Tautomeric self-dimerization and molecular recognition properties of 2-aminopyrimidinone derivatives as triple hydrogen-bonding modules in molecular assemblies

Article abstract of DOI:10.1002/ejoc.200500010

A triple hydrogen-bonding module based on 6-alkynyl-2-amino-3H-pyrimidin-4- one was developed such as for self-dimerization and for nucleobase recognition processes. The strength of the module for the self-dimerization was determined by NMR and fluorimetric analyses in chloroform (ΔG₂₉₈ = -22 to -23 kJ/mol). DFT calculations and X-ray structure analysis showed that the self-dimerization consists of the three-point hydrogen-bonding including two kinds of tautomers of the module in an ADD·DAA mode. Selective recognition of the module for a cytidine derivative was also observed, and the free energy change for the complexation (ΔG₂₉₈ = -31 kJ/mol) is one of the highest values among triple hydrogen-bonded complexes so far reported. Wiley-VCH Verlag GmbH & Co. KGaA, 2005.

Full text of DOI:10.1002/ejoc.200500010

FULL PAPER
Tautomeric Self-Dimerization and Molecular Recognition Properties of
2-Aminopyrimidinone Derivatives as Triple Hydrogen-Bonding Modules in
Molecular Assemblies
Hajime Abe,[a] Masayoshi Takase,[a] Yasuhiro Doi,[a] Shinya Matsumoto,[b]
Masaru Furusyo,[c] and Masahiko Inouye*[a,d]
Dedicated to the memory of our teacher, Prof. Masaru Matsuoka, deceased January, 2002
Keywords: Molecular recognition / Self-assembly / Nucleobases / Hydrogen bonds / Tautomerism
A triple hydrogen-bonding module based on 6-alkynyl-2-
amino-3H-pyrimidin-4-one was developed such as for self-
dimerization and for nucleobase recognition processes. The
strength of the module for the self-dimerization was deter-
mined by NMR and fluorimetric analyses in chloroform
(ΔG298 = –22 to –23 kJ/mol). DFT calculations and X-ray
structure analysis showed that the self-dimerization consists
of the three-point hydrogen-bonding including two kinds of
tautomers of the module in an ADD·DAA mode. Selective
recognition of the module for a cytidine derivative was also
observed, and the free energy change for the complexation
(ΔG298 = –31 kJ/mol) is one of the highest values among tri-
ple hydrogen-bonded complexes so far reported.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
ral requirements for building strong and well-defined as-
semblies. While the latter, quadruple ones produce much
stronger self-dimerized complexes, the limitation for the
synthetic versatilities of them may offset the advantages. On
the other hand, triple hydrogen bondings are seen in many
natural environments, especially in double-helical DNAs, so
that their information for the binding as well as their re-
sources will readily be available. Of course, homodimeriza-
tion is intrinsically impossible for the triple hydrogen-bond-
ing modules because of the odd number with respect to the
hydrogen-bonding units. We thought that this contradictory
issue may be overcome by use of tautomerism of an ADD-
type molecule to an AAD one; thus, an ADD·DAA triple
hydrogen-bonding pattern could be constructed from a sin-
gle molecular component.
Introduction
Because hydrogen bonding is a vectorial and easily tun-
able noncovalent interaction, the hydrogen bonds play a
leading role in creating self-assembled molecular architec-
tures.[1–3] Multiple hydrogen-bonding arrays composed of
plural hydrogen-bond acceptor (A) and donor (D) groups
have been widely used for such purposes taking advantage
of homo- and heterodimerization characteristics of the ar-
rays. In the simplest example, double hydrogen-bonding
modules self-dimerized in a manner of an AD·DA pattern
such as dimers of carboxylic acids, while quadruple hydro-
gen-bonding modules exhibited ADAD·DADA and
AADD·DDAA ones.[3] Although the former is easily incor-
porated into the molecular structures, the relatively low
binding energy of the double hydrogen bonding lacks gene-
Isocytosines, as representative 2-aminopyrimidin-4-ones
have been known to exist as a mixture of their tautomers.
The composition of the tautomers depends not only on the
nature of media but also on the presence of hydrogen-bond-
ing substrates. Conventionally, the tautomerism was studied
mainly based on two kinds of the N–H tautomers, 2-amino-
3H-pyrimidin-4-one (ADD type) and 2-amino-1H-pyrimi-
din-4-one (AAD type). As the tautomers show different ab-
sorption bands, the changes of the ratio were monitored by
UV/Vis spectroscopy[4,5] and by magnetic circular dichro-
ism.[4] In an EtOH solution, isocytosine mainly exists as the
3H-tautomer form, and in an aqueous solution, the equilib-
rium with the 1H-tautomer takes place.[4] The interaction
[a] Faculty of Pharmaceutical Sciences, Toyama Medical and Phar-
maceutical University,
Toyama 930-0194, Japan
Fax: +81-76-434-5049
E-mail: inouye@ms.toyama-mpu.ac.jp
[b] Faculty of Education and Human Sciences, Yokohama
National University,
Yokohama 240-8501, Japan
[c] Analysis Technology Research Center, Sumitomo Electric In-
dustries Ltd.,
Itami 664-0016, Japan
[d] PRESTO, Japan Science and Technology Agency (JST),
Japan
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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DOI: 10.1002/ejoc.200500010
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for isocytosine with creatinine (AAD type) increased the N-Acyl-2-amino-3H-pyrimidin-4-one Derivatives 3
ratio of the 3H-tautomer.[5] The dimeric forms
(ADD·DAA) of isocytosine between the two tautomers
As a starting point for this project, we chose N-acyl-2-
were confirmed in crystalline[6,7] and co-crystalline states.[8] amino-3H-pyrimidin-4-one as a self-dimerization module.
It was also reported that ADD·DAA-type self-dimerization Commercially available 2-amino-4-chloro-6-hydroxypyrimi-
of isocytosine was mediated by H+ in crystal[6a,9] or ESI dine (1) was converted to N-octanoyl derivative 2, which
conditions.[10] Recently, in argon matrices or in gas phase, was alkynylated with tri-n-butyl(trimethylsilylethynyl)stan-
isocytosine was shown to exist predominantly as 2-amino- nane by Stille coupling to give the desired compound 3
1
pyrimidin-4-ol (ADA or ADD-type tautomer according to (Scheme 1). The spectroscopic properties such as H and
the geometry of OH bond) accompanied with a small part 13C NMR and mass spectra of 3 were in agreement with
of the 3H-tautomer on the basis of its vibrational analy- the assigned structure. The solubility of compound 3 was
ses,[11] and this observation was supported by theoretical found to be enough for permitting its binding examinations
analyses.[11–13] However, no systematic and comprehensive in less polar solvents such as CHCl3 and CH2Cl2.
investigations on 2-aminopyrimidin-4-one derivatives as hy-
For the self- and cross-associations of 3, 7, and 9 (see
drogen-bonding modules were carried out especially in below), the tautomerism of the monomer (e.g. between
solutions. Thus, the full potential of their triple hydrogen- ADD, AAD, ADA, and DAD) may participate before the
bonding motifs for self-dimerization processes remains elus- dimerization, and the dimer thus formed may also exist in
ive as it does in many other examples. Here we report tauto- tautomerism between three- and two-point hydrogen-
meric self-dimerization of 2-aminopyrimidin-4-one deriva- bonded complexes (e.g. between AAD·DAA, AAD·DDA,
tives as well as their molecular recognition abilities for nuc- and ADD·DDA; the hydrogen-bonded parts are in italics).
leobases in detail.
Practically, it was impossible to evaluate each equilibrium
constant for those possible tautomeric systems precisely.
Thus, in the following discussion, “formal association con-
stants” KЈdim and KЈa, obtained from the curve-fitting
analyses for the plotting curves involving the influences of
the tautomeric systems, were used for the evaluation of the
strength of self- and cross-association. In the present study,
fortunately, most of the plotting curves obtained fitted well
into the theoretical curves assuming simple dimerization or
1:1 complexation.
Results and Discussion
Molecular Design of Basic Skeletons
The solubility of the molecules that possess multiple hy-
drogen-bonding arrays is inherently poor in less polar sol-
vents since the molecules can interact with each other
through the hydrogen bonds to exist as network polymers
of high molecular weight. Thus, improvement of their solu-
bilities is essential not only for accurately assessing the
intermolecular interactions in their “discrete” states but
also for conducting their synthetic operations. To add solu-
bility in less polar solvents but not to interfere with the
hydrogen-bonding abilities, a long acyl or alkyl chain was
introduced at 2-amino groups on 2-aminopyrimidin-4-ones.
To the carbon-6 of the aminopyrimidinone ring, were
linked alkynyl substituents that can modify the basicity of
the hydrogen-bonding sites and act as a versatile linker for
applying the aminopyrimidinones as a hydrogen-bonding
module in complexed molecular assemblies (Figure 1). The
latter reason will be documented in terms that ethynyl
groups can easily be connected to a variety of aromatic and
vinylic compounds by palladium-catalyzed cross-coupling
reactions (see also below).
The self-association tendency of 3 was first tested by
plotting the relations of the 1H NMR chemical shifts of the
NH(exo) against the concentration of 3 in CDCl3 (Figure
S1, Supporting Information). However, the formal associa-
tion constant was unexpectedly low (KЈdim = 13 6 m–1).
Cross-association of 3 (as an ADD-type molecule) was also
studied with the lipophilic cytidine derivative 10C (as a
DAA-type molecule, Scheme 2). When 1 equiv. of 10C was
1
added to a 1.0×10–3 m CDCl3 solution of 3, the H NMR
signals of the NH protons were slightly shifted downfield
by 0.11, 0.34, and 0.20 ppm for NH(endo), NH(exo) of 3,
and NH2 of 10C, respectively, indicating the presence of
complementary triple hydrogen bonds (Figure 2). Quantita-
tive assessment for the binding was carried out under the
conditions in which the influence of self-association of not
only 3 but also 10C is relatively small. The 1:1 stoichiome-
try was confirmed by Job’s plots for the chemical shift of
NH(exo) protons of 3 (Figure S2, Supporting Information).
The formal association constant (KЈa) for the cross-associa-
tion was 1.11 0.02×102 m–1, calculated by using an itera-
tive curve-fitting analysis of the chemical shifts of NH(exo)
1
for 3 in H NMR titration (Figure S3, Supporting Infor-
mation). As free energy changes (ΔG) can be calculated
from association constants using ΔG = –RTlnKa, the bind-
ing of 3 and 10C yielded a stabilization energy (–ΔG295) of
11.6 kJ/mol. Systematic comparison of experimental –ΔG
has been investigated, in which the values of ca. 20–30 kJ/
mol were reported for the complexation by the amide–
Figure 1. A tautomeric dimerization through an ADD·DAA-type
triple hydrogen-bonding of 2-amino-3H-pyrimidin-4-one (left) and
2-amino-1H-pyrimidin-4-one (right) tautomers.
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Scheme 1. Synthesis of 3, 7, and 9; key: (a) n-octanoyl chloride, DMAP, DMF, 0 °C to room temp., 5 h, 77%; (b) [Pd(PPh3)4], tri-n-
butyl(trimethylsilylethynyl)stannane, toluene, 80 °C, 5 h, 81%; (c) NaH, K2CO3, DMF, 0 °C, 1 h, then MOMCl, 0 °C to room temp.,
24 h, 87%; (d) LiAlH4, THF, reflux, 1 h, 56%; (e) aq. HCl, THF, room temp., 1 h, 100%; (f) [Pd(PPh3)4], tri-n-butyl(trimethylsilylethynyl)-
stannane, xylene, 120 °C, 3 h, 22%; (g) 1-ethynylpyrene, [Pd(PPh3)4], Et3N, THF, 60 °C, 12 h, 54%; (h) aq. HCl, THF, room temp., 1 h,
94%.
amide-type ADD·DAA triple hydrogen bonds.[1] Thus,
the –ΔG value obtained for 3 and 10C was significantly
small compared to those for the previously exploited pairs
having the same triple hydrogen-bonding pattern.
Figure 2. A possible complementary triple hydrogen-bonding re-
cognition mode between 3 or 7 (ADD tautomer) and the cytidine
derivative 10C (DAA).
The reason for the low self- and cross-association abili-
ties of 3 was searched through its stable conformations by
quantum chemical calculations. B3LYP level hybrid density
functional theory (DFT) and 6-31G(d,p) basis sets were ap-
plied for geometry optimizations and vibrational frequency
analysis for using zero point energy (ZPE) correction. For
simplification of the calculations, ethynyl and acetyl groups
were substituted for (trimethylsilyl)ethynyl and n-octanoyl
groups of 3, respectively. The relative energies calculated for
Scheme 2. Lipophilic nucleosides.
eight tautomeric and conformational isomers 3a–h were
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Scheme 3. Calculated relative stabilities of isomers 3a–h; some substituents in 3 were simplified (see text); positive values indicated the
degree of the instabilities from the most stable isomer 3g; the hydrogen-bonding mode is shown in the parentheses.
shown in Scheme 3, in which positive values indicated the fully be applied for using these modules to incorporate into
degree of the instabilities from the most stable isomer 3g. self-assembling units.
1H NMR dilution experiments of 7 in CDCl3 at 22 °C
The six-membered intramolecular hydrogen bonding may
revealed that at Յ 4.0×10–3 m, the signals of the NH and
NCH2 protons gradually shifted upfield with decreasing the
concentration (Figure S4A, Supporting Information). A
vapor pressure osmometry (VPO) analysis of 7 showed the
apparent molecular weight as 625 g/mol at the concentra-
tion range from 2.5×10–3 to 2.5×10–2 m, suggesting the di-
mer formation of 7 (Mw = 319.5 g/mol). The formal associ-
ation constant for the self-dimerization (KЈdim) was calcu-
stabilize the conformation in 3g, while the desired 3e or 3f
as an ADD partner rather yields the electrostatic repulsion
between the lone electron pairs of the pyrimidinone-1N and
the exo-methyl or exo-amide-O. When 3 self-dimerizes in
an ADD·DAA manner between 3e,f and 3b, the loss in the
energy would arise resulting from the rotation about the
pyrimidinone–amide axis in 3g and also from the tautomer-
ism of 3g to 3b. The energy loss might be too large to be
compensated by the newly developed triple hydrogen-bond-
ing interaction. In the case of the cross-association to the
cytidine derivative 10C, the same matter occurred to result
in the observed weak interaction.[14]
1
lated by a curve-fitting method for the H NMR chemical
shifts of the NCH2 protons, assuming that all the self-asso-
ciated complexes exist as a dimer (Figure S4B, Supporting
Information). The KЈdim value was 6.5 0.3×103 m–1, which
gives ΔG295 as –22 kJ/mol.
The strong self-dimerization abilities of N-alkyl-2-amino-
pyrimidinone derivatives were also studied by using UV/Vis
and fluorescence spectroscopy. We investigated the relations
Self-Dimerization of N-Alkyl-2-amino-3H-pyrimidin-4-one
Derivatives 7 and 9
For suppression of the intramolecular hydrogen bond in of the absorbances (in the cases of 7 and 9) and fluores-
3, the carbonyl groups of the exo-amide should be reduced cence emission intensities (in the case of 9) upon their con-
to methylene groups. Thus, we newly designed N-alkyl-2- centrations, respectively. At a lower concentration of the
amino-3H-pyrimidin-4-one as a self-dimerization module. substrate, the absorbance fits in proportion to the concen-
After MOM-protection of 2 to 4, N-octanoyl group was tration, obeying Beer’s law. If deviation is observed from
reduced with LiAlH4 to yield amine 5. Acidic deprotection the linearity over a certain concentration, it means that self-
produced an N-alkyl parent skeleton 6, which was alkynyl- interaction through the corresponding electron orbital be-
ated to 7 by Stille coupling. On the other hand, chloro sub- comes significant between two ground state molecules.
stituent on 5 was replaced with 1-pyrenylethynyl group Thus, the contribution of the intermolecular π-interaction
using Sonogashira reaction to afford 8, followed by MOM- (π-stacking) of 7 can be ruled out for its self-dimerization
deprotection to a fluorescent module 9 (Scheme 1). As ex- process, since the absorbance of 7 at both 250 and 325 nm
pected in “Molecular Design of Basic Skeletons” chapter obeyed Beer’s law at the concentration range from 1.0×10–5
(described above), the alkynyl function on the carbon-6 was to 2.0×10–3 m in CHCl3 (Figure S5, Supporting Infor-
found to be a versatile building block for constructing fur- mation). Although no change for the shape of the absorp-
ther sophisticated modules, and this technique can success- tion spectra was observed during the dilution at that con-
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centration range, the self-dimerization of 7 was surely con- tautomeric and conformational isomers 7a–f, we calculated
1
firmed on the basis of the H NMR dilution experiments the relative energies by use of DFT(B3LYP) method and 6-
(see above). The shape of the absorption spectra for 9 also 31G(d,p) basis sets. In Scheme 4, the relative stabilities of
showed no change at the concentration range from the seven isomers were shown. Among the isomers, the 2-
5.0×10–6 to 2.0×10–4 m in CHCl3 (data not shown). These
findings indicate that π-stacking interactions are not impor-
tant for the self-dimerization process in 7 and 9. On the
other hand, fluorescence spectra are much sensitive to the
changes for the electronic nature of the substrates such as
in the cases for hydrogen bonds. The fluorescence spectra
of 9 were measured in CHCl3 under various concentrations.
The relative emission intensities at 450 nm well fitted into
the theoretical curve calculated for the self-dimerization
(KЈdim = 1.1 0.2×104 m–1) (Figure S6, Supporting Infor-
mation), and the corresponding ΔG298 for 9 was –23 kJ/mol,
which was close to that for 7 obtained on the basis of the
NMR analysis. Noteworthy is that these values of KЈdim and
ΔG are comparable to the reported ones for ADD·DAA-
type heterodimeric complexes.[1] Fluorescence lifetime for 9
was also measured at 1.0×10–5 m, in which the monomer
form predominates. The fluorescence decay curve of 9 (Fig-
ure S7, Supporting Information) was due to a one-compo-
nent system in CHCl3 (τ = 1.97 0.01 ns), i.e., the pyrenyl
module 9 showed only one kind of emission from the
monomer form.
1H NMR, UV/Vis, and fluorescence data of 7 and 9 im-
plied that these N-alkyl-2-amino-3H-pyrimidin-4-one deriv-
atives exist as a dimeric form over a certain concentration
in less polar solvents through the triple hydrogen-bonding
interactions. The dimerization mode of the pyrimidinones,
however, remained to be clarified. Again quantum chemical
calculations were used for solving this question in a manner
Scheme 5. The representative structures and their calculated relative
similar to those conducted for N-acyl ones. In the present
stabilities of self-dimerized complexes of 7; some substituents in 7
were simplified (see text); negative values indicated the degree of the
case, ethynyl and ethyl groups were substituted for (trimeth-
ylsilyl)ethynyl and n-octyl groups of 7, respectively. For the stabilities from the double of the total energy of monomeric 7c.
Scheme 4. Calculated relative stabilities of isomers 7a–f; some substituents in 7 were simplified (see text); positive values indicated the
degree of the instabilities from the most stable isomer 7c; the hydrogen-bonding mode is shown in the parentheses.
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aminopyrimidin-4-ol 7c (DAD type) was predicted to be sis. Slow evaporation of a CDCl3 solution of 7 gave wet
most stable in accordance with the reported calculations for single crystals. Unfortunately, crystal data of good quality
isocytosine.[12,13] The calculation indicated that its confor- have not been attained to distinguish their isomers because
mational isomer 7cЈ (AAD) was slightly less stable than 7c of the disorder of terminal trimethylsilyl and octyl groups.
by 18.9 kJ/mol, probably because of loss of the weak intra- Nevertheless, the obtained structure showed the notable
molecular hydrogen-bonding between the hydroxy OH and intermolecular interactions between two molecules of 7
the pyrimidine-3N.
(Figure 3). They form complementary triple hydrogen-
Some of possible dimerized structures for 7 were sub- bonding in an exact 1:1 ratio, which consists of two kinds
jected to similar calculations. Three reasonable dimers of its tautomers perhaps in an ADD·DAA mode as seen in
7a·7b, 7a·7cЈ, and 7c·7f were studied as shown in Scheme 5, the literature.[6,8,9]
while the monomer components of 7d,e were omitted be-
cause of their relatively high instabilities. Among the three,
unexpectedly, the ADD·DAA pair 7a·7b, which includes the
less stable isomer 7b, was predicted to be most stable. The
Nucleobase Recognition Abilities of N-Alkyl-2-amino-3H-
pyrimidin-4-one Derivatives 7 and 9
DAD·ADA-type dimer 7c·7f would be disadvantageous be-
cause of repulsive secondary interactions.[1,15] The differ-
The molecular recognition abilities of the N-alkyl-2-ami-
ence between the two ADD·DAA dimers, 7a·7b and 7a·7cЈ, nopyrimidin-4-ones with nucleobases were investigated by
would be due to the difference in hydrogen-accepting abili- 1H NMR spectroscopy. When 1 equiv. of the cytidine deriv-
ties of the oxygen functionalities on 7b and 7cЈ: the former ative 10C was added to a CDCl3 solution of 7 (1.0×10–3 m),
is carbonyl and the latter is hydroxy groups.[16] Thus, at le- several characteristic changes were observed in their spec-
ast from the calculations, the self-dimerization mode in 7 tra. Both the signals for the NH protons of endo-amide and
was supposed as 7a·7b form depicted in Scheme 5 (top).
exo-amino groups on 7 were largely shifted downfield by
2.25 and 2.67 ppm, respectively. Although the signal for one
proton of amino groups on 10C was also shifted downfield
from 5.04 to 9.36 ppm, that for the other amino proton
shifted slightly upfield to 4.96 ppm in contrast (Figure 4).
These phenomena will be explained by the formation of a
complementary triple hydrogen-bonding interaction be-
tween 7 and 10C as shown in Figure 2.[17] In the case of
10C alone, the two amino protons are not distinguishable
Crystal Structure Analysis of N-Alkyl-2-amino-3H-
pyrimidin-4-one Derivative 7
To evaluate the mode of this self-dimerization, determi-
nation of the crystal structure of 7 was tried by X-ray analy-
1
in the H NMR spectrum because the 4-amino substituent
rotates freely around the cytosine ring faster than the NMR
time scale (part C in Figure 4). Generally, hydrogen bonds
tend to fix the covalent bonds participated in the hydrogen-
bonding against the rotation. Thus, when 10C bound to 7,
the two amino protons on 10C were no longer identical and
appeared at different chemical shifts. Another notable point
was that N–CH2 protons in 7 showed splits after the associ-
ation with 10C, indicating the formation of a chiral complex
between the chiral 10C and the achiral 7. However, the
strong recognition ability of 7 to 10C and self-association
tendency of 7 did interfere with quantitative experiments
for determining the association constants by use of NMR
spectroscopy.
The fluorescence emission spectra of 9 changed upon the
addition of 10C in CHCl3 under rather diluted conditions
required for assessing the association constant (Յ
1.0×10–5 m). When 10C was added incrementally to a
CHCl3 solution of 9 (1.0×10–6 m), two new emission bands
appeared at λmax = 414, 433 nm (Figure 5). There are iso-
emmisive points during this titration, which suggest the pre-
dominance of only two kinds of fluorescent species in the
mixture, i.e., the monomer 9 and the complex 9·10C. The
analyses for the complexation were performed by measuring
changes of the emission intensities at 410 nm. The 1:1 ratio
of 9 and 10C in the complex was confirmed by Job’s plot
(Figure S8, Supporting Information). The KЈa value was
calculated to be 3.1 0.1×105 m–1 by a curve-fitting
Figure 3. Crystal structure of 7; intermolecular triple hydrogen-
bonds are displayed as broken lines; hydrogen atoms are omitted;
the molecules are only depicted in one of the two disordered con-
formations; for details, see Experimental Section.
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Figure 5. Fluorescent titration of 9 with 10C; conditions: 9
(1.0×10–6 m), 10C (0 to 10 equiv.), λex = 375 nm, CHCl3, 25 °C;
inset shows the curve-fitting analysis based on the relative intensity
at 410 nm; asterisks are marked on the isoemissive points.
of the chemical shifts of all the NH protons were observed,
compared to the cases for 10C. The results were summa-
rized in Table 1. Furthermore, in the fluorescent titration of
9, no meaningful changes were observed upon the addition
of a large excess of 10G, 10A, and 10U. This nucleobase
selectivity of the modules for cytosine is interesting, and
possibly is due to the relative stability of the ADD structure
among its tautomers, being supported by quantum chemi-
cal calculations (see Supporting Information).
Figure 4. 1H NMR (500 MHz) spectra of (A) 7, (B) 7·10C, and (C)
10C in CDCl3; conditions: 7 (1.0×10–3 m), 10C (1.0×10–3 m),
22 °C; the signal (b) in (B) was assigned by the correlation with
NCH2 protons on COSY analyses.
Conclusions
In summary, we have developed a new class of triple hy-
method. Thus, the change in free energy for the complex- drogen-bonding modules, 6-alkynyl-2-amino-3H-pyrimidin-
ation (ΔG298 = –31 kJ/mol) is one of the highest values 4-one derivatives 3 and 7. In CDCl3, the N-alkylated 7 was
among reported ones in artificial ADD·DAA-type hydro- demonstrated to strongly self-dimerize by 1H NMR experi-
gen-bonding modules,[1] naturally occurring cytosine–gua- ments, while the N-acylated 3 showed much weaker dimer-
nine base pairs,[18] and their derivatives.[19]
ization. DFT calculations and X-ray structure analysis
These N-alkyl-2-amino-3H-pyrimidin-4-one modules showed that the self-association of 7 is based on the
were also found to have high selectivities to cytosine com- ADD·DAA-type three-point hydrogen-bonding consisted
pared to other kinds of nucleobases. The affinities of 7 and of two kinds of its tautomers. A pyrene fluorophore was
9 were surveyed using lipophilic nucleosides 10G, 10A, and connected to the hydrogen-bonding module by Sonogashira
1
10U (Scheme 2) on the basis of H NMR and fluorescence reaction to afford 9, which realized quantitative analyses
analyses. When 1 equiv. of these nucleosides were added to for the strong associations. The fluorimetric titration of 9
a CDCl3 solution of 7 (1.0×10–3 m), only small downfields revealed its selective and strong recognition of the module
1
Table 1. H NMR chemical shifts of NH protons on the addition of the lipophilic nucleosides to 7.[a]
Substrates
δ[NH(7-endo)] [ppm]
δ[NH(7-exo)] [ppm]
δ[NH(nucleobase)] [ppm]
7[b]
11.22
5.57
10C[b]
7·10C[b]
10G
5.04
13.47
11.46
11.19
11.19
8.24
5.94
5.52
5.55
9.36, 4.96
12.19, 5.68
12.29, 5.46
7.85
8.01
5.45
7·10G
10U
7·10U
10A
7·10A
5.47
[a] Conditions: 7 (1.0×10–3 m) and/or 10 (1.0×10–3 m) in CDCl3, 22 °C. [b] The spectra were shown in Figure 4.
Eur. J. Org. Chem. 2005, 2931–2940
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H. Abe, M. Takase, Y. Doi, S. Matsumoto, M. Furusyo, M. Inouye
FULL PAPER
poured into water (900 mL) and extracted with AcOEt
(100 mL×4). The AcOEt extract was washed with water
(200 mL×2) and brine (100 mL×2) subsequently, dried with
Na2SO4, and the solvents evaporated. The residue was purified by
silica gel column chromatography (hexane/AcOEt, 9:1) to afford 4
as colorless solid (2.8 g, 87%). M.p. 65–66 °C. 1H NMR (500 MHz,
CDCl3): δ = 0.88 (t, J = 7.3 Hz, 3 H), 1.26–1.38 (m, 8 H), 1.69–
1.72 (m, 2 H), 2.76 (t, J = 7.5 Hz, 2 H), 3.53 (s, 3 H), 5.52 (s, 2 H),
6.49 (s, 1 H), 7.83 (br. s, 1 H) ppm. 13C NMR (125 MHz, CDCl3):
δ = 14.1, 22.6, 24.7, 29.1, 29.2, 31.7, 37.5, 57.8, 93.1, 102.1, 156.4,
for a cytosine base. The binding of 9 with cytosine was also
predicted to occur in a similar ADD·DAA mode.
Experimental Section
General Remarks: NMR spectra were recorded with a Varian
UNITY plus 500 instrument. Chemical shifts were given in ppm
relative to TMS (1H, 0.0 ppm) or CDCl3 (13C, 77.0 ppm). IR spec-
tra were obtained with a JASCO FTIR-460plus spectrometer. High
and low resolution mass spectra were taken with a JEOL JMS-
AX505HAD (EI) or a JEOL AccuTOF JMS T100LC (ESI) instru-
ments. Elemental analyses were performed with a Perkin–Elmer
2400II instrument. Melting points were measured with a Yanaco
MP-500D instrument and not corrected. UV/Vis and fluorescence
spectra were taken with a JASCO V-560 and a JASCO FP-6500
spectrometer, respectively. Vapor pressure osmometry (VPO) analy-
ses were performed with a Gonotec OSMOMAT 070 instrument.
Commercially available materials were used as purchased. Lipo-
philic nucleotides 10C,[20] 10G,[20] 10T,[21] and 10U[21] were prepared
according to the procedures in literature.
161.6, 170.0, 173.6 ppm. IR (KBr): ν = 3286, 2954, 2927, 2852,
˜
1689, 1563 cm–1. EI MS: m/z = 315 [M+]. C14H22ClN3O3 (315.8)
calcd. C 53.25, H 6.83, N 13.31; found C 53.20, H 6.83, N 13.30.
4-Chloro-6-(methoxymethoxy)-2-(octylamino)pyrimidine (5): To a
THF (10 mL) suspension of LiAlH4 (0.23 g, 6.0 mmol) was added
a THF (10 mL) solution of 4 (0.95 g, 3.0 mmol) dropwise at room
temperature. The suspension was slowly warmed and refluxed for
1 h. The resulting mixture was cautiously poured into an AcOEt/
satd. aq. NaHCO3/ice mixture and was extracted with AcOEt
(20 mL×3). The AcOEt extract was washed with satd. aq.
NaHCO3 twice and brine once, dried with Na2SO4, and the sol-
vents evaporated. The concentrated residue was purified by silica
gel column chromatography (hexane/AcOEt, 10:1) to afford 5 as
6-Chloro-2-(octanoylamino)-3H-pyrimidin-4-one (2): To an ice-cold
(0 °C) suspension of 2-amino-4-chloro-6-hydroxypyrimidine (1)
(4.4 g, 30 mmol) and 4-(dimethylamino)pyridine (DMAP) (8.1 g,
66 mmol) in DMF (60 mL) was added dropwise octanoyl chloride
(5.4 g, 33 mmol). The mixture was stirred for 5 h and slowly
brought to room temperature. The resulting solution was poured
into ice-water (600 mL), and the mixture was stirred for 10 h. The
precipitate formed was filtered and recrystallized from AcOEt to
afford colorless fibrous crystals of 2 (6.1 g, 77%). M.p. 236–237 °C.
1H NMR (500 MHz, CDCl3): δ = 0.89 (t, J = 7.0 Hz, 3 H), 1.28–
1.36 (m, 8 H), 1.69–1.72 (m, 2 H), 2.44 (t, J = 7.5 Hz, 2 H), 6.24
(s, 1 H), 8.50 (br. s, 1 H), 11.91 (br. s, 1 H) ppm. 13C NMR
(125 MHz, [D6]DMSO): δ = 13.9, 22.1, 24.2, 28.3, 28.4, 31.1, 36.0,
1
colorless solid (0.51 g, 56%). M.p. 33–35 °C. H NMR (500 MHz,
CDCl3): δ = 0.88 (t, J = 7.3 Hz, 3 H), 1.26–1.35 (m, 10 H), 1.53–
1.60 (m, 2 H), 3.34–3.39 (m, 2 H), 3.51 (s, 3 H), 5.1–5.5 (br. m, 3
H), 6.07 (s, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 14.2,
22.7, 26.9, 29.28, 29.34, 29.5, 31.8, 41.6, 57.5, 92.2, 95.2, 96.2,
161.2, 161.7, 170.1 ppm. IR (KBr): ν = 3269, 2926, 2855, 1604,
˜
1579, 1536 cm–1. ESI HRMS: calcd. for C14H24ClN3NaO2 [M +
Na+] 324.1455; found 324.1447.
6-Chloro-2-(octylamino)-3H-pyrimidin-4-one (6): To a THF (6 mL)
solution of 5 (0.30 g, 1.0 mmol) was added 6 n HCl (6 mL), and
the mixture was stirred for 1 h at room temperature. The resulting
mixture was diluted with water (30 mL), made alkaline with
Na2CO3, and extracted with CHCl3 (10 mL×3). The CHCl3 ex-
tract was washed with brine and evaporated to afford 6 as colorless
solid (0.26 g, 100%). Further purification was carried out by silica
gel column chromatography (CH2Cl2/MeOH, 9:1). M.p. 161–
162 °C. 1H NMR (500 MHz, CDCl3): δ = 0.88 (t, J = 7.0 Hz, 3 H),
1.25–1.38 (m, 10 H), 1.57–1.63 (m, 2 H), 3.38–3.42 (m, 2 H), 5.72
(s, 1 H), 6.64 (br. s, 1 H), 11.30 (br. s, 1 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 14.2, 22.7, 26.9, 29.2, 29.33, 29.35, 31.9,
106.9, 107.0, 151.0, 158.0, 159.8, 176.7 ppm. IR (KBr): ν = 3092,
˜
2925, 2857, 1667, 1599, 1558 cm–1. EI HRMS: m/z calcd. for
C12H18ClN3O2 [M+] 271.1088; found 271.1084.
2-(Octanoylamino)-6-(trimethylsilylethynyl)-3H-pyrimidin-4-one (3):
To a toluene (50 mL) suspension of 2 (0.50 g, 1.8 mmol) and
[Pd(PPh3)4] (0.21 g, 0.18 mmol) was added tri-n-butyl(trimethylsily-
lethynyl)stannane (2.1 g, 5.4 mmol) dropwise during 3 h at 80 °C.
The mixture was stirred additionally for 2 h at that temperature,
cooled to room temperature, and concentrated under a reduced
pressure. The resulting residue was purified by silica gel column
chromatography (hexane/AcOEt, 9:1) to give 3 (0.50 g, 81%). Fur-
ther purification can be done by recrystallization from hexane/Ac-
OEt (10:1) to afford colorless fibrous crystals. M.p. 167–174 °C. 1H
NMR (500 MHz, CDCl3): δ = 0.24 (s, 9 H), 0.87 (t, J = 7.0 Hz, 3
H), 1.26–1.33 (m, 8 H), 1.64–1.70 (m, 2 H), 2.38 (t, J = 7.5 Hz, 2
H), 6.30 (s, 1 H), 8.14 (br. s, 1 H), 11.81 (br. s, 1 H) ppm. 13C
NMR (125 MHz, [D6]DMSO): δ = –0.6, 13.9, 22.1, 24.2, 28.28,
28.35, 31.1, 36.0, 98.3, 101.9, 112.2, 112.4, 146.6, 151.4, 159.8,
41.3, 99.7, 153.8, 162.6, 164.7 ppm. IR (KBr): ν = 3259, 2953, 2929,
˜
2848, 1671, 1623 cm–1. EI HRMS: calcd. for C12H20ClN3O [M+]
257.1295; found 257.1297.
2-(Octylamino)-6-(trimethylsilylethynyl)-3H-pyrimidin-4-one (7): A
xylene (30 mL) solution of 6 (179 mg, 0.69 mmol) and [Pd(PPh3)4]
(80 mg, 0.07 mmol) was heated to 120 °C, then to the mixture was
added
tri-n-butyl(trimethylsilylethynyl)stannane
(1.34 g,
3.45 mmol) in one portion. The mixture was stirred for 3 h at
120 °C, cooled to room temperature, and diluted with CHCl3
(30 mL). The organic layer was washed with brine twice, dried with
Na2SO4, and the solvents evaporated. The resulting residue was
purified by silica gel column chromatography (CH2Cl2/MeOH,
10:1) twice and preparative reverse phase HPLC (COSMOSIL
5SL-II, Nacalai Tesque, Inc.; MeOH/water, 9:1) to afford 7 (48 mg,
22%) as colorless solid. M.p. 34–36 °C. 1H NMR (500 MHz,
CDCl3): δ = 0.25 (s, 9 H), 0.88 (t, J = 7.0 Hz, 3 H), 1.28–1.39 (m,
10 H), 1.57–1.62 (m, 2 H), 3.39–3.43 (m, 2 H), 5.86 (s, 1 H), 6.56
(br. s, 1 H), 11.22 (br. s, 1 H) ppm. 13C NMR (125 MHz, CDCl3):
δ = –0.34, 14.2, 22.7, 26.9, 29.27, 29.33, 29.34, 31.9, 41.1, 98.3,
176.6 ppm. IR (KBr): ν = 3154, 2925, 2856, 1647 cm–1. EI HRMS:
˜
m/z calcd. for C17H27N3O2Si [M+] 333.1873; found 333.1870.
4-Chloro-6-(methoxymethoxy)-2-(octanoylamino)pyrimidine (4): To
an ice-cold (0 °C) suspension of NaH (0.44 g, 11 mmol; commercial
60% dispersion was washed thoroughly with hexane prior to use)
and K2CO3 (3.0 g, 22 mmol) in DMF (200 mL) was slowly added
2 (2.7 g, 10 mmol). After stirring for 1 h at 0 °C, chloromethyl
methyl ether (MOMCl) (0.89 g, 11 mmol) was added to the suspen-
sion. The mixture was stirred for an additional 24 h, being slowly
warmed from 0 °C to room temperature. The resulting mixture was
2938
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2005, 2931–2940

2-Aminopyrimidinones as Triple Hydrogen-Bonding Modules in Molecular Assemblies
FULL PAPER
102.6, 105.8, 150.9, 154.7, 164.7 ppm. IR (KBr): ν = 3312, 3145,
rhombic, Pnna, Z = 8, a = 27.907(2), b = 17.7080(7), c =
8.3452(4) Å, Dcalcd. = 1.029 g/cm3, 20154 reflections were collected,
4255 unique (Rint = 0.078), 1357 observed [I Ͼ 2σ(I)], 198 parame-
ters, R1 = 0.136, wR2 = 0.329. GOF = 1.23, refinement on F2. The
data were collected with a Rigaku Raxis-CS imaging plate dif-
fractometer with a graphite-monochromated Mo-Kα radiation
(40 kV, 100 mA) to a maximum 2θ value of 55° at –50 °C under
cold N2 gas flow. The camera length was set to be 143.5 mm from
the crystal. A total of 56 (Δφ = 3°) images were measured using an
oscillation technique. An absorption correction was not applied
and a correction for secondary extinction was applied. The struc-
tures were solved by the direct method (SIR92[24]) and refined by
least-squares calculations using the teXsan program package.[25] All
non-hydrogen atoms were refined anisotropically except for the dis-
ordered terminal two carbon atoms of the octyl group. These car-
bon atoms were refined on the assumption that they are disordered
in two conformations with 50% occupancy. The hydrogen atoms
were located on the calculated positions and not refined.
˜
2958, 2928, 2857, 1667, 1610 cm–1. EI HRMS: calcd. for
C17H29N3OSi [M+] 319.2080; found 319.2061.
4-(Methoxymethoxy)-2-(octylamino)-6-(1-pyrenylethynyl)pyrimidine
(8): A mixture of 5 (150 mg, 0.50 mmol), 1-ethynylpyrene[22]
(120 mg, 0.55 mmol), and [Pd(PPh3)4] (58 mg, 0.05 mmol) in Et3N
(10 mL)–THF (10 mL) was stirred at 60 °C for 12 h. The resulting
mixture was evaporated and subjected to silica gel column
chromatography (benzene to benzene/MeOH, 100:1) to afford 8 as
yellow solid (130 mg, 54%). M.p. 110–113 °C. 1H NMR (500 MHz,
CDCl3): δ = 0.89 (t, J = 7.0 Hz, 3 H), 1.25–1.41 (m, 10 H), 1.59–
1.64 (m, 2 H), 3.44–3.46 (br. m, 2 H), 3.57 (s, 3 H), 5.2 (br. s, 1 H),
5.55 (s, 2 H), 6.47 (s, 1 H), 8.03–8.26 (m, 8 H), 8.65 (d, J = 9.0 Hz,
1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 14.2, 22.8, 27.1,
29.36, 29.45, 29.7, 31.9, 41.6, 57.5, 90.0, 91.9, 116.1, 124.3, 124.4,
124.6, 125.5, 126.0, 126.1, 126.4, 127.3, 128.4, 128.82, 128.83,
130.3, 131.1, 131.2, 132.1, 132.7, 144.5, 152.2, 162.4 ppm. IR
(KBr): ν = 3243, 2922, 2852, 2213, 1616, 1560 cm–1. ESI HRMS:
˜
calcd. for C32H34N3O2 [M + H+] 492.2651; found 492,2636.
CCDC-259922 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
2-(Octylamino)-6-(1-pyrenylethynyl)-3H-pyrimidin-4-one (9): To a
THF (2 mL) solution of 8 (49 mg, 0.1 mmol) was added 6 n HCl
(2 mL), and the mixture was stirred for 1 h at room temperature.
The resulting mixture was diluted with water (10 mL), made alka-
line with Na2CO3, and extracted with CHCl3 (10 mL×5). The
CHCl3 extract was washed with brine and evaporated to afford 9
as yellow solid (44 mg, 94%). Further purification was carried out
by recrystallization from EtOH. M.p. 217–221 °C. 1H NMR
(500 MHz, CDCl3): δ = 0.81 (t, J = 7.0 Hz, 3 H), 1.24–1.49 (m, 10
H), 1.69–1.74 (m, 2 H), 3.53–3.57 (m, 2 H), 6.22 (s, 1 H), 6.24 (br.
s, 1 H), 8.05–8.27 (m, 8 H), 8.65 (d, J = 9.0 Hz, 1 H), 11.69 (br. s,
1 H) ppm. 13C NMR (125 MHz, [D6]DMSO): δ = 13.9, 22.1, 26.3,
28.67, 28.70, 29.0, 31.3, 88.9, 94.1, 115.2, 123.3, 123.5, 124.6, 125.0,
126.3, 126.9, 127.2, 128.9, 129.3, 130.0, 130.4, 130.7, 131.65,
1
Supporting Information: Figures S1–S8, H NMR spectra for 2–9,
the details of the calculations for the structures shown in Schemes
3–5, cytosine, guanine, and 7a·cytosine and 7a,b,f·guanine com-
plexes.
Acknowledgments
The authors are grateful to Professor Kazuhiko Mizuno (Osaka
Prefecture University) for fluorescence lifetime measurements and
Professor Atsuhiro Osuka (Kyoto University) and Professor Hi-
royuki Furuta (Kyushu University) for vapor pressure osmometry
analyses.
131.67, 148.5, 154.9 ppm. IR (KBr): ν = 3299, 3154, 2923, 2852,
˜
2208, 1661, 1609 cm–1. ESI HRMS: calcd. for C30H30N3O [M +
H+] 448.2389; found 448.2385.
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Evaluation of Association: The dilution, titration, and Job’s analyses
for 3 and 7 were performed by 1H NMR at 500 MHz in CDCl3,
and those for 9 were carried out in CHCl3 using a fluorometer. For
the analyses, CHCl3 and CDCl3 were stored over K2CO3 and 4-Å
molecular sieves (MS), and filtered before use. The binding con-
stants were calculated from the titration curve by using an iterative
least-squares curve-fitting method.[23]
Measurement of Fluorescence Lifetime of 9: Fluorescence life time
of 9 was measured by time correlation, a single-photon counting
methodology using a Horiba NAES-550 nanosecond fluorometer.
The excitation wavelength was 400 nm and emissions were detected
in the range of 380–500 nm. These measurements were performed
at concentrations of 1.0×10–5 m under Ar. The fluorescence decay
profile was analyzed on the basis of the following equation: F(t) =
F0 exp(–t/τ).
Computational Method: Quantum chemical calculations were car-
ried out with the Gaussian 98 program. The evaluation of the total
electronic energies was performed by the use of DFT(B3LYP)
method and 6-31G(d,p) basis sets.
X-ray Structure Studies: The single crystals of compound 7 were
obtained by slow evaporation from a CDCl3 solution as very wet
crystals. Structure analysis at room temperature showed disordered
terminal trimethylsilyl and octyl groups. At –50 °C, the disorder of
the trimethylsilyl group was solved whereas the octyl group was
still disordered. Crystal data: C17H29N3OSi, Mw = 319.52, ortho-
Eur. J. Org. Chem. 2005, 2931–2940
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H. Abe, M. Takase, Y. Doi, S. Matsumoto, M. Furusyo, M. Inouye
FULL PAPER
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Received: January 07, 2005
Published Online: June 2, 2005
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