Adaptation in constitutional dynamic libraries and networks, switching between orthogonal metalloselection and photoselection processes

Article abstract of DOI:10.1021/ja504813r

Constitutional dynamic libraries of hydrazones ^aA^bB and acylhydrazones ^aA^cC undergo reorganization and adaptation in response to a chemical effector (metal cations) or a physical stimulus (light). The set of hydrazones [¹A¹B, ¹A²B, ²A¹B, ²A ²B] undergoes metalloselection on addition of zinc cations which drive the amplification of Zn(¹A²B)₂ by selection of the fittest component ¹A²B. The set of acylhydrazones [E-¹A¹C, ¹A²C, ²A¹C, ²A²C] undergoes photoselection by irradiation of the system, which causes photoisomerization of E- ¹A¹C into Z-¹A¹C with amplification of the latter. The set of acyl hydrazones [E-¹A¹C, ¹A³C, ²A¹C, ²A ³C] undergoes a dual adaptation via component exchange and selection in response to two orthogonal external agents: a chemical effector, metal cations, and a physical stimulus, light irradiation. Metalloselection takes place on addition of zinc cations which drive the amplification of Zn( ¹A³C)₂ by selection of the fittest constituent ¹A³C. Photoselection is obtained on irradiation of the acylhydrazones that leads to photoisomerization from E-¹A ¹C to Z-¹A¹C configuration with amplification of the latter. These changes may be represented by square constitutional dynamic networks that display up-regulation of the pairs of agonists ( ¹A²B, ²A¹B), (Z-¹A ¹C, ²A²C), (¹A³C, ²A¹C), (Z-¹A¹C, ²A ³C) and the simultaneous down-regulation of the pairs of antagonists (¹A¹B, ²A²B), (¹A ²C, ²A¹C), (E-¹A¹C, ²A³C), (¹A³C, ²A ¹C). The orthogonal dual adaptation undergone by the set of acylhydrazones amounts to a network switching process.

Full text of DOI:10.1021/ja504813r

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Article
Adaptation in Constitutional Dynamic Libraries and Networks, Switching
between Orthogonal Metalloselection and Photoselection Processes
Ghislaine Vantomme, Shimei Jiang, and Jean-Marie Lehn
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 05 Jun 2014
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Adaptation in Constitutional Dynamic Libraries and Networks,
Switching between Orthogonal Metalloselection and Photoselection
Processes
‡
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Ghislaine Vantomme, Shimei Jiang,† Jean-Marie Lehn*
Laboratoire de Chimie Supramoléculaire, Institut de Science et d’Ingénierie Supramoléculaires (ISIS), Université
de Strasbourg, 8 allée Gaspard Monge, 67000 Strasbourg, France
a
a
ABSTRACT: Constitutional dynamic libraries of hydrazones AbB and acylhydrazones AcC undergo reorganization
and adaptation in response to a chemical effector (metal cations) or a physical stimulus (light). The set of hydrazones
1
[1A1B, A2B, 2A1B, 2A2B] undergoes metalloselection on addition of zinc cations which drive the amplification of
Zn(1A2B)2 by selection of the fittest component 1A2B. The set of acylhydrazones [E-1A1C, 1A2C, 2A1C and A2C] under-
2
goes photoselection by irradiation of the system, which causes photoisomerization of E-1A1C into Z-1A1C with amplifi-
cation of the latter. The set of acyl hydrazones [E-1A1C, 1A3C, 2A1C, 2A3C] undergoes a dual adaptation via component
exchange and selection in response to two orthogonal external agents: a chemical effector, metal cations, and a physical
stimulus, light irradiation. Metalloselection takes place on addition of zinc cations which drive the amplification of
1
Zn(1A3C)2 by selection of the fittest constituent A3C. Photoselection is obtained on irradiation of the acylhydrazones
that leads to photoisomerization from E-1A1C to Z-1A1C configuration with amplification of the latter. These changes
may be represented by square constitutional dynamic networks that display up-regulation of the pairs of agonists (1A2B,
2A1B), (Z-1A1C, A2C), (1A3C, 2A1C), (Z-1A1C, A3C) and the simultaneous down-regulation of the pairs of antagonists
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(1A1B, A2B), (1A2C, A1C), (E-1A1C, A3C), (1A3C, A1C). The orthogonal dual adaptation undergone by the set of
2
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2
2
acylhydrazones amounts to a network switching process.
INTRODUCTION
ics by shape switching on cation coordination to the
NNN and NNO tridentate binding sites respectively;[9]
2) configurational dynamics on E to Z photoisomeriza-
tion stabilized by internal hydrogen bonding with the
pyridine moiety;[10] 3) constitutional dynamics, by
component exchange via the reversible C=N bond.[1,2]
We have investigated the ability of a DCL to undergo dou-
ble adaptation by studying its response to two orthogonal
agents: a chemical effector[4], e.g. a metal cation, and a
physical stimulus[3], light irradiation. To this end, selec-
tion and adaptation have been analyzed for different DCLs
of four constituents each, chosen among the hydrazones
On the way toward higher levels of complexity in chem-
ical systems, constitutional dynamic chemistry (CDC)[1]
gives access to constitutional dynamic libraries (CDLs)
by the generation of chemical diversity on both the
molecular and supramolecular levels through the ex-
change of components between the constituents of the
system, implementing either reversible covalent reac-
tions[1,2] or labile non-covalent interactions respective-
ly. CDC allows for variation and operates selection on
dynamic constitutional diversity in response to the
pressure of either chemical or physical agents to
achieve adaptation of CDLs, thus enabling adaptive
chemistry.[1,3-5] The set of dynamically interconverting
constituents of a CDL forms a network, a constitutional
dynamic network (CDN),[1,6] that can be represented in
a schematic way by a weighted graph,[7] where the links
between the constituents describe the relationships
between the members of a set, their agonistic or antag-
onistic behavior, as well as their relative weights. CDNs
are adaptive systems, as the weights of their verti-
ces/nodes and of their connections/links respond to
the application of a physical stimulus or a chemical
effector, which may modify the CDL distribution by
amplification/up-regulation of the responsive constitu-
ent(s) and its (their) agonist(s) and down-regulation of
the antagonists.[6] On the molecular level, a CDL is
based on constituents interconverting via reversible
chemical reactions and is thus a dynamic covalent li-
brary (DCL). Based on previous work from our group,[8]
pyridyl-hydrazones and pyridyl-acylhydrazones present
the very attractive feature of being triple dynamic enti-
ties capable of undergoing: 1) conformational dynam-
aAbB and the acylhydrazones AcC shown in Figure 1, that
a
were generated from the condensation products of alde-
hydes or ketones (fragments aA) with hydrazines (frag-
ments bB) or hydrazides (fragments cC). These sets of
constituents were subjected either to interaction with
metal cations or to light irradiation in conditions allowing
for component exchange, thus leading to adaptation
through orthogonal selection processes, respectively
metalloselection (Schemes 2, 4-5) or photoselection
(Schemes 3-5). They form square CDNs that undergo
network switching in response to these two independent
external agents.
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1. Adaptation in a DCL of hydrazones
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1.1 Component exchange in the two DCLs of hydra-
zones [1A1B, 1A2B, 2A1B, 2A2B] and [3A2B, 3A3B,
4A2B, 4A3B]
Based on previous work in our laboratory,[8a] we first in-
vestigated the set of four hydrazones 1A1B, 1A2B, 2A1B
2
and A2B. It may be generated either by mixing equimo-
lecular quantities of each individually synthesized constit-
uent or by randomization of just two constituents, for
example 1A1B and 2A2B, through component exchange
(Scheme 1). Hydrazones are kinetically inert under neutral
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conditions as a result of C=N̅ ꢀN̅ conjugation which de-
creases the electrophilicity of the C=N bond, making them
too stable for use in dynamic covalent libraries. Reported
exchange processes feature hydrazones bearing electron-
withdrawing groups.[11] To circumvent this problem, we
investigated means of facilitating exchange of the carbonyl
and hydrazine components of hydrazones. Three different
exchange procedures via hydrolysis and recondensation
were developed: i) metal ion or acid catalysis under mi-
crowave heating, ii) organo-catalysis with aniline[12] and
iii) introduction of methyl groups in order to twist and
destabilize the hydrazone connection by steric strain. All
Figure 1. Structures of the hydrazones aAbB and acylhy-
drazones aAcC obtained by condensation of aldehydes and
ketones with hydrazines and hydrazides. The fragments
originating from the aldehyde and ketone components are
designated by the letter A and the fragments originating
from the hydrazines by the letter B and from the hydra-
zides by the letter C. All compounds are shown in the E
configuration about the C=N double bond.
1
the exchange reactions were monitored by H NMR spec-
troscopy (see the Figures in SI for exchange processes
studied here).
RESULTS
Scheme 1. Generation of the set of
four hydrazones 1A1B, 1A2B, 2A1B
and 2A2B by component exchange
1
between either A2B and 2A1B (top
left) or 1A1B and 2A2B (top right)
giving the same statistical distribu-
tion of the dynamic library.
i) Metal ion catalysis. Hydrazone exchange has been
catalyzed by scandium (III) triflate,[4a,13] under intense
microwave heating.[14] When a solution of the two hy-
that only benzaldehyde is formed during the exchange
due to the greater sensitivity of its imines to hydrolysis
compared to 2-pyridinecarboxaldehyde. This hydra-
zone exchange can also be catalyzed in the same condi-
tions by addition of 20 mol% trifluoroacetic acid in-
stead of scandium triflate. The component scrambling
reaction is expected to proceed through a transimina-
tion, hydrolysis/recondensation process.
drazones A1B and A2B (10 mM each) in 4:1 acetoni-
trile/water was heated to 170°C in a microwave oven in
presence of scandium triflate (2 mM) during 20
minutes (under 12 bar), the full set of four constituents
1
2
1
2
2
1A1B, A2B, A1B and A2B was formed by component
exchange at the C=N site, with a distribution of
1
32/17/21/18% of A1B/1A2B/2A1B/2A2B together with
ii) Organo-catalysis. The hydrazone exchange has also
been performed by organo-catalysis, via the addition of
aniline (10% in volume, about 100 eq.) to a 10 mM
12% hydrolysis (see the 1H NMR spectrum in SI, Figure
S1).[14] The same distribution was generated starting
2
1
1
from A1B and A2B in the same conditions. In both
acetonitrile solution of the two hydrazones A1B and
cases, A1B was present in both the E and Z configura-
2A2B in presence of trifluoroacetic acid (2 mM). Com-
1
tions (63% and 37% respectively). Furthermore, when
either E-1A1B or Z-1A1B was subjected separately to
these conditions for constitutional exchange, the same
3/2 mixture of the two configurational isomers E-1A1B
and Z-1A1B was obtained (Figure S2-S3). One may note
ponent exchange occurred and the equilibrium between
1
1
the hydrazones A1B, A2B, 2A1B and 2A2B was ob-
tained after one day at 25°C, giving a distribution of
1
32/21/21/26% of A1B/1A2B/2A1B/2A2B respectively.
1
No hydrolysis was observed in the NMR H spectrum
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after the exchange (Figure S4). In this case, almost 50% The deformation induced in the coordination site by
of E-1A1B was converted into Z-1A1B indicating an E/Z
interconversion mechanism in the course of the catalyt-
ic process. Other organo-catalysts have also been tested
for the exchange (see SI section S1.1.ii). One may note
that organo-catalysis by aniline or related compounds
provides an entry into the equilibration of C=N based
dynamic covalent libraries[12] in rather mild conditions,
a feature that may have significant usefulness for a
wide variety of adaptation/selection processes under
the action of different effectors/stimuli and for systems
of much greater complexity than the present ones.
the two methyl groups does however not preclude the
formation of transition metal complexes by the triden-
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tate ligand A2B. The X-ray crystallographic determi-
nation of the solid-state molecular structure of the
hydrazone 3A2B complexed with zinc (II) cations shows
a torsion angle of 39° between the planes of H3CꢀC=N
̅
and the =NꢀNꢀCH3 fragments (Figure 2e,f).
̅
̅
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iii) Strain activation in the DCL of hydrazones A2B,
3A3B, 4A2B and 4A3B. We hypothesized that steric
strain caused by CH3/CH3 interaction on introduction
of methyl groups at both the C=N carbon and the hy-
drazone ꢀN
fragment,[15] thus decreasing conjugation within the
C=NꢀN fragment. As a result, one would expect an in-
crease of the reactivity of the hydrazone bond, facilitat-
ing component exchange between C, doubly-
̅ ꢀ sites would markedly twist the C=N̅ ꢀN̅
̅
̅
Figure 2. Two views of the solid state molecular structures
5
2
of the methylated hydrazones A3B, A3B and Zn(3A2B).
(a) In 5A3B, the phenylꢀC(CH3)=N
ꢀ moiety lies in the plane
of the figure while the =NꢀN(CH3)ꢀphenyl moiety is located
̅
N
methylated hydrazones such as A3B and A2B. These
expectations were confirmed by the X-ray crystallo-
graphic determination of the solid-state molecular
structure of the hydrazone 5A3B (a nitro group has
been introduced so as to obtain a solid at 25°C, as the
3
4
̅
̅
in a plane making a dihedral angle of about 61°. (c) Solid
state molecular structure of the hydrazone 2A3B in the
5
plane of the figure.[16] (b,d) Perpendicular views for A3B
(b) and 2A3B[16] (d) showing clearly the torsion angle in
3
5A3B. (e) In the hydrazone A2B complexed with the zinc
hindered hydrazone A2B, 3A3B, 4A2B and 4A3B are
liquids at 25°C, Figure 2). The dihedral angle between
3
(II) cations, the pyridineꢀC(CH3)=N̅ ꢀ moiety lies in the
plane of the figure while the =NꢀN(CH3)ꢀpyridine moiety is
̅
̅
the planes containing the CH3ꢀC=N
̅
and the =N
̅ ꢀN̅ ꢀCH3
located in a plane making a dihedral angle of about 39°.
The carbon C6 and the nitrogen N3 are disordered. The
complexes are bridged through ZnCl42- anions (Figure S6).
(f) Perpendicular view for Zn(3A2B). Protons and chloride
anions are omitted for clarity.
fragments in A3B amounts to 61°, compared to a tor-
5
sion angle of only 2° in the corresponding HꢀC=N̅ ꢀN̅ ꢀ
CH3 unit of A3B[16], showing clearly the twist imposed
in the hydrazone unit by the steric interaction between
the two methyl groups. In addition, as a further indica-
2
tion of decreased conjugation, the ꢀN̅ (CH3)ꢀ nitrogen
1.2 Metalloselection in the three DCLs of hydrazones:
site is partially pyramidilized in A3B (N is located at a
distance of 0.3 Å from the plane containing the three
connected NCC atoms) whereas it is planar in 2A3B. An
increase in reactivity on deconjugation is well docu-
mented, for instance in the sensitivity of out-of-plane
distorted amide groups to nucleophiles.[17] Indeed, a
marked increase in component exchange rate between
hydrazones was observed: when the two hydrazones
3A3B and 4A2B were mixed in 10 mM acetonitrile solu-
tion in presence of scandium triflate (2 mM) at 60°C
during 8 hours, the full set 3A2B, 3A3B, 4A2B and 4A3B
was formed (Figure S5). Thus, these hydrazones bear-
ing sterically hindering methyl groups present a strain-
activated reactivity closer to that of imines. For com-
5
1
2
2
[1A1B, A2B, A1B, A2B], [3A2B, 3A3B, 4A2B, 4A3B]
and [3A2B, 3A3B, 5A2B, 5A3B]
1
1
2
2
The four hydrazones A1B, A2B, A1B and A2B were
selected to analyze the adaptation of the set in response
to the addition of zinc cations. Pyridyl-hydrazones are
known to form stable complexes with a variety of metal
cations by coordination to the NNN tridentate site.[18]
This is the case for the hydrazone A2B, compared to
1
the other hydrazones which present only bidentate or
monodentate sites. Hydrazones 1A1B and 2A2B (10 mM
each) were treated with zinc (II) triflate (5 mM) under
equilibrating conditions either with or without added
scandium triflate (2 mM, see above) in 10 mM 4:1 ace-
tonitrile/water solution and heated at 170°C in the
microwave oven during 20 minutes. In both cases, the
dynamic library underwent reorganization to amplify
parison, the hydrazones A1B and A2B did not show
any component exchange at 60°C in the same condi-
tions.
1
2
1
the hydrazone A2B in the form of its Zn(1A2B)2 com-
The same methylated hydrazone exchange has also
been performed by organo-catalysis: aniline (10% in
volume, about 100 eq.) was added to an acetonitrile
plex as well as simultaneously its agonist 2A1B. The
distribution obtained was 14/29/38/11% for the con-
solution of the two hydrazones 3A3B and A2B (10 mM
4
1
stituents A1B/1A2B/2A1B/2A2B respectively, together
1
with 8% hydrolysis, A2B being in the form of the com-
each) in presence of trifluoroacetic acid (2 mM). The
exchange was observed and the equilibrium between
plex Zn(1A2B)2 (Scheme 2, Figure S8). The distribution
of the constituents did not change by further heating.
This set of hydrazones thus displays an amplification of
the hydrazones A2B, 3A3B, A2B and 4A3B was ob-
tained after 6 hours at 60°C. The presence of aniline
did not induce an acceleration as important as seen
above, probably due to hindrance of aniline addition on
the C=N carbon in the methylated hydrazones.
3
4
2
both 1A2B (12%) and A1B (17%), whereas the amounts
1
2
of A1B and A2B decrease markedly, representing the
adaptation of the system to the addition of zinc triflate
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by metalloselection, as shown in Scheme 2. One may triflate indicates that in the latter case, the zinc ions
1
2
3
4
note that there was 8% hydrolysis, exclusively coming
from the benzaldehyde moiety, and not the pyridine-2-
carboxaldehyde. Furthermore, the fact that similar
results were obtained with or without added scandium
both facilitate the equilibration and are incorporated in
the final set of products.
ments on addition of zinc
cations driven by amplifica-
tion of the fittest constituent
1A2B that forms the most sta-
ble zinc complex. For clarity,
only the major components
Zn(1A2B)2 and 2A1B are repre-
sented on the right hand
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1
side. A2B is indicated as its
Zn complex Zn(1A2B)2. (mid-
dle) Distribution of the con-
stituents of the DCL before
(middle left) and after (mid-
dle right) addition of the zinc
cations showing adaptation
driven by an effector. (bot-
tom) Representation of the
library adaptation as
square CDN showing agonist
amplification and down-
a
regulation of the antagonists.
Error on % determination: ~
5%.
Scheme 2. (top) Adaptation of the DCL of four hydrazone constit-
1
1
2
2
uents A1B, A2B, A1B, A2B by metallo-selection of the A, B frag-
The metalloselection on this same set of four hydra-
A number of experiments have been performed with
the aim of inducing photoselection by photogeneration
of Z-1A1B from the E-1A1B form within the set of hy-
drazones 1A1B, 1A2B, 2A1B and 2A2B. However, on
irradiation of a solution of the preformed hydrazones
(10 mM each in 4:1 acetonitrile/water; see Experi-
mental Part) no amplification of Z-1A1B by E-1A1B to Z-
1A1B conversion was obtained in the scandium triflate
catalyzed equilibrating conditions (see above, 1.1 i). In
fact, the hydrazone exchange gave the same 3/2 E/Z
mixture as in absence of irradiation (see SI). Attempts
to increase the quantity of Z isomer by irradiation of
the solution in these conditions directly inside the mi-
crowave oven were unsuccessful (Figure S11-S12). Pho-
toselection in conditions of hydrazone exchange
through organo-catalysis by aniline (see above 1.1 ii)
also failed. It thus appears that light-induced photose-
lection by E-1A1B to Z-1A1B conversion is incompatible
with the conditions required for component exchange.
As no photoselection could be achieved with the hydra-
1
1
2
2
zones A1B, A2B, A1B and A2B was also studied in
milder conditions, by means of organo-catalysis with
aniline to establish equilibration conditions. Hydra-
1
2
zones A1B and A2B (10 mM each) were treated with
zinc (II) triflate (5 mM) in presence of aniline (10% in
volume, about 100 eq.) in acetonitrile solution and
heated at 80°C during six hours. The dynamic library
underwent again reorganization as presented above
giving a distribution 4/45/44/7% for the constituents
1A1B/1A2B/2A1B/2A2B respectively, with almost no
hydrolysis, 1A2B being in the form of the complex
Zn(1A2B)2 (Figure S9).
The adaptation of the set of methylated hydrazones
3A2B, 3A3B, A2B and A3B under metalloselection in
presence of zinc cations could be achieved at lower
temperature (60°C overnight) without added catalyst,
in line with the easier component exchange in these
hydrazones (see above). It gave the same selection and
4
4
amplification of Zn(3A2B)2 and A3B. The distribution
4
a
obtained was 42/5/6/47% for the constituents
3A2B/3A3B/4A2B/4A3B respectively, together with
almost no hydrolysis, 3A2B being in the form of the
complex Zn(3A2B)2 (Figure S10). The distribution of
the constituents did not change on further heating. The
addition of mercury or lead cations led to similar re-
sults. However, this system will not be further de-
scribed, because it cannot be used for photoselection
due to the absence of N-H bond to stabilize the Z pho-
toisomer by hydrogen bonding (see below).
zones AbB, we turned our attention to the acylhydra-
zones aAcC.
2. Adaptation in a DCL of acylhydrazones
2.1 Component exchange in the three DCLs of acylhy-
1
2
2
1
2
drazones [1A1C, A2C, A1C, A2C], [1A1C, A3C, A1C,
2A3C] and [3A3C, 3A2C, 4A3C, 4A2C]
A number of examples of acylhydrazone exchange in
presence of Brönsted acid catalyst have been described
in the literature.[3c,4c,4d,9b,19] Thus, component exchange
among acylhydrazones appears to take place more easi-
1.3 Attempts of photoselection in the DCL of hydra-
zones [1A1B, 1A2B, 2A1B, 2A2B]
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4
ly than for hydrazones. Indeed, conjugation of the hy-
drazone ꢀNꢀ site with the carbonyl group may be ex-
pected to decrease its conjugation with the C=N bond,
the solid-state molecular structure of A2C (Figure 3).
The dihedral angle between the H3CꢀC=N and the =N
ꢀCH3 found in 4A2C amounts to a torsion of 126°,
1
2
3
4
5
6
7
8
̅
̅
̅ ꢀ
̅
N̅
5
which thus becomes more reactive towards nucleo-
philes/water. On the other hand, a goal of the present
study was to design a DCL that would be susceptible to
achieve both metalloselection and photoselection. To
this end, DCLs based on different components were
explored.
about twice larger than in the hydrazone A3B, due to
the conjugation of the acylhydrazone ꢀNꢀ site with the
carbonyl group, which reduces the conjugation within
the C=NꢀN fragment, increasing the single bond char-
acter to the N-N bond and allowing for a larger twist
angle. As a consequence, in 3:2 acetonitrile/water solu-
tion in presence of scandium triflate (2 mM) at 60°C
during 12 hours full hydrolysis took place and in pure
acetonitrile component exchange of the hindered
acylhydrazones 3,4A2,3C was observed, but together
with 50% hydrolysis (Figure S17). The very large
amount of hydrolysis is indicative of the instability of
theses methylated acylhydrazones compared to the
non-methylated ones.
̅
̅
̅
First, when the two acylhydrazones 1A2C and 2A1C
were mixed in 10 mM 3:2 acetonitrile/water solution in
presence of scandium triflate (2 mM) at 60°C during 12
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1
hours, exchange occurred, yielding the full set A1C,
2
2
1A2C, A1C and A2C in an almost statistical distribu-
tion of constituents: 25/23/28/22% respectively with
2% hydrolysis (Figure S13). No change was observed on
further heating. The same distribution was obtained
1
2
1
when starting from A1C and A2C. In both cases, A1C
was obtained as a mixture of the E and Z configurations
(respectively 75% and 25%). Again, component ex-
change among acylhydrazones could be achieved in
much milder conditions under organo-catalysis by the
addition of aniline (1% in volume, about 10 eq.). It went
to thermal equilibrium after just two hours at 25°C and
the expected statistical distribution was obtained:
27/23/27/21% of 1A1C/1A2C/2A1C/2A2C respectively
with only 2% hydrolysis (Figure S14). Again, the E and
As in the case of the hydrazones above, the strain-
induced twist within the C=N̅ ꢀN̅ fragment is reduced by
metal ion coordination, as found in the solid molecular
structure in the acylhydrazone complex Zn(3A2C) (Fig-
ure 3).
1
Z configurations were obtained for A1C (respectively
48% and 52%).
1
1
2
2
However, in the A1C, A2C, A1C, A2C set, the metal
cation complexation ability of A1C and A2C may be
too similar to allow for any significant metalloselection.
In order to increase the metal cation binding ability of
the NNO coordination site of one of the constituents
(see below, section 2.3), a DCL containing a benzhydra-
zide component bearing a para-dimethylamino substit-
uent was studied. Thus, in the same conditions as
above, in presence of scandium triflate, the two acylhy-
1
1
Figure 3. Views of the solid state molecular structures of
1
2
drazones A3C and A1C underwent exchange, yielding
the acylhydrazones 4A2C, 4A1C[20] and Zn(3A2C). (a)
1
1
the full set A1C, A3C, 2A1C and 2A3C in an almost
statistical distribution of constituents: 24/25/20/23%
respectively with 8% hydrolysis (Figure S15). The E and
4A2C: the phenyl-C(CH3)=N
̅
ꢀ moiety lies in the plane of
(CH3)ꢀC(=O)ꢀphenyl moiety is
located in a plane making a dihedral angle of about 126°.
(b) 4A1C[20]: the phenylꢀC(CH3)=N
ꢀ moiety lies in the plane
of the figure while the =NꢀNHꢀC(=O)ꢀphenyl moiety is
the figure while the =N̅-N̅
Z configurations were obtained for A1C in the same
̅
1
̅
̅
proportions as above. The same distribution was ob-
tained when starting from A1C and 2A3C. Again, in
1
located in a plane making a dihedral angle of about 18°,
showing clearly a smaller torsion angle than in 4A2C. (c)
presence of aniline, thermal equilibrium was reached
after just one hour at 25°C, giving the expected statisti-
cal distribution with equal amounts of the four constit-
uents: 26/25/23/24% of 1A1C/1A3C/2A1C/2A3C respec-
tively with only 2% hydrolysis (Figure S16). Again, both
Zn(3A2C): the pyridineꢀC(CH3)=N
̅
ꢀ moiety lies in the plane
of the figure while the =N̅ ꢀN̅ (CH3)ꢀC(=O)ꢀphenyl moiety is
located in a plane making a dihedral angle of about 45°.
(d) Perpendicular view for Zn(3A2C). See Figure S18 for a
structure of the corresponding Pb(3A2C) complex. Protons
and tetrafluoroborate counterions are omitted for clarity.
the E and Z configurations were obtained for A1C as
1
above. One may note that here also, hydrolysis in the
course of the exchange gives only benzaldehyde, in view
of the greater sensitivity of its acylhydrazones 2A1C and
2A3C compared to those of 2-pyridinecarboxaldehyde.
2.2 Photoselection in the DCL of the acylhydrazones
[E-1A1C, 1A2C, 2A1C, 2A2C]
Strain activation in the DCL of acylhydrazones A3C,
3
4
3A2C, A3C and 4A2C. The activation of exchange by
Photoselection was first investigated on the set of par-
ent acylhydrazones E-1A1C, 1A2C, 2A1C and 2A2C.
Based on earlier results,[8] in this set, only the E-1A1C is
expected to undergo photoisomerization, due to the
presence of both the N-H bond and the pyridine N site,
which allow for the formation of an internal hydrogen
bond stabilizing the Z isomer. On the other hand, this
strain achieved for hydrazones (see above) has also
been tested in the present case of acylhydrazones. The
introduction of a methyl group at both the C=N carbon
and the acylhydrazone ꢀN
nounced twist in the C=N
firmed by the X-ray crystallographic determination of
̅
ꢀ sites induces again a pro-
ꢀNꢀC=O fragment, as con-
̅
̅
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Page 6 of 19
set does not perform metalloselection (see below). A the library constituents obtained was 40/9/8/38% of
Z-1A1C/1A2C/2A1C/2A2C respectively, with 5% hydrol-
ysis (Figure S19, Scheme 3). With respect to the distri-
bution obtained without irradiation, 25/23/28/22% for
1A1C/1A2C/2A1C/2A2C respectively (see above section
2.1), the present data represent a photoinduced ampli-
fication (by about 15%) of both Z-1A1C and its agonist
2A2C in the DCL and defines its response/adaptation to
irradiation by light with generation of a new distribu-
tion of constituents.
1
2
3
4
5
6
7
8
3:2 acetonitrile/water solution of the two acylhydra-
zones A2C and A1C (10 mM each) was treated with a
catalytic amount of scandium triflate (2 mM) to achieve
equilibration conditions, and the mixture was irradiat-
ed at 25°C. After four hours of irradiation, a change in
1
2
1
the composition of the library was observed in the H
NMR spectrum of the solution. 99% of the acylhydra-
zone E-1A1C was isomerized into Z-1A1C and the equili-
brating library had undergone reorganization to pro-
mote the metastable state Z-1A1C. The distribution of
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that forms the metastable Z
isomer. For clarity, only the
major components Z-1A1C
2
and A2C are represented on
the right hand side. (bottom)
Distribution of the constitu-
ents of the DCL before (left)
and after (right) light irradi-
ation. Error on % determina-
tion:
~
5%.
Scheme 3. Adaptation of the DCL of four constituents E-1A1C, 1A2C,
2A1C and 2A2C by photo-selection of the A, C fragments on light
1
irradiation driven by amplification of the fittest constituent A1C
2.3 Metalloselection and photoselection in the DCL of
the strong effect of the para-dimethylamino group in
the former.
acylhydrazones [E-1A1C, 1A3C, 2A1C, 2A3C]
Metalloselection was then studied on the DCL of
acylhydrazones 1A1C, 1A3C, 2A1C and 2A3C by the addi-
tion of zinc triflate (5 mM) in 3:2 acetonitrile/water
solution. No catalyst was needed, as the zinc cations act
both as catalyst and effector (see also section 1.2). As
discussed above, in this set, the zinc cation should form
Metalloselection. Pyridyl-acylhydrazones bind metal
cations by their tridentate NNO coordination site.[21] In
order to achieve metalloselection in a DCL of acylhy-
drazones, the metal cation must select between NNO
units presenting different binding abilities, due, for
instance, to the presence of substituents that modify
the interaction strength of the carbonyl oxygen site.
Indeed, when a 1/1 mixture of the only slightly different
1
1
the most stable complex with A3C compared to A1C.
Indeed, at 25°C, the dynamic library had underdone
reorganization in 12 hours (or less) to promote the
acylhydrazone forming the Zn(1A3C)2 complex (Figure
S23). The distribution obtained was 9/41/36/12% for
the constituents 1A1C/1A3C/2A1C/2A3C respectively,
1
1A2C and A1C was treated with 0.5 eq. of zinc salt,
almost the same amounts of the two complexes
Zn(1A2C)2 (about 45%) and Zn(1A1C)2 (about 55%)
were obtained, indicating no significant preference for
either coordination site.
with 2% hydrolysis, A3C being in the form of the com-
1
plex Zn(1A3C)2 (Scheme 4, left). It did not change on
In contrast, a marked difference in metal cation bind-
ing ability may be expected to exist between the acylhy-
further heating. These percentages indicate an up-
1
2
regulation of 17% of A3C and 13% of its agonist A1C
and a down-regulation of the two antagonists and rep-
resent an adaptation of the DCL to the addition of zinc
triflate by amplification of both Zn(1A3C)2 and 2A1C
(see below Scheme 5, left).
1
1
drazones A1C and A3C, resulting from the presence
on the 3C fragment of an electron donor para-
dimethylamino group expected to increase the basicity
of the carbonyl and thus the strength of its interaction
with a metal cation. Indeed, the electron donor effect of
the dimethylamino group was confirmed by the com-
The same metalloselection on the DCL of acylhydra-
zones 1A1C, 1A3C, 2A1C and 2A3C was studied in milder
conditions under organo-catalysis with aniline. The
acylhydrazones 1A1C and 2A3C (10 mM each) were
treated with zinc (II) triflate (5 mM) under equilibrat-
ing conditions in presence of aniline (1% in volume,
about 10 eq.) in 10 mM acetonitrile solution and left at
25°C during thirty minutes (Figure S24). The dynamic
library underwent reorganization to promote the
1
1
parison of the IR spectra of A3C and A1C. The C=O
stretching frequency of the A3C carbonyl group is at
1
1645.4 cm-1, which is about 2.5 cm-1 smaller than that in
1A2C, in agreement with electron donation into the
C=O bond of A3C. As a consequence, treating a 1/1
1
mixture of A3C and A1C with 0.5 eq. of zinc salt,
showed the almost exclusive formation of Zn(1A3C)2
(about 85%) with respect to Zn(1A1C)2, demonstrating
1
1
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Journal of the American Chemical Society
acylhydrazone Zn(1A3C)2 and its agonist 2A1C, in a
similar way as described above.
1
2
3
4
5
6
7
8
ents E-1A1C, 1A3C, 2A1C and
2A3C by modification of the
distributions under (left)
metalloselection on addition
of zinc (II) metal cation via
the formation of the fittest
complex
Zn(1A3C)2
and
(right) photoselection by
photo-isomerization of E-
1A1C into Z-1A1C on light irra-
diation. Distribution of the
constituents of the DCL be-
fore (middle), after metal-
loselection (bottom left) and
after photoselection (bottom
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1
right). A3C is indicated as its
Zn complex Zn(1A3C)2. For
clarity, only the structures of
the major components are
represented on the right and
left hand sides. For the CDN
representation, see Scheme 5
below. Error on % determi-
nation:
~
5%.
Scheme 4. Adaptation of the DCL of four acylhydrazone constitu-
Photoselection. In order to achieve both metallo and
photoselection on the same system, irradiation was
conducted on the DCL that showed metalloselection in
response to the binding of zinc cations (see above,
Scheme 4, left). Thus, irradiation for four hours at 25°C
2.4 Reversible metalloselection and photoselection
1
with the DCL of acylhydrazones [1A1C, A3C, 2A1C,
2A3C]
For completeness, the reversibility of the selection
processes investigated has been studied. Starting first
from the mixture of Z-1A1C and 2A3C obtained via pho-
toselection, heating at 80°C regenerates the original
complete library, with Z to E thermal-back conversion
and acylhydrazone equilibration. Subsequently, the
addition of zinc cations and heating gives the same
metalloselection as observed previously with simulta-
of
a 3:2 acetonitrile/water solution of equimolar
amounts (10 mM each) of the acylhydrazones A3C and
2A1C, containing scandium triflate (2 mM) as catalyst
to achieve equilibrating conditions, transformed quan-
titatively E-1A1C into Z-1A1C, producing the set of four
constituents Z-1A1C/1A3C/2A1C/2A3C in a distribution
of 31/21/9/29% respectively, together with 10% hy-
drolysis (Scheme 4, right), as observed by 1H NMR
(Figure S25). Further irradiation caused more hydroly-
sis. This distribution indicates an overall amplification
1
2
neous amplification of the Zn(1A3C)2 and A1C agonist
constituents.
Conversely, starting from the distribution obtained by
metalloselection, decomplexation of Zn(1A3C)2 was
achieved by addition of tetrabutylammonium thiocya-
nate (2 eq. with respect to ZnII ions), which coordinates
the zinc cations more strongly. The mixture was then
irradiated for four hours at 25°C in presence of scandi-
um triflate (0.2 eq.) as catalyst and an increase of the
of the two agonists Z-1A1C and A3C by about 7%. It
2
represents the response of a DCL to the application of
light as an orthogonal stimulus with respect to metal
cation binding. The amplification observed is smaller
than that obtained for metalloselection (see above),
probably as a consequence of the larger amount of
hydrolysis, itself related to the donor effect of the para-
2
constituents Z-1A1C and A3C on the orthogonal diago-
3
nal was observed, yielding the same library distribution
as previously obtained by photoselection. Reversibility
was also achieved by the addition of potassium hexacy-
anoferrate (1 eq. with respect to ZnII ions) instead of
tetrabutylammonium thiocyanate, with however 10%
more hydrolysis.
These results establish the reversibility of the two selec-
tion processes, interconverting two different constitu-
ent distributions via the intermediate formation of the
complete library, and confirm the possibility to switch
between metalloselection and photoselection.
dimethylamino group of C, which may be expected to
1
render the C=N function in A3C more susceptible to
hydrolysis.
For both DCLs, 1A1C/1A2C/2A1C/2A2C (section 2.2)
1
and A1C/1A3C/2A1C/2A3C (this section,above), pho-
toselection in conditions of acylhydrazone exchange
through organo-catalysis by aniline failed, as both con-
1
figurations E and Z of A1C were generated (48% and
52% respectively), as in the case of the hydrazones (see
section 1.3 above).
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2.5 CDN representation of the metalloselection and
photoselection processes
metal cations and light. The comparison of the varia-
1
2
3
4
5
6
7
8
tion in constituent distribution obtained for metal-
loselection (Scheme 5, left) and photoselection
(Scheme 5, right) on the respective application of metal
cations and of light irradiation, reveals an up-
regulation of the agonists located on the two different
diagonals, respectively [Zn(1A3C)2 and 2A1C] and [Z-
1A1C and 2A3C], together with a down-regulation of the
corresponding antagonists [E-1A1C and 2A3C] and
[1A3C and 2A1C]. This behavior corresponds to the
operation of an orthogonal network switching (see also
ref 6d) in response to two different agents by constitu-
tional selection (Scheme 5).
The processes reported herein concern CDLs of four
members. They form CDNs that can be represented as
square weighted graphs,[7] where vertices correspond to
the four constituents while diagonals and edges de-
scribe respectively agonistic and antagonistic relation-
ships between the members of a set. The relative
weights of the vertices and links respond to the applica-
tion of a chemical effector, metal ions, or of a physical
stimulus, light, in an adaptive fashion.
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58
59
60
Thus, the set of four acylhydrazones E-1A1C, 1A3C,
2A1C and 2A3C forms a square CDN responding both to
Scheme 5. Weighted graph
representation of the square
1
2
CDN of E-1A1C, A3C, A1C and
2A3C constituents. The adap-
tation to addition of metal
cation, metalloselection, is
represented by the selection
and amplification of the
Zn(1A3C)2 and 2A1C diagonal
(left). The adaptation to pho-
to-irradiation,
photoselec-
tion, is represented by the
selection and amplification
2
of the Z-1A1C and A3C diago-
nal (right). The diagonals
and edges of the square link
respectively agonistic (+) and
antagonistic (-) constituents.
1A3C is indicated in the form
of its complex Zn(1A3C)2.
In the case of the four hydrazones studied above, only
metalloselection on addition of zinc triflate could be
obtained (section 1.2). The corresponding square CDN
displays an up-regulation of Zn(1A2B)2 together with its
addition of metallic cation and light irradiation
(Scheme 4-5). Metalloselection is observed on addition
of zinc cations which drive the amplification of
1
Zn(1A3C)2 by selection of the fittest constituent A3C,
2
agonist A1B and a down-regulation of the two antago-
with simultaneous reorganization increasing the
nists 1A1B and 2A2B, as shown in Scheme 2.
2
amount of agonist A1C and decreasing the amounts of
the antagonists 1A1C and 2A3C. Photoselection pro-
ceeds by irradiation of the system, leading to pho-
toisomerization of E-1A1C into Z-1A1C with amplifica-
tion of the latter, up-regulation of 2A3C and down-
regulation of 1A3C and 2A1C.
CONCLUSIONS
The results described above achieve the modulation of
a CDL by two different agents, a further step in the
design and operation of complex adaptive networks.
They present a number of features that lead to the fol-
lowing conclusions.
3) The adaptation processes are reversible via the in-
termediate restoration of the full library.
1) CDLs of hydrazones and acylhydrazones have been
generated through component exchange reactions im-
plementing different types of catalytic processes involv-
ing metal ions, organo-catalyst and strain activation.
4) This CDL forms a square CDN that displays network
switching as it undergoes orthogonal adaptation in
response to metallo- and photo-selection.
1
2) The CDL of the four acylhydrazones E-1A1C, A3C,
5) The overall distribution of constituents within a CDN
and its regulation may be considered as an information
storage and processing system depending on and char-
2A1C and 2A3C undergoes adaptation by orthogonal
constitutional response to two external agents: the
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Lee, A. Chem. Commun. 2009, 2192-2194. d) Ingerman, L.
acteristic of the agent(s) acting on it. The information
A.; Waters, M. L. J. Org. Chem. 2009, 74, 111–117. e)
Belenguer, A. M.; Friscic, T.; Day, G. M.; Sanders, J. K. M.
Chem. Sci. 2011, 2, 696-700.
(4) For chemical effectors see for instance: a) Giuseppone, N.;
Schmitt, J.-L.; Lehn, J.-M. J. Am. Chem. Soc. 2006, 128,
16748-16763. b) Ulrich, S.; Lehn, J.-M. J. Am. Chem. Soc.
1
2
3
4
5
6
7
8
can be erased via the reversibility of the process. More-
over, one may note that on removal of the effec-
tor/stimulus, the system enters an out-of-equilibrium
state where it keeps memory of the encoded infor-
mation, thus ensuring fast recall on renewed presenta-
tion of the agent. Such work is being pursued in this
laboratory.
2009, 131, 5546-5559. c) Klein,
J.M.; Saggiomo, V.; Reck, L.;
Lu¨
ning, U.; Sanders, J. K. M. Org. Biomol. Chem. 2012, 10,
60-66. d) Sreenivasachary, N.; Lehn, J.-M. Proc. Natl. Acad.
Sci. USA 2005, 102, 5938-5948. e) For constitutional dynam-
ics on a metal coordination center, see for instance: Epstein,
D. M.; Choudhary, S.; Churchill, R. M.; Keil, K. M.; Eliseev, A.
V.; Morrow, J. R. Inorg. Chem. 2001, 40, 1591-1596. Goral,
V.; Nelen, M. I.; Eliseev, A. V.; Lehn, J.-M. Proc. Natl. Acad.
Sci. USA 2001, 98, 1347-1352. Dumitru, F.; Legrand, Y.-M.;
Petit, E.; van der Lee, A.; Barboiu, M. Dalton Trans 2012, 41,
11860-11865. Legrand, Y.-M.; van der Lee, A.; Barboiu, M.
Inorg. Chem. 2007, 46, 9540-9547.
9
ASSOCIATED CONTENT
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Supporting Information. Synthesis and analysis of
compounds, 1H NMR spectra, X-ray structures. This mate-
rial is available free of charge via the Internet at
http://pubs.acs.org. CCDC 1006337-1006347 contain the
supplementary crystallographic data for this paper. These
data can be obtained free of charge from the Cambridge
(5) For a few examples of switching of imine compounds
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Crystallographic
www.ccdc.cam.ac.uk/data_request/cif.
Data
Centre
via
AUTHOR INFORMATION
Corresponding Author
lehn@unistra.fr
Present Addresses
†
Permanent address: State Key Laboratory of Supramo-
lecular Structure and Materials, College of Chemistry, Jilin
University 2699 Qianjin Avenue, Changchun 130012, P. R.
China
ACKNOWLEDGMENTS
‡ Dedicated to Professor Koji Nakanishi.
We thank Lydia Brelot and Corinne Bailly for the X-ray
crystal structure determinations and the microanalysis
and mass services of the Université de Strasbourg. We
thank the ANR (2010 BLAN-717-1 grant) and the ERC
(Advanced Research Grant SUPRADAPT 290585) for
financial support. G. V. thanks the Ministère de
l’Enseignement Supérieur et de la Recherche for a doctoral
fellowship. S. J. gratefully acknowledges support from the
State Administration of Foreign Affairs, P. R. China by the
111 Project (B06009).
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