Enantiopure water-soluble [Fe4L6] cages: Host-guest chemistry and catalytic activity

Article abstract of DOI:10.1002/anie.201302136

Inside information: The new enantiopure cage molecule ΔΔΔ Δ-Fe₄L₆ (and its enantiomer, ΛΛ ΛΛ-Fe₄L₆) was prepared by subcomponent self-assembly. It binds a range of organic guests (A, see scheme) in its cavity and distinguishes between the enantiomers of a chiral organic guest. Host ΔΔΔΔ-Fe₄L₆ is also a catalyst for the hydrolysis (giving B and C) of the neurotoxic organophosphate dichlorvos. Copyright

Full text of DOI:10.1002/anie.201302136

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Communications
DOI: 10.1002/anie.201302136
Host–Guest Chemistry
Enantiopure Water-Soluble [Fe4L6] Cages: Host–Guest
Chemistry and Catalytic Activity**
Jeanne L. Bolliger, Ana M. Belenguer, and Jonathan R. Nitschke*
Angewandte
Chemie
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Host–guest chemistry has its origin in biological processes
involving molecular recognition through noncovalent inter-
actions, as for example when substrates bind to enzymes. Over
the last decade, organic capsules[1] and self-assembled coor-
dination cages[2] have been prepared that are able to
encapsulate a variety of guests, increase the rates of chemical
reactions,[1c,3] change the course of reactions involving encap-
sulated molecules,[2i,4] or to stabilize otherwise unstable
species.[5] Self-assembled metal–organic capsules based on
chiral ligands are of special interest because they have
a chirotopic internal void, which can not only enable
enantioselective guest recognition and separation but can
also provide an asymmetric microenvironment for stereose-
lective reactions.[6]
Scheme 1. a) 1. NaOH, EtOH, 2. 3-chloro-1,2-propanediol; b) 4-nitro-
phenylboronic acid, K2CO3, 0.05 mol% [2,6-bis[(di-1-piperidinylphos-
phino)amino]phenyl] palladium(II) chloride;[8] c) H2, 10% Pd/C.
Small guest molecules have been observed[7] to be
encapsulated by a water-soluble self-assembled tetrahedral
M4L6 cage prepared by subcomponent self-assembly from
amine, aldehyde and FeII precursors. Herein we show how the
use of a longer diamino terphenylene subcomponent, bearing
chiral glyceryl groups, allows the enantioselective formation
of larger water-soluble [Fe4L6] capsules. This new cage
encapsulates a wider range of guests, including larger
molecules, such as chiral natural products. We also demon-
strate our cageꢀs ability to accelerate catalytically the
hydrolysis of the acetylcholine esterase inhibitor insecticide
dichlorvos, which shares key chemical features with the class
of organophosphate chemical warfare agents (CWAs).
Diaminoterphenylenes 4, (S,S)-4, and (R,R)-4 were pre-
pared in three steps from diiodohydroquinone (1) as shown in
Scheme 1. The studies described below were carried out using
aqueous stock solutions of DDDD-5 (or LLLL-5 or 5)
prepared from enantiopure (S,S)-4 (or (R,R)-4 or 4), 2-
formylpyridine, and FeIISO4 in a 6:12:4 ratio (Scheme 2).
Experimental details and characterization data are provided
in the Supporting Information.
Scheme 2. a) Enantioselective formation of DDDD-5 from (S,S)-4, 2-
formylpyridine, and FeIISO4 by subcomponent self-assembly; b) Host–
guest chemistry of DDDD-5. Top right: D-[FeL3] corner.
A solution of the deep-purple capsule DDDD-5 gave
FTICR mass spectra consistent with an [Fe4L6]8+ formulation
(Figure S009 in the Supporting Information). Its hydrody-
namic radius, determined from DOSY NMR spectroscopy,
was (15.25 Æ 0.62) ꢁ, which is consistent with the value of
16.1 ꢁ derived from the model shown in in Figure 1. This
model was energy-minimized using the universal force field
(UFF) of ArgusLabs[9] (Figure S005).
The shortest FeII···FeII distance of DDDD-5 is calculated to
be approximately 17.1 ꢁ while the bis-bidentate ligand
forming the edge of the tetrahedron has a total length of
approximately 26.3 ꢁ (distance H2···H2’; Scheme 2). We infer
[*] Dr. J. L. Bolliger, Dr. A. M. Belenguer, Dr. J. R. Nitschke
Department of Chemistry, University of Cambridge Lensfield Road
Cambridge, CB2 1EW (UK)
E-mail: jrn34@cam.ac.uk
Homepage: http://www-jrn.ch.cam.ac.uk
[**] This work was supported by the Swiss National Science Foundation
(SNSF) and the European Research Council. We thank the EPSRC
Mass Spectrometry Service at Swansea for conducting FT-ICR MS
experiments.
Figure 1. Molecular model of DDDD-5 from molecular mechanics
calculations with ArgusLabs through the universal force field (UFF).
Black C, gray H, violet Fe, blue N, red O.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201302136.
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that the glyceryl substituents not only make the cage water
soluble but also serve to close the faces of the cage, thereby
forming a hydrophobic cavity with the glyceryl hydroxy
groups directed outward. Based on the molecular model, the
volume of the cavity of DDDD-5 was calculated to be 418 ꢁ3.
This calculation employed a virtual probe with a radius of
3.0 ꢁ (instead of the usual 1.4 ꢁ), which was the smallest size
that remained in the cavity throughout the calculations
(Figure S008). We would therefore expect the void of
DDDD-5 to exceed our calculated value.
We found that the stereochemistry of the glyceryl groups
dictated the handedness of the iron(II) stereocenters, despite
the distance between these stereochemical elements. The
capsules formed from the enantiopure subcomponents (S,S)-4
and (R,R)-4 gave rise to mirror-image circular dichroism
(CD) spectra (Figure S004) indicating enantioselective for-
mation of a [M4L6]8+ cage with all the metal centers having
either D or L configuration.[2d,6a] By comparing the sign of the
Cotton effect at the metal-to-ligand charge-transfer (MLCT)
transition with observations for similar [FeII(diimine)3] com-
plexes[10] and [Fe4L6]8+ capsules,[11] we were able to infer that
subcomponent (S,S)-4 formed DDDD-5 and its enantiomer
(R,R)-4 led to the formation of LLLL-5. The use of diamine
4, prepared from racemic starting material, resulted in
a mixture of capsules 5, which exhibited no optical activity
(Figure S004).
The large hydrophobic cavities of water-soluble metal–
organic capsules DDDD-5, LLLL-5, and 5 were expected to
bind a variety of hydrophobic guest molecules (Sche-
me 2b),[1c,4,5a,12] as was observed. The characteristics of the
three classes of guests (Figure 2a–c), which are encapsulated
in DDDD-5, are detailed below (more extensive discussion is
in the Supporting Information); divisions between classes are
not sharp. We infer that non-encapsulated molecules (Fig-
ure 2d) are either too large or too hydrophilic to bind.
The first class of guests (Figure 2a) consists of the largest
molecules that can fit within the host cavity. None of these
guests was observed to saturate the available host population.
The addition of an excess (15–30 equivalents) of one of these
molecules to an aqueous solution of DDDD-5 resulted in the
appearance of a new set of 1H NMR resonances attributed to
the guest, although none of these molecules was sufficiently
water soluble to allow their 1H NMR spectra to be recorded in
D2O in the hostꢀs absence. Integration of the guest peaks
indicated approximately 18% encapsulation of cyclodode-
cane, and 45% of 1,3,5-triisopropylbenzene (Table S1 pro-
vides a complete list). DOSY measurements indicated that
the host and guests of this class diffused at rates comparable
to that of the free host (Table S2), and nuclear Overhauser
effect (nOe) cross peaks were observed between host and
guest signals.
Figure 2. Prospective guest molecules for host DDDD-5: a) larger
hydrophobic guests that bound weakly (slow exchange as determined
by NMR spectroscopy); b) medium-sized hydrophobic guests that
bound strongly (slow exchange as determined by NMR spectroscopy);
c) smaller guests for which fast exchange was observed; d) com-
pounds that were not encapsulated.
proton signals of these hydrophobic guests experienced an
upfield shift compared to the guestsꢀ chemical shifts in the
absence of host; this observation is consistent with what has
been observed in other cases of hydrophobic guest binding in
water.[2i,5c,6b,7]
The third class of guests (Figure 2c) are either small
(cyclopentane), water-soluble (dichlorvos), or both (ben-
zene), and exhibited fast exchange between their free and
encapsulated states as detected by 1H NMR and DOSY
experiments. NOe cross peaks indicated encapsulation of
these guest molecules. Further discussion of the cycloalkanes,
a representative set of guests in this class, is in the Supporting
Information (Figure S011).
The second class of guests consists of slightly smaller,
hydrophobic molecules (Figure 2b). These molecules appear
to be suitably sized for the void of DDDD-5, forming 1:1 host–
guest complexes. Only one species was observed in solution,
assigned to guestꢀDDDD-5. In DOSY spectra, guests of this
class were observed to diffuse at the same rate as the host
(Table S2); the observation of host–guest nOe cross peaks
lends further support for the inference of encapsulation. The
Host DDDD-5 interacted differentially with the two
1
enantiomers of limonene, as shown by the H NMR spectra
of Figure 3. The diastereomeric host–guest complexes (R)-
limoneneꢀDDDD-5 and (S)-limoneneꢀDDDD-5 enable dis-
tinction of both enantiomeric guests, thereby allowing the
host to be used as an encapsulative chiral-shift reagent. When
racemic limonene was used, both diastereomeric host–guest
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(DVMP, minor). In the presence of 1 mol% of DDDD-5, the
rate of hydrolysis of dichlorvos at pH 7 increased.
Control experiments involving the addition of 12 mol% of
2-formylpyridine, 6 mol% of (S,S)-4, 4 mol% of FeSO4, or
4 mol% of a mononuclear iron complex formed from 2-
formylpyridine and aniline to the buffered solution at pH 7
showed no acceleration of the rate of hydrolysis of dichlorvos
(Figures S013–S019). Similarly, acceleration of dichlorvos
hydrolysis was not observed in the presence of the tightly
binding hydrophobic guests cyclooctane or bibenzyl, which
we infer to have blocked the cavity of DDDD-5. The addition
of the slightly water-soluble guest 1-adamantylmethanol only
decreased the rate of DDDD-5-catalyzed dichlorvos hydrol-
ysis by a small degree (Figures S014 and S015). Although
dichlorvos is water soluble and observed to undergo rapid
exchange between bound and unbound states on the NMR
timescale, nOe cross peaks indicated the formation of a host–
guest complex (Figure S149). We infer that the hydrolysis
products DMP and DVMP most likely are not encapsulated
because in the NMR spectra their chemical shifts do not
change in the presence of DDDD-5 (Figures S017b and
S017c).
Possible mechanistic explanations for this catalytic accel-
eration include the involvement of the hydroxy groups in
a manner similar to those involved in CWA hydrolysis by
cylodextrins[14e] or to the recognition of the CWA Soman
recently demonstrated by Sambrook, Gale et al.[15] Polar-
ization of the encapsulated dichlorvos by the positively
charged cage molecule would also facilitate nucleophilic
attack at the phosphorus center. To our knowledge, this is the
first example of the use of a metal–organic capsule to increase
the rate of hydrolysis of an organophosphate.
Figure 3. 1H NMR spectra (500 MHz, D2O) of diastereomeric host–
guest complexes upon encapsulation of chiral guests in DDDD-5. Top:
(R)-limoneneꢀDDDD-5; middle: diastereomeric mixture (R)-limone-
neꢀDDDD-5 and (S)-limoneneꢀDDDD-5; bottom: (S)-limone-
neꢀDDDD-5.
complexes were detected by 1H NMR spectroscopy, but
preferential encapsulation of one enantiomer over the other
was not observed at 298 K or 278 K.
Since DDDD-5 has a large cavity in combination with
flexible glyceryl groups that surround the pores on the faces
of the tetrahedral [M4L6] capsule, we were not surprised to
observe fast exchange with small organic guests for which
a smaller rigid [M4L6] capsule would appear to be more
suitable.[7] Even large, slowly exchanging guests were
observed to be fully encapsulated after less than one hour.
We infer the flexible glyceryl substituents to allow DDDD-5
both to dynamically open its pores and to adapt the volume of
its void to the size of the encapsulated guest, thus enabling the
binding of guests too large for optimal encapsulation in
accordance with the 55% rule.[13]
Organophosphates are widely used as pesticides and
CWAs and much effort has been devoted to the investigation
of new methods of hydrolysis of organophosphates to less
toxic compounds.[14] As shown in Figure 4, DDDD-5 acts as
a catalyst in the hydrolysis of the pesticide and CWA simulant
dichlorvos, generating the products dimethyl phosphoric acid
(DMP, major) and dichlorovinylmethyl phosphoric acid
In conclusion, we have prepared the new enantiopure
cage molecules DDDD-5 and LLLL-5 by subcomponent self-
assembly. Considering that the chiral centers are remote from
the metal corners, the formation of a single cage diastereomer
is remarkable. Cage DDDD-5 was observed to bind a wide
range of organic guests, enabling distinction between the
enantiomers of a chiral organic guest. Host DDDD-5 also
served as a catalyst for the hydrolysis of the neurotoxic
organophosphate dichlorvos. In future work we will explore
the enantioselective encapsulation of chiral guests and inves-
tigate the binding and hydrolysis of other organophosphates
with DDDD-5 and its analogues.
Received: March 13, 2013
Published online: June 20, 2013
Keywords: chirality · host–guest systems · organophosphates ·
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self-assembly · supramolecular chemistry
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