Self-complementary purines by quadruple hydrogen bonding

Article abstract of DOI:10.1039/b610239e

The first discrete, self-complementary, quadruply hydrogen-bonded complexes based on the 2,6-diaminopurine (DAP) scaffold have been prepared; regioselective urea formation at the C(2) amino group of the heterocycle allows intermolecular dimerization (K

Full text of DOI:10.1039/b610239e

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Self-complementary purines by quadruple hydrogen bonding{
Alisha M. Martin, Roslyn S. Butler, Ion Ghiviriga, Rachel E. Giessert, Khalil A. Abboud and
Ronald K. Castellano*
Received (in Austin, TX, USA) 21st July 2006, Accepted 16th August 2006
First published as an Advance Article on the web 7th September 2006
DOI: 10.1039/b610239e
prefers anti; DeUG prefers syn).6,7 With a preorganized ADDA
The first discrete, self-complementary, quadruply hydrogen-
bonded complexes based on the 2,6-diaminopurine (DAP)
scaffold have been prepared; regioselective urea formation at
the C(2) amino group of the heterocycle allows intermolecular
dimerization (Kdim y 1–1.6 6 103 M21 in CDCl3) through a
DADA hydrogen bonding motif.
edge and free from competing tautomeric/conformational equili-
bria, DeUG is particularly well-suited to forming tight hetero-
dimeric (complementary) complexes (Kassoc . 107 M21) with
DAAD partners.6 Likewise, both UG and DeUG are designed to
only weakly self-associate and do so by various DA motifs in
CDCl3 (Kassoc for UG y 230 M21; Kdim for DeUG 5 880 M21).6
Herein, we present the first discrete, self-complementary, quad-
ruply hydrogen-bonded complexes based on purines using the
tautomerically-stable 2,6-diaminopurine (DAP) platform (Fig. 1).
Upon regioselective urea formation at the C(2) amino group of
DAP, two intramolecularly hydrogen-bonded, low-energy (anti)
conformers of the ureidodiaminopurine (UDAP),8 1N1 and 1N3
(interconverted through a single C–N bond rotation), are
accessible,9 where the latter is preorganized for intermolecular
dimerization via a DADA hydrogen bonding motif.
Nucleobases are readily available heterocycles for the construction
of self-complementary, quadruply hydrogen-bonded complexes,
among which the pyrimidines have been extensively explored.1,2
For example, the UPy unit of Meijer et al. (derived from
isocytosine) has found applications that span materials science due
to its exceedingly high dimerization constant in organic solution
(Kdim y 107 M21 in CDCl3) via an accessible DDAA3 hydrogen
bonding arrangement.1,4 Surprisingly little work has considered
urea-functionalized purines in this vein, although the bicycles boast
additional sites for functionalization, an expanded p-surface5 and
untapped mechanisms to control assembly strength/dynamics via
the modulation of ring electronics remote from the dimer
hydrogen bonding interface.
Synthetic considerations and X-ray crystallography guided the
choice of substituents shown in Fig. 1; the synthesis of 1a illustrates
the design and execution (Scheme 1). The route begins from
commercially available (or routinely prepared10) 6-chloro-2-
aminopurine (2), derived from guanine. Substituted benzyl
substituents were selected for the N(9) position, primarily due to
their known convenient installation by N-alkylation11 and decent
organic solubility-imparting properties. Standard alkylation
affords 3a at room temperature, its yield somewhat diminished
by the unavoidable formation of the N(7) regioisomer.12
Subsequent displacement of the 6-chloro group with ammonia
To this end, Zimmerman and co-workers have only recently
shown that urea-functionalized guanine (UG) and 7-deazaguanine
(DeUG), unlike UPy, are tautomerically stable (preferring the
N(1)–H tautomer), and that the anti/syn conformational equili-
brium can be controlled by atomic mutation in the fused ring (UG
Department of Chemistry, University of Florida, P.O. Box 117200,
Gainesville, FL 32611, USA. E-mail: castellano@chem.ufl.edu;
Fax: +1 352 846 0296; Tel: +1 352 392 2752
{ Electronic supplementary information (ESI) available: Synthesis,
characterization, copies of 1H NMR spectra for all new compounds,
additional NMR data for 1a (gHMBC, NOESY and VT NMR), and
dimerization data for 1a and 1b. See DOI: 10.1039/b610239e
Fig. 1 Intramolecular hydrogen bonding and intermolecular dimeriza-
tion of ureidodiaminopurine (UDAP) 1.
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solution,16 it does inspire strategies to achieve conformational
control in the UDAP monomers. Consistent with the solid state
data for 5, the chemical shift of its urea Hc proton in CDCl3
(y5 mM) is significantly deshielded to d 11.4 (relative to TMS);
Hb appears at yd 7.2, a value that correlates with the limiting
upfield chemical shift (also for Hb) of monomeric 1 (dmonomer), as
discussed below.
The solution-phase dimerization of 1a and 1b could be analyzed
through routine 1H NMR measurements in CDCl3; representative
data for 1a are shown in Fig. 3. A 2-D NMR (gHMBC)
experiment in CDCl3 at y2 mM was first used to assign the urea
proton chemical shifts (ESI{). The peak at d y12 arises from
intramolecularly hydrogen-bonded Hc, while the Hb signal,
deshielded due to intermolecular hydrogen bonding, appears at
d y9. Dilutions were performed at 25 uC from y5 to y0.1 mM;
five selected spectra are shown in Fig. 3. The Hb resonance was
monitored as it moved upfield throughout the series17 (the Ha
signal could not be followed due to peak broadness and overlap)
and the data was fitted to a non-linear binding equation using
standard software.18 The dimerization constant (Kdim) emerges as
1100 ¡ 360 M21 for 1a (1200 ¡ 200 M21 for the run shown) and
1600 ¡ 380 M21 for 1b, similar values that are the average of four
independent runs in each case. Furthermore, the downfield and
upfield limiting chemical shifts for Hb of 1 appear from the
calculations (ddimer 5 10.1 ¡ 0.1; dmonomer 5 7.2 ¡ 0.1), and are
consistent with variable temperature (VT) NMR experiments
(vide infra) and model compound 5 (vide supra). Finally, while
dimer formation necessarily requires that 1a (and 1b) adopts the
1N3 conformation, direct evidence that this conformation is
populated in solution comes through a NOESY spectrum. Key
NOEs are identified between the N(9) trimethylbenzyl substituent
and both the urea phenyl and Hc protons (ESI{).
Scheme 1 Representative UDAP synthesis; preparation of 1a.
provides 4a. We next found that while most isocyanates react
unusually sluggishly with 4a,13 aryl isocyanates appear to enjoy a
significant reactivity advantage. Hence, treatment of 4a with
phenylisocyanate in the presence of pyridine exploits the
differential nucleophilicity of its C(2) and C(6) amino groups,14
forming 1a regioselectively. Functionalized aryl isocyanates are
equally effective in this reaction. Compound 1b, bearing alkoxy
substituents, was prepared similarly (ESI{) and offers a modest
increase in organic solubility.
Of additional consideration at the design stage was the steric
compatibility of the N(9) benzyl and urea phenyl substituents in
the desired 1N3 conformation.15 We were pleased to find that the
X-ray structure (Fig. 2) of model compound 5 (ESI{) indeed
shows that the desired mode of intramolecular hydrogen bonding
…
to N(3) is accessible through a planar arrangement (N(3) N(12) 5
2.74 s).{ Also observed in the solid state is a near edge-to-face
relationship between the two aromatic substituents (angle between
the least-squares planes of the aromatic rings 5 86.3u); while the
rings are slightly offset with respect to one another in this
orientation (center-to-center distance 5 5.42 s), they are in close
contact (closest carbon–carbon distance 5 3.67 s).16 Although this
type of interaction is expected to be relatively weak in organic
Importantly, VT 1H NMR studies performed with 1a in CDCl3
confirm that dimerization by quadruple hydrogen bonding is the
predominant mode of assembly in the concentration range studied
(ESI{). Upon cooling a y2 mM solution from 55 to 255 uC, the
Fig. 3 1H NMR spectra (500 MHz) of 1a in CDCl3 (25 uC) at the
following concentrations (from bottom to top): 4.7, 2.9, 1.5, 0.59 and
0.16 mM. Data at five additional concentrations was used in the
calculation of Kdim (ESI{). See Fig. 1 for the atom labelling scheme.
Fig. 2 Left: Intramolecular hydrogen bonding of model ureidopurine 5
in the solid state (ellipsoids drawn at the 50% probability level). Right: The
side view of a CPK representation shows the extent of contact achievable
for the two phenyl rings in the N(3) hydrogen-bonded conformer.
4414 | Chem. Commun., 2006, 4413–4415
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chemical shift of Hc moves downfield from d 11.8 to d 12.4. Hb, on
the other hand, shifts even more substantially from d 8.1 to d 10.2
(yddimer for Hb calculated from dilution studies), in accordance
with its intermolecular hydrogen bonding. Also significantly, the
amino protons N(Ha/a9) decoalesce at y5 uC. The chemical shift of
proton Ha9 appears at d y5.9 and remains there as the
temperature is lowered,19 while Ha, participatory in dimer
formation, moves downfield from d 8.4 (5 uC) to d 9.3 (255 uC).
Given that the UDAP derivatives dimerize somewhat more
weakly (by 10-fold) than the most comparable DADA (self-
complementary) quadruple hydrogen bonding system (the alkyl
ureidotriazines of Meijer and co-workers9,20), there is additional
optimization to do and subtleties to be understood. We would
expect the Kdim of 1 to be affected by (a) the interaction of the urea
and N(9) substituents and (b) the use of aryl rather than the more
commonly employed alkyl ureas.9,21 We initiated explorations of
‘‘(a)’’ by preparing the N(7)-alkylated regioisomer of 1a (ESI{).
We were surprised to find that this regioisomer does not dimerize
by quadruple hydrogen bonding in CDCl3;22 hence, interaction
between the N(9) and urea substituents appears to be an important
(and modifiable) parameter in these systems. Along the same lines,
we studied the intrinsic 1N1 vs. 1N3 conformational preference by
computation. When a substituent in the N(9) position is too small
to interact appreciably with the phenylurea group, such as methyl
(1, where R 5 H), computation (MP2/6–31G*//HF/6–31G*)
shows that the 1N1 and 1N3 conformers are essentially isoenergetic,
y0.55 kcal mol21 in favour of the desired 1N3 conformer in the
gas phase. This leaves the monomer conformational equilibrium,
and also likely Kdim, easily perturbed. We are currently developing
the synthetic chemistry to test ‘‘(b)’’.
1 R. P. Sijbesma, F. H. Beijer, L. Brunsveld, B. J. B. Folmer,
J. Hirschberg, R. F. M. Lange, J. K. L. Lowe and E. W. Meijer,
Science, 1997, 278, 1601–1604; F. H. Beijer, R. P. Sijbesma,
H. Kooijman, A. L. Spek and E. W. Meijer, J. Am. Chem. Soc.,
1998, 120, 6761–6769; F. H. Beijer, H. Kooijman, A. L. Spek,
R. P. Sijbesma and E. W. Meijer, Angew. Chem., Int. Ed., 1998, 37,
75–78; S. H. M. So¨ntjens, R. P. Sijbesma, M. H. P. van Genderen and
E. W. Meijer, J. Am. Chem. Soc., 2000, 122, 7487–7493.
2 V. G. H. Lafitte, A. E. Aliev, P. N. Horton, M. B. Hursthouse, K. Bala,
P. Golding and H. C. Hailes, J. Am. Chem. Soc., 2006, 128, 6544–6545.
3 This nomenclature is used throughout the paper: D 5 hydrogen bond
donor; A 5 hydrogen bond acceptor.
4 L. Brunsveld, B. J. B. Folmer, E. W. Meijer and R. P. Sijbesma, Chem.
Rev., 2001, 101, 4071–4097; A. W. Bosman, L. Brunsveld, B. J. B.
Folmer, R. P. Sijbesma and E. W. Meijer, Macromol. Symp., 2003, 201,
143–154; R. P. Sijbesma and E. W. Meijer, Chem. Commun., 2003, 5–16
and references therein.
5 D. W. Guo, R. P. Sijbesma and H. Zuilhof, Org. Lett., 2004, 6,
3667–3670.
6 T. Park, S. C. Zimmerman and S. Nakashima, J. Am. Chem. Soc., 2005,
127, 6520–6521; T. Park, E. M. Todd, S. Nakashima and S. C.
Zimmerman, J. Am. Chem. Soc., 2005, 127, 18133–18142; H. C. Ong
and S. C. Zimmerman, Org. Lett., 2006, 8, 1589–1592; T. Park and
S. C. Zimmerman, J. Am. Chem. Soc., 2006, 128, 11582–11590.
7 For multimeric hydrogen-bonded assemblies of guanines (e.g.
G-quartets) see: J. T. Davis, Angew. Chem., Int. Ed., 2004, 43,
668–698 and references therein.
8 Not shown are the two lowest energy syn-conformers (non-hydrogen-
bonded), calculated at the molecular mechanics level (Amber* and
MM3* in CHCl3) to be y5 kcal mol21 higher in energy (for R 5 H in
Fig. 1).
9 These features have been discussed for various urea-functionalized
heterocycles. See ref. 1 and F. H. Beijer, R. P. Sijbesma, J. Vekemans,
E. W. Meijer, H. Kooijman and A. L. Spek, J. Org. Chem., 1996, 61,
6371–6380.
10 Eur. Pat., EP 543095, 1993.
11 E. Camaioni, S. Costanzi, S. Vittori, R. Volpini, K. N. Klotz and
G. Cristalli, Bioorg. Med. Chem., 1998, 6, 523–533.
12 The regioisomeric mixture depends to some extent on the size of the
electrophile, as the equivalent alkylation with 3,5-diheptyloxybenzyl
bromide yields the desired N(9) isomer in over 80% yield (ESI{).
13 Poor reactivity has also been observed with guanine derivatives (see
ref. 6). In our experience, the nucleophilicity of the amino group on C(2)
is very sensitive to the C(6) substituent. With a deactivating –Cl group in
this position (i.e. 3a), even reactivity with aryl isocyanates is poor.
Strongly activating groups, such as N(CH3)2 (preparation of 5), see
conversion to the urea in minutes at room temperature.
14 S. Porcher and S. Pitsch, Helv. Chim. Acta, 2005, 88, 2683–2704.
15 Ribose groups may be accommodated but have yet to be completely
explored due to their chemical lability during our initial studies (for
similar observations, see ref. 6): A. M. Martin and R. E. Giessert,
unpublished work.
16 E. A. Meyer, R. K. Castellano and F. Diederich, Angew. Chem., Int.
Ed., 2003, 42, 1210–1250.
17 The upfield shift of Hc with dilution demonstrates weakening, through
induction, of the intramolecular hydrogen bond upon dimer decom-
plexation (see ref. 6 for related observations).
18 B. R. Peterson, Associate 1.6, PhD thesis, University of California, Los
Angeles, 1994.
19 This demonstrates that the Hoogsteen edge of the molecule is not
engaged in measurable hydrogen bonding at these concentrations and
temperatures (see ref. 6).
To conclude, the first self-complementary, quadruply hydrogen
bonding purines have been prepared from the readily-available 2,6-
diaminopurine scaffold. The monomers are routinely synthesized
and should offer unique handles (and bioinspired strategies) for the
control of association strength through their multiple substitution
sites, some remote from the hydrogen bonding interface. Their
expanded p-surfaces will facilitate their association into stacked
assemblies and more complex architectures. Explorations in these
directions are currently under way.
We are grateful to the University of Florida and the Research
Corporation (Research Innovation Award (RI-1198) to R. K. C.)
for financial support. R. S. B. and R. E. G. were funded through
University of Florida Alumni Fellowships. K. A. A. wishes to
acknowledge the National Science Foundation and the University
of Florida for funding the X-ray equipment. We are grateful to
Prof. Blake R. Peterson (Penn State) for providing a copy of
Associate 1.6 for the calculation of dimerization constants and
Prof. Adrian Roitberg (UF) for computational time.
20 Comparisons between multiply (.3) hydrogen-bonded systems are not
straightforward. For a discussion, see: O. Lukin and J. Leszczynski,
J. Phys. Chem. A, 2002, 106, 6775–6782.
21 Although the arylurea Hc proton is more acidic (the pKa (DMSO) for
urea is 26.7 and for diphenylurea is 19.6; see: F. G. Bordwell, Acc.
Chem. Res., 1988, 21, 456–463), its carbonyl is a correspondingly weaker
base.
22 While Hc is intramolecularly hydrogen-bonded (d 11.5), Hb is only
modestly deshielded (d 7.8). Weaker DA-type hydrogen bonding may be
operative due to a preferred 1N1 conformation and/or distortion at the
C(6) amino group.
Notes and references
{ Crystal data for 5: C21H21N7O (M 5 387.45), monoclinic, space group
P21/n, radiation type 5 Mo-Ka, l 5 0.71073 s, a 5 9.0629(6),
b 5 19.8629(13), c 5 11.3182(7) s, a 5 c 5 90, b 5 106.862 (1)u,
V 5 1949.9(2) s3, Z 5 4, m 5 0.087 mm21, Dc 5 1.320 g cm23
,
F(000) 5 816, T 5 173(2) K, 4406 independent reflections (Rint 5 0.0337),
final R indices (272 parameters) [I . 2s(I)] were R1 5 0.0374, wR2 5 0.0966
(using 3194 reflections), GOF 5 1.063. Refinement was done using F2.
CCDC 615504. For crystallographic data in CIF or other electronic format
see DOI: 10.1039/b610239e
This journal is ß The Royal Society of Chemistry 2006
Chem. Commun., 2006, 4413–4415 | 4415