Self-Assembly of Enantiopure Pd12Tetrahedral Homochiral Nanocages with Tetrazole Linkers and Chiral Recognition

Article abstract of DOI:10.1021/jacs.0c03551

Enantiopure acceptors (R,R)M and (S,S)M [where M = (N1,N1,N2,N2-tetramethylcyclohexane-1,2-diamine)Pd(NO3)2] have been used to design enantiopure Pd(II) tetrahedral cages. Self-assembly of [1,4-di(1H-tetrazol-5-yl)benzene] (H2L1) with chiral acceptors (R,

Full text of DOI:10.1021/jacs.0c03551

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Article
Self-Assembly of Enantiopure Pd12 Tetrahedral Homochiral
Nano-Cages with Tetrazole Linkers and Chiral Recognition
Prodip Howlader, Ennio Zangrando, and Partha Sarathi Mukherjee
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c03551 • Publication Date (Web): 21 Apr 2020
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Self-Assembly of Enantiopure Pd12 Tetrahedral Homochiral Nano-
Cages with Tetrazole Linkers and Chiral Recognition
Prodip Howlader,a Ennio Zangrandob and Partha Sarathi Mukherjee*a
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a Department of Inorganic and Physical Chemistry, Indian Institute of Science, Bangalore, 560012, India
b Department of Chemical and Pharmaceutical Sciences, University of Trieste, Trieste 34127, Italy
ABSTRACT: Enantiopure acceptors (R,R)M and (S,S)M [where M = (N1,N1,N2,N2-tetramethylcyclohexane-1,2-
diamine)Pd(NO3)2] have been used to design enantiopure Pd(II) tetrahedral cages. Self-assembly of [1,4-di(1H-tetrazol-5-
yl)benzene] (H2L1) with chiral acceptors (R,R)M and (S,S)M yielded enantiopure homochiral tetrahedral cages (ΛΛΛΛ)T1 and
(ΔΔΔΔ)T1, respectively. This strategy was further extended by using [2,6-di(1H-tetrazol-5-yl)naphthalene] (H2L2) with
(R,R)M and (S,S)M to obtain water soluble enantiopure tetrahedral nano-cages (ΛΛΛΛ)T2 and (ΔΔΔΔ)T2, respectively. In
order to obtain assembly with larger cavity for potential use in enantioselective recognition, [4,4'-di(1H-tetrazol-5-yl)-1,1'-
biphenyl ] (H2L3) was used as the linker which also resulted in the formation of water soluble enantiopure tetrahedral cages
(ΛΛΛΛ)T3 and (ΔΔΔΔ)T3 upon treatment with (R,R)M and (S,S)M, respectively. The present cages represent unusual
examples of enantiopure tetrahedral cages of square planar metal ions. Finally, T3 cages have been employed in host-guest
study as they offer the largest hydrophobic cavity. Encapsulation of chiral guest molecules such as [(R/S)-1,1'-binaphthalene]-
2,2'-diol] (B) and [(R/S)-2,2'-diethoxy-1,1'-binaphthalene] (EtB) has been performed in order to successfully establish the
asymmetric nature and enantiopurity of the tetrahedral cavity. The host T3 showed certain selectivity towards one
enantiomer over the other. (ΛΛΛΛ)T3 preferred R-EtB over S-EtB (75:25) because of better fitting within the chiral cavity
(Λ/R pair), whereas (ΔΔΔΔ)T3 favoured S-EtB instead of R-EtB (Δ/S pair ratio = 73:27) with almost similar selectivity.
Introduction
comes to square-planar metal ions such as Pd(II) and Pt(II)
due to a planar and symmetric coordination with the ligand
units, we generally obtain symmetric and achiral
architectures.4m,4o,13
Supramolecular chemistry has mainly focused on the design
and construction of discrete assemblies that may
potentially simulate the activity of enzymes.1 Such synthetic
nano-containers can function at physiological pH. They
consist of confined nano-space of specific shapes and sizes,
which allow guest encapsulation and recognition including
stabilization of reactive intermediates.2 Moreover, such
molecular containers have been used as efficient catalysts
that can alter chemical reactions in terms of both the rate
and selectivity.3 However, the efficiency of a molecular
vessel depends on the size and symmetry of the confined
cavity.4 Introduction of asymmetry into the confined nano-
space can enhance its ability to selectively encapsulate
chiral guest molecules.5-6 Recently, supramolecular
chemists have focused on the self-assembly of chiral
architectures that may express stereospecific properties on
a number of levels. One of the powerful aspects of self-
assembly is that it can generate chiral architectures even
without using any chiral building block.7 Although the
incorporation of chiral organic stereo-center has been the
common approach to develop functional chiral molecules,
the basic principle of self-assembly may provide chirality as
a consequence of symmetry breaking.8 Incorporation of
chiral ligand backbone9 and stereogenic metal centres10
(generally octahedral metal ions) is an easy and efficient
strategy to design chiral molecular containers.4j,11 There
have been many reports on synthesis of homochiral
architectures with the help of octahedrally coordinated
metal ion such as Fe(III), Co(III) as well as chiral cages by
assembling chiral ligand backbone12. However, when it
Although, we can easily obtain chiral cages by introducing a
chiral acceptor into the assembly, the chirality obtained in
this case would only be present at the exterior or at the cage
corners, while cavity would likely to be symmetric in
nature.14 For example Stang and co-workers had used metal
corners capped with chiral auxiliaries such as [M1(R)-
BINAP(OTf)2] (M1 = Pd(II) or Pt(II), BINAP = 2,20-
bis(diphenylphosphino)-1,10-binaphthalene) to synthesize
chiral macrocycles.14b Similarly, Fujita and co-workers have
reported the synthesis of chiral cages by introducing
cyclohexane-1,2-diamine bound chiral Pd(II) acceptors.10a
Such systems may not be potential for chiral recognition
into their confined cavity despite of their overall
enantiopure nature. We have shown that using di-/tri-
tetrazole linkers one can obtain homochiral tetrahedral
molecular containers (ΛΛΛΛ/ΔΔΔΔ) even using symmetric
square planar Pd(II) metal ions.15 The unusual and special
binding modes of such tetrazole linkers are the pivotal
factors in accessing chirality in such supramolecular
architectures using Pd(II) square-planar metal centre as
one of the building units. However, obtaining enantiopure
such cages from racemic mixture (ΛΛΛΛ/ΔΔΔΔ) is very
challenging. Enantiopure cages may have potential in
selective chiral recognition.
Herein, we report the synthesis of enantiopure
homochiral tetrahedral cages of square planar Pd(II) ion by
the self-assembly of a series of di-tetrazole linkers. Our
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strategy for achieving enantiopure M12L4 architectures Results and Discussion
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without any resolution involves the addition of a chiral
fragment into the metal acceptor unit.10a We fancied that
this chiral unit on the metal acceptor would control the
helicity of the architecture and direct a diastereoselective
process which would provide an enantioenriched assembly.
Therefore, enantiopure chiral acceptors (R,R)M and (S,S)M
[M=(N1,N1,N2,N2-tetramethylcyclohexane-1,2-
Design Strategy for Enantiopure Pd(II) Tetrahedral
Cages:
Benzene-1,4-ditetrazole (H2L1), upon treatment with
achiral acceptor cis-[(tmeda)Pd(NO3)2], yielded
a
tetrahedral homochiral molecular cage T which exists as a
racemic mixture of (ΛΛΛΛ)T and (ΔΔΔΔ)T as established
from low temperature 1H NMR and single crystal-XRD
structure analysis (tmeda = N’,N’,N”,N”-tetramethyethane-
1,2-diamine).15 Our objective was to isolate/synthesize
enantiopure form in order to use for chiral recognition.
Chiral resolution with several chiral anions was
attempted16; however, the inability of T to bind with larger
anions did not allow the process to be successful. Therefore,
we anticipate that by introducing chiral induction effect17 of
a chiral group attached to the nano-cage T may result in the
formation of either one of the enantiomers in enantiopure
form. The feasibility of this synthetic process lies in the
symmetry information encoded into the acceptor units of
the enantiomers. Basically, the tmeda part of the acceptor M
can adopt two enantiomeric conformers, let’s call them E1
and E2 (Figure 1). Nonetheless, most of the supramolecular
discrete architectures that are reported in the literature are
achiral in nature; therefore, these conformers (E1 & E2)
experience a symmetrical environment in most of the
assemblies, where both of them behave equally in terms of
their stability in that particular environment.
diamine)Pd(NO3)2] were designed and synthesized by the
treatment of chiral amines with PdCl2 followed by reaction
with AgNO3. The enantiopure tetrahedral cages (ΛΛΛΛ)T1
and (ΔΔΔΔ)T1 were obtained from the reaction of [1,4-
di(1H-tetrazol-5-yl)benzene] (H2L1) with the chiral
acceptors (R,R)M and (S,S)M respectively, in aqueous
medium.
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Scheme 1. Schematic representation of the synthesis of
enantiopure tetrahedral nano-cages T1, T3 and T2 from
the chiral acceptors (R,R)M and (S,S)M.
This unique outcome enticed our attention towards larger
tetrahedra to examine the generality of this strategy and in
a similar fashion, [2,6-di(1H-tetrazol-5-yl)naphthalene]
(H2L2) was treated with (R,R)M and (S,S)M to produced
water soluble enantiopure tetrahedral nano-cages
(ΛΛΛΛ)T2 and (ΔΔΔΔ)T2, respectively (Scheme 1). In order
to obtain assembly with larger cavity, [4,4'-di(1H-tetrazol-
5-yl)-1,1'-biphenyl ] (H2L3) was used as the ligand unit and
the reactions resulted in the formation of water soluble
enantiopure tetrahedral cages (ΛΛΛΛ)T3 and (ΔΔΔΔ)T3.
Although all the synthesized assemblies contain internal
cavity with triangular open windows, T3 was chosen as a
host while exploring host-guest chemistry, because it offers
the largest hydrophobic cavity. In order to establish the
asymmetric nature of the nano-space, chiral guest
molecules such as (R/S)-B (B = BINOL) have been
encapsulated and we observed that the tetrahedral cavity
interacts with R/S enantiomers of BINOL in different
manner, thus proving the existence of a chiral cavity.
Moreover, employment of alkylated derivatives of BINOL
(R/S-EtB) showed better interaction with the aromatic
walls of the cage. Finally, by using a racemic mixture of (±)-
EtB for encapsulation, the asymmetric cavity shows certain
selectivity towards one enantiomer of EtB over the other.
Figure 1. Design strategy for the chiral metal acceptors (R,R)M
and (S,S)M to synthesize enantiopure homochiral cages.
However, in case of T the conformers E1 and E2
experience an asymmetric environment as the Pd3 triangles
at each vertex of the molecular tetrahedron is chiral in
nature (has a handedness of ∆ or Λ depending on the
binding modes of the tetrazole units). Therefore, it is
expected that one of the conformers will be favoured by a
Pd3 triangle having a specific chirality in order to obtain a
low energy configuration. This idea was supported by the
crystal structure of T reported by our group.15 A careful
investigation of the crystal structure of T revealed that the
∆ isomer is composed of E2 conformers whereas, the Λ
isomer contains only the E1 conformers of M. Thus, one can
expect to assemble a ∆ isomeric architecture from a cis-
blocked Pd(II) 90° acceptor where the -N-C-C-N- moiety has
a fixed E2 geometry and vice versa. These fixed E1 and E2
configurations of the blocking chelating amines can be
imitated by incorporating chiral cyclohexane diamines to
synthesize chiral 90° acceptors such as cis-(R,R)- and
(S,S)(1,2-cyclohexanediamine)Pd(II) (CDM). Therefore,
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(R,R) isomer comprises of E1, whereas (S,S) consists of E2 chiral phase and therefore the enantiopurity of the complex.
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configuration of the -N-C-C-N- moiety. However, self-
assembly of CDMs with the ligand L1 formed precipitate in
water and no tetrahedral assemblies were obtained. This is
probably due to the absence of any substitution at the N-
centres of the acceptor unit which cannot transfer the chiral
information from the acceptor unit to the ligand unit of the
expected nano-cage.
Finally, circular dichroism (CD) spectrum was recorded to
understand the chirality of the cavity (Figure 2b). The CD
spectrum shows a positive cotton effect near 275 nm
generated from the ligands, which confirms the presence of
a single isomeric cage. The enantiomeric tetrahedral cage
(ΔΔΔΔ)T1 was synthesized from the self-assembly of (S,S)M
and H2L1 in 2:1 molar ratio in water. The 1H NMR spectrum
is equivalent to its enantiomer counterpart (ΛΛΛΛ)T1.
Finally, CD spectrum of (ΔΔΔΔ)T1 was obtained as exactly
mirror image to that of (ΛΛΛΛ)T1. This certainly confirms
the formation of the enantiomeric cage (ΔΔΔΔ)T1.
Nonetheless, this idea can be extended for other
polytetrazole ligands such as H2L2 and H2L3 to synthesize
enantiopure homochiral tetrahedral cages.
Thus, synthesis of methyl substituted CDMs was
necessary to achieve the current objective. The enantiopure
chiral acceptors (R,R) and (S,S) [(N1,N1,N2,N2-
tetramethylcyclohexane-1,2-diamine)Pd(NO3)2] [(R,R)M
and (S,S)M] were synthesized from the N-methylation
reaction of [(1R,2R)-cyclohexane-1,2-diamine] and
subsequent reaction with PdCl2 followed by treatment with
AgNO3 to give yellow solids as pure form. The (R,R)
[(N1,N1,N2,N2-tetramethylcyclohexane-1,2-
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Synthesis and Characterization of Enantiopure Cages of
T2 and T3:
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diamine)PdCl2] was characterized by H NMR and single
Although tetrahedral cages could not be accessed from the
self-assembly of the achiral acceptor [(N1,N1,N2,N2-
tetramethylethane-1,2-diamine)Pd(NO3)2] with H2L2, the
same was attempted by employing the chiral acceptors
(R,R)M and (S,S)M. The aforementioned synthetic
procedure was employed to obtain the enantiomeric pairs
of tetrahedral cages of T2. However, similar treatment of 2
equivalents of (R,R)M with one equivalent of H2L2 in water
produced a polymeric precipitate. Interestingly, when the
same reaction was carried out in a H2O/MeOH (1:1)
medium, a clear solution was obtained, which indicated the
formation of discrete assembly. The product was isolated as
pure form by the treatment of THF into the cage solution to
get white precipitate.
crystal XRD as well. Finally, both the (R,R)M and (S,S)M
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complexes were characterized by H NMR spectroscopy. It
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is worth mentioning that the H NMR spectra of these
acceptors contain seven aliphatic peaks (two N-methyl
protons, and five C-H protons) due to the presence of two
chiral centres. Finally, both the isomers were used for the
self-assembly reaction with different poly-tetrazole linkers.
Synthesis and Characterization of Enantiopure Cages of
T1:
Treatment of (R,R)M with H2L1 in 2:1 molar ratio in water
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at 65 °C produced a clear solution after 6 h. The H NMR
spectrum of the isolated product in D2O displayed the
presence of single aromatic proton peak at 9.11 ppm along
with multiple aliphatic peaks ranging from 3.52 to 1.06 ppm
for the metal acceptor. 1H DOSY analysis of the same
solution showed a single diffusion for all the peaks, which
suggests the formation of a single component (Figures S4,
S6). To confirm the helicity of the resulting tetrahedron,
single crystals were grown by acetone vapour diffusion into
the aqueous solution of the cage. Single crystal XRD analysis
unequivocally confirmed the formation of a (ΛΛΛΛ)T1
isomer by the chiral induction effect of (R,R)M acceptor
(Figure 2).
Figure 3. 1H NMR spectra of the ligand H2L2 (bottom) in DMSO-
d6 and tetrahedral cage (ΛΛΛΛ)T2 (top) in D2O.
1H NMR spectrum of the isolated product in D2O
displayed three highly de-shielded aromatic proton peaks
at 9.99, 8.84 and 8.18 ppm having the same integration
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value (Figure 3). H DOSY spectrum displayed the same
diffusion coefficient for all the peaks, which suggests the
formation of single product (Figure 5). All the individual
aromatic peaks were assigned with the help of 1H-1H COSY
and NOESY spectra (Figures S9, S10). Interestingly, the 1H-
1H COSY spectrum also revealed the presence of fourteen
aliphatic proton peaks ranging from 3.53 to 1.02 ppm for
the acceptor unit. Although, the unassembled acceptor
(R,R)M contains only seven peaks at the aliphatic region
ranging from 3.18 to 1.08 ppm, the presence of fourteen
Figure 2. (a) Single crystal XRD structure of (ΛΛΛΛ)T1; Colour
code; grey: Carbon, blue: Nitrogen and brown: Palladium; all
the H atoms were removed for better clarity. (b) CD spectra of
both the isomers (ΛΛΛΛ)T1 and (ΔΔΔΔ)T1.
The tetrahedral cage (ΛΛΛΛ)T1 was crystallized in chiral
space group P212121 (Figure 2a), where the asymmetric unit
contains the whole tetrahedron. Moreover, the determined
Flack parameter of 0.05(9) confirms the presence of a single
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peaks for the tetrahedral cage can be explained in terms of
additional asymmetry present in these homochiral
tetrahedral cages.
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ESI-MS of T2 was recorded with the PF6 analogue in
acetonitrile. The presence of several major peaks at m/z =
2065.69, 1513.00, 1181.39, 960.35 and 802.42 for the
charged fragments, [(ΛΛΛΛ)T2·9 PF6]3+, [(ΛΛΛΛ)T2·8
PF6]4+, [(ΛΛΛΛ)T2·7 PF6]5+, [(ΛΛΛΛ)T2·6PF6]6+ and
[(ΛΛΛΛ)T2·5PF6 ]7+ respectively, confirms the formation of
a M12L6 tetrahedral assembly (Figure 4). CD spectrum was
recorded in order to determine the helichirality of the
product, which shows a similar pattern like (ΛΛΛΛ)T1
where a positive cotton effect is observed for the ligand
units at 260 nm (Figure 5). This ascertains the formation of
enantiopure tetrahedral nano-cage (ΛΛΛΛ)T2.
Figure 5: (a) Energy minimized structure of (ΛΛΛΛ)T2. Colour
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codes: blue, Carbon; deep-blue, Nitrogen; and brown,
Palladium. (b) CD spectra of both the isomers (ΛΛΛΛ)T2 and
(ΔΔΔΔ)T2.
Treatment of H2L3 with (R,R)M in a 1:2 molar ratio in
water/methanol mixture produced white precipitate,
which is insoluble in water and other organic solvents,
suggesting the formation of polymeric product. Therefore,
the self-assembly was carried out in DMSO at 70 °C for 8 h
of stirring. The product was isolated as off-white solid
powder which is soluble in water. The 1H NMR spectrum of
this white powder in D2O showed the presence of two
deshielded peaks at 8.82 and 8.15 ppm in the aromatic
region with multiple peaks for the acceptor unit ranging
from 3.55 to 1.19 ppm (Figure 6). 1H DOSY study confirmed
the formation of single product. Finally, ESI-MS was
recorded with the PF6‾ analogue of the complex in
acetonitrile, which confirms the formation of a M12L6
tetrahedral assembly. The presence of several major peaks
at 2117.73, 1552.03, 1212.63, 986.38 and 824.74 for the ion
fragments
[(ΛΛΛΛ)T3·9PF6]3+,
[(ΛΛΛΛ)T3·8PF6]4+,
and
[(ΛΛΛΛ)T3·7PF6]5+,
[(ΛΛΛΛ)T3·6PF6]6+
[(ΛΛΛΛ)T3·5PF6]7+ respectively, confirms the formation of
a M12L6 tetrahedral assembly (Figure S15). Finally, analysis
of CD spectrum showed a similar pattern like (ΛΛΛΛ)T1 and
(ΛΛΛΛ)T2 with a positive cotton effect observed for the
ligand units at 260 nm (Figure S14). Following the same
procedure, the other enantiomer (ΔΔΔΔ)T3 was obtained
and characterized. Unfortunately, several attempts to
obtain single crystals suitable of XRD analysis remained
unsuccessful. Therefore, the geometry of (ΛΛΛΛ)T3 was
optimized by semiempirical method with a PM6 basis set
(Figures S14, 16).
Figure 4: (a) 1H DOSY NMR spectrum of the nanocage
(ΛΛΛΛ)T2 in D2O and (b) ESI-MS spectra of the PF6 analogue of
(ΛΛΛΛ)T2 in acetonitrile.
The same procedure was followed to obtain the other
enantiomer (ΔΔΔΔ)T2 and also characterized by several
spectroscopic methods along with CD, which shows cotton
effects mirror image to the (ΛΛΛΛ) isomer. Though we were
able to grow single crystals of both the isomers of T2, but it
was not possible to obtain a structural model after careful
analysis of the collected single crystal XRD data. Thus, the
geometry of (ΛΛΛΛ)T2 was optimized by semiempirical
method with a PM6 basis set (Figure 5).
Figure 6: 1H NMR spectra of the ligand H2L3 (bottom) in DMSO-
d6 and tetrahedral cage (ΛΛΛΛ)T3 (top) in D2O.
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guest molecules such as R/S-B, much information about the
enantiopurity could not be obtained as all the guest proton
peaks are broad in nature. The broadness of the guest peaks
is a result of inefficient interaction with the aromatic wall of
the hydrophobic cavity. Therefore, for an efficient
interaction a bulkier guest molecule would guarantee lower
degrees of freedom inside the cavity due to a better fitting.
In order to demonstrate this, we have synthesized alkylated
Host-Guest Chemistry: Chiral Recognition
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Due to enantiopure nature, these edge-directed homochiral
cages are expected to be suitable for encapsulation of chiral
organic molecules of different shapes and sizes. However,
the tetrahedron T3 has the largest hydrophobic cavity
encompassed by six biphenyl moieties along the edges
which can participate into π-π interaction with the guest
molecules. Although it was demonstrated that the
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R/S-B, i.e. R/S-diethylbinol (R/S-EtB). As expected, the H
NMR spectra of the resulting host-guest complexes like R/S-
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tetrahedral cages are homochiral with the help of H NMR,
⊂
⊂
EtB (ΔΔΔΔ)T3 and R/S-EtB ( ΛΛΛΛ)T3 contain sharp
guest peaks for aromatic as well as alkyl protons (Figure 7).
A significant upfield shift of the host aromatic protons along
with the guest protons was observed. The methyl protons
of R/S-EtB appeared at a highly shielded region (below -0.5
ppm) which suggests the presence of strong interaction
between the guest molecule and the hydrophobic aromatic
SC-XRD along with CD spectroscopy; however, it is
necessary to establish whether the nano-space is chiral in
nature. To ascertain this, we introduced chiral enantiopure
guest molecules such as BINOL (B) to interact with the
enantiopure homochiral cages (ΔΔΔΔ/ΛΛΛΛ)T3. If the
nano-cavity is chiral in nature, in principle it will interact
with R and S-B in distinct manner to give diastereomeric
host-guest complexes. For example, (ΔΔΔΔ)T3 would form
host-guest complex with R and S-BINOL (R/S-B) to give
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1
wall. The H NMR spectra of all the diastereomers contain
only a single methyl peak which again confirms the
enantiopurity of the cages. During observation of the methyl
proton peak positions, we could notice that R-EtB⊂(
ΛΛΛΛ)T3 contains a more shielded proton peak (-0.9 ppm)
than that of S-EtB⊂( ΛΛΛΛ)T3 (-0.7 ppm). This indicates the
presence of a stronger host-guest interaction in R/Λ isomer
than in S/Λ one. This different interaction was tested again
by taking a racemic mixture of R/S-EtB as guest and
⊂
⊂
diastereomeric pair R-B (ΔΔΔΔ)T3 and S-B (ΔΔΔΔ)T3,
respectively. Similarly, treatment with (ΛΛΛΛ)T3 would
⊂
⊂
result into the formation of R-B ( ΛΛΛΛ)T3 and S-B
ΛΛΛΛ)T3. It is worth noting that R-B (ΔΔΔΔ)T3 and S-B
(ΛΛΛΛ)T3 are enantiomeric in nature and would have
the same spectral pattern, so as the pair S-B (ΔΔΔΔ)T3
( ΛΛΛΛ)T3. Interestingly, the host-guest
complexation experiment with R/S-B resulted in the same
outcome (Figure S17). In all the cases encapsulation was
observed and was confirmed from H NMR spectroscopy,
(
⊂
⊂
⊂
1
⊂
and R-B
(ΛΛΛΛ)T3 as the host. The H NMR spectrum with the
racemic guest displayed a much more complex pattern
(Figure 7). However, presence of two methyl peaks was
observed, which indicates the encapsulation of both the
isomers. Moreover, due to these un-equal interactions the
R/Λ isomer exists in higher amount than the S/ Λ isomer
(75:25, calculated ratio from the integration value).
1
which showed a significant upfield shift of the aromatic
protons of the cage. Aromatic peaks for BINOL were much
upfield shifted (7 to 5 ppm) and appeared as broad peaks.
⊂
⊂
Moreover, the pair R-B (ΔΔΔΔ)T3 and S-B (ΔΔΔΔ)T3
1
presented non-identical H NMR spectra, confirming the
asymmetric (chiral) nature of the confined cavity presented
by these homochiral tetrahedral cages.
Figure 8: Energy optimized geometry of the host-guest
⊂
⊂
complexes. (a) S-EtB (ΛΛΛΛ)T3 and (b) R-EtB ( ΛΛΛΛ)T3.
Finally, to understand the nature of interaction we tried
to crystallize one of the host-guest complexes; however, all
the attempts remained unsuccessful. Therefore, energy
⊂
optimized structures of the diastereomers R-EtB
⊂
(ΛΛΛΛ)T3 and S-EtB (ΛΛΛΛ)T3 were obtained by
computational studies. Moreover, single point energies
were calculated using DFT which confirms the fact that the
R/Λ isomer is energetically more favourable than the S/Λ
one (Figure 8).
Figure 7: 1H NMR spectra of the host-guest complexes of the
enantiopure cages (ΔΔΔΔ/ΛΛΛΛ)T3 with (R/S)-
diethylbinol in D2O.
Conclusion
In conclusion, chiral acceptors (R,R)M and (S,S)M have been
successfully designed and synthesized in order to obtain
enantiopure tetrahedral cages. Finally, a new enantiopure
tetrahedron (ΛΛΛΛ)T1 has been synthesized by the
treatment of (R,R)M with H2L1 in aqueous medium where
Although, we have successfully established the chiral
nature of the cavity by treating it with enantiopure chiral
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the chiral unit on the metal acceptor controls the helicity of (N1,N1,N2,N2-tetramethylcyclohexane-1,2-diamine)PdCl2
Page 6 of 10
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2
3
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8
the architecture and directs a diastereoselective process
which produces an enantiopure assembly. The obtained
assembly was fully characterized by various spectroscopic
techniques and the enantiopurity of the complex was
confirmed by single crystal XRD structure analysis and CD
study. Applying the same strategy, we also obtained the
enantiomer (ΔΔΔΔ)T1 in pure form. This idea was then
successfully extended to synthesize enantiopure cages with
larger cavity size (T2 and T3) by employing linkers
containing larger aromatic aperture such as naphthalene
and biphenyl (L2 and L3). T2 and T3 showed similar pattern
in the CD spectra as that of T1, which confirms the helicity
of the newly synthesized cages. These cages (T1-T3)
represent uncommon examples of enantiopure tetrahedral
cages of square planar Pd(II). All the assemblies are edge
directed with all the edges of the tetrahedron occupied by
the linker, thus forming triangular windows which can
allow guest molecule to enter into the hydrophobic cavity.
However, while exploring host guest chemistry, T3 was
selected as a host because it offers the largest hydrophobic
cavity with big triangular windows. Moreover, to
understand the asymmetric nature of the host cavity, chiral
guest molecules such as (R/S)-B have been introduced and
it was found that the cavity interacts with the isomers of
BINOL (R or S) in different manner providing non-identical
1H NMR spectra, thus proving that the cavity is in fact chiral
in nature. In order to establish a stronger binding with the
hydrophobic wall, alkylated derivatives of BINOL (R/S-EtB)
have been used as organic guests. As expected, we observed
a better interaction of the guest molecules with the
aromatic walls resulting in sharp peaks for the guest
protons. Finally, a racemic mixture of (±)-EtB was used for
encapsulation, indicating that the asymmetric cavity shows
certain selectivity towards one enantiomer of EtB over the
other.
(347.0 mg, 1.0 mmol) was stirred with a 5 mL aqueous
solution of AgNO3 (340.0 mg, 2.0 mmol) in dark for
overnight. The filtrate was then isolated, and bright-yellow
powder was obtained as pure (R,R)M or (S,S)M after
removal of water. Yield: 380.0 mg (95%). H NMR(D2O) δ
(ppm): 3.18 (t, 1H), 2.68 (s, 3H), 2.58 (s, 3H), 2.09 (d, 1H),
1.69 (d, 2H), 1.43 (d, 1H) and 1.13 (t, 1H).
1
Synthesis of (ΛΛΛΛ)T1 and (ΔΔΔΔ)T1:
9
To a clean glass vial containing a 4 mL aqueous solution of
(R,R)M or (S,S)M (40.0 mg, 1.0 mmol) white powder of H2L1
(10.7 mg, 0.05 mmol) was added followed by stirring at 70
°C for 6 h to give a clear solution. White solid of the
enantiopure cage (ΛΛΛΛ)T1 or (ΔΔΔΔ)T1 was isolated after
treating the aqueous solution with excess volume of THF.
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
1
Yield: 35.6 mg (80%). H NMR(D2O) δ (ppm): 9.11 (s, 4H),
3.52 (s, 2H), 3.26 (s, 2H), 3.14 (s, 6H), 2.81 (s, 6H), 2.64 (s,
6H), 2.18 (s, 2H), 1.92 (broad, 8H), 1.71 (broad, 4H) and
1.13 (s, 2H).
Synthesis of (ΛΛΛΛ)T2 and (ΔΔΔΔ)T2:
To a clean glass vial containing a (2+2) mL (H2O+MeOH)
solution of (R,R)M or (S,S)M (40.0 mg, 1.0 mmol) white
powder of H2L2 (10.7 mg, 0.05 mmol) was added followed
by stirring at 70 °C for 8 h to give a clear solution. White
solid of the enantiopure cage (ΛΛΛΛ)T2 or (ΔΔΔΔ)T2 was
isolated after treating the clear solution with excess volume
1
of THF. Yield: 37.4 mg (81%). H NMR(D2O) δ (ppm): 9.99
(s, 2H), 8.84 (d, 2H), 8.18 (broad, 2H), 3.53 (s, 2H), 3.23 (s,
6H), 3.16 (broad, 4H), 2.90 (s, 6H), 2.66 (s, 6H), 2.20 (s, 2H),
1.92 (broad, 8H), 1.70 (broad, 4H), 1.44 (broad, 4H), 1.18 (s,
2H) and 1.02 (s, 2H). ESI-MS (CH3CN) (m/z): 2065.69
[(ΛΛΛΛ)T2·9PF6]3+, 1513.00 [(ΛΛΛΛ)T2·8PF6]4+, 1181.39
[(ΛΛΛΛ)T2·7PF6]5+, 960.35 [(ΛΛΛΛ)T2·6PF6]6+ and 802.42
[(ΛΛΛΛ)T2·5PF6]7+.
Synthesis of (ΛΛΛΛ)T3 and (ΔΔΔΔ)T3:
Experimental Section:
Materials and Methods
To a glass vial containing DMSO solution of (R,R)M or (S,S)M
(40.0 mg, 1.0 mmol) white powder of H2L3 (14.5 mg, 0.05
mmol) was added followed by stirring at 70 °C for 6 h to give
a clear solution. White solid of the enantiopure cage
(ΛΛΛΛ)T3 or (ΔΔΔΔ)T3 was isolated after treating the clear
solution with excess volume of THF. Yield: 42.0 mg (87%).
1H NMR(D2O) δ (ppm): 8.83 (s, 4H), 8.16 (s, 4H), 3.55 (s, 2H),
3.34 (s, 2H), 3.15 (s, 6H), 2.89 (broad, 8H), 2.62 (s, 6H), 2.21
(s, 2H), 2.08 (broad, 8H), 1.75 (broad, 4H), 1.51 (s, 2H), and
1.19 (broad, 4H). ESI-MS (CH3CN) (m/z): 2117.73
[(ΛΛΛΛ)T3·9PF6]3+, 1552.03 [(ΛΛΛΛ)T3·8PF6]4+, 1212.63
[(ΛΛΛΛ)T3·7PF6]5+, 986.38 [(ΛΛΛΛ)T3·6PF6]6+ and 824.74
[(ΛΛΛΛ)T3·5PF6]7+.
All the reagents were purchased from different commercial
sources and used without further purification. NMR spectra
were recorded on a Bruker 400 MHz spectrometer and the
1
chemical shifts (δ) in the H NMR spectra are reported in
ppm relative to tetramethylsilane (Me4Si) as internal
standard (0.0 ppm) or proton resonance resulting from
incomplete deuteration of the solvents (CD3)2SO (2.51 ppm)
and D2O (4.79 ppm). Electrospray ionization mass
spectrometry (ESI-MS) experiments were carried out on a
Q-TOF ESI-MS instrument. All the dicyano derivatives18 and
[(R,R) or (S,S)]-N1,N1,N2,N2-tetramethylcyclohexane-1,2-
diamine.2HCl salt19 have been synthesized following the
literature procedure.
ASSOCIATED CONTENT
Additional NMR, SCXRD parameters and ESI-MS spectra. “This
material is available free of charge via the Internet at
http://pubs.acs.org.”
Synthesis of (R,R)M and (S,S)M:
To a flame dried round bottom flask (R,R) or (S,S)-
N1,N1,N2,N2-tetramethylcyclohexane-1,2-diamine.2HCl
(1.46 g, 6.0 mmol) was taken in 10 mL of water followed by
the addition of PdCl2 (0.531 g, 3.0 mmol). The mixture was
stirred at 50 °C overnight to give yellow precipitate. The
precipitate was then filtered and washed thoroughly with
water followed by vacuum drying to give [(R,R)- or (S,S)]-
(N1,N1,N2,N2-tetramethylcyclohexane-1,2-diamine)PdCl2
as pure form. Yield: 650.0 mg (62%). [(R,R)- or (S,S)]-
AUTHOR INFORMATION
Corresponding Author
* psm@iisc.ac.in (P. S. Mukherjee)
ACKNOWLEDGMENT
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Self-Assembly of Enantiopure Pd12 Tetrahedral Homochiral Nano-
Cages with Tetrazole Linkers and Chiral Recognition
Prodip Howlader,a Ennio Zangrandob and Partha Sarathi Mukherjee*a
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