Selective amine recognition driven by host-guest proton transfer and salt bridge formation

Article abstract of DOI:10.1021/jo301730m

The stepwise synthesis of ionizable p-tert-butylcalix[5]arenes 1a·H and 1b·H, featuring a fixed cone cavity endowed with a carboxyl moiety at the narrow rim, is described. Single-crystal X-ray analyses have shown that in the solid state 1a·H and 1b·H adopt a cone-out conformation with the carboxylic OH group pointing in, toward the bottom of the aromatic cavity, as a result of a three- or two-center hydrogen-bonding pattern between the carboxyl group and the phenolic oxygen atom(s). The affinity of amines for calix[5]arene derivatives 1a·H and 1b·H was probed by ¹H NMR spectroscopy and single-crystal X-ray diffraction studies. These carboxylcalix[5]arenes are shown to selectively recognize linear primary amines - over branched, secondary, and tertiary amines - by a two-step process involving a proton transfer from the carboxyl to the amino group to provide the corresponding alkylammonium ion, followed by binding of the latter inside the cavity of the ionized calixarene. Proton transfer occurs only with linear primary amines, that is, when the best size and shape fit between host and substrate is achieved, while the other amines remain in their noncompeting unprotonated form. The role of the solvent in the ionization/complexation process is discussed. Structural studies on the n-BuNH₂ complexes with 1a·H and 1b·H provide evidence that binding of the in situ formed n-BuNH₃⁺ substrate to the cavity of the ionized macrocycle is ultimately secured, in the case of 1a·H, by the formation of an unprecedented salt-bridge interaction.

Full text of DOI:10.1021/jo301730m

Article
pubs.acs.org/joc
Selective Amine Recognition Driven by Host−Guest Proton Transfer
and Salt Bridge Formation
Calogero Capici,†,∥ Giuseppe Gattuso,† Anna Notti,† Melchiorre F. Parisi,*,† Sebastiano Pappalardo,*,‡
Giovanna Brancatelli,§ and Silvano Geremia*,§
†Dipartimento di Scienze Chimiche, Universita
̀
̀
di Messina, viale F. Stagno d’Alcontres 31, 98166 Messina, Italy
‡Dipartimento di Scienze Chimiche, Universita
di Catania, viale A. Doria 6, 95125 Catania, Italy
§Centro di Eccellenza in Biocristallografia, Dipartimento di Scienze Chimiche e Farmaceutiche, Universita
1, 34127 Trieste, Italy
̀
di Trieste, via L. Giorgieri
S
* Supporting Information
ABSTRACT: The stepwise synthesis of ionizable p-tert-
butylcalix[5]arenes 1a·H and 1b·H, featuring a fixed cone
cavity endowed with a carboxyl moiety at the narrow rim, is
described. Single-crystal X-ray analyses have shown that in the
solid state 1a·H and 1b·H adopt a cone-out conformation with
the carboxylic OH group pointing in, toward the bottom of the
aromatic cavity, as a result of a three- or two-center hydrogen-
bonding pattern between the carboxyl group and the phenolic
oxygen atom(s). The affinity of amines for calix[5]arene
derivatives 1a·H and 1b·H was probed by 1H NMR
spectroscopy and single-crystal X-ray diffraction studies.
These carboxylcalix[5]arenes are shown to selectively
recognize linear primary aminesover branched, secondary, and tertiary aminesby a two-step process involving a proton
transfer from the carboxyl to the amino group to provide the corresponding alkylammonium ion, followed by binding of the
latter inside the cavity of the ionized calixarene. Proton transfer occurs only with linear primary amines, that is, when the best size
and shape fit between host and substrate is achieved, while the other amines remain in their noncompeting unprotonated form.
The role of the solvent in the ionization/complexation process is discussed. Structural studies on the n-BuNH2 complexes with
1a·H and 1b·H provide evidence that binding of the in situ formed n-BuNH3+ substrate to the cavity of the ionized macrocycle is
ultimately secured, in the case of 1a·H, by the formation of an unprecedented salt-bridge interaction.
on the use of “ionizable” macrocycles (e.g., crown ethers,
azacrown ethers, calix[4]arenes).6 This approach was originally
suggested by Bartsch and co-workers7 to improve liquid−liquid
extraction of alkali-metal cations from the aqueous to the
organic phase by an ion-exchange mechanism and then widely
used to target other metal ions.8 Rather surprisingly, however,
the potential of ionizable macrocycles, other than crown
ethers,9,10 to simultaneously behave as host molecules and as
counterions of protonated amino-containing organic analytes
has scarcely been investigated.11
INTRODUCTION
■
Ion-pair association is one of the main obstacles a neutral
receptor has to overcome to efficiently bind charged substrates.
This phenomenon is particularly pronounced in low-polarity
organic solvents, where both receptor and counterion compete
for the same ionic species. As a result of this competition, which
contributes to the overall complexation equilibrium, the
apparent host−guest association constant is often substantially
lower than expected.1
Over the years, several strategies have been devised to bypass
this problem. Earlier approaches relied on the use of weakly
coordinating counterions to minimize the effect of ion pairing
and hence provide more “naked” ionic species readily available
for complexation.2,3 More recently, receptors for ion-pair
recognition based on multisite hetero(poly)topic molecules
capable of binding the entire salt speciesas either separated
or contact ion pairshave been developed.4 In parallel, the so-
called “dual host” strategy, reliant on the simultaneous and
synergic action of two independent receptors with opposite
affinities, has also been successfully pursued.5 A conceptually
different way of circumventing the effects of ion pairing relies
RESULTS AND DISCUSSION
■
Inspired by the clever extraction strategy outlined above as well
as by nature, which makes ample use of salt bridges and other
close-range electrostatic interactions,12 it was decided to
develop a new family of receptors for primary amines13
based on carboxylcalix[5]arenes14in consideration of the
known affinity of these macrocycles for linear alkylammo-
Received: August 18, 2012
Published: October 8, 2012
© 2012 American Chemical Society
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nium15 and alkanediyldiammonium16 ions.17,18 These ionizable
calixarenes were expected to selectively form “internal” (endo
cavity) ion-pair complexes with appropriately sized and shaped
amines as a result of the spontaneous transfer of a proton from
the host to the guest (vide infra). To this end, calix[5]arenes
1a·H and 1b·H (Scheme 1)bearing a carboxyl group at their
rim, points toward the bottom of the calixarene cavity, bringing
the carbonyl oxygen atom within hydrogen-bond distance of
the included alkylammonium guest. “Removal” of that tert-butyl
group (i.e., conversion of the ester moiety into a carboxyl one)
was then conceived as a convenient way to generate a smart
receptor capable, in principle, of undergoing an acid−base
reaction with an amine substrate and then firmly holding the
resultant alkylammonium cation inside its cavity, by taking
advantage of the additional stabilization provided by electro-
static ion-pairing interactions.
a
Scheme 1. Synthesis of Calix[5]arenes 1a·H and 1b·H
Carboxylcalix[5]arenes 1a·H and 1b·H were synthesized
from penta-tert-butyl-tetrakis(4-methylpentyloxy)calix[5]-
arene22 (2) and penta-tert-butyl(benzyloxy)calix[5]arene23
(4), respectively, as depicted in Scheme 1. Accordingly,
alkylation of tetraether 2 with tert-butyl bromoacetate, in the
presence of K2CO3 as a base, provided the monoester derivative
3 (92% yield). Removal of the tert-butyl group by TFA
treatment yielded 1a·H (66%). Calix[5]arene 1b·H, on the
other hand, was synthesized in four steps starting from
monoether 4, which was exhaustively alkylated with tert-butyl
bromoacetate in the presence of K2CO3 to afford tetraester 5 in
81% yield. Catalytic hydrogenolysis (Pd/C) of the benzyl
protecting group provided hydroxycalix[5]arene 6 (89%),
which was alkylated with benzyl bromoacetate/K2CO3 to
yield the mixed pentaester 7 (80%). Finally, debenzylation with
H2 and Pd/C provided the acid derivative 1b·H in 94% yield.
The two monoacid derivatives were characterized by NMR
spectroscopy and single-crystal XRD analysis. Both molecules
1
display H NMR spectra consistent with a Cs-symmetric cone-
out conformation.15a,24 This nonregular cone conformation23 is
substantiated by downfield resonances for the hydrogen atoms
of the tert-butylphenoxy ring bearing the carboxyl moiety
(relative to those of the remaining aryl units) which, together
with the presence of a carboxyl hydrogen peak (δ 10.2 and 10.1
ppm for 1a·H and 1b·H, respectively), suggest the likely
presence of an intramolecular hydrogen bonding between the
carboxyl group and the phenolic oxygen atoms of 1a·H and
1b·H (vide infra).
a
Legend: (a) BrCH2CO2C(CH3)3, K2CO3, CH3CN, reflux, 24 h; (b)
TFA, CHCl3, room temperature, 4 h; (c) H2, Pd/C, AcOEt, room
temperature, 5-6 h; (d) BrCH2CO2Bn, K2CO3, CH3CN, reflux, 24 h.
Single-crystal X-ray analyses of 1a·H and 1b·H (from
CHCl3/CH3CN) fully support the structural assignments
carried out in solution (Figure 1, see also Figure S1 and
Table S1 in the Supporting Information). In the solid state both
derivatives adopt similar cone-out conformations,15a,24 wherein
three tert-butylphenoxy rings are leaning outward with respect
to the cavity of the macrocycle, whereas the remaining two
(namely, B and B′ for 1a·H and C and B′ for 1b·H) are nearly
perpendicular to the calixarene reference plane passing through
the five bridging methylene groups (see Table S2 in the
Supporting Information for the relevant dihedral angles). In
both cases, the calixarene aromatic cavity is filled by an
acetonitrile solvent molecule, held inside the macrocycle by a
number of CH−π interactions (Figure 1a and Table S3
(Supporting Information)). The four pendant groups at the
narrow rim take on an extended conformation, and the carboxyl
OH group points in, toward the bottom of the aromatic cavity.
Close comparison of the two structures reveals that ring A of
1a·H is more markedly tilted away from the axis of the cavity
than the corresponding ring of 1b·H (151.4(1) and 132.68(6)°
for 1a·H and 1b·H, respectively) (Figure S1 in the Supporting
Information). This conformational difference is associated with
a different H-bond pattern involving the carboxyl group (Figure
1b). While in 1a·H the carboxyl group forms a strong three-
center intramolecular hydrogen bond with the phenolic oxygen
narrow rimwere selected as synthetic targets, as they derive
from the two most efficient calix[5]arene-based linear
alkylammonium receptors known to date, namely penta-tert-
butylpentakis(4-methylpentyloxy)calix[5]arene15d (8) and
penta-tert-butylpentakis(tert-butoxycarbonylmethoxy)calix[5]-
arene19 (9).20
Key information for their design was gathered from earlier
DFT calculations21 and single-crystal XRD data15a on the
inclusion complexes of calix[5]arene pentaester 9 with n-
hexylammonium and n-butylammonium ions, respectively.
Specifically, these studies had revealed that one of the (tert-
butoxycarbonyl)methoxy substituents, present at the narrow
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The affinity of amines for calix[5]arenes 1a·H and 1b·H was
initially probed by adding an equimolar amount of n-
butylamine to a solution of each of them (1 mM in CDCl3/
CD3OD, 9/1). As expected, protonation of the target amine
occurred and inclusion of the latteras the corresponding
alkylammonium ioninside the calixarene cavity was revealed
25
1
by H NMR spectroscopy (Figure 2).
endo-Cavity inclusion of the n-butylammonium ion is
unambiguously demonstrated by the appearance, in the high-
field region of the spectra (−0.02 to −2.02 and −0.47 to −1.85
ppm for n-BuNH3 ⊂1a− and n-BuNH3 ⊂1b−, respectively), of
a set of resonances consistent with an n-butyl moiety positioned
inside a calix[5]arene cavity and experiencing the shielding
effect of the surrounding aryl rings (Figures 2b,d). In line with
several other cases of positively charged calix[5]arene/
alkylammonium complexes,15 association/dissociation of the
+
+
“overall neutral” n-BuNH3 ⊂1a− and n-BuNH3 ⊂1b− com-
plexes was found to be slow on the NMR time scale, giving rise
to distinct sets of resonances for both complexed and free
species present at equilibrium. As a result, direct integration of
the pertinent peaks provided the association constants for the
two complexes (Ka = (3.21 0.3) × 104 and (1.13 0.1) ×
104 M−1, corresponding to ca. 84 and 74% complexation for n-
+
+
Figure 1. Crystallographic structures of calix[5]arenes 1a·H and 1b·H:
(a) side views showing the presence of an acetonitrile solvent molecule
filling the cavity; (b) top views displaying the presence of
intramolecular H bond(s) between the carboxyl group and the
phenolic oxygen atom(s) (the acetonitrile molecule has been omitted
for clarity).
+
+
BuNH3 ⊂1a− and n-BuNH3 ⊂1b−, respectively). The higher
affinity of n-BuNH2 for 1a·H with respect to 1b·H was also
confirmed by an independent competition experiment (carried
out on a 1/1/1 mixture of the amine and the two host
molecules) that revealed the preferential formation of n-
atoms linked to rings B and C (O···O distances 2.625(9) and
2.874(9) Å), in the case of 1b·H a weaker two-center hydrogen
bond, between the corresponding carboxyl group and the
phenolic oxygen of ring B (O···O = 2.995(3) Å), is observed
(Figure 1b). The different H-bond strengths and consequently
the closer proximity of the oxymethylenecarboxyl moiety to the
bottom of the cavity and the wider outward inclination of ring
A, may reflect a superior H-bond acceptor ability of the
phenolic oxygen atoms present in 1a·H with respect to those of
1b·H (linked to 4-methylpentyl and tert-butoxycarbonylmethyl
pendant moieties, respectively). The distance of the hydroxyl
oxygen atom from the calixarene reference plane of −1.712(8)
and −2.614(2) Å for 1a·H and 1b·H, respectively, quantifies
the major conformational difference between the two macro-
cycles.
BuNH3 ⊂1a− over n-BuNH3 ⊂1b− (ca. 60 to 40%; see Figure
S6 in the Supporting Information).
+
+
Solvent was found to play a crucial role in the overall
ionization/complexation process. Accordingly, the degree of
complexation between n-BuNH2 and both receptors increases
significantly (52, 84, and >99% for 1a·H; 10, 74, and >99% for
1b·H) on going from neat CDCl3 to CDCl3/CD3OD (9/1)
and then to CDCl3/CF3CD2OD (9/1) (Figures S7 and S8 in
the Supporting Information). Most likely, the presence in
solution of a protic solvent enhances the acidity of the carboxyl
moiety of 1a·H and 1b·H. Specifically, CD3OD and
CF3CD2OD act as increasingly stronger H-bond donors toward
+
+
Figure 2. 1H NMR spectra (500 MHz, CDCl3/CD3OD 9/1 v/v, 25 °C, 1 mM): (a) 1a·H; (b) n-BuNH3 ⊂1a−; (c) 1b·H; (d) n-BuNH3 ⊂1b−. The
▽
symbols
and ∗ indicate the resonances of the α-CH2 group of the free guest and the residual solvent signals, respectively.
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the carboxyl group, thus facilitating the formation of
butylammonium ions. Moreover, the presence of polar protic
solvents, such as CD3OD and CF3CD2OD, favors the charge-
separation step and contributes at the same time to the
stabilization of the ion-pair complex, by efficiently solvating it
once it has formed (see X-ray studies below).
The host−guest complexes were characterized by X-ray
analysis of single crystals obtained in the presence of n-BuNH2
from trifluoroethanol (TFE) solutions of 1a·H and 1b·H,
respectively.26 Both crystal structures show the formation of a
supramolecular host−guest salt (that is, an “internal” ion-paired
+
host−guest complex) having a n-BuNH3 cation bound inside
the cavity of the ionized carboxylate-calixarene (Figure 3). The
Figure 4. Section of the electron density map (2Fo − Fc, contour level
1.4 σ, purple) and the residual electron density map (mFo − DFc,
+
contour level 3 σ, red) observed for the n-BuNH3 ⊂1a− complex,
showing the position of the hydrogen atoms involved in H bonds
(green dashed line).
range; see Figure 3 and Table S3 (Supporting Information)) as
well as the carboxylate moiety of the host (N···O distance
2.779(5) Å). Additional CH−π interactions29 are also observed
+
between the α- and β-CH2 groups of the n-BuNH3 ion and
rings B, B′, C, and C′ of the host (Table S3).15a,b,17a Three TFE
solvent molecules surround the carboxylate group and interact
with it via hydrogen bonds (Figure 3). In contrast with the n-
BuNH3 ⊂1a− structure, no salt bridge interaction is observed
+
in the crystallographic structure of the n-BuNH3 ⊂1b−
+
complex. In this case, the cationic guest is anchored inside
the cavity by H bonds with four phenolic oxygen atoms (N···O
distances in the 2.805(8)−2.949(8) Å range) and an additional
carbonyl oxygen from the ester moiety linked to ring B′ (N···O
distance 2.786(9) Å; see Figure 3 and Table S3). The
carboxylate group is pointing away from the cavity (N···O
distance 5.41 Å) and is solvated by three TFE molecules.
Unlike the case for previously reported calix[5]arene host
molecules (e.g., 8 and 9) that show no detectable affinity for
amines,20 the new generation of ionizable calix[5]arenes
selectively derivatized with a single carboxyl moiety at the
narrow rimtakes advantage of both molecular (acid−base)
and supramolecular (host−guest) interactions to optimize
matching with their specific substrates. Calixarenes 1a·H and
1b·H play an active role in the complexation process, by
generating their own substrate in situ. That is, amines are the
species present in solution, but alkylammonium ions are the
substrates that internally bind to the ionized macrocycle. In
practical terms, the stoichiometric proton transfer from the
built-in carboxyl group to the amine provides an ammonium
iondevoid of an “external”, and hence competitive, counter-
ionreadily available for ion pairing with the anionic host. The
effectiveness of this recognition/binding behavior is notably
confirmed by a control complexation experiment carried out,
under conditions identical with those used above, between
calixarenes 1·H and n-butylammonium picrate (Figure S9 in the
Supporting Information). When calixarenes 1a·H and 1b·H are
asked to act as nonionized receptors for a salt species, they
retain their affinity for butylammonium ions but, lacking the
additional stabilizing contribution provided by the electrostatic
interaction of ion pairing, only succeed in binding 60 and 52%
+
Figure 3. Crystallographic structures of the n-BuNH3 ⊂1a− and n-
+
BuNH3 ⊂1b− complexes: (a) side views showing the different
orientation of the carboxylate group in the two complexes and the
presence of a salt bridge interaction only in the case of n-
BuNH3+⊂1a−; (b) top views highlighting the presence of
intermolecular H bonds between host and guest. In both structures
the carboxylate moiety is surrounded by hydrogen-bonded TFE
solvent molecules. The carbon atoms of the guest and the solvent
molecules are depicted in magenta and blue, respectively.
proton transfer from the carboxyl moiety of 1a·H to the amino
group of n-BuNH2 with the formation of a salt bridge (similar
to those commonly found in proteins27 and in other
supramolecular systems28) is clearly confirmed by the residual
electron density maps reported in Figure 4. In comparison to
previously reported crystallographic structures of calix[5]arene/
n-BuNH3 ion complexes, in the case of n-BuNH3 ⊂1a− the
positively charged nitrogen atom is seen well below the
macrocycle reference plane (distances −0.938(1), −0.616(6),
+
+
0.133(3), and −0.13(5) [−0.55(2)] Å for n-BuNH3 ⊂1a−, n-
+
15b
15a
BuNH3 ⊂1b−, n-BuNH3 ⊂8,
and n-BuNH3 ⊂9, respec-
+
+
+
tively). These data emphasize the key role played by a salt-
bridged carboxylate/ammonium ion pair in the stabilization of
the endo-cavity complex n-BuNH3 ⊂1a−.
+
In n-BuNH3 ⊂1a−, the n-butylammonium ion is held in
place by a network of four intermolecular H-bond interactions
involving the NH3 group of the guest and three phenolic
oxygen atoms (N···O distances in the 2.868(4)−2.934(4) Å
+
of the available guest (apparent Ka = (3.82 0.2) × 103 and
+
+
(2.22
0.2) × 103 M−1 for n-BuNH3 ⊂1a·H and n-
+
BuNH3 ⊂1b·H, respectively).
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Figure 5. 1H NMR spectra (500 MHz, CDCl3/CD3OD 9/1 v/v, 25 °C): (a) [1a·H] = 1 mM; (b) [1a·H] = [n-Bu3N] = 1 mM; (c) [1a·H] = [n-
■ ◆
▽
Bu3N] = [n-Bu2NH] = 1 mM; (d) [1a·H] = [n-Bu3N] = [n-Bu2NH] = [n-BuNH2] = 1 mM. The symbols
the α-CH2 group of n-Bu3N, n-Bu2NH, and n-BuNH2 and the residual solvent signals, respectively.
,
,
, and ∗ indicate the resonances of
To investigate the binding selectivity of calixarene 1a·H,
different (tertiary, secondary, and primary) potential amine
substrates were progressively added to a solution (CDCl3/
potential well, promoting proton transfer exclusively when size
and shape complementarity between host and guest matches.
Given that the only acidic protons available to the pool of
amines tested derive from the carboxyl group of the calixarene,
the stoichiometric matching allows only the best-fitting
substrate to be protonated, leaving the other amine(s) in
their noncompeting, unprotonated form. The combination of
these findings indicates that the overall recognition/proto-
nation/binding process of n-BuNH2 by 1a·H is highly selective.
1
CD3OD, 9/1 v/v) of the receptor and H NMR spectra were
regularly taken after each addition (Figure 5). Titration of a 1
mM solution of 1a·H with 1 equiv of n-Bu3N did not result in
any guest endo-cavity inclusion and, surprisingly, produced no
evidence in favor of amine protonation (Figure 5b).30 Similarly,
subsequent addition of 1 equiv of the secondary amine n-
Bu2NH again resulted in no inclusion or protonation (Figure
5c).30 On the other hand, final addition to the solution of 1
equiv of n-BuNH2 induced proton transfer from the carboxyl
moiety of 1a·H to the primary amine, producing the expected
endo-cavity inclusion complex (Figure 5d).
CONCLUSION
■
In conclusion, calix[5]arene receptors have been equipped with
a carboxyl group at their narrow rim to allow selective
complexation of linear primary amines. This functionalization
converts a class of receptors specific only for cationic species
into new derivatives able to capture neutral molecules.
Carboxylcalix[5]arenes show remarkable binding properties,
being capable of recognizing linear primary amines and
selectively promoting them to alkylammonium ion guests by
means of a proton transfer mechanism that turns “dormant”
substrates into “active” ones. By this mechanism, the mere
presence of the calixarene cavity and the driving force provided
by the endo-cavity inclusion of a suitable guest directs
protonation only toward the best-fitting substrate(s). For-
mation of overall neutral ion-paired host−guest complexes is
secured by a number of hydrogen-bonding and CH−π
interactions as well asin the case of 1a·Han unprecedented
salt bridge, acting as an additional close-range electrostatic
interaction. We are currently investigating the possibility of
assembling molecular capsules from diamines and ionizable
(bis)calixarene receptors.
In a similar fashion, selectivity of 1a·H for n-BuNH2 vs
isomeric iso-, sec-, and tert-butylamine was tested by an
analogous NMR titration experiment (Figure S11 in the
Supporting Information). Branched amines such as s- and t-
BuNH2 were neither protonated30 nor included in the cavity of
1a·H, whereas addition of the less hindered i-BuNH2 led to the
formation of ca. 13% of the corresponding i-BuNH3 ⊂1a−
+
complex. However, when n-BuNH2 was added to the mixture, i-
BuNH3+ ions were extruded from the cavity of 1a− (as i-BuNH2
molecules) and the more stable n-BuNH3 ⊂1a− complex was
+
formed (ca. 80%).
Assuming that in a CDCl3/CD3OD solution the carboxylic
hydrogen atom of 1a·H is held within the cavity by an
intramolecular hydrogen bond network, similar to that
observed in the solid state (Figure 1b), the inability of its
carboxyl group to donate a proton to n-Bu2NH or n-Bu3N
suggests that proton transfer from the calixarene to the amine is
prevented by an unfavorable energy trade between hydrogen
bond breakage and simple “exo-cavity” salt formation. This
experiment demonstrates that, regardless of the basicity of the
amine used, proton transfer from 1a·H to the substrate only
occurs when formation of a salt bridge stabilizing the “internal”
EXPERIMENTAL SECTION
■
General Considerations. Melting points were determined on a
Kofler hot stage apparatus and are uncorrected. Unless otherwise
stated, 1H and 13C NMR spectra were recorded at 25 °C in CDCl3, at
500 and 125 MHz, respectively. Chemical shifts are reported in ppm
and are referenced to the residual solvent (δH 7.26 ppm and δC 77.0
ion-pair complex is allowed (i.e. n-BuNH3 ⊂1a−). According to
+
these data, the formation of a salt-bridged complex acts as a
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1
ppm). Where present, H NMR peak assignments follow from COSY
1.14 (3 × s, 2:1:2 ratio, 45H), 1.38, 1.47 (2 × s, 1:1, 36H), 3.21, 3.33,
3.41 (3 × d, J = 14.2, 14.2, and 15.6 Hz, 2:2:1 ratio, 5H), 4.20 and 4.49
(AB system, J = 15.6 Hz, 4H), 4.33 and 4.44 (AB system, J = 15.7 Hz,
4H), 4.34 (s, 2H), 4.71, 4.74, 4.89 (3 × d, J = 14.2, 14.2, and 15.7 Hz,
2:2:1 ratio, 5H), 6.51 and 6.67 (AB system, J = 2.4 Hz, 4H), 6.98 and
7.12 (AB system, J = 2.4 Hz, 4H), 7.07 (s, 2 H), 7.21 (t, J = 7.3 Hz,
1H), 7.34 (t, J = 7.3 Hz, 2H), 7.49 (d, J = 7.3 Hz, 2H) ppm; 13C NMR
δ 28.0, 28.2, 29.4, 31.2, 31.4, 31.5, 33.8, 34.00, 34.03, 70.7, 71.8, 75.2,
80.9, 81.0, 125.49, 125.52, 125.54, 125.7, 126.2, 126.6, 127.6, 128.5,
133.2, 133.26, 133.32, 133.5, 134.0, 139.5, 145.1, 145.2, 145.3, 152.0,
152.2, 152.6, 168.8, 169.2 ppm; ESI-MS m/z 1380.3 [M + Na]+,
1396.8 [M + K]+. Anal. Calcd for C86H116O13: C, 76.07; H, 8.61.
Found: C, 76.01; H, 8.58.
experiments. 13C NMR spectra were acquired with the attached proton
test (APT) technique. Mass spectra were measured on an ion trap
electrospray instrument. Anhydrous solvents were either obtained
commercially or dried by standard methods prior to use, while other
chemicals were reagent grade, used without further purification.
Column chromatography was performed on silica gel (Merck, 230−
400 mesh). All reactions were carried out under an argon atmosphere.
5,11,17,23,29-Pentakis(1,1-dimethylethyl)-35-hydroxy-31,32,33,34-
tetrakis(4-methylpentyloxy)calix[5]arene22 (2), and 5,11,17,23,29-
pentakis(1,1-dimethylethyl)-31-benzyloxy-32,33,34,35-tetrakis-
(hydroxy)calix[5]arene23 (4) were synthesized according to published
procedures.
Synthetic Procedures. 5,11,17,23,29-Pentakis(1,1-dimethyleth-
yl)-31-tert-butoxycarbonylmethoxy-32,33,34,35-tetrakis(4-
methylpentyloxy)calix[5]arene (3). A stirred mixture of calix[5]arene
2 (350 mg, 0.305 mmol), tert-butyl bromoacetate (178 mg, 0.915
mmol), and K2CO3 (126 mg, 0.915 mmol) in CH3CN (50 mL) was
heated to reflux for 24 h. After evaporation of the solvent, the solid
residue was partitioned between CHCl3 (50 mL) and aqueous 0.1 M
HCl (30 mL). The organic layer was washed with water (2 × 30 mL),
dried over MgSO4, and concentrated under reduced pressure to yield,
after recrystallization from MeOH/CH2Cl2, ester 3 (354 mg, 92%) as
5,11,17,23,29-Pentakis(1,1-dimethylethyl)-31,32,33,34-tetrakis-
(tert-butoxycarbonylmethoxy)-35-hydroxycalix[5]arene (6). A sus-
pension of 5 (231 mg, 0.170 mmol) and 5% Pd/C (40 mg) in AcOEt
(50 mL) was stirred at room temperature in the presence of H2 for 5
h. The mixture was filtered through Celite, and the filtrate was
concentrated to dryness under reduced pressure to give 6 as a colorless
solid (192 mg, 89%): mp 192−194 °C; 1H NMR δ 0.65, 1.23, 1.29 (3
× s, 2:2:1 ratio, 45H), 1.50, 1.53 (2 × s, 1:1 ratio, 36H), 3.22, 3.34,
3.42 (3 × d, J = 14.0, 14.2, and 14.5 Hz, 1:2:2 ratio, 5H), 4.13 and 4.49
(AX, J = 15.6, Hz, 4H), 4.32 and 4.74 (AX, J = 15.5 Hz, 4H), 4.61,
4.71, 4.92 (3 × d, J = 14.2, 14.5, and 14.0 Hz, 2:2:1 ratio, 5H), 6.40
and 6.60 (AB system, J = 2.0 Hz, 4H), 6.47 (s, 1H), 7.10 (s, 2H), 7.14
and 7.22 (AB system, J = 2.5 Hz, 4H) ppm; 13C NMR δ 28.2, 28.3,
29.1, 30.0, 31.4, 30.9, 31.5, 31.7, 33.7, 33.9, 34.1, 71.4, 72.2, 81.3, 81.6,
124.6, 124.8, 125.9, 126.0, 126.1, 126.5, 132.3, 132.7, 133.9, 134.1,
141.8, 145.5, 146.0, 150.6, 152.0, 152.1, 168.7, 169.7 ppm; ESI-MS m/
z 1290.3 [M + Na]+, 1306.1 [M + K]+. Anal. Calcd for C79H110O13: C,
74.85; H, 8.75. Found: C, 75.04; H, 8.84.
5,11,17,23,29-Pentakis(1,1-dimethylethyl)-31-benzyloxycarbonyl-
methoxy-32,33,34,35-tetrakis(tert-butoxycarbonylmethoxy)calix-
[5]arene (7). A stirred mixture of 6 (183 mg, 0.144 mmol), benzyl
bromoacetate (68 μL, 0.432 mmol), and K2CO3 (60 mg, 0.432 mmol)
in CH3CN (30 mL) was heated at reflux for 24 h. The mixture was
cooled, and the inorganic salts were filtered, washed with CHCl3, and
disposed. The combined organic layers were concentrated under
reduced pressure, and the residue that was left gave a powdery
precipitate after addition of CH3OH. Crystallization of this solid from
MeOH/CHCl3 afforded mixed pentaester 7 in 80% yield (163 mg):
mp 196−199 °C; 1H NMR δ 0.94, 1.03, 1.09 (3 × s, 2:2:1 ratio, 45H),
1.41, 1.44 (2 × s, 1:1 ratio, 36H), 3.29, 3.35, 3.38 (3 × d, J = 14.5, 14.5,
and 14.7 Hz, 2:2:1 ratio, 5H), 4.47 and 4.53 (AB system, J = 15.6 Hz,
4H), 4.58 (s, 4H), 4.65 (s, 2H), 4.74, 4.80, 4.82 (3 × d, J = 14.5, 15.0,
and 14.3 Hz, 2:1:2 ratio, 5H), 5.22 (s, 2H), 6.73 and 6.79 (AB system,
J = 2.5 Hz, 4H), 6.87 and 6.92 (AB system, J = 2.5 Hz, 4H) 6.97 (s,
2H), 7.27−7.41(m, 5H) ppm; 13C NMR δ 28.09, 28.12, 30.2, 31.2,
31.28, 31.33, 31.4, 33.8, 33.9, 34.0, 66.1, 70.4, 71.27, 72.33, 80.96,
80.98, 125.56, 125.64, 125.7, 125.9, 126.0, 128.0, 128.3, 128.4, 133.1,
133.2, 133.3, 133.4, 133.7, 136.0, 145.35, 145.36, 145.44, 151.8, 151.9,
152.3, 169.0, 169.2, 170.0 ppm; ESI-MS m/z 1438.5 [M + Na]+. Anal.
Calcd for C88H118O15: C, 74.65; H, 8.40. Found: C, 74.31; H, 8.56.
5,11,17,23,29-Pentakis(1,1-dimethylethyl)-31-carboxymethoxy-
32,33,34,35-tetrakis(tert-butoxycarbonylmethoxy)calix[5]arene
(1b·H). A solution of 7 (150 mg, 0.106 mmol) and 5% Pd/C (28 mg)
in AcOEt (20 mL) was stirred at room temperature in the presence of
H2 for 6 h. The suspension was filtered through Celite, and the filtrate
was evaporated under reduced pressure to give calixarene 1b·H as a
colorless crystalline solid (132 mg, 94%): mp 125−128 °C; 1H NMR δ
0.77, 1.14, 1.25 (3 × s, 2:2:1 ratio, C(CH3)3, 45H), 1.45, 1.50 (2 × s,
1:1 ratio, OC(CH3)3, 36H), 3.26, 3.37, 3.46 (3 × d, J = 13.8, 14.3, and
15.9 Hz, 2:2:1 ratio, ArCH2Ar, 5H), 4.09 (s, OCH2CO2H, 2H), 4.29
and 4.82 (AX, J = 16.1 Hz, OCH2CO2tBu, 4H), 4.44 and 4.61 (AB
system, J = 15.6 Hz, OCH2CO2tBu, 4H), 4.69, 4.87, 5.01 (3 × d, J =
15.9, 14.3, and 13.8 Hz, 1:2:2 ratio, ArCH2Ar, 5H), 6.45 and 6.65 (AB
system, J = 2.5 Hz, ArH, 4H), 6.99 and 7.12 (AB system, J = 2.4 Hz,
ArH, 4H), 7.21 (s, ArH, 2H), 10.08 (br s, CO2H, 1H) ppm; 13C NMR
δ 28.1, 28.2, 29.2, 31.4, 31.8, 31.1, 31.4, 31.5, 33.7, 34.0, 34.1, 70.8,
71.4, 72.0, 81.3, 81.5, 125.4, 125.5, 125.7, 126.0, 126.4, 132.0, 133.28,
1
a colorless solid: mp 177−181 °C; H NMR δ 0.95 (d, J = 6.9 Hz,
24H), 0.96, 1.07, 1.08 (3 × s, 2:1:2 ratio, 45H), 1.31−1.37 (m, 8H),
1.45 (s, 9H), 1.62 (septet, J = 6.9 Hz, 4H), 1.81−1.95 (m, 8H), 3.26,
3.29 (2 × d, J = 14.7 and 16.0 Hz, 3:2 ratio, 5H), 3.52−3.73 (m, 8H),
4.54, 4.56, 4.69 (3 × d, J = 13.7, 15.1, and 14.2 Hz, 2:1:2 ratio, 5H),
4.54 (s, 2H), 6.81 and 6.83, (AB system, J = 2.0 Hz, 4H), 6.94 (s, 2H),
6.97 and 6.99 (AB system, J = 2.0 Hz, 4H) ppm; 13C NMR δ 22.80,
22.81, 22.88, 28.1, 28.21, 28.24, 28.3, 28.4, 29.46, 29.53, 30.3, 31.3,
31.4, 31.5, 33.92, 33.96, 33.98, 35.2, 71.0, 74.1, 74.3, 80.8, 125,16,
125.20, 125.4, 125.9, 133.38, 133.41, 133.7, 133.9, 134.0, 144.50,
144.54, 144.8, 152.6, 152.7, 152.8, 168.9 ppm; ESI-MS m/z 1284.4 [M
+ Na]+, 1300.4 [M + K]+. Anal. Calcd for C85H128O7: C, 80.90; H,
10.22. Found: C, 80.69; H, 10.45.
5,11,17,23,29-Pentakis(1,1-dimethylethyl)-31-carboxymethoxy-
32,33,34,35-tetrakis(4-methylpentyloxy)calix[5]arene (1a·H). A sol-
ution of 3 (330 mg, 0.262 mmol) was dissolved in CHCl3/CF3CO2H
(1/1, v/v, 6 mL) and stirred for 4 h at room temperature. Solvents
were removed under reduced pressure and the crude product
crystallized from MeOH/CH2Cl2 to afford 1a·H (208 mg, 66%):
mp 97−101 °C; 1H NMR δ 0.91, 0.94 (2 × d, J = 6.8 Hz, CH(CH3)2,
24H), 0.92, 1.01, 1.32 (3 × s, 2:2:1 ratio, C(CH3)3, 45H), 1.21−1.27
(m, OCH2CH2CH2, 8H), 1.56−1.66 (m, CH(CH3)2, 4H), 1.85−1.99
(m, OCH2CH2, 8H), 3.30 (d, J = 13.9 Hz, ArCH2Ar, 5H), 3.73−3.80
(m, OCH2CH2, 4H), 3.84−3.95 (m, OCH2CH2, 4H), 3.90 (s,
OCH2CO, 2H), 4.45, 4.50, 4.51 (3 × d, J = 14.0, 13.8, and 14.2 Hz,
2:2:1 ratio, ArCH2Ar, 5H), 6.79 and 6.84 (AB system, J = 2.3 Hz, ArH,
4H), 6.82 and 6.91 (AB system, J = 2.3 Hz, ArH, 4H), 7.27 (s, ArH,
2H), 10.20 (br s, CO2H, 1H) ppm; 13C NMR δ 22.6, 22.67, 22.69,
27.79, 27.81, 27.9, 28.0, 29.3, 29.9, 30.0, 31.2, 31.4, 31.6, 33.9, 34.2,
34.86, 34.92, 69.7, 75.5, 75.6, 124.7, 125.2, 125.5, 126.0, 126.6, 133.1,
133.3, 133.6, 134.1, 134.2, 145.2, 145.4, 146.1, 150.9, 152.1, 152.5,
170.2 ppm; ESI-MS m/z 1206.6 [M + H]+, 1228.5 [M + Na]+, 1244.4
[M + K]+. Anal. Calcd for C81H120O7: C, 80.68; H, 10.03. Found: C,
80.52; H, 10.18.
5,11,17,23,29-Pentakis(1,1-dimethylethyl)-35-benzyloxy-
31,32,33,34-tetrakis(tert-butoxycarbonylmethoxy)calix[5]arene (5).
A mixture of monoether 4 (205 mg, 0.228 mmol), tert-butyl
bromoacetate (534 mg, 2.736 mmol), and K2CO3 (378 mg, 2.736
mmol) in CH3CN (30 mL) was refluxed for 24 h. After cooling, the
inorganic salts present in the reaction mixture were collected by
filtration, washed with CHCl3, and disposed, while the combined
organic layers were evaporated to dryness. The resulting oily residue
was treated with petroleum ether (50 mL), and the additional salts
precipitated out removed by suction filtration. The filtrate was washed
with water (2 × 30 mL), dried over MgSO4, and concentrated under
reduced pressure to yield, upon recrystallization from MeOH/CHCl3,
1
tetraester 5 (251 mg, 81%): mp 187−190 °C; H NMR δ 0.83, 1.13,
9673
dx.doi.org/10.1021/jo301730m | J. Org. Chem. 2012, 77, 9668−9675

The Journal of Organic Chemistry
Article
1
and IR spectra, and H and 13C NMR characterization spectra
for all new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
133.34, 133.5, 134.1, 145.5, 146.2, 150.5, 152.9, 153.0, 169.2, 169.3,
169.8 ppm: ESI-MS m/z 1348.3 [M + Na]+. Anal. Calcd for
C81H112O15: C, 73.38; H, 8.52. Found: C, 73.05; H 8.68.
1H NMR Titration Experiments. All spectra were recorded at 500
MHz and at 25 °C. Prior to use, CDCl3 was filtered through neutral
aluminum oxide to remove any traces of acid. Percentages of
complexation (required for the calculation of the corresponding
association constants, Ka) were determined by direct 1H NMR analysis
of the peak (host, ArH; guests, α-CH2) intensity ratio of equimolar
solutions. A set of three different equimolar sample solutions was
examined for each Ka determination. NMR samples were prepared by
adding aliquots of solutions of the relevant amines (8 μL, [amine] =
0.1 M in CDCl3; CDCl3/CD3OD 9/1, v/v or CDCl3/CF3CD2OD 9/
1, v/v) to a solution of the receptor ([1·H] = 1 × 10−3 M in CDCl3;
CDCl3/CD3OD 9/1, v/v or CDCl3/CF3CD2OD 9/1, v/v).
AUTHOR INFORMATION
Corresponding Author
*E-mail: mparisi@unime.it; spappalardo@unict.it; sgeremia@
■
units.it.
Present Address
∥Present address: Facolta
̀
di Scienze e Tecnologia, Libera
di Bolzano, piazza Universita 5, 39100 Bolzano, Italy.
Universita
̀
̀
Notes
The authors declare no competing financial interest.
X-ray Diffraction Studies. Colorless crystals of calix[5]arenes
1a·H and 1b·H suitable for X-ray analysis were obtained by slow
evaporation at room temperature of 5/1 CHCl3/CH3CN mixtures.
ACKNOWLEDGMENTS
■
+
Rodlike crystals of n-BuNH3 ⊂1a− were obtained by slow evaporation
The MIUR (PRIN-2009A5Y3N project) is gratefully acknowl-
edged for financial support of this research.
of a 2,2,2-trifluoroethanol (TFE) solution containing 1a·H and n-
butylamine in a 1:6 molar ratio. On the other hand, cocrystallization of
1b·H and n-BuNH2 was carried out by the sitting drop technique, as
the evaporation method proved to be unsuccessful. To a solution of
1b·H in TFE (25 mM) was added n-BuNH2 in a 1:4 molar ratio. The
sitting drop contained 4 μL of a 1b·H/n-BuNH2 solution (30 mg/mL)
and 4 μL of a TFE solution containing polyethylene glycol 300 (PEG-
300) in the 10−60% (v/v) range. Drops were equilibrated against 1
mL of the TFE-PEG solution (reservoir). Block-shaped colorless
crystals grew in 2 months.
REFERENCES
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+
+
Crystals of 1a·H, 1b·H, n-BuNH3 ⊂1a−, and n-BuNH3 ⊂1b− were
all of small dimensions and contained a large amount of solvent
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The electron density map and the refinement of the 1a·H structure
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sites. Furthermore, restraints were introduced to account for the
anisotropic thermal parameters of carbon atoms in the pendant 4-
methylpentyl chains (including the severely disordered terminal C4NB
atom), using the card SIMU. Disordered solvent molecules reside in
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1a·H. To investigate the solvent-containing cavities, the SQUEEZE
function of the PLATON program was used.35 A residual density of
226 electrons/cell, found in the voids of 1a·H (corresponding to about
12% of the cell volume), was attributed to three chloroform and two
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ASSOCIATED CONTENT
■
S
* Supporting Information
CIF files, figures, and tables giving crystal data for compounds
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1a·H, 1b·H, n-BuNH3 ⊂1a−, and n-BuNH3 ⊂1b− (CCDC
+
+
reference numbers 853682, 853681, 871289 and 871290,
respectively), additional X-ray plots and H and 13C NMR,
1
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(30) Treatment of n-Bu3N, n-Bu2NH, n-BuNH2, i-BuNH2, s-BuNH2,
and t-BuNH2 with an equimolar amount of the model p-tert-
butylphenoxyacetic acid (in CDCl3/CD3OD, 9/1 v/v) results in the
expected protonation of the amines to the corresponding ammonium
1
salts. Accordingly, the H NMR resonances of the pertinent α-CH2
groups (β-CH3 in the case of t-BuNH2) undergo a downfield shift (see
Figure S10 in the Supporting Information).
(14) For an example of a calix[5]arene bearing two carboxyl groups
at the upper rim, see: Haino, T.; Matsumura, K.; Harano, T.; Yamada,
K.; Saijyo, Y.; Fukazawa, Y. Tetrahedron 1998, 54, 12185−12196.
(15) (a) Gattuso, G.; Notti, A.; Pappalardo, S.; Parisi, M. F.; Pilati,
T.; Terraneo, G. CrystEngComm 2012, 14, 2621−2625. (b) Gattuso,
G.; Notti, A.; Pappalardo, S.; Parisi, M. F.; Pilati, T.; Resnati, G.;
Terraneo, G. CrystEngComm 2009, 11, 1204−1206. (c) Gargiulli, C.;
Gattuso, G.; Liotta, C.; Notti, A.; Parisi, M. F.; Pisagatti, I.; Pappalardo,
S. J. Org. Chem. 2009, 74, 4350−4353. (d) Arnaud-Neu, F.;
Fuangswasdi, S.; Notti, A.; Pappalardo, S.; Parisi, M. F. Angew.
Chem., Int. Ed. 1998, 37, 112−114. (e) Ferguson, G.; Notti, A.;
Pappalardo, S.; Parisi, M. F.; Spek, A. L. Tetrahedron Lett. 1998, 39,
1965−1968.
(31) Battye, G. G.; Kontogiannis, L.; Johnson, O.; Powell, H. R.;
Leslie, A. G. W. Acta Crystallogr. 2011, D67, 271−281.
(32) Otwinowski, Z.; Minor, W. Methods Enzymol. 1997, 276, 307−
326.
(33) Burla, M. C.; Caliandro, R.; Camalli, M.; Carrozzini, B.;
Cascarano, G. L.; De Caro, L.; Giacovazzo, C.; Polidori, G.; Siliqi, D.;
Spagna, R. J. Appl. Crystallogr. 2007, 40, 609−613.
(34) Sheldrick, G. M. Acta Crystallogr. 2008, A64, 112−122.
(35) Spek, A. L. Acta Crystallogr. 1990, A46, C34.
(16) (a) Brancatelli, G.; Capici, C.; Gattuso, G.; Geremia, S.; Notti,
A.; Pappalardo, S.; Parisi, M. F.; Sortino, S.; Vittorino, E. Chem. Asian
J. 2012, 7, 50−54. (b) Gattuso, G.; Notti, A.; Pappalardo, A.; Parisi, M.
F.; Pisagatti, I.; Pappalardo, S.; Garozzo, D.; Messina, A.; Cohen, Y.;
Slovak, S. J. Org. Chem. 2008, 73, 7280−7289. (c) Garozzo, D.;
Gattuso, G.; Kohnke, F. H.; Malvagna, P.; Notti, A.; Occhipinti, S.;
Pappalardo, S.; Parisi, M. F.; Pisagatti, I. Tetrahedron Lett. 2002, 43,
7663−7667.
(17) For examples of calix[6]arene-based alkylammonium receptors,
see: (a) Darbost, U.; Giorgi, M.; Reinaud, O.; Jabin, I. J. Org. Chem.
2004, 69, 4879−4889. (b) Casnati, A.; Jacopozzi, P.; Pochini, A.;
Ugozzoli, F.; Cacciapaglia, R.; Mandolini, L.; Ungaro, R. Tetrahedron
1995, 51, 591−598. (c) Takeshita, M.; Nishio, S.; Shinkai, S. J. Org.
Chem. 1994, 59, 4032−4034. (d) Odashima, K.; Yagi, K.; Tohda, K.;
Umezawa, Y. Anal. Chem. 1993, 65, 1074−1083.
(18) For calix[7]arene-based alkylammonium receptors, see: Gaeta,
C.; Talotta, C.; Farina, F.; Campi, G.; Camalli, M.; Neri, P. Chem. Eur.
J. 2012, 18, 1219−1230.
(19) Barrett, G.; McKervey, M. A.; Malone, J. F.; Walker, A.; Arnaud-
Neu, F.; Guerra, L.; Schwing-Weill, M.-J.; Gutsche, C. D.; Stewart, D.
R. J. Chem. Soc., Perkin Trans. 2 1993, 1475−1479.
(20) Calix[5]arenes 8 and 9 selectively bind the n-butylammonium
ion, supplied as a picrate salt (log Ka = 5.80 and 6.47, respectively15d
)
but do not show any detectable affinity for the corresponding amine.
(21) Gattuso, G.; Notti, A.; Parisi, M. F.; Pisagatti, I.; Amato, M. E.;
Pappalardo, A.; Pappalardo, S. Chem. Eur. J. 2010, 16, 2381−2385.
(22) Garozzo, D.; Gattuso, G.; Notti, A.; Pappalardo, A.; Pappalardo,
S.; Parisi, M. F.; Perez, M.; Pisagatti, I. Angew. Chem., Int. Ed. 2005, 44,
4892−4896.
(23) Stewart, D. R.; Krawiec, M.; Kashyap, R. P.; Watson, W. H.;
Gutsche, C. D. J. Am. Chem. Soc. 1995, 117, 586−601.
(24) De Salvo, G.; Gattuso, G.; Notti, A.; Parisi, M. F.; Pappalardo, S.
J. Org. Chem. 2002, 67, 684−692.
(25) Carboxyl → carboxylate and amino → ammonium group
1
conversion in solution is supported by additional IR and H and 13C
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