Donor/acceptor-substituted chiral molecular clips - Synthesis and host-guest complex formation

Article abstract of DOI:10.1002/ejoc.201200112

The synthesis, separation, and characterization of some substituted stereoisomeric dimethylene-bridged molecular clips bearing donor or acceptor groups at the tips of the naphthalene sidewalls and two acetoxy, hydroxy, or methoxy groups at the central ben

Full text of DOI:10.1002/ejoc.201200112

Job/Unit: O20112
/KAP1
Date: 10-05-12 09:59:38
Pages: 12
FULL PAPER
DOI: 10.1002/ejoc.201200112
Donor/Acceptor-Substituted Chiral Molecular Clips – Synthesis and
Host–Guest Complex Formation
Frank-Gerrit Klärner,*[a] Süreyya Madenci,[a] Mireia Campañá Kuchenbrandt,[a]
Dieter Bläser,[b] Roland Boese,[b] Gaku Fukuhara,[c] and Yoshihisa Inoue*[c]
Keywords: Donor-acceptor systems / Electrostatic interactions / Host-guest systems / Charge transfer / Pi interactions
The synthesis, separation, and characterization of some sub-
stituted stereoisomeric dimethylene-bridged molecular clips
bearing donor or acceptor groups at the tips of the naphth-
alene sidewalls and two acetoxy, hydroxy, or methoxy groups
at the central benzene spacer unit are reported. The host–
guest complex formation was studied for these substituted
molecular clips as host molecules with 1,2,4,5-tetracyano-
benzene (TCNB), N-methyl-p-(methoxycarbonyl)pyridinium
iodide (Kosower’s salt, KS), and N-methylnicotinamide
iodide (NMNA) as guest molecules. The binding constants,
Ka, and the complexation-induced 1H NMR shifts of the guest
signals, Δδmax, obtained by NMR titration experiments, are
compared with those reported for the parent diacetoxybenz-
ene, hydroquinone, or dimethoxybenzene clips. The diacet-
oxybenzene clip, bearing donor pyrrolidinyl groups at the
tips of both naphthalene sidewalls, forms the most stable
plexation-induced 1H NMR shifts of the guest signals provide
good evidence that in each complex the guest molecule is
clipped between the naphthalene sidewalls of the host mole-
cule by attractive aromatic π–π and CH–π interactions, as
suggested by force-field calculations. This structural assign-
ment of the complexes is further confirmed by a single-crys-
tal structure of the KS complex of the mono-nitro-substituted
clip, which resembles the complex structure of the parent clip
with KS. The good correlation between the clip’s electrostatic
potential surface (EPS; calculated by DFT for the donor- or
acceptor-substituted molecular clips) and the host–guest
complex stability confirms the assumption that in chloroform
solution the host–guest binding (resulting from attractive aro-
matic π–π and CH–π interactions) is largely electrostatic in
nature, whereas the EPS values do not correlate with the
binding constants found in methanol solution, indicating that
complexes with TCNB and KS, overwhelming the corre- additional binding forces (resulting for example from solvo-
sponding complexes of the parent clip and the clips bearing
one nitro or methoxycarbonyl group at the tip of one naph-
thalene sidewall. The clips bearing two acceptor groups (two
nitro or methoxycarbonyl groups) at the tips of both naphth-
alene sidewalls do not form any complex with TCNB, KS, or
NMNA within the limits of NMR detection. The large com-
phobic effects) contribute to the host–guest binding. The sep-
arated optically active diacetoxybenzene clips substituted by
one or two methoxycarbonyl groups at the naphthalene side-
walls are a good starting point for future studies of chiral
molecular recognition and organic catalysis.
organic cations inside the host cavity by using aromatic π–π
and CH–π interactions as dominating noncovalent binding
forces.[3] Electron-rich guest molecules are not bound by
these molecular tweezers and clips. The high selectivity to-
ward electron-poor guest molecules was explained with
markedly negative electrostatic potential surfaces (EPS) cal-
culated for the concave faces of these molecules, which are
complementary to the positive electrostatic potential sur-
faces of the preferentially bound guest molecules.[4] This
finding suggests that the host–guest binding in these com-
plexes is predominantly electrostatic in nature.
In this work, we studied the effect of donor and acceptor
substituents attached to the tips of the naphthalene side-
walls of dimethylene-bridged clips on the host–guest com-
plex formation to gain further information on the noncova-
lent host–guest binding mode. We asked the question: how
and to what extent is the host–guest complex stability corre-
lated with the clip’s EPS modulated by substituents. A com-
putational study by Wheeler and Houk shows convincingly
Introduction
Efficient synthetic host molecules with the capability for
selective binding of guest molecules play a key role in the
design of higher organized chemical systems, which are im-
portant for the understanding of molecular recognition and
self-assembly processes.[1] Recently, we have described the
synthesis and some supramolecular properties of a family
of host molecules termed molecular tweezers and clips that
are well preorganized due to their belt-type concave–convex
topography (Figure 1).[2] They preferentially bind electron-
deficient aromatic and aliphatic guest molecules as well as
[a] Institut für Organische Chemie, Universität Duisburg-Essen,
45117 Essen, Germany
E-mail: frank.klaerner@uni-duisburg-essen.de
[b] Institut für Anorganische Chemie, Universität Duisburg-Essen,
45117 Essen, Germany
[c] Department of Applied Chemistry, Osaka University,
2-1 Yamada-oka, Suita 565-0871, Japan
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200112.
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F.-G. Klärner, Y. Inoue et al.
FULL PAPER
reported the synthesis and separation of chiral molecular
clips of type 4a’ [R1 = OAc, R2 = CO2(–)-menthyl].[8] One
of the separated enantiomers showed a chiral discrimi-
nation toward d- and l-Trp-OMe·H+ by a factor KD/KL =
3.5.
According to quantum-chemical calculations, multiple
substitution of the benzene tweezer by acceptor groups such
as fluorine, oxygen, or nitrile should lead to an “umpolung”
of the EPS so that these compounds are expected to host
anions.[9] In this work we synthesized the quinone clips
meso/rac-14 substituted by nitro groups at the tips of
naphthalene sidewalls. The EPS of meso-14 (Figure 9) is cal-
culated to be relatively positive inside the clip cavity com-
pared to the rest of the clip molecules studied in this work.
However, a 1:1 mixture of meso/rac-14 binds neither elec-
tron-rich guest molecules (such as aminobenzene deriva-
tives or phenolates) nor electron-poor guest molecules
(Scheme 6). Evidently, binding of anions by these types of
host molecules needs a further increase in the positive EPS
by the introduction of additional acceptor groups as sub-
stituents.
Figure 1. Structures of the tetramethylene-bridged tweezers and the
tri- and dimethylene-bridged clips.
that significant changes in the EPS of aromatic systems
arise from inductive through-space effects of substituents;
π-resonance plays no discernible role.[5] Therefore, we se-
lected the nitro and ester group as acceptors and the amino
group as donor, which were already known to increase the
positive or negative EPS of arene derivatives substituted
with these groups.[5,6] In this work we synthesized the mo-
lecular clips 3–10 and 11–13 substituted by a nitro, ester,
or amino function at the tip of naphthalene sidewalls and
compared their supramolecular properties with those of the
parent clips of type 1 (Figure 2).[7]
Results and Discussion
Synthesis of Chiral Molecular Clips Disubstituted at the
Tips of the Naphthalene Sidewalls
The synthesis of substituted naphthalene clips 2a,c–5a,c
was performed by a method analogous to that used for the
parent naphthalene clips 1a,c (R1 = OAc, OMe; R2 = H).[7]
N-Bromosuccinimide (NBS) mediated bromination of the
o-xylene derivatives 14 substituted at C-4 by a bromo, nitro,
or methoxycarbonyl group (R2 = Br, NO2, or CO2CH3) led
to the corresponding tetrabromo-o-xylene derivatives 15 in
yields of 54, 80, and 80%, respectively. The N-benzoylglyc-
ine methyl ester derivative 15 (R2 = CONHCH2CO2CH3)
was prepared by the NBS-mediated bromination of 3,4-di-
methylbenzoyl chloride 14 (R2 = COCl, yield: 70%) fol-
lowed by reaction with 3,4-bis(dibromo)methylbenzoyl
chloride 15 (R2 = COCl) and the HCl adduct of glycine
methyl ester (H3N+–CH2–CO2CH3 Cl–) in the presence of
triethylamine in tetrahydrofuran (THF) at 0 °C (yield:
90%). The meso/rac mixture of the clips 2a, 2c, 3a, 3c, 4a,
4c, or 5c was synthesized in a one-pot reaction starting with
the 1,4-elimination of bromine from the corresponding sub-
stituted tetrabromo-o-xylene derivative 15 by sodium iod-
ide, leading to the dibromo-o-quinodimethane derivatives
16 as transient intermediates, which react as dienes with
the benzonorbornadiene derivatives 17 as bisdienophiles in
Figure 2. Dimethylene-bridged molecular clips bearing electron-do-
nor and/or electron-acceptor substituents at the central benzene
spacer unit and/or naphthalene sidewalls.
The molecular clips studied in this work are chiral. Com- repetitive Diels–Alder reactions leading to the bis-adducts
pounds 2–10 exist in one meso and two enantiomeric con- 18 (Scheme 1). Compounds 18 are not stable under the con-
figurations, and 11–13 in enantiomeric configurations only. ditions of the reaction and spontaneously eliminate four
The optically active stereoisomers of these compounds are equivalents of hydrogen bromide leading to the desired mo-
certainly good candidates for future investigations of chiral lecular clip as mixtures of the corresponding meso- and rac-
molecular recognition and organic catalysis. Recently, we isomers. The yields and product ratios are given in Table 1.
2
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Donor/Acceptor-Substituted Chiral Molecular Clips
meso/rac-3c, meso/rac-4c, and meso/rac-5c by MPLC (me-
dium-pressure liquid chromatography) on silica gel with
ethyl acetate/n-heptane eluent of varying ratios. The MPLC
separation of meso/rac-5c is shown in Figure 3 as a repre-
sentative example.
Scheme 1. General scheme for the synthesis of molecular clips (di-
substituted at the naphthalene sidewalls): Repetitive Diels–Alder
reactions of benzonorbornadiene derivatives 17 as bisdienophile
with o-quinodimethane derivatives 16 as diene produce cycload-
ducts of type 18, which undergo subsequent HBr elimination under
the reaction conditions employed leading to the molecular clips
meso/rac-1 to 5. The o-quinodimethane derivatives 16 are generated
in situ from tetrabromo-o-xylene derivatives 15 by 1,4-Br2 elimi-
nation. The tetrabromo-o-xylenes 15 are prepared by NBS medi-
ated bromination of the corresponding o-xylenes 14 (NBS = N-
bromosuccinimide; DMF = N,N-dimethylformamide).
Figure 3. MPLC separation of meso/rac-5c on silica gel with ethyl
acetate as an eluent.
The mixture of ester-substituted clips meso/rac-4a did
not show any separation under the chromatographic condi-
tions mentioned above. However, this mixture could be sep-
arated into meso-4a and enantiomeric (+)-4a and (–)-4a by
chiral HPLC on a Chiralcel OD column (n-heptane/2-pro-
panol, 75:25; Figure 4, left), as was the case with the re-
lated, previously published, optically active (–)-menthyl es-
ter-substituted clips 4aЈ [R1 = OAc, R2 = CO2(–)-menth-
yl].[8] The separated optically active enantiomers were as-
signed on the basis of their mirror-imaged CD spectra as
(+)-4a and (–)-4a (Figure 4, right).
Table 1. Product ratios and yields of molecular clips 2–5 synthe-
sized by the route shown in Scheme 2.
R1
R2
Product ratio
Yield [%]
OAc
OCH3
OAc
OCH3
OAc
OCH3
OCH3
Br
Br
NO2
NO2
CO2CH3
CO2CH3
meso/rac-2a (3:2)
meso/rac-2c (3:2)
meso/rac-3a (1:1)
meso/rac-3c (1:1)
meso/rac-4a (1:1)
meso/rac-4c (1:1)
60
50
20
58
80
93
76
The syntheses of the derivatives meso/rac-6c, -6b, -8c,
-8b, or -9b starting from the diacetoxybenzene or dimeth-
oxybenzene clips meso/rac-3a, -4a, or -4c are summarized
CONHCH2CO2CH3 meso/rac-5c (1:1)
The product mixtures (Table 1) could be separated by li- in Schemes 2 and 3. Base-mediated hydrolysis either of the
quid chromatography into the corresponding meso and ra- mixture or of the separated meso-3a and rac-3a led to the
cemic isomers, in the case of meso/rac-2a and meso/rac-2c dinitro-substituted hydroquinone clips meso-3b and rac-3b.
by HPLC on a column packed with achiral silica gel The mixture of meso/rac-3b was oxidized with 2,3-dichloro-
[Knauer Eurospher 100 Si, eluted with n-hexane/tert-butyl 5,6-dicyano-1,4-benzoquinone (DDQ) to the corresponding
methyl ether (85:15)] and in the case of meso/rac-3a, quinone clips meso/rac-14 (Scheme 2). The hydroquinone
Figure 4. Left: HPLC chromatograms of mixtures of meso/rac-4a (top) and of the separated stereoisomers (+)-4a, meso-4a, (–)-4a (Chi-
ralcel OD; n-heptane/2-propanol, 75:25). Right: CD spectra of the separated (+)-4a (black) and (–)-4a (light grey) in 2,2,2-trifluoroethanol.
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F.-G. Klärner, Y. Inoue et al.
FULL PAPER
clips meso/rac-6b and meso/rac-8b, bearing carboxylic acid meso/rac-2c with pyrrolidine.[10] Cleavage of the methoxy
or amide functions at the naphthalene sidewalls, were pre- groups of meso/rac-10c with BBr3 produced the correspond-
pared in two and three steps, respectively, starting from the ing hydroquinone clips meso/rac-10b, which were converted
methoxybenzene clips meso/rac-4c (Scheme 3). The meth- by reaction with acetic anhydride into diacetoxy derivatives
oxy group of the dicarboxylic acid meso/rac-6c (obtained meso/rac-10a (Scheme 4).
from meso/rac-4c by saponification) were cleaved with BBr3,
leading to the corresponding hydroquinone clips meso/rac-
6b. Aminolysis of the carboxylic acid groups of meso/rac-6c
and subsequent cleavage of the methoxy groups with BBr3
gave the desired hydroquinone clips meso/rac-8b. The ester
groups of meso/rac-4c were reduced with lithium aluminum
hydride to produce the dimethoxybenzene clips meso/rac-9c
substituted with hydroxymethyl groups at the naphthalene
sidewalls, whereas all ester groups of meso/rac-4a were re-
duced with lithium aluminum hydride leading to the hy-
droxymethyl-substituted hydroquinone clips meso/rac-9b.
Scheme 4. Synthesis of the dipyrrolidinyl-substituted molecular
clips meso/rac-10c,b,a. [Pd2(dba)3] = tris(dibenzylideneacetone)di-
palladium(0), BINAP = rac-2,2Ј-bis(diphenylphosphanyl)-1,1Ј-bi-
naphthyl.
The structures of the new clip molecules were assigned
on the basis of their spectra. As a consequence of the mo-
lecular symmetry, the 1H NMR spectra of the separated
meso and racemic diastereomers of the diacetoxybenzene-
or dimethoxybenzene-substituted clips 3a,c, 4a,c, and 5c are
lene sidewalls, starting from the diacetoxybenzene clips meso/rac- clearly different from each other. The two O(CO)CH3
Scheme 2. Synthesis of the hydroquinone and quinone clips
meso/rac-3b or -14, each bearing nitro-substituents at the naphtha-
3a.
groups or the two OCH3 groups in each meso-configured
clip are not equivalent, giving two separate sets of 1H NMR
signals for the methyl protons, whereas the same protons of
the corresponding racemate or optically active clip only
show a single signal, in agreement with its symmetry. This
assignment was confirmed in the case of the separated clips
meso-4a, (+)-4a, and (–)-4a by their CD spectra (Figure 4)
and, in the case of meso-5c, by X-ray analysis (Figure 5).
The single-crystal structure of meso-5c shows an unusually
short distance of 6.9 Å between the tips of the naphthalene
sidewalls compared to the distance of 11.4 Å found in the
single-crystal structure of clip 1a.[6] The compression of
Scheme 3. Synthesis of the molecular dimethoxybenzene clips
meso/rac-6c, -8c and hydroquinone clips meso/rac-6b, -8b, and -9b,
bearing carboxyl, amide, and hydroxymethyl groups at the naphth-
alene sidewalls, by selective transformation of the methoxy or
acetoxy groups of the central spacer unit as well as the meth-
oxycarbonyl groups at the naphthalene sidewalls in meso/rac-4c and
meso/rac-4a, respectively.
The donor-substituted dimethoxybenzene clips meso/rac-
10c bearing pyrrolidinyl groups at the tips of the naphth-
alene sidewalls were prepared by palladium-catalyzed sub-
stitution of the bromide functions in the molecular clips Figure 5. Single-crystal structure of meso-5c.
4
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Donor/Acceptor-Substituted Chiral Molecular Clips
the sidewalls in meso-5c evidently results from the weak with the tetrabromo-o-xylene derivatives 15 (R2 = CO2CH3
intramolecular CH···O hydrogen bonds between the or NO2) led to the racemate of the desired mono-nitro- or
CONHCH2CO2CH3 substituents (Figure 5).
mono-methoxycarbonyl-substituted clips rac-11a or rac-12a
(Scheme 5). Saponification of rac-11a and rac-12a with so-
dium hydroxide in the presence of phenylhydrazine at room
temperature gave the corresponding hydroquinone clips rac-
11b and rac-12b in almost quantitative yields. In the case of
rac-12a, the acetyl functions were also selectively hy-
drolyzed in the presence of the methoxycarbonyl groups un-
der these conditions.
Synthesis of Chiral Molecular Clips Monosubstituted at the
Tip of One Naphthalene Sidewall
We first attempted to prepare molecular clips of type 11 or
12 (mono-substituted at the tip of one naphthalene sidewall)
by conducting the reaction with equimolar amounts of
The structures of the new molecular clips were assigned
bisdienophile 17a and tetrabromo-o-xylene 15 (R2 = H). on the basis of their spectra. The H NMR spectra of the
This reaction, however, led to a complex mixture of prod- hydroquinone clips rac-11b and rac-12b are concentration-
ucts containing, beside the desired 1:1 adduct 23, the 1:2 dependent, the signals assigned to the protons attached to
adduct (clip 1a) and unreacted 17a, which was difficult to naphthalene sidewalls were shifted toward larger δ values
separate. A rational synthesis of these clips began with the upon dilution (see Figures S2 and S3 in the Supporting In-
preparation of the naphtho-substituted dienophile 23. The formation), indicating that these clips form weak dimers
Diels–Alder reaction of 1,3-cyclopentadiene with the that are comparable to molecular clips with extended aro-
known quinone 21 (accessible from benzonorbornadiene matic sidewalls.[12] The enantiomers of the methoxycarb-
19a in two steps as shown in Scheme 5)[11] gave a 65:35 mix- onyl-substituted clip 12a could again be separated by
ture of syn- and anti-22, which was easily separated by HPLC on a chiral column (Figure 6, left). The separated
MPLC. The reaction of 23 (resulting from base-mediated enantiomers (+)-12a and (–)-12a showed the expected mir-
enolization and acetylation of the keto function in syn-22) ror-imaged CD spectra (Figure 6, right).
1
Scheme 5. Synthesis of racemic molecular clips (monosubstituted at the tip of one naphthalene sidewall). DDQ = 2,3-dichloro-5,6-
dicyano-1,4-benzoquinone, DMAP = 4-(dimethylamino)pyridine.
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F.-G. Klärner, Y. Inoue et al.
FULL PAPER
Figure 6. Left: HPLC chromatogram of the mixture of rac-12a (Chiralcel OD; n-heptane/2-propanol 75:25). Right: CD spectra of the
separated enantiomers (+)-12a (grey) and (–)-12a (black) in 2,2,2-trifluoroethanol.
Host–Guest Complex Formation; Structural and
Thermodynamic Parameters
plex formation was found for the molecular clips 3a, 3b and
4a, 4b (disubstituted with these acceptor groups) within the
limits of H NMR detection. However, molecular clips 10a
and 10c (disubstituted with the donor pyrrolidinyl groups)
formed stable complexes with TCNB and KS.
1
The magnetic anisotropy of the clip arene units makes
1H NMR spectroscopy a sensitive probe for uncovering the
binding of a guest molecule inside the clip cavity. The host–
guest complex formation can be easily detected by pro-
1
nounced upfield shifts of the H NMR signals of the guest
protons (toward smaller δ values) upon addition of the clip
as host molecule. In all binding processes reported here the
host–guest association and dissociation are fast processes
with respect to the NMR timescale. Thus, the maximum
1
complexation-induced H NMR shifts, Δδmax, of the guest
signals and the binding constants, Ka, could be determined
1
by H NMR titration (Δδmax = δ0 – δC; where δ0, δC are the
chemical shifts of the protons of the free and complexed
guest molecule, respectively). In these experiments the de-
pendence of the complexation-induced 1H NMR shifts,
Δδobs, of the guest signals on the host concentration, [H]0,
at a constant guest concentration, [G]0 = fixed, is measured
as described in the Exp. Section (Δδobs = δ0 – δobs, where
Scheme 6. Structures and electrostatic potential surface (EPS), cal-
culated by DFT using structures optimized by AM1 (B3LYP/6-
31G**//AM1)[16] of the guest molecules: 1,2,4,5-tetracyanobenzene
(TCNB), N-methyl-p-(methoxycarbonyl)pyridinium iodide (Ko-
sower’s salt, KS), and N-methylnicotinamide iodide (NMNA). The
color code ranges from –30 (red) to +45 kcal/mol (blue) for TCNB,
and from –30 (red) to +125 kcal/mol (blue) for the pyridinium salts:
KS and NMNA. The listed molecular electrostatic potentials
(MEP in kcal/mol) were calculated at the marked positions.
1
δobs is the chemical H NMR shift of the guest proton ob-
served in the presence of the host molecule and, hence, the
weighted average between δ0 and δC).[13] The complex for-
mation between the parent diacetoxy- or dihydroxy-substi-
The large Δδmax values of the guest protons determined
tuted clip 1a or 1b and TCNB as guest molecule was also for the complexes of the substituted molecular clips (see
detected by the observation of a new absorption band at Tables 2 and 3) are of comparable size to those found for
λmax = 416 nm in the UV/Vis spectra of equimolar mixtures complexes of the parent clips 1a and 1b.[6] These findings
of 1a or 1b and TCNB in CHCl3 solution, which was as- indicate that the substituents attached to the naphthalene
signed to the charge-transfer band of the host–guest com- sidewalls have no significant effect on the complex struc-
plex TCNB·1a and TCNB·1b, respectively.
tures and that, in each complex, the guest molecule is
In this work, we investigated the potential host–guest bound inside the clip cavity as shown by the single-crystal
complex formation of TCNB, KS, and NMNA as guest structures of the complexes of KS as a guest molecule and
molecules (Scheme 6) with the acceptor-substituted molecu- the diacetoxybenzene clip 1a[7] or its nitro-substituted deriv-
lar clips 3a,b, 4a,b, 11a,b, and 12a,b and the donor-substi- ative 3a as host molecules (Figure 7).
tuted clips 10a,c in two solvents, chloroform and methanol.
The experimentally determined complex structures agree
The results are shown in Table 2 and Table 3; the ultimate well with structures predicted by force field calculations
chemical shifts upon complexation (δC) and, hence, the (MMFF 94).[14] In all structures the aromatic ring of the
Δδmax values were determined by the least-squares fits of guest molecule (TCNB, KS, or NMNA) is calculated to be
the NMR titration data (see the Supporting Information). clipped between the naphthalene sidewalls of the host mole-
The molecular clips 11a, 12a and 11b, 12b (monosubsti- cule (Figure 8). In the host–guest complex structures the
tuted with a nitro or methoxycarbonyl acceptor group at protons attached to the benzene ring of TCNB or to the
the tip of one naphthalene sidewall) formed host–guest aromatic ring of KS are no longer equivalent to each other,
complexes with all three guest molecules, whereas no com- pointing either towards the central spacer unit or to the
6
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Donor/Acceptor-Substituted Chiral Molecular Clips
1
Table 2. Binding constants Ka [M–1] and maximum complexation-induced H NMR shifts of the guest signals Δδmax [ppm] (Δδmax = δ0 –
δC, where δ0 and δC are the chemical shifts of free and complexed guest protons, respectively) determined for the host–guest complex
formation of molecular clips as host molecules and TCNB or KS as guest molecules by 1H NMR titration experiments performed in
CDCl3 at 25 °C.
Host
Guest: TCNB
Ka
Guest: KS
Ka
Δδmax
Δδmax
Ha
Ha
Hb
Hc
Hd
He
R1 = OAc
1a: R2 = H
140Ϯ14[a]
36Ϯ5
–
45Ϯ5
–
3.4
2.1
–
3.6
–
137Ϯ14[a]
41Ϯ5
Ͻ 10
60Ϯ10
Ͻ 10
1380Ϯ140
1.8
1.0
–
1.0
–
2.4
2.1
1.6
1.2
–
0.8
–
–0.1
11a: R2 = NO2
3a: R2 = NO2
12a: R2 = CO2CH3
4a: R2 = CO2CH3
10a: R2 = N(C4H8)
1.7
2.2
1.1
1.7
0.7
1.1
–
780Ϯ110
4.1
1.7
0.03
R1 = OH
1b: R2 = H
2180Ϯ200[a]
precipitation
–
270Ϯ30
–
3.6
1080Ϯ110[a]
1045Ϯ10
Ͻ 10
1760Ϯ180
–
2.8
1.2
–
3.5
–
2.4
1.3
–
0.3
–
0.1
–
–0.9
11b: R2 = NO2
3b: R2 = NO2
12b: R2 = CO2CH3
4b: R2 = CO2CH3
–
3.6
–
2.3
0.9
1.0
–
R1 = OMe
1c: R2 = H
Ͻ 7[a]
214Ϯ14
–
3.5
not determined
117Ϯ2
10c: R2 = N(C4H8)
2.1
2.4
1.3
0.9
0.2
[a] Ref.[7]
1
Table 3. Binding constants Ka [M–1] and maximum complexation-induced H NMR shifts of the guest signals Δδmax [ppm] (Δδmax = δ0 –
δC, where δ0 and δC are the chemical shifts of free and complexed guest protons, respectively) determined for the host–guest complex
1
formation of molecular clips as host molecules and NMNA or KS as guest molecules by H NMR titration experiments performed in
CD3OD at 25 °C.
Host
Guest: NMNA
Ka
Guest: KS
Ka
Δδmax
Δδmax
Ha Hb
Hc
Hd
He
Ha
Hb
Hc
Hd
He
R1 = OAc
1a: R2 = H
109Ϯ11[a]
190Ϯ14
–
125Ϯ5
Ͻ 10
2.5 3.3
1.3 1.8
–
1.0 1.3
–
3.5
2.0
2.1
1.2
2.7
1.4
–
–
1.9
–
1.2
–
12a: R2 = CO2CH3
4a: R2 = CO2CH3
11a: R2 = NO2
3a: R2 = NO2
143Ϯ14
–
82Ϯ10
–
2.2
1.4
1.4
0.9
1.0
0.7
–
–
1.6
1.1
1.1
R1 = OH
1b: R2 = H
251Ϯ30
150Ϯ15
–
320Ϯ40
Ͻ 10
1.0 2.6
0.9 2.3
–
1.1 2.3
–
1.6
1.4
1.1
1.0
0.8
–
280Ϯ30
380Ϯ15
–
170Ϯ20
–
2.7
1.5
–
0.8
–
2.5
1.4
0.8
0.5
0.3
0.2
–
–
12b: R2 = CO2CH3
4b: R2 = CO2CH3
11b: R2 = NO2
3b: R2 = NO2
1.9
1.9
0.8
0.9
0.6
0.4
–
[a] Determined in CD3OD/CDCl3 (7:1); B. Rademacher, F.-G. Klärner, unpublished results.
open end of the clip molecule. Thus, separate signals are
The TCNB and KS complexes of the diacetoxybenzene
1
expected for these protons in the H NMR spectra of the clips in chloroform solution show a clear sequence in their
1
complexes. The observation of only one shifted H NMR stability depending on the donor and acceptor substituents
guest signal for each TCNB complex and two guest signals at the naphthalene sidewalls. The molecular clip 10a (substi-
for each KS complex is good evidence for dynamic complex tuted with two pyrrolidinyl donor groups) forms the most
structures, which means that the rotation of the guest mole- stable complexes, whereas no complex formation was de-
cule inside the clip cavity and the mutual host–guest associ- tected for the clips 3a or 4a (each substituted with two nitro
ation and dissociation are fast processes with respect to the or two methoxycarbonyl acceptor groups). The complexes
NMR timescale. Thus, in each complex, the observed NMR of the monosubstituted clips 11a and 12a are less stable
signals of these protons are averaged, which is comparable than those of the parent clip 1a. The following sequences
to the corresponding host–guest complexes of the tetra- of decreasing stability were found: TCNB·10a Ͼ TCNB·1a
methylene-bridged tweezers and trimethylene-bridged clips, Ͼ TCNB·12a ≈ TCNB·11a Ͼ TCNB·4a, TCNB·3a and
for which separate signals for the guest protons were ob- KS·10a Ͼ KS·1a Ͼ KS·12a ≈ KS·11a Ͼ KS·4a, KS·3a
served at very low temperature.[15]
(Table 2). The finding that the TCNB and KS complexes of
Eur. J. Org. Chem. 0000, 0–0
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F.-G. Klärner, Y. Inoue et al.
FULL PAPER
plexes of monosubstituted clips 11b and 12b are also sub-
stantially stabilized by these hydrogen bonds. The KS com-
plex of methoxycarbonyl-substituted clip 12b is even more
stable than that of clip 1b and the complex of the nitro-
substituted clip 11b is as stable as that of clip 1b (Table 2).
However, the hydroquinone clips 3b and 4b (each substi-
tuted with two acceptor groups) did not show any complex
formation with TCNB or KS as guest molecule within the
limits of NMR detection comparable to the diacetoxybenz-
ene clips 3a and 4a. The dimethoxybenzene clip 1c was
already known to be a very weak binder.[6] The methoxy
groups in 1b were calculated by force field computations to
point toward the clip cavity in the lowest energy conforma-
tion so that these groups have to rotate while the guest mo-
lecule enters the clip cavity. This conformational change
costs additional energy. The donor groups in 10c apparently
more than compensate for the disadvantage associated with
the methoxy groups so that the complex formation of 10c
with TCNB and KS is observed. However, the complexes
TCNB·10c and KS·10c are significantly less stable than
TCNB·10a and KS·10a. In methanol solution the depen-
dence of the complex stabilities on the substituents is less
pronounced (Table 3). The molecular clips 3a, 4a and 3b,
4b (each substituted with two acceptor groups) also show
no complex formation with NMNA and KS as guest mole-
cules in methanol. It is remarkable that the complexes of
the hydroquinone clips 1b and 12b are substantially less
stable in methanol than in chloroform. This observation
supports the assumption that the hydrogen bonds contrib-
ute significantly to complex stability in chloroform. These
bonds are less important in the protic solvent methanol.
Figure 7. Single-crystal structures of host–guest complexes of KS
(counterion: I3– instead of I–) with the parent clip 1a [(a) front view,
(b) side view],[7] and of the mono-nitro-substituted clip 11a [(c)
front view, (d) side view].
the hydroquinone clip 1b in chloroform solution are more
stable than the corresponding complexes of 1a, was already
explained with the OH functions in 1b binding the guest
molecules by OH···N hydrogen bonds in addition to the
aromatic π–π and CH–π interactions.[6] Evidently, the com-
Figure 8. Structures of host–guest complexes calculated by force field computations (MMFF 94).
8
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Donor/Acceptor-Substituted Chiral Molecular Clips
Finally, we calculated the electrostatic potential surface
Indeed, the stabilities of the complexes of diacetoxyben-
values (EPS) of the molecular clips to answer the question zene clips 1a, 3a, 4a, 10a, 11a, and 12a with the guest mole-
that was posed in the introduction: whether or not the clip’s cules TCNB and KS in chloroform solution correlate well
EPS modulated by the donor or acceptor substituents is with the MEP values shown in Figure 9 and Figure S1. In
correlated with the host–guest complex stability. Thus, the Figure 10, the logKa values obtained for the complexation
EPS values of the clips (Figure 9) were calculated by DFT of TCNB, KS, and NMNA with 1a, 10a, 11a, and 12a in
using the structures optimized by AM1.[16] The EPS of the CDCl3 and CD3OD are plotted against the sum of the
aromatic rings of the clip molecules (Figure 9) were calcu- products of –MEP(host) and MEP(guest), i.e., –ΣMEP(H)i-
lated to be all negative and, hence, complementary to the MEP(G) (i = 1–2, corresponding to each of the host’s pe-
positive EPS of the guest molecules (Scheme 6). An excep- ripheral aromatic rings), as a measure of the electrostatic
tion is the quinone clip meso-14, which shows a slightly pos- interactions between host and guest. Although the logKa
itive EPS for its aromatic rings (Figure 9). According to the value is not rigorously proportional to the ΣMEP(H)i-
experimentally determined and calculated complex struc- MEP(G) value even in CDCl3, the donor-disubstituted clip
tures, the aromatic ring of each guest molecule is clipped 10a, showing the most negative MEP values, forms the
between the terminal benzene rings of the naphthalene side- most stable host–guest complexes, whereas monosubsti-
walls. Thus, certainly the aromatic host–guest π–π interac- tuted clips 11a and 12a (showing different MEP values at
tions between these rings contribute to the host–guest bind- the unsubstituted and substituted peripheral aromatic ring)
ing in addition to the aromatic CH–π interaction between forms complexes that are less stable than those of unsubsti-
the guest molecule and the central aromatic clip spacer unit. tuted clip 1a. Finally, the acceptor disubstituted clips 3a
Therefore, the molecular electrostatic potentials (MEP) and 4a, which do not form host–guest complexes, show the
were calculated at the marked positions in the center of the least negative MEP values. In methanol there is not such a
peripheral benzene rings (Figure 9) as well as in the center clear correlation between the MEP values of the clips and
of the aromatic spacer unit (see the Supporting Infor- the binding constants Ka, but also in this solvent the ac-
mation, Figure S1). The changes in the MEP values (caused ceptor disubstituted clips 3a,b and 4a,b do not show any
by these substituents) calculated for central benzene rings tendency to bind the guest molecules NMNA and KS. This
(ranging from –21.0 kcal/mol for meso-10a to –4.3 kcal/mol finding suggests that, in protic solvents, forces other than
for meso-3a, Figure S1) are similar to those calculated for electrostatic interactions, for example the solvophobic ef-
the peripheral benzene rings (ranging from –24.3 for meso- fects, are also important for host–guest binding.
10a to –4.5 kcal/mol for meso-3a, Figure 9).
Figure 9. Electrostatic potential surfaces (EPS) of the substituted molecular clips (R1 = OAc: R2 = H, NO2, CO2CH3, or NC4H4; R1 =
OH, R2 = NO2) and the dinitro-substituted quinone clip meso-14 calculated by DFT using the structures optimized by AM1 (B3LYP/6-
31G**//AM1).[16] The color code ranges from –25 kcal/mol (red) to +25 kcal/mol (blue). The listed molecular electrostatic potentials
(MEPs in kcal/mol) were calculated at the marked positions.
Eur. J. Org. Chem. 0000, 0–0
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F.-G. Klärner, Y. Inoue et al.
FULL PAPER
host–guest complex stability confirms the assumption that,
in chloroform solution, the host–guest binding (resulting
from attractive aromatic π–π and CH–π interactions) is
largely electrostatic in nature, whereas in methanol solution
additional binding forces (for example solvophobic effects)
contribute to the host–guest binding. The optically active
molecular clips (+)-4, (–)-4a and (+)-12a, (–)-12a are a good
starting point for future studies of chiral molecular recogni-
tion and organic catalysis.
Experimental Section
Synthesis of the New Molecular Clips: See Supporting Information.
Figure 10. logKa values plotted against –ΣMEP(H)iMEP(G) for
complexation of TCNB (diamond) and KS (circle) with 1a, 10a,
11a, and 12a in CDCl3 and of KS (square) and NMNA (triangle)
with 1a, 11a, and/or 12a in CD3OD.
General Experimental Details: IR spectra were recorded with a Bio-
Rad FTS 135 spectrometer. UV/Vis spectra were recorded with a
J+M Tidas FG Cosytec RS 422 spectrometer. 1H NMR,
13C NMR, DEPT, H,H-COSY, C,H-COSY, NOESY, HMQC,
HMBC, and 1H NMR titration experiments were recorded with
Bruker AMX 300 and DRX 500 spectrometers. Residual undeuter-
ated solvent was used as an internal standard. The 1H and 13C
NMR signals were assigned by the 2D experiments mentioned
above. Positions of the protons of the methano bridges are indi-
cated by the letters i (inside, towards the center of the molecule)
and a (outside, away from the center of the molecule). MS were
recorded with a Fison Instruments VG ProSpec 3000 (70 eV). All
melting points are uncorrected. Column chromatography (liquid
chromatography) was conducted with Florisil (Rotichrom, 60–
100 mesh, Roth) or silica gel (0.063–0.2 mm). Preparative MPLC
were conducted with a SL12S21 250/25 Column, with silica gel
from KronLab. All solvents were distilled prior to use.
Conclusions
Dimethylene-bridged molecular clips bearing donor or
acceptor groups at the naphthalene sidewalls and acetoxy,
hydroxy, and methoxy groups at the central benzene spacer
unit were synthesized as shown in Schemes 1, 2, 3, 4, and
5. The mixtures of the diastereomeric clips meso/rac-2a,c,
-3a,c, -4a,c or -5c [prepared in one-pot reactions starting
from the substituted tetrabromo-o-xylene derivative 15
(R2 = Br, NO2, CO2CH3, or CONHCH2CO2CH3) and the
bisdienophile 17a,c] could be separated by HPLC or
MPLC. The donor-substituted clips meso/rac-10a,b,c were
prepared by palladium-catalyzed substitution of the
bromide groups in meso/rac-2c by pyrrolidine, leading to
meso/rac-10c and subsequent transformation of the meth-
Determination of the Binding Constants, Ka, and the Complexation-
1
Induced H NMR Shift of the Guest Protons, Δδmax, by NMR Ti-
tration Experiments: The binding constants Ka and the complex-
1
ation-induced H NMR shifts of the guest protons Δδmax were de-
oxy groups of 10c into hydroxy groups (10b) and finally termined by NMR titration experiments. In each experiment the
total guest concentration was kept constant and the total host con-
into acetoxy groups (10a). The reaction of the “half-clip”
23 with tetrabromo-o-xylene derivative 15 (R2 = NO2 or
CO2CH3) leads to the racemate of the molecular clips 11a
or 12a (each monosubstituted at one naphthalene sidewall).
In the case of the methoxycarbonyl-substituted clips 4a and
12a, the stereoisomers were separated by HPLC on a chiral
column and the separated enantiomers of each compound
were assigned on the basis of their CD spectra. The host–
guest complex formation was studied by 1H NMR titration
experiments for the substituted molecular clips 3a,b, 4a,b,
10a,c, 11a,b, and 12a,b as host molecules and TCNB, KS,
and NMNA as guest molecules, and the results were com-
pared with those of the parent clips 1a, 1b, and 1c. The
centration was varied, as described.[15]
Crystallographic data (excluding structure factors) for the struc-
tures reported in this paper have been deposited with the Cam-
bridge Crystallographic Data Centre. CCDC-864941 (for meso-5c)
and -864942 (for rac-11b) contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Supporting Information (see footnote on the first page of this arti-
cle): DFT calculations of the electrostatic potential surfaces (EPS)
of molecular clips, the procedures of the synthesis of the new mo-
lecular clips, determination of the binding constants, Ka, and the
complexation-induced 1H NMR shifts of the guest protons, Δδmax
,
1
complexation-induced H NMR shifts of the guest signals
1
by H NMR titration experiments, UV/Vis spectra of clips 1a, 1b,
and 1* (R1 = OAc, OH; R2 = H), TCNB, and the host–guest com-
plexes between TCNB and these clips, and the crystal structure
data of meso-5c and host–guest complex KS·rac-11a.
provide good evidence that in each complex the guest mole-
cule is clipped between the naphthalene sidewalls of the
host molecules by attractive aromatic π–π and CH–π inter-
actions, as is also suggested by force-field calculations (Fig-
ure 8). This structural assignment of the complexes is fur-
ther confirmed by the single-crystal structure of the KS
complex of mono-nitro-substituted clip 11a (Figure 7),
which resembles the complex structure of the parent clip
1a with KS. The good correlation between the clip EPS
Acknowledgments
This work was supported by the Deutsche Forschungsgemeinschaft
(DFG) (to F.-G. K.) and, in part, by the Japan Society for the Pro-
motion of Science (to Y. I. and G. F.) and the Nikko Memorial
modulated by the donor or acceptor substituents and the Foundation (to G. F.). We thank Professor F. Vögtle and Ms. A.
10 Eur. J. Org. Chem. 0000, 0–0
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Donor/Acceptor-Substituted Chiral Molecular Clips
Chem. Eur. J. 2007, 13, 2473–2479; G. Fukuhara, F.-G.
Klärner, T. Mori, T. Wada, Y. Inoue, Photochem. Photobiol.
Sci. 2008, 7, 1493–1500.
Kaufmann (University of Bonn, Germany) for assistance with
HPLC separation of meso-4a, (+)-4a, (–)-4a, and (+)-12a, (–)-12a
and for recording the CD spectra of the optically active stereoiso-
mers. Y. I. thanks the Alexander von Humboldt Stiftung for gener-
ous support for his stay in Germany.
[9] J. M. Hermida-Ramón, C. M. Estévez, Chem. Eur. J. 2007, 13,
4743–4749; J. M. Hermida-Ramón, M. Mandado, M. Sánchez-
Lozano, C. M. Estévez, Phys. Chem. Chem. Phys. 2010, 12,
164–169.
[10] J. Louie, J. F. Hartwig, Tetrahedron Lett. 1995, 36, 3609–3612;
A. S. Guram, R. A. Rennels, S. L. Buchwald, Angew. Chem.
1995, 107, 1456; Angew. Chem. Int. Ed. Engl. 1995, 34, 1348–
1350; J. P. Wolfe, S. L. Buchwald, J. Org. Chem. 2000, 65, 1144–
1157.
[11] G. Jansen, B. Kahlert, F.-G. Klärner, R. Boese, D. Bläser, J.
Am. Chem. Soc. 2010, 132, 8581–8592.
[1] For reviews, see: J. M. Lehn, Supramolecular Chemistry. Con-
cepts and Perspectives, Wiley-VCH, Weinheim, Germany, 1995;
H.-J. Schneider, A. Yatsimirsky, Principles and Methods in Sup-
ramolecular Chemistry, Wiley-VCH, Weinheim, 2000; J. W.
Steed, J. L. Atwood, Supramolecular Chemistry, 2nd ed., Wiley,
Chichester, UK, 2009.
[2] For reviews, see: F.-G. Klärner, B. Kahlert, Acc. Chem. Res.
2003, 36, 919–932; F.-G. Klärner, M. Campanˇa Kuchenbrandt,
Synthesis of molecular tweezers and clips by the use of a molecu-
lar Lego set and their supramolecular functions, in: Strategies
and Tactics in Organic Synthesis (Ed.: M. Harmata), Academic
Press, Elsevier, Amsterdam, 2008, vol. 7, chapter 4, p. 99–153.
[3] For reviews, see: L. M. Salonen, M. Ellermann, F. Diederich,
Angew. Chem. Int. Ed. 2011, 50, 4808–4842.
[12] F.-G. Klärner, B. Kahlert, A. Nellesen, J. Zienau, C. Ochsen-
feld, T. Schrader, J. Am. Chem. Soc. 2006, 128, 4831–4841; B.
Branchi, V. Balzani, P. Ceroni, M. Campaná Kuchenbrandt, F.-
G. Klärner, D. Bläser, R. Boese, J. Org. Chem. 2008, 73, 5839–
5851.
[13] Ka and Δδmax were determined by a nonlinear regression analy-
sis using the program TableCurve 5.01, SYSTAT Software
analogous to the computer programs HOSTTEST, C. S. Wil-
cox, N. M. Glagovich, University of Pittsburg, USA, and Asso-
ciate V. 1.6; B. Peterson, Ph. D. Thesis, University of California
at Los Angeles, USA.
[4]
M. Kamieth, F.-G. Klärner, F. Diederich, Angew. Chem. 1998,
110, 3497; Angew. Chem. Int. Ed. 1998, 37, 3303–3306; F.-G.
Klärner, J. Panitzky, D. Preda, L. T. Scott, J. Mol. Model. 2000,
6, 318–327.
[14] The calculation of the complex structures was performed with
force field MMFF94 implemented in Spartan’04, Wave-
function, Inc., Irvine, CA, USA.
[5] S. E. Wheeler, K. N. Houk, J. Am. Chem. Soc. 2008, 130,
10854–10855; S. E. Wheeler, K. N. Houk, Mol. Phys. 2009, 107,
749–760; S. E. Wheeler, K. N. Houk, J. Chem. Theory Comput.
2009, 5, 2301–2312.
[6] S. Mecozzi, A. P. West Jr., D. A. Dougherty, Proc. Natl. Acad.
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1062–1080.
[7] F.-G. Klärner, J. Panitzky, D. Bläser, R. Boese, Tetrahedron
2001, 57, 3673–3687; F.-G. Klärner, J. Polkowska, J. Panitzky,
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1423.
1
[15] The H NMR spectrum of complex TCNB·1a in CDCl3 does
not show any broadening or splitting of the signal assigned to
the guest protons by cooling the sample from room tempera-
1
ture to –60 °C, in contrast to the H NMR signal assigned to
the TCNB protons in the complexes of the trimethylene-
bridged clip and the diacetoxynaphthalene tweezer (R = OAc,
Figure 1). M. Lobert, H. Bandmann, U. Burkert, U. P. Büchele,
V. Podsadlowski, F.-G. Klärner, Chem. Eur. J. 2006, 12, 1629–
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[16] The calculation of the complex structures was performed with
DFT and AM1 implemented in Spartan’04, Wavefunction,
Inc., Irvine, CA, USA.
[8] G. Fukuhara, S. Madenci, J. Polkowska, F. Bastkowski, F.-G.
Klärner, Y. Origane, M. Kaneda, T. Mori, T. Wada, Y. Inoue,
Received: January 31, 2012
Published Online: ᭿
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Date: 10-05-12 09:59:38
Pages: 12
F.-G. Klärner, Y. Inoue et al.
FULL PAPER
Host–Guest Systems
New donor/acceptor-substituted chiral
molecular clips form host–guest complexes
with 1,2,4,5-tetracyanobenzene (TCNB),
N-methyl-p-(methoxycarbonyl)pyridinium
iodide (Kosower’s salt), and N-methyl-
nicotinamide iodide (NMNA) through
charge-transfer and CH–π interactions.
F.-G. Klärner,* S. Madenci,
M. C. Kuchenbrandt, D. Bläser, R. Boese,
G. Fukuhara, Y. Inoue* ................... 1–12
Donor/Acceptor-Substituted Chiral Mol-
ecular Clips – Synthesis and Host–Guest
Complex Formation
Keywords: Donor-acceptor systems / Elec-
trostatic interactions / Host-guest systems /
Charge transfer / Pi interactions
12
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