Design and Enantioresolution of Homochiral Fe(II)-Pd(II) Coordination Cages from Stereolabile Metalloligands: Stereochemical Stability and Enantioselective Separation

Article abstract of DOI:10.1021/jacs.8b11152

The stereochemistry of chiral-at-metal complexes is much more abundant, albeit complicated, than chiral-at-carbon compounds, but how to make use of stereolabile metal-centers remains a formidable challenge due to the highly versatile coordination geometry of metal ions and racemization/epimerization problem. We demonstrate herein a stepwise assembly of configurationally stable [Pd₆(FeL₃)₈]²⁸⁺ (Δ/-MOCs-42) homochiral octahedral cages from unstable D₃-symmetry tris-chelate-Fe type metalloligands via strong face-directed stereochemical coupling and facile chiral-induced resolution processes based on stereodifferentiating host-guest dynamics. Kinetic studies reveal that the dissociation rate of MOC-42 cages is 100-fold slower than that of Fe-metalloligands and the racemization is effectively inhibited, making the cages retain their chirality over extended periods of time (>5 months) at room temperature. Recyclable enantioseparation of atropisomeric compounds has been successfully achieved, giving up to 88% ee.

Full text of DOI:10.1021/jacs.8b11152

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Article
Design and Enantioresolution of Homochiral Fe(II)-Pd(II)
Coordination Cages from Stereolabile Metalloligands:
Stereochemical Stability and Enantioselective Separation
Ya-Jun Hou, Kai Wu, Zhang-Wen Wei, Kang Li, Yu-Lin Lu, Cheng-Yi Zhu,
Jing-Si Wang, Mei Pan, Ji-Jun Jiang, Guangqin Li, and Cheng-Yong Su
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 04 Dec 2018
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Design and Enantioresolution of Homochiral Fe(II)-Pd(II) Co-
ordination Cages from Stereolabile Metalloligands: Stereo-
chemical Stability and Enantioselective Separation
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Ya-Jun Hou,† Kai Wu,† Zhang-Wen Wei,† Kang Li,† Yu-Lin Lu,† Cheng-Yi Zhu,† Jing-Si Wang† Mei
Pan,† Ji-Jun Jiang,† Guang-Qin Li,† and Cheng-Yong Su*,†,‡
†MOE Laboratory of Bioinorganic and Synthetic Chemistry, Lehn Institute of Functional Materials, School of Chemistry,
Sun Yat-Sen University, Guangzhou 510275, China
‡State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China.
Supporting Information Placeholder
ABSTRACT: The stereochemistry of chiral-at-metal complexes is much more abundant, albeit complicated, than chiral-at-carbon
compounds, but how to make use of stereolabile metal-centers remains a formidable challenge due to highly versatile coordination
geometry of metal ions and racemization/epimerization problem. We demonstrate herein a stepwise assembly of configurationally
stable [Pd6(FeL3)8]28+ (/-MOCs-42) homochiral octahedral cages from unstable D3-symmetry tris-chelate-Fe type metalloligands
via strong face-directed stereochemical coupling and facile chiral-induced resolution processes based on stereodifferentiating host-
guest dynamics. Kinetic studies reveal that the dissociation rate of MOC-42 cages is 100-fold slower than Fe-metalloligands and the
racemization is effectively inhibited, making the cages retain their chirality over extended periods of time (> 5 months) at room
temperature. Recyclable enantioseparation of atropisomeric compounds has been successfully achieved, giving up to 88% ee.
INTRODUCTION
supramolecular architectures.11,27,28,40-42 On the hand, formation
of metal-organic cages (MOCs) has been proven an unique
strategy for effective chirality communication/transformation
and stereochemical control owing to mechanical coupling
between chiral vertices/edges.3,9,24,43-47 However, feasible enan-
tioresolution process for spontaneously formed cage enantio-
mers and their potential application are still demanding.43-46
We previously reported stepwise assembly of heterometallic
Pd(II)-Ru(II) MOCs-1652 and succeeded in synthesis of homo-
chiral /-MOCs-16 based on the kinetic inertness of /-Ru-
metalloligands.24 Herein, we expand this stepwise strategy to
the stereolabile tris-chelate-Fe type metalloligand which is
much more convenient for synthesis, demonstrating its excel-
lent stabilization when incorporated into Fe(II)-Pd(II) octahe-
dral MOCs-42 (Scheme 1). A strong face-directed stereochem-
ical coupling is verified from racemization kinetic studies, and
practical chiral-induced resolution processes are established,
giving enantiopure /-MOCs-42 with substantial stereo-
chemical stability competent for reusable enantioseparation of
racemic atropisomers.
Supramolecular chirality in coordination chemistry is plentiful
because of not only numerous chiral information brought
about by chiral ligands in the coordination sphere, but also
enormous stereogenic metal-centers generated by a large vari-
ety of stereoconfigurations from versatile coordination geome-
try.1-9 However, synthesis and predetermination of chiral-at-
metal complexes from achiral ligands are very cumbersome as
many possible stereoisomers have to be separated and notori-
ous racemization or epimerization phenomena occur for stere-
olabile metal-centers.10-16 As a keystone of coordination chem-
istry, the D3-symmetry tris-chelate-M complexes of octahedral
geometry with chirality simply originated from propeller-like
arrangement of bidentate ligands are vigorously studied in
chiral induction/recognition,17-21 enantioseparation,22-24 asym-
metric catalysis,25-27 and pharmaceuticals.28,29 Nevertheless, in
contrast to the kinetically inert stereogenic metal-centers like
in Ru(phen)32+, the chiral complexes of first-row transition
metals which is abundant and easy access to synthesis are of-
ten highly liable to racemize, hampering their application to-
wards enantioseparation, catalysis and pharmaceuticals.
The chiral tris-chelate-Fe complexes are known for their
good chemical but low stereoconfigurational stability, and
earlier research disclosed a racemization mechanism compris-
ing relatively faster intramolecular racemization and slower
ligand dissociation paths.30-34 Much efforts were made on sta-
bilization of configurationally labile Fe-centers, including
introduction of optically active counterions,35,36 modification
of ligands with chiral groups,37,38 utilization of connecters be-
tween adjacent ligands,39 and integration of chiral centers into
RESULTS AND DISCUSSION
Stepwise assembly of racemic MOC-42. The FeL3
2+
metalloligand was prepared by a fast and mild reaction
between Fe(BF4)26H2O and 2-(pyridin-3-yl)-1H-imidazo[4,5-
f][1,10]phenanthroline (L) in DMSO solution at room
temperature (RT, molar ratio Fe:L = 1:3). Without tedious
purification, Pd(CH3CN)4(BF4)2 was directly added into above
reaction solution (Fe:Pd = 4:3), and the assembly converged
on the formation of sole heteronuclear [Pd6(FeL3)8](BF4)28
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Scheme 1. Synthetic route for stereolabile FeL32+ racemate and stereostable Pd6(FeL3)828+ /-MOCs-42. Two chiral-induced enantioresolution processes
by addition of R/S-BINOLs are illustrated, through a post-assembly process after rac-MOCs-42 cages formation and an in situ-assembly process during
1
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secondary assembly, leading to enantiomeric or diastereoisomeric products following distinct kinetic and thermodynamic resolution mechanisms
.
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(desinated as MOC-42 neglecting anions) coordination cage
homochiral -MOC-42 (abbr. -MOC-42) and
-MOC-42 (abbr. -MOC-42) as racemic rac-
MOCs-42 (Scheme 1 and Figure S6).
o
either at 80 C for 5 hr or at RT for 22 hr (Scheme 1). The
1
solution structure of the cage has been well established by H
1
1
1
NMR, H-1H COSY, H DOSY, MS spectra and H NMR
titration experiments52 (Figures 1a and S1-4), in which the
cage size was estimated by DOSY analysis as 32 Å in diame-
ter (Figure S2, lg D = -10.04), and the cage formula was iden-
tified by the high resolution electrospray ionization time of
flight mass spectrometry (HR ESI-TOF-MS) with a series of
successively valent {[Pd6(FeL3)8]28++nBF4 }(28-n)+ species (Fig-
-
ure S4). The stepwise assembly manner of MOC-42 was testi-
fied by the controlled experiments via altering the feeding
order of Fe2+, Pd2+ salts and L ligand (Figure S5). It is evident
2+
that the primary assembly of FeL3 metalloligand before the
secondary assembly with Pd2+ is prerequisite. In case Pd2+ has
a chance to react with the free L ligand either before adding
Fe2+ or simultaneously with Fe2+, the product will diverse from
MOC-42 and cannot convert to MOC-42 even by heating. This
indicates a preferential directing effect of FeL32+ metalloligand
in the assembly of heterometallic Fe(II)-Pd(II) cage, implying
that the good thermodynamic stability of MOC-42 relies
mainly on retarded Fe-L dissociation rate rather than stonger
competition over Pd-L coordination (vide infra).
Homoconfiguration of individual cages in rac-MOCs-42.
28+
The definite Pd6(FeL3)8 cage structure was unveiled from
the single-crystal diffraction analysis of the crystals obtained
by vapor diffusion of THF into the water solution of MOC-42,
which displays a similar truncated octahedon as our earlier
reported Pd6(RuL3)828+ MOC-16 (Figures 2 and S6),52 in full
agreement with above solution structural characterization. The
structural analysis discloses that each individual cage in rac-
MOCs-42 comprises eight same handed FeL32+ metalloligands.
This is indicative of effective chirality communication among
eight labile /-FeL32+ stereogenic centers,3,24,48 revealing that
2+
1
2+
the specific stereochemical information of one face-FeL3
Figure 1. (a) H NMR spectra of L and FeL3 in DMSO-d6, and
MOC-42, R-BINOL@-MOC-42 and R-BINOL in DMSO-
d6/D2O (1/5, v/v, 400 MHz, 298 K). Proton shifts shown by the
centers can be exactly transformed to others via the bridging
Pd2+-vertices, thus controlling the homoconfiguration of the
whole cage. Since coordination of L ligand with Fe2+ in lack of
any chiral factor should always lead to equal amount of - and
1
arrows. (b) H NMR enantiodifferentiation experiments for cap-
ture of R/S-BINOLs by /-MOCs-42 (DMSO-d6/D2O, 1/5, v/v,
400 MHz, 298 K). Red circles denote signals of encapsulated
guests.
2+
2+
-FeL3 to form rac-FeL3 racemate, the stereoselective
secondary assembly with Pd2+ is expected to give equivalent
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(Figure 2 and S6). Furthermore, the obtained chiral crystals
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were washed with diethyl ether for several times and
redissolved in CH3CN to perform UV-Vis absorption and CD
spectra measurements. As shown in Figure 3a, two
enantiomers exhbit mirrored CD signals with the maximum
peak at 300 nm reflecting -* transition of L at 283 nm. The
1
first Cotton effect around 550 nm corresponds to the MLCT
2+
absorption band of FeL3 metalloligand, showing positive
signal for -MOC-42 and opposite one for -MOC-42, which
is in accordance with analogous chiral tris-chelate-Fe
complexes.23,38
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The above post-assembly method is applied for resolution of
homochiral /-MOCs-42 after stable racemic MOCs-42 are
formed. Considering the stereoconfigurational lability of free
Figure 2. Crystal structures of -MOC-42 showing internal void
by yellow ball (left) and S-BINOL@-MOC-42 with each cage
(in space-filling mode) capturing eight S-BINOL guests (in
capped-sticks mode) onto the window pockets.
2+
FeL3 itself and steady interconversion between - and -
2+
FeL3 isomers,30-34 we are interested to know if it is possible
to control the in situ stereoselective assembly of MOC-42 by
Chiral-induced resolution of /-MOCs-42. To verify
addition of chiral auxiliary.35 Thus, we introduced enantiopure
2+
stereocontrol and stablization of labile - and -FeL3 in the
2+
R- or S-BINOLs to rac-FeL3 and Pd2+ mixture before the
cage formation, we added enantiopure R- or S-BINOLs in a
solution of rac-MOCs-42 to drive slow cocrystallization via
vapor diffusion of diethyl ether, and single-crystals of S-
BINOL@-MOC-42 and R-BINOL@-MOC-42 enantiomers
were successfully obtained, respectively. This means a post-
assembly process for enantiomeric resolution of rac-MOCs-42
by virtue of chiral R- or S-BINOL guests is feasible as
illustrated in Scheme 1, which is based on the chiral-induced
slow cocrystallization of thermodynamic S-BINOL@-MOC-
42 or R-BINOL@-MOC-42, respectively (Figure S6 and
Table S1-4). In this way, chiral BINOLs act not only as
cocrystallizing reagents, but also as enantioselectors. The
single-crystal analysis confirms the absolute self-organization
secondary assembly step (designated as in situ-assembly pro-
cess shown in Scheme 1), and CD spectra were employed to
monitor configuration transformation. As seen from Figure 3b,
upon addition of excess R- or S-BINOLs and stoichiometric
Pd2+ in together to a solution of rac-FeL32+ to form initial mix-
ture, the first Cotton effect resembling - or -MOC-42 ap-
peared, indicating chiral-induced intermediate formation of
enantioexcess - or -MOC-42, respectively. In contrast, no
CD signals can be detected in absence of enantiopure BINOLs
during rac-MOC-42 assembly. The CD signals remarkably
increased along reaction time, suggesting an effective templat-
ing assembly of one enantiomer of the cage from a racemic
mixture of rac-FeL32+ induced by enantiopure BINOL, and the
best CD profile was obtained for precipitating product by add-
ing diethyl ether. It is also noticeable that, during this in situ-
2+
of eight - or -FeL3 in either -MOC-42 or -MOC-42
cages, and each homochiral cage encapsulate eight S- or R-
BINOLs guests into its pocket of windows, respectively
Figure 3. (a) CD and UV-Vis absorption spectra of homochiral /-MOCs-42 obtained by different resolution processes (2.0×10-6 M in CH3CN, 298 K).
“Post” or “in situ” represent post- or in situ-assembly processes, “R or S” refer to R- or S-BINOLs, “crys” or “ppt” means crystallization or precipitation,
respectively. (b) CD spectra recorded during in situ-assembly process (2.0×10-6 M, CH3CN, 298 K). (c,d) Stereochemical stability of /-Fe(phen)3(PF6)2
(c, 1.6×10-5 M in CH3CN) and /-MOCs-42 (d, 2.0×10-6 M in D2O) depending on time at RT. (e,f) UV-Vis absorption spectra showing dissociation of
2+
FeL32+ (0.8 mM, 1 eq.) and rac-MOC-42 (0.1 mM, 0.125 eq. vs. FeL32+) in 25% CH3CN aqueous solution containing 1 M H2SO4 (2,500 eq. H+ vs. FeL3
)
at 35.0(±0.1) oC. Spectra were measured after 20 times dilution of the original solution.
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assembly process, complex CD signals appeared in UV region,
Page 4 of 9
Cage stabilization effect. Stereochemical stability of the
resulting homochiral /-MOCs-42 was investigated by CD
spectra with comparison to the classic /-Fe(phen)3(PF6)2
enantiomers freshly resolved55 (Figure S16). As seen from
Figure 3d, the CD profile of /-MOCs-42 are maintained in
D2O at RT even after 5 months, while a rapid decay of CD
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implying presence of intermediate stereoisomers possible for
configuration transformation to a major enantioexcess product,
2+
owing to a reason that rac-FeL3 becomes biased towards an
2+
enantiomeric excess of one hand of FeL3 induced by the
chiral BINOL, especially during the secondary assembly with
Pd2+. Upon fast precipitation, the homochiral /-MOCs-42
were obtained as major product, justifying effectiveness of this
in situ-assembly method.
2+
signals is observed for /-Fe(phen)3 with a half-life period
less than
3 min (Figure 3c), evidently proving the
stereoconfiguration around Fe-centers is strongly fixed by
cage integrity. The specific optical rotation tests disclose less
Different from above post-assembly cocrystallization pro-
cess, the CD signals of homochiral /-MOCs-42 in situ-
induced by R/S-BINOLs display opposite guest-host correla-
tion, namely, R-BINOLs inducing formation of -MOC-42,
while S-BINOLs inducing -MOC-42, in reverse to the co-
crystallization of S-BINOL@-MOC-42 and R-BINOL@-
MOC-42 enantiomers (Figure 3a). This means the post-
assembly and in situ-assembly processes show different for-
mation mechanism of homochiral /-MOCs-42. To further
understand enantiomer selection between /-MOCs-42 and
R/S-BINOLs, slow single-crystal cultivation from the in situ-
assembly reaction mixture was carried out. Structural analysis
revealed that, similar with the post-assembly cocrystallization
from rac-MOCs-42, the R- or S-BINOLs cocrystallized with
- or -MOCs-42, respectively, despite the solution is domi-
nated by the opposite cage stereoconfigurations. Moreover, the
in situ chiral-induced cage enantiomers, either from precipita-
tion or cocrystallization, show significantly enhanced Cotton
effects when compared to the resolved products from post-
assembly process (Figure 3a), suggesting the in situ-assembly
process represents a better approach with superior enantiopuri-
ty of homochiral product than the post-assembly process. We
attribute the fast precipitation by virtue of chiral-induced in
situ-assembly to kinetic resolution, while the slow cocrystalli-
zation with chiral BINOLs in both post- and in situ-assembly
processes to thermodynamic resolution (Scheme 1). The dis-
tinct stereoselectivity between /-MOCs-42 and R/S-
BINOLs in kinetic and thermodynamic resolution processes
can be easily understood from our previous study on the host-
guest interaction dynamics between analogous RuL32+-based
/-MOCs-16 and R/S-BINOLs.24 In solution, the -MOC-42
cage may capture R-BINOL via a faster and low energy path
than S-BINOL, thus templated formation of -MOC-42 is
kinetically favored, and vice versa for the chiral-induced for-
mation of -MOC-42 by S-BINOL. On the contrary, slow
cocrystallization may be thermodynamically favored for the S-
BINOL@-MOC-42 and R-BINOL@-MOC-42 enantiomers
which demands high activation energy. This speculation is
supported by the distinct solution dynamics between a pair of
host-guest diastereoisomers whereas the similarity between a
9
o
than 6% decay even after heating at 60 C for one day (/-
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MOCs-42: []25 (c = 0.04, CH3CN), , +1316.6, , -1281.5;
D
decrease after heating, []25D, , -79.0, , -54.1), also
verifying the stereostability of the homochiral cages. In order
to explore the racemization process of /-MOCs-42 in
contrast to /-FeL32+, an acidic solution has to be used to
accelerate dissociation,31 and the kinetics experiments were
carried out with UV-Vis spectral measurements under
guidance of pseudo first-order reaction theory (see details in
SI). We firstly checked the chemical stability of MOC-42 (0.1
mM) in CD3CN/D2O (1/4, v/v) mixture containing different
amount of D2SO4 by 1H NMR (Figure S17). The proton
signals became well resolved and retained the overal partern
up to 8 M D+ concentration when measured immediately,
suggesting strong chemical stability against acid. When keep
2+
the acidic solution for 6 days, dissociation of a few free FeL3
was observed for the solutions above 4 M D+. Thus a solution
containing 2 M D+ (2500 eq. D+) was chosen for stability
study. As shown in Figure 3e and 3f, the maximum absorption
peak of 1MLCT at 520 nm nearly disappears for FeL32+ after 1
o
d’s standing at 35.0(±0.1) C, yet only slightly dropped for
MOC-42 under the same condition even after 21 d. H NMR
spectra confirmed that the cage structure remained unchanged
after 21 d’s acidic treatment (Figure S18).
Table 1. Kinetic and thermodynamic parameters of race-
mizationa
1
T
kd
Ea
≠G
≠H
≠S
Compds
oC
10-4 min-1 kcal mol-1 kJ mol-1 kJ mol-1 J K-1 mol-1
2+
FeL3
21.0 2.42
25.0 6.43
30.0 14.0
35.0 31.2
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
30.3
± 0.9
101.5 124.4 76.9
± 3.7
b
MOC-42 21.0
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
25.0 0.065
30.0 0.171
35.0 0.384
32.5
± 1.4
-
112.7 133.3 69.4
± 6.0
1
cFe(phen)32+25.0 42
-
-
-
-
-
-
pair of host-guest enantiomers as revealed by the H NMR
enantiodifferentiation experiments (Figure 1b).24,53,54 An esti-
mation of guest binding constants by 1H NMR titration exper-
iments and Hill equation analysis also confirm a stronger host-
guest interaction for the thermodynamically favored pairs than
the kinetic preferred ones (Figure S7-14). Optimization of the
in situ-assembly precipitation conditions disclosed that, the
excess amount of chiral BINOLs and reaction temperature
impact the enantiopurity of the resolved homochiral /-
32.1
± 0.5
-
dFe(PBS)34- 25.0 16.8e
-
-
-
-
31.1e
130
± 20
90
± 15
aIn 20% CH3CN aqueous solution containing 0.5 M H2SO4. Initail
2+
concentration: FeL3
(0.04 mM); MOCs-42 (0.005 mM).
bSpectral change is too tiny to distinguish within observation time.
o
cIn 1 M HCl, Ref 31. In water containing 0.2 mM of Ni(ClO4)2,
d
MOCs-42, addition of 72 eq. enantiopure BINOLs at 80 C
Ref 22. eCalculated from Ref 22.
leading to the highest optical purity thereof best enantioresolu-
tion (Figure S15).
To obtain detailed kinetic information for the dissociation
(kd) and non-dissociative intramolecular racemization (kr) rate
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constants, more extreme conditions were applied with dilute
MOCs-42 obtained from in situ-process precipitation. Three
racemic atropisomers were tested: rac-BINOL, rac-6-Br-
FeL32+ (0.04 mM, 1 eq.) and MOCs-42 (0.005 mM, 0.125 eq.)
in 25% CH3CN aqueous solution containing 1 M H2SO4
(25000 eq. H+) at variable temperatures (Figures S19-22). By
virtue of time- and temperature-dependent decrease of the
1
2
3
4
5
6
7
8
BINOL
bifendatatum.
(6,6’-dibromo-1,1’-bi-2-naphthol)
Before enantioseparation
and
experiments,
rac-
homochiral /-MOC-42 samples were washed with diethyl
ether for several times until no signals of BINOLs in the
filtrate can be detected on HPLC spectra. Firstly, the host-
guest stereochemical interactions between the pairs of /-
MOCs-42 and R/S-BINOLs was examined by 1H NMR
enantiodifferentiation experiments (Figure 1b and S23), of
which two pairs of S-BINOL@-MOC-42, R-BINOL@-
MOC-42 and S-BINOL@-MOC-42, R-BINOL@-MOC-42
diastereomers and two pairs of R-BINOL@-MOC-42, S-
1
characteristic MLCT absorption intensity around 520 nm, the
kd values were easily calculated, as well as the apparent
activation energy (Ea) and Gibbs energy of activation ≠G
according to Arrhenius and Erying--Polanyi equations (see SI
for detailed data processing). The effort to obtain kr of MOC-
42 from CD measurement failed because the contribution of
intramolecular racemization in MOC-42 is trivial, which is in
9
10
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12
13
14
15
16
17
18
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23
24
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26
27
28
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31
32
33
34
35
36
37
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39
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41
42
43
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45
46
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48
49
50
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52
53
54
55
56
57
58
59
60
2+
stark contrast to Fe(phen)3 in which kr is about 1 order of
magnitude faster than kd.30-34 As listed in Table 1 and S5, the
BINOL@-MOC-42
and
S-BINOL@-MOC-42,
R-
2+
dissociation rates kd of FeL3 are comparable with those of
BINOL@-MOC-42 enantiomers are formed. The results
obviously display distinguishable solution dynamics between
the host-guest diastereomeric pairs and enantiomers pairs.24 In
addition, CD spectral enantiodifferentiation experiments for
/-MOCs-42 and R/S-BINOLs or R/S-6-Br-BINOLs also
confirmed the distinct enantioselective interactions between
the host-guest enantiomers and diastereoisomers (Figures 4
and S24, Table S6), implying specific stereochemical
recognition dynamics as seen from the difference in the first
Cotton effect. Under above guidance of recognition effect
between homochiral /-MOCs-42 and atropisomeric
enantiomers with specific configuration matching,24 either a
homogeneous or a heterogeneous methods were employed for
enantioseparation of racemic atropisomers (see details in SI).
A kinetically driven separation procedure is found the same as
homochiral /-MOCs-16 analogues do.24 The enantiomeric
excess (ee%) values were determined by high-performance
liquid chromatography (HPLC, Figures S25-29) and listed in
Table 2. All pairs of atropisomers were successfully resolved
with the highest ee values reaching to 66% in one cycle of
enantioseparation. A relatively low performance in resolving
R/S-bifendatatum enantiomers was found, which were known
to gradually racemize in solution at RT.56,57 As an efficient
antidote for liver, R-bifendatatum has high biological activities
while S-bifendatatum has no pharmacological activities at all.
Therefore, further effort is underway to enantioseparate this
pharmacologically active molecule with chirality enrichment
and stabilization by the aid of cage effect. In order to further
improve enantiomeric purity, successive separation of R/S-
BINOLs and R/S-6-Br-BINOLs was applied by recycle of
/-MOCs-42, which increase the ee values up to 88% for
R/S-6-Br-BINOLs in just two cycles while 86% for R/S-
BINOLs in four cycles (Table 2). The stereochemical stability
of /-MOCs-42 during separation processes was tested by
CD measurements (Figure S30), and the little CD signals
change proves reusability of enantiomeric /-MOCs-42.
Table 2. Enantioselective separation resultsa
known tris-chelate-Fe compounds (Table S5), amounting to
nearly 2 order of magnitude larger than those of MOC-42
under the same conditions, indicating 100-fold slower
dissociation of FeL32+ after incorporated in cage structure. The
Ea of MOC-42 is a little higher than that of FeL32+, suggesting
the stabilization effect arises from kinetic factor rather than
lower energy barrier of FeL32+ than MOC-42. Furthermore, the
≠
higher Gibbs energy G of MOC-42 is both contributed from
increased enthalpy ≠H and decreased entropy ≠S in compraison
with those of FeL32+, revealing that dissociative racemization
2+
of MOC-42 is also thermodynamically disfavored than FeL3
.
These kinetic and thermodynamic results account for intrinsic
stereostability of chiral /-MOCs-42, in which the
2+
mechanical coupling among eight face-FeL3 stereogenic
centers are synergistically enhanced through six bridging Pd-
vertices, and racemization of homochiral /-MOCs-42 has to
involve multiple synchronous configuration transformation,48
thus entirely inhibited in normal conditions.
Figure 4. CD enantiodifferentiation experiments for interactions
between /-MOCs-42 (2.0×10-6 M) and R/S-6-Br-BINOLs
(CH3CN/H2O, 1/100, v/v, 298 K). MOC-42+6-Br-BINOL repre-
sents superposition of individual spectra of each components for
comparison. Local zoom spectra show difference of Cotton effect
of 1MLCT absorption at 550 nm.
-MOC-42
R,S ratio ee
-MOC-42
R,S ratio ee
Compds
rac-BINOL
65:35
30
60
20
56
76
86
80
35:65
17:83
39:61
21:79
13:87
8:92
-30
rac-6-Br-BINOL 80:20
rac-bifendatatum 60:40
-66
-22
-58
-74
-84
-88
rac-BINOLb
rac-BINOLc
rac-BINOLd
78:22
88:12
93:7
Enantioseparation of atropisomers. The facial resolution
and sufficient stereostability of enantiopure /-MOCs-42
pave the way for practical application. Based on our previous
finding that homochiral /-MOCs-16 analogues can separate
atropisomeric enantiomers of C2-symmetry,24 we carried out
enantioseparation experiments using the excellent optical /-
rac-6-Br-BINOLb 80:20
6:94
aee, enantiomeric excess, %. b-dSecond, third and fourth cycles,
respectively.
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Journal of the American Chemical Society
Page 6 of 9
2+
CONCLUSIONS
tion of FeL3 (224.3 mg, 0.2 mmol). Then 2 mL DMSO con-
taining Pd(CH3CN)4(BF4)2 (66.7 mg, 0.15 mmol) was added
into the above solution with stirred. Either after heated at 80
oC for 5 hr or stirred at RT for 22 hr, 30 mL ethyl acetate was
added to precipitate the product, which was then centrifuged,
washed with ethyl acetate, and dried in vacuum at RT to yield
a carmine powder confirmed to be the target rac-MOC-42,
[Pd6(FeL3)8](BF4)28 (160 mg, 60%). 1H NMR (400 MHz,
DMSO-d6/D2O, 1/5, v/v, 298 K): ꢀ 10.01 (s, 24H), 9.17 (s,
24H), 8.82 (d, J = 8.4 Hz, 24H), 8.71 (m, 24H), 7.74 (m, 24H),
7.56 (s, 24H), 7.46 (m, 48H), 7.37 (m, 72H). HR ESI-TOF-
1
2
3
4
5
6
7
8
In summary, we present an easy strategy to stabilize stereo-
labile tris-chelate-Fe type stereogenic metal-centers via step-
wise assembly of homochiral Fe-Pd heterometallic cages for
practical application purpose. Excellent enantiopurity of the
/-MOCs-42 is achieved through an in situ-assembly process
for enantioresolution of rac-MOCs-42, of which the chiral-
induced precipitation leads to kinetic resolution while cocrys-
tallization leads to thermodynamic resolution, both are superi-
or to the normal post-assembly process. The intrinsic stereo-
chemical stability of homochiral /-MOCs-42 are thoroughly
studied, unveiling strong mechanical coupling among chiral
face-FeL32+ centers to lead to 00-fold slow of dissociation rate
and entire inhibition of configurational racemization. Success-
ful enantioselective separation is accomplished for racemic
atropisomers, giving good ee value via a successive enanti-
oseparation process by recycling /-MOCs-42. This work
provide a new avenue to make use of economic albeit stereo-
labile metal ions in stereochemistry and relevant applications.
Moreover, owing the MLCT absorption in visible region and
redox behavior of Fe3+/Fe2+, the present homochiral cages may
have potential in asymmetric photocatalysis and photoelec-
tronic devices.
9
MS:
m/z
calcd.
for
[C432H264N120B19F76Pd6Fe8]9+
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
-
{[Pd6(FeL3)8]28++19BF4 } 1096.6022, found 1096.5987; for
[C432H264N120B18F72Pd6Fe8]10+
{Pd6(FeL3)8]28++18BF4 }
-
978.2416, found 978.2382; for [C432H264N120B17F68Pd6Fe8]11+
{[Pd6(FeL3)8]28++17BF4 } 881.4003, found 881.3992.
-
Syntheses of homochiral /-MOC-42. The homochiral
- or -MOCs-42 were obtained through two chiral-induced
enantioresolution processes by addition of chiral R- or S-
BINOLs. One is post-assembly resolution of cages via slow
cocrystallization with R- or S-BINOLs after the secondary
assembly of rac-MOCs-42 enantiomeric pairs, and the other is
an in situ-assembly process during secondary assembly of
enantiomeric - or -MOCs-42 as major products templated
by R- or S-BINOLs, followed by fast precipitation or slow
cocrystallization. The slow cocrystallization proceeds via a
thermodynamic resolution mechanism, while the fast precipi-
tation follows a kinetic resolution mechanism.
(1) Post-assembly process. Slow cocrystallization of /-
MOCs-42 with R/S-BINOLs. To 1 mL CH3CN solution of
rac-MOC-42 (5.3 mg, 1 eq.) was added powder of enantiopure
R- or S-BINOLs (3.4 mg, 24 eq.). After filtration, the solution
was transferred to several 1 mL glass tubes and placed in di-
ethyl ether atmosphere. After 2 weeks’ standing, red block
single-crystals suitable for single-crystal X-ray diffraction
were obtained. The crystals were collected and washed by
diethyl ether for several times until no BINOLs in the filtrate
were detectable by HPLC, and then dried in vacuum at RT
(yield 0.5 mg, 9%).
EXPERIMENTAL DETAILS
General. All reagents and solvents were used as commer-
cially purchased without additional purification. 2-(pyridin-3-
yl)-1H-imidazo[4,5-f][1,10]phenanthroline (L) was prepared
as described in the literature.58 1H NMR, 1H-1H COSY and 1H
DOSY spectra were recorded on Bruker AVANCE III 400
(400 MHz). Chemical shifts were quoted in parts per million
(ppm) referenced to the appropriate solvent peak. The data
were processed by MestReNova software. HR ESI-TOF-MS
spectra were measured on Bruker maXis 4G ESI-Q-TOF with
Tunningmix purchased from Agilent as calibrating agent. Data
analysis was processed on Bruker DataAnalysis program. Sin-
gle crystal reflection intensity data were collected at 150 K on
an Agilent SuperNova single crystal diffractometer using Cu
radiation (λ = 1.5418 Å). The structures were solved by direct
methods and refined using the SHELXTL program package.
UV-Vis and CD spectra were measured by a Shimadzu UV-
3600 UV-Vis-NIR spectrophotometer and a JASCO J-810
spectropolarimeter equipped with temperature controllers,
respectively. Optical rotations were recorded on an Anton Paar
MCD-200 polarimeter. HPLC was performed by Agilent-2000
equipped with Daicel chiral chromatographic columns and a
UV detector with detection wavelength of 254 nm.
(2) In situ-assembly process. (a) Slow cocrystallization of
2+
/-MOCs-42 with R/S-BINOLs. FeL3 (112 mg, 0.1 mmol)
and enantiopure R- or S-BINOLs (258 mg, 0.9 mmol) were
mixed up in advance and dissolved by 10 mL CH3CN in a 50
mL round-bottom flask equipped with a magnetic stir bar.
Then 2 mL CH3CN containing Pd(CH3CN)4(BF4)2 (33.3 mg,
0.075 mmol) was added into the above solution with stirring.
o
The solution was heated to 80 C and reacted for 22 hr, after
Synthesis of metalloligands FeL32+. Fe(BF4)26H2O (101.3
mg, 0.3 mmol) and L (267.6 mg, 0.9 mmol) were mixed in a
25 mL round-bottom flask equipped with a magnetic stir bar.
After addition of 9 mL DMSO (Superdry, J&K Seal), the mix-
ture turned claret color as the reactants were dissolved, which
was then stirred at RT for 1 hr. Precipitation by adding ethyl
which the resulting solution was cooled to RT, filtered and
transferred to several 1 mL glass tubes, then placed in diethyl
ether atmosphere. After 2 weeks’ standing, red block single
crystals suitable for structural analysis were obtained, collect-
ed and washed by diethyl ether for several times until no
BINOLs in the filtrate were detectable by HPLC, and then
dried in vacuum at RT (yield 11.5 mg, 8.6%). (b) Fast precipi-
tation of /-MOC-42 with R/S-BINOLs. The procedure was
similar to above slow cocrystallization except for direct pre-
cipitation by addition of 40 mL diethyl ether to the resulting
solution. The precipitate was isolated by centrifugation and
washed by diethyl ether for several times until no BINOLs in
the filtrate were detectable by HPLC, and then dried in vacu-
um at RT to yield a carmine powder (121 mg, 91%).
2+
acetate yield a scarlet solid as FeL3 metalloligands (yield
318.0 mg, 94.5%), which were confirmed by 1H NMR spectra
1
as well as HR ESI-TOF-MS. H NMR (400 MHz, DMSO-d6,
298 K): ꢀ 14.58 (s, 3H), 9.50 (s, 3H), 9.14 (d, J = 7.7 Hz, 3H),
9.07 (d, J = 9.2 Hz, 3H), 8.79 (d, J = 4.4 Hz, 3H), 8.63 (d, J =
8.3 Hz, 3H), 7.82 (d, J = 19.6 Hz, 6H), 7.77-7.67 (m, 9H). HR
2+
ESI-TOF-MS: m/z calcd. for [C54H33N15Fe]2+ (FeL3
)
473.6192, found 473.6189.
Synthesis of rac-MOC-42. To a 50 mL round-bottom flask
containing a magnetic stir bar was added 6 mL DMSO solu-
ASSOCIATED CONTENT
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Journal of the American Chemical Society
Electron-Transfer and Excited State Quenching Reactions of a Chiral
Ruthenium Complex Possessing a Helical Structure. J. Phys. Chem. A
1999, 103 (29), 5645-5654.
Supporting Information
1
2
3
4
Details of syntheses, characterization, spectra, resolution, separa-
tion, kinetics and crystallography (CIF). This material is available
free of charge via the Internet at http://pubs.acs.org.
(20) Hamada, T.; Ohtsuka, H.; Sakaki, S. Novel photo-induced de-
racemization of [Co(acac)3] (acac = acetylacetonate) with a chiral
ruthenium(II)
complex,
Δ-[Ru(menbpy)3]2+
(menbpy = 4,4′-
Reaction
AUTHOR INFORMATION
bis{(1R,2S,5R)-(−)-menthoxycarbonyl}-2,2′-bipyridine).
5
6
7
8
mechanism and significant effects of solvent and anion. J. Chem. Soc.,
Dalton Trans. 2001, (6), 928-934.
Corresponding Author
*cesscy@mail.sysu.edu.cn.
(21) Bolliger, J. L.; Belenguer, A. M.; Nitschke, J. R. Enantiopure
Water-Soluble [Fe4L6] Cages: Host–Guest Chemistry and Catalytic
Activity. Angew. Chem. Int. Ed. 2013, 52 (31), 7958-7962.
(22) Yamagishi, A. Optical resolution and racemization reaction of
tris(bathophenanthrolinedisulfonato)iron(II): absence of an intramo-
lecular racemization path in aqueous solution. Inorg. Chem. 1986, 25
(1), 55-57.
(23) Yamagishi, A. Optical Resolution and Asymmetric Syntheses
by use of Adsorption on Clay Minerals. J. Coord. Chem. 1987, 16 (2),
131-211.
9
ACKNOWLEDGMENT
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This work was supported by the NSFC (21821003, 21720102007,
21573291, 21890380), LIRT Project of GPRTP (2017BT01C161)
and the FRF for the Central Universities for funding.
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