Ephedrinium-based protic chiral ionic liquids for enantiomeric recognition

Article abstract of DOI:10.1002/chir.20920

We report the synthesis of a series of novel structurally related protic chiral ionic liquids (PCILs) derived from ephedrines. Enantiopure norephedrine, ephedrine, and methylephedrine were neutralized by use of fluorinated acids, bis(trifluoromethanesulfonyl)imide, and bis(pentafluoroethanesulfonyl)imide to afford six PCILs with protonated primary, secondary, and tertiary amines. The goal of this study is to investigate the influence of structure on both chiral recognition abilities and physicochemical properties of these closely related PCILs. The newly synthesized PCILs were characterized by use of nuclear magnetic resonance (NMR), thermal gravimetric analysis, differential scanning calorimetry, circular dichroism (CD), mass spectrometry, and elemental analysis. The PCILs were thermally stable up to 220°C and had glass transition temperatures between -60 and -30°C. Both enantiomers of the PCILs retained chirality throughout the synthesis as demonstrated by use of CD measurements. More interestingly, these ephedrinium PCILs displayed strong chiral recognition capabilities as evidenced by peak splitting of the chemical shift of the trifluoro group of potassium Mosher's salt by use of ¹⁹F-NMR. In addition, these PCILs demonstrated enantiomeric recognition capabilities toward a range of structurally diverse analytes using steady-state fluorescence spectroscopy.

Full text of DOI:10.1002/chir.20920

CHIRALITY 23:54–62 (2011)
Ephedrinium-Based Protic Chiral Ionic Liquids
for Enantiomeric Recognition
*
SERGIO L. DE ROOY, MIN LI, DAVID K. BWAMBOK, BILAL EL-ZAHAB, SANTHOSH CHALLA, AND ISIAH M. WARNER
Department of Chemistry, Louisiana State University, Baton Rouge, Louisiana
Contribution to the Proceedings of the 21st International Symposium on Chirality [ISCD 21]
ABSTRACT
We report the synthesis of a series of novel structurally related protic chiral
ionic liquids (PCILs) derived from ephedrines. Enantiopure norephedrine, ephedrine, and meth-
ylephedrine were neutralized by use of fluorinated acids, bis(trifluoromethanesulfonyl)imide,
and bis(pentafluoroethanesulfonyl)imide to afford six PCILs with protonated primary, second-
ary, and tertiary amines. The goal of this study is to investigate the influence of structure on
both chiral recognition abilities and physicochemical properties of these closely related PCILs.
The newly synthesized PCILs were characterized by use of nuclear magnetic resonance
(NMR), thermal gravimetric analysis, differential scanning calorimetry, circular dichroism
(CD), mass spectrometry, and elemental analysis. The PCILs were thermally stable up to 2208C
and had glass transition temperatures between 260 and 2308C. Both enantiomers of the PCILs
retained chirality throughout the synthesis as demonstrated by use of CD measurements. More
interestingly, these ephedrinium PCILs displayed strong chiral recognition capabilities as evi-
denced by peak splitting of the chemical shift of the trifluoro group of potassium Mosher’s salt
by use of 19F-NMR. In addition, these PCILs demonstrated enantiomeric recognition capabilities
toward a range of structurally diverse analytes using steady-state fluorescence spectroscopy.
C
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Chirality 23:54–62, 2011.
2010 Wiley-Liss, Inc.
KEY WORDS: chiral recognition; fluorescence; circular dichroism; fluorine NMR; Mosher’s salt
INTRODUCTION
base.28 In general, the use of stronger acids and/or bases
leads to increased proton transfer and subsequently higher
ionicity, i.e., the presence of a higher number of ionic spe-
cies and fewer neutral species. PILs have recently proven
successful for heterogeneous catalysis and for the synthesis
of polymeric materials that are good proton conductors in
fuel cells.29–32 However, relatively few studies have been per-
formed where physicochemical properties of structurally
related PILs were investigated. In one study, the ionic con-
ductivity and thermal properties of 21 ILs, prepared through
the reaction of various amines with tetrafluoroboric acid,
were investigated. The measured properties appeared to be
dependent on both cation and anion structure.33 In another
study, the physicochemical properties of a series of alkylam-
monium-based PILs with different organic and inorganic
anions were studied.34 In the same study, the authors sug-
gested that PILs could possibly be synthesized through
rational design aimed at specific applications.
Over the last decade, an increased interest in the study
of ionic liquids (ILs) has been observed from data in the liter-
ature.1,2 ILs are essentially low-melting organic salts consist-
ing of bulky organic cations and typically inorganic anions.
Room-temperature ILs are liquid at room temperature and
were first reported by Walden in 1914.3 ILs have unique
physicochemical properties including high ionic conductivity,
low vapor pressure, stability in air, and a wide range of solva-
tion properties.4,5 Such properties have allowed for the appli-
cation of ILs in a variety of different areas, which include sep-
arations,6 catalysis,7 electrochemistry,8 and spectroscopy.9
Chiral ionic liquids (CILs) are ILs containing a chiral cat-
ion,10 anion,11 or both.12 Since their inception, various types
of CILs have been prepared.11–19 A number of CILs such as
(3-chloro-2-hydroxypropyl)trimethylammonium bis((trifluoro-
methyl)sulfonyl)imide have been prepared through facile
methods derived from commercially available chiral precur-
sors.20 However, other CILs such as the isomannide-derived
CIL reported elsewhere required a series of more elaborate
synthesis steps.21 CILs have been used in gas chromatogra-
phy as stationary phases,22,23 as catalysts in organic synthe-
sis,24 and also as chiral selectors and solvents in fluores-
cence spectroscopy.20,22–25 Leitner and coworkers have
reported the first use of a CIL in combination with a racemic
catalyst where the CIL blocked one of the catalyst ligands,
thus resulting in enantioselective hydrogenation.26 Another
CIL was synthesized through alkylation of phenethylamine,
followed by ion exchange for potential use as a chiral electro-
chemical sensor.27
Ephedrine is an alkaloid that functions as a decongestant,
stimulant, and appetite suppressant.35–37 It belongs to a group
of precursors that have been used for synthesizing CILs from
the chiral pool. Wasserscheid et al. reported an aprotic N,N-
dimethylephedrinium IL using a three-step synthesis, which
included a Leuckart–Wallach reaction with (2)-(1R, 2S)-
Additional Supporting Information may be found in the online version of this
article.
Contract grant sponsor: National Science Foundation (NSF); Contract grant
number: CHE-0911118; Contract grant sponsor: Phillip West Endowment.
*Correspondence to: Isiah M. Warner, Department of Chemistry, Louisiana
State University, Baton Rouge, LA 70803. E-mail: iwarner@lsu.edu
Received for publication 10 November 2009; Accepted 14 July 2010
DOI: 10.1002/chir.20920
Protic ionic liquids (PILs) are ILs formed through the
transfer of protons from a Bronsted acid to a Bronsted
Published online 2 November 2010 in Wiley Online Library
(wileyonlinelibrary.com).
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VV
2010 Wiley-Liss, Inc.

EPHEDRINIUM-BASED PCILs FOR ENANTIOMERIC RECOGNITION
55
Fig. 1. Structures of PCIL cations (A) [NorHeph1], (B) [HEph1], (C) [MeHEph1] and anions (D) [Tf2N2] and (E) [BETI2].
including acetonitrile and dichloromethane were of HPLC grade (J.T.
Baker, Philipsburg, NJ). Deuterated solvents such as chloroform-d1,
D2O, and dimethyl sulfoxide-d6 were obtained from Sigma-Aldrich (Mil-
waukee, WI). All reagents were used without further purification. Triply
deionized ultrapure water (18.2 MX) obtained using an Elga model
PURELAB UltraTM water filtration system was used in the study.
ephedrine, followed by alkylation with dimethylsulfate and ion
exchange with lithium bis(trifluoromethylsulfonyl)imide
([Li][Tf2N]).38 A green, solvent-less method was subsequently
developed for the synthesis of similar CILs. For example, (1R,
2S)-N-methylephedrine was alkylated with bromoalkanes
under microwave irradiation followed by ion exchange.39 This
method yielded aprotic ephedrinium CILs with different alkyl
chain lengths and anions. Several N,N-dimethylephedrinium-
based ILs were also used for the enantiomeric gas chromato-
graphic separation of a series of chiral compounds such as
chiral alcohols (including diols), chiral sulfoxides, chiral epox-
ides, and acetylated amines.23 In addition, the aprotic ephedri-
nium CIL reported earlier was also used for asymmetric gly-
cine alkylation in the presence of optically active orthopalla-
dated phenanthrylamine as a phase transfer catalyst.38,40
The objective of this study is to synthesize protic chiral
ionic liquids (PCILs) derived from structurally related alka-
loids such as norephedrine (NorEph), ephedrine (Eph), and
methylephedrine (MeEph) through facile acid–base neutrali-
zation with fluorinated imide acids (Fig. 1). This leads to the
formation of a series of primary, secondary, and tertiary
amine-based PCILs, respectively. Thus, the PCILs described
here are all protic in contrast to the aprotic ephedrinium
CILs reported elsewhere.38 Herein, we report the effects of
the degree of alkylation (varying hydrogen-bonding capabil-
ity, van der Waals bonding, and steric hindrance) on the
physicochemical properties and chiral recognition abilities of
these ephedrinium-based PCILs.
General Instrumental Methods
1H-NMR (400 MHz) and 13C-NMR (100 MHz) spectra were acquired
by use of a Bruker AV-400 spectrometer. The 1H-NMR and 13C-NMR
chemical shifts are given in parts per million (d) with respect to TMS as
an internal standard. 19F-NMR (236 MHz) spectra were acquired on a
Bruker DPX 250 NMR spectrometer. Solvents used for preparing the
samples were DMSO-d6 for 1H-NMR and 13C-NMR and CDCl3 for 19F-
NMR. Elemental analyses were conducted by Atlantic Microlab (Atlanta,
GA). Samples were also analyzed with mass spectrometry on a Hitachi
MS-8000 3DQ LC-ion trap mass spectrometer with electrospray and
APCI ionization methods in both the positive and negative ion mode.
The moisture contents of synthesized PCILs were measured using a
Mettler Toledo DL32 Karl-Fischer Coulometric titrator. CD measure-
ments were obtained by analyzing 1 mM methanolic solutions at room
temperature in 4-mm quartz cuvettes on a Jasco-710 spectropolarimeter.
Thermal stability was measured with a TGA Q50 thermogravimetric ana-
lyzer (TA Instruments) by heating 10 mg of sample under nitrogen at a
rate of 158C min21 from 25 to 5508C. Similarly, glass transition and melt-
ing point were investigated with a DSC Q 100 differential calorimeter
(TA Instruments, USA) by cooling a 5–10 mg sample of PCIL to 2808C
and subsequently heating it at a rate of 58C min21 to 1508C.
Fluorescence analyses were performed in the steady-state mode on a
Spex Fluorolog-3 spectrofluorimeter (model FL3-22TAU3; Jobin Yvon
Edison, NJ) equipped with a 450-W Xe lamp and R928 PMT emission de-
tector. Excitation and emission wavelengths with 3-nm bandpasses were
selected as well as an integration time of 0.1 s per point. Fluorescence
data were corrected by taking the quotient of the analyte signal and the
reference signal. Excitation emission matrix (EEM) scans were per-
formed with excitation from 250 to 400 nm and emission spectra col-
lected between 250 and 500 nm. The step sizes used for the excitation
and emission scans were 2.5 and 5 nm, respectively.
EXPERIMENTAL
Chemicals and Materials
L-(2)-Norephedrine, D-(1)-norephedrine, (2)-ephedrine, (1)-ephed-
rine, (2)-N-methylephedrine, (1)-N-methylephedrine, racemic Mosher’s
acid, and bis(trifluoromethanesulfonyl)imide were purchased from
Sigma-Aldrich (Milwaukee, WI). Enantiomerically pure chiral analytes of
propranolol (PROP), 1-(9-anthryl)-2,2,2-trifluoroethanol (TFAE), 1,10-
binaphthyl-2,20-diamine (BNA), 1,10-binaphthyl-2,20-diyl hydrogen phos-
phate (BNP), glucose, and serine were also purchased from Sigma-
Aldrich (Milwaukee, WI). Bis(pentafluoroethane)sulfonimide was pur-
chased from SynQuest Laboratories (Alachua, FL). All solvents used
Representative Procedure: Synthesis of [MeHEph][Tf2N]
MeEph (0.50 g, 3.31 mmol) was dissolved in water and reacted with
equimolar bis(trifluoromethanesulfonyl)imide by slow addition and stir-
ring to obtain [MeHEph][Tf2N] (Scheme 1). The neutralization reaction
Chirality DOI 10.1002/chir

56
DE ROOY ET AL.
Scheme 1. Synthesis of [MeHEph][Tf2N].
[BETI2] for [NorHEph][Tf2N] and [NorHEph][BETI] was
confirmed by strong peaks observed at m/z 5 279.18 and
379.19 (Supporting Information Fig. S1).
was performed in an ice bath for 6 h. The mixture was subsequently
stirred at room temperature for 12 h. After water was removed in vacuo
by freeze-drying, a viscous colorless liquid was obtained. The viscous
PCIL was further purified by washing with small amounts of triple dis-
tilled water and freeze-dried by lyophilization. [MeHEph][Tf2N], color-
less liquid, 90.3%, 1H-NMR (250 MHz, DMSO-d6) d (ppm): 7.40 (s, 3H),
7.30 (s, 2H), 76.2 (s, 3H), 5.22 (d, 1H), 3.47 (m, 1H), 2.81 (s, 1H), 1.0 (d,
J 5 6.8 Hz, 3H). 13C-NMR d (ppm): 142.0, 128.7 127.9, 126.2, 121.6,
118.4, 115.2, 114.2, 69.0, 66.0, 41.2, 7.4. Anal Calcd for C13H18F6N2O5S2:
C, 33.88; H, 3.90; N, 6.08. Found: C, 34.09; H, 3.81; N, 6.09.
To determine whether configurational integrity was main-
tained throughout the synthesis, circular dichroism (CD)
was used to compare the bands of the starting materials and
the IL products. The CD spectra of both enantiomers of
MeEph and IL derived therefrom, [MeHEph][Tf2N], are
shown in Figure 2. The relative peak intensities of both enan-
tiomers of MeEph and [MeHEph][Tf2N] remain constant
throughout the synthesis, suggesting that chirality was main-
tained.
After purification, followed by freeze-drying overnight and
subsequent purging with argon gas, the water content of the
PCILs was determined using coulometric Karl-Fischer titra-
tion. The water content of the PCILs varied between 50 and
150 ppm (Table 1). All other PCILs were characterized in the
same manner as [MeHEph][Tf2N]. The PCILs were viscous
liquids with [NorHEph][Tf2N] and [HEph][Tf2N] having
higher viscosities at room temperature.
RESULTS AND DISCUSSION
Synthesis and Characterization of Ephedrine-Based PCILs
The synthesized PCILs (Scheme 1) were characterized
1
using H- and 13C-NMR, elemental analysis, and electrospray
1
ionization mass spectrometry (ESI-MS). The results from H-
and 13C-NMR were in agreement with the chemical structures
of the PCILs and were further confirmed with elemental analy-
1
sis. The respective H- and 13C-NMR spectra were also com-
pared with those of the precursors from which the PCILs were
derived. As expected, the spectra were similar, because the
chemical structures of the product PCILs were comparable to
those of the corresponding chiral precursors. Fluorine (19F)-
NMR was used to confirm the success of neutralization (intro-
duction of fluorinated anions). Mass spectrometry was con-
ducted in the positive and negative ion mode. In the Support-
ing Information (Fig. S1), the respective mass spectra are
illustrated for [NorHEph][Tf2N], [HEph][Tf2N], and
[MeHEph][Tf2N] PCILs. In the positive ion mode a strong
peak is observed for each of the respective parent ions with
m/z 5 152.10, 166.12, and 180.13 confirming their presence.
In the negative ion mode, the presence of [Tf2N2] and
Thermal Properties of PCILs
The thermal stabilities of the PCILs were studied by use of
thermal gravimetric analysis (TGA). Samples were heated
under nitrogen atmosphere at a rate of 158C min21 from
room temperature up to 6008C. Thermal decomposition of
the PCILs ranged between 230 and 2508C with onset temper-
atures around 4008C (Table 2). PILs with ammonium, imida-
zolium, and other heterocyclic cations generally exhibit good
thermal stabilities and low melting points with [Tf2N2]
anions.41,42 The ephedrinium-based PCILs with [Tf2N2]
anions had higher thermal stability than those with [BETI2]
Fig. 2. Circular dichroism of enantiomers (1 and 2) of (A) 10 mM MeEph and (B) 10 mM MeHEphTf2N in methanol.
Chirality DOI 10.1002/chir

EPHEDRINIUM-BASED PCILs FOR ENANTIOMERIC RECOGNITION
57
TABLE 1. Moisture content of PCILs measured by
Karl-Fischer titration
higher chiral recognition ability was obtained by forming
PCILs from the neutral NorEph (Fig. 3). These results sug-
gest the presence of a positive charge as an important factor
for chiral discrimination by an ion-pair interaction. Rizvi and
Shamsi have reported that electrostatic interactions between
the acidic analyte and cationic IL micelle played a profound
role in enantioseparation.47 In another study, Wasserscheid
and coworkers have reported an asymmetric synthesis that
solely relied on the strength of ion pairing in a CIL to induce
high chirality in an asymmetric hydrogenation reaction.48
This work demonstrates the importance of ion-pair interac-
tions in chiral induction or chirality transfer. The chiral rec-
ognition abilities of the [Tf2N2]-containing PCILs including
NorHEph, HEph, and MeHEph were also compared, i.e., the
effect of the degree of amine alkylation on Mosher’s salt
peak splitting was investigated (Fig. 4). The recorded values
for these PCILs in the presence of Mosher’s salt were 12.7,
5.7, and 4.3 Hz, respectively (Fig. 4). In addition to a larger
peak splitting, the 19F-NMR change in chemical shift for
[NorHEph][Tf2N] was also highest. Thus, it appears that as
the extent of hydrogen bonding decreases and steric hin-
drance increases (i.e., going from the primary to the tertiary
ephedrinium-based PCIL), chiral recognition ability of PCILs
toward Mosher’s salt decreased. Analysis of peak splitting
for the [BETI2]-containing PCILs showed almost identical
results. A control experiment was performed to determine
the role of the [Tf2N2] anion in chiral recognition. The chiral
recognition abilities of [NorHEph][Cl], [HEph][Cl], and
[MeHEph][Cl] were determined, and it was found that chiral
recognition ability of PCILs with Tf2N2 as anions was much
higher than that of ionic compounds with Cl2 as anions (Sup-
porting Information Fig. S23). Chiral recognition studies per-
formed by Wilhelm and coworkers indicate that the counter-
anions used in CILs play an important role in chiral discrimi-
nation. A 10-fold increase in peak splitting was observed
when 19F-NMR was carried out on Mosher’s salt in the pres-
ence of enantiopure CIL with [Tf2N2] as counterion com-
pared with [BF42] as the counterion.
PCIL
H2O content (ppm)
Mass (mg)
[NorHEph][Tf2N]
[HEph][Tf2N]
[MeHEph][Tf2N]
[NorHEph][BETI
[HEph][BETI]
93.0
99.8
150.1
53.2
55.9
47.5
7.2
10.0
14.1
5.3
8.6
[MeHEph][BETI]
11.8
anions (Table 2). These results were consistent with earlier
reports for ammonium-based ILs in which the PILs with
[Tf2N2] anions had higher thermal stability than those that
contained [BETI2] anions.43
Differential scanning calorimetry was used to determine
the thermal transitions of the PCILs occurring throughout
the heating and cooling steps of the samples. The PCILs
were cooled from room temperature to 2808C, followed by
heating to 1508C at a rate of 58C min21 under nitrogen. Crys-
tallization and melting transitions were not observed for the
PCILs under these conditions. A glass transition (Tg)
between 260 and 2208C was found for the PCILs increasing
in the order [NorHEph][Tf2N], [HEph][Tf2N], and
[MeHEph][Tf2N]. The [BETI2]-containing PCILs had higher
Tg values than the [Tf2N2]-containing PCILs because of the
higher polarizability of these anions.44 The [BETI2]-contain-
ing PCILs showed an opposite trend in Tg values.
Enantiomeric Recognition Studies of PCILs Toward
Racemic Mosher’s Salt Using 19F-NMR
Enantiomeric recognition capabilities of the PCILs were
investigated by using a previously described method in
which CILs derived from aminobutanol, valine, and methyle-
phedrine were dissolved in a deuterated solvent with racemic
Mosher’s salt.38 The chemical shift differences or peak split-
tings of the two diastereomeric associates were measured by
use of 19F-NMR, where the extent of peak splitting of CF3 in
Mosher’s salt was related to the strength of diastereomeric
interactions. Mosher’s salt was obtained by neutralization of
Mosher’s acid solution with an equimolar solution of potas-
sium hydroxide and subsequent freeze-drying and lyophiliza-
tion. The feedstock solution for the 19F-NMR tests was pre-
pared by dissolving 121.3 mg of racemic Mosher’s salt (0.45
mmol) and 119.5 mg of crown ether (18C6, 0.45 mmol) in 15
ml CDCl3 as previously reported.45 The 18C6 was added to
increase the solubility of potassium Mosher’s salt in chloro-
form-d1 by forming a complex between potassium and crown
ether.46 For 19F-NMR analysis, a fivefold molar excess of re-
spective PCIL with regard to potassium Mosher’s salt was
dissolved in 0.5 ml of the feedstock solution.
Enantiomeric Recognition of Chiral Analytes by PCILs
Through the Use of Steady-State Fluorescence
Spectroscopy
After confirming enantioselectivity of the PCILs for
Mosher’s salt with 19F-NMR, further investigations were per-
formed using fluorescence spectroscopy. Recently, a fluores-
cence spectroscopic method was reported for investigating
chiral recognition between a CIL and each enantiomeric form
of various fluorescent drug analytes.49 The two enantiomeric
forms of chiral drug analytes exhibited different fluorescence
TABLE 2. Thermal properties of ephedrinium PCILs
The chiral recognition ability of the precursor NorEph was
compared with that of the PCIL [NorHEph][Tf2N]. In the ab-
sence of either NorEph or [NorHEph][Tf2N], a single peak
of 270.50 Hz chemical shift was observed for the potassium
Mosher’s salt racemate. In the presence of NorEph or the
[NorHEph][Tf2N], peak splittings were observed, which are
related to the strength of the diastereomeric interactions
between potassium Mosher’s salt racemate and the chiral
compounds. The significantly greater peak splitting of potas-
sium Mosher’s salt with PCIL [NorHEph][Tf2N] versus non-
charged precursor NorEph as chiral selector suggests that a
PCIL
Tg (8C)a
Tstart (8C)b
Tonset (8C)c
[NorHEph][Tf2N]
[NorHEph][BETI]
[HEph][Tf2N]
[HEph][BETI]
[MeHEph][Tf2N]
[MeHEph][BETI]
253.9
227.1
248.6
231.2
241.3
233.1
216.4
222.0
248.0
249.2
242.6
231.3
414.8
382.5
417.5
383.5
436.3
391.3
aGlass transition temperature.
bThe beginning decomposition temperature.
cThe temperature at which the sample loses weight at the fastest speed.
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DE ROOY ET AL.
Fig. 3. 19F-NMR (CDCl3) spectra of potassium Mosher’s salt (A) without chiral selector and with (B) (1S,2R)-NorEph and (C) (1S,2R)-NorHEphTf2N chiral
selector.
Fig. 4. 19F-NMR (CDCl3) spectra of potassium Mosher’s salt (A), potassium Mosher’s salt with (1S,2R)-NorHEphTf2N as chiral selector (B), potassium
Mosher’s salt with (1S,2R)-HEphTf2N as chiral selector (C), and potassium Mosher’s salt with (1S,2R)-MeHEphTf2N as chiral selector (D).
Chirality DOI 10.1002/chir

EPHEDRINIUM-BASED PCILs FOR ENANTIOMERIC RECOGNITION
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Fig. 5. (A) UV–vis spectrum of 10 mM MeHEphTf2N in methanol. (B) Fluorescence of neat MeHEphTf2N excited at 260 nm with front-face illumination.
intensities with the CIL as a result of specific diastereomeric
complexes being formed. This method could therefore be
used to determine the presence of a particular enantiomer in a
given sample. Alanine-based and more recently a phenylala-
nine-based CIL were also synthesized in our laboratory and
investigated for enantiomeric recognition.25,50,51
The PCILs reported in this study are intrinsically fluores-
cent and could therefore also be used for probing nonfluores-
cent enantiomers by monitoring their intrinsic fluorescence
intensities.
orescence for the PCILs and the fluorescent chiral analytes,
an EEM scan was run with excitation wavelengths ranging
from 250 to 400 nm. The enantioselectivities of the PCILs
were judged based on differences in the fluorescence bands
with respect to shape and intensity, upon binding to different
enantiomeric forms of the analyte. Based on the results
obtained, it could be determined which PCIL exhibited the
highest enantioselectivity for a particular analyte. Because
the PCILs and the chiral analytes were both fluorescent, the
fluorescence signal intensity was monitored for the PCIL
between 270 and 320 nm and for the analyte peaks between
320 and 520 nm (Supporting Information Fig. S22). To
amplify the differences in signal intensities, i.e., to clearly dis-
tinguish between fluorescence signals of both enantiomers,
mean centered plots (MCPs) were used. The difference was
calculated between the average and individual fluorescence
spectra for each enantiomer. As a result, a negative MCP
spectrum was obtained for the lower intensity peak and a
positive MCP spectrum for the higher intensity peak. Thus,
MCP plots aid to easily differentiate between individual enan-
tiomers in the presence of PCILs (Fig. 7).
In the absence of PCILs, the difference in fluorescence in-
tensity between both enantiomers of the chiral analyte was
negligible (below 1%) in the control tests (Supporting Infor-
mation Fig. S24). The fluorescence of TFAE enantiomers
was measured in the presence of [Nor][HephTf2N],
[HEph][Tf2N], and [MeHEph][Tf2N] in aqueous solution.
The difference in fluorescence intensity was more pro-
nounced for [NorHeph][Tf2N] (Fig. 7). A similar trend was
observed for PROP (Supporting Information Fig. S22). In the
case of BNA and BNP, the difference in fluorescence inten-
sity was however more pronounced for [MeHEph][Tf2N].
Thus, [NorHeph] [Tf2N] appeared to be a better chiral selec-
tor for TFAE and PROP, whereas [MeHeph][Tf2N] exhibited
better chiral recognition for BNA and BNP. The fluorescence
and MCP spectra for TFAE in [NorHeph][Tf2N] and BNA in
[MeHeph][Tf2N] are shown in Figure 7. In addition to fluo-
rescent analytes, nonfluorescent analytes were also investi-
gated. Although the PCILs were intrinsically fluorescent,
their chiral recognition abilities as seen by their fluorescence
Intrinsic Fluorescence of PCILs
The absorption maxima for the ephedrinium PCILs were
found to occur at 257 nm, as illustrated for [MeHEph][Tf2N]
(Fig. 5). To determine the optimum intrinsic fluorescence,
an EEM scan was run for neat [MeHEph][Tf2N]. As seen in
Figure 5, a sharp fluorescence peak was recorded at around
292 nm for this PCIL. Measurements were performed in a
reduced-volume cuvette (0.4 ml) with front-face illumination to
minimize inner-filter effects. Because of the relatively high vis-
cosity of [NorHEph][Tf2N] and [HEph][Tf2N], fluorescence
measurements of the neat PCILs were limited to that of
[MeHEph][Tf2N]. To compare the PCILs as chiral selectors,
they were dissolved in water at concentrations of 30 mM. Sol-
ubility in water decreased in the order of [NorHEph][Tf2N],
[HEph][Tf2N], and [MeHEph][Tf2N], suggesting a decrease
in hydrogen-bonding ability for the PCILs.
Enantiomeric Recognition of Fluorescent and Nonfluorescent
Analytes by Use of Fluorescence Spectroscopy
Fluorescence spectroscopy was used to determine the chi-
ral recognition capability of the PCILs for fluorescent and
nonfluorescent analytes in aqueous solution. A series of ana-
lytes of pharmaceutical and biological significance were
investigated. The fluorescent analytes included PROP, BNA,
TFAE and BNP. The nonfluorescent analytes investigated
included serine and glucose (Fig. 6).
Enantiomers for each analyte were prepared at 10 lM con-
centrations in 30 mM of aqueous PCILs solutions containing
[Tf2N2] anions. To determine the wavelength-dependent flu-
Chirality DOI 10.1002/chir

60
DE ROOY ET AL.
Fig. 6. Fluorescent analytes (A) propranolol, (B) 1-(9-anthryl)-2,2,2-trifluoroethanol, (C) 1,10-binaphthyl-2,20-diamine, (D) 1,10-binaphthyl-2,20-diyl hydrogen
phosphate, and nonfluorescent analytes (E) glucose, (F) serine.
intensities were not significantly different from one another.
The fluorescence and MCP spectra for serine in
[MeHEph][Tf2N] are shown in Figure 8. In contrast to the
fluorescent analytes, there was no pronounced signal
observed above 350 nm for the nonfluorescent analytes.
The results obtained suggest that the chiral interactions
between the PCILs and chiral analytes in solution are
strongly affected by hydrogen bonding and hydrophobic
interactions between PCILs and chiral analytes similar to chi-
ral molecular micelles. The more polar analytes such as
Fig. 7. A. Fluorescence spectrum of 10 lM TFAE in aqueous solution with 30 mM [NorHEph][Tf2N] as chiral selector. B. Fluorescence spectrum of 10 lM
BNA in aqueous solution with 30 mM [MeHEph][Tf2N] as chiral selector.
Chirality DOI 10.1002/chir

EPHEDRINIUM-BASED PCILs FOR ENANTIOMERIC RECOGNITION
61
Fig. 8. Fluorescence spectrum of 10 lM serine in 30 mM aqueous solution with [NorHEph][Tf2N] as chiral selector.
LITERATURE CITED
TFAE and PROP may interact more favorably with [NorHEph]
[Tf2N] as a result of hydrogen bond-donating groups in the
PCIL and hydrogen-bond acceptors in the analytes (Supporting
Information Fig. S25). The less polar BNP interact more favor-
ably with [MeHEph][Tf2N], because both compounds have
lower hydrogen-bonding capabilities (Supporting Information
Fig. S26).
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