Encapsulating zinc(ii) within a hydrophobic cavity

Article abstract of DOI:10.1039/c2dt30529a

A new macrobicyclic ligand has been prepared, and it is shown to bind Zn²⁺ on the inside. The ligand consists of a triamido(amine) motif to coordinate the metal ion and a narrow, hydrophobic channel above the metal binding site.

Full text of DOI:10.1039/c2dt30529a

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Encapsulating zinc(II) within a hydrophobic cavity†
Deanna L. Miller and Connie C. Lu*
Received 5th March 2012, Accepted 7th May 2012
DOI: 10.1039/c2dt30529a
encapsulated by the calix[6]cryptand family.4 To achieve a wider
A new macrobicyclic ligand has been prepared, and it is
shown to bind Zn2+ on the inside. The ligand consists of a
triamido(amine) motif to coordinate the metal ion and a
narrow, hydrophobic channel above the metal binding site.
breadth of coordination compounds, we targeted a new triamido
(amine) proligand, or compound 5 in Scheme 1, because this
motif has been demonstrated to support mid-to-late transition
metals and their reactivity with small molecules, e.g. O2.5
Of note, the hydrocarbon cap in 5 is the first example, to our
knowledge, of a hydrophobic cavity that avoids the use of
carbon-heteroatom linkages in its construction.
The synthesis of the proligand begins with the previously
reported 1,3,5-tri(3-butenyl)benzene 1,6 and builds complexity
in a linear sequence as shown in Scheme 1. Hydroboration of 1
with 9-BBN generates 2, which is subjected to Suzuki–Miyaura
coupling with 4-methyl iodobenzoate in the next step to form
the tricarboxylic ester 3. Hydrolysis of 3 under basic conditions,
followed by an acidic workup, provides the tricarboxylic acid 4.
The last step of the proligand synthesis is the selective
one-to-one coupling of 4 with tren, or tris(2-aminoethyl)amine.
This key transformation was achieved by using 2,2′-dipyridyl
disulfide and triphenylphosphine to create the amide linkages of
proligand 5.7 From commercially available starting materials, 5
was isolated in 5 steps with an overall yield of ∼30%.
To demonstrate that proligand 5 can chelate transition metal
ions, we began the metallation studies with zinc(II) because of its
redox inertness and diamagnetism. The metallation conditions
were directly adapted from Borovik et al. as shown in Fig. 2 to
yield the anionic zinc coordination complex, [K(DMA)n][Zn(L)]
6, in 90% yield.5 The aryl region of the proton NMR spectra is
distinctly different for proligand 5 and complex 6, which pro-
vided good evidence that the metallation reaction was successful.
Notably, the amide protons of the proligand (triplet at 7.7 ppm)
are missing in the proton NMR spectrum of 6. Definitive
proof was obtained in the form of an X-ray crystal structure of 6
(vide infra).
Biomimetic models of metalloenzymes seek to recreate the
active site, from the metal-binding pocket to the second coordi-
nation sphere.1 Sterically bulky ligands are often used to protect
the metal site, and may even impart size selectivity in reactions
with substrates. The ideal extent of steric bulk, however, is often
empirical. Too much steric bulk may inhibit reactivity of the
metal center, or worse, interfere with the coordination of the
ligand to the metal.
A complementary strategy is to protect the metal through an
encapsulating ligand. Macrobicyclic ligands bind and protect
metal centers without needing steric bulk. They provide a well-
defined cavity and have the potential to gate substrates in and out
of the cavity. However, the coordination chemistry of macro-
bicyclic ligands is not well developed, primarily because such
ligands can be challenging to prepare.2 Representatives of two
encapsulating ligand families are shown in Fig. 1.3
The coordination chemistry of these two families is signifi-
cantly restricted by the limited ligand variants in each family.
For instance, only Zn2+ and Cu1+/2+ ions have been shown to be
To obtain crystals of 6 suitable for an X-ray diffraction study,
the potassium countercation was swapped with [PPh4]+. The
structure of [PPh4][Zn(L)] (6′) revealed a trigonal monopyrami-
dal coordination geometry for zinc (Fig. 3a).‡ The molecular
symmetry is nearly C3 (Fig. 3b) with a dramatic twisting of the
ligand arms by 40 to 43°. The bond distances between the
zinc center and the N-donors are for Zn–Nap, 2.128(2) Å, and
for Zn–Neq, 1.985(2) Å, on average. These distances are quite
similar to those reported by Cummins and Nocera for the two
zinc ions in their dizinc-cryptand complex (ave Zn–Nap 2.162 Å,
ave Zn–Neq 1.973 Å), which has a similar first coordination
sphere to our complex.8
Fig. 1 Representatives of two ligand families that successfully bind
transition metals and create well-defined cavities.
Department of Chemistry, 207 Pleasant St SE, Minneapolis, MN, USA.
E-mail: clu@umn.edu
†Electronic supplementary information (ESI) available: Experimental
section including synthetic details and additional spectroscopic data.
CCDC 870365. For ESI and crystallographic data in CIF or other elec-
tronic format see DOI: 10.1039/c2dt30529a
Compound 6 may be considered a rudimentary model for
active sites of metalloenzymes containing hydrophobic channels.
7464 | Dalton Trans., 2012, 41, 7464–7466
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Scheme 1 Synthetic route to the proligand 5.
Fig. 2 (top) Scheme of the metallation reaction to form 6. (bottom)
Comparison of the aryl regions of the H NMR spectra (500 MHz, d6-
DMSO) of 5 (in black) and 6 (in red) with corresponding peak assign-
ments (labelled in blue).
Fig. 3 (a) Molecular structure of 6′ shown at 30% probability level.
Hydrogen atoms, solvent, and countercation were omitted. Top view of
6′ as (b) ball-and-stick model, or as (c) space-filling model with the aryl
cap removed for better visualization of the cavity.
1
The length between the zinc center and the centroid of the aryl
ring is nearly one nanometer (9.58 Å), and the cylindrical cavity
is narrow (Fig. 3c). Hence, substrate access to the metal site
should be size selective. In Cummins’ and Nocera’s cryptand
systems, which have a similarly narrow cavity, cyanide ligands
were reported to bind the two opposing metals in the cryptand
pocket.8 Because of the flexibility of its longer ligand arms, 6
should be able to accommodate linear diatomics and perhaps
even slightly larger molecules.
The flexibility of the methylene linkers in 6 has been investi-
gated through density functional theoretical studies (M06-L,
Gaussian09). Prior to obtaining the crystal structure of 6, we per-
formed a geometry optimization on a hypothetical structure, and
found convergence to a local minimum solution. This structure
has a cavity height (measured from the zinc center to the cen-
troid of the aryl ring) of 8.27 Å. A second geometry optimization
was performed starting from the crystal structure coordinates.
The result is a lower energy solution by 11.3 kcal mol−1
,
wherein the cavity height of 9.29 Å is expectedly closer to that
observed in the crystal structure. A comparison of these two
optimized structures indicates that the cavity can readily adopt
conformations with cavity height changes of at least ∼1 Å at
room temperature.
Host–guest chemistry of 6 was canvassed with coordinating
molecules, e.g. CH3CN, DMF, and DMSO, as well as nonpolar
substrates, e.g. pentane, hexane, benzene and trifluorotoluene. In
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92.8190(10)°, γ = 90.00°, V = 6649.2(7) Å3, T = 173(2) K, space group
P2(1)/n, Z = 4, 9502 reflections measured, 13 959 independent reflec-
tions (Rint = 0.0000). The final R1 values were 0.0523 (I > 2σ(I)). The
final wR(F2) values were 0.1247 (I > 2σ(I)). The final R1 values were
0.0857 (all data). The final wR(F2) values were 0.1371 (all data).
all cases, the reactions were unproductive as determined by
proton NMR spectroscopy in DMSO-d6. The lack of reactivity
can be rationalized by considering two factors: (1) the Lewis
acidity of the Zn2+ center is significantly attenuated by the
ligand’s three anionic amide groups; and (2) the cavity is so
narrow that it would exclude most of these substrates based on
their size. Possible avenues for future research include extending
the coordination chemistry to more reactive transition metals as
well as expanding the cavity size by increasing the number of
methylene linkers in the ligand arms.
1 R. Breslow, Acc. Chem. Res., 1995, 28, 146.
2 J. K. M. Sanders, Chem.–Eur. J., 1998, 4, 1378.
3 (a) I. Jabin and O. Reinaud, J. Org. Chem., 2003, 68, 3416; (b) Y. Makita,
K. Sugimoto, K. Furuyoshi, K. Ikeda, S. Fujiwara, T. Shinike and
A. Ogawa, Inorg. Chem., 2010, 49, 7220; (c) B. Chatelet, E. Payet,
O. Perraud, P. Dimtirov-Raytchev, L.-L. Chapellet, V. Dufaud, A. Martinez
and J.-P. Dutasta, Org. Lett., 2011, 13, 3706.
4 (a) U. Darbost, M.-N. Rager, S. Petit, I. Jabin and O. Reinaud, J. Am.
Chem. Soc., 2005, 127, 8517; (b) G. Izzet, J. Zeitouny, H. Akdas-Killig,
Y. Frapart, S. Ménage, B. Douziech, I. Jabin, Y. L. Mest and O. Reinaud,
J. Am. Chem. Soc., 2008, 130, 9514. For examples of Zn2+ and Cu1+/2+
encapsulation in other macrocyclic systems, see: ref. 3b (c) L. Wang, J.-
C. Chambron and E. Espinosa, New J. Chem., 2009, 33, 327;
(d) P. Mateus, R. Delgado, P. Brandão and V. Félix, Chem.–Eur. J., 2011,
17, 7020.
5 (a) M. Ray, B. S. Hammes, G. P. A. Yap, A. L. Rheingold and A.
S. Borovik, Inorg. Chem., 1998, 37, 1527; (b) C. E. MacBeth, A.
P. Golombek, V. G. Young Jr., C. Yang, K. Kuczera, M. P. Hendrich and
A. S. Borovik, Science, 2000, 289, 938; (c) R. L. Shook, S. M. Peterson,
J. Greaves, C. Moore, A. L. Rheingold and A. S. Borovik, J. Am. Chem.
Soc., 2011, 133, 5810.
6 J. K. Twibanire, H. Al-Mughaid and T. B. Grindley, Tetrahedron, 2010,
66, 9602.
7 E. J. Stoner, G. Negrón, R. Gaviño, H. Lönnberg, 2,2-Dipyridyl Disulfide,
in Encyclopedia of Reagents for Organic Synthesis, J. Wiley & Sons, Ltd,
2008, DOI: 10.1002/047084289x.rd455.pub3.
8 (a) G. E. Alliger, P. Müller, L. H. Do, C. C. Cummins and D. G. Nocera,
Inorg. Chem., 2011, 50, 4107; (b) G. E. Alliger, P. Müller, C. C. Cummins
and D. G. Nocera, Inorg. Chem., 2010, 49, 3697.
Acknowledgements
We thank Alexander F. Mullikin (UROP) for giving synthetic
assistance. DLM thanks Bess Vlaisavljevich and Lindsay Hinkle
for assistance with computing and using PLATON, respectively.
Computing resources were provided by the Minnesota Super-
computing Institute. Crystallography resources were provided by
the X-ray Crystallography Laboratory (UM). We gratefully
acknowledge the donors of the American Chemical Society
Petroleum Research Fund (50395-DNI3) and the Initiative for
Renewable Energy and the Environment (UM) for financial
support of this research.
Notes and references
‡Crystal data for 6′: C73H77N4O4PZn, M = 1170.73, monoclinic, a =
13.1597(8) Å, b = 34.881(2) Å, c = 14.5029(9) Å, α = 90.00°, β =
7466 | Dalton Trans., 2012, 41, 7464–7466
This journal is © The Royal Society of Chemistry 2012