Bridging of resorcin[4]arenes in the chair conformation to cavitands having two pairs of axial and equatorial substituents

Article abstract of DOI:10.1021/jo9810258

Cavitands 18-22 were prepared in 29-90% yield by bridging of the chair- methylresorcin[4]arenes 3-7 with bromochloromethane. According to X-ray analysis of cavitand 19 and 1-D and 2-D NMR spectroscopy for 18, the cavitands possess a stereochemistry with t

Full text of DOI:10.1021/jo9810258

J . Org. Chem. 1998, 63, 8259-8265
8259
Br id gin g of Resor cin [4]a r en es in th e Ch a ir Con for m a tion to
Ca vita n d s Ha vin g Tw o P a ir s of Axia l a n d Equ a tor ia l Su bstitu en ts
Oskar Middel,† Willem Verboom,† Ron Hulst,‡ Huub Kooijman,§ Anthony L. Spek,§ and
David N. Reinhoudt*,†
Laboratory of Supramolecular Chemistry and Technology and Laboratory of Chemical Analysis,
University of Twente, P.O. Box 217, NL-7500 AE Enschede, The Netherlands, and Bijvoet Center for
Biomolecular Research, Crystal and Structural Chemistry, Utrecht University, Padualaan 8,
NL-3584 CH Utrecht, The Netherlands
Received May 29, 1998
Cavitands 18-22 were prepared in 29-90% yield by bridging of the chair-methylresorcin[4]arenes
3-7 with bromochloromethane. According to X-ray analysis of cavitand 19 and 1-D and 2-D NMR
spectroscopy for 18, the cavitands possess a stereochemistry with two adjacent aryl substituents
in the axial position and the two others in the equatorial position. The starting methylresorcin-
[4]arenes 3-7 were obtained exclusively in the chair conformation in 30-98% yield upon
condensation of 2-methylresorcinol with aryl aldehydes.
Ch a r t 1
In tr od u ction
Cavitands1 are attractive building blocks for the con-
struction of synthetic receptors because they have a rigid,
bowl-shaped cavity that can be used as a platform for
the attachment of ligating groups.2 The cavity is formed
by linking pairs of the eight adjacent phenolic groups of
a resorcin[4]arene.
We are interested in methyl-substituted cavitands,
because this methyl group provides a handle for upper
rim functionalization. For instance, they can be easily
(partly) converted via bromomethyl into aminomethyl-
cavitands, which we have used for the preparation of
(carbamoylmethyl)phosphoryl (CMPO)-functionalized cav-
itands3 and (thio)urea-containing, cavitand-based anion
receptors.4
Ho¨gberg5 described the condensation of various ben-
zaldehydes with resorcinol. Although the resorcin[4]-
arenes formed can have four different conformations,
crown (rccc, C4v), boat (rcct, C2v), chair (rctt, C2h), and sad-
dle (rtct, D2d), he found that only two different stereo-
isomeric octols were formed, namely, the chair and the
crown conformers (Chart 1). The ratio of both isomers
depends on the reaction conditions, with the chair (1) and
the crown conformers being the kinetically and thermo-
dynamically determined products, respectively.6 The
combination of a reversible aldol condensation and the
difference in solubility of both isomers determines the
outcome of the reaction. This was confirmed by Cram et
al.7 for the condensation of a series of substituted
benzaldehydes with (substituted) resorcinol(s). They also
found7 that the condensation of 2-methylresorcinol with
benzaldehyde gave methylresorcin[4]arene 2 exclusively
in the chair conformation (>97%), indicating the possible
influence of the methyl group on the conformation of the
methylresorcin[4]arene (Chart 2).8-10
* Fax: 0031534894645. E-mail: smct@ct.utwente.nl.
† Laboratory of Supramolecular Chemistry and Technology.
‡ Laboratory of Chemical Analysis.
§ Bijvoet Center for Biomolecular Research.
(1) For reviews, see: (a) Cram, D. J .; Cram, J . M. Container
Molecules and Their Guests. In Monographs in Supramolecular
Chemistry; Stoddart, J . F., Ed.; The Royal Society of Chemistry:
Cambridge, 1994. (b) Timmerman, P.; Verboom, W.; Reinhoudt, D. N.
Tetrahedron 1996, 52, 2663.
(7) 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.
(2) (a) Sorrell, T. N.; Pigge, F. C. J . Org. Chem. 1993, 58, 155. (b)
Boerrigter, H.; Lugtenberg, R. J . W.; Egberink, R. J . M.; Verboom, W.;
Reinhoudt, D. N.; Spek, A. L. Gazz. Chim. Ital. 1997, 127, 709.
(3) (a) Boerrigter, H.; Verboom, W.; Reinhoudt, D. N. J . Org. Chem.
1997, 62, 7148. (b) Boerrigter, H.; Verboom, W.; Reinhoudt, D. N.
Liebigs Ann./ Rec. 1997, 2247.
(4) Boerrigter, H.; Grave, L.; Nissink, J . W. M.; Chrisstoffels, L. A.
J .; van der Maas, J . H.; Verboom, W.; de J ong, F.; Reinhoudt, D. N. J .
Org. Chem. 1998, 63, 4174.
(8) When the more polar boronic acid substituted benzaldehyde was
condensed with 2-methylresorcinol in a 2:1 mixture of ethanol and HCl
(37% in water), a mixture of chair and crown conformers was obtained,
which was due to the higher solubility of both products. Lewis, P. T.;
Davis, C. J .; Saraiva, M. C.; Treleaven, W. D.; McCarley, T. D.;
Strongin, R. M. J . Org. Chem. 1997, 62, 6110.
(9) For a recent example, see: Curtis, A. D. M. Tetrahedron Lett.
1997, 38, 4295.
(10) We found that condensation of 2-methylresorcinol with aliphatic
aldehydes exclusively affords resorcin[4]arenes in the crown con-
formation.2b,3,4
(5) Ho¨gberg, A. G. S. J . Am. Chem. Soc. 1980, 102, 6046.
(6) Weinelt, F.; Schneider, H.-J . J . Org. Chem. 1991, 56, 5527.
10.1021/jo9810258 CCC: $15.00 © 1998 American Chemical Society
Published on Web 10/27/1998

8260 J . Org. Chem., Vol. 63, No. 23, 1998
Middel et al.
Ch a r t 2
same yields whereas the conformation remained un-
changed. This smooth formation of methylresorcin[4]-
arenes 3-7 and, in particular, the ability to synthesize
methylresorcin[4]arene 6 in 30% yield (when starting
from resorcinol, the corresponding resorcin[4]arene was
not formed7) can be explained in terms of a higher
electron density in 2-methylresorcinol than that in re-
sorcinol. The electrophilic attack on the methylresorcinol
by the benzaldehyde residues and, consequently, the ring
closure of the tetramers to the methylresorcin[4]arenes
3-7 will be faster. The insolubility of 3-7 in the solvent
mixture used results in the exclusive formation of the
“kinetic” chair conformers.5,6 Selectivity was lost when a
10:1 mixture of ethanol and HCl (37% in water) was used,
in the case of methylresorcin[4]arene 4, this 10:1 mixture
gave a mixture of crown and chair conformers in a 3:5
ratio. Moreover, the yield of the condensation dropped
from 98% to 25% because of the large amount of non-
resorcin[4]arene side products formed.
Ca vita n d F or m a tion . Despite the unfavorable chair
conformation of methylresorcin[4]arenes 3-7, treatment
with 6-8 equiv of bromochloromethane in the presence
of K2CO3 in DMF at 65 °C allowed faster formation of
the bowl-shaped cavitands 18-22 than that in the
corresponding reaction starting from crown-resorcin[4]-
arenes,13 in 29-90% yield. X-ray analysis and various
NMR techniques (vide infra) confirmed that the lower
rim aryl substituents have a different orientation, namely,
adjacent substituents in pairs in an axial and an equato-
rial orientation.
In the literature, so far only resorcin[4]arenes in the
crown conformation were bridged to give the correspond-
ing cavitands with all substituents in the axial position.1
On the basis of an NMR study, Dalcanale et al.11 have
reported that the chair conformer of the resorcin[4]arene
derived from resorcinol and 1-heptanal is in equilibrium
with its crown conformer as a result of a ring-inversion
conformational process. The crown conformer could be
trapped by a bridging reaction with 2,3-dichloroquinoxa-
line to give the corresponding cavitand (which has two
axial and two equatorial lower rim substituents) in 5%
yield.11,12
In this paper, we describe a general route to cavitands,
with yields up to 90% and starting from aryl-substituted
methylresorcin[4]arenes in the chair conformation. The
relative stereochemistry of the aryl-substituted cavitands,
namely, two adjacent substituents paired in an axial and
an equatorial orientation has been proven by X-ray
analysis and various NMR techniques.
The formation of the cavitands 18-22 is most probably
the result of an equilibrium between resorcin[4]arenes
3-7 in the chair conformation and the corresponding
crown conformers 13-17, the latter being trapped by
reaction with bromochloromethane (Scheme 1). The
crown conformers 13-17 are energetically less favored
because of the repulsion between the equatorial aryl
substituents and the hydroxyl groups. However, this will
partly be compensated for by hydrogen-bond formation
between the hydroxyl groups.14
In contrast to the example of Dalcanale et al.11 (vide
supra), the crown conformers 13-17 could not be ob-
1
served at various temperatures with H NMR spectros-
1
copy. In an H NMR experiment with a solution of chair-
methylresorcin[4]arene 4 and K2CO3 in DMF-d7 at 65 °C,
the corresponding crown conformer 14 could also not be
observed. Instead, a very complex reaction mixture was
obtained.15
Resu lts a n d Discu ssion
Syn th esis. Condensation of 2-methylresorcinol with
p-methoxy-, p-bromo-, p-cyano-, p-nitro-, and m-nitroben-
zaldehyde in a refluxing 1:1 mixture of ethanol and HCl
(37% in water) afforded 30-98% yields of the correspond-
ing methylresorcin[4]arenes 3-7 exclusively in the chair
conformation after the crude reaction mixture was washed
with a small amount of cold methanol. Neither in the
filtrate nor upon acetylation of the crude reaction mixture
(to give 8-12) could other conformers be detected.
Compared to the yields of the corresponding condensa-
tions with unsubstituted resorcinol,5-7 the yields of 3-7
are higher. Reaction times of up to 4 weeks afforded the
It was not possible to isolate partly bridged intermedi-
ates from the reaction of resorcin[4]arene 4 with 2.5 equiv
1
of bromochloromethane. In the H NMR spectrum of the
crude reaction mixture, only fully bridged cavitand 19
and starting material could be identified; cavitand 19 was
isolated in 15% yield. Apparently, the formation of the
(13) Tucker, J . A.; Knobler, C. B.; Trueblood, K. N.; Cram, D. J . J .
Am. Chem. Soc. 1989, 111, 3688.
(14) Lippmann, T.; Wilde, H.; Pink, M.; Schafer, A.; Hesse, M.;
Mann, G. Angew. Chem., Int. Ed. Engl. 1993, 32, 1195.
(15) In part, the complex reaction mixture might be the result of
deprotonation of the acidic triarylmethane hydrogen atom and subse-
quent quinone methide formation. This may also be the reason for the
lower yields of some of the cavitands. Though a pseudorotation is not
possible for chair-resorcin[4]arenes,5 in a NOESY experiment with 4,
an exchange cross-signal was observed between the resonances of both
different methyl groups when the reaction conditions used for cavitand
synthesis were applied. This may be explained by a planar anion,
formed by deprotonation at the acidic methine position, in which both
methyl groups are magnetically equivalent.
(11) Abis, L.; Dalcanale, E.; du Vosel, A.; Spera, S. J . Chem. Soc.,
Perkin Trans. 2 1990, 2075.
(12) Because the substituent-methine bonds have the ability to
rotate through the ring during cavitand formation and because the
chair conformer of a resorcin[4]arene has lower rim methyl substitu-
ents, this conformer can be fully bridged to a cavitand with all the
substituents in the axial orientation. Moran, J . R.; Karbach, S.; Cram,
D. J . J . Am. Chem. Soc. 1982, 104, 5826.

Bridging of Resorcin[4]arenes
J . Org. Chem., Vol. 63, No. 23, 1998 8261
Sch em e 1. P r op osed Mech a n ism for th e F or m a tion of Ca vita n d s 18-22
first bridge is the rate-determining step for cavitand
formation. This is in contrast to the “classical” crown-
resorcin[4]arenes (i.e., those lacking a methyl group
between the hydroxyl groups) for which the introduction
of the final bridge proved to be the most difficult.16
The functional groups at the aryl substituents can
easily be transformed; and this is illustrated by the
reduction of cavitand 22 to the corresponding tetraamine
23 using Raney nickel and hydrazine monohydrate and
the subsequent treatment of cavitand 23 with trifluoro-
acetic anhydride in pyridine to give the tetratrifluoro-
acetamide 24.
X-r a y An a lysis. Crystallization of cavitand 19 from
toluene gave single crystals suitable for X-ray analysis.
The crystal structure (Figure 1a) clearly shows that two
adjacent aryl substituents are in the axial orientation and
the other two are in the equatorial orientation. The
vertical plane of symmetry in the structure corresponds
with the NMR data (vide infra). The crystal structure
contains four toluene molecules for each cavitand. These
slightly disordered solvent molecules are gathered into
interconnected channels running parallel to all three unit
cell axes. The total volume of these channels amounts to
40% of the unit cell volume. Because of this large solvent
content, only a limited number of interactions between
the cavitand molecules exists. The two most interesting
of these, those involving the cavity created by the
cavitand “bowl” and those involving the cavity created
by the lower rim substituents, are depicted in Figure 1b.
The first interaction shows one of the bromophenyl
groups inside the cavitand “bowl”. The shortest distances
are found between the bromo atom and the methylene
bridges. The second interaction occurs between the two
molecules related by a crystallographic inversion center.
The bromo atom of one molecule is located directly
against the π systems of two axial bromophenyl groups
of the neighboring symmetry-related molecule.17 A π-π
interaction with another equatorial bromophenyl group
of that molecule completes the interaction. These two
interactions link the molecules into a two-dimensional
network, perpendicular to the b axis.
F igu r e 1. (a) X-ray crystal structure of cavitand 19 at 30%
probability level. Hydrogen atoms and toluene solvent mol-
ecules have been omitted for clarity. (b) Interactions of the
equatorial substituents and the cavitand bowl of cavitand 19
in the crystal structure. Hydrogen atoms have been omitted
for clarity.
nonsymmetric structure, with groups aligned either at
half of 1 and 5 or to both sides (2-4, 6, 7, and half of 1
and 5) of a plane of symmetry.
NMR An a lysis. The 1H NMR spectra of cavitands 18-
24 reveal the molecular structure in terms of symmetry
operators. The 1H NMR spectrum of cavitand 18, for
example, clearly shows that hydrogen atoms at positions
2-4, 6, and 7 give doubled signals integrating in a 1:1
manner (Figure 2). Hydrogen atoms at positions 1 and
5, however, resonate as three signals in a 1:2:1 fashion.
Because this was only found for these two groups, it is
clear that the cavitands have to possess an inherently
The broadening of one of the two methoxy signals
indicates that there are different modes of freedom for
the lower rim aryl substituents. From the NMR data, it
follows that two different spatial orientations are present
for the lower rim aryl substituents for which all observa-
tions made can be accounted for.
1
Subsequently, 2-D H NMR spectroscopy was carried
out to distinguish between these two possible spatial
orientations and to assign the signals in the 1-D 1H NMR
spectrum.
(16) Timmerman, P.; Boerrigter, H.; Verboom, W.; van Hummel, G.
J .; Harkema, S.; Reinhoudt, D. N. J . Inclusion Phenom. Mol. Recognit.
Chem. 1995, 18, 1.
(17) Reddy, D. S.; Craig, D. C.; Desiraju, G. R. J . Am. Chem. Soc.
1996, 118, 4090.
1H-1H relayed COSY of cavitand 18 shows the through-
bond connectivities between the two different sets of
methylene bridge hydrogen atoms, with the first set at δ

8262 J . Org. Chem., Vol. 63, No. 23, 1998
Middel et al.
F igu r e 2. 1H NMR spectrum of cavitand 18 showing the doubled and tripled signals.
4.37 and 4.46 (Hin) and the second at around δ 6.00 (Hout).
Also, two AB-spin systems are recognized in the aromatic
region: one set is located at δ 6.88 and 7.17 whereas the
other set is located at δ 6.94 and 7.40. Several long-range
4
COSY connections arising from J coupled patterns can
be identified; the most important is the connection
between the signal at δ 4.99 (methine H) and the signals
at δ 6.90 and 7.04 (CH-aromatic), respectively.
To properly assign the hydrogen atoms in view of the
large induced shifts, 1H-13C heteronuclear multiple-
quantum coherence (HMQC) spectroscopy was applied.
1
All the H-13C connections were identified, of which the
most elucidative are the connections between δ 41.6 and
56.1 (13C) and δ 6.42 and 4.99 (1H), respectively. This
large difference in chemical shift between these two
identically attached hydrogens is the result of a strong
difference in magnetic shielding. It is important to note
that the signal at δ 6.42 is proven by HMQC to belong to
two of the methine hydrogen atoms and not to a CH of
one of the aromatic systems.
The use of rotating-frame Overhauser enhancement
spectroscopy (ROESY) and NOESY (Figure 3) leads to
the elucidation of the spatial orientation of the different
F igu r e 3. NOESY spectrum of cavitand 18.
groups mentioned. Through-space contacts are limited
because of the apparent structural aspects, and non-
equivalent contacts are traced for the inner-placed aro-
matic hydrogen atoms (5 in Figure 2) at δ 6.90, 7.04, and
7.16 with the aromatic hydrogens meta to the methoxy
at the aryl substituents, as expected. The signal at δ 7.04
interacts with that at δ 7.17, and the resonance at δ 7.16
interacts with that at δ 7.40 whereas the resonance at δ
6.90 shows cross contacts with both signals of the
substituents mentioned before. Corresponding nonequiv-
alent contacts are observed between the hydrogen atoms
of the methyl groups (1 in Figure 2) and the hydrogen
atoms at the methylene bridge resonating at δ 4.37 and
4.46 (Hin).
contacts. This observation, in addition to the large
difference in chemical shifts for these methine hydrogen
atoms, indicates a completely different orientation of the
substituents at the lower rim.
Variation of both the temperature and the solvent from
-65 (CDCl3) to +100 °C (C6D5NO2) does not alter any of
our observations, except for the fairly large shift differ-
ences for the aromatic hydrogen atoms (5), which is
probably due to the solvent effect of using C6D5NO2
instead of CD2Cl2 or CDCl3. The various NMR techniques
also prove the relative stereochemistry of cavitands 18-
24 with two adjacent axial and equatorial substituents
at the lower rim.
In contrast to the methine hydrogen atoms at δ 4.99
(4 in Figure 2) having a contact with two of the three
inner-placed aromatic hydrogen atoms (5 in Figure 2),
the methine hydrogen atoms at δ 6.42 do not exhibit any
In this paper, we demonstrated that aryl-substituted
methylresorcin[4]arenes in the chair conformation, via
the corresponding crown conformer, can easily be con-

Bridging of Resorcin[4]arenes
J . Org. Chem., Vol. 63, No. 23, 1998 8263
2,8,14,20-T e t r a k is (4-b r o m o p h e n y l)-5,11,17,23-t e t -
t r a m e t h y lp e n t a c y c lo [19.3.1.13,7.19,13.115,19]o c t a c o s a -
1(25),3,5,7(28),9,11,13(27),15,17,19(26),21,23-dodecaen -4,6,-
10,12,16,18,22,24-octol (4): yield 14.34 g (98%) of pink solid;
verted into the corresponding cavitands which have two
adjacent axial and two equatorial aryl substituents.
Because of the relative stereochemistry at the lower rim,
this type of cavitand represents an interesting class of
compounds for various applications. For instance, suit-
able functional groups at the aryl substituents may allow
the formation of large boxes via either metal coordination
or hydrogen bonding. Work in this direction is currently
being conducted.
1
mp > 320 °C; H NMR [250 MHz; (CD3)2SO] δ 1.91 (s, 6 H),
2.08 (s, 6 H), 5.27 (s, 2 H), 5.63 (s, 4 H), 6.13 (s, 2 H), 6.57 (d,
2
2J AB ) 8.5 Hz, 8 H), 7.08 (d, J AB ) 8.5 Hz, 8 H), 7.60 (br s, 4
H), 7.70 (br s, 4 H); 13C NMR [(CD3)2SO] δ 150.6, 143.4, 131.3,
129.9, 127.7, 122.5, 121.6, 118.1, 111.1, 110.7, 48.6, 9.9, 9.7;
FAB MS m/z 1160.6 (M+, calcd 1160.0). Anal. Calcd for C56H44
Br4O8‚3.5H2O: C, 54.79; H, 4.19. Found: C, 54.50; H, 4.22.
-
2,8,14,20-T e t r a k is (4-c y a n o p h e n y l)-5,11,17,23-t e t -
r a m e t h y lp e n t a c y c lo [19.3.1.13 ,7 .19 ,1 3 .11 5 ,1 9 ]o c t a c o s a -
1(25),3,5,7(28),9,11,13(27),15,17,19(26),21,23-dodecaen -4,6,-
10,12,16,18,22,24-octol (5): yield 10.56 g (89%) of white solid;
Exp er im en ta l Section
Gen er a l. Melting points are uncorrected. Mass positive
(FAB) spectra were obtained using m-nitrobenzyl alcohol as a
matrix. Column chromatography was performed using silica
gel 60 from Merck. All reactions were carried out under an
argon atmosphere, and solvents were purified, if necessary,
by standard procedures prior to use. Ethanol (95%) was used
as received. DMF and pyridine were stored over 4 Å molecular
sieves. The presence of solvents in the analytical samples was
1
mp > 320 °C; H NMR [300 MHz, CDCl3/CD3OD] δ 2.04 (s, 6
H), 2.15 (s, 6 H), 4.94 (s, 2 H), 5.79 (s, 4 H), 6.11 (s, 2 H), 6.83
2
2
(d, J AB ) 8.4 Hz, 8 H), 7.28 (d, J AB ) 8.4 Hz, 8 H); FAB MS
m/z 946.9 ([M - H]-, calcd 947.3). Anal. Calcd for C60H44N4O8‚
2.0 H2O: C, 73.16; H, 4.91; N, 5.69. Found: C, 73.02; H, 4.58;
N, 5.42.
2,8,14,20-T e t r a k i s (4-n i t r o p h e n y l)-5,11,17,23-t e t -
r am eth ylpen tacyclo[19.3.1.13,7.19,13.115,19]octacosa-1(25),3-
5,7(28),9,11,13(27),15,17,19(26),21,23-d od eca en -4,6,10,12,-
16,18,22,24-octol (6): yield 3.83 g (30%) of white solid; mp >
320 °C; 1H NMR [250 MHz, (CD3)2SO] δ 1.91 (s, 6 H), 2.09 (s,
6 H), 4.81 (s, 2 H), 5.88 (2 × s, 4 H), 6.10 (s, 2 H), 6.87 (d, 2J AB
1
confirmed by H NMR spectroscopy.
NMR. All spectra were recorded at ambient temperature
(30 °C) unless stated otherwise. 1H and 13C NMR spectra were
recorded at 250, 300, and 400 MHz in CDCl3 unless stated
otherwise. The chemical shifts are expressed relative to CHCl3
for 1H NMR (at δ 7.26) and 13C NMR (at δ 76.91). NOESY,18
ROESY,19 total correlation spectroscopy (TOCSY) (MLEV 17),20
and COSY21 were performed using standard Varian pulse
programs. The TOCSY (MLEV 17) experiments were per-
formed with mixing times of 30 ms. The mixing times of the
NOESY experiments ranged from 10 to 90 ms. The mixing
time of the ROESY experiments consisted of a spin lock pulse
of 2 kHz field strength with a duration of 30 ms, typically. All
2-D experiments were collected using 2-D hypercomplex data22
and Fourier transformed in the phase-sensitive mode after
weighting with shifted square sine-bells or shifted Gaussian
functions. NMR data were processed by the standard VnmrS
software packages on the Unity 400 WB host computers (SUN
IPX and Sparc stations). Concentrations of the samples used
were typically in the 5 mM range.
Gen er a l P r oced u r e for th e P r ep a r a tion of Meth ylr e-
sor cin [4]a r en es 3-7. 2-Methylresorcinol (6.20 g, 50 mmol)
was dissolved in a mixture of ethanol (20 mL) and HCl (37%
in water, 20 mL), and the appropriately substituted benzal-
dehyde (50 mmol) was added portion wise at 0 °C over a period
of 1 h. The reaction mixture was refluxed for at least 48 h,
and after the mixture was cooled to room temperature, the
precipitate formed was collected by filtration and made acid-
free (pH 7) by washing it with water. The solid material was
washed twice with cold methanol (20 mL) and dried in vacuo.
The methanol washings mainly contained noncyclic impurities
in addition to a small amount of the cyclic product that also
consisted of the chair conformer.
2
) 8.8 Hz, 8 H), 7.72 (d, J AB ) 8.8 Hz, 8 H), 9.12 (s, 4 H), 9.43
(s, 4 H); FAB MS m/z 1027.6 ([M - H]-, calcd 1027.3). Anal.
Calcd for C56H44N4O16‚1H2O: C, 64.24; H, 4.43; N, 5.35.
Found: C, 64.23; H, 4.20; N, 5.30.
2,8,14,20-T e t r a k i s (3-n i t r o p h e n y l)-5,11,17,23-t e t -
r a m e t h y lp e n t a c y c lo [19.3.1.13 ,7 .19 ,1 3 .11 5 ,1 9 ]o c t a c o s a -
1(25),3,5,7(28),9,11,13(27),15,17,19(26),21,23-dodecaen -4,6,-
10,12,16,18,22,24-octol (7): yield 9.45 g (74%) of white solid;
1
mp > 320 °C; H NMR [250 MHz, (CD3)2NCDO] δ 1.95 (s, 6
H), 2.14 (s, 6 H), 4.75 (s, 2 H), 5.92 (s, 4 H), 6.20 (s, 2 H), 6.96-
7.04 (m, 12 H), 7.38 (s, 4 H), 7.52-7.63 (m, 4 H), 7.82 (s, 4 H);
FAB MS m/z 1028.9 (M+, calcd 1028.3). Anal. Calcd for
C
56H44N4O16: C, 65.37; H, 4.31; N, 5.44. Found: C, 65.29; H,
4.26; N, 5.28.
Gen er a l P r oced u r e for th e Acetyla tion of Meth ylr e-
sor cin [4]ar en es 3-7.Toa suspension ofthecrudemethylresorcin-
[4]arenes 3-7 [prepared from 0.1 mmol of 2-methylresorcinol
and 0.1 mmol of the appropriately substituted benzaldehyde,
in pyridine (10 mL)] was added a 50-fold excess of acetic
anhydride at 0 °C. After the reaction mixture was stirred for
1 h, the clear solution was evaporated to dryness. Subsequent
TLC analysis showed only one product in addition to the
baseline spot. Purification by column chromatography (SiO2,
chloroform/diethyl ether ) 1:9) yielded the pure acetylated
methylresorcin[4]arenes 8-12.
4,6,10,12,16,18,22,24-Octa a cetoxy-2,8,14,20-tetr a k is(4-
m e t h o x y p h e n y l)-5,11,17,23-t e t r a m e t h y lp e n t a c y c lo -
[19.3.1.13,7.19,13.115,19]oct a cosa -1(25),3,5,7(28),9,11,13(27),-
15,17,19(26),21,23-d od eca en e (8): yield 99 mg (76%) of white
2,8,14,20-Te t r a k is(4-m e t h oxyp h e n yl)-5,11,17,23-t e t -
r a m e t h y lp e n t a c y c lo [19.3.1.13 ,7 .19 ,1 3 .11 5 ,1 9 ]o c t a c o s a -
1(25),3,5,7(28),9,11,13(27),15,17,19(26),21,23-dodecaen -4,6,-
10,12,16,18,22,24-octol (3): yield 8.37 g (69%) of off-white
solid; mp > 320 °C; 1H NMR [250 MHz; (CD3)2SO] δ 1.91 (s, 6
H), 2.09 (s, 6 H), 3.64 (s, 12 H), 5.35 (s, 2 H), 5.55 (s, 4 H),
1
solid; mp > 320 °C; H NMR (250 MHz) δ 1.79 (s, 6 H), 1.91
(s, 6 H), 2.12 (s, 12 H), 2.16 (s, 12 H), 3.40 (s, 12 H), 5.13 (br
s, 4 H), 5.78 (br s, 2 H), 6.20 (s, 2 H), 6.50-6.80 (m, 16 H);
FAB MS m/z 1306.2 ([M + 2H]+, calcd 1306.5). Anal. Calcd
for C76H72O20: C, 69.93; H, 5.56. Found: C, 69.60; H, 5.26.
4,6,10,12,16,18,22,24-Octa a cetoxy-2,8,14,20-tetr a k is(4-
b r o m o p h e n y l)-5,11,17,23-t e t r a m e t h y lp e n t a c y c lo -
[19.3.1.13,7.19,13.115,19]oct a cosa -1(25),3,5,7(28),9,11,13(27),-
15,17,19(26),21,23-d od eca en e (9): yield 136 mg (90%) of
white solid; mp > 320 °C; 1H NMR (300 MHz) δ 1.76 (s, 6 H),
1.87 (s, 6 H), 2.07 (br s, 12 H), 2.16 (br s, 12 H), 5.19 (br s, 4
H), 5.72 (br s, 2 H), 6.08 (br s, 2 H), 6.55-6.8 (br m, 8 H),
7.1-7.3 (m, 8 H); FAB MS m/z 1501.1 {[M + H]+, calcd 1500.1
2
2
6.12 (s, 2 H), 6.43 (d, J AB ) 8.5 Hz, 8 H), 6.54 (d, J AB ) 8.5
Hz, 8 H), 7.22 (s, 4 H), 7.55 (s, 4 H); FAB MS m/z 968.1 (M+,
calcd 968.4). Anal. Calcd for C60H56O12‚3.5H2O: C, 69.82; H,
6.15. Found: C, 70.01; H, 6.32.
(18) (a) J eener, J .; Meier, B. H.; Ernst, R. R. J . Chem. Phys. 1979,
71, 4546. (b) Neuhaus, D.; Williamson, M. In The Nuclear Overhauser
Effect in Structural and Conformational Analysis, VCH Publishers:
Cambridge, 1989.
(based on highest isotope signal)}. Anal. Calcd for C72H60
-
(19) Bothner-By, A. A.; Stephens, R. L.; Lee, J .; Warren, C. D.;
J eanloz, R. W. J . Am. Chem. Soc. 1984, 106, 811.
(20) Bax, A.; Davis, D. J . Magn. Reson. 1985, 65, 355.
(21) Bax, A.; Freeman, R. J . Magn. Reson. 1981, 44, 542.
(22) States, D. J .; Haberkorn, R. A.; Ruben, D. J . J . Magn. Reson.
1982, 48, 286.
Br4O16‚2pyridine: C, 59.36; H, 4.25; N, 1.69. Found: C, 59.72;
H, 4.28; N, 1.59.
4,6,10,12,16,18,22,24-Octa a cetoxy-2,8,14,20-tetr a k is(4-
c y a n o p h e n y l )-5 ,1 1 ,1 7 ,2 3 -t e t r a m e t h y l p e n t a c y c l o -
[19.3.1.13,7.19,13.115,19]oct a cosa -1(25),3,5,7(28),9,11,13(27),-

8264 J . Org. Chem., Vol. 63, No. 23, 1998
Middel et al.
15,17,19(26),21,23-d od eca en e (10): yield 117 mg (90%) of
white solid; mp > 320 °C; 1H NMR (300 MHz) δ 1.52 (s, 6 H),
1.61 (s, 6 H), 1.80 (br s, 24 H), 4.8-5.3 (br s, 2 H), 5.12 (br s,
4 H), 5.83 (br s, 2 H), 6.4-6.7 (m, 8 H), 6.95-7.1 (m, 8 H);
FAB MS m/z 1286.5 (M+, calcd 1286.3). Anal. Calcd for
d i o x o c i n o [5,4-i :5′,4′-i ′]b e n z o [1,2-d :5,4-d ′]b i s [1,3]-
ben zod ioxin (20) was isolated after flash chromatography
(SiO2, CHCl3, Rf ) 0.4) as a white solid crystallizing from the
eluent: yield 1.09 g (90%); mp > 320 °C; 1H NMR (250 MHz)
δ 1.57 (s, 3 H), 1.67 (s, 6 H), 1.76 (s, 3 H), 4.0-4.3 (m, 4 H),
2
2
C
76H60N4O16‚0.5 H2O: C, 70.53; H, 4.75; N, 4.33. Found: C,
4.63 (s, 2 H), 5.26 (d, J AB ) 6.2 Hz, 2 H), 5.62 (d, J AB ) 6.3
70.27; H, 4.68; N, 4.34.
Hz, 2 H), 5.62 (s, 2 H), 6.02 (s, 1 H), 6.18 (s, 2 H), 6.78 (s, 2 H),
2
2
4,6,10,12,16,18,22,24-Octa a cetoxy-2,8,14,20-tetr a k is(4-
n i t r o p h e n y l )-5 ,1 1 ,1 7 ,2 3 -t e t r a m e t h y l p e n t a c y c l o -
[19.3.1.13,7.19,13.115,19]oct a cosa -1(25),3,5,7(28),9,11,13(27),-
15,17,19(26),21,23-d od eca en e (11): yield 34 mg (25%) of
6.98 (d, J AB ) 7.9 Hz, 4 H), 7.11 (d, J AB ) 8.0 Hz, 4 H), 7.28
2 2
(d, J AB ) 7.9 Hz, 4 H), 7.36 (d, J AB ) 8.0 Hz, 4 H); 13C NMR
δ 155.6, 154.9, 154.0, 153.3, 146.2, 145.8, 137.8, 136.4, 135.4,
135.1, 131.7, 129.9, 128.0, 126.5, 119.2, 118.5, 110.2, 109.8,
98.5, 97.8, 60.4, 21.0, 14.2; FAB MS m/z 997.4 ([M + H]+, calcd
997.3). Anal. Calcd for C64H44N4O8‚1.0CHCl3: C, 73.31; H, 4.24;
N, 5.30. Found: C, 73.12; H, 4.35; N, 5.06.
1
white solid; mp > 320 °C; H NMR [300 MHz, CDCl3/(CD3)2-
SO] δ 1.75 (s, 6 H), 1.87 (s, 6 H), 2.00 (br s, 24 H), 5.37 (br s,
4 H), 5.48 (br s, 2 H), 6.15 (br s, 2 H), 6.85 (m, 8 H), 7.71 (m,
8 H); FAB MS m/z 1365.5 ([M + H]-, calcd 1365.4). Anal. Calcd
for C72H60N4O24‚0.1 CHCl3: C, 62.88; H, 4.40; N, 4.07. Found:
C, 62.66; H, 4.35; N, 4.17.
7,11,15,28-Te t r a m e t h yl-1,21,23,25-t e t r a k is(4-n it r o-
p h en yl)-2,20:3,19-d im et h en o-1H ,21H ,23H ,25H -b is[1,3]-
d i o x o c i n o [5,4-i :5′,4′-i ′]b e n z o [1,2-d :5,4-d ′]b i s [1,3]-
ben zod ioxin (21) was isolated after flash chromatography
(SiO2, EtOAc, Rf ) 0.7) as an orange solid: yield 0.46 g (42%);
4,6,10,12,16,18,22,24-Octa a cetoxy-2,8,14,20-tetr a k is(3-
n i t r o p h e n y l )-5 ,1 1 ,1 7 ,2 3 -t e t r a m e t h y l p e n t a c y c l o -
[19.3.1.13,7.19,13.115,19]oct a cosa -1(25),3,5,7(28),9,11,13(27),-
15,17,19(26),21,23-d od eca en e (12): yield 56 mg (41%) of
white solid; mp > 320 °C; 1H NMR (250 MHz) δ 1.85 (s, 6 H),
1.94 (s, 6 H), 2.09 (br s, 24 H), 5.44 (br s, 4 H), 7.13 (br s, 4 H),
7.26-7.32 (m, 8 H), 7.85-7.88 (m, 4 H), 8.60-8.65 (m, 8 H);
FAB MS m/z 1365.5 ([M + H]-, calcd 1365.4). Anal. Calcd for
1
mp > 320 °C; H NMR [300 MHz, CDCl3/(CD3)2SO] δ 2.01 (s,
2
3 H), 2.04 (s, 6 H), 2.06 (s, 3 H), 4.41 (d, J AB ) 5.8 Hz, 2 H),
4.43 (d, 2J AB ) 5.6 Hz, 2 H), 5.18 (s, 1 H), 5.59 (s, 2 H), 6.03 (d,
2
2J AB ) 5.8 Hz, 2 H), 6.05 (d, J AB ) 5.6 Hz, 2 H), 6.38 (br s, 2
H), 6.42 (s, 1 H), 7.01 (br s, 2 H), 7.34 (m, 4 H), 7.58 (m, 4 H),
8.08 (m, 4 H), 8.27 (m, 4 H); FAB MS m/z 1076.1 (M+, calcd
1076.3). Anal. Calcd for C60H44N4O16‚2.5H2O: C, 64.34; H, 4.12;
N, 4.98. Found: C, 64.37; H, 4.48; N, 4.75.
C
72H60N4O24‚0.3CHCl3: C, 61.98; H, 4.34; N, 4.00. Found: C,
62.04; H, 4.31; N, 4.17.
Gen er a l P r oced u r e for th e P r ep a r a tion of Ca vita n d s
18-22. A suspension of the methylresorcin[4]arenes 3-7 (1
mmol), bromochloromethane (0.79 g, 6.0 mmol, 6 equiv), and
K2CO3 (3.0 g, large excess) in DMF (50 mL) was stirred at 65
°C for 10 h. After the reaction mixture cooled to room
temperature, the excess of base was filtered off, and the solvent
was removed in vacuo. The residue was taken up in chloroform
(200 mL) and washed twice with water (100 mL). After the
organic layer was dried over MgSO4, the solution was concen-
trated to approximately 5 mL and directly put on a silica gel
column.
7,11,15,28-Te t r a m e t h yl-1,21,23,25-t e t r a k is(3-n it r o-
p h en yl)-2,20:3,19-d im et h en o-1H ,21H ,23H ,25H -b is[1,3]-
d i o x o c i n o [5,4-i :5′,4′-i ′]b e n z o [1,2-d :5,4-d ′]b i s [1,3]-
ben zod ioxin (22) was isolated after flash chromatography
(SiO2, EtOAc, Rf ) 0.7) as an orange solid: yield 0.31 g (29%);
mp > 320 °C; 1H NMR (400 MHz) δ 1.92 (s, 3 H), 2.01 (s, 6 H),
2
2
2.10 (s, 3 H), 4.37 (d, J AB ) 5.8 Hz, 2 H), 4.42 (d, J AB ) 6.2
2
Hz, 2 H), 4.99 (s, 2 H) 5.59 (d, J AB ) 5.8 Hz, 2 H), 6.01 (d,
2J AB ) 6.2 Hz, 2 H), 6.58 (s, 2 H), 6.87 (s, 1 H), 6.92 (s, 1 H),
2
6.95 (s, 2 H), 7.20-7.42 (m, 10 H), 7.80 (d, J AB ) 8.9 Hz, 1
2
H), 8.03 (d, J AB ) 8.8 Hz, 1 H), 8.05 (s, 2 H), 8.33 (s, 2 H);
1,21,23,25-Tet r a k is(4-m et h oxyp h en yl)-7,11,15,28-t et -
r a m eth yl-2,20:3,19-d im eth en o-1H,21H,23H,25H-bis[1,3]-
d i o x o c i n o [5,4-i :5′,4′-i ′]b e n z o [1,2-d :5,4-d ′]b i s [1,3]-
ben zod ioxin (18) was isolated after flash chromatography
(SiO2, CHCl3/EtOAc ) 1:1, Rf ) 0.6) as an off-white solid: yield
FAB MS m/z 1075.9 (M-, calcd 1076.3). Anal. Calcd for
C
60H44N4O16‚2.5H2O: C, 64.34; H, 4.12; N, 4.98. Found: C,
64.37; H, 4.48; N, 4.75.
7,11,15,28-Tetr a m eth yl-1,21,23,25-tetr a k is(3-tr iflu or o-
a ceta m id oph en yl)- 2,20:3,19-dim eth en o-1H,21H,23H,25H-
bis[1,3]d ioxocin o[5,4-i:5′,4′-i′]ben zo[1,2-d :5,4-d ′]bis[1,3]-
ben zod ioxin (24). Cavitand 22 (1.0 g, 0.93 mmol) and Raney
nickel (cat. amount in H2O) were suspended in a mixture of
EtOH (20 mL) and acetic acid (1 mL). Hydrazine monohydrate
(5 mL, large excess) was added, and the mixture was refluxed
for 24 h. Filtration and evaporation of the solvent yielded the
crude tetraamine 23 which, for purification reasons, was
directly converted to the tetratrifluoroacetamide by dissolving
it in CH2Cl2 (20 mL) and pyridine (5 mL) and adding trifluo-
roacetic anhydride (2 mL, large excess). The reaction mixture
was stirred at room temperature for 24 h, and the solvent was
removed. Chromatography (SiO2, EtOAc/CH2Cl2/Et3N ) 10:
5:1, Rf ) 0.8) gave cavitand 24 as a white solid: yield 0.74 g
(52%); mp > 320 °C; 1H NMR (400 MHz; mixture of rotamers)
1
382 mg (38%); mp > 320 °C; H NMR (400 MHz) δ 1.95 (s, 3
H), 2.04 (s, 6 H), 2.12 (s, 3 H), 3.78 (s, 6 H), 3.83 (s, 6 H), 4.37
2
2
(d, J AB ) 6.0 Hz, 2 H), 4.46 (d, J AB ) 6.6 Hz, 2 H), 4.99 (s, 2
2
2
H), 5.73 (d, J AB ) 6.0 Hz, 2 H), 6.04 (d, J AB ) 6.6 Hz, 2 H),
6.42 (s, 2 H), 6.88 (d, 2J AB ) 8.0 Hz, 4 H), 6.90 (s, 1 H), 6.94 (d,
2J AB ) 8.4 Hz, 4 H), 7.04 (s, 2 H), 7.16 (s, 1 H), 7.17 (d, J AB
)
2
8.0 Hz, 4 H), 7.40 (d, J AB ) 8.4 Hz, 4 H); 13C NMR δ 157.9,
157.6, 155.2, 154.4, 137.9, 137.5, 136.2, 136.0, 132.4, 132.0,
130.1, 129.9, 128.2, 128.0, 127.1, 127.0, 125.6, 125.3, 124.1,
113.4, 113.2, 98.5, 97.8, 56.1, 55.3, 55.2, 41.6, 10.6, 10.5, 10.5;
FAB MS m/z 1016.9 (M+, calcd 1016.4). Anal. Calcd for
2
C
64H56O12‚2.5CHCl3: C, 60.85; H, 4.49. Found: C, 60.85; H,
4.49.
1,21,23,25-Tet r a k is(4-b r om op h en yl)-7,11,15,28-t et r a -
2
m e t h yl-2,20:3,19-d im e t h e n o-1H ,21H ,23H ,25H -b is[1,3]-
d i o x o c i n o [5,4-i :5′,4′-i ′]b e n z o [1,2-d :5,4-d ′]b i s [1,3]-
ben zod ioxin (19) was isolated after flash chromatography
(SiO2, CHCl3, Rf ) 0.4) as a white solid crystallizing from the
eluent: yield 1.09 g (90%); mp > 320 °C; 1H NMR (400 MHz)
δ 1.92 (s, 3 H), 1.95 (s, 6 H), 1.98 (s, 3 H), 4.36 (d, J AB ) 7.1
2
Hz, 2 H), 4.40 (d, J AB ) 6.8 Hz, 2 H), 4.96 (s, 1 H), 5.61 (d,
2
2J AB ) 7.1 Hz, 2 H), 5.96 (d, J AB ) 6.8 Hz, 2 H), 6.42 (s, 2 H),
6.99 (s, 1 H), 7.07 (m, 2 H), 7.14-7.18 (m, 4 H), 7.25 (m, 2 H),
7.28 (m, 2 H), 7.29 (br s, 2 H), 7.32 (m, 2 H), 7.33 (br s, 2 H),
7.63 (m, 2 H), 7.96 (m, 2 H), 8.07 (br m, 2 H), 8.12 (br m, 2 H);
13C NMR δ 155.4, 154.8, 142.6, 142.1, 137.6, 137.0, 135.9,
135.7, 132.2, 129.1, 129.0, 127.7, 127.5, 126.6, 125.6, 125.2,
123.7, 119.3, 118.5, 118.3, 98.9, 98.2, 60.8, 42.9, 10.9, 10.7; FAB
MS m/z 1341.2 ([M + H]+, calcd 1341.3). Anal. Calcd for
2
δ 1.91 (s, 3 H), 2.00 (s, 6 H), 2.10 (s, 3 H), 4.33 (d, J AB ) 6.0
2
Hz, 2 H), 4.42 (d, J AB ) 6.6 Hz, 2 H), 4.92 (s, 2 H), 5.68 (d,
2
2J AB ) 6.0 Hz, 2 H), 6.03 (d, J AB ) 6.6 Hz, 2 H), 6.40 (s, 2 H),
6.89 (s, 1 H), 6.93 (s, 2 H), 6.96 (s, 1 H), 7.06 (d, 2J AB ) 8.0 Hz,
2
2
4 H), 7.33 (d, J AB ) 8.4 Hz, 4 H), 7.43 (d, J AB ) 8.0 Hz, 4 H),
7.50 (d, J AB ) 8.4 Hz, 4 H); 13C NMR δ 155.4, 154.5, 153.8,
C68H48F12N4O12‚0.7 H2O: C, 60.33; H, 4.15; N, 3.68. Found:
C, 60.33; H, 4.50; N, 3.78.
2
153.1, 139.5, 139.3, 137.2, 136.6, 135.7, 135.4, 131.1, 130.9,
129.0, 127.4, 126.8, 126.1, 124.7, 124.7, 123.7, 120.1, 119.5,
98.5, 97.7, 55.9, 42.0, 10.3, 10.2, 10.1; FAB MS m/z 1210.1
([M+2H]-, calcd 1210.0). Anal. Calcd for C60H44Br4O8‚
0.5CHCl3: C, 57.11; H, 3.53. Found: C, 57.12; H, 3.54.
1,21,23,25-Tet r a k is(4-cya n op h en yl)-7,11,15,28-t et r a -
m e t h yl-2,20:3,19-d im e t h e n o-1H ,21H ,23H ,25H -b is[1,3]-
Cr ysta l Da ta for Ca vita n d 19. C60H44Br4O8‚4C7H8: Mr )
1949.74, colorless, plate-shaped crystal (0.1 × 0.4 × 0.5 mm),
orthorombic, space group Pccn (No. 56) with a ) 20.8586(19)
Å, b ) 24.551(2) Å, c ) 28.182(3) Å, V ) 14432(2) Å3, Z ) 8,
Dx ) 1.455 g cm-3, F(000) ) 6460, µ(Mo KR) ) 22.9 cm-1
,
19 422 reflections measured, 13 135 independent, (0.7° < θ <

Bridging of Resorcin[4]arenes
J . Org. Chem., Vol. 63, No. 23, 1998 8265
25.4°, ω scan, T ) 150 K, Mo KR radiation, graphite mono-
chromator, λ ) 0.710 73 Å) on an Enraf-Nonius CAD4 turbo
diffractometer on a rotating anode. Data were corrected for
Lp effects and for a linear decay of 6% of the reference
reflections but not for absorption. The structure was solved
by automated direct methods (SHELXS-97).23 Refinement on
F2 was carried out by full-matrix least-squares techniques
(SHELXL-97)24 for 743 parameters; no observance criterion
was applied during refinement. Refinement converged at a
final wR2 value of 0.2518, R1 ) 0.0964 (for 5538 reflections
with F0 > 4σ (F0), S ) 1.003. Hydrogen atoms were included
in the refinement on calculated positions riding on their carrier
atoms.
Ack n ow led gm en t. This work was supported in part
(O.M. and A.L.S.) by The Netherlands Foundation of
Chemical Research (SON) with financial aid from The
Netherlands Organization for Scientific Research (NWO).
Su p p or tin g In for m a tion Ava ila ble: Supporting Infor-
mation Available: X-ray data for cavitand 19, including tables
of atomic coordinates, bond lengths, and bond angles (27
pages). This material is contained in libraries on microfiche,
immediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
Disorder models were introduced to describe the toluene
solvent molecules. A final difference Fourier showed no
residual density outside -0.65 and +1.18 e Å-3. Atomic
coordinates, bond lengths and angles and thermal parameters
have been deposited at the Cambridge Crystallographic Data
Centre; see Notice to Authors, issue no. 1.
J O9810258
(23) Sheldrick, G. M. SHELXS-97: Program for Crystal Structure
Solution, University of Go¨ttingen; Go¨ttingen, Germany, 1997.
(24) Sheldrick, G. M. SHELXL-97: Program for Crystal Structure
Refinement; University of Go¨ttingen; Go¨ttingen, Germany, 1997.