Discovery of an all-donor aromatic [2]catenane

Article abstract of DOI:10.1039/d0sc04317f

We report herein the first all-donor aromatic [2]catenane formed through dynamic combinatorial chemistry, using single component libraries. The building block is a benzo[1,2-b:4,5-b′]dithiophene derivative, a π-donor molecule, with cysteine appendages that allow for disulfide exchange. The hydrophobic effect plays an essential role in the formation of the all-donor [2]catenane. The design of the building block allows the formation of a quasi-fused pentacyclic core, which enhances the stacking interactions between the cores. The [2]catenane has chiro-optical and fluorescent properties, being also the first known DCC-disulphide-based interlocked molecule to be fluorescent.

Full text of DOI:10.1039/d0sc04317f

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DOI: 10.1039/D0SC04317F
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Discovery of an all-donor aromatic [2]catenane
Tiberiu-M. Gianga,a,b Edwige Audibert,a Anamaria Trandafir,a Gabriele Kociok-Köhn,c G. Dan Pantoșa*
Received 00th January 20xx,
Accepted 00th January 20xx
We report herein the first all-donor aromatic [2]catenane formed through dynamic combinatorial chemistry, using single
component libraries. The building block is a benzo[1,2-b:4,5-b’]dithiophene derivative, a -donor molecule, with cysteine
appendages that allow for disulfide exchange. The hydrophobic effect plays an essential role in the formation of the all-
donor [2]catenane. The design of the building block allows the formation of a quasi-fused pentacyclic core, which enhances
the stacking interactions between the cores. The [2]catenane has chiro-optical and fluorescent properties, being also the
first known DCC-disulphide-based interlocked molecule to be fluorescent.
DOI: 10.1039/x0xx00000x
DCC exploits the reversible nature of certain covalent bonds
(disulphide,31–33 imine,12,34,35 etc.) and has emerged as an
efficient method for catenane synthesis. In DCC, simple building
Introduction
Catenanes have become a curiosity since their advent about
half a century ago.1–3 Two main strategies have been developed
in parallel for their syntheses: metal-templated synthesis4–9 and
dynamic combinatorial chemistry (DCC).3,10–16 After the
statistical catenation era (where the interlocked molecules
were produced by statistical threading), Jean-Pierre Sauvage
pioneered the metal-templated synthesis.4 This approach takes
advantage of the preorganisation of the ligands around
transition metal cations followed by the catenation step
(mechanical bond formation). The metal ion can then be
removed to obtain a purely organic interlocked molecule.4,6 In
contrast to this, the active metal templation method, which
includes click-chemistry17 and other copper catalysed
reactions,6,18,19 is based on the catalytic properties of some
transition metals that have allowed the synthesis of catenanes.
Another, less common, strategy is using alkali metal cations as
templates.20 The metals can also be part of the macrocycle
forming the catenane.21,22 The strategies described above rely
on a template (the metal cation) to bring together the species
involved in the catenation process. In contrast to these, there
are methods that take advantage of hydrogen and halogen
bonding, π-π interactions, and the hydrophobic effect in order
to provide the necessary preorganisation in catenane synthesis
via ring closing metathesis,23 amide bond formation or DCC. The
Vögtle24 and Hunter25 groups were able to synthesise catenanes
using hydrogen-bonding. Chloride,26 bromide27,28 and iodide28
anions allow halogen bonding (anion templation) that has also
led to catenated species. Anion templation was also done via
hydrogen bonding.29,30
blocks are mixed together and react until the thermodynamic
equilibrium is reached. The catenane formation has been driven
by aromatic - stacking interactions and hydrophobic
effect.32,36,37 The hydrophobic effect is
a non-covalent
interaction that uses the ability of molecules with hydrophobic
cores to “shield” themselves from aqueous media through
stacking. The hydrophobic effect has been used in DCC and non-
DCC syntheses. Highlights of the latter include examples from
the Stoddart group, which have assembled a catenane using the
cavity of a beta-cyclodextrin,38 and Fujita’s group whose
“magical rings” yielded a [2]catenane quantitatively in the
presence of high salt concentration.21
One of the most common types of catenane is the one in
which four aromatic units are held together by non-covalent
aromatic - stacking interactions.12,21,27,33,37,39–51 Among these,
the studies reported in the literature mostly focus on donor-
acceptor-based catenanes in which electron donor and electron
acceptor aromatics stack to form a DADA (D = donor, A =
acceptor) sequence.47,52–56 Of all the possible combinations of
four aromatic units stacking in a [2]catenane structure, the all-
donor structure has only been reported by Stoddart et al. albeit
with non-aromatic cores (Scheme 1a).10 In that report the all-
donor catenane was synthesised via a 4e- reduction of a classical
DADA [2]catenane. The all-donor catenane is peculiar because
of highly unfavourable electronic repulsions of aromatic donor
units. Herein, we report the spontaneous self-assembly of an
all-donor aromatic [2]catenane from a dynamic combinatorial
library (Scheme 1c).
a. Department of Chemistry, University of Bath, BA2 7AY, Bath, U.K.
b. Current address: Beamline B23, Diamond Light Source, Ltd., Chilton, Didcot OX11
0DE, U.K.
c. Materials and Chemical Characterisation Facility (MC2), University of Bath, BA2
7AY, Bath, U.K.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
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Computational studies on the two cores indicaVtieewdAtrhticalet OiBnDlinTe
is slightly less electron rich that BDT, Qzz = -22 B vs. -23 B,
a)
DOI: 10.1039/D0SC04317F
respectively. The syntheses of cysteine appended building
blocks are described in Scheme 2. They start with either 1,4-
dibromo-2,5-dimethylbenzene (for BDT) or 1,5-dibromo-2,4-
dimethylbenzene (for iBDT) which are converted to the
corresponding esters of BDT and iBDT over three and four steps,
respectively. The esters are then hydrolysed to give the
dicarboxylic acids 5 and 9 (Scheme 2). The building blocks for
dynamic combinatorial libraries (DCLs) are generated by the
NHS (N-hydroxysuccinimide) activation of the acids followed by
coupling with L- or D-S(Trt)-Cys-OH and finally trifluoroacetic
acid deprotection to give the free thiols 1 and 2 (L- enantiomers,
Scheme 2; 1* the D– enantiomer of 1, Scheme S1).
The absorption profile of the BDT precursor 6 shows a
bathochromic shift compared to that of iBDT 10 (max = 393 nm
vs. 350 nm, respectively), suggesting a larger band gap for iBDT
compared to BDT and a better electron delocalisation in BDT
(Fig. 1b). Compound 6 displays a more complex spectrum than
10, with bands at 333 nm and 282 nm, indicating different
electronic properties of the structural isomers. At lower energy,
b)
DDDD
This work
DADA
DADD
ADDA
AADA
AAAA
c)
HOOC
H
O
O
NH
O
O
S
S
S
S
COOH
COOH
S
S
HN
HOOC
O
O
O
O
S
S
H H
HH
H
N
O
S
HN
O
S
S
O
O
O
NH
HOOC
S
S
N
H
S
O
COOH
HH
S
O
NH
O
HN
HOOC
S
COOH
H
Scheme 1 a) The previously published all-donor [2]catenanes by Stoddard group;
b) the arrangement described in this paper along with the other types of
[2]catenanes stacking published by Sanders group (red
-
-donor,
dialkoxyanphthalene, blue - -acceptor, naphthalenediimide) and c) the chemical
structure of the all-donor aromatic [2]catenane synthesised in the paper.
the BDT has
a larger extinction coefficient than iBDT
(393nm=11400 L mol-1 cm-1, 350nm=4640 L mol-1 cm-1, Fig. S28-
29). The BDT derivatives are more emissive than their iBDT
counterparts – the quantum yield of BDT 6 in CHCl3 is 0.075,
whereas that of iBDT 10 is 0.0079 (Fig. 1c). The chirality of the
aminoacid is transferred onto both aromatic cores as indicated
by their circular dichroism (CD) spectra in CHCl3. The molar
ellipticities of BDT 6 and iBDT 10 are comparable above 300 nm,
however below 300 nm, the BDT’s ellipticity is about 7x lower
than that of iBDT. (Fig. 1a).
Structural proof for BDT precursor 6 came from solving the
X-ray diffraction pattern of crystals grown from a solution of
acetone and trifluoroethanol. In the X-ray crystal structure (Fig.
2) a hydrogen bond between the amide NH and methoxy O
(N···O 2.771 Å, ∡N-H-O 138°) is observed. This enables the
system to adopt a pseudopentacyclic structure (three aromatic
cores from benzodithiophene and two cycles held together by
hydrogen bonding between amide and one of the methoxy
groups), which makes the amide coplanar with the aromatic
core, thus providing a larger π surface.
Results and discussion
We have designed two isomeric -donor building blocks for
DCC: benzo[1,2-b:4,5-b’]dithiophene (BDT), 1, and benzo[1,2-
b:5,4-b’]dithiophene (iBDT), 2, Scheme 2. The difference
between the two building blocks is the connectivity of the
benzodithiophene which changes the symmetry of the core: C2h
for BDT and C2v for iBDT.
Br
Br
O
(nBu)OOC
O
HOOC
S
HO
O
b
c, d, e
COO(nBu)
OH
S
COOH
O
Br
Br
5 (31%)
4 (89%)
3
f, g
O
S
HS
O
S
TrtS
h
NH
O
O
HN
S
NH
O
S
HOOC
COOH
SH
HOOC
COOH
STrt
O
HN
O
O
6 (78%)
1 (81%)
O
S
O
a)
b)
(nBu)OOC
Br
COO(nBu)
c, d, e
OH
O
HO
a, b
40
20
1
S
O
Br
Br
Br
0.8
0.6
0.4
0.2
0
0
9 (21%)
8 (67%)
7
-20
-40
-60
-80
6
10
6
10
f, g
250
300
350
λ (nm)
400
450
500
250
300
350
400
450
500
λ (nm)
HOOC
HS
O
S
HOOC
TrtS
O
O
O
COOH
SH
COOH
STrt
h
NH
O
NH
O
HN
HN
O
c)
S
S
S
O
0.08
TrtS
HOOC
O
S
NH
O
O
S
6 =
COOH
STrt
0.06
0.04
0.02
0
2 (50%)
10 (91%)
HN
O
6
10
Scheme
2 Synthesis of 1 (top) and 2 (bottom) starting from 1,4-
dibromoterephthalic acid and 1,5-dibromo-2,4-dimethylbenzene, respectively.
The yields under products are over the steps reported in each case. Experimental
HOOC
TrtS
O
S
O
COOH
STrt
NH
O
HN
conditions: (a) KMnO4 (2.2 equiv), BuOH/H2O (1:1), 120 oC, 12 hr; (b) n-BuOH,
t
10 =
H2SO4, 120 oC, 12 hr; (c) (i) Pd2dba3 (0.05 equiv), dppf (0.1 equiv), 2-ethylhexyl
S
O
thioglycolate (2.4 equiv), Pr2EtN (5 equiv), 100 oC, 15 hr; (ii) BuOK (2.9 equiv),
DMF, 100 oC, 3 hr; (d) MeI (4 equiv), K2CO3 (5 equiv), DMF, N2, r.t., o/n; (e) NaOH
2 M, MeOH, reflux, o/n; (f) EDC HCl (4 equiv), NHS (4 equiv), DMF, r.t., o/n; (g) S-
trityl-L-cysteine (2.2 equiv), N2, r.t. o/n; (h) TFA, Et3SiH, r.t., 30 min.
i
t
360
410
460
510
560
λ (nm)
Fig. 1 a) The circular dichroism (CD), b) the UV-vis and c) the fluorescence spectra
of precursors 6 and 10.
2 | J. Name., 2012, 00, 1-3
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H
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DOI: 10.1039/D0SC04317F
HOOC
HOOC
H
O
O
NH
O
O
S
S
S
S
H-H
COOH
S
S
HN
O
O
O
O
S
S
H H
HH
H
N
O
S
COOH
HN
O
S
S
O
O
O
NH
HOOC
S
S
N
H
S
O
COOH
HH
S
O
NH
O
HN
HOOC
S
COOH
H
Fig. 2 a) Top view of the X-ray structure of 6 showing the presence of the quasi-
pentacyclic core through the hydrogen bonding (dashed line) between NH and
OMe. b) side view and c) solid state packing structure of 6 viewed along the crystal
a-axis. All H atoms, except NH, have been removed for clarity. (C – grey, H – white,
O – red, N – blue, S – yellow) – CCDC: 2006236.
The solid state supramolecular packing is dominated by the
trityl interdigitation and an off-centred aromatic stacking
between the BDT cores. Carboxylic acid dimerization is
observed between two neighbouring molecules, organising the
BDTs in two anti-parallel π-tapes separated by 3.2 Å on average.
Individual DCLs of 1 and 2 were prepared by dissolving the
building blocks in water at pH 8. The libraries were stirred in
closed capped vials, allowing for atmospheric oxidation for at
least three days before analysis. The DCL of 1 contained only a
homodimer based on HPLC and LC-MS studies. Increasing the
ionic strength of the DCL by adding 1 M NaNO3 led to the
formation of a new species. LC-MS analysis of this DCL (Fig. 3)
indicated that the new compound has a shorter retention time
despite having double m/z compared to the homodimer, which
suggested an interlocked nature for the species.
The MS and isotope pattern analyses of the peak
corresponding to this new compound have indicated that it
contains four BDT units, while the MS/MS analysis supports the
assumption of an interlocked (catenated) structure of the
molecule (i.e. no fragment with m/z higher than a dimer – Fig.
S33 and S34 for LC-MS characterisation). The species (a
[2]catenane) was isolated for further characterisation.
H-H
Fig. 4 Partial 2D NOESY (red) spectrum (500 MHz, 298 K) of all-donor L-
[2]catenane. The solvent (H2O) was referenced at 4.79 ppm.
In the 1H NMR spectrum we observe that the two signals
corresponding to the aromatic cores are more shielded than the
analogous ones of the homodimer (Fig. S35-36). This indicates
that in the [2]catenane the aromatic protons are shielded due
to the close proximity of the π surfaces in structure. The 2D
NOESY analysis shows cross peaks between the protons in the
aromatic region, suggesting an offset parallel arrangement of
the aromatic cores (Fig. 4 and Fig. S37-38). All the analytical data
for this species allows us to designate it as the first ever all-
donor catenane obtained through DCC. Attempts to enhance
the yield of this [2]catenane by increasing the salt content
(NaNO3) to 5 and 10 M had a minor influence on its formation,
with a maximum yield of 15% being obtained at all salt
concentrations (Fig. S39). The yield was determined by
1
integration of the H NMR spectrum of a static DCL; the yield
determined by integrating the HPLC chromatogram was 12%,
the discrepancy is likely due to the broadening of the HPLC
peaks. As expected, the enantiomeric library (starting from D-
BDT, 1*) gave a quasi-identical distribution with the formation
of the enantiomeric all-donor [2]catenane.
O
COOH
STrt
O
HN
O
S
TrtS
S
NH
5 mM (total concentration)
HOOC
O
pH 8
1 M NaNO3
The [2]catenane and 1 homodimer have similar absorption
spectra with both compounds displaying λmax at 407 nm (Fig.
5a). The bands in the spectrum of interlocked molecule are
broader than those in homodimer spectrum due to a lower
symmetry of the former. The CD spectra of 1 and 1*
homodimers are mirror images, as expected, as the compounds
are enantiomers. On the other hand, the CD spectrum of the
catenane has a different signature with lower ellipticity than the
dimers (Fig. 5b). We also took advantage of the fluorescent
properties of the building blocks and recorded the emission
spectra of the dimer and catenane, in which we observed Stoke
shifts of 51 and 66 nm, respectively. The quantum yields of both
catenane and homodimer 1 have been calculated using
fluorescein as standard.
15%
5.0
6.0
7.0
Time (min)
8.0
9.0
Fig. 3 Reverse-phase HPLC analysis of 1 (5 mM concentration) in the presence of
1 M NaNO3, showing the formation of an all-donor catenane in 15% yield (based
on 1H NMR integration).
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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been detected and a gradual increase of the baseline with
increasing MeOH content of mobile phase the has been
observed.
1.8
1.6
1.4
1.2
1
0.8
0.6
0.4
0.2
0
0.012
0.008
0.004
0
a)
View Article Online
DOI: 10.1039/D0SC04317F
HOOC
O
S
O
COOH
SH
NH
O
HN
O
5 mM (total concentration)
pH 8
HS
S
250
350
450
λ (nm)
550
650
b)
80
40
0
6.0
6.5
7.0
7.5
8.0
8.5
9.0
9.5
10.0 10.5 11.0 11.5 12.0 12.5 13.0
1* homodimer
1 homodimer
Time (min)
Fig. 6 Reverse-phase HPLC analysis of 2 (5 mM concentration) without any
additives (the compound with the triangle contains three extra methyl groups).
-40
-80
all-donor
[2]catenane
In order to understand the stark difference in behaviour for
DCLs of 1 and 2 we turned our attention to molecular modelling.
The self-complementary stacking interactions between the
cores of the isomer building blocks is influenced by the
electronic properties of their  systems. The electron
250
350
λ (nm)
450
Fig. 5 a) The UV-vis spectra (solid lines) of the 1* homodimer (blue) and all-donor
[2]catenane (red) and their respective fluorescence spectra (dotted lines) and b) delocalisation in the two monomer cores has been analysed by
the CD spectra of 1* homodimer (blue), 1 homodimer (green) and all-donor
[2]catenane (red). The UV-vis and CD spectra are normalised.
ACID (anisotropy of the current -induced- density) calculations,
(Fig. 7 e,f), which show the flux of delocalised electrons in -rich
molecules. Both cores result to be conjugated and aromatic as
shown by a diatropic (clockwise) ring current. Therefore, the
electron delocalisation in the BDT and iBDT cores does not yield
itself as a decisive reason for the different behaviour of DCL of
1 and 2.
The results indicated that the catenane is almost five times
(cat= 0.033, dimer= 0.007) more fluorescent than the dimer
(quantum yields). To the best of our knowledge, this is the first
example of an interlocked molecule made via disulphide DCC
that fluoresces.
A 1:1 mixed library containing 1 and 1*, in the absence of
the salt, formed at equilibrium three species: 1 homodimer, 1*
homodimer and the heterodimer (Fig. S46). The equilibrated
library in which the hydrophobic effect was augmented by
adding 1 M NaNO3, contains the heterodimer, the enantiomeric
homodimers,
a heterotetramer, and a hetero all-donor
[2]catenane (Fig. S47). The hetero all-donor mixed chirality
[2]catenane was formed in slightly higher proportion than the
homochiral [2]catenanes from enantiopure libraries (18% vs.
12%, respectively).
Analysis of DCLs prepared by dissolving building block 2 (L-
iBDT) in water at basic pH (8), followed by oxidation in
atmospheric conditions revealed a very different speciation
when compared to the analogous DCLs of 1 (Fig. 6). At
equilibrium, the library contained two main species: a dimer
and a tetramer. The minor species in the DCL consisted of a
pentamer, a trimer and two methylated impurities of the dimer
and the tetramer, respectively. The tetramer (as well as the
pentamer) is a macrocycle and not an interlocked molecule as
indicated by the MS/MS analysis where fragments with masses
higher than a dimer were present (Fig. S54 and S57).
Fig. 7 Chemical structures (a,b) and overlapping spheres optimized geometries of
(isovalue 0.05 e/bohr3) of the BDT and iBDT cores (e,f).
homodimers of
1 and 2 (c, d). Anisotropy induced current densities (ACID) plots
Furthermore, the geometry optimisation (M06-2X/6-
311G/H2O) of the stacked homodimeric aromatic cores
(without any linkage between them and omitting the OMe
substituents) reveals that both core pairs stack in a similar
Addition of 1 M NaNO3 changes the library distribution
significantly (Fig. S52). The HPLC analysis of this DCL indicates
the formation of oligomeric species as no major peaks have
4 | J. Name., 2012, 00, 1-3
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3 G. Gil-Ramírez, D. A. Leigh and A. J. Stephens, Angew. Chem.
fashion with an average distance between the two cores being
3.256 Å (iBDT) and 3.311 Å (BDT) (Fig. S59), leading to the
conclusion that the interaction between them (at this level of
theory) is comparable. The relaxed geometries of the
homodimers of 1 and 2 (M06-2X/6-31G/H2O) shown in Fig. 7 c,d
demonstrate the different conformation adopted by the two
systems: the BDT structure possesses a cavity in which another
aromatic core can be threaded through while the iBDT dimer
adopts a self-complementary geometry which closes the gap
between the π surfaces. In the case of the latter, we postulate
that the presence of the methoxy groups on the same side of
the fused tricyclic system imposes steric demands that prevent
aromatic stacking in aqueous media. Furthermore, calculations
at the same theory level of the enthalpy of formation for each
dimer from its constituent building blocks indicates that the
energy release in the formation of the dimer of 1 is 28.6
View Article Online
Int. Ed., 2015, 54, 6110–6150.
DOI: 10.1039/D0SC04317F
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homodimer of 2. The difference in the enthalpies of formation
and in the geometries adopted by the two dimers could be the
reason why the all-donor [2]catenane forms in the DCL of 1 and
is not present in the DCL of 2.
The different outcomes of the DCLs of these isomers show
the powerful nature of DCC, how selective it can be, and how
narrow the barrier between interlocked and non-interlocked
molecules is.
Conclusions
In conclusion, we report herein the synthesis and
characterisation of the first aromatic all-donor [2]catenane
based on a benzodithiophene core using the DCC approach. The
key structural feature is the formation of an extended aromatic
core, quasi-pentacyclic, through a set of strong NH···OMe
hydrogen bonds. The catenation of two BDT dimers happens
only when the hydrophobic effect is increased by the addition
of an inorganic salt. The isomeric iBDT, despite having the same
quasi-pentacyclic fused core does not form [2]catenane due to
the relative position of the two sulphur atoms which change the
stacking geometry of the cores. The all donor [2]catenane is the
first chiral emissive interlocked molecule synthesised via DCC
that can be used in chiroptical applications, which we
endeavour to investigate.
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Acknowledgements
This work was funded by the EPSRC (DTA TMG, AT) and the
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GA text:
An all-donor [2]catenane has been synthesised via dynamic combinatorial chemistry.
It features stacked benzodithiopnenes which are quasi-pentacyclic through hydrogen
bonding.
GA figure: