Tri- and tetraurea piperazine cyclophanes: Synthesis and complexation studies of preorganized and folded receptor molecules

Article abstract of DOI:10.1002/chem.201001695

A series of symmetrical tri- and tetrameric N-ethyl- and N-phenylurea-functionalized cyclophanes have been prepared in nearly quantitative yields (86-99%) from the corresponding tri- and tetraamino-functionalized piperazine cyclophanes and ethyl or phenyl

Full text of DOI:10.1002/chem.201001695

DOI: 10.1002/chem.201001695
Tri- and Tetraurea Piperazine Cyclophanes: Synthesis and Complexation
Studies of Preorganized and Folded Receptor Molecules
Kari Raatikainen, N. Kodiah Beyeh, and Kari Rissanen*[a]
Abstract: A series of symmetrical tri-
and tetrameric N-ethyl- and N-phenyl-
urea-functionalized cyclophanes have
been prepared in nearly quantitative
yields (86–99%) from the correspond-
ing tri- and tetraamino-functionalized
piperazine cyclophanes and ethyl or
phenyl isocyanates. Their conforma-
tional and complexation properties
have been studied by single-crystal X-
ray diffraction, variable-temperature
NMR spectroscopy, and ESI-MS analy-
sis. The rigid 27-membered trimeric cy-
clophane skeleton assisted by a seam
of intramolecular hydrogen bonds re-
sults in a preorganized ditopic recogni-
tion site with an all-syn conformation
of the urea moieties that, complement-
ed by a lipophilic cavity of the cyclo-
phane, binds molecular and ionic
guests as well as ion pairs. The all-syn
conformation persists in acidic condi-
tions and the triprotonated triurea cy-
clophane binds an unprecedented
ing of the 36-membered cyclophane
skeleton. In the gas phase, the essential
role of the urea moieties in the binding
was demonstrated by the formation of
monomeric 1:1 complexes with K+,
TMA+, and TMP+ as well as the ion-
pair complexes [KI+K]+, [TMABr+
TMA]+ and [TMPBr+TMP]+. In the
positive-mode ESI-MS analysis, ion-
pair binding was found to be more pro-
nounced with the larger tetraurea cy-
clophanes. In the negative mode, owing
to the large size of the binding site, a
general binding preference towards
larger anions, such as the iodide, over
smaller anions, such as the fluoride,
was observed.
À
anion pair, H2PO4 ···HPO42À, in the
solid state. The tetra-N-ethylurea cyclo-
phane is less rigid and demonstrates an
induced-fit recognition of diisopropyl
ether in the solid state. The guest was
encapsulated within the lipophilic inte-
rior of a quasicapsule, formed by intra-
molecular hydrogen-bond-driven fold-
Keywords: cyclophanes
·
host–
guest systems · receptors · supra-
molecular chemistry · urea · X-ray
diffraction
Introduction
receptors, particular interest has for a long time focused on
macrocyclic or macropolycyclic structures,[3,4] and more re-
cently on rigid or semi-rigid macrocyclic receptor molecules
that act as platforms onto which specific functional groups
for noncovalent interactions can be attached.[5]
Host–guest chemistry[1] has for a long time been one of the
most intensively studied fields of supramolecular chemistry[2]
yielding numerous novel host molecules capable of selective
binding of specific molecular or ionic species through a mul-
titude of noncovalent interactions. The design of hosts with
such binding properties utilizes the principles of molecular
recognition, which originate from the realm of biology, in-
cluding factors like steric and interactional complementarity,
the contact area, and the total number of common interac-
tion sites between the host and the guest.[2] Among synthetic
Urea-derivatized calixarenes are a particularly versatile
and well-studied family of macrocyclic receptors that,
through strong hydrogen bonds from the urea moiety,[6]
show excellent halide-ion binding properties.[7] Additional
sensing groups, such as ferrocene, have been attached to the
urea moiety thereby enabling the detection of guests by op-
tical and electrochemical methods.[8] Ditopic recognition by
the calixarene p-donor cavity coupled with hydrogen-bond-
ing urea moieties on the upper rim also provides an appro-
priate binding site for organic anions[9] or neutral hydrogen-
bonding molecules[10] as well as amino acids.[11] This unique
ditopic nature of urea-derivatized calixarenes has also been
applied to ion-pair binding.[12]
[a] M. Sc. K. Raatikainen, Dr. N. K. Beyeh, Prof. K. Rissanen
Department of Chemistry, Nanoscience Center
University of Jyvꢀskylꢀ
Survontie 9, 40014 Jyvꢀskylꢀ (Finland)
Fax : (+35)8142602672
E-mail: kari.t.rissanen@jyu.fi
The role of rigid molecular platforms is to preorganize
the appropriately functional moieties to the desired spatial
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201001695.
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FULL PAPER
orientations for binding. Besides calixarenes[7–12] and resorci-
narenes,[13–15] little attention has been paid to other types of
macrocyclic platforms as cores for urea-functionalized re-
ceptors. One such less-studied family of compounds are pi-
perazine-reinforced cyclophanes.[16] Piperazine, a cyclic bis-
secondary diamine with a 1,4-diazacyclohexane skeleton,
easily undergoes N-alkylation reactions with bis-functional-
ized spacer molecules to yield cyclic oligomers (piperazino-
phanes) under high-dilution conditions.[16,17] By using an ap-
propriate spacer, the rigidity and cavity size can be tuned
and suitable functional groups can be attached for further
derivatization.[18] Recently we reported the synthesis of tri-
and tetraamino piperazine cyclophanes 1 and 2 in which the
aniline subunit was used as the functionalized spacer mole-
cule (Scheme 1).[18] Structurally strained triamino cyclo-
can occur by an induced fit between the host and the
guest.[2] The conformations and solid-state complexation
properties of the title compounds were studied by variable-
temperature NMR spectroscopy and single-crystal X-ray dif-
fraction. The gas-phase host–guest behavior was studied by
electrospray ionization (ESI) mass spectrometry in which
the supramolecular complexes are formed without solvent
or crystal-packing effects.[19]
Results and Discussion
Synthesis: The synthetic route to urea cyclophanes 3 and 4
is depicted in Scheme 2. Parent cyclophanes 1 and 2 have
previously been prepared by the reaction of piperazine and
Scheme 2. Synthetic routes to 3a, 3b, 4a, and 4b.
Scheme 1. The chemical structures and hydrogen-bond-driven conforma-
tions of 1 and 2.
1,3-bis(bromomethyl)-2-nitrobenzene under high-dilution
conditions followed by the reduction of the nitro groups
with stannous(II) chloride in concentrated HCl solution.[18]
The resulting amine-functionalized cyclophanes were dis-
solved in chloroform or dichloromethane and treated with
an excess of ethyl or phenyl isocyanates. The isocyanates re-
acted readily with the amino groups to yield the correspond-
ing tri- and tetraurea cyclophanes 3a, 3b, 4a, and 4b with
yields of 93, 86, 93, and 99%, respectively (see the Experi-
mental Section).
phane 1 has an all-syn conformation of the amino groups in
the solid state. Larger and more flexible tetraamino cyclo-
phane 2 folds into a very compact shell-like Pac-Man con-
formation due to a robust seam of circular intramolecular
hydrogen bonds (Scheme 1) with an ability to form 1:1 in-
clusion complexes with suitably sized guest molecules.[18]
Herein we report a synthetic route to a small family of
tri- and tetraurea piperazine cyclophanes with N-ethylurea
(3a and 4a) and N-phenylurea (3b and 4b) as the functional
groups. The trimeric cyclophane with urea groups in the all-
syn conformation should provide a preorganized C3-symmet-
ric hydrogen-bonding donor site with six quite acidic hydro-
gen atoms for the binding of molecular or anionic guests.
Flipping the urea groups through 1808 would provide a simi-
lar site for cationic guests by binding to the urea carbonyl
oxygen atoms. In the case of urea-functionalized tetrameric
cyclophane, the seam of intramolecular hydrogen bonds
would be lost, leading to greater conformational freedom.
However, the binding process of a particular guest may re-
quire a built-in flexibility of the host whereby complexation
X-ray crystallography: Crystals for X-ray diffraction analysis
were obtained from methanol solutions of 3a, 3b, and 4a
(unfortunately no single crystals were obtained from 4b)
into which vaporized diisopropyl ether was allowed to dif-
fuse at ambient temperature to yield crystal structures of
IIIa (3a·
N
2 ACHTUNGTREN[GUN H2O] [iPr2O]), IIIb (3b·ACHTUNGTERN[NUGN MeOH]3), and
IV (4a·[MeOH] ·HCTUNGTRENNUNG
T
wards anionic guests was further investigated by co-crystalli-
zation with tetramethylphosphonium (TMP) chloride and
bromide, tetramethylammonium (TMA) iodide, or tetrabu-
tylammonium (TBA) dihydrogen phosphate in a molar ratio
of 1:1. The crystallizations were performed in acetone solu-
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K. Rissanen et al.
tion by dropwise addition of methanol to first solubilize 3a
and then addition of the appropriate guest. X-ray-quality
co-crystals were obtained only for the TMP chloride com-
plex IIIa·ACHTUNGTRENNUNG[TMPCl] (3a·CAHTUNGTREN[NGUN TMPCl] · [MeOH]5). For the other
salts, attempts at co-crystallization in the presence of protic
MeOH did not produce X-ray-quality crystals. To probe the
effects of an acidic crystallization environment, 3a was also
crystallized from an ethanol solution carefully acidified
(about 5% v/v) with concentrated phosphoric acid, which
yielded crystals of IIIa·CATHUGNNERT[NNUG H3PO4]2 (3a·AHCUTNRTGENN[GUN H3PO4]2·ACHTNUGERTN[NUGN MeOH]4·
[H2O]4).
IIIa crystallizes in a monoclinic crystal system in space
group C2/c, the asymmetric unit containing one cyclophane,
two methanol, one water, and one diisopropyl ether solvent
molecule (Figure 1). As expected, the all-syn conforma-
tion[18] was retained and thus IIIa has an intramolecular
cavity with a nearly perfect C3-symmetric orientation of the
urea groups. The geometry of the cavity, calculated from the
centroid of the cyclophane (C3, atoms N46, N52, and N55),
gave angles of 126, 120, and 1148 for N46···C3···N52,
N52···C3···N58, and N58···C3···N46, respectively. The corre-
sponding C3···N46, C3···N52, and C3···N58 distances, 4.71,
4.96, and 4.38 ꢂ, reveal a relatively large cavity suitable for
3À
Figure 2. Molecular modeling[20a] of 3a and the PO4 ion reveals strong
hydrogen bonds and a nearly perfect spatial fit into the cavity formed by
the three urea groups.
À
N52 H···O57 and the solvent-
mediated hydrogen-bond pat-
tern (Figure 1b).
Crystalline host–guest com-
plex IIIa·ACTHNUTRGNEU[GN TMPCl], obtained
from a 1:1 mixture of 3a and
TMPCl, crystallizes in a triclinic
¯
unit cell in space group P1. The
all-syn conformation of the host
is nearly identical to that of
IIIa despite the completely dif-
ferent lattice environment. The
chloride anion is complexed in
a “corner” of the urea cavity
and bound by four hydrogen
bonds, one to the ethylurea
group and three to MeOH sol-
À
Figure 1. a) Crystal structure of IIIa with solvent molecules having been omitted for clarity and b) the self-
complementary dimer structure of IIIa stabilized by intermolecular hydrogen bonds.
molecular guests or large tetrahedral anions like phosphate
vent molecules (Figure 3). The remaining urea N H donors
N46 and N52 are also involved in hydrogen bonding with
methanol molecules, which further extends the complex hy-
drogen-bond network (see Table 1). In the cavity of the cy-
clophane, two of the methanol solvents (O74 and O87) are
positioned below and above the ClÀ guest. Owing to the
three-fold molecular symmetry of the host, the other two
methanol solvents (O67 and O78) and the ClÀ guest are
equally disordered (occupancy 1/3) between three equiva-
lent sites, that is, in the corners of the cavity. The TMP
cation is trapped tightly into the intermolecular cavity that
is formed by the phenylurea subunits of three adjacent cy-
clophanes (Figure 3b). In addition to the cation···p interac-
tions, the oxygen atoms of the urea moieties point towards
the positive phosphorus atom with O45···P61, O51···P61, and
O57···P61 distances of 3.45, 3.51, and 3.50 ꢂ, respectively.
3À
or sulfate. Molecular modeling[20] of 3a and the PO4 ion
revealed strong hydrogen bonds and a nearly perfect spatial
fit in the cavity formed by the three urea groups (Figure 2).
À
The lower urea N H moieties (N43, N55, and N49) form in-
tramolecular hydrogen bonds with piperazine nitrogen
atoms leading to a clockwise- or anti-clockwise-oriented
À
(urea)N H···N(piperazine) pattern, which additionally sta-
bilizes the all-syn conformation (Table 1). Despite the iden-
tical cyclophane skeletons, the intramolecular cavity in the
triamino cyclophane 1 is nearly closed due to its twisted
conformation, whereas the ethylurea groups in 3a make the
conformation more open and symmetrical. Crystal packing
reveals that molecules of 3a form self-complementary
dimers in which the ethylurea groups of the adjacent cyclo-
phanes serve as guest moieties. The dimer is stabilized by
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Tri- and Tetraurea Piperazine Cyclophanes
FULL PAPER
Table 1. Specified hydrogen bonds for IIIa, IIIa·ACTHNUTRGNE[NUG TMPCl], IIIb, IIIa·-
ACHTUNGTRENNUNG
IIIa·ACTHUNRGTNE[UNG H3PO4]2 crystallizes in a trigonal unit cell in space
group P31. Every second tertiary amino group, one in each
piperazine moiety, is protonated resulting in a triprotonated
cyclophane skeleton, which clearly reinforces the all-syn
conformation of 3a (Figure 4). The triprotonated state of
the trimeric cyclophane is favored even in the presence of
strong acids like HCl due to the small cyclic structure and
limited conformational freedom.[21] The low-energy chair
conformation[22] of the piperazine is not altered because the
hydrogen atoms in the ammonium ion moieties point out-
wards from the macrocycle and the free electron pairs of the
second piperazine nitrogen atoms are oriented inwards, ap-
propriately acting as hydrogen-bond acceptors from the
urea groups forming the seam of intramolecular hydrogen
bonds (Figure 4a, Table 1). In addition to protonation, the
phosphoric acid solution was used to study the role of the
phosphate anion. As indicated by molecular modeling stud-
ies,[20] the size and shape of the binding cavity should favor
tetrahedral anions and thus lead to phosphate binding. How-
IIIa·
ACHTUNGTRNE[NUNG TMPCl]
Hydrogen bond Length
[ꢂ]
Angle Hydrogen bond Length
Angle
[8]
[8]
[ꢂ]
À
À
N43 H···N8
2.880(3) 137(2) N43 H···N39
2.834(3) 138(2) N49 H···N11
2.838(3) 139(2) N55 H···N25
3.066(5) 133(3) N46 H···O78
2.851(4)
2.893(3)
2.861(4)
2.757(9)
2.906(8)
3.307(5)
3.026(11)
3.200(9)
2.684(14)
2.880(6)
2.900(4)
134(5)
135(5)
131(5)
150(5)
168(6)
169(5)
178
177
173
171
162
À
À
N49 H···N22
À
À
N55 H···N36
À
À
N46 H···O68
À
À
O68 H···O72
2.739(5)
2.712(7)
2.969(4)
2.853(6)
174 N52 H···O76
161 N58 H···Cl73
180 O74 H···Cl73
159 O87 H···Cl73
À
À
O71 H···O68
À
À
O72 H···O61
À
À
N58 H···O71
À
À
N52 H···O57
2.838(3) 174(3) O76 H···O74
À
À
O72 H···O51
2.729(3)
179 O93 H···N22
À
O91 H···N36
IIIb
Hydrogen bond Length Angle Hydrogen bond
[ꢂ] [8]
IIIa·ACTHNGUETRNNU[G H3PO4]2
Length
[ꢂ]
Angle
[8]
À
À
N43 H···N8
2.893(3) 135(2) N8 H···O64
2.590(8) 170
2.668(9) 151
2.649(8) 171
2.871(9) 113
2.833(9) 110
2.867(8) 111
2.933(17) 172
2.893(12) 145
2.881(10) 161
2.679(10) 175
2.583(8) 166
2.630(14) 168
À
À
N53 H···N22
2.826(3) 134(2) N22 H···O63
2.816(3) 135(2) N36 H···O65
3.12(2) 172(2) N43 H···N39
À
À
N63 H···N36
ever, in IIIa·ACTHUNTRGNE[UNG H3PO4]2, the anions are not fully deprotonated
À
À
N66 H···O75
À
2À
À
À
and are present as H2PO4 and HPO4 ions. The dihydro-
O75 H···O81
2.67(2)
2.788(7)
178 N49 H···N11
145 N55 H···N25
161 N46 H···O79A
À
À
O81 H···O79
gen phosphate and hydrogen phosphate ions form a [P=
À
À
O79 H···O55A 3.132(7)
À À
O···H O P] hydrogen-bonded anion pair (Figure 4a), which
À
À
O74 H···O79
2.832(4) 175(3) N52 H···O74
2.956(4) 165(3) N58 H···O68
is partially included in the cavity formed by the urea moiet-
ies. The dihydrogen phosphate acts as an anchor for the
binding. One of its P=O oxygen atoms (O68) is directly hy-
drogen-bonded to one urea group (N58) and through a
methanol and water (O72A and O79A) hydrogen-bonded
chain to a second urea group (N46). The second P=O
oxygen atom (O70) is bound to the third urea group (N52)
through a methanol (O74) molecule. The cyclophanes are
packed into a 2D honeycomb network similar to that of
À
À
N46 H···O74
À
O62 H···O70
O69 H···O65
O72A H···O68
O79A H···O72A 2.819(18) 179
À
À
À
À
O74 H···O70
2.664(10) 163
IV
Length
Hydrogen bond
Angle
[8]
[ꢂ]
À
N7 H···N77
2.835(4)
2.873(3)
2.794(3)
2.823(3)
131(3)
128(3)
137(3)
137(3)
IIIa·ACTHNURGTNE[NUG TMPCl]. Now the hydrogen phosphate, which sits on
the tip of the whole complex, fits exactly into the trigonal
hole in the above layer and is bound to three cyclophanes
À
N67 H···N74
À
N27 H···N34
À
N47 H···N37
À
À
through charge-assisted N8 H···O64, N22 H···O63, and
À
N36 H···O65 hydrogen bonds (Figure 4b). The dihydrogen
phosphate–hydrogen phosphate pair thus acts as an anchor
between the off-set stacked 2D layers.
X-ray analysis of the phenylurea analogue 3b (Figure 5)
shows the monoclinic space group P21/n. The asymmetric
unit contains one cyclophane and three methanol solvent
molecules. In spite of the phenyl moieties, the structure of
the host shows the same all-syn conformation with nearly
identical intramolecular cavity diameters as in 3a. The cent-
roid (C3) calculated from the atoms N46, N56, and N66
gives angles of 128, 116, and 1168 for N46···C3···N56,
N56···C3···N66, and N66···C3···N46 and contact distances of
4.87, 4.87, and 4.25 ꢂ for C3···N46, C3···N52, and C3···N55,
Figure 3. a) The hydrogen-bond interaction pattern in IIIa·ACTHNUTRGNEUG[N TMPCl], with
only one position of the disordered ClÀ anions shown and the MeOH
molecules bound to it. b) Partial view of the entrapment of the TMP
cation between three adjacent cyclophanes.
À
À
respectively. However, the N C (C54 N56) bond of one
urea group is rotated through 1808, which results in a hori-
zontally oriented phenyl moiety that blocks the cavity. The
all-syn conformation is stabilized by intramolecular hydro-
À
The good steric and interactional complementarity of the
cavity for the TMP+ guest is illustrated in Figure 3b. This
trigonal interaction geometry of the cation and the cyclo-
phane extends to a two-dimensional honeycomb network.
gen bonding between the lower N H moiety of the urea
groups and piperazine nitrogen atoms with similar clockwise
À
or anticlockwise orientations of the N H···N contacts to
those in IIIa and IIIa·
[TMPCl] (Table 1). Figure 6 shows the
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K. Rissanen et al.
semblance to the Pac-Man con-
formation of the parent cyclo-
phane 2, yet is less compactly
folded. Owing to its increased
flexibility, the 36-membered cy-
clophane is actually wrapped
around the diisopropyl ether
guest, showing induced-fit bind-
ing with the flexible receptor,
which results in a 1:1 capsule-
type inclusion complex stabi-
À
lized by N7 H···N(piperazi-
À
À
N27
ne)N···H N67
and
À
H···N(piperazine)N···H N47
hydrogen-bond patterns
(Table 1). The N-ethylurea
groups point outwards from the
capsule and the remaining
Figure 4. a) The hydrogen-bond interaction pattern in IIIa·
tween the H2PO4···HPO4 ion pair and 3a. b) View of the 2D layer of cyclophanes showing entrapment of the
[H3PO4]2 that stabilizes the complex formed be-
2À
À
upper rim of N H donors form
hydrogen phosphate.
Figure 6. View of the methanol-mediated dimeric structure in IIIb.
hydrogen-bond chain links through methanol solvent mole-
cules to the adjacent complexes resulting in an extended 3D
network.
Close examination of the X-ray structures of 1, 2, IIIa,
IIIb, IV, and the previously studied acyclic analogues[18,23] re-
vealed that intramolecular hydrogen bonding occurs when
the donor hydrogen atom and the acceptor piperazine nitro-
gen atom are separated by five covalent bonds that form a
Figure 5. View of the crystal structure of IIIb. Solvent molecules have
been omitted for clarity.
À
À
centrosymmetric dimer of two cyclophanes linked by two
cyclohexane-type ring through N···H interactions. In 4a,
only two of the piperazines are available for such hydrogen
bonding. In the case of 2, all four piperazine subunits are
available to form the corresponding hydrogen bonds and
thus a more compact conformation, the Pac-Man motif,
dominates. When the diisopropyl ether guest was omitted
from IV, a void volume[24] of 262 ꢂ3 was obtained, which
gives a rough estimate of the size of the intramolecular
cavity in 4a. The intramolecular cavity in IV is more than
twice as large as the cavity in the Pac-Man conformation of
cyclophane 2[18,21] (110 ꢂ3) and thus it can accommodate
larger guests, such as diisopropyl ether with a molecular vol-
À
À
À
N46 H···O74 H···O79A H···O55A hydrogen-bonded chains
involving two of the three methanol solvent molecules.
Although the all-syn conformation is characteristic of tri-
meric cyclophanes 1, 3a, and 3b, the tetrameric analogues
were expected to adopt the Pac-Man conformation of the
parent cyclophane 2 or modified versions of this conforma-
tion. Unfortunately, only 4a produced single crystals with
structure IV (monoclinic, space group P21/a). The asymmet-
ric unit consists of one cyclophane, one diisopropyl ether,
and six methanol solvent molecules. Figure 7 shows that the
cyclophane is folded into a conformation that has some re-
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Tri- and Tetraurea Piperazine Cyclophanes
FULL PAPER
positive and negative ion
modes. The mass spectra re-
corded in the complexation ex-
periments with the tetrameric
cyclophanes 2, 4a, and 4b and
potassium iodide (KI) are do-
minated by peaks that corre-
spond to the protonated urea
cyclophane and the potassium
adducts (Figure 9). Urea groups
that are correctly spatially situ-
ated are known to bind anions
strongly and this is manifested
in the binding of ion pairs in
the gas phase, as evidenced by
ions such as [4a+KI+K]+
(m/z 1301) and [4b+KI+K]+
Figure 7. View of a) the crystal structure of IV (methanol solvent molecules have been omitted for clarity,
b) empty IV, and c) the capsule-type complex with diisopropyl ether.
ume[20b] of 135 ꢂ3, which thus follows nicely the 55% rule
by Mecozzi and Rebek.[25]
NMR spectroscopy: The 1H NMR spectra of the cyclo-
phanes 3a,b and 4a,b were recorded by using CD3OD as
solvent. The dynamic behavior of 3a was examined further
through variable-temperature NMR spectroscopy experi-
ments. The spectra were recorded in the temperature range
of 333 to 213 K and the effect of temperature on the spectra
is illustrated in Figure 8. At 333 K, the CH3 of the N-ethylur-
ea groups appears as a triplet at d=1.14 ppm and the CH2
protons as a quartet at d=3.19 ppm. The diastereotopic pi-
perazine NCH2 and benzylic ArCH2N protons are averaged
to give broad singlets at d=2.30 and 3.48 ppm, respectively.
The aromatic protons appear as a triplet at d=7.07 ppm and
a doublet at d=7.25 ppm. These sharp signals can be ex-
plained by the fast dynamics of the cyclophanes at higher
temperatures. At 303 K, the signal of the benzylic protons is
split into two resonances whereas the piperazine signal
broadens and splits at lower temperatures. At 213 K, the
signal for the diastereotopic piperazine protons is split into
six signals. The dynamics, that is, the chair–chair intercon-
version and the ring rotation of the piperazines as well as
flipping of the aryl units, at this temperature is clearly re-
stricted and does not show any further changes below
213 K. In conclusion, the change in the dynamics at 213 K is
suggested to arise from the intramolecular hydrogen-bond-
stabilized conformation, which should finally lead to the all-
syn conformation in the crystalline state. The insolubility of
the cyclophanes in nonpolar solvents and most of the polar
aprotic solvents rendered the anion-binding studies impossi-
ble in solution.
Figure 8. 1H NMR spectra of 3a in CD3OD at different temperatures. At
333 K, the compound shows broad signals arising from diastereotopic pi-
perazine protons that further broaden as the temperature reduces and fi-
nally split into six signals at 213 K. The benzyl protons also split into two
separate doublets at 213 K, which indicates a rigid all-syn conformation.
The single broad signal at higher temperatures can be explained by fast
dynamics.
Mass spectrometry: The urea cyclophanes 3 and 4 can easily
be ionized and transferred intact into the mass spectrometer
by using the ESI technique with methanol as the spray sol-
vent. Gas-phase complexation studies of the cyclophanes
with potassium, TMA, and TMP salts were studied in the
(m/z 1493; Figure 9). The isotope patterns obtained in the
experiments agree with those simulated on the basis of natu-
ral abundances. Complexation was not observed with the
amino-functionalized reference cyclophane 2, which signifies
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14559

K. Rissanen et al.
the mass spectra of the urea-
containing cyclophanes show in-
tense signals of [3a+TMP]+
(m/z 913) and [3b+TMP]+
(m/z 1057) corresponding to 1:1
complexes with the TMP cation
(Figure 10). A similar trend was
witnessed when TMA and TMP
salts were mixed with the cyclo-
phane hosts and the mixture in-
jected into the mass spectrome-
ter (see the Supporting Infor-
mation).
Size selectivity was also ob-
served in the complexing ability
of the trimeric and tetrameric
cyclophane receptors towards
organic salts. Owing to their
larger size, the tetrameric cyclo-
phanes are better hosts for ion-
pair binding. Taking the com-
plexation of TMPBr as an ex-
ample, signals corresponding to
the ion-pair binding of the salts
Figure 9. ESI-MS showing the complexation of KI with a) 2, b) 4a, and c) 4b. Insets: Experimental and calcu-
lated isotope patterns.
[4a+TMPBr+TMP]+
1357) and [4b+TMPBr+
(m/z
the enhanced complexing ability of the urea-containing cy-
clophanes. Steric effects were also observed in the general
complexing behavior of the receptors, as seen by the prefer-
ence of ion-pair binding by the tetrameric cyclophanes over
the trimeric cyclophanes. Ion-pair binding with the trimeric
TMP]+ (m/z 1549) were clearly detected in the mass spectra
(Figure 11). A similar trend was observed when comparing
the complexation of all the other organic salts with the cy-
clophane receptors (see the Supporting Information).
cyclophanes
is
generally
weaker, as based on the ob-
served intensities and peaks
corresponding to [3a+HBr+
H]+ (m/z 941) and [3a+
HBr+K]+ (m/z 979). Proton-
ated [3a2 +H]+ (m/z 1646),
[3b2 +H]+ (m/z 1935), and po-
tassium-containing [3a2 +K]+
(m/z 1684) dimers are also de-
tected in the gas phase (see the
Supporting Information).
The
amino-functionalized
reference cyclophanes 1 and 2
did not show any gas-phase
binding of the larger TMA and
TMP salts. Addition of TMA
and TMP salts to the reference
compounds only led to signals
corresponding to the protonat-
ed receptor. The urea groups
are therefore essential for the
binding of organic cations.
Taking the complexation of the
trimeric cyclophanes 1, 3a, and
Figure 10. ESI-MS showing the complexation of TMPBr with a) 1, b) 3a, and c) 3b. Insets: Experimental and
3b with TMPBr as an example, calculated isotope patterns.
14560
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Chem. Eur. J. 2010, 16, 14554 – 14564

Tri- and Tetraurea Piperazine Cyclophanes
FULL PAPER
donating and accepting sites on
urea groups and piperazine
moieties as well as the appro-
priately rigidified structures of
the trimeric cyclophanes (3a
and 3b) leads to hydrogen-
bond-stabilized all-syn confor-
mations in which all urea
groups are oriented on the
same side of the cyclophane.
The resulting cavity with a C3-
symmetric coordination sphere
of strong hydrogen-bonding
donors provides potential bind-
ing sites for molecular or anion-
ic guests, which was demon-
strated by molecular modeling
studies and the co-crystalliza-
tion of trimeric cyclophane and
TMPCl (IIIa·ACTHNUTRGENUG[N TMPCl]). The
less-strained structures of the
tetrameric cyclophanes with
less preorganized orientations
Figure 11. ESI-MS showing the complexation of TMPBr with a) 3a, b) 4a, c) 3b, and d) 4b. Insets: Experimen-
tal and calculated isotope patterns.
Taking the binding of KI by
the tetrameric cyclophanes as
an example in the negative ion
mode, intense peaks corre-
sponding to the binding of the
iodide anion by the urea-con-
taining hosts [4a+I]À (m/z
1223) and [4b+I]À (m/z 1415)
were observed in the mass spec-
tra whereas an intense signal
corresponding to [2+HI+I]À
(m/z 1067) was observed with
reference
compound
2
(Figure 12). A similar trend was
observed with all the other
host/guest mixtures. A general
size preference for halide-anion
binding was observed. The
lowest intensities were observed
with fluorides whereas the high-
est intensities were observed
with iodides (see the Supporting
Information).
Figure 12. Negative ESI-MS showing the complexation of KI with a) 2, b) 4a, and c) 4b. Insets: Experimental
and calculated isotope patterns.
Conclusion
of the urea binding moieties provide a large and lipophilic
intramolecular cavity. In the crystalline state, 4a forms a hy-
The reactions of alkyl or aryl isocyanates and amine-func-
tionalized trimeric triamino and tetrameric tetraamino pi-
perazine cyclophanes offer a straightforward route to the
construction of new urea-functionalized cyclophanes (3a,
3b, 4a, and 4b). Single-crystal structure determinations re-
vealed that a proper spatial proximity of the hydrogen-bond
drogen-bond-stabilized capsule-like inclusion complex with
diisopropyl ether with excellent steric complementarity.
The host–guest properties of the cyclophanes towards po-
tassium, tetramethylammonium, and tetramethylphosphoni-
um salts were also investigated in the gas phase by ESI mass
spectrometric techniques. The larger tetrameric cyclophane
Chem. Eur. J. 2010, 16, 14554 – 14564
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14561

K. Rissanen et al.
À
À
Owing to the low data resolution in IIIa·ACHTNURGTNEUNG[H3PO4]2, the N H and O H hy-
hosts (4a and 4b) are the most suitable for ion-pair binding,
which was mainly observed in the positive ion mode. In the
negative ion mode, a general preference was observed for
the anion binding of larger anions, such as iodide, over
smaller anions, like fluoride.
drogen atoms could not be located from the electron density map and
hence they were calculated with the riding atom model to give the ideal-
ized hydrogen bond positions. The protonated piperazine nitrogen atoms
were deduced from the close proximity of phosphate anions. In the case
À
of IIIa, the water O H hydrogen atoms could not be located from the
electron density map but instead deduced from the idealized hydrogen
bond positions and refined with the riding atom model. Residual electron
density in IIIa and IIIa·ACTHNUTRGNEUG[N TMPCl], due to the unresolved solvent molecule
disorder, was treated by PLATON squeeze.[24] Detailed crystallographic
data for all structures are summarized in Table 2.
Experimental Section
Mass spectrometry: The mass spectrometric studies were performed with
a micromass LCT ESI-TOF instrument equipped with a Z geometry elec-
trospray ion source. Samples were introduced into the source as metha-
nol solution mixtures of the hosts and the salts at flow rates of
30 mLminÀ1. A constant spray and the highest intensities were achieved
with a capillary voltage of 4200–4500 V at a source temperature of 808C
and a dissolvation temperature of 1208C with a sample cone voltage of
5–60 V. Because the instrument does not permit MS/MS experiments, the
fragmentation behavior of the samples was examined by in-source frag-
mentation-induced collisions with the gas molecules present in the ion
source. For this purpose, the ions were accelerated to different kinetic en-
ergies by tuning the sample cone voltage to different settings. At low
voltage, the ions are not significantly accelerated and undergo fragmenta-
tion only to a minor extent upon collision with the surrounding gas mole-
cules. With a high sample cone voltage, the ions approach the sample
cone at a higher velocity and collisions with the surrounding gas lead to
more pronounced fragmentations.
General remarks: All chemicals and solvents were reagent grade, pur-
chased commercially and used as such. Cyclophanes 1 and 2 were synthe-
sized following previously reported procedures.[18] 1H and 13C NMR spec-
tra were recorded with a Bruker Avance DRX 500 FT NMR spectrome-
ter operating at 500 MHz for 1H NMR spectra and at 126 MHz for
13C NMR spectra. All spectra were recorded in CD3OD at 608C unless
otherwise stated (using the center solvent peak at d=3.31 ppm and at
d=49.15 ppm of TMS as internal references for the 1H and 13C NMR
spectra, respectively). Mass spectra were obtained by using a Micromass
(ESI-TOF) spectrometer. Elemental analyses were carried out by using a
VariolEL instrument from Elementar Analysensysteme. Melting points
were measured with a Mettler Toledo FP62 apparatus.
X-ray crystallography:[26] Suitable crystals of IIIa, IIIa·
ACHTUNGTREN[NGNU TMPCl], IIIa·-
ACHTUNGTRENNUNG[H3PO4]2, IIIb, and IV for single-crystal X-ray diffraction analysis were
selected and analyses were performed by using a Bruker Kappa Apex II
diffractometer with graphite-monochromatized MoKa (l=0.71073 ꢂ) ra-
diation for IIIa, IIIa·ACHTUNGTRENNUNG[TMPCl], IIIa·ACHUTTGNREN[NNGU H3PO4]2, and IV and CuKa (l=
Synthesis
1.54184 ꢂ) radiation for IIIb. COLLECT software[27] was used for the
data measurement and DENZO-SMN[28] for the processing. Structures
were solved by direct methods with SIR97[29] and refined by full-matrix
least-squares methods with WinGX software,[30] which utilizes the
General procedure for the preparation of 3a, 3b, 4a, and 4b: Ethyl or
phenyl isocyanate was added to a solution of the cyclophane in chloro-
form or dichloromethane and the resulting mixture was stirred for 24 h at
ambient temperature under nitrogen atmosphere. A bulky white precipi-
tate of the ethylurea-substituted derivative was collected by filtration and
washed with copious amounts of dichloromethane and diethyl ether. The
phenylurea-substituted derivatives were obtained from the reaction mix-
ture as colorless crystals when mixed with acetonitrile and collected by
filtration.
SHELXL-97 module.[31] All C H hydrogen positions were calculated in
À
idealized positions by using a riding atom model after anisotropic refine-
À
ment of all non-hydrogen atoms in the structure. All N H hydrogen
atoms were located from the electron density map and refined with re-
strained bond distances using isotropic displacement parameters of
À
1.2 Ueq of the attached nitrogen atom. Most of the O H hydrogen atoms
were located from the electron density map and refined as a rotating
3a: Cyclophane 1 (64.0 mg, 0.105 mmol), chloroform (0.65 mL), and
ethyl isocyanate (0.037 mL, 0.472 mmol). Yield: 80 mg, 93%; m.p. 2228C;
group by using the same (1.2 Ueq) isotropic displacement parameters.
Table 2. Crystallographic data for IIIa, IIIa·
N
ACHTUNGTRENNUNG
Crystal
IIIa
U
IIIa·
A
IIIb
IV
formula
space group
a [ꢂ]
b [ꢂ]
c [ꢂ]
C
C2/c
51.30H85.20N12O6.70
C54H98ClN12O8P
P1
C49H96N12O19P2
P31
13.9673(5)
13.9673(5)
29.2072(12)
90
90
120
4934.5(3)
3
C60H78N12O6
P21/n
18.6515(3)
12.8679(2)
25.8001(4)
90
107.1990(10)
90
5915.28(16)
4
C71H124N16O11
P21/a
15.9913(4)
15.8319(3)
32.4111(7)
90
101.8160(10)
90
8031.7(3)
4
¯
28.5875(4)
16.1250(2)
28.1471(4)
90
116.4560(10)
90
15.7470(4)
15.9632(4)
16.0730(4)
66.7102(13)
78.8183(13)
61.1826(15)
3251.49(14)
2
a [8]
b [8]
g [8]
V [ꢂ3]
Z
11616.3(3)
8
T [K]
123(2)
1.118
0.075
123(2)
1.134
0.139
123(2)
1.231
0.140
173(2)
1.194
0.632
123(2)
1.139
0.078
1calcd [gcmÀ3
]
m [mmÀ1
qmax [8]
]
25.0
27.5
25.0
63.47
27.5
q comp. [%]
no. reflections
parameters
restraints
0.995
10187
718
0.992
14822
768
24
0.995
9522
690
626
0.988
9568
774
16
0.998
18436
938
58
0
R1 [I>2s(I)]
wR2 [I>2s(I)]
GOF on F2
0.0639
0.1567
1.047
0.435
À0.334
0.0825
0.1965
1.043
0.811
À0.593
0.0967
0.2406
1.024
0.704
À0.415
0.0621
0.1619
1.065
0.452
À0.239
0.0772
0.1558
1.09
0.669
À0.353
DFmax [eꢂÀ3
]
DFmin [eꢂÀ3
]
14562
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Chem. Eur. J. 2010, 16, 14554 – 14564

Tri- and Tetraurea Piperazine Cyclophanes
FULL PAPER
1H NMR (500 MHz, CD3OD): d=1.15 (t, 3J=6.95 Hz, 9H), 2.31 (s,
24H), 3.21 (q, 3J=7.00 Hz, 6H), 3.49 (s, 12H), 7.07 (t, 3J=7.13 Hz, 3H),
7.26 ppm (d, 3J=7.61, 6H); 13C NMR (126 MHz, CD3OD): d=15.85,
36.49, 53.77, 60.61, 126.37, 130.62, 134.20, 138.56, 159.38 ppm; elemental
analysis calcd (%) for C45H66N12O3·CHCl3: N 19.5, C 63.1, H 7.8; found:
N 19.7, C 63.1, H 7.8.
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3b: Cyclophane 1 (50.0 mg, 0.082 mmol), dichloromethane (0.50 mL),
and phenyl isocyanate (0.0401 mL, 0.369 mmol). Yield: 68 mg, 86%; m.p.
2188C; 1H NMR (500 MHz, CD3OD): d=2.16 (s, 24H), 3.37 (d, 3J=
13.25 Hz, 6H), 3.57 (d, 3J=12.96 Hz, 6H), 7.04–7.40 ppm (m, 24H);
13C NMR (126 MHz, CD3OD): d=53.77, 60.85, 123.08, 125.47, 126.35,
130.12, 130.50, 134.01, 138.09, 140.52, 156.91 ppm; elemental analysis
calcd (%) for C57H66N12O3·CH2Cl2: N 17.0, C 69.6, H 6.8; found: N 17.2,
C 69.8, H 6.8.
4a: Cyclophane 2 (60 mg, 0.074 mmol), dichloromethane (0.60 mL), and
ethyl isocyanate (0.035 mL, 0.443 mmol). Yield: 75 mg, 93%; m.p. 2118C;
1H NMR (500 MHz, 308C, CD3OD): d=1.12 (t, 3J=7.20 Hz, 12H), 2.41
(s, 32H), 3.18 (q, 3J=7.20 Hz, 8H), 3.50 (s, 16H), 7.11 (t, 3J=7.55 Hz,
4H), 7.28 ppm (d, 3J=7.60, 8H); 13C NMR (126 MHz, CD3OD): d=
15.93, 36.39, 49.66, 60.53, 126.73, 130.58, 135.41, 138.22, 159.33 ppm; ele-
mental analysis calcd (%) for C60H88N16O4·CH2Cl2: N 19.9, C 64.4, H 7.9;
found: N 19.8, C 64.2, H 8.0.
4b: Cyclophane 2 (50 mg, 0.061 mmol), dichloromethane (0.50 mL), and
phenyl isocyanate (0.0435 mL, 0.369 mmol). Yield: 78 mg, 98%; m.p.
2068C; 1H NMR (500 MHz, 308C, CD3OD): d=2.30 (s, 32H), 3.49 (s,
3
3
16H), 7.00 (t, J=7.35 Hz, 4H), 7.11 (t, J=7.61 Hz, 4H), 7.25–7.7.30 (m,
16H), 7.39 ppm (d, 3J=7.55 Hz, 8H); 13C NMR (126 MHz, CD3OD): d=
53.96, 60.96, 122.04, 124.83, 126.58, 129.68, 130.42, 134.65, 137.65, 140.78,
156.41 ppm; elemental analysis calcd (%) for C76H88N16O4·CH2Cl2: N
16.8, C 69.0, H 6.7; found: N 16.9, C 69.0, H 6.8.
Acknowledgements
Financial support from the Academy of Finland (no. 212588 and 218325)
and the National Graduate School of Organic Chemistry and Chemical
Biology is gratefully acknowledged. We thank Spec. Lab. Technician
Reijo Kauppinen for his help in recording the NMR spectra.
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Received: June 15, 2010
Revised: September 10, 2010
Published online: November 12, 2010
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Chem. Eur. J. 2010, 16, 14554 – 14564