Chiral thiouronium salts: Synthesis, characterisation and application in NMR enantio-discrimination of chiral oxoanions

Article abstract of DOI:10.1039/c2nj40632b

Chiral thioureas and functionalised chiral thiouronium salts were synthesised starting from the relatively cheap and easily available chiral amines: (S)-methylbenzylamine and rosin-derived (+)-dehydroabietylamine. The introduction of a delocalised positiv

Full text of DOI:10.1039/c2nj40632b

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Chiral thiouronium salts: synthesis, characterisation
and application in NMR enantio-discrimination
of chiral oxoanions†‡
Cite this: NewJ.Chem., 2013,
37, 515
Magdalena B. Foreiter, H. Q. Nimal Gunaratne,* Peter Nockemann,
Kenneth R. Seddon, Paul J. Stevenson and David F. Wassell
Chiral thioureas and functionalised chiral thiouronium salts were synthesised starting from the relatively
cheap and easily available chiral amines: (S)-methylbenzylamine and rosin-derived (+)-dehydroabietylamine.
The introduction of a delocalised positive charge to the thiourea functionality, by an alkylation reaction
at the sulfur atom, enables dynamic rotameric processes: hindered rotations about the delocalised CN
and CS bonds. Hence, four different rotamers/isomers may be recognised: syn–syn, syn–anti, anti–syn
and anti–anti. Extensive 1H and 13C NMR studies have shown that in hydrogen-bond acceptor solvents,
such as perdeuteriated dimethyl sulfoxide, the syn–syn conformation is preferable. On the other hand,
when using non-polar solvents, such as CDCl3, the mixture of syn–syn and syn–anti isomers is
detectable, with an excess of the latter. Apart from this, in the case of S-butyl-N,N0-bis(dehydroabietyl)-
thiouronium ethanoate in CDCl3, the 1H NMR spectrum revealed that strong bifurcated hydrogen
bonding between the anion and the cation causes global rigidity without signs of hindered rotamerism
observable on the NMR time scale. This suggested that these new salts might be used as NMR
discriminating agents for chiral oxoanions, and are indeed more effective than their archetypal guanidinium
analogues or the neutral thioureas. The best results in recognition of a model substrate, mandelate, were
obtained with S-butyl-N,N0-bis(dehydroabietyl)thiouronium bistriflamide. It was confirmed that the chiral
recognition occurred not only for carboxylates but also for sulfonates and phosphonates. Further 1H NMR
studies confirmed a 1 : 1 recognition mode between the chiral agent (host) and the substrate (guest);
binding constants were determined by 1H NMR titrations in solutions of DMSO-d6 in CDCl3. It was also
found that the anion of the thiouronium salt had a significant influence on the recognition process: anions
with poor hydrogen-bond acceptor abilities led to the best discrimination. The presence of host–guest
hydrogen bonding was confirmed in the X-ray crystal structure of S-butyl-N,N0-bis(dehydroabietyl)-
thiouronium bromide and by computational studies (density functional theory).
Received (in Montpellier, France)
16th October 2012,
Accepted 14th November 2012
DOI: 10.1039/c2nj40632b
www.rsc.org/njc
Introduction
QUILL Research Centre, School of Chemistry and Chemical Engineering,
The Queen’s University of Belfast, Belfast BT9 5AG, Northern Ireland, UK.
E-mail: quill@qub.ac.uk
The chemistry of abiotic receptor compounds for a particular
species usually mimics natural systems. In the case of natural
anion receptors, the archetypal example of an anion binding
host is the guanidinium ion, which naturally occurs as a part of
arginine residues.1 Since then, many synthetic guanidinium-
based anion hosts have been designed and synthesised,2
including chiral guanidinium derivatives, which feature strong
interactions with chiral oxoanions (Fig. 1a).3 The essential
feature of the guanidinium cation for attracting the anionic
species is the two N–H groups, carrying a delocalised positive
charge, which are not only a source of a strong hydrogen
bonding, but are also directed in space to form a familiar
† Electronic supplementary information (ESI) available: Copies of 1H and 13C
NMR spectra for (S)-a-methylbenzyl isothiocyanate, 1a, [2a][NTf2]; 1H, 13C, COSY
and 1H–13C HSQC NMR spectra of dehydroabietyl isothiocyanate, 1b, 1c, [2c]Cl,
[2a][NTf2], [2c][NTf2], [2c][CH3CO2], [2c][NO3] and [2c][OTf]; 1H, 13C, COSY,
1H–13C HSQC and 1H–15N HSQC NMR spectra of [2a]Br, [2b]Br and [2c]Br; a table
with NMR traces used for determination of peak non-equivalences in
tetrabutylammonium salts of chosen racemic acids; Cartesian coordinates of
isomeric structures of [2a]+ optimised at the RHF/3-21G* level; Cartesian
coordinates of [2c][3a] and [2c][3d] complexes optimised at the RB3LYP/STO-G*
level, visualisation of [2c][3d] complexes, and complete ref. 28. CCDC 882873. For
ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c2nj40632b
‡ This article is dedicated to Professor A. P. De Silva and Dr Tobias J. Lotz.
c
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Fig. 1 Examples of chiral carboxylate hosts used as NMR enantio-discriminating
agents: (a) guanidinium derivative, [A]Cl,3a (b) thiourea derivative, B,4 and (c)
imidazolium derivative, [C][NTf2], which is a chiral ionic liquid (with
bis(trifluoromethyl)sulfonylamide anion, [NTf2]).5
Fig. 2 A model illustrating how novel chiral salts of the generic type [cation]Y can
interact with chiral oxoanions (e.g. carboxylates, sulfonates, or phosphonates) via
hydrogen bond recognition; the hydrogen bonding has been encoded using
Etter’s topographical analysis.20,21
hydrogen-bond donor motif. The same features may be also
recognised in the thiouronium system, which has not been
widely explored for anion binding.6
NMR discrimination of chiral analytes (Fig. 1c).5,17 The unique
properties of ionic liquids, and their wide ‘tuning’ opportunities
combined with a designed functionality, have often delivered a
competitive advantage compared to conventional, non-ionic
systems.18
Here, we present an effective approach to enantio-recognition
of chiral anions using new chiral S-alkylthiouronium salts
(Fig. 2), which incorporate a combination of (a) a positively-
charged thiourea function as a source of Coulombic attraction
to the anionic substrate; (b) a receptor group for chiral carboxylates
and analogues as a hydrogen-bonding donor in the form of a
thiouronium cation; and (c) the use of a relatively low-cost and
easily available source of chirality, e.g. the cation is based on
rosin-derived (+)-dehydroabietylamine, denoted Ab.19 Attention
here is mainly focussed on the enhancement in binding inter-
actions resulting from introduction of a positive charge on the
chiral thioureas.
Thiouronium (formerly known as ‘thiuronium’, ‘pseudo-
thiouronium’ or ‘isothiouronium’) salts are materials used in
a range of applications, many of which have been patented.7
They are utilised as stabilisers for vulcanised rubber,7a as
chelating agents for noble metals,7b as fire-resistant agents,7c
and for protein extraction.7d However, thiouronium salts are
easily hydrolysed by bases,8 and thus these conditions must be
avoided. Moreover, thiouronium salts have an important role as
reaction intermediates in the synthesis of thiols8 and guanidinium
salts,9 and they are also used as peptide coupling agents.10
Recently, Abai et al. described a series of S-alkylthiouronium
ionic liquids, which were investigated for the desulfurisation of
diesel.11 However, in all of these reports, only the achiral
thiouronium salts were studied.
While not much interest has been shown in chiral thiouronium
salts, their precursors – chiral thioureas – are well known,
especially as effective chiral catalysts used in organic trans-
formations such as asymmetric Michael addition.12 Their roles
as fluorescent anion sensors13 and amino acid receptors14 have
also been reported. Theoretically, it is possible to alter known
properties of thioureas through the alkylation of the sulfur
atom. The resultant steric hindrance, as well as the Coulombic
repulsive forces between the thiouronium cations, could
drastically reduce the self-association of the thiourea unit via
hydrogen bond interactions.1 Moreover, the hydrogen-bonding
relationship of the thiouronium receptor centre with appro-
priate substrates could then be enhanced when compared to
thioureas.15 The easiest way to examine the binding properties
of chiral anion receptors, such as novel chiral thiouronium
salts, is via NMR analysis of the chiral discrimination. At
present, only one report describes structurally simple chiral
thioureas as chiral discriminating agents for a-hydroxy and
a-amino carboxylates, Fig. 1b.4
Results and discussion
Synthesis and characterisation
The synthesis of chiral thiouronium salts essentially relies on a
three-step reaction path (Scheme 1). In step one, a chiral
primary amine was treated with carbon disulfide in the
presence of a DCC to form isothiocyanate. This was then treated
There is current interest in searching for new chiral tools
that will provide a quick, cheap and facile way of determining
enantiomeric purity, and offer an advantage over chiral
HPLC.16 Chiral thiouronium salts may be a useful alternative
to existing chiral anion binding systems. Additionally, when
designed in the appropriate manner, these compounds could
be an interesting and novel contribution to the family of chiral
ionic liquids that have been applied as chiral agents for the
Scheme 1 Synthesis of the chiral thioureas, 1, and S-alkylthiouronium salts,
2 (R = butyl, Y = halide, DCC = N,N0-dicyclohexylcarbodiimide).
c
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Table 1 Physical properties of synthesised compounds
Compound
Tm/1C
Tdeca/1C
[a]2D0(c 1.0 (CHCl3))
[M]2D0 b
Form
1a
[2a]Br
[2a][NTf2]
1b
[2b]Br
[2b][NTf2]
1c
[2c]Cl
[2c]Br
199.6ꢀ200.9
137.5
—
+104.4
+125.2
+96.0
+14.2
+34.8
+18.6
+14.3
ꢀ11.0
ꢀ19.2
ꢀ16.4
ꢀ5.7
+296.9
+527.6
+596.8
+72.8
+203.8
+146.2
+87.6
ꢀ77.6
ꢀ143.9
ꢀ130.7
ꢀ54.1
ꢀ144.2
+68.0
White solidc
Creamy solid
Colourless liquidd
White solid
Yellowish solid
Colourless glass
White solid
Yellowish solid
White solid
White solid
151.4
219.1
183.9
158.4
231.9
200.5
160.1
210.0
151.9
227.5
169.0
189.9
158.9
–38.1e
101.6ꢀ102.4
79.2
13.9e
139.0ꢀ141.0
58.4e
128.2
[2c]I
75.4e
[2c][NTf2]
[2c][NO3]
[2c][OTf]
[2c][CH3CO2]
44.3
49.1
54.7
49.0
White solid
White solid
White solid
White solid/glass
ꢀ19.7
+8.3
+16.2
+118.1
a
b
Decomposition temperature determined using thermal gravimetric analysis (TGA). Molar rotation calculated from [a]2D0 ꢁ M/100, where M is the
molar mass. Product known from the literature4 (Tm 199ꢀ200 1C, [a]D20 + 114.2 (c 1.05, CHCl3)). d20 1.3232 g cmꢀ3, Z20 4.704 Pa s with a water
c
d
e
content of 186 ppm. Glass transition temperature (Tg) determined using differential scanning calorimetry (DSC).
with a second chiral amine, R0*NH2, to form the disubstituted rotation between [2a]Br and [2a][NTf2], [2b]Br and [2b][NTf2],
chiral thiourea; the second amine may or may not be identical to and [2c]Br and [2c][NTf2] (69.2, 57.6 and 89.8 units respectively).
that used in the first step. Treatment of these thioureas with Surprisingly, the molar rotation of halides with [2c]+ shows an
haloalkanes resulted in the formation of novel salts. For unifor- unusual pattern. As the molar mass of the halide increases, the
mity, the alkylation was confined to a butyl group, as the length of concentration of active species decreases, so we would expect
simple hydrocarbons does not play a significant role in the that the values of specific rotation will change monotonically
binding process and chiral recognition.22 In order to tune the from chloride, through bromide to iodide. In contrast, repeated
physical properties of the products, a fourth step of anion measurements showed unquestionably that the most laevo-
exchange was conducted in some cases, principally for rotatory is the bromide, then the iodide and lastly the chloride.
bis(trifluoromethyl)sulfonylamide (bistriflamide), [NTf2]ꢀ. Thus, Whereas for other anions, it is expected that the degree of
a series of novel chiral thioureas, 1, and their corresponding interaction will change according to their size and shape: for
chiral S-butylthiouronium salts, [2]Y, with chiral appendages halides they are sterically and electronically similar. However,
and associated anions were synthesised, as described.
analysis of the 1H and 13C NMR spectra suggested a likely
Collected physical property data (Table 1) for the new explanation (vide infra).
compounds show interesting trends. The highest melting
points belong to the chiral thioureas 1a and 1c. Alkylation of
these compounds to form halide salts causes a drop in the
melting point; metathesis to bulkier anions, such as [NTf2]ꢀ,
lowers the melting point even further. These salts may be
classified as belonging to the family of chiral ionic liquids.18a,23
Indeed, while [2a]Br melts at 137.5 1C, [2a][NTf2] is a liquid at
room temperature. Also, in the case of the S-butylbis-N,N0-
(dehydroabietyl)thiouronium cation, [2c]+, the difference
between the melting point of [2c]Br and the other salts, [2c]Y,
where Y = [NTf2], [OTf], [CH3CO2], or [NO3], is at least 70 1C. As
is typical for ionic liquids, the thermal stability of the thio-
uronium bistriflamides is much greater than for the halides, as
the decomposition mechanism involves nucleophilic attack of
the anion on the cation.18a Indeed, [2a][NTf2], [2b][NTf2] and
[2c][NTf2] have decomposition temperatures over 200 1C, and
they are the most thermally stable salts described here.
Measured optical rotations of the products showed significant
differences, not only between chiral thioureas and the corres-
ponding thiouronium salts, but also between salts with the same
cation but different anions. In this case, molar rotation should be
more relevant than specific rotation, as then the molar concen-
tration of the optically active species is taken into account.
Rotamerism and isomerism in chiral thiouronium salts
Thiourea 1a was formed as a single diastereoisomer, reflecting
the high enantiopurity (98%) of the a-(S)-methylbenzylamine
(1-phenylethan-1-amine) used in its preparation. Thiourea 1a
belongs to the C2 point group, and contains a C2 axis of
rotation, hence only one set of peaks was observed for the
methyl and methine groups of the amino components in
thiourea. On conversion to the thiouronium salt (Scheme 1),
the C2 symmetry was reduced to C1, and different signals could
now be observed for the methyl, methine, and N–H groups of
the two amino components. Because the bond order in the two
central C–N and C–S bonds is greater than one, there is also the
possibility of slow hindered rotation about these bonds,24 lead-
ing to four possible isomeric/rotameric forms namely: syn–syn,
syn–anti, anti–syn, and anti–anti of salt [2a]Br (Scheme 2).25
Scheme 2 The four possible isomeric/rotameric forms of the thiouronium cation,
As Table 1 shows, there is a significant difference in molar generated due to hindered rotation about the CQN bond and the CQS bond.
c
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Fig. 3 The 1H–13C HSQC spectrum (400 and 101 MHz) of [2a]Br (in DMSO-d6 at 20 1C). Red signals indicate CH and CH3 groups; blue signals indicate CH2 groups.
Since each of these forms will produce two sets of amino
The third indicator was derived from a NOESY experiment
signals, there is potential for the NMR spectra to be very (Fig. 4). In general NOESY spectra show cross peaks for nuclei
complex indeed. In reality, the 1H and 13C NMR spectra of which share a common relaxation pathway. Normally, this
compound [2a]Br were remarkably simple in DMSO-d6 as a involves through-space dipole–dipole relaxation between the
solvent, giving the impression that only one rotamer was nuclei, which is distance dependent and leads to the well known
present (Fig. 3). This could mean either that only one of the nuclear Overhauser effect. However, chemical exchange is also a
four possible rotamers was present in solution, or that there relaxation mechanism and can lead to cross peaks in NOESY
was a mixture of rotamers, undergoing rapid interconversion spectra. These two distinct contributions to NOESY spectra can
on the NMR time scale, resulting in a time-averaged spectrum. be distinguished from each other, in small molecules, as dipole–
This latter supposition is incorrect, as two sets of signals for the dipole coupling leads to an increase in signal intensity (the
chiral methine *CH and the methyl CH3 groups were observed, nuclear Overhauser effect) whilst chemical exchange leads to a
ruling out at least some fast bond rotations. It is known that decrease in signal intensity (saturation transfer).27 The NOESY
rotation about a partial sulfur–carbon double bond is faster spectrum of compound [2a]Br does indeed show a strong cross
than rotation around a partial nitrogen–carbon double bond, as peak between the two methine protons in the two different
the NC bond is about 25 kJ molꢀ1 stronger,24a,b reflecting the environments (Fig. 4a), proving that these two nuclei are linked
poor overlap between a 3p orbital on the sulfur and a 2p orbital by a relaxation pathway. Selective saturation of the methine
on the carbon. It is therefore probable that when the rotation of signal at d 5.54 ppm led to a decrease in intensity of the other
the CQN bond is slow on the NMR timescale, rotation around methine signal (at d 5.16 ppm) to zero, proving that saturation
the CQS bond will be in the intermediate range.
transfer by chemical exchange was the dominant process,
Furthermore, there was fluxional behaviour observed, demon- confirming slow rotation about the CQS bond.
strating slow rotation on the NMR timescale around the CQS bond
Finally, it was recognised that the hydrogen atoms in the
leading to chemical exchange between the CHN signals in the methylene group adjacent to sulfur are diastereotopic, and give
proton and carbon NMR spectra. There were four indicators of this. rise to complicated signals at d 3.25 and 3.18 ppm (Fig. 3).
Firstly, the signals, particularly *CH, were very broad, indicating a However these signals are sharp, as is the carbon signal with
slow chemical exchange process on the NMR timescale (Fig. 3).26 which they are correlated; in other words, neither is displaying
Secondly, in the HSQC spectrum, each individual methine any fluxional activity. This can only happen in the syn–syn and
hydrogen showed correlation to the carbon atom to which it was anti–anti isomers (Scheme 2), as rotation around the CQS bond
attached, in both the different environments (Fig. 3). This can only generates the same molecule and hence is not fluxional with
be explained by rotation around the CQS bond occurring during respect to the S–CH2 signal. Intuitively, one would expect a
the evolution time of the HSQC experiment.
large difference in chemical shift positions for the two *CH
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Fig. 4 Chosen fragments of the NOESY spectrum for (a) [2a]Br and its *CH region; and (b) [2c]Br and its NH region. The experiments were performed in (a) DMSO-d6
and in (b) CDCl3 using 1H–1H NMR correlation (400 MHz) at 20 1C.
Table 2 The number of detected isomers of chiral thiouronium salts, using
1H NMR spectroscopy (4001MHz) at 20 1C
peaks in the syn–syn isomer, due to the position of the butyl
group. In fact, a large difference (of 0.5 ppm) was observed
(Fig. 3). If the compound was the anti–anti isomer, then a large
chemical shift difference in the NH peaks would be expected for
the same reason, which was not observed.
Compound
Solvent
No. of isomers
Ratioa
[2a]Brb
DMSO-d6
DMSO-d6
DMSO-d6
DMSO-d6
DMSO-d6
CDCl3
1
1
2
2
2
2
2
1
2
2
1
1
1
1
1
—
—
[2a][NTf2]b
In further justification of this conclusion, it should be noted [2b]Br
3 : 2c
3 : 2c
1 : 8
1.8 : 2
0.9 : 2
—
[2b][NTf2]
[2c]Cl
[2c]Cl
that DMSO can readily participate in hydrogen-bonding. It is
more than likely that a bifurcated hydrogen-bond interaction
between the thiouronium cation and the solvent (Scheme 3) is [2c]Brd
CDCl3
C6D6
[2c]Brd
stabilising the syn–syn rotamer over all other possible forms of
[2c]Brd
CDCl2CDCl2
CDCl3
DMSO-d6
DMSO-d6
DMSO-d6
DMSO-d6
CDCl3
3 : 1
1 : 2.6
—
—
—
—
—
this compound (Scheme 2). In addition, the 1H-NMR spectrum
[2c]I
of [2a]Br in CDCl3 (not illustrated) was found to be very [2c]I
[2c][NTf2]
[2c][OTf]
[2c][NO3]
complex, due to the absence of strong hydrogen bonds, and
hence no stabilisation of one specific rotamer.
The same detailed analysis of the 1H NMR spectra was [2c][MeCO2]
performed for the rest of the chiral thiouronium salts.
a
Determined by integration of multiple NMR peaks; ratio between
syn–syn and syn–anti isomers. b 1H NMR spectrum recorded at
300 MHz. Ratio between syn–syn and syn–anti isomer with respect
to the dehydroabietyl group. Salt insoluble in DMSO-d6.
Table 2 shows how the number of isomers can be influenced
by both the nature of the N-substituents and by the solvent. In
the case of [2a]Y and [2b]Y, the change in the counterion from
bromide to bistriflamide does not influence the number of
isomers detected, nor the ratio of the isomers (for [2b]Y). These
results are in agreement with the findings of Kim and
coworkers,24c who demonstrated that the counterion in anthra-
cene derivatives of thiouronium salts had no influence on the
ratio of the isomers. For compound [2b]Br, in which the two
amino groups are different, rotation about the CQS bond leads
to a doubling of the peaks. The two resulting isomers are
present in the ratio 3 : 2, as shown in Scheme 4.
c
d
Scheme 4 An illustration of the isomers (syn–syn :syn–anti 3 : 2) present in a solution
of [2b]Br in DMSO-d6 (pink) which are distinguishable by 1H NMR spectroscopy. Blue
and green indicate different environments for the N–H groups. The stereochemistry
of the isomers was assigned with respect to the dehydroabietyl group.
Interestingly, in the case of [2c]Y salts, the number of
isomers depends on solvent as well as on counteranion type
(Table 2). Even for different halides of [2c]+, changes in ratios
between isomers are observable. In general, when using
DMSO-d6 as an NMR solvent, the syn–syn isomer is detectable
(Schemes 2 and 3). In non-polar solvents, on the other hand,
the N–H signal region is more complex, with broader peaks,
suggesting the presence of more than one isomer.
Scheme 3 An illustration of hydrogen-bond interaction between the thiouronium
cation and dimethylsulfoxide (dmso) stabilising the syn–syn rotamer; the hydrogen
bonding has been encoded using Etter’s topographical analysis.20,21
c
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Focussing on the bromide salt [2c]Br in CDCl3 as an example,
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one of the isomers has the N–H groups in two different
environments, corresponding to the two equally intense signals
at d 9.06 and 8.62 ppm (Fig. 4b). This feature is found only with
the syn–anti isomer (Scheme 2). The second isomer of [2c]Br
has only one signal for the N–H groups, at d 10.35 ppm, weaker
in intensity than the other two signals, and represents either a
syn–syn or an anti–anti isomer. The NOESY spectrum of [2c]Br
shows a strong cross peak between all N–H protons (Fig. 4b).
This proves that these nuclei are linked by a relaxation pathway,
as was discussed in the case of the methine proton in [2a]Br.
Selective saturation of any one of the N–H signals leads to a
decrease in intensity of the others to zero, as anticipated.
Hence, again, there is fluxional behaviour, demonstrating slow
rotation about the CS bond as well as the CN bond, with the CN
bond dominating the isomeric distribution.
Fig. 6 Energy profile showing energy differences between isomers syn–syn,
anti–syn and anti–anti in the gas phase of [2a]+, as an example of a thiouronium
cation. The geometries were optimised at the RHF/3-21G* level using Gaussians 98
(Gaussian Inc.).28
Examining the single crystal structure of [2c]Br, further
evidence for the restricted rotation about the CN bond is
found (Fig. 5), where only the anti–syn conformer is observed.
Formation of crystals with anti–syn isomerism suggests the high
stability of that conformation in the solid state. This contrasts
with the situation in solution, where the syn–syn isomer is also
observed. Indeed, computational analysis of the differences in
energies between the syn–syn, anti–syn and anti–anti conforma-
tions of the thiouronium cation in the gas phase showed that the
anti–syn conformer possessed the lowest energy (Fig. 6).
Noteworthy, when this cation is dissolved in a strong hydrogen-
bond acceptor solvent (e.g. DMSO), the formation of a stable
hydrogen-bonded motif (R12(6), Scheme 3) inverts the relative
stability of these conformers with the syn–syn now becoming
the most stable.
non-polar solvents, such as trichloromethane. Returning to the
molar optical rotation results shown in Table 1, the mixture
of stable isomers in different ratios (Table 2) for each [2c]Y
(Y = Cl, Br or I) observed in trichloromethane at 20 1C is the
reason for the unusual order of these values, and probably is
connected with the differing hydrogen-bond acceptor abilities
of the three halide ions.
Further confirmation of the importance of the anion in the
relative stability of the conformers can be found in the case of
[2c][MeCO2] in CDCl3, where only one set of sharp signals was
observable in the 1H NMR spectrum, and no signal was visible
in the region of N–H protons. The most probable explanation
here is that the ethanoate ion forms a very strong hydrogen-
bond motif (R22(8), Fig. 2) with the two N–H bonds of the cation,
even stronger than the R12(6) motif formed with DMSO
(Scheme 3).20,21 Thus, there is preferential stabilisation of
the syn–syn conformer, resulting in the disappearance (total
broadening) of the N–H signal, due to a dynamic process
indicating exchange of the proton between oxygen atoms in
the ethanoate anion with the nitrogen atoms in the thiouronium
cation. So, despite the potential complexity in this system, the
syn–syn rotamer can still be locked in as the dominant form.
To summarise, integration of the N–H signals indicates
an excess of syn–anti isomer over syn–syn isomer of [2c]Y in
Crystallography
Crystallographic data (see Experimental section) for [2c]Br
reveals many other interesting features than the confirmation
of the structure and contributes to the discussion above about
isomerism of the thiouronium cation. Strong hydrogen bonding
between the anion and the cation is observed (Fig. 7a). The
bromide ion is hydrogen bonded to two different cations via a
N–Hꢂ ꢂ ꢂBrꢂ ꢂ ꢂH–N pattern (H1ꢂ ꢂ ꢂBr, 2.54 Å; Brꢂ ꢂ ꢂH2, 2.58 Å), as
shown in Fig. 7a. Additionally, some weaker C–Hꢂ ꢂ ꢂBr hydrogen
bonding interactions were found (Fig. 5),29 ranging from 2.78 to
2.97 Å (Table 3).
The packing of the crystal structure of [2c]Br is dominated by
neighbouring cationic and anionic channels along the b axis,
Fig. 7b and c. The powder diffraction pattern of [2c]Br is in
Fig. 5 A partial crystal structure of [2c]Br, showing a view of a single pair of ions.
c
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Fig. 8 Comparison of the powder diffraction patterns of [2c]Cl and [2c]Br
(exact, red line, and simulated, black line, from single crystal data).
good agreement with the simulated powder diffraction pattern
of the single crystal structure determination (Fig. 8), demon-
strating that the crystal examined was typical for the bulk
synthetic material. Furthermore, examination of the powder
diffraction patterns of [2c]Cl and [2c]Br (Fig. 8) shows that these
salts are isostructural.
Chiral NMR discrimination of oxoanions
The rotamerism/isomerism of the chiral thiouronium salts
revealed an interesting feature connected with the ethanoate
anion. In the case of [2c][CH3CO2] the isomerism was not
detected at room temperature on the NMR time scale
(Table 2). Moreover the 1H NMR spectrum of this compound
is sharp and clear, in contrast to the spectra with other anions,
which are broad and confusing. This suggested that, probably,
the binding of the ethanoate by the thiouronium moiety caused
the rigid and stable conformation of [2c]+. As discussed in the
Introduction, Fig. 2 is the best representation of the interaction
of the thiouronium cation with the oxoanion. Then, as this
system is chiral, it may ‘recognise’ enantiomers of the oxoa-
nions differently, and show non-equivalent signals in the
1H NMR spectrum. The first choice of possible substrates was
the chiral carboxylates. It is known that when a hydrogen-bond
acceptor group is negatively charged, the hydrogen-bond
strengths are enhanced.15a,30 Also, in the case of the thiouro-
nium system, it may be expected that a strong interaction with
the carboxylates, of the type illustrated in Fig. 2, featuring two
parallel hydrogen bonds forming a R22(8) network, would lead to
a thermodynamically stable host–guest interaction, locking the
structure of the cation into a single isomeric form. Hence, a
simple chiral carboxylate was selected as a model substrate, a
racemic tetrabutylammonium mandelate, [N4444][3a]:
Fig. 7 The crystal structure of [2c]Br: (a) hydrogen-bonding interactions of the
bromide anion with two adjacent [2c]+ cations (part of one of the [2c]+ cations
was omitted for clarity); (b) a perspective view of the anion channel; (c) a
perspective view of the cation channel. The prime (’) character in atom labels
indicates that these atoms are at equivalent positions (ꢀx, ꢀ1/2 + y, ꢀz).
Table 3 Distances Hꢂ ꢂ ꢂBr1 and angles D–Hꢂ ꢂ ꢂBr1 showing hydrogen bonding
interactions
Connection
D–Hꢂ ꢂ ꢂBr1
Distance/ Distancea/Å Distancea/Å Anglea/1
Å D–H
Hꢂ ꢂ ꢂBr1
Dꢂ ꢂ ꢂBr1
D–Hꢂ ꢂ ꢂBr1
N1–H1ꢂ ꢂ ꢂBr1
0.86
0.86
2.54
2.58
2.97
2.84
2.78
3.285(2)
3.317(3)
3.773(3)
3.800(3)
3.703(3)
146
145
141
172
158
N2–H2ꢂ ꢂ ꢂBr1
C11–H11Bꢂ ꢂ ꢂBr1 0.96
C22–H22BꢂꢂꢂBr1
0.97
The tetrabutylammonium counterion to the chiral carboxy-
C42–H42Bꢂ ꢂ ꢂBr1 0.97
1
late was not chosen at random. The first H NMR experiments
a
Br1 at (ꢀx, 1/2 + y, ꢀz).
were conducted with a tetramethylammonium salt of mandelate,
c
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Table 4 Determination of peak non-equivalences with [N4444][3a] as a model
substrate in the presence of different thiouronium salts as chiral agents, using
1H NMR spectroscopy (300 MHz) in CDCl3 at 20 1Ca
[N1111][3a], as a substrate, [2a]Br as a chiral agent, and CDCl3 as
a solvent. In this case, [N1111]Br precipitated from the solution.
In order to prevent this precipitation, a bulkier (more hydro-
phobic) cation was selected, [N4444]+. When this was used, no
precipitation occurred.
Agent
None
CH peak
Ddb/ppm
The optimum design of the experiment is as follows: the
model substrate (0.03 mmol) was dissolved in CDCl3 (0.7 cm3)
in the presence of 1a–c or [2a–c]Y (0.03 mmol) and the 1H NMR
spectrum recorded. The methine proton from the chiral centre
0
1a
0.013
0.017
1
of mandelate is visible in the H NMR spectrum as a singlet at
around 4.8 ppm. The 1H NMR traces embedded in Table 4 show
an evolution of the discriminating properties changing with the
structural diversity of the chiral agent. Upon the addition of a
chiral agent, the singlet of the methine proton in the mandelate
appears now as two resonances, one associated with
(R)-mandelate, and the other associated with (S)-mandelate.
As each occurs at a different chemical shift, they must each be
bound strongly within a stable structural entity. Alkylation of
the sulfur atom (to form the novel salts [2a]Br or [2a][NTf2])
causes an increase in the Dd value (difference of shift values
between the peaks of the non-equivalent enantiomers)
compared with thiourea 1a (as described in the literature4).
Moreover, the chemical shift difference between the two enan-
tiomers is found to be a function of both the cation and the
anion of the chiral agent. Thus, if the anion is kept constant
and the cation changed i.e. [2a]Br, [2b]Br and [2c]Br, the
difference in chemical shift ranges from 0.017 to 0.035 to
0.097 ppm, respectively. Similarly, if the cation is kept the same
i.e. [2c]Br and [2c][NTf2], a smaller but still significant change
in the chemical shift is observed from 0.097 to 0.110 ppm.
A noticeable feature is that a methine proton from the
(S)-methylbenzyl group, which is a part of salts [2a]Y and [2b]Y,
moved upfield compared to thioureas 1a and 1b respectively.
Hence, in some cases, the methine quartet is visible very
close to, or even superposing on, the substrate chiral proton
peak. This was not the case for [2c]Y salts. Furthermore, the Dd
value increases about ten times when comparing [2c]Br with
the thiourea, 1c. The effect intensifies after the anion exchange
from bromide to [NTf2]ꢀ, as the latter is more weakly coordi-
nating with the thiouronium cation than the bromide anion.31
In conclusion, the best enantio-discriminating results, even on
[2a]Brc
[2a][NTf2]c
0.017
1b
0
[2b]Brc
[2b][NTf2]c
1c
0.035
0.043
0.009
[2c]Br
0.097
[2c][NTf2]
[2c][NTf2]
0.110
(R)-Enantiomer
[2c][NTf2]
(S)-Enantiomer
a
All samples were prepared by mixing the substrate (0.03 mmol) with
a chiral agent (0.03 mmol) in CDCl3 (0.7 cm3). Difference of CH
b
shift values between peaks of opposite enantiomers of mandelate.
c
A methine proton signal from the methylbenzyl group present in
the chiral agent is visible.
1
relatively low frequency H NMR spectrometers, were obtained
with [2c][NTf2] and the assignment of the individual enantio- (with the exception of [N4444][3c] and [N4444][3l]). In some examples,
mers was confirmed by using optically pure (R)-mandelate and a full resolution of the chiral peaks was observed with no
(S)-mandelate as substrates, which resulted in single reso- interference, while in other cases partial overlap occurred.
nances being observed (Table 4). Therefore, further research The problem of overlapping was particularly significant when
was focussed on this compound as a model chiral agent.
the methine group occurred as e.g. overlapping quartets after
The NMR studies were continued with other oxoanions as complexation of [N4444][3b]. However, the situation could be
substrates and [2c][NTf2] as the chiral agent. As Table 5 shows, resolved by a partial NMR decoupling experiment, which
a group of fourteen racemic mixtures of chiral carboxylic acids, collapses the quartets into singlets, followed by integration of
as well as sulfonic and phosphonic acids, were analysed. All these singlets to yield the enantiomeric purity of the sample.
analytes were in the form of tetrabutylammonium salts, Nevertheless, the selection of substrates for NMR discrimina-
[N4444][3a–n], and in each case the complexation process tion relies on avoiding a superposition of important substrate
between [2c][NTf2] and the substrate [N4444][3] could be signals with receptor signals in the spectrum. In the case of
observed by the proton peak non-equivalence of the methine [2c][NTf2], it provides a useful 1H NMR spectral window for
proton connected with the chiral centre of the substrate chiral discrimination research in the range from 3.5 ppm to
c
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Table 5 Determination of peak non-equivalences of emboldened protons
(in drawn structures) in tetrabutylammonium salts of chosen racemic acids in the
presence of [2c][NTf2], using 1H NMR spectroscopy (300 MHz) in CDCl3 at 20 1Ca
Code of salt
Racemic acid
Ddb/ppm
[N4444][3a]
0.110
[N4444][3b]
[N4444][3c]
0.070
0.091c
0.045d
Fig. 9 (a) Determination of the enantiomeric purities of [N4444][(R)-3a] in the
presence of [2c][NTf2] using 1H NMR spectroscopy (400 MHz) in CDCl3 at 20 1C.
Theoretical % ee values calculated from the mass of enantiomers used for
preparing the analytes are given for comparison with practical % ee values, based
on the integration of methine peaks (indicated in parentheses). (b) The
correlation between the theoretical and practical % ee values.
[N4444][3d]
[N4444][3e]
0.030
0.058 (CH)
0.031 (Ac)
0.022 (Ac)
0.107 (Ar-NH)
[N4444][3f]
theoretical and observed enantiomeric excess (% ee), when
using just one equivalent of agent with respect to the substrate
in a CDCl3 solution.
[N4444][3g]
[N4444][3h]
0.030
0.102e (2JHF = 50.2 Hz)
0.374f (2JHF = 50.3 Hz)
Molecular recognition mode
NMR study
0.058 (CH)
0.129 (NH)
The molecular recognition behaviour of the new chiral agents
was further investigated. There is no doubt that the thiouro-
nium moiety, containing N–H groups as sources of hydrogen
bonds, is the receptor centre for the oxoanions, in an analogous
way to that already established for guanidinium salts. For the
thiouronium complexes with oxoanions, a binding pattern
featuring two parallel hydrogen bonds may be described by
the R22(8) descriptor (Fig. 2).20,21 The same descriptor is found
in the guanidinium system.
[N4444][3i]
[N4444][3j]
[N4444][3k]
0.047
0.038
The fact is that the initial NMR experiments on enantio-
discrimination have shown (vide supra) that the complexation
results in a locked conformation of the single isomeric form of
the cation. This can be see clearly in Fig. 10, by comparing the
well resolved and simple spectrum of a 1 : 1 complex of
[2c][NTf2] and [N4444][3a] with the conformational freedom
exhibited by the uncomplexed [2c][NTf2]. As the thiouronium
moiety recognises the oxoanions, it may be suspected that the
1 : 1 complexation ratio is an optimum for this system. Indeed,
1H NMR experiments carried out with increasing molar equiva-
lents of [2c][NTf2] added to the model substrate [N4444][3a]
confirmed that the optimum stoichiometry of the adduct is
indeed 1 : 1 (Fig. 11). These new reagents are truly competitive
with those known from the literature, especially the extant
chiral ionic liquids, where an excess of 3 to even 24 equivalents
[N4444][3l]
0.018
[N4444][3m]
0.006
0.013
[N4444][3n]
a
All samples were prepared by mixing carboxylate salt (0.03 mmol) with
[2c][NTf2] (0.03 mmol) in CDCl3 (0.7 cm3). Difference of shift values
b
c
between peaks of opposite enantiomers. Proton peaks from the
methoxy group are superimposed on proton peaks from [2c][NTf2] but
still visible. Results of 19F NMR (282 MHz) experiment in CDCl3 at
d
e
20 1C. Results of 1H NMR (400 MHz) experiment in CDCl3 at 20 1C.
f
Results of 19F NMR (376 MHz) experiment in CDCl3 at 20 1C.
6.5 ppm, and then above 7.5 ppm, which for a-substituted is required for satisfying results in the chiral NMR discrimina-
carboxylates is usually sufficient.
tion.17 Moreover, they may be considered as simple synthetic
The possibility of determining enantiomeric purities was analogues to the naturally occurring receptor centres in
proved by a 400 MHz 1H NMR experiment using the model enzymes, since each receptor centre recognises and saturates
substrate [N4444][3a] and agent [2c][NTf2] (Fig. 9). Indeed, a with a single substrate. They are hence ‘abiotic’ or ‘biomimetic’
linear correlation (R2 = 0.993) was confirmed between the receptor systems, analogous to Lehn’s archetypal guanidinium
c
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Fig. 10 Comparison between the 1H NMR spectrum of uncomplexed [2c][NTf2] (red trace) and complexed with [N4444][3a] (black trace) using 1H NMR spectroscopy
(300 MHz) in CDCl3 at 20 1C.
no evidence for self-association of either the cation [2a]+ or the
neutral thiourea 1a in the range of concentration from 1.7 to
50 mM. Further, when the guest [N4444][3a] was compared with
its precursor – mandelic acid (Fig. 12b), the results revealed
that, as in the case of host, the self-interactions of [3a]ꢀ are also
undetectable in these experiments. However, free mandelic
acid shows the expected self-association, which is normally
found for carboxylic acids.32 In conclusion, for the determina-
1
tion of host–guest interactions by H NMR spectroscopy, it is
correct to ignore both host–host and guest–guest interactions
as these are too weak to be detected.
Next, the stoichiometry of the host–guest interaction was
examined. The Job’s plot, Fig. 13a, confirmed the 1 : 1 stoichio-
metry of the interaction between [2c]+ and [3a]ꢀ, as the
Fig. 11 Determination of the optimum ratio of chiral agent [2c][NTf2] to model
maximum appears at ca. 0.5 mol fraction.33 The 500 MHz
substrate [N4444][3a] required for NMR discrimination of using 1H NMR
1H NMR titration experiments in CDCl3, Fig. 13b, showed that
spectroscopy (400 MHz) in CDCl3 at 20 1C.
the determination of the binding constants for each enantio-
mer of the guest [N4444][3a] and optically pure [2c][NTf2] is
impossible in this solvent. Sharp NMR isotherms which pro-
substrates, less than one equivalent would be sufficient for an
duce two straight lines that intersect at the [host]/[guest] ratio
system (Fig. 1a).3a Another promising feature is that, for some
effective determination of the ee of the chiral analyte, hence
giving increased sensitivity.
corresponding to the stoichiometry of the complex (Fig. 13b)
indicate that the binding constants are too large to be properly
determined by the NMR method (K > 105 Mꢀ1).34 Thus, there
Thermodynamic binding study
was a need to use an additive, which will decrease the degree of
Determination of possible self-association interactions between binding between [3a]ꢀ and [2c]+, and then allow for generation
the chiral agent (host) and the chiral substrate (guest) is of classic 1 : 1 NMR binding isotherms,34 from which a reduced
important for a full description of the binding process. Hence, binding constant can be estimated. A series of trials with
the self-association equilibrium for the model agent, here different additives (MeOD and DMSO-d6) in different concen-
[2a][NTf2], and its molecular analogue, thiourea 1a, was deter- trations (1–10% v/v) in CDCl3 showed that the optimum NMR
mined (Fig. 12a). Examining Fig. 12a, there is an impression of titration data were obtained in a solution of 10% v/v DMSO-d6
a general trend of chemical shift increasing with increasing in CDCl3, and in this system the reduced binding constant K
concentration. However, closer inspection reveals that the could be determined for the interaction between [2c][NTf2] and
difference in chemical shift between the lowest and highest [N4444][3a] (Fig. 13c and Table 6). The methodology for deter-
concentrations is less than three standard deviations (3s), and mination of equilibrium constants is explained in detail in the
hence there is no significant difference between these values. In Experimental section. Generally, the method is based on a
other words, within the errors of the NMR experiments, there is classic equation for the binding isotherm, adapted to NMR
c
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Fig. 12 Dependence of 1H NMR (400 MHz, 20 1C) chemical shifts on concentration for (a) [2a][NTf2] and 1a in DMSO-d6 and (b) [N4444][3a] and mandelic acid in MeOD.
Fig. 13 1H NMR data (500 MHz; CDCl3; 27 1C) for (a) the Job’s plot (’ (S)-enantiomer; & (R)-enantiomer);33 (b) the titration of [N4444][3a] (cconst = 2 mM) with
[3c][NTf2] in CDCl3 expressing the well defined NMR binding isotherms indicative of a binding constant, K > 105 Mꢀ1 for the interaction between [2c][NTf2] and
[N4444][3a];34 and (c) the 1 : 1 NMR binding isotherms used for estimation of a reduced binding constant K for the interaction between [2c][NTf2] and [N4444][3a] in
10% v/v DMSO-d6 in CDCl3.35 Dd is the chemical shift difference of the methine proton peaks between free and complexed mandelate; X is the mole fraction; d is the
chemical shift of the methine proton peaks in mandelate; c is the concentration (mol lꢀ1); ceq in the concentration in the equilibrium state required for proper binding
constant K estimation. For curves (c), the trend lines were fitted using non-linear regression analysis.
Table 6 Binding constants for complexes between selected chiral host and guests using 1H NMR spectroscopy (500 MHz) in CDCl3 at 20 1C
Host
Guest
Ka/Mꢀ1
NMR solvent
DGb/kJ molꢀ1
[2a][NTf2]
[2a][NTf2]
[2b][NTf2]
[2b][NTf2]
[2c][NTf2]
[2c][NTf2]
[2c][NTf2]
[2c][NTf2]
(S)-[N4444][3a]
(R)-[N4444][3a]
(S)-[N4444][3a]
(R)-[N4444][3a]
(S)-[N4444][3a]
(R)-[N4444][3a]
(S)-[N4444][3a]
(R)-[N4444][3a]
K >105
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
oꢀ28.72
oꢀ28.72
oꢀ28.72
oꢀ28.72
oꢀ28.72
oꢀ28.72
ꢀ22.23
K >105
K >105
K >105
K >105
K >105
7413 ꢃ 1235
10% v/v DMSO-d6 in CDCl3
10% v/v DMSO-d6 in CDCl3
20 283 ꢃ 5231
ꢀ24.74
a
b
Binding constants were calculated from the equation defined in the experimental part. Gibbs free energy calculated from ꢀRT ln(K).
spectroscopy,35 and the curve fitting was accomplished by mandelate over the (S)-enantiomer by [2c]+, even for reduced values
standard non-linear regression analysis.36 NMR titrations were of binding constants with DMSO-d6. A chiral recognition energy
also carried out with hosts [2a][NTf2] and [2b][NTf2] using DDG calculated from ꢀRTln(K(S)/K(R)) is equal to 2.51 kJ molꢀ1 for
[N4444][3a] as a guest (Table 6). Results showed that, for hosts [2c][NTf2] as a host for mandelate as a substrate.
functionalised with an (S)-methylbenzyl group, the binding
The reason for such a strong interaction may lay not only in
with a model substrate in CDCl3 is also too strong to have K the combination of the hydrogen bonding and Coulombic
accurately determined (vide supra).34 Thus the only determina- forces. The structure of the thiouronium salts may also lead
tion of the preference of binding (R)-[3a]+ over (S)-[3a]+ by to additional interactions such as stacking interactions, espe-
[2c][NTf2] is provided by NMR titration experiments in a cially in the case of dehydroabietyl as the N-substituent. As seen
solvent mixture of 10% v/v DMSO-d6 in CDCl3. Indeed, there in Fig. 14a, for [2a][NTf2], there is a much lower probability of
is a threefold difference in binding of the (R)-enantiomer of direct p–p interactions with the guest, but at the same time a
c
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Fig. 14 The schematic visualisation of possible stacking interactions occurring between the model mandelate anion, [3a]ꢀ, and (a) [2a]+, (b) [2b]+ and (c) [2c]+.
substrate has better access to the receptor centre of the host.
Organisation of the results in order of increasing Dd
A more complex situation exists for [2b][NTf2] (Fig. 14b): on one reveals the character of competition between the anions for
side of this host centre, there is an a-methylbenzyl group, and on the thiouronium receptor centre:
the other side there is a dehydroabietyl group. This case presents a
[NTf2]ꢀ > [OTf]ꢀ > Iꢀ > Brꢀ > [NO3]ꢀ > Clꢀ > [CH3CO2]ꢀ
unique combination of more open access for the guest, deriving
from the (S)-methylbenzyl substituent, with p–p interactions
between the guest and the dehydroabietyl aromatic ring. Finally,
[2c][NTf2] has an ideal structure to support the binding of a
phenyl-functionalised guest via stacking interactions (Fig. 14c),
but at the same time structurally developed substituents, like
dehydroabietyl groups, can limit access to the receptor centre.
Thus, increasing values of Dd were observed from ethanoate,
through halides, to bis(trifluoromethyl)sulfonylamide. This
order appears to reflect the hydrogen-bonding acceptor abilities
of the anions, but the precise basicity of anions in ionic liquids
is not known. The order as suggested by the Kamlet–Taft
solvatochromic b parameter is37,38
Clꢀ > Brꢀ > Iꢀ > [CH3CO2]ꢀ > [NO3]ꢀ > [OTf]ꢀ > [NTf2]ꢀ
Anion influence
Thus, as may have been anticipated, the competition
between anions reflects more than simple basicity, and clearly
must feature at least a steric factor and a recognition of the
topological pattern (Fig. 2). In general, anion binding selectivity
in the absence of specific chemical recognition between the
anion and the host cation should follow the order of decreasing
anion hydrophobicity (as indicated by the Hofmeister series):1
When involving a cation that acts as a host for anions, obviously it
is in competition with the cation from the guest.1 A similar
competition should be recognised between the anions of the guest
and the host. Indeed, when comparing the bromide and the
bis(trifluoromethyl)sulfonylamide accompanying the same cation
(Table 4), there is a noticeable effect on methine peak non-
equivalences in [N4444][3a], influenced by the anion of the chiral
host. Thus, the 1H NMR spectra were recorded for the S-butyl-N,N0-
bis(dehydroabietyl)thiouronium cation with different anions
(Table 7). The main factor taken into consideration is again the
Dd of the methine peak from the model substrate (guest): Table 7
clearly shows a strong influence from the nature of the host’s anion.
An additional interesting observation during this investigation was
a significant shift of the N–H peaks in the 1H NMR spectrum of the
complexes between the model substrate and [2c]Y salts.
Iꢀ > [NO3]ꢀ > Brꢀ > Clꢀ c [CH3CO2]ꢀ
When comparing this series with the results for anion
competition observed here (note that bistriflamides are extre-
mely hydrophobic), they follow a similar trend.
Results showing that the N–H peak from the host is moving
downfield with the higher value of Dd (Table 7) prove that
stronger hydrogen bonding interactions are occurring between
the receptor centre and the guest anion, ruling out the host
counterion.39 In other words, mandelate is more strongly
bonded than the host’s anion because of a combination of
its hydrophobicity, hydrogen-bond pattern recognition, and
steric size.
To conclude, the competition between the host and guest
anions for binding with [2c]+ has a significant implication for
chiral recognition, viz. the greater the competition, the smaller
the discrimination. Thus, in order to examine the substrates
with lower hydrogen-bonding acceptor abilities, it is necessary to
use non-competing anions in the chiral agent, such as [NTf2]ꢀ.
Table 7 Determination of peak non-equivalences with [N4444][3a] as a model
substrate in the presence of the [2c]Y as chiral host, using 1H NMR spectroscopy
(300 MHz) in CDCl3 at 20 1Ca
Yꢀ
Ddb/ppm
dN–Hc/ppm
[CH3CO2]ꢀ
Clꢀ
0.013
0.072
0.083
0.097
0.101
0.107
0.110
8.935
11.707
11.908
11.835
11.861
11.976
12.006
[NO3]ꢀ
Brꢀ
Iꢀ
[OTf]ꢀ
[NTf2]ꢀ
a
Computational study
All samples were prepared by mixing the guest (0.03 mmol) with [2c]Y
b
(0.03 mmol) in CDCl3. Difference of CH shift values between peaks of
c
Computational optimisation analyses for the two enantiomers of
opposite enantiomers of mandelate. Chemical shift of the N–H protons
[3a]ꢀ with [2c]+ were performed to investigate the origin of the
from [2c]+ observed as a broadened peak in the H NMR spectrum.
1
c
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Fig. 15 Optimised structures for (a) [2c][(S)-3a] and (b) [2c][(R)-3a]. Each host–guest pair is illustrated by two different views, the left one emphasising the importance
of hydrogen bonding, the right one emphasising the resulting distances between the butyl side chain from the host, [2c]+, and the phenyl group from the guest, [3a]ꢀ.
The geometries were optimised at the RB3LYP/STO-3G level using Gaussians 98 (Gaussian Inc.).28
enantio-discrimination connected with the chiral thiouronium the chiral centre, which is spatially close to the carboxylate group,
salts. The results of density functional theory (DFT) calculations a stabilising intramolecular five-membered ring is formed. This
(RB3LYP/STO-3G)28 on the optimised structures of the complexes intramolecular hydrogen bond reduces the electron density on the
between [2c]+ and [(S)-3a]ꢀ, as well as [(R)-3a]ꢀ, are illustrated in carboxylate oxygen and hence weakens the intermolecular hydrogen
Fig. 15. Although it is realised that this is a rather low level bond formed by the same oxygen atom to the thiouronium moiety,
calculation, and caution should be exercised when examining the Fig. 16a. This is confirmed by analysing the features of the
energy predictions, it does well illustrate some of the key features computed structure [2c][3d], Fig. 16b. Here, there is no intra-
of the system. As the anion approaches the recognition site within molecular hydrogen bond, as the –OH group was replaced by the
the host cation, the cation responds by changing its conformation –CH3 group, and in addition methyl is electron-releasing, whereas
to accommodate the anion. In other words, the more tightly hydroxyl is an electron-attracting group. The net effect is that the
bound the anion, the more rigid the new conformation of the oxygen atoms of the carboxylate group are more negatively
cation becomes. In addition, as [3a]ꢀ possesses an –OH group at charged in [2c][3d] than they are in [2c][3a], and therefore the
Fig. 16 Hydrogen bond distances and differences in energies between complexes of [2c]+ and (a) enantiomers of [3a]ꢀ; (b) enantiomers of [3d]ꢀ obtained by
optimisation at the RB3LYP/STO-3G level using Gaussians 98 (Gaussian Inc.).28 Parts of the [2c]+ cations were omitted for clarity.
c
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NJC
hydrogen bonds from the former are on average 0.03 Å shorter required simple purification, as described in the literature.19
than in the latter. Dichloromethane was stored closed over molecular sieves, and
However, the differences in energy for both complexes of the diethyl ether was stored over sodium. All flash chromatography
opposite enantiomers of [2c][3a] (0.44 kJ molꢀ1) and [2c][3d] was performed using Aldrich Silica gel, Merck grade 10180
1
(0.30 kJ molꢀ1) are too small to be significant, given the level of (70–230 mesh). H NMR spectra were recorded at 300, 400 or
the calculation.
500 MHz. 13C NMR spectra were recorded at 101 MHz. 19F NMR
spectra were recorded at 376 MHz. Two-dimensional correla-
tion NMR spectra (COSY), heteronuclear single quantum cor-
relation NMR spectra (HSQC) and nuclear Overhauser effect
NMR spectra (NOESY) were recorded at 400 MHz (1H NMR
traces) and 101 MHz (13C NMR traces). Melting points Tm (mp)
were determined in capillaries (uncorrected) or by DSC analysis.
Glass transition temperatures Tg were obtained using DSC
analysis (N2 atmosphere, 5ꢀ10 1C minꢀ1 scan rate). Decom-
position temperatures Tdec were determined with TGA analysis
(N2 atmosphere, 10 1C minꢀ1 scan rate). Optical rotations [a]2D0
were determined on a digital polarimeter at 20 1C in CHCl3 as a
solvent. The exact mass was obtained using high-resolution
mass spectrometry (Waters – LCT PREMIER instrument) with
electrospray ionisation (EI). Combustion elemental analysis
was performed for all new products. Karl-Fisher titration for
water content W, density d20 and viscosity Z20 determination
was performed for room temperature chiral ionic liquid
product ([2a][NTf2]).
Conclusions
A series of chiral thiouronium salts, [2]Y, was developed and used
for chiral discrimination of oxoanions, e.g. mandelate, using NMR
spectroscopy. The performance of these salts was superior to that
of the uncharged molecular precursors, the chiral thioureas.
It was confirmed that the alkylation reaction of the sulfur
atom induced delocalisation of the positive charge through the
p-orbitals of the {CN2S} core. Because of this delocalisation,
rotation about the CN bonds exists, but with restricted char-
acter. Hence, the thiouronium cations should exhibit discrete
rotamers, as confirmed by the broadened and complex NMR
signals. Indeed, extensive NMR studies confirmed that the
interconversion of the rotamers was dependent on tempera-
ture, the nature of the N-substituents, the NMR solvent, and the
counterion, as well as influencing the optical rotation.
However, in the case of [2c][CH3CO2], the 1H NMR spectrum
revealed a rigid conformation of the cation–anion system, due
to strong hydrogen bonding interactions, which produced a
sharp set of 1H NMR signals. This observation triggered an
extensive study of the chiral discrimination between oxoanions,
especially carboxylates, by these new chiral salts.
The best results were obtained with [2c][NTf2] as a chiral
agent, and it was found to be comparable, or better, in
performance than existing systems in the literature. An addi-
tional advantage here is the relatively easy synthesis of this
agent with a low cost chiral auxiliary. Apart from other chiral
carboxylate substrates, chiral sulfonates and phosphonates
could also be recognised and discriminated.
By changing the molar concentration of the chiral agent over
the chiral substrate, it was confirmed that a 1 : 1 ratio is the
optimum for the formation of the complex between [2c][NTf2]
and the model substrate, and this is enough for an effective
discrimination process.
Crystal data
Crystal data for [2c]Br were collected using
a Bruker
Nonius Kappa CCD diffractometer with a FR591 rotating
anode and a molybdenum target at ca. 120 K in a dinitrogen
stream.40 Lorentz and polarisation corrections were applied.
The structure was solved by direct methods. Hydrogen-
atom positions were located from difference Fourier maps
and a riding model, with fixed thermal parameters (Uij
=
1.2Ueq for the atom to which they are bonded, 1.5 for methyl),
was used for subsequent refinements. The function minimised
was S[o(|F0|2 ꢀ |Fc|2)] with reflection weights oꢀ1 = [s2 |F0|2 +
(g1P)2 + (g2P)] where P = [max|F0|2 + 2|Fc|2]/3. The SHELXTL
package and OLEX2 were used for structure solution and
refinement.41 Formula: C45H69N2SBr; MW: 749.99 g molꢀ1
;
crystal size: 0.15 ꢁ 0.15 ꢁ 0.1 mm; crystal system: monoclinic;
As the binding constants are large in CDCl3 (K > 105 Mꢀ1), it
was necessary to determine reduced binding constants by the
addition of DMSO-d6. Even under these conditions, a three-fold
difference in binding of (R)-mandelate over (S)-mandelate was
observed, which is competitive with other systems used for
chiral discrimination.
space group: P21; a: 11.543(2) Å; b: 11.5238(17) Å; c: 15.689(3) Å;
a: 90.001; b 100.072(4)1; g 90.001; V: 2054.8(6) Å3; Z: 2; Dcalc.
:
1.212 g cmꢀ3; crystal shape: block; crystal colour: colourless;
m: 1.083 mmꢀ1; F(000): 808; measured reflections: 14 473;
unique reflections: 12 111(Rint = 0.0310); parameters refined:
451; Goof on F2: 0.870; final R indexes [I > 2s (I)]: R1 = 0.0535,
wR2 = 0.0630; final R indexes [all data] R1 = 0.0829, wR2 = 0.0759;
Flack parameter 0.018(6), CCDC 882873.
Using this kind of receptor may also be useful for the
physical separation of racemic mixtures.
Experimental section
X-ray powder diffraction data
General information
XRD data were collected using a PANalytical’s X’PERT Pro
MPD powder diffractometer equipped with a Cu-K X-ray
(l = 1.542 Å) source. The 2y range was 41ꢀ901, with a step size
of 0.0161.
All reagents and solvents were obtained from commercial
suppliers and were used without further purification unless
otherwise stated. (+)-Dehydroabietylamine (60% grade)
c
528 New J. Chem., 2013, 37, 515--533
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Paper
General procedure for the synthesis of chiral isothiocyanates
(300 MHz, DMSO-d6) d 7.74 (br s, 2H, 2 ꢁ NH), 7.46–7.04
(m, 10H, Ar CH), 5.42 (br s, 2H, 2 ꢁ CH), 1.39 (d, J = 6.9 Hz,
6H, 2 ꢁ CH3); 13C NMR (75 MHz, DMSO-d6) d 180.80 (SQC),
144.26 (C), 128.26 (CH), 126.67 (CH), 126.02 (CH), 52.24 (CH),
22.44 (CH3); calcd for C17H20N2S: C 71.79, H 7.09, N 9.85,
S 11.27%; found: C 71.47, H 7.11, N 9.76, S 11.19%. HRMS-ESI
(m/z) calcd for C17H21N2S [M + H]+ 285.1425, found 285.1426.
N-(S)-a-Methylbenzyl-N0-dehydroabietylthiourea (1b). White
solid (1.71 g, 76%); Rf = 0.68 (SiO2, hexane : CH3CO2Et 2 : 1); mp
101.6–102.4 1C; [a]2D0 = 14.2 (c = 1.0, CHCl3); 1H NMR (400 MHz,
DMSO-d6) d 7.79 (d, J = 6.5 Hz, 1H, N–H), 7.31–7.04 (m, 6H, Ar
CH, N–H), 7.14 (d, J = 8.2 Hz, 1H, Ar0 CH), 6.95 (dd, J = 8.1,
1.8 Hz, 1H, Ar0 CH), 6.83 (d, J = 1.5 Hz, 1H, Ar0 CH), 5.42 (br s,
1H, CH), 3.51 (br s, 1H, NCH1), 3.31 (br s, 1H, NCH2), 2.78 (sep,
J = 7.0 Hz, 1H, CH), 2.79–2.62 (m, 2H, CH2), 2.25 (br d, J =
12.3 Hz, 1H, CHH), 1.91–1.63 (m, 2H, CH2), 1.63–1.48 (m, 2H,
CH2), 1.37 (d, J = 6.9 Hz, 3H, CH3), 1.43–1.25 (m, 3H, CH, CH2),
1.25–1.04 (m, 1H, CHH), 1.17 (d, J = 7.0 Hz, 6H, 2 ꢁ CH3), 1.12
(s, 3H, CH3), 0.85 (s, 3H, CH3); 13C NMR (101 MHz, DMSO) d
182.47 (SQC), 147.03 (C), 144.85 (C), 144.35 (C), 134.47 (C),
128.12 (CH), 126.50 (CH), 126.38 (CH), 125.90 (CH), 124.01
(CH), 123.49 (CH), 53.81 (CH2), 52.07 (CH), 44.21 (CH), 37.96
(C), 37.40 (CH2), 36.94 (C), 35.74 (CH2), 32.88 (CH), 29.52 (CH2),
25.07 (CH3), 24.01 (CH3), 23.86 (CH3), 22.25 (CH3), 18.80 (CH3),
18.45 (CH2), 18.20 (CH2); calcd for C29H40N2S: C 77.63, H 8.99, N
6.24, S 7.15%; found: C 78.11, H 8.72, N 6.37, S 7.06%. HRMS-ESI
(m/z) calcd for C29H41N2S [M + H]+ 449.2990, found 449.2985.
N,N0-Bis(dehydroabietyl)thiourea (1c). White solid (0.85 g,
91%); Rf = 0.63 (SiO2, hexane : CH3CO2Et 2 : 1); mp 139–1411C;
Chiral isothiocyanates were prepared by analogy to reported
procedures.42 At 0 1C under N2, to a solution of 1 eq. of N,N0-
dicyclohexylcarbodiimide and 1 eq. of chiral amine in dry Et2O
ether 3 eq. of CS2 was added dropwise. The reaction was
allowed to warm slowly to 20 1C, and then stirred overnight.
TLC was used to confirm when the reaction was complete.
Then, the precipitated by-product (N,N0-dicyclohexylthiourea)
was removed by filtration, and the solvent with an excess of CS2
was evaporated under reduced pressure. The residue was
purified by column chromatography (SiO2, hexane).
(S)-a-Methylbenzyl isothiocyanate. Colourless liquid (2.43 g,
81%); Rf = 0.43 (SiO2, hexane); [a]2D0 = 16.6 (c = 1.02, CHCl3);
1H NMR (300 MHz, CDCl3) d 7.43–7.25 (m, 5H, Ar CH), 4.90
(q, J = 6.8 Hz, 1H, CH), 1.66 (d, J = 6.8 Hz, 3H, CH3); 13C NMR
(75 MHz, CDCl3) d 140.09 (C), 132.18 (NQCQS), 128.85 (CH),
128.15 (CH), 125.36 (CH), 56.98 (CH), 24.93 (CH3). Calcd for
C9H9NS: C 66.22, H 5.56, N 8.58, S 19.64%; found: C 66.03,
H 5.60, N 8.55, S 19.44%. HRMS-EI (m/z) calcd for C9H9NS [M]+
163.0456, found 163.0478.
Dehydroabietyl isothiocyanate. Colourless dense oil (1.00 g,
87%); Rf = 0.23 (SiO2, hexane); [a]2D0 = –47.1 (c = 1.0, CHCl3);
1H NMR (400 MHz, CDCl3) d 7.17 (d, J = 8.2 Hz, 1H, Ar CH), 7.00
(d, J = 8.2, 1H, Ar CH), 6.89 (s, 1H, Ar CH), 3.37 (dd, J = 65.8, 14.0
Hz, 2H, CH2-NCS), 2.98–2.85 (m, 2H, CH2), 2.82 (sep, J = 6.8 Hz,
1H, CH), 2.29 (br dt, J = 12.6, 2.7 Hz, 1H, CHH), 1.84–1.62
(m, 4H, CHH, C0HH, CH2), 1.59 (dd, J = 12.1, 2.4 Hz, 1H, C0HH),
1.54–1.35 (m, 3H, CH, CH2), 1.22 (d, J = 6.9 Hz, 6H, 2 ꢁ CH3),
1.21 (s, 3H, CH3), 0.96 (s, 3H, CH3); 13C NMR (101 MHz, CDCl3)
d 146.50 (C), 145.76 (C), 134.32 (C), 129.98 (NCS), 126.83 (CH),
124.32 (CH), 124.01 (CH), 56.64 (CH2), 45.58 (CH), 38.39 (C),
38.10 (CH2), 37.54 (C), 36.35 (CH2), 33.43 (CH), 30.11 (CH2),
25.15 (CH3), 23.95 (2 ꢁ CH3), 19.03 (CH2), 18.57 (CH2), 18.10
(CH3). Calcd for C21H29NS: C 77.01, H 8.92, N 4.28, S 9.79%;
found: C 77.15, H 8.74, N 4.12, S 9.49%. HRMS-EI (m/z) calcd for
1
[a]2D0 = 14.3 (c = 1.0, CHCl3); H NMR (400 MHz, CDCl3) d 7.15
(d, J = 8.2 Hz, 2H, 2 ꢁ Ar CH), 6.98 (dd, J = 8.1, 1.7 Hz, 2H, 2 ꢁ Ar
CH), 6.88 (s, 2H, 2 ꢁ Ar CH), 5.75 (br s, 2H, 2 ꢁ NH), 3.36 (br m,
4H, 2 ꢁ NCH2), 2.98–2.74 (m, 4H, 2 ꢁ CH2), 2.83 (sep, J = 6.9 Hz,
2H, 2 ꢁ CH), 2.27 (br d, J = 12.7 Hz, 2H, 2 ꢁ CHH), 1.95–1.55
(m, 8H, 2 ꢁ CHH, 2 ꢁ CH2, 2 ꢁ C0HH), 1.51–1.16 (m, 8H, 2 ꢁ
C0HH, 2 ꢁ CH, 2 ꢁ CH2), 1.22 (d, J = 6.9 Hz, 12H, 4 ꢁ CH3), 1.20
(s, 6H, 2 ꢁ CH3), 0.96 (s, 6H, 2 ꢁ CH3); 13C NMR (101 MHz,
CDCl3) d 182.92 (CQS), 146.85 (C), 145.68 (C), 134.49 (C), 126.84
(CH), 124.03 (CH), 123.84 (CH), 55.28 (CH2), 45.71 (CH), 38.23
C
21H29NS [M]+ 327.2021, found 327.2042.
General procedure for the synthesis of chiral thioureas
Chiral thioureas were prepared by analogy to reported proce- (CH2), 37.73 (C), 37.42 (C), 36.74 (CH2), 33.40 (CH), 29.97 (CH2),
dures.42 At 0 1C, under dinitrogen, 1 eq. of the chiral amine was 25.17 (CH3), 23.95 (2 ꢁ CH3), 19.08 (CH2), 18.65 (CH2), 18.46
added dropwise to a solution of 1 eq. of a chiral isothiocyanate (CH3); calcd for C41H60N2S: C 80.33, H 9.87, N 4.57, S 5.23%;
in dry CH2Cl2. Then, the cooling bath was removed and the found: C 80.30, H 9.69, N 4.52, S 5.38%. HRMS-ESI (m/z) calcd
mixture was stirred overnight at 20 1C. In the case of 1a, the for C41H61N2S [M + H]+ 613.4555, found 613.4569.
product precipitated during the reaction. When the absence of
General procedure for the synthesis of chiral thiouronium salts
starting materials in the reaction mixture was confirmed by
TLC, the product was collected by filtration, washed with Alkylation reactions were prepared by analogy to reported
CH2Cl2 and diethyl ether, and dried in vacuo. For the other procedures.11 A solution of thiourea (1 eq.) and 1-halobutane
thioureas, which were readily soluble in CH2Cl2, after the (1.05–6 eq.) in EtOH was heated under reflux for 24 h
completion of the reaction, the solvent was evaporated and (1-iodobutane required 65 1C, 1-bromobutane required 80 1C,
the residue was purified by column chromatography (SiO2, both reactions in a standard reflux apparatus, and 1-chloro-
hexane : CH3CO2Et 2 : 1).
butane required 90 1C in a sealed glass tube). The consumption
N,N0-Bis((S)-a-methylbenzyl)thiourea (1a). White solid of thiourea was monitored by TLC and the reaction time was
(1.16 g, 82%); Rf = 0.37 (SiO2, hexane : CH3CO2Et 2 : 1); mp extended if necessary. When TLC indicated the end of the
199.6–200.9 1C (lit.4 mp 199–200 1C); [a]2D0
=
104.4 reaction, the solvent and the excess of haloalkane were evapo-
(c = 1.0, CHCl3), (lit.4 [a]D25 +114.2 (c 1.05, CHCl3)); 1H NMR rated under reduced pressure. Products were dried in vacuo.
c
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NJC
Note: Since NMR spectra of thiouronium salts are influ- 1.18 (br s, 15H, 4 ꢁ CH3, C0H3), 1.05 (s, 3H, C0H3), 0.96 (s, 3H,
enced by hindered rotamerism about partial double bonds C00H3), 0.85 (s, 3H, C00H3), 0.75 (s, 3H, CH3); 13C NMR (101 MHz,
CQN and CQS, in some cases a mixture of rotamers/isomers CDCl3) d 168.13 (CQS), 146.74 (C), 145.58 (C), 134.45 (C), 126.76
1
is recognised and H NMR is then appropriately described by (CH), 123.89 (CH), 123.67 (CH), 54.53 (CH2), 45.76 (CH0), 44.46
partial integration of protons or additional notations, e.g. for (CH0), 39.64 (C), 38.13 (CH2), 37.42 (CH2), 33.67 (C), 33.40 (CH),
the same CH3 group available in two isomers: d 0.90–0.75 30.74 (CH2), 29.82 (CH2), 25.17 (CH3), 23.94 (CH3), 21.66 (CH2),
(m, 0.5 ꢁ 3H, C0 0H3), 0.49 (s, 0.5 ꢁ 3H, C0 0H3).
19.24 (CH2), 18.34 (CH3), 13.38 (CH3); calcd for C45H69N2SBr:
S-Butyl-N,N0-bis((S)-a-methylbenzyl)thiouronium bromide C 72.06, H 9.27, N 3.74, S 4.28%; found: C 72.01, H 9.30, N 3.67,
([2a]Br). Creamy solid (0.78 g, 99.5%); mp 137.46 1C; [a]D20
=
S 4.25%. HRMS-ESI (m/z) calcd for C45H69N2S [M – Br]+ 669.5181,
125.2 (c = 1.0, CHCl3); 1H NMR (300 MHz, DMSO-d6) d 9.55 found 669.5143.
(d, J = 7.3 Hz, 2H, 2 ꢁ NH), 7.65–6.83 (m, 10H, Ar CH), 5.54 (br s,
S-Butyl-N,N0-bis(dehydroabietyl)thiouronium chloride ([2c]Cl).
1H, C0H), 5.16 (br s, 1H, C0H), 3.20 (ddt, J = 27.6, 13.6, 7.1 Hz, Yellowish solid (0.13 g, 99%); Tg 58.36 1C; [a]2D0 = –11.0 (c = 1.0,
2H, S–CH2), 1.59 (d, J = 6.2 Hz, 6H, 2 ꢁ CH3), 1.33–0.95 (m, 4H, CHCl3); 1H NMR (400 MHz, DMSO-d6) d 9.37 (br s, 0.73H, NH),
2 ꢁ CH2), 0.67 (t, J = 7.1 Hz, 3H, CH3); 13C NMR (75 MHz, 9.22 (br s, 0.79H, NH), 7.97 (br s, 0.18H, NH), 7.21–7.00 (m, 2H,
DMSO-d6) d 165.62 (CQS), 141.89 (C), 140.87 (C), 128.56 (CH), 2 ꢁ Ar CH), 6.92 (d, J = 7.9 Hz, 2H, 2 ꢁ Ar CH), 6.84 (m, 2H, 2 ꢁ
127.84 (CH), 127.47 (CH), 126.27 (CH), 125.85 (CH), 55.71 (CH), Ar CH), 3.80 (br s, 0.79H, N–CH2), 3.54–3.10 (m, 2.6H, N–CH2,
53.12 (CH), 32.63 (CH2), 30.73 (CH2), 22.29 (CH3), 21.22 (CH3), 2H, S–CH2), 3.08–2.58 (m, 4H, 2 ꢁ CH2), 2.75 (sep, J = 8.0 Hz,
20.80 (CH2), 13.22 (CH3); calcd for C21H29N2SBr: C 59.85, 2H, 2 ꢁ CH), 2.22 (br dd, J = 19.5, 10.6 Hz, 2H, 2 ꢁ C0HH),
H 6.94, N 6.65, S 7.61%; found: C 60.05, H 6.74, N 6.65, 2.00–1.74 (m, 2H, 2 ꢁ C00HH), 1.75–1.27 (m, 14H, 2 ꢁ C0 0HH,
S 7.69%. HRMS-ESI (m/z) calcd for C21H29N2S [M ꢀ Br]+ CH2, 2 ꢁ CH2, 2 ꢁ CH, 2 ꢁ CH2), 1.26–1.04 (m, 7H, 2 ꢁ C0HH,
341.2051, found 341.2064, calcd for [Br]ꢀ 78.9183, 80.9163, CH2, C0H3), 1.22 (br s, 12H, 4 ꢁ CH3), 1.01 (br s, 3H, C0H3), 0.92
found 78.9182, 80.9162.
(br s, 3H, C0 0H3), 0.81 (br s, 3H, C0 0H3), 0.65 (br s, 3H, CH3); 13C
S-Butyl-N-(S)-a-methylbenzyl-N0-dehydroabietylthiouronium NMR (101 MHz, DMSO-d6) d 168.16 (CQS), 146.69 (C), 144.91
bromide ([2b]Br). Yellowish solid (0.54 g, 83%); mp 79.2 1C; (C), 134.14 (C), 126.27 (CH), 123.86 (CH), 123.44 (CH), 54.59
[a]2D0 = 34.8 (c = 1.0, CHCl3); 1H NMR (400 MHz, DMSO-d6) d 9.48 (CH2), 53.41 (CH2), 44.92 (CH), 43.99 (CH), 37.74 (CH2), 36.93
(br d, J = 71.6 Hz, 1H, MeBz-NH, ratio 3 : 2), 8.80 (br d, J = (C), 36.23 (CH2), 35.47 (C), 32.87 (CH), 32.16 (CH2), 30.98 (CH2),
171.2 Hz, 1H, Ab-NH, ratio 3 : 2), 7.38 (s, 2H, Ar CH), 7.35–6.90 29.37 (CH2), 25.06 (CH3), 23.91 (CH3), 21.12 (CH2), 18.18 (CH2),
(m, 3H, Ar CH), 7.22–7.01 (m, 1H, Ar CH), 7.01–6.90 (m, 1H, 18.03 (CH3), 17.86 (CH2), 13.09 (CH3); calcd for C45H69N2SCl: C
Ar CH), 6.86 (s, 1H, Ar CH), 5.28 (br d, J = 72.7 Hz, 1H, CH, ratio 76.60, H 9.86, N 3.97, S 4.54%; found: C 76.18, H 10.15, N 3.94,
2 : 3), 3.74–3.05 (m, 4H, N–CH2, S–CH2), 2.95–2.70 (m, 3H, CH2, S 4.49%. HRMS-ESI (m/z) calcd for C45H69N2S [M ꢀ Cl]+
CH), 2.36–1.98 (m, 1H, C0HH), 1.98–1.44 (m, 5H, C0 0HH, CH2, 669.5181, found 669.5182.
CH2), 1.54 (br s, 3H, CH3), 1.44–1.27 (m, 4H, C0 0HH, CH, CH2),
S-Butyl-N,N0-bis(dehydroabietyl)thiouronium iodide ([2c]I).
1.26–1.05 (m, 3H, C0HH, CH2), 1.14 (d, J = 7.4 Hz, 6H, 2 ꢁ CH3), White solid (0.13 g, 99%); Tg 75.38 1C; [a]2D0 = –16.4 (c = 1.0,
1.02 (s, 3H, CH3), 0.92 (s, 0.6 ꢁ 3H, C0H3), 0.90–0.75 (m, 0.5 ꢁ CHCl3); 1H NMR (400 MHz, DMSO-d6) d 8.88 (br s, 2H, 2 ꢁ NH),
3H, C0 0H3), 0.70 (s, 0.3 ꢁ 3H, C0H3), 0.49 (s, 0.5 ꢁ 3H, C0 0H3); 7.11 (br s, 2H, 2 ꢁ Ar CH), 6.93 (d, J = 8.1 Hz, 2H, 2 ꢁ Ar CH),
13C NMR (101 MHz, DMSO-d6) d 166.78 (CQS), 146.62 (C), 6.85 (m, 2H, 2 ꢁ Ar CH), 3.53 (br d, J = 52.2 Hz, 2H, N–CH2),
145.00 (C), 141.86 (C), 133.92 (C), 128.57 (CH), 127.67 (CH), 3.30–3.06 (m, 4H, N–CH2, S–CH2), 2.88 (br s, 2H, CH2), 2.76
126.30 (CH), 126.18 (CH), 125.82 (CH), 123.96 (CH), 123.58 (sep, J = 6.8 Hz, 2H, CH), 2.24 (br dd, J = 12.1, 11.0 Hz, 2H, 2 ꢁ
(CH), 123.38 (CH), 55.76 (CH), 53.21 (CH), 54.70 (CH2), 52.77 C0HH), 1.90–1.47 (m, 4H, 2 ꢁ CH2), 1.53 (quin, J = 7.2 Hz, 2H,
(CH2), 44.47 (CH), 43.50 (CH), 37.89 (C), 37.07 (C), 35.37 (CH2), CH2), 1.50–1.27 (m, 10H, 2 ꢁ CH2, 2 ꢁ CH2, 2 ꢁ CH), 1.27–1.06
32.91 (CH), 32.42 (CH2), 31.13 (CH2), 30.51 (CH2), 29.57 (CH2), (m, 7H, 2 ꢁ C0HH, CH2, C0H3), 1.13 (br s, 12H, 4 ꢁ CH3), 1.02
29.13 (CH2), 25.07 (CH3), 23.95 (CH3), 22.21 (CH3), 20.99 (CH2), (br s, 3H, C0H3), 0.93 (br s, 3H, C0 0H3), 0.81 (br s, 3H, C0 0H3), 0.70
18.55 (CH2), 18.19 (CH3), 17.96 (CH2), 13.33 (CH3), 12.90 (CH3); (t, J = 7.3 Hz, 3H, CH3); 13C NMR (101 MHz, DMSO-d6) d 168.49
calcd for C33H49N2SBr: C 67.67, H 8.43, N 4.78, S 5.47%; found: (SQC), 146.69 (C), 145.00 (C), 134.04 (C), 126.27 (CH), 123.88
C 68.21, H 8.96, N 5.22, S 5.28%. HRMS-ESI (m/z) calcd (CH), 123.53 (CH), 54.96 (CH2), 53.61 (CH2), 45.08 (CH), 44.17
for C33H48N2SBr [M ꢀ H]+ 583.2722, found 583.2732, calcd for (CH), 38.61 (C), 37.71 (CH2), 36.93 (C), 36.09 (CH2), 32.86 (CH),
[M ꢀ Br]+ 505.3616, found 505.3516.
32.19 (CH2), 30.84 (CH2), 29.12 (CH2), 24.96 (CH3), 23.91 (CH3),
S-Butyl-N,N0-bis(dehydroabietyl)thiouronium bromide ([2c]Br). 21.10 (CH2), 18.57 (CH2), 18.17 (CH2), 17.91 (CH3), 17.66 (CH2),
White solid (0.68 g, 93%); mp 128.2 1C; [a]D20 = –19.2 (c = 1.0, 13.09 (CH3); calcd for C45H69N2SI: C 67.81, H 8.73, N 3.51,
1
CHCl3); H NMR (400 MHz, CDCl3) d 10.35 (br s, 0.68H, NH), S 4.02%; found: C 67.34, H 8.39, N 3.53, S 4.04%. HRMS-ESI
9.06 (br s, 0.75H, NH), 8.62 (br s, 0.72H, NH), 7.09 (br s, 2H, 2 ꢁ (m/z) calcd for C45H69N2S [M ꢀ I]+ 669.5181, found 669.5093.
Ar CH), 7.00–6.76 (m, 4H, 4 ꢁ Ar CH), 4.23 (br s, 0.76H, N–CH2),
General procedure for metathesis reaction
3.73–2.98 (m, 3.8H, N–CH2, 2H, S–CH2), 2.91 (br s, 4H, 2 ꢁ
CH2), 2.79 (sep, J = 6.8 Hz, 2H, 2 ꢁ CH), 2.36–1.91 (m, 4H, 2 ꢁ Metathesis reactions were performed by mixing a CH2Cl2 solution
C0HH, CH2), 1.89–1.54 (m, 8H, CH2, 2 ꢁ CH2, 2 ꢁ C0 0HH), 1.54–1.37 of thiouronium bromide (1 eq.) with an aqueous solution
(m, 4H, 2 ꢁ C00HH, 2 ꢁ CH), 1.37–1.24 (m, 4H, 2 ꢁ C0HH, CH2), (or suspension) of a salt containing the desired anion (1 eq.).
c
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The sources of anions were Li[NTf2], Ag[NO3], Ag[OTf] or 2.35–2.10 (m, 2H, 2 ꢁ C0HH), 1.94–1.47 (m, 8H, 2 ꢁ CH2, 2 ꢁ
Ag[CH3CO2]. Then the by-products were collected by filtration, CH2), 1.53 (quin, J = 7.6 Hz, 2H, CH2), 1.47–1.25 (m, 6H, 2 ꢁ CH,
the organic phase was separated, dried with MgSO4, and 2 ꢁ CH2), 1.28–1.08 (m, 7H, 2 ꢁ C0HH, CH2, CH3), 1.13 (br s,
the solvent removed by evaporation. The product was then 12H, 4 ꢁ CH3), 1.02 (s, 3H, CH3), 0.93 (s, 3H, CH3), 0.82 (s, 3H,
dried in vacuo.
CH3), 0.70 (t, J = 7.3 Hz, 3H, CH3); 13C NMR (101 MHz, DMSO-d6)
S-Butyl-N,N0-bis((S)-a-methylbenzyl)thiouronium bis{(trifluoro- d 168.54 (CQS), 146.64 (C), 145.00 (C), 134.04 (C), 126.26 (CH),
methyl)sulfonyl}amide ([2a][NTf2]). Colourless liquid (0.13 g, 123.87 (CH), 123.52 (CH), 119.45 (q, J = 323.3 Hz, CF3), 55.01
96%); Tg –38.10 1C; [a]D20 = 96.0 (c = 1.0, CHCl3); d20 1.3232 g mlꢀ1
;
(CH2), 53.61 (CH2), 45.04 (CH), 44.18 (CH), 38.56 (C), 37.72
Z20 4.704 Pa s; W 186 ppm; 1H NMR (400 MHz, DMSO-d6) d 9.47 (CH2), 36.93 (C), 36.07 (CH2), 32.87 (CH), 32.13 (CH2), 30.83
(d, J = 7.0 Hz, 2H, 2 ꢁ NH), 7.65–6.81 (m, 10H, 10 ꢁ Ar CH), 5.39 (CH2), 29.30 (CH2), 24.98 (CH3), 23.86 (CH3), 21.10 (CH2), 18.55
(br s, 1H, C0H), 5.17 (br s, 1H, C0H), 3.19 (ddt, J = 20.7, 13.4, (CH2), 18.12 (CH2), 17.88 (CH3), 17.68 (CH2), 13.07 (CH3); calcd
6.9 Hz, 2H, S–CH2), 1.59 (br s, 6H, CH3), 1.22 (q, J = 7.2 Hz, 2H, for C47H69F6N3O4S3: C 59.41, H 7.32, N 4.42, S 10.12%; found:
CH2), 1.14 (quin, J = 7.2 Hz, 2H, CH2), 0.70 (t, J = 7.2 Hz, 3H, C 59.68, H 7.39, N 4.43, S 10.52%. HRMS-ESI (m/z) calcd for
CH3); 13C NMR (101 MHz, DMSO-d6) d 165.67 (CQS), 141.77
C
45H69N2S [M ꢀ NTf2]+ 669.5181, found 669.5080, calcd for
(C), 140.72 (C), 128.60 (CH), 127.93 (CH), 126.18 (CH), 125.81 C2NO4S2F6 [NTf2]ꢀ 279.9173, found 279.9162
(CH), 124.30 (CH), 119.5 (q, J = 323.2 Hz, CF3), 55.59 (CH), 53.01
S-Butyl-N,N0-bis(dehydroabietyl)thiouronium triflate ([2c][OTf]).
(CH), 32.47 (CH2), 30.68 (CH2), 22.15 (CH3), 21.07 (CH3), 20.82 White solid (0.11 g, 92%); mp 54.72 1C; [a]2D0 = 8.3 (c =
(CH2), 13.17 (CH3); calcd for C23H29F6N3O4S3: C 44.44, H 4.70, 1.0, CHCl3); 1H NMR (400 MHz, DMSO-d6) d 8.89 (br s, 2H,
N 6.76, S 15.47%; found: C 44.32, H 4.91, N 6.74, S 15.45%. 2 ꢁ NH), 7.11 (br s, 2H, 2 ꢁ Ar CH), 6.93 (d, J = 8.2 Hz, 2H, 2 ꢁ
HRMS-ESI (m/z) calcd for C21H29N2S [M ꢀ NTf2]+ 341.2051, Ar CH), 6.85 (br d, J = 13.6 Hz, 2H, 2 ꢁ Ar CH), 3.75–3.15 (m, 4H,
found 341.2044, calcd for C2NO4S2F6 [NTf2]ꢀ 279.9173, found 2 ꢁ N–CH2), 3.30–3.10 (m, 2H, S–CH2), 2.88 (br s, 4H, 2 ꢁ CH2),
279.9166.
2.76 (sep, J = 6.8 Hz, 2H, 2 ꢁ CH), 2.38–2.10 (m, 2H, 2 ꢁ C0HH),
S-Butyl-N-(S)-a-methylbenzyl-N0-dehydroabietylthiouronium 1.91–1.49 (m, 8H, 2 ꢁ CH2, 2 ꢁ CH2), 1.53 (quin, J = 7.2 Hz, 2H,
bis{(trifluoromethyl)sulfonyl}amide ([2b][NTf2]). Colourless CH2), 1.48–1.25 (m, 6H, 2 ꢁ CH, 2 ꢁ CH2), 1.24–1.05 (m, 7H, 2 ꢁ
soft glass (0.13 g, 89%); Tg 13.9 1C; [a]2D0 = 18.6 (c = 1.0, CHCl3); C0HH, CH2, CH3), 1.13 (br s, 12H, 4 ꢁ CH3), 1.02 (s, 3H, CH3),
1H NMR (400 MHz, DMSO-d6) d 9.42 (br d, J = 46.1 Hz, 1H, 0.93 (s, 3H, CH3), 0.81 (s, 3H, CH3), 0.70 (t, J = 7.3 Hz, 3H, CH3);
MeBz-NH, ratio 3 : 2), 8.72 (br d, J = 194.5 Hz, 1H, Ab-NH, ratio 13C NMR (101 MHz, DMSO-d6) d 168.52 (CQS), 146.72 (C),
3 : 2), 7.51–6.91 (m, 5H, Ar 5 ꢁ CH), 7.13 (br s, 1H, Ar CH), 6.97 145.02 (C), 134.02 (C), 126.28 (CH), 123.89 (CH), 123.54 (CH),
(br s, 1H, Ar CH), 6.88 (s, 1H, Ar CH), 5.21 (quin, J = 6.7 Hz, 1H, 121.61 (q, J = 132.31 Hz, CF3), 55.01 (CH2), 53.57 (CH2), 45.05
CH), 3.65–3.25 (m, 2H, N–CH2), 3.45–3.05 (m, 2H, S–CH2), (CH), 44.18 (CH), 38.59 (C), 37.74 (CH2), 36.95 (C), 36.10 (CH2),
3.00 – 2.65 (m, 3H, CH, CH2), 2.36–2.01 (m, 1H, C0HH), 1.90– 32.88 (CH), 32.14 (CH2), 30.85 (CH2), 29.14 (CH2), 25.01 (CH3),
1.65 (m, 2H, CH2), 1.64–1.45 (m, 5H, CH, CH2, CH2), 1.44–1.28 23.88 (CH3), 21.12 (CH2), 18.57 (CH2), 18.20 (CH2), 17.91 (CH3),
(m, 4H, C0 0HH, CH2, CH), 1.27–1.08 (m, 2H, C0HH, 0.3 ꢁ C0H3), 17.67 (CH2), 13.10 (CH3); calcd for C46H69F3N2O3S2: C 67.44,
1.16 (br d, J = 6.7 Hz, 6H, 2 ꢁ CH3), 1.07–1.00 (m, 1H, C00HH), H 8.49, N 3.42, S 7.83%; found: C 67.91, H 8.96, N 3.29, S 7.12%.
1.04 (s, 2H, 0.6 ꢁ C0H3), 0.94 (s, 0.6 ꢁ 3H, CH3), 0.89 (br s, 0.5 ꢁ HRMS-ESI (m/z) calcd for C45H69N2S [M ꢀ OTf]+ 669.5181, found
3H, CH3), 0.71 (s, 0.3 ꢁ 3H, CH3), 0.52 (s, 0.5 ꢁ 3H, CH3); 669.5120, calcd for CO3F3S [OTf]ꢀ 148.9520, found 148.9505.
13C NMR (101 MHz, DMSO-d6) d 166.82 (SQC), 146.60 (C),
S-Butyl-N,N0-bis(dehydroabietyl)thiouronium nitrate ([2c][NO3]).
145.02 (C), 141.79 (C), 133.87 (C), 128.58 (CH), 127.70 (CH), White solid (0.12 g, 83%); mp 49.1 1C; [a]2D0 = –19.7 (c = 1.0,
126.28 (CH), 126.07 (CH), 125.72 (CH), 123.95 (CH), 123.58 CHCl3); 1H NMR (400 MHz, DMSO-d6) d 8.91 (br s, 2H, 2 ꢁ NH),
(CH), 119.45 (q, J = 323.2 Hz, CF3), 55.62 (CH), 54.87 (CH2), 7.11 (br s, 2H, 2 ꢁ Ar CH), 6.93 (d, J = 8.1 Hz, 2H, 2 ꢁ Ar CH),
53.14 (CH), 52.79 (CH2), 44.50 (CH), 43.61 (CH), 37.85 (C), 6.85 (br d, J = 12.9 Hz, 2H, 2 ꢁ Ar CH), 3.67–3.15 (m, 4H, 2 ꢁ
37.10 (C), 35.33 (CH2), 32.89 (CH), 32.32 (CH2), 31.09 (CH2), N–CH2), 3.28–3.09 (m, 2H, S–CH2), 2.88 (br s, 4H, 2 ꢁ CH2), 2.76
30.42 (CH2), 29.50 (CH2), 29.13 (CH2), 25.00 (CH3), 23.91 (CH3), (sep, J = 6.8 Hz, 2H, 2 ꢁ CH), 2.35–2.12 (m, 2H, 2 ꢁ C0HH),
22.14 (CH3), 20.97 (CH2), 18.53 (CH2), 18.16 (CH3), 17.94 1.93–1.58 (m, 8H, 2 ꢁ CH2, 2 ꢁ CH2), 1.53 (quin, J = 7.4 Hz, 2H,
(CH2), 13.26 (CH3), 12.86 (CH3); calcd for C35H49F6N3O4S3: CH2), 1.49–1.29 (m, 6H, 2 ꢁ CH, 2 ꢁ CH2), 1.28–1.15 (m, 7H, 2 ꢁ
C 53.49, H 6.28, N 5.35, S 12.24%; found: C 53.54, H 5.71, N 5.46, C0HH, CH2, CH3), 1.13 (br s, 12H, 4 ꢁ CH3), 1.02 (s, 3H, CH3),
S 11.93%. HRMS-ESI (m/z) calcd for C33H49N2S [M ꢀ NTf2]+ 0.93 (s, 3H, CH3), 0.81 (s, 3H, CH3), 0.70 (t, J = 7.3 Hz, 3H, CH3);
505.3616, found 505.3590, calcd for C2NO4S2F6 [NTf2]ꢀ 13C NMR (101 MHz, DMSO-d6) d 168.54 (CQS), 146.71 (C),
279.9173, found 279.9173.
145.01 (C), 134.07 (C), 126.27 (CH), 123.91 (CH), 123.53 (CH),
S-Butyl-N,N0-bis(dehydroabietyl)thiouronium bis{(trifluoro- 54.80 (CH), 53.54 (CH), 45.07 (CH2), 44.16 (CH2), 38.71 (C),
methyl)sulfonyl}amide ([2c][NTf2]). White solid (0.37 g, 98%); 37.73 (CH2), 36.95 (C), 36.08 (CH2), 32.87 (CH), 32.15 (CH2),
mp 44.29 1C; [a]2D0 = –5.7 (c = 1.0, CHCl3); H NMR (400 MHz, 30.85 (CH2), 29.28 (CH2), 23.91 (CH3), 23.88 (CH3), 21.11 (CH2),
1
DMSO-d6) d 8.88 (br s, 2H, 2 ꢁ NH), 7.11 (br s, 2H, 2 ꢁ Ar CH), 18.58 (CH2), 18.17 (CH2), 17.91 (CH3), 17.69 (CH2), 13.10 (CH3);
6.93 (d, J = 8.2 Hz, 2H, 2 ꢁ Ar CH), 6.85 (br d, J = 12.9 Hz, 2H, calcd for C45H69N3SO3: C 73.82, H 9.50, N 5.74, S 4.38%; found:
2 ꢁ Ar CH), 3.70–3.24 (m, 4H, 2 ꢁ N–CH2), 3.29–3.09 (m, 2H, C 73.87, H 9.26, N 5.58, S 4.41%. HRMS-ESI (m/z) calcd for
S–CH2), 2.88 (br s, 4H, 2 ꢁ CH2), 2.79 (sep, J = 6.8 Hz, 2H, 2 ꢁ CH),
C
45H69N2S [M ꢀ NO3]+ 669.5181, found 669.5225.
c
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S-Butyl-N,N0-bis(dehydroabietyl)thiouronium ethanoate of free host at equilibrium, [host]0 is the total concentration of
([2c][CH3CO2]). White solid/glass (0.19 g, 78%); mp 49.00 1C; added host, [guest]0 is the total concentration of guest. When
[a]2D0 = +16.2 (c = 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) d 7.15 Ddobs was plotted against [host], a curve fitting was performed
(d, J = 8.2 Hz, 2H, 2 ꢁ Ar CH), 6.97 (dd, J = 1.61, 8.2 Hz, 2H, 2 ꢁ according to eqn (1) using SigmaPlot software,48 which resulted
Ar CH), 6.87 (s, 2H, 2 ꢁ Ar CH), 3.23 (dd, J = 13.0, 31.5 Hz, 4H, in the determination of K. The associated errors refer to 2s
2 ꢁ N–CH2), 2.91–2.68 (m, 8H, S–CH2, 2 ꢁ CH2, 2 ꢁ CH), 2.24 about the mean.
(br d, J = 12.7 Hz, 2H, 2 ꢁ C0HH), 1.82 (s, 3H, CH3CO2ꢀ), 1.90–
Computational studies
1.46 (m, 12H, 2 ꢁ CH2, 2 ꢁ CH2, CH2, 2 ꢁ CH), 1.48–1.24
(m, 8H, 2 ꢁ C0HH, 2 ꢁ CH2, CH2), 1.22 (d, J = 6.9 Hz, 12H, 4 ꢁ
The starting structures for geometry optimisations were generated
using HyperChemTM Release 8.0.749 with the MM+ level followed
by the semi-empirical PM3 level. Then the final calculation was
done using Gaussians 98 (Gaussian Inc.) with the RHF/3-21G*
level for optimisation of thiouronium isomers and the RB3LYP/
STO-3G level for optimisations of host–guest complexes.28
CH3), 1.19 (s, 6H, 2 ꢁ CH3), 0.92 (s, 6H, 2 ꢁ CH3), 0.84 (t, J =
7.3 Hz, 3H, CH3); 13C NMR (101 MHz, CDCl3) d 178.34
(CH3CO2), 163.03 (CQS), 147.37 (C), 145.37 (C), 134.73 (C),
126.75 (CH), 124.16 (CH), 123.69 (CH), 57.57 (CH2), 45.78 (CH),
38.42 (CH2), 38.18 (C), 37.46 (C), 36.43 (CH2), 33.43 (CH), 32.61
(CH2), 32.30 (CH2), 30.19 (CH2), 25.32 (CH3), 23.98 (CH3), 23.28
(CH3CO2), 21.91 (CH2), 19.03 (CH2), 18.68 (CH2), 18.66 (CH3),
13.49 (CH3); calcd for C47H72N2SO2: C 77.42, H 9.95, N 3.84, S
4.40%; found: C 77.84, H 9.92, N 4.08, S 3.86%. HRMS-ESI (m/z)
calcd for C45H69N2S [M ꢀ CH3CO2]+ 669.5181, found 669.5212.
Acknowledgements
We are very grateful to QUILL and its Industrial Advisory Board for
funding, and also wish to thank Prof. A. Prasanna de Silva, Prof.
Christopher R. Strauss, Dr Marijana Blesic, Dr Johan Jacquemin,
Miłosz Grabski and Tiina Laaksonen for advice, and Richard
Murphy and Dr Mark Russell for technical support. P.N. thanks
the EPSRC for a RCUK fellowship. The EPSRC UK National
Crystallography Service (NCS) and the CBER QUB are acknowl-
edged for single crystal and powder XRD data, respectively.
Preparation of chiral guests
N-Acetylation reactions on phenylalanine, tryptophan,43 and
3,4-dihydroxyphenylalanine44 were performed according to a
literature method. Racemisation of (S)-naproxen was performed
according to the literature.45 Preparation of 1-phenylethylsulfonic
acid,46 and 1-phenylethylphosphonic acid,47 were conducted
according to the literature. One equivalent of tetrabutyl-
ammonium hydroxide, [N4444][OH], in the form of a 1 M solution
in methanol, was added dropwise to one equivalent of a chiral
acid dissolved or suspended in methanol. After 1ꢀ12 h, the
solvent was evaporated and the residue was dried in vacuo.
Notes and references
1 J. W. Steed, Supramolecular Chemistry, John Wiley & Sons,
Ltd, Chichester, 2009.
2 (a) F. P. Schmidtchen and M. Berger, Chem. Rev., 1997, 97,
1609–1646; (b) R. J. Fitzmaurice, G. M. Kyne, D. Douheret
and J. D. Kilburn, J. Chem. Soc., Perkin Trans. 1, 2002,
841–864; (c) M. D. Best, S. L. Tobey and E. V. Anslyn, Coord.
Chem. Rev., 2003, 240, 3–15.
3 (a) A. Echavarren, A. Galan, J. M. Lehn and J. De Mendoza,
J. Am. Chem. Soc., 1989, 111, 4994–4995; (b) A. Galan,
D. Andreu, A. M. Echavarren, P. Prados and J. De Mendoza,
J. Am. Chem. Soc., 1992, 114, 1511–1512.
Titration experiments and binding constant determination
The solution of the guest (cconst = 2 mM) was used for prepara-
tion of the host solution (c = 11.7–46.6 mM) to maintain a
constant concentration of the guest. In an NMR tube, the guest
solution (0.5 cm3) was titrated by 5 ml doses of a host solution
using a microsyringe; sample zero and each one after addition
1
of a dose was analysed using H NMR spectroscopy (500 MHz;
300.0 K). Data from these experiments were plotted to create a
1 : 1 NMR binding isotherm, which represents the equilibrium:
´
´
4 M. Hernandez-Rodrıguez and E. Juaristi, Tetrahedron, 2007,
63, 7673–7678.
guest + host " [(guest)(host)].
5 B. Altava, D. S. Barbosa, M. Isabel Burguete, J. Escorihuela
and S. V. Luis, Tetrahedron: Asymmetry, 2009, 20, 999–1003.
6 (a) W.-S. Yeo and J.-I. Hong, Tetrahedron Lett., 1998, 39,
8137–8140; (b) Y. Kubo, M. Tsukahara, S. Ishihara and
S. Tokita, Chem. Commun., 2000, 653–654; (c) H. R. Seong,
D. S. Kim, S. G. Kim, H. J. Choi and K. H. Ahn, Tetrahedron
Lett., 2004, 45, 723–727; (d) M. Orlowska, M. Mroczkiewicz,
K. Guzow, R. Ostaszewski and A. M. Klonkowski, Tetrahedron,
2010, 66, 2486–2491; (e) W. S. Yeo and J. I. Hong, Tetrahedron
Lett., 1998, 39, 3769–3772.
Using NMR spectroscopy, the latter may be mathematically
described by eqn (1) and (2):35,36
DdcK½hostꢄ
Ddobs
¼
ð1Þ
ð2Þ
1 þ K½hostꢄ
ꢀ
ꢁ
Ddobs
Ddc
½hostꢄ ¼ ½hostꢄ0 ꢀ ½guestꢄ0
The binding constants, K, were determined from eqn (1), where
[host] is the molar concentration of the host, Ddobs is the
observed chemical shift change for a given [host], Ddc is the
chemical shift change between a pure sample of the complex
and the free component at saturation, [host] is the concentration
7 (a) C. Blanchard and S. Pagano, Eur. Pat.,, EP1517799 (A1),
2005; (b) M. D. Scaia, D. R. Eaton, R. J. Hoekstra and
E. A. Haupfear, US Pat., US20060106248A1, 2006;
(c) T. Kazuhiro and I. Terukazu, Ger. Pat., DE2062559A,
c
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Paper
1972; (d) J. V. Hagen, U. Michelsen and M. Wehsling, World 27 J. K. M. Sanders and B. K. Hunter, Modern NMR spectroscopy:
Pat., WO2008/58604 A1, 2008. a guide for chemists, Oxford University Press, 1993.
8 F. A. Carey and R. J. Sundberg, Advanced organic chemistry: 28 M. J. Frisch, et al., Gaussian 98, Revision A.9, Gaussian, Inc.,
Reactions and synthesis, Springer, New York, NY, 2007. Pittsburgh, PA, 1998.
9 D. M. Kneeland, K. Ariga, V. M. Lynch, C. Y. Huang and E. V. 29 J. A. van den Berg and K. R. Seddon, Cryst. Growth Des.,
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