Synthesis of a preorganized hybrid macrobicycle with distinct amide and amine clefts: Tetrahedral versus spherical anions binding studies

Article abstract of DOI:10.1021/jo401504f

A new C_3v symmetric amido-amine hybrid macrobicycle, L is synthesized toward anion recognition in its protonated states. L contains tri-amide and tetra-amine clefts separated by p-phenylene spacers. The solid-state structure of methanol-encapsulated L exhibits an overall cavity length of ～12.0 A where the amide and amine -NH protons are converged toward the center of the respective cavities. Conformational analysis of L in solution is established by NOESY NMR. Anion binding of [H₃L] ³⁺ with spherical (Cl^-, Br^-, I^-) and tetrahedral (ClO₄^-, SO₄^2-) anions are carried out by isothermal titration calorimeter in dimethylsulfoxide. The association of halides with [H₃L]³⁺ is endothermic and entropy driven. However, association of tetrahedral anions is exothermic in nature and both entropy- and enthalpy-driven. The overall association constants show the following order: HSO₄^- > Br^-> Cl^- ≈ ClO₄^-. Single crystal X-ray structures of ClO₄^- and Br^- complexes of protonated L show encapsulation of ClO₄^- in the amide cleft of [H ₂L]²⁺ (complex 1) and encapsulation of Br^- in the ammonium cleft of [H₃L]³⁺ (complex 2). Further, preorganization of L toward encapsulation of spherical and tetrahedral anions is established by comparing its amide, amine, and overall cavity dimensions with 1 and 2.

Full text of DOI:10.1021/jo401504f

Article
pubs.acs.org/joc
Synthesis of a Preorganized Hybrid Macrobicycle with Distinct
Amide and Amine Clefts: Tetrahedral versus Spherical Anions
Binding Studies
Subrata Saha, Bidyut Akhuli, Sourav Chakraborty, and Pradyut Ghosh*
Department of Inorganic Chemistry, Indian Association for the Cultivation of Science, 2A & 2B Raja S. C. Mullick Road, Kolkata 700
032, India
S
* Supporting Information
ABSTRACT: A new C3v symmetric amido-amine hybrid macrobicycle, L is synthesized toward anion
recognition in its protonated states. L contains tri-amide and tetra-amine clefts separated by p-
phenylene spacers. The solid-state structure of methanol-encapsulated L exhibits an overall cavity
length of ∼12.0 Å where the amide and amine -NH protons are converged toward the center of the
respective cavities. Conformational analysis of L in solution is established by NOESY NMR. Anion
binding of [H3L]3+ with spherical (Cl−, Br−, I−) and tetrahedral (ClO4 , SO42−) anions are carried out
−
by isothermal titration calorimeter in dimethylsulfoxide. The association of halides with [H3L]3+ is
endothermic and entropy driven. However, association of tetrahedral anions is exothermic in nature
and both entropy- and enthalpy-driven. The overall association constants show the following order:
HSO4 > Br−> Cl− ≈ ClO4 . Single crystal X-ray structures of ClO4 and Br− complexes of
−
−
−
protonated L show encapsulation of ClO4 in the amide cleft of [H2L]2+ (complex 1) and
−
encapsulation of Br− in the ammonium cleft of [H3L]3+ (complex 2). Further, preorganization of L
toward encapsulation of spherical and tetrahedral anions is established by comparing its amide, amine,
and overall cavity dimensions with 1 and 2.
affinities. Herein we report a new amido-amine hybrid
preorganized macrobicyclic C3v symmetric host (L, Figure 1)
INTRODUCTION
■
Recognition of anions by synthetic receptors has been one of
the most rapidly growing fields of supramolecular chemistry in
the past decade.1−7 Anions play various essential roles in the
chemical and biological processes that encourage synthetic
chemists to develop new classes of receptors.8,9 Receptor-
substrate binding site complementarity and solvation effects are
important factors that must be considered in the designing
aspects of any new receptor. The preorganization of the
receptor is an essential feature to address the guest binding
selectivity. Since the discovery of katapinands for halide
recognition, a large number of macrobicyclic systems have
been studied for recognition of anions and their various
chemistries.10−17 Most popular in this series is anion
recognition by polyammonium cryptands.18−30 Later on,
polyamide-based macrobicyclic neutral receptors have shown
different new features in this area.31−37 One of the most
interesting properties of macrobicyclic receptors is the
recognition of multiple anions such as HF2 , HCl2 , etc.
within a polyammonium cage.38,39 A few examples of
recognition of a cation and an anion in the heteroditopic
macrobicyclic hosts are also known in the literature.40−45 Thus
most of the cryptands studied for anionic guests are
accompanied by a polyamine/polyammonium cavity or
polyamide environment. However, the incorporation of
polyamine and polyamide functionalities into a suitable
macrobicyclic ligand make them attractive receptors mainly
because of the balanced combinations of both electrostatic and
hydrogen-bonding interactions with significantly higher anion
Figure 1. Cartoon picture of the hybrid macrobicycle L with distinct
amide and amine clefts.
having two distinct clefts, one polyamide and another
polyamine, in good yield. Further attempt is made to
understand the binding of anions with spherical size such as
chloride, bromide, and iodide and tetrahedral anions such as
perchlorate and sulfate. Importantly, solid-state structural
analysis shows preferential encapsulation of perchlorate
(tetrahedral) in the polyamide cleft of [H2L]2+ and bromide
(spherical) in the polyammonium pocket of [H3L]3+. To the
best of our knowledge this represents the first example of a
hybrid macrobicycle with distinct amide and amine clefts that
−
−
Received: July 11, 2013
© XXXX American Chemical Society
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a
Scheme 1
a
(i) Chloroacetyl chloride, CH2Cl2, NEt3, 81%; (ii) 4-hydroxy-benzaldehyde, CH3CN, K2CO3, 78%; (iii) tren, CH3OH, CH2Cl2, NaBH4, 65%.
Figure 2. Single crystal X-ray structure of L shows (a) encapsulation of one methanol molecule having hydrogen bonding interactions with the
amide protons of L and (b) cavity dimension of L (H atoms along with lattice water molecules are omitted for clarity).
shows compartmental binding of tetrahedral versus spherical
anions in its protonated states.
the presence of triethylamine gives I in good yield. Compound
II is obtained upon reaction between I and 4-hydroxybenzal-
dehyde in acetonitrile in the presence of anhydrous K2CO3.
High dilution reaction between tris(2-aminoethyl)amine (tren)
and II in dichloromethane/methanol (dropwise addition) at
room temperature resulted the desired heteroditopic host, L, in
good yield (∼65%).
RESULTS AND DISCUSSION
■
Ligand Design. Design of the amine- and amide-based
heteroditopic macrobicylic cage arose from our curiosity to
develop receptors for compartmental recognition of different
anions. We have chosen ammonium and amide as recognition
elements in our design to segregate the cage of the
macrobicyclic receptor for anions of different basicity. Tris(2-
aminoethyl)amine, tren-based polyammonium, and mesitylene-
based tripodal acyclic amide receptors have shown enormous
potential toward recognition of various anions in their
clefts.46−51 Thus it would be interesting to have a hybrid new
generation cage receptor with mesitylene-based tri-amides and
tren-based ammonium recognition clefts that are well separated
by suitable spacers for the recognition of anion. It is also
expected that the presence of the aromatic spacers in the
receptor architecture would contribute to its rigidity, which can
favor the preorganization and also can decrease the solvation
effect of the receptor.
Conformational Analysis. The structural information and
conformational geometry of L was determined by solid-state
structural analysis and solution-state NOESY NMR study.
Single crystals of L suitable for X-ray diffraction studies were
obtained by slow evaporation of a methanol/dichloromethane
solution at room temperature. The asymmetric unit contains L
with three water molecules and two methanol as solvent of
crystallization. The crystal structure of L shows that all of the
amide and amine moieties are orientated in such a way that the
attached hydrogen atoms are pointed inside the cavity of the
macrobicycle (Figure 2a). This type of arrangement of all of the
hydrogen bond donor atoms could facilitate better interaction
with the anionic guest by encapsulating it within the cavity.
Therefore these groups are well preorganized for the
interaction with an anionic guest. The three amide groups are
apart from each other with an average N···N distance of 5.65 Å
(Table 6S in Supporting Information). One methanol is
occupied in the amide cleft, whereas the other solvent
Synthesis. The new amido-amine-based macrobicycle, L is
synthesized according to Scheme 1 in three steps. Reaction of
chloroacetyl chloride with the tri-amine 1,3,5-tris-
(aminomethyl)-2,4,6-trimethylbenzene in dichloromethane in
B
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molecules are located outside the macrobicyclic host. The
amide groups are oriented in such a way that amide hydrogen
atoms are directed toward its cavity and hydrogen bonded to
the encapsulated methanol with bond distances of N1···O8 =
3.291 Å and N3···O8 = 3.173 Å. The distance between the
centroid of the mesitylene moiety (Cg) to the bridge head
nitrogen atom (N5) of L is 12.19 Å, which indicates a large
cavity of L for accommodation of guest species (Figure 2b).
Further, the secondary amines of the tren subunit are separated
from each other with an average distance of 4.14 Å, which
makes the amine clefts slightly smaller compared to that of the
amide clefts. Structural analysis further reveals that the three p-
phenylene moieties of L impose a conformational rigidity and
also work as spacers to segregate the amide and amine clefts
distinctly.
out similarly (Figures 22S and 24S in Supporting Information).
However, complexation of TBAI with [H3L](PF6)3 turns out to
be very weak to be reliably quantified by an ITC titration.52
Thermodynamic parameters for the complexation of [H3L]-
(PF6)3 with different anions are summarized in Table 1. The
overall association constants KT are calculated from stepwise
binding constants K1, K2, and K3, which are evaluated on the
basis of the sequential binding model.53 The calculated overall
association constants follow the order as HSO4− > Br− > Cl− ≈
−
ClO4 .
The higher overall association constant for Br− compared to
that of the Cl− could be due to better fitting of Br− into the
ammonium cleft of the host (as obtained from the solid-state
structure of the bromide complex, which is discussed later). In
cases of Cl− and Br− an endothermic binding pattern is
observed along with very high positive entropy values,
indicating an entropy-driven association of spherical anion
1
The H NMR spectroscopic studies are performed to obtain
the information about the conformational behavior of L in
1
with [H3L]3+ in DMSO. On the other hand, binding of ClO4
−
solution. The H NMR spectra of L in CDCl3 and DMSO-d6
−
show different chemical shifts for amide -NH protons and some
other spectral features (Figures 8S and 9S in Supporting
Information). Down field shift of 0.98 ppm of the amide -NH
proton in DMSO-d6 compared to that in CDCl3 indicates a
higher degree of solvation for L in DMSO-d6. The NOESY
spectrum of L in CDCl3 (Figure 3) clearly shows five cross
and HSO4 in DMSO are exothermic in nature. However, the
binding of these tetrahedral anionic guests to the [H3L]3+ is
found to be both entropy- and enthalpy-driven (Table 1). A
relatively high entropic contribution, TΔS, in all of the cases
suggests a better fitting of the anionic guests somewhere in the
amido-ammonium hybrid host cavity, which eventually releases
host/guest-associated solvent molecules to the system during
complexation.
Structural Analysis. Single crystals of perchlorate complex
of L and 1 suitable for X-ray diffraction studies were obtained
upon protonation of L with perchloric acid in an acetonitrile/
water mixture by slow evaporation. The complex 1 crystallized
in an orthorhombic space group Pbca. The structure shows that
the asymmetric unit of 1 contains a protonated macrobicycle,
[H2L]2+, two perchlorate ions, two water molecules, and one
acetonitrile as solvent of crystallization (Figure 5a). Structural
analysis of 1 shows bis-protonation of L with one encapsulated
perchlorate ion in the amide compartment, and the ammonium
pocket is occupied by one water molecule (Figure 5a). An
imaginary plane passing through the three p-phenylene spacers
of L separates the receptor into two distinct hydrogen bonding
clefts, mesitylene-based tri-amide (N1, N2, N3) and tren-based
ammonium/amine (N4, N6, N7) pockets (Figure 20S in
Supporting Information). It is clearly evident from the single
crystal X-ray structure of 1 that perchlorate resides in the amide
pocket, 2.48 Å above the imaginary plane, whereas the water
molecule resides in the ammonium pocket 1.86 Å below the
imaginary plane (Figure 20S in Supporting Information).
The encapsulated perchlorate ion is involved in two N−H···
O hydrogen bonding interactions with amide proton centers
(N2 and N3). Two oxygen atoms (O14, O13) of the
perchlorate are hydrogen bonded with N−H···O bond
distances of 2.26 and 2.35 Å, respectively (Table 4S in
Supporting Information). Oxygen atom (O19) of the
encapsulated water molecule is in three strong hydrogen
bonding interactions with the ammoninum/amine centers with
N−H···O bond distances in the range of 1.83−2.11 Å. In the
complex 1 the distance between the centroid of the mesitylene
moiety and the bridge head nitrogen atom is 11.31 Å, which is
quite similar as observed in case of free receptor L (12.19 Å).
Single crystals of bromide complex of L and 2 are grown
upon protonation of L with hydrobromic acid in an
acetonitrile−water mixture on slow evaporation. Complex 2
crystallizes in a monoclinic system in the P21/c space group
having a protonated macrobicycle [H3L]3+, three bromide ions,
Figure 3. (a) 2D NOESY spectrum shows five spatial 1H−1H coupling
of L. (b) Chemical structure of one of the arm of L showing the
interactions between the labeled protons.
peaks that correspond to the following interactions: Ha−Hb,
Hc−Hd, He−Hf, Hf−Hg, and Hi−Ha. All five cross-peaks in
solution are consistent with the solid-state conformation of L in
which similar spatial arrangement for the corresponding proton
pairs are observed (Figure 2).
Solution-State Anion Binding Studies. Receptor L in its
protonated state, [H3L](PF6)3, is explored for binding of
spherical and tetrahedral anions such as Cl−, Br−, I−, HSO4 ,
−
−
and ClO4 as their tetrabutylammonium salts by isothermal
titration calorimeter (ITC) in dry DMSO. Hexafluorophos-
−
phate (PF6 ) salt of the protonated L is used as host in this
investigation. PF6− has been chosen as counteranion because of
its poor hydrogen bond acceptor ability; it would not bind to
the host significantly. Figure 4 shows two representative
binding isotherms obtained by titrating [H3L](PF6)3 with the
solution of TBABr and TBAClO4, respectively.
Binding studies of chloride and hydrogen sulfate with
[H3L](PF6)3 using TBACl and TBAHSO4 are also carried
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Figure 4. ITC traces and binding isotherms for (a) titrations of receptor [H3L]3+ (1 mM) with TBABr (38 mM) and (b) titrations of receptor
[H3L](PF6)3 (0.98 mM) with TBAClO4 (44.4 mM) in dry DMSO at 298 K. The upper panel shows the heat pulses experimentally observed in each
titration step. The lower panel reports the respective time integrals translating as the heat changed for each aliquot and its coherence to a sequential
binding model.
Table 1. Association Constants Ka, Gibbs Energies ΔG, Enthalpies ΔH, and Entropies TΔS Associated with the Complexation
of TBACl, TBABr, TBAClO4, and TBAHSO4 with Receptor [H3L](PF6)3 in Dry DMSO at 298 K
guests
assoc constants Ka (M−1
)
ΔH (cal/mol)
TΔS (cal/mol/deg)
ΔG (cal/mol)
TBACl
K1 = 6.69E2 12
K2 = 1.54E3 34
K3 = 3.7E2 6.7
KT = 3.81E8 11.82
K1 = 3.13E3 80
K2 = 1.39E3 44
K3 = 1.29E2 2.6
KT = 5.61E8 31.62
K1 = 1.22E3 66
K2 = 1.10E3 90
K3 = 2.76E2 13
KT = 3.7E8 32.17
K1 = 1.11E4 340
K2 = 5.16E2 12
K3 = 1.27E2 2.4
KT = 7.27E8 156.93
ΔH1 = 3447 40.8
ΔH2 = −2490 51.2
ΔH3 = 1826 18.4
TΔS1 = 7301
TΔS2 = 1859.5
TΔS3 = 5334.2
ΔG1 = −3854
ΔG2 = −4349.5
ΔG3 = −3508.2
TBABr
ΔH1 = 427.3 4.47
ΔH2 = 52.42 8.10
ΔH3 = 1233 19.2
TΔS1 = 5185.2
TΔS2 = 4350.8
TΔS3 = 4112.4
ΔG1 = −4757.9
ΔG2 = −4298.4
ΔG3 = −2879.4
TBAClO4
TBAHSO4
ΔH1= −105.4 3.39
ΔH2 = 40.91 5.24
ΔH3 = −151.0 4.14
TΔS1 = 4112.4
TΔS2 = 4172.0
TΔS3 = 3188.6
ΔG1 = −4217.8
ΔG2 = −4131.1
ΔG3 = −3339.6
ΔH1 = −661.0 2.98
ΔH2 = −1323 21
ΔH3 = 117.1 43.8
TΔS1 = 4857.4
TΔS2 = 2378.0
TΔS3 = 2980
ΔG1 = −5518.4
ΔG2 = −3701.0
ΔG3 = −2862.9
one water molecule, and one acetonitrile (Figure 5b). In
complex 2, L is in the triprotonated [H3L]3+ state. The receptor
[H3L]3+ encapsulates one bromide ion and an acetonitrile in its
compartments. Interestingly, a reverse order in anion and
solvent encapsulation is observed in case of 2 when compared
with the single crystal X-ray of 1. The encapsulated bromide
ion in [H3L]3+ occupies the ammonium compartment, whereas
the amide pocket is engaged with one acetonitrile molecule.
The encapsulated bromide (Br3) resides in the ammonium
pocket, 1.50 Å below the imaginary plane, whereas water
molecule resides in amide pocket 2.71 Å above the imaginary
plane (Figure 20S in Supporting Information). The bromide
ion (Br3) is in H-bonding interactions with three protonated
ammonium centers (N4, N6, N7) with N−H···Br distances in
the range of 2.36−2.62 Å (Table 5S in Supporting
Information). The distance between centroid of the bridge
head mesitylene to bridge head nitrogen atom is measured as
11.96 Å, which is pretty close to the values obtained in cases of
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Figure 5. Single crystal X-ray structure of (a) complex 1; perchlorate is in the amide compartment of [H2L]2+, and water is in ammonium pocket.
(b) Complex 2; bromide is in the ammonium compartment of [H3L]3+, whereas acetonitrile is in ammonium pocket. (H atoms and counteranions
along with lattice water molecules are omitted for clarity.)
protons of the macrobicyclic host were interpreted by NOESY NMR
spectroscopy in CDCl3.
L and 1. It is important to mention that the cleft size of the
amide and amine/ammonium of the macrobicycle after
encapsulation of the anionic guest into the corresponding
clefts remains almost the same compared to that of the
methanol encapsulated L (Table 6S in Supporting Informa-
tion). This indeed suggests the preorganization of the receptor
design toward anion recognition.
Isothermal Titration Calorimetric (ITC) Studies. Titration
experiments were carried out at 298 K in dry dimethylsulfoxide
(DMSO). A solution of [H3L](PF6)3 in DMSO was taken in the cell.
This solution was then titrated with 30 injections of 10 μL of anion
solutions prepared in DMSO. An interval of 220 s was allowed
between each injection, and the stirring speed was set at 329 rpm. The
obtained data was processed using Origin 7.0 software supplied with
the instrument and fitted to a sequential binding model. Blank titration
of anion into solvent was also performed and subtracted from the
corresponding titration to remove any effect from the heats of dilution
from the titrant. The studies of the effect of both the anions were
repeated twice with two different batches of [H3L](PF6)3 and showed
good reproducibility.
X-ray Crystallography. Crystals suitable for single crystal X-ray
diffraction studies were selected from the mother liquor and immersed
in paratone oil, then mounted on the tip of a glass fiber, and cemented
using epoxy resin. Intensity data for the crystals L, 1, and 2 were
collected using Mo Kα (λ = 0.7107 Å) radiation on a single crystal X-
ray diffractometer equipped with CCD area detector at 298/150 K.
The data integration and reduction were processed with SAINT55
software. An empirical absorption correction was applied to the
collected reflections with SADABS.56 The structures were solved by
direct methods using SHELXTL57 and were refined on F2 by the full-
matrix least-squares technique using the SHELXL-9758 program
package. Graphics were generated using PLATON59 and MERCURY
2.3.60 The non-hydrogen atoms were refined anisotropically till
convergence. In the cases of complexes L, 1, and 2 the hydrogen atoms
were geometrically fixed at idealized positions. In the cases of
complexes 1 and 2, even though the data were collected at 150 K, the
hydrogen atoms attached to the lattice water molecule could not be
located from the difference Fourier map. In case of complex 1, one of
the oxygen atoms (O13) of the encapsulated perchlorate ion was
disordered at two sites, and the occupancy factors were refined using
the FVAR command of the SHELXTL program and isotropically
refined. In the case of complexes 2, even though the data was collected
at 150 K several times, we were unable to assign electron density for
solvent molecules in the unit cell. The routine SQUEEZE61 was
applied to intensities data of complexes 2 to take into account the
disordered solvent molecules. The number of electrons found in the
CONCLUSION
■
A new hybrid macrobicylic host with two distinct cavities
consisting of amine and amide as potential recognition
elements for anionic guests is synthesized for the first time.
The overall cavity dimension of this hybrid macrobicycle is
relatively large, having two distinct compartments of different
environments that have potential for guest encapsulation. The
solid-state conformation of L matches well with the solution-
state conformation obtained from NOESY NMR. Both
solution-state ITC and single crystal X-ray study confirm
binding of anions of different dimensionalities with the
protonated host. The ITC study demonstrates selectivity
toward hydrogen sulfate over other anions studied in DMSO.
Exothermic versus endothermic processes are observed in cases
of tetrahedral and spherical anions, respectively. Preorganiza-
tion and compartmental recognition of anions with different
dimensionalities are established with the newly designed hybrid
amido-amine receptor. This type of host with new anion
recognition property could be useful in the development of
hetero multianionic receptors that can recognize anions of
different dimensions in a single molecular entity.
EXPERIMENTAL SECTION
■
General Details. The reagents were obtained from commercial
suppliers and used as received without further purification unless
otherwise indicated. 1,3,5-Tris(aminomethyl)-2,4,6-trimethylbenzene
was synthesized using a previously reported procedure.54 Peak
1
assignments in the H NMR spectra were confirmed by using H,H-
COSY spectra of selected compounds. DEPT spectra were used to
interpret the 13C NMR spectra. The special interactions between the
E
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solvent-accessible void is close to that expected for one CH3CN
molecule in the unit cell.
obtained as pure product. Yield: ∼0.064g (64%). 1H NMR (300 MHz,
DMSO-d6): δ (ppm) 2.38 (s, 9H, Ar-CH3), 2.60 (br, 6H,
NCH2CH2NH), 4.11 (s, 6H, Ar-CH2), 4.50 (m, 12H), 7.04 (d, 6H,
J = 9 Hz), 7.31 (d, 6H, J = 9 Hz), 7.37(t, 3H, J = 6 Hz), 8.48 (br, 6H).
13C NMR (125 MHz, DMSO-d6): δ (ppm) 16.39 (CH3), 37.94
(CH2), 42.74 (CH2), 49.27 (CH2), 49.43 (CH2), 67.50 (CH2),
115.73(Ar-C), 124.19 (Ar-C), 131.95 (Ar-C), 133.14 (Ar-C), 137.09
(Ar-C), 158.29 (Ar-C), 167.11 (CO). ESI-MS of 1 at m/z 992.0,
892.1, and 792.2 and 396.6 corresponded to [H3L.2ClO4]+,
[H2L.ClO4]+, [HL]+, [H2L]2+/2 respectively. Anal. Calcd for
C45H59N7O14Cl2: C, 54.43; H, 5.99; N, 9.87. Found: C, 54.32; H,
6.12; N, 9.75.
Complex 2. Compound L (0.1 mmol, 0.079 g) was dissolved in 10
mL of CH3OH/CH2Cl2 (1:1), and a few drops of hydrobromic acid
were added to the stirring solution. The reaction mixture was stirred
for another 4 h. A precipitate developed which was filtered and
collected after repeated washing with diethyl ether. The off-white solid
was crystallized in an acetonitrile/water mixture, and the crystals were
isolated as product. Yield: 0.071 g (68%). 1H NMR (500 MHz,
DMSO-d6): δ 2.38 (s, 9H, Ar-CH3), 2.65 (br, 6H, NCH2CH2NH),
2.80 (br, 6H, NCH2CH2NH), 4.16 (s, 6H, Ar-CH2NHCH2), 4.51 (s,
12H, COCH2O, ArCH2NHCO), 7.01 (d, 6H, J = 10 Hz, Ar-H), 7.41
(s, 3H, NHCO), 7.47 (d, 6H, J = 10 Hz, Ar-H); 13C NMR (125 MHz,
DMSO-d6): δ (ppm) 16.41 (CH3), 34.80 (CH2), 37.90 (CH2), 43.17
(CH2), 49.32 (CH2), 67.61 (CH2), 115.44(Ar-C), 124.42 (Ar-C),
132.23 (Ar-C), 133.12 (Ar-C), 137.08 (Ar-C), 158.15 (Ar-C), 167.08
(CO). ESI-MS of 2 at m/z 792.2 and 396.6 corresponded to
[HL]+and [H2L]2+/2 respectively. However, no peak was found along
with the counteranion, bromide. Anal. Calcd for C45H60N7O6Br3: C,
52.23; H, 5.84; N, 9.48. Found: C, 52.18; H, 5.91; N, 9.37.
CCDC-903584(L), CCDC-903583 (1), and CCDC-903582 (2)
contain the supplementary crystallographic data for this paper.
Compound I. In a 100-mL round bottomed flask was dissolved 0.6
g (2.9 mmol) of 1,3,5-tris(aminomethyl)-2,4,6-trimethylbenzene in 50
mL of dry dichloromethane. About 1.4 mL (10 mmol) of dry
triethylamine was added to the above solution. The mixture was
allowed to stir at 0 °C temperature in a nitrogen atmosphere for 15
min. Then 0.716 mL (9 mmol) of chloroacetyl chloride in 25 mL of
dry dichloromethane was taken in a 50-mL pressure equalizer funnel.
This solution was added dropwise for a period of 1 h with constant
stirring 0 °C temperature. After the addition, the reaction mixture was
allowed to stir at room temperature in a nitrogen atmosphere for
another 7 h. The precipitate was filtered and washed three times with 2
M HCl, saturated NaHCO3 solution and saturated NaCl solution. The
off white solid was isolated and dried over vacuum to yield the desired
product I. Yield: 1.025 g (81%). HRMS (ESI): m/z calcd for
1
C18H24Cl3N3O3Na [M + Na]+ 458.0781, found 458.0781. H NMR
(500 MHz, DMSO-d6): δ (ppm) 2.29 (s, 9H, Ar-CH3), 4.03 (s, 6H,
-CH2Cl), 4.35 (d, 6H, J = 5 Hz, Ar-CH2), 8.20 (br, 3H, CONH). 13
C
NMR (125 MHz, DMSO-d6): δ (ppm) 16.31(CH3), 38.94 (CH2),
42.99 (CH2), 132.92 (Ar-C), 137.16 (Ar-C), 166.15 (CO).
Compound II. In a 250-mL round-bottomed flask was dissolved
0.873 g (2 mmol) of I in 100 mL of acetonitrile. K2CO3 (2 g, 15
mmol) and 4-hydroxybenzaldehyde (0.85 g, 7 mmol) were added to
that solution at room temperature. The reaction mixture was allowed
to stir at 80 °C in nitrogen atmosphere for 24 h. The precipitate was
filtered and repeatedly washed with water. This off-white solid,
compound II was dried and was used in the next step without further
purification. Yield: 1.08 g (78%). HRMS (ESI): m/z calcd for
C39H39N3O9Na [M + Na]+ 716.2584, found 716.2584. 1H NMR (500
MHz, DMSO-d6): δ (ppm) 2.32 (s, 9H, Ar-CH3), 4.41 (d, 6H, J = 5
Hz, Ar-CH2), 4.65 (s, 6H, COCH2O), 7.09 (d, 6H, J = 10 Hz, Ar-CH),
7.85 (d, 6H, J = 10 Hz, Ar-CH), 8.13 (t, 3H, J = 5 Hz, NH), 9.85 (s,
3H, -CHO). 13C NMR (125 MHz, DMSO-d6): δ (ppm) 16.33 (CH3),
38.44 (CH2), 67.18 (CH2), 115.56 (Ar-C), 130.49 (Ar-C), 132.15 (Ar-
C), 132.97 (Ar-C), 137.13 (Ar-C), 163.26 (Ar-C), 167.10 (CO),
191.79 (-CHO).
[H3L](PF6)3. Complex 2 (100 mg, 0.1 mmol) was dissolved in
CH3OH/H2O (1:1) (10 mL). Then, 100 mg of potassium
hexafluorophosphate dissolved in water (5 mL) was added into the
above solution and stirred for 4 h. The white precipitate was filtered,
washed with wate,r and dried in vacuo to isolate the product. Yield: 61
1
mg (50%). H NMR (300 MHz, DMSO-d6): δ 2.37 (s, 9H, Ar-CH3),
2.56 (br, 6H, NCH2CH2NH), 2.85 (br, 6H, NCH2CH2NH), 4.10 (s,
6H, Ar-CH2NHCH2), 4.50 (s, 12H, COCH2O, ArCH2NHCO), 6.98
(d, 6H, J = 8.7 Hz, Ar-H), 7.35 (d, 6H, J = 8.7 Hz, Ar-H), 7.41 (s, 3H,
NHCO); 13C NMR (125 MHz, DMSO-d6): δ (ppm) 16.35 (CH3),
37.84 (CH2), 42.93 (CH2), 49.48 (CH2), 49.82 (CH2), 67.55 (CH2),
115.52 (Ar-C), 124.55 (Ar-C), 132.10 (Ar-C), 133.16 (Ar-C), 137.08
(Ar-C), 158.09 (Ar-C), 167.06 (CO). ESI-MS of [H3L](PF6)3 at m/z
792.1 and 396.6 corresponded to [HL]+and [HL]2+/2, respectively.
However, no peak was found along with counteranion, hexafluor-
ophosphate. Anal. Calcd for C45H60N7O6P3F18: C, 43.95; H, 4.92; N,
7.97. Found: C, 44.11; H, 4.81; N, 8.12.
Macrobicycle L. In a 500-mL three-neck round-bottom flask, two
necks were fitted with 100 mL pressure equalizers and another for
nitrogen atmosphere. Compound II (0.3 g, 0.43 mmol) in 50 mL of
dichloromethane in one pressure equalizer and tris(2-aminoethyl)-
amine (tren, 0.065 mL, 0.43 mmol) dissolved in 50 mL of methanol in
another pressure equalizer were added drop by drop to 100 mL of
methanol with stirring. After complete addition, the reaction mixture
was stirred for another 24 h. Sodium borohydride 0.95g (2.6 mmol)
was added to the reaction mixture and stirred for 6 h. The reaction
mixture was filtered, and the filtrate was evaporated at low pressure.
The solid was dissolved in 100 mL of water, and the precipitate was
filtered and dried to yield the desired product L as white solid. Yield:
0.22 g (65%). HRMS (ESI): m/z calcd for C45H58N7O6 [M + H]+
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details, synthesis, ITC, and crystallographic data
in CIF format. This material is available free of charge via the
Internet at http://pubs.acs.org.
1
792.4449, found 792.4443. H NMR (300 MHz, CDCl3): δ 2.44 (s,
9H, Ar-CH3), 2.57 (t, 6H, J = 5.4 Hz, NCH2CH2NH), 2.72 (t, 6H, J =
5.4 Hz, NCH2CH2NH), 3.59 (s, 6H, Ar-CH2NHCH2), 4.45 (s, 6H,
COCH2O), 4.65 (d, 6H, J = 4.2 Hz, ArCH2NHCO), 6.28 (br, 3H,
NHCO), 6.66 (d, 6H, J = 8.7 Hz, Ar-H), 6.96 (d, 6H, J = 8.7 Hz, Ar-
H). 1H NMR (300 MHz, DMSO-d6): δ (ppm) 2.36 (s, 9H, Ar-CH3),
2.40 (br, 12H, NCH2CH2NH), 3.53 (s, 6H, Ar-CH2NHCH2), 4.42 (s,
6H, COCH2O), 4.50 (d, 6H, J = 6 Hz, ArCH2NHCO), 6.82 (d, 6H, J
= 9 Hz, Ar-H), 7.11 (d, 6H, J = 9 Hz, Ar-H), 7.26 (t, 3H, J = 6 Hz,
NHCO). 13C NMR (125 MHz, DMSO-d6): δ (ppm) 16.24 (CH3),
37.85 (CH2), 47.27 (CH2), 52.79 (CH2), 54.78 (CH2), 67.74 (CH2),
115.00 (Ar-C), 129.41 (Ar-C), 133.25 (Ar-C), 134.28 (Ar-C), 136.97
(Ar-C), 156.39 (Ar-C), 167.32 (CO).
Complex 1. Compound L (0.1 mmol, 0.079 g) was dissolved in 10
mL of CH3OH/CH2Cl2 (1:1), and few drops of perchloric acid were
added to the stirring solution. The reaction mixture was stirred for
another 6 h. A precipitate developed, which was filtered and collected
after repeated washing with diethyl ether. The off-white solid was
AUTHOR INFORMATION
Corresponding Author
*E-mail: icpg@iacs.res.in.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
P.G. gratefully acknowledges the Department of Science and
Technology (DST), New Delhi, India for financial support
through a Swarnajayanti Fellowship. S.S. and B.A. acknowledge
CSIR for a SRF. X-ray diffraction of L, 1, and 2 were performed
at DST funded National single crystal X-ray facility at the
department of Inorganic Chemistry, IACS.
F
dx.doi.org/10.1021/jo401504f | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
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