Octadentate ligands containing 2,3-dihydroxybenzamide and 2,3-dihydroxyterephthalamide coordinating subunits on a tetrapodal amine backbone for chelation of actinides

Article abstract of DOI:10.1002/ejoc.200400080

The linear octadentate ligand 3,4,3-LICAM(C) (2) is one of the most effective chelating agents for Pu^IV that is not acutely toxic; however, at physiological pH, due to the weak acidity of the catechol hydroxy groups and the large proton dependence of the complexation reaction, only three of the four catecholate subunits are coordinated to Pu^IV. To overcome this disadvantage, a new topological class of octadentate ligands based on tetrapodal amine backbones and 2,3-dihydroxyterephthalamide (3) (TAM) binding units were designed and synthesized. The amide substituents provide a handle by which the functionality of the ligand can be readily modified, and this synthetic strategy and procedure can be extended to prepare a variety of new multidentate metal-coordination and extraction agents. A streamlined synthesis for the terephthalamides, both symmetric and asymmetric, was recently reported. In this work, the synthetic details of their incorporation into octadentate systems for use as coordination or extraction agents for Pu^IV or other metals in the +4 oxidation state are described. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.

Full text of DOI:10.1002/ejoc.200400080

FULL PAPER
Octadentate Ligands Containing 2,3-Dihydroxybenzamide and
2,3-Dihydroxyterephthalamide Coordinating Subunits on a Tetrapodal Amine
Backbone for Chelation of Actinides
Jide Xu,[a] Anne E. V. Gorden,[a] and Kenneth N. Raymond*[a]
Keywords: Actinide / Ligand design / Macrocylic ligands / Siderophore / Synthetic methods
The linear octadentate ligand 3,4,3-LICAM(C) (2) is one of
the most effective chelating agents for PuIV that is not acutely to prepare a variety of new multidentate metal-coordination
toxic; however, at physiological pH, due to the weak acidity and extraction agents. streamlined synthesis for the
of the catechol hydroxy groups and the large proton depend- terephthalamides, both symmetric and asymmetric, was re-
and this synthetic strategy and procedure can be extended
A
ence of the complexation reaction, only three of the four cate-
cholate subunits are coordinated to PuIV. To overcome this
disadvantage, a new topological class of octadentate ligands
cently reported. In this work, the synthetic details of their
incorporation into octadentate systems for use as coordina-
tion or extraction agents for PuIV or other metals in the +4
based on tetrapodal amine backbones and 2,3-dihydroxy- oxidation state are described.
terephthalamide (3) (TAM) binding units were designed and
synthesized. The amide substituents provide a handle by ( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
which the functionality of the ligand can be readily modified,
Germany, 2004)
Introduction
effective than CaNa3-DTPA;[6] however, 3,4,3-LICAM(C)
(2) was only marginally effective for reducing the lung bur-
den of inhaled Pu,[7] and treatment with 3,4,3-LICAM(C)
(2) caused potentially radiologically damaging amounts of
Pu to be transferred to and deposited in the kidneys of sev-
eral species (Figure 1).[8] From this, it was determined that
at physiological pH, the weak acidity of the catechol
hydroxy groups and the eight-proton stoichiometry of the
complexation reaction prevent 3,4,3-LICAM(C) (2) from
forming an octadentate PuIV complex. With only three of
the four catecholate subunits coordinated to PuIV, the sta-
bility of the Pu complexes at pH 7.4 only slightly exceed
that of the FeIII complex, and at pH lower than 7.4, the
PuIV complexes with 3,4,3-LICAM(C) (2) are unstable.[9,10]
Therefore, a more effective tetrakis catechoyl-based ligand
would be one with increased acidity and a greater predis-
position towards binding.
The 2,3-dihydroxyterephthalamide (TAM) ligating group
3 (see Figure 2), while similar in structure to the cat-
echolamide groups found naturally occurring in sidero-
phores, is substantially more acidic than the CAM ligating
group, is less sensitive to oxidation, and displays the great-
est affinity for the ferric ion of any catecholate deriva-
tive.[11,12] These properties are believed to be derived from
the strong hydrogen bonding between the amide proton and
the ortho hydroxy group. Structural characterizations of me-
tal complexes of this class of ligands with iron (Fe)[13] and
with thorium (Th), as an analog for plutonium (Pu),[14,15]
exhibit this hydrogen-bonding motif. An eight-coordinate
geometry is generally preferred by PuIV, and a preorganized
Nature has responded to the problem of the low bioavail-
ability of Fe due to the insolubility of Fe(OH)3 by de-
veloping selective, high-affinity FeIII-sequestering agents,
called siderophores.[1] The great specificity of the sideroph-
ores towards FeIII, the toxicity of PuIV, and its chemical
similarities to FeIII, inspired the development of analogous
sequestering agents for PuIV.[2] Previously, catecholate-based
ligands have been investigated in the formation of metal
coordination complexes in large part due to their high affin-
ity for high-oxidation-state metals.[3Ϫ5] Ligands containing
four catechol-binding subunits connected by a suitable mo-
lecular backbone were predicted to form stable eight-coor-
dinate complexes with PuIV. This has been the foundation
of an ongoing program of research resulting in the design
and synthesis of numerous octadentate ligands for PuIV
chelation and is the subject of a recent extensive review.[2]
The ligand of this group found to be the most effective
tetracatecholate ligand for PuIV chelation, 3,4,3-LICAM(S)
(1) (which is toxic), and the nontoxic 3,4,3-LICAM(C) (2)
promoted as much or more Pu excretion from mice and
dogs at a dosage of 30 µmol kgϪ1 as an equimolar amount
of CaNa3-DTPA, and at lower dosages it was much more
[a]
Department of Chemistry and Chemical Science Division,
Lawrence Berkeley Laboratory, University of California at
Berkeley,
Berkeley, California, 94720 USA
Fax: (internat.) ϩ1-510-486-5283
E-mail: Raymond@socrates.berkeley.edu
3244
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200400080
Eur. J. Org. Chem. 2004, 3244Ϫ3253

Octadentate Ligands with a Tetrapodal Amine Backbone for Chelation of Actinides
FULL PAPER
Figure 1. Tetracatecholate ligands 3,4,3-LICAM(S) (1) and 3,4,3-LICAM(C) (2)
tetrapodal tetra-terephthalamide ligand should provide a CAM(C) ligands were also designed and charac-
proper coordination environment for chelating PuIV. Based terized.[18Ϫ20]
on this hypothesis, a new structural class of ligands was
designed, incorporating ‘‘H-shaped’’ tetra-primary-amine
backbones and the 2,3-dihydroxyterephthalamide ligating
subunits (Figure 2) in both open and closed or macro-
tricyclic architectures.[16]
Results and Discussion
The synthetic routes for different types of octadentate
We recently reported a streamlined synthesis for the ligands are shown in Schemes 1Ϫ4. Methyl 4-chloro-
terephthalamides (e.g. 3, Figure 2), both symmetric and carbonyl-2,3-dimethoxybenzoate (9),[21,22] 3-[(2,3-Di-
asymmetric.[14] Earlier work has carefully detailed their ef- methoxyphenyl)carbonyl]thiazolidine-2-thione
(22),[23]
ficiency as chelating agents for FeIII [11] and more recently, and the terephthalamide derivative 26[13] were prepared
the results of peripheral charge variation on the stability of as described previously. TAEC [N,NЈ,NЈЈ,NЈ"-tetra-
the FeIII complexes.[17] In this work, the synthetic details kis(2-aminoethyl)-1,4,8,11-tetraazacyclotetradecane, 7][24]
of their incorporation into octadentate systems for use as and PENTEN [N,N,NЈ,NЈ-tetrakis(2-aminoethyl)ethylene-
coordination or extraction agents for PuIV or other metals diamine, 6][25] were synthesized following the published
in the ϩ4 oxidation state and the effects of changes in the method. N,N,NЈ,NЈ-tetrakis(2-aminoethyl)propanediamine
fundamental octadentate framework are described. In order and N,N,NЈ,NЈ-tetrakis(2-aminoethyl)butanediamine were
to optimize the ligand design, corresponding octadentate prepared by a similar method. Like the CAM ligands, TAM
linear TAM ligands, H-CAM, Oxo-H-CAM, and H- ligands can be used to create a wide variety of ligand sys-
Figure 2. Octadentate terephthalamide ligands
Eur. J. Org. Chem. 2004, 3244Ϫ3253
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3245

J. Xu, A. E. V. Gorden, K. N. Raymond
FULL PAPER
tems by attaching them to various backbones. This strategy (7), in CH2Cl2 to the acyl chloride, 2,3-dimethoxybenzoyl
can be extended to prepare a variety of multidentate chloride (8).[23] Purification by flash chromatography on sil-
sequestering agents with unique geometries using other ica gel (1Ϫ6% MeOH gradient in CH2Cl2 as eluent) pro-
amines or modified chelating subunits or combinations of vides the methoxy-protected H(2,2)-CAM 10 (75% yield) or
subunits.
the methoxy-protected TAEC-CAM 18 (80% yield) as a
The synthetic scheme for the TAM chelating subunits be- pale yellow oil. This product was deprotected with the ad-
gins with the inexpensive, commercially available catechol. dition of BBr3 by syringe to the above methoxy-protected
The carboxylation of catechol is followed by conversion of ligand 10 or 18 in anhydrous CH2Cl2 at Ϫ78 °C. The slurry
these carboxy groups to methyl esters, then methyl protec- was warmed to room temperature and stirred continuously
tion of the catecholate oxygen atoms and saponification of for four days. After returning the reaction mixture to Ϫ78
the esters to the carboxylic acid, which can then be con- °C, methanol was added. The mixture was then heated to
verted into the acyl chloride or thiazolamide. This pro- boiling with water to hydrolyze the remaining borate ester.
cedure differs from the synthesis of CAM ligands in that it The H(2,2)-CAM (11) (100% yield) or TAEC-CAM (19)
requires the saponification of both the esters as opposed to (65% yield) that precipitated upon cooling was collected by
one in the case of the CAM ligands. The acid chloride- or filtration and dried under vacuum at 60 °C overnight.
thiazolamide-activated TAM provides the required func-
tionalization to treat the ligand with a variety of amines to and NEt3 in anhydrous THF was added to 4-chlorocar-
serve as the backbone for the higher denticity system. After bonyl-2,3-dimethoxybenzoic acid methyl ester (9),[21]
When a solution of the appropriate H(n,2)-tetraamine
a
amidation to add a chelating unit to the backbone, amino- white precipitate immediately formed. This reaction mix-
lysis of the second with an excess of amine results in the ture was stirred overnight at room temperature and filtered.
TAM ligand. The hydroxyl-protecting groups can then be Evaporation of the filtrate in vacuo yielded a viscous oil,
cleaved by treatment with an excess of BBr3. In the alterna- which was purified by flash chromatography on silica gel
tive streamlined methodology, the protection of the phe- (2Ϫ4% MeOH gradient in CH2Cl2 as eluent) to give the
nolic oxygen atoms is not required as the direct activation fully methoxy-protected product [H(n,2)-CAM(C) 12, 14,
of the 2,3-dihydroxyterephthalic acid with sulfuryl chloride 16 or TAEC-CAM(C) (20)] as a yellow oil, which, when
is followed directly by reaction with an amine.[26]
deprotected with BBr3 as described above, resulted in the
The general procedure for the synthesis of the octadent- carboxylated CAM product 13,15,17, or 21 in good yield
ate CAM ligands H(2,2)-CAM (11) and TAEC-CAM (19) (Scheme 1).
(Scheme 1) begins with the addition of a solution of the
Following a similar procedure (Scheme 2), diethylenetri-
desired tetraamine, PENTEN H(2,2)-amine (6) or TEAC amine in CH2Cl2 was added to 22.[23] The crude product
Scheme 1. Synthesis of octadentate catecholamide ligands; reagents and conditions: (i) CH2Cl2, room temp., 24 h; (ii) 1. BBr3, CH2Cl2,
Ϫ78 °C, under Ar; 2. MeOH, Ϫ78 °C; 3. H2O, 100 °C (iii) anhydrous THF, Et3N
3246
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 3244Ϫ3253

Octadentate Ligands with a Tetrapodal Amine Backbone for Chelation of Actinides
FULL PAPER
was purified by chromatography on silica gel (1Ϫ3% MeOH give a white solid (63% yield). The methoxy-protected oxo-
gradient in CH2Cl2 as eluent) to give pure 23 (87% yield) H(2,2)-MeTAM 29, deprotected with excess BBr3 as de-
as a pale yellow oil. Compound 23, Et3N, and oxalyl chlo- scribed for the deprotection of CAM ligands, yielded 30 as
ride were combined in anhydrous THF at Ϫ78 °C, and the a beige powder in 85% yield.
reaction mixture was stirred at 25 °C for 4 hours and before
Following the same procedure using n-propylamine in
being evaporated to dryness and an aqueous work up. The place of the methylamine solution, yields compound 33.
crude product was purified by chromatography on silica gel The pure product was obtained as a white foam (89% yield).
(3Ϫ6% MeOH gradient in CH2Cl2 as eluent) to give the Preparation of Me8Oxo-H(2,2)-PrTAM (32) was carried
methoxy-protected oxo-H(2,2)-CAM 24 as a pale yellow oil out in a procedure similar to the synthesis of Me8Oxo-
(63% yield), which, after deprotection with an excess of H(2,2)-MeTAM (29), except that 29 was used as the start-
BBr3 as described above, yielded 25 as a white powder ing material instead of 28. Purification by column chroma-
(89% yield).
tography (4Ϫ10% MeOH in CH2Cl2) gave Me8Oxo-H(2,2)-
Scheme 3 depicts the synthesis of the Oxo-TAM ligands PrTAM (32) as a white solid (71%). Me8Oxo-H(2,2)-
beginning from the diethylenetriamine derivative 27. This PrTAM (32), deprotected with excess BBr3 as described for
intermediate product can be produced through the slow ad- the deprotection of the other CAM ligands, yielded 33 as a
dition of a solution of diethylenetriamine in CH2Cl2 to a beige powder in 78% yield.
solution of terephthalamide derivative 26[13] in CH2Cl2 con-
The H(2,2)-MeTAM (37), H(2,2)-EtTAM (38), and
taining 2% MeOH. After the addition, the reaction mixture H(2,2)-PrTAM (39) ligands can be obtained using a gen-
was passed through a silica gel column, and eluted with 2% eral procedure based on that for the CAM(C) ligands
MeOH in CH2Cl2 to remove most of the excess terephthal- (Scheme 4). A solution of PENTEN H(2,2)-amine (6) and
amide derivative 26, while 27 was retained on the silica col- NEt3 in anhydrous THF was added to the benzoate 9[21]
umn. The appropriate fractions of a gradient elution in anhydrous THF by cannula under nitrogen, immedi-
(5Ϫ10% MeOH in CH2Cl2) were collected and concen- ately forming a white precipitate. The reaction mixture was
trated to produce 27 (75% yield) as a white foam. A solu- stirred overnight under nitrogen at room temperature, and
tion of 27 in CH2Cl2 was reacted with methylamine in the triethylamine hydrogen chloride-precipitate by-product
MeOH. The crude product, isolated by column chromatog- was collected by filtration. Concentration of the filtrate in
raphy on silica gel (6Ϫ12% MeOH ϩ0.2% Et3N in vacuo yielded a viscous oil, which was purified by chroma-
CH2Cl2), yielded the 28 as a white solid (85% yield). The tography on silica gel (2Ϫ4% MeOH in CH2Cl2) to give
methoxy-protected Oxo-H(2,2)-MeTAM 29 was then syn- the methoxy-protected CAM(C) species 34 as pale yellow
thesized by coupling two molecules of 28 with oxalyl chlo- oil. Compound 34 was mixed with methanol and a 1 
ride by adding the reagent with stirring to a solution of 28 aqueous NaOH solution. The reaction mixture was heated
and Et3N in anhydrous THF at Ϫ30 °C. The reaction mix- to reflux temperature for 4 hours and then evaporated to
ture was stirred at 25 °C for 4 hours and concentrated by dryness. The residue was dissolved in H2O and acidified
evaporation. The residue was dissolved in dichloromethane to pH 2 using 6  HCl. The methoxy-protected CAM(C)
and washed successively with aqueous 1  HCl and water. tetraacid species 35 settled as a pale yellow oil. The crude
The crude product was purified by column chromatography product was dissolved in dry THF, filtered, and coevapo-
on silica gel (6Ϫ12% MeOH ϩ 0.2% Et3N in CH2Cl2) to rated with anhydrous THF three times to remove water.
Scheme 2. Synthesis of octadentate oxo-catecholamide ligands 1, Oxo-H(2,2)-CAM; reagents and conditions: (i) anhydrous THF, Et3N;
(ii) 1. Et3N, anhydrous THF, oxalyl chloride, Ϫ78 °C; 2. 25 °C, 4 h; 3. CH2Cl2, aqueous workup, 1  HCl; (iii) 1. BBr3, CH2Cl2, Ϫ78
°C, under Ar; 2. MeOH, Ϫ78 °C; 3. H2O, 100 °C
Eur. J. Org. Chem. 2004, 3244Ϫ3253
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3247

J. Xu, A. E. V. Gorden, K. N. Raymond
FULL PAPER
Scheme 3. Synthesis of octadentate oxo-catecholamide ligands; reagents and conditions 2: (i) CH2Cl2 containing 2% MeOH; (ii) NH2Me,
MeOH, room temp., 4 h; (iii) Et3N, anhydrous THF, oxalyl chloride, Ϫ30 °C; (iv) 1. BBr3, CH2Cl2, Ϫ78 °C, under Ar; 2. MeOH, Ϫ78
°C; 3. H2O, 100 °C
At Ϫ10 °C, under argon, N-hydroxysuccinimide and 1,3- stable complexes with metal ions having high charge-to-ra-
dicyclohexylcarbodiimide were added to 35 in THF. After dius ratio, such as Fe3ϩ, Ce4ϩ, Pu4ϩ, and so forth.
1
stirring for 24 hours, an appropriate backbone amine in
The crystal structure, H and 13C NMR spectra of the
THF was added with stirring. The dichlorourethane solids protected Me8BH(2,2)-CAM, previously reported, indi-
were removed by filtration, and the filtrate was evaporated cated that it has effective D2h symmetry both in the solid
1
to dryness and purified by chromatography on silica gel state and in solution. The H NMR spectra taken of the
(4Ϫ6% MeOH in CH2Cl2) to give the corresponding oc- related free macrotricyclic octadentate ligand, BH(2,2)-
tadentate 2,3-dimethoxyterephthalamide ligand as a pale CAM (5), and its stable complex, K4CeBH(2,2)-CAM, also
yellow oil, which was then deprotected with BBr3 as above revealed that they have effective D2h symmetry, suggesting
to give 37, 38, or 39. The linear octadentate terephthal- some predisposition of the ligand for the expected highly
amide ligand 3,4,3-LIMeTAM (41) was synthesized and symmetrical eight-coordinated cage-complex formation, al-
purified by the same procedure as for the H(2,2)-TAMs, though this cannot be concluded definitively without struc-
except that spermine (40) was used instead of PENTEN tural evidence.[19]
6 (Scheme 5).
The isolated ligands are white to pale yellow in color. In
general, they are not very hygroscopic and are obtained as
micro-crystalline or amorphous solids. While DFO-Me-
Conclusion
TAM and 3,4,3-LIMeTAM melt sharply, the other octad-
The PuIV complexes with tetracatechoylate ligands are
entate compounds having tertiary nitrogen atoms decom- functionally hexadentate at physiological pH.[8,10] In the
pose slowly upon heating. The most distinctive feature of case of 3,4,3-LICAM(C), the Pu complex becomes pro-
1
the H NMR spectra of H-CAMs and Oxo-H-CAM is the gressively less stable as the pH is reduced below pH 7.4. In
presence of two doublets and one triplet in the aromatic vivo, hexadentate binding, whether structural or functional,
region arising from the catechoylamide ring protons: the is manifested by retention of Pu in the mouse of 30 to 35%
triplet appears at δ ϭ 6.4Ϫ6.7 ppm, the two doublets ap- of control, and instability of the Pu complexes at pH lower
pear at δ ϭ 6.9Ϫ7.0 and 7.2Ϫ7.4 ppm. The infrared spectra than 7.4 causes large Pu residues (Ͼ 150% of control) to be
of the isolated compounds display a strong band at deposited in kidneys and soft tissue.[8,10] In separate studies
1610Ϫ1640 cmϪl due to the amide groups. These octadent- using PuIV-injected mice, none of the ligands described in
ate ligands are in general slightly soluble in water. They this report [composed of CAM, CAM(C), or TAM metal-
have pKa1Јs in range of 6Ϫ8, and the pH of a saturated binding groups] promoted significantly more Pu excretion
solution is typically neutral. These compounds should form than an equimolar amount of 3,4,3-LICAM(C), from
3248
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 3244Ϫ3253

Octadentate Ligands with a Tetrapodal Amine Backbone for Chelation of Actinides
FULL PAPER
Scheme 4. Synthesis of octadentate 2,3-dihydroxyterephthalamide ligands; reagents and conditions: (i) 1. anhydrous THF, Et3N, under
N2; 2. under N2, room temp., 12 h; (ii) 1. aqueous workup, MeOH, 1  NaOH; 2. 100 °C, 4 h; 3. H2O, 6  HCl; (iii) THF, Ϫ10 °C,
under Ar, N-hydroxysuccinimide, 1,3-dicyclohexylcarbodiimide; (iv) 24 h, room temp., THF, RNH2; (v) 1. BBr3, CH2Cl2, Ϫ78 °C, under
Ar; 2. MeOH, Ϫ78 °C; 3. H2O, 100 °C
Scheme 5. Synthesis of 3,4,3-LIMeTAM; reagents and conditions: (i) 1. anhydrous THF, under N2; 2. under N2, room temp., 12 h; (ii)
1. aqueous workup, MeOH, 1  NaOH; 2. 100 °C, 4 h; 3. H2O, 6  HCl; (iii) THF, Ϫ10 °C, under Ar, N-hydroxysuccinimide, 1,3-
dicyclohexylcarbodiimide; (iv) 24 h, room temp., THF, MeNH2; (v) 1. BBr3, CH2Cl2, Ϫ78 °C, under Ar; 2. MeOH, Ϫ78 °C; 3. H2O,
100 °C
which it is inferred that these are also functionally hexaden- vivo, the MeTAM binding group was found to be almost
tate for PuIV chelation at physiological pH. All but four equally effective in tetrameric ligands based on spermine or
of this related series of ligands [3,4,3-LIMeTAM, BH(2,2)- PENTEN, and replacement of the ethylene bridge by Oxo-
CAM, DFO-MeTAM, and its FeIII complex] were found to H(2,2)- or by propylene or butylene bridges reduced the
deposit PuIV in the kidneys in excess of the control value, stability of the Pu complexes, supporting the usefulness of
indicating that their PuIV complexes are not stable at re- the PENTEN backbone for octadentate ligands.[29]
duced pH. This deposition of the heavy metal at the re-
Previously, the synthesis and, in some cases, evaluation
duced pH of the kidney is held to be the cause of some of in vivo PuIV chelation by siderophore analogs with
toxicity found with other CAM ligands previously stud- linear,[6,30,32Ϫ34] tripodal[34Ϫ36] macrocyclic,[6] and macrob-
ied,[27,28] and is one reason for ongoing research and the icyclic topologies have been reported,[13,37] including an ap-
continued development of new ligand systems.[29Ϫ31]
proach similar to this using ‘‘H-shaped’’ tetrapodal hexa-
Several conclusions on the desirable characteristics for an amine backbone systems in the design of hydroxypyridi-
in vivo, chelating ligand for PuIV can now be drawn. In none-based chelating ligands for actinides. The hydroxypyr-
comparison to the 3,4,3-LICAM(C) system, the attachment idinonate or HOPO (2-hydroxy-1-methyl-3- or 1-hydroxy-
of the TAM functional group to the spermine backbone 2-pyridinone abbreviated as Me-3,2-HOPO or 1,2-HOPO)
improved the stability of the Pu chelate at the low pH of ligands possesing increased acidity and solubility, were
renal tubular urine somewhat, diminishing the problem of found to further improve PuIV chelation in mice while still
dissociation of the PuIV complex within the kidneys. In maintaining the stability of the PuIV complex at the reduced
Eur. J. Org. Chem. 2004, 3244Ϫ3253
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3249

J. Xu, A. E. V. Gorden, K. N. Raymond
FULL PAPER
pH of the kidney.[36] Recently, mixed TAM-HOPO systems
have been investigated as PuIV decorporation agents.[30]
These mixed systems have also been used to prepare com-
plexes with GdIII for the development of higher relaxivity-
contrast agents for MRI.[38,39]
reaction mixture to Ϫ78 °C, methanol (20 mL) was added. The
mixture was then warmed to 25 °C; then heated to boiling with
water (100 mL) to hydrolyze the remaining borate ester. The
H(2,2)-CAM (11) (100% yield) or TAEC-CAM (19) (65% yield)
that precipitated upon cooling was collected by filtration and dried
under vacuum at 60 °C overnight.
As shown in Schemes 1Ϫ4, various approaches were de-
signed to prepare octadentate ligands bearing CAM,
CAM(C), and TAM chelating subunits. Amide substituents
provide a handle by which the functionality of the ligand
can be readily modified, and this synthetic strategy has been
extended to prepare a variety of new multidentate ligand
systems. Although Pu complexes of the TAM ligands were
found to be more stable at reduced pH than the previously
described CAM-based ligands, the increase in acidity from
CAM-based ligands to TAM-based systems did not mark-
edly increase the coordination of PuIV, as there was no dra-
matic increase in PuIV excretion seen in in vivo testing in
the mouse model.[29] These systems remain attractive for
use as actinide-selective extraction agents in environmental
applications or waste-remediation systems due to their rela-
tive ease of synthesis and comparative stability.
H(2,2)-CAM (11): M.p. 215 °C, total yield 75%. C38H44N6O12; [M
ϩ H]ϩ calcd. 776.81; found 777. 1H NMR (400 MHz, [D6]DMSO):
δ ϭ 3.53 (s, 8 H, CH2N), 3.82 (s, 8 H, CH2N), 3.88 (s, 4 H, CH2N),
6.70 (t, J ϭ 7.8 Hz, 4 H, Ar H), 6.97 (d, J ϭ 7.6 Hz, 4 H, Ar H),
7.41 (d, 4 H, Ar H), 9.2 (s, 4 H, NH) ppm. 13C NMR (100 MHz,
[D6]DMSO): δ ϭ 34.1, 51.8,115.3, 117.9, 118.3, 119.2, 146.2, 149.2,
170.2 ppm.
TAEC-CAM (19): M.p. 186°C, total yield 52%. C46H60N8O12; [M
ϩ H]ϩ calcd. 917.04; found 917. 1H NMR (400 MHz, [D6]DMSO):
δ ϭ 1.80 (br., 4 H, CH2), 2.80Ϫ3.00 (br., 16 H, CH2), 3.35, 3.54
(br., 16 H, CH2), 6.70 (t, J ϭ 7.8 Hz, 4 H, Ar H), 6.90 (d, J ϭ 7.7
Hz, 4 H, Ar H), 7.30 (d, J ϭ 8.0 Hz, 4 H, Ar H), 8.90 (s, 4 H,
NH) ppm. 13C NMR (100 MHz, DMSO): δ ϭ 37.4, 46.6, 48.2,
51.2, 55.0, 115.7, 119.5, 120.1, 146.5, 150.4, 170.8 ppm.
Synthesis of Octadentate CAM(C) Ligands H(n,2)-CAM(C) 13, 15,
17 and TAEC-CAM(C) (21)
General Procedure: See Scheme 1. A solution of the appropriate
H(n,2)-tetraamine (0.3 mmol) and NEt3 (0.2 mL, 1.5 mmol) in an-
hydrous THF (10 mL) was added to the benzoate derivative 9[21]
(0.39 g, 1.5 mmol) in anhydrous THF (20 mL). A white precipitate
immediately formed. The reaction mixture was stirred at room tem-
perature overnight in a stoppered flask and filtered. Evaporation
of the filtrate in vacuo yielded a viscous oil, which was purified by
flash chromatography on silica gel (2Ϫ4% MeOH gradient in
CH2Cl2 as eluent) to give the fully methoxy-protected product as a
pale yellow oil in good yield (65Ϫ85% yield). It was deprotected
with BBr3 as described for octadentate CAM ligands (60Ϫ85%
yield).
Experimental Section
General Remarks: Unless otherwise noted, materials were used as
obtained commercially without further purification. Benzoate
9,[21,22] benzamide derivative 22[23] and terephthalamide derivative
26[13] were prepared as described in previous publications. TAEC
[N,NЈ,NЈЈ,NЈ-tetrakis(2-aminoethyl)-1,4,8,11-tetraazacyclotetra-
decane, 7][24] and PENTEN [N,N,NЈ,NЈ-tetrakis(2-aminoethyl)ethy-
lenediamine, 6][25] were synthesized following the published
method, N,N,NЈ,NЈ-tetrakis(2-aminoethyl)propanediamine and
N,N,NЈ,NЈ-tetrakis(2-aminoethyl)butanediamine were prepared by
a similar method. Syntheses of macrotricyclic DFO-MeTAM (4,
Figure 2) and BH(2,2)-CAM (5) have been published in earlier
works.[19,20]
H(2,2)-CAM(C) (13): M.p. 220°C, total yield 54%. C42H44N6O20;
[M ϩ H]ϩ calcd. 952.85; found 953.5. 1H NMR (400 MHz,
[D6]DMSO: δ ϭ 3.10 (s, 4 H, CH2), 3.15 (s, 8 H, CH2), 3.60 (s, 16
H, CH2), 7.10 (s, 8 H, Ar H), 8.90 (br. s, 4 H, NH), 12 (br., 8 H,
phenol H) ppm. 13C NMR (125 MHz, D2O-NaOD): δ ϭ 37.5,
51.8, 53.3, 115.0, 118.2, 119.8, 120.0, 153.7, 157.4, 171.2, 176.9
ppm.
The synthetic routes for different types of octadentate ligands are
shown in Schemes 1Ϫ4. Mass spectroscopic data were obtained
with an Atlas MS-12, a consolidated 12Ϫ110B, or a Kratos MS50
1
spectrometer. The H and 13C NMR spectra were recorded with a
H(3,2)-CAM(C) (15): M.p. 237°C. C43H46N6O20; [M ϩ H]ϩ calcd.
966.88; found 967.1 . H NMR (400 MHz, [D6]DMSO: δ ϭ 2.02
(br., 2 H, NCH2CH2), 3.12 (br. s, 12 H, NCH3), 3.54 (br. s, 8 H,
NHCH2), 7.19 (br. s, 8 H, Ar H), 8.97 (br. s, 4 H, NH) ppm. 13C
NMR (100 MHz, D2O-NaOD): δ ϭ 23.7, 37.2, 52.5, 53.2, 116.7,
117.7, 119.3, 120.5, 152.7, 154.5, 170.9, 176.3 ppm. (Total yield
55%).
UCB-250, a Bruker AM-400 or a Bruker DRX500 spectrometer.
Elemental analyses were performed by the Microanalytical Labora-
tory, College of Chemistry, University of California, Berkeley.
1
Synthesis of Octadentate CAM Ligands H(2,2)-CAM and TAEC-
CAM (11, 19)
General Procedure: See Scheme 1. A solution of the appropriate
tetraamine, PENTEN [H(2,2)-amine) or TEAC, (0.5 mmol) in
CH2Cl2(50 mL) was added to benzamide derivative 22[23] (0.60 g,
2.2 mmol) with stirring. The mixture was stirred at 25 °C for 24 h
and the solvent was removed. The crude product was purified by
flash chromatography on silica gel (1Ϫ6% MeOH gradient in
CH2Cl2 as eluent) to give the methoxy-protected H(2,2)-CAM 10
(75% yield) or the methoxy-protected TAEC-CAM 18 (80% yield)
as a pale yellow oil. The product was deprotected as follows: Under
argon, BBr3 (1.5 mL, neat) was added dropwise by a syringe, with
H(4,2)-CAM(C) (17): M.p. 245°C. C44H48N6O20; [M ϩ H]ϩ calcd.
980.91; found 981.4 [M ϩ H]ϩ, 1003 [M ϩ Na]ϩ. 1H NMR
(400 MHz, [D6]DMSO: δ ϭ 1.76 (br. s, 4 H, CH2), 3.26 (br. s, 4 H,
NCH2), 3.36 (br. s, 8 H, NCH2), 3.69 (br. s, 8 H, NHCH2), 7.22
(d, J ϭ 8.5 Hz, 4 H, Ar H), 7.31 (d, J ϭ 8.5 Hz, 4 H, Ar H), 9.15
(br. s, 4 H, NH), 12.0 (br., 4 H, phenol H) ppm. 13C NMR
(100 MHz, D2O-NaOD): δ ϭ 24.4, 37.1, 53.1, 54.3, 113.1, 117.4,
119.4, 121.2, 155.8, 161.7, 171.6, 178.0 ppm. (Total yield 56%).
stirring, to the above methoxy-protected ligand 10 or 18 (0.4 mmol) TAEC-CAM(C) (21): M.p. 256 °C. C50H60N8O20; [M ϩ H]ϩ calcd.
in anhydrous CH2Cl2 (20 mL) at Ϫ78 °C. The slurry was warmed 1093.08; found 1093.3 [M ϩ H]ϩ, 1115.0 [M ϩ Na]ϩ. 1H NMR
to 25 °C and stirred continuously for 4 days. After returning the
3250
(400 MHz, [D6]DMSO: δ ϭ 1.81 (br. s, 4 H, CH2), 3.04 (br. s, 24
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2004, 3244Ϫ3253

Octadentate Ligands with a Tetrapodal Amine Backbone for Chelation of Actinides
H, CH2N), 3.54 (br. s, 8 H, CH2N), 7.23 (d, J ϭ 8.6 Hz, 4 H, Ar Hz, 2 H, Ar H), 7.80 (d, J ϭ 8.2 Hz, 2 H, Ar H), 8.23 (br., 2 H,
FULL PAPER
H), 7.32 (d, J ϭ 8.7 Hz, 4 H, Ar H), 9.01 (br. s, 4 H, NH), 12.1
(br., 4 H, phenol H) ppm. 13C NMR (100 MHz, D2O-NaOD): δ ϭ
36.9, 47.3, 48.4, 51.0, 54.3, 113.4, 118.6, 119.7, 120.0, 154.8, 160.3,
171.5, 177.2 ppm. (Total yield 50%).
NH) ppm.
Compound 28: A solution of 27 (721 mg, 1 mmol) in CH2Cl2
(50 mL) was added to methylamine (4 mmol) in MeOH (2 mL) and
stirred for 4 h. The crude product, isolated by column chromatog-
raphy on silica gel (6Ϫ12% MeOH ϩ0.2% Et3N in CH2Cl2), gave
28 as a white solid (442 mg, 85% yield). 1H NMR (250 MHz,
CDCl3) δ ϭ 2.96 (t, J ϭ 5.9 Hz, 4 H, NCH2), 3.03 (d, J ϭ 4.8 Hz,
6 H, NHCH3), 3.64 (q, J ϭ 5.7 Hz, 4 H, CH2N), 3.87 (s, 6 H,
OCH3), 3.91 (s, 6 H, OCH3), 7.77 (s, 4 H, Ar H), 7.81 (s, 2 H,
NH), 8.12 (t, J ϭ 5.1 Hz, 2 H, NH) ppm.
Synthesis of Oxo-H-CAM (25)
N,N"-Bis(2,3-dimethoxybenzamidoethyl)amine (23): (Scheme 2);
Diethylenetriamine (0.3 g, 3 mmol) in CH2Cl2 (50 mL) was added
to benzamide derivative 22 (1.89 g, 6.4 mmol),[23] and the yellow
solution was stirred at 25 °C for 12 h. The crude product was puri-
fied by chromatography on silica gel (1Ϫ3% MeOH gradient in
CH2Cl2 as eluent) to give pure 23 (1.06 g, 2.61 mmol, 87% yield)
Me8Oxo-H(2,2)-MeTAM (29): The methoxy-protected Me8Oxo-
H(2,2)-MeTAM (29) was synthesized by coupling two molecules of
28 with oxalyl chloride as follows: oxalyl chloride (100 mg,
0.79 mmol) was added with stirring to 28 (840 mg, 1.54 mmol) and
Et3N (1 mL, 10 mmol) in anhydrous THF (25 mL) at Ϫ30 °C. The
reaction mixture was stirred at 25 °C for 4 h and the solvents eva-
porated to dryness. The residue was dissolved in dichloromethane
and washed successively with aqueous HCl (1) and water. The
resultant crude product was purified by column chromatography
on silica gel (6Ϫ12% MeOH ϩ 0.2% Et3N in CH2Cl2) to give a
1
as a pale yellow oil. H NMR (250 MHz, CDCl3): δ ϭ 1.64 (br., 2
H, NH), 2.92 (t, J ϭ 6.0 Hz, 4 H, NCH2), 3.59 (q, J ϭ 5.8 Hz, 4
H, NCH2), 3.88 (s, 12 H, OCH3), 7.02 (d, J ϭ 8.1 Hz, 2 H, Ar H),
7.13 (t, J ϭ 8.0 Hz, 2 H, Ar H), 7.66 (d, J ϭ 7.9 Hz, 2 H, Ar H),
8.32 (br. s, 2 H, NH) ppm.
Me8Oxo-H(2,2)-CAM (24): Compound 23 (815 mg, 2 mmol), Et3N
(1 mL, 10 mmol) in anhydrous THF (25 mL), and oxalyl chloride
(130 mg, 1.03 mmol) were combined at Ϫ78 °C, and the reaction
mixture was stirred at 25 °C for 4 h and the solvents evaporated to
dryness. The residue was dissolved in CH2Cl2 and washed success-
ively with aqueous HCl (1) and water. The crude product was
purified by chromatography on silica gel (3Ϫ6% MeOH gradient
in CH2Cl2 as eluent) to give methoxy-protected Oxo-H(2,2)-CAM
as a pale yellow oil (519 mg, 0.45 mmol, 63% yield). 1H NMR
(250 MHz, CDCl3): δ ϭ 3.4Ϫ3.6 (br. m, 8 H, NCH2), 3.74 (br. s,
8 H, CH2N), 3.8Ϫ3.9 (m, 24 H, OCH3), 7.06 (tt, J ϭ 7.94 Hz, 4
H, Ar H) 7.45 (d, J ϭ 7.73 Hz, 4 H, Ar H), 7.59 (d, J ϭ 7.73 Hz,
4 H, NH), 8.14 (t, J ϭ 5.0 Hz, 4 H, NH), 8.37 (br. s, 4 H, NH) ppm.
ϩFAB MS (TG/G): m/z ϭ 917.3 [M ϩ H]ϩ. C46H56N6O14·0.5H2O
(926.004): calcd. C 59.67, H 6.20, N 9.07; found C 60.07, H 6.02,
N 8.61.
1
white solid (519 mg, 63% yield). H NMR (250 MHz, CDCl3) δ ϭ
3.03 (d, J ϭ 4.8 Hz, 12 H, NCH3), 3.45Ϫ3.65 (br. m, 8 H, NCH2),
3.76 (br. s, 8 H, CH2N), 3.87Ϫ3.93 (m, 24 H, OCH3), 7.55Ϫ7.75
(m, 8 H, Ar), 7.75Ϫ7.95, (m, 4 H, NH), 8.231 (br. t, J ϭ 5.27 Hz,
2 H, NH), 8.29 (br., 2 H, NH) ppm. ϩFAB MS (TG/G): m/z ϭ
1145.8 [M ϩ H]ϩ.
Oxo-H(2,2) MeTAM (30): The methoxy-protected Me8Oxo-H(2,2)-
MeTAM (29) (500 mg, 0.44 mmol), deprotected with excess BBr3
as described for the deprotection of CAM ligands, yielded 30 as a
beige powder in 85% yield. M.p. 271 °C. C46H52N10O18; [M ϩ H]ϩ
calcd. 1032.99; found 1033.6. 1H NMR (400 MHz, [D6]DMSO):
δ ϭ 2.79 (d, J ϭ 4.0 Hz, 12 H, NCH2), 3.41 (br. s, 8 H, NCH2),
3.56 (br. s, 8 H, NHCH2), 7.19 (s, 4 H, Ar H), 7.24 (s, 4 H, Ar H),
8.82 (br. q, J ϭ 4.3 Hz, 4 H, NH), 9.00 (br. s, 4 H, NH), 12.44 (d,
J ϭ 6.7 Hz, 2 H, phenol H), 12.85 (d, J ϭ 9.0 Hz, 2 H, phenol H)
ppm. 13C NMR (100 MHz, D2O-NaOD): δ ϭ 25.1, 37.4, 40.9,
43.1, 46.4, 108.7, 115.8, 115.9, 117.2, 117.4, 149.9, 150.1, 150.2,
165.3, 168.7, 168.8, 169.2 ppm.
Oxo-H(2,2)-CAM (25): The methoxy-protected compound 24
(500 mg, 0.44 mmol), deprotected with an excess of BBr3 as de-
scribed earlier in the deprotection of 10 and 18, yielded 25 as a
white powder (371 mg, 89% yield). M.p. 145°C. C38H40N6O14 [M
ϩ
H]ϩ; calcd. (804.78); found 805.1. 1H NMR (400 MHz,
[D6]DMSO): δ ϭ 3.55,3.58 (sϩs, 16 H, NCH2), 6.46 (t, J ϭ 7.93
Hz, 4 H, Ar H), 6.90 (d, J ϭ 7.78 Hz, 4 H, Ar H), 7.22 (d, J ϭ
7.41 Hz, 8 H, Ar H), 8.78 (s, 2 H, NH), 8.92 (s, 2 H, NH), 8.94
(br. s, 2 H, phenol H), 12.55 (br. s, 2 H, phenol H) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ ϭ 36.3, 37.5, 43.2, 46.4, 114.8, 115.0,
117.2, 118.1, 119.0, 146.2, 149.6, 165.3, 170.1, 170.2 ppm.
Compound 31: Compound 31 was prepared by the same procedure
as 28, with one exception: n-propylamine was used in place of the
methylamine solution. The pure product was obtained as a white
1
foam (535 mg, 89% yield). H NMR (250 MHz, CDCl3): δ ϭ 1.01
(t, J ϭ 7.4 Hz, 6 H, CH3), 1.69 (br. q, J ϭ 7.2 Hz, 4 H, CH2),
2.958 (t, J ϭ 5.9 Hz, 4 H, NCH2), 3.44 (q, J ϭ 5.9 Hz, 4 H, CH2N),
3.61 (q, J ϭ 5.8 Hz, 4 H, CH2N), 3.88 (s, 6 H, OCH3), 3.93 (s, 6
H, OCH3), 7.83 (br. s, 4 ArH ϩ 2 NH), 8.14 (br., 2 H, NH) ppm.
Synthesis of Octadentate Oxo-2,3-dihydroxyterephthalamide Li-
gands 30, 33
Me8Oxo-H(2,2)-PrTAM (32): Preparation of Me8Oxo-H(2,2)-
PrTAM (32) was carried out on a 1.5 mmol scale in a procedure
similar to the synthesis of Me8Oxo-H(2,2)-MeTAM (30), except 31
was used as the starting material instead of 28. Purification by col-
umn chromatography (4Ϫ10% MeOH in CH2Cl2) gave Me8Oxo-
Compound 27: See Scheme 3.
A solution of diethylenetriamine (520 mg, 3 mmol) in CH2Cl2
(250 mL) was added over the course of 16 h to a stirred solution
of terephthalamide derivative 26[13] (50 g, 0.125 mol) in 98%
CH2Cl2/2% MeOH (3 L). The reaction mixture was passed through H(2,2)-PrTAM (32) as a white solid (667 mg, 71% yield). 1H NMR
a silica gel column, and eluted with 2% MeOH in CH2Cl2 to re-
move most of the 26, while 27 was retained on the silica column.
The appropriate fractions of a gradient elution (5Ϫ10% MeOH in
CH2Cl2) were collected and the solvents evaporated to dryness to
produce 27 as a white foam (1.63 g, 75% yield). 1H NMR
(250 MHz, CDCl3): δ ϭ 2.95 (t, J ϭ 5.8 Hz, 4 H, CH2N), 3.44 (t,
(250 MHz, CDCl3): δ ϭ 1.015 (tt, J ϭ 7.4 Hz, 12 H, CH3), 1.67
(sext., J ϭ 7.2 Hz, 8 H, CH2), 3.42 (q, J ϭ 6.6 Hz, 8 H, NCH2),
3.47Ϫ3.65 (br. m, 8 H, NCH2), 3.76 (br. s, 8 H, CH2N), 3.85Ϫ3.95
(m, 24 H, OCH3), 7.55Ϫ7.75 (m, 8 H Ar H), 7.75Ϫ7.95, (m, 4 H,
NH), 8.23 (t, J ϭ 5.2 Hz, 2 H, NH), 8.29 (br., 2 H, NH) ppm.
ϩFAB MS (NBA): m/z ϭ 1257.6 [M ϩ H]ϩ. C62H84N10O18
J ϭ 7.3 Hz, 4 H, CH2N), 3.63 (q, J ϭ 5.7 Hz, 4 H, CH2N), 3.89 (1257.424): calcd. C 59.25, H 6.73, N 11.13; found C 59.49, H 6.85,
(d, 12 H, OCH3), 4.65 (t, J ϭ 7.3 Hz, 4 H, CH2S), 7.10 (d, J ϭ 8.2 N 11.03.
Eur. J. Org. Chem. 2004, 3244Ϫ3253
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3251

J. Xu, A. E. V. Gorden, K. N. Raymond
FULL PAPER
Oxo-H(2,2)-PrTAM (33): Me8Oxo-H(2,2)-PrTAM (32) (500 mg,
0.44 mmol), deprotected with excess BBr3 as described for the de-
protection of the other CAM ligands, yielded 33 as a beige powder
H(2,2)-PrTAM (39): M.p. 186Ϫ188°C. C54H72N10O16; [M ϩ H]ϩ
calcd. 1117.24; found 1117. 1H NMR (400 MHz, [D6]DMSO): δ ϭ
0.87 (t, J ϭ 7.18 Hz, 12 H, NCH3), 1.5 (m, 8 H, CH2), 2.74 (br. s,
8 H, CH2N), 3.2 (br. s, 12 H, NCH2), 3.4 (br. s, 8 H, NCH2), 7.26
in 78% yield. M.p. 276°C. C54H68N10O18; [M ϩ H]ϩ calcd. 1145.20;
1
found 1145.7. H NMR (400 MHz, [D6]DMSO): δ ϭ 0.91 (t, J ϭ (s, J ϭ 8.85 Hz, 8 H, Ar H), 8.82 (s, 8 H, NH), 13.0 (br., phenol
7.4 Hz, 12 H, CH3), 1.50 (m, 8 H, CH2), 3.21 (br. s, 8 H, NCH2), H) ppm. 13C NMR (100 MHz, D2O-NaOD): δ ϭ 12.0, 23.2, 37.0,
3.42 (br. s, 8 H, NCH2), 3.58 (br. s, 8 H, NCH2), 7.20 (m, 8 H, Ar
H), 8.70Ϫ9.10 (m, 8 H, NH), 12.4 (br. s, 4 H, phenol H), 12.8 (br.
s, 4 H, phenol H) ppm. 13C NMR (100 MHz, D2O-NaOD): δ ϭ
11.4, 22.0, 36.3, 37.5, 40.8, 43.0, 46.3, 108.7, 115.5, 115.7, 117.2,
117.3, 149.9, 150.1, 150.3, 165.2, 168.7, 168.9, 169.1 ppm.
51.8, 53.9, 112.3, 112.4, 117.2, 117.4, 166.2, 166.4, 172.5, 172.9
ppm.
Synthesis of Octadentate 3,4,3-LIMeTAM (41): See Scheme 5. This
linear octadentate terephthalamide ligand was synthesized and
purified by the same procedure as for the H(2,2)-TAMs, except
spermine (40) was used instead of PENTEN (6). Unlike the highly
symmetric PENTEN derivatives, the NMR spectra of compound
41 shows a complicated mode, probably due to the existence of
several conformers in the solution. M.p. 223Ϫ225°C. C46H54N8O16
[M ϩ H]ϩ; calcd. 974.99 found 975.2. 1H NMR (400 MHz,
[D6]DMSO): δ ϭ 1.2Ϫ2.0 (br. m, 8 H, CH2), 2.7Ϫ2.8 (m, 12 H,
NCH3), 3.0Ϫ3.6 (br. m, 12 H, NHCH2), 6.6Ϫ7.4 (br. m, 8 H, ArH),
Synthesis of Octadentate H(2,2)-MeTAM (37), H(2,2)-EtTAM (38),
and H(2,2)-PrTAM (39) Ligands. General Procedure: See Scheme 4.
A solution of PENTEN [6, H(2,2)-amine) (0.6 mmol) and NEt3
(0.4 mL, 3 mmol] in anhydrous THF (30 mL) was added to 4-
chlorocarbonyl-2,3-dimethoxybenzoic acid methyl ester (9)[21]
(0.78 g, 3 mmol) in anhydrous THF (40 mL) by a Teflon cannula
under nitrogen. A white precipitate immediately formed upon ad-
dition. The reaction mixture was stirred at room temperature over-
night under N2, and the triethylamine hydrogen chloride precipitate
was collected by filtration. Evaporation of the filtrate in vacuo
yielded a viscous oil, which was purified by chromatography on
silica gel (2Ϫ4% MeOH in CH2Cl2) to give the fully methoxy-pro-
tected CAM(C) species 34 as pale yellow oil.
Compound 34 (0.5 mmol) was mixed with methanol (20 mL) and
aqueous NaOH (1) solution (5 mL). The reaction mixture was
heated to reflux temperature for 4 h and then evaporated to dry-
ness. The residue was dissolved in H2O (15 mL) and acidified to
pH 2 using 6  HCl. The methoxy-protected CAM(C) tetraacid
species 35 settled as a pale yellow oil. It was dissolved in dry THF,
filtered, and coevaporated with anhydrous THF three times to re-
move any water left as an azeotrope, then carried directly to the
next reaction procedure.
At Ϫ10 °C, under argon, N-hydroxysuccinimide (0.23 g, 2 mmol)
and DCC (0.41 g, 2 mmol) were added to the above tetraacid spec-
ies 35 in anhydrous THF (20 mL). After stirring for 24 h, an appro-
priate backbone amine (4 mmol primary amine) in anhydrous THF
(10 mL) was added with stirring. The DCU solids were removed
by filtration, and the filtrate was evaporated to dryness and purified
by chromatography on silica gel (4Ϫ6% MeOH in CH2Cl2) to give
the corresponding octadentate 2,3-dimethoxyterephthalamide as a
pale yellow oil. It was deprotected with BBr3 as described for the
octadentate CAM ligands.
8.6Ϫ9.3 (br. m, 6 H, NH), 12.0Ϫ13.0 (m, 4 H, phenol H) ppm. 13
C
NMR (100 MHz, D2O-NaOD): δ ϭ 25.3, 26.2, 26.3, 28.4, 29.2,
37.2, 37.3, 37.6, 44.9, 48.5, 50.3, 111.6, 111.8, 112.0, 112.1, 112.2,
112.3, 112.4, 113.2, 113.3, 116.7, 116.8, 117.0, 117.1, 117.2, 125.5,
125.6, 125.7, 157.5, 157.6, 157.9, 164.9, 165.0, 165.2, 165.9, 166.1,
166.2, 166.4, 171.6, 171.9, 172.1, 172.4, 172.5, 172.6, 173.2, 173.3,
173.4, 176.4, 176.5, 176.6 ppm.
Acknowledgments
This work was supported by the Director, Office of Energy Re-
search, Office of Basic Energy Sciences, Chemical Sciences Div-
ision, United States Department of Energy under contract number
DE-AC03-76F00098, the National Institute of Environmental
Health Sciences through grant number ES02698, and futher sup-
port was provided by the Environmental Management Science Pro-
gram through grant number 81936. We thank Dr. P. W. Durbin and
Ms. B. Kullgren for their studies with these ligands as decorpor-
ation agents for actinides in vivo.
[1]
A. Stintzi, C. Barnes, J. Xu, K. N. Raymond, PNAS 2000, 97,
10691Ϫ10696.
[2]
A. E. V. Gorden, J. Xu, K. N. Raymond, P. W. Durbin, Chem.
Rev. 2003, 103, 4207Ϫ4282.
K. N. Raymond, G. Müller, B. F. Matsanke, in Topics in Cur-
[3]
rent Chemistry (Ed.: F. L. Boschke), Springer-Verlag, Berlin,
Heidelberg, 1984, 50Ϫ102.
H(2,2)-MeTAM (37): M.p. 173Ϫ175°C. C46H56N10O16; [M ϩ H]ϩ
calcd. 1005.02; found 1005 [M ϩ H]ϩ, 1027 [M ϩ Na]ϩ. 1H NMR
(400 MHz, [D6]DMSO): δ ϭ 2.81 (d, J ϭ 4.0 Hz, 12 H, NHCH3),
3.4 (br., 12 H, NCH2), 3.7 (br., 8 H, NCH2), 7.30 (d, J ϭ 8.7 Hz,
4 H, Ar H), 7.37 (d, J ϭ 8.7 Hz, 4 H, Ar H), 8.93 (br. d, J ϭ 4.0
Hz, 4 H, terminal NH), 9.13 (br. s, 4 H, NH), 12.2 (br., phenol H),
13.1 (br., phenol H) ppm. 13C NMR (100 MHz, D2O-NaOD): δ ϭ
26.3, 37.2, 51.8, 53.8, 112.8, 112.9, 117.4, 117.5, 163.9, 164.2, 172.4,
173.0 ppm.
[4]
K. N. Raymond, Coord. Chem. Reviews 1990, 105, 136Ϫ153.
[5]
J. R. Telford, K. N. Raymond, in Comprehensive Supramolecu-
lar Chemistry (Eds.: J. L. Atwood, J. E. D. Davies, D. D. Mac-
Nicol, F. Vögtle), Elsevier Science Ltd., Oxford, 1996, vol. 1,
245Ϫ266.
P. W. Durbin, N. Jeung, E. S. Jones, F. L. Weitl, K. N. Ray-
mond, Rad. Res. 1984, 99, 85Ϫ105.
G. N. Stradling, J. W. Stather, S. A. Gray, J. C. Moody, M.
[6]
[7]
Ellender, A. Hodgson, Human Toxicol. 1986, 5, 77Ϫ84.
P. W. Durbin, D. L. White, N. Jeung, F. L. Weitl, L. C. Uhlir,
[8]
H(2,2)-EtTAM (38): M.p. 178Ϫ180°C. C50H64N10O16; [M ϩ H]ϩ
calcd. 1061.13; found 1061.7. 1H NMR (400 MHz, [D6]DMSO):
δ ϭ 1.04 (t, J ϭ 7.1 Hz, 12 H, NCH3), 3.22 (quin., J ϭ 6.7 Hz, 8
H, NCH2), 3.54 (br. s, 12 H, NCH2), 3.64 (br. s, 8 H, NCH2), 7.22
(s, J ϭ 8.8 Hz, 8 H, Ar H), 7.29 (s, J ϭ 8.8 Hz, 8 H, Ar H), 8.85
(t, J ϭ 5.3 Hz, 4 H, NH), 9.08 (br. s, 4 H, NH), 12.2 (br., phenol
H), 12.9 (br., phenol H) ppm. 13C NMR (100 MHz, D2O-NaOD):
δ ϭ 15.0, 34.9, 37.2, 51.9, 53.8, 112.8, 112.9, 117.4, 117.6, 163.9,
172.0, 172.4 ppm.
E. S. Jones, F. W. Bruenger, K. N. Raymond, Health Phys.
1989, 56, 839Ϫ855.
[9]
M. Kappel, K. N. Raymond, Inorg. Chem. 1982, 21,
3437Ϫ3442.
[10]
M. J. Kappel, H. Nitsche, K. N. Raymond, Inorg. Chem. 1985,
24, 605Ϫ611.
T. M. Garrett, P. W. Miller, K. N. Raymond, Inorg. Chem.
1989, 28, 128Ϫ133.
T. M. Garrett, M. E. Cass, K. N. Raymond, J. Coord. Chem.
1992, 25, 241Ϫ253.
[11]
[12]
3252
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 3244Ϫ3253

Octadentate Ligands with a Tetrapodal Amine Backbone for Chelation of Actinides
FULL PAPER
[13]
[14]
[26]
[27]
T. B. Karpishin, T. D. P. Stack, K. N. Raymond, J. Am. Chem.
Soc. 1993, 115, 182Ϫ192.
C. J. Gramer, K. N. Raymond, Org. Lett. 2001, 3, 2827Ϫ2830.
R. D. Lloyd, F. W. Bruenger, C. W. Mays, D. R. Atherton, C.
W. Jones, G. N. Taylor, W. Stevens, P. W. Durbin, N. Jeung, E.
S. Jones, M. J. Kappel, K. N. Raymond, F. L. Weitl, Rad.
Chem. 1984, 99, 106Ϫ128.
C. W. Mays, R. D. Lloyd, C. W. Jones, F. W. Bruenger, G. N.
Taylor, P. W. Durbin, D. White, K. N. Raymond, Health Phys.
1986, 50, 530Ϫ534.
C. J. Gramer, dissertation thesis, University of California
(Berkeley), 2001 Ϫ and references cited therein.
C. J. Gramer, K. N. Raymond, Inorg. Chem., to be submitted.
A system of abbreviated nomenclature was devised for the syn-
thetic multi(catechoylamide) ligands based on CAM as an
acronym for catecholamide groups. The numbers in the prefix
(separated by commas) indicate the number of methylene
groups in the connecting chains. This system has been extended
to the tetrakis(catecholamide) ligands, by the use of H(m,n)-
CAM, H(m,n)-CAM(C), H(m,n)-TAM, Oxo-H(m,n)-CAM,
and Oxo-H(2,2)-TAM as acronyms for the corresponding li-
gands.
J. D. Van Horn, C. J. Gramer, B. OЈSullivan, K. M. C. Jurchen,
D. M. J. Doble, K. N. Raymond, C. R. Chimie 2002, 5,
359Ϫ404.
The details of the preparation and structural characterization
of ligand 4 and the preparation and characteristic solution be-
havior of 5 have been described in earlier works.
J. Xu, T. D. P. Stack, K. N. Raymond, Inorg. Chem. 1992, 31,
4903Ϫ4905.
[15]
[16]
[28]
[29]
[30]
[31]
P. W. Durbin, B. Kullgren, N. Jeung, J. Xu, S. J. Rodgers, K.
N. Raymond, Hum. Exp. Toxicol. 1996, 15, 352Ϫ360.
J. Xu, P. W. Durbin, B. Kullgren, S. N. Ebbe, L. C. Uhlir, K.
N. Raymond, J. Med. Chem. 2002, 45, 3963Ϫ3971.
P. W. Durbin, B. Kullgren, J. Xu, K. N. Raymond, M. H.
´
Henge-Napoli, T. Bailly, R. Burgada, Rad. Prot. Dosim. 2003,
[17]
[18]
105, 503Ϫ508.
[32]
P. W. Durbin, N. Jeung, S. J. Rodgers, P. N. Turowski, F. L.
Weitl, D. L. White, K. N. Raymond, Radiat. Prot. Dosim. 1989,
26, 351Ϫ358.
L. C. Uhlir, P. W. Durbin, N. Jeung, K. N. Raymond, J. Med.
Chem. 1993, 36, 504Ϫ509.
P. W. Durbin, B. Kullgren, J. Xu, K. N. Raymond, Int. J. Rad-
iat. Biol. 2000, 76, 199Ϫ214.
[33]
[34]
[35]
[36]
[37]
[19]
[20]
[21]
[22]
[23]
[24]
[25]
Z. Hou, D. W. Whisenhunt Jr., J. Xu, K. N. Raymond, J. Am.
Chem. Soc. 1994, 116, 840Ϫ846.
F. L. Weitl, K. N. Raymond, P. W. Durbin, J. Med. Chem.
1981, 24, 203Ϫ206.
P. Stutte, W. Kiggen, F. Vögtle, Tetrahedron 1987, 43,
2065Ϫ2074.
Y. Nagao, T. Miyasaka, Y. Hagiwaru, E. Fujita, J. Chem. Soc.,
Perkin Trans. 1 1984, 183Ϫ187.
I. Murase, M. Mikuriya, H. Sonoda, Y. Fukuka, S. Sida, J.
Chem. Soc., Dalton Trans. 1986, 953Ϫ959.
P. W. Durbin, B. Kullgren, J. Xu, K. N. Raymond, Radiat. Prot.
Dosim. 1994, 53, 305Ϫ309.
J. Xu, B. Kullgren, P. W. Durbin, K. N. Raymond, J. Med.
Chem. 1995, 38, 2606Ϫ2614.
T. J. McMurry, M. W. Hosseini, T. M. Garrett, F. E. Hahn, Z.
E. Reyes, K. N. Raymond, J. Am. Chem. Soc. 1987, 109,
7196Ϫ7198.
D. M. J. Doble, M. Botta, J. Wang, S. Aime, A. Barge, K. N.
Raymond, J. Am. Chem. Soc. 2001, 123, 10758Ϫ10759.
D. M. J. Doble, M. Melchior, B. OЈ Sullivan, C. Siering, J. Xu,
V. Pierre, K. N. Raymond, Inorg. Chem. 2003, 42, 4930Ϫ4937.
Received February 6, 2004
[38]
[39]
B. K. Wagnon, S. C. Jackels, Inorg. Chem. 1989, 28,
1923Ϫ1927.
Eur. J. Org. Chem. 2004, 3244Ϫ3253
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3253