Generation of dynamic constitutional diversity and driven evolution in helical molecular strands under Lewis acid catalyzed component exchange

Article abstract of DOI:10.1002/anie.200460343

A stir in the library: The efficient Sc(OTf)₃-catalyzed transimination of helical oligo-hydrazone strands has been utilized to yield a highly diverse constitutional dynamic library through assembly, dissociation, and exchange of components. Thi

Full text of DOI:10.1002/anie.200460343

Communications
Constitutional Dynamics
Generation of Dynamic Constitutional Diversity
and Driven Evolution in Helical Molecular
Strands under Lewis Acid Catalyzed Component
Exchange**
Nicolas Giuseppone, Jean-Louis Schmitt, and
Jean-Marie Lehn*
Constitutional dynamic chemistry (CDC)[1] rests on the
implementation of dynamic features that act on the consti-
tution of molecular[2] as well as supramolecular[3] entities
[*] Dr. N. Giuseppone, J.-L. Schmitt, Prof. Dr. J.-M. Lehn
Institut de Science et d’IngØnierie SupramolØculaires
8 AllØe Gaspard-Monge, BP 70028
67083 Strasbourg cedex (France)
Fax: (+33)3-9024-5140
E-mail: lehn@isis.u-strasbg.fr
[**] This work was supported by a predoctoral fellowship from the
Minist›re de la Jeunesse, de la Recherche et de la Technologie
(J.-L.S.).
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DOI: 10.1002/anie.200460343
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Chemie
through reversible covalent bonds and noncovalent interac-
tions,respectively. Dynamic constitutional diversity is gen-
erated by exchange and recombination of components,as
expressed in particular by the recently developed dynamic
combinatorial chemistry.[4] CDC operates in the self-assem-
bly[5] of well-defined molecular or supramolecular species
which is driven by molecular information and recognition
processes.
perform component exchange,[9b] thus indicating their high
stability even at elevated temperature and/or in the presence
of acid. As a model system for the exploration of potential
exchange catalysts,cross-over experiments between the
dihydrazone compound A and the dihydrazine B in chloro-
form at 608C were performed first (Figure 2). Only 7% of A
Control of the folding of molecular strands has been the
subject of intense recent activity[6] in view of its significance in
both chemistry and biology. In particular,the generation of
helical species[6–8] may be enforced through the implementa-
tion of specific helicity codons based on nonbonded inter-
actions in polyheterocyclic strands[7] or on hydrogen-bonding
subunits.[8] The self-assembly of helical strands by formation
of reversible hydrazone-type bonds between suitably
designed hydrazino and carbonyl components[9,10] gives,in
principle,access to dynamic libraries of molecular helices.
We report here a system that brings together the three
major features mentioned above: constitutional dynamics,
self-assembly,and control of helical folding.
The generation of dynamic constitutional diversity for
both biological and materials science purposes depends on
the availability of suitable chemical connections that are
=
reversible in the desired conditions. The C N unit,which is
present in imines,hydrazones,and oximes,in principle offers
highly attractive potentialities to CDC,provided that fast and
efficient reversibility in organic solvents is achieved.
Zinc(ii) ions are known to catalyze transimination of Schiff
bases[11] and have been found in our research group to
accelerate component exchange in polyimine materials.[12] We
now describe the efficient Lewis acid catalyzed exchange of
hydrazones and apply the results to the generation of a
constitutional dynamic library of helical strands incorporating
hydrazone bonds that is capable of assembling,dissociating,
and exchanging components. Moreover,we demonstrate that
these libraries can undergo driven evolution in the presence
of suitable metal ions to express [2 ” 2] grid-type metal
complexes preferentially from the mixture of helices. These
processes are illustrated schematically in Figure 1.[13]
Figure 2. Evolution with time of the composition of a model hydra-
zone/hydrazine mixture A and B followed by 1H NMR spectroscopy
under ZnII catalysis; c(A)=c(B)=50 mm.[13]
was consumed after 48 h in these conditions without catalyst
and slow degradation of constituents of the mixture had taken
place. Extensive decomposition into unidentified compounds
other than C–E occurred under acid catalysis (20 mol%
CF3CO2H). In contrast,addition of 20 mol% Zn(BF 4)2·8H2O
led to complete exchange with a half-life of 10 h,without
observable degradation. The statistical distribution of the
products at equilibrium indicates the nonspecific interaction
of the ZnII ions with the different compounds and the
isoenergetic nature of the library.[4a] As in the case of
The condensation of pyrimidine-derived difunctional
hydrazine and carbaldehyde building blocks leads to helic-
ity-encoded oligomeric[9a] and polymeric[9b] molecular strands.
These strands have been found to resist many attempts to
Figure 1. Schematic representation of the processes occurring in the present system. Left: Lewis acid catalyzed generation of dynamic constitu-
tional diversity in helical molecular strands involving compounds 1 and B of Figure 3 (1 is shown in both its extended and its preferred helical
forms);[9,13] right: evolution of the dynamic library towards formation of a [2”2] grid driven by suitable metal ions.
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imines,[11,12] the reaction proceeds through a transimination
process; indeed,in similar conditions the pyrimidine 46,-
biscarboxaldehyde analogue of B and dihydrazone A did not
show any detectable exchange after three days.
These promising results prompted us to explore the
catalytic activity of other Lewis acids for the model exchange
reaction depicted in Figure 3. The data indicated that the
activity was directly correlated with the ionic radius of the
trivalent metallic ions assayed,with scandium triflate being
the most powerful Lewis acid catalyst for hydrazone scram-
bling. Moreover,utilization of scandium triflate in the
exchange between compounds A and B (Figure 2) resulted
in the half-reaction being reached after only 20 minutes,a 30-
fold acceleration compared to the results obtained with
Zn(BF4)2·8H2O.
To test the efficiency and generality of the system we
turned to compound 1,[9a] a one-turn helical strand containing
four hydrazone groups,which was expected to be much more
reluctant to undergo component exchange (Figure 4,equili-
brium (a)) than the shorter related structures (A, C, D, F,
Figure 2),as a consequence of its folding and the resulting
lower accessibility of its hydrazone sites. Compound 1 never-
theless underwent exchange of its two bishydrazine compo-
nents with compound B in 48 h when mixed in a stoichio-
metric ratio in the presence of 20 mol% (namely,5 mol% per
hydrazone site of 1) Sc(OTf)3 in chloroform at 608C. The
equilibrium was reached after about 48 h as indicated by
NMR spectroscopy and mass spectrometry. Extensive
exchange had taken place after 48 h even with only 4%
catalyst (that is,1% per site),although the reaction was much
slower. The constituents of the mixture could be separated
and identified by HPLC/ESMS. The data analysis demon-
strated that full recombination between 1 and B had taken
place,with the generation of the set of compounds 1–28
containing expanded helices with up to ten hydrazone sites
(more than three helical turns).[9] Moreover,all the possible
cross-combinations with phenyl and/or methoxyphenyl moi-
eties were generated for each size of helical strand,thus
highlighting the efficiency of the reorganization process. In
Figure 3. Comparative catalytic activity of different trivalent Lewis acids
M(OTf)3 for the exchange of hydrazones (right) as a function of ionic
radius (left); c(B)=c(G)=5 mm at 608C in CDCl3. The conversion is
measured by following, through integration of the 1H NMR signal, the
decrease of compound G over 15 h, which was the time required for
reaching equilibrium in the case of the most active catalyst, Sc(OTf)3.
In the same conditions, the conversions for the uncatalyzed and for
the Zn(OTf)2- or Zn(BF4)2-catalyzed reactions were 1% and 30%,
respectively.[13]
Figure 4. Generation of a highly diverse recombination library of helicity-encoded molecular strands from the one-turn/four-sites helical com-
pound 1 (c=50 mm) and the dihydrazine B (c=50 mm) using Sc(OTf)3 (20 mol%) as a catalyst in CDCl3 at 608C; 28 constituents were identified
by LC/MS (bottom left) and direct introduction ESI/TOF (bottom center) mass spectrometry, as indicated (bottom right).[13]
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the same conditions but under acid catalysis (20 mol%
CF3CO2H) less than 5% of 1 was converted into compounds
11 and 3; degradation of the dihydrazine B had also started
(as shown by NMR analysis and LC/MS).[14]
and direct introduction ESI/TOF mass spectroscopy showed
that,in addition to an increase of 5 (and of 4 to a lesser
extent),the main effect observed when three equivalents of
Zn(OTf)2 were added to the mixture was the formation of
mononuclear [Zn22],[Zn( 2)(3)],and [Zn 32] complexes,thus
leading to a huge amplification of the single site ligands 2 and
3 in the library compared to the equilibria (a) and (b). This
observation may be explained as resulting from the adapta-
tion of the system to generate the ligands providing the sites
required for most complete zinc coordination.
Finally,the dynamic library of helical structures under
equilibrating conditions was treated with Zn(OTf)2 (1 equiv
with respect to the inital amount of compound 1),which is
known to self-assemble with two-site ligands such as 5,to
yield [2 ” 2] grid-type complexes in acetonitrile (Figure 5,
equilibrium (b)).[15] The formation of [Zn454] as the major
tetranuclear grid together with the [Zn4534] and [Zn45242]
analogues was observed by ESI/TOF mass spectroscopy using
direct injection. The HPLC trace (b) (displaying the ligands
resulting from dissociation of the complexes on the column)
and the ESMS data indicated a marked increase in the
amount of 5,which forms the [2 ” 2] grid structure,accom-
panied by a decrease in the larger helical species compared to
the initial equilibrium (a). Moreover,Zn II ions favored for-
mation of 5 over 4,which contains a more bulky central group
that hinders the formation of the homoleptic grid complex
[Zn444]. These observations indicate that addition of ZnII ions
had driven the evolution of the dynamic set towards the
expression of the ligand 5 under the pressure of the formation
of the (less bulky) grid-type complex by dissociation and
recombination of the subunits of the helical strands. The
evolution was also found to depend on the concentration of
ZnII ions,as was demonstrated by using three equivalents of
its triflate salt (Figure 5,equilibrium ( c)). The HPLC trace
The data reported here demonstrate the ability of
ScIII ions to efficiently catalyze the exchange of the compo-
=
N
nents of hydrazones (and,by extension,of any C
functionality) in organic medium and to establish a library
of equilibrating entities,a feature of crucial importance for
CDC. The method provides a general and efficient procedure
for establishing dynamic behavior in sets of discrete mole-
cules (in particular bioactive ones) and in materials (such as
polymers). It also allowed the generation of a highly diverse
dynamic combinatorial library of oligomeric helical strands
from two constituents undergoing assembly,dissociation,and
exchange processes. Addition of ZnII ions subsequently
shifted this library towards the selective amplification of
specific ligand constituents,driven by the formation of [2 ”
2] gridlike complexes (Figure 1). From a broader perspective,
the results described illustrate the ability of constitutional
dynamic systems to respond to environmental parameters and
to perform effector-driven evolution toward the fittest con-
Figure 5. Driven evolution of the dynamic library (a) towards the generation of the [2”2] grid complex [Zn454] (bottom left: HPLC traces; bottom
right: ESMS direct injection) by addition of 1 (b) or 3 (c) equivalents of Zn(OTf)2 (CD3CN; 608C; 24 h) to the library (a), preequilibrated as in
Figure 4 (20 mol% Sc(OTf)3; CDCl3; 608C; 48 h), and then evaporated and redissolved in CD3CN; the equilibrium was not significantly affected
by the change in solvent. The identification of compounds 1–28 is given in Figure 4. Compounds 4 and 5 are identical to F and A, respectively.[13]
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stituent,an essential feature characterizing the adaptive and
evolutive nature of CDC under the pressure of external
factors.
Received: April 16,2004
Published Online: July 14,2004
Keywords: combinatorial chemistry · Lewis acids ·
.
molecular evolution · scandium · self-assembly
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