Substituent control over dimerization affinity of triply hydrogen bonded heterodimers

Article abstract of DOI:10.1021/ol102619u

Linear arrays of hydrogen bonds represent important elements of the supramolecular toolkit for receptor design, assembly of supramolecular polymers, and other well-defined supramolecular structures. It is illustrated that remote substituent effects contro

Full text of DOI:10.1021/ol102619u

ORGANIC
LETTERS
2011
Vol. 13, No. 2
240-243
Substituent Control over Dimerization
Affinity of Triply Hydrogen Bonded
Heterodimers
Adam Gooch,† Andrea M. McGhee,† Maria L. Pellizzaro,† Christopher I. Lindsay,§
and Andrew J. Wilson*,†,‡
School of Chemistry and Astbury Centre for Structural Molecular Biology, UniVersity
of Leeds, Woodhouse Lane, Leeds LS2 9JT, U.K., and Huntsman Polyurethanes,
EVerslaan 45, 3078 EVerberg, Belgium
a.j.wilson@leeds.ac.uk
Received November 1, 2010
ABSTRACT
Linear arrays of hydrogen bonds represent important elements of the supramolecular toolkit for receptor design, assembly of supramolecular
polymers, and other well-defined supramolecular structures. It is illustrated that remote substituent effects control dimerization affinity in a
predictable manner using a conformer independent ureidoimidazole DDA motif and its amidoisocytosine based AAD partner.
The design and synthesis of linear arrays of hydrogen
bonds,1-5 capable of high affinity and high fidelity interac-
tion6,7 with complementary partners, is a key area in modern
supramolecular chemistry. Such motifs form important
components of supramolecular polymers5,8-10 and other
well-defined supramolecular assemblies.11 A number of
strategies and control features can be employed to tune the
dimerization affinity of both homo and heterocomplementary
arrays.1,2,5 In addition to the number of hydrogen bonds, the
arrangement12-14 and spacing between donors (D)/acceptors
(A)15 within an array play a key role, as do the tauto-
† School of Chemistry, University of Leeds.
‡ Astbury Centre for Structural Molecular Biology, University of Leeds.
§ Huntsman Polyurethanes.
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10.1021/ol102619u  2011 American Chemical Society
Published on Web 12/14/2010

meric16-18 and conformational preferences.19-23 It has been
shown that tautomeric and conformational preferences of
linear arrays can be modulated through remote substituent
effects.16,20,24 In contrast, the ability to predictably control
dimerization affinity through electronic substituent effects
has not been demonstrated; however, this feature has been
noted to play a role. As early as 1967, Kyogoku and co-
workers25 noted variation in the stability of adenine-thymine/
uracil pairs incorporating substituents directly attached to the
pyrimidine/purine ring systems. Meijer and co-workers also
highlighted a prominent role for acylation, in controlling
dimerization affinity of synthetic DAD-ADA arrays.26 Al-
though some systems exhibit the expected increase in
dimerization affinity due to addition of the electron-
withdrawing acyl group, others do not because of changes
in the preferred conformation that result upon acylation.
Herein we illustrate experimentally that remote substituent
effects control dimerization affinity in a predictable manner
for a series of DDA-AAD arrays. In addition, we present
theoretical evidence from molecular modeling studies to
support our findings.
Figure 1
available to compounds 1a and 2a.
. Possible tautomeric and conformational configurations
In this study we exploited the ureidoimidazole 2a and
amidoisocytosine 1a motifs previously introduced by our
group.23 The ureidoimidazole motif 2a is suitable for
studying remote electronic substituent effects because al-
though the hydrogen-bonding array may adopt two tauto-
meric configurations, these are very similar and either of the
conformations that must be adopted as a consequence of the
enforced intramolecular hydrogen bonding presents a DDA
array (Figure 1). For 1a, intramolecular hydrogen bonding
limits the tautomeric and conformational diversity available
to the amidoisocytosine motif. Two different tautomers are
possible, only one of which presents the required AAD array.
Similarly to the syntheses of AAD 1a and conformer
independent DDA 2a,23 we synthesized a series of these
compounds with different substituents in the para position
of the aromatic ureido/amido ring system as illustrated in
Scheme 1. Syntheses of Compounds 1 and 2
1
Scheme 1 (see Supporting Information for details). The H
NMR spectra of all compounds exhibit broad resonances for
the NH protons, which is consistent with fast interconversion
between all possible tautomers and conformers.
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1H NMR titrations were performed in deuterated chloro-
form and analyzed using HypNMR27 (see Supporting
Information for procedural details). Dimerization constants
were also obtained for each compound (see Supporting
Information); however, in concordance with our earlier
observations for the parent compounds 1a and 2a, all of the
compounds were found to exhibit negligible self-association/
dimerization. This factor was therefore not considered further
in our determination of the association constants. With the
available compound set, we were able to perform a sufficient
number of titrations with both amidoisocytosine 1a (X )
H) and ureidoimidazole 2a (Y ) H), where the substituent
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Org. Lett., Vol. 13, No. 2, 2011
241

amide bond insulates against electronic substituent effects,30
and this seems reasonable here; electron-withdrawing groups
destabilize positive charge development on the carbonyl
carbon, making it a poorer intramolecular hydrogen-bond
acceptor, but stabilize negative charge development on the
NH nitrogen, making it a better hydrogen-bond donor. The
two properties effectively cancel one another, and there is
little meaningful change across the series.
In the absence of detailed structural information, we turned
to molecular modeling to provide support for these results.
Calculations at B3LYP/6-31G* basis set using Gaussian0331
on the binding conformation of the monomers were per-
formed, and electrostatic potential surfaces were added
(Figure 3). The potential along the recognition face of the
ureidoimidazole series varies significantly depending on the
substituent present, whereas there is less of a change for
the amidoisocytosine series. The amidoisocytosine pyridone
functional group has a significant negative potential that is
unaffected by proximal substituents. In contrast the ure-
idoimidzaole has a positive potential centered on the urea
group that changes considerably depending on the substituent.
Mulliken analysis32 (see Supporting Information) supports
the visual confirmation of the effect.
1
Table 1. Association Constants Determined by H NMR
Titrations (300 MHz, CDCl3) for the Interaction between
Compounds 1 and Compounds 2
complex
Ka × 103 M-1
complex
Ka × 103 M-1
1a·2a
1b·2a
1c·2a
1d·2a
1e·2a
33 ( 16
41 ( 3.9
25 ( 20
18 ( 13
10 ( 7.9
1a·2b
1a·2c
1a·2d
1a·2e
1a·2f
3.8 ( 2.1
3.8 ( 2.2
1.9 ( 0.8
16 ( 8.4
8.1 ( 2.8
84 ( 22
1a·2 g
1a·2 h
86 ( 34
on the complementary partner is varied, to establish a trend
in each case. Each titration was performed in triplicate with
the standard deviation given as the error. For the amidoiso-
cytosine series association toward 2a ranges from 40,000
M-1 (Y ) OMe) to 10,000 M-1 (Y ) CO2Me) (Table 1);
this 4-fold variation represents a minor effect. In contrast,
the variation in association constants for binding of 1a to
the ureidoimidazole series is much more dramatic, covering
almost 2 orders of magnitude from 3800 M-1 (Y ) OMe)
to 86,000 M-1 (Y ) CO2Me).
1
The error in determining association constants using H
NMR titration can be high; indeed, an order of magnitude
variation in the association constants determined for the
thymine-diamidopyridine interaction has been reported.26,28
However, for this internally consistent set of experiments,
the ureidoimidazole series qualitatiVely correlates with the
Hammett parameter σ (Figure 2).29 For the ureidoimidazole
series a simplistic explanation for the effect can be made on
the basis of electron-withdrawing substituents on the phenyl
ring of the ureidoimidazole stabilizing negative charge
development on the nitrogen atom of the NH donor, making
it a more effective hydrogen bond donor and leading to a
higher Ka. For the amidoisocytosine series the situation is
more complicated. It has previously been suggested that the
Figure 3. Electronic potential surfaces for (a) amidoisocytosine and
(b) ureidoimidazole series with different substituents (tBu group
on ureidoimidazole not included in electronic structure calculations).
In conclusion we have illustrated that dimerization affinity
of linear arrays can be predictably controlled through remote
substituents. We expect these observations to be broadly
applicable to other linear arrays. In terms of using such arrays
for supramolecular assembly, the implications are 2-fold: (a)
the ability to systematically control dimerization affinity
means an appropriate array from the available toolkit can
be selected and functionalized as necessary without recourse
Figure 2. Hammett plots for the interaction of 2a with 1a-1e and
for the interaction of 1a with 2a-2h (conditions for determination
of association constants as for Table 1).
242
Org. Lett., Vol. 13, No. 2, 2011

to design and synthesis of new motifs, and (b) an appropriate
choice of linking chemistry to the array can be selected that
has a predictive effect when the array is to be employed as
a component of a self-assembling system. For instance, given
the key role of dimerization affinity in supramolecular
polymers5,8-10 and the use of ester33 and ether34-36 linkages
to append hydrogen bonding groups to polymer chains, this
is likely to have a significant effect on polymer properties.
It is worth noting in this context that high affinity motifs
are not a prerequisite for supramolecular polymerization;
supramolecular polymers have previously been described
where dimerization constants are smaller than the magnitude
of the effects described in the current study.37 Our group
will explore this avenue of investigation in the future.
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Acknowledgment. This work was supported by the
Leverhulme Trust [F/00122/AN] and EPSRC [EP/C007638/
1].
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Wallingford CT, 2004. See Supporting Information for full reference.
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Supporting Information Available: Synthetic procedures,
characterization, details of electronic structure calculations,
details of binding studies, and additional titration curves. This
material is available free of charge via the Internet at
http://pubs.acs.org.
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AdV. Mater. 2005, 17, 2824–2428.
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