An Exploration of Induced Supramolecular Chirality Through Association of Chiral Ammonium Ions and Tartrates with the Achiral Host Cucurbit[7]uril

Article abstract of DOI:10.1002/ijch.201700112

The chiral amines (R,R and S,S)-1-amino-2-benzyloxycyclopentane and (R and S)-α-methylbenzylamine were converted to ammonium (D and L) hydrogen tartrate salts and induced chiroptic effects were investigated following encapsulation in Q[7]. Significant chiroptic differences were observed in ORD and CD spectra for the two amines. The optical spectra were performed as a precursor study to a potential method for enantiomer separation, utilising Q[7] encapsulation in conjunction with enantio-pure hydrogen tartrates. An enantiomeric excess was achieved for the two antipodes of 1-amino-2-benzyoxycyclopentane but not for those of α-methylbenzylamine. However, material differences of crystallinity or the formation of a glass were observed for the latter amine induced by the different antipodes of hydrogen tartrate. ¹H NMR spectra of aminobenzyloxycyclopentane showed back-folding of the two rings with complete encapsulation in Q[7], leading to a secondary helical structure observed in CD spectra.

Full text of DOI:10.1002/ijch.201700112

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DOI: 10.1002/ijch.201700112
An Exploration of Induced Supramolecular Chirality
Through Association of Chiral Ammonium Ions and
Tartrates with the Achiral Host Cucurbit[7]uril
[a]
[a]
[a]
[a]
Wenjing Wu, Michael P. Cronin, Lynne Wallace, and Anthony I. Day*
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Abstract: The chiral amines (R,R and S,S)-1-amino-2-benzy- tartrates. An enantiomeric excess was achieved for the two
loxycyclopentane and (R and S)-a-methylbenzylamine were antipodes of 1-amino-2-benzyoxycyclopentane but not for
converted to ammonium (D and L) hydrogen tartrate salts those of a-methylbenzylamine. However, material differences
and induced chiroptic effects were investigated following of crystallinity or the formation of a glass were observed for
encapsulation in Q[7]. Significant chiroptic differences were the latter amine induced by the different antipodes of
1
observed in ORD and CD spectra for the two amines. The hydrogen tartrate. H NMR spectra of aminobenzyloxycyclo-
optical spectra were performed as a precursor study to a pentane showed back-folding of the two rings with complete
potential method for enantiomer separation, utilising Q[7] encapsulation in Q[7], leading to a secondary helical
encapsulation in conjunction with enantio-pure hydrogen structure observed in CD spectra.
Keywords: supramolecular chirality · cucurbituril · chiral guest encapsulation · induced chirality
[
10]
[11]
1. Introduction
choices as do chiral phase transfer agents or ion exchange
but chiral separation by crystallisation will also remain as a
significant method while it provides the lowest cost choice.
With advances in supramolecular chemistry, especially
host-guest chemistry, the preparation and separation of chiral
compounds has also been a significant research topic for chiral
Important industrial processes for the synthesis of ingredients
and products with chiral activity are restricted by cost and
physical limitations imposed by the requirement for large
[
1–4]
scale.
These limitations then determine the choices avail-
[
12,13]
able for the most efficient route to a product, whether it is
through asymmetric synthesis, the separation of enantiomeric
mixtures or a combination of both. One of the most cost
effective approaches to the efficient synthesis of pure chiral
commercial products is the utilization of synthetic procedures
involving enantio-pure reagents or precursors at a critical step
during synthesis. Many relatively small synthetic molecules
that could be applicable to this purpose are racemic and
therefore require bulk methods to separate out the desired
enantiomer. A method frequently practiced by industry for
large-scale purification involves a crystallisation process using
hosts and achiral hosts.
The subject of this report is the
use of the achiral molecular host, cucurbit[7]uril (Q[7]) as a
potential tool for the separation of chiral amines by enhancing
the separation properties of an auxiliary chiral agent in
crystallisation. We report a preliminary exploration towards a
proof of concept, combining the chiral crystallisation selectiv-
ity of an optically pure tartrate and encapsulated racemic
ammonium salts.
Yuan et al in 2007, reported the formation of chiral
supramolecular structures via encapsulation of the pure
enantiomers of an ammonium naphthyl derivative in Q[7] and
were the first to demonstrate a chiroptic effect of spectroscopic
enhancement and band changes relative to the free ammonium
naphthyl derivative.
example was reported, the generality of this phenomenon to
chiral molecules encapsulation in Q[n] was not certain. As
such, part of our objective was to investigate two additional
examples for chiroptic changes. Our approach was first to
[1,5,6]
a chiral auxiliary agent.
Some important examples of
chiral auxiliary agents in use are the pure racemates of tartaric
acid and a number of tartaric acid derivatives.
agents are relatively inexpensive, available in large quantities
and are non-toxic.
One group of molecules of particular interest as chiral
precursors are amines, which have become increasingly
important to industry in their use as defined enantiomers in
pharmaceuticals, agrochemicals and chemical product syn-
thesis. Numerous chromatographic methods are available and
these are constantly being improved as they are of primary
importance as analytical methods for R&D,
situations of no choice are used for bulk chiral separation.
Recent improvements in larger scale chiral separations using
[
2,5,6]
[14]
These
However, given that only a single
[
a] W. Wu, M. P. Cronin, L. Wallace, A. I. Day
Chemistry, School of PEMS, University of New South Wales
Canberra, Australian Defence Force Academy, Canberra, ACT
[
1,7–9]
and in
2
600, Australia
E-mail: a.day@adfa.edu.au
Supporting information for this article is available on the WWW
under https://doi.org/10.1002/ijch.201700112
[3]
supercritical fluid chromatography look promising for future
Isr. J. Chem. 2018, 58, 1–9
© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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examine the encapsulation of enantio-pure ammonium salts,
and then secondly, to add a chiral auxiliary external to the
cavity but as an integral component in the supramolecular
structure to determine the effect. From this it was anticipated
that the optical spectral changes (CD or ORD), would provide
an insight into the potential influence of a chiral auxiliary. The
final test of the chiral influence of the auxiliary in this study
was crystallisation with the objective of achieving an
enantiomeric excess controlled by the auxiliary and hopefully
enhanced by the Q[7].
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2. Results and Discussion
Figure 2. The relative change in molar optical rotation [M]4 at
36
+
different ratios of [Q[7]]/ABC ] in aqueous solution at 208C for
To undertake this study the chiral properties of the combina-
tion of two enantio-pure ammonium salts of (R,R and S,S)-1-
+
À
+
À
(
blue) R-ABC Cl and (orange) S-ABC Cl at 2 mM.
+
amino-2-benzyloxycyclopentane (R or S-ABC , the meso was
not included in the study, Figure 1) and (R and S)-a-
two wavelengths was that the shorter wavelength gave more
intense initial molar rotations, otherwise the response to Q[7]
additions gave a similar trend. Significantly the decrease in
+
methylbenzylamine (R or S-MBA ) encapsulated in Q[7]
were established by recording their ORD and CD spectra. This
was expected to demonstrate whether these combinations
+
molar rotation of ABC with increasing proportion of Q[7] is
1
4
would follow the phenomena previous reported and if not
what could we learn from the differences.
in contrast to the response of the previously reported chiral
naphthyl derivative which was shown to increase with
[
14]
increasing proportions of Q[7].
An attempt to conduct a similar experiment with R- or S-
+
MBA chloride salt was restricted by limited solubility as the
Q[7] was added, and significantly smaller molar rotations at
À
2 mM. However, this problem was not relevant when the Cl
À
ion was replaced by either L- or D-HT . In this case the ORD
+
À
spectra of R- or S-MBA and L- or D-HT salts were
recorded with the addition of Q[7]. The result was indicative
of two supramolecular diastereomeric forms where in one
form R-MBA L-HT and S-MBA D-HT (the positive [+
ve] and negative [Àve] respectively) the molar rotations
increase (more +ve and Àve) as the ratio of Q[7] was
increased (Figure 3a). Precipitation begins to occur beyond a
mole ratio of 0.9. In contrast, the alternative diastereomeric
form R-MBA D-HT and S-MBA L-HT (+ve and Àve
respectively) the molar rotations decrease (less +ve and Àve)
as the ratio of Q[7] was increased (Figure 3b). In this latter
case precipitation occurred beyond a mole ratio of 1.1.
Figure 1. Representative enantiomers of the two chiral ammonium
+
+
salts ABC and MBA .
+
À
+
À
The first steps, were to verify that an observable effect by
ORD and/or CD could be measured for ammonium salts as
+
+
+
À
+
À
chlorides of R- or S-ABC and R- or S-MBA , then as the
next step, the chloride ion was replaced by L and D hydrogen
À
tartrate ions (L- or D-HT ) for each enantiomer in turn, for R-
+
+
or S-ABC and R or S-MBA and to measure the induced
chiroptic effects. This information was intended to help to
In comparison, the two supramolecular ‘racemic forms’ of
À
+
À
+
À
+
À
+
determine whether a chiral anion such as HT had the
R-ABC D-HT /S-ABC L-HT and R-ABC L-HT /S-ABC
À
potential to act as a chiral auxiliary in a crystallisation process
for the separation of a racemic amine with Q[7] as a
facilitator.
D-HT with addition of Q[7] show a regular decrease in molar
rotation for the former, with convergence near zero and a more
complex change for the latter (a and b respectively). The R-
ABC L-HT /S-ABC D-HT combinations shown in Fig-
ure 4b indicate a decrease in the magnitude of the molar
rotations and a convergence to zero at a mole ratio of ~0.75
with addition of Q[7]. At a higher ratio of Q[7] the sign of the
molar rotations are reversed reaching a maximum at a mole
+
À
+
À
2.1 Optical Rotary Dispersion Spectra (ORD)
The ORD spectra recorded as molar optical rotations at 436
+
+
À
+
and 546 nm for each of the enantiomers of ABC as their
ratio of 1.2. These combinations S-ABC L-HT /R-ABC D-
+ +
À
À
À
chloride salts, gave a significant chiroptic effect. At both
wavelengths as the proportion of Q[7] was increased to a mole
ratio of 1:1, the molar rotation decreased ~20 fold (Figure 2,
and SI, Figure S1 for [M]546). The only difference between the
HT and S-ABC D-HT /R-ABC L-HT (Figure 4a and b
respectively) could be designated as supramolecular antipodes
on the basis of their reflected ORD behaviours. Curiously, the
+
À
initial ORD molar optical rotations of S-ABC L-HT /R-
Isr. J. Chem. 2018, 58, 1–9
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Figure 3. The relative change in molar optical rotation [M]
at
36
4
+
À
Figure 4. The relative change in molar optical rotation [M]
at
36
different ratios of [Q[7]/MBA HT ] in aqueous solution at 208C for,
4
+
À
+ +
+
À
+
À
different ratios of [Q[7]/ABC HT ] in aqueous solution at 208C for,
a) (green) R- MBA L-HT and (blue) S- MBA D-HT ; and b) (red)
À
À
+
À
+
À
a) (pink) S-ABC L-HT /(blue) R-ABC D-HT ; and b) (yellow) S-
+ +
R-MBA D-HT and (orange) S-MBA L-HT . All at 2 mM.
À
À
ABC D-HT /(pink) R-ABC L-HT . All at 2 mM.
+
À
ABC D-HT (680 and - 610 respectively, Figure 4a) were not
equivalent. However, each of the individual components was
with maximum attainable upfield shifts at 1:1 (Q[7]: guest).
+
MBA @Q[7] in particular showed relatively sharp coupling
À
verified to be equiv. prior to HT salt formation (as an
for the guest proton resonances and a clear differentiation of
the aromatic protons centrally located within the cavity
(between 0.62–0.9 ppm, SI, Figure S16). A binding constant
example see Figure 2). Significantly the initial molar optical
+
À
+
rotations of the combinations S-ABC D-HT /R-ABC L-
À
+
HT were substantially different (270 and À410 respectively).
was established for MBA @Q[7] by adding portions of Q[7]
+
À
Consequently these combinations are significantly different in
their CD spectra as well (see SI, Figure S9).
to a D O solution of R-MBA D-HT . The clearly defined
2
upfield shift difference of the CH proton resonances was
3
Small differences in the initial molar optical rotation ORD
plotted against [Q[7]/MBA] and curve fitted as a 1:1 complex
+
À
6
À1
points for the combinations of MBA HT (no Q[7]) were
(10 M , SI).
The establishment of a binding constant for R-ABC
+
À
+
<10%, far less significant than the ABC HT combinations.
The differences may indicate a pairing of ammonium tartrate
salts under aqueous conditions even before the addition of
Q[7].
There are clear differences between the two racemic forms
of both the Q[7]]/MBA HT sets and the Q[7]]/ABC HT ]
sets. It was anticipated that these differences could indicate
that separation may have a chance.
1
@Q[7] was not as accessible by H NMR as the proton
resonances were not as clearly definable until close to 1:1
binding. However, a binding constant was established for this
association complex by using a curve-fitting model applied to
the data obtained from the ORD titration of Figure 2.
[
15]
+
À
+
À
1
Consistent with its H NMR and the ORD a 1:1 binding
5
model was assumed, which gave an approximate K of 10
a
1
+
À1
+
+
By H NMR each combination of ABC @Q[7] and
MBA @Q[7] showed spectra where all protons attached to
M
indicating that ABC and MBA have similar binding
+
constants (SI, Figure S3).
carbon were encapsulated within the cavity of Q[7] with
clearly defined upfield shifted proton resonances. The
exchange kinetics on the NMR timescale were moderate, with
no definable free and bound guest resonances only averages
As mentioned above all protons attached to carbon on
+
+
either MBA or ABC had upfield shifted resonances when
+
encapsulated in Q[7]. This was anticipated for MBA but was
+
surprising in the case of ABC . In the latter example, this
Isr. J. Chem. 2018, 58, 1–9
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indicates that both rings are cavity bound requiring a fold-
back to allow cavity accommodation (Figure 5). In addition,
an examination of the chemical shift differences between the
+
+
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either ABC or MBA shows only a very small downfield
shift of <0.1 ppm, which may indicate a weak association.
Carboxylic acid binding to Q[7] has been reported as
+
À
+
resonances of free R-ABC D-HT and R-ABC @Q[7] D-
significant but upon deprotonation forms the carboxylate ion
at which point binding becomes unfavourable.
there are at least two circumstances where the repulsion of the
À
[17–24]
HT reveals that not only are all CÀH’s shifted upfield but that
However,
the methylene protons at C-3 of the cyclopentane, show
unusually large upfield shifts of 1.5 and 1.7 ppm (SI, Table S2,
Figure S12). A central cavity location, plus a shielding effect
as a consequence of proximity to the centre of the phenyl ring
is consistent with a back-folding arrangement. The modeled
À
negative ÀCO2 ion by the electronegative portal is limited.
These are when there is a zwitterion as in amino acids or a
À
pseudozwitterion such as ÀCO and pyridinium ions in the
2
[
23,24]
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same molecule.
In consideration of these conditions it was
À
structure shown in Figure 5, correlates well with the small
shift for the CHÀN (0.08 and ppm) where the NH sits at the
anticipated that the HT ion in conjunction with an ammonium
ion located within a portal could operate in a similar fashion.
This was also rationalised by considering a portal association
that would be facilitated by the remaining CO H and two OH
groups of the HT ion, which would H-bond to the portal.
The ORD of D-tartaric acid at 436 and 546 nm was
recorded following incremental additions of Q[7] up to a mole
ratio of 1.4:1 (Q[7] : D-tartaric acid) and this showed changes
in the molar rotation in an increasing positive direction which
plateaued at 1:1 (SI, Figure S4). A curve-fitted model
+
3
portal and the relatively smaller shift for the para HÀAr
compared to meta and ortho supporting its location near the
opposite portal (0.47, 0.61 and 0.89 respectively). Also the
benzyl CH2 as diastereotopic protons, were substantially
differentiated in their individual chemical shifts, consistent
with one pointing toward the geometric centre of the cavity
and the other toward the portal (1.08 and 0.29 respectively).
The NOESY spectrum also supports the fold-back with strong
cross correlations between the ortho-Ar protons and CH2
protons of C-3 (SI, Figure S13 and S14). The structural
representations shown in Figure 5, were derived through
modelling. This was achieved by first orientating the two rings
2
À
indicated that an approximate K for (tartaric acid)@Q[7]
~10 M assuming a 1:1 binding. The mode of binding for
tartaric acid is assumed to be portal as there are no shifted
a
7
À1
1
resonances by H NMR with the addition of Q[7]. The lack of
+
of the ABC molecule in a fold-back state consistent with the
a downfield shift may only be indicative of a high exchange
rate (generally portal interactions give only small shifts even
for slower exchange rates).
In this study the HT is relevant and to test this for portal
association the influence of a chiral guest@host was removed,
+
NOESY correlations. Then the back-folded ABC was placed
+
in the cavity of Q[7] with the NH located near a portal and
3
[16]
À
the structure minimised. The minimised model was found to
1
be also consistent with H NMR chemicals shifts relative to
+
cavity depth (complete table of chemical shifts SI, Table S2).
while maintaining the possible relationship to a bound NH3
and the portal. This was achieved in the form of the achiral
benzyl ammonium ion together with the hydrogen tartrate
+
À
(BzNH3 D-HT ), which was compared in the absence and
presence of Q[7]. The ORD showed a small positive increase
2
À1
in the molar rotation (40 degcm dmol ) at 436 nm, following
the addition of Q[7] but this was not as significant as the
change found for tartaric acid discussed above. Further
evidence to this point is discussed in the subsequent text
below.
2.2 Circular Dichroism Spectra (CD)
In addition to ORD the CD spectra were also recorded in order
to further evaluate the potential for the use of Q[7] as a tool
for enantiomeric separation.
+
Figure 5. A portal view of Q[7] showing the two rings of ABC back-
+
folded (LHS) and a side view of ABC showing the relative
arrangements of the two rings to each other and highlighting C-3’s
proximity to the centre of the phenyl ring (RHS).
CD was also used to further investigate the question of an
À
association of the HT ion with an internally bound portal
ammonium ion, which could have ion-ion interaction together
with secondary portal binding to the CO H and OH groups as
2
+
H-bonding. In the case of the achiral guest BzNH and D-
3
1
+
À
By H NMR it has been established that both MBA and
HT the CD spectra showed
a
slight decrease by
7 degM cm for BzNH3 @Q[7] D-HT (IS, Figure S7).
This change suggest that the D-HT ion does associate with
+
À1
À1
+
À
ABC were fully encapsulated within the cavity of Q[7] but
the association of HT can only be tentatively determined to
have close proximity to the portal. HT as the counterion to
À
À
À
the portal and the cavity bound ammonium ions to form chiral
supramolecular species.
Isr. J. Chem. 2018, 58, 1–9
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Focusing then on the chiral cavity bound guests the CD
spectra revealed significant differences between the free guest
R- or S-MBA HT and (R- or S-MBA )@Q[7] HT . In the
+
À
+
À
+
À
+
case of R-MBA D-HT and R-MBA L-HT there was a
reduction in magnitude of the molar ellipticity without a
change in the sign following encapsulation. In addition, the
minima was blue shifted by >3 nm (SI, Figure S8). Compar-
+
À
+
À
ing S-MBA D-HT and S-MBA L-HT free and encapsu-
lated in Q[7] revealed the significant reduction in magnitude
of the molar ellipticity of S-MBA L-HT as a consequence of
+
Q[7] association. S-MBA D-HT in contrast only resulted in
a small blue shift (3 nm) and no change in intensity (Figure 6).
+
À
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1
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1
1
1
1
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1
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À
+
À
Figure 7. The CD spectra comparing free R- or S-ABC as the Cl , to
encapsulation in Q[7] at a ratio of 1:1.
+35 and +26 respectively). Reflected in character but not in
+
À
intensity was a CD spectrum of R-ABC @Q[7] L-HT with a
negative ellipticity and negative minima at 212 and 227 nm
([q] À53 and À21 respectively) as shown in Figure 8a. In
+
À
contrast, the combinations R-ABC @Q[7] D-HT and S-
+
À
ABC @Q[7] L-HT gave mirrored CD spectra but with single
absorption bands at 215 nm ([q] +136 and À136, Figure 8b).
+
À
The two enantiomers R- and S- ABC @Q[7] HT adopt
helical arrangements in opposite directions as a consequence
of the complete cavity encapsulation and back-folding of the
two rings (SI, Figure S14). The relative orientation of the two
back-folded rings together with the relative twist left or right,
is supported by the cross correlation found in NOESY spectra
previously discussed. The phenyl ring is offset to the cyclo-
pentyl ring where the centre of the phenyl ring sits above C-3
of the cyclopentyl ring.
+
À
À
Figure 6. The CD spectra of free as S-MBA (D-HT or L-HT ) and
+
À
+
the encapsulated forms S-MBA @Q[7] D-HT and S-MBA @Q[7]
À
L-HT in water 1.5 mM.
The features of the CD spectral bands, especially those of
Figure 8a, may indicate some secondary structure effects of
the twist in the supramolecular forms S-ABC @Q[7] D-HT
+
and R-ABC @Q[7] L-HT . The alternative combinations
shown in figure 8b have featureless curves.
The data obtained from both ORD and CD spectra
suggested that Q[7] with encapsulated chiral ammonium guest
exhibits a significant association with a chiral anion such as
HT . The question then was, can this association be used as a
method for the separation of enantiomeric mixtures and would
Q[7] provide any advantage?
+
À
Distinguished from the above example, adding 1 equiv. of
+
+
À
À
Q[7] to R-ABC and S-ABC as Cl salts, showed a
pronounced change in their CD spectra. An inversion of the
sign of ellipticity for each enantiomer and an enhancement to
+
give a maxima for R-ABC @Q[7] and an enhanced minima
for S-ABC @Q[7], each mirrored at 218 nm (Figure 7). A
small red shift (4 nm) also occurred relative to ABC in the
+
+
À
absence of Q[7].
+
À
CD spectra of the combinations of R-ABC D-HT /S-
+
À
+
À
+
À
ABC L-HT and S-ABC D-HT /R-ABC L-HT were then
compared. To each of these combinations Q[7] was added at a
ratio of 1:1(SI, Figure S9). Close examination of the CD
spectra after Q[7] was added led to two interesting observa-
2.2 Crystallisation Toward Enantiomeric Excess
+
À
tions. The combination S-ABC @Q[7] D-HT showed a
One of the objectives in this process of the separation of
racemic mixtures using the auxiliary HT was intended as an
À
positive ellipticity with two maxima at 212 and 226 nm ([q]
Isr. J. Chem. 2018, 58, 1–9
© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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+
À
+
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Figure 8. CD spectra comparing the four combinations of enantiomers of ABC @Q[7] HT . a) The near mirrored pair S-ABC @Q[7] D-HT
+
À
+
À
+
À
and R-ABC @Q[7] L-HT . b) The alternative mirrored pair R-ABC @Q[7] D-HT and S-ABC @Q[7] L-HT .
+
À
aid in a crystallisation in water, as a green approach to the
purification of enantiomers. Racemic mixtures of MBA and
MBA HT combinations, in methanol is known to be an
effective method for the separation of R- and S- MBA through
repetitive crystallisation. When MBA is encapsulated in Q[7]
+
+
À
25
ABC were prepared as HT salts in water and Q[7] was
added to give a final mole ratio of 1:1:1. It was found that
the separation of its enantiomers becomes ineffective.
+
À
À
the complexes MBA @Q[7](D-HT or L-HT ) were highly
soluble in water and were very resistant to crystallisation.
+
À
À
ABC @Q[7](D-HT or L-HT ) also had high solubility in
water but crystals were obtained. The crystals obtained from a
3. Conclusion
+
1
single crop of the ABC complex were shown by H NMR to
contain the three components as in the original ratio of 1:1:1.
It has been found that the Q[7] induces a significant chiroptic
effect shown both in ORD and CD spectra. The two examples
presented, which have similar binding constants, show differ-
ent effects, which is likely to be as a consequence of the
binding orientations of the encapsulated chiral ammonium ion
in combination with the tartrate counterion. It has been shown
that the chiral anion HT has an association role as part of the
supramolecular structure leading to additional chiroptic
effects. The close association of HT to a Q[7] cavity-bound
achiral ammonium ion was demonstrated by CD spectra as
well as significant changes to CD and ORD spectra of
different enantiomer combinations of the complex ABC
@Q[7]HT . The chiral HT was clearly able to imprint an
influence upon the complex enabling a selectivity toward a
significant ee as much as ~33% for ABC . However, in the
case of MBA @Q[7]HT neither enantiopure forms of HT
À
However, the combination with D-HT as the anion gave R-
+
ABC with an ee of 33% whereas the alternative anion L-
À
+
HT gave S-ABC with an ee of 12%. Curiously these
crystalline forms correspond to the mirrored pair in Figure 8b.
The intention in these experiments was to demonstrate a
proof of concept and therefore recrystallisation was not
investigated for optimisation. Attempts to initiate crystallisa-
tion of MBA @Q[7]D-HT by the addition of a small portion
of MeOH to a hot solutions led to a plastic material upon
cooling. Removing this material from the solution resulted in
it setting relatively quickly as a glass. Mechanically pulling
the material in its plastic state from its self drew out fine
strands, which formed glassy fibres within sec. This glass
À
À
+
À
+
À
À
+
1
+
À
À
material by H NMR showed that the ratio of the complex
+
À
MBA @Q[7] D-HT was maintained at a ratio of 1:1:1 for
each component. Analysis by ORD showed no enantio-
selection. In contrast, a hot water solution of the racemic
were effective. A possible explanation for this negative result
may relate to the depth of encapsulation within the cavity of
+
the chiral CHÀNH3 group, as the magnitude of the upfield
+
À
mixture of MBA @Q[7]L-HT with a small portion of
MeOH added promoted crystallisation upon cooling. Crystal-
lisation by this approach was reproducible and facile.
However, these crystals also showed no enantio-selection and
again the composition was maintained at a ratio of 1:1:1.
shift of these proton resonances were significantly different
+
+
Dd 0.33 and 0.08 ppm for MBA and ABC respectively.
While crystallisation may not be the best approach to
achieving enantiopure ammonium ions with the aid of Q[7]
the partial success in achieving selectivity suggests alternative
Isr. J. Chem. 2018, 58, 1–9
© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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techniques such as chromatography could be applicable. In
addition, tartrate may not be an ideal choice and an alternative
chiral auxiliary anion with a greater propensity to crystallisa-
tion may improve the outcome.
ABC @Q[7]HT proved amenable to enantio-selectivity
but was also interesting from two other perspectives. The
back-folding of the two rings enabling complete accommoda-
tion within the Q[7] cavity; and the relative orientation of the
two rings leading to complementary twists or the beginnings
of a helical structure.
Each of the chiral starting amines and the tartrates were
individually verified by ORD and CD, and were found to have
exact mirror spectra for each enantiomeric pair.
+
À
4.2 ORD Study
Q[7] was added as a solid repeatedly to the salt solutions in
accurate increments of ~0.1–0.2 moleequiv. At each addition
solutions were thoroughly mixed and sonicated to facilitate the
dissolution of Q[7]. Generally 8 additions were carried out for
each analysis.
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+
À
MBA @Q[7]HT was also significant in the formation of
a material of glass in the supramolecular combination of
+
À
MBA @Q[7]D-HT as opposed to the ready crystallisation of
+
À
MBA @Q[7]L-HT indicating a packing arrangement dic-
tated by the chirality of at least the anion in spite of its
inability to influence enantio-selectivity in crystallisation.
4.3 CD Study
Each combination of chiral amine/Q[7]/tartaric acid were
prepared in water or D O in ratios of 1:1:1 respectively. The
2
1
4. Experimental Section
ratios were verified by H NMR, following preparation as
concentrated D O samples ~35 mM and diluting with H O to
2
2
4.1 General
1.5 mM solution for analysis. Samples prepared directly in
H O gave indistinguishable results by CD.
2
1
H NMR spectra were recorded at 400 MHz at 258C unless
otherwise stated. Spectra were referenced to 4.78 ppm using
1
the residual H signal of D O. 1D spectra were recorded with
4.4 Crystallisation of Racemic Q[7] Complexes
2
between 16 and 64 transients. With water suppression and a
saturation time of 1 s, NOESY spectra were acquired using
2048 data points in t2 (with a spectral width of 4200 Hz) for
400 t1 values with a pulse repetition rate of 1.5 s with 16–128
scans per fid. Mixing times of 400 ms were used.
+
Racemic MBA was used to prepare the complexes MBA
À
+
À
@Q[7] D-HT and MBA @Q[7] L-HT . These complexes
were prepared in high purity water and concentrated with
warming then extended periods of cooling in a repetitive
+
À
All sample solutions were prepared in high purity water.
Sonication was used to assist in dissolution of Q[7] where
necessary. All solutions for ORD were at a concentration of
2 mM. ORD were recorded on a polarimeter at l=546 and
436 nm at 208C using a microcell of 10 cm length and a
process. No crystals were obtained for MBA @Q[7] D-HT
only a very viscous plastic layer at the bottom. Repeating the
process with small additions of MeOH while hot gave, after a
cooling period, a similar plastic material. Removing this
1
material and leaving it in the air gave a glass. The H NMR
3
+
À
volume of 1 cm . CD spectra were recorded on a CD
spectrum of the glass was identical to MBA @Q[7] D-HT
1:1:1 (SI). The ORD showed no enantio-selectivity. The
spectrometer in the wavelength range of 205–250 nm at 208C
using a rectangular quartz cell (path length 1 mm) and all
solutions were at a concentration of 1.5 mM.
+
À
complex MBA @Q[7] L-HT under similar conditions
crystallised readily to give colourless crystals. The ORD in
this case also showed no enantio-selectivity however, the ratio
of each component was also 1:1:1.
Chemicals used benzylamine, (R)-a-methyl benzylamine,
(S)-a-methyl benzylamine, (R,R)-1-amino-2-benzyloxycyclo-
pentane, (S,S)-1-amino-2-benzyloxycyclopentane, D-tartaric
acid and L-tartaric acid were all obtained from commercial
sources and used without purification. Cucurbit[7]uril was
+
Racemic ABC was used to prepare the complexes ABC
À
+
À
@Q[7] D-HT and ABC @Q[7] L-HT . These complexes
were prepared in high purity water and concentrated with
warming then extended periods of cooling in a repetitive
[
26]
prepared according to our previously reported procedure.
1
Hydrochloride salts were prepared by the addition of 32%
HCl (0.1 mL) to the relevant amine (1 mmol). The excess acid
was removed in vacuo and the remaining salts were left to dry
in a desiccator.
process until crystallisation occurred. By H NMR these
+
À
crystals were identical to the spectra of ABC @Q[7] D-HT
+
À
or ABC @Q[7] L-HT with component ratios of 1:1:1 (SI).
The molar rotations were measured before and after the guest
was displaced with adamantly ammonium chloride (solid ~1
equiv), which resulted in an increase, as would be expected for
The tartrate salts were prepared as solutions (H O or D O
2
2
depending on the application) in mole ratios of 1:1 of the
relevant tartaric acid added to the relevant amine and these
solutions were made up to a volume suitable to give
concentrations specified above.
+
the free ABC (see Figure 4). The molar rotation was
determined using Figure 4a, this was consistent with enantio-
+
À
+
À
selectivity for S-ABC L-HT and R-ABC D-HT [q] 80
À1
2
and À200 degdmol cm , calculating for 12 and 33% ee
respectively.
Isr. J. Chem. 2018, 58, 1–9
© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.ijc.wiley-vch.de
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Supporting Information Available: Additional ORD and
CD spectra are available. Details of the determination of
binding constants through curve fitting of ORD titration data
[11] J. P. Smuts, X.-Q. Hao, Z. Han, C. Parpia, M. J. Krische, D. W.
Armstrong, Anal. Chem. 2014, 86, 1282–1290.
[
12] R. Nishioka, S. Harada, J. Chromatogr. 2016, 37, 65–71.
[13] V. Mandadapu, A. I. Day, A. Ghanem, Chirality 2014, 26, 712–
23.
14] L. Yuan, R. Wang, D. H. Macartney, Tetrahedron: Asymmetr.
007, 18, 483–487.
1
1
or H NMR titration data is also available. H NMR spectra of
each ammonium guest encapsulated in Q[7] has been provided
7
[
+
together with the NOESY spectrum of R-ABC @Q[7] D-
2
À
HT .
[15] N. F. Ghazali, D. A. Patterson, A. G. Livingston Chem Comm.
2004, 962–963.
[
16] Modelling was performed with HyperChem 8.0.10 where the
+
ABC molecule was back-folded manually consistent with the
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Acknowledgements
NOESY correlations then placed in an optimised Q[7] cavity and
minimised in molecular mechanics MM+ which maintained a
back-folded state.
This work was supported by the UNSW Canberra, Postgradu-
ate Student Research Scholarship program.
[
17] W. S. Jeon, K. Moon, S. H. Park, H. Chun, Y. H. Ko, J. Y. Lee,
E. S. Lee, S. Samal, N. Selvapalam, M. V. Rekharsky, V.
Sindelar, D. Sobransingh, Y. Inoue, A. E. Kaifer, K. Kim, J.
Amer. Chem. Soc. 2005, 127, 12984–12989.
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FULL PAPER
W. Wu, M. P. Cronin, L. Wallace, A. I.
Day*
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An Exploration of Induced
Supramolecular Chirality Through
Association of Chiral Ammonium
Ions and Tartrates with the Achiral
Host Cucurbit[7]uril
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