Synthetic hosts for molecular recognition of ureas

Article abstract of DOI:10.1021/jo201191x

Four hosts (7-10) containing 2,6-bisamidopyridine- and 2,5-bisamidopyrrole- bearing pyridyl or 1,8-naphthyridyl groups have been prepared and their structures studied by a combination of multinuclear NMR spectroscopy and X-ray crystallography. Their behav

Full text of DOI:10.1021/jo201191x

ARTICLE
pubs.acs.org/joc
Synthetic Hosts for Molecular Recognition of Ureas
†
†
†
‡
‡
ꢀ
ꢀ
Dolores Santa María, M. Angeles Farrꢀan, M. Angeles García, Elena Pinilla, M. Rosario Torres,
Josꢀe Elguero,§ and Rosa M. Claramunt*,†
†Departamento de Química Orgꢀanica y Bio-Orgꢀanica, Facultad de Ciencias, UNED, Senda del Rey 9, E-28040 Madrid, Spain
‡Departamento de Quimica Inorganica I, CAI de Difracciꢀon de Rayos X, Facultad de Ciencias Quimicas, Universidad Complutense
de Madrid, E-28040 Madrid, Spain
§Instituto de Química Mꢀedica (CSIC), Centro de Química Orgꢀanica 'Manuel Lora Tamayo', Juan de la Cierva 3, E-28006 Madrid, Spain
S Supporting Information
b
ABSTRACT: Four hosts (7ꢀ10) containing 2,6-bisamidopyr-
idine- and 2,5-bisamidopyrrole-bearing pyridyl or 1,8-naphthyr-
idyl groups have been prepared and their structures studied by a
combination of multinuclear NMR spectroscopy and X-ray
crystallography. Their behavior in molecular recognition of
urea derivatives, including (+)-biotin methyl ester, has been
approached by molecular modeling (Monte Carlo conforma-
tional search, AMBER force field). The minimum energy values
for the complexes are correlated with the experimental binding energies determined by means of 1H NMR titrations.
’ INTRODUCTION
trimerization of the “amideꢀpyridine” and “amideꢀnaphthyridine”
motifs.7
In all the supramolecular situations described as hostꢀguest
chemistry, collections of molecules are glued together by weak
forces, predominantly hydrogen bonds (HB).1,2 The comple-
mentariness is so relevant that the definition of the host and the
guest is somewhat arbitrary (usually the hosts are larger than the
guests). Ureas are compounds rich in HBs, both donor and
acceptor,3,4 and so there are many hostꢀguest compounds held
together by HBs belonging, in part, to ureas. From this very large
number of complexes involving ureas, those with urea in the host
(ureas as receptors) are more abundant than those where the
urea is the guest (molecular recognition of ureas).
Our interest lies in this last topic, and between 2004 and 2010
we have published six papers dealing with the molecular recogni-
tion of biologically relevant ureas, including drugs.5ꢀ10 Host
design for ureas and related binding compounds usually includes
amide NꢀH as hydrogen bond donors (HBD, in red) as well as
nitrogen atoms of basic heterocycles such as pyridines and
naphthyridines as hydrogen bond acceptors (HBA, in blue).
The first three hosts used (Chart 1)5,6 were Thummel’s host 1,
based on the acidity of indolic NꢀH in lieu of amides NꢀH;11
and hosts 2 and 3 were previously reported by Goswami et al.12,13
Many other hosts for ureas recognition were described in chrono-
logical order by Goswami;14,15 by Gozin;16 by Gale;17 by Boyer;18
by Ghosh and Sen;19,20 Goswami;21 by Yatsimirsky;22 by
Roesky;23 and by Ghosh.24 Some hosts were prepared by Ghosh
specifically for biotin salt,25 while related pyridine-based oligoa-
mides were prepared by Gunnlaugsson as DNA-targeting supra-
molecular binders.26
In the present work we report the synthesis and molecular
recognition properties of four hosts: N,N0-bis(6-methylpyridin-
2-yl)-2,6-pyridinedicarboxamide (7),27 N,N0-bis(7-methyl-
1,8-naphthyridin-2-yl)-2,6-pyridinedicarboxamide (8), N,
N0-bis(6-methylpyridin-2-yl)-3,4-diphenyl-1H-pyrrole-2,5-dicarbox-
amide (9), and N,N0-bis(7-methyl-1,8-naphthyridin-2-yl)-3,4-di-
phenyl-1H-pyrrole-2,5-dicarboxamide (10) (Chart 3). As we will
explain later on, the host properties of compound 7 cannot be
measured.
These hosts are structurally related to previously reported
ones. For instance, 7 is the dechlorinated analogue of 4 and the
7/8 pair is just Goswami’s 2/3 pair where the central benzene has
been replaced by a pyridine ring. Some structures loosely related
to 7 and 8 have been reported (11,22 12,26 and 13,18 Chart 4),
whereas pyrrolic hosts 9 and 10 have been inspired by the
pioneering work of Gale et al. (14,28 15,29 and 16,30 Chart 5).
Our goal has two avenues, the first one is the study of the
binding changes when the central core shifts from pyridine (hosts
7 and 8) to pyrrole (hosts 9 and 10). The second one tries to
improve the binding constants by replacing the picoline arms
(hosts 7 and 9) by naphthyridines (hosts 8 and 10). The two
accepting nitrogens of each naphthyridine will give rise to extra
HBs and consequently stabilize the formed complexes.
’ RESULTS AND DISCUSSION
The binding properties of receptors 7ꢀ10 (Chart 3) have
been studied with the four guests (17ꢀ20) depicted in Chart 6.
Bearing this in mind, hosts 4ꢀ6 were prepared (Chart 2).
The first one 4 contains, in addition to Goswami’s host 2, a
pyridine nitrogen6 whereas hosts 5 and 6 explore the advantages of
Received: June 8, 2011
Published: July 08, 2011
r
2011 American Chemical Society
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Chart 1. Hosts 1ꢀ3
Chart 2. Hosts 4ꢀ6
Chart 3. Hosts 7ꢀ10
from Monte Carlo conformational searches. The interaction
energy for the complex is obtained using eq 1.
Einteraction ¼ Emin ðcomplexÞ ꢀ Emin ðhostÞ ꢀ Emin ðguestÞ
ð1Þ
Minimum energy values for complexes are gathered in Table 1,
and the minimum energy conformations for hosts 7ꢀ10 are
shown in Figure 1. In all cases the formation of two intramole-
cular hydrogen bonds is responsible for the most stable con-
formation. Hosts 7 and 8 show a synꢀsyn conformation that
allows the preorganization of the two amide hydrogen atoms
inward for optimal guest binding. However, in hosts 9 and 10 the
formation of two intramolecular hydrogen bonds between the
pyrrolic NH and amide CO groups determine the preferred
antiꢀanti conformation.
The interaction modes (Figure 2) for the complexes with (+)-
biotin methyl ester (17), 2-imidazolidone (18), and N,N0-
trimethylenurea (19) are much alike and in accordance with
the usual binding mode for this kind of compounds through the
urea moiety. Attention must be paid to the case of barbital (20) as
it uses only the carbonyl group with all hosts (see Supporting
Information). The main reason for that particular behavior is that
20, a voluminous guest due to the ethyl groups in position 5,
sterically hinders the urea binding into the hosts cleft (see 8:20
and 10:20 in Figure 2); it was already reported by us in other
complexes.6 In all cases the hosts are in the synꢀsyn conforma-
tion, and selected parameters for the intermolecular hydrogen
bonds involved in hostꢀguest binding are given in the Support-
ing Information.
As shown in Charts 1 and 2 above, only Thummel used the HB
acidity of the indolic NH instead of the hydrogen bond donor
capability of amides.11 In order to take advantage of both effects,
hosts 9 and 10 were designed. They combine both amide and
pyrrole NH hydrogen bond donor motifs. Thus, the four hosts of
Chart 3 should allow determination, by comparison with hosts 2
and 3, of the best option: to replace a benzene with a pyridine,
adding one more HBA site, or to replace a benzene by a pyrrole,
adding one more HBD site.
Molecular Modeling. All complexes have been modeled using
Monte Carlo conformational search with the AMBER force field.
This procedure affords the most probable conformation of the
complex and allows us to get useful information about the binding
mode of the guest. The structure of the complexes is created from
minimum energy conformations of hosts and guests, obtained
Hosts 8 and 10, bearing naphthyridine units, give rise to more
stable complexes than those formed by hosts 7 and 9, containing
pyridine moieties, due to the formation of bifurcated hydrogen
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Chart 4. Hosts 11ꢀ13
Chart 5. Hosts 14ꢀ16
Chart 6. The Four Guests Studied in the Present Work
Table 1. Interaction Energy Values: Emin (kJ molꢀ1) for the
Complexes of Hosts 7ꢀ10 with the Studied Guests
guest
7
8
9
10
biotin methyl ester (17)
2-imidazolidone (18)
N,N’-trimethyleneurea (19)
barbital (20)
68.0
51.7
57.7
74.8
70.5
57.5
64.8
43.7
46.2
59.1
72.0
52.1
54.8
90.9
59.5
108.5
signals and the coupling constants magnitude, and gs-COSY, gs-
HMQC, and gs-HMBC bidimensional experiments.
bonds between the NH urea groups and the N10/N80 naphthyr-
idine nitrogens (see 8:18 and 10:17 in Figure 2).
The deshielded proton signals at 10.99 and 11.40 ppm of hosts
7 and 8 containing the 2,6-bisamidopyridine central core corre-
spond to the NH amide protons involved in an intramolecular
hydrogen bond with the pyridine nitrogen atom, showing a
preference for the synꢀsyn conformation. However, in hosts 9
and 10 the deshielded NH pyrrole signals at 10.44 and 10.54 ppm,
and the upfield amide NH signals at 7.97 and 8.37 ppm, indicate
the preferred antiꢀanti conformation, with formation of two
intramolecular hydrogen bonds between the NH pyrrole and the
CO amide groups. These results are in agreement with the
predicted minimum energy conformations (Figure 1) discussed
in Molecular Modeling.
On the other hand, in the complexes formed by hosts 9 and 10
the additional hydrogen bond arising from the pyrrolic NH
compensates energetically for the necessary conformational change
in the receptor (from antiꢀanti to synꢀsyn) to bind guests.
Syntheses and Structural Characterization of Hosts 7ꢀ10:
NMR and X-ray Crystallography. Hosts 7 and 8 were synthe-
sized according to Scheme 1, starting from 2,6-pyridinedicarbo-
nyl dichloride that was reacted with 2 equiv of either 2-amino-6-
methylpyridine or 2-amino-7-methyl-1,8-naphthyridine and 4
equiv of triethylamine at room temperature.
Our attempts to prepare hosts 9 and 10 using 3,4-diphenyl-
1H-pyrrole-2,5-dicarbonyl dichloride in similar conditions failed,
due to the inherent instability of the pyrrole dichloride and to the
formation by self-condensation of dimeric species.31 However
when the dichloride was slowly added at 0 °C over an excess of
the corresponding amine (8 equiv), the pure hosts could be
obtained in moderate yields.
A complete characterization of all hosts was carried out by
NMR spectroscopy in CDCl3 as solvent (see Supporting In-
formation). For symmetry reasons, besides the isochronous
atoms in the central bisamido ring: pyridine (C2/C6 and C3/
C5) and pyrrole (C2/C5 and C3/C4), these molecules show
equivalent methylpyridinyl, methylnaphthyridinyl, and phenyl
groups. Full assignment of protons and carbons was achieved by
careful analysis of the chemical shift values, multiplicity of the
Finally, the 15N NMR chemical shifts were assigned using gs-
HMQC and gs-HMBC (1Hꢀ N) correlation experiments that
15
1
also allowed us to measure the JNH coupling constant of the
amide nitrogen (see Experimental Section). The pyridine N1 in 7
and 8 and the naphthyridine N10 in 8 and 10 could not be
detected under the aforementioned conditions, so we proceeded
1
to record the 1D spectra with an inverse gated H decoupling
technique. Due to the insolubility of compound 8, either in
CDCl3 or inDMSO-d6, no signalwas observed in this experiment.
Crystals of sufficient quality for X-ray diffraction were ob-
tained only for two hosts: 8 (C25H19N7O2) from chloroform,
and 10 (C36H27N7O2 SOC2H6 1/2H2O) from dimethyl sulf-
3
3
oxide (all trials to crystallize 10 in chloroform or other solvents
were unsuccessful), and both compounds crystallize in the C2/c
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Figure 1. The minimum energy conformations of hosts: synꢀsyn in 7 and 8, antiꢀanti in 9 and 10.
Scheme 1. Synthesis of hosts 7ꢀ10
sulfoxide molecule bonded by hydrogen bonds were identified
in the structural determination; this compound crystallizes with a
half water molecule, and the geometry (antiꢀsyn conformation)
appears to be different from that found in solution and predicted
in the Monte Carlo conformational search.
Molecular modeling of the complex formed by 10 with
dimethyl sulfoxide resulted in a minimum energy conformation
of ꢀ29.7 kJ molꢀ1 in which the solvent (DMSO) locates into the
cleft of the host in a synꢀsyn conformation as in the other
complexes. However the antiꢀsyn conformation found in the
solid state is only 4.4 kJ molꢀ1 higher in energy, and the inclusion
of a half molecule of water and packing forces compensate for it,
accounting for the experimental geometry (See Figure 3 for both
conformations).
In both compounds the molecules are held together by normal
van der Waals forces expanding into columns along the crystal-
lographic a axis in 8 (Figure 4) and c axis in 10 (Figure 5).
Selected bond distances and angles as well as hydrogen bonds
(HBs) are given in the Supporting Information.
Figure 2. The minimum energy conformations of some complexes
where all hosts are in the synꢀsyn conformation.
monoclinic space group (see Experimental Section and Support-
ing Information for the ORTEP views).
Compound 8 contains a 2-fold axis, and there is only a half
molecule in the asymmetric unit. The molecule, presenting a
synꢀsyn conformation, is not planar, with a dihedral angle of
18.8(1)° between the pyridine unit and the best least-squares
Binding Constant Quantification. Experimental versus
Theoretical Data. 1H NMR titrations in CDCl3 at 300 K have
been performed to quantify the interactions between hosts 7ꢀ10
plane N2 C9 (naphthyridine moieties). For 10, one crystal-
3 3 3
lographic nonplanar independent molecule and a dimethyl
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Figure 3. The minimum energy conformations of complex 10:DMSO.
Figure 4. Part of the crystal structure of 8 showing the packing along the
crystallographic b axis.
and biotin methyl ester (17), 2-imidazolidone (18), N,N0-
trimethylenurea (19), and barbital (20) as guests. The hostꢀ
guest binding constants (Kb) have been measured using the Chemical
Induced Shifts (CIS) on the NH signal of the amide groups for hosts
7 and 8, and on two independent signals, NH proton in the pyrrole
nucleus and NH signal of the amide groups for hosts 9ꢀ10.6
As we have previously proved, a careful determination of the
best concentrations of host and guest must be carried out to
measure the binding constants with the lowest error.5 All the
titrations have been performed in such a way that the saturation
fractions of both host and guest are between 20% and 80%,
avoiding situations where the chemical induced shifts, of the
monitored protons, are zero. Under these conditions, a soft
titration curve, with no linear behavior, is obtained and the data
are nonlinearly fitted by the use of the appropriate software,
obtaining curves like the one shown in Figure 6.
At this point a special comment needs to be made concerning
the measurement of binding constants in the case of host 7. All
our assays afforded erratic values that are not useful. The fact that
this host presents a particular affinity for water27 gave rise, even
applying extreme dryness manipulation conditions, to a short-
range of CIS unable to provide reliable values of Kb, neither by
direct titrations nor by competitive ones. Therefore, we will
continue our discussion using the already measured6 binding
constant of 4-chloro-N,N0-bis(6-methylpyridin-2-yl)-2,6-pyridi-
nedicarboxamide (4), the chlorinated analogue of 7.
Figure 5. Part of the crystal structure of 10 showing the packing in the
unit cell.
The experimental binding constants Kb (Mꢀ1) with the four
guests 17ꢀ20 measured for complexes of host 8 plus the already
measured binding constants of 4 are gathered in Table 2, and
those with hosts 9 and 10 in Table 3.
In our previous papers we found a quite good correlation
between experimental binding constants and predicted interac-
tion energies, and because of that we are confident that this is a
correct approximation to the study of these systems.5ꢀ7
If data of Tables 1, 2, and 3 are compared, the correlation
matrix shows that there are no good linear relationships. In
general, the compound that behaves differently is barbital (20)
which is the most structurally distinct. The interaction energies of
guests 18 and 19 are related [Emin(18) = (0.92 ( 0.21)Emin(19),
n = 4, R2 = 0.90] as are the energy changes but much worse
[ΔG(18) = (0.70 ( 0.33)ΔG(19), n = 4, R2 = 0.69]. Both series
of points are represented in Figure 7.
If quantitatively the results are not as good as expected,
qualitatively and in a simplified way, both Emin and ΔG indicates
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that the best host for biotin methyl ester is 10 (naphthyridine-
pyrrole) followed by 8 (naphthyridine-pyridine). For the three
other guests while Emin accounts for 8 followed by 10, ΔG
indicates the contrary. In conclusion, in the studied hosts the
binding properties of those bearing naphthyridine are better than
those containing pyridine, but pyrrole and pyridine central cores
are comparable.
The hosts we describe here are difficult to compare with the
previous ones because the data for the binding constants were in
some cases determined in different conditions (host 3 labeled * in
Figure 8).5,6 From the present work it results that host 10
(pyrrole/naphthyridine) is the best we have found, followed by
8 (pyridine/naphthyridine) or 4 (pyridine/pyridine).
’ EXPERIMENTAL SECTION
General Methods. Melting points for compounds 7ꢀ10 were
determined by DSC. Thermograms (sample size 0.003ꢀ0.0010 g) were
recorded at the scanning rate of 5.0 °C minꢀ1
.
Materials. The four guests are commercially available: biotin methyl
ester (methylbiotin, 17) (>99%, dried under vacuum), 2-imidazolidone
(18) (96%, recrystallized from ethyl acetate), N,N0- trimethyleneurea
(19) (>98%, recrystallized from ethyl acetate), and barbital (20)
(>99%). The starting reagents were obtained from commercial suppliers
and used as received without further purification. Solvents were purified
and dried with use of standard procedures.
Synthesis of N,N0-Bis(6-methylpyridin-2-yl)-2,6-pyridine-
dicarboxamide (7). A mixture of 2,6-pyridinedicarboxylic acid
(1 g, 5.98 mmol) and oxalyl chloride (15 mL) was heated at 40 °C until
a clear solution was obtained. Aftercooling, the excess of oxalyl chloride was
eliminated under reduced pressure, yielding 2,6-pyridinedicarbonyl
dichloride as a brown solid, which was recrystallized from hexane. Then,
the dichloride (1.55 g, 6.56 mmol) in 20 mL of dry CHCl3 was added to a
solution of 2-amino-6-methylpyridine (1.63 g, 15.09 mmol) and triethy-
lamine (3.05 g, 30.176 mmol) in 25 mL of dry CHCl3. The reaction
mixture was stirred for 4 h at room temperature, after which the solvent
was removed under reduced pressure. The resulting solid was recrystal-
lized from methanol to give pure 7 (1.48 g, 65% yield): mp 234.2 °C (lit.27
234ꢀ235 °C); 1H NMR (CDCl3) δ (ppm) 10.99 (s, 2 H, CONH), 8.51
(d, 2 H, J = 7.7, H-3,5), 8.32 (d, 2 H, J = 8.2 Hz, H-30), 8.14 (t,1 H, J = 7.7,
H-4), 7.69 (t, 2 H, J = 7.8 Hz, H-40), 6.99 (d, 2 H, J = 7.5, H-50), 2.57 (s,
6H, CH3); 13C NMR (CDCl3) δ (ppm) 161.7 (CO), 156.9 (C60), 150.4
(C20), 148.2 (C2), 139.4(C4), 138.9 (C40), 125,7(C3/C5), 119.6 (C50),
111.3(C30), 24.0 (CH3); 15N NMR (CDCl3) δ (ppm) ꢀ90.2 (N1),
ꢀ103.7 (N10), ꢀ248.3 (1JNH = 90 Hz, HNCO).
There are two possible strategies when preparing hosts for
ureas: (i) either a flexible universal host that recognizes a family
of related ureas but with poor selectivity for any of them, or (ii) a
preordained host specific for a given urea derivative. Future
improvements are expected in both directions.
Synthesis of 2-Amino-7-methyl-1,8-naphthyridine. 2,6-
Diaminopyridine (4.20 g, 38.5 mmol) was dissolved in 31 mL of
H3PO4 and heated at 90 °C under argon atmosphere. Then, 5.67 mL
(90%, 38.5 mmol) of 3-oxobutanal dimethyl acetal from a pressure-
Figure 6. Titration curve for the complex 10:17.
Table 2. Experimental Binding Constants Kb (Mꢀ1) and Free
Energy Changes ΔG (kJ molꢀ1) at 300 K for the Complexes of
Hosts 4 and 8
guest
Kb(4)
ΔG(4)
Kb(8)
ΔG(8)
17
18
19
20
3600 ( 640
141 ( 25
100 ( 18
274 ( 74
ꢀ20.4
ꢀ12.3
ꢀ11.5
ꢀ14.0
3429 ( 300
655 ( 112
276 ( 46
ꢀ20.3
ꢀ16.2
ꢀ14.0
ꢀ15.2
Figure 7. Plot of the energies of guests 18 and 19. The trendline
corresponds to Emin(ΔG)(18) = 0.95 Emin(ΔG)(19), n = 8, R2 = 0.998.
438 ( 50
Table 3. Experimental Binding Constants Kb (Mꢀ1) and Free Energy Changes ΔG (kJ molꢀ1) at 300 K for the Complexes of Hosts
9 and 10
guest
Kb(9) NH amide
Kb(9) NH pyrrole
average Kb(9)
ΔG(9)
Kb(10) NH amide
Kb(10) NH pyrrole
average Kb(10)
ΔG(10)
17
18
19
20
171 ( 17
171 ( 24
341 ( 72
ꢀ
145 ( 13
166 ( 22
336 ( 72
101 ( 24
158
168
338
101
ꢀ12.6
ꢀ12.8
ꢀ14.5
ꢀ11.5
9717 ( 1382
1447 ( 139
2427 ( 111
468 ( 137
9148 ( 1243
1400 ( 139
2338 ( 131
517 ( 55
9432
1423
2382
492
ꢀ22.8
ꢀ18.1
ꢀ19.4
ꢀ15.5
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Figure 8. Kb values determined in this work (bold) and in our previous publications.
compensated addition funnel was slowly added and the mixture heated
to 115 °C for 3.5 h. After cooling and adding ice, ammonia solution was
added to pH 8.5 to 9.0. Precipitated salts were removed and the aqueous
solution extracted with CHCl3 (5 ꢁ 100 mL). The organic phase was
dried over SO4Na2 and then the CHCl3 removed in a rotary evaporator.
The brown solid obtained was purified by column chromatography on
neutral alumina (CH2Cl2/CH3OH 98:2), yielding 3.53 g of 2-amino-7-
methyl-1,8-naphthyridine (57.5%): mp 176.9 [lit.32 175ꢀ185 °C
Synthesis of 3,4-Diphenyl-1H-pyrrole-2,5-dicarbonyl Dichlor-
ide. First, the corresponding 2,5-dicarboxylic acid was prepared according to
the Steglich et al. procedure33 described for related pyrroles: to a solution of
phenylpyruvic acid (2.12 g, 12.9 mmol, 1.0 equiv) in dry THF (120 mL)
under argon at 78 °C was added dropwise with stirring 10.3 mL of nBuLi
(2.5 M in hexane, 25.75 mmol, 2.0 equiv). After the mixtrue was stirred for an
additional 25 min, a solution of iodine (1.64 mg, 6.45 mmol, 0.5 equiv) in
20 mL of THF was added dropwise. The mixture was heated to room
temperature, and a slow stream of ammonia was passed through for 10 min.
After saturation with ammonia, 0.70 mL (6.43 mmol, 0.5 equiv) of TiCl4 in
20 mL of dry hexane was added, leading to a suspension of brown color which
in a period of 24 h evolved to pale yellow. The reaction was poured into
150 mL of 2 N NaOH, and the aqueous phase was washed with ethyl acetate
(2ꢁ 50 mL). The pH was adjusted to 4 with HCl, and the aqueous phase was
extracted with ethyl acetate (4 ꢁ 150 mL). The combined organic phases
were washed with brine, dried with Na2SO4, filtered, and evaporated under
vacuum. The crude was washed with 1 mL of MeOH previously cooled
in a refrigerator, resulting in 3,4-diphenyl-1H-pyrrole-2,5-dicarboxylic acid
(466 mg, 20%): mp 249.3 °C (melt) and 270.3 °C (decomp) [lit.34 273ꢀ
293 °C (decomp)].
1
(crude), 217ꢀ218 °C (toluene)]; H NMR (CDCl3) δ (ppm) 7.80
(d, 1 H, 3J6-H = 8.0 Hz, 5-H), 7.78 (d, 1 H, 3J3-H = 8.6 Hz, 4-H), 7.05 (d, 1
H, 6-H), 6.70 (d, 1 H, 3-H), 5.11 (sa, 2 H, NH2), 2.66 (s, 3 H, CH3); 13
C
NMR (CDCl3) δ (ppm) 162.0 (C7), 159.5 (C2), 156.2 (C8a), 137.9
(C4), 136.1 (C5), 118.8 (C6), 115.3 (C4a), 111.4 (C3), 25.3 (CH3).
Synthesis of N,N0-Bis(7-methyl-1,8-naphthyridin-2-yl)-2,6-
pyridinedicarboxamide (8). Diacid dichloride (1 g, 4.90 mmol)
dissolved in 20 mL of dry CH2Cl2 was slowly added to a solution of 2-
amino-7-methyl-1,8-naphthyridine (1.57 g, 9.86 mmol) and Et3N (1.98 g,
19.6 mmol) in 100 mL of CH2Cl2 under inert atmosphere. The mixture was
stirred overnight at room temperature and then washed twice with 1 M HCl.
The organic phase was dried over SO4Na2, and the solvent was removed
under reduced pressure. The residue obtained was purified by column
chromatography on silica gel (CH2Cl2/CH3OH 98:2), yielding 220 mg of
Diacid dichloride was obtained by reaction of 3,4-diphenyl-1H-
pyrrole-2,5-dicarboxylic acid (326 mg, 1.06 mmol) with 8.5 mL of
thionyl chloride at reflux overnight. The reaction was allowed to cool,
and removing the excess of thionyl chloride under reduced pressure
afforded 3,4-diphenyl-1H-pyrrole-2,5-dicarbonyl dichloride as a beige
solid (320 mg, 87.6%): 1H NMR (CDCl3) δ (ppm) 10.01 (br s, 1 H,
1-NH), 7.25 (m, 6 H, m-H, p-H), 7.10 (m, 4 H, o-H); 13C NMR
(CDCl3) δ (ppm) 156.0 (CO), 135.8 (Cipso), 130.5 (C3/C4), 130.3
(Co), 128.3 (Cp), 127.9 (Cm), 125.1 (C2/C5).
host 8 (10%): mp 352.8 °C; 1H NMR (CDCl3) δ (ppm) 11.40 (br s, 2 H,
3
CONH), 8.74 (d, 2 H, 3J4 -H = 8.7 Hz, 30-H), 8.57 (d, 2 H, J4-H = 7.7 Hz,
0
3
0
0
3,5-H), 8.26 (d, 2 H, 4 -H), 8.21 (t, 1 H, 4-H), 8.07 (d, 2 H, J6 -H = 8.4 Hz,
50-H), 7.33 (d, 2 H, 60-H), 2.83 (s, 6 H, CH3);13CNMR (CDCl3) δ(ppm)
163.6 (C70), 162.5 (CO), 154.4 (C8a0), 153.2 (C20), 148.8 (C2/C6), 139.6
(C4), 139.4 (C40), 136.4 (C50), 126.1 (C3/C5), 122.0 (C60), 118.8 (C4a0),
15
114.5 (C30), 25.55 (CH3); N NMR (CDCl3) δ (ppm) ꢀ79.4 (N80),
ꢀ245.6 (1JNH = 89.5 Hz, HNCO); Anal. Calcd for C25H19N7O2 1.2 H2O:
Synthesis of N,N0-Bis(6-methylpyridin-2-yl)-3,4-diphenyl-
1H-pyrrole-2,5-dicarboxamide (9). A solution of 3,4-diphenyl-
C, 63.74; H, 4.58; N, 20.81; Found: C, 63.70; H, 4.69; N, 21.15.
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Table 4. Crystal Data and Structure Refinement for Hosts 8
and 10
stirred first for 2 h more at 0 °C and then allowed to warm to room
temperature and finally stirred at room temperature for 90 h. Removal of
the solid and evaporation of the CH2Cl2 in vacuo gave a residue that was
purified by column chromatography on silica gel (dichloromethane/
methanol 98:2) to yield compound 10 (144 mg, 28.0%): mp 242.8 °C;
crystal data
8
10
CCDC Number
empirical formula
812043
812044
1H NMR (CDCl3) δ (ppm) 10.54 (br s, 1 H, 1-NH), 8.50 (d, 2 H,
C25H19N7O2
2[(C36H27N7O2)
(SOC2H6) 1/2H2O]
3
J4 -H = 9.0 Hz, 30-H), 8.37 (br s, 2 H, CO-NH), 8.12 (d, 2 H, 40-H), 7.98
0
(d, 2 H, 3J6 -H = 8.2 Hz, 50-H), 7.39 (m, 6 H, m-H, p-H), 7.27 (m, 4 H,
3
0
o-H), 7.24 (d, 2 H, 60-H), 2.72 (s, 6 H, CH3); 13C NMR (CDCl3)
δ (ppm) 163.2 (C70), 159.1 (CO), 154.6 (C8a0), 153.0 (C20), 138.7
(C40), 136.4 (C50), 131.6 (Cipso), 130.6 (Co), 129.3 (Cm), 129.0 (Cp),
128.2 (C3/C4), 124.5 (C2/C5), 121.6 (C60), 118.7 (C4a0), 115.1 (C30),
25.6 (CH3). 15N NMR (CDCl3) δ (ppm) ꢀ80.3 (N80), ꢀ110.7 (N10),
ꢀ226.7 (N1), ꢀ239.1 (1JNH = 92.4 Hz, HNCO); Anal. Calcd for
C36H27N7O2 0.8 H2O: C, 71.58; H, 4.77; N, 16.23; Found: C, 71.66;
H, 4.92; N, 16.09.
formula weight
wavelength (Å)
crystal system
space group
a (Å)
449.47
1353.56
0.71073
monoclinic
C2/c
0.71073
monoclinic
C2/c
10.594(1)
19.501(2)
11.647(1)
111.836(2)
2233.7(4)
4
37.009(2)
13.0987849
14.0975(5)
95.401(3)
6803.7(4)
4
b (Å)
c (Å)
β (deg)
volume (Å3)
NMR Spectroscopy. NMR spectra were recorded at 300 K (9.4 T,
400.13 MHz for 1H, 100.62 MHz for 13C, and 40.56 MHz for 15N) with a
5-mm inverse-detection H-X probe equipped with a z-gradient coil.
Chemical shifts (δ in ppm) are given from internal solvent CDCl3 7.26
for 1H and 77.0 for 13C, and for 15N NMR, nitromethane was used as
Z
density (calculated)
(mg/m3)
1.337
1.321
13
13
external standard. gs-HMQC (1Hꢀ C), gs-HMBC (1Hꢀ C), gs-
absorption coefficient
0.090
0.146
HMQC (1Hꢀ N), and gs-HMBC (1Hꢀ N), were carried out with
the standard pulse sequences35 to assign the 1H, 13C, and 15N signals. 1D
15N NMR spectra were obtained with an inverse gated 1H decoupling
technique using a 5-mm direct-detection QNP probe equipped with a
z-gradient coil. Complete details for the 1H NMR titrations are given in
the Supporting Information.
15
15
(mmꢀ1
)
F(000)
936
2840
θ range (deg)
2.09 to 25.0
ꢀ12/ꢀ23/ꢀ13 to
12/23/12
8525
2.61 to 25.0
ꢀ32/ꢀ13/ꢀ15 to
44/15/16
15263
index ranges
reflections collected
Crystal Structure Determination. Suitable crystals for X-ray
diffraction experiments were obtained by crystallization of C25H19N7O2
(8) in chloroform and C36H27N7O2 SOC2H6 1/2H2O (10) from
independent reflections
1949 [R(int) = 0.0530] 5999[R(int) = 0.0219]
data/restraints/parameters 1949/0/155
5999/0/447
3
3
Ra[I > 2σ(I)] (ref obsd) 0.0409 (960)
0.0535 (3892)
dimethyl sulfoxide. Data collection for both compounds were carried
out at room temperature on a CCD diffractometer using graphite-
monochromated Mo KR radiation (λ = 0.71073 Å) operating at 50 kV
and 25 kV, respectively. In both cases, data were collected over a
hemisphere of the reciprocal space by combination of three exposure
sets. Each exposure of 20 s for (8) and 10 s for (10) covered 0.3 in ω.
The cell parameters were determined and refined by a least-squares fit
of all reflections. The first 100 frames were recollected at the end of the
data collection to monitor crystal decay, and no appreciable decay was
observed. A summary of the fundamental crystal and refinement data is
given in Table 4.
RwFb (all data)
0.1301
0.1688
2 2
a ∑||Fo| ꢀ |Fc||/∑|Fo|. b {∑[w(Fo ꢀ Fc2)2]/∑[w(Fo ) ]}1/2
.
2
1H-pyrrole-2,5-dicarbonyl dichloride (320 mg, 0.93 mmol) in THF
(13 mL) was slowly added (for 1 h) to a solution of the 2-amino-6-
methylpyridine (805 mg, 7.44 mmol) and triethylamine (377 mg,
3.72 mmol) in THF (20 mL) at 0 °C under an inert atmosphere. A
white precipitate of triethylammonium chloride was produced instantly.
The reaction mixture was stirred first for 3 h more at 0 °C, then slowly
allowed to rise at room temperature (2.5 h) and finally stirred at room
temperature for 64 h. Removal of the solid and evaporation of the THF
in vacuo gave a orange residue that was washed with water (5 ꢁ 10 mL).
After drying, the solid was purified by column chromatography on silica
gel (dichloromethane/methanol 98:2) to yield compound 9 (153 mg,
The structures were solved by direct methods and refined by full-
matrix least-squares procedures on F2 (SHELXL-97).36 All non-hydro-
gen atoms were refined anisotropically. In both cases, all hydrogen atoms
bonded to carbon atoms were included in calculated positions and
refined, riding on the respective carbon atoms. The hydrogens bonded
to nitrogen atoms, H1 bonded to N1 atom for (8), and H1, H4, and H5
bonded to N1, N4, and N5 atoms for (10) were located in a difference
Fourier synthesis, included and not refined.
Molecular Modeling. MacroModel v.8.1, with the GB/SA model
for chloroform, was used to perform the molecular simulations of hosts,
guests, and complexes.37 All calculations were achieved with Monte
Carlo (MC) conformational analyses.38 Minimization is carried out
using the PolakꢀRibiere conjugate gradient (PRCG) optimizer39 as
implemented in the program version, and the energy gradient was
chosen as the convergence criteria with a value of 0.05 and at least 2000
iterations. All MC calculations were performed with MCMM (Monte
Carlo multiple minimum) method, and the variables were torsion angles,
molecule coordinates, or both. The minimization method was PRCG
with the same characteristics as described above. In a typical MC run a
MCMM is never performed with less than 8000 steps. To carry out the
search, both torsional rotations in host and guest and translation/
rotation (10 Å/360°) of the guest are performed, and for all the MC,
1
33.7%): mp 201.6 °C; H NMR (CDCl3) δ (ppm) 10.44 (br s, 1 H,
1-NH), 7.99 (d, 2 H, 3J4 -H = 8.1 Hz, 30-H), 7.97 (s, 2 H, CO-NH), 7.53
0
(t, 2 H, 40-H), 7.39 (m, 6 H, m-H, p-H), 7.31 (m, 4 H, o-H), 6.80 (d, 2 H,
3
J4 -H = 7.5 Hz, 50-H), 2.28 (s, 6 H, CH3); 13C NMR (CDCl3) δ (ppm)
0
158.2 (CO), 157.1 (C60), 150.1 (C20), 138.2 (C40), 132.3 (Cipso), 130.8
(Co), 129.1 (Cm), 128.4 (Cp), 127.3 (C3/C4), 124.6 (C2/C5), 119.1
(C50), 110.9 (C30), 24.0 (CH3); 15N NMR (CDCl3) δ (ppm) ꢀ95.8
(N10), ꢀ228.5 (N1), ꢀ240.6 (1JNH = 88.8 Hz, HNCO); Anal. Calcd for
C30H25N5O2 1/2 H2O: C, 72.56; H, 5.28; N, 14.10; Found: C, 72.34; H,
5.35; N, 14.08.
Synthesis of N,N0-Bis(7-methyl-1,8-naphthyridin-2-yl)-3,4-
diphenyl-1H-pyrrole-2,5-dicarboxamide (10). A solution of 3,4-
diphenyl-1H-pyrrole-2,5-dicarbonyl dichloride (300 mg, 0.87 mmol) in
CH2Cl2 (13 mL) was slowly added (for 1,5 h) to a solution of the
2-amino-7-methyl-1,8-naphtyridine (1.11 g, 6.96 mmol) and triethyla-
mine (352 mg, 3.48 mmol) in CH2Cl2 (70 mL) at 0 °C under an inert
atmosphere. A white precipitate was produced. The reaction mixture was
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The Journal of Organic Chemistry
ARTICLE
a cutoff is applied to van der Waals, electrostatic, and H-bond interac-
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Supporting Information. 1H and 13C NMR spectra for
S
b
hosts 8ꢀ10, experimental details for molecular modeling NMR
titrations, and selected data for the X-ray crystal structures of 8
and 10. This material is available free of charge via the Internet at
http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: rclaramunt@ccia.uned.es.
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’ ACKNOWLEDGMENT
This work is supported by Grants CTQ2007-62113 and
CTQ2010-16122 (Ministerio de Ciencia e Innovaciꢀon, MICINN,
Spain).
’ DEDICATION
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In Memoriam of our friend Professor Rafael Suau.
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