Conformational flexibility of tetralactam macrocycles and their intermolecular hydrogen-bonding patterns in the solid state

Article abstract of DOI:10.1002/chem.200900331

Despite their rigid scaffold, tetralactam macrocycles (TLMs) display a remarkable degree of conformational flexibility, as revealed by analysis of the corresponding X-ray crystal structures. This flexibility is not limited to the rotatability of the TLM amide groups but also applies to the m-xylene rings, and it thus has a great impact on the overall shape of the macrocycle cavity. The conformational properties of the TLMs give rise to a broad variety of intermolecular hydrogen-bonding patterns, including infinite ladders, an interesting catemer motif, and short C-H... O=C hydrogen bonds. These results are in accord with previous theoretical calculations, support a structural model proposed earlier for an interpretation of scanning tunneling microscopy images, and substantially contribute to the understanding of the adaptability of macrocyclic scaffolds, which is crucial for guest binding or templated syntheses with TLMs.

Full text of DOI:10.1002/chem.200900331

DOI: 10.1002/chem.200900331
Conformational Flexibility of Tetralactam Macrocycles and Their
Intermolecular Hydrogen-Bonding Patterns in the Solid State
Sascha S. Zhu,[a, b] Martin Nieger,[c] Jçrg Daniels,[d] Thorsten Felder,[a] Iordan Kossev,[e]
Thomas Schmidt,[f] Moritz Sokolowski,[e] Fritz Vçgtle,[f] and Christoph A. Schalley*[a]
Abstract: Despite their rigid scaffold,
tetralactam macrocycles (TLMs) dis-
play a remarkable degree of conforma-
tional flexibility, as revealed by analysis
of the corresponding X-ray crystal
structures. This flexibility is not limited
to the rotatability of the TLM amide
groups but also applies to the m-xylene
rings, and it thus has a great impact on
the overall shape of the macrocycle
cavity. The conformational properties
of the TLMs give rise to a broad varie-
ty of intermolecular hydrogen-bonding
patterns, including infinite ladders, an
are in accord with previous theoretical
calculations, support a structural model
proposed earlier for an interpretation
of scanning tunneling microscopy
images, and substantially contribute to
the understanding of the adaptability
of macrocyclic scaffolds, which is cru-
cial for guest binding or templated syn-
theses with TLMs.
ꢀ
interesting catemer motif, and short C
H···O=C hydrogen bonds. These results
Keywords: conformational flexibili-
ty · hydrogen bonds · macrocycles ·
supramolecular chemistry · tetralac-
tams
Introduction
they are widely used not only as hosts for small guest mole-
cules[1,3] but also as ring components in mechanically inter-
locked architectures, such as pseudorotaxanes,[4] rotaxanes,[5]
and catenanes.[2,6] These easily accessible, chemically stable
macrocycles bear four amide groups that are capable of
forming hydrogen-bonding patterns, on which guest binding
and templated syntheses of catenanes and rotaxanes are
based.
Since their first preparation more than a decade ago, Hunt-
erꢀs tetralactam macrocycles (“TLMs”)[1,2] have gained more
and more importance in supramolecular chemistry, because
[a] Dipl.-Chem. S. S. Zhu, Dr. T. Felder, Prof. Dr. C. A. Schalley
Institut fꢁr Chemie und Biochemie, Freie Universitꢂt Berlin
Takustrasse 3, 14195 Berlin (Germany)
According to theoretical calculations,[7] TLMs exhibit a
certain degree of conformational flexibility, in that the
amide groups and the m-xylene rings can quite easily be ro-
tated. This essential structural feature certainly contributes
to enhancing the versatility of TLMs as building blocks in
supramolecular chemistry, because they keep their overall
shape but can nevertheless adapt to the special steric re-
quirements of their binding partners. One can safely assume
that the secondary amide groups in the TLMs are trans con-
Fax : (+49)30-838-55817
E-mail: schalley@chemie.fu-berlin.de
[b] Dipl.-Chem. S. S. Zhu
Current address:
Kekulꢃ-Institut fꢁr Organische Chemie und Biochemie
Universitꢂt Bonn
Gerhard-Domagk-Strasse 1, 53121 Bonn (Germany)
[c] Dr. M. Nieger
Laboratory of Inorganic Chemistry, Department of Chemistry
P.O.Box 55, 00014 University of Helsinki (Finland)
ꢀ
figured. Rotation about the amide C N bond is thus unfav-
orable. Theory predicts a barrier lower than 30 kJmolꢀ1 for
rotation of the whole amide group from an Ain (with an
amide group with the NH moiety converging into the
cavity) into an Aout (with an amide NH moiety pointing
away from the cavity) conformation. Consequently, an all-
in, a 3-in-1-out, and two different 2-in-2-out[8] conformations
are predicted to be accessible within an energy range of ap-
proximately 8 kJmolꢀ1.[7] Significant strain is, however, gen-
erated when both amides of the same isophthalamide adopt
[d] Dr. J. Daniels
Institut fꢁr Anorganische Chemie, Universitꢂt Bonn
Gerhard-Domagk-Strasse 1, 53121 Bonn (Germany)
[e] Dr. I. Kossev, Prof. Dr. M. Sokolowski
Institut fꢁr Physikalische und Theoretische Chemie, Universitꢂt Bonn
Wegelerstrasse 12, 53115 Bonn (Germany)
[f] Dr. T. Schmidt, Prof. Dr. F. Vçgtle
Kekulꢃ-Institut fꢁr Organische Chemie und Biochemie
Universitꢂt Bonn
Gerhard-Domagk-Strasse 1, 53121 Bonn (Germany)
5040
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FULL PAPER
the Aout conformation and so, for example, a 1-in-3-out con-
formation is unfavorable in energy. Herein, three aspects of
these structural features are discussed, based on the X-ray
crystal structures of TLMs 1–5 (Scheme 1): 1) the conforma-
tional freedom of the amide groups, 2) the effects of the
presence of guests on the cavity shape and the orientation
of the m-xylene rings, and 3) intermolecular hydrogen-bond
formation in the crystals.
of 1,[11] 2,[12] and 3.[13] Note that TLM 3 is an exceptional
case, because two different conformers (3A and 3B) coexist
in the crystal structure in a 1:2 ratio.
The first aspect to be discussed is the amide conforma-
tions in the solid state (Figure 1). The all-in conformer is ob-
served for TLMs 1, 3A, and 5, whereas 2 and 3B adopt the
2-in-2-out conformation and 4+ adopts the 3-in-1-out confor-
mation. According to calculations,[7] the all-in conformation
is the slightly more favorable one and enables the formation
of two bifurcated hydrogen bonds for guest binding within
the TLM cavity. Thus, this conformation was not only found
in the crystal structures of 1 and 3A, in which solvent mole-
cules and Clꢀ anions are hydrogen bonded to the four Ain
protons. It is also observed in the crystal structures of TLM-
containing [2]rotaxanes[14] and [2]pseudorotaxanes,[4] in
which the axle is hydrogen bonded to the TLM part in the
same manner. By contrast, the less common 3-in-1-out con-
former has one “inverted” amide group, Aout, which can
serve both as a hydrogen-bond donor for the exterior and as
an acceptor for the interior of the cavity. The latter is essen-
tial for TLM-containing [2]catenanes, which form an inter-
esting network of six hydrogen bonds between the two
wheels. This pattern is not only observed in the crystal struc-
tures[6b,15] of the final catenanes but is also believed to play a
pivotal role in their templated synthesis.[7] TLM 4+ is unique
in being the only TLM so far that displays a 3-in-1-out con-
formation in the solid state without being incorporated in a
catenane. A second Aout group is present in the 2-in-2-out
conformation, which has been observed in the solid-state
Results and Discussion
X-ray-quality crystals[9] of TLMs 4+ and 5 (Scheme 1) were
obtained in different ways: 4+ was crystallized by slow evap-
oration of CDCl3, whereas needlelike crystals of 5 were ob-
tained through gradient vacuum sublimation at 1ꢅ10ꢀ5 mbar
and a sublimation temperature of 600–630 K.[10] For compar-
ison, we include the previously published crystal structures
Scheme 1. Chemical structures of tetralactam macrocycles 1–5.
Figure 1. X-ray crystal structures of: a) 1, b) 2, c) 3A, d) 3B, e) 4+, and f) 5, all shown as ball-and-stick representations. Hydrogen bonds to guest mole-
cules or anions are shown as red, dotted lines. Color code: C gray, Cl green, F yellow, H white, I purple, N blue, O red. H atoms (except amide protons)
and other solvents or anions that are not hydrogen bonded to the TLMs are omitted for clarity. The two insets display the space-filling representations
for 1 and 5, to highlight the “open-doors” and “closed-doors” conformations.
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5041

C. A. Schalley et al.
structures of 2[12] and 3 (conformer 3B). This conformation
is less effective for guest binding but facilitates the forma-
tion of intermolecular hydrogen-bond networks (for inter-
molecular hydrogen-bonding distances, see Table 1). Thus,
the solid-state structures of 1–5 ideally confirm the theoreti-
cal predictions. The all-in, 3-in-1-out, and 2-in-2-out confor-
mations all exist in the crystals and, therefore, must be quite
close in energy and connected through rather low barriers
for amide-group rotation.
Although the conformations of the amide groups affect
the cavity shape by slightly distorting its rhomboid form, an
overall open cavity is still retained, as long as the m-xylene
moieties are more or less perpendicular to the overall plane
of the macrocycle. In almost all crystal structures of TLMs
known so far, guests such as solvent molecules or anions are
present inside the cavity. The m-xylene rings accommodate
the guests by adopting tilt angles of between 568 and 908 rel-
ative to the macrocycle plane[16] (Table 2). This is, for exam-
ple, true for 1 and 2, which both host two ethyl acetate mol-
ecules in their cavities (Figure 1a and b). Chloride anions
are the guests in the crystal of 3, which implies that at least
some of the TLM pyridine rings are protonated. For 3A and
3B, the tilt angles are also within the range mentioned
above. The only exception is the crystal of TLM 5. This crys-
tal was obtained by sublimation of the macrocycle and is
thus—in contrast to all other examples—entirely free of sol-
vent and guest molecules. In 5, the two m-xylene rings (X1)
are nearly coplanar with the macrocycle plane, with tilt
angles as low as 4.68 (Figure 1 f, Table 2). This causes the
open macrocyclic cavity to be partly closed. We call this
structure the “closed-doors” conformation. A comparison of
the space-filling representations of the structures of 1 and 5
(insets in Figure 1) shows the differences between the open
and the closed cavities. The closed-doors conformation of 5
might be advantageous in that it allows a more compact
packing, but it is unsuitable for hosting guests. The marked
differences in the tilt angles of the m-xylene rings depend
on the presence of guest molecules and, thus, confirm that
the macrocycle is quite easily able to adapt to the guest mol-
eculesꢀ shapes.
The reason for the realization of different amide confor-
mations is specific intermolecular hydrogen-bonding pat-
terns (for H-bond lengths, see Table 1). The binding energy
liberated upon the formation of intermolecular hydrogen
bonds counterbalances the small energy differences between
the different conformations. We will not discuss 1 here, be-
cause no intermolecular hydrogen bonds are found within
the crystal. The all-in conformation in 1 merely results in
the binding of two ethyl acetate molecules inside the cavity.
Besides the formation of one hydrogen bond to each of
the two ethyl acetate guest mol-
ecules inside the cavity, the 2-
in-2-out conformer in the crys-
Table 1. Intermolecular hydrogen bonds for 2–5[a] between the atoms labeled in Figure 1. See also Figures 2–4.
ꢀ
ꢀ
ꢀ
ꢀ
tal of 2 forms a pair of intermo-
Donor H···Acceptor (D H···A)
d
[ꢆ]
(D H)
d
[ꢆ]
N
d
[ꢆ]
E
aACTHNGUTERNN(UG DHA)
[8]
ꢀ
lecular N H···O=C hydrogen
2[b]
3[b]
N1 H1···O1
N1B H1B···O1A
N2B H2B···O2A
N4 H4···I1
C1 H1···O1
C3 H3···O3
C1 H1···O2
C2 H2···O2
0.89
0.88
0.88
0.88
0.98
0.98
0.98
0.95
0.89
0.86
2.13
1.99
1.98
2.93
2.36
2.49
2.49
2.16
2.09
2.37
3.01
2.85
2.81
3.77
3.10
3.21
3.28
3.03
2.97
3.21
171.5
166.7
157.0
159.4
131.2
129.4
138.1
151.8
177.1
167.5
ꢀ
bonds between the two symme-
try-equivalent Aout H1 protons
and Ain O1 oxygen atoms of
two neighboring molecules.
Each TLM molecule 2 is thus
connected with its neighbors
through a total of four hydro-
gen bonds and becomes a self-
complementary building block,
which assembles into a hydro-
gen-bonded homopolymer with
the shape of an infinite ladder
[c]
ꢀ
[c]
ꢀ
ꢀ
4+
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
5[b]
N1 H1···O1
N2 H2···O1
ꢀ
ꢀ
[a] Hydrogen bonds with a hydrogen···acceptor distance (dACHTNUTRGNE(NUG H···A)) of more than 2.5 ꢆ (except for amide–
iodine interactions) are not listed in the table. [b] Symmetry transformations used to generate equivalent
atoms: ꢀx+1, ꢀy+1, ꢀz+1. [c] A and B denote the two crystallographically independent molecules found in
the crystal of 3.
Table 2. Tilt angles [8] relative to the macrocycle plane for 1–5.
Angles between the macrocycle plane and m-xylene planes[a]
Angles between the macrocycle plane and amide planes[b]
1
2
60.4
68.8
82.9
56.2
77.9
4.6
60.4
68.8
82.9
64.4
80.8
4.6
83.1
75.0
85.9
70.6
82.5
88.7
83.1
75.0
85.9
86.2
87.9
88.7
16.7 (Ain)
32.6 (Ain)
11.5 (Ain)
16.7 (Ain)
32.6 (Ain)
11.5 (Ain)
16.2 (Ain)
27.1 (Ain)
22.8 (Ain)
30.7 (Ain)
30.7 (Ain)
44.4 (Aout
)
44.4 (Aout
24.7 (Ain)
25.4 (Ain)
36.4 (Ain)
50.3 (Ain)
)
3A[c]
3B[c]
4+
24.7 (Ain)
11.0 (Aout
8.1 (Aout
)
)
16.5 (Aout
27.4 (Ain)
50.3 (Ain)
)
5
22.8 (Ain)
Av.[d]
71.9
24.2 (Ain)
21.6 (Aout
)
[a] The m-xylene plane is defined by the least-squares fit plane through all six aromatic carbon atoms of the corresponding m-xylene ring. [b] The amide
ꢀ ꢀ
plane is defined by the least-squares fit plane through the four atoms H N C=O of the corresponding amide group. [c] A and B denote the two crystal-
lographically independent molecules found in the crystal of 3. [d] Av.: Average value from the dataset of ten TLMs or TLM-containing compounds (X-
ray structures of TLMs 1–5 and CCDC-182/213, CCDC-161428, CCDC-253084, CCDC-687762, the supplementary data of which can be obtained free of
charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif).
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Tetralactam Macrocycles
FULL PAPER
(Figure 2a). To allow this H-bonding pattern to form, the
isophthaloyl units of two adjacent molecules are stacked
upon each other and the amide groups of 2 must be signifi-
cantly tilted out of the overall macrocycle plane. The devia-
tion from coplanarity of 44.48[17] is unusually large for TLMs
(Table 2). Quite interestingly, the same hydrogen-bonding
motif has been observed recently for monolayers of 5 on
In contrast to 2, the 2-in-2-out conformation of 3 (3B) co-
exists in a 2:1 ratio with the corresponding all-in conforma-
tion (3A)[18] in the solid state. This results in a quite differ-
ent hydrogen-bonding pattern: The two conformers are in-
ꢀ
terconnected by intermolecular N H···O=C bonds between
all of the Aout protons of 3B and all of the Ain oxygen atoms
of 3A. Thus, a hydrogen-bonded “copolymer” is formed,
again as an infinite ladder (Figure 2b). Furthermore, the Ain
protons of 3A and 3B interact with chloride anions.
AuACHTUNGTRENNUNG(111) surfaces by ultrahigh-vacuum scanning tunneling
microscopy (UHV-STM). The solid-state structure of 2 thus
nicely supports the structural model that was based on the
STM images and theoretical calculations of TLM trimers.[10]
Variations of this pattern have been observed by STM: Two
different types of domains have been observed in the mono-
layer of 5, one in which infinite ladders of macrocycles
cover the surface and one in which trimers of 5 exist with
the same H-bonding pattern as that found in the crystal of
2.[10]
In the X-ray crystal structure of 4+, all of the solvent mol-
ecules and half of the counteranions cannot be fully re-
solved because they are disordered. The other half of the
iodide anions can be located within the crystal lattice. Each
of these iodide anions (I1 in Figure 1e) is connected to two
TLMs through weak hydrogen bonds to their Ain protons
(H4 in Figure 1e; Figure 3b). The intermolecular hydrogen-
bonding pattern is quite unusual (Figure 3a and c), in that
Figure 2. Hydrogen-bonding patterns of a) 2 and b) 3, shown in a combination of stick, ball-and-stick, and space-filling representations (H atoms, except
for the amide protons, are omitted for 3). Hydrogen bonds appear as red, dotted lines. Color code: C gray, Cl green, F yellow, H white, I purple, N blue,
O red. The cartoons illustrate the patterns in which amide groups are involved.
Figure 3. Hydrogen-bonding pattern of 4+: a) View along crystallographic axis c and b) view along crystallographic axis b, shown in a combination of
ꢀ
stick, ball-and-stick, and space-filling representations, with hydrogen bonds appearing as red, dotted lines. c) Enlarged view of the bifurcated C H···O=C
hydrogen bond of 4+. d) View parallel to the macrocycle plane of 4+, whch shows the two Ain groups pointing into different hemispheres that are sepa-
rated by the macrocycle plane. Color code: C gray, Cl green, F yellow, H white, I purple, N blue, O red.
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C. A. Schalley et al.
ꢀ
four C H···O=C interactions are observed 1) between the
Ain O1 oxygen atom and the pyridinium methyl H1 proton
of the adjacent macrocycle, 2) between the Aout O3 oxygen
atom and the m-xylyl methyl H3 proton, 3) between the Ain
O2 oxygen atom and the pyridinium methyl H1 proton, and
4) between the Ain O2 oxygen atom and the pyridinium
ꢀ
ꢀ
ortho H2 proton. Together with the N H···I interactions,
the first two hydrogen bonds build up an infinite zigzag
stack of TLM 4+ molecules (Figure 3b), whereas the last
two interactions constitute a bifurcated hydrogen bond (Fig-
ure 3c) that leads to the assembly of an infinite chain within
the crystal structure (Figure 3a). In addition, the fourth hy-
ꢀ
drogen bond is an exceptionally short C H···O=C hydrogen
[19]
ꢀ
bond (Table 1; d
N
U
To-
gether with the D H···A angle of 151.88, one can assume
ꢀ
this bond to be relatively strong. N H···O=C interactions
are absent in the solid-state structure of 4+. In particular,
the seemingly predestined Aout H3 proton does not form any
hydrogen bonds to adjacent TLMs, as it does in 2, which
ꢀ
thus indicates that the C H···O=C bonds energetically com-
ꢀ
pensate for the lack of N H···O=C interactions.
A further remarkable finding in the X-ray crystal struc-
ture of 4+ is the “divergence” of the two Ain groups bound
to the pyridinium moiety. The proton of one Ain group
points to the iodine atom on the lower side, while the
proton of the other Ain group points to the upper side.
Hence, they point into different hemispheres that are sepa-
rated by the macrocycle plane (Figure 3d). This is unique
because two Ain groups in the same isophthaloyl unit nor-
mally point into the same hemisphere, as observed in all
other crystal structures of TLMs. The absence of rather
strong H-acceptors (such as a carbonyl oxygen atom in ethyl
acetate or a chloride anion) in the interior of the cavity
could be a possible reason for this unusual conformational
property of the amides.
In the crystal structure of 5, the all-in conformation com-
bined with the closed-doors conformation leads to a very in-
teresting hydrogen-bonding motif: The H1 proton (Fig-
Figure 4. a) Hydrogen-bonding pattern of 5, shown in a combination of
stick, ball-and-stick, and space-filling representations (all H atoms omit-
ted). A cartoon illustrates the patterns in which amide groups are in-
volved. b) Enlarged view of the amide catemer motif in 5. c) Schematic
representation of this catemer motif. Color code: C gray, Cl green, F
yellow, H white, I purple, N blue, O red.
ꢀ
ure 1 f) of the O1=C N1H1 amide group forms an intermo-
lecular hydrogen bond to the O1 oxygen atom, which is part
of the same amide group, in the adjacent TLM (Figure 4a).
The TLMs are arranged in a herringbone pattern with an
angle of approximately 908 between them. In this manner, a
ꢀ ꢀ
ꢀ ꢀ
quite remarkable catemer motif, [O=C N H···O=C N
H···]1, is obtained (Figure 4b and c).[20] The catemer motif is
unprecedented in that the secondary amide group involved
is an integral (and not peripheral) part of a macrocycle. This
infinite chain of hydrogen bonds runs through the crystal
along the “spine” of the herringbone motif, in marked con-
trast to the ladders observed for 2 and 3, in which the hydro-
gen bonds are oriented more or less parallel with the ladder
axis. Furthermore, this interaction is supported by a some-
is—to the best of our knowledge—the largest out-of-plane
angle observed so far for TLMs in the solid state (Table 2).
The quite compact, intermolecular hydrogen-bonding pat-
terns observed for 2 and 5 certainly depend on the confor-
mational properties of the TLMs. Nevertheless, they are
also determined by the substituents attached to the TLM
periphery. For example, if R1 (Scheme 1) in 2 were a tert-
butyl group instead of a hydrogen atom, the overlapping
pattern of the isophthaloyl units would probably be distort-
ed and the structure observed for unsubstituted 2 might not
form. The fact that a tert-butyl substituent disturbs such hy-
drogen-bonding patterns most likely contributes significantly
to the much higher solubility of tert-butyl-substituted TLMs
in unpolar solvents.
ꢀ
what longer and therefore probably weaker N H···O=C
bond between the amide H2 proton and the same O1
oxygen atom. As a consequence of the hydrogen bonds, two
of the four amide groups exhibit an unusually high deviation
(50.38) from coplanarity with the macrocycle plane, which
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Tetralactam Macrocycles
FULL PAPER
1H; NH), 7.67 (s, 1H; NH), 8.18 ppm (dd, 3J(H,H)=7.6 Hz, 4J
ACTHNUTRGENNUG ACHTUNGTRENNUNG(H,F)=
Conclusions
7.6 Hz, 2H; ArH); 13C NMR (62.9 MHz, CDCl3): d=18.1, 19.0, 23.0,
26.5, 37.2, 45.0, 121.5, 123.0, 123.2, 125.3, 127.0, 130.5, 134.7, 134.9, 137.6,
140.1, 149.0, 161.5 ppm; 19F NMR (235 MHz, CDCl3): d=ꢀ117.15 ppm;
FAB-MS: m/z (%): 792.4 (100) [M+H]+.
The detailed analysis of the solid-state structures of 1–5 un-
covered several quite remarkable features of the TLMs
under study. Although the overall macrocycle scaffold is
quite rigid, it can easily adapt to the space requirements of
guests inside the cavity because of the almost-free rotatabili-
ty of the amide groups and the m-xylene rings. The TLM
conformation changes significantly into the closed-doors
structure when no guest is present. Together with the pe-
ripheral substituents, the conformational properties lead to
a variety of interesting intermolecular hydrogen-bonding
patterns. For instance, 5 reveals a notable catemer motif,
TLM 2: A solution of isophthaloyl dichloride (264 mg, 1.3 mmol) in dry
CH2Cl2 (250 mL) and a mixture of 6 (1031 mg, 1.3 mmol) and triethyl-
amine (0.4 mL) in dry CH2Cl2 (250 mL) were simultaneously added drop-
wise to dry CH2Cl2 (1000 mL), while the system was kept under argon at-
mosphere. The addition was completed after 7 h, and the solution was
left overnight with stirring. The solvents were evaporated, the residue
was taken up in chloroform, and the solution was washed with water.
The combined organic phases were dried over Na2SO4 and concentrated
in vacuo. The residue was subjected to column chromatography (silica
gel,
73,75,132,136,203,205,263,265-octamethyl-8,12,21,25-tetraaza-7,13,20,26-
(1,4),10,23
(1,3)-hexabenzenadispiro[5.7.514.76]hexacosaphane-9,11,22,24-
elution
with
CH2Cl2/MeOH
(25:1)),
and
102-fluoro-
whereas 4+ exhibits several C H···O=C interactions, includ-
ꢀ
A
ACHTUNGTRENNUNG
ing a remarkably short one. Our findings do not only pro-
vide support for previous theoretical predictions and STM
experiments but will also be advantageous for crystal engi-
neering. A more profound understanding of the rigidity/flex-
ibility balance in TLMs will also help in the design of tem-
plated syntheses of supramolecular assemblies involving
TLMs.
tetrone (2) was obtained as a colorless solid (613 mg, 0.66 mmol, 51%):
Rf =0.42 (CH2Cl2/MeOH (25:1)); m.p. >3008C; 1H NMR (250 MHz,
CDCl3/CD3OD (5:1)): d=1.27 (br, 4H; CH2), 1.36 (br, 8H; CH2), 1.88 (s,
12H; ArCH3), 1.90 (s, 12H; ArCH3), 2.07 (br, 8H; CH2), 6.68 (s, 4H;
3
3
ArH), 6.72 (s, 4H; ArH), 7.14 (t, J
(H,H)=7.7 Hz, 1H; ArH), 7.71 (dd, 3J
2H; ArH), 7.74 (dd, 3J(H,H)=7.7 Hz, 4J
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
G
E
ACHTUNGTRENNUNG
G
8.08 ppm (s, 1H; ArH); 19F NMR (235 MHz, CDCl3/CD3OD (5:1)): d=
ꢀ111.2 ppm; FAB-MS: m/z (%): 923.5 (100) [M+H]+.
TLM 4+: Methyl iodide (0.25 mL, 4 mmol) was added to a solution of
TLM 3 (38.6 mg, 0.04 mmol)[13] in CH3CN (2 mL) and CHCl3 (0.5 mL).
The mixture was left for 48 h with stirring. A yellowish precipitate was
obtained, which was filtered and dried in vacuo to yield 235-tert-butyl-
73,75,105,132,136,203,205,263,265-nonamethyl-8,12,21,25-tetraaza-105-azonia-
Experimental Section
General methods: Reagents were purchased from Sigma–Aldrich, Merck,
or Fluka and used as received. Solvents such as dichloromethane and
ethyl acetate were dried and distilled by the usual laboratory methods
prior to use. Thin-layer chromatography (TLC) was carried out on TLC
plates precoated with silica gel 60 F254 from Merck. Silica gel (0.04–0.063,
0.63–0.100 mm; Merck) was used for column chromatography. 1H NMR
and 13C NMR spectra were recorded by using Bruker 250 and 500 MHz
instruments. FAB-MS spectra were recorded by using a Concept 1H in-
strument from Kratos Analytical Ltd. with the matrix m-nitrobenzyl alco-
hol. ESI-MS spectra were recorded by using a Bruker APEX IV Fourier-
transform ion-cyclotron-resonance (FT-ICR) mass spectrometer with an
Apollo electrospray ion source equipped with an off-axis 708 spray
needle. Melting points were determined with a Kofler Mikroskop-Heiz-
tisch apparatus (Reichert). The following abbreviations are used: Ar:
aryl; py: pyridyl; TLM: tetralactam macrocycle (with a generic structure
as shown in Scheme 1). For the nomenclature of TLMs, see refer-
ence [21].
7,13,20,26
9,11,22,24-tetrone iodide (4+Iꢀ) as
0.026 mmol, 65%): M.p. >3008C;
[D7]dimethylformamide ([D7]DMF)): d=1.39 (s, 9H; CAHCTUNGTRENNUNG
ACHUTGTNREN(NUG 1,4),10,23ACHTNUGTRENNUNG
a
4H; CH2), 1.62 (br, 8H; CH2), 2.16 (s, 12H; ArCH3), 2.21 (s, 12H;
ArCH3), 2.45–2.50 (br, 8H; CH2), 4.81 (s, 3H; N+CH3), 7.22 (s, 4H;
4
4
ArH), 7.25 (s, 4H; ArH), 8.18 (d, J
ACHTUNGTRENNUNG
G
ACHTUNGTRENNUNG
2H; ArH(py)), 10.03 (br, 1H; ArH(py)), 10.62 ppm (br, 2H; NH);
13C NMR (125 MHz, [D7]DMF): d=18.9, 19.1, 23.5, 26.8, 31.4, 32.4, 34.7,
45.5, 49.3, 119.3, 119.5, 126.3, 126.5, 128.5, 130.4, 132.6, 133.7, 134.1,
135.3, 135.5, 135.6, 144.0, 148.8, 153.0, 160.8, 165.7 ppm; FT-ICR-MS
(ESI+, from MeOH): m/z (%): 976.6 (100) [M]+; HRMS (ESI+): m/z
calcd for C64H74N5O4+: 976.5735 [M]+; found: 976.5701.
X-ray crystallography: Single-crystal X-ray diffraction studies for TLMs
4+ and 5 were carried out on a Nonius Kappa-CCD diffractometer at
100(2) K (4) and 123(2) K (5) with MoKa radiation (l=0.71073 ꢆ).
Direct methods (SHELXS-97 software) were used for structure solution,
and refinement was carried out by using the SHELXL-97 software (full-
matrix least-squares on F2). H atoms were localized by difference elec-
tron-density determination and refined by using a riding model (H(N)
free) with the SHELX-97 software.[9]
TLM 5: Compound 5 was synthesized according to the literature proce-
dure.[1]
2-Fluoroisophthaloyl dichloride: This compound (used for the synthesis
of compound 6) was synthesized in three steps from 2,6-dimethylaniline.
The aniline was first converted into 2-fluoro-m-xylene by a Schiemann
reaction,[22] which was then oxidized with potassium permanganate to
form 2-fluoroisophthalic acid.[23] In the last step, chlorination with sulfo-
nyl chloride furnished 2-fluoroisophthaloyl dichloride.[24]
X-ray crystallographic data for 1 (CCDC-Refcode: PIGDOY):[11] Color-
less crystals; C68H80N4O4·3C4H8O2·2CH2Cl2; M=1451.5; crystal size
¯
0.23ꢅ0.25ꢅ0.55 mm; triclinic; space group P1 (no. 2); a=11.616(4), b=
N,N’-Bis{4-[1-(4-amino-3,5-dimethylphenyl)cyclohexylidene]-2,6-dime-
thylphenyl}-2-fluoroisophthalamide (6): 1,1-Bis(4-amino-3,5-dimethylphe-
nyl)cyclohexane (10 g, 31 mmol)[1,25] and triethylamine (1.4 mL) were dis-
solved in dry CH2Cl2 (50 mL). A solution of 2-fluoroisophthaloyl dichlor-
ide (1.08 g, 4.9 mmol) in dry CH2Cl2 (100 mL) was added dropwise over
4 h, while the system was kept under an argon atmosphere at room tem-
perature. The mixture was left overnight with stirring. The solvents were
then evaporated, and the product was isolated after column chromatogra-
phy (silica gel, elution with CHCl3/EtOAc (4:1)) as a colorless solid
(2.7 g, 3.4 mmol, 69%): Rf =0.1 (CHCl3/EtOAc (4:1)); m.p. 172–1738C;
1H NMR (250 MHz, CDCl3): d=1.40–1.60 (br, 12H; CH2), 2.10–2.30 (br,
8H; CH2), 2.14 (s, 12H; ArCH3), 2.25 (s, 12H; ArCH3), 6.95 (s, 4H;
11.941(2), c=15.920(3) ꢆ; a=71.95(2), b=77.37(2), g=80.44(2)8; V=
2037.2(9) ꢆ3; Z=1; 1 (calcd)=1.183 mgmꢀ3; F
ACHTNUTRGNEG(UN 000)=776; m (CuKa)=
1.77 mmꢀ1; T=200(2) K; 6548 reflections measured (2qmax =1208); 6056
unique reflections (Rint =0.117); 443 parameters; 409 restraint parame-
ters; R1 (I>2s(I))=0.160; wR2=0.426 (all data). Due to the disordered
solvent (C4H8O2 and CH2Cl2) only the conformation, the nature of the in-
clusion, and the hydrogen-bond path between the host and the two in-
cluded C4H8O2 molecules could be determined.
X-ray
crystallographic
data
for
2:[12]
Colorless
crystals,
C60H63FN4O4·3C4H8O2·2CHCl3; M=1426.19; crystal size 0.17ꢅ0.28ꢅ
0.40 mm; triclinic; space group P-1 (no. 2); a=11.325(1), b=12.466(1),
c=13.983(1) ꢆ; a=85.06(1), b=79.29(1), g=72.31(1)8; V=1847.1(3) ꢆ3;
ArH), 7.02 (s, 4H; ArH), 7.40 (t, 3J
ACHTUNGTNER(NUNG H,H)=7.6 Hz, 1H; ArH), 7.62 (s,
Chem. Eur. J. 2009, 15, 5040 – 5046
ꢄ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
5045

C. A. Schalley et al.
Z=1; 1 (calcd)=1.282 mgmꢀ3; F
G
[7] a) W. Reckien, S. Peyerimhoff, J. Phys. Chem. A 2003, 107, 9634–
9640; b) C. A. Schalley, W. Reckien, S. Peyerimhoff, B. Baytekin, F.
Vçgtle, Chem. Eur. J. 2004, 10, 4777–4789.
293(2) K; 5781 reflections measured (2qmax =1208); 5487 unique reflec-
tions (Rint =0.046); 441 parameters, 111 restraint parameters; R1 (I>
2s(I))=0.123; wR2 (all data)=0.408. TLM 2 crystallizes in a centrosym-
metric space group with half a molecule in the asymmetric unit because
the macrocycles are disordered in two directions. The fluorine substituent
is, thus, randomly distributed over two inversion-related positions in the
crystal.
[8] If the macrocycle is divided into two halves by a plane bisecting the
two isophthalamides, we can distinguish one 2-in-2-out conforma-
tion, in which the Aout groups lie in the same half, from another 2-
in-2-out conformation, in which the Aout groups lie in different
halves. The latter is observed in the crystal structures.
[9] G. M. Sheldrick, Acta Crystallogr. Sect. A 2008, 64, 112–122.
[10] I. Kossev, W. Reckien, B. Kirchner, T. Felder, M. Nieger, C. A.
Schalley, F. Vçgtle, M. Sokolowski, Adv. Funct. Mater. 2007, 17,
513–519.
X-ray crystallographic data for 4+: Cuboid yellow crystals;
C64H74N5O4I0.5; M=1040.73; crystal size 0.12ꢅ0.15ꢅ0.19 mm; monoclin-
ic; space group C12/c1 (no. 15); a=27,9903(5), b=17.1774(3), c=
30.9747(6) ꢆ; b=107.148(1)8; V=14230.6(4) ꢆ3; Z=8;
(calcd)=
T=100(2) K;
54127 reflections measured (2qmax =558); 15809 unique reflections (Rint
0.972 mgmꢀ3
;
F
G
m
[11] C. Fischer, M. Nieger, O. Mogck, V. Bçhmer, R. Ungaro, F. Vçgtle,
Eur. J. Org. Chem. 1998, 155–161.
[12] M. Nieger, T. Schmidt, F. Vçgtle, private communication, 2004,
CCDC-245578 (CCDC-Refcode: YAFDOZ). TLM 2 was crystal-
lized by slow evaporation of the solvents CHCl3/EtOAc.
[13] B. Baytekin, S. S. Zhu, B. Brusilowskij, J. Illigen, J. Ranta, J. Huus-
konen, K. Rissanen, L. Kaufmann, C. A. Schalley, Chem. Eur. J.
2008, 14, 10012–10028.
[14] a) P. Ghosh, G. Federwisch, M. Kogej, C. A. Schalley, D. Haase, W.
Saak, A. Lꢁtzen, R. M. Gschwind, Org. Biomol. Chem. 2005, 3,
2691–2700; b) B. A. Blight, J. A. Wisner, M. C. Jennings, Chem.
Commun. 2006, 4593–4595.
[15] H. Adams, F. J. Carver, C. A. Hunter, J. Chem. Soc. Chem.
Commun. 1995, 809–810.
[16] The macrocycle plane is defined by the least-squares fit plane
through the two quaternary cyclohexane carbon atoms and the four
amide a-carbon atoms.
0.075); 670 parameters; 0 restraint parameters; R1 (I>2s(I))=0.0505;
wR2 (all data)=0.1153.
X-ray crystallographic data for 5: Colorless crystals; C60H64N4O4; M=
905.15; crystal size 0.10ꢅ0.20ꢅ0.25 mm; monoclinic; P21/c (no. 14); a=
15.0288(2), b=9.5142(1), c=18.3963(2) ꢆ; b=108.246(1)8; V=
2498.18(5) ꢆ3; Z=2; 1 (calcd)=1.203 mgmꢀ3; F
ACHTNUTRGNE(NUG 000)=968; m (MoKa)=
0.075 mmꢀ1; T=123(2) K; 35555 reflections measured (2qmax =558); 5705
unique reflections (Rint =0.048); 317 parameters; 2 restraint parameters;
R1 (I>2s(I))=0.0383; wR2 (all data)=0.0975.
CCDC-245578 (2), CCDC-687761 (3), CCDC-709648 (4+), and CCDC-
709644 (5) 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.
[17] 44.48 is the angle between the plane of the Aout groups (formed by
the four atoms H13, N13, C14, and O14) and the macrocycle plane
of 2. With regard to all of the crystal structures of TLMs, this is the
largest angle between the plane of an Aout amide group and the mac-
rocycle plane.
[18] Compound 3 crystallizes in a centrosymmetric space group, and in
the crystal structure, the all-in conformer 3A is disordered in terms
of the position of the pyridine group and the tert-butylbenzene
group.
Acknowledgements
This research has been funded by the Deutsche Forschungsgemeinschaft
(grant nos.: SFB 624 and SFB 765) and the Fonds der Chemischen Indus-
trie (FCI). C.A.S. thanks the FCI for a Dozentenstipendium. S.S.Z.
thanks the Studienstiftung des deutschen Volkes for a PhD scholarship.
[19] To the best of our knowledge, no other example for a similarly short
[1] This type of macrocycle was first reported in: C. A. Hunter, J.
Chem. Soc. Chem. Commun. 1991, 749–751.
[2] F. Vçgtle, S. Meier, R. Hoss, Angew. Chem. 1992, 104, 1628–1631;
Angew. Chem. Int. Ed. Engl. 1992, 31, 1619–1622.
ꢀ
ꢀ
aryl-C H···O=C NH hydrogen bond is known. A comparably short
hydrogen bond with a carboxylate oxygen atom as the acceptor has
been reported in: A. Abu-Rayyana, Q. Abu-Salem, N. Kuhn, C.
Maichle-Mossmer, E. Mallah, M. Steimann, Z. Naturforsch. B 2008,
63, 1015–1019. Calculations on comparable hydrogen bonds with
[3] Selected examples: a) S. Y. Chang, H. S. Kim, K. J. Chang, K. S.
Jeong, Org. Lett. 2004, 6, 181–184; b) G. Kleefisch, C. Kreutz, J.
Bargon, G. Silva, C. A. Schalley, Sensors 2004, 4, 136–146.
[4] Selected example: B. A. Blight, K. A. Van Noortwyk, J. A. Wisner,
M. C. Jennings, Angew. Chem. 2005, 117, 1523–1528; Angew. Chem.
Int. Ed. 2005, 44, 1499–1504.
[5] Selected examples: a) F. Vçgtle, M. Hꢂndel, S. Meier, S. Ottens-Hil-
debrandt, F. Ott, T. Schmidt, Liebigs Ann. 1995, 739–743; b) P. Lin-
nartz, S. Bitter, C. A. Schalley, Eur. J. Org. Chem. 2003, 4819–4829;
c) P. Ghosh, G. Federwisch, M. Kogej, C. A. Schalley, D. Haase, W.
Saak, A. Lꢁtzen, R. M. Gschwind, Org. Biomol. Chem. 2005, 3,
2691–2700; d) B. A. Blight, X. Wei, J. A. Wisner, M. C. Jennings,
Inorg. Chem. 2007, 46, 8445–8447.
ꢀ
methyl C H groups as the donors have been reported in: C. E. Can-
nizzaro, K. N. Houk, J. Am. Chem. Soc. 2002, 124, 7163–7169.
[20] For related amide catemers, see: S. S. Kuduva, D. Blꢂser, R. Boese,
G. R. Desiraju, J. Org. Chem. 2001, 66, 1621–1626.
[21] H. A. Favre, D. Hellwinkel, W. H. Powell, H. A. Smith, S. S. C. Tsay,
Pure Appl. Chem. 2002, 74, 809–834.
[22] M. S. Nasir, B. I. Cohen, K. D. Karlin, J. Am. Chem. Soc. 1992, 114,
2482–2494.
[23] J. W. Ladbury, C. F. Cullis, Chem. Rev. 1958, 58, 403–438, and refer-
ences therein.
[24] K. M. Doxsee, M. Feigel, K. D. Stewart, J. W. Canary, C. B. Knobler,
D. J. Cram, J. Am. Chem. Soc. 1987, 109, 3098–3107.
[25] C. A. Hunter, J. Am. Chem. Soc. 1992, 114, 5303–5311.
[6] Selected examples: a) C. A. Hunter, J. Am. Chem. Soc. 1992, 114,
5303–5311; b) Q. Y. Li, E. Vogel, A. H. Parham, M. Nieger, M.
Bolte, R. Frohlich, P. Saarenketo, K. Rissanen, F. Vçgtle, Eur. J.
Org. Chem. 2001, 4041–4049; c) X. Y. Li, J. Illigen, M. Nieger, S.
Michel, C. A. Schalley, Chem. Eur. J. 2003, 9, 1332–1347.
Received: February 6, 2009
Published online: April 16, 2009
5046
www.chemeurj.org
ꢄ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 5040 – 5046