Three step vs one pot synthesis and X-ray crystallographic investigation of heptadentate triamide cyclen (1,4,7,10-tetraazacyclododecane) based ligands and some of their lanthanide ion complexes

Article abstract of DOI:10.1016/j.tet.2003.10.086

The synthesis of several lanthanide complexes from the tris alkylated cyclen (1,4,7,10-tetraazacyclododecane) ligands 1 and 2 is described. The syntheses of 1 and 2 were investigated by means of two different synthetic routes (Method 1 and Method 2). The first of these involves the mono protection of cyclen using 4-methoxyphenylsulfonyl chloride, followed by alkylation of the remaining three secondary amines of cyclen, and deprotection using solvated Na(s). Using this approach only 1 was successfully formed. The X-ray crystal structure of the intermediate, 9 and the corresponding La(III) complex, 9.La is presented. The second method involved the direct synthesis of the two ligands in a single step. The X-ray crystallography of the Eu(III) complex of one of these ligands is presented. Whereas, Method 1 yielded the product 1 in high purity, but in low overall yield, Method 2 gave higher yields for both ligands (~50% for both).

Full text of DOI:10.1016/j.tet.2003.10.086

Tetrahedron 60 (2004) 105–113
Three step vs one pot synthesis and X-ray crystallographic
investigation of heptadentate triamide cyclen
(1,4,7,10-tetraazacyclododecane) based ligands and some of their
lanthanide ion complexes
a
a
b
Thorfinnur Gunnlaugsson,a Joseph P. Leonard, Sinead Mulready and Mark Nieuwenhuyzen
,
,
*
*
aDepartment of Chemistry, Trinity College Dublin, Dublin 2, Ireland
bSchool of Chemistry, The Queen’s University of Belfast, Belfast BT9 5AG, Northern Ireland, UK
Received 14 August 2003; revised 7 October 2003; accepted 30 October 2003
Abstract—The synthesis of several lanthanide complexes from the tris alkylated cyclen (1,4,7,10-tetraazacyclododecane) ligands 1 and 2 is
described. The syntheses of 1 and 2 were investigated by means of two different synthetic routes (Method 1 and Method 2). The first of these
involves the mono protection of cyclen using 4-methoxyphenylsulfonyl chloride, followed by alkylation of the remaining three secondary
amines of cyclen, and deprotection using solvated Na(s). Using this approach only 1 was successfully formed. The X-ray crystal structure of
the intermediate, 9 and the corresponding La(III) complex, 9.La is presented. The second method involved the direct synthesis of the two
ligands in a single step. The X-ray crystallography of the Eu(III) complex of one of these ligands is presented. Whereas, Method 1 yielded the
product 1 in high purity, but in low overall yield, Method 2 gave higher yields for both ligands (,50% for both).
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
the need for stable lanthanide complexes arises. Yu et al.
have demonstrated that stable Tb(III) [2.2.2] cryptates can
be sensitized in aqueous solutions when coordinated with
acac, a b-diketonate chelate.8 This requires the displace-
ment of the two labile water molecules from the Tb(III)
complex. Nocera et al. have shown aromatic carboxylates to
act in a similar manner with Tb(III) [2.2.2] cryptates.9 In
work reported by Diamandis, sensitization of Eu(III) and
Tb(III) EDTA complexes at pH 11–12 using a number of
aromatic carboxylate compounds such as 5-flurosalicylic
acid was demonstrated.10 Reinhoudt et al. also showed
similar results using an EDTA-bis(b-cyclodextrin).11 Parker
et al. have reported the synthesis of heptadentate cyclen
based lanthanide complexes, which showed great promise
as sensors for bicarbonate.12 Studies carried out in solutions
containing MES buffer with pH ranging between 6.4 and 7.3
demonstrated that stable lanthanide complexes could be
produced that can detect the presence of anions under near
physiological conditions. As discussed, in many of the
above cases, coordination to the anionic species displaces
the two bound water molecules from the Tb(III) or Eu(III)
complexes. However, in this case the coordinating species
was not a sensitizer. Instead, its presence as a coordinated
species was detected by changes in the emission lifetimes of
the lanthanide ion.
The design and synthesis of sensors for anions and neutral
molecules has been an area of immense study in recent
years.1 The use of metal complexes as sensors in such
situations has been discussed in many of these studies.1,2
Metal complexes can form metal–ligand interactions with
anions that are significantly stronger than hydrogen
bonding, or other interactions commonly exploited for
anion recognition.3 For instance Fabrizzi et al. have
demonstrated the use of Zn(II) complexes as sensors for
aromatic carboxylates such as p-nitro benzoic acid.4 Also
Pallavicini et al. have employed Cu(II) complexes with
tetraaza ligands that can detect coumarin 343.5 The use of
metal complexes for sensing anions has not been confined to
transition metals alone. Lanthanides such as Tb(III) and
Eu(III) have been shown to displace cations, such as Ca(II),
that can be found in the binding sites of proteins; such
binding sites contain anionic groups to complex the cation.6
Excitation of surrounding aromatic residues (such as
tyrosine or phenylalanine) in these proteins can result in
sensitization of the lanthanide, producing a lanthanide
emission.7 With the ultimate goal of anion detection in vivo
Keywords: Supramolecular chemistry; Macrocycles; Lanthanide ions;
Cyclen.
We have been interested in the development of lanthanide
luminescent devices and we have synthesized several
*
Corresponding authors. Tel.: þ353-1-608-3459; fax: þ353-1-671-2826
(T.G.); e-mail addresses: gunnlaut@tcd.ie; jleonard@tcd.ie
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.10.086

106
T. Gunnlaugsson et al. / Tetrahedron 60 (2004) 105–113
Table 1. Data collection and structural refinement details for 9, La.9 and Eu.2
Structural formula
C25H42Cl3N7O6S (9)
C29H46F9N7O16S4La (La.9)
C20H35F9N7O16S3Eu (Eu.2)
M
675.07
1186.88
0.34£0.28£0.24
Monoclinic
P21/c (4)
13.4113(12)
115527(10)
29.089(2)
90
90.684(2)
90
4506.6(7)
1.749
2396
1048.69
0.36£0.23£0.10
Triclinic
P-1 (2)
8.992(4)
13.112(5)
17.623(7)
79.370(6)
82.503(6)
71.816(6)
1934.3(14)
1.800
1048
1.899
2–50
0.0618
6732
0.1688(0.0623)
Crystal size (mm)
Crystal system
Space group (Z)
a (A)
b (A)
0.18£0.16£0.08
Orthorhombic
Pbca (8)
16.886(2)
9.6598(13)
38.899(5)
90
˚
˚
˚
c (A)
a (8)
b (8)
g (8)
U (A
Dc (g cm23
F(000)
m(Mo Ka) (mm21
v scans; 2u range (8)
Rint
Unique reflections
wR2(R1)
90
90
3
˚
6345.1(15)
1.413
2848
0.405
2–45
0.1796
4150
0.2795(0.0944)
)
)
1.244
3–57
0.0359
10295
0.0991(0.0364)
Eu(III) and Tb(III) complexes as luminescent switches,13
sensors14 and logic gate mimics.15 We have also developed
several lanthanide based ribonuclease mimics for the
cleavage of mRNA and RNA mimic compounds.16 These
compounds have all been based on tetrasubstitued cyclen
complexes, which possess a single metal bound water
molecule. The synthesis of such compounds is usually
achieved in good yields by reacting 4 equiv. of the pendent
arm with cyclen.17 However, the formation of unsaturated
heptadentate ligands is a much more challenging task.12a,18
The purpose of the work described herein was to synthesis
heptadentate ligands 1 and 2 and their Eu(III) and Tb(III)
complexes Eu.1, Eu.2, Tb.1 and Tb.2. Furthermore, these
complexes were to be evaluated for their ability to
coordinate and sense aromatic carboxylates.19 All these
complexes are expected to be photophysically ‘silent’ upon
excitation as no sensitizing groups have been incorporated
into ligands, 1 and 2 and so no indirect excitation of the
lanthanides can occur. The work presented herein concerns
the synthesis of the two ligands 1 and 2 using two different
synthetic methods (Method 1 and Method 2), and the
analysis of some of the intermediates and final products
using X-ray crystallography (Table 1). We have recently
discussed the photophysical properties of these molecules
and their ability to detect aromatic carboxylates such as
salicylic acid over Aspirin.19
Scheme 1. The synthetic route undertaken in Method 1. Whereas, ligand 2 was not obtained by this method, ligand 1 was made in overall 9% yield.

T. Gunnlaugsson et al. / Tetrahedron 60 (2004) 105–113
107
The resulting crude product contained a by-product that was
determined to be a bis aryl sulfonamide cyclen ligand.
Purification by silica gel column chromatography using
90:10 MeCN/MeOH provided 5 in 53% yield. This product
was identified from its 1H NMR spectrum by the presence of
two doublets at 7.72 and 7.01 ppm and a singlet at 3.88 ppm
resulting from the presence of the aromatic group.
Alkylation of 5 using 6 or 7 was carried out in DMF at
80 8C using Cs2CO3 as a base and KI to afford 8 or 9,
respectively. The a-chloroamides 6 and 7 were produced
from chloroacetyl chloride with the appropriate amine
following published procedures.22 Purification of the
tertiary amide 8 was achieved with alumina column
chromatography using 97:3 EtOAc/MeOH giving the
desired compound as an oil in 50% yield. The secondary
amide 9 was purified with alumina column chromatography
using CH2Cl2/MeOH (1–5%) to give 9 as oil in 41% yield.
Both 8 and 9 were characterised by NMR spectroscopy,
ESMS, accurate mass and infrared analysis and in the case
of 9 by X-ray crystallography. Figure 1 illustrates the crystal
structure of 9 and clearly shows the presence of three mono
methyl acetamide pendent arms attached to cyclen, along
with the p-methoxyphenylsulphonamide protection. A
summary of selected bond angles and bond lengths is
shown in Table 2.
Figure 1. Diagram showing the conformation of ligand 9. Hydrogen atoms
and the disorder are not shown for clarity. Ellipsoids at 30%. A CHCl3
molecule was also found in the unit cell for this structure.
2. Results and discussion
Synthesis of ligands 1 and 2 involved tris N-alkylation of
cyclen 3, a macrocycle with four potential alkylation sites.
The syntheses of such regioslective N-functionalisation of
tetraazcycloalkanes is an important area of research.20
However, often the emphasis has been on developing
methods for mono-protection of such macrocyles, which
can then be further derivatised, followed by deprotection of
the initial protection group.21 In order to synthesize the
proposed ligands herein, two possible synthetic routes were
attempted. The first route, Method 1 is shown in Scheme 1,
and is based upon the use of a single N-protection of cyclen,
3, in one of its four positions using 1 equiv. of p-methoxy-
phenylsulfonyl chloride, 4. This technique was first
developed by Parker et al.12a,b Synthesis of 5 involved
dropwise addition of a CHCl3 solution of 4 into a CHCl3
solution of 3 in the presence of triethyl amine at 36–39 8C.
We were also able to form the La(III) complex of 9, La.9 by
refluxing Lanthanum triflate in EtOH. Upon cooling, hexane
was added, ca. 5% and the solution kept cold whereupon
crystals were formed. The X-ray crystal structure of this
complex is shown in Figure 2, where the ion is coordinated
to the four nitrogens of the cyclen ring, the oxygens of the
carboxylic amides and to one of the oxygen of the
sulfonamide. The average N· · ·La and O· · ·La bond lengths
for the coordination of the cyclen ring were 2.855 and
˚
2.494 A, respectively. Whereas, the distance of the
sulfonamide oxygen O· · ·La distance was found to be
˚
2.694 A. A summary of selected bond angles and bond
lengths is shown in Table 2. Furthermore, the lanthanide ion
˚
was coordinated to a single triflate (O· · ·La¼2.554 A) and
˚
ethanol molecule (O· · ·La¼2.577 A), giving rise to 10
coordinated environments, as expected for La(III) which has
˚
Table 2. Selected bond lengths (A) and bond angles (8)
(Tb.1)
(9)
(Eu.2)
(La.9)
(Eu.1)
Tb1 O15
Tb1 O27
Tb1 O20
Tb1 O1W
Tb1 O2W
Tb1 N1
Tb1 N10
Tb1 N7
Tb1 N4
2.348(3)
2.326(3)
2.368(3)
2.429(3)
2.441(3)
2.600(4)
2.656(3)
2.637(4)
2.642(4)
C1 C2
C3 C4
C5 C6
C7 C8
N1 C1
N1 C8
C19 O19
C23 O23
C27 O27
C19 N20
C23 N24
C27 N28
N1 S1
1.490(13)
1.425(13)
1.520(13)
1.494(10)
1.497(9)
1.481(11)
1.255(10)
1.247(13)
1.244(11)
1.314(11)
1.334(13)
1.301(12)
1.630(8)
Eu1 O14
Eu1 O22
Eu1 O18
Eu1 O1W
Eu1 O2W
Eu1 N1
Eu1 N10
Eu1 N7
Eu1 N4
2.377(6)
2.393(6)
2.399(6)
2.448(6)
2.485(6)
2.673(7)
2.618(7)
2.670(7)
2.678(7)
La1 O5
La1 O4
La1 O3
La1 O13
La1 O1SS
La1 O2
La1 N1
La1 N10
La1 N7
La1 N4
2.458(2)
2.512(2)
2.514(2)
2.554(2)
2.577(2)
2.694(2)
2.989(3)
2.842(3)
2.808(3)
2.784(3)
Eu1 O15
Eu1 O25
Eu1 O19
Eu1 O1W
Eu1 O2W
Eu1 N1
Eu1 N10
Eu1 N7
Eu1 N4
2.342(5)
2.364(5)
2.378(5)
2.418(5)
2.421(5)
2.605(6)
2.624(6)
2.625(6)
2.647(6)
O27 Tb1 N10
O20 Tb1 N7
O15 Tb1 N4
01W Tb1 02
65.41(11)
64.53(11)
65.68(11)
71.80
O22 Eu1 N7
O18 Eu1 N4
O14 Eu1 N1
O1W Eu1 02W
65.98(19)
65.5(2)
66.1(2)
70.9(2)
O5 La1 N10
O4 La1 N7
O3 La1 N4
O2 La1 N1
62.57(8)
61.33(7)
63.42(7)
50.94(7)
O25 Eu1 N10
O19 Eu1 N7
O15 Eu1 N4
O1W Eu1 02W
65.39(19)
64.10(19)
65.13(19)
72.17
S1 O10
S1 O9
1.440(6)
1.431(6)
N–C–C–O
N–C–C–O
N–C–C–O
5.6(7)
25.6(6)
26.5(6)
N–C–C–O
N–C–C–O
N–C–C–O
230.0(7)
232.7(1)
236.4(5)
N–C–C–O
N–C–C–O
N–C–C–O
245.0(4)
227.8(4)
31.8(4)
N–C–C–O
N–C–C–O
N–C–C–O
22.5(11)
227.6(10)
225.4(10)

108
T. Gunnlaugsson et al. / Tetrahedron 60 (2004) 105–113
Figure 2. Diagram showing the conformation and binding mode of the La(III) complex La.9 (La.9·(CF3SO3)3·EtOH). Hydrogen atoms and lattice anions are
not shown for clarity. Ellipsoids at 30%. Three triflate molecules and one ethanol molecuel was also found in the unit cell for this structure.
higher coordination requirements than Eu(III) and Tb(III).
Furthermore, the complex adopts a square antiprismatic
geometry in solid state, with average N–C–C–N angle of
261.558. Unfortunately, this complex was found to be
unstable and decomposed when dissolved in several
solvents, because of this, complete characterizations was
not possible. However, it is an important structure
since not many La-cyclen structures are known in the
literature.17,23,24
variations were attempted using this direct alkylation
method, such as high dilution addition of 6 to 3, by varying
the rate addition and concentration of the two reagents, but
maintaining the ratio of the reagents (the ratio of 3 to either
6 or 7 was kept as 1:3 or 1:3.1). On many occasions a
number of by products were observed and electro spray
mass spectral analysis of the reaction mixture showed the
presence of mono, bis, tris and tetra-alkylated cyclen.
However, these were difficult to isolate successfully and in
high purity by column chromatography. Furthermore, the
temperature at which these additions were carried out at was
also modulated, from 20!80 8C, and the use of other
solvents such as DMF, were also investigated. However, a
successful method was developed, which we present herein.
This involved stirring of 3 in a solution of MeCN at 65 8C.
To this solution 3 equiv. of 6 or 7 was added in a single
addition and the resulting solution was stirred at 65 8C for
72 h. In the case of 1, the product was isolated as a viscous
oil in a 52% yield following purification on an alumina
column using 97:3 CH2Cl2/MeOH(NH3), while 2 was
isolated in a 59% yield as a white solid following
precipitation from ether. Of the two synthetic methods
attempted the direct alkylation of 3 was determined to be the
most efficient synthetic route for the synthesis of 1 and 2,
with yields over 50% from a one step synthesis compared to
total yields of 9% for 1 and 0% for 2 using the initial three
step synthesis (Method 1).
The final step in the synthesis of 1 and 2 involved
deprotection of 8 and 9 using Birch conditions. This was
carried out by stirring a THF solution of either 8 or 9 in the
presence of Na metal and liquid ammonia at 260 8C.25
Isolation of these products from the reaction solution
involved acid base extraction, which in the case of 2 failed
to give the required product, even when continuous
extraction techniques were used. However, ligand 1 was
isolated in a low yield of 36%, and in 9% overall yield from
3. The results of this final step in the synthesis of 1 and 2
indicated that this synthetic pathway was not sufficient to
synthesize the desired ligands and another method was
required. The second route was thus attempted.
The second synthetic route, Method 2, is shown in Scheme
2, and involved direct alkylation of 3 with 3 equiv. of 6 or 7
to yield 1 and 2, respectively in a single step. A number of
7
Scheme 2. The one-pot syntheses of 1 and 2.

T. Gunnlaugsson et al. / Tetrahedron 60 (2004) 105–113
109
sensors for the population of the Tb(III) and Eu(III) excited
states. This work will be the subject of future publications.
The synthesis of the lanthanide complexes Eu.1, Tb.1, Eu.2
and Tb.2 involved refluxing 1 and 2 with Eu(III) and Tb(III)
as their triflate salts in freshly dried MeCN (Scheme 3).
Upon cooling to room temperature the solutions were
poured into stirring solutions of dry ether, and in all cases an
oily residue was produced. These oils were collected by
decanting the organic layers and the resulting residues were
rinsed with either CH2Cl2 or CHCl3. The resultant
complexes were all isolated as powders in yields of ca.
95% after exhaustive drying under vacuum over P2O5 for
approximately two weeks. These complexes were charac-
terised by elemental analysis, ESMS, accurate mass, IR and
NMR spectroscopy. Similar results were observed for all of
these complexes. The 1H NMR spectrum showed the
presence of the paramagnetic metal centers, as indicated
by several broad resonances appearing over a large ppm
range as in the case Eu.2 where these appeared at 27.04,
14.96, 11.44, 5.20, 3.68, 2.76, 2.41, 1.55, 20.09, 21.84,
24.93, 27.35, 210.77, 212.31, 216.66, respectively.
Similar results were observed for the other three complexes.
These results indicated that all adapted square antiprismatic
geometry in solution.16,17,24 ESMS and accurate mass
analysis proved very useful in characterization of these
complexes. All four complexes gave similar spectra, which
consisted of MþH peaks for the complex with one and two
triflate counter anions present. In some instances MþH peak
for the complex along with a large number of MþHnþ
Triflatex/Zn (x¼0–3, n¼1–3) peaks were found in the
ESMS. The peaks generated compared well with the
theoretical isotope model, as shown in Figure 4, for Eu.1.
It should be noted that the presence of the bound water
molecules was not seen during analysis by mass spec-
troscopy. From IR spectroscopy the single carbonyl
stretching frequency occurring at 1643 cm21 in 2 was
Figure 3. The 1H NMR spectrum (400 MHz, CDCl3) of 1, showing the
C2-symmetry. (Inset: NH peak at 9.98 ppm.)
Ligands 1 and 2 were characterized using standard
techniques. However, both were hygroscopic and elemental
analysis of these ligands was not possible. Nevertheless,
(ESMS) accurate mass spectroscopy was obtained for both.
1
The H NMR spectra of both ligands clearly reflect a C2
symmetry. This C2 symmetry runs along an axis through the
unalkylated amine in position 1 and the tertiary amine in
1
position 7 of the cyclen ring. The H NMR spectrum of 1
shown in Figure 3, revealed the presence of one N–H
singlet at 9.98 ppm. The two a-protons for the pendant arms
appeared as singlets at 3.59 and 3.56 ppm (in a ratio of 2:4),
respectively. From C–H cosy experiments the five singlets
observed between 3.08 and 2.83 ppm were representative of
both the cyclen CH2 and methyl acetamide CH3 protons.
1
The H NMR spectrum for 2 showed similar character-
istics.19 The 13C NMR spectra for both 1 and 2 contained 10
signals. For 1 this consisted of two quaternary resonances at
170.3 and 170.2 ppm corresponding to the carboxylic amide
carbonyls of the pendant arms. Two CH2 resonance signals
at 55.5 and 53.8 ppm were assigned to the pendant arms.
Another four CH2 signals observed from 51.7 to 46.7 ppm
correspond to the cyclen ring. The two final signals were
found at 36.4 and 35.3 ppm and correspond to the acetamide
methyl groups. A similar 13C NMR spectrum was obtained
for 2.19 We are currently modifying these two ligands by
functionalising the remaining amino moiety with various
a-amides such as dipeptides and peptide conjugates, as well
as incorporating various chomrophores as antennae and
shifted when complexed to Eu(III) or Tb(III) to 1639 cm21
,
an indication that the pendent arms were indeed bound to
the metal center.22 Crystals of Eu.1 Eu.2 and Tb.2 were
obtained that were suitable for X-ray crystallographic
determination. We have shown the structure of the Eu.1
and Tb.2 in our previous publications (selective bond angles
and bond lengths are shown for comparison in Table 2).18,19
Scheme 3. The formation of the Eu(III) and Tb(III) complexes of 1 and 2.

110
T. Gunnlaugsson et al. / Tetrahedron 60 (2004) 105–113
Figure 4. The electro spray mass spectrum of Eu.1 (bottom) and the calculated isotopic pattern (top).
˚
similar with an average value of ca. 2.43 A. This bond
˚
length was longer in Eu.2 with an average of ca. 2.47 A. The
Crystals of Eu.2 were obtained by slow evaporation from
solutionsofMeCN. Thestructure ofEu.2isshowninFigure 5.
angle that these two water molecules bind to the metal
center was also of importance, since the nature of the
binding mode with carboxylate anions would depend on the
bite angle between the two water molecules. For Eu.1
the O1W-Eu-O2W bite angle was measured to be 72.178
whereas, for Tb.1 the O1W-Tb-O2W bite angle was
measured to be 71.808 and for Eu.2 the O1W-Eu-O2W
bite angle was measured to be 70.868. Recently, Dickins
et al.12b,c reported that related three-arm cyclen complexes
can form bidentate adducts with organic anions such as
acetate, citrate, glycinate, and lactate through four and five
member chelates. The bite angles for all of these complexes
All of the structures adopted a square antiprism geometry in
the solid state, a common geometry for tetraamide and
carboxylate-substituted lanthanide complexes of cyclen,
where the metal center was coordinated to the four nitrogens
of the macrocycle ring and the three oxygens of the
carboxylic amide pendent arms. The Ln(III)–N and
Ln(III)–O bond lengths were of similar length in all three
complexes with average distances of ca. 2.64 A and ca.
˚
2.37 A, respectively. Furthermore, all the crystal structures
showed the presence of the two metal bound water
molecules. For Eu.1 and Tb.1 these bond lengths were
˚
Figure 5. The X-ray crystal structure of Eu.2 (Eu2 (CF3SO3)·(H2O)2), showing the seven coordination of the ligand and the two metal bounded water
molecules. Hydrogen bonds and lattice anions have been omitted for clarity. Three triflate anions were also found in the unit cell.

T. Gunnlaugsson et al. / Tetrahedron 60 (2004) 105–113
111
1
were between 54 and 698. In the case of acetate, this binding
was bidentate and occurred through both of the carboxylate
oxygens. From these reports and the bite angles calculated
for Eu.1, Tb.1 and Eu.2 it was proposed that aromatic
carboxylates would bind in a similar bidentate manner to all
the complexes, expelling the two water molecules. This was
indeed found to be the case as we have recently reported
where the Tb(III) emission of both Tb.1 and Tb.2 was
‘switched on’ (due to the population of the 5D4 excited state
of the lanthanide ion through an energy transfer mechanism,
involving the excitation of the singlet state of the salicylic
acid, followed by intersystem crossing to the triplet state) in
the presence of salicylic acid, whereas, no sensitization of
the excited state of the lanthanide ion was observed for
Aspirin.19 Furthermore, no binding was found to occur for
the Eu(III) complexes, which was caused by much weaker
binding to these ions than to the Tb(III) centers.
pressed discs. H NMR spectra were recorded at 400 MHz
using a Bruker Spectrospin DPX-400 instrument. Tetra-
methylsilane (TMS) was used as an internal reference
standard, with chemical shifts expressed in parts per million
(ppm or d) downfield from the standard. 13C NMR were
recorded at 100 MHz using a Bruker Spectrospin DPX-400
instrument. 19F NMR were recorded at 376 MHz using a
Bruker Spectrospin DPX-400 instrument. Mass spec-
troscopy was carried out using HPLC grade solvents.
Mass spectra were determined by detection using Electro-
spray on a Micromass LCT spectrometer, using a Shimadzu
HPLC or Water’s 9360 to pump solvent. The whole system
was controlled by MassLynx 3.5 on a Compaq Deskpro
workstation.
4.1.1. 1-(4-Methoxy-phenylsulphonyl)-1,4,7,10-tetraaza-
cyclododecane (5). To a 500 mL three neck RBF, (3)
1,4,7,10-tetraazacyclododecane (1.00 g, 5.8 mmol) was
added along with CHCl3 (50 mL). To this was added
TEA (4.11 g, 40 mmol) which was heated at 36–39 8C.
4-Methoxy phenyl sulphonyl chloride (1.20 g, 5.8 mmol) in
CHCl3 (100 mL) was added dropwise over a 5-hour period.
The solution was then left stirring overnight. The solution
temperature was maintained at 36–39 8C. This solution was
reduced to approximately 50 mL upon which a white solid
was produced that was removed by filtration and the
resulting organic solution was reduced to dryness under
vacuum to produce a white solid, 1.6 g (80.0%). This was
then purified by silica column chromatography using 90:10,
MeCN/MeOH (53% recovery), to yield 0.56 g (28% yield)
of 5 as a white solid. Mp¼137–140 8C. Calculated for
C15H27N4O3S: [MþH peak] m/z¼343.1804. Found:
343.1806; dH (CDCl3, 400 MHz) 7.72 (d, J¼9.0 Hz, 2H,
Ar-H), 7.01 (d, J¼8.6 Hz, 2H, Ar-H), 3.88 (s, 3H), 3.40 (d,
J¼4.5 Hz, 4H, CH2), 3.18 (d, J¼5.0 Hz, 4H, CH2), 3.00 (d,
J¼4.0 Hz, 4H, CH2), 2.87 (d, J¼5.0 Hz, 4H, CH2); dC
(CDCl3, 100 MHz) 162.9, 128.8, 114.1, 55.2, 49.3, 48.5,
48.2, 45.5; Mass Spec (MeCN, ESþ) m/z expected: 342.2.
3. Conclusion
In summary we have synthesized two amide based ligands 1
and 2 using two different synthetic methods. Whereas, the
former of these involved three steps, only giving one of the
desired products, the second method was quite successful,
giving the desired ligands in ca. 50% overall yield in a
single step. Even though this method requires elaborate
chromatographic purification for one of these products (1)
the second product was easily obtained by precipitation
methods. We were able to obtained both crystals of the
ligand 9 the La(III) complex of 9, one of the intermediates
from Method 1. It clearly showed the ability of the ligand to
coordinate to the La(III) ion, despite the presence of the
sulfonamide. We were also able to grow crystals of three of
the four complexes made from 1 and 2. To the best of our
knowledge these were the first examples of such X-ray
crystal structures of such heptadentate tri-arm amide based
cyclen complexes. The structure of Eu.2 was reported
herein, showing the metal ion coordinating to all the seven
coordination sites of the ligand, as well as to two water
molecules. As we have demonstrated in our former
publication,18,19 these water molecules could be removed
by aromatic carboxylates, in the case of Tb.1 and Tb.2. Of
the two synthetic methods investigated herein, Method 2 is
superior to Method 1. We are currently improving the use of
this method and employing it to develop several peptide
based heptadentate tri-arm ligands for the use as molecular
sensors and as catalysts for the hydrolysis of mRNA.
Found: 343.2 (MþH); 365.1 (MþNa); IR nmax (cm21
)
3432, 3095, 3008, 2842, 1712, 1594, 1492, 1438, 1363,
1261, 1222, 1155, 1091, 1052, 1024, 927, 890, 842, 804,
761, 701, 561, 530, 466.
4.2. General synthesis of 1 and 2
Compound 5, 0.68 g (2.0 mmol) was placed in a 100 mL
three neck RBF. To this was added 7, (0.64 g, 6.0 mmol) [or
6, 3.1 equiv. in the case of 8], Cs2CO3 (1.95 g, 6.0 mmol)
and KI (1.0 g, 5.3 mmol). To this was added dry DMF
(12 mL). The reaction was freeze pump thawed twice. The
flask was then filled with argon and the reaction was stirred
at 80 8C overnight. The resulting solution was then filtered
through a celite plug filter and reduced by rotatory
evaporation. The resulting residue was dissolved in CHCl3
and washed with water (2£50 mL), and brine (2£50 mL).
The organic layer was isolated, dried over K2CO3 and
reduced under vacuum, to produce a viscous oil. This was
then purified by alumina column chromatography using
CH2Cl2/MeOH (1–5%).
4. Experimental
4.1. General
Starting materials were obtained from Sigma Aldrich, Strem
Chemicals and Fluka. Columns were run using Silica gel 60
(230–400 mesh ASTM) or Aluminum Oxide (activated,
Neutral, Brockmann I STD grade 150 mesh). Solvents were
used at GPR grade unless otherwise stated. Infrared spectra
were recorded on a Mattson Genesis II FTIR spectro-
photometer equipped with a Gateway 2000 4DX2-66
workstation. Oils were analysed using NaCl plates, solid
samples were dispersed in KBr and recorded as clear
4.2.1. 2-[4,7-Bis-dimethylcarbamoylmethyl-10-(4-meth-
oxy-phenylsulfonyl)-1,4,7,10-tetraaza-cyclododec-1-yl]-
N,N-dimethyl-acetamide (8). 600 mg was purified by

112
T. Gunnlaugsson et al. / Tetrahedron 60 (2004) 105–113
alumina column chromatography using 97:3, EtOAc/
MeOH, to yield 320 mg of 8 as a pale yellow viscous oil.
Calculated for C27H48N7O6S: [MþH peak] m/z¼598.3387.
Found: 598.3389; dH (CDCl3, 400 MHz) 7.62 (d, J¼9.0 Hz,
2H, Ar-H), 6.94 (d, J¼9.0 Hz, 2H, Ar-H), 3.79 (s, 6H), 3.56
(m, 6H), 3.26 (m, 8H), 3.08–2.90 (m, 12H), 2.87–2.81 (m,
10H); dC (CDCl3,100 MHz) 173.6, 169.3, 163.1, 129.4,
114.2, 55.3, 55.2, 54.5, 53.8, 53.6, 53.2, 51.1, 36.3, 36.1,
34.9; Mass Spec (MeOH, ESþ) m/z expected: 597.78.
2852, 1637, 1508, 1475, 1402, 1338, 1261, 1103, 1064,
1022, 881, 806, 769, 667, 649, 574, 484.
4.2.4. 2-(4,10-Bis-methylcarbamoylmethyl-1,4,7,10-tet-
raaza-cyclododec-1-yl)-N-methyl-acetamide Eu(III)
(Eu.2). 94.7 mg, (0.22 mmol) of 2 and 0.26 mmol of
Eu(III) triflouromethane sulphonate [Eu(SO3CF3)3] was
added to a 25 mL single necked RBF which contained
10 mL of freshly dried acetonitrile. The solution was freeze
thawed three times, placed under an argon atmosphere and
left stirring at 82 8C for 24 h. The resulting solution was
cooled to room temperature and then dropped slowly onto
100 mL of dry diethyl ether. The diethyl ether was poured
off to leave Eu.2 as oil that was washed with CH2Cl2 and
dried under high vacuum. Yield .95%. Calculated for
C20H35N7O12F9S3Eu·(H2O)2(CH2Cl2)2: C, 22.19; H, 3.64;
N, 8.24. Found: C, 22.29; H, 3.74; N, 8.38. Calculated for
C17H36N7O3Eu:[MþH peak] m/z¼539.2092. Found:
539.2087. Calculated for C18H36N7O6F3SEu:[MþH(Trif)]
m/z¼688.1612. Found: 688.1548. Calculated for C19H36N7-
O9F6S2Eu:[MþH(Trif)2] m/z¼837.1133. Found: 837.1181;
dH(MeOD, 400 MHz) 27.04, 14.96, 11.44, 5.20, 3.68, 2.76,
2.41, 1.55, 20.09, 21.84, 24.93, 27.35, 210.77, 212.31,
216.66; dF(MeOD, 376 MHz) 280.45. Mass Spec (MeCN,
ESþ) m/z expected: 538.2. Found: 539.2 (MþH), 668.1
(MþH(Trif)), 837.1 (MþH(Trif)2); IR nmax(cm21) 3455,
3386, 3297, 3143, 3000, 2933, 2885, 1639, 1587, 1465,
1419, 1288, 1245, 1160, 1091, 1027, 725, 638, 576, 516.
Found: 598.4 (MþH), 620.6 (MþNa); IR nmax (cm21
)
3438, 2962, 2923, 2854, 1735, 1646, 1508, 1457,
1398, 1340, 1261, 1155, 1091, 1022, 867, 804, 701, 559,
474.
4.2.2. 2-[4-(4-Methoxy-phenylsulfonyl)-7,10-bis-methyl-
carbamoylmethyl-1,4,7,10-tetraaza-cyclododec-1-yl]-N-
methyl-acetamide (9). 455 mg of 9 was produced as a
viscous oil. Calculated for C24H42N7O6S: [MþH peak]
m/z¼556.2917. Found: 556.2906; dH (CDCl3, 400 MHz);
7.91 (bs, 1H N–H), 7.72 (d, J¼8.5 Hz, 2H), 7.63 (bs, 2H,
N–H), 7.02 (d, J¼9.0 Hz, 2H), 3.88 (s, 3H, OCH3), 3.47 (s,
4H, CH2), 3.42 (s, 2H, CH2) 3.18 (bs, 8H, CH2), 2.96 (s,
6H), 2.82 (m, 8H, CH2), 2.08 (s, 3H); dC(CDCl3, 100 MHz)
171.5, 171.2, 129.4, 114.4, 58.51, 58.10, 55.58, 53.74,
53.33, 53.04, 49.46, 36.35, 31.31, 25.9, 25.8; Mass Spec
(MeOH, ESþ) m/z expected: 555.3. Found: 556.6, (MþH),
578.6 (MþNa); IR nmax (cm21) 3421, 3077, 2925, 2854,
1654, 1596, 1542, 1457, 1409, 1338, 1261, 1155, 1093,
1022, 841, 840, 728, 698, 559.
4.3. X-ray crystallography
The experimental results for 1 from Method 1 was identical
to that obtained for Method 2, which has previously been
reported.19
Data were collected on a Bruker SMART diffractometer
with graphite monochromated Mo Ka radiation. A crystal
was mounted on to the diffractometer at low temperature
under dinitrogen at ca. 120 K. Cell parameters were
obtained from 300 to 500 accurately centered reflections.
v/f Scans were employed for data collection and Lorentz
and polarisation corrections were applied.
4.2.3. 2-(4,10-Bis-dimethylcarbamoylmethyl-1,4,7,10-
tetraaza-cyclododec-1-yl)-N,N-dimethyl-acetamide (1).
The ligand 8, 0.39 g (0.70 mmol) was placed in a 100 mL
3 necked RBF. To this was added dry THF (30 mL) and
ethanol (0.3 mL). This was attached to a cold finger
condenser and the apparatus was placed into a dry ice/IPA
bath where the temperature was dropped to 260 8C. Dry ice
and IPA was also added to the condenser. Liquid NH3 was
added to the reaction vessel through the cold finger
condenser (approximately 40 mL). Sodium metal (1.2 g,
0.05 mol) was added to this solution. The reaction was left
stirring at 260 8C for 4 h during which time the yellow
solution turned dark blue. The solution was allowed to warm
up to room temperature and left stirring overnight. To this
solution THF (20 mL) was added to dissolve the excess
(unused) sodium present. Concentrated HCl was added until
the solution was at pH 1 and then extracted with DCM.
The pH of the solution was then adjusted to pH 14 using
KOH pellets and then extracted with chloroform and
reduced to yield the desired product. 100 mg (36% yield)
of 1 was isolated as a clear residue. Calculated for
The structure was solved using direct methods26 and the
non-hydrogen atoms were refined with anisotropic
thermal parameters. Hydrogen-atom positions were
located from difference Fourier maps and fully refined.
2
P
2
The function minimised was
[w(lFol 2lFcl )] with
2
reflection weights w 21¼[s 2lFol þ(g1P)2þ(g2P)] where
2
2
P¼[maxlFol þ2lFcl ]/3. Additional material available
from the Cambridge Crystallographic Data Centre com-
prises relevant tables of atomic coordinates, bond lengths
and angles, and thermal parameters Crystallographic data
(excluding structure factors) for the structures in this paper
have been deposited with the Cambridge Crystallographic
Data Centre as supplementary publication numbers
CCDCC: copies of the data can be obtained, free of charge,
on application to CCDC, 12 Union Road, Cambridge CB2
1EZ, UK (fax: þ44-1223-336033 or e-mail: deposit@ccdc.
cam.ac.uk).
C20H42N7O3:[MþH
peak]
m/z¼428.3344.
Found:
428.3349; dH(CDCl3, 400 MHz) 9.98 (broad s, 1H, N–H),
3.59 (s, 2H, CH2–acetamide), 3.56 (s, 4H, CH2–aceta-
mide), 3.08 (s, 8H), 3.03 (s, 3H), 2.95 (s, 6H), 2.88 (s, 10H),
2.83 (s, 7H); dC(CDCl3, 100 MHz) 170.3, 170.2, 55.5, 53.8,
51.7, 50.6, 49.7, 46.7, 36.4, 35.3; Mass Spec (MeOH, ESþ)
m/z expected: 427.59. Found: 428.33 (MþH), 450.30
(MþNa), 472.30 (MþK); IR nmax(cm21) 3434, 2927,
Acknowledgements
We thank Kinerton Ltd., Enterprise Ireland (Postgraduate
Scholarships to SM and JPL), National Pharamaceutidal
Biotechnology Center, Bio Research Ireland and Trinity

T. Gunnlaugsson et al. / Tetrahedron 60 (2004) 105–113
113
´ ´
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J. Am. Chem. Soc. 2003, 125, 12062. (b) Gunnlaugsson, T.;
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College Dublin for financial support. We thank Dr Steven
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