Engineering Light-Mediated Bistable Azobenzene Switches Bearing Urea d -Aminoglucose Units for Chiral Discrimination of Carboxylates

Article abstract of DOI:10.1021/acs.joc.6b00200

The symmetrical molecular receptors 1a and 1b consisting of a photochemically addressable azobenzene tether functionalized with urea hydrogen-bonding groups and d-carbohydrates as chiral selectors were developed to achieve control over the chiral recognition of α-amino acid-derived carboxylates. The photo- and thermally interconvertible planar E-1 and concaved Z-1 were found to exhibit different affinities, selectivities, and binding modes toward these biologically important anions in a highly polar medium (DMSO + 0.5% H₂O). Binding affinity for the same enantiomerically pure guest was up to 3 times higher for E-1 than for Z-1 (cf. parameter β). In addition, the rate of thermal Z → E isomerization was found to depend on the chiral binding ability of Z-1, i.e., more strongly bound carboxylate enantiomer as well as higher enantiomer concentration caused faster relaxation to E-1.

Full text of DOI:10.1021/acs.joc.6b00200

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Article
Engineering Light-Mediated Bistable Azobenzene Switches bearing
Urea D-aminoglucose Units for Chiral Discrimination of Carboxylates
Kajetan D#browa, Patryk Niedba#a, and Janusz Jurczak
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00200 • Publication Date (Web): 08 Apr 2016
Downloaded from http://pubs.acs.org on April 10, 2016
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Engineering Light-Mediated Bistable Azobenzene Switches
bearing Urea D-aminoglucose Units for Chiral Discrimination
of Carboxylates
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Kajetan Dąbrowa,* Patryk Niedbała and Janusz Jurczak*
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland.
ABSTRACT: The symmetrical molecular receptors 1a and 1b consisting of a photochemically addressable azobenzene
tether functionalized with urea hydrogen-bonding groups and D-carbohydrates as chiral selectors were developed to
achieve control over the chiral recognition of α-amino acid derived carboxylates. The photo- and thermally-
interconvertible planar E-1 and concaved Z-1 were found to exhibit different affinities, selectivities, and binding modes
toward these biologically important anions in a highly polar medium (DMSO + 0.5% H2O). Binding affinity for the same
enantiomerically pure guest was up to 3 times higher for E-1 than for Z-1 (cf. parameter β described in Table 1). In addi-
→
tion, rate of thermal Z E isomerisation was found to depend on the chiral binding ability of Z-1, i.e. more strongly bound
carboxylate enantiomer as well as higher enantiomer concentration caused faster relaxation to E-1.
INTRODUCTION
In natural systems, recognition and transport of chiral ions, ranging from simple amino acids, up to more complex pep-
tides, is mainly realized by highly specialized receptors.1 Frequently these bioreceptors act as switches, for which corre-
sponding conformational state may be selectively triggered by external stimuli, such as temperature, pH, ion gradient,
and light.2 Recognition of chiral molecules by artificial systems, however, still remains a great challenge, despite a re-
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markable progress that has been made in supramolecular chemistry3 during the past two decades, particularly in the field
of ion recognition.4 Indeed, a relatively small number of receptors exhibiting high level of chiral recognition (expressed as
α = KR/KS ≥ 2),5 arise mainly from the fact that such synthetic molecular receptors have to distinguish between subtle
structural differences in isoenergetic enantiomers, and this process is likely not purely static.6 Lessons from Nature sug-
gest that many weak, directional noncovalent interactions (i.e. H-bonds and London dispersion forces), originating from
receptor constituents with a rational spatial arrangement, have to be taken into account to render such interactions
strong and specific. The mutual interplay of these interactions, however, is hardly to predict in silico, in particular when
solvent effects are also included. Nonetheless, to help in designing potential chiral anion receptors one can take ad-
vantage of the three-point-attachment concept, which assumes that at least three interactions need to exist between the
receptor and guest molecules.7 This empirical rule of thumb is mostly implemented by installing chiral scaffolds in the
proximity of an anion binding pocket previously proven to be effective for achiral anions, e.g. a urea group is tailored for
carboxylate binding.8 A chiral barrier is usually introduced by installing carbohydrates9 or amino acids,10 and also binaph-
thyl derivatives.11 Recently, we exploited the former approach in the construction of receptors able to efficiently differenti-
ate chiral carboxylates (with α up to 4),9a,c-d and even to predict their configuration.9b Furthermore, although switching of
a receptor’s binding properties was already employed for the recognition of achiral guest, both charged12,13 and electrically
neutral,14 it utilization in chiral recognition is, to the best of our knowledge, limited only to neutral guests.15 Of a number
of stimuli which can potentially be used as triggers for such transformation,16 the unique features of light, i.e. its un-
matched spatial resolution and electrically neutral character, render it particularly useful.16-18 Moreover, light-triggered
transformation is generally reversible and can be easily fine-tuned to selectively affect only the chosen molecules. The
photoactive moieties that are often applied in such transformations include diaryl- and dithienylethene, spiropyrane, and
azobenzene (AB) derivatives.16,19-20 Among these, the latter appear to be the most useful owing to their synthetic availabil-
ity, robustness, and large-amplitude structural changes between extended (E) and folded (Z) isomers.21 The latter feature
has been utilized for the construction of photoresponsive supramolecular catalysts.12c,14c,22 For example, an AB chromo-
phore was employed for the photocontrol of basicity,22a nucleoside coupling,14c solvolysis,12c,22b,c Knoevenagel condensa-
tion,22d and Morita–Baylis–Hillman reaction.22e Very recently, we have shown that light can be used for control of the
benzoate binding by the model phenylurea receptor 4 based on the robust azobenzene tether.13d Inspired by these results,
we envisioned that exchanging the achiral phenyl group for a carbohydrate scaffold should enable light-mediated control
over the receptor’ chiral discrimination properties toward anionic species. Furthermore, since kinetic rate of thermal Z→E
isomerisation was found to strictly depends on the anion binding properties of the achiral 4, we were interested in evalu-
ating a possible influence of enantiomeric carboxylate on this process. In this study, we explored this concept of dynamic
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recognition by synthetizing and evaluating chiral anion binding properties of new hybrid receptors 1 (Scheme 1). The
thermodynamically stable near planar receptors E-1 were synthetized in good yields by reacting 4,4’-diaminoazobenzene 2
with either known β-D-glucopyranose isocyanates 3a or 3b.
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RESULTS AND DISCUSSION
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Scheme 1. Synthesis of receptors E-1 and their isomerization to Z-1 (switchable core shown in blue, anion bind-
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ing sites in green, and chiral barrier in gray), structure of reference achiral receptor 4.
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The V-shaped Z-1 receptors were then produced by E→Z isomerization driven by irradiation with UVA light (368 nm, 60
W). They spontaneously re-equilibrated with first-order kinetics at rates (t =65 and 144 min for Z-1a and Z-1b, respective-
½
ly) similar to those previously reported for model achiral receptor 4 (t =108 min).13d The binding properties of receptors 1
½
1
were investigated in DMSO-d6 + 0.5% H2O by titration under H NMR control or by isothermal Z→E isomerization titra-
tion under UV-Vis control. The anion coordination mode changes from 1:1 + 1:2 to exclusively 1:1 (host-guest) when E-1
interconverts to Z-1.23 To clarify the comparison between association constants for E- and Z-1, the Ka mentioned in the
main text for E-1 refers to the first association constant (Ka,1). As model anions we chose various carboxylates, given that
amino acids as well as more complex peptides and proteins exist in such form under physiological conditions. Several
reports indicate that binding affinities toward model chiral anions (e.g. mandelate) are almost an order of magnitude
smaller than those for model achiral ones (e.g. benzoate),5 which means that artificial chiral receptors need to be inher-
ently potent in achiral anion recognition.24 Therefore, we firstly determined binding properties of receptors 1a and 1b
’
toward model achiral acetate and benzoate (Table 1). The association constants (Ka s) for benzoate with receptors Z-1 were
virtually equal and, as in the case of achiral receptor 4, considerably smaller than for E-1. The lower binding ability of
receptors Z-1 suggests that in this folded conformation two para-substituted urea-sugar groups are still far away from
each other, thus preventing their potential cooperativity effect. This may suggest that binding of the carboxylate anion is
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occurring on the periphery of the chiral receptors Z-1. In addition, one can assume that acidity of the NH urea protons is
reduced in the Z-conformation, which results from the weaker π-electron conjugation as compared with planar E-
isomer.24
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Table 1. Stability constants Ka (M-1) for receptors 1 with model achiral carboxylates in DMSO-d6+0.5%
H2O at 298 Ka
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[b]
[c]
Entry
Receptor
anion
Ka,E-isomer
836
Ka,Z-isomer
756[d]
192
-
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6
MeCO2
1a
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PhCO2
306
-
MeCO2
870
816[d]
1b
-
PhCO2
316
105
4[e]
PhCO2
989
231
-
[a] determined using 1H titration; anions added as tetrabutylammonium (TBA) salts; estimated errors are ±10% (detailed error estimates are given in Table S2); [b]
titration carried out in the dark; [c] titration conducted immediately after the UV irradiation; [d] determined using isothermal Z→E isomerization titration under UV-
Vis control; [e] data taken from ref. 13d.
Receptors E-1 bound acetate more strongly than benzoate, in line with the basicity of these anions in DMSO (acetate is
more basic than benzoate). These differences were, however, rather small (the Ka ratio for E-1 with acetate vs benzoate is
~2.7), which suggests π-π interactions between rings of benzoate and β-D-glucopyranose; moreover, in another study we
very recently found similar favorable interactions involving sugar moieties.9a-b Determination of Ka for receptors Z-1 with
1
acetate, on the other hand, proved impossible under H NMR titration, owing to very rapid thermal re-equilibration to E-
1, after the addition of one equivalent of acetate (Figure S10). Such acceleration of thermal rate constants results from
efficient anion-mediated electron density transfer to the N=N bond of Z-1.13d In order to determine these values we have
taken advantage from the Z→E isomerization titration procedure which allow accurate determination for both Ka and rate
constant for the saturated complex of Z-receptor with an anion (kHG) for processes with slow and fast kinetics.13d These
values are comparable for both Z-1a and Z-1b which indicates that, unlike for benzoate, the steric hindrance generated by
bulky sugar moieties in both isomers of 1 is insufficient to prevent strong binding with small acetate, since the Ka values
for Z-1 are only slightly lower than for E-1. Nonetheless, sufficiently high affinities for the achiral carboxylates prompted
us to carry out more comprehensive studies to elucidate the chiral properties of receptors 1. As model chiral guests, we
chose mandelate (Man) and tert-butyloxycarbonyl- NH-protected phenylalanine (Phe) and tryptophan (Trp) which are
typically employed for the chiral recognition studies.5c
Initial titration experiments with mandelates revealed that receptors 1 bound them very weakly (Ka ~20 M-1) and without
any selectivity towards particular enantiomer. Similar anion binding behavior was observed for structurally related aro-
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matic ureas having identical sugar moieties as in receptor 1b.9c Presumably, presence of decreased negative charge density
on the carboxylate group, resulting from intramolecular hydrogen bonding with the hydroxyl group, is responsible for the
weak interaction of Man with receptors 1.5a-b,10 Nevertheless, the values obtained for other carboxylates were high enough
to be considered reliable and are presented in Table 2.
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Table 2. Stability constants Ka (M-1) for receptors 1 with model chiral carboxylates in DMSO-d6+0.5% H2O
at 298 K a
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E-isomer
Z-isomer
entry
receptor
Anion
abs. conf.
β [e]
[b]
[d]
Ka
α[c]
Ka
α[c]
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8
D
L
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30
0.45
0.66
0.38
0.41
0.52
0.64
0.39
0.25
1a
1b
1a
1b
Phe
Phe
Trp
Trp
1.61
1.00
89
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31
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46
76
58
D
L
1.19
1.12
1.61
1.25
1.48
1.31
53
D
L
143
127
124
77
D
L
[a] estimated errors are <15% for E-1 and <20% for Z-1 (detailed error estimates are given in Table S3); anions added as tetrabutylammonium (TBA) salts; Man –
mandelate, Phe – phenylalanine, Trp - tryptophan; [b] titration carried out in the dark; [c] α = KD·KL-1; [d] titration conducted immediately after the UV irradiation; [e]
see main text for the definition.
Analysis of this data reveals some general trends. Firstly, just as previously mentioned, receptors E-1 bind anions 2-3 times
more strongly than Z-1. Secondly, E- and Z-isomers of receptors 1 prefer carboxylates derived from D-amino acids (except
E-1a, which binds L-Phe more strongly than D-Phe). Analysis of the shift changes of the sugar protons induced by the
addition of the D-enantiomeric guests suggest additional interactions, e.g. titration of receptors 1a with D-Trp causes
moderate downfield shift of the anomeric proton whereas addition of L-Trp to 1a has virtually no effect on this resonance.
A similar trend was observed for the receptors bearing chiral substituents derived from D-glucose.5b,9c-d Thirdly, both
receptors 1a and 1b bind Trp stronger than Phe. Since the bulkiness and relative basicity of the carboxylate group are
comparable for both Phe and Trp, the preference for Trp anion is likely attributed to a favorable intermolecular interac-
tion between anion and receptor, in particular between indole NH proton and carbonyl group of the sugar moieties. This
assumption is supported by the observation that indole NH proton show a moderate downfield shift (up to 0.25 ppm)
upon complexation with receptors 1. Notably, larger chemical shift changes are observed for more stable complexes, e.g.
for receptor Z-1a the changes are ꢀδ = 0.20 ppm for D-Trp vs ꢀδ = 0.14 ppm for L-Trp, respectively. Furthermore, reso-
nances of all sugar acetyl groups, which are excellent indicators of the chiral binding event,9 shifted upfield during titra-
tion, indicating interaction with a negative charge of an anion as well as with a ring current of its aromatic ring. The high-
est enantioselectivity was observed for receptor 1a (entries 1-2 for E-isomer and entries 5-6 for Z-isomer). In contrary,
receptor 1b exhibits rather low enantioselectivity (except E-1b with Trp), despite the fact that the corresponding Ka within
E- and Z-isomers change substantially. In the case of receptor 1a, this feature allows for a temporal light-driven “turn-off”
of the chiral discrimination of Phe, i.e. stable E-1a binds D-Phe stronger than L-Phe (α = 1.61), whereas no such preference
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is observed for transient Z-1a (α = 1.00). This moderate level of enantioselectivity of Z-1a is clearly visible in the different
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behavior of 1H NMR signals of urea protons during titrations with Trp (Figure 1a).
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Figure 1. Patterns of chemical shift changes for aliphatic urea protons in receptor 1a (a) and 5 (b) during 1H NMR titration with
D-Trp (blue points) and L-Trp (colored in red); E-isomer (closed symbols), Z-isomer (open symbols); gray lines represent fitted
binding isotherms; aromatic urea protons exhibit similar binding behavior (see ESI).
One can see that the binding pattern for the urea protons demonstrate that E-1a binds Trp stronger than Z-1a (i.e. chang-
es in the chemical shifts are higher in the former case) as well as that D-Trp is bound stronger than L-Trp. In addition,
contrary to Z-isomer, slight differences between urea protons for E-1a and D- vs L-Trp indicates weak chiral recognition
properties. In order to exploit if the second urea-sugar moiety is required to achieve enantioselective recognition we de-
cided to synthetize reference receptor 5 and evaluate its binding properties with Trp anions (Figure 1b). Furthermore, in
contrast to receptors 1, the lack of second urea group induces that both E- and Z-isomers of receptor 5 should only form
1:1 complexes with carboxylates. The 1H NMR titrations reveal that compound 5, similarly to receptor E-1a (Figure 1a), was
not able to differentiate between enatiomeric Trp, with Kas identical within the experimental error (for D-Trp the values
are Ka = 109 M-1 vs Ka = 97 M-1, and for L-Trp Ka = 98 M-1 vs Ka = 105 M-1, for E-5 vs Z-5, respectively). This clearly indicates
that second urea-sugar moiety is crucial to achieve enantiodifferentiation between Trp for the Z-isomer of receptor 1a.
This is in line with our previous report on the chiral discrimination by static sugar receptors based on diindolylmethane
scaffold.9d
Although receptors 1 exhibit rather moderate chiral recognition it should be emphasized that high level of enantiodis-
crimination is not very common in supramolecular chemistry of carboxylates, even for static molecular receptors. On the
other hand, from the point of view of modern chiral stationary phases in HPLC or GC the selectivity at a level of 1.1 is not
only sufficient but even optimal value.5a,7 In view of these facts, chiral recognition properties of model dynamic receptors 1
are encouraging and further work is needed to fine-tune their selectivities for particular chiral carboxylates.
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It should be highlighted that to date, to describe chiral recognition, parameter α (i.e. KR/KS or KD/KL) describing the dis-
crimination ratio between enantiomers of the guest has solely been employed. In Nature, however, the vast majority of
so-called chiral natural products exist in enantiomerically pure form. Therefore, in order to compare synthetic receptors
for the same enantiomerically pure guest, whose binding properties in principle depend on its state, as is the case here,
we propose to use the normalized binding amplification parameter β (Equation 1).
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ꢂꢃꢄꢃꢅ ꢆ ꢂꢃꢇꢈꢃꢈꢉ
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ꢊ
(1)
ꢀ ꢁ
ꢂꢃꢄꢃꢅ
ꢂꢃꢄꢃꢅ ꢁ ꢋꢌꢍꢎꢏꢂꢃꢇꢈꢃꢈꢉꢐ; ꢂꢃꢇꢈꢃꢈꢉꢑ; … ; ꢂꢃꢇꢈꢃꢈꢉꢒꢓꢔ
,where ꢂꢃꢄꢃꢅ is the highest association constant Ka from the set of possible states of the receptor and ꢂꢇꢈꢃꢈꢉ is the Ka in
ꢊ
ꢃ
any other state. The value of parameter β is always located between 0 and 1 which easily allows for evaluation of the rela-
tive discrimination ability of the switchable receptor for both achiral and chiral guests. For example, the value of β close
to 0 indicates no difference of Ka between states, whereas value of β close to 1 indicate very strong preference for one of
the receptor state toward guest molecule. In this work receptors 1 can exist only in two states (i.e. E- or Z-isomer), ꢂꢃꢄꢃꢅ is
higher for E-isomer, and so β = (Ka,E – Ka,Z)/Ka,E. The highest β parameter was observed for the binding of receptor 1a with
L-enantiomer of the guest, i.e. L-Phe and L-Trp were bound almost three times stronger by E-1a than Z-1a (β = 0.66 for L-
Phe and β = 0.64 for L-Trp, respectively). In contrast, parameter β for receptors 1b does not exceed 0.4 which further con-
firms weaker chiral discrimination properties of the 1-aminoglucose pedant arm.
To evaluate a possible influence of enantiomeric carboxylate on the rate of Z→E thermal back-isomerisation we conduct-
ed additional experiments similar to those performed for achiral acetate, in which we studied how the rate constant of the
Z→E isomerization depends on the amount of Trp added (Figure 2).
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Figure 2. Changes in observed rate constant (kobs.) of thermal Z→E isomerization of receptors Z-1a (squares) and Z-1b (triangles)
upon addition of D-Trp (colored in blue) and L-Trp (colored in red) at 298±0.1K along with calculated values of Ka,Z, kenh
(kHG/kH), and R2 (inset table); cZ-1 = 5∙10-5 M; kH – rate constant without anion added; kHG – rate constant for saturated complex.
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In addition, this procedure allows for direct comparison with values of Ka, and so α, derived from H NMR titrations. In
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supramolecular recognition of chiral species, the quality and reliability of
α is a serious issue when the Ka for correspond-
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ing enantiomers cannot be accurately determined.5a,26 Furthermore, some of the reported enantioselectivities which act as
the golden standard are actually consequences of experimental errors.5a,26d As can be seen from Figure 2, the excellent fit of
the data points to the equation derived for a simple 1:1 binding mode (see Experimental section and Fig. S67-68 for the
residual analysis) clearly confirms stochiometry of the complexes of receptors Z-1 with enantiomeric carboxylates. The Ka
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1
value for Z-1a is slightly higher than that obtained from H NMR titration experiments, e.g. for D-Trp the values are Ka =
126 M-1 vs Ka = 68 M-1, and for L-Trp Ka = 85 M-1 vs Ka = 46 M-1, for UV-Vis vs 1H NMR, respectively. However, for Z-1b these
differences are negligible. Overall, the enantiomeric discrimination α for receptors Z-1a is virtually equal to that obtained
from 1H NMR titrations (1.49 vs 1.48), whereas for Z-1b it is slightly lower (1.06 vs 1.31, for UV-Vis vs 1H NMR, respectively).
Given that the determined parameters are insensitive to the receptor concentration and considering the excellent calcu-
lated fit (R2>0.999 and χ2 ≅ 10-12-10-11), the results derived from UV-Vis isothermal titration are likely to be more reliable. In
addition, the thermal rate constant enhancement kenh (i.e. kHG/kH) for Z-1a ranges from 5.2 for L-Trp to 5.8 for D-Trp, i.e.
D-enantiomer causes faster relaxation to E-1a, whereas nearly identical rates (kenh = 19) for Z-1b independently prove that
virtually no chiral differentiation is occurring in this case. Since the anion is not consumed during reaction, one can as-
sume that anion acts as “catalyst” of this thermal back-isomerisation process.
In conclusion, by combining together sugar scaffolds, urea groups, and azobenzene moiety, we obtained two new chiral
receptors able to selectively sense biologically important chiral carboxylates. Since the binding affinities toward chiral
carboxylates differ between photoswitchable E- and Z-isomers, we have shown, for the first time, that light can be used
for switching of the chiral recognition, allowing even for the complete “turn-off” of this phenomenon. Furthermore, since
the stability of Z-isomers of 1 is a anion and temperature dependent, one can consider chiral anion and temperature as
factors allowing for predictable step-wise control of the chiral event, with the chiral properties of the receptor increasing-
ly resembling those of the E-isomer as time passes.
EXPERIMENTAL SECTION
Materials and Methods. All the reagents were used as received. The solvents were dried by distillation over the appro-
priate drying agents. All reactions were performed avoiding moisture by standard procedures and under a nitrogen at-
mosphere. Flash column chromatography was performed on silica gel (230−400 mesh), thin-layer chromatography (TLC)
1
was carried out on aluminum sheets precoated with silica gel. H NMR and 13C NMR spectra were recorded on Varian
Mercury 400 instrument at 400 and 100 MHz. NMR signals were assigned with the help of DEPT, COSY, HMBC, HMQC,
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and NOESY experiments. Proton and carbon chemical shifts are reported in ppm (δ) (CDCl3, H NMR δ = 7.26 and 13C
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NMR δ = 77.26 or DMSO-d6, H NMR δ = 2.54 and 13C NMR δ = 39.52). J coupling constants values are reported in Hz.
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Melting points are uncorrected. High resolution mass spectra (HRMS) were recorded using ESI-TOF technique. The UV-
Vis spectra were recorded at 298K on spectrophotometer equipped with a Peltier thermostated cell holder (temperature
accuracy ± 0.1 °C).
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Compound 2 was prepared as previously described13d and known sugar isocyanates 3a and 3b were prepared as described
in Scheme 2. Caution! All operations with phosgene should be carried in a well ventilated hood, and the rotary evaporator
should be equipped with a water jet pump to adsorb the unreacted gaseous phosgene.
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Scheme2. Synthesis of the sugar isocyanates 3a and 3b.
2-deoxy-2-[[(4-methoxyphenyl)methylene]amino]-β-D-glucopyranose (7): The compound was synthesized accord-
ing to the adapted procedure of Silva et al.27 D-glucosamine hydrochloride 6 (30.0 g, 139 mmol) was dissolved in 1M NaO-
Haq (150 mL) and then freshly distilled p-anisaldehyde (17.0 mL, 139 mmol) was added. The mixture was stirred at rt for 1
h. The white precipitate was filtered off, washed with cold water (250 mL), EtOH-Et2O mixture (250 mL, 1:1, v/v), and
dried under high-vacuum yielding product 7 (33.1 g, 80%), m.p. 174oC, [αD] = +29o (c = 1.0 M, DMSO). 1H NMR (400 MHz,
DMSO): δ = 8.12 (s, 1H), 7.69 (d, J = 8.8 Hz, 2H), 6.99 (d, J = 8.8 Hz, 2H), 6.53 (d, J = 6.6 Hz, 1H), 4.92 (d, J = 5.3 Hz, 1H),
4.82 (d, J = 5.6 Hz, 1H), 4.70 (t, J = 7.1 Hz, 1H), 4.55 (t, J = 5.8 Hz, 1H), 3.79 (s, 3H), 3.76 – 3.70 (m, 1H), 3.56 – 3.39 (m, 2H),
13
3.28 – 3.20 (m, 1H), 3.19 – 3.10 (m, 1H), 2.80 (t, J = 8.9, 1H). C NMR (100 MHz, DMSO): δ = 161.3, 161.1, 129.7, 129.1, 113.9,
95.7, 78.2, 76.9, 74.6, 70.4, 61.3, 55.3.
1,3,4,6-Tetra-O-acetyl-2-deoxy-2-[[(4-methoxyphenyl)methylene]amino]-β-D-glucopyranose (8): The compound
was synthesized according to the adapted procedure of Potter et al.28 To the cold mixture of 7 (12.0 g, 41.0 mmol) in pyri-
dine (65 mL), acetic anhydride (36.0 mL) and then DMAP (0.12 g, 1.00 mmol) were added subsequently at 0oC. The reac-
tion was stirred until it became a homogenous solution and then overnight at rt. The solution was poured into ice-cold
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water (350 mL), the white precipitate was filtered off, washed with cold water (2 x 50 mL), Et2O (2 x 50 mL), and recrystal-
lized from EtOH yielding white crystals of product 8 (17.9 g, 94%), m.p. 169oC, [αD] = +96o (c = 1.0, CHCl3). 1H NMR (400
MHz, DMSO): δ = 8.28 (s, 1H), 7.66 (d, J = 8.8 Hz, 2H), 6.99 (d, J = 8.8 Hz, 2H), 6.08 (d, J = 8.2 Hz, 1H), 5.45 (t, J = 9.7 Hz,
1H), 4.98 (t, J = 9.6 Hz, 1H), 4.30 – 4.18 (m, 2H), 4.05 – 3.97 (m, 1H), 3.79 (s, 3H), 3.45 (t, J = 9.6, 1H), 2.02 (s, 3H), 1.98 (s,
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6H), 1.82 (s, 3H). C NMR (100 MHz, DMSO): δ = 170.0, 169.4, 169.0, 168.6, 164.4, 161.8, 129.9, 128.3, 114.2, 92.5, 72.4, 72.3,
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71.6, 67.8, 61.7, 55.4, 20.5, 20.4, 20.2.
1,3,4,6-Tetra-O-acetyl-2-amino-2-deoxy-β-D-glucopyranose (9): The compound was synthesized according to the
adapted procedure of Potter et al.28 To the solution of 8 (15.0 g, 32.3 mmol) in refluxing acetone (80 mL), 5M aqueous
solution of HCl (8 mL) was added dropwise. After ca. 5 min a white precipitate started to form. After vigorous stirring for
30 min, the reaction was cooled to rt, the precipitate was filtered off, and washed successively with acetone (2x20 mL) and
Et2O (2x50 mL). The crude product was recrystallized from MeOH yielding white crystals of product 9 (10.1 g, 90%), m.p.
230oC, [αD] = +33o (c = 1.0, MeOH). 1H NMR (400 MHz, DMSO): δ = 8.91 (s, 3H), 5.93 (d, J = 8.6 Hz, 1H), 5.37 (t, J = 9.8 Hz,
1H), 4.92 (t, J = 9.5 Hz, 1H), 4.18 (dd, J = 12.2, 4.0 Hz, 1H), 4.06 – 3.95 (m, 2H), 3.54 (t, J = 9.5 Hz, 1H), 2.17 (s, 3H), 2.02 (s,
3H), 1.99 (s, 3H), 1.97 (s, 3H). 13C NMR (100 MHz, DMSO): δ = 170.0, 169.8, 169.3, 168.7, 90.1, 71.6, 70.3, 67.8, 61.3, 52.2, 21.0,
20.9, 20.5, 20.4.
2,3,4,6-Tetra-O-acetyl-1-bromo-1-deoxy-α-D-glucopyranose (11): The compound was synthesized according to the
adapted procedure of Potter et al.28 To a vigorously stirred mixture of commercially available β-D-Glucose pentaacetate 10
(27.2 g, 69.0 mmol) in glacial AcOH (115 mL), 33% HBr in AcOH (100 mL) was carefully added dropwise and the resulting
yellow solution was at rt overnight. Then the reaction mixture was poured into cold water (1500 mL), the initially formed
precipitate was filtered off and dissolved in CHCl3 (400 mL). The filtrate was extracted with CHCl3 (2 x 100 mL) and the
combined organic extracts were successively washed with saturated NaHCO3 (2 x 250 mL), water (2 x 60 mL), and brine (2
x 120 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was evaporated off at T ≤ 30oC. The crude
product was recrystallized from Et2O /petroleum ether mixture yielding white solid of anomerically pure 11 (33.1 g, 70%),
m.p. 86oC, [αD] = -195o (c = 1.0, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 6.60 (d, J = 4.0 Hz, 1H), 5.54 (t, J = 9.7 Hz, 1H), 5.15
(t, J = 9.5 Hz, 1H), 4.82 (dd, J = 10.0, 4.0 Hz, 1H), 4.35 – 4.25 (m, 2H), 4.12 (d, J = 10.4 Hz, 1H), 2.09 (s, 3H), 2.08 (s, 3H), 2.04
(s, 3H), 2.02 (s, 3H). 13C NMR (100 MHz, CDCl3): δ = 170.6, 170.0, 169.9, 169.6, 86.7, 72.2, 70.7, 70.3, 67.3, 61.0, 20.79, 20.78,
20.75, 20.68.
2,3,4,6-Tetra-O-acetyl-1-azide-1-deoxy-β-D-glucopyranose (12): The compound was synthesized according to the
adapted procedure of Takahashi et al.29 NaN3 (7.6 g, 117 mmol) and 11 (15.7 g, 38.0 mmol) were suspended in anhydrous
DMF (150 mL) and the resulting suspension was stirred at 50oC for 2h. The solvent was evaporated off at T ≤ 40oC and the
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residue was partitioned between CHCl3 (200 mL) and water (100 mL). The aqueous phase was discarded and organic
phase was successively washed with water (2 x 100 mL), saturated NaHCO3 (2 x 100 mL), and brine (100 mL). The organic
layer was dried over anhydrous Na2SO4, the solvent was evaporated off, and the crude yellow product was washed with
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cold Et2O yielding pure 12 (12.1 g, 80%) in the form of white solid, m.p. 128oC, [αD] = +30o (c = 1.0, CHCl3). H NMR (400
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MHz, CDCl3): δ = 5.21 (t, J = 9.5 Hz, 1H), 5.09 (t, J = 9.7 Hz, 1H), 4.94 (t, J = 9.2 Hz, 1H), 4.64 (d, J = 8.9 Hz, 1H), 4.26 (dd, J =
12.5, 4.8 Hz, 1H), 4.16 (dd, J = 12.5, 2.3 Hz, 1H), 3.79 (ddd, J = 10.0, 4.7, 2.3 Hz, 1H), 2.09 (s, 3H), 2.07 (s, 3H), 2.02 (s, 3H),
2.00 (s, 3H). 13C NMR (100 MHz, CDCl3): δ = 170.7, 170.2, 169.4, 169.3, 88.0, 74.1, 72.7, 70.7, 68.0, 61.8, 20.8, 20.7 (s, 2C).
2,3,4,6-Tetra-O-acetyl-1-amino-1-deoxy-β-D-glucopyranose (13): The compound was synthesized according to the
adapted procedure of Ichikawa et al.30 To the solution of 12 (6.7 g, 18.0 mmol) in EtOAc (200 mL) and Et3N (3 mL), sus-
pension of Pd/C (0.7 g, 5%wt) in EtOAc (10 mL) was carefully added. The mixture was then vigorously stirred under a H2
atmosphere (1 atm.) until TLC analysis showed complete consumption of the azide (t ~ 12h). The solution was filtered
over a pad of Celite™ and washed thoroughly with EtOAc (~200 mL). The solvent was evaporated and the crude product
was recrystallized from the minimum amount of EtOAc at rt yielding white crystals of 13 (5.7 g, 86%), m.p. 115oC. 1H NMR
(400 MHz, CDCl3): δ = 5.22 (d, J = 9.6 Hz, 1H), 5.02 (t, J = 9.7 Hz, 1H), 4.81 (d, J = 9.6 Hz, 1H), 4.22 (d, J = 4.8 Hz, 1H), 4.18
(dd, J = 6.2, 2.8 Hz, 2H), 4.09 (dd, J = 12.3, 2.2 Hz, 1H), 3.73 – 3.63 (m, 1H), 2.07 (s, 3H), 2.05 (s, 3H), 2.00 (s, 3H), 1.99 (s,
3H). 13C NMR (100 MHz, CDCl3): δ = 170.8, 170.3 (s, 2C), 169.7, 85.0, 73.2, 72.8, 72.1, 68.8, 62.4, 20.9, 20.9, 20.74, 20.73.
1,3,4,6-Tetra-O-acetyl-2-deoxy-2-isocyanato-β-D-glucopyranose (3a): The compound was synthesized according to
the procedure of Ávalos et al.31 To the solution of amine hydrochloride 9 (3.8 g, 10.0 mmol) in a heterogeneous mixture of
CH2Cl2 (50 mL) and saturated NaHCO3 solution (80 mL), 20% solution of COCl2 in PhCH3 (2.5 eq, 25.0 mmol, 13.2 mL) was
added at 0oC. After 30 minutes of virguous stirring the phases were separated and the organic layer was washed with brine
(50 mL) and dried over anhydrous MgSO4. The solvent was evaporated off at T ≤ 30oC and the crude product was recrys-
tallized from Et2O/petroleum ether mixture, yielding white crystals of 3a (3.50 g, 95%), m.p. 75oC, [αD] = +33o (c = 1.0,
CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 5.59 (d, J = 8.6 Hz, 1H), 5.14 (t, J = 9.8 Hz, 1H), 5.00 (t, J = 9.7 Hz, 1H), 4.28 (dd, J =
12.5, 4.4 Hz, 1H), 4.07 (dd, J = 12.5, 2.0 Hz, 1H), 3.88 – 3.81 (m, 1H), 3.80 – 3.73 (m, 1H), 2.17 (s, 3H), 2.08 (s, 3H), 2.05 (s, 3H),
2.01 (s, 3H). 13C NMR (100 MHz, CDCl3): δ = 170.6, 169.9, 169.7, 168.8, 126.8, 92.6, 73.4, 73.0, 67.6, 61.5, 57.0, 20.9, 20.8, 20.6
(s, 2C).
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2,3,4,6-Tetra-O-acetyl-1-deoxy-1-isocyanato-β-D-glucopyranose (3b): The compound was synthesized according to
the modified procedure of Ávalos et al.31 To the solution of amine 13 (3.47 g, 10.0 mmol) in a heterogeneous mixture of
CH2Cl2 (50 mL) and saturated NaHCO3 solution (80 mL), 20% solution of COCl2 in PhCH3 (2.5 eq, 25.0 mmol, 13.2 mL) was
added at 0oC. After 30 minutes of virguous stirring the phases were separated and the organic layer was washed with brine
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(50 mL) and dried over anhydrous MgSO4. The solvent was evaporated off at T ≤ 30oC and the crude product was recrys-
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tallized from Et2O/petroleum ether mixture, yielding white crystals of 3b (3.40 g, 90%), m.p. 117oC (lit. 117-119oC)28. H
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NMR (400 MHz, CDCl3): δ = 5.18 (t, J = 9.6 Hz, 1H), 5.10 (t, J = 9.7 Hz, 1H), 4.99 (t, J = 9.1 Hz, 1H), 4.79 (d, J = 8.8 Hz, 1H),
4.23 (dd, J = 12.5, 4.8 Hz, 1H), 4.13 (dd, J = 12.5, 2.2 Hz, 1H), 3.75 (ddd, J = 9.9, 4.8, 2.3 Hz, 1H), 2.09 (s, 3H), 2.08 (s, 3H), 2.02
(s, 3H), 2.00 (s, 3H). 13C NMR (100 MHz, CDCl3): δ = 170.71, 170.24, 169.38, 169.34, 127.16, 82.85, 74.15, 72.56, 67.90, 61.71,
20.83, 20.66 (s, 2C), 20.63.
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Receptor E-1a: 4,4’-aminoazobenzene 2 (0.423 g, 2.0 mmol) and 1,3,4,6-tetra-O-acetyl-2-deoxy-2-isocyanato-β-D-
glucopyranose 3a (1.64 g, 4.4 mmol) were refluxed in MeCN (20 mL) for 12h under argon atmosphere. The precipitate was
filtered off, washed with hot MeCN (~ 50 mL), suspended in Et2O (20 mL), and vigorously stirred for 10 minutes. The
orange solid was filtered off and dried at high vacuum to afford title compound E-1a (1.21 g, 63%), m.p. 245oC, [αD] = +24o
(c = 1.0, DMSO). 1H NMR (400 MHz, DMSO): δ = 9.09 (s, 2H), 7.76 (d, J = 8.9 Hz, 4H), 7.57 (d, J = 8.9 Hz, 4H), 6.32 (d, J =
9.4 Hz, 2H), 5.91 (d, J = 8.7 Hz, 2H), 5.38 (t, J = 9.9 Hz, 2H), 4.92 (t, J = 9.6 Hz, 2H), 4.20 (dd, J = 12.3, 4.4 Hz, 2H), 4.10 –
3.87 (m, 6H), 2.05 (s, 6H), 2.02 (s, 6H), 1.99 (s, 6H), 1.93 (s, 6H). 13C NMR (100 MHz, DMSO): δ = 170.1, 169.8, 169.3, 169.0,
154.3, 146.6, 142.8, 123.4, 117.8, 92.1, 72.4, 71.3, 68.2, 61.6, 52.9, 20.6, 20.5, 20.4 (s, 2C). HRMS (ESI, MeOH): m/z [M+Na]+
calc. for C42H50N6O20Na 981.2972, found: 981.2953. Anal. calc. for C42H50N6O20: C 52.61, H 5.26, N 8.76, found: C 50.99, H
5.36, N 8.39.
Receptor E-1b. 4,4’-aminoazobenzene 2 (0.43 g, 2.0 mmol) and 2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl isocyanate 3b
(1.64 g, 4.4 mmol) were refluxed in MeCN (20 mL) for 12h under argon atmosphere. The precipitate was filtered off,
washed with hot MeCN (~ 50 mL), suspended in Et2O (20 mL), and vigorously stirred for 10 minutes. The orange solid was
filtered off and dried at high vacuum to afford title compound E-1b (1.30 g, 68%), m.p. 217oC, [αD] = -57o (c = 1.0, DMSO).
1H NMR (400 MHz, DMSO): δ = 9.14 (s, 2H), 7.79 (d, J = 8.9 Hz, 4H), 7.59 (d, J = 9.0 Hz, 4H), 7.00 (d, J = 9.7 Hz, 2H), 5.39
(dt, J = 21.0, 9.5 Hz, 4H), 4.93 (dt, J = 14.0, 9.6 Hz, 4H), 4.22 – 4.07 (m, 4H), 3.99 (d, J = 10.4 Hz, 2H), 2.00 (s, 12H), 2.00 (s,
13
6H), 1.95 (s, 6H). C NMR (100 MHz, DMSO): δ = 170.1, 169.6, 169.5, 169.4, 153.8, 146.9, 142.3, 123.5, 118.1, 78.2, 72.7, 71.8,
70.3, 68.1, 61.9, 20.6, 20.5, 20.4 (s, 2C). HRMS (ESI, MeOH): m/z [M+Na]+ calc. for C42H50N6O20Na 981.2978, found:
981.3012. Anal. calc. for C42H50N6O20: C 52.61, H 5.26, N 8.76, found: C 50.94, H 5.37, N 8.66.
Receptor E-5. 4-aminoazobenzene (0.20 g, 1.01 mmol) and 1,3,4,6-tetra-O-acetyl-2-deoxy-2-isocyanato-β-D-
glucopyranose 3a (0.42 g, 1.12 mmol) were refluxed in MeCN (10 mL) for 12h under argon atmosphere. The solvent was
evaporated and the orange residue was suspended in Et2O (~20 mL), and vigorously stirred for 30 minutes. The orange
solid was filtered off and recrystallized from aqueous MeOH to yield orange needle-like crystals of title compound E-5
(0.44 g, 77%), m.p. 232-233oC, [αD] = +9.8o (c = 1.06, MeOH). 1H NMR (400 MHz, DMSO): δ = 9.13 (s, 1H), 7.89 – 7.77 (m,
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4H), 7.64 – 7.46 (m, 5H), 6.34 (d, J = 9.4 Hz, 1H), 5.92 (d, J = 8.7 Hz, 1H), 5.38 (dd, J = 10.3, 9.5 Hz, 1H), 4.93 (t, J = 9.6
Hz, 1H), 4.20 (dd, J = 12.3, 4.5 Hz, 1H), 4.11 – 4.05 (m, 1H), 4.03 (dd, J = 10.3, 8.0 Hz, 1H), 3.96 (dd, J = 20.0, 10.1 Hz,
1H), 2.05 (s, 3H), 2.02 (s, 3H), 1.99 (s, 3H), 1.94 (s, 3H). 13C NMR (100 MHz, DMSO): δ = 170.0, 169.7, 169.2, 169.0, 154.3,
152.1, 146.4, 143.5, 130.7, 129.3, 123.8, 122.2, 117.8, 92.1, 72.4, 71.3, 68.3, 61.6, 52.9, 20.6, 20.5, 20.4. HRMS (ESI, MeOH):
m/z [M+Na]+ calc. for C27H30N4O10Na 593.1860, found: 593.1856. Anal. calc. for C27H30N4O10: C 56.84, H 5.30, N 9.82, found:
C 56.86, H 5.43, N 9.91.
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Photoisomerisation studies. For photochemical production of samples enriched in Z isomer, we used a custom-made
Rayonet type photoreactor, equipped with eight blacklight fluorescent lamps (nominal power = 9W, λmax = 368 nm) and
with an effective air cooling system to maintain fixed temperature (≤ 26oC) inside photoreactor chamber. To ensure ho-
mogenous irradiation, sample was spinned at 4 rpm. Blue light irradiation experiments were carried out with SMD Power-
LED bulb (3.3 W, λmax = 410 nm). Photoisomerisation of receptors 1 was carried out in quartz cuvette (V = 3.5 ml, l = 10
mm) or in quartz NMR tube (φ = 5 mm, l = 7 in, limit 600 MHz). Time required to reach photostationary state (PSS) using
UV or blue-light was found to be ca. 30 s for diluted receptor solution (c ~ 10-5 M) and ~30 min for the concentrated re-
ceptor solution (c ~ 10-2 M). The rate of thermal Z→E isomerization of pure Z-1 and their anion complexes were calculated
by monitoring the absorption change of Z and E isomers in the dark at T = 298.0±0.1 K. The observed first-order rate (kobs.
)
is an average of the kobs. determined by Marquard non-linear technique at four different wavelengths as implemented in
Cary WinUV Software 5.0.0.999. Practically linear (R2 ≥ 0.998) Arrhenius and Eyring plots indicate that during thermal
back-isomerization of pure Z-1 only one mechanism occurs (Table S1).
Titration experiments. Tetrabutylammonium (TBA) salts were used as a source of anions. TBACH3CO2 and
TBAC6H5CO2 were purchased from Sigma Aldrich and chiral carboxylic acids (mandelic acid, N-Boc-protected PheCO2H
and TrpCO2H) from TCI Europe. TBA salts of chiral carboxylates were prepared by the addition of a standardized solution
of TBAOH in methanol (~1.0 M, 1.0 equivalent, Sigma Aldrich) to the corresponding solution of mandelic acid or N-Boc-
protected PheCO2H and TrpCO2H in methanol. The resulting mixture was stirred for 1 h and solvent was evaporated off
to yield a crude salt which was further dried under high vacuum over solid P4O10. HPLC grade water was added to the
commercially available DMSO-d6 of 99.80% isotopic purity or non-deuterated DMSO (≥99.5%) to obtain 0.5% water con-
centration.
1H NMR titrations procedure: The DMSO solution of a receptor (ca. 10-2 M) was titrated in an NMR tube with the 0.1-0.2
M solution of a respective TBA salt. The solution of the salt contained a certain amount of the receptor in order to keep
receptor concentration constant during the titration; 16 to 20 data points were recorded, depending on the shape of the
titration curve. However, it was important to choose such volumes of aliquots so that most of the data points could occur
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in close proximity of the inflection point of the respective titration curve. Such a procedure allows for more precise calcu-
lation of the binding constants. Moreover, we took into account the shift changes of all protons present in the receptor
and guest molecules. In all cases DMSO-d6 + 0.5% H2O was used as a solvent mixture. Titration of pure E-1 was conducted
in the amber NMR tube and titration of a mixture of E- and Z-1 was conducted in the quartz NMR tube (φ = 5 mm, l = 7 in,
limit 600 MHz). In the latter case photoisomerisation of E-1 was carried out before anion was added. A nonlinear curve
fitting for 1:1 or 1:2 binding model was carried out with the HypNMR 2008 Software32 and allow the determination of glob-
al association constant. Determination of Ka’s for Z-1 was carried out using fully relaxed values of Ka’s for E-1 which were
generally similar to those obtained during titration of pure E-1 in the dark. However, when fitting algorithm failed to
converge, fixed values of Ka’s for E-1 were instead used to determine Ka for Z-1.
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Isothermal Z→E isomerization titration procedure: The DMSO solution of a receptor 1 enriched in Z isomer (ctotal
=
5•10-5 M) was titrated in an NMR tube with the 0.1-0.2 M solution of a respective TBA salt. The kinetics without and with
anion added were recorded and analyzed to give kobs as described in section “Photoisomerisation studies”. Time required
for the total relaxation to E-1 was ~2-3 h. Usually no less than 15 kinetics were recorded, depending on the shape of the
titration curve. The experimental data points, i.e. kobs. determined for various amounts of guest added ([G]0), were then
ꢜ ꢞ
ꢝ
ꢖꢘ ꢚ,ꢛ
ꢕ
ꢖ
ꢗꢕ
ꢙ
fitted to equation:13d
ꢟ, where kH is kobs. without anion added. A least-squares fitting procedure gave pa-
ꢜ
ꢝ
ꢞ
ꢟ
ꢠꢗꢙ
ꢚ,ꢛ
rameters of interest, i.e. Ka,Z and kHG
.
ASSOCIATED CONTENT
Supporting Information
Electronic Supplementary Information (ESI) available: detailed experimental procedures for intermediates and receptors, struc-
1
ture analysis, and description of H, 13C NMR and UV-Vis titrations. This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
* E-mail: janusz.jurczak@icho.edu.pl
* E-mail: kajetan.dabrowa@icho.edu.pl
ACKNOWLEDGMENT
We would like to acknowledge Poland’s National Science Centre (project 2011/02/A/ST5/00439) for financial support and Dr.
Filip Ulatowski for the critical evaluation of the manuscript.
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