Crystal structures of 8-arylethynyl substituted guanosine derivatives: Are hydrogen-bonded ribbons a surprise?

Article abstract of DOI:10.1039/c1ce05618b

Crystal structures of two 8-arylethynyl substituted guanosines reveal twisted hydrogen-bonded ribbon superstructures, contrasting a previous report of guanine quartet formation from 8-aryl derivatives. The structural switch is attributed to the stabilizat

Full text of DOI:10.1039/c1ce05618b

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COMMUNICATION
Crystal structures of 8-arylethynyl substituted guanosine derivatives: are
hydrogen-bonded ribbons a surprise?†
ꢀ
Jaebum Lim and Ognjen S. Miljanic
*
ꢁ
Received 24th May 2011, Accepted 19th June 2011
DOI: 10.1039/c1ce05618b
Crystal structures of two 8-arylethynyl substituted guanosines
reveal twisted hydrogen-bonded ribbon superstructures, contrasting
a previous report of guanine quartet formation from 8-aryl deriva-
tives. The structural switch is attributed to the stabilization of
the ribbon through intermolecular [p/p] stacking between the
optimally positioned electron-poor arylethynyl substituents and
electron-rich guanine nuclei.
Naturally occurring DNA and RNA nucleobases, as well as their
synthetic derivatives, are commonly used motifs in supramolecular
chemistry1 on account of their low cost and well-established
propensity for intermolecular association through hydrogen bonding
and [p/p] stacking. In addition, ribose- and deoxyribose-substituted
nucleobases—known respectively as nucleosides and deoxynucleo-
sides—are readily available chiral (and enantiopure) building blocks.
Among the five nucleobases, guanine has the most diverse supra-
molecular chemistry, as it can self-assemble into discrete dimers and
tetramers, or extended ribbon- and helix-shaped structures.2 The
most common mode of guanine self-assembly is an infinite guanine
ribbon, stabilized by pairs of [C6–O10/H–N11] and [N7/H–N1]
hydrogen bonds (Scheme 1A). Alternatively, discrete guanine quar-
tets3 (Scheme 1B) can be formed when four guanine nuclei organize
into a cyclic tetramer through four [C6–O10/H–N1] and four [N7/
H–N11] hydrogen bonds. Guanine quartets’ symmetry, convergent
geometry, and ability to complex cations make it a versatile and often
used component of functional supramolecular assemblies,2 including
ion transporters,4 gelators,5 liquid crystals,6 drug-delivery vehicles,7
and DNA-based molecular machines.8
What determines whether a given guanine derivative will assemble
into a ribbon or a quartet superstructure? Traditionally, guanine
quartets were favoured only in the presence of a templating metal
cation (e.g. K+) that would be pseudo-chelated by the four carbonyl
oxygens of the quartet structure. However, in a seminal 2000 report,
Sessler and coworkers9 challenged this view by demonstrating that
compound 1 (Scheme 1C) forms a quartet superstructure without
Department of Chemistry, University of Houston, Houston, TX,
77204-5003, USA. E-mail: miljanic@uh.edu; Fax: +1 713 743-2709; Tel:
+1 832 842-8827
Scheme 1 Guanine derivatives can assemble into infinite guanine
ribbons (A) or discrete guanine quartets (B). The latter superstructure is
typically templated by a metal cation; compound 1 (C), however, forms
guanine quartet superstructures without a templating cation.
† Electronic supplementary information (ESI) available: Synthetic
procedures and spectral characterization for all new compounds, and
CIFs for 3 and 4. CCDC reference numbers 806420 and 806421. See
DOI: 10.1039/c1ce05618b
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metal cation assistance. The authors postulated that steric effects
were responsible for the switch. The presence of a (4-dimethylamino)
phenyl substituent in the 8-position of the guanine ring system dis-
torted the ribose substituent into an unprecedented syn-orientation
with respect to the guanine (torsion angle of 42.5ꢀ),10 apparently
forcing the formation of the quartet.
In this communication, we present the crystal structures of two 8-
alkynyl substituted guanine derivatives 3 and 4 (Scheme 2) which
organize into highly twisted hydrogen bonded ribbons, despite the
presence of a substituent in the 8-position. We explain this return to
ribbon superstructures as a consequence of [p/p] interactions
between the electron-poor arylethynyl substituents and electron-rich
guanine nuclei, which were enabled by the optimal match between the
dimensions of 3/4 and the pitch of the guanine ribbon.
Within the guanine ring system, carbon C8 represents the only
position that can be substituted without disturbing any of the
hydrogen-bonding functionalities; sp2-character of this carbon
makes it amenable to transition metal-catalyzed carbon–carbon
bond forming reactions. Much recent interest has been devoted to
the study of 8-alkynyl substituted guanine derivatives; the elec-
tronic properties and rigid geometry of the C^C triple bond in
these compounds make them appealing precursors to fluorescent
monitors of DNA conformations,11 hydrogen-bonded porous
materials,12 organic nanoparticles,13 and novel supramolecular
ensembles.14 However, little is known about the solid-state orga-
nization of this class of modified guanines—a May 2011 search of
Cambridge Structural Database (CSD) revealed no reports of
guanine derivatives with an alkyne subunit.
Compounds 3 and 4 were synthesized (Scheme 2) by a Sonogashira
coupling15 of 8-bromo-20,30,50-tri-O-acetylguanosine (2)16 with
4-ethynylbenzonitrile and 4-ethynylpyridine, respectively. Single
crystals of 3 and 4 were formed by layering their CHCl3 solutions
(8 mg mLꢁ1 for 3; 4 mg mLꢁ1 for 4) with pentane (3) or hexane (4).
Compounds 3 and 4 crystallize in P212121 space group, and are
almost isostructural. Each compound crystallizes with two disordered
molecules of CHCl3 per molecule of guanine derivative.‡
The crystal structure of compound 3 (Fig. 1A) is characterized by
the syn-conformation of the ribose substituent relative to the guanine
nucleus, with a 10.5ꢀ torsional angle between the guanine and ribose
moieties.10 The cyano-substituted phenyl ring is disordered over two
closely related orientations (only one is shown in Fig. 1A), and the
triple bond is slightly bent, with C^C–C angles ranging between
Fig. 1 (A) Crystal structure of 3. (B) Top view of a twisted hydrogen-
bonded guanine ribbon within the superstructure of 3. Hydrogen bonds
ꢂ
ꢂ
are highꢀlighted in green. Contact 1: N/H 2.09 A, N/N 2.95 A, N–H/
ꢀ
ꢂ
ꢂ
N 167.6 . Contact 2: O/H 1.98 A, O/N 2.92 A, N–H/O 161.1 , C]
O/H 128.9ꢀ. (C) Side view of a twisted guanine ribbon (ribose substit-
uents removed for clarity) highlights the 37.6ꢀ angle between the planes of
ꢂ
adjacent guanine nuclei, and a 3.39 A distance between parallel planes,
consistent with [p/p] stacking. Disordered solvent (CHCl3) molecules
are omitted. C—gray, H—white, N—blue, and O—red.
173.8ꢀ and 179.5ꢀ (across both orientations). Aryl and guanine
moieties are essentially coplanar—interplanar angle is 7.0ꢀ. The
supramolecular structure of 3 (Fig. 1B) reveals infinite guanine
ribbons, wherein each guanine nucleus acts as a hydrogen bond17
donor in two interactions, and as an acceptor in another two (see
caption to Fig. 1 for distances and angles). Hydrogen-bonded
guanine ribbons in the superstructure of 3 are twisted, as illustrated in
the side-view in Fig. 1C. The angle defined by the planes of adjacent
hydrogen-bonded guanine rings is 37.6ꢀ, representing the most highly
twisted guanine ribbon reported to date.18 Molecules of 3 reside in
two alternating sets of parallel planes and the distance between two
ꢂ
adjacent planes in each set is 3.39 A. This distance is consistent with
Scheme 2 Synthesis of alkynylated guanosine derivatives 3 and 4.
5310 | CrystEngComm, 2011, 13, 5309–5312
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a [p/p] slipped–stacked interaction between the electron-poor 4-
cyanophenyl ring and the electron-rich guanine nucleus.19
Given the structural similarity between Sessler’s compound 1 and
our derivatives 3 and 4, the difference in their supramolecular orga-
nization is unexpected. Since all three systems are characterized by
complex substituents in the 8-position and the syn-relationship
between the ribose and guanine moieties, some more subtle structural
variations must be responsible for the switch to ribbon structures in 3
and 4.20 We propose that the combination of geometric and electronic
factors stabilizes the twisted ribbon superstructure relative to the
guanine quartet. Fig. 1 and 2 suggest efficient [p/p] stacking between
the alternating guanine nuclei and electron-poor arylethynyl substit-
uents. This is a reasonable proposition for 3 and 4, since their electron-
poor cyanophenyl and pyridyl groups should be electronically
complementary to the electron-rich guanine; in 1, the electronics would
be mismatched, since (4-dimethylamino)phenyl substituent would be
electron-rich as well. In addition, geometric factors play a role: the ꢂ4
Pyridine derivative 4 is virtually isostructural with 3 (Fig. 2). The
molecular structure shows disorder only in the solvent molecules. The
triple bond in 4 is slightly bent (C^C–C angles are 174.7ꢀ and
178.7ꢀ), pyridine and guanine moieties are at a low 4.0ꢀ angle relative
to each other, and guanine and ribose are syn to each other (torsional
angle 7.2ꢀ).10 Just like in the case of 3, compound 4 organizes into
ꢂ
infinite guanine ribbons, stabilized by [N1–H/N7] (2.10 A) and
ꢂ
[N11–H/O10–C6] (2.09 A) hydrogen bonds. Analogous to 3, these
ribbons are twisted, with adjacent guanine planes defining an angle of
36.3ꢀ, and parallel (every other) planes positioned at a distance of
ꢂ
3.23 A.
ꢂ
A long –C^C– unit in 3 and 4 projects their pendant substituents into
an optimal position to stack with the guanine nucleus two sites away in
the emerging ribbon superstructure. The shorter linker length in 1
would not have allowed such a match. Finally, the steric bulk of the
acyl group on the ribose substituents—acetyl (3/4) vs. isobutyryl (1)—
might be contributing to the observed absence of [p/p] stacking in 1,
as its (4-dimethylamino)phenyl group effectively gets buried amongst
the large isobutyryl groups from the neighboring molecules.21
In summary, we have synthesized two new arylethynyl-substituted
guanosine derivatives, whose solid-state structures reveal hydrogen-
bonded ribbon superstructures despite the presence of a substituent in
the 8-position. These results suggest that the balance between guanine
ribbon and quartet superstructures is more subtle than previously
thought, with both steric and electronic factors playing a role. Our
future work in this area is aimed at synthesizing and crystallizing
a series of functionalized guanosine derivatives with minimal struc-
tural differences that would help us dissect the steric and electronic
effects guiding their self-assembly. Results of these studies will be
reported in due course.
We thank Dr James D. Korp (University of Houston) for the
collection and refinement of crystallographic data, and gratefully
acknowledge the financial support of this research by the Welch
Foundation (grant no. E-1768), the donors of the American Chem-
ical Society Petroleum Research Fund (ACS-PRF), University of
Houston (UH) and its Grant to Advance and Enhance Research, and
the Texas Center for Superconductivity at UH.
Notes and references
‡ Crystal data for 3: C27H24Cl6N6O8, Mr ¼ 773.22, 0.45 ꢃ 0.30 ꢃ 0.08
ꢂ
ꢂ
mm, orthorhombic, P212121, a ¼ 9.726(8) A, b ¼ 10.525(2) A, c ¼ 34.007
(2) A, V ¼ 3481.5(4) A , Z ¼ 4, rcalcd ¼ 1.475 g cmꢁ3, m ¼ 0.548 mmꢁ1
,
3
ꢂ
ꢂ
2qmax ¼ 47.08ꢀ, T ¼ 223(2) K, 15 676 reflections collected, 5190 reflec-
tions independent [Rint ¼ 0.062], 389 parameters, R1 ¼ 0.059, wR2
¼
0.169 for reflections with I > 2s(I), and R1 ¼ 0.096, wR2 ¼ 0.206 for all
data, GOF ¼ 1.038, max/min residual electron density +0.61/ꢁ0.33 eꢁ
ꢂ
A
ꢁ3. Crystal data for 4: C25H24Cl6N6O8, Mr ¼ 749.20, 0.45 ꢃ 0.20 ꢃ 0.05
ꢂ
ꢂ
Fig. 2 (A) Crystal structure of 4. (B) Top view of a twisted hydrogen-
bonded guanine ribbon within the superstructure of 4. Hydrogen bonds
mm, orthorhombic, P212121, a ¼ 9.754(1) A, b ¼ 10.353(1) A, c ¼ 31.859
(3) A, V ¼ 3217.4(6) A , Z ¼ 4, rcalcd ¼ 1.547 g cmꢁ3, m ¼ 0.590 mmꢁ1
,
3
ꢂ
ꢂ
2qmax ¼ 47.28ꢀ, T ¼ 223(2) K, 13 581 reflections collected, 4782 reflec-
ꢂ
ꢂ
are highꢀlighted in green. Contact 1: N/H 2.10 A, N/N 2.95 A, N–H/
tions independent [Rint ¼ 0.079], 415 parameters, R1 ¼ 0.058, wR2
¼
ꢀ
ꢂ
ꢂ
N 164.3 . Contact 2: O/H 2.09 A, O/N 2.89 A, N–H/O 153.5 , C]
O/H 130.2ꢀ. (C) Side view of a twisted guanine ribbon (ribose substit-
uents removed for clarity) highlights the 36.3ꢀ angle between the planes of
0.124 for reflections with I > 2s(I), and R1 ¼ 0.120, wR2 ¼ 0.169 for all
data, GOF ¼ 1.218, max/min residual electron density +0.44/ꢁ0.41 eꢁ
ꢁ3
ꢂ
A
.
ꢂ
adjacent guanine nuclei, and a 3.23 A distance between parallel planes,
consistent with [p/p] stacking. Disordered solvent (CHCl3) molecules
are omitted. C—gray, H—white, N—blue, and O—red.
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structure code: WISROF).
10 This angle is defined as the torsional angle between four points: (1) C4
on the guanine nucleus, (2) N9 on the guanine nucleus, (3) C1’ of the
ribose ring, and (4) the ribose ring centroid.
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17 Bond lengths between heavy atoms and hydrogen have not been
normalized to neutron-diffraction determined values.
18 According to this formalism, a perfectly planar guanine ribbon would
be characterized by a twisting angle of 0ꢀ, while a guanine quartet
would have a A twisted ribbon is thus
180ꢀ twisting angle.
a distortion of a ribbon in the direction of a quartet. For other
highly twisted guanine ribbons, see: (a) T. Sato, M. Seko,
R. Takasawa, I. Yoshikawa and K. Araki, J. Mater. Chem., 2001,
11, 3018 (interplanar angle 36.3ꢀ); (b) R. Takasawa, I. Yoshikawa
and K. Araki, Org. Biomol. Chem., 2004, 2, 1125 (interplanar angle
31.6ꢀ).
19 C. A. Hunter and J. K. M. Sanders, J. Am. Chem. Soc., 1990, 112,
5525.
20 CSD reports ten crystal structures of guanine derivatives with a non-
hydrogen substituent in the 8-position (not counting compounds 3
and 4). Virtually all of these structures feature a syn-relationship
between the guanine nucleus and the ribose substituent, with
torsional angles varying between 2.7 and 53.2ꢀ. Despite the
structural similarity, this family of crystal structures shows no
general pattern of guanine–guanine hydrogen bonding. Nine of the
ten reports are structures crystallized from H2O as the solvent,
which significantly disturbs guanine–guanine hydrogen bonding.
Structure codes: BEHLIJ, BGUAOS10, BRGUOS, COXNEI,
DEMXEY, FUYKEP, IGUANM, MOXFIO, TONBEE, and
WISROF.
21 Other, even more subtle, effects cannot be fully excluded. These could
include: (a) significantly lower guanine–ribose torsional angles in 3
and 4, relative to 1 (i.e. 3 and 4 are ‘‘more syn’’ than 1); (b) solvent
effects (disordered CHCl3 molecules established short contacts with
guanine nuclei), or (c) weak [C–H/X] hydrogen bonds established
between a-hydrogens on cyanophenyl and pyridyl rings and
carbonyl oxygens within ribose acetyl groups (see: G. R. Desiraju
and T. Steiner, The Weak Hydrogen Bond In Structural Chemistry
and Biology, Oxford University Press, Oxford, 1999). We believe
that these effects are too small in magnitude to lead to such
a pronounced shift in the hydrogen bonding patterns.
5312 | CrystEngComm, 2011, 13, 5309–5312
This journal is ª The Royal Society of Chemistry 2011