Mix and match backbones for the formation of H-bonded duplexes

Article abstract of DOI:10.1039/c5sc04467g

The formation of well-defined supramolecular assemblies involves competition between intermolecular and intramolecular interactions, which is quantified by effective molarity. Formation of a duplex between two oligomers equipped with recognition sites displayed along a non-interacting backbone requires that once one intermolecular interaction has been formed, all subsequent interactions take place in an intramolecular sense. The efficiency of this process is governed by the geometric complementarity and conformational flexibility of the backbone linking the recognition sites. Here we report a series of phosphine oxide H-bond acceptor AA 2-mers and phenol H-bond donor DD 2-mers, where the two recognition sites are connected by isomeric backbone modules that vary in geometry and flexibility. All AA and DD combinations form stable AA·DD duplexes, where two cooperative H-bonds lead to an increase in stability of an order of magnitude compared with the corresponding A·D complexes that can only form one H-bond. For all six possible backbone combinations, the effective molarity for duplex formation is approximately constant (7-20 mM). Thus strict complementarity and high degrees of preorganisation are not required for efficient supramolecular assembly. Provided there is some flexibility, quite different backbone modules can be used interchangeably to construct stable H-bonded duplexes.

Full text of DOI:10.1039/c5sc04467g

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Mix and match backbones for the formation of H-
bonded duplexes†
Cite this: DOI: 10.1039/c5sc04467g
a
a
b
a
*
Giulia Iadevaia, Alexander E. Stross, Anja Neumann and Christopher A. Hunter
The formation of well-defined supramolecular assemblies involves competition between intermolecular
and intramolecular interactions, which is quantified by effective molarity. Formation of a duplex
between two oligomers equipped with recognition sites displayed along a non-interacting backbone
requires that once one intermolecular interaction has been formed, all subsequent interactions take
place in an intramolecular sense. The efficiency of this process is governed by the geometric
complementarity and conformational flexibility of the backbone linking the recognition sites. Here we
report a series of phosphine oxide H-bond acceptor AA 2-mers and phenol H-bond donor DD 2-mers,
where the two recognition sites are connected by isomeric backbone modules that vary in geometry
and flexibility. All AA and DD combinations form stable AA$DD duplexes, where two cooperative H-
bonds lead to an increase in stability of an order of magnitude compared with the corresponding A$D
complexes that can only form one H-bond. For all six possible backbone combinations, the effective
molarity for duplex formation is approximately constant (7–20 mM). Thus strict complementarity and
high degrees of preorganisation are not required for efficient supramolecular assembly. Provided there
is some flexibility, quite different backbone modules can be used interchangeably to construct stable
H-bonded duplexes.
Received 20th November 2015
Accepted 18th December 2015
DOI: 10.1039/c5sc04467g
www.rsc.org/chemicalscience
pyridinecarboxamide oligomers that form double helices due
to aromatic stacking interactions.7c,d Anderson synthesized
Introduction
zinc porphyrin oligomers that assemble into ladders in the
presence of 1,4-diazabicyclo[2.2.2]octane (DABCO). A linear
increase in stability with the length of the ladder was observed,
which indicates cooperative duplex formation, and when olig-
omers of different lengths were mixed in the presence of
DABCO, only length complementary ladders were formed.7e,f
deMendoza described guanidinium oligomers that form
double helices held together by H-bonding interactions with
the sulfate counterions.7g Hunter reported oligoamides that
form duplexes via H-bonding and edge-to-face aromatic inter-
actions. An increase in stability with increasing length was
observed indicating cooperative assembly.7h,i Gong reported
oligoamides containing different sequences of H-bond donor
and H-bond acceptor sites that show sequence selective duplex
formation.7j–o Chen reported self-complementary oligomeric
hydrazide oligomers and amidourea oligomers both of which
form H-bonded duplexes.7p–r Different length spacers between
the H-bonding sites were used to obtain selective assembly of
complementary oligomers. Krische reported aminotriazine and
diaminopyridazine oligomers that form H-bonded duplexes.7s,t
Yashima described oligomers that form helical duplexes
through salt bridge interactions between amidinium and
carboxylate sites.7u–w These systems show sequence selective
and length selective duplex formation, and a template strand
bearing two amidinium binding sites was used to direct the
Linear polymers equipped with complementary recognition
sites have the potential to reproduce the functional properties
of nucleic acids: sequence selective duplex formation, tem-
plated synthesis, self-replication and forced evolution.1 Modi-
ed versions of DNA have been prepared, where the phosphate
linker,2,3 the sugar,4 the backbone or the base pairing system5
have been replaced, and these systems all form stable
duplexes.6 The success of these systems suggests that it might
be possible to make completely different classes of synthetic
information molecule that bear no resemblance to their bio-
logical counterparts.
A number of synthetic systems that form duplexes via
different non covalent interactions have been reported.7 Lehn
described oligo(2,20-bipyridine) ligands that self-assemble into
length specic helical duplexes in the presence of a metal ion.7a
Lehn also reported ligands containing sequences of bidentate
(bipyridine) and tridentate (terpyridine) binding sites which
form sequence specic helicates depending on the properties
of the metal directing the assembly.7b Huc and Lehn described
aDepartment of Chemistry, University of Cambridge, Lenseld Road, Cambridge CB2
1EW, UK. E-mail: herchelsmith.orgchem@ch.cam.ac.uk
bDepartment of Chemistry, University of Sheffield, Sheffield S3 7HF, UK
† Electronic supplementary information (ESI) available: Detailed experimental
procedures with spectroscopic characterization data, 31P NMR titration spectra
and binding isotherms. See DOI: 10.1039/c5sc04467g
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synthesis of a complementary strand bearing two carboxylate and were found to have similar effective molarities for the
units.7x We recently reported a new class of linear oligomeric system in Fig. 1. Duplex formation requires that K EM [ 1 to
molecules that form stable duplexes via the formation of ensure that once the rst intermolecular H-bond is made, all
multiple cooperative H-bonding interactions (Fig. 1).8 Speci- subsequent intramolecular H-bonds are highly favoured, and
cally, oligomers equipped with phenol H-bond donors formed there is no competition from intermolecular interactions that
1 : 1 complexes with oligomers equipped with phosphine oxide would lead to uncontrolled aggregation (intermolecular
H-bond acceptors. The stability of the duplex increases by of an channel in Fig. 2). For the system shown in Fig. 1, K EM z 5, so
order of magnitude for every additional H-bond formed.
duplex formation is reasonably efficient, but there are partially
The efficiency of duplex formation is determined by the bound states present where the H-bonding interactions are
stepwise equilibria shown in Fig. 2.9 The rst interaction in broken some of the time. There are two strategies to improve
duplex assembly is an intermolecular H-bond which has an duplex formation: increase K by changing the H-bonding
association constant K (z300 Mꢀ1 for the phosphine oxide– groups, or increase EM by changing the supramolecular archi-
phenol H-bond). The second H-bond is an intramolecular tecture. In this paper, we explore the effect of backbone archi-
interaction with an equilibrium constant K EM, where EM is the tecture on the effective molarity for duplex formation.
effective molarity for the intramolecular process (z10 mM for
The design of the oligomer architecture in Fig. 1 is modular.
the duplex in Fig. 1). All subsequent H-bonds are intramolecular Fig. 3 illustrates the basic blueprint. The recognition modules
(blue), the chemistry used to synthesise oligomers (red) and the
backbone (black) have been incorporated into the chemical
structure in Fig. 1, such that different properties of the system
can be independently varied, i.e. one module can be changed
without affecting the other two. Fig. 3 illustrates how the
backbone can be changed, but keeping the reductive amination
chemistry that was used for synthesis of the compounds in
Fig. 1 and the same phosphine oxide–phenol recognition
module. Here we investigate changing the constitution of the
backbone by measuring the effect of the three isomeric back-
bone modules in Fig. 3 on the EM for duplex formation for
different combinations of AA and DD 2-mers. Each backbone
module is each composed of an aromatic ring and two methy-
lene groups, but differences in connectivity leads to a variation
in the geometry and exibility of the motif linking the recog-
nition modules. The nomenclature N8/C8/N7 indicates the
atom to which the recognition module is attached and the
length of the linker. The C8 backbone has three exible meth-
ylene groups connecting the recognition sites, while the N8 and
N7 backbones each have two. Thus the N8 backbone is relatively
rigid and extended, the N7 backbone is rigid and shorter, and
Fig. 1 The duplex formed by a phenol 4-mer (DDDD) and a phosphine
oxide 4-mer (AAAA). R is a 2-ethylhexoxy group that provides solubility
in toluene (the anti-parallel structure is shown, but the parallel struc-
the C8 backbone is exible, so that it can explore both elongated
and compact conformations.
ture is also possible).
Fig. 2 Stepwise assembly of a duplex from two complementary oligomers. There is an intermolecular channel that leads to cross-linked
polymeric networks and an intramolecular channel that leads to duplex formation. K is the association constant for formation of an intermo-
lecular interaction between two complementary H-bonding sites (blue bars), EM is the effective molarity for formation of an intramolecular
interaction, and c is the operating concentration.
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Fig. 3 A blueprint for duplex forming molecules. There are three key design elements: one module which defines the chemistry for the synthesis
of oligomers (red), the recognition module which controls intermolecular binding (blue) and the backbone module which links these
components together. Three isomeric backbone modules are shown (R are sites for attachment of solubilising groups). Adapted from ref. 8.
Results and discussion
Synthesis
The N8 and N7 backbones were accessed by reductive amina-
tion of dialdehydes with anilines bearing the recognition
groups. The H-bond donor aniline 4-aminophenol is commer-
cially available. The H-bond acceptor aniline bearing a phos-
Scheme 2
phine oxide group was synthesized as shown in Scheme 1. Di-t-
butyl(chloro)phosphane was treated with formaldehyde to give
alcohol 1, which was reacted with 4-uoro-nitrobenzene in the
presence of K2CO3 to give 2.10 Reduction of 2 gave aniline 3b.
In order to determine effective molarities, H-bond acceptor
and donor 1-mers are required to measure the intermolecular
association constant K. The H-bond donor parameter of 3-
dimethylaminophenol is somewhat lower than the value for
phenol (a ¼ 3.5 compared with 3.8), which suggests that there
may be a substituent effect on the strengths of H-bonding
interactions involving donors attached to the C8 backbone
compared with donors attached to the N7 and N8 backbones.11
The 1-mers corresponding to the N7 and N8 backbones, 4a and
4b (A and D), were therefore synthesized from 3a or 3b by
reductive amination with 2-methoxybenzaldehyde (Scheme 2).12
The 1,4-dialdehyde 9 required for the N8 backbone was
synthesised using a sequence of bromomethylation–acetyla-
tion–reduction–oxidation reactions as shown in Scheme 3.13
The 1,3-dialdehdye 12 required for the N7 backbone was
Scheme 3
prepared from dimethyl 5-hydroxyisophthalate: alkylation of
the phenol group with 2-ethylhexylbromide, followed by
reduction of the esters with LiAlH4 gave diol 11, and oxidation
of 11 with PCC gave 12 (Scheme 3).
Scheme 1
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Compounds 13a and 13b were synthesized by reacting two
equivalents of anilines 3a or 3b with dialdehyde 9 (Scheme
4a). A further reductive amination step was used to cap 13a
and 13b with 2-methoxybenzaldehyde to give 14a and 14b, the
N8 backbone DD and AA 2-mers. Similarly 15a was synthe-
sized by reductive amination of dialdehyde 12 with aniline 3a
(Scheme 4b). Compound 15b was obtained by reacting dia-
ldehyde 12 and two equivalents of aniline 3b to obtain the
diimine, which was then reduced with NaBH4 to give 15b.
Compounds 15a and 15b were then capped by with
2-methoxybenzaldehyde under reductive amination condi-
tions to obtain 16a and 16b, the N7 backbone DD and AA
2-mers (Scheme 4b).
Fig. 4 C8 backbone 1-mers (A and D) and 2-mers (AA and DD).8
The C8 backbone AA and DD 2-mers belong to the family of
oligomers illustrated by the AAAA and DDDD 4-mers in Fig. 1.
The synthesis of these compounds (18a and 18b) and the cor-
responding 1-mers (17a and 17b) used to determine effective
molarities was reported previously (Fig. 4).8
Binding studies
Binding studies for pairwise combinations of the AA and DD 2-
mers were carried out by means of 31P NMR titrations in
toluene. The corresponding 1-mers, A and D, were used to
measure the strength of a single intermolecular phenol–phos-
phine oxide H-bond. The H-bond acceptor phosphine oxides
were used as the host, and a large increase in the 31P NMR
chemical shi was observed upon guest addition in all cases,
which is indicative of H-bond formation.14 The titration data
were t to a 1 : 1 binding isotherm to obtain the association
constants and limiting complexation-induced changes in
chemical shi (Table 1). The association constants for the two
A$D complexes are similar, which indicates that substituent
effects on the phenol–phosphine oxide H-bond are not signi-
cant in these systems. The association constants for the AA$DD
complexes are signicantly larger than the values for the cor-
responding A$D complexes in all cases, which implies that two
H-bonds are formed in a cooperative manner in the 2-mer
duplexes. The large limiting complexation-induced changes in
31P NMR chemical shi, Dd, observed for the AA$DD complexes
support this conclusion. Effective molarities for the formation
of the second intramolecular H-bond in the AA$DD complexes
were determined using eqn (1), and the values are reported in
Table 1.
KðAA$DDÞ
EM ¼
(1)
2
2KðA$DÞ
The effective molarities are very similar for all backbone
combinations, indicating that the ability to form a duplex does
not depend strongly on the conformational properties of the
backbone in these systems. The values of EM in Table 1 are
consistent with the values found for other supramolecular
systems which generally fall in the window 10–1000 mM.15,16
Fig. 5 illustrates the six different backbone combinations
investigated in this paper. The backbones units all have two
methylene groups, and it seems that these linkages provide
sufficient exibility to allow the backbones to adapt to quite
different geometrical requirements. The outcome is that any
backbone combination leads to stable duplex formation, and
the duplex architecture illustrated in Fig. 3 is truly modular with
respect to the backbone component.
Scheme 4
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Table Association constants (K), effective molarities (EM) and
Chemical Science
1
duplex (black) is the major species present in a 1 : 1 mixture of
AA and DD (z50%). The partially bound open complex (blue) is
also signicantly populated (z20%), and the 2 : 1 AA$DD2
complex (green) dominates in the presence of excess DD. The
titration data were also analysed using a 2 : 1 binding isotherm
to allow for the formation of this species towards the end of the
titration, but the association constants determined for the 1 : 1
complexes were not signicantly affected.
limiting complexation-induced changes in chemical shift obtained by
fitting 31P titration data in toluene at 298 K to a 1 : 1 binding isotherm
Complexes Backbone K/Mꢀ1
Dd31P/ppm EM/mM K EM
A$D
4a$4b
250 ꢁ 10
350 ꢁ 20
5.0
4.9
17a$17b8
There are important implications of the results in Table 1 and
the speciation diagram in Fig. 6 for the formation of longer
duplexes from the building blocks described in this paper. As
the lengths of the oligomers increase, the stabilities of the fully
assembled duplexes will increase in proportion to (K EM)N,
where N is the number of recognition modules. Although, the
number of possible competing complexes will increase with N,
the stabilities of these complexes will not increase proportion-
ately, so off-pathway complexes will become increasingly less
signicant as N increases. Fig. 6b shows that even for N ¼ 2, the
values of K EM are sufficiently high that intermolecular
processes leading to the formation of higher order complexes or
polymeric aggregates do not compete with duplex formation at
mM concentrations (<3% in total for a 1 mM mixture of AA and
DD compared with 58% of the two 1 : 1 complexes). On the other
hand, partially bound states of the duplex will be signicantly
populated for longer oligomers. Unless there is cooperative
coupling of neighbouring H-bonding interactions along
a duplex, the probability of breaking a H-bond will be inde-
pendent of N and proportional to (K EM)ꢀ1. Previous results on
the C8 backbone oligomers conrm that the C8$C8 combination
with K EM ¼ 3 is capable of propagating the assembly longer
duplexes (e.g. the AAAA$DDDD complex illustrated in Fig. 1)
AA$DD
14a$14b
16a$16b
18a$18b8
16a$14b
14a$18b
16a$18b
N8$N8
N7$N7
C8$C8
N7$N8
N8$C8
N7$C8
2500 ꢁ 200 4.0
1200 ꢁ 400 6.9
1900 ꢁ 600 5.3
900 ꢁ 200 6.6
1400 ꢁ 200 3.7
20 ꢁ 2
10 ꢁ 3
8 ꢁ 3
5 ꢁ 1
2 ꢁ 1
3 ꢁ 1
2 ꢁ 1
3 ꢁ 1
2 ꢁ 1
7 ꢁ 2
11 ꢁ 2
7 ꢁ 1
920 ꢁ 60
6.0
Table 1 also lists the values of K EM for the six different
backbone combinations. The values are similar for all of the
duplexes, and in all cases K EM is greater than one, indicating
that intramolecular H-bonding is favoured. However, the values
of K EM are not very much greater than one, which implies that
the partially bound open complex shown in Fig. 6a is populated
to a signicant extent. The open complex could also aggregate,
and the other species that competes with formation of the
closed doubly H-bonded 1 : 1 duplex is formation of a 2 : 1
complex (Fig. 6a). Fig. 6b illustrates the speciation of AA for
titration of DD into 1 mM AA for K EM ¼ 5. Under these
conditions, the population of polymeric aggregate (red) is
negligible, and this will always be the case when the concen-
tration of one of the oligomers is less than 1/K (z3 mM). The
Fig. 5 Six different backbone combinations that lead to equally stable duplexes. The C8 backbone is highlighted in purple, the N8 backbone in
orange, and the N7 backbone in green. The anti-parallel structure of 18a$18b is shown, but the parallel structure is also possible.
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association constants for formation of the AA$DD complexes
(103 Mꢀ1) are all an order of magnitude higher than the asso-
ciation constants for formation of the corresponding A$D
complexes (102 Mꢀ1), which can only form one H-bond. In
addition, the complexation-induced changes in 31P NMR
chemical shi are indicative of fully H-bonded complexes in all
cases, indicating that all six backbone combinations lead to
duplex formation with cooperative formation of two H-bonds.
The values of EM measured for intramolecular H-bond forma-
tion leading to duplex formation are remarkably insensitive to
the nature of the backbone (7–20 mM). Thus any of the back-
bone modules described in this paper could be used inter-
changeably to construct stable H-bonded duplexes of longer
oligomers. There is no strong dependence of EM on geometric
complementarity or conformational exibility. It seems that
provided the backbone has sufficient exibility to allow the H-
bonding sites to connect, the precise choice of linker is not
critical.
Acknowledgements
We thank the EPSRC and ERC for funding.
Notes and references
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