A light-induced reversible phase separation and its coupling to a dynamic library of imines

Article abstract of DOI:10.1039/c3sc53130a

Irradiation of a 3:2 acetonitrile-water solution of the bis-pyridyl hydrazone 1 and calcium chloride causes a photo-induced phase separation, due to an increase in free calcium cations as a consequence of the photo-conversion of 1 from its E form to the Z

Full text of DOI:10.1039/c3sc53130a

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A light-induced reversible phase separation and its
coupling to a dynamic library of imines†‡
Cite this: Chem. Sci., 2014, 5, 1475
*
Ghislaine Vantomme, Nema Hafezi and Jean-Marie Lehn
Irradiation of a 3 : 2 acetonitrile–water solution of the bis-pyridyl hydrazone 1 and calcium chloride
causes photo-induced phase separation, due to an increase in free calcium cations as
a
a
consequence of the photo-conversion of 1 from its E form to the Z configuration. Complexation
studies confirmed that the former binds calcium more strongly that the latter. Acid-catalyzed back-
conversion from 1-Z to 1-E, followed by basification, leads to the regeneration of the initial single
phase. The process thus involves a photo-thermal cycle with reversible interconversion between
monophasic and biphasic states. In the presence of a dynamic library of imines generated from
hydrophilic and hydrophobic aldehyde and amine components,
a coupling to the phase
interconversion processes is achieved, leading to a dynamic redistribution of the imine constituents,
whereby amplification of the most lipophilic and the most hydrophilic imine constituents, in the
organic and the aqueous phase, respectively, is achieved by component selection. The system thus
undergoes an adaptation by the up-regulation of the fittest constituent for its specific phase. The
process is reversible, regenerating the initial distribution of constituents upon phase reunification. It
also represents the coupling of a dynamic covalent library to out-of-equilibrium conditions resulting
from the photo-generation of a kinetically trapped entity.
Received 12th November 2013
Accepted 9th December 2013
DOI: 10.1039/c3sc53130a
www.rsc.org/chemicalscience
photo-induced electron transport.9d Unrelated cases of photo-
induced phase separation have been reported.10 Furthermore,
Introduction
we have recently shown that photoisomerization of a ligand in a
supramolecular solid-state assembly leads to the release of
metal cations,11 a process that may allow for phase separation of
a binary liquid mixture.6
Binary liquid mixtures which can separate into two distinct
phases by the action of a physical stimulus or a chemical
effector have been extensively used over the years in the puri-
cation of components of mixtures,1 the development of bulk
membranes,2 the extraction of proteins,3 etc. They may also be
implemented for the modulation of the composition of
dynamic libraries, generated by dynamic covalent processes,4
and subjected to biphasic as well as to three-phase transport
conditions.5 We have recently described the coupling of such
dynamic covalent systems to reversible phase separation and
have shown that they respond by adaptation of their constitu-
ents to phase distribution through component selection.6
The induction of a phase separation by light may attract
particular interest due to its potential applications in light
controlled actuators,7 photo-driven drug delivery,8 and trans-
port across bulk liquid membranes,9 involving for instance
In our earlier exploration of the response of dynamic cova-
lent systems of imine constituents to phase separation,6 the
phase separations were produced by the addition of a chemical
effector (such as an inorganic salt or a carbohydrate) or by a
physical stimulus (e.g. temperature) to partition a mixture of
acetonitrile (AN) and water (W). Other prior work from our
laboratory demonstrated the photorelease of potassium ions
from photoswitchable acyl hydrazones.11 We now realize the
merging of these two processes by coupling phase separation
through photo-induced cation release with a dynamic covalent
system undergoing constituent redistribution by component
exchange.
More specically, we demonstrate herein, (i) the use of light
as a non-invasive technique for inducing a phase separation of a
binary mixture of two bulk solvents, AN and W, by the light-
induced release of a divalent cation (calcium) from its complex
(1-E,Ca)Cl2 with the photo-responsive ligand 1, that undergoes
photo-isomerization from its E form, 1-E, to the weaker binding
Z state, 1-Z,12,13 (ii) the reversibility of this system by acid cata-
lysed thermal back-isomerization followed by basication
leading to reunication of the binary mixture into a single
´
´
Laboratoire de Chimie Supramoleculaire, Institut de Science et d'Ingenierie
´
´
´
Supramoleculaires (ISIS), Universite de Strasbourg, 8 allee Gaspard Monge, 67000
Strasbourg, France. E-mail: lehn@unistra.fr
† Dedicated to Professor Andrew D. Hamilton for his 60th birthday.
‡ Electronic supplementary information (ESI) available: Synthesis of (a-d,6-d)1-E,
UV spectra, 1H NMR spectra, Job plots, tting for the determination of binding
constants, and X-ray structures. CCDC 971152–971155 and 971407. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/c3sc53130a
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passing that no observable strong complex was formed between
1-E and magnesium or calcium ions in dilute aqueous
solutions.14e
For the present purpose, as well as in view of the broader
signicance of the complexation of the biologically important
calcium cation, a closer examination was warranted. Indeed,
crystals of three different complexes of 1-E with calcium cations
could be obtained, depending on the counterion, by vapor
diffusion of diisopropylether into a solution of 1-E and a
calcium salt in AN or methanol (see the captions of Fig. 2, 3 and
4). The X-ray crystal structures of all three were determined,
unequivocally demonstrating the ability of 1-E to form
Fig. 1 Photoisomerization of the ligand 1-E, forming the (1-E,Ca)Cl2
complex, to the 1-Z form, inducing an increase of free Ca2+ cations in
the solution, thus causing phase separation. Phase reunification occurs
by back conversion of 1-Z to 1-E via sequential protonation and complexes with calcium cations.
restoration of the initial pH with triethylamine (see text). For clarity,
One of the complexes was found to be a dimeric anion
bridged complex of 1 : 1 stoichiometry (Fig. 2).
only the 1-Z form and the generation of free calcium ions are repre-
sented on the right hand side. The single phase used had the
composition AN–W 3 : 2 v/v, i.e. 34% AN and 66% W mole percent in
all experiments.
The second complex has a 2 : 1 stoichiometry [(1-E)2,Ca]Cl2,
with each Ca2+ ion bound in an octa-coordinated fashion
involving the six nitrogen sites of two 1-E ligands and two
chloride anions (Fig. 3). In addition, each chloride anion is
hydrogen bonded to one of the N–H sites of the pyridyl-hydra-
zone of another complex (see Fig. 1, ESI‡).
Finally, other crystals were obtained which yielded a 3 : 1
complex (Fig. 4), in which the calcium ion interacts with the
nine nitrogen sites of the three 1-E ligands. Complexes of all
three stoichiometries have been observed by 1H NMR (see Fig. 5
below and Fig. 5 in the ESI‡).
phase (Fig. 1), and (iii) the successful coupling of the photo-
thermal reversible process to a dynamic covalent library of
imines that responds to a change in the medium by adaptation
of its composition.
Results
Binding constants of 1-E and 1-Z with calcium cations. When a
suspension of 1-E (355 mM) in 3 : 2 AN–W was treated with
CaCl2 (305 mM), instead of the CaCl2-induced phase separation
Calcium binding and photo-induced reversible phase
separation by the hydrazone 1
Rationale. The photo-induced phase separation produced in expected on the basis of our previous work,6 a rapid uptake of 1-
the present work utilizes the ability of a pyridyl hydrazone E into solution was observed, giving rise to a single-phase
ligand (1) to form complexes with calcium ions (see below). This homogeneous solution at 25 ꢀC. The reverse experiment was
hydrazone has orthogonally responsive features,12 comprising also performed, wherein a solution of 3 : 2 AN–W was phase
(1) constitutional dynamics as well as double-congurational separated with CaCl2 and subsequently treated with 1.2 eq. of
dynamic properties, (2) complexation to a cation with its NNN 1-E with respect to CaCl2. Again, the rapid uptake of 1-E was
tridentate binding site,14 and (3) E to Z photochemical isomer- observed, this time accompanied by phase reunication of the
ization about the CH]N bond, stabilized by an internal AN–W biphase. Thus, it became clear that the observed
hydrogen bond to the pyridine moiety.12,15 The latter two are behaviour was due to the complexation of the calcium ions by
exploited here to produce a reversible phase separation induced 1-E in the homogeneous AN–W solution. The stability constant
by light. Upon irradiation of a 1 : 1 solution of 1 and calcium of the complex (1-E,Ca)Cl2 in 3 : 2 AN–W was found to be 11.0 ꢁ
chloride in a 3 : 2 (v/v) AN–W mixture, photo-isomerization of
1-E to 1-Z decreases the amount of the (1-E,Ca)Cl2 complex
present. As a consequence, calcium ions are expected to be
released, since they bind more weakly to the photogenerated 1-Z
form (see below), thus leading to an increase in the concen-
tration of free cations (Fig. 1). Reaching the ionic threshold is
expressed visibly at the macroscopic scale by the phase sepa-
ration of the AN–W mixture into a biphase. In all experiments
and results reported below the composition of the homogenous
medium was 3 : 2 AN–W v/v, i.e. 34% AN and 66% W mole
percent. In order to substantiate these expectations, the calcium
complexation ability of both forms 1-E and 1-Z were rst Fig. 2 (Left) Solid state molecular structure of the dimeric complex
formed from two (1-E,Ca)OTf2 1 : 1 complexes by bridging through
investigated.
two triflate counterions. (Right) View of an isolated 1 : 1 (1-E,Ca2+
)
Calcium binding by hydrazone 1
Isolation and structures of complexes of 1-E with calcium
cations. Pyridyl-hydrazone 1-E was examined over forty years ago
complex. Protons and triflate counterions are omitted for clarity.
Crystals were obtained by vapor diffusion of diisopropylether into a
solution of 1-E and Ca(OTf)2 in AN.‡ (Gray ¼ carbon; red ¼ oxygen;
as a multidentate ligand for transition metals.14 It was noted in blue ¼ nitrogen; purple ¼ calcium; yellow ¼ fluoride; orange ¼ sulfur).
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Fig. 4, ESI‡). It is also in line with NMR data in pure AN (see
below). While the crystal structures conrm the formation of
complexes of Ca2+ with 1-E, the coordination of the cation with
two or three ligands is not apparent in solution, presumably
due to the weakness of the binding of a second and third ligand
in the AN–W medium and to the low sensitivity of the detection
methods.
In order to obtain more information about the relative
calcium binding abilities of the 1-E and 1-Z forms, the
complexation was also studied in pure AN, instead of the binary
3 : 2 AN–W medium, where the binding by 1-Z is too weak for
reliable determination under the experimental conditions used.
1H NMR titration measurements on the progressive addition of
Ca(OTf)2 to 1-E in AN at ꢂ40 ꢀC show the presence of three
complexes of 1 : 1, 2 : 1 and 3 : 1 ligand–cation stoichiometry
and of the free ligand in slow exchange (Fig. 5 and ESI Fig. 5‡).
Simple integration of the N–H proton signals provided the
corresponding binding constants of 1-E with Ca2+: log b([(1-
E)n,Ca](OTf)2) ¼ 3.5 (n ¼ 1), 6.3 (n ¼ 2), 7.9 (n ¼ 3) ꢁ 0.3. The Job
Fig. 3 Solid state molecular structure of the [(1-E)2,Ca]Cl2 complex.
Protons are omitted for clarity. Crystals were obtained by vapor
diffusion of diisopropylether into a solution of 1-E and CaCl2 in
methanol.‡ (Gray ¼ carbon; green ¼ chloride; blue ¼ nitrogen; purple
¼ calcium).
1
plot from the H NMR titration data shows two complexes of
3 : 1 and 1 : 1 stoichiometry for increasing amounts of Ca(OTf)2
ꢀ
in AN at 25 C (see Fig. 7, ESI‡).
The binding constant of 1-Z with Ca2+ was found to be log
b((1-Z,Ca)(OTf)2) ¼ 2.6 ꢁ 0.3 at 25 ꢀC in AN as determined by 1H
Fig. 4 Two views of the solid state molecular structure of the 3 : 1 [(1-
E)3,Ca](ClO4)2 complex. (Left) One 1-E ligand lies in plane and the two
others are in perpendicular planes. (Right) A perpendicular view to that NMR titration on the progressive addition of Ca(OTf)2 to 1-Z
on the left. Perchlorate anions and protons are omitted for clarity. The
C17 and N6 atoms are disordered over two identical positions. Crystals
were obtained by vapor diffusion of diisopropylether into a solution of
(see Fig. 8, ESI‡). In this case, slow exchange was not observed at
ꢂ40 ꢀC, so the binding constants could not be directly evaluated
as in the case of the 1-E form. The 1 : 1 stoichiometry of (1-
1-E and Ca(ClO4)2 in methanol.‡ (Gray ¼ carbon; blue ¼ nitrogen;
Z,Ca)(OTf)2 in AN agrees with a Job plot of the 1H NMR data at
purple ¼ calcium).
25 ꢀC (see Fig. 9, ESI‡). To conrm the stronger binding of Ca2+
to 1-E compared to 1-Z in the same conditions, a 1H NMR
competition experiment was performed at ꢂ40 ꢀC in an AN
solution of Ca(OTf)2, 1-E and 1-Z (10 mM each). The resulting
spectrum was compared to that obtained with 1-E alone in the
presence of Ca(OTf)2 (10 mM each in AN; see Fig. 10, ESI‡). The
results showed a change in the relative integration values of the
1H NMR signals corresponding to the loss of 0.19 eq. Ca2+ from
the (1-E,Ca)(OTf)2 and [(1-E)2,Ca](OTf)2 complexes, due to
binding by 1-Z, which is in agreement with the binding
constants calculated above. The binding of Ca2+ by 1-Z may be
expected to occur in a bidentate fashion, in line with the
observations made for the acylhydrazone analogue 3 of the
hydrazone 1 (see below).
Photo-induced reversible phase separation with the hydra-
zone 1. It was mentioned previously that 1-E undergoes photo-
Fig. 5 A portion of the 400 MHz 1H NMR spectrum of a solution of 1-E
isomerization to the metastable 1-Z conguration, stabilized by
and Ca(OTf)2 (10 mM each) in AN-d3 at ꢂ40 ꢀC showing the presence
of the two complexes (1-E,Ca)(OTf)2 and [(1-E)2,Ca](OTf)2. The 3 : 1
complex and the free ligand are observable at different stoichiometries
of 1-E and Ca(OTf)2 (see Fig. 5, ESI‡).
an intramolecular hydrogen bond.12 As shown above, calcium
binding is weaker for 1-Z than for 1-E, so that on irradiation the
amount of (1-E,Ca)Cl2 complex decreases and calcium cations
are released, thus restoring their kosmotropic properties and
inducing a phase separation (Fig. 1). Aer four hours of light
exposure (see Experimental, ESI‡) of a 3 : 2 AN–W solution of
1.4 Mꢂ1 at 25 ꢀC, as determined by UV-vis spectroscopy and 355 mM 1 and 305 mM CaCl2 in a thermostated bath at 25 C,
ꢀ
1
conrmed by H NMR titration data obtained on the progres- 68% of 1-E was isomerized into 1-Z and the AN–W mixture had
sive addition of CaCl2 to 1-E (see Fig. 2 and 3, ESI‡). The 1 : 1 separated into two phases due to the release of 115 mM of free
stoichiometry in AN–W agreed, within experimental accuracy, calcium ions into the solution, as calculated from the amounts
1
ꢀ
with a study by Job's method using H NMR data at 25 C (see of 1-E and 1-Z present in the solution (obtained by integration of
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the corresponding 1H NMR signals), using the calcium binding
constant of 1-E obtained above in AN–W and assuming that the
binding of Ca2+ by 1-Z is negligible in these conditions. The
amounts of each phase of 1, the (1-E,Ca)Cl2 complex and
calcium cations before and aer light irradiation are given in
Table 1. The isomerization of 1-E was followed by 1H NMR
(Fig. 6). The compositions of the separated phases were 84% W
(in mole percent) (both v/v and mole % are used) for the bottom
aqueous phase and 57% AN for the top organic phase. The
phase separation was visible aer one hour of irradiation but
the difference in AN–W composition of the two phases
increased further on longer irradiation.
Phase reunication is expected to be obtained by back
conversion of 1 from the Z to the E conguration. However, such
reunication of the biphasic solution did not take place in the
course of one month at 25 ꢀC, indicating the high kinetic
stability of 1-Z. Nevertheless, on acidication by addition of
hydrochloric acid (>37% solution, about 2.5 eq. with respect to
1-E to reach a pH of about 1.0), the back conversion from 1-Z to
1-E occurred in less than 5 minutes, as observed by 1H NMR at
25 ꢀC. The two phases were then still separated due to the
protonation of 1-E, which is incapable of binding Ca2+ ions.
Subsequent basication of the solution by addition of triethyl-
amine (1.1 eq. with respect to hydrochloric acid, to reach the
initial pH of 9.5), allowed for the regeneration of the (1-E,Ca)Cl2
complex in the solution and hence, produced a single AN–W
phase.16 The newly reunied solution can be irradiated again to
obtain a phase separation, thus conrming the reversibility of
the process.
Fig. 6 Aromatic proton portion of the 400 MHz 1H NMR spectra of a
solution of 355 mM 1-E and 305 mM of CaCl2 in 3 : 2 AN–W before
light irradiation (a) and after light irradiation in the aqueous (b) and
organic (c) phases.
The N-methylated hydrazone 2-E did not cause the reuni-
cation of the AN–W biphase induced by CaCl2, underscoring the
importance of the acidic, ionisable N–H bond,17 which rein-
forces the electron density at the NH nitrogen site in 1-E,
whereas the presence of the methyl group in 2-E leads to weaker
complexation of calcium cations (see ESI, Fig. 11 and 12‡ for
more details).18
Calcium binding and photo-induced reversible phase
separation by the acyl-hydrazone 3
Table 1 Concentrations of 1, the (1-E,Ca)Cl2 complex and calcium
In view of the constitutional similarity of acyl-hydrazones with
pyridyl-hydrazones and their wide range of possible structural
variations, as well as for comparison purposes, some studies
were also conducted with the acyl-hydrazone 3.
cations before and after light irradiationa
Before irradiation
Aer irradiation
Isolation and structures of complexes of 3-E and 3-Z with
calcium cations. Solid state molecular structures were deter-
mined by X-ray crystallography for two complexes of the acyl-
hydrazone 3. One of them is a dimeric association of two neutral
2 : 1 3-E:Ca2+ complexes with the ligands in their ionised form
at the N–H site (see more details and Fig. 14 in the ESI‡). The
other one is a 2 : 1 3-Z:Ca2+ complex, [(3-Z)2,Ca](OTf)2, that
conrms in this case the binding of Ca2+ by the Z form of the
ligand. It shows the formation of a dimer between two 3-Z
ligands and two triate anions with the Ca2+ cation bound to
each ligand in a bidentate N,O fashion (Fig. 7).
[1] total (mM)
355
305
355
0
160
195
110
355
[Ca2+] total (mM)
[1-E] (mM)
305 (45 OPh, 540 APh)
115 (160 OPh, 60 APh)
240 (440 OPh, 30 APh)
35
80
225
115
[1-Z] (mM)
[1-E] free (mM)
[(1-E,Ca)Cl2] (mM)
[Ca2+] free (mM)
[Ca2+]-released (mM)
a
Irradiation for 4 h for an initial single phase solution in 3 : 2 AN–W.
Concentrations were calculated using the stability constant
determined (see text). Aer photo-induced phase separation, the two
phases had the composition: 57% AN in the top organic phase and
84% W in the aqueous bottom phase (in mole percent). The total
fractions summed over the two phases were 68% of 1-Z and 32% of 1-
E in part free and in part complexed by CaCl2. The concentrations in
each phase (organic, OPh, and aqueous, APh) are also indicated. The
amount of calcium in each phase was determined by atomic
absorption (values in parentheses, second line, ꢁ2%).
Binding constants of 3-E and 3-Z with calcium cations. In order
to obtain information about the binding of calcium cations by
3-E and 3-Z, spectroscopic experiments were performed. The
stability constant of the complex (3-E,Ca)Cl2 in 3 : 2 AN–W was
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with the case of 1-Z, phase reunication was achieved aer 48
ꢀ
hours at 40 C without the addition of acid, purely by thermal
3-Z to 3-E back-conversion. Thermal Z to E conversion is thus
easier for the acylhydrazone than for its pyridyl analog, a
property that may be of broader interest for establishing photo-
ꢀ
thermal E–Z interconversion cycles. The temperature of 40 C
was low enough so as not to produce phase reunication by
itself.
Coupling of photo-induced phase separation to component
selection and constitutional adaptation in a dynamic library
of imines
The phase separation of an organo-aqueous AN–W mixture
leads to the formation of two distinct solvent environments
from a single one. These two media differ considerably from the
homogenous phase in their physico–chemical properties, and
promote in a constitutional dynamic system, the formation of
the ttest compounds in their respective environments.6 Thus,
we extended the previous study to the coupling of the present
photo-induced phase separation process to a dynamic covalent
library responding to these different solvent environments,
along the overall process represented in Fig. 8.
A dynamic covalent library of imines was generated from
hydrophilic–hydrophobic pairs of aldehydes and amines. Thus,
the aldehydes 4 and 5 were reacted with the amines 6 and 7 to
give the imines 8–11 (Scheme 1).6 A 40 mM solution of equi-
molar amounts of compounds 4–7 in 3 : 2 AN–W, together with
305 mM CaCl2, produced a given distribution of imines, as
Fig.
7 Solid state molecular structure of the [(3-Z)2,Ca](OTf)2
complex. Crystals were obtained by slow vapor diffusion of diisopro-
pylether into a solution of 3-Z and Ca(OTf)2 in AN.‡ (Gray ¼ carbon;
white ¼ hydrogen; red ¼ oxygen; blue ¼ nitrogen; purple ¼ calcium;
yellow ¼ fluoride; orange ¼ sulfur).
found to be 13.2 ꢁ 1.34 Mꢂ1 at 25 ꢀC, from analysis of the UV-vis
spectroscopy titration data obtained by the progressive addition
of CaCl2 to 3-E (see Fig. 15, ESI‡). The 1 : 1 stoichiometry in AN–
W was conrmed by Job's method using 1H NMR data at 25 ꢀC
(see Fig. 16, ESI‡). No evidence of the formation of a complex
between 3-Z and CaCl2 in the AN–W mixture was obtained from
analysis of the UV-vis spectroscopy titration data obtained by
the progressive addition of CaCl2 to 3-Z. Therefore, as for 1-E
and 1-Z above, the binding constants and stoichiometries for
the calcium complexes of 3-E and 3-Z were also studied in pure
AN. The binding constants of 3-E and 3-Z with Ca2+ were found
to be log b([(3-E)n,Ca](OTf)2) ¼ 3.1 (n ¼ 1), 6.4 (n ¼ 2) ꢁ 0.3 and
log b([(3-Z)n,Ca](OTf)2) ¼ 2.6 (n ¼ 1), 5.0 (n ¼ 2) ꢁ 0.3, respec-
tively, as determined by 1H NMR titration of the progressive
addition of Ca(OTf)2 to 3 at 25 ꢀC in AN (see Fig. 17 and 18,
ESI‡). In this case, the exchange was fast on a NMR time scale,
so that the evaluation of the stability constants was based on the
shis of specic signals on calcium addition as well as on a
competition experiment between the two forms (see Fig. 17–19,
ESI‡). The 2 : 1 stoichiometry of [(3-E)2,Ca](OTf)2 and [(3-
1
Z)2,Ca](OTf)2 in ꢀAN was conrmed by Job's method using H
NMR data at 25 C (see Fig. 20 and 21, ESI‡).
Photo-induced reversible phase separation with the acyl-hydra-
zone 3. Photo-induced phase separation was also obtained with
the pyridyl-acylhydrazone 3-E, as with 1-E (see above), by
conversion to the corresponding 3-Z form. However, a larger
amount of 3-E (400 mM, 1.3 eq. with respect to CaCl2) was Fig. 8 Representation of the coupling of a dynamic library of imines,
derived from lipophilic and hydrophilic amines and aldehydes, to the
photo-thermal reversible phase separation cycle comprising: (left to
right) the photo-isomerization (stimulus hn) of ligand 1-E to its 1-Z
needed to reunify the phase separated by 305 mM of CaCl2. Aer
4 hours of light irradiation, 71% of 3-E was isomerized into 3-Z.
The compositions of the two phases were 85% W for the
aqueous phase and 44% AN for the organic phase, showing a
form leads to a decrease in the amount of (1-E,Ca)Cl2 complex,
inducing the release of free Ca2+ cations (effectors) into the solution
less efficient phase separation than with 1-E, conrmed by the and simultaneous phase separation, and (right to left) the thermal
(stimulus D) back-conversion of 1-Z to 1-E, causing phase reunifica-
tion. The dynamic library responds by reversible component selection
and adaptation to the single–double phase interconversion. For clarity,
the small amounts of mixed (amphiphilic) constituents distributed in
quantity of CaCl2 found in each phase by atomic absorption
(100 mM OPh, 455 mM APh, compared with the data for 1-E in
Table 1). This behaviour may be attributed to the occurrence of
binding of Ca2+ to 3-Z, as indeed seen in the solid state (see
both phases are not represented in the phase separated state at the
above) and to the interaction between 3-Z and water. In contrast right. Similarly, the free 1-E and calcium ions are not shown (middle).
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Scheme 1 Dynamic covalent library of the imine constituents 8 (hydrophilic–hydrophilic), 11 (hydrophobic–hydrophobic) and 9 and 10
(amphiphilic), generated by the reaction of the hydrophobic–hydrophilic pairs of salicylaldehyde 4 and 5 and amine 6 and 7 components.
1
observed by H NMR and quantied by integrating the CH]N was hydrolysed before phase separation and 37% was hydro-
proton signals against an external standard. The four imines lysed aer phase separation). To minimize the hydrolysis, the
possess either hydrophilic–hydrophilic (8), hydrophobic– experiments described here were performed at the highest
hydrophobic (11), or amphiphilic (9 and 10) properties. The concentration of the library components that could be used
choice of aldehydes and amines was determined by the high (40 mM). Higher concentrations of the library caused a phase
formation propensity of salicylaldimines19 and their stability separation due to the charged components. The distribution of
towards light irradiation.
the library in the two phases depended on the content of AN and
The derivative of 1 deuterated in positions a and 6 (see ESI‡) W in each phase, and was modied by a change in the AN and W
was prepared to facilitate the integration of the CH]N proton content.
NMR signals which would otherwise overlap with the proton
Phase reunication was thereaer obtained by back conver-
signals of 1-E. In 3 : 2 AN–W in the presence of (a-d,6-d)1-E (8.8 sion from 1-Z to 1-E. First, on addition of hydrochloric acid
eq. with respect to the library components, 355 mM) and CaCl2 (>37% solution, about 2.5 eq. with respect to 1-E to reach a pH
(7.7 eq. with respect to the library components, 305 mM), 72% of about 1.0) into the biphasic AN–W at 25 ꢀC 1-Z was converted
of imine constituents 8–11 were formed and 28% of aldehydes to 1-E in its protonated form. In this acidic medium, the library
and amines 4–7 were le due to hydrolysis. The library pre- of imines was totally hydrolysed. Thereaer, basication of the
sented a 20/18/26/36% distribution for the imine constituents 8/ biphase with triethylamine (1.1 eq. with respect to hydrochloric
9/10/11, respectively (see Fig. 22 in the ESI‡).
acid, to reach the initial pH) led to the restoration of the single
Phase separation was performed by irradiating a solution of phase with, as initially, a distribution of 24/19/27/29% of 8/9/10/
355 mM (a-d,6-d)1-E and 305 mM CaCl2 in the presenceꢀ of 11, respectively. The quantity of charged species in the solution
40 mM of each of the library components 4–7 for 9 h at 25 C, was increased by the addition of the acid and the base, leading
which gave a 49% conversion of 1-E into 1-Z, causing the release to a slight change in the distribution of imines. The entire
of Ca2+ cations into the solution, as shown above. The compo-
sition of the separated phases obtained had the same AN and W
content as in the absence of the library aer 4 h irradiation.
Thus, a longer irradiation time was required in the presence of
the library to achieve a similar composition of the two separated
phases.
The dynamic library underwent reorganization on phase
separation to promote the bis-hydrophilic 8 in the aqueous
phase and the bis-hydrophobic 11 in the organic phase. The
distribution obtained was 0/0/10/90% in the organic phase and
70/27/3/0% in the aqueous phase for the imine constituents 8/9/
10/11, respectively (Fig. 9). The total fraction (summed over
both phases) amounted to 30% of 8 and 52% of 11, as compared
to 20% of 8 and 37% of 11 in the starting homogeneous phase
(see Fig. 23 in the ESI‡). These percentages indicate an overall Fig. 9 The distribution of the dynamic covalent library of the four
different imine constituents 8–11 (40 mM each), in the presence of
305 mM CaCl2, upon phase separation of a 3 : 2 AN–W solution into a
biphasic system by light irradiation for 9 h. The relative amounts in the
respective phases, aqueous (blue, left) and organic (yellow, right), were
amplication/up-regulation of 8 and 11 on photo-induced
phase separation and represent an adaptation of the system to
the creation of two separate media. One may note that there was
somewhat more hydrolysis aer phase separation, which
determined by integration of the corresponding –CH]N proton
reduced the total amount of library imine constituents (28% signals against an external standard.
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constituents with respect to a specic phase and restoration of
the initial library upon phase reunication. The system thus
performs an adaptation by up-regulation of the ttest constit-
uents through component selection.
(6) The behaviour of the coupled system described here may
be represented within the framework of constitutional dynamic
networks4j,6,20 as a photo-induced switching between a 2D
(square) and a 3D (square prism) network state (Fig. 10).
(7) The light-induced changes in environment described
above may be considered as
a photoswitchable liquid
membrane system where the organic phase represents the
membrane. Exchanges take place at the interface leading to a
redistribution of the dynamic library of imines. This process
may in principle be implemented in a three phase active
transport system, whereby the phase separation establishes a
photo-induced non-equilibrium state to drive a substrate
through the membrane, eventually by a carrier mechanism.21
Such a transport system would have the attractive feature of
creating a potential by a clean stimulus, light, acting via a
macroscopic phase separation.
Fig. 10 Splitting of a 2D (square) into a 3D (square prism) constitu-
tional dynamic network by photo-induced liquid–liquid phase sepa-
ration and phase transfer of the interconverting constituents AB, A0B0,
A0B and AB0 across the interface (green plane) with adaptation to each
phase through component exchange. The diagonals of the square
prism link agonistic (+) constituents, the vertical edges link antago-
nistic (ꢂ) constituents across the interface. 2D relationships are
conserved in each phase.
process was repeated in the same set up, underlining its
reversibility. On multiple cycling, the salt content changes, thus
limiting the number of cycles.
Acknowledgements
We thank Annie Marquis for the analysis of the stability
constant data by ChemEquili, Professor Christopher A. Hunter
for the program used to determine binding constants, Lydia
Conclusions
The results reported above show a system performing a Brelot and Corinne Bailly for the X-ray crystal structure deter-
reversible modulation of a liquid mixture between single and minations and Jean-Louis Schmidt for the DOSY analysis. We
double phase states and demonstrate its coupling to a consti- thank the ANR (2010 BLAN-717-1 grant) and the ERC (Advanced
tutional dynamic library by a combination of photochemical Research Grant SUPRADAPT 290585) for nancial support. G.V.
`
´
and thermal processes (Fig. 8). They lead to several conclusions. thanks the Ministere de l'Enseignement Superieur et de la
(1) Light-irradiation of a single phase solution of the pho- Recherche for a doctoral fellowship. N.H. thanks the ANR and
toswitchable hydrazone 1-E and calcium chloride in AN–W the ERC grants for postdoctoral fellowships.
results in the isomerization of 1-E into its isomer 1-Z and causes
a photo-induced phase separation, resulting from an increase
Notes and references
in free Ca2+ cations in the solution, due to the weaker binding of
these cations to 1-Z. The ionic threshold of the cation concen-
tration is visible at the macroscopic scale by the separation of
the single AN–W phase.
(2) The phase separation is reversible and may be repeated.
The light-triggered biphasic AN–W solution was reunied by
back-conversion from 1-Z to 1-E, in the presence of acid.
Subsequent basication restores the initial single phase
solution.
(3) Acyl-hydrazones such as 3 undergo similar interconver-
sions and, in principle, give access to a wide range of potential
modulating ligands.
(4) The overall process consists of a photo-thermal cycle,
whereby a photo-induced out-of-equilibrium state, at both the
molecular (metastable Z form) and macroscopic levels, is
restored to thermodynamic equilibrium by a thermal process
(this is strictly so for the acyl-hydrazones 3-E/3-Z and aided by
acid catalysis for the pyridyl analogues 1-E/1-Z).
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other alkali and alkaline-earth metal chlorides such as
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when phase separation had been caused by means of these
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fragmentation of
a
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binding of 1-E with transition metal cations is much
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are soluble in AN.
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