Hydrogen-bond-mediated self-assembly of 26-membered diaza tetraester crowns of 3,5-disubstituted 1 h -pyrazole. Dimerization study in the solid state and in CDCl3 solution

Article abstract of DOI:10.1021/jo2012835

By using an improved synthetic method reported earlier, the cyclic stannoxanes obtained from RN-diethanolamine (R = Me, Bu) and dibutyltin oxide have been reacted with 1H-pyrazole-3,5-dicarbonyl dichloride to afford 26-membered diaza tetraester crowns (1, R = Me; 3, R = Bu) and 39-membered triaza hexaester crowns (2, R = Me; 4, R = Bu). The new structures were identified from their analytical and spectroscopic (¹H and ¹³C NMR, FAB-MS, and/or ESI-MS) data. Both diaza tetraester crowns (1 and 3), containing two 1H-pyrazole units, self-assemble into dimeric species through the formation of four hydrogen bonds involving the two NH pyrazole groups and the two tertiary amine groups of both crowns, as proved by X-ray crystallography and NMR analysis. Preliminary NMR, ESI-MS, MALDI-TOF-MS, and molecular modeling studies suggest that, in CDCl₃ solution, 1 interacts with ethyleneurea (ETU), affording 1:1, 2:1, and 2:2 1-ETU complexes.

Full text of DOI:10.1021/jo2012835

ARTICLE
pubs.acs.org/joc
Hydrogen-Bond-Mediated Self-Assembly of 26-Membered Diaza
Tetraester Crowns of 3,5-Disubstituted 1H-Pyrazole. Dimerization
Study in the Solid State and in CDCl3 Solution
Felipe Reviriego,† Pilar Navarro,*,† Vicente J. Arꢀan,† Maria Luisa Jimeno,† Enrique García-Espa~na,*,‡
Julio Latorre,‡ and Maria J. R. Yunta§
†Instituto de Química Mꢀedica and Centro de Química Orgꢀanica Lora-Tamayo CSIC, Juan de la Cierva 3, 28006 Madrid, Spain
‡Departamento de Química Inorgꢀanica, Instituto de Ciencia Molecular, Universidad de Valencia, Edificio de Institutos de Paterna,
Profesor Josꢀe Beltrꢀan 2, 46980 Paterna (Valencia), Spain
§Departamento de Química Orgꢀanica, Facultad de Química, Universidad Complutense de Madrid, Avda Complutense s/n, 28040
Madrid, Spain
S Supporting Information
b
ABSTRACT: By using an improved synthetic method reported
earlier, the cyclic stannoxanes obtained from RN-diethanolamine
(R = Me, Bu) and dibutyltin oxide have been reacted with 1H-
pyrazole-3,5-dicarbonyl dichloride to afford 26-membered diaza
tetraester crowns (1, R = Me; 3, R = Bu) and 39-membered triaza
hexaester crowns (2, R = Me; 4, R = Bu). The new structures were
identified from their analytical and spectroscopic (1H and 13C NMR,
FAB-MS, and/or ESI-MS) data. Both diaza tetraester crowns (1 and 3), containing two 1H-pyrazole units, self-assemble into
dimeric species through the formation of four hydrogen bonds involving the two NH pyrazole groups and the two tertiary amine
groups of both crowns, as proved by X-ray crystallography and NMR analysis. Preliminary NMR, ESI-MS, MALDI-TOF-MS, and
molecular modeling studies suggest that, in CDCl3 solution, 1 interacts with ethyleneurea (ETU), affording 1:1, 2:1, and 2:2
1ꢀETU complexes.
’ INTRODUCTION
3,5-disubstituted NH-pyrazoles by the combined use of 13C and/
or 15N-CP/MAS solid-state NMR spectroscopy and X-ray
crystallography, showing that they self-assemble, forming a
variety of hydrogen-bonded cyclic dimers, trimers, and tetramers.7
On the basis of this principle, Ochsenfeld et al. have recently
presented an elegant study about the insertion of pyrazole units
in a peptide which associates intermolecularly, giving rise to
nanorosette-type structures in water.8 Low-temperature NMR
experiments conducted in a freonic solvent have proved that the
interaction of 3-methylpyrazole and 3-amino-5-methylpyrazole
with the protected tripeptide L-Val-L-Val-L-Val-tBu gives rise to
2:2 complexes in which the peptides display an antiparallel
association, with the pyrazole units symmetrically capping both
sides.9 Also, aminopyrazoleꢀpeptide hybrid ligands were shown
to undergo a specific interaction with amyloid plaques developed
in Alzheimer’s disease.10
Hydrogen bonding is the favorite intermolecular force in self-
assembling systems by virtue of its directionality, specificity, and
biological relevance.1,2 Whereas self-assembly may be taken as a
simple collection and aggregation of components into a confined
entity, self-organization is considered as the spontaneous but
information-directed generation of organized functional struc-
tures under equilibrium conditions.3 In such structures, hydro-
gen bonds exhibit typical grouplike behavior, and acting together
they become much stronger (cooperativity). Fundamental studies
on these phenomena have gradually developed a new discipline
so-called “noncovalent synthesis”, based on the reversible for-
mation of multiple hydrogen bonds.4
Most natural building blocks, such as carbohydrates, amino
acids, and nucleic acids, offer a rich source of H-bond donors and
acceptors. Hydrogen-bonding interactions in DNA/RNA sys-
tems have recently inspired the use of such motifs to stabilize a
range of synthetic structures, and it has led to the formation of a
number of novel ensembles. Reference 5 collects several reviews
covering this interesting topic.
We have recently reported that the interaction of the sodium
pyrazolate salt of diethyl 1H-pyrazole-3,5-dicarboxylate with (+)-
amphethamine, β-phenethylamine, and homoveratrylamine hy-
drochlorides leads to interesting crystal structures in which the
ammonium cations and pyrazolate anions are interconnected
In this respect, 1H-pyrazole can be an appropriate building
block, since it has both hydrogen donor and acceptor sites in
adjacent positions which can build up a self-complementary
hydrogen-bonded assembly.6 Elguero et al. have examined many
Received: July 3, 2011
Published: September 12, 2011
r
2011 American Chemical Society
8223
dx.doi.org/10.1021/jo2012835 J. Org. Chem. 2011, 76, 8223–8231
|

The Journal of Organic Chemistry
ARTICLE
Chart 1
between them through extended hydrogen-bond networks,
forming hetero double-helical structures.11 However, studies
on the reversible self-assembly of pyrazole-containing systems
in aprotic organic solution are scarce.12
Here, we report the first examples of a hydrogen-bonded
guided dimerization occurring in a macrocycle containing pyr-
azole units. The dimerization occurs both in the solid state and
reversibly in chloroform solution by simultaneous self-assembly
basis of their analytical and spectroscopic data (FAB-MS and/or
1
ESI-MS, H and 13C NMR). In both series, the two triaza
hexaester crowns 2 and 4 were obtained as pure amorphous
solids. However, crystallization of both diaza tetraester crowns 1
and 3 from acetonitrile afforded crystals suitable for X-ray
diffraction studies, which demonstrated that, after crystallization,
both compounds adopt the dimeric structure 10[L1]2 (mp
214ꢀ216 °C) and 30[L3]2 (mp 189ꢀ190 °C), respectively
(see Chart 1 and Figures 1 and 2).
of four NH (pyrazole)
(see Chart 1).
NR (tertiary amine) hydrogen bonds
3 3 3 3
The asymmetric unit of 10 consists of a macrocyclic unit and
one acetonitrile molecule. The macrocyclic unit displays 2-fold
symmetry with both methyl groups and pyrazole units oriented
toward the same side of the macrocyclic plane defined by the
ether oxygen atoms and the tertiary nitrogens at the middle of the
bridges (Figure 1).
Additionally, preliminary studies of the interaction of these
systems with ethyleneurea (ETU) have been carried out in order
to assess the behavior of these dimers in the presence of a
complexing agent able to form competitive hydrogen bonds.
The most interesting aspect of this structure is revealed when
the asymmetric unit is grown in a search for hydrogen bond
contacts. Each macrocycle is associated with another equivalent
unit rotated by 90° through a four-hydrogen-bond network,
forming dimers (Figure 1, left). The hydrogen bonds are
established between the pyrazole NH groups as the hydrogen-
bond donors and the central tertiary nitrogen atoms as the
hydrogen-bond acceptors (N1 N3, 2.886 Å; N1ꢀH N3,
’ RESULTS AND DISCUSSION
Previously, some of us reported a synthetic procedure for the
obtention of a 26-membered N-methyl-substituted macrocycle
([L], R = Me; Chart 1) containing two 1H-pyrazole units.13
Now, by improving the above synthetic procedure as depicted in
Scheme 1, the reaction of 1H-pyrazole-3,5-dicarbonyl dichloride
with the cyclic stannoxane 2,2-dibutyl-6-methyl-6-aza-1,3-dioxa-
2-stannacyclooctane has led to the isolation of the expected diaza
tetraester crown 1 (MH+ m/z 479) in 10% yield with a high
degree of purity. In addition, in the same reaction a new triaza
hexaester crown of larger size (39-membered) containing three
1H-pyrazole units 2 (MH+ m/z 718) was isolated in low yield
(1%) (Scheme 1).
Following a similar synthetic scheme, the reaction of the cyclic
stannoxane obtained from N-butyldiethanolamine and dibutyltin
oxide with 1H-pyrazole dichloride afforded two new 26- and 39-
membered macrocycles with structures 3 (MH+ m/z 563) and 4
(MH+ m/z 844) in similar yields (10% and 1%, respectively)
(Scheme 1). All these structures (1ꢀ4) were established on the
3 3 3
3 3 3
1.959 Å and 165.3°). The different dimers in the crystal structure
do not show hydrogen bonds between them or with the
acetonitrile molecules which are located in special positions
(see Figure 2).
The crystal structure of compound 30 is analogous to that of
compound 10, but in this case, the asymmetric unit shows two
slightly different macrocyclic units (units A and B, Figure 1,
right) and a water molecule. Each macrocycle presents 2-fold
symmetry with an elongated ellipsoidal disposition analogous to
that observed for compound 10. Again, the most interesting
aspect of this crystal structure is the observation of hydrogen-
bonded dimers on growing the asymmetric unit. Different from
8224
dx.doi.org/10.1021/jo2012835 |J. Org. Chem. 2011, 76, 8223–8231

The Journal of Organic Chemistry
ARTICLE
Scheme 1
The effect of temperature was evaluated by recording variable-
temperature 1H NMR spectra of a 0.01 M solution of compounds
1 and 3 in CDCl3. Activation parameters of dimerization (ΔHq =
+20.2 ( 0.8 kcal molꢀ1, ΔSq = ꢀ15.9 ( 2 cal molꢀ1 Kꢀ1
for compound 1 and ΔHq = +18.4 ( 0.8 kcal molꢀ1, ΔSq =
ꢀ12.8 ( 2 cal molꢀ1 Kꢀ1 for compound 3) were calculated from
Eyring plots14 (see Figure 2S in the Supporting Information).
Dimers 10 and 30 and monomers 1 and 3 show significant
differences in their 13C NMR spectra (see Table 1).
In 1 and 3, the pyrazole carbon atoms C-3 and C-5, the
carbonylic atoms C-6 and C-60, and the pairs of methylene
carbons C-7,70 and C-8,80 are magnetically equivalent due to the
prototropic equilibrium of the pyrazole ring.15 However, in 10
and 30 the NH NR (R = Me, Bu) hydrogen bonds break the
3 3 3
magnetic equivalence of the pyrazole environment, and conse-
quently, the carbon atoms closer to the pyrazole sp2 nitrogens
C-3, C-6, C-7, and C-8 appear at lower field than C-5, C-60, C-70,
and C-80 carbon atoms, which lie at the side of the macrocycle
where hydrogen bonding occurs.
To check the complexing ability of these dimer entities in the
presence of substrates that can form competitive hydrogen
bonds, we have performed NMR and MS studies of a system
containing 1 and N,N0-ethyleneurea (ETU). As observed by 1H
NMR, it is clear that addition of increasing amounts of ETU to a
16.41 mM solution of 1 in CDCl3 displaces the monomerꢀ
dimer equilibrium toward the monomer (Figure 3S in the
Supporting Information). However, starting from a more con-
centrated solution of compound 1 in CDCl3 (30 mM)—in
which the dimer species is predominant—the 1H and 13C NMR
spectra show that addition of 3 equiv of ETU is not enough to
completely displace the monomerꢀdimer equilibrium to the
monomer species. It was also noted that the NH(ETU) and
CO(ETU) signals experience high-field shifts (0.10 and 0.11
ppm, respectively), which suggest that ETU is simultaneously
breaking the NH NR hydrogen bonds belonging to the dimer
3 3 3
species and interacting with the monomer units of compound 1
(see Figure 4S and Table 1S in the Supporting Information). On
the other hand, the analysis by electrospray spectroscopy (ESI-
MS) (positive mode) of a 18.8 mM solution of 1 in chloroform
after addition of 3 equiv of ETU showed peaks at m/z 587.2
(20%) and 1065.3 (0.3%) consistent with the formation of 1:1
and 2:1 1ꢀETU complexes, respectively. Further evidence for
the formation of 1ꢀETU complexes was also obtained from
MALDI-TOF-MS. The spectra of compound 1 treated with 3
equiv of ETU using DCTB as the matrix in the absence and in the
presence of NaI as cationizing agent (Figures 6SA and 6SB and
Table 3S in the Supporting Information) In addition, the same
spectra show significant peaks at m/z 1107.2, 1105.2, 1079.2,
1063.2, and 1039.2 corresponding to the partial loss of side chain
fragments which suggest the formation of a 2:2 or 2:1 1ꢀETU
complex.
the case for 10, here the dimers are formed between units A and B,
preserving the same four-hydrogen-bond pattern which implies
NꢀH pyrazole groups as hydrogen donors and tertiary nitrogen
atoms at the middle of the chain as hydrogen bond acceptors
(N1A N3B, 2.866 Å; N1AꢀH1A N3B, 2.058 Å and
3 3 3
3 3 3
156.7°; N1B N3A, 2.933 Å; N1BꢀH1B N3A, 2.097 Å
3 3 3
3 3 3
and 164.3°). As pointed out for 10, also for 30 the different dimers
do not show any hydrogen-bonding interaction between them.
1H NMR spectra of 1 and 3 in CDCl3 at 298 K showed the
resonances of each compound split into two sets of peaks. In order
to understand and assign those spectra, we carried out a series of
variable-concentration experiments. The intensity of the peaks
showed concentration dependence, suggesting the existence of an
intermolecular dynamic equilibrium due to an autoassociation
process. An additional EXSY experiment showing exchange
correlation bands between monomer and dimer resonances
corroborated this result. Figure 3 illustrates the dependence on
concentration of the 1H NMR spectra of compounds 1 and 3.
For our compounds the dimerization process, 2 M = D, is in
the slow exchange condition on the NMR time-scale. Therefore,
separate bands are observed at characteristic frequencies for the
monomer and dimer species, labeled as M and D in Figure 3.
Using appropriate equations (see Figure 1S in the Supporting
Information), the dimerization constants for compounds 1 and
The above data together with those obtained by molecular
modeling studies suggest that new (ETU)CO HN(Pz) and
3 3 3
(ETU)NH OCꢀPz hydrogen bonds may be involved in the
3 3 3
formation of 1:1, 2:1, and 2:2 1ꢀETU complexes (see Figure 4
and Figure 7S in the Supporting Information).
’ CONCLUSIONS
By improving a synthetic method previously reported by some
of us,13 the cyclic stannoxanes obtained from RN-diethanola-
mine (R = Me, Bu) and dibutyltin oxide react with 1H-pyrazole-
3 were calculated to be 53.9 ( 0.9 and 97.0 ( 1.3 Mꢀ1
respectively.
,
8225
dx.doi.org/10.1021/jo2012835 |J. Org. Chem. 2011, 76, 8223–8231

The Journal of Organic Chemistry
ARTICLE
Figure 1. Hydrogen-bonded dimer formed in 10 (left) and 30 (right). In both dimers two molecules are linked by four hydrogen bonds involving NꢀH
groups of pyrazole as donors and tertiary amine as the hydrogen bond acceptors. Hydrogen atoms are not included.
3,5-dicarbonyl dichloride to give 26-membered diaza tetraester
crowns containing two 1H-pyrazole rings, 1[L1] (R = Me) and
3[L3] (R = Bu), in 10% yield. In the same reactions were also
obtained triaza hexaester crowns of larger size (39 membered)
containing three 1H-pyrazole rings, 2[L2] (R = Me) and 4[L4]
(R = Bn), in 1% yield.
show peaks at m/z 587.2 and 1065.3, consistent with the
formation of 1:1 and 2:1 1ꢀETU complexes; MALDI-TOF-
MS measured for the solid state of compound 1 treated with 3
equiv of ETU using DCTB as matrix also shows a peak at m/z
1065.2, which is in agreement with the 2:1 1ꢀETU complex
detected by ESI-MS. In addition, significant peaks corresponding
to the partial loss of side chain fragments which suggest the
formation of a 2:2 1ꢀETU complex were shown. Finally,
Crystallization of both 26-membered diaza tetraester crowns
1[L1] and 3[L3] from acetonitrile afforded crystals suitable for
X-ray diffraction studies which demonstrated that, after crystal-
lization, the 1H-pyrazole units self-assemble into the dimeric
species 10[L1]2 and 30[L3]2, respectively. In both cases, the
dimerization occurs through the formation of four hydrogen
bonds involving the two NH pyrazole groups and the two tertiary
molecular modeling studies suggest that new (ETU)CO
3 3 3
HN(Pz) and (ETU)NH OCꢀPz hydrogen bonds may be
3 3 3
involved in the formation of 1:1, 2:1, and 2:2 1ꢀETU complexes.
The studies here presented provide the first crystallographi-
cally solved examples of hydrogen-bonded guided dimerization
of pyrazole macrocycles. Work is now in progress to selectively
isolate and evaluate the stability constants of 2:1 or 2:2 1ꢀETU
complexes and other complexes obtained by interaction of
different urea derivatives with the monomerꢀdimer species
reported here.
1
amine groups of both crowns. A H NMR study of 1 and 3 in
CDCl3 solution at variable concentration as well as EXSY
experiments at 298 K showed the existence of an intermolecular
dynamic equilibrium due to an autoassociation process; the
dimerization constants for compounds 1 and 3 were calculated
to be 53.9 ( 0.9 Mꢀ1 and 97.0 ( 1.3 Mꢀ1, respectively.
Activation parameters of dimerization (ΔHq = +20.2 kcal molꢀ1
,
ΔSq = ꢀ15.9 cal molꢀ1 Kꢀ1 for compound 1 and ΔHq = +18.4
kcal molꢀ1, ΔSq = ꢀ12.8 cal molꢀ1 Kꢀ1 for compound 3) were
calculated from Eyring plots.14
’ EXPERIMENTAL SECTION
General Considerations. All reagents were of commercial quality
from freshly opened containers. Thionyl chloride was freshly distilled
prior to use. Pyrazole-3,5-dicarboxylic acid hydrate, dibutyltin oxide, N-
methyldiethanolamine, N-butyldiethanolamine, and reagent-quality sol-
vents were used without further purification. The organic reactions were
monitored by thin-layer chromatography (TLC) on precoated alumi-
num sheets of silica gel 60 PF254. Flash column chromatography was
performed in the indicated solvent system on silica gel (particle size
0.040ꢀ0.063 mm). Melting points were determined with a hot-stage
microscope. 1H and 13C NMR spectra were recorded with 300, 400, and
To check the complexing ability of these dimer entities in the
presence of substrates that can form competitive hydrogen
bonds, we performed NMR, MS, and molecular modeling studies
of a system containing 1 and N,N0-ethyleneurea (ETU). NMR
studies suggest that ETU simultaneously breaks the NH NR
3 3 3
hydrogen bonds belonging to the dimer species and interacts
with the monomer units of compound 1. The ESI-MS of a
solution of 1 in chloroform after the addition of 3 equiv of ETU
8226
dx.doi.org/10.1021/jo2012835 |J. Org. Chem. 2011, 76, 8223–8231

The Journal of Organic Chemistry
ARTICLE
Figure 2. View of a part of the crystal packing of 10, showing the dimeric units.
500 MHz spectrometers at room temperature, employing DMSO-d6 or
CDCl3 as solvent. The chemical shifts are reported in parts per million
(ppm) from tetramethylsilane but were measured against the solvent
Cyclization Reaction. The suspension obtained above was vigor-
ously stirred and heated to 60 °C under argon. Then, a solution of 1H-
pyrazole-3,5-dicarbonyl dichloride (2.21 g, 11.49 mmol) in dry di-
methoxyethane (90 mL) was added dropwise over a period of 2 h.
When the addition was complete, the reaction was allowed to proceed
for 24 h at the same temperature (60 °C) and the mixture was then
cooled to room temperature. The organic solvent was evaporated to
dryness to give a solid material which was exhaustively extracted in a
Soxhlet apparatus with boiling n-hexane until the tin salts were elimi-
nated. The solid residue was suspended in water and the aqueous
solution treated with 5% aqueous sodium hydroxide until pH 7ꢀ8 and
extracted with chloroform. The organic layer was evaporated to dryness,
affording a white solid, which was purified by flash column chromatog-
raphy, with CH2Cl2ꢀMeOH mixtures as eluents (100:1 to 10:1).
Methyl-Substituted Derivatives 1[L1] and 2[L2]. 6,19-Dimethyl-
3,9,16,22-tetraoxa-6,12,13,19,25,26-hexaazatricyclo[22.2.1.111,14]-
octacosa-1(26),11(28),13,24(27)-tetraene-2,10,15,23-tetraone (1[L1]).
The fraction with Rf = 0.48 (CH2Cl2ꢀMeOH, 10:1) afforded the pure
tetraester crown 1[L1] as a white solid (270 mg, 10%): mp 214ꢀ216 °C
(MeCN). 1H NMR (DMSO-d6, 300 MHz): δ 14.40 (s, 2H, NH), 6.91
(s, 2H, H-4), 4.33 (t, 8H, J = 4.7 Hz, 7-H), 2.74 (t, 8H, J = 4.7 Hz, H-8),
2.30 ppm (s, 6H, H-100). 13C NMR (DMSO-d6, 75 MHz): δ 160.4
(broad signal, CO-6,60), not observed (C-3,5), 110.4 (C-4), 61.9 (C-7),
55.1 (C-8), 42.6 ppm (C-100). FAB-MS (m/z (%)): 957 (5) [2MH+],
479 (100) [MH+]. Anal. Calcd for C20H26N6O8: C, 50.21; H, 5.48; N,
17.56. Found: C, 50.14; H, 5.40; N, 17.36.
1
signals. H and 13C assignments were performed on the basis of 2D-
homonuclear (gCOSY, EXSY) and heteronuclear NMR experiments
(gHSQC and gHMBC).
FAB mass spectra were measured using a m-nitrobenzyl alcohol
(NBA) matrix.
1H-Pyrazole-3,5-dicarbonyl Dichloride. A suspension of 1H-
pyrazole-3,5-dicarboxylic acid hydrate (2.00 g, 11.49 mmol) in freshly
distilled thionyl chloride (350 mL) was heated at 140 °C for 2 h. The hot
reaction mixture was filtered, and the resulting solution was evaporated
to dryness to give the title compound (2.16 g, 11.22 mmol) as a white
solid (mp 72ꢀ74 °C; lit.16 mp 72ꢀ74 °C) in 98% yield.
Preparation of 26- and 39-Membered Aza Ester Crowns
1ꢀ4. The synthesis was performed in two reaction steps using
dibutyltin oxide, N-methyl- or N-butyldiethanolamine and 1H-pyra-
zole-3,5-dicarbonyl dichloride as starting materials following the general
procedure indicated above.
6-Substituted 2,2-Dibutyl-6-aza-1,3-dioxa-2-stannacy-
cloctane. To a solution of the corresponding N-substituted diethano-
lamine (11.49 mmol) in dry toluene (200 mL) was slowly added solid
dibutyltin oxide (2.85 g, 11.49 mmol). The reaction mixture was refluxed
for 2 h, and the water formed in the cyclocondensation was removed by
azeotropic distillation. The resulting suspension was diluted into dry
toluene (260 mL) and collected to be used in the following step.
8227
dx.doi.org/10.1021/jo2012835 |J. Org. Chem. 2011, 76, 8223–8231

The Journal of Organic Chemistry
ARTICLE
Figure 3. 1H NMR spectra in CDCl3 at different concentrations. (A) Compound 1: (a) 1.944 ꢁ 10ꢀ2 M; (b) 0.748 ꢁ 10ꢀ2 M; (c) 0.335 ꢁ 10ꢀ2 M.
(B) Compound 3: (a) 1.002 ꢁ 10ꢀ2 M; (b) 0.385 ꢁ 10ꢀ2 M; (c) 0.209 ꢁ 10ꢀ2 M.
8228
dx.doi.org/10.1021/jo2012835 |J. Org. Chem. 2011, 76, 8223–8231

The Journal of Organic Chemistry
ARTICLE
Table 1. Comparison of Monomer Species 1[L1] and 3[L3]
13C NMR Chemical Shifts (δ (ppm)) with Those of Dimers
10[L1]2 and 30[L3]2 in CDCl3 Solution
compd CO-6,60 C-3,5 C-4 C-7,70 C-8,80 C-100 C-200 C-300 C-400
1[L1]
10[L1]2 162.7 143.0 110.5 62.9 55.9 44.4
160.0 136.0 62.3 54.2
159.8 139.5 111.6 60.1 51.3 50.8 25.0 20.7 14.0
30[L3]2 162.9 142.9 110.3 64.0 54.0 55.5 25.3 20.6 13.9
160.0 135.6 62.9 49.7
159.5 139.4 111.7 59.7 55.5 39.9
3[L3]
Figure 4. Calculated model for the 2:1 1ꢀETU complex.
6,19,32-Trimethyl-3,9,16,22,29,35-hexaoxa-6,12,13,19,25,26,32,-
38,39-nonaazatetracyclo[35.2.1.111,14.124,27]dotetraconta-1(39),1-
1(41),13,24(42),26,37(40)-hexaene-2,10,15,23,28,36-hexaone (2[L2]).
The fraction with Rf = 0.26 (CH2Cl2ꢀMeOH, 10:1) afforded a small
amount of the pure hexaester crown 2[L2] as a pure amorphous solid
(30 mg, 1%). 1H NMR (DMSO-d6, 400 MHz): δ 14.58 (broad signal,
3H, NH), 6.82 (s, 3H, H-4), 4.31 (t, 12H, J = 5.2 Hz, H-7), 2.77 (t, 12H,
J = 5.2 Hz, H-8), 2.30 ppm (s, 9H, H-100). 13C NMR (DMSO-d6, 100
MHz): δ 159.5 (CO-6,60), 138.6 (broad signal, C-3,5), 110.3 (C-4), 62.1
(C-7), 55.0 (C-8), 42.0 ppm (C-100). FAB-MS (m/z (%)): 718 (45)
[MH+], 479 (17) [(2M/3 + 1)+], 240 (22) [(M/3 + 1)+]. Anal. Calcd
for C30H39N9O12: C, 50.21; H, 5.48; N, 17.56. Found: C, 50.07; H, 5.36;
N, 17.33.
(m/z (%)): 844.4 (100) [MH+]. IR (KBr, cmꢀ1): 3435 (NH); 1729
(CO). Anal. Calcd for C39H57N9O12: C, 55.50; H, 6.81; N, 14.94.
Found: C, 55.32; H, 6.52; N, 14.78.
Kdim Determination. In order to determine dimerization con-
1
stants for compounds 1 and 3, H NMR dilution experiments were
performed with the following procedure:14 0.5 mL samples of each
compound in CDCl3, at a known concentration (0.0194 M for 1 and
0.0100 M for 3), were prepared. For each sample, aliquots of CDCl3
were added successively to the NMR tube, and the 1H NMR spectrum,
at 298 K, was recorded after each addition. At least 20 different
concentrations ranging from 0.004 to 0.019 M for 1 and from 0.002
to 0.010 M for 3 were used for the Kdim determination. Molar fractions
were determined by integration of different pairs of monomer and dimer
resonances to different concentrations. Kdim values were obtained from
the slope of a linear-regression line, plotting u/2(1 ꢀ u)2 against [H0]
(eq 5 in the Supporting Information). The effect of temperature was
Butyl-Substituted Derivatives 3[L3] and 4[L4]. 6,19-Dibutyl-3,9,-
16,22-tetraoxa-6,12,13,19,25,26-hexaazatricyclo[22.2.1.111,14]octa-
cosa-1(26),11(28),13,24(27)-tetraene-2,10,15,23-tetraone (3[L3]).
The fraction with Rf = 0.54 (CH2Cl2ꢀMeOH, 10:1) afforded the pure
tetraester crown 3[L3] as a white solid (310 mg, 10%): mp 189ꢀ190 °C
(MeCN). 1H NMR (DMSO-d6, 400 MHz): δ 14.46 (s, 2H, NH), 6.92
(s, 2H, H-4), 4.28 (t, 8H, J = 4.5 Hz, H-7), 2.78 (t, 8H, J = 4.5 Hz, H-8),
2.45 (t, 4H, J = 6.4 Hz, H-100), 1.35 (m, 4H, H-200), 1.26 (m, 4H, H-300),
0.80 ppm (t, 6H, J = 7.3 Hz, H-400). 13C NMR (DMSO-d6, 100 MHz): δ
160.6 (very broad signal, CO-6), 158.90 (very broad signal, CO-60),
143.0 (very broad signal, C-3), 134.6 (very broad signal, C-5), 110.5 (C-
4), 62.67 (C-7), 53.7 (C-100), 52.5 (C-8), 29.2 (C-200), 19.7 (C-300), 13.9
ppm (C-400). FAB-MS (m/z (%)): 1125.3 (1.3) [2MH+], 563.3 (100)
[MH+], 282 (23) [(M/2 + 1)+]. ESI-MS (m/z (%)): 1147 (18) [2M +
Na+], 563.3 (100) [MH+]. IR (KBr, cmꢀ1): 3436 (NH); 1732, 1719
(CO). Anal. Calcd for C26H38N6O8: C, 55.50; H, 6.81; N, 14.94. Found:
C, 55.49; H, 6.69; N, 14.90.
6,19,32-Tributyl-3,9,16,22,29,35-hexaoxa-6,12,13,19,25,26,32,38,39-
nonaazatetracyclo[35.2.1.111,14.124,27]dotetraconta-1(39),11(41),-
13,24(42),26,37(40)-hexaene-2,10,15,23,28,36-hexaone (4[L4]). The
fraction with Rf = 0.48 (CH2Cl2ꢀMeOH, 10:1) afforded a small amount
of the pure hexaester crown 4[L4] as a pure amorphous solid (25 mg,
1%). 1H NMR (DMSO-d6, 400 MHz): δ 14.43 (broad signal, 3H, NH),
6.90 (s, 3H, H-4), 4.27 (t, 12H, J = 4.6 Hz, H-7), 2.77 (t, 12H, J = 4.6 Hz,
H-8), 2.50 (t, 4H, J = 6.7 Hz, H-100), 1.32 (m, 6H, H-200), 1.23 (m, 6H,
H-300), 0.78 ppm (t, 9H, J = 7.1 Hz, H-400). 13C NMR (DMSO-d6. 100
MHz): δ 159.7 (CO-6,60), 139.0 (C-3,5), 110.4 (C-4), 62.9 (C-7), 53.7
(C-8), 52.2 (C-100), 29.1 (C-200), 19.6 (C-300), 13.7 ppm (C-400). ESI-MS
1
further evaluated for compounds 1 and 3, by recording the H NMR
spectra of a 0.01 M solution at 25, 30, 35, 40, and 45 °C.
Heteroassociation Studies of Macrocycle 1 with N,N0-
Ethyleneurea (ETU). By Mass Spectrometry. Experimental Section.
Massspectra recorded inCHCl3 solutionbyelectrospray ionization (ESI)
in the positive ion detection mode were acquired using a commercial
spectrometer with a QTOF hybrid analyzer. Those recorded by matrix
assisted laser desorption ionization (MALDI-TOF) were recorded in
the positive ion detection mode, using 2-[(2E)-3-(4-tert-butylphenyl)-
2-methylprop-2-enylidene]malononitrile (DCTB)17 as the matrix and
sodium iodide as a cationizing agent.
MALDI Sample Preparation. DCTB matrix solution was made to a
concentration of 10 mg mLꢀ1 in dichloromethane (DCM), and the NaI
solution was made to a concentration of 2 mg mLꢀ1 in acetone. The
sample solution was made as follows: to a 30 mM solution of compound
1 in CHCl3 was added a 90 mM solution of ETU in CHCl3. In a plastic
snap-top lid sample vial, 5 μL of the sample solution was vortex-mixed
with 20 μL of DCTB and with 0.5 μL of NaI solution. A 0.5 μL portion of
the final mixture was spotted onto the sample plate and allowed to dry,
leaving an opaque crystal layer.
By Molecular Modeling Calculations. Experimental Section. Mo-
lecular modeling studies were carried out using the AMBER18 method
implemented in the Hyperchem 7.5 package,19 modified by the inclusion
of appropriate parameters.20 In each case, all possible complexes were
built and optimized, taking into account the structures showing
8229
dx.doi.org/10.1021/jo2012835 |J. Org. Chem. 2011, 76, 8223–8231

The Journal of Organic Chemistry
ARTICLE
stabilizing interactions, such as additional hydrogen bonds, by use of the
“simulated annealing” procedure carrying out molecular dynamics
calculations at 400 K.
species 10[L1]2 in the absence and in the presence of 3 equiv of
1
ETU, and a comparison with H and 13C NMR data of the
predominant species 1[L1] (Table 1S), mass spectroscopy
studies giving ESI-MS of a 1ꢀETU mixture in molar ratio 1:3
([1] = 18.8 mM) measured in CHCl3 solution (Figure 5S), most
significant peaks of ESI-MS consistent with the formation of 1:1
or 2:1 1ꢀETU complexes (Table 2S), MALDI-TOF-MS data of
a 30 mM sample of compound 1 in Cl3CD after the addition of 3
equiv of ETU, spectra measured in the solid state by using DCTB
as matrix in the absence (A) and in the presence of NaI (B) as
cationizing agents (Figure 6S), and most significant peaks of
MALDI-TOF-MS arising with partial lost of side chain fragments
consistent with the formation of 2:2 or 2:1 1ꢀETU complexes
(Table 3S), molecular modeling calculations detailing complexes
with ETU (A, 1:1 1ꢀET; B, 2:1 1ꢀETU; C 2:2 1ꢀETU),
(Figure 7S), and CIF files giving crystallographic data for 10 and
30. This material is available free of charge via the Internet at
http://pubs.acs.org.
All calculations were carried out in vacuo with constant dielectric
value. In the absence of explicit solvent molecules, a constant dielectric
factor qualitatively simulates the presence of nonpolar solvents, as it
takes into account the fact that the intermolecular electrostatic interac-
tions should not die off appreciably with distance as in the gas phase. The
relative binding energies of complexes under study were calculated by
subtracting the energies of the macrocycle (as monomer or dimer) and
N,N0-ethyleneurea (ETU) units from the minimum complex energy
Ec ¼ Ecomplex ꢀ ðEmacrocycle þ EETU
Þ
for the 1:1 and 2:1 complexes and
Ec ¼ Ecomplex ꢀ ðEmacrocycle þ 2EETU
Þ
for the 2:2 complex.
Starting structures for macrocycle monomer and dimer were built by
using Hyperchem capabilities. Its geometry was minimized to a max-
imum energy gradient of 0.1 kcal Åꢀ1 molꢀ1 with the AMBER force
field, using the PolakꢀRibiere (conjugate gradient) minimizer, and the
simulated annealing procedure was used to cover all conformational
space. This geometry, in accordance with the X-ray structure, was always
used in calculations of host/guest complexes. Different possible orienta-
tions of ETU units with respect to the macrocycle or its dimer were built
by docking the structure of the ETU in the vicinity of the macrocycle and
then minimizing the energy of the complex with no restraints.
X-ray Crystallographic Analysis of 1 and 3. Single crystals of 1
and 3 suitable for X-ray analysis were obtained by slow evaporation of
CH3CN solutions of the compounds. The data collection strategy was
calculated with the program COLLECT.21 Data reduction and cell
refinement were performed with the programs HKL DENZO and
SCALEPACK.22 Data collection was performed at 293 K on a Nonius
Kappa-CCD single-crystal diffractometer, using Mo Kα radiation (λ =
0.7173 Å). The crystal structure was solved by direct methods, using the
program SIR-97.23 Anisotropic least-squares refinement was carried out
with SHELXL-97.24
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: iqmnt38@iqm.csic.es (P.N.); enrique.garcia-es@uv.es
(E.G.-E.).
’ ACKNOWLEDGMENT
Financial support from the Spanish Ministry of Science and
Innovation (CTQ2009-14288-CO4-01 and CONSOLIDER IN-
GENIO 2010 CSD2010-00065 Projects and Fondos FEDER) is
gratefully acknowledged.
’ REFERENCES
(1) Lehn, J.-M. Supramolecular Chemistry-Concepts and Perspectives;
VCH: Weinheim, Germany, 1995; pp 124ꢀ138. Fredericks, J. R.;
Hamilton, A. D. In Comprehensive Supramolecular Chemistry; Atwood,
J. L., Davies, J. E. D., MacNicol, D. D., V€ogtle, F., Eds.; Elsevier: New
York, 1996; pp 565ꢀ594. Zimmerman, S. C.; Corbin, P. S. Struct.
Bonding (Berlin) 2000, 94, 63–94. Krische, M. J.; Lehn, J. M. Struct.
Bonding (Berlin) 2000, 94, 3–30.
(2) Jeffrey, G. A.; Saenger, W. Hydrogen Bonding in Biological
Structures; Springer-Verlag: Berlín, 1991.
(3) Lehn, J.-M. Chem. Rev. 2007, 36, 151–160. Lehn, J.-M. Proc. Natl.
Acad. Sci. U.S.A. 2002, 99, 4763–4768.
(4) Prins, L. J.; Reinhoudt, D. N.; Timmerman, P. Angew. Chem., Int.
Ed. 2001, 40, 2382–2426.
(5) Sessler, J. L.; Lawrence, C. M.; Jayawickramarajah, J. Chem. Soc.
Rev. 2007, 314–325. Sivakova, S.; Rowan, S. T. Chem. Soc. Rev. 2005,
34, 9–21. Davis, J. T. Angew. Chem., Int. Ed. 2004, 43, 668–698.
(6) Bertolasi, V.; Gilli, P.; Ferretti, V.; Gilli, G.; Fernandez-Casta~no,
C. Acta Crystallogr. 1999, B55, 985–993.
(7) Klein, O.; Aguilar-Parrilla, F.; Lopez, J. M.; Jagerovic, N.; Elguero,
J.; Limbach, H.-H. J. Am. Chem. Soc. 2004, 126, 11718–11732 and
references therein.
(8) Rzepecki, P.; Hochdrffer, K.; Scahller, T.; Zienau, J.; Harms, K.;
Ochsenfeld, C.; Xie, X.; Schrader, T. J. Am. Chem. Soc. 2008, 130,
586–591.
(9) Wang, W.; Weisz, K. Chem. Eur. J. 2007, 13, 854–861.
(10) Rzepecki, P.; Schrader, T. J. Am. Chem. Soc. 2005, 127,
3016–3025.
Crystal Data for 10: C20H26N6O8 C2H3N, Mr = 519.52, colorless,
3
0.20 ꢁ 0.15 ꢁ 0.10 mm3, tetragonal, space group I41/a, a = b =
13.1070(2) Å, c = 30.35107 Å, V = 5214.10(16) Å3, Z = 8, R = 0.0979 and
Rw = 0.2266 for all observed reflections (2784) and 168 parameters.
Crystal Data for 30: C26H37N6O8, Mr = 569.62, colorless, 0.20 ꢁ 0.12
ꢁ 0.10 mm3, monoclinic, space group C2/c, a = 15.8510(3) Å, b =
31.3650(10) Å, c = 13.622084) Å, β = 119.4050(10)°, V = 5899.9(3) Å3,
Z = 8, R = 0.0972, Rw = 0.2075 for all observed reflections (6471) and
366 parameters.
’ ASSOCIATED CONTENT
Supporting Information. 1H and 13C spectra of the new
S
b
compounds 2ꢀ4, NMR solution studies of compounds 1 and 3,
giving the thermodynamics for the dimerization constants of 1
and 3 in CDCl3, experimental plots for obtaining the dimeriza-
1
tion constants by H NMR (Figure 1S), Eyring plots for
compounds 1 and 3 (Figure 2S), hetero-association of Com-
pound 1 with ETU by NMR spectroscopy. 1H NMR spectra of
a 16.41 mM solution of 1 in CDCl3 with different concentrations
of ETU (from 0.24 to 9.56 mM) (Figure 3S), a comparison of the
1H NMR spectra of the predominant dimer species 10[L1]2
(30 mM solution of 1 in CDCl3) in the absence and in the
presence of ETU (90 mM in CDCl3) with that of the predominant
monomer species 1[L1] (3.5 mM of 1 in CDCl3) (Figure 4S),
1H and 13C NMR (δ (ppm)) data of the predominant dimer
(11) Reviriego, F.; Rodríguez-Franco, M. I.; Navarro, P.; García-
Espa~na, E.; Liu-Gonzalez, M.; Verdejo, B.; Domꢀenech, A. J. Am. Chem. Soc.
2006, 128, 16458–16459. Reviriego, F.; Sanz, A.; Navarro, P.; Latorre, J.;
8230
dx.doi.org/10.1021/jo2012835 |J. Org. Chem. 2011, 76, 8223–8231

The Journal of Organic Chemistry
ARTICLE
García-Espa~na, E.; Liu-Gonzalez, M. Org. Biomol. Chem. 2009, 7, 3212–
3214.
(12) Ikeda, C.; Nugahara, N.; Motegi, E.; Yoshioka, N.; Inoue, H.
Chem. Commun. 1999, 1759–1760.
(13) Sanz, A. M.; Navarro, P.; Goꢀmez-Contreras, F.; Pardo, M.;
Pꢁepe, G.; Samat, A. Can. J. Chem. 1998, 76, 1174–1179.
(14) Sandstr€om, J. Dynamic NMR Spectroscopy; Academic Press:
New York, 1982.
(15) Arꢀan, V. J.; Kumar, M.; Molina, J.; Lamarque, L.; Navarro, P.;
García-Espa~na, E.; Ramirez, J. A.; Luis, S. V.; Escuder, B. J. Org. Chem.
1999, 64, 6135–6146.
(16) Campayo, L.; Bueno, J. M.; Navarro, P.; Ochoa, C.; Jimenez-
Barbero, J.; Pꢁepe, G.; Samat, A. J. Org. Chem. 1997, 62, 2684–2693.
(17) Wyatt, M. F. EPSRC National Mass Spectrometry Service
Centre (NMSSC), Swansea University, SA2 8PP, U.K., htpp://www,
swan.ac.uk/nmssc/.
(18) Cornell, W. D.; Cieplak, P.; Bayly, C. I.; Gould, I. R.; Merz,
K. M., Jr.; Ferguson, D. M.; Spelmeyer, D. C.; Fox, T.; Caldwell, J. W.;
Kollman, P. A. J. Am. Chem. Soc. 1995, 117, 5179–5197.
(19) Hyperchem 7.5, Hypercube Inc.
(20) Miranda, C.; Escartí, F.; Lamarque, L.; Yunta, M. J. R.; Navarro,
P.; García-Espa~na, E.; Jimeno, M. L. J. Am. Chem. Soc. 2004,
126, 823–833. Campayo, L.; Pardo, M.; Cotillas, A.; Jauregui, O.; Yunta,
M. J. R.; Cano, C.; Gꢀomez-Contreras, F.; Navarro, P.; Sanz, A. M.
Tetrahedron 2004, 60, 979–986. Reviriego, F.; Navarro, P.; García-
Espa~na, E.; Albelda, M. T.; Frías, J. C.; Domꢁenech, A.; Yunta, M. J. R.;
Costa, R.; Ortí, E. Org. Lett. 2008, 10, 5099–5102.
(21) COLLECT; Nonius BV, 1997ꢀ2000.
(22) Otwinowski, Z.; Minor, W. Methods Enzymol. 1997, 276, 307–326.
(23) Altomare, A.; Burla, M. C.; Camalli, M.; Cascarano, G. L.;
Giacovazzo, C.; Guagliardi, A.; Moliterni, A.G. G.; Polidori, G.; Spagna,
R. J. Appl. Crystallogr. 1999, 32, 115–119.
(24) Sheldrick, G. M. SHELX97: Programs for Crystal Structure
Analysis (Release 97-2), University of G€ottingen, G€ottingen, Germany,
1997.
8231
dx.doi.org/10.1021/jo2012835 |J. Org. Chem. 2011, 76, 8223–8231