Merging constitutional and motional covalent dynamics in reversible imine formation and exchange processes

Article abstract of DOI:10.1021/ja302793c

The formation and exchange processes of imines of salicylaldehyde, pyridine-2-carboxaldehyde, and benzaldehyde have been studied, showing that the former has features of particular interest for dynamic covalent chemistry, displaying high efficiency and fast rates. The monoimines formed with aliphatic α,ω-diamines display an internal exchange process of self-transimination type, inducing a local motion of either "stepping-in- place" or "single-step" type by bond interchange, whose rate decreases rapidly with the distance of the terminal amino groups. Control of the speed of the process over a wide range may be achieved by substituents, solvent composition, and temperature. These monoimines also undergo intermolecular exchange, thus merging motional and constitutional covalent behavior within the same molecule. With polyamines, the monoimines formed execute internal motions that have been characterized by extensive one-dimensional, two-dimensional, and EXSY proton NMR studies. In particular, with linear polyamines, nondirectional displacement occurs by shifting of the aldehyde residue along the polyamine chain serving as molecular track. Imines thus behave as simple prototypes of systems displaying relative motions of molecular moieties, a subject of high current interest in the investigation of synthetic and biological molecular motors. The motional processes described are of dynamic covalent nature and take place without change in molecular constitution. They thus represent a category of dynamic covalent motions, resulting from reversible covalent bond formation and dissociation. They extend dynamic covalent chemistry into the area of molecular motions. A major further step will be to achieve control of directionality. The results reported here for imines open wide perspectives, together with other chemical groups, for the implementation of such features in multifunctional molecules toward the design of molecular devices presenting a complex combination of motional and constitutional dynamic behaviors.

Full text of DOI:10.1021/ja302793c

Article
pubs.acs.org/JACS
Merging Constitutional and Motional Covalent Dynamics in
Reversible Imine Formation and Exchange Processes
Petr Kovarícek and Jean-Marie Lehn*
̌
̌
Laboratoire de Chimie Supramolec
́
ulaire, Institut de Science et d’Ingen
́
ierie Supramolec
́
ulaires (ISIS), Universite
́
de Strasbourg, 8
allee Gaspard Monge, Strasbourg 67000, France
́
S
* Supporting Information
ABSTRACT: The formation and exchange processes of
imines of salicylaldehyde, pyridine-2-carboxaldehyde, and
benzaldehyde have been studied, showing that the former
has features of particular interest for dynamic covalent
chemistry, displaying high efficiency and fast rates. The
monoimines formed with aliphatic α,ω-diamines display an
internal exchange process of self-transimination type, inducing
a local motion of either “stepping-in-place” or “single-step”
type by bond interchange, whose rate decreases rapidly with the distance of the terminal amino groups. Control of the speed of
the process over a wide range may be achieved by substituents, solvent composition, and temperature. These monoimines also
undergo intermolecular exchange, thus merging motional and constitutional covalent behavior within the same molecule. With
polyamines, the monoimines formed execute internal motions that have been characterized by extensive one-dimensional, two-
dimensional, and EXSY proton NMR studies. In particular, with linear polyamines, nondirectional displacement occurs by
shifting of the aldehyde residue along the polyamine chain serving as molecular track. Imines thus behave as simple prototypes of
systems displaying relative motions of molecular moieties, a subject of high current interest in the investigation of synthetic and
biological molecular motors. The motional processes described are of dynamic covalent nature and take place without change in
molecular constitution. They thus represent a category of dynamic covalent motions, resulting from reversible covalent bond
formation and dissociation. They extend dynamic covalent chemistry into the area of molecular motions. A major further step
will be to achieve control of directionality. The results reported here for imines open wide perspectives, together with other
chemical groups, for the implementation of such features in multifunctional molecules toward the design of molecular devices
presenting a complex combination of motional and constitutional dynamic behaviors.
(dynamers).7b,c It deserves particular attention in view of the
1. INTRODUCTION
Dynamic covalent chemistry (DCC)1,2 rests on the implemen-
ubiquity of the amino function in substances of interest in
chemistry, biology,7c,d and materials science.7a As it proceeds
tation of reversible covalent reactions for the generation of
with the liberation of water, its dynamic character depends on
dynamic covalent/combinatorial libraries (DCLs) of constitu-
and may be controlled by the presence of water.
ents from the reversibly connecting components. The
elaboration of DCLs presents two major requirements: (1)
To further extend its scope in the realm of DCC, we
undertook the exploration of the imine forming and exchange
high and (as much as possible) fast conversion of components
reactions of a number of aldehydes with typical amines. It led
into equilibrating library constituents; (2) fast component
much further than simple molecular reactivity and recognition,
exchange and incorporation with concomitant reequilibration
uncovering some remarkable features involving both constitu-
of constituents on addition of extraneous components to the
equilibrating set. A third feature of much interest is the ability
of a DCL to respond to external physical stimuli or chemical
effectors, and thus to undergo adaptation.
tional and motional covalent processes.
We herewith report specially attractive processes involving
the imines of salicylaldehyde (SALAL),3b,8 adding novel facets
to the chemistry of this extensively investigated molecule. They
Among the reversible covalent reactions one may consider
display remarkable formation and exchange features, of much
the condensation of an amino group with a carbonyl
interest for DCC,8d,e and may act as an “imine clip”, whereby
functionality to form an imine/Schiff base is of special interest.
an internal hydrogen bond is established between imine
nitrogen and the neighboring hydoxyl group. We have
furthermore found that imines formed by SALAL with
oligoamines (such as ethylene diamine, diethylene triamine,
It has been widely explored across the various types of CN
compounds (regular imines, hydrazones, acylhydrazones,
oximes) as well as in terms of its physicochemical features.1−4
Reversible imine formation processes have been imple-
mented for the search of biologically active substances,5 for the
generation of dynamic nanoarchitectures1,2,6 and for the
development of dynamic materials,7 such as dynamic polymers
Received: March 29, 2012
Published: May 14, 2012
© 2012 American Chemical Society
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etc..) display intramolecular nondirectional motional processes,
involving transfer of the salicylidene group between amino
groups by reversible covalent bond formation, that bear relation
to the synthetic molecular “machines”9 and biological motor
proteins10 areas, very actively investigated in recent times. We
complement these results by a comparison with the behavior of
pyridine-2-carboxaldehyde (PYRAL)11,12 and of benzaldehyde
(BENZAL)13 as reference compounds. Imine formation by the
related pyridoxal-5-phosphate has been extensively studied in
the literature, in view of its importance as biological
cofactor,8a,14 and the present data may also have implications
for the related transamination reactions.
Group transfer through making and breaking of covalent
bonds has been described for several functional groups, such as
acyl or borinyl transfer.15 The dynamic behavior of imines is of
special interest (see in particular ref 1c) in view of its
widespread role in chemistry1,2 and biochemistry5 as well as in
materials science.7
rates of formation, and high rates of exchange, a mixed
aqueous−organic solvent, aqueous acetonitrile (CH3CN/H2O,
7/3), was chosen, which in addition to ensuring a wide range of
solubility also allowed the observation of novel dynamic
features.
With the selection of n-propylamine as common amine
partner, the reaction with the three aldehyde counterparts,
SALAL, PYRAL, and BENZAL, was investigated under
reversible conditions. Imine formation from aldehyde and n-
propylamine (20 mM each) was directly observed by 1H NMR
in CD3CN/D2O (7:3 v/v) solution (2 M triethanolamine
buffer, pH = 8.73 0.01, uncorrected for deuterium isotope
effect, throughout the measurements).
Although PYRAL reacted fastest, SALAL showed both high
conversion and high formation rate (in agreement with the
literature data),3b,8b possibly involving a stabilizing “imine clip”
effect by formation of a hydrogen bond between the imine
nitrogen and the neighboring OH group. The presence of such
a hydrogen bond has been extensively documented in
numerous crystal structures.17
To further analyze the origin of the observed reactivity,
kinetic experiments were performed on a series of substituted
derivatives of SALAL. The calculated rate constants fitted very
well a second-order kinetic model and correlated with the
corresponding Hammett σp constants (see Supporting
Information [SI], part 3). They increase with increasing
electron-withdrawing character of the substituent in para
position to the hydroxyl group. This result is in line with the
role of hydrogen bonding on the reactivity of SALAL, described
in literature, although direct comparison is difficult due to the
different conditions used.8b,18
In more general terms, the results reported here represent a
combination of constitutional and motional dynamic covalent
processes (a feature envisaged earlier16) within the same
system, as illustrated schematically in Scheme 1. They lead to
Scheme 1. Schematic Representation of the Merging of
Constitutional and Motional Dynamic Covalent Processes,
Involving: the Reversible Formation of Imines from a
Carbonyl Compound (red object) and a Terminal Diamine
(left), the Exchange of Diamines through Transimination
(blue frame) and the Back and Forth Motion of the Carbonyl
Moiety between the Terminal Amine Sites (red frames)
Transimination (i.e., amine exchange) experiments were
conducted by addition of isopentylamine to the equilibrated
solution of the formation reaction (thus decreasing the initial
concentration to 18.2 mM), and the process of formation of the
1
new imine was again followed by H NMR. Exchange was too
fast for the imines formed by BENZAL and PYRAL with
propylamine, and thus only results for SALAL were obtained.
The kinetic data for both formation and exchange are given in
Table 1. Interestingly, this imine exchange was found to follow
Table 1. Kinetic Data for Imine Formation with n-
Propylamine (top) and for Amine Exchange of the Resulting
Imine with i-Pentylamine (bottom)
a
aldehyde
k [10−3 M−1 s−1
]
conversion [%] half-life [s]
R2
BENZAL
SALAL
61.1 0.9
71.4 0.4
20
77
61
818
700
248
0.88
0.99
0.98
the notion of Dynamic Covalent Motions (DCMs), concerning
motions that result from reversible covalent bond formation
and dissociation within molecules, rather than by changes in
noncovalent arrangements within supramolecular architectures.
By extension, the processes uncovered also bear on the design
of nanochemical devices of artificial as well as biological
significance, whereby simple (ald)imine systems represent
prototypes of entities that may undergo both intramolecular
displacement motions and intermolecular exchange of their
parts, thus enabling, in principle, adaptation by structural
variation.
PYRAL
202
2
n-
propylimine
of
conversion to i-
pentylimine [%]
half-life
a
k·K [M−1 s−1
]
[s]
R2
BENZAL
SALAL
−
50
50
50
<20
76
−
0.97
0.73 0.02
PYRAL
−
<20
−
a
The half-life indicated is calculated from the rate constant and initial
concentration of 20 mM or 18.2 mM, respectively; study was
performed in a mixture of CD3CN/D2O (7:3 v/v) with triethanol-
amine buffer (pH = 8.73) with 20 mM starting concentration of
reagents (aldehyde + n-propylamine) in 1:1 ratio and then followed by
NMR. Exchange experiments were performed on samples equilibrated
for 3 days, adding 1 equiv of i-pentylamine (decreasing initial
concentration to 18.2 mM) and followed by NMR.
2. RESULTS AND DISCUSSION
2.1. Salicylaldimine Formation and Exchange Pro-
cesses. In order to promote high efficiency of formation, high
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first-order kinetics at the pH used (8.73). Very extensive studies
of carbonyl + amine reactions have been performed,3,8
indicating that formation or breakdown of the intermediate
carbinolamine (hemiaminal) may be rate determining, depend-
ing on conditions, e.g., pH. The same holds for amine exchange
involving an aminal intermediate.3 Explanation of the kinetic
model is given in the SI, part 3.
The rate of intermolecular amine exchange in the present
case was found to be concentration dependent, as expected for
an intermolecular process (Table 1.). Thus, dependence on
concentration is a signature, and will be taken as such, of the
intermolecular nature of a given process in the much more
complex cases involving diamines and polyamines to be
discussed below.
In fact, transimination can be performed as exchange of
either the amine part (discussed above) or the aldehyde part.
Thus, addition of 1 equiv of SALAL to the equilibrium mixture
of PYRAL + n-propylamine (Table 1) leads to a reequilibration
of the mixture giving 24% and 76% of the n-propylimines of
PYRAL and SALAL, respectively. Similarly, when equilibrated
mixtures of PYRAL + i-pentylamine and SALAL + n-
propylamine are combined, reequilibration takes place again
to give an equimolar mixture of n-propyl- and i-pentylimines of
PYRAL (45%) and SALAL (55%).
Figure 1. Oligoamines and aldehydes used in this study and their
condensation products with an aldehyde: aminal, monoimine, and bis-
imine.
1
A 1/1 mixture of SALAL and C2-DA displayed very broad H
NMR signals for the CH2 groups and broadened signals for the
imine protons, whereas the signals of the aromatic protons were
sharp. Signal integration showed that these bands belonged to
the monoimine (∼55% based on aldehyde). The bis-imine
(∼45% based on aldehyde) was also formed but presented the
expected sharp peaks, while the aminal of SALAL is not
observed if the imine can be formed, as documented in the
literature.20 Moreover, no signal was observed for a −CH(O)-
(N) proton corresponding to the hemiaminal that would form
by addition of a water molecule to the imine (expected around
5−5.5 ppm). The presence of the very broad peaks at a
chemical shift between those expected for CH2 protons next to
the CN group and next to an NH2 group was interpreted as
indicating the operation of a kinetic process in the monoimine,
whereby the two CH2 groups exchange at a rate compatible
with the NMR time scale.
Both experiments illustrate the constitutional exchange
expected for exchanging aldehyde/amine systems.
2.2. Motional and Constitutional Dynamics in
Salicylaldimines of Aliphatic Diamines: Intramolecular
Group Transfer and Intermolecular Component Ex-
change. (a) The amine exchange process on imines may
occur either by hydrolysis followed by recondensation or by
addition of the new amine to the imine double bond to give a
gem-diamine/aminal intermediate. The latter may be facilitated
by the “imine clip” effect and involves trivalent/tetravalent
interchange at the carbon center, as reversible conversion
between imine and aminal occurs. It follows that, if the amine
groups undergoing exchange are linked, as in α,ω-aliphatic
diamines, an intriguing situation presents itself, whereby
intramolecular self-exchange takes place, with bonding fluctua-
tion on imine−aminal−imine interconversion, via a cyclic
aminal that may or may not be present in significant amount,
depending on the relative stability of the two entities in the
conditions used (Scheme 2). Such a process thus performs a
motional-type displacement of two molecular moieties relative
to one another.
1
Variable-temperature (VT) H NMR measurements showed
a coalescence of the two broad signals at a temperature of about
37 °C (Figure 2). The corresponding rate was found to be
independent of the concentration and of the ratio between
SALAL and C2-DA, indicating that the process was intra-
molecular. Thus, NMR line-shape analysis was performed in the
temperature range of 10−75 °C (steps of 5 °C) at three
different concentrations (4, 20, and 100 mM) and three
different ratios (2:1, 1:1 and 1:2) of reagents. In all cases, the
Scheme 2. Mechanism of the Intramolecular Exchange
Process Displayed by the Monoimines formed by SALAL
with Aliphatic Diamines H2N−(CH2)n−NH2
same coalescence temperature of 37
1 °C was observed,
which clearly confirmed that the process was of intramolecular
nature, independent of concentration as expected for such a
unimolecular reaction at equilibrium. Furthermore, line-shape
analysis (see SI, Figure SI-05-1) gave very consistent rate data
suitable for fitting the Eyring equation to obtain the activation
enthalpy ΔH = 9.3 kcal mol−1 and entropy ΔS = −15.8 cal
mol−1 K−1. The rate of exchange was also examined for the
effect of pH. The coalescence temperature of the two
methylene signals of the monoimine was found to be
independent of pH in the range 9.3−12.0; below pH 9 only
very small amounts of monoimine were formed and for pH
above 12 the acetonitrile/water mixture tended to phase
separate. For all following results, the pH of the mixture was
adjusted to 10.7 0.1 by DCl or NaOD.
Indeed, the reactions of the aldehydes with the simple
aliphatic diamines H2N−(CH2)n−NH2 (Figure 1) turned out
to follow such a scheme. When SALAL, BENZAL, and PYRAL
were mixed with a diamine in chloroform, a mixture of
1
monoimine and bis-imine was obtained, and sharp H NMR
signals were observed, as one would expect19 (see SI, Figures
SI-04-1 and SI-04-2). However, the situation was very different
when the same reactions were run in CD3CN/D2O (7:3 v/v).
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1
Figure 2. Variable-temperature 400 MHz H NMR of the CH2−CH2
signals of N-salicylidene-1,2-diaminoethane, the monoimine of SALAL
with C2-DA, in the temperature range 25−55 °C from bottom to top
(steps of 5 °C) in CD3CN/D2O (7:3 v/v). The sharp signal at 2.6
ppm (#) is free C2-DA, the singlet at 3.95 ppm (*) is the signal of the
methylene groups of the bis-imine. The water signal moving with
temperature in the 3.5−4.0 ppm region has been truncated for clarity.
Figure 3. Two dimensional covariant NOESY spectrum of SALAL
with en2N3 in CDCl3/CD3CN (1:1 v/v) at 50 mM concentration of
both regents in 1:1 ratio. Diagonal signal assignment: a is methine
signal of imine and bis-imine, b is N−CH2− group of the imines, c
is −CH2−NH2 of the imines, d contain signals of unreacted en2N3.
Cross-peak assignment: 1 is imine-to-aminal exchange cross-peak, 2 is
intramolecular imine exchange cross-peak, 3 is intermolecular
exchange cross-peak. Diagonally symetrical peaks are labeled with
prime.
Intermolecular exchange with the free diamine present in
solution was also observed but could not be quantified because
of the breadth of the corresponding signal in the monoimine
with which exchange is taking place.
The mechanism of intramolecular exchange between the two
methylene groups N−CH2 and H2N−CH2 in the mono-
imine requires going through a cyclic aminal form as shown in
Scheme 2 for the case of SALAL and C2-DA. Such a process
represents an intramolecular molecular motion involving the
continuous exchange of the salicylidene group between the two
ends of the C2-DA molecule in a binary rhythm of either
“stepping-in-place” or “single-step” type.
Table 2. Inter- and Intramolecular Exchange Rates for End-
to-End Transfer (see Scheme 2) in Monoimines of
Aldehydes and Aliphatic Diamines [Hz] in 1:1 Ratio at 25
°C in CD3CN/D2O (7:3 v/v) and 20 mM Concentration
n =
H2N−(CH2)n−NH2
2
3
4
5
SALAL strongly prefers the monoimine state,19 and the
presence of aminal was only detected by two-dimensional (2D)
1H NMR NOESY studies via cross-peaks between imine and
aminal protons, although the aminal proton is hardly visible in
the 1D 1H NMR spectrum. The corresponding NOESY
spectrum is shown in Figure 3 as a typical illustration.
(b) In order to investigate the possibility of exchange
between more distant terminal amino groups, similar line shape
SALAL
b
intra
365
187
10
−
a
a
inter
−
0.22
−
0.32
PYRAL
intra
0.17
0.5
1
1.4
0.60
c
c
aminal opening r′
aminal closing r
0.44
1.35
−
−
74
a
1
Exchange observed, but broad signal shapes or low intensities prevent
b c
analysis and/or H NMR EXSY studies (see SI, part 8) were
quantification. Exchange not observed. No aminal signals observed
conducted with the longer aliphatic diamines H2N−(CH2)n−
NH2, C3-DA, putrescine (C4-DA, n = 4), and cadaverine (C5-
DA, n = 5). The independence of the rate of exchange of the
two N−CH2 groups from concentration was taken as diagnostic
of the intramolecular nature of the process. The rates of end-to-
end exchange decreased rapidly on chain lengthening, as may
be expected (Table 2), going from 365 Hz for C2-DA down to
10 Hz for n = 4 in C4-DA and to not observable for n = 5, as
the intermolecular exchange becomes faster than the intra-
molecular one (see also c below).
The intramolecular process was similarly observed with
PYRAL and BENZAL, but at widely different rates (Table 2).
With C2-DA and C3-DA, PYRAL forms stable cyclic aminals
which predominate over the imines in solution. Nevertheless,
dynamic equilibrium between the ring and chain forms takes
in the spectrum; therefore, value can not be calculated.
place and can be quantified. To make the rates of such
exchanges comparable with other end-to-end exchanges, they
were calculated according to Scheme 2 from the residence
times 1/r and 1/r′ of the protons in the two sites, as [2(1/r +
1/r′)]−1 where r is rate of ring closing and r′ is rate of ring
opening, as determined by EXSY NMR. Since the cyclic
intermediate is symmetrical, the chance of opening on each
nitrogen site is the same, giving 50% probability to go back and
50% probability to perform end-to-end exchange. For C4-DA
and C5-DA no aminals are observed.
PYRAL showed much slower intramolecular exchange than
SALAL as well as the presence of both the monoimine and the
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aminal in a ratio of about 1:2.7 for C2-DA. With C2-DA or C3-
DA, the intermediate aminal is the major species present in the
solution,20 in clear contrast to salicylaldehyde, where aminal is
not seen. On the other hand, this observation supports the
existence of cyclic aminal as intermediate of intramolecular
exchange, even when it is not detected. The formation of
intermediate geminal diamines has been studied in detail for
pyridoxal-5-phosphate.14b,d
each) gave an H NMR spectrum containing the CHN
proton signals of the mono- and bis-imines formed, together
with broad signals for the CH2−CH2 protons, resulting from
the superposition of the corresponding signals of each
monoimine (see Figure 4, below and Figure SI-07-4 in SI).
Similarly to PYRAL, BENZAL also gave a mixture of imine
and cyclic aminal, but here the imine was the major product, in
agreement with published results.20 The signal shape in this
case disqualifies EXSY for evaluation of the exchange rates, and
the coexistence of both imine and aminal prevents the end-to-
end exchange rate determination by line-shape analysis,
allowing only a rough estimation of ∼15 Hz. However, VT-
NMR in the range 25−75 °C again showed signal broadening
but coalescence could not be reached (see Figures SI-04-11 and
SI-04-12 in SI). Thus, the phenomenon is general and lends
itself to a variety of far-reaching extensions (see below).
(c) Intermolecular constitutional exchange may occur by
reaction of free diamine with monoimine and compete with
the intramolecular process. It can be observed by 2D-NMR
spectra where cross-peaks indicate exchange between free
diamine and monoimine giving the very same imine and free
diamine. Indeed, cross-peaks in the 1H NMR NOESY spectrum
of SALAL with C3-DA in CD3CN:D2O (7:3 v/v) were
indicative of an intermolecular exchange (see Scheme SI-07-1
in SI). The intermolecular nature of the process was confirmed
by the concentration dependence of the exchange rate, which
was much slower than the intramolecular process (Table 2).
EXSY H NMR studies offer a powerful access to both the
intermolecular and the intramolecular exchange rates (see SI,
part 8). The data for SALAL and C5-DA gave a good fit for first
order kinetics.
Furthermore, due to formation of bis-imine, another
intermolecular process can be observed where two monoimines
react to give the bis-imine and free diamine. The rates of
intermolecular exchange can be evaluated by EXSY (SI, parts 7
and 8) and, unlike the intramolecular process, they are
concentration dependent (following first order kinetic, vide
supra). The rates of the intra- and intermolecular exchange
processes are given in Table 2.
Figure 4. Modulating the internal motion speed by introducing
substituents on salicylaldehyde core. The 400 MHz H NMR spectra
1
of the methylene signals of the monoimines of C2-DA with substituted
derivatives of SALAL; from bottom to top: 4-diethylamino-, 5-
hydroxy-, no substitution, 5-chloro-, and 5-nitro-salicylaldehyde. In the
bottom spectrum, the signals left of the water signal (at 3.9 ppm) are
those of the methylene groups of the bis-imine, the methylene group
next to the monoimine nitrogen, the methylenes of the ethyl groups,
the methylene group next to the amino nitrogen of the monoimine,
the methylene groups of the free C2-DA. Note: the peaks of the ethyl
groups of 4-diethylaminosalicylaldehyde have been truncated for
clarity, and the underlying methylene signal (dotted line) has been
reconstituted by deconvolution.
21
1
These data indicate again the occurrence of equilibration and
constitutional dynamics by intermolecular exchange of both the
amino and the salicyledene groups.
e) Taken together, the data above indicate that monoimines
of α,ω-diamines undergo both internal and intermolecular
exchanges of components, thus merging motional and constitu-
tional dynamics. The internal process amounts to a stepping-in-
place when the initial imine is regenerated backward from the
intermediate aminal and to taking a single step forward when the
salicylidene group goes over to the other nitrogen site (Scheme
2).
2.3. Controlling the Speed of Intramolecular Group
Transfer. As the intramolecular group transfer process
described above is of motional type (see also below), it is of
much interest to be able to modulate its speed. There are
several ways to achieve such a control.
2.3.1. Introduction of Substituents. The aromatic core of
salicylaldehyde allows for a wide range of substitution in up to
four positions. Introducing various substituents from electron-
withdrawing to electron-donating, both the electrophilicity of
the carbonyl (or imine) and the acidity of the OH group are
modified. These two factors markedly influence the rate of the
internal motion of C2-DA as can be seen in Figure 4, showing
the signals of the two CH2 groups of the monoimine. The
spectrum of the monoimine of C2-DA with the most electron-
donating 4-diethylamino group substituted SALAL shows two
well separated signals with visible triplet structure of the signals.
The less electron-donating 5-hydroxy group gives two well
separated but broad signals, similar to SALAL itself. The
electron-withdrawing 5-chloro derivative presents only one
(d) It was shown above (Table 2) that imines formed by
SALAL with diamines present two dynamic features: intra-
molecular motion and intermolecular exchange. When only one
diamine is present in the solution, the intermolecular exchange
results in the same composition of the mixture as before the
reaction in a degenerate process. However, when there are two
or more different diamines present, the imine can react with
either of these amines, thus undergoing constitutional change
by transimination. In the simple case where SALAL was mixed
with 1 equivalent of both C2-DA and C3-DA (each component
1
at 20 mM concentration in CD3CN/D2O 7:3 v/v), the H
NMR spectrum showed the intramolecular motions in both
monoimines (although the signals of the C2-DA and C3-DA
monoimines are very close and very broad and therefore cannot
be separated), while 2D-EXSY experiments revealed incorpo-
ration of both diamines into the monoimines with rates of
intermolecular exchange similar to those obtained with only
one diamine at the same concentration (0.45 0.05 for C2-DA
and 0.34 0.01 Hz for C3-DA).
In the same manner, addition of 5-chloro-SALAL to an
equilibrated mixture of 5-hydroxy-SALAL and C2-DA (1 equiv
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broad signal for both CH2 groups with a coalescence
temperature around 12 °C. The most electron-withdrawing
substituent, 5-nitrosalicylaldehyde, displays only one relatively
sharp signal for both CH2 groups. The composition of the
mixtures (monoimine, bis-imine, free aldehyde) is given in the
SI for the five cases studied (SI, Table SI-05-3).
different effects, one may expect to be able to cover a range of
rates even much larger than the 4 orders of magnitude achieved
here.
2.4. From Stepping-in-Place to Taking Steps. The
intramolecular exchange process described above for simple
aliphatic α,ω-diamine molecules (Scheme 2) becomes partic-
ularly attractive when one considers its extension to more
complex polyamino molecules.
VT-1H-NMR experiments were performed for four deriva-
tives (4-diethylamino, 5-chloro, 5-hydroxy, and 5-nitro) of
SALAL and the spectra were evaluated by line-shape analysis to
obtain the rates of motion. These rates were then also fitted by
the Eyring equation, and activation parameters were calculated.
The values obtained are given in SI, Table SI-05-3.
(a) In the case of the branched trisamine compound tren
(tris(2-aminoethyl)amine), EXSY studies enable insight into
the behavior of the reaction mixture it generates with SALAL
(1:1 ratio, 20 mM) in CD3CN/D2O (7:3 v/v), where three
different imines are observed: monoimine (59%), bis-imine
(28%), and trisimine (10%) and 3% of aldehyde remains
unreacted. Cross-peaks in the NOESY spectrum revealed
multiple exchange processes involving specific signals. The data
from the azomethine signals indicate that the imines are
interchanging intermolecularly between themselves rather than
reacting with the small amount of available aldehyde. In the
aliphatic region, the spectrum is much more complicated.
Nevertheless, the same exchange pattern as described for the
azomethine protons can be observed here as well. Furthermore,
exchange cross-peaks of N−CH2− protons with H2N−
CH2− protons are clearly visible. Among all the exchange
processes, two concentration-independent ones, clearly assign-
able to monoimine and bis-imine intramolecular interchanges
(Scheme 3), could be evaluated with rates of 3.84 0.16 and
1.13 0.18 Hz, respectively.
The range of motion speeds (see Table 3) is remarkably
wide: while substitution by a slightly electron-donating 5-
Table 3. Rates of Internal Exchange Motion in the
Monoimines of C2-DA with Substituted Derivatives of
SALAL, at 25 °C in CD3CN/D2O (7:3 v/v, pH maintained at
10.7 0.1)
substituent on
4-Et2N 4-OH 5-OH
20 108 148
H
5-Cl
5-NO2
SALAL
motion rate [Hz]
365
1040 ∼17 000
hydroxy group lowers the rate to approximately half of that of
unsubstituted SALAL, the strong electron-donor 4-diethylami-
no group drops the rate to as low as 5% of its original value. A
4-hydroxy substitution has an effect very similar to that of a 5-
hydroxy group, although the activation enthalpy is close to that
of the 4-diethylamino group, differing mostly in activation
entropy (see SI, Table SI-05-3). Introducing electron-with-
drawing groups has an even larger effect: the weakly electron-
accepting 5-chlorosalicylaldehyde increases the motion rate 3
times compared to SALAL. The strongest electron-acceptor,
the 5-nitro group, shoots the motion rate up into the range of
∼17 kHz, a 50-fold increase in speed, thus covering a range of 3
orders of magnitude!
Scheme 3. Intramolecular Exchange Processes in the Mono-
and bis-imine Formed by SALAL with the Triamine Tren
2.3.2. Solvent Composition. The rate of intramolecular
exchange in the SALAL-C2-DA monoimine is also very
dependent on the composition of the solvent. Gradually
changing the CD3CN/D2O solvent composition from 5:5 to
6:4, 7:3, 8:2, and 9:1, the coalescence temperature of the CH2
1H NMR signals increased from 29 °C to 32, 37, 46, and 80 °C,
respectively, corresponding to rates of internal motion at 25 °C
from 552, to 442, 365, 226, and 158 Hz, respectively. In pure
d3-acetonitrile the rate of intramolecular exchange is only 7 Hz
at 25 °C, and obviously coalescence cannot be reached since
the boiling point of acetonitrile is 82 °C. The exchange rates
have been determined by line-shape analysis over a range of
temperatures of about 50 °C and used to calculate the Eyring
activation parameters (see SI, part 8). It is thus possible to
modulate the rate of the process by changing the nature or the
composition of the solvent in a much more delicate way
compared to core substitution.
(b) A second category of polyamines consists of linear
polyamines. The behavior observed above for monoimines of
diamines suggests an especially intriguing extension into the
area of motional dynamics involving relative displacements of
two linked molecules. The end-to-end transfer of an aldehyde
residue on a diamine unit, together with the formation of an
intermediate aminal, leads to envision systems where the
aldehyde moiety would effect a back-and-forth, nondirectional
“walk” along a polyamine chain such as diethylenetriamine
(en2N3) and its longer analogues, triethylenetetraamine
(en3N4) and tetraethylenepentamine (en4N5), as well as the
biogenic amines spermine and spermidine, which contain
amino sites separated by two, three, or four methylene groups
(Figure 1).
Such processes, where a given molecule moves along another
one, are of great interest as nanomechanical molecular devices
both in biology and in nanoscience,7,22 two areas of high
current activity. There are numerous cases of motor proteins
(of the dyenin, myosin, and kinesin types) performing
displacements along another protein acting as molecular track
(e.g., actin or tubulin) in cells.10 The design of synthetic
systems effecting analogous molecular motions has also
attracted much attention.22 The present case would represent
a very simple implementation of such a behavior. One may
further note that, whereas in the biological systems the
attachment of the molecules and the walking process involve
(c) Finally, temperature variation allows for a very gradual
modification of exchange rates.
In total, the speed of internal group displacement motion
may be modulated easily in three different ways: coarse
adjustment by introduction of substituents on the SALAL core,
more gentle adjustment by changing the solvent composition,
and fine-tuning by temperature. Of course, other factors may
affect the speed of this process, such as pH (see SI, part 4),
addition of a chemical effector, etc. By a combination of these
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formation and rupture of supramolecular interactions, in the
present case, the motion is enabled by dynamic covalent bond
forming and breaking. Furthermore, whereas two mechanisms of
displacement have been envisaged for the biological motions
(hand-over-hand and inchworm),22,23 the mechanism of the
motional process envisioned here (Scheme 4) would be of the
beneficial, because it makes the spectra much easier to decipher
compared to PYRAL, which forms multiple aminals and mixed
imine-aminals, leading to a complex H NMR spectrum, very
difficult to unravel and impossible to quantify. On the other
hand, when salicylidenpropylamine is treated with N,N′-
dimethylethylenediamine in CDCl3 the aminal is obtained
with K = 1.4, as the imine cannot form.
1
To investigate whether the aldehyde moiety is indeed
“walking” along the polyamine track molecule, the oxa-analogue
of en3N4, where the two internal nitrogens are replaced by
oxygens, O2-en3N2, was studied. The absence of the secondary
amines on the track prevents formation of aminals and iminium
states and, indeed, prevents intramolecular exchange as the
observed process was found to be concentration dependent,
indicating intermolecular exchange, with first-order kinetics.
The exchange rate values were 0.30 0.02 and 0.17 0.02 Hz
for 20 and 8 mM solutions, respectively. The case of O-en2N2
is discussed in SI, part 10.
Scheme 4. Mechanism of the Dynamic Intramolecular
Inchworm-Type Motion of a Salicylidene Residue along an
Oligoamine Chain
To further support the “walking” mechanism, the derivative
of en3N4 with two SALAL moieties attached as imines and a
third one forming a central aminal (bis-imine-aminal),
Sal3en3N4, was synthesized24 and treated with methoxyamine,
expecting that it would first react with the imine double bond
and thus release one of the terminal NH2 groups. As SALAL
prefers to form a terminal imine, the group of the central
aminal should thereafter move from the central position toward
the end of the en3N4 molecule, through a lateral aminal to the
terminal nitrogen site, to give a bisimine (Scheme 5). Reacting
inchworm type and be processive,22a as the two moieties
remain attached along the way. Nevertheless, detachment can
occur by intermolecular reaction with an external partner (such
as a solvent molecule or an amine group) at the terminal imine
or an intermediate immonium state.
Scheme 5. Representation of the Reaction of Sal3en3N4 with
Methoxyamine, Removing One Terminal Salicylidene
Residue (left) and Performing Intramolecular Steps
(bottom) Shifting the Central Salicylidene Group to the
a
When 2D-EXSY 1H NMR measurements were performed on
the reaction of SALAL with en2N3 or en3N4, cross-peaks
indicated that intramolecular exchange was taking place
between the two ends of the polyamine moiety. In the case
of en4N5 it could not be observed, as it is probably so slow that
it is hidden under faster intermolecular exchange. The data
from these EXSY experiments are given in Table 4. The
Terminal Site (right)
Table 4. Intramolecular and Intermolecular Exchange Rates
for SALAL and Linear Polyamines
a
The signal assignment refers to the kinetic experiment in Figure 5.
polyamine
en2N3
en3N4
en4N5
b
intramolecular rate [Hz]
intermolecular rate [Hz]
0.60 0.05
0.28 0.03
−
a
b
b
−
−
0.40 0.04
a
Rate of first-order intermolecular exchange given at 20 mM
Sal3en3N4 with one equivalent of methoxyamine (free base) in
CDCl3 at 25 °C gradually gave rise to the signals of
monoimine-aminal. A steady-state concentration was reached,
and no further increase in concentration was observed as this
monoimine-aminal subsequently transformed into the α,ω-
bisimine of en3N4. The corresponding kinetic profile is shown
in Figure 5. Because the reaction was run in CDCl3 with no free
SALAL present, an intermolecular mechanism can be excluded,
thus confirming the linear displacement process (see Scheme 5
and Figure 5, details in SI, part 9). Further evidence in favor of
the motion of the SALAL moiety along the en3N4 chain is
provided by the observation that N1,N4,N4-tris(o-hydroxyphe-
nylmethyl) triethylenetetramine is formed as a minor product
in the borohydride reduction of Sal3en3N4. The presence of a
terminal amine bearing two aldehyde residues may be explained
as resulting from the shift of the aldehyde residue of the central
b
concentration of both reagents. Not observed.
intermolecular exchange rate for 20 mM solutions of both
components in CD3CN/D2O (7:3 v/v) fits again very well with
first-order kinetics. The intermolecular exchange process would
correspond to the falling-off in biological motor systems.10,22
In fact, the mere existence of intramolecular exchange is not
sufficient proof that the aldehyde residue is really moving along
the polyamine strand. Indeed, a long chain might adopt a
conformation which would allow a direct “jump”-type, end-to-
end transfer of the aldehyde unit from one terminal nitrogen to
the second terminal free NH2, even though the results obtained
with cadaverine, C5-DA, indicate that such a distant jump is not
very likely to happen. The strong preference for imine
formation over aminal in the case of SALAL is here very
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observe the consecutive steps in the displacement process along
the molecular track.26
3. CONCLUSION
The results described herein on processes occurring in amine−
aldehyde systems lead to a number of conclusions.
(1) The remarkable reactivity features of salicylaldehyde
toward amines to form imines with high formation
efficiency and high exchange rates, make this carbonyl
compound highly suited for applications in dynamic
covalent chemistry.
(2) A stepping-in-place or a single-step motion by internal
degenerate exchange occurs in monoimines formed by
aliphatic α,ω-diamines with salicylaldehyde, pyridine-2-
carboxaldehyde, and benzaldehyde itself, depending on
whether the aldehyde-derived group remains on the same
nitrogen or moves to the other one.
Figure 5. Kinetic data for the reaction of Sal3en3N4 with methoxy-
amine. Signals are assigned in Scheme 5: signal H7 corresponds to the
monoimine of SALAL and en3N4 which is formed due to relatively
slow reaction between Sal3en3N4 and methoxyamine. “Signal sum”
represents the sum of the signals of aminals, imines, and oxime
(described in Scheme 5), integrated with respect to an internal
standard of n-butanol. For full NMR traces see SI, part 9.
(3) Speed control of the internal motion by varying specific
parameters (substituents, medium composition, temper-
ature, etc.) may be achieved, up to high rates of motion.
This property, studied here for diamines, should also
apply to polyamines (see point 4) and represents a
particularly sought after feature of molecular motors.27
(4) The behavior displayed by imines, described herein,
allows for intramolecular linear displacement of a
molecular group along another one, by nondirectional
shift of the aldehyde residue along linear polyamines
serving as molecular tracks. It represents a simple,
prototypical implementation of intramolecular processes
of motional-type, an area of high current interest in
biological as well as synthetic systems.9,10,22,27 A major
challenge is to introduce directionality, as has been
realized in other instances.22,27
aminal over to the terminal nitrogen site through an
intermediate iminium state.24b
The existence of such an iminium species cannot be
confirmed by NMR experiments due to its short half-life
under the conditions used. However, one might be able to trap
it by participation of a neighboring nucleophilic group. To this
end, sodium 2-formylbenzoate was reacted with one equivalent
of en2N3 in CD3CN/D2O (7:3 v/v) and compared to the
reaction with propylamine and C2-DA (see SI, part 6 for
experimental details).25 While propylamine and C2-DA give
only imine, a new peak appeared at 5.12 ppm in the reaction
with en2N3 (Figure 6.). By extensive multidimensional NMR
characterization (see SI, part 6), it was assigned to the O−CH−
N proton of the amino-lactone generated by internal addition
of the carboxylate to the iminium expected to form as a
transient species in the displacement process. This observation
points to the possibility of trapping the iminium species
occurring as intermediates along a polyamine chain and to
(5) The intramolecular displacement processes described
involve a valency increase at the connecting and moving
center. This feature may be implemented in a number of
other cases involving different centers in various
functional groups.15
(6) (a) Within the general framework of constitutional
dynamic chemistry,28 the present group displacement
processes are of dynamic covalent nature. They imple-
ment the reversible formation of covalent bonds without
constitutional change, thus preserving constitution while
generating molecular motion. They are thus covalently
dynamic but constitutionally static, and extend dynamic
covalent chemistry into the area of molecular motions.
(b) Within the framework of molecular motional devices,
the processes described here represent a category of
Dynamic Covalent Motions, resulting from reversible
covalent bond formation and dissociation. The exten-
sively studied motional processes in rotaxanes, catenanes,
and related entities are of a dynamic noncovalent nature,
occurring at the supramolecular level and involving
displacements induced by changes in noncovalent
interactions. On the other hand, motions may be
generated by conformational or configurational
changes.16,27,29
Figure 6. Comparison of the 1H NMR spectra of sodium 2-
formylbenzoate reacted with propylamine (blue), C2-DA (red), and
en2N3 (green). The signal of the O−CH−N proton of the
aminolactone formed is indicated. Full NMR characterization is
given in SI, part 6.
(7) The coexistence of intramolecular group transfer and
intermolecular group exchange in the processes displayed
by imines represents the merging of motional and
constitutional dynamics within the same system.
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(e) Ramstrom, O.; Lehn, J.-M. In Comprehensive Medicinal Chemistry
̈
Looking ahead, the results reported above suggest numerous
extensions in the area of constitutional dynamic covalent
processes, such as group transfer between sites in branched
polyamines, pattern formation on reversible multiple attach-
ment to polyfunctional amines, oriented motions along a track
seeking the thermodynamically most stable patterns or
kinetically the most easily accessible ones, exploiting internal
self-catalysis, operating fluxional degenerate exchange through
continuous bond breaking−bond making processes (that
present analogies to the epitomic molecule bullvalene30) in
multifunctional carbonyl as well as amine molecules. The
processes described here, together with their molecular motor-
type features31 make imines a class of compounds presenting a
particularly rich and wide palette of structural, conformational,
and configurational features,31b as well as of constitutional and
motional dynamic behaviors.
II; Triggle, D., Taylor, J., Eds.; Elsevier Ltd.: Oxford, 2007; pp 959.
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ASSOCIATED CONTENT
* Supporting Information
■
S
All experimental details, NMR spectra, and calculations. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
lehn@unistra.fr
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Universite
́
de Strasbourg for a doctoral fellowship
́
to Petr Kovarı
̌
ce
̌
k as well as the CNRS and the ANR 2010
BLAN-717-1 project for financial support.
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