Synthesis soluble non-ion transition metal manganese(II), cobalt(II), nickel(II) complexes of diethylenetriamine-N,N′,N″-tri(acetyl-p-hydroxybenzoyl hydrazine)- N,N″- bisacetic acid as potential contrast enhancement agent

Article abstract of DOI:10.1080/15533174.2013.831895

A novel ligand, diethylenetriamine-N,N′,N″-tri(acetyl-p-hydroxybenzoyl hydrazine)-N,N″-bisacetic acid, and its three soluble non-ion transition metal complexes, ML· nH₂O (M = Mn, n = 4; M = Co, Ni, n = 2) have been synthesized and characterized on the basis of elemental analysis, molar conductivities, ¹H NMR, FAB-MS, TG-DTA analysis, and IR methods. In addition, relaxivity of complexes are determined, The relaxivity (R₁) of MnL, CoL, NiL, and Gd(DTPA)^2- used as control are 6.33, 2.71, 2.60, and 4.34L·mmol^-1·s^-1, respectively. The spin-lattice relaxivity of MnL are larger than that of Gd(DTPA)^2-. The results showed that complex of MnL may be a potential MRI contrast agent with high spin-lattice relaxivity, good solubility, low osmotic pressure due to non-ion complex.

Full text of DOI:10.1080/15533174.2013.831895

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Synthesis Soluble Non-Ion Transition Metal
Manganese(II), Cobalt(II), Nickel(II) Complexes
of Diethylenetriamine-N,N′,N″-tri(acetyl-p-
hydroxybenzoyl hydrazine)- N,N″- Bisacetic Acid as
Potential Contrast Enhancement Agent
Xue-Li Zhanga, Ding-Wa Zhangb, Hui-Jiao Zhanga, Shi-Ni Hea & Yao-Ting Chena
a College of Chemistry and Chemical Engineering, Shenzhen University, Guangdong, P. R.
China
b School of Chemistry and Chemical Engineering, Provincial Key Laboratory of Coordination
Chemistry, Jingganshan University, Jiangxi, P. R. China
Accepted author version posted online: 01 Jul 2014.Published online: 09 Oct 2014.
To cite this article: Xue-Li Zhang, Ding-Wa Zhang, Hui-Jiao Zhang, Shi-Ni He & Yao-Ting Chen (2015) Synthesis Soluble Non-Ion
Transition Metal Manganese(II), Cobalt(II), Nickel(II) Complexes of Diethylenetriamine-N,N′,N″-tri(acetyl-p-hydroxybenzoyl
hydrazine)- N,N″- Bisacetic Acid as Potential Contrast Enhancement Agent, Synthesis and Reactivity in Inorganic, Metal-
Organic, and Nano-Metal Chemistry, 45:3, 346-349, DOI: 10.1080/15533174.2013.831895
To link to this article: http://dx.doi.org/10.1080/15533174.2013.831895
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Synthesis and Reactivity in Inorganic, Metal-Organic, and Nano-Metal Chemistry (2015) 45, 346–349
Copyright © Taylor & Francis Group, LLC
ISSN: 1553-3174 print / 1553-3182 online
DOI: 10.1080/15533174.2013.831895
Synthesis Soluble Non-Ion Transition Metal Manganese(II),
Cobalt(II), Nickel(II) Complexes of Diethylenetriamine-N,N0,
N00-tri(acetyl-p-hydroxybenzoyl hydrazine)- N,N00- Bisacetic
Acid as Potential Contrast Enhancement Agent
XUE-LI ZHANG1, DING-WA ZHANG2, HUI-JIAO ZHANG1, SHI-NI HE1, and YAO-TING CHEN1
1College of Chemistry and Chemical Engineering, Shenzhen University, Guangdong, P. R. China
2School of Chemistry and Chemical Engineering, Provincial Key Laboratory of Coordination Chemistry, Jingganshan University,
Jiangxi, P. R. China
Received 15 June 2013; accepted 27 July 2013
A novel ligand, diethylenetriamine-N,N0,N00-tri(acetyl-p-hydroxybenzoyl hydrazine)-N,N00-bisacetic acid, and its three soluble non-
ion transition metal complexes, ML¢ nH2O (M D Mn, n D 4; M D Co, Ni, n D 2) have been synthesized and characterized on the
basis of elemental analysis, molar conductivities, 1H NMR, FAB-MS, TG-DTA analysis, and IR methods. In addition, relaxivity of
complexes are determined, The relaxivity (R1) of MnL, CoL, NiL, and Gd(DTPA)2– used as control are 6.33, 2.71, 2.60, and
4.34L¢mmol¡1¢s¡1, respectively. The spin-lattice relaxivity of MnL are larger than that of Gd(DTPA)2¡. The results showed that
complex of MnL may be a potential MRI contrast agent with high spin-lattice relaxivity, good solubility, low osmotic pressure due
to non-ion complex.
Keywords: diethylenetriamine-N, N0, N00-tri(acetyl-p-hydroxybenzoyl hydrazine)-N, N00-bisacetic acid, transition metal complexes,
relaxation properties, MRI contrast agent
Introduction
synthesized, and relaxivity of complexes and Gd(DTPA)2–
were determined in water solution. The relaxivity of MnL was`-
Magnetic resonance imaging (MRI) is at present well estab- larger than that of Gd(DTPA)2¡. The results showed that com-
lished as a safe and efficient imaging technique for the human plex of MnL may be a potential MRI with low osmotic
body in clinical diagnosis.[1] Therefore, studying MRI contrast pressure due to non-ion complex and high relaxivity.
agents is more important. Several types of paramagnetic metal
ion-chelate complexes with various ligands have been proposed
for use as contrast-enhancing agents in MRI.[1–3] Gd
Experimental
(DTPA)2¡ was well-established contrast agent in clinical use
for MRI due to its high relaxivity, high chemical stability, and
low toxicity.[3] However, its passive and nonspecific distribu-
tion in vivo limits its utility in focal lesion detection, and more-
over its ionic characteristic leads to some side effects associated
with its hyperosmolality at clinical dose.[1,4,5] In attempts to
decrease the side effects and improve the tissue- and/or organ-
specificity, considering that p-hydroxybenzoyl hydrazine mole-
cule holds a hydroxyl which can enhance affinity to water and
hydrazide is a very useful medicament that we designed and
synthesized a novel ligand from DTPA and p-hydroxybenzoyl
hydrazine. Its three soluble non-ion transition metal complexes
holding promise of magnetic resonance imaging were
Materials
All MCO3 (M D Mn, Co, Ni) compounds were purchased
from Shanghai Yuelong Chemical Works. DTPA, EDTA
and p-hydroxybenzoyl hydrazine were purchased from
Shanghai Reagent Factory. All other chemicals used were of
analytical grade.
Measurements
Carbon, hydrogen, and nitrogen were analyzed on an Elemen-
tal Vario EL analyzer. The metal content of the complexes
were determined by titration with EDTA. Melting points of the
compounds were determined on an XT4-100£ microscopic
melting point apparatus (Beijing Electrooptical Instrument
Factory, China). The IR spectra were obtained in KBr discs on
a Nicolet 5-DX spectrometer in the 4000–400 cm¡1 region.
Address corresponding to Ding-Wa Zhang, School of Chemistry
and Chemical Engineering, Jingganshan University, Jiangxi,
343009, P. R. China. E-mail: zhangdingwa@hotmail.com.

Potential Contrast Enhancement Agents
347
Fig. 1. The synthetic route of the ligand.
1H NMR spectra were recorded on a Varian VR 300-MHz into filtrate, and a large amount of white precipitate separated
spectrometer. Conductivity measurement was performed in out. Filter and was washed three times with a little EtOH.
DMF with a DDS-11A conductometer at 25ꢀC (Shanghai Finally, product was dried in a vacuum with P4O10. Recrystalli-
Jingke Instrument Factory, China). The thermal behavior was zation from H2O-Et2O-EtOH gained the final product. Yield:
monitored on a PCT-2 differential thermal analyzer (Beijing 88.9%. Melting point: 239–240ꢀC. 1H NMR (300 MHz, D2O):
Guangxue Instrument Factory, China). Mass spectrum was d2.56, 2.73 (s, each 4H, -NCH2CH2N-), d2.91 (s, 10H, -CO-
performed on a VG ZAB-HS (FAB) instrument.
CH2-N-), d3.34 (s, 6H, -NH-NH-), d6.90 (t, 6H, J D 7.8, J D
Relaxation time of complexes were measured referring to 7.2, Ar-H). d7.41 (t, 6H, J D 7.8, J D 7.2, Ar-H), d7.85 (d, 3H, J
literature[6] on a Bruker AC-80 NMR spectrophotometer, D 7.8, Ar-H), 10.44 (s, 2H, -COOH). FAB-MS: m/z D 796.
using the INVREC Au program at a 90ꢀ pulse width tp (90ꢀ) The synthetic route is shown in Figure 1.
D 2.8ms by an inversion-recovery pulse sequence.
Ligand was easily soluble in water, DMF, and DMSO;
slightly soluble in ethanol; insoluble in acetone, chloroform,
and Et2O; and quite stable at room temperature and normal
pressure. Elemental analysis and empirical formulas are
showed in Table 1. Elemental analysis was in good agree-
ment with the structure. Mass spectrum reveals that the
molecular ion peak was in accordance with the given struc-
ture. 1H NMR and IR were conformed to the given structure.
Preparation of Ligand
The ligand was synthesized as following: iethylenetriamine
d
pentaacetic bi-anhydride (DTPAA) prepared according to
references.[7,8]
p-hydroxybenzoyl hydrazine (3 mmol) was dissolved in
25 cm3 of distilled water, put with DTPAA (1 mmol) and
5 cm3 of pyridine (Py) into the aqueous solution, and stirred for
24 h at room temperature. H2O and Py were removed under
Preparation of Complexes
reduced pressure, and the residue was diluted with H2O and fil- First, 1 mmol of ligand was dissolved in 25 cm3 of water to
trated. Then drop the solution of EtOH and Et2O (v/v D 1/2) form a homogeneous solution which pH is approximately 3.
Table 1. Elemental analyses and molar conductivity.
C%
N%
H%
M
L
Empirical formula
Yield (%)
88.9
Color
white
(Calcd.)%
(Calcd.)%
(Calcd.)%
(Calcd.)%
S¢cm2¢mol¡1
H2L
52.58
15.75
5.27
16.2
C35H41N9O13
MnL¢4H2O
C35H47N9O17Mn
CoL¢2H2O
(52.83)
45.26
(45.66)
47.89
(47.30)
37.44
(47.31)
(15.84)
13.73
(13.69)
14.07
(14.18)
11.512
(11.19)
(5.19)
5.21
(5.15)
4.78
(4.88)
4.80
(4.88)
(16.7)
5.72
(5.97)
6.59
(6.63)
6.53
(6.61)
97.6
98.0
98.1
light yellow
white
12.6
12.1
13.0
C35H43N9O15Co
NiL¢2H2O
light green
C35H43N9O15Ni

348
Zhang et al.
Table 2. Some main IR data of the ligand and its complexes.
Table 3. Thermal analyses data of the compounds.
Da M.p. H2O Loss Decomposition (ꢀC)
Compound
H2L MnL¢4H2O CoL¢2H2O NiL¢2H2O
ꢀC
(Calcd.)%
t1
t2
t3
n OH
n NH
3500b 3218-3487b 3220-3444b 3225-3422b
Compound
H2L
MnL¢4H2O 98–110
CoL¢2H2O 102–115
NiL¢2H2O 104–114
3186w
3184m
3189m
3185
240
378
n CHO (COOH) 1707s
dHOH
n C-N
nas (CO2
ns (CO2
n(M-O)
7.75 (7.82) 355
4.01 (4.06) 362
4.11 (4.05) 365
409
411
407
522
527
524
1574s
1215m
1550m
1398m
515w
1582s
1217w
1552m
1410m
521w
1571s
1218
1547m
1395m
518w
1226w
¡
)
¡
)
s D strong; m D medium; w D week; b D bread.
3218–3487 cm¡1 in the complexes. The peak at around
1571–1582 cm¡1 is assigned to dHOH, which shows that there
is the coordinating H2O in the complexes. The carboxylic
Then excess MnCO3 was added to the system which was n(CHO) of free ligands is at 1707 cm¡1,which does not appear
¡
stirred on a water bath until the pH of the system is approxi- in the complexes. However, two new vibrations of CO2 for
mately 7. The excess MnCO3 was filtered off. Then the filtrate nas and ns show themselves at 1550 and 1398 cm¡1, the
was concentrated on a water bath until it is nearly dry. The 4n(nas-ns) of which is approximately equal to 152 cm¡1. The
light yellow powder was obtained after the mother liquor was IR spectra obtained when the sodium salt of the ligands is
removed. Finally, dry it in vacuum with P4O10. Yield: 97.6%. used as a control show that its nas and ns are at 1550 and
Other complexes were synthesized by the same way. Yield: 1410 cm¡1, respectively, and 4n(nas-ns) is 140 cm¡1, suggest-
CoL D 98.0%, NiL D 98.1%.
ing that carboxyl oxygen atom coordinated to metal ion with
single-dentate.[10] The vibration at 1226 cm¡1 in the ligand
was shifted to 1215 cm¡1, indicating the M-N band is really
formed but weak.[10] A new peak for the complex at 515 is
assigned to nM-O. This further confirms that the coordinate
bond has formed between ligand and metal ion. The ligand
provided three nitrogen atoms, five carboxyl oxygen atoms
bonding to metal ion. At least one water molecule takes part
in coordination to metal ion confirming DAT-TG.
Results and Discussion
The Composition and General Character of Complexes
All of complexes are easily soluble in water, DMF, and
DMSO; slightly soluble in ethanol, insoluble in acetone, chlo-
roform, and Et2O; quite stable at room temperature and nor-
mal pressure; and not sensitive to light. Elemental analyses
and empirical formula are showed in Table 1. The elemental
analyses show that the formulas of the complexes are ML ꢁ
nH2O (M D Mn, n D 4; M D Co, Ni, n D 2). Elemental anal-
ysis was in good agreement with the structures, respectively.
The molar conductivities of the complexes are around 12.1–
13.0 S¢cm2¢mol¡1 in DMF (Table 1), showing that all com-
plexes are non-electrolytes in DMF.[9]
Thermal Analyses
Some data of thermal analyses are listed in Table 3. The
DTA curves of ligand have an endothermic peak at 240ꢀC,
but there is no weight lost on the corresponding TG curves,
showing that this is a phase transition process, which is the
same as the melting point of the ligand. In addition, there is
one exothermic peak for the ligand at 278ꢀC. The complexes
have an endothermic peak between 98ꢀC and 115ꢀC. The cor-
responding TG curves show that the weight loss is equal to
Infrared Spectra
The main stretching frequencies of the IR spectra of the two water molecule or four water molecules. The results are
ligands and their complexes are tabulated in Table 2. It can in accordance with the composition of the complexes as
be found that the characteristic absorption peaks of all com- determined by elemental analyses. Three exothermic peaks
plexes are similar. In the spectra of H2L, the carboxylic appear around 355–557ꢀC. The initial temperature of decom-
n(COOH) appears at 3500 cm¡1, the peak is absent in the position is greater than 278ꢀC, which indicates that the ther-
complexes, but there is
a
broad peak at around mal stability of the complexes is higher than that of the free
Table 4. Relaxivity of the complexes.
Compound
[M]/ mmol¢L¡1
t0/s
T1/s
(1/T1)p/s¡1
R1/mmol¢L¢s¡1
Temp./ ꢀC
H2O
5.40
0.95
1.80
1.85
0.90
0.128
0.729
0.385
0.375
0.770
35
35
35
35
35
MnL¢4H2O
CoL¢2H2O
NiL¢2H2O
Gd-DTPA
0.095
0.095
0.094
0.148
0.601
0.257
0.247
0.642
6.33
2.71
2.60
4.34

Potential Contrast Enhancement Agents
349
Fig. 2. Measurement of relaxation time of MnL.
ligand which decomposed at 3478ꢀC, showing that there may
be large conjugation in the chelate ring in the complexes.
Funding
The project was supported by the National Natural Science
Foundation (81060118, 81071144), Jiangxi Provincial Depart-
ment of Education’s Item of Science and Technology
(GJJ09341), and Jinggangshan University Natural Science
Item (JZ0813).
Relaxivity of the Complexes in Water Solution
The enhancement value of the relaxation rate of the complex
for water protons is calculated by the equation.[6]
References
.1=T1/p D .1=T1/o ¡ .1=T1/d
R1 D .1=T1/p=[M]
1. Caravan, P.; Ellison, J. J.; McMurry, T. J.; Lauffer, R. B. Gadolin-
ium(III) chelates as MRI contrast agents: structure, dynamics, and
applications. Chem. Rev. 1999, 99, 2293–2352.
2. Weinmann, H. J.; Brash, R. C.; Press, W. R.; Wesby, G. E. Charac-
teristics of gadolinium-DTPA complex: a potential NMR contrast
agent. Am. J. Roentgenol. 1984, 142, 619–622.
3. Rizkalla, E. N.; Choppin, G. R. Thermodynamics of complexation
of lanthanide ions by N-methylenediamine-N,N,N-triacctic acid.
Inorg. Chem. 1986, 25, 2327–2330.
4. Chang, C. A. Magnetic resonance imaging contrast agents: design
and physicochemical properties of gadodiamide. Invest. Radiol.
1993, 28, 22–25.
5. Schmitt-Willich, H.; Brehm, M.; Ewers, C. L. J.; Michl, G.; Muller-
Fahrnow, A.; Petrov, O.; Platzek, J.; Raduchel, B.; Sulzle, D. Syn-
thesis and physicochemical characterization of a new gadolinium
chelate: The liver-specific Magnetic resonance imaging contrast
agent Gd-EOB-DTPA. Inorg. Chem. 1999, 38, 1134–1144.
6. Geigy, J. R. Fr. Patent 1,548,888, 1987.
7. Hnatowich, D. J.; Layne, W. W.; Childs, R. L. The preparation and
labeling of DTPA-coupled albumin. Int. J. Appl. Radiat. Isot. 1982,
33, 327–332.
Where (1/T1)o is the observed solvent relaxation rate in the
presence of a paramagnetic species, (1/T1)d is the solvent
relaxation rate in the absence of a paramagnetic species, and
(1/T1)p represents the additional paramagnetic contribution.
[M] is the concentration of paramagnetic metal ion.
The relaxivity mainly consists of two components: the
inner-sphere and outer-sphere relaxivity. The high relaxivity
is favorable of tissue imaging. The relaxivity (R1) of com-
plexes and Gd(DTPA)2¡ used as a control were given in
Table 4. The results showed that the spin-lattice relaxivity of
MnL was larger than that of Gd(DTPA)2¡. Measurement of
relaxation time of MnL was showed in Figure 2.
8. Yang, Z.Y.; Li, F.S.; Yang, L.; Yang, R. D. Synthesis and relaxiv-
ity of polycarboxylic hydrazone rare earth complexes. Chin. Sci.
Bull. 2000, 20, 1844–1850.
9. Geary, W. J. The use of conductivity measurements in organic sol-
vents for the characterization of coordination compounds. Coord.
Chem. Rev. 1971, 7, 81–85.
Conclusion
Taken together, non-ion complexes of MnL derivative from
diethylene triamine pentaacetic acid and benzoyl hydrazine
are prospective MRI contrast agent with high spin-lattice
relaxivity and stability, low cost, good solubility and binding
affinity for the serum protein.
10. Nakamoto, K. Infrared and Raman Spectra Inorganic and Coordina-
tion Compounds; Wiley, New York, 1976.