Synthesis of N-substituted pyrido[4,3-d]pyrimidines for the large-scale production of self-assembled rosettes and nanotubes

Article abstract of DOI:10.1021/jo4019792

N-substituted pyrido[4,3-d]pyrimidines are heterocycles which exhibit the asymmetric hydrogen bonding codes of both guanine and cytosine at 60 angles to each other, such that the molecules self-organize unambiguously into a cyclic hexamer, assembled via 18 intermolecular hydrogen bonds. The synthesis is straightforward and can be concluded in six steps from the commercially available malononitrile dimer. X-ray crystallographic analysis of the supermacrocyclic structure shows an undulating disk with a ca. 10.5 A cavity, the centers of which do not overlap sufficiently to describe a channel in the solid state. However, AFM, SEM, and TEM imaging in solution reveals the formation of 1D nanostructures in agreement with their self-assembly into rosette supermacrocycles, which then stack linearly to form rosette nanotubes.

Full text of DOI:10.1021/jo4019792

Article
pubs.acs.org/joc
Synthesis of N‑substituted Pyrido[4,3‑d]pyrimidines for the Large-
Scale Production of Self-Assembled Rosettes and Nanotubes
†
†
†
‡
†
,†
Asuman Durmus, Gorkem Gunbas, Steven C. Farmer, Marilyn M. Olmstead, Mark Mascal,*
‡
‡
‡
,‡,§,∥
Belete Legese, Jae-Young Cho, Rachel L. Beingessner, Takeshi Yamazaki, and Hicham Fenniri*
†
Department of Chemistry, University of California Davis, 1 Shields Avenue, Davis, California 95616, United States
‡
Department of Chemistry and National Institute for Nanotechnology, University of Alberta, 11421 Saskatchewan Drive, Edmonton,
Alberta T6G 2M9, Canada
§
Department of Chemical Engineering, Northeastern University, 360 Huntington Avenue, Boston Massachusetts 02115, United
States
∥
Qatar Biomedical Research Institute, Qatar Foundation, P.O. Box 5825, Doha, Qatar
*
S Supporting Information
ABSTRACT: N-substituted pyrido[4,3-d]pyrimidines are het-
erocycles which exhibit the asymmetric hydrogen bonding
codes of both guanine and cytosine at 60° angles to each other,
such that the molecules self-organize unambiguously into a
cyclic hexamer, assembled via 18 intermolecular hydrogen
bonds. The synthesis is straightforward and can be concluded
in six steps from the commercially available malononitrile
dimer. X-ray crystallographic analysis of the supermacrocyclic
structure shows an undulating disk with a ca. 10.5 Å cavity, the
centers of which do not overlap sufficiently to describe a channel in the solid state. However, AFM, SEM, and TEM imaging in
solution reveals the formation of 1D nanostructures in agreement with their self-assembly into rosette supermacrocycles, which
then stack linearly to form rosette nanotubes.
INTRODUCTION
ensemble of 18 intermolecular hydrogen bonds, with each base
hybrid pairing contributing an association energy of 29.7 kcal
mol . Recently, base hybrids with functional side chains (such
■
The two principal branches of supramolecular chemistry, host−
guest complexation and molecular self-assembly, have each
yielded prodigious fruit in their respective spheres of science.
While the former has provided a basis for multiple sequestering
and sensing technologies, the latter has become largely
associated with the burgeoning fields of crystal engineering
and nanotechnology. In particular, materials that self-assemble
into nanotubes have been the focus of intense activity, due to
their potential to engage in selective (ionic, electronic,
−1
6
as 2), enabling the co-organization of virtually any species in
4
,5,7
the hexagonal periphery have been reported.
The synthesis
of G∧C derivatives using nucleophilic aromatic substitutions,
reductive amination, and cross-coupling chemistry have also
been reported as a means to functionalize the resulting
4
,5,7
assemblies.
Concurrent with these studies and continuing to the present
1
time, several other cyclic, self-organized H-bonding systems
photonic) transport processes.
Despite the ongoing interest in populating the supra-
molecular toolkit with new descriptions of noncovalent
8
have been described in the literature. Interest remains high, for
example, in the cyclic guanine quadruplex observed in nucleic
9
2
acids and two-dimensional patterning for the selective
bonding, recent examples being anion−π interactions and
10
3
adsorption of guest entities onto surfaces. But perhaps the
most attractive opportunity presented by disk-shaped assem-
blies is to stack them, and if there is a void in the center of the
disk large enough to accommodate a separate species, a
nanotube is the result. While this behavior was previously
demonstrated in the case of nucleobase hybrid roset-
halogen bonding, the hydrogen bond remains prominent in
the design of both solution and solid-state self-organizing
systems, due to its strength and directionality, witnessed by the
extent to which it occurs in nature across a variety of functional
and structural roles.
G∧C nucleobase hybrid 1 possesses the hydrogen-bonding
faces of both guanine and cytosine at 60° angles to each other,
defining an algorithm for the generation of hexagonal order on
4
d,5b−d,11
tes,
the synthetic approaches to the subunits have
5c,d
generally involved considerable effort. Furthermore, despite
4,5
the extensive characterization of aggregates of these species by a
the supramolecular scale. The presentation of reciprocal,
asymmetric hydrogen-bonding codes (i.e., DDA-AAD, where A
=
H-bond acceptor, D = H-bond donor) permits no ambiguity
Received: September 6, 2013
Published: October 16, 2013
in the recognition process and results in a highly robust
©
2013 American Chemical Society
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4
d,5c,d,11
variety of spectroscopic and imaging techniques,
only a
with in situ generated trimethylsilyl iodide to target compounds
single solid-state structure of a DDA-AAD coded species (1 )
3.
6
4a
has been reported to date. Here, we describe an efficient and
short synthetic approach to the new hexamer-forming G∧C
hybrid 3, its X-ray crystal structure, and the imaging of the
rosette nanotubes (RNTs) generated therefrom.
We succeeded in crystallizing 3a by heating a small sample in
12
DMSO and cooling the solution slowly to room temperature.
The molecule crystallizes in the triclinic P1 space group, with
̅
three independent molecules of 3a in the asymmetric unit along
with three molecules of dimethyl sulfoxide. Two such units
related by inversion merge together to form the super-
macrocyclic structure shown in Figure 1a. The hydrogen
bonds between the six molecules of 3a range from 2.768 Å
(N···O) to 2.899 Å (N···N). In addition, the other NH2
hydrogen is engaged in intramolecular hydrogen bonding to
its neighboring carbonyl oxygen at an average N···O distance of
2.656 Å, giving a total of 24 hydrogen bonds per hexamer. Six
DMSO molecules around the periphery and two in the interior
of the hexamer contribute another eight hydrogen bonds to the
overall structure. All three side chains differ conformationally,
RESULTS AND DISCUSSION
■
A key design feature in our synthetic strategy resides in the
placement of the side chain in target molecule 3, which
branches off the N-1 position of the cytosine ring. We reasoned
that, by introducing the side chain in this position late in the
synthesis, protection−deprotection schemes would be avoided
in cases where the tail group terminates with a functional group,
such as in 2. Also, the redundant NH donor group in 1 is
substituted in 3, which renders the molecule less hydrophilic
and less prone to pyridine−hydroxypyridine tautomerism,
effectively locking the hydrogen-bonding array of the cytosine
ring in the correct AAD configuration, regardless of the solvent
type used for subsequent self-assembly.
with one showing all anti relationships along the C chain, the
7
second showing one gauche conformation, and the third
showing two gauche conformations. As shown in Figure 1b,
the hexamer is not flat but undulating, with the maximum
deviation from the mean plane defined by the 60 ring atoms
being 0.480 Å (C5A) or, if the substituent atoms directly
connected to the rings are included, 0.798 Å (N5A). The cavity
enclosed by the six subunits, measured from opposing
nitrogens or opposing oxygens, is between 10.4 and 10.6 Å
across. The hexamers do not stack in a tubelike fashion in the
solid state but rather as offset rings. A portion of this motif is
shown in Figure 1c. The resulting void spaces accommodate
the alkyl chains and also solvent molecules. Interestingly, this
result is at variance with the only other crystal structure of a
A simple, six-step approach to 3 is shown in Scheme 1. Two
derivatives were prepared, one with an n-heptyl chain (3a) for
a
Scheme 1
4a
G∧C hexamer, i.e. that of 1, in which case the hexamers
overlapped with one another to describe channels that
extended through the crystal. However, the units did not
stack in the traditional sense but were separated by about 20 Å
along the channel axis, unlike the case in 3b, where the
hexamers approach each other at stacking distances as close as
3
.2 Å.
a
Reagents and conditions: (a) 33% HBr−HOAc, 79%; (b) CH COCl,
While crystals of 3a from DMSO revealed the hexameric
3
pyridine, 80%; (c) Cl CCONCO, CH Cl ; (d) NaOMe, MeOH, 73%
over two steps; (e) NaH, NaI, RBr, DMF, 75% (8a), 64% (8b); (f)
TMSCl, NaI, MeCN, 76% (3a), 96% (3b).
3
2
2
organization of the motifs in the solid state, the limited
solubility of this material proved challenging for the self-
assembly studies in solution. In contrast to 3a, compound 3b
with the longer aliphatic n-hexadecyl side chain had good
solubility in a variety of solvents at room temperature, notably
cyclohexane (2.4 × 10− M). Time-dependent SEM, TEM,
STEM, and AFM studies (Figure 2 a−e and Figures S1−S4
(Supporting Information)) showed that 3b self-assembles into
RNTs within 10 min. The average diameter of single RNTs
measured by TM-AFM was 3.8 ± 0.3 nm. This is lower than
the TEM measurement of 4.8 ± 0.3 nm and the predicted value
of 4.4 nm (Figure S7 (Supporting Information)), as a result of
4
crystallization studies and one with a better solubilizing n-
hexadecyl chain (3b) to facilitate nanotube formation in
solution. Thus, the commercial malononitrile dimer 4 was
cyclized in HBr/AcOH to the pyridine derivative 5. Acetylation
of 5 took place at the more nucleophilic amino group to give 6,
which permitted selective aminocarbonylation with trichlor-
oacetyl isocyanate and subsequent base-induced ring closure
with concurrent substitution of the bromo group to give 7.
Alkylation of 7 proceeds smoothly in DMF to give the
nucleobase hybrid precursors 8, which can be demethylated
13
the tip-induced compression of the nanotubes.
The self-assembly of 3b (2.4 × 10− M) was also studied
5
using UV−visible spectroscopy. As shown in the time-
1
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Figure 1. (a) Top view of X-ray crystal structure of (3a) showing the hydrogen bonding array. (b) Side view showing the undulation of the central
6
supermacrocyclic ring. (c) Portion of the stacking motif of the (3a) hexamers. Solvent molecules are omitted for clarity.
6
−4
Figure 2. SEM images of 3b (2.4× 10 M) in cyclohexane at (a) 10 min (b) 2 days, and (c) 12 days. (d) TEM and (e) AFM images of 3b in
−
4
−5
cyclohexane (2.4 × 10 M) at 10 min and 2 days, respectively. (f) Time-dependent UV−visible spectra of 3b in cyclohexane (2.4 × 10 M). Scale
bars are given in nm.
dependent spectra (Figure 2f and Figure S5 (Supporting
Information)), 3b presented three maxima at 217, 247, and 310
nm. When the self-assembly was monitored over a period of 3
h, a hypochromic effect was observed, which is indicative of
increased π−π stacking interactions and the growth of the
CONCLUSION
■
We have described a synthetic approach to the preparation of
G∧C nucleobase hybrids in the form of self-assembling, N1-
substituted pyrido[4,3-d]pyrimidines which are only 6 steps
from the commercially available malononitrile dimer, represent-
ing a significant improvement on our earlier 10−12-step
syntheses. In this demonstration work, pivotal intermediate 7
was simply alkylated to provide material for crystallographic
and microscopic analysis, but it has the potential to act as a
1
4
nanotubes. A 10-fold dilution of the stock solution of 3b to a
−5
concentration of 2.4 × 10 M did not alter the UV−visible
spectra, suggesting that the RNTs are kinetically stable (data
not shown).
1
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vehicle for the co-organization of a variety of species in a
hexagonal array by substitution with functional tailgroups. The
N1-heptyl pyrido[4,3-d]pyrimidine 3a could be crystallized,
and an X-ray structure determination confirmed the presence of
in the gas phase. Among the 270 conformations generated by the 1000
steps of the MCMM search, we selected one conformation (Figure S7a
(Supporting Information)), which can form the six-membered rosette
ring (Figure S7b (Supporting Information)) having a diameter of 4.4
nm, in agreement with the AFM and TEM measurements.
the (3a) hexamer assembled by 18 hydrogen bonds. The
6
The association of 3 was modeled on that of 4,7-diamino-1-
methylpyrido[4,3-d]pyrimidine-2,5(1H,6H)-dione. Calculations were
performed at the density functional B3LYP/6-31G** level of theory
using the Gaussian09 program. Default methods and SCF convergence
criteria were applied. Solution geometries and energies were computed
using the self-consistent isodensity polarized continuum model (SCI-
supermacrocyclic ring encloses a ca. 10.5 Å cavity, although
there is only partial overlap of the hexamers in the crystal and
no channels in the structure. The N1-hexadecyl pyrido[4,3-
d]pyrimidine 3b, on the other hand, undergoes rapid self-
assembly into RNTs in cyclohexane. AFM, SEM, and TEM
imaging studies showed the formation of 1D nanostructures
with cross sections in excellent agreement with the modeled
outer diameter of the RNTs.
1
7
PCM) as implemented in Gaussian09.
,6-Diamino-2-bromonicotinonitrile (5). A modification of the
4
1
8
method of Carboni et al. was used: a solution of the malononitrile
dimer 4 (1.00 g, 7.57 mmol) in 33% HBr/HOAc (10 mL) was stirred
overnight and then poured into a mixture of saturated aqueous
EXPERIMENTAL SECTION
X-ray Crystal Structure Determination of 3a. Clusters of
triangular plates were obtained from DMSO solution. The crystal
selected for data collection was a colorless needle of dimensions 0.010
NaHCO (90 mL) and ethyl acetate (3 mL). The resulting precipitate
■
3
was filtered and washed with water to give 5 as an off-white solid (1.27
1
g, 79%): H NMR (400 MHz, DMSO-d ) δ 6.64 (s, 2H), 6.51 (s, 2H),
6
5
.57 (s, 1H); 13C NMR (100 MHz, DMSO-d ) δ 161.1, 157.9, 144.2,
6
1
17.5, 86.9, 85.8.
×
0.020 × 0.220 mm. The crystal was mounted in a 90 K nitrogen cold
N-(4-Amino-6-bromo-5-cyanopyridin-2-yl)acetamide (6). A
stream on the goniometer head of a diffractometer equipped with a
CCD detector. Data were collected with the use of synchrotron
radiation (λ = 0.8856 Å) at Beamline 11.3.1 at the Advanced Light
Source, Lawrence Berkeley Laboratory. The structure was solved by a
dual-space method (SHELXT) and refined by full-matrix least squares
on F2 (SHELXL-2012). One of the three DMSO molecules is
disordered over two orientations. The relative occupancies are
19
modification of the method of Szczepankiewicz et al. was used: to a
solution of 5 (10.1 g, 47.3 mmol) in dry pyridine (100 mL) was slowly
added acetyl chloride (9.0 mL, 9.9 g, 0.13 mol) at 0 °C. The mixture
was stirred at 0 °C for 45 min, and then cold water (500 mL) was
added and the resulting precipitate was filtered and washed with cold
15
1
water to give 6 as a light brown solid (9.76 g, 80%): H NMR (400
MHz, DMSO-d ) δ 10.62 (s, 1H), 7.48 (s, 1H), 7.28 (s, 2H), 2.0 (s,
0.874(3)/0.126(3). The minor orientation was refined as a rigid
6
3H); 13C NMR (100 MHz, DMSO-d
) δ 170.4,160.0, 153.3, 143.4,
group. In the minor orientation, isotropic displacement parameters
were employed; in addition, one of the carbon atoms was assigned a
fixed isotropic parameter of 0.08 in order to achieve convergence. All
other non-hydrogen atoms were refined with anisotropic displacement
parameters. R1 (7038 reflections with I > 2σ(I)) = 0.0748, wR2 (all
6
116.5, 95.8, 90.8, 24.6.
4,7-Diamino-5-methoxypyrido[4,3-d]pyrimidin-2(1H)-one
(
7). To a solution of 6 (6.41 g, 25.1 mmol) in dry CH Cl (1.2 L) was
2
2
added trichloroacetyl isocyanate (6.0 mL, 9.5 g, 50 mmol), and the
mixture was stirred at room temperature for 2 days. The reaction was
quenched with water (90 mL) followed by addition of saturated
aqueous sodium bicarbonate (600 mL). The layers were separated,
and the aqueous phase was washed (×5) with a 5% isopropyl alcohol/
DCM mixture. The organic fractions were combined and dried over
9
948 data) = 0.231, 690 parameters, 0 restraints.
Sample Preparation for TEM, SEM, and AFM Imaging
Studies. The G∧C base 3b was dissolved in cyclohexane (0.5 mg/
mL) by sonicating for 5 min at room temperature. The samples were
aged at room temperature for the specified time period and then
diluted to the stated concentration prior to imaging.
MgSO , and the solvent was evaporated. The resulting solid was
4
SEM samples were prepared by depositing the solutions on carbon-
coated 400 mesh copper grids and blotting after 10 s. All samples were
air-dried and heated on a hot plate under vacuum for 10 min prior to
imaging to remove any residual solvents. SEM and STEM images were
obtained without negative staining at a 10−30 kV accelerating voltage,
dissolved in dry methanol (480 mL), and a solution of sodium
methoxide prepared from sodium (5.09 g, 221 mmol) and methanol
(725 mL) was added. The mixture was stirred at room temperature for
1 h and then heated at reflux overnight. The solvent was evaporated,
acetic acid (35 mL) was added, and the resulting precipitate was
20 μA, and a working distance of 5−8 mm on a high-resolution cold
filtered and washed with water to give 7 as an off-white solid (3.78 g,
1
field emission SEM and ultrahigh-resolution cold field emission SEM.
TEM samples were prepared by depositing a droplet of the RNT
solution on a carbon-coated 400 mesh copper grid, followed by
blotting after 10 s. The samples were then stained by depositing one
droplet of uranyl acetate (2% in water or acetonitrile) for 120 s each.
The grid was then blotted and dried in air with the use of a vacuum
hot plate. TEM investigations were carried out on a 200 kV Schottky
field emission TEM instrument equipped with an in-column Ω filter.
Bright field TEM images were acquired using energy filtered zero loss
beams (slit width 10 eV).
73%): mp >320 °C dec; H NMR (400 MHz, DMSO-d ) δ 11.19 (br
6
s, 1H), 9.02 (br s, 1H), 8.09 (s, 1H), 7.06 (s, 2H), 5.73 (s, 1H), 3.91
(s, 3H); 13C NMR (100 MHz, DMSO-d ) δ 162.6, 161.7, 159.9, 153.4,
6
151.3, 83.6, 83.1, 54.4; ESI-HRMS calcd for C H N O [M + H]
8
9
5
2
208.0829, found 208.0826.
4,7-Diamino-1-heptyl-5-methoxypyrido[4,3-d]pyrimidin-
2(1H)-one (8a). To a solution of 7 (0.200 g, 0.965 mmol) in dry
DMF (40 mL) was added 60% sodium hydride (57.9 mg, 1.45 mmol),
and the mixture was stirred at room temperature for 15 min. 1-
Bromoheptane (0.310 mL, 0.345 g, 1.93 mmol) and sodium iodide
(20.0 mg, 0.133 mmol) were added, and the mixture was stirred for 4
days. The reaction was quenched by the addition of MeOH (20 mL),
and the solvent was evaporated. The residue was chromatographed on
For the AFM measurements, clean HOPG (highly ordered pyrolytic
2
graphite) substrates (1 × 1 cm ) were prepared and the samples were
deposited by spin coating at 3500 rpm for 30 s. Sample surfaces were
observed using a Digital Instruments/Veeco Instruments MultiMode
Nanoscope IV AFM equipped with an E scanner. For obtaining
optimized height profiles, silicon cantilevers with low spring constants
of 4.5 N/m were used in tapping mode (TM-AFM). To obtain a clear
image, low scan rates (0.5−1 Hz) and amplitude set points (1 V) were
chosen during the measurements.
silica gel (10% methanol/DCM) to give 8a (0.221 g, 75%) as an off-
1
white solid: mp 145−147 °C; H NMR (400 MHz, DMSO-d ) δ 8.00
6
(br s, 1H), 7.56 (s, 1H), 6.83 (s, 2H), 5.78 (s, 1H), 3.92 (s, 3H),
3.81−3.75 (m, 2H), 1.54−1.47 (m, 2H), 1.29−1.19 (m, 8H), 0.82 (t, J
= 6.9 Hz, 3H); 13C NMR (100 MHz, DMSO-d ) δ 162.6, 161.3, 160.7,
6
154.7, 151.6, 84.9, 82.4, 54.3, 43.2, 31.7, 28.9, 27.0, 26.8, 22.5, 14.4;
Modeling. Monte Carlo Multiple Minimum (MCMM) procedure
was carried out to search for the C16 side chain conformations that are
in agreement with TEM and AFM measurements (Figure S6
ESI-HRMS calcd for C H N O [M + H] 306.1925, found 306.1928.
15
23
5
2
4,7-Diamino-1-heptylpyrido[4,3-d]pyrimidine-2,5(1H,6H)-
dione (3a). To a solution of 8a (0.480 g, 1.57 mmol) in dry
acetonitrile (175 mL) were added sodium iodide (1.50 g, 9.99 mmol)
and chlorotrimethylsilane (0.836 mL, 0.715 g, 6.59 mmol). The
16
(Supporting Information)). The motif was modeled using the
OPLS2005 force field, and the geometry optimization was carried out
1
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Article
reaction flask was protected from light and the mixture was heated at
reflux for 2 h. The mixture was poured into pH 7 aqueous phosphate
buffer (0.4 M, 150 mL). The resulting precipitate was filtered, washed
with EtOAc, and recrystallized from DMSO to give 3a as an off-white
solid (0.349 g, 76%): mp >325 °C dec; H NMR (400 MHz, DMSO-
d6/3 drops of d-TFA) δ 11.92 (s, 1H), 9.54 (s, 1H), 8.78 (s, 1H), 7.8
Office of Basic Energy Sciences, of the U.S. Department of
Energy under Contract No. DE-AC02-05CH11231. Support
from the Natural Science and Engineering Research Council of
Canada, the National Research Council of Canada, the
University of Alberta, and Northeastern University are
gratefully acknowledged.
1
(
br s, 2H), 5.54 (s, 1H), 3.78−3.70 (m, 2H), 1.57−1.48 (m, 2H),
13
1
.33−1.15 (m, 8H), 0.82 (t, J = 6.0 Hz, 3H); C NMR (100 MHz,
DMSO-d ) δ 162.0, 157.0, 156.3, 152.4, 148.0, 83.1, 77.7, 43.6, 31.6,
6
REFERENCES
■
2
2
8.8, 26.7, 26.5, 22.4,14.3; ESI-HRMS calcd for C H N O [M + H]
14 21 5 2
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2
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1
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6
(
br s, 1H), 7.58 (br s, 1H), 6.84 (s, 2H), 5.79 (s, 1H), 3.92 (s, 3H),
3
.81−3.74 (m, 2H), 1.54−1.47 (m, 2H), 1.29−1.16 (m, 26H), 0.81 (t,
13
J = 7.0 Hz, 3H); C NMR (100 MHz, DMSO-d ) δ 162.6, 161.4,
6
1
2
60.6, 154.6, 151.6, 84.8, 82.5, 54.3, 43.2, 31.7, 29.52 (5C overlapped),
9.51, 29.48, 29.45, 29.3, 29.2, 27.0, 26.8, 22.5, 14.4; ESI-HRMS calcd
for C H N O [M + H] 432.3333, found 432.3330.
24
41
5
2
4
,7-Diamino-1-hexadecylpyrido[4,3-d]pyrimidine-2,5-
(
1H,6H)-dione (3b). To a solution of 8b (0.170 g, 0.393 mmol) in
dry acetonitrile (60 mL) were added sodium iodide (0.438 g, 2.92
mmol) and chlorotrimethylsilane (0.245 mL, 0.209 g, 1.93 mmol).
The reaction flask was protected from light and the mixture was heated
at reflux for 2 h. The mixture was poured into pH 6.5 aqueous
phosphate buffer (0.4 M, 50 mL). The resulting precipitate was filtered
and washed with EtOAc and then with MeOH to give 3b as an off-
(6) Computational modeling was carried out at the density functional
B3LYP/6-31G(d,p) level of theory using the Gaussian09 program
(Gaussian, Inc., Wallingford, CT, 2004, 2009; full Gaussian 09
reference in Supporting Information). Default methods and SCF
convergence criteria were applied.
1
white solid (0.158 g, 96%): mp >305 °C dec; H NMR (400 MHz,
DMSO-d , 3 drops of d-TFA) δ 11.90 (s, 1H), 9.54 (s, 1H), 8.71 (s,
6
1
H), 7.8 (br s, 2H), 5.54 (s, 1H), 3.79−3.71 (m, 2H), 1.57−1.48 (m,
13
2
H), 1.30−1.13 (m, 26H), 0.84−0.76 (m, 3H); C NMR (100 MHz,
(
7) Mascal, M.; Farmer, S. C.; Arnall-Culliford, J. R. J. Org. Chem.
2006, 71, 8146.
8) Supramolecular Macrocycle Synthesis by H-bonding Assembly
DMSO-d ) δ 162.0, 156.9, 156.2, 152.4, 147.9, 83.1, 77.7, 43.6, 31.7,
6
2
9.5 (8C overlapped), 29.4, 29.2, 26.7, 26.6, 22.5, 14.3; ESI-HRMS
(
calcd for C H N O [M + H] 418.3177, found 418.3172.
23
39
5
2
(review): Ballester, P.; de Mendoza, J. In Modern Supramolecular
Chemistry; Diederich, F., Stang, P. J., Tykwinski, R. R., Eds.; Wiley-
VCH: Weinheim, Germany, 2008 pp 69.
ASSOCIATED CONTENT
Supporting Information
■
(9) Lipps, H. J.; Rhodes, D. Trends Cell Biol. 2009, 19, 414.
*
S
(10) (a) Theobald, J. A.; Oxtoby, N. S.; Phillips, M. A.; Champness,
Text, figures, tables, and a CIF file giving the full citation for
Gaussian09, Cartesian coordinates and energies for all
calculations used in this work, experimental details for the X-
ray crystal structure determination of 3a, numbering scheme for
the X-ray crystal structure determination of 3a, crystallographic
data 3a, experimental details of the imaging of 3b, UV−vis
studies of the aggregation of 3b, modeling of the aggregation of
N. R.; Beton, P. H. Nature 2003, 424, 1029. (b) Rai
Slater (nee Phillips), A. G.; Champness, N. R.; Buck, M. Chem. Sci.
012, 3, 84.
11) (a) Moralez, J. G.; Raez, J.; Yamazaki, T.; Motkuri, R. K.;
Kovalenko, A.; Fenniri, H. J. Am. Chem. Soc. 2005, 127, 8307.
b) Johnson, R. S.; Yamazaki, T.; Kovalenko, A.; Fenniri, H. J. Am.
̈ ̈
sanen, M. T.;
́
2
(
(
Chem. Soc. 2007, 129, 5735. (c) Borzsonyi, G.; Beingessner, R. L.;
Yamazaki, T.; Cho, J.-Y.; Myles, A. J.; Malac, M.; Egerton, R.;
Kawasaki, M.; Ishizuka, K.; Kovalenko, A.; Fenniri, H. J. Am. Chem.
Soc. 2010, 132, 15136.
1
13
3
8
b, and H and C NMR data for compounds 3a,3b, 5−7, and
a,b. This material is available free of charge via the Internet at
http://pubs.acs.org.
(12) Since the hexamer crystallizes out of DMSO, a reviewer
suggested we recalculate the H-bonding energy of the assembly in this
AUTHOR INFORMATION
Corresponding Authors
E-mail for M.M.: mjmascal@ucdavis.edu.
E-mail for H.F.: h.fenniri@neu.edu.
Notes
■
solvent. Whereas the gas-phase association energy for each pairing was
−1
−1
2
9.7 kcal mol , in DMSO this value decreases to 18.4 kcal mol ,
*
which amounts to a 40% reduction. Although the pairing is less
effective in solvent, there is still ample driving force to assemble the
hexamer.
*
(
13) (a) Cho, J.-Y.; Fenniri, H. Imaging Microsc. 2010, 4, 33.
b) Bustamante, C.; Vesenka, J.; Tang, C. L.; Rees, W.; Guthold, M.;
Keller, R. Biochemistry 1992, 31, 22.
14) A hypochromic effect is commonly observed in nucleic acid.
The authors declare no competing financial interest.
(
ACKNOWLEDGMENTS
■
(
We thank the Advanced Light Source, Beamline 11.3.1,
Lawrence Berkeley Laboratory, for support. The Advanced
Light Source is supported by the Director, Office of Science,
Upon self-assembly and formation of a double helix, the two maxima
in the UV region undergo a hypochromic shift. When the double helix
is melted, the extinction coefficient increases to its original (molecular)
1
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dx.doi.org/10.1021/jo4019792 | J. Org. Chem. 2013, 78, 11421−11426

The Journal of Organic Chemistry
Article
state, resulting in a hyperchromic effect. This phenomenon is used to
investigate the cooperative nature of the self-assembly process in
nucleic acids. We use the same strategy to establish the cooperative
4d
nature of RNT self-assembly.
15) Sheldrick, G. M. SHELXL-2012; University of Go
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1
(
Liu, B.; Zhao, H.; Serby, M. D.; Xin, Z.; Liu, M.; Gum, R. J.; Haasch,
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