1-(1)-dehydroabietylimidazolium salts as enantiomer discriminators for NMR spectroscopy

Article abstract of DOI:10.1071/CH16545

Nine new (+)-dehydroabietylimidazolium salts were synthesised and studied as chiral solvating agents for several different racemic aromatic and non-aromatic carboxylate salts. These cationic chiral solvating agents resolve racemic ionic analytes better than non-ionic ones. Bis(dehydroabietylimidazolium) bis(trifluoromethanesulfonimide) gave the best discrimination for the enantiomers of carboxylate salts. Its resolution behaviour was studied by an NMR titration experiment, which indicated 1 : 1 complexation with the racemic analyte. The dehydroabietylimidazolium salts were also useful in enantiomeric excess (ee) determinations, and for the recognition of chirality of racemic aromatic and nonaromatic a-substituted carboxylic acids.

Full text of DOI:10.1071/CH16545

CSIRO PUBLISHING
Aust. J. Chem.
Full Paper
http://dx.doi.org/10.1071/CH16545
1-(1)-Dehydroabietylimidazolium Salts as Enantiomer
Discriminators for NMR Spectroscopy
A
B
A
H. Q. Nimal Gunaratne, Tiina Laaksonen, Kenneth R. Seddon, and
Kristiina Wahala
¨ ¨ ¨
B C D
, ,
A
QUILL Research Centre, School of Chemistry and Chemical Engineering, The Queen’s
University of Belfast, Belfast BT9 5AG, Northern Ireland, UK.
B
Department of Chemistry, University of Helsinki, A. I. Virtasen aukio 1, PO Box 55,
FI-00014 University of Helsinki, Finland.
C
Medicum, PO Box 21, FI-000140 University of Helsinki, Finland.
D
Corresponding author. Email: kristiina.wahala@helsinki.fi
Nine new (þ)-dehydroabietylimidazolium salts were synthesised and studied as chiral solvating agents for several
different racemic aromatic and non-aromatic carboxylate salts. These cationic chiral solvating agents resolve racemic
ionic analytes better than non-ionic ones. Bis(dehydroabietylimidazolium) bis(trifluoromethanesulfonimide) gave the
best discrimination for the enantiomers of carboxylate salts. Its resolution behaviour was studied by an NMR titration
experiment, which indicated 1 : 1 complexation with the racemic analyte. The dehydroabietylimidazolium salts were also
useful in enantiomeric excess (ee) determinations, and for the recognition of chirality of racemic aromatic and non-
aromatic a-substituted carboxylic acids.
Manuscript received: 27 September 2016.
Manuscript accepted: 3 February 2017.
Published online:
8 March 2017.
p–p stacking, and ion–ion interactions.[5] Aromatic moieties
in chiral solvating agents can enable p–p stacking but, more
importantly, they can also provide shielding, which increases
resolution.[4,6] Therefore, most of the chiral solvating agents
developed are aromatic and they can be used for both aromatic
and non-aromatic chiral compounds.[7] Electronegative
groups and hydrogen donor and acceptor groups are able to
provide the needed interaction to create a host–guest com-
plex.[4,5] Bulky substituents are also useful, as they can
obstruct complex formation for the other enantiomer, thus
increasing the chemical shift difference.[1] In the case of an
ionic chiral solvating agent, the counter ion will also have an
effect on the degree of resolution. Counter ions with a delo-
calised charge are often favoured as they have been observed
to increase resolution.[8]
Introduction
The determination of enantiomeric purity is an important aspect
of synthetic chemistry and various methods have been devel-
oped for this purpose. The two most commonly used analytical
techniques to determine the enantiomeric excess (ee) of
chiral compounds are the separation of enantiomers using chiral
HPLC, or their treatment with chiral derivatising agents or chiral
solvating agents, followed by NMR spectroscopic analysis.
Owing to the development of higher-field instruments, NMR
spectroscopy has become more sensitive,[1] and the ee may be
determined up to a 94–99 % level.[2] This allows reliable,
accurate, and expedient ee determinations,[3] required particu-
larly in pharmaceuticals development. Minimal sample prepa-
ration, ease of use, and fast analyses make NMR spectroscopy an
optimal tool for quick ee determinations.
The NMR spectra of enantiomers are indistinguishable as
their chemical environments are identical. To differentiate the
enantiomers, a diastereomeric environment is required. This can
be created by using chiral auxiliary compounds such as chiral
solvating agents, paramagnetic chiral shift reagents, chiral
liquid crystals, or chiral derivatising agents.[4,5] Chiral solvating
agents are most often employed owing to their ease of use. Both
neutral and ionic chiral solvating agents have been developed,
although the latter have gained less attention.[4,5]
The use of chiral solvating agents is based on the complex-
ation between the chiral solvating agent (host) and the two
enantiomers of the chiral substrate (guest), to generate two
diastereomeric ‘complexes’.[4,5] Complexation between a host
and guest depends on interactions such as hydrogen bonding,
Our aim was to develop and investigate new ionic chiral
solvating agents, as they have not been widely studied. The resin
derivative (þ)-dehydroabietylamine is known to have an enan-
tiomeric recognition ability towards chiral carboxylic acids[9]
but, apart from recent work from our group,[10,11] (þ)-
dehydroabietylamine has not been used as a chiral solvating
agent. As it is readily available, cheap, and derived from
renewable resources, has a bulky structure, and contains both
an aromatic moiety and an amino group that may also be
converted to the cationic form, it should provide an ideal starting
material for cationic chiral solvating agents. Although some
cationic chiral solvating agents have been reported, their reso-
lution ability has been scantily studied. In most cases, the
developed chiral solvating agents have only been tested with
Journal compilation ꢀ CSIRO 2017
www.publish.csiro.au/journals/ajc

B
H. Q. N. Gunaratne et al.
ꢀ
1. Br(CH2)2Br,
base
2. HC(OEt)3,
Xꢁ
H
H
[NH4][BF4]
H
N
N
NH2
HCHO,
OCHCHO,
NH4OH
HCHO, OCHCHO,
HCl
3a
3b
X ꢂ [BF4]
X ꢂ [NTf2]
Li[NTf2]
ꢀ
Xꢁ
H
2
3
N
H
1
N
H
4
5
N
N
1a
HNTf2
2a X ꢂ Cl
PhCH2Br
[NH4][BF4] or
Li[NTf2]
2b X ꢂ [BF4]
2c
X ꢂ [NTf2]
ꢀ
ꢀ
Xꢁ
ꢁ
H
[NHTf2]
H
N
N
NH
N
4a X ꢂ Br
[NH4][BF4] or
Li[NTf2]
1b
4b X ꢂ [BF4]
4c
X ꢂ [NTf2]
Scheme 1. Synthesis of (þ)-dehydroabietylimidazole (1a), and (þ)-dehydroabietylimidazolium (1b, 2, and 4) and
(þ)-dehydroabietylimidazolinium (3) salts.
one guest.[12] A lack of comparison with several compounds
hinders the establishment of the full potential of a developed
chiral solvating agent in enantiomeric resolutions. The resolution
ability of newly developed cationic chiral solvating agents has
been more extensively investigated in a few cases only,[10,13]
predominantly with racemic aromatic carboxylic acids.[10,12–14]
The favoured test compound has been Mosher’s acid (3,3,3-
trifluoro-2-methoxy-2-phenylpropanoic acid), used either as
such[14] or in its anionic[12] form.
Here, 10 different (þ)-dehydroabietylimidazolium or
(þ)-dehydroabietylimidazolinium chiral solvating agents were
prepared (Scheme 1). Their effectiveness as chiral discrimina-
tors was extensively investigated, along with the effect of the
anion on the resolution, the effect of the aromatic functionality,
and the question as to whether it is better for the guest to be
neutral or anionic. The enantiomeric resolution of neutral guests
by ionic chiral solvating agents has rarely been studied, and
when the guest is a carboxylic acid, it has usually been converted
to the anion.[10–13] Mosher’s acid was used as a test compound as
it enables detection by both 1H and 19F NMR spectroscopy. In
order to carry out a systematic study, the best-performing chiral
solvating agent was used in the resolution of seven different
carboxylate salts, to establish its applicability in resolving both
aromatic and non-aromatic racemic carboxylic acids.
Experimental
General
All reagents and solvents were obtained from commercial sup-
pliers (Sigma Aldrich) and were used without further purification
unless otherwise stated. (þ)-Dehydroabietylamine was purchased
as60% grade(SigmaAldrich) andpurifiedbyamethod described
in the literature[15] with slight modifications (see below). Flash
chromatography was performed on 40–63-mesh silica gel.
Microwave syntheses were performed using the CEM Focused
MicrowaveTM Synthesis System (Model Discover). Melting
points were determined on a digital melting point apparatus
(Bu¨chi B 545). Optical rotations were determined on a digital
polarimeter (Jasco DIP-1000) at 228C in trichloromethane as
solvent. The exact mass measurements were performed by high-
resolution mass spectrometry (HRMS) (Brucker MicroTOF LC)
with electrospray ionisation (ESI).
Compound Characterisation
NMR experiments were performed using Varian Unity Inova
500 and Varian Mercury Plus 300 instruments at 278C. 1H NMR
spectra were recorded with 4–16 transients, 4085–8000-Hz
spectral width, and 1.9-s acquisition time at 500 MHz.
13C NMR spectra were recorded with 576–1500 transients,

Enantiomer Discriminators for NMR Spectroscopy
C
20000–31446-Hz spectral width, and 1.8-s acquisition time at
125 or 75 MHz. 19F NMR spectra were recorded with 16–32
transients, 19047-Hz spectral width, 5.0-s relaxation delay, and
1.0-s acquisition time at 470 MHz. All 2D HSQC (heteronuclear
single-quantum correlation) spectra (see Supplementary Mate-
rial) were recorded using the Varian Unity Inova 500 instrument
with 4 transients, 128–300 increments, 8000–4085-Hz spectral
widths in the 1H-dimension, 22955–31446-Hz spectral widths in
the 13C-dimension, 1.0–2.0-s relaxation delays, and 0.128-s
acquisition time. TMS was used as the reference compound in
NMR measurements. The chemical shift scale of 19F was fixed
by applying absolute, indirect referencing by calculating the
frequency position for 0.0 ppm in the 19F chemical shift scale
from the 1H chemical shift scale. To differentiate the proton and
carbon signals of aromatic and imidazolium and 2-imidazolinium
structures, the subscript Ar (CHAr) is used for aromatic and im
(CHim) for imidazolium and 2-imidazolinium.
product was dried under vacuum, and recrystallised from a
diethyl ether/pentane mixture. Yield 2.5 g, 41.7 %; white solid;
mp 107.68C. [a]22 ꢀ25.9560 (c, 10.0 mg cmꢀ3, CHCl3). dH
D
(500 MHz, CDCl3) 1.00 (s, 3H, CH3), 1.21 (d, J 6.92, 6H,
2 ꢁ CH3), 1.23 (s, 3H, CH3), 1.28 (m, 1H, CHH), 1.33 (m, 1H,
CHH), 1.35 (m, 1H, CH), 1.38 (m, 1H, CHH), 1.70 (m, 2H,
CH2), 1.87 (m, 2H, CH2), 2.25 (dt, J ꢀ13.1, 3.5, 1H, CHH), 2.81
(sep., J 6.9, CH), 2.89 (m, 1H, CHH), 2.96 (ddd, J ꢀ16.9, 6.7,
2.4, 1H, CHH), 3.70 (d, J ꢀ14.0, 1H, CHH), 3.86 (d, J ꢀ14.0,
1H, CHH), 6.83 (t, J 1.1, 1H, CHim), 6.88 (d, J 2.1, 1H, CHAr),
6.97 (dd, J 8.3, 2.1, 1H, CHAr), 6.99 (t, J 1.1, 1H, CHim), 7.12 (d,
J 8.3, 1H, CHAr), 7.38 (t, J 1.1, 1H, CHim). dC (500 MHz, CDCl3)
18.59 (CH2), 18.77 (CH3), 19.40 (CH2), 24.07 (CH3), 24.09
(CH3), 25.69 (CH3), 29.94 (CH2), 33.56 (CH), 36.72 (CH2),
37.68 (C), 38.08 (C), 38.13 (CH2), 45.06 (CH), 58.45 (CH2),
121.12 (CHim), 124.12 (CHAr), 124.23 (CHAr), 126.97 (CHAr),
128.81 (CHim), 134.19 (CAr), 138.73 (CHim), 145.90 (CAr),
146.84 (CAr). m/z (HRMS-ESI) 337.2635; calcd for C23H33N2
[M þ H]þ 337.2638.
Preparations
Purification of (1)-Dehydroabietylamine
Synthesis of 1-(þ)-Dehydroabietylimidazolium
Bis{(trifluoromethyl)sulfonyl}amide) (1b)
Crude 60 % (þ)-dehydroabietylamine (42.0 g) was dissolved
in toluene (70.0 cm3) and ethanoic acid (9.65 g) in toluene
(30.0 cm3) was slowly added. The salt was left to crystallise in
the refrigerator. The product was collected by filtration and
washed with hexane (30.0 cm3). (þ)-Dehydroabietylamine
ethanoate was recrystallised from methanol. (þ)-Dehydroabie-
tylamine ethanoate (21.0 g) was dissolved in hot water and 10 %
aqueous NaOH solution (28.0 cm3) was added. (þ)-Dehydroa-
bietylamine was extracted with diethyl ether (50.0 cm3) and the
organic phase was washed with water until neutral, and then
dried over anhydrous sodium sulfate. The solvent was evaporat-
ed, and the resultant (þ)-dehydroabietylamine was dried under
vacuum to yield a white solid; yield 37.0 g, 88.2 %; mp 44.28C
Bistriflamidic acid (80 mg, 2.97 mM, 1.0 equiv.) was added
to compound 1a (0.10 g, 2.97 mmol, 1.0 equiv.) in dichloro-
methane (0.5 cm3) at 08C. After stirring the reaction mixture for
1 h at room temperature, water (3.0 cm3) was added, the two
layers separated, and the organic phase was washed with water
(3 ꢁ 2.0 cm3). The organic solvent was evaporated and the
product dried under vacuum. Yield 0.18 g, 96.8 %; amorphous
solid at room temperature. [a]22D ꢀ23.2360 (c, 10.0 mg cmꢀ3
,
CHCl3). dH (500 MHz, CDCl3) 1.05 (s, 3H, CH3), 1.21 (d, J 7.0,
6H, 2 ꢁ CH3), 1.24 (s, 3H, CH3), 1.25 (m, 1H, CHH), 1.29 (m,
1H, CH), 1.31 (m, 1H, CHH), 1.41 (dt, J ꢀ12.6, 2.9, 1H, CHH),
1.72 (m, 2H, CH2), 1.89 (m, 2H, CH2), 2.31 (dt, J ꢀ12.7, 3.2, 1H,
CHH), 2.82 (sep., J 7.0, CH), 2.87 (m, 1H, CHH), 3.01 (ddd, J
ꢀ17.8, 8.4, 2.2, 1H, CHH), 4.06 (d, J ꢀ14.3, 1H, CHH), 4.06 (d,
J ꢀ14.3, 1H, CHH), 6.90 (d, J 1.9, 1H, CHAr), 6.99 (dd, J 8.1,
1.9, 1H, CHAr), 7.13 (d, J 8.1, 1H, CHAr), 7.14 (t, J 1.5, 1H,
CHim), 7.33 (t, J 1.5, 1H, CHim), 8.40 (t, J 1.5, 1H, CHim). dC
(500 MHz, CDCl3) 18.22 (CH3), 18.31 (CH2), 19.32 (CH2),
24.03 (CH3), 24.08 (CH3), 25.57 (CH3), 29.69 (CH2), 33.57
(CH), 36.59 (CH2), 37.76 (C), 37.97 (CH2), 38.08 (C), 45.62
(CH), 60.92 (CH2), 119.82 (q, J 320.8, CF3), 120.67 (CHim),
123.28 (CHim), 124.14 (CHAr), 124.33 (CHAr), 127.10 (CHAr),
133.90 (CAr), 136.04 (CHim), 146.23 (CAr), 146.36 (CAr). m/z
(HRMS-ESI) 337.2630 calcd for [C23H33N2]þ [M]þ 337.2638;
279.9177, calcd for [C2F6NO4S2]ꢀ 279.9167.
(lit. 44–458C[16]). [a]22 þ44.3480 (c, 10.0 mg cmꢀ3, CHCl3).
D
dH (500 MHz, CDCl3) 0.89 (s, 3H, CH3), 1.22 (s, 3H, CH3), 1.22
(d, J 7.0, 6H, 2 ꢁ CH3), 1.33 (m, 2H, CH2), 1.39 (m, 1H, CHH),
1.52 (dd, J ꢀ11.8, 3.3, 1H, CH), 1.69 (m, 2H, CH2), 1.74 (m, 2H,
CH2), 2.30 (dt, J ꢀ13.1, 1.7, 1H, CHH), 2.40 (d, J ꢀ13.5, 1H,
CHH), 2.61 (d, J ꢀ13.5, 1H, CHH), 2.82 (sep., J 7.0, CH), 2.88
(m, 2H, CH2), 6.89 (d, J 1.9, 1H, CHAr), 7.00 (dd, J 8.1, 1.9, 1H,
CHAr), 7.18 (d, J 8.1, 1H, CHAr). dC (500 MHz, CDCl3) 18.78
(CH2), 18.90 (CH3), 18.90 (CH2), 24.11 (CH3), 24.13 (CH3),
25.37 (CH3), 30.31 (CH2), 33.58 (CH), 35.36 (CH2), 37.36 (C),
37.53 (C), 38.70 (CH2), 45.00 (CH), 53.99 (CH2), 123.96
(CHAr), 124.38 (CHAr), 126.94 (CHAr), 134.84 (CAr), 145.67
(CAr), 147.63 (CAr). m/z (HRMS-ESI) 286.2540; calcd for
C20H32N [M þ H]þ 286.2529.
Synthesis of 1-Dehydroabietylimidazole (1a)
Synthesis of 1,3-Bisdehydroabietylimidazolium
Chloride (2a)
(þ)-Dehydroabietylamine (5.0 g, 17.54 mmol, 1.0 equiv.)
was dissolved in 2-propanol (10.0 cm3) and 25 % aqueous
ammonium hydroxide solution (2.70 cm3, 17.54 mmol,
1.0 equiv.) was added. A mixture of a 40 % aqueous solution of
glyoxal (2.17 cm3, 18.94 mmol, 1.08 equiv.) and 35% aqueous
solution of methanal (1.49 cm3, 18.94 mmol, 1.08 equiv.) in
2-propanol (20.0 cm3) was added dropwise to the reaction
mixture, which was kept at 808C for 4 h and left to stir at room
temperature overnight. Water (20.0 cm3) was added to the
reaction mixture, which was then extracted with diethyl ether
(40.0 cm3). The organic phase was washed with water until
neutral and dried over anhydrous magnesium sulfate. The
organic phase was filtered and the solvent evaporated; the crude
Formaldehyde (35 % aqueous solution; 0.14 cm3, 1.75 mmol,
1.0 equiv.) was added dropwise to (þ)-dehydroabietylamine
(1.0 g, 3.51 mmol, 2.0 equiv.) in toluene (10.0 cm3) at 08C and
the reaction mixture was allowed to warm to room temperature.
A mixture of aqueous hydrochloric acid (35 %, 0.16 cm3,
1.75 mmol, 1.0 equiv.) and 40 % glyoxal (0.20 cm3, 1.75 mmol,
1.0 equiv.) was added dropwise to the reaction mixture at 08C,
which was allowed warm to room temperature, and then heated
for 24 h at 808C. The solvent was removed by evaporation and
the crude product dried under vacuum, purified by column
chromatography (1 : 9 methanol/CH2Cl2), and crystallised from
a CH2Cl2/EtO2CMe mixture. Yield 0.73 g, 64.5 %; white solid;

D
H. Q. N. Gunaratne et al.
mp 220.58C. [a]20 ꢀ66.4120 (c, 10.0 mg cmꢀ3, CHCl3). dH
66.8 %; white solid; mp 210.48C. [a]22D ꢀ45.1400 (c, 10.0 mg
cmꢀ3, CHCl3). dH (500 MHz, CDCl3) 0.97 (s, 6H, 2 ꢁ CH3),
1.20 (s, 6H, 2 ꢁ CH3), 1.21 (m, 2H, 2 ꢁ CHH), 1.22 (d, J 6.9,
12H, 4 ꢁ CH3), 1.30 (m, 2H, 2 ꢁ CH), 1.31 (m, 2H, 2 ꢁ CHH)
1.50 (dt, J ꢀ13.1, 2H, 2 ꢁ CHH), 1.63 (m, 4H, 2 ꢁ CH2), 1.76
(m, 2H, 2 ꢁ CHH), 1.84 (m, 2H, 2 ꢁ CHH), 2.28 (dt, J ꢀ13.5,
3.3, 2H, 2 ꢁ CHH), 2.79 (m, 2H, 2 ꢁ CHH), 2.82 (sep., J 6.9, 2H,
2 ꢁ CH), 2.97 (m, 2H, 2 ꢁ CHH), 3.40 (d, J ꢀ14.8, 2H, 2 ꢁ
CHH), 3.44 (d, J ꢀ14.8, 2H, 2 ꢁ CHH), 4.03 (m, 4H, 2 ꢁ CH2),
6.88 (d, J 2.0, 2H, 2 ꢁ CHAr), 6.98 (dd, J 8.2, 2.0, 2H, 2 ꢁ CHAr),
7.12 (d, J 8.2, 2H, 2 ꢁ CHAr), 7.91 (m, 1H, CH). dC (500 MHz,
CDCl3) 18.26 (2 ꢁ CH2), 18.45 (2 ꢁ CH3), 18.67 (2 ꢁ CH2),
23.81 (2 ꢁ CH3), 23.87 (2 ꢁ CH3), 25.28 (2 ꢁ CH3), 29.54 (2 ꢁ
CH2), 33.32 (2 ꢁ CH), 36.65 (2 ꢁ CH2), 37.40 (2 ꢁ C), 37.91
(2 ꢁ CH2), 38.21 (2 ꢁ C), 45.29 (2 ꢁ CH), 52.54 (2 ꢁ CH2),
59.55 (2 ꢁ CH2), 123.92 (2 ꢁ CHAr), 123.98 (2 ꢁ CHAr),
126.78 (2 ꢁ CHAr), 133.78 (CAr), 145.80 (2 ꢁ CAr), 146.45
(2 ꢁ CAr), 161.75 (CH). m/z (HRMS-ESI) 607.4995; calcd for
[C43H63N2]þ [M]þ 607.4986.
D
(500 MHz, CDCl3) 1.03 (s, 6H, 2 ꢁ CH3), 1.11 (m, 2H, 2 ꢁ
CHH), 1.15 (m, 2H, 2 ꢁ CHH), 1.19 (s, 6H, 2 ꢁ CH3), 1.21 (d, J
6.9, 12H, 4 ꢁ CH3), 1.24 (m, 2H, 2 ꢁ CH), 1.43 (dt, J ꢀ12.7, 2.8,
2H, 2 ꢁ CHH), 1.53 (m, 2H, 2 ꢁ CHH), 1.62 (m, 2H, 2 ꢁ CHH),
1.88 (m, 2H, 2 ꢁ CHH), 2.05 (m, 2H, 2 ꢁ CHH), 2.19 (dt,
J ꢀ13.0, 3.2, 2H, 2 ꢁ CHH), 2.81 (sep., J 6.9, 2H, 2 ꢁ CH),
2.89 (m, 2H, 2 ꢁ CHH), 2.99 (dd, J ꢀ17.4, 6.7, 2H, 2 ꢁ CHH),
4.13 (d, J ꢀ14.0, 2H, 2 ꢁ CHH), 4.37 (d, J ꢀ14.0, 2H, 2 ꢁ CHH),
6.89 (d, J 1.9, 2H, 2 ꢁ CHAr), 6.96 (dd, J 8.2, 1.9, 2H, 2 ꢁ CHAr),
7.07 (d, J 8.2, 2H, 2 ꢁ CHAr), 7.11 (s, 2H, 2 ꢁ CHim), 10.78 (s,
1H, CHim). dC (500MHz, CDCl3) 18.22 (2ꢁ CH3), 18.42 (2ꢁ
CH2), 19.22 (2ꢁ CH2), 24.04 (2ꢁ CH3), 24.08 (2ꢁ CH3), 25.50
(2ꢁ CH3), 29.72 (2ꢁ CH2), 33.53 (2ꢁ CH), 36.61 (2ꢁ CH2),
37.65 (2ꢁ C), 37.97 (2ꢁ CH2), 38.19 (2ꢁ C), 45.43 (2 ꢁ CH),
60.50 (2ꢁ CH2), 122.75 (2ꢁ CHim), 124.03 (2 ꢁ CHAr), 124.09
(2ꢁ CHAr), 126.98 (2ꢁ CHAr), 134.09 (2ꢁ CAr), 140.99 (CHim),
146.00 (2ꢁ CAr), 146.51 (2ꢁ CAr). m/z (HRMS-ESI) 605.4824;
calcd for [C43H61N2]þ [M]þ 605.4829.
Synthesis of N,N0-Bisdehydroabietyl-1,2-diaminoethane
Synthesis of 3-Benzyl-1-dehydroabietylimidazolium
Bromide (4a)
(þ)-Dehydroabietylamine (1.0 g, 3.51 mmol, 2.0 equiv.),
1,2-dibromoethane (0.15 cm3, 1.75 mmol, 1.0 equiv.), and
Na2CO3 (0.18 g, 1.75 mmol, 1.0 equiv.) were added to a micro-
wave tube with 2-propanol. The reaction mixture was microwave-
irradiated (110 W at 1108C) for 2 h. The solvent was
evaporated and the solid triturated with diethyl ether, collected
by filtration, and then mixed with diethyl ether (20.0cm3) and
aqueous sodium hydroxide (2.0 M, 10.0 cm3). The organic phase
was washed with water until neutral and dried over anhydrous
sodium sulfate. The organic phase was filtered and the solvent
evaporated. The solid product was dried under vacuum and
purified by flash chromatography (1: 9 MeOH/CH2Cl2). Yield
(þ)-Dehydroabietylimidazole (0.3 g, 0.891 mmol, 1.0
equiv.), benzyl bromide (0.168 g, 0.117 cm3, 0.981 mmol, 1.1
equiv.), and CHCl3 (0.3 cm3) were added to a microwave tube.
The reaction mixture was irradiated (110 W at 1108C) for 1 h.
The product was quenched with diethyl ether, filtered, and dried
under vacuum. Yield 0.42 g, 93.7 %; white solid; mp 152.98C.
[a]22 ꢀ27.0920 (c, 10.0 mg cmꢀ3, CHCl3). dH (500 MHz,
D
CDCl3) 1.07 (s, 3H, CH3), 1.22 (d, J 6.9, 6H, 2 ꢁ CH3), 1.22
(s, 3H, CH3), 1.23 (m, 1H, CH), 1.28 (m, 1H, CHH), 1.30 (m, 1H,
CHH), 1.48 (m, 1H, CHH), 1.71 (m, 2H, CH2), 1.89 (m, 1H,
CHH), 2.27 (dt, J ꢀ13.0, 1H, CHH), 2.62 (dd, J ꢀ13.5, 7.6, 1H,
CHH), 2.82 (sep., J 6.9, CH), 2.82 (m, 1H, CHH), 3.01 (dt,
J ꢀ17.6, 6.3, 1H, CHH), 4.16 (d, J ꢀ14.1, 1H, CHH), 4.26 (d,
J ꢀ14.1, 1H, CHH), 5.60 (s, 2H, CH2), 6.89 (d, J 1.2, 1H, CHAr),
6.98 (dd, J 8.2, 1.2, 1H, CHAr), 7.11 (d, J 8.2, 1H, CHAr), 7.15
(m, 1H, CHim), 7.21 (m, 1H, CHim), 7.34 (m, 3H, 3 ꢁ CHAr),
7.46 (m, 2H, 2 ꢁ CHAr), 10.75 (m, 1H, CHim). dC (500 MHz,
CDCl3) 18.32 (CH2), 18.46 (CH3), 19.31 (CH2), 24.05 (CH3),
24.09 (CH3), 25.56 (CH3), 29.84 (CH2), 33.55 (CH), 36.60
(CH2), 37.75 (C), 37.98 (CH2), 38.14 (C), 45.49 (CH), 53.50
(CH2), 60.86 (CH2), 121.09 (CHim), 123.74 (CHim), 124.07
(CHAr), 124.21 (CHAr), 127.12 (CHAr), 129.15 (CHAr), 129.58
(CHAr), 129.64 (CHAr), 132.99 (CAr), 134.11 (CAr), 138.78
(CHim), 146.09 (CAr), 146.47 (CAr). m/z (HRMS-ESI)
427.3118; calcd for [C30H39N2]þ [M]þ 427.3108.
0.78g, 74.3%; white solid; mp 63.88C. [a]22 þ43.3160
D
(c, 10.0mgcmꢀ3, CHCl3). dH (500 MHz, CDCl3) 0.91 (s, 6H,
2 ꢁ CH3), 1.20 (s, 6H, 2 ꢁ CH3), 1.23 (d, J 7.0, 12H, 4 ꢁ CH3),
1.37(m, 2H, 2 ꢁ CHH), 1.38(m, 4H, 2 ꢁ CH2), 1.57(dd,J ꢀ12.3,
2.7, 2H, 2 ꢁ CH), 1.60 (m, 4H, 2 ꢁ CH2), 1.71 (m, 2H, 2 ꢁ CHH),
1.75 (m, 2H, 2 ꢁ CHH), 2.23 (dt, J ꢀ12.8, 3.3, 2H, 2 ꢁ CHH),
2.32 (d, J ꢀ11.8, 2H, 2 ꢁ CHH), 2.51 (d, J ꢀ11.8, 2H, 2 ꢁ CHH),
2.70 (s, 4H, 2 ꢁ CH2), 2.82 (sep., J 7.0, 2H, 2 ꢁ CH), 2.88 (m, 4H,
2 ꢁ CH2), 6.87 (d, J 1.7, 2H, 2 ꢁ CHAr), 6.98 (dd, J 8.1, 1.6, 2H,
2 ꢁ CHAr), 7.16 (d, J 8.1, 2H, 2 ꢁ CHAr). dC (500 MHz, CDCl3)
18.98 (4ꢁ CH2), 19.35 (2ꢁ CH3), 24.14 (4ꢁ CH3), 25.47 (2ꢁ
CH3), 30.46 (2ꢁ CH2), 33.58 (2ꢁ CH), 36.39 (2 ꢁ CH2), 37.18
(2ꢁ C), 37.55 (2ꢁ C), 38.58 (2 ꢁ CH2), 45.62 (2ꢁ CH), 50.02
(2ꢁ CH2), 61.61 (2ꢁ CH2), 123.91 (2ꢁ CHAr), 124.41 (2ꢁ
CHAr), 126.89 (2 ꢁ CHAr), 134.88 (CAr), 145.54 (2 ꢁ CAr),
147.64 (2ꢁ CAr). m/z (HRMS-ESI) 597.5132; calcd for
C42H65N2 [M þ H]þ 597.5142.
Synthesis of Guests
N-Acetylation of phenylalanine was performed according to the
literature procedure.[17] Preparation of tetrabutylammonium
salts of acids was performed by adding tetrabutylammonium
hydroxide (1.0 M in methanol, 1.0 equiv.) to the racemic acid
(1.0 equiv.) in methanol. After stirring for 3 h, the solvent was
removed by evaporation and the product was dried under
vacuum.
Synthesis of 1,3-Bisdehydroabietyl-2-
dihydroimidazolinium Tetrafluoroborate (3a)
A microwave tube was loaded with N,N0-bisdehydroabietyl-1,
2-diaminoethane (0.5 g, 0.84 mmol, 1.0 equiv.), triethylortho-
formate (0.14 cm3, 0.84 mmol, 1.0 equiv.), ammonium tetra-
fluoroborate (88 mg, 0.84 mmol, 1.0 equiv.), and 2-propanol
(1.0 cm3). The reaction mixture was irradiated (140 W at 1108C)
for 40 min. The solvent was removed by evaporation and diethyl
ether (5.0 cm3) was added. The mixture was then filtered and the
resultant solid dried under reduced pressure followed by recrys-
tallisation from a methanol/ethanenitrile mixture. Yield 0.41 g,
General Procedure for Anion Exchange
Anion-exchange reactions were performed according to litera-
ture procedures.[14a] Li[NTf2] (NTf2 ¼ bis(trifluoromethane)
sulfonamide) or ammonium tetrafluoroborate solution (1.0 M,
1.0 equiv.) was added to the chiral solvating agent (1.0 equiv. in

Enantiomer Discriminators for NMR Spectroscopy
E
dichloromethane) at room temperature and the mixture stirred
for 1 h. The phases were separated by gravity and the organic
phase was washed with water (3 ꢁ 10 cm3). The organic phase
was concentrated and dried under vacuum.
CHH), 2.29 (dt, J ꢀ13.2, 3.2, 2H, 2 ꢁ CHH), 2.78 (m, 2H,
2 ꢁ CHH), 2.82 (sep., J 6.9, 2H, 2 ꢁ CH), 2.99 (dd, J ꢀ17.1, 7.0,
2H, 2 ꢁ CHH), 3.35 (d, J ꢀ14.8, 2H, 2 ꢁ CHH), 3.44 (d,
J ꢀ14.8, 2H, 2 ꢁ CHH), 4.03 (m, 4H, 2 ꢁ CH2), 6.89 (d, J 1.7,
2H, 2 ꢁ CHAr), 6.99 (dd, J 8.3, 1.7, 2H, 2 ꢁ CHAr), 7.12 (d, J 8.3,
2H, 2 ꢁ CHAr), 7.75 (m, 1H, CH). dC (500 MHz, CDCl3) 18.43
(2 ꢁ CH2), 18.65 (2 ꢁ CH3), 18.96 (2 ꢁ CH2), 24.06 (2 ꢁ CH3),
24.12 (2 ꢁ CH3), 25.51 (2 ꢁ CH3), 29.70 (2 ꢁ CH2), 33.58 (2 ꢁ
CH), 37.05 (2 ꢁ CH2), 37.65 (2 ꢁ C), 38.14 (2 ꢁ CH2), 38.56
(2 ꢁ C), 45.54 (2 ꢁ CH), 52.78 (2 ꢁ CH2), 59.89 (2 ꢁ CH2),
119.96 (q, J 320.6, CF3), 124.16 (2 ꢁ CHAr), 124.31 (2 ꢁ CHAr),
127.03 (2 ꢁ CHAr), 133.87 (CAr), 146.16 (2 ꢁ CAr), 146.56
(2 ꢁ CAr), 161.37 (CH). m/z (HRMS-ESI) 607.4967; calcd for
[C43H63N2]þ [M]þ 607.4986; 279.9157; calcd for
[C2F6NO4S2]ꢀ 279.9167.
1,3-Bisdehydroabietylimidazolium
Tetrafluoroborate (2b)
Yield 0.21 g, 94.2 %; white solid; mp 186.98C (recrystal-
lised from CH2Cl2/EtOCOMe). [a]20 ꢀ67.5760 (c, 10.0 mg
D
cmꢀ3, CHCl3). dH (500 MHz, CDCl3) 0.99 (s, 6H, 2 ꢁ CH3),
1.03 (m, 2H, 2 ꢁ CHH), 1.10 (m, 2H, 2 ꢁ CHH), 1.14 (m, 2H,
2 ꢁ CH), 1.18 (s, 6H, 2 ꢁ CH3), 1.21 (d, J 7.0, 12H, 4 ꢁ CH3),
1.35 (dt, J ꢀ12.6, 3.2, 2H, 2 ꢁ CHH), 1.46 (m, 2H, 2 ꢁ CHH),
1.60 (d, J ꢀ13.6, 3.2, 2H, 2 ꢁ CHH), 1.84 (m, 2H, 2 ꢁ CHH),
1.98 (m, 2H, 2 ꢁ CHH), 2.14 (dt, J ꢀ13.1, 3.6, 2H, 2 ꢁ CHH),
2.82 (sep., J 7.0, 2H, 2 ꢁ CH), 2.86 (m, 2H, 2 ꢁ CHH), 2.98
(dd, J ꢀ17.5, 6.7, 2H, 2 ꢁ CHH), 4.09 (d, J ꢀ13.2, 2H,
2 ꢁ CHH), 4.16 (d, J ꢀ13.2, 2H, 2 ꢁ CHH), 6.90 (d, J 1.9,
2H, 2 ꢁ CHAr), 6.97 (dd, J 8.2, 1.9, 2H, 2 ꢁ CHAr), 7.06 (d, J
8.2, 2H, 2 ꢁ CHAr), 7.10 (d, J 1.6, 2H, 2 ꢁ CHim), 9.20 (s, 1H,
CHim). dC (500 MHz, CDCl3) 18.21 (2 ꢁ CH3), 18.35 (2 ꢁ
CH2), 18.99 (2 ꢁ CH2), 24.06 (2 ꢁ CH3), 24.09 (2 ꢁ CH3),
25.51 (2 ꢁ CH3), 29.64 (2 ꢁ CH2), 33.54 (2 ꢁ CH), 36.38 (2 ꢁ
CH2), 37.61 (2 ꢁ C), 37.95 (2 ꢁ CH2), 38.06 (2 ꢁ C), 45.29
(2 ꢁ CH), 60.27 (2 ꢁ CH2), 123.12 (2 ꢁ CHim), 124.06 (4 ꢁ
CHAr), 126.96 (2 ꢁ CHAr), 134.10 (2 ꢁ CAr), 139.70 (CHim),
145.95 (2 ꢁ CAr), 146.53 (2 ꢁ CAr). m/z (HRMS-ESI)
605.4837; calcd for [C43H61N2]þ [M]þ 605.4829.
3-Benzyl-1-dehydroabietylimidazolium
Tetrafluoroborate (4b)
Yield 0.099 g, 97.5 %; white solid; mp 113.48C. [a]22
D
ꢀ29.9880 (c, 10.0 mg cmꢀ3, CHCl3). dH (500 MHz, CDCl3)
1.01 (s, 3H, CH3), 1.19 (m, 1H, CH), 1.20 (s, 3H, CH3), 1.22 (d,
J 6.8, 6H, 2 ꢁ CH3), 1.23 (m, 1H, CHH), 1.28 (m, 1H, CHH),
1.40 (dt, J ꢀ12.5, 1H, CHH), 1.68 (m, 2H, CH2), 1.87 (m, 2H,
CH2), 2.26 (dt, J ꢀ13.4, 1H, CHH), 2.74 (m, 1H, CHH), 2.82
(sep., J 6.8, 1H, CH), 2.96 (dd, J ꢀ13.5, 6.1, 1H, CHH), 4.04 (d,
J ꢀ14.3, 1H, CHH), 4.11 (d, J ꢀ14.3, 1H, CHH), 5.36 (s, 2H,
CH2), 6.88 (d, J 1.8, 1H, CHAr), 6.98 (dd, J 8.1, 1.8, 1H, CHAr),
7.11 (d, J 8.1, 1H, CHAr), 7.15 (m, 1H, CHim), 7.18 (m, 1H,
CHim), 7.33 (m, 3H, 3 ꢁ CHAr), 7.38 (m, 2H, 2 ꢁ CHAr), 9.07
(m, 1H, CHim). dC (500 MHz, CDCl3) 18.17 (CH3), 18.34
(CH2), 19.12 (CH2), 24.08 (CH3), 24.12 (CH3), 25.57 (CH3),
29.75 (CH2), 33.58 (CH), 36.38 (CH2), 37.74 (C), 37.97 (C),
38.00 (CH2), 45.62 (CH), 53.60 (CH2), 61.00 (CH2), 121.50
(CHim), 124.11 (CHim), 124.22 (CHAr), 124.26 (CHAr), 127.12
(CHAr), 129.08 (CHAr), 129.63 (CHAr), 129.66 (CHAr), 132.92
(CAr), 134.11 (CAr), 137.43 (CHim), 146.07 (CAr), 146.52
(CAr). m/z (HRMS-ESI) 427.3118; calcd for [C30H39N2]þ
[M]þ 427.3108.
1,3-Bisdehydroabietylimidazolium Bis{(trifluoromethyl)
sulfonyl}amide (2c)
Yield 0.25 g, 92.6 %; white solid; mp 199.08C (recrystal-
lised from CH2Cl2/pentane). [a]22 ꢀ31.8200 (c, 10.0 mg
D
cmꢀ3, CHCl3). dH (500 MHz, CDCl3) 0.99 (s, 6H, 2 ꢁ CH3),
1.04 (m, 2H, 2 ꢁ CHH), 1.05 (m, 2H, 2 ꢁ CHH), 1.16 (m, 2H,
2 ꢁ CH), 1.19 (s, 6H, 2 ꢁ CH3), 1.21 (d, J 6.9, 12H, 4 ꢁ CH3),
1.36 (dt, J ꢀ12.3, 2H, 2 ꢁ CHH), 1.49 (m, 2H, 2 ꢁ CHH), 1.63
(m, 2H, 2 ꢁ CHH), 1.90 (m, 4H, 2 ꢁ CH2), 2.17 (dt, J ꢀ12.8,
2.3, 2H, 2 ꢁ CHH), 2.82 (sep., J 6.9, 2H, 2 ꢁ CH), 2.84 (m, 2H,
2 ꢁ CHH), 3.01 (ddd, J ꢀ17.3, 6.0, 1.7, 2H, 2 ꢁ CHH), 4.09 (d,
J ꢀ13.9, 2H, 2 ꢁ C,HH), 4.16 (d, J ꢀ13.9, 2H, 2 ꢁ CHH), 6.89
(d, J 1.8, 2H, 2 ꢁ CHAr), 6.97 (dd, J 8.1, 1.8, 2H, 2 ꢁ CHAr),
7.06 (d, J 8.1, 2H, 2 ꢁ CHAr), 7.10 (s, 2H, 2 ꢁ CHim), 8.62 (s,
1H, CHim). dC (500 MHz, CDCl3) 17.92 (2 ꢁ CH2), 18.11
(2 ꢁ CH3), 18.81 (2 ꢁ CH2), 23.83 (2 ꢁ CH3), 23.86 (2 ꢁ CH3),
25.26 (2 ꢁ CH3), 29.32 (2 ꢁ CH2), 33.33 (2 ꢁ CH), 36.30 (2 ꢁ
CH2), 37.41 (2 ꢁ C), 37.69 (2 ꢁ CH2), 37.94 (2 ꢁ C), 44.98
(2 ꢁ CH), 60.45 (2 ꢁ CH2), 119.95 (q, J 321.0, CF3), 123.22
(2 ꢁ CHim), 123.86 (2 ꢁ CHAr), 123.97 (2 ꢁ CHAr), 126.76
(2 ꢁ CHAr), 133.59 (2 ꢁ CAr), 138.00 (CHim), 145.92 (2 ꢁ
CAr), 146.10 (2 ꢁ CAr). m/z (HRMS-ESI) 605.4814; calcd for
[C43H61N2]þ [M]þ 605.4829; 279.9160; calcd for
[C2F6NO4S2]ꢀ 279.9167.
3-Benzyl-1-dehydroabietylimidazolium
Bis{(trifluoromethyl)sulfonyl}amide (4c)
Yield 0.13, g 92.7 %; amorphous solid at room temperature.
[a]22 ꢀ25.3600 (c, 10.0 mg cmꢀ3, CHCl3). dH (500 MHz,
D
CDCl3) 1.02 (s, 3H, CH3), 1.18 (m, 1H, CHH), 1.19 (m, 1H,
CH), 1.22 (d, J 6.9, 6H, 2 ꢁ CH3), 1.22 (s, 3H, CH3), 1.29 (m,
1H, CHH), 1.41 (m, 1H, CHH), 1.71 (m, 2H, CH2), 1.87 (m, 2H,
CH2), 2.29 (dt, J ꢀ12.4, 1H, CHH), 2.73 (m, 1H, CHH), 2.82
(sep., J 6.9, 1H, CH), 2.96 (dt, J 17.1, 3.7, 1H, CHH), 4.06 (d,
J ꢀ14.1, 1H, CHH), 4.10 (d, J ꢀ14.1, 1H, CHH), 5.34 (s, 2H,
CH2), 6.88 (d, J 1.6, 1H, CHAr), 6.99 (dd, J 8.3, 1.6, 1H, CHAr),
7.12 (d, J 8.3, 1H, CHAr), 7.14 (m, 2H, 2 ꢁ CHim), 7.24 (m, 1H,
CHAr), 7.32 (m, 2H, 2 ꢁ CHAr), 7.37 (m, 2H, 2 ꢁ CHAr), 8.80
(m, 1H, CHim). dC (300 MHz, CDCl3) 18.21 (CH3), 18.30 (CH2),
19.14 (CH2), 24.06 (CH3), 24.10 (CH3), 25.58 (CH3), 29.68
(CH2), 33.58 (CH), 36.52 (CH2), 37.77 (C), 37.99 (C), 38.07
(CH2), 45.46 (CH), 53.92 (CH2), 61.12 (CH2), 119.96 (q, J
320.6, CF3), 121.45 (CHim), 124.11 (CHim), 124.22 (CHAr),
124.31 (CHAr), 127.14 (CHAr), 129.00 (CHAr), 129.82 (CHAr),
129.99 (CHAr), 132.16 (CAr), 133.93 (CAr), 137.16 (CHim),
146.22 (CAr), 146.38 (CAr). m/z (HRMS-ESI) 427.3122; calcd
for [C30H39N2]þ [M]þ 427.3108; 279.9167; calcd for
[C2F6NO4S2]ꢀ 279.9167.
1,3-Bisdehydroabietyl-2-dihydroimidazolinium Bis
{(trifluoromethyl)sulfonyl}amide (3b)
Yield 0.45 g, 82.7 %; white solid; mp 88.88C. [a]22
D
ꢀ31.8520 (c, 10.0 mg cmꢀ3, CHCl3). dH (500 MHz, CDCl3)
0.978 (s, 6H, 2 ꢁ CH3), 1.17 (m, 2H, 2 ꢁ CHH), 1.21 (s, 6H,
2 ꢁ CH3), 1.22 (d, J 6.9, 12H, 4 ꢁ CH3), 1.29 (m, 2H, 2 ꢁ CHH),
1.30 (m, 2H, 2 ꢁ CH), 1.47 (dt, J ꢀ12.3, 3.0, 2H, 2 ꢁ CHH), 1.62
(m, 4H, 2 ꢁ CH2), 1.75 (m, 2H, 2 ꢁ CHH), 1.84 (m, 2H, 2 ꢁ

F
H. Q. N. Gunaratne et al.
Results and Discussion
Table 1. The 1H and 19F NMR chemical shift differences (Dd) between
the R and S enantiomers of racemic Mosher’s acid 5 and its tetrabuty-
lammonium salt 6 in the presence of various (1)-dehydroabietylimida-
zole chiral solvating agents (500 MHz) in CDCl3 at 278C
The syntheses of (þ)-1-dehydroabietylimidazole (1a) and the
nine derived imidazolium salts 1b–4c were performed as shown
in Scheme 1. To obtain 1a, (þ)-dehydroabietylamine was
treated with aqueous NH3, glyoxal, and aqueous formaldehyde
in 2-propanol at 808C (41 %). The salt 1b was formed (96 %)
from 1a by reaction with HNTf2 in CH2Cl2 at 08C. Compound
2a was obtained from (þ)-dehydroabietylamine, glyoxal,
aqueous formaldehyde, and aqueous hydrochloric acid (64 %)
in toluene. 3a was prepared via N,N0-bisdehydroabietyl-1,
ꢁ
H3CO
CF3
H3CO
CF3
OH
O
ꢀ
[N4444
]
O
O
5
6
Host : guest
5: Dd/ppm; (Hz)
1H (OCH3) 19F (CF3)
6: Dd/ppm; (Hz)
1H (OCH3) 19F (CF3)
2-diaminoethane, in
a
one-pot reaction from (þ)-
dehydroabietylamine, 1,2-dibromoethane, and Na2CO3 in
2-propanol with microwave heating (74 %), followed by the
addition of CH(OEt)3 and [NH4][BF4] in 2-propanol (66 %). For
improved shielding ability, 1a was quaternised with benzyl
bromide under microwave irradiation to give 4a. It is known that
more delocalised and bulky anions generally enhance binding
between the cationic chiral solvating agent and (ionic or
molecular) chiral substrate owing to weaker binding between
the cation and anion of the chiral solvating agent.[8] To tune the
binding properties of 2a, 3a, and 4a, anion exchange was per-
formed with [NH4][BF4] and Li[NTf2] to obtain 2b–c, 3b, and
4b–c in high yield. The delocalisation and increased size of the
anion also affect the physical properties of the ionic chiral sol-
vating agents.[8] For instance, the melting points of 4a, 4b, and
4c decrease as the bulkiness and delocalisation of anion increase
(mp of Br . [BF4] . [NTf2]).
1a
1b
2a
2b
2c
3a
3b
4a
4b
4c
1 : 1
2 : 1
1 : 1
2 : 1
1 : 1
2 : 1
1 : 1
2 : 1
1 : 1
2 : 1
1 : 1
2 : 1
1 : 1
2 : 1
1 : 1
2 : 1
1 : 1
2 : 1
1 : 1
2 : 1
0.0092 (4.6) 0.031 (14.8) 0.000
0.011 (5.7) 0.041 (19.3) 0.000
0.000
0.000
0.002 (0.99) 0.000
0.000 0.000
0.0044 (2.2) 0.024 (11.4)
0.0042 (2.1) 0.026 (12.2)
0.0056 (2.8) 0.000
0.0091 (4.5) 0.000
0.0071 (3.5) 0.000
0.0099 (5.0) 0.000
0.002 (1.0) 0.000
0.000
0.000
0.000
0.000
0.074 (35.0)
0.080 (37.7)
0.092 (43.5)
0.102 (47.9)
0.0029 (1.5) 0.110 (49.8)
0.0061 (3.0) 0.110 (49.9)
0.000
0.000
0.000
0.000
0.007 (3.3) 0.000
0.015 (7.0) 0.000
0.060 (28.1)
0.077 (36.4)
0.065 (30.6)
0.074 (34.7)
0.028 (13.4)
0.033 (15.7)
0.034 (15.7)
0.036 (17.0)
0.034 (15.8)
0.032 (15.3)
0.0019 (1.0) 0.000
0.000
0.000
0.000
0.000
0.000
0.000
0.000
0.000
0.000
0.000
0.000
0.000
0.000
0.000
0.000
0.000
0.000
0.000
The chiral discrimination of racemic carboxylic acids and
their respective carboxylate anions by (þ)-1-dehydroabietyli-
midazole (1a) and its imidazolium salt derivatives (1b–4c) was
examined with Mosher’s acid (5; F3CC(OCH3)(Ph)COOH) and
its tetrabutylammonium ([N4444]þ) salt (6). The effect of the
concentration of the chiral solvating agent was also investigated,
because it is known that higher concentrations generally
enhance the enantiomeric resolution between R and S enantio-
mers (Dd).[4,5] As polar solvents can dissolve salts, and protic
solvents may interfere in hydrogen-bond formation,[13a] CDCl3
was chosen as a solvent for the NMR studies, performed by
dissolving the chiral solvating agent (1.0 or 2.0 equiv.) in a stock
solution containing 5 or 6 (0.5 cm3; 1.0 equiv., 22.0 mM).
According to the results obtained from the NMR experiments
(Table 1 and Fig. 1), the chiral solvating agents 1b–4c resolved
the enantiomers of 6 very efficiently (Dd 11.4–49.9 Hz). The
best results were obtained with 2c (0.11 ppm, 49.8 Hz). Also, the
enantiomers of 5 were resolved, butwitha Dd less than that with 6.
Only 1a gave notably better discrimination for 5 (19.3 Hz)
compared with 1b–4c (0.88–7.0 Hz). This indicates that resolu-
tion using 1b–4c is highly dependent on the ionic nature of the
guest and vice versa in the case of 5. Although ionic hosts
(1b–3b and 4c) were able to discriminate 5, the neutral 1a failed
to discriminate 6, making the ionic chiral solvating agents more
versatile than a neutral one as the former also discriminate
0.0017 (0.8) 0.000
0.000 0.000
To determine which features affect the resolutionof 5 and 6 by
an ionic host (1b–4c), the effect of the structure of the cation and
its counter anion was examined. The discrimination of enantio-
mers of 6 was enhanced by a bulky chiral substituent on the
imidazolium N-3, an aromatic ionic unit, and an anion with a
more delocalised charge ([NTf2]ꢀ versus Clꢀ). In the case of 5,
resolution was enhanced by a bulky substituent at the N-3 site, a
non-aromatic ionic unit, and an anion with a more localised
charge (Clꢀ versus [BF4]ꢀ). For example, 1b, lacking a substitu-
ent at N-3, resolves the enantiomers of 6 less efficiently than 4c,
which has a benzyl group as the N-3 substituent. This indicates
that the presence and nature of an imidazolium N-3 substituent is
important for resolution. When comparing 4a–c with 3a, b and
2a–c, where the imidazolium nucleus carries two (þ)-dehydroa-
bietyl groups, the discrimination is distinctly improved. An
additional contribution to binding comes from hydrophobic and
p–p stacking effects due to the substituents on the imidazolium
unit. This can be seen from the simplified models in Fig. 2,
illustrating a tentative complex structure. On comparing 3a, b and
2a–c, it is clearly seen that the aromaticity ofthe ionic centre has a
beneficial influence on Dd (e.g. 2c versus 3b). Similar behaviour
was noted with 5, and also in this case, a bulky side chain at N-3
enhanced the resolution. The non-aromatic ionic centre (3a,
7.0 Hz) was noted to give a better resolution for 5 than for an
aromatic one (2a–2c, 1.0–5.0 Hz).
neutral species. For 6 and 5, Dd was found to be larger in the 19
F
NMR spectra than in the 1H NMR spectra. The ionic 1b–4c gave
larger resolutions in 1H NMR spectra in the case of 5 compared
with 6. This may be due to a different host–guest complex
structure formed between the neutral guest and the ionic host,
compared with the situation when both are ionic. The increase of
chiral solvating agent concentration to 2.0 equiv. did not cause a
significant increase in Dd (,0.0–8.0 Hz). Also, in some cases
(1b, 2c, 3b, and 4c), the resolution was decreased owing to an
increased host concentration.
No explicit counter anion effects on the discrimination of
molecular guests could be seen. In a 1 : 1 stoichiometry, [NTf2]ꢀ
(2c, 3b, and 4c) gave the best resolution, as non-hydrogen-
bonding anions (such as [NTf2]ꢀ) allow bonding between the

Enantiomer Discriminators for NMR Spectroscopy
G
1H NMR
(a)
19F NMR
1:1
1a
1b
2a
2b
2c
3a
3b
4a
4b
4c
2:1
1:1
2:1
1a
1b
2a
2b
2c
3a
3b
4a
4b
4c
3.60
(b)
3.55
3.55
2:1
3.50
ꢁ71.5
ꢁ72.0
ꢁ71.5
ꢁ72.0
Chemical shift [ppm]
1H NMR
19F NMR
1:1
1:1
2:1
1a
1a
1b
2a
2b
2c
3a
3b
4a
4b
4c
1b
2a
2b
2c
3a
3b
4a
4b
4c
3.65
3.60
3.55
3.65
3.60
ꢁ70.0 ꢁ70.5 ꢁ71.0
ꢁ70.0 ꢁ70.5 ꢁ71.0
Chemical shift [ppm]
Fig. 1. 1H (OCH3) and 19F (CF3) NMR spectra of (a) 5, and (b) 6 from the resolution of enantiomers with chiral
solvating agents 1a–4c in 1 : 1 and 2 : 1 host : guest ratio.
∗
R
O
N
O
N
ꢁ
H
H
H
ꢀ
Fig. 2. A model illustrating how the cation of 2c may interact with (left) a carboxylate anion, and (right) Mosher’s
carboxylate. Hydrogen atoms have been omitted for clarity.
host and the carboxylate to occur more efficiently due to their
‘loose’ association with the host cation. However, when the
concentration was increased, [BF4]ꢀ gave slightly better results
in the case of 3a and 4a. This phenomenon may be due to
aggregation between the host and guest due to the increased
concentration of host. In the case of 5, the effect of a counter
anion was also noted, although in this case, the delocalisation of
charge in the anion did not seem to increase resolution. An anion
with a more localised charge favoured resolution, and among
those, the size of the anion (Clꢀ versus [BF4]ꢀ) seemed to play a
crucial role.
As 2c gave the best resolution (49.9 Hz), its enantiomeric
discriminating power was further investigated by titration to
find the optimum conditions for complexation. It is important to
establish the structure of the complex in order to evaluate how
much chiral solvating agent will be needed for optimal

H
H. Q. N. Gunaratne et al.
(a)
(b)
ꢁ70.45
ꢁ70.50
ꢁ70.55
ꢁ70.60
ꢁ70.65
ꢁ70.70
0.10
0.05
0
2
4
6
0
0
1
2
3
4
5
6
ꢁ0.05
ꢁ0.10
ꢁ0.15
c (2c) [mM]
c (2c) [mM]
(c)
(d)
0.04
0.02
0.20
0.15
0.10
0.05
0
0
0.2
0.4
0.6
0.8
ꢁ0.02
ꢁ0.04
ꢁ0.06
0
0
2
4
6
c (2c) [mM]
[H]/([G] ꢀ [H])
Fig. 3. (a) The chemical shifts of S (þ) and R (D) enantiomersof 6 (c, 2.0 mM); (b) the change of chemical shift
of R and S enantiomers of 6; (c) Dd between R and S enantiomers of 6 as a function of concentration of 2c; (d)
Job’s plot ([H], concentration of host; [G], concentration of guest).
(a)
(b)
3:1
2:1
1:1
0:1
3.66
3.64
3.62
3.60
ꢁ70.3ꢁ70.4ꢁ70.5ꢁ70.6ꢁ70.7ꢁ70.8ꢁ70.9
Chemical shift [ppm]
Chemical shift [ppm]
Fig. 4. The change of chemical shift of R and S enantiomers of 6 in (a) the 1H NMR spectra, and (b) the 19F NMR
spectra.
resolution. It also helps to evaluate if it is practical to increase the
amount of host over the stoichiometric amount. A solution of
guest 6 (0.5 cm3, 2.0 mM) was measured into an NMR tube and
titrated with 0.5 mm3 doses of a host solution of 2c (46.6 mM).
Figs 3a and 4 show the chemical shifts of S and R enantiomers as
a function of host concentration. Also, the change in the
chemical shifts of enantiomers was determined (Fig. 3b) from
the titration experiment. The Dd was not large enough in the 1H
NMR spectra (Fig. 4) for a reliable indication of complexation
and only data from 19F NMR spectra were used. The Dd change
between S and R enantiomers as a function of host concentration
(Fig. 3c) suggests that maximal resolution is obtained when the
concentrations of host and guest are the same (2.0 mM, 1.0
equiv.), corresponding to 1 : 1 complexation. Also, a Job’s

Enantiomer Discriminators for NMR Spectroscopy
I
80.3 ee% (S)
(theor. 80 ee%)
85
80
75
70
65
60
55
50
45
72.3 ee% (S)
(theor. 75 ee%)
70.9 ee% (S)
(theor. 70 ee%)
62.1 ee% (S)
(theor. 60 ee%)
50.2 ee% (S)
45
65
85
(theor. 55 ee%)
ee theoretical [%]
ꢁ70.4 ꢁ70.5 ꢁ70.6 ꢁ70.7
Chemical shift [ppm]
Fig. 5. Correlation between theoretical and experimental ee% values of enantiomerically enriched samples of 6 (2c used as
chiral solvating agent) by 19F NMR spectroscopy (470 MHz, CDCl3, 278C). Measured values are based on the peak areas from
line fitting of the CF3 peak.
plot[18] based on data obtained from a titration experiment
(Fig. 3d) confirmed the 1 : 1 complex stoichiometry.
Table 2. Determination of chiral discrimination of seven racemic
tetrabutylammonium carboxylate salts in the presence of 2c, using 1H
NMR (500 MHz, CDCl3, 278C) spectroscopy
The applicability of 2c in ee measurements by NMR spec-
troscopy was investigated employing a solution of racemic 6 and
enantiomerically pure S-6 (2.0 mM). Mixtures of enantiomeri-
cally enriched samples were prepared in an NMR tube (0.5 cm3,
1.0 equiv.) and 2c (22.5 cm3, 46.6 mM, 1.0 equiv.) was added.
The determined ee% values are in line with the expected values
(Fig. 5), showing that 2c can be reliably used in ee
determinations.
Compound [N4444
]
þ salt of racemic
Dd
[ppm]
carboxylic acid
[Hz]
7
8
Me
0.000
0.0
4.8
4.4
3.0
ꢁ
CHMe2 0.0096
O
H
0.0087
0.006
O
CH2
To obtain more information about the resolution behaviour
of 2c, its ability to discriminate between enantiomers of various
a-substituted racemic carboxylic acids was studied. Acids were
converted to their tetrabutylammonium salts, as 2c showed
better resolution towards ionic species, due to stronger interac-
tions through ionic and hydrogen bonding. The experiments
were performed by adding a solution of 2c (46.6 mM, 22.5 cm3,
1.0 equiv.) to a solution of the guest (2.0 mM, 0.5 cm3,
1.0 equiv.). The results indicate (Table 2) that 2c can resolve
both aromatic and non-aromatic a-substituted carboxylic acids.
The best resolution was obtained with 11 but no essential
differences between the Dd values of 7–10, 12, and 13 were
detected. This is in contrast to a previous study[7a] suggesting
that the presence of an aromatic ring (in the carboxylic acid) is
necessary for good signal separation. In addition, 2c not only
resolved the proton at the chiral centre of 7, but also the prochiral
CH2 and isopropyl groups. Such long-range effects are rare
because usually only the nuclei close to the chiral centre and the
nuclei adjacent to the site of association of the chiral reagent can
be resolved.[1] The long-range effect may indicate the asym-
metric shape of the pseudo-cavity present in the host (Fig. 2).
According to the results, 2c efficiently resolves chiral carboxylic
acids with a large polar group at the a-position (e.g. 11) or those
with a crowded a-position (e.g. 6).
Me
H
0.0065
0.0047
3.2
2.3
O
ꢁ
O
O
9
H
0.0077
3.9
OH
ꢁ
O
O
10
11
Me
H
0.000
0.0
2.8
OH
ꢁ
0.0055
O
O
Me
H
0.041
0.000
0.019
20.6
0.0
HN
O
NH
9.7
Oꢁ
O
12
13
Me
H
0.0021
0.0033
1.1
1.6
Br
ꢁ
O
O
Although the peaks of 7–10, 12, and 13 were not properly
baseline-resolved (Dd 2.3–4.8 Hz), the determinations of ee
were nevertheless feasible with special techniques. For instance,
the recently published pure shift experiments,[19,20] or J-
H
0.0044
2.19
ꢁ
O
O
N
H
1
resolved,[21] RESolved-TOCSY (RES-TOCSY),[22,10c] and H
O
homonuclear decoupling experiment (HOMODEC)[23,24]

J
H. Q. N. Gunaratne et al.
HOMODEC
1H
3.64
3.60
3.56
1.52
1.50
3.72
3.68
Chemical shift [ppm]
Chemical shift [ppm]
Chemical shift [ppm]
7
8
8
(CH)
(CH3)
(CH)
HOMODEC
1H
4.04
4.00
6.64
6.60
4.44
4.40
Chemical shift [ppm]
Chemical shift [ppm]
Chemical shift [ppm]
10
11
12
(CH)
(NH)
(CH)
Fig. 6. HOMODEC spectra of carboxylic acids 7, 8, 10–12 with their 1H spectra. All HOMODEC spectra have been
processed by using Gaussian enhancement.
techniques can be used for ee determinations in cases where
1
the baseline resolution is insufficient for integration in the H
low signal-to-noise ratio from low-molarity samples in shorter
time(Fig. 7). Ingeneral, when usingofthese types ofexperiments
(e.g. RES-TOCSY, pure shift, HOMODEC), the success of
baseline resolution is dependent on the peak resolution and peak
width. When resolution is higher than peak width (dependent on
shimming quality, sample, and natural line width), baseline
resolution can be achieved. When the peak width is larger than
the achieved resolution, baseline resolution may be achieved by
utilising window functions. However, there are some limitations
that can be seen in the spectra of 8 (CH) and 12 (Fig. 6). In the
cases where multiplicity edition does not work owing to overlap,
techniques such as RES-TOCSY can be applied. Also, when
HOMODEC-type experiments cannot be used owing to several
coupling partners (carboxylic acid 13) and hardware limitations,
RES-TOCSY can be used for solving the problem (Fig. 7)
NMR spectra. To demonstrate the use of specialised NMR
techniques in situations where baseline resolution has not
been achieved, we used a 1H homonuclear decoupling experi-
ment (HOMODEC) with carboxylic acids 7, 8, and 10–13
(Figs 6 and 7). In addition, we inspected the possible enantio-
meric resolution of three carboxylic acids (7, 11, 12) by using
HSQC (2.0 mM solution). Only in the case of 11 could
resolution be detected (6.15 Hz, 0.049 ppm) (see Supplemen-
tary Material).
In HOMODEC, multiplicity can be simplified by decoupling
one coupling partner (or more, depending on the hardware and
software available). The advantage of HOMODEC compared
with pure shift is that the former gives well-resolved spectra with

Enantiomer Discriminators for NMR Spectroscopy
K
H
H
H
H
O
O
ꢂ CH
ꢂ CH2
OH
OH
N
H
N
H
H
H
O
O
1H
HOMODEC
Pure shift
RES-TOCSY
Δd
Δd
ꢁ2
0
Δd
Δd
2
4.12 4.10 4.08
4.12 4.10 4.08
4.12 4.10 4.08
4.12 4.10 4.08
2.35
2.30
Chemical shift [ppm]
Chemical shift [ppm]
Chemical shift [ppm]
Chemical shift [ppm] Chemical shift [ppm]
CH CH2
CH
CH
CH
Fig. 7. Ordinary 1H (,2 min), HOMODEC (,7 min), pure shift (,1 h), and RES-TOCSY (,1 h) NMR spectra from carboxylic acid 13 (2.0 mM solution).
Conclusions
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[3] (a) K. S. Heo, M. H. Hyun, Y. J. Cho, J. J. Ryoo, Chirality 2011, 23,
New (þ)-dehydroabietylimidazolium chiral solvating agents
were synthesised and tested for the resolution of Mosher’s acid
(5) and its tetrabutylammonium salt (6). All nine cationic chiral
solvating agents resolved 6 highly efficiently. The best reso-
lution of the enantiomers of 6 was obtained with 2c. The
enantiomers of 5 were also resolved and gave better resolution
281. doi:10.1002/CHIR.20910
(b) S. H. Grimm, L. Allmendinger, G. Hoefner, K. T. Wanner, Chi-
rality 2013, 25, 923. doi:10.1002/CHIR.22235
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1
in the H NMR spectra compared with 6, which was better
resolved in the 19F NMR spectra. The behaviour of 6 in reso-
lution was further studied by titration, which indicated a 1 : 1
complexation between the host and guest. Further studies also
showed that cationic chiral solvating agents such as 2c can be
expediently used for the determination of enantiomeric
excesses of other chiral racemic carboxylates. The enantio-
meric resolution of seven racemic a-substituted carboxylic
acids was carried out with 2c, showing that acids containing
polar group(s) at the a-site can be resolved efficiently. Addi-
tionally, there is no strict requirement for the presence of an
aryl substituent in the carboxylic acid, allowing a wider
diversity of the guest substrates. The new (þ)-dehy-
droabietylimidazolium chiral solvating agents constitute a
biorenewable approach to ee determination.
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Data of H and 13C NMR spectra and HSQC spectra of syn-
thesised products 1a–4c are available on the Journal’s website.
Acknowledgements
(b) C. Bolchi, L. Fumagalli, B. Moroni, M. Pallavicini, E. Valoti,
Tetrahedron Asymmetry 2003, 14, 3779. doi:10.1016/J.TETASY.
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We thank Dr S. Heikkinen for his help with NMR spectroscopic studies, and
QUILL and its staff for the opportunity for TL and KW to visit their
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