of bio-organic interest) as
well as iii) regioselective and functional selective derivatization of
compounds bearing different amino groups[35,77]. The results
provide a glance at the behaviour of sets of competing
constitutional dynamic processes displaying kinetic and
thermodynamic complexity and leading to the emergence of
advanced features such as present in out-of-equilibrium states [78]
and non-linear kinetics [79] in constitutional dynamic systems.
3
4 + A + D + E +
F
[d]
1.4
3.5
21
-
27
29
35
16
9
58
63
65
[d]
-
[d]
[d]
-
-
[a] Reaction times indicate the time at which data were collected [b] Error
in 1H-NMR integration: 5%. [c] n.d.; not determined. [d] Compound not
formed.
To summarize, imine formation from aldehyde 4 with
different amino derivatives (A, D, E, and F) in CD3OD at 25oC,
was dominated by imine 4A at early times indicating that this
imine was in all cases the kinetic product. The most stable imines
were 4D and especially 4F (thermodynamic products).
In
Experimental Section
contrast to the case of aldehyde 3, compound 4E did not form
significantly (about 4 %) when in competition in the presence of
all four amino compounds (A, D, E, and F). That 4F is markedly
favoured thermodynamically, possibly due to the higher basicity
of the hydrazine amino group (and therefore also of the hydrazine
=N- site), resulting in stronger hydrogen bonding with the phenolic
hydroxyl group of the salicyl residue.
General aspects: All reagent and solvents were purchased at the highest
commercial quality and used without further purification. Reagent: Sodium
5-formyl-2-methoxybenzenesulfonate was purchased from Janssen
Chimica (96%). Pentylamine (98.5%), O-methoxylamine (98%), O-
benzylhydroxylamine (99%), methylhydrazine (98%), 2-pyridyl aldehyde
(99%), phenylhydrazine (97%), benzhydrazide (98%), NaH2PO4 (99%),
and Na2HPO4 (99%) were purchased from Sigma Aldrich. Salicylaldehyde
(99%) and pyridoxal-5-phosphatehydrate (98%) were purchasedfrom Alfa
Aesar. Deuterated solvents were purchased from Euriso-TOP and used
without further purification. Column chromatography (CC): Gedurun silica
gel 60 (230 – 400 mesh, 40-63 m, Merck). 1H and 13C NMR spectra were
recorded on a Bruker Avance 400 spectrometer; referenced to the solvent;
 in ppm, J in Hz. Solution pH was measured with a Mettler Toledo pH
meter.
Conclusions
The results described herein constitute an investigation of
kinetic and thermodynamic features of imine formation between
several aldehydes and different types of amine compounds. The
formation, in aqueous phosphate buffer solutions at different pD
values of imines derived from sulfobenzaldehyde 1 and amino
derivatives A, B, and C occurs with a conversion efficiency in the
order 1B>1C (1A was not formed) at pD 5.0, 1C1B>1A at pD
8.5, and 1C>1B>1A at pD 11.4. Imine formation from pyridoxal
phosphate 2 and the same amino derivatives separately was
found to be very efficient in the order 2B>2C and 2A not being a
significant component. The behaviour of the dynamic covalent
libraries (DCLs) generated from the competitive reactions of an
aldehyde with an equimolar mixture of amino compounds was the
most interesting and gave indications for kinetic selectivities as
reflected in the time evolution of the fractions of the different
entities pictured in the curves and their crossings shown in
Figures 3-6 above. For the DCLs formed by sulfobenzaldehyde 1
and pyridoxal phosphate 2 with the three amino derivatives A, B,
and C, the kinetic and thermodynamic products under all
conditions were 1B/2B and 1C/2C, respectively. The favoured
compounds in an acidic medium were the oximes 1B and 2B,
whereas in basic solution the hydrazones 1C and 2C were formed
preferentially. The reaction of 2-pyridinecarboxaldehyde 3 and
salicylaldehyde 4 with each of the amino derivatives A, D, E, and
F in organic solution (methanol) showed that the sequence of
preferential product formation was in the order A < E < D < F. The
DCLs generated from the reaction of pyridine-2-aldehyde 3 or
salicylaldehyde 4 with equimolar mixtures of different amino
derivatives (A, D, E, and F), showed that the kinetic product was
always the imine 3A or 4A while the thermodynamic products
were 3D and 3F or 4D and 4F respectively. A particularly
significant result of this work resides in the kinetic behaviour of
the formation of the different constituents, displaying kinetic
selectivity, with crossings of the curves describing the relative
amounts of the constituents along the course of the reaction (see
Figures 3b,c and 4a,c) until reaching thermodynamic selectivity,
with however no firm indication that equilibrium had been
achieved. One may note that competition between imine
formation by different amino compounds may lead to out-of-
Compounds
The imine products have been isolated and characterized. Only the
imines formed from pyridoxal phosphate could not be isolated (see SI).
General procedures for the study of kinetic and thermodynamic
experiments
A typical protocol was realised by the preparation in a NMR tube of a
fresh solution of the compounds in D2O, CD3OD, CD3CN, and sodium
phosphate buffer solution. All reactions with aldehyde and amine were
carried out at room temperature with a final concentration of 20 mM and
a total volume of 600 L.
The buffer concentration was 160 mM in all cases and buffer solutions
at different pDs were made to pD 5.0 (NaH2PO4/Na2HPO4 + NaOD), pD
8.5 (NaH2PO4/ Na2HPO4 + NaOD), and pD 11.4 (NaH2PO4/Na2HPO4
NaOD). The pD was calculated using pD = pH + 0.4[47]
1) For imine formation studies: A NMR tube was first charged with
solvent. Then, the prepared solutions 200 L of aldehyde and amine (60
mM in both) were added to the NMR tube to obtain a final volume of 600
L. The NMR tubes were topped with Teflon caps to keep a constant
volume(concentration).1H-NMR spectrawere measuredimmediatelyafter
mixing.
2) For the competition reactions: The stock solutions (120 mM) were
prepared using the desired solvents. A NMR tube was first charged with
1,4-dioxane (100 L) followed by the addition of 100 L of each solution.
Finally, aldehyde was added and 1H-NMR spectra were measured
immediately after mixing and at least 8 acquisitions of the 1H-NMR spectra
were obtained for each time point.
+
.
The course of imine formation was followed by means of the signal of
the –CH=N- proton of the imine products in the 1H-NMR spectra. The %-
formation of imine was determined by integration of the imine signal of the
products referenced to the signal of an internal standard
(1,4-
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Acknowledgements
We thank the ERC (Advanced Research Grant SUPRADAPT
290585) for financial support. S.K. thanks the Khon Kaen
University (Thailand) and the Franco-Thai scholarship program
for a doctoral fellowship as well as the Thai Visiting Scholar 2017
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doctoral fellowship and the Vierrectoría de Investigaciones and
CENM from Universidad del Valle for their valuable financial
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Keywords: kinetic selectivity • thermodynamic • imine formation
• dynamic covalent chemistry
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Text for Table of Contents
Sirinan Kulchat, Manuel N. Chaur, and
Jean-Marie Lehn
Kinetic Selectivity and
Thermodynamic Features of
Competitive Imine Formation in
Dynamic Covalent Chemistry
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