Reassembly self-sorting triggered by heterodimerization

Article abstract of DOI:10.1039/c1cc13288a

We report herein a five-component self-sorted system comprising molecular clips that form heterodimers 1·4 and 8·11, and homodimer 14·14 in C₆D₅CD₃/CDCl₃. The three component self-sorting mixture comprising 1·1, 8·8, and 14·14 undergoes triggered reassembly self-sorting upon addition of 4·4 and 11·11. The Royal Society of Chemistry 2011.

Full text of DOI:10.1039/c1cc13288a

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COMMUNICATION
Reassembly self-sorting triggered by heterodimerizationw
Li-Ping Cao,a Jun-Gang Wang,a Jiao-Yang Ding,a An-Xin Wu*a and Lyle Isaacs*b
Received 2nd June 2011, Accepted 17th June 2011
DOI: 10.1039/c1cc13288a
We report herein a five-component self-sorted system comprising
molecular clips that form heterodimers 1ꢀ4 and 8ꢀ11, and homodimer
14ꢀ14 in C6D5CD3/CDCl3. The three component self-sorting mix-
ture comprising 1ꢀ1, 8ꢀ8, and 14ꢀ14 undergoes triggered reassembly
self-sorting upon addition of 4ꢀ4 and 11ꢀ11.
The ability to adapt the constitution of a complex mixture—in a
stimuli responsive manner—is of critical importance for both
biological systems and toward the preparation of molecular
machines. For example, in biology a change in concentration
of specific ions or compounds (e.g. Ca2+, acetylcholine) lead to
signal transduction (e.g. binding, conformational change, cata-
lytic events) that result in a change in the behavior of the system.1
The current generation of molecular machines (e.g. shuttles,
rotors, etc.) commonly respond to a chemical, photochemical,
or electrochemical stimulus by an intramolecular conformational
change involving the translocation of a macrocycle along a
thread.2 Important steps toward the further development of
molecular machines include: (1) the simultaneous orthogonal
operation of two or more molecular machines in a common
medium, (2) methods that allow communication between ma-
chines, and (3) methods to reconfigure the composition of the
system in response to environmental stimuli. As an approach
toward such systems that operate simultaneously and ortho-
gonally within a complex mixture we,3 and others,4 are developing
high fidelity self-sorting processes. As a further step toward
reconfigurable functional systems, we have used chemical stimuli
to trigger compositional changes within complex biomimetic self-
sorting systems (e.g. non-natural folding oligomers and allosteric
control of enzymatic activity).5 Of highest relevance to this paper
is the elegant self-sorting system based on heterodimerization of
a series of sterically encumbered calixarene tetraureas reported by
Chart 1 Chemical structures of molecular clips 1–15. RQCO2Et.
Previously, we have studied the dimerization and self-sorting
behavior of molecular clips which possess disparate arrange-
ments of their H-bonding arms (e.g. 7 and (ꢁ)-10, Chart 1).3a–d
Molecular clips that possess similar geometrical arrangements of
their H-bonding arms (e.g. 1 and 7) generally do not undergo
self-sorting, but rather form mixtures of homodimers and hetero-
dimers. Some specific combinations of molecular clips (1 and 4)
selectively form heterodimers (1ꢀ4) presumably due to a
combination of steric and electronic effects.3c As a continuation
of this line of inquiry we decided to prepare additional molecular
clips that undergo selective heterodimerization that function as
chemical stimuli to induce component reassembly within a
multicomponent mixture.
Building on our previous work we synthesized derivatives of
molecular clips 7 and (ꢁ)-10 that bear H-bonding amide and
urea arms, respectively, that differ in the nature (e.g. electron
withdrawing or electron donating) of the substituents. The
synthesis of cis-diamide clips (2, 3, 5, and 6) and trans-diurea
clips (e.g. (ꢁ)-8–(ꢁ)-13) proceeds by the reduction of the
corresponding dinitro compound (H2, Pd/C, DMF) followed
by acylation (CH2Cl2, Et3N, RCOCl or RNCO) in good yield
(Supporting Information). In accord with expectations,3a–d the
1H NMR of 1–13 in CDCl3 solution (Supporting Information,
Fig. S1–S10) show a doubling of resonances that is consistent
with the formation of homodimers. We were fortunate to
obtain single crystals of 3 and (ꢁ)-13 and determined their
structures by X-ray crystallography.z Fig. 1 shows stereoviews
of the structures of homodimer 3ꢀ3 and homodimer 13ꢀ13 in
the crystal. Both dimeric assemblies benefit from p–p inter-
actions between the substituted o-xylylene rings. In addition,
3ꢀ3 benefits from two intramolecular and two intermolecular
Bohmer.6 Herein, we report a three component self-sorted mix-
¨
ture comprising homodimers 1ꢀ1, 8ꢀ8, and 14ꢀ14 that undergoes
stepwise transformation upon addition of 4ꢀ4 and 11ꢀ11 to
generate a five component self-sorting mixture comprising 14ꢀ14
and heterodimers 1ꢀ4 and 8ꢀ11.
a Key Laboratory of Pesticide & Chemical Biology, Ministry of
Education, Central China Normal University, 152 Luoyu Road,
Wuhan 430079, P. R. China. E-mail: chwuax@mail.ccnu.edu.cnb;
Fax: +86 027 67867129; Tel: +86 027 67867129
b Department of Chemistry and Biochemistry, University of Maryland,
College Park, Maryland 20742, USA. E-mail: lisaacs@umd.edu
w Electronic supplementary information (ESI) available: Synthesis
and characterization of molecular clips and their assemblies. CCDC
782746–782748. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c1cc13288a
c
8548 Chem. Commun., 2011, 47, 8548–8550
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Fig. 1 Stereoviews of the X-ray structures of: (a) 3ꢀ3, (b) (+)-13ꢀ
(ꢂ)-13, (c) (+)-15ꢀ(ꢂ)-15. Color code: C, grey; H, white; N, blue;
O, red; Cl, green; F, green; H-bonds, red-yellow striped.
Fig. 2 1H NMR spectra (5 mM, C6D5CD3/CDCl3 = 5 : 1, v/v,
600 MHz, RT) for (a) (+)-8ꢀ(ꢂ)-8, (b) (+)-11ꢀ(ꢂ)-11, (c) (+)-8ꢀ
(ꢂ)-11 and (ꢂ)-8ꢀ(+)-11, (d) 1ꢀ4, (e) 1ꢀ4 and 8ꢀ11, (f) 14ꢀ14, (g) 1ꢀ4,
8ꢀ11, and 14ꢀ14, (h) 1ꢀ1, 8ꢀ8, and 14ꢀ14, and (i) 1ꢀ4, (+)-8ꢀ(ꢂ)-8, and
14ꢀ14. Color code: (+)-8ꢀ(ꢂ)-8, red; (+)-11ꢀ(ꢂ)-11, blue; 8ꢀ11, purple;
1ꢀ4, green; 14ꢀ14, aqua; 1ꢀ1, orange.
H-bonds whereas 13ꢀ13 features four intermolecular H-bonds.
Because (ꢁ)-13 is chiral and racemic the dimeric assembly 13ꢀ13
could comprise either a racemic mixture of the homochiral forms
((+)-132 and (ꢂ)-132) or the heterochiral form (+)-13ꢀ(ꢂ)-13.
In the crystal we observe the heterochiral heterodimer (+)-13ꢀ
(ꢂ)-13 because this geometry results in four H-bonds.
processes based on H-bonding interactions and attributed this
behavior to relative acid/base strength of the H-bond donors and
acceptors.8 In our situation, the more acidic NH H-bond donors
of pentafluorophenyl amide 4 or 3,5-bis(trifluoromethyl)phenyl
urea (ꢁ)-11 complements the more basic H-bond accepting CQO
groups of methyl amide 1 or ethyl urea (ꢁ)-8, resulting in a
preference to form heterodimers.9 As an alternative path to obtain
structural information on heterodimers we synthesized (ꢁ)-15,
which bears one CH3CONH and one C6F5CONH side arm
(Chart 1). We were fortunate to obtain X-ray quality crystals of
heterochiral dimer (+)-15ꢀ(ꢂ)-15 from CHCl3/MeOH and solve
its structure (Fig. 1c).z In accord with the above predictions, the
more acidic C6F5CONH group donates a H-bond to the more
basic CH3CONH H-bond accepting group. The dimeric structure
also benefits from p–p interactions between subsituted o-xylylene
walls. In this manner, the crystal structure of (+)-15ꢀ(ꢂ)-15
provides corroborating evidence for the importance of electronic
effects in these heterodimerization selective processes.
Once we had shown that molecular clips 1–13 form well
defined dimeric assemblies in CDCl3 solution we decided to
investigate their capacity for selective heterodimerization.
Accordingly, we prepared binary mixtures of molecular clips
(1–7; (ꢁ)-8–(ꢁ)-13) and determined the mole fraction (wAB) and
heterodimerization equilibrium constant (Keq) for heterodimer
(wAB) by 1H NMR integration relative to the resonances of
the known homodimers (ESI,w Table S1).3c Among the cis-
diamides 1–7 the previously reported heterodimer between
molecular clips 1 and 4 was most heterodimer selective with
w
AB = 0.92 (Keq = 576).3d For binary mixtures of trans-diurea
clips (ꢁ)-8–(ꢁ)-13 in CDCl3 solution, roughly statistical mix-
tures of homodimers and heterodimers were observed in most
cases. However, the binary mixture comprising (ꢁ)-8 and
(ꢁ)-11 displayed high levels of heterodimer selectivity (wAB
=
0.92; Keq = 540). The 1H NMR spectra recorded for (ꢁ)-8,
(ꢁ)-11, and an equimolar mixture of (ꢁ)-8 and (ꢁ)-11 in
C6D5CD3/CDCl3 (5: 1) are shown in Fig. 2a–c to illustrate
the highly heterodimer selective process.7 Based on the crystal
structure of the related diurea clip (ꢁ)-13 (Fig. 1b) we formulate
the assembly formed from (ꢁ)-8 and (ꢁ)-11 as the racemic
heterochiral heterodimer ((+)-8ꢀ(ꢂ)-11 and (ꢂ)-8ꢀ(+)-11).
Unfortunately, we were unable to obtain single crystals of
heterodimers 1ꢀ4 or 8ꢀ13 which might provide insight into the
factors that promote selective heterodimerization of 1ꢀ4 and (+)-8ꢀ
(ꢂ)-11. Previously, Rebek has observed similar heterodimerization
Having established that a mixture 1 and 4 selectively form
heterodimer 1ꢀ4 and that a mixture of (ꢁ)-8 and (ꢁ)-11
selectively forms a racemic mixture of heterochiral hetero-
dimer (+)-8ꢀ(ꢂ)-11 and (ꢂ)-8ꢀ(+)-11 we wondered whether
these preferences would be maintained within a mixture of all
four components.3a–d Fig. 2c–e shows the H-bonding region of
the 1H NMR spectra for mixtures of 1 and 4, (ꢁ)-8 and (ꢁ)-11,
and 1, 4, (ꢁ)-8, and (ꢁ)-11 which establish that the four
component mixture undergoes high fidelity self-sorting to yield
1ꢀ4 and the racemic mixture (+)-8ꢀ(ꢂ)-11 and (ꢂ)-8ꢀ(+)-11.
We investigated the robustness of this four component mixture
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 8548–8550 8549

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We thank the National Natural Science Foundation of China
(Grant No. 20872042 and 21032001 to A.-X.W.) and the NSF
(CHE-0615049 and CHE-1110911 to L.I.) for financial support.
The research was supported in part by the PCSIRT (No.
IRT0953 to A.-X.W.). We thank Prof Y.-J. Pan for HRMS
and Prof Z.-P. Yao for ESI-MS measurements.
Notes and references
Scheme 1 Stepwise construction of a five component self-sorting
mixture by reassembly self-sorting triggered by heterodimerization.
z Crystal data for 3ꢀ(ClCH2CH2Cl): C46H48Cl2F6N10O16, Mr = 1181.84,
Monoclinic, space group C2/c,
a = 31.260(11), b = 13.333(5),
c = 27.209(10) A, Z = 8, V = 10504(6) A3, Dc = 1.495 g cmꢂ3, m =
0.224 mmꢂ1, ymax = 25.001, F(000) = 4880, reflections collected/unique,
36605/9236 (Rint = 0.0878), final R indices [I 4 2s(I)] R1 = 0.0705,
wR2 = 0.1929, R indices (all data) R1 = 0.1271, wR2 = 0.2233, GOF =
0.998 for all data. CCDC-782748. Crystal data for (ꢁ)-13ꢀ(CH2Cl2)2ꢀ
comprising 1ꢀ4 and 8ꢀ11 to changes in temperature and concen-
tration. Over the 218–323 K temperature range and the 5 mM to
25 mM we do not observe new resonances in the 1H NMR
spectrum (ESIw). Taken together, these results establish that this
self-sorting system displays slow kinetics of exchange on the
NMR time scale and possesses high thermodynamic stability.3e,4k
To test the limits of the number of molecular clips that would
undergo high fidelity self-sorting we synthesized 14 which has a
distinct spatial arrangement of its H-bonding groups.3d We
prepared an equimolar solution comprising 1, 4, (ꢁ)-8, (ꢁ)-11,
and 14 and measured its 1H NMR spectrum (Fig. 2g). The
1H NMR spectrum of the mixture is simply equal to the sum of
the NMR spectra of 1ꢀ4, 8ꢀ11, and 14ꢀ14 (Fig. 2e and f) which
indicates that this five-component system undergoes self-sorting.
This five component mixture represents the largest number of
self-sorting clips that we have prepared to date. Beyond the sheer
number of simultaneously self-sorting molecular clips, we believe
that the stepwise construction of this five component self-sorting
system is significant (Scheme 1). For example, a mixture of 1,
(ꢁ)-8, and 14 undergoes a high fidelity self-sorting process to
yield a mixture of 1ꢀ1, (+)-8ꢀ(ꢂ)-8, and 14ꢀ14 (Fig. 2h). Addition
of 4ꢀ4 acts as a chemical stimulus that triggers the disassembly of
1ꢀ1 and reassembly into the four component self-sorting mixture
comprising 1ꢀ4, (+)-8ꢀ(ꢂ)-8, and 14ꢀ14 (Fig. 2i). Subsequently,
addition of (+)-11ꢀ(ꢂ)-11 triggers the reassembly to the five
component self-sorting system comprising 1ꢀ4, 14ꢀ14, and the
racemate (+)-8ꢀ(ꢂ)-11 and (ꢂ)-8ꢀ(+)-11 (Fig. 2g). We propose
the term reassembly self-sorting for processes triggered by
chemical stimuli that result in the transformation of a self-sorting
state into a different self-sorting state. This type of stimuli
responsive behavior is commonplace in systems—like nucleic
acid dimerization—based on heterodimer selective processes.
In summary, we have described the synthesis of several
molecular clips that undergo homodimerization driven by
p–p interactions and H-bonds. We find that binary mixtures
of 1 and 4 and (ꢁ)-8 and (ꢁ)-11 undergo selective hetero-
dimerization (w1ꢀ4 = 0.92; w8ꢀ11 = 0.92) driven by H-bonds
between the most acidic NH H-bond donor and the most basic
CQO H-bond acceptor. Mixtures of four (1, 4, (ꢁ)-8, and
(ꢁ)-11) and even five (1, 4, (ꢁ)-8, (ꢁ)-11, and 14) molecular
clips undergo well defined self-sorting processes. Most inter-
estingly, we find that stepwise addition of 4ꢀ4 and (+)-11ꢀ
(ꢂ)-11 to a self-sorting mixture of 1ꢀ1, (+)-8ꢀ(ꢂ)-8, and 14ꢀ
14 results in a reassembly self-sorting process triggered by
selective heterodimerization. We believe that heterodimer
selective processes offer routes to reconfigure complex systems
in a stimuli responsive manner that will become useful in the
next generation of molecular machines.
%
(CH3OH): C57H62Cl6N12O17, Mr = 1399.89, Triclinic, space group P1,
a = 14.4991(10), b = 15.5113(11), c = 116.0201(11) A, Z = 2, V =
3161.4(4) A3, Dc = 1.471 g cmꢂ3, m = 0.351 mmꢂ1, ymax = 25.501,
F(000) = 1452, reflections collected/unique, 20709/11641 (Rint =
0.1005), final R indices [I 4 2s(I)] R1 = 0.0746, wR2 = 0.2021, R
indices (all data) R1 = 0.0843, wR2 = 0.2108, GOF = 1.078 for all data.
CCDC-782746. Crystal data for (ꢁ)-15ꢀ(CHCl3)3: C40H36Cl9F5N6O10,
%
Mr = 1174.80, Triclinic, space group P1, a = 10.5648(10), b =
15.5841(14), c = 16.8119(15) A, Z = 2, V = 2444.4(4) A3, Dc
=
1.596 g cmꢂ3, m = 0.596 mmꢂ1, ymax = 27.501, F(000) = 1192,
reflections collected/unique, 28452/10910 (Rint = 0.0845), final R indices
[I 4 2s(I)] R1 = 0.0567, wR2 = 0.1414, R indices (all data) R1 = 0.0834,
wR2 = 0.1534, GOF = 0.955 for all data. CCDC-782747.
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c
8550 Chem. Commun., 2011, 47, 8548–8550
This journal is The Royal Society of Chemistry 2011