Macrocyclic cyclo[n]malonates - Synthetic aspects and observation of columnar arrangements by X-ray crystallography

Article abstract of DOI:10.1002/ejoc.200500921

A variety of achiral and chiral macrocyclic oligomalonates were synthesised in a one-step procedure through condensation of malonyl dichloride with α,ω-diols. We have investigated the applicability of this method by varying the length and type of the spac

Full text of DOI:10.1002/ejoc.200500921

FULL PAPER
DOI: 10.1002/ejoc.200500921
Macrocyclic Cyclo[n]malonates – Synthetic Aspects and Observation of
Columnar Arrangements by X-ray Crystallography
Nikos Chronakis,[a] Torsten Brandmüller,[b] Christian Kovacs,[b] Uwe Reuther,[b]
Wolfgang Donaubauer,[b] Frank Hampel,[b] Felix Fischer,[c] François Diederich,*[c] and
Andreas Hirsch*[b]
Keywords: Cyclo[n]malonates / Cyclisation / Columnar stacking / Intermolecular interactions / Crystallography
A variety of achiral and chiral macrocyclic oligomalonates
were synthesised in a one-step procedure through condensa-
tion of malonyl dichloride with α,ω-diols. We have investi-
gated the applicability of this method by varying the length
and type of the spacers in the diol. Product distribution analy-
sis revealed that the preferential formation of monomeric, di-
meric, or trimeric macrocyclic malonates can be controlled by
choosing diols with specific spacers connecting the hydroxy
groups. Of special interest are the macrocyclic bismalonates,
as they show pronounced crystallisability and arrange into
columnar motifs in the solid state. They feature distinctive
dihedral angles: all ester moieties adopt anti conformations
whereas the planes of the carboxy moieties of each malonate
residue arrange in an approximately orthogonal fashion. The
latter geometry is enforced by the macrocyclic structures, as
revealed by a conformational search in the Cambridge Struc-
tural Database. The X-ray diffraction data show that
C=O···H–C, and C–O···H–C hydrogen bonds stabilise the co-
lumnar arrangement of the dimeric rings with formation of
tubular assemblies.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
was reported in 1933 by Hill and Carothers;[7] the main
interest in macrocyclic dilactones (and tetralactones) at that
time involved their use in the perfume industry. The prepa-
ration of a series of cyclic monomalonate esters (2) with
oligoether chains was described by Bradshaw and co-
workers,[8] and their ability to complex ions such as Na+,
K+, or Ba2+ was investigated. “Dimeric” macrolactones in-
corporating two malonate moieties have been prepared
either by condensation of malonyl dichloride with ethyl-
eneglycol at low temperatures under high-dilution condi-
tions[9] or by treatment of dipotassium malonate with o-
bis(bromomethyl)benzene at ordinary dilution, as reported
by Drewes and Riphagen for the synthesis of 3[10]
(Scheme 1). Furthermore, a metal-ion-templated synthesis
involving the transesterification of dimethyl malonate with
ethylene- or diethyleneglycol (Scheme 1) has been intro-
duced by Thulin and Vögtle,[11] yielding the bis- and trisma-
lonate macrocycles 4, 5, and 6.[12]
We have recently reported[13] a simple synthesis of new
macrocyclic malonates, such as 7 (Scheme 1), by the con-
densation of malonyl dichloride with a variety of α,ω-alk-
anediols. The reactions were performed in dichloromethane
under high-dilution conditions, with pyridine as a base, pro-
viding facile access to a variety of cyclo[n]alkylmalonates
with varying lengths of the bridging alkyl chains and ring
sizes. Purification was accomplished by flash column
chromatography on silica gel, and the newly synthesised
macrocycles were studied for the regioselective remote func-
tionalisation of [60]fullerene through multiple Bingel ad-
Introduction
Essential activities of a living organism depend on the
relative concentrations of alkali metal cations inside and
outside the cell.[1] Ionophores are molecular vehicles that
transport ions across biological membranes, an important
function at the cellular level. Several antibiotics can selec-
tively induce ion transport across the cellular membrane.[2,3]
Valinomycin, enniatin, nonactin, and enterobactin are ex-
amples of naturally occurring macrocyclic ionophores with
structures controlled by repetitive amide and/or ester
bonds.[4] Since the seminal discovery of the crown ethers by
Pedersen,[5] a plethora of nonnatural macrocycles, mimick-
ing the properties of the natural ionophores, have been pre-
pared by a variety of synthetic approaches. A first compre-
hensive review covering the synthesis and the cation-bind-
ing properties of synthetic ionophores, including macro-
cyclic di- and tetralactones, was published by Bradshaw et
al. in 1979.[6]
The synthesis of the first macrocyclic bislactone, com-
pound 1 (Scheme 1), incorporating a malonate ester moiety,
[a] Department of Chemistry, University of Cyprus,
P. O. Box 20537, 1678 Nicosia, Cyprus
[b] Institut für Organische Chemie, Universität Erlangen-
Nürnberg,
Henkestrasse 42, 91054 Erlangen, Germany
Fax: +49-9131-8526864
E-mail: andreas.hirsch@chemie.uni-erlangen.de
[c] Laboratorium für Organische Chemie, ETH-Hönggerberg HCI,
8093 Zürich, Switzerland
E-mail: diederich@org.chem.ethz.ch
2296
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 2296–2308

Macrocyclic Cyclo[n]malonates
FULL PAPER
of the chain length, thereby giving facile access to supramo-
lecular tubular assemblies with formation of porous crys-
tals.
Results and Discussion
General Procedure for the Synthesis of Macrocyclic
Oligomalonates
Macrocyclic malonates were synthesised as shown in
Scheme 2. A solution of malonyl dichloride (2 equiv.) in
CH2Cl2 was added very slowly to a solution of the diol X
(1 equiv.) and pyridine (2 equiv.) in CH2Cl2, at a maximum
diol concentration of about 30 mmol·L–1. FAB MS analysis
of the crude mixture revealed the formation of macrocycles
incorporating up to nine diol repeat units in most cases.
The cyclomalonates can be obtained in pure form by flash
column chromatography on silica gel (eluent: EtOAc/
CH2Cl2), the elution sequence following the size of the
macrocycles, with the smaller rings eluting first. In this
Scheme 1. Cyclic oligomalonate esters reported in the literature.
ditions.[13,14] Here we report a detailed study on the synthe-
sis of macrocyclic malonates from malonyl dichloride and
appropriate α,ω-diols. We focus our interest on the effect of
the natures and chain lengths of the alkyl spacers connect-
ing the hydroxy groups of the diol and on how these proper-
ties affect the product distribution between monomeric, di-
meric, and trimeric cyclomalonates formed in the condensa-
tion reaction. Exclusively cyclo[n]malonates such as 7, con-
taining one type of spacer only (m = n), are considered in
this study. Furthermore, we report the preparation of a
series of chiral, nonracemic mono-, bis-, and trismalonate
macrocycles through the use of enantiomerically pure diols
of different chain lengths. A remarkable observation involv-
ing the bismalonate macrocycles is their pronounced ability
to crystallise on slow diffusion of pentane into their dichlo-
romethane solutions. X-ray crystallography revealed that
the cyclobismalonates arrange in columnar structures with
formation of a channel (pore) in the middle of each column.
Scheme 2. Synthesis of macrocyclic oligomalonates by condensa-
The dimensions of the channels can be tuned by variation tion of malonyl dichloride with diols.
Table 1. Distributions and physical properties of the oligomalonate macrocycles obtained from condensation reactions betwee malonyl
dichloride and alkanediols.
Entry (X)
Diol
Monomer (Xa)
Dimer (Xb)
Trimer (Xc)
Yield[a]
State
Yield[a]
State
Yield[a]
State
(%)
(%)
(%)
8
HO–(CH2)3–OH
HO–(CH2)5–OH
HO–(CH2)8–OH
HO–(CH2)11–OH
HO–(CH2)12–OH
HO–(CH2)13–OH
HO–(CH2)14–OH
HO–(CH2)15–OH
HO–(CH2)16–OH
HO–(CH2)20–OH
not formed
–
17
16
16
12
8
14
14
10
10
5
white solid
white solid
white solid
white solid not isolated
white solid not isolated
white solid not isolated
waxy solid
waxy solid not isolated
waxy solid
waxy solid
11
8
9
colourless oil
yellowish oil
yellowish oil
9
traces
traces
traces
traces
4
6
9
yellowish oil
yellowish oil
yellowish oil
yellowish oil
colourless oil
colourless oil
colourless oil
white solid
white solid
10
11
12
13
14
15
16
17
–
–
–
7
waxy solid
–
waxy solid
waxy solid
11
16
5
3
[a] Isolated yield. Some of the yields are reported with an accuracy of 1% for the sake of uniformity.
Eur. J. Org. Chem. 2006, 2296–2308
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2297

F. Diederich, A. Hirsch et al.
FULL PAPER
study we have isolated the monomeric (Xa), dimeric peaks with the relative isolated (molar) yields of the puri-
(Xb), and trimeric (Xc) malonate macrocycles (Tables 1, 2, fied products, as determined by gravimetric methods. This
and 3).
provides an ideal tool for the optimisation of the product
distribution, since the relative molar yield of the cyclo[n]-
octylmalonates plotted against n can be perfectly fitted to
a Lorentzian function (Figure 1). It was found that the
product distribution is virtually independent of the diol
concentration over a range of 15–35 mmol·L–1. The only
effect is a decrease in the total yield with increasing concen-
tration. The main factor governing the product distribution
seems to be the duration of the malonyl dichloride addition.
Table 2. Distributions and physical properties of the oligomalonate
macrocycles derived from condensation reactions between malonyl
dichloride and aromatic diols and diols containing heteroatoms in
the spacer.
[a] Isolated yield. Some of the yields are reported with an accuracy
of 1% for the sake of uniformity. [b] The reaction was performed
at a diol concentration of 0.166 mol·L–1. The macrocycles were sep-
arated by GPC with tetrahydrofuran as eluent.
Table 3. Distributions and physical properties of the oligomalonate
macrocycles obtained from condensations between malonyl dichlo-
ride and optically active diols.
Figure 1. Lorentz fit of the relative molar yields for the cyclo[n]
octylmalonates determined from FAB mass spectrometry.
It should be noted here that the isolated yields of the
macrocyclic malonates are not high, ranging from 2 to 17%
in the case of the bismalonates (Tables 1, 2, and 3). In prin-
ciple, the yields could be improved by use of multi-step
methods involving tedious protecting-group chemistry, ulti-
mately allowing a single final intramolecular ring closure.
However, our original goal was to find a quick route to the
oligomalonate macrocycles in order to test them for regiose-
lectivity in Bingel macrocyclisations with C60.
[a] Isolated yield. Some of the yields are reported with an accuracy
of 1% for the sake of uniformity.
The relative yields of the macrocycles can be easily ob-
tained from the FAB mass spectra of the crude reaction
mixture, as the peak intensities correlate exactly with the
Condensation of Malonyl Dichloride with α,ω-Alkanediols
The distribution of the different (mono-, bis-, and tris-)
relative isolated yields of the corresponding compounds. cyclomalonates formed in a cyclisation reaction between
This was demonstrated for the cyclo[n]octylmalonates by malonyl dichloride and a diol would be expected to depend
comparison of the relative intensities of the molecular ion on both the length and the nature of the chain connecting
2298
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 2296–2308

Macrocyclic Cyclo[n]malonates
FULL PAPER
the hydroxy groups. In order to investigate the effect of the ates formed during cyclisations with malonyl dichloride, the
chain length, we subjected a series of alkanediols (8–17), diols 18–22 shown in Table 2 were examined. The behaviour
differing in carbon chain length, to cyclisation with malonyl of benzene-1,4-dimethanol (18) was found to correspond to
dichloride; the results are summarised in Table 1. The fol- that of short-chain alkanediols. Macrocycles up to non-
lowing conclusions can be drawn from the reported data:
amers were formed and separated by GPC, whereas the cy-
a) The monomalonate macrocycles Xa were formed only in clic monomalonate 18a was not detected in the crude reac-
traces when diols containing three to twelve methylene units tion mixture. In diols 19, 20 and 21 the rigid core was re-
were utilised, whereas the formation of the monomeric tained but oxygen or nitrogen heteroatoms were introduced
rings was favoured when long-chain alkanediols were used into the side chains.[16] In this case, the formation of mono-
(16–17).
meric 19a, 20a, 21a and dimeric 19b, 20b and 21b is fav-
b) The yields of the cyclic dimers Xb and trimers Xc tended oured, and they were isolated in yields ranging from 5 to
to decrease with increasing chain length of the diol, while at 16%. The trimeric malonates 19c, 20c and 21c are only
the same time the formation of polymeric products became minor products of these transformations. This trend is most
pronounced.
pronounced when triethyleneglycol 22 is used as diol. The
c) The monomeric malonates Xa with up to C15 alkyl spa- monomeric 22a is formed as the major product in 38%
cers exist as highly viscous oils while monomers with larger yield, while the formation of the trimeric 22c is completely
ring sizes are isolated as solids.
suppressed.
d) The bismalonates Xb with up to C13 alkyl spacers are all
The different macrocyclisation behaviour of triethyleneg-
crystalline solids, whereas diols containing more than 14 lycol (22) and the corresponding octane-1,4-diol (10) can
methylene units afford dimers that are isolated as waxy ma- be readily explained in terms of different conformational
terials.
preferences. Whereas all-alkyl chains clearly prefer all-anti
e) The trimeric malonates Xc have a morphological appear- torsion angles, triethyleneglycol prefers gauche conforma-
ance similar to that of the monomeric counterparts. Thus, tions of its O–C–C–O fragments (gauche effect).[17] The
trimeric macrocycles with short spacers exist as highly vis- “folding” induced by the gauche dihedral angles presumably
cous oils while the long-alkyl-chain derivatives are isolated preorganises 22 for the formation of the monomeric macro-
as waxy solids.
cycle. The condensation between malonyl dichloride and
An interesting observation concerns the melting points triethyleneglycol under solid–liquid phase-transfer catalysis
of the cyclobismalonates: the macrocycles containing C11– conditions with KF as a base and template, benzyltrieth-
C16 alkyl chains with even numbers of carbon atoms have ylammonium chloride as catalyst and dichloromethane as
slightly higher melting points than their neighbouring solvent has been reported.[18] In this case, macrocycles with
homologues with odd numbers of carbon atoms, thus show- more than three malonate units were also obtained, poss-
ing a behaviour similar to that of linear alkanes (Fig- ibly as a result of cation templating effects.
ure 2).[15] This behaviour – along with their X-ray struc-
tures – is evidence of the highly ordered structures of such
macrocycles in the solid state.
Chiral Cyclomalonates
In a next step we targeted the preparation of chiral, non-
racemic macrocycles. For this purpose, diols (–)-23, (+)-24,
(–)-26 and (–)-28 (Table 3) were subjected to cyclisation
with malonyl dichloride under the experimental conditions
reported above. (4R,5R)-2,2-Dimethyl-1,3-dioxolane-4,5-di-
methanol [(–)-23] is commercially available, while (–)-26 and
(–)-28 were synthesised as shown in Scheme 3. The synthe-
sis of (+)-24 has been reported previously.[19]
Diol (–)-23 (Table 3) showed a behaviour similar to that
of short-chain alkanediols, resulting in the formation of op-
tically active macrocycles with up to nine repeat units, as
confirmed by FAB MS of the crude reaction mixture. Mo-
nomeric ent-23a was not detected, and the cyclisation with
malonyl dichloride afforded dimeric (+)-23b as the major
product. In the case of diol (+)-24, with two longer C4
chains emanating from the five-membered ring, the mono-
meric and dimeric rings were formed in equal yields, while
the yield of the trimeric ring was significantly lower, as was
also observed with longer-chain alkanediols (Table 1). Di-
meric (+)-23b and (+)-24b are readily crystallisable solids,
Figure 2. Diagram of the melting points of the cyclo[2]alkylmalon-
ates vs. the number of carbon atoms in the alkyl spacers.
Condensation of Malonyl Dichloride with Aromatic Diols
and Diols Containing Heteroatoms in the Spacers
To investigate the influence of the nature of the organic whereas the corresponding trimeric rings exist as highly vis-
chains in the diols on the distributions of the cyclic malon- cous oils. The enantiomerically pure diols (–)-26 and (–)-28,
Eur. J. Org. Chem. 2006, 2296–2308
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2299

F. Diederich, A. Hirsch et al.
FULL PAPER
Scheme 3. Synthesis of the optically active diols (–)-26 and (–)-28.
bearing glycolic chains, gave results similar to those ob- X-ray Crystallographic Study of the Macrocyclic
tained with triethyleneglycol, with monomeric (–)-26a and Bismalonates
(–)-28a being formed as the major products in 28 and 33%
yields, respectively. The corresponding bis- and trismalon-
A common characteristic of the bismalonates synthesised
ates were formed as minor products, and their separation in this study (Tables 1, 2, and 3) is their ability to form
by column chromatography proved to be tedious, due to colourless, X-ray quality crystals when pentane slowly dif-
their high polarities and low yields. Trimeric ent-26c was fuses into their dichloromethane solutions. This crystallisa-
isolated in impure form, while the column chromatographic tion method was applied to all bismalonates except for 18b,
separation of ent-28c on SiO2 could not be accomplished. which afforded crystals suitable for X-ray analysis on slow
Finally, in contrast to the crystalline states of the dimeric concentration of its chloroform solution. Only the bisma-
rings obtained from diols (–)-23 and (+)-24, the bismalon- lonates containing glycol chains or long alkyl chains could
ates ent-26b and ent-28b exist as highly viscous oils.
not be crystallised but rather yielded highly viscous oils.
Figure 3. Columnar arrangement of 10b (left),[13] 12b (center),[13] and 9b (right) in single crystals: a) Intermolecular C–H···O hydrogen
bonds between neighbouring molecules of 10b in the stacks and measured Cx···Oy distances. b) Columnar structure of 10b. c) Intermo-
lecular C–H···O hydrogen bonds between neighboring molecules of 12b and measured Cx···Oy distances. d) Columnar structure of 12b.
e) Intermolecular C–H···O hydrogen bonds and C–H···H–C interactions between neighbouring molecules of 9b and measured Cx···Oy
and Cx···Cy distances. f) Columnar structure of 9b.
2300
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 2296–2308

Macrocyclic Cyclo[n]malonates
FULL PAPER
Tubular structures[20] are versatile functional modules in whereas benzene rings of the same kind of molecules (A
nanoconstruction and the supramolecular approach[21] has or B) adopt a parallel alignment and sit atop each other.
been used extensively to produce well-defined organic Molecules of the same kind pack in columnar stacks that
nanotubes. Among the different molecule-based synthetic are stabilised by several intermolecular C–H···O hydrogen
strategies, the self-assembly or stacking of macrocycles of- bonds [d(C···O) = 3.332 and 3.425 Å] between malonate
fers the potential to create hollow tubular structures in the C=O groups and aliphatic and aromatic C–H residues.
solid state. Cyclic peptides,[22] cyclic oligosaccharides, phen- Interestingly, there are also close C–H···O contacts between
ylene macrocycles, coil-ring-coil block copolymers and malonate carbonyl groups and benzene C–H units as well
cyclodextrins have been successfully used as molecular as with the favourably polarised, acidic malonate CH2
building blocks, and their self-assembly to form tubular groups.
structures has been examined.[23] Recently, we reported[13]
the crystal structures of bismalonates 10b and 12b. These
macrocycles crystallise in perfectly rectangular shapes, with
the molecules arranging into columnar structures (Figure 3)
forming very narrow inner channels with dimensions de-
pending on the lengths of the alkyl chains in the macrocy-
cle. Distinct dihedral-angle preferences are apparent: the
alkyl chains, as would be expected, prefer the all-anti con-
formation, whereas the two carboxy planes in each malon-
ate moiety are nearly orthogonal to one another [torsion
angles between the planes through C–O–C(O)–C and CЈ–
CЈ(OЈ)–OЈ–C average 77°]. Space-filling-model representa-
tions show that the inner space in each macrocycle is nearly
filled with hydrogen atoms engaged in favourable intramo-
lecular van der Waals interactions. The columnar assem-
blies are also stabilised by intermolecular CH···CH van der
Waals interactions. In addition, several intermolecular C–
H···O hydrogen bonds[24] presumably make important con-
tributions to the stabilities of the columnar stacks. Such
intermolecular contacts [d(C···O) distances between 3.198
and 3.562 Å] are seen between the C=O groups and the
methylene groups of the malonates (C18 in 10b, C14 in 12b)
and the terminal methylene groups of the diols (C20 in 10b,
C12 in 12b). As a result of the inductive effect of the neigh-
bouring oxygen atoms, these CH2 moieties are particularly
favourably polarised to participate in C–H···O interactions.
Figure 4. Molecular structure and columnar arrangement of 18b.
a) X-ray crystal structure of 18b with numbering of atoms. b)
Space-filling representation of the molecular structure. c) Align-
Like the bismalonates 10b and 12b, macrocycle 9b (Fig-
ure 3) crystallises in a rectangular shape with a nearly filled
internal macrocyclic void. Again the tubular structures are
held together by intermolecular C–H···O hydrogen bonds
[d(C···O) = 3.361–3.438 Å] between the C=O residues of the
malonates and the methylene groups of the malonate (C4)
and terminal methylene groups of the diol (C2). Additional
ment of the two molecules A and B with different structures found
in the unit cell, intermolecular C–H···O hydrogen bonds and C–
H···C=O interaction between molecules of the same kind in a co-
lumnar alignment and between molecules of a different kind, and
measured C···O and C···C distances. d) Columnar structure formed
by molecule A.
The asymmetric unit cell of a single crystal of optically
short C–H···O contacts are seen between neighbouring active bismalonate (+)-23b showed a rectangularly shaped
molecules in different stacks [d(C···O) = 3.440–3.571 Å]. macrocycle with a nearly closed internal cavity (Figure 5).
Whereas the inner pores in the columnar stacks of 9b, As in the previously discussed structures, the molecules or-
10b and 12b are nearly completely filled by C–H residues ganise into columnar stacks held together by van der Waals
engaged in through-space van der Waals interactions, the interactions and C–H···O=C hydrogen bonding, with
bridging of the two malonate residues by p-xylylene moie- d(C···O) = 3.414 Å. A variety of intermolecular C–H···O
ties in [7.7]paracyclophane 18b opens up a void space. The hydrogen bonds, involving not only the carbonyl oxygen
molecule crystallises in a rectangular shape, and the two atoms but also the ether oxygen atoms of the malonate ester
benzene rings adopt a coplanar parallel-shifted orientation residues, are also seen between macrocycles in neighbouring
(Figure 4). The normal distance between the two parallel stacks. Similar structural features are observed for (+)-24b
benzene planes amounts to 5.867 Å (centroid–centroid dis- (Figure 5); these include: a) a nearly closed macrocyclic cav-
tance) and the centres of the rings are parallel shifted by ity, b) assembly of the macrocycles into columnar stacks
5.550 Å. The unit cell contains two differently oriented promoted by intermolecular C–H···O hydrogen bonds, and
molecules A and B. The dihedral angle between the planes c) stabilisation of the crystal lattice by additional C–H···O
of the benzene rings in molecules A and B is 38.91°, hydrogen bonds between molecules in neighbouring stacks.
Eur. J. Org. Chem. 2006, 2296–2308
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2301

F. Diederich, A. Hirsch et al.
FULL PAPER
Figure 5. Molecular structure and columnar arrangement of (+)-23b (top) and (+)-24b (bottom). a) X-ray crystal structures with number-
ing of atoms. b) Space-filling representation of the molecular structures. c) C–H···O hydrogen bonds and C–H···H–C interactions between
molecules in a columnar alignment and their measured distances. d) Columnar structures showing the channels formed in the crystal.
Figure 6. Molecular structure and columnar arrangement of 29 in the crystal. a) X-ray crystal structure of 29 and numbering of atoms.
b) Space-filling representation of the supramolecular dimer. c) Intermolecular C–H···O hydrogen bonds between dimers of the same
stack. d) Unit cell representation with the C–H···O hydrogen bond between molecules A and B. e) Columnar structure formed by the
dimers. f) Measured distances for hydrogen bonds O–H···O and C–H···O.
2302
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 2296–2308

Macrocyclic Cyclo[n]malonates
FULL PAPER
Hydrogen Bond-Assisted Formation and Columnar Stacking clustering at dihedral angles Θ1 [R1–O–C(O)–C] = Θ4 [R4–
of Supramolecular Cyclobismalonates
O–C(O)–C] = 0°. A total of 584 (86%) of the investigated
structures lie within a range of 10°. The few exceptions to
this preference are observed in malonates with either one
or two ester groups incorporated in small-ring lactone
structures adopting the energetically unfavourable syn con-
formation.
The synthesis of cyclobismalonates through condensa-
tions between malonyl dichloride and appropriate diols
proved to be an easy method to access this family of macro-
cycles, the only disadvantage being the low product yields.
The ability of these molecules to crystallise in columnar
structures forming an inner channel prompted us to adopt
a simpler approach for the formation of the dimeric rings
and to investigate the possibility of their tubular stacking.
We therefore investigated a supramolecular approach by
forming a bismalonate macrocycle with intermolecular hy-
drogen bonding between two identical subunits. For this
purpose, 4,4Ј-malonylbis(butanoic acid) (29) was synthe-
sised as described before[25] and allowed to crystallise by
slow concentration of its chloroform solution, yielding crys-
tals suitable for X-ray analysis.
With respect to the dihedral angles Θ2 and Θ3 (O=C–C–
C), the results of the search are not as homogeneous. Re-
cent publications applying low-temperature matrix-isolation
infrared spectroscopy and quantum mechanical calcula-
tions at the DFT(B3LYP)/6-311++G** and MP2/
6-31++G** levels of theory to dimethyl malonate predict
two types of low-energy conformers.[27] One is characterised
by C2 symmetry, with both torsion angles being around
120°. The second shows C1 symmetry and a “gauche” con-
formation. The energies of these minima were calculated to
be very similar, separated only by barriers of 1.5 kJ·mol–1
for the conversion of the two possible C2 conformers to the
“gauche” conformers and of 1.8 kJ·mol–1 for the intercon-
version of the four “gauche” conformers. Our CSD search
reflects these preferences although the clustering is not as
pronounced as in the earlier case. Out of 683 malonate moi-
eties found, 318 (47%) adopt a C2 conformation showing a
O=C–C–C torsion angle of 100° Ͻ Θ2 Ͻ 150° or –150°
The crystal structure (Figure 6) shows that two molecules
are held together by intermolecular linear hydrogen bonds
[d(C···O) = 2.656 and 2.669 Å] between the carboxylic
groups, resulting in the formation of a supramolecular cy-
clobismalonate in the solid state. The unit cell contains two
pairs of different molecules 29 (A and B), oriented nearly
perpendicularly to one another. A C–H···O=C hydrogen
bond with d(C···O) = 3.334 Å is observed between A and
B. The supramolecular bismalonate dimers behave similarly
to the covalent analogues and form columnar structures
with an inner channel (Figure 6). Again, the columnar
stacks are stabilised by short C–H···O contacts, which
clearly represent the prominent directional intermolecular
interactions in the assemblies of both the covalent and the
supramolecular dimers.
Conformational Analysis of Malonates
Malonates bearing two COOMe ester groups have
proven preferentially to adopt anti ester orientations [Fig-
ure 7a; anti is defined for the orientation of the bonds R1–
O and C(O)–C(R2,R3)].[26] The rotational barrier around
the ester bond leading to the higher-energy syn conformer
has been shown to be as large as 30 kJ·mol–1.[27,28] The pref-
erence for the anti conformation originates from both steric
and stereoelectronic (nǞσ*) factors. A Cambridge Struc-
tural Database (CSD version 5.26) search of 526 crystal
structures containing a total of 683 malonate moieties of
the general type R1OOC–CR2R3–COOR4 (with R1, R4 be-
ing carbon-terminated residues and R2, R3 being hydrogen
or any other carbon residue) clearly supports the previous
Figure 7. a) General graphical representation of the geometrical
parameters used for the CSD search. b) Scatterplot correlating the
pair of torsion angles (θ1, θ4). c) Scatterplot correlating the pair
of torsion angles (θ2, θ3) (filled squares represent parameters for
results. The scatterplots (Θ1 vs. Θ4, Figure 7b) show distinct molecules described in this article).
Eur. J. Org. Chem. 2006, 2296–2308
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2303

F. Diederich, A. Hirsch et al.
FULL PAPER
Ͻ Θ3 Ͻ –100°, respectively (Figure 7c). Since the potential ties enforced by more extended, rigid spacers will be pur-
energy surface is calculated to be rather flat, the structures sued in future work. This study indeed raises expectations
with “gauche” conformations only show a widespread ag- that such systems should have the potential to form colum-
glomeration in the scatter diagram. In the case of one tor- nar assemblies featuring pores for molecular recognition
sion angle being close to 0°, a tendency for the second tor- and transport.
sion angle to lie in the range of 80–110° can be observed.
In cases in which either steric repulsion or cyclic structures
induce other than the expected conformations, the devia-
Experimental Section
General: All starting materials were purchased from commercial
sources or were prepared by known literature procedures. The sol-
vents were dried by standard techniques. Reactions were monitored
by thin layer chromatography on silica gel 60F254 (Merck) alumin-
ium plates. Products were isolated by flash column chromatography
(FC) (silica gel 60, particle size 0.04–0.0063 nm, Merck) and GPC
tion from these predictions is greater.
The structures presented in this article clearly reflect the
latter case. The preferred torsion angles are induced by the
macrocyclic structure rather than by preferential geometries
of the malonate moieties, leading to three “C2-like” confor-
mations and nine “gauche-like” conformations, all of them
lying out of the boundaries discussed above (Figure 7c).
1
(BioBeads S-X1 from Bio-Rad). H NMR and 13C NMR spectra
were recorded with JEOL JNM EX 400, JEOL JNM GX 400,
JEOL A 500 MHz and Bruker Avance 300 MHz spectrometers.
The chemical shifts are given in ppm relative to the appropriate
solvent peak as standard reference. The resonance multiplicity is
indicated as s (singlet), d (doublet), t (triplet), q (quartet), quint
(quintet), m (multiplet), or combinations of these. Broad reso-
nances are designated with br. Mass spectra were measured with
a Micromas Zab (FAB) Finnigan MAT 900 spectrometer with 3-
nitrobenzyl alcohol as the matrix. MALDI mass spectra were re-
corded with an IonSpec Fourier Transform (FT) instrument with
2,5-dihydrobenzoic acid (DHB) as a matrix. IR spectra were re-
corded with a Bruker FT-IR IFS 88. The spectra were measured as
KBr pellets or as films on NaCl plates. Optical rotations were mea-
sured with a Perkin–Elmer Model 341 polarimeter. Elemental
analyses were carried out with an EA 1110 CHNS machine from
CE Instruments. X-ray crystallographic analysis was performed
with an Enraf–Nonius MACH 3 diffractometer. Calculations were
carried out with SHELX software; the graphics were generated
with the Mercury 1.3 program. The purities of the achiral and chi-
ral macrocyclic oligomalonates isolated in this study were higher
than 98% as confirmed by TLC analysis and 1H NMR spec-
troscopy. Compounds 10b, 10c, 12b, 16a, 16b and 16c,[13] 20a, 20b,
20c, 21a and 21b,[16] (+)-24a, (+)-24b and (+)-24c[19] and 29[25] were
synthesised and characterised previously.
Conclusions
The synthesis of macrocyclic malonates through conden-
sations between malonyl dichloride and chiral or achiral di-
ols is a versatile one-step method providing cyclomalonates
with a variety of organic spacers connecting the malonate
ester moieties. The selectivity towards the preferential for-
mation of monomeric, dimeric, or trimeric ring structures
was tuned by varying the natures and lengths of the spacers
in the diols, as demonstrated by the results obtained with
alkanediols or diols bearing more rigid aromatic spacers or
spacers with heteroatoms. The majority of the bismalonates
synthesised showed pronounced crystallisability. The X-ray
crystal structures of these macrocycles – both achiral and
chiral – feature a large number of common characteristics:
(i) The dihedral angle between the planes of the two car-
boxy groups in a malonate tends to adopt values around 90
30°. A conformational search in the CSD suggests that
these conformational preferences are largely enforced by the
macrocyclic structure. In all cases, anti ester conformations
are observed.
Synthesis of Diols (–)-26 and (–)-28
(ii) The macrocycles assemble into columnar stacks, form-
ing narrow channels and pores extending through the entire
single crystals. Filling of the pores is favoured by intramo-
lecular van der Waals interactions between methylene units
in the dimers.
(1R,2R)-trans-1,2-Bis[2-ethoxycarbonyl-1-oxaethyl]cyclohexane [(–)-
25]: Boron trifluoride–diethyl ether (0.1 mL) was added slowly un-
der N2 and with magnetic stirring to an ice-cooled solution of ethyl
diazoacetate (90% in CH2Cl2, 1.98 mL, 19.12 mmol) and (1R,2R)-
trans-cyclohexane-1,2-diol (1 g, 8.62 mmol) in dry CH2Cl2 (15 mL).
After the addition was complete, stirring was continued at room
temperature for 1 h, and then at 45 °C for 1 h. The solution was
(iii) The most noticeable directional intermolecular interac-
tions between neighbouring molecules in the columnar
structures are C–H···O hydrogen bonds between the oxygen neutralised by addition of NaHCO3 and filtered, and the solvent
was evaporated under reduced pressure. The diester product was
purified by flash column chromatography on SiO2 with a mixture
of hexane/EtOAc (1:1) as eluent. Yellow oil, yield 1.375 g (55%).
atoms of the malonate residues – with a preference for the
participation of the C=O units – and polarised aromatic C–
H and aliphatic CH2 moieties. The distances of these C–
H···O contacts vary between d(C···O) = 3.198 and 3.571 Å
and are therefore in the range of those reported in the litera-
ture.[24] Such intermolecular C–H···O interactions are also
observed between molecules of neighbouring columns. Re-
markably, a similar tubular stacking was also observed for
supramolecular bismalonate macrocycles formed by car-
[α]2D2 = –38 (c = 0.00239, CHCl3). H NMR (300 MHz, CDCl3): δ
1
2
2
= 4.29 (d, J = 16.4 Hz, 2 H), 4.21 (d, J = 16.4 Hz, 2 H), 4.16 (q,
3J = 7.1 Hz, 4 H), 3.27 (m, 2 H), 2.02, (m, 2 H), 1.64 (m, 2 H),
1.24 (t, J = 7.1 Hz, 6 H), 1.22 (m, 4 H) ppm. 13C NMR (75 MHz,
3
CDCl3): δ = 171.41, 83.54, 68.41, 61.05, 30.83, 24.07, 14.57 ppm.
IR (CH Cl ) νmax = 3675, 3600, 3293, 3055, 2943, 2866, 1755, 1606,
˜
2
2
1452, 1353, 1332, 1263, 1214, 1150, 1119, 1029, 1008, 986, 911,
boxylic acid dimerisation between two identical malonates 848, 760, 746, 725, 712 cm–1. MS (FAB, NBA): m/z = 289
[M + H]+.
with terminal carboxylates.
The supramolecular and covalent construction of macro-
cyclic bis- and trismalonates with more preorganised cavi- (–)-25 (1.37 g, 4.75 mmol) was reduced with LiAlH4 in dry THF in
(1R,2R)-trans-1,2-Bis[2-hydroxyethoxy]cyclohexane [(–)-26]: Diester
2304
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 2296–2308

Macrocyclic Cyclo[n]malonates
FULL PAPER
the usual manner. Diol (–)-26 was obtained as a yellowish oil. Yield
0.95 g (98%). [α]2D2 = –54.5 (c = 0.00332, CHCl3). 1H NMR
(300 MHz, CDCl3): δ = 3.75 (m, 2 H), 3.69 (m, 4 H), 3.55 (m, 2
H), 3.26 (s, 2 H, –OH), 3.20 (m, 2 H), 2.04 (m, 2 H), 1.66 (m, 2
H), 1.17 (m, 4 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 82.96,
3J = 5.7 Hz, 8 H), 3.34 (s, 4 H), 1.96 (quint, 3J = 5.7 Hz, 4 H)
ppm. 13C NMR (100.4 MHz, CDCl3): δ = 165.91, 60.80, 42.10,
26.67 ppm. IR (KBr): ν
= 3015, 2972, 2929, 2909, 1754, 1735,
˜
max
1470, 1429, 1415, 1385, 1362, 1282, 1229, 1154, 1118, 1086, 1060,
1008, 977, 897, 758, 682, 615, 561 cm–1. MS (FAB, NBA): m/z =
71.26, 62.58, 31.11, 24.36 ppm. IR (CH Cl ) ν
= 3675, 3443, 289 [M + H]+. C12H16O8 (288.25): calcd. C 50.00, H 5.59; found C
˜
max
2
2
3054, 2940, 2864, 1725, 1606, 1452, 1366, 1277, 1257, 1210, 1118,
1093, 1057, 1005, 937, 885, 827, 760, 747, 731, 708 cm–1. MS (FAB,
NBA): m/z = 205 [M + H]+.
49.90, H 5.65.
Cyclo[3]propylenemalonate 8c: Colourless, highly viscous oil, yield
241 mg (11.2%, based on propanediol). 1H NMR (400 MHz,
3
(1R,2R)-trans-1,2-Bis[5-ethoxycarbonyl-1,4-dioxapentyl]cyclo-
hexane [(–)-27]: Boron trifluoride–diethyl ether (0.2 mL) was added
slowly under N2, with magnetic stirring over a period of 0.5 h, to
an ice-cooled solution of (–)-26 (2.19 g, 10.7 mmol) and ethyl di-
azoacetate (90% in CH2Cl2, 2.61 mL, 25.20 mmol) in dry CH2Cl2
(50 mL). The reaction mixture was stirred at room temperature for
2 h and was then neutralised by the addition of NaHCO3 and fil-
tered. The solvent was evaporated under reduced pressure and the
product was purified by flash column chromatography on SiO2
with a mixture of hexane/EtOAc (1:1) as eluent. Yellow oil, yield
1.5 g (37.3%). [α]2D3 = –27 (c = 0.00212, CHCl3). 1H NMR
CDCl3): δ = 4.21 (t, J = 6.2 Hz, 12 H), 3.36 (s, 6 H), 1.99 (quint,
3J = 6.2 Hz, 6 H) ppm. 13C NMR (100.4 MHz, CDCl3): δ = 166.22,
61.89, 41.55, 27.51 ppm. IR (film): ν
= 2968, 2906, 1734, 1460,
˜
max
1414, 1335, 1152, 1044, 893, 765, 666 cm–1. MS (FAB, NBA): m/z
= 433 [M + H]+.
Synthesis of Macrocycles 9b and 9c: The synthesis was performed
according to the General Procedure, with pentanediol (6.89 g,
20 mmol) being subjected to the condensation reaction with malo-
nyl dichloride. Compounds 9b and 9c were isolated by flash column
chromatography on SiO2 with a mixture of CH2Cl2/EtOAc (95:5)
as eluent.
3
(300 MHz, CDCl3): δ = 4.17 (q, J = 7.1 Hz, 4 H), 4.12 (s, 4 H),
3.74 (m, 4 H), 3.66 (m, 4 H), 3.16 (m, 2 H), 1.95 (m, 2 H), 1.61
(m, 2 H), 1.24 (t, 3J = 7.1 Hz, 6 H), 1.16 (m, 4 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 170.96, 82.43, 71.69, 69.80, 69.09, 61.12,
Cyclo[2]pentylenemalonate 9b: White solid, yield 551 mg (16%,
1
based on pentanediol), m.p. 71 °C. H NMR (400 MHz, CDCl3):
3
δ = 4.13 (t, J = 5.6 Hz, 8 H), 3.35 (s, 4 H), 1.65 (m, 8 H), 1.43 (m,
4 H) ppm. 13C NMR (100.4 MHz, CDCl3): δ = 166.34, 65.30,
30.60, 24.00, 14.60 ppm. IR (KBr): ν
= 3447, 2926, 2858, 2363,
˜
max
1730, 1654, 1648, 1636, 1570, 1559, 1540, 1534, 1522, 1517, 1507,
1453, 1420, 1384, 1353, 1314, 1273, 1245, 1220, 1168, 1122, 1069,
1046, 933, 896, 850, 842, 815, 781, 688, 608, 578, 520, 464,
414 cm–1. MS (FAB, NBA): m/z = 377 [M + H]+.
42.00, 27.90, 22.92 ppm. IR (KBr): ν
= 2987, 2958, 2899, 2876,
˜
max
1742, 1721, 1477, 1418, 1372, 1320, 1277, 1241, 1166, 1134, 1061,
1029, 1004, 976, 938, 912, 866, 804, 769, 739, 696, 598, 577, 519,
456, 420 cm–1. MS (FAB, NBA): m/z = 345 [M]+. C16H24O8
(344.36): calcd. C 55.81, H 7.02; found C 55.91, H 7.29.
(1R,2R)-trans-1,2-Bis[2-(2-hydroxyethoxy)ethoxy]cyclohexane [(–)-
28]: Diester (–)-27 (1.3 g, 3.45 mmol) was reduced with LiAlH4 in
dry THF in the usual manner. Diol (–)-28 was isolated as a colour-
Cyclo[3]pentylenemalonate 9c: Yellowish, highly viscous oil, yield
275 mg (8%, based on pentanediol). 1H NMR (400 MHz, CDCl3):
less oil. Yield 0.97 g (96%). [α]2D3 = –29 (c = 0.00286, CHCl3). H
1
3
δ = 4.11 (t, J = 5.4 Hz, 12 H), 3.33 (s, 6 H), 1.60 (m, 12 H), 1.41
(m, 6 H) ppm. 13C NMR (100.4 MHz, CDCl3): δ = 166.21, 65.15,
NMR (300 MHz, CDCl3): δ = 3.67 (m, 16 H), 3.31 (m, 2 H), 3.31
(s, 2 H, –OH), 3.23 (m, 2 H), 2.03 (m, 2 H), 1.66 (m, 2 H), 1.17
(m, 4 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 82.70, 73.09,
41.93, 27.75, 22.81 ppm. IR (KBr): ν
= 2961, 2920, 2853, 1744,
˜
max
1477, 1332, 1263, 1217, 1138, 1099, 1022, 975, 910, 892, 852, 802,
720. 676, 616, 584, 470 cm–1. MS (FAB, NBA): m/z = 516 [M]+.
71.37, 69.39, 62.11, 30.90, 24.31 ppm. IR (CH Cl ) ν = 3682,
˜
max
2
2
3584, 3451, 3053, 2938, 2865, 2304, 1737, 1605, 1547, 1452, 1353,
1261, 1099, 1004, 895, 760, 746, 724, 697 cm–1. MS (FAB, NBA):
m/z = 293 [M + H]+.
Synthesis of Macrocycles 11a, 11b and 11c: The synthesis was per-
formed according to the General Procedure, with undecane-1,11-
diol (3.76 g, 20 mmol) being subjected to the condensation reaction
with malonyl dichloride. Compounds 11a, 11b and 11c were iso-
lated by flash column chromatography on SiO2 with a mixture of
CH2Cl2/EtOAc (90:10) as eluent.
General Procedure for the Synthesis of the Cyclomalonates: The diol
(15 mmol, 1.0 equiv.) was dissolved under argon in dry CH2Cl2
(1 L) in a dry 2-L round-bottomed flask fitted with a gas inlet, a
dropping funnel (500 mL), and a magnetic stirrer, followed by the
addition of pyridine (2.0 equiv.). Subsequently, a solution of malo-
nyl dichloride (2.0 equiv.) in dry CH2Cl2 (500 mL) was added drop-
wise over a period of 8 h. After stirring at room temperature for
2 d, the mixture was concentrated with a rotary evaporator and
filtered through a silica gel plug (6×6 cm) with CH2Cl2/EtOAc
(50:50) as eluent to remove polymeric material and pyridine salts.
The solution was concentrated and the crude product was sepa-
rated by flash column chromatography on silica gel with a mixture
of CH2Cl2/EtOAc as eluent. The order of elution was monomalon-
ate, bismalonate, trismalonate macrocycles.
Cyclo[2]undecylenemalonate 11b: White solid, yield 614 mg (12%),
1
3
m.p. 87 °C. H NMR (400 MHz, CDCl3): δ = 4.14 (t, J = 6.4 Hz,
8 H), 3.35 (s, 4 H), 1,61 (m, 8 H), 1.27 (m, 16 H) ppm. 13C NMR
(100.4 MHz, CDCl3): δ = 166.54, 65.58, 42.09, 29.52, 29.50, 29.25,
25.90 ppm. IR (KBr): ν
= 2929, 2856, 2687, 2362, 2344, 1737,
˜
max
1461, 1411, 1385, 1277, 1152, 1034, 892, 803, 723, 691, 581, 502,
409 cm–1. MS (FAB, NBA): m/z = 513 [M]+.
Synthesis of Macrocycles 13a, 13b and 13c: The synthesis was per-
formed according to the General Procedure, with tridecane-1,13-
diol (4.32 g, 20 mmol) being subjected to the condensation reaction
with malonyl dichloride. Compounds 13a, 13b and 13c were iso-
lated by flash column chromatography on SiO2 with a mixture of
CH2Cl2/EtOAc (90:10) as eluent.
Synthesis of Macrocycles 8b and 8c: The synthesis was performed
according to the General Procedure, with propanediol (1.14 g,
15 mmol) being subjected to the condensation reaction with malo-
nyl dichloride. Compounds 8b and 8c were isolated by flash column
chromatography on SiO2 with a mixture of CH2Cl2/EtOAc (70:30)
as eluent.
Cyclo[2]tridecylenemalonate 13b: White solid, yield 796 mg (14%),
1
3
m.p. 93 °C. H NMR (500 MHz, CDCl3): δ = 4.11 (t, J = 6.4 Hz,
8 H), 3.33 (s, 4 H), 1.61 (m, 8 H), 1.24 (m, 36 H) ppm. 13C NMR
(125 MHz, CDCl3): δ = 166.54, 65.59, 42.07, 29.61, 29.55, 29.27,
Cyclo[2]propylenemalonate 8b: White solid, yield 356.5 mg (16.5%,
1
based on propanediol). H NMR (400 MHz, CDCl3): δ = 4.18 (t,
28.49, 25.88 ppm. IR (KBr): ν
= 2961, 2920, 2853, 1744, 1477,
˜
max
Eur. J. Org. Chem. 2006, 2296–2308
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2305

F. Diederich, A. Hirsch et al.
FULL PAPER
1332, 1263, 1217, 1138, 1099, 1022, 975, 910, 892, 852, 802, 676,
the cyclo[n]benzene-1,4-dimethylenemalonates was achieved by
GPC chromatography with THF as eluent.
616, 584, 470 cm–1. MS (FAB, NBA): m/z = 569 [M]+.
Cyclo[2]benzene-1,4-dimethylenemalonate (18b): White solid, yield
270 mg (6.5%, based on benzene-1,4-dimethanol), m.p. 122.8 °C.
1H NMR (300 MHz, CDCl3): δ = 7.12 (s, 8 H), 5.15 (s, 8 H), 3.51
(s, 4 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 166.34, 135.65,
Synthesis of Macrocycles 14a, 14b and 14c: The synthesis was per-
formed according to the General Procedure, with tetradecane-1,14-
diol (4.60 g, 20 mmol) being subjected to the condensation reaction
with malonyl dichloride. Compounds 14a, 14b and 14c were iso-
lated by flash column chromatography on SiO2 with a mixture of
CH2Cl2/EtOAc (98:2) as eluent.
128.37, 67.10, 42.59 ppm. IR (KBr): νmax = 3453, 2994, 2971, 2947,
˜
1735, 1654, 1648, 1559, 1518, 1463, 1449, 1423, 1376, 1324, 1271,
1238, 1202, 1137, 1032, 1022, 986, 942, 919, 888, 844, 820, 791, 753,
677, 639, 615, 557, 508, 456, 435 cm–1. MALDI-FT-MS (DHB):
m/z = 435 [M + Na]+. C22H20O8 (412.39): calcd. C 64.07, H 4.89;
found C 63.73, H 5.13.
Cyclo[1]tetradecylenemalonate 14a: Colourless oil, yield 356 mg
(6%). MS (FAB, NBA): m/z = 298 [M]+.
Cyclo[2]tetradecylenemalonate 14b: Waxy solid, yield 835 mg
1
3
(14%), m.p. 104 °C. H NMR (500 MHz, CDCl3): δ = 4.12 (t, J
= 6.4 Hz, 8 H), 3.33 (s, 4 H), 1.61 (m, 8 H), 1.24 (m, 44 H) ppm.
13C NMR (125 MHz, CDCl3): δ = 166.54, 65.61, 42.07, 29.70,
Cyclo[3]benzene-1,4-dimethylenemalonate (18c): Yellowish, highly
viscous oil, yield 90 mg (1.5%, based on benzene-1,4-dimethanol).
1H NMR (300 MHz, CDCl3): δ = 7.25 (s, 12 H), 5.11 (s, 12 H),
3.44 (s, 6 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 166.83, 136.06
128.88, 66.93, 41.57 ppm. MALDI-FT-MS (DHB): m/z = 641 [M
+ Na]+.
29.65, 29.59, 29.28, 28.51, 25.87 ppm. IR (KBr): νmax = 2980, 2931,
˜
2860, 1745, 1479, 1335, 1260, 1220, 1115, 1095, 1020, 971, 900,
860, 832, 802, 655, 610, 585, 466 cm–1. MS (FAB, NBA): m/z = 596
[M]+. C34H60O8 (596.84): calcd. C 68.42, H 10.13; found C 67.99,
H 10.08.
Synthesis of Macrocycles 19a, 19b and 19c: The synthesis was per-
formed according to the General Procedure, with 3,3Ј-[1,2-phenyl-
enebis(oxy)]bis(propan-1-ol) (4.53 g, 20 mmol) being subjected to
the condensation reaction with malonyl dichloride. Compounds
19a and 19b were isolated by flash column chromatography on SiO2
with a mixture of CH2Cl2/EtOAc (80:20) as eluent.
Cyclo[3]tetradecylenemalonate 14c: Waxy solid, yield 418 mg (7%).
1H NMR (400 MHz, CDCl3): δ = 4.10 (t, J = 6.2 Hz, 12 H), 3.31
(s, 6 H), 1.60 (m, 12 H), 1.23 (m, 66 H) ppm. 13C NMR (125 MHz,
CDCl3): δ = 166.50, 65.60, 42.06, 29.68, 29.65, 29.57, 29.27, 28.50,
25.85. MS (FAB, NBA): m/z = 895 [M]+.
Cyclo[2]-[O,OЈ-bis(3-oxypropoxy)phenyl]malonate 19b: White solid,
1
yield 688 mg, (12%), m.p. 67 °C. H NMR (400 MHz, CDCl3): δ
Synthesis of Macrocycles 15a, 15b and 15c: The synthesis was per-
formed according to the General Procedure, with pentadecane-
1,15-diol 4.88 g (20 mmol) being subjected to the condensation re-
action with malonyl dichloride. Compounds 15a, 15b and 15c were
isolated by flash column chromatography on SiO2 with a mixture
of CH2Cl2/EtOAc (95:5) as eluent.
3
3
= 6.96 (m, 8 H), 4.35 (t, J = 6.1 Hz, 8 H), 4.12 (t, J = 5.9 Hz, 8
H), 3.40 (s, 4 H), 2.14 (m, 8 H) ppm. 13C NMR (100.4 MHz,
CDCl3): δ = 166.35, 149.97, 122.92, 118.46, 67.27, 62.40, 42.27,
28.58 ppm. IR (KBr): ν
= 2950, 2887, 2361, 1763, 1752, 1728,
˜
max
1654, 1648, 1451, 1283, 1226, 1157, 1046, 995, 951, 770, 749, 610,
565, 420 cm–1. MS (FAB, NBA): m/z = 588 [M]+. C30H36O12
(588.60): calcd. C 61.22, H 6.16; found C 60.81, H 6.12.
Cyclo[2]pentadecylenemalonate 15b: Waxy solid, yield 625 mg
1
3
(10%), m.p. 104 °C. H NMR (400 MHz, CDCl3): δ = 4.12 (t, J
= 6.6 Hz, 8 H), 3.35 (s, 4 H), 1.62 (m, 8 H), 1.24 (m, 44 H) ppm.
13C NMR (100.4 MHz, CDCl3): δ = 166.64, 65.62, 41.75, 29.59,
Synthesis of Macrocycles 22a and 22b: The synthesis was performed
according to the General Procedure, with triethyleneglycol (2 g,
13.3 mmol) being subjected to the condensation reaction with mal-
onyl dichloride. Compounds 22a and 22b were isolated by flash
column chromatography on SiO2 with EtOAc as eluent.
29.53, 29.47, 29.18, 28.42, 25.77 ppm. IR (KBr): νmax = 2961, 2920,
˜
2853, 1744, 1477, 1332, 1263, 1217, 1138, 1099, 1022, 975, 910,
892, 852, 802, 720. 676, 616, 584, 470 cm–1. MS (FAB, NBA): m/z
= 624 [M]+.
Cyclo[1]triethyleneglycolmalonate 22a: Yellowish, highly viscous oil,
yield 1119.2 mg (38.5%, based on triethyleneglycol). 1H NMR
(400 MHz, CDCl3): δ = 4.30 (t, 3J = 4.3 Hz, 4 H), 3.71 (t, 3J =
4.3 Hz, 4 H), 3.60 (s, 4 H), 3.39 (s, 2 H) ppm. 13C NMR
(100.4 MHz, CDCl3): δ = 166.10, 69.35, 68.41, 64.26, 42.37 ppm.
Synthesis of Macrocycles 17a, 17b and 17c: The synthesis was per-
formed by the General Procedure, with eicosane-1,20-diol (6.29 g,
20 mmol) being subjected to the condensation reaction with malo-
nyl dichloride. Compounds 17a, 17b and 17c were isolated by flash
column chromatography on SiO2 with a mixture of CH2Cl2/EtOAc
(98:2) as eluent.
IR (film): ν
= 2955, 2910, 2867, 1733, 1451, 1415, 1387, 1354,
˜
max
1306, 1214, 1149, 1086, 1048, 946, 924, 848, 666 cm–1. MS (FAB,
NBA): m/z = 219 [M + H]+.
Cyclo[2]eicosylenemalonate 17b: Waxy solid, yield 362 mg (5%),
m.p. 125 °C. 1H NMR (400 MHz, CDCl3): δ = 4.10 (t, 3J = 6.6 Hz,
8 H), 3.30 (s, 4 H), 1.61 (m, 8 H), 1.26 (m, 64 H) ppm. 13C NMR
(100.4 MHz, CDCl3): δ = 166.29, 65.40, 41.81, 28.85, 28.80, 28.70,
Cyclo[2]triethyleneglycolmalonate 22b: Yellowish, highly viscous oil,
yield 367.5 mg (12.6%, based on triethyleneglycol). 1H NMR
(400 MHz, CDCl3): δ = 4.28 (t, 3J = 4.7 Hz, 8 H), 3.69 (t, 3J =
4.7 Hz, 8 H), 3.62 (s, 8 H), 3.43 (s, 4 H) ppm. 13C NMR
(100.4 MHz, CDCl3): δ = 166.38, 70.67, 68.84, 64.67, 41.42 ppm.
28.38, 28.06, 27.97, 27.70, 25.64 ppm. IR (KBr): νmax = 2928, 2854,
˜
2361, 2343, 1736, 1467, 1385, 1321, 1270, 1240, 1218, 1183, 1150,
IR (film): ν
= 2953, 2875, 1734, 1452, 1413, 1370, 1355, 1331,
˜
max
1019, 727, 691, 585, 478 cm–1. MS (FAB, NBA): m/z = 765 [M]+.
1273, 1140, 1045, 964, 856, 734, 666 cm–1. MS (FAB, NBA): m/z =
437 [M + H]+.
Synthesis of Macrocycles 18b and 18c: A solution of malonyl di-
chloride (0.96 mL, 10 mmol) in dry CH2Cl2 (10 mL) was added
dropwise under N2 over a period of 1 h to a mixture of
benzene-1,4-dimethanol (1.38 g, 10 mmol) and pyridine (1.6 mL,
20 mmol) in dry CH2Cl2 (50 mL). After stirring at room tempera-
ture for 12 h, the mixture was concentrated and chromatographed
on SiO2 with a mixture of EtOAc/hexane (3:1) as eluent. A white
solid (500 mg) was isolated as a single fraction. The separation of
Synthesis of Macrocycles (+)-23b and ent-23c: The synthesis was
performed according to the General Procedure, with (4R,5R)-2,2-
dimethyl-1,3-dioxolane-4,5-dimethanol [(–)-23, 1 g, 6.17 mmol] be-
ing subjected to the condensation reaction with malonyl dichloride.
Compounds (+)-23b and ent-23c were isolated by flash column
chromatography on SiO2 with mixtures of CH2Cl2/EtOAc (80:20
and 70:30, respectively).
2306
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 2296–2308

Macrocyclic Cyclo[n]malonates
FULL PAPER
Cyclo[2]-[(4R,5R)-2,2-dimethyl-1,3-dioxolane-4,5-dimethyl]malonate
(+)-23b: White solid, yield 485 mg (17%, based on the diol), m.p.
(m, 8 H), 3.76–3.57 (m, 24 H), 3.42 (s, 4 H), 3.16 (m, 4 H), 1.96
(m, 4 H), 1.63 (m, 4 H), 1.17 (m, 8 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 166.93, 82.76, 71.43, 69.78, 69.13, 65.13, 41.66, 30.97,
24.23 ppm. MS (FAB, NBA): m/z = 721 [M + H]+.
1
157.4 °C. [α]2D2 = +3.4 (c = 0.00537, CHCl3). H NMR (300 MHz,
CDCl3): δ = 4.27 (m, 8 H), 4.04 (m, 4 H), 3.46 (s, 4 H), 1.40 (s, 12
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 163.50, 108.52, 73.63,
X-ray Analysis: The structures were solved by direct methods
(SIR97)[29] and refined by full-matrix least-squares analysis
(SHELXL-97),[30] with use of an isotropic extinction correction.
All heavy atoms were refined anisotropically, hydrogen atoms iso-
tropically, with hydrogen positions being based on stereochemical
considerations. CCDC-288520 (9b), -290106 (18b), -288517 (23b),
-288518 (24b) and CCDC-288519 (29) contain the supplementary
crystallographic 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.
63.09, 39.38, 24.74 ppm. IR (KBr): ν
= 3439, 2991, 2941, 2359,
˜
max
1746, 1727, 1701, 1696, 1684, 1653, 1647, 1636, 1559, 1521, 1507,
1473, 1458, 1420, 1378, 1329, 1263, 1221, 1166, 1152, 1127, 1089,
1059, 1018, 1005, 913, 893, 843, 668, 626, 587, 536, 512, 491, 458,
419 cm–1. MS (FAB, NBA): m/z = 461 [M + H]+. C20H28O12
(460.43): calcd. C 52.17, H 6.13; found C 52.09, H 5.97.
Cyclo[3]-[(4R,5R)-2,2-dimethyl-1,3-dioxolane-4,5-dimethyl]malonate
ent-23c: Colourless, highly viscous oil, yield: 185 mg (4.3%, based
on the diol). 1H NMR (300 MHz, CDCl3): δ = 4.26 (m, 12 H), 4.02
(m, 6 H), 3.46 (s, 6 H), 1.38 (s, 18 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 163.77, 108.32, 73.64, 62.93, 38.89, 24.72. MS (FAB,
NBA): m/z = 691 [M + H]+.
X-ray Crystal Structure of 9b: Crystal data at 173(2) K for
C16H24O8 (344.35). Monoclinic, space group P21/c, Dc
=
1.323 g cm–3, Z = 2, α = 4.68710(10), b = 22.9169(11), c =
8.24710(10) Å, β = 102.567(2)°, V = 864.63(5) Å3. Bruker–Nonius
Kappa-CCD diffractometer, Mo-Kα radiation, λ = 0.71073 Å, µ =
0.106 mm–1. A colourless crystal of 9b (linear dimensions ca.
0.30×0.30×0.15 mm) was obtained by slow diffusion of pentane
into a CH2Cl2 solution. Number of measured and unique reflec-
tions are 2699 and 1480, respectively (Rint = 0.0443). Final R(F) =
0.0394, wR(F2) = 0.0820 for 109 parameters and 987 reflections
with I Ͼ 2σ(I) and 2.68° Ͻ θ Ͻ 25.02° (corresponding R values
based on all 1480 reflections are 0.0762 and 0.0930, respectively).
Synthesis of Macrocycles (–)-26a and ent-26b: Diol (–)-26 (0.90 g,
4.4 mmol) was treated with malonyl dichloride according to the
General Procedure, with (–)-26a and ent-26b being isolated by flash
column chromatography on SiO2 with a mixture of CH2Cl2/EtOAc
(70:30 and 60:40, respectively).
Cyclo[1]-[(1R,2R)-trans-1,2-bis(2-hydroxyethoxy)cyclohexyl]-
malonate (–)-26a: White solid, yield 340 mg (28.4%, based on the
diol), m.p. 43 °C. [α]2D2 = –2.5 (c = 0.00497, CHCl3). 1H NMR
2
3
3
(300 MHz, CDCl3): δ = 4.41 (ddd, J = 11.9 Hz, J = 3.3 Hz, J =
2
3
3
1.8 Hz, 2 H), 4.06 (ddd, J = 11.9 Hz, J = 9.3 Hz, J = 2.4 Hz, 2
H), 3.66 (m, 4 H), 3.31 (s, 2 H), 3.02 (m, 2 H), 1.93 (m, 2 H), 1.60
(m, 2 H), 1.09 (m, 4 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
X-ray Crystal Structure of 18b: Crystal data at 193(2) K for
C22H20O8 (412.38). Monoclinic, space group P21/c (no. 14), Dc =
1.457 g cm–3,
Z = 2, a = 11.7989(4), b = 5.8463(2), c =
166.49, 82.30, 68.24, 64.87, 42.79, 30.98, 24.50 ppm. IR (KBr): ν
˜
max
14.1202(5) Å, β = 105.132(2)°, V = 940.24(6) Å3. Bruker–Nonius
Kappa-CCD diffractometer, Mo-Kα radiation, λ = 0.7107 Å, µ =
= 3456, 2838, 2867, 1737, 1653, 1636, 1559, 1452, 1270, 1134, 1042,
952, 891, 850, 685, 584, 473 cm–1. MS (FAB, NBA): m/z = 273 [M
+ H]+. C13H20O6 (272.29): calcd. C 57.34, H 7.40; found C 57.03,
H 7.68.
0.112 mm–1.
A colourless crystal of 18b (linear dimensions
0.25×0.23×0.15 mm) was obtained by slow concentration of a
CHCl3 solution. Numbers of measured and unique reflections are
3720 and 2151, respectively (Rint = 0.033). Final R(F) = 0.041,
wR(F2) = 0.105 for 147 parameters and 1680 reflections with I Ͼ
2σ(I) and 1.79° Ͻ θ Ͻ 27.49° (corresponding R values based on all
2151 reflections are 0.056 and 0.119, respectively).
Cyclo[2]-[(1R,2R)-trans-1,2-bis(2-hydroxyethoxy)cyclohexyl]-
malonate ent-26b: Yellowish, highly viscous oil, yield 50 mg (2%,
based on the diol). 1H NMR (300 MHz, CDCl3): δ = 4.23 (m, 8
H), 3.76 (m, 8 H), 3.40 (s, 4 H), 3.12 (m, 4 H), 1.95 (m, 4 H), 1.63
(m, 4 H), 1.15 (m, 8 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
166.94, 83.09, 67.98, 65.63, 41.69, 31.07, 24.26 ppm. MS (FAB,
NBA): m/z = 545 [M + H]+.
X-ray Crystal Structure of (+)-23b: Crystal data at 173(2) K for
C20H28O12 (460.42). Orthorhombic, space group P212121, Dc
=
=
1.408 g cm–3,
Z = 4, a = 8.7037(3), b = 15.5372(2), c
16.0611(4) Å, V = 2171.96(10) Å3. Bruker–Nonius Kappa-CCD
Synthesis of Macrocycles (–)-28a and ent-28b: Diol (–)-28 (0.85 g,
2.91 mmol) was treated with malonyl dichloride according to the
General Procedure, with (–)-28a and ent-28b being isolated by flash
column chromatography on SiO2 with EtOAc as eluent.
diffractometer, Mo-Kα radiation, λ = 0.71073 Å, µ = 0.117 mm–1.
A
colourless
crystal
of
(+)-23b
(linear
dimensions
0.25×0.25×0.25 mm) was obtained by slow diffusion of pentane
into a CH2Cl2 solution. Numbers of measured and unique reflec-
tions are 4953 and 4953, respectively (Rint = 0.000). Final R(F) =
0.0349, wR(F2) = 0.0820 for 289 parameters and 4323 reflections
with I Ͼ 2σ(I) and 2.54° Ͻ θ Ͻ 27.48° (corresponding R values
based on all 4953 reflections are 0.0437 and 0.0864, respectively).
Cyclo[1]-[(1R,2R)-trans-1,2-bis[2-(2-hydroxyethoxy)ethoxy]cyclo-
hexyl]malonate (–)-28a: Yellowish, highly viscous oil, yield 350 mg
(33.4%, based on the diol). [α]2D4 = –14.7 (c = 0.00335, CHCl3). 1H
NMR (300 MHz, CDCl3): δ = 4.24 (m, 4 H), 3.85–3.53 (m, 12 H),
3.37 (s, 2 H), 3.11 (m, 2 H), 1.94 (m, 2 H), 1.60 (m, 2 H), 1.13 (m,
4 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 166.61, 83.23, 71.74,
X-ray Crystal Structure of (+)-24b: Crystal data at 173(2) K for
C28H44O12 (572.63). Triclinic, space group P1, Dc = 1.309 g cm–3,
Z = 1, a = 7.8292(16), b = 8.1741(16), c = 11.902(2) Å, α =
87.96(3)°, β = 75.89(3)°, γ = 79.54(3)°, V = 726.4(3) Å3. Bruker–
70.22, 69.16, 65.78, 42.39, 31.38, 24.53 ppm. IR (KBr): ν
=
˜
max
3442, 2937, 2865, 2359, 1844, 1830, 1734, 1701, 1696, 1684, 1676,
1670, 1663, 1653, 1647, 1636, 1628, 1617, 1576, 1570, 1559, 1540,
1534, 1522, 1517, 1507, 1499, 1490, 1473, 1458, 1419, 1384, 1262,
1110, 1038, 801, 668, 458, 419 cm–1. MS (FAB, NBA): m/z = 361
[M + H]+. C17H28O8 (360.40): calcd. C 56.66, H 7.83; found C
56.28, H 7.65.
Nonius Kappa-CCD diffractometer, Mo-Kα radiation,
λ =
0.71073 Å, µ = 0.102 mm–1. A colourless crystal of (+)-24b (linear
dimensions 0.25×0.20×0.10 mm) was obtained by slow diffusion
of pentane into a CH2Cl2 solution. Numbers of measured and
Cyclo[2]-[(1R,2R)-trans-1,2-bis[2-(2-hydroxyethoxy)ethoxy]cyclo- unique reflections are 6507 and 6507, respectively (Rint = 0.000).
hexyl]malonate ent-28b: Yellowish, highly viscous oil, yield 40 mg
(1.9%, based on the diol). H NMR (300 MHz, CDCl3): δ = 4.27
Final R(F) = 0.0415, wR(F2) = 0.0993 for 361 parameters and 5593
reflections with I Ͼ 2σ(I) and 2.73° Ͻ θ Ͻ 27.47° (corresponding
1
Eur. J. Org. Chem. 2006, 2296–2308
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2307

F. Diederich, A. Hirsch et al.
FULL PAPER
S. F. Nielsen, R. E. Asay, D. R. K. Masihdas, E. D. Flanders,
L. D. Hansen, R. M. Izatt, J. J. Christensen, J. Chem. Soc., Per-
kin Trans. 1 1976, 2505–2508; d) M. D. Thompson, J. S. Brad-
shaw, S. F. Nielsen, C. T. Bishop, F. T. Cox, P. E. Fore, G. E.
Maas, R. M. Izatt, J. J. Christensen, Tetrahedron 1977, 33,
3317–3320.
R values based on all 6507 reflections are 0.0522 and 0.1060,
respectively).
X-ray Crystal Structure of 29: Crystal data at 173(2) K for
C11H16O8 (276.24). Monoclinic, space group P21/n, Dc
=
=
1.454 g cm–3,
Z
=
4, 10.7635(3), 4.6693(1), c
a
=
b
=
[9] P. Margaretha, F. P. Schmook, H. Budzikiewicz, O. E. Polan-
sky, Monatsh. Chem. 1968, 99, 2539–2548.
[10] S. E. Drewes, B. G. Riphagen, J. Chem. Soc., Perkin Trans. 1
1974, 323–327.
[11] B. Thulin, F. Vögtle, J. Chem. Res. (S) 1981, 256.
[12] H. Singh, M. Kumar, P. Singh, S. Kumar, J. Chem. Res. (S)
1988, 132–133.
[13] U. Reuther, T. Brandmüller, W. Donaubauer, F. Hampel, A.
Hirsch, Chem. Eur. J. 2002, 8, 2261–2273.
25.6082(6) Å, β = 101.426(2)°, V = 1261.51(5) Å3. Bruker–Nonius
Kappa-CCD diffractometer, Mo-Kα radiation, λ = 0.71073 Å, µ =
0.126 mm–1. A colourless crystal of 29 (linear dimensions ca.
0.35×0.20×0.20 mm) was obtained by slow concentration of a
CHCl3 solution. Number of measured and unique reflections are
4058 and 2211, respectively (Rint = 0.0147). Final R(F) = 0.0323,
wR(F2) = 0.0848 for 180 parameters and 1885 reflections with I Ͼ
2σ(I) and 1.62° Ͻ θ Ͻ 25.01° (corresponding R values based on all
2211 reflections are 0.0394 and 0.0904, respectively).
[14] C. Thilgen, S. Sergeyev, F. Diederich, Top. Curr. Chem. 2004,
248, 1–61.
[15] a) A. Baeyer, Ber. Chem. Ges. 1877, 10, 1286–1288; b) R. Boese,
H.-C. Weiss, D. Bläser, Angew. Chem. Int. Ed. 1999, 38, 988–
992.
Acknowledgments
[16] M. Diekers, C. Luo, D. M. Guldi, A. Hirsch, Chem. Eur. J.
2002, 8, 979–991.
[17] J. Dale, Tetrahedron 1974, 30, 1683–1694.
[18] Z. Zhou, D. I. Schuster, S. R. Wilson, J. Org. Chem. 2003, 68,
7612–7617.
We thank the Deutsche Forschungsgemeinschaft DFG (HI 468/
14-1) and the Swiss National Science Foundation for support of
this work. We thank P. Seiler for the crystal structure analysis of
18b.
[19] N. Chronakis, A. Hirsch, Chem. Commun. 2005, 29, 3709–
3711.
[1] R. Levin, The Living Barrier, Heinemann, London, 1969.
[2] Y. A. Ovchinnikov, V. T. Ivanov, M. Shkrob, Membrane Active
Complexones, Elsevier, Amsterdam, 1974.
[20] P. F. H. Schwab, M. D. Levin, J. Michl, Chem. Rev. 1999, 99,
1863–1933.
[21] J-M. Lehn, Supramolecular chemistry: concepts and perspec-
tives, VCH, Weinheim, 1995.
[22] a) R. M. Ghadiri, R. J. Granja, A. R. Milligan, E. D. Mc-Ree,
N. Khazanovich, Nature 1993, 366, 324–327; b) R. M. Ghadiri,
R. J. Granja, K. L. Buehler, Nature 1994, 369, 301–304.
[23] M. A. B. Block, C. Kaiser, A. Khan, S. Hecht, Top. Curr.
Chem. 2005, 245, 89–150.
[24] R. K. Castellano, Curr. Org. Chem. 2004, 8, 845–865.
[25] M. Braun, U. Hartnagel, E. Ravanelli, B. Schade, C. Boettcher,
O. Vostrowsky, A. Hirsch, Eur. J. Org. Chem. 2004, 9, 1983–
2001.
[3] E. Grell, T. Funck, F, Eggers, in Membranes (Ed.: G. Elsen-
man), Marcel Dekker, New York, N.Y., 1974, vol. III.
[4] a) Y. A. Ovchinnikov, V. T. Ivanov, “The Cyclic Peptides”, in
The Proteins (Eds.: H. Neurath, R. L. Hill), 3rd ed., Academic
Press, New York, 1982, vol. V; b) W. Burgermeister, R. Wink-
ler-Oswatitsch, in Topics in Current Chemistry Inorganic Bio-
chemistry II, Springer-Verlag, Berlin, 1977, vol. 69, p. 91; c) W.
Keller-Schierlein, in Progress in the Chemistry of Organic Natu-
ral Products (Ed.: L. Zechmeister), Springer-Verlag, Vienna,
New York, 1973, vol. 30, p. 313; d) R. M. Izatt, J. J. Chris-
tensen, Progress in Macrocyclic Chemistry, Wiley, New York,
1979, vol. 1, p. 243.
[26] D. Pitea, F. Gatti, B. Marcandalli, J. Chem. Soc., Perkin Trans.
2 1983, 9, 1747–1753.
[5] C. J. Pedersen, J. Am. Chem. Soc. 1967, 89, 7017–7036.
[6] J. S. Bradshaw, G. E. Maas, R. M. Izatt, J. J. Christensen,
Chem. Rev. 1979, 79, 37–52.
[7] J. W. Hill, W. H. Carothers, J. Am. Chem. Soc. 1933, 55, 5031–
5039.
[8] a) R. M. Izatt, J. D. Lamb, G. E. Maas, R. E. Assay, J. S. Brad-
shaw, J. J. Christensen, J. Am. Chem. Soc. 1977, 99, 2365–2366;
b) J. S. Bradshaw, L. D. Hansen, S. F. Nielsen, M. D. Thomp-
son, R. A. Reeder, R. M. Izatt, J. J. Christensen, J. Chem. Soc.,
Chem. Commun. 1975, 874–875; c) J. S. Bradshaw, C. T. Bishop,
[27] S. Lopes, L. Lapinski, R. Fausto, Phys. Chem. Chem. Phys.
2002, 4, 5952–5959.
[28] E. Vilaseca, J. Phys. Chem. 1993, 97, 1684–1693.
[29] A. Altomare, M. Burla, M. Camalli, G. Cascarano, C. Giacov-
azzo, A. Guagliardi, A. G. G. Moliterni, G. Polidori, R.
Spagna, J. Appl. Crystallogr. 1999, 32, 115–119.
[30] G. M. Sheldrick, SHELXL-97 Program for the Refinement of
Crystal Structures, University of Göttingen, Germany, 1997.
Received: November 24, 2005
Published Online: March 17, 2006
2308
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 2296–2308