Rational ligand design for metal ion recognition. Synthesis of a N-benzylated N2S3-donor macrocycle for enhanced silver(I) discrimination

Article abstract of DOI:10.1039/b613636m

The design and synthesis of the dibenzyl-N-substituted, 17-membered ring was carried out on the basis of four previously documented ligand design strategies for achieving Ag(I) discrimination was studied. Macrocycle was prepared by direct N-benzylation of

Full text of DOI:10.1039/b613636m

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Rational ligand design for metal ion recognition. Synthesis of a N-benzylated
N2S3-donor macrocycle for enhanced silver(I) discrimination†
Ioana M. Vasilescu,a David J. Bray,b Jack K. Clegg,b Leonard F. Lindoy,*b George V. Meehan*a and Gang Weib
Received 19th September 2006, Accepted 20th September 2006
First published as an Advance Article on the web 29th September 2006
DOI: 10.1039/b613636m
Four previously documented ligand design strategies for
achieving Ag(I) discrimination have been applied to the
design of a new N-benzylated N2S3-donor macrocycle; the
latter shows high selectivity for Ag(I) over Co(II), Ni(II),
Cu(II), Zn(II), Cd(II) and Pb(II) in log K and bulk membrane
transport studies.
We have previously reported the synthesis of an extended series
of 16- to 19-membered, dibenzo-substituted macrocycles incor-
porating oxygen, nitrogen and/or sulfur heteroatoms.1 These
rings were synthesised as part of an investigation of structure–
function relationships underlying discrimination behaviour within
the above seven metal-ion series. Several examples of such
discrimination are documented;2–4 for example, step-wise ‘tuning’
of the donor set present within 17-membered rings of type 1
resulted in >109 discrimination for Ag(I) over Pb(II)4—metals that
are found together in nature. However discrimination for Ag(I)
over Cu(II),5 while less spectacular, was still ∼104.
system (which forms three five-membered and two six-membered
chelate rings when all donors bind to a central metal ion). In this
context it is noted that the X-ray structures of the 1 : 1 (Ag+: L)
complexes, where L = 1 with X = S, Y = O,4 X = S, Y = NH7 and
X = S, Y = S8 (all 17-membered rings) confirm coordination of all
five macrocyclic ring donors to silver in each case (with no other
ligands present in the coordination sphere). A third observation,
was that the presence of a NHCH2CH2XCH2CH2 NH (X = O or
S) donor atom sequence, rather than the corresponding sequence
with X = NH, also promotes enhanced silver discrimination;
even though the absolute log K values tend to be smaller when
X = O. Finally, in a number of studies by us and others,9 it
has been well documented that N-benzylation of a secondary
amine donor in a variety of aza macrocyclic systems leads to
enhanced discrimination for silver over a range of transition
and post-transition metal ions—behaviour we have previously
termed ‘selective detuning’.10 For example, it has been reported
that N-benzylation of the nitrogen donors in a number of mixed
nitrogen–oxygen donor macrocycles leads to enhanced metal ion
discrimination for Ag(I) within the transition and post transition
metal ions mentioned previously.11,12
Related behaviour to the above has been reported for the
tetra-N-benzylated derivative of cyclam (tbc), which shows both
substantial affinity and selectivity for Ag(I).13 For example, in
bulk liquid (water–dichloromethane–water) membrane transport
experiments14 it was found that silver (as its perchlorate) was
the only cation transported by tbc relative to the perchlorates of
lithium, sodium, potassium, ammonium, caesium, barium, lead,
calcium, magnesium, cobalt, nickel, copper and zinc under the
conditions employed.
In our previous (wide-ranging) studies involving ligands of type
1 four design elements that influence the discrimination for Ag(I)
over the above transition and post-transition ions are documented:
(i) the macrocyclic ring size, (ii) the macrocyclic donor set, (iii)
macrocyclic donor atom sequence and (iv) the nature of any
donor atom substituents present. We have now applied the ‘lessons
learnt’ in the these studies to the design and synthesis of the new
macrocyclic ligand 2 which was thus anticipated to yield enhanced
discrimination for Ag(I) over the other six transition and post-
transition ions mentioned above.
In the previous studies, as expected from a consideration of
HSAB theory,6 it was confirmed that progressive substitution of
thioether sulfur atoms for oxygen in an O3N2-donor ring of type
1 led to increased silver ion discrimination. A second general
observation was that both the strength of binding as well as
silver ion discrimination tended to peak for the 17-membered ring
In the present study, the design and synthesis of the dibenzyl-N-
substituted, 17-membered ring 2 (which contains a S3N2-donor set
as well as a desired-N–S–N-donor atom sequence) was carried out
based on all four design elements mentioned earlier. Macrocycle
2 was prepared by direct N-benzylation of its unsubstituted
precursor 1 (X = Y = S) using benzyl bromide in acetonitrile
in the presence of sodium hydrogen carbonate as base.‡
Stability constants for the 1 : 1 complexes of 2 with Co(II),
Ni(II), Cu(II), Zn(II), Cd(II), Ag(I) and Pb(II) were investigated
potentiometrically by the pH titration method in 95% methanol
aSchool of Pharmacy and Molecular Sciences, James Cook University,
Townsville, Q. 4811, Australia
bCentre for Heavy Metals Research, School of Chemistry, University of
Sydney, NSW, 2006, Australia. E-mail: lindoy@chem.usyd.edu.au;
Fax: +61 2 9351 3329; Tel: +61 2 9351 4400
† Electronic supplementary information (ESI) available: Details of X-ray
determination. See DOI: 10.1039/b613636m
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Table 1 Log K values for the 1 : 1 complexes of 1 (X = Y = S) and 2 in 95% methanol (I = 0.1, Et4NClO4) at 25.0 ◦
C
Ligand
Co(II)
Ni(II)
Cu(II)
Zn(II)
Cd(II)
Ag(I)
Pb(II)
c
c
1a,b
2
<3.5
<3
8.1
3.6
∼3.3
<3
12.4
8.7
∼3
∼3
<3
<3
a X = Y = S. b Values from ref. 2–4. c Precipitation or slow approach to equilibrium prevented log K determination.
(I = 0.1, Et4NClO4; 25.0 ◦C) under identical conditions to
those described previously;9 use of this solvent system allowed
comparison with the log K values determined previously.
The results are summarised in Table 1. As for its non-
dibenzylated derivative 1 (X = Y = S), 2 shows clear discrimination
for Ag(I) over the remaining six metals, with the silver complex
being at least 105 more stable than any of the remaining complexes
investigated. In particular, Ag(I)/Cu(II) discrimination is almost
an order of magnitude higher for the latter ligand even though (and
as expected) steric15 and electronic influences on N-benzylation of
1 (X = Y = S) result in a general reduction of the respective
log K values for the complexes of 2. Once again the results
provide an example of ‘selective detuning’ of the type described
previously.9,10 A rationale for N-alkylation in related macrocyclic
systems favouring monovalent over divalent metal-ion binding has
been presented elsewhere.16,17
As might be predicted, the ESI mass spectrum of a mixture of 2
and Ag(I) nitrate in a methanol–acetonitrile mixture yielded a peak
corresponding to formation of the 1 : 1 complex, AgL+ (L = 2)
and a solid complex of this stoichiometry was isolated as its hexa-
fluorophosphate salt on reaction of silver hexafluorophosphate
with 2 in acetonitrile–dichloromethane.§
Bulk membrane (H2O–CHCl3–H2O) transport studies across
a pH gradient were performed employing 2 as the ionophore in
a ‘concentric cell’ apparatus described previously.18 The aqueous
source phase was buffered at pH 4.9 and contained an equimolar
solution of the nitrate salts of Co(II), Ni(II), Zn(II), Cu(II), Cd(II),
Pb(II) and Ag(I), each at a concentration of 1 × 10−2 M. The
Fig. 1 An ORTEP plot of the [Ag2]+ cation in [Ag2]PF6·MeCN shown
with 50% probability ellipsoids. Solvent acetonitrile and counter-ion
omitted for clarity.
chloroform phase contained 2 at 1 × 10−3 M. The aqueous
receiving phase was buffered at pH 3.0 0.1 and the transport
runs were terminated after 24 h; these are identical conditions to
those employed previously.19
Sole transport selectivity for Ag(I) was observed; that is, silver
was transported with a flux corresponding to 137 × 10−7 moles
per 24 h while no transport of the other six metals present in the
source phase occurred.
The X-ray structure of [Ag2]PF6·CH3CN (Fig. 1) shows that
the Ag(I) ion is bound to all donor atoms of 2 in the complex
cation and adopts a ‘tight’ (see the space-filling representation
given in Fig. 2), distorted trigonal bipyramidal geometry.¶ This
is in keeping with the presence of the strong ligand to silver
coordination inferred from the solution studies. Interestingly, there
is an acetonitrile molecule present in the lattice but it is not
coordinated despite the known affinity of this solvent for Ag(I).
Based on the results from previous studies aimed at elucidating
the factors underlying Ag(I) ion discrimination, we have carried
out the rational design and synthesis of the new macrocyclic ligand
2. While theory dictates that stability and transport behaviour need
not necessarily parallel each other, for the present system this was
found to occur. In both cases, 2 shows substantial discrimination
Fig. 2 A space-filling depiction of the X-ray structure of the complex
cation in [Ag2]PF6·MeCN.
5116 | Dalton Trans., 2006, 5115–5117
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for silver over the other six transition and post transition
metal ions investigated. Apart from the prospect of employing
2 for the sensing or separation of Ag(I), the study serves to
exemplify the use of a stepwise strategy for the rational design of
a ligand system that, in the present case, results in significantly
enhanced discrimination for Ag(I).
4H, C6H4CH2, 7.19–7.50, m, 18H, aromatic. 13C NMR (CD3CN) d
27.16, 30.04, 51.24, 56.49, 57.76, 124.98, 125.92, 127.86, 128.40, 129.21,
130.24, 131.94, 133.42, 134.27, 135.77. Crystals of X-ray quality were
obtained on slow evaporation of an acetonitrile solution of the above
product.
¶ X-Ray
structure
determination:
[Ag2]PF6·MeCN.
Formula
C36H41AgF6N3PS3, M 864.74, Monoclinic, space group P21/c (#14), a
˚
˚
˚
˚
9.1249(14) A, b 24.720(4) A, c 16.670(3) A, b 101.913(3), V 3679.3(10) A,
We thank the Australian Research Council for support.
Dc 1.561 g cm−3, Z 4, crystal size 0.348 × 0.158 × 0.120 mm, colourless,
−1
˚
prism, temperature; 150(2) K, k(MoKa) 0.71073 A, l(MoKa) 0.823 mm
,
T(SADABS)min,max 0.777, 0.906, 2h = 56.64◦, hkl range −12 12, −32 32,
Notes and references
−22 21, N 36352, Nind 8880(Rmerge 0.0501), Nobs 6610(I > 2r(I)), Nvar 452,
residuals* R1(F) 0.0383, wR2(F2) 0.0894, GoF(all) 1.016, Dmin,max −0.314,
‡ Synthesis of 1 (X = Y = S): This was prepared by a modification of a pre-
viously described method.1 2,2-Diaminoethylthioether (257.9 mg, 2 mmol)
was dissolved in absolute ethanol (250 ml) and added dropwise over a
period of 3 h to a solution of 2,2ꢀ-ethane-1,2-diyl(thio)bisbenzaldehyde
(609.5 mg, 2 mmol) in absolute ethanol (600 ml). The reaction mixture
was refluxed for 3 h, then sodium borohydride added with minimum
delay (1.0 g, 25 mmol) and refluxing continued for 12 h. The solvent was
removed on a rotary evaporator and the resulting solid was dissolved in
dichloromethane (50 ml) and 1 M sodium hydroxide solution (15 ml) was
added. The mixture was shaken and the organic layer was removed and
the sodium hydroxide solution was again extracted with dichloromethane
(50 ml). The combined organic extracts were washed with saturated sodium
chloride (20 ml), then taken to dryness on a rotary evaporator. The
resulting white solid was recrystallised from acetonitrile (493 mg, 63%). 1H
NMR (CDCl3) d 2.13, br s, 2H, NH; 2.73–2.77, m, 4H, SCH2CH2N; 2.84–
2.88, m, 4H, SCH2CH2N; 3.23, s, 4H, SCH2CH2S; 3.87, s, 4H, ArCH2;
7.18–7.34, m, 8H, C6H4. 13C NMR (CDCl3) d 32.9, 33.9, 48.2, 52.3,
126.9, 127.9, 130.6, 130.8, 134.2, 140.7. These data correspond to those
reported previously for this compound; the above procedure resulted in a
significantly enhanced yield over that reported for the existing preparation.
§ Synthesis of 2: Sodium hydrogen carbonate (1.32 g, 15.7 mmol) was
added with stirring to a solution of 1 (X = Y = S) (0.350 g, 0.8 mmol) in
acetonitrile (50 ml) and the mixture was heated to reflux. Benzyl bromide
(0.306 g, 1.79 mmol) in acetonitrile (75 ml) was added dropwise over
1.5 h. The reaction mixture was filtered and the filtrate was taken to
dryness on a rotary evaporator. The solid that remained was partitioned
between water (50 ml) and dichloromethane (100 ml). The organic layer
was separated and the water layer was washed with a further 2 × 50 ml of
dichloromethane. The combined organic fractions were backwashed with
water (50 ml), dried over anhydrous sodium sulfate, filtered, and the solvent
removed on a rotary evaporator. The resulting solid was recrystallised
from acetone–methanol (1 : 1) containing small amounts of acetonitrile
and dichloromethane (Yield, 0.326 g, 63.8%). (Found: C, 69.87; H, 6.18; N,
4.85%. C34H38N2S3 requires C, 69.48; H, 6.55; N, 4.73%). 1H NMR (CDCl3)
d 2.58–2.63, m, 4H, SCH2CH2N; 2.71–2.76, m, 4H, SCH2CH2N; 3.16, s,
4H, SCH2CH2S; 3.56, s, 4H, C6H5CH2; 3.73, s, 4H, ArCH2; 7.14–7.43, m,
18H, arom. 13C NMR (CDCl3) d 28.7, 33.9, 54.4, 57.0, 57.7, 126.1, 126.8,
127.4, 128.1, 128.6, 129.8, 130.0, 135.1, 139.3, 140.5. MS ESI (methanol):
m/z = 571.2 (M + H)+; when Ag(I) nitrate was added to the ligand sample
the ESI (methanol–acetonitrile) spectrum also yielded a peak at m/z =
679.3 corresponding to (M + Ag)+. Synthesis of [Ag(2)]PF6·0.5CH3CN:
AgPF6 (53 mg, 0.21 mmol) in acetonitrile (4 ml) was added to 2 (118 mg,
0.21 mmol) in dichloromethane (2 ml). Diethyl ether vapour was slowly
diffused into this solution to yield needle-like crystals which were filtered
off and washed with diethyl ether. These crystals were crushed and dried
under vacuum before microanalysis. (143 mg, 84%). Mp 126–128 ◦C. MS
(ESI): m/z = 679.3 (M + Ag)+ (Found: C, 49.84; H, 4.98; N, 4.03%.
0.608 e−
−3. *R1 = RꢁFo| − |Fcꢁ/R|Fo| for Fo > 2r(Fo); wR2 =
˚
A
2
(Rw(Fo − Fc2)2/R(wFc2)2)1/2 all reflections w = 1/[r2 (Fo2)+(0.0406P)2 +
1.5802P] where P = (Fo + 2Fc2)/3. CCDC reference number 616061.
2
For crystallographic data in CIF or other electronic format see DOI:
10.1039/b613636m
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1
C34H38AgF6N2 PS3·0.5CH3CN requires C, 49.80; H, 4.72; N, 4.15%). H
NMR (CD3CN) d 2.63–2.69, m, 4H, SCH2CH2N, 2.95–3.00, m, 4H,
SCH2CH2N, 3.36, s, 4H, SCH2CH2S, 3.66, s, 4H, C6H5CH2, 3.70, s,
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This journal is
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©