Synthesis and anion recognition properties of shape-persistent binaphthyl-containing chiral macrocyclic amides

Article abstract of DOI:10.3762/bjoc.8.109

We report on the synthesis and characterization of novel shape-persistent, optically active arylamide macrocycles, which can be obtained using a one-pot methodology. Resolved, axially chiral binol scaffolds, which incorporate either methoxy or acetoxy functionalities in the 2,2′ positions and carboxylic functionalities in the external 3,3′ positions, were used as the source of chirality. Two of these binaphthyls are joined through amidation reactions using rigid diaryl amines of differing shapes, to give homochiral tetraamidic macrocycles. The recognition properties of these supramolecular receptors have been analyzed, and the results indicate a modulation of binding affinities towards dicarboxylate anions, with a drastic change of binding mode depending on the steric and electronic features of the functional groups in the 2,2′ positions.

Full text of DOI:10.3762/bjoc.8.109

Synthesis and anion recognition properties
of shape-persistent binaphthyl-containing chiral
macrocyclic amides
Marco Caricato1, Nerea Jordana Leza1, Claudia Gargiulli2,
Giuseppe Gattuso2, Daniele Dondi1 and Dario Pasini*1,3
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2012, 8, 967–976.
1Department of Chemistry, University of Pavia, Viale Taramelli 10,
27100 Pavia, Italy, 2Department of Organic and Biological Chemistry,
University of Messina, Viale F. Stagno d'Alcontres 31,
doi:10.3762/bjoc.8.109
Received: 08 March 2012
Accepted: 23 May 2012
Published: 28 June 2012
98166 Messina, Italy and 3INSTM Research Unit, Department of
Chemistry, University of Pavia, 27100 Pavia, Italy
Email:
This article is part of the Thematic Series "Molecular switches and cages".
Guest Editor: D. Trauner
Dario Pasini* - dario.pasini@unipv.it
* Corresponding author
© 2012 Caricato et al; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
amides; anion recognition; chirality; macrocycles; molecular switches;
supramolecular chemistry
Abstract
We report on the synthesis and characterization of novel shape-persistent, optically active arylamide macrocycles, which can be
obtained using a one-pot methodology. Resolved, axially chiral binol scaffolds, which incorporate either methoxy or acetoxy
functionalities in the 2,2' positions and carboxylic functionalities in the external 3,3' positions, were used as the source of chirality.
Two of these binaphthyls are joined through amidation reactions using rigid diaryl amines of differing shapes, to give homochiral
tetraamidic macrocycles. The recognition properties of these supramolecular receptors have been analyzed, and the results indicate
a modulation of binding affinities towards dicarboxylate anions, with a drastic change of binding mode depending on the steric and
electronic features of the functional groups in the 2,2' positions.
Introduction
Macrocyclic molecules possessing a high degree of shape are usually enhanced by limiting the number of conformations
persistency act as molecular cages, and the scientific interest for accessible to the covalent cyclic structure (resulting in preorga-
such compounds is certainly increasing [1-4]. Support for this nization [5]); (b) shape persistency is a requirement for the
statement arises from consideration in two main areas of formation of organic nanotubes by means of supramolecular
interest: (a) the recognition properties towards suitable guests organization of macrocycles in the third dimension [6-12].
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Amide functionalities are hydrogen-bonding tools of wide- macrocyclic cavity is given by the presence of stable, six-
spread use for the conformational stabilization of nanostruc- membered intramolecular hydrogen bonds between the
tures. Noticeable examples can be found in the field of protected (in the form of methyl ether) phenol moieties in the
foldamers [13,14] or in the design of assembled architectures 2,2' positions and the NH protons of the amide functionalities in
functioning as artificial ion-channel mimics [15]. Amide func- the neighboring 3,3' positions of the binaphthyl units. Macro-
tionalities are also widely used for their hydrogen bonding cycle (R,R)-1 showed modest binding affinities towards
capability in the context of anion complexation. Several macro- carboxylate anions, yet detectable binding of proper difunc-
cyclic systems capable of effective anion recognition and tional carboxylates.
discrimination have been previously reported [16-18]. Binol
(1,1'-binaphthyl-2,2'-diol) based synthons are popular in the We deemed it to be very interesting to increase the availability
recent literature; given their robustness, they are frequently used of hydrogen-bond donors within the macrocycle cavity, and to
to impart or transfer chiral information, not only in the field of unlock the hydrogen-bonding capability of the amide NHs to
asymmetric synthesis and catalysis, but also in materials science their full potential for anion recognition. The former could in
[19-24].
principle be achieved by unmasking the phenolic oxygen atoms
in the 2,2' positions of the binaphthyl skeletons. As for the
During the course of our ongoing efforts dealing with the use of latter, the introduction of another protecting group, sterically
binol-based synthons for the production of functional, oriented and electronically modulating the hydrogen-bond accepting
nanomaterials and chiroptical sensors [25-30], we have reported capability of the phenolic oxygen, was needed.
on the design, synthesis and characterization of a rigid, opti-
cally active tetraamidic macrocycle with recognition capabili- In this paper, we present the exploitation of these strategies,
ties towards anions (Figure 1) [31].
resulting in the synthesis and characterization of three novel
binaphthyl-based macrocycles, and the evaluation of their
potential as supramolecular receptors for aliphatic bidentate
carboxylate anions.
Results and Discussion
Design, synthesis and spectroscopic charac-
terization
Reactions to deprotect the phenolic oxygens, performed directly
on (R,R)-1 as a substrate and attempted under various reaction
conditions, proved completely unsuccessful with degradation of
the macrocyclic structure occurring in all cases. On the basis of
the introductory considerations mentioned earlier, we set out to
exploit two orthogonal synthetic strategies (Figure 1, bottom):
(1) A direct amidation of the carboxylic acids in the 3,3' posi-
tions, in the presence of the free phenolic oxygens in the 2,2'
positions. Literature precedents for such amidation using
aromatic amines in the presence of vicinal phenol moieties
(which compete since they are comparable in nucleophilicity
with aromatic amines) are rare [32,33]. As already reported
[31], test reactions on model compounds gave disappointing
results. The use of benzylic amines, more nucleophilic than
arylamines, and therefore competing less with the phenolic
moieties in the 2,2' positions, was envisaged as a potential solu-
tion and was therefore actively pursued. (2) The use of milder
(with respect to methyl ether) protecting groups for the phenolic
functionalities in the 2,2' positions; we focused on the use of
compound 3, bearing acetyl protecting groups, since its syn-
thesis has been reported, and the deprotection of these groups
usually occurs under mild basic conditions [34]. Aromatic
amines, as in (R,R)-1, could in principle be used.
Figure 1: Structure of the macrocycle (R,R)-1 (top), and synthetic
strategies for the production of novel amide-containing, axially chiral
macrocycles (bottom).
In fact, macrocycle (R,R)-1 could be obtained efficiently (62%
in the macrocyclization step) through a sequential, convergent
methodology. It is a 32-membered macrocycle whose cyclic
backbone is composed exclusively of sp2-hybridized carbon and
nitrogen atoms. An additional internal rigidification of the
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Beilstein J. Org. Chem. 2012, 8, 967–976.
Preliminary synthetic work was performed on model com- Alternative one-pot amidation procedures, performed directly
pounds to test the reaction conditions. Both enantiomerically with the aromatic carboxylic acid and the benzylic amine
pure (R)-2 and (R)-3 and racemic (RS)-2 and (RS)-3 were used (method ii) using carbonyldiimidazole (CDI) [36], successfully
routinely in the experiments described in the following. used by us in the past [29], were instead less than satisfactory.
Regarding approach (1), direct generation of the carboxylic acid Both protocols were applied with commercially available
chloride (with SOCl2, or oxalyl chloride and DMF; method i), monoprotected benzylic diamine 4c; in both cases, however, the
followed by reaction with benzylamine (4a) in the presence of desired product 5c could not be isolated. It is likely that the
Et3N as the acid scavenger gave compound 5a in excellent BOC protecting group is not compatible with the presence of
yields (93%) after purification by column chromatography the free phenolic groups in our substrates.
(Scheme 1). The yield was higher in our hands than the one
previously reported [35].
Switching to approach (2), when compound 3 was allowed to
react with benzylamine (4a) or aniline (4b), only the aryl
derivate 6b was obtained in good yield. Compound 6b could be
efficiently deprotected under the reported conditions (K2CO3/
MeOH) to give 5b. When the monoprotected aryl amine 4d was
allowed to react with compound 3 using the same reaction
conditions, however, compound 6d could not be efficiently
synthesized. The low yield obtained in this step discouraged us
from pursuing a stepwise methodology for the macrocycliza-
tion, which had been used in the case of (R,R)-1 [31].
In order to quickly evaluate the potential of acetyl-protected
tetraamidic macrocyles as analogues of (R,R)-1, we proceeded
to directly cyclize equimolar amounts of optically pure,
resolved (R)-3 (via formation of the corresponding diacyl chlo-
ride) and commercially available diaryl amines 8 and 9, under
classical high-dilution conditions [13] which were successful
for the synthesis of compound 6b. Indeed, homochiral macrocy-
cles (R,R)-10, (R,R)-11 and (R,R)-12 could be isolated after
extensive purification by column chromatography, although in
disappointingly low yields (0–5% isolated yield, Scheme 2).
Furthermore, macrocycle (R,R)-13 could not be isolated at all.
The low quantities of macrocycles (R,R)-10 and (R,R)-11
obtained prevented us from exploring the cleavage of the acetyl
functionalities.
Scheme 1: Reagents and conditions: (i) SOCl2, CHCl3 or (COCl)2,
DMF, CH2Cl2 then amine, Et3N, CH2Cl2 or (ii) CDI, THF.
Scheme 2: Structure and synthesis of the macrocycles discussed in this paper.
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Beilstein J. Org. Chem. 2012, 8, 967–976.
1H NMR spectra for all compounds were relatively simple (see
Experimental and Supporting Information File 1), reflecting the
structural symmetry found in precursors (C2 molecular
symmetry) and in homochiral macrocycles 10–12 (D2 molec-
ular symmetry). The peaks for the NH proton resonances of the
amide functionalities are sharp in S(6)-type [37] hydrogen-
bonded systems, such as those between the NH and the neigh-
boring methoxy groups in (R,R)-1 and (R,R)-12. The NH proton
resonances, however, could not be assigned either in the series
of compounds 5, or in the acetoxy protected compounds 6 and
macrocycles 10,11, as they are broad or below the baseline, so
as to indicate unlocked (thus potentially more available to
incoming guests), conformationally mobile NH groups
(Table 1).
There are also substantial differences in the resonances of the H
4,4' protons of the binaphthyl skeleton, which are usually most
sensitive to variations in the substitution pattern (and thus, in
the electronic structure) within the naphthyl systems of the
binaphthyl units.
The UV–vis spectra of macrocycles (R,R)-10 and (R,R)-11,
recorded in solvents possessing different solvating and
hydrogen-bonding abilities (CH2Cl2, EtOH), showed little
solvent dependence, with λmax around 230 nm in all cases, and
with well-defined shoulders just below 300 nm. Comparison
with data available on parent systems [31] reveals that the
spectra cannot be explained as the sum of those generated by
the two major aromatic chromophoric components (the naph-
Figure 2: UV and CD (EtOH) spectra of macrocycles (R,R)-10,
(R,R)-11 and (R,R)-12 in the range 220–400 nm.
thyl rings of the binaphthyl units and the aryl moieties of the bathochromically shifted shoulder, centered at 320 nm (quite
spacing units); electronic communication between them is different from (R,R)-10). The CD spectra (in EtOH) show
present (Figure 2).
activity associated with all active UV chromophores and more
marked activity for the macrocycle (R,R)-10, with exciton
It is interesting to note how the spectra of macrocycle (R,R)-12, couplet signals greater in intensity than the ones of the other
bearing methoxy protected phenols, showed the most macrocycles.
Table 1: Selected chemical shifts for compounds in CDCl3 (25 °C).a
Entry
Compound
NH
Binol-H 4,4'b
OCH3
COCH3
OH
1
2
4
5
6
7
8
9
5a
5b
9.88
n. d.c
n. d.
8.74
8.85
8.47
8.46
8.58
8.58
9.06
9.00
—
—
—
—
12.44
10.31
—
6b
—
1.83
1.84
1.82
1.83
—
6d
n. d.
—
—
(R,R)-10
(R,R)-11
(R,R)-12
(R,R)-1
n. d.
—
—
n. d.
—
—
10.45
10.00
3.32
3.53
—
—
—
aAll spectra recorded at 5–10 mM sample concentration. bResonances related to the singlet corresponding to the proton in the 4,4' positions of the
binol skeleton. cn. d. = broad or not identified.
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Beilstein J. Org. Chem. 2012, 8, 967–976.
Molecular modeling
atom bridges. In fact, the two trifluoromethyl-containing macro-
Molecular modeling was performed on the structures of macro- cycles ((R,R)-11 and (R,R)-13) have a more square-like geom-
cycles (R,R)-10, (R,R)-11 and (R,R)-12, and on the hypothetical etry, which seems to be associated with the smaller imposed
macrocycle (R,R)-13, in order to have an estimate of macro- angle of the sp3-hybridized carbon atom in the spacing units.
cyclic cavities, and to gather information on the relative orienta- The dimensions of the macrocycles are essentially identical for
tion of the functional groups involved in the binding the homologous sets of (R,R)-11 and (R,R)-13 (14 Å × 15.7 Å),
phenomena. Preliminary conformational structures were opti- and of (R,R)-10 and (R,R)-12 (12.5 Å × 16.2 Å). In the case of
mized by using the semiempirical PM3 method [38]. The (R,R)-1, the macrocycle cavity is more square-like, with the
geometries were then subjected to further refinement by using four amides all at a quite similar distance (ca. 6–7 Å). In the
DFT B3LYP/6-31G(d) methods. In order to locate conformers case of 10–13, however, there is a substantial differentiation in
having the minimum energy, the structures obtained by prelimi- distances between the two sets of amide functionalities, those
nary optimization were then subjected to molecular dynamics linked to each different binaphthyl unit within the macrocycle.
cycles and subsequent reoptimization [28]. The most stable (R,R)-11 and (R,R)-13 possess slightly less distorted molecular
minimized structures of the macrocycles are shown in Figure 3, conformations in which a C2 overall molecular symmetry seems
in which the distances between the four hydrogen atoms of the to be retained. In fact, the dihedral angles of the binaphthyl
NH amide groups within each macrocycle are reported (in units within the macrocycle are identical in the case of (R,R)-11
angstroms).
(76.1°) and of (R,R)-13 (79.5°), whereas they differ slightly in
the case of the more distorted (R,R)-10 (70.8 and 72.6°) and
The two macrocycles bearing aryloxy ether spacers ((R,R)-10 (R,R)-12 (85.9 and 85.6°). Molecular modeling does not give
and (R,R)-12) have a rectangular overall geometry, probably as clear hints as to why macrocycle (R,R)-13 could not be
a consequence of the imposed dihedral angle of the oxygen obtained.
Figure 3: Minimized molecular structures of (from top left to bottom left, clockwise): (R,R)-10, (R,R)-11, (R,R)-13 and (R,R)-12 (distances between the
H atoms of the NH amide groups are given in angstroms).
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Beilstein J. Org. Chem. 2012, 8, 967–976.
The shortest distances between the symmetry-related NH expected, a change of the electronic structure of these units
groups, shown in Figure 3, are compatible with the insertion of upon complexation; these peaks were used for the calculation of
either glutarate or succinate. In fact, the calculated dimensions the association constants, by using a 1:1 model equation (see
of the two carboxylates are 5.3 Å for succinate and 6.5 Å for Experimental).
glutarate, considering their fully extended conformation. These
data rationalize the preference shown in the case of macrocycle Alternative binding models (i.e., stoichiometries) produced
12 for succinate; in detail, they suggest that the binding mode much poorer and hence unacceptable fitting of the titration data.
involves two NH groups linked to the same binaphthyl unit, In the case of (R,R)-12, we examined dicarboxylate anions such
rather than a complexation mode in which the bidentate guests as glutarate and succinate, in order to have a direct point of
are extended across the cavities of the macrocycles. These find- comparison with (R,R)-1 (Table 2).
ings also explain why, in the presence of bulkier acetoxy groups
on the binaphthyl units, this recognition mechanism in 10 and
Table 2: Binding constants (M−1) for the 1:1 complexes between
11 is suppressed and alternative mechanisms take place (see
(R,R)-12 or (R,R)-1 and dicarboxylate anions in CDCl3.a
below).
Entry
Macrocycle
Succinate
Glutarate
Complexation studies
1
(R,R)-12
(R,R)-1
34 ± 3
n. d.
21 ± 13
30 ± 12
1H NMR titration experiments showed that the addition of
anionic guests, in the form of their tetrabutylammonium salts,
produced progressive chemical-shift variations, along with a
broadening of the peaks belonging to the amide NH protons,
indicating that these groups were engaged in hydrogen bonding
with the carboxylate guests with a fast-exchanging equilibrium
2b
aMeasured by 1H NMR (500 MHz, 298 K, CDCl3) using tetrabutyl-
ammonium salts. bData taken from Ref. [31]; n. d. = not determined.
on the NMR time scale. Complexation-induced shifts on other Succinate was found to bind better than glutarate to macrocycle
resonances of the binaphthyl residues (Figure 4) indicated, as (R,R)-12, probably as its length is more suited than glutarate to
Figure 4: Aromatic region of the 1H NMR (CDCl3, 500 MHz, 25 °C) spectra of macrocycle (R,R)-12 (2.8 mM, bottom) and at the end of the titration
with tetrabutylammonium succinate ([(R)-7] = 2.8 mM, [(CH2CO2)2(Bu4N)2] = 28 mM, top). Asterisks indicate the residual solvent peaks.
972

Beilstein J. Org. Chem. 2012, 8, 967–976.
fit into the cavity of 12 by interacting simultaneously with two 1H and 13C NMR spectra were recorded from solutions in
different NH groups placed on the same binaphthyl residue (see CDCl3 on a 200, 300 or 500 MHz spectrometer with the solvent
above, molecular modeling), possibly in a cooperative fashion residual proton signal or tetramethylsilane as the standard. The
[39].
UV–vis spectroscopic studies were recorded by using commer-
cially available spectrophotometers. Mass spectra were
Similar titrations were carried out on (R,R)-10 and (R,R)-11, recorded by using an electrospray ionization instrument. Optical
bearing acetoxy substituents in the 2,2' positions of the binaph- rotations were measured on a polarimeter with a sodium lamp
thyl skeletons, which are certainly bulkier than the methoxy (λ = 589 nm) and are reported as follows: [α]Drt (c = g (100 mL
substituents present in (R,R)-12. A very different behavior was solution)−1). CD spectroscopy was performed by using a spec-
observed for both macrocycles: The 1H NMR spectra in CDCl3, tropolarimeter; spectra were recorded at 25 °C at a scanning
upon addition of both anionic guests, became very complex, speed of 50 nm min−1 and were background corrected.
with a complete loss of the initial symmetry. From the prelimi-
nary data in our hands, it is clear that there is a slow-exchanging Compound 5a [35]. SOCl2 (1.1 mL) was added to a solution of
equilibrium on the NMR time scale: the bulkier acetoxy group compound (RS)-2 (250 mg, 0.67 mmol, 1 equiv) in dry CHCl3
presumably inhibits a binding mechanism based on a fast (10 mL) and the solution was heated under reflux overnight.
host–guest exchange. A slow encapsulation mechanism, with Then, the solution was concentrated in vacuo and the crude
multiple modes of binding of the difunctional anionic guests product was added to a solution of benzylamine cooled to 0 °C
within the macrocycle, or the formation of aggregates of several (430 mg, 4.00 mmol, 6 equiv) in dry CH2Cl2 (10 mL). After
macrocyclic units, held by the bifunctional anionic guests being stirred overnight at rt, the reaction mixture was quenched
binding to a single amide of each macrocycle, cannot be ruled with 1 M HCl (30 mL), extracted with CH2Cl2 (3 × 25 mL), and
out at the present stage. Further studies are in progress to dried (Na2SO4). The solution was filtered and concentrated in
unravel the behavior of these acetoxy-bearing macrocycles. vacuo to yield pure 5a (340 mg, 93%). 1H NMR (CDCl3,
300 MHz, 25 °C) δ 12.44 (s, 2H, OH), 9.88 (s, 2H, NH), 8.74
Conclusion
(s, 2H, binaphthyl), 7.91 (d, 2H, binaphthyl), 7.37 (m, 14H,
We have reported the synthesis and characterization of three phenyl + binaphthyl), 6.98 (d, 2H, binaphthyl), 4.60 (d, CH2).
novel homochiral macrocycles, built upon resolved 1,1'-binaph- Alternative method: A solution of CDI (162 mg, 2.01 mmol,
thyl scaffolds, which incorporate either methoxy or acetoxy 3 equiv) in THF (12 mL) was added to a solution of (R)-2
functionalities in the 2,2' positions, and carboxylic functionali- (250 mg, 0.668 mmol, 1 equiv) in THF (20 mL). The solution
ties in the external 3,3' positions. After evaluation of the was stirred for 1.5 h at rt, and then a solution of benzylamine
synthetic strategy through test reactions on model compounds, (0.146 mL, 1.34 mmol, 2 equiv) in THF (12 mL) was added and
the macrocycles were obtained through one-pot amidation the mixture was stirred for 15 h. The reaction mixture was
reactions by using two different rigid diarylamines and high- concentrated in vacuo, and the crude product was purified by
dilution conditions, although in low isolated yields (0–5%). column chromatography (hexane/AcOEt 9:1) to yield 5a
The macrocycle bearing less sterically demanding methoxy (44 mg, 12%).
substituents is an effective supramolecular receptor for dicar-
boxylate anions, with a preference for glutarate (Ka = 34 M−1 Compound 6b. (COCl)2 (0.137 mL, 1.57 mmol, 8 equiv) and
for the 1:1 complex in CDCl3), as measured by 1H NMR spec- one drop of DMF were added to a solution of compound (R)-3
troscopy. With the acetoxy groups installed within the macro- (90 mg, 0.196 mmol, 1 equiv) and dry CH2Cl2 (10 mL). The
cyclic framework, a drastic change of binding mode occurs, solution was heated under reflux for 2 h. After 1 h at rt the solu-
with slow aggregation equilibria on the NMR time scale.
tion was concentrated in vacuo, the crude product was dissolved
in dry CH2Cl2 (5 mL), and a solution of 4b (0.045 mL,
0.49 mmol, 2.5 equiv) and Et3N (0.082 mL, 0.59 mmol,
Experimental
General. All commercially available compounds were 3 equiv) in dry CH2Cl2 (5 mL) was added. The resulting solu-
purchased from commercial sources and used as received. tion was heated under reflux for 2 h. After cooling, the reaction
Racemic or (R)-2 [40,41], racemic or (R)-3 [42], 4c [43], 4d mixture was quenched with brine (20 mL), extracted with
[44] and (R)-7 [45] were prepared according to literature pro- CH2Cl2 (3 × 25 mL), and dried (Na2SO4). The crude product
cedures. THF (Na), CH2Cl2 (CaH2) and CHCl3 (4 Å molecular was purified by column chromatography (hexane/AcOEt 8:2 to
sieves) were dried before use. Analytical thin-layer chromatog- 7:3) to yield 6b (44 mg, 37%). 1H NMR (CDCl3, 300 MHz,
raphy was performed on silica gel, chromophore-loaded, 25 °C) δ 8.47 (s, 2H, binaphthyl), 8.10 (s, 2H, binaphthyl), 8.03
commercially available plates. Flash chromatography was (m, 2H, phenyl), 7.60 (m, 6H, binaphthyl + phenyl), 7.37 (m,
carried out by using silica gel (pore size 60 Å, 230–400 mesh). 4H, binaphthyl), 7.22 (m, 4H, phenyl), 1.83 (s, 6H, –COCH3).
973

Beilstein J. Org. Chem. 2012, 8, 967–976.
Compound 5b. K2CO3 (91 mg, 0.66 mmol, 8 equiv) and H2O (O-CqOCH3), 163.5 (O-CqON), 154.6 (Cq), 143.1 (Cq), 133.8
(10 mL) were added to a solution of compound 6b (44 mg, (Cq), 133.3 (CH), 131.2 (Cq) 131.0 (Cq), 129.0 (CH), 128.7
0.082 mmol, 1 equiv) and CH3OH (10 mL). Then, the solution (2CH), 128.0 (Cq), 127.0 (CH), 126.4 (CH), 125.1 (Cq), 121.1
was stirred for 4 h at rt. The reaction mixture was quenched (CH), 119.7 (2CH), 20.4 (COCH3); ESIMS m/z: 1267.5
with 1 M HCl, extracted with CH2Cl2 and dried (Na2SO4). The ([M + Na]+, 100%).
solution was filtered and concentrated in vacuo and the crude
product was purified by column chromatography (hexane/ Macrocycle (R,R)-11. The title compound was prepared by
AcOEt 7:3) to yield 5b (25 mg, 68%). 1H NMR (CDCl3, following the same procedure used for 10 but with diamine 9
300 MHz, 25 °C) δ 10.31 (brs, 2H, OH), 8.85 (s, 2H, binaph- used instead of 8. The crude product was purified by column
thyl), 7.97 (m, 2H, binaphthyl), 7.82 (m, 4H, phenyl), 7.40 (m, chromatography (CH2Cl2/AcOEt 98:2) to yield (R,R)-11
8H, binaphthyl + phenyl), 7.17 (m, 4H, binaphthyl). The data (18 mg, 4%). [α]D25 +56° (c 0.0015, CH2Cl2); 1H NMR
are consistent with those reported in the literature [46].
(CDCl3, 75 MHz, 25 °C) δ 8.58 (s, 4H, binaphthyl), 8.25 (s, 4H,
phenyl), 8.07 (d, 4H, phenyl), 7.40 (m, 24H, binaphthyl + phe-
Compound 6d. (COCl)2 (0.28 mL, 3.21 mmol, 8 equiv) and nyl), 1.83 (s, 12H, COCH3); 13C NMR (CDCl3, 75 MHz,
one drop of DMF were added to a solution of compound 3 25 °C) δ 168.9 (O-CqOCH3), 163.8 (O-CqON), 143.0 (Cq),
(184 mg, 0.402 mmol, 1 equiv) and dry CH2Cl2 (15 mL). Then, 138.1 (Cq), 133.9 (Cq), 131.3 (CH), 131.1 (2CH), 130.9 (Cq),
the solution was heated at reflux for 2 h. After 1 h at rt the solu- 129.6 (Cq), 129.0 (CH), 128.9 (CH), 127.9 (Cq), 127.1 (CH),
tion was concentrated in vacuo and the crude product was 126.3 (CH), 125.1 (Cq), 119.2 (2CH), 20.4 (CH3); ESIMS m/z:
dissolved in dry CH2Cl2 (10 mL). This solution and a solution 1535.1 ([M + Na]+, 100%).
of 4d (300 mg, 1 mmol, 2.5 equiv) in dry CH2Cl2 (10 mL) were
added dropwise at the same rate over a period of 1 h to a solu- Macrocycle (R,R)-12. The title compound was prepared by
tion of Et3N (0.279 mL, 2 mmol, 5 equiv) in dry CH2Cl2 following the same procedure used for 10 but with (R)-7 used
(10 mL). The resulting solution was heated under reflux for 2 h. instead of (R)-3. The crude product was purified by column
After cooling, the reaction mixture was quenched with brine chromatography (CH2Cl2/AcOEt 99:1) to yield (R,R)-12 (6 mg,
(20 mL), extracted with CH2Cl2 (3 × 25 mL) and dried 5%). [α]25D +170° (c 0.0015, CH2Cl2); 1H NMR (CDCl3,
(Na2SO4). The crude product was purified by column chroma- 300 MHz, 25 °C) δ 10.44 (s, 4H, NH), 9.07 (s, 4H, binaphthyl),
tography (CH2Cl2/AcOEt 10:0 to 9:1) to yield 6d (61 mg, 8.15 (d, 4H, binaphthyl), 7.78 (d, 8H, phenyl), 7.56 (t, 4H,
15%). 1H NMR (CDCl3, 300 MHz, 25 °C) δ 8.46 (s, 2H, binaphthyl), 7.45 (t, 4H, binaphthyl), 7.27 (d, 4H, binaphthyl),
binaphthyl), 8.04 (s, 4H, binaphthyl), 7.56 (d, 6H, binaphthyl + 7.02 (d, 4H, phenyl), 3.33 (s, 12H, O-CH3); 13C NMR (CDCl3,
phenyl), 7.35 (m, 6H, binaphthyl + phenyl), 6.97 (d, 8H, phe- 75 MHz, 25 °C) δ 162.3 (O-CqON), 154.0 (Cq), 153.5 (Cq),
nyl), 1.84 (s, 6H, -COCH3), 1.53 (s, 18H, t-Bu).
135.2 (Cq), 134.5 (CH), 133.9 (Cq), 130.4 (Cq), 129.9 (CH),
129.0 (CH), 126.0 (CH), 125.3 (CH+Cq), 124.9 (Cq), 121.0
Macrocycle (R,R)-10. (COCl)2 (0.381 mL, 4.38 mmol, 8 equiv) (2CH), 119.3 (2CH), 62.0 (OCH3); ESIMS m/z: 1155.4
and one drop of DMF were added to a solution of compound ([M + Na]+, 10%).
(R)-3 (250 mg, 0.546 mmol, 1 equiv) in dry CH2Cl2 (20 mL).
The solution was heated under reflux for 2 h. After 1 h at rt the 1H NMR complexation experiments. All spectra were
solvent was removed in vacuo and the crude product was recorded at 500 MHz and at 298 K. Ka values for the complexa-
dissolved in dry CH2Cl2 (35 mL). This solution and a solution tion of (R,R)-12 with (n-Bu4N+)2X2− (X2− = −O2C(CH2)2CO2−,
of 8 (109 mg, 0.546 mmol, 1 equiv) in dry CH2Cl2 (35 mL) −O2C(CH2)3CO2−) were assessed by nonlinear treatment of the
were added dropwise at the same rate over a period of 1 h to a data obtained from 1H NMR titration experiments. Samples
solution of Et3N (0.228 mL, 1.64 mmol, 3 equiv) in dry CH2Cl2 were prepared by adding to a 0.5 mL solution of the host (5 mM
(35 mL). The resulting solution was heated under reflux in CDCl3) successive aliquots of a stock solution of the guest
overnight. After cooling, the reaction mixture was quenched (62.5 mM in CDCl3), up to a final volume of 0.9 mL. Eight
with brine (50 mL), extracted with CH2Cl2 (3 × 50 mL) and values of δobs for the H-4 resonances were collected by keeping
dried (Na2SO4). The solution was filtered and concentrated in the [host] to [guest] ratio in the (1:0.25)–(1:10) interval.
vacuo, and the crude product was purified by column chroma- Nonlinear regression analysis of δobs versus [guest], using the
tography (CH2Cl2/AcOEt 9:1) to yield (R,R)-10 (7 mg, 4%). WinEQNMR for Windows software package [47], provided the
[α]D25 +101° (c 0.001, CH2Cl2); 1H NMR (CDCl3, 75 MHz, Ka value.
25 °C) δ 8.58 (s, 4H, binaphthyl), 8.05 (m, 8H, phenyl), 7.50
(m, 16H, binaphthyl + phenyl), 6.97 (d, 8H, binaphthyl), 1.82 Molecular modeling. Geometry optimizations for the struc-
(s, 12H, -COCH3); 13C NMR (CDCl3, 75 MHz, 25 °C) δ 168.7 tures presented were carried out, first by using the semiempir-
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Beilstein J. Org. Chem. 2012, 8, 967–976.
13.Gong, B. Acc. Chem. Res. 2008, 41, 1376–1386.
ical PM3 method, and then refined at the B3LYP/6-31G(d)
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computer facility by using the Gaussian 09, Revision C.01
package [49].
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Supporting Information
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Supporting Information File 1
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Additional NMR and MS spectra for the macrocyles, and
Cartesian coordinates for the calculated geometries
discussed in the paper.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-8-109-S1.pdf]
23.Ma, L.; Mihalcik, D. J.; Lin, W. J. Am. Chem. Soc. 2009, 131,
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Acknowledgements
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Support from the University of Pavia, University of Messina,
MIUR (Programs of National Relevant Interest PRIN grants
2004-033354 and 2009-A5Y3N9), the CINECA Supercom-
puter Center, with computer time granted by the ISCRA
NANOCHIR project (HP10CKIGGH), and, in part, from
CARIPLO Foundation (2007–2009) and INSTM-Regione
Lombardia (2010–2012), is gratefully acknowledged.
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