Dynamic combinatorial donor-acceptor catenanes in water: Access to unconventional and unexpected structures

Article abstract of DOI:10.1021/jo101981p

We describe here the assembly of new types of donor-acceptor [2]catenanes from dynamic combinatorial libraries (DCL) in water. These new catenanes contain both the donor and acceptor components in at least one of the interlocked rings, thereby possessing

Full text of DOI:10.1021/jo101981p

pubs.acs.org/joc
Dynamic Combinatorial Donor-Acceptor Catenanes in Water: Access to
Unconventional and Unexpected Structures
Ho Yu Au-Yeung, G. Dan Pantos-,†,* and Jeremy K. M. Sanders*
University Chemical Laboratory, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, U.K.
†Current address: Department of Chemistry, University of Bath, Bath BA2 7AY, U.K.
g.d.pantos@bath.ac.uk; jkms@cam.ac.uk
Received October 11, 2010
We describe here the assembly of new types of donor-acceptor [2]catenanes from dynamic combinatorial
libraries (DCL) in water. These new catenanes contain both the donor and acceptor components in at
least one of the interlocked rings, thereby possessing unusual and unexpected DAAD or DADD stacking
sequences of the π units in their structures. The efficiency of the catenane assembly process can be
enhanced by manipulating the DCL equilibrium in a variety of ways: adding a guest, changing the
building block stoichiometries, or increasing the library concentration or the ionic strength of the solvent.
The formation of catenanes and their constitutions are found to be dependent on subtle differences in the
geometry, dimension, and flexibility of the donor building blocks.
Introduction
for many years been intriguing and challenging targets for
chemists. With our increasing understanding of intermole-
cular interactions, a variety of templated catenane syntheses
based on metal-ligand coordination,1 hydrogen bonding,2
hydrophobic interactions,3 π-π interactions,4 and anion
recognition5 have been developed. As a result of their inter-
locked structure and the possibility of exerting control on
their mechanical motions, catenanes represent a promising
class of molecules for incorporation into functional materials,6
particularly those based on electronically complementary units.
From pure laboratory curiosity to their promising poten-
tial in the development of molecular devices, catenanes have
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DOI: 10.1021/jo101981p
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Published on Web 02/08/2011
J. Org. Chem. 2011, 76, 1257–1268 1257
2011 American Chemical Society

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Stoddart et al. have extensively studied donor-acceptor (DA)
catenanes based on the cationic π-deficient paraquat and
neutral π-rich systems such as hydroquinone, dioxynaphtha-
lene (DN), and tetrathiafulvalene.7 We have developed several
catenane and rotaxane systems based on neutral acceptor units
such as pyromellitic diimide or naphthalenediimide (NDI),
initially in organic solvents.8 Conventional wisdom and current
understanding of donor-acceptor interactions have led until
now to most of these catenanes being designed and synthesized
with the apparently obvious and presumed most favorable
alternate parallel arrangement of the π-rich and π-deficient
units, to give a DADA stack in the final structure. However, is
the apparently obvious conventional wisdom necessarily cor-
rect? If one designs and builds only DADA catenanes, then the
feasibility and properties of structures with other configura-
tions will remain unknown. We report here a detailed study of
donor-acceptor catenane synthesis in water using the dynamic
combinatorial approach and show that hitherto unknown and
apparently unfavorable configurations are in fact readily ac-
cessible. These investigations led us to the discovery of the first
nonclassical DA [2] catenanes containing two different donor
moieties and allowed us to propose a decisional flowchart that
predicts the formation of catenanes as a function of the donor
geometry.
FIGURE 1. Schematic representation of DA [2]catenane in (a) the
most usual DADA stacking, (b) the new DAAD stacking, and (c)
the , Gemini, nonparallel conformation. Aromatic π-donor (DN)
and π-acceptor (NDI) units are represented by purple and green
cartoons, respectively.
We have recently described in preliminary form the use of
donor-acceptor interactions in DCL systems9 and their
application in the dynamic combinatorial synthesis of cate-
nanes in water.10 To our surprise, a [2]catenane containing
two interlocked DA dimers was assembled from an NDI and
a DN dithiol building block. The interlocking of the two DA
units means that the conventional DADA stacking order
(Figure 1a) seen in most earlier catenanes is not possible in
this molecule. Instead a new DAAD structure (Figure 1b) is
formed; this structure is confirmed by NMR studies.10c We
believe that the conventional DADA [2]catenane cannot form
in this system because the small cavity of the acceptor dimer
does not allow the threading of a donor moiety through it.9b
Subsequent studies showed that slight structural modifications
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1258 J. Org. Chem. Vol. 76, No. 5, 2011

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FIGURE 2. Acceptor (A) and donor (D2-D5) building blocks and their cartoon representations.
of the donor building block led to the formation of two new and
surprising [2]catenanes. One of the catenanes contains an unex-
pected stack of three donor and one acceptor units (DADD),
whereas the other (DAAD) is conformationally flexible: one
of its abundant conformations exhibits an arrangement of the
π units that is reminiscent of , the astrological Gemini sign
(Figure 1c).
To construct and control supramolecular structures based
on donor-acceptor systems, a more detailed understanding
of the scope, limitations, and geometries of the underlying
donor-acceptor interactions is required. One of the most
fruitful ways to uncover subtle supramolecular interactions is
by dynamic combinatorial chemistry (DCC).11 In DCC, build-
ing blocks are connected to each other through reversible bonds
to form a pool of interconverting compounds, the dynamic
combinatorial library (DCL). This reversibility allows the DCL
to be under thermodynamic control, the most stable species
being selected by the system according to the specific condi-
tions. This selection approach is well-known for its ability to
generate unexpected structures12 that not only bypass the major
synthetic challenges of conventional covalent chemistry but
also can teach us something new about molecular interactions.
Following our initial communications on the behavior of
DCLs containing either acceptors or donors9 and on the
assembly of donor-acceptor catenanes from aqueous DCLs,10
we now describe the effect of subtle structural changes of the
donor component on the resulting DCLs. Donor (D) building
blocks with different substitution patterns and linker chain
lengths (Figure 2) were prepared and studied in DCLs in the
presence of the same NDI acceptor (A) building block. An effi-
cient one-step assembly of donor-acceptor catenanes contain-
ing different donor components is also described. Detailed
studies were performed on the solution structure and the con-
formations of the new catenanes.
Results and Discussion
All of the building blocks used in this study follow the
same design, with a central flat hydrophobic aromatic sur-
face bearing two cysteine-decorated hydrophilic side arms.
While the role of the central aromatic cores is to engage in
donor-acceptor and hydrophobic interactions, the amino
acid component provides both the thiol functionality for
reversible disulfide exchange and the carboxylate group for
water solubility. Seven DN-derived donor building blocks
were prepared and studied. According to the length of the
alkyl chain linking the cysteine with the DN core, these
building blocks can be divided into “short” (D1a, D2a, D3,
D4, and D5) and “long” (D1b and D2b) groups. Five dif-
ferent positional isomers of the “short” donor were synthe-
sized for exploring the effect of the geometry of the building
block on catenane assembly in a DCL. The two “long”
(11) (a) Herrmann, A. Org. Biomol. Chem. 2009, 7, 3195. (b) Ladame, S.
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Bruin, B.; Hauwert, P.; Reek, J. N. H. Angew. Chem., Int. Ed. 2006, 45, 2660.
(12) Other examples of catenane discovery from DCLs: (a) Chung,
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M.-K.; White, P. S.; Lee, S. J.; Gagne, M. R. Angew. Chem., Int. Ed. 2009,
48, 8683. (b) West, K. R.; Ludlow, R. F.; Corbett, P. T.; Besenius, P.;
Mansfeld, F. M.; Cormack, P. A.G.; Sherrington, D. G.; Goodman, J. M.;
Stuart, M. C. A.; Otto, S. J. Am. Chem. Soc. 2008, 130, 12218. (c) Lam,
R. T. S.; Belenguer, A.; Roberts, S. L.; Naumann, C.; Jarrosson, T.; Otto, S.;
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FIGURE 3. Structures of DN- and NDI-guests G-1 and G-2 and of heterodimer 1.
donors were used for the study of the effect of building block
flexibility and dimension. The “long” donor building blocks
were prepared only for the symmetrical and most commonly
used 1,5- and 2,6-DN.
A, D1a, D1b, D2a, and D2b were synthesized as previously
described.9,10 Isomeric D3, D4, and D5 were prepared by a
similar procedure to that for D1 and D2 (see Experimental
Section and Supporting Information for details). A typical
DCL was set up by dissolving a mixture of the NDI acceptor
and the appropriate DN donor in water to give a total buil-
FIGURE 4. HPLC analysis of a 1:1 v/v mixture of 5 mM DCLs
equilibrated for 5 days of A and of D1a after 15 min without (a) and
with (b) DTT. Absorbance was recorded at 292 nm.
ding block concentration of 5 mM, followed by adjustment
of the pH to 8 using aqueous NaOH. The library solution
was air-oxidized, equilibrated in a capped vial for 5 days by
which time it had reached a stationary state, and analyzed by
HPLC/LCMS.
(see below) also has no influence on the DCL composition. This
suggests that the hypothetical larger structures that can be in
principle created using A and D1a are thermodynamically
unfavorable relative to the obviously very stable and entropi-
cally favorable heterodimer. The cavity of this heterodimer
is, as in the case of the NDI dimer, too small to allow threading
of an aromatic group, precluding the formation of a simple
[2]catenane.
DCL of A and D1a. HPLC and LCMS analyses of the DCL
solution prepared from the acceptor A and the “short” 1,5-DN
donor D1a showed the DA dimer 1 (Figure 3) to be the major
library member with over 90% yield at stationary state (see
Supporting Information). A small amount of the donor mono-
mer was also observed (ca. 5%), but no NDI-only disulfide
macrocycles, although the DN and NDI components are
present in equimolar quantities and therefore the amount of
DN monomer should be matched by an NDI-only species.13
The high yield of 1 (90%) in the DCL suggests that the mutual
recognition of the donor-acceptor building blocks is highly
efficient. This library was at thermodynamic equilibrium as
demonstrated by reinitiating the disulfide exchange with 15%
dithiothreitol (DTT, Figure 4) in a new library composed of a
1:1 mixture of a pre-equilibrated acceptor only DCL with a pre-
equilibrated D1a only DCL. The library obtained after 15 min
of mixing in the presence of DTT mirrored the DCL set up from
the unoxidized building blocks.14 Addition of the DN donor
guest G-1 or the NDI acceptor guest G-2 as potential templates
(Figure 3) did not lead to any change in the library compo-
sition.15 Increasing the solvent ionic strength, which promotes
hydrophobic effects and encourages catenane formation16
DCL of A and D1b. If the inability to produce a catenane
from a DCL of D1a and A is related to the size of the macro-
cycles, replacing the donor component with the slightly
longer homologue D1b should result in catenane formation
in the library. A diverse DCL containing at least seven macro-
cycles was obtained from A and D1b (1:1 molar ratio, 5 mM,
Figure 5).10c To our delight, one of the library members (Cat-1)
was identified as a [2]catenane by mass spectrometry.17 ESI-MS
(negative ion) showed that the doubly charged molecular ions
of both Cat-1 and macrocycle 2 have an m/z of 1007.1, corre-
sponding to a tetramer containing two of each of the building
blocks. Different daughter ions, however, were observed in the
fragmentation spectra of these two isomers. In the tandem MS
spectrum of Cat-1, the largest fragment observed has an m/z of
963.0, corresponding to the mass of a decarboxylated hetero-
dimer 3. No other homodimeric fragments were observed,
indicating that Cat-1 is a [2]catenane consisting of two identical
interlocked dimers 3, each dimer being formed from one of each
of the donor and the acceptor units. On the other hand, trimeric
fragments (m/z = 1575.1, 1511.1, 1448.1, 1403.0) and hetero-
dimeric but no homodimeric fragments were found in the MS/
MS spectrum of 2, showing that it has a cyclic structure with an
alternate [-D-A-D-A-] arrangement.
(13) The absence of an NDI-only library member is probably due to the
small quantity and the elution profile that resulted in a small broad signal in
the chromatogram, which is masked by the background noise of the UV
trace.
(14) A second experiment using the isolated heterodimer 1 as starting
point for DCL indicated also that 1 is the thermodynamic and not the kinetic
product. See Supporting Information for details.
(15) It was shown previously that the use of guests G-1 and G-2 can induce
amplifications of the NDI- and DN-only macrocycles in DCLs from the
respective building blocks. See ref 9 for details.
(16) (a) Fujita, M.; Ibukuro, F.; Hagihara, H.; Ogura, K. Nature 1994,
367, 720. (b) Fujita, M.; Ibukuro, F.; Ogura, K. J. Am. Chem. Soc. 1995, 117,
4175.
(17) (a) Liu, J.; West, K. R.; Bondy, C. R.; Sanders, J. K. M. Org. Biomol.
Chem. 2007, 5, 778. (b) Poulsen, S.-A.; Gates, P. J.; Cousins, G. R. L.;
Sanders, J. K. M. Rapid Commun. Mass Spectrom. 2000, 14, 44.
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FIGURE 6. HPLC analysis of 5 mM DCLs from D2a and A in
molar ratio of (a) 1:1, (b) 1:1 with 1 M NaNO3, (c) 3:1 with 1 M
NaNO3, and (d) 5:3 with 1 M NaNO3. Peaks corresponding to
catenanes are highlighted. Absorbance was measured at 260 nm.
FIGURE 5. HPLC analysis of a DCL from A and D1b (1:1 molar
ratio, 5 mM). The catenane structure is shown in the inset, and its
peak is highlighted at 5 min. Absorbance was measured at 292 and
380 nm.
a template. Even though the assembly of Cat-1 is not favorable
in the DCL containing G-2, it does not necessarily mean that
Cat-1 does not interact with this guest, but rather that there are
other library members that are better receptors for G-2 and the
equilibrium is shifted toward their formation.18
To take full advantage of the dynamic nature of the catenane
synthesis, various strategies were used to increase the yield of
Cat-1 in the DCL. One obvious way to promote the formation
of Cat-1 at the expense of smaller products is to exploit Le
Chatelier’s principle and increase the concentration of the DCL.
At 2 mM of total building block concentration (1:1 A and D1b),
no catenane was detected; at 5 mM building block concentra-
tion, the catenane corresponds to ca. 10% of the DCL material;
the yield of Cat-1 further increases to ca. 25% at a total
concentration of 10 mM. Another way to favor the catenane
formation is to increase the solvent ionic strength. Since more
hydrophobic surface is buried in the compact catenane than in
its constituent dimers 3, the equilibrium should be shifted
toward the formation of the former in a solvent of higher ionic
strength. A series of DCLs at different NaNO3 content was
prepared. Consistent with our expectation, it was found that
the ratio of Cat-1 in the DCL increases with increasing ionic
strength, with ca. 40% of the DCL material observed as the
catenane in the library containing 1 M NaNO3. Theuseofother
inorganic salts such as NaCl, KCl, and K2SO4 produced a
similar effect. This indicates that the increase in concentration
of Cat-1 is due to the increase of the solvent’s ionic strength
rather than specific interactions with the inorganic ions. As-
sembly of Cat-1 in the DCL can also be templated by the donor
guest G-1. Amplification of Cat-1 from ∼10% to ∼15% was
observed in the DCL templated by G-1 (5 mM of equimolar
amount of building blocks, 2.5 mM of guest). This observation
not only shows that the catenane can be a host for G-1 but also
supports the proposed DAAD π-stacked conformation, where-
by intercalation of the donor guest in the catenane central
cavity completes the alternate DADAD stacking sequence. On
the other hand, no catenane was detected when G-2 was used as
DCL of A and D2a. Next, we studied the effect of the
geometry of the donor building block on catenane produc-
tion. In contrast to its 1,5-isomer D1a, the 2,6-isomer D2a
combined with the acceptor A gives a diverse DCL contain-
ing a range of macrocycles from dimer to tetramer (Figure 6).
Surprisingly, the two [2]catenanes Cat-2 and Cat-3 were iden-
tified in this DCL.10b As with catenane Cat-1, the interlocked
nature of Cat-2 and Cat-3 was first revealed by their MS and
MS/MS spectra (Figure 7). Analogously to Cat-1, Cat-2 con-
tains two identical interlocked dimers 4, with each dimer con-
taining both the donor and the acceptor units. By contrast,
catenane Cat-3 is both unusual and unexpected. It contains
three donor units and only one acceptor unit: a heterodimer
4 interlocks with a donor homodimer 5 to form a DADD
π stacking sequence in its catenated structure. As described
above, the proportion of Cat-2 and Cat-3 in the DCL can
be increased by increasing the solvent polarity. The two
catenanes, however, were not amplified by the template
G-1, presumably because they have smaller cavities than
Cat-1. The efficiency of catenane assembly in the DCL can
also be enhanced by using a building block stoichiometry
that favors the formation of both the catenanes. In a DCL
prepared with 5:3 mol equiv of D2a and A (5 mM total
concentration, 1 M NaNO3), Cat-2 and Cat-3 represent 45%
and 30% of the library material, respectively, corresponding to
75% total catenation efficiency.
As interactions between electron-rich donors are repulsive,19
the formation of catenane Cat-3 is surprising. For most report-
ed donor-acceptor catenanes, donor-acceptor interactions
are not considered as the main driving force for their for-
mation.8f,20 Hydrophobic effects seem to play an important
(18) A recent simulation study showed that if there are interactions
between library members of a DCL, then depending on the strength of the
interactions, the relative abundance of the members may be amplified,
diminished, or unchanged in the library by a template. See: Orrillo, A. G.;
Furlan, R. L. E. J. Org. Chem. 2010, 75, 211.
(19) Hunter, C. A.; Sanders, J. K. M. J. Am. Chem. Soc. 1990, 112, 5525.
(20) Houk, K. N.; Menzer, S.; Newton, S. P.; Raymo, F. M.; Stoddart,
J. F.; Williams, D. J. J. Am. Chem. Soc. 1999, 23, 897.
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FIGURE 7. Tandem MS fragmentation spectra of molecular ion of (a) Cat-2 and (b) Cat-3. A fragmentation amplitude of 0.3 V was used. The
structure of the DADD catenane, Cat-3, is presented in the inset.
FIGURE 8. Comparison of the dimensions of all of the positional isomers of DN used in this study. The interoxygen distances represent
averages of all of the corresponding structures present in Cambridge Structural Database v. 5.31.
role in the formation of Cat-3 in water. However, no
catenane was produced in DCLs containing only the
donor building blocks even under high ionic strength
condition (5 mM of D2a, or 2.5 mM each of D1a and
D2a, 1 M NaNO3).21 Stabilization from the DAD stacks,
therefore, cannot be excluded.
Comparing D1a and D2a, two very different DCLs with
the same acceptor A were obtained, although the two donors
possess identical thiol side arms. The difference in the
geometry of the donor building blocks (1,5- vs 2,6-positions
of the naphthalene) is therefore responsible for the difference
in DCL distribution. First, because of the different geometry
of the two donors, the catenane formation from the DA
dimer 1 may be unfavorable because of steric clash of the
flexible straps in the catenane. The steric repulsion is likely to
be relieved in the case of the isomeric 4 because the disulfide
side chains now have a different orientation with respect to
the DA units. Second, because the side arms lie on the long
axis of the naphthalene, the disulfide macrocycles from D2a
are slightly larger than those from D1a (Figure 8). This slight
expansion may allow catenation of the dimer 4 for which 1,
its isomer, may be just too tight. Third, the difference in the
stereo- and electronic properties of the two donors also
affects the stacking with the NDI acceptor, which in turn
alters the stability and relative ratio of different macrocycles
FIGURE 9. HPLC analysis of 5 mM DCLs from D2b and A in
(21) A DCL of 5 mM of D1a in the presence of 1 M NaNO3 did not
molar ratio of (a) 1:1, (b) 1:1 with 1 M NaNO3, (c) 3:1 with 1 M
NaNO3, and (d) 1:1 with 2.5 mM of G-1. Peaks corresponding to
Cat-4 are highlighted. Absorbance was measured at 260 nm.
produce an all-donor catenane either (see Supporting Information). Mixed
DCLs of both 1,5- and 2,6-DN building blocks were used to maximize the
possibility of assembly of an all-donor catenane.
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FIGURE 10. HPLC analysis of DCLs of Aand D3 (1:1 molar ratio, 5 mM) in (a) the absence of salt and (b) the presence of 1 M NaNO3. The [-D-A-D-]
trimer is illustrated in the three possible isomers with the connecting positions on the DN labeled. Absorbance was measured at 283 nm.
FIGURE 11. MS/MS fragmentation spectra of the molecular ion of Cat-5.
in the DCL.22 Similar arguments govern the formation of
[2]catenanes from the other “short” DN building blocks used
in this study (see below).
Unlike the DCL from the homologue D2a, only one
catenane containing two of each of the DA units was pro-
duced from the library of the more flexible D2b. No DADD
catenane analogous to Cat-3 was detected in the DCL even
with 3 equiv of the donor building block under high ionic
strength (Figure 9c). Presumably, the favorable interactions
that lead to the formation of this catenane are outweighed by
the increased entropic cost of incorporating three of the
flexible donor building blocks in an interlocked structure,
and therefore its formation is unfavorable in the thermo-
dynamically controlled DCL.
DCL of A and D3. The 1,6-DN, D3, may be viewed in
terms of connectivity as “intermediate” between the 1,5- and
2,6-DNs (D1a and D2a). In the DCL (1:1 A and D3, 5 mM),
four library members (one cyclic monomer, one cyclic dimer
and two cyclic trimers) were observed at stationary state
(Figure 10, MS/MS data Figure 11).23 The diversity of the
DCL increased with the solvent ionic strength, when seven
different macrocycles including the [2]catenane Cat-524 were
observed. Amplification of the [-D-A-D-] cyclic trimer at
DCL of A and D2b. Parallel to the comparison between
D1a and D1b, the corresponding DCL of D2b was studied. In
the DCL from A and D2b (1:1, 5 mM, Figure 9), in addition
to several monomer, dimers, and trimers, four tetramers were
detected at stationary state. MS showed that three of these four
tetramers (Cat-4, 6, and 7) are composed of two each of the
building blocks. The three isomers showed different fragmen-
tation behavior and were differentiated by tandem MS: molec-
ular ion of Cat-4 directly fragmented into the dimer 8, and
therefore is a [2]catenane. NMR studies showed that Cat-4 has
a
, the astrological Gemini sign, arrangement of the π units as
one of the observed conformations along with the parallel
DAAD stacked one.10a Compounds 6 and 7 showed sequential
fragmentations, consistent with the cyclic [-D-A-D-A-] and
[-D-D-A-A-] structures, respectively, as suggested by the pre-
sence of homodimeric daughter ions in the MS/MS spectrum
of the latter. As with its isomer Cat-1, Cat-4 was amplified
by the guest G-1 and under high ionic strength condition
(1 M NaNO3).
(23) As a result of the asymmetry of the 1,6-DN, there are different
structural isomers for macrocycles containing more than one donor unit.
(24) As a result of the directionality of the DA dimer, there should be a
pair of diastereoisomers of Cat-5. The small quantity of the compound in the
DCL, however, limited its efficient preparation and purification in sufficient
amount for further studies.
(22) Asakawa, M.; Ashton, P. R.; Boyd, S. E.; Brown, C. L.; Gillard,
R. E.; Kocian, O.; Raymo, F. M.; Stoddart, J. F.; Tolley, M. S.; White,
A. J. P.; Williams, D. J. J. Org. Chem. 1997, 62, 26.
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FIGURE 12. HPLC analysis of DCL of A and D4 (1:1 molar ratio,
5 mM) in (a) the absence of salt and (b) the presence of 1 M NaNO3.
Absorbance was measured at 292 nm.
FIGURE 13. HPLC analysis of DCL of A and D5 (1:1 molar ratio,
5 mM) in (a) the absence of salt and (b) the presence of 1 M NaNO3.
Absorbance was measured at 380 nm.
ca. 22 min was also observed, probably indicating that this
trimer can fold and adopt a more compact and stable structure
under high ionic strength condition.
require a lengthy synthesis in which different donor units are
incorporated stepwise. The selective binding of the acceptor
to different donors is used as a handle for controlling molecular
motions in such systems.4a,e-h,7b,7i,7k-7m To facilitate catenane
formation and analytical efficiency, we selected to prepare
the DCLs from a mixture of A/D1b/D2a and A/D2a/D2b
building blocks. The three donor building blocks were
chosen for their efficient catenane formation, and the com-
bination of donors of different masses in a library enabled
easy LCMS characterization, avoiding difficulties of creat-
ing isomers.
While the DCL of D1a and A is limited to two library
members with no catenane and that of D2a and the same
NDI building block is diverse with 10 library members con-
taining catenanes Cat-2 and Cat-3, the “intermediate” D3
produced a DCL with an intermediate diversity (4 and 7 library
members at low and high salt content, respectively) and an in-
termediate propensity for catenane formation, i.e., only under
conditions of high ionic strength.
DCL of A and D4. Similar to the DCL containing D1a, the
heterodimer was identified as the major macrocycle contain-
ing both building blocks, in a DCL of the 1,7-DN, D4, and A
(1:1 D4:A, 5 mM). No catenane or significant change in
library composition was observed under high ionic strength
conditions (1 M NaNO3, Figure 12). The yield of the DA
dimer was around 50%, the remaining material in the DCL
being present as the donor monomer and acceptor dimer. The
closer spatial arrangement of the two thiol side chains in the
7-DN perhaps results in less ring strain in the corresponding
cyclic monomer, and therefore the favorable interactions pre-
sent in the mixed macrocycles do not provide enough energy to
compensate for the entropic costs of intermolecular reactions.
DCL of A and D5. The DCL derived from the 2,7-DN, D5,
is again quite different: in a low-salt DCL (1:1 D5:A, 5 mM),
the most abundant donor-acceptor macrocycle at station-
ary state is the [-A-D-A-] cyclic trimer, instead of the dimer seen
in all the other DCLs under the same conditions (Figure 13).
Donor-acceptor interactions play a less significant role
in this library as only around one-third of the library material
is incorporated into donor-acceptor macrocycles, the re-
maining components being found in the donor monomer and
acceptor dimer (see Supporting Information). No catenane
was formed by increasing the solvent ionic strength, but am-
plifications of the acceptor tetramer and the [-A-D-A-A-]
tetramer were observed.
In a DCL containing the 1,5- and 2,6-DNs with respec-
tively the “long” and “short” linkers (1:1:1 of A/D1b/D2a,
5 mM), a diverse range of macrocycles including the previously
described catenanes Cat-2 and Cat-3 from the “short” 2,6-DN
were obtained (Figure 14). No catenane containing D1b was
observed in this low-salt DCL, presumably due to the higher
entropic cost of incorporating the flexible building block into
an interlocked structure. Increasing the ionic strength by
addition of 1 M NaNO3 to the library resulted in the for-
mation of two new catenanes Cat-6 and Cat-7, both contain-
ing all three types of building blocks.25 Catenane Cat-6 has
two of each of the acceptor and donor units and is composed
of two interlocked DA dimers, one from the “long” 1,5-DN
and the other from the “short” 2,6-DN. On the other hand,
Cat-7 is another DADD [2]catenane, with a donor homo-
dimer from the “short” 2,6-DN interlocked with a DA dimer
from the “long” 1,5-DN.
The catenane Cat-6 containing two different DN building
blocks was isolated from the DCL and purified for NMR
characterization. The asymmetry of this system provides an
eloquent set of 1H and COSY spectra, allowing detailed con-
clusions to be drawn about the structure (Figure 15).
In the DCL prepared from A and the two 2,6-DNs, the
“short” D2a and the “long” D2b (1:1:1, 5 mM), no significant
amounts of interlocked library members were observed under
low-salt conditions (Figure 16). However, addition of 1 M
DCL of A and Mixture of Ds. The ability to generate more
diverse catenane structures from DCLs was investigated
by mixing more than one donor building block in a DCL;
in particular, catenanes containing more than one type of
donor unit were possible products. Such catenanes usually
(25) Molecular modeling studies were carried out at molecular mechanics
level using the Amber99 and OPLS forcefields. See Supporting Information
for details.
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FIGURE 14. HPLC analysis of a 5 mM DCL of A, D1b, and D2a in 1:1:1 molar ratio in (a) the absence of salt and (b) the presence of 1 M
NaNO3. Absorbance was measured at 260 nm. Peaks corresponding to catenanes are highlighted.
only one kind of donor building block and have been des-
cribed above. The new DAAD [2]catenane Cat-8 is com-
posed of two different interlocked DA dimers, one from D2a
and the other from D2b, as indicated by tandem MS (Figure 17).
Cat-9 is again another DADD [2]catenane, with a donor
homodimer from the “short” 2,6-DN (D2a) interlocked with
the DA dimer from the “long” D2b.25
The successful formation of the four [2]catenanes Cat-1-4
described in previous sections indicates that the dimers 3, 4,
5, and 8 are suitable for interlocking; therefore the formation
of the four new mixed-DNs catenanes Cat-6-9 is perhaps
predictable as these represent the other possible combina-
tions arising from interlocking of these dimers. No catenanes
from only the “long” D1b, D2b, or both were observed in
either DCLs, indicating the relatively higher entropic cost
of interlocking two of these flexible dimers in the DCLs.
Because of the lack of efficient determination of precise abun-
dances of different macrocycles in these complex libraries, it
was not possible to determine whether the distribution of the
catenanes is statistical or biased toward some of the cate-
nated structures. Nevertheless, the efficient formation of such
asymmetrical catenanes, which otherwise requires stepwise
functionalization, in just one step using a dynamic combinatorial
FIGURE 15. Partial COSY spectrum (500 MHz, D2O, 317 K,
5.5-8.5 ppm) of Cat-6. Signals from a DA dimer [-A-D1b-] impurity
are labeled by a blue diamond. The structure of the DADD
catenane, Cat-6, is presented in the inset.
method has been demonstrated, highlighting the attraction
of thermodynamically controlled synthesis.
Conclusion
NaNO3 led to the amplifications of five different catenanes.
Three of these (Cat-2, Cat-3, and Cat-4) are derived from
The efficient assembly of nine donor-acceptor [2]catenanes
in aqueous dynamic combinatorial libraries from simple
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FIGURE 16. HPLC analysis of a 5 mM DCL of A, D2a, and D2b in 1:1:1 molar ratio in (a) the absence of salt and (b) the presence of 1 M
NaNO3. Absorbance was measured at 260 nm. Peaks corresponding to catenanes are highlighted.
FIGURE 17. Tandem MS spectra of (a) Cat-8 and (b) Cat-9.
acyclic dithiol building blocks has been described. None of
these catenanes has the conventional alternating DADA struc-
ture, possessing instead either a DAAD or DADD arrange-
ment of the π units. The yield of these interlocked structures
can be enhanced by increasing solvent ionic strength through
addition of an inorganic salt to the aqueous DCLs. Some of
the flexible catenanes (Cat-1 and Cat-4) can also be tem-
plated by an appropriate guest. By systematically varying the
substitution positions and the linker length of the donor
building blocks, we discovered that subtle changes in geo-
metry, dimension, and flexibility of the building block can
have significant effects on the DCL diversity, product type,
and properties of the resulting catenanes. A fine balance of
all these structural features has to be taken into account
when designing building blocks for successful catenane as-
sembly in DCL. For the ”short”-DN building blocks used in
this study a decisional flowchart can be used to describe the
DCL behavior of these π-rich isomers when mixed with the
same NDI building block (Figure 18). The catenane forma-
tion is predicated by presence in the library of either the
heterodimer (for the DAAD structures) and donor homo-
dimer (for the DADD ones). The presence of an acceptor
unit, A, which forms a very tight homodimer that does not
allow threading through its cavity is required for the forma-
tion of [2]catenanes displaying unconventional arrange-
ments of the π units. We are currently investigating how
acceptor moieties with longer side chains interact with the
donor building blocks described here.
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FIGURE 18. Decisional flowchart describing the determinants for [2]catenane formation for libraries containing one “short”-DN and one
NDI building blocks.
FIGURE 19. Synthesis of building blocks D3, D4, and D5 (precursors I, II, III, and IV follow the same nomenclature, in which I3 is the 1,6-,
I4 is the 1,7-, and I5 is the 2,7-isomer).
The dynamic combinatorial synthesis of catenanes we
have discussed here not only represents an efficient alter-
native for the preparation of these topologically interesting
and complex molecules but also highlights the discovery of
unexpected structures and advances and complements our
understanding of weak donor-acceptor interactions.
added 0.5 M NaOH (200 mL). The mixture was vigorously
stirred in room temperature for 8 h and poured into 1 M HCl
(200 mL). The precipitate formed was collected by filtration,
washed with Et2O, and dried. For actual amounts and yields,
please see Supporting Information.
General Procedures for the Synthesis of the Active Ester III3,
III4, and III5. A mixture of the DN-acid II and N-hydroxylsuc-
cinimide was dissolved in DMF (50 mL) and cooled with an ice
Experimental Section
bath. EDC HCl was added to the solution, and the mixture was
3
stirred in the melting ice bath for 15 min. Stirring was continued
at room temperature for a further 8 h. Volatiles were removed
by a rotary evaporator. The residue was redissolved in acetone
(10 mL) and added dropwise to a stirring solution of 1 M HCl
(200 mL). The precipitate formed was collected by filtration and
dried in vacuo. For actual amounts and yields, please see Sup-
porting Information.
General Procedures for the Synthesis of the DN Methyl Ester
I3, I4, and I5 (see Figure 19)26. To a solution of dihydroxy-
naphthalene in acetone (200 mL) were added finely ground
K2CO3 and methyl bromoacetate. The mixture was heated
to reflux for 8 h. The resulting solution was filtered, and Et2O
(100 mL) was added and washed successively with 1 M HCl
(50 mL), water (50 mL), and brine (50 mL). Solvents from the
organic layer were removed, and the crude solid was used in the
next step without further purification. For actual amounts and
General Procedures for the Synthesis of the Trityl Protected
DNs IV3, IV4, and IV5. To a mixture of the active ester III
and S-trityl-L-cysteine in DMF (50 mL) was added Et3N. The
solution was stirred under N2 for 8 h at room temperature. Solvent
was removed, and the residue redissolved in acetone (10 mL).
The acetone solution was added dropwise to a vigorously stirred
solution of 1 M HCl (200 mL). The yellowish-brown solid was
collected by filtration and dried. For actual amounts and yields,
please see Supporting Information.
yields, please see Supporting Information.
General Procedures for the Synthesis of the DN Acid II3, II4,
and II5. To a solution of the methyl ester I in THF (150 mL) was
(26) Hagihara, S.; Gremaud, L.; Bollot, G.; Mareda, J.; Matile, S. J. Am.
Chem. Soc. 2008, 130, 4347.
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General Procedures for the Synthesis of Building Blocks D3,
D4, and D5. To a Schlenk tube charged with the trityl protected
compound IV was added degassed TFA under N2. The solution
was stirred at room temperature for 1.5 h, triethylsilane was
added, and the mixture was stirred for an additional 30 min.
Volatiles were removed in vacuo. The yellow solid left was washed
with Et2O (50 mL).
1 H, β), 3.11 (dd, J = 5.0 Hz, 14.1 Hz, 1 H, β), 2.87 (dd, J =
9.4 Hz, 14.2 Hz, 1 H, β). 13C{1H} NMR (125.74 MHz, DMSO-
d6, 300 K): δ (ppm) 171.4, 167.7, 155.4, 152.5, 129.7, 129.4,
125.7, 125.3, 123.9, 120.8, 120.7, 120.0, 118.8, 102.3, 101.4, 67.3,
66.8, 54.2, 541, 25.5, 25.4. HRMS (ESIþ) calcdfor C20H23N2O8S2
[M þ H]þ (m/z) 483.0896, found 483.0912.
Synthesis of D5. Quantities as follows. IV5: 0.5 g, 0.51 mmol.
TFA: 5 mL, 65 mmol. SiEt3H: 0.4 mL, 2.5 mmol. Yield: 0.16 g,
Synthesis of D3. Quantities as follows. IV3: 1.0 g, 1.03 mmol.
TFA: 10 mL, 130 mmol. SiEt3H: 0.8 mL, 5 mmol. Yield: 0.33 g,
1
63%. Mp: 94-96 °C (dec). H NMR (400 MHz, DMSO-d6,
1
65%. Mp: 87-90 °C (dec). H NMR (400 MHz, DMSO-d6,
300 K): δ (ppm) 12.94 (br, 2 H, COOH), 8.38 (d, J = 8.0 Hz, 2 H,
NH), 7.79 (d, J = 8.9 Hz, 2 H, DN), 7.19 (d, J = 2.5 Hz, 2 H,
DN), 7.11 (dd, J = 8.9 Hz, 2.5 Hz, 2 H, DN), 4.68 (s, 4 H,
OCH2), 4.51 (dt, 4.6 Hz, 7.7 Hz, 2 H, R), 2.98-2.93 (m, 2 H, β),
2.90-2.83 (m, 2 H, β), 2.43 (t, J = 8.5 Hz, 2 H, SH). 13C{1H}
NMR (100.62 MHz, 5:1 acetone-d6/DMSO-d6, 300 K): δ (ppm)
168.4, 157.2, 136.6, 130.0, 117.1, 108.1, 67.9, 54.6, 26.4. HRMS
(ESIþ) calcd for C20H23N2O8S2 [M þ H]þ (m/z) 483.0896,
found 483.0911.
300 K): δ (ppm) 8.40 (d, J = 6.0 Hz, 1 H, NH), 8.38 (d, J =
5.8 Hz, 1 H, NH), 8.24 (d, J=9.2 Hz, 1 H, DN), 7.40-7.34 (m,
2 H, DN, DN), 7.31 (d, J=2.4 Hz, 1 H, DN), 7.26 (dd, J=
2.6 Hz, 9.2 Hz, 1 H, DN), 6.81 (dd, J=1.5 Hz, 7.1 Hz, 1 H, DN),
4.76 (s, 2 H, OCH2), 4.71 (s, 2 H, OCH2), 4.56-4.49 (m, 2 H, R),
3.00-2.86 (m, 4 H, β, SH). 13C{1H} NMR (125.74 MHz,
DMSO-d6, 300 K): δ (ppm) 171.5, 167.8, 135.5, 126.9, 123.7,
120.3, 120.0, 117.8, 107.5, 104.2, 67.2, 66.8, 54.2, 54.1, 25.5,
25.4. HRMS (ESIþ) calcd for C20H23N2O8S2 [M þ H]þ (m/z)
483.0896, found 483.0926.
Acknowledgment. We thank the Croucher Foundation,
Pembroke College, and EPSRC for financial support and
Dr. Ana Belenguer for maintaining the HPLC laboratory.
Synthesis of D4. Quantities as follows. IV4: 0.6 g, 0.62 mmol.
TFA: 6 mL, 78 mmol. SiEt3H: 0.4 mL, 2.5 mmol. Yield: 0.17 g,
55%. Mp: 113-115 °C (dec). 1H NMR (400 MHz, DMSO-d6,
300 K): δ (ppm) 8.63 (d, J = 8.8 Hz, 1 H, NH), 7.92 (d, J=
8.8 Hz, 1 H, NH), 7.84 (d, J = 9.0 Hz, 1 H, DN), 7.49 (d, J=
8.3 Hz, 1 H, DN), 7.45 (d, J = 2.6 Hz, 1 H, DN), 7.30 (t, J =
8.2 Hz, 1 H, DN), 7.27 (dd, J = 2.6 Hz, 9.0 Hz, 1 H, DN), 7.03
(d, J = 7.6 Hz, 1 H, DN), 4.84 (d, J = 16.4 Hz, 2 H, OCH2),
4.73-4.62 (m, 4 H, OCH2, R, R), 3.48 (dd, J = 3.5 Hz, 14.8 Hz,
Supporting Information Available: Detailed procedure for
building block synthesis and library preparations, HPLC/LCMS
methods, and mass and NMR spectra of isolated macrocycles.
This material is available free of charge via the Internet at http://
pubs.acs.org.
1268 J. Org. Chem. Vol. 76, No. 5, 2011