Facile, high-yielding synthesis of deepened cavitands: A synthetic and theoretical study

Article abstract of DOI:10.1080/10610278.2011.593633

A wide variety of 2-methyl-resorcinol-based deepened cavitands were synthesised from readily available reagents in a fourstep procedure with overall yields of up to 62%. A systematic variation of the rim was carried out by building up a flexible upper aro

Full text of DOI:10.1080/10610278.2011.593633

This article was downloaded by: [University of Connecticut]
On: 26 February 2013, At: 01:08
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer
House, 37-41 Mortimer Street, London W1T 3JH, UK
Supramolecular Chemistry
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/gsch20
Facile, high-yielding synthesis of deepened
cavitands: a synthetic and theoretical study
Zsolt Csók a , Tamás Kégl a , László Párkányi b , Ágnes Varga c , Sándor Kunsági-Máté c &
László Kollár a
a Department of Inorganic Chemistry, University of Pécs, Ifjúság 6, H-7624, Pécs,
Hungary
b X-ray Diffraction Laboratory, Institute of Structural Chemistry, Chemical Research
Center, Hungrian Academy of Science, Pusztaszeri 59-67, H-1025, Budapest, Hungary
c Department of General and Physical Chemistry, University of Pécs, Ifjúság 6, H-7624,
Pécs, Hungary
Version of record first published: 06 Jul 2011.
To cite this article: Zsolt Csók , Tamás Kégl , László Párkányi , Ágnes Varga , Sándor Kunsági-Máté & László Kollár (2011):
Facile, high-yielding synthesis of deepened cavitands: a synthetic and theoretical study, Supramolecular Chemistry, 23:10,
710-719
To link to this article: http://dx.doi.org/10.1080/10610278.2011.593633
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to
anyone is expressly forbidden.
The publisher does not give any warranty express or implied or make any representation that the contents
will be complete or accurate or up to date. The accuracy of any instructions, formulae, and drug doses
should be independently verified with primary sources. The publisher shall not be liable for any loss, actions,
claims, proceedings, demand, or costs or damages whatsoever or howsoever caused arising directly or
indirectly in connection with or arising out of the use of this material.

Supramolecular Chemistry
Vol. 23, No. 10, October 2011, 710–719
Facile, high-yielding synthesis of deepened cavitands: a synthetic and theoretical study
a
Zsolt Csok *, Tamas Kegl , Laszlo Parkanyi , Agnes Varga , Sandor Kunsagi-Mate and Laszlo Kollar
a
b
c
a
´ ´c
´
´
´
´
´
´
´
´
´
´
´
´
´
a
b
Department of Inorganic Chemistry, University of Pecs, Ifjusag 6, H-7624 Pecs, Hungary; X-ray Diffraction Laboratory, Institute of
´
´ ´
´
Structural Chemistry, Chemical Research Center, Hungrian Academy of Science, Pusztaszeri 59-67, H-1025 Budapest, Hungary;
c
´ ´ ´ ´
Department of General and Physical Chemistry, University of Pecs, Ifjusag 6, H-7624 Pecs, Hungary
(Received 8 December 2010; final version received 9 May 2011)
A wide variety of 2-methyl-resorcinol-based deepened cavitands were synthesised from readily available reagents in a four-
step procedure with overall yields of up to 62%. A systematic variation of the rim was carried out by building up a flexible
upper aromatic wall on the rigid cavitand platform through CH2, CH2O and CH2OCH2 spacers. These aromatic walls were
further extended by a Suzuki cross-coupling reaction. Full characterisation of the synthesised cavitands was carried out. The
solid-state structure of tetrakis(phenoxymethyl)cavitand was determined by X-ray crystallography. Gas-phase theoretical
calculations for this molecule predict the presence of weak T-shaped interactions between the upper phenyl rings. The host–
guest complex formation ability of two deepened cavitand hosts towards 4-chloro-benzotrifluoride was proved by
photoluminescence method.
Keywords: supramolecular chemistry; host–guest systems; cavitands; p interactions
1. Introduction
important part in constructing large molecular capsules
with increased internal cavities (8). On the other hand,
these non-covalent systems often suffer from relative
instability, functional group intolerance and insolubility in
organic solvents.
The ‘molecule within a molecule’ concept was first
introduced by Cram (1). Since then, there has been an ever
growing interest in molecular containers having expanded
inner cavities capable of housing sizable or multiple
guests. Molecular containers are of particular interest in
separation science, drug-delivery systems and molecular
sensing and recognition (2). Host molecules are able to
shield their guests from the exterior solution, which might
cause radical changes in their physical and/or chemical
properties. This phenomenon was demonstrated well, e.g.
in the stabilisation of short-lived reaction species such as
cyclobutadiene (3). Furthermore, the encapsulation of
guest molecules within an extended cage and subsequent
release of the products may result in their use as nanosized
reactor chambers (4).
First-generation cavitands (9) based on resorcin[4]
arenes (10) are conformationally rigid, bowl-shaped
molecules, and thus, are ideal platforms for accommodating
small molecules, ions or both. Various synthetic strategies
have been developed to produce deepened cavitands with an
open end. The depth of the cavitands was increased either
by Suzuki cross-coupling reactions (11) or by bridging the
resorcinarene hydroxyl groups with 1,4-diazine derivatives
(12). The latter family of cavitands was developed further
into one of the largest synthetic hosts, which are able to
complex extended adamantane and pyridine derivatives of
˚
up to 19A in length (13). Surprisingly, only a few studies
Several synthetic methodologies were developed to
increase the inner volume of molecular containers. The
covalent synthesis of the first closed-surface carcerand and
its carceplex (5) has inspired a number of researchers to
prepare structurally well-defined container compounds
and determine their host–guest binding properties (6).
However, these synthetic procedures mostly involve
intricate reaction routes that are frequently combined
with low isolated yields, which make their application
rather limited. Recently, dynamic covalent chemistry has
been effectively utilised to overcome such difficulties (7).
Self-assembly through metal–ligand interactions, van der
Waals forces and, mainly, hydrogen bonding also plays an
utilise the convenient Williamson etherification on the rim
of the cavitand skeleton (14). Herein, we report a facile,
high-yielding synthetic procedure and full characterisation
of a novel family of deepened cavitands.
2. Results and discussion
2.1 Synthetic studies
This series of deepened cavitands was synthesised in four
simple, high-yielding steps, starting from 2-methylresor-
cinol and acetaldehyde (Scheme 1). The obtained
tetrakis(methyl)resorcin[4]arene (15) (1) was bridged by
*Corresponding author. Email: zscsok@gmail.com
ISSN 1061-0278 print/ISSN 1029-0478 online
q 2011 Taylor & Francis
http://dx.doi.org/10.1080/10610278.2011.593633
http://www.tandfonline.com

Supramolecular Chemistry
711
Scheme 1. Synthetic route for the deepened cavitands.
BrCH2Cl (2) (16), and selectively brominated according to
Sorrell and Pigge (17) using azobisisobutyronitrile as a
catalyst to afford tetrakis(bromomethyl)cavitand (3) in
80% combined yield. Cavitand 3 was then reacted with an
excess of various aliphatic alcohols and phenols in the
presence of an adequate base to give the corresponding
tetrakis(alkoxymethyl) (5, 6, 10) and tetrakis(aryloxy-
methyl)cavitands (7–9) in high (60–78%) isolated yields.
These reactions proceeded well at room temperature;
however, full etherification was only seen at 708C after
16 h. Sodium hydroxide was used to deprotonate phenol
derivatives, whereas K2CO3 was sufficient to carry out the
reaction with methanol. Sodium hydride was used for the
preparation of 10. All these cavitands turned out to be pure
after carrying out a simple work-up procedure, except for
compound 8 that required further purification. Cavitand 3
was also reacted with PhB(OH)2 under typical Suzuki-
reaction conditions to yield tetrabenzylcavitand (11).
The presence of an unidentified minor component made
purification by column chromatography inevitable, which
dramatically decreased the yield to 24% in this coupling
reaction. Compound 9, bearing four aryl iodide moieties,
was used to further extend the aromatic walls of the cavity
in a Suzuki cross-coupling reaction (Scheme 2). This
reaction provided cavitand 12 with a considerably large,
hydrophobic pocket in good yield (59%).
We also describe a simple method for the synthesis of
tetrakis(hydroxymethyl)cavitand (4). This key intermedi-
ate was previously prepared either by LiAlH4 reduction of
tetraesters (5, 18) or by hydrolysis of the tetra(acetox-
ymethyl)cavitand (19). Here, we propose NaOH hydroly-
sis of 3 that affords 4 in excellent yield (81%). Tetrol 4 was
used to synthesise 10 using the easily available benzyl
bromide derivative (see Section 4, Method B).
All compounds possess a high degree of symmetry (C4)
due to the complete, fourfold etherification, which is
reflected in their simple 1H NMR spectra. The formation of
the alkyl(aryl)oxymethyl cavitands was best followed by

´
Z. Csok et al.
712
Scheme 2. Synthesis of tetrakis(4-phenyl-phenoxymethyl)cavitand (12).
the unique downfield shifts of the methylene-spacer
(ArCH2O) protons (Figure 1). Upon carrying out the
Suzuki cross-coupling reaction, this singlet resonance was
upfield shifted to 3.71 ppm in cavitand 11. The chemical
shifts of the methyleneoxy-bridge (OCH2O) protons are
also characteristic; they appear as a sharp pair of doublets
indicating the inherent rigidity of the cavitand framework.
All signals of the ‘parent’ cavitand skeleton are broadened
in CDCl3 in the 1H NMR spectrum of compound 6,
whereas the resonances of the C12 alkyl chain remain sharp
(Figure 1). However, the observed line broadening
disappears upon changing the NMR solvent to DMSO-d6.
Compound 6 bearing long alkyl chains resembles the
cavitand obtained by ring-opening metathesis poly-
merisation of caprolactam (20). The structural assignments
of this cavitand family were also confirmed by 13C NMR
and MALDI-TOF-MS measurements. The matrix [2,
5-dihydroxybenzoic acid (DHB)] and the solvents used
contain sodium ions; thus, sodium adducts are commonly
detected by MALDI-TOF-MS. The mass shifts were only
[M þ 22]þ instead of the expected [M þ 23]þ due to the
difference in the average mass that is always higher than
monoisotopic mass, and because of the inhomogeneous
matrix/sample mixture layer, which is quite usual with
DHB. In these cases, a mass shift of 0.2–0.3 Da was
obtained according to the appeared double peaks.
Colourless single crystals of 7 suitable for X-ray
crystallography were obtained from a CHCl3/MeOH
recrystallisation chamber. The molecular structure of 7 is
shown in Figure 2. Dihedral angles formed by the planes of
the C1· · ·C6 rings are 76.68 (A/B, A/C, B/D, C/D) and
57.58 (A/D, B/C). Each ring forms two different dihedral
angles with its neighbours, i.e. the dihedral angles
alternate. The C8· · ·C13 ring planes behave differently.
They form identical dihedral angles with their neighbours
(83.68) and a different one across the macrocycle (38.98).
Characteristic torsion angles of the linkers joining the
structural units range from 91.48 to 100.98 (Table 1).
2.2 Theoretical studies
The geometry of compound 7 was optimised at the
PBEPBE/6-31G(d,p) level of theory, and the resulting
structure is shown in Figure 3. The minimum-energy
structure exhibits symmetry very close to C4. Most of the
computed structural parameters (bond length, bond angles
and torsion angles) are in reasonable agreement with the
X-ray structure of 7. The deviation from C4v symmetry to
C4 is a consequence of the deviation of dihedral angle
(C6ZC1ZC7ZO4) from 2908 to 277.88 (276.48 in the
X-ray structure). The rotation of the phenoxy groups
around the C1ZC7 axis (and the analogous carbon–
carbon bonds) results in a subtle change in the bond
lengths as well as in the natural population analysis (NPA)
charges of the aromatic rings and the OCH2O bridges of
the cavitand skeleton. The CZC distances in the aromatic
1
Figure 1. Partial H NMR spectra of 5–9 and 11, W and £
˚
rings are somewhat elongated compared to 1.403 A in
benzene, optimised at the same level of theory as 7.
denote the spacer methylene and methyne protons, respectively
(
stands for the residual protons of CH Cl ).
2
*
2

Supramolecular Chemistry
713
Figure 2. (a) Molecular diagram of 7 with the atomic numbering (hydrogen atoms are omitted for clarity). Atomic displacement
ellipsoids represent 40% probabilities. (b) Top view of the molecule. Symmetry generated parts are drawn in green, blue and red colours.
Carbon atoms are denoted by bar numbers.
The main difference between the computed and the
experimental structures is the significantly closer arrange-
ment of the four phenoxymethyl groups, which can be
attributed to weak interactions of the neighbouring rings
causing a slight contraction of the C12ZC13 bond. In
contrast to the T-shaped p–p interactions described in the
literature (21), in which the first ring is oriented towards the
centre of the second one, these intramolecular interactions
can be attributed mainly to the interactions between the
inner ortho(or meta)-positioned hydrogen and the ortho (or
meta) carbon of the perpendicularly orientated neighbour-
ing ring (see Figure 3). These non-contact distances are
by the H . . . C interactions between the perpendicular rings
forming a four-sided wall, and additionally, an upper and a
lower plane having one ring critical point (RCP) for each.
Figure 5 shows the Laplacian distribution f2r(r) in the
plane of the T-shaped interaction. Several other ring
structures are predicted within 7 with another CCP in the
centre of the cavitand backbone.
Espinosa et al. (22) proposed a simple formula
expressing the relationship between the hydrogen bond
energy and the local potential energy density V(r) in the
bond critical point (BCP) with the proportionality factor
being in volume atomic units:
˚
estimated to be 3.522 and 3.141 A, respectively.
1
The molecular graph of 7 (Figure 4) obtained within
the framework of the quantum theory of atoms in
molecular (QTAIM) analysis exhibits a cage critical
point (CCP), revealing a cage formed by the aromatic rings
of the phenoxymethyl substituents. This cage is outlined
EHB
¼
VðrCPÞ:
ð1Þ
2
The local potential energy density V(rCP) can be
obtained from the topological parameters using the local
˚
Table 1. Characteristic bond distances (A) and torsion angles (8).
C1ZC2
C2ZC3
C3ZC4
C2ZO1
C3ZC15
O1ZC14
C7ZO4
C8ZC13
1.399(7)
1.376(7)
1.399(7)
1.398(6)
1.536(7)
1.418(6)
1.438(5)
1.390
1.390
1.390
92.5(5)
98.8(5)
91.4(5)
C1ZC6
C5ZC6
C4ZC5
C6ZO3
C15ZC16
C1ZC7
O4ZC8
C13ZC12
C11ZC10
1.400(7)
1.388(7)
1.398(7)
1.405(6)
1.531(7)
1.509(6)
1.344
1.390
1.390
1.390
C12ZC11
C10ZC9
C9ZC8
C4ZC3ZC15ZC6a
C1ZC2ZO1ZC14
O1ZC14ZO3aZC6a
C4ZC5ZC15aZC3a
C2ZO1ZC14ZO3a
C14ZO3aZC6aZC1a
93.3(5)
292.0(5)
100.9(5)
Note: Atoms marked with a indicate neighbouring structural units.

´
Z. Csok et al.
714
Figure 3. Structure of 7 computed at the PBEPBE/6-31G(d,p)
˚
level of theory. Selected bond distances are in A. NPA charges are
in italics.
Figure 4. Molecular graph of 7 (top view). The colour scheme
identifying the critical points is as follows: red for BCPs; yellow
for RCPs and green for CCPs. The nuclear maxima are denoted
by larger spheres.
form of the virial equation:
incoming, appropriate guest molecule can enter the cavity
with a low-activation barrier.
É2
4m
VðrCPÞ ¼
72rðrCPÞ 2 2GðrCPÞ;
ð2Þ
where G is the local electronic kinetic energy density.
Using Equation (1) the interaction energy is estimated
to be 0.7 and 1.5 kcal/mol for the C . . . H interactions with
2.3 Host–guest complexation studies
As preliminary studies, the host–guest complex formation
ability of two deepened cavitand molecules (7 and 8)
towards 4-chloro-benzotrifluoride (13) was investigated by
photoluminescence (PL) method in chloroform
˚
distances 3.522 and 3.141 A, respectively. Thus, the overall
stabilisation energy for the T-shaped interactions of the
upper aromatic walls is ,10 kcal/mol, suggesting that an
Figure 5. Laplacian distribution of 7 illustrating the ‘T-shaped’ interaction between two phenyl rings. Solid lines indicate charge
concentrations (f2r(r) , 0), whereas dashed lines (f2r(r) . 0) show charge depletions. BCPs are indicated by dark grey, whereas the
RCP is light grey. Bond paths (lines of maximum electron density) linking nuclei and zero-flux surfaces (which partition the molecule into
its constituent atoms) are designated with solid lines.

Supramolecular Chemistry
715
isolation from the bulk medium can be more effective.
Theoretical calculations suggest that the formation of a
host–guest complex might take place via a small activation
barrier. This novel series of deepened cavitands may be
useful for complexing electron-poor aromatics, such as
nitroaromatics, benzotrifluorides, and so on due to the
presence of a flexible binding pocket with tunable electron
density. Indeed, two of these deepened cavitands (7 and 8)
behave as hosts and show the formation of 1:1 complexes
with 4-chloro-benzotrifluoride as a guest. Furthermore,
cavitand 9, bearing four aryl iodide moieties, may serve as
a potential intermediate for further functionalisation of this
cavitand family, as demonstrated in the synthesis of
cavitand 12.
Figure 6. Job’s plot of the interaction of host 8 with 4-chloro-
benzotrifluoride (13).
4. Experimental
4.1 General procedures and materials
(see Section 4). The Benesi–Hildebrand method com-
bined with the van’t Hoff theory was applied to calculate
the thermodynamic parameters of the molecular associ-
ation. The results justified the presence of the host–guest
complexes in solution with considerable concentration and
possessing 1:1 stoichiometry. Figure 6 shows Job’s plot of
the interaction of host 8 with 13. However, our
experiments show significantly different thermodynamics
for the complex formation. Although these host–guest
interactions are associated with almost the same Gibbs-
free energy changes at room temperature (DG ¼ 226.8 -
kJ/mol for 7:13 and DG ¼ 227.2 kJ/mol for 8:13,
respectively), the enthalpy change is much higher when
the complex of 7 is formed (DH ¼ 236.8 kJ/mol for 7:13
and DH ¼ 229.2 kJ/mol for 8:13, respectively). The
entropy changes were found to be considerably different
(DS ¼ 233.5 J/K mol for 7:13 and DS ¼ 26.7 J/K mol for
8:13, respectively). The well-known enthalpy–entropy
compensation may be responsible for this unexpected
phenomenon, which is probably due to the steric hindrance
of the methyl groups located on the upper phenyl rings of
compound 8. The stability constants Kass at room-
temperature were determined to be 4.9 £ 105 dm3/mol
for 7:13 and 5.8 £ 105 dm3/mol for 8:13 complexes,
respectively.
All reagents and solvents were purchased from Aldrich
(Budapest, Hungary). For the synthesis of 10, tetrahy-
drofuran (THF) was distilled from sodium/benzophenone
under argon atmosphere, and the reaction was carried out
under Ar by using standard Schlenk-techniques. General
work-up procedure is as follows: the reaction mixture was
partitioned between CH2Cl2 (30 ml) and water (30 ml).
The organic phase was separated, and the aqueous phase
was extracted with another portion of CH2Cl2 (30 ml). The
combined organic phases were washed with water
(2 £ 30 ml), dried over MgSO4 and evaporated to dryness.
The residue was treated with MeOH, and the resulting
1
precipitate was collected by filtration. H and 13C NMR
spectra were recorded at 258C in CDCl3 on a Varian Inova
400 spectrometer at 400.13 and 100.62 MHz, respectively.
1
The H and 13C chemical shifts (d), reported in parts per
million (ppm) downfield, are referenced to residual CHCl3
(7.26 ppm) and to the carbon resonance of CDCl3
(77.00 ppm), respectively. MALDI-TOF spectra were
obtained on an Autoflex II TOF/TOF spectrometer (Bruker
Daltonics, Bremen, Germany) in positive ion modes, using
a 337 nm pulsed nitrogen laser (accelerating voltage:
20.0 kV, matrix: DHB).
4.2 Crystallography
3. Conclusions
CCDC-795580 contains the supplementary crystallo-
graphic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
In sum, Williamson etherification provides easy access to a
wide variety of deepened cavitands from readily available,
inexpensive alcohols. The synthesised cavitands exhibit
high stability and good solubility in most organic solvents.
The upper aromatic walls are attached to a rigid cavitand
platform through CH2, CH2O and CH2OCH2 spacers.
Hence, this ‘upper cavity’ of the molecule possesses some
flexibility, which allows potential guest molecules to enter
and to be more or less surrounded by the walls of the host.
In this way, the entrapment of guest molecules and their
Crystal data: C64H56O12; MW: 1017.09; colourless;
block size: 0.37 £ 0.35 £ 0.35 mm; tetragonal space group
˚
˚
P4/ncc (No. 130); a ¼ 15.4744(13) A; c ¼ 25.423(2) A;
0.076 mm21; F(0 0 0) ¼ 2144.
V ¼ 6087.7(9) A ; Z ¼ 4; Dx ¼ 1.110 g cm23; m ¼
3
˚
Data collection: Intensity data were collected on a
Rigaku R-Axis Rapid diffractometer with Mo-Ka radiation

´
Z. Csok et al.
716
˚
(l ¼ 0.71075 A) at room temperature. A total of 46,012
reflections were collected of which 1602 were unique,
Rint ¼ 0.067. Numerical absorption correction (23) was
applied to the data (the minimum and maximum
transmission factors were 0.975 and 0.986). The crystals
General work-up procedure, white solid (m ¼ 185 mg,
78%).
1H NMR (CDCl3): 1.75 (d, J ¼ 7.5 Hz, 12H, CH3CH);
3.32 (s, 12H, OCH3); 4.27 (s, 8H, ArCH2O); 4.39 (d,
J ¼ 7.2 Hz, 4H, inner of OCH2O); 5.02 (q, J ¼ 7.5 Hz, 4H,
CHCH3); 5.85 (d, J ¼ 7.2 Hz, 4H, outer of OCH2O); 7.25
(s, 4H, Ar). 13C NMR (CDCl3): 16.04 (CH3CH); 31.06
(CH3CH); 58.45 (OCH3); 64.38 (ArCH2O); 99.52
(OCH2O); 119.86; 123.89; 138.70; 153.54. MS: 791.24
[M þ 22]þ.
˚
diffract poorly, andthe resolutionofthe dataislimitedto1 A.
Structure solution and refinement: The structure was
solved with direct methods and refined by anisotropic full-
matrix least-squares refinement (24) on F 2. Hydrogen
positional coordinates were calculated from assumed
geometries and were not refined. Difference electron
density maps indicate the presence of highly disordered
solvent molecules. The SQUEEZE procedure of program
PLATON (25) was applied, and the solvent-free data were
used in further refinement cycles (solvent accessible
4.3.3 Tetrakis(dodecanoxymethyl)cavitand (6)
To the THF (10 ml) solution of 881 mg (4.73 mmol) of 1-
dodecanol, 5 ml of 0.95 M aqueous NaOH solution was
added, and was left stirring for 30 min. This solution was
then slowly added to the THF (10 ml) solution of 285 mg
(0.3 mmol) of 3. The reaction mixture was stirred at 708C
for 16 h. General work-up procedure, white solid
(m ¼ 249 mg, 60%).
3
˚
volume 1309.0 A , total electron count 162 e). Atoms of
the C8· · ·C13 phenyl ring were fitted to a regular hexagon
and treated as a rigid group throughout the refinement.
A total of 1602 reflections were used for the refinement
of 158 parameters (R ¼ 0.1043, wR2 ¼ 0.2403 for all
intensity data; R ¼ 0.0798, wR2 ¼ 0.2189 for 1332
[I . 2s(I)], goodness of fit ¼ 1.10). The minimum and
1H NMR (CDCl3): 0.88 (t, J ¼ 6.8 Hz, 12H); 1.26 (br
m, 72H); 1.56 (quint, J ¼ 6.8 Hz, 8H); 1.76 (d, J ¼ 6.8 Hz,
12H, CH3CH); 3.63 (t, J ¼ 6.8 Hz, 8H, OCH2R); 4.56 (br
m, 12H, outer of OCH2O overlapping with ArCH2O); 5.03
(br s, 4H, CHCH3); 5.91 (br s, 4H, outer of OCH2O); 7.25
(s, 4H, Ar). 13C NMR (CDCl3): 14.08; 16.04 (CH3CH);
22.67; 25.74; 29.33; 29.42; 29.60 (triple intensity); 29.70;
31.13 (CH3CH); 31.90; 32.81; 55.37 (ArCH2O); 63.09;
99.74 (OCH2O); 119.62; 126.35; 139.05; 153.21.
maximum final residual electron density was 20.23,
23
˚
˚
0.18 eA . A cavity of 2.34 A radius is inside the cavitand
moiety (the centre of the sphere is at 0.250, 0.250 and
0.400). The whole molecule was generated by the
1/2 2 y,x,z; 1/2 2 x, 1/2 2 y,z and y,1/2 2 x,z symmetry
operations (Figure 2).
4.3 Synthetic procedures
4.3.1 Tetrakis(hydroxymethyl)cavitand (4)
4.3.4 Tetrakis(phenoxymethyl)cavitand (7)
To the THF (30 ml) solution of 1 g (1.04 mmol) of 3, 30 ml
of 1 M aqueous NaOH solution was added. The reaction
mixture was stirred at 708C for 48 h. The reaction mixture
was partitioned between CH2Cl2 (60 ml) and water
(30 ml). The organic phase was separated, and the aqueous
phase was extracted with another portion of CH2Cl2
(30 ml). The combined organic phases were washed with
0.5% aq. HCl solution (30 ml), water (60 ml) and dried
over MgSO4. Evaporation of the solvent yielded a light
yellow solid (m ¼ 600 mg, 81%).
To the THF (10 ml) solution of 200 mg (0.21 mmol) of 3,
2 ml of 1 M aqueous solution of NaOPh (freshly prepared
from phenol and NaOH) was added. The reaction mixture
was stirred at 708C for 16 h. General work-up procedure,
white solid (m ¼ 160 mg, 75%).
1H NMR (CDCl3): 1.83 (d, J ¼ 7.4 Hz, 12H, CH3CH);
4.69 (d, J ¼ 7.3 Hz, 4H, inner of OCH2O); 4.91 (s, 8H,
ArCH2O); 5.10 (q, J ¼ 7.4 Hz, 4H, CHCH3); 5.77 (d,
J ¼ 7.3 Hz, 4H, outer of OCH2O); 6.94 (m, 12H, Ph); 7.25
(m, 8H, Ph); 7.40 (s, 4H, Ar). 13C NMR (CDCl3): 16.19
(CH3CH); 31.22 (CH3CH); 60.45 (ArCH2O); 100.10
(OCH2O); 114.58; 120.50; 121.01; 122.77; 129.51;
138.90; 154.04; 158.71. MS: 1039.20 [M þ 22]þ.
1H NMR (CDCl3): 1.77 (d, J ¼ 6.9 Hz, 12H, CH3CH);
4.44 (d, J ¼ 6.8 Hz, 4H, inner of OCH2O); 4.54 (s, 8H,
ArCH2O); 5.03 (q, J ¼ 6.9 Hz, 4H, CHCH3); 5.91 (d,
J ¼ 6.8 Hz, 4H, outer of OCH2O); 7.26 (s, 4H, Ar). 13C
NMR (CDCl3): 16.02 (CH3CH); 31.09 (CH3CH); 55.36
(CH2OH); 99.67 (OCH2O); 119.61; 126.25; 139.03;
153.10. MS: 735.17 [M þ 22]þ.
4.3.5 Tetrakis(mesytoxymethyl)cavitand (8)
To the THF (10 ml) solution of 920 mg (6.76 mmol) of
2,4,6-trimethylphenol, 10 ml of 0.68 M aqueous NaOH
solution was added, and was left stirring for 30 min. This
light-violet solution was then slowly added to the THF
(10 ml) solution of 400 mg (0.41 mmol) of 3. The reaction
mixture was stirred at 708C for 16 h. General work-up
4.3.2 Tetrakis(methoxymethyl)cavitand (5)
To the THF (15 ml) solution of 300 mg (0.31 mmol) of 3,
10 ml of MeOH and 689 mg (4.96 mmol) of K2CO3 were
added. The reaction mixture was stirred at 708C for 16 h.

Supramolecular Chemistry
717
procedure, white solid (m ¼ 350 mg, 72%). An analytically
pure sample was obtained by column chromatography
(silica gel; eluent:benzene, Rf ¼ 0.51).
5.60 (d, J ¼ 7.1 Hz, 4H, outer of OCH2O); 7.20–7.40 (m,
24H, Ar and Ph). 13C NMR (CDCl3): 16.10 (CH3CH);
31.11 (CH3CH); 61.72 (ArCH2O), 72.85 (OCH2Ph), 99.53
(OCH2O); 119.88; 123.84; 127.76; 128.32 (double
intensity); 130.09; 138.71; 153.72. MS: 1095.53
[M þ 22]þ.
1H NMR (CDCl3): 1.85 (d, J ¼ 7.4 Hz, 12H, CH3CH);
2.22 (s, 12H, ArCH3); 2.27 (s, 24H, ArCH3); 4.50 (d,
J ¼ 7.2 Hz, 4H, inner of OCH2O); 4.61 (s, 8H, ArOCH2);
5.18 (q, J ¼ 7.4 Hz, 4H, CHCH3); 6.00 (d, J ¼ 7.2 Hz, 4H,
outer of OCH2O); 6.81 (s, 8H, Ar); 7.42 (s, 4H, Ar). 13C
NMR (CDCl3): 16.17 (CH3CH); 16.24 (ArCH3); 20.57
(ArCH3); 31.31 (CH3CH); 64.19 (OCH2); 100.20
(OCH2O); 120.49; 122.96; 129.54; 130.74; 133.47;
139.24; 153.29; 153.98. MS: 1207.68 [M þ 22]þ.
4.3.8 Tetrabenzylcavitand (11)
To the toluene (60 ml) solution of 1.04 g (1 mmol) of 3,
under Ar atmosphere 12 mg (0.05 mmol) of Pd(OAc)2,
28 mg (0.1 mmol) of PPh3, 1.15 g (8.3 mmol) of K2CO3
and 760 mg (6.2 mmol) of PhB(OH)2 were added. The
reaction mixture was vigorously stirred at 1008C for 16 h.
After cooling, it was filtered through a layer of Celite, and
evaporated to dryness. Column chromatography (silica
gel; eluent:benzene/n-hexane ¼ 4:1, Rf ¼ 0.64) yielded
the product as white solid (229 mg, 24%).
1H NMR (CDCl3): 1.72 (d, J ¼ 7.4 Hz, 12H, CH3CH);
3.71 (s, 8H, ArCH2Ph); 4.29 (d, J ¼ 6.9 Hz, 4H, inner of
OCH2O); 4.98 (q, J ¼ 7.4 Hz, 4H, CHCH3); 5.90 (d,
J ¼ 6.9 Hz, 4H, outer of OCH2O); 7.15–7.26 (m, 24H, Ar
and Ph). 13C NMR (CD2Cl2): 19.66 (CH3CH); 31.66
(ArCH2Ar); 32.14 (CH3CH); 99.86 (OCH2O); 119.33;
126.67; 127.35; 128.85; 129.19; 139.74; 141.01; 153.49.
MS: 975.50 [M þ 22]þ; 953.44 [M]þ.
4.3.6 Tetrakis(4-iodo-phenoxymethyl)cavitand (9)
To the THF (10 ml) solution of 740 mg (3.36 mmol) of 4-
iodophenol, 10 ml of 0.34 M aqueous NaOH solution was
added, and was left stirring for 30 min. This solution was
then slowly added to the THF (10 ml) solution of 200 mg
(0.21 mmol). The reaction mixture was stirred at 708C for
16 h. General work-up procedure, white solid
(m ¼ 215 mg, 67%).
1H NMR (CDCl3): 1.81 (d, J ¼ 7.4 Hz, 12H, CH3CH);
4.59 (d, J ¼ 7.3 Hz, 4H, inner of OCH2O); 4.86 (s, 8H,
ArCH2O); 5.07 (q, J ¼ 7.4 Hz, 4H, CHCH3); 5.73 (d,
J ¼ 7.3 Hz, 4H, outer of OCH2O); 6.66 (d, J ¼ 8.7 Hz, 8H,
Ar); 7.38 (s, 4H, Ar); 7.54 (d, J ¼ 8.7 Hz, 8H, Ar). 13C
NMR (CDCl3): 16.13 (CH3CH); 31.20 (CH3CH); 60.62
(OCH2); 83.30; 99.95 (OCH2O); 116.84; 120.71; 122.31;
138.39; 138.95; 153.93; 158.44. MS: 1542.77 [M þ 22]þ.
4.3.9 Tetrakis(4-phenyl-phenoxymethyl)cavitand (12)
To the toluene (20 ml) solution of 380 mg (0.25 mmol) of
9, under Ar atmosphere 2.9 mg (0.013 mmol) of Pd(OAc)2,
6.8 mg (0.026 mmol) of PPh3, 276 mg (2 mmol) of K2CO3
and 183 mg (1.5 mmol) of PhB(OH)2 were added. The
reaction mixture was vigorously stirred at 808C for 2 days.
After cooling, it was filtered through a layer of Celite, and
evaporated to dryness. The residue was treated with
MeOH, and the resulting precipitate was collected by
filtration (195 mg, 59%).
1H NMR (CDCl3): 1.85 (d, J ¼ 7.4 Hz, 12H, CH3CH);
4.73 (d, J ¼ 7.3 Hz, 4H, inner of OCH2O); 4.97 (s, 8H,
ArCH2Ph); 5.12 (q, J ¼ 7.4 Hz, 4H, CHCH3); 5.82 (d,
J ¼ 7.3 Hz, 4H, outer of OCH2O); 6.99 (d, J ¼ 8.5 Hz, 8H,
Ph); 7.27–7.53 (m, 32H, Ar and Ph). 13C NMR (CD2Cl3):
16.20 (CH3CH); 31.26 (CH3CH); 60.66 (ArCH2O);
100.17 (OCH2O); 114.89; 120.62; 122.78; 126.65;
128.17; 128.70; 134.12; 138.95; 140.55; 154.08; 158.25.
MS: 1343.41 [M þ 22]þ.
4.3.7 Tetrakis(benzyloxymethyl)cavitand (10)
Method A: To the THF (10 ml) solution of 0.26 ml
(2.5 mmol) of benzyl alcohol, 100 mg (2.5 mmol) of 60%
NaH was added, and the mixture was left stirring for
30 min. Then, THF (10 ml) solution of 300 mg
(0.31 mmol) of 3 was slowly added. The reaction mixture
was stirred at 708C for 16 h and it was poured into 30 ml
0.1 N HCl. Then 30 ml of CH2Cl2 was added, the organic
phase was separated and the aqueous phase was extracted
with another portion of CH2Cl2 (30 ml). The combined
organic phases were washed with water (2 £ 30 ml), dried
over MgSO4 and evaporated to dryness. The residue was
treated with MeOH, and the resulting precipitate was
collected by filtration. White solid, m ¼ 230 mg (69%).
Method B: To the THF (10 ml) solution of 200 mg
(0.28 mmol) of 4, 90mg (2.24 mmol) of 60% NaH was
added, and the mixture was left stirring for 30min. Then
0.27ml (2.24 mmol) of benzyl bromide was slowly added.
The reaction mixture was stirred at 708C for 16h. Work-up
as described in Method A. White solid, m ¼ 160 mg (53%).
1H NMR (CDCl3): 1.74 (d, J ¼ 7.3 Hz, 12H, CH3CH);
4.28 (m, 12H, ArCH2O overlapped with inner of OCH2O);
4.47 (s, 8H, OCH2Ph); 5.00 (q, J ¼ 7.3 Hz, 4H, CHCH3);
4.4 Computational details
The geometry of 7 was calculated without any symmetry
constraints using the gradient-corrected exchange func-
tional developed by Perdew et al. (26) in combination with
a correlation functional, developed also by the same

´
Z. Csok et al.
718
(4) Vriezema, D.M.; Aragones, M.C.; Elemans, J.A.A.W.;
Cornelissen, J.J.L.M.; Rowan, A.E.; Nolte, R.J.M. Chem.
Rev. 2005, 105, 1445–1489.
(5) (a) Cram, D.J.; Karbach, S.; Kim, Y.H.; Baczynskyj, L.;
Kalleymeyn, G.W. J. Am. Chem. Soc. 1985, 107, 2575–
2576; (b) Cram, D.J.;; Karbach, S.; Kim, Y.H.; Baczynskyj,
L.; Marti, K.; Sampson, R.M.; Kalleymeyn, G.W. J. Am.
Chem. Soc. 1988, 110, 2554–2560.
(6) (a) Warmuth, R.; Yoon, J. Acc. Chem. Res. 2001, 34,
95–105; (b) Jasat, A., Sherman, J.C. Chem. Rev. 1999, 99,
931–967.
(7) Liu, X.; Warmuth, R. J. Am. Chem. Soc. 2006, 128,
14120–14127.
authors, and denoted as PBEPBE. The 6-31G(d,p) basis set
(27) was used throughout this study. For the stationary
point, the Hessian was evaluated to characterise the
genuine minimum (no imaginary frequency). NPA and
natural bond orbital analysis (28) were carried out at the
same level of theory as the one used for geometry
optimisation. For the calculations, the Gaussian 03 suite of
programs was used (29). QTAIM analysis of the wave
function was carried out with the AIM2000 software (30)
to investigate the electron density of the optimised
structure.
(8) (a) Heinz, T.; Rudkevich, D.M.; Rebek, J., Jr. Angew. Chem.
Int. Ed. Engl. 1999, 38, 1136–1139; (b) MacGillivray, L.R.;
Atwood, J.L. Nature 1997, 389, 469–472; (c) Cave,
G.W.V.; Ferrarelli, M.C.; Atwood, J.L. Chem. Commun.
2005, 2787–2789; (d) MacGillivray, L.R.; Diamente, P.R.;
Reid, J.L.; Rippmeester, J.A. Chem. Commun. 2000, 359–
360; (e) Botta, B.; Cassani, M.; D’Acquarica, I.; Subissati,
D.; Zappia, G.; Delle Monache, G. Curr. Org. Chem. 2005,
9, 1167–1202.
(9) (a) Moran, J.R.; Karbach, S.; Cram, D.J. J. Am. Chem. Soc.
1982, 104, 5826–5828; (b) Cram, D.J., Karbach, S., Kim,
H.E., Knobler, C.B., Maverick, E.F., Ericson, J.L.,
Helgeson, R.C. J. Am. Chem. Soc. 1988, 110, 2229–2237.
(10) Timmerman, P.; Verboom, W.; Reinhoudt, D.N. Tetrahe-
dron 1996, 52, 2663–2704.
4.5 Host–guest complexation experiments
The host–guest complex formation ability of two
deepened cavitands (7 and 8) towards 4-chloro-benzotri-
fluoride (13) was investigated using PL method in
chloroform. Samples containing 1024 M of 7 or 8 were
prepared for these experiments, and the PL spectra of the
host molecules were recorded both in the absence and in
the presence of 4-chloro-benzotrifluoride as a guest. The
concentration of the guest was varied from 1 £ 1024 M up
to 9 £ 1024 M through 1 £ 1024 M steps. The samples
were excited at 395 nm and the PL peak of the host
obtained at 430 nm was used for data evaluation. A highly
sensitive Fluorolog t3 spectrofluorometric system (Jobin-
Yvon/SPEX) was used for data collection; a photon
counting method with 0.2 s integration time was applied.
Excitation and emission bandwidths were set to 1 nm. One
millimetre layer thickness of the fluorescent probes with
front face detection was used to eliminate the inner filter
effect. The stoichiometry of the formed complexes was
checked by Job’s method. The Benesi–Hildebrand method
was used to determine the stability constants at all
temperatures (31). The van’t Hoff theory was applied to
calculate the thermodynamic parameters of the
interactions.
(11) (a) Ma, S.; Rudkevich, D.M.; Rebek, J., Jr. J. Am. Chem.
¨
Soc. 1998, 120, 4977–4981; (b) Aakeroy, C.B.; Schultheiss,
N.; Desper, J. Org. Lett. 2006, 12, 2607–2610.
(12) (a) Moran, J.R.; Ericson, J.L.; Dalcanale, E.; Bryant, J.A.;
Knobler, C.B.; Cram, D.J. J. Am. Chem. Soc. 1991, 113,
5707–5714; (b) Tucci, F.C.; Rudkevich, D.M.; Rebek, J., Jr.
J. Org. Chem. 1999, 64, 4555–4559.
(13) (a) Starnes, S.D.; Rudkevich, D.M.; Rebek, J., Jr. J. Am.
Chem. Soc. 2001, 123, 4659–4669; (b) Tucci, F.C.; Renslo,
A.R.; Rudkevich, D.M.; Rebek, J., Jr. Angew. Chem. Int. Ed.
2000, 39, 1076–1079.
(14) (a) Barrett, E.S.; Irwin, J.L.; Picker, K.; Sherburn, M.S.
Austr. J. Chem. 2002, 55, 319–325; (b) Boerrigter, H.;
Verboom, W.; van Hummel, G.J.; Harkema, S.; Reinhoudt,
D.N. Tetrahedron Lett. 1996, 37, 5167-5170.
(15) Tunstad, L.M.; Tucker, J.A.; Dalcanale, E.; Weiser, J.;
Bryant, J.A.; Sherman, J.C.; Helgeson, R.C.; Knobler, C.B.;
Cram, D.J. J. Org. Chem. 1989, 54, 1305–1312.
(16) Roman, E.; Peinador, C.; Mendoza, S.; Kaifer, A.E. J. Org.
Chem. 1999, 64, 2577–2578.
Acknowledgements
(17) Sorrell, T.N.; Pigge, F.C. J. Org. Chem. 1993, 58, 784–785.
(18) Dueno, E.E.; Bisht, K.S. Tetrahedron 2004, 60,
10859–10868.
(19) Pellet-Rostaing, S.; Nicod, L.; Chitry, F.; Lemaire, M.
Tetrahedron Lett. 1999, 40, 8793–8796.
This work was supported by Science, Please! Research Team on
Innovation (SROP-4.2.2/08/1/2008-0011). Z.C. and T.K. thank
the Bolyai Grants of the Hungarian Academy of Sciences. The
authors also thank the Supercomputer Center of the National
Information Infrastructure Development (NIIF) Program, and
´
´
L. Mark (University of Pecs) for carrying out the MS
experiments.
(20) Wu, R.; Al-Azemi, T.F.; Bisht, K.S. Chem. Commun. 2009,
1822–1824.
(21) Hobza, P.; Selzle, H.L.; Schlag, E.W. J. Am. Chem. Soc.
1994, 116, 3500–3506.
(22) Espinosa, E.; Molins, E.; Lecomte, C. Chem. Phys. Lett.
1998, 285, 170–173.
References
(23) Higashi, T. NUMABS, rev. 2002; Rigaku/MSC, Inc., 1998.
(24) Sheldrick, G.M. Acta Cryst. 2008, A64, 112–122.
(25) Spek, A.L. J. Appl. Cryst. 2003, 36, 7–13.
(26) Perdew, J.P.; Burke, K.; Ernzerhof, M. Phys. Rev. Lett.
1996, 77, 3865–3868.
(1) Cram, D.J. Nature 1992, 356, 29–36.
(2) Cram, D.J.; Cram, J.M. Container Molecules and their
Guests; Royal Society of Chemistry: Cambridge, 1994.
(3) Cram, D.J.; Tanner, M.E.; Thomas, R. Angew. Chem. Int.
Ed. Engl. 1991, 30, 1024–1027.

Supramolecular Chemistry
719
(27) Hehre, W.J.; Ditchfield, R.; Pople, J.A. J. Chem. Phys.
1972, 56, 2257–2261.
(28) Glendening, E.D.; Reed, A.E.; Carpenter, J.E.; Weinhold, F.
NBO Version 3.1.
Salvador, P.; Dannenberg, J.J.; Zakrzewski, V.G.;
Dapprich, S.; Daniels, A.D.; Strain, M.C.; Farkas, O.;
Malick, D.K.; Rabuck, A.D.; Raghavachari, K.; Foresman,
J.B.; Ortiz, J.V.; Cui, Q.; Baboul, A.G.; Clifford, S.;
Cioslowski, J.; Stefanov, B.B.; Liu, G.; Liashenko, A.;
Piskorz, P.; Komaromi, I.; Martin, R.L.; Fox, D.J.; Keith,
T.; Al-Laham, M.A.; Peng, C.Y.; Nanayakkara, A.;
Challacombe, M.; Gill, P.M.W.; Johnson, B.; Chen, W.;
Wong, M.W.; Gonzalez, C.; Pople, J.A. Gaussian 03,
Revision B.05; Gaussian, Inc. Pittsburgh, PA, 2003.
(29) Frisch, M.J.; Trucks, G.W.; Schlegel, H.B.; Scuseria, G.E.;
Robb, M.A.; Cheeseman, J.R.; Montgomery, J.A. Jr.;
Vreven, T.; Kudin, K.N.; Burant, J.C.; Millam, J.M.;
Iyengar, S.S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi,
M.; Scalmani, G.; Rega, N.; Petersson, G.A.; Nakatsuji, H.;
Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;
Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.;
Klene, M.; Li, X.; Knox, J.E.; Hratchian, H.P.; Cross, J.B.;
Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R.E.;
Yazyev, O.; Austin, A.J.; Cammi, R.; Pomelli, C.;
Ochterski, J.W.; Ayala, P.Y.; Morokuma, K.; Voth, G.A.;
¨
¨
¨
(30) Biegler-Konig, F.W.; Schonbom, J. AIM2000;, 2.0 ed. Buro
fu¨r Innovative Software: Bielefeld, Germany, 2002.
(31) Benesi, H.; Hildebrand, J. J. Am. Chem. Soc. 1949, 71,
2703–2707.