Ion-pair complexation with a cavitand receptor

Article abstract of DOI:10.1002/chem.201000573

The capability of resorcinarenes to bind anions within the alkyl feet at the lower rim has been exploited as the starting point for developing a new cavitand able to engulf contact ion pairs of primary ammonium salts in chlorinated solvents with association constants (K_ass) in the range of 10³10⁴M^-1. Methylene bridges were introduced into the upper rim to freeze the resorcinarene in the cone conformation with the four H_down protons converging in the lower pocket, thereby maximizing the CH-anion interactions responsible for the anion binding. Four additional phosphate moieties were introduced into the lower rim in close prox-imity to the anionic site to provide hydrogen-bonding-acceptor P=O groups and promote cation complexation at the bottom of the cavitand. The binding ability of the synthesized ligands was analyzed by ¹H NMR spectroscopy and, when possible, by isothermal titration calorimetry (ITC); the data were in agreement when complementary techniques were used.

Full text of DOI:10.1002/chem.201000573

FULL PAPER
DOI: 10.1002/chem.201000573
Ion-Pair Complexation with a Cavitand Receptor
Francesca Tancini,[a] Thomas Gottschalk,[b] W. Bernd Schweizer,[b]
FranÅois Diederich,*[b] and Enrico Dalcanale*[a]
Dedicated to Professor Albert Eschenmoser at the occasion of his 85th birthday
Abstract: The capability of resorcinar-
with the four Hdown protons converging
in the lower pocket, thereby maximiz-
ing the CH–anion interactions respon-
sible for the anion binding. Four addi-
tional phosphate moieties were intro-
duced into the lower rim in close prox-
imity to the anionic site to provide hy-
enes to bind anions within the alkyl
feet at the lower rim has been exploit-
ed as the starting point for developing
a new cavitand able to engulf contact
ion pairs of primary ammonium salts in
chlorinated solvents with association
constants (Kass) in the range of 103–
104 mꢀ1. Methylene bridges were intro-
duced into the upper rim to freeze the
resorcinarene in the cone conformation
drogen-bonding-acceptor P=O groups
and promote cation complexation at
the bottom of the cavitand. The bind-
ing ability of the synthesized ligands
1
was analyzed by H NMR spectroscopy
and, when possible, by isothermal titra-
tion calorimetry (ITC); the data were
in agreement when complementary
techniques were used.
Keywords: cavitands
· CH–anion
interactions · host–guest systems ·
hydrogen bonds · ion pairs
Introduction
ple, in salt extraction, solubilization, or as membrane trans-
fer agents.[4]
The development of synthetic receptors able to mimic non-
covalent interactions in nature and to bind charged species
efficiently and selectively is a topic of great interest in
supramolecular chemistry. Although in recent years consid-
erable effort has been devoted to the realization of specific
cation[1] or anion[2] receptors, more recently attention has
been focused on the design of heterotopic ion-pair recep-
tors[3] that feature simultaneous complexation of both cat-
ionic and anionic species. These systems are particularly in-
triguing because of their potential applications in biological
processes, environmental protection, and industry, for exam-
So far, research into ion-pair receptors has mainly been
focused on calixpyrroles,[5] calixarenes,[6] and crown ethers
coupled with azamacrocycles,[7] which feature NH– and CH–
anion interactions for anions and cation–dipole and cation–
p interactions for the positively charged species.
Herein we introduce a new cavitand receptor capable of
selective ion-pair complexation by a synergistic combination
of CH–anion and hydrogen-bonding interactions. Enhance-
ment of the CH–anion interactions by rigidification of the
upper rim of the resorcinarene scaffold followed by func-
tionalization of the lower rim with hydrogen-bond-acceptor
units has led to the formation of an efficient ion-pair recep-
tor for primary ammonium halides.
[a] Dr. F. Tancini, Prof. Dr. E. Dalcanale
Dipartimento di Chimica Organica ed Industriale
and Unitꢀ INSTM, UdR Parma, Universitꢀ degli Studi di Parma
Viale G. P. Usberti 17/a, 43124 Parma (Italy)
Fax : (+39)0521-905472
Results and Discussion
Our starting point was the observation of several crystal
structures of resorcinarene[8] and cavitand[9] complexes
formed with charged species in which the anion is included
within the alkyl feet pocket at the lower rim due to multiple
CH–anion interactions with the Hdown aromatic hydrogen
atoms[10,11] and the ArCHCH2 a-methylene units of the
chains.[12] To maximize these interactions, we decided to in-
troduce four methylene bridges into the resorcinarene upper
E-mail: enrico.dalcanale@unipr.it
[b] Dr. T. Gottschalk, Dr. W. B. Schweizer, Prof. Dr. F. Diederich
Laboratorium fꢁr Organische Chemie, ETH Zꢁrich
Hçnggerberg, HCI, CH-8093 Zurich, Switzerland
Fax : (+41)44-632-1109
E-mail: diederich@org.chem.ethz.ch
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201000573.
Chem. Eur. J. 2010, 16, 7813 – 7819
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
7813

rim to form a molecule preorganized in the cone conforma-
tion with all Hdown protons converging inwards without at-
tributing any specific binding property to the resulting shal-
low cavity.[13] Subsequent functionalization of the lower rim
was then devised to insert additional binding motifs in close
proximity to the anionic site and thereby promote contem-
poraneous cation complexation (Figure 1).
(cavitand 2) or the volume
available for the guest was re-
duced (cavitand 3).[17]
The binding properties of
cavitand 1 were examined in
[D6]acetone by 1H NMR titra-
tion using TBAC as the guest.
The largest complexation-in-
duced change in the chemical
shifts of the receptor protons is
the downfield movement by
+0.78 ppm of the aromatic
Hdown protons (Figure 2), which
is indicative of their interaction with a bound chloride
anion.[10a] Consistent with this hypothesis is the smaller
downfield shift observed for the nearby ArCHCH2 protons
of the receptor alkyl chains (Dd=+0.45 ppm). No shifts
were observed for the protons of the host phenyl groups or
for signals related to the quaternary ammonium guest.
Changes were not even observed for the receptor Hup or
OCH2O protons and thus cation complexation is excluded
at both the lower and upper rims.
Figure 1. Schematic representation of the target receptor and of the com-
plexation strategy.
Once the 1:1 stoichiometry for the anion complexation
had been verified by the continuous variation method (Job
plot analysis), the association constant (Kass) was evaluated
by monitoring the downfield shift of the Hdown signal of the
receptor (see the Supporting Information for details of the
fitting equations used). The low value ((25ꢁ2)mꢀ1) found is
a result of the energy required to separate the anionic and
cationic moieties of the guest.
Hydrocarbon-footed cavitands 1–3: Theoretical calculations
based on PM3 semiempirical methods using SPARTAN08[14]
suggested that the target receptor 1, with four phenyl-ended
feet, provided an optimal spatial arrangement for the com-
plexation of tetra-n-butylammonium chloride (TBAC) at the
bottom of the cavitand bowl. The phenyl groups should bind
the cation by additional cation–p interactions,[15] thereby
leading to ion-pair complexation.
Receptor 1 was prepared as shown in Scheme 1. First, re-
sorcinarene 7 was obtained by acid-catalyzed condensation
between resorcinol and 5-phenylpentanal. Subsequently the
upper rim was functionalized with methylene bridges by re-
action with bromochloromethane in the presence of K2CO3.
Model receptors 2 and 3, which feature four hexyl or phe-
nylethyl feet, respectively, at the lower rim, were also pre-
pared by known literature procedures.[16] In both of these
cases, the binding affinity for TBAC was expected to be
lower than in the case of the target receptor 1 because
either the stabilizing cation–p interactions were removed
Control experiments repeated under the same conditions
with cavitands 2 and 3 revealed that 1) removal of the
phenyl units reduces the association constant (Kass-
A
length between the cavitand and the terminal phenyl rings
totally suppresses complexation (no TBAC binding was ob-
served with 3).
The same titrations were conducted with cavitand 1 in
CDCl3 and in [D6]DMSO to evaluate the effect of solvent
on TBAC complexation. Both solvents completely sup-
pressed anion binding (see Figures S5 and S6 in the Support-
ing Information), which indicates that both tightly associat-
Scheme 1. Synthesis of target receptor 1. Reagents and conditions: a) EtOH/HCl, 24 h, RT; 72 h, 808C, 71%; b) BrCH2Cl, dry DMF, overnight, 808C,
75%.
7814
www.chemeurj.org
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 7813 – 7819

Ion-Pair Complexation with a Cavitand Receptor
FULL PAPER
posed to three different tetra-n-
butylammonium salts, namely,
the chloride (TBAC), bromide
(TBAB), and iodide (TBAI).
The changes in the chemical
shifts of the diagnostic Hdown
and ArCHCH2 protons and the
Kass values obtained from
1H NMR
titrations
in
[D6]acetone are reported in
Table 1. In each case, a 1:1 stoi-
chiometry for the complexation
was determined by the continu-
ous variation method.
No significant counterion
effect was revealed by compar-
ing the Kass values. Even more
compelling is the limited im-
provement in Kass on moving
from cavitand 1 to 4. A supple-
mentary 31P NMR titration in
[D6]acetone was carried out
(see Figure S8 in the Support-
Figure 2. Partial 1H NMR spectra (T=258C) in [D6]acetone recorded during the titration of receptor 1 with
TBAC. [1]=2.0 mm.
ed[18] (chloroform) and solvated ([D6]DMSO)[19] ion pairs
are unsuitable for cavitand 1.
Table 1. Observed changes in chemical shifts[a] and calculated Kass values
in the titrations of 4 with TBA halides.
Guest
Dd
N
Dd
A
Kass [mꢀ1
]
Phosphate-footed cavitand 4: The next step was the replace-
ment of the phenyl groups in 1 with four phosphotriester
residues, which are well known for their ability to bind posi-
tively charged species, such as ammonium cations, through
cation–dipole and hydrogen-bonding interactions.[9,20]
TBAC
TBAB
TBAI
+0.88
+0.67
+0.41
+0.51
+0.48
+0.42
150ꢁ30
140ꢁ10
73ꢁ3
[a] Observed at [4]=3.7 mm and [TBAC]=575.6 mm, [TBAB]=
643.5 mm, and [TBAI]=384.1 mm. Dd=dsaturationꢀdfree
.
The phosphate esters were installed according to the syn-
thetic sequence shown in Scheme 2. First, the hydroxy-
footed resorcinarene 8[16b] was treated with bromochlorome-
thane in the presence of K2CO3 to afford methylene-bridged
cavitand 9. This cavitand was then converted into 4 by treat-
ment with trimethyl phosphite and tetrabromomethane.
To test the influence of pure cation–dipole interactions in
the absence of any hydrogen bonding, cavitand 4 was ex-
ing Information) to assess the effective role of the phos-
phate ester units. The recorded change in the 31P NMR
chemical shift upon addition of 12 equiv of TBAC to 4 (c=
3.7 mm) was negligible (Dd=ꢀ0.005 ppm). Thus, the expect-
ed cation–dipole interactions between the phosphotriesters
and the tetrabutylammonium are negligible and the role of
Scheme 2. Synthesis of target receptor 4. Reagents and conditions: a) BrCH2Cl, dry DMF, overnight, 808C, 63%; b) CBr4, PACHTUNRGTNEUNG(OMe)3, 2.5 h, RT; H2O/
CH2Cl2, 40 min, RT, 36%.
Chem. Eur. J. 2010, 16, 7813 – 7819
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7815

F. Diederich, E. Dalanale et al.
cavitand 4 is limited to that of a simple anion receptor. Also
in this case, the use of CDCl3 as solvent led to the complete
suppression of TBAC complexation, as in the case of 1.
Because pure cation–dipole interactions did not suffice to
bind quaternary ammonium cations, additional hydrogen-
bonding interactions were introduced into the system by
switching to primary ammonium countercations. n-Octylam-
monium salts were selected because of their solubility in
chlorinated organic solvents in which hydrogen bonding is
enhanced. In this way, the four P=O moieties of cavitand 4
also acted as hydrogen-bond acceptors.[21] The data for the
complexation of 4 with the octylammonium halide (Clꢀ,
Brꢀ, and Iꢀ) salt series in CDCl3 at 258C are summarized in
Table 2.
upfield shift of the phosphate signal is observed for all three
guests (see Figure S17 in the Supporting Information and
Table 2).[22]
With octylammonium bromide as the guest, a Kass value
one order of magnitude higher than that of the correspond-
ing chloride was determined (Table 2). With the iodide salt,
larger variations in the chemical shifts of all diagnostic sig-
nals were recorded. However, the corresponding Kass value
could not be determined exactly because of a too high stan-
dard deviation in the curve fitting, which is a result of the
incomplete solubility of octylammonium iodide in CDCl3 at
room temperature at the concentrations required for
1H NMR studies.
The same titrations were repeated with cavitands 1 and 2
in CDCl3 as control experiments. In both cases the cavitand
signals were unaffected by the presence of octylammonium
chloride (see Figures S10 and S11 of the Supporting Infor-
mation).
Table 2. Observed changes in chemical shifts[a] and Kass values in the ti-
trations of 4 with n-octylammonium halides.
Guest
Dd
(Hdown
)
Dd
ACHTUNGTRENNUNG
The binding of octylammonium salts by 4 was also moni-
tored by isothermal titration calorimetry (ITC) to overcome
the solubility problems[23] as well as to analyze the enthalpic
and entropic contributions to complexation (Table 3).
G
R
N
G
]
C8H17NH3Clꢀ +0.23
C8H17NH3Brꢀ +0.55
+0.19
+0.49
+0.79
+0.20
+0.57
+0.96
C8H17NH3I ꢀ
+0.56
n.d.[b]
[a] Observed
at
[4]=5.2 mm
and
dsaturationꢀdfree. [b] Data not suitable for the determination of Kass
and
[C8H17NH3Brꢀ]=403.1 mm,
Table 3. Thermodynamic parameters and Kass values for the ITC titration
of 4 with octylammonium halides in chloroform at 258C.
.
Guest
DH
[kJmolꢀ1
TDS
DG
Kass
[mꢀ1
G
]
R
]
G
]
U
]
1
The variation in the H NMR chemical shifts upon titra-
tion of cavitand 4 with octylammonium bromide are illus-
trated in Figure 3. In these titration experiments we moni-
tored not only the usual downfield shift of the cavitand
Hdown protons, diagnostic of anion binding, but also the
downfield shift of the guest NH resonances, which are indi-
cative of cation hydrogen bonding with the P=O groups
(Figure 3).
C8H17NH3Clꢀ
C8H17NH3Brꢀ
C8H17NH3I ꢀ
n.d.[a]
ꢀ7.1ꢁ0.3
ꢀ18.3ꢁ0.3
ACHTUNGTRENNUNG
17.1ꢁ0.4
8.3ꢁ0.2
ꢀ24.2ꢁ0.2
ꢀ26.6ꢁ0.8
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
[a] Data not suitable for thermodynamic evaluation. [b] Qualitative aver-
age value.
In the case of octylammonium chloride, the low Kass
value, close to the detection limit of the technique,[24] jeopar-
dized a quantitative evaluation. The qualitative estimate ob-
tained (1200<Kass <2000) is
The presence of NH···O=P hydrogen bonding was con-
firmed by the corresponding 31P NMR titration in which an
comparable with the value de-
termined by 1H NMR titration
(1300<Kass <1700mꢀ1, Table 2).
In the other two cases, the data
fitted well a 1:1 binding profile
with association constants in
the range of 104 mꢀ1 with
a
higher affinity for the iodide
compound than for the bro-
mide. In this latter case, in
which Kass was also determined
precisely by 1H NMR titration,
a perfect match of the experi-
mental results was obtained
(Tables 2 and 3).
The energetic signatures re-
vealed that the binding is both
enthalpy and entropy driven.
The observed trend in the en-
Figure 3. Partial 1H NMR spectra (T=258C) in CDCl3 recorded during the titration of receptor 4 with octyl-
ACHTUNGTRENNUNGammonium bromide. In the titration, the host concentration was kept constant at 5.2 mm.
7816
www.chemeurj.org
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 7813 – 7819

Ion-Pair Complexation with a Cavitand Receptor
FULL PAPER
(121 MHz) spectrometer. Electrospray ionization (ESI) MS experiments
were performed on a Bruker maXis ESI-Q-TOF spectrometer and EIMS
were recorded on a Waters Micromass AutoSpec Ultima spectrometer.
Melting points were determined by using a Bꢁchi B-540 capillary melting
point apparatus.
thalpic contribution can be rationalized by recalling that, in
apolar solvents, the recognition of ion pairs increases with a
reduction in the electrostatic interactions between the anion
and cation.[25] The opposite entropic trend can be attributed
to the different degree of solvation in the ion-pair series,
which decreases with decreasing charge density of the anion
(Clꢀ >Brꢀ >Iꢀ).[26] Because extensive guest desolvation is re-
quired for ion-pair binding by 4, the release of more struc-
tured solvent molecules leads to a higher entropic desolva-
tion gain. The two terms partially balance each other in the
resulting DG values. The positive TDS contribution to the
complexation free enthalpy implies that the entropy losses
due to conformational freezing of the host upon binding,
and to the reduction in translational freedom in the newly
formed complexes, are more than compensated by the de-
solvation of both components.
ITC studies were performed by using an isothermal titration Microcal
VP-ITC microcalorimeter thermostatted at 258C. Experimental titration
curves were analyzed with the MicroCal Origin 5.0 program. DH, DS,
and Kass values were calculated as the average of a set of independent ex-
periments; the DG value is given by: DG=DHꢀTDS.
The standard deviations for DH, DS, and Kass were calculated from Equa-
tion (1) where n is the number of independent experiments, xi is the
value recorded in the i experiment, and x¯ is the average value for x. The
standard deviation for DG was calculated according to Equation (2).
vffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi
u
n
P
u
t
ꢀ
ðxiꢀxÞ
nꢀ1
ð1Þ
i¼1
p
p
2
2
dðDGÞ ¼ f½ð@G=@KassÞdðKassÞꢄ g ¼ ½ðꢀRTdðKassÞ=KassÞ ꢄ ¼ RTdðKassÞ=Kass
ð2Þ
Conclusion
The enthalpies of dilution of the hosts and guests were determined in
separate experiments, being negligible. All the measurements were car-
ried out by titrating a solution of the host (in the cell) with a solution of
the guest (in the syringe).
CH–anion interactions coupled with hydrogen bonding to
P=O groups have been exploited to realize the efficient ion-
pair cavitand receptor 4 for primary ammonium halides.
The key feature characterizing the host is the presence of a
preorganized pocket for anion binding in close proximity to
four hydrogen-bond-accepting P=O groups. The introduc-
tion of the four phosphate units changes completely the cav-
itand complexation properties, transforming the weak anion
binder 1 in acetone into the strong ion-pair receptor 4 in
chloroform.
5-Phenylpentan-1-ol: LiAlH4 (3.42 g, 8.98ꢃ10ꢀ2 mol) was suspended in
dry diethyl ether (220 mL). The mixture was cooled to 08C and a solu-
tion of 5-phenylvaleric acid (4.00 g, 2.24ꢃ10ꢀ2 mol) in dry diethyl ether
(22 mL) was added dropwise. The mixture was stirred at room tempera-
ture for 4 h. The system was then cooled to 08C and H2O (3.4 mL) was
slowly added followed by an aqueous 3m solution of KOH (3.4 mL) and
by further H2O (11.4 mL). The mixture was stirred at 08C for 1 h. The
crude was filtered and the organic phase dried over MgSO4. The resulting
solution was concentrated to dryness to afford 5-phenylpentan-1-ol as a
colorless oil (3.14 g, 86%). 1H NMR (300 MHz, CDCl3, 258C): d=7.29
The search for optimal cation-binding units has shown
that hydrogen bonding is more effective than cation–p and
cation–dipole interactions in apolar media.
(t, 3J
3J(H,H)=6.3 Hz, 2H; CH2OH), 2.64 (t, 3J
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
A
1.72–1.62 (m, 4H; CH2CH2OH+CH2CH2Ph), 1.47–1.40 ppm (m, 2H;
CH2CH2CH2OH); 13C NMR (75 MHz, CDCl3, 258C): d=142.60, 128.43,
128.31, 125.70, 62.92, 35.94, 32.67, 31.31, 25.44 ppm; HRMS (EI): m/z:
calcd for C11H13+: 146.1095 [MꢀH2O]+; found: 146.1090.
1
The experimental Kass values determined by H NMR ti-
trations have been validated by complementary ITC titra-
tions. The finding that the complexation is also entropy
driven can be attributed in part to the preorganization of
the anion pocket, which does not undergo major conforma-
tion changes upon complexation. Thus, entropic losses from
host–guest complexation do not compensate for the gains
from the partial desolvation of the bound ion pairs.
5-Phenylpentanal (6):
A solution of 5-phenylpentanol (3.14 g, 1.92ꢃ
10ꢀ2 mol) in dry CH2Cl2 (50 mL) was rapidly added to a suspension of
PCC (6.19 g, 2.87ꢃ10ꢀ2 mol) in dry CH2Cl2 (60 mL) at room temperature.
The mixture turned black becoming homogeneous and then a black solid
was deposited on the walls of the flask. The reaction was stirred at room
temperature for 3 h. Then the solution was decanted and the black resi-
due was washed several times with CH2Cl2. The collected organic phases
were partially concentrated and finally filtered through a plug of silica
(eluent: CH2Cl2) to afford 6 as a pale-yellow oil (2.59 g, 83%). 1H NMR
(300 MHz, CDCl3, 258C): d=9.76 (t, 3J
ACHTUNGTRENNUNG
3
1
Experimental Section
(tt, J
G
G
+
Hpara), 2.65 (t, 3J
1.68 ppm (m, 4H; CH2CH2CHO+CH2CH2Ph); 13C NMR (75 MHz,
CDCl3, 258C): d=202.57, 141.97, 128.41, 128.12, 125.87, 43.77, 35.66,
30.89, 21.71 ppm; HRMS (EI): m/z: calcd for C11H13O+: 160.0888
[MꢀH2]+; found: 160.0880.
General: All commercial reagents were ACS reagent grade and used as
received. CH2Cl2 was dried by distillation over CaH2 according the stan-
dard procedures. Dry DMF (DMF puriss. ꢂ99.5% (GC), over molecular
sieves) and dry pyridine (Pyridine absolute, over molecular sieves, H2O
ꢃ0.005%) were purchased from Aldrich and used as received; dry dieth-
yl ether (Diethyl ether purum ꢂ99.8%(GC), over molecular sieves) was
purchased from Fluka and used as received. Silica gel column chromatog-
raphy was performed by using silica gel 60 (Fluka 230–400 mesh ASTM)
and alumina chromatography was performed by using MP Alumina B,
Akt. I (MP Biomedicals Germany GmbH). 1H NMR spectra were ob-
tained with a Varian Gemini 300 (300 MHz) or Mercury 300 (300 MHz)
spectrometer. All chemical shifts (d) are reported in ppm relative to the
proton resonances resulting from incomplete deuteriation of the NMR
solvents. 31P NMR spectra were obtained with a Varian Mercury 300
Compound 7: A solution of resorcinol (1.76 g, 1.60ꢃ10ꢀ2 mol) in absolute
ethanol (16 mL) was cooled to 08C and an aqueous 37% HCl solution
(3.3 mL) was added. A solution of 6 (2.59 g, 1.60ꢃ10ꢀ2 mol) in absolute
ethanol (15 mL) was slowly added over a 20 min period. The solution
was allowed to warm at room temperature and stirred for 1 d. After 24 h,
the reaction was slowly heated to 808C and stirred at reflux for 3 d. No
precipitate formed during this period. The red solution was cooled to
08C and added to H2O (150 mL). The voluminous precipitate was stirred
for 20 min and finally collected by filtration to afford the desired resorci-
narene 7 as an orange solid (2.88 g, 71%). M.p. >3008C (slow decompo-
Chem. Eur. J. 2010, 16, 7813 – 7819
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7817

F. Diederich, E. Dalanale et al.
1
sition); H NMR (300 MHz, [D6]acetone, 258C): d=8.50 (s, 8H; ArOH),
(brs, 3H; NH3), 2.98 (m, 2H; CH2NH3), 1.77 (m, 2H; CH2CH2NH3),
7.56 (s, 4H; ArHdown), 7.26–7.13 (m, 20H; Hortho +Hmeta +Hpara), 6.27 (s,
1.37–1.27 (m, 10H; (CH2)5CH2CH2NH3), 0.87 ppm (t, 3J
ACHTNGUTERN(UNG H,H)=6.6 Hz,
3H; CH2CH3); 13C NMR (75 MHz, CDCl3, 258C): d=40.06, 31.72, 29.05,
28.97, 27.68, 26.54, 22.59, 14.06 ppm; HRMS (ESI): m/z: calcd for
C8H20N+: 130.1590 [MꢀCl]+; found: 130.1584; elemental analysis calcd
(%) for C8H20NCl: C 57.99, H 12.16, N 8.45, Cl 21.40; found: C 58.28, H
12.14, N 8.38, Cl 21.25.
4H; ArHup); 4.34 (t, 3J(H,H)=8.1 Hz, 4H; ArCH), 2.59 (t, 3J
ACHTUNGTRENNUNG AHCTUNGTRNEN(UGN H,H)=
5.7 Hz, 8H; CH2Ph), 2.32 (m, 8H; ArCHCH2), 1.68 (m, 8H;
ArCHCH2CH2), 1.43 ppm (m, 8H; CH2CH2Ph); 13C NMR (75 MHz,
[D6]acetone, 258C): d=152.77, 143.53, 129.13, 129.03, 126.45, 125.49,
125.20, 103.80, 36.66, 34.18, 34.04, 32.22, 28.66 ppm; HRMS (ESI): m/z:
calcd for C68H73O8+: 1017.5300 [M+H]+; found: 1017.5321.
n-Octylammonium bromide (11):[28] An excess of aqueous 47% HBr
(3 mL) was added to a solution of octylamine (2.00 mL, 1.21ꢃ10ꢀ2 mol)
in Et2O (20 mL). The resulting mixture was stirred at room temp. for 1 h.
The solvent was removed in vacuo and the product recrystallized from
acetone at 08C (2.52 g, quant.). White crystals; m.p. 207–2088C (lit.:[29]
Compound 1: In a dried Schlenk tube, resorcinarene 7 (2.00 g, 1.97ꢃ
10ꢀ3 mol) was dissolved in dry DMF (40 mL). Oven-dried K2CO3 (2.56 g,
1.97ꢃ10ꢀ2 mol) was added followed by bromochloromethane (5.11 mL,
7.87ꢃ10ꢀ2 mol). The mixture was stirred at 808C overnight and then
poured into 1m HCl (150 mL). An orange solid deposited on the walls of
the flask. The solution was decanted and the solid dissolved in CH2Cl2.
The resulting organic solution was dried over MgSO4 and then concen-
trated to dryness. The crude was finally purified by column chromatogra-
phy (SiO2; CH2Cl2) to afford cavitand 1 as a white solid (1.57 g, 75%).
M.p. >3108C (slow decomposition); 1H NMR (300 MHz, [D6]acetone,
1
203–2068C); H NMR (300 MHz, CDCl3, 258C): d=7.93 (brs, 3H; NH3),
3.04 (m, 2H; CH2NH3), 1.81 (m, 2H; CH2CH2NH3), 1.40–1.27 (m, 10H;
(CH2)5CH2CH2NH3), 0.88 ppm (t, 3J
ACHTNUTRGNEUNG(H,H)=6.6 Hz, 3H; CH2CH3);
13C NMR (75 MHz, CDCl3, 258C): d=40.32, 31.86, 29.19, 29.07, 27.65,
26.71, 22.78, 14.30 ppm; HRMS (ESI): m/z: calcd for C8H20N+: 130.1590
[MꢀBr]+; found: 130.1589; elemental analysis calcd (%) for C8H20NBr:
C 45.72, H 9.59, N 6.66, Br 38.02; found: C 45.68, H 9.34, N 6.67, Br
37.82.
258C): d=7.58 (s, 4H; ArHdown), 7.26–7.15 (m, 20H; Hortho +Hmeta
+
Hpara), 6.54 (s, 4H; ArHup), 5.74 (d, 3J
AHCTUNGTRENNUNG
3J
ACHTUNGTRENNUNG(H,H)=8.1 Hz, 4H; ArCH), 4.47 (d, JCAHTUNGTRENNUNG
3
n-Octylammonium iodide (12):[29] An excess of aqueous 57% HI (3 mL)
was added to a solution of octylamine (2.00 mL, 1.21ꢃ10ꢀ2 mol) in Et2O
(20 mL). The resulting mixture was stirred at room temp. for 1 h. The sol-
vent was then removed in vacuo and the product recrystallized from
hexane (3.05 g, quant.). Pale-yellow solid; m.p. 205–2068C; 1H NMR
(300 MHz, CDCl3, 258C): d=7.52 (brs, 3H; NH3), 3.14 (m, 2H;
CH2NH3), 1.86 (m, 2H; CH2CH2NH3), 1.42–1.27 (m, 10H;
3
(t, JACHTUNGTRENNUNG
ArCHCH2CH2), 1.45 ppm (m, 8H; CH2CH2Ph); 13C NMR (75 MHz,
[D6]acetone, 258C): d=155.91, 143.35, 139.46, 129.16, 129.13, 126.53,
122.89, 117,48, 100.39, 37.31, 36.56, 32.30, 29.88, 28.35 ppm; HRMS
(ESI): m/z: calcd for C72H72O8Na+: 1087.5119 [M+Na]+; found:
1087.5121.
(CH2)5CH2CH2NH3), 0.88 ppm (t, 3J
ACHTNUTRGNEUNG(H,H)=6.6 Hz, 3H, CH2CH3);
Compound 9: In a dried Schlenk tube, propanol-footed resorcinarene
(3.00 g, 4.17ꢃ10ꢀ3 mol)[8b] was dissolved in dry DMF (40 mL). Oven-
dried K2CO3 (7.00 g, 4.17ꢃ10ꢀ2 mol) was added followed by bromo-
chloromethane (10 mL, 1.67ꢃ10ꢀ1 mol). The mixture was stirred at 808C
overnight. The solvent was then removed in vacuo and the crude sus-
pended in 1m HCl (150 mL), filtered, and purified by flash chromatogra-
phy (SiO2; CH2Cl2/MeOH, 9:1) to afford cavitand 9 as a white solid
(2.02 g, 63%). M.p. >3008C (slow decomposition); 1H NMR (300 MHz,
[D6]acetone, 258C): d=7.61 (s, 4H; ArHdown), 6.51 (s, 4H; ArHup), 5.71
13C NMR (75 MHz, CDCl3, 258C): d=40.67, 31.86, 29.20, 29.06, 27.45,
26.82, 22.80, 14.31 ppm; HRMS (ESI): m/z: calcd for C8H20N+: 130.1590
[MꢀI]+; found: 130.1584; elemental analysis calcd (%) for C8H20NI: C
37.37, H 7.84, N 5.45, I 49.35; found: C 37.09, H 7.72, N 5.39, I 49.54.
Acknowledgements
(d, 3J
4.47 (t, 3J
A
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
The exchange research stay of F.T. at the ETH was supported by the
Swiss National Science Foundation and by INSTM. We are grateful to
Prof. Dr. C. Schalley (FU Berlin) for early mass spectrometric observa-
tions that triggered this project. We thank Dr. C. Thilgen (ETH) for help
with the nomenclature.
CHout), 3.51 (m, 8H; CH2OH), 2.40 (m, 8H; ArCHCH2), 1.46 ppm (m,
8H; ArCHCH2CH2); 13C NMR (75 MHz, [D6]acetone, 258C): d=155.91,
139.55, 123.43, 117.26, 100.37, 62.33, 37.55, 32.33, 26.93 ppm; HRMS
(ESI): m/z: calcd for C44H48O12Na+: 791.3038 [M+Na]+; found:
791.3060.
Compound 4: CBr4 (0.79 g, 2.39ꢃ10ꢀ3 mol) was added to a suspension of
cavitand 9 (0.30 g, 3.90ꢃ10ꢀ4 mol) in dry pyridine (6 mL) and the mixture
stirred at room temp. for 10 min. The suspension was cooled to 08C and
trimethyl phosphite (0.23 mL, 1.95ꢃ10ꢀ3 mol) was added. The solution
was stirred at room temp. for 2.5 h and then H2O/CH2Cl2 (1:1, 10 mL)
was added and stirring was continued for 40 min. The solvents were re-
moved in vacuo and the crude was purified by flash chromatography on
basic alumina (CH2Cl2/EtOH, 96:4). The product obtained was suspend-
ed in H2O and recovered by filtration as a pale-pink solid (0.17 g, 36%).
M.p. >2908C (slow decomposition); 1H NMR (300 MHz, [D6]DMSO,
[1] a) J. M. Lehn, Pure Appl. Chem. 1979, 51, 979–997; b) R. Ungaro,
A. Pochini in Calixarenes: A Versatile Class of Macrocyclic Com-
pounds, Series Topics in Inclusion Science, Vol. 3 (Ed.: J. Vicens, V.
Bçhmer), Springer, Heidelberg, 1990, pp. 127–147; c) G. W. Gokel,
A. Nakano, Crown Compd. 1992, 1–26; d) E. Grell, R. Warmuth,
Pure Appl. Chem. 1993, 65, 373–379; e) H. Huang, L. Mu, J. He, J.-
P. Cheng, J. Org. Chem. 2003, 68, 7605–7611.
[2] a) S. E. Matthews, P. D. Beer, Supramol. Chem. 2005, 17, 411–435;
b) J. L. Sessler, P. A. Gale, W.-S. Cho in Monographs in Supramolec-
ular Chemistry (Ed.: J. F. Stoddart), RSC, Cambridge, 2006; c) V.
Amendola, L. Fabbrizzi, Chem. Commun. 2009, 513–531; d) C. Cal-
tagirone, P. A. Gale, Chem. Soc. Rev. 2009, 38, 520–563; e) K. Salor-
inne, D. P. Weimann, C. A. Schalley, M. Nissinen, Eur. J. Org. Chem.
2009, 6151–6159.
258C): d=7.57 (s, 4H; ArHdown), 6.56 (s, 4H; ArHup), 5.73 (d, 3J
7.5 Hz, 4H; CHin), 4.61 (t, 3J(H,H)=7.6 Hz, 4H; ArCH), 4.40 (d, 3J-
(H,H)=7.5 Hz, 4H; CHout), 4.07 (m, 8H; CH2OP(O)), 3.66 (d, J
ACHTUNGTRNE(NUNG H,H)=
AHCTUNGTRENNUNG
3
A
ACHTUNGTRNE(NUNG H,P)=
11.1 Hz, 24H; OCH3), 2.46 (m, 8H; ArCHCH2), 1.66 ppm (m, 8H;
ArCHCH2CH2); 13C NMR (75 MHz, [D6]DMSO, 258C): d=157.01,
140.59, 124.82, 119.57, 101.68, 69.57, 56.76, 38.49, 30.98, 27.59 ppm;
31P NMR (121 MHz, [D6]DMSO, 258C): d=2.17 ppm (s, P(O)); IR;
HRMS (ESI): m/z: calcd for C52H68O24P4Na+ 1223.2943 [M+Na]+;
found: 1223.2950.
[3] a) P. A. Gale, Coord. Chem. Rev. 2003, 240, 191–221; b) “Ion Pair
Recognition by Ditopic Receptors”: B. D. Smith in Macrocyclic
Chemistry: Current Trends and Future Perspectives (Ed.: K. Gloe),
Springer, Dordrecht, 2005, pp. 137–152.
n-Octylammonium chloride (10):[27] An excess of aqueous 36% HCl
(3 mL) was added to a solution of octylamine (2.00 mL, 1.21ꢃ10ꢀ2 mol)
in Et2O (20 mL). The resulting mixture was stirred at room temp. for
20 min. The solvent was removed under reduced pressure and the prod-
uct recrystallized from Et2O (1.98 g, quant.). White solid; m.p. 204–
2058C (lit.:[28a] 197–1988C); 1H NMR (300 MHz, CDCl3, 258C): d=8.28
[4] a) D. M. Rudkevich, J. D. Mercer-Chalmers, W. Verboom, R.
Ungaro, F. de Jong, D. N. Reinhoudt, J. Am. Chem. Soc. 1995, 117,
6124–6125; b) N. Pelizzi, A. Casnati, A. Friggeri, R. Ungaro, J.
Chem. Soc. Perkin Trans. 2 1998, 1307–1312;
c) D. J. White, N. Laing, H. Miller, S. Parson, S. Coles, P. A. Tasker,
Chem. Commun. 1999, 2077–2078.
7818
www.chemeurj.org
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 7813 – 7819

Ion-Pair Complexation with a Cavitand Receptor
FULL PAPER
[5] a) R. Custelcean, L. H. Delmau, B. A. Moyer, J. L. Sessler, W.-S.
Cho, D. Gross, G. W. Bates, S. J. Brooks, M. E. Light, P. A. Gale,
Angew. Chem. 2005, 117, 2593–2598; Angew. Chem. Int. Ed. 2005,
44, 2537–2542; b) M. P. Wintergerst, T. G. Levitskaia, B. A. Moyer,
J. L. Sessler, L. H. Delmau, J. Am. Chem. Soc. 2008, 130, 4129–
4139; c) J. L. Sessler, S. K. Kim, D. E. Gross, C.-H. Lee, J. S. Kim,
V. M. Lynch, J. Am. Chem. Soc. 2008, 130, 13162–13166; d) D. E.
Gross, F. P. Schmidtchen, W. Antonius, P. A. Gale, V. M. Lynch, J. L.
Sessler, Chem. Eur. J. 2008, 14, 7822–7827.
[6] a) A. Arduini, G. Giorgi, A. Pochini, A. Secchi, F. Ugozzoli, J. Org.
Chem. 2001, 66, 8302–8308; b) A. Arduini, E. Brindani, G. Giorgi,
A. Pochini, A. Secchi, J. Org. Chem. 2002, 67, 6188–6194; c) M. D.
Lankshear, A. R. Cowley, P. D. Beer, Chem. Commun. 2006, 612–
614; d) A. Senthilvelan, I.-T. Ho, K.-C. Chang, G.-H. Lee, Y.-H. Liu,
W.-S. Chung, Chem. Eur. J. 2009, 15, 6152–6160.
[7] a) M. J. Deetz, M. Shang, B. D. Smith, J. Am. Chem. Soc. 2000, 122,
6201–6207; b) T. Tozawa, Y. Misawa, S. Tokita, Y. Kubo, Tetrahe-
dron Lett. 2000, 41, 5219–5223; c) J. M. Mahoney, A. M. Beatty,
B. D. Smith, J. Am. Chem. Soc. 2001, 123, 5847–5848; d) J. M. Ma-
honey, J. P. Davis, A. M. Beatty, B. D. Smith, J. Org. Chem. 2003, 68,
9819–9820; e) M. K. Chac, J.-I. Lee, N.-K. Kim, K.-S. Jeong, Tetra-
hedron Lett. 2007, 48, 6624–6627.
[8] a) A. Shivanyuk, K. Rissanen, E. Kolehmainen, Chem. Commun.
2000, 1107–1108; b) H. Mansikkamꢄki, M. Nissinen, K. Rissanen,
Chem. Commun. 2002, 1902–1903; c) H. Mansikkamꢄki, M. Nissi-
nen, C. Schalley, K. Rissanen, New J. Chem. 2003, 27, 88–97.
[9] E. Biavardi, M. Favazza, A. Motta, I. L. Fragala, C. Massera, L.
Prodi, M. Montalti, M. Melegari, G. Condorelli, E. Dalcanale, J.
Am. Chem. Soc. 2009, 131, 7447–7455.
[14] SPARTAN’08, Wavefunction, Inc., USA.
[15] a) J. C. Ma, D. A. Dougherty, Chem. Rev. 1997, 97, 1303–1324;
b) E. A. Meyer, R. K. Castellano, F. Diederich, Angew. Chem. 2003,
115, 1244–1287; Angew. Chem. Int. Ed. 2003, 42, 1210–1250.
[16] a) L. M. Tunstad, J. A. Tucker, E. Dalcanale, J. Weiser, J. A. Bryant,
J. C. Sherman, R. C. Helgeson, C. B. Knobler, D. J. Cram, J. Org.
Chem. 1989, 54, 1305–13012; b) B. C. Gibb, R. G. Chapman, J. C.
Sherman, J. Org. Chem. 1996, 61, 1505–1509.
[17] For the interactions of nonbridged resorcinarenes with quaternary
ammonium ions, see: H. Mansikkamꢄki, C. Schalley, M. Nissinen, K.
Rissanen, New J. Chem. 2005, 29, 116–127.
[18] a) H. Mo, A. Wang, P. Stone Wilkinson, T. C. Pochapsky, J. Am.
Chem. Soc. 1997, 119, 11666–11673; b) C. Hasselgren, K. Fisher, S.
Jagner, I. Dance, Chem. Eur. J. 2000, 6, 3671–3678.
[19] a) R. H. Erlich, E. Roach, A. I. Popov, J. Am. Chem. Soc. 1970, 92,
4989–4990; b) J. H. Exner, E. C. Steiner, J. Am. Chem. Soc. 1974,
96, 1782–1787; c) M. R. Crampton, I. A. Robotham, J. Chem. Res.
1997, 22–23; d) J. R. Pliego, J. M. Riveros, Phys. Chem. Chem. Phys.
2002, 4, 622–1627; e) O. N. Kalugin, A. K. Adya, M. N. Volobuev,
Y. V. Kolesnik, Phys. Chem. Chem. Phys. 2003, 5, 1536–1546.
[20] a) R. M. Yebeutchou, F. Tancini, N. Demitri, S. Geremia, R. Mendi-
chi, E. Dalcanale, Angew. Chem. 2008, 120, 4580–4584; Angew.
Chem. Int. Ed. 2008, 47, 4504–4508; b) E. Biavardi, G. Battistini, M.
Montalti, R. M. Yebeutchou, L. Prodi, E. Dalcanale, Chem.
Commun. 2008, 1638–1640; c) B. Gadenne, M. Semeraro, R. M. Ye-
beutchou, F. Tancini, L. Pirondini, E. Dalcanale, A. Credi, Chem.
Eur. J. 2008, 14, 8964–8971.
[21] J. L. Cook, C. A. Hunter, C. M. R. Low, A. Perez-Velasco, J. G.
Vinter, Angew. Chem. 2007, 119, 3780–3783; Angew. Chem. Int. Ed.
2007, 46, 3706–3709.
[22] F. E. Evans, N. O. Kaplan, FEBS Lett. 1979, 105, 11–14.
[23] The guest concentration required by ITC is much lower than that re-
quired by NMR spectroscopy and thus complete octylammonium
iodide solubilization can occur in CHCl3 at room temperature.
[24] J. L. Sessler, D. E. Gross, W.-S. Cho, V. M. Lynch, F. P. Schmidtchen,
G. W. Bates, M. E. Light, P. A. Gale, J. Am. Chem. Soc. 2006, 128,
12281–12288.
[10] For examples of aromatic CH–anion interactions, see: a) D.-W.
Yoon, H. Hwang, C.-H. Lee, Angew. Chem. 2002, 114, 1835–1837 ;
Angew. Chem. Int. Ed. 2002, 41, 1757–1759; b) K. Chellappan, N. J.
Singh, I.-C. Hwang, J. W. Lee, K. S. Kim, Angew. Chem. 2005, 117,
2959–2963; Angew. Chem. Int. Ed. 2005, 44, 2899–2903; c) V. S.
Bryantsev, B. P. Hay, J. Am. Chem. Soc. 2005, 127, 8282–8283; <
lit d>W. J. Belcher, M. Fabre, T. Farhan, J. W. Steed, Org. Biomol.
Chem. 2006, 4, 781–786.
[11] a) C. H. Lee, H.-K. Na, D.-W. Yoon, D.-H. Won, W.-S. Cho, V. M.
Lynch, S. V. Schevchuk, J. L. Sessler, J. Am. Chem. Soc. 2003, 125,
7301–7306; b) S. O. Kang, D. VanderVelde, D. Powell, K. Bowman-
James, J. Am. Chem. Soc. 2004, 126, 12272–12273; c) Q.-Y. Chen,
C.-F. Chen, Tetrahedron Lett. 2004, 45, 6493–6496.
[12] For examples of nonaromatic CH–anion interactions, see: a) C. A.
Ilioudis, D. A. Tocher, J. W. Steed, J. Am. Chem. Soc. 2004, 126,
12395–12402; b) H. Maeda, Y. Kusunose, Chem. Eur. J. 2005, 11,
5661–5666.
[25] a) S. Roelens, R. Torriti, J. Am. Chem. Soc. 1998, 120, 12443–12452;
b) V. Bçhmer, A. Dalla Cort, L. Mandolini, J. Org. Chem. 2001, 66,
1900–1902.
[26] “Isothermal Titration Calorimetry”: F. P. Schmidtchen in Encyclope-
dia of Supramolecular Chemistry (Eds.: J. E. Atwood, J. W. Steed),
Taylor & Francis, Botta Raton, 2007.
[27] a) C. F. Purchase, O. P. Goel, J. Org. Chem. 1991, 56, 457–459;
b) C.-L. Chang, M.-K. Leunga, M.-H. Yang, Tetrahedron 2004, 60,
9205–9212.
[13] Even though Schalley et al. have demonstrated that methylene-
bridged cavitands are able to bind anionic species in the gas phase,
no evidence has ever been shown of such an affinity between anions
and methylene-bridged cavitands in solution, in which the solvent
effect cannot be neglected. For anion binding with methylene-
bridged cavitands in the gas phase, see: S. S. Zhu, H. Staats, K.
Brandhorst, J. Grunenberg, F. Gruppi, E. Dalcanale, A. Lꢁtzen, K.
Rissanen, C. A. Schalley, Angew. Chem. 2008, 120, 800–804; Angew.
Chem. Int. Ed. 2008, 47, 788–792.
[28] This compound is commercially available from Acros Organics,
CAS 142-95-0.
[29] M. L. Rojas-Cervantes, B. Casal, P. Aranda, M. Savirꢅn, J. C.
Galvꢆn, E. Ruitz-Hitzky, Colloid Polym. Sci. 2001, 279, 990–1004.
Received: March 4, 2010
Published online: June 10, 2010
Chem. Eur. J. 2010, 16, 7813 – 7819
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7819