Chiral NH-controlled supramolecular metallacycles

Article abstract of DOI:10.1021/jacs.6b11422

Chiral NH functionalities-based discrimination is a key feature of Nature's chemical armory, yet selective binding of biologically active molecules in synthetic systems with high enantioselectivity poses significant challenges. Here we report the assembly of three chiral fluorescent Zn₆L₆ metallacycles from pyridyl-functionalized Zn(salalen) or Zn(salen) complexes. Each of these metallacycles has a nanoscale hydrophobic cavity decorated with six, three, or zero chiral NH functionalities and packs into a three-dimensional supramolecular porous framework. The binding affinity and enantioselectivity of the metallacycles toward α-hydroxycarboxylic acids, amino acids, small molecule pharamaceuticals (L-dopa, D-penicillamine), and chiral amines increase with the number of chiral NH moieties in the cyclic structure. From single-crystal X-ray diffraction, molecular simulations, and quantum chemical calculations, the chiral recognition and discrimination are attributed to the specific binding of enantiomers in the chiral pockets of the metallacycles. The parent metallacycles are fluorescent with the intensity of emission being linearly related to the enantiomeric composition of the chiral biorelevant guests, which allow them to be utilized in chiral sensing. The fact that manipulation of chiral NH functionalities in metallacycles can control the enantiorecognition of biomolecular complexes would facilitate the design of more effective supramolecular assemblies for enantioselective processes. (Figure Presented).

Full text of DOI:10.1021/jacs.6b11422

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Article
Chiral NH-Controlled Supramolecular Metallacycles
Jinqiao Dong, Chunxia Tan, Kang Zhang, Yan Liu, Paul J. Low, Jianwen Jiang, and Yong Cui
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b11422 • Publication Date (Web): 06 Jan 2017
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Chiral NH-Controlled Supramolecular Metallacycles
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Jinqiao Dong,† Chunxia Tan,† Kang Zhang,‡ Yan Liu,*,† Paul J. Low,¶ Jianwen Jiang,‡ and Yong
Cui*,†,⊥
†
School of Chemistry and Chemical Technology and State Key Laboratory of Metal Matrix
Composites, Shanghai Jiao Tong University, Shanghai 200240, China
‡
Department of Chemical and Biomolecular Engineering, National University of Singapore, 4
Engineering Drive 4, 117576, Singapore
¶
School of Chemistry and Biochemistry, University of Western Australia, 35 Stirling Highway,
Crawley, WA 6009, Australia
⊥ Collaborative Innovation Center of Chemical Science and Engineering, Tianjin 300072, China
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ABSTRACT: Chiral NH functionalitiesꢀbased discrimination is a key feature of Nature’s
chemical armory, yet selective binding of biologically active molecules in synthetic systems with
high enantioselectivity poses significant challenges. Here we report the assembly of three chiral
fluorescent Zn6L6 metallacycles from pyridylꢀfunctionalized Zn(salalen) and/or Zn(salen)
complexes. Each of these metallacycles has a nanoscale hydrophobic cavity decorated with six,
three or zero chiral NH functionalities and packs into a threeꢀdimensional supramolecular porous
framework. The binding affinity and enantioselectivity of the metallacycles toward αꢀ
hydroxycarboxylic acids, amino acids, small molecule pharamaceuticals (Lꢀdopa, Dꢀ
penicillamine) and chiral amines increase with the number of chiral NH moieties in the cyclic
structure. From singleꢀcrystal Xꢀray diffraction, molecular simulations and quantum chemical
calculaitons, the chiral recognition and discrimination are attributed to the specific binding of
enantiomers in the chiral pockets of the metallacycles. The parent metallacycles are fluorescent
with the intensity of emission being linearly related to the enantiomeric composition of the chiral
bioꢀrelevant guests, which allow them to be utilized in chiral sensing. The fact that manipulation
of chiral NH functionalities in metallacycles can control the enantiorecognition of biomolecular
complexes would facilitate the design of more effective supramolecular assemblies for
enantioselective processes.
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INTRODUCTION
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We live in a chiral world. Nature exhibits a remarkable degree of specificity in the chiral
recognition of biomolecules, leading to the mirror image arrangements of the two forms eliciting
quite different biological responses.1 In particular, chiral NH functionalities have played a key
role in the origin of homochirality in living systems such as DNA, RNA, peptides and enzymes.2
For example, carbohydrate recognition by active enzymes involve a wide range of biological
processes, including protein folding and trafficking, cell–cell recognition, and many aspects of
immune response.3 Therefore, the detection and differentiation of biomolecular by NHꢀbased
receptors are significant in the fields of synthetic, medicinal and biological chemistry. Recently,
Davis and coꢀworkers successfully realized a series of synthetic supramolecular receptors
containing numerous NH functionalities for highꢀaffinity binding of polysaccharides,4
carbohydrates,5ꢀ6 glucose,7 and oꢀglcNAc derivatives.8 To date, however, only few reported
receptors bearing chiral NH functionalities have been designed to detect and discriminate
biologically substrates such as carbohydrates, amino acids, amines and important drug
compounds.9ꢀ12 Nevertheless, the development of biomimetic receptors and the understanding of
entiorecognition mechanism with wellꢀcontrolled chiral NH functionalities have not yet been
achieved.
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The Nature’s chiroselective phenomena have motivated the quest for synthetic materials with
enantioselective capability. Interestingly, chiral supramolecular coordination complexes (SCCs),
similar structures with many functional enzymes in living organs, can be constructed by
spontaneous coordinationꢀdriven selfꢀassembly,13ꢀ16 thereby leading to a large number of
molecular architectures, including discrete chiral metallacycles with wellꢀdefined internal
cavities with size, shape and functional tunability. This provides the impetus for applications in
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enantioselective separation,17ꢀ19 catalysis,20ꢀ22 and molecular recognition.11ꢀ12,15 Among them,
lightꢀemitting metallacycles have received considerable attention because of their potential
applications in chemical sensing and biotechnology.23 In particular, Stang and coꢀworkers have
recently reported tetraphenylethylene (TPE) metallacycles or metallacages with aggregationꢀ
induced emission (AIE) behavior for whiteꢀlight emission,24 nitroaromatics sensing,25 anion
sensing,26 and turnꢀon fluorescence by tobacco mosaic virus (TMV).27 However, lightꢀemitting
sensor materials based on ultraꢀstable chiral supramolecular metallacycles are relatively
underdeveloped despite their prospects as advanced functional porous materials for chiral liquid
or gas sensing.28 Up to date, the development of wellꢀcontrolled and desired chiral NH
functionalities in fluorescent metallacycles as biomimetic receptors is still substantially
challenging in supramolecular chemistry.2,14
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To address the issue, it requires the exploration of new chiral building blocks which can not
only provide chiral NH functionalities, but also keep high fluorescent emission in metallacycles.
As partially reduced analogues of metallosalen complexes, metallosalalen complexes29 are
endowed with higher flexibility and conjugate structures; moreover, the builtꢀin chiral
asymmetric NH functionalities would improve its chiral discrimination. Recently, we have
reported a chiral Zn6(salen)6 metallacycles assembled from a enantiopure pyridylꢀfunctionalized
metallosalen complex.17 The metallacycle was readily assembled into a tubular supramolecular
structure capable of recognizing chiral alcohols, but failed to discriminate other important
substrates such as sugar acids, amino acids and amino acidꢀrelated drugs. With these
considerations in mind and inspired by Zn6(salen)6 synthesis, we envision that the reduction of
salenꢀbased hexamer into salalenꢀbased analogs bearing these additional asymmetric chiral NH
functionalities in the cyclic structure may improve its enantioselective discrimination towards a
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wider range of bioꢀrelevant molecular systems. In this article, we report a strategy for the
assembly of three chiral NHꢀcontrolled supramolecular metallacycles Zn6(salalen)6,
Zn6(salalen)3(salen)3 and Zn6(salen)6, and demonstrate their use as fluorescent chiral receptors
for αꢀhydroxycarboxylic acids, amino acids, amines and selected small pharamceutical
molecules, with high binding affinity and enantioselectivity. We directly observe the key role of
chiral NH functionalities in the metallacycles that lead to mornitoring the chiral recognition and
discrimination of biomolecules. Xꢀray diffraction measurements, molecular simulations and
quantum chemical calculaitons are conducted to provide structural and microscopic insights into
the experimentally observed enantiorecognition.
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RESULTS AND DISCUSSION
Synthesis and Characterization of Chiral NH-Controlled Metallacycles. The salen ligand
H2L0 and metallacycle 3 (Zn6L0 ) were prepared as previously reported.17,30 Herein, the salalen
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ligand H2L1 was prepared in an overall 79% yield by the Schiffꢀbase condensation of enantiopure
1,2ꢀdiaminocyclohexane and 3ꢀtertꢀbutylꢀ5ꢀ(4ꢀpyridyl)salicylaldehyde, followed by reduction
with NaBH4 and further condensation with the corresponding salicylaldehyde (Figure S1 and
Figure S5). The discrete hexagonal metallacycles [Zn6L1 ]·8MeOH·4H2O (1) and
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[Zn6L0 L1 ]·6MeOH·2H2O (2) were obtained by heating Zn(OAc)2·2H2O with H2L1 or a mixture
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of H2L0 and H2L1 (a 1:1 molar ratio) in DMF and MeOH at 80 °C (Figure 1aꢀc). Complex 1
containing six free chiral NH groups emitted cyan fluorescence under UVꢀlight (λex = 365 nm), 2
having three chiral NH groups emitted cyanꢀgreen fluorescence, whereas 3 with zero NH groups
emitted yellow fluorescence (Figure 1gꢀi). Notably, attempts to prepare salalenꢀbased Zn6L1 by
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direct reduction of the salenꢀbased Zn6L0 were unsuccessful. All 1, 2 and 3 are sparsely soluble
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in THF and DMSO (metallacycle 1 is slightly more soluble than another two), and are insoluble
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in water and other common organic solvents. Unfortunately, the poor solubility prevented us to
obtain satisfactory 1H NMR spectra of 1ꢀ3. The Fourier transform infrared spectroscopy (FTꢀIR)
spectra showed the peaks located at 1590 and 1320 cmꢀ1, which correspond to the C=N vibration
and CꢀN vibration of 1ꢀ3, respectively. The difference is that the NꢀH stretching vibration were
observed in metallacycle 1 and 2 (3420 cmꢀ1) and nonexistent in 3, indicating the salalen ligand
H2L1 in the two cyclic structures (Figure S13).
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The metallacyclic complexes 1 [Zn6L1 ], 2 [Zn6L0 L1 ] and 3 [Zn6L0 ] were prepared as shown
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in Figure 1, with singleꢀcrystal Xꢀray diffraction studies revealing the formation of the
isostructural chiral metallacycles (Figure 1dꢀf). In each case, the Zn centers adopt a distorted
square pyramidal geometry with the equatorial plane occupied by the central N2O2 donors of one
L ligand and the apical position by one pyridine from the imine side arm of another L. Each ZnL
unit thus utilizes one pyridyl group to coordinate another Zn atom building a hexameric
metallacyclic complex with an inner void diameter of 1.2 nm × 1.2 nm and six pendent pyridine
moieties decorating the periphery of the cyclic core. The three pairs of tertꢀbutyl groups from the
ligands L are arranged above and below the metallacyclic cavity (Figure 2a,b). Three kinds of
supramolecular interactions direct the packing of 1ꢀ3 in parallel along the crystallographic cꢀaxis
into 3D supramolecular porous frameworks without interpenetration (Figure 2cꢀg): (1) Strong
CH···π (2.87 ~ 3.10 Å) interactions between the butyl group and the conjugated phenyl ring of
adjacent metallacycles along cꢀaxis; (2) The faceꢀtoꢀface intermolecular π−π (3.59 ~ 3.78 Å)
interactions between the adjacent two rings, each Zn6L6 unit is engaged in six sets of such π−π
stackings; (3) Interlocking of cyclohexyl groups on adjacent metallacycle along aꢀaxis and bꢀaxis
causes the strong hydrophobic interactions (Figure S10ꢀS12). The bond lengths of 1 and 2 are
typical of salan (CꢀN, 1.42 ~ 1.52 Å) and salen (C=N, 1.23 ~ 1.29 Å) structural motifs. In both
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cases, the NH groups of the L1 ligands are oriented toward the outside of metallacyclic cavities
and exposed to the interstitial pores accessible to guest molecules, offering potential for
stereoselective host–guest interactions. They are rare examples of coordination assemblies with
builtꢀin chiral functionalities with crystallographically and the potential for studies of host−guest
interactions and supramolecular chemistry.11ꢀ12,18
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The coꢀexistence of the ligands H2L1 and H2L0 in a 1:1 molar ratio in 2 was directly confirmed
by single crystal Xꢀray diffraction of C=N and CꢀN bonds (Figure 1e and Figure S11), which
was also proved by 1H NMR after decomposition of the complex with aqueous hydrochloric acid
(Figure S2ꢀS4). Xꢀray photoelectron spectroscopy (XPS) showed that the content of C=N
species31 in highꢀresolution C1s spectra is gradually increased with the increasement of salen
ligand H2L0 from 1 to 3 (4.63%, 9.27% and 14.55% for 1, 2 and 3, respectively) (Figure 2h). On
the other hand, the highꢀresolution N1s spectra showed a gradually decrease of CꢀN species31ꢀ32
(48.38%, 34.19% and 6.47% for 1, 2 and 3, respectively) and increase of C=N species (13.44%,
22.77% and 45.67% for 1, 2 and 3, respectively) from 1 to 3 (Figure 2i), the relative content of
C−N/C=N is 3.60, 1.50 and 0.14 from 1 to 3, respectively, which is in accord with the formation
of metallacycles 1ꢀ3 by salalen (1, six H2L1), salalen/salen (2, three H2L1 and three H2L0) or
salen (3, six H2L0). The formation of these metallacycles was also supported by ESIꢀMS (Figure
S6, S8ꢀS9).
Solidꢀstate CD spectra of 1 and 2 constructed from (R)ꢀ and (S)ꢀenantiomers of H2L are mirror
images of each other, indicating their enantiomeric relationship (Figure 2j). The optical band
gaps (Eg) of 1ꢀ3 were estimated to be 2.84, 2.82 and 2.77 eV (Figure S16), from the electronic
spectra and the relationship [F(R)hv]2 = hvꢀEg, where hv is the corresponding phonon energy, and
R is the diffuse reflectance.33 These results indicate that 1ꢀ3 are a new type of semiconductor
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fluorescent metallacycles. The phase purity of the bulk samples was established by comparing
the observed and simulated powder Xꢀray diffraction (PXRD) (Figure S19). PLATON
calculations indicated the presence of 27.8 and 26.6% void space in 1 and 2,34 respectively. TGA
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o
revealed that the solvent molecules could be removed from 1 and 2 in the 80–150 C range
(Figure S20). PXRD experiments suggested that the samples retained their structural integrity
and crystallinity upon removal of the guest molecules. Their permanent porosity was confirmed
by their N2 adsorption isotherms at 77 K. After desolvation, 1 and 2 exhibited a TypeꢀI sorption
behavior, with a BET surface area of 490 m2 gꢀ1 and 475 m2 gꢀ1, respectively (Figure S21). Note
that 3 has a BET surface area of 504 m2 gꢀ1.17
Enantioselective Binding and Biosensing. Metallacycles 1ꢀ3 possess strong fluorescent in
THF with an emission maximum around 465 nm. The presence of chiral cavities and NH groups
in the metallacyclic compelxes 1ꢀ3 promoted the exploration of enantioselective recognition of
important αꢀhydroxycarboxylic acids such as mandelic acid (MA) and sugar acids (Figure 3).
When (R)ꢀ1 was treated with enantioꢀpure MA (1.0 × 10ꢀ3 M), the UVꢀVis spectrum remained
unchanged, indicative of the stability of the host structure (Figure S17). In contrast to the
absorption spectrum, however, the emission was quenched but the rate of change with LꢀMA was
faster than that with DꢀMA (Figure S23). The intensity of (R)ꢀ1 was maximally decreased to
62.3% and 83.2% of the original value by Lꢀ and DꢀMA, respectively. In accordance with the
Stern−Völmer (SꢀV) equation, the measured absorbance I0/I at 465 nm varied as a function of
[mM] in a linear relationship (R2 > 0.9900), suggesting 1:1 stoichiometry of the interaction
between MA and the host (R)ꢀ1.35 The KSV constants were calculated as 10059 ± 350 Mꢀ1 with Lꢀ
MA and 3857 ± 80 Mꢀ1 with DꢀMA, giving an enantioselectivity factor KSV(Rꢀ1ꢀL)/KSV(Rꢀ1ꢀD) of
2.61 ± 0.15 (Figure 3a). The opposite trend in selectivity was observed for quenching of (S)ꢀ1
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with Lꢀ and DꢀMA, for which the factor KSV(Sꢀ1ꢀD)/KSV(Sꢀ1ꢀL) was 2.59 ± 0.12 (Figure S26), further
confirming enantioselectivity in the fluorescent recognition. From control experiments, the free
salalen ligand H2L1 did not show obvious enantioselectivity under otherwise identical conditions
(Figure S27), suggesting a betterꢀdefined chiral environment conferred by the cyclic structure
imposed by the metal coordination environment.
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After titration with LꢀMA, the quantum yield (Φfl) of 1 decreased from 12.75 to 9.44%, the
hostꢀguest adducts of 1 and the MA analyte was also suggested by ESIꢀMS (Figure S7). The
static nature of the complexation is suggested by consistent fluorescence lifetimes of the host
before and after titration with LꢀMA (lifetime τ0 : 2.908 ns vs 2.897 ns, Figure S28). Complex of
the analyte with metallacycle 1 in the ground state via supramolecular interactions including
hydrogen bonding followed by the generation of an emissive electronꢀtransfer excited state or
energy transfer may be responsible for the fluorescence change. Furthermore, the apparent
quenching constant Kq (Kq = KSV/τ0) for the metallacycles 1 with LꢀMA system is evaluated to be
3.46 × 1012 Mꢀ1 sꢀ1, which is even 2 orders of magnitude higher than that of conventional
bimolecular diffusion based quenching mechanisms (∼1010 Mꢀ1 sꢀ1).36 In addition, exposure of
(R)ꢀ1 to MA (0.56 mM) with enantiomeric compositions ranging from −100 to 100%
enantiomeric excess (ee) relative to the L enantiomer (Figure 3i) revealed that the quenching
level (I0/I) was linearly correlated with the ee of MA (R2 = 0.9971). The ee values of MA
samples thus can be rapidly determined by a simple fluorescence quenching measurement with 1.
This finding represents a significant step forward in the development of new generation chiral
supramolecular sensors for applications.
The addition of enantioꢀpure MA to solutions of (R)ꢀ2 or (R)ꢀ3 in THF also caused a decrease
in the emission intensity, but with lower enantioselectivity. The KSV(Rꢀ2ꢀL)/KSV(Rꢀ2ꢀD) ratio is 1.75 ±
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0.13 and the KSV(Rꢀ3ꢀL)/KSV(Rꢀ3ꢀD) is 1.24 ± 0.10 (Table S7, Figure S32ꢀS33). The decrease in KSV
constants and enantioselectivity factors in the order 1 > 2 > 3 is consistent with the total number
of chiral NH groups within the cyclic structures, indicating the key role of these moieties in the
recognition of chiral guests.
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Interestingly, the metallacyclic system displayed enantioselective binding with a range of sugar
acids, including Dꢀglucuronic acid, Dꢀgalacturonic acid, Dꢀgluconic acid, Dꢀglucaric acid and
tartaric acid. The selectivity factors KSV(Sꢀ1)/KSV(Rꢀ1) were determined as 3.73 ± 0.29, 2.12 ± 0.15,
2.84 ± 0.21 and 3.34 ± 0.28, respectively (Figure 3bꢀd and Table 1). Although 1 is
enantioselective to tartaric acid, the SꢀV plot became nonlinear (Figure S34). Again,
metallacycles 2 and 3 are also enantioselective to sugar acids. For example, the KSV(Sꢀ2 or 3)/KSV(Rꢀ2
or 3) values with Dꢀgluconic acid were found to be 2.00 ± 0.11 and 1.60 ± 0.09 (Table S8, Figure
S39ꢀS40), respectively, both of which are again smaller than 1 (3.73 ± 0.29). The
enantioselectivity factors of 1 for Dꢀglucuronic acid and Dꢀgalacturonic acid are obviously larger
than the wellꢀknown sensors of bisbinaphthyl biboronicꢀacids for sugar acids (3.7 vs 2.0 and 2.1
vs 1.2),37 whereas the values of Dꢀgluconic acid and Dꢀglucaric acid are comparable with those
of the boronicꢀacid system.
Metallacycle 1 is also stable and highly enantioselective towards a variety of amino acids
(Figure S17). When 1 was treated with Lꢀvaline, Lꢀleucine, Lꢀthreonine, Lꢀphenylalanine and Lꢀ
tryptophan (1.0 × 10ꢀ3 M), respectively, the decrease rates of fluorescence for (R)ꢀ1 were faster
than those of (S)ꢀ1. The KSV(Rꢀ1)/KSV(Sꢀ1) values were calculated as 4.86 ± 0.37, 2.99 ± 0.23, 2.54 ±
0.19, 3.15 ± 0.24 and 2.46 ± 0.17 (Figure 3eꢀh and Table 1), respectively. Although many
synthetic receptors for enantioselective recognition of amino acids have been synthesized, no
assembled receptors have been reported to exhibit such high enantioselectivity.11ꢀ12,38ꢀ40 Again, 1
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also showed higher enantioselectivity toward amino acids than 2 and 3. For example, the
enantioselectivity factor KSV(Rꢀ2)/KSV(Sꢀ2) and KSV(Rꢀ3)/KSV(Sꢀ3) with Lꢀphenylalanine were 1.58 ±
0.09 and 1.05 ± 0.06 for 2 and 3 (Table S9, Figure S48ꢀS49), respectively, which are much
smaller than 3.15 ± 0.24 of 1.
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More importantly, metallacycle 1 could also detect chiral drugs such as Lꢀdopa (a drug for
Parkinson's disease) and Dꢀpenicillamine (a drug for Rheumatoid arthritis and Chronic active
hepatitis). Obviously, the rates of fluorescence decrease of (R)ꢀ1 caused by Lꢀdopa and Dꢀ
penicillamine were faster than that of (S)ꢀ1 (Figure 4a,b). The constants KSV(Rꢀ1) of Dꢀ
penicillamine and Lꢀdopa are up to 85995 ± 2600 and 78841 ± 2200 Mꢀ1 (Table 1), respectively,
the KSV(Rꢀ1)/KSV(Sꢀ1) ratio with Lꢀdopa and Dꢀpenicillamine are 6.05 ± 0.44 and 5.27 ± 0.43
(Figure 4e,f), respectively. Fluorescence photographs also clearly showed that (R)ꢀ1 was
quenched more quickly than (S)ꢀ1 upon titration with Lꢀdopa (Figure 4c,d). The detection limit
(3σ/KSV, σ is standard deviation of this detection method) of Lꢀdopa and Dꢀpenicillamine are
calculated to be 5.46 × 10ꢀ4 M and 5.01 × 10ꢀ4 M, respectively. The low detection concentration
and the high quenching constant for Lꢀdopa and Dꢀpenicillamine drugs reveal that 1 is an
excellent chiral biosensor for sensitive and selective detection of bioꢀactive molecules. To the
best of our knowledge, this is the first example of enantioselective biosensing of Lꢀdopa and Dꢀ
penicillamine chiral drugs with high quenching constants and enantioselectivity factors. Given
that the detection of these chiral drug analytes can be done immediately upon mixing with 1
without any extra sample treatment such processes may be a useful path toward medical drug
monitoring.
Enantioselective Gas Sensing of Chiral Amines. Chiral discrimination of amine vapors play
an important role in olfactory perception of biological systems,41 and the mimicry of such
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systems for sensing odours through the development of “artificial noses” is an area of
considerable interest.42ꢀ43 The fluorescence spectra of metallacycles 1 in thin layer forms were
monitored upon exposure to the saturated vapor of chiral amines for varied and specified periods
of time.12,44 When (R)ꢀ1 was exposed to the 1ꢀphenylethylamine (1ꢀPEA) vapor, the emission at
475 nm was shifted to 465 nm and enhanced by both the R and S enantiomers, but the rate caused
by (S)ꢀ1ꢀPEA was much faster than that by the (R)ꢀenantiomer (Figure 5a,b). The enhancement
percentages of (R)ꢀ and (S)ꢀ1ꢀPEA were 29% and 113% after 240 s, with the I/I0 ratios of 1.29
and 2.13 (Figure 5c), respectively. The enantioselectivity factor [ef = (IS/I0ꢀ1)/(IR/I0ꢀ1)]12 was
determined as 3.90 ± 0.52. Timeꢀresolved fluorescence measurements of (R)ꢀ1 after addition of
(S)ꢀ1ꢀPEA showed only a slight change in decay rate, the fluorescence lifetimes (τ0 : 1.480 ns vs
2.350 ns) remained almost unchanged (Figure S50), and PXRD measurement indicated that 1
remained highly crystalline after exposure to (S)ꢀ1ꢀPEA saturated vapors (Figure S19). All these
are the indicative of the stability of the host. The sensing had short times and might be wellꢀ
suited to perform a quick analysis of enantiomers of secondary amines and their derivatives.
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Control experiments indicated that the solid (R)ꢀH2L1 ligands showed almost no fluorescence
change with (S)ꢀ or (R)ꢀ1ꢀPEA and no enantioselectivity (Figure S51). Note that, under otherwise
identical conditions, the I/I0 ratio of (R)ꢀ2 and (R)ꢀ3 was increased to 1.46 and 1.30, 1.28 and
1.23 by (S)ꢀ and (R)ꢀ1ꢀPEA, with an ef of 1.53 ± 0.23 and 1.22 ± 0.18 for (R)ꢀ2 and (R)ꢀ3 (Figure
S52ꢀS53), respectively, smaller than that observed for (R)ꢀ1 (3.90 ± 0.52) (Figure 5d). This
experimental result again illustrates the key role of chiral NH functionalities in the
enantioselective gas sensing. Significant enantioselective fluorescence enhancements of (R)ꢀ1
with other chiral amines such as 1ꢀphenylpropylamine (1ꢀPPA) and 1,2ꢀcyclohexanediamine
(CDA) were also observed. In both cases, the rate of increase caused by the (S)ꢀenantiomer was
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also faster than that caused by the (R)ꢀenantiomer (Figure S54ꢀS55). The ef values by (R)ꢀ1 were
calculated as 1.80 ± 0.22 and 2.70 ± 0.35 for 1ꢀPPA and CDA, respectively. The
enantioselectivity decreased in the order 1ꢀPEA > CDA > 1ꢀPPA.
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Single-Crystal X-ray Diffraction Analyses of the Host-Guest Adducts. Although it was not
possible to obtain singleꢀcrystal structures of 1 containing encapsulated sugar acids, amino acid
or 1ꢀPEA, crystals suitable for Xꢀray analysis were obtained from crystallization of (R)ꢀ1 with
racemic 2ꢀbutylamine or 2ꢀbutanol. The Xꢀray singleꢀcrystal structures indicated that (R)ꢀ1
trapped (S)ꢀ2ꢀbutanol and (S)ꢀ2ꢀbutylamine from the racemic mixture to form [(R)ꢀ1·6(S)ꢀ2ꢀ
butanol·6H2O] and [(R)ꢀ1·6(S)ꢀ2ꢀbutylamine·9H2O] (Figure 6aꢀd), respectively. The desorbed
guest molecules from (R)ꢀ1 was analyzed by using HPLC on a chiral support, which showed that
the enantiomeric excess value was 99.4% for (S)ꢀ2ꢀbutylamine and 97.5% for (S)ꢀ2ꢀbutanol
(Figure S56), respectively, In fact, 1 is among the best porous materials for enantioseparation of
2ꢀbutanol17ꢀ18 and is superior to our best demonstrated metal organic frameworks (MOFs) for 2ꢀ
butylamine (99.4% vs 82 % ee).45
As shown in Figure 6, six (S)ꢀ2ꢀbutanol or (S)ꢀ2ꢀbutylamine molecules are trapped in six
pockets of the metallacycles and each of them is involved with different supramolecular
interactions: hydrogen bonds with coꢀcrystallized water molecules through its amine or hydroxyl
group (N···O = 2.886 ~ 3.068 Å, and O···O = 3.168 ~ 3.190 Å), hydrophobic interactions with
metallosalalen units through its methyl and ethyl groups, respectively. Notably, there are three
pairs of six or nine water molecules in the macrocycle cavity, which are related by threeꢀfold
symmetry and form a distorted trigonal prismꢀshaped structure. Although the chiral NH groups
of the salalen ZnL1 complexes are not directly engaged in supramolecular interactions with guest
molecules, they, together with the Zn atoms and phenyl rings, create a chiral microꢀenvironment
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in the metallacycle. In this way, the host transfers its chirality to the structural organisation of the
water and organic molecules. Therefore, the specific recognition of 1 for enantiomers of
secondary amines and alcohols is attributed to the confinement of the chiral pockets induced by
chiral Zn(salalen) units, additionally it is enhanced by the supramolecular interactions between
host and guest molecules.
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Molecular Simulations. To microscopically elucidate the observed enantioselective
adsorption of 2ꢀbutanol and 2ꢀbutylamine in (R)ꢀ1, molecular simulations were conducted
(Figures S57ꢀS60). The binding energies of a single (S)ꢀ and (R)ꢀ2ꢀbutanol molecule with (R)ꢀ1
are −76.59 ± 4.63 kJ molꢀ1 and −70.22 ± 5.58 kJ molꢀ1, respectively. As for a single (S)ꢀ and (R)ꢀ
2ꢀbutylamine molecule, the binding energies are −74.41 ± 1.75 kJ molꢀ1 and −71.71 ± 1.20 kJ
molꢀ1, respectively. This indicates that the (S)ꢀenantiomers of 2ꢀbutanol and 2ꢀbutylamine have
stronger interactions than their (R)ꢀcounterparts with (R)ꢀ1. The adsorption isotherms of racemic
mixtures of (S)ꢀ/(R)ꢀ2ꢀbutanol and (S)ꢀ/(R)ꢀ2ꢀbutylamine in (R)ꢀ1 are shown in Figures 6gꢀh. The
difference in binding energies is then responsible for the enantioselective adsorption.46ꢀ47
Density Functional Theory Calculations. Density functional theory (DFT) calculations were
conducted on metallacyclic hosts and typical analytes to better understand the different
fluorescence emissions of metallacycles in the presence of various analytes such as amines (turnꢀ
on) or sugar acids and amino acids (turnꢀoff). Based on the results of DFT calculations (Figure
7), the energies of the lowest unoccupied molecular orbitals (LUMO) of (R)ꢀ1 (ꢀ1.759 eV), (R)ꢀ2
(ꢀ1.725 eV) and (R)ꢀ3 (ꢀ1.608 eV) are below the LUMO energies of 1ꢀPEA (0.166 eV) and 1ꢀ
PPA (0.160 eV), which allows an efficient electron transfer from 1ꢀPEA and 1ꢀPPA to
metallacycle 1ꢀ3 resulting in fluorescence enhancement (donorꢀacceptor electronꢀtransfer
mechanism44,48). This was also observed in other porous materials such as porous organic
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frameworks (POFs),49 covalent organic frameworks (COFs),50 and MOFs.44,51 In the case of
fluorescence quenching by Lꢀdopa, Dꢀglucuronic acid and LꢀMA in THF, although the
calculation DFT results do not follow electronꢀtransfer mechanism (Figures S61ꢀS62), the energy
transfer contributes significantly in fluorescence quenching and should also be considered. The
electronic absorption spectra show that all these guests absorb excitation energy used in the
sensing experiment (Figure S63ꢀS64). This suggests that competition between the metallacyclic
hosts and the sugar acids or amino acids guests for excitation energy may also contribute to the
quenching of emission from the metallacycles. Similar phenomena were also observed in
luminescent MOFs.51
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As aboveꢀmentioned, the enantioselectivity in fluorescence response may result from the
formation of different diastereomeric complexes. Singleꢀcrystal diffraction, molecular
simulations and DFT calculations indicated that the (S)ꢀenantiomers of the analytes would be
bound to (R)ꢀ1 more strongly than (R)ꢀenantiomers. As a consequence, the rates of energy
transfer from (R)ꢀ1 to the (S)ꢀenantiomers of αꢀhydroxycarboxylic acids and amino acids are
faster than those to the (R)ꢀenantiomers, leading to enantioselective fluorescence quenching. In
contrast, the rates of electron transfer of from (S)ꢀ1ꢀPEA to (R)ꢀ1 was faster than that to the (R)ꢀ
enantiomer, giving rise to enantioselective fluorescence enhancement. Notably, the strength of
hostꢀguest interactions is greatly influenced by the number of chiral NH groups within the
metallacycle structure, and so the selectivity and affinity of metallacycles 1ꢀ3 to the analytes
decrease in the order 1 > 2 > 3.
CONCLUSIONS
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In summary, the endogenous precisely adjusted selfꢀassembly approach presented here opens a
new avenue for constructing novel chiral NHꢀcontrolled supramolecular metallacycles with highꢀ
affinity and enantioselectivity binding of biologically active molecules. The assembly of
metallosalalens and/or metallosalens affords chiral fluorescent Zn6L6 metallacycle 1ꢀ3 bearing
six, three and zero NH groups that could be packed through strong supramolecular interactions to
generate porous architectures with permanent porosity. The metallacycles are capable of
enantioselective discrimination of the enantiomers of sugar acids and amino acids through
fluorescence quenching in solution and the enantiomers of 1ꢀPEA through fluorescence
enhancement in a crystalline state. The selectivity and binding affinity are greatly affected by the
available NH groups in the metallacycles, which decrease significantly from 1 to 2 and to 3.
From singleꢀcrystal Xꢀray diffraction, molecular simulations and DFT calculations, the intrinsic
chiral recognition and discrimination are attributed to the specific binding of enantiomers in the
chiral microꢀenvironment of the crystalline metallacycles. The enantioselective fluorescence
change was also explained by the donorꢀacceptor electronꢀtransfer mechanism. Manipulation of
chiral NH functionalities in metallacycles can control the enantiorecognition of biomolecular
complexes, which may provide new opportunities for the assembly of more effective chiral
supramolecular materials for enantioselective processes.
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Zn(salen)
Zn(salalen)
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Figure 1. Selfꢀassembly of chiral NHꢀcontrolled supramolecular metallacycles (R)ꢀ1 (a) from Zn(salalen)
and (R)ꢀ3 (c) from Zn(salen). (R)ꢀ2 (b) was achieved by Zn(salalen) and Zn(salen) with 1:1 ratio. The Xꢀ
ray crystal structures of chiral metallacycles 1 (d), 2 (e) and 3 (f). Colour coding: Zn; green, O; red, N;
blue, C atoms of Zn(salalen); cyan, C atoms of Zn(salen); orange. Fluorescent photographs of asꢀ
synthesized crystals of (R)ꢀ1 (g), (R)ꢀ2 (h) and (R)ꢀ3 (i) (λex = 365 nm; inset: optical photographs).
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Figure 2. (a) Sideꢀon view of (R)ꢀ1. (b) The top view of six hydrophobic chiral pockets in (R)ꢀ1. (c) Two adjacent
metallacycles (R)ꢀ1 rings, the rings overlap but do not catenate. (d) Packing of (R)ꢀ1 to generate a nanotube along
the crystallographic cꢀaxis. (e) The extended structures are generated that one ring is shown forming with six other
rings through supramolecular interactions. (f) Representation of the connectivity of the arrangement in Fig (e). (g)
Packing of (R)ꢀ1 to generate a 3D nanoporous structure viewed along the cꢀaxis. Colour coding: Zn; green, O; red,
N; blue, the different colour of C atoms in one ring are shown for clarity. Highꢀresolution C1s (h) and N1s (i) XPS
spectra of metallacycles 1ꢀ3. (j) Solid CD spectra of chiral metallacycle 1 and 2 at room temperature.
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Figure 3. (a) Stern−Völmer plots of (R)ꢀ1 titration with Lꢀ and DꢀMA. (b,d) Stern−Völmer plots of (R)ꢀ
and (S)ꢀ1 titration with Dꢀglucuronic acid, Dꢀgluconic acid and Dꢀglucaric acid, respectively. (e,h)
Stern−Völmer plots of (R)ꢀ and (S)ꢀ1 titration with Lꢀvaline, Lꢀleucine, Lꢀthreonine, Lꢀphenylalanine,
respectively; The concentrations of 1 are 2.0 × 10ꢀ6 M in THF and the concentrations of all the acids are
1× 10ꢀ3 M. (i) Plot of I0/I vs the enantiomeric excess of LꢀMA at a fixed concentration of 0.56 mM. (j)
The compared enantioselectivity factors of chiral metallacycle 1, 2 and 3 by mandelic acid, Dꢀgluconic
acid and Lꢀphenylalanine, respectively. (k) The chemical structures of αꢀhydroxycarboxylic acids and
amino acids used in the study.
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Figure 4. (a,b) Fluorescence emission spectra of (R)ꢀ and (S)ꢀ1 (2.0 × 10ꢀ6 M in THF) upon titration with
Lꢀdopa (c = 1× 10ꢀ3 M, λex = 350 nm). Fluorescence photographs of (R)ꢀ1 (c) and (S)ꢀ1 (d) upon titration
with Lꢀdopa (0 ꢀL, 10 ꢀL, 20 ꢀL, 30 ꢀL, 40 ꢀL, 50 ꢀL, 60 ꢀL, respectively. λex = 365 nm). (e,f)
Stern−Völmer plots of (R)ꢀ and (S)ꢀ1 titration with Lꢀdopa and Dꢀpenicillamine (1× 10ꢀ3 M)
.
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Figure 5. (a,b) Fluorescence enhancement upon the exposure of thin films of (R)ꢀ1 to the saturated vapors
of (R)ꢀ and (S)ꢀ1ꢀPEA (λex = 375 nm). (c) Timeꢀdependent fluorescence enhancement of (R)ꢀ1 by (R)ꢀ and
(S)ꢀ1ꢀPEA. (d) The compared enhancement percentages of (R)ꢀH2L1, (R)ꢀ1, (R)ꢀ2 and (R)ꢀ3 by (R)ꢀ and
(S)ꢀ1ꢀPEA after 4 mins, respectively.
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Figure 6. The Xꢀray crystal structures of six (S)ꢀ2ꢀbutanol·6H2Oꢀadsorbed (a) and (S)ꢀ2ꢀbutylamine·9H2Oꢀadsorbed
(d) in the chiral pocket of (R)ꢀ1. Hexamer of six (S)ꢀ2ꢀbutanol (b) and (S)ꢀ2ꢀbutylamine (e) with water molecular
through hydrogen bonds in a slipped parallel conformation in the chiral pocket. The side view of six (S)ꢀ2ꢀ
butanol·6H2Oꢀadsorbed (c) and (S)ꢀ2ꢀbutylamine·9H2Oꢀadsorbed (f) in the chiral pocket generated nanotubes
through strong supramolecular interactions. Colour coding: Zn; green, O; red, N; blue, C is gray in (R)ꢀ1. (S)ꢀ2ꢀ
butanol and (S)ꢀ2ꢀbutylamine molecules using spaceꢀfilling model are colored as follows: (S)ꢀ2ꢀbutanol: C, blue; O,
red; Water; green. (S)ꢀ2ꢀbutylamine: C, purple; O, blue; Water; green. Adsorption isotherms of racemic mixtures in
(R)ꢀ1: (S)ꢀ/(R)ꢀ2ꢀbutanol (g) and (S)ꢀ/(R)ꢀ2ꢀbutylamine (h) from molecular simulations.
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LUMO
(0.160)
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Figure 7. HOMOꢀLUMO energy profiles of 1ꢀPEA, 1ꢀPPA, (R)ꢀ1, (R)ꢀ2 and (R)ꢀ3 in vacuum.
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Table 1. Stern−Völmer binding constant and enantioselectivity factor of (R)ꢀ1 and (S)ꢀ1 upon
titration with different sugar acids and amino acids.
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ASSOCIATED CONTENT
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Supporting Information.
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Experimental details on synthesis of characterization salalen ligands H2L1 and metallacycles 1ꢀ3,
fluorescence sensing of αꢀhydroxycarboxylic acids, amino acids and chiral amines, molecular
simulations and DFT calculations are provided in the Supplementary Information. This material
is available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: yongcui@sjtu.edu.cn
*Eꢀmail: liuy@sjtu.edu.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We gratefully acknowledge the financial support of the NSFC (21025103, 21371119, 21431004
and 21401128), the “973” Program (2014CB932102 and 2012CB8217), SSTCꢀ12XD1406300
and 14YF1401300, the National University of Singapore and the Ministry of Education of
Singapore (Rꢀ279ꢀ000ꢀ474ꢀ112 and Rꢀ279ꢀ000ꢀ437ꢀ112).
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