Structure of pyrimidinocyclophanes in solution by NMR

Article abstract of DOI:10.1016/j.tet.2006.04.064

The conformations and self-associative properties of novel pyrimidinocyclophanes with a substituted nitrogen atom in a spacer have been studied using several independent NMR methods (NOE, aromatic shielding effect, 2D DOSY, GIAO DFT chemical shift calcula

Full text of DOI:10.1016/j.tet.2006.04.064

Tetrahedron 62 (2006) 7021–7033
Structure of pyrimidinocyclophanes in solution by NMR
*
Leisan Galiullina, Anton Nikolaev, Vyacheslav Semenov, Vladimir Reznik and Shamil Latypov
Arbuzov Institute of Organic and Physical Chemistry, Kazan Science Centre of Russian Academy of Sciences,
4
20088, Kazan, Arbuzov Street 8, Russian Federation
Received 18 October 2005; revised 1 April 2006; accepted 20 April 2006
Available online 22 May 2006
Abstract—The conformations and self-associative properties of novel pyrimidinocyclophanes with a substituted nitrogen atom in a spacer
have been studied using several independent NMR methods (NOE, aromatic shielding effect, 2D DOSY, GIAO DFT chemical shift calcula-
tions, DNMR) in a variety of solvents, in acidic and basic media. At room temperature the title compounds in neutral solution are in slow
exchange on the NMR time-scale and exist in a folded conformation. In the acidic medium protonation occurs at the bridge nitrogen, and
that leads to dramatic modifications of the structure and dynamics of the compound. The protonated form exists at the equilibrium of ‘folded’
and ‘extended’ conformers. Moreover, the protonated form is prone to association and can be effectively described as a dimer at room
temperature.
Ó 2006 Elsevier Ltd. All rights reserved.
1
. Introduction
them consist of nucleic acids or their derivatives linked by
a polymethylene spacer with another nucleic bases (pyrimi-
dines or purines or their combination) or with aromatic or
Nucleotide bases and their derivatives play a crucial role
in different processes in biochemistry, pharmacology, and
medicinal chemistry. Therefore, there have been constant
efforts to investigate such systems and their properties by
different experimental and theoretical methods . These
efforts attest to the great interest currently focused on under-
standing and controlling nucleotide base interactions.
However, in spite of the remarkable progress in this area
there is still a lot to be understood. There are no clear ideas
about the forces that control and stabilize primary, second-
ary, and supramolecular structure of the synthetic and bio-
logical systems containing nucleotide bases, particularly
5
c–i,6
heteroaromatic system.
The analysis of hypochromic
1
and in very few cases of H NMR effects can provide
insights into geometry, which is controlled by weak non-
covalent interactions (hydrogen bonding (HB), van der
Waals (vdW)). However, the very flexible nature of the pro-
posed acyclic models allows one to establish only the fact of
folded/unfolded conformation or complexed/not complexed
structure and no exact 3D solution structure can be obtained
in most cases.
1
1
c,2
The use of macrocyclic molecules containing nucleic bases
and their derivatives as models seems to be more promising
because even with the same flexible spacers, NMR and UV
effects are stronger, probably due to the higher rigidity of
macrocycles versus acyclic analogues. For example, in the
case of purinophanes and pyrimidinophanes high field shifts
for purine and pyrimidine protons and remarkably increas-
ing hypochromic effects were observed in comparison with
3
nucleic acids and their complexes with proteins. It is well
known that hydrogen bonding is crucial in the determination
of the conformational and supramolecular structures of the
systems with nucleotide bases. However, such strong stabi-
lization is controlled not only by hydrogen bonding, the
mechanism of the interactions seems to be more compli-
2
i,4
cated, and new hypotheses have been developed.
Most
of the investigations are theoretical, thus experimental
studies have become a necessity.
their acyclic counterparts both in CDCl and aqueous solu-
3
tion. At the same time, although these data are an indirect
7
indication of stacking between various nucleic bases in these
macrocycles, there has been little success in the determina-
tion of the 3D geometry of macrocycles in solution by NMR.
To promote these investigations some simpler model sys-
tems are needed, which can offer an access to control and
subtle structural variations the effects of which can be
5
assessed and comprehended at the molecular level. To
NMR techniques have proven to be powerful tools in the
conformational analysis of biologically important macro-
cycles such as peptides and proteins. However, in the case
develop such systems, modeling interactions between
nucleic acids and proteins or intercalating agents, a variety
of new compounds has been synthesized. Almost all of
8
of macrocycles containing nucleic acid bases, the problem
is more complicated: due to the diversity of weak inter-
actions of similar energy (weak HB, vdW interactions) these
*
Corresponding author. E-mail: lsk@iopc.knc.ru
0
040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.04.064

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L. Galiullina et al. / Tetrahedron 62 (2006) 7021–7033
Scheme 1.
compounds in solution are in equilibrium in a variety of con-
formations of close energy, and no folded-structure-specific
NOEs were seen.
appropriate amine in n-BuOH in the presence of K CO
2 3
under heating (Scheme 2). The yields of the macrocycles
are poor (17 and 19%), and attempts to increase them were
unsuccessful. In particular, the reactions were carried out
under high-dilution conditions, n-BuOH was substituted
by other solvents, and salts of transition metals as catalysts
were introduced into reaction mixtures. However, the yields
of the obtained pyrimidinocyclophanes didn’t exceed 20%.
It seems that the reactions are subjected mainly to statistic
factors.
7
b,9
Moreover, the equilibrium between different tautomeric
forms and the contribution of protonated forms is very prob-
1
0
able. Thus nucleotide macrocycles have to be essentially
flexible and a variety of different structural forms can be ex-
pected. Moreover, association or self-association processes
may take place, thus additionally complicating the structure
1
1
determination problem. In addition, the dispersion of the
signals in H NMR is worse than in the spectra of peptides.
1
Therefore, it is clear that macrocycles containing pyrimidine
bases are difficult objects for NMR investigation.
We faced such problems when we started a new project
concerning macrocycles with three pyrimidine fragments.
y
Our attempts to make use of variable temperature NMR
experiments were of little success: at low temperatures
extensive broadening of most signals in proton NMR was
observed, and it was not possible to derive conclusions about
conformational and/or supramolecular structure from those
experiments.
Scheme 2.
Compounds 3, 4, and 5 were prepared by procedures re-
ported earlier.
7
b
2.2. Conformational structure
Only recently we have obtained new macrocycles (1, 2)
The full assignment of signals in proton and carbon spectra
of 1 was carried out by 2D COSY, HSQC, HMBC, and
(
Scheme 1), which can be considered as cyclophanes con-
taining pyrimidine rings in place of aromatic unit, called
z13
NOESY methods. The analysis started from the thymine
fragment, for which signals can be easily assigned, e.g.,
1
2
14
pyrimidinocyclophanes. These macrocyclic compounds
allowed us insight into their 3D structures in solution and,
perhaps, to propose an explanation why the line shape evolu-
tion for previous compounds was so dramatic and difficult
to analyze. Here we report our recent results on the structure
and association properties of new pyrimidinocyclophanes in
solution.
starting from C(6)thyH by COSY, HSQC, and HMBC cor-
relation techniques. The key correlations to distinguish H2
and H12 of the aliphatic spacers are between C(6)thy/H2
and C(4)thy/H12 in HMBC, and C(6)thyH/H2 in NOESY.
The –N–CH –Ph fragment was also unequivocally assigned
2
in the same manner starting from the aromatic fragment. The
H6/H8 and the C6/C8 show correlations with NCH –Ph car-
2
1
bons and protons, respectively. Thus, the fully assigned H
NMR spectrum of 1 is shown in Figure 1.The most important
2. Results
and interesting resonances are those of the H2 and H12 pro-
tons: it is quite unexpected that geminal CH
2
.1. Synthesis
protons at C2
2
(and C12) are nonequivalent. One could expect rapid flip-
Pyrimidinocyclophanes 1 and 2 were prepared by amination
of 1,3-bis(bromopentyl)thymine 7 with 2–3-fold excess of
ping of the long aliphatic chain around a thymine fragment
and therefore the geminal protons at the benzylic positions
should be chemically equivalent due to the fast exchange
on the NMR time-scale and only one signal would be
y
Results of low temperature NMR investigation of macrocycles containing
one 6-methyluracil and two 2-thio-4-amino-6-methylpyrimidine units are
in preparation and will be published elsewhere.
z
All details can be found in Supplementary data.

L. Galiullina et al. / Tetrahedron 62 (2006) 7021–7033
7023
1
Figure 1. H NMR spectrum of 1 in CDCl
3
at T¼303 K.
observed for H2 and H12 protons. For example, for macro-
cycles possessing thymine and two 3,6-dimethyluracil
moieties linked by similar aliphatic spacers (3) one observes
field shifts for these protons in comparison with the spectrum
for the model compound 5 (Fig. 2b) where there is no such
effect. Finally, comparison of the calculated and experimen-
tal chemical shifts for the H2 and H12 protons in this confor-
1
H NMR spectra for these protons that correspond to fast
exchange when nꢀ4 and these spectra are very similar to
7
b
mation is in good agreement with this conclusion. In fact,
the thymine ring is magnetically anisotropic, and chemical
shifts of vicinal protons depend strongly on their exact posi-
tion in respect to the thymine plane (angle around N–C2 and
N–C12 bonds). Therefore, we searched for the stable con-
x
those observed for acyclic analogues (4).
These results imply that this compound is conformationally
rigid, at least in the neighborhood of the thymine fragment:
the chemical shifts of the geminal H12a/H12b and the H2a/
H2b protons reflect their position with respect to the plane of
the thymine ring.
1
5
formers of 1 by the MM method (program ChemOffice)
and found that the ‘folded’ structure (Fig. 3a) corresponds
to energy minima, and nonempirical H chemical shift cal-
1
1
6
culation in the frame of GIAO DFT approach shows quite
good correspondence between the experimental and theoret-
ical chemical shifts for this geometry (Fig. 3b). This addi-
tionally supports our conclusion about the conformational
structure of 1 because even a small discrepancy in geometry
would have been reflected in chemical shifts of the vicinal
protons.
At the same time, there is broadening in the spectrum at
T¼303 K that might be due to some exchange processes.
In order to explore this process, low temperature experi-
ments were carried out. These experiments in CDCl in
3
the range of temperatures from 303 to 213 K did not show
any remarkable modification of the NMR parameters, par-
ticularly for H2 and H12. Only some low field shifts for
C(6)thyH and 5-Me were detected, and minimal modification
Thus, we have concluded that compound 1 in CDCl pre-
3
of the line shape for CH Ph protons was observed.
2
dominantly exists in a folded conformation (Fig. 3a).
1
Such line shape evolution can be interpreted as if the title
compounds (macrocycles) exist basically in one form. Only
some minor process near to the bridging nitrogen (N-inver-
sion and/or rotation around N–CH ) might be the reason why
2
the N–CH proton spectrum is slightly modified at lower
2
In addition, H NMR experiments at different concentrations
were carried out in order to see whether this molecule
is prone to association. In proton spectra only minimal
changes were observed when concentration changed from
1 to 50 mmol/l. Thus, we concluded that the molecule in
temperature.
CDCl solution exists as a monomer in folded form.
3
The conformational structure of 1 has been established by
three NMR techniques. First of all, there are NOEs at
T¼213 K between the phenyl and 5-Me protons (Fig. 2)
that are due to the close proximity of these protons. In addi-
In general, the fact that this molecule exists in a folded con-
formation and exchange is slow in NMR time-scale is quite
an unexpected result. For example, for pyrimidinophane
with one thymine and two 3,6-dimethyluracil fragments
(3, 4) the exchange is fast even for aliphatic spacer
(–CH –) with n¼4, moreover, for n¼5 the spectrum is
tion, there are deshielding effects of phenyl ring on C(6)thy
and 5-Me protons (Fig. 2b). As one can see, there are low
H
2
n
very similar to that observed for acyclic analogue 4. This
suggests that there may be some extra interactions, which
stabilize this folded conformation of 1.
x
Results of NMR investigation of pyrimidinophane 3 and acyclic analogue
4
are under preparation and will be published elsewhere.

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L. Galiullina et al. / Tetrahedron 62 (2006) 7021–7033
1
Figure 2. H NMR (a, b) and NOE spectra (c, d) (t
braces).
m
¼0.6 s) of compounds 1 and 5 in CDCl : (a) 5 at T¼303 K; (b–d) 1 at T¼213 K (irradiated atoms shown in
3
In this case several noncovalent interactions may be consid-
ered as a contribution to stabilization. There are a number of
publications concerning this subject but there are still many
uncertainties in the energy gain due to these interactions. In
fact, most of these reports are based on theoretical results
and there are only little experimental data. Moreover, even
amongst the theoretical estimations there is dispersion in
values of energies depending on the method used to cal-
culate particular interaction, level of theory, choice of the
model system, and the model to account for the solvent
donors or acceptors. If this assumption is correct then polar
solvents should disrupt such intramolecular interactions and
1
a,18
destabilize the folded conformation.
To verify this idea
1
the H NMR spectra in different polar solvents at room tem-
perature were obtained, and it was found that replacement of
CDCl by acetone, acetonitrile, and methanol only has insig-
3
nificant effect on the spectra, particularly on indicative H2
and H12 resonances. Therefore, we concluded that dynamics
and equilibrium of 1 in these solvents are essentially the
same. Thus, HB can probably be excluded from the inter-
actions that stabilize this conformation.
3
a,b,17
effects.
In fact, from the variety of possible interactions in this sys-
tem the HB is the strongest one. There are several polar
atoms and groups (C]O, N, C(5)thyH) that may be proton
It is possible that aromatic p–p (e.g., face-to-edge) inter-
actions may take place in this case.
3
a,b
Recently, the role
of different aromatic–aromatic and aromatic–aliphatic inter-
actions has been reviewed and, according to calculations,
3
b
stabilization of up to 3.2 kcal/mol could be expected. To
check if these interactions work in this case the model com-
pound with aliphatic substituent instead of phenyl ring on
1
bridged nitrogen (2) was synthesized and H NMR experi-
ments were carried out.
1
The H NMR spectrum of 2 is shown in Figure 4. For com-
parison the spectrum of 1 is also given. As one can see, the
H2 and H12 proton signals are very similar. Taking into
Figure 3. (a) 3D structure (left) and (b) correlation of experimental and cal-
culated (GIAO B3LYP/6-31G(d)//RHF/6-31G) H chemical shifts for 1
1
(right).

L. Galiullina et al. / Tetrahedron 62 (2006) 7021–7033
7025
1
Figure 4. H NMR spectra of 2 (top, R¼butyl, C¼12 mM) and 1 (bottom, R¼Bzl, C¼7 mM) in CDCl
3
at T¼303 K. *Undetermined admixture.
account the strong anisotropy of the thymine ring and almost
equal chemical shifts of the H2 and H12 protons in 1 and 2,
we can conclude that geometries of these molecules are
effectively the same.
CDCl the geminal CH protons were not equivalent and
3 2
resonate at 4.5 and 3.2 ppm. At intermediate concentrations
of acid their signals broadened extensively, and then close to
full protonation, one exchange averaged signal was observed
for each of these protons.
1
Low temperature H NMR experiments were also in good
agreement with this conclusion. In addition, NOE between
Such line shape evolution can be explained either by ex-
change between two symmetric forms that becomes fast in
NMR time-scale or/and stabilization of the additional form
in which the chemical shifts of these protons differ from
those in the folded conformation.
5-Me and the aliphatic substituent at N unambiguously
proves that 2 in solution exists also in folded conformation.
Thus both compounds are in an identical folded conforma-
tion irrespective to the nature of the substituent at bridge
nitrogen, and no indication of p–p ‘edge-to-face’ interactions
was obtained for the title compounds. Most probably, the
realization of the folded conformation for such systems is
explained by the structure of polymethylene spacers and
the number of methylene groups.
In order to determine the structure of the protonated form(s),
NMR experiments with variation of the temperature were
carried out (Fig. 6). As the temperature decreases, the signals
of the H2 and H12 protons start to collapse and finally at
T¼223 K the spectrum corresponds to slow exchange of sev-
eral forms. The lines, in addition, are extensively broadened,
perhaps due to self-association.
2
.3. Protonation and association
1
Another aspect of our efforts was to explain why the H
NMR spectra of 1 still remain well resolved at lower tem-
perature and correspond to one conformation, with no indi-
cations of association even at temperatures close to the
solvent’s m.p. For macrocycles containing other pyrimidine
bases, however, extensive broadening of signals was seen
even at moderately low temperature.
Unfortunately, due to ambiguous line shape evolution and
extensive broadening it is difficult to determine the number
of components in equilibrium and to assign the signals in the
low temperature H spectra to corresponding groups in order
to establish their conformational structure.
1
Therefore to the association of the title compound in solution
under protonation and particularly at low temperature (cor-
responding extensive broadening of the lines in H spectra)
1
We supposed that other macrocycles are prone to association
due to the existence of protonated or charged forms.
1
0
we tried to estimate effective volume of the molecule by the
measurement of self-diffusion coefficient.
1
0a,19
Therefore, we decided to try to provoke protonation of
compound 1 too.
Translation
self-diffusion coefficients were measured by 2D DOSY
method with bipolar gradients. Every value was averaged
over two–three measurements. The results are shown in
Figure 7. It was established that at room temperature the
coefficient is approximately 1.5 times larger in pure
1
H NMR experiments in CDCl with titration by CF COOH
3
3
(
6) at room temperature have demonstrated marked modifi-
cation of the spectra (Fig. 5). Some changes could be
expected due to protonation of the bridge nitrogen, and
therefore vicinal CH protons (H6, H8, CH Ph) should
CDCl than in a solution of the 1:1 mixture of compounds
3
1
9
1 and 6. Then according to Stock’s model the effective
radius of the protonated form is about 1.5 of the radius of
noncharged molecule. Therefore, the effective volume of
the charged form is twice as large as the noncharged one.
Thus if in neutral solution 1 exists as monomer, protonation
leads to association of the molecule into dimer.
2
2
reflect this process. However, the most important is the
observed line shape evolution of the H2 and H12 protons:
as the concentration of acid is increased the signals of these
protons start to broaden and then finally they coalesce. It
is particularly apparent for the H2 protons, while in pure

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L. Galiullina et al. / Tetrahedron 62 (2006) 7021–7033
1
Figure 5. Dependence of H NMR spectra of mixture 1+6 on the 1:6 ratio in CDCl
3
at T¼303 K.
In addition, the self-diffusion coefficient was measured at
lower temperatures (Fig. 7). The temperature dependence of
the self-diffusion coefficient for neutral molecule can be well
explained by its dependence directly on temperature and
indirectly on viscosity. At the same time for the protonated
form this dependence reflects also the fact that at low
temperature higher associates become more stable and low
temperature self-diffusion coefficient corresponds to four
molecular associates. Thus association isthermodynamically
more favorable than the monomeric form in acidic media.
differences were observed for C(2) , C(4) , C(5) , and
thy thy thy
C6/8. None of them were seen in the acidic medium due to
extensive broadening. Therefore, we concluded that this
could be due to equilibrium of the forms where these carbons
have large chemical shift differences.
To check this hypothesis we carried out several experiments
with variation of temperature. As mentioned above, the
evolution of the proton NMR spectra was dramatic but it
was very difficult to follow these changes and to ascribe it
either to slowing down of exchange between the conformers
and/or to association effect. Therefore, we tried to run simi-
In the next step we tried to get insight into the conformations
of the protonated form. Room temperature H NMR spectra
of the protonated form in solution are much broadened and
1
13
lar C experiments at lower temperature, but due to low
concentration a regular spectrum could not be accumulated,
1
3
13
cannot be used for spectra-structure correlations. The
NMR spectrum of 1 at room temperature also cannot be
C
and information on C chemical shifts of carbons directly
bonded to protons was obtained only from 2D HSQC spectra
(Fig. 9).
used to determine the conformational structure. However,
1
3
a comparison of C spectra with those for the nonprotonated
form shows (Fig. 8) that they are different and this difference
may be due to the contribution of some additional con-
formers. As can be seen from Figure 8, most spectacular
As can be seen in Figure 9, the number of carbon signals in
the low temperature spectrum is twice that at room temper-
ature (for carbons C2, C12, C6, C8, CH Ph). Therefore,
2

L. Galiullina et al. / Tetrahedron 62 (2006) 7021–7033
7027
1
3
Figure 6. Temperature-dependent H NMR spectra for a mixture of 1+6 (1:6) in CDCl .
we concluded that this spectrum corresponds to a two-com-
ponent equilibrium. Moreover, comparison of room temper-
ature chemical shifts with low temperature data and analysis
of CH correlation data allowed us to assign signals as shown
in Figure 9.
As can be seen, chemical shifts for the carbons in one form
(except for the C6/8 and C2) are very similar to those ob-
served in the nonprotonated form in CDCl at room temper-
ature, while for another conformer they are different.
Particularly important is the difference for the C6/8 and
C12 carbons of the spacer: Dd are ca. 8 and 4 ppm, respec-
tively.
3
Thus, we can conclude that the first form has a conformation
similar to nonprotonated form, i.e. folded conformation.
Some differences in chemical shifts of C6, C8, and C2 can
be explained by the change of the local structure upon
N-protonation. The analysis of the chemical shift difference
for the second form allowed us to conclude that the observed
low field shifts with respect to the folded form’s shifts for
C6, C8 carbons can be attributed to g-effects on these car-
bons due to a change of orientation around C4–C5 and
C10–C9 bonds that leads to extended conformation shown
schematically in Figure 10. Thus, the title compound in
solution upon protonation exists in equilibrium of two forms,
one being folded and the second being extended.
In addition, the extended form is very prone to association
and its structure can be accessed by high field shifts for
H4, H10 protons at low temperature. Namely, in such
z
Figure 7. Temperature dependences of self-diffusion coefficients for 1 and
1+6 (1:1) in CDCl
3
.
dimers (trimer, tetramer, and higher associates) the protons

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L. Galiullina et al. / Tetrahedron 62 (2006) 7021–7033
13
3
Figure 8. C NMR spectra of 1 (a) and 1+6 (1:6) (b) at room temperature in CDCl .
Figure 11. Schematic presentation of dimer of 1.
3. Discussion
Besides the particular data related to this type of compounds
the protonation site and conformational structure in solution
and in protonated form) there are two questions that have
general interest: (1) the mechanism of stabilization of such
strained forms and (2) the mechanism of stabilization of as-
sociates and their structure. (1) Folded conformations appear
to be stabilized by the ‘edge-to-face’ p–p interactions.
Different authors estimate such interactions in the range of
(
1
13
3
b
Figure 9. Fragment of 2D HSQC ( H– C) spectrum of 1+6 (1:6) at
T¼223 K in CDCl
0
.9–2.6 kcal/mol. At this point, however, its magnitude
3
.
and its value in solution remain unclear. In particular there
are almost no experimental data.
at C4 and C10 of spacer of one molecule are located in the
shielding cone of the phenyl ring of another molecule
According to our experiments there is no indication of such
interactions in the ground state in the title compounds. In the
case of such interactions, the energy barrier of interconver-
sion between symmetric conformers would increase for 1
versus 2 (when butyl is changed for Bzl) and it should affect
(
Fig. 11). Therefore, at lower temperature the contribution of
the higher associates, which have similar NMR parameters,
increases and this leads to high field shift of H4, H10
protons.
Figure 10. Schematic presentation of the equilibrium of folded and extended conformations of 1.

L. Galiullina et al. / Tetrahedron 62 (2006) 7021–7033
7029
NMR line shape (broadening or coalescence temperature).
Some broadening at room temperature is very similar in
both compounds (1 and 2) and this proves that exchange
rate is very much the same in these compounds irrespective
of the substituent at the bridge nitrogen atom.
effects in the mixture of solvents: alcohol/water (methanol/
water, 2/1). NMR experiments at room temperature with
titration by HCl showed similar evolution of the line shape
z
as observed in CDCl under titration with CF COOH.
3
3
The most spectacular were the changes of the H2/H12 pro-
tons signals: they start to broaden extensively upon the addi-
tion of ca. 1 equiv of HCl. Moreover, these changes are
reversible: when equimolar NaOH was added the reverse
evolution of the line shape was seen.
(
2) To explain the stabilization of such associates under pro-
tonation and also the mechanism an additional argument in
favor of the structure depicted in Figure 11 is the chemical
shift of C(2)thy]O. It is likely that this oxygen atom par-
ticipates in binding when dimer and higher associates are
formed. There is no signal for this carbon in the room
This fact demonstrates that being regulated by the solution
pH, 3D and supramolecular association may be a means of
recognition and modulation of that recognition.
1
3
temperature C spectra although other signals are present.
Unfortunately due to low S/N at low temperature we were
(
1
3
not able to obtain the C NMR spectra.) Based on this ob-
servation we concluded that its signal is much broadened
at room temperature, which might take place if the chemical
shift of this carbon in above-mentioned conformers (forms)
is substantially different. This difference may originate from
the bonding by the C]O group if, e.g., HB are formed in one
of the forms. Indeed, GIAO DFT calculations of chemical
shifts (with RHF/6-31G optimized geometry) for 1 with
C(2)thy]O involved in HB with three ethyl amine cation
as example of proton donor group and for 1 which is not
involved in HB predict maximal differences just for C(2)thy
4. Conclusion
The title macrocycles in solution exist in a folded conforma-
tion with bridge N substituents proximal to the thymine Me
and H . The barrier of interconversion is very high.
5
A small amount of acid in solution may protonate the com-
pounds and change dramatically not only the conformation
but also the supramolecular structure. Interactions (HB) of
protons vicinal to protonated nitrogen with carbonyl oxygen
+
(+4.4 ppm) and C(5)thy (+5.4 ppm, positive signs mean
low field shifts in HB complex).
(N CH/O]C) are strong when compared to other non-
covalent ones, and this result strongly supports the theo-
retical prediction. The role of such interactions may
be important if one takes into account that protonation in
physiological solutions occurs very often. The supramolec-
ular association of designed macrocycles and closely related
natural systems can be regulated by the solution pH.
Which group could donate proton to this group to form HB?
There are different options: first of all, N H could participate
+
in such bonding. Such bonds can be excluded as dominant,
however, because the chemical shift of this proton does
not depend remarkably on temperature. Second, vicinal to
+
protonated nitrogen the N CH protons may give HB, which
2
are in total even stronger than classical HB, as it was recently
proposed theoretically.
5. Experimental
5.1. General
1
0b,17c
Three such groups can interact
with C]O and in doing so stabilize such associates. This
can explain the low field shift of these protons when the tem-
perature decreases. In this structure high field shifts have to
be observed for the protons at C4 and C10 of the bridges due
to the shielding effect of the phenyl ring.
NMR experiments were recorded with a Bruker AVANCE-
600 spectrometer (14.1 T) equipped with a pulsed gradient
unit capable of producing magnetic field pulse gradients in
the z-direction of 56 G/cm. All spectra were acquired in
a 5-mm inverse probehead in 5-mm tubes. Chemical shifts
(ppm) are internally referenced to the TMS signal (0 ppm)
According to theory, enormous stabilization (90–95 kcal/
mol in the gas phase were calculated for the [N –C–H/
+
1
7c
1
13
O]C] model)
can be expected due to these hydrogen
in all cases. Complete assignments of the H and
C
bonds although solvent effects have to diminish such interac-
tions to some extent (energy drops to 20 kcal/mol in CHCl3).
In order to verify this hypothesis we carried out additional
NMR spectra of the title compounds were accomplished
by 2D COSY, TOCSY, HSQC, HMBC, and NOESY experi-
ments. In some cases 1D DPFGNOE method in rotating
frame was used to measure NOEs. A Hermite-shaped
pulses were used for selective irradiation.
1
21
H NMR experiments for the protonated form in CDCl3
with titration by DMSO as HB disrupting solvent. Indeed,
the change of the spectra was observed and it can be ascribed
to the increase of the monomeric form.
In order to minimize convection effects, 2D DOSY experi-
ments were performed using the bipolar pulse longitudinal
eddy current delay (BPPLED) pulse sequence. The duration
of the magnetic field pulse gradients (d) was optimized for
each diffusion time (t) in order to obtain 1–5% residual sig-
nal with maximum gradient strength. The pulse gradients (g)
were incremented from 2 to 95% of the maximum gradient
strength in a linear ramp. All diffusion coefficients reported
are means of at least three measurements.
Such dependence of the conformational structure and asso-
ciation on acid concentration models a real situation where
2
0
properties change with the solution pH. In physiological
systems pH in aqueous solution may vary from 1.9 up to
10.4 and this can effectively produce changes in the struc-
ture, which are responsible for definite properties.
Unfortunately, this compound dissolves poorly in water and
we could not demonstrate the above statement directly in
For DNMR spectroscopy, a standard unit calibrated using
a methanol reference controlled the probe temperature; the
‘
physiological’ solvents. However, we were able to see these

7030
L. Galiullina et al. / Tetrahedron 62 (2006) 7021–7033
samples were allowed to equilibrate for 15 min at each tem-
perature before recording spectra.
29.0 mmol), and catalytic amount TBA$HSO in n-BuOH
4
(250 mL) compound 7 (3.0 g, 7.08 mmol) in n-BuOH solu-
tion (100 mL) was added and stirring was continued for
ꢁ
by CHCl , filtering, and concentration of CHCl solution
Most of the solvents and all the reagents were commercial
and used without further purification. All dry solvents
were prepared according to the standard procedures and
stored over molecular sieves.
11.5 h at 70–75 C. After evaporating the solvent, treating
3
3
residue was eluated through column with Al O by 2:1
2
3
ether/petroleum ether mixture. From the fractions of the
eluent, thyimidinocyclophane 2 was obtained in a yield of
2
2
ꢁ
Molecular mechanics (employing the MM2 force field)
0.45 g (19%); mp 44–45 C; HRMS found m/z 335.2570,
C H N O required 335.2573, m/z 292.2020, C H N O
16 26 3 2
were performed with CS Chem3D Ultra 6.0 (CambridgeSoft
Corp.) on a AuthenticAMD Athlon (Im)computer. Chemical
shifts were determined within the DFT framework using
a hybrid exchange-correlation functional, B3LYP, at the
1
9
33
3
2
required 292.2025; MS (EI) m/z 335 (M+, 13), 292 (Mꢂ43,
1
100), 278 (Mꢂ57, 8). H NMR (600.0 MHz, CDCl ) d
3
H
(ppm) 0.85 (3H, m, (CH ) CH ), 1.12 (2H, m, J¼7 Hz,
2
3
3
2
3
6
metry optimizations were done at the ab initio RHF/6-31G
-31G(d) level as implemented in Gaussian 98. Full geo-
(CH ) CH CH ), 1.15–1.28 (9H, m, H
2
), 1.34 (2H,
m, J¼7.4 Hz, CH CH C H ), 1.42 (1H, m, H ), 1.57 (1H,
2
2
3
3,4,5,9,10
2
2
2
5
11
1
13
level. All data were referred to TMS ( H and C) chemical
shifts that were calculated at the same conditions.
m, H ), 1.75 (1H, m, H ), 1.86 (3H, s, C(5) Me), 2.11–
11 3 thy
2.25 (6H, m, H ), 2.32 (2H, m, CH C H ), 3.09 (1H, m,
6
,8
2 3 7
H ), 3.92 (1H, m, H ), 4.21 (1H, m, H ), 4.42 (1H, m,
2
12
12
1
3
The mass spectra (EI) were obtained on a Finnigan MAT-212
mass spectrometer (resolution was 1000, direct inlet of the
sample into the ion source, energy of ionizing electrons
was 70 eV, electron emission current was 1 mA). Melting
points were measured on a Boetius hot-stage apparatus
and are uncorrected. Thin-layer chromatography was per-
formed on Silufol-254 plates; visualization was carried out
with UV light. For column chromatography neutral Al O
H ), 6.83 (1H, s, C(6)thyH); C NMR (150.9 MHz, CDCl3)
2
dC (ppm) 13.2 (C(5) Me), 14.0 ((CH ) CH ), 20.4
thy
2 3
3
((CH ) CH CH ), 22.4 (C ), 27.4 (C ), 27.8 (C ), 28.0
2
2
2
3
5,9
10
3
(C ), 30.1 ((CH ) CH CH ), 40.9 (C ), 49.0 (C ), 52.8
2
4
2 2
2
3
12
(C ), 55.0 (CH C H ), 110.0 (C(5)thy), 138.7 (C(6)thy),
6
,8
2 3 7
153.1 (C(2) ), 163.5 (C(4)thy).
thy
8,14,23,26,27-Pentamethyl-1,6,8,14,16,21-hexaazatetracyclo-
]heptacosa-10(27),12(26),23(24)-triene-
2
3
6
,10 12,16
(activity II) was used. Chemicals and reagents were pur-
chased from Lancaster or Aldrich Chemical companies.
[19,3,1,1 ,1
7,9,13,15,22,25-hexaone (3), 1,3-bis[4-(3,6-dimethylura-
cil-1-yl)butyl-1-]thymine (4), 1,3-dibutylthymine (5) were
prepared by known procedures.
7
b
Thyimidinocyclophanes 1 and 2 were prepared by the
reaction of 1,3-bis(5-bromopentyl)thymine (7) with benzyl-
amine or butylamine.
5.1.3. 8,14,23,26,27-Pentamethyl-1,6,8,14,16,21-hexaaza-
]heptacosa-10(26),12(27),
6
,10 12,16
tetracyclo-[19.3.1.1 .1
23(24)-triene-7,9,13,15,22,25-hexaone (3). HRMS found
m/z 526.2530 C H N O required 526.2540; MS (EI)
5.1.1. 7-Benzyl-15-methyl-1,7,13-triazabicyclo[11.3.1]-
heptadeca-15-en-14,17-dione (1). At 90 C to a stirred mix-
ꢁ
ture of benzylamine (2.14 g, 20 mmol) and K CO (2.95 g,
2
6 34 6 6
+
+
+
m/z 527 (M+1) (23), 526 (M) (78), 511 (Mꢂ15) (100),
373 (38), 333 (18), 292 (37), 235 (17), 206 (31), 193 (48),
181 (63), 166 (46), 153 (52), 141 (21), 127 (22), 122 (19).
2
3
2
1 mmol) in n-BuOH (250 mL) compound 7 (4.1 g,
.7 mmol) in n-BuOH solution (100 mL) was added and stir-
9
ring was continued for 7 h at 100–110 C. The solvent was
ꢁ
distilled off and the residue was treated by CHCl , filtered,
1
{
H NMR (600.0 MHz, CDCl , 303 K) d (ppm) 1.49–1.57
3 H
(4H, m, N(1)thy(CH ) CH CH ; N(3) (CH ) CH CH ),
2 2 2 2 thy 2 2 2 2
3
concentrated, and transferred to a column with Al O .
2
1.62–1.69 (4H, m, N(1)thyCH CH (CH ) ; N(1) CH CH
2 2 2 2 thy 2 2
3
Elution with ether gave thyimidinocyclophane 1 in a yield
ꢁ
(CH ) ), 1.92 (3H, s, C(6) CH ), 2.06 (3H, s, C(5)thyMe),
2 2 ur1 3
2.11 (3H, s, C(6)ur2CH ) 3.39 (3H, s, N(3) CH ), 3.40
3 ur1 3
of 0.6 g (17%); mp 130–131 C; HRMS found m/z
3
3
69.2420, C H N O required 369.2416; MS (EI) m/z
2
(3H, s, N(3)ur2CH ), 3.75 (2H, m, N(1) CH (CH )), 3.87
3 thy 2 2
(2H, s, C(5)ur1CH C(5)ur ), 3.89–4.01 (6H, m, N(3)thyCH2
2 2
2
31
3
2
69 (M+, 94), 368 (Mꢂ1, 42), 340 (Mꢂ29, 33), 278
1
(
Mꢂ91, 95), 250 (Mꢂ119, 29), 91 (100). H NMR
(CH ) ; N(1) (CH ) CH ; N(3) (CH ) CH ), 6.91 (1H, s,
2 3 thy 2 3 2 thy 2 3 2
1
3
(
600.0 MHz, CDCl , 303 K) d (ppm) 1.16–1.44 (8H, m,
3
C(6)thyH); C NMR (150.9 MHz, CDCl , 303 K) d (ppm)
3 C
H
(
CH2)4,5,9,10), 1.48 (1H, m, H ), 1.64 (1H, m, H ), 1.8
3
13.0 (C(5)thyMe), 16.5 (C(6)ur1CH ), 16.7 (C(6)ur2CH3),
3
11
(
1H, m, H ), 1.9 (1H, m, H ), 2.04 (3H, s, C(5)thyMe),
1
22.1 (C(5)ur1CH C(5)ur2), 23.2 (N(1)thyCH CH C H ), 23.7
2
1
3
2
2 2 4
2
.32 (4H, m, H6,8), 3.18 (1H, m, H ), 3.38 and 3.46 (2H,
2
(N(3)thyCH CH C H ), 27.1 (N(1) (CH ) CH CH ), 27.8
2 2 2 4 thy 2 2 2 2
AB, J¼13.0 Hz, CH Ph), 4.03 (1H, m, H ), 4.28 (1H, m,
(N(3)thy(CH ) CH CH ), 28.0 (N(3) CH ), 28.5 (N(3)
2 2 2 2 ur1 3 ur2
CH ), 40.7 (N(3) CH (CH ) ), 44.6 (N(1) (CH ) CH ),
3 thy 2 2 3 thy 2 3 2
2
12
H ), 4.48 (1H, m, H ), 6.97 (1H, s, C(6) H), 7.16 (2H,
1
2
2
thy
d, J¼6.7 Hz, Ar
), 7.21 (1H, t, J¼6.7 Hz, Arpara), 7.26
44.9 (N(3)thy(CH ) CH ), 48.9 (N(1) CH (CH ) ), 109.6
2 3 2 thy 2 2 3
ortho
1
3
(
2H, t, J¼7.4 Hz, Ar ); C NMR (150.9 MHz, CDCl
(C(5)thy), 110.5 (C(5)ur1), 111.0 (C(5)ur2), 138.4 (C(6)thy),
148.6 (C(6)ur1), 149.0 (C(6)ur2), 151.2 (C(2)thy), 151.8
(C(2)ur1), 151.9 (C(2)ur2), 162.8 (C(4)ur1), 163.0 (C(4)ur2),
163.7 (C(4)thy).
meta
3,
3
2
4
03 K) d (ppm) 13.2 (C(5) Me), 22.6 (C ), 22.9 (C ),
C thy 9 5
6.3 (C ), 27.1 (C ), 27.3 (C ), 27.9 (C ), 40.5 (C ),
1
1
10
4
3
12
9.0 (C ), 53.5 (C ), 59.0 (CH Ph), 109.4 (C(5)thy), 126.4
2
6,8
2
(
1
Arpara), 127.8 (Armeta), 128.4 (Arortho), 138.6 (Aripso),
52.0 (C(2)thy), 163.9 (C(4)thy).
5.1.4. 1,3-Bis[4-(3,6-dimethyluracil-1-yl)butyl-1-]thy-
mine (4). Found (%): C, 58.41; H, 6.74; N, 16.37.
5
.1.2. 7-Butyl-15-methyl-1,7,13-triazabicyclo[11.3.1]hep-
ꢁ
{
tadeca-15-en-14,17-dione (2). At 70 C to a stirred mixture
of n-butylamine (2.07 g, 28.4 mmol), K CO (4.00 g,
thy—thymine unit, and ur2—3,6-dimethyluracil attached to N(1)thy and
N(3)thy, respectively.
2
3

L. Galiullina et al. / Tetrahedron 62 (2006) 7021–7033
7031
1
C H N O required (%): C, 58.35; H, 6.66; N, 16.33. H
2
Supplementary data
5
34
k
6
6
NMR (600.0 MHz, CDCl , 303 K) d (ppm) 1.66–1.76
H
3
(
2
8H, m, N(1)thyCH (CH ) CH ; N(3) CH (CH ) CH ),
2
.26 (6H, s, C(6) CH ), 3.30 (6H, s, 2N(3) CH ), 3.33
ur 3 ur 3
Supplementary data associated with this article can be found
in the online version, at doi:10.1016/j.tet.2006.04.064
2 2
2
thy
2
2 2
2
(
3H, s, C(5) Me), 3.84 (4H, t, J¼7 Hz, N(1) (CH ) CH ;
thy
thy
2 3
2
N(3) (CH ) CH ), 3.92 (4H, t, J¼7 Hz, N(1) CH (CH ) ;
thy 2 3 2 thy 2 2 3
N(3) CH (CH ) ), 5.59 (2H, s, 2 C(5) H), 7.06 (1H, s,
ur
References and notes
thy
2
1
2 3
3
C(6)thyH); C NMR (150.9 MHz, CDCl , 303 K) d (ppm)
3
C
1
C H ), 25.8 (N(3) CH CH C H ), 26.1 (N(1) (CH ) CH
3.0 (C(5)thyMe), 19.7 (C(6) CH ), 25.0 (N(1) CH CH
1. (a) Saenger, W. Principles of Nucleic Acid Structures; Springer:
New York, NY, 1984; (b) Chen, Sh.; Zhang, Q.; Wu, Xu;
Schultz, P. G.; Ding, Sh. J. Am. Chem. Soc. 2004, 126, 410–
411; (c) Chifotides, H. T.; Koshlap, K. M.; Perez, L. M.;
Dunbar, K. R. J. Am. Chem. Soc. 2003, 125, 10703–10713.
2. (a) Corbin, P. S.; Zimmerman, S. C.; Thiessen, P. A.; Hawryluk,
N. A.; Murray, T. J. J. Am. Chem. Soc. 2001, 123, 10475–
ur
3
thy
2
2
2
4
thy
2
2
2
4
thy
2 2
2
CH ), 26.3 (N(3) (CH ) CH CH ), 27.8 (N(3) CH ), 40.7
2
thy
2 2
2
2
ur
3
(
N(3)thyCH (CH ) ), 44.3 (N(1) (CH ) CH ), 44.9 (N(3)
2 2 3 thy 2 3 2 thy
(
CH ) CH ), 48.7 (N(1) CH (CH ) ), 101.6 (C(5) ),
2 3 2 thy 2 2 3 ur
1
10.0 (C(5)thy), 138.5 (C(6)thy), 151.0 (C(6) ), 151.3
ur
(
C(2)thy), 152.2 (C(2) ), 162.3 (C(4) ), 163.7 (C(4)thy).
ur ur
1
0488; (b) Giedroc, D. P.; Cornish, P. V.; Hennig, M. J. Am.
5
9
9
.1.5. 1,3-Dibutylthymine (5). Found (%): C, 65.44; H,
.37; N, 11.85. C H N O required (%): C, 65.51; H,
Chem. Soc. 2003, 125, 4676–4677; (c) Chifotides, H. T.;
Koshlap, K. M.; Perez, L. M.; Dunbar, K. R. J. Am. Chem.
Soc. 2003, 125, 10714–10724; (d) Sontjens, Serge H. M.; van
Genderen, Marcel H. P.; Sijbesma, Rint P. J. Org. Chem. 2003,
68, 9070–9075; (e) Janke, E. M. Basilio; Limbach, H.-H.;
Weisz, K. J. Am. Chem. Soc. 2004, 126, 2135–2141; (f) Lai,
J. S.; Kool, E. T. J. Am. Chem. Soc. 2004, 126, 3040–3041; (g)
Poner, J.; Jureka, P.; Hobza, P. J. Am. Chem. Soc. 2004, 126,
10142–10151; (h) Grunenberg, J. J. Am. Chem. Soc. 2004,
126, 16310–16311; (i) Swart, M.; Guerra, C. F.; Bickelhaupt,
F. M. J. Am. Chem. Soc. 2004, 126, 16718–16719; (j) Hobza,
P.; Sponer, J.; Czeck. Chem. Rev. 1999, 99, 3247–3276.
1
3 22 2 2
1
.30; N, 11.75. H NMR (600.0 MHz, CDCl , 303 K) d
3
H
(
ppm) 0.87–0.94 (6H, m, N(1)thy(CH ) CH N(3) (CH )
2 3 3; thy 2 3
CH ), 1.28–1.36 (4H, m, N(1) (CH ) CH CH ; N(3)
thy
3
thy
2 2
2
3
(
CH ) CH CH ), 1.56 (2H, m, J¼7.8 Hz, N(1)thyCH2
2
2
2
3
CH C H ), 1.62 (2H, m, J¼7.8 Hz, N(3) CH CH C H ),
2 2 5 thy 2 2 2 5
1
.88 (3H, s, C(5) Me), 3.66 (2H, t, J¼7.3 Hz, N(1)thyCH2
2 2 3 thy 2 2 2 3
thy
(
6
3
CH ) CH ), 3.9 (2H, t, J¼7.3 Hz, N(3) CH (CH ) CH ),
1
3
.92 (1H, s, C(6) H); C NMR (150.9 MHz, CDCl ,
thy 3
03 K) dC (ppm) 13.0 (C(5)thyMe), 13.7 (N(1)thy(CH2)3
CH ), 13.8 (N(3) (CH ) CH ), 19.8 (N(1) (CH ) CH
2 2
3
thy
2 3
3
thy
2
CH ), 20.3 (N(3) (CH ) CH CH ), 29.7 (N(3) CH CH
3
3. (a) Tsuzuki, S.; Honda, K.; Uchimaru, T.; Mikami, M.; Tanabe,
K. J. Am. Chem. Soc. 2002, 124, 104–112; (b) Ribas, J.;
Cubero, E.; Luque, F. J.; Orozco, M. J. Org. Chem. 2002, 67,
7057–7065; (c) Lin, C.-H.; Tour, J. J. Org. Chem. 2002, 67,
thy
2 2
2
3
thy
2
2
C H ), 31.2 (N(1) CH CH C H ), 41.3 (N(3) (CH )
2 3
2
5
thy
2
2
2
5
thy
CH ), 49.2 (N(1) (CH ) CH ), 109.6 (C(5)thy), 138.3
3
thy
2 3
3
(
C(6)thy), 151.4 (C(2)thy), 163.8 (C(4)thy).
7
761–7768; (d) Huang, N.; MacKerell, A. D., Jr.. J. Phys.
5
1
.1.6. 1,3-Bis(5-bromopentyl)thymine (7). A solution of
,5-dibromopentane (155.9 g, 677.8 mmol) in DMF
Chem. A 2002, 106, 7820–7827; (e) Rozas, I.; Alkorta, I.;
Elguero, J. J. Am. Chem. Soc. 2000, 122, 11154–11161; (f)
Tatko, Ch. D.; Waters, M. L. J. Am. Chem. Soc. 2004, 126,
2028–2034; (g) Yohannan, S.; Faham, S.; Yang, D.; Grosfeld,
D.; Chamberlain, A. K.; Bowie, J. U. J. Am. Chem. Soc.
2004, 126, 2284–2285; (h) Alonso, J. L.; Antolinez, S.;
Blanco, S.; Lesarri, A.; Lopez, J. C.; Caminati, W. J. Am.
Chem. Soc. 2004, 126, 3244–3249; (i) Arbely, E.; Arkin, I. T.
J. Am. Chem. Soc. 2004, 126, 5362–5363; (j) Sinnokrot,
M. O.; Sherrill, C. D. J. Am. Chem. Soc. 2004, 126, 7690–
7697; (k) Gschwind, R. M.; Armbruster, M.; Zubrzycki, I. Z.
J. Am. Chem. Soc. 2004, 126, 10228–10229; (l) Reiter, S. A.;
Nogai, S. D.; Karaghiosoff, K.; Schmidbaur, H. J. Am. Chem.
Soc. 2004, 126, 15833–15843.
(
of 14.4 g (84.7 mmol) of disodium salt of thymine in DMF
90 mL) was added dropwise with stirring to a suspension
ꢁ
which it was evaporated in a vacuum and the residue was
(
150 mL). The mixture was stirred for 5 h at 50–60 C, after
treated with 150 mL of CHCl . The precipitate that formed
3
was filtered off. The solution was concentrated and submit-
ted to chromatography over Al O . The column was suc-
cessively washed with petroleum ether and a 2:1 ether/
petroleum ether mixture. From ether/petroleum ether mix-
ture fractions compound 6 was obtained as oil in a yield of
2
3
15.9 g (45%): MS (EI) m/z 426 (M+, 9), 424 (M+, 22),
422 (M+, 10), 346 (28), 345 (88), 344 (28), 343 (88), 275
(
C, 42.47; H, 5.70; N, 6.60; Br, 37.67. Found: C, 42.48; H,
75), 195 (86), 140 (100). Anal. Calcd for C H Br N O :
4. (a) Bickelhaupt, F. M. Chem.—Eur. J. 1999, 5, 3581–3594;
Angew. Chem. 1999, 111, 3120–3122; J. Am. Chem. Soc.
2000, 122, 4117–4128; (b) Rozas, I.; Alkorta, I.; Elguero, J.
J. Phys. Chem. A 2001, 105, 10462–10467; (c) Chen, D.;
Meena; Sharma, S. K.; McLaughlin, L. W. J. Am. Chem. Soc.
2004, 126, 70–71; (d) Wesolowski, T. A. J. Am. Chem. Soc.
1
5
24
2 2 2
1
5
7
3
.81; N, 6.53; Br, 37.75. H NMR (400 MHz, CDCl ) d
3 H
.01 (s, 1H), 3.95 (2H, t, J¼7 Hz), 3.73 (2H, t, J¼7 Hz),
.42 (4H, m), 1.93 (3H, s), 1.89 (4H, m), 1.76–1.58 (4H,
m), 1.50 (4H, m).
2
004, 126, 11444–11445; (e) Sessler, J. L.; Jayawickramarajah,
J.; Sherman, C. L.; Brodbelt, J. S. J. Am. Chem. Soc. 2004, 126,
11460–11461.
Acknowledgements
5
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J. R.; Luque, F. J.; Orozco, M. J. Am. Chem. Soc. 2004, 126,
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Kool, E. T. J. Am. Chem. Soc. 2004, 126, 1102–1109; (d)
Liu, H.; Lynch, S. R.; Kool, E. T. J. Am. Chem. Soc. 2004,
This study was financially supported in part by the Russian
Foundation for Basic Research (Project 05-03-32497-a,
No. 05-03-32558-a).
1
26, 6900–6905; (e) Polak, M.; Seley, K. L.; Plavec, J. J. Am.
Chem. Soc. 2004, 126, 8159–8166; (f) Moody, E. M.;
k
thy—thymine unit, ur—two 3,6-dimethyluracil units.

7032
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