A modular ditopic crown-shielded phosphate ion-pair receptor

Article abstract of DOI:10.1039/b409132a

The synthesis of a modular hybrid receptor containing both an aza macrocycle and crown ether is described; a complete thermodynamic characterisation of the binding properties, in water, of the zinc(II) complex of the receptor towards phosphate is presente

Full text of DOI:10.1039/b409132a

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A modular ditopic crown-shielded phosphate ion-pair receptor{
Patrick Gunning,a Andrew C. Benniston*b and Robert D. Peacock*a
a Department of Chemistry, Joseph Black Building, University of Glasgow, Glasgow, UK G12 8QQ.
E-mail: bob@chem.gla.ac.uk; Fax: 144 (0)141 330 4888; Tel: 144 (0)141 330 4375
b Molecular Photonics Laboratory, University of Newcastle, Newcastle upon Tyne, UK NE1 7RU.
E-mail: a.c.benniston@ncl.ac.uk; Fax: 144 (0)191 222 6929; Tel: 144 (0)191 222 5706
Received (in Cambridge, UK) 17th June 2004, Accepted 16th July 2004
First published as an Advance Article on the web 20th August 2004
The synthesis of a modular hybrid receptor containing both
macrocycles are commercially available or may be synthesized and
a wide range of amino acids (or dipeptide units) can be used as the
linker. The dibenzocrown-8-carboxylic acid was synthesized by a
modification of standard methods14 which allow variation of the
number of oxygen atoms in the crown and the position of the
carboxylic acid unit on the aromatic ring. Chiral receptors may also
be synthesized using enantiopure linking groups such as glutamic
acid.
The receptor described here (L) consists of cyclen joined to the
dibenzo-24-crown-8 unit via a glycine bridge. The zinc(II) complex
was prepared by the addition of equimolar quantities of zinc
triflate and NMR titration experiments confirmed that the zinc
ion binds to the aza and not the oxa crown in a 1 : 1 ratio.
Molecular modeling of Zn(H2O)L clearly demonstrates the zinc(II)
macrocycle and crown residing in close proximity, ideal for
substrate binding (see Electronic Supplementary Information{).
Potentiometric pH titrations determined the pKa of the attached
water to be 7.4 (¡ 0.1). This value is in good agreement with
previous and more recent work by Mareque-Rivas using tetraaza-
ligand systems.15
The ability of Zn(H2O)L to bind phosphate and substituted
phosphates was assessed by 1H NMR, UV–visible and isothermal
calorimetry (ITC).{ In order to identify the effect of the attached
crown ether, the binding ability of Zn(H2O)cyclen was measured
under identical experimental conditions (pH 7.4 HEPES buffer
(10 mM) in aqueous solution; 0.25 mM substrate, 5 mM ligand).
We chose to use mono sodium (and potassium) dihydrogen
phosphate in order to have one mole of the cation per phosphate
available for binding to the crown ether. However at pH 7.4 the
phosphate is in the dianionic form [HPO4]22 and is thus bound as
the 22 ion. The results are presented in Table 1.
The first point to be taken from the table is the large binding
constant for the [HPO4]22 anion in aqueous solution. Comparable
binding constants have been reported recently by Anslyn (2.5 6
104)1b and Ren (4.2 6 103 buffered; 2.4 6 104 unbuffered).16
Secondly potassium phosphate binds approximately twice as
strongly to Zn(H2O)L as does the sodium salt, whereas the binding
of sodium and potassium phosphate to Zn(H2O)cyclen is essen-
tially identical. Since the oxa crown is of such a size as to favor
binding K1 over Na1,17 this result strongly suggests that the oxa
crown is binding the cation and thus that Zn(H2O)L is an ion pair
receptor. This is further supported by ITC evidence that shows
Zn(H2O)L not binding either NaClO4 or KClO4 under identical
experimental conditions. Most importantly Zn(H2O)L binds
[HPO4]22 between three and six times more strongly than the
Zn cyclen control demonstrating the enhanced binding provided by
the oxa-crown arm. p-Nitrophenyl phosphate binds to essentially
the same extent to the two substrates within experimental error.
Finally the bulkier glycophosphate is bound more strongly by
Zn(H2O)cyclen than by Zn(H2O)L.
an aza macrocycle and crown ether is described; a complete
thermodynamic characterisation of the binding properties, in
water, of the zinc(II) complex of the receptor towards
phosphate is presented and the parameters are compared to
those of the aza macrocycle precursor.
Mimicking natural enzymes using artificial systems has been the
impetus for many research groups1–7 over the past twenty years. In
seminal work by Kimura and co-workers8 it was shown that zinc(II)
complexes of the azamacrocycles 1,5,9-triazacyclododecane and
1,4,7,10-tetraazacyclododecane (cyclen) bind a water molecule with
a pKa value that is dramatically reduced when compared to that of
a free water molecule. Owing to the generation of this nucleophilic
centre these complexes catalytically hydrolyse the ester groups of
simple substrates.9
More recently the next stage in the development of artificial
enzymes has included secondary structures such as cyclodextrins,10
dendrimers,11 and cavitands12 attached to the macrocyclic core.
These groups tend to mimic the second coordination sphere and
beyond and serve to protect reactants, bind substrates and promote
reactions. However, these secondary host sites generally do not
possess multiple specific groups that could promote simultaneous
H-bonding, p–p stacking and dipole–dipole interactions which is
more reminiscent of the protein structure of enzymes. At the heart
of many artificial enzyme mimics is an anion receptor. For this
reason both anion and ion pair receptors are currently of great
interest.13
In this communication we report the synthesis and binding
properties of a hybrid anion receptor in which an aza macrocycle
moiety is attached to an aromatic crown ether polycycle via an
amino acid bridging unit. The synthetic approach (Scheme 1) is
modular allowing all three parts of the molecule to be varied giving
access to a wide variety of receptors. A number of tri- and tetra-aza
Scheme 1 (a) N-Cbz-glycine, DCC, DMAP, DCM, rt; (b) 10% Pd/C, 1,4-
cyclohexadiene, EtOH, rt; (c) dibenzocrown-8-carboxylic acid, DCC,
DMAP, DCM, rt; (d) TFA–DCM, rt.
In addition to stability constants, however, ITC provides the
DH0 for the interaction of ligand and substrate and thus a complete
thermodynamic characterization of the binding process. We believe
this is the first time that such an analysis has been performed on a
ditopic receptor based on an azamacrocycle and simultaneously on
the parent complex. The results clearly show that in every case
binding to Zn(H2O)cyclen is exothermic, whereas binding to
{ Electronic supplementary information (ESI) available: details of
experimental work, ITC traces, selected 1H NMR data and molecular
modelling. See http://www.rsc.org/suppdata/cc/b4/b409132a/
2 2 2 6
C h e m . C o m m u n . , 2 0 0 4 , 2 2 2 6 – 2 2 2 7
T h i s j o u r n a l i s ß T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

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Table 1 Thermodynamic data for the binding of various substrates to Zn(H2O)L and Zn(H2O)cyclen in HEPES buffer at pH 7.4 at 25 uC
Ligand : substrate
binding ratioa
DG0/
DH0/
2TDS0/
Ligand
Substrate
K 6 104
kcal mol21b
kcal mol21
kcal mol21
Zn(H2O)L
Zn(H2O)L
Zn(H2O)cyclen
Zn(H2O)cyclen
Zn(H2O)L
Zn(H2O)cyclen
Zn(H2O)L
Zn(H2O)cyclen
2 : 1
2 : 1
1 : 1
1 : 1
1 : 1
1 : 1
1 : 1
1 : 1
Na[H2PO4]
K[H2PO4]
Na[H2PO4]
K[H2PO4]
Sodium glycerophosphate
Sodium glycerophosphate
Disodium 4-nitrophenylphosphate
Disodium 4-nitrophenylphosphate
4.93 ¡ 0.72c
9.32 ¡ 1.60c
1.60 ¡ 0.09d
1.52 ¡ 0.19d
0.48 ¡ 0.06d
0.87 ¡ 0.04d
0.39 ¡ 0.04d
0.51 ¡ 0.21d
26.39
26.78
25.74
25.70
25.02
25.38
24.90
25.05
3.47 ¡ 0.17
2.44 ¡ 0.09
23.25 ¡ 0.08
23.89 ¡ 0.24
0.48 ¡ 0.02
21.63 ¡ 0.06
0.58 ¡ 0.04
20.45 ¡ 0.19
9.86
9.22
2.49
1.81
5.50
3.75
5.48
4.60
a Binding stoichiometry was confirmed by 1H NMR titration experiments19 (see ESI). b Calculated from DGu ~ DHu2TDSu. c mol22 dm6.
d mol21 dm3.
Zn(H2O)L is endothermic. The binding of substrate to Zn(H2O)L
is driven by the large positive entropy term. If a simple subtraction
is made between the parameters for Na[H2PO4] bound to
Notes and references
1 (a) S. L. Tobey and E. V. Anslyn, J. Am. Chem. Soc., 2003, 125, 14807–
14815; (b) S. L. Tobey and E. V. Anslyn, J. Am. Chem. Soc., 2003, 125,
Zn(H2O)cyclen and to Zn(H2O)L it is apparent that on going
10963–10970.
from the simple aza macrocycle to the receptor, this results in a
2 (a) B. N. Trawick, A. T. Daniher and J. K. Bashkin, Chem. Rev., 1998,
DDH0 of 16.72 kcal mol21 and a DTDS0 of 17.37 kcal mol21
98, 939–960; (b) W. H. Jr. Chapman and R. J. Breslow, J. Am. Chem.
producing an overall DDG0 of 20.65 kcal mol21. We propose that
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the explanation for this effect is that there is a ‘‘pocket’’ of
hydrogen-bonded water trapped between the [OH]2 ion (at pH 7.4)
attached to the zinc ion, and the oxa crown ether. Binding of an
anion to the zinc results in the expulsion of the water requiring an
input of energy but generating a large amount of entropy. This
explanation has been put forward to explain binding in natural
systems,18 and to account for substrate binding in a copper-based
artificial system.1b
The DTDS0 for binding sodium and potassium phosphate to
both receptors are essentially the same within experimental error
while the DDH0 is significantly less positive for the potassium salt
suggesting that the K1 ion is being bound to some extent in the oxa
crown cavity.
10 D. K. Leung, J. H. Atkins and R. Breslow, Tetrahedron Lett., 2001, 42,
6255–6258.
11 (a) M. Enomoto and T. Aida, J. Am. Chem. Soc., 1999, 121, 874–875;
(b) L. Lui and R. Breslow, J. Am. Chem. Soc., 2003, 125, 12110–12111.
12 H. Boerrigter, L. Grave, J. W. M. Nissink, L. Chrisstoffels, J. H. Van der
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14 J. W. Jones, L. N. Zakharov, A. L. Rheingold and H. W. Gibson, J. Am.
Chem. Soc., 2002, 124, 1378–1379.
15 J. C. Mareque-Rivas, R. Prabaharan and R. T. Mart´ın de Rosales,
Chem. Commun., 2004, 76–77.
16 J. E. Barker, Y. Lui, N. D. Martin and T. Ren, J. Am. Chem. Soc., 2003,
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In conclusion, we have shown that hybrid azamacrocycle-
crown polycycle receptors offer a new dimension in anion
recognition and binding. Since the modular approach gives us
flexibility in the design and functionality of the receptor, there is
great scope to bind other phosphate-based substrates such as
organophosphates found in nerve gases and insecticides. Further-
more, optimization of the crown polycycle size and number of
azamacrocycle metal ion sites should lead to enhanced binding
of substrates and reactivity, which will be explored in second-
generation models.
We thank the EPSRC for a studentship (to PG) and Prof
A. Cooper and Margaret Nutley for help with the ITC mea-
surements. Molecular modeling calculations performed by Ben
Allen (MPL) are greatly appreciated.
17 H. K. Frensdorff, J. Am. Chem. Soc., 1971, 93, 600–606.
18 D. B. Smithrud, T. B. Wyman and F. Diederich, J. Am. Chem. Soc.,
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19 M. J. Hynes, J. Chem. Soc., Dalton Trans., 1993, 311–312.
C h e m . C o m m u n . , 2 0 0 4 , 2 2 2 6 – 2 2 2 7
2 2 2 7