Allosteric effects in a ditopic ligand containing bipyridine and tetra-aza-crown donor units

Article abstract of DOI:10.1002/chem.201103217

Artificial allosterism: A ditopic ligand, which contains both bipyridine and tetra-aza-crown binding sites, coordinates one Cu^II through all four N-donors of the tetradentate aza-crown unit. Reaction at the bipyridine site with another Cu^I

Full text of DOI:10.1002/chem.201103217

DOI: 10.1002/chem.201103217
Allosteric Effects in a Ditopic Ligand Containing Bipyridine and Tetra-aza-
crown Donor Units
Cara E. Sutton,[a] Lindsay P. Harding,[a] Michaele Hardie,[b]
Thomas Riis-Johannessen,*[c] and Craig R. Rice*[a]
Interest in artificial allosteric systems is largely due to the
importance of allostery in regulating the catalytic activity of
enzymes. Artificial allosteric systems are often ditopic li-
gands, molecules that contain two binding sites capable of
interacting with other molecular species such as anions and
cations.[1] The system is termed allosteric when substrate
binding at one site of the ditopic ligand causes conforma-
tional changes that modify the properties of the other,
chemically remote, site; in other words, the sites are me-
chanically coupled. A classic example of this is the work of
Rebek et al.[1a] They demonstrated that the selectivity of s-
block cation transport across a liquid–liquid membrane, by a
crown ether unit linked in the 3,3’-positions to 2,2’-bipyri-
dine (bipy), can be tuned by coordination of a d-block metal
to the bipy site.[1a] Since then, various other systems have
been reported, amongst which are examples of how allostery
can regulate overall molecular structure,[2a] binding specifici-
ty[2b] and catalytic activity.[3] Despite the impressive efforts
undertaken to characterise these systems and their allosteric
behaviour, however, structural and thermodynamic ration-
ales for the observed phenomena are often sparse.
The ligand L was synthesised in two steps from 3,3’-diami-
no-2,2’-bipyridine (Scheme 1 and the Supporting Informa-
Scheme 1. Synthesis of ditopic ligand L; Ts=tosyl.
tion) and its single crystal X-ray structure determined
(Figure 1).[4] In the solid state, the two pyridine rings are
twisted, with an NCCN torsion angle of 110(1)8. Steric re-
straints in the aza-macrocycle prevent these rings from
adopting the coplanar transoid geometry favoured by bipy
systems with hydrogen-bond donors in the 3,3’-position.[5,6]
In this paper we report the synthesis and coordination
properties of a ditopic ligand containing bipy and tetra-aza-
crown N-donor units. Both sites complex CuII dications, but
the donor mode of the latter is controlled by the binding
state of the bipy unit. An allosteric effect, characterised by
negatively cooperative binding of a second CuII ion, is as-
signed to the tetra-aza-crown being able to coordinate
through only three of its N-donors when the bipy site is oc-
cupied.
Figure 1. Solid-state structure of the ditopic ligand L.
[a] Dr. C. E. Sutton, Dr. L. P. Harding, Dr. C. R. Rice
School of Applied Sciences, University of Huddersfield
Huddersfield HD1 3DH (UK)
Spectrophotometric titrations of CuCl2·2H2O into a solu-
tion of the ligand ([L]tot =10ꢀ4 m, MeCN) caused complex
variations in the UV/Vis spectra (see the Supporting Infor-
mation), which were satisfactorily modelled by the six ab-
sorbing species (CuII, L and four complexes, see Figure 2) in
Equations (1), (2), (3) and (4):[7]
Fax : (+44)(0)1484-450-408
E-mail: c.r.rice@hud.ac.uk
[b] Dr. M. Hardie
School of Chemistry, University of Leeds
Leeds LS2 9J (UK)
[c] Dr. T. Riis-Johannessen
Institut des Sciences et Ingꢀnierie Chimiques
ꢁcole Polytechnique Fꢀdꢀrale de Lausanne (EPFL)
1015 Lausanne (Switzerland)
CuIIþ2L , ½CuðLÞ2ꢁ2þ log b1C;u2;L ¼ 16:8ð4Þ
CuIIþL , ½CuðLÞꢁ2þ log bC1;u1;L ¼ 11:0ð4Þ
ð1Þ
ð2Þ
E-mail: riisjoh@googlemail.com
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201103217.
3464
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Chem. Eur. J. 2012, 18, 3464 – 3467

COMMUNICATION
the Cu–Clax distance is 2.4026(6) ꢃ. A further feature of in-
terest is the bipy NCCN torsion angle, which decreases from
110(1)8 in the free ligand to 62(1)8. This reduction occurs so
that the amine substituents on the 3,3’-positions of bipy are
optimally aligned for binding the metal ion.
Reaction of [Cu(L)Cl]+ with a further equivalent of
CuCl2·2H2O in MeOH gives a green crystalline solid for
which X-ray diffraction shows the dicopper complex
[Cu2(L)Cl4] in Figure 4.[9] In the crystal, the ligand coordi-
Figure 2. Calculated speciation diagram for complexes of L with CuII
([L]tot =10ꢀ4 m).
3CuIIþ2L , ½Cu3ðLÞ2ꢁ6þ log b3C;u2;L ¼ 31:6ð6Þ
2CuIIþL , ½Cu2ðLÞꢁ4þ log b2C;u1;L ¼ 16:0ð4Þ
ð3Þ
ð4Þ
Figure 4. Solid-state structure of the chloro-bridged dinuclear complex
[Cu2(L)Cl4]2.
Chloride adducts for all species were observed in the gas-
phase during parallel ESI-MS titrations (see the Supporting
Information). The formation of four complexes is not unex-
pected given both 1) the diverse coordination modes a
ligand such as L is potentially capable of achieving and
2) the presence of a coordinating solvent (MeCN) and the
Clꢀ counterion, which can stabilise coordinatively unsaturat-
ed species.
nates one CuII ion through the bipy donor unit and another
CuII ion through the aza-crown macrocycle. The former is
ꢀ
bound by the two nitrogen atoms of bipy (Cu Nbipy
2.056(3) and 2.060(3) ꢃ) and two (roughly) equatorial chlo-
:
ꢀ
ride ligands (Cu Cleq: 2.296(1) and 2.314(1) ꢃ). The remain-
ing axial site is occupied by a bridging chloride ligand from
ꢀ
another molecule of [Cu2(L)Cl4] (Cu m-Clax: 2.742(1) ꢃ),
For [Cu(L)2]2+ we reasonably assume that the CuII ion is
coordinated by the bipy imine donors of two ligands, where-
as in the 1:1 complex [CuL]2+ it is coordinated by the tetra-
dentate aza-crown of one ligand. The structure of the latter
complex has been confirmed by an X-ray diffraction study
on crystals grown from a solution containing equimolar
CuCl2·2H2O and L (Figure 3).[8]
The copper ion is indeed coordinated by the four nitrogen
atoms of the tetra-aza macrocycle. An axial chloride ligand
completes the coordination sphere, giving the CuII centre a
five-coordinate distorted square-pyramidal geometry. The
giving rise to a chloro-bridged dimer in the solid state.
The trinuclear complex [Cu3(L)2]6+ implied by the UV/
Vis titrations was not characterised in the solid state. How-
ever, it was observed in the gas phase. The ESI-MS of a so-
lution containing a 3:2 Cu/L ratio shows an intense peak at
m/z 964 that corresponds to the complex cation
[Cu3(L)2Cl5]+ (see the Supporting Information). We suspect
that it is structurally related to the [Cu2(L)Cl4] complex: in-
stead of being
a chloro-bridged dimer, however, two
[Cu(L)Cl]+-type complexes are held together by interaction
of the four bipy N-donors with a central CuII ion. The aza-
crown-bound CuII ion of [Cu2(L)Cl4] (and presumably
[Cu3(L)2Cl5]+) is again five-coordinate, but it acquires its
distorted square pyramidal geometry from three nitrogen
atoms in the aza-crown and two chloride ions. The aza-
crown therefore now acts as a tridentate donor. The two
“outer” aza nitrogen atoms and the two chloride ligands lie
ꢀ
Cu Naza bond lengths range from 2.008(2)–2.083(2) ꢃ and
ꢀ
roughly in an equatorial plane (Cu Naza: 2.021(3) and
ꢀ
2.088(3) ꢃ; Cu Cleq: 2.281(1) and 2.359(1) ꢃ). One of the
“inner” aza nitrogen atoms lies in the elongated axial posi-
ꢀ
tion (Cu Naza: 2.464(3) ꢃ), whereas, at 3.355(3) ꢃ, the re-
maining inner nitrogen is too remote to be considered as
bonding to the CuII centre. The bipy NCCN torsion angle of
31(1)8 is severely reduced from that observed in either the
free ligand or the mononuclear complex [Cu(L)Cl]+. This
reduction is required for the bipy unit to chelate the CuII
ion, and it is clearly too great for both of the “inner” aza ni-
trogen atoms to be able to complex the other CuII ion at the
Figure 3. Solid-state structure of the complex cation [Cu(L)Cl]+.
Chem. Eur. J. 2012, 18, 3464 – 3467
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www.chemeurj.org
3465

C. R. Rice, T. Riis-Johannessen et al.
À
Á
DECuCu ¼ RT ln uCuCu ¼ þ21:6kJmolꢀ1
ð16Þ
same time; at least one of them is constrained so that its hy-
drogen is directed towards the metal, hindering any poten-
The term uCuCu, from which the intermetallic interaction
value of DECuCu ¼ þ21:6kJmolꢀ1 is derived, equates to Erco-
laniꢄs allosteric cooperativity index a.[12] This parameter is
typically expressed as the ratio of the (statistically correct-
ed) experimental formation constant of a given multi-com-
ponent assembly to its equivalent hypothetical (non-cooper-
ative) one. The value of a will be greater than 1 in the case
of positive cooperativity and less than 1 in the case of nega-
tive cooperativity.[12] In the present case the value of a is
given by Equation (17):
ꢀ
tial Cu N interaction.
We have applied the extended site-binding model[10] to es-
timate the degree to which the binding of a first CuII ion by
L affects its affinity for a second CuII ion. This approach
allows the cumulative formation constants for equilibria
(1)–(4) to be modelled by one or more microscopic interac-
tion parameters and a statistical factor (w). The latter (w)
can be computed using a well-established procedure[11]
based on the symmetries of the participating species (see
Cu
aza
Cu
bipy
the Supporting Information). Defining 1) f and f as the
microscopic affinities of CuII for the aza-crown and bipy
ꢀ
ꢁ
À
Á
LL/RT
sites, respectively, and 2) a Boltzmann factor uLL =eꢀDE
a ¼ bC2;u1;L=wCu;L = fCu ꢂ fCu ¼ 10ꢀ3:7 ðꢃ 1Þ
ð17Þ
2;1
bipy
aza
as the inter-ligand interaction between the two coordinating
bipy units (in, for example, [Cu(L)2]2+ and [Cu3(L)2]6+), we
can express the cumulative formation constants of
[Cu(L)2]2+ and [Cu(L)]2+ as the following:
which indicates that severe negative cooperativity accompa-
nies the successive binding of two CuII ions to the ditopic re-
ceptor L. Although electrostatic repulsion between the en-
tering cations cannot be ruled out as a possible source of
this energy cost, such effects are known to be largely com-
pensated for by favourable solvation changes associated
with the increase in total charge when polymetallic recep-
tors undergo a sequential increase in nuclearity.[13] It is more
probable, therefore, that the repulsive interaction has a
structural basis: as seen in the solid state, when the bipy
unit acts as a bidentate chelate the resulting planarity forces
the two “inner” nitrogen atoms at the 3,3’-positions to ap-
proach one another, causing one to be an axially elongated
donor and outright preventing the other from coordinating
CuII at all. The corresponding energy cost of
DECuCu ¼ þ21:6kJmolꢀ1 thus reflects the entropic and en-
thalpic losses associated with the aza-crown being able to
coordinate through only three of its nitrogen atoms when
the bipy site is bound to a CuII ion. This applies irrespective
of the order in which the two sites are occupied: The struc-
tural rearrangements caused by secondary binding of CuII to
ꢀ
À
ꢁ
Cu;L
1;2
Cu;L
1;2
Cu
bipy
ð5Þ
ð6Þ
b
b
¼ w
¼ w
ꢂ
f
2ꢂuLL
Á
Cu;L
1;1
Cu;L
1;1
Cu
aza
ꢂ f
CuCu
Introduction of a second Boltzmann factor, uCuCu =eꢀDE
/
RT, accounting for the energy cost incurred by simultaneous
binding of both the bipy and aza-crown sites, likewise allows
us to write the following Equations (7) and (8):
ꢀ
ꢀ
ꢁ
ꢁ
2 À
Á À Á À
Á
2
2
Cu;L
3;2
Cu;L
3;2
Cu
bipy
Cu
aza
b
b
¼ w
¼ w
ꢂ
ꢂ
f
f
ꢂ uLL ꢂ f
ꢂ uCuCu
ð7Þ
ð8Þ
À
Á À
Á
Cu;L
2;1
Cu;L
2;1
Cu
bipy
Cu
aza
ꢂ f
ꢂ uCuCu
for [Cu3(L)2]6+ and [Cu2(L)]4+, respectively. Converting
Equations (5), (6), (7) and (8) into their logarithmic forms
then gives four simultaneous equations from which we cal-
culate the following values (see the Supporting Information
for full details):
ꢀ
the bipy site will require one of the Cu Naza bonds to break.
Alternatively, if the bipy unit is considered as the primary
binding site, the aza-crown is already locked in a conforma-
tion that prevents it from binding a second CuII ion through
all four N-donors.
Cu
bipy
log ðf Þ ¼ 7:8
ð9Þ
ð10Þ
ð11Þ
ð12Þ
Cu
In conclusion, we have presented structural and thermo-
dynamic evidence to show how the binding mode and affini-
ty of a ditopic aza-crown/bipy ligand can be influenced by
allosteric interactions. The results provide an interesting in-
sight into the mechanism of site interaction in artificial allo-
steric systems: the two sites are mechanically coupled
through conformational restraints. Possible applications for
regulating the catalytic activity in for example, dioxygen ac-
tivation and phosphodiester cleavage reactions are currently
being explored.
log ðf Þ ¼ 10:3
aza
log ðuLLÞ ¼ 0:02
log ðuCuCuÞ ¼ ꢀ3:7
Subsequent conversion into absolute energies gives the fol-
lowing final values:
ꢀ
ꢁ
Cu
bipy
DgCu;bipy ¼ RT ln f
¼ ꢀ44:9kJmolꢀ1
ð13Þ
À
Á
Cu
aza
DgCu;bipy ¼ RT ln f
¼ ꢀ59:3kJmolꢀ1
ð14Þ
ð15Þ
Acknowledgements
À
Á
DEL;L ¼ RT ln uLL ¼ ꢀ0:1kJmolꢀ1
We thank the University of Huddersfield for funding (CES).
3466
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Chem. Eur. J. 2012, 18, 3464 – 3467

Allosteric Effects in a Ditopic Ligand
COMMUNICATION
33, 943; b) H. Gampp, M. Maeder, C. J. Meyer, A. D. Zuberbꢆhler,
Talanta 1985, 32, 133.
Keywords: allosterism · aza-crown compounds · cooperative
effects · copper · N ligands
[8] Crystal data for Cu2C16H22N6Cl2·MeCN·0.5MeCO2Et; 0.2ꢅ0.075ꢅ
0.05 mm; Mr =517.94, Monoclinic; C2/c; a=18.9791(5), b=
15.7030(4), c=16.1009(5) ꢃ; b=103.9230(10)8; V=4657.6(2) ꢃ3;
Z=8;
Z’=1;
1c =1.360 Mgmꢀ3
;
F
G
mACHTUNGTRENNUNG(CuKa)=
[1] a) J. Rebek, Jr., J. E. Trend, R. V. Wattley, S. J. Chachravorti, J. Am.
Chem. Soc. 1979, 101, 4333; b) J. Rebek, Jr., R. V. Wattley, J. Am.
Chem. Soc. 1980, 102, 4853; c) J. Rebek, Jr., Acc. Chem. Res. 1984,
17, 258; for other examples of artificial allosteric systems, see: d) T.
Nabeshima, Coord. Chem. Rev. 1996, 148, 151; e) S. Shinkai, M.
Ikeda, A. Sugasaki, M. Takeuchi, Acc. Chem. Res. 2001, 34, 494;
f) Y. Kobuke, Y. Satoh, J. Am. Chem. Soc. 1992, 114, 789; g) P. D.
Beer, A. S. Rothin, J. Chem. Soc. Chem. Commun. 1988, 52; h) S. K.
Dutta, D. Gan, M. W. Perkovic, Eur. J. Inorg. Chem. 2003, 2812;
i) S. A. McFarland, N. S. Finney, Chem. Commun. 2003, 388; j) T.
Nabeshima, Y. Yoshihira, T. Saiki, S. Akin, E. Horn, J. Am. Chem.
Soc. 2003, 125, 28; k) H.-J. Schneider, F. Werner, J. Chem. Soc.
Chem. Commun. 1992, 490.
[2] a) C. J. Baylies, L. P. Harding, J. C. Jeffery, T. Riis-Johannessen,
C. R. Rice, Angew. Chem. 2004, 116, 4615; Angew. Chem. Int. Ed.
2004, 43, 4515; b) C. J. Baylies, T. Riis-Johannessen, L. P. Harding,
J. C. Jeffery, R. Moon, C. R. Rice, M. Whitehead, Angew. Chem.
2005, 117, 7069; Angew. Chem. Int. Ed. 2005, 44, 6909.
[3] a) S. Takebayashi, M. Ikeda, M. Takeuchi, S. Shinkai, Chem.
Commun. 2004, 420; b) N. C. Gianneschi, S. T. Nguyen, C. A.
Mirkin, J. Am. Chem. Soc. 2005, 127, 1644.
3.595 mmꢀ1; T=100 K; l
ACHTUNGTRENNUNG
tions; 4348 unique reflections (Rint =0.0456). The structure was re-
fined on F2 to Rw =0.1052; R=0.0399 (4348 reflections with I>
2s(I)) and GOF=1.061 on F2 for 242 refined parameters. Largest
difference peak and hole 1.383 and ꢀ0.805 eꢃꢀ3. CCDC 710579
contains the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/
cif.
[9] Crystal data for {Cu2C16H22N6Cl4·1.5MeOH·0.5H2O}2; 0.18ꢅ0.10ꢅ
0.02 mm; Mr =1246.68; Monoclinic; C2/c; a=33.163(4), b=
11.0684(16), c=14.2704(18) ꢃ; b=102.902(6)8; V=5105.9(12) ꢃ3;
Z=4, Z’=0.5; 1c =1.622 Mgmꢀ3
;
F
G
mACHTUNGTRENNUNG(MoKa)=
2.111 mmꢀ1; T=150 K; l
ACHTUNGTRENNUNG
flections. The crystal was pseudo-merohedrally twinned by rotation
about the crystallographic c-axis (twin law: ꢀ1 0 ꢀ1, 0 ꢀ1 0, 0 0 1);
reflections were therefore not merged. The structure was refined on
F2 to Rw =0.1538; R=0.0600 (20151 reflections with I>2s(I)) and
GOF=1.080 on F2 for 301 refined parameters and 2 restraints. Larg-
est difference peak and hole 1.965 and ꢀ0.499 eꢃꢀ3. The refined
fractional occupancy of the minor crystal domain converged to
0.08313(84). CCDC 710580 contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[4] Crystal data for C16H22N6; 0.6ꢅ0.6ꢅ0.6 mm; Mr =298.40, Monoclin-
ic, P21/n, a=9.0171(8), b=10.4120(9), c=16.4432(15) ꢃ; b=
92.592(2)8; V=1542.2(2) ꢃ3; Z=4; Z’=1; 1c =1.285 Mgmꢀ3
ACHTUNGTRENNUNG(000)=640; mACHTUNGTRENNUNG ACHUTNGTRENN(NUG MoKa)=0.71073 ꢃ;
;
F-
(MoKa)=0.082 mmꢀ1; T=100 K; l
15305 measured reflections; 3806 unique reflections (Rint =0.0284).
The structure was refined on F2 to Rw =0.0986; R=0.0384 (3806 re-
flections with I>2s(I)) and GOF=0.771 on F2 for 287 refined pa-
[10] a) J. Hamacek, M. Borkovec, C. Piguet, Chem. Eur. J. 2005, 11,
5217; b) J. Hamacek, M. Borkovec, C. Piguet, Chem. Eur. J. 2005,
11, 5227.
[11] a) G. Ercolani, C. Piguet, M. Borkovec, J. Hamacek, J. Phys. Chem.
B 2007, 111, 12195; b) N. Dalla-Favera, J. Hamacek, M. Borkovec,
D. Jeannerat, F. Gumy, J.-C. G. Bꢆnzli, G. Ercolani, C. Piguet,
Chem. Eur. J. 2008, 14, 2994.
[12] G. Ercolani, L. Schiaffino, Angew. Chem. 2011, 123, 1800; Angew.
Chem. Int. Ed. 2011, 50, 1762.
[13] a) G. Canard, C. Piguet, Inorg. Chem. 2007, 46, 3511; b) T. Riis-Jo-
hannessen, N. Dalla-Favera, T. K. Todorova, S. M. Huber, L Gagliar-
di, C. Piguet, Chem. Eur. J. 2009, 15, 12702.
rameters. Largest difference peak and hole 0.350 and ꢀ0.207 eꢃꢀ3
.
CCDC 710578 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
[5] C. R. Rice, S. Onions, N. Vidal, J. D. Wallis, M. C. Senna, M. Pilking-
ton, H. Stoeckli-Evans, Eur. J. Inorg. Chem. 2002, 1985.
[6] a) C. Naumann, H. Langhals, Synthesis 1990, 279; b) J. Rebek, Jr.,
R. V. Wattley, J. Heterocycl. Chem. 1980, 17, 749.
[7] See the Supporting Information for experimental details. Treatment
of titration data performed with the SPECFIT program; a) H.
Gampp, M. Maeder, C. J. Meyer, A. D. Zuberbꢆhler, Talanta 1986,
Received: October 12, 2011
Published online: February 23, 2012
Chem. Eur. J. 2012, 18, 3464 – 3467
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
3467