A zinc-salophen/bile-acid conjugate receptor solubilized by CTABr micelles binds phosphate in water

Article abstract of DOI:10.1039/c3ob40724a

Receptor 1, composed of two deoxycholic acid moieties appended to a Zn-salophen complex, was prepared, characterized and tested for anion binding by ¹H NMR and UV-vis spectroscopic techniques. While in polar DMSO, 1 is able to bind phosphate (K = ～700 M^-1), the addition of water severely diminishes the association. In a 1: 9 water-DMSO mixture, the binding constant K is only ca. 20 M^-1. Notably, in an aqueous solution of CTABr micelles (CTABr 10 mM, cmc = ～1 mM), the zinc-salophen conjugate 1, due to its two non-polar bile-acid moieties, becomes solubilized and, most importantly, it almost completely recovers its binding ability towards phosphate, displaying a remarkable affinity (K = ～450 M^-1) in water. is

Full text of DOI:10.1039/c3ob40724a

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A zinc–salophen/bile-acid conjugate receptor
solubilized by CTABr micelles binds phosphate in
Cite this: Org. Biomol. Chem., 2013, 11,
4585
water†
Received 11th April 2013,
Accepted 30th May 2013
Ondřej Jurček,a Massimo Cametti,*b Marta Pontini,‡a Erkki Kolehmainena and
DOI: 10.1039/c3ob40724a
Kari Rissanen*a
www.rsc.org/obc
Receptor 1, composed of two deoxycholic acid moieties appended
As evidenced by many authors, anion binding presents
to Zn–salophen complex, was prepared, characterized and several additional challenges compared to cation binding,
a
tested for anion binding by 1H NMR and UV-vis spectroscopic related to the greater size (compared to isoelectronic cations),
techniques. While in polar DMSO, 1 is able to bind phosphate (K = the smaller charge density, and their varying shapes and geo-
∼700 M−1), the addition of water severely diminishes the associ- metries and pH sensitivities. Moreover, in protic solvents and
ation. In a 1 : 9 water–DMSO mixture, the binding constant K is water, solvation/hydration energies for anions are usually high
only ca. 20 M−1. Notably, in an aqueous solution of CTABr micelles and this represents a severe obstacle to binding, which
(CTABr 10 mM, cmc = ∼1 mM), the zinc–salophen conjugate 1, explains the paucity of anion receptors able to be effective in
due to its two non-polar bile-acid moieties, becomes solubilized water or aqueous media.1a–c
and, most importantly, it almost completely recovers its binding
In general, among the plethora of different intermolecular
ability towards phosphate, displaying a remarkable affinity (K = interactions available, metal coordination is considered one of
∼450 M−1) in water.
the most efficient a receptor could rely on. In organic solvents,
metal sites are established as excellent binding centres for
anions.1,5 However, translating the same systems in water has
turned out to be difficult. Firstly, simple neutral metal com-
plexes are usually insoluble in water and this requires the
introduction of synthetic modifications, which naturally
should avoid any possible interference with the binding site.
Furthermore, once the solubility issues are solved, the
affinities observed could be lower than expected.6 A completely
different approach aims at constructing a “protective” environ-
ment around the receptor binding site that could serve as a
shield for the binding event from the competing bulk water.
Among a few successful attempts in this direction,7 a demon-
stration of the above concept for the binding of anions was
achieved by using aqueous CTABr micelles as carriers for a
simple UO2–salophen receptor.7a In that case, a strong binding
to fluoride in water, unattainable without the micellar environ-
ment, was indeed observed.
Despite the effective strong Lewis acid character and anion
binding aptitude of UO2–salophen complexes,8 uranium is
mildly radioactive and this severely limits any possible exploi-
tation of their properties in real-world applications. Hence, the
need to study other metal centers able to bind anions, for
instance, Zn(II) cation, is evident. It is well known that Lewis
basic groups are excellent axial ligands for Zn–salen and –salo-
phen complexes, and this explains why they have recently
attracted attention in a number of structural,9 catalytic10 and
host–guest chemistry studies.11
Introduction
Anions are ubiquitous in the natural world and their recog-
nition and binding constitute a central theme in Supramolecu-
lar Chemistry.1 In particular, phosphates – major components
in bio-mineralised materials, such as exoskeletons and bones,2
and essential parts of DNA and RNA3 – have prominent impor-
tance in biological processes, but also they represent signifi-
cant environmental hazards for their widespread use as
fertilizers. Hence, the development of species able to bind
phosphate and phosphorylated molecules efficiently and selec-
tively has attracted increasing attention in the last few
decades.4
aLaboratory of Organic Chemistry, Department of Chemistry, P.O. Box 35, 40014
Jyväskylä, Finland. E-mail: kari.t.rissanen@jyu.fi; Fax: +358 14 260 2501;
Tel: +358 50 562 3721
bDepartment of Chemistry, Materials and Chemical Engineering “Giulio Natta”,
Politecnico di Milano, Via Mancinelli 7, 20131 Milano, Italy.
E-mail: massimo.cametti@chem.polimi.it
†Electronic supplementary information (ESI) available: Additional information
on the absorption and binding properties of 1 in the presence of phosphate and
acetate anions in DMSO, a 9 : 1 DMSO–water mixture and water (10 mM CTABr);
31P-NMR; details of the full NMR assignment and numbering of the compounds
1 and 4. See DOI: 10.1039/c3ob40724a
‡Current address: School of Chemistry, University of Manchester, Manchester
Institute of Biotechnology, 131 Princess Street, Manchester, M1 7DN, UK.
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Anion binding properties in DMSO
While in weakly coordinated solvents, tetra-coordinated Schiff
base Zn(II)-complexes are known to auto-saturate their metal
coordination sphere by formation of dimeric species and/or
aggregates,9 in coordinating solvents such as DMSO, they
usually exist in the monomeric form and adopt a square pyra-
midal configuration at their metal centre, where the solvent is
axially coordinated. The replacement of the solvent axial
ligand by stronger donating species (amines, anions, etc.) is
known to produce significant changes in the optical pro-
perties, which can be easily monitored by UV-vis spectroscopy.
We initially investigated the anion binding properties of recep-
Scheme 1 Molecular formula of the Zn–salophen/bile-acid conjugate 1.
Here we report on the novel zinc–salophen/bile-acid receptor 1
(Scheme 1) constituted by a central Zn–salophen complex, conju-
gated with two deoxycholate amido moieties at both sides linked
by Huisgen copper-catalyzed click reaction. Receptor 1 is solubil-
ized easily in aqueous CTABr micelles. Under such conditions,
the 1·CTABr system maintains its ability to bind phosphate by
displaying a remarkable affinity. Receptor 1 represents the first
example of a metal–salophen complex specifically designed to be
incorporated into a micellar system. In this respect, bile acid moi-
eties were chosen as ideal structural units due to their proven
affinity for lipophilic membranes.12 Huisgen copper-catalyzed
click chemistry13 was employed as a convenient method to
connect the two structural elements, viz., the metal–salophen
unit and the bile acid moieties together into the new receptor 1.
1
tor 1 in DMSO, where it is soluble at 25 °C, by H-NMR titra-
tion experiments in which the time averaged signals of the
receptor were monitored as a function of increasing concen-
tration of the target anion, added as TBA salt. This preliminary
test allows also a direct comparison of the binding ability of 1
with other anion receptors reported in the recent literature.1a–c
DMSO is becoming a very popular solvent to test binding since
it might be considered as the upper limit in terms of competi-
tiveness among common aprotic solvents. As an example of a
typical experiment, the titration between a 2 mM solution of
the receptor 1 and (TBA)H2PO4 is shown in Fig. 1a. Clearly, all
Results and discussion
Synthesis
5-Azidomethyl-2-hydroxybenzaldehyde (3) was prepared in two
steps by transformation of salicylaldehyde to a corresponding
chloromethyl precursor, which was subsequently converted
into azide.14 Propargyl amide 2 was prepared via amidation of
deoxycholic acid by propargyl amine in the presence of DCC
and DMAP. Compounds 2 and 3 were connected by Huisgen
copper-catalyzed click chemistry to form the 1,2,3-triazole ring
and give compound 4. Two units of 4 were merged together by
formation of bis-Schiff base with ortho-phenylenediamine in
order to afford the final ligand. Subsequent addition of Zn(II)
salt (one-pot) led to the receptor 1 in 80% yield (Scheme 2).
Fig. 1 (a) Chemical shift variations observed for signals of 2 mM 1 upon
addition of increasing amounts of (TBA)H2PO4 (from bottom to top) in DMSO-
d6 at 300 K; (b) a plot of the chemical shift variations observed for the imine
CHvN signal of 1 vs. (TBA)X concentration (X = Cl−, AcO−, H2PO4−) in DMSO-d6
at 300 K (lines represent best fit curves for each data set).
Scheme 2 Synthetic procedure for 1.
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the receptor protons display a shift upon addition of increas-
The UV-vis spectrum of compound 1 in water (1% DMSO,
ing aliquots of the anion (from bottom to top). With the excep- CTABr 10 mM) displays unstructured absorption with two main
tion of the signal around 8.15 ppm,15 the observed chemical bands around 295 and 400 nm, hypsochromic shifted with
shifts are shielded (upfield) and they were interpreted as due respect to those observed in DMSO (299 and 403 nm, respect-
to the increase of electron density on the salophen framework ively). The close adherence to the Lambert–Beer law at different
upon formation of the negatively charged [1-phosphate]− wavelengths (ESI†) indicates the absence of significant aggrega-
complex. The anion is expected to interact with the Zn(II) tion phenomena within the range of concentrations explored.
centre via
a
coordinative bond thus forming
a
penta-
A plot of the UV-vis absorption changes of the 1·CTABr
system upon addition of (TBA)H2PO4 in water (10 mM CTABr,
coordinated square pyramidal complex.11
A plot of the observed δ of iminic protons versus the phos- 1% DMSO) is shown in Fig. 2a. The most evident effect is
○
phate ( ) concentration is shown in Fig. 1b, along with the δ related to the decrease of intensity of the characteristic band
variations observed upon addition of Cl− ( ) and acetate (
centered at 400 nm by increasing the anion concentration.
●
▼
)
anions. Each data set can be easily fitted by making use of a Three isosbestic points (284, 321 and 372 nm) can be easily
non-linear least squares method and applying a 1 : 1 binding spotted, hinting at the presence of two species, viz., 1 and
isotherm equation. Measurements were run in duplicate and [1-phosphate]− complex, responsible for the absorption. Profiles
the σ-weighted average of the association constants16 for each of the absorbance (at 355 and 400 nm) versus phosphate con-
anion is reported in Table 1. Acetate and phosphate anions are centration are shown in Fig. 2b. Data analysis confirms the
bound to 1 to a similar extent, while chloride displays a lower presence of a 1 : 1 equilibrium and affords an association con-
affinity. In the case of phosphate, the association constant was stant K of 450 30 M−1 (Δε = −8050 and 3240 at 400 and
also confirmed by independent UV-vis titration experiments 355 nm, respectively).17 This figure is, remarkably, of the same
(see the ESI†). In the case of (TBA)H2PO4, 31P NMR was also order of magnitude of the binding in DMSO (ca. 60%) and
attempted but without success (see the ESI†).
demonstrates that the micellar environment has an influence
Not surprisingly, addition of water to the DMSO solution not only on the solubility of 1 in water, but also on its affinity
strongly reduced the binding. For example, in a 1 : 9 water–
DMSO mixture, the association constant K for phosphate
drops to ca. 20 M−1 (see Fig. S1 in the ESI†). This finding,
again, illustrates the intrinsic difficulty that anion receptors
encounter in the presence of a strongly competing solvent. In
pure water, had 1 been soluble, a negligible association could
be expected.
Anion binding properties in CTABr–water
Although the Zn–salophen receptor 1 is insoluble in water, its
two amphiphilic deoxycholic acid moieties enhance its lipo-
philic nature and strongly affect the solubility in organic
pseudo-phases (viz., micelle). Consequently, 1 can be solubil-
ized into aqueous CTABr micelles. The solubilization process
is availed by adding a concentrated DMSO solution of 1 into
the CTABr–water solution to
a final 99 : 1 water–DMSO
mixture, which becomes coloured of an intense yellow. The
solubilization of 1 in the presence of CTABr is effective only
above the critical micellar concentration (cmc) of CTABr (ca.
1 mM), whereas sodium dodecyl sulphate (SDS) and sodium
deoxycholate systems, below and above their cmc, do not yield
appreciable results.
Table 1 Association constants (K, M−1) for complexes between Zn–salophen
complex 1 and selected anions in DMSO-d6 at 300 K
Anion
K ( σ)
Δδ (CHvN), ppm
Chloride
Phosphate
215
5
−0.186
−0.177
—
−0.205
—
720 30
(680 30, Δε403 = −1740)a
830 50
Fig. 2 (a) Absorption spectra taken over the course of the titration of a 1%
DMSO–water solution of 1 (0.1 mM) with (TBA)H2PO4 in the presence of CTABr
(10 mM) at 25 °C; (b) a plot of the absorbance (355 and 400 nm) vs. phosphate
concentration and best fit curves, represented as full lines.
Acetate
Phosphatea,b
20 3 (Δε403 = −5450)
a By UV-vis spectroscopy; b in DMSO–water 9 : 1.
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for phosphate anion whose binding can be achieved also in investigate the influence of different bile-acid derivatives either
water (having in mind that in a 1 : 9 water–DMSO mixture the symmetrically or non-symmetrically decorating the central
affinity is ca. 22 times lower). The selectivity of the binding binding unit, aiming at an increased complex’s solubility.
was also tested over chloride and acetate. Interestingly, ana-
logous titration experiments with (TBA)Cl do not show any sig-
nificant variation of the absorption of 1, thus indicating
Experimental section
absence of binding. Spectral variations in the visible region are
General methods
observed upon addition of (TBA)AcO under the same experi-
All the materials were purchased and used as received. 5-Azido-
methyl-2-hydroxybenzaldehyde (3) was prepared by following a
published procedure.14 The 1H and 13C NMR spectra were
recorded using Bruker Avance DPX250 and DRX500 FT NMR
spectrometers. Mass spectra were recorded by ESI-TOF Bruker
instrument model Micromass LCT. DLS studies were per-
formed on the N5 Submicron particle size analyzer.
mental conditions. However, the data do not lend themselves
to a simple analytical interpretation. Indeed, the initial linear
dependence of Abs vs. AcO− concentration is followed, at con-
centration above ca. 0.01 M, by a second linear tract having a
smaller slope, but with no indication of reaching any plateau
(see the ESI†). Such a trend is not consistent with a simple 1 : 1
binding event, despite the presence of isosbestic points.
Leaving quantitative information aside, the comparison of the
absorption response of 1 to the addition of acetate and phos-
phate strongly suggests a higher affinity for the latter anion
Synthesis
N-(Prop-2-yn-1-yl)-3α,12α-dihydroxy-5β-cholan-24-amide (2).
(see Fig. 6S in the ESI†). However, preliminary data collected Deoxycholic acid (1.92 g; 4.9 mmol) was dissolved in THF
by DLS show that the addition of acetate (especially at concen- (40 mL), and then DMAP (59 mg; 0.5 mmol) and propargyl
tration higher than 0.01 M) might have an effect on the size of amine (0.84 mL; 12.2 mmol) were added under stirring. After
the CTABr micelles. This introduces an additional variable to cooling down the reaction mixture with an ice-water bath, DCC
the supramolecular system which needs to be fully analyzed.
(1.31 g; 6.4 mmol) was added. The reaction mixture was stirred
overnight at room temperature and then filtered off and urea
precipitated. The mixture was diluted with dichloromethane
(30 mL) and washed with 1 M HCl (15 mL), sat. NaHCO3 (10 mL)
and brine (20 mL). The organic layer was dried over Na2SO4 and
Conclusions
Anion binding in water by abiotic receptors remains a chal- the solvents were removed under reduced pressure. The crude
lenge, especially if the comparison with natural anion binders, product was purified by column chromatography on silica gel
such as anion binding proteins,18 is elicited. Despite being not using acetone–dichloromethane 3 : 1 as an eluent. The analytical
well investigated, one practicable strategy to obtain high data for compound 2 were similar to those already published.22
affinities in water might rely on making the binding event to
N-{[1-(3-Formyl-4-hydroxybenzyl)-1H-1,2,3-triazol-4-yl]methyl}-
occur in a more favourable environment. Micellar interior and/ 3α,12α-dihydroxy-5β-cholan-24-amide (4). (+)Sodium L-ascor-
or surface could provide an alternative environment to a given bate (26 mg; 1 × 10−4 mol) and CuSO4·5H2O (42 mg;
receptor, thus improving the affinity for the target analyte. 0.2 mmol) were added in one portion to a stirred mixture of
Here, the Zn–salophen/bile-acid conjugate, 1, insoluble in propargyl deoxycholanamide (2) (300 mg; 0.7 mmol) in water
pure water and scarcely able to bind phosphate in 9 : 1 DMSO– (2 mL) and ethanol (4 mL). Subsequently, a solution of 3
water, becomes solubilized into aqueous CTABr micelles (124 mg; 0.7 mmol) in ethanol (1 mL) was added. The reaction
(10 mM). More importantly, in this novel environment, 1 is mixture was stirred for 2 h at room temperature and then left
capable of binding phosphate with an affinity similar to that under reflux until TLC showed the complete conversion. The
in pure DMSO and, remarkably, more than 20 times higher solvent was evaporated. Product 4 was obtained in 95% yield,
than that measured in 9 : 1 DMSO–water. Also, the selectivity after column chromatography, using dichloromethane–metha-
over chloride anion improves significantly.
nol 10 : 1 as an eluent. 1H NMR (500 MHz, CDCl3): δ = 11.04 (s,
Considering the average aggregation number of micelles 1H, C3′-OH), 9.87 (s, 1H, H-1′), 7.55 (s, 1H, H-27), 7.52 (d, J7′,5′
made of CTABr at 10 mM around 300 K (of the order of 102) and = 2.3 Hz, 1H, H-7′), 7.46 (dd, J5′,4′ = 8.5 Hz, J5′,7′ = 2.3 Hz, 1H,
the relative concentration of 1 and the surfactants monomer H-5′), 6.99 (d, J4′,5′ = 8.5 Hz, 1H, H-4′), 6.56 (t, JNH,25 = 5.4 Hz,
(1 : 100), we expect that, approximately, each micelle contains 1H, –NH–), 5.47 (s, 2H, H-8′), 4.45 (d, J25,NH = 5.4 Hz, 2H,
no more than a single Zn–salophen/bile-acid conjugate 1.
H-25), 3.94 (br. s, 1H, H-12), 3.60 (m, 1H, H-3), 1.99–2.33 (2 ×
This work demonstrates the validity of a less conventional m, 2H, H-23), 0.95–1.95 (steroidal 26H), 0.91 (d, J20,21 = 6.1 Hz,
approach in the study of binding in solution, and highlights the 3H, H-21), 0.90 (s, 3H, H-19), 0.64 (s, 3H, H-18); 13C NMR
importance of the 1·CTABr system as an efficient phosphate (CDCl3): δ = 196.0 (C-1′), 173.8 (C-24), 162.5 (C-3′), 145.3 (C-26),
receptor in water, also in the light of the possibility of its use in 136.2 (C-5′), 134.6 (C-7′), 127.5 (C-2′), 123.5 (C-27), 120.0 (C-6′),
anion transport through lipophilic membranes.19 Work is in pro- 118.8 (C-4′), 73.1 (C-12), 71.7 (C-3), 53.4 (C-8′), 48.3 (C-14), 46.9
gress to explicate the effect of different metal ions and formal (C-17), 46.5 (C-13), 42.1 (C-5), 36.4 (C-8), 36.0 (C-4), 35.2 (C-1,
charge (trivalent metals such as Al(III),20 or Fe(III),21 would C-20), 34.7 (C-25), 34.1 (C-10), 33.6 (C-9), 33.1 (C-23), 31.5 (C-22),
generate a “+1” species) on the metal salophen moiety and to 30.5 (C-2), 28.7 (C-11), 27.5 (C-16), 27.1 (C-6), 26.1 (C-7), 23.6
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(C-15), 23.1 (C-19), 17.4 (C-21), 12.7 (C-18) ppm; MS (ESI-TOF)
m/z (%): 629.36 (100) [M + Na]+, 1235.82 (8) [2M + Na]+.
Notes and references
Zn–salophen complex (1). Compound 4 (200 mg; 0.3 mmol)
was dissolved in methanol (3 mL) and the solution was refluxed
at 50 °C for 30 min. Subsequently, ortho-phenylenediamine
(18 mg; 0.2 mmol) in methanol (1 mL) and Zn(AcO)2·2H2O
(80 mg; 0.4 mmol) in methanol (1 mL) were added. The reaction
mixture turned orange after the addition of the amine com-
pound and then yellow after the addition of the zinc salt. The
reaction mixture was stirred and left under reflux (55 °C) over-
night. The product was observed on a TLC plate as a yellow spot
fluorescent at 365 nm and it precipitated out from the reaction
mixture after cooling it down (0 °C, in the fridge). Product 1 was
obtained as a yellow crystalline solid in 80% yield. 1H NMR
(500 MHz, DMSO-d6): δ = 8.99 (s, 2H, H-1′), 8.23 (t, JNH,25 = 5.5
Hz, 2H, –NH–), 7.90 (dd, J11a′,11b′ = 3.4 Hz, J10′,11a′ = 6.1 Hz, 2H,
H-11′), 7.85 (s, 2H, H-27), 7.44 (d, J7′,5′ = 2.3 Hz, 2H, H-7′), 7.38
(dd, J11a′,11b′ = 3.4 Hz, J10′,11a′ = 6.1 Hz, 2H, H-10′), 7.25 (dd, J5′,4′
= 8.8 Hz, J5′,7′ = 2.3 Hz, 2H, H-5′), 6.69 (d, J4′,5′ = 8.8 Hz, 2H,
H-4′), 5.39 (s, 4H, H-8′), 4.45 (d, JOH,12 = 4.2 Hz, 2H, C-12-OH),
4.24 (d, J25,NH = 5.5 Hz, 4H, H-25), 4.16 (d, JOH,3 = 4.0 Hz, 2H,
C-3-OH), 3.77 (br. s, 2H, H-12), 3.33 (m, 2H, H-3), 1.96–2.10 (2 ×
m, 4H, H-23), 0.97–1.79 (steroidal 48H), 0.88 (d, J20,21 = 6.1 Hz,
6H, H-21), 0.83 (s, 6H, H-19), 0.55 (s, 6H, H-18); 13C NMR
(DMSO-d6): δ = 172.6 (C-24), 172.0 (C-3′), 162.5 (C-1′), 145.3
(C-26), 139.3 (C-9′), 136.2 (C-7′), 134.6 (C-5′), 127.5 (C-10′), 123.5
(C-4′), 122.3 (C-27), 120.0 (C-6′), 118.8 (C-2′), 116.6 (C-11′), 71.0
(C-12), 69.9 (C-3), 52.6 (C-8′), 48.6 (C-14), 46.1 (C-17), 46.0 (C-13),
41.6 (C-5), 36.3 (C-8), 35.6 (C-4), 35.1 (C-20), 35.0 (C-1), 34.2
(C-25), 33.8 (C-10), 32.9 (C-9), 32.3 (C-23), 31.6 (C-22), 30.2 (C-2),
28.6 (C-11), 27.2 (C-16), 27.0 (C-6), 26.1 (C-7), 23.5 (C-15), 23.1
(C-19), 17.1 (C-21), 12.4 (C-18) ppm; MS (ESI-TOF) m/z (%):
405.10 (100), 875.48 (48), 1369.83 (10) [M + Na]+.
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NMR titration. Titrations were performed by addition of
increasing small volumetric aliquots of a concentrated solu-
−
tion of the (TBA)X salts (X = Cl−, H2PO4 and AcO−) via a
Hamilton syringe to 0.6 ml of a fresh solution of 1 (2 mM)
placed in the NMR tube. All spectra were recorded on a Bruker
Avance DRX500 spectrometer (500 MHz) at 300 K. Relaxation
delay = 5 s; SW = 12 ppm; TD = 32 K, LB = 0.2 Hz; NS = 32. RG
was adjusted at high TBA salt concentration.
UV titration studies. They were carried out on a LAMBDA
850 UV-vis spectrophotometer stabilized at 300 K. A DMSO
stock solution of 1 was added to 2 mL of a 10 mM CTABr water
solution in the quartz cuvette obtaining a final concentration
equal to 0.1 mM. Increasing aliquots of a concentrated solu-
tion of the anion, in the form of tetrabutylammonium salt,
were added and the spectra recorded.
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Acknowledgements
The authors gratefully acknowledge the Programma per Giovani
Ricercatori “Rita Levi Montalcini” 2009 (MC), the Academy of
Finland (KR, project numbers 122350, 140718, 265328 and
263256) and the University of Jyväskylä for financial support.
This journal is © The Royal Society of Chemistry 2013
Org. Biomol. Chem., 2013, 11, 4585–4590 | 4589

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Communication
Organic & Biomolecular Chemistry
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Struct. Rep. Online, 2010, 66, m1090.
ꢀ
ꢁ ꢀ
ꢁ
P
P
K ¼
N Ki=σ2i
=
N 1=σ2i , where σ corresponds to the 22 S. Ikonen, H. Macíčková-Cahová, R. Pohl, M. Šanda and
i
i
single measurement fit error.
M. Hocek, Org. Biomol. Chem., 2010, 8, 1194–1201.
4590 | Org. Biomol. Chem., 2013, 11, 4585–4590
This journal is © The Royal Society of Chemistry 2013