Buffering heavy metal ions with photoactive CrownCast cages

Article abstract of DOI:10.1002/ejic.201000673

Historically, caged compounds have been used to interrogate the biological activity of organic molecules by using light; however, R. Tsien and others have developed methodologies over the last three decades for using nitrobenzyl-derived caged complexes to

Full text of DOI:10.1002/ejic.201000673

FULL PAPER
DOI: 10.1002/ejic.201000673
Buffering Heavy Metal Ions with Photoactive CrownCast Cages
Hannah W. Mbatia,[a] Daniel P. Kennedy,[a] Casey E. Camire,[a] Christopher D. Incarvito,[b]
and Shawn C. Burdette*[a]
Keywords: Caged Compounds / Macrocycles / Fluorescent probes / Mercury / Lead
Historically, caged compounds have been used to interrogate
the biological activity of organic molecules by using light;
however, R. Tsien and others have developed methodologies
over the last three decades for using nitrobenzyl-derived
caged complexes to study the signaling behavior of Ca2+. A
series of cation-selective N-phenyl-azamacrocyclic receptors
integrated with a 4,5-dimethoxy-2-nitrobenzyl (DMNB) pho-
toactive group act as cages for divalent metal ions. The un-
caging mechanism of these complexes involves a photoreac-
tion that converts the nitrobenzhydrol, which is para to the
Mg2+. CrownCast-2 (5) is derived from the Hg2+-selective
10-phenyl-1,4-dioxa-7,13-dithia-10-azacyclopentadecane
(AT215C5, 4) receptor. Aqueous binding studies demonstrate
that CrownCast-2 binds tightly to Hg2+, but the strong sulfur–
mercury interactions in the complex mitigate the release of
the metal ion upon photolysis. Based on previous reports of
metal selectivity, CrownCast-3 (7), which possesses a 16-phen-
yl-1,4,7,10,13-pentaoxa-16-azacyclooctadecane (A18C6, 6)
receptor, was designed to act as a Pb2+ cage. Initial spectro-
scopic investigations suggest the uncaged ligand binds Pb2+
aniline nitrogen atom, into the corresponding nitrosobenzo- with higher affinity than the parent cage. To address this un-
phenone. Resonance delocalization of the aniline into the
distal carbonyl group of the photoproduct attenuates the
ability of the nitrogen atom to interact with the guest. Crown-
expected observation, a turn-on fluorescence sensor for Pb2+
that couples the A18C6 ligand with a 4,4-difluoro-4-bora-
3a,4a-diaza-s-indacene (BODIPY) fluorophore was synthe-
Cast-1 (3) utilizes a 13-phenyl-1,4,7,10-tetraoxa-13-azacyclo- sized. In contrast to the titration data, photolysis of
pentadecane (A15C5, 2) receptor. Binding studies with
CrownCast-1 revealed a modest selectivity for Ca2+; how-
ever, differences in the measured binding affinity upon
photolysis suggest that CrownCast-1 is better suited to cage
[Pb(CrownCast-3)]2+ in the presence of PbSensor-1 (16) dem-
onstrates that the uncaged ligand, CrownUnc-3 (15), binds
Pb2+ with a lower affinity than the caged o-nitrobenzhydrol
macrocycle.
Introduction
In an analogous manner, two different strategies have been
developed for releasing metal ions photochemically by
using nitrobenzyl-based chelators. The first strategy uses
photoinduced uncaging to initiate a carbon–heteroatom
bond-cleavage reaction that fragments a multidentate li-
gand.[11] The uncaging event increases free metal ion con-
centrations through the reduction of chelate effects. Alter-
natively, the uncaging reaction can introduce a carbonyl
group para to a metal-bound aniline atom.[12] After photol-
ysis, the aniline nitrogen lone pair becomes resonance-delo-
calized onto the carbonyl group, which decreases the inter-
action between the metal ion and the nitrogen atom (Fig-
ure 1). By decreasing the bonding interaction, the binding
affinity of the uncaged chelator is reduced. This strategy
was initially developed by Tsien and co-workers to investi-
gate Ca2+ signaling,[13] and recently expanded to cage Zn2+
and other metal ions.[14–16] All the caged complexes utilizing
the attenuation of aniline ligand interactions consist of the
receptor incorporated into a nitrobenzhydrol caging scaf-
fold. We have coined the term Cast as a shorthand no-
menclature for the nitrobenzhydrol class of cages since it is
evocative of the casting out of the metal ion upon exposure
to light.
The first use of nitrobenzyl protecting groups to mask
the functions of phosphates was reported over 30 years
ago.[1,2] Subsequently, nitrobenzyl functionalities have be-
come a powerful technique to interrogate the functions of
amino acids,[3] proteins,[4] nucleotides,[5,6] and steroids in
biological systems.[7] These tools are commonly referred to
as cages because of their ability to prevent bioactive mole-
cules from engaging in normal functions until they are re-
leased by using light.[8–10] Since very few biological events
in animals are driven by light, nitrobenzyl cages provide a
convenient methodology to control the introduction of spe-
cies into model systems with minimal interference.
[a] Department of Chemistry, University of Connecticut,
55 North Eagleville Road, Storrs, CT 06269-3060, USA
Fax: +1-860-486-2981
E-mail: shawn.burdette@uconn.edu
[b] Department of Chemistry, Yale University,
225 Prospect Street, P. O. Box 208107, New Haven, CT 06520-
8107, USA
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejic.201000673.
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S. C. Burdette et al.
FULL PAPER
Figure 1. Uncaging action of Cast cages. Resonance delocalization of the anilino lone pair onto the carbonyl oxygen atom reduces the
interaction between the nitrogen atom and the metal ion, which lowers the binding affinity.
Macrocyclic crown ethers are among the most recogniz-
able receptors for metal ions; numerous sensors and molec-
Results and Discussion
ular devices exploit the unique properties of these li-
New Synthetic Methodologies Applied to the Synthesis of
CrownCast-1
gands.[17–23] Initially, we designed a cage that utilized a 13-
phenyl-1,4,7,10-tetraoxa-13-azacyclopentadecane receptor
(A15C5, 2) to develop new synthetic strategies for preparing
In a preliminary communication, we described three syn-
Cast ligands.[15] The crown ether macrocycle was chosen as thetic routes to CrownCast-1.[15] The first utilizes the tri-
a surrogate for other ligands that could potentially be in- methylsilyl trifluoromethanesulfonate (TMSOTf) assisted
compatible with some of the synthetic manipulations being electrophilic aromatic substitution reaction pioneered by
screened. During these studies, we discovered that the Tsien and Zucker (Scheme 1, Entry A).[12] According to the
change in binding affinity between the caged and uncaged reported procedures, CrownCast-1 was prepared in 33%
version of the CrownCast-1 (3) for certain divalent metal yield after the removal of the TMS group and purification.
ions was almost an order of magnitude larger than that In our related work with ZinCast cages,[14] we found that
measured for glycol-bis(2-aminoethylether)-N,N,NЈ,NЈ-tet- these methodologies were incompatible with some func-
raacetic acid (EGTA) based nitrobenzhydrol cages for Ca2+
.
tional groups, so alternative synthetic procedures for ac-
The name CrownCast incorporates the Cast nomenclature cessing Cast cages were explored. The first alternative in-
with a descriptor of the receptor. Although A15C5 does not volves the assembly of a benzophenone scaffold, followed
preferentially interact with any particular metal ion, other by reduction to the benzhydrol structure of CrownCast-1
macrocyclic ligands can more effectively discriminate be- (Scheme 2A). This strategy works well with ZinCast-1, but
tween different guests based on the composition of the do- the yield of the reduction step in the presence of the A15C5
–
nor groups and the size of the cleft. Coupling of a more ligand is low, presumably because the reactivity of the BH4
selective receptor with the uncaging behavior of the Crown- anion is attenuated by binding of the sodium cation to the
Cast system could therefore provide new caged complexes macrocycle. The final approach involves two successive Pd-
for biologically and environmentally important metal ions catalyzed cross-coupling reactions[24,25] to provide Crown-
like Hg2+ and Pb2+
.
Cast-1 in 72% yield in four steps (Scheme 2B). The number
Scheme 1. Synthesis of CrownCast cages.
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Buffering Heavy Metal Ions with Photoactive CrownCast Cages
Scheme 2. New synthetic methodologies applied to the synthesis of CrownCast-1.
of steps in this route can be reduced to three by direct iodin- an A18C6 receptor could therefore act as a cage for Pb2+
.
ation of the aniline ring instead of bromination followed by Both Hg2+ and Pb2+ participate in deleterious interactions
a lithium/halogen exchange to introduce the iodine substit- with biomolecules,[41] and tools such as cages have the po-
uent. Whereas the one-step TMSOTf reaction remains the tential to provide insight into the mechanisms of these pro-
method of choice to prepare Cast cages, the Pd methodolo- cesses.
gies provide a practical alternative when this method cannot
be used to access the desired structures.
CrownCast-2 (5) and CrownCast-3 (7) were prepared in
good yields by using the TMSOTf route (Scheme 1, En-
tries B and C). The Pd cross-coupling methodologies were
not screened for CrownCast-2 owing to the possibility of
catalyst poisoning by the thioether groups. In addition, the
Design and Synthesis of CrownCast-2 and CrownCast-3
Replacement of the ether oxygen atoms in the 7- and 13- benzophenone route also proved impractical for preparing
positions of A15C5 with thioethers provides the ligand CrownCast-2 since poly(phosphoric acid) causes decompo-
10-phenyl-1,4-dioxa-7,13-dithia-10-azacyclopentadecane sition of the thioethers. Although the alternative methods
(AT215C5, 4). Several fluorescent sensors that are selective were incompatible with the AT215C5 ligand, performing a
for Hg2+ have been constructed by using this recep- dilute version of the TMSOTf reaction (0.01  instead of
tor.[20,21,26–38] The selectivity derives primarily from favor- 0.2 ), by using 2,6-lutidine as the base, and delivering the
able sulfur–mercury interactions. In a manner analogous to TMSOTf in small portions during the course of the reac-
our design rational of FerriCast for Fe3+ [16]
we reasoned tion, the CrownCast-2 TMS ether was obtained in higher
,
that the established selectivity of the AT215C5 receptor in yields than when applying the originally reported pro-
sensors would translate into a caged complex for Hg2+. In cedures. Yields of CrownCast-3 were also higher by using
addition to heteroatom substitution, expansion of the these customized procedures. The modifications appear to
A15C5 ring by one ethylene glycol unit provides the corre- reduce the formation of malachite green like byproducts,[42]
sponding 16-phenyl-1,4,7,10,13-pentaoxa-16-azacycloocta- which are responsible for reduced yields of the desired
decane (A18C6, 6) ligand. In the parent crown ethers, 15- products. The intermediate TMS ether precursor was con-
crown-5 has a slight preference for Na+ over K+, whereas verted into the desired benzhydrol upon treatment with F–.
18-crown-6 has the opposite selectivity.[39,40] In the corre- KF can be used as the source of F– instead of tetrabutylam-
sponding N-aryl-azamacrocycles, A18C6 has some prefer- monium fluoride (TBAF) in the deprotection of Crown-
ence for Pb2+ [20]
size of the binding cavity. A CrownCast ligand containing catalyst.
,
a large divalent metal ion, based on the Cast-3 since the A18C6 receptor can act as a phase-transfer
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S. C. Burdette et al.
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Uncaging Mechanism of CrownCast Cages
In the presence of metal ions, the quantum yields of all
the CrownCast ligands increase slightly (Table 1), a typical
property of this class of ligands.[15,46] The metal ions
screened correspond to those of the desired applications;
therefore, Hg2+ was selected for CrownCast-2 and Pb2+ for
CrownCast-3. Photolysis was carried out by using concen-
trations of M2+ in which binding to the corresponding pho-
toproducts would be negligible, therefore allowing for direct
spectrophotometric measurements of CrownUnc concen-
trations over the course of the photolysis. The limitation in
using low-intensity illumination is the slow photolysis with
a half-life of several hours. Typically, caged complexes are
employed in biological investigations by using flash photol-
ysis techniques.[47] The flash techniques expose samples to
a high number of photons on very short time scales. Future
studies will address the photochemical properties of these
and other related compounds with flash techniques.
The exposure of the CrownCast ligands to light initiates
a Norrish type II photoreaction that converts the benzhyd-
rol into the corresponding benzophenone (Scheme 3).[43–45]
The conversion of the cage into the uncaged form can be
quantified by monitoring the changes in the λmax value of
the CrownCast and CrownUnc (the uncaged, benzophe-
none version of the Cast ligands) that appear at λ = 270
and 350 nm, respectively. The CrownUnc benzophenone
molecules absorb with higher extinction coefficients owing
to the more conjugated aromatic backbone. In CH3CN
solution, by using λ = 350 nm with a 150 W source, the
quantum yields of CrownCast-2 and CrownCast-3 were de-
termined to be 3.4 and 1.7%, respectively (Table 1). Each
CrownUnc was prepared in bulk by photolysis of the corre-
sponding CrownCast to obtain the precise extinction coeffi-
cients of both the caged and uncaged ligand, which allows
accurate measurements of the quantum yields by using
spectrophotometric techniques. The quantum yields ob- Metal-Binding Properties of CrownCast-1 and -3
tained for the two new apo-CrownCast ligands are compar-
The interaction between the CrownCast cages with
able to both CrownCast-1 and other related nitrobenzhyd-
various divalent cations was assessed spectrophotometri-
rol derived cages.[15,46]
cally in CH3CN (Table 2). Monitoring of the disappearance
of the aniline-derived absorption band at λ ≈ 270 nm allows
the metal ion affinity of the cages to be quantified (Fig-
ure 2). In an analogous manner, the metal ion binding in-
duced erosion of the charge-transfer band at λ ≈ 350 nm in
the CrownUnc derivatives allows the binding strength to be
addressed.
In addition to the previously studied alkali earth metal
ions Zn2+ and Cd2+ [15]
the interaction between CrownCast-
,
1 with Hg2+ and Pb2+ was also investigated. Whereas the
affinity for the heavy metals for the cage is similar in magni-
tude to that of Ca2+, the change upon uncaging is signifi-
cantly smaller than with the harder cations. While best de-
scribed as a cage for Mg2+ in CH3CN owing to the ∆Kd Ͼ
200, the measurements indicate that CrownCast-1 behaves
as a cage for all the divalent metal ions tested except Pb2+
,
in which ∆Kd Ͻ 1. A ∆Kd value of Ͻ 1 suggests the
CrownUnc-1 binds more tightly than the caged ligand;
however, two mitigating factors should be considered when
interpreting this data. First, the spectrophotometric assay
relies on the interaction between the aniline nitrogen atom
and the metal ion guest. Whereas uncaging decreases the
electron density on the nitrogen atom that weakens the do-
nor ability, the unchanged crown ether ligand can still coor-
dinate the metal ion. A softer Pb2+ ion in the receptor after
uncaging may interact with the aniline nitrogen atom more
readily than harder alkali earth metal ions. Second, the ab-
sorption of the CrownCast at λ = 270 nm appears to be a
complicated feature, or combination of transitions, whereas
the λ ≈ 350 nm peak of the CrownUnc appears to be a well-
behaved charge-transfer band associated with the benzo-
phenone. These two factors may lead to deviation from ex-
pected spectroscopic behavior when the binding strength
does not change significantly upon uncaging.
Scheme 3. Synthesis of CrownUnc ligands.
Table 1. Quantum yields of photolysis for CrownCast ligands and
their corresponding metal complexes in CH3CN (25 µ) by using
a 150 W Xe source at λ = 350 nm.
Compound/complex
ε [cm–1–1]
(λ = 350 nm)
φphotolysis [%] Efficiency φϫε
CrownCast-1
CrownCast-2
CrownCast-3
5300
5000
7200
5300
5300
5000
5700
7200
0.5Ϯ0.2
3.4Ϯ0.2
1.7Ϯ0.1
0.7Ϯ0.2
1.6Ϯ0.6
4.2Ϯ0.2
3.2Ϯ0.7
4.0Ϯ0.1
27
169
121
37
[Ca(CrownCast-1)]2+[a]
[Zn(CrownCast-1)]2+[b]
[Hg(CrownCast-2)]2+[c]
[Hg(CrownCast-3)]2+[c]
[Pb(CrownCast-3)]2+[d]
85
208
187
291
[a] [Ca(ClO4)2] = 125 µ (5.0 equiv.). [b] [Zn(ClO4)2] = 1.25 m
(50 equiv.). [c] [Hg(ClO4)2] = 25 µ (1.0 equiv.). [d] [Pb(ClO4)2] =
25 µ (1.0 equiv.). The CrownCast was saturated, but binding to
the corresponding CrownUnc was negligible.
The metal-binding properties of CrownCast-3 with the
heavier metal ions are similar to those observed in Crown-
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Buffering Heavy Metal Ions with Photoactive CrownCast Cages
Table 2. Dissociation constants [µ] of CrownCast cages and CrownUnc photoproducts with metal perchlorates in CH3CN.[a]
Mn+ rion [Å][b]
CrownCast-1
Uncaged
CrownCast-2
Uncaged
CrownCast-3
Uncaged
Caged
∆Kd
Caged
∆Kd
Caged
∆Kd
Na+
K+
1.02
1.38
0.72
1.00
1.18
1.35
0.74
0.95
1.19
1.19
1330Ϯ10
3500Ϯ100
64Ϯ7
14Ϯ2
48Ϯ1
79Ϯ3
161Ϯ8
68Ϯ1
8.1Ϯ0.1
10.8Ϯ0.3
NB[c]
NB
13100Ϯ700
600Ϯ100
2200Ϯ200
3100Ϯ100
NB
NB
23Ϯ3
8.4Ϯ0.1
NA[d]
NA
205
43
46
39
NA
NA
2.8
NB
NB
NB
NB
NB
NB
NB
NB
NB
NB
NB
NB
NA
NA
NA
NA
NA
NA
NA
NA
1.5
168Ϯ4
178Ϯ1
2050Ϯ80
11.6Ϯ0.1
9.78Ϯ0.07
12.4Ϯ0.6
198Ϯ5
57.7Ϯ0.9
6.8Ϯ0.3
11.3Ϯ0.3
NB
NB
1550Ϯ50
8.8Ϯ0.3
6.68Ϯ0.06
7.80Ϯ5
NB
165Ϯ2
15.3Ϯ0.1
7.4Ϯ0.1
NA
NA
1.3
0.76
0.68
0.63
NA
2.9
Mg2+
Ca2+
Sr2+
Ba2+
Zn2+
Cd2+
Hg2+
Pb2+
1200Ϯ200
520Ϯ50
6.9Ϯ0.3
25Ϯ5
NB
NB
10.4Ϯ0.5
1630Ϯ30
2.3
0.65
0.78
65
[a] The 1:1 M/L binding constants were calculated with XLfit. [b] Ionic radii are for coordination number = 6. [c] No binding observed
(NB): Metal binding was not observed when the ligand was exposed to Ͼ5000 equiv. of M2+. [d] Not applicable (NA): The value for
∆Kd could not be accurately assessed, because no value for the Kd required to do the calculation was available.
sensors.[19,50,51] The selectivity of PbSensor-1 was tested by
recording the fluorescence output of the sensor in the pres-
ence of various cations (Figure 3). Of all the species
screened only Sr2+, Ba2+, and Hg2+ illicit a response from
the sensor. These competing species also interact strongly
with CrownCast-3. An additional increase in emission is
observed when excess Pb2+ is introduced into the solution
containing competing metal ions. With the exception of the
slight preference for Pb2+, PbSensor-1 behaves identically
to the analogous BODIPY sensors that utilize the A15C5
macrocycle instead of A18C6.[50,51]
Figure 2. Titration of 25 µ CrownCast-3 with Pb(ClO4)2 in
CH3CN. The excess absorbance at λ = 270 nm was fitted to a 1:1
binding isotherm (inset). The error bars represent the variance in
the measurements over three trials.
Cast-1, including the ∆Kd Ͻ 1 for Pb2+. Unexpectedly, how-
ever, the alkali earth metal ions also exhibited ∆Kd Ͻ 1. To
further probe the metal-ion binding properties of Crown-
Cast-3, the A18C6 receptor was integrated with a BODIPY
fluorophore to generate a novel turn-on fluorescent sensor
for Pb2+ (17, PbSensor-1). Similar fluorescent sensors based
on macrocyclic ligands have been reported,[45] and we have
shown that uncaging a metal ion using a fluorescent probe
as a competitive ligand provides an independent demon-
Scheme 4. Synthesis of PbSensor-1.
stration of analyte release.[14,16,48]
PbSensor-1 (17) was prepared by converting compound
6 into the corresponding aldehyde followed by assembly of
Photolysis of 12 µ [Pb(CrownCast-3)]2+ in the presence
the BODIPY sensor with the standard multi-step, one-pot of 1.0 µ PbSensor-1 at λ = 350 nm with a 150 W source
procedure (Scheme 4).[49] Metal ion binding to the A18C6 resulted in an increase in the measured fluorescence output
receptor of PbSensor-1 interrupts a charge transfer between (Figure 4). Emission enhancements observed during the
the aniline moiety and the BODIPY fluorophore. photolysis indicated the in situ formation of the
PbSensor-1 exhibits a 1600-fold enhancement in the inte- [Pb(PbSensor-1)]2+ complex, which has a Kd value of
grated fluorescence intensity when titrated with Pb2+ in 0.93Ϯ0.01 µ. Absorbance measurements during the pho-
CH3CN. PbSensor-1 (λmax = 496 nm, ε = 88000 cm–1 –1) tolysis indicate the formation of the apo-photoproduct
is essentially nonfluorescent (φ ≈ 0), whereas [Pb(PbSensor- CrownUnc-3 at λ = 350 nm. This fluorescence assay indi-
1)]2+ (λmax = 499 nm, ε = 89,000 cm–1 –1) has an emission cates that the introduction of the carbonyl group in
quantum yield of 0.74. Although heavy metal ions usually CrownUnc-3 does weaken the A18C6 receptor’s affinity for
quench fluorescence, the decoupling of the aniline donor Pb2+ compared to CrownCast-3, although the decrease can-
and the BODIPY fluorophore provided unique turn-on not be quantified accurately by absorption spectroscopy.
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Figure 3. Fluorescence selectivity of PbSensor-1 (17) with 1.0 equiv. of M (gray bars) and 1.0 equiv. Mn+ + 10 equiv. Pb2+ (black bars).
The assay was carried out with 1.0 µ PbSensor in CH3CN, λex = 470 nm, λem = 480–650 nm.
ca. 2.4 Å, whereas the Hg–N distances are ca. 0.15 Å
longer, which is consistent with the thiophilic nature of
Hg2+. A stable dithioether–Hg2+ adduct, which is held in
proximity to weaker ligands by the macrocyclic ligand,
provides the most likely explanation for the modest ∆Kd
value. We hypothesize that the thioether ligands force the
interaction between the aniline nitrogen atom and the
Hg2+ ion in CrownCast-2; therfore, uncaging does not sig-
nificantly change the stability of the CrownUnc-2 com-
plex.
Whereas neither CrownCast-1 nor CrownCast-3 bind
any of the metal ions screened in aqueous solution, the
AT215C5 receptor of CrownCast-2 binds Hg2+ in water. Al-
though the binding is weaker and an organic cosolvent is
required to maintain solubility of the ligand, CrownCast-2
behaves as an Hg2+ cage in aqueous solution (20 m
HEPES, 20% EtOH, pH = 7). The Kd value of the caged
ligand is 15.3Ϯ0.5 µ, and that of the uncaged ligand is
430Ϯ2 µ, which gives a ∆Kd value of 28. None of the
other divalent metal ions screened interfere with Hg2+ bind-
ing and the quantum yields remains constant {CrownCast-
2: φ = 2.9%; [Hg(CrownCast-2)]2+: φ = 3.3%}.
Figure 4. Photolysis of 25 µ CrownCast-3, 12 µ Pb(ClO4)2, and
1.0 µ PbSensor-1 (16) in CH3CN with a 150 W source. The solu-
tion was photolyzed at λphotolysis = 350 nm, and the sensor excited
at λex = 470 nm (slit widths = 5.0 nm). The solution was equili-
brated at 23 °C for 0.5 h prior to photolysis. The absorbance spec-
tra are represented as thick lines with absorption features centered
at λ ≈ 270 and 350 nm and the emission spectra as thin lines with
a λmax ≈ 500 nm.
Hg2+ Binding Properties of CrownCast-2
In CrownCast-2, the oxygen atoms closest to the aniline
Titrations were performed in buffered solutions at pH =
group are substituted for softer sulfur donors. As a result, 7;[32,35] however, m concentrations of K+ and Na+ inter-
minimal spectrophotometric changes in the spectrum of fere with the accurate measuring of the Hg2+-induced
CrownCast-2 were observed upon saturation of the changes in the absorption spectrum. Since both K+ and
AT215C5 receptor with Ͼ5000 equiv. of various alkaline Na+ are abundant in biological systems, the practical appli-
earth metal ions. The thioether ligands clearly provide the cations of CrownCast-2 may be limited. Whereas others
AT215C5 receptor with a strong preference for heavy metal have demonstrated Hg2+ binding to AT215C5 in buffered
ions over alkali and alkaline earth metal ions, although solution, none of the experiments were carried out under
Pb2+ exhibits a ∆Kd Ͻ 1 like CrownCast-1 and CrownCast- simulated physiological conditions of constant ionic
3. Unexpectedly, the ∆Kd of CrownCast-2 upon uncaging strength. Independent measurement of Na+ and K+ binding
of Hg2+ is quite small (≈ 2). To further elucidate the revealed that both interact very weakly with the macrocycle
origins of the modest ∆Kd values, we analyzed the Hg2+ ligand. Protonation of the aniline nitrogen atom could also
complex of AT215C5 by X-ray crystallography. The interfere with metal ion binding in aqueous solution; how-
[Hg(AT215C5)](ClO4)2 structure serves as a model for the ever, the anilino nitrogen atom in related macrocyclic Cast
[Hg(CrownCast-2)]2+ complex formed during the binding cages has a pKa Ͻ 4, which is consistent with measurements
studies. The complex reveals that both Hg–S distances are in similar systems.[52–55]
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Buffering Heavy Metal Ions with Photoactive CrownCast Cages
were visualized with λ = 254 and 365 nm light and I2 or Br2 vapor.
1H and 13C NMR spectra were recorded with a Bruker 400 MHz
NMR instrument, and chemical shifts are reported in ppm on the
Conclusion
Three members of the CrownCast family of metal ion
cages and the respective photoproducts have been synthe- δ scale relative to tetramethylsilane. IR spectra were recorded with
a Nicolet 205 FT-IR instrument, and the samples were prepared
as KBr pellets. High-resolution mass spectra were recorded at the
University of Connecticut mass spectrometry facility with a micro-
mass Q-Tof-2TM mass spectrometer operating in positive ion mode.
The instrument was calibrated with Glu-fibrinopeptide B 10 pmol/
µL by using a 50:50 solution of CH3CN/H2O with 0.1% acetic
acid. The compounds 13-phenyl-1,4,7,10-tetraoxa-13-azacyclopen-
tadecane (A15C5, 2),[56] 10-phenyl-1,4-dioxa-7,13-dithia-10-azacy-
clopentadecane (AT215C5, 4),[57] 16-phenyl-1,4,7,10,13-pentaoxa-
16-azacyclooctadecane (A18C6, 6),[58] [4-(1,4,7,10-tetraoxa-13-aza-
sized and characterized. Metal ion binding affinity and
selectivity of the caged ligands is analogous to trends ob-
served in unrelated chelators utilizing the same receptors.
The basis of the selectivity and affinity depends on the
match between the diameter of the metal cation and the
size of the macrocyclic cavity. In addition, expected trends
in hard–soft acid–base behavior are observed. Whereas the
decrease in binding affinity upon uncaging reflects the de-
creased electron density on the aniline nitrogen atom, the
nature of the other ligands greatly influences the magnitude cyclopentadecane)phenyl]-(4,5-dimethoxy-2-nitrophenyl)-methanol
(CrownCast-1, 3),[15] and [4-(1,4,7,10-tetraoxa-13-azacyclopenta-
of the change. In CrownCast-2 (Figure 5) for example, the
decane)phenyl]-(4,5-dimethoxy-2-nitrosophenyl)-methanone
two thioether ligands enhance the selectivity of the cage for
(CrownUnc-1, 13)[15] were prepared as previously described.
Hg2+, but also stabilize the metal complex sufficiently to
force an interaction with the aniline nitrogen atom after un- (4,5-Dimethoxy-2-nitrophenyl)[4-(4,7-dioxa-1,10-dithia-13-azacyclo-
caging. Thus, the ∆Kd value of CrownCast-2 with Hg2+ is
octadec-13-yl)phenyl]methanol (5, CrownCast-2): 2,6-Di-tert-butyl-
4-methylpyridine (158 mg, 0.768 mmol) and TMSOTf (118 µL,
0.650 mmol) were added, in one portion, to a solution of 4 (164 mg,
0.500 mmol) and ortho-nitroveratraldehyde (1) (161 mg,
0.650 mmol) in CH2Cl2 (3.0 mL). The resulting dark blue/green
low, which could limit its potential applications as a cage.
The examination of X-ray structures with model ligands
supports this hypothesis. Although none of the macrocycles
prove ideal for aqueous applications, the analysis of the
solution was stirred at 23 °C for 16 h. The solution was diluted with
data gathered in this study will assist in the design of future
CH2Cl2 (50 mL), washed with brine (50 mL), dried with MgSO4,
caged complexes. The construction of cages suitable for in-
filtered, and the solvents were evaporated to dryness. Flash
vestigating the detrimental biological activity of Hg2+ and
chromatography on silica with EtOAc/petroleum ether (1:1) af-
forded 74 mg (24%) of the TMS ether as a yellow foam (Rf = 0.31).
Pb2+ is ongoing.
The TMS ether was dissolved in CH2Cl2 (3.0 mL), and TBAF (1 )
in THF (850 µL, 0.85 mmol) was added with stirring over 5 min.
Flash chromatography on silica with EtOAc/petroleum ether (1:1)
furnished 5 as yellow foam (60 mg, 92%). Rf = 0.20 (silica; EtOAc/
1
petroleum ether, 1:1). H NMR (400 MHz, CDCl3): δ = 7.64 (s, 1
H, phenyl H), 7.54 (s, 1 H, phenyl H), 7.19 (dd, J = 8 Hz, 2 H,
phenyl H), 6.60 (dd, J = 8 Hz, 2 H, phenyl H), 6.50 (s, 1 H, OH),
4.01 (s, 3 H), 3.96 (s, 3 H), 3.83 (m, 4 H), 3.64 (m, 8 H), 2.88 (m,
4 H), 2.72 (m, 4 H), 2.49 (s, 1 H) ppm. 13C NMR (100 MHz): δ =
153.6,147.9, 146.8, 140.2, 135.0, 129.8, 128.7, 111.8, 110.3, 108.4,
74.5, 71.6, 71.0, 56.7, 56.6, 52.1, 31.4, 29.7 ppm. IR (thin film): ν
˜
= 3474, 2915, 2886, 2858, 1606, 1512 (νas NO2), 1266 (νs NO2)
cm–1. HRMS (ESI+): calcd. for MNa+ 561.1705; found 561.1719.
(4,5-Dimethoxy-2-nitrophenyl)[4-(1,4,7,10,13-pentaoxa-16-azacyclo-
octadec-16-yl)phenyl]methanol (7, CrownCast-3): Compound 6
(554 mg, 1.00 mmol) in CH2Cl2 (100 mL) was added to a mixture
of ortho-nitroveratraldehyde (1) (448 mg, 1.30 mmol) and 2,6-luti-
dine (284 µL, 1.50 mmol). TMSOTf (385 µL, 1.30 mmol) was
added dropwise to the resulting solution at 23 °C. The reaction
mixture was stirred for 1 h, before the addition of fresh aliquots of
TMSOTf (385 µL, 1.30 mmol) and 2,6-lutidine (284 µL,
1.50 mmol). The mixture was stirred for a further 5 h. The reaction
was quenched with water (100 mL), the organic phase isolated, and
the aqueous phase extracted with CH2Cl2 (50 mL, ϫ3). The or-
ganic fractions were pooled and concentrated to dryness. CH3CN
(5.0 mL) and KF (473 mg, 5.00 mmol) dissolved in a minimal
amount of water (ca. 1 mL) were added to the residue. The reaction
mixture was stirred for 12 h, concentrated to dryness, and the resi-
due was dissolved in water (50 mL). The aqueous mixture was ex-
tracted with CH2Cl2 (50 mL, ϫ 3), the organic fractions were
pooled, dried with an excess of MgSO4, and filtered by gravity. The
filtrate was dried under vacuum and subjected to flash chromatog-
raphy on basic alumina with neat EtOAc to furnish 7 as a yellow
oil (538 mg, 60.1 %). Rf = 0.22 (alumina; EtOAc). 1H NMR
Figure 5. ORTEP diagram of the CrownCast-2 model complex
[Hg(AT215C5)(ClO4)](ClO4) showing 50% thermal ellipsoids. Hy-
drogen atoms and disordered, noncoordinating perchlorate anions
are omitted for clarity.
Experimental Section
General Procedures: All the materials were of research grade or
spectro-grade in the highest purity commercially available from
Acros Organics or TCI America. Dichloromethane, toluene, and
thf were sparged with argon and dried by passage through a Seca
Solvent Purification System. All chromatography and TLC were
performed on silica (230–400 mesh) from Silicycle unless otherwise
specified. Activated basic alumina (ca. 150 mesh) was obtained
from Acros Organics. TLC plates were developed with mixtures of
EtOAc/hexanes or CH2Cl2/methanol unless otherwise specified and
Eur. J. Inorg. Chem. 2010, 5069–5078
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5075

S. C. Burdette et al.
FULL PAPER
(400 MHz, CDCl3): δ = 7.64 (s, 1 H, phenyl H), 7.54 (s, 1 H, phenyl were added. The resulting red solution was stirred at 23 °C for 2 h.
H), 7.14 (dd, J = 8 Hz, 2 H, phenyl H), 6.62 (dd, J = 8 Hz, 2 H, TLC analysis indicated formation of the corresponding dipyrrome-
phenyl H), 6.48 (s, 1 H, phenyl H), 4.19 (s, 3 H, OCH3), 3.97 (s, 3
thane (Rf = 0.20; silica; 5% CH3OH/CH2Cl2). Then 2,3-dichloro-
H, OCH3), 3.67 (m, 24 H, OCH2), 2.48 (s, 1 H, OH) ppm. 13C 5,6-dicyanoquinone (ddq; 688 mg, 3.03 mmol, 1.10 equiv.) was
NMR (100 MHz): δ = 153.5, 147.9, 147.8, 140.0, 135.1, 129.5, added causing the immediate formation of a dark purple solution.
128.5, 111.6, 110.4, 108.3, 71.6, 71.0, 71.0, 70.9, 68.9, 56.6, 56.6,
After 1 h, TLC analysis indicated formation of the dipyrrin (Rf ≈
0). Hünig’s base (6.0 mL, 34.4 mmol) was slowly added to the solu-
tion, and small amounts of a highly colored solid precipitated from
the solution. BF3·OEt2 (6.0 mL, 47.3 mmol) was added dropwise
to the mixture. After 3 h, the mixture was analyzed by TLC, and
the desired BODIPY compound was observed as an orange-col-
ored spot (Rf = 0.5). The solution was washed with brine (100 mL),
the biphasic mixture filtered by vacuum, the organic phase isolated,
dried with an excess of MgSO4, filtered, and the filtrate concen-
trated to dryness. The residue was adsorbed onto a minimal
amount of silica and firstly subjected to flash chromatography on
silica (50 g) with a gradient of 0–5% CH3OH/CH2Cl2, before
chromatography on a plug of basic alumina with a gradient of 0–
2% CH3OH in CH2Cl2 provided a nearly pure compound. The
isolated compound was recrystallized from boiling CH3OH
(30 mL) to furnish the desired compound as a bright orange crys-
talline solid (90 mg, 5.6%). M.p. Ͼ 260 °C (decomp.) 1H NMR
(400 MHz, CDCl3): δ = 7.01 (dd, J = 8 Hz, 2 H, aromatic H), 6.75
(dd, J = 8 Hz, 2 H, aromatic H), 5.96 (s, 2 H, 2,6-H BODIPY),
3.74 [t, J = 8.0 Hz, 4 H, N(CH2CH2)2], 3.67 (m, 20 H, CH2), 2.54
(s, 6 H, methyl H), 1.49 (s, 6 H, methyl H) ppm. 13C NMR
(100 MHz): δ = 154.8, 148.5, 143.3, 132.3, 129.1, 122.0, 121.0,
51.5 ppm. IR (thin film): ν = 3399, 2915–2860, 1610, 1513 (ν
˜
as
NO2), 1267 (νs NO2) cm–1. HRMS (ESI+): calcd. for MNa+
551.2605; found 551.2583.
(4,5-Dimethoxy-2-nitrosophenyl)[4-(4,7-dioxa-1,10-dithia-13-azacyclo-
octadec-13-yl)phenyl]methanone (14): A solution of 5 (21.6 mg,
40.1 µmol) in CH3CN (4.0 mL) sealed in a quartz cuvette was irra-
diated with a 1000 W source for 4 h. The solvent was removed un-
der reduced pressure and subjected to flash chromatography on
silica with EtOAc/hexanes (13:20) to furnish the product as an
orange foam (20.4 mg, 97.6%). Rf = 0.28 (silica; EtOAc/hexanes,
1
13:20). H NMR (400 MHz,CDCl3): δ = 7.77 (dd, J = 8 Hz, 2 H,
phenyl H), 7.14 (s, 1 H, phenyl H), 6.68 (dd, J = 10 Hz, 2 H, phenyl
H), 6.34 (s, 1 H, phenyl H), 4.11 (s, 3 H, OCH3), 4.05 (s, 3 H,
OCH3), 3.97 (m, 4 H, NCH2), 3.82 (m, 8 H, OCH2), 2.91 (m, 4 H,
SCH2), 2.89 (m, 4 H, SCH2) ppm. 13C NMR (100 MHz): δ = 193.9,
160.1, 156.0, 151.4, 150.1, 140.2, 133.0, 127.2, 110.9, 109.9, 91.9,
74.6, 70.9, 57.0, 56.4, 52.2, 31.6, 29.6 ppm. IR (thin film): ν = 2921,
˜
2854, 1645 (νCO), 1586 (νNO) cm–1. HRMS (ESI+): calcd. for
MNa+ 543.1600; found 543.1628.
(4,5-Dimethoxy-2-nitrosophenyl)[4-(1,4,7,10,13-pentaoxa-16-azacyclo-
octadec-16-yl)phenyl]methanone (15): Prepared from 7 according to
the same procedure as that for 14. Compound 15 was obtained as
a yellow oil (48 %). Rf = 0.32 (alumina; EtOAc). 1H NMR
(400 MHz,CDCl3): δ = 7.74 (dd, J = 10 Hz, 2 H, phenyl H), 7.14
(s, 1 H, phenyl H), 6.63 (dd, J = 10 Hz, 2 H, phenyl H), 6.33 (s, 1
H, phenyl H), 4.28 (s, 3 H, OCH3), 4.23 (s, 3 H, OCH3), 3.70 (m,
24 H, OCH2) ppm. 13CNMR (100 MHz): δ = 193.8, 160.1, 156.0,
152.4, 150.1, 140.4, 132.8, 126.9, 110.8, 109.9, 91.8, 71.1, 71.03,
112.0, 71.0, 71.0, 70.9, 68.7, 51.4, 14.9, 14.7 ppm. IR (thin film): ν
˜
= 2958, 2903, 2869, 1609, 1543, 1524, 1513, 1190, 1157, 1081, 973
cm–1. HRMS (ESI+): calcd. for MNa+ 608.3083; found 608.3061.
General Spectroscopic Methods: All solutions were prepared with
spectrophotometric grade solvents. The metal perchlorate salts
were obtained from Stem or EM Science and used as received.
Absorption spectra were recorded with a Cary 50 UV/Vis spectro-
photometer under the control of a Pentium IV based PC running
the manufacturer-supplied software package. Spectra were rou-
tinely acquired at 25 °C, in 1-cm path length quartz cuvettes with
a total volume of 3.0 mL. Analytical photolysis measurements were
performed with a Hitachi F-4500 spectrophotometer under the
control of a Pentium IV PC running the FL Solutions 2.0 software
package. Excitation was provided by a 150 W Xe lamp (Ushio Inc.)
operating at a current of 5 A. Photolysis reactions were conducted
at 25 °C, in 1 cm quartz cuvettes with a total volume of 3.0 mL by
using, unless otherwise stated, 10 nm slit widths and a photomulti-
plier tube power of 700 V. Preparative scale photolysis measure-
ments were carried out by using a 1000 W Xe small-arc lamp. Solu-
tions of 3, 5, and 7 (ca. 20–40 mg) in CH3CN (4.0 mL) were irradi-
ated in a 1 cm quartz cuvette for 4 h and the conversion checked
periodically by TLC. Quantum yields of fluorescence[59] and pho-
tolysis[15,16] were measured according to reported procedures.
70.99, 70.96, 68.6, 57.0, 56.4, 51.7 ppm. IR (thin film): ν = 2920–
˜
2864, 1645 (νCO), 1586 (νNO) cm–1. HRMS (ESI+): calcd. for
MNa+ 555.2319; found 555.2311.
4-(1,4,7,10,13-Pentaoxa-16-azacyclooctadec-16-yl)benzaldehyde
(16): POCl3 (0.60 mL, 6.5 mmol, 2.0 equiv.) was added dropwise
to a chilled solution (4 °C) of 16-phenyl-1,4,7,10,13-pentaoxa-16-
azacyclooctadecane (6) (1.11 g, 3.27 mmol) in DMF (10.0 mL).
The solution was warmed to 23 °C and stirred for 16 h. The re-
sulting pale blue-green solution was diluted with iced water
(50 mL). The pH was adjusted to 6.4–6.8 by the addition of solid
K2CO3 and the heterogeneous mixture extracted with EtOAc (2ϫ
50 mL). The organic fractions were pooled, dried with excess
MgSO4, filtered, and the filtrate was concentrated to dryness under
vacuum. Flash chromatography on silica with CH2Cl2/CH3OH
(19:1) furnished the product as a pale-yellow oil (1.04 g, 86.9%).
Rf = 0.5 (silica; CH2Cl2/CH3OH, 19:1). 1H NMR (400 MHz,
CDCl3): δ = 9.73 (s, 1 H, CHO), 7.72 (dd, J = 12 Hz, 2 H, aromatic
H), 6.74 (dd, J = 16 Hz, 2 H, aromatic H), 3.74 [s, 4 H,
N(CH2CH2)2], 3.67 (s, 20 H, CH2) ppm. 13C NMR (100 MHz): δ
= 190.3, 152.9, 132.3, 125.5, 111.2, 71.1, 71.0, 71.0, 70.9, 68.6,
Binding Constants: Stock solutions of CrownCast-1, -2, or -3,
CrownUnc-1, -2, or -3 and the metal perchlorate salts of Na+, K+,
Mg2+, Ca2+, Sr2+, Ba2+, Zn2+, Cd2+, Hg2+, and Pb2+ were prepared
in m concentration in spectrophotometric grade CH3CN. A 25 µ
solution of the ligand was prepared in 3000 µL of CH3CN and
titrated in triplicate with each of the metal salt stock solutions.
Absorbance spectra were corrected for dilution by multiplying the
measured absorbance by Equation (1):
51.7 ppm. IR (thin film): ν = 2867, 2735, 1677, 1546, 1525, 1171,
˜
1119 cm–1. HRMS (ESI+): calcd. for MNa+ 390.1893; found
390.1923.
4,4-Difluoro-1,3,5,7-tetramethyl-8-(16-phenyl-1,4,7,10,13-pentaoxa-
(V0 – Vadd)/V0
(1)
16-azacyclooctadec-16-yl)-4-bora-3a,4a-diaza-s-indacene (17):
A
solution of 16 (1.01 g, 2.76 mmol) in CH2Cl2 (300 mL) was de-
gassed with a gentle stream of N2 for 15 min, and 2,4-dimethylpyr-
role (625 µL, 6.07 mmol, 2.20 equiv.) and TFA (30 µL, 15 mol-%)
in which V0 is the initial volume and Vadd is the added volume of
the titrant. The conditional dissociation constant (Kd) was calcu-
5076
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Inorg. Chem. 2010, 5069–5078

Buffering Heavy Metal Ions with Photoactive CrownCast Cages
lated by fitting data with the linear least-squares fitting program
XLfit.[60]
Table 4. Selected interatomic distances [Å] and angles [°] for
[Hg(AT215C5)(ClO4)](ClO4).
Hg(1)–S(1)
Hg(1)–S(2)
Hg(1)–N(1)
Hg(1)–O(4)
Hg(1)–O(5)
Hg(1)–O(6)
2.417(2)[a]
2.413(2)
2.550(7)
2.612(12)
2.515(6)
2.464(6)
S(1)–Hg(1)–S(2)
S(1)–Hg(1)–N(1)
S(1)–Hg(1)–O(4)
S(1)–Hg(1)–O(5)
S(1)–Hg(1)–O(6)
S(2)–Hg(1)–N(1)
S(2)–Hg(1)–O(4)
S(2)–Hg(1)–O(5)
S(2)–Hg(1)–O(6)
N(1)–Hg(1)–O(5)
N(1)–Hg(1)–O(6)
O(5)–Hg(1)–O(6)
139.15(9)[a]
83.66(18)
84.5(2)
76.42(16)
141.90(17)
83.23(18)
110.0(2)
143.16(16)
78.78(17)
94.7(2)
Collection and Reduction of X-ray Data: Structural analysis was
carried out at the X-ray Crystallographic Facility at Yale Univer-
sity. Crystals were covered with oil, and a colorless plate with ap-
proximate dimensions of 0.10ϫ0.10ϫ0.10 mm was mounted on a
glass fiber at room temperature and transferred to a Rigaku
RAXIS RAPID imaging plate area detector with graphite-mono-
chromated Cu-Kα radiation (λ = 1.54187 Å) controlled by a PC
running the Rigaku CrystalClear software package.[61] The data
were collected at a temperature of –180Ϯ1 °C to a maximum 2θ
value of 136.5°. The data were corrected for Lorentz and polariza-
tion effects. The structure was solved by direct methods[62] and ex-
panded by using Fourier techniques.[63] The space group was deter-
mined by examining systematic absences and confirmed by the suc-
cessful solution and refinement of the structure. The non-hydrogen
atoms were refined anisotropically. Hydrogen atoms were refined
by using the riding model. All calculations were performed by using
the CrystalStructure crystallographic software package except for
refinement,[64] which was performed by using SHELXL-97.[62] Se-
lected crystallographic information is summarized in Tables 3 and
4, and a 50% thermal ellipsoid plot is shown in Figure 5. CCDC-
784279 contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
101.9(2)
65.6(2)
[a] Estimated standard deviations in the last digit(s). Atom labels
are provided in Figure 5.
Acknowledgments
This work was supported by the University of Connecticut, the
University of Connecticut Research Foundation (grant PD09-0154)
and the by National Science Foundation (NSF) (grant CHE-
0955361).
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Empirical formula
Formula mass
Space group
a [Å]
b [Å]
c [Å]
C18H28Cl2HgN2O10S2
768.04
P2/c
17.015(2)
9.8744(13)
14.9947(19)
90
α [°]
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β [°]
92.022(3)
90
2517.7(6)
4
2.026
65.627
223
γ [°]
V [Å3]
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ρcalcd. [gcm–3]
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µ [cm–1]
T [K]
Total no. data
No. unique data
Observed data[a]
No. parameters
R [%][b]
15846
5679
5679
348
0.0750
0.1173
1.32/–1.10
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Max/min peaks [e/Å]
[a] Observation criterion: IϾ2σ(I). [b] R = Σ ||Fo| – |Fc||/Σ |Fo|. [c]
wR2 = {Σ[w(Fo – Fc ) ]/Σw(Fo2)2}1/2
.
2
2 2
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Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectroscopic data of all new compounds;
absorption data, difference spectrum and fitting of binding iso-
therm for all titrations of CrownCast and CrownUnc ligands with
all metal ions screened; absorption changes in CrownCast ligands
and [M(CrownCast)]2+ upon irradiation with light used to calculate
quantum yields; fluorescence titration and binding isotherm for
Pb2+ and PbSensor-1.
Eur. J. Inorg. Chem. 2010, 5069–5078
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Published Online: September 29, 2010
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