Sequence-selective assembly of tweezer molecules on linear templates enables frameshift-reading of sequence information

Article abstract of DOI:10.1038/nchem.699

Information storage and processing is carried out at the level of individual macromolecules in biological systems, but there is no reason, in principle, why synthetic copolymers should not be used for the same purpose. Previous work has suggested that mon

Full text of DOI:10.1038/nchem.699

ARTICLES
PUBLISHED ONLINE: 27 JUNE 2010 | DOI: 10.1038/NCHEM.699
Sequence-selective assembly of tweezer
molecules on linear templates enables
frameshift-reading of sequence information
Zhixue Zhu, Christine J. Cardin, Yu Gan and Howard M. Colquhoun
*
Information storage and processing is carried out at the level of individual macromolecules in biological systems, but there
is no reason, in principle, why synthetic copolymers should not be used for the same purpose. Previous work has
suggested that monomer sequence information in chain-folding synthetic copolyimides can be recognized by tweezer-type
molecules binding to adjacent triplet sequences, and we show here that different tweezer molecules can show different
1
sequence selectivities. This work, based on H NMR spectroscopy in solution and on single-crystal X-ray analysis of
tweezer–oligomer complexes in the solid state, provides the first clear-cut demonstration of polyimide chain-folding and
adjacent-tweezer binding. It also reveals a new and entirely unexpected mechanism for sequence recognition, which, by
analogy with a related process in biomolecular information processing, may be termed ‘frameshift-reading’. The ability of
one particular tweezer molecule to detect, with exceptionally high sensitivity, long-range sequence information in chain-
folding aromatic copolyimides is readily explained by this novel process.
he idea that digital information might be encoded at the set of molecular machinery—is how co-monomer sequences are
7
molecular level as a linear sequence of monomer residues in to be read .
8
,9
T
a copolymer chain first crystallized some fifty years ago with
We have recently begun, as have others , to explore the possi-
1–3
4
the discovery of the structure and function of DNA, a linear, bility that synthetic copolymers might, in principle, be used to
high-molecular-weight organopolyphosphate in which the infor- store and process digital information. Several groups have described
mation represented by its nucleotide monomer sequences was the development of small, p-electron-rich, aromatic tweezer mol-
5
10–18
found to ultimately specify the amino-acid sequences of proteins . ecules
, and we have recently shown that certain molecules of
Viewed purely as digital information, however, DNA—with its this type can recognize and bind to specific triplet sequences in
1
9–22
four co-monomers—is far more complex than strictly necessary, high-molecular-weight aromatic copolyimides
. Binding occurs
because even the simplest two-monomer copolymer is the logical by means of sterically and electronically complementary p–p
6
23–31
equivalent of a string of binary numbers . It is significant that, in stacking
and hydrogen bonding between the tweezer molecules
biology, no specific information is ever written to DNA. Random and monomer residues (Fig. 1). As in many supramolecular systems
3
2–40
copying errors may be captured by evolution, but the key where aromatic p–p stacking plays a key role
, this interaction
problem—solved in life by the operation of a dauntingly intricate results in very large, ring-current-induced complexation shifts of
O
O
O
O
O
O
O
O
S
O
S
O
S
O
S
O
N
N
N
N
N
N
O
O
O
O
O
O
O
O
O
O
O
O
NH
HN
NH
HN
NH
HN
O
O
S
S
O
O
S
S
O
O
S
O
O
S
S
O
O
O
O
O
O
O
O
O
O
I
I
S
I
Figure 1 | Proposed19–21 chain folding of a polyimide-sulfone and multiple tweezer binding at adjacent triplet sequences. Defining the diarylene-
′
pyromellitimide unit as ‘I’ and the bis(arylsulfonyl)-4,4 -biphenylene residue as ‘S’, each tweezer molecule binds to the triplet monomer sequence ‘SIS’
...
through a combination of complementary p–p stacking and NH O¼C hydrogen bonding. (Note that adjacent triplets are overlapping, because each ‘S’
residue interacts with two tweezer molecules.).
Department of Chemistry, University of Reading, Whiteknights, Reading RG6 6AD, UK. *e-mail: h.m.colquhoun@rdg.ac.uk
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.699
ARTICLES
O
CF3
O
CF3
O
O
S
O
S O
N
N
N
N
O
O
N
N
O
O
O
O
N
N
O
O
O
O
O
O
O
O
O
O
1
2
O
S
O S
O
O
F3C
O
O
F3C
O
O
O
CF3
O
S
O
S
O
O
S
O
S
O
O
O
N
N
O
O
O
O
N
O
O
O
N
O
O
NH2
NH
HN
O
O
F3C
N
O
N
O
O
O
NH2
H2N
O
S
O S
O
O
O
O
4
5
6
F3C
3
F3C
O
O
O
S
O
O
N
N
O
O
O
N
N
O
NH
HN
O
O
O
O
O
O
NH
HN
H
N
N
O
O
O
O
O
S
Fe
O
7
8
9
10
CF3
O
11
Random 1:1 copolymer
13
O
O
N
O
O
O
O
S
O
O
O
N
O
O
O
O
S
O
S
O
N
N
O
O
O
O
CF3
CF3
N
O
S
O
O
N
O
O
S
O
O
S
O
O
n
O
O
m
m
12
1
H NMR resonances arising from the associating components, here oligomers, both linear and macrocyclic. This work finally validates
involving triplet binding sequences19,20. Moreover, NMR data for a the hypothesis of polyimide chain-folding and adjacent-tweezer
range of copolymers show that the tweezer molecules are able to binding, and also reveals a novel mechanism for sequence recog-
‘
read’ sequences that are more extended than simple triplets, by a nition, which, by analogy with a related process in biomolecular
mechanism that we have suggested may involve polymer chain- information processing, we term ‘frameshift-reading’. This wholly
21
folding and multiple adjacent-tweezer binding . In the presence unexpected result explains, for the first time, the ability of one par-
of the tweezer, co-monomer sequences in which two, one or no ticular tweezer molecule to detect, with extraordinarily high sensi-
tweezer molecules can be bound at sequences adjacent to the tivity (see Supplementary Information), long-range sequence
22
central diimide binding site are found to give three separate information in chain-folding aromatic copolyimides .
2
1
diimide resonances . Adjacent-tweezer binding to a chain-folded
polyimide (Fig. 1) would produce additional ring-current shielding Results and discussion
of the ‘observed’ diimide protons (highlighted in blue in the figure), Diimide oligomers 1, 2 and 3 were synthesized by chemical imidi-
4
1
so providing a possible mechanism for the detection of extended zation of mixtures of diamine 4 and the end-capping monoamine
sequence information.
5 with either pyromellitic dianhydride (for 1) or 1,4,5,8-naphthalene-
Here, we report the synthesis and characterization (both in sol- tetracarboxylic dianhydride (for 2 and 3), in the presence of acetic
ution and, crystallographically, in the solid state) of discrete com- anhydride. The products were fractionated by column chromato-
plexes between tweezer molecules and fully defined diimide graphy to afford pure, single oligomers. Attempts to grow
654
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Figure 2 | X-ray structure (two perpendicular views) of a 2:1 complex [8 11] between ferrocenyl tweezer molecule 8 and bis-pyromellitimide oligomer 1.
2
The two tweezer molecules are shown in blue to distinguish the different components of the assembly. The electron-rich pyrenyl ‘arms’ of adjacent tweezers
′
interact with electron-poor pyromellitimide and 4,4 -biphenylenedisulfone units in the oligoimide to generate discrete p stacks containing seven alternating
donor and acceptor aromatic p systems. Tweezer–oligomer binding also involves an essentially linear hydrogen bond (shown in magenta) between an amide
.
..
NH group of each tweezer molecule and a pyromellitimide carbonyl-oxygen atom (H O ¼ 2.26 Å).
diffraction-quality single crystals of complexes between these provide very good evidence for 2:1 (tweezer:oligomer) stoichiometry
oligomers and the previously reported tweezer molecules 6 and 7 of binding, with peaks found at x ¼ 0.39 and 0.32, respectively (cf.
were unsuccessful, but a new type of tweezer (8) containing a ferro- theoretical values of 0.33 for 2:1 and 0.50 for 1:1 binding).
cenyl substituent (but with an otherwise similar structure to tweezer Remarkably however, Job analyses of complexation between the
molecule 6) ultimately gave well-formed crystals of a 2:1 complex internally hydrogen-bonded tweezer 9 and oligomers 1 and 2
with oligoimide 1. The X-ray structure of [8 11] is shown in showed a clear-cut preference for 1:1 binding, with the latter plots
2
1
9–21
Fig. 2, from which it is evident that the previously hypothesized
adjacent binding of tweezer molecules does indeed occur. In tweezer–oligomer binding model established from the structure of
8211], the two tweezer molecules are related by a crystallographic complex [8 11] (Fig. 2) thus fails completely for tweezer molecule 9.
peaking at x ¼ 0.50 and 0.48, respectively (Fig. 3). The 2:1
[
2
inversion centre, and bind to the terminal diimide residues of the However, computational modelling (molecular mechanics with
oligomer. Chain folding of the oligomer leads to the formation of charge equilibration) quickly showed that 1:1 complexation
a multiple p stack comprising seven electronically complementary
components (four electron-rich tweezer arms, two electron-deficient
1
.8
′
pyromellitimide residues and one electron-deficient 4,4 -biphenylene-
1.6
...
disulfone unit). A strong hydrogen bond (N–H O¼C¼2.26 Å,
.
..
/
N–H O¼1738) is found between each tweezer molecule and a
1.4
.2
1.0
.8
0.6
.4
carbonyl group of its bound pyromellitimide residue.
1
The perpendicular distance in the crystal between each proton of
a pyromellitimide residue and the mean plane of a non-adjacent
pyrenyl ring (see Fig. 2) is ꢀ10.5 Å, very close to the value of
0
1
0.8 Å predicted by an earlier computational modelling study of
21
the corresponding tweezer–polymer complex . This brings the
diimide protons well within the ‘0.1 ppm shielding radius’ of the
adjacently bound pyrenyl residue, calculated at ꢀ12.0 Å (ref. 42).
Consequently, in addition to the large complexation shift of the
diimide resonance resulting from tweezer binding at the diimide
unit, additional upfield shifts of the diimide resonance are predicted
0
0.2
0
0
0.1
0.2
0.3
0.4
2]
[2]+[9]
0.5
and
0.6
[2]
0.7
0.8
0.9
1
(
and observed) when tweezer binding is possible at one or both
[
21
=
=
adjacent sequences in a chain-folded polymer . The crystal struc-
[2]+[8]
ture of [8 11] thus provides a clear-cut demonstration of the
2
chain folding and adjacent binding proposed for the detection of Figure 3 | Job plots for complexation of 8 (dashed line) and 9 (solid line)
1
long-range sequence information by tweezer molecules 6, 7 and 8. with bis(diimide) oligomer 2, based on H NMR complexation shifts of the
Confirmation that the adjacent-tweezer binding observed in the aromatic diimide resonances in chloroform/hexafluoropropan-2-ol
crystal can also occur in solution was provided by Job plots for com- (6:1 v/v). Samples had 6 mM total concentration of tweezer and oligomer.
plexation of tweezer molecule 8 with oligoimides 1 and 2 in chloro- The observed peak abscissa values of 0.32 and 0.48 indicate 2:1 and 1:1
form/hexafluoropropan-2-ol(6:1 v/v),usingthecomplexationshifts stoichiometries of binding (tweezer/oligomer) for tweezers 8 and 9,
(Dd) of the singlet diimide resonance in each case. These plots respectively (theoretical values are 0.33 and 0.50).
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a
b
Figure 4 | Minimized computational models (molecular mechanics with charge equilibration) of the 1:1 complex between tweezer molecule
and the bis-pyromellitimide oligomer 1 (a), and the 2:1 complex between tweezer molecule 9 and the tris-diimide oligomer 3 (b). Intramolecular
9
hydrogen bonds are shown in magenta. In complex [9 þ3] (b) the two tweezer molecules are shown approaching from opposite sides of the oligomer chain,
2
although the system is dynamic, and simultaneously complexed tweezer molecules could in fact be bound syn or anti to one another. Van der Waals surfaces
(
2.4 × covalent radii) demonstrate the high degree of shape-complementarity between tweezer molecule 9 and the chain-folded oligoimides. The outer
surfaces of the tweezer arms interact with the pyromellitimide units in both models.
O
O
CF3
O
O
S
O
S O
O
O
N
N
O
O
O
N
O
O
O
O
N
N
O
O
c
b
d
e
a
b'
c'
O
N
O
S
O S
O
O
O
O
CF3
3
Δδ = 0.14 ppm
Δδ = 0.24 ppm
Δδ = 0.23 ppm
d/e
a
b/b'
8.8
8.6
8.4
8.2
8.0
7.8
7.6
7.4
7.2
7.0 ppm
1
Figure 5 | H NMR spectra showing complexation shifts of different resonances for tris-diimide oligomer 3 (lower trace) in the presence of tweezer
molecule 9, at 1:1 (centre trace) and 1:2 (upper trace) molar ratios, respectively. The relative complexation shifts are entirely consistent with the model
′
′
shown in Fig. 4b, in that the protons of the central diimide unit (a: Dd ¼ 0.23 ppm) and 4,4 -biphenylene groups (b/b : Dd ¼ 0.24 ppm) are shielded in the
model by the aromatic ring currents of two pyrenyl groups, whereas the protons of the outer diimide units (d/e: Dd ¼ 0.14 ppm) are shielded by only one
such group. Note that the chemical inequivalence of protons d and e (formally an AB system) is only revealed on tweezer complexation. Spectra were run at
5
00 MHz in CDCl /hexafluoropropan-2-ol (6:1 v/v) at 50 8C and 2 mM total concentration.
3
656
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Figure 6 | X-ray structure of the complex between macrocycle 11 and tweezer molecule 9, showing molecular stacking along the crystallographic
a-direction. Tweezer molecules are shown in blue, emphasizing the alternation of the complementary donor (pyrenyl) and acceptor (diimide and
.
..
biphenylenedisulfone) subunits in the p stack. Intramolecular hydrogen bonds (N–H O¼C) are shown in magenta. The tweezer molecule clearly binds at
′
the 4,4 -biphenylenedisulfone site, but the outer faces of its arms are both able to p-stack, in the crystal, with strongly electron-accepting diimide units.
There is thus a very close analogy between this structure and the model (Fig. 4b) for the binding of tweezer molecule 9 to chain-folding oligomer 3, and by
extension to polymers 12 and 13.
between tweezer molecule 9 and diimide oligomers 1 and 2 could be molecule 8 and analogues such as 6 and 7 have two convergent
′
accounted for in terms of tweezer binding at the 4,4 -biphenylene- N–H groups, each of which can form an intermolecular hydrogen
disulfone unit of the oligomer (Fig. 4a). This gives rise to a five-com- bond to the carbonyl group of a diimide residue in a poly- or oligo-
ponent, complementary p stack in which the diimide residues imide chain (Fig. 2). This would obviously promote tweezer binding
interact with the outer faces of the tweezer arms rather than with at the diimide unit, now leading to complementary p–p stacking
their inner faces as in complex [8 11] (Fig. 2).
between the diimide ring and the inner surfaces of the tweezer
2
A closely related structure was found, computationally, for the arms. As a result, the diamide-type tweezers invariably show selec-
complex between the tris-diimide oligomer 3 and tweezer molecule tive binding at the sequence ‘SIS’ (refs 19,20,21).
9
(Fig. 4b), where two molecules of the tweezer bind at consecutive,
We were unable to isolate diffraction-quality crystals of the pro-
biphenylene-centred ‘ISI’ sequences (Fig. 1). This model leads to the posed 1:1 oligoimide complex [1þ9], but the modelled bipheny-
1
prediction that the H NMR resonances of oligomer 3 associated lene-centred binding mode was indeed identified for tweezer
with the biphenylene units and the central diimide residue (all of molecule 9 by a single-crystal X-ray study of the 1:1 complex
which are shielded by two tweezer–pyrenyl groups) should show
significantly greater complexation shifts (Dd) with tweezer 9 than
those arising from the terminal diimide groups, which are shielded
by only a single pyrene unit. As shown in Fig. 5, this prediction is
borne out in practice, with Dd values (2:1 molar ratio of tweezer
molecule 9 to the tris-diimide oligomer 3) of 0.23 and 0.24 ppm
Table 1 | Graphical representation of frameshift-reading
resulting from the different sequence-recognition
characteristics of tweezer molecules 6, 7, 8 and 9.
Tweezer molecule
Monomer sequence
Pyrene units
Proximal Distal
for protons H and H
contrasting with a Dd value of only
a
b/b’
0.14 ppm for the AB system representing the protons (Hd/e) of
the terminal diimide units. The spectra shown in Fig. 5 were
obtained at 50 8C (fast exchange conditions), because room-temp-
erature spectra were significantly broadened, suggesting an
approach to slow exchange between bound and unbound species.
The different sequence selectivities of tweezer molecules 8 (SIS)
and 9 (ISI) may be accounted for on the basis of their different
hydrogen-bonding characteristics. Historically, tweezer-type mol-
ecules have invariably been found to bind small aromatic guests
through a mechanism analogous to chelation in coordination chem-
6
9
6
9
, 7, 8
S I S I S I S
S I S I S I S
S I S I S F S
S I S I S F S
2
2
2
1
2
2
1
, 7, 8
1
1
0–16
istry, that is, by using the inner surfaces of their tweezer arms
.
S F S I S F S
S F S I S F S
However, when the guest molecule is a chain-folding oligomer or
polymer, it is entirely feasible that—depending on the detailed geo-
metrical parameters and conformational flexibility of the tweezer—
p stacking of the diimide residues to the outer faces of the tweezer
arms could be preferred. Energetically, it makes no difference which
face of the pyrenyl residue interacts with the diimide. Indeed, in the
absence of other types of interaction, outer-face complexation might
even be the norm, and it is clearly favoured for the intramolecularly
hydrogen-bonded diester tweezer 9 (Figs 4– 6), leading to com-
plexation at the sequence ‘ISI’. In contrast, the diamide tweezer
6, 7, 8
9
2
0
0
0
The ‘observed’ protons at the central diimide unit (in green) in the first sequence are shielded to a similar
extent by the pyrenyl residues of both types of tweezer (two proximal and two distal pyrenes).
However, with tweezer molecule 9, the presence of a non-binding hexafluoroisopropylidene-diimide
F) unit at one or both adjacent sites has a more drastic effect on the number of pyrenes shielding
the diimide protons. As a result, the chemical shifts of the three sequences are much more strongly
(
differentiated by aromatic ring-current shielding in the presence of 9 than 6, 7 or 8.
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.699
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a
O
O
O
O
O
O
O
O
O
O
O
O
S
S
S
S
N
N
N
N
N
N
O
O
O
O
O
O
O
O
O
O
O
O
NH
HN
NH
HN
NH
HN
O
O
S
S
O
O
S
S
O
O
S
S
O
O
S
S
O
O
O
O
O
O
O
O
O
O
I
I
I
b
O
O
O
O
O
O
O
O
O
O
O
O
S
S
S
S
N
N
N
N
N
N
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
H S
O2
N
O
O
O
S
S
H S
H S
O2
O2
N
N
O
O
O
O
I
S
I
S
I
S
Figure 7 | Chain folding and multiple binding to different polyimide triplet sequences by different tweezer molecules. Defining the diarylpyromellitimide
unit as ‘I’ and the bis(arylsulfonyl)biphenylene residue as ‘S’, each tweezer molecule binds either to monomer sequence ‘SIS’ (tweezer 6, Fig. 7a) or to ISI
.
..
(
tweezer 9, Fig. 7b). The tweezer–polymer hydrogen-bonding interaction (NH O¼C) found with diamide tweezers such as 6 and 8, but not with the diester
tweezer 9, is possible only for binding at sequence SIS. It should be noted that, following the frameshift, the right-hand tweezer molecule in the lower
diagram is too distant from the ‘observed’ protons (shown in blue) to play any role in ring-current shielding.
between 9 and an analogous macrocyclic oligoimide 11. Here, in place at this residue. Specifying the pyromellitimide unit as ‘I’, the
contrast to all previous tweezer–diimide assemblies for which struc- hexafluoroisopropylidene-diphthalimide group as ‘F’, and the biphe-
tural data are available1
9–21,43
, the imide unit of 11 does not represent nylene-disulfonyl-diamine residue as ‘S’, the allowed septet sequences
the central binding site for the tweezer molecule, which instead binds in this copolymer (centring on the pyromellitimide unit observed by
′
1
at the 4,4 -biphenylene–disulfone unit. However, as with tweezer mol-
H NMR) are then [–SISISIS–], [–SFSISIS– or –SISISFS–] and
ecule 6, where binding to macrocycle 11 occurs at the diimide [–SFSISFS–]. The structure of complex [8 þ1] reported here,
2
43
21
residue , the new macrocycle–tweezer complex [9þ11] packs to gen- together with previous spectroscopic studies , establishes that these
erate an ‘infinite’, complementary stack in which p-electron-deficient sequences can bind three, two and one tweezer molecule of type 8,
diimide residues alternate with p-electron-rich pyrenyl units (Fig. 6). respectively, at their SIS triplet sequences (note that the ‘S’ units are
Conceptually, ring-opening polymerization of the macrocycles in shared or ‘overlapping’ under this terminology). Tweezer binding
such an infinite stack would generate a tweezer-bound, chain-folded at SIS results in large upfield shifts (.2.5 ppm) for the central
homopolymer, with the tweezer molecules located on the diimide resonance in each case, but additional shielding from the
′
4
,4 -biphenylenedisulfone units (‘S’). The diimide residues (‘I’) adjacently bound tweezer(s) present produces further (small) com-
would again stack onto the outer surfaces of the tweezer arms. plexation shifts, so resolving a different diimide resonance for each
The structure of [9þ11] thus confirms that, in a chain-folded different septet sequence. The key point is that the central diimide
polymer, tweezer 9 favours binding to the sequence ‘ISI’ rather residue can bind a molecule of type 8 in all three sequences of this
than to ‘SIS’. Moreover, further analysis shows that this particular type (Table 1).
sequence selectivity provides an immediate explanation for the
Conversely, tweezer 9 binds predominantly at the sequence ‘ISI’
exceptional power of 9 to reveal long-range sequence information and only very weakly, if at all, at the directionally degenerate
1
22
in the H NMR spectra of high-molecular-weight copolyimides .
sequences FSI and ISF. As a result, the central diimide protons of
Consider the 1:1 copolymer 13, in which the hexafluoroisopropy- the septet sequences are now much more sharply differentiated in
lidene-diphthalimide groups generate entirely non-tweezer-binding terms of their susceptibility to ring-current shielding by complexing
sequences. Here, the steric bulk of the hexafluoroisopropylidene unit tweezer molecules. As shown for 9 in Table 1, two tweezer molecules
and the twisted orientation of the two connected phthalimide bind to [–SISISIS–], one to [–SFSISIS– or –SISISFS–] and none to
groups combine to ensure that direct tweezer binding cannot take [–SFSISFS–]. Consequently, interaction with 9 means that the
658
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NATURE CHEMISTRY DOI: 10.1038/NCHEM.699
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central diimide residues in these septet sequences are shielded washed with methanol and dried at 80 8C for 3 h. The crude product was purified
by column chromatography (dichloromethane:methanol 99:1, v/v), giving 1 as a
pale yellow, crystalline solid (0.36 g, 27%). M.p. 309 8C; H NMR (700 MHz,
directly by two, one and no pyrenyl units, respectively. This is a
very different situation from that described for complexation of 8
to the same sequences, where the central, ‘observed’ diimide
1
CDCl :hexafluoropropan-2-ol 6:1, v/v) d (ppm) ¼ 8.49 (s, 4H), 7.97 (d, J ¼ 8.6 Hz,
3
4
H), 7.90 (d, J ¼ 9.0 Hz, 4H), 7.77 (d, J ¼ 7.9 Hz, 2H), 7.75 (s, 2H),
protons are shielded directly by two pyrenyl residues in all cases. 7.71 (d, J ¼ 8.5 Hz, 4H), 7.70 (t, J ¼ 7.9 Hz, 2H), 7.66 (d, J ¼ 7.9 Hz, 2H),
7
7
.60 (t, J ¼ 8.1 Hz, 2H), 7.33 (dm, 2H), 7.19 (dm, 2H), 7.18 (t, J ¼ 2.1 Hz, 2H),
The novel sequence selectivity discovered in this work for tweezer
molecule 9 (that is, ‘ISI’ rather than ‘SIS’) thus provides a simple
explanation for the extraordinarily high sensitivity to this tweezer
13
.17 (d, J ¼ 9.0 Hz, 4H); C NMR (62.5 MHz, CDCl :hexafluoropropan-2-ol 6:1,
3
v/v) d (ppm) ¼ 165.7, 165.5, 162.4, 155.8, 144.9, 140.9, 137.4, 137.3, 134.3, 132.8,
1
1
32.3, 131.5, 131.3, 130.5, 130.4, 129.9, 128.9, 128.4, 126.3, 123.7, 123.6, 123.4, 121.3,
20.1, 118.9, 118.8; IR (Nujol): 1,774, 1,713 (imide nC ¼ O), 1,369 (nC–N), 1,241
1
of H NMR resonances associated with long-range sequence infor-
22
21
mation . Conversely, the ‘anomalous’ behaviour of copolyimide (nC–O–C), 1,107 cm ; MS (MALDI-TOF): m/z ¼ 1,357. Calcd. for
1
þ
[
(
C70H36F N O S þ Na] 1,357. Analysis (calcd., found for C
H F N O S2): C
70 36 6 4 14
H NMR resonances in the presence of tweezer molecule 9 can
6
4
14
2
62.97, 62.64), H (2.72, 2.88), N (4.19, 4.12%). Oligomers 2 and 3 were synthesized
now be seen, in conjunction with Table 1, to provide strong evidence
that this molecule does indeed display a general preference for
binding to the triplet sequence ‘ISI’ rather than ‘SIS’.
and isolated by an analogous method, replacing pyromellitic dianhydride with
,4,5,8-naphthalenetetracarboxylic dianhydride.
1
In reality the situation is not quite so clear-cut, because even the
Synthesis of the ferrocenyl tweezer molecule 8. A suspension of 5-bromoisophthalic
diimide resonance arising from the ‘non-9-binding’ sequence acid (0.245 g, 1.00 mmol) in thionyl chloride (10 ml) was stirred at reflux under dry
nitrogen for 2 h. Evaporation of excess thionyl chloride under reduced pressure gave an
[
–SFSISFS–] does undergo a small upfield shift in the presence of
off-white solid. This residue was dissolved in dichloromethane (50 ml), and
-pyrenemethylamine hydrochloride (0.536 g, 2.00 mmol) and triethylamine (1 ml)
were added to the solution. The mixture was stirred at room temperature overnight,
this tweezer. It is already known that 9 can bind weakly to a
diimide residue , and because the NMR experiments described
1
22
here all show fast exchange between bound and unbound tweezer and the resulting solid was filtered, washed with water (3 × 30 ml) and methanol
molecules, it seems that the strong ‘ISI’ complexation proposed (2 × 40 ml), and dried to yield a cream crystalline solid (0.659 g, 95%). To a
suspension of this bromo-substituted tweezer molecule (0.336 g, 0.500 mmol) in
for tweezer 9 will be dynamically superimposed on much weaker
toluene (500 ml) was added tetrakis(triphenylphosphine)palladium(0) (0.029 g,
‘
SIS’ binding, with both mechanisms operating simultaneously on
0
.025 mmol), ferroceneboronic acid (0.120 g, 0.520 mmol) and sodium carbonate
0.106 g, 1.00 mmol) in water (5 ml). The mixture was heated under reflux for
stant K , measured (using the UV–Vis dilution method, based on 2 days, cooled and diluted with toluene (200 ml) and water (200 ml). The organic
the NMR timescale. Consistent with this, the 1:1 association con-
(
a
the charge-transfer band at 551 nm) for the binding of tweezer mol- phase was washed with 5% HCl, then with water, dried over MgSO , and evaporated
4
to dryness. The crude product was purified by column chromatography
(dichloromethane as eluent) to give 8 as a yellow, crystalline solid (0.284 g, 73%
ecule 9 to the chain-folding oligomer 2, was found in this work to be
2
1
21 22
780 M , more than five times higher than the value (140 M
)
of
1
yield), m.p. 243 8C; H NMR (250 MHz, DMSO-d ) d (ppm) ¼ 9.41 (t, J ¼ 5.4 Hz,
6
Ka for the binding of 9 to the simple diimide 10. In the context of
2H), 8.54 (d, J ¼ 9.3 Hz, 2H), 8.33–8.25 (m, 9H), 8.21 (d, J ¼ 1.5 Hz, 2H), 8.16 (s, 4H),
this 500% increase in binding constant, it should be noted that 8.15–8.04 (m, 4H), 5.28 (d, J ¼ 5.4 Hz, 4H), 4.88 (s, 2H), 4.38 (s, 2H), 4.01
13
the experimental error in binding constants determined by the (s, 5H); C NMR (62.5 MHz, DMSO-d
) d (ppm) ¼ 166.2, 140.3, 135.0, 133.2,
31.1, 130.7, 130.5, 128.5, 128.0, 127.8, 127.4, 127.3, 127.1, 126.6, 125.6, 125.5, 125.1,
24.6, 124.4, 124.3, 123.6, 83.7, 69.8, 69.7, 67.0, 43.5; IR (Nujol): 1,620 (nC ¼ O),
6
1
1
1
UV–Vis dilution method is normally of the order of 15% (ref. 44).
We have thus established, through studies of fully defined oligo-
mers and their tweezer complexes, that two different designs of
21
,376 (nC-N), 845 cm ; MS (MALDI-TOF): m/z ¼ 777. Calcd. for
þ
þ
[
C52H36FeN O þ H] , 777; for [C
H
FeN O þ Na] , calcd. 799; found 799;
2
2
52 36
2 2
tweezer molecules (exemplified by 8 and 9) have structures that Analysis (calcd., found for C52
H FeN O ): C (80.41, 79.95), H (4.67, 4.66),
36 2 2
are complementary to two different triplet sequences in chain- N (3.61, 3.59%).
folding polyimide sulfones. This situation is faintly reminiscent of
the relationship between the different tRNAs (each having a differ- Received 13 January 2010; accepted 10 May 2010;
ent ‘binding codon’) and mRNA (ref. 45). Correspondingly, homo- published online 27 June 2010
polyimide 12 can be represented as the sequence . . .SISISISISIS. . .,
with tweezer molecules 6, 7 and 8 binding to the triplets ‘SIS’, while
the present work shows that tweezer molecule 9 binds preferen- 1. Watson, J. D. & Crick, F. H. C. A structure for deoxyribose nucleic acid. Nature
tially to the sequence ‘ISI’, so that the ‘reading frame’ for 9 can be
thought of as being shifted to the left or right by a single
monomer residue (Fig. 7).
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Acknowledgements
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Z.Z. and H.M.C. designed the synthetic and spectroscopic experiments and interpreted the
resulting data. Z.Z. carried out the experiments and co-wrote the paper. C.J.C. and Y.G.
undertook the crystallographic work, including structure solution, refinement and data
analysis. H.M.C. conceived and supervised the project, generated the graphics and
wrote the paper.
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Additional information
The authors declare no competing financial interests. Supplementary information and
chemical compound information accompany this paper at www.nature.com/
naturechemistry. Reprints and permission information is available online at http://npg.nature.
com/reprintsandpermissions/. Correspondence and requests for materials should be
addressed to H.M.C.
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