Regioselectively N-functionalised 14-membered azapyridinomacrocycles bearing trialkanoic acid side chains as ligands for lanthanide ions

Article abstract of DOI:10.1002/ejoc.200400264

Four 14-membered azamacrocycles 2a-d, each containing a pyridine moiety and three acetic and/or propionic acid pendent arms, were prepared from regioselectively functionalised polyamines. The stability constants of the lanthanide complexes (La, Pr, Nd, Eu, Gd, Tb, Er, Yb, Lu) formed with the triacetic acid compound 2a were determined by spectroscopic methods (luminescence and/or UV/Vis spectroscopy). Other characteristics of the luminescent Eu^III and Tb^III complexes formed with the triacetic acid derivative 2a were also evaluated. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.

Full text of DOI:10.1002/ejoc.200400264

FULL PAPER
Regioselectively N-Functionalised 14-Membered Azapyridinomacrocycles
Bearing Trialkanoic Acid Side Chains as Ligands for Lanthanide Ions
[a]
[b]
[a]
[c]
´
Fabienne Dioury, Isabelle Sylvestre, Jean-Michel Siaugue, Veronique Wintgens,
[a]
[a]
[d]
[a]
´
Clotilde Ferroud, Alain Favre-Reguillon, Jacques Foos, and Alain Guy*
Keywords: Lanthanides / Luminescence / Macrocyclic ligands / N,O ligands / UV/Vis spectroscopy
Four 14-membered azamacrocycles 2a−d, each containing a
pyridine moiety and three acetic and/or propionic acid pen-
dent arms, were prepared from regioselectively func-
tionalised polyamines. The stability constants of the lanthan-
ide complexes (La, Pr, Nd, Eu, Gd, Tb, Er, Yb, Lu) formed
with the triacetic acid compound 2a were determined by
spectroscopic methods (luminescence and/or UV/Vis spec-
troscopy). Other characteristics of the luminescent EuIII and
TbIII complexes formed with the triacetic acid derivative 2a
were also evaluated.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2004)
Introduction
structural requirements that govern the formation of com-
plexes with lanthanides in terms of kinetics and thermo-
During the past decades, chelating agents based on aza- dynamics. In order to evaluate the influence of the macro-
macrocyclic backbones have proved to be extremely valu- cyclic size, together with the size of the chelation rings in-
able for the generation of aqueous stable lanthanide com- volving the cation, we report here the synthesis of the
plexes. In particular, aminocarboxylate derivatives have homologous 14-membered azapyridinomacrocycles 2aϪd
been shown to form highly stable lanthanide chelates,[1] and (Figure 1). The complexing properties of compound 2a
have consequently found valuable medical applications, towards various lanthanide cations were examined, together
either as diagnostic[2] or as therapeutic agents.[3] On the with further characteristics of the luminescent europium
other hand, the separation of f-elements is of interest for and terbium complexes.
the development of depollution processes, in particular for
the backend of nuclear fuel cycle.[4] f-Element group separ-
ation (lanthanides versus actinides) and separations of indi-
vidual members of the two groups are difficult, due to their
very similar chemical properties in solution.[5] However, the
radius size of the cation and/or its degree of hardness could
constitute discriminating factors.
We have previously reported the synthesis of the 12-mem-
bered azapyridinomacrocycles 1aϪd (Figure 1) and a pre-
liminary evaluation of their capability to chelate Eu3ϩ
cation.[6] In the context of a program aimed at the synthesis
of selective ionophores, we are interested in establishing the
Figure 1. Azapyridinomacrocycles as ligand for lanthanide cations
[a]
Laboratoire de Chimie Organique Ϫ UMR CNRS 7084, Case
´
303, Conservatoire National des Arts et Metiers,
We identified macrocyclic pyridine derivatives 1 and 2 as
valuable targets for the complexation of lanthanide cations
for various reasons:
Ϫ the presence of seven potential O- or N-donor atoms
would satisfy the electronic demand of lanthanide cations,
known for having coordination numbers of 8 or 9;[7] more-
over, the hard/hard interactions between the two compo-
nents might ensure good stability of the corresponding
complex,
´
2 rue Conte, 75003 Paris, France
Fax: (internat.) ϩ 33-1-42710534
E-mail: guy@cnam.fr
[b]
[c]
Department of Chemistry, University of Leeds,
Leeds, LS2 9JT, UK
`
Laboratoire de Recherches sur les Polymeres Ϫ UMR CNRS
7581, CNRS, Bat. H,
2Ϫ8 rue Henri Dunant, B. P. 28, 94320 Thiais, France
Laboratoire des Sciences Nucleaires, Case 304, Conservatoire
[d]
´
´
National des Arts et Metiers,
´
2 rue Conte, 75003 Paris, France
4424
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DOI: 10.1002/ejoc.200400264
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Azapyridinomacrocycles Bearing Trialkanoic Acid Side Chains as Ligands for Lanthanide Ions
FULL PAPER
Ϫ the macrocyclic backbone, by diminishing the degree
of free rotation, might preorganise the chelation sites, which
could be valuable for rapid complexation kinetics,
Ϫ this azapyridinomacrocyclic skeleton allows studies of
the effect of small structural changes on the complexation
properties; indeed, both the size of the macrocyclic cavity
and the sizes of chelation cycles involving the cation, the
nature of the side chains as ligating moiety and the nature
of substitutions on the diaminoalkyl subunits could be
studied, and
Ϫ the presence of a pyridine moiety (i) constitutes an-
other element of rigidification, (ii) introduces a less hard
nitrogen atom, which is a possible discriminating element
for the selective f-element complexation, (iii) offers posi-
tions for the introduction of an anchor group, thus ex-
tending the application areas, and (iv) allows the evaluation
of the complexing properties of the ligand by spectro-
scopic methods.
Results and Discussion
Synthesis of the 14-Membered Azapyridinomacrocyclic
Ligands 2a؊d
Two different routes for the synthesis of the targeted mol-
ecules 2aϪd can be envisaged, as shown in Scheme 1. Route
A appears to be the more straightforward, as macrocycles
Scheme 1
2aϪd would result from N-alkylation(s) of the known tetra-
azamacrocycle 3.[8] This route is particularly well adapted
to the synthesis of macrocycles 2a and 2b, with identical oped a new synthetic route involving the macrocyclic tri-
side chains (n ϭ m), while for macrocycles 2c and 2d, with tert-butyl ester 4a. When the parent macrocycle 3 was
different side chains attached at nitrogen atoms, the syn- treated with an excess of tert-butyl bromoacetate in the
thetic challenge of Route A lies in the regioselective func- presence of K2CO3, the desired alkylated product could not
tionalisation of the two sets of secondary amines. Route B be isolated. Replacement of the base by Ag2CO3 as halide
constitutes an alternative approach if parent macrocycle 3 scavenger, together with strict control of the reaction time
cannot be alkylated or if the N-alkylation step is not re- (a prolonged time results in degradation products), pro-
gioselective, but this latter route lacks divergence as it re- vided the desired alkylated product 4a in 81% yield. On the
quires the preliminary synthesis of different N-func- other hand, if a large excess of tert-butyl acrylate was
tionalised polyamine blocks.
heated at reflux in a concentrated methanolic solution of
Our initial work followed the more obvious Route A. The macrocycle 3, the desired azapyridinomacrocycle 4b, bear-
parent macrocycle 3 was prepared as described previously[8] ing three tert-butyl propanoate side chains, was isolated in
(Scheme 2). The synthesis of the azapyridinomacrocycle 2a, 90% yield. Upon treatment with dry hydrogen chloride in
bearing three acetic acid side chains, through acidic hy- diethyl ether, salt-free poly(aminocarboxylic acids) 2a and
drolysis of the corresponding triethyl ester has been report- 2b were isolated in ca. 75% yields by simple filtration fol-
ed,[9a] but involved an N-alkylation step that occurred with lowed by an anion-exchange resin filtration step.
35% yield. The preparation of the corresponding tripotas-
J. Costa and R. Delgado have determined the acidity
sium salt resulting from alkaline hydrolysis of the trimethyl constants of azamacrocycle 3, and it appears that the sec-
ester has also been reported.[9b] We thus tried to obtain tris- ondary amines adjacent to the pyridine moiety NHα are
(carboxyalkyl)macrocycles 2a and 2b by direct alkylation more basic than that opposed to the pyridine moiety NHβ
with sodium chloroacetate or acrylic acid, respectively. On (see Scheme 2).[11] As a consequence, we thought that a dif-
treatment of macrocycle 3 with a small excess of sodium ference in nucleophilicity might be exploitable for the two
chloroacetate (3.5 mol-equiv.) in a pH-controlled medium sets of nitrogen atoms as well. The parent macrocycle 3 was
(pH Ն 10) and at a temperature rising from 40 to 75 °C, thus treated with a twofold molar excess of tert-butyl
the desired product 2a was obtained together with a dialkyl- bromoacetate in the presence of Ag2CO3. Monitoring of
ated one (2a/dialkylated product, 80:20). However, treat- the reaction over 7 d revealed the coexistence of a large
ment of compound 3 with a large excess of acrylic acid in amount of starting material 3 and trialkylated compound
water at 70 °C gave the desired macrocycle 2b in 81% 4a, together with other product(s), probably partially alkyl-
yield.[10] In order to prepare compound 2a, we have devel- ated. The NHα regioselective alkylation of macrocycle 3
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A. Guy et al.
FULL PAPER
more convenient route B1 to obtain macrocycles selectively
N-alkylated on the nitrogen atom opposite to the pyridine
moiety.
Scheme 3. Macrocyclisation processes envisaged for the preparation
of regioselectively N-functionalised azapyridinomacrocycles 2c
and 2d
Scheme 2. Synthesis of macrocycles 2a and 2b by Route A; reagents
and conditions: (a) see ref.[8], (b) acrylic acid, H2O, 70 °C, over-
night; (c) for 4a: tert-butyl bromoacetate (12 equiv.), Ag2CO3 (2.5
equiv.), THF, room temp., 1 h; for 4b: tert-butyl acrylate (13 equiv.),
MeOH, 70 °C, 40 h; (d) HCl, Et2O; (e) tert-butyl bromoacetate
(2 equiv.), Ag2CO3 (2 equiv.), THF, room temp., 7 d or tert-butyl
bromoacetate (2.5 equiv.), NaOH (2.5 equiv.), CH2Cl2/H2O, room
temp., 16 h; (f) tert-butyl acrylate (2 equiv.), MeOH, 70 °C, 20h
The trifluoroacetyl group has been widely used as amine
protecting group, thanks to its ease of removal under mild
conditions and its selective introduction (primary versus
secondary amines) through the use of ethyl trifluoroacetate
as a mild transferring agent.[15] For our purpose, it ap-
peared to be a protecting group of choice, as it can be selec-
tively cleaved in the presence of the tert-butyl ester protec-
tion we planned to use on the polyamino acid skeleton. The
with 2-(chloromethyl)pyridine[12] and benzyl chloride[13] in diacetamide 5 was thus obtained in a quantitative yield by
the presence of sodium hydroxide in a biphasic dichloro- treatment of 1,7-diamino-4-azaheptane with 2 mol-equiv. of
methane/water mixture had been reported to produce the ethyl trifluoroacetate (Scheme 4). The alkylation of the re-
targeted dialkylated derivatives in 75 and 55% yields, sulting secondary amine was then achieved with tert-butyl
respectively. When we extended these conditions to the al- bromoacetate or tert-butyl acrylate, to afford the corre-
kylation of compound 3 with a slight excess of tert-butyl sponding aminoalkanoates 7a and 7b in high yields (91%).
bromoacetate the system proved to be more reactive than
Unfortunately, under standard conditions (NaBH4/EtOH
the previous one, completion of the reaction being reached or NH3/MeOH/H2O or K2CO3/MeOH/H2O), all attempts
after 16 h. Unfortunately, it lacked selectivity, as a mixture to cleave the acetamide groups of compounds 7a and 7b
of at least three products, including the trialkylated 4a, was gave mixtures of two or three polar products inseparable by
recovered. An attempt to introduce two propanoic side normal-phase chromatography. It should be noted that the
chains selectively on the NHα secondary amine by treat- complexity of the mixture was a function of reaction tem-
ment with a twofold molar excess of tert-butyl acrylate also perature and time. An analogous trifluoroacetamide bear-
failed, as starting material 3 and trialkylated compound 4b ing an N-tert-butoxycarbonyl group had been reported to
were recovered together with side products.
be quantitatively cleaved with a methanolic aqueous am-
Given that Route A appeared unsuitable for the prep- monia solution.[15b] We thus prepared compound 7c by
aration of macrocycles 2c and 2d bearing different side treatment of trifluoroacetamide 5 with a stoichiometric
chains attached to nitrogen atoms, we turned our attention amount of 2-(tert-butoxycarbonyloximino)-2-phenylaceto-
to Route B, involving a prior chemoselective N-func- nitrile (BOC-ON) in the presence of triethylamine. Under
tionalisation of the polyamine skeleton. Two macrocyli- the previously reported conditions,[15b] the trifluoroacet-
sation processes, equivalent in terms of number of steps, can amide cleavage occurred to provide the diamine 9c in a
be envisaged as shown in Scheme 3: a reductive templated quantitative yield. This was evidence that the alkanoic side
amination involving copper() ion, which takes place in chains of compounds 7a and 7b were involved in the forma-
aqueous medium[8,11,14] (Route B1), or a nucleophilic sub- tion of side products during the acetamide cleavage step. In
stitution requiring a polar solvent and relatively high di- order to identify the natures of these side products, we de-
lution conditions[6a,9b] (Route B2). We first considered the cided to treat the crude mixtures arising from 7a with an
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Azapyridinomacrocycles Bearing Trialkanoic Acid Side Chains as Ligands for Lanthanide Ions
FULL PAPER
Figure 2. Derivatised side products recovered from the trifluoroace-
tamides 7a and 7b cleavage step
bonate gave the functionalised primary diamines 9a and 9b
in medium (not optimised) to quantitative yields. The re-
ductive copper()-templated amination attempts with 2,6-
pyridinedicarboxaldehyde were unsuccessful in producing
the mono-N-alkylated macrocycles 10a and 10b efficiently.
The lack of reactivity of primary diamines 9a and 9b could
be attributable to their coordinating alkanoate side chains,
which may prevent the suitable coordination of dialdehyde
and α,ω-diamine around the templating metal ion that
would favour the cyclisation.
The failure of route B1 (see Scheme 3) to produce the
macrocyclic intermediates for the preparation of the re-
gioselectively N-functionalised azapyridinomacrocycles 2c
and 2d prompted us to envisage route B2, involving the pre-
viously prepared disulfonamides 8a and 8b (Scheme 5).
When these disulfonamides were treated with 2,6-bis-
(bromomethyl)pyridine according to the previously re-
ported macrocyclisation procedure,[6] the corresponding ex-
pected macrocycles 14a and 14b were isolated in 71 and
51% yields, respectively. Cleavage of the sulfonamide sub-
units with thiophenol in the presence of sodium carbonate
gave the monofunctionalised compounds 10a and 10b,
bearing transannular secondary amine functions, in high
yields.
Scheme 4. Synthesis by route B1; reagents and conditions: (a) for
5: CF3CO2Et (2 equiv.), CH3CN, room temp., 15 h; for 6: see
ref.[16], (b) for 7a: tert-butyl bromoacetate (1.3 equiv.), DIPEA (1.3
equiv.), CH3CN, reflux, 5 h; for 7b: tert-butyl acrylate (3.5 equiv.),
MeOH, room temp., 1 d; for 7c: BOCϪON (1.2 equiv.), TEA (1.5
equiv.), THF, room temp., 1 d; for 8a: tert-butyl bromoacetate (3
equiv.), TEA (6 equiv.), THF, reflux, 1 d; for 8b: tert-butyl acrylate
(large excess), CH2Cl2/MeOH (3:1), 70 °C, 1 d; (c) from 7aϪc: aq.
NH3, MeOH or from 7a and 7b: NaBH4, EtOH or K2CO3, MeOH/
H2O; from 8a and 8b: PhSH (3 equiv.), Na2CO3 (8 equiv.), DMF,
room temp., overnight; (d) see ref.[8]
excess of benzyloxycarbonyl chloride in the presence of
triethylamine. The resulting mixtures were composed of
products 11Ϫ13, separable by normal-phase chromato-
graphy (Figure 2). For a prolonged reaction time in the
acetamide cleavage step (1 d at reflux), the two major prod-
ucts isolated were identified as compounds 11 and 13, while
a shorter reaction time (3 h at reflux were necessary for the
starting material to be consumed) resulted in the isolation
of compounds 11, 12 and 13. This latter experiment, show-
ing the coexistence of side product 11 and partially depro-
tected product 12 just after the total consumption of start-
ing material, convinced us to abandon the trifluoroacetyl
protecting group in favour of the 2-nitrobenzenesulfonyl
one. Indeed, we had previously reported a procedure for
the selective transformation of a primary amine into the
corresponding sulfonamide with a secondary amine remain-
ing unchanged.[16] Moreover, the cleavage conditions for
such sulfonamides proved to be compatible with tert-butyl
The versatile compounds 10a and 10b were further alkyl-
ated with tert-butyl acrylate and tert-butyl bromoacetate,
respectively, to give the corresponding macrocyclic tris(tert-
butyl carboxylates) 4d and 4c in 57 and 77% yields. Final
cleavage of the tert-butyl carboxylate functions with dry hy-
drogen chloride afforded the desired regioselectively func-
tionalised azapyridinomacrocycles 2c and 2d.
Complexing Properties of the Azamacrocycle 2a
A. Preliminary Assays
In buffered aqueous medium (pH ϭ 8.0), the chromo-
alkanoate subunits, as they enabled us to prepare regioselec- phoric ligand 2a is characterised in the UV region by an
absorption band due to π-π* transitions, with λmax.
tively functionalised azapyridinomacrocycles 1c and 1d.[6]
ϭ
Alkylation of disulfonamide 6 was achieved either with 261.5 nm and εmax. ϭ 3918 dm3·molϪ1·cmϪ1 (Figure 3, dot-
tert-butyl bromoacetate or with tert-butyl acrylate and ted line). In the presence of EuCl3, a red shift of the π-π*
yielded the corresponding aminoalkanoates 8a and 8b in transitions was observed, and is indicative of perturbation
85 and 91% yields, respectively (see Scheme 4). Subsequent produced by interaction between the coordinating metal ion
treatment with thiophenol in the presence of sodium car- and ligand 2a (Figure 3, solid line).
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A. Guy et al.
FULL PAPER
dence of in situ formation of an europium chelate that gives
rise to a through-space energy transfer from the excited
chromophore to the adjacent complexed lanthanide
(antenna effect[17]). The use of pyridine as luminophore is
responsible for a large Stokes shift (Ͼ 250 nm), so that there
is no overlap of the metal-centred emission bands with the
ligand-centred absorption band (Figure 3). As would be ex-
5
pected, all emissions arise from the D0 state, and the most
5
7
intense bands corresponding to the D0 Ǟ Fj (∆J ϭ 0, 1,
2, 3, 4) transitions are observed. The spectrum is dominated
5
7
by the D0 Ǟ F2 transition centred on the 613 nm peak
and integrating to 46% of total emission.
A similar study was carried out with the propionate de-
rivative 2b, which shows an absorption band in the UV re-
gion with λmax.
ϭ
262.5 nm and εmax.
ϭ
3294
dm3·molϪ1·cmϪ1. Unfortunately, it proved to be ineffective
for complexation of EuIII ion, as reflected in an absence
of UV-spectrum deformation together with the absence of
luminescence emission on excitation at λmax.. This dramatic
loss of complexing ability with enlargement of the N-ap-
pended arms from acetate to propionate encouraged us to
characterise only the all-acetate derivative 2a.
Scheme 5. Synthesis of azapyridinomacrocycles 2c and 2d by route
B2; reagents and conditions: (a) 2,6-bis(bromomethyl)pyridine (1.2
equiv.), Na2CO3 (5 equiv.), DMF, 100 °C, 1 d; (b) PhSH (3.3
equiv.), Na2CO3 (10 equiv.), DMF, room temp., 5Ϫ15 h; (c) for 4d:
tert-butyl acrylate/MeOH (6:1), 70 °C, overnight; for 4c: (i) tert-
butyl bromoacetate (5.5 equiv.), Ag2CO3 (0.3 equiv.), THF, room
temp., 1 h; (ii) HCl; (iii) Na2S; (d) HCl, Et2O, room temp., over-
night
B. Stoichiometry of the EuIII Complex Formed with
Triacetate Ligand 2a
Since the validity of the stability constant evaluation de-
pended both on the correctness of the assumptions made
concerning the species in solution and on the attainment of
equilibrium at the time of the measurement, the stoichi-
ometry of the previously examined europium chelate was
first determined and all solutions were subsequently al-
lowed to equilibrate until no more spectroscopic variation
was detectable.
The stoichiometry of the EuIII complex formed with li-
gand 2a was determined by a mol ratio method.[18] In order
to furnish a constant amount of excitation energy to the
system, a set of HEPES-buffered aqueous samples contain-
ing ligand 2a with increasing amounts of EuCl3 was ir-
radiated at the isosbestic point (262 nm). Through monitor-
ing of the luminescence intensity (615 nm) as a function of
the amount of EuCl3, a binding curve was obtained (Fig-
ure 4). Since the ligand concentration is well below the sta-
bility constants known for such complexes,[9b,19] the ti-
tration curve should exhibit an abrupt change of slope cor-
responding to the stoichiometric ratio. As expected, the
curve exhibited a break when an equimolar amount of
EuCl3 (relative to initial ligand concentration) was added,
thus being consistent with a 1:1 stoichiometry for the EuIII
chelate formed with ligand 2a.[20]
Figure 3. Absorption spectra of free ligand 2a (dotted line) and of
ligand 2a in the presence of EuCl3 (solid line, 200Ϫ320 nm) in
HEPES-buffered aqueous medium (pH ϭ 8.0); sensitised emission
spectrum (solid line, 550Ϫ750 nm) obtained by irradiation at
262 nm of the previous buffered aqueous solution of ligand 2a
and EuCl3
C. Determination of the Stability Constants of LnIII
Complexes Formed with Ligand 2a
In the absence of the antenna ligand 2a, irradiation at
262 nm (ligand-centred transition) of a buffered aqueous
EuIII-containing solution did not induce EuIII lumi-
nescence. However, the introduction of the chromophoric
In a general case, the complexation of a lanthanide cation
ligand 2a gave rise to the well-known structured EuIII emis- Ln3ϩ with a trianionic ligand L3Ϫ is described by Equa-
sion spectrum (see Figure 3, solid line), thus providing evi- tion (1).
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Azapyridinomacrocycles Bearing Trialkanoic Acid Side Chains as Ligands for Lanthanide Ions
FULL PAPER
(3)
Equation (3) shows that, for a given complex and for
fixed initial concentrations of lanthanide salt and ligand,
the luminescence intensity I is a function only of the pH.
In order to determine the stability constant of the complex
studied (KEu), we thus prepared a set of samples at different
pH values. Then, in order to furnish a constant amount of
excitation energy to the system, we determined the isosbes-
tic point from the absorption spectra of this set of samples
(Figure 5). The presence of such a point was consistent with
the assumption of a two-state chromophoric system: the
free ligand and a unique mononuclear EuIII chelate as pre-
viously examined. The set of samples was thus irradiated
at the isosbestic point (262 nm) and gave a binding curve
(Figure 6). The fitting of the theoretical curve obtained
from Equation (3) to the experimental data provided a log
KEu value of 9.54.
Figure 4. Binding curve resulting from monitoring of the lumi-
nescence intensity (615 nm) of samples containing 37.4 µ of li-
gand 2a (L0) and varying amounts of EuCl3 (Eu0: 0Ϫ150 µ) in
0.085  of KCl and 0.015  HEPES-buffered medium (pH ϭ 8.0);
the luminescence results from a UV light excitation at 262 nm; the
full circles represent actual data points and the solid line represents
the theoretical fit of data with log KEu ϭ 9.54 and Imax. ϭ 0.997
(1)
In the case of acid compounds such as ligand 2a, how-
ever, the complexation of the lanthanide cation Ln3ϩ is the
result of an ion-exchange process with the protons of the
ligand as described by Equation (2), with 0 Յ i Յ 4 as
only four of the seven basic centres of ligand 2a could be
protonated in such a medium.[9a]
(2)
Hence, depending on its intrinsic basicity, each ligand has
a different response to the proton competition, which limits
the metal ion binding providing the LnIII chelate, rep-
resented as LnL.
Figure 5. UV absorbance spectra of ligand 2a (50.00 µ) in the
presence of EuCl3 (56.25 µ) in MES-buffered aqueous medium
(0.015 ) and KCl (0.085 ); the pH varies from 5.38 to 7.52
2. LnIII Complexes (Ln: La, Pr, Nd, Eu, Gd, Tb, Er, Yb,
Lu): Stability Constants Determined by UV-Light
Absorption Spectroscopy
1. EuIII Complex: Stability Constants Determined by
Sensitised EuIII Luminescence
Given that luminescence properties characterised only a
In the case of europium (Ln ϭ Eu) and under the con- few lanthanide cations, we were interested in developing an
dition that a constant amount of energy is furnished to the alternative method of evaluation of stability constants.
studied system, the luminescence intensity I is proportional
The deformation of the absorption spectrum of ligand 2a
to the concentration of the EuIII chelate EuL.[21] Further- induced by the addition of a lanthanide salt (see Figure 3)
more, if it assumed that there is no hydrolysis of the (aquo)- is consistent with the implication of the chromophoric
metal ion, no participation of the buffer in the cation com- group in the complexation process. As a consequence, UV/
plexation, and a unique EuIII chelate, the intensity can be Vis absorption spectroscopy appeared to be a method of
expressed as a function of the pH and KEu by Equation (3), choice to determine stability constant of complexes, as it
Ϫ1
with αH ϭ 1 ϩ Ka1 10ϪpH ϩ Ka1 Ka2 10Ϫ2pH ϩ Ka1 Ka2 requires less unconventional laboratory equipment.
Ka3 10Ϫ3pH ϩ Ka1 Ka2 Ka3 Ka4 10Ϫ4pH, where Kai represents
We have previously shown that a two-state chromophoric
the stepwise protonation constant of the fully deprotonated system occurs; as a consequence, for a fixed wavelength λ,
ligand 2a,[9a] Eu0 and L0 stand for the initial concentrations the total absorbance of the solution Aλ is the sum of the
of EuCl3 and ligand, respectively, and Imax. is the lumi- absorbance of the uncomplexed chromophoric ligand
nescence intensity for total complexation of the ligand.
LH(4Ϫi)(1Ϫi)ϩ (0 Յ i Յ 4) and that of the lanthanide chelate
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A. Guy et al.
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Figure 6. Binding curve resulting from monitoring of the lumi-
nescence intensity (615 nm) of samples containing 50.00 µ of li-
gand 2a and EuCl3 (56.25 µ) as a function of the pH (0.015 
MES-buffered solutions with 0.085  of KCl); the luminescence re-
sults from UV light excitation at 262 nm; the full circles represent
actual data points and the solid line represents the theoretical fit
of data with log KEu ϭ 9.54
Figure 7. Binding curve resulting from monitoring of the relative
absorbance at 277 nm (A277 Ϫ A0277) of samples containing 50.00
µ of ligand 2a and EuCl3 (56.25 µ) as a function of the pH
(0.015  MES-buffered solutions with 0.085  of KCl); the full
circles represent actual data points and the solid line represents the
theoretical fit of data with log KEu ϭ 9.59
LnL (see Equation (2)]. With the same assumptions as
made before, and in addition that all species obey Beer’s
Table 1. Stability constants of the complexes formed with ligand 2a
and some lanthanide cations, determined at ambient temperature
law and that all the uncomplexed forms of ligand
(1Ϫi)ϩ
Ln
pH range
Number
of samples
Isosbestic
point [nm]
log KLn [a]
LH(4Ϫi)
have the same extinction coefficient, the ab-
sorbance Aλ can be expressed as a function of pH and KLn
Ϫ1
as given in Equation (4), where αH is the parameter de-
La
Pr
Nd
Eu
Gd
Tb
Er
7.57Ϫ5.64
5.66Ϫ7.35
5.53Ϫ7.53
5.38Ϫ7.52
5.29Ϫ7.61
7.54Ϫ5.66
7.56Ϫ5.58
7.75Ϫ5.06
7.58Ϫ5.52
13
15
15
17
14
12
14
15
12
261.0
261.5
262.0
262.0
262.0
261.0
262.0
261.5
261.5
8.7(2)
9.50(8)
9.50(2)
9.59(4)[b]
9.34(6)
9.68(6)
10.00(6)
10.24(8)
10.07(7)
λ
fined in Equation (3), A0 is the absorption of free ligand,
λ
Amax is the maximum absorption corresponding to the to-
tal complexation of the ligand, and Ln0 and L0 are the
initial concentrations of lanthanide salt LnCl3 and ligand,
respectively.
Yb
Lu
[a]
Unless mentioned, the number in parentheses represents the er-
[b]
ror in the last digit based on nine experiments.
three experiments.
Error based on
(4)
For a fixed wavelength λ, by plotting the variation of the
absorption (Aλ Ϫ A0λ ) as the function of the pH, a binding
curve should be obtained and, by fitting of the theoretical
curve obtained from Equation (4) to the experimental data,
the sought-after log KLn value should be determined. To
validate this approach, we first carried out the experiment
with the Eu3ϩ cation (Figure 7). The agreement of the log
KEu value found by the emission spectroscopic method and
by the new technique encouraged us to determine the sta-
bility constants of other lanthanide complexes formed with
ligand 2a.
Analogous experiments were thus carried out with eight
other lanthanide salts LnCl3 (Ln: La, Pr, Nd, Gd, Tb, Er,
Yb, Lu), and the results are listed in Table 1. On the whole,
the affinity of Ln3ϩ cations for ligand 2a rises slowly along
the lanthanide series (Figure 8). The greatest difference oc-
curs between the two extreme elements lanthanum and yt-
terbium, with a difference of about 1.5 in log KLn values.
This result is consistent with those already reported, as the
Figure 8. Stability constants of lanthanide complexes formed with
ligand 2a
Further Characterisation of the Luminescent EuIII and TbIII
Complexes Formed with Ligand 2a
The rate constants for depopulation of the excited state
difference in log KLn obtained with macrocyclic polyami- and the overall quantum yields for EuIII and TbIII species
noacetates never exceed 3.5.[1b,1c,22]
were measured in H2O and D2O and are given in Table 2.
4430
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Eur. J. Org. Chem. 2004, 4424Ϫ4436

Azapyridinomacrocycles Bearing Trialkanoic Acid Side Chains as Ligands for Lanthanide Ions
FULL PAPER
Table 2. Other properties of the complexes formed with ligand 2a and the luminescent Eu3ϩ or Tb3ϩ cations
Complex
Rate constants [msϪ1
kD2O
]
Hydration state
Luminescence quantum yield (exp. error 10%)
[a]
[a]
[c]
[e]
kH2O
∆k[b]
∆kcorr
q[d]
qЈcorr
ΦH2O
ΦD2O
[Eu ʚ 2a]
[Tb ʚ 2a]
2.56
0.66
0.64
0.31
1.92
0.35
1.67
0.29
2.0
1.5
2.00
1.44
0.015
0.215
0.064
0.391
[a]
[b]
[c]
Experimental error 5%.
∆k ϭ kH2O Ϫ kD2O
.
See ref.[23b]: corrections of Ϫ0.25 msϪ1 and Ϫ0.06 msϪ1 have been applied for
europium and terbium species, respectively, to allow for the quenching effect of closely diffusing OH oscillators (outer-sphere water
molecules). [d] See ref.[23a]: q ϭ ALn·∆k with AEu ϭ 1.05 ms and ATb ϭ 4.2 ms; the uncertainty in q is approximately Ϯ 0.5 water molecules.
[e]
See ref.[23b]: qЈcorr ϭ ALnЈ·∆kcorr with AEuЈ ϭ 1.2 ms and ATbЈ ϭ 5 ms.
The measurement of the rates of depopulation allows the Experimental Section
estimation of the hydration state of the lanthanide com-
plexes in solution.[23] For the europium species, the values
General Remarks
obtained with empirical equations established by Horrocks
or Parker are consistent with the presence of two coordi-
nated water molecules. The nonintegral values found for the
terbium species suggest that other considerations should be
taken into account in order to establish the correction fac-
tor. However, the presence of at least one water molecule in
the first coordination sphere is consistent with the higher
value of the luminescence quantum yield measured in D2O
than in H2O, as it reflects the deactivating effect of vi-
brational quenching by OH oscillators coordinated to the
metal ion. Finally, both of these results are in agreement
with the expected hepta-coordinating nature of ligand 2a,
since lanthanide cations prefer coordination numbers of 8
or 9.[7] Moreover, these complexes appears to be potential
candidates for labelling purposes, as the luminescence quan-
tum yields are consistent with those reported for related
macrocyclic triacetic ligand species.[24,25]
Syntheses of the Ligands: All reactions were monitored for com-
pletion by thin layer chromatography (TLC) performed on pre-
coated silica gel plates (Merck 60 F254); TLC plates were viewed
under UV and in an iodine chamber. Preparative chromatography
was performed by elution from columns of Silica Gel 60 (particle
size 0.040Ϫ0.063 mm). 1H and 13C NMR spectra were recorded
with a Bruker AM 400 spectrometer; external references: for solu-
1
tions in CDCl3 and CD3OD: TMS (δ ϭ0.00 ppm for both H and
13C); for solutions in D2O, dioxane (δ ϭ 67.4 ppm for 13C) and 3-
trimethylsilyl-1-propanesulfonic acid sodium salt (δ ϭ0.00 ppm for
1H). Proton signal assignments were made by first-order analysis
of the spectra and analysis of 2D 1H-1H correlation maps (COSY).
The 13C NMR assignments were supported by 2D 13C-1H corre-
lation maps (HETCOR). In the assignments of these NMR signals.
‘‘Nos’’ is used as the abbreviation for 2-nitrobenzenesulfonyl.
Coupling constants J are measured in Hz. Coupling patterns are
described by abbreviations: s (singlet), d (doublet), t (triplet), dd
(doublet of a doublet), m (multiplet), bs (broad singlet). High-reso-
lution mass spectra were taken in the positive-ion mode either by
chemical ionisation (CI-HRMS) with CH4 as the ionising gas or
by fast atom bombardment (FAB-HRMS) with ‘‘Magic Bullet’’ as
the matrix. Unless stated otherwise, all reagents were purchased
from commercial sources and were used without additional purifi-
cation.
Conclusion
In order to evaluate the influence of the size of the che-
lation rings on the stability of complexes formed between
lanthanide cations and azapyridinomacrocycles bearing
three alkanoic acid side chains, four 14-membered macro-
cycles 2aϪd were synthesised. Compounds 2a and 2b, with
identical side chains, were straightforwardly obtained by al-
kylation of the parent macrocycle 3, while compounds 2c
and 2d, with mixed pendent arms, required the preparation
of appropriate triamine blocks.
Characterisation of Ligand 2a: The UV/Vis spectra were recorded
with a Cary-100 Scan spectrophotometer operating with Cary-
WinUV software. The UV-light-induced EuIII luminescence mea-
surements were recorded with an SLM Aminco 8100 spectrofluori-
meter; corrected spectra were obtained with account being taken
of the wavelength-dependent response of the instrument. The data
analyses were performed by use of an iterative least-squares fitting
procedure; this was done with the Solver function of Microsoft
Excel which applies a nonlinear regression method. The pro-
The characterisation of these ligands in terms of com- tonation constants of ligand 2a used in these calculations were
10.27, 7.90, 5.18 and 2.4.[9a] The fluorescence quantum yields were
plexing ability in aqueous medium revealed the dramatic
measured at 293 K and determined by comparison with that of
effect of the enlargement of the pendent arms. Indeed, the
quinine sulfate in aqueous sulfuric acid solution (1 ), for which
acetate derivative 2a was able to form stable complexes with
a reference yield of 0.55 was taken.[26] The luminescence lifetimes
lanthanide cations (8.7Յ log KLn Յ 10.2), while no com-
plexation occurred with the homologous propionate 2b.
measurements were carried out at 293 K and were determined at
600 nm by excitation with a B.M. Industries frequency-quadrupled
Nd-YAG laser (266 nm, pulse duration 8 ns FWHM) with use of
a Tektronix 9310 oscilloscope to monitor the output signal of the
Moreover, ligand 2a exhibited a slight selectivity of com-
plexation along the lanthanide series (∆log KLn ഠ 1.5). This
result encouraged us to pursue this project; the study of the
influence of the nature of the ligating side chains is now
in progress.
photomultiplier. The water was distilled and then deionised with a
Millipore system, and this was used throughout. All glassware was
thoroughly rinsed with such a treated water. All LnCl3 salts were
Eur. J. Org. Chem. 2004, 4424Ϫ4436
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 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4431

A. Guy et al.
FULL PAPER
purchased from Aldrich Chemical Co as their purest hexa-or hep- CH2Cl2/MeOH (15 mL). After 24 h of stirring at 70 °C, the crude
tahydrated form (Ն 99.9%) and were used as received. [4-(2- mixture was concentrated under reduced pressure. The orange oil
Hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) and 2-(N- obtained was purified by chromatography on silica gel (EtOAc/n-
morpholino)ethanesulfonic acid (MES) were purchased as sodium
salts from Aldrich Chemical and Sigma Co, respectively. KCl was
purchased from Aldrich Chemical Co in its purest form. The pH
values of the solutions were measured with a pHM 220 Radiometer
Copenhagen pH-meter. Stock solutions (ca. 10 m) of LnCl3
heptane, 5:5 to 10:0) and yielded the title compound 8b as a yellow
oil (6.49 g, 10.31 mmol, 91%). 1H NMR (400 MHz, CDCl3, 25 °C):
δ
ϭ 1.41 [s, 9 H, C(CH3)3], 1.70 [m, 4 H, N(CH2CH2-
3
CH2NHNos)2], 2.30 (t, JH,H ϭ 7.3 Hz, 2 H, NCH2CH2CO2tBu),
2.46 [t, JH,H ϭ 6.3 Hz, 4 H, N(CH2CH2CH2NHNos)2], 2.71 (t,
3
3
(Ln ϭ La, Pr, Nd, Eu, Gd, Tb, Er, Yb, Lu) were titrated by 3JH,H ϭ 7.3 Hz, 2 H, NCH2CH2CO2tBu), 3.14 [t, JH,H ϭ 6.3 Hz,
´
ICPϪAES at the CNRS Service Central d’Analyse (Departement
4 H, N(CH2CH2CH2NHNos)2], 6.24 (broad m, 2 H, NH),
7.70Ϫ7.75 (m, 4 H, CHAr), 7.82Ϫ7.84 (m, 2 H, CHAr), 8.10Ϫ8.12
(m, 2 H, CHAr) ppm. 13C NMR (100 MHz, CDCl3, 25 °C):
´
d’Analyse Elementaire, 69390 Vernaison, France). The concen-
tration of the ligand stock solution (ca. 0.1 ) was determined by
titration with standardised EuIII solution at pH ϭ 8 on equilibrated
samples through sensitised EuIII luminescence.
δ
ϭ 26.3 [N(CH2CH2CH2NHNos)2], 28.1 [C(CH3)3], 32.1
(NCH2CH2CO2tBu), 42.8 [N(CH2CH2CH2NHNos)2], 48.8
(NCH2CH2CO2tBu), 51.6 [N(CH2CH2CH2NHNos)2], 80.7
[C(CH3)3], 125.2, 131.0, 132.7, 133.5 (CHAr), 133.6, 148.0
(Cquat,Ar), 171.9 (CO2tBu) ppm. CI-HRMS: m/z calcd. for
C25H36N5O10S2 630.1904, found 630.1891 [M ϩ H]ϩ.
1. Preparation of the Functionalised Triamines 8a and 8b
N-{3-[3-(2-Nitrobenzenesulfonylamino)propylamino]propyl}-2-
nitrobenzenesulfonamide (6): A solution of 2-nitrobenzenesulfonyl
chloride (21.28 g, 96.0 mmol, 2 equiv.) in THF (350 mL) was added
dropwise at 0 °C under argon (over 5 h) to a suspension of 1,7-
diamino-4-azaheptane (7 mL, 49.1 mmol) and anhydrous NaHCO3
(16.3 g, 194 mmol) in anhydrous THF (350 mL). The resulting mix-
ture was warmed to room temperature and stirred overnight. The
crude mixture was concentrated under reduced pressure and then
taken up in water (300 mL) and CH2Cl2 (800 mL). The aqueous
layer was further extracted with CH2Cl2 (2 ϫ 200 mL). The com-
bined organic layers were dried (Na2SO4) and concentrated under
reduced pressure. The crude product was chromatographed on sil-
ica gel (CH2Cl2/MeOH, 92:8 to 90:10) and gave the title compound
2. Preparation of the Triamines 9a and 9b. General Procedure for
the Cleavage of Sulfonamide Subunits from Functionalised Triamines
8a and 8b: In a typical procedure, a solution of triamine 8a or 8b
(3.06 mmol) in anhydrous DMF (50 mL) was cannulated into a
three-necked flask containing anhydrous Na2CO3 (2.57 g,
24.25 mmol). Thiophenol (1.0 mL, 9.74 mmol) was then added and
the suspension was stirred at room temperature under argon over-
night. The reaction mixture was concentrated under reduced pres-
sure, and the obtained crude orange oil was pre-purified by fil-
tration on a silica gel pad [CH2Cl2/MeOH, 10:0 to 0:10 then
MeOH/aq. NH3 (30%), 7:3]. The resulting oil was further purified
by chromatography on silica gel [CH2Cl2/MeOH, 5:5 to 0:10 then
MeOH/aq. NH3 (30%), 7:3].
1
6 as a white solid (13.9 g, 27.65 mmol, 56%). H NMR (400 MHz,
CDCl3, 25 °C): δ ϭ 1.72 [m, 4 H, NH(CH2CH2CH2NHNos)2],
3
2.71 [t, JH,H ϭ 6.1 Hz, 4 H, NH(CH2CH2CH2NHNos)2], 3.20 [t,
3JH,H ϭ 6.1 Hz, 4 H, NH(CH2CH2CH2NHNos)2], 7.69Ϫ7.76 (m, tert-Butyl [Bis(3-aminopropyl)amino]acetate (9a): The title com-
4 H, CHAr), 7.82Ϫ7.84 (m, 2 H, CHAr), 8.12Ϫ8.14 (m, 2 H, CHAr
ppm. 13C NMR (100 MHz, CDCl3, 25 °C): 28.6 (0.751 g, 3.06 mmol, quantitative yield). 1H NMR (400 MHz,
[NH(CH2CH2CH2NHNos)2], 43.2 [NH(CH2CH2CH2NHNos)2], CD3OD, 25 °C): δ ϭ 1.47 [s, 9 H, C(CH3)3], 1.66 [m, 4 H,
)
pound was obtained from amine 8a as an amorphous, white solid
δ
ϭ
48.1 [NH(CH2CH2CH2NHNos)2], 125.2, 131.2, 132.7, 133.4
N(CH2CH2CH2NH2)2], 2.58 [t, 3JH,H
ϭ
6.9 Hz,
6.7 Hz,
4
4
H,
H,
(CHAr), 133.5, 148.0 (Cquat,Ar) ppm. CI-HRMS: m/z calcd. for N(CH2CH2CH2NH2)2], 2.76 [t, 3JH,H
ϭ
C18H24N5O8S2 502.1066, found 502.1064 [M ϩ H]ϩ.
N(CH2CH2CH2NH2)2], 3.22 (s, 2 H, NCH2CO2tBu) ppm. 13C
NMR (100 MHz, CD3OD, 25 °C): δ ϭ 28.4 [C(CH3)3], 29.7
[N(CH2CH2CH2NH2)2], 40.9 [N(CH2CH2CH2NH2)2], 53.5
[N(CH2CH2CH2NH2)2], 57.1 (NCH2CO2tBu), 82.5 [C(CH3)3],
173.0 (CO2tBu) ppm. CI-HRMS: m/z calcd. for C12H28N3O2
246.2182, found 246.2187 [M ϩ H]ϩ.
tert-Butyl {Bis[3-(2-nitrobenzenesulfonylamino)propyl]amino}acetate
(8a): tert-Butyl bromoacetate (7.5 mL, 46.14 mmol, 3 equiv.) was
added to a solution of triamine 6 (7.83 g, 15.61 mmol) and triethyl-
amine (13 mL, 101.5 mmol) in THF (120 mL). The reaction mix-
ture was heated at reflux for 24 h and was then concentrated under
reduced pressure. The crude oil obtained was purified by chroma-
tography on silica gel (n-heptane/EtOAc, 5:5 to 2:8); the title com-
pound 8a was obtained as a yellow oil (8.17 g, 13.27 mmol, 85%).
tert-Butyl 3-[Bis(3-aminopropyl)amino]propionate (9b): The title
compound was obtained from amine 8b as an amorphous, white
1
solid (0.365 g, 1.41 mmol, 46%). H NMR (400 MHz, CD3OD, 25
1H NMR (400 MHz, CDCl3, 25 °C): δ ϭ 1.40 [s, 9 H, C(CH3)3], °C):
δ
ϭ
1.45 [s,
9
H, C(CH3)3], 1.62 [m,
4
2
4
4
2
H,
H,
H,
H,
H,
3
3
1.71 [m, 4 H, N(CH2CH2CH2NHNos)2], 2.59 [t, JH,H ϭ 6.3 Hz, N(CH2CH2CH2NH2)2], 2.38 (t, JH,H
ϭ
7.1 Hz,
7.2 Hz,
7.0 Hz,
7.1 Hz,
4 H, N(CH2CH2CH2NHNos)2], 3.15 (s, 2 H, NCH2CO2tBu), 3.19 NCH2CH2CO2tBu), 2.47 [t, 3JH,H
ϭ
[broad m, 4 H, N(CH2CH2CH2NHNos)2], 6.45 (broad m, 2 H,
N(CH2CH2CH2NH2)2], 2.65 [t, 3JH,H
ϭ
3
NH), 7.67Ϫ7.74 (m, 4 H, CHAr), 7.79Ϫ7.81 (m, 2 H, CHAr), N(CH2CH2CH2NH2)2], 2.73 (t, JH,H
ϭ
8.10Ϫ8.13 (m, 2 H, CHAr) ppm. 13C NMR (100 MHz, CDCl3, 25 NCH2CH2CO2tBu) ppm. 13C NMR (100 MHz, CD3OD, 25 °C):
°C): δ ϭ 26.7 [N(CH2CH2CH2NHNos)2], 28.1 [C(CH3)3], 42.7
[N(CH2CH2CH2NHNos)2], 52.2 [N(CH2CH2CH2NHNos)2], 55.5 (NCH2CH2CO2tBu),
(NCH2CO2tBu), 81.5 [C(CH3)3], 125.1, 131.0, 132.7, 133.3 (CHAr), (NCH2CH2CO2tBu), 52.6 [N(CH2CH2CH2NH2)2], 81.6 [C(CH3)3],
δ
ϭ
28.4 [C(CH3)3], 31.0 [N(CH2CH2CH2NH2)2], 34.3
41.0 [N(CH2CH2CH2NH2)2], 50.6
133.7, 148.0 (Cquat,Ar), 170.4 (CO2tBu) ppm. CI-HRMS: m/z calcd.
173.8 (CO2tBu) ppm. CI-HRMS: m/z calcd. for C13H30N3O2
for C24H34N5O10S2 616.1747, found 616.1735 [M ϩ H]ϩ.
260.2338, found 260.2337 [M ϩ H]ϩ.
tert-Butyl
3-{Bis[3-(2-nitrobenzenesulfonylamino)propyl]amino}- 3. General Procedure for Macrocyclisations. Treatment of 2,6-Bis-
propionate (8b): A solution of tert-butyl acrylate (50 mL, 0.34 mol,
30 equiv.) in a 2:1 mixture of CH2Cl2/MeOH (30 mL) was added
to a solution of triamine 6 (5.68 g, 11.32 mmol) in a 1:1 mixture of
(bromomethyl)pyridine with Disulfonamides 8a and 8b: In a typical
procedure, a suspension of the disulfonamide 8a or 8b (3.89 mmol)
and anhydrous Na2CO3 (2.15 g, 20.3 mmol) was stirred in anhy-
4432
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2004, 4424Ϫ4436

Azapyridinomacrocycles Bearing Trialkanoic Acid Side Chains as Ligands for Lanthanide Ions
FULL PAPER
drous DMF (100 mL) at 100 °C under argon for 2 h. A solution
0:10, then MeOH/aq. NH3 (32%), 7:3]. The chromatographed
of 2,6-bis(bromomethyl)pyridine (1.31 g, 4.86 mmol) in anhydrous product was dissolved in CH2Cl2 (100 mL) and the cloudy solution
DMF (100 mL) was then added dropwise (during 5 h) and the mix-
ture was stirred for an additional 1 h. The crude mixture was con-
centrated and the residue was taken up in CH2Cl2 (250 mL). The
organic phase was washed with an aqueous solution of NaOH
(0.1 , 2 ϫ 70 mL) and was then dried with sodium sulfate and
concentrated.
was filtered. The filtrate was concentrated, yielding the title com-
pound 10a as a light brown oil (0.990 g, 2.81 mmol, 95%). 1H
NMR (400 MHz, CDCl3, 25 °C): δ ϭ 1.42 [s, 9 H, C(CH3)3], 1.74
3
[m, 4 H, N(CH2CH2CH2NH)2], 2.50 [t, JH,H ϭ 5.8 Hz, 4 H,
N(CH2CH2CH2NH)2], 2.55 [t, 3JH,H
ϭ
5.8 Hz,
4
H,
N(CH2CH2CH2NH)2], 3.14 (s, 2 H, NCH2CO2tBu), 3.88 (s, 4 H,
3
CPyrCH2NH), 6.98 (d, JH,H ϭ 7.6 Hz, 2 H, m-CHAr), 7.52 (dd,
tert-Butyl
{3,11-Bis(2-nitrobenzenesulfonyl)-3,7,11,17-tetraazabi-
3JH,H ϭ 3JH,HЈ ϭ 7.6 Hz, 1 H, p-CHAr) ppm. 13C NMR (100 MHz,
CDCl3, 25 °C): δ ϭ 27.0 [N(CH2CH2CH2NH)2], 28.2 [C(CH3)3],
46.3 [N(CH2CH2CH2NH)2], 52.0 [N(CH2CH2CH2NH)2], 54.3
(CPyrCH2NH), 55.3 (NCH2CO2tBu), 80.9 [C(CH3)3], 120.4 (m-
CHAr), 136.4 (p-CHAr), 159.1 (Cquat,Ar), 170.7 (CO2tBu) ppm. CI-
HRMS: m/z calcd. for C19H33N4O2 349.2604, found 349.2599
[M ϩ H]ϩ.
cyclo[11.3.1]heptadeca-1(17),13,15-trien-7-yl}acetate (14a): The title
compound was obtained from the sulfonamide 8a as a light brown,
amorphous solid (1.99 g, 2.77 mmol, 71%) after chromatography
1
on silica gel (n-heptane/EtOAc, 4:6 to 0:10). H NMR (400 MHz,
CDCl3, 25 °C):
N(CH2CH2CH2NNos)2], 2.39 [t, JH,H
δ ϭ 1.37Ϫ1.45 [m, 13 H, C(CH3)3 and
3
ϭ
6.7 Hz,
4
H,
N(CH2CH2CH2NNos)2], 3.00 (s, 2 H, NCH2CO2tBu), 3.30 [t,
3JH,H ϭ 7.6 Hz, 4 H, N(CH2CH2CH2NNos)2], 4.56 (s, 4 H,
tert-Butyl 3-{3,7,11,17-Tetraazabicyclo[11.3.1]heptadeca-1(17),13,
15-trien-7-yl}propionate (10b): After 5 h of stirring at room tem-
perature, the Na2CO3 was filtered off through a Celite pad and
washed with CH2Cl2. The filtrate was concentrated and the crude
product was purified by chromatography on neutral activated alu-
minium oxide (CH2Cl2/MeOH, 10:0 to 8:2) to yield the title com-
3
C
PyrCH2NNos), 7.45 [d, JH,H ϭ 7.7 Hz, 2 H, m-CHAr (Pyr)],
7.62Ϫ7.73 [m, 7 H, CHAr (Nos) and p-CHAr (Pyr)], 8.00Ϫ8.03 [m,
2 H, CHAr (Nos)] ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ ϭ
26.7
[N(CH2CH2CH2NNos)2],
28.2
[C(CH3)3],
47.0
[N(CH2CH2CH2NNos)2], 51.2 [N(CH2CH2CH2NNos)2], 54.2
(CPyrCH2NNos), 57.8 (NCH2CO2tBu), 80.9 [C(CH3)3], 123.2 [m-
CHAr (Pyr)], 124.2, 130.6, 131.8 [CHAr (Nos)], 133.1 [Cquat,Ar
(Nos)], 133.6 [CHAr (Nos)], 138.3 [p-CHAr (Pyr)], 148.1 [Cquat,Ar
(Nos)], 155.9 [Cquat,Ar (Pyr)], 170.6 (CO2tBu) ppm. CI-HRMS: m/
z calcd. for C31H39N6O10S2 719.2169, found 719.2171 [M ϩ H]ϩ.
1
pound 10b as an orange oil (0.901 g, 2.48 mmol, 84%). H NMR
(400 MHz, CDCl3, 25 °C): δ ϭ 1.32 [s, 9 H, C(CH3)3], 1.73 [m, 4
3
H, N(CH2CH2CH2NH)2], 2.24 (t, JH,H
ϭ
7.2 Hz,
2
H,
H,
H,
H,
ϭ
NCH2CH2CO2tBu), 2.41 [t, 3JH,H
N(CH2CH2CH2NH)2], 2.53 [t, 3JH,H
N(CH2CH2CH2NH)2], 2.65 (t, 3JH,H
ϭ
5.7 Hz, 4
ϭ
ϭ
6.2 Hz,
7.2 Hz,
4
2
3
tert-Butyl 3-{3,11-Bis(2-nitrobenzenesulfonyl)-3,7,11,17-tetraazabi-
cyclo[11.3.1]heptadeca-1(17),13,15-trien-7-yl}propionate (14b): The
title compound was obtained from sulfonamide 8b as a light orange
oil (1.46 g, 1.99 mmol, 51%) after chromatography on silica gel (n-
NCH2CH2CO2tBu), 3.90 (s, 4 H, CPyrCH2NH), 6.99 (d, JH,H
3
3
7.6 Hz, 2 H, m-CHAr), 7.53 (dd, JH,H ϭ JH,HЈ ϭ 7.6 Hz, 1 H, p-
CHAr) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ ϭ 27.2
[N(CH2CH2CH2NH)2], 28.0 [C(CH3)3], 31.5 (NCH2CH2CO2tBu),
46.1 [N(CH2CH2CH2NH)2], 47.7 (NCH2CH2CO2tBu), 51.4
[N(CH2CH2CH2NH)2], 53.9 (CPyrCH2NH), 80.2 [C(CH3)3], 120.7
(m-CHAr), 136.7 (p-CHAr), 158.6 (Cquat,Ar), 172.1 (CO2tBu) ppm.
CI-HRMS: m/z calcd. for C20H35N4O2 363.2760, found 363.2757
[M ϩ H]ϩ.
1
heptane/EtOAc, 4:6 to 0:10). H NMR (400 MHz, CDCl3, 25 °C):
δ ϭ 1.31 [s, 9 H, C(CH3)3], 1.39 [m, 4 H, N(CH2CH2CH2NNos)2],
2.13Ϫ2.17 [m, 6 H, N(CH2CH2CH2NNos)2(CH2CH2CO2tBu) or
3
N(CH2CH2CH2NNos)2(CH2CH2CO2tBu)], 2.48 (t, JH,H
ϭ
3
6.8 Hz, 2 H, NCH2CH2CO2tBu), 3.26 [t, JH,H ϭ 7.4 Hz, 4 H,
N(CH2CH2CH2NNos)2 or N(CH2CH2CH2NNos)2], 4.54 (s, 4 H,
CPyrCH2NNos), 7.43 [d, JH,H ϭ 7.7 Hz, 2 H, m-CHAr (Pyr)],
3
5. N-Alkylations of Macrocyclic Intermediates
7.62Ϫ7.73 [m, 7 H, CHAr (Nos) and p-CHAr (Pyr)], 8.00Ϫ8.02 [m,
tert-Butyl {3,11-Bis(tert-butoxycarbonylmethyl)-3,7,11,17-tetraaza-
bicyclo[11.3.1]heptadeca-1(17),13,15-trien-7-yl}acetate (4a): tert-Bu-
tyl bromoacetate (2.3 mL, 15.58 mmol, 12 equiv.) was added to a
suspension of compound 3 (0.301 g, 1.28 mmol) and Ag2CO3
(0.899 g, 3.26 mmol, 2.5 equiv.) in anhydrous THF (10 mL). After
1 h of stirring at room temperature, the reaction mixture was co-
oled and acidified to pH ϭ 1 with an aqueous solution of HCl (ca.
6 , 2.5 mL, ca. 15 mmol). The mixture was stirred at 0 °C for
an additional 0.5 h, and Na2S·9H2O (10.6 g, 44.1 mmol) was then
added. After dilution with H2O (5 mL), the basic suspension was
stirred for 3 h and was then warmed to room temperature. The
black solid was filtered through a Celite pad and was then washed
with CH2Cl2. The filtrate was concentrated and the resulting aque-
ous phase was extracted with CH2Cl2 (5 ϫ 40 mL). The organic
phase was dried (Na2SO4) and concentrated to give a crude orange
oil that was purified by chromatography on neutral activated alu-
minium oxide (n-heptane/EtOAc, 7:3 to 5:5) to give the title com-
pound 4a as a yellow oil (0.603 g, 1.04 mmol, 81%). 1H NMR
(400 MHz, CDCl3, 25 °C): δ ϭ 1.34 [s, 9 H, N(CH2CH2CH2-
2 H, CHAr (Nos)] ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ ϭ
26.2
[N(CH2CH2CH2NNos)2],
28.1
[C(CH3)3],
33.8
(NCH2CH2CO2tBu), 47.3, 50.7 [N(CH2CH2CH2NNos)2], 51.1
(NCH2CH2CO2tBu), 54.4 (CPyrCH2NNos), 80.2 [C(CH3)3], 123.1
[m-CHAr (Pyr)], 124.2, 130.6, 131.8 [CHAr (Nos)], 133.0 [Cquat,Ar
(Nos)], 133.7 [CHAr (Nos)], 138.2 [p-CHAr (Pyr)], 148.1 [Cquat,Ar
(Nos)], 156.0 [Cquat,Ar (Pyr)], 171.8 (CO2tBu) ppm. CI-HRMS: m/
z calcd. for C32H41N6O10S2 733.2326, found 733.2326 [M ϩ H]ϩ.
4. General Procedure for the Cleavage of Sulfonamide Subunits from
Functionalised Macrocycles 14a and 14b: In a typical procedure, a
solution of macrocycle 14a or 14b (2.96 mmol) in anhydrous DMF
(200 mL) was cannulated into a three-necked flask containing an-
hydrous Na2CO3 (3.20 g, 30.22 mmol). Thiophenol (1 mL,
9.74 mmol) was then added.
tert-Butyl {3,7,11,17-Tetraazabicyclo[11.3.1]heptadeca-1(17),13,15-
trien-7-yl}acetate (10a): After stirring overnight at room tempera-
ture, the reaction mixture was concentrated and then taken up in
CH2Cl2 (200 mL). The organic layer was washed with water (100 NCH2CO2tBu)2{CH2CO2C(CH3)3}], 1.39Ϫ1.44 [m, 22 H,
mL). The aqueous layer was further extracted with CH2Cl2 (3 ϫ
100 mL). The combined organic layers were dried (Na2SO4) and
then concentrated under reduced pressure. The crude product was
purified by chromatography on silica gel [CH2Cl2/MeOH, 10:0 to
N{CH2CH2CH2NCH2CO2C(CH3)3}2], 2.45 [broad t,
4
H,
N(CH2CH2CH2NCH2CO2tBu)2 or N(CH2CH2CH2NCH2CO2t-
Bu)2], 2.55 [t, 3JH,H ϭ 7.3 Hz, 4 H, N(CH2CH2CH2NCH2CO2tBu)2
or N(CH2CH2CH2NCH2CO2tBu)2], 2.92 [s,
2
H, N(CH2-
Eur. J. Org. Chem. 2004, 4424Ϫ4436
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 4433

A. Guy et al.
FULL PAPER
CH2CH2NCH2CO2tBu)2(CH2CO2tBu)],
3
3.33
[s,
4
H,
N(CH2CH2CH2NCH2CO2tBu)2], 2.50 (t, JH,H ϭ 7.3 Hz, 2 H,
NCH2CH2CO2tBu), 2.56 [t, 3JH,H
7.4 Hz, H,
N(CH2CH2CH2NCH2CO2tBu)2], 3.38 (s, 4 H, NCH2CO2tBu),
N(CH2CH2CH2NCH2CO2tBu)2], 3.86 (s, 4 H, CPyrCH2N), 7.19 [d,
ϭ
4
3JH,H ϭ 7.6 Hz, 2 H, m-CHAr (Pyr)], 7.54 [dd, JH,H
ϭ ϭ
3JH,HЈ
3
7.6 Hz, 1 H, p-CHAr (Pyr)] ppm. 13C NMR (100 MHz, CDCl3, 25 3.92 (s, 4 H, CPyrCH2N), 7.24 [d, JH,H ϭ 7.6 Hz, 2 H, m-CHAr
3
3
3
°C):
[N{CH2CH2CH2NCH2CO2C(CH3)3}2{CH2CO2C(CH3)3}], 50.6, 13C NMR (100 MHz, CDCl3, 25 °C):
51.5 [N(CH2CH2CH2NCH2CO2tBu)2], 56.6 [N(CH2CH2CH2- [N(CH2CH2CH2NCH2CO2tBu)2], 28.1, 28.3 [NCH2CO2C(CH3)3
NCH2CO2tBu)2(CH2CO2tBu)], 57.3 [N(CH2CH2CH2NCH2- and NCH2CH2CO2C(CH3)3], 33.8 (NCH2CH2CO2tBu), 50.7
CO2tBu)2], 60.6 (CPyrCH2N), 80.4, 80.8 [{N(CH2CH2CH2- (NCH2CH2CO2tBu), 51.0 [N(CH2CH2CH2NCH2CO2tBu)2], 51.6
δ
ϭ
25.4 [N(CH2CH2CH2NCH2CO2tBu)2], 28.1, 28.2
(Pyr)], 7.58 [dd, JH,H ϭ JH,H ϭ 7.6 Hz, 1 H, p-CHAr (Pyr)] ppm.
δ
ϭ
25.2
NCH2CO2C(CH3)3}2{CH2CO2C(CH3)3}], 122.8 (m-CHAr), 136.6 [N(CH2CH2CH2NCH2CO2tBu)2], 57.5 (NCH2CO2tBu), 60.6
(p-CHAr), 158.1 (Cquat,Ar), 170.7, 170.9 [N(CH2CH2CH2- (CPyrCH2N), 80.9 [NCH2CO2C(CH3)3 and NCH2CH2CO2C-
NCH2CO2tBu)2(CH2CO2tBu)] ppm. FAB-HRMS: m/z calcd. for (CH3)3], 122.8 (m-CHAr), 136.6 (p-CHAr), 158.2 (Cquat,Ar), 170.8
C31H53N4O6 577.3965, found 577.3959 [M ϩ H]ϩ.
(NCH2CO2tBu and NCH2CH2CO2tBu) ppm. CI-HRMS: m/z
calcd. for C32H55N4O6 591.4122, found 591.4124 [M ϩ H]ϩ.
tert-Butyl 3-{3,11-Bis[2-(tert-butoxycarbonyl)ethyl]-3,7,11,17-tetra-
azabicyclo[11.3.1]heptadeca-1(17),13,15-trien-7-yl}propionate (4b):
tert-Butyl acrylate (50 mL, 341 mmol) was added to a solution of
compound 3 (6.01 g, 25.65 mmol, 13 equiv.) in MeOH (7 mL).
After 40 h of stirring at 70 °C with protection from light, the crude
mixture was concentrated under reduced pressure. The obtained
crude dark brown oil was purified by chromatography on silica gel
(CH2Cl2/EtOAc, 10:0 to 0:10), and the title compound 4b was iso-
lated as an orange oil (14.37 g, 23.22 mmol, 90%). 1H NMR
tert-Butyl 3-{11-[2-tert-Butoxycarbonyl)ethyl]-7-(tert-butoxycarbon-
ylmethyl)-3,7,11,17-tetraazabicyclo[11.3.1]heptadeca-1(17),13,15-
trien-3-yl}propionate (4d): tert-Butyl acrylate (12 mL, 81.9 mmol)
was added to a solution of compound 10a (2.086 g, 5.986 mmol)
in MeOH (2 mL). The solution was stirred at 70 °C overnight and
was then concentrated under reduced pressure. The obtained crude
orange oil was purified by chromatography on silica gel (EtOAc)
to provide the title compound 4d as a yellow oil (2.783 g,
4.601 mmol, 77%). 1H NMR (400 MHz, CDCl3, 25 °C): δ ϭ
1.33Ϫ1.40 {m, 13 H, N(CH2CH2CH2NCH2CH2CO2tBu)2-
[CH2CO2C(CH3)3]}; 1.45 [s, 18 H, NCH2CH2CO2C(CH3)3],
2.41Ϫ2.49 [m, 12 H, N(CH2CH2CH2NCH2CH2CO2tBu)2],
2.90Ϫ2.93 [m, 6 H, N(CH2CH2CH2NCH2CH2CO2tBu)2(CH2-
(400 MHz, CDCl3, 25 °C):
δ ϭ 1.29Ϫ1.34 {m, 13 H,
N(CH2CH2CH2NCH2CH2CO2tBu)2[CH2CH2CO2C(CH3)3]}, 1.42
{s, 18 H, N[CH2CH2CH2NCH2CH2CO2C(CH3)3]2}, 2.07 (t,
3JH,H
ϭ
7.3 Hz,
2
H, N(CH2CH2CH2NCH2CH2CO2t-
6.2 Hz, H,
Bu)2(CH2CH2CO2tBu), 2.16 [t, 3JH,H
ϭ
4
3
CO2tBu)], 3.68 (s, 4 H, CPyrCH2N), 7.19 [d, JH,H ϭ 7.6 Hz, 2 H,
N(CH2CH2CH2NCH2CH2CO2tBu)2], 2.39Ϫ2.46 [m, 10 H,
N(CH2CH2CH2NCH2CH2CO2tBu)2(CH2CH2CO2tBu)], 2.89 [t,
3JH,H ϭ 7.2 Hz, 4 H, N(CH2CH2CH2NCH2CH2CO2tBu)2], 3.66 (s,
4 H, CPyrCH2N), 7.15 [d, 3JH,H ϭ 7.6 Hz, 2 H, m-CHAr (Pyr)], 7.51
3
m-CHAr (Pyr)], 7.56 [dd, JH,H
ϭ
3JH,HЈ ϭ 7.6 Hz, 1 H, p-CHAr
(Pyr)] ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ ϭ 25.1
[N(CH2CH2CH2NCH2CH2CO2tBu)2], 28.1, 28.2 [NCH2CO2C-
(CH3)3 and NCH2CH2CO2C(CH3)3], 33.8 (NCH2CH2CO2tBu),
50.7 [N(CH2CH2CH2NCH2CH2CO2tBu)2 or N(CH2CH2CH2-
NCH2CH2CO2tBu)2], 51.4 (NCH2CH2CO2tBu), 51.6 [N(CH2CH2-
CH2NCH2CH2CO2tBu)2 or N(CH2CH2CH2NCH2CH2CO2tBu)2],
56.2 (NCH2CO2tBu), 60.4 (CPyrCH2N), 80.3 [NCH2CO2C(CH3)3
and NCH2CH2CO2C(CH3)3], 122.8 (m-CHAr), 136.5 (p-CHAr),
158.4 (Cquat,Ar), 171.0, 172.2 (NCH2CO2tBu and NCH2-
CH2CO2tBu) ppm. CI-HRMS: m/z calcd. for C33H57N4O6
605.4278, found 605.4272 [M ϩ H]ϩ.
3
[dd, JH,H ϭ3JH,HЈ ϭ 7.6 Hz, 1 H, p-CHAr (Pyr)] ppm. 13C NMR
(100 MHz, CDCl3, 25 °C):
δ
ϭ
24.7 [N(CH2CH2-
CH2NCH2CH2CO2tBu)2], 28.1, 28.2 {N[CH2CH2CH2NCH2-
CH2CO2C(CH3)3]2[CH2CH2CO2C(CH3)3]}, 33.6 [N(CH2CH2CH2-
NCH2CH2CO2tBu)2(CH2CH2CO2tBu)], 33.9 [N(CH2CH2CH2-
NCH2CH2CO2tBu)2], 50.6 [N(CH2CH2CH2NCH2CH2CO2tBu)2],
51.0 [N(CH2CH2CH2NCH2CH2CO2tBu)2(CH2CH2CO2tBu)], 51.5
[N(CH2CH2CH2NCH2CH2CO2tBu)2], 51.8 [N(CH2CH2CH2-
NCH2CH2CO2tBu)2], 60.5 (CPyrCH2N), 79.8, 80.2 {N[CH2CH2-
CH2NCH2CH2CO2C(CH3)3]2[CH2CH2CO2C(CH3)3]}, 122.7 (m-
CHAr), 136.4 (p-CHAr), 158.4 (Cquat,Ar), 172.1 [N(CH2-
6. General Procedure for the Cleavage of tert-Butyl Groups from
Macrocyclic Tri-tert-butyl Esters 4aϪd: In a typical procedure, a
solution of HCl in Et2O (2.5 , 250 mL) was added to a solution
of macrocyclic tri-tert-butyl ester 4a, 4b, 4c or 4d (4.60 mmol) in
Et2O (25 mL) and the reaction mixture was stirred overnight. The
white solid formed was filtered and washed with Et2O.
CH2CH2NCH2CH2CO2tBu)2(CH2CH2CO2tBu)]
ppm.
FAB-
HRMS: m/z calcd. for C34H59N4O6 619.4435, found 619.4432 [M
ϩ H]ϩ.
tert-Butyl 3-{3,11-Bis(tert-butoxycarbonylmethyl)-3,7,11,17-tetra-
azabicyclo[11.3.1]heptadeca-1(17),13,15-trien-7-yl}propionate (4c): 3,7,11,17-Tetraazabicyclo[11.3.1]heptadeca-1(17),13,15-triene-
tert-Butyl bromoacetate (0.6 mL, 4.06 mmol) was added to a sus-
pension of compound 10b (0.266 g, 0.734 mmol) and Ag2CO3
3,7,11-triacetic Acid (2a): The crude solid was purified by chroma-
tography on an ion-exchange resin (Dowex 1X8-50, formate form,
(0.347 g, 1.258 mmol) in THF (20 mL). After 1 h of stirring at elution with 0.02  formic acid) to provide the title compound as
room temperature, the crude mixture was cooled and acidified with
a white solid that became deliquescent on standing under ambient
an aqueous solution of HCl (3 , 1 mL). Na2S·9H2O (0.6 g, conditions (1.43 g, 3.50 mmol, 76%). 1H NMR (400 MHz,
2.50 mmol) was then added, the mixture was stirred for 3 h, and D2O, pD ഠ 3Ϫ4, 25 °C): δ ϭ 2.50 [m, 4 H, N(CH2CH2-
the black solid was filtered through a Celite pad and then washed
CH2NCH2CO2H)2], 3.44 [t, 3JH,H
ϭ
6.6 Hz,
4
H,
with CH2Cl2. The filtrate was concentrated and the crude product N(CH2CH2CH2NCH2CO2H)2 or N(CH2CH2CH2NCH2CO2H)2],
3
was purified by chromatography on neutral activated aluminium
oxide (gradient: CH2Cl2 then n-heptane/EtOAc, 10:0 to 7:3) to give
the title compound 4c as a yellow oil (0.247 g, 0.418 mmol, 57%).
3.58 [t, JH,H ϭ 7.7 Hz, 4 H, N(CH2CH2CH2NCH2CO2H)2 or
N(CH2CH2CH2NCH2CO2H)2], 3.99 [s, 6 H, N(CH2CH2CH2-
NCH2CO2H)2(CH2CO2H)], 4.77 (s, 4 H, CPyrCH2N), 7.72 [d,
3
1H NMR (400 MHz, CDCl3, 25 °C):
δ
ϭ
1.37 [s,
22
9
H,
H,
3JH,H ϭ 7.8 Hz, 2 H, m-CHAr (Pyr)], 8.12 [dd, JH,H
ϭ
3JH,HЈ
ϭ
NCH2CH2CO2C(CH3)3],
1.39Ϫ1.53
{m,
7.8 Hz, 1 H, p-CHAr (Pyr)] ppm. 13C NMR (100 MHz, D2O, pD ഠ
3
N[CH2CH2CH2NCH2CO2C(CH3)3]2}; 2.12 (t, JH,H ϭ 7.3 Hz, 2 3Ϫ4, 25 °C): δ ϭ 20.6 [N(CH2CH2CH2NCH2CO2H)2], 51.5, 54.0
3
H, NCH2CH2CO2tBu), 2.25 [t, JH,H
ϭ
6.0 Hz,
4
H,
[N(CH2CH2CH2NCH2CO2H)2], 58.9, 59.0 [CPyrCH2N and
4434
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 4424Ϫ4436

Azapyridinomacrocycles Bearing Trialkanoic Acid Side Chains as Ligands for Lanthanide Ions
FULL PAPER
N(CH2CH2CH2NCH2CO2H)2(CH2CO2H) or N(CH2CH2CH2-
CPyrCH2N), 128.4 (m-CHAr), 142.8 (p-CHAr), 152.3 (Cquat,Ar),
NCH2CO2H)2(CH2CO2H)], 59.9 [N(CH2CH2CH2NCH2CO2- 172.1, 179.5 [N(CH2CH2CH2NCH2CH2CO2H)2(CH2CO2H)] ppm.
H)2(CH2CO2H) or N(CH2CH2CH2NCH2CO2H)2(CH2CO2H)],
FAB-HRMS: m/z calcd. for C21H33N4O6 437.2400, found 437.2397
129.1 (m-CHAr), 143.2 (p-CHAr), 152.1 (Cquat,Ar), 171.7, 172.0 [M ϩ H]ϩ.
[N(CH2CH2CH2NCH2CO2H)2(CH2CO2H)] ppm. FAB-HRMS:
7. Preparation of the Samples for Spectroscopic Studies on Ligand
2a
m/z calcd. for C19H29N4O6 409.2087, found 409.2117 [M ϩ H]ϩ.
3-{3,11-Bis(2-carboxyethyl)-3,7,11,17-tetraazabicyclo[11.3.1]hepta-
deca-1(17),13,15-trien-7-yl}propionic Acid (2b): The crude solid was
purified by chromatography on an ion-exchange resin (Dowex
1X8-50, formate form, elution with 0.02  formic acid) to provide
the title compound as a white solid that became deliquescent on
standing under ambient conditions (1.55 g, 3.45 mmol, 75%). 1H
NMR (400 MHz, D2O, pD ഠ 3Ϫ4, 25 °C): δ ϭ 2.49 [m, 4 H,
a. Stoichiometry of the EuIII Complex: The pH of an aqueous stock
solution containing HEPES (sodium salt, 0.015 ), KCl (0.085 )
and ligand 2a (3.74 10Ϫ5 ) was adjusted to pH ϭ 8.1 with an
aqueous solution of HCl. A series of 15 samples was prepared in
separate sealed containers with various concentration of EuCl3
ranging from 0 to 1.5 10Ϫ4 . After incubation at 60 °C overnight,
the samples were allowed to cool to room temperature and were
monitored by absorption spectroscopy (λ ϭ 269 nm) until no
further spectral change was detected (typically 24 h). In order to
furnish a constant amount of excitation energy to the system, the
set of samples was irradiated at their isosbestic point (262 nm) and
the luminescence intensity of each sample was measured at 615 nm
N(CH2CH2CH2NCH2CH2CO2H)2], 2.73Ϫ2.81 [m,
N(CH2CH2CH2NCH2CH2CO2H)2(CH2CH2CO2H)],
6
H,
3.44Ϫ3.59
[m, 14 H, N(CH2CH2CH2NCH2CH2CO2H)2(CH2CH2CO2H)],
3
4.71 (s, 4 H, CPyrCH2N), 7.69 [d, JH,H ϭ 7.8 Hz, 2 H, m-CHAr
(Pyr)], 8.08 [dd, 3JH,H ϭ 3JH,HЈ ϭ 7.8 Hz, 1 H, p-CHAr (Pyr)] ppm.
13C NMR (100 MHz, D2O, pD ഠ 3Ϫ4, 25 °C): δ ϭ 20.4
[N(CH2CH2CH2NCH2CH2CO2H)2], 32.4, 32.5 [N(CH2CH2CH2-
NCH2CH2CO2H)2(CH2CH2CO2H)], 50.4, 52.6, 54.0, 55.4
(dominant emission peak corresponding to the 5D0
Ǟ
7F2 tran-
sition) at ambient temperature.
[N(CH2CH2CH2NCH2CH2CO2H)2(CH2CH2CO2H)], 59.3 (CPyrC- b. Determination of the Stability Constants of the LnIII Complexes:
H2N), 128.7 (m-CHAr), 143.1 (p-CHAr), 152.5 (Cquat,Ar), 178.6,
An aqueous stock solution containing MES (sodium salt, 0.015 ),
179.3 [N(CH2CH2CH2NCH2CH2CO2H)2(CH2CH2CO2H)] ppm. KCl (0.085 ) and ligand 2a (5.00 ϫ 10Ϫ5 ) was prepared. For
FAB-HRMS: m/z calcd. for C22H35N4O6 451.2557, found 451.2538 each lanthanide, a slight excess of LnCl3 salt was added (5.5 ϫ 10Ϫ5
[M ϩ H]ϩ.
to 6.3 ϫ 10Ϫ5 ) and a series of samples (12 to 17) was prepared in
separate sealed containers at various pH values by addition of an
aqueous solution of HCl. After incubation at 60 °C for 24 h, the
samples were cooled to room temperature. EuIII-Sensitised Lumi-
nescence: The samples were monitored by EuIII luminescence emis-
sion spectroscopy measured at 615 nm (5D0 Ǟ 7F2 transition) until
no further spectral change was detected (typically 7 d). When the
equilibrium was reached, the samples were irradiated at their isos-
bestic point (262 nm) and the luminescence intensity of each
sample was measured at 615 nm at ambient temperature. The series
was analysed twice. Absorption Spectroscopy: The samples were
monitored by absorption spectroscopy (269 nm) until no further
spectral change was detected (typically 7 d). When the equilibrium
was reached, the absorption spectra were recorded at ambient tem-
perature in the 200Ϫ320 nm range. Each series of samples was ana-
lysed three times, and the determination of the stability constant
was carried out each time at three wavelengths chosen in the spec-
tral region exhibiting the highest absorption intensity amplitude
(269, 273 and 277 nm).
3-{3,11-Bis(carboxymethyl)-3,7,11,17-tetraazabicyclo[11.3.1]hepta-
deca-1(17),13,15-trien-7-yl}propionic Acid (2c): The crude solid was
purified by gel filtration (Sephadex G-10 eluting with water) to
provide the title compound as a white solid that became deli-
quescent on standing under ambient conditions (1.47 g, 3.47 mmol,
1
75%). H NMR (400 MHz, D2O, pD ഠ 1, 25 °C): δ ϭ 2.49 [m, 4
3
H, N(CH2CH2CH2NCH2CO2H)2], 2.97 (t, JH,H ϭ 6.7 Hz, 2 H,
NCH2CH2CO2H), 3.47Ϫ3.60 [m, 10 H, N(CH2CH2CH2-
NCH2CO2H)2(CH2CH2CO2H)], 4.16 (s, 4 H, NCH2CO2H), 4.78
3
(s, 4 H, CPyrCH2N), 7.71 [d, JH,H ϭ 7.8 Hz, 2 H, m-CHAr (Pyr)],
3
8.10 [dd, JH,H
ϭ
3JH,HЈ ϭ 7.8 Hz, 1 H, p-CHAr (Pyr)] ppm.13C
NMR (100 MHz, D2O, pD
ഠ
1, 25 °C):
δ
ϭ
19.7
[N(CH2CH2CH2NCH2CO2H)2], 31.4 (NCH2CH2CO2H), 50.1,
53.2, 53.5 [N(CH2CH2CH2NCH2CO2H)2(CH2CH2CO2H)], 58.5,
58.6 (NCH2CO2H and CPyrCH2N), 129.3 (m-CHAr), 143.0 (p-
CHAr),
151.8
(Cquat,Ar),
170.9,
176.0
[N(CH2CH2-
CH2NCH2CO2H)2(CH2CH2CO2H)] ppm. FAB-HRMS: m/z calcd.
for C20H31N4O6 423.2244, found 423.2243 [M ϩ H]ϩ.
C. Lifetime and Quantum Yield Measurements of the Luminescent
EuIII and TbIII Complexes: Samples containing HEPES (sodium
salt, 0.015 ), KCl (0.085 ), ligand 2a (5.23 10Ϫ5 ) and LnCl3
(Ln ϭ Eu, Tb; 7.90 10Ϫ5 ) were prepared in H2O (D2O). The
pH (pD) was adjusted with an aqueous solution of HCl (DCl) to
8.0 (8.4).
3-{11-(2-Carboxyethyl)-7-(carboxymethyl)-3,7,11,17-tetraaza-
bicyclo[11.3.1]heptadeca-1(17),13,15-trien-3-yl}propionic Acid (2d):
The crude solid was purified by chromatography on an ion-ex-
change resin (Dowex 1X8-50, formate form, elution with 0.02 
formic acid) to provide the title compound as a white solid that
became deliquescent on standing under ambient conditions (1.43 g,
1
3.27 mmol, 71%). H NMR (400 MHz, D2O, pD ഠ 3Ϫ4, 25 °C):
[1] [1a]
δ ϭ 2.50 [m, 4 H, N(CH2CH2CH2NCH2CH2CO2H)2], 2.68 (t,
W. P. Cacheris, S. K. Nickle, A. D. Sherry, Inorg. Chem.
3JH,H ϭ 6.2 Hz, 4 H, NCH2CH2CO2H), 3.44 [t, JH,H ϭ 6.3 Hz,
1987, 26, 958Ϫ960. [1b] E. T. Clarke, A. E. Martell, Inorg. Chim.
Acta 1991, 190, 37Ϫ46.
3
[1c]
B. Cathala, C. Picard, L. Cazaux,
4
H, N(CH2CH2CH2NCH2CH2CO2H)2 or N(CH2CH2CH2-
`
P. Tisnes, M. Momtchev, Tetrahedron 1995, 51, 1245Ϫ1252.
NCH2CH2CO2H)2], 3.49Ϫ3.56 [m, 8 H, NCH2CH2CO2H and
N(CH2CH2CH2NCH2CH2CO2H)2 or N(CH2CH2CH2NCH2-
CH2CO2H)2], 3.85 (s, 2 H, NCH2CO2H), 4.70 (s, 4 H, CPyrCH2N),
[2]
[2a] G. E. Kiefer, D. J. Bornhop, US Patent, US 5,928,627, 1999.
[2b]V. Jacques, J. F. Desreux, Top. Curr. Chem. 2002, 221,
123Ϫ164.
[2c]
A. Beeby, S. W. Botchway, I. M. Clarkson, S.
3
3
7.68 [d, JH,H ϭ 7.8 Hz, 2 H, m-CHAr (Pyr)], 8.06 [dd, JH,H
3JH,HЈ ϭ 7.8 Hz, 1 H, p-CHAr (Pyr)] ppm. 13C NMR (100 MHz,
D2O, pD 3Ϫ4, 25 °C): 20.4 [N(CH2CH2CH2-
ϭ
Faulkner, A. W. Parker, D. Parker, J. A. G. Williams, J. Photo-
[2d]
chem. Photobiol. B 2000, 57, 83Ϫ89.
I. Hemmilae, V. M.
[2e]
ഠ
δ ϭ
Mukkala, H. Takalo, J. Alloys Comp. 1997, 249, 158Ϫ162.
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NCH2CH2CO2H)2], 32.3 (NCH2CH2CO2H), 51.1, 52.2, 55.5
[N(CH2CH2CH2NCH2CH2CO2H)2], 59.2, 59.3 (NCH2CO2H and
Eur. J. Org. Chem. 2004, 4424Ϫ4436
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 4424Ϫ4436