Synthesis and preliminary structural and binding characterization of new enantiopure crown ethers containing an alkyl diarylphosphinate or a proton-ionizable diarylphosphinic acid unit

Article abstract of DOI:10.1002/ejoc.201101769

New enantiopure crown ethers containing either an ethyl diarylphosphinate moiety [(S,S)-4 to (S,S)-7] or a proton-ionizable diarylphosphinic acid unit [(S,S)-8 to (S,S)-11] have been synthesized. Electronic circular dichroism (ECD) studies on the complexa

Full text of DOI:10.1002/ejoc.201101769

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DOI: 10.1002/ejoc.201101769
Synthesis and Preliminary Structural and Binding Characterization of New
Enantiopure Crown Ethers Containing an Alkyl Diarylphosphinate or a
Proton-Ionizable Diarylphosphinic Acid Unit
György Székely,[a] Barbara Csordás,[b] Viktor Farkas,[b] József Kupai,[a] Peter Pogány,[c]
Zsuzsanna Sánta,[d] Zoltán Szakács,[d] Tünde Tóth,[a,e] Miklós Hollósi,[b] József Nyitrai,[a][†]
and Péter Huszthy*[a,e]
Keywords: Molecular recognition / Host–guest systems / Crown compounds / Phosphorus / Circular dichroism / NMR
titration / DFT calculations
New enantiopure crown ethers containing either an ethyl di-
arylphosphinate moiety [(S,S)-4 to (S,S)-7] or a proton-ioniz-
able diarylphosphinic acid unit [(S,S)-8 to (S,S)-11] have
been synthesized. Electronic circular dichroism (ECD) stud-
ies on the complexation of these new enantiopure crown
ethers with the enantiomers of α-(1-naphthyl)ethylammo-
studies showed appreciable enantiomeric recognition with
heterochiral [(S,S)-crown ether plus either (R)-1- or (R)-2-
NEA] preference. Theoretical calculations found three sig-
nificant intermolecular hydrogen bonds in the complexes of
(S,S)-9. Furthermore, preference for heterochiral complexes
was also observed, in good agreement with ECD results.
nium perchlorate (1-NEA) and with α-(2-naphthyl)ethylam- Complex formation constants were determined by NMR ti-
monium perchlorate (2-NEA) were also carried out. These
tration for four selected crown ether/NEA pairs.
the pharmaceutical, food, pesticide, and cosmetics indus-
tries, as well as in environmental analysis.[6]
Introduction
Optically active crown ethers have received a great deal
Since Cram and co-workers synthetized the first optically
of attention in many fields of chemistry because these chiral active crown ethers containing binaphthyl units[7] – which
host molecules can be very effective enantioselective sensors displayed excellent enantiomeric recognition capabilities for
and selectors for the different enantiomers of various guest protonated primary organic amines,[8] leading to effective
molecules.[1–3] These optically active receptors can discrimi- enantioseparation techniques[9–11] – a great number of dif-
nate between the enantiomers of protonated primary or- ferent enantiopure crown ethers have been prepared for
ganic amines,[4,5] which are the basic building blocks of bio- similar purposes. These research activities have been well
molecules. Primary organic amines are also formed during documented.[1–6,12–1]
the degradation of amino acids or serve as neurotransmit-
1
Recently the synthesis and characterization (IR, H, 13C,
ters. The enantiomers of biogenic amines can have different and 31P NMR, as well as MS) of a new family of chiral
pharmacological and toxicological effects, so their enantio- crown ethers containing either an alkyl diarylphosphinate
selective sensing and separation are of great importance in component or a proton-ionizable diarylphosphinic acid unit
have been described (see Figure 1). ECD spectroscopic
[a] Department of Organic Chemistry and Technology, Budapest
University of Technology and Economics,
Szent Gellért tér 4, PO Box 91, 1111 Budapest, Hungary
Fax: +36-1-4633297
E-mail: huszthy@mail.bme.hu
[b] Protein Modelling Group of the Hungarian Academy of
Sciences, Eötvös Loránd University,
Pázmány Péter sétány 1/A, PO Box 32, 1518 Budapest, 112,
Hungary
[c] Department of Inorganic and Analytical Chemistry, Budapest
University of Technology and Economics,
Szent Gellért tér 4, 1111 Budapest, Hungary
[d] Spectroscopic Research Division,
Gedeon Richter Plc., Gyömro˝i út 19–21, PO Box 27,
1475 Budapest 10, Hungary
[e] Research Group for Alkaloid Chemistry of the Hungarian
Figure 1. Reported enantiopure crown ethers containing either an
alkyl diarylphosphinate or a proton-ionizable diarylphosphinic
acid unit.
Academy of Sciences,
Szent Gellért tér 4, PO Box 91, 1521 Budapest, Hungary
[†] Deceased August 25, 2011
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studies on the enantiopure chiral crown compounds (R,R)- ethers (S,S)-4 to (S,S)-11 were probed by ECD spec-
1, (R,R)-2, and (R,R)-3 were also reported.[15]
troscopy with 1-NEA and α-(2-naphthyl)ethylammonium
ECD spectra of the crown ether (R,R)-1, containing the perchlorate (2-NEA) in MeCN solution. No estimates for
methyl phosphinate unit, were measured in solvents of dif- the binding constants emerged from ECD experiments, so
1
ferent polarities: 2,2,4-trimethylpentane (isooctane, iOc), these were determined for selected systems by H NMR ti-
MeCN, MeOH, and 2,2,2-trifluoroethanol (TFE).[15] The tration. Four titrations were performed, allowing investiga-
characteristic feature of the ECD spectra in all four solvents tion of the chiral discrimination of (S,S)-9 with regard to
1
is a negative Bb exciton couplet. ECD spectra of the pro- the enantiomers of 1-NEA and study of the possible roles
ton-ionizable crown ether (R,R)-3 were measured in H2O, of phosphinic acid and ethyl ester groups in complexation
MeOH, MeCN, and TFE [(R,R)-3 is not soluble in iOc]. A
similar negative 1Bb exciton couplet was found only in H2O
and MeOH, whereas in MeCN and TFE a strong asymmet-
ric positive band appears below 230 nm in the far-UV re-
gion.
The unique ECD spectrum of the crown ether (R,R)-3,
containing the phosphinic acid unit, in MeCN[15] prompted
us to consider the possibility of dimerization of the crown
ether through the POOH groups. X-ray crystallographic
studies on the parent achiral crown ether [with hydrogen
atoms instead of methyl groups in the macro ring of (R,R)-
3] confirmed dimer formation by (R,R)-3.[16]
According to ECD measurements, crown ether (R,R)-1,
containing the methyl phosphinate unit, interacts with α-
(1-naphthyl)ethylammonium perchlorate (abbreviated as 1-
NEA) but does not discriminate between its enantiomers.
ECD spectra also clearly show that crown ether (R,R)-3,
containing the phosphinic acid unit, does not bind 1-NEA
at a 1:1 molar ratio and does not discriminate between its
enantiomers.
In an attempt to explore the complexing capabilities and
enantiomer discriminating power of crown ethers contain-
ing either a phosphinate or a phosphinic acid unit, 18-
crown-6 ethers and 21-crown-7 ethers containing methyl or
octyl substituents at positions 6/16 and 7/15, respectively
[(S,S)-4, (S,S)-5, (S,S)-6, (S,S)-7 (Scheme 1; for nomencla-
Figure 2. a) Nomenclature of 18-crown-6 ethers containing a phos-
ture see Figure 2, a) and (S,S)-8, (S,S)-9, (S,S)-10, (S,S)-11
phinate or a phosphinic acid unit, respectively. b) Nomenclature of
21-crown-7 ethers containing a phosphinate or a phosphinic acid
(Scheme 2; for nomenclature see Figure 2, b)] were synthe-
sized. The discriminating capabilities of the new crown unit, respectively.
Scheme 1. Preparation of new macrocycles containing diarylphosphinic acid ethyl ester moieties.
2
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A New Type of Chiral Crown Ether
in titrations of (R)-1-NEA with (S,S)-9 and (S,S)-5. Guest- phosphinic acid moiety, respectively, were characterized by
sided regioselectivity could also be examined from titrations ECD spectroscopy similarly to the previously reported 6,16-
of (S,S)-9 with 1- and 2-NEA.
dimethyl-substituted chiral crown ethers (R,R)-1 and (R,R)-
2.[15] The opposite sign of the spectra of the crown ethers
(S,S)-4 to (S,S)-7 is the consequence of the (S,S) configura-
tion of the chirality centers; the intensities of the bands of
the positive 1Bb couplets are similar. The spectral character-
istics of the dioctyl-substituted crown ethers, regardless of
the different cavity sizes (18-crown-6 or 21-crown-7 ether),
are also similar.
Crown ethers (S,S)-8 to (S,S)-11 were intended for use
for the transport of metal ions and enantiomers of proton-
ated primary arylalkylamines through a water/dichloro-
methane/water bulk liquid membrane system. Effective
transport requires lipophilic side chains such as octyl
groups. The rationale behind the choice of methyl and octyl
side chains was investigation of the effects of their different
lipophilicities on the ECD spectra. The 7,15-dioctyl-substi-
tuted 18-crown-6-type crown ether (S,S)-6 has a spectrum
that is the mirror image of that of (R,R)-2.[15] Compounds
(S,S)-4 (R = Me) and (S,S)-6 (R = Oct) each feature a weak
1Bb couplet with a rather strong positive 1La band (Fig-
ure 3).
The oligoethylene glycol moieties of the 21-crown-7-type
molecules [(S,S)-5 and (S,S)-7] have flexible conformations.
The ECD spectra are determined by the aromatic chromo-
phores and the chiral centers at positions 7 and 18.
The ECD spectrum of 7,18-dimethyl-substituted 18-
crown-6-type crown ether (S,S)-8, containing a phosphinic
acid unit, is similar to the spectrum of (R,R)-3[15] but the
sign of the bands is positive because of the (S,S) configura-
tion of the chiral centers (Figure 4, a,b). The spectrum is
marked by one strong positive band centered between
205 nm and 210 nm, whereas the other crown ethers (S,S)-
9, (S,S)-10, and (S,S)-11 containing the phosphinic acid
unit show three bands below 210 nm and a broad negative
1La band at about 227 nm (Figure 3, c,d). The three short-
wavelength bands are of low intensity. Crown ethers (S,S)-
9, (S,S)-10, and (S,S)-11 might exist in MeCN as mixtures
of dimers (Figure 4, a,b) and monomers showing a negative
band near 200 nm (Figure 4).
If the spectra of the complexes of enantiomers are signifi-
cantly different, enantiomer discrimination is very probable.
If the spectra are the same or similar, enantiomer discrimi-
nation can be ruled out. ECD spectra should be measured
at different host/guest molar ratios. The chiral discriminat-
ing capabilities of crown ethers (S,S)-4 to (S,S)-7, each con-
taining an ethyl phosphinate moiety, and of crown ethers
(S,S)-8 to (S,S)-11, each containing a phosphinic acid unit,
were tested with α-(1-naphthyl)ethylammonium perchlorate
(1-NEA) and α-(2-naphthyl)ethylammonium perchlorate
(2-NEA). The solvent was MeCN and the experiments were
carried out at 1:1 molar ratios of the crown ether and 1- or
2-NEA.
Scheme 2. Preparation of new proton-ionizable crown ethers con-
taining diarylphosphinic acid units.
Results and Discussion
Synthesis
The new enantiopure dialkyl-substituted macrocycles
(S,S)-4 to (S,S)-7 were prepared as shown in Scheme 1.
The corresponding oligoethylene glycol ditosylate deriva-
tives (S,S)-12 to (S,S)-15 (see Scheme 1) were synthesized
from the previously reported enantiopure dimethyl-substi-
tuted oligoethylene glycols (S,S)-16[17] and (S,S)-17[18] and
from the previously reported enantiopure dioctyl-substi-
tuted oligoethylene glycols (S,S)-18[17] and (S,S)-19[17] by
treatment with tosyl chloride in a CH2Cl2/H2O mixture in
the presence of the strong base KOH. This procedure was
based on the previously described synthesis of the dioctyl-
substituted tetraethylene glycol ditosylate (S,S)-14.[19]
The enantiopure ligands (S,S)-4 and (S,S)-5 (see
Scheme 1) were then prepared from the reported ethyl bis(2-
hydroxyphenyl)phosphinate (20)[20] and enantiopure di-
methyl-substituted tetraethylene glycol ditosylate (S,S)-12
or enantiopure dimethyl-substituted pentaethylene glycol
ditosylate (S,S)-13, respectively, at 50 °C in DMF in the
presence of K2CO3 as a base by the procedure[15] described
for the synthesis of the similar macrocycles (R,R)-1 and
(R,R)-2 (see Figure 1). The enantiopure macrocycles (S,S)-
6 and (S,S)-7 (see Scheme 1) were prepared in a similar
manner from 20[20] and dioctyl-substituted tetraethylene
glycol ditosylate (S,S)-14 or enantiopure dioctyl-substituted
pentaethylene glycol ditosylate (S,S)-15.
Enantiopure proton-ionizable ligands (S,S)-8 to (S,S)-11,
each containing a diarylphosphinic acid unit, were prepared
from the corresponding dimethyl- and dioctyl-substituted
macrocycles (S,S)-4 to (S,S)-7, each containing an ethyl
phosphinate moiety, by acidic hydrolysis at elevated tem-
perature in the presence of a dioxane/10% aqueous HCl
(1:1) mixture (see Scheme 2) in a procedure based on that
described[15] for the synthesis of (R,R)-3 (see Figure 1).
Disubstituted 18-crown-6-type ligands (S,S)-4 and (S,S)-
6 form complexes with (R)- and (S)-1-NEA and with (R)-
Electronic Circular Dichroism (ECD) Spectroscopy
The new crown ethers (S,S)-4 to (S,S)-7 and (S,S)-8 to and (S)-2-NEA at 1:1 crown ether/NEA ratios. On the basis
(S,S)-11, containing either an ethyl phosphinate unit or a of band intensities, the spectra of the heterochiral [(S,S)-
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Figure 4. a) ECD spectra of phosphinic acid (S,S)-8 in MeCN
(black), (S,S)-8 plus (R)-1-NEA complex (red), (S,S)-8 plus (S)-1-
NEA complex (green), (R)-1-NEA (dashed red line), (S)-1-NEA
(dashed green line). b) ECD spectra of crown ether (S,S)-8 in
MeCN (black), crown ether (S,S)-8 plus (R)-2-NEA complex (red),
crown ether (S,S)-8 plus (S)-2-NEA complex (green), (R)-2-NEA
(dashed red line), (S)-2-NEA (dashed green line). c) ECD spectra
of phosphinic acid (S,S)-9 in MeCN (black), (S,S)-9 plus (R)-1-
NEA complex (red), (S,S)-9 plus (S)-1-NEA complex (green), (R)-
1-NEA (dashed red line), (S)-1-NEA (dashed green line). d) ECD
spectra of (S,S)-9 in MeCN (black), crown ether (S,S)-9 plus (R)-2-
NEA complex (red), crown ether (S,S)-9 plus (S)-2-NEA complex
(green), (R)-2-NEA (dashed red line), (S)-2-NEA (dashed green
line).
Figure 3. a) ECD spectra of the ethyl phosphinate (S,S)-4 in MeCN
(black), (S,S)-4 plus (R)-1-NEA complex (red), (S,S)-4 plus (S)-1-
NEA complex (green), (R)-1-NEA (dashed red line), (S)-1-NEA
(dashed green line). b) ECD spectra of (S,S)-4 in MeCN (black),
(S,S)-4 plus (R)-2-NEA complex (red), (S,S)-4 plus (S)-2-NEA
complex (green), (R)-2-NEA (dashed red line), (S)-2-NEA (dashed
green line). c) ECD spectra of ethyl phosphinate (S,S)-6 in MeCN
(black), (S,S)-6 plus (R)-1-NEA complex (red), (S,S)-6 plus (S)-1-
NEA complex (green), (R)-1-NEA (dashed red line), (S)-1-NEA
(dashed green line). d) ECD spectra of (S,S)-6 in MeCN (black),
(S,S)-6 plus (R)-2-NEA complex (red), (S,S)-6 plus (S)-2-NEA
complex (green), (R)-2-NEA (dashed red line), (S)-2-NEA (dashed
green line).
4
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crown ether plus either (R)-1- or (R)-2-NEA] complexes dif- MeCN shows a broad positive band. Crown ethers (S,S)-9,
fer more from the spectra of the (S,S)-crown ethers 4 and (S,S)-10, and (S,S)-11 also show strong solvent dependence.
6 than those of the homochiral [(S,S)-crown ether plus
either (S)-1- or (S)-2-NEA] ones. The most intense short-
wavelength bands appear in the spectra of the heterochiral
complexes of 2-NEA (Figure 3).
Computational Results
The goal of the computations was to determine the main
binding characteristics of (S,S)-9 with all four guests (R)-
and (S)-1-NEA and (R)- and (S)-2-NEA. Calculations
showed the 2-NEA complexes to be more stable than those
of 1-NEA; the energy differences between the two R
enantiomers and between the two S enantiomers were both
9–10 kJmol–1. Three important hydrogen bonding interac-
tions were found in the complexes. One hydrogen bond is
formed between one R-NH3+ hydrogen and the phosphanyl
The ECD spectra of the complexes of 7,18-dimethyl and
7,18-dioctyl-substituted 21-crown-7-type ligands (S,S)-5
and (S,S)-7 are similar to those of the complexes of the
smaller ring size 18-crown-6 ligands (S,S)-4 and (S,S)-6 but
the band intensities are smaller. The longer-wavelength
band (near 220 nm) of the 21-crown-7 ethers (S,S)-5 and
(S,S)-7 shows more definite changes upon complex forma-
tion (spectra not shown).
The short-wavelength regions of the ECD spectra of the
heterochiral 2-NEA complexes of (S,S)-4 and (S,S)-6 are
each marked by an asymmetric positive exciton couplet at
about 200 nm (Figure 3).
+
oxygen (P=O); the other two hydrogen atoms of R-NH3
are bound to O11 and O17, respectively (see Figure 6a–d).
The intermolecular hydrogen bonding between the phos-
phanyl hydroxyl group (P–OH) and either O5 or O8 of
(S,S)-9 strains the structure, so these structures are 10–
20 kJmol–1 higher in energy than the ground state geometry
of the given configuration. The hydrogen bonds of the most
stable structures are given in Table 1. The stability order of
the complexes was found to change in the following order:
(S)-1-NEA/(S,S)-9 Ͻ (R)-1-NEA/(S,S)-9 and (S)-2-NEA/
(S,S)-9 Ͻ (R)-2-NEA/(S,S)-9. In the case of 1-NEA slightly
greater discrimination was found than for 2-NEA, although
this difference is negligible, with significant uncertainty
caused by multiple factors both in the complex structure
and the structural differences of the different stereoisomers
of NEA. Note that this relates to isolated molecules without
consideration of the solvent effects.
The spectra of 1-NEA and 2-NEA complexes with crown
ether phosphinic acids feature weak bands. The ECD spec-
tra of the homochiral [(S,S)-crown ether plus (S)-1-NEA]
and heterochiral [(S,S)-crown ether plus (R)-1-NEA] com-
plexes of phosphinic acids (S,S)-8 and (S,S)-9 (R = Me) are
similar below 210 nm but differ significantly above 220 nm
(Figure 4). The spectra of the homochiral 1-NEA com-
plexes of phosphinic acids (S,S)-10 and (S,S)-11 (R = Oct)
are similar to the ECD spectra of the uncomplexed ligands
(spectra not shown). The heterochiral complexes show sig-
nificantly different ECD spectra marked by one positive 1Bb
1
band below 210 nm and a strong La band above 220 nm.
The ECD spectra of the homochiral 2-NEA complexes of
ligands (S,S)-8 to (S,S)-11 are also similar to the spectra of
the uncomplexed crown compounds (Figure 4). In contrast,
the ECD spectra of the heterochiral 2-NEA complexes differ
significantly [see the spectrum of (S,S)-9 and (R)-2-NEA].
We measured ECD spectra of (S,S)-8 in MeCN, MeOH,
and H2O (Figure 5). The spectrum in H2O shows an intense
short-wavelength positive couplet, similarly to the spectra
of 6,16-dimethyl-substituted (R,R)-3.[15] The spectrum in
MeOH also has a low-wavelength couplet but its intensity
is lower than in H2O (Figure 5). The spectrum measured in
Table 1. Calculated hydrogen bonds in the ground state structures
(values given in Å).
Structure
N–H(1)···O=P N–H(2)···O11
N–H(3)···O17
(R)-1-NEA/(S,S)-9
(S)-1-NEA/(S,S)-9
(R)-2-NEA/(S,S)-9
(S)-2-NEA/(S,S)-9
1.58
1.59
1.70
1.76
1.95
1.92
1.96
1.86
1.96
1.89
1.99
1.96
NMR Titrations
1H NMR titration is a powerful tool for characterization
of complex formation[24] between a crown ether (CE) and a
guest (G), yielding the association constant of the presumed
1:1 complex (K = [G·CE][G]–1[CE]–1). Because of the
amounts of materials available, a single NMR sample of the
host was prepared and a 10ϫ concentrated guest solution in
the same solvent was gradually added to this NMR tube to
minimize dilution of the host. 1H NMR spectra were recorded
to observe the effects of complex formation on the chemical
shifts of both constituents. To assign the highly overlapping
host phenyl and guest naphthyl proton signals and the host
aliphatic protons, 2D TOCSY spectra were also run at each
titration point. The observed chemical shift versus total con-
centration ratio cG/cCE datasets of the most responsive host
and guest protons are plotted in Figures 7, 8, 9, and 10.
Figure 5. Far-UV ECD spectra of (S,S)-8 in H2O (blue), MeOH
(red), and MeCN (black).
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Figure 7. Chemical shift changes upon complexation (Δδ) as func-
tions of the guest/host concentration ratio for selected protons of
(S,S)-9 host and (R)-1-NEA guest (abs. values); CIS: chemically
induced shift.
Figure 8. Chemical shift changes upon complexation (Δδ) as func-
tions of the guest/host concentration ratio for selected protons of
(S,S)-9 host and (S)-1-NEA guest (abs. values).
For better visualization and comparison, Δδ values (the
observed chemical shift minus that of the uncomplexed host
or guest, recorded in a separate experiment) are depicted.
These datasets were evaluated by simultaneous nonlinear
curve fitting (see Experimental for details) to yield the bind-
ing constant and the maximum changes of chemical shifts
upon complexation, the so-called limiting chemical shift
displacements (Δδmax; see Figure 11, values given in ppb).
These latter correspond to “plateaus” in Figure 7–Figure 10
that could be reached with a large excess of the guest ensur-
ing 100% complexation (experimentally inaccessible be-
cause of solubility limitations).
Most previous complexation studies on crown ethers
have been performed in CDCl3, because this inert solvent
enhances the intermolecular association (through hydrogen
bonds of the ammonium group in our case). However, the
solubilities of our 1-NEA and 2-NEA ligands required the
Figure 6. Predictions of typical host–guest interactions between the
novel crown ethers and the NEA ligands based on DFT calcula-
tions: a) (S,S)-9 with (R)-1-NEA; b) (S,S)-9 with (S)-1-NEA;
c) (S,S)-9 with (R)-2-NEA; d) (S,S)-9 with (S)-2-NEA.
6
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A New Type of Chiral Crown Ether
Figure 9. Chemical shift changes upon complexation (Δδ) as func-
tions of the guest/host concentration ratio for selected protons of
(S,S)-9 host and (R)-2-NEA guest (abs. values).
Figure 10. Chemical shift changes upon complexation (Δδ) as func-
tions of the guest/host concentration ratio for selected protons of
(S,S)-5 host and (R)-1-NEA guest (abs. values).
Figure 11. Chemical shift changes upon full complexation (Δδmax
)
use of CD3OD (10% v/v) as a cosolvent. This is known to
decrease the binding constants, but their magnitudes re-
mained in the range measureable by NMR titration.[25]
In the case of the crown ether (S,S)-9, three titrations
were performed with the following ligands: (R)-1-NEA, (S)-
in ppb for selected protons of a) (S,S)-9 host and (R)-1-NEA guest;
b) (S,S)-9 host and (S)-1-NEA guest; c) (S,S)-9 host and (R)-2-
NEA guest; d) (S,S)-5 host and (R)-1-NEA guest.
During titration of (R)-2-NEA with (S,S)-9, extremely
1-NEA, and (R)-2-NEA. (R)-1-NEA showed a binding af- closely overlapping aromatic signals were observed for the
finity (K = 167Ϯ8) more than more than double that of its guest at 500 MHz, so chemical shifts could be analyzed
S enantiomer (K = 70Ϯ3). This can be explained in terms only for its aliphatic methine and methyl protons. These
of the generally observed higher stabilities of the heterochi- aliphatic nuclei showed Δδmax values similar to those for
ral complexes [i.e., (R,R)-crown ether/(S)-arylalkylammon- (R)-1-NEA. From the crown ether perspective, though,
ium salt or (S,S)-crown ether/(R)-arylalkylammonium salt] Δδmax for the phenyl proton ortho to the oxygen (H-4, H-
in relation to those of homochiral complexes [i.e., (S,S)- 21) differs considerably and the crown ether methyl signal
crown ether/(S)-arylalkylammonium salt or (R,R)-crown here shows Δδmax = –35 ppb, whereas practically no change
ether/(R)-arylalkylammonium salt].[14,26] The significantly was observed in complexation with (R)-1-NEA. These dif-
different Δδmax values found for both host and guest pro- ferences indicate different orientations of the regioisomeric
tons (see Figure 11, a) might be indicative of differing bind- guests within the host cavity, which is also reflected by the
ing geometries of the two enantiomers.
larger binding constant for (R)-2-NEA (K = 216Ϯ14).
Eur. J. Org. Chem. 0000, 0–0
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P. Huszthy et al.
FULL PAPER
The two sides of the (S,S)-5 host molecule become dia- tions predicting the 2-NEA to be a stronger binder than
stereotopic, leading to the potential inequivalence of all car- 1-NEA. On comparison of the results for the analogous
bon-bound protons and thus to the doubling of most reso- phosphinic acid and phosphinate ester crown ethers, the ob-
nance signals. This is expected because the phosphorus served changes in chemical shifts are much larger in the
atom here is a prochiral center, whereas in the phosphinic ester case, but the binding constants turned out to be nearly
acid analogue (S,S)-9 its =O and –OH substituents are the same.
quasi-equivalent, due either to fast proton exchange even in
an aprotic solvent such as CDCl3 or to the formation of a
hypothesized homodimer.[15] Nevertheless, 2D TOCSY al- Experimental Section
1
lowed its almost complete H NMR assignment and, inter-
estingly, three- to fivefold increases in Δδmax values in rela-
tion to (S,S)-9 were found. However, the affinity towards
General: Infrared spectra were recorded with a Zeiss Specord IR 75
spectrometer. Optical rotations were measured with a Perkin–
Elmer 241 polarimeter that was calibrated by measurement of the
the same guest (R)-1-NEA remained virtually the same (K
= 171Ϯ3). This contrasts with the ECD results, in which
the ester host was a stronger binder than the phosphinic
acid in acetonitrile, but the use of a different, CD3OD-con-
taining solvent mixture in NMR might influence both the
binding preferences and the propensity to homodimer for-
mation.
optical rotations of both enantiomers of menthol. NMR spectra
were recorded at 298 K either with a Bruker DRX 500 Avance spec-
trometer or with an Agilent (Varian) NMRS 500 fitted with a HCN
PFG Triple Resonance 13C-Enhanced Cold Probe, both operating
at 500 MHz for 1H and 125 MHz for 13C, or with a Bruker 300
1
Avance spectrometer (operating at 300 MHz for H, 75.5 MHz for
13C, and 121.5 MHz for 31P). The chemical shifts were referenced
1
to TMS (for H, 13C) or H3PO4 (for 31P).
Mass spectra were recorded with a ZQ 2000 MS instrument
(Waters Corp.) by the ESI method. Elemental analyses were per-
formed in the Microanalytical Laboratory of the Department of
Organic Chemistry, Institute of Chemistry, L. Eötvös University,
Budapest, Hungary. Melting points were measured with a Boetius
micro-melting point apparatus. Starting materials were purchased
from Sigma–Aldrich Corporation unless otherwise noted. Silica gel
(Merck, 60 F254) and aluminium oxide plates (Merck, 60 F254 neu-
tral type E) were used for TLC. Aluminium oxide (neutral, acti-
vated, Brockman I) and silica gel 60 (70–230 mesh, Merck) were
used for column chromatography. Ratios of solvents for the eluents
are given in volumes [mL/mL]. Solvents were dried and purified by
well-established[27] methods. Concentration was carried out under
reduced pressure unless otherwise stated. Electronic circular di-
chroism measurements were performed with a Jasco Dichro-
graph J-810 instrument at room temperature and a 0.02 cm quartz
cell for measurements between 185 and 250 nm and a 0.1 cm cell
between 250 and 330 nm. The spectra were averages of five scans.
The concentration of crown ethers was 0.5 mm.
Conclusions
The synthesis and characterization of a new type of chi-
ral crown ethers containing either an alkyl diarylphosphi-
nate moiety [(S,S)-4 to (S,S)-7] or a diarylphosphinic acid
unit [(S,S)-8 to (S,S)-11] have been achieved.
Because of the presence of the aryl substituents the ECD
1
1
1
spectra are rich in bands in the Bb, La, and Lb regions
(190–250 nm and 260–330 nm, respectively). In MeCN their
heterochiral complexes [(S,S)-crown ether plus (R)-1- or
(R)-2-NEA] show more intense spectra than their homo-
chiral [(S,S)-crown ether plus (S)-1- or (S)-2-NEA] counter-
parts. The band intensities of the 18-crown-6-type com-
plexes are greater than those of the 7,18-dimethyl- and 7,18-
dioctyl-substituted 21-crown-7-type complexes.
The ECD spectra and the chiral discriminating capabili-
ties of the crown ethers (S,S)-8 to (S,S)-11, each containing
a phosphinic acid moiety, differ notably from those of the
crown ethers (S,S)-4 to (S,S)-7, each containing an ethyl
phosphinate moiety. All of the ligands (S,S)-8 to (S,S)-11
have low-intensity ECD spectra in MeCN. They show
strong solvent dependence (Figure 5). This is a clear sign of
the dimer- or aggregate-forming capabilities of the POOH
groups of crown ethers (S,S)-8 to (S,S)-11, as described[15]
earlier for (R,R)-3.
Quantum chemical calculations focusing on geometry optimization
were carried out with use of the Becke3–Lee–Yang–Parr exchange-
correlation functional[21,22] in conjunction with the 6–31G** basis
set. The starting structure of (S,S)-9 was built up by modification
of the available Cartesian coordinates obtained by X-ray diffraction
study of (R,R)-1.[16] All the quantum chemical calculations were
performed with the Gaussian 03 program.[23] The computed geo-
metries were visualized with the aid of the GaussView 3.09 pro-
gram.
Theoretical calculations showed that three important hy-
The NMR titrations were performed with the VNMRS-500 spec-
drogen bonds are formed between (S,S)-9 and the enantio- trometer described above in a CD3Cl/CD3OD (9:1 v/v) solvent mix-
ture (both Ͼ99.8% deuterium, Merck, Germany). In each titration
series, the initial concentration of the 600 μL crown ether solution
was accurately set to around 5 mm; on addition of the guest solu-
tion (50 mm) to this NMR tube with analytical pipettes [100 or
1000 μL, Eppendorf (Hamburg, Germany)] with Ϯ0.1 to 1 μL pre-
cision, the ligand concentration was varied between 0 and 20–
25 mm. The temperature within the RF coil was controlled with an
accuracy of Ϯ0.5 °C and a precision of Ϯ0.1 °C during the ti-
trations. The 1H spectra were recorded by collection of 64–128 k
data points over a spectral width of 16 ppm, with use of a recycling
mers of 1-NEA and 2-NEA. Steric effects play important
roles in the final structures. The heterochiral [(R)-NEA plus
(S,S)-9] complexes proved to be more stable than the homo-
chiral ones.
Complex formation constants were determined for four
selected crown ether/NEA systems by NMR titrations, and
these also affirmed the preference of the formation of
heterochiral complexes over homochiral ones (ca. twofold
difference in K, equals ΔK = 0.38). The experimental results
are in accordance with the results of the theoretical calcula- delay (at+d1) of Ͼ6 s and co-addition of eight transients. Spectrum
8
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Date: 09-05-12 11:23:01
Pages: 13
A New Type of Chiral Crown Ether
processing included no apodization and zero filling to 512 k yielded
a digital resolution of 0.01 Hz. H NMR chemical shifts were cal-
was immersed in an oil bath and the temperature of the reaction
mixture was raised to 50 °C and kept at this temperature with vig-
orous stirring until TLC analysis showed the total consumption of
the starting ditosylate (S,S)-12 (11 d). The solvent was removed at
40 °C and the residue was taken up in a mixture of ice/water
(350 mL) and CH2Cl2 (500 mL). The aqueous phase was extracted
with CH2Cl2 (4 ϫ 200 mL). The combined organic phase was
shaken with H2O (300 mL), dried with MgSO4, and filtered, and
the solvent was removed. The crude product was purified by
chromatography on silica gel with a dioxane/hexane (1:3) mixture
as eluent to give (S,S)-4 (7.22 g, 58%) as a viscous oil. Rf = 0.25
(aluminium oxide TLC, EtOH/toluene 1:40), Rf = 0.30 (silica gel
TLC, dioxane/hexane 1:3). [α]2D6 = –0.95 (c = 2.21, CH2Cl2). 1H
NMR (500 MHz, CDCl3, 25 °C): δ = 0.97 (d, JH,H = 6 Hz, 3 H)
and 0.99 (d, JH,H = 6 Hz, 3 H, CH3 groups attached to the macro
ring), 1.29 (t, JH,H = 7 Hz, 3 H, O-ethyl CH3), 2.91–3.04 (m, 3 H,
OCH2), 3.04–3.12 (m, 1 H, OCH2), 3.24–3.40 (m, 5 H, OCH2),
3.43–3.50 (m, 1 H, OCH2), 3.67–3.70 (m, 1 H, OCH2), 3.75–3.77
(m, 1 H, OCH2), 3.86–3.96 (m, 1 H, OCH), 4.04–4.10 (q, 2 H, ethyl
OCH2), 4.12–4.19 (m, 1 H, OCH), 6.94–6.98 [m, 2 H, ArC(4)H,
ArC(18)H], 6.99–7.06 [m, 2 H, ArC(2)H, ArC(20)H], 7.39–7.46 [m,
2 H, ArC(3)H, ArC(19)H], 7.87–7.91 [m, 1 H, ArC(1)H, ArC(21)-
H], 8.02–8.06 [m, 1 H, ArC(1)H, ArC(21)H] ppm. 13C NMR
(75.5 MHz, CDCl3, 25 °C): δ = 16.70 (d, J = 6.8 Hz, O-ethyl CH3),
17.30, 17.87 (CH3 groups attached to the macro ring), 60.55 (d, J
= 5.7 Hz, O-ethyl CH2), 69.70, 70.00, 71.13, 71.37, 72.74, 72.78
(OCH2 groups), 75.59, 75.68 (OCH groups), 112.53 (d, J = 7.5 Hz,
ArC4, ArC18), 112.80 (d, J = 8.1 Hz, ArC4, ArC18), 120.28 (d, J =
12.2 Hz, ArC2, ArC20), 120.34 (d, J = 13.0 Hz, ArC2, ArC20),
120.68 (d, J = 136.5 Hz, ArC21a, ArC22a), 121.59 (d, J = 147.7 Hz,
ArC21a, ArC22a), 133.17 (d, J = 1.4 Hz, ArC3, ArC19), 133.48 (d, J
≈ 5.6 Hz, ArC1, ArC21), 133.53 (d, J ≈ 2.0 Hz, ArC3, ArC19), 135.46
1
ibrated to the signal of internal TMS (δ =0.00 ppm). Standard 2D
TOCSY and if necessary also 2D HSQC and HMBC spectra were
also recorded with VnmrJ 3.1 software and use of Chempack to
confirm signal assignments.
Evaluation of the recorded 1H NMR chemical shift titration curves
is based on the following principles.[25] With the assumption of a
simple 1:1 stoichiometry, the complex formation is characterized
by the binding (association) constant K = [G·CE][G]–1[CE]–1. If the
kinetics of complexation are rapid on the chemical shift timescale,
the observed chemical shift (δCE,i) of the ithcarbon-bound proton
of the crown ether varies gradually between its limiting values for
the free host (δiCE) and the complex (δGi ·CE).
where x denotes molar fraction. The measured chemical shift
change upon addition of a certain amount of the ligand is called
the chemical shift displacement (ΔδCE,i = ΔδCE,i – δCi E), whereas its
limiting value for an infinite excess of the ligand is the limiting
chemical shift displacement (ΔδϱCE,i[28] = δGi ·CE – δCi E); δCE,i is deter-
mined at the starting point of titration (no guest added).
Similar relationships and definitions hold for the observed chemi-
cal shift of the jth guest proton:
The chemical shift change of the jthguest proton upon full complex-
ation is ΔδϱG,j = δGj ·CE – δjG
(d, J = 7.4 Hz, ArC1, ArC21), 160.55 (d, J = 3.5 Hz, ArC4a
ArC17a), 161.02 (d, J = 5.0 Hz, ArC4a, ArC17a) ppm. 31P NMR
,
1
δG,i is determined from the H spectra of the guest stock solution
(121.5 MHz, CDCl , 25 °C): δ = 26.72 ppm. IR (KBr): νmax = 3440,
˜
3
in a separate experiment.
3093, 3062, 2977, 2931, 2872, 1591, 1576, 1474, 1444, 1375, 1281,
1232, 1222, 1210, 1164, 1142, 1133, 1102, 1089, 1021, 945, 807,
777, 758, 567 cm–1. MS: m/z = 464.50 [M + 1]+. C24H33O7P
(464.49): calcd. C 62.06, H 7.16, P 6.67; found C 61.80, H 7.17, P
6.52.
The equilibrium concentrations [G] and [CE] are calculated for
each titration point from the total (analytical) concentrations cG
and cCE by solving the mass balance equation,
CG = [G] + [G·CE] = [G](1+ K)[CE] (3)
CCE = [CE] + [G·CE] = [CE](1+ K)[G] (4)
25-Ethoxy-7,18-dimethyl-6,7,9,10,12,13,15,16,18,19-decahydro-
25H-dibenzo[q,t][1,4,7,10,13,16,19]hexaoxa-λ5-phosphacyclohenicos-
in-25-one [(S,S)-5]: See Scheme 1. Optically active ligand (S,S)-5
was prepared in the same way as described above for its analogue
(S,S)-4 by starting from ethyl bis(2-hydroxyphenyl)phosphinate
(20, 5.32 g, 19.1 mmol), dimethyl-substituted pentaethylene glycol
ditosylate (S,S)-13 (11.0 g, 19.1 mmol), finely powdered anhydrous
K2CO3 (26.0 g, 188 mmol), and pure DMF (300 mL). White vis-
cous oil; yield 6.14 g (63%). Rf = 0.30 (aluminium oxide TLC,
EtOH/toluene 1:40), Rf = 0.18 (silica gel TLC, dioxane/hexane 1:3).
[α]2D5 = –6.15 (c = 1.56, CHCl3). 1H NMR (500 MHz, CDCl3,
25 °C): δ = 1.01 (d, JH,H = 6 Hz, 3 H, 7-Me), 1.06 (d, JH,H = 6 Hz,
3 H, 18-Me), 1.30 (t, JH,H = 7 Hz, 3 H, O-ethyl CH3), 3.02–3.22
(m, 4 H, OCH2, 2ϫOCH), 3.25–3.33 (m, 3 H, OCH2), 3.37–3.44
(m, 2 H, OCH2), 3.46–3.51 (m, 5 H, OCH2), 3.64–3.67 (m, 1 H,
Input data for the multivariate data evaluation were the total con-
centrations cCE and cG (their ratio was checked from the integrals
of the non-overlapping methyl doublets of CE and G), chemical
shifts of the free components (δG,i and δCE,i in Hz) and the observed
chemical shift values in Hz for the host and guest protons most
influenced by complexation (these are plotted in Figure 7–Fig-
ure 10). The OPIUM program[29] was used to perform least-squares
fitting of Eqs. (1) and (2) to these datasets to determine the com-
mon parameter K as well as the complex-specific chemical shift
δGi ·CE (or δGj ·CE) for each nucleus involved in the calculation. The
obtained binding constant was fixed and multiple linear regression
was carried out with the same program to determine δGi ·CE for the
less responsive nuclei.
22-Ethoxy-7,15-dimethyl-6,7,9,10,12,13,15,16-octahydro-22H-di- Hx-19), 3.73–3.77 (m, 1 H, Hx-6), 3.86–3.96 (m, 1 H, O-ethyl CH2),
benzo[n,q][1,4,7,10,13,16]pentaoxa-λ5-phosphacyclooctadecin-22-one
[(S,S)-4]: See Scheme 1. Ethyl bis(2-hydroxyphenyl)phosphinate
(20, 7.46 g, 26.8 mmol), dimethyl-substituted tetraethylene glycol
ditosylate (S,S)-12 (14.5 g, 27.3 mmol),[30] and finely powdered an-
hydrous K2CO3 (26.0 g, 188 mmol) were mixed with vigorous stir-
ring in dry DMF (330 mL) at room temp. under Ar. After the reac-
tion mixture had been stirred at room temp. for 10 min, the flask
3.97–4.03 (m, 2 H, Hy-6, Hy-19), 4.11–4.19 (m, 1 H, O-ethyl CH2),
6.88–6.97 [m, 2 H, ArC(4)H, ArC(21)H], 7.01–7.11 [m, 2 H, ArC-
(2)H, ArC(23)H], 7.39–7.50 [m, 2 H, ArC(3)H, ArC(22)-
3
H], 7.92 [dd, 1 H, ArC(1)H], 8.03 [dd, JP,H = 14.5, JH ortho
=
7.6 Hz, 1 H, ArC(24)H] ppm. 13C NMR (75.5 MHz, CDCl3,
25 °C): δ = 16.50 (d, J = 6.8 Hz, O-ethyl CH3), 17.53 (7-Me), 17.84
(18-Me), 60.70 (d, 2JP,C = 5.7 Hz, O-ethyl CH2), 69.00, 69.09, 70.71,
Eur. J. Org. Chem. 0000, 0–0
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P. Huszthy et al.
FULL PAPER
70.94, 71.01, 71.07 (OCH2), 72.36 (C-19), 72.85 (C-6) 74.40 (C-18), (2.8 g, 62%) as a pale yellow oil. Rf = 0.52 (Al2O3 TLC, EtOAc/
3
3
74.75 (C-7), 112.19 (d, JP,C = 7.5 Hz, ArC21), 112.52 (d, JP,C
=
=
hexane 1:2 + 5% HCl). [α]2D5 = –19.54 (c = 1.71,CH2Cl2). 1H NMR
(500 MHz, CDCl3, 25 °C): δ = 0.88 (t, JH,H = 7 Hz, 3 H) and 0.89
(t, JH,H = 7 Hz, 3 H, octyl CH3 groups), 1.12–1.41 (m, 31 H, 14
8.3 Hz, ArC4), 120.13 (d, JP,C = 137.0 Hz) and 121.02 (d, JP,C
1
1
148.2 Hz, ArC24a, ArC25a), 120.51 (d, JP,C = 12.1 Hz) and 120.60
3
(d, 3JP,C = 13.1 Hz, ArC2, ArC23), 133.30 (d, 4JP,C = 2.0 Hz, ArC3), octyl CH2, O-ethyl CH3), 2.92–3.05 (m, 2 H, OCH2), 3.11–3.29 (m,
133.44 (d, 2JP,C = 4.9 Hz, ArC1), 133.61 (d, JP,C = 1.8 Hz, ArC22),
4 H, OCH2), 3.31–3.40 (m, 2 H, OCH2), 3.40–3.51 (m, 6 H, OCH2),
4
135.33 (d, JP,C = 7.6 Hz, ArC24), 160.20 (d, JP,C = 3.5 Hz) and 3.66–3.73 (m, 1 H, OCH2), 3.76–3.83 (m, 1 H, OCH2), 3.84–3.92
2
2
160.67 (d, JP,C = 5.1 Hz, ArC4a, ArC20a) ppm. 31P NMR
(m, 1 H, OCH), 3.93–4.02 (m, 2 H, O-ethyl CH2), 4.08–4.18 (m, 1
2
(121.5 MHz, CDCl , 25 °C): δ = 27.25 ppm. IR (KBr): νmax = 2970, H, OCH), 6.85–6.96 [m, 2 H, ArC(4)H, ArC(21)H], 6.98–7.10 [m,
˜
3
2929, 2869, 1590, 1474, 1441, 1375, 1280, 1235, 1214, 1135, 1090,
1023, 950, 817, 756 cm–1. MS: m/z = 508.55 [M + 1]+. C26H37O8P
(508.55): calcd. C 61.41, H 7.33, P 6.09; found C 61.13, H 7.28, P
5.82.
2 H, ArC(2)H, ArC(23)H], 7.37–7.50 [m, 2 H, ArC(3)H, ArC(22)-
H], 7.86–7.96 [m, 1 H, ArC(1)H, ArC(24)H], 8.01–8.11 [m, 1 H,
ArC(1)H, ArC(24)H] ppm. 13C NMR (75.5 MHz, CDCl3, 25 °C):
δ = 14.31 (octyl CH3 groups), 16.64 (d, J = 6.9 Hz, O-ethyl CH3),
22.87, 25.44, 25.63, 29.49, 29.52, 29.79, 29.84, 29.98, 32.07, 32.09,
32.57, 32.95 (octyl CH2 groups), 60.48 (d, J = 5.6 Hz, O-ethyl
CH2), 70.40, 70.62, 70.75, 70.97, 71.22, 71.38, 71.56, 72.45 (OCH2
groups), 78.90, 79.15 (OCH groups), 112.18 (d, J = 7.5 Hz, ArC4,
ArC21), 112.61 (d, J = 8.0 Hz, ArC4, ArC21), 120.57 (d, J =
13.0 Hz, ArC2, ArC23),120.70 (d, J = 135.9 Hz, ArC24a, ArC25a),
121.63 (d, J = 150.8 Hz, ArC24a, ArC25a), 133.34 (d, J = 2.1 Hz,
ArC3, ArC22), 133.51 (d, J = 4.6 Hz, ArC1, ArC24), 133.73 (d, J =
1.9 Hz, ArC3, ArC22), 135.56 (d, J = 7.5 Hz, ArC1, ArC24), 160.28
22-Ethoxy-7,15-dioctyl-6,7,9,10,12,13,15,16-octahydro-22H-di-
benzo[n,q][1,4,7,10,13,16]pentaoxa-λ5-phosphacyclooctadecin-22-one
[(S,S)-6]: See Scheme 1. Optically active ligand (S,S)-6 was pre-
pared in the same way as described above for its analogue (S,S)-4
by starting from ethyl bis(2-hydroxyphenyl)phosphinate (20,
169 mg, 0.586 mmol), dioctyl-substituted tetraethylene glycol ditos-
ylate (S,S)-14 (426 mg, 0.586 mmol), finely powdered anhydrous
K2CO3 (0.81 g, 5.86 mmol), and pure DMF (11 mL). The crude
product was purified by chromatography first on aluminium oxide
with EtOAc/hexane (1:5) as eluent followed by chromatography on
silica gel with dioxane/toluene (1:6) as eluent to give (S,S)-6
(252 mg, 65%) as a pale yellow oil. Rf = 0.48 (Al2O3 TLC, EtOAc/
(d, J = 3.6 Hz, ArC4a, ArC20a), 160.79 (d, J = 5.0 Hz, ArC4a
ArC20a) ppm. 31P NMR (121.5 MHz, CDCl3, 25 °C): δ =
26.09 ppm. IR (neat): ν = 2922, 2854, 1590, 1578, 1467, 1442,
,
˜
max
1389, 1378, 1349, 1324, 1280, 1240, 1220, 1161, 1135, 1090, 1036,
947, 875, 825, 804, 755, 713, 609, 567 cm–1. MS: m/z = 704.93 [M
+ 1]+. C40H65O8P (704.92): calcd. C 68.15, H 9.29, P 4.39; found
C 67.92, H 9.09, P 4.55.
hexane 1:2 + 5% HCl). [α]2D5 = –5.6 (c = 1.00, CH2Cl2). H NMR
1
(500 MHz, CDCl3, 25 °C): δ = 0.88 (t, JH,H = 7 Hz, 3 H) and 0.89
(t, JH,H = 7 Hz, 3 H, octyl CH3 groups), 1.11–1.42 (m, 31 H, 14
octyl CH2, O-ethyl CH3), 2.67–2.81 (m, 2 H, OCH2), 2.99–3.15 (m,
2 H, OCH2), 3.20–3.40 (m, 5 H, OCH2), 3.45–3.54 (m, 1 H, OCH2),
3.66–3.74 (m, 1 H, OCH2), 3.74–3.83 (m, 1 H, OCH2), 3.85–3.96
(m, 1 H, OCH), 4.02–4.11 (m, 2 H, O-ethyl CH2), 4.11–4.20 (m, 1
H, OCH), 6.88–6.98 [m, 2 H, ArC(4)H, ArC(18)H], 6.98–7.09 [m,
2 H, ArC(2)H, ArC(20)H], 7.37–7.50 [m, 2 H, ArC(3)H, ArC(19)-
H], 7.84–7.94 [m, 1 H, ArC(1)H, ArC(21)H], 7.99–8.11 [m, 1 H,
ArC(1)H, ArC(21)H] ppm. 13C NMR (75.5 MHz, CDCl3, 25 °C):
δ = 14.16 (octyl CH3 groups), 16.53 (d, J = 6.8 Hz, O-ethyl CH3),
22.72, 25.30, 25.37, 29.32, 29.35, 29.59, 29.72, 29.81, 31.91, 31.94,
32.04, 32.81 (octyl CH2 groups), 60.35 (d, J = 5.7 Hz, O-ethyl
CH2), 70.59, 70.89, 71.07, 71.31, 71.80, 71.90 (OCH2 groups),
79.98, 80.11 (OCH groups), 112.35 (d, J = 7.4 Hz, ArC4, ArC18),
112.76 (d, J = 8.2 Hz, ArC4, ArC18), 120.59 (d, J = 146.2 Hz,
ArC21a, ArC22a), 120.22 (d, J = 12.5 Hz, ArC2, ArC20), 121.55 (d,
J = 147.9 Hz, ArC21a, ArC22a), 132.99 (d, J = 1.6 Hz, ArC3,
ArC19), 133.15 (d, J = 4.6 Hz, ArC1, ArC21), 133.40 (d, J = 1.6 Hz,
ArC3, ArC19), 135.26 (d, J = 7.5 Hz, ArC1, ArC21), 160.47 (d, J =
3.5 Hz, ArC4a, ArC17a), 160.96 (d, J = 5.0 Hz, ArC4a, ArC17a) ppm.
31P NMR (121.5 MHz, CDCl3, 25 °C): δ = 26.62 ppm. IR (neat):
22-Hydroxy-7,15-dimethyl-6,7,9,10,12,13,15,16-octahydro-22H-di-
benzo[n,q][1,4,7,10,13,16]pentaoxa-λ5-phosphacyclooctadecin-22-one
[(S,S)-8]: See Scheme 2. Aqueous HCl solution (10% w/w, 214 mL)
was added at room temp. to a vigorously stirred solution of op-
tically active macrocycle (S,S)-4 (2.6 g, 5.6 mmol), containing the
ethyl diarylphosphinate moiety, in freshly distilled dioxane
(214 mL). The flask was immersed in an oil bath and the tempera-
ture of the reaction mixture was raised to 80 °C and kept at this
temperature with vigorous stirring until TLC analysis show the to-
tal consumption of the starting material (4 d). After the reaction
was complete, the volatile components were removed by distillation
at 30 °C. The residue was taken up in toluene (50 mL) and the
solvent was removed. This procedure was repeated and the crude
product was dried with KOH pellets under reduced pressure. The
white solid material was recrystallized from dibutyl ether with ad-
dition of charcoal to give pure (S,S)-8 (1.27 g, 52%) as white crys-
tals; m.p. 265–269 °C (dibutyl ether). Rf = 0.48 (silica gel TLC,
MeOH/ClCH2CH2Cl 1:4). [α]2D5 = +46.45 (c = 0.92, CH2Cl2). 1H
NMR (500 MHz, [D6]DMSO, 25 °C): δ = 1.10 (d, JH,H = 6 Hz, 6
H, CH3 groups attached to the macro ring), 3.26–3.34 (m, 1 H,
OCH2), 3.54–3.70 (m, 5 H, OCH2), 3.70–3.79 (m, 2 H, OCH2),
3.79–3.88 (m, 2 H, OCH2), 3.88–3.99 (m, 2 H, OCH2), 4.03–4.16
(m, 2 H, OCH), 6.88–7.04 [m, 4 H, ArC(2)H, ArC(4)H, ArC(18)-
H, ArC(20)H], 7.29–7.44 [m, 2 H, ArC(3)H, ArC(19)H], 7.50–7.69
[m, 2 H, ArC(1)H, ArC(21)H] ppm. 13C NMR (75.5 MHz, [D6]-
DMSO, 25 °C): δ = 15.75 (CH3 groups attached to the macro ring),
68.03, 70.51, 73.50 (OCH2 groups), 75.78 (OCH groups), 114.79
(d, J = 8.0 Hz, ArC4, ArC18), 122.23 (d, J = 12.2 Hz, ArC2, ArC20),
129.91 (d, J = 132.2 Hz, ArC21a, ArC22a), 132.96 (d, J = 1.9 Hz,
ArC3, ArC19), 134.74 (d, J = 8.2 Hz, ArC1, ArC21), 161.24 (d, J =
2.4 Hz, ArC4a, ArC17a) ppm. 31P NMR (121.5 MHz, [D6]DMSO,
ν
max = 3069, 2924, 2855, 1578, 1475, 1443, 1390, 1378, 1350, 1280,
˜
1239, 1219, 1162, 1141, 1091, 1036, 948, 822, 804, 754, 711, 680,
610, 566 cm–1. MS: m/z = 660.88 [M + 1]+. C38H61O7P (660.87):
calcd. C 69.06, H 9.30, P 4.69; found C 68.82, H 9.09, P 4.95.
25-Ethoxy-7,18-dioctyl-6,7,9,10,12,13,15,16,18,19-decahydro-25H-
dibenzo[q,t][1,4,7,10,13,16,19]hexaoxa-λ5-phosphacyclohenicosin-25-
one [(S,S)-7]: See Scheme 1. Optically active ligand (S,S)-7 was pre-
pared in the same way as described above for its analogue (S,S)-4
by starting from ethyl bis(2-hydroxyphenyl)phosphinate (20, 1.8 g,
6.48 mmol), dioctyl-substituted pentaethylene glycol ditosylate
(S,S)-15 (5.0 g, 6.48 mmol), finely powdered anhydrous K2CO3
(25.0 g, 0.181 mol), and pure DMF (160 mL). The crude product
was purified by chromatography first on aluminium oxide with
EtOAc/hexane (1:2.5) as eluent followed by chromatography on sil-
ica gel with MeCN/EtOH/toluene (1:2:40) as eluent to give (S,S)-7
25 °C): δ = 15.82 ppm. IR (KBr): ν
= 3401, 2976, 2935, 2880,
˜
max
1712, 1589, 1576, 1480, 1440, 1375, 1342, 1275, 1244, 1182, 1135,
1093, 1046, 1033, 995, 979, 940, 818, 761, 713, 649, 581 cm–1. MS:
10
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

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/KAP1
Date: 09-05-12 11:23:01
Pages: 13
A New Type of Chiral Crown Ether
1
m/z = 436.20 [M + 1]+. C22H29O7P (436.44): calcd. C 60.54, H 6.70,
P 7.10; found C 60.35, H 6.81, P 7.02.
(1:2:20)]. [α]2D5 = +10.14 (c = 1.04, CH2Cl2). H NMR (500 MHz,
CDCl3, 25 °C): δ = 0.82–0.97 (m, 6 H, octyl CH3 groups), 1.15–
1.51 (m, 28 H, octyl CH2 groups), 3.06–3.23 (m, 2 H, OCH2), 3.23–
3.65 (m, 12 H, OCH2), 3.79–3.92 (m, 2 H, OCH2), 3.92–4.10 (m, 2
H, OCH), 6.83–7.10 [m, 4 H, ArC(2)H, ArC(4)H, ArC(21)H,
ArC(23)H], 7.36–7.52 [m, 2 H, ArC(3)H, ArC(22)H], 7.72–7.91 [m,
2 H, ArC(1)H, ArC(24)H], 8.43 (brs, 1 H, OH) ppm. 13C NMR
(75.5 MHz, CDCl3, 25 °C): δ = 14.33 (octyl CH3 groups), 22.89,
25.62, 29.50, 29.81, 29.89, 31.65, 32.09 (octyl CH2 groups), 70.02,
70.85, 71.28, 72.07 (OCH2 groups), 78.82 (OCH groups), 112.22
(d, J = 8.7 Hz, ArC4, ArC21), 120.68 (d, J = 13.6 Hz, ArC2, ArC23),
122.27 (d, J = 143.3 Hz, ArC24a, ArC25a), 133.40 (ArC3, ArC22),
134.08 (d, J = 7.4 Hz, ArC1, ArC24), 160.46 (d, J = 3.0 Hz, ArC4a,
ArC20a) ppm. 31P NMR (121.5 MHz, CDCl3, 25 °C): δ =
25-Hydroxy-7,18-dimethyl-6,7,9,10,12,13,15,16,18,19-decahydro-
25H-dibenzo[q,t][1,4,7,10,13,16,19]hexaoxa-λ5-phosphacyclohenicos-
in-25-one [(S,S)-9]: See Scheme 2. Proton-ionizable macrocycle
(S,S)-9 was obtained by starting from ethyl ester (S,S)-5 (4.0 g,
7.86 mmol) and following the procedure described above for the
acid hydrolysis of macrocycle (S,S)-4; yield 2.6 g (69%) white crys-
tals; m.p. 157–158 °C (dibutyl ether). Rf = 0.41 (silica gel TLC,
acetic acid/ClCH2CH2Cl 1:2). [α]2D4 = +33.15 (c = 1.03, CH2Cl2).
1H NMR (500 MHz, CDCl3, 25 °C): δ = 1.11 (d, JH,H = 6.5 Hz, 6
H, CH3 groups attached to the macro ring), 3.52–3.66 (m, 12 H,
OCH2), 3.66–3.73 (m, 2 H, OCH), 3.94–4.00 (dAB, Jgem = 9.6 Hz,
4
2ϫ 2 H, OCH2-6, OCH2-19), 6.86–6.95 [dd, JP,H = 5.6, JH ortho
=
29.09 ppm. IR (neat): ν
= 2922, 2853, 1591, 1577, 1477, 1466,
˜
max
8.0 Hz, 2 H, ArC(4)H, ArC(21)H], 6.95–7.04 [m, 2 H, ArC(2)H,
ArC(23)H], 7.41–7.52 [m, 2 H, ArC(3)H, ArC(22)H], 7.66–7.78
1442, 1378, 1349, 1280, 1241, 1137, 1089, 1044, 1021, 942, 800,
753, 713, 682, 613, 557 cm–1. MS: m/z = 676.40 [M + 1]+.
C38H61O8P (676.87): calcd. C 67.43, H 9.08, P 4.58; found C 67.23,
H 8.81, P 4.65.
3
[ddd, JP,H = 15.0, JH ortho = 7.4, JH meta = 1.2 Hz, 2 H, ArC(1)H,
ArC(24)H] ppm. 13C NMR (75 MHz, CDCl3): δ = 17.12 (CH3),
68.88, 70.94, 71.12 (C-9,10,12,13,15,16), 72.90 (C-6, C-19), 74.42
3
(C-7, C-18), 112.21 (d, JP,C = 7.2 Hz, ArC4, ArC21), 120.76 (d,
General Procedure for the Preparation of Ditosylates (S,S)-13 and
(S,S)-15: See Scheme 1. Tosyl chloride (2.0 g, 10.5 mmol) and aque-
3JP,C = 13.3 Hz, ArC2, ArC23), 122.26 (d, 1JP,C = 142.9 Hz, ArC24a
,
ArC25a), 133.53 (ArC3, ArC22), 134.15 (d, JP,C = 8.4 Hz, ArC1, ous KOH (50% w/w, 12 mL) were added successively at 0 °C to a
2
ArC24), 160.37 (ArC4a, ArC20a) ppm. 31P NMR (121.5 MHz, vigorously stirred solution of diol (S,S)-17 or (S,S)-19 (4.8 mmol)
CDCl , 25 °C): δ = 28.16 ppm. IR (neat): νmax = 3350, 2873, 1591, in CH2Cl2 (80 mL). The reaction mixture was stirred vigorously at
˜
3
1577, 1480, 1441, 1392, 1374, 1353, 1337, 1281, 1247, 1122, 1085,
0 °C for 5 min and then at room temp. for 48 h. Water (90 mL) and
CH2Cl2 (60 mL) were added to the mixture and the phases were
1044, 992, 972, 950, 886, 833, 757, 737, 725, 697, 643, 576 cm–1.
MS: m/z = 481.20 [M + 1]+. C24H33O8P (480.49): calcd. C 59.99, shaken thoroughly. The phases were separated, and the aqueous
H 6.92, P 6.45; found C 59.80, H 6.81, P 6.33.
phase was shaken with CH2Cl2 (2ϫ20 mL). The combined organic
phase was dried with anhydrous MgSO4 and filtered, and the sol-
vent was removed. The crude product was purified as described
below for each compound to result in the ditosylates (S,S)-13 and
(S,S)-15.
22-Hydroxy-7,15-dioctyl-6,7,9,10,12,13,15,16-octahydro-22H-di-
benzo[n,q][1,4,7,10,13,16]pentaoxa-λ5-phosphacyclooctadecin-22-one
[(S,S)-10]: See Scheme 2. Proton-ionizable macrocycle (S,S)-10 was
obtained by starting from ethyl ester (S,S)-6 (155 mg, 0.23 mmol)
and following the procedure described above for the acid hydrolysis
of macrocycle (S,S)-4. The crude product was purified by
chromatography on silica gel with MeCN/EtOH/toluene (2:5:20) as
eluent to give (S,S)-10 (97 mg, 60%) as a brown oil. Rf = 0.50 [silica
(2S,13S)-2,13-Dimethyl-3,6,9,12-tetraoxatetradecane-1,14-diyl
Bis(4-methylbenzenesulfonate) [(S,S)-13]: See Scheme 1. Ditosylate
(S,S)-13 was prepared as described above in the General Procedure
by starting from diol (S,S)-17 (9.0 g, 33.8 mmol), tosyl chloride
(15.5 g, 81.8 mmol), and aqueous KOH (50% w/w, 85 mL). The
crude product was purified by chromatography on silica gel with
gel TLC, MeCN/EtOH/toluene (2:5:20)]. [α]2D7 = +27.60 (c = 1.00,
1
CH2Cl2). H NMR (500 MHz, CDCl3, 25 °C): δ = 0.89 (t, JH,H
=
6 Hz, 6 H, octyl CH3), 1.18–1.52 (m, 28 H, 14 octyl CH2), 3.32– acetone/hexane (1:3) as eluent to give ditosylate (S,S)-13 (17.6 g,
3.49 (m, 2 H, OCH2), 3.49–3.71 (m, 8 H, OCH2), 3.88–4.11 (m, 4 91%) as a pale yellow oil. Rf = 0.15 (silica gel TLC, acetone/hexane
H, OCH2, OCH), 6.83–6.94 [m, 2 H, ArC(4)H, ArC(18)H], 6.94–
1:3). [α]2D5 = –7.33 (c = 1.06, CHCl3). 1H NMR (300 MHz, CDCl3,
7.07 [m, 2 H, ArC(2)H, ArC(20)H], 7.38–7.52 [m, 2 H, ArC(3)H, 25 °C): δ = 1.12 (d, J = 8 Hz, 6 H, CH3 groups attached to the
ArC(19)H], 7.59–7.73 [m, 2 H, ArC(1)H, ArC(21)H], 8.01 (brs, 1 chiral centers), 2.44 (s, 6 H, ArCH3), 3.53–3.74 (m, 14 H, OCH2,
H, OH) ppm. 13C NMR (75.5 MHz, CDCl3, 25 °C): δ = 14.33 (oc-
tyl CH3 groups), 22.88, 25.72, 29.48, 29.75, 29.89, 31.60, 32.08 (oc-
tyl CH2 groups), 70.17, 71.16, 71.71 (OCH2 groups), 78.76 (OCH
OCH), 3.89–4.00 (m, 4 H, CH2OTs), 7.34 [d, J = 8 Hz, 4 H, ArC-
(3)H, ArC(5)H], 7.78 [d, J = 8 Hz, 4 H, ArC(2)H, ArC(6)H] ppm.
13C NMR (75.5 MHz, CDCl3, 25 °C): δ = 16.93, 21.81, 69.06,
groups), 111.81 (d, J = 8.0 Hz, ArC4, ArC18), 120.69 (d, J = 70.77, 70.85, 72.79, 73.64, 128.12, 130.02, 133.13, 144.98 ppm. IR
13.1 Hz, ArC2, ArC20), 121.50 (d, J = 137.9 Hz, ArC21a, ArC22a),
(neat): νmax = 2871, 1598, 1452, 1355, 1307, 1292, 1189, 1174, 1095,
˜
133.64 (d, J = 1.3 Hz, ArC3, ArC19), 134.31 (d, J = 8.1 Hz, ArC1, 1019, 981, 956, 813, 789, 706, 688, 665, 624, 575, 553, 450,
ArC21), 160.44 (ArC4a, ArC17a) ppm. 31P NMR (121.5 MHz, 406 cm–1. MS: m/z = 574.70, [M + 1]+. C26H38O10S2 (574.70): calcd.
CDCl , 25 °C): δ = 27.9 ppm. IR (neat): ν
= 3066, 2923, 2854, C 54.34, H 6.66, S 11.16; found C 54.14, H 6.84, S 11.01.
˜
3
max
1701, 1661, 1618, 1591, 1577, 1476, 1441, 1395, 1375, 1346, 1337,
1280, 1241, 1140, 1090, 1044, 1021, 942, 825, 788, 753, 702, 613,
598, 554 cm–1. MS: m/z = 632.80 [M + 1]+. C36H57O7P (632.82):
calcd. C 68.33, H 9.08, P 4.89; found C 68.04, H 8.95, P 4.73.
(2S,13S)-2,13-Dioctyl-3,6,9,12-tetraoxatetradecane-1,14-diyl Bis(4-
methylbenzenesulfonate) [(S,S)-15]: See Scheme 1. Ditosylate (S,S)-
15 was prepared as described above in the General Procedure by
starting from diol (S,S)-19 (4.0 g, 8.6 mmol), tosyl chloride (3.62 g,
25-Hydroxy-7,18-dioctyl-6,7,9,10,12,13,15,16,18,19-decahydro- 19.0 mmol), and aqueous KOH (50% w/w, 24 mL). The crude
25H-dibenzo[q,t][1,4,7,10,13,16,19]hexaoxa-λ5-phosphacyclohenicos- product was purified by chromatography on silica gel with toluene
in-25-one [(S,S)-11]: See Scheme 2. Proton-ionizable macrocycle and then EtOAc/hexane (1:3) as eluents to give ditosylate (S,S)-15
(S,S)-11 was obtained by starting from ethyl ester (S,S)-7 (250 mg,
0.35 mmol) and following the procedure described above for the
acid hydrolysis of macrocycle (S,S)-4; yield 140 mg (59%) as a pale
yellow oil. Rf = 0.23 [silica gel TLC, MeCN/EtOH/toluene
(7.7 g, 53%) as a pale yellow oil. Rf = 0.15 (silica gel TLC, EtOAc/
hexane 1:5). [α]2D5 = –4.55 (c = 1.01, CH2Cl2). 1H NMR (300 MHz,
CDCl3, 25 °C): δ = 0.87 (t, JH,H = 7 Hz, 6 H, octyl CH3), 1.23–
1.43 (m, 28 H, 14 octyl CH2), 2.44 (s, 6 H, ArCH3), 3.45–3.68 (m,
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
11

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/KAP1
Date: 09-05-12 11:23:01
Pages: 13
P. Huszthy et al.
FULL PAPER
[13] R. M. Izatt, C. Y. Zhu, P. Huszthy, J. S. Bradshaw, Enantio-
meric Recognition in Macrocycle–Primary Ammonium Cation
Systems, in: Crown Compounds: Toward Future Applications
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[14] R. M. Izatt, T. M. Wang, J. K. Hathaway, X. X. Zhang, J. C.
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[15] P. Huszthy, V. Farkas, T. Tóth, G. Székely, M. Hollósi, Tetrahe-
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14 H, OCH2, OCH), 3.93–4.02 (m, 4 H, CH2OTs), 7.34 [d, J =
8 Hz, 4 H, ArC(3)H, ArC(5)H], 7.79 [d, J = 8 Hz, 4 H, ArC(2)H,
ArC(6)H] ppm. 13C NMR (75.5 MHz, CDCl3, 25 °C): δ = 14.29,
21.83, 22.83, 25.25, 29.41, 29.64, 29.73, 31.55, 32.03, 69.89, 70.75,
70.89, 71.75, 76.81, 128.14, 130.03, 133.12, 144.98 ppm. IR (neat):
ν
max = 2928, 2880, 2856, 1960, 1920, 1696, 1600, 1544, 1496, 1484,
˜
1460, 1424, 1364, 1320, 1296, 1224, 1176, 1160, 1096, 1052, 976,
880, 816, 792, 740, 668, 652, 552, 540 cm–1. MS: m/z = 771.10 [M
+ 1]+. C40H66O10S2 (771.08): calcd. C 62.31, H 8.63, S 8.32; found
C 62.12, H 8.88, S 8.14.
[17] I. Kovács, P. Huszthy, F. Bertha, D. Sziebert, Tetrahedron:
Asymmetry 2006, 17, 2538–2547.
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Financial support by the Hungarian Scientific Research Fund
(OTKA K81127, to P. H.; PD71910, to T. T.; PD71817, to V. F.)
and a Szabó Zsuzsa Doctoral Scholarship (to J. K.) is gratefully
acknowledged. This work is assocaited with the scientific program
of the “Development of quality-oriented and harmonized R+D+I
strategy and functional model at BME” project, supported by the
New Hungary Development Plan (project ID: TÁMOP-4.2.1/B-09/
1/KMR-2010-0002). We wish to express our sincere thanks to Pro-
fessor Csaba Szántay Jr. for his kind help in the discussion of NMR
titrations.
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Tóth, P. Huszthy, Tetrahedron: Asymmetry 2011, 22, 684–689.
Received: December 8, 2011
Published Online: ᭿
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: B11769
/KAP1
Date: 09-05-12 11:23:01
Pages: 13
A New Type of Chiral Crown Ether
Chiral Crown Ethers
G. Székely, B. Csordás, V. Farkas,
J. Kupai, P. Pogány, Z. Sánta,
Z. Szakács,, T. Tóth, M. Hollósi,
J. Nyitrai, P. Huszthy* .................... 1–13
Synthesis and Preliminary Structural and
Binding Characterization of New Enantio-
pure Crown Ethers Containing an Alkyl
Diarylphosphinate or a Proton-Ionizable
Diarylphosphinic Acid Unit
Enantiopure crown ethers containing either
an ethyl phosphinate [(S,S)-4 to (S,S)-7] or
a phosphinic acid moiety [(S,S)-8 to (S,S)-
11] were synthesized and complexation
with the enantiomers of 1- and 2-NEA was
studied. Calculations showed three import-
ant hydrogen bonds between (S,S)-9 and
each enantiomer of 1-NEA and 2-NEA.
Appreciable enantiomeric recognition and
heterochiral preference were found.
Keywords: Molecular recognition / Host–
guest systems / Crown compounds / Phos-
phorus / Circular dichroism / NMR ti-
tration / DFT calculations
Eur. J. Org. Chem. 0000, 0–0
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